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Atta-ur-Rahman (Ed.), Studies in Natural Products Chemistry, Vol. 12 © 1993 Elsevier Science Publishers B.V. All rights reserved. 275
Hydroxylated Indolizidines and their Synthesis Janine Cossy and Pierre Vogel
1. Introduction
The indolizidine (octahydroindolizine) ring system is found in bewildering profusion in
nature. A large proportion of alkaloids incorporate this moiety, ranging from bicyclic alkaloids to
some highly complex structures like those of Aspidosperma alkaloids.1 In this review surveying
the literature until June 1991, we shall be concerned exclusively with simple indolizidine
alkaloids and analogues possessing at least one hydroxyl or acetoxy group and, except for
indolizomycin ((-)-31) and cyclizidine ((-)-32) whose skeletons are annulated to three-membered
rings, with those structures which are not annulated to other carbocycles.
The alkaloids under survey can be classified into two main sub-groups: (A) the hydroxy-
and polyhydroxyindolizidines not substituted by carbon substituents (Table 1) and (B) those that
are alkylated or arylated on the ring (Table 2). The former sub-group includes (-)-swainsonine
((-)-5) and (+)-castanosrjermine ((+)-7), two potent inhibitors of mannosidases and glucosidases,
respectively, enzymes that are essential in the biosynthetic processing of polysaccharides and
glycoproteins.2 Because the removal of specific mannosyl and glucosyl residues from the
glycoprotein surface of viral envelopes plays a crucial role in host cell recognition and
replication, glycosidase inhibitors show promise for chemotherapeutic treatment of viral diseases,
including AIDS.3 The transformation of normal cells to cancer cells is known to be accompanied
by changes in the composition of the sugar side-chains of glycoproteins. Levels of glycosidase
enzymes are raised in the serum of some cancer patients, and are thought to be involved in the
process of metathesis. Polyhydroxylated indolizidines that are carbohydrate analogues in which
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Table 1. Naturally occurring hydroxy- and polyhydroxyindolizidines that are not substituted
by alkyl or aryl groups.5
(-)-l (+)-2 (-)-3 (-)-4: slaframine
(-)-5: swainsonine (-)-6: swainsonine N-oxide (+)-7: castanospermine
(+)-8: 6-ep/-castanospermine (+)-9: 7-deoxy-6-^/-castanospermine
the oxygen atom of the pyranose or furanose ring has been replaced by a nitrogen function
(sugar-shape alkaloids4) are being used to investigate the role of glycosidases in these processes.
A notable consequence of these properties has been an upsurge of interest in the synthesis of
natural polyhydroxylated indolizidine alkaloids and of unnatural analogues for structure-activity
studies.
This account will be concerned with the syntheses of natural and unnatural hydroxy and
polyhydroxyindolizidine derivatives. We have chosen to classify them according to the number of
hydroxy (or acetoxy) groups they bear.
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Table 2. Naturally occurring C-substituted hydroxy- and polyhydroxyindolizidines
Ph
H O i
ν Me
10: crepidamine
13: elaeocarpine
16: elaeokanine Ε
Me O H ' ? Η
Me Η
23: N-oxide of pumiliotoxin 323 A
H O I H O
(-)-12: elaeokanine C
^ 11: dendrocrepine
(+)-14: isoelaeocarpine
Me O H * Η
(+)-15: isoelaeocarpicine
1 7: R ,= Me
2 ; R"=H pumiliotoxin A
(307A,
; 307A")
H O Η Me
18:R'= Me H O Ή
19:R'= n-C 4H 9;RM=H
20:R'= n-C 3H 7;R"=H
; R"=H : pumiliotoxin Β (323 A )
: pumiliotoxin 251 D
: pumiliotoxin 237 A
21: R'= M
^ uH i
R' -
H : pumiliotoxin 267 C
« ^ c „ , -
Me XO H
22: R'= *» R"=OH · pumiliotoxin 267 D , C H 2 -
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Table 2 (continued)
M2 P
H
H 2 4: R= n
"C
3H
7
(+)-25: R= n-C4H9
Me
: allopumiliotoxin 253 A
: allopumiliotoxin 267 A
26: R= M e " " γ " ^C H
2 ~ : allopuiruliotoxin Β (323B';
OH 323 B")
HO Me
(+)-27: R= Me^Y^^ 0 ^^ 2 "" : allopumiliotoxin 339 A
OH
Me OH ' ? H HO Me
28: R= M e ' ^ Y ^ ^ 0 ^ " : allopumiliotoxin 339 B
OH
29: N-oxide of allopumiliotoxin 267 A
OMe
MeO
MeO
O OH
^N
^ H
MeO
η μ Me
9 « v ϊ ! .*0H
OH
(+)-30: 13a-hydroxysepticine (-)-31: indolizomycin (-)-32: cyclizidine
2. The 1-hydroxyindolizidines (octahydroindolizin-l-ols)
Detailed studies on the biosynthesis (see sections 13, 14) of (-)-slaframine ((-)-4) and
(-)-swainsonine ((-)-5) in the fungus Rhizoctonia leguminicola has shown that (-)-(lR,8aS)-
1-hydroxyindolizidine ((-)-l) is present in the fungus together with traces of (+)-(lS,8aS)-l-
hydroxyindolizidine ((+)-2).6a (-)-l was also found in the diablo locoweed (Astragalus oxyphysus)
which produces (-)-swainsonine.6b
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H HO
0 H H
V W H H
(-)-l (trans) (+)-2 (eis)
A first synthesis of racemic cis-l-hydroxyindolizidine ((±)-l) was proposed by Sternbach
and Kaiser in 1952.7 Hydrogénation (50 atm.) of (±)-l-oxoindolidizine ((±)-33) in AcOH in the
presence of platinum catalyst afforded a mixture of amino-alcohols whose picrates were
recrystallized to give pure picrate of (±)-2. Ketone (±)-33 was obtained according to the method
of Clemo and Ramage8 (Scheme 1) by alkylation of (±)-ethyl picolate with ethyl 3-bromo-
propanoate followed by Dieckmann cyclization and decarboxylation.
Scheme 1
^COOEt ^COOEt
Ν +
Β Γ ν- ^ Ο Ο Ο Β * CT
\ / x / ^ C O O E t (±)-ethyl picolate
NaH S > Λ reduction
Η 0
> (±)-l + (±)-2
(±)-33
Aaron and co-workers9 studied the hydrogénation of (±)-33 in the presence of various
catalysts such as Pt0 2, Rh/C or Pd/C and obtained mixture in which the racemic eis isomer (±)-2
was the major product that could be isolated pure by fractional distillation. Because of
intramolecular hydrogen bonding of the hydroxy group with the amine function, as evidenced by
IR spectroscopy,9 the eis isomer (±)-2 is more volatile than the trans isomer (±)-l. Reduction of
(±)-33 with K/EtOH in benzene afforded a 91:9 mixture of (±)-l and (±)-2.9
Another approach to the synthesis of 1-hydroxyindolizidines is based on the thermal,
intramolecular aminolysis of a 9:1 mixture of the erythro and threo ethyl ß-hydroxy-ß-(2-
piperidyOpropanoate (35) which gives a 1:9 mixture of the trans and ds-3-oxo- 1-hydroxy-
indolizidines (36 + 37).10 These lactams were separated by column chromatography and reduced
(by Clemmensen or with L i A l H 4)10 into (±)-2 and (±)-l, respectively.
9 Compound 35 was
obtained by reduction of ethyl ß-oxo-ß-(2-pyridyl)propanoate (34) (Scheme 2 ) .10
In 1987, Harris and Harris11 presented a first approach to the preparation of the four
diastereomers of 1-hydroxyindolizidines ((-)-l, (+)-2, (+)-l, (-)-2) in high optical purity. Racemic
1-oxoindolizidine ((±)-38) can be resolved by fractional crystallization of the (+)-3-bromo-
camphor-8-sulfonic acid ((+)-BCS) salt from acetone.12 The configuration of (-)-(S)-38 was
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Scheme 2
(±)-l (±)-2
established by conversion into (+)-(S)-indolizidine.13 The enantiomeric (-)-(R)-indolizidine had
been obtained by ambiguous transformations into (+)-coniine which was correlated with
D-pipecolic acid.14 Because of the extremely facile racemization of optically active
Scheme 3
(-)-l (lR,8aS) (+)-2 (lS,8aS) (-)-2 (lR,8aR) (+)-l (lS,8aR)
1-oxoindolizidine, its reduction with NaBH4 into mixture of eis and rrans-1-hydroxyindolizidines
does not allow one to isolate these compounds with high optical purity. However, the salt formed
with either enantiomer of BCS can be obtained pure and remains stable. Thus, treatment of (±)-38
with (+)-BCS in acetone gave a (+)-BCS salt which was reduced with NaBH4 in EtOH to give a
mixture of (-)-l and (+)-2 that were separated by ion-exchange resin chromatography. Similarly,
treatment of (±)-38 with (-)-BCS gave the corresponding diastereomeric (-)-BCS salt whose
reduction with NaBH4 afforded (-)-2 and (+)-l (Scheme 3 ) .11
Carrie and co-workers15a
have developed a new approach (Scheme 4) to the indolizines
based on transformation of the optically pure tricarbonyl(diene)iron complex 39. The reaction of
the lithium enolate of tert-butyl acetate with 39 led to a 2:1 mixture of alcohols 40 and 41
separated by flash chromatography. Decomplexation of each isomer with cerium (IV) salt in
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MeOH gave dienol 42 whose hydroxyl group was protected as an acetate. Hydrolysis of the
terr-butyl ester under acidic conditions, followed by reduction with BHyMe^S complex gave the
corresponding primary alcohol that was esterified as a tosylate. Reaction of the latter with NaN3
in DMSO afforded azide 44. Reduction of the azide 45 with Ph3P in aqueous THF liberated the
corresponding primary amine which cyclized spontaneously. The crude reaction mixture was then
heated in the presence of (iPr)2NH giving a 4:1 mixture of indolizidines 46 and 47 which were
separated by chromatography.
Scheme 4
Fe(CO)3 Fe(CO)3 Fe(CO)3
pH LiCH2COOtBu
F— I I ( -CHO
39 E=COOMe 40
OH
CH2C00tBu 41
,ΟΗ
CH2C00tBu
Ce(NH 4) 2(N0 3) 6
1.HC1, AcOEt
2. BHyMe^S 3. TsCl, pyr.
4. NaN3, DMSO
COOtBu
42
44
OAc
Ac 20 , pyr.
K 2C 0 3
MeOH'
OAc
l.Ph3P
2. (iPr)2NH
COOtBu
43
An enantioselective synthesis of (-)-l and (+)-2 have been reported recently by Takahato
and co-workers15b
based on the Sharpless kinetic resolution of N-benzyloxycarbonyl-3-hydroxy-
4-pentenylamine ((±)-48). Asymmetric epoxidation of (±)-48 gave a mixture of (S)-48 (44%), the
epoxy alcohol 49 (33%) and the pyrrolidine (2R,3R)-50 (14%) (Scheme 5). Stereoselective
intramolecular amidomercuration of (S)-48 with Hg(OCOCF3)2 in tetrahydrofuran followed by
the radical Michael addition with methyl acrylate in the presence of NaBH(OMe)3 provided 52.
Catalytical hydrogenolysis in MeOH led to indolizidinone 53 whose reduction with LiAlH 4 gave
(+)-2. Mitsunobu displacement reaction on 53 gave 54 which was reduced with LiAlH 4 into (-)-l.
Sibi and Christensen16 have proposed recently a synthesis of (+)-(lS,8aS)-l-hydroxyindo-
lizidine ((+)-2) which implies a Wittig condensation of the L-prolinal derivative 56 with the
three-carbon synthon 57 giving alcohol 58. An intramolecular cyclization via mesylate
(methanesulfonate) 59 afforded (+)-2. The L-prolinal derivative 56 was obtained from the
protected 3-ketoproline ethyl ester 55 through enantioselective reduction with baker's yeast
(immobilized with calcium alginate) followed by interchange of the Cbz (benzoyl) to the BOC
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Scheme 5 OH
Η Ν '
Cbz
(±)-48
tBuOOH >
D-(-)-DIPT Ti(0-i-Pr)4
Cbz:PhCH2OCO DIPT: diisopropyl tartrate
Ο
OH
I OH
Ο C b z N ^ y
50
OH
OH C b z N ^ y
Ph3P, PhC02H
EtOOCN=NCOOEt
(-)-l
NaBH(OMe)3
X0 2Me
OH
(+)-2
(rm-butyloxycarbonyl) protecting group and protection of the hydroxy group as rm-butyldi-
methylsilyl ether (TBDMS).
B0 2C OTBDMS
Baker's yeast >
+ C lGPh 3P
e(CH 2) 3OH
57
BOC
(±)-55
Cbz = PhCH2OCO TBDMS = t-BuMe2Si BOC = t-BuOCO LiHMDS = (Me3Si)2NLi
56
(+)-2 < -
LiHMDS I OTBDMS
OR 58 R=H 59 R=CH 3S0 2
Mixtures of isomeric 1-hydroxy-1-methylindolizidines ((±)-60, (±)-61) and 1-hydroxy-1-
phenylindolizidines((±)-62, (±)-63) were obtained from the reaction of 1-oxoindolizidine ((±)-38,
(Scheme 3) with the appropriate Grignard reagent. The resulting alcohols were separated by
chromatographic and distillation techniques.17 Lactams 65 which are reduced into (±)-62 and
H Me |_| OH Ph
(±)-60 (±)-61
CÖ0H
(±)-62
... Ph
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283
(±)-63 with LiAlH 4, were obtained by a cyclization reaction consecutive to the catalytic
hydrogénation of the 2-pyridylcarbinol 64 in acetic acid.18 Other potential precursors of (±)-62
and (±)-63 were prepared by Gramain and co-workers19 using an intramolecular photoreduction
Ph OH Ph
COOEt
H2, Pd/C
AcOH
L1AIH4 > (±)-62, (±)-63
64 65
of a carbonyl group by a lactam. The methodology (Scheme 6) implies a regioselective
abstraction of an hydrogen atom α to the nitrogen atom of the amide group in 66 by the triplet
excited state (η, π*) of the benzoyl moiety, leading to the diradical intermediate 67 which cyclizes
into (±)-68 (18%) and (±)-69 (27%).
HO^ Ph
66 67
For their synthesis of dl-camptothecin, Rapoport and co-workers20 have developed a
synthesis of racemic l-hydroxyindolizidine-6-carboxylic acid (71) (the relative configuration was
not established). The bicyclic keto-acid 70, obtained in 85% yield from pyridine-2,5-dicarboxylic
acid (Scheme 7) was reduced with NaBH4 in aqueous methanol into 71. This compound was then
converted into other 1-hydroxyindolizine derivatives 72.
Scheme 7
/ v ^ C O O H COOEt
COOEt
OR'
EtOOC
OH
N ,
70
HOOC
Ö 72 R=H, CH3CH2(C02Me)CH, OH, OAc R'=H, Ac
NaBH4
ISL
71
MeOH/H20
3. The 2-hydroxyindoIizidines (octahydroindolizin-2-ols)
The 2-hydroxyindolizidines have not been found yet in nature. In 1937, Clemo and
Metcalfe21a
reported on the synthesis of (±)-2-oxoindolizine (±)-73 (Scheme 8). The latter was
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reduced with sodium amalgam in EtOH into a mixture of trans-2-hydroxyindolizidine ((±)-76)
and isopelletierine (74). Two minor components of the reduction mixture were l-(2-piperidyl)-
propan-2-ol (75) and ris-2-hydroxyindolizidine ((±)-77).9 Catalytic hydrogénation (Rh/C) or
L1AIH4 reduction of (±)-73 gave (±)-76 and (±)-77 which were separated and purified by column
chromatography.9 Addition of EtMgBr to (±)-73 gave a mixture of the 2-ethyl-2-hydroxyindolizi-
Scheme 8
œCOOEt K/xylene
COOEt
ClCH2COOEt, K 2C 0 3
f ^ Y ^ COOEt
Na/Hg^
EtOH
(±)-73
NH
74
OH
NH
75
a* OH
(±)-76 R=H (±)-78 R=Et
(±)-77 R=H (±)-79 R=Et
dine (±)-78 and (±)-79.21 The relative configuration (trans vs eis) of the 2-hydroxyindolizidines
was established by Aaron and co-workers.9 The trans-isomer (±)-76 was more volatile than the
c/i-isomer (±)-77 and because of weak intramolecular hydrogen bonding between the hydroxy
and amine functions in (±)-76, as evidenced by IR spectroscopy.
The Dieckmann condensation of ethyl 2-[l-(2-ethoxycarbonylmethyl)piperidinyl]-propa-
noate gave 3-methyl-2-oxo-indolizidine (80) whose reduction with Zn/Hg and concentrated
aqueous HCl led to a mixture of diastereomeric 3-methyl-2-hydroxyindolizidines (81) .2 1b
Η Η
r ^ Y ^ C O O E t . r ^ S ^ \ _ Z n
/ H g .
^ N y C O O E t
Me
HCl OH
80 Me Me
81
4. The 5-hydroxy-4-oxyindolizidines
The 3-hydroxy- and 5-hydroxyindolizidines being aminals are not expected to be stable
compounds, and this may explain why these systems have not been described yet. Nevertheless,
the corresponding N-oxides are expected to be stable compounds. This is illustrated by the work
of Green and Lamchen22 who have obtained the 3,3-dimethyl-8-nitro-4-oxy-octahydroindolizi-
din-5-ol derivative 82 (probably the stereoisomer where the hydroxy and nitro groups occupy
equatorial positions) through condensation of 2,2-dimethyl-5-nitromethylpyiTolidin-l-ol and
propenal in the presence of NaOMe.
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285
NO,
NaOMe
HO
N 2 π
82
5. The 6-hydroxyindolizidines (octahydroindo!izin-6-oIs)
No synthesis of 6-hydroxyindolizidines have been reported yet. There are very rare
compounds in nature also. The three alkaloids, crepidine (83),23 crepidamine (10), and
dendrocrepine (11), isolated from Dendrobium crepidatum}A are the unique representatives of
this class of natural hydroxyindolizidines.
Ph Me Η ι vO H
83 10
Crepidine (83) whose structure was established by X-ray diffraction studies2315
forms
methiodide (84) with Mel which undergoes alkaline degradation with 2 Ν NaOH at 20°C into the
optically inactive amorphous base 85.24
Na<
Me Η Ρ" H O n..l^lAr 0H
[ φ Y... Me
V V - > ιθ
1 HM Me H
84
Crepidamine (10), which is optically inactive, has an IR spectrum in CC14 typical ( V 0H =
3470 cm"1) for a trans-fusion of the rings in the indolizidine system allowing for OH—Ν bonding.
10 ΕΐΟΗ,Δ^
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Crepidamine is easily isomerized into isocrepidamine (86) by boiling in EtOH, as indicated
here-above. The IR spectrum of 86 also shows ( V 0H = 3290 cm"1) strong intramolecular OH - Ν
bonding.
Dendrocrepine (11), which is optically inactive, is easily isomerized to isodendrocrepine
(87) by boiling in EtOH or by chromatography on neutral alumina.
H
11
6. The 7-hydroxyindoIizidines (octahydroindolizin-7-oIs)
The first 7-hydroxyindolizidine derivatives were reported by Holden and Rapen25 in 1963.
Treatment of 7-oxoindolizidine (88), prepared according to Scheme 9, by EtMgl and led to a
7-ethyl-7-hydroxyindolizidine whose relative configuration was not determined (89a or 90a).
Scheme 9
7 Cu/Zn Ν COOEt AcOH Ν COOEt toluene k ^ N ^ y
Η EtOOC
Η EtOOC EtOOC
Η 88
88 RM HO •«
RM: EtMgl RM: PhLi RM: 2,6-Me2C6H3Li
89 R
Et Ph 2,6-(Me)2C6H3
H
90
Beckett and co-workers26a
reacted phenyllithium with 88 and obtained the racemic
7-hydroxy-7-phenylindolizidines 89a and 90a which were separated by fractional crystallization.
The derivative 90c was obtained in a similar way by reacting 88 with 2,6-dimethylphenyl-
lithium.26b
The aryl substituted 7-hydroxyindolizidines and their acetates showed a weak
antitremorine action in the mouse.26 Parent compounds (±)-89d was obtained by reduction of 88
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with potassium in EtOH. The trans isomer (±)-90d was the major product of catalytic
hydrogénation (Ru/C) of 88. Compound (±)-90d is slightly more volatile than (±)-89d and shows
typical OH--N bonding in its IR spectrum.27
CHO
NHo
EtOH,
pH3 '
HCl, heat
eZn/Hg " 88
E=COOEt
An earlier method for the preparation of 88 was proposed by Lions and Willison,26 it
involves the condensation of γ-aminobutyraldehyde with diethyl acetone dicarboxylate and
formaldehyde in EtOH at pH 3, followed by decarboxylation of the ketodiester in boiling dilute
HCl with a trace of zinc amalgam (Scheme 10). A third approach to the preparation of
(±)-7-oxoindolizidine (88) has been proposed by Stevens and co-workers29 (Scheme 11).
Condensation of 1,2-dichloroethane with benzenesulfenylacetonitrile in the presence of a strong
base (lithium diisopropylamide: LDA) gave the cyclopropanecarbonitrile derivative 91 whose
reduction with diisobutylaluminium hydride (DIBAH) gave the corresponding aldehyde 92. The
latter condensed with primary amine 93 to give the cyclopropane aldimine 94 that rearranged on
heating to 95. Acidic treatment led to 96 whose desulfurization with Raney nickel and acidic
hydrolysis afforded 88.
Scheme 11
CI-
CI-
SPh
CN
LDA
91
SPh
CN
DIBA: SPh
CHO
92
88
MeO
MeO'
SPh SPh
HCl
MeOH
N H 2
R
93
SPh
96 R= CHpCHp-C-CHq
Ο ο
95
Ν \ Ri !
94
During the last 15 years cationic π-cyclization of N-acyliminium ion intermediates has
been applied in the synthesis of various heterocyclic systems.30"
36 The method is illustrated in
Scheme 12 for the synthesis of 7-hydroxy-3-oxoindolizidine derivatives.
Mitsunobu coupling of succinimide with allylic alcohol gave imide 97 which was reduced
selectively into 98 with NaBH4 in slightly acidic EtOH. Treatment of 98 with formic acid
engendered the formation of the N-acyliminium ion intermediate 99 which underwent
electrophilic cyclization into the secondary alkyl cation intermediate 100. The latter was
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Scheme 12
97 98
99 100 MeOH ι— (±)-101 R=HCOO HCl L>(±)-102 R=H
quenched by formic acid and gave (±)-101 nearly quantitatively as a crystalline product. The
reaction was highly stereoselective, giving the c/s-isomer in which the formate moiety occupies
an equatorial position (by ^ - N M R ) .31 Hydrolysis of (±)-101 with aqueous MeOH/HCl gave the
crystalline alcohol (±)-102. Cyclization of the (E)-pentenyl and (E)-hexenyl derivatives 103 and
104 under similar conditions afforded the corresponding methyl and ethyl derivative (±)-105 and
(±)-106 with high stereoselectivity. The equatorial positions for both formate and alkyl groups,
and the axial H-C(8a) configuration follow from the values of the H-H vicinal coupling constant
in their !H-NMR spectra.
103 R=Me (±)-105 R=Me 104 R=Et (±)-106 R=Et
This method, developed by Speckamp and co-workers,30"
32 is quite general and has been
applied to the preparation of rrû^-7-formyloxy-8a-methylindolizidine (107) by HCOOH
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treatment of l-but-3-enyl-5-hydroxy-5-methyl-pyrrolidin-2-one30b
and to the synthesis of the
Elaeocarpus alkaloid elaeokanine A (110).32 In a model study, the protected allyloxy derivative
108 was cyclized into 109 in only 20% yield. (±)-Elaeokanine A ((±)-110) was finally obtained
following the sequence of reactions shown in Scheme 13.
Scheme 13 / \
Treatment of the oxoindole derivative 111 with the Meerwein's reagent Et3OBF4,
followed by neutralization with aqueous K 2 C 0 3 gave a mixture of the expected iminoether 112
and about 5-10% yield of the 7-hydroxy-7-methyl-5-oxoindolizidine derivative 113 (configuration
at C(7) unknown).37 The formation of product 113 can be interpreted in terms of formation of the
Scheme 14
114 115 116
iminium salt intermediate 114 which can equilibrate with the a-ethoxyenamine 115 (Scheme 14).
The latter undergoes an intramolecular cross-aldolisation giving the iminium ion intermediate 116
whose neutralization with aqueous K 2C 0 3 affords finally 113.37
7. Elaeokanine C
Elaeokanine C ((-)-12) is an Elaeocarpus alkaloid38 which was isolated from the leaves of
Elaeocarpus kaniensis by Johns and co-workers.39 This compound is a irani-7-hydroxyindolizi-
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290
dine derivative which could be derived biosynthetically from the condensation of ornithine and a
Cg-polyketide.
In 1979, Tufariello and A l i40 described the first general approach to the total syntheses of
(±)-elaeokanine A ((±)-10) and (±)-elaeokanine C ((±)-12) based on nitrone cycloaddition
(Scheme 15). The cycloaddition of 1-pyrroline-l-oxide with pentene is highly regio- and
stereoselective and furnishes isoxazolidine 117 in 72% yield. Catalytic hydrogénation (Pd/C) of
Scheme 15
119 120 H
(±)-12 121
117 gave the ß-aminoalcohol 118 whose oxidation (Jones) afforded ketone 119. Addition of
acrolein to 119 gave the unstable adduct 120 which on treatment with concentrated HCl led to a
separable 3:1 mixture of (±)-12 and enal 121. Treatment of 120 with r-BuOK gave (±)-110 and
121 in a 4:1 ratio.
Scheme 16
(±)-126 (±)-125
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291
An alternative approach (Scheme 16) based on cycloaddition of a nitrone has been
proposed by Kametani and co-workers.41 The 1,3-dipolar addition of nitrone 1-pyrroline-l-oxide
to enone 122 afforded 123. Exchange of the protecting tetrahydrofuranyl group by a mesylate led
to the formation of the quaternary ammonium salt 124. Reduction with zinc powder in 50%
aqueous acetic acid gave (±)-125, which is the 7-epimer of (±)-elaeokanine C. Oxidation of
(±)-125 led to diketone (±)-126 which was converted into (±)-12 by the usual procedure.39,42
Watanabe and co-workers43 described a synthesis of (±)-12 based on the condensation of
2-ethoxy-pyrroline and ethyl 3-oxopent-5-enoate (Scheme 17). Selective reduction of 127 with
LiAlH4 gave the rra^w-indolizidine derivative 128 in 90% yield. Reduction of the ethylene acetal
Scheme 17
, 7 E t 0
4 .
Li A 1 H 4
E=COOEt
(±)-126 < r
127 128
l .C 3H 7MgBr
2.C1O3 3. HBr/H20
H O . Y
l .HO OH
2. L1AIH4
NCS, Me2S H
130 129
of 128 with L1AIH4 gave alcohol 129. Oxidation with N-chlorosuccinimide and dimethylsulfide
led to aldehyde 130. The Grignard reaction of 130 with Ai-propylMgBr, followed by Jones
oxidation afforded a ketone. Hydrolysis of its ethylene acetal moiety led to diketone (±)-126
which was then converted into (±)-12.
Scheme 18
OMe
131
l .HO Q H >
2. NaOH ^ Η
134
(±)-12 HCl
E=COOEt
HCl
135
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292
Shono and co-workers44 have prepared (±)-elaeokanine C ((±)-12) in five steps from
l-(methoxycarbonyl)-2-methoxypyrroline (131) (Scheme 18). A four carbon atom chain was
introduced at the α-position of 131 on treating it with TiCl4 and then with the silyl enol ether 132.
The keto-ester 133 so-obtained was protected with ethylene glycol and the ester moiety was
hydrolyzed under alkaline conditions to give pyrrolidine derivative 134. N-alkylation of 134 with
bromoacetal 135 led to 136 which underwent aldol condensation in the presence of HCl, giving
(+H2.
Another approach to the synthesis of (±)-12 has been presented by Flitsch and Pandl45
which features an intramolecular Wittig-Horner cyclization of 137 to generate the bicyclic enone
138 (Scheme 19). Acylation of 138 with butyryl anhydride and SnCl4 afforded 139 whose
reduction with LiAlH 4 gave a mixture of isomeric diols 140. Jones oxidation furnished dione
(±)-126. Oxidation with pyridinium chlorochromate did not give 126 but a mixture of (±)-110 and
about 30% of either (±)-12, (±)-125 or another stereomer.
Scheme 19
In 1971 Onaka46 had proposed that the biogenesis of the majority of Elaeocarpus
alkaloids implies intermediate 142. In 1988 Gribble and co-workers have envisaged convergent,
biomimetically patterned syntheses of (±)-110, (±)-12 and (±)-125 by using 142. Their approach
(±)-125 (±)-12 (±)-110
Page 19
293
implies an indolizidine ring formation based on a tandem Mannich-aldol condensation between
S-O-A^pyuoliniumyljpropanal (142) and benzyl 3-oxohexanoate (Scheme 20). The method
allows for a regiospecific introduction of the hydroxyl group at C(7) of the indolizidine system,
but does not control its relative configuration. Acidic treatment of 141 engenders the pyrrolinium
ion intermediate 142, which condenses with benzyl 3-oxohexanoate into a mixture of alcohols
143. Catalytic hydrogenolysis of the benzylic group followed by chromatographic separation on
silica gel afforded (±)-12 and its epimer (±)-125 (selectivity 1:3). On treatment with 8M HCl,
these two compounds led to (±)-elaeokanine A ((±)-110).
8. The 8-hydroxyindoIizidines (octahydroindolizin-8-oIs)
The first synthesis of a 8-hydroxyindolizidine derivatives has been reported by Leonard
and co-workers.48 Dieckmann condensation of ethyl 4-[l-(2-ethoxycarbonylpyrrolidinyl)]butyrate
in the presence of EtONa gave 144, which was decarboxylated and afforded the amino-ketone
145.49 Reduction with LiAlH4 gave an amino-alcool whose IR spectrum ( V 0 H = 3333 cm"
1) was
typical of ds-8-hydroxyindolizidine 146 allowing for intramolecular OH-Ν bonding. Reduction
of the ketoester 144 with NaBH4 afforded mixture of the substituted 8-hydroxyindolizidines
147.50
HCl
144
I NaBH4
OH
EtOOC H
147
Gramain and co-workers19 have obtained precursors of 8-substituted 8-hydroxyindolizi-
dines 149 by photo-induced annulation of N-alkylated pyrrolidinones 148 (see also Scheme 6,
synthesis of 1-hydroxyindolizidines).
hv
148
Page 20
294
9. The pumiliotoxins
Neotropical frogs of the family Dendrobatidae have elaborated an array of more than 200
alkaloids,51 some of them, in the skin, serve in "chemical defense" against predators. They have
high pharmacological activity on nerve and muscle.52 Pumiliotoxin Β (now called pumiliotoxin
323 A) was first isolated by Daly and co-workers from the Panamanian frog Dendrobates pumilio
together with the close analog pumiliotoxin A (now called pumiliotoxin 307 A ' , 307 A " ) :53 The
key to the structure of pumiliotoxin A class of dendrobatid alkaloids was obtained through X-ray
analysis of a relatively simpler member, pumiliotoxin 251 D (19), isolated from Ecuadoran frog,
Dendrobates tricolor.54 The structure of 17 and 18 were deduced from RMN studies. The
absolute configuration (15R,16R) of the diol moiety in the side chain of 18 was established by
comparison of the ozonolysis product from 18 diacetate with the synthetic 3,4-diacetoxy-2-
pentanone derived from L-(+)-tartaric acid,55 and independently through total synthesis of 18 (see
Scheme 22).56 The (15S,16S)-erythro diastereomer of pumiliotoxin Β was discovered in the skin
of an Australian myobatrachid frog, Pseudophryne coriaceaP
Me 15 J<s.
Me OH
R=
R=
C H2 " : pumiliotoxin A (307A'; 307 A") (17)
: pumiliotoxin Β (323 A) (18)
: pumiliotoxin 251 D (19) R= n-C4H9
Pumiliotoxin Β has been shown to be a powerful myotonic5 8 , 59
and cardiotonic agent,59
which selectively effects calcium ion translocation across membranes.60 Cardiac effects have
been observed with other dendrobatid alkaloids of the pumiliotoxin A class, as well as with some
simpler synthetic analogues, although pumiliotoxin Β is the most active compound of this group
to have been studied to date.61a
Recently, Daly and co-workers61b
discovered the new alkaloids N-oxides of pumiliotoxin
323 A (23) and allopumiliotoxin 267 A (29) in the skin of Dendrobates speciosus, a species
localized from the highlands of western Panama.
Me OH Me OH
The first synthesis of pumiliotoxin 251 D (19) was presented by Overman and Bell in
1981.62 Their approach is enantioselective and highly convergent; it transforms hept-l-yn-3-one
and N-benzyloxycarbonyl-L-proline methyl ester (150) in 10 steps into 19, featuring the use of an
Page 21
295
iminium ion-vinylsilane cyclization step to generate the indolizidine ring system (Scheme 21).
L-proline derivative 150 was converted to epoxide 151 in a four step sequence. Condensation of
151 with the silylvinylalane 152 afforded the bicyclic carbamate 153 whose hydrolysis gave
amino-alcohol 154. Treatment of 154 with paraformaldehyde produced cyclopentanooxazolidine
155 whose rearrangement under acidic conditions (camphorsulfonic acid) afforded pumiliotoxin
251 D (19). The same synthetic method allowed Overman and co-workers to prepare pumiliotoxin
Β (323 A )6 3 (Scheme 22), pumiliotoxin A (307 A ' ) (Scheme 23)
04 on choosing the appropriate
trimethylsilylvinylalanate reagent in the epoxide ring opening of 151. An alternative way to the
synthesis of (+)-155 pumiliotoxin A (307 A " )6 5 makes use of the diethylaluminium chloride
activation of the epoxide ring opening of 151 and nucleophilic addition of a acetylide reagent 157.
In this case the cyclization of the intermediate formaldiminium ion was accomplished in the
presence of sodium iodide (Scheme 23).
Me Scheme 21 Η
MeOOC t> l .MeMgl nBu
150 COOBn
2. SOCl2, pyr.
3. mCPBA
4. separation
eAI(i-Bu)2Me
( * ) / = < Li® SiMe3
COOBn
Me Η
151 152 EuO
H O Me Η
nBu r=
pumiliotoxin 251 D (18)
Overman and Lesuisse66 have prepared various (E)-alkylidene analogues of pumilioto-
xin A through Lewis-acid-catalyzed intramolecular heteroene reaction of enone 159 (Scheme 24).
The latter system was obtained optically pure by condensing methyl prolinate with the allylic
bromide 158, followed by saponification of the methyl ester and conversion into the
corresponding methyl ketone 159 on treatment with methyllithium. The A1C13 promoted
heteroene reactions of 159 led to a 3:1 mixture of the 6-(E)- and 6-(Z)-alkylidene-8-hydroxy-8-
methylindolizidines 160 and 161, respectively. The same procedure was applied by Dike et al.67
to prepare the 6-methylidene derivative 164 via enal 163 derived from methyl prolinate and
bromide 162 (Scheme 24).
Page 22
296
Scheme 22
BnO-AI(i-Bu)2Me
ϋφ +151
SiMe3
'BnO / ι, ο · V
N- - / 2. H2CO, EtOH, H
+
< Μ
*> X 3 .LVNH3 4. Swern
Me OH ? Η
Me OH
tBuPh2Si-0 Me
LCH 2C1 2, 40°C^
^Ph3 2. L1AIH4, THF Η Ο ^ ) Ν < " " <f Ό 3. Ba(OH)2
Scheme 23 θ Al(i-Bu)2
= < Li® > ς Η SiMe3 +151
18 (+)-pumiliotoxin Β (323 A )
Me OH
OBn
+ 151
OBn 157
nBuLi, Et2AlCl Ψ
pumiliotoxin A (307 A ' )
Me O H ,
BnO
l .Ba(OH) 2
COOBn 2.H 2CO,H+
Nal
BnO
Me
Scheme 24
Λ ΜβΟΟΟ --ΡΛ
R Br « R Br
158 R=nBu 162 R=H
L K 2C Q 3, D M F
2. LiOH/THF, H 20 H*
3. MeLi/Et20 159 R=nBu
163 R=H
Me OH
RM 160 R'=H, R"=nBu
161 R'=nBu, R"=H
Page 23
297
10. The allopumiliotoxins
Congeners of the pumiliotoxins with a 7-hydroxy substituent have been placed in the
subclass of the allopumiliotoxins.51,68
Overman and co-workers have also developed a general
synthetic method of these alkaloids in optically pure forms. A first approach,69 which converted
N-BOC-L-proline to (+)-allopumiliotoxin 267 A ((+)-25) and (+)-allopumiliotoxin 339 Β
((+)-27), is based on the cross-aldol reaction of (7R,8aS)-8-hydroxy-8-methyl-7-oxoindolizidine
((-)-27) with (R)-2-methylhexanal (Scheme 25). Indolizidinone (-)-169 was prepared in high
enantiomeric purity from the L-proline thioester 165 whose reaction with LiMe2Cu provided
methyl ketone 166. Treatment of 166 with CF3COOH followed by concentration and reaction of
the resulting trifluoroacetate salt with 5 equivalents of 1-lithio-l-methoxyallene afforded 167.
This unstable compound, which results from cyclic-Cram diastereoselectivity, was treated with
p-toluenesulfonic acid and gave the bicyclic enol ether 168 (35-40% yield). Hydrolysis of 168
afforded indolizidinone (-)-169. Conversion of (-)-169 to its lithium dianion with Ph3CLi,
followed by reaction with (R)-2-methylhexanal gave a 1:1 mixture of two major aldols 170.
Dehydration gave 171 as the major product (41%). Reduction of 171 under the Luche
conditions70 (NaBH^CeCy produced the equatorial alcohol 172, the 7-epimer of
allopumiliotoxin 267 A (28), in nearly quantitative yield. Reduction of 171 with LiAlH4 provided
a 6:1 mixture of 172 and (+)-25, from which pure (+)-25 could be isolated in low yield.
Scheme 25
B O C '
MePH
l.CF3COOH M ^ \ X ^ \ TosOH
MeO
2. MeO
M e ?H,
165 166
R= S R=Me
167 168
l.Ph3CLi, Et20, 0°C
2. Ο Me 1 M ( R )
H nBu nBu
(CF 3C0) 20 ^
DBU DMAP, 0°C
N ,
()-169
ο %p H
H
Me
DM AP=2- (dime thy lamino)pyridine
H O A
M e ? H LiAlH,
10
Me (+)-25: (+)-allopumiliotoxin 267 A
Page 24
298
The more complex (+)-allopumiliotoxin 339 Β ((+)-27) was prepared in a similar
fashion69 (Scheme 26). The cross-aldolisation of (-)-169, with (R)-4-(benzyloxy)-2-methylbutanal
gave an aldol mixture which eliminated one equivalent of water to engender enone (-)-173. After
reduction (NaBItyCeCy, followed by selective protection of the secondary alcohol as a
t-butyldimethylsilyl ether, (-)-173 was then converted into aldehyde 174. Wittig-Horner
condensation of 174 with the enantiomerically pure ylide 175 provided (E)-enone 176. Selective
reduction of the ketone moiety with LiAlH 4 followed by desilylation afforded (+)-allopumilio-
toxin 339 Β ((+)-27).
R=tBuMe2Si
R'=tBuPh2Si 176 (+)-27: allopumiliotoxin 339 Β
The stereospecific iminium ion-vinylsilane cyclization methodology developed by
Overman and co-workers to prepare (+)-pumiliotoxin Β (Scheme 22) and related alkaloids
(Scheme 21, 23) has been used also to assemble the basic skeleton of the allopumiliotoxin A
alkaloids (Scheme 27).71 L-proline was converted into carbamate 177. When treated with iodine
in CH3CN, a single iodocarbamate 178 was obtained.56 Silver nitrate-assisted displacement of the
iodide by nitrate anion, followed by reduction with zinc led an alcohol that was protected as a
SEM (trimethylsilylethoxymethyl) acetal 179. Hydrolysis of the carbamate with KOH in aqueous
ethanol led to pyrrolidine derivative which was protected with a cyanomethyl group to give 180.
Benzylation of the secondary alcohol, removal of the SEM protecting group and Swern oxidation
afforded aldehyde 181. The cerium reagent 182, prepared from the corresponding lithium inter-
mediate reacted with 181 to give alcohols 183 (51%) and 184 (20%). The latter compounds were
converted to allopumiliotoxin derivative (+)-187 and (-)-188 by treatment with A g N 0 3 in ethanol
(the cyanide is solvolyzed into the iminium ion intermediate 185 which react in a intramolecular
fashion with the secondary alcohol to give the corresponding cyclopentaoxazines (186a and
186ß). Treatment with camphorsulfonic acid and excess of paraformaldehyde, followed by
debenzylation provided the allopumiliotoxin derivatives (+)-187 (11,15-bis-nor-methylallo-
pumiliotoxin 267 A ) and (-)-188 in 37% and 39% overall yields, respectively, from 183 and 184.
Trost and Scanlan72 have proposed an alternative synthesis of (+)-allopumiliotoxin 339 Β
Page 25
299
Scheme 27
N ^ y CH3CN'
COOBn
177
l.KOH, EtOH, H 20
2. ICH2CN, Et3N, THF
nBu SiMe3
182 CeCI2
THF, -78°C
1. A g N 0 3
2.Zn,NH4OAc
3.SEM-C1 y -N
-
Ο Ο
178 SEM=CH2OCH2CH2SiMe3 179
OH j , Me^ -*
H
1. BnBr, KH^
2. LiBF4
3. Swern
AgNQ 3
EtOH
23°C
BnO u M e , ? "
N C - J
181
SiMeo 183 R'=H, R"=OH 184 R'=OH, R"=H
BnO Me Me3Si,
186a: H-C(7ß)
186ß: H-C(7a)
1. camphor-S03H 2. (CH 20) n, CH3CN, 100°C^
3. Li/NH3, THF, -78°C
185
Me OH
(+)-187 R'=H, R"=OH
(0-188 R'=OH, R"=H
((+)-26) based on palladium-induced indolizidine ring formation (Scheme 28). The N-BOC-
protected L-proline was converted into methyl ketone 189. Deprotection with CF3COOH afforded
salt 190 which added the titanate 191 diastereoselectivity to give 192 after treatment with
Scheme 28
Ο
CF3COOH^
Η H O O C v ^
BOC- B O C ^
Η
CH2C12
Me OH
190 C F 3 ^ 0 2®
l.Me30BF4
CH2C12
2. NaOH, H 20 192
Page 26
300
(CF 3CO) 20. Treatment of 192 with Meerwein's salt, Me3OBF4, led to epoxide 193 whose
treatment with 5 molar % of (dibenzalacetone)3Pd2-CHCl3 and 12 mol % of phosphite 194 gave
hexahydroindolizin-8-ol derivative 195 (66-73%). Hydroxyl-directed epoxidation of the trifluoro-
acetate salt of 195 with CF 3C0 3H provided the vinyl epoxide 196. Palladium(0)-catalyzed
condensation of 196 and allyl sulfone 197 furnished 198 whose desulfonylation produced 199.
Threo-selective LiAlH4 reduction of the conjugated enone 199 and desilylation afforded
(+)-allopumiliotoxin 339 Β ((+)-28).
11. The 8a-hydroxyindoIizidines (octahydroindolizin-8a-oIs)
Infrared73 and ultraviolet studies
74 on salts of substituted 5-hydroxy-l-azacyclononan-6-
ones have shown that depending on the nature of the 1-substituent, the salt can exists either as a
monocyclic ammonium form 200 or as a 8a-hydroxyindolizidium form 201.
Bhutani and co-workers75 have isolated the five phenanthroindolizidine alkaloids 202 -
206 from Tylophora hirsuta, a plant native of the Jammu region in India. While 202 - 205 are in
fact phenanthrene annulated 8-hydroxyindolizidines, 206 is a 8a-hydroxyindolizidine derivative.
The structure of these alkaloids has been deduced from their spectral data.
Indolizomycin ((-)-31) is a new antibiotic produced by bioengineering. Umezawa and
co-workers76 achieved a protoplast fusion of two non-antibiotic-producing strains (Streptomyces
teryimanensis HM16 and Streptomyces grisline NPI-1). New clones were elaborated from which
a particular strain (SK2-52) was especially effective in producing antibiotic indolizomycin
Page 27
301
OMe 206: 13a-hydroxysepticine
((-)-29) whose structure and absolute configuration (except for centre C(8a)) was established by
spectral data and X-ray crystallography analysis of the derivative 207 ((lS,2R,3S,7S,8S,8aR)-7-
chloro-8-hydroxy-1,2-methylene-3-[( lE,3E,5E)-5-methyl-1,3,5-heptatrienyl]octahydroindolizi-
dine) obtained by NaBH4 reduction of (-)-31 in MeOH and addition of HCl to the epoxide moiety.
A total synthesis of (±)-indolizomycin has been proposed recently by Danishefsky and
co-workers,77 starting with the bicyclic anhydride 208 which was converted to imide 209 on
treatment with N-(triphenylphosphoranylidene)-ß-alanine methyl ester (Scheme 29). Reduction of
209 with NaBH4 in MeOH afforded a carbinol amide. Treatment of the corresponding
methoxy-lactam with TiCl4-allyltrimethylsilane led to 210. Treatment of 210 with Lawessons'
reagent (2,4-bis(4-methoxyphenyl)-l,3,2,X,54,X
5-dithiadiphosphetane-2,4-di thione)
78 gave
thiolactam 211 which was transformed into 212 through a three-step sequence. The diazoketone
212 was heated in benzene with Rh(OAc)2 and furnished a thioenone which was desulfurized to
213 on treatment with W-2 Raney nickel in acetone. Reaction of 213 with Me3OBF4 generated an
iminium salt 214 which was reduced directly with NaBH4 to give enol ether 215. Reaction with
2-(trimethylsilyl)ethyl chloroformate (TEOC-C1) afforded enone 216 whose nucleophilic
epoxidation with alkaline hydrogen peroxide furnished a mixture of the corresponding epoxy
ketones 217. Treatment of this mixture with hydrazine afforded a single allylic alcohol, 218.
202: R'=OMe, R"=H; tylohirsutine 203: R'=OMe, RM=H: 13a-methyltylohirsutine
205: R'=R"=OH; tylohirsutidine 204: R'=RM=OH: 13a-methyltyohirsutidine
Page 28
302
Scheme 29
2. MeOH,
Ο 3.· SiMeo
208: Z=0 TiCl,
209: Z=NCH2CH2COOMe
Η
1. Rh(OAc)2 °
2. W2-Ra-Ni acetone
210
M e 3O ® B F 4
0
211: X=OMe
212: X=CHN 2
213
MeO
214
. θ \ v 4 ^ Ο
NaBH4
TEOC-CI 0 , :
V ' ' ' X 7
PhH, 20°C L ^ N ^ /H N a O H
TEOC
W " λ
215 216
TEOC
217
TEOC: Me3SiCH2CH20C0-
OH O ^ OR
H 2NNH 2 r ^ ^ X ? mCPBA
* — * TE0C Η w
218 219 R=H 220 R=t-BuMe2Si
l.O*
2. M e ^
Ο OSiMe2t-Bu O . OSiMe,t-Bu Li S0 2Ph ο OSiMe2t-Bu
v y y ^ N ^ Z H 1 ^ 2 > k / N ^ H 224
Μθ
> k / ^ H TEOC
w 2.Ph*P TEOC '*=\ 2. Ac 20 TEOC '*
CHO
221 Z=0 222 Z=CHOMe
223 225 AcO
0 „ OR
l.Na(Hg) ^ \"^^7
2.HI0 4,THF k ^ N ^ H
TEOC TEOC
Bu4NF
S02Ph
> (±)-31
226 R=t-BuMe2Si )Τ=Λ 227 R=H 228
Page 29
303
Epoxidation with mCPBA led to 219 which was protected as its tri-n-butylsilyl ether 220.
Oxidation of 220 with ozone, followed by work-up with dimethyl sulfide gave rise to aldehyde
221 which was subjected to the action of (methoxymethylene)triphenylphosphorane to give a
mixture of (E)- and (Z)-enol ethers 222. Photooxygenation of 222, followed by reduction of the
resultant hydroperoxide with triphenylphosphorine afforded enal 223. Reaction of lithio sulfone
224 with aldehyde 223 was followed by acetylation (Ac 20) of the resulting lithium alkoxide and
produced 225. Desulfonylation with sodium amalgam afforded triene 226 whose tri-n-butylsilyl
ether could be cleaved selectively with IN H I 0 4 in THF into alcohol 227. Oxidation of 227 with
tetra-n-propylammonium permthenate afforded ketourethane 228, which upon fluoride ion
(tetrabutylammonium fluoride) induced removal of the TEOC protective group, and gave
(±)-indolizomycin (±)-31).
12. The 1,2-dihydroxyindoIizidines (octahydroindoIizin-l,2-dioIs)
Harris and co-workers have found that (-)-(lS,2R,8aS)-indolizidine-l,2-diol ((-)3) is a
minor metabolite of the fungus Rhizoctonia leg uminieο la19 that can be converted to
(-)-swainsonine ((-)-5) in thé fungus.6 It is of biosynthetic significance that (-)-3 differs from (-)-5
in the configuration of centre C(8a); the 8a-epimeric diol could not be detected among the
fermentation products (see the biosynthesis of (-)-slaframine and (-)-swainsonine, § 13, 14).
Racemic (±)-(lRS,2SR,8aRS)-indolizidine-l,2-diol ((±)-3) has been prepared for the first time by
Colegate et al.80 in 1984 (Scheme 30) starting with 3-pyrroline obtained through by
zinc/hydrochloric acid reduction of pyrrole. The corresponding methylurethane 229 was
deprotonated with lithium diisopropylamide (LDA) in the presence of 1,4-dibromobutane, leading
to carbamate 230 which was then treated with a catalytic amount of Os0 4 in t-BuOH/H202 to
produce the cis-dio\ 231. Further reaction with (CH3)3SiI, followed by methanolysis of the
resulting trimethylsilylcarbamate and cyclization afforded ((±)-3. The same synthetic approach
was used by the Harris' group to prepare (±)-3.79
Scheme 30
MeOOC JO 229
l.Me 3SiI Ξ
2. MeOH 3. Na 2C0 3 (-)-3 (+)-3
The C(8a)-epimer (-)-235 of (-)-3 was derived from (-)-swainsonine ((-)-5) as shown in
Scheme 31.79 Protection of (-)-5 as an acetonide gave 232 which reacted with CS2 and Mel to
produce thiocarbonate 233. Barton reduction with tri-n-butylstannane81 afforded 234 which was
hydrolyzed under acidic conditions to produced (lS,2R,8aR)-indolizidine-l,2-diol ((-)-235),
characterized as its diacetate 236 ([a] not given).
Page 30
304
Me2C(OMe)2
pTosOH, acetone
MeS
(-)-swainsonine ((-)-5)
S
Λ , Η
(n-Bu)3SnH^
xylene, Δ .Ν ,
234
NaOH, CS2
(n-Bu)4NHS04
benzene Mel
Η OR
(0-235 R=H 236 R=Ac
Recently, Pearson and Lin1 18
have reported a very efficient enantioselective synthesis of
(0-swainsonine (Scheme 49). The same approach was applied to the preparation of (0-235, as
shown here-below.
HO cf. Scheme 49
O .
.„0
® Q 0
NaBH4
MeOH ' (0-235
Both enantiomers (+)-(lR,2S,8aR)- ((+)-3) and (0-(lS,2R,8aS)-l,2-dihydroxyindolizidine
((-)-3) have been prepared by Heitz and Overman82 by short sequences of reactions which diverge
from amide 239 derived from D-isoascorbic acid (Scheme 32). Aminolysis of the enantiomerical-
ly pure lactone acetonide 237, available on a large scale in 75% from D-isoascorbic acid, by the
Scheme 32
Ο 237
Me3Si " NHo
238
R= Me3Si C H 2C H 2
240
R e v
241
Η Ρ H OH
l.H 2/Pd-C,EtOAc^ f^C^y
Ν /^ 2. Li A1H4, Et20 N
\ 3. 2N HCl, 80°C 242 (+)-3
Page 31
305
Scheme 32 (continued)
247 248
aminobutenylsilane 238 in the presence of Me 3Al gave amide 239. Parikh83 oxidation (Me^SO,
S03-pyridine) led to hydroxy lactame 240 as a 4:1 mixture of stereoisomers whose acetate
derivative underwent cyclization in the presence of BF3OEt2, probably via intermediate 241 to
give the bicyclic compound 242. Catalytic hydrogénation of the C=C double bond, followed by
LiAlH 4 reduction of the lactam moiety and acidic hydrolysis of the acetonide afforded (+)-3.
Mesylation of the primary alcohol of 239, followed by cyclization in the presence of NaH
in THF gave lactam 243 whose treatment with Lawesson's reagent led to 244. Reduction of the
iminium ion intermediate 245 (engendered with Meerwein's salt) with super-hydride (LiBEt3H)
afforded 246. Treatment with cupric triflate generate the iminium salt 247 that underwent
cyclization with the vinylsilane moiety to produce 248 which was then converted into (-)-3
following standard sequence of transformations.
Applying the method of acyliminium ion cyclization developed by Wijnberg and
Speckamp32 (see Scheme 12), Karisawa and co-workers
84 have converted (R,R)-tartaric acid into
l,2-dihydroxy-hexahydro-3(2H)-indolidinones (Scheme 33). (3R,4R)-3,4-bis(benzyloxy)succinic
anhydride (249) derived from (R,R)-tartaric acid85 was treated with NH 3 to afford the
corresponding succinimide 250. Mitsunobu reaction of but-3-enol with 250 gave 251. Reduction
of 251 with NaBH4 and treatment with 12N HCl in dry EtOH led to a mixture of formates 253a, b
and 254a, b (53%). Saponification with IN KOH led to a mixture of the corresponding four
alcohols which were separated by preparative thin layer chromatography on silica gel. Oxidation
with pyridinium chlorochromate produced diketone 255 and 256. Starting from the succinimide
derivative 252, diketone 257 was obtained in a similar fashion.
(-)-Cyclizidine ( -)-32) is a unique alkaloid belonging to the class of 1,2-dihydroxy-
indolizidines. It has been r->und in Streptomyces species NCIB 11649 isolated from a hedgerow
soil sample originating from Greater Manchester, a region of England.86 Except for its absolute
Page 32
306
Scheme 33 BnO
ο
OBn
1. NaBH4
OBn > 2. HCl
OBn RO,
OBn
R=OCHO
249 Z=0 250 Z=NH 251 Z=NCH2CH2CH=CH2
252 Z=NCH2CH2CH=C(H)Et (E)
253a + 253b
I .KOHI
X3> ο
254a + 254b
OBn
l.KOHl 2. pyr.
Η
OBn
ClCr03H
OBn
OBn
256
configuration its structure was established by X-ray crystallography. The compounds is
biologically active. The Streptomyces species shows low activity against Botrytis allii, though
cyclizidine itself is not responsible for this activity. Cyclizidine does, however, show
non-selective immunostimulatory properties, and its secondary monoacetate causes a reduction in
frequency of beats of cultured heart cells, an effect seen with certain ß-blocking drugs.
Me
32
Other dihydroxyindolizidine derivatives such as (+)-(6R,7S,8aR)-dihydroxyindolizidine
will be presented in the section of the analogues castanospermine (Section 17).
13. Slaframine
(-)-Slaframine ((-)-4) is produced by the fungus Rhizoctonia leguminicola which after
metabolic activation binds to muscarinic acetylcholine receptor sites.87 This alkaloid is
responsible for excessive salivation in livestock if they consume mould-infested feedstuff. Studies
on (-)-slaframine have indicated that it has potential value both as research tool for the isolation of
the acetylcholine receptor sites and as a medicinal agent for the treatment of the cystic fibrosis
syndrone, since it stimulates pancreatic secretion.88 Furthermore (-)-slaframine is of interest as a
stimulator of the para sympathomimetic exocrine glands. Studies have indicated that the
stimulation is brought about by a metabolite of (-)-slaframine rather than by the alkaloid itself.
Page 33
307
Slaframine structure has been established in 1968 by Broquist and co-workers.89 The
biosynthesis of this alkaloid has been studied.6,90
The alkaloid derives form L-lysine via
L-pipecolic acid 258, 1-oxoindolizidine 33 and 1-hydroxyindolizidines (-)-l and (+)-2 (Scheme
34). Using racemic eis and trans 1-hydroxyindolizidines6 labelled at C( l ) and C(3) with
deuterium, Harris and co-workers observed that the eis isomer is utilized much better than the
trans isomer (-)-l, the latter undergoes, apparently, oxidation back to ketone 33 before conversion
to the alkaloid. It is noteworthy that the carbonyl carbon atom of pipecolic acid (258) is
incorporated into (-)-slaframine, an unusual occurrence in alkaloid biosynthesis. The two
additional carbon atoms required to form the pyrrolidine ring are contributed by acetate via
malonate.90c
Presumably, pipecolyl acetate is an intermediate, although direct proof for its
involvement is lacking.6
Scheme 34
L-lysine
, N H 2
COOH
H
C= COOH
NH
258
COOH
259 33 OAc
(-)-4 (-)-l (trans) (+)-2 (eis)
Total syntheses of racemic slaframine ((±)-4) have been reported by Rinehart,92 Gensler,
93
Weinreb,94 Harris,
95 and Flitsch.
96 A formal total synthesis has been proposed by Shono.
97 It is
interesting to note that the racemate is produced in each synthesis (see here-below), even when
optically active materials such as L-glutamic acid (Scheme 36), or L-lysine (Scheme 39) are used
as starting materials. The first synthesis presented by Rinehard and co-workers92 in 1970 (Scheme
35) transforms 2-bromo-5-nitropyridine (260) to 5-acetamido-2-ethoxycarbonylpyridine (261) by
Scheme 35
l . ^ l N COOEt ^ A 1. CuCN
2. H2SC>4/EtOH l^iT COOEt
260
3. H 2/Pt0 2
4. A c 20
Η 0
AcN ι Η
2. COOEt
AcNJ
/ Η
'COOEt
261 262
Page 34
308
Scheme 36
270 E=COOMe 271 272
In their approach (Scheme 37) to the synthesis of (±)-slaframine, Weinreb and
co-workers94 used an intramolecular imino Diels-Alder cycloaddition to produce the indolizidine
skeleton and to establish the requisite relative configuration of centres C(6) and C(8a) only. Diene
a modification of the route of Schmidt-Thomé and Goebel.98 Hydrogénation of 261 over Pt0 2
gave ethyl 5-acetamidopipecolate whose heating with ethyl acrylate led to the product of
1,4-addition 262. Cyclization of 262, using t-BuOK in toluene, gave the unstable ß-ketoester 263
whose hydrolysis and decarboxylation on heating with 8N HCl afforded ketone 264. Reduction
with NaBH4 and acetylation produced a mixture of l-acetoxy-6-acetamidoindolizidines 265.
Careful chromatography on alumina separated the four diastereomers in proportions 1:1.4:4:5.
One of them (the third one) was deacetylated by boiling with hydrazine hydrate. The product,
deacetylated (±)-slaframine, was converted with benzylchloroformate to N-carbobenzyloxyslafra-
mine (266). Acetylation with A c 20 and then hydrolysis with 30% HBr in AcOH furnished
(±)-slaframine.
In 1973, Gensler and Hu proposed a more stereoselective approach (Scheme 36)93 which
started with ethyl N-(ß-eth,oxycarbonylethyl)-5-oxopyrrolidine-2-carboxylate (267) derived from
L-glutamic acid and acrylonitrile. Cyclization with EtONa produced 268 which was completely
racemized. Decarboxylation of 268 in hot HCl was accompanied by lactam ring hydrolysis,
giving the 3-oxopyrrolidine acid 269. Hydrogénation of 269 over a platinum catalyst in methanol
led to the eis alcohol of 270. Alkylation of 270 on the amino moiety with methyl bromoacetate
afforded 271 and 272. Dieckmann cyclization of 271 + 272 gave rise to indolizidine 273. Decar-
boxylation of 273 with acid produced an hydroxyketone which was first acetylated to 274. The
corresponding oxime (mixture of syn and and forms) was hydrogenated to give (±)-slaframine.
Page 35
309
Scheme 37
OHC- + L i C H 2^ OR
NR 275
E=COOMe, R^-BuMe^Si
OR
H Ov J ^ - E
l.t-BuMe2SiCl R 0
V
2. (HCHO)n
Cs 2C0 3, THF
3. Ac20/pyr. O'
F ^ N H
-OAc
, N ^ / 2. as for 281
Ο (±)-285: (±)- 1-ep/-slaframine
aldehyde 275 which was treated with the carbanion derived from bis(trimethylsilyl)acetamide,
followed by an acidic work-up, afforded ß-hydroxy-amide 276. The corresponding t-butyldi-
methylsilyl ether was then converted into the acylimine precursor 277 by treatment with
paraformaldehyde and Cs 2C0 3 followed by acetylation. Thermolysis of 277 in refluxing
o-dichlorobenzene afforded a separable 1:1.8 mixture of bicyclic lactams 278 and 279. The
intramolecular Diels-Alder reaction occurs probably through the intermediate acylimine 280.
Catalytic hydrogénation of adduct 278 gave 281. The "incorrect" epimer 279 was inverted by a
sequence involving cleavage of the silyl ether with HC1/THF, giving an alcohol which was
converted into the corresponding ketone 282 with CrO^pyridine in CH2C12 whose reduction with
9-borabicyclo[3.3.1]nonane in THF was completely stereoselective and produced alcohol 283.
Hydrolysis of the ester group of 281 (KOH/MeOH) gave the corresponding acid which was
subjected to a standard Curaus rearrangement sequence (EtOCOCl/pyridine; NaN3; BnOH)
affording carbamate lactam 284. Reduction of carbamate lactam 284 with diborane in THF, then
acidic treatment to hydrolyze the silyl ether and acetylation of the liberated alcohol, followed by
catalytic hydrogenolysis gave racemic slaframine ((±)-4). A similar procedure was used to
convert 279 into \-epi-slaframine ((±)-285).
Schneider and Harris95 (Scheme 38) presented in 1984 a method converting 2-chloro-5-
nitropyridine (286) in ten steps into (±)-slaframine (5% overall yield). The key step is the
formation of the indolizidine skeleton via a KH-induced cyclization of N-acetylpipecolate ester
Page 36
310
287 to give ß-ketolactam 288. The relative configuration of C(6) and C(8a) is established during
catalytic reduction of picolinate ester, and the eis relationship is maintained during the cyclization
process. The relative configuration of C( l ) is set via stereoselective reduction of ß-ketolactam
288 with L-selectride (lithium tri-sec-butylborohydride) to cis-l-hydroxyindolizidine derivative
289. Reduction of lactam 289 with diborane followed by detosylation with sodium metal in
Scheme 38
ammonia gave (±)-290. Selective acetylation of the alcoholic function of (±)-290 in acetic acid-
HC1 afforded (±)-slaframine.
The synthetic intermediate 287 (Scheme 38) has been prepared recently by Shono and
co-workers97 starting from L-lysine (Scheme 39). Namely, the anodic oxidation (in MeOH,
MeONa) of α-Ν-acetyl-e-N-tosyl-L-lysine methyl ester (291) in the presence of KI gave the
rearranged product 292 in its racemic form. The formation of 292 can be interpreted by the attack
of amide 291 by the electrochemically generated postive halogen species I® to form a first
Scheme 39
Page 37
311
intermediate 293. The base-induced elimination of HI gives imine 294 which rearranges into 295.
Another electrophilic additions of I® on the enamine followed by methanolysis engenders adduct
296. The latter undergoes intramolecular displacement of the iodide by the tosylamide moiety to
generate unstable aziridine derivative 297 that is methanolyzed to the dimethyl acetal 292. The
acid-catalyzed intramolecular cyclization of 292, followed by hydrogénation gave 293 which
was transesterified (EtOH/HCl) to (±)-287.
Flisch and co-workers96 (Scheme 40) have developed an interesting approach to the
synthesis of indolizidinones from thalidomide (298) and cyclopropylphosphonium salts 299.
These two reagents react in the presence of potassium hydride in hot toluene to give the
Scheme 40
304 (±)-305: (±)-6-ep/-slaframine
OAc
300 (R=H) (±)-slaframine
corresponding α,β-unsaturated lactams 300. Allylic oxidation of 300 (R=H) with Pb(OAc)4 led to
the 8-acetoxy derivative 301 with high regio and stereoselectivity. Under acidic conditions, 300
(R=H) was isomerized into 302 whose oxidation with Pb(OAc)4 afforded a 5.5:1 mixture of the
desired 1-acetoxy derivatives 303 and 301. Hydrogénation of 303 on Wilkinson's catalyst and
then detosylation with hydrazine gave lactam 304. Reduction with diborane in THF, followed by
acetylation of the alcoholic moiety with AcOH/HBr produced racemic 6-e/?/-slaframine ((±)-305).
When the allylic oxidation of 300 (R=H) with Pb(OAc)4 was carried out in the presence of
Page 38
312
triethylamine, 17% of the expected acetate 301 was obtained together with 34% of the 6-epimeric
derivative 306 which could be converted, as in the case of 303 - (±)-305 to (±)-slaframine.
The first enantioselective synthesis of (-)-slaframine has been reported by Pearson and
Bergmeir in 1991" (Scheme 41). A doubly protected version of L-glutamic acid was prepared by
converting N-benzyl-L-glutamic acid (307) to its N-carbobenzyloxy derivative 308. Diborane
reduction of both carboxylic acid moieties afforded the corresponding diol 309. Selective
silylation of 309 produced 310, presumably because of the differing steric and electronic
environments of the two hydroxyl groups. Conversion of 310 to the azide 311 was accomplished
with a Mitsunobu reaction. Deprotection of 311 and oxidation of the primary alcohol gave azido
aldehyde 313. Stereoselective Wittig reaction of the aldehyde 313 with a silyloxy-substituted
ylide produced the (Z)-alkene 314 whose epoxidation with m-chloroperbenzoic acid was
non-selective, leading to diastereomeric epoxides 315 and 316 in equal amounts. Separation of
315 and 316 was carried out by HPLC. Tosylation of 315 gave 317. Selective reduction of the
azide moiety of 317 by catalytic hydrogénation over Pd/C gave the corresponding primary amine
which was not isolated but was directly heated in refluxing ethanol containing K 2C 0 3 . An
intramolecular epoxide opening and subsequent alkylation of resulting secondary amine by the
terminal tosylate ensued, affording the indolizidine 319. Acetylation of the secondary alcohol of
319 gave 320, which was deprotected to (-)-slaframine ((-)-4) by hydrogenolysis over palladium
on charcoal. A similar sequence of reactions transformed the epoxy tosylate 318 to
(-)-1,8a-di-e/?/-slaframine ((-)-321).
Scheme 41
COOH BH 3THF
ΒηΝΓ COOH BnN ι ι R Cbz
307 R=H 308 R=BnOCO=Cbz
0 R 1. Mitsunobu r s /
0 R (COCl) 2DMSO
OH 2. R n N ^N
3
309 R=H 310 R=t-Bu3Me2Si
BnN ι Cbz
Et3N, CH2C12
311 R=t-Bu3Me2Si 312 R=H
r^N^°Ph 3P(CH 2) 3OH Brg>
B n N ^ N 3 KN(SiMe 3) 2;THF^B n r ;J
Cbz
313
LrVPd-C 2. Δ, EtOH, K 2C 0 3
Cbz
314 315 R=H 317 R=Ts
OAc
3. Ac20/pyr.
316 R=H 318 R=Ts
Ψ Η OAc
319 R=H 320 R=Ac
(-)-slaframine (-)-321: (-)-1,8a-di-ep/- slaframine
Page 39
313
(-)-5 (-)-swainsonine (-)-6
((_)_4)ioo,i05 ^ v e ry l ow concentration of (-)-(lS,2R,8aS)-indolizidine-l,2-diol ((-)-3).79 X-ray
crystallography of the diacetate of (-)-swainsonine confirmed the relative configuration of the
alkaloid.106
Application of the Horeau's procedure107
to the 1,2-acetonide indicate (R) absolute
configuration at C(8) and hence the overall absolute configuration, which was subsequently
confirmed by several enantiospecific syntheses (see below). Ingestion by cattle of plants (e.g.
spotted locoweed, Astragalus lentiginosus, Texas locoweed, Astragalus emoryanus or the white
locoweed, Oxytropis sericae) containing (-)-swainsonine is known to give rise to chronic
neurological disease called locoism. In the plants, (-)-swainsonine is often accompanied by its
N-oxide ((-)-6). (-)-Swainsonine is an inhibitor of some α-D-mannosidases involved in the
biosynthesis and catabolism of glycoproteins2,108
and has immunostimulatory properties and
possible use in cancer chemotherapy.109
(-)-3
Biosynthetic studies on (-)-swainsonine have all related to its occurrence in Rhizoctonia
leguminicola, and most of these studies have been carried out in parallel with studies on the
14. Swainsonine
The alkaloid swainsonine ((-)-5: (lS,2R,8R,8aR)-octahydroindolizine-l,2,8-triol), was
first isolated in 1973 from the fungus Rhizoctonia leguminicola by Broquist and al.1 00
Swainsonine has also been shown to be present ni loco weed Swainsona canescens}01 Astragalus
lengitiginosus,102
Astragalus emoryanus,103
and oxytropis sericea}02 as well as in the fungus
Metarhizium anisopliae F 3622.104
In R. leguminicola it occurs along with (-)-slaframine
Page 40
314
biosynthesis of (-)-slaframine (Scheme 34), which also occurs in the fungus.100
As found for
(-)-slaframine, the piperidine ring and carbon atom C( l ) of (-)-swainsonine are derived from
L-lysine via pipecolic acid (259) while the carbon atoms C(2) and C(3) come from acetate via
malonate.90c
'd A common pathway appears to operate as far as (S)-l-oxoindolizidine ((-)-38),
which is then reduced from the Si-face in the biosynthesis of (-)-slaframine, and from the Re-face
in the biosynthesis of (-)-swainsonine.6 Feeding experiments with deuterium labelled
1-hydroxyindolizidines and L-[3H]pipecolic acid suggested that the route to (-)-swainsonine
involves diol (-)-3 which equilibrate with iminium ion 323. The latter is oxidized to 324 which
leads to (-)-swainsonine (Scheme 42).
Because (-)-swainsonine has four contiguous chiral carbon centres corresponding to those
of either 3-amino-3-deoxy-D-mannose or 4-amino-4-deoxy-D-mannose it was quite logical to
reach the alkaloid from one or the other carbohydrate derivative 325 or 326. In 1984 there have
been four independent reports presenting similar enantiospecific syntheses of (-)-swainsonine
applying this principle. One of them, due to Richardson and co-workers110
converts methyl
HO OH H ?
HO OH Η Ξ
325 326
α-D-glucopyranoside (327) to methyl 3-amino-3-deoxy-a-D-mannopyranoside hydrochloride
(330) (Scheme 43)1 11
via the dialdehyde 328 and its condensation with nitromethane to give 329,
followed by hydrogénation over Raney Nickel catalyst. When 330 was treated with
benzyloxycarbonyl chloride and the crude N-benzyloxycarbonyl derivative was immediately
treated with tosyl chloride, it gave tosylate 331. Hydrogenolysis of the benzyl carbamate in 331
and then boiling in ethanolic sodium acetate gave an 3,6-imino derivative which was protected as
the benzyl carbamate 332. Acidic hydrolysis of 332 furnished 333 which was condensed with
ethanethiol in the presence of HCl to give dithioacetal 334. The corresponding triacetate 335 was
l . N a l O y H ^
( W 2
'N a H C
° 3 * H i 7 | 1 OMe
HO—ι
l . C H 3N 0 2 J Ο
2 .N«/EtOH* f ^ j ^ 3. H 3 0
+ HO OMe
329 HO TsO-
, 0 " Ί 0 i.H2Pd/c n N
n
H C b z
ΗΟΛ r O M e i l S U
H O " r
O M e EtOH
HO OMe
2. HCl
330 331 3. CBzCl
332
Page 41
315
Scheme 43 (continued)
HO
HCl
- λ " Λ Cbz
AcON
CbzN OAc
HO
334 R=H 335 R=Ac
Ac
336 R=CHO 337 R=CH=CH-COOEt
338 AcO
EtOOC OAc] OAc
BH^Me^S
THF
338 339
(-)-swainsonine MeOH
OAc
• OAc
MeONa
converted into the aldehydo-hexose 336 whose reaction with ethoxycarbonylmethylenetriphenyl-
phosphorane gave the Wittig product 337 (1:1 mixture of (E)- and (Z)-isomers). Catalytic
hydrogénation released the amino group which attacked both the ethoxycarbonyl and 2-O-acetyl
groups to give a 1:1 mixture of cyclic lactam 338 and the product of Ο - Ν acetyl migration 339.
Selective reduction of the lactam moiety of 338 with BH^M^S complex led to tri-O-acetyl-
(-)-swainsonine (340). Conventional O-deacetylation of 340 gave crystalline (-)-swainsonine.
The strategy proposed by Suami and co-workers112
is similar to that of Richardson; it
converts methyl 3-acetamido-2,4,6-tri-0-acetyl-3-deoxy-a-D-mannopyranoside (341) in 15
synthetic steps to (-)-swainsonine via the diethylthioacetal tosylate 342 (Scheme 44).
Scheme 44
D-glucose -
AcO
AcO
1.HC1, Δ
- VC 2 .Ac 20
CHNAc Ο
OMe 3.NaOMe, MeOH 7. H 30
+
5.Ph3CCl,pyr. BnO u 0 Bn
6. BnBr, NaH EtS
EtS
4. EtSH
341
BnO
1. NaOH/H2Q
2. HgCl2/CaC03
3. Ph3P=CHCOOEt
OBn
• OBn
8. TsCl/pyr.
l.H2/RaneyNi
2. KOH/H20/EtOH
OBn
342 OTs
BnO
COOEt
(-)-swainsonine < -LLiAlH/THF
OBn
« OBn
2. Pd(OH)2/cyclohexene
The strategy of Takaya and co-workers113
utilizes D-mannose as starting material
(Scheme 45) which was converted first into methyl 6-0-benzoyl-2,3-0-isopropylidene-a-D-talo-
Page 42
316
pyranoside (343). Mesylation of 343 in pyridine, followed by hydrolysis of the acetonide afforded
344. SN2 displacement of the mesylate with sodium azide in DMF led to the 4-azido-4-deoxy-D-
mannose derivative 345. The vicinal diol moiety was reprotected as an acetonide and the primary
alcoholic group liberated by saponification of the benzoate, giving 346. Oxidation of 346 with
sulfur trioxide/pyridine complex, triethylamine, and DMSO produced the corresponding aldehyde
which was condensed with (methoxycarbonylmethylidene)triphenylphosphorane in THF to give
347. Catalytic hydrogénation (Pd black) of 347, followed by refluxing in MeOH afforded lactam
348. Reaction of 348 with BH 3THF, followed by deprotection of the acetonide and methyl
pyranoside with BC13 in CHC13 produced 349 which was immediately reduced with NaBH3CN in
MeOH to give (-)-swainsonine.
Scheme 45
l.MsCl/pyr.
OMe 2. CF3COOH/MeOH
BzO
MsO
- > \/ \ NaïtyDMF < O H O H > >
\ V I no°c OMe
D-mannose
BzO
343
HO
344
COOMe
Ο l. Me2C (OMe) 2,He
w?H ?>
>|2.KOH/MeOH
>
OMe
l.pyr. S0 3,
Et3N, DMSO >
2. Ph3P=CHCOOMe OMe Ypjp
l.H2/Pd black
MeOH .
1. BH 3THF
348
« OH NaBH3CN
H20/MeOH
pH=6-7
- > (-)-swainsonine
Similarly to the work of Takaya,113
the method of Fleet and co-workers114
(Scheme 46)
features the conversion of benzyl a-D-mannopyranoside (350) to a protected 4-azido-4-deoxy-cc-
D-mannose derivative 353. The process involves selective protection of 350, formation of the
triflate (trifluoromethanesulfonate) 352 which was treated with NaN3 in DMF. Fluoride anion
induced hydrolysis of the silyl ether of 353 and liberated the 6-hydroxy group which was then
oxidized to the corresponding aldehyde, followed by treatment with (formylmethylidene)tri-
phenylphosphorane, to give crystalline azidoaldehyde 354. Catalytic hydrogénation (Pd/C) of 354
in MeOH led to the formation of the secondary amine 355; this conversion required reduction of
the olefinic moiety, reduction of the azide group to an amine and subsequent intramolecular
reductive amination of the amino-aldehyde. Removal of the anomeric benzyl group in 355 was a
slow process which required hydrogenolysis over palladium black catalyst in acetic acid. This
caused the liberation of the corresponding lactol which was in equilibrium with an open
amino-aldehyde which underwent a reductive amination to form l,2-0-isopropylidene-(-)-
Page 43
317
Scheme 46
HO ~Ί ο 1. t-BuPh2SiCl/
HO ^ " " ^ 0
imidazole
350
NaN^/DMF
2. Me2C(OMe) 2
°B n
Me 2CO,H- H0
OSiPh2(t-Bu) OSiPh2(t-Bu)
TIO J — Ο LPCC/CH2C12 _ \ / ^ '
O ' ^ O 2. NaBHVEtOH _
OBn 3. (CF3S02)20/pyr. O Bn
351 352 CHO
OSiPh2(t-Bu)
Ο
OBn
353
1. Bu4N+F7THF^
2. PCC/CH2C12
3. Ph3P=CHCHO
H2/Pd-C/MeOH
OBn
(fei H2/Pd black/AcOH
Η
I CF3COOH H 90
swamsomne
OBn
355 356
swainsonine (356). Acidic hydrolysis furnished finally (-)-swainsonine.
In 1985, Hashimoto and co-workers115
reported a short, enantiospecific synthesis of
(-)-swainsonine from D-mannose by a route involving a double cyclization of 363 (Scheme 47).
D- mannose was converted into the partially protected oxime 357 in two steps.116
Reduction of
the oxime group in 357 with LiAlH 4, followed by protection of the resulting amine with
(CF 3CO) 20 and treatment of the resulting amide with methanesulfonyl chloride provided
mesylate 358. Partial hydrolysis of the acetonide groups in 358 was performed by treatment with
tosylic acid in aqueous methanol, and followed by neutralization with Amberlite IRA-400 (OH"
type) to produce the epoxide 360 via 359. Oxidation of 360 with Collins reagent gave the
aldehyde 361, which, without purification, was condensed with (ethoxycarbonylmethylidene)-
triphenylphosphorane in THF yielding a 3:1 mixture of the (E)- and (Z)-acrylate derivatives 362.
Treatment of 362 with NaBH4 in boiling EtOH/CF3CH2OH (10:1) afforded the 5-oxoindolizidine
364 (32%) together with 365 (23%), these products being easily separated by column
chromatography on silica gel. The transformation 362 - 364 + 365 involves 1,4-reduction of the
α,β-unsaturated ester moiety, deacylation of the terminal amide followed by attack of the
liberated amino group in 363 onto the epoxide moiety (at C(4) to give 364, and at C(5) to give
365); the pyrrolidine intermediate cyclizes then with the ethyl carboxylate, giving a lactam that is
reduced with NaBH4 in the ionizing solvent mixture EtOH/CF3CH2OH. Compounds 364 and 365
were deprotected under acidic conditions to produce (-)-swainsonine and it stereomer (-)-366,
respectively. The latter compound has a mitogenic activity and mannosidase inhibitory activity
somewhat weaker than those of (-)-swainsonine.
Page 44
318
Scheme 47
D-mannose 2. H 2NOHHCl
NaHC03
H
357
l.LiAlHyTHF
NOH 2.(CF 3CO) 20,CH 2C? °M s
3. MsCl, pyr.
NH I
C O C F 3
358
H20/MeOH/H+ HO, >
O H | HO
OMs ^ NH C O C F 3 N H C O C F 3
359 360
Cr03pyr.
C H 2C 1 2 ^ i C H
Ph3P=CHOOEt
NHCOCFo EtOOC
NaBH4
CF3CH2OH/EtOH
1:10
361 362
HO
X 364 365
(-)-swainsonine
(-)-366
One of the shortest strategy has been proposed by Cha and co-workers in 1989117
who
converted 2,3-O-isopropylidene-D-erythrose (367) to (-)-swainsonine in seven steps via an
intramolecular 1,3-dipolar cycloaddition of an azide (Scheme 48). Coupling 367 with
(3-ethoxycarbonylpropyl)triphenylphosphonium bromide gave the primary alcohol 368.
Treatment of 368 with tosyl chloride, followed by the displacement of the tosyl group with NaN3
in DMF led to the reactive azide 370 that underwent fast intramolecular cycloaddition to give the
unstable triazoline 371 which decomposed into the imino ester 372. The corresponding acid 373
underwent cyclization on heating in toluene, producing 374. Oxidative hydroboration of 374
afforded 364 as single stereomer (91%) which was deprotected to give (-)-swainsonine.
In 1990, Pearson and Lin1 18
reported a route (Scheme 49) to the indolizidines very similar
to that of Cha,1 17
which converted 367 to (-)-swainsonine in four separate vessels and in an
Η Ο - η O - V "
I ^ O H 0 H W 0 H l \ L J / ^ 1 . Μ ^ Ο Ο , Η
+ O H
H O 1
Page 45
319
Scheme 48
Ο "
367
EtOOC
OH
P h 3 Px
^ ^ C O O E t
B r ^
KN(Me 3Si) 2
THF, -78°C
COOEt
χ
-N,
368 R=OH 369 R=OTs 370 R=N 3
N , COOR
372 R=Et 373 R=H
374
(-)-swainsonine HCl
THF 364 <r
l . B 2H 6
2. H 20 2/KOH
overall yield of 39%. Wittig reaction of 367 with (4-chlorobutyl)triphenylphosphonium bromide
gave 375 (86%) whose primary alcoholic moiety was substituted by an azido group via a
Mitsunobu reaction. The stable azide 376 (76%) was heated in benzene to produce the observable
OH-NMR) bicyclic imonium salt 377 which eliminated one equivalent of HCl on addition of
t-BuNH2 to the crude reaction mixture. Direct hydroboration of 378 led to hydrogénation of the
enamine, probably because of t-BuNH2-HCl which protolyses the intermediate alkylborane. Thus
t-BuNH2HCl was neutralized by KN(Me 3Si) 2 to reduce the chance of protolysis, and then
oxidative work-up with hydrogen peroxide and NaOAc (instead of NaOH) led to a 70% yield of
364 (based on 376).
Scheme 49
3 67 + PhoP'
KN(Me 3Si) 2 HO >
THF, -78°C
° x ° 375
Ph3P, EN=NE THF
376
PhH l.t-BuNH2
Ξ 2. KN(Me 3Si) 2
377
378
1. BH3THF
2. H 20 2, NaOAc - > 364
HCl^
THF" (-)-swainsonine
Page 46
320
Miller and Chamberlin119
have proposed a synthesis of (-)-swainsonine (Scheme 50)
based on acyliminium ion cyclization (cf. Scheme 12, 32, 33). D-lyxose was protected as its
2,3-O-cyclohexylidene derivative 379 on treatment with 1-methoxycyclohexene and BF 3Et 20 in
THF. Oxidation of the furanose 379 under the Fétizon's conditions120
afforded lactone 380 whose
treatment with 2-(4-aminobutylidene)-l,3-dithiane, followed by oxidation with lead tetraacetate
in acetonitrile to give a mixture of epimeric hydroxy lactams 381. Mesylation of 381 in CH2C12
followed by the addition of CH 3CN which accelerates the formation of the acyliminium ion
intermediate 382 by increasing the solvent polarity, led to the single diastereomer 383 isolated in
60% yield. The ketene dithioacetal 383 was converted into the α-bromoester with
N-bromosuccinimide in ethanol, followed by treatment with DBU in THF to give the
α,β-unsaturated ester 384. Catalytic hydrogénation of 384 was a difficult reaction. Treatment of
384 with Meerwein's salt, followed by addition of NaBH3CN reduced the lactam moiety and also
the C=C double bond, giving 385 as a single product. The a-hydroxylation of the ethyl
carboxylate, followed by LiAlH 4 reduction gave a vicinal diol which was cleaved with NaI0 4.
The resulting ketone 386 was reduced selectively with Na/NH3 into the desired, partially
protected swainsonine derivative 387. Removal of the cyclohexylidene ketal on treatment with
Scheme 50
Page 47
321
concentrated HCl produced (-)-swainsonine. The strategy shown in Scheme 50 has also been
applied by the same authors to the synthesis of (+)-castanospermine (see Scheme 65).
All the synthetic methodologies presented in Scheme 43-50 used a carbohydrate as
starting material and chain elongation through a Wittig reaction. In the next approach (Scheme
51) presented by Ikota and Hanaki121
in 1987, the starting material is (R)-glutamic acid and the
chain elongation involves the nucleophilic addition of an organo-copper reagent to a
pyrrolidinecarbaldehyde intermediate. (R)-glutamic acid was first converted selectively to the
protected a's-diol 389 via butenolide 388. Protection of the diol as an acetonide, followed by
LiAlH4 reduction of the lactone moiety gave a diol whose selective mesylation of the primary
alcohol moiety followed by displacement by NaN 3 afforded the corresponding azide 391.
Reduction of the azido group with hydrogen on palladium black catalyst in ethanol liberated the
corresponding primary amine which immediately displaced the secondary mesylate in a
intramolecular fashion with inversion of the configuration, giving a pyrrolidine derivative which
was N-benzylated (392). Exchange of the isopropylidene protective group with benzylic groups,
acidic hydrolysis of the trityl ether and S wem oxidation produced aldehyde 393. Reaction with
allylmagnesium chloride led to a 3:1 mixture of 394 and 395. Addition of the corresponding
Scheme 51
(R)-glutamic - > / \ OTr acid O ^ s ^ X y morpholine
0 N-oxide
HO OH
0s0 4 ^ ( 1. Me2C(OMe) 2, H+
OTr >
3. MsCl, pyr. Tr=Ph3C
X 388
, / 2. L1AIH4, Et20
acetone, H 20 339
χ Ο Ο l .NaN 3 \ # l.H,/Pd/EtOH
O ' Ο
OTr 2. MsCl
390
BnO OBn
I Η Bn
393
1. BnBr/NaH 394 >
2. B2H6/THF
3. H202/NaOH
THF, -78°C
394 395
BnO OBn
LMsCl, pyr. OBn >
2.H2/Pd-C k . N ,
(-)swainsonine
Page 48
322
allylcuprate gave a 1:3 mixture of 394 and 395. Protection of the alcoholic function in 395 as a
benzylic ether, followed by oxidative hydroboration of the terminal olefin afforded 396 whose
mesylation gave to corresponding mesylate. Catalytic hydrogenolysis of the benzyl groups
liberated the pyrrolidine moiety which cyclized onto the mesylate to give (-)-swainsonine. The
same sequence of reactions applied to 394 led to the isolation of (-)-8-e/?/-swainsonine ((-)-397).
Starting from (S)-glutamic acid instead of (R)-glutamic acid, Dcota and Hanaki122
prepared by the
same procedure, (-)-l-epz-swainsonine ((-)-398), and (-)-l,8-di-ep/-swainsonine ((-)-399).
Scheme 51 bis
1
(-)-399: (-)-l,8-di-ep/-swainsonine (-)-398: (-)-l-epi-swainsonine
In the strategy proposed by Hart and co-workers123
(Scheme 52) which uses D-(-)-tartaric
acid as starting material, the formation of the indolizidine ring is based on a radical cyclization
involving an intramolecular addition of an α-acylamino radical onto an acetylene moiety.
Sequential treatment of D-tartaric acid with acetyl chloride, ammonia, and acetyl chloride again
gave crystalline imide 400. Sequential treatment of 4-pentyn-l-ol with 2-equivalents of nBuLi
and Me3SiCl, followed by aqueous acid led to acetylene 401. Mitsunobu coupling of 400 and 401
afforded imide 402 (86%). Reduction of 402 with NaBH4, followed by acetylation of the resulting
alcohol 403 gave triacetate 404 (62%). Finally, treatment with thiophenol and a catalytic amount
of p-toluenesulfonic acid produced the radical precursor 405 (92%). Treatment of 405 with
tri-n-butyltin hydride and azobis(isobutyronitrile) (AIBN) in benzene under reflux gave indolizi-
dinones 407 (31%) and 408 (39%) along with reduction product 406 (11%). Protodesilylation of a
mixture of 406 - 408 using p-toluenesulfinic acid in aqueous acetonitrile gave olefin 409 which
was separated from unchanged 406 by column chromatography. Ozonolysis of 409, followed by
reduction of the resulting crude ketone 410 with NaBH4, completed the synthesis of 411 (68%).
Inversion of alcohol at C( l ) in 411 was accomplished in the following way. Treatment of 411
with pivaloyl chloride (PivCl) gave 412. Ammonolysis of the acetates with methanolic ammonia,
and the resulting diol was acylated by using PivCl to afford diester 413 (67%) and triester 414
(20%) separated by column chromatography. The alcoholic function of 413 was esterified with
triflic anhydride and the resulting triflate displaced with anhydrous KOAc in the presence of
18-crown-6-ether in DMF. Acetylation of the crude product gave 415. Treatment of lactam 415
with Lawesson's reagent gave thiolactam 416. Desulfurization of 416 using Raney nickel,
followed by treatment with MeNH 2 produced (-)-swainsonine (14% overall yield, 15 steps from
imide 400).
Page 49
323
Scheme 52
HOOC -0 H
HOOC
OAc
1. AcCl
2. NH 3 0 H
3. AcCl
D-(-)-tartaric acid
Me3Si.
1. NaBH4
2. Ac 20, Et3N
3. PhSH, TsOH
Me3Si
υ OH
401
Me3Si,
Ph3P/THF N-COOEt N-COOEt
OAc
' OAc
Me3Si
AIBN
OAc
402
LTsOH • OAc
CH 3CN/H 20
2. (tyMe^S
403 X=OH
404 X=OAc
405 X=SPh
406 X=H
407(E)
408 (Z)
OAc
05 409 Z=CH 2
410 Z=0
l . N H ^ e O H
2. PivCl
• OAc NaBH
413
1. Tf 20
2. AcOK, 18-Cr-6
DMF
3. Ac 20/Et 3N
OAc PivO
• OAc PivCl
OAc
• OAc
412
PivO OPiv
-.ι OPiv
"· OAc
414
1. Raney Ni^
EtOH 2. MeNH 2
(-)-swainsonine
415 Z=0 416 Z=S
(p-MeOC6H4PS2)2
toluene
In 1985, Sharpless and co-workers124
reported on a first total synthesis of (-)-swainsonine
not starting from a carbohydrate or amino-acid derivative. Their approach employs the
methodology of the Katsuki-Sharpless125
asymmetric epoxidation of allylic alcohols (Scheme
53).1 26
Alkylation of N-benzyl-p-toluenesulfonamide with an excess of frartJ-l,4-dichloro-2-
butene gave the allylic chloride 417 whose treatment with NaOAc in DMF, followed by
hydrolysis afforded allylic alcohol 419. Asymmetric epoxidation of 419 with t-butyl
hydroperoxide (t-BuOOH) in toluene in the presence of 1.5 equivalent of (-)-diisopropyl tartrate
((-)-DIPT) and 1.2 equivalent of Ti(0-i-Pr)4 in CH2C12 at -20°C produced epoxide 420 in 95%
enantiomeric excess. Treatment of 420 with PhSH and 0.5N NaOH in t-butanol gave a diol which
was benzylated to 421. Oxidation of the sulfide 421 with m-chloroperbenzoic acid (mCPBA) in
CH2C12 led to the sulfoxide 422. Treatment of 422 with acetic anhydride, trifluoroacetic
Page 50
324
Scheme 53
TsNHBn+r l.NaH Katsuki-
2. NaOAc 3. K2C03/MeOH
417 X=C1 418 X=OAc 419 X=OH
LPhSH/NaOH >
2. BnBr/NaH nBu4M/THF
OBn mCPBA
OBn
OBn 1. LiAlH4, THF
2. (COCl)2, DMSO
DBu, CH2C12
1. DIB AH
l.DCC, DMSO pyrH+TfO"
2. Ph3P=CHCOOEt'
3. [HN=NH]
A c 90
(CF 3C0) 20
2,6-lutidine
Ο II
(EtO)2PCH2COOEt
NaH, PhCH3
Katsuki-
Sharpless epoxidation
426
OBn
COOEt
OBn
428
l .C 1 0H 8Na
2. t-BuMe^SiOTf Et3N/CH2Cl2 CÖOEt
OBn R'O OBn
DIBAH • OBn
429 R=H 430 R=R'=t-BuMe2Si
(-)-swainsonine OBn
432
anhydride and 2,6-lutidine induced a Pummerer rearrangement with formation of 423. Complete
reduction of 423 with LiAlH4, followed by Swern oxidation to 424 proceeded without
epimerization. Wittig-Homer reaction of 424 with triethyl phosphonoacetate gave ester 425
((E)/(Z) 32:1) whose reduction with diisobutylaluminium hydride (DIBAH) in toluene led to the
Page 51
325
corresponding allylic alcohol 426. Asymmetric epoxidation under similar conditions as for the
transformation 419 - 420 afforded epoxy alcohol 427 (diastereomeric ratio >321:1, by HPLC).
The final two carbon atoms required for the swainsonine backbone were added by Moffatt
oxidation of 427, followed by addition of ethoxycarbonyl(methylidene)triphenylphosphorane.
Diimide reduction of the resulting α,β-unsaturated ester furnished 428. The tosyl protecting group
of 428 was removed with sodium naphthalide with concomitant ring closure to pyrrolidine 429.
Protection of the alcohol moiety using t-butyldimethylsilyl triflate gave 430 whose ester group
was reduced with DIBAH to produce alcohol 431. Mesylation of 431 gave directly salt 432 whose
hydrogenolysis and then desilylation on Dowex 50 W-X8 ( H+ form) afforded (-)-swainsonine
((-)-5).
15. Swainsonine stereomers
Because (-)-swainsonine is a very potent inhibitor of glycosidases involved in the
biosynthesis of oligosaccharides, a great deal of synthetic efforts were aimed at the preparation of
stereomers and analogues of this alkaloid. Many of the methodologies presented above for the
synthesis of (-)-swainsonine can be applied successfully to their preparation, as already illustrated
in Scheme 51 bis by the conversion of (R)-glutamic acid into (-)-8-ep/-swainsonine ((-)-397), and
of (S)-glutamic acid into (-)-l,8-di-e/?i-swainsonine ((-)-399) and (-)-l-ep/-swainsonine ((-)-398).
Other synthetic approaches to these 1,2,8-trihydroxyindolizidines and to stereomers (-)-433,
(+)-434, (-)-435 and (-)-436 will be summarized in this section.
(+)-434 (2,8-di-^0 (-)-435 (2,8a-di-epz) (-)-436 (8,8a-di-ep/)
In 1985, Takaya and co-workers127
converted D-glucose to (+)-2,8-di-e/?/-swainsonine
((+)-434) and to (-)-397 (Scheme 54). Treatment of 3-azido-3-deoxy-l,2-0-isopropylidene-a-D-
-glucofuranose (437) (derived from D-glucose1 2 2
) with an excess of mesyl chloride in pyridine
gave the dimesylate 438. Deprotection of the acetonide with CF3COOH/H20 (9:1) followed by
treatment with (ethoxycarbonylmethylidene)triphenylphosphorane in THF provided 439 whose
catalytic hydrogénation (H 2, 3.5 atm. Pd/C) yielded (lS,2R,8S,8aR)-2-0-mesyl-5-oxo-l,2,8-tri-
hydroxyindolizidine (440), together with 5,8-imino-7-0-mesyl-2,3,5,8-tetradeoxy-D-g/wa?-
octano-l,4-lactone (441) in 19% and 30% yield, respectively. The lactone 441 gave 440 (89%) on
heating in DMF/EtOH (1:4). Trimethylsilylation of 440, followed by reduction of the lactam
(-)-398 (1-épi) (-)-397 (S-epi) Μ "4 33
(8a-epö (.)_399 (1,8-di-epi)
Page 52
326
moiety with boran dimethylsulfide complex in THF afforded (-)-442. Displacement of the
mesylody group in (-)-442 by sodium benzoate in DMF (120°C) in a SN2 fashion led to the
product (+)-443. Removal of the benzoyl group in (+)-443 with MeONa/MeOH gave (+)-434.
Scheme 54
D-glucose
R O — ,
l .H.O®
R O — , ,OMs
.OH
OH
COOEt
= J H2/Pd-C^
· " " OMs
439
1. (Me3)2SiNH 440 — >
Me3SiCl
2. BH 3Me 2S
HO Ξ Η OH
« OMs
<-)-442
HO OH
PhCOONa
DMF
NaOMe
MeOH (+)-434
(+)-443
Selective mesylation of the primary alcohol moiety in 437 led to mesylate 444.
Deprotection of the acetonide group in 444 with CF3COOH/H20, followed by Wittig reaction
gave 445. Catalytic hydrogénation afforded lactam (+)-446. The alcoholic functions in (+)-446
were protected as trimethylsilyl ethers and reduction of the lactam moiety with BH 3Me 2S
complex produced (-)-397 (Scheme 55).
Scheme 55
MsO—ι
437
MsO—, ,OH Ο
MsO K 3 Ν 1 .Η 3Οφ
Ο
444
2. Ph3P=CHCOOEt
. OH
(+)-446
(0-397
In 1986, Suami and co-workers128
converted methyl 3-acetamido-2-0-acetyl-4,6-0-
benzylidene-3-deoxy-a-D-glucopyranoside (447) and methyl 3-acetamido-2-0-acetyl-3-deoxy-
4,6-di-O-mesyl-a-D-glucopyranoside into (-)-8-^/?/-swainsonine ((-)-397) (Scheme 56) and
(-)-l,8-di-ep/-swainsonine ((-)-399) (Scheme 57), respectively, following procedures very similar
to those (Scheme 44) developed by these authors for their synthesis of (-)-swainsonine ((-)-5).
Page 53
327
Scheme 56
D-glucose
-NAc
7 0 OMe
z*
OAc
T s O -
AcOH/H 20 - O NHAc^
1. NaH/DMF
447
1. MeONa/MeOH
A c ô ^ Y Ô M e2'
E t S H^
C 1 Τ Τ \ OBn
OAc 3. BnBr/NaH EtS A c N ^ /
l. Ο . Pd(OH) 2/C
.TsCVpyr. H Ö ^ ^ T OMe 2. Ac20/pyr.
OAc
BnO O B nL H
êC 1
2 B n
? H ?B n
Exs^X^f 2. 2-Ph3P=CHCOOEt
BnO
1. H2/Ra-Ni^
2. KOH
OBn
"• OBn-2. Ac20/pyr.
OBn
OAc 1. BH3-Me2S
2. IN HCl, IRAI 400 (OH) V MeOH (-)-397
Scheme 57
1. AcOH/H20
i - O M s
J - o . 447
i . A c u ü / n 9u χ * v 1. AcONa/H20 AcO
OAc
BnO OBn AcO
1. MeONa/MeOH
2. EtSH, HCl > Τ I V h OBn >
Ξ Η OAc
EtS A c N ^ y OAc
(-)-399
Suami and co-workers129
also prepared (-)-8a-epz-swainsonine ((-)-433) starting from
methyl 3-azido-4,6-0-benzylidene-3-deoxy-a-D-altropyranoside (449) obtained by regioselective
epoxy ring opening of methyl 2,3-anhydro-4,6-0-benzylidene-a-D-mannopyranoside (448) with
with NaN3 (Scheme 58). Hydrolysis of 449 with aqueous acetic acid, followed by protection of
the primary alcohol with Ph3CCl/pyridine gave 450. O-Benzylation of 450, followed by acetolysis
in Ac 20 with a catalytic amount of H 2S0 4 provided 451. O-Deacetylation, followed by Wittig
olefination with (ethoxycarbonylmethylidene)triphenylphosphorane gave a 1:1 mixture of the (E)-
and (Z)-olefins 452. Hydrogénation on Raney nickel afforded 453 whose intramolecular
cyclization leading to 454 was accomplished by addition of p-tosyl chloride. Reduction of the
lactam 454 with BHyM^S complex in THF and deprotection furnished (-)-8a-e/?i-swainsonine
((-)-433). A preliminary assay of (-)-433 for α-mannosidase inhibitory activity was investigated.
Against human α-D-mannosidase, (-)-433 exhibited a 93% inhibition at ImM concentration at pH
4. Under the same conditions, (-)-swainsonine showed a 99% inhibition.130
Page 54
328
Scheme 58
~ Ph-<~O NaN3 :> Ph-<O~oO 1. AcOHJH20 :>D-glucose ~ ---;;;;-o OMe' 0 OMe 2. TrCVpyr., DMAP
DMAP=dimethylaminopyridine N3448 449
Tro~ 1. BnBrlNaHAcO~ 1. NaOMe/MeOHHO > BnO OAe > eOOMe
HO OMe2. AC20/H+ BnO 2. Ph3P=CHCOOEt BnON3 N3 N3
450 451 452
~Bn~~H(""'OH
o OH453
TsCVpyr.:>
~Bn~:~""'OH :»
o454
(-)-433
A synthesis of (-)-8-epi-swainsonine «-)-397) has also been proposed by Fleet andco-workersl31 (Scheme 59). They convened first D-glucose into the tosylate salt of 3,6-dideoxy3,6-imino-l,2-0-isopropylidene-a-D-glucofuranose (459) via diacetone glucose (455).Pyridinium chlorochromate oxidation of 455 gave the corresponding ketone which was reducedselectively by NaBH4 to give diacetone allose 456. Esterification with (CF3S02)O and subsequentdisplacement of the triflate with azide anion led to 457. The 5,6-0-isopropylidene protectinggroup in 457 was removed selectively by mild acid hydrolysis to give diol 458. Reaction of 458with TsCI in pyridine gave a primary tosylate whose hydrogenation over palladium black inethanol furnished crystalline tosylate salt of 459 (53% from 455). Reaction of 459 withdimethylphosphonoacetic acid in the presence of dicyclohexylcarbodiimide (DCC) gave amide460. Treatment with aqueous CF3COOH fonned the corresponding lactol 461. With 3 equivalentsof K2C03 and one equivalent of 18-crown-6 ether in DMF, 461 underwent intramolecularWadswonh-Emmons reaction to give an a,~-unsaturated lactam which on hydrogenation inethanol in the presence of palladium black led to 462. The corresponding triacetate 463 wasreduced with BH3·M~S complex and furnished the borane adduct 464. Deacetylation withMeONa/MeOH and destruction of the borane-amine complex with aqueous trifluoroacetic acidafforded (-)-8-epi-swainsonine «-)-397).
In their synthesis of (-)-8a-epi-swainaonine «-)-433) (Scheme 58), Tadano and co-workersconverted D-glucose into piperidone 453.130 453 was also transformed into (-)-2,8a-di-epi
swainsonine «-)-435) in a few synthetic steps132 (Scheme 60). O-Sulfonylation of 453 withexcess of MsCI gave octahydro-5-oxoindolizine-l,2,8-triol 465. Displacement of the mesyloxygroup in 465 by benzoate anion in DMF followed by debenzoylation with NaOMe/MeOH gave467. Reduction of the lactam 467 with BH3·M~S complex followed by deprotection of the benzylethers with iodotrimethylsilane, produced (-)-435.
Page 55
329
Scheme 59 χ Ο—ι
Ό — χ Ο—j
Ο —
) = ° \ Ο Η ^ > i-pcc r Ν D-glucose ^ > Vi / I => V V
Η 30+ ^ 1 ° ^ ^ 2. NaBH4 } — f O HO
Ο -455
χ Ο—«
Ο —
HO—ι
HO — AcOH/H20
MeOH
456
l.TsCVpyr.
l . T f 20
2. NaN 3'
HO
*"" Ο
T s ° e " P V Η Η
0
457
Ο II
(MeO)2PCH2COOH
HO 458 459
DCC > Ο
// N-" « Ο
(MeO)2P,
HO
Ο // Ν
(MeO)2P
OH
OH
HO 460 461
OR AcO = Η OAc
1. K 2C 0 3
18-Cr-6
2. H2/Pd
BH3MeoS - O R >
THF
1. MeONa/MeOH '•OAc
Ν / 2. CF3COOH
462 R=H 463 R=Ac 464
BH 3 (-)-8-epi-swainsonine
Starting from the azido sugar 449 (see Scheme 58), the same authors obtained 8,8a-di-
epi-swainsonine ((-)-436) as outlined in Scheme 61. The hydroxy group at C(2) of 449 was
benzylated, the benzylidene protective group removed with aqueous acetic acid and the resulting
Page 56
330
triol acetylated with acetic anhydride in the presence of H 2S0 4. This provided 468 that was
deacetylated with MeONa to give 469. Selective silylation of the primary alcohol in 469,
followed by Wittig olefination gave 470 which was converted into the acetonide 471. Reduction
of the azido group and hydrogénation of the double bond in 471, followed by desilylation with
tetrabutylammonium fluoride furnished 2-piperidone 472. Debenzylation under Hanessian
conditions (cyclohexene, EtOH, Pd(OH)2 on charcaol)133
provided 473 whose treatment with
MsCl in pyridine gave the corresponding dimesylate that cyclized into 474. SN2 displacement of
the 8-O-mesyloxy group with benzoate anion, followed by usual lactam reduction and removal of
the protective groups produced (-)-8,8a-di-ep/-swainsonine ((-)-436).
Scheme 61
1. BnBr/NaH
R O - .
J-(> 449
2. AcOH/H20 3. Ac 20/H
+
4. MeONa/MeOH
OAc 1. t-BuMe^SiCl/pyr.
2. Ph3P=CHCOOEt
468 R=Ac 469 R=H
-OH
BnO yr=^ COOEt
470 R^t-BuMe^Si
M e ^ O M e ^ ^ , ° A —
< £ MsCl/pyr.^
472 R=Bn, R,=t-BuMe2Si
473 R=R'=H
MsO
J^ Λ BzONa '
• OH
475 (-)-436 (8,8a-di-<?/?0
Concurrent with their stereoselective synthesis of (-)-swainsonine (Scheme 48), Kim and
Cha1 34
reported divergent syntheses of (-)-S-epi ((-)-397), (-)-8a-e/?i ((-)-433) and (-)-8,8a-di-e/?z-
swainsonine ((-)-436) starting from the common intermediates 479 and 480 derived from
2,3-0-isopropylidene-L-erythrose (476), as shown in Scheme 62. Epoxidation of olefin 479 with
3-chloroperbenzoic acid (mCPBA, NaHC03 in CH2C12) gave a 1:1 mixture of epoxides 481 and
482 that were separated by column chromatography on silica gel. Each epoxide was than
converted to the desired alkaloid (-)-433 and (-)-397 in three steps (50-60% overall yield, see
Scheme 62). Haloamidation of alkene 480 with N-bromosuccinimide in 5:2 dimethoxy-
ethane/water at 0°C gave pyrrolidine 485. When 485 (4:1 mixture of diastereomers) was
subjected to lactonization procedure on boiling in xylene in the presence of silica gel, the major
stereomer which reacted faster than the minor one cyclized preferentially to afford lactone 486.
Subsequent deprotection with sodium naphthalenide of the tosyl group of 486 yielded the
corresponding indolizidine lactam, which was then converted to (-)-436 by LiAlH 4 reduction in
Page 57
331
Scheme 62
Η 0" ^ Ν l .HONH 2HCl HO
2. LiAlH/THF 1. Swern ox.
Ö 0 3.ClC02Bn,or J0
^ pTsCl/NaHC03 Γ aqueous NaHC0 3
X
476 477 X=NHCOOBn^NHCbz 479 X=NCbz E=COOEt 478X=NHTs 480X=NHTs
2. E(CH 2) 3PPh 3
+Br > "
, M°
KN(SiMe3)2/THF χ
• l . H ^ d - C
7 \ 2. EtOH, Δ Ο
HO ~ \
NHCbz 484
Ψ
Η / > Λ _ < £ 1. BH 3THF
2. 6N HCl
HO Η OH
(-)-433 (8a-*?p0
..... O H
(-)-397 (8-epi)
NBS 480 >
HO H pH
Ο xylene TsN^ Δ
485 486
THF, followed by acidic hydrolysis of the acetonide moiety.
Ο 2. LiAlH 4
3. 6 M HCl
•·• OH
(-)-436 (8,8a-di-epö
(-)-8,8a-Di-6p/-swainsonine ((-)-436) was found to be a powerful competitive inhibitor of
human acidic (lysosomal) cc-D-mannosidase, with a value of Ki of 2-10"6 M at pH 4.0, the
optimum pH for this enzyme. This compares with a value of Ki of 7-10"8 M for (-)-swainsonine
acting on the same enzyme under identical conditions. In contrast, (-)-2,8a-di-e/?i-swainsonine
((-)-435) did not inhibit ct-D-mannosidase but caused slight activation (+15%) as it did for
ß-D-mannosidase, α-D-galactosidase, and a-D-glucosidase. It was however a weak inhibitor of
ß-D-galactosidase (-30%), α-L-arabinosidase (-21%), and ß-D-xylosidase (-13%), suggesting that
it inhibits the broad specificity of cytosolic ß-D-galactosidase in human liver.1 32
Alteration of the
configuration of C(8a) of swainsonine did not abolish the inhibitory activity of this alkaloid
toward a-mannosidase.129,131
Elbein and co-workers have demonstrated that alteration of the
configuration of (-)-swainsonine at either C(2) or C(8) separately abolishes inhibitory activity
Page 58
332
toward α-D-mannosidases.135
Colgate and co-workers80 have shown that (-)-8-deoxyswainsonine
((-)-235; see Scheme 31 for a synthesis) is a much weaker and less specific inhibitor of
cc-mannosidase than (-)-swainsonine. This fact points to the importance of the 8-hydroxy group
for spacial recognition by the enzyme.
16. Castanospermine
(+)-Castanospermine ((+)-7: (lS,6S,7R,8R,8aR)-tetrahydroxyindolizidine) is an alkaloid
isolated first in 1981 by Hohenschultz et al.1 36
from seeds of the monotypic Australian rainforest
and riverine tree Castanospermum australe. More recendy,137
it has been found in dried pod of
Alexa leiopetala Sandwith and in seven other species of the same genus. The structure (relative
configuration) of (+)-7 was established by X-ray radiocrystallography first,136
and then (absolute
configuration) through chemical correlation by Bernotas and Ganem.138
Castanospermine has
generated much interest because it is a potent inhibitor of various glucosidases including lysomal
a-glucosidase,139
a- and ß-glucosidases in fibroblast extracts,139
the glycoprotein processing
enzyme glucosidase I1 40
as well as being a powerful inhibitor of ß-xylosidase139
and sucrase.141
The ability of (+)-7 to disrupt glycoprotein processing has resulted in the use of this compound to
modify biosynthesis; it might provide more insight into the role of oligosaccharides in
glycoprotein faction.2,142
Very interesting is the fact that (+)-7 is able to inhibit experimental
metastasis of some cancers.143
Furthermore, it inhibits replication of human immunodeficiency
virus (HIV) syncytium formation144
and other virus replication.145
6-O-Butyrylcastanospermine
(+)-7 (+)-487
((+)-487)1 46
shows considerable promise as a chemotherapeutic agent against AIDS. It has been
found that (+)-487 and AZT (3,-azido-3*-deoxythymidine) can operate synergistically in the
inhibition of HIV replication in vitro.1 47
(+)-Castanospermine has also been described to be a
plant growth regulator,148
and insect antifeedant,149
an allergic encephalomyelitis150
and a
disaccharidase inhibitor with implications for the treatment of diabetes mellitus.151
Furthermore,
it could become a possible therapeutic agent against cytomegalovirus.152
Ganem and Bernotas138
have proposed a first synthesis of (+)-7 which was inspired
logically form the resemblance of (+)-7 with D-glucopyranose. A short synthesis of
1-deoxynojirimycin (l,5-dideoxy-l,5-imino-D-glucitol) from D-glucose was developed153
and
then an efficient two carbon chain elongation process (via the corresponding aldehyde 495) was
found to complete the synthesis of (+)-7 (Scheme 63) .1 54
Methyl tri-O-benzyl-6-bromo-a-D-glucopyranoside (489) was prepared in 73% overall
Page 59
333
Scheme 63
l.MeOH, H+
D-glucose > 2. Ph3CCl, pyn 3. BnCl, NaH " 4. AcOH, H 20
Zn/AcOH I ) N H B| BnNH<
BnO NaBH3CN
OMe BnO
Ί NHBn > f ( 0 B n \
3nO ^ | OBn
488 489
l .Hg(CF 3COO) 2
THF 2. ligand exchange
B n0
3. NaBH4-DMF-02
491 X=HgBr 493 X=OH
OBn
Λ—N-Bn
BnO I OBn
492 X=HgBr 494 X=OH
490
CHO
493 - ^ Π ^ Β η Ο BnO A S
OBn
,SiMe3 1 v ^ J ^ N B n
L (V
C H2
C 12 ^
TiCVCH.Cl, Β η θ Λ ^ ^ \ 2 .NaBH^tOH B
ßn0
OBn
496
HO
495
OH
NBn l.MsCl,pyr.
yield from methyl a-D-glucopyranoside.155
When heated at reflux in a mixture of HO Ac-washed
zinc dust in n-propanyl alcohol/water (19:1) containing benzylamine and NaBH3CN, reductive
ring opening occurred with concomitant reductive amination to afford aminoalkene 490 (91%).
The intramolecular aminomercuration of 490 with mercuric trifluoroacetate in anhydrous THF led
to 491 (61%) and 492 (39%) after neutralization, ligand exchange and flash chromatography.
Epimer 491 was converted to alcohol 493 with NaBH4/DMF and 0 2. Swern oxidation of 493 gave
the corresponding aldehyde that underwent a highly stereoselective chelation-controlled Sakurai
reaction to produce 496 with a diastereomeric excess larger than 90%. The high selectivity of that
reaction was interpreted in terms of chelate formation between TiCl4 and the a-aminocarbonyl
group of 495, with approach of the allylic nucleophile from the less hindered face. Ozonolysis of
496, followed by NaBH4 reduction and exhaustive hydrogenolysis afforded (+)-castanospermine
(55%, based on 496, 19% overall yield from methyl a-D-glucopyranoside). The same synthetic
approach has been applied to prepare several stereomers of castanospermine (see Scheme 70).
Hashimoto and co-workers presented in 1985 an alternative approach to the synthesis of
(+)-castanospermine that uses D-mannose as starting material (Scheme 64).1 56
Protection of
D-mannose with acetone in the presence of H 2S0 4 and CuS04, followed by reduction with
LiAlH4 afforded the corresponding mannitol derivative 498.1 57
Benzoylation with BzCl and
pyridine afforded ester 499 selectively. The secondary hydroxy group in 499 was protected as a
Page 60
334
Scheme 64
D-mannose l.Me 2CO, H 2SQ 4 Q'
CuS04
2. LÎA1H4/THF
3. BzCl/pyr.
N ^ O O-V" L t
-B u M e
2 S i C l
OH
498 R=H R=t-BuMe2Si 499 R=Bz
^/~o o V J • -
N
0 1.H2N0HHC1 K 2CO :
MeOH V 0
Vj 2. NaOH/MeOH^O. 3. DMSO/DCC
OR pyr./PhH
500
1.Η,Οφ
2. LiAlH4
OR' CHO 3. CbzCl
501
1. MsCl/pyr.
2. MeONa/MeOH
Cr03pyr.
CH2C12 ' Η Ο NHCbz
505 506
(+)-7 (-ySUd-epi)
Page 61
335
t-butyldimethylsilyl ether on treatment with t-BuMe^l and imidazole. Saponification of the
benzoate and Moffatt oxidation of the liberated primary alcohol gave aldehyde 500 which was
equilibrated with the more stable 2-epimer 501 using K 2C 0 3 in methanol. The corresponding
oxime was reduced with LiAlH4 and the resulting amine protected as a benzylcarbamate (502).
Partial hydrolysis of 502 using TsOH in aqueous methanol, followed by treatment with
tetrabutylammonium fluoride produced triol 503. Selective mesylation with MsCl/pyr., followed
by treatment with MeONa/MeOH led to the epoxides 504 and 505. Prolonged reaction time
converted 504 to 505. Oxidation of 505 with Collin's reagent gave aldehyde 506 which reacted
with t-butyl lithioacetate, providing a 3:2 mixture of 507 and 508. Protection of the secondary
alcohols 507 and 508 as t-butyldimethylsilyl ethers, followed by catalytic hydrogénation on 10%
Pd-C in MeOH, yielded the corresponding amine that afforded the indolizidinones 511 (31%) and
512 (20%) on heating in methoxyethanol. Under usual conditions, 511 was converted to
(+)-castanospermine ((+)-7) and 512 to (-)-l-ep/-castanospermine ((-)-513).
Miller and Chamberlin119
applied the method of acyliminium ion cyclization in an elegant
approach to the synthesis of (+)-castanospermine (Scheme 65). Preparation of the requisite
hydroxylactam 515 began with 6-0-acetyl-2,3,4-tri-0-benzyl-D-glucono-l,5-lactone (514),158
which was treated with 2-[3-aminopropopylidene]-l,3-dithiane, followed by Pb(OAc)4 oxidation,
to afford the expected hydroxylactam 515 contaminated with the open-chain aldehyde from which
it is formed. This mixture was treated with AcOH, giving a mixture of epimeric 515 which was
cyclized on adding MsCl and Et3N in CH2C12, giving a 1:1 mixture of indolizidinones 516 and
517 (84%). After chromatographic separation, 516 was oxidized with singlet oxygen and the
ketone so-obtained was reduced with lithium tri-t-butoxyaluminium hydride to give a 5:1 mixture
Page 62
336
of C( l ) epimers, favoring the undesired diastereomer. However L-Selectride (lithium tri-s-butyl-
borohydride 1M in THF) gave exclusively the desired epimer 519 (39%). Treatment of lactam
519 with borane-dimethyl sulfide complex, followed by catalytic hydrogenolysis of the benzyl
ethers in MeOH/HCl gave (+)-castanospermine. Under similar conditions 517 was converted into
(+)-1,8a-m-€p^castanospermine ((+)-518).
Anzeveno and co-workers159
described in 1990 a syntheis of (+)-castanospermine in 10
steps (13% overall yield) starting from the protected glucuronolactone160
521 (Scheme 66). Swern
oxidation of 521 gave ketolactone 522. Its benzyloxime was reduced with hydrogen over
Scheme 66
(+)-7 (0-513 (\-epi)
Page 63
337
palladium catalyst and the resulting amine protected as the t-butylcarbamate 523. Intermediate
523 contains four contiguous chiral carbon centres with the D-gluco configuration required in
(+)-castanospermine for centres C(6), C(7), C(8) and C(8a). Chain elongation is realized through
simultaneous addition of lithium di-wö-propylamide and ethyl acetate in tetrahydrofuran. The
resulting hemiacetal 524 was then reduced via catalytic hydrogénation (PrO^ into a 7:2 mixture
of isomers 525 and 526. When using NaBH4 in EtOH, a 1:3 mixture of 525 and 526 was obtained.
The desired diol 525 was separated by flash chromatography over silica gel whose carbamate
moiety was hydrolyzed with formic acid. The resulting amino ester was cyclized during
purification over Dowex 1x2 basic ion exchange resin, affording 527. Reduction of 527 with
LiAlH4 gave 528, which upon treatment with 90% CF3COOH at 0°C, followed by catalytic
hydrogénation over Pt on charcoal gave (+)-castanosperrnine. Caning 526 through the same series
of reactions as described for 525 gave (-)-l-e/?/-castanospermine ((-)-513).
A chemoenzymatic synthesis of (+)-castanospermine has been proposed recently by Sih
and co-workers161
(Scheme 67). Steroselective reduction of the proline derivative 529 with the
yeast Dipodascus sp. gave (+)-530 in 80% chemical yield and >99% optical purity. Alternatively,
(+)-530 may also be obtained via the enantioselective hydrolysis of (±)-531 using microbial
lipases such as Candida cylindracea or Pseudomonas sp. (AK). Protection ot the alcoholic
function in (+)-530 as a t-butyldimethylsilyl ether, treatment with 20% CF 3C0 2H in CH2C12
removed the BOC protecting group and the resulting salt added to methyl acrylate in the presence
of triethylamine to give 533. Acyloin condensation of 533 in the presence of an excess of
trimethylsilyl chloride afforded 534. Stirring 534 with an excess of DBU in CH2C12 led to a
mixture of 535 and 536 which were converted to 537 on treatment with trimethylsilyl chloride
and lithium hexamethyldisilazane at -78°C. Hydroboration with BHyMe^S, followed by oxidative
work-up with trimethylamine oxide in refluxing toluene (oxidation of the amine-borane complex)
gave a separable mixture of 538 (15%), 539 (24%), and 540 (32%). Desilylation of 539 afforded
(+)-castanospermine ((+)-7). Similarly, tosylate of 538 gave (+)-6-deoxycastanospermine
((+)-541) and 540 yielded (+)-6,7-di-ep/-castanospermine ((+)-542).
Scheme 67
MeO
M 0
I
BOC
529 (+)-530
Dipodascus sp. MeO >
t-BuMe^SiC^MeO
imidazole
R=t-BuMe2Si
l .CF 3C0 2H
yeast MeO
MeOOC
2· = V ™ i , , Et3N
C O O Me MeOOC
OAc
(±)-531
Page 64
338
Scheme 67 (continued)
538 539 540
(+)-541 (6-deoxy) (+)-7 (+)-542 (6,7-di-ep/)
In 1991, Gerspacher and Rapoport162
reported on the syntheses of (+)-castanospermine
and (+)-6-ep/-castanospermine ((+)-8) starting from D-glucono-ô-lactone (543) (Scheme 68). The
manno azide 544 was derived from 543 in three steps163
and was then hydrogenated in the
presence of palladium on charcoal. The resulting amine 545 was protected by a 9-phenyl-
fluoren-9-yl group under standard conditions produce 546. The ester moiety in 546 was converted
into an aldehyde group through DIB AH reduction and then Corey-Kim oxidation164
to give 547
which was configurationally stable. Addition of vinylmagnesium bromide in THF to 547 afforded
a mixture of allylic alcohols 548 which was oxidized (Corey-Kim) to an α,β-unsaturated ketone.
1,4-Addition of HBr in ether to the unsaturated ketone gave 549. Treatment of the crude 549 with
NaHC03/Na3C03 in water effected the cyclization into the corresponding pyrrolidine whose diol
moiety was selectively acetylated with A c 20 and pyridine to produce 550. The remaining
unprotected hydroxy group was esterified with triflic anhydride in pyridine. The resulting triflate
was diplaced in a SN2 fashion with acetate anion to give 551. Reduction of the ketone 551 with
NaBH4, followed by saponification of the acetates led to 552. Selective tosylation of the primary
alcohol in 552 gave 553 that was subsequently cyclized during catalytic hydrogenolysis of the
9-phenylfluoren-2-yl amine in the presence of NaOAc. The resulting partially protected alkaloid
was finally treated under acidic conditions to afford (+)-castanospermine ((+)-7).
Except for the approach of Sih and co-workers161
(Scheme 67) that involves enzymatic
reduction of a keto-proline derivative or the enantioselective yeast hydrolysis of a racemic ester
derived from proline, all the syntheses of (+)-castanospermine presented above use a carbohydrate
Page 65
339
l.Tf20/pyr. Q>
2. NaN 3
3. H2/Pd-C
E=COOMe 544 X=N 3
545 X=NH 2
1. PfBr, Et3N^ ρ
Pb(N0 3) 2
>
Pf=9-phenylfluroen-9-yl
546 547
l . N C S . M e ^
2.HBr,Et20 ' H 20
NHPf
548
AcO
l . N a H C O ^ a ^
2. Ac20/pyr.
549
l.H2/Pd-C, NaOAc
2. CF3COOH
3. Dowex 50 W (+)-7
(D-glucose, D-mannose) as starting material. In order to introduce in the system an amine
function and to allow for anionic type of condensation leading to a 2 carbon atom chain
elongation, many steps of selective hydroxy group protection and deprotection are required,
making most of these synthetic methods quite laborious. Moreover, in several instance, tedious
separations of isomeric mixtures of synthetic intermediates are necessary. The first
Page 66
340
non-carbohydrate route to (+)-castanospermine and derivatives (see next section) has been
realized by Vogel and co-workers in 1989.1 6 5 , 1 66
The "naked sugar" (-)-(lS,4S)-7-oxabicyclo-
[2.2.1]hept-5-en-2-one ((-)-555), obtained by saponification of the Diels-Alder adducts 554 of
furan to 1-cyanovinyl (lR')-camphanate or of furan to Γ-cyanovinyl (lS,5R,7S)-3-ethyl-2-oxo-
6,8-dioxa-3-azabicyclo[3.2.1]octan-7-^Jc<9-carboxylate)167,168
(Scheme 69), was converted to
(+)-castanosperrnine in 15.2% overall yield; the method is highly stereoselective and requires the
isolation of the intermediate products, without chromatographic separation of stereomers. Since
(+)-(lR,4R)-7-oxabicyclo[2.2.1]hept-5-en-2-one ((+)-555) is as readily available as (-)-555
(-)-castanospermine and its derivatives can be also be prepared with the same ease.
Treatment of enone (-)-555 with BnOSiMe3 and trimethylsilyl triflate in CH2C12 gave the
dibenzylacetal (-)-556 which reacted rapidly with Br2 in CH2C12 at -90°C to give (+)-558 isolated
in 98% yield. The reaction involves probably an endo benzyloxy group transfer via oxonium ion
Scheme 69
ο 0 ° R '
ψ or ^ o / ^ J R*=
-CO
(lR)-camphanoyl
1. NaOMe/MeOH
2. CH 20 (recovery of the chiral auxiliary R*OH)
Ο
+ R*OH
(-)-555
SADO(Et)-O
(-)-555 BnOSiMe,
TfOSiMe3
Br2/CH2C12
OBn
(-)-556
Ο
-90°C
MeO
Ο Br
OBn
^O ι Bn
H ?0
NaHC03
557
BnO
Ο MeOH
SOClo BnO
(+)-558
1. DIBAH
(+)-559
COOMe MeO
COOMe
MeO
C1CH2C0C1
2. MsCl/pyr.
3. NH3/EtOH/H20 BnO Br
(-)-562 X=CH2OH
(-)-563 X=CH2OMs
564 X=CH 2NH 2
pyr./CH2Cl2 BnO
1. Ac 20/H 20
2. P(OEt)3
(0-565 R=H
(+)-566 R=COCH2Cl
Page 67
341
Scheme 69 (continued)
572 573 574
intermediate 557. Baeyer-Villiger oxidation of (+)-558 with mCPBA/NaHC03 in CH2C12 gave
lactone (+)-559 (95%). Treatment of (+)-559 with MeOH and SOCl2 led to a 4:1 mixture of the
methyl furanosides (-)-560 and (+)-561 (100%) from which (+)-561 could be separated by crystal-
lization and requilibrated by treatment with MeOH/SOCl2. Reduction of (-)-560 with diisobutyl-
aluminium hydride (DIBAL) in THF/toluene gave alcohol (-)-562 (100%), the bromide being not
reduced under these conditions. The corresponding mesylate (-)-563 obtained by treatment with
MsCl/pyridine in CH2C12 was not isolated but directly mixed with ammonia in aqueous ethanol.
This afforded the primary amine 564 which subsequently cyclized to generate the pyrrolidine
derivative (-)-565. Crude (-)-565 reacted with C1CH2C0C1 in pyridine/CH2Cl2 and furnished
crystalline chloroacetamide (+)-566 (79% based on (-)-560). Under similar conditions, the minor
furanoside (+)-561 was decomposed! The methyl furanoside moiety in (+)-566 was transformed
into the corresponding acetyl furanoside 567 by treament with Ac 20/H 2S0 4. Arbuzov reaction of
567 and P(OEt)3 gave the corresponding phosphonoacetamide 568, which was not isolated and
treated immediately with K 2C 0 3 in EtOH, giving 570 which arose from the intramolecular
Horner-Emmons condensation of intermediate aldehyde 569. Acetylation (Ac20/dimethylamino-
pyridine) of 570 afforded (+)-571 (49% based on (-)-560). Endo face epoxidation of the α,β-un-
saturated lactam (+)-571 could not be achieved by direct epoxidation for reasons of steric
Page 68
342
hindrance. However, addition of Br2 in the presence of AgOAc/Ac20 afforded a 1.5:1 mixture of
the monobromides 573 and 574. This mixture was methanolyzed with MeOH and S0C12 and then
treated with a polymeric base, 2-(t-butylimino)-2-((diethylamino)imino)-l,3-dimethylperhydro-
1,3,2-diazaphosphorine on polystyrene (BEMP) to give epoxide 575. Without purification, water
was added to the crude epoxide. The latter was hydrolyzed in the presence of the same base
(BEMP/CH3CN/H20, 100°C) and then acetylated to yield lactam (+)-576. Usual reduction of the
lactam and acetate, and then hydrogenolysis of the 8-O-benzyl ether produced (+)-castano-
spermine. In this approach, the chiral auxiliary (R*OH), is recovered at an early stage of the
synthesis. The chiral acid SADO(Et)-OH was derived from (S,S)-tartaric acid. The enantiomeric
chiral auxiliary RADO(Et)-OH is derived from (R,R)-tartaric acid,1 68
thus the same method can
be applied to the total synthesis of (-)-castanospermine.
17. Castanospermine stereomers and analogues
Because of the precious biological properties of (+)-castanospermine, there has been an
intense effort toward the obtention of stereomers of this alkaloid and of derivatives in which the
hydroxy groups are replaced by other functions or by hydrogen atoms. The alkaloid (+)-6-epi-
castanosperime ((+)-8) has been found together with (+)-castanospermine in Castanospermum
australe136
and Alexa leiopetala.131,169
Ganem and co-workers,154
reported the first synthesis of
this natural compound. The method (Scheme 70) is the same as that developed for the synthesis of
(+)-castanospermine (Scheme 63 ) , the starting material being D-mannose instead of D-glucose
(Scheme 70).
Scheme 70
BnO
BnO
BnO'
BnO OH Ξ Η 1.0 3
2. NaBH4 > 3. MsCl, Et3N H O 4. H2/Pd-C
TicivcH 2ci 2 B n 0.
(+)-8 (6-epi)
Since 6-^p/-castanospermine obtained in this synthesis was levorotatory instead of
dextrorotatory as found for the natural alkaloid ( [ a ] D = +2°, MeOH), Ganem and co-workers154
suggested that natural (+)-6-ep/-castanospermine has the configuration of L-mannose rather than
that of D-mannose for C(6), C(7), C(8) and C(8a). Fleet and co-workers,170
however prepared (+)-
and (-)-6-e/?/-castanospermine from L- and D-gulonolactone, respectively (Scheme 71) and found
that their original assignment for the absolute configuration of the natural (+)-6-ep/-castano-
spermine was correct. The negative optical activity reported by Ganem and co-workers for their
synthetic alkaloid arouse probably from the contamination by (-)-l,6-di-€p/-castanospermine a
compound also prepared by Fleet and co-workers170
(Scheme 71) and for which a specific optical
rotation of -72° (MeOH) was measured.
Treatment of L-gulonolactone with acetone/dimethoxypropane and p-toluenesulfonic acid
Page 69
343
gave 577 whose selective hydrolysis with aqueous acetic acid afforded diol 578. The primary
alcohol was selectively protected by reaction with t-BuMe^SiCl and imidazole in DMF (-30°C) to
give silyl ether 579. Esterification of the remaining free hydroxyl group with trifluoro-
methanesulfonic anhydride and pyridine in CH2C12 gave a triflate which was displaced with NaN3
in DMF to yield protected 5-azido-5-deoxy-D-mannonolactone 580. Hydrogénation of the azide
580 produced an amine which spontaneously cyclized into lactam 581.1 71
Benzylation of 581
with NaH and benzyl bromide in the presence of a catalytic amount of Bu4N+I" in THF gave 582
which, with L1AIH4/AICI3 in THF, afforded the tertiary amine 583. The silyl group was removed
during the reduction. Swern oxidation of the primary alcohol group in 583 (Me^SO, (COCl)2,
Et3N) gave the corresponding aldehyde which added vinylmagnesium bromide to give a 1:1
mixture of diastereomer 584. Treatment with t-BuMe^SiCl/imidazole, followed by oxidative
Scheme 71
Ο Ο Me2CO/Me2C(OMe)2 0 = ^ \ AcOH/H20 0
-OH T s O H
HO O H1- O H
L-gulonolactone 577
imidazole
OR' OR
l . T f 20 , Et3N OH : 1_9>
Ο 6 L
O R 2.NaN 3
X 579 R=t -BuMe2Si
BnO OH 1. Swern
578
ρ OR
— N 3 l.H2/Pd-C
.0 2. BnBr/NaH
\_fr=° Bu4NI
580
0 * ^ \ ^N Bn
2. - ^ M g B r
BnO OH
581 R'=H 582 R'=Bn
583 584
l.t-BuMe^SiCl, Et3N^
2. B 2H 6 *
3. H 20 2/KOH
BnO OR = Η
585
χ :
BnO OR Ξ Η Ξ
586
R=t -BuMe2Si
OH
585 l.MsCl, NEt3
2. H2/Pd
3. CF3COOH/H20
HO H OH
586
(+)-8 (6-epi) (-)-587 (1,6-di-e/?/;
Page 70
344
hydroboration gave separable alcohols 585 (25%) and 586 (19%). Treatment of 585 with
MsCl/Et3N, followed by catalytic hydrogénation over palladium black and deprotection with
aqueous CF3COOH gave (+)-6-ep/-castanospermine ((+)-8). Likewise, the less polar alcohol 586
was converted into (-)-l,6-di-^/-castanospermine ((-)-587).
(+)-6-£p/-castanospermine was also prepared recently by Gerspacher and Rapoport162
(Scheme 72). The synthetic intermediate 549 (see Scheme 68) was cyclized on treatment with
NaHC03 and Na 2C0 3 into 588. Reduction of 588 with NaBH4 gave triol 589 whose selective
tosylation with N-methyltosylimidazolium inflate in the presence of N-methylimidazole gave
tosylate 590 (66%), 8% of a ditosylate and 15% of unreacted triol 589. Removal of the phenyl-
fluorenyl group by hydrogenolysis in the presence of Pd on charcoal in methanol liberated the
pyrrolidine moiety which underwent intramolecular displacement reaction with the tosylate to
give 591. Acidic hydrolysis of the acetonide furnished (+)-6-e/?/-castanospermine ((+)-8).
Scheme 72
Starting with D-galactose, Ganem and co-workers154
prepared (-)-8-ep/-castanospermine
((-)-594; Scheme 73) following the same procedure as that developed for their syntheses of
(+)-castanospermine (Scheme 63) and (+)-6-ep/-castanospermine (Scheme 70). The addition of
allylmagnesium chloride to aldehyde 495 derived from D-glucose (Scheme 63) gave a 32:68 mix-
ture of allylic alcohols 496 and 595. While 496 was converted to (+)-castanospermine, the same
sequence of reactions applied to 595 provided (-)-l-e/?/-castanospermine (Scheme 74). The stereo-
mer (-)-l-epz-castanospermine ((-)-513) had been prepared for the first time by Hashimoto and
co-workers in 1985 (see Scheme 64)1 56
and later by Anzeveno and co-workers (Scheme 66).1 59
Scheme 73
D-galactose
592 593 (0-594 (S-epi)
Page 71
345
The syntheses of pure stereomers (+)-l,8a-di-ep/- ((+)-518) (Scheme 65) and (+)-6,7-di-
-e/?/-castanospermine ((+)-542) (Scheme 67) have already been described in the preceding
section.
Scheme 74
BnO
BnOx%i
BnO OH = H
BnO OH = Η Ξ
(+)-7 ((+)-castanospermine) (0-513 (l-epi)
In 1991, Liv and co-workers172
presented a synthesis (Scheme 75) of 6-acetamido-6-
deoxy-castanospermine (603) from natural (+)-castanospermine ((+)-7). Treatment of (+)-7 with
2.2 equivalents of PhCOCl in pyridine provided selectively 6,7-di-O-benzoylcastanospermine
hydrochloride 596. Treatment of 596 with an excess of (MeO)2CMe2 in the presence of TsOH
gave 597. The benzoyl group were then removed by reaction with MeONa/MeOH to provide
1,8-O-isopropylidenylcastanospermine (598).1 73
Treatment of 598 with benzyl chloroformate in
Et3N gave 599. Treatment of 599 with p-bromobenzoyl chloride and Et3N led to 600. Removal of
the acetonide protective group, followed by peracetylation and selective deprotection of the
6-hydroxyl group by transfer hydrogenolysis (Pd-C, cyclohexene) gave alcohol 601 which was
Scheme 75
(+)-7 PhCOCl.
BnO
pyr. BnO
(MeO) 2CMe^
TsOH =
BnO
BnO
1. NaOMe/MeOH
2. CbzCl, Et3N
597
p-BrC6H4COCl, Et3N R O
CbzO
l.HCl/MeOH
2. Ac20/pyr.
598 R=H 599 R=Cbz
OAc
3. cyclohexene, Pd-C
600 R'=p-BrC6H4CO
R O . l.MsCl, Et3N
2. Nal, AcOEt ^
3. NaN3, DMF
601 R'=p-BrC6H4CO
R'O OAc
1. MeONa/MeOH
2. H2/Pd-C
602
Page 72
346
mesylated and converted into azide 602 upon successive invertive displacements with Nal and
NaN3. Methanolysis, followed by catalytic hydrogénation and N-acetylation afforded 603, a
compound that inhibits mammalian ß-N-acetyl-glucosaminidases at or below 1 μΜ.
Vogel and co-workers166
have shown that one of the synthetic intermediates they obtained
in their total, asymmetric synthesis of (+)-castanospermine can be converted readily and with high
stereoselectivity into 6-deoxy-6-substituted-castanospermine derivatives. The method is
illustrated in Scheme 76 with the synthesis of (+)-6-deoxy-6-fluorocastanospermine ((+)-606).
Treatment of epoxy lactam 575 with HFEt 3N led to a stereoselective ring opening of the epoxyde
Scheme 76
(+)-541 (+)-606
moiety with attack of C(6) by the fluoride anion. After acetylation 604 was isolated. Reduction
under the standard conditions (BH3-Me2S/THF), followed by acidic hydrolysis of the acetates
afforded the partially protected 6-deoxy-6-fluorocastanospermine 605. Catalytic hydrogenolysis
of the benzylic ether gave (+)-606. When 575 was reduced with BHyMe^S complex, (+)-8-0-
benzyl-6-deoxy-castanospermine was obtained. Debenzylation afforded (+)-6-deoxy-castano-
spermine ((+)-541).1 66
This compound was prepared also by Sih and co-workers161
(see Scheme
67).
Since (+)-(lR,4R)-7-oxabicyclo[2.2.1]hept-5-en-2-one is as readily available as its
(-)-enantiomer used to prepare epoxy lactam 575, the method of Vogel and co-workers can also
be applied to prepare the enantiomeric (-)-6-deoxy-castanospermine ((-)-541) (-)-6-deoxy-6-
fluorocastanospermine ((-)-606).
Because O-acyl derivatives of (+)-castanospermine are as much as 20 times more active
than castanospermine itself in inhibiting human immonodeficiency virus (HIV) replication1463
a
great deal of work has been carried out in order to develop regioselective acylation methods.
Enzyme-catalyzed acylation of (+)-castanospermine has been found quite useful in this purpose as
illustrated in Scheme 77.1 7 4
·1 75
A facile chemical selective acylation on the 6-hydroxyl group of (+)-castanospermine has
Page 73
347
Scheme 77
, x n R'COOR (+)-7 — >
HO
H9 H OCOR'
subtilisin, pyridine
H0
lipase CV
— > , THF, 72% Η 0
χ χ Ο' ^ '
Ν
+ R O H
R'=alkyl, aryl, α-aminoalkyl
RM=C1CH2CH2-, C13CCH2-, F3CCH2-, CH2=CH-
subtilisin
phosphate buffer
pH 6.0, 64%
HO |_j OH
been realized by Anderson and co-workers176
(Scheme 78). In a typical procedure, (+)-7 and
dibutyltin oxide were heated under reflux in dry methanol. Then Et3N and an acid chloride
RCOC1 were added. Only the products of 6-0-acylation were isolated after flash chromatography
over silica gel.
Scheme 78
Bu3SnO (+)-7 — >
MeOH
In 1987, Richardson and co-workers have developed enantiospecific syntheses of
(+)-(6S,7R,8R,8aR)-trihydroxyindolizidine (+)-613, 1-deoxy-castanospermine (Scheme 79) ,1 77
and (+)-(6R,7S,8S,8aR)-trihydroxyindolizidine (+)-621 (Scheme 80), together with the synthesis
of (+)-(6R,7S,8aR)-dihydroxyindolizidine (Scheme 81).1 78
D-glucose was converted into the
partially protected form 6071 79
using the method of Van Cleve and co-workers.180
Oxidation of
alcohol 607 with pyridinium chlorochromate in the presence of molecular sieves gave the
corresponding aldehyde which reacted with (ethoxycarbonylmethylidene)triphenylphosphorane to
yield 608. Catalytic hydrogénation of the C=C double bond in 608, followed by reduction of the
ester moiety with LiAlH 4 afforded a primary alcohol which reacted with methanesulfonyl
chloride and triethylamine to furnish 609. Its reaction with NaN3 gave the corresponding azide
610. Debenzylidenation according to the Hanessian procedure181
(NBS in refluxing CC14)
afforded an idose derivative whose azide moiety was reduced with SnCl2 in MeOH to provide the
corresponding amine 611 which underwent intramolecular displacement of the bromide with
production of pyrrolidine 612 in boiling ethanol containing sodium acetate. The benzyloxy-
carbonyl derivative of 612 treated with aqueous acid gave a furanose which afforded (+)-613 after
hydrogenolysis of the benzyl carbamate (Scheme 79) .1 83
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348
Scheme 79 H O — ι
HO —
D-glucose -H 30
+/H 20
>
1.4-N02C6H4COCl/pyr.
2. PhCHO/ZnCl2
O - J
r—OH
O .
l.Pyr. Cr03Cl PI
2. EtOOCCH=PPh3
Ba(OH)2/MeOH
607
l.H2/Pd-C
2. LiAlH4/Et20 Ph-
3. MsCl/Et3N
608 4. NaN3
l.NBS/CCl4
BaC03
SnCl9,MeOH
609 X=OTs 610 X=N 3
EtOH, Δ ^ Ν H
NaOAc
611 (+)-613
The syntheses of 6,7,8-trihydroxyindolizidine (+)-621 and of 6,7-dihydroxyindolizidine
(+)-6251 78
start from methyl 2-azido-4,6-0-benzylidene-2-deoxy-a-D-altropyranoside (614)1 82
(Scheme 80). Hydrolysis of the benzylidene acetal of 614 using aqueous acetic acid gave a triol
whose selective tosylation yielded 615. Catalytic hydrogénation and subsequent cyclization in the
presence of AcONa gave 2,6-imino-altroside, which was isolated as benzyl carbamate 616.
Treatment of 616 with ethanethiol and concentrated HCl led to thioacetal 617 which was
converted into the tri-O-benzyl derivative 618. Dethioacetalization using HgCl2 and CdC03 in
aqueous acetone gave aldehyde 619. Classical chain extension with (ethoxycarboxylmethyli-
dene)triphenylphosphorane afforded an α,β-unsaturated ester which was hydrogenated and then
treated with NaOAc in refluxing ethanol to produce lactam 620. Usual debenzylation, lactam
reduction and deprotection afforded (+)-621. The 8a-epimer of (+)-621 ((-)-366) has been
prepared by Hashimoto and co-workers115
(see Scheme 47).
The synthesis of (+)-625 (Scheme 81) started with thioacetal 617 which was triacetylated
and then dethioacetalated as above. Wittig chain elongation with (ethoxycarbonylmethylidene)-
triphenylphosphorane, followed by deacetylation with MeONa in MeOH led to diol 622. Catalytic
hydrogénation of the diene moiety, followed by cyclization of the liberated amine afforded a 15:1
mixture of lactams 623 and 624 epimeric at C(8a). The major isomer 623 was acetylated.
Reduction with BH3-Me2S complex in THF, followed by Zemplen de-O-acetylation produced
(+)-625.1 84
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349
Scheme 80
D-glucose NaN,
OMe MeOCH2CH2OH
OMe
1. AcOH/H2Q^
2. TsCl, pyr.
l.HyPd-C
2. AcONa 0 Me
3.BnOCOCl
NCbz
614 EtS SEt
l.EtSH,HCl I M u - > RO J — NÇbz
OMe 2. BnBr/NaH
615
HO OH
616
HgCl2
B n0
> CdC03
CHO
NCbz
OBnOBn>
619
BnO
1. Wittig >
2. H2/Pd-C
3. NaOAc/EtOH
617 R=H 618 R=Bn
l.H2/Pd-C/AcOH
2. Ac20/pyr.
3. BH 3Me 2S
4. MeONa/MeOH
620
HO
HO
HO
(+)-621 ( 1 -deoxy-6,8-di-e/?/-castanospermine)
Scheme 81
*COOEt l.Ac20/pyr.
2. HgCl2/CdCQ3 Λ> \ H2/Pd-C
3. Wittig
4. NaOMe/MeOH HQ QH 622
HO
(-)-366
HO
624
623 1. Ac20/pyr.
> 2. BH 3Me 2S 3. NaOMe/MeOH
H o X ^ (+)-625
Recently, Richardson and co-workers185
converted 2,3:4,5-di-0-isopropylidene-ß-D-
fructopyranose (626) into (-)-l-deoxy-6-ep/- ((-)-631) and (+)-l-deoxy-6,8a-di-€7?/-castano-
spermine ((+)-632). Extension of the carbon skeleton of 626 by oxidation, followed by a Wittig
reaction using (ethoxycarbonylmethylidene)triphenylphosphorane and hydrogénation gave the
oct-4-ulose derivative 627 which was transformed into 1-azido-1,2,3-trideoxy-D-örfruMö-oct-4-
ulose (628). Catalytic hydrogenolysis of the acide, followed by reductive amination between the
Page 76
350
resulting 1-amino-substituent and the 4-keto group gave a mixture of pyrrolidines 629 and 630.
After sulfonylation at the terminal alcohol, the pyrrolidines were cyclized to give, after de-O-
acetylation, the new 1-deoxy-castanospermine stereomers (-)-631 and (+)-632, respectively.
These compounds were found to inhibit the action of α-L-fucosidase but neither was a good
inhibitor of ct-mannosidase.
Scheme 82
D-fructose
626
l.PCC >
2. Wittig
3. H2/Pd-C
-COOEt
627
L L i A l H 4
2. MsCl, pyr. >
3. NaN3
628 629 630
629
l.CbzCl 2. MsCl
HO
HO = H
3. H2/Pd-C NaHC03
4. MeONa/MeOH
HO
HO
HO = Η
630
(-)-631
H o X ^
(+)-632
In 1990, Molyneux and co-workers186
discovered a new alkaloid from the seeds of
Castanospermum australe and identified it as (+)-7-deoxy-6-e/7/-castanospermine ((+)-9). The
alkaloid is the first trihydroxyindolizidine to be isolated from this plant and may represent an
intermediate in the biosynthesis pathway to (+)-castanospermine. It inhibits amyloglucosidase and
yeast a-glucosidase but it is significantly less active as a glucosidase inhibitor than its isomer
(-)-swainsonine and the tetrahydroxylated alkaloids (+)-castanospermine and 6-epi-castano-
spermine.
Page 77
351
Note Added in Proof.
We became aware of the following relevant papers during the period of June 1991 -
October 1991. Husson and co-workers187
converted the chiral 2-cyano-6-oxazolo-piperidine 633
into 3-methylidolizidine-l,2-diols 643 and 635, analogues of indolizidine-l,2-diol alkaloids
(Scheme 83). The synthesis commenced with 1,2-addition of the conjugate base of 633 on
crotonaldehyde leading to 636 with enantioselective formation of the first hydroxyl group.
Epoxidation of the double bond followed by hydrogenolysis of the benzyl appendage led to the
amino-epoxides 637 and 638. Cyclization of the latter afforded 634 and 635, respectively.
Scheme 83
Comins and Hong,1 88
reported the first asymmetric synthesis of (+)-elaeokanine A
((+)-110) and (+)-elaeokanine C ((+)-12) (Scheme 84). Reaction of chiral 1-acylpyridinium salt
639, prepared in situ from 4-methoxy-3-(triisopropylsilyl)pyridine and the chloroformate of
(-)-8-(4-phenoxyphenyl)menthol, with Grignard reagent 640 in THF/toluene gave the alcohol 641
(82%, d.e. 94%). After purification by column chromatography, 641 was converted to the chloride
642 (89%) by treatment with triphenylphosphine and N-chlorosuccinimide. On removal of the
chiral auxiliary with MeONa in MeOH, concomitant cyclization occurred to give enone 643
(84%). Treatment of 643 with LDA and dimethylcarbamyl chloride gave the amide 644 and the
corresponding eis diastereomer in a ratio 97:3 (92% yield). The silyl group in 644 was removed
with oxalic acid in MeOH to provide 645 (e.e.: >98%; 96% yield). Catalytic hydrogénation over
washed Pt0 2 afforded a 95:5 mixture of 646 and 647 (96%). Treatment of 646 with anhydrous
Scheme 84
639 R*=(-)-8-(4-phenoxyphenyl)menthyl 641 642
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352
(+)-12 (+)-110
CeClß, and n-propylmagnesium chloride gave a 66% yield of (+)-elaeokanine C ((+)-12), the
enantiomer of natural (-)-elaeokanine C ((-)-12). Treatment of (+)-12 with NaOH/MeOH gave
(+)-elaeokanine A ( (+ ) - ! 10) in 30% yield.
Daly and co-workers189
have isolated new pumiliotoxins and allopumiliotoxins from
dendrobatid poison frogs. The proposed structures for these alkaloids are shown below:
Me HO / H
Me HO ί Η
Pumiliotoxins (PTXs)
209 F
225 F
251 D
307 Β
307 F
R = Me
R=CH2OH
R = n-Bu
R =
R =
Me
Allopumilliotoxins
225 E R = Me
309D R =
325A7325A" R =
0-methyl 323B R =
OMe
O-methyl307A R =
erythrO'FTX-B R =
Wong and co-workers190
have presented a complete characterization of castanospermine
N-oxide (648) obtained via H 20 2 oxidation of castanospermine ((+)-7) according to the procedure
reported first by Sawl et al. in 1984.191
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353
A stereoselective total synthesis of (+)-castanospermine ((+)-7) has been achieved via a
non-carbohydrate approach by Ina and Kibayashi192
(Scheme 85). Sharpless oxidation of the
allylic alcohol 649 gave the epoxide 650. Treatment with Et2AlN(Bn)2 led to 651. Protections of
Scheme 85
OH Et2AlN(Bn)2
CH2C12
20°C
R=(tBu)Me2Si
1. AcCl/Et3N
2. MeOCH2Cl (i-Pr)2NEt
650
OMe
MeO'
l .L iAlH 4
2. DMSO
(COCl)2
OH
OAc
COOEt 1. L i A H V E t p ,
2. (tBu)Me2SiCl'
imidazole
3. Mitsunobu
0 R l.LiAlH4/Et20
2. (nBu)4NF
3. TsCl, pyr.
4. H 2/Pd(OH) 2
5. Et3N, heat
MeOH reflux
<+)-7
the primary and secondary alcoholic moieties in 651 were achieved by treatment with AcCl/Et3N
first, then with MeOCH2Cl and Hiinig's base. Reduction of the acetate with LiAlH4 followed by
oxidation gave the aldehyde 653 which was condensed with the conjugate base of ethyl acetate to
Page 80
354
provide a 89:11 mixture of the diastereomeric alcohols 654 and 655. Standard transformations
furnished 656 the acetate of which was reduced with LiAlH4, the two silyl ether moieties of
which were removed by treatment with (n-Bu)4NF. Selective tosylation of the primary alcoholic
groups, followed by hydrogenolysis of the dibenzylamine and heating with Et3N afforded the
partially protected derivative 657 which on boiling with HCl and MeOH gave (+)-castano-
spermine ((+)-7).
Acknowledgments. We wish to thank Dr. A. Duprat for his help in collecting the literature data
covered in this review. We are grateful also to Mrs. Annelis Carrupt for the typing of the
manuscript and to the "Fonds Herbette" (Lausanne) for financial support
Page 81
355
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