1 T H E AL,KALOIDS. VOL. 42 Copyright 0 1992 hy Academic Press. Inc.
All righta of reproduction in any form reserved.
2 MAURI LOUNASMAA A N D A R T 0 TOLVANEN
I. Introduction
The eburnamine-vincamine alkaloids have been reviewed in this trea- tise three times, twice by Taylor, in 1965 (I) and 1968 (2), and once by Dopke in 1981 (3). Since then, the number of publications dealing with the synthesis and pharmacology of these compounds has increased dramati- cally. Detailed yearly summaries covering synthetic work in the area have been compiled by Saxton (4-ZZ), who has also published a short review (12). The present chapter covers the literature up to the end of 1990.
Figure 1 shows the two title bases, (-)-eburnamine [ (-)-1] and (+)+in- camine [ (+)-21, containing the characteristic five-ring system. The normal numbering systems, that of Chemical Abstracts and the biogenetic num- bering of Le Men and Taylor (I3) , are illustrated for compounds (-)-1 and (+)-2, respectively. The numbering of Le Men and Taylor is adopted in this work. Compounds having the (20R,21R) [(20p,21p)] configuration (1) are usually classified as the eburnane type (“eburna” skeleton), and those with the (20S,21S) [(20a,21a)] configuration (2) as the vincane type (“vinca” skeleton).
We retain the established trivial names for the true alkaloids. The reader is reminded, however, that the names (-)-eburnamine [ (-)-11 and (+)-eburnamine [ (+)-11, and (+)-isoeburnamine [ (+)-141 and (-)-isoe- burnamine [ (-)-14], are often interchanged in the literature. To avoid confusion, the prefix “iso” is replaced in this chapter by the prefix “epi” [thus “( +)-16-epieburnamine” is used, not “( +)-16-isoeburnamine”].
Besides the eburnamine and vincamine alkaloids, we include the struc- turally related indole alkaloids of the schizozygane group, which are as- sumed to be formed from an Aspidosperma precursor (14). (+)-Schizozy- gine [ (+)-31], the major alkaloid of Schizozygia cuffaeoides (Boj.) Baill., is a typical example of these bases in which C-16 is attached to C-2, giving rise to additional rings. The three related alkaloids of the pentacyclic type,
0 6 0 6
‘ 21
(-)- 1 FIG. I . Ring systems of (-beburmamine [(-)-11 and (+)-vincamine [ (+)-21.
1. EBURNAMINE-VINCAMINE ALKALOIDS 3
(-)-schizophylline [ (-)-441, (+)-andrangine [ (+)-111, and (- )-vallesami- dine [ (-)-151 are also included, although they lack the true five-ring skele- ton of the eburnamine-vincamine alkaloids. The first members of the tacamine (pseudovincamine) group of alkaloids were recently found in nature, and the properties and chemistry of these bases are evaluated. Likewise, bisindole alkaloids containing an eburnane or related unit are presented.
The structures of the known eburnamine-vincamine alkaloids are de- picted in Table I . Each alkaloid is provided with its trivial name (vide infra), CAS registry number, melting point (solvent in parentheses), and optical rotation (concentration and solvent in parentheses). Table I1 lists the bases in order of increasing molecular weight. The plant sources for each compound are given, together with the molecular formula and addi- tional names.
11. Occurrence
The eburnamine-vincamine alkaloids occur in the plant family Apocy- naceae. To date, the main types of these alkaloids have been found, in addition to several Hunteria and (Vinca) species, in the following genera: Amsonia, Aspidosperma, Catharanthus, Comularia, Craspidospermum, Crioceras, Cyclocotyla, Haplophyton, Kopsia, Leuconotis, Melodinus, Pandaca, Pleiocarpa, Rhazya, Strempeliopsis, Tabernaemontana, and Voacanga. Alkaloids of the schizozygane group have been detected exclu- sively in Schizozygia caffaeoides. (-)-Vallesamidine, the pentacyclic al- kaloid related to the schizozygane group, has been isolated from Vallesia dichotoma. Alkaloids of the tacamine group have so far been found only in two Tabernaemontana species (cf. Table 11).
111. Syntheses
Much effort has been invested in the synthesis of eburnamine- vincamine alkaloids. Without doubt, the potential pharmacological activ- ity of many compounds of this type has been the principal incentive. Reviews on the earlier synthetic achievements have been published (124,125). We describe in the following the most characteristic synthetic
(+)-l6-Epieburnamine (-)-l6-Epieburnamine ( + )-0-Methyl- 16-epi- [(+)-141 [( -)-141 eburnamine [(+)do] r420i-x4-71 r 19877-9n-81 r 7 x i x ~ x 3 ~ - - L ' - - - ' -- ' 1
Abbreviations used: n.d.. not determined; n r . , not recorded. " Arbitrary stereochemistry. ' Name in the original paper 0-ethyleburnamine.
,I Name in the original paper 20-oxoeburnamine. ' Revised stereochemistry (cf. Ref 250).
Name in the original paper 20-hydroxyeburnamine.
C-20-C-21 relationship still awaits confirmation. Unexpected sign of [ a l D .
The original value of - 120" seems to be erroneous (cf. Ref 221) . ' The sign of [a]D in the original paper varies. ' Unexpected stereochemistry at C-16. ' Tentative structure. ' Unexpected C-20-C-21 relationship.
TABLE I1 EBURNAMINE-VINCAMINE ALKALOIDS OF PLANT ORIGIN
108 89 95,109-1 I I 66, I 12,250 97,98 113-1 17 44 118 36 27 119 56 120 28,121 118 37 51,253 20 122 123
' Criocerus longiJorus has been renamed Criocerus dipludenigorus (16). Confusion exists concerning the sign of the isolated compound.
22 MAURl LOUNASMAA A N D A R T 0 TOLVANEN
approaches to the eburnamine-vincamine skeleton, with emphasis on achievements since 1978."
A. SYNTHESES OF EBURNAMINE
Bartlett and Taylor Synthesis of (+-)-Eburnamine (l), (+)-16- Epieburnamine (14), and (+)-Eburnamonine (8)
Soon after their isolation from Hunteria eburnea, the three main bases in the eburnane series, 1, 14, and 8, were synthesized from lactone 70 by Bartlett and Taylor (Scheme 1) (22). The D-E ring junction was initially considered to be trans, but later studies revealed it to be cis (vide infra). To prepare 70, 4-ethylphenol (72) was reacted with the chloroform-derived carbene to yield adduct 73, which was hydrogenated to cyclohexanone derivative 74 (Scheme 2). This was oxidized to dicarboxylic acid 75, hydrolysis of which gave lactone 70.
Recently Magnus and Brown employed a different route to lactone 70 (and lactone 77) (Scheme 3) (126). Diels-Alder reaction of 2-ethylacrolein with 1,3-butadiene in the presence of AlC13, followed by acetalization, gave adduct 76. Oxidation of 76 under phase-transfer conditions and treat- ment with 2 M HC1 gave a mixture of lactones 70 and 77, which was converted to 8.
SCHEME 1 . Bartlett and Taylor synthesis of (2)-eburnamine (l), (2)-16-epieburnamine (14), and (*)-eburnamonine (8). Reagents: i , tryptamine, AcOH, 100°C. then polyphosphoric acid (PPA), 100°C; ii, LiAlH4, Et20; iii, Cr03, pyridine.
* In general, we present the synthetic schemes startingfrom the intermediate which is next to be reacted with tryptamine [3-(2-aminoethyl)indole] or tryptophyl bromide [3-(2- bromoethyl)indole].
1. EBURNAMINE-VINCAMINE ALKALOIDS 23
0 OH
iv Q L&+ g ii 0 G H 0 q -70
Cl2CH C$CH C12CH
...
72 73 74 75
SCHEME 2. Bartlett and Taylor synthesis of lactone 70. Reagents: i , CHCI3, aq. NaOH; ii, HZ, Pd/C, EtOH; iii, conc HN03 , heat; iv, HzO, sealed tube, 210°C.
76 70 77
SCHEME 3. Magnus and Brown synthesis of lactone 70. Reagents: i, KMn04, H20, tri-n-decylammonium chloride, C6H6, then 2 M HCI.
2. Barton and Harley-Mason Synthesis of (+)-Eburnamine (1) A second route to eburnamine (1) was developed by Barton and Harley-
Mason (127). As in the synthesis by Bartlett and Taylor, tryptamine was condensed with a suitable oxoester (78) to give lactam 79 (Scheme 4).
CHO COOMe
/-y HO
HO 78 79 80
SCHEME 4. Barton and Harley-Mason synthesis of (?)-eburnamine (1). Reagents: i, tryptamine; ii, OsO,; iii, Na1O4; iv, LiAIH,.
3. Gibson and Saxton Synthesis of (+)-Eburnamine (1)
A slightly different approach to (+)-eburnamine (1) was presented by Gibson and Saxton (128). Proceeding via the homoeburnamenine lactam
24 MAURI LOUNASMAA A N D A R T 0 TOLVANEN
85, eburnamine (1) was obtained in six steps from diol 82 (Scheme 5). Lactam 85 was also converted to homoeburnamenine (88), which the authors later used in their synthesis of (*)-vincamine (2) (170). In addition to the above, eburnamine (1) has been obtained in connection with syntheses of eburnamonine (8) (vide infru).
COOEt - 84%
H
82
...
86% 27%
HO
84
HO
% 88
SCHEME 5. Gibson and Saxton synthesis of (&)-eburnamine (1). Reagents: i , tryptamine, 150-160°C; ii , aq. NaIO4, EtOH; i i i , AcOH, 50-60°C. then separation of isomers; iv, O s 0 4 , pyridine; v , P ~ ( O A C ) ~ , MeOH, room temperature, then K2C03, reflux; vi, LiAIH4, Et20, reflux.
B. SYNTHESES OF EBURNAMONINE I . Wenkert and Wickberg Synthesis of (?)-Eburnamonine (8)
Racemic eburnamonine (8) was first synthesized by Bartlett and Taylor, via eburnamine (1) (Scheme 1). However, the correct relative configura- tion at C-20 and C-21 (cis) was not confirmed until later by Wenkert and Wickberg (129), using a different route. Wenkert and Wickberg introduced the first use of the key enamine 92, later known as “Wenkert’s enamine” (Scheme 6). Starting from the bromoester 89 and tryptamine, enamine 92 (isolated as the iminium perchlorate 91) was obtained in two steps. Al- kylation of enamine 92 with ethyl iodoacetate, followed by reduction and base treatment, gave (+)-eburnamonine (8).
1. EBURNAMINE-VINCAMINE ALKALOIDS 25
CIO - COOMe I_ BrT 70% H
I 91 I 89 90
24% 60%
0 EtOOC
92 93 8
SCHEME 6. Wenkert and Wickberg synthesis of (2)-eburnamonine (8). Reagents: i , trypt- amine, K2C03, n-BuOH, reflux; ii, POCI,, benzene, reflux. then aq. NaCIO,; iii, aq. NaOH, toluene, dimethyl sulfoxide (DMSO); iv, ICH,COOEt, I I O T , 4 hr; v, H2, Pd/C, EtOH. then NaOEt/EtOH.
2. Other Routes to Wenkert's Enamine (92)
Enamine 92, which is more conveniently isolated and used as its imi- nium perchlorate salt 91, has become a widely used intermediate in the synthesis of compounds of the eburnamine-vincamine type. There are several other ways to prepare 92, besides that described above, and a short description of these follows.
a. Wenkert and Wickberg. Wenkert and Wickberg first prepared ena- mine 92 (iminium perchlorate 91) in 1962 in connection with their synthesis of flavopereirine (130) (Scheme 7). Piperidine derivative 94 was oxidized
94 95 96
91
SCHEME 7. Wenkert and Wickberg synthesis of iminium perchlorate 91. Reagents: i, Hg(OAc)2, aq. AcOH, IOO"C, then H2S, then NaBH,; ii, Hg(OAch, aq. AcOH, IOO"C, then H2S, then NaC10,.
26 MAURI LOUNASMAA A N D ART0 TOLVANEN
with Hg(OAc)* and cyclized to 95 and 96. Similar treatment applied to 95 gave the iminium perchlorate 91.
One of the first applications of the modified Polonovski reaction was the synthesis of enamine 92 by Potier and co-workers (131). Pyridinium salt 98 (Scheme 8), prepared from 3-ethylpyridine (97) and tryptophyl bromide, was reduced with NaBH4 to tetrahydropyridine 99, which was cyclized to indoloquinolizidine 100. Base-catalyzed isomeriza- tion yielded the enamine 92, though spectroscopic data for this were not reported.
b. Potier ef al.
97 98' 99' QIzpLV \ 100%
100 92
SCHEME 8. Potier et al. synthesis of enamine 92. Reagents: i , tryptophyl bromide; ii , NaBH4; iii, H202, then trifluoroacetic anhydride (TFAA) followed by 2 N HCl, 70°C; iv, tert-BuOK, DMSO, 100°C.
c . Szantay et al. Szantay and co-workers prepared iminium perchlo- rate 91 in connection with their first vincamine synthesis (132), by conden-
SCHEME 9. Szfintay et a/ . synthesis of iminium perchlorate 91. Reagents: i , tryptamine, xylene, reflux; ii, POC13, reflux; iii, aq. NaOH, then 70% HC104.
1. EBURNAMINE-VINCAMINE ALKALOIDS 27
sing lactone 101 with tryptamine and cyclizing the intermediate amide 102 (Scheme 9). Lactone 101 was obtained in three steps from diethyl ethylma- lonate.
d. Szuntay et al. and Danieli et a / . The route to iminium perchlorate 91 via P-carboline 107 was first achieved by Szfintay’s group (133) (Scheme 10). Butyric acid (104) and tryptamine were reacted to give salt 105, which after heating yielded amide 106. Cyclization with POCl3, and base treat- ment, gave imine 107, which was then allowed to react with methyl acry- late. The resulting ketone was subjected to Wolff-Kishner conditions, but the desired iminium perchlorate 91 was isolated only in poor yield. Later Danieli and co-workers (134) converted imine 107 to iminium perchlorate 91 in good yield by using a 1,3-dihalogenopropane to create the fourth ring.
104 105 I
... 111
39%
107 I
SCHEME 10. Szantay et a / . and Danieli et a/ . syntheses of iminium perchlorate 91. Re- agents: i, tryptamine, EtOAc; ii, 190-200°C; iii, POCI,, reflux; iv, CH2=CHCOOMe, then Wolff-Kishner; v, l-bromo-3-chloropropane, N-ethyldiisopropylamine, CH,CN, reflux, then LiC104.
e. Chen and Guo. An interesting route to Wenkert’s enamine (92) in which tryptamine was not used as a reagent was described by Chen and Guo (135). The starting compounds, phthalimide 108 and ethyl 3- oxohexanoate (109), were converted in six steps to imine 107 (Scheme 1 I ) . Alkylation of 109 with 108 afforded phthalimide 110. This was hydrolyzed to disodium salt 111, which was treated with benzenediazonium chloride to form hydrazone 112. Dehydration with acetic anhydride gave phtha- limide 113, which was transformed to the tryptamine derivative 114 via Fischer indole synthesis. Deprotection of the amino group also effected
28 MAURI LOUNASMAA AND ART0 TOLVANEN
108 109 110
40% H
COOH OONa 07%
- 111 112
vi
0 “NH 60% 95%
113 0 114 9- vii QJ-7+-&
I 91 I
107
SCHEME 1 I . Chen and Guo synthesis of iminium perchlorate 91. Reagents: i , NaOEt; ii, NaOH; iii, PhN,CI, 0-5°C; iv, Ac20; v, HCI, AcOH, heat; vi, NH2-NH2, then HCI followed by 10% NH,OH; vii, see Scheme 10.
ring closure to give imine 107. Imine 107 was converted to iminium perchlorate 91 by the methods of Scheme 10.
f. Lounasmaa er al. An entry to Wenkert’s enamine (92) employing the modified Polonovski reaction was developed by Lounasmaa and co- workers (136) (Scheme 12). 3-Benzyloxypyridine (115) was alkylated with tryptophyl bromide, and the salt obtained (116) was reduced with NaBH4 to afford tetrahydropyridine 117. The indole nitrogen was protected with di-terr-butyl dicarbonate [(BOC)20] and the tert-butoxycarbonyl (B0C)- protected compound 118 was then subjected to modified Polonovski reac- tion conditions to give a-aminonitrile 119. Deprotection of 119 with tri- fluoroacetic acid (TFA) and subsequent acid-induced cyclization gave the indoloquinolizidine 120, which was converted to a mixture of epimeric
1. EBURNAMINE-VINCAMINE ALKALOIDS 29
115 116 117
88% Boc
OBn
118 119 120
56% 90%
HO HO
121 122 92
SCHEME 12. Lounasmaa er ul. synthesis of enamine 92. Reagents: i , tryptophyl bromide; i i , NaBH4, MeOH; iii. (BOC)IO. 4-dimethylaminopyridine (DMAP), CH2CIZ; iv, 3-chloro- perbenzoic acid (m-CPBA), then TFAA. then aq. KCN; v. TFA. then 50% AcOH; vi, HCOzNH4, Pd/C, MeOH, reflux: vii. Swern oxidation. then EtMgBr: viii, TFA. reflux.
alcohols 121 by catalytic transfer hydrogenation. Swern oxidation of this mixture, followed by immediate treatment with EtMgBr, again gave a mixture of alcohols (122). Dehydration of the mixture in refluxing TFA yielded Wenkert's enamine (92) directly. The mixture of epimeric alcohols 121 could similarly be converted to enamine 153 (cf. Scheme 19).
g. Atta-ur-Rahman and Sultana Synthesis of Indoloquinolizidines 126 (Dihydro Derivatives of Wenkert's Enamine). A short synthesis of indol- oquinolizidines 126 (mixture of diastereomers) was described by Atta-ur- Rahman and Sultana (137). Aldehyde ester 123 was condensed with trypt- amine to afford a mixture of lactams 124 and 125 (Scheme 13). LiAIH4 reduction of this mixture gave 126, the oxidation of which has been de- scribed earlier (130).
3. Schlessinger et a/. Synthesis of (+)-Eburnamonine (8) and (+-)-Eburnamine (1)
Schlessinger and colleagues (138) began their synthesis of 8 (Scheme 14) from acid chloride 127, which was obtained in three steps from tert-butyl butyrate. Alkylation of tryptamine with 127 gave amide 128, which was
30 MAURl LOUNASMAA AND ART0 TOLVANEN
123 124 125
H 9 H 126 '
SCHEME 13. Atta-ur-Rahrnan and Sultana synthesis of indoloquinolizidines 126. Re- agents: i, tryptamine, 15% AcOH, reflux; ii, LiAIH,/Et,O, room temperature.
127 128 I 90'
90% H
MeOOC MeOOC MeOOC
129 130 131
85:15
8 , vii 132
96%\
... 111
vi
92%
SCHEME 14. Schlessinger et a/. synthesis of (t)-eburnamonine (8) and (*)-eburnamine (1). Reagents: i, tryptamine hydrochloride, LiH, tetrahydrofuran (THF); ii, KH, THF; iii, lithium diisopropylarnide (LDA), BrCH2COOMe, -78°C; iv, P0Cl3, CH3CN, then aq. LiCIO,; v, H2, Pd/C, MeOH; vi, NaOMe/MeOH; vii, LiAIH4, THF, then 0.1 M NaOMe/ MeOH, 70T, 12 hr.
1. EBURNAMINE-VINCAMINE ALKALOIDS 31
cyclized to lactam 90 (cf. Scheme 6). The LDA-derived dianion of 90 was alkylated with methyl bromoacetate, yielding lactam ester 129. Bischler- Napieralski cyclization of 129, followed by treatment with lithium perchlo- rate, afforded the tetracyclic iminium perchlorate 130. Hydrogenation of this salt gave a mixture of diastereomeric esters 131, which was cyclized by base to eburnamonine (8) and 21-epieburnamonine (132) (6 : 1). A 3 : 2 mixture of eburnamine (1) and 16-epieburnamine (isoeburnamine, 14) was obtained after an ordinary LiAlH4 reduction of 8.
4. Buzas et a / . First Synthesis of (5)-Eburnamonine (8)
Buzas and co-workers (139) presented a short entry to (-+)-eburna- monine (8) in 1976, which is one of the numerous syntheses that start from Wenkert's enamine (92) (Scheme 15). Enamine 92 was alkylated with 2-chloroacrylonitrile to give directly the pentacycle 133, isolated as the perchlorate salt. Reduction of 133 with zinc afforded the nitrile 134 (along with its 21-epimer), which was oxidized to eburnamonine (8).
42% 83%
NC NC
133 134 92
% 8
SCHEME 15. Buzas et al. synthesis of (&)-eburnamonine (8). Reagents: i, CH2= C(CI)CN, CHlClz, then HC104; ii, Zn dust, EtOH, conc HCI; iii, separation of isomers; iv, lithium cyclohexylisopropylamide, THF, hexamethylphosphoric triamide (HMPA), -78"c, 0 2 .
5 . Szantay et al. First Synthesis of (+)-Eburnamonine (8)
Szantay's group published their first synthesis of (*)-eburnamonine (8) in 1977 (140) (Scheme 16). The unsaturated oxoester 135 was prepared in seven steps from diethyl malonate. Reaction of 135 with p-carboline salt 136 and base-induced cyclization of the intermediate salt 137 gave the tetracycle 138 (plus its 21-epimer). Treatment of 138 with a stronger base led to lactam formation (pentacycle 139). The 0x0 group was removed by converting pentacycle 139 to its tosyl hydrazone 140, which was then
32 MAURI LOUNASMAA A N D A R T 0 TOLVANEN
MeOOC
55% 0 H
135 136 137
40% 45%
MeOOC 0
138 139 140
SCHEME 16. Szantay et 01. synthesis of (2)-eburnamonine (8). Reagents: i . -; i i , Et3NI MeOH, then separation of isomers; i i i , rert-BuONa, toluene; iv. 4-toluenesulfonylhydrazide, I N HCI; v , NaBH3CN, N,N-dimethylformamide (DMF)/sulfolane. 4-TsOH. 110°C. Ts stands for tosyl (4-toluenesulfonyl-).
reduced with sodium cyanoborohydride to give (+)-eburnamonine (8), from which the optical antipodes were resolved.
6. Winterfeldt ef al. Synthesis of (+)-Eburnamine (1) and (2)-Eburnamonine (8)
Winterfeldt and colleagues based their tactics on the regioselective ring opening of suitable cyclopropane derivatives (141) (Scheme 17). Cyclopro- pane carboxaldehyde 141, prepared by the method of Warner (142), was condensed with tryptamine to give adduct 142 as the major product, together with its 21-epimer. Reaction of 142 with the lithium enolate of methyl cyanoacetate caused cyclopropane ring opening to yield tetracycle 143 as the sole product. After cleavage of the methoxycarbonyl group and lactam ring closure, oxolactam 144 was produced. Lactam ring opening of 144 gave the p-oxoester 145, and base and acid treatment of this, followed by reduction of intermediate dilactam 71, gave (+)-eburnamonine (8). Dilactam 71 was also reduced to (2)-eburnamine (1) either directly (LiAlH4) or via lactam 87 [LiB(Et)3H].
Some years later, Winterfeldt and co-workers (143) published an asym- metric synthesis of the cyclopropane 141, thereby offering an enantio-
1. EBURNAMINE-VINCAMINE ALKALOIDS 33
COOMe
O H C F COOMe 76%
/""' "'TOOMe COOMe
141 142 OOMe
37%\ 09% Iviii
SCHEME 17. Winterfeldt et a/. synthesis of (?)-eburnamine (1) and (?)-eburnamonine (8). Reagents: i, tryptamine: ii, NCCH2COOCH3, LiH, DMF; iii, LiI/DMF, then KF/AcOH, or RO-, then H'; iv, Et@PFb, CH2Clz, then hydrolysis: v, NaOMe/MeOH: vi, TFA; vii, Et30PFb, then NaBH4/1 ,2-dimethoxyethane (DME); viii, LiB(Et),H, THF; ix, LiAIH4, THF.
selective access to both (+)- and (-)-eburnamonine. Michael addition of 2-methylenebutanal with bromomalonate 147 gave cyclopropane 149 via 148 (Scheme 18). Base hydrolysis of 149, followed by treatment with diazomethane, afforded the enantiomerically pure key intermediate (+)-141.
147 148 149 (+)-141
R=(exo-diphenylmethyI)isobornyl-
SCHEME 18. Winterfeldt er ul. asymmetric synthesis of intermediate 141. Reagents: i. CH,=C(Et)CHO. NaH, cyclohexane; ii. KOH/MeOH. -20°C. then CH2N2/EtZ0.
34 MAURI LOUNASMAA AND ART0 TOLVANEN
7. Martel ef af. Synthesis of (+)-Eburnamonine (8)
In the eburnamonine synthesis developed by Martel and co-workers ( I # # ) , the ethyl group was introduced in the final conjugate addition step (Scheme 19). As a means of preparing the unsaturated ester 156, trypt- amine was first alkylated with ethyl 5-bromopentanoate (150) to furnish the lactam 151. Bischler-Napieralski cyclization of 151 and base treatment of the intermediate iminium perchlorate 152 gave the enamine 153. When 153 was reacted with benzoyl peroxide, salt 154 was formed, from which benzoate 155 was liberated with base. Under Wittig-Horner reaction conditions, benzoate 155 was transformed to the unsaturated ester 156. (2)-Eburnamonine (8) was obtained after 1 ,4-addition of ethyl magnesium bromide, followed by in situ cyclization of the intermediate 157.
In the same publication ( I # # ) , Martel's group offered a second route to ester 156 (Scheme 20). Lactol 158 (prepared in five steps from dihydro- pyran) was condensed with tryptamine. Acid treatment of the afforded imine 159 and chlorination/cyclization of the intermediate p-carboline 160 yielded ester 156.
B-CooEt -L 59%
150
153
6OOEt
156
151 152
P h C O O w I P h C O O w
154 -I 155 -
SCHEME 19. Martel ef a/ . synthesis of (2)-eburnamonine (8). Reagents: i , tryptamine, KzCO3, n-BuOH, reflux; i i , P0Cl3, N,N-dimethylaniline, then 70% HCIO,; iii, aq. NH3, aq. EtOH; iv, benzoylperoxide, hydroquinone, dioxane, then aq. NH3 ; v, (Et0)2POCH2COOEt, NaH, DME; vi, EtMgBr, Cu2CI2, THF.
1. EBURNAMINE-VINCAMINE ALKALOIDS 35
aH -COOEt - loo% TpoH-& vH- 40% 156
158 159 OoEt 160 COOEt
SCHEME 20. Martel et al. synthesis of intermediate 156. Reagents: i , tryptamine, ben- zene; ii, 6 N HCI, EtOH; iii, S0Cl2, benzene, pyridine.
8. Wenkert et al. Second Synthesis of (+)-Eburnamonine (8) Wenkert and co-workers (145-147) have presented two parallel routes
to (+)-eburnamonine (8) proceeding via the lactone intermediate 163 (Scheme 21). Lactone 163 was prepared either by alkylation of tryptamine with bromolactoll62 or by alkylation of aminolactone 161 with tryptophyl bromide. (+)-Eburnamonine (8) was formed by subjecting lactone 163 to thermolysis (60% yield) or prolonged acid treatment (giving a 1.35 : 1 mixture of 8 and its 21-epimer 132, 87% total yield). The bromolactol intermediate 162 in the synthesis was prepared in four steps from dihydro- pyran 164 (146) (Scheme 22). The bicyclic aminolactone 161 was synthe- sized in four steps from tetrahydropyridine 169 (147) (Scheme 23). Alterna- tively, as the yield of the first step was poor, compound 171 was prepared via a thioketal in three steps from 169 (41% overall).
6. + o&Js-& H O q I I
>b 0
H H 0
161 163 8 Br 2
162
SCHEME 21. Wenkert et al. synthesis of (?)-eburnamonine (8). Reagents: i , tryptophyl bromide, phase-transfer catalysis; i i , tryptamine; iii, 250"C, 0.01 Torr, 0.5 hr or AcOH, lOO"C, 48 hr.
36 MAURl LOUNASMAA A N D A R T 0 TOLVANEN
SCHEME 22. Wenkert et al. synthesis of bromolactoll62. Reagents: i , N,CHCOOEt, Cu bronze; ii, dilute acid hydrolysis; iii, BBr3, CH,C12; iv, 1% HCI, dioxane, 80°C.
9. Other Routes to Aminolactone 161
Three Japanese groups have presented alternative routes to amino- lactone 161.
a. Ban et al. Ban and collaborators described two routes to 161, both starting from piperidone ester 173. In the first route (148), piperidone carboxylic acid 179 was prepared from 173 via a six-step chain elongation procedure, and the anodic oxidation of this afforded the piperidone lactone 180 (Scheme 24). Lactone 180 was subsequently transformed to amino- lactone 161 via thiolactam 181. The second synthesis of 161 by Ban’s group
...
r 2 C y T Z ii
A A AOOMe
169 170 171
172 161
SCHEME 23. Wenkert et a/. synthesis of aminolactone 161. Reagents: i , LiAlH4, dioxane, reflux; ii, CICOOMe, Et3N, THF; iii, N2CHCOOEt, Cu bronze, 135°C; iv, aq. KOH, (HOCH2CH2)20,100°C.
1. EBURNAMINE-VINCAMINE ALKALOIDS 37
/ / / ...
COOEt - ii
09% 0
COOEt - 02%
k 173 174 175
iv
69% d
0 I Bn
V - [pCooH] vi
60%
176 177 178
COOH 2 0 -
72-76% 77% I H
H H
180 181
I H
179
0
161
SCHEME 24. Ban ef al. first synthesis of aminolactone 161. Reagents: i. benzyl bromide, NaH, DMF; ii, alkaline hydrolysis; iii, S0Cl2, benzene, O T , then CH2N2; iv. PhCOOAg, MeOH; V, alkaline hydrolysis; vi, Na, NH, liquid; vii, 50 mA, 4 F/mol, aq. CH3CN, E 4 N + c104-; viii, P4S10, THF, room temperature; ix, Raney Ni, EtOH, reflux.
(149) used the same starting compound 173, but the chain was lengthened in a slightly different manner (Scheme 25).
Hanaoka and co-workers synthesized aminolactone 161 in nine steps from carbamate 190 (150) (Scheme 26). After introducing the ethyl group by standard techniques, they applied allylic rearrangement of 193 to furnish the secondary alcohol 194. Claisen rearrangement and successive oxidation, esterification, and hydrogenation gave the aminoes- ter 198, which was lactonized by sodium hypochlorite-induced N- chlorination.
The latest access to aminolactone 161 was introduced by Shono and co-workers (151) (Scheme 27). Lactone 161 was synthesized
b. Hanaoka et al.
c. Shono et al.
38 MAURI LOUNASMAA AND ART0 TOLVANEN
i i iii
98% I
Qn Bn
174 182
COOEt I_ 02% 0
A 0
173
L
183
dCN -
IV 4 83%
An
184
An
185
COOH 2 8.0.. 2 100%
I An A COOMe
186 187 188
189 161
SCHEME 25. Ban et al. second synthesis of aminolactone 161. Reagents: i, benzyl bro- mide, NaH, DMF; iii, LiAIH4, Et20; iii, methanesulfonyl chloride (MsCI), Et3N, Et20; iv, NaCN, EtOH, reflux; v, conc H2S04, MeOH, reflux; vi, NaOH, aq. EtOH; vii, H2, EtOH, W K , 60 psi; viii, CICOOMe, 10% NaOH, 0-5°C; ix, 30 mA, 2.7 F/mol, Et4N+ c104-, CH3CN; x, aq. KOH, dioxane, 18-crown-6, reflux.
in six steps from tetrahydropyridine 199 by the application of a new method for introducing an active methylene group to the 3 position of the piperidine ring.
10. Buzas et al. Second Synthesis of (?)-Eburnamonine (8) Buzas and co-workers (152) reported a simple conversion of lactam acid
203 to (2)-eburnamonine (8) (Scheme 28). Acid 203 was prepared from the corresponding ester 129, which Schlessinger's group had used in their synthesis of eburnamonine (cf. Scheme 14). Unfortunately, the reduction of iminium perchlorate 204, obtained from 203 after Bischler-Napieralski cyclization, gave only a 1 : 4 mixture of eburnamonine (8) and 21-
1. EBURNAMINE-VINCAMINE ALKALOIDS
I II iii - 89% 57%
I Cbz AOOEt 6,bz
190 191 192
94%
39
193 194 195
6 C O O H & $cooMe ... ~ ' O o M e 2 161 Abz Lbz A 196 197 198
SCHEME 26. Hanaoka e f al. synthesis of aminolactone 161. Reagents: i, aq. KOH, EtOH, reflux, then benzyloxycarbonyl chloride (CbzCI); ii, Jones oxidation; iii, EtMgBr, Et2O; iv, 1% HCI, acetone, reflux; v, Et-0-CH=CH2, Hg(OAc)*, 200°C; vi, AgN03. aq. KOH, aq. EtOH; vii, CH2N2/Et20; viii, H2. Pd/C, MeOH; ix, aq. NaOCI, then aq. KOH, reflux.
iii dLe Tiz i
69% -
I I kOOMe COOMe COOCHJ
199 171 200
d c o o M e COOMe
[&:'I % (fJO 2 161 AOOMe kOOMe AOOMe
20 1 202 189
SCHEME 27. Shono et al. synthesis of aminolactone 161. Reagents: i, EtMgBr, [1,3- bis(diphenylphosphino)propane]nickel chloride [Ni(dppp)C12]; ii, terf-BuOCIIMeOH; iii, di- methyl malonate, Tic&, Et3N; iv, KOH/MeOH, heat; v, DMF, heat; vi, hydrolysis.
40 MAURl LOUNASMAA A N D A R T 0 T O L V A N E N
H 80% 86% 1:4
HOOC
203 204
SCHEME 28. Buzas rt crl . second synthesis of (+)-eburnamonine (8). Reagents: i , POCIj. toluene. reflux. then aq. LiCIO,; i i , Zn powder. 65% AcOH.
epieburnamonine (132), although a simple analog, (E)-noreburnamonine, was obtained as the sole product (58% yield).
1 1 . Levy et ul. Synthesis of (+)-Eburnamonine (8)
A modification of the classic Wenkert and Wickberg synthesis (Scheme 6) was the basis of the approach adopted by Levy and co-workers (153) (Scheme 29). Oxoester 123 (cf. Scheme 13) was condensed with trypt- amine to give enamide 205, reduction of which afforded the unstable enamine 206. Alkylation of 206 with ethyl iodoacetate yielded the diaster- eomeric esters 208, which were directly cyclized to eburnamonine (8) and 21-epieburnamonine (132) ( 1 : 1 ) .
123 205 206
1:l
EtOOC EtOOC
208
SCHEME 29. Levy et a / . synthesis of (2)-eburnamonine (8). Reagents: i. tryptamine. toluene, reflux, Dean-Stark; ii. LiAIH4. THF. 0°C; iii, ICHZCOOEt, K,CO,, CH,CN, 60°C. then saponification followed by acidification.
12. Szantay et al. Synthesis of (-)-Eburnamonine [ (-)-81
Szantay and co-workers (154) started their asymmetric synthesis of (-)-eburnamonine [vincamone, (-)-81 from Wenkert’s enamine (as its irniniurn perchlorate 91, Scheme 30). Alkylation of 91 with diethyl methy-
1. EBURNAMINE-VINCAMINE ALKALOIDS 41
94% 79% EtOOC EtOOC
EtOOC EtOOC \ 91 209 210
72% 73% 73%
HON -\ HON -\ 212 213
EtOOC EtOOC HOOC
HOOC \ 21 1
QJpL%Z@J& 98% 90%
NC H N g o g
215 (-1-8 \ \ \
214
SCHEME 30. Szantay ef ( I / . synthesis of (-keburnamonine [ (-)-S]. Reagents: i , CH,=C(COOEt),, ferr-BuOK. CH2Cl2; ii . Hz. Pd/C, DMF; iii, aq. KOH. EtOH: iv. aq. NaN02. AcOH. then resolution with D-dibenzoyltartaric acid; v , aq. NaOH. EtOH. reflux; vi, decalin. 180°C: vii, NaOMe/MeOH. reflux: viii, aq. HCI, 80°C.
lenemalonate yielded iminium perchlorate 209, and hydrogenation of 209 gave diester 210. Partial hydrolysis afforded the monoester 211, which was converted to oxime 212. After resolution the desired optical isomer was hydrolyzed to amino acid 213. Refluxing of 213 in decalin effected decar- boxylation and dehydration to yield nitrile 214, which after successive base and acid treatments gave (-)-eburnamonine [ (3-81.
Szantay’s group found yet another way to prepare racemic nitrile 214 (155) (Scheme 31) . They reacted enamine 92 with paraformaldehyde and converted the resulting trans-alcohol 216 to benzoate 217. The chromic acid oxidation product of 217 was isolated as iminium perchlorate 218, which was hydrogenated to cis-benzoate 219, the epimer of 217. The benzoyl group was then displaced by the cyano group in the usual manner.
13. Magnus et (11. Synthesis of (+)-Eburnamonine (8)
Rearrangement of an intermediate of the Aspidosperrna type was the key step in the eburnamonine synthesis of Magnus and co-workers (156) (Scheme 32). The pentacyclic amide 223, prepared in three steps from the indole derivative 221 and carbonate 222, was treated with cyanogen
42 MAURI LOUNASMAA A N D ART0 TOLVANEN
68% 96% 65%
HO PhCOO
92 216 217
34% q v_ 89% 9 V l _ Z l 4 45%
PhCOO PhCOO MsO
216 219 220
SCHEME 31. Szantay ef al. synthesis of intermediate 214. Reagents: i, paraformaldehyde, CHZCIZ, reflux; ii, PhCOCI, pyridine; iii, NaZCr2O7, AcOH, then 70% HC104; iv, H2, Pd/C, acetone; v, KOH/EtOH, reflux, then MsCI, pyridine; vi, NaCN, DMSO.
0
CH2 &O2Ar
221 0 0 223
& / + \ N " '%" \ ' c, 907. ArOp u
224 (43%) "% 225 (56%) 71
SCHEME 32. Magnus et a / . synthesis of (?)-eburnamonine (8). Reagents: i, ClCN, diox- ane, room temperature; ii, SOCIz, pyridine; iii, HCI, MeOH, room temperature; iv, LiAIH4, EtzO, then CrO,, pyridine.
1. EBURNAMINE-VINCAMINE ALKALOIDS 43
chloride to give the cis-chlorohydrin 224 and the geminal dichloroimine 225. The latter compound rearranged easily under acidic conditions to dilactam 71 (cf. Scheme l ) , which was converted to (*)-eburnamonine (8) by consecutive reduction and oxidation procedures. 14. Fuji et af. Synthesis of (-)-Eburnamonine [ (3-81
In connection with studies on the enantioselective synthesis of several alkaloids of the Aspidosperma and Hunteria types, Fuji and co-workers (157) presented a short synthesis of (-)-eburnamonine [ (-)-81 (Scheme 33). (S )-Lactone 226, prepared from a previously described intermediate (158), was condensed with tryptamine to the diastereomeric lactam alco- hols 227 and 228 (1 : 1 ; 227 could be epimerized to 228). The cis-alcohol 228 was oxidized to the known dilactam 71, which was then converted to (-)-eburnamonine [ (-)-81 in the usual manner. Alternatively, the lactam carbonyl of compound 228 was first reduced with LiA1H4 and the product oxidized to (-)-eburnamonine.
84% COOH H
ii HO i \ 228
\ - 226 227
\ \ 71 (-1-8
SCHEME 33. Fuji et a/ . synthesis of (-)-eburnamonine [(-MI. Reagents: i , tryptamine, AcOH, reflux. then NaOH/MeOH; ii , epimerization with BF3.0Et2; iii, Cr03, pyridine; iv, LiAIH4, Et20, then iii.
C. SYNTHESES OF EBURNAMENINE Synthetic routes to eburnamenine (4) itself are few in number because
the alkaloid is easily obtained via dehydration from eburnamine (1). This facile method of preparation has been used by several groups ( I 7,18,22).
44 MAURl LOUNASMAA AND ART0 TOLVANEN
I. Coffen et al. Synthesis of (2)-Dihydroeburnamenine (237)
The first independent approach to the eburnamenine skeleton was that of Coffen and co-workers (159), who in 1974 synthesized racemic di- hydroeburnamenine (237), an alkaloid isolated from natural sources only recently (see Section IX). The starting indole 229, prepared from 2- fluorobenzaldehyde and 2-quinuclidone hydrochloride via a benzylidene- quinuclidone rearrangement, was converted in eight steps to the target compound 237 (Scheme 34).
2. Takano el al. Synthesis of (2)-Eburnamenine (4)
Three years later, in 1977, Takano and co-workers (160) presented a novel synthesis of racemic eburnamenine (4) (Scheme 35). Tryptamine was condensed with the key lactone 238 to afford amide 239. Compound 239 was cyclized with phosphorus oxychloride, and the product was iso- lated as iminium perchlorate 240. Reduction of 240 with a bulky reagent, lithium tri-tert-butoxyaluminum hydride, gave a single diastereomer 241, and cleavage of the dithiane group led directly to eburnamenine (4).
229 230 23 1
56%
237
SCHEME 34. Coffen et a/ . synthesis of (5)-dihydroeburnamenine (237). Reagents: i, acryl- amide, terr-BuOK, dioxane/EtOH, reflux; ii, aq. HCHO. aq. Me2NH, AcOH, EtOH, reflux; iii, Met, DMSO, 50°C then aq. NaCN, 100°C. I hr; iv, B2Hb, THF, then c o w HCI, EtOH; v. Hg(OAc)2, disodium ethylenediaminetetraacetic acid (Na2EDTA), HzO, 100°C; vi, Zn, AcOH; vii, Fktizon reagent, benzene. reflux. 4 days: viii, 97% NH2NH2, EtOH, reflux, then KOH, HOCH2CH20H, reflux.
1. EBURNAMINE-VINCAMINE ALKALOIDS 45
238 239 240
241 4
SCHEME 35. Takano et ul. synthesis of (&)-eburnamenine (4). Reagents: i , tryptamine, 160°C; ii, POC13, reflux, then CH2Cl2, reflux, then aq. LiCIO,; iii, LiAl(tert-BuO),H, THF; iv, Mel, aq. CH,CN.
A few years later Takano’s group succeeded in an enantioselective synthesis of (-)-eburnamenine [ (-)-41 (161). From lactone 242 (162) the key intermediate, dithianelactone (+)-238, was obtained in six steps (Scheme 36). The optically active dithianamine (3 -241 was then prepared from (+)-238 and converted to (-)-eburnamenine [ (-)-41, and to (+)-eburnamine [ (+)-11 and (-)-eburnamonine [ (-)-81. Other asymmetric synthetic routes to intermediate 250 have been formulated by groups led by Fuji (157), Meyers (163, and Fukumoto (164).
D. PARTIAL SYNTHESES OF EBURNAMONINE
1. Cartier et al. Synthesis of (-)-Eburnamonine [ (3 -81
Cartier and co-workers (165) transformed the previously prepared ho- moeburnamonine (251) (166) to (-)-eburnamonine [vincamone, (-1-81 via Beckmann rearrangement of oxime 252 (Scheme 37).
2. Lewin and Poisson Synthesis of (-)-Eburnamonine [ (-)-81
Lewin and Poisson (167) successfully converted (+)-apovincamine [( +)-331 to (-)-eburnamonine [vincamone, (-)-81. (+)-Apovincamine was saponified to acid 253, which was subsequently treated with bromine (Scheme 38). Intermediate 254 that formed was then subjected to acid treatment; after decarboxylation and elimination, (-)-eburnamonine was obtained.
46 MAURI LOUNASMAA A N D A R T 0 TOLVANEN
TrO I - 65% 86%
244 L
242 243
LOHC-l."JTZ TZ vi
\ 249
250
\
(+)-238
SCHEME 36. Takano et al. asymmetric synthesis of lactone 238. Reagents: i , LDA. ally1 bromide, THF; ii, LDA, EtBr, THF; iii, B2H6.Me2S, cyclohexene, THF, then aq. NaOH, H202, EtOH, 50"C, then aq. NaOH/MeOH, reflux; iv, conc HCI, MeOH; v, NaOH, aq. MeOH, then COz, aq. NaI04; vi, HSCHzCH2CHzSH, 4-TsOH. toluene, reflux. Tr stands for trityl (triphenylmethyl).
31 % 40%
\ 214 \
25 1
SCHEME 37. Cartier ef al. synthesis of (-)-eburnamonine [(-)-81. Reagents: i, terf- BuONO; ii, P0Cl3, pyridine, -10°C + room temperature; iii, KOH/MeOH, reflux, then conc HCI (pH I), reflux.
1. EBURNAMINE-VINCAMINE ALKALOIDS 47
\ HOOC+
\ M e O O C w
253 \ (+)-33
254
... Ill
SCHEME 38. Lewin and Poisson synthesis of (-)-eburnamonine [(-)-8] from (+)-apovin- camine [(+)-331. Reagents: i , saponification; ii , Br2, H 2 0 ; iii, 0.2 N HCI, IOO'C, 48 hr.
E. SYNTHESES OF VINCAMINE 1. Kuehne Synthesis of (2)-Vincamine (2)
The pioneering work on the synthesis of vincamine (2) was carried out by Kuehne (168) in 1964 startingfrom aldehyde ester 256 (Scheme 39). The important intermediate 259 ("Kuehne's intermediate") was later synthe- sized by several other routes (vide infra). The low yield (3%) of the final oxidation of 259 is a major drawback of Kuehne's approach, but improve- ments have been made by other workers (vide infra).
COQMe
MeOOC MeOOC \ 258 \
256 257
3%
MeOOC \ 2 -\
259
MeOOC aw 2
H \ MeOOC
\ 259
SCHEME 39. Kuehne synthesis of (?)-vincamine (2). Reagents: i , tryptamine, H', room temperature, then heat; ii, PS5; iii, separation of diastereomers; iv, Raney Ni; v , 4- nitrosodimethylaniline, triphenylmethylsodium, then acid hydrolysis.
48 MAURI LOUNASMAA A N D ART0 TOLVANEN
2. Gibson and Saxton Synthesis of (*)-Vincamine (2)
The preliminary paper describing the following approach to (2)-vinca- mine (2) appeared in 1969 (169) (Scheme 40). The key intermediate, homo- eburnamenine (88), was prepared earlier in connection with the authors’ synthesis of eburnamine (cf. Scheme 5,88 drawn as its optical antipode). The full experimental details were reported in 1977 (170).
~ j L @ J & L ~ 2 2 37% HO 81% 6%
HO \ HO \ 26 1 260
\ 88
SCHEME 40. Gibson and Saxton synthesis of (?)-vincamine (2). Reagents: i , 0 ~ 0 4 , pyri- dine. NazSzOr; i i , SO,.pyridine, wet DMSO, Et,N: i i i , NaOH, MeOH; iv, CH2N2, EbO.
3. Potier et ul. Synthesis of (+)-Vincamine (2) and (2)-Desethylvincamine (266)
Potier and co-workers, in 1972, were the first to report use of Wenkert’s enamine (92) and its desethyl analog 153 (cf. Scheme 19) in a synthesis of (2)-vincamine (2) and (+)-desethylvincamine (265), respectively (Scheme 41) (171). q jL 5 r - L 3 ill_ ...
R H2C
MeOOC R H2C
MeOOC 92 (R=Et) 263 264 153 (R=H)
2
266
(I)-vincamine (R=Et), 25% f r o m 92
(i)-desethylvincamine (R=H), 30% f r o m 153
SCHEME 41. Potier CI al. synthesis of (2bvincamine (2) and (2)-desethylvincamine (265). Reagents: i , CHZ=C(CH2Br)COOMe; i i , NaBH,; i i i . Os04, H104.
I . EBURNAMINE-VINCAMINE ALKALOIDS 49
4. Szantay et al. Synthesis of (+)-Vincamine (2) and (+)-Vincamine [(+)-21
Another approach to vincamine (2) via Wenkert’s enamine (92) was reported by the Hungarian group led by Szantay in 1973 (172). By the time their full paper appeared in 1977 (132), they had accomplished an asym- metric modification of the route (Scheme 42).
...
70% 05% ROOC ROOC
AcO AcO \ 92 266 267
(-)-vincamine (R=(-)-rnenthyl)
MeOOC
HO \ 268
SCHEME 42. Szintay et a / . synthesis of (2)-vincamine (2) and (+)+incarnine [(+)-2l. Reagents: i , methyl or (-)-menthy1 ester of a-acetoxyacrylic acid, room temperature, then 70% HCIO,; ii, H2, Pd/C, MeOH; i i i , HCVMeOH; iv, Ag2C03/Celite. xylene. reflux.
5. Schlessinger et al. Synthesis of (?)-Vincamine (2)
Schlessinger and co-workers used the same lactam (90) in their vinca- mine synthesis as earlier in their synthesis of eburnamine (1) (138,173) (Scheme 43).
6. Oppolzer et al. First Synthesis of (+)-Vincamine [(+)-21
In their first asymmetric synthesis of (+)-vincamine [ (+)-21, Oppolzer and co-workers used a chiral tricyclic aldehyde intermediate (277) (1 74). As the final step, (+)-vincamine was synthesized from apovincamine (33) (Scheme 44).
7. Oppolzer et al. Second Synthesis of (+)-Vincamine [(+)-21
The key intermediate in the second asymmetric synthesis by Oppolzer and co-workers (175) was the tetracyclic aldehyde 286 (“Oppolzer’s al- dehyde”), later used in other approaches to vincamine and its derivatives.
50 MAURI LOUNASMAA AND ART0 TOLVANEN
I 90
98% I 93% %loLiii 99%
MeOOC MeOOC
MeS M eS 269 270
95% 98% 05%
MeOOC MeOOC
Me -S \ I I 273 0
\ MeS 27 1
SCHEME 43. Schlessinger et al. synthesis of (2)-vincamine (2). Reagents: i , LDA, methyl 2-methylthioacrylate, THF; i i , POCI,, CH,CN, reflux, then aq. LiCIO,; iii, LiAl(tert- BuO),H, THF; iv, m-CPBA; v, NaH, THF; vi, AcCI, then NaOMe/MeOH.
An interesting modification of the Mannich reaction was employed in the preparation of this compound (Scheme 45). The synthesis of vincamine proceeded via Kuehne’s intermediate (259), with a known method being used to create the a-oxolactam 288.
8. Other Routes to Oppolzer’s Aldehyde (286)
Since the first synthesis of aldehyde 286 by Oppolzer et al., four other approaches have been presented. These are briefly discussed below.
a. Danieli et al. A short and efficient route to aldehyde 286 starting from Wenkert’s enamine (92) was published by Danieli et al. (134,176) (Scheme 46). Iminium perchlorate 91 was refluxed with formalin in the presence of Hunig’s base (N-ethyldiisopropylamine) in acetonitrile, affor- ding alcohol 216 directly. Oxidation (Swern or Pfitzner-Moffatt) of 216 gave aldehyde 286, and this was then equilibrated to a mixture of al- dehydes 285 and 286, from which the desired cis isomer 286 was separated by chromatography.
The first synthesis of aldehyde 286 to bypass the somewhat tedious equilibration-separation process of the two
b. Govindachari and Rajeswari.
1. EBURNAMINE-VINCAMINE ALKALOIDS 51
COOEt
(Et0)2H L O T S : i
\ 51 %
274 275
276
SCHEME 44. Oppolzer et a / . first synthesis of (+)-vincarnine [(+)-2]. Reagents: i , trypt- arnine; ii , imidazole, 130°C; iii, aq. AcOH; iv, (MeO)2POCH(OMe)COOMe, NaH, THF; v, P0Cl3, then aq. NaC10,; vi, H2, Pd/C. CH,CI,/EtOH, H20 , Et3N; vii, HBdAcOH; viii, HBr,, -78°C; ix, 10 N aq. KOH.
former methods was presented by Govindachari and Rajeswari (177) (Scheme 47). Oxoester 289, prepared from diethyl ethylmalonate and acrolein via Michael addition, was condensed with tryptamine to an imine, which was immediately reduced with NaBH4 to give the secondary amine 290. Cyclization of 290 to lactam 291 was effected in refluxing xylene, with a Dean-Stark trap used to remove the methanol that formed. Bischler- Napieralski cyclization of 291, followed by treatment with aqueous Li- C104, afforded the perchlorate salt 292. Several methods to reduce this salt were presented. High stereoselectivity was achieved when salt 292 was subjected to catalytic hydrogenation to yield the target cis-ester 293. Stan- dard LiA1H4 reduction of 293 gave alcohol 294, which was subsequently converted to Oppolzer’s aldehyde (286) via Pfitzner-Moffatt oxidation.
A 3 E r H C-0-SiMe -t m N -[y$]- 74%
ll f J Me3Si -0-C-
H
282 283 Br- 284
40% 86% 68%
OHC
285 286
\ 287
\ 286 \
83% 68% 29%
MeOOC HO-
252 \ 25 1 \ 259
SCHEME 45. Oppolzer et a/. second synthesis of (+)-vincamine [(+)-2]. Reagents: i, (iPr)2NEt, DMF; ii, separation of diastereomers: i i i , resolution with (+)-malic acid; iv, (Et0)2POCH2COOEt, NaH, DMF; v, H2, PdlC, EtOH: vi. (Me3W2NNa; vii, tert- BuONO, (Me3W2NNa, toluene; viii, aq. HCHO/aq. HCI or (NH4)2Ce(N03)6/MeOH; ix, NaOMe/MeOH.
...
95% 88%
\ 91 216 285
- \
L 45% WN, O H C W
286 \
SCHEME 46. Danieli et a/. synthesis of Oppolzer’s aldehyde (286). Reagents: i, aq. HCHO, N-ethyldiisopropylamine, CH3CN, reflux; ii, dicyclohexylcarbodiimide (DCC), DMSO, H3P04; iii, tert-BuOK, tert-BuOH; 40°C; iv, separation of isomers.
1. EBURNAMINE-VINCAMINE ALKALOIDS 53
...
EtOOC
29 1
EtOOC
EtOOC 289 290
CHO 75%
65% 100% 38%
EtOOC EtOOC
292 293 294 \
% OHC \
286
SCHEME 47. Govindachari and Rajeswari synthesis of Oppolzer's aldehyde (286). Re- agents: i , tryptamine, toluene, reflux, then NaBH,/MeOH; i i . xylene. reflux; i i i . POCI,. benzene, reflux, then aq. LiCIO,; iv. H2. PdlC. MeOH, Et3N: v, LiAIH,. THF; vi. DCC, DMSO, H,P04.
c. Langlois er ul. Langlois's group meanwhile announced their highly stereoselective route to aldehyde 286. Two alternative key reactions were offered: photolysis of oxaziridines (178) and, in particular, an imino- Diels-Alder reaction (179). In the imino-Diels-Alder reaction, imine 283 was reacted with methyl pentadienoate to a mixture of esters 295 and 296 (Scheme 48). The ester mixture was deprotonated with LDA-HMPA and alkylated with ethyl iodide to give indoloquinolizidine 297. Hydrogenation in the presence of Raney Ni gave the saturated ester 298. This was reduced with LiAlH4 to alcohol 294, which then was oxidized with S03-pyridine/ DMSO to aldehyde 286, smoothly and in high yield.
Rapoport and co-workers (180) presented the first enantioselective route to aldehyde (-)-286 (Scheme 49). Chiral diester 299, prepared via several routes from L-aspartic acid, was alkylated with tryptophyl bromide to give 300. This compound was cyclized to a 1 : 5.7 mixture of indoloquinolizidine 298 and its 2 I-epimer (which was efficiently recycled to 298) by hydrolyzing the rert-butyl ester moiety and treating the crude acid with PhPOC12. The tetracyclic ester 298 was then converted to aldehyde (-)-286 in the manner described above (cf. Scheme 48).
d. Rupoport et al.
54 MAURI LOUNASMAA A N D ART0 TOLVANEN
I __t
69% 70% H
MeOOC MeOOC
283 295 296
96% 96% 90%
MeOOC
297 294 \ 298 \
O H C W \
286
SCHEME 48. Langlois et al. synthesis of Oppolzer's aldehyde (286). Reagents: i , methyl pentadienoate, chlorobenzene, 120°C; ii , LDA, THF, HMPA, EtI; iii, Raney Ni; iv, LiAIH4, THF; v , S03.pyridine, DMSO, Et3N.
/ iii
9 6% -
MeOOC
298 \
H
299 300
q c - p Q n & HOCH2 i OHC
\ (-)-286 \
294
SCHEME 49. Rapoport et al. asymmetric synthesis of Oppolzer's aldehyde [ (-)-286]. Reagents: i , tryptophyl bromide, NaHC03, CH3CN, 70°C, 21 hr; ii , AcOH, i-PrOH, HzO, 100"C, 15 hr, then PhPOClz, 100"C, 15 min; iii, LiA1H4, THF; iv, S03.pyridine, DMSO, Et,N.
1. EBURNAMINE-VINCAMINE ALKALOIDS 55
9. Wenkert el al. Synthesis of (+)-Vincamine [ (+)-21
Another route to (+)-vincamine [ (+)-21 using Wenkert’s enamine (92) as starting material appeared in 1982 (181) (Scheme 50). Alkylation of 92 with methyl bromopyruvate 2,4-dinitrophenylhydrazone (301) gave salt 302, and, because of the bulky side chain, KBH4 reduction of this afforded exclusively the cis product 303. The optically active hydrazone (+)-303, obtained after resolution with (-)-0,O-dibenzoyltartaric acid, was re- duced with iron in methanolic hydrogen chloride. Immediate nitrosation of the intermediate amines with aqueous NaN02 gave (+)-vincamine (2) [54% yield from (+)-3031.
NH 93% 70% MeOOC
92
SCHEME 50. Wenkert et al. synthesis of (+)-vincamine [(+)-21. Reagents: i, Et3N, EtOAc; ii, KBH4, CH3CN. AcOH; iii, resolution with (-)-0,O-dibenzoyltartaric acid; iv, Fe powder, HCUMeOH, then aq. NaNOz.
10. Langlois er al. Synthesis of (+)-Vincamine (2)
The novel approach of Langlois er af. to Oppolzer’s aldehyde (286) (uide supra) was the basis for their synthesis of (*)-vincamine (2) (179). A direct conversion of aldehyde 286 to vincamine (2) was achieved by condensing 286 with an enolate of methyl isocyanoacetate, followed by acidic and basic workup. In a one-pot experiment, (+-)-vincamine was obtained in 45% yield from 286. Better yields were obtained, however, by isolating the intermediate lactam 308 and treating it consecutively with methanolic hydrogen chloride and sodium carbonate. The different stages of this elegant synthesis are detailed in Scheme 5 1 .
56 MAURl LOUNASMAA A N D ART0 TOLVANEN
309 -. L
SCHEME 51. Langlois et al. synthesis of (?)-vincamine (2). Reagents: i , CNCH2- COOCH3, rert-BuOK; ii. H20 ; iii. HCI/MeOH; iv, Na2C03/MeOH; v , H20.
1 1. Trojanek et al. Synthesis of (+)-Vincamine (2)
The reaction between Wenkert's enamine (92) and 2-chloroacrylonitrile, exploited earlier in a synthesis of the eburna skeleton (cf. Scheme 1 3 , was reexamined by Trojanek and co-workers (182) (Scheme 52). The initially obtained salt 133, isolated as a perchlorate, was found to be a mixture of epimers. Reduction of 133 with zinc dust in aqueous acetic acid afforded a mixture of four nitriles, from which the target diastereomer 312 was sepa- rated. Hydrolysis and subsequent esterification with diazomethane gave deoxyvincamine (313, 41%) epimeric at C-16, together with the corre- sponding amide (27%) of retained configuration. This was transformed to 313 by alkaline hydrolysis and esterification. In the final step of the synthe- sis the LDA enolate of ester 313 was oxidized with MOOS * Py * HMPA complex to introduce the hydroxyl group. Unfortunately, the hydroxyl
1. EBURNAMINE-VINCAMINE ALKALOIDS 57
SCHEME 52. Trojanek eta/ . synthesis of (*)-vincamine (2). Reagents: i, 2-chloroacryloni- trile, CH2CI2: i i , Zn dust, aq. AcOH; i i i , separation of isomers: iv, conc HCI, reflux. then CHIN2; V , LDA, MoO5.Py.HMPA (Py is pyridine).
approaches mainly from the less hindered bottom side, producing a 1 : 8 mixture of (+)-vincamine (2) and its 16-epimer (43).
12. Lounasmaa and Tolvanen Synthesis of (+)-Vincamine (2)
Another approach to (2)-vincamine (2) starting from Oppolzer’s al- dehyde (286) was recently reported by Lounasmaa and Tolvanen (183) (Scheme 53). Methyl (dimethy1amino)acetate was used as a condensing reagent to transform aldehyde 286 to the a-oxolactam 288, a known pre-
-
49%
OHC
286 M e N
315 \ - Me2N OH \
314
78% MeOOC 11*1 -
\ 2 -\ 31 1
\ 288
0
... 111
96%
SCHEME 53. Lounasmaaand Tolvanen synthesis of (2)-vincamine (2). Reagents: i , LDA, Me2NCH2COOMe, THF, DMSO; ii, Ac20, pyridine, DMAP; iii, AcOH/H20: iv, Na2C03/ MeOH.
58 MAURI LOUNASMAA AND A R T 0 TOLVANEN
cursor of vincamine. The reaction of 286 with an LDA enolate of methyl (dimethy1amino)acetate gave a-dimethylamino-P-hydroxylactam 314. De- hydration of 314 with Ac20/pyridine/DMAP afforded the labile enamino- lactam 315, which was hydrolyzed without isolation to the known oxo- lactam 288. Conversion of 314 to 288 proceeded in nearly quantitative yield, and an 8 : 1 mixture of (-+)-vincamine (2) and (r)-16-epivincamine (43) was obtained after base-catalyzed ring opening of 288 and subsequent ring closure of intermediate 311.
13. Rapoport et al. Synthesis of (+)-Vincamine [(+)-2]
Rapoport and co-workers (180), after developing an efficient synthesis of Oppolzer’s aldehyde in optically pure form [(-)-2861 (cf. Scheme 491, used the method of Langlois et af. (cf. Scheme 51) to convert (-)-286 to (+)-vincamine [ (+)-21 (Scheme 54).
OHC MeOOC 1-
~
\ H \ (+)-2
OHC-HN 308 (-)-266
SCHEME 54. Rapoport et a / . synthesis of (+)-vincarnine [ (+ ) -2 ] . Reagents: i, CNCH2- COOCH3, tert-BuOK, THF; ii, HCI/MeOH, reflux, 4 hr, then Na2C03/MeOH.
F. FORMAL SYNTHESES OF VINCAMINE
Homoeburnamonine (251) and Kuehne’s intermediate (259) are the most common key intermediates in the reported formal syntheses of vincamine.
1. Buzas et al. Synthesis of (+)-Homoeburnamonine (251)
Buzas and co-workers (184) synthesized the important vincamine inter- mediates 251 and 88 by exploiting the reaction of Wenkert’s enamine (92) with acrolein (Scheme 55) after the manner of Schut et al. (185) in the desethyl series. From iminium perchlorate 91 as the starting compound, the pentacyclic salt 316 was obtained in 94% yield. Reduction of salt 316 with Zn in aqueous acetic acid gave homoeburnamine (317), and chromic oxidation of this permitted the isolation of homoeburnamonine (251), a precursor in many vincamine syntheses. Dehydration of homoeburnamine (317) was effected in refluxing toluene to afford homoeburnamenine (88), which has been converted to (+)-vincamine (2) by Gibson and Saxton (vide supra).
59 1. EBURNAMINE-VINCAMINE ALKALOIDS
\ 88
\ 25 1
SCHEME 55. Buzas et ul. synthesis of (2)-homoeburnamonine (251). Reagents: i , CH2=CH-CHO, Et3N, CH2CI2, room temperature: i i . Zn powder, aq. AcOH: iii, toluene, reflux; iv, Cr03, pyridine, Et3N; v, LiAIH4, THF.
2 . Szantay et al. Synthesis of Kuehne’s Intermediate (259)
The Pictet-Spengler reaction between 2-(ethoxycarbony1)tryptamine and aldehyde 256 was investigated by Szantay and co-workers (186) (Scheme 56). Although the approach offered a short entry to Kuehne’s intermediate (259), it suffered from poor selectivity and low yields.
I--- 7
OHC COOMe %&... MeOOC
256 319 \
O H C 6 C O O M e i_ T N H OOHY 3 ‘I-& ’r o & 259
256
SCHEME 56. Szantay et ul. synthesis of Kuehne’s intermediate (259). Reagents: i , 2- (ethoxycarbonyl)tryptamine, AcOH, reflux; i i , AcOH, reflux, then conc H2S04/MeOH and separation of isomers; iii, P4S10, then Raney Ni.
3. Irie and Ban Synthesis of (2)-Homoeburnamonine (251)
Extending their studies on the electrochemical synthesis of amino- lactones started in the eburnane series (cf. Scheme 25), Irie and Ban (187) prepared piperidine acid 320 via Arndt-Eistert reaction from 188. This acid was then converted in five steps to imino ester325 (Scheme 57). Imino ester 325 was subsequently transformed to (+)-homoeburnamonine (251) in two steps (Scheme 58). Alkylation of 325 with tryptophyl bromide gave, after separation of isomers, Kuehne’s intermediate (259), which was cy- clized with base to 251 according to Oppolzer et af. (175) in 11% total yield.
60 MAURI LOUNASMAA A N D A R T 0 TOLVANEN
...
COOMe I kO8Me
320 321 322
cflo kOflMe boo] -& h 0 O M e
323 324 325
SCHEME 57. Irie and Ban synthesis of iminoester 325. Reagents: i , 30 mA, 8.2 F/mol, EtdN+ C104-, MeOH; ii, HCOOH; iii, H2, Pt02, EtOAc; iv, KOH, aq. dioxane, 18-crown-6; V, CH2N2.
4. SzAntay et al. Syntheses of (+)-Homoeburnamonine [ (+)-2511
Two enantioselective routes to (+)-homoeburnamonine [ (+ )-2511 were developed by Szantay and co-workers (188). In the first route (Scheme 59) iminium perchlorate 329, prepared in two steps from L-tryptophan methyl ester hydrochloride and 2-ethyl-5-chlorovaleroyl chloride (327), was reac- ted with diethyl methylenemalonate to give salt 330. Hydrolysis of 330, first with acid and then with alkali, afforded, after treatment with perchlo- ric acid, diacid 331, which on heating to 160-170°C in decalin lost COZ from the chiral carbon. Thus, the monocarboxylic acid 332 was obtained in
70%
MeOOC \
325 326 259
\ 25 1
SCHEME 58. Irie and Ban synthesis of (2)-homoeburnamonine (251). Reagents: i , trypto- phyl bromide, toluene, reflux, then separation of isomers; ii , (Me3W2NLi, toluene, room temperature.
1. EBURNAMINE-VINCAMINE ALKALOIDS 61
COOMe iii
97% __c
327 328 329
d d 40% / 92% 97%
HOOC HOOC MeOOC
MeOOC \ 332
\ 33 1 \
330
\ (+)-25 1
SCHEME 59. Szantay et C J ~ . synthesis of (+)-homoeburnamonine [ (+)-251]. Reagents: i , L-tryptophan methyl ester hydrochloride, pyridine; i i , P0Cl3, benzene, reflux, then 70% HCIO,; iii, CHZ=C(COOEt)2, tert-BuOK, CH,CI,; iv, 10% HCI, EtOH. reflux, then NaOH/ EtOH, then 70% HCIO,; v , decalin, 160-170°C; vi. H,. Pd/C, DMF, then P0Cl3, room temperature, followed by basification.
nearly quantitative yield. Hydrogenation of 332 in DMF, followed by treatment of the epimeric acid mixture with POCI3 to effect intramolecular acylation, gave (+)-homoeburnamonine [ (+)-2511 as the dominant isomer, in addition to its trans isomer.
The alternative route of Szantay et al. to (+)-331 (Scheme 60) (188) was a modification of the hornoeburnamine synthesis by Buzas and co-workers (cf. Scheme 55) . The reaction of iminium perchlorate 329 with acrolein gave adduct 333, which was oxidized to lactam 334 with slight racemi- zation. Cleavage of the lactam ring of 334 with aqueous ethanolic NaOH resulted in the formation of the diacid (+)-331 in 68% yield.
5 . Takano et al. Synthesis of (+)-Homoeburnamonine [(+)-2511
Takano and co-workers developed an enantioselective entry to (+)- homoeburnamonine [ (+)-2511 (189). The non-indole starting material in this synthesis (Scheme 61) was the chiral hydroxylactone 335, which was condensed with tryptamine to give amide 83 (cf. Scheme 5) . Sodium periodate cleavage of the glycol moiety of 83 afforded the epimeric mixture 84 via dialdehyde 336. Racemic 84 had previously been used in the eburna-
62 MAURI LOUNASMAA A N D A R T 0 TOLVANEN
COOMe COOMe
56% 68% (+)-331
\ 329 333 \ 334
SCHEME 60. Szkntay et al. synthesis of (+)-331. Reagents: i, acrolein, CHzClz, tert- BuOK; ii, Cr03/silica gel; iii, aq. NaOH/EtOH, then 70% HC104.
mine synthesis by Gibson and Saxton (128). Differing from their approach, however, Takano et af. cyclized hemiacetal84 with a catalytic amount of 4-toluenesulfonic acid in refluxing methanol to the two methoxylactams 337 (28%) and 338 (34%). The unwanted trans-lactam 337 could be con- verted to the desired cis-lactam 338 by reexposing it to the same cycli- zation conditions. Finally, compound 338 was reduced with borane/ dimethyl sulfide to methoxy derivative 339, which was hydrolyzed with pyridinium 4-toluenesulfonate in refluxing THF; the amino alcohol ob- tained was then oxidized with pyridinium dichromate to (+)-homoeburna- monine [ (+)-2511.
\ 339
v-vi
51 % -
\ (+)-25 1
SCHEME 61. Takano et a / . synthesis of (+)-homoeburnamonine [ (+)-251]. Reagents: i, tryptamine, Me3AI, benzene, reflux; ii, NaI04, aq. MeOH; iii, 4-TsOH, MeOH, reflux; iv, B2H,/Me2S, THF, reflux; v, pyridinium 4-toluenesulfonate (PPTS), aq. THF, reflux; vi, pyridinium dichromate (PDC), CH2Cl2.
1. EBURNAMINE-VINCAMINE ALKALOIDS 63
6. Lounasmaa and Jokela Synthesis of Kuehne’s Intermediate (259)
Lounasmaa and Jokela (190) applied the modified Polonovski reaction in a short synthesis of Kuehne’s vincamine intermediate (259) (Scheme 62). The protected a-aminonitrile 340 was converted to its enamine equivalent 341, and this was alkylated with methyl acrylate. Acid-induced cyclization gave a 1 : 1 mixture of compound 259 and its 21-epimer.
340
1:l MeOOC
I 34 1
epimer
SCHEME 62. Lounasmaa and Jokela synthesis of Kuehne’s intermediate (259). Reagents: i , AgBF4, 1,2-dichIoroethane; ii , CH2=CHCOOMe, CHzClz, MeOH; iii, HCUMeOH.
G . PARTIAL SYNTHESIS OF VINCAMINE AND DERIVATIVES FROM
ASPIDOSPERMA BASES
Le Men and co-workers (191) found in 1972 that the Aspidosperma base (-)-vincadifformine [ (3-3431 rearranged under oxidative conditions to (+)-vincamine [ (+)-21 and derivatives, thus supporting in virro the pre- sumed biogenetic connections between the Aspidosperma and Vinca alkaloids (192). Variations of their method have appeared since in the lit- erature, and many of them are used in the commercial production of (+)- vincamine. The more important reactions are briefly reviewed here; for a more complete description, see Saxton’s review (193).
1. Peracid Oxidation of (-)-Vincadifformine [ (-)-3431
Initially, Le Men and colleagues oxidized (-)-vincadifformine [ (- 1-3431 with lead tetraacetate, which, after acid treatment, yielded a mixture of (+)-vincamine [ (+)-21 (36%), (-)-16-epivincamine [ (-1-431, and (+)-apovincamine [ (+)-331 (191). When 4-nitroperbenzoic acid was used as oxidant, (+)-vincamine and (-)-16-epivincamine were obtained in 66 and 21% yield, respectively (Scheme 63). Zsadon and co-workers (194)
64 MAURI LOUNASMAA A N D A R T 0 TOLVANEN
0-
(-)-343 344 345
SCHEME 63. Le Men et a / . synthesis of (+)-vincarnine [(+)-2] from (-)-vincadifforrnine [(-)-3431. Reagents: i , 4-nitroperbenzoic acid; i i , Ph3P, AcOH.
investigated this rearrangement reaction using perbenzoic acid as oxidant. Yields of (+)-vincamine and its Ibepimer were about the same as in the method of Le Men et a / .
2. Copper Sulfate-Induced Oxidation of (-)-Vincadifformine [ (3-3431
A single-step oxidation procedure for converting (-)-vincadifformine [ (3-3431 to (+)-vincamine [ (+)-21 and (-)- 16-epivincamine [ (9-431 was introduced by Paracchini and Pesce (195). The two alkaloids were formed in 30 and 15% yield, respectively, when (-)-343 was heated in aqueous hydrochloric acid in the presence of copper sulfate pentahydrate with oxygen being bubbled through the solution.
3. Ozonization of (-)-Vincadifformine [ (-)-3431 and (-)-Tabersonine [ W-3471
A milder modification of the above rearrangement was investigated by Danieli and co-workers (196). When (-)-vincadifformine [ (3-3431 was subjected to ozonization at room temperature, hydroxyindolenine 345 was obtained in 78% yield. When the reaction was conducted at elevated
I . EBURNAMINE-VINCAMINE ALKALOIDS 65
temperature (60"C), a 7 : 3 mixture of (+)-vincamine and its 16-epimer was directly formed in 74% yield. Similarly, (-)-tabersonine [ (9-3471 gave a 14,15-dehydro derivative of 345 or (+)-14,15-dehydrovincamine [ (+)-351 and its 16-epimer [ (+)-361, depending on temperature.
(-)-347
4. Photooxidation of (-)-Vincadifformine [ (- )-3431
Levy and co-workers (297) irradiated the hydrochloride of (-)-vinca- difformine [ (-)-3431 in methanol using methylene blue as a sensitizer (Scheme 64). Oxindole 350 was obtained as the main product (40%), in addition to a 5 : 1 mixture (10%) of (+)-vincamine [(+)-21 and (-1-16- epivincamine [ (3-431. Mechanistically, the reaction was suggested to proceed via intermediate 345.
Danieli and colleagues (198) studied the same reaction and found that a dye-sensitized photooxidation of (-)-vincadifformine [ (3-3431 gave (+)-vincamine [ (+)-21 in good yield. Irradiation of (-)-343 in aqueous methanol with Rose Bengal as a sensitizer, in the presence of sodium thiosulfite and 2 N NaOH, allowed the intermediate hydroxyindolenine
__t 345 - ( + ) - Z + (-1-43
OOMe
(-)-343 348
OOMe
L 349 350
SCHEME 64. Levy e t a / . photooxidation of (-)-vincadifforrnine hydrochloride [ (-)-M3]. Reagents: i , hv, rnethylene blue. MeOH.
66 MAURI LOUNASMAA A N D A R T 0 TOLVANEN
345 (82%) to be isolated. However, if the irradiated solution was instead heated with aqueous acetic acid, (+)-vincamine [ (+)-21 and its 16-epimer [ (-)-431 were obtained in 46 and 30% yield, respectively.
5. Thermal Rearrangements
Hugel and LCvy (199) found that the rearrangement of some compounds of the aspidospermane type to compounds of the vincane type also takes place under thermolytic conditions. As an example, compound 345 gave (+)-vincamine [ (+)-21, (-)-16-epivincamine [ (-)-431, (+)-apovincamine [ (+ 1-33], or (-)-eburnamonine [ (-)-81, depending on temperature.
6. Rearrangements of Nitroindolenines
Yet another rearrangement of (-)-vincadifformine [ (-)-343] was re- cently reported by Lewin and co-workers (200). (-)-Vincadifformine was converted to a 16-nitroindolenine, from which (-)-eburnamonine [(-)-81 was obtained in three steps. Rearrangements of the corresponding 16- chloroindolenines, leading to apovincamine, have been investigated by the same group (201,202).
7. Rearrangement via Radical Coupling
Fremy’s salt was used as an oxidant when Palmisano and co-workers (203) converted tabersonine (347), via several intermediates, to 1 4 , s dehydrovincamine (35) and its epimer (36). The mechanism of this skeletal rearrangement, proceeding via radical coupling at C- 16, was discussed.
H. PARTIAL SYNTHESES OF VINCAMINE FROM OTHER PRECURSORS
1. Lewin and Poisson Synthesis of (+)-Vincamine [ (+)-2] from (+)-Apovincamine [ (+)-331
In connection with their conversion of (+)-apovincamine [ (+)-331 to (-)-eburnamonine [vincamone, (-)-81 (cf. Scheme 38), Lewin and Poisson (167) transformed (+)-apovincamine [(+)-331 to (+)-vincamine [ (+)-21 in a three-step sequence (Scheme 65). Bromination of (+)-33 (perchlorate salt) in methanol gave intermediate 351, hydrogenolysis of which gave 0- methylvincamine 352 and small amounts of the starting apovincamine [ (+)-331. Mild acid hydrolysis of 352 furnished a 3 : 1 mixture of (+)-vinca- mine [ (+)-2] and (-)- 16-epivincamine [ (-)-431 in good overall yield from (+)-33.
1. EBURNAMINE-VINCAMINE ALKALOIDS 67
SCHEME 65. Lewin and Poisson synthesis of (+)-vincamine [ (+)-21 from (+)-apovin- camine [(+)-331. Reagents: i , Br,, MeOH, room temperature; ii, H,, PtOz, MeOH; iii, 0.5 N HCI, acetone.
2. Winterfeldt et af. Synthesis of (+)-Apovincaminal [ (+)-357]
An asymmetric route to both vincamine enantiomers was introduced by Winterfeldt and co-workers (143). Starting from the chiral cyclopropane (+)-141 (cf. Scheme 18), they obtained both (+)- and (-)-eburnamonine. A five-step transformation of (-)-eburnamonine [ (3-81 to (+ )-apovincami- nal [ (+)-357] was presented (Scheme 66). Methylenation of [ (-)-8], fol- lowed by radical bromination, yielded the unsaturated bromide 354. This was transformed, via acetate 355, to alcohol 356, which was oxidized to
70% 53% 92%
\ 354
\ 353 \
(-1-8
90% 75%
\ 357
\ 356 \
355
SCHEME 66. Winterfeldt et a / . synthesis of (+)-apovincaminal [ (+)-3571. Reagents: i. CH2Br2, Zn dust, TiCI4, THF, -78°C + 0°C; ii, N-bromosuccinimide (NBS). THF. room temperature; iii, KOAc, AcOH, reflux; iv, KOH/MeOH; v, MnO,, CH2CI2, room temper- ature.
68 MAURI LOUNASMAA A N D A R T 0 TOLVANEN
(+)-apovincaminal [ (+)-3571. Conversion of (+)-357 to (+)-2 had been reported earlier (174,204).
3. SzAntay et al. Synthesis of (+)-Vincamine [(+)-21 from (-)-Eburnamonine [ (-)-81
Szantay and colleagues (205) transformed (-)-eburnamonine [vinca- mone, (-)-8] to (+)-vincamine [(+)-21 in three simple steps, of which the final one was a diazomethane-assisted homologation (Scheme 67). (-)-Eburnamonine [ (-)-8] was oxidized to a-0x0 lactam 358, the lactam ring of 358 was opened with base, and the resulting a-0x0 acid 359 was treated with diazomethane to afford (+)-vincamine [ (+)-23 directly.
I. SYNTHESES OF APOVINCAMINE 1. Danieli et af. Synthesis of (+)-Apovincamine (33)
Danieli and co-workers (134) developed a direct conversion of Oppol- zer's aldehyde (286) to apovincamine (33) (Scheme 68). The reaction of aldehyde 286 with methyl chloroacetate in the presence of tert-BuOK gave the P-hydroxy ester 363. With a longer reaction time apovincamine (33) was obtained directly in 84% yield. A three-step transformation of apovin- camine (33) to vincamine (2) was also achieved. Hydrogenation of apovin- camine (33) gave a mixture of dihydroapovincamines 364 and 313, the base-catalyzed oxidation of which afforded 16-epivincamine (43). Sub- sequent base-induced epimerization of 43 in refluxing p-xylene yielded a thermodynamic mixture (8 : 2) of vincamine (2) and 16-epivincamine (43).
44% 98%
HOOC \ \ \
(-1-8 358 359
SCHEME 67. SzAntay et al. preparation of (+)+incarnine [ (+)-2] from (-)-eburnamonine [(-MI. Reagents: i, tert-BuONO, tert-BuOK. benzene, then 15% HCI, 100°C; ii, 10% NaOH. MeOH, 3 min; iii, CH2N2.
1. EBURNAMINE-VINCAMINE ALKALOIDS 69
84% 100%
OHC MeOOC ' \ \
286 363 33
364 313 43
SCHEME 68. Danieli cr al. synthesis of (2)-apovincamine (33) and (2)-vincamine (2). Reagents: i, methyl chloroacetate, terr-BuOK, benzene, room temperature; ii, Hz, Pd/C, MeOH; iii, Na/NH3 liquid, THF; iv, N,N,N',N'-tetramethylguanidine, p-xylene, reflux.
2. SzAntay et al. Syntheses of (+)-Apovincamine [(+)-331
SzBntay and collaborators have presented several routes to apovin- camine (33) in their series of synthetic studies on the Vinca alkaloids (206,207). Oximes (+)-252 {prepared from (+)-homoeburnamonine [(+)-2511, cf. Scheme 59} (208) and (+)-2l2 (after transesterification to its methyl analog, cf. Scheme 30) (154) were both transformed to (+)-33 by acid treatment.
3. Christie and Rapoport Synthesis of (+)-Apovincamine [ (+)-331
Christie and Rapoport (209) examined the use of pipecolic acid deriv- atives in the asymmetric synthesis of apovincamine [(+)-331 (Scheme 69). Optically pure pipecolate 365 (R = 1-phenylpropyl) was obtainable via several routes from L-asparagine. Alkylation of 365 with tryptophyl bro- mide, followed by hydrogenolysis, gave amino acid 366 (R = H), and cyclization of this with phenylphosphonic dichloride afforded a 3 : 2 mix- ture of tetracyclic nitrile 367 and its trans isomer. Alkylation of 367 with methyl bromoacetate at the indole nitrogen gave ester nitrile 368, which was converted to the p-0x0 ester 369 by treatment with base and acid hydrolysis. Reduction of 369 to alcohol 363 with NaBH4 and subsequent dehydration by mesylation/elimination furnished optically pure (+)- apovincamine [ (+)-331.
70 MAURI LOUNASMAA A N D A R T 0 TOLVANEN
ii iii
/ &CN
\ 365 366 367
56% 90% 55%
MeOOC MeOOC ~
368 369 363 \ 0 =\ O H \
\ (+)-33
SCHEME 69. Christie and Rapoport synthesis of (+)-apovincamine [(+)-331. Reagents: i , tryptophyl bromide, NaHC03, CH3CN, reflux; i i , H2, 50 psi, Pd/C, MeOH/EtOAc, then PhPOC12,95"C, then saturated NaHCO,. EtOAc, and separation of isomers; i i i , NaH, DMF, BrCH,COOMe; iv, LDA, -78°C; v, NaBH4, MeOH; vi, MsCI, Et,N, CH2C12, O T , then 1,8-diazabicyclo[5.4.O]undec-7-ene (DBU), 100°C.
J. SYNTHETIC STUDIES TOWARD CUANZINE
1. Danieli er al . Synthesis of Cuanzine Intermediate 378
The promising pharmacological effects of (-)-cuanzine [ (-)-55] in- spired Danieli's group to devise a synthesis of this hexacyclic alkaloid (21 0). Targeted at an aldehyde intermediate easily convertible to cuanzine ( 5 9 , the synthesis starts from 2-methoxyphenylhydrazine (370) (Scheme 70). Reaction of 370 with 2-methoxy- 1-tosylpyrrolidine in refluxing AcOH yielded the protected tryptamine derivative 371. Cyclization of 371 to imine 372 was performed by intramolecular sulfonamidomethylation, cleavage of the intermediate sulfonamide, and, finally, dehydrogenation with PhIO. Reaction of 372 with methyl pentadienoate gave a 1 : 1 mixture of isomers 373 and 374 in 69% yield. Alkylation of this mixture with BrCH2CH20THP was effected with potassium hydride in DMF. The re- sulting compound (375) was deprotected with acid, and lactonization took place directly, affording pentacycle 376. After reductian of 376 to diol377, the fifth ring was created by oxidizing the diol with Hg(0Ac)z in the
1. EBURNAMINE-VINCAMINE ALKALOIDS 71
i F H - T s G 2 69% IV
M e 0 P N H - N H z M e M e
370 37 1 372
95% Me
MeOOC
373 374 375
56% M e
376 377 378
SCHEME 70. Danieli et a / . synthesis of cuanzine intermediate 378. Reagents: i. 2- methoxy-I-tosylpyrrolidine, AcOH, reflux; ii, 1,3,5-trioxane, CHzClz, CH3S03H; iii, Red-Al [sodium bis(2-methoxyethoxy)aluminum hydride in toluene], THF, reflux, then PhlO, CH2- CIZ, room temperature; iv, methyl pentadienoate, PhCI, reflux; v, BrCH2CH20THP, KH. DMF, -25°C + room temperature; vi, 2 N HCI, aq. MeOH, room temperature; vii, LiAIH4. THF, 0°C; viii, Hg(OAc),, NaZEDTA, aq. THF, 90°C, then 2 N NaOH, NaBH4. THP is tetrahydropyranyl-.
presence of Na2EDTA. Subsequent reduction with NaBH4 gave the target pentacyclic alcohol 378.
2. Langlois et al. Synthesis of (_+)-12-Desmethoxycuanzine (389)
Langlois and co-workers recently applied their successful results in the synthesis of vincamine (2) (vide supra) to the preparation of a cuanzine analog (211) (Scheme 71). The mixture of indoloquinolizidines 295 and 296 (cf. Scheme 48) was alkylated with ICH2CH20THP to give ester 379. The ester group of 379 was then reduced to afford alcohol 380, which was acetylated to 381. The other hydroxyl group of 381 was deprotected, and the resulting alcohol 382 was subjected to cyclization. Treatment of 382 with 12-KI03 gave the pentacyclic iodoenamine 383. Hydrogenation of 383 over Pt02 in methanol, followed by hydrolysis of the reduced acetate 384, afforded alcohol 385 in high yield. Alcohol 385 was then oxidized (SO3. pyridine, DMSO) to the key aldehyde 386, an analog of Oppolzer's aldehyde (286).
72 MAURI LOUNASMAA AND ART0 TOLVANEN
... 295 + 298 - 2
60%
HOCHz / -0THP
MeOOC i / -0THP
379 380
95% 53%
381 382
0
OHC-HN
SCHEME 71. Langlois et al. synthesis of (*)-desmethoxycuanzine (389). Reagents: i. LDA, HMPA, THF, -70°C + -40°C. then ICH2CH20THP; i i , LiAIH4. THF, -70°C; iii. Ac20, pyridine, room temperature; iv, 4-TsOH, MeOH, H20 , reflux; v, 12, KI03 , AcOH, dioxane, H20 , room temperature: vi, H2, Pt02 , MeOH: vii, 2 M K2C03/MeOH, room temperature: viii, SOypyridine, DMSO, Et3N, room temperature; ix, lithium hexamethyl- disilazane (UHMDS), CNCH2COOMe, THF, -70°C + -40°C; x, 0.2 M HCUMeOH, then Na2C03/MeOH.
The reactions that the authors used in their vincamine synthesis were then applied (179), with some modifications, to the synthesis of 389. Li- HDMS was preferred as the base when aldehyde 386 was condensed with methyl isocyanoacetate to yield a mixture of lactam 387 (23%) and ester 388 (63%). Acidic and basic treatment of this mixture afforded (?)-12- desmethoxycuanzine (389) and its 16-epimer (2 : 1) in 95% yield. The ap- proach constitutes the first total synthesis of the cuanzine skeleton.
K. PARTIAL SYNTHESES OF ( -)-CRASPIDOSPERMINE AND ( -)-CRIOCERINE
(-)-Craspidospermine [ (-)-501 and (-)-criocerine [ (3-341, which con- tains the 15,16-ether linkage, have been partially synthesized from natu- rally occurring precursors.
1. EBURNAMINE-VINCAMINE ALKALOIDS 73
1. CavC et al. Synthesis of (-)-Criocerine [(-1-34]
A short synthesis of (-)-criocerine [ (-)-341 was presented in connection with its first isolation by Cave and co-workers (72). (+)-14,15- Dehydrovincamine [ (+)-35] was converted into its N-oxide 390, and this was treated with trifluoroacetic anhydride (modified Polonovski reaction) to give the conjugated iminium intermediate 391. Intramolecular nucleo- philic addition afforded [(-)-341 (Scheme 72). By an analogous method, Potier and co-workers (131) synthesized (-)-craspidospermine [(-)-SO] from (+)-14,15-dehydrovincine [ (+)-Sll.
MeOOCw MeOOC"
\ 39 1 \
390 \ (+)-35
\ (-)-34
SCHEME 72. CavC et a / . synthesis of (-)-criocerine [(-)-34]. Reagents: i , H202. CHCIJ MeOH; ii , TFAA, CH2CI2.
2. Beugelmans et al. Synthesis of (-)-Craspidospermine [ (-)-501 and (-)-Criocerine [ (-)-341
A partial synthesis of (-)-craspidospermine and (-)-criocerine via pho- tooxidation of tertiary amines was presented by Beugelmans et al. (212). Irradiation of (+)-14,15-dehydrovincine [ (+)-51] gave the conjugated imi- nium intermediate 392 which, in analogy to the formation of (-)-34 above, led to (-)-craspidospermine [(-)-SO] (Scheme 73). Compound (-)-SO was also obtained from (+)-51 under different photooxidative conditions (acetone, high pressure lamp). Under these same conditions (+)-vinca- mine [(+)-2] could be directly converted to (-)-criocerine [ (9-341.
MeOOC"" \
( - ) -50
Me0
MeOOC"" MeOOC~~i t = /
\ 392
\ (+)-51
SCHEME 73. Beugelmans et ul. synthesis of (-)-craspidospermine [(-)-SO]. Reagents: i , methylene blue, 0 2 . methanol, high pressure lamp, 6 hr, or acetone, high pressure lamp, 3 hr.
74 MAURl LOUNASMAA A N D A R T 0 TOLVANEN
3. Le Men et al. Synthesis of (-)-Criocerine [(-)-341
(+)-14,15-Dehydrovincamine [ (+)-351, obtained from (-)-tabersonine [ (9-3471 (vide supra), was converted to (-)-criocerine [ (-)-341 in a two- step procedure by Le Men and colleagues (213) (Scheme 74). Oxidation of (+)-35 with iodine and potassium iodate gave 14-iodocriocerine (3931, which was transformed under acidic conditions to (-)-34.
I MeOOC'"' \
(-)-34
93%
MeOOC'"' \
393
SCHEME 74. Le Men er ul. synthesis of (-)-criocerine [(-)-MI. Reagents: i, 12, K I 0 3 , AcOH, aq. dioxane, room temperature 24 hr; ii, 10% NH4CI, 5 N HCI, 90T, 1 hr or AcOH, NaOAc, 90°C. 3 hr.
\ (+)-35
L. SYNTHESES OF TACAMINE AND DERIVATIVES 1. Le Men et al. Synthesis of (-)-Pseudovincamine [(-)-45]
The first synthetic studies in the tacamine (pseudovincamine) series were carried out some years before the isolation of the natural products. In 1978 Le Men and co-workers (214) obtained (-)-pseudovincamine [ (--451 and (-)- 16-epipseudovincamine [ (-)-421 from (-)-pseudovincadifformine [ (-)-3961 by applying the peracid-induced oxidative rearrangement (191) (Scheme 75). (-)-Pseudovincadifformine was prepared, via (-)-pseudo- tabersonine [ (-)-3951, from (+)-catharanthine [ (+)-3941 by Kutney's method (215).
2. Levy et al. Synthesis of (*)-Pseudovincamone (Tacamonine, 10)
LCvy and co-workers (216) converted enamide 205, previously prepared for the synthesis of eburnamonine (cf. Scheme 29), to enamine 398 (Scheme 76) [for large-scale preparations, a one-pot conversion of oxoes- ter 123 to amide 397 (60%) was possible]. In this modification of Wenkert's eburnamonine synthesis (cf. Scheme 6), alkylation of enarnine 398 (an analog of Wenkert's enamine 92) with ethyl iodoacetate and reduction of the intermediate iminium salts gave the esters 399 and 400. These were cyclized to the corresponding pseudovincamones 401 and 10 (taca- monine), respectively.
1. EBURNAMINE-VINCAMINE ALKALOIDS 75
89% OOMe COOMe
(+)-394 (-)-395
ca 5:7 26% HOat*n . -
M e 0 0 F I R - - - .
OOMe
(-)-396 (-)-45 (-)-42
SCHEME 75. Le Men et a / . synthesis of (-)-pseudovincarnine [(-)-451 from (+)-catha- ranthine [(+)-3941. Reagents: i , H2, PtOr, MeOH; ii, 4-nitroperbenzoic acid, benzene, then Ph3P. AcOH.
COOCHJ i
92%
I 397 I 123 205
I 40 1 10 I
SCHEME 76. Levy e t a / . synthesis of (*I-pseudovincamone (10). Reagents: i, tryptamine, benzene, then NaBH4, MeOH; ii, H2, PtO,, EtOH, AcOH, NaOAc; iii. POC13, toluene, reflux, then aq. NazCO,; iv, ICH2COOEt, CH3CN, reflux, then Zn, 65% AcOH; v, Ba(OH)*, dioxane, then TFAA; vi, NaOMe. MeOH.
76 MAURI LOUNASMAA A N D A R T 0 TOLVANEN
3. Lounasmaa et al. Synthesis of Intermediate 408
A synthetic route to pseudovincamines via the modified Polonovski reaction was developed by Lounasmaa and co-workers (217) (Scheme 77). Pyridine ester 402, prepared in eight steps from pyridine-3,5-dicarboxylic acid, was alkylated with tryptophyl bromide to give salt 403. Catalytic hydrogenation of 403 yielded piperidine 404. This intermediate was then cyclized as follows. Compound 405, the indole nitrogen-protected deriv- ative of 404, was converted to its N-oxide, and this was reacted with trifluoroacetic anhydride and then potassium cyanide to afford the two a-aminonitriles 406 and 407. Treatment of isomer 406 with silver tetrafluo- roborate, followed by acid treatment, led to tetracyclic ester 408.
COOMe
402 403 404
MeOOC MeOOC MeOOC
405 I 407 I
50% I v
SCHEME 77. Lounasmaa et al. synthesis of intermediate 408. Reagents: i , tryptophyl bromide; i i , H2, PtO2, MeOH; iii, BOC20, phase-transfer catalysis; iv, H202. CHCIJMeOH, 55°C. then TFAA. CH2C12, followed by aq. KCN; v , AgBF4, THF, room temperature, then HCI/MeOH, 60°C.
4. Szantay et al. Synthesis of (2)-Tacamine (45) and (t)-Apotacamine (32)
The first total synthesis of the newly isolated alkaloids tacamine (45) and apotacamine (16,17-anhydrotacamine, 32) was developed by Szantay’s group (218). Salt 409, the iminium perchlorate of enamine 398, provided the starting compound (Scheme 78). This was reacted with tert-butyl
1 . EBURNAMINE-VINCAMINE ALKALOIDS 77
__t
24% 80% 53%
MeOOC
409 410 411
MeOOC
2 7 %
MeOOC
SCHEME 78. Szantay et al. synthesis of (+)-tacamine (45) and (+)-apotacarnine (32). Reagents: i, tert-butyl acrylate, CHzClz. Et,N, then aq. NaOH followed by NaBH,; ii, separation of isomers; iii, P0Cl3, CHC13, reflux; iv, tert-BuONO, tert-BuOK, toluene: v, NaOMeIMeOH, reflux; vi. Na2S205, HzS04, aq. AcOH. reflux: vii. conc H2S04. MeOH. reflux.
acrylate, and the three isomeric esters obtained after reduction of the iminium salt were separated by TLC. Cyclization of the ester 410 with POC13 afforded lactam 411, and oxidation of this with tert-butyl nitrite gave oxime 412 as a mixture of E and Z isomers. Refluxing oxime 412 in methanol with concentrated sulfuric acid led directly to (2)-apotacamine (32). If oxime 412 was instead treated with sodium methoxide in methanol, the oxime ester 413 was obtained. Refluxing in dilute acetic acid with sulfuric acid and sodium pyrosulfite converted 413 to (+)-tacamine (43, and sulfuric acid treatment of 413 led to (r)-apotacamine (32) in 47% yield. In an alternative route, iminium perchlorate 409 was alkylated with ethyl bromopyruvate oxime to give 413 directly.
M. SYNTHESES IN THE SCHIZOZYGINE SERIES
To date, the only alkaloids of the schizozygine group that have been targets for synthetic work are (-)-vallesamidine [ (-)-15] and (-)-strem- peliopine [ (-)-91.
78 MAURI LOUNASMAA A N D A R T 0 TOLVANEN
1. Le Men et al. Partial Synthesis of (+)-Vallesamidine [(+)-151
In 1971 Le Men and co-workers (219) found that indolenine 414, derived from (-)-tabersonine [ (-)-347](220), rearranged to a pentacyclic indoline (415) when treated with zinc in acetic acid at 100°C (Scheme 79). N- Formylation of 415, followed by reduction with LiAIH4, afforded an N- methyl derivative (416). Catalytic hydrogenation of the double bond of 416 gave (+)-vallesamidine [ (+)-151, the optical antipode of the naturally oc- curring alkaloid (-)-vallesamidine [ (-)-15].
(-)-347 414 415 -\
416 \ (+)- 15 -\
SCHEME 79. Le Men rf al. synthesis of (+)-vallesamidine [(+)-15]. Reagents: i . 4 N HCI, 110°C; ii, Zn, AcOH, CuSO,, 10O-llO"C; iii , CH3COOCH0, then LiAIH,; iv, H2, PtO,.
2. Hajicek and Trojanek Synthesis of (-)-Strempeliopine [ (-)-91
The above rearrangement was exploited by HajjiCek and Trojanek (221) in their synthesis of (-)-strempeliopine [ (3-91 from (+)-l&methylene- vincadifformine [ (+)-4171 (Scheme 80). The starting compound 417, which was prepared by Kuehne's method (222), was hydrolyzed and decarbox- ylated to indolenine 418. This was then subjected to the conditions de- scribed above (Zn, AcOH, CuSO4.SH20, 102"C), resulting in the forma- tion of indoline 419. Finally, (-)-strempeliopine [ (-)-91 was obtained from 419 after N-formylation and ozonolysis of the side-chain double bond. This synthetic sequence also confirmed the absolute configuration of (-)-strem- peliopine [ (-)-91.
3. Heathcock ef al. Synthesis of (?)-Vallesamidine (15) The first total synthesis of (?)-vallesamidine (15) was recently presented
by Heathcock and co-workers (223) (Scheme 81). Michael addition of acrylonitrile to 2-ethylcyclopentanone (421) gave nitrile 422 as the major
1. EBURNAMINE-VINCAMINE ALKALOIDS 79
iii
42% H
417 418
H H
SCHEME 80. Hajjicek and Trojanek synthesis of (-)-strempeliopine [ (-)-9]. Reagents: i, alkaline hydrolysis, then benzene, reflux; ii, Zn, AcOH, CuS04.5H20, 102°C; iii, CH3- COOCHO, room temperature, 9 hr; iv, 03, MeOH, 1 M HCI, then 30% aq. H 2 0 2 .
iii
42% __t
42 1 422 423
424
iV
99%
425
H H
V - 77%
H
426
vi
90%
SCHEME 81. Heathcock ef a / . synthesis of (+.)-vallesamidine (15). Reagents: i , CH,=CHCN, NaOEt, THF; ii, H2. Raney Ni, KOH, MeOH; iii, 2-nitrocinnamic acid, ammonium 2-nitrocinnamate, dioxane, reflux; iv, H2. PtO,, MeOH; v, NBS, CH,Cl2, then AgNO3, aq. MeOH, room temperature; vi, NaBH3CN, aq. AcOH, 50"C, then aq. HCHO, NaBH3CN, room temperature; vii, LiAIH4, THF, reflux.
80 MAURI LOUNASMAA A N D A R T 0 TOLVANEN
product. Hydrogenation of the cyano group with Raney nickel afforded directly the bicyclic imine 423. Reaction of imine 423 with 2-nitrocinnamic acid in the presence of ammonium 2-nitrocinnamate in dioxane gave lac- tam 424, which, after hydrogenation, afforded the aniline derivative 425. This was cyclized with N-bromosuccinimide to a bromolactam of un- known structure which, after hydrolysis, gave pentacyclic hydroxylactam 426 (77%) and the corresponding methoxylactam (20%, convertible to 426). Removal of the hydroxyl group and N-methylation were carried out in one step with sodium cyanoborohydride in aqueous acetic acid, fol- lowed by addition of formalin to afford lactam 427. Finally, reduction of 427 with LiAlH4 in T H F gave (*)-vallesamidine (15).
N. SYNTHESES OF Brs EBURNAMINE-VINCAMINE ALKALOIDS Some of the bis eburnamine-vincamine alkaloids have been prepared by
partial synthesis from suitable natural monomeric alkaloids by an acid- catalyzed condensation reaction, originally developed by Biichi and co- workers (224). Based on this methodology, (+)-strempeliopidine [ (+)-58] has been synthesized from aspidospermidine (428) and eburnamine (1) ( 4 4 , (+)-kopsoffine [ (+)-611 from (-)-kopsinine [ (-)-4291 and (+ 1-eburnamine [ (+)-1] ( I I9), (- )-pleiomutine [ ( - ) -a] from (-)-pleiocar- pinine [(-)-4301 and (-)-eburnamine [ (-)-l] (28,I2I ), and (+)-ten& causine [ (+)-661 from the hydrochloride of 1 1-methoxytabersonine (431) (37) and 14,lS-dehydroeburnamine (6). (-)-Pleiomutine [( -)-641 has also been prepared via a modified Eschweiler-Clark N-methylation from (- )-norpleiomutine [ (- 1-62] (56).
428
A COOMe
(-)-429
(-)-430 43 1
1. EBURNAMINE-VINCAMINE ALKALOIDS 81
H
OOMe 432 (-)-429
SCHEME 82. Magnus and Brown synthesis of (-)-kopsinine (431).
(-)-Norpleiomutine [ (-)-621 is the only “dimer” in the series that has been synthesized from two completely synthetic monomers. Magnus and Brown (126) reported an asymmetric synthesis of (-)-62 proceeding via an acid-induced coupling of (-)-kopsinine [ (-)-4291 and (-)-eburnamine [(-)-11. Both starting compounds were prepared by total synthesis, (-)-429 in 13 steps from the tetracyclic amine 432 (Scheme 82) and (-)-1 by a modification of the Bartlett and Taylor synthesis (cf. Schemes 1 and 3). Finally, (-)-kopsinine [ (-)-4291 and (-)-eburnamine [ (-)-11 (and its 16-epimer) were refluxed in 2% hydrochloric acid for 7 hr, yielding (-)-norpleiomutine [ (-)-621 (Scheme 83). * + w i \ OOMe \ HUB8 H =G
(-)-429 (-)- 1
\
OOMe (-)-62
SCHEME 83. Magnus and Brown synthesis of (-)-norpleiomutine [ (-)-621. Reagents: i , 2% HCI, reflux, 7 hr.
IV. Reactions
Investigations on the chemical modification of (+)-vincamine, aimed at finding pharmacologically more effective derivatives, began in the 1960s. The first studies on the structure elucidation of (+)-vincamine [ (+)-21
82 MAURI LOUNASMAA AND ART0 TOLVANEN
showed that (+)-vincamine could be converted via different routes to (-)-eburnamonine [vincamone, (-)-81, an alkaloid that at the time had not been found in plants. These reactions have been reviewed by Gesztes and Clauder (225). Also, the reverse transformation, namely, vincamine from eburnamonine, has been achieved (see Section 111).
(+)-Apovincamine [ (+)-331, an alkaloid from Tubernuemontuna rigidu, can be prepared from vincamine by dehydration. Aware of this, Lorincz and co-workers (226) discovered that vincamine could easily be converted to an analog of apovincamine, ethyl apovincaminate (RGH-4405, Cavin- ton, Vinpocetine, etc., 433). This compound has been found be pharmaco- logically more effective than vincamine itself (see Section VII).
\ 433
Reactions of the iminium salt 281, derived from (+)-apovincamine [( +)-331 (cf. Scheme 44), with various nucleophiles were investigated by FYaffli and Hauth (227). Different analogs of vincamine were obtained when alcohols, amines, or thiols were used. Direct addition of alcohols and thiols to the 16,17-double bond of (-)-eburnamenine [(-)-41 similarly yielded the corresponding derivatives of eburnamine.
Derivatives of vincamine having a halogen atom, usually bromine, in the aromatic ring possess significant therapeutic effects (see Section VII). They can be prepared by direct halogenation of vincamine (228), by rear- rangement of suitable Aspidosperma precursors (229), or by synthesis from halogen-containing starting materials (230). In a patent publication (231), vincamine was treated with bromine in the presence of ferric chloride to yield a mixture of 9-, lo-, and I I-bromo derivatives of vinca- mine. Another method for the halogenation of indole alkaloids was re- ported by Megyeri and Keve (232). When vincamine was treated with bromodimethylsulfonium bromide in the presence of ferric chloride, a mixture of bromovincamines was obtained in a ratio that depended on the quantity of the reagents.
Nitration of (+)-vincamine [ (+)-21 and (-)-eburnamonine [vincamone, (-)-8l was studied by Sarlet and Hannart (233). Nitration of (+ 1-2 or (-)-8 in acetic acid gave predominantly the corresponding 1 I-nitro derivatives
1. EBURNAMINE-VINCAMINE ALKALOIDS 83
(with small amounts of 9-nitro compounds). Furthermore, ( - ) - I 1- nitroeburnamonine (1 1 -nitrovincamone) was converted in three steps (re- duction-diazotization-methylation) to (-)- 1 1 -methoxyeburnamonine [vincinone, (-)-281.
\ (-)-ZEl
While studying the structure and stereochemistry of bisindole alkaloids, Takano and co-workers (234) conducted model experiments where (-)-vindoline [ (-)-4341 was coupled with both optically active and race- mic eburnamenine. Finally, Szantay and colleagues (235) studied the be- havior of (+)-vincamine [ (+)-21, (-)-eburnamonine [ (9-83, and ethyl apovincaminate (433) under the Polonovski reaction conditions. They found treatment of the N-oxides of (+)-2 and (-)-8 with acetic anhydride to give rise to bisindole products.
(-)-434
V. Biosynthesis
The principal features of the biosynthesis of eburnamine-vincamine alkaloids were studied in the 1960s. Wenkert suggested in 1961 that eburnamine-vincamine alkaloids might be biogenetically related to the Aspidosperma group of alkaloids (192,236-238). In that case the bio- synthetic formation of vincamine would follow the geissoschizine (435)- stemmadenine (436)-secodine (437)-vincadifformine (343) pathway (Scheme 84). Wenkert’s hypothesis has since been supported by several in v i m conversions of the aspidospermane type skeleton to the vincane type skeleton (vide supra). The biosynthesis of vincamine has been surveyed by Kutney (239).
84 MAURl LOUNASMAA AND ART0 TOLVANEN
435 436 437 MeOOC
HO OOMe
343 2
SCHEME 84. Possible biosynthetic formation of vincamine (2).
The biosynthesis of eburnamine-vincamine alkaloids has not been ex- amined as thoroughly as that of some other indole alkaloids. However, incorporation studies performed on Vinca minor by Kutney and co- workers (240,241), Verzar-Petri (242,243), and Clauder and co-workers (244) in the late 1960s and early 1970s showed that geissoschizine (435) and tabersonine (347) were transformed to vincamine (2). These results indi- cate the close relationship of the Vinca bases to the Aspidosperma family of indole alkaloids. Wenkert’s original hypothesis is further confirmed in the tacamine series, where the alkaloids are most probably derived from pseudovincadifformine (49).
The biosynthesis of the schizozygane alkaloids has been discussed by KompiS and co-workers (14). These alkaloids, too, very likely arise from precursors of the Aspidosperma type. In uitro synthesis of (+)-vallesami- dine [ (+)-151 from an Aspidosperma percursor, performed by Le Men and co-workers (cf. Scheme 79), supports this conclusion.
Seeking to compare the alkaloid patterns of cell suspensions and differ- entiated plants, and also from a biosynthetic point of view, Pawelka and Stockigt (245) studied the production of indole alkaloids in cell suspension cultures of Rhazya srricta Decsne. Eleven main alkaloids were identified after a 15-hr experiment. In addition to compounds of the Aspidosperma, Corynanthe, Strychnos, and secodine types, two alkaloids of the eburnane type, namely, (+)-eburnamine [ (+)-11 and (+)-eburnamonine [(+)-8], were formed. A corresponding report concerning the production of Vinca alkaloids, especially vincamine, by cell cultures of Vinca minor has ap- peared in the patent literature (246).
1. EBURNAMINE-VINCAMINE ALKALOIDS 85
VI. Spectroscopy
The structures of the eburnamine-vincamine alkaloids have been eluci- dated by conventional spectroscopic methods (UV, IR, NMR, MS), but structures have been confirmed by X-ray crystallography for only five members: (-)-vallesamidine [ (--151 ( 6 3 , (+)+incarnine [ (+-21 (247 , 14,lS-dehydro- 16-epieburnamine (14,15-dehydrovincanol, 7) (248), (-)-eburnamonine [vincamone, (-)-81 (249), and (-)-cuanzine [ (-)-551 (250). In this section, we briefly discuss the use of nuclear magnetic resonance methods ( 'H-NMR and I3C-NMR spectroscopy) and mass spectrometry in the chemistry of eburnamine-vincamine alkaloids.
A. 'H-NMR SPECTROSCOPY
Structure elucidation of the eburnamine-vincamine alkaloids coincided with the first steps in the field of NMR spectroscopy. Only some of the obvious resonances in the spectra, those of methoxy groups, for example, could be assigned to the proposed structure. As an example, vincamine (2) could be distinguished from its 16-epimer (43) by the difference in the chemical shift of the methoxycarbonyl group (6 3.80 and 6 3.65, respec- tively, the C-21 H (6 3.92 versus 6 3.62), and the C-18 methyl (60.90 versus 6 0.82). In the unnatural isomers with the C/D-trans junction, the chemical shift of C-21 H is shifted upfield (to around 6 3.0). Low-field NMR studies on vincamine and its isomers were published by Danieli and co-workers (251).
Modern high-field 'H-NMR techniques make it possible to measure the chemical shifts and coupling constants of all protons in a molecule. Com- plete or nearly complete 'H-NMR spectra for some of the eburnamine- vincamine alkaloids have been published (252), and these data can be used in the characterization of new compounds of this type. A number of basic skeletons with their proton chemical shift values are depicted in Fig. 2.
B. 13C-NMR SPECTROSCOPY
Danieli and co-workers have recorded the I3C-NMR spectra of (+)+in- camine [ (+)-21 and some of its isomers (251); on the basis of the data they drew stereochemical conclusions regarding the structures of the com- pounds. One of the striking features of the 13C-NMR spectra of compounds of eburnamine-vincamine type is the interaction of C-3 with C-6, which is due to the cis junction between rings C and D. The 13C-NMR resonances of
FIG. 3. I3C-NMR data of some eburnamine-vincarnine alkaloids. Spectra were recorded in CDC13. *Signals not assigned in the original paper. **Synthetic product [missing shifts of C-13 and C-15 in ethyl apovincaminate (433) are 133.8 and 27.1, respectively; cf. Ref. 2351. ",b9ignals may be interchanged.
these carbon atoms occur at higher field than the corresponding reso- nances of the trans isomers. I3C-NMR methods have allowed several other stereochemical problems of these alkaloids to be solved. Figure 3 presents typical skeletal types together with their carbon chemical shift values.
C. MASS SPECTROMETRY The mass spectral fragmentation of eburnamine-vincamine alkaloids by
ordinary electron impact ionization (EI) has been thoroughly dealt with in earlier papers (254-258), and only the main features are described here. Some common losses from the molecular ion are presented, and the appar- ent structures of the formed ions are displayed.
1. (M - I ) +
The (M - 1)+ peak is due to the loss of a hydrogen radical, and the ion is fairly abundant, especially with 16,17-dihydro skeletons. Structure b rep- resents the most probable structure.
N / R'
R
2. (M - 18)+.
Eburnamine-vincamine alkaloids having a hydroxyl group, usually at C-16, easily lose a molecule of water either thermally before ionization (eburnamine-type compounds in particular) or from their molecular ion (e.g., from c).
3. (M - 29)'
An ethyl radical is cleaved either directly or via a retro-Diels-Alder (RDA) process in the C ring.
1 . EBURNAMINE-VINCAMINE ALKALOIDS 93
a e f
%’+. HO HO
MeOOC
g h
4. (M - 59)’
The (M - 59)+ peak corresponds to the loss of a methoxycarbonyl group (COOCH3) from the appropriate molecular ions.
5 . (M - 70)+
The formation of the (M - 70)+ ion (k), which is especially abundant with eburnamenine-type alkaloids, is postulated to proceed via the RDA reaction described above, followed by the loss of the radical CH2=NCH2CH2CH2. .
6. (M - 102)+,
The (M - 102)+. peak is detected in the mass spectra of vincamine-type alkaloids (which have both a methoxycarbonyl and a hydroxyl group at C-16). This elimination of a pyruvic ester group was earlier thought to involve the RDA process noted above.
94 MAURI LOUNASMAA A N D A R T 0 TOLVANEN
The effects of stereoisomerism on the fragmentation of vincamine and its isomers have recently been discussed in more detail by Tamas and co-workers (259), who have also proposed an alternative mechanism for the formation of the (M - 102)+. ion.
I n
VII. Pharmacology
Many plants containing eburnamine-vincamine alkaloids were in medi- cinal use long before the isolation and characterization of their active principles. The primary achievements in the medicinal use of these natural products have been documented in earlier reviews (124,260-264). In this section, we discuss some of the more recent developments in the pharma- cological research on eburnamine-vincamine alkaloids, particularly the important cerebral vasodilatory agents (-)-eburnamonine [vincamone, (-1-81 and (+)-vincamine [(+)-21.
A. EBURNAMONINE AND DERIVATIVES
Of the optical antipodes of eburnamonine, the (-) form [ (-)-8] has been found to be more active than the (+) form [(+)-81. Aurousseau and co- workers (265) have compared the pharmacological properties of (+)-vinca- mine and (+)- and (-)-eburnamonine. All three drugs increased arterial vertebral blood flow, but only (-)-eburnamonine increased internal maxil- lary venous pressure. (+)-Eburnamonine was practically inactive in a rheoencephalogical test, whereas (+)-vincamine and (-)-eburnamonine both increased the systolic flow. All three compounds had hypotensive
1. EBURNAMINE-VINCAMINE ALKALOIDS 95
effects, but (+)-eburnamonine was less effective than vincamine or (-)-eburnamonine. In addition to its lower toxicity, (-)-eburnamonine was found to be a more active and selective cerebral vasodilator than (+)-eburnamonine.
Aurousseau and co-workers (266) studied the cerebral protecting activ- ity of (-)-eburnamonine on three anoxic disorders and compared the results with vincamine. They found that (-)-eburnamonine increased the survival time of mice submitted to hypobaric hypoxia and produced a slight hypothermia. Vincamine was more efficient in increasing the sur- vival time and produced a strong hypothermia. Hypobaric hypoxia- induced amnesia was found to be antagonized by (-)-eburnamonine, whereas vincamine displayed no effect. (-)-Eburnamonine prevented the increase of thalamic evoked potentials induced by acute cerebral ischemia in cats, an activity that also has been described with vincamine (267).
Lacroix and co-workers have also published other comparative studies on eburnamonine and vincamine. In a study on the antihypoxic effect of (-)-eburnamonine they found that, in curarized rats, (-)-eburnamonine decreased the electroencephalographic modifications induced by acute asphyxic anoxia (268). The same authors investigated the influence of (-)-eburnamonine and (+)-vincamine on the 2,3-diphosphoglycerate (2,3- DPG) blood level in awake rats, in the presence and absence of cyanide- induced hypoxia (269). The increase of 2,3-DPG effected by (+)-2 or (-)-8 was suggested to be the result of a metabolic stimulation, and this could in part explain the antihypoxic properties of the two alkaloids.
Intravenous (i.v.) injection of (-)-eburnamonine into anesthetized guinea pigs induced a moderate constriction of bronchia (270). This was partially antagonized by atropine and brompheniramine and almost com- pletely inhibited by papaverine. Similar results were obtained with vinca- mine, but papaverine did not completely inhibit the bronchoconstriction caused by vincamine. The bronchoconstrictor activity of vincamine was found to be more intense and more durable than that of eburnamonine. In yet another study, Lacroix et al. (271) compared the cerebral metabolic and hemodynamic activities of (-)-eburnamonine and (+)-vincamine. The results indicated the superiority of (-)-8 over (+)-2 in these activities.
The effects of acute and chronic treatment with (-)-eburnamonine on the tissue supply of oxygen were studied by Ferretti and co-workers (272). The results showed a significant increase in the 2,3-DPG values, and the changes probably depended on the dose and mode of administration of (-)-eburnamonine. The effect of chronic treatment with (-)-eburna- monine and some other drugs on the enzymatic activities in rat brain was tested by Benzi and co-workers (273). (-)-Eburnamonine was found, as a function of time, to increase the activity of mitochondria1 cytochrome
96 MAURI LOUNASMAA A N D A R T 0 TOLVANEN
oxidase in all tests. Simultaneously, a decrease in the activity of citrate synthase and an increase in the activity of lactate dehydrogenase were noticed.
In later work, Benzi and co-workers (274) investigated the effects of (-)-eburnamonine and vincamine teprosilate (vincamine theophylline sul- fonate, Teproside, vide infra), in addition to other drugs, during posthy- poglycemic recovery. Different, or even contrasting, interferences were observed on glycolytic metabolites, amino acids, and energy-rich phos- phates. In yet another study, Benzi et al. (275) evaluated the influence of aging and exogenous substances on cerebral energy metabolism in posthy- poglycemic recovery.
B. (+)-VINCAMINE AND DERIVATIVES
(+)-Vincamine [(+)-21, the major alkaloid of Vinca minor, is, phar- macologically, the most comprehensively studied alkaloid in the eburna- mine-vincamine group. Some 30 papers dealing with the pharmacology of vincamine appear every year. In the 1970s, Numbers 6A (1977) and 10 ( 1976) of Arzneimittel-Forschung (Drug Research) were devoted to the pharmacology of vincamine and its close analog ethyl apovincaminate, respectively. Vincamine has been demonstrated to have favorable effects in numerous cerebral disorders. Reviews on the pharmacology of vinca- mine and its derivatives have been published by Hava (276) and Szporny (277).
In studies on the effect of drugs used in cerebral anoxic disorders on the electrical responsiveness of corticospinal neurons in cats subjected to cerebral ischemia, Boulu and co-workers (278) found that vincamine did not significantly modify the disappearance times of electrocortical activity (ECoG) or indirect pyramidal tract responses, nor the recovery delay of ECoG. However, vincamine improved recovery times of the indirect cor- ticopyramidal response.
Nistico and co-workers investigated the peripheral effects of vincamine in various in vitro and in vivo preparations (279), as well as the central effects of vincamine in intact and "encephale isole" fowl preparations (280). The experiments on the peripheral effects showed that in some preparations vincamine had a weak 5-hydroxytryptamine-like activity (279). It was suggested that the central vasodilator effects could be a consequence of a partial agonist effect at 5-hydroxytryptamine receptor sites. In their study on the central effects the authors concentrated on the behavioral, electrocortical, and body temperature effects of vincamine in young and adult fowl (280). The behavioral and electrocortical arousal that
1. EBURNAMINE-VINCAMINE ALKALOIDS 97
vincamine induced was proposed to be due to a generalized action on the brain stem at the cortical level.
Kanig and Hoffmann determined 32P incorporation into adenosine phos- phates (AMP, ADP, and ATP) in rat brain after oral administration of vincamine (281). After daily dosing of vincamine over 2 weeks, the incor- poration of 32P into AMP and ADP increased. This was explained by an acceleration of the pentose phosphate shunt (AMP) and an activation of adenylate kinase (ADP).
Vincamine was tested in rabbits in three dosages in an electronystag- mographic study by Hamann et al. (282). The duration and rate of the postrotatory nystagmus were reduced, while the frequency was unaf- fected. Compared with other tested substances, vincamine showed a be- havior typical of some antivertiginous drugs. Comparative data strength- ened the hypothesis that vincamine has a specifically vestibular action, in addition to its other effects on the central nervous system.
Sprumont and Lintermans (283) have presented autoradiographic evi- dence for the passage of vincamine through the blood-brain barrier. To explain the possible action of vincamine on brain function, the cellular components of the central nervous system should be considered, not just the hemodynamics of the cerebral circulation. A review of vincamine and other drugs acting on the rheological properties of blood has been pub- lished by Heiss (284).
Cattani and co-workers performed a series of studies on the vincamine- papaverine association (285). An intravenously administered vincamine- papaverine mixture was found to decrease the toxic effect of lethal doses of KCI to a larger extent than vincamine alone, whereas papaverine was completely ineffective. Investigation of the protective effect of a vin- camine-papaverine mixture showed it to exhibit an a-blocking-like effect.
Effects of vincamine on EEG sleep patterns in man were investigated in a pilot study by Albizzati et al. (286). A single dose of vincamine induced a significant decrease in sleep stage four, a decrease in REM stages that approached statistical significance, and an increase in REM latency in subjects showing low baseline values of this parameter. These data con- firm the awakening and antidepressant action of vincamine observed in previous studies in both animals and man.
Lapis et af. (287,288) studied the biochemical effects of vincamine and some of its derivatives on the cyclic AMP system in uitro in mouse brain and in uiuo in mouse plasma. All compounds potentiated the nor- adrenaline-stimulated value of intracellular cyclic AMP in brain. The re- sults strongly suggest that the skeleton of vinca alkaloids has a special membrane effect. Effects of vincamine and (+)-eburnamine [vincanol,
98 MAURI LOUNASMAA A N D A R T 0 TOLVANEN
(+)-11 on biological membranes and lipoproteins were studied spectro- fluorometrically in uitro by Laszlovszky (289); both alkaloids were found to change the initial values of ANS-membrane binding.
Drug action on the aging brain has been studied by Benzi and co- workers. They measured the age-dependent changes of some cerebral enzyme activities in rats in the presence of suitable drugs (290). In particu- lar, the effect of vincamine on enzymatic activities related to energy transduction was studied in several areas of the cerebral cortex of dog brain (291). Vincamine increased the activity of cytochrome oxidase, but no differences were found in mitochondria1 enzyme activities between control animals and treated ones in all tested brain areas.
The effect of vincamine and two other drugs on the firing rate of Locus coeruleus neurons was studied by Olpe and Steinmann (292). Vincamine, when administered intraperitoneally (i.p.), increased the firing rate of noradrenergic neurons in animals anesthetized with chloral hydrate.
Olpe et al. (293) also investigated the action of vincamine on the physiol- ogy of the CA1 region of in uitro hippocampal slice preparations. At concentrations of 1, 10, and 100 p M , a 5-min perfusion with vincamine did not affect the synaptically mediated activation of pyramidal neurons evoked by stimulation of the Schaffer commissural fiber system. The effect of vincamine on the excitability of the pyramidal neurons was investigated by studying its effect on the antidromically elicited field potential and the input-output relation of Schaffer commissural fiber in- put. No effect on either of the two parameters was seen at a vincamine concentration of 100 K M . Vincamine did, however, attenuate both the posttetanic (PTP) and long-term potentiation (LTP) evoked by repetitive stimulation of the Schaffer commissural fiber system. At a vincamine concentration of 100 p M , PTP was significantly reduced and LTP was almost completely suppressed.
In addition to its vascular properties, vincamine may decrease blood flow in the hyperemic, perifocal zones, thereby inducing an inverse steal phenomenon. Such an effect has been demonstrated to occur in stroke patients. Studies performed by Nowicki et al. (294) demonstrated that vincamine also possesses direct metabolic actions, which lead to a better preservation of cellular ATP-synthesizing capacity. The experiments showed that Ca2+ may be involved in the pathogenesis of brain ischemia. The same research group has published two other general articles on cerebral ischemia and anti-ischemic drugs (295,296).
Mondadori and co-workers (297) found that vincamine potentiated the anticonvulsant effects of some antiepileptic drugs in animal tests. This could provide a means of compensating the memory disturbances in epi- leptic patients.
1. EBURNAMINE-VINCAMINE ALKALOIDS 99
Effects of vincamine on experimental cerebral infarction were investi- gated in a pilot study by Ritschel et al. (298). Unilateral ligation of the common carotid artery was performed in 134 Mongolian gerbils. In all groups the carotid artery was ligated 6 days after start of the dosing. The animals were observed for a further 6 days after carotid artery ligation. Whereas vincamine had no effect on the percentage of animals in each group dying after carotid ligation, the extent of stroke lesion, measured histometrically, was significantly reduced 0, < 0.05) in the animals treated with vincamine. In verification of these initial findings Ritschel and co- workers (299) later found that treatment with vincamine caused a signifi- cant increase in survival, reduction of cerebral lesion in survivors, and functional recovery of locomotor activity.
Hagstadius et al. (300) investigated the effects of vincamine and bromo- vincamine (brovincamine, BV 26-723, 438) on mental functions and re- gional cerebral blood flow (rCBF) using the 133Xe inhalation method. Treatment with vincamine effected a significant increase in the global CBF level and reduction of initial right-left asymmetry of hemispheric means. No effects were seen in regional flow patterns, but performance scores on a verbal memory test increased significantly. For bromovincamine, no significant effect on the global rCBF level was indicated, the number of ischemic regions decreased, and performance on two memory tests im- proved. No significant changes in overall psychiatric ratings were ob- served for any of the treatment periods.
Recently, Sun and Takeuchi (301) studied the calcium antagonist effects of bromovincamine in snail neurons and compared the results with vinca- mine. Vincamine proved inactive against herpes simplex type 1 (HSV-1) virus in a screening test carried out by Alarcon et al. (302).
The in uiuo effect on rat brain ornithine decarboxylase (ODC) of RU 24722 (vindeburnol, 439), vincamine, and other drugs used for the treat- ment of senile cerebral insufficiency was investigated by Cousin et al. (303). RU 24722 induced a dose-dependent increase in brain ODC, which is a rate-limiting enzyme in the biosynthesis of polyamines. Of the other drugs investigated, vincamine induced an important increase in corticoste- rone blood levels but had no effect on rat brain ODC.
100 MAURl LOUNASMAA A N D ART0 TOLVANEN
439
Various alkyltin and alkyllead compounds are known to produce selec- tive edema of the central nervous system. Borzeix and Cahn (304) studied the cerebral antiedematous effect of vincamine and its derivatives and found that these compounds (especially vincamine teprosilate, Teproside) are able to prevent the occurrence of triethyltin-induced edema, whereas xanthine and papaverine do not. They suggested that the xanthine part potentiates the vincamine effects in vincamine teprosilate. Triethyltin- induced brain edema was also used as a model by Linee et al. (303, who studied the action of some drugs used in the treatment of cerebrovascular disorders. The test drugs were administered either during tin intoxication (preventive protocol) or after the brain edema was well developed (cura- tive protocol). Under the former conditions, both (-)-eburnamonine and (+)-vincamine were found active. In the latter application (-)-eburna- monine was found to favor and accelerate regression of the brain edema.
The direct effect of vincamine on vascular smooth musculature was studied by Bettini et al. They investigated the effect on electrical and mechanical responses of the vascular muscles to angiotensin I1 for both coronary (306) and hepatic (307) arteries and of the Taenia coli muscles (308) of the guinea pig. Vincamine was found to induce relaxation of the vascular and visceral musculature and to reduce the electrical and me- chanical responses to angiotensin 11. Bettini and co-workers concluded that there is no specific antagonism between vincamine and angiotensin 11, but the mechanism of action of vincamine probably lies in its capacity to modify the flow of calcium across the cell membrane. To further support these findings, Bettini et al. (309) investigated the influence of vincamine on the response of isolated hepatic arteries to adrenalin, in the presence of inhibitors of the synthesis of prostaglandins and of calcium entry blockers, and after pharmacological blocking of the preceptors. Vincamine was found to reduce the response, by an amount that increased or decreased in pace with the rise and fall of the calcium concentration in the medium.
Marteau ef al. (310) investigated the effects of 16 vasodilators on the intrahepatic vasoconstriction induced by norepinephrine in isolated per- fused rat liver. However, vincamine was unable to antagonize the effects of norepinephrine.
Araki and co-workers (31 1 ) studied the effects of some drugs on com-
1. EBURNAMINE-VINCAMINE ALKALOIDS I01
plete ischemia (gasping) induced by decapitation and cyanide intoxication in mice. Eburnamonine prolonged the duration of gasping. Vincamine and its analogs were found to be effective for treating cyanide intoxication, and it was concluded that this is a characteristic property of vincamine.
Cazin et al. used alveolar macrophages in studies on antianoxic drugs (312). Vincamine did not show any activity in their model of normoxia, but it revealed an interesting protective effect in anaerobiosis. ATP content decreased and deoxyglucose incorporation increased under treatment, demonstrating that vincamine is able to maintain cell metabolic activity for a long period of time after the beginning of hypoxic trial. Vincamine appears to stimulate cell energetic metabolism both in the anabolic phase and in the catabolic phase.
Effects of RU 24722 (439) and vincamine in the conscious gerbil during recirculation after transient ischemia were studied by Formento et al. (313). Cerebral energy metabolism and the alanine/glutamate ratio were evaluated in gerbils 6, 24, and 48 hr after ischemia (10 min) induced by clamping both common carotid arteries. At the end of ischemia, the energy substrates were reduced, while lactate and pyruvate levels and the alanine/glutamate ratio were increased. In a second part of the experiment RU 24722 or vincamine was administered subcutaneously 15 min, and 10, 24, and 34 hr after ischemia. RU 24722 completely inhibited the increase in lactate levels observed 24 and 48 hr after ischemia, improved the pyruvate recovery, and normalized the alanine/glutamate ratio, but vincamine had no effect on any of these. The ability of RU 24722 to prevent the postisch- emic lactate accumulation associated with the normalization of the alanine/ghtamate ratio indicates that it should improve the capacity for postischemic cerebral metabolic recovery and that it also has a different biochemical profile from that of vincamine.
Two new salts of vincamine, vincamine a-ketoglutarate and vincamine adenylate, were compared with vincamine in a study by Aiache et al. (314). Owing to higher solubility, the absorption of the two salts, after oral administration in man, was faster than that of the base itself. The effect of vincamine teprosilate on brain lysosomal enzyme activity was investigated by Federico and D’Amore (315). Intraperitoneal injection of the drug caused an activation of almost all enzymes. Vincamine hydrochloride has been biopharmaceutically and pharmacokinetically evaluated by Ritschel and Agrawala (316).
Ethyl apovincaminate (433, see Section IV) is in medical use in several countries for the treatment of cognitive and behavioral symptoms associ- ated with vascular and degenerative disorders of the central nervous sys- tem (263). The hemodynamic profile of vincamine and ethyl apovincami- nate (433) has been studied by Caravaggi et al. (317). Both compounds
102 MAURl LOUNASMAA AND ART0 TOLVANEN
\ 433
were found to induce peripheral vasodilation in all experimental models, but their action on systemic blood pressure and heart rate was clearly influenced by anesthesia and was different according to the anesthetic used. In conscious animals an increase in both heart rate and systemic blood pressure was observed, concomitantly with an increase in femoral and vertebral blood flow and a decrease in renal blood flow. A subsequent decrease in resistance was shown in the renal vascular bed when all the other measured hemodynamic parameters had returned to control values. The greater increase of vertebral blood flow versus femoral blood flow for the same increment of cardiac output was taken as an indirect demonstra- tion of the selectivity of the two drugs for the cerebral circulation.
The acute effects of vincamine and ethyl apovincaminate on the cerebral blood flow were compared by Lim et af. (318). They were unable to confirm that either drug produces useful changes in the cerebral blood flow of healthy patients. Moreover, side effects such as bradycardia, faintness, and tinnitus were observed.
Nikolova and co-workers (319) studied the antihypoxic effect of some drugs used in the pharmacotherapy of cerebrovascular diseases. Three different models of hypoxia were tested. Vincamine and ethyl apovincami- nate, both of which are vasoactive and also stimulate brain metabolism, were effective in incomplete ischemia and less effective in anoxic hypoxia. Ethyl apovincaminate was also effective in hemic hypoxia.
Ethyl apovincaminate (433) has been reported to have beneficial effects in the treatment of cerebral ischemia. King and Narcavage (320) compared the effects of 433 and vincamine and two other drugs in the Fischer rat model of cerebral ischemia. On acute b i d . administration (25- 100 mg/kg i.p.), both ethyl apovincaminate and vincamine significantly increased latency to ischemic convulsion in a dose-related manner, but neither drug significantly altered survival time. Ethyl apovincaminate, but none of the other drugs, caused a dose-related increase in the latency to ischemic convulsion after daily dosing for 5 days.
King (321) examined the protective effects of ethyl apovincaminate and structurally related drugs on the lethal consequences of hypoxia in mice. Ethyl apovincaminate was compared with two structurally related al- kaloids [ (+)-vincamine and (-)-eburnamonine] for activity in protecting mice from the lethal effects of hypoxia. Furthermore, DeNoble and col-
1. EBURNAMINE-VINCAMINE ALKALOIDS 103
leagues (322,323) found that ethyl apovincaminate enhances retrieval of a step-through passive avoidance response. Tests performed on rats indi- cated that 433 has cognition-activating properties. Okuyama and Aihara (324) found that eburnamonine and ethyl apovincaminate had no effect on transcallosal responses in urethane-anesthetized rats.
Calcium antagonist activity of ethyl apovincaminate and vincamine in models of cerebral ischemia was compared with reference calcium antago- nists by Poignet and co-workers (325). Both vincamine and ethyl apovin- caminate possessed only weak calcium antagonist activity. Ethyl apovin- caminate exhibited protective effects in several animal models of hypoxia and ischemia, but the authors assumed that the calcium antagonist activity of ethyl apovincaminate was only partly responsible for these effects.
Groo and co-workers (326) found that ethyl apovincaminate and, to a lesser degree, vincamine were effective in the prevention of a hypoxia- induced learning deficit in spontaneously hypertensive rats. Later, the same research group (327) examined whether these compounds are able to prevent a hypoxia-induced conditioned avoidance deficit in rats. Ethyl apovincaminate antagonized the disruptive effect of hypoxia in the 1.25- 5.0 mg/kg dose range, whereas vincamine exerted protective activity only in the highest dose tested (20 mg/kg).
In a recent study, Machova and co-workers (328) investigated the tra- chealis responses induced by vincamine and ethyl apovincaminate. On the basis of their results the authors concluded that the contractile and relax- ant actions of vincamine and ethyl apovincaminate on the guinea pig trachealis may be due to the generation of prostaglandins and to changes in membrane. Ca” fluxes and/or intracellular Ca2+ distributions.
The metabolism of vincamine, epivincamine (43), ethyl apovincaminate (433), and (+)-eburnamine [ (+)-13 has been investigated by Szporny and co-workers (329). When vincamine or epivincamine was incubated with rat liver homogenates, 6a- and 6P-hydroxy derivatives of these compounds were formed. The metabolism and pharmacokinetics of vincamine and its derivatives have been reviewed by Vereczkey (330).
C. OTHER EBURNAMINE-VINCAMINE ALKALOIDS
The pharmacological properties of (+)-eburnamine [ (+)-11 in most cases have been studied in connection with eburnamonine or vincamine (vide supra). The Voacanga chalotiana alkaloid (-)-cuanzine [ (-)-55] has been found to possess vasodilating, antihypertensive, and antiarrhythmic properties (252,331). This finding has contributed to recent synthetic ef- forts toward cuanzine (see Section 111).
104 MAURI LOUNASMAA A N D ART0 TOLVANEN
VIII. Perspectives
The eburnamine-vincamine alkaloids form a compact group of indole alkaloids, including at present 70 bases (May 1991, see Section 1x1. Unfor- tunately, some of the structures remain incompletely solved, and in some cases there are differing opinions about the correct absolute configuration. It is to be hoped that, at the very least, the present confusion regarding the derivatives of eburnamine will be avoided in future publications.
The pharmacological importance of some members of the eburnamine- vincamine group ensures that the development of new synthetic routes to these alkaloids will continue. In particular, the search for more potent and less toxic derivatives can be expected to intensify in the future.
The relatively new technique of producing organic compounds with the help of cell suspension cultures opens up new avenues for alkaloid manu- facturing. So far, however, this technique has not been widely applied to the eburnamine-vincamine alkaloids. Another revolution may be on the horizon in the field of gene technology, but it is difficult to predict how fast these techniques will develop to rival organic synthesis.
IX. Addendum
Since the completion of our manuscript (literature was covered up to the end of 1990), the isolation of five new alkaloids of the eburnamine- vincamine group has been reported (as of December 31, 1991). The 16,17- dihydro derivative of eburnamenine (237) was isolated from the roots of Rhazya stricta by Atta-ur-Rahman and co-workers (332). Dihydroe- burnamenine (237) was originally prepared from eburnamenine by Bartlett and Taylor (22) and Biemann and co-workers (In, and the total synthesis was achieved by Coffen and co-workers (159) (cf. Scheme 34).
(-)-Celastromeline [ (-)-4401 and (-)-celastromelidine [ (-)-4411, two novel dimeric alkaloids, were isolated by Mehri and co-workers (333) from Melodinus celastroides. The examination of Kopsia larutensis by Pais and co-workers (334) yielded two new monomeric alkaloids, named eburna- minol and larutensine, for which structures (-)-442 and (+)-443 were proposed. It seems to us, however, that the two compounds, according to the signs of their [ a ] ~ values, should be presented as their mirror images. The correct name for the former one is (-)-16-epieburnaminol.
1. EBURNAMINE-VINCAMINE ALKALOIDS 105
(-)-440 (-) -44 I
(-)-442 (+)-443
14,15-Dehydrovincine (51) was isolated from the trunk of Melodinus suaveofens by Ye and co-workers (335).
14-Iodocriocerine (393), a known precursor of criocerine (34), was pre- pared from vincamine by Szantay and co-workers (336). The procedure constitutes a formal synthesis of this alkaloid. Szantay and collaborators (337) have also published an approach to the synthesis of the cuanzine skeleton, which was applied to the preparation of desmethoxycuanzine (389). Cuanzine (55) has been the synthetic target of two other groups as well. Palmisano and co-workers (338) described the first total synthesis of (+-)-cuanzine in early 1991. Shortly thereafter, a second total synthesis was achieved by Ortuno and Langlois (339), who applied their earlier studies on the desmethoxy derivative (cf. Scheme 71) to the synthesis of cuanzine itself.
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108 MAURI LOUNASMAA AND ART0 TOLVANEN
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110 MAURI LOUNASMAA A N D ART0 TOLVANEN
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1. EBURNAMINE-VINCAMINE ALKALOIDS 111
173. J. L. Herrmann, R. J. Cregge, J. E. Richman, C. L. Semmelhack, and R. H. Schless-
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I12 MAURl LOUNASMAA AND ART0 TOLVANEN
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