Total Synthesis of (–)-Himandrine
Adam T. HoyeCurrent LiteratureOctober 3, 2009
M. Movassaghi,* M. Tjandra and J. QiJ. Am. Chem. Soc. 2009, 131, 9648-9650
H
H
OMe
H
N
OBz
HO
OMe
OMe
H
H H
H
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Structure of (–)-Himandrine
Carbon Skeleton Simplification:
H
H
OMe
H
N
OBz
HO
OMe
OMe
H
H H
H
MeO2COBz
HOMe
HN
MeH
HOH
HH
NN
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Galbulimima Alkaloids
28 isolated alkaloids categorized into Class I, II and III
Characterized by piperidine moiety and “caged” structure
-Isolated from bark of Galbumimia belgraveana native tonorthern Australia and Papua-New Guinea-Biological Properties- potent muscarinic antagonist
Papuans (who tend to use this drug the most) boil the bark and theleaves together with another plant, called Homalomena[2], in orderto make tea…It is similar to strong marijuana which induces asimilar slumber like feeling
http://en.wikipedia.org/wiki/Galbulimima_belgraveana
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Galbulimima syntheses
Class III syntheses:Mander (Australian Nat. Univ.) : Galbulimima 13 (racemic) 2003Movassaghi (MIT): (+)- and (—)-GB 13 2006Chackalamannil (Schering-Plough): (—)-Himgaline 2006Evans (Harvard): (+)-GB 13 and (+)-Himgaline (antipodes) 2007
Class II syntheses:Movassaghi: TITLE PAPER
Class I syntheses (selected):Hart (Ohio State) 1995Chackalamannil (Schering-Plough) 1996Baldwin (Oxford) 2005
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Polyacetate Proposal (Taylor)
Mander, L. N.; Prager, R. H.; Rasmussen, M.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1967, 20, 1705-1718
CCOC
CO
COC C CO
H2CH2C
COC
CO
CCO
COC
CO2HOCC CO
CO
C
N
C
C
O
O O
OO
O
CCO
O
NH3
O
N
OH
O
N
OH
O O
N
OH
Class I
Himbacine etc.
HimbadineGB 13Himgaline
HO2C
MeO2C
MeO2C
Himandrine
Himandridine
Class III
Class II
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Baldwin Type I SynthesisLinear polyketide precursor
Tchabenenko, K., Adlington, R. M.; Cowley, A. R.; Baldwin, J. E. Org. Lett. 2005, 7, 585-588.
O
Me
CO2H
O O
Me
N
Me
R
O
Me
O
O
NR
Me
Me
O
H
H
H
O
NR
Me
Me
O
H
H
H
H
O
NR
Me
Me
O
H
H
H
H
Biological
Diels-Alder
iminiumreduction
(R = Me, Himgravine)
Class I
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Baldwin
O
Me
O
H O OP(OMe)2
O
BocHN Me
DIPEA, LiCl, MeCN50% O
Me
O
O NHBoc
Me
O
N
Me
Me
O
H
H
H
Boc1. TFA, DCM,0 °C to rt,then NaBH3CN
H
O
N
Me
Me
O
H
H
H
BocH
O
N
Me
Me
O
H
H
H
BocH
22% (3 steps)H2, PtO2, EtOH
TFA, DCM, then HCHO,NaBH4CN, MeCN
60%
separable
2. Boc2O, NEt3,DCM
O
N
Me
Me
O
H
H
H
MeH
(+)-Himbacine
Tchabenenko, K., Adlington, R. M.; Cowley, A. R.; Baldwin, J. E. Org. Lett. 2005, 7, 585-588.
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Evans’ ApproachClass III: Galbulimima Alkaloid 13
N
O
O
O
BnOR
H
H
CH2OR
O Xc
Me2AlCl
PhMe, -30 °C81 %
single diastereomer
1. LiSEt
2. DIBAL-H
A
H
H
H
O NHBoc
Me
HO
H
OHN Me
H
H HO
(+)-GB 13
HN Me
O
HH
H
HO
Aldol
H
H
H
Xc
O OR
IMDA adduct
H
Evans, D. A.; Adams, D. J. J. Am. Chem. Soc. 2007, 129, 1048-1049
O
PO
(CH2)3Me
NHBoc
A
OMeOMe
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Evans’ ApproachClass III: Galbulimima Alkaloid 13
Evans, D. A.; Adams, D. J. J. Am. Chem. Soc. 2007, 129, 1048-1049
Roskamp reaction
H
H
H
O NHBoc
Me
O H
H
H
H
O NHBoc
Me
N2O
O
SnCl2
O
OO
H
H
H
O NHBoc
Me
OO
OAllyl
LiOMe,LiClO4
62%(3 steps)
11 steps(+)-GB 13
H
OHN Me
H
H HO
(+)-GB 13
HN Me
O
HH
H
HO
Aldol
H
H
H
Xc
O OR
IMDA adduct
H
R
O
H R
O O
OEt
N2 CO2Et
SnCl2
J. Org. Chem. 1989, 54, 3258-3260
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Biosynthetic Proposal (Movassaghi)
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(+)- and (—)-GB 13 Movassaghi
Br
Br
Br
Me
TBSO N
Me
TBSO
OO
Pd(PPh3)4,Tl2CO3
THF, H2O75%
OTBS
Me B(OH)2 CuI, K2CO3,PhMe, 110 °C
95%
O
HN
O1. TBAF2. MnO2
3. TBSOTf,NEt3, DCM, -78 °C
93%(3 steps)
NTBSO
OO
NTBSO
OO
OHC
NH
HCHO
TBSOHH
O
O
4,5-dihydrolMesCl2Ru=CH(o
=iPrO)Ph
acroleinCH2Cl2
85%
toluene
90 °C82%
>20:1 endo:exo
Movassaghi, M.; Hunt, D. K.; Tjandra, M. J. Am. Chem. Soc. 2006, 128, 8126-8127
H
H
NH
HO
MeH
H H
H
H
OH
H
HN
OH
MeH
HH
H
H
O
OH
HNH
MeH
HOH
HH
OH
HHN
MeH
OHH
HH
Carbonyl protection
(+) and (—) configuration?
(±)
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(+)- and (—)-GB 13 Movassaghi
Movassaghi J. Am. Chem. Soc. 2006, 128, 8126-8127
NH
Me
Me
Cl
IMe
NHBoc
MVK, AIBN,nBu4SnH, DIPEA, PhMe,reflux
53%
Me
NHBoc
O
Me
HCl, H2O
69%
1. nBuLi
N
Me
Li
NH
HCHO
TBSOHH
O
O
2. Martinsulfurane
81%
THF, 85%
NH
HTBSO
HH
O
O
N
Me
NBS, NaHCO3;
nBu4SnH, AIBN,benzene, 90 °C
55%(2 steps)
H
H
N
H
O
O
NMe O
TBS
H
H
H
N
HNMe
H
HH
O
O
TBSO(HF)3·NEt3
H
H
N
HNMe
H
HH
O
O
O
H
Aldol
thenNaBH4
H
H
NH
HO
MeH
H H
H
H
N
O
OH
H
HN
OH
MeH
HH
H
H
N
O
O
separable34% 36%
5-exo-trig
1:1d.r.
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(+)- and (—)-GB 13 Movassaghi
H
H
NH
HO
MeH
H H
H
H
N
O
O
1. CbzCl,65%
2. IBX, TsOH,PhH, DMSO
80% H
H
N
HO
MeH
H H
H
H
OCbz
TMSI;HCl;NaOH
89%H
H
NH
HO
MeH
H H
H
H
O
Absolute stereochemical configuration of (—)-galbulimimaalkaloid 13 confirmed
[α]D= -64 (c 0.06, CHCl3)lit. [α]D= -84 (CHCl3)
Movassaghi J. Am. Chem. Soc. 2006, 128, 8126-8127
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Class II vs. Class III
H
H
NH
HO
MeH
H H
H
H
O H
H
OMe
H
N
OBz
HO
OMe
OMe
H
H H
H
(—)-GB 13 (—)-Himandrine
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Title PaperTBSO
Me
B(OH)2
B
OHHO
from MacMillian'sD-proline cat. !-oxidation
OMe
Br
Br
5 steps
OMeBr
TBSO
Me
B
Pd(PPh3)4,TlCO3,97%
OMeN
TBSO
MeO
2- azetidinone,CuI, 85%
OMeN
TBSO
O
1. TBAF2. SO3·pyr
3. TBSOTf,NEt3
67%(3 steps)
OMeN
TBSO
O
OHC[Ru],
acrolein
85%
BHT, N,N-diethylanaline
MeCN, 95 °C75%
5:1 d.r.
CHO
TBSO
NH
H
HOMe
O
H1. TiCl4, DCM, -78 °C
2. Martin sulfurane57%
(2 steps) H
H
OMe
H
N
H
H
O
O
Mukaiyama aldol
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Title Paper
H
H
OMe
H
N
H
H
O
ON
Me
LiH
H
OMe
H
N
H
O
O
N
Me
H
HH
H
H
OMe
H
N
H
O
O
NH
Me
H
HH
H
H
OMe
H
N
HO
MeH
H H
H
NO
H
CuBr·SMe2
1.
2. NaBH4
3. CBzCl
Cbz
Aldol
TsOH
81%H
H
OMe
H
N
HO
MeH
H H
HCbz O
H POCl3, DMF
H
H
OMe
H
N
HO
MeH
H H
H
Cbz OH
N
Cl
HMe
MeClH
Vilsmeierreagent
71%
H
H
OMe
H
N
MeH
H H
H
Cbz O
O
H
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Title Paper
H
H
OMe
H
N
MeH
H H
H
Cbz O
O
H 1. DDQ
2. NaClO23.; CH2N2 H
H
OMe
H
N
HO
MeH
H H
H
OO
OMeCbz
H
61%(3 steps)
1. TMSI, DCM, 66%
2. (HF)3·NEt3, 90%H
H
OMe
H
NH
HO
MeH
H H
H
OO
OMe
H
H
H
OMe
H
NH
HO
MeH
H H
H
OO
OMe
HNCS
MeCN,rt, 45 min H
H
OMe
H
NH
HO
MeH
H H
HO
OMeOH
H
H
OMe
H
N
HO
MeH
H H
HO
OMeO
H
H
OMe
H
N
HO
MeH
H H
HO
OMeO
1. NaBH4, 90%
2. BzCl, pyr, 87%H
H
OMe
H
N
HO
MeH
H H
HO
OMeOBz
(—)-Himandrine26 steps
89%
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Mechanistic Investigation
H
H
OMe
H
NH
HO
MeH
H H
H
OO
OMe
H CD3OD
H
H
OMe
H
ND
DO
MeH
H H
H
OO
OMe
D
CH3OH
9 9
Proton delivery assisted by amineC(9) stereochem. config. preserved
H
H
OMe
H
NH
HO
MeH
H H
H
OO
OMe
H
H
H
OMe
H
N
HO
MeH
H H
HO
OMeOH
H
OMe
H
NH
HO
MeH
H H
H
OO
OMe
Cl
N
O
O
Cl
H
H
OMe
H
N
HO
MeH
H H
H
OO
OMe
H
Cl
allylicdisplacement
Light-sensitive
Isolable, disappears over course of rxn
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Mechanistic Investigation
H
H
OMe
H
N
HO
MeH
H H
H
OO
OMe
H
Cl
CD3OD
H
H
OMe
H
N
DO
MeH
H H
H
OO
OMe
H9
Cl
9
No C(9) exchange(supports intramolecular deprotonation)
H
H
OMe
H
NH
HO
MeH
H H
H
OO
OMe
H
H
H
OMe
H
N
HO
MeH
H H
HO
OMeO
H
H
OMe
H
N
HO
MeH
H H
H
OO
OMe
H
Cl
Intermolecular transfer of Cl
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Conclusions
-The first enantioselective total synthesis of a class IIGalbulimima alkaloid has been reported in 26 overall steps
-Late-stage spirocyclic N-C(9) bond construction
-2 key concepts- synthetic design and mechanisticinvestigation
-“Biologically inspired synthesis”
-Sensitivity of intermediates
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