Total Synthesis of Akuammiline Alkaloid (−)-Vincorine via Intramolecular Oxidative Coupling
Zi, W.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2012, 134, 9126.
Current literatureGong Xu
2012-11-15
OMe
N
N
H COOMe
Me
HMe
(-)-Vincorine
1
Yasui, Y.; Kinugawa, T.; Takemoto, Y. Chem. Commun. 2009, 4275.
NN
COOMeH
Me
MeO
vincorine
NN
COOMe
Me
echitamine
HO
Me
HON
N
COOMeH
Me
MeO
ceylanine
CHONN
OOOH
• Characteristic bicyclic framework fused with 1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b]indole skeleton
• Exhibit a broad range of important bioactivities, including anticancer activity
• Vincorine is an alkaloid isolated from Vinca minor L
2
Synthesis of Tetracycle 6 from Tetrahydrocarboline 1
Zhang, M.; Huang, X.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2009, 131, 6013.
3
Zhang, M.; Huang, X.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2009, 131, 6013.
4
(a) Na/naphthalenide (10 equiv),THF, -78 0C, 2 h;(d) Mukaiyama's reagentEt3N (4 equiv), CH2Cl2, rt, 12 h65% of 14 from 12
N NTs
13
OTBSO HO
MeO
Boc
N
MeO
BocN O
OTBS
14
(a) LDA (3 equiv), TiCl(OiPr)3(6 equiv), CH3CHO (10 equiv),THF, -78 0C, 12 h;
(b) DCC (5 equiv), CuCl (10 equiv),benzene, reflux, 12 h,65% of E-15a and Z-15b in a 4:1 ratiofrom 14.
N
MeO
BocN O
OTBS
E-15a
+ N
MeO
BocN O
OTBS
Z-15b
4:1
H
H
noe
N
MeO
BocN
OTBSDIBAL-H
or LiAlH4
18
Zhang, M.; Huang, X.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2009, 131, 6013.
DCC:
N C N
5
Completion of the total syntheses of (+−)-Vincorine
N
MeO
BocN O
OTBS
E-15a
NNH
COOMeMeO
Boc
TBSONaOMe, MeOH/CH2Cl2 1:1,0 0C, 48 h,
83% of E-16a and traceamount of Z-16b
E-16a
DIBAL-H (4 equiv), -78 0C,CH2Cl2, 30 min, 95%
NNH
MeO
Boc
TBSO
17
HO(a) Cl3CCN (3 equiv), PPh3(3 equiv), rt, 30 min, CH2Cl2;
(b) KI (0.3 equiv), K2CO3(4 equiv), CH3CN, 60 0C, 12 h,93% yield from 17;
N
MeO
BocN
OTBS
18
(a) 40% HF, CH3CN/CH2Cl2(1:1), rt, 8 h, 91%;
(b) Dess-Martin reagent(2 equiv), CH2Cl2, rt, 30 min,89% yield from 18
N
MeO
BocN
O
19
(a) NaClO2 (6 equiv), NaH2PO4(3 equiv), t-BuOH/CH3CN/H2O2:2:1, rt, 30 min;
(b) CH2N2, Et2O, rt, 30min, 82% yield from 19
N
MeO
BocN
20
O
O (a) TMSOTf (2 equiv), CH2Cl2,0 0C, 30 min
(b) HCHO, NaBH3CN,CH3CN/AcOH (10:1), rt, 30 min,75% yield from 20
N
MeO
MeN
O
O
(+-)-Vincorine Zhang, M.; Huang, X.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2009, 131, 6013.
6
Retrosynthesis analysis for (−)-Vincorine
OMe
N
N
H COOMe
Me
H
Me
(-)-VincorineOMe
HN
BocN
H COOMe
Me
H
21
OTBS214
27 16
15
OMe
N
BocHN
COOMeCOOMe
Me
H
22
OTBS
716
15
oxidative coupling
HN
MeO
NHBoc
OTBS
MeOOC COOMe
7
15
16organocatalyzedMichael addition
HN
MeO
NHBoc
MeOOC COOMe
7
+CHO
SeAr2324 25 (Ar = 2-NO2C6H4)
Zi, W.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2012, 134, 9126.
7
Preparation of the oxidative coupling precursor 23
Zi, W.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2012, 134, 9126.
8
Completion of the total syntheses of (−)-Vincorine
Zi, W.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2012, 134, 9126.
OMe
HN
BocN
COOMeCOOMe
Me
H
OTBS
716
15
33
9
• 18 steps from commercially available 5-methoxytryptamine in an overall yield of
5%.
• Key elements in this synthesis:
Pd-catalyzed direct C−H functionalization of indole derivatives;
organocatalyzed asymmetric Michael addition of aldehydes to alkylidene
malonates;
intramolecular oxidative coupling between indole and malonate moieties.
• A promising synthetic strategy for assembling other Akuammiline-type alkaloids.
10
Thank you!
11
Cascade reaction for the assembly of tetracyclic skeleton
Shen, L.; Zhang, M.; Wu, Y.; Qin, Y. Angew. Chem. Int. Ed. 2008, 47, 3618.
12
Reactions based on Mukaiyama's reagent
Mukaiyama, T. Angew Chem Int Ed Engl. 1979, 18, 707
13
Palladium-Catalyzed Intermolecular Alkenylation of Indoles by Solvent-Controlled Regioselective C-H Functionalization
• C3 Functionalization: 10% Pd(OAc)2, Cu(OAc)2 (1.8 equiv), DMF/DMSO (10:1) • C2 Functionalization: 20% Pd(OAc)2 , tBuOOBz (0.9), 1,4-dioxane/AcOH (3:1)
Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. Angew. Chem. Int. Ed. 2005, 44, 3125 –3129
14
Fujiwara, Y.; Moritani, I.; Danno, S.; Asano, R.; Teranishi, S.J. Am. Chem. Soc. 1969, 7166
Oestrich, M. The Mizoroki-Heck Reaction; John Wiley & Sons, 2009, p. 14
15
Garg, N.K.; Caspi, D.D.; Stoltz, B.M. Synlett 2006, 18, 3081
16
Favored and unfavored conformations during the oxidative coupling
Zi, W.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2012, 134, 9126.
