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Total synthesis of Akuammiline alkaloid (-)vincorine via intramolecular oxidative coupling Weiwei Zi, Weiqing Xie, and Dawei Ma J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja303602f • Publication Date (Web): 22 May 2012 Downloaded from http://pubs.acs.org on May 22, 2012
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Journal of the American Chemical Society
Total Synthesis of Akuammiline Alkaloid (-)-Vincorine via Intramolecular Oxidative Coupling Weiwei Zi, Weiqing Xie and Dawei Ma* State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China Supporting Information Placeholder In our previous work, we achieved the first asymmetric total ABSTRACT: An asymmetric total synthesis of Akuammiline synthesis of (-)-communesin F via formation of the spiroalkaloid (-)-vincorine (18 steps from 5-methoxytryptamine, indoline intermediate 8 through an intramolecular oxidative 5% overall yield) is described. The key steps include Pdcoupling of 3-substituted indole 7 (Figure 2).10 As an extencatalyzed direct C-H functionalization of indole derivatives, sion of this work, we designed another type of intramolecular organocatalyzed asymmetric Michael addition of aldehydes to oxidative coupling11 by using compounds 9 as the substrates, alkylidene malonates, as well as intramolecular oxidative couin which the coupling might occur between indole and malopling between indole and malonate moieties. nate moieties. If this reaction worked, we would be able to obtain tricyclic intermediates 10, which could be used for synthesizing vincorine and related alkaloids. 3,4a-Disubstituted-2,3,4,4a-tetrahydro-1H-carbazole-4carboxylic acid methyl ester (1) and its heteroatom captured form (2) are highly congested polycyclic ring systems,1 which are common skeletons for Akuammiline-type alkaloids, such as strictamine (3),2 scholarisine A (4),3 vincorine (5)4 and aspidophylline A (6).5 Because of their interesting biological activity and inspiring architecture, these alkaloids have garnered considerable interest in the synthetic community.6-9 In 2009, Qin group completed the first total synthesis of (±)-vincorine,7 in which their intramolecular cyclopropanation and subsequent ring-opening strategy was employed for elaborating a key tricyclic intermediate. Quite recently, Garg and coworkers reported the total synthesis of (±)-aspidophylline A by utilizing the interrupted Fischer indolization reaction as a key step,8 and Smith group disclosed an elegant synthesis of (+)-scholarisine A that is featured with a reductive cyclization cascade to form the cage-shaped tricyclic intermediate.9 Figure 2. Two types of intramolecular oxidative coupling pathways 4
Me N
TBSO
21
N
Me
2
BocN HN
H CO2Me 15
7 16
H
H
OMe (-)-Vincorine (5)
OMe
MeO2C Boc N
TBSO
H CO2Me
16
OMe 12
MeO2C
MeO
CO2Me
16
H N
+
15 H CO2Me CO2Me
7
11
CHO
Me
N
CO2Me
MeO
BocHN
Me
15 7
SeAr
Figure 1. Representative Akuammiline alkaloids and their common carbazole carboxylate skeleton
14
NHBoc
15 (Ar = 2-NO2C6H4)
13 NHBoc
Figure 3. Retrosynthetic analysis for (-)-vincorine (5)
ACS Paragon Plus Environment
OTBS
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With this idea in mind, we proposed a retrosynthetic analysis for (-)-vincorine as shown in Figure 3. Disconnection of the N4-C21 bond of (-)-vincorine would give rise to aminal intermediate 11, which could be derived from carbazole carboxylate 12. The latter could be accessed from 13 via the type II oxidative coupling pathway, while olefin 13 could be constructed via an organocatalyzed Michael addition12 of aldehyde 15 to alkylidene malonate 14 and subsequent transformations. Scheme 1 H N MeO
Boc N
a, b 71% MeO
NH2
16 Boc N
MeO
NHBoc
MeO2C Boc N
MeO2C Boc N
g 75%
MeO
MeO2C Boc N
h, i
CHO
NHBoc
14
CO2Me 15
CO2Me
77%
18
c, d 81%
NHBoc
17
e, f
OH
CO2Et
CO2Me CHO
94% MeO
MeO 20 NHBoc
N H
19
Ph Ph OTMS
21
SeAr
NHBoc
Ar = 2-NO2C6H 4
MeO2C
j, k 84% CO2Me
R N
OTBS
MeO l, 74%
22: R = Boc NHBoc 13: R = H
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O-TMS protected diphenylprolinol 19 in MeCN at 0 oC for 3 days. In this case, the desired Michael adduct 20 were isolated with 75% yield as a diastereomeric mixture in a ratio of 5:1. After failing to increase diastereoselectivity by changing solvents, reaction temperatures and catalysts, we decided to use this mixture for further conversion. Accordingly, oxidation of the aryl selenide part in 20 followed by Et3N-mediated elimination produced olefin 21 as a mixture of E- and Z-isomers. The ratio was about 1.7:1, which could be enhanced to 30:1 by exposing on UV light (360 nm) for 16 hours. Noteworthy is that using both bases and acids as catalysts for this isomerization failed to give any satisfactory results. Unfortunately, the ee value of 21 was only 64% (enantiomer ratio was about 82:18) as determined by chiral HPLC. This probably originates from moderate diastereoselectivity at the C15 position during the formation of 20. Next, reduction of the aldehyde 21 and protection the resultant alcohol with TBS delivered 22 in 84% yield. Finally, selective removal of the Boc protecting group in indole part15 was achieved by treatment with silica gel at low pressure to furnish 13 with 73% yield. With the diester 13 in hand, we attempted the crucial intramolecular oxidative coupling (Scheme 2). Deprotonation of 13 with two equivalent LHMDS, followed by adding a solution of iodine at -78 oC only gave the desired coupling product 23 in a low yield (
