Total Synthesis of Akuammiline Alkaloid (−)-Vincorine via

An asymmetric total synthesis of the Akuammiline alkaloid (−)-vincorine (18 steps from 5-methoxytryptamine, 5% overall yield) is described. The key ...
2 downloads 11 Views 350KB Size
Subscriber access provided by George Mason University Libraries & VIVA (Virtual Library of Virginia)

Communication

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

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Journal of the American Chemical Society is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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

Journal of the American Chemical Society

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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

Page 2 of 5

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 (