A Concise Total Synthesis of the Notoamides C and D

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114123310/ABSTRACT

From Prof. Robret M. Williams' group at Colorado State University

This paper came out a while back in ACIEE EarlyView and now is in print. It details the research aiming at total synthesis and biosynthesis of fungi metabolites notoamides C and D and their related prenylated indole alkaloid cousins, namely the notoamides A and B, norgeamides A, B, C, and D and Stephacidin A. For Stephacidin A, its total synthesis and biomimetic synthesis had been written about before in an early entry of this blog.

As seen in the scheme that follows, it is thought that indole 11 is the common biosynthetic intermediate of all the alkaloids mentioned. In the biosynthesis of notoamides C (3) and D (4), oxidation of the C2-C3 bond in the indole ring is involved, after which, the intermediate epoxide takes different reaction paths.

For the formation of 4, epoxidation of indole C2-C3 bond is followed by openning-trapping with nitrogen of tryptophyl amide to form the pyrroloindole system. As for 3, after oxidation of C2-C3 bond, pinacol-type rearrangement follows to give the oxindole system.

After the intermediate 11 was identified, the synthesis of this intermediate could be traced back to the simpler fragments of glycine, (S)-proline and the gramine derivative 13.

Indole 11 could then be put together as shown in the scheme below.

Indole 18 could be separated from 11 by chromatography. When 11 was subjected to oxidation with oxaziridine 19, notoamides C, and D and the 3-epi-notoamide C were isolated in the combined yields of about 86% (3 (28 %), 20 (48%), 4, and 2,3-epi-notoamide (10% combined)).

The conversion of the oxidized intermediate was proposed to occur as followed.

Notoamide C should arise from the oxidation from the alpha-face of 11 and notoamide D would arise from beta-face oxidation. The fact that the oxindole species of 3 is usually isolated in a more dominant amount than N-tryptophyl trapping of 4 may imply that besides the role of nitrogen of indole in the ring openning of epoxide, oxygen atom in the pyranyl ring may also assist in the ring openning. The authors were not able to use modeling to rationalize the occurance of oxindole in higher amount.

However, the hypothesis of the pyranyl ring participation was tested by replacing the pyran ring with BocO group at the 6-position of the indole nucleus. The electron-withdrawing Boc group should attenuate the electronic effect of oxygen into the ring. This should change the outcome in term of products distribution of the reaction (more N-trapping and less pinacol-type rearrangement to oxindole).

This indeed was the case as shown in the scheme below.

Compound 29 failed to be oxidized by oxaziridine 19. But when 29 was exposed to oxygen in the presence of methylene blue, only products 30 and 31 were obtained as a result of trapping the intermediates (both alpha-face and beta-face oxidations) with tryptophyl amide nitrogen and no oxindole was detected. Therefore, by changing the electronic property of the indole ring (ie, oxygen at the 6-position), the pathway of the reaction can be controlled and/or altered.

The oxidation-pinacol rearrangement sequence of indole to give oxindole in this synthesis is believed to be the first example of the transformation where the oxindole was obtained directely from indole after oxidation. This represents a more convenient way in accessing oxindole nucleus from indole than the traditional multi-step method, which typically consists of chlorination at C3 with hypochlorite, followed by hydration to form 2-hydroxy-3-chloro-indoline (chlorohydrin), then pinacol-type migration of hydride concurrent with dechlorination.

These are pretty nice total syntheses and biomimetic systhetic studies.