Enantioselective Total Synthesis of the Osteoclastogenesis Inhibitor (+)-Symbioimine

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114188062/ABSTRACT

From Prof. Regan J. Thomson's group at Northwestern University, Evanston, IL

A short synthesis of (+)-Symbioimine (1) was recently reported in ACIEE EarlyView. The synthesis an unusual intramolecular Diels-Alder reaction of conjugated cyclic iminium ion intermediate. Compound 1 is believed to find potential uses in preventative treatment of osteroporosis and possibly as an anti-inflammatory therapeutic agent.

In their retro, it was thought that the allylic methyl group in 3 would impose a poor facial selectivity for an exo [4+2] cycloaddition; not enough to drive the reaction to the desired stereochemistry. However, the cyclic iminium species 4 with its stereo-defined allylic methyl group was believed to impose a stronger preference for an endo cycloaddition to provide cycloadducut 5 with good desired stereochemistry. This cycloadduct then could undergo an epimerization to adjust its stereochemistry to an all trans ring junction of 1.

Diene 13 was identified as the needed Diels-Alder precursor and the synthetic route was devised as shown in the scheme below.

Starting from aldehyde 6, HWE olefination proceeded with good yield to provide 7 with excellent E/Z selectivity (>11:1). Conversion to methyl ketone 8 could be performed through Weinreb amide in one step for a small scale or a two-step protocol is necessary for a larger scale synthesis. Mukaiyama aldol of enol ether 9 with acetal 11, followed by the Staudinger-aza-Wittig reaction sequence then provided the key compound 13 in excellent yield.

Heating 13 with TFA effected the formation of 14 followed by cycloaddition-epimerization allowed a rapid access to the imine 16. Treatment of 16 with TFAA then afforded 17 in good overall yield as a single diastereomer. The structure of 17 was characterized with nOe experiments, and could be converted back to 16 under mild reaction conditions by treatment with K2CO3/MeOH.

Treatment of 16 with BBr3 (global demethylation), followed by selective sulfation finally afforded the natural product 1. This synthesis has showcased the use of the dihydropyridinium species (14) in a rare Diels-Alder reaction, which could find more uses in the future. The lower yield of the cycloaddition was probably due to the generation of other unavoidable pyridine derivatives. However, this Diels-Alder reaction may provide a direct support in the biosynthesis of 1. Overall, this is a very nice and short synthesis that could provide rapid access to 1 and its analogs.

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.

A Concise, Biomimetic Total Synthesis of Stephacidin A and Notoamide B

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114123312/ABSTRACT

From Prof. Robert M. Williams' group at Colorado State University and Prof. Sachiko Tsukamoto's group at Kanazawa University

Both titled compounds are marine natural products, exhibiting cytotoxicity against various human tumor cell lines.

This is a nice synthesis which also establishes biomimetic synthetic relationship between stephacidin A and notoamide B. The total synthesis of stephacidin A started first with the main feature being an intramolecular Diels-Alder reaction of the prenylated indole and in situ generated azadiene to give the desired cycloadduct in good diastereoselectivity and great yield [syn:anti = 2.4 (61%):1.0 (25%)].

The biosynthetic pathway from stephacidin A to notoamide B was then tested by exposing stephacidin A to an oxaziridine. The indole in the stephacidin A was oxidized to 2-oxo-indole, followed by an in situ pinacol-type rearrangement/ring contraction to give the desired spiro-oxindole core of notoamide B (73%). The authors also noted that this was the first example of using oxaziridine to effect such transformation to give spiro-oxindole efficiently. Further studies of scope of such reaction sequence with oxaziridine are ongoing.