Agelastatin synthesis

The carbene-insertion pathway has recently been applied in total asymmetric syntheses of the anti-leukemic alkaloid, (—)-agelastatin A, and the dibromo analog, (-)-agelastatin B (02JA9060, 02JOC7096). Treatment of the (oxazolidinonyl)propynyliodonium triflate 250 with sodium />-toluenesulfinate leads to a mixture of the bicyclic oxazolidinone 251 and the carbenic rearrangement product 252 (Scheme 70) compound 251 is a key intermediate in the agelastatin synthesis. 

Scheme 7 Cyclopentene ring closure in the presence of urethane and sulfonamido groups in total synthesis of agelastatin (38) [30]...

The aziridination of alkenes catalysed by [CuCl(IPr)] complex 150 was used in a key step of the total synthesis of (+)-agelastatin 152 (Scheme 5.39) [44], The aziridination occurs in presence of 50 mol% of 150 in 52% yield. It is important to note that 150 was the only complex able to promote the aziridination of 149, an electron-deficient cyclopentene. 

The numerous excellent synthetic procedures published by A.C. Richardson also continue to be relied upon by contemporary organic chemists because of their great practicality and reproducibility. Indeed, a recent highly cited enantiospecific total synthesis of the antitumor agent, (—)-agelastatin A, justly testifies to this fact it exploits the remarkably useful Hough-Richardson aziridine as a key synthetic intermediate in the eventual published route to this complex natural product. 

SCHEME 8. Hale and Domostoj s use of die Hough-Richardson aziridine in their 2004 enantiospecific total synthesis of die antitumor alkaloid (—)-agelastatin A. 

Alkene Metathesis in Total Synthesis Valienamine, Agelastatin and Tonantzitlolone... 

Applications to natural product synthesis probe the limits of any synthetic method, as situations arise that would never have been considered in the course of first developing the method. Recent syntheses of valienamine 6, agelastatin 9 and tonantzitlolone 15 pressed the limits of ring-closing metathesis. 

The conclusion that this synthesis plan was no longer tenable, seemed inescapable. And so, wiser but no further along, we decided to salvage what we could from this exercise and export that information into a second-generation approach to agelastatin A that was designed to avoid this stereochemical pitfall. 

Stien D, Anderson GT, Chase CE, Koh Y, Weinreb SM (1999) Total Synthesis of the Antitumor Marine Sponge Alkaloid Agelastatin A. J Am Chem Soc 121 9574... 

Feldman KS, Saunders JC, Wrobleski ML (2002) Alkynyliodonium Salts in Organic Synthesis. Development of a Unified Strategy for the Syntheses of (-)-Agelastatin A and (-)-Agelastatin B. J Org Chem 67 7096... 

Asymmetric syntheses of agelastatin A rapidly followed Weinreb s racemic synthesis, with Feldman and coworkers publishing the first stereospecific approach to the natural enantiomer [68,69]. This route employed a chiral alkynyliodonium triflate-alkylidenecarbene-cyclopentene transformation to form the key intermediate 69 from which (—)-6S could be efficiently assembled. Hale et al. initially reported a chiral formal synthesis of (—[-agelastatin A through the enantiospedfic preparation of an advanced intermediate from Weinreb s racemic route [70] and later described a total... 

The intramolecular Michael addition of (—(-pyrrole 149 to give compound (—)-150, an intermediate in the asymmetric synthesis of an unique cytotoxic tetracyclic alkaloid (—)-Agelastatin A, was effected using CS2CO3 (Equation 27) <1998JOC7594, 1999JA9574, 2006ARK120>. 

This interesting chemistry has been apphed in natural product synthesis, especially in the context of the marine alkaloid agelastatin A. In 1999 the first total synthesis of racemic agelastatin A was achieved by Weinreb [70] (Scheme 24). Key intermediate 95 was synthesized via the already mentioned allylic amination sequence, this time using the new sulfodiimide 91. As an-... 

Scheme 24 Application of a Type E rearrangement in the total synthesis of agelastatin A...

Recently Trost et al. succeeded in the total synthesis of (+)-agelastatin A using Pd-catalyzed asymmetric allyUc alkylations [71]. In the course of this study they prepared piperazinone 98 which was amenable to allylic amina-tion via sulfodiimide 78 (Scheme 25). In the context of Weinreb s synthesis the authors claim 99 to be a suitable intermediate for the synthesis of the (-)-enantiomer of agelastatin A. 

In 1999 it was again Weinreb who used this chemistry in the context of the total synthesis of the marine sponge alkaloid agelastatin A (Scheme 59, see also Scheme 24) [70]. This time M-sulfinyl methylcarbamate 231 was used to yield cycloadduct 233 which was opened to allylic sulfoxide 234. Heating in HMPTA/EtOH delivered via [2,3]-a rearrangement a mixture of the desired cyclized carbamate 236 and the open-chain transesterification product 237, which also cyclized under the influence of base. 

Scheme 59 Excerpt from an agelastatin A synthesis featuring the combined application of a sulfinylcarbamate cycloaddition and a ME rearrangement...

Methylenation of complex aminoaldehyde derivative 315 (Scheme 102) has been achieved [141] using methyl PT sulfone and KHMDS in THE Noteworthy, neither Wittig, Tebbe nor Peterson olefination could be employed in this case. The diene 317 was further used in the synthesis of (-)-Agelastatin 318. 

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