Asymmetric agelastatin

The asymmetric allylic alkylation (AAA) reaction has been adapted for use with pyrrole nucleophiles <06JACS6054>. For example, treatment of pyrrole 55 and cyclopentene 56 with a palladium catalyst in the presence of a chiral additive gave pyrrole 57 in up to 92% ee. The latter was elaborated into piperazinone-pyrrole natural product, agelastatin A 94. 

Davis FA, Deng J (2005) Asymmetric Total Syntheses of (-)-Agelastatin A Using Sulfini-mine (/V-Sullinyl Inline) Derived Methodologies. Org Lett 7 621... 

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. 

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>. 

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. 

The first asymmetric synthesis of (-)-agelastatin A was achieved by Feldman and Saunders in July 2002, whilst we were in the middle of our own synthetic campaign on this compound. 

Trost BM, Dong G (2006) New class of nucleophiles for palladium-catalyzed asymmetric allylic alkylation. Total synthesis of agelastatin A. J Am Chem Soc 128 6054-6055... 

Davis, F.A. and Deng, (. (2005) Asymmetric total synthesis of (—)-agelastatin A using sulfinimine (N-sulfinyl imine) derived methodologies. Org. Lett., 7, 621-623. 

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