Echinosporin, synthesis

Mechanistic analysis of some key reactions employed in the Smith (—)-echinosporin synthesis... 

The slow oxidation of primary alcohols, particularly MeOH, is utilized for the oxidation of allylic or secondary alcohols with allyl methyl carbonate without forming carbonates of the alcohols to be oxidized. Allyl methyl carbonate (564) forms 7r-allylpalladium methoxide, then exchange of the methoxide with a secondary or allylic alcohol 563 present in the reaction medium takes place to form the 7r-allylpalladium alkoxide 565, which undergoes elimination of j3-hydrogen to give the ketone or aldehyde 566. The lactol 567 was oxidized selectively with diallyl carbonate to the lactone 568 without attacking the secondary alcohol in the synthesis of echinosporin[360]. 

In cycloadditions of enones to alkenes novel strategies have been adopted for ring expansion of the cycloadducts, either by the choice of appropriate alkenes, e.g. 2-(trimethylsiloxy)buta-1,3-diene,70 vmv-2-trimethylsiloxybuten-2-oales71 or 3,3-dimethylcyclopropene,72 or by using 3-oxo-l-cyeloalkene-l-carboxylates as enones.73 Asymmetric [2 + 2] photocycloaddition of cyclopent-2-enone to a (+ )-dihydrofuran acetonide constitutes the cornerstone of the synthetic strategy in the first total synthesis of the novel antitumor metabolite ( )-echinosporin.74 The cycloaddition product 25 from treatment of 2-(2-carbomethoxyethyl)-2-cyclopentenone (24) with ethene has been used as a precursor for the preparation of tricyclo[4.2.0.01,4]octane.75... 

Recently, the same group104 has reported the first total synthesis of the novel antitumor metabolite (—)-echinosporin 224. The synthesis is based on an asymmetric [2 + 2] photocycloaddition, which constitutes the cornerstone of the synthetic strategy (Scheme 48). 

Echinosporin (XK-213) is a novel antitumour antibiotic isolated1 from the fermentation broths of Streptomyces echinosporus. It is of great pharmacological interest on account of its significant anticancer effects in several rodent tumour models. (—)-Echinosporin was recently synthesised in enantiomerically pure form by A.B. Smith and coworkers starting from L-ascorbic acid.2 Their synthesis is described below. 

Scheme 6.3 Smith s total synthesis of (-)-echinosporin from L-ascorbic acid.

Smith s synthesis of (—)-echinosporin stands out for its good stereo-and regiocontrol at every stage. Its large number of highly chemoselective reactions, and its use of an asymmetric [2 + 2]-photocycloaddition reaction for constructing the m-fused 6,5-bicyclic core are also commendable. The latter reaction provides a beautiful illustration of how properly harnessed photochemistry can be decisively deployed for the stereocontrolled synthesis of complex natural products. 

Oxidation of the dienolate of (17) with (+)-( ) affords a-hydroxy ester (18), a key intermediate in the enantioselective synthesis of the antibiotic echinosporin (eq 19) whereas oxidation of enolates derived from 1,3-dioxin vinylogous ester (19) gives rise to both a - and y-hydroxylation depending on the reaction conditions (eq 20). With (+)-( ) the lithium enolate of (19) gives primarily the a -hydroxylation product (20), while the sodium enolate gives )/-hydroxylation product (21). Only low levels of asymmetric induction (ca. 16% ee) are found in these oxidations. Birch reduction products are also asymmetrically hydroxylated in situ by (+)-( ) (eq 21). ... 

Smith and co-workers utilized the Bamford-Stevens reaction en route to a total synthesis of echinosporin 51. Tosylhydrazone 49 was heated with sodium in ethylene glycol to afford key intermediate 50 on large scale. Dihydrofuran 50 was then taken through a further ten steps to afford echinosporin 51. 

A novel enzyme which releases 2,7-anhydro-a-lV-acetylneuraminic acid fiom glycoproteins has been identified in the leech Macrobdella decora, and the fungus Peziza echinospora has enzymic activity that degrades a-(1 4)-D-glucans e.g. starch) to 1,5-anhydro-D-ftuctose and thence to the cyclopentane antibiotic echinosporin. The synthesis of 3,6-anhydro-a and p-cyclodextrins is discussed in Chapter 4. 

Smith, A.B., III, Sulikowski, GA., Suhkowsld, M.M. and Fujimoto, K. (1992) Applications of an asymmetric [2+2]-phobxydoaddition total synthesis of (—)-echinosporin. Construction of an advanced 11-deo prostaglandin intermediate. Journal cf the American Chemical Society, 114, 2567-2576. 

Indeed the slow oxidation of primary alcohols enables the use of external allylating agents as oxidants. For example, unprotected lactol 102 was selectively oxidized with diallyl carbonate 103 to yield lactone 104. Lactone 104 was subsequently used in the synthesis of echinosporin. 

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