Tirandamycic acid synthesis

Desperation can be an important stimulant for the development of new methodology and our next example exemplifies creative circumvention necessitated by the failure of more conventional methods for cleaving a MEM ether during a synthesis of Tirandamycic Acid, Ireland and co-workers497 resorted to n-BuLi in heptane to generate a vinyl ether 270 2 (by elimination of lithium methoxide from 270.1) which was subsequently hydrolysed with mercury(II) acetate [Scheme 4.270] and the method has been used by others,498-499... 

Exo- and endo-cyclic ring closure reactions using 0-nucleophiles transform oxocarbenium ions into cyclic acetals. As an example of an endocyclic cyclization, epoxide ring opening of (96) with lithium dimethyl cuprate, and subsequent treatment of the resulting alcohol with acid, smoothly gives the bicyclic acetal (97), ° a key intermediate in the total synthesis of tirandamycic acid (Scheme 47). ... 

A Concise Approach to (-)-Tirandamycin A (2) and (+)-Tirandamycic Acid (3). Tirandamycin A (2) is a representative member of a novel class of naturally-occurring antibiotics that are characterized by the presence of an enolized 3-dienoyl tetramic acid moiety coupled with the unusual dioxabicyclo[3.3.1]nonane ring system. In addition to its antimicrobial activity, 2 inhibits bacterial DNA-directed RNA polymerase, and it interferes with oxidative phosphorylation. Early synthetic work in this area focused upon the preparation of (+)-tirandamycic acid (3), " which is a degradation product of tirandamycin A (2). The first major achievement in this area was Ireland s synthesis of 3 from D-glucose, but more recently 2 has also been prepared by total synthesisOur own investigations in this area culminated in a facile, asymmetric synthesis of 26, which played a pivotal role in Ireland s synthesis of 2 and Schlessinger s synthesis of 3. ... 

In 1981 Ireland et al. [106] reported the total synthesis of tirandamycic acid (Scheme 4.113). Rearrangement of the Z-sUyl ketene acetal via a boat transition state afforded a 81 19 ratio of diastereomers. Similar rearrangements were employed by Ireland in the synthesis of the structurally related (-t)-streptolic acid [107] and by Kishi et al. in the synthesis of the C27-C38 fragment of the halichon-drins [108]. 

Having thus established the main stereochemical features, the Claisen rearrangement of glycal esters could be further utilized to provide key intermediates for a number of natural product syntheses Carbohydrates served as starting materials in the total synthesis of the ionophore antibiotics lasalocid A 43 by Ireland et al. [15] and indanomycin 46 by Ley et al. [16] (Scheme 8), as well as the 3-acyl tetramic acid antibiotics tirandamycic acid 49 [17] and (+)-streptolic acid 52 [18] (Ireland et al.. Scheme 9). Several further examples have been reported in the literature [19-21]. 

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