Tirandamycic acid

The most complex application of the Ireland-Claisen rearrangement is Ireland s synthesis of monensin A (Fig. 4.2). Claisen rearrangements were ultimately used to establish the C4-C5, C12-C13, and C16-C17 bonds. 

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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... 

Here again, rearrangement reactions proved useful for the formation of carbon-carbon bonds at the anomeric center. This reaction was originally devised for the construction of C-glycosides [270-272], but was used with some success in several syntheses like those of nonactic acid [273], tirandamycic acid [274] and streptolic acid [275]. 

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). ... 

We now wish to record some of the details of our recent investigations in this area that have culminated in the design of highly concise entries to (+)-KDO (1), (-)-tirandamycin A (2) and (+)-tirandamycic acid (3), (+)-Prelog-Djerassi lactone (4), and the seco-sicids of the aglycones of the erythromycins A (6) and B (7) our basic plan for the total syntheses of macbecin (8) and the closely related substance herbimycin A (9) will also be outlined... 

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. ... 

Tirandamycic acid (47), the acyl side-chain of (45c), has been prepared in optically active form from a carbohydrate precursor, and some key intermediates in the route are shown in Scheme 7. ... 

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]. 

The utilization of sugars as a source of cheap, chiral starting materials continues to flourish. Thus, D-glucose serves as the starting material in syntheses of tirandamycic acid (117), tylonolide (118), and carbomycin B (119) and leucomycin A3 (120). ... 

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