Aglycons seco acids

The construction of the naturally derived narbomycin and tylosin-aglycones by Masamune and coworkers employ identical methodology for seco-acid formation. In each case, Peterson alkenadon of a functionalized aldehyde (not shown) and the silyl ketones (96 R = SiMes Scheme 36) or (99 Scheme 37) efficiently introduced the required ( )-a,3-unsaturation. Silyl ketone formation is accomplished in each case through cuprate acylation by an activated carboxylic acid derivative. Formation of an acid chloride was not possible in the sensitive tylosin-aglycone intermediate however, selective acylation of the silylcuprate proceeded at the pyridyl thiol ester moiety of (98) and not with the r-butyl thiol ester. In a related investigation, (97), an advanced intermediate for 6-deoxyerythronolide B, was obtained from (95) via addition of lithium diethylcuprate to the acid chloride (84% yield). In all the above cases, no addition was observed at the f-butyl thiol ester. 

Aldol condensation between ketone 307 and aldehyde 298 afforded the E,E)-dienone 308 in 41% yield. Nonselective reduction of the C-9 ketone and base hydrolysis then produced a 77% yield of the seco acids 309. Lactonization utilizing the Corey thiopyridyl ester method and selective oxidation of the C-9 allylic hydroxyl group afforded the protected aglycone 310 in 59% yield. 

In retrospect, our design for a seco acid precursor to the aglycon core... 

The resulting seco-acid methyl ester 131 was treated with nBu4NF( ) to remove the silyl ethers then saponified to afford the deprotected seco-acid. Macrolactonization with DCC followed by selective silylation of the C-5 hydroxl group afforded aglycone 132. Disaccharide 133 (derived from natural avermectin Bi, see disaccharide section) was then attached to the aglycone to afford penultimate intermediate 134. The crucial deconjugation of the C-2,3... 

Tylonolide hemiacetal (33), the aglycone of the antibiotic tylosin, possesses an anti 14-hydroxymethyl-15-acyloxy stereochemistry conveniently contained in 26, which may be viewed as the western half of 33. In order to prepare the eastern half of 33, an aldol reaction leading to the desired syn stereochemistry at C-3 and C-4 is exploited. The reaction of achiral aldehyde 27 with the S-boron enolate 28 proceeds with the expected diastereofacial selectivity to provide, in a combined yield of 80% after O-silylation, a separable mixture of 29 (derived from the / -enantiomer of 27) and 30 (from the S-enantiomer of 27). Subsequent functional group transformation of 30 ultimately leads to the a-(TMS)methylketone 31. The anion of 31, generated with lithium hexamethylsilazide in THF at — 78 °C, undergoes a Peterson condensation with 26 to afford in 60% yield the seco-diC d 32. Treatment of 32 with 70% acetic acid at 85 °C for one hour affords 33 in 60% yield. The attractive feature of this... 

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... 

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