Enantioselective Synthesis of a C1-C9 Moiety of Tylonolide, Tylosin Aglycon

Abstract

In an approach to the C1-C9 eastern part 2 of tylonolide, aglycon of tylosin 1, an extension of the Hoppe reaction was, in a first key step, carried out between carbamate 6 and optically active aldehyde 5a and γ-lactol 5b. The latter gave the expected 7b adduct in 85% yield. After a homologation sequence, the C1-C7 fragment 14b was prepared and submitted to a second allylation reaction with crotyl N,N-diisopropyl carbamate to deliver compound 16 in 80% yield as a C1-C9 moiety of tylonolide.In a synthetic approach towards tylosin 1, 1 a macrocyclic antibiotic, construction of the eastern part C1-C9 moiety 2 of the tylonolide, aglycon of tylosin, was envisaged via the enantiospecific preparation of either C1-C7 3 or C2-C7 4 fragment. Preliminary works were directed to the construction of the C2-C7 part 4 and to the stereospecific introduction of substituents at C3, C4, C5 and C6 (Scheme 1). For this purpose we decided to build the C2-C7 fragment using an allylation reaction. Scheme 1For an enantioselective preparation of homoallylic alcohol C2-C7 4 we reported 2 a model study of allylation reaction between optically active aldehyde or lactol and racemic titanated crotyl N, Ndiisopropylcarbamate. 3 In the present work we describe the results obtained in another application and extension of the Hoppe reaction by reaction with ε−alkoxyallyl carbamate 6, 2 in a synthetic approach to the C2-C7 part of the tylosin aglycon.When 2 equivalents of carbamate 6 were treated with 4 equivalents of nBuLi/TMEDA at -78°C and then with 6 equivalents of Ti(O i Pr) 4 , the resulting allyltitanate reacted at -78°C with aldehyde 5a to lead in 60% yield to both isomers 7a and 8a in a 70:30 ratio (Scheme 2, table 1, entry 1). Scheme 2The best result was found when 3 equivalents of carbamate 6 were employed and the reaction temperature maintained at 0°C for 4 hours; under these conditions compound 7a was isolated in 70% yield and compound 8a in 5% yield (75% overall yield, 7a/8a = 94:6, table 1, entry 4).For this observed and surprising increasing selectivity (7a/8a = 70:30 to 94:6), it clearly appears that the yield of major compound 7a did not Downloaded by: NYU. Copyrighted material.

Asymmetric Deprotonation with Alkyllithium–(−)‐Sparteine

“…As a result, the reaction It has been demonstrated by Pancrazi, Ardisson and coworkers that an efficient kinetic resolution takes place when an excess (2 equivalents) of the racemic titanated alkenyl carbamate rac-334a (R 1 = Me) is allowed to react with the enantiopure ω-hydroxyaldehyde 341 or alternatively the corresponding γ -lactol 340, since the mismatched pair contributes to a lower extent to the product ratio (equation 91) 251 . Under best conditions, the ratio of the enantiomerically pure diastereomers 3,4-anti-4,5-syn (342) and 3,4-anti-4,5-anti (343) is close to 14:1.…”

“…Applications in target synthesis include the natural products (+)-quercus lactone (347c) and (+)-eldanolide (347e) 253 . The reagent 334a has also been applied in total syntheses of more complicated natural products: dihydroavermectin B 1b by Julia and coworkers 256 , tylonolide 251 and rac-tylonolide 257 by Ardisson, Pancrazi and coworkers, and jaspamide 258 and herboxidiene 259 by Kocienski and coworkers.…”