Ansamycin reactions

A reiterative application of a two-carbon elongation reaction of a chiral carbonyl compound (Homer-Emmonds reaction), reduction (DIBAL) of the obtained trans unsaturated ester, asymmetric epoxidation (SAE or MCPBA) of the resulting allylic alcohol, and then C-2 regioselective addition of a cuprate (Me2CuLi) to the corresponding chiral epoxy alcohol has been utilized for the construction of the polypropionate-derived chain ]R-CH(Me)CH(OH)CH(Me)-R ], present as a partial structure in important natural products such as polyether, ansamycin, or macro-lide antibiotics [52]. A seminal application of this procedure is offered by Kishi s synthesis of the C19-C26 polyketide-type aliphatic segment of rifamycin S, starting from aldehyde 105 (Scheme 8.29) [53]. 

In order to apply tartrate ester-modified allyl- and crotylboronates to synthetic problems,23 Roush and Palkowitz undertook the stereoselective synthesis of the C19-C29 fragment 48 of rifamycin S, a well-known member of the ansamycin antibiotic group24 (Scheme 3.1u). The synthesis started with the reaction of (S,S)-43E and the chiral aldehyde (S)-49. This crotylboration provided the homoallylic alcohol 50 as the major component of an 88 11 1 mixture. Compound 50 was transformed smoothly into the aldehyde 51, which served as the substrate for the second crotylboration reaction. The alcohol 52 was obtained in 71% yield and with 98% diastereoselectivity. After a series of standard functional group manipulations, the alcohol 53 was oxidized to the corresponding aldehyde and underwent the third crotylboronate addition, which resulted in a 95 5 mixture... 

Aminopolyhydroxynaphthalenes. This NH, synthon was used to convert the protected bromopolyhydroxynaphthalene derivative I to the protected aminopolyhydroxy-naphthalene derivative 2, the aromatic nucleus of an ansamycin. One advantage of this amination is the satisfactory yield, which occurs in spite of the steric factors usually observed in the reaction of bromides with potassium azide. 

Ansamycins - The structures, reactions, physical properties and biosynthe-sis of these antibiotics were reviewed.98 Protostreptovaricins I-IV were described as precursors of the streptovaricins.99 Also, the biosynthetic sequence damavaricin D - SvD -> SvC SvB, SvJ was determined.100 The isolation and structure of actamycin was reported.101 An immunosuppresent effect in mice of rifamycin and streptovaricin a..alogues correlated with toxicity but not with in vitro activity.102 The plasma decline of ethynyl-estradiol after administration of rifamycin was quantified in humans.103... 

Macrolides and Related Compounds. - Complex phosphonates continue to be used in the construction of carbon skeletons and in cyclisation reactions, as exemplified by the synthesis of didesepoxyrhizoxin, the biogenetic precursor of the antitumour agent rhizoxin, via intramolecular olefination of (225). (+)-Trienomycins A and F, members of a family of ansamycin antibiotics, have been synthesised using a double Wittig reaction of the diphosphonium salt (226) as a key step. The reaction produces a mixture of isomers including 21% of the required (all- ) product. 

The lactam functional group is encountered in numerous macrocychc lactams like, for example, the inacrocy-clic polyamine alkaloids and the ansamycin antibiotics. Lactam formation can be achieved by intramolecular reaction between acyl chloride and amine functional... 

In a further exanple. Smith and Wan exploited the nucleophilic capability of l-phenyl-2-tetrazoline-5-thione in the Mitsunobu reaction, followed by oxidation to the sulfone with hydrogen peroxide and ammonium heptamolybdate tetrahydrate as a key step in a synthesis of the ansamycin antiobiotic, (+ )-thiazinotrienomycin-E (eq 8). Importantly, use of the phenyltetrazolylthione-derived sulfone gave an 13Z ratio of 10 1 in this coupling whereas the more conventional benzthiazole-2-thiol-derived system resulted in a selectivity of only 1.5 1 in favor of the -isomer. 

Nearly all of the structures assigned to the ansamycins rest, ultimately, on x-ray investigations. Consequently, little attention will be paid in this section to those degradative reactions which allowed the assignment of the structures of individual antibiotics by chemical means. Instead, the degradations will be covered in Section III, which describes the reactions of the compounds. 

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