title: Total syntheses of pamamycin 607 and methyl nonactate: stereoselective cyclisation of homoallylic alcohols that had been prepared with remote stereocontrol using allylstannanes.
abstract: The tin(IV) chloride mediated cyclisation of (Z)-homoallylic alcohols using phenylselenenyl chloride or phthalimide in the presence of a Lewis acid followed by reductive removal of the phenylselenenyl group was found to give 2,5-cis-disubstituted tetrahydrofurans with excellent stereocontrol. Using this procedure, (2S,4S,8R,6Z)-9-benzyloxy-2-tert-butyldiphenylsilyloxy-8-methylnon-6-en-4-ol (11), prepared stereoselectively via the tin(iv) chloride promoted reaction between the (R)-5-benzyloxy-4-methylpent-2-enyl(tributyl)stannane (3) and (S)-3-tert-butyldiphenylsilyloxybutanal (10), gave (2S,3R,6S,8S)-1-benzyloxy-8-tert-butyldiphenylsilyloxy-3,6-epoxy-2-methylnonane (13) after deselenation. This tetrahydrofuran was selectively deprotected, oxidized and esterified to give methyl nonactate (2). Having established this synthesis of 2,5-cis-disubstituted tetrahydrofurans, it was applied to complete a synthesis of pamamycin 607 (1). (2S,3R,6S,8R)-1-Benzyloxy-8-[N-methyl-N-(toluene-4-sulfonyl)amino]-3,6-epoxy-2-methylundecane (35) was prepared stereoselectively from (R)-3-[N-(toluene-4-sulfonyl)-N-methylamino]hexanal (32) by reaction with the stannane 3 followed by cyclisation of the resulting alkenol 33 and deselenation. Following debenzylation and oxidation, an aldol reaction of the aldehyde 37 using the lithium enolate of 2,6-dimethylphenyl propanoate (61) gave mainly the 2,3-anti-3,4-syn-adduct 48. After protection of the secondary alcohol as its tert-butyldimethylsilyl ether 49, reduction using DIBAL-H and oxidation, the resulting aldehyde, (2S,3S,4R,5R,8S,10R)-3-tert-butyldimethylsilyloxy-2,4-dimethyl-5,8-epoxy-10-[N-methyl-N-(toluene-4-sulfonyl)amino]tridecanal (62), was taken through to the bis-tetrahydrofuran 65 by repeating the sequence of the reactions with the stannane 3, cyclisation and deselenation. The N-(toluene-4-sulfonyl) group was then replaced by an N-(tert-butoxycarbonyl) group and O-debenzylation and oxidation gave the carboxylic acid 70 that corresponds to the C(1)-C(18) fragment of pamamycin 607 (1). Similar chemistry was used to prepare the C(1')-C(11') fragment 89 of the pamamycin, except that in this case the configuration of the secondary alcohol introduced by the allylstannane reaction had to be inverted using a Mitsunobu reaction before the cyclisation. Esterification of the carboxylic acid of the C(1)-C(18)-fragment 70 using the alcohol 89 of the C(1')-C(11') fragment followed by selective deprotection, macrocyclisation, N-deprotection and N-methylation gave pamamycin 607 (1) that was identical to a sample of the natural product.
authors.affiliation: School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK.
authors.forename: Olivier
authors.initials: O
authors.lastname: Germay
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Moore
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Thomas
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003500:Cyclization; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D010084:Oxidation-Reduction; D020005:Propanols / Q000737:chemistry*; D013237:Stereoisomerism; D017971:Tin Compounds / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D005663:Furans; D018942:Macrolides; D020005:Propanols; D017971:Tin Compounds; C514123:methyl nonactate; C470905:pamamycin-607; C023599:stannous chloride; C006463:allyl alcohol