Total Syntheses of (+)-Tedanolide and (+)-13-Deoxytedanolide

Abstract

Convergent total syntheses of the potent cytotoxins (+)-tedanolide (1) and (+)-13-deoxytedanolide (2) are described. The carbon framework of these compounds was assembled via a stereoselective aldol reaction that unifies the C(1)-C(12) ketone fragment 5 with a C(13)-C(23) aldehyde fragment 6 (for 13-deoxytedanolide) or 52 (for tedanolide). Multiple obstacles were encountered en route to (+)-1 and (+)-2 that required very careful selection and orchestration of the stereochemistry and functionality of key intermediates. Chief among these issues was the remarkable stability and lack of reactivity of hemiketals 33b and 34 that prevented the tedanolide synthesis from being completed from aldol 4. Key to the successful completion of the tedanolide synthesis was the observation that the 13-deoxy hemiketal 36 could be oxidized to C(11,15)-diketone 38 en route to 13-deoxytedanolide. This led to the decision to pursue the tedanolide synthesis via C(15)-(S)-epimers, since this stereochemical change would destabilize the hemiketal that plagued the attempted synthesis of tedanolide via C(15)-(R) intermediates. However, use of C(15)-(S) configured intermediates required that the side chain epoxide be introduced very late in the synthesis, owing to the ease with which the C(15)-(S)-OH cyclized onto the epoxide of intermediate 50.

Total Syntheses and Biological Reassessment of Lactimidomycin, Isomigrastatin and Congener Glutarimide Antibiotics

“…The subsequent Fráter–Seebach alkylation could also be performed on a 10 gram scale 46. In concord with a downstream Evans aldol reaction,47 this robust route allowed the four chiral centers decorating this building block to be set with high selectivity 48. Routine protecting group and oxidation state management led to aldehyde 31 , which was chain‐extended by a Julia olefination with sulfone 32 49 to give the required enyne motif.…”

Enantioselective Total Synthesis of Amphidinolide F

“…Next, careful deprotection at C 18 under aqueous acidic conditions followed by oxidation yielded the sensitive C 15 , C 18 -diketone. Finally, global desilylation using Et 3 N•3HF [27] provided synthetic amphidindolide F ( 3 ) which matched with the natural material ( 1 H, 13 C, [α] D ). [2] …”

Synthesis of C9‐C13 and C15‐C21 Subunits of Discodermolide

“…The synthesis of C15-C21 subunit of discodermolide began with the homologation of Roche ester derived alcohol 11 through oxidation and Wittig reaction to provide ester 12 (Scheme 2). [18] It is pertinent to note that the protecting group present in 11 plays a major role in the outcome of Wittig reaction. When p-methoxy benzyl was chosen as the protecting group, partial racemization of the asymmetric center in the resulting α,β-unsaturated ester was observed.…”

“…When p-methoxy benzyl was chosen as the protecting group, partial racemization of the asymmetric center in the resulting α,β-unsaturated ester was observed. [18] Reduction of ester 12 with LiAlH 4 afforded the allylic alcohol 13, which under a substrate-controlled m-CPBA oxidation [19] afforded epoxy alcohol 14 in 14 : 1 diastereomeric ratio ( 1 H NMR). It is noteworthy that under the Sharpless asymmetric epoxidation [20] conditions the same epoxy alcohol 14 was obtained in 7 : 1 diastereomeric ratio only.…”