Sulfanylation of 1,3-dithiane anions by 5-(alkylsulfanyl)-1-phenyltetrazoles

Abstract

An unusual reaction between 1,3-dithiane anions and by 5-(alkylsulfanyl)-1-phenyltetrazoles has been discovered in which the dithiane anion formally displaces the 1-phenyltetrazole ring from sulfur to provide a sulfanylated dithiane. KeywordsTetrafibricin; Total synthesis; 1,3-Dithianes; 5-(Alkylsulfanyl)-1-phenyltetrazoles; Nucleophilic additions; Sulfanylations; Sulfur chemistryThe natural product tetrafibricin 1 was isolated in 1993 by Kamayama and coworkers, and they assigned its two-dimensional constitution by a battery of spectroscopic methods 1 . The compound has a linear carbon backbone featuring 11 stereocenters (10 with hydroxy groups and one with a methyl group), is a tetraene, with three isolated trans double bonds, and assorted other functional groups. In 2003, Kishi and coworkers assigned the threedimensional structure (configuration) of 1 without resorting to derivatization or degradation by comparing NMR spectra of the natural product in both chiral and achiral solvents to an NMR database of fragment spectra 2 . Roush 3 and Cossy 4 have described syntheses of fragments of 1.We have advanced a retrosynthetic strategy in Fig. 1 of the disassembled tetrafibricin 1 into six main fragments 2-7. Though the synthesis has not yet been completed, all of the fragments have been made, and assorted couplings have been established 5 . Along the way to making the C21-C30 fragment 4, we encountered an unusual reaction between a dithiane anion 6 and a 5-(alkylsulfanyl)-1-phenyltetrazoles. Herein we describe this reaction, which, in the context of the tetrafibricin synthesis, proved to be a temporary roadblock. We also describe a straightforward detour around this roadblock to complete the synthesis of a modified C21-C30 fragment. RESULTS AND DISCUSSIONThe two fragments 13 and 17 needed to make 4 were synthesized as shown in Scheme 1. Oxidation 7 of commercially available dioxolane alcohol (S)-8 to aldehyde 9 was followed by the Wittig reaction and non-selective epoxidation of the resulting alkene 10 to give a

Enantio- and Diastereoselective Synthesis of (E)-1,5-syn-Diols: Application to the Synthesis of the C(23)−C(40) Fragment of Tetrafibricin

“…The stereostructure of 15 was assigned by Kishi based on NMR database technology and NMR measurements in chiral solvents 3b. Syntheses of fragments of tetrafibricin have been reported by Cossy,12 Curran,13 Friestad,14 and our group 15…”

Synthesis of C1–C20 and C21–C40 fragments of tetrafibricin

“…Epoxide ( R )- 10 is readily available in 96% ee by Jacobsen hydrolytic kinetic resolution of the corresponding racemate (prepared by silylation and epoxidation of pent-4-en-1-ol) 6b,10. Reaction of ( R )- 10 with lithio-1,3-dithane followed by trapping with TBS-triflate afforded 11 in 83% yield.…”

“…We have described routes to several fragments and have joined a single C21–C30 fragment with quasiisomers of other fragments in a fluorous mixture synthesis (FMS) of four stereoisomers of the C21–C40 fragment of tetrafibricin 6. This work featured Kocienski-Julia reactions, which have also recently been exploited by Friestad to make a C24-C40 fragment 7…”

“…The recently published FMS fragment synthesis6 was patterned after the route described herein. The retrosynthetic analysis of tetrafibricin is outlined in Figure 2.…”

Asymmetric Alcohol C–H Allylation and syn-Crotylation: C9–C20 of Tetrafibricin

“…Tetrafibricin has garnered interest with regard to the study of fibrinogen binding, platelet aggregation and as treatment of arterial thrombosis, 5 which in turn has evoked interest in its preparation via total synthesis. Despite efforts reported from the laboratories of Cossy, 6 Curran, 7 Friestad, 8 Roush 9 and the present author, 10 including the syntheses of a protected derivative of the natural product by Curran 7d and of N -acetyl dihydrotetrafibricin methyl ester by Roush, 9c the total synthesis of tetrafibricin remains an unmet challenge.…”