Synthetic Studies on a Pachastrissamine Sulfur Analogue: Synthesis of a 4-<i>epi</i>-Sulfur Analogue

Abstract

A versatile synthetic procedure for a sulfur analogue of pachastrissamine (jaspine B), which involves the tandem thiolation-cyclization of a 1,4-ditosylate to construct a tetrahydrothiophene ring, was developed. Nucleophilic amino substitution of a tetrahydrothiophene-4-sulfonate with unexpected retention of the configuration afforded the sulfur analogue of 4-epi-pachastrissamine.Key words pachastrissamine; analogue; tetrahydrothiophene; thiolation; cyclization; neighboring group participation Pachastrissamine (1, jaspine B) is a natural anhydrophytosphingosine derivative that has an all-cis-2,3,4-trisubstituted tetrahydrofuran structural framework and was isolated from the marine sponges Pachastrissa sp.1) and Jaspis sp.2) in 2002 and 2003, respectively (Fig. 1). It exhibits cytotoxic activity against various cancer cell lines [1][2][3][4][5][6][7][8][9] and induces programmed cell death, such as autophagy 6) and apoptosis 7-10) in some cancer cells. Owing to its interesting structural features and significant biological properties, many researchers have reported the total synthesis of 1 [3][4][5][6][7] and its stereoisomers 5,6,[20][21][22][23][24][25][26][27][28][29][31][32][33][34][35][36][37][38][39][40][41] to date. In addition, several analogues of 1 have been synthesized and their biological activities have been investigated. 7,[42][43][44][45][46][47] Kim and colleagues reported the synthesis of the sulfur analogue 4 from D-ribo-phytosphingosine and 4 exhibited higher cytotoxicity against several cancer cell lines than 1.46) Because sulfur-containing heterocycles such as thiosugars often exhibit various interesting biological activities 48) and a sulfur atom can exist in multiple oxidized forms, replacement of the oxygen atom in the ring of 1 by a sulfur atom serves as a potential way to produce new drug candidates. Very recently, we succeeded in the synthesis of 1, 2-epi-pachastrissamine 2, and the 2-epi-aza analogue 3. 31) Our synthetic route to 1-3 would be useful for the synthesis of their derivatives bearing various alkyl side chains, because inexpensive diethyl D-tartrate is employed as a starting material and the alkyl side chain is introduced at a later stage. Here, we report studies on the synthesis of a sulfur analogue of pachastrissamine, which is based on the synthetic strategy for 1-3, and the synthesis of the 4-epi-sulfur analogue 5.Our strategy to synthesize 4 is outlined retrosynthetically in Chart 1. On the basis of our previous syntheses of 1-3, 31) the desired analogue 4 would be derived from the tetrahydrothiophene 6 via S N 2-type amination at the 4-position. Because olefin cross-metathesis of sulfur-containing compounds is often problematic, [49][50][51][52] we planned to extend the alkyl side chain before the introduction of a sulfur atom. The thiophene ring system would be created by stepwise thiolation-cyclization via the 4-mercapto-1,2-diol 7 from 8, which would be converted from the 3,4-anti-homoallylic alcohol 9 using olefin cross-metathesis. Compound 9 has already been prepa...

Total Synthesis of Sphingofungin E and 4,5-Di-<i>epi</i>-sphingofungin E

“…Recently, we reported total synthesis of 1 and 2 from the same intermediate 5, which was derived from commercially available diethyl D-tartrate using rhodium(II)-catalyzed C-H amination, following stereoselective vinylation 45,46) (Chart 1). As part of our synthetic investigations of sphingosine natural products, [47][48][49][50][51] herein, we report the total synthesis of 3 and 4,5-di-epi-sphingofungin E (4) from the intermediate 5 via antipodal stereoselective dihydroxylations. …”