Total synthesis of the macrolactone core of migrastatin, formal synthesis of (+)-ratjadone A, and towards the synthesis of sphingofungin F

Abstract

The thesis entitled “Total synthesis of the macrolactone core of migrastatin, formal synthesis of (+)-ratjadone and Towards the total synthesis ofsphingofungin F” is divided into three chapters and an appendix highlighting synthesis of fully protected 1-deoxy-8a-epi-castanospermine.

First chapter of the thesis describes the total synthesis of macrolactone analogue of migrastatin from chiral furyl carbinol and further application of the approach in the synthesis towards arenicolide C.

Section A of chapter 1 describes the enantiospecific total synthesis of the macrolactone core of marine macroloide migrastatin.Enantiospecific total synthesis of macrolactore coreof migrastatin was accomplished in ~11 % overall yield in 13 linear steps using chiral furyl carbinol obtained through asymmetric non-Evans type aldol reaction of furfural with thiazolidinonethione. Key steps in the present approach includes oxidative ring opening of furan and its use as a four-carbon synthon, SN2 displacement of a functionalized allyl bromide and ring closing metathesis (RCM) to obtain the macrolactone. (The part of this work has been published: J. Org. Chem. 2019, 22, 14974-14979)

Section B of chapter 1 highlights the efforts towards the synthesis of arenicolide C.Synthetic studies towards arenicolides A and C macrolactone is envisioned by coupling of the three fragments viz. C1-C8 trienoic acid fragment, C9-C18 allylic alcohol fragment, and the C19-C25 unsaturated ester fragment. The C19-C25 fragment is synthesized expanding the furyl carbinol. The key step includes Grieco elimination and Mislow rearrangement.

Second chapter of the thesis describes the formal total synthesis of (+)-ratjadone A. Synthesis of the tetrahydropyran fragment was accomplished from malic acid.Evans aldol reaction of the aldehyde (derived from malic acid), Lipase mediated enzymatic resolution of the allylic alcohol and the Pd-catalyzed intramolecular SN2’ cyclization as proposed by Ueinishi were the key steps in the synthesis of the THP unit. The synthesis of tetrahydropyran unit is achieved in 11 overall steps. (The Part of this work has been published: Tetrahedron 2021, 78, 131824)

Third chapter of the thesis describes the synthesis towards sphingofungin F.Sphingofungins possesses a long lipid chain and a polar polyhydroxy amino acid group consisting of challenging quaternary centre, four consecutive chiral centres and a trans olefinic group at the polar head. The challenging polar head group is envisioned by the addition of thiazole as a formyl equivalent to the chiral ketimine, obtained from the corresponding ketone and Ellmansulfinamide. The ketone was synthesized from the bis-Weinrebamide of tartaric acid. The hydrophobic side chain was attached through cross metathesis.

The synthesis of fully protected 1-deoxy-8a-epi-castanospermineis described in the appendix. The synthesis showcased the use of -keto phosphonate derived from L-tartaric acid and Overmann rearrangement as the key step.