Catalytic Asymmetric Synthesis of Phthioceranic Acid, a Heptamethyl-Branched Acid from Mycobacterium tuberculosis

Abstract

The first total synthesis of phthioceranic acid (1) has been achieved by an iterative catalytic asymmetric 1,4-addition protocol. This method provides a robust and high-yielding route for the preparation of 1,3-oligomethyl (deoxypropionate) arrays. After the desired number of methyl groups has been introduced, these arrays can be further functionalized at both ends to polymethyl-substituted lipids such as phthioceranic acid, a heptamethyl-branched fatty acid from the virulence factor Sulfolipid-I (2), found in Mycobacterium tuberculosis.

Total synthesis, stereochemical elucidation and biological evaluation of Ac2SGL; a 1,3-methyl branched sulfoglycolipid from Mycobacterium tuberculosis

“…2), among other polyketides. [27][28][29][30] Taking advantage of this knowledge, the synthesis of 4 has been attempted with the nal goal of generating a synthetic sample of 1. To elucidate the stereochemistry of the C17 stereocenter of 4, an initial synthetic route has been devised.…”

“…28,29 Repetition of steps e, f and g (Schemes 1 and 2) led to thioester 13 with all eight methyl substituents in a 1,3-array as present in natural 4. The 21 steps, starting from 10, were performed in an excellent 14% overall yield, affording 13 as a single stereoisomer without formation of anti-product (for the 1 H-NMR spectrum, see ESI †).…”

“…In Scheme 4, the most advanced common intermediate for both 3 and 4 is 19, 29 with seven methyl branches installed. 27 In order to obtain 4, we planned to introduce the eighth methyl branch via copper-catalyzed allylic substitution.…”

S-Phenyl 4-methoxybenzothioate

“…For background to and applications of thioesters, see : Agapiou & Krische (2003); Choi et al (2003); El-Azab & Abdel-Aziz (2012); Horst et al (2007); Howell et al (2006); Jew et al (2003); Liebeskind & Srogl (2000); McGarvey et al (1986); Ozaki et al (2003); Shah et al (2002); Yang & Drueckhammer (2001). For related structures and the synthesis of similar compounds, see: Barbero et al (2003).…”

“…Recently, the α-β-unsaturated thioester analogs have been successfully applied for asymmetric additions which allow the access to chiral intermediates for the synthesis of more complex compounds. Furthermore, they were used in natural product synthesis and also are acting as biologically relevant substances finding application for in vivo tumor suppression (Agapiou & Krische (2003); Barbero et al, 2003;Choi et al, 2003;Horst et al, 2007;Howell et al, 2006;Jew et al, 2003;Liebeskind & Srogl 2000;McGarvey et al, 1986;Ozaki et al, 2003;Shah et al, 2002;Yang & Drueckhammer, 2001). Owing to these applications of thioesters, the title compound (I) was synthesized.…”