Total synthesis and mass spectrometric analysis of a Mycobacterium tuberculosis phosphatidylglycerol featuring a two-step synthesis of (R)-tuberculostearic acid

Abstract

We report the total synthesis of (R)-tuberculostearic acid-containing Mycobacterium tuberculosis phosphatidylglycerol (PG). The approach features a two-step synthesis of (R)-tuberculostearic acid, involving an (S)-citronellyl bromide linchpin, and the phosphoramidite-assisted assembly of the full PG structure. Collision-induced dissociation mass spectrometry of two chemically-synthesized PG acyl regioisomers revealed diagnostic product ions formed by preferential loss of carboxylate at the secondary (sn-2) position.

α-Glucuronosyl and α-glucosyl diacylglycerides, natural killer T cell-activating lipids from bacteria and fungi

“…R-TBSA was prepared analogously by tandem alkene cross-metathesis of (S)-2,6-dimethyltetradecene (prepared in one step from (R)-citronellyl bromide 15 ) with ethyl 6-heptenoate using Hoveyda-Grubbs II catalyst and in situ reduction using hydrogen, followed by saponication. 16 As reported by Shah et al 17 allyl a-D-glucopyranoside was converted to the methoxyacetate by treatment with MeOAcCl/ pyr, treated with mCPBA to obtain a 1:0.95 mixture of 2 0 R/2 0 S epoxides, then subjected to hydrolytic kinetic resolution using S,S-Jacobsen's catalyst to provide the stereopure 2 0 R-epoxide (Fig. 2B).…”

The Chiral Target of Daptomycin Is the 2R,2′S Stereoisomer of Phosphatidylglycerol

“…We chose to use phosphoramidite chemistry as this approach has been used by others to prepare PGs and allows for good control over the additions to the phosphorous centre without acyl migration (Scheme 1). [38][39][40] The two enantiomers of alcohol 5 were prepared based upon a procedure reported by Lee et al [41] Commercially available chiral alcohols S-1 or R-1 were treated with benzyl bromide (BnBr)/sodium hydride (NaH) to give benzyl ethers 2, and then the acetal in 2 was hydrolyzed to give diols 3. Myristic acid was then coupled to the hydroxy groups in 3 using N,N'-dicyclohexylcarbodiimide (DCC)/4-dimethylaminopyridine (DMAP) to give esters 4.…”

Chemical Synthesis of Cell Wall Constituents of Mycobacterium tuberculosis

“…In 2017, the Williams group reported the total synthesis of the CD1d presented TBSA-containing phosphatidylglycerol (Scheme 42). 213 The tuberculostearic acid 322 was synthesized in just two steps from (S)-citronellyl bromide 333, by first executing a copper-catalyzed Grignard alkylation followed by a one-pot alkene cross-metathesis with 6-heptenoic acid and subsequent double bond hydrogenation. This sequence proceeded with an overall yield of 72% and is the shortest route of tuberculostearic acid 322 to date.…”