Scalable Synthesis of the Potent HIV Inhibitor BMS‐986001 by Non‐Enzymatic Dynamic Kinetic Asymmetric Transformation (DYKAT)

Abstract

Described herein is the synthesis of BMS‐986001 by employing two novel organocatalytic transformations: 1) a highly selective pyranose to furanose ring tautomerization to access an advanced intermediate, and 2) an unprecedented small‐molecule‐mediated dynamic kinetic resolution to access a variety of enantiopure pyranones, one of which served as a versatile building block for the multigram, stereoselective, and chromatography‐free synthesis of BMS‐986001. The synthesis required five chemical transformations and resulted in a 44 % overall yield.

Synthesis of carbon‐14 and stable isotope labeled Censavudine

“…The intended use of the labeled analog, the known metabolism, the length of the synthesis and the cost of the labeled starting materials all have to be considered when developing a labeling strategy. Looking at the synthetic route being used to produce unlabeled 1, [7][8][9] it was clear the shortest and least expensive route to carbon-14 labeled 1 would be to incorporate the label into the thymine base. A metabolism study using unlabeled 1 suggested the nucleoside base would not be the best site for the carbon-14 label from a safety standpoint.…”

“…The reported procedure to install the acetylene in the sugar used 2.5 eq of trimethylsilylacetylene. 9 This procedure as described would be unacceptable for the synthesis of labeled material since using such a large excess of the labeled starting material would give the desired product in an unsustainably low radiochemical yield. A series of probe reactions with varying amounts of unlabeled trimethylsilylacetylene and ketone 4 were conducted as shown in Table 1 in an attempt to optimize the yield of 5 in the reaction in Scheme 1.…”

“…Carbon-14 labeled 1 was synthesized as described in the literature with modifications for the maximization of radiochemical yields (Scheme 2). [7][8][9] Carbon-14 labeled trimethylsilylacetylene (150 mCi) was deprotonated and added to the chiral ketone 4 (1.2 eq) to produce alcohol [ 14 C]-5 in a 40% radiochemical yield (60 mCi) after preparative HPLC. Hydrolysis of the benzoate ester on the anomeric position of [ 14 C]-5 yielded a rapidly equilibrating mixture of the pyranose ([ 14 C]-6) and furanose ([ 14 C]-7) isomers.…”

“…The shortest and most cost‐effective synthetic route to carbon‐14 labeled 1 with the label in the sugar needed to be developed. The first steps in the synthetic route used to produce unlabeled 1 , 7–9 (Scheme 1) involved initial thiolation of 2 affording thioether 4 which was reacted with trimethylsilylacetylene to give alcohol 5 . Analyzing this sequence, it was clear the most direct labeling route would be to incorporate the label into the acetylene moiety of the sugar.…”

De Novo Synthesis of Mono‐ and Oligosaccharides via Dihydropyran Intermediates

“…[28] Researchers at Bristol-Myers Squibb reported ad ynamic kinetic enantioselective acylation (DKEA) of several lactols with either two hydrogen or two methyl substituents on the 5-position to the corresponding esters with up to 88 % ee (Scheme10). [29] Commercially available( À)-levamisole was used as the catalystf or this DKEA reaction. An elegants ynthesis of anti-HIV drug BMS-986001w as accomplished in five steps by using this method.…”