Internationale Ausgabe: DOI: 10.1002/anie.201502290 Organocatalysis Deutsche Ausgabe: DOI: 10.1002/ange.201502290 Scalable Synthesis of the Potent HIV Inhibitor BMS-986001 by Non- Enzymatic Dynamic Kinetic Asymmetric Transformation (DYKAT)** Adrian Ortiz,* Tamas Benkovics, GregoryL. Beutner, Zhongping Shi, Michael Bultman, Jeffrey Nye, Chris Sfouggatakis, and David R. Kronenthal 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 syn- thesis required five chemical transformations and resulted in a 44 % overall yield. Since the FDA approval of azidothymidine (AZT) in 1987 as the first NRTI (nucleoside reverse transcriptase inhibitor) treatment of the HIV virus, the scientific community has been continuously searching for safer and more efficacious thera- pies. The last 20 years of research in this area has resulted in vastly improved therapeutics and treatment strategies. [1] Despite these improvements, viral drug resistance [2] and side-effects to the prescribed therapies remain outstanding issues. [3] BMS-986001 (1) is a thymidine NRTI which has been developed to maintain the in vivo antiviral activity demon- strated by other NRTI)s, but lacks the associated toxicity side effects. Recent clinical data has shown this investigational therapy to be effective in reducing viral load while exhibiting a significantly improved safety profile, when compared to the standard of care. [4] To aid the development of this compound, a unique, expedient, and scalable synthesis of 1 was required. The development of this new route resulted in several interesting observations, and the development of two organo- catalytic transformations to set key structural and stereo- chemical elements as described herein. Retrosynthetic analysis of the targeted structure 1 led us to define pyranone (S)-3 as the key enantioenriched building block from which a substrate-controlled, diastereoselective synthesis was envisioned (Figure 1). In the forward sense, a diastereoselective 1,4 addition of an arylthiol and subse- quent 1,2-addition of the alkyne moiety would provide the pyranose 6b. Next, a ring tautomerization/acylation sequence and a subsequent Vorbrüggen reaction could be employed to convert the pyranose ring into the desired furanose nucleo- side 12. Finally, oxidation of the thioether and thermolysis of the resulting sulfilimine could install the required C2 C3 dehydrofuranose moiety present in 1. The success of this strategy hinged on the accessibility of optically enriched (S)-3. Similar structural pyranone derivatives have demonstrated broad utility as versatile building blocks in organic synthesis, [5] and as key components in the development of new synthetic methods. [6] However, all previous approaches to (S)-3 and similar derivatives suffered from unsatisfactory yields, [7] and required the use of either chiral chromatography, derivatiza- tion, or enzyme-mediated resolution to impart high enantio- purity. Our previously published work (Scheme 1a) employed an enzymatic resolution by destructive transesterification to deliver (S)-3a in high purity and enantioselectivity, but in moderate overall yield (26 % from 2a). [8] To increase both efficiency and overall yield, a dynamic kinetic asymmetric transformation (DYKAT) was considered for the acylation of the racemic lactol 2a (Scheme 1 b). Limited precedence existed for this transformation biocata- lytically, and most reports achieved only low to moderate enantioselectivity. [9] In fact, in our hands, screening of more than 100 enzymes led to either the undesired isomer [(R)- 3a] [10] or (S)-3a with low selectivity. Despite the emergence of a number of catalysts shown to resolve secondary alcohols by way of non-enzymatic selective acylations, [11] to the best of our knowledge, there have been no reports of a small molecule facilitating this important transformation on a lactol. An initial screen of organocatalysts resulted in low levels of conversion and/or selectivity. Surprisingly, the best result was achieved using levamisole (A), an inexpensive and Figure 1. Retrosynthetic analysis of BMS-986001 (1). Bz = benzoyl. [*] Dr. A. Ortiz, Dr. T. Benkovics, Dr. G.L. Beutner, Dr. Z. Shi, Dr. M. Bultman, Dr. J. Nye, Dr. C. Sfouggatakis, Dr. D. R. Kronenthal Chemical Development, Bristol-Myers Squibb 1 Squibb Drive, New Brunswick, NJ 08903 (USA) E-mail: Adrian.Ortiz@bms.com [**] We thank Dr.’s R. Parsons, R. Waltermire, and M.D. Eastgate for supporting this work, Dr.’s Charles Pathirana and David Ayers for assistance with structural elucidation, Merrill Davies for help with chiral separation, and Jonathan Marshall for MS analysis. We would also like to thank Prof. Phil Baran for helpful discussions in the drafting of this manuscript. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201502290. Angewandte Chemie 7291 Angew. Chem. 2015, 127, 7291 –7294 # 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim