Yong-Li Zhong

Practical and cost-effective manufacturing route for the synthesis of a β-lactamase inhibitor.

Compound 1, a potent and irreversible inhibitor of β-lactamases, is in clinical trials with β-lactam antibiotics for the treatment of serious and antibiotic-resistant bacterial infections. A short, scalable, and cost-effective route for the production of this densely functionalized polycyclic molecule is described.

Development of a practical, asymmetric synthesis of the hepatitis C virus protease inhibitor MK-5172.

The development of a practical, asymmetric synthesis of the hepatitis C virus (HCV) protease inhibitor MK-5172 (1), an 18-membered macrocycle, is described.

Catalytic Asymmetric Synthesis of an HIV Integrase Inhibitor

An efficient synthesis of HIV integrase inhibitor (S)-(-)-1 via a unique asymmetric hydrogenation of a mixture of imines/enamine 5a-5b/5c is described. Hydrogenation of the imines/enamine by a Rh(I)-Josiphos complex afforded 6 in 90% yield and 90% ee. Amide formation completed the synthesis of 1 in 58% overall yield from 2, which is readily available from 3,4-dihydro-2H-pyran in a seven-step sequence. A deuterium labeling study suggests the asymmetric hydrogenation proceeds predominantly via the enamine tautomer.

A Polar Radical Pair Pathway To Assemble the Pyrimidinone Core of the HIV Integrase Inhibitor Raltegravir Potassium

The UN and WHO currently estimate that 40 million people are living with HIV/AIDS worldwide. Combination therapies using reverse transcriptase and protease inhibitors have been highly successful, but the emergence of drug resistance prompts a search for alternative treatments. A rapidly expanding area of HIV/AIDS research targets a third enzyme, integrase, the catalyst responsible for the integration of proviral DNA into the host cell chromosome. Research at Merck has led to the identification of raltegravir potassium (1), a potent and well-tolerated HIV-1 integrase inhibitor that targets strand transfer, the second of two catalytic cycles mediated by the integrase enzyme. Raltegravir potassium (1) consists of a central hydroxypyrimidinone heterocyclic core that is rapidly assembled by a two-component coupling reaction between amidoxime 2 and dimethyl acetylenedicarboxylate (DMAD) to give 3Z/3E, followed by a thermal rearrangement to give product 4 (Scheme 1). Amidoxime–DMAD adduct isomers 3Z and 3E are converted to hydroxypyrimidinone 4 at significantly different rates: 3Z, the major isomer, reacts at a temperature of 125 8C within 2 h, while 3E only rearranges at an elevated temperature of 135 8C within 5 h. Plausible mechanisms for this reaction involving [1,3] and [3,3] shifts are shown in Scheme 2. N-enriched rearrangement precursors 3Z*/3E* (65:35) were synthesized. Thermolysis of 3Z*/3E* resulted in the formation of hydroxypyrimidinone 4’*, in which the N label was unexpectedly found to be exclusively at the position ortho to the ester substituent. Since this outcome is not consistent with a [3,3]-sigmatropic rearrangement mechanism (4’’*), a formal [1,3] rearrangement must have occurred. An in-depth experimental and computational study of the mechanism has now shown that the apparently attractive concerted [3,3]-pericyclic route is eschewed in favor of a direct N O cleavage to form a polar radical pair (PRP) with a substantial preference for recombination. Quantum mechanical calculations were used to determine how models 6Z and 6E, with CO2Me replacing CBz, undergo transformation to 5, a model for pyrimidinone 4. B3LYP density functional theory, as implemented in Gaussian03, was used to compute optimized geometries of intermediates and transition states. Energies were obtained from a calibration involving a smaller computational model where G3(MP2)B3, a high-accuracy method, and B3LYP energetics were compared (other functionals and methods involving CCSD(T) were also compared, see Supporting Information for details). As summarized in Scheme 3, the tautomerization of amidoxime adducts 6Z/E to 7Z/E is endothermic by 12 kcalmol . Acid-base catalysis is required to form 7, since concerted [1,3]-hydrogen shifts have prohibitively high barriers. Although the activation energies of the allowed [3,3] shifts of 7Z/E are 25 kcalmol 1 (cf. TS5), these rearScheme 1. Synthesis of raltegravir potassium. Cbz=benzyloxycarbonyl.

A Concise and Atom-Economical Suzuki–Miyaura Coupling Reaction Using Unactivated Trialkyl- and Triarylboranes with Aryl Halides

A concise and atom-economical Suzuki-Miyaura coupling of trialkyl- and triarylboranes with aryl halides is described. This new protocol represents the first general, practical method that efficiently utilizes peralkyl and peraryl groups of the unactivated trialkyl- and triarylboranes for the Suzuki-Miyaura coupling reaction.

Unusual Pyrimidine Participation: Efficient Stereoselective Synthesis of Potent Dual Orexin Receptor Antagonist MK-6096

An asymmetric synthesis of dual orexin receptor antagonist MK-6096 (1) is described. Key steps for the trans-2,5-disubstituted piperidinyl ether fragment include a biocatalytic transamination, a trans-selective Mukaiyama aldol, and a regioselective pyridyl SNAr process. The pyrimidyl benzoic acid was synthesized via a Negishi coupling and a nitrile hydrolysis. Coupling of the two fragments via a catalytic T3P-mediated amidation completed the synthesis. Unusual behaviors in the hydrolysis of pyrimidyl benzonitrile and the amide coupling of the pyrimidyl benzoic acid are also described.

Synthesis of antifungal glucan synthase inhibitors from enfumafungin.

An efficient, new, and scalable semisynthesis of glucan synthase inhibitors 1 and 2 from the fermentation product enfumafungin 3 is described. The highlights of the synthesis include a high-yielding ether bond-forming reaction between a bulky sulfamidate 17 and alcohol 4 and a remarkably chemoselective, improved palladium(II)-mediated Corey-Yu allylic oxidation at the highly congested C-12 position of the enfumafungin core. Multi-hundred gram quantities of the target drug candidates 1 and 2 were prepared, in 12 linear steps with 25% isolated yield and 13 linear steps with 22% isolated yield, respectively.

Asymmetric Synthesis of Functionalized trans-Cyclopropoxy Building Block for Grazoprevir

A practical and asymmetric synthesis of a functionalized trans-cyclopropoxy building block for the preparation of the HCV NS3/4a protease inhibitor grazoprevir is reported. Intramolecular SN2 displacement-ring closure, followed by a Baeyer-Villiger oxidation, yields the desired trans-cyclopropanol with full control of diastereoselectivity. A terminal alkyne is then effectively installed using LiNH(CH2)2NEt2. Starting from (S)-epichlorohydrin, the cyclopropoxy building block is prepared in 51% overall yield with >99.8% optical purity without isolation of any intermediates.

Process Chemistry in Antiviral Research

This article reviews antiviral therapies that have been approved for human use during the last decade, with a focus on the process chemistry that enabled access to these important drugs. In particular, process chemistry highlights from the practical syntheses of the HCV drugs sofosbuvir (Gilead), grazoprevir (Merck), and elbasvir (Merck), the HIV therapy darunavir (Tibotec) and the influenza treatment peramivir (BioCryst) are presented.