https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

Enzyme-catalyzed reactions have begun to transform pharmaceutical manufacturing, offering levels of selectivity and tunability that can dramatically improve chemical synthesis. Combining enzymatic reactions into multistep biocatalytic cascades brings additional benefits. Cascades avoid the waste generated by purification of intermediates. They also allow reactions to be linked together to overcome an unfavorable equilibrium or avoid the accumulation of unstable or inhibitory intermediates. We report an in vitro biocatalytic cascade synthesis of the investigational HIV treatment islatravir. Five enzymes were engineered through directed evolution to act on non-natural substrates. These were combined with four auxiliary enzymes to construct islatravir from simple building blocks in a three-step biocatalytic cascade. The overall synthesis requires fewer than half the number of steps of the previously reported routes.

Design of an in vitro biocatalytic cascade for the manufacture of islatravir

Competition experiments were used to determine that the 4-OH of a 2-deoxy-2-azidoglucose derivative is more reactive than that of the corresponding N-phthalimido glucose derivative which, in turn, is more easily glycosylated than the N-acetyl derivative. Glycosylation of the 4-OH groups of the N,N-diacetyl and N-acetyl-N-benzyl glucosamine was also found to be superior to that of the simple N-acetyl substance. The 3-O-picolinyl ether of a 4,6-O-benzylidene-protected N-acetylglucosamine was shown to have a strong intramolecular hydrogen bond to the adjacent acetamide group. This interaction does not persist in the 3-O-picolinyl-6-O-benzyl N-acetylglucosamine derivative, owing to a probable competing hydrogen bond between the 4-OH and the picolinyl ether. However, in the 3-O-picolinyl-4-O-benzyl N-acetylglucosamine regioisomer the picolinyl-acetamide hydrogen bond persists and leads to an enhancement of reactivity of the 6-OH, over and above that in the corresponding 3-O-benzyl ether, due to disruption of the typical intermolecular amide hydrogen bonding scheme. It is demonstrated that the picolinyl ether is readily removed by hydrogenolysis at atmospheric pressure and room temperature.

Why are the hydroxy groups of partially protected N-acetylglucosamine derivatives such poor glycosyl acceptors, and what can be done about it? A comparative study of the reactivity of N-acetyl-, N-phthalimido-, and 2-azido-2-deoxy-glucosamine derivatives in glycosylation. 2-Picolinyl ethers as reactivity-enhancing replacements for benzyl ethers.

Fluorinated Nucleosides: Synthesis and Biological Implication

The evolution of antiviral nucleoside analogues: A review for chemists and non-chemists. Part II: Complex modifications to the nucleoside scaffold

Regioselective de-O-benzylation with Lewis acids

A series of 2′-deoxy, 2′,3′-unsaturdted and 2′,3′-dideoxynucleoside analogues, which have an additional methyl group at the 4′-position, have been synthesized. When evaluated for their inhibitory activity against HIV in MT-4 cell, 2′-deoxy-4′-C-methyl nucleosides exhibited potent activity. †This paper is dedicated to Dr. Yoshihisa Mizuno on the occasion of his 75th birthday.

Synthesis and Biological Evaluation of 4′-C-Methyl Nucleosides †

Working hypotheses to solve the critical problems of the existing highly active anti-retroviral therapy were proposed. The study based on the hypotheses proved the validity of the hypotheses and resulted in the development of 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine, a nucleoside reverse transcriptase inhibitor, with highly potent activity against all HIV-1, very favorable toxic profiles, and stability in plasma. The nucleoside will prevent or delay the emergence of drug-resistant HIV-1 variants and be an ideal therapeutic agent for both HIV-1 and HBV infections.

2′-deoxy-4′-C-ethynyl-2-fluoroadenosine: A nucleoside reverse transcriptase inhibitor with highly potent activity against wide spectrum of HIV-1 strains, favorable toxic profiles, and stability in plasma

Synthesis of 4′-C-fluoromethylnucleosides as potential antineoplastic agents

Enantiomeric separation of carboxylic acids having chiral centers remote from the carboxyl group by labelling with a chiral fluorescent derivatization reagent

Hiroshi Ohrui

Papers

Regioselective de-O-benzylation with Lewis acids

Synthesis and Biological Evaluation of 4′-C-Methyl Nucleosides †

2′-deoxy-4′-C-ethynyl-2-fluoroadenosine: A nucleoside reverse transcriptase inhibitor with highly potent activity against wide spectrum of HIV-1 strains, favorable toxic profiles, and stability in plasma

Synthesis of 4′-C-fluoromethylnucleosides as potential antineoplastic agents

Enantiomeric separation of carboxylic acids having chiral centers remote from the carboxyl group by labelling with a chiral fluorescent derivatization reagent