Oxalates as Activating Groups for Alcohols in Visible Light Photoredox Catalysis: Formation of Quaternary Centers by Redox-Neutral Fragment Coupling.

Alkyl oxalates are new bench-stable alcohol-activating groups for radical generation under visible light photoredox conditions. Using these precursors, the first net redox-neutral coupling of tertiary and secondary alcohols with electron-deficient alkenes is achieved.

Quinones as dienophiles in the Diels-Alder reaction: history and applications in total synthesis.

In the canon of reactions available to the organic chemist engaged in total synthesis, the Diels-Alder reaction is among the most powerful and well understood. Its ability to rapidly generate molecular complexity through the simultaneous formation of two carbon-carbon bonds is almost unrivalled, and this is reflected in the great number of reported applications of this reaction. Historically, the use of quinones as dienophiles is highly significant, being the very first example investigated by Diels and Alder. Herein, we review the application of the Diels-Alder reaction of quinones in the total synthesis of natural products. The highlighted examples span some 60 years from the landmark syntheses of morphine (1952) and reserpine (1956) by Gates and Woodward, respectively, through to the present day examples, such as the tetracyclines.

Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic.

As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.

Two approaches to the aromatic core of the aminonaphthoquinone antibiotics.

Two complementary approaches are presented for the synthesis of the quinone chromophores of the naphthoquinone ansamycins and related natural products. The first involves the use of an improved protocol for the manganese(III) acetate mediated cyclization of 5-aryl-1,3-dicarbonyl compounds to ß-naphthols, leading to the simple, scalable preparation of building blocks suitable for the synthesis of naturally occurring aminonaphthoquinones. The second approach involves the Diels-Alder reaction of a series of new, ester-containing Danishefsky-type dienes with N-protected aminobenzoquinones to allow more expeditious access to similar intermediates.

Natural products containing a diazo group.

Although diazo compounds are probably best known for their involvement as versatile intermediates in modern synthetic organic chemistry, a small number of such compounds also occur naturally. Many of the early examples, such as azaserine, originally isolated in the 1950s, have antitumour properties and consist of modified α-amino acids. More recently, other more complex diazo compounds have been isolated from natural sources, and these include diazobenzoquinones, diazonaphthoquinones, such as the SF2415 and A80915 antibiotics, and the diazofluorene-based kinamycins and lomaiviticins. This report will cover the isolation, biosynthesis, biological activity and synthesis of natural products containing a diazo group.

Synthesis of amino-1,4-benzoquinones and their use in Diels-Alder approaches to the aminonaphthoquinone antibiotics.

A new protocol for the synthesis of protected amino-1,4-benzoquinones by oxidation of the corresponding 2,5-dimethoxyaniline derivatives using PhI(OAc)(2) or PhI(OCOCF(3))(2) in water containing 2.5% methanol is reported. The process represents an improvement over previously reported methods, both in terms of yield and number of steps, and in the range of nitrogen protecting groups that it tolerates. A number of novel aminobenzoquinones were prepared and subsequently used as dienophiles in Diels-Alder reactions to form building blocks for the synthesis of the aminonaphthoquinone antibiotics such as salinisporamycin.

Nine-Step Stereoselective Synthesis of Islatravir from Deoxyribose.

A stereoselective nine-step synthesis of the potent HIV nucleoside reverse transcriptase translocation inhibitor (NRTTI) islatravir (EfdA, MK-8591) from 2-deoxyribose is described. Key findings include a diastereodivergent addition of an acetylide nucleophile to an enolizable ketone, a chemoselective ozonolysis of a terminal olefin and a biocatalytic glycosylation cascade that uses a unique strategy of byproduct precipitation to drive an otherwise-reversible transformation forward.

Synthesis of Islatravir Enabled by a Catalytic, Enantioselective Alkynylation of a Ketone.

The synthesis of the potent anti-HIV investigational treatment islatravir is described. The key step in this synthesis is a highly enantioselective catalytic asymmetric alkynylation of a ketone. This reaction is a rare example of the asymmetric addition of an alkyne nucleophile to a ketone through ligand-accelerated catalysis that was performed on a greater than 100 g scale. By leveraging a multienzyme cascade, a highly diastereoselective aldol-glycosylation was used to complete the target in eight steps.

A concise total synthesis of (+/-)-anthecularin.

A total synthesis of the novel sesquiterpene anthecularin 1, isolated from Greek Anthemis auriculata, based on an intramolecular [5+2] (1,3-dipolar) cycloaddition involving the oxidopyrylium ion 12 derived from the furanmethanol 9, is described.

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

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.

Beyond optical rotation: what's left is not always right in total synthesis.

This work describes the application of vibrational (VCD) and electronic (ECD) circular dichroism spectroscopy to solve the longstanding debate around the absolute configuration of (+)-frondosin B (1). The absolute configuration of (+)-1 could confidently be assigned as (R) using these spectroscopic techniques. The discrepancy in the optical rotation (OR) values obtained in previous studies can be attributed to an undetected minor impurity (ca. 7%) that arose unexpectedly in a key step late in the synthesis. Additionally, the conditions used in the final step of the previous reports for demethylation to form the natural product proceeded with significant loss of enantiopurity. The large OR measured for the impurity at its observed level, when compared to the small rotation for the less enantiopure natural product 1, led to a measured OR value for the synthetic material that had the opposite sign of the natural product.

Toward the total synthesis of hygrocin B and divergolide C: construction of the naphthoquinone-azepinone core.

A highly regioselective Diels-Alder approach toward the bioactive natural products hygrocin B and divergolide C is presented. The route uses an unusual benzoquinone-azepinone dienophile prepared in 8 steps from ethyl 8-methoxy-1-naphthoate, by a route which includes, as key steps, a Birch alkylation and a Beckmann rearrangement of a tetralone oxime, both of which are demonstrated on multigram scale. The naphthoquinone-azepinone core is suitably functionalized for addition of the ansa-chain, found in the natural products.

Total synthesis of mevashuntin.

The total synthesis of (±)-mevashuntin, a structurally unique naturally occurring pyrano-naphthoquinone-thiazolone, is described. The route is centered upon a late stage regioselective Diels-Alder reaction between two highly functionalized components, as well as an improved protocol for the one pot synthesis of benzothiazolones from ortho-bromoaryl isothiocyanates. The strategy results in a highly convergent route, providing access to the natural product in 11 steps from 3-(4-methoxyphenoxy)propanol and confirming its relative stereochemistry.

Synthesis of parvistemin A via biomimetic oxidative dimerization.

The first synthesis of the naturally occurring benzoquinone dimer parvistemin A is reported. The key step is the late stage iron(III) mediated dimerization of a 1,2,4-trihydroxyarene to give the natural product in good yield, a phenol oxidative coupling that is believed to be biomimetic. The route proceeds in seven steps from an inexpensive commercially available acetophenone in 14% overall yield.