Nickel/Photoredox-Catalyzed Methylation of (Hetero)aryl Chlorides Using Trimethyl Orthoformate as a Methyl Radical Source.

Methylation of organohalides represents a valuable transformation, but typically requires harsh reaction conditions or reagents. We report a radical approach for the methylation of (hetero)aryl chlorides using nickel/photoredox catalysis wherein trimethyl orthoformate, a common laboratory solvent, serves as a methyl source. This method permits methylation of (hetero)aryl chlorides and acyl chlorides at an early and late stage with broad functional group compatibility. Mechanistic investigations indicate that trimethyl orthoformate serves as a source of methyl radical via ß-scission from a tertiary radical generated upon chlorine-mediated hydrogen atom transfer.

Synthesis of Acrylamides via the Doebner-Knoevenagel Condensation.

A selective synthesis of acrylamides had been developed using the Doebner-Knoevenagel condensation. The reaction occurs under mild conditions at ambient temperatures, tolerates a wide array of functional groups, and affords the E-isomer with high selectivity. The reported method expands the scope of this classic reaction to a class of industrially important products and as well as to the use of aliphatic aldehydes. An organocatalytic mechanism has been proposed, and the ability to scale the process has been demonstrated.

Mild, Redox-Neutral Formylation of Aryl Chlorides through the Photocatalytic Generation of Chlorine Radicals.

We report a redox-neutral formylation of aryl chlorides that proceeds through selective 2-functionalization of 1,3-dioxolane through nickel and photoredox catalysis. This scalable benchtop approach provides a distinct advantage over traditional reductive carbonylation in that no carbon monoxide, pressurized gas, or stoichiometric reductant is employed. The mild conditions give unprecedented scope from abundant and complex aryl chloride starting materials.

Asymmetric synthesis of highly functionalized tetrahydropyran DPP-4 inhibitor.

A practical synthesis of a highly functionalized tetrahydropyran DPP-4 inhibitor is described. The asymmetric synthesis relies on three back-to-back Ru-catalyzed reactions. A Ru-catalyzed dynamic kinetic resolution (DKR) reduction establishes two contiguous stereogenic centers in one operation. A unique dihydropyran ring is efficiently constructed through a preferred Ru-catalyzed cycloisomerization. Hydroboration followed by a Ru-catalyzed oxidation affords the desired functionalized pyranone core scaffold. Finally, stereoselective reductive amination and subsequent acidic deprotection afford the desired, potent DPP-4 inhibitor in 25% overall yield.

One-step synthesis of 1-chloro-3-arylacetone derivatives from arylacetic acids.

A practical one-step method has been developed to prepare α-chloroketones from readily available, inexpensive phenylacetic acid derivatives. The method utilizes the unique reactivity of an intermediate Mg-enolate dianion, which displays selectivity for the carbonyl carbon of chloromethyl carbonyl electrophiles. Decarboxylation of the intermediate occurs spontaneously during the reaction quench. The utility of the reaction products has been demonstrated through the total synthesis of the natural product cimiracemate B.

Synthesis of the HCV protease inhibitor Vaniprevir (MK-7009) using ring-closing metathesis strategy.

A highly efficient synthesis of Vaniprevir (MK-7009) has been accomplished in nine linear steps and 55% overall yield. The key features of this synthesis include a cost-effective synthesis of the isoindoline subunit and efficient construction of the 20-membered macrocyclic core of Vaniprevir (MK-7009) utilizing ring-closing metathesis technology. A high-performing ring-closing metathesis protocol has been achieved by simultaneous slow addition of the ruthenium catalyst (0.2 mol %) and the diene substrate at a concentration of 0.13 M.

Asymmetric synthesis of telcagepant, a CGRP receptor antagonist for the treatment of migraine.

A highly efficient, asymmetric synthesis of telcagepant (1), a CGRP receptor antagonist for the treatment of migraine, is described. This synthesis features the first application of iminium organocatalysis on an industrial scale. The key to the success of this organocatalytic transformation was the identification of a dual acid cocatalyst system, which allowed striking a balance of the reaction efficiency and product stability effectively. As such, via an iminium species, the necessnary C-6 stereogenicity was practically established in one operation in >95% ee. Furthermore, we enlisted an unprecedented Doebner-Knoevenagel coupling, which was also via an iminium species, to efficiently construct the C3-C4 bond with desired functionality. In order to prepare telcagepant (1) in high quality, a practical new protocol was discovered to suppress the formation of desfluoro impurities formed under hydrogenation conditions to <0.2%. An efficient lactamization facilitated by t-BuCOCl followed by a dynamic epimerization-crystallization resulted in the isolation of caprolactam acetamide with the desired C3 (R) and C6 (S) configuration cleanly. Isolating only three intermediates, the overall yield of this cost-effective synthesis was up to 27%. This environmentally responsible synthesis contains all of the elements required for a manufacturing process and prepares telcagepant (1) with the high quality required for pharmaceutical use.

Asymmetric synthesis of a potent, aminopiperidine-fused imidazopyridine dipeptidyl peptidase IV inhibitor.

A practical asymmetric synthesis of a novel aminopiperidine-fused imidazopyridine dipeptidyl peptidase IV (DPP-4) inhibitor 1 has been developed. Application of a unique three-component cascade coupling with chiral nitro diester 7, which is easily accessed via a highly enantioselective Michael addition of dimethyl malonate to a nitrostyrene, allows for the assembly of the functionalized piperidinone skeleton in one pot. Through a base-catalyzed, dynamic crystallization-driven process, the cis-piperidionone 16a is epimerized to the desired trans isomer 16b, which is directly crystallized from the crude reaction stream in high yield and purity. Isomerization of the allylamide 16b in the presence of RhCl(3) is achieved without any epimerization of the acid/base labile stereogenic center adjacent to the nitro group on the piperidinone ring, while the undesired enamine intermediate is consumed to <0.5% by utilizing a trace amount of HCl generated from RhCl(3). The amino lactam 4, obtained through hydrogenation and hydrolysis, is isolated as its crystalline pTSA salt from the reaction solution directly, as such intramolecular transamidation has been dramatically suppressed via kinetic control. Finally, a Cu(I) catalyzed coupling-cyclization allows for the formation of the tricyclic structure of the potent DPP-4 inhibitor 1. The synthesis, which is suitable for large scale preparation, is accomplished in 23% overall yield.

Chemoselectivity of the Ru-catalyzed cycloisomerization reaction for the synthesis of dihydropyrans; application to the synthesis of L-forosamine.

The chemoselectivity of a Ru-catalyzed cycloisomerization reaction has been established. The preference for O- capture of the vinylidene intermediate allows for the synthesis of 4-aminodihydropyrans that are valuable synthetic intermediates. The synthetic utility of these structures has been demonstrated in the synthesis of l-forosamine.

Tandem silylformylation-crotylsilylation/Tamao oxidation of internal alkynes: a remarkable example of generating complexity from simplicity.

The rhodium-catalyzed tandem silylformylation-crotylsilylation reaction has been extended to include internal alkynes. Tamao oxidation of the initial product leads to the production of a substituted enol, which undergoes highly diastereoselective tautomerization. The resulting one-pot procedure fashions three new stereocenters, a ketone, and a terminal alkene from a butenyl group, a propynyl group, a silyl hydride, H2O2, and CO.

One-step RhCl3-catalyzed deprotection of acyclic N-allyl amides.

A convenient one-step RhCl3-catalyzed deprotection of acyclic N-allyl amides is described. Preliminary mechanistic studies reveal that the key to the success of the one-step deprotection process is the dual function of RhCl3 in alcohol solvents. Reaction of RhCl3 with n-PrOH not only provides an active rhodium hydride species to catalyze isomerization of N-allyl amides to corresponding enamides but also generates a crucial catalytic amount of HCl to convert the enamides to deallylated amides through N,O-acetal exchange.

Divergent synthesis of complex polyketide-like macrolides from a simple polyol fragment.

[structure: see text] Three stereochemically and structurally complex non-natural polyketide macrolides have been synthesized from the same simple polyol precursor. That this polyol fragment is rapidly available in quantity is key to the practicality of these syntheses and allows the targeting of more highly complex and "natural product-like" macrolides.

Tandem intramolecular silylformylation-crotylsilylation: highly efficient synthesis of polyketide fragments.

Polyketide fragments may be rapidly and efficiently assembled in the tandem intramolecular silylformylation-crotylsilylation of alkenes and alkynes. The reactions establish up to three new stereocenters with good-to-excellent diastereoselectivity, and the use of the reaction in an iterative sense is demonstrated. In addition, a new dihydrosilane alcoholysis reaction has been developed, leading to a highly efficient sequence.