Can classical and modern chemical C-H oxidation reactions complement biotransformation in the synthesis of drug metabolites? We have surveyed the literature in an effort to try to answer this important question of major practical significance in the pharmaceutical industry. Drug metabolites are required throughout all phases of the drug discovery and development process; however, their synthesis is still an unsolved problem. This Review, not intended to be comprehensive or historical, highlights relevant applications of chemical C-H oxidation reactions, electrochemistry and microfluidic technologies to drug templates in order to access drug metabolites, and also highlights promising reactions to this end. Where possible or appropriate, the contrast with biotransformation is drawn. In doing so, we have tried to identify gaps where they exist in the hope to spur further activity in this very important research area.

A visible-light-driven Minisci protocol that employs an inexpensive earth-abundant metal catalyst, decacarbonyldimanganese Mn (CO) , to generate alkyl radicals from alkyl iodides has been developed. This Minisci protocol is compatible with a wide array of sensitive functional groups, including oxetanes, sugar moieties, azetidines, tert-butyl carbamates (Boc-group), cyclobutanes, and spirocycles. The robustness of this protocol is demonstrated on the late-stage functionalization of complex nitrogen-containing drugs. Photophysical and DFT studies indicate a light-initiated chain reaction mechanism propagated by Mn(CO) . The rate-limiting step is the iodine abstraction from an alkyl iodide by Mn(CO) .

A metal-free photoredox C-H alkylation of heteroaromatics from readily available carboxylic acids using an organic photocatalyst and hypervalent iodine reagents under blue LED light is reported. The developed methodology tolerates a broad range of functional groups and can be applied to the late-stage functionalization of drugs and drug-like molecules. The reaction mechanism was investigated with control experiments and photophysical experiments as well as DFT calculations.

The isolation, quantitation, and characterization of drug metabolites in biological fluids remain challenging. Rapid access to oxidized drugs could facilitate metabolite identification and enable early pharmacology and toxicity studies. Herein, we compared biotransformations to classical and new chemical C-H oxidation methods using oxcarbazepine, naproxen, and an early compound hit (phthalazine 1). These studies illustrated the low preparative efficacy of biotransformations and the inability of chemical methods to oxidize complex pharmaceuticals. We also disclose an aerobic catalytic protocole (CuI/air) to oxidize tertiary amines and benzylic CH's in drugs. The reaction tolerates a broad range of functionalities and displays a high level of chemoselectivity, which is not generally explained by the strength of the C-H bonds but by the individual structural chemotype. This study represents a first step toward establishing a chemical toolkit (chemotransformations) that can selectively oxidize C-H bonds in complex pharmaceuticals and rapidly deliver drug metabolites.

The optimization of a new class of small molecule PCSK9 mRNA translation inhibitors is described. The potency, physicochemical properties, and off-target pharmacology associated with the hit compound (1) were improved by changes to two regions of the molecule. The last step in the synthesis of the congested amide center was enabled by three different routes. Subtle structural changes yielded significant changes in pharmacology and off-target margins. These efforts led to the identification of 7l and 7n with overall profiles suitable for in vivo evaluation. In a 14-day toxicology study, 7l demonstrated an improved safety profile vs lead 7f. We hypothesize that the improved safety profile is related to diminished binding of 7l to nontranslating ribosomes and an apparent improvement in transcript selectivity due to the lower strength of 7l stalling of off-target proteins.

Avisible-light-driven Minisci protocol that employs an inexpensive earth-abundant metal catalyst, decacarbonyldimanganese Mn 2 (CO) 10 ,t og enerate alkylr adicals from alkyl iodides has been developed. This Minisci protocol is compatible with awide arrayofsensitive functional groups,including oxetanes,s ugar moieties,a zetidines,t ert-butyl carbamates (Boc-group), cyclobutanes,a nd spirocycles.T he robustness of this protocol is demonstrated on the late-stage functionalization of complex nitrogen-containing drugs.P hotophysical and DFT studies indicate al ight-initiated chain reaction mechanism propagated by CMn(CO) 5 .T he rate-limiting step is the iodine abstraction from an alkyl iodide by CMn(CO) 5 . Scheme 1. Photomediated Minisci CÀHalkylation of N-heteroarenes.

Due to a combination of their promising anticancer properties, limited supply from the marine sponge source and their unprecedented molecular architecture, spirastrellolides represent attractive and challenging synthetic targets. A modular strategy for the synthesis of spirastrellolide A methyl ester, which allowed for the initial stereochemical uncertainties in the assigned structure was adopted, based on the envisaged sequential coupling of a series of suitably functionalised fragments; in this first paper, full details of the synthesis of these fragments are described. The pivotal C26-C40 DEF bis-spiroacetal was assembled by a double Sharpless asymmetric dihydroxylation/acetalisation cascade process on a linear diene intermediate, configuring the C31 and C35 acetal centres under suitably mild acidic conditions. A C1-C16 alkyne fragment was constructed by application of an oxy-Michael reaction to introduce the A-ring tetrahydropyran, a Sakurai allylation to install the C9 hydroxyl, and a 1,4-syn boron aldol/directed reduction sequence to establish the C11 and C13 stereocentres. Two different coupling strategies were investigated to elaborate the C26-C40 DEF fragment, involving either a C17-C25 sulfone or a C17-C24 vinyl iodide, each of which was prepared using an Evans glycolate aldol reaction. The remaining C43-C47 vinyl stannane fragment required for introduction of the unsaturated side chain was prepared from (R)-malic acid.

The marine macrolide spirastrellolide A (1, Scheme 1) is a potent and selective protein phosphatase inhibitor, causing premature cell entry into mitosis.[1] Synthetic interest [2] in the spirastrellolides derives not only from their unique molecular architecture, but also from their potential as lead structures for the development of novel anticancer agents. [3] In the preceding communication, [2] we described our optimized and scalable approach to the construction of the key C17-C40 bisspiroacetal intermediate 3, which forms the foundation of our strategy towards these challenging natural products. Herein, we report the completion of the first total synthesis of spirastrellolide A methyl ester (2, Scheme 1), as well as the single-crystal X-ray diffraction analysis of an advanced intermediate that reveals the conformation of the spirastrellolide macrocycle and plays a vital role in our end-game strategy.A summary of our synthetic plan, which was designed to provide maximum flexibility in terms of fragment coupling and diastereomer selection, is outlined in Scheme 1. This optimized retrosynthesis leads to three key subunits-the C17-C40 aldehyde 3, the C1-C16 alkyne 4, and the C43-C47 stannane 5. The planned completion of the total synthesis of spirastrellolide A methyl ester (2) would thus proceed through the union of aldehyde 3 with alkyne 4, with subsequent elaboration to introduce the BC spiroacetal domain, and macrolactonization to generate the 38-membered macrolide core. A series of manipulations at C40 (in the truncated side chain) would precede the end game of the synthesis, which would involve a cross-coupling reaction with stannane 5 to install concurrently the 40E and 43Z double bonds as well as the terminal a-hydroxy ester in structure 2.The first requirement for this synthetic plan was the preparation of the C1-C16 alkyne 4. We have previously reported the synthesis of a close relative of this alkyne [4] by using Jacobsens hydrolytic kinetic resolution of epoxides. [5] Building on this earlier work, installation of a PMB ether was now required at C1 such that our envisaged BC-spiroacetalization step would result in simultaneous deprotection at this position. The most convenient point to undertake this modification was deemed to be the vinyl dibromide 6 (Scheme 2). Thus, selective desilylation at C1 was followed by formation of the PMB ether under mild conditions by using PMB trichloroacetimidate. Subsequent conversion of the vinyl dibromide into the alkyne 4 proceeded uneventfully on treatment with base (66 % yield, over 3 steps). [6] The union of the C1-C16 and C17-C40 subunits through addition of the lithium anion of alkyne 4 to the DEF aldehyde Scheme 1. Spirastrellolide A (1), its methyl ester (2), and retrosynthetic analysis leading to key building blocks 3-5. PMB = para-methoxybenzyl, TBS = tert-butyldimethylsilyl, TES = triethylsilyl.