Christopher J. Cordier

Natural products as an inspiration in the diversity-oriented synthesis of bioactive compound libraries

This review describes how the structures of natural products have provided an insipration for new synthetic methodology which yields libraries of diverse bioactive compounds.

Catalytic Enantioselective Cross-Couplings of Secondary Alkyl Electrophiles with Secondary Alkylmetal Nucleophiles: Negishi Reactions of Racemic Benzylic Bromides with Achiral Alkylzinc Reagents

We have developed a nickel-catalyzed method for the asymmetric cross-coupling of secondary electrophiles with secondary nucleophiles, specifically, stereoconvergent Negishi reactions of racemic benzylic bromides with achiral cycloalkylzinc reagents. In contrast to most previous studies of enantioselective Negishi cross-couplings, tridentate pybox ligands are ineffective in this process; however, a new, readily available bidentate isoquinoline-oxazoline ligand furnishes excellent ees and good yields. The use of acyclic alkylzinc reagents as coupling partners led to the discovery of a highly unusual isomerization that generates a significant quantity of a branched cross-coupling product from an unbranched nucleophile.

Enantioconvergent Cross-Couplings of Racemic Alkylmetal Reagents with Unactivated Secondary Alkyl Electrophiles: Catalytic Asymmetric Negishi α-Alkylations of N-Boc-Pyrrolidine

Although enantioconvergent alkyl-alkyl couplings of racemic electrophiles have been developed, there have been no reports of the corresponding reactions of racemic nucleophiles. Herein we describe Negishi cross-couplings of racemic α-zincated N-Boc-pyrrolidine with unactivated secondary halides, thus providing a one-pot, catalytic asymmetric method for the synthesis of a range of 2-alkylpyrrolidines (an important family of target molecules) from N-Boc-pyrrolidine, a commercially available precursor. Preliminary mechanistic studies indicated that two of the most straightforward mechanisms for enantioconvergence (dynamic kinetic resolution of the organometallic coupling partner and a simple β-hydride elimination/β-migratory insertion pathway) are unlikely to be operative.

Toward the Total Synthesis of the Brasilinolides: Stereocontrolled Assembly of a C1−C19 Polyol Segment

Two highly convergent syntheses of a fully protected C1-C19 polyol subunit of the brasilinolide family of immunosuppressive macrolides are described, exploiting boron-mediated 1,5-anti aldol couplings to form the C8-C9 and C13-C14 bonds.

Toward the total synthesis of the brasilinolides: construction of a differentially protected C20-C38 segment.

An efficient, convergent synthesis of a differentially protected C20-C38 segment of the brasilinolides is described. Iterative 1,4-syn aldol additions and ketone reductions were employed to construct the two related stereotetrads, while a sequence of Horner-Wadsworth-Emmons (HWE) coupling, CBS reduction, and Sharpless AE installed the epoxy alcohol functionality.

Catalytic Nucleophilic Fluorination of Secondary and Tertiary Propargylic Electrophiles with a Copper–N‐Heterocyclic Carbene Complex

A catalytic method for the nucleophilic fluorination of propargylic electrophiles is described. Our protocol involves the use of a Cu(NHC) complex as the catalyst and is suitable for the preparation of secondary and tertiary propargylic fluorides without the formation of isomeric fluoroallenes. Preliminary mechanistic investigations suggest that fluorination proceeds via copper acetylides and that cationic species are involved.

An efficient method for synthesising unsymmetrical silaketals: substrates for ring-closing, including macrocycle-closing, metathesis

Diisopropylsilyl ethers were activated with N-bromosuccinimide, and reacted with a fluorous-tagged alcohol, to yield tethered substrates for ring-closing metathesis reactions.

A Fluorous-Tagged “Safety Catch” Linker for Preparing Heterocycles by Ring-Closing Metathesis

A fluorous-tagged “safety catch” linker is described for the synthesis of heterocycles with use of ring-closing metathesis. The linker facilitiates the purification of metathesis substrates, the removal of the catalyst, the functionalization of the products, and the release of only metathesis products. The synthesis of a range of heterocycles is described.

Reaching the Target: Small Molecules Aim to Probe Barrier Quality

The field of chemical genetics is based on the premise that small molecules can be used to perturb macromolecular function and, hence, to give insight into complex biological mechanisms. For the systematic exploration of biology, this approach is usually considered to require a small-molecule partner for each protein target; indeed, one goal for chemical genomics is the identification of a small-molecule probe for each function of every protein. Nonetheless, some of the most exciting strategic applications of chemical probes in biology challenge this paradigm. The combination of small-molecule probes with classical genetic approaches, for example, can offer particularly valuable insights into protein function. For families of proteins with highly conserved active sites, the discovery of chemical probes that are selective for a specific protein is extremely challenging. However, by engineering the ATP-binding site, it is possible to design ligands that essentially target only the (mutant) protein kinase of interest. The combination of the chemical genetic approach with reverse classical genetics has, therefore, given remarkable insight into the biological mechanisms controlled by protein kinases; representative examples include the molecular mechanisms that underpin cell-cycle regulation, endocytosis, neurotrophin signalling and trafficking between cellular compartments.