Kap-Sun Yeung

A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design

Electron deficient, bivalent sulfur atoms have two areas of positive electrostatic potential, a consequence of the low-lying σ* orbitals of the C-S bond that are available for interaction with electron donors including oxygen and nitrogen atoms and, possibly, π-systems. Intramolecular interactions are by far the most common manifestation of this effect, which offers a means of modulating the conformational preferences of a molecule. Although a well-documented phenomenon, a priori applications in drug design are relatively sparse and this interaction, which is often isosteric with an intramolecular hydrogen-bonding interaction, appears to be underappreciated by the medicinal chemistry community. In this Perspective, we discuss the theoretical basis for sulfur σ* orbital interactions and illustrate their importance in the context of drug design and organic synthesis. The role of sulfur interactions in protein structure and function is discussed and although relatively rare, intermolecular interactions between ligand C-S σ* orbitals and proteins are illustrated.

Friedel–Crafts acylation of indoles in acidic imidazolium chloroaluminate ionic liquid at room temperature

Abstract A practical and convenient protocol has been developed for the acidic 1-ethyl-3-methylimidazolium chloroaluminate ionic liquid (generated from 1-ethyl-3-methylimidazolium chloride (EmimCl) and aluminium chloride ( X (AlCl 3 ), mole fraction X =0.67–0.75) promoted Friedel–Crafts acylation of indoles at room temperature. The simple experimental procedure provides 3-substituted indoles in good to high yields with less electron rich indole ring systems.

Ligand-Enabled β-C–H Arylation of α-Amino Acids Using a Simple and Practical Auxiliary

Pd-catalyzed β-C-H functionalizations of carboxylic acid derivatives using an auxiliary as a directing group have been extensively explored in the past decade. In comparison to the most widely used auxiliaries in asymmetric synthesis, the simplicity and practicality of the auxiliaries developed for C-H activation remains to be improved. We previously developed a simple N-methoxyamide auxiliary to direct β-C-H activation, albeit this system was not compatible with carboxylic acids containing α-hydrogen atoms. Herein we report the development of a pyridine-type ligand that overcomes this limitation of the N-methoxyamide auxiliary, leading to a significant improvement of β-arylation of carboxylic acid derivatives, especially α-amino acids. The arylation using this practical auxiliary is applied to the gram-scale syntheses of unnatural amino acids, bioactive molecules, and chiral bis(oxazoline) ligands.

The total synthesis of swinholide A. Part 4: Synthesis of swinholide A and isoswinholide A from the protected monomeric seco acid, pre-swinholide A

Abstract Swinholide A and isoswinholide A were synthesised in 7 steps from the fully protected seco acid 4 . Key steps include: ( i) bimolecular acylation, 7 + 10 → 12 , ( ii ) selective hydrolysis of the methyl ester, 16 → 17 , and ( iii ) regioselective macrolactonisation. 17 → 18 . The monomeric lactone analogues 2 and 5 were prepared by regioselective macrolactonisation of the seco acid 6 , where the ring size was controlled by variation of the reaction conditions.

Diverse ortho-C(sp2)–H Functionalization of Benzaldehydes Using Transient Directing Groups

Pd-catalyzed C-H functionalizations promoted by transient directing groups remain largely limited to C-H arylation only. Herein, we report a diverse set of ortho-C(sp2)-H functionalizations of benzaldehyde substrates using the transient directing group strategy. Without installing any auxiliary directing group, Pd(II)-catalyzed C-H arylation, chlorination, bromination, and Ir(III)-catalyzed amidation, could be achieved on benzaldehyde substrates. The transient directing groups formed in situ via imine linkage can override other coordinating functional groups capable of directing C-H activation or catalyst poisoning, significantly expanding the scope for metal-catalyzed C-H functionalization of benzaldehydes. The utility of this approach is demonstrated through multiple applications, including late-stage diversification of a drug analogue.

The total synthesis of swinholide A. Part 3: A stereocontrolled synthesis of (−)-pre-swinholide A.

Two coupling strategies for (−)-pre-swinholide A were devised based on the analysis in Scheme 1. In the first route, a boron-mediated aldol reaction between the ethyl ketone 19 and the aldehyde 3 was used to construct the C15-C16 bond with moderate diastereoselectivity. In the second route, a Mukaiyama aldol reaction between the methyl ketone 54 and the aldehyde 4 introduced the C18-C19 bond with complete stereocontrol.

Discovery and Preclinical Characterization of the Cyclopropylindolobenzazepine BMS-791325, A Potent Allosteric Inhibitor of the Hepatitis C Virus NS5B Polymerase.

Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.

Highly potent non-peptidic inhibitors of the HCV NS3/NS4A serine protease

Screening of a diverse set of bisbenzimidazoles for inhibition of the hepatitis C virus (HCV) serine protease NS3/NS4A led to the identification of a potent Zn(2+)-dependent inhibitor (1). Optimization of this screening hit afforded a 10-fold more potent inhibitor (46) under Zn(2+) conditions (K(i)=27nM). This compound (46) binds also to NS3/NS4A in a Zn(2+) independent fashion (K(i)=1microM). The SAR of this class of compounds under Zn(2+) conditions is highly divergent compared to the SAR in the absence of Zn(2+), suggesting two distinct binding modes.

The total synthesis of scytophycin C. Part 1: stereocontrolled synthesis of the C1C32 protected seco acid

Abstract A stereocontrolled synthesis of the C1C32 seco acid derivative 9 for scytophycin C (1) was completed in 14 steps (18.2% yield, 85% ds) from aldehyde (S)-18. Key steps include: (i) the asymmetric crotylboration of (S)-18 to give homoallylic alcohol 15; (ii) the boron-mediated aldol construction of aldehyde 14 from (S)-17; (iii) the Ba(OH)2-promoted HWE reaction, 13 + 14 → 31; (iv) the highly stereocontrolled Mukaiyama aldol coupling between silyl enol ether 33 and aldehyde 11 to give adduct 10; (v) the chemoselective reduction at C17 of ketone 10 to produce 1,3-syn-diol 34.

Chapter 5.3 Five-membered ring systems: Furans and benzofurans

Publisher Summary This chapter reviews papers that were published in 2006 on the reactions and syntheses of furans, benzofurans, and their derivatives. Like 2005, many new naturally occurring molecules containing tetrahydrofuran and dihydrofuran rings were identified in 2006. Several examples reported in 2006 demonstrate that 2-substituted furans underwent spirocyclization at the 2-position. The reaction of a furan tethered at the 2-position to an iminium ion gave a spiro-2,5-dihydrofuran derivative as the sole diastereoisomer. This spirocyclization that proceeded irrespective of the length of the carbon linker was employed to construct the ABC tricyclic core of manzamine A. Spirocyclization was also the reaction pathway under radical conditions if furan was tethered to a radical precursor at the 2-position. When furans were tethered to silyl enol ethers at the 2-position, spiroannulation also occurred at the 2-position under electrochemical conditions. Furan that was loaded on a soluble dendritic polyglycerol support could be efficiently oxidized electrochemically to a 2,5-dihydro-2,5-dimethoxyfuran, which served as an intermediate in the synthesis of a pyrrole library.