John Y. L. Chung

A General Procedure for the Preparation of β-Ketophosphonates

A mild, high-yielding procedure for the preparation of beta-ketophosphonates is described. The condensation is general with respect to the ester and phosphonate, and the products are obtained in high yields within minutes at 0 degrees C. The reaction procedure is operationally simple and amenable to large-scale preparations.

Diastereoselective Friedel−Crafts Alkylation of Indoles with Chiral α-Phenyl Benzylic Cations. Asymmetric Synthesis of Anti-1,1,2-Triarylalkanes

The reactions of chiral benzyl carbocations bearing alpha-phenyl substituents with N-sulfonylated indoles afford 1,1,2-triarylalkanes with anti-selectivities. This outcome is a reversal of facial diastereoselectivity relative to Bachs alpha-alkyl-bearing benzyl cations. The reactions are promoted by either a Brønsted acid (TFA) or Lewis acid (BF3.OEt2), offering differential diastereoselectivities and reactivities. The electronic properties of both reacting partners strongly influence the reaction rates and the product diastereoselectivities and appear to operate under kinetic control. This chemistry provides an efficient access to sterically congested tetrasubstituted ethanes.

Practical chemoenzymatic synthesis of a 3-pyridylethanolamino β3 adrenergic receptor agonist

Abstract A chemoenzymatic synthesis of β 3 agonist 1 suitable for large scale preparation is described. The key chiral 3-pyridylethanolamine intermediate ( R )- 7 was prepared via an improved Neber rearrangement and a yeast-mediated asymmetric reduction. The tetrazolone fragment of the molecule was constructed via a dipolar cycloaddition between 1-(cyclopentyl)-3-propylazide and p -chlorosulfonyl phenylisocyanate. Sulfonamide coupling of these two intermediates under Shotten-Baumann conditions, followed by a borane reduction of the amide afforded 1 in 20–32% overall yield from 3-acetylpyridine.

Asymmetric synthesis of cis-2,5-disubstituted pyrrolidine, the core scaffold of β3-AR agonists.

A practical, enantioselective synthesis of cis-2,5-disubstituted pyrrolidine is described. Application of an enzymatic DKR reduction of a keto ester, which is easily accessed through a novel intramolecular N→C benzoyl migration, yields syn-1,2-amino alcohol in >99% ee and >99:1 dr. Subsequent hydrogenation of cyclic imine affords the cis-pyrrolidine in high diastereoselectivity. By integrating biotechnology into organic synthesis and isolating only three intermediates over 11 steps, the core scaffold of β3-AR agonists is synthesized in 38% overall yield.

A practical synthesis of fibrinogen receptor antagonist MK-383. selective functionalization of (S)-tyrosine

Abstract A practical 4-step synthesis of fibrinogen receptor antagonist MK-383, N-(n-butanesulfonyl)-O-(4-(4-piperidinyl)-butyl)-(S)-tyrosine, is accomplished in 48% overall yield from (S)-tyrosine. Highlights include: (1) the dual use of 4-picoline as a masked form of piperidine, and as a nucleophile precursor for a 3-carbon homologation with 3-bromo-1-chloropropane; (2) the use of trimethylsilyl groups for temporary protection of phenolic and carboxylate oxygens of (S)-tyrosine that enable selective N-sulfonylation to be carried out in high yield; (3) the selective phenolic O-alkylation of the tyrosine derivative in high yield with no racemization using aqueous KOH/DMSO; and (4) the selective hydrogenation of the pyridine ring in the presence of the tyrosine ring using Pd/C in acetic acid.

Asymmetric hydrogenation of 3-alkylidene-2-piperidones using Noyori's catalyst. Effect of N-substituents on the enantioselectivity

Abstract The enantioselectivity in the asymmetric hydrogenation of 3-alkylidene-2-piperidones catalyzed by BINAP-Ru(II) complex was found to be significantly effected by the internal substituents on the lactam nitrogen, affording the corresponding 3-alkyl-2-piperidones in 52–92% ee.

Asymmetric Synthesis of Cyclic Indole Aminals via 1,3-Stereoinduction

A general and efficient asymmetric synthesis of cyclic indoline aminals was developed with a high level of 1,3-stereoinduction through a dynamic crystallization-driven condensation. Dehydrogenation of the indoline aminals with potassium permanganate produced the corresponding cyclic indole aminals in high yields and excellent enantioselectivities. This general methodology was successfully applied to the synthesis of a wide variety of chiral cyclic indoline aminals and indole aminals with aromatic and aliphatic functional groups.

Friedel-crafts cyclization of 2-(3-indolythio) propionic acids. An unusual rearrangement leading to 4-sulfur-substituted tricyclic indoles

Abstract The intramolecular Friedel-Crafts acylation of 2-(3-indolythio)propionic acid 1 has been found to undergo an unprecedented rearrangement to provide a novel tricyclic indole having the sulfur substituted on C-4 rather than on the expected C-3. A mechanism for its formation is proposed. This rearrangement also proceeded with good optical retention when a chiral substrate was used.

AN IMPROVED PREPARATION OF 2-AZABICYCLO[2.2.2]OCTANE

ABSTRACT An improved preparative four-step synthesis to isoquinuclidine tosylate salt 4 has been demonstrated in 70% overall yield from p-aminobenzoic acid (PABA) 1. Hydrogenation of PABA 1 affords 4-aminocyclohexane carboxylic acid 2 as an 80 : 20 mixture of cis- and trans-isomers. Heating the mixture at 250°C effected epimerization and cyclization to provide the bicyclic lactam 3. Subsequent Red-Al reduction and treatment with tosic acid furnished the desired bicyclic amine, tosylate salt 4.

Preparation of crystalline P-nitrobenzyl 2-formyl carbapenems by oxidative cleavage

Crystalline 1beta-methyl-2-formyl carbapenem pNB esters were prepared by osmium-mediated oxidative cleavage of the corresponding 2-vinyl derivatives. Reduction of the 2-formyl compounds gave the corresponding 2-hydroxymethyl derivatives, which are key intermediates for the anti-MRS carbapenem candidate (1).