Tony Y. Zhang

Key green chemistry research areas—a perspective from pharmaceutical manufacturers

In 2005, the ACS Green Chemistry Institute (GCI) and the global pharmaceutical corporations developed the ACS GCI Pharmaceutical Roundtable to encourage the integration of green chemistry and green engineering into the pharmaceutical industry. The Roundtable has developed a list of key research areas. The purpose of this perspective is to summarise how that list was agreed, provide an assessment of the current state of the art in those areas and to highlight areas for future improvement.

AN EASILY PREPARED, AIR AND MOISTURE STABLE, RESIN-BOUND PALLADIUM CATALYST FOR SUZUKI CROSS-COUPLING REACTIONS

Abstract An air and moisture stable polymer supported palladium catalyst easily prepared from a commercial available thiourea resin Deloxan ® THP was found to enable Suzuki cross-coupling reactions to be carried out in high yields and convenient manner.

Cryptophycins-309, 249 and other cryptophycin analogs: preclinical efficacy studies with mouse and human tumors.

SummaryCryptophycins-1 and 52 (epoxides) were discovered to have in-vitro and in-vivo antitumor activity in the early 1990s. The chlorohydrins of these, Cryptophycins-8 and 55 (also discovered in the early 1990s) were markedly more active, but could not be formulated as stable solutions. With no method to adequately stabilize the chlorohydrins at the time, Cryptophycin-52 (LY 355073) entered clinical trials, producing only marginal antitumor activity. Since that time, glycinate esters of the hydroxyl group of the chlorohydrins have been synthesized and found to provide stability. Three of the most active were compared herein. Cryptophycin-309 (C-309) is a glycinate ester of the chlorohydrin Cryptophycin-296. The glycinate derivative provided both chemical stability and improved aqueous solubility. After the examination of 81 different Cryptophycin analogs in tumor bearing animals, C-309 has emerged as superior to all others. The following %T/C and Log Kill (LK) values were obtained from a single course of IV treatment (Q2d × 5) against early staged SC transplantable tumors of mouse and human origin: Mam 17/Adr [a pgp (+) MDR tumor]: 0%T/C, 3.2 LK; Mam 16/C/Adr [a pgp (−) MDR tumor]: 0%T/C, 3.3 LK; Mam 16/C: 0%T/C, 3.8 LK; Colon 26: 0%T/C, 2.2 LK; Colon 51: 0%T/C, 2.4 LK; Pancreatic Ductal Adenocarcinoma 02 (Panc 02): 0%T/C, 2.4 LK; Human Colon HCT15 [a pgp (+) MDR tumor]: 0%T/C, 3.3 LK; Human Colon HCT116: 0%T/C, 4.1 LK. One additional analog, Cryptophycin-249 (C-249, the glycinate of Cryptophycin-8), also emerged with efficacy rivaling or superior to C-309. However, there was sufficient material for only a single C-249 trial in which a 4.0 LK was obtained against the multidrug resistant breast adenocarcinoma Mam-16/C/Adr. C-309 and C-249 are being considered as second-generation clinical candidates.

Recent Advances in the Synthesis and Applications of Benzo[b]thiophenes

Abstract Recent developments in the application and synthesis of benzo[b]thiophenes are reviewed, with an emphasis on various cyclization methodologies leading to the heterocyclic core structure.

A novel imidazol-2-ylidene as a ligand for palladium-catalyzed synthesis of oxyindoles from o-haloanilides

Abstract Oxyindoles were formed in good yields from 2-bromo- or chloroanilide in the presence of a base and a novel palladium imidazol-2-ylidene complex, through a process of metal-catalyzed intramolecular arylation of amide enolates. A wide range of substrates, including electron rich aryl chlorides, were found active under the catalysis of this non-phosphinic, easily prepared ligand–metal system.

Regioselective synthesis of 2-chloro-3-pyridinecarboxylates

Abstract 2-Chlorocyanoacetate was found to undergo base-catalyzed Michael addition to α,β-unsaturated ketones or aldehydes to afford 5-oxopentenenitrile derivatives. In the presence of anhydrous HCl, these compounds cyclize to yield 2-chloro-3-pyridinecarboxylates. The process is highly regiospecific and useful in the synthesis of 2,3-disubstituted pyridines.

Palladium-catalyzed intramolecular arylation of an anilide enolate, application to an efficient formal total synthesis of physovenine

An expedient formal total synthesis of the calabar alkaloid physovenine was reported. The key step involves an oxindole synthesis via palladium-catalyzed intramolecular arylation of o-bromoanilide.

An efficient and practical synthesis of diphenyl cyanomethylenephosphonate: Applications to the stereoselective synthesis of cis-α,β-unsaturated nitriles

Abstract Diphenyl cyanomethylenephosphonate (PhO) 2 POCH 2 CN was prepared as a stable crystalline solid in high yield in a single step from acetonitrile, LDA, and (PhO) 2 P(O)Cl. The potassium ylide generated from this compound afforded α,β-unsaturated nitriles upon reacting with aldehydes, with a stereoselectivity of 64–100% favoring the cis -isomer.

Enantioselective Syntheses of 1-Carbacephalosporins from Chemoenzymically Derived β-Hydroxy-α-Amino Acids: Applications to the Total Synthesis of Carbacephem Antibiotic Loracarbef

Abstract Serine hydroxymethyltransferase (SHMT) derived from recombinant E. coli was found to be able to catalyze the condensation between glycine and 4-pentenaldehyde, affording enantiopure l -erythro-2-amino-3-hydroxy-6-heptenoic acid (AHHA) in high yield and throughput. Conversion of this chiral intermediate of biosynthetic origin to the oral carbacephalosporin antibiotic loracarbef (Lorabid®) via β-lactam forming reactions and subsequent Dieckmann cyclization was achieved.

Enantioselective synthesis of the carbacephem antibiotic loracarbef via Mitsunobu and Dieckmann cyclization from an unnatural amino acid

The nucleus of the carbacephem antibiotic loracarbef was synthesized in a highly efficient and enantioselective fashion from 2S,3S-2-amino-3-hydroxy-6-heptenoic acid (AHHA), which was derived from enzyme-catalyzed condensation of glycine and 4-pentenaldehyde. The bicyclic framework of this compound was established through sequential Mitsunobu reaction and aldol condensations.