Enantioselective Synthesis of 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) via Enzymatic Desymmetrization.

An enantioselective synthesis of the potent anti-HIV nucleoside EFdA is presented. Key features of stereocontrol include construction of the fully substituted 4'-carbon via a biocatalytic desymmetrization of 2-hydroxy-2-((triisopropylsilyl)ethynyl)propane-1,3-diyl diacetate and a Noyori-type asymmetric transfer hydrogenation to control the stereochemistry of the 3'-hydroxyl bearing carbon. The discovery of a selective crystallization of an N-silyl nucleoside intermediate enabled isolation of the desired β-anomer from the glycosylation step.

A novel crystallization-induced diastereomeric transformation based on a reversible carbon-sulfur bond formation. Application to the synthesis of a gamma-secretase inhibitor.

This paper describes a remarkably efficient process for the preparation of gamma-secretase inhibitor 1. The target is synthesized in only five steps with an overall yield of 58%. The key operation is a highly selective and practical, crystallization-driven transformation for the conversion of a mixture of tertiary benzylic alcohols into the desired sulfide diastereomer with 94:6 dr.

A practical synthesis of a gamma-secretase inhibitor.

A practical and scaleable synthesis of the gamma-secretase inhibitor 1 is reported. The inhibitor consists of a central trisubstituted cyclohexane core with appended propionic acid, 2,5-difluorophenyl, and 4-chlorophenylsulfonyl moieties. Two alternative synthetic strategies, proceeding by way of a common disubstituted cyclohexanone derivative 5, were studied.

The conformational bias of aryl, arylsulfonyl geminally substituted tertiary carbon centers: applications in substrate-based stereocontrol.

Intramolecular nitrile oxide-olefin cycloaddition to form hexahydrobenzisoxazole 14, which engenders a phenylsulfonyl, 2,5-difluorophenyl geminally substituted carbon substructure, proceeds with up to 99% ds. A rationalization of the high level of substrate-based stereo-induction observed in this and related ketone and acrylonitrile metallohydride reductions, supported by single crystal X-ray crystallography, is presented.

Practical asymmetric synthesis of a non-peptidic alphavbeta3 antagonist.

The development of a practical and highly convergent synthesis of an alpha(v)beta3 antagonist is described. The two key fragments present in this compound, a tetrahydropyrido[2,3-b]azepine ring system and a chiral 3-aryl-5-oxopentanoic acid, were constructed independently and then coupled at a late stage using a Wittig reaction. The pyridoazepine moiety was prepared from N-Boc 6-chloro-2-aminopyridine via directed ortho-metalation/alkylation followed by in situ cyclization.

In situ moisture determination of a cytotoxic compound during process optimization.

A simple and safe prototype apparatus was designed and adapted for the in situ determination of the moisture content of a cytotoxic compound (9-fluorenylmethyl-protected doxorubicin-peptide conjugate, or Fm-DPC) by near-infrared absorbance spectroscopy during optimization of the chemical isolation procedure. The cytotoxic nature of the compound restricts one's ability to safely sample such drying processes for more traditional means of moisture determination for fear of hazardous solids dusting, hence in situ sampling approaches are of great importance. These concerns also exist for the process development laboratory, where despite the smaller scale of operations, the volume of experiments (hence cytotoxic samples) required to define a chemical process is often more significant.

Employment of on-line FT-IR spectroscopy to monitor the deprotection of a 9-fluorenylmethyl protected carboxylic acid peptide conjugate of doxorubicin.

A method for accurately determining the end-point, >98% conversion, of the deprotection reaction of a highly toxic 9-fluorenylmethyl (Fm) ester 1b to its corresponding carboxylate 1d in real time by FT-IR spectroscopy is reported. Advantages of this method over analysis by conventional chromatographic means include real time determination of the end-point of a reaction that is time sensitive to by-product formation, and elimination of sampling a highly toxic reaction mixture. The FT-IR method is based on monitoring, in real time, the disappearance of the Fm ester carbonyl band for 1b at 1737 cm(-1), during deprotection by piperidine, and calibration models were established by Partial Least Squares (PLS) regression analysis with high performance liquid chromatography (HPLC) as reference.