Leland Otto Weigel

Asymmetric synthesis and absolute stereochemistry of LY248686

Abstract Reduction of 3-(dialkylamino)-1-aryl-1-propanones with a 2:1 complex of [(2R,3S-(+)-4--dimethylamino-l,2-diphenyl-3-methyl-2-butanol] (8) and lithium aluminum hydride (LAH) provided the corresponding 1,3-aminoalcohols in high ees (80–88%). This process was developed and applied to the synthesis of LY248686 (1), a potent inhibitor of serotonin (5HT) and norepinephrine (NE) uptake. Absolute configurations have been established by single crystal x-ray analysis.

The Application of High-Throughput Synthesis And Purification To The Preparation Of Ethanolamines

Abstract A 48 compound library of structurally diverse ethanolamines was prepared using a parallel synthesis approach. The synthetic paradigm employed a solution phase epoxide-opening reaction followed by rapid purification by ion exchange chromatography to yield products with near-analytical purity. An array of epoxides and primary amines, arranged in an 8×6 matrix, were reacted in the presence of an in situ silylating agent to form 48 individual compounds with an average yield of 75% and an average purity of 92.3%.

Alkylation of N-trimethylsilylated primary amines with arylethylene oxides. An efficient synthesis of 1-phenethanolamines

Abstract Reaction of unhindered N-trimethylsilylated primary amines with styrene oxide derivatives provides good yields of 1-phenethanolamines after acidic hydrolysis during work-up. This methodology results in much better conversions and higher yields when compared to direct equimolar alkylations.

Enantioselective synthesis of loracarbef from sodium erythorbate

Abstract Sodium erythorbate ( 7 ) has been converted to loracarbef ( 1 ). Oxidation of sodium erythorbate to D -erythronolactone ( 8 ) followed by selective monotosylation and treatment with sodium ethoxide provided ethyl (2 S ,3 R )-4-hydroxy-2,3-epoxybutyrate ( 10 ). Swern oxidation of this epoxide into the aldehyde ( 11 ), imine formation with tert -butylglycinate and an enantioselective Staudinger reaction with phthalimidoacetyl chloride afforded the (3 S ,4 S )- cis - β-lactam ( 13 ). Appropriate functional group manipulations followed by a Dieckmann condensation, chlorination, and protecting group removals gave the enantiomerically pure nucleus of loracarbef ( 24 ).

Enantioselective synthesis of the 6,8-dioxabicyclo-[3.2.1]octane skeleton by asymmetric dihydroxylation

Abstract Sharpless asymmetric dihydroxylation (AD) of 6-hepten-2-one with AD-mix-α® followed by acidification gives (1S,SR)-5-methyl- 6,8-dioxabicyclo[3.2.1]octane in moderate ee. This methodology defines a two-pot enantioselective construction of the (−)- frontalin and brevicomin skeleton from the corresponding 2-alkyl-1,3-dithiane and 5-bromo-1-hexene derivatives.

SNAR REACTIONS OF 2-HALOARYLSULFOXIDES WITH ALKOXIDES PROVIDE A NOVEL SYNTHESIS OF THIOTOMOXETINE

Abstract A five step synthesis of thiotomoxetine ( 2 ) is described. Installation of the aryl ether was accomplished using a highly efficient S N Ar fragment coupling between amino alcohol ( 4 ) and a 1-halo-2-methylsulfinylbenzene (X = F or Cl) followed by a selective reduction of the arylsulfoxide moiety.

Scope of phthalimido chemistry I. Extension of utility by conversion to the opcb protecting group.

Abstract The scope of the phthalimido protecting group (PhthN-) is extended by reaction with pyrrolidine. The resulting o -pyrrolidinocarbonylbenzamide (“OPCB-”) represents a base/nucleophile stable derivative of the parent, which reverts to the imide form upon treatment with acid. This methodology allows utilization of this protecting group (as the OPCB form in synthetic sequences requiring basic/nucleophilic reaction conditions.

An efficient acylation/base-catalyzed cyclization of thioureas affords N,N′-disubstituted thiobarbituric acids

Abstract Acylation of 1,3-disubstituted thioureas with methyl malonyl chloride followed by base-catalyzed cyclization leads to the preparation of 1,3-disubstituted-2-thiobarbituric acids in high yield.

A diastereoselective tandem metalloenamine alkylation/aza-annulation of β-tetralones expedites the synthesis of benzoquinolinones

Abstract In one operation, metalloenamines derived from R -phenylethylamine (PEA) and a β-tetralone were treated with an electrophile followed by acrylic anhydride. The unpurified lactams were reduced to give 10b-angular benzoquinolinones (BQs).