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1.
J Org Chem ; 77(7): 3297-310, 2012 Apr 06.
Article in English | MEDLINE | ID: mdl-22423625

ABSTRACT

An efficient, new, and scalable semisynthesis of glucan synthase inhibitors 1 and 2 from the fermentation product enfumafungin 3 is described. The highlights of the synthesis include a high-yielding ether bond-forming reaction between a bulky sulfamidate 17 and alcohol 4 and a remarkably chemoselective, improved palladium(II)-mediated Corey-Yu allylic oxidation at the highly congested C-12 position of the enfumafungin core. Multi-hundred gram quantities of the target drug candidates 1 and 2 were prepared, in 12 linear steps with 25% isolated yield and 13 linear steps with 22% isolated yield, respectively.


Subject(s)
Alcohols/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Chrysenes/chemistry , Chrysenes/chemical synthesis , Echinocandins/chemistry , Glucosyltransferases/antagonists & inhibitors , Glycosides/chemistry , Palladium/chemistry , Triterpenes/chemistry , Catalysis , Molecular Structure , Stereoisomerism
2.
J Am Chem Soc ; 132(20): 7138-52, 2010 May 26.
Article in English | MEDLINE | ID: mdl-20443561

ABSTRACT

The total synthesis of the originally assigned structure of vannusal B (2) and its diastereomer (d-2) are described. Initial forays into these structures with model systems revealed the viability of a metathesis-based approach and a SmI(2)-mediated strategy for the key cyclization to forge the central region of the molecule, ring C. The former approach was abandoned in favor of the latter when more functionalized substrates failed to enter the cyclization process. The successful, devised convergent strategy based on the SmI(2)-mediated ring closure utilized vinyl iodide (-)-26 and aldehyde fragment (+/-)-86 as key building blocks, whose lithium-mediated coupling led to isomeric coupling products (+)-87 and (-)-88 (as shown in Scheme 17 in the article). Intermediate (-)-88 was converted, via (-)-89 and (-)-90/(+)-91, to vannusal B structure 2 (as shown in Scheme 18 in the article), whose spectroscopic data did not match those reported for the natural product. Similarly, intermediate (+)-25, obtained through coupling of vinyl iodide (-)-26 and aldehyde (+/-)-27 (as shown in Scheme 13 in the article) was transformed via intermediates (-)-97 and (+)-98 (as shown in Scheme 19 in the article) to diastereomeric vannusal B structure (+)-d-2 (as shown in Scheme 19 in the article) which was also proven spectroscopically to be non-identical to the naturally occurring substance. These investigations led to the discovery and development of a number of new synthetic technologies that set the stage for the solution of the vannusal structural conundrum.


Subject(s)
Spiro Compounds/chemistry , Spiro Compounds/chemical synthesis , Aldehydes/chemistry , Cyclization , Iodides/chemistry , Samarium/chemistry , Stereoisomerism
5.
J Org Chem ; 70(8): 3021-30, 2005 Apr 15.
Article in English | MEDLINE | ID: mdl-15822960

ABSTRACT

A practical, chromatography-free catalytic asymmetric synthesis of a potent and selective PDE4 inhibitor (L-869,298, 1) is described. Catalytic asymmetric hydrogenation of thiazole ketone 5a afforded the corresponding alcohol 3b in excellent enantioselectivity (up to 99.4% ee). Activation of alcohol 3b via formation of the corresponding p-toluenesulfonate followed by an unprecedented displacement with the lithium enolate of ethyl 3-pyridylacetate N-oxide 4a generated the required chiral trisubstituted methane. The displacement reaction proceeded with inversion of configuration and without loss of optical purity. Conversion of esters 2b to 1 was accomplished via a one-pot deprotection, saponification, and decarboxylation sequence in excellent overall yield.


Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Combinatorial Chemistry Techniques , Cyclic N-Oxides/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Pyridines/chemical synthesis , Cyclic N-Oxides/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 4 , Enzyme Inhibitors/pharmacology , Magnetic Resonance Spectroscopy , Molecular Structure , Pyridines/pharmacology , Stereoisomerism
6.
J Org Chem ; 68(7): 2633-8, 2003 Apr 04.
Article in English | MEDLINE | ID: mdl-12662032

ABSTRACT

A large-scale, chromatography-free synthesis of a potent and selective Cathepsin K inhibitor 1 is reported. The key asymmetric center was installed by addition of (R)-pantolactone to the in situ-generated ketene 4a. The final step of the convergent synthesis of 1 was completed via Suzuki coupling of aryl bromide 7a with unprotected aryl piperazine boronic acid 13. Residual palladium and iron generated in the Suzuki coupling were efficiently removed from crude 1 via a simple extractive workup using lactic acid.


Subject(s)
Cathepsins/antagonists & inhibitors , Combinatorial Chemistry Techniques , Enzyme Inhibitors/chemical synthesis , Palladium/chemistry , Pentanoic Acids/chemical synthesis , Piperazines/chemical synthesis , Catalysis , Cathepsin K , Enzyme Inhibitors/pharmacology , Indicators and Reagents , Magnetic Resonance Spectroscopy , Molecular Structure , Pentanoic Acids/pharmacology , Piperazines/pharmacology , Stereoisomerism
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