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Total synthesis of tetrahydrolipstatin and stereoisomers via a highly regio- and diastereoselective carbonylation of epoxyhomoallylic alcohols.

Mulzer M, Tiegs BJ, Wang Y, Coates GW, O'Doherty GA - J. Am. Chem. Soc. (2014)

Bottom Line: The synthesis of THL was accomplished in 10 steps and 31% overall yield from an achiral ynone.Key to the success of the approach is the use of a bimetallic [Lewis acid](+)[Co(CO)4](-) catalyst for a late-stage regioselective carbonylation of an enantiomerically pure cis-epoxide to a trans-β-lactone.The success of this route to THL and its stereoisomers also demonstrated the practicality of the carbonylation catalyst for complex molecule synthesis as well as its functional group compatibility.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Chemical Biology, Northeastern University , Boston, Massachusetts 02115, United States.

ABSTRACT
A concise enantioselective synthesis of tetrahydrolipstatin (THL) and seven stereoisomers has been achieved. The synthesis of THL was accomplished in 10 steps and 31% overall yield from an achiral ynone. Key to the success of the approach is the use of a bimetallic [Lewis acid](+)[Co(CO)4](-) catalyst for a late-stage regioselective carbonylation of an enantiomerically pure cis-epoxide to a trans-β-lactone. The success of this route to THL and its stereoisomers also demonstrated the practicality of the carbonylation catalyst for complex molecule synthesis as well as its functional group compatibility.

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Synthesis of THL (1): Carbonylation of MOM-ProtectedEpoxide 5bReagents and conditions:(a)MOMCl, DIPEA, CH2Cl2, 0 °C, 85%; (b) [ClTPPAl][Co(CO)4] (1 mol %), CO (900 psi), THF,50 °C, 81%; (c) BF3·OEt2, 1,2-ethanedithiol,CH2Cl2, 0 °C, 83%; (d) N-Cbz-l-leucine, DCC, DMAP, CH2Cl2,rt, 93%; (e) Pd/C (10% wt/wt, 10 mol %), H2 (1 atm), AcOCHO,rt, 80%. ClTPP = meso-tetra(4-chlorophenyl) porphyrinato,DCC = N,N′-dicyclohexylcarbodiimide,DMAP = 4-dimethylaminopyridine.
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sch5: Synthesis of THL (1): Carbonylation of MOM-ProtectedEpoxide 5bReagents and conditions:(a)MOMCl, DIPEA, CH2Cl2, 0 °C, 85%; (b) [ClTPPAl][Co(CO)4] (1 mol %), CO (900 psi), THF,50 °C, 81%; (c) BF3·OEt2, 1,2-ethanedithiol,CH2Cl2, 0 °C, 83%; (d) N-Cbz-l-leucine, DCC, DMAP, CH2Cl2,rt, 93%; (e) Pd/C (10% wt/wt, 10 mol %), H2 (1 atm), AcOCHO,rt, 80%. ClTPP = meso-tetra(4-chlorophenyl) porphyrinato,DCC = N,N′-dicyclohexylcarbodiimide,DMAP = 4-dimethylaminopyridine.


Total synthesis of tetrahydrolipstatin and stereoisomers via a highly regio- and diastereoselective carbonylation of epoxyhomoallylic alcohols.

Mulzer M, Tiegs BJ, Wang Y, Coates GW, O'Doherty GA - J. Am. Chem. Soc. (2014)

Synthesis of THL (1): Carbonylation of MOM-ProtectedEpoxide 5bReagents and conditions:(a)MOMCl, DIPEA, CH2Cl2, 0 °C, 85%; (b) [ClTPPAl][Co(CO)4] (1 mol %), CO (900 psi), THF,50 °C, 81%; (c) BF3·OEt2, 1,2-ethanedithiol,CH2Cl2, 0 °C, 83%; (d) N-Cbz-l-leucine, DCC, DMAP, CH2Cl2,rt, 93%; (e) Pd/C (10% wt/wt, 10 mol %), H2 (1 atm), AcOCHO,rt, 80%. ClTPP = meso-tetra(4-chlorophenyl) porphyrinato,DCC = N,N′-dicyclohexylcarbodiimide,DMAP = 4-dimethylaminopyridine.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4120994&req=5

sch5: Synthesis of THL (1): Carbonylation of MOM-ProtectedEpoxide 5bReagents and conditions:(a)MOMCl, DIPEA, CH2Cl2, 0 °C, 85%; (b) [ClTPPAl][Co(CO)4] (1 mol %), CO (900 psi), THF,50 °C, 81%; (c) BF3·OEt2, 1,2-ethanedithiol,CH2Cl2, 0 °C, 83%; (d) N-Cbz-l-leucine, DCC, DMAP, CH2Cl2,rt, 93%; (e) Pd/C (10% wt/wt, 10 mol %), H2 (1 atm), AcOCHO,rt, 80%. ClTPP = meso-tetra(4-chlorophenyl) porphyrinato,DCC = N,N′-dicyclohexylcarbodiimide,DMAP = 4-dimethylaminopyridine.
Bottom Line: The synthesis of THL was accomplished in 10 steps and 31% overall yield from an achiral ynone.Key to the success of the approach is the use of a bimetallic [Lewis acid](+)[Co(CO)4](-) catalyst for a late-stage regioselective carbonylation of an enantiomerically pure cis-epoxide to a trans-β-lactone.The success of this route to THL and its stereoisomers also demonstrated the practicality of the carbonylation catalyst for complex molecule synthesis as well as its functional group compatibility.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Chemical Biology, Northeastern University , Boston, Massachusetts 02115, United States.

ABSTRACT
A concise enantioselective synthesis of tetrahydrolipstatin (THL) and seven stereoisomers has been achieved. The synthesis of THL was accomplished in 10 steps and 31% overall yield from an achiral ynone. Key to the success of the approach is the use of a bimetallic [Lewis acid](+)[Co(CO)4](-) catalyst for a late-stage regioselective carbonylation of an enantiomerically pure cis-epoxide to a trans-β-lactone. The success of this route to THL and its stereoisomers also demonstrated the practicality of the carbonylation catalyst for complex molecule synthesis as well as its functional group compatibility.

Show MeSH