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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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Rationale for loss of regiocontrol for epoxides 28 and 30.
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fig2: Rationale for loss of regiocontrol for epoxides 28 and 30.

Mentions: We hypothesized that the loss in regioselectivity for substrates 28 and 30 could be the result of hydrogen bondinginteractions (Figure 2). This hydrogen bondinginteraction in turn could lower the barrier for pathway a to the regioisomeric β-lactone. To test this hypothesis, weinvestigated the carbonylation of epoxides 31, ent-24, ent-29, and 32. When the N-formyl group wasremoved as in epoxide 31 (entry 5), the carbonylationoccurred to give β-lactone 37 with complete controlof regioselectivity. Interestingly, when the N-formylgroup was replaced with the less acidic N-Cbz group,the high regioselectivity returned. Thus, epoxides ent-24, ent-29, and 32 carbonylated to form β-lactones ent-21, ent-38, and ent-39 as single regioisomers (entries 6–8;75%, 80%, 74%, respectively).


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)

Rationale for loss of regiocontrol for epoxides 28 and 30.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Rationale for loss of regiocontrol for epoxides 28 and 30.
Mentions: We hypothesized that the loss in regioselectivity for substrates 28 and 30 could be the result of hydrogen bondinginteractions (Figure 2). This hydrogen bondinginteraction in turn could lower the barrier for pathway a to the regioisomeric β-lactone. To test this hypothesis, weinvestigated the carbonylation of epoxides 31, ent-24, ent-29, and 32. When the N-formyl group wasremoved as in epoxide 31 (entry 5), the carbonylationoccurred to give β-lactone 37 with complete controlof regioselectivity. Interestingly, when the N-formylgroup was replaced with the less acidic N-Cbz group,the high regioselectivity returned. Thus, epoxides ent-24, ent-29, and 32 carbonylated to form β-lactones ent-21, ent-38, and ent-39 as single regioisomers (entries 6–8;75%, 80%, 74%, respectively).

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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