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Enantioselective construction of remote quaternary stereocentres.

Mei TS, Patel HH, Sigman MS - Nature (2014)

Bottom Line: Small molecules that contain all-carbon quaternary stereocentres-carbon atoms bonded to four distinct carbon substituents-are found in many secondary metabolites and some pharmaceutical agents.This method provides direct access to quaternary all-carbon-substituted β-, γ-, δ-, ε- or ζ-aryl carbonyl compounds, because the unsaturation of the alkene is relayed to the alcohol, resulting in the formation of a carbonyl group.The method described allows access to diverse molecular building blocks containing an enantiomerically enriched quaternary centre.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, The University of Utah, 315 South, 1400 East, Salt Lake City, Utah 84112, USA.

ABSTRACT
Small molecules that contain all-carbon quaternary stereocentres-carbon atoms bonded to four distinct carbon substituents-are found in many secondary metabolites and some pharmaceutical agents. The construction of such compounds in an enantioselective fashion remains a long-standing challenge to synthetic organic chemists. In particular, methods for synthesizing quaternary stereocentres that are remote from other functional groups are underdeveloped. Here we report a catalytic and enantioselective intermolecular Heck-type reaction of trisubstituted-alkenyl alcohols with aryl boronic acids. This method provides direct access to quaternary all-carbon-substituted β-, γ-, δ-, ε- or ζ-aryl carbonyl compounds, because the unsaturation of the alkene is relayed to the alcohol, resulting in the formation of a carbonyl group. The scope of the process also includes incorporation of pre-existing stereocentres along the alkyl chain, which links the alkene and the alcohol, in which the stereocentre is preserved. The method described allows access to diverse molecular building blocks containing an enantiomerically enriched quaternary centre.

No MeSH data available.


Approaches to constructing acyclic all-carbon quaternary stereocentersa, Conventional enantioselective, catalytic approaches. α-functionalization of carbonyls (I). β-functionalization of carbonyls (II). α-quaternary centers adjacent to alkene (III). b, Proposed modular strategy using a redox relay enantioselective Heck reaction of trisubstituted alkenes and resulting mechanistic analysis.
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Figure 1: Approaches to constructing acyclic all-carbon quaternary stereocentersa, Conventional enantioselective, catalytic approaches. α-functionalization of carbonyls (I). β-functionalization of carbonyls (II). α-quaternary centers adjacent to alkene (III). b, Proposed modular strategy using a redox relay enantioselective Heck reaction of trisubstituted alkenes and resulting mechanistic analysis.

Mentions: The quaternary stereocenter is a common structural motif in many natural products and pharmaceuticals1-3. However, the synthesis of these stereocenters in a catalytic and enantioselective manner represents a formidable challenge, especially in acyclic systems4. Typically, quaternary stereocenters are prepared from substrates with pre-existing functional groups adjacent to the site of reaction, whereas methods to access quaternary stereocenters distant from such groups present a significant, ongoing synthetic hurdle. The most common enantioselective and catalytic approaches utilize a carbonyl as a functional handle, wherein α-functionalization, via alkylation or aldol reactions4,5, can be accomplished through the reaction of enolate equivalents (I in Fig. 1a)6-11. Enantioselective β-functionalization of a carbonyl can be accomplished through 1,4-conjugate addition-type processes using various transition metals and coupling partners (II in Fig. 1a)12-16. A powerful alternative to the carbonyl as a pre-installed functional group is the allylic electrophile17-19 or nucleophile20, which yields a quaternary center adjacent to an alkene (III, Fig. 1a)21-23. However, in all of these approaches, the location of C–C bond formation relative to the functional group is strictly defined, which does not allow one to directly install a quaternary chiral center at more remote sites.


Enantioselective construction of remote quaternary stereocentres.

Mei TS, Patel HH, Sigman MS - Nature (2014)

Approaches to constructing acyclic all-carbon quaternary stereocentersa, Conventional enantioselective, catalytic approaches. α-functionalization of carbonyls (I). β-functionalization of carbonyls (II). α-quaternary centers adjacent to alkene (III). b, Proposed modular strategy using a redox relay enantioselective Heck reaction of trisubstituted alkenes and resulting mechanistic analysis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4007023&req=5

Figure 1: Approaches to constructing acyclic all-carbon quaternary stereocentersa, Conventional enantioselective, catalytic approaches. α-functionalization of carbonyls (I). β-functionalization of carbonyls (II). α-quaternary centers adjacent to alkene (III). b, Proposed modular strategy using a redox relay enantioselective Heck reaction of trisubstituted alkenes and resulting mechanistic analysis.
Mentions: The quaternary stereocenter is a common structural motif in many natural products and pharmaceuticals1-3. However, the synthesis of these stereocenters in a catalytic and enantioselective manner represents a formidable challenge, especially in acyclic systems4. Typically, quaternary stereocenters are prepared from substrates with pre-existing functional groups adjacent to the site of reaction, whereas methods to access quaternary stereocenters distant from such groups present a significant, ongoing synthetic hurdle. The most common enantioselective and catalytic approaches utilize a carbonyl as a functional handle, wherein α-functionalization, via alkylation or aldol reactions4,5, can be accomplished through the reaction of enolate equivalents (I in Fig. 1a)6-11. Enantioselective β-functionalization of a carbonyl can be accomplished through 1,4-conjugate addition-type processes using various transition metals and coupling partners (II in Fig. 1a)12-16. A powerful alternative to the carbonyl as a pre-installed functional group is the allylic electrophile17-19 or nucleophile20, which yields a quaternary center adjacent to an alkene (III, Fig. 1a)21-23. However, in all of these approaches, the location of C–C bond formation relative to the functional group is strictly defined, which does not allow one to directly install a quaternary chiral center at more remote sites.

Bottom Line: Small molecules that contain all-carbon quaternary stereocentres-carbon atoms bonded to four distinct carbon substituents-are found in many secondary metabolites and some pharmaceutical agents.This method provides direct access to quaternary all-carbon-substituted β-, γ-, δ-, ε- or ζ-aryl carbonyl compounds, because the unsaturation of the alkene is relayed to the alcohol, resulting in the formation of a carbonyl group.The method described allows access to diverse molecular building blocks containing an enantiomerically enriched quaternary centre.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, The University of Utah, 315 South, 1400 East, Salt Lake City, Utah 84112, USA.

ABSTRACT
Small molecules that contain all-carbon quaternary stereocentres-carbon atoms bonded to four distinct carbon substituents-are found in many secondary metabolites and some pharmaceutical agents. The construction of such compounds in an enantioselective fashion remains a long-standing challenge to synthetic organic chemists. In particular, methods for synthesizing quaternary stereocentres that are remote from other functional groups are underdeveloped. Here we report a catalytic and enantioselective intermolecular Heck-type reaction of trisubstituted-alkenyl alcohols with aryl boronic acids. This method provides direct access to quaternary all-carbon-substituted β-, γ-, δ-, ε- or ζ-aryl carbonyl compounds, because the unsaturation of the alkene is relayed to the alcohol, resulting in the formation of a carbonyl group. The scope of the process also includes incorporation of pre-existing stereocentres along the alkyl chain, which links the alkene and the alcohol, in which the stereocentre is preserved. The method described allows access to diverse molecular building blocks containing an enantiomerically enriched quaternary centre.

No MeSH data available.