Download Enantiodivergent conversion of chiral secondary alcohols into

Enantiodivergent conversion of chiral
secondary alcohols into tertiary
alcohols
Aggarwal et al.
Nature 2008, 456, 778.
Contents
•Previous Methods
•Background literature
•Results
•Rationalization
•Summary (comparison to other methods)
Introduction-
Proposal
Proposed synthesis of tertiary alcohols through addition
of chiral carbenoids to boron reagents
Introduction-
Previous Methods
Common strategy for preparing chiral tertiary alcohols through
face selective addition of nucleophiles to ketones.
Introduction-
Previous Methods
Dosa and Fu, J. Am. Chem. Soc. 1998, 120, 445.
Introduction-
Previous Methods
Ramon & Yus, Tetrahedron Lett. 1998, 39, 1239.
Yus et al., Tetrahedron Asymmetry. 2005, 16, 3341.
Introduction-
Previous Methods
Walsh et. Al. Synlett. 2004, 749.
Walsh et al. J. Am. Chem. Soc. 2005, 127, 16416.
Gau et al. Angew. Chem. Int. Ed. 2007, 46, 5373.
Background
H
O
CH3CCl2Li
Ph B
O
H
Cl Cl
O
Me
B
Ph O
ZnCl2
Cl O
Ph C B
Me O
H
92% de
EtMgBr
Me O
Et C B
Ph O
H
88% de
H2O2
Me
Et C OH
Ph
84% ee
Matteson et al. Heteroatom Chem. 1989, 1, 65.
Background
Interact with lithium cation
Low energy LUMO
Hoppe et. al., Angew. Chem. Int. Ed. 1990, 29, 1424.
Hoppe et. al., Tetrahedron 1994, 50, 6097.
Hoppe et. al., Eur. J. Org. Chem. 1999, 3519.
Background
Aggarwal et. al., Angew. Chem. Int. Ed. 2007, 46, 7491.
Results
Results
Results –
Alcohol scope
Results –
Cyclic Alcohols
Results- Summary
Rationalisation
Summary – Limitations
•Only works for aryl alcohols
•Aryl boranes (e.g. Ph-9-BBN) incompatible due to protodeboronation
during aqueous oxidative work-up
•Indanol-derived carbamate gives same enantiomer (retention) with
triethyl borane or ethylboronic acid
(pyramidalization of geometrically constrained carbanion)
Summary –
advantages over
existing methods
•Broad scope
•Works with branched alkyl, vinyl and heteroaryl groups
•Readily available substrates (2o alcohols & boranes/boronic esters)
•Alkyl, alkenyl or aryl group can be added
•Intermediate tertiary boronic esters can be transformed into a range of
functional groups with retention of configuration (e.g. amination)
•Can form either enantiomer of a tertiary alcohol from a single enantiomer
of a seconday alcohol