Enantioselective Synthesis of Axially Chiral Spiro[3.3]heptanes by Site-Selective C–H Functionalization

TL;DR

This paper presents a new method for making axially chiral spiro compounds with high selectivity using a rhodium catalyst.

Contribution

A highly selective rhodium-catalyzed C–H functionalization method for axially chiral spiro[3.3]heptanes is developed.

Findings

The method achieves up to 92% yield, >20:1 regioselectivity, >20:1 diastereoselectivity, and 99% enantioselectivity.

The dirhodium catalyst's structure and noncovalent interactions enable conformation sorting and site selectivity.

The N-phthalimido group is ideal for further derivatization into amine and amide derivatives.

Abstract

The enantioselective
synthesis of axially chiral 2,6-disubstituted
spiro[3.3]­heptanes is challenging because the differentiating functionalities
are far apart from each other. The known enantioselective methods
to generate these compounds have relied on the use of enzymatic processes.
The current study achieves a highly regio-, diastereo-, and enantioselective
entry to the 2,6-disubstituted spiro[3.3]­heptanes by desymmetrizing
2-substituted spiro[3.3]­heptanes using rhodium-catalyzed C–H
functionalization by donor/acceptor carbenes derived from aryldiazoacetates
and styryldiazoacetates. The optimum catalyst is dirhodium tetrakis­(4,4′-(3,5-ditertbutylphenyl)-6,6′-dichlorobinaphthylphosphate)
(Rh2(S-MegaBNP)4), which adopts
a D4-symmetric structure. The optimum functionality on
the spiro[3.3]­heptane is the N-phthalimido group,
which is ideally suited for further derivatization to a range of amine
and amide derivatives. Under the optimized conditions, the C–H
functionalization products can be generated in up to 92% yield, >20:1
rr, >20:1 dr, and 99% ee. Computational studies revealed that the
catalyst is relatively rigid and both the orientation of the bound
carbene and the approaching substrate are controlled by their necessary
alignment in hydrophobic grooves between tert-butyl
groups of adjacent ligands. The diastereoselectivity is controlled
by selective C–H functionalization of one of the equilibrating
enantiomers of the 2-substituted spiro[3.3]­heptane, hence achieving
conformation sorting. These studies reveal that bowl-shaped dirhodium
catalysts are capable of subtle site selectivity caused by secondary
noncovalent interactions with the catalyst wall.

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