Enantioselective Synthesis of Spirolactones and Spirolactams Under Low Catalyst Loadings

TL;DR

This paper presents a highly efficient and enantioselective method for synthesizing spirocyclic compounds using a rhodium catalyst at extremely low loadings.

Contribution

A novel Rh2-catalyzed [2+1] cyclopropanation method for spirocyclopropanes with exceptional enantioselectivity and turnover numbers.

Findings

The reaction achieves up to 98% yield and 98% ee with 0.00005 mol% catalyst.

7-membered diazo compounds provide enhanced stereocontrol but require low temperatures.

The method enables the synthesis of 5-oxa and 5-azaspiro[2.5]octanones with high efficiency.

Abstract

The stereoselective
construction of spirocyclic compounds
as medicinally
relevant scaffolds is of considerable current interest. One underexplored
area in this field is the asymmetric synthesis of spirocyclopropanes
via transition-metal catalysis, using α-diazo lactones and lactams
as carbene precursors. In this study, we report a Rh2(S-p-PhTPCP)4-catalyzed [2 +
1] cyclopropanation between 3-diazo δ-lactones and lactams and
a wide range of alkene substrates, enabling the facile synthesis of
5-oxa and 5-azaspiro[2.5]­octanones in yields up to 98%, reasonable
levels of diastereoselectivity (up to 11:1 d.r.), and high levels
of enantioselectivity (up to 98% ee). The reaction
can be run with 0.00005 mol % of catalyst, resulting in 1,740,000
TON, while maintaining stereocontrol. The ring size of the diazo compound,
in conjunction with the reaction temperature, has a considerable influence
on the reaction. While the reaction with the 5-membered system gave
diminished stereoselectivity, the 7-membered counterpart gave enhanced
stereocontrol (>30:1 d.r., 99% ee), but the reaction
needed to be carried out at low temperatures to avoid a side-reaction
caused by a 1,2-hydride shift.

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