# 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.

## Key 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.