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Rapid assembly of complex cyclopentanes employing chiral, α,β-unsaturated acylammonium intermediates

Abstract

With the intention of improving synthetic efficiency, organic chemists have turned to bioinspired organocascade or domino processes that generate multiple bonds and stereocentres in a single operation. However, despite the great importance of substituted cyclopentanes, given their prevalence in complex natural products and pharmaceutical agents, the rapid, enantioselective assembly of these carbocycles lags behind cyclohexanes. Here, we describe a Michael–aldol-β-lactonization organocascade process for the synthesis of complex cyclopentanes utilizing chiral α,β-unsaturated acylammonium intermediates, readily generated by activation of commodity unsaturated acid chlorides with chiral isothiourea catalysts. This efficient methodology enables the construction of two C–C bonds, one C–O bond, two rings and up to three contiguous stereogenic centres delivering complex cyclopentanes with high levels of relative and absolute stereocontrol. Our results suggest that α,β-unsaturated acylammonium intermediates have broad utility for the design of organocascade and multicomponent processes, with the latter demonstrated by a Michael–Michael–aldol-β-lactonization.

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Figure 1: Natural products and pharmaceutical agents bearing complex cyclopentanes and accessible cyclopentyl systems employing the described NCMAL process.
Figure 2: Generation and reactivity of the chiral unsaturated acylammonium 3, with contrast to related chiral intermediates 4–6, and a proposed catalytic cycle leading to bicyclic-β-lactones 14.
Figure 3: Rapid molecular complexity generation, structural modifications of cyclopentane products, and extensions of both accessible Michael donors and unsaturated acylammonium intermediates.
Figure 4: Proposed transition-state arrangements to rationalize the stereochemical outcome of the NCMAL and extension to a multicomponent cascade process.

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Acknowledgements

This work was supported by the National Science Foundation (CHE- 1112397) and the Robert A. Welch Foundation (A-1280), together with partial support from the National Institutes of Health (GM 069874). The authors thank N. Harvey for synthesis of HBTM and assistance with early studies of the NCMAL. N. Bhuvanesh (Center for X-ray Analysis, TAMU) and W. K. Russell (Laboratory for Biological Mass Spectrometry, TAMU) secured X-ray crystal structure and mass data, respectively.

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Contributions

G.L. initiated the studies of the α,β-unsaturated acylammonium intermediate from acid chlorides. D.R., G.L. and M.E.S. were involved in the design of experiments for exploration of the NCMAL. D.R. and K.N.V. conceived and developed the three-component NCMAL process. G.L., M.E.S., K.N.V. and R.L.M. performed the experiments. D.R., G.L. and M.E.S. composed the manuscript with input from all authors.

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Correspondence to Daniel Romo.

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The authors declare no competing financial interests.

Supplementary information

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Supplementary information (PDF 6254 kb)

Supplementary information

Crystallographic data for compound (+)-S16 (CIF 16 kb)

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Crystallographic data for compound (±)-14k (CIF 14 kb)

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Crystallographic data for compound (±)-14m (CIF 15 kb)

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Crystallographic data for compound (+)-14p (CIF 15 kb)

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Crystallographic data for compound (±)-14q (CIF 15 kb)

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Crystallographic data for compound (±)-14t (CIF 14 kb)

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Crystallographic data for compound (±)-14v (CIF 13 kb)

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Crystallographic data for compound (±)-14x (CIF 12 kb)

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Crystallographic data for compound (-)-24 (CIF 27 kb)

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Liu, G., Shirley, M., Van, K. et al. Rapid assembly of complex cyclopentanes employing chiral, α,β-unsaturated acylammonium intermediates. Nature Chem 5, 1049–1057 (2013). https://doi.org/10.1038/nchem.1788

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