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Enzymatic construction of highly strained carbocycles

Chen, Kai and Huang, Xiongyi and Kan, S. B. Jennifer and Zhang, Ruijie K. and Arnold, Frances H. (2018) Enzymatic construction of highly strained carbocycles. Science, 360 (6384). pp. 71-75. ISSN 0036-8075. http://resolver.caltech.edu/CaltechAUTHORS:20180405-130352978

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Abstract

Small carbocycles are structurally rigid and possess high intrinsic energy due to their ring strain. These features lead to broad applications but also create challenges for their construction. We report the engineering of hemeproteins that catalyze the formation of chiral bicyclobutanes, one of the most strained four-membered systems, via successive carbene addition to unsaturated carbon-carbon bonds. Enzymes that produce cyclopropenes, putative intermediates to the bicyclobutanes, were also identified. These genetically encoded proteins are readily optimized by directed evolution, function in Escherichia coli, and act on structurally diverse substrates with high efficiency and selectivity, providing an effective route to many chiral strained structures. This biotransformation is easily performed at preparative scale, and the resulting strained carbocycles can be derivatized, opening myriad potential applications.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1126/science.aar4239DOIArticle
http://science.sciencemag.org/content/360/6384/71PublisherArticle
http://www.sciencemag.org/content/360/6384/71/suppl/DC1PublisherSupplementary Materials
ORCID:
AuthorORCID
Chen, Kai0000-0002-3325-3536
Huang, Xiongyi0000-0001-7156-8881
Kan, S. B. Jennifer0000-0001-6371-8042
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. This is an article distributed under the terms of the Science Journals Default License. Received for publication November 8, 2017. Accepted for publication February 6, 2018. We thank D. K. Romney, S. C. Hammer, and S.-Q. Zhang for helpful discussions and comments on the manuscript; C. K. Pier, O. F. Brandenberg, and A. M. Knight for sharing hemeprotein variants; K. Ding (D. J. Anderson Lab, Caltech) and J. Li (R. H. Grubbs Lab, Caltech) for generous donation of materials and reagents; S. C. Virgil and the Caltech Center for Catalysis and Chemical Synthesis, N. Torian and the Caltech Mass Spectrometry Laboratory, and M. K. Takase, L. M. Henling, and the Caltech X-ray Crystallography Facility for analytical support; and B. M. Stoltz for use of polarimeter and chiral gas chromatography equipment. Funding: Supported by NSF Division of Molecular and Cellular Biosciences grant MCB-1513007; Ruth L. Kirschstein NIH Postdoctoral Fellowship F32GM125231 (X.H.); and NSF Graduate Research Fellowship grant DGE-1144469 and the Donna and Benjamin M. Rosen Bioengineering Center (R.K.Z.). R.K.Z. is a trainee in the Caltech Biotechnology Leadership Program. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the funding organizations. Author contributions: conceptualization, K.C.; methodology, K.C.; validation, K.C. and X.H.; formal analysis, K.C., X.H., S.B.J.K., and R.K.Z.; writing (original draft), K.C. and F.H.A.; writing (review and editing), X.H., S.B.J.K., and R.K.Z.; funding acquisition, F.H.A.; supervision, F.H.A. Competing interests: K.C., X.H., and S.B.J.K. are inventors on patent application (CIT-7744-P) submitted by California Institute of Technology that covers biocatalytic synthesis of strained carbocycles. Data and materials availability: All data are available in the main text or the supplementary materials. Plasmids encoding the enzymes reported in this study are available for research purposes from F.H.A. under a material transfer agreement with the California Institute of Technology. Crystallographic coordinates and structure factors have been deposited with the Cambridge Crystallographic Data Centre (www.ccdc.cam.ac.uk) under reference number 1815089 for compound 4d.
Funders:
Funding AgencyGrant Number
NSFMCB-1513007
NIH Postdoctoral FellowshipF32GM125231
NSF Graduate Research FellowshipDGE-1144469
Donna and Benjamin M. Rosen Bioengineering CenterUNSPECIFIED
Caltech Biotechnology Leadership ProgramUNSPECIFIED
Record Number:CaltechAUTHORS:20180405-130352978
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20180405-130352978
Official Citation:Enzymatic construction of highly strained carbocycles BY KAI CHEN, XIONGYI HUANG, S. B. JENNIFER KAN, RUIJIE K. ZHANG, FRANCES H. ARNOLD Science 06 Apr 2018: Vol. 360, Issue 6384, pp. 71-75 DOI: 10.1126/science.aar4239
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:85640
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:05 Apr 2018 20:14
Last Modified:05 Apr 2018 20:14

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