Abstract
Achieving control over higher-order stereogenicity is a long-standing goal in stereoselective catalysis to deliberately address more than a twofold number of stereoisomers per stereogenic unit. Current methods allow control over 2n stereoisomers and their configurations are routinely assigned using the descriptors (R) and (S) or related binary codes. In contrast, conformational analysis extends beyond this dualistic treatment of stereoisomerism, which constitutes an unmet challenge for catalyst stereocontrol. Here, we report that sixfold stereogenicity is tractable by stereoselective catalysis. By controlling a configurationally stable stereogenic axis with six large rotational barriers, a catalytic [2 + 2 + 2] cyclotrimerization selectively governs the formation of one of six stereoisomers with up to 0:0:2:98:0:0 stereocontrol. Moreover, the stereoselectivity is redirectable by stereodivergent catalysis, providing four of the six stereoisomers as major stereoisomers. The underpinnings of conformational analysis and stereoselective catalysis are thereby conceptually reunited. Novel molecular architectures featuring distinct chemical topologies and unexplored chemical designs are anticipated from catalyst control over higher-order stereogenicity.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Data availability
Experimental details, supplementary methods, NMR spectra and crystallographic data are available in the main text and the Supplementary Information. Other data are available from the authors upon reasonable request. Supplementary crystallographic data for the quasi-racemate between (+ap)-2c/(−ap)-2d and (±)-3b can also be obtained from the Cambridge Crystallographic Data Center at www.ccdc.cam.ac.uk/structures (CCDC 2004118 and 1999568).
Change history
03 June 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41929-021-00645-7
References
Jacobsen, E. N., Pfaltz, A. & Yamamoto, H. Comprehensive Asymmetric Catalysis, vols. I–III (Springer, 1999).
Miyashita, A. et al. Synthesis of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), an atropisomeric chiral bis(triaryl)phosphine, and its use in the rhodium(i)-catalyzed asymmetric hydrogenation of α-(acylamino)acrylic acids. J. Am. Chem. Soc. 102, 7932–7934 (1980).
Bringmann, G. et al. Atroposelective synthesis of axially chiral biaryl compounds. Angew. Chem. Int. Ed. 44, 5384–5427 (2005).
Clayden, J., Moran, W. J., Edwards, P. J. & LaPlante, S. R. The challenge of atropisomerism in drug discovery. Angew. Chem. Int. Ed. 48, 6398–6401 (2009).
Gustafson, J. L., Lim, D. & Miller, S. J. Dynamic kinetic resolution of biaryl atropisomers via peptide-catalyzed asymmetric bromination. Science 328, 1251–1255 (2010).
Wencel-Delord, J., Panossian, A., Leroux, F. R. & Colobert, F. Recent advances and new concepts for the synthesis of axially stereoenriched biaryls. Chem. Soc. Rev. 44, 3418–3430 (2015).
Canfield, P. J. et al. A new fundamental type of conformational isomerism. Nat. Chem. 10, 615–624 (2018).
Clayden, J. Non-biaryl atropisomers: new classes of chiral reagents, auxiliaries, and ligands? Angew. Chem. Int. Ed. 36, 949–951 (1997).
Bonne, D., Bao, X. & Rodriguez, J. Enantioselective synthesis of atropisomers with multiple stereogenic axes. Angew. Chem. Int. Ed. 59, 12623–12634 (2020).
Finocchiaro, P., Gust, D. & Mislow, K. Separation of conformational stereoisomers in a triarylmethane. J. Am. Chem. Soc. 95, 8172–8173 (1973).
Mislow, K. & Siegel, J. Stereoisomerism and local chirality. J. Am. Chem. Soc. 106, 3319–3328 (1984).
Eliel, E. L. & Wilen, S. H. Stereochemistry of Organic Compounds (Wiley, 1994).
Nicolaou, K. C., Boddy, C. N. C. & Siegel, J. Does CIP nomenclature adequately handle molecules with multiple stereoelements? A case study of vancomycin and cognates. Angew. Chem. Int. Ed. 40, 701–704 (2001).
Walsh, P. J. & Kozlowski, M. C. Fundamentals of Asymmetric Catalysis (University Science Books, 2009).
Ototake, N., Nakamura, M., Dobashi, Y., Fukaya, H. & Kitagawa, O. Highly selective stereodivergent synthesis of separable amide rotamers, by using Pd chemistry, and their thermodynamic behavior. Chem. Eur. J. 15, 5090–5095 (2009).
Nakamura, S., Yasuda, H. & Toru, T. Diastereoselective reaction of [1-(2,4,6- triisopropylphenylsulfinyl)-2-naphthyl]methanimines via diastereomeric rotamers. Tetrahedron Asymmetry 13, 1509–1518 (2002).
Lassaletta, J. M., ed. Atropisomerism and Axial Chirality (World Scientific Publishing, 2019).
Wolf, C. Dynamic Stereochemistry of Chiral Compounds (Royal Society of Chemistry, 2008).
Quack, M. How important is parity violation for molecular and biomolecular chirality? Angew. Chem. Int. Ed. 41, 4618 (2002).
Chang, Y.-P. et al. Specific chemical reactivities of spatially separated 3-aminophenol conformers with cold Ca+ ions. Science 342, 98–101 (2013).
Isaka, M., Tanticharoen, M., Kongsaeree, P. & Thebtaranonth, Y. Structures of cordypyridones A−D, antimalarial N-hydroxy- and N-methoxy-2-pyridones from the insect pathogenic fungus Cordyceps nipponica. J. Org. Chem. 66, 4803–4808 (2001).
Jones, I. L., Moore, F. K. & Chai, C. L. L. Total synthesis of (±)-cordypyridones A and B and related epimers. Org. Lett. 11, 5526–5529 (2009).
Nakamura, M. & Ōki, M. Restricted rotation involving the tetrahedral carbon. XV. Restricted rotation about a \({\mathrm{C}}_{{\mathrm{sp}}^3}{\hbox{--}}{\mathrm{C}}_{{\mathrm{sp}}^2}\) bond in 9-aryltriptycene derivatives. Bull. Chem. Soc. Jpn. 48, 2106–2111 (1975).
Yamamoto, G., Nakamura, M. & Ōki, M. Restricted rotation involving the tetrahedral carbon. XVI. Isolation of stable rotamers about a sp3–sp3 carbon bond. Bull. Chem. Soc. Jpn. 48, 2592–2596 (1975).
Ford, W. T., Thompson, T. B., Snoble, K. A. J. & Timko, J. M. Hindered rotation in 9-arylfluorenes. Resolutions of the mechanistic question. J. Am. Chem. Soc. 97, 95–101 (1975).
Yamamoto, G., Suzuki, M. & Ōki, M. Restricted rotation involving the tetrahedral carbon. XLV. Appearance of a maximum in the rotational barriers of 9-(1,1-dimethyl-2-phenylethyl)triptycenes at a medium-sized peri-substituent. Bull. Chem. Soc. Jpn. 56, 306–313 (1983).
Ōki, M. The Chemistry of Rotational Isomers (Springer, 1993).
Di Iorio, N., Filippini, G., Mazzanti, A., Righi, P. & Bencivenni, G. Controlling the C(sp3)–C(sp2) axial conformation in the enantioselective Friedel–Crafts type alkylation of β-naphthols with inden-1-ones. Org. Lett. 19, 6692–6695 (2017).
Browne, W. R. & Feringa, B. L. Making molecular machines work. Nat. Nanotech. 1, 25–35 (2006).
Kelly, T. R. et al. Progress toward a rationally designed, chemically powered rotary molecular motor. J. Am. Chem. Soc. 129, 376–386 (2007).
Werner, A. Über eine neue Isomerieart bei Kobaltverbindungen und Verbindungen mit asymmetrischem Kobalt und Kohlenstoff. Helv. Chim. Acta 1, 5–32 (1918).
Shibata, T., Fujimoto, T., Yokota, K. & Takagi, K. Iridium complex-catalyzed highly enantio- and diastereoselective [2+2+2] cycloaddition for the synthesis of axially chiral teraryl compounds. J. Am. Chem. Soc. 126, 8382–8383 (2004).
Gutnov, A. et al. Cobalt(i)‐catalyzed asymmetric [2+2+2] cycloaddition of alkynes and nitriles: synthesis of enantiomerically enriched atropoisomers of 2‐arylpyridines. Angew. Chem. Int. Ed. 43, 3795–3797 (2004).
Tanaka, K., Nishida, G., Wada, A. & Noguchi, K. Enantioselective synthesis of axially chiral phthalides through cationic [Rhi(H8‐binap)]‐catalyzed cross alkyne cyclotrimerization. Angew. Chem. Int. Ed. 43, 6510–6513 (2004).
Tanaka, K. Transition‐metal‐catalyzed enantioselective [2+2+2] cycloadditions for the synthesis of axially chiral biaryls. Chem. Asian, J. 4, 508–518 (2009).
Link, A. & Sparr, C. Stereoselective arene formation. Chem. Soc. Rev. 47, 3804–3815 (2018).
Klyne, W. & Prelog, V. Description of steric relationships across single bonds. Experientia 16, 521–568 (1960).
Cahn, R. S., Ingold, C. & Prelog, V. Specification of molecular chirality. Angew. Chem. Int. Ed. 5, 385–415 (1966).
Xie, J.-H. et al. Synthesis of spiro diphosphines and their application in asymmetric hydrogenation of ketones. J. Am. Chem. Soc. 125, 4404–4405 (2003).
Zimmerman, H. E., Sulzbach, H. M. & Tollefson, M. B. Experimental and theoretical exploration of the detailed mechanism of the rearrangement of barrelenes to semibullvalenes: diradical intermediates and transition states. J. Am. Chem. Soc. 115, 6548–6556 (1993).
Acknowledgements
Financial support for this work was provided by the Swiss National Science Foundation (SNSF), award number BSSGI0-155902/1 (C.S.), the University of Basel and the NCCR Molecular Systems Engineering Phase II of the SNSF, award number 182895 (C.S.). We thank A. Prescimone for X-ray crystallography.
Author information
Authors and Affiliations
Contributions
C.S., R.M.W., X.W., C.F. and R.B. conceived the study, designed the experiments and analysed the data. R.M.W, X.W., C.F. and R.B. performed the experiments and D. H. carried out the NMR studies. C.S. wrote the manuscript with input from all authors.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Peer review information Nature Catalysis thanks Jean Rodriguez and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Supplementary Information
Supplementary methods, Figs. 1–19, Tables 1–10 and references.
Supplementary Data 1
This file contains the crystal data for the quasi-racemate of (+ap)-2c and (−ap)-2d (CCDC 2004118).
Supplementary Data 2
This file contains the rtf data for the quasi-racemate of (+ap)-2c and (−ap)-2d (CCDC 2004118).
Supplementary Data 3
This file contains the crystal data for (±)-3b (CCDC 1999568).
Supplementary Data 4
This file contains the rtf data for (±)-3b (CCDC 1999568).
Rights and permissions
About this article
Cite this article
Wu, X., Witzig, R.M., Beaud, R. et al. Catalyst control over sixfold stereogenicity. Nat Catal 4, 457–462 (2021). https://doi.org/10.1038/s41929-021-00615-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41929-021-00615-z
This article is cited by
-
NHC-catalyzed enantioselective access to β-cyano carboxylic esters via in situ substrate alternation and release
Nature Communications (2023)
-
Construction of C-B axial chirality via dynamic kinetic asymmetric cross-coupling mediated by tetracoordinate boron
Nature Communications (2023)
-
Diastereo- and atroposelective synthesis of N-arylpyrroles enabled by light-induced phosphoric acid catalysis
Nature Communications (2023)
-
Catalyst control over pentavalent stereocentres
Nature Communications (2023)
-
Chalcogen bond-guided conformational isomerization enables catalytic dynamic kinetic resolution of sulfoxides
Nature Communications (2022)