Science - USA (2022-06-10)

through a single recrystallization (40 g isolated,
dr >20:1, er >99:1).
The isolated products of these Michael CIDT
reactions can be transformed to value-added
products in subsequent steps that capitalize
on the embedded functionality without com-
promising the integrity of the extant asym-
metric centers (Fig. 5, B and C) ( 21 ). Ketone
additions using organocerium reagents ( 22 , 23 )
delivered a variety of tertiary alcohols containing
synthetically useful functional handles, includ-
ing the alkyl (5a), vinyl (5b), allyl (5c), alkynyl
(5d), and aryl (5e) groups, in good to excellent
diastereoselectivity. Secondaryb-hydroxy amide
5f was obtained in 95% yield as a single di-
astereomer through titanium (IV)-mediated
diastereoselective reduction ( 24 ). Pyrrolidine
5g was synthesized in a single step in excel-
lent diastereoselectivity through Zn-mediated
reductive cyclization ( 25 ), and from that point
the amide could be converted to its derived
tertiary amine5h in moderate yield.
This work establishes a foundation for
crystallization-induced diastereomer trans-
formations operating on two configuration-
ally labile asymmetric centers, enabled in this
instance by the Dixon chiral iminophosphorane
Brønsted superbase. The results of the pre-
sent study suggest that expanded opportu-
nities may exist for the productive merger
of divergent, partially selective first-stage
asymmetric catalysis with crystallization-
driven second-stage stereoconvergence. A
key to the generalization and future growth
of such platforms that capitalize on their

myriad benefits will be the development of

robust predictive tools based on, among other

things, analysis of crystal packing and ma-

chine learning.

REFERENCES AND NOTES

1. V. Farina, J. T. Reeves, C. H. Senanayake, J. J. Song,Chem.
   Rev. 106 , 2734–2793 (2006).


2. J. Blacker, C. E. Headley, inGreen Chemistry in the
   Pharmaceutical Industry, A. S. Wells, M. T. Williams, Eds.
   (Wiley, 2010); pp. 269–288.


3. M. D. Eastgate, M. A. Schmidt, K. R. Fandrick,Nat. Rev. Chem.
   1 , 0016 (2017).


4. O. Méndez-Lucio, J. L. Medina-Franco,Drug Discov. Today 22 ,
   120 – 126 (2017).


5. S. Cailleet al., J. Org. Chem. 84 , 4583–4603 (2019).


6. S. Caille,Science 364 , 635 (2019).


7. K. Lovato, P. S. Fier, K. M. Maloney,Nat. Rev. Chem. 5 ,
   546 – 563 (2021).


8. P. J. Walsh, M. C. Kozlowski,Fundamentals of Asymmetric
   Catalysis(University Science Books, 2009).


9. K. B. Hansenet al., J. Am. Chem. Soc. 131 , 8798– 8804
   (2009).


10. G. P. Howell,Org. Process Res. Dev. 16 , 1258–1272 (2012).


11. D. J. Kirwan, C. J. Orella, inHandbook of Industrial
    Crystallization, A. S. Myerson, Ed. (Elsevier, ed. 2, 2002);
    pp. 249–266.


12. A. Kolarovič, P. Jakubec,Adv. Synth. Catal. 363 , 4110– 4158
    (2021).


13. K. M. J. Brands, A. J. Davies,Chem. Rev. 106 , 2711– 2733
    (2006).


14. E. Reyes, U. Uria, J. L. Vicario, L. Carrillo,Org. React. 90 ,1– 898
    (2016).


15. H. T. Openshaw, N. Whittaker,J. Chem. Soc. 1461 – 1471 (1963).


16. P. J. Pyeet al.,Chemistry 8 , 1372–1376 (2002).


17. M. C. Prieto-Ramírezet al., Adv. Synth. Catal. 360 , 4362– 4371
    (2018).


18. M. Formica, D. Rozsar, G. Su, A. J. M. Farley, D. J. Dixon,
    Acc. Chem. Res. 53 , 2235–2247 (2020).


19. S. Nahm, S. M. Weinreb,Tetrahedron Lett. 22 , 3815– 3818
    (1981).


20. S. P. Lathrop, T. Rovis,J. Am. Chem. Soc. 131 , 13628– 13630
    (2009).
    21. D. A. Evans, M. D. Ennis, T. Le, N. Mandel, G. Mandel,J. Am.
    Chem. Soc. 106 , 1154–1156 (1984).
    22. T. Imamotoet al., J. Org. Chem. 49 , 3904–3912 (1984).
    23. T. Imamoto, Y. Sugiura, N. Takiyama,Tetrahedron Lett. 25 ,
    4233 – 4236 (1984).
    24. G. Bartoliet al., Tetrahedron Lett. 42 , 8811–8815 (2001).
    25. Z. X. Jiaet al., Chemistry 18 , 12958–12961 (2012).

ACKNOWLEDGMENTS

We thank B. Ehrmann and D. Weatherspoon (UNC Department of

Chemistry Mass Spectrometry Core Laboratory) for assistance

with mass spectrometry analysis; M. ter Horst (UNC Department of

Chemistry NMR Core Laboratory) for assistance with NMR

analysis; and H. King (UNC Department of Chemistry) for

experimental contributions.Funding:This work was supported by

the National Institute of General Medical Sciences, National

Institutes of Health (grant R35 GM 118055 to J.S.J. and grant F31

GM137697 to P.d.J.C.).Author contributions:P.d.J.C. and J.S.J.

conceived the study. P.d.J.C., W.R.C., and J.S.J. designed,

implemented, and analyzed the experiments. C.H.C. performed the

x-ray diffraction studies. P.d.J.C., W.R.C., and J.S.J. wrote the

manuscript.Competing interests:The authors declare no

competing interests.Data and materials availability:

Experimental procedures and characterization data are available in

the supplementary materials. The crystallographic data for this

paper can be obtained free of charge from the Cambridge

Crystallographic Data Centre (www.ccdc.cam.ac.uk/data_request/

cif) using the following accession codes: CCDC 2089311, 2128977,

2144952-2144957, 2145282, 2149929-2149931, 2154042-2154043,

2168282, and 2168284.License information:Copyright © 2022

the authors, some rights reserved; exclusive licensee American

Association for the Advancement of Science. No claim to original

US government works. https://www.science.org/about/science-

licenses-journal-article-reuse

SUPPLEMENTARY MATERIALS

science.org/doi/10.1126/science.abo5048

Materials and Methods

Figs. S1 to S8

Tables S1 to S19

NMR Spectra

References ( 26 – 50 )

Submitted 7 February 2022; accepted 6 May 2022

10.1126/science.abo5048

de Jesús Cruzet al., Science 376 , 1224–1230 (2022) 10 June 2022 7of7

RESEARCH | REPORT