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Synthesis 2023; 55(13): 2047-2052
DOI: 10.1055/a-2016-4548
paper

Hexafluoroisopropanol-Induced Facial Selectivity in a Hindered Diels–Alder Reaction

David J. P. Kornfilt  ‡
a   Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA 02142, USA
,
Brian T. Chamberlain‡
a   Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA 02142, USA
,
Isabelle Chataigner
b   Sorbonne Université, CNRS, Laboratoire de Chimie Théorique, LCT, 75005 Paris, France
c   Normandie Université, UNIROUEN, CNRS, INSA Rouen, COBRA Laboratory, 76000 Rouen, France
,
Riccardo Spezia
b   Sorbonne Université, CNRS, Laboratoire de Chimie Théorique, LCT, 75005 Paris, France
,
Florence F. Wagner∗
a   Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA 02142, USA
› Author AffiliationsThis work was funded by the Slim Initiative for Genomic Medicine in the Americas (SIGMA), a collaboration of the Broad Institute with the Carlos Slim Foundation.
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Abstract

BRD4780 is a small molecule that can selectively clear mutant MUC1-fs protein in mucin kidney disease models. Prior syntheses of BRD4780 were unsuitable for preparation on large scale. In this manuscript, HFIP is described as a unique solvent that allowed the key Diels–Alder reaction to proceed with >20:1 endo diastereoselectivity, enabling the kg-scale preparation of BRD4780 for further studies.

Key words

Diels–Alder reaction - nitroalkene - BRD4780 - mucin-1 kidney disease - HFIP

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2016-4548.
  • Supporting Information


Publication History

Received: 14 December 2022

Accepted after revision: 19 January 2023

Accepted Manuscript online:
19 January 2023

Article published online:
20 March 2023

© 2023. Thieme. All rights reserved

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  • References

    • 1a Hubbard RD, Miller BL. J. Org. Chem. 1998; 63: 4143
      Crossref
    • 1b Nicolaou KC, Snyder SA, Montagnon T, Vassilikogiannakis G. Angew. Chem. Int. Ed. 2002; 41: 1668
      CrossrefPubMed
    • 1c Corey EJ, Guzman-Perez A. Angew. Chem. Int. Ed. 1998; 37: 388
      CrossrefPubMed
  • 2 Lam Y.-h, Cheong PH.-Y, Blasco Mata JM, Stanway SJ, Gouverneur V, Houk KN. J. Am. Chem. Soc. 2009; 131: 1947
    CrossrefPubMed
  • 3 Dvela-Levitt M, Shaw JL, Greka A. Trends Mol. Med. 2021; 27: 394
    CrossrefPubMed
  • 4 Munk SA, Lai RK, Burke JE, Arasasingham PN, Kharlamb AB, Manlapaz CA, Padillo EU, Wijono MK, Hasson DW, Wheeler LA, Garst ME. J. Med. Chem. 1996; 39: 1193
    CrossrefPubMed
  • 5 Corsello SM, Bittker JA, Liu Z, Gould J, McCarren P, Hirschman JE, Johnston SE, Vrcic A, Wong B, Khan M, Asiedu J, Narayan R, Mader CC, Subramanian A, Golub TR. Nat. Med. 2017; 23: 405
    CrossrefPubMed
  • 6 Dvela-Levitt M, Kost-Alimova M, Emani M, Kohnert E, Thompson R, Sidhom EH, Rivadeneira A, Sahakian N, Roignot J, Papagregoriou G, Montesinos MS, Clark AR, McKinney D, Gutierrez J, Roth M, Ronco L, Elonga E, Carter TA, Gnirke A, Melanson M, Hartland K, Wieder N, Hsu JC, Deltas C, Hughey R, Bleyer AJ, Kmoch S, Živná M, Barešova V, Kota S, Schlondorff J, Heiman M, Alper SL, Wagner F, Weins A, Golub TR, Lander ES, Greka A. Cell 2019; 178: 521-535.e23
    CrossrefPubMed
  • 7 Takenaka N, Sarangthem RS, Seerla SK. Org. Lett. 2007; 9: 2819
    CrossrefPubMed
  • 8 Wittkopp A, Schreiner PR. Chem. Eur. J. 2003; 9: 407
    CrossrefPubMed
  • 9 Denmark SE, Cramer CJ, Sternberg JA. Helv. Chim. Acta 1986; 69: 1971
    CrossrefPubMed
  • 10 Denmark SE, Moon YC, Senanayake CB. W. J. Am. Chem. Soc. 1990; 112: 311
    CrossrefPubMed
  • 11 Çelebi-Ölçüm N, Ess DH, Aviyente V, Houk KN. J. Am. Chem. Soc. 2007; 129: 4528
    CrossrefPubMed
  • 12 Ruiz-Lopez MF, Assfeld X, Garcia JI, Mayoral JA, Salvatella L. J. Am. Chem. Soc. 1993; 115: 8780
    Crossref
  • 13 Cativiela C, García JI, Mayoral JA, Salvatella L. Can. J. Chem. 1994; 72: 308
    CrossrefPubMed
  • 14 Cativiela C, García JI, Gil J, Martínez RM, Mayoral JA, Salvatella L, Urieta JS, Mainar AM, Abraham MH. J. Chem. Soc., Perkin Trans. 2 1997; 653
    Crossref
  • 15 Motiwala HF, Armaly AM, Cacioppo JG, Coombs TC, Koehn KR. K, Norwood VM. IV, Aubé J. Chem. Rev. 2022; 122: 12544
    CrossrefPubMed
  • 16 Jasiński R, Koifman O, Barański A. Open Chem. 2011; 9: 1008
    CrossrefPubMed
  • 17 Yang Y.-F, Yu P, Houk KN. J. Am. Chem. Soc. 2017; 139: 18213
    CrossrefPubMed