Concise Enantioselective Synthesis of Oxygenated Steroids Via Sequential Copper(II)-Catalyzed Michael Addition/Intramolecular Aldol Cyclization Reactions

Overview

Journal J Am Chem Soc

Publisher American Chemical Society

Specialty Chemistry

Date 2015 Oct 23

PMID 26491886

Citations 13

Authors

Nathan R Cichowicz

Will Kaplan

Yaroslav Khomutnyk

Bijay Bhattarai

Zhankui Sun

Pavel Nagorny

Affiliations

Soon will be listed here.

Abstract

A new scalable enantioselective approach to functionalized oxygenated steroids is described. This strategy is based on chiral bis(oxazoline) copper(II) complex-catalyzed enantioselective and diastereoselective Michael reactions of cyclic ketoesters and enones to install vicinal quaternary and tertiary stereocenters. In addition, the utility of copper(II) salts as highly active catalysts for the Michael reactions of traditionally unreactive β,β'-enones and substituted β,β'-ketoesters that results in unprecedented Michael adducts containing vicinal all-carbon quaternary centers is also demonstrated. The Michael adducts subsequently undergo base-promoted diastereoselective aldol cascade reactions resulting in the natural or unnatural steroid skeletons. The experimental and computational studies suggest that the torsional strain effects arising from the presence of the Δ(5)-unsaturation are key controlling elements for the formation of the natural cardenolide scaffold. The described method enables expedient generation of polycyclic molecules including modified steroidal scaffolds as well as challenging-to-synthesize Hajos-Parrish and Wieland-Miescher ketones.

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References

Quasdorf K, Overman L . Catalytic enantioselective synthesis of quaternary carbon stereocentres. Nature. 2014; 516(7530):181-91. PMC: 4697831. DOI: 10.1038/nature14007. View

Yeung Y, Chein R, Corey E . Conversion of Torgov's synthesis of estrone into a highly enantioselective and efficient process. J Am Chem Soc. 2007; 129(34):10346-7. DOI: 10.1021/ja0742434. View

Newman D, Cragg G . Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod. 2012; 75(3):311-35. PMC: 3721181. DOI: 10.1021/np200906s. View

Evans D, Adams D, Kwan E . Progress toward the syntheses of (+)-GB 13, (+)-himgaline, and himandridine. new insights into intramolecular imine/enamine aldol cyclizations. J Am Chem Soc. 2012; 134(19):8162-70. DOI: 10.1021/ja3001776. View

Alexakis A, Backvall J, Krause N, Pamies O, Dieguez M . Enantioselective copper-catalyzed conjugate addition and allylic substitution reactions. Chem Rev. 2008; 108(8):2796-823. DOI: 10.1021/cr0683515. View

Yang J, Li W, Jin Z, Liang X, Ye J . Enantioselective Michael reaction of α-alkyl-β-keto esters and enones under multifunctional catalysis. Org Lett. 2010; 12(22):5218-21. DOI: 10.1021/ol102256v. View

Mukai K, Urabe D, Kasuya S, Aoki N, Inoue M . A convergent total synthesis of 19-hydroxysarmentogenin. Angew Chem Int Ed Engl. 2013; 52(20):5300-4. DOI: 10.1002/anie.201302067. View

Xiao Q, Jackson J, Basak A, Bowler J, Miller B, Zakarian A . Enantioselective synthesis of tatanans A-C and reinvestigation of their glucokinase-activating properties. Nat Chem. 2013; 5(5):410-6. PMC: 4126512. DOI: 10.1038/nchem.1597. View

Deng W, Jensen M, Overman L, Rucker P . A Strategy for Total Synthesis of Complex Cardenolides. J Org Chem. 1996; 61(20):6760-6761. DOI: 10.1021/jo961209r. View

10.

Zhang M, Liu N, Tang W . Stereoselective total synthesis of hainanolidol and harringtonolide via oxidopyrylium-based [5 + 2] cycloaddition. J Am Chem Soc. 2013; 135(33):12434-8. PMC: 3798225. DOI: 10.1021/ja406255j. View

11.

Sibi M, Liu M . Enantioselective conjugate addition of hydroxylamines to pyrazolidinone acrylamides. Org Lett. 2002; 3(26):4181-4. DOI: 10.1021/ol016807t. View

12.

Wu F, Hong R, Khan J, Liu X, Deng L . Asymmetric synthesis of chiral aldehydes by conjugate additions with bifunctional organocatalysis by cinchona alkaloids. Angew Chem Int Ed Engl. 2006; 45(26):4301-5. DOI: 10.1002/anie.200600867. View

13.

Baik T, Luis A, Wang L, Krische M . A diastereoselective metal-catalyzed [2+2] cycloaddition of bis-enomes. J Am Chem Soc. 2001; 123(27):6716-7. DOI: 10.1021/ja010800p. View

14.

Zhang H, Sridhar Reddy M, Phoenix S, Deslongchamps P . Total synthesis of ouabagenin and ouabain. Angew Chem Int Ed Engl. 2008; 47(7):1272-5. DOI: 10.1002/anie.200704959. View

15.

Evans D, Scheidt K, Johnston J, Willis M . Enantioselective and diastereoselective Mukaiyama-Michael reactions catalyzed by bis(oxazoline) copper(II) complexes. J Am Chem Soc. 2001; 123(19):4480-91. DOI: 10.1021/ja010302g. View

16.

Douglas C, Overman L . Catalytic asymmetric synthesis of all-carbon quaternary stereocenters. Proc Natl Acad Sci U S A. 2004; 101(15):5363-7. PMC: 397386. DOI: 10.1073/pnas.0307113101. View

17.

Desimoni G, Faita G, Anker Jorgensen K . Update 1 of: C2-symmetric chiral bis(oxazoline) ligands in asymmetric catalysis. Chem Rev. 2011; 111(11):PR284-437. DOI: 10.1021/cr100339a. View

18.

Agapiou K, Cauble D, Krische M . Copper-catalyzed tandem conjugate addition-electrophilic trapping: ketones, esters, and nitriles as terminal electrophiles. J Am Chem Soc. 2004; 126(14):4528-9. DOI: 10.1021/ja030603l. View

19.

Jung M, Davidov P . Efficient synthesis of a tricyclic BCD analogue of ouabain: Lewis acid catalyzed Diels-Alder reactions of sterically hindered systems. Angew Chem Int Ed Engl. 2002; 41(21):4125-8. DOI: 10.1002/1521-3773(20021104)41:21<4125::AID-ANIE4125>3.0.CO;2-E. View

20.

Liu Y, Han S, Liu W, Stoltz B . Catalytic enantioselective construction of quaternary stereocenters: assembly of key building blocks for the synthesis of biologically active molecules. Acc Chem Res. 2015; 48(3):740-51. PMC: 6410712. DOI: 10.1021/ar5004658. View