Chiral Polyoxygenated Tertiary Alcohols through Kiyooka Aldol Reaction

Abstract

Here we present our work on a Kiyooka aldol protocol for the stereoselective synthesis of tertiary alcohols. In the obtained products, three oxygenated carbon atoms that could further be differentiated flank the chiral tertiary alcohol. This methodology can be applied to simple aromatic or aliphatic aldehydes and more complex substrates bearing a chiral center in the α- and/or β-position. For complex substrates, an unexpected dependency between stereoselectivity and double-bond geometry of the ketene acetal was observed. Furthermore, applications in or towards the synthesis of natural products are presented.

1 Introduction

2 Scope of the Reaction

3 Synthetic Applications

4 Conclusion

Key words

aldol reaction - tertiary alcohols - ketene acetal - stereoselective synthesis - double-bond geometry

Publication History

Received: 20 January 2022

Accepted after revision: 17 February 2022

Accepted Manuscript online:
17 February 2022

Article published online:
23 March 2022

• References

• 1 New address: University of California, Berkeley, California 94720, USA.
• 2 Kiyooka S.-i, Kaneko Y, Komura M, Matsuo H, Nakano M. J. Org. Chem. 1991; 56: 2276
• 3a Bülow L, Naini A, Fohrer J, Kalesse M. Org. Lett. 2011; 13: 6038
• 3b Lücke D, Kalesse M. Chem. Eur. J. 2019; 25: 10080

Selected examples for the addition of an enolate to a ketone:
• 4a Xu X.-Y, Tang Z, Wang Y.-Z, Luo S.-W, Cun L.-F, Gong L.-Z. J. Org. Chem. 2007; 72: 9905
• 4b Li P, Zhao J, Li F, Chan AS. C, Kwong FY. Org. Lett. 2010; 12: 5616
• 4c Alcoberro S, Gómez-Palomino A, Solà R, Romea P, Urpí F, Font-Bardia M. Org. Lett. 2014; 16: 584
• 4d Konda S, Guo Q.-S, Abe M, Huang H, Arman H, Zhao JC.-G. J. Org. Chem. 2015; 80: 806
• 4e Wang P, Li H.-F, Zhao J.-Z, Du Z.-H, Da C.-S. Org. Lett. 2017; 19: 2634
• 4f Thomson CJ, Barber DM, Dixon DJ. Angew. Chem. Int. Ed. 2020; 59: 5359
• 4g Li K, Sun X, Li L, Zha Z, Zhang F.-L, Wang Z. Chem. Eur. J. 2021; 27: 581

Selected examples for aldol reactions with oxygenated enolates:
• 5a Heathcock CH, Hagen JP, Jarvi ET, Pirrung MC, Young SD. J. Am. Chem. Soc. 1981; 103: 4972
• 5b Heathcock CH, Pirrung MC, Young SD, Hagen JP, Jarvi ET, Badertscher U, Märki H.-P, Montgomery SH. J. Am. Chem. Soc. 1984; 106: 8161
• 5c Battaglia A, Barbaro G, Giorgianni P, Guerrini A, Bertucci C, Germia S. Chem. Eur. J. 2000; 6: 3551
• 5d Onodera Y, Suzuki T, Kobayashi S. Org. Lett. 2011; 13: 50
• 6 Barth R, Roush WR. Org. Lett. 2010; 12: 2342
• 7a Evans DA, Barrow JC, Leighton JL, Robichaud AJ, Sefkow M. J. Am. Chem. Soc. 1994; 116: 12111
• 7b Evans DA, Trotter BW, Barrow JC. Tetrahedron 1997; 53: 8779
• 8 Aggarwal VK, Masters SJ, Adams H, Spey SE, Brown GR, Foubister AJ. J. Chem. Soc., Perkin Trans. 1 1999; 155
• 9a Peter D, Brückner R. Chem. Eur. J. 2017; 23: 12104
• 9b Peter D, Brückner R. Eur. J. Org. Chem. 2018; 6256
• 10 Hayashi Y, Shoji M, Yamaguchi J, Sato K, Yamaguchi S, Mukaiyama T, Sakai K, Asami Y, Kakeya H, Osada H. J. Am. Chem. Soc. 2002; 124: 12078
• 11a Xu Q.-M, Zou Z.-M, Xu L.-Z, Yang S.-L. Chem. Pharm. Bull. 2005; 53: 826
• 11b Xu Q.-M, Liu Y.-L, Zou Z.-M, Yang S.-L, Xu L.-Z. J. Asian Nat. Prod. Res. 2009; 11: 24
• 11c Asami Y, Kakeya H, Onose R, Yoshida A, Matsuzaki H, Osada H. Org. Lett. 2002; 4: 2845
• 11d Goto T, Kishi Y, Takahashi S, Hirata Y. Tetrahedron 1965; 21: 2059
• 11e Chevallier C, Bugni TS, Feng X, Harper MK, Orendt AM, Ireland CM. J. Org. Chem. 2006; 71: 2510
• 11f Fushimi S, Nishikawa S, Shimazu A, Seto H. J. Antibiot. 1989; 42: 1019
• 12 Konrad DB, Kicin B, Trauner D. Synlett 2019; 30: 383

Selected examples for Mukaiyama aldol reactions showing a dependency of the selectivity on the double-bond geometry of the ketene acetal:
• 13a Kobayashi S, Uchiro H, Fujishita Y, Shiina I, Mukaiyama T. J. Am. Chem Soc. 1991; 113: 4247
• 13b Kobayashi S, Horibe M. Synlett 1993; 855
• 13c Evans DA, Yang MG, Dart MJ, Duffy JL, Kim AS. J. Am. Chem. Soc. 1995; 117: 9598
• 14 Lücke D, Kalesse M. Chem. Eur. J. 2021; 27: 7085
• 15a Wittig G, Geissler G. Justus Liebigs Ann. Chem. 1953; 580: 44
• 15b Wittig G, Schöllkopf U. Chem. Ber. 1954; 87: 1318
• 16a Horner L, Hoffmann HM. R, Wippel HG. Chem. Ber. 1958; 91: 61
• 16b Horner L, Hoffmann HM. R, Wippel HG, Klahre G. Chem. Ber. 1959; 92: 2499
• 16c Wadsworth WS, Emmons WD. J. Am. Chem. Soc. 1961; 83: 1733
• 17a Griffith WP, Ley SV, Whitcombe GP, White AD. J. Chem. Soc., Chem. Commun. 1987; 1625
• 17b Ley SV, Norman J, Griffith WP, Marsden SP. Synthesis 1994; 639
• 18a Julia M, Paris J.-M. Tetrahedron Lett. 1973; 14: 4833
• 18b Blakemore PR, Cole WJ, Kocieński PJ, Morley A. Synlett 1998; 26