Intramolecular Enolate Alkylation: From Steroids through Cladiellins to Isolaurallene

On the eve of my retirement, it is my great pleasure to dedicate this account to Professors Steven Weinreb and Gilbert Stork for their insightful tutelage and inspiration throughout my career.

Abstract

This account of the author’s contributions over his career attempts to sketch out a research arc that stretches all the way from very simple beginnings, taking inspiration from the steroidal trans-hydrindane problem, to the development of a general strategy for the stereoselective construction of cycloalkanecarboxylates via a folding and allylic strain controlled intramolecular ester enolate alkylation, with applications thereof to the total syntheses of natural products of modest complexity. Examination of the corresponding S_N2′ version of this methodology led to a serendipitous discovery that ultimately produced the olefin geometry dependent intramolecular amide enolate alkylation. Applications and extensions of this methodology have enabled completely substrate-controlled asymmetric total syntheses of diverse medium-ring oxacyclic marine natural products, and a fortuitous discovery along the way involving an organoselenium-based method led to an intriguing biomimetic synthesis of Laurencia metabolites. Observations are made regarding aspects of a research career in retrospect.

1 Introduction

2 Intramolecular S_N2 Enolate Alkylation

3 Intramolecular S_N2′ Enolate Alkylation

4 Synthesis of α,α′-cis-Disubstituted Medium-Ring Oxa­cyclic Marine Natural Products

5 Synthesis of α,α′-trans-Disubstituted Medium-Ring Oxa­cyclic Marine Natural Products

6 General Synthetic Plan for Dioxabicyclic Bromoallene ­Marine Natural Products Having either a 2,10-Dioxabi­cyclo[7.3.0]dodecene or 2,9-Dioxabicyclo[6.3.0]undecene Skeleton

7 Conclusion

Key words

intramolecular enolate alkylation - natural products - substrate-controlled synthesis - medium-ring ethers - ring-closing metathesis

• References

• 1 Ahn SH, Kim D, Chun MW, Chung W. Tetrahedron Lett. 1986; 27: 943
• 2 Kim D, Kim HS. J. Org. Chem. 1987; 52: 4633
• 3 Kim D, Ahn SK, Bae H, Choi WJ, Kim HS. Tetrahedron Lett. 1997; 38: 4437
• 4 Kim D, Kim IH. Tetrahedron Lett. 1997; 38: 415
• 5 Stork G, Leonia NJ. US Patent 2793233, 1957 ; Chem. Abstr. 1958, 52, 441.
• 6 Tokoroyama T, Tsukamoto M, Iio H. Tetrahedron Lett. 1984; 25: 5067
• 7 Tokoroyama T, Kusaka H. Can. J. Chem. 1996; 74: 2487
• 8 Stork G, Cohen JF. J. Am. Chem. Soc. 1974; 96: 5270
• 9a Kim D, Lee YK, Jang YM, Kim IO, Park SW. J. Chem. Soc., Perkin Trans. 1 1990; 3221
• 9b Kim D, Kwak YS, Shin KJ. Tetrahedron Lett. 1994; 35: 9211
• 10a Kim D, Lim JI. Tetrahedron Lett. 1995; 36: 5035
• 10b Kim D, Lee J, Shim PJ, Lim JI, Jo H, Kim S. J. Org. Chem. 2002; 67: 764
• 10c Kim D, Lee J, Shim PJ, Lim JI, Doi T, Kim S. J. Org. Chem. 2002; 67: 772
• 11 Kitahara T, Mori K. Tetrahedron 1984; 40: 2935
• 12 Bartlett PA, Green FR. III. J. Am. Chem. Soc. 1978; 100: 4858
• 13 Stork G, Raucher S. J. Am. Chem. Soc. 1976; 98: 1583
• 14 Hoffmann RW, Kemper B. Tetrahedron Lett. 1982; 23: 845
• 15 For a recent review on intramolecular S_N2′ reactions, see: Devambatla RK. V, Velagaleti R, Yarravarapu N, Fleming FF. Tetrahedron 2012; 68: 2925
• 16 Kim D, Lim JI, Shin KJ, Kim HS. Tetrahedron Lett. 1993; 34: 6557
• 17 Jo H, Lee J, Kim H, Kim S, Kim D. Tetrahedron Lett. 2003; 44: 7043
• 18 Kim D, Kim HS, Yoo JY. Tetrahedron Lett. 1991; 32: 1577
• 19 Kim D, Choi WJ, Hong JY, Park IY, Kim YB. Tetrahedron Lett. 1996; 37: 1433
• 20 Choi WJ, Kim D unpublished results.
• 21 Kim H, Choi WJ, Jung J, Kim S, Kim D. J. Am. Chem. Soc. 2003; 125: 10238
• 22 Smith AB. III, Empfield JR. Chem. Pharm. Bull. 1999; 47: 1671
• 23 Baek S, Jo H, Kim H, Kim H, Kim S, Kim D. Org. Lett. 2005; 7: 75
• 24a Evans DA, Ennis MD, Mathre DJ. J. Am. Chem. Soc. 1982; 104: 1737
• 24b Crimmins MT, Emmitte KA, Katz JD. Org. Lett. 2000; 2: 2165
• 25 Burke SD, Deaton DN, Olsen RJ, Armistead DM, Blough BE. Tetrahedron Lett. 1987; 28: 3905
• 26 Nahm S, Weinreb SM. Tetrahedron Lett. 1981; 22: 3815
• 27a Iida H, Yamazaki N, Kibayashi C. J. Org. Chem. 1986; 51: 3769
• 27b Clark JS, Holmes AB. Tetrahedron Lett. 1988; 29: 4333
• 28a Dyson BS, Burton JW, Sohn T, Kim B, Bae H, Kim D. J. Am. Chem. Soc. 2012; 134: 11781 ; and references cited therein
• 28b Hooz J, Gilani SS. H. Can. J. Chem. 1968; 46: 86
• 29 Kim B, Lee M, Kim MJ, Lee H, Kim S, Kim D, Koh M, Park SB, Shin KJ. J. Am. Chem. Soc. 2008; 130: 16807
• 30 Sohn T, Kim MJ, Kim D. J. Am. Chem. Soc. 2010; 132: 12226
• 31 For a review on the total synthesis of C-2–C-11 cyclized cembranoids, see: Ellis JM, Crimmins MT. Chem. Rev. 2008; 108: 5278
• 32a Crimmins MT, Brown BH. J. Am. Chem. Soc. 2004; 126: 10264
• 32b Crimmins MT, Brown BH, Plake HR. J. Am. Chem. Soc. 2006; 128: 1371
• 33 Kim H, Lee H, Kim J, Kim S, Kim D. J. Am. Chem. Soc. 2006; 128: 15851
• 34 Bernardelli P, Moradei OM, Friedrich D, Yang J, Gallou F, Dyck BP, Doskotch RW, Lange T, Paquette LA. J. Am. Chem. Soc. 2001; 123: 9021
• 35 Barrett AG. M, Godfrey CR. A, Hollinshead DM, Prokopiou PA, Barton DH. R, Boar RB, Joukhadar L, McGhie JF, Misra SC. J. Chem. Soc., Perkin Trans. 1 1981; 1501
• 36a Clark JS, Berger R, Hayes ST, Thomas LH, Morrison AJ, Gobbi L. Angew. Chem. Int. Ed. 2010; 49: 9867
• 36b Clark JS, Berger R, Hayes ST, Senn HM, Farrugia LJ, Thomas LH, Morrison AJ, Gobbi L. J. Org. Chem. 2013; 78: 673
• 37 For a successful application that is a notable exception, see: Kim H, Lee H, Lee D, Kim S, Kim D. J. Am. Chem. Soc. 2007; 129: 2269
• 38 Suzuki M, Takahashi Y, Mitome Y, Itoh T, Abe T, Masuda M. Phytochemistry 2002; 60: 861
• 39 Kurata K, Furusaki A, Suehiro K, Katayama C, Suzuki T. Chem. Lett. 1982; 1031
• 40 Suzuki M, Kurosawa E, Furusaki A, Katsuragi S, Matsumoto T. Chem. Lett. 1984; 1033
• 41 Lowe G. Chem. Commun. 1965; 411
• 42 Jeong W, Kim MJ, Kim H, Kim S, Kim D, Shin KJ. Angew. Chem. Int. Ed. 2010; 49: 752
• 43a Gaunt MJ, Hook DF, Tanner HR, Ley SV. Org. Lett. 2003; 5: 4815
• 43b Lainé D, Fujita M, Ley SV. J. Chem. Soc., Perkin Trans. 1 1999; 1639
• 44 Keck GE, Boden EP. Tetrahedron Lett. 1984; 25: 265
• 45 Kim B, Cheon G, Park J, Lee H, Kim H, Kim S, Kim D. Heterocycles 2007; 74: 171
• 46a Crimmins MT, Emmitte KA. J. Am. Chem. Soc. 2001; 123: 1533
• 46b Crimmins MT, Emmitte KA, Choy AL. Tetrahedron 2002; 58: 1817
• 46c Crimmins MT, Powell MT. J. Am. Chem. Soc. 2003; 125: 7592
• 47 Kim MJ, Sohn T, Kim D, Paton RS. J. Am. Chem. Soc. 2012; 134: 20178
• 48 Kim S, Ahn KH. J. Org. Chem. 1984; 49: 1717
• 49 Grese TA, Hutchinson KD, Overman LE. J. Org. Chem. 1993; 58: 2468
• 50a Stork G, Gardner JO, Boeckman RK. Jr, Parker KA. J. Am. Chem. Soc. 1973; 95: 2014
• 50b Stork G, Boeckman RK. Jr. J. Am. Chem. Soc. 1973; 95: 2016

For recent reviews on nitrile anion cyclizations, see:
• 51a Fleming FF, Wei Y, Liu W, Zhang Z. Tetrahedron 2008; 64: 7477
• 51b Fleming FF, Gudipati S. Eur. J. Org. Chem. 2008; 5365

For details of this intramolecular nitrile anion alkylation (90′ → 91′), see:
• 52a Jeong W. Ph.D. Thesis. Seoul National University; Republic of Korea: 2010. the results are comparable to those reported in connection with our isolaurallene synthesis: (b) See also ref. 47
• 53 Park J, Kim B, Kim H, Kim S, Kim D. Angew. Chem. Int. Ed. 2007; 46: 4726
• 54 Fukuzawa A, Kurosawa E. Tetrahedron Lett. 1979; 20: 2797
• 55 Lyakhova EG, Kalinovsky AI, Dmitrenok AS, Kolesnikova SA, Fedorov SN, Vaskovsky VE, Stonik VA. Tetrahedron Lett. 2006; 47: 6549
• 56 Suzuki M, Takahashi Y, Matsuo Y, Masuda M. Phytochemistry 1996; 41: 1101
• 57 The two ratios in parentheses for the Overman protocol in Schemes 35–37 represent the results from the titanium (trimethylsilyl)acetylide addition and copper-catalyzed anti-S_N2′ reaction, respectively.
• 58 Kim G, Sohn T, Kim D, Paton RS. Angew. Chem. Int. Ed. DOI: , doi: 10.1002/anie.201308077.
• 59 Chao W, Weinreb SM. Org. Lett. 2003; 5: 2505
• 60 Snyder SA, Brucks AP, Treitler DS, Moga I. J. Am. Chem. Soc. 2012; 134: 17714