The Nicholas Reaction: A Powerful Tool for the Stereoselective Synthesis of Bioactive Compounds

Abstract

Polyether units are a frequent heterocyclic fragment present in numerous natural products of great biological importance and constitute significant synthons for the synthesis of pharmacologically relevant compounds. Likewise, compounds having ­stereochemically defined alkyl-branched hydrocarbon chains are widespread in nature and the development of new synthetic ­methodologies to achieve their preparation in high yields and levels of stereocontrol is currently a challenging endeavour in organic synthesis. In this account, we describe our own approach to the stereoselective synthesis of bioactive compounds using the Nicholas reaction, the discovery of unexpected reaction pathways as well as some unreported results. The scope of the title reaction, within our research interests, and its synthetic applications are outlined. ­Reference to important related work from others in the field is also included.

• 1 Introduction

• 2 Synthesis of Symmetrical and Unsymmetrical Linear ­Propargylic Ethers

• 3 Synthesis of Cyclic Propargylic Ethers

• 3.1 Primary and Secondary Alcohols as Nucleophiles

• 3.2 Epoxides as Nucleophiles

• 4 Asymmetric Intermolecular Nicholas Reaction

• 5 Synthesis of Homopropargylic Ketones

• 6 Intramolecular Propargylic Reduction

• 7 Summary

Key words

alkynes - cobalt complexes - Nicholas reaction - stereoselective synthesis - natural products - ethers

References and Notes

• 3a Nicolaou KC. Sorensen EJ. In Classics in Total Synthesis   Wiley-VCH; Weinheim: 1996. 
• 3b Nicolaou KC. Snyder SA. In Classics in Total Synthesis   Vol. 2:  Wiley-VCH; Weinheim: 2003. 
• 4a Asymmetric Synthesis   Morrison JD. Academic Press; New York: 1985. 
• 4b Comprehensive Asymmetric Catalysis   Jacobsen EN. Pfaltz A. Yamamoto H. Springer; New York: 1999. 
• 5a Yasumoto T. Murata M. Chem. Rev.  1993,  93:  1897 
• 5b Gallimore AR. Spencer JB. Angew. Chem. Int. Ed.  2006,  45:  4406 
• For recent reviews on the synthesis of marine polycyclic ethers, see:
• 6a Inoue M. Chem. Rev.  2005,  105:  4379 
• 6b Nakata T. Chem. Rev.  2005,  105:  4314 
• 7 Álvarez E. Díaz MT. Pérez R. Ravelo JL. Regueiro A. Vera JA. Zurita D. Martín JD. J. Org. Chem.  1994,  59:  2848 
• 8a Nicolaou KC. Hwang C.-K. Duggan ME. Reddy KB. Marron BE. Macgarry DG. J. Am. Chem. Soc.  1986,  108:  6800 
• 8b Schreiber SL. Kelly SE. Porco JA. Sammakia T. Suh EM. J. Am. Chem. Soc.  1988,  110:  6210 
• 8c Robinson RA. Clark JS. Holmes AB. J. Am. Chem. Soc.  1993,  115:  10400 
• 9 Kotsuki H. Synlett  1992,  97 
• 10a Yamada J. Asano T. Kadota I. Yamamoto Y. J. Org. Chem.  1990,  55:  6066 
• 10b Fum GC. Grubbs RH. J. Am. Chem. Soc.  1992,  114:  5426 
• 10c Berger D. Overman LE. Renhowe PA. J. Am. Chem. Soc.  1993,  31:  9305 
• 11a Boivin TLB. Tetrahedron  1987,  43:  3309 
• 11b Nicolaou KC. Prasad CVC. Somers PK. Hwang C.-K. J. Am. Chem. Soc.  1989,  111:  5335 
• 11c Suzuki T. Sato O. Hirama M. Tetrahedron Lett.  1990,  37:  4349 
• 12 Dictionary of Natural Products   4th Suppl., Vol. 11:  Buckingham J. Chapman & Hall; New York: 1998. 
• 13 Comprehensive Organic Synthesis   Vol. 3:  Trost BM. Fleming I. Pergamon Press; Oxford: 1991. 
• 14 Faulkner DJ. Nat. Prod. Rep.  1999,  16:  155 
• 15a Abiko A. Masamune S. Tetrahedron Lett.  1996,  37:  1081 
• 15b Birkbeck AA. Enders D. Tetrahedron Lett.  1998,  39:  7823 
• 16a Norte M. Fernández JJ. Padilla A. Tetrahedron Lett.  1994,  35:  3413 
• 16b Calter MA. Guo X. Liao W. Org. Lett.  2001,  3:  1499 
• 16c Calter MA. Guo X. Liao W. J. Org. Chem.  2001,  66:  7500 
• For comprehensive reviews on the chemistry uses of cobalt-complexed propargylic cations and related, see:
• 17a Nicholas KM. Acc. Chem. Res.  1987,  20:  207 
• 17b Welker ME. Curr. Org. Chem.  2001,  5:  785 
• 17c Green JR. Curr. Org. Chem.  2001,  5:  809 
• 17d Müller TJJ. Eur. J. Org. Chem.  2001,  2021 
• 17e Teobald BJ. Tetrahedron  2002,  58:  4133 
• 17f Fryatt R. Christie SDR. J. Chem. Soc., Perkin Trans. 1  2002,  447 
• 17g For an interesting study on site selectivity of nucleophile incorporation in 3-acetoxycyclohept-1-en-4-ynedicobalt hexacarbonyl, see: DiMartino J. Green JR. Tetrahedron  2006,  62:  1402 
• 18 Gachkova N. Cassel J. Leue S. Kann N. J. Comb. Chem.  2005,  7:  449 ; and references therein
• 19a Schore NE. In Comprehensive Organometallic Chemistry II   Vol. 12:  Hegedus LS. Pergamon; Oxford: 1995.  Chapter 7.2. p.403 
• 19b Krafft ME. Cheung YY. Wright C. Cali R. J. Org. Chem.  1996,  61:  3912-3915  ; and references cited therein
• 20 For the first approach to the induction of enantioselectivity in the Nicholas C-C coupling version, see: Montaña AM. Cano M. Tetrahedron  2002,  58:  933 
• 21 Schreiber SL. Klimas MT. Sammakia T. J. Am. Chem. Soc.  1987,  109:  5749 
• 22 Muehldorf AV. Guzmán-Pérez A. Kluge AE. Tetrahedron Lett.  1994,  35:  8755 
• 23 Melikan GC. Bright S. Monroe T. Handcastle KI. Ciurash J. Angew. Chem., Int. Ed. Engl.  1998,  37:  161 
• 24 Bradley DH. Khan MA. Nicholas KM. Organometallics  1989,  8:  554 
• 25 Caffyn AJM. Nicholas KM. J. Am. Chem. Soc.  1993,  115:  6438 
• 26 Betancort JM. Martín VS. Padrón JM. Palazón JM. Ramírez MA. Soler MA. J. Org. Chem.  1997,  62:  4570 ; and references cited therein
• 27a March J. Advanced Organic Chemistry   John Wiley & Sons; New York: 1992. 
• 27b Brummond KM. Kent JL. Tetrahedron  2000,  56:  3263 
• 28 Jenner G. Tetrahedron Lett.  1988,  29:  2445 
• 29 For an extraordinary application of the Williamson reaction to the preparation of alcohol protecting groups, see: Green TW. Protective Groups in Organic Synthesis   John Wiley & Sons; New York: 1999. 
• 30 Díaz DD. Martín VS. Tetrahedron Lett.  2000,  41:  9993 
• 31 Díaz DD. Martín T. Martín VS. Org. Lett.  2001,  3:  3289 
• 32 For the first example of the synthesis of 1,4-difunctionalized but-2-yne complexes by a double Nicholas reaction, see: Seiichi T. Takumichi S. Kunio O. Synlett  1992,  70 
• 33a Palazón JM. Martín VS. Tetrahedron Lett.  1995,  36:  3549 
• 33b Betancort JM. Martín T. Palazón JM. Martín VS. J. Org. Chem.  2003,  68:  3216 
• 34 For an efficient synthesis of oxaspiro[m.n] skeletons based on the Nicholas reaction, see: Chisato M. Haruhisa Y. Misato S. Miyoji H. Tetrahedron  2002,  58:  2755 
• 35 Betancort JM. Rodríguez CM. Martín VS. Tetrahedron Lett.  1998,  39:  9773 
• 36 For the influence of a secondary carbinol to control the cyclization stereochemistry in isolated rings, see: Díaz DD. Betancort JM. Crisóstomo FRP. Martín T. Martín VS. Tetrahedron  2002,  58:  1913 
• 37 Katsuki T. Martín VS. Organic Reactions   Vol. 48:  Paquette LA. Wiley; New York: 1996.  p.1-299  
• 38 Palazón JM. Soler MA. Martín VS. Tetrahedron Lett.  1993,  34:  5471 
• 39 Ramírez MA. Padrón JM. Palazón JM. Martín VS. J. Org. Chem.  1997,  62:  4584 
• 40 Nicolaou KC. Hwang C.-K. Marron BE. DeFress SA. Couladourus EA. Abe Y. Carroll PJ. Snyder JP. J. Am. Chem. Soc.  1990,  112:  3040 
• 41 Crisóstomo FRP. Carrillo R. Martín T. Martín VS. Tetrahedron Lett.  2005,  45:  2829 
• 42 Díaz DD. Ramírez MA. Ceñal JP. Saad R. Tonn CE. Martín VS. Chirality  2003,  15:  148 
• 43 Takase M. Morikawa T. Abe H. Inouye M. Org. Lett.  2003,  5:  625 
• 44 Christie SDR. Davoile RJ. Elsegood MRJ. Fryatt R. Jones RCF. Pritthard GJ. Chem. Commun.  2004,  2474 
• 45 Lebold TP. Carson CA. Kerr MA. Synlett  2006,  364 
• 46 Crisóstomo FRP. Martín T. Martín VS. Org. Lett.  2004,  6:  565 
• 48 Davies JE. Hope-Weeks LJ. Mays MJ. Raithby PR. Chem. Commun.  2000,  1411 
• 49 Shea KM. Closser KD. Quintal MM. J. Org. Chem.  2005,  70:  9088 
• 50a Lee H. Kim H. Baek S. Kim S. Kim D. Tetrahedron Lett.  2003,  44:  6609 
• 50b Carreno MC. Mazery RD. Urbano A. Colobert F. Solladié G. Org. Lett.  2004,  6:  297 
• 50c Lee HJ. Kim HS. Yoon T. Kim B. Kim S. Kim H.-D. Kim D. J. Org. Chem.  2005,  70:  8723 
• 53 Ortega N. Martín T. Martín VS. Org. Lett.  2006,  8:  871 
• The endo-complexes need reductive decomplexation procedures to successfully achieve the synthesis of the corresponding cyclic systems:
• 54a Hosokawa S. Isobe M. Tetrahedron Lett.  1998,  39:  2609 
• 54b Nakamura T. Matsui T. Tanino K. Kuwajima I. J. Org. Chem.  1997,  62:  3032 
• 55 Young DG. Burlison JA. Peters U. J. Org. Chem.  2003,  68:  3494 
• 56 Kira K. Tanda H. Hamajima A. Baba T. Takai S. Isobe M. Tetrahedron  2002,  58:  6485 ; and references cited therein
• 57a Isobe M. Yenjai C. Tanaka S. Synlett  1994,  11:  916 
• 57b Yenjai C. Isobe M. Tetrahedron  1998,  54:  916 
• 57c Isobe M. Hosokawa S. Kira K. Chem. Lett.  1996,  473 
• 57d Hosokawa S. Isobe M. J. Org. Chem.  1999,  64:  37 
• 57e Saeeng R. Isobe M. Tetrahedron Lett.  1999,  40:  1911 
• 57f For a review, see: Isobe M. Nishizawa R. Hosokawa S. Nishikawa T. Chem. Commun.  1998,  2665 
• 58a Mukai C. Sugimoto Y.-I. Miyazawa K. Yamaguchi S. Hanaoka M. J. Org. Chem.  1998,  63:  6281 
• 58b Mukai C. Yamaguchi S. Ichiryu T. Hanaoka M. J. Org. Chem.  2000,  65:  6761 
• 59 Mukai C. Yamaguchi S. Sugimoto Y. Miyakoshi N. Kasamatsu E. Hanaoka M. Tetrahedron  2000,  56:  2203 
• 60 Quintal MM. Closser KD. Shea KM. Org. Lett.  2004,  6:  4949 
• 61 Schreiber SL. Sammakia T. Crowe WE. J. Am. Chem. Soc.  1986,  108:  3128 
• In order to avoid elimination by-products, all reactions were carried out at -20 °C. See:
• 63a Saksena AK. Green MJ. Mangiaracina P. Wong JK. Kreutner Gulbenkian AR. Tetrahedron Lett.  1985,  26:  6423 
• 63b Melikyan GG. Mineif O. Vostrowsky O. Bestmann HJ. Synthesis  1991,  633 
• 63c Berger D. Overman LE. J. Am. Chem. Soc.  1997,  119:  2446 
• 64a Mancuso AJ. Huang S.-L. Swern D. J. Org. Chem.  1978,  43:  2480 
• 64b Schmieder-van de Vondervoort L. Bouttemy S. Padrón JM. Le Bras J. Muzart J. Alsters PL. Synlett   2002,  243 
• 65 Majetich G. Zhang Y. Dreyer G. Tetrahedron Lett.  1993,  34:  449 
• 66a Kende AS. Fludzinski P. Hill JH. Swenson W. Clardy J. J. Am. Chem. Soc.  1984,  106:  3551 
• 66b Nagasawa T. Taya K. Kitamura M. Suzuki K. J. Am. Chem. Soc.  1996,  118:  8949 
• 67 Soler MA. Martín VS. Tetrahedron Lett.  1999,  40:  2815 
• 68 Saksena AK. Green MJ. Mangiaracina P. Wong JK. Kreutner W. Gulbenkian AR. Tetrahedron Lett.  1985,  26:  6423 
• 69 Díaz DD. Martín VS. Tetrahedron Lett.  2000,  41:  743 
• 70 Díaz DD. Martín VS. Org. Lett.  2000,  2:  335 
• 71a Brandsma L. In Preparative Acetylenic Chemistry   Elsevier; Amsterdam: 1988.  p.39-40 
• 71b Comprehensive Organic Synthesis   Vol. 3:  Trost BM. Fleming I. Pergamon Press; Oxford: 1991.  p.271-292  
• 72 Díaz DD. Ramírez MA. Martín VS. Chem. Eur. J.  2006,  12:  2593 
• 73 Díaz DD. Martín VS. J. Org. Chem.  2000,  65:  7896 
• 74 Díaz DD. Crisóstomo FRP. Martín VS. Isr. J. Chem.  2001,  41:  297 

1

Present address: Departamento de Química Orgánica, Universidad Autónoma de Madrid, 28049 Madrid, Spain.

2

Present address: Phenomix Corporation, 5871 Oberlin Dr., San Diego, CA 92126, U.S.A.

47

(a) Unpublished results. (b) X-ray data can be obtained directly from the authors upon request.

51

We had difficulties separating both diastereoisomers. At the present time we cannot ensure which isomer is predominant.

52

Montmorillonite K-10 has been recently reported as a convenient acid component in the Nicholas reaction, see ref. 41.

62

These complexes possess an outstanding resolution under silica gel chromatography and both diastereoisomers can be readily separated in this way.