Synlett 2003(7): 0903-0921
DOI: 10.1055/s-2003-39285
ACCOUNT
© Georg Thieme Verlag Stuttgart ˙ New York

Cycloadditions of Nonstabilized 2-Azaallyllithiums (2-Azaallyl Anions) and Azomethine Ylides with Alkenes: [3+2] Approaches to Pyrrolidines and Application to Alkaloid Total Synthesis

William H. Pearson*, Patrick Stoy
Department of Chemistry, University of Michigan, Ann Arbor, Michigan, 48109-1055, USA
Fax: +1(734)7632307; e-Mail: wpearson@umich.edu;
Further Information

Publication History

Received 9 August 2002
Publication Date:
20 May 2003 (online)

Abstract

The [3+2] cycloaddition of 2-azaallyl anions with al­kenes represents an attractive strategy for the synthesis of substituted pyrrolidines. Although cycloadditions of 2-azaallyl anions stabilized by aryl and ester groups have been known for more than three decades, only recently have versions bearing simply hydrogen or alkyl groups been discovered. These nonstabilized 2-azaallyl anions are generated by the low temperature transmetalation of (2-azaallyl)stannanes with alkyllithiums. The resulting nonstabilized 2-azaallyllithiums undergo cycloaddition with certain alkenes and alkynes in both intra- and intermolecular modes to yield pyrrolidine or pyrroline cycloadducts. The methodology has been extended to 2-azapentadienyllithiums, heteroatom-substituted 2-azaallyllithiums, and polymer-supported 2-azaallyllithiums. Asymmetric 2-azaallyl anion cycloadditions have also been investigated. Nonstabilized azomethine ylides may also be generated from (2-azaallyl)stannanes via an N-alkylation/destannylation or N-protonation/destannylation sequence. Together, the cycloaddition of nonstabilized 2-azaallyllithiums and azomethine ylides with alkenes allows access to a broader range of pyrrolidines, since these species have complimentary reactivity profiles.

  • 1 Introduction

  • 2 Background: 2-Azaallyl Anions

  • 2.1 Semistabilized 2-Azaallyl Anions

  • 2.2 Stabilized 2-Azaallyl Anions

  • 2.3 Nonstabilized 2-Azaallyl Anions

  • 3 Methodology Development

  • 3.1 Initial Attempts at Generating Nonstabilized 2-Azaallyl Anions

  • 3.2 Tin-Lithium Exchange on (2-Azaallyl)stannanes

  • 4 Cycloaddition of Simple Nonstabilized 2-Azaallyllithiums

  • 4.1 Preparation of (2-Azaallyl)stannanes

  • 4.2 Anionophiles and Quenches

  • 4.3 Mechanism and Stereoselectivity

  • 5 Variations on a Theme: Related Cycloadditions

  • 5.1 Cycloadditions on Solid Support

  • 5.2 2-Azapentadienyllithiums

  • 5.3 Heteroatom-Substituted 2-Azaallyllithiums

  • 5.4 Enantioselective Cycloadditions

  • 5.5 Higher-Order Cycloadditions

  • 6 Other Uses of (2-Azaallyl)stannanes

  • 6.1 Azomethine Ylide Generation and Cycloaddition

  • 6.2 Nucleophilic Additions to (2-Azaallyl)stannanes

  • 7 Synthesis of Alkaloids

  • 7.1 Intramolecular Cycloadditions

  • 7.1.1 Amabiline and Augustamine

  • 7.1.2 Mesembranes

  • 7.1.3 Coccinine

  • 7.1.4 Crinine and 6-Epicrinine

  • 7.1.5 Approach to 6a-Epipretazettine

  • 7.2 Intermolecular Cycloadditions

  • 7.2.1 Lepadiformine Isomers

  • 7.2.2 Lapidilectine B

  • 7.2.3 Indolizidine 239CD

  • 8 Commentary

    References

  • 1 Current address: Berry & Associates, Inc., 2642 Bishop Circle East, Dexter, Michigan, 48130, USA
  • 2 Ingold CK. Shoppee CW. J. Chem. Soc.  1929,  1199 
  • 3 Hauser CR. Flur IC. Kantor SW. J. Am. Chem. Soc.  1949,  71:  294 
  • 4a Kauffmann T. Angew. Chem., Int. Ed. Engl.  1974,  13:  627 
  • 4b Kauffmann T. Berg H. Köppelmann E. Angew. Chem., Int. Ed. Engl.  1970,  9:  380 
  • 5 Tsuge O. Kanemasa S. Hatada A. Matsuda K. Bull. Chem. Soc. Jpn.  1986,  59:  2537 
  • 6 Tsuge O. Kanemasa S. Hatada A. Matsuda K. Chem. Lett.  1984,  801 
  • 7 Achiwa K. Imai N. Motoyama T. Sekiya M. Chem. Lett.  1984,  2041 
  • 8 Imai N. Achiwa K. Chem. Pharm. Bull.  1987,  35:  2646 
  • 9 Tsuge O. Kanemasa S. Yamada T. Matsuda K. J. Org. Chem.  1987,  52:  2523 
  • 10 Dehnel A. Lavielle G. Tetrahedron Lett.  1980,  21:  1315 
  • 11 Houwing HA. van Leusen AM. J. Heterocycl. Chem.  1981,  18:  1127 
  • 12 Fouchet B. Joucla M. Hamelin J. Tetrahedron Lett.  1981,  22:  3397 
  • 13 Grigg R. Sridharan V. In Advances in Cycloaddition   Vol. 3:  Curran DP. JAI Press; Greenwich CT: 1993.  p.161-204  
  • 14 Kanemasa S. Tsuge O. In Advances in Cycloaddition   Vol. 3:  Curran DP. JAI Press; Greenwich CT: 1993.  p.99-159  
  • 15 Kanemasa S. In Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products   Padwa A. Pearson WH. John Wiley & Sons; New York: 2002.  p.755-815  
  • 16 Harwood LM. Vickers RJ. In Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products   Padwa A. Pearson WH. John Wiley & Sons; New York: 2002.  p.169-252  
  • 17 Grigg R. Kemp J. Tetrahedron Lett.  1978,  2823 
  • 18 Kanemasa S. Yamamoto H. Wada E. Sakurai T. Urushido K. Bull. Chem. Soc. Jpn.  1990,  63:  2857 
  • 19 Terao Y. Aono M. Achiwa K. Heterocycles  1988,  27:  981 
  • 20 Tsuge O. Kanemasa S. Matsuda K. Chem. Lett.  1984,  1827 
  • 21 Pearson WH. Walters MA. Oswell KD. J. Am. Chem. Soc.  1986,  108:  2769 
  • 22 A single report of the use of an unactivated alkene in a cycloaddition with a 2-azaallyl anion preceded this work wherein Kauffmann’s 1,3-diphenyl-2-azaallyllithium was used to capture ethylene that was generated by the base-promoted decomposition of THF, see: Kamata K. Terashima M. Heterocycles  1980,  14:  205 
  • 23 Pearson WH. Walters MA. Harter WG. In Electronic Conference on Trends in Heterocyclic Chemistry   Royal Society of Chemistry; Cambridge UK: 1996. Paper No. 60; http://www.ch.ic.ac.uk/ectoc/echet96/papers/060/index.htm
  • 25 Kauffmann T. Habersaat K. Köppelmann E. Angew. Chem., Int. Ed. Engl.  1972,  11:  291 
  • 26 Wiberg KB. Breneman CM. LePage TJ. J. Am. Chem. Soc.  1990,  112:  61 
  • 27 Pearson WH. Szura DP. Harter WG. Tetrahedron Lett.  1988,  29:  761 
  • 28 Pearson WH. Szura DP. Postich MJ. J. Am. Chem. Soc.  1992,  114:  1329 
  • 29 Pearson WH. Postich MJ. J. Org. Chem.  1992,  57:  6354 
  • 30 Chong JM. Park SB. J. Org. Chem.  1992,  57:  2220 
  • 31 Pearson WH. Ren Y. J. Org. Chem.  1999,  64:  688 
  • 32 Kauffmann T. Ahlers H. Hamsen A. Schulz H. Tilhard H.-J. Vahrenhorst A. Angew. Chem., Int. Ed. Engl.  1977,  16:  119 
  • 33 Pearson WH. Mi Y. Tetrahedron Lett.  1997,  38:  5441 
  • 34 Pearson WH. Jacobs VA. Tetrahedron Lett.  1994,  35:  7001 
  • 35 Pearson WH. Stevens EP. Tetrahedron Lett.  1994,  35:  2641 
  • 36 Pearson WH. Stevens EP. J. Org. Chem.  1998,  63:  9812 
  • 37 Pearson WH. Stevens EP. Aponick A. Tetrahedron Lett.  2001,  42:  7361 
  • 38 Pearson WH. Clark RB. Tetrahedron Lett.  1997,  38:  7669 
  • 39 Pearson WH. Mi Y. Lee IY. Stoy P. J. Am. Chem. Soc.  2001,  123:  6724 
  • 40 Clark RB. Pearson WH. Org. Lett.  1999,  1:  349 
  • Carbolithiation reviews:
  • 41a Knochel P. In Comprehensive Organic Synthesis   Vol. 4:  Trost BM. Fleming I. Pergamon; New York: 1991.  p.865-911  
  • 41b Bailey WF. Ovaska TV. In Advances in Detailed Reaction Mechanisms   Vol. 3:  Coxon JM. JAI Press; Greenwich CT: 1994.  p.251-273  
  • 41c Marek I. J. Chem. Soc., Perkin Trans. 1  1999,  535 
  • For lithium-ene reactions of allylic organolithiums with alkenes see the following references and the earlier work cited therein:
  • 42a Dieters A. Hoppe D. Angew. Chem. Int. Ed.  1999,  38:  546 
  • 42b Cheng D. Zhu S. Liu X. Norton SH. Cohen T. J. Am. Chem. Soc.  1999,  121:  10241 
  • 42c Cheng D. Knox KR. Cohen T. J. Am. Chem. Soc.  2000,  122:  412 
  • 43 Sauers RR. Tetrahedron Lett.  1996,  37:  7679 
  • 44 Neumann F. Lambert C. Schleyer PVR. J. Am. Chem. Soc.  1998,  120:  3357 
  • 45 Kauffmann T. Köppelmann E. Angew. Chem., Int. Ed. Engl.  1972,  11:  290 
  • 46 For a structure proof of one of Kauffmann’s cycloaddition products see: Ivanov PM. Mikhova BP. Spassov SL. J. Mol. Struct.  1996,  377:  19 
  • 47 Pearson WH. Barta NS. Kampf JW. Tetrahedron Lett.  1997,  38:  3369 
  • 48 Pearson WH. Mans DM. Kampf JW. Org. Lett.  2002,  4:  3099 
  • 49 For a brief study on the cycloaddition of Kauffmann’s 1,3-diphenyl-2-azaallyllithium with cycloheptatriene see: Bower DJ. Howden MEH. J. Chem. Soc., Perkin Trans. 1  1980,  672 
  • 50a Vedejs E. West FG. Chem. Rev.  1986,  86:  941 
  • 50b Vedejs E. In Advances in Cycloaddition   Vol. 1:  Curran DP. JAI Press; Greenwich CT: 1988.  p.33-51  
  • 50c Tominaga Y. Hojo M. Hosomi A. Yuki Gosei Kagaku Kyokaishi  1992,  50:  48 
  • Other routes to nonstabilized azomethine ylides include decarboxylative methods and the deprotonation of tertiary amine N-oxides. For leading references see:
  • 51a Tsuge O. Kanemasa S. Ohe M. Takenaka S. Bull. Chem. Soc. Jpn.  1987,  60:  4079 
  • 51b Ardill H. Grigg R. Sridharan V. Surendrakumar S. Tetrahedron  1988,  44:  4953 
  • 51c Chastanet J. Roussi G. J. Org. Chem.  1988,  53:  3808 
  • 52a Achiwa K. Imai N. Inaoka T. Sekiya M. Chem. Pharm. Bull.  1984,  32:  2878 
  • 52b Imai N. Achiwa K. Chem. Pharm. Bull.  1987,  35:  593 
  • 53 Pearson WH. Clark RB. Tetrahedron Lett.  1999,  40:  4467 
  • 54 Pearson WH. Aponick A. Organic Lett.  2001,  3:  1327 
  • 55 Pearson WH. Lovering FE. J. Am. Chem. Soc.  1995,  117:  12336 
  • 56 Pearson WH. Lovering FE. J. Org. Chem.  1998,  63:  3607 
  • 57 Pearson WH. Lian BW. Angew. Chem., Int. Ed. Engl.  1998,  37:  1724 
  • 58 Pearson WH. Lovering FE. Tetrahedron Lett.  1994,  35:  9173 
  • 59 Pearson WH. Postich MJ. J. Org. Chem.  1994,  59:  5662 
  • 60 Martin SF. Davidsen SK. Puckette TA. J. Org. Chem.  1987,  52:  1962 
  • 61 Biard JF. Guyot S. Roussakis C. Verbist JF. Vercauteren J. Weber JF. Boukef K. Tetrahedron Lett.  1994,  35:  2691 
  • 62 Werner KM. de los Santos JM. Weinreb SM. Shang M. J. Org. Chem.  1999,  64:  686 
  • 63 Werner KM. de los Santos JM. Weinreb SM. Shang M. J. Org. Chem.  1999,  64:  4865 
  • 64 Sun P. Sun C. Weinreb SM. Org. Lett.  2001,  3:  3507 
  • 65 Sun P. Sun C. Weinreb SM. J. Org. Chem.  2002,  67:  4337 
  • 66 Abe H. Aoyagi S. Kibayashi C. Tetrahedron Lett.  2000,  41:  1205 
  • 67 Abe H. Aoyagi S. Kibayashi C. J. Am. Chem. Soc.  2000,  122:  4583 
  • 68 Lepadiformine has also been synthesized by Greshock and Funk: Greshock TJ. Funk RL. Org. Lett.  2001,  3:  3511 
  • 69 Marshall JA. Garofalo AW. J. Org. Chem.  1993,  58:  3675 
  • 70 Ardakani MA. Smalley RK. Tetrahedron Lett.  1979,  4769 
  • 71 Azadi-Ardakani M. Alkhader MA. Lippiatt JH. Patel DI. Smalley RK. Higson S. J. Chem. Soc., Perkin Trans. 1  1986,  1107 
24

Pearson, W. H.; Walters, M. A.; Rosen, M. K.; Harter, W. G. Arkivoc 2002, in press.