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DOI: 10.1055/s-2003-39285
Cycloadditions of Nonstabilized 2-Azaallyllithiums (2-Azaallyl Anions) and Azomethine Ylides with Alkenes: [3+2] Approaches to Pyrrolidines and Application to Alkaloid Total Synthesis
Publication History
Publication Date:
20 May 2003 (online)
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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.
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1 Introduction
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2 Background: 2-Azaallyl Anions
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2.1 Semistabilized 2-Azaallyl Anions
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2.2 Stabilized 2-Azaallyl Anions
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2.3 Nonstabilized 2-Azaallyl Anions
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3 Methodology Development
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3.1 Initial Attempts at Generating Nonstabilized 2-Azaallyl Anions
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3.2 Tin-Lithium Exchange on (2-Azaallyl)stannanes
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4 Cycloaddition of Simple Nonstabilized 2-Azaallyllithiums
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4.1 Preparation of (2-Azaallyl)stannanes
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4.2 Anionophiles and Quenches
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4.3 Mechanism and Stereoselectivity
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5 Variations on a Theme: Related Cycloadditions
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5.1 Cycloadditions on Solid Support
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5.2 2-Azapentadienyllithiums
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5.3 Heteroatom-Substituted 2-Azaallyllithiums
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5.4 Enantioselective Cycloadditions
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5.5 Higher-Order Cycloadditions
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6 Other Uses of (2-Azaallyl)stannanes
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6.1 Azomethine Ylide Generation and Cycloaddition
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6.2 Nucleophilic Additions to (2-Azaallyl)stannanes
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7 Synthesis of Alkaloids
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7.1 Intramolecular Cycloadditions
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7.1.1 Amabiline and Augustamine
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7.1.2 Mesembranes
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7.1.3 Coccinine
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7.1.4 Crinine and 6-Epicrinine
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7.1.5 Approach to 6a-Epipretazettine
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7.2 Intermolecular Cycloadditions
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7.2.1 Lepadiformine Isomers
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7.2.2 Lapidilectine B
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7.2.3 Indolizidine 239CD
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8 Commentary
Key words
organolithium - anionic cycloaddition - heterocycles - alkaloid synthesis - tin-lithium exchange
- 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 ProductsPadwa 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 ProductsPadwa 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
References
Pearson, W. H.; Walters, M. A.; Rosen, M. K.; Harter, W. G. Arkivoc 2002, in press.