Synthesis of Polyhydroxylated Pyrrolidines and Aziridinopyrrolidines from [4π+2π] Cycloadducts of Cyclopentadiene and Imines/2H-Azirines

Abstract

The synthesis of 2-functionalized 3,5-bis(hydroxymethyl)pyrrolidines from readily available polycyclic Diels-Alder adducts by a reaction sequence involving three steps is described. The same methodology has been applied to obtain the aziridine counterparts from the corresponding methyl 2-azatricyclo[3.2.1.0^2,4]oct-6-ene-4-carboxylates. The key steps in the synthetic strategy are dihydroxylation with osmium tetroxide/N-methylmorpholine N-oxide, oxidative cleavage with sodium periodate, and reduction using sodium borohydride or lithium aluminum hydride; overall yields ranged from 40-60%.

Keywords

asymmetric synthesis - cycloadditions - dihydroxylations - aziridinopyrrolidines - polyhydroxylated pyrrolidines

References and Notes

• 1a Iminosugars: From Synthesis to Therapeutic Applications   Compain P. Martin OR. Wiley; Chichester: 2007. 
• 1b Cipolla L. Fernandes MR. Gregori M. Airoldi C. Nicotra F. Carbohydr. Res.  2007,  342:  1813 
• 1c Liao W. Ibrahem I. Cordova A. Chem. Commun.  2006,  674 
• 1d McDonnell C. Cronin L. O’Brien JL. Murphy PV. J. Org. Chem.  2004,  69:  3565 
• 1e Cipolla L. LFerla B. Nicotra F. Curr. Top. Med. Chem.  2003,  3:  485 
• 2 Watson AA. Fleet GWJ. Asano N. Molyneux RJ. Nash RJ. Phytochemistry  2001,  56:  265 
• 3 Asano N. Nash RJ. Molyneux RJ. Fleet GWJ. Tetrahedron: Asymmetry  2000,  11:  1645 
• 4a Cox T. Lachmann R. Hollack C. Aerts J. van Welly S. Hrebicek M. Platt F. Butters T. Dwek R. Moyses C. Gow I. Elstein D. Zimran A. Lancet  2000,  355:  1481 
• 4b Kolter T. Angew. Chem. Int. Ed.  1997,  36:  1955 
• 5 Dwek RA. Butters TD. Platt FM. Zitzmann N. Nat. Rev. Drug Disc.  2002,  1:  65 
• 6a Pearson WH. Hembre EJ. J. Org. Chem.  1996,  61:  5546 
• 6b Pearson WH. Guo L. Tetrahedron Lett.  2001,  42:  8267 
• 6c Fleet GWJ. Nash RJ. Fellows LE. Parekh RJ. Rademacher TW. Chem. Lett.  1986,  1051 
• 7 Greimel P. Spreitz J. Stutz AE. Wrodniggm TM. Curr. Top. Med. Chem.  2003,  3:  513 
• 8 Fleet GWJ. Karpas A. Dwek RA. Fellows LE. Tyms AS. Petursson S. Namgoong SK. Ramsden NG. Smith PW. Son JC. Wilson FX. Witty DR. Jacob GS. Rademacher TW. FEBS Lett.  1988,  237:  128 
• 9a Davis FA. Fang T. Goswami R. Org. Lett.  2002,  4:  1599 
• 9b Merino I. Laxmi SYR. Flórez J. Barluenga J. J. Org. Chem.  2002,  67:  648 
• 9c Mitchinson A. Nadin A. J. Chem. Soc., Perkin Trans. 1  2000,  2862 
• 10a Coleman RS. Kong J.-She. J. Am. Chem. Soc.  1998,  120:  3538 
• 10b Coleman RS. Richardson TE. Carpenter AJ. J. Org. Chem.  1998,  63:  5738 
• 11 Mulzer J. Becker R. Brunner E. J. Am. Chem. Soc.  1989,  111:  7500 
• 12 Alves MJ. García-Mera X. Vale MLC. Santos TP. Aguiar FR. Rodríguez-Borges JE. Tetrahedron Lett.  2006,  47:  7595 
• 13 Rodríguez-Borges JE. García-Mera X. Fernández F. Lopes VHC. Magalhães AL. Cordeiro MNDS. Tetrahedron  2005,  61:  10951 
• 14a Bhullar P. Gilchrist TL. Maddocks P. Synthesis  1997,  271 
• 14b Alves MJ. Gilchrist TL. J. Chem. Soc., Perkin Trans. 1  1998,  299 
• 14c Gilchrist TL. Mendonça R. Synlett  2000,  1843 
• 14d Alves MJ. Bickeley JF. Gilchrist TL. J. Chem. Soc., Perkin Trans. 1  1999,  1399 
• 14e Gilchrist TL. Aldrichimica Acta  2001,  34:  51 
• 14f Álvares SP. Alves MJ. Azoia NG. Bickeley JF. Gilchrist TL. J. Chem. Soc., Perkin Trans. 1  2002,  1911 
• 14g Alves MJ. Gilchrist TL. Fortes AG. Lemos A. Martins C. Synthesis  2005,  5555 
• 14h Timen AS. Fischer A. Somfai P. Chem Commun.  2003,  1150 
• 14i Timen AS. Somfai P. J. Org. Chem.  2003,  68:  9958 
• 15a García MD. Caamaño O. Fernández F. Abeijon P. Blanco JM. Synthesis  2006,  73 
• 15b Bickley JF. Gilchrist TL. Mendonça R. ARKIVOC  2002,  (vi):  192 ; http://www.arkat-usa.org/home
• 16 Bailey PD. Londesbrough DJ. Hancox TC. Heffernan JD. Holmes AB. J. Chem. Soc., Chem. Commun.  1994,  2543 
• 18a Vale MLC. Rodríguez-Borges JE. Caamaño O. Fernández F. García-Mera X. Tetrahedron  2006,  62:  9475 ; and references cited therein
• 18b Bailey PD. Brown GR. Korber F. Reed A. Wilson RD. Tetrahedron: Asymmetry  1991,  2:  1263 
• 19 Alves MJ. Gilchrist TL. Tetrahedron Lett.  1998,  39:  7579 
• 20 The recovered alcohol {[α]_D ²⁵ -25.2 (c 0.5, CHCl₃)}, was identified as (-)-8-phenylmenthol by comparison of its spectroscopic and specific rotation data with those reported in literature: Fernández F. García-Mera X. López C. Rodríguez G. Rodríguez-Borges JE. Tetrahedron: Asymmetry  2000,  11:  4805 

17

The crystallographic data (excluding structure factors) for structure of 5b have been deposited at the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 240700. Empirical formula: C₃₀H₃₈N₂O₂. Formula weight: 458.62. Crystal size: 0.38 × 0.37 × 0.28 mm³. Crystal system: orthorhombic. Space group: P2₁2₁2₁. Unit cell dimensions: a = 10.912 (3) Å, b = 12.029 (3) Å, c = 19.685 (3) Å, α = 90°, β = 90°, γ = 90°. D _calc = 1.179 mg/m³. F(000) = 992. R1 = 0.0710, wR2 0 0.0772. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: [phone] or e-mail: [e-mail]].