Cross-Metathesis of Chiral N-tert-Butylsulfinyl Homoallylamines: Application to the Enantioselective Synthesis of Naturally Occurring 2,6-cis-Disubstituted Piperidines

Abstract

The synthesis of piperidine alkaloids (+)-dihydropinidine (1), (+)-isosolenopsin (2a), (+)-isosolenopsin A (2b), and (2R,6R)-6-methylpipecolic acid (3a) hydrochlorides, based on cross-metathesis of chiral N-tert-butylsulfinyl homoallylamines with methyl vinyl ketone, is presented.

Key words

cross-metathesis - piperidine alkaloids - pipecolic acid derivatives - stereoselective allylation

References and Notes

• 1 Schneider M. In Alkaloids: Chemical and Biological Perspectives   Vol. 10:  Pelletier SW. Pergamon; Oxford: 1996.  p.55-299  
• For recent reviews on the stereoselective synthesis of 2,6-dialkylpiperidines, see:
• 2a Bates RW. Sa-Ei K. Tetrahedron  2002,  58:  5957 
• 2b Buffat MGP. Tetrahedron  2004,  60:  1701 
• 3 Attygale AB. Xu SC. McCormick KD. Meinwald J. Blankespoor CL. Eismer T. Tetrahedron  1993,  49:  9333 
• 4a For leading references on the enantioselective synthesis of dihydropinidine, see: Ciblat S. Besse P. Papastergiou V. Veschambre H. Canet JL. Troin Y. Tetrahedron: Asymmetry  2000,  11:  2221 ; and references therein
• 4b To verify the NMR data, see: Wang X. Dong Y. Sun J. Xu X. Li R. Hu Y. J. Org. Chem.  2005,  70:  1897 
• 5a For the absolute configuration of isosolenopsins, see: Leclerq S. Thirionet I. Broeders F. Daloze D. Vander Meer R. Braeekman JC. Tetrahedron  1994,  50:  8465 
• 5b

  For leading references on the enantioselective synthesis of isosolenopsins, see ref. 4.

• For leading references on cis-6-methylpipecolic acid, see:
• 6a Swarbrick ME. Gosselin F. Lubell WD. J. Org. Chem.  1999,  64:  1993 
• 6b Davis FA. Zhang H. Lee SH. Org. Lett.  2001,  3:  759 
• 6c Troin Y. Carbonnel S. Heterocycles  2002,  57:  1807 
• 7a Deslongchamps P. Stereoelectronic Effects in Organic Chemistry   Pergamon; New York: 1983.  Chap. 6.
• 7b Stevens RV. Acc. Chem. Res.  1984,  17:  289 ; and references therein
• 7c Ryckman DM. Stevens RV.
  J. Org. Chem.  1987,  52:  4274 
• 8a Randl S. Blechert S. J. Org. Chem.  2003,  68:  8879 
• 8b Randl S. Blechert S. Tetrahedron Lett.  2004,  45:  1167 
• 8c Gebauer J. Blechert S. Synlett  2005,  2826 
• 8d Dewi-Wülfing P. Gebauer J. Blechert S. Synlett  2006,  487 
• For recent reviews, see:
• 9a Connon SJ. Blechert S. Angew. Chem. Int. Ed.  2003,  42:  1900 
• 9b Hoveyda AH. Gillingham DG. Van Veldhuizen JJ. Kataoka O. Garber SB. Kingsburry JS. Harrity JPA. Org. Biomol. Chem.  2004,  2:  8 
• 10a For ring opening of chiral oxiranes with vinylmagnesium bromide, see: Fürstner A. Thiel OR. Kindler N. Bartkowska B. J. Org. Chem.  2000,  65:  7990 
• 10b For synthesis of chiral homoallylamines using this approach, see: Randl S. Blechert S. J. Org. Chem.  2003,  68:  8879 
• 10c

  See also ref. 8d.

• 11 Foubelo F. Yus M. Tetrahedron: Asymmetry  2004,  15:  3823 
• 12a Davis FA. Wu Y. Org. Lett.  2004,  6:  1269 
• 12b Dirscherl G. Rooshenas P. Schreiner PR. Lamaty F. König B. Tetrahedron  2008,  64:  3005 
• For selected reviews, see:
• 13a Ellman JA. Owens TD. Tang TP. Acc. Chem. Res.  2002,  35:  984 
• 13b Ellman JA. Pure Appl. Chem.  2003,  75:  39 
• 13c Zhou P. Chen BC. Davis FA. Tetrahedron  2004,  60:  8003 
• 14 N-tert-Butanesulfinylimines are readily prepared from aldehydes and N-tert-butanesulfinamides (Ss and Rs are commercially available in >99% ee), following the procedure reported in: Liu G. Cogan DA. Owens TD. Tang TP. Ellman JA. J. Org. Chem.  1999,  64:  1278 
• Allylation of tert-butylsulfinimines has also been reported by other authors using different metals and conditions. For selected examples, see:
• 15a Cogan DA. Liu G.-C. Ellman JA. Tetrahedron  1999,  55:  8883 
• 15b Li S.-W. Batey RA. Chem. Commun.  2004,  1382 
• 15c Kolodney G. Sklute G. Perrone S. Knochel P. Marek I. Angew. Chem. Int. Ed.  2007,  46:  9291 
• Poisoning of Pd and Pt catalysts is well documented. See for instance:
• 17a Bartholomew CH. Agarwal PK. Katzer JR. Adv. Catal.  1982,  31:  135 
• 17b Barbier J. Lamy-Pitara E. Marecot P. Boitiaux JP. Cosyns J. Verna F. Adv. Catal.  1990,  37:  279 
• 20 The procedure was adapted from: Larcheveque M. Haddad M. Tetrahedron: Asymmetry  1999,  10:  4231 
• For selected examples, see:
• 21a Mannaioni G. Alesiani M. Carla V. Natalini B. Marinozi M. Pelliciari R. Moroni F. Eur. J. Pharmacol.  1994,  251:  201 
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• 21c Ornstein PL. Schoepp DD. Arnold MB. Jones ND. Deeter JB. Lodge D. Leander JD. J. Med. Chem.  1992,  35:  3111 
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16

Preparation of Compound 6c: A solution of amine 5c (165 mg, 0.50 mmol), methyl vinyl ketone (140 mL, 1.65 mmol) and Hoveyda-Blechert ruthenium catalyst (31 mg, 0.05 mmol) in anhyd CH₂Cl₂ (10 mL) was stirred for 60 h at
45 ˚C. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, hexane-EtOAc) to give the title compound (137 mg, 0.37 mmol) as a pale brown oil; [α]_D ^²8 +20.0 (c 0.32, CHCl₃). IR (neat): 3226, 1673, 1626 cm^-¹. ^¹H NMR (300 MHz, CDCl₃):
δ = 6.83 (dt, J = 16.0, 7.5 Hz, 1 H), 6.15 (d, J = 16.0 Hz, 1 H), 3.33-3.42 (m, 1 H), 3.09 (d, J = 7.7 Hz, 1 H), 2.51-2.56 (m, 2 H), 2.27 (s, 3 H), 1.22-1.55 (m, 20 H), 1.21 (s, 9 H), 0.88 (t, J = 7.6 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃):
δ = 198.3, 143.5 (CH), 133.9 (CH), 56.1, 56.0 (CH), 39.5 (CH₂), 35.7 (CH₂), 31.8 (CH₂), 29.4 (CH₂), 29.25 (CH₂), 29.2 (CH₂), 27.0 (Me), 25.6 (CH₂), 22.55 (CH₂), 22.5 (Me), 14.0 (Me). LRMS (MALDI): m/z = 372.281 [M + H], 394.286 [M + Na].

18

General Procedure for the Reductive Amination of Cross-Metathesis Products: A flame-dried flask was cooled under a stream of argon and charged with Wilkinson’s catalyst (50 mg, 0.05 mmol) and a solution of the corresponding enone (1.10 mmol) in EtOH (5.0 mL). A balloon of H₂ was connected to the flask and the reaction mixture was stirred at r.t. overnight. After changing the solvent to n-hexane-t-BuOMe (1:1), the resulting suspension was filtered through a short pad of Celite to remove the solid Ph₃PO. The organic solution was concentrated (15 Torr) and the crude aminoketone was dissolved in MeOH (3 mL) and 4 M HCl in dioxane (1.5 mL) was added at 0 ˚C. After 1 h stirring at the same temperature, solvents were evaporated under vacuum. The residue was dissolved in citrate-phosphate buffer (1.5 mL) and THF (1.5 mL), adjusting the pH to 5 with 1 M NaOH if necessary. To this solution was added NaCNBH₃ (50 mg, 0.80 mmol) at
0 ˚C and the mixture was stirred for 3 h at 23 ˚C. The reaction mixture was basified with 15% NaOH (10 mL) and extracted with CH₂Cl₂ (3 × 20 mL). The organic layer was washed with brine, dried over K₂CO₃ and concentrated (15 Torr) to afford the desired piperidines as pale yellow oils. The corresponding hydrochlorides were crystallized using ethereal HCl and recrystallization from EtOH-EtOAc (1:3) afforded pure products (cis/trans >99:1), having spectral data identical with those reported in literature.^4b

19

Specific rotations obtained for hydrochlorides 1, 2a, and 2b:
(+)-Dihydropinidine hydrochloride: [α]_D ^²0 +14.2 (c 0.66, EtOH) {Lit.^4a [α]_D ^²0 +14.1 (c 1.0, EtOH)}.
(+)-Isosolenopsin hydrochloride: [α]_D ^²0 +10.2 (c 0.93, CHCl₃) {Lit.^4a [α]_D ^²0 +11.1 (c 0.92, CHCl₃)\.
(+)-Isosolenopsin A hydrochloride: [α]_D ^²0 +11.0 (c 1.00, CHCl₃) {Lit.^4a [α]_D ^²0 +10.0 (c 1.17, CHCl₃)}.