Concise Enantioselective Syntheses of (+)-L-733,060 and (2S,3S)-3-Hydroxypipecolic Acid by Cobalt(III)(salen)-Catalyzed Two-Stereocenter Hydrolytic Kinetic Resolution of Racemic Azido Epoxides

Abstract

An efficient synthesis of the 2,3-disubstituted piperidines (+)-L-733,060 and (2S,3S)-3-hydroxypipecolic acid (≥99% ee) in high optical purity from commercially available starting materials is described. The strategy involves a cobalt-catalyzed hydrolytic kinetic resolution of a racemic azido epoxide with two stereocenters and an intramolecular reductive cyclization as key reactions.

Key words

azides - epoxides - stereoselective synthesis - Wittig reactions - cyclizations - piperidines

• References

• 1a Schneider MJ In Alkaloids: Chemical and Biological Perspectives . Vol. 10. Pelletier SW. Pergamon; Oxford: 1996: 155
• 1b Fodor GB, Colasanti B In Alkaloids: Chemical and Biological Perspectives . Vol. 3. Pelletier S. W., Wiley-Interscience; New York: 1985: 1
• 1c Buffat MG. P. Tetrahedron 2004; 60: 1701
• 1d Laschat S, Dickner T. Synthesis 2000; 1781
• 1e Felpin F.-X, Lebreton J. Eur. J. Org. Chem. 2003; 3693
• 1f Weintraub PM, Sabol JS, Kane JM, Borcherding DR. Tetrahedron 2003; 59: 2953
• 2a Baker R, Harrison T, Swain CJ, Williams BJ. EP 0528495, 1993
• 2b Harrison T, Williams BJ, Swain CJ, Ball RG. Bioorg. Med. Chem. Lett. 1994; 4: 2545
• 3 Desai MC, Lefkwitz SL, Thadeo PF, Longo KP, Snider RM. J. Med. Chem. 1992; 35: 4911
• 4 McLaughlin NP, Evans P. J. Org. Chem. 2009; 75: 518
• 5 Ferreira F, Greck C, Genet JP. Bull. Soc. Chim. Fr. 1997; 134: 615
• 6 Wijdeven MA, Willemsen J, Rutjes FP. J. T. Eur. J. Org. Chem. 2010; 2831
• 7a Bilke JL, Moore SP, O’Brien P, Gilday J. Org. Lett. 2009; 11: 1935
• 7b Davis FA, Ramachandar T. Tetrahedron Lett. 2008; 49: 870
• 7c Liu R.-H, Fang K, Wang B, Xu M.-H, Lin G.-Q. J. Org. Chem. 2008; 73: 3307
• 7d Emmanuvel L, Sudalai A. Tetrahedron Lett. 2008; 49: 5736
• 7e Cherian SK, Kumar P. Tetrahedron: Asymmetry 2007; 18: 982
• 7f Oshitari T, Mandai T. Synlett 2006; 3395
• 7g Kandula SR. V, Kumar P. Tetrahedron: Asymmetry 2005; 16: 3579
• 7h Yoon Y.-J, Joo J.-E, Lee K.-Y, Kim Y.-H, Oh C.-Y, Ham W.-H. Tetrahedron Lett. 2005; 46: 739
• 7i Huang P.-Q, Liu L.-X, Wei B.-G, Ruan Y.-P. Org. Lett. 2003; 5: 1927
• 7j Bhaskar G, Rao BV. Tetrahedron Lett. 2003; 44: 915
• 7k Takahashi K, Nakano H, Fijita R. Tetrahedron Lett. 2005; 46: 8927
• 7l Liu L.-X, Ruan Y.-P, Guo Z.-Q, Huang P.-Q. J. Org. Chem. 2004; 69: 6001
• 7m Lemire A, Grenon M, Pourashraf M, Charette AB. Org. Lett. 2004; 6: 3517
• 7n Prevost S, Phansavath P, Haddad M. Tetrahedron: Asymmetry 2010; 21: 16
• 7o Kumaraswamy G, Pitchaiah A. Tetrahedron 2011; 67: 2536
• 7p Garrido NM, García M, Sánchez R, Díez D, Urones J. Synlett 2010; 387
• 7q Mizuta S, Onomura O. RSC Adv. 2012; 2: 2266
• 7r Pansare SV, Paul EK. Org. Biomol. Chem. 2012; 10: 2119
• 7s Tsai M.-R, Chen B.-F, Cheng C.-C, Chang N.-C. J. Org. Chem. 2005; 70: 1780
• 8a Chattopadhyay SK, Roy SP, Saha T. Synthesis 2011; 2664
• 8b Lemire A, Charette AB. J. Org. Chem. 2010; 75: 2077
• 8c Chiou WH, Lin GH, Liang CW. J. Org. Chem. 2010; 75: 1748
• 8d Chung HS, Shin WK, Choi SY, Chung YK, Lee E. Tetrahedron Lett. 2010; 51: 707
• 8e Yoshimura Y, Ohara C, Miyagawa T, Takahata H. Heterocycles 2009; 77: 635
• 8f Wang B, Run-Hua L. Eur. J. Org. Chem. 2009; 2845
• 8g Kumar PS, Baskaran S. Tetrahedron Lett. 2009; 50: 3489
• 8h Cochi A, Burger B, Navarro C, Pardo DG, Cossy J, Zhao Y, Cohen T. Synlett 2009; 2157
• 8i Yoshimura Y, Ohara C, Imahori T, Saito Y, Kato A, Miyauchi S, Adachi I, Takahata H. Bioorg. Med. Chem. 2008; 16: 8273
• 8j Pham V.-T, Joo J.-E, Tian Y.-S, Chung Y.-S, Lee K.-Y, Oh C.-Y, Ham W.-H. Tetrahedron: Asymmetry 2008; 19: 318
• 8k Ohara C, Takahashi R, Miyagawa T, Yoshimura Y, Kato A, Adachi I, Takahata H. Bioorg. Med. Chem. Lett. 2008; 18: 1810
• 8l Liu L.-X, Peng Q.-L, Huang P.-Q. Tetrahedron: Asymmetry 2008; 19: 1200
• 8m Alegret C, Ginesta X, Riera A. Eur. J. Org. Chem. 2008; 1789
• 8n Chavan SP, Harale KR, Dumare NB, Kalkote UR. Tetrahedron: Asymmetry 2011; 22: 587
• 8o Chavan SP, Dumare NB, Harale KR, Kalkote UR. Tetrahedron Lett. 2011; 52: 404
• 8p Chavan SP, Harale K, Pawar KP. Tetrahedron Lett. 2013; 54: 4851
• 8q Jourdant A, Zhu J. Tetrahedron Lett. 2000; 41: 7033
• 8r Kumar P, Bodas MS. J. Org. Chem. 2005; 70: 360
• 8s Kalamkar NB, Kasture VM, Dhavale DD. J. Org. Chem. 2008; 73: 3619
• 8t Kokatla HP, Lahiri R, Kancharla PK, Doddi VR, Vankar YD. J. Org. Chem. 2010; 75: 4608
• 8u Liang N, Datta A. J. Org. Chem. 2005; 70: 10182
• 8v Kim IS, Oh JS, Zee OP, Jung YH. Tetrahedron 2007; 63: 2622
• 8w Bodas MS, Kumar P. Tetrahedron Lett. 2004; 45: 8461
• 9a Reddy RS, Chouthaiwale PV, Suryavanshi G, Chavan VB, Sudalai A. Chem. Commun. 2010; 46: 5012
• 9b Tokunaga M, Larrow JF, Kakiuchi F, Jacobsen EN. Science 1997; 277: 936
• 9c Devalankar DA, Sudalai A. Tetrahedron Lett. 2012; 53: 3213
• 10a Nunez MT, Martin VS. J. Org. Chem. 1990; 55: 1928
• 10b Carlsen PH. J, Katsuki T, Martin VS, Sharpless KB. J. Org. Chem. 1981; 46: 3936
• 11 Hydrolytic Kinetic Resolution of Azido Epoxide 6 AcOH (0.014 g, 0.24 mmol) was added to a solution of (S,S)-(salen)Co(II) complex (0.024 mmol, 0.5 mol%) in toluene (1 mL), and the mixture was stirred at 25 °C in open air for 30 min. During this time the color changed from orange–red to a dark brown. The solution was then concentrated under reduced pressure to give the Co(III)–salen complex as a brown solid. To this were added the racemic azido epoxide 6 (0.84 g, 4.85 mmol) and H₂O (0.043 g, 2.42 mmol) at 0 °C, and the resulting mixture was stirred at 0 °C for 14 h. When the reaction was complete (TLC), the crude product was purified by column chromatography [silica gel, PE–EtOAc] to give chiral azido epoxide 7 (9:1 PE–EtOAc) and the chiral azido diol 8 (1:1 PE–EtOAc) in pure form. (2R,3S)-3-Azido-3-phenylpropane-1,2-diol (8) Yellow liquid; yield: 450 mg (48%, 98% ee); [α]_D ²⁵ +188 (c 1, CHCl₃) (lit.9a –188 for the antipode). IR (CHCl₃): 1602, 2099, 2932, 3052, 3392 (br) cm^–1. ¹H NMR (200 MHz, CDCl₃): δ = 3.30 (dd, J = 11.5, 6.0 Hz, 1 H), 3.44 (d, J = 11.5 Hz, 1 H), 3.80 (br s, 1 H), 3.62–3.94 (m, 1 H), 4.52 (d, J = 8.1, 1 H), 7.28–7.35 (m, 5 H). ¹³C NMR (50 MHz, CDCl₃): δ = 2.8, 68.1, 75.0, 127.5, 128.7, 128.9, 136.2. Anal. Calcd for C₉H₁₁N₃O₂: C, 55.95; H, 5.74; N, 21.75. Found: C, 56.10; H, 5.65; N, 21.60; HPLC: Chiral OD-H column, hexane–i-PrOH (90:10, 0.5 mL/min), 254 nm; t _R(major) = 14.84 min, t _R(minor) = 15.57 min. (2S)-2-[(R)-Azido(phenyl)methyl]oxirane (7) Yellow liquid; yield: 400 mg (47%); [α]_D ²⁵ –120 (c 1, CHCl₃) (lit.^9a +120 for the antipode). IR (CHCl₃): 2105, 2932, 3025 cm^–1. ¹H NMR (200 MHz, CDCl₃): δ = 2.73–2.84 (m, 2 H), 3.23–3.29 (m, 1 H), 4.25 (d, J = 6.1, 1 H), 7.35–7.47 (m, 5 H). ¹³C NMR (50 MHz, CDCl₃): δ = 44.6, 54.6, 66.8, 127.2, 128.8, 128.9, 135.7. Anal. Calcd for C₉H₉N₃O: C, 61.70; H, 5.18; N, 23.99. Found: C, 61.79; H, 5.14; N, 23.90.
• 12 (2S,3S)-3-{[3,5-Bis(trifluoromethyl)benzyl]oxy}-2-phenylpiperidine [1; (+)-L-733,060] Colorless oil; yield: 110 mg (89%), [α]_D ²⁵ +35.2 (c 0.66, CHCl₃) {lit.^7j +34.29 (c 1.32, CHCl₃)}. IR (neat): 1277, 1370, 2950 cm^–1. ¹H NMR (CDCl₃, 200 MHz): δ = 1.40–2.04 (m, 3 H), 2.22 (br d, J = 13 Hz, 1 H), 2.60 (s, 1 H), 2.76–2.81 (m, 1 H), 3.23–3.38 (m, 1 H), 3.66 (s, 1 H), 3.84 (s, 1 H), 4.12 (d, J = 12.0 Hz, 1 H), 4.54 (d, J = 12.2 Hz, 1 H), 7.20–7.50 (m, 7 H), 7.78 (s, 1 H). ¹³C NMR (CDCl₃, 50 MHz): 20.6, 27.5, 47.1, 64.0, 70.5, 77.2, 120.9, 124.1, 127.7, 128.5, 128.7, 128.9, 131.2, 141.6, 142.3. Anal. Calcd for C₂₀H₁₉F₆NO: C, 59.55; H, 4.75; N, 3.47. Found: C, 59.52; H, 4.81; N, 3.56. (2S,3S)-3-Hydroxypiperidine-2-carboxylic Acid [3; (2S,3S)-3-Hydroxypipecolic Acid] Colorless solid; yield: 20 mg (68%); mp 232 °C; [α]_D ²⁵ +14.2 (c 1, H₂O) {lit.^8f [α]_D ²³ +14.5 (c 0.4, H₂O)}. IR (neat): 1685, 3420 cm^–1. ¹H NMR (200 MHz, D₂O): δ = 1.62–1.80 (m, 2 H), 2.00–2.08 (m, 2 H), 3.10 (s, 1 H), 3.32–3.39 (m, 1 H), 3.80 (d, J = 7.6 Hz, 1 H), 4.10–4.17 (m, 1 H). ¹³C NMR (50 MHz, D₂O): δ = 20.0, 30.1, 43.9, 62.5, 65.9, 171.3. Anal. Calcd for C₆H₁₁NO₃: C, 49.65; H, 7.64; N, 9.65. Found: C, 49.60; H, 7.69; N, 9.70.