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.

 

MissingLinkText

Key words

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

Chiral 2,3-disubstituted piperidine moieties with a β-hydroxy functional groups are found in numerous natural products and are common subunits in drugs and drug candidates.[1] Selected examples include (+)-L-733,060 (1)[2] and (+)-CP-99,994 (2),[3] both potent and selective nerokinin-1 substance P receptor antagonists; febrifugine (4),[4] an antimalarial agent; (-)-swainsonine (5),[5] an inhibitor of lysosomal α-mannosidase and a potent anticancer drug; and (2S,3S)-3-hydroxypipecolic acid [3; (2S,3S)-3-hydroxypiperidine-2-carboxylic acid],[6] a key precursor in the syntheses of 4 and 5 (Figure [1]).

Figure 1 Biologically active 2,3-disubstituted piperidines

Because of the biomedical importance of the products, the synthesis of these β-hydroxy piperidines has attracted much attention in recent years; however, many of the synthetic approaches employ starting materials from the chiral pool and involve enzymatic resolution as a key reaction.[7] [8]

Scheme 1 Reagents and conditions: (a) (S,S)-(salen)Co(III)OAc (0.5 mol%), H₂O (0.49 equiv), 0 °C, 14 h; (b) TBSCl (2 equiv), imidazole, CH₂Cl₂, 25 °C, 12 h; yield 98%. (c) CSA, MeOH, 0 ^○C, 6 h, yield 95%; (d) Dess–Martin periodinane, CH₂Cl₂, 25 °C, 1 h, yield 98%; (e) (EtO)₂POCH₂CO₂Et, NaH, THF, 0 to 25 °C, 3 h, yield 94%; (f) 10% Pd/C, H₂ (1 atm), MeOH, 25 °C, 12 h, then EtOH, reflux, 1 h, yield 85%; (g) TBAF, THF, 0–25 °C, 2 h, yield 96%; (h) (i) BH₃·SMe₂, THF, reflux, 10 h; (ii) (Boc)₂O, Et₃N, DMAP (cat.), CH₂Cl₂, 0 to 25 °C, 12 h, yield 76% (two steps); (i) 3,5-bis(trifluoromethyl)benzyl bromide, NaH, DMF, 80 °C, 12 h, yield 85%; (j) TFA, CH₂Cl₂, 0 to 25 °C, 18 h, yield 89%.

We recently reported a flexible method that involves a ­cobalt-catalyzed hydrolytic kinetic resolution (HKR) of racemic azido epoxides with two contiguous stereocenters to generate the corresponding diols and epoxides in high optical purities (97–99% ee) in a single step.[9a] Here, we report a short enantioselective synthesis of two important bioactive molecules, (+)-L-733,060 (1) and (2S,3S)-3-hydroxypipecolic acid (3), based on a two-stereocenter HKR of racemic azido epoxides.

The synthesis of (+)-L-733,060 (1; Scheme [1]) commenced with the racemic azido epoxide 6, prepared from commercially available cinnamyl alcohol by our previously reported procedure.[9a] The racemic azido epoxide 6 was subjected to HKR with (S,S)-salen–cobalt(III) acetate complex[9b] (0.5 mol%) and water (0.49 equiv), which gave the corresponding diol 8 (48%, 98% ee) and chiral epoxide 7 (47%) in high optical purity. The diol 8 was readily separated from epoxide 7 by simple flash column chromatography on silica gel.

Both free hydroxy groups in diol 8 were protected to give the disilyl ether derivative 9, which was then selectively deprotected to give the monosilyl ether 10 in 95% yield. Dess–Martin oxidation of 10 gave the crude aldehyde 11 in 98% yield; this underwent a Wittig–Horner reaction to give the corresponding (E)-azido ester 12 in 94% yield. Intramolecular reductive cyclization of 12 by hydrogenation over 10% palladium/carbon gave the cis-2,3-disubstituted piperidinone 13 in 85% yield. Deprotection of the silyl group in 13 with tetrabutylammonium fluoride gave the lactam 14. Reduction of lactam 14 with borane–dimethyl sulfide in tetrahydrofuran, followed by protection of the secondary amine gave the syn-amino alcohol 15 in 76% yield for the two steps. Having constructed the ­piperidine core with the desired syn stereochemistry, we O-alkylated amino alcohol 15 with 3,5-bis(trifluoromethyl)benzyl bromide in the presence of sodium hydride to give the protected amine 16. Finally, deprotection under acidic conditions gave L-733,060 (1) in 89% yield (overall yield 19% from 6 in ten steps).

The synthesis of (2S,3S)-3-hydroxypipecolic acid (3; Scheme [2]) commenced from (2Z)-but-2-ene-1,4-diol, which was converted into the azido aldehyde 17 by HKR, as we previously reported.[9c] The key intermediate 20 (Scheme [2]) was readily synthesized from 17, essentially by following a similar sequence of reactions to that shown in Scheme [1]. Wittig olefination and intramolecular reductive cyclization gave the trans-2,3-disubstituted piperidinone core 19 in 90% yield with an intact benzyloxy group. Reduction of piperidinones 19 with borane–dimethyl sulfide followed by protection in situ gave trans-piperidine derivative 20 in 80% yield. Hydrogenation of 20 over palladium/carbon in methanol at 70 psi gave the corresponding alcohol 21 in 96% yield. Finally, oxidation of alcohol 21 with ruthenium(II) chloride and sodium periodate,[8f] [10] followed by removal of both protecting groups under acidic condition (6 M aq HCl), completed the synthesis of (2S,3S)-3-hydroxypipecolic acid (3; overall yield 43% from 17 in six steps). The ¹H and ¹³C NMR and other spectra of (+)-L-733,060 (1) and (2S,3S)-3-hydroxypipecolic acid (3) were in complete agreement with the values reported in the literature.[7d] [7e] [8f] [o]

Scheme 2 Reagents and conditions: (a) (EtO)₂POCH₂CO₂Et, NaH, THF, 0–25 °C, 1 h, yield 93%; (b) 10% Pd/C, H₂ (1 atm), MeOH, 25 °C, 24 h, yield 90%; (c) BH₃·SMe₂, THF, reflux, 6 h, then Na₂CO₃, (Boc)₂O, CH₂Cl₂/H₂O (1:1), 25 °C, 12 h, yield 80%; (d) 10% Pd/C, H₂ (70 psi), MeOH, 25 °C, 24 h, yield 96%; (e) (i) RuCl₃ (2 mol%), NaIO₄ (4 equiv), MeCN/CCl₄/H₂O (1:1:3), 25 °C, 30 min; (ii) 6 M aq HCl, reflux, 2 h, yield 68% (two steps).

In summary, we have developed short and practical enantioselective syntheses of (+)-L-733,060 (1) and (2S,3S)-3-hydroxypipecolic acid (3) with good overall yields and high optical purities (ee ≤99%). The key reaction in each case was a cobalt-catalyzed HKR of a racemic azido epoxide with two stereocenters. The other operationally simple reaction sequences included a Wittig reaction and an intramolecular reductive cyclization. The synthetic strategy has significant potential for further extension to other stereoisomers and related analogues of multifunctional ­piperidine alkaloids, owing to the flexibility available in syntheses of racemic azido epoxides with various stereochemical combinations and various substituents.

 

MissingLinkText

Acknowledgment

D.A.D. and P.V.C. thank CSIR, New Delhi for the award of research fellowships. The authors are also grateful to Dr. V. V. Ranade, chair of the Chemical Engineering and Process Development Division, for his constant encouragement and support.

• 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.