An efficient access to conformationally rigid amino acid analogues with a piperidine skeleton

Synlett

Volumn , Issue 10, 2010, Pages 1501-1504

  Purkayastha, Nirupam ^a   Haufe, Günter ^a  

^a UNIVERSITY OF MÜNSTER   (Germany)

Author keywords

Constrained amino acids; Pipecolic acid; Piperidine; Reductive amination; Stereoselectivity

Indexed keywords

4 AMINO 6 TERT BUTYL N METHYLPIPERIDINE 2 CARBOXAMIDE; AMINO ACID DERIVATIVE; ISOBUTYL 4 (2 AMINOETHYL) 6 TERT BUTYL 2 (METHYLCARBAMOYL)PIPERIDINE 1 CARBOXYLIC ACID; ISOBUTYL 6 TERT BUTYL 4 (CYANOMETHYL) 2 (METHYLCARBAMOYL)PIPERIDINE 1 CARBOXYLIC ACID; ISOBUTYL 6 TERT BUTYL 4 (CYANOMETHYLENE) 2 (METHYLCARBAMOYL)PIPERIDINE 1 CARBOXYLIC ACID; PIPECOLIC ACID DERIVATIVE; PIPERIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; DRUG STRUCTURE; ENANTIOMER; HETERONUCLEAR MULTIPLE BOND CORRELATION; HETERONUCLEAR SINGLE QUANTUM COHERENCE; HORNER WADSWORTH EMMONS REACTION; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; NUCLEAR OVERHAUSER EFFECT; PROTEIN CONFORMATION; STEREOCHEMISTRY; SYNTHESIS;

EID: 77953254848     PISSN: 09365214     EISSN: 14372096     Source Type: Journal    
DOI: 10.1055/s-0029-1219948     Document Type: Article

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36. (2S,4R,6R)-4-Amino-6-tert-butyl-N-methylpiperidine-2- carboxamide (4) NH4OAc (3.27 g, 42.4 mmol) and NaBH3CN (266 mg, 4.24 mmol) were added to a solution of ketone 2 (50 mg, 0.24 mmol) in anhyd MeOH (6 mL) in the presence of MS 4 . The resulting mixture was stirred at r.t. for 30 h. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography on basic alumina with CH2Cl2 to give the corresponding amine 4 as orange oil with the contamination of 4% 4S-epimer (epi-4). Yield 36 mg (72%); [a]D 20 29.0 (c 1.0, CH2Cl2). 1H NMR (600 MHz, CDCl3): d = 0.92 (s, 9 H), 1.651.75 (m, 1 H), 1.791.90 (m, 1 H), 2.422.44 (m, 1 H), 2.532.56 (m, 1 H), 2.752.83 (m, 5 H), 3.433.47 (m, 1 H), 6.64 (br s, 1 H). 13C NMR (150 MHz, CDCl3): d = 26.1, 26.5, 33.4, 41.9, 44.0, 44.2, 57.8, 61.6, 172.7. ESI-MS: m/z calcd for C11H23N3O: 214.1919 [M + H]+, 236.1738 [M + Na]+; found: 214.1901 [M + H]+, 236.1721 [M + Na]+. MS (EI): m/z (%) = 144 (60), 100 (40), 80 (100).
37. (2S,6R)-Isobutyl-6-tert-butyl-4-(cyanomethylene)-2- (methylcarbamoyl) piperidine-1-carboxylate (7) To a solution of LDA (3.4 mL, 6.12 mmol) in anhyd THF (10 mL) at r.t. under argon was added a solution of diethyl cyanomethylphosphonate (0.8 mL, 5.1 mmol), and the mixture was stirred for 10 min. A solution of compound 6 (532 mg, 1.7 mmol) in anhyd THF (20 mL) was added, and the resulting mixture was stirred at r.t. until conversion was complete (ca. 60 min, as monitored by TLC). The reaction was quenched with H2O (30 mL) and extracted with CH2Cl2 (3 15 mL). The combined organic extracts were dried with anhyd Na2SO4, filtered, evaporated under reduced pressure and subsequently purified by chromatography on silica gel (cyclohexaneEtOAc, 1:1) to give compound 7 as an inseperable mixture of E/Z (1:1) isomers (determined by crude 1H NMR). Yield 548 mg (96%); [a]D 20 31.0 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): d = 0.800.94 (m, 15 H), 1.701.73 (m, 1 H), 1.842.07 (m, 4 H), 2.612.77 (m, 2 H), 2.77 (s, 3 H), 3.853.92 (m, 2 H), 4.194.29 (m, 1 H), 4.89 (br s, 1 H), 4.90 (br s, 1 H, olefinic proton for the other isomer). 13C NMR (75 MHz, CDCl3): d = 19.2, 26.4, 27.1, 28, 37.8, 41.1, 56.0, 57.5, 60.5, 73.0, 115.3, 125.0, 158.0, 162.2, 171.7. ESI-MS: m/z calcd for C18H29N3O3: 336.2287 [M + H]+, 358.2106 [M + Na]+; found: 336.2271 [M + H]+, 358.2092 [M + Na]+.
38. (2S,4R,6R)-Isobutyl-6-tert-butyl-4-(cyanomethyl)-2- (methylcarbamoyl) piperidine-1-carboxylate (8) A 1.0 M solution of L-Selectride in THF (3.76 mL, 3.76 mmol) was added dropwise to a 1:1 E/Z mixture of compound 7 (315 mg, 0.94 mmol) dissolved in anhyd THF (20 mL) at 78 C under argon, and the mixture was stirred for 20 h at 78 C. The reaction mixture was warmed up to 0 C, and then sat. aq NH4Cl (30 mL) was added carefully with stirring at 0 C. After extraction with EtOAc (3 15 mL), the combined organic layers were dried with anhyd Na2SO4, filtered, and the solvents evaporated in vacuo followed by purification of the residue by silica gel column chromatography (cyclohexaneEtOAc, 70:30) to afford 8 (exclusively one diastereomer from 1H NMR) as yellow oil. Yield 211 mg (67%); [a]D 20 43.0 (c 1.0, CHCl3). 1H NMR (600 MHz, CDCl3): d = 0.85 (s, 9 H), 0.93 (d, 3JH,H = 6.7 Hz, 6 H), 1.191.24 (m, 1 H), 1.351.41 (m, 1 H), 1.911.98 (m, 1 H), 2.182.25 (m, 2 H), 2.372.40 (m, 1 H), 2.55 (br s, 1 H), 2.73 (d, 3JH,H = 6.0 Hz, 3 H), 3.783.80 (m, 1 H), 3.93 3.95 (m, 1 H), 4.134.15 (m, 1 H), 4.804.83 (m, 1 H), 6.86 (br s, 1 H). 13C NMR (151 MHz, CDCl3): d = 19.4, 24.8, 25.1, 25.8, 26.6, 28.3, 29.7, 30.1, 37.2, 52.6, 57.9, 72.9, 118.0, 159.8, 172.9. ESI-MS: m/z calcd for C18H31N3O3: 338.2443 [M + H]+, 360.2263 [M + Na]+; found: 338.2442 [M + H]+, 360.2265 [M + Na]+.
39. (2S,4R,6R)-Isobutyl-4-(2-aminoethyl)-6-tert-butyl-2- (methylcarbamoyl) piperidine-1-carboxylate (5) A solution of 8 (50 mg, 0.15 mmol) in anhyd THF (2 mL) was added to a suspension of LiAlH4 (5 mg, 0.15 mmol, 1 equiv) in anhyd THF (3 mL) at 0 C. The reaction was stirred for 1 h at r.t. and then quenched with aq 2 M HCl (2 mL) at 0 C. The compound was extracted with EtOAc (3 5 mL). The combined organic layers were washed with sat. aq NaHCO3 (5 mL), brine (5 mL), dried over Na2SO4, and evaporated. Purification of the residue was done by silica gel column chromatography (cyclohexaneEtOAc, 70:30) to afford 5 as colorless oil. Yield 41 mg (82%); [a]D 20 28.0 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): d = 0.84 (s, 9 H), 0.910.95 (m, 8 H), 1.131.27 (m, 3 H), 1.751.98 (m, 3 H), 2.222.33 (m, 2 H), 2.722.81 (m, 5 H), 3.793.98 (m, 3 H), 4.754.77 (m, 1 H), 6.88 (br s, 1 H). 13C NMR (75 MHz, CDCl3): d = 19.5, 26.0, 28.0, 28.4, 28.6, 30.6, 31.2, 37.2, 39.2, 41.0, 50.3, 53.3, 72.7, 159.7, 173.5. ESI-MS: m/z calcd for C18H35N3O3: 342.2756 [M + H]+; found: 342.2758 [M + H]+.