Synlett, Table of Contents Synlett 2020; 31(04): 355-358DOI: 10.1055/s-0039-1690771 letter © Georg Thieme Verlag Stuttgart · New York A New Synthesis of l-Hydroxypipecolic Acid Zedong Zhang , Zhihua Sun∗ College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620, P. R. of China Email: sungaris@gmail.com Email: zhihuasun@sues.edu.cn › Author Affiliations Recommend Article Abstract Buy Article All articles of this category Abstract A new synthetic approach toward l-hydroxypipecolic acid is described. This reaction sequence involves eight steps overall, starting from commercially available and inexpensive l-glyceraldehyde acetal. The strategy makes use of readily available reagents and can be used as a preparative synthesis of l-hydroxypipecolic acid. Most of the reaction steps proceed with moderate-to-good yields and do not require any unusual or expensive reagents. Key words Key words l-hydroxypipecolic acid - chiral piperidines - l-glyceraldehyde acetal - preparative synthesis - six-membered heterocycle Full Text References References and Notes 1 Watson PS, Jiang B, Scott B. Org. Lett. 2000; 2: 3679 2 Hong H, James G, Lu J, Zhang N, Yu W, Liu F, Li Y, Huang X, Gao J, Zhang K, Ma Y, Wei J. WO2018082030A1, 2018 . 3 Seki M. JP201540200A, 2015 4 Takehara J, Murai M, Ohtnai T, Maeda T, Hidaka T. WO2015099126A1, 2015 5 Brown JM, Leppard SJ, Oakes J, Thornthwaite D. Chirality 2000; 12: 496 6 Babu KC, Reddy RN, Rao SY, Venkateshwarlu P, Madhusudhan G. Synth. Commun. 2012; 42: 2624 7 Chandra Babu K, Buchi Reddy R, Naresh E, Ram Mohan K, Madhusudhan G, Mukkanti K. J. Chem. 2013; DOI: Article ID 475032 8 Chandra Babu K, Vysabhattar R, Srinivas KS. V, Nigam S, Madhusudhan G, Mukkanti K. Tetrahedron: Asymmetry 2010; 21: 2619 9 Lakshmi Kantam M, Mahendar K, Sreedhar B, Choudary BM. 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Heterocycles 2008; 76: 569 17 Characterization data for new compounds (R)-N-{(E)-3-[(R)-2,2-Dimethyl-1,3-dioxolan-4-yl]propylidene}-2-methylpropane-2-sulfinamide (3) Sulfinamide 3 (62 g, 98%) was isolated as an orange oil; [α]D 25 –24.7 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.08 (t, J = 4.1 Hz, 1 H), 4.20–4.08 (m, 1 H), 4.06–4.03 (m, 1 H), 3.56–3.47 (m, 1 H), 2.71–2.51 (m, 2 H), 1.93–1.80 (m, 2 H), 1.38 (d, J = 3.9 Hz, 3 H), 1.31 (d, J = 4.0 Hz, 3 H), 1.17 (d, J = 4.1 Hz, 9 H). 13C NMR (101 MHz, CDCl3): δ = 168.6, 109.0, 75.0, 69.1, 56.6, 32.3, 29.1, 26.9, 25.6, 22.3. HRMS (ESI): m/z [M + H]+ calcd for C12H24NO3S+: 262.1471; found: 262.1470. (R)-N-{(R)-1-Cyano-3-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]propyl}-2-methylpropane-2-sulfinamide (4) The obtained crude product was purified by recrystallization from EtOAc to yield 4 (51.3 g, 99%) as a white solid; [α]D 25 +31.4 (c 1.0, CHCl3); mp 97.3–97.6 °C; dr = 83%. HPLC [YMC-Pack ODS-A column (5 mm particle size, 4.6 mm × 150 mm), H2O/MeOH = 10:90, 1 mL/min, 210 nm, 25 °C]: t R1 = 8.944 min, t R2 = 9.390 min. 1H NMR (400 MHz, CDCl3): δ = 4.35 (dd, J = 14.2, 7.4 Hz, 1 H), 4.19 (d, J = 7.8 Hz, 1 H), 4.12–4.08 (m, 2 H), 3.58 (q, J = 6.4 Hz, 1 H), 2.08–2.04 (m, 2 H), 1.85–1.81 (m, 2 H), 1.44 (s, 3 H), 1.37 (s, 3 H), 1.26 (s, 9 H). 13C NMR (101 MHz, CDCl3): δ = 119.0, 110.7, 75.2, 70.5, 57.0, 45.8, 31.8, 29.3, 26.7, 25.6, 22.5. HRMS (ESI): m/z [M + H]+ calcd for C13H25N2O3S+: 289.1580; found: 289.1582. (R)-N-[(1R,4R)-1-Cyano-4,5-dihydroxypentyl]-2-methylpropane-2-sulfinamide (5) The obtained crude product was purified by silica gel column chromatography (CH2Cl2/MeOH = 4:1) to yield 5 (34.4 g, 78%) as a white solid; [α]D 25 –24.5 (c 1.0, CHCl3); mp 84.8–88.6 °C. 1H NMR (400 MHz, CDCl3): δ = 5.14 (d, J = 8.0 Hz, 1 H), 4.37–4.27 (m, 1 H), 4.04 (s, 1 H), 3.82–3.62 (m, 3 H), 3.53 (dd, J = 10.6, 6.9 Hz, 1 H), 2.09 (dd, J = 14.5, 7.1 Hz, 2 H), 1.71 (dd, J = 14.1, 6.7 Hz, 2 H), 1.26 (s, 9 H). 13C NMR (101 MHz, CDCl3): δ = 119.8, 71.6, 66.2, 57.5, 46.1, 31.3, 28.7, 22.7. HRMS (ESI): m/z [M + H]+ calcd for C10H20N2O3S+: 249.1267; found: 249.1266. (R)-N-{(R)-1-Cyano-3-[(R)-oxiran-2-yl]propyl}-2-methylpropane-2-sulfinamide (6) The obtained crude product was purified by silica gel column chromatography (PE/EtOAc = 1:1) to yield 6 (26.8 g, 84% yield) as an orange oil; [α]D 25 +27.9 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 4.39 (d, J = 8.0 Hz, 1 H), 4.34–4.25 (m, 1 H), 2.97 (d, J = 3.6 Hz, 1 H), 2.82 (t, J = 4.0 Hz, 1 H), 2.57 (s, 1 H), 2.19–2.06 (m, 2 H), 2.03 (d, J = 10.8 Hz, 1 H), 1.62 (dd, J = 14.2, 7.1 Hz, 1 H), 1.25 (s, 9 H). 13C NMR (101 MHz, CDCl3): δ = 119.0, 57.2, 51.3, 47.2, 46.1, 31.5, 28.0, 22.5. HRMS (ESI): m/z [M + H]+ calcd for C10H18N2O2S+: 231.1162; found 231.1161. (2S,5S)-1-[(R)-tert-Butylsulfinyl]-5-hydroxypiperidine-2-carbonitrile (7) The obtained crude product was purified by silica gel column chromatography (PE/EtOAc = 1:1) to yield 7 (3.45 g, 67%) as an orange oil; [α]D 25 +34.3 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 4.39 (d, J = 6.2 Hz, 1 H), 4.03 (d, J =5.5 Hz, 1 H), 3.03 (s, 1 H), 2.84 (s, 1 H), 2.62 (s, 1 H), 2.13 (s, 3 H), 1.77 (s 1 H), 1.27 (s, 9 H). 13C NMR (101 MHz, CDCl3): δ = 118.6, 56.9, 51.19, 47.7, 47.0, 31.4, 28.1, 22.4. HRMS (ESI): m/z [M + H]+ calcd for C10H18N2O2S+: 231.1162; found: 231.1161 Supplementary Material Supplementary Material Supporting Information
