CLC number: TQ463
On-line Access: 2024-08-27
Received: 2023-10-17
Revision Accepted: 2024-05-08
Crosschecked: 2016-01-25
Cited: 0
Clicked: 3964
Xiao-zhong Wang, Xia Wang, Ying-qi Chen, Li-yan Dai, Xing-cong Li. Asymmetric synthesis of N-protected 3-methylpiperidin-2-one and its diastereoisomer[J]. Journal of Zhejiang University Science A, 2016, 17(2): 163-170.
@article{title="Asymmetric synthesis of N-protected 3-methylpiperidin-2-one and its diastereoisomer",
author="Xiao-zhong Wang, Xia Wang, Ying-qi Chen, Li-yan Dai, Xing-cong Li",
journal="Journal of Zhejiang University Science A",
volume="17",
number="2",
pages="163-170",
year="2016",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.A1500008"
}
%0 Journal Article
%T Asymmetric synthesis of N-protected 3-methylpiperidin-2-one and its diastereoisomer
%A Xiao-zhong Wang
%A Xia Wang
%A Ying-qi Chen
%A Li-yan Dai
%A Xing-cong Li
%J Journal of Zhejiang University SCIENCE A
%V 17
%N 2
%P 163-170
%@ 1673-565X
%D 2016
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.A1500008
TY - JOUR
T1 - Asymmetric synthesis of N-protected 3-methylpiperidin-2-one and its diastereoisomer
A1 - Xiao-zhong Wang
A1 - Xia Wang
A1 - Ying-qi Chen
A1 - Li-yan Dai
A1 - Xing-cong Li
J0 - Journal of Zhejiang University Science A
VL - 17
IS - 2
SP - 163
EP - 170
%@ 1673-565X
Y1 - 2016
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.A1500008
Abstract: This paper reports the asymmetric synthesis of an important pharmaceutical intermediate (3S)-1-[(1R)-2-hydroxy-1-phenylethyl]-3-methylpiperidin-2-one (compound 1) from commercially available d-plenylglycinol and delta-valerolactone. During the alkylation process, the hydroxyl group can be protected or unprotected, resulting in a different consumption of s-BuLi, and leading to a different diastereomeric excess (de) of compound 1. When 1-[(1R)-2-hydroxy-1-phenylethyl]-piperidin-2-one (compound 2) was alkylated with 2.5 eq. of s-BuLi, compound 1 was obtained as a single isomer detected by chiral high performance liquid chromatography (HPLC) columns with an overall yield of 91%. With the hydroxyl group protected, (R)-1-(2-[(tert-butyldimethylsil) oxy]-1-phenylethyl) piperidine-2-one (compound 6) could be alkylated with 1.5 eq. of s-BuLi, giving compound 1 and its diastereoisomer 8 in a ratio of 1:2.5 and a yield of methylation of 90%. Compounds 1 and 8 could be separated completely and easily by flash chromatography. The absolute configuration of compound 8 was determined by single-crystal X-ray analysis. The mechanism of the alkylation process is discussed based on experimental results.
This article describes the use of a chiral auxiliary for the asymmetric synthesis of 3-methylpiperidin-2-one. Key the success of this approach is the discovery of a highly diastereoselective alkylation of lithium elongate dianions of N-hydroxy phenethyl substituted piperidin-2-one.
[1]Amat, M., Llor, N., Hidalgo, J., et al., 2003. Enantioselective synthesis of piperidine, indolizidine, and quinolizidine alkaloids from a phenylglycinol-derived δ-lactam. The Journal of Organic Chemistry, 68(5):1919-1928.
[2]Amat, M., Escolano, C., Llor, N., et al., 2005. Alkylation of phenylglycinol-derived bicyclic lactams. Enantioselective synthesis of 3-alkylpiperidines. Archive for Organic Chemistry, 2005(9):115-123.
[3]Bailey, P.D., Millwood, P.A., Smith, P.D., 1998. Asymmetric routes to substituted piperidines. Chemical Communications, (6):633-640.
[4]Baussanne, I., Travers, C., Royer, J., 1998. Asymmetric synthesis of 3-substituted pyrrolidones via [alpha]-alkylation of a chiral non-racemic [gamma]-lactam. Tetrahedron: Asymmetry, 9(5):797-804.
[5]Bensa, D., Coldham, I., Feinäugle, P., et al., 2008. Synthesis of carboxylic amides by ring-opening of oxazolidinones with Grignard reagents. Organic & Biomolecular Chemistry, 6(8):1410-1415.
[6]Burgess, L.E., Meyers, A., 1992. A simple asymmetric synthesis of 2-substituted pyrrolidines and 5-substituted pyrrolidinones. The Journal of Organic Chemistry, 57(6):1656-1662.
[7]Castro, C.A., Juárez, P.J., Gnecco, D., et al., 2005. Efficient preparation of (1′R)-(−)-1-(2′-hydroxy-1′-phenylethyl) piperidin-2-one: synthesis of (2′S,3R)-(+)-stenusine. Tetrahedron: Asymmetry, 16(5):949-952.
[8]Cohen, F., Patel, S., 2014. Preparation of C-linked Heterocycloalkyl Substituted Pyrimidines as Inhibitors of DLK Useful for Treating Neurodegeneration Diseases and Disorders. WO Patent 2014177524.
[9]Hartmann, R.W., Reichert, M., Göhring, S., 1994. Novel 5-alpha-reductase inhibitors-synthesis and structure-activity studies of 5-substituted 1-methyl-2-pyridones and 1-methyl-2-piperidones. European Journal of Medicinal Chemistry, 29(11):807-817.
[10]Isobe, T., Fukuda, K., Ishikawa, T., 2000. Modified guanidines as potential chiral superbases. 3. Preparation of 1,4,6-triazabicyclooctene systems and 1,4-disubstituted 2-iminoimidazolidines by the 2-chloro-1,3-dimethylimidazolinium chloride-induced cyclization of guanidines with a hydroxyethyl substituent. The Journal of Organic Chemistry, 65(23):7779-7785.
[11]Jadav, P., Bahekar, R., Shah, S.R., et al., 2014. Design, synthesis and biological evaluation of novel aminomethyl-piperidones based DPP-IV inhibitors. Bioorganic & Medicinal Chemistry Letters, 24(8):1918-1922.
[12]Kosugi, T., Mitchell, D.R., Fujino, A., et al., 2012. Mitogen-activated protein kinase-activated protein kinase 2 (mapkap-k2) as an antiinflammatory target: discovery and in vivo activity of selective pyrazolo[1,5-a]pyrimidine inhibitors using a focused library and structure-based optimization approach. Journal of Medicinal Chemistry, 55(15):6700-6715.
[13]Laube, T., Dunitz, J.D., Seebach, D., 1985. On the interaction between lithium enolates and secondary-amines in solution and in the crystal. Helvetica Chimica Acta, 68(5):1373-1393.
[14]Meyers, A.I., Brengel, G.P., 1997. Chiral bicyclic lactams: useful precursors and templates for asymmetric syntheses1. Chemical Communications, 1997(1):1-8.
[15]Micouin, L., Varea, T., Quirion, J.C., et al., 1994. Asymmetric synthesis, XXX, synthesis of 3-substituted piperidines from chiral non-racemic lactams. Tetrahedron Letters, 35(16):2529-2532.
[16]Old, D.W., Dinh, D.T., Kedzie, K.M., et al., 2005. Treatment of Inflammatory Bowel Disease with Prostaglandin Piperidine Analogs. US Patent 20050171062.
[17]Pati, H.N., Das, U., Das, S., et al., 2009. The cytotoxic properties and preferential toxicity to tumour cells displayed by some 2,4-bis(benzylidene)-8-methyl-8-azabicyclo [3.2.1]octan-3-ones and 3,5-bis(benzylidene)-1-methyl-4-piperidones. European Journal of Medicinal Chemistry, 44(1):54-62.
[18]Philippe, N., Levacher, V., Dupas, G., et al., 1996. Diastereoselective alkylation of homochiral 1,2,3,4-tetrahydroisoquinolin-3-one. A potential route to enantiomerically pure 4-substituted tetrahydroisoquinolines. Tetrahedron: Asymmetry, 7(2):417-420.
[19]Philippe, N., Levacher, V., Dupas, G., et al., 2000. Diastereoselective protonation of lactam enolates derived from (R)-phenylglycinol. A novel asymmetric route to 4-phenyl-1,2,3,4-tetrahydroisoquinolines. Organic Letters, 2(15):2185-2187.
[20]Rai, B., Kumar, A., 2013. Synthesis, characterization and biocidal activity of some Schiff base and its metal complexes of Co (II), Cu (II) and Ni (II). Oriental Journal of Chemistry, 29(3):1187-1191.
[21]Reichard, G.A., Grice, C.A., Shih, N.Y., et al., 2002. Preparation of oxime dual NK1/NK2 antagonists with reduced NK3 affinity. Bioorganic & Medicinal Chemistry Letters, 12(17):2355-2358.
[22]Semak, V., Escolano, C., Arróniz, C., et al., 2010. A practical procedure for the removal of the phenylethanol moiety from phenylglycinol-derived lactams. Tetrahedron: Asymmetry, 21(20):2542-2549.
[23]Wang, Y., Zhang, Y., Zheng, L., et al., 2013. Four new alkaloids from the fermentation broth of armillaria mellea. Helvetica Chimica Acta, 96(2):330-337.
[24]Wuensch, T., Meyers, A., 1990. Asymmetric synthesis of 4,4-disubstituted 1-naphthalenones. Diastereoselectivity as a function of metal alkoxides. The Journal of Organic Chemistry, 55(14):4233-4235.
[25]Zarate, A., Orea, L., Juarez, J.R., et al., 2014. Diastereoselective approach to cis-4-methyl/thiol-pipecolic esters based on RCM reaction and conjugate Michael addition. Synthetic Communications, 44(19):2838-2847.
Open peer comments: Debate/Discuss/Question/Opinion
<1>