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Review
. 2015 Dec 24;17(1):17.
doi: 10.3390/ijms17010017.

Enzymatic Kinetic Resolution of 2-Piperidineethanol for the Enantioselective Targeted and Diversity Oriented Synthesis

Dario Perdicchia  1 , Michael S Christodoulou  2 , Gaia Fumagalli  3 , Francesco Calogero  4 , Cristina Marucci  5 , Daniele Passarella  6
Affiliations
Review

Enzymatic Kinetic Resolution of 2-Piperidineethanol for the Enantioselective Targeted and Diversity Oriented Synthesis

Dario Perdicchia et al. Int J Mol Sci. .

Abstract

2-Piperidineethanol (1) and its corresponding N-protected aldehyde (2) were used for the synthesis of several natural and synthetic compounds. The existence of a stereocenter at position 2 of the piperidine skeleton and the presence of an easily-functionalized group, such as the alcohol, set 1 as a valuable starting material for enantioselective synthesis. Herein, are presented both synthetic and enzymatic methods for the resolution of the racemic 1, as well as an overview of synthesized natural products starting from the enantiopure 1.

Keywords: 2-piperidineethanol; alkaloid synthesis; enzymatic resolution; piperidine alkaloids.

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Figures

Figure 1
Figure 1
Structure of 2-piperidineethanol (1) and the corresponding N-protected aldehyde (2).
Scheme 1
Scheme 1
Synthesis of 2-piperidineethanol derivatives suitable for hydrolysis by pig liver esterase. iPr: isopropyl.
Scheme 2
Scheme 2
Enzymatic kinetic resolutions of racemic 3 and 4. PLE: pig liver esterase; e.e.: enantiomeric excess.
Scheme 3
Scheme 3
Enzymatic kinetic resolutions of racemic 7. PPL: porcine pancreas lipase. Fmoc: 9-fluorenylmethyl carbamate.
Scheme 4
Scheme 4
Enzymatic enantioselective acylation of racemic 9. Pg: protecting group.
Scheme 5
Scheme 5
Optimized protocol. (a) AcOCH=CH2, hexane, 20 °C, 190 min (45%); (b) PrCOOCH=CH2, MTBE, 20 °C, 11.5 h (30%), flash chromatography (AcOEt-hexane 1:9); (c) CH3OH, Na2CO3; and (d) AcOCH=CH2, MTBE, 20 °C, 46 h (48%). PPL: porcine pancreas lipase; PS: Lipase PS; Pr: propyl; Ac: acetyl; Boc: tert-butyl carbamate.
Scheme 6
Scheme 6
Oxidation reaction mediated by laccase. TEMPO: 2,2,6,6-tetramethyl-1-piperidinyloxy.
Scheme 7
Scheme 7
Retrosynthetic analysis of the synthesis of aloperine.
Scheme 8
Scheme 8
Synthesis of intermediate (R)-17. TBAF: tetrabutylammonium fluoride. TMS: trimethylsilyl.
Scheme 9
Scheme 9
Synthesis of the alkaloid boehmeriasin A. (a) (4-methoxyphenyl)magnesium bromide; (b) DMP; (c) TMSCl, MeOH; (d) 2-bromo-4,5-dimethoxyphenylacetic acid, DIPEA, 1-(Bis(dimethylamino) methylene)-1H-1,2,3-triazolo(4,5-b)pyridinium 3-oxid hexafluorophosphate (HATU); (e) KOH, EtOH; (f) Pd(OAc)2, K2CO3, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′-biphenyl)-2-amine; and (g) LiAlH4.
Scheme 10
Scheme 10
Enantioselective synthesis of the alkaloid dumetorine. (a) CH2=CHCH3CH2MgBr, (+)-β-methoxydiisopinocamphenylborane; (b) CH2=CHCOCl; (c) Grubb’s II catalyst; (d) TFA (trifluoroacetic acid); and (e) CH2O, NaBH3CN.
Scheme 11
Scheme 11
Enantioselective synthesis of the alkaloids sedamine, allosedamine, sedridines, and ethylnorlobelols.
Scheme 12
Scheme 12
Synthesis of the alkaloid (−)-coniine.
Scheme 13
Scheme 13
Enantioselective synthesis of the alkaloid (−)-epidihydropinidine. (a) imidazole, tert-butyldimethylsilyl chloride (TBDMSCl); (b) N,N,N′,N′-Tetramethylethylenediamine (TMEDA), sec-BuLi, Et2O, −78 °C, MeSO4; (c) Na2CO3, MeOH; and (d) Dess-Martin reagent.
Scheme 14
Scheme 14
Enantioselective synthesis of bicyclic derivative 45.
Scheme 15
Scheme 15
Synthesis of derivative 48.
Scheme 16
Scheme 16
Synthesis of derivative 51.
Figure 2
Figure 2
Structures of the alkaloids (−)-oncinotine, (−)-isooncinotine, and (−)-stellettamide B.
Figure 3
Figure 3
Structures of the alkaloids (+)-vertine and (+)-lythrine.
Figure 4
Figure 4
Structures of the alkaloids (+)-myrtine, (−)-lupinine, and (+)-epiepiquinamide.
Figure 5
Figure 5
Structures of the alkaloids (−)-cermizine C, (−)-senepodine G, and (+)-cermizine D.
Figure 6
Figure 6
Structures of the alkaloids psylloborine A and isopsylloborine A.
Figure 7
Figure 7
Structures of the tetraponerines T3, T4, T7, and T8.
Figure 8
Figure 8
Structure of (+)-conhydrine and general structure of 4-(2-(piperidin-2-yl)ethoxy)quinoline derivatives.
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