Concise Enantioselective Synthesis of Naturally Active (S)-3-Hydroxypiperidine

Article abstract of DOI:10.1080/00397911.2015.1033428

A short and efficient enantioselective synthesis of natural product (S)-3-hydroxypiperidine has been achieved starting from commercially available raw materials employing two catalytic routes: (i) cocatalyzed hydrolytic kinetic resolution (HKR) of racemic methyl-3-(oxiran-2-yl)propanoate; (ii) proline-catalyzed α-aminooxylation followed by Horner-Wardsworth-Emmons olefination in high enantiomeric purity (97% ee) and high overall yield (38%). (Chemical Equation Presented).

Full text of DOI:10.1080/00397911.2015.1033428

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Concise Enantioselective Synthesis of
Naturally Active (S)-3-Hydroxypiperidine
Soumen Deya, Pratibha U. Karabala & Arumugam Sudalaia
a Chemical Engineering and Process Development Division,
CSIR–National Chemical Laboratory, Pune, India
Accepted author version posted online: 03 Apr 2015.Published
online: 03 Apr 2015.
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To cite this article: Soumen Dey, Pratibha U. Karabal & Arumugam Sudalai (2015) Concise
Enantioselective Synthesis of Naturally Active (S)-3-Hydroxypiperidine, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 45:13, 1559-1565,
DOI: 10.1080/00397911.2015.1033428
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Synthetic Communications1, 45: 1559–1565, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1033428
CONCISE ENANTIOSELECTIVE SYNTHESIS OF
NATURALLY ACTIVE (S)-3-HYDROXYPIPERIDINE
Soumen Dey, Pratibha U. Karabal, and Arumugam Sudalai
Chemical Engineering and Process Development Division, CSIR–National
Chemical Laboratory, Pune, India
GRAPHICAL ABSTRACT
Abstract A short and efficient enantioselective synthesis of natural product (S)-3-
hydroxypiperidine has been achieved starting from commercially available raw materials
employing two catalytic routes: (i) cocatalyzed hydrolytic kinetic resolution (HKR) of
racemic methyl-3-(oxiran-2-yl)propanoate; (ii) proline-catalyzed a-aminooxylation
followed by Horner–Wardsworth–Emmons olefination in high enantiomeric purity (97%
ee) and high overall yield (38%).
Keywords Asymmetric synthesis; bioactivity; enantioselectivity; natural products;
organocatalysis
INTRODUCTION
The functionalized piperidines are among the most ubiquitous heterocyclic
building blocks of natural and synthetic compounds with potential biological activi-
ties.[1] In particular, piperidine-3-ol (1 and 2) is an attractive target because of its
widespread occurrence in bioactive natural products such as psuedoconhydrine (3)[2]
and cassine (4).[3] Medicinally, important examples containing 3-piperidinol fragments
Received February 5, 2015.
Address correspondence to Arumugam Sudalai, Chemical Engineering and Process Development
Division, CSIR–National Chemical Laboratory, Pashan Road, Pune 411 008, India. E-mail: a.sudalai@
ncl.res.in
1559

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S. DEY, P. U. KARABAL, AND A. SUDALAI
include cholinotoxic agents, antihypertensives and calcium antagonists, 2,3-oxydos-
qualine cyclase inhibitors, 5-HT4 agonists, nootropics, antiarrhythmic, and anticancer
agents.[4] With these potential applications, our synthetic plan focused on the prep-
aration of (S)-3-hydroxypiperidine (1), one of the potential building blocks. So far,
access to these enantiomers of 3-hydroxypiperidine (1 and 2) has been realized
through fractional crystallization of tetranilic acid diastereomers[5] or chemoenzy-
matic synthesis.[6] Total synthesis of 1 has also been described from (S)-malic acid,
[7]
L-glutamic acid,[7] or a carbohydrate precursor.[8] Nevertheless, long reaction
sequences, poor overall yields, and dependence on chiral pool resources are the main
drawbacks of the reported methods.
In recent years, organocatalysis has become the main focus of research because
of the emergence of organocatalyzed tandem transformations[9] and their application
to the synthesis of complex organic molecules that are accessible in a one-pot
procedure. Gratifyingly, Jacobsen’s hydrolytic kinetic resolution (HKR),10 which
uses readily accessible Co-based chiral salen complexes as catalyst and water as
the only reagent to afford chiral epoxides and diols of good ee in excellent yields,
has been comprehensively studied in recent years to reveal its mechanistic and syn-
thetic aspects.[11] As part of our research program aimed at achieving asymmetric
synthesis of biologically active molecules,[12] herein we report highly efficient
enantioselective synthesis of (S)-piperidine-3-ol (1).
RESULTS AND DISCUSSION
The complete synthetic scheme for (S)-3-hydroxypiperidine (1) is shown in
Scheme 1. The commercially available allylic alcohol 6 was subjected to Johnson–
Claisen rearrangement[13] with triethyl orthoacetate in the presence of a catalytic
amount of hexanoic acid to give olefinic acid 7 in 80% yield. Acyclic olefinic acid 7
was then subjected to iodolactonization (I2, CH3CN, 0 °C, 24 h) to give iodolactone
8 in 85% yield. Methanolysis of iodolactone 8 under basic conditions produced the
required racemic epoxy ester (ꢀ)-9 in 70% yield. The terminal epoxy ester (ꢀ)-9
Figure 1. Some of the structures of 3-hydroxy piperidine units present in bioactive molecules.

SHORT SYNTHESIS OF (S)-3-HYDROXYPIPERIDINE
1561
Scheme 1. (i) MeC(OEt)3, hexanoic acid, 80–150 °C, 3 h, 80%; (ii) I2, CH3CN, 0 °C, 24 h, 85%; (iii)
MeOH, Na2CO3, reflux, 3 h, 70%; (iv) (R, R)-CoIII(salen) complex (0.5 mol %), H2O (0.49 equiv), 0 to
25 °C, 12 h; (v) MsCl, Et3N, CH2Cl2, 0 °C, 1 h, 92%; (vi) NaN3, DMF, 80 °C, 3 h, 95%; (vii) 20% Pd
(OH)2, H2 (1 atm), MeOH, 12 h, 25 °C, 98%; (viii) BH3 · SMe2, THF, reflux, 12 h, 87%.
was then subjected to HKR with (R, R)-salen Co(III)OAc complex (0.5 mol%) and
H2O (0.49 equiv), which produced the corresponding chiral epoxide 10 (50%, 98%
ee) and chiral c-butyrolactone[14] 11 (48%, 97% ee) in good optical purity. The forma-
tion of c-butyrolactone 11 was confirmed from its infrared (IR) spectrum, which
showed two strong absorption bands at tmax 1620 and 3438 cm–1 corresponding to lac-
tone carbonyl and hydroxyl functionality respectively. The optical purity of lactone 11
was found to be 97% ee, based on comparison of its specific rotation with the reported
25
25
value; [a]D þ l1.8 (c 1, CHCl3) [lit.[14d] [a]D þ 53.5 (c 3.17, CHCl3)]. The subsequent
mesylation of lactone alcohol 11 gave the mesylate 12 in 92% yield. The SN2 displace-
ment of mesylate 12 with azide ion produced the corresponding azide 13 (NaN3,
dimethylformamide [DMF], 80 °C) in 95% yield. Azide 13 was then subjected to
intramolecular reductive cyclization over Pd(OH)2=H2 (1 atm) to afford piperidinone
core 14 in 98% yield. The reduction of imide carbonyl in 14 was finally carried out
with BH3 · SMe2 to give (S)-3-hydroxypiperidine (1) in 87% yield (overall yield
17%). However, poor overall yield (17%) and long reaction sequences in the HKR
route prompted us to take an alternative route for its synthesis via organocatalysis.
In this approach, the synthesis of 1 started from 1,3-propanediol 15, which was
transformed to its 3-azidopropan-1-ol 17 in 70% yield via the standard sequences of

1562
S. DEY, P. U. KARABAL, AND A. SUDALAI
Scheme 2. (i) MsCl, Et3N, DMAP, CH2Cl2; (ii) NaN3, DMF, 80 °C, 70% (over two steps); (iii) PCC,
CH2Cl2, 25 °C, 2 h, 98%; (iv) L-proline, PhNO, CH3CN, 24 h, –20 °C, then triethyl phosphono acetate,
DBU, LiCl, 0 °C, 2 h; (v) H2 (1 atm), 10% Pd=C, MeOH, 25 °C, 2 h, 65% (over three steps).
monomesylation and then azide dispacement. The primary alcohol 17 on PCC
oxidation gave aldehyde 18 (98% yield). The aldehyde 18 was then subjected to
sequential L-proline-catalyzed aminooxylation[15] followed by HWE olefination [L-
proline (30 mol%), PhNO, CH3CN, 24 h, –20 °C, then triethyl phosphono acetate,
DBU, LiCl, 0 °C, 2 h] gave the intermediate c-aminoxy-a,b-unsaturated ester A in
situ, which was then immediately subjected to reductive cyclization without further
purification [H2 (1 atm), 10% Pd=C, MeOH, 25 °C, 2 h] furnishing piperidinone 14
in 65% yield (Scheme 2). Finally, piperidinone 14 on reduction with BH3 · SMe2 in
tetrahydrofuran (THF) provided the target molecule 1 in 87% yield (overall yield
38%). The synthetic (S)-3-hydroxy piperidine (1) was identical in all spectral respects
to the natural product.[16] The enantiomeric purity of 1 was determined to be 97%
25
ee based on the comparison of its specific rotation with the reported values [a]D
–
25
7.3 (c 2.5, MeOH) [lit.[8] [a]D –7.5 (c 2, MeOH)].
EXPERIMENTAL
All the chemicals and reagents were obtained commercially. Solvents were pur-
ified and dried by standard procedures prior to use. Optical rotations were measured
using sodium D line on a Jasco-181 digital polarimeter. IR spectra were recorded on
1
a Thermo Scientific–Nicolet 380 FT-IR and absorption is expressed in cm–1. H
NMR and13C NMR spectra were recorded on Brucker AC-200 spectrometer unless
mentioned otherwise. Elemental analysis was carried out on a Carlo Erba CHNS-O
analyzer. Purification was carried out using column chromatography (60–120 mesh).
Enantiomeric excesses were determined on Agilent high-performance liquid chroma-
tography (HPLC) instrument equipped with a suitable chiral column.
(S)-5-Hydroxypiperidin-2-one (14)
From HKR route. To a solution of azide 13 (1.5 g, 10.62 mmol) in dry MeOH
was added 20% Pd(OH)2 (0.037 g, 0.53 mmol), and the reaction mixture was stirred

SHORT SYNTHESIS OF (S)-3-HYDROXYPIPERIDINE
1563
under an atmosphere of H2 (1 atm) for 24 h at 25 °C. After completion of the reaction
(monitored by thin-layer chromatography, TLC), the catalyst was filtered over celite
and the filtrate was concentrated under reduced pressure to provide crude hydroxy-
lactam, which was purified by column chromatography using ethyl acetate=methanol
(9:1) as eluent to obtain pure hydroxylactam 14 (1.19 g, 98%).
From organocatalytic route. Nitrosobenzene (3.4 g, 30.27 mmol) and
L-proline (0.64 g, 6.0 mmol) were added to a precooled solution of aldehyde 18 (3 g,
30.27 mmlol) in CH3CN (100 mL) at –20 °C. The reaction was then stirred at –20 °
C for 24 h, followed by the addition triethyl phosphono acetate (10.1 g, 45.4 mmol),
DBU (6.9 g, 45.4 mmol), and LiCl (1.4 g, 33.29 mmol) at 0 °C for 2 h. After completion
of the reaction (monitored by TLC), it was quenched with saturated solution of
ammonium chloride. Then solvent was evaporated and the organic layer was
extracted with EtOAc (3 × 50 mL). The combined EtOAc layers were dried over
anhydrous Na2SO4 and concentrated to give the crude c-aminooxy-a,b-unsaturated
ester A, which was directly used for the next step without purification.
To a stirred solution of crude c-aminooxy-a,b-unsaturated ester A in MeOH
(50 mL) was added 10% Pd=C (0.16 g, 1.51 mmol) under H2 (1 atm) at 25 °C. The
reaction mixture was stirred for 2 h at the same temperature. After completion of
reaction (monitored by TLC), it was filtered through celite (EtOAc eluent), and the
solvent was evaporated under reduced pressure to afford the crude compound, which
was purified by column chromatography using ethyl acetate=methanol (9:1) as eluent
25
to obtain pure hydroxylactam 14 (2.2 g, 65%). Yield: 2.2 g, 65%; [a]D –13.3 (c 1,
MeOH) [lit.[4a] [a]D –12.4 (c 0.5, MeOH)]; IR (CHCl3, cm–1): tmax 1636, 1652,
25
1
3439; H NMR (200 MHz, MeOH-d4): d 1.72–1.87 (m, 2 H), 2.12–2.27 (m, 1 H),
2.32–2.49 (m, 1 H), 3.03–3.12 (dd, J ¼ 4.8 and 12.7 Hz, 1 H), 3.20–3.22 (m, 1 H),
3.27–3.35 (dd, J ¼ 3.9 and 12.7 Hz, 1 H), 3.92–4.01 (m, 1 H);13C NMR (50 MHz,
MeOH-d4): d 28.1, 28.8,49.4, 63.8, 174.5. Anal. calcd. for C5H9NO2 requires C,
52.16; H, 7.88; found: C, 52.15; H, 7.85%.
(S)-Piperidin-3-ol (1)
BH3 · SMe2 (0.95 mL, 8.68 mmol) was added dropwise to a solution of lactam 14
(1.2 g, 10.43 mmol) in dry THF (20 mL), at 0 °C under an N2 atmosphere, and the
mixture was then refluxed for 6 h. After the reduction was complete (monitored by
TLC), tetrahydrofuran (THF) was removed under reduced pressure to give the crude
product, which was purified by column chromatography with silica gel using pet-
roleum ether=ethyl acetate (6:4) as eluent to give pure 1. Yield: 0.91 g; 85%; viscous
liquid; [a]D –7.3 (c 1.3, MeOH) [lit.4a [a]D –7.5 (c 2, MeOH)]; IR (CHCl3, cm–1):
tmax 1636, 1652, 3439;1H NMR (200 MHz, MeOH-d4): d 1.55–1.64 (m, 2 H), 1.67–
1.77 (m, 2 H), 2.60–2.62 (m, 1 H), 3.04–3.12 (m, 2 H), 3.19–3.23 (m, 1 H), 3.65–3.74
(m, 1 H).13C NMR (50 MHz, MeOH-d4): d 23.5, 32.8, 45.9, 53.3, 66.2. Anal. calcd.
for C5H10NO requires C, 59.37; H, 10.96; found: C, 59.33; H, 10.91%.
25
25
CONCLUSIONS
In conclusion, we have successfully demonstrated the use of HKR and organo-
catalytic sequential a-aminooxylation followed by HWE reaction for the concise

1564
S. DEY, P. U. KARABAL, AND A. SUDALAI
synthesis of (S)-piperidine-3-ol (1) (38% overall yield from organocatalysis; 97% ee).
Simple reaction transformations, good overall yield, and the requirement of a
relatively low amount of inexpensive and nontoxic proline as the catalyst are the
features of our strategy. This flexible approach will find broad applications to the
synthesis of other naturally occurring 3-hydroxypiperidine analogs.
ACKNOWLEDGMENT
The authors are thankful to V. V. Ranade, Head, Chemical Engineering and
Process Development Division, for his encouragement and support.
FUNDING
S. D. thanks the Council of Scientific and Industrial Research, New Delhi, for
the award of a senior research fellowship.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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