A formal asymmetric synthesis of (2S,4R)-4-hydroxypipecolic acid via Co(III)(salen)-catalyzed two stereocentered HKR of racemic azido epoxide

Article abstract of DOI:10.1016/j.tetlet.2015.01.113

An efficient formal synthesis of (2S,4R)-4-hydroxypipecolic acid has been achieved in high optical purity (99% ee) from readily available benzaldehyde. The strategy employs an iodine-induced intramolecular cyclization of a carbonate and Co-catalyzed Hydro

Full text of DOI:10.1016/j.tetlet.2015.01.113

Tetrahedron Letters 56 (2015) 1263–1265
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Tetrahedron Letters
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A formal asymmetric synthesis of (2S,4R)-4-hydroxypipecolic acid via
Co(III)(salen)-catalyzed two stereocentered HKR of racemic azido
epoxide
Rohit B. Kamble a, Shubhankar Haribhau Gadre b, Gurunath M. Suryavanshi a,
⇑
a Chemical Engineering & Process Development Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, Maharashtra, India
b Indian Institute of Technology Kanpur, Kanpur 208016, Uttar Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient formal synthesis of (2S,4R)-4-hydroxypipecolic acid has been achieved in high optical purity
(99% ee) from readily available benzaldehyde. The strategy employs an iodine-induced intramolecular
cyclization of a carbonate and Co-catalyzed Hydrolytic Kinetic Resolution (HKR) of two stereocentered
racemic azido epoxide as the key reactions to construct chiral 1,3-amino alcohol functionality.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 12 December 2014
Revised 12 January 2015
Accepted 15 January 2015
Available online 22 January 2015
Keywords:
Azido epoxide
Hydrolytic kinetic resolution
Piperidine
Iodocyclization
The synthesis of chiral functionalized pipecolic acids is of con-
siderable interest since this structural unit is widely found in bio-
logically active natural products and synthetic pharmaceuticals.1
In particular, (2S,4R)-4-hydroxypipecolic acid 1 (Fig. 1) is a natu-
rally occurring non proteinogenic amino acid, isolated from the
leaves of Calliandra pittieri and Strophantus scandeus.2 It is a constit-
uent of cyclodepsipeptide antibiotics such as virginiamycin S2.3 It
is also a key precursor in the syntheses of NMDA receptor antago-
nists4 and HIV-protease inhibitor such as palinavir 2.5 In addition,
4-hydroxypipecolic acid derivatives have been used in protein
design to study its conformational effect in peptidomimetics.6
Due to its potential biomedical importance, considerable effort
has been directed toward the enantioselective synthesis of 1.7,8
However several of them suffer from certain limitations such as
the use of chiral building blocks,7 inefficient separation of diastere-
ing 1,2-diols in high optical purity.10 As part of our research
program aimed at developing enantioselective synthesis of biolog-
ically active molecules,11 here we report a short enantioselective
synthesis of (2S,4R)-4-hydroxypipecolic acid, for the first time by
employing two stereocentered HKR of racemic 1,3-azido epoxide
(Schemes 1 and 2).
Our synthesis of (2S,4R)-4-hydroxypipecolic commenced with
commercially available benzaldehyde 3, which on treatment with
zinc allylbromide gave phenylbutenol 4 in 82% yield (Scheme 1).
The phenylbutenol 4 was then readily transformed into racemic
syn-1,3-epoxy alcohol 7 in three steps:12 (i) homoallylic alcohol 4
was protected as its tert-butyl carbonate 5 in 92% yield (di-tert-
butyldicarbonate, DMAP and CH3CN); (ii) diastereoselective
iodine-induced carbonate cyclization of 5 furnished iodocarbonate
derivative 6 in 80% yield (NIS, CH3CN, À40 °C to 0 °C, 12 h); and (iii)
methanolysis of 6 under basic conditions gave racemic syn-epoxy
alcohol 7. The syn-epoxy alcohol 7 was further subjected to mesy-
lation reaction followed by treatment with NaN3 in DMF at 50 °C.
This produced the required racemic anti-1,3-azido epoxide 8 in
83% yield with complete inversion at benzylic position as con-
firmed by 13C NMR. Compound 8 was then subjected to HKR with
(R,R)-salen CoIII(OAc)9 complex (0.5 mol %) and H2O (0.49 equiv),
which produced the corresponding chiral azido diol 913 (48% and
99% ee) and the chiral azido epoxide 10 (49% and 98% ee) in high
optical purity. Compounds 9 and 10 were readily separated by a
simple flash column chromatographic purification.
oisomers,7c expensive reagents7m and
steps,7f,8e etc.
a lengthy number of
Jacobsen’s Hydrolytic Kinetic Resolution (HKR) with chiral
cobalt catalysts has been comprehensively studied to afford chiral
epoxides and diols of high ee’s in excellent yields.9 Recently, a two-
stereocentered HKR is also known for terminal epoxides bearing
adjacent C–O, C–N and C–C binding substituents to furnish enan-
tiopure syn or anti alkoxy and azido epoxides and the correspond-
⇑
Corresponding author. Tel.: +91 20 25902396.
E-mail address: gm.suryavanshi@ncl.res.in (G.M. Suryavanshi).
http://dx.doi.org/10.1016/j.tetlet.2015.01.113
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

1264
R. B. Kamble et al. / Tetrahedron Letters 56 (2015) 1263–1265
OH
O
H
CONHtBu
O
N
N
N
H
N
O
OH
N
H
COOH
N
(2S,4R)-4-hydroxypipecolic acid (1)
palinavir (2)
Figure 1. Structures of (2S,4R)-4-hydroxypipecolic acid 1 and palinavir 2.
O
OH
O
OR
O
O
O
i
iii
iv
Ph
Ph
I
Ph
H
Ph
Ph
3
(+)-7
-
(+)-4, R = H
(+)-6
-
-
ii
(+)-5, R = Boc
-
N3
N3 OH
N3
O
vi
O
v
OH
Ph
Ph
(+)-10
(-)-9
(+)-8
-
48% yield, 99% ee
49% yield, 98% ee
Scheme 1. Reaction conditions: (i) 3-bromoprop-1-ene, Zn, NH4Cl, THF/H2O, 25 °C, 2 h, 82%; (ii) (Boc)2O, DMAP, CH3CN, 25 °C, 5 h, 92%; (iii) NIS, CH3CN, À40 °C to 0 °C, 12 h,
80%; (iv) K2CO3, MeOH, 0 °C to 25 °C, 4 h, 95%; (v) (a) MsCl, NEt3, CH2Cl2, 0 °C, 45 min.; (b) NaN3, DMF, 50 °C, 4 h, 83% over two step; (vi) (R,R)-CoIII(salen) (0.5 mol %), H2O
(0.49 equiv), 0–25 °C, 12 h.
N3 OH
N3 OH
N3 OH
i
ii
CN
OH
OTs
Ph
Ph
iii
Ph
9
12
11
OH
OH
N3 OH
O
ref. 7(l)
v
OH
Ph
OR
N
H
O
N
H
Ph
O
13, R = H
14, R = OEt
15
(2S, 4R)-1
iv
Scheme 2. Reaction conditions: (i) TsCl, NEt3, Bu2SnO, DMAP, 0 °C, 2 h, 98%; (ii) NaCN, EtOH/H2O (4:1), 25 °C, 24 h, 80%; (iii) 3 M NaOH, aq H2O2, 12 h, 50 °C, 93%; (iv) cat.
H2SO4, EtOH, reflux, 4 h, 84%; (v) 10% Pd/C, MeOH, 25 °C, 12 h, 87%.
Azido diol 9 was further used for the synthesis of (2S,4R)-4-
hydroxy pipecolic acid (Scheme 2). Selective monotosylation of
primary hydroxyl group of azido diol 9 afforded compound 11
(TsCl, NEt3, Bu2SnO, DMAP, 0 °C). It was then subjected to nucleo-
philic displacement with NaCN to give nitrile 12 in 80% yield. The
structure of 12 was confirmed by its characteristic IR frequencies
(2100 and 2253 cmÀ1) due to azide and nitrile functions, respec-
tively. Hydrogen peroxide catalyzed hydrolysis of the nitrile 12
in aqueous NaOH produced acid 13, which was converted to the
ethyl ester 14 in 84% yield via acid catalyzed esterification (cat.
H2SO4, EtOH, reflux). Finally, the ethyl ester 14 was subjected to
intramolecular reductive cyclization over Pd/C, H2 (1 atm) to pro-
vide the known key intermediate cis-2,4-disubstituted piperidi-
none 15 (overall yield 12%). The spectral data and optical
rotation of the synthesized key intermediate cis-2,4-disubstituted
piperidinone 15 are in good agreement with reported values.7l,14
Hence this Letter constitutes a formal synthesis of (2S,4R)-4-
hydroxy pipecolic acid 1.
In conclusion, a formal asymmetric synthesis of 4-hydroxy pip-
ecolic acid (1) is described with good overall yield and high optical
purity, that are achieved using two-stereocentered Co-catalyzed
HKR of racemic anti-1,3-azido epoxide. This synthetic strategy
has significant potential for the synthesis of a variety of other bio-
logically important molecules containing 1,3-amino alcohol
functionality.
Acknowledgments
R.B.K. thanks CSIR, New Delhi for the award of Senior Research
Fellowship. The authors are also thankful to Dr. V. V. Ranade, Chair,
Chemical Engineering and Process Development Division for his
constant encouragement and support.

R. B. Kamble et al. / Tetrahedron Letters 56 (2015) 1263–1265
1265
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Supplementary data associated with this article can be found, in
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113.
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13. Physical and spectral data for (2S,4S)-4-azido-4-phenylbutane-1,2-diol (9)
25
Yield: 48%, yellow colored liquid, [
a]
D
À98.29 (c 1, CHCl3); IR: (CHCl3, cmÀ1
)
3455, 2094; 1H NMR (200 MHz, CDCl3): d 1.75–1.90 (m, 2H), 2.44 (br s, 1H), 2.88
(br s, 1H), 3.45–3.54 (m, 1H), 3.72–3.77(m, 1H), 3.97–4.10 (m, 1H), 4.76–4.83
(dd, J = 5.2, 9.5 Hz, 1H), 7.26–7.40 (m, 5H); 13C NMR (50 MHz, CDCl3): d 40.0,
62.7, 66.7, 68.9, 126.7, 128.4, 128.9, 139.8; HRMS (m/z): calculated [M+Na]+ for
C10H13O2N3Na+: 230.0900 found: 230.0897; Optical purity: 99% ee determined
by HPLC analysis (Chiral OD-H column, n-hexane/2-propanol (85:15), 0.5 mL/
min, 254 nm). Retention time: tminor = 21.50 and tmajor = 25.69 min.
14. Physical and spectral data for (4S,6S)-4-hydroxy-6-phenylpiperidin-2-one (15)
25
Yield: 87%; colorless solid, mp 215 °C {lit.7l mp 211–213 °C}; [
a]
D
À51.80 (c 1,
20
MeOH) {lit.7l
[
a
]
À51.9 (c 0.56, MeOH)}; IR: (neat, cmÀ1): 3355, 3030, 1651; 1
H
D
NMR (200 MHz, MeOH-d4): d 1.52–1.70 (q, J = 12.6 Hz, 1H), 2.21–2.37 (m, 2H),
2.64–2.74 (m, 1H), 4.03–4.17 (m, 1H), 4.47–4.54 (dd, J = 4.3, 11.3 Hz, 1H), 4.75
(br s, 1H), 7.29–7.37 (m, 5H); 13C NMR (50 MHz, MeOH-d4): d 41.5, 42.8, 56.3,
65.7, 127.5, 129.1, 130.0, 143.6, 174.2; HRMS (m/z): calculated [M+Na]+ for
C
11H13O2NNa+: 214.0838 found: 214.0834.