Concise enantioselective syntheses of (+)-L-733,060 and (2 S,3 S)-3-hydroxypipecolic acid by cobalt(III)(salen)-catalyzed two-stereocenter hydrolytic kinetic resolution of racemic azido epoxides

Article abstract of DOI:10.1055/s-0033-1340074

An efficient synthesis of the 2,3-disubstituted piperidines (+)-L-733,060 and (2S,3S)-3-hydroxypipecolic acid (≥99% ee) in high optical purity from commercially available starting materials is described. The strategy involves a cobalt-catalyzed hydrolytic

Full text of DOI:10.1055/s-0033-1340074

102▌
LETTER
lCettoerncise Enantioselective Syntheses of (+)-L-733,060 and (2S,3S)-3-Hydroxy-
pipecolic Acid by Cobalt(III)(salen)-Catalyzed Two-Stereocenter Hydrolytic
Kinetic Resolution of Racemic Azido Epoxides
(+)-L-733,060 and (2S,3S)-3-Hydroxypipecolic Acid
Dattatray A. Devalankar, Pandurang V. Chouthaiwale, Arumugam Sudalai*
Chemical Engineering & Process Development Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune,
Maharashtra 411008, India
Fax +91(20)25902676; E-mail: a.sudalai@ncl.res.in
Received: 21.08.2013; Accepted after revision: 01.10.2013
ral pool and involve enzymatic resolution as a key
Abstract: An efficient synthesis of the 2,3-disubstituted piperi-
reaction.7,8
dines (+)-L-733,060 and (2S,3S)-3-hydroxypipecolic acid (≥99%
ee) in high optical purity from commercially available starting ma-
terials is described. The strategy involves a cobalt-catalyzed hydro-
lytic kinetic resolution of a racemic azido epoxide with two
stereocenters and an intramolecular reductive cyclization as key re-
actions.
We recently reported a flexible method that involves a
cobalt-catalyzed hydrolytic kinetic resolution (HKR) of
racemic azido epoxides with two contiguous stereocenters
to generate the corresponding diols and epoxides in high
optical purities (97–99% ee) in a single step.9a Here, we
report a short enantioselective synthesis of two important
bioactive molecules, (+)-L-733,060 (1) and (2S,3S)-3-hy-
droxypipecolic acid (3), based on a two-stereocenter HKR
of racemic azido epoxides.
Key words: azides, epoxides, stereoselective synthesis, Wittig re-
actions, cyclizations, piperidines
Chiral 2,3-disubstituted piperidine moieties with a β-hy-
droxy functional groups are found in numerous natural
products and are common subunits in drugs and drug can-
didates.1 Selected examples include (+)-L-733,060 (1)2
and (+)-CP-99,994 (2),3 both potent and selective neroki-
nin-1 substance P receptor antagonists; febrifugine (4),4
an antimalarial agent; (-)-swainsonine (5),5 an inhibitor of
lysosomal α-mannosidase and a potent anticancer drug;
and (2S,3S)-3-hydroxypipecolic acid [3; (2S,3S)-3-hy-
droxypiperidine-2-carboxylic acid],6 a key precursor in
the syntheses of 4 and 5 (Figure 1).
The synthesis of (+)-L-733,060 (1; Scheme 1) com-
menced with the racemic azido epoxide 6, prepared from
N3
N3
N3
a
Ph
Ph
Ph
OH
+
O
O
OH
( )-6
(–)-7 (2R,3S)
(+)-8 (2S,3R)
47%
48%
b
N3
O
N3
N3
H
e
d
CF3
Ph
OEt
Ph
OR2
Ph
O
OTBS
12
OR1
OTBS
11
OH
O
H
N
9, R1 = R2 = TBS
O
c
CF3
OH
f
10, R1 = TBS, R2 = H
OMe
N
H
N
Ph
N
Ph
H
H
O
1
2
3
R4
Boc
Ph
N
CF3
N
HN
i
OH
h
OH
OH
N
O
Ph
O
Ph
OH
O
OR3
13, R3 = TBS
OH
15
N
N
CF3
N
16, R
4 = Boc
H
g
j
4
5
1, R4 = H
14, R3 = H
Figure 1 Biologically active 2,3-disubstituted piperidines
Scheme 1 Reagents and conditions: (a) (S,S)-(salen)Co(III)OAc
(0.5 mol%), H2O (0.49 equiv), 0 °C, 14 h; (b) TBSCl (2 equiv), imid-
azole, CH2Cl2, 25 °C, 12 h; yield 98%. (c) CSA, MeOH, 0 C, 6 h,
○
Because of the biomedical importance of the products, the
synthesis of these β-hydroxy piperidines has attracted
much attention in recent years; however, many of the syn-
thetic approaches employ starting materials from the chi-
yield 95%; (d) Dess–Martin periodinane, CH2Cl2, 25 °C, 1 h, yield
98%; (e) (EtO)2POCH2CO2Et, NaH, THF, 0 to 25 °C, 3 h, yield 94%;
(f) 10% Pd/C, H2 (1 atm), MeOH, 25 °C, 12 h, then EtOH, reflux, 1 h,
yield 85%; (g) TBAF, THF, 0–25 °C, 2 h, yield 96%; (h) (i)
BH3·SMe2, THF, reflux, 10 h; (ii) (Boc)2O, Et3N, DMAP (cat.),
CH2Cl2, 0 to 25 °C, 12 h, yield 76% (two steps); (i) 3,5-bis(trifluoro-
methyl)benzyl bromide, NaH, DMF, 80 °C, 12 h, yield 85%; (j) TFA,
CH2Cl2, 0 to 25 °C, 18 h, yield 89%.
SYNLETT 2014, 25, 0102–0104
Advanced online publication: 12.11.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340074; Art ID: ST-2013-B0807-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
(+)-L-733,060 and (2S,3S)-3-Hydroxypipecolic Acid
103
commercially available cinnamyl alcohol by our previ-
ously reported procedure.9a The racemic azido epoxide 6
was subjected to HKR with (S,S)-salen–cobalt(III) acetate
complex9b (0.5 mol%) and water (0.49 equiv), which gave
the corresponding diol 8 (48%, 98% ee) and chiral epox-
ide 7 (47%) in high optical purity. The diol 8 was readily
separated from epoxide 7 by simple flash column chroma-
tography on silica gel.
N3
H
N3
O
a
BnO
BnO
O
OEt
OTBS
OTBS
18
17
OTBS
OR
OTBS
c
b
OBn
N
O
N
Boc
H
19
Both free hydroxy groups in diol 8 were protected to give
the disilyl ether derivative 9, which was then selectively
deprotected to give the monosilyl ether 10 in 95% yield.
Dess–Martin oxidation of 10 gave the crude aldehyde 11
in 98% yield; this underwent a Wittig–Horner reaction to
give the corresponding (E)-azido ester 12 in 94% yield.
Intramolecular reductive cyclization of 12 by hydrogena-
tion over 10% palladium/carbon gave the cis-2,3-disubsti-
tuted piperidinone 13 in 85% yield. Deprotection of the
silyl group in 13 with tetrabutylammonium fluoride gave
the lactam 14. Reduction of lactam 14 with borane–di-
methyl sulfide in tetrahydrofuran, followed by protection
of the secondary amine gave the syn-amino alcohol 15 in
76% yield for the two steps. Having constructed the
piperidine core with the desired syn stereochemistry, we
O-alkylated amino alcohol 15 with 3,5-bis(trifluorometh-
yl)benzyl bromide in the presence of sodium hydride to
give the protected amine 16. Finally, deprotection under
acidic conditions gave L-733,060 (1) in 89% yield (over-
all yield 19% from 6 in ten steps).
20, R = Bn
d
21, R = H
OH
O
e
OH
N
H
•HCl
3
Scheme 2 Reagents and conditions: (a) (EtO)2POCH2CO2Et, NaH,
THF, 0–25 °C, 1 h, yield 93%; (b) 10% Pd/C, H2 (1 atm), MeOH,
25 °C, 24 h, yield 90%; (c) BH3·SMe2, THF, reflux, 6 h, then Na2CO3,
(Boc)2O, CH2Cl2/H2O (1:1), 25 °C, 12 h, yield 80%; (d) 10% Pd/C,
H2 (70 psi), MeOH, 25 °C, 24 h, yield 96%; (e) (i) RuCl3 (2 mol%),
NaIO4 (4 equiv), MeCN/CCl4/H2O (1:1:3), 25 °C, 30 min; (ii) 6 M aq
HCl, reflux, 2 h, yield 68% (two steps).
intramolecular reductive cyclization. The synthetic strate-
gy has significant potential for further extension to other
stereoisomers and related analogues of multifunctional
piperidine alkaloids, owing to the flexibility available in
syntheses of racemic azido epoxides with various stereo-
chemical combinations and various substituents.
The synthesis of (2S,3S)-3-hydroxypipecolic acid (3;
Scheme 2) commenced from (2Z)-but-2-ene-1,4-diol,
which was converted into the azido aldehyde 17 by HKR,
as we previously reported.9c The key intermediate 20
(Scheme 2) was readily synthesized from 17, essentially
by following a similar sequence of reactions to that shown
in Scheme 1. Wittig olefination and intramolecular reduc-
tive cyclization gave the trans-2,3-disubstituted piperidi-
none core 19 in 90% yield with an intact benzyloxy group.
Reduction of piperidinones 19 with borane–dimethyl sul-
fide followed by protection in situ gave trans-piperidine
derivative 20 in 80% yield. Hydrogenation of 20 over pal-
ladium/carbon in methanol at 70 psi gave the correspond-
ing alcohol 21 in 96% yield. Finally, oxidation of alcohol
21 with ruthenium(II) chloride and sodium periodate,8f,10
followed by removal of both protecting groups under
acidic condition (6 M aq HCl), completed the synthesis of
(2S,3S)-3-hydroxypipecolic acid (3; overall yield 43%
Acknowledgment
D.A.D. and P.V.C. thank CSIR, New Delhi for the award of re-
search fellowships. The authors are also grateful to Dr. V. V. Ranade,
chair of the Chemical Engineering and Process Development Divi-
sion, for his constant encouragement and support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
experimental procedures and spectral data for compounds 7–21.SnugIifop
maotrinSnguIpfomin
r
t
rorat
t
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colic acid (3) were in complete agreement with the values
reported in the literature.7d,7e,8f,o
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hydroxypipecolic acid (3) with good overall yields and
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 102–104

104
D. A. Devalankar et al.
LETTER
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(11) Hydrolytic Kinetic Resolution of Azido Epoxide 6
AcOH (0.014 g, 0.24 mmol) was added to a solution of (S,S)-
(salen)Co(II) complex (0.024 mmol, 0.5 mol%) in toluene (1
mL), and the mixture was stirred at 25 °C in open air for 30
min. During this time the color changed from orange–red to
a dark brown. The solution was then concentrated under
reduced pressure to give the Co(III)–salen complex as a
brown solid. To this were added the racemic azido epoxide
6 (0.84 g, 4.85 mmol) and H2O (0.043 g, 2.42 mmol) at 0 °C,
and the resulting mixture was stirred at 0 °C for 14 h. When
the reaction was complete (TLC), the crude product was
purified by column chromatography [silica gel, PE–EtOAc]
to give chiral azido epoxide 7 (9:1 PE–EtOAc) and the chiral
azido diol 8 (1:1 PE–EtOAc) in pure form.
(2R,3S)-3-Azido-3-phenylpropane-1,2-diol (8)
Yellow liquid; yield: 450 mg (48%, 98% ee); [α]D25 +188 (c
1, CHCl3) (lit.9a –188 for the antipode). IR (CHCl3): 1602,
2099, 2932, 3052, 3392 (br) cm–1. 1H NMR (200 MHz,
CDCl3): δ = 3.30 (dd, J = 11.5, 6.0 Hz, 1 H), 3.44 (d,
J = 11.5 Hz, 1 H), 3.80 (br s, 1 H), 3.62–3.94 (m, 1 H), 4.52
(d, J = 8.1, 1 H), 7.28–7.35 (m, 5 H). 13C NMR (50 MHz,
CDCl3): δ = 2.8, 68.1, 75.0, 127.5, 128.7, 128.9, 136.2.
Anal. Calcd for C9H11N3O2: C, 55.95; H, 5.74; N, 21.75.
Found: C, 56.10; H, 5.65; N, 21.60; HPLC: Chiral OD-H
column, hexane–i-PrOH (90:10, 0.5 mL/min), 254 nm;
tR(major) = 14.84 min, tR(minor) = 15.57 min.
(2S)-2-[(R)-Azido(phenyl)methyl]oxirane (7)
Yellow liquid; yield: 400 mg (47%); [α]D25 –120 (c 1,
CHCl3) (lit.9a +120 for the antipode). IR (CHCl3): 2105,
2932, 3025 cm–1. 1H NMR (200 MHz, CDCl3): δ = 2.73–
2.84 (m, 2 H), 3.23–3.29 (m, 1 H), 4.25 (d, J = 6.1, 1 H),
7.35–7.47 (m, 5 H). 13C NMR (50 MHz, CDCl3): δ = 44.6,
54.6, 66.8, 127.2, 128.8, 128.9, 135.7. Anal. Calcd for
C9H9N3O: C, 61.70; H, 5.18; N, 23.99. Found: C, 61.79; H,
5.14; N, 23.90.
(12) (2S,3S)-3-{[3,5-Bis(trifluoromethyl)benzyl]oxy}-2-
phenylpiperidine [1; (+)-L-733,060]
Colorless oil; yield: 110 mg (89%), [α]D25 +35.2 (c 0.66,
CHCl3) {lit.7j +34.29 (c 1.32, CHCl3)}. IR (neat): 1277,
1370, 2950 cm–1. 1H NMR (CDCl3, 200 MHz): δ = 1.40–
2.04 (m, 3 H), 2.22 (br d, J = 13 Hz, 1 H), 2.60 (s, 1 H), 2.76–
2.81 (m, 1 H), 3.23–3.38 (m, 1 H), 3.66 (s, 1 H), 3.84 (s, 1
H), 4.12 (d, J = 12.0 Hz, 1 H), 4.54 (d, J = 12.2 Hz, 1 H),
7.20–7.50 (m, 7 H), 7.78 (s, 1 H). 13C NMR (CDCl3, 50
MHz): 20.6, 27.5, 47.1, 64.0, 70.5, 77.2, 120.9, 124.1, 127.7,
128.5, 128.7, 128.9, 131.2, 141.6, 142.3. Anal. Calcd for
C20H19F6NO: C, 59.55; H, 4.75; N, 3.47. Found: C, 59.52; H,
4.81; N, 3.56.
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(2S,3S)-3-Hydroxypiperidine-2-carboxylic Acid [3;
(2S,3S)-3-Hydroxypipecolic Acid]
25
Colorless solid; yield: 20 mg (68%); mp 232 °C; [α]D
+14.2 (c 1, H2O) {lit.8f [α]D23 +14.5 (c 0.4, H2O)}. IR (neat):
1685, 3420 cm–1. 1H NMR (200 MHz, D2O): δ = 1.62–1.80
(m, 2 H), 2.00–2.08 (m, 2 H), 3.10 (s, 1 H), 3.32–3.39 (m, 1
H), 3.80 (d, J = 7.6 Hz, 1 H), 4.10–4.17 (m, 1 H). 13C NMR
(50 MHz, D2O): δ = 20.0, 30.1, 43.9, 62.5, 65.9, 171.3. Anal.
Calcd for C6H11NO3: C, 49.65; H, 7.64; N, 9.65. Found: C,
49.60; H, 7.69; N, 9.70.
(9) (a) Reddy, R. S.; Chouthaiwale, P. V.; Suryavanshi, G.;
Chavan, V. B.; Sudalai, A. Chem. Commun. 2010, 46, 5012.
(b) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E.
Synlett 2014, 25, 102–104
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