Formal syntheses of (2R,3R)-3-hydroxy pipecolic acid and (2R,3S)-3-hydroxy pipecolic acid from l-ascorbic acid

Article abstract of DOI:10.1016/j.tetlet.2014.12.103

Formal syntheses of both cis and trans 3-hydroxy pipecolic acids is achieved from l-ascorbic acid. Present synthesis describes use of chiral pool approach in which epimerization, Staudinger reaction and Cyclization reactions were employed as key steps.

Full text of DOI:10.1016/j.tetlet.2014.12.103

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
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Formal syntheses of (2R,3R)-3-hydroxy pipecolic acid
and (2R,3S)-3-hydroxy pipecolic acid from L-ascorbic acid
⇑
Subhash P. Chavan , Nilesh B. Dumare, Kailash P. Pawar
Division of Organic Chemistry, CSIR-NCL (National Chemical Laboratory), Pune 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Formal syntheses of both cis and trans 3-hydroxy pipecolic acids is achieved from L-ascorbic acid. Present
Received 1 October 2014
Revised 16 December 2014
Accepted 17 December 2014
Available online xxxx
synthesis describes use of chiral pool approach in which epimerization, Staudinger reaction and
Cyclization reactions were employed as key steps.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Epimerization
Cyclization
L
-Ascorbic acid
3-Hydroxy pipecolic acid
Chiral piperidine framework of alkaloid compounds has gained
great deal attention due to their promising biological activity and
structural features. Piperidine alkaloids from monohydroxyl piper-
idine to polyhydroxy piperidine framework compounds are
involved in various biological processes. Recently it has been
reported that non-natural piperidine core compounds are also
involved in various carbohydrate biological processes. Functional-
ized piperidine framework is an important constituent of many nat-
ural and synthetic compounds having medicinal significance.1 cis-
3-Hydroxy pipecolic acid 1 forms an important core for tetrazomine
32 which possesses antitumor antibiotic activity. trans-3-Hydroxy
pipecolic acid 2 is an important constituent for swainsonine 4,3
(+)-prosopinine 5 and (+)-febrifugine 64 which are biologically
active molecules. The remarkable biological activities and struc-
tural features of derivatives of compounds 1 and 2 have motivated
many organic chemists towards their syntheses. The synthetic chal-
lenge is the construction of piperidine framework and installation
of hydroxy functionality in a stereoselective manner. In literature,5
various protocols have been reported. In continuation of our work
towards synthesis of piperidine alkaloids,6 herein, we wish to
report syntheses of both cis and trans-pipecolic acid precursors 1a
and 2a (Scheme 1) from a common precursor by employing simple
reaction conditions and commercially available starting materials
reductive intramolecular N-alkylation. Azide
accessed from ester 8. Ester 8 could be derived from alcohol 9
which can be readily generated from -ascorbic acid 10.
Synthesis of 3-hdroxypipecolic acid began from a commercially
available chiral material viz. ascorbic acid 10. Ascorbic acid was
transformed to alcohol 9 by the known literature protocol.7 Alcohol
9 was oxidized to corresponding aldehyde 11 which without
purification was subjected to two carbon Wittig homologation to
7 can be easily
L
provide
fin 13 was obtained exclusively after performing Wittig Horner
reaction conditions.8 Double bond of
,b-unsaturated ester 12
a,b-unsaturated ester 12 (E/Z 9:1) (in Scheme 2). trans ole-
a
was reduced using Pd/(OH)2 as catalyst and HCOONH4 as hydrogen
source9 in methanol under reflux condition to furnish ester 8 in
92% yield (in Scheme 3). Interestingly, epimerization of the allylic
centre was observed to furnish product 8, as a mixture of diaste-
reomers, which was confirmed by NMR spectroscopy. Several
attempts to avoid epimerization met with failure. So, it was
decided to carry forward inseparable diastereomeric mixture 8
for further steps and separate them at the later stage. Thus,
inseparable diastereomeric mixture of ester 8 was subjected to
reduction. The ester functionality of compound 8 was reduced by
using LiBr and NaBH4 to furnish alcohol 14 in 88% yield.10 Alcohol
14 was converted into its mesylate derivative followed by the
treatment with NaN3 in DMF at 80 °C to furnish azide 15 in 70%
yield (over two steps).11 Terminal acetonide moiety of compound
15 was deprotected using AcOH/H2O (8:2) at room temperature
to obtain diol 16 in 85% yield. Our initial attempt was conversion
of diol 16 to its mono TBS derivative 17. However, conversion of
diol 16 to mono TBS derivative 17 by using TBSCl, imidazole in
like L-ascorbic acid 10 as the chiral template (Fig. 1).
According to retrosynthetic plan (Scheme 1), it was envisioned
that diols 1a and 2a could be easily generated from azide 7 via
⇑
Corresponding author. Tel.: +91 20 25902289; fax: +91 20 25902629.
E-mail address: sp.chavan@ncl.res.in (S.P. Chavan).
http://dx.doi.org/10.1016/j.tetlet.2014.12.103
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Chavan, S. P.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2014.12.103

2
S. P. Chavan et al. / Tetrahedron Letters xxx (2015) xxx–xxx
OH
OBn
OBn
H
O
O
c
f
b
a
O
O
12 and 13
OH
O
N
OH
OH
N
COOEt
14
8
N
H
OH
O
H
O
H
OMe
N
H
2
N
H
NH
OBn
O
OBn
OBn
OH
OH
1
Tetrazomine
O
d
g
e
HO
HO
HO
3
O
HO
N
N
O
HO
OH
TBSO
OH
H
15
7
O
16
17
N3
N3
N3
HO
N
H
N
H
OH
8
N
OBn
OBn
O
(-)-Prosopinine
BnO
TBSO
MsO
(-)-Swainsonine
(+)-Febrifugine
MsO
TBSO
5
4
6
+
TBSO
N
Boc
18
Figure 1. Alkaloids with 3-hydroxy pipecolic acid fragment.
N3
NHBoc
19
OBn
BnO
Scheme 3. Reagents and conditions: (a) Pd(OH)2/C, HCOONH4, MeOH, reflux, 2 h,
92%; (b) LiBr, NaBH4, MeOH/H2O, 3 h, 88%; (c) (i) MsCl, TEA, DCM, 0 °C, 30 min, (ii)
NaN3, DMF, 90 °C, 6 h, 70% (over two steps); (d) AcOH/H2O (8:2), rt, 85%; (e) TBSOTf,
TEA, DCM, 0 °C, 30 min, 90%; (f) MsCl, TEA, DCM, 0 °C, 30 min, 92%; (g) (i) PPh3,
benzene/H2O (9:1), reflux, (ii) (Boc)2O, TEA, DMAP (Cat.), THF, rt, 50% (over two
steps).
R1
R2
MsO
O
TBSO
HO
N
O
COOEt
Boc
7
N3
8
1a; R1 = H, R2 = OH;
2a;
BnO
BnO
BnO
HO
R1 = OH, R2 = H
a
OH
+
HO
HO
HO
TBSO
HO
BnO
N
N
N
Boc
Boc
O
Boc
O
O
18
O
20
21
OH
10
BnO
HO
HO
HO
HO
9
b
c
N
N
Scheme 1. Retrosynthetic analysis.
HOOC
N
H
Boc
Boc
1a
20
1
BnO
HO
HO
HO
HO
b
OH
d
OBn
HO
HO
HO
a
b
N
N
O
HOOC
N
H
2
O
Boc
Boc
2a
O
10
21
OH
O
9
Scheme 4. Reagents and conditions: (a) TBAF, THF, 0 °C to rt, 80%; (b) Pd(OH)2, H2,
MeOH, rt, 85%; (c) Ref. 5a; (d) Ref. 6a.
OBn
OBn
O
O
O
c
O
The column separated benzyl ether compounds 20 and 21 were
separately subjected to hydrogenation to provide diol 1a and 2a,
respectively, in 85% yields. The spectroscopic properties and rota-
tion values of compounds ent-1a and 2a were in good agreement
with the reported one. The chiral purity of trans-diol 2a was estab-
lished by chiral HPLC analysis. Diols 1a13 and 2a14 were further
elaborated to the cis and trans-pipecolic acids (1 and 2) by the
known literature protocol.5a,6a
COOEt
O
12
E:Z 9:1
11
d
OBn
O
O
COOEt
13
In conclusion, we have achieved the formal syntheses of
(2R,3R)-3-hydroxy pipecolic acid 1 and (2R,3S)-3-hydroxy pipeco-
lic acid 2 by utilizing epimerization and reductive cyclization as
the key step from the common precursor.
Scheme 2. Reagents and conditions: (a) Ref. 7; (b) Swern oxidation or IBX, EA,
reflux, 3 h; (c) PPh3CHCOOEt, DCM, 0 °C to rt, overnight, 80% (over two steps); (d)
(EtO)2P(O)CH2COOEt, NaH, benzene, 80% (over two steps).
Acknowledgements
DMF or DCM as the solvent was found to be less productive. This
issue was solved by selective protection by using TBSOTf, TEA in
DCM at 0 °C to provide O-TBS derivative 17 in 90% yield.6c Second-
ary hydroxy group of compound 17 was converted to its mesyl
derivatives using MsCl, TEA in DCM at 0 °C to afford O-mesylate
compound 7 in 92% yield. Our next concern was cyclization which
was achieved by employing Staudinger reaction conditions12 using
PPh3 in benzene/H2O followed by treatment with (Boc)2O to fur-
nish cyclic carbamate 18 in 50% yield along with uncyclized carba-
mate 19 in 10% yield. The O-TBS deprotection of compound 18 was
achieved using TBAF in THF solvent to furnish the column separa-
ble hydroxy methyl compounds 20 and 21 in 80% (dr 6:4) yield (in
Scheme 4).
NBD and KPP thank CSIR, New Delhi, India, for financial support.
The authors thank Dr. H.B. Borate for helpful discussions and CSIR,
New Delhi, India, for financial support as part of XII Five Year plan
programme under title ACT (CSC-0301).
Supplementary data
Supplementary data (supplementary material includes experi-
mental details 1H, 13C NMR spectra and HRMS for new compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.12.103.
Please cite this article in press as: Chavan, S. P.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2014.12.103

S. P. Chavan et al. / Tetrahedron Letters xxx (2015) xxx–xxx
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25
13. Spectral data for 1a: mp: 115–117 °C, lit.5a 114–116 °C; yield: 85%; [
a
]
À24 (c
D
0.7, MeOH); lit.5a for ent-1a [ 20 +23.1 (c 1.03, MeOH); IR (CHCl3, cmÀ1): 3448,
a]
D
2934, 1686; 1H NMR (400 MHz, CDCl3): d 1.48 (s, 9H), 1.59–1.82 (m, 4H), 2.89
(br s, 1H), 3.68–3.80 (m, 2H), 3.92–4.01 (m, 1H), 4.11 (dd, J = 6.0 & 11.0 Hz, 1H),
4.25–4.34 (m, 1H); 13C NMR (100 MHz, CDCl3): d 23.7, 28.2, 28.3, 39.5, 55.9,
59.2, 69.3, 80.3, 155.6; ESIMS (m/z): 232.3 (M+H)+; HRMS (Na+) calcd for
C
11H21NO4: 231.1470. Found: 231.1484.
25
14. Spectral data for 2a: mp: 133–135 °C; [
a
]
À27.58 (c 1.0, MeOH); IR (CHCl3,
D
cmÀ1): 3435, 1666; 1H NMR (200 MHz, CD3OD): d 1.15–1.29 (m, 1H), 1.39 (s,
9H), 1.61–1.82 (m, 3H), 2.69–2.82 (m, 1H), 3.45–3.61 (m, 2H), 3.89–3.92 (m,
2H), 4.08–4.16 (m, 1H); 13C NMR (125 MHz, C2D6SO + CDCl3 + CCl4): d 18.95,
26.57, 28.15, 39.79, 59.13, 59.91, 63.83, 79.12, 155.92; HRMS (Na+): calcd for
C11H21NO4: 231.1484. Found: 231.1470; GCMS (m/z): 231.
Please cite this article in press as: Chavan, S. P.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2014.12.103