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S. P. Chavan et al. / Tetrahedron Letters 55 (2014) 6423–6426
utilized serine derivatives as the precursor.13a–f The two
approaches had incorporated
-glucose13g,h while -proline13i and
-glycal13j were utilized to incorporate chirality. To the best of
our knowledge, based on literature survey, only one synthesis
has been reported to access cis 3-hydroxypipecolic acid enantio-
mers from the common starting material.13f
The potential application of 3-hydroxypipecolic acids coupled
with our continued interest towards the development of efficient
and practical approaches towards piperidine alkaloids,13k,14 led
us to explore a new method towards their synthesis. We herein
report the stereoselective syntheses of both the antipodes of cis
3-hydroxypipecolic acid starting from cis aziridine-2-carboxylate
as the common synthetic precursor which could be easily derived
syntheses of (R) and (S)-pipecolic acid.14e In continuation of our
work, cis-aziridine-2-carboxylate 7 was reduced using LAH/THF
to give alcohol 12 in 90% yield. The hydroxyl group of compound
12 was protected as its benzyl ether using benzyl bromide and
NaH in DMF to furnish benzyl ether 13 in 95% yield. Compound
13 was subjected to acetonide deprotection using PTSA/MeOH to
afford diol 14 in 85% yield. Diol 14 on oxidative cleavage using
sodium metaperiodate in acetone/water provided aldehyde which
was used as such for Wittig olefination with PPh3CHCO2Et and cat-
alyst benzoic acid in refluxing toluene (a method used for the for-
mation of E as major isomer)17 to furnish compound 8 in 85% yield
D
L
D
over two steps. The resultant a,b-unsaturated ester aziridine 8 was
subjected to regio and stereoselective aziridine ring opening reac-
tion in acidic conditions18 (TFA, 2 equiv) by water as nucleophile to
form vicinal amino alcohol 9. Once the stereocentres at amine and
hydroxyl functionality of amino-alcohol 9 were fixed with the
desired stereochemistry, the hydroxyl group of amino-alcohol 9
was selectively protected as its TBS ether derivative 15 using TBSCl,
imidazole and catalyst DMAP under reflux condition in dichloro-
methane with 90% yield. Compound 15 on hydrogenation using
10% Pd(OH)2 in ethanol19 underwent concomitant double bond
reduction, selective N-debenzylation and cyclization to furnish
desired stereoisomer lactam 16 in 88% yield with requisite piperi-
dine skeleton. Further, lactam 16 was reduced to amine using
BH3ÁDMS to furnish crude amine, which without purification was
protected as its N-Boc derivative using Boc-anhydride and triethyl-
amine as the base to give intermediate 17 in 80% yield. Intermedi-
ate 17 is well reported in the literature and can be converted into
(2S,3R)-3-hydroxypipecolic acid 1 in three steps in 73% yield.20
Spectral and analytical data of compound 17 thus obtained are in
good agreement with reported one.24 Thus, this constitutes the
formal synthesis of (2S,3R)-3-hydroxypipecolic acid 1 (Scheme 2).
The formal synthesis of enantiomeric (2R,3S)-3-hydroxypipe-
colic acid ent-1 (Scheme 3) started with common synthetic precur-
sor viz. cis-aziridine-2-ester 7 which on propagation from ester
side using DIBAL-H reduction to crude aldehyde followed by Wittig
from
Aziridine-2-carboxylates have been considered as prominent
precursors towards the synthesis of and b-amino acid building
D-mannitol diacetonide.
a
blocks because of their inherent ability towards nucleophilic ring
opening reactions.15 In spite of that, aziridines are relatively less
explored compared to their oxygenated three-membered ring part-
ner and even termed as ‘ugly cousins’ of oxiranes15c because of
their less reactivity and selectivity towards ring opening by nucle-
ophiles. However, proper manipulations of functionalities attached
to the aziridine ring can greatly enhance their reactivity and
improve their applicability as important synthons towards the
preparation of various amino building blocks. The desymmetriza-
tion of cis aziridine-2-carboxylate 7 (having latent plane of symme-
try element) by nucleophilic ring opening at either side of aziridine
ring would generate enantiomeric amines. In an attempt to exploit
this aspect of aziridine 7 as shown in retrosynthetic analysis
(Scheme 1), it was envisioned that desired syn 1,2-amino-alcohol
stereochemistry of piperidine skeleton of cis-3-hydroxypipecolic
acid viz. 1 and ent-1 can be achieved from respective amino-alco-
hols 9 and 11 having requisite chirality. The amino-alcohols 9 and
11 in turn can be accessed by regio and stereoselective aziridine
ring opening reaction of appropriate
a,b-unsaturated aziridine
esters 8 and 10 by the hydroxyl group as the nucleophile. The
required aziridines 8 and 10 can be easily prepared by regioselec-
tive functionalization on either side of cis aziridine-2-carboxylate
7. Ester and acetonide functionalities of aziridine 7 can serve as a
handle for desymmetrization.
homologation gave
a,b-unsaturated aziridine-ester 10. Aziridine
RO
BnO
EtO2C
O
OH
Actual synthesis began with cis-aziridine-2-carboxylate 7 which
O
c
a
O
was prepared from
D-mannitol diacetonide using known literature
OH
O
procedure.16 We recently exploited cis aziridine 7 towards the total
N
N
N
Bn
Bn
Bn
b
HO
OH
7
14
R=H, 12
R=Bn, 13
HO2C
N
H
N
H
CO2H
1
1
ent-
BnO
d
CO2Et
e
BnO
CO2Et
CO2Et
BnO
f
BnHN
BnHN
EtO2C
OH
O
N
Bn
8
OTBS
OH
HO
CO2Et
9
15
BnHN
O
O
BnO
NHBn
9
11
OH
OTBS
g
OTBS
h
ref. 20
N
H
CO2H
O
N
H
EtO2C
N
CO2Et
OBn
Boc OBn
BnO
O
EtO2C
Bn
O
O
(2S,3R)-3-hydroxy
pipecolic acid
16
17
1
N
N
N
Bn
Scheme 2. Reagents and conditions: (a) LAH, THF, 0 °C, 1 h, 90%; (b) BnBr, NaH, cat.
TBAI, DMF, 95%; (c) PTSA, CH3OH, 85%; (d) (1) NaIO4, (CH3)2CO/H2O (2:1), (2)
Ph3PCHCO2Et, cat. PhCO2H, PhMe, reflux, 85% (over two steps); (e) TFA, CH3CN/H2O
(9:1), 85%; (f) TBSCl, Imd, cat. DMAP, CH2Cl2, reflux, 90%; (g) H2, 10% Pd(OH)2/C,
EtOH, 88%; (h) (1) BH3ÁDMS, THF, (2) (Boc)2O, CH2Cl2, Et3N, 80% (over two steps).
Bn
8
7
10
Scheme 1. Retrosynthetic analysis for cis-3-hydroxypipecolic acid.