Enantioselective syntheses of (R)-pipecolic acid, (2R,3R)-3-hydroxypipecolic acid, β-(+)-conhydrine and (-)-swainsonine using an aziridine derived common chiral synthon

Article abstract of DOI:10.1039/c5ra06429e

Concise total syntheses of (R)-pipecolic acid, (R)-ethyl-6-oxopipecolate, (2R,3R)-3-hydroxypipecolic acid and formal syntheses of β-(+)-conhydrine, (-)-lentiginosine, (-)-swainsonine and 1,2-di-epi-swainsonine have been accomplished starting from a common chiral synthon. The present strategy employs regioselective aziridine ring opening, Wittig olefination and RCM as the key chemical transformations.

Full text of DOI:10.1039/c5ra06429e

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Journal Name
RSCPublishing
ARTICLE
Enantioselective syntheses of (R)-pipecolic, (2R,3R)-3-
hydroxypipecolic acid, βꢀ(+)-conhydrine and (-)-
swainsonine using aziridine derived common chiral
synthon
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Subhash P. Chavan,* Lalit B. Khairnar, Kailash P. Pawar, Prakash N. Chavan and Sanket
A. Kawale
DOI: 10.1039/x0xx00000x
www.rsc.org/
Concise total syntheses of (R)ꢀpipecolic acid, (R)ꢀethylꢀ6ꢀoxopipecolate, (2R,3R)ꢀ3ꢀhydroxypipecolic acid
and formal syntheses of βꢀ(+)ꢀconhydrine, (ꢀ)ꢀlentiginosine, (ꢀ)ꢀswainsonine and ꢀ1,2ꢀdiꢀepiꢀswainsonine
have been accomplished starting from the common chiral synthon. Present strategy employs regioselective
aziridine ring opening, Wittig olefination and RCM as the key chemical transformations
.
Introduction
OH
OH
OH
H
N
(S)ꢀPipecolic acid 1, is a cyclic nonꢀproteinogenic amino
OH
OH
N
CO2H
N
acid1 and its natural, non natural derivatives have found
widespread applications in therapeutic chemistry (Figure 1).
Pipecolic acid acts as an integral framework of many
N
CO2H
H
H
H
(R)ꢀpiperidinꢀ
2ꢀylmethanol 2
(2 ,3 )ꢀ3ꢀHydroxyꢀ
pipecolic acid 3
R
R
(S)ꢀPipecolic acid 1
(ꢀ)ꢀSwainsonine 4
OH
OH
H
OH
H
pharmaceutically
important
molecules
such
as
immunosuppressors rapamycin,2 FK506, immunomycin,3 the
antitumor antibiotic sandramycin,4 local anaesthetics like
O
N
CO2Et
OH
OH
H
N
N
(R)ꢀEthyl 6ꢀoxopiperidine
ꢀ2ꢀcarboxylate 7
bupivacaine and ropivacaine.5 Similarly (
R
)ꢀpipecolic acid ent
ꢀ
(ꢀ)ꢀLentiginosine 6
(+)ꢀ1,2ꢀdiꢀepiꢀswainsonine 5
OH
1
is a key constituent of the histone deacetylase (HDAC)
OH
OH
N
O
inhibitors recognized as the potential anticancer drugs.6 (
Piperidinꢀ2ꢀylmethanol , a reduced analogue of ent
used as a precursor in the synthesis of (–)ꢀlentiginosine
R
)ꢀ
OH
OH
N
N
N
H
N
H
8
2
ꢀ
1
has been
, a
O
H
8
O
O
6
(+)ꢀProsopinine 8
(+)ꢀProsophylline 9
(+)ꢀFebrifugine 10
CH2OH
naturally occurring alkaloid having amyloꢀglucosidase enzyme
inhibition properties.7 3ꢀHydroxypipecolic acids are important
scaffolds with piperidine skeleton and found in many
biologically significant molecules.8
hydroxypipecolic acid is a cyclic
H
N
O
OH
NH
O
N
O
OH
N
N
Transꢀ(–)ꢀ(2
R,3R)ꢀ3ꢀ
N
H
H
N
H
H
3
β
ꢀhydroxyꢀ ꢀamino acid
α
OMe
O
that has been used as a precursor in the synthesis of (–)ꢀ
(+)ꢀIsofebrifugine 11
Tetrazomine 12
swainsonine 4,9 a potent antiꢀcancer drug and specific inhibitor
anaesthetic and antibiotic activities.12 cis Stereoisomer of 3ꢀ
hydroxypipecolic acid is main constituent of (+)ꢀisofebrifugine
Fig 1: Pipecolic acid and its derivatives.
of αꢀDꢀmannosidase.10 The stereochemistry of enantiomer of
3
is found in (+)ꢀfebrifugine, a potent antimalarial agent,11 and its
reduced analogues were found as important structure motif’s of
(+)ꢀprosopinine and (+)ꢀprosophylline which exhibit analgesic,
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ARTICLE
DOI: 10.1039/C5RA06429E
and chemoselective nucleophilic ring opening reactions.21
Inspite of that, aziridines are relatively less explored compared
to their three membered analog oxiranes due to less reactivity
and selectivity towards ring opening reactions. However these
drawbacks can be overcome by proper manipulations of
functional groups attached to aziridine ring.
which also shows antimalarial activity and of tetrazomine 12
which shows antitumor antibiotic activities.13 Oxopipecolate
7
has been utilized in medicinal chemistry and to prepare an
important class of antitumor agents and is useful for the
synthesis of pipecolic acid derivatives (Figure 1).14 Pipecolic
acid and its 3ꢀhydroxy derivatives have also been incorporated
in peptides which can induce a βꢀturn with resultant therapeutic
significance15 and are also useful as organocatalysts.16 In
general, pipecolic acid and its diverse functionalities are useful
chiral building blocks for the synthesis of a variety of
Thus as shown in the retrosynthetic plan (Scheme 1), it was
envisioned that all of the six piperidine alkaloids could be derived
from aziridine carboxylic acid 13 as the common precursor. For the
synthesis of pipecolic acid as well as 3ꢀhydroxypipecolic acid, it was
surmised that vinyl aziridine ester 14 would serve as ideal substrate.
The vinyl aziridine ester 14 could be readily derived from aziridine
ester 13 by chain propagation from the acetonide side. Ester 14 by
proper choice of reaction conditions could be converted to (R)ꢀethylꢀ
6ꢀoxoꢀpipecolate 7, which serves as an important intermediate for
pipecolic acid derivatives.14 Compound 7 in turn can be further
converted to the intermediate 15, a precursor for the synthesis of (−)ꢀ
pharmaceutically important molecules.
Owing to their importance, enantiomerically pure syntheses
of pipecolic acid and its derivatives has gained wide attention
and have been extensively reviewed.17,18,19 As part of our
continued interest toward development of efficient and practical
synthetic routes to piperidine alkaloids.20 Herein we report an
alternate practical and efficient syntheses of (
ent , ( )ꢀethylꢀ6ꢀoxopipeclate , (2 ,3 )ꢀ3ꢀhydroxypipecolic
acid and formal synthesis of (−)ꢀswainsonine , (+)ꢀ1,2ꢀdiꢀ
epiꢀswainsonine and (–)ꢀlentiginosine from trans aziridineꢀ
R
)ꢀpipecolic acid lentiginosine22 and (R)ꢀpipecolic acid entꢀ1. Aziridine ester 14 on
ꢀ
1
R
7
R R
regio and stereoselective ring opening under acidic condition by
hydroxyl group could be converted to aminoꢀalcohol 27 which could
be further transformed to trans 3ꢀhydroxypipecolic acid 3. Similarly,
aziridine ester 13 on propagation from ester side would furnish α,βꢀ
unsaturated ester aziridine 17 which on regio and stereoselective ring
opening by hydroxy group followed by cyclization, Nꢀallylation and
RCM would give intermediate 18, enantiomer of which is well
explored towards the synthesis of (+)ꢀswainsonine entꢀ4 and (–)ꢀ
8,8aꢀdiꢀepiꢀswainsonine entꢀ5.23
3
4
5
6
2ꢀcarboxylate 13 as the common synthetic precursor derived
from commercially available and cheap starting material viz. Dꢀ
mannitol diacetonide. We have earlier described syntheses of
R
and
S pipecolic acids 3ꢀhydroxy pipecolic acid from cis
aziridine.20
Results and Discussions
The synthetic endeavor for pipecolic acid and derivatives started
with readily available and cheap starting material Dꢀmannitol
diacetonide 19 (Scheme 2). Accordingly, Dꢀmannitol diacetonide 19
Enantiomerically pure aziridines have been considered to be
prominent precursors in the synthesis of natural and unnatural
amino compounds due to their inherent ability to undergo regio
OH
H
OH
H
NaIO4
OH
O
O
H
(Ph3)3PCBrCO2Et
DCM, rt, 85%
aq. NaHCO3
O
O
OH
OH
N
N
H
CO2H
OH
N
H
N
O
DCM, rt
O
OH
O
1
ent-
6
O
19
20
OH
OH
4
OH
5
O
Br
TMSOTf
O
BnNH2
OH
OTBS
H
O
EtO2C
EtO2C
DCM
0°C, 90%
TEA, PhMe
0°C to rt, 68%
OH
N
N
N
H
CO2H
O
N
21
Bn
13
Boc
18
15
3
OH
1, NaIO4, (CH3)COꢀH2O (2:1)
CO2Et
OH
EtO2C
EtO2C
N
2. (EtO)2POCH2CO2Et
NaH,THF
0°C, 70% over 2 steps
EtO2C
OH
N
NHBn
Bn
O
CO2Et
Bn
22
14
EtO2C
O
N
H
CO2Et
O
BnHN
OH
27
7
17
1.LAH, THF, 0°C to rt
10% Pd/C, NH4CO2
EtOH, 60 °C, 85%
O
N
CO2Et 2, (Boc)2O, NaHCO3
THFꢀH2O (2:1)
N
H
Boc
O
CO2Et
EtO2C
OH
CO2Et
Bn
70% over 2 steps
7
15
N
N
O
Bn
14
16
1. TFA, DCM
2. KMnO4, 3N H2SO4
73% over 2 steps
CO2H
N
O
H
O
EtO2C
(R)ꢀpipecolic acid ent-1
N
13
Bn
Scheme 2: Synthesis of (R)ꢀpipecolic acid entꢀ1.
Scheme 1: Retrosynthetic analysis for target compounds.
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5RA06429E
on diol cleavage using NaIO4 yielded acetonide protected (
R
)ꢀ 13, attention was diverted to regioselective ring opening of
glyceraldehyde 20 which on Wittig olefination using aziridine ring in compound 13 by water as the nucleophile. In
bromophosphorane24 in dichloromethane afforded bromoester the next step, when compound 14 was treated with TFA (2
21. The GabrielꢀCromwell reaction of 2ꢀacrylic carboxylate equiv.) in CH3CN–H2O (9:1), it underwent regio and
derivative 21 with benzyl amine in toluene as solvent furnished stereoselective nucleophilic ring opening reaction using water
trans aziridineꢀ2ꢀcarboxylate 13 as the major isomer via as nucleophile to afford
γꢀhydroxyꢀδꢀaminoꢀα,βꢀconjugated
conjugate addition, proton transfer and SN2 ring closure in 68% ester 16 as the only isomer in 76% yield (Scheme 2). Selective
yield.25 The trans aziridine 13 was readily obtained by column protection of hydroxyl group of aminoꢀalcohol 16 was achieved
chromatography. Acetonide trans aziridine 13 was deprotected using TBSCl, imidazole and cat. DMAP in refluxing
using TMSOTf/CH2Cl2 at 0 °C,26 to furnish diol 22 in excellent dichloromethane to furnish TBS ether 23 in 85% yield. The
yield (90%). Diol 22 was then subjected to sodium crucial step viz. reductive cyclization of 23 was carried out
metaperiodate mediated oxidative cleavage to yield crude under hydrogenation conditions using hydrogen gas and
aldehyde which was subjected to HornerꢀWadsworthꢀEmmons palladium hydroxide over carbon in ethanol to provide amide
olefination to afford α,βꢀunsaturated aziridineꢀester 14 in 70% 24 in 85% yield (Scheme 3). In next step amido ester 24 was
yield over two steps. This α,βꢀunsaturated aziridine carboxylate subjected to selective reduction of amide functionality using
14 (Scheme 2) when subjected to palladium mediated transfer borane dimethyl sulfide complex in anhydrous THF to furnish
hydrogenation conditions,25b,27 underwent one pot efficient the amino ester 25 in 78% yield. Finally the global deprotection
regioselective aziridine ring cleavage with concomitant olefin involving ester hydrolysis as well as TBS group deprotection of
reduction,
as the key step to give access to (
85% yield. Pipecolate was further converted to (
piperidinemethanol 15 over two steps using LAH induced agreement with the reported one.28
Nꢀdebenzylation and cyclisation of resultant amine 25 was carried out in a single step using 6N HCl to provide
R
)ꢀethylꢀ6ꢀoxopipecolate in 91% yield. The spectral
7
in (2
R
,3
R
)ꢀ3ꢀhydroxypipecolic acid
3
7
R
)ꢀNꢀBocꢀ2ꢀ data and optical rotation values of 3 thus obtained were in good
In order to ascertain the chiral purity, the lactam 25 was
subjected to reduction using lithium aluminum hydride in
lactam/ester reduction followed by protection of resulting crude
aminoꢀalcohol as ꢀBoc derivative in 97% ee by HPLC
analysis )ꢀ ꢀBocꢀ2ꢀpiperidinemethanol 15 can be utilized as
a precursor towards synthesis of (−)ꢀlentiginosine 6 22
compound 15 was converted to ( )ꢀpipecolic acid ent
N
anhydrous THF followed by NꢀBoc protection to provide
Nꢀ
. (R N
Boc derivative 26. The chiral HPLC analysis of the 26 revealed
that the chiral purity was ~97% ee (Scheme 4). Thus the total
.
Finally
R
ꢀ1 by Boc
synthesis of trans (2
accomplished in 24.6% overall yield in 8 steps from trans
aziridine 13
R,3R)ꢀ3ꢀhydroxypipecolic acid 3 was
deprotection using TFA followed by oxidation using KMnO4 in
aqueous 3 N H2SO4. The synthesis of ( )ꢀpipecolic acid has
been achieved in 27% overall yields while ( )ꢀethylꢀ6ꢀoxoꢀ
pipecolate was achieved in 54% overall yield from trans
.
R
R
OTBS
CO2Et
1. LAH, THF
0 °C to reflux
O H
aziridineꢀ2ꢀcarboxylate 13 respectively
.
O H
O
N
H
N
2. (Boc)2O, NaHCO 3
NHBn
OH
Boc
THFꢀH2O (2:1)
75% over 2 steps
TFA
24
26
CO2Et
CO2Et
EtO2C
EtO2C
N
CH3CNꢀH2O (9:1)
0C to rt, 76%
Scheme 4: Synthesis of diol 26
.
Bn
14
16
Our endeavor towards formal synthesis of (–)ꢀswainsonine 4 and
(+)ꢀ1,2ꢀdiꢀepiꢀswainsonine 5 started with aziridineꢀ2ꢀcarboxylate 13
whose acetonide moiety was kept intact as a masked aldehyde while
ester group was propagated to give transꢀaziridineꢀα,βꢀunsaturated
ester 17. Thus trans aziridneꢀ2ꢀcarboxylate 13 on reaction with
DIBALꢀH (1.2 eq.) yielded aldehyde which was used as such for the
next step, HornerꢀWadsworthꢀEmmons reaction on the resultant
NHBn
H2, 10% Pd/C
TBSCl, Imd
CO2Et
EtO2C
cat. DMAP, DCM
reflux, 85%
NaOAc, EtOH
85%
OTBS
23
OTBS
OTBS
HCl, 6N
BH3—DMS
reflux, 91%
O
N
H
CO2Et
THF, rt, 78%
N
H
CO2Et
aldehyde furnished α,βꢀunsaturated trans aziridine ester 17 in 75%
yield over two steps. Following the aziridine ring opening reaction
under acidic conditions, compound 17 gave amino alcohol 27
(Scheme 5). Hydroxyl functionality of this aminoꢀalcohol 27 was
protected as its TBS ether 28 in 90% yield. Compound 28 on
Palladium mediated hydrogenation/hydrogenolysis afforded lactam
29 in 92% yield. Allylation of lactam 29 was carried out using allyl
bromide and NaH in DMF as the solvent to give Nꢀallylated lactam
30 in 85% yields. Lactam 30 was exposed to 80% aqueous acetic
acid at 80 °C to furnish diol 31 by selective deprotection of terminal
24
25
OH
N
H
CO2H
(2R,3R)ꢀ3ꢀHydroxypipecolic acid 3
Scheme 3: Synthesis of (2R,3R)ꢀ3ꢀhydroxy pipecolic acid 3.
After achieving the site selective functional group acetonide functionality in presence of secondary –OTBS group in
75% yield.29 After failing to convert 1,2ꢀdiol functionality of the
transformation at the acetonide group of aziridineꢀ2ꢀcarboxylate
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compound 31 into corresponding alkene in one step using bicyclic lactam 18 having requisite indolizidine skeleton of
PPh3/I2/imidazole,30 it was cleaved using NaIO4 in acetoneꢀwater to
swainsonine. Enantiomer of 18 and its convertion to entꢀ4 and entꢀ5
is well documented in the literature. The spectral data of 18 were in
good agreement with the reported one except for the sign of optical
rotation (Scheme 5).
1. DIBALꢀH,
DCM, ꢀ78°C,
O
O
O
O
EtO2C
EtO2C
Bn
2. (EtO)2POCH2CO2Et,
NaH, THF, 0 °C,
75% over 2 steps
N
N
Additionally, aziridine ester 17 when subjected to transfer
hydrogenation conditions yielded lactam 33 in excellent yield.
Lactam 33 is key intermediate towards the syntheses of βꢀ(+)ꢀ
conhydrine and its analogues (Scheme 6).32
Bn
13
17
O
TFA,
CH3CNꢀH2O (9:1),
OH
TBSCl, Imd,
cat. DMAP,
O
EtO2C
0 °C to rt., 80%
DCM, reflux, 90%
NHBn
27
Conclusions
OTBS
H
In conclusion, an efficient enantioselective total synthesis (R)ꢀ
pipecolic acid entꢀ1, (R)ꢀethylꢀ6ꢀoxopipecolate 7 and trans (2R,3R)ꢀ
3ꢀhydroxypipecolic acid 3. A concise formal synthesis of (−)ꢀ
swainsonine 4, (+)ꢀ1,2ꢀdiꢀepiꢀswainsonine 5 and (−)ꢀlentiginosine 6
have also been achieved from trans aziridineꢀ2ꢀcarboxylate 13 as the
common chiral synthon. The notable features of these syntheses are
regio and stereoselective Wittig olefination, ring closing metathesis,
reductive cyclisation and regio and stereoselective aziridine ring
opening as key chemical transformations.
O
TBSO
H2, 10% Pd(OH)2/C,
MeOH, 92%
O
O
N
H
O
EtO2C
O
NHBn
28
29
OTBS
H
OTBS
H
NaH, allyl bromide,
cat. TBAI,
Aq. 80% AcOH,
80 °C, 75%
N
O
O
N
O
OH
DMF, 85%;
O
OH
30
31
Syntheses are operationally simple and practical in terms of
overall yield. The trans aziridine ester synthon was found to be a
versatile highly efficient for the synthesis of various piperidine
skeletons.
OTBS
OTBS
H
1.NaIO4,
acetoneꢀwater (2:1)
Grubbs'
2ndgen. catalyst,
H
O
N
2. Ph3PCHCO2Et,
DCM, 75%,
over 2 steps
O
N
DCM, reflux, 80%.
Experimental
General information:
CO2Et
32
18
All reagents and solvents were used as received from the
manufacturer. HRMS (ESI) were recorded on ORBITRAP
mass analyzer (Thermo Scientific, Q Exactive). Mass spectra
were measured with ESI ionization in MSQ LCMS mass
spectrometer. IR spectra were recorded on a PerkinꢀElmer
Infrared Spectrophotometer Model 68B or on a PerkinꢀElmer
1615 FT Infrared spectrophotometer. Melting points of solids
were measured in Buchi melting point apparatus and are
uncorrected. Optical rotation values were recorded on Pꢀ2000
OH
H
OTBS
ref. 23
OH
H
ref. 23a
H
OH
N
OH
O
N
N
OH
(+)ꢀ1,2ꢀdiꢀepiꢀswainsonine 5
OH
18
(ꢀ)ꢀswainsonine 4
Scheme 5: Synthesis of (ꢀ)ꢀswainsonine
4
and (+)ꢀ1,2ꢀdiꢀepiꢀswainsonine 5.
1
polarimeter at 589 nm. H (200 and 400 MHz) and 13C (50 and
furnish the crude aldehyde which, without purification, was
subjected to 2ꢀcarbon Wittig homologation in dichloromethane to
yield α,βꢀunsaturated ester 32 in 75% yield over two steps. Finally
100 MHz) NMR spectra were recorded on Bruker and Bruker
Advance 400 spectrometers, using a 1:1 mixture of CDCl3 and
CCl4 as solvent. The chemical shifts (
δ ppm) and coupling
performing
the
ring
closing
metathesis
reaction
on
constants (Hz) are reported in the standard fashion with
reference to chloroform, δ 7.27 (for 1H) or the central line (77.0
ppm) of CDCl3 (for 13C). In the 13C NMR spectra, the nature of
the carbons (C, CH, CH2, or CH3) was determined by recording
the DEPTꢀ135 spectra. The following abbreviations were used
to explain the multiplicities: br = broad, s = singlet, d = doublet,
t = triplet, q = quartet. The reaction progress was monitored by
the TLC analysis using thin layer plates precoated with silica
gel 60 F254 (Merck) and visualized by fluorescence quenching
or iodine or by charring after treatment with ethanolic solution
of ninhydrin or anisaldehyde. Merck’s flash silica gel (230ꢀ400
mesh) was used for column chromatography.
Scheme 6: Synthesis of key intermediate 33
Experimental:
compound 32 using Grubbs’ 2nd generation catalyst31 in refluxing
anhydrous dichloromethane gave access to key intermediate viz.
(
S
)-Ethyl
2-bromo-3-(2,2-dimethyl-1,3-dioxolan-4-
)ꢀglyceraldehyde
yl)acrylate (21):33 Freshly prepared
(
R
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DOI: 10.1039/C5RA06429E
acetonide 20 (5.24 g, 0.020 mol) from diꢀOꢀisopropylidene (D)ꢀ
mannitol 19 was taken in CH2Cl2 (75 mL). To this was added a
(2
R
,3
R
)-Ethyl
-1-benzyl-3-((
S
)-1,2-
(22):
dihydroxyethyl)aziridine-2-carboxylate
solution of ethyl 2ꢀbromoꢀ2ꢀ(triphenylphosphoranylidene)
To a stirred, iceꢀcold solution of the aziridine acetonide 13
(0.163 g, 0.53 mmol) in anhydrous CH2Cl2 (2 mL) under an
inert atmosphere, was added TMSOTf (0.24 mL, 1.3 mmol)
through a syringe. The resulting reaction mixture was stirred at
the same temperature for 1 h, followed by quenching the
reaction by addition of a saturated aqueous NaHCO3 solution.
After stirring the mixture for 5 min, the organic layer was
separated and the aqueous layer was saturated with solid NaCl
and extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were dried over anhydrous Na2SO4 and filtered.
Concentration of the solvent under reduced pressure and
column chromatographic purification (pet. etherꢀethyl acetate,
7:3) of the residue provided the pure acetonideꢀcleaved product
22 as a thick liquid (0.127 g). Rf: 0.4 (pet. etherꢀethyl acetate,
acetate34
(18.8 g, 0.044 mol) in CH2Cl2 (150 mL) and stirred for
2 h at room temperature. Organic layer was separated and
aqueous layer was extracted with CH2Cl2. Combined organic
layer was dried over anhydrous Na2SO4, filtered and solvent
was evaporated under reduced pressure. Residue was purified
by column chromatography using pet. ether: ethyl acetate
(95:5) to give bromoester 21 (E/Z = 7:93). Rf: 0.5 (pet. etherꢀ
ethyl acetate, 9:1); Yield: 10.5 g, 84% over two steps; IR
1
(CHCl3, cmꢀ1): νmax 2980, 1720, 1620; H NMR (200 MHz,
CDCl3+CCl4):
3H), 3.70 (dd,
δ
J
1.36 (t,
= 6.6 & 8.3 Hz, 1H), 4.27 (q,
= 6.6 Hz, 1 H); 13
14.1, 25.5, 26.4, 62.6, 68.0,
75.5, 110.2, 116.7, 144.0, 161.4. MS (ESI): m/z: 279 (M+H)+.
(2 ,3 )-Ethyl 1-benzyl-3-(( )-2,2-dimethyl-1,3-dioxolan-4-
yl)aziridine-2-carboxylate (13): 8.37 g (0.030 mol) of
bromoacrylate was dissolved in dry toluene (100 mL) and the
J
= 8.0 Hz, 3H), 1.41 (s, 3H), 1.46 (s,
J
= 8.0 Hz, 3H),
4.95 (dd,
J
= 6.7 & 13.3 Hz, 1H), 7.36 (d,
J
C
NMR (125 MHz, CDCl3+CCl4):
δ
25
25
D
1:1); Yield: 90%; [α] +20.22 (
D
c
2.1, CHCl3), {Lit35 [α]
R
R
S
+19.6 (
c
0.56, CHCl3)}; IR (CHCl3, cmꢀ1): νmax 3588, 3369,
2927, 1727, 1603, 1454, 1371, 1193; H NMR (200 MHz,
1
3
CDCl3+CCl4):
1H), 2.75 (d,
1H), 3.61 (br s, 1H), 3.96 (s, 2H), 4.15 (q, J = 7.2 Hz, 2H),
7.27ꢀ7.31 (m, 5H); 13C NMR (50 MHz, CDCl3+CCl4):
14.1,
δ
1.23 (t,
J = 7.2 Hz, 3H), 2.52 (t, J = 2.9 Hz,
solution was stirred. To this stirred solution was added 3.21 g
(0.030 mol) of benzylamine and 3.03 g (0.030 mol) of
triethylamine at −5 °C. The reaction mixture was stirred for 24
h at room temperature. Solvent was filtered on simple filter
paper, residue was again washed with toluene (20 mL) and
concentrated under reduced pressure to yield yellow oil of trans
aziridine 13 as major isomer and cis aziridine 33 as minor
isomer in ratio of 9:1 which were separated using flash
chromatography (pet. etherꢀethyl acetate, 9:1). Yield: 75%; For
13ꢀ Yield: 68%; For 33ꢀ Yield: 7%
J
= 2.9 Hz, 1H), 3.26ꢀ3.32 (m, 1H), 3.44ꢀ3.50 (m,
δ
37.4, 46.4, 54.4, 61.3, 65.2, 69.1, 127.5, 128.5, 128.6, 138.4,
168.5; MS (ESI): m/z: 266.13 (M+H) +, 288.10 (M+Na)+;
HRMS: Calculated for C14H20O4Nꢀ266.1387, foundꢀ266.1385.
(2
yl)aziridine-2-carboxylate (14): Diol 22 (0.21 g, 0.79 mmol)
was dissolved in acetone–water (3 mL, 2:1) at 0 C, treated
with sodium metaperiodate (0.203 g, 0.95 mmol) and stirred at
15 C for 15 min. The reaction was quenched using ethylene
R,3S)-Ethyl 1-benzyl-3-((E)-3-ethoxy-3-oxoprop-1-en-1-
°
(2R,3R)-Ethyl 1-benzyl-3-((S)-2,2-dimethyl-1,3-dioxolan-4-
yl)aziridine-2-carboxylate (13): Rf: 0.5 (pet. etherꢀethyl
acetate, 8:2); IR (CHCl3, cmꢀ1): νmax 2984, 1728, 1599, 1107.
°
glycol (0.01 mL), extracted with CH2Cl2 (3 × 15 mL), washed
with brine, dried over anhydrous sodium sulfate, filtered and
concentrated to afford crude aldehyde which was used as such
25
25
D
[α] +52.41 (
D
c
1, CHCl3), {Lit.1 [α] +52.8 (
c
1, CHCl3)}.1H
NMR (200 MHz, CDCl3+CCl4):
(s, 3 H), 1.42 (s, 3 H), 2.48 (t,
Hz, 1H), 3.63ꢀ3.68 (m, 1H), 3.86ꢀ3.97 (m, 3H), 4.07ꢀ4.17 (m, was added triethyl phosphonoacetate (0.31 mL, 1.58 mmol)
3H ), 7.27ꢀ7.32 (m, 5H); 13C NMR (50 MHz, CDCl3+CCl4):
slowly at 0 °C and stirred for 10 minutes. The aldehyde from
δ
1.19 (t,
J
= 8 Hz, 3H), 1.34 for next reaction. To a stirred solution of NaH (0.038 g, 1.58
J
= 2.4 Hz, 1H), 2.63 (d,
J
= 2.4 mmol, prewashed with ꢀhexane) dissolved in THF (2 mL),
n
δ
14.0, 25.5, 26.6, 37.2, 47.4, 54.8, 60.1, 66.4, 75.9, 109.5, 126.9, above reaction dissolved in dry THF (3 mL) was added and
128.1, 138.8, 168.5; MS (ESI): m/z: 306.71 [M+H]+; HRMS: stirring continued for another 2 h at same temperature until
Calculated for C17H24NO4ꢀ306.1700, foundꢀ306.1694.
(2 ,3 )-Ethyl 1-benzyl-3-(( )-2,2-dimethyl-1,3-dioxolan-4-
completion of reaction. The reaction was quenched with
saturated aqueous NH4Cl (10 mL) and extracted with ethyl
S
R
S
yl)aziridine-2-carboxylate (33): Rf: 0.4 (pet. etherꢀethyl acetate (3 × 10 mL). The combined organic layers were then
acetate, 8:2); IR (CHCl3, cmꢀ1): νmax 2986, 1728, 1600, 1107; washed with brine (10 mL), dried over anhydrous Na2SO4,
25
D
25
D
1
filtered and concentrated in vacuo. Purification on flash column
chromatography (pet. etherꢀethyl acetate, 9:1) furnished
compound 14 (0.168 g) as thick colorless oil. Rf: 0.5 (pet. etherꢀ
[α] −9.7 (
c
1, CHCl3), {Lit.1 [α] −9.9 (
c 1, CHCl3)}; H
NMR (200 MHz, CDCl3+CCl4):
1.37 (s, 3H), 2.08 (t, = 6.7 Hz, 1H), 2.23 (d,
3.42 (d, = 13.0 Hz, 1H), 3.66 (dd, = 6.0 & 8.0 Hz, 1H), 3.89ꢀ
3.97 (m, 2H), 4.11ꢀ4.22 (m, 3H), 7.27ꢀ7.35 (m, 5H); 13C NMR CHCl3); IR (CHCl3, cmꢀ1): νmax 2926, 2850, 1720, 1651, 1456,
δ
1.18 (t, 3H), 1.27 (s, 3 H),
J
J
= 6.7 Hz, 1H),
25
D
ethyl acetate, 4:1); Yield: 0.168 g, 70%; [α]
−36 (c 1,
J
J
1
(50 MHz, CDCl3+CCl4):
δ
14.1, 25.3, 26.8, 40.4, 47.8, 61.0, 1368, 1265, 1180, 1030; H NMR (200 MHz, CDCl3+CCl4):
δ
63.2, 66.9, 75.2, 109.6, 127.2, 127.9, 128.2, 137.2 , 168.9; MS 1.22ꢀ1.32 (m, 6H), 2.55ꢀ2.73 (m, 1H), 2.46ꢀ3.17 (m, 1H), 3.84ꢀ
(ESI): m/z: 306.18 [M+H]+; HRMS: Calculated for C17H24NO4ꢀ 4.20 (m, 8H), 6.05ꢀ6.25 (m,1H), 6.60ꢀ6.89 (m, 1H); 13C NMR
306.1700, foundꢀ306.1698.
(50 MHz, CDCl3+CCl4): δ 14.0, 14.1, 42.9, 45.9, 54.4, 60.2,
61.1, 123.3, 127.6, 127.9, 128,2, 138.4, 145.3, 165.4, 167.8;
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

RSC Advances
Page 6 of 12
VJieowuArrtnicalelONnlainme e
ARTICLE
DOI: 10.1039/C5RA06429E
1
doubling of peaks in H and 13C is attributed to invertomerism; Kromacil 5ꢀAmycoat column (250 × 4.6 mm) isopropanol/nꢀ
MS (ESI): m/z: 303.28 (M)+, 326.21 (M+Na)+; HRMS: hexane = 4:96; flow rate 0.5 ml/min, λ = 210 nm) retention time
Calculated for C17H21NO4Naꢀ326.1363, foundꢀ326.1358.
)-Ethyl 6-oxopiperidine-2-carboxylate (7): To a stirred
(min): rt1 = 22.07 (major); rt2 = 24.02 (>97% ee).
(R)-Piperidine-2-carboxylic acid (ent-1): To a solution of
(
R
solution of compound 14 (0.15 g, 0.49 mmol) in ethanol (5 mL) alcohol 15 (0.1 g, 0.465 mmol) in CH2Cl2 (5 mL) at 0 °C, was
was added ammonium formate (0.27 g, 4.9 mmol) and 10% slowly added TFA (0.1 mL, 1.3 mmol) and the reaction mixture
Pd/C (0.05 g) and refluxed for 1 h under nitrogen atmosphere. was stirred at same temperature for 0.5 h, concentrated and
Reaction mass was filtered through celite, dried and column resulting salt was used as such for next step. To a solution of
purified (pet. ether: ethyl acetate, 10:90) to yield 0.071 g of salt from above step in 3N H2SO4 (4.5 mL) at 10 °C, was
amideꢀester
25
7 as colourless liquid. Rf: 0.3 (ethyl acetate); Yield: slowly added KMnO4 (0.12 g, 0.744 mmol) and the reaction
25
, [α] −13.7
D
85%; [α] +13.4 (c ꢀ7
1.4, CHCl3) {Lit.36 for ent
mixture was stirred at room temperature for 3 h, filtered
through a pad of Celite and concentrated. ( )ꢀPipecolic acid
ent was isolated after elution on Dowex 50WꢀX4 ionꢀ
exchange column (NH4OH, 1 N). Yield: 0.044 g, 73%; Rf: 0.4
(CH2Cl2ꢀMeOHꢀNH4OH, 9:1:1%); MP: 271ꢀ273 °C; lit.38 271ꢀ
D
R
(
c
0.3, CHCl3)}; IR (CHCl3, cmꢀ1): νmax 2958, 1739, 1666,
ꢀ
1
1
1468, 1198; H NMR (200 MHz, CDCl3+CCl4):
δ 1.30 (t, J =
7.3 Hz, 3H), 1.78ꢀ1.98 (m, 3H), 2.20ꢀ2.22 (m, 1H), 2.36ꢀ2.47
(m, 2H), 4.1 (dd, = 5.5 & 7.0 Hz, 1H), 4.24 (qd, = 1.2 & 7.3
Hz, 2H), 6.65 (br s, 1H); 13C NMR (100 MHz, CDCl3+CCl4):
14.1, 19.2, 25.2, 30.7, 54.7, 61.9, 170.7, 171.9; MS (ESI): m/z
J
J
25
25
D
274 °C; [α] +24.9 (
D
c
1.15, H2O) {Lit.5 [α] +25.8 (
c 1,
δ
:
1
H2O)}; H NMR (400 MHz, D2O):
δ
1.46ꢀ1.64 (m, 3H), 1.73ꢀ
194.08 (M+Na)+; HRMS: Calculated for C8H14O3Nꢀ172.0968, 1.80 (m, 2H), 2.14ꢀ2.18 (m, 1H), 2.87ꢀ2.94 (m, 1H), 3.31ꢀ3.54
foundꢀ172.0966. (m, 1H), 3.78 (dd,
= 8.0 Hz & 10.0 Hz, 1H); 13C NMR (100
MHz, D2O): 21.5, 21.6, 26.0, 44.0, 57.2, 172.2; MS (ESI):
J
δ
(
R
)-tert-Butyl 2-(hydroxymethyl)piperidine-1-carboxylate
(15): To a stirred suspension of LAH (0.22g, 5.85 mmol) in dry m/z: 152.28 (M+Na) +.
THF (5 mL) was added amide (0.2 g, 1.17 mmol) dissolved in
7
(4
R
,5
R,
E)-Diethyl
5-(benzylamino)-4-hydroxyhex-2-
dry THF (5 mL) slowly at 0 °C via syringe under inert enedioate (16): To a stirred solution of ester 14 (1.18 g, 3.89
atmosphere (N2 gas). After stirring for 24 h at room mmol) in CH3CN:water (9:1, 20 mL) was added TFA (0.45
temperature, the reaction mixture was cooled to 0 °C, quenched mL, 7.79 mmol) drop wise at 0 ºC. The reaction mixture was
carefully with minimum amount of water followed by 15% slowly warmed to room temperature and stirred until complete
NaOH (0.25 mL). Again water (1 mL) was added and stirred disappearance of starting material (~ 5ꢀ6 h). Reaction was
for 0.5 h at room temperature. Anhydrous Na2SO4 was added quenched by excess NaHCO3, water (10 mL) was added and
and stirring continued for another 0.5 h. Filtration through organic mass was extracted with ethyl acetate (3 × 15 mL).
Celite and concentration under vacuum gave crude amine Combined organic layers were washed with brine, dried over
which was used as such for next reaction. To a solution of anhydrous Na2SO4, filtered and concentrated under reduced
amine in THF: water (5 mL, 1:1) was added solid NaHCO3 (0.2 pressure followed by column chromatographic purification
g, 2.34 mmol) and (Boc)2O (0.536 mL, 2.34 mmol) and then using ethyl acetate:pet ether (15:85) to yield 0.95 g of aminoꢀ
the mixture was vigorously stirred at room temperature for 6 h. alcohol 16 as thick liquid. Rf: 0.5 (pet etherꢀethyl acetate, 7:3);
25
D
The reaction mixture was extracted with ethyl acetate (3 × 10
mL), washed with brine, dried over anhydrous Na2SO4, filtered,
concentrated in vacuo and purified by column chromatography
(pet. ether–ethyl acetate, 8:2) to afford 15 as a white solid. Rf:
Yield: 76% over two steps; [α]
+20 (
c
0.5, CHCl3); IR
(CHCl3, cmꢀ1): νmax 3554, 3359, 2980, 1720, 1620; H NMR
1
(200 MHz, CDCl3+CCl4): 1.26ꢀ1.34 (m, 6H), 3.53 (d,
1H), 3.68 (d, = 13 Hz, 1H), 3.94 (d, = 13 Hz, 1H), 4.13ꢀ
4.28 (m, 4H), 4.52ꢀ4.56 (m, 1H), 6.08 (dd, = 2 & 15.5 Hz,
1H), 6.75 (dd,
= 4.0 & 15.5 Hz, 1H), 7.27ꢀ7.30 (m, 5H); 13C
J = 5Hz,
J
J
0.5 (pet. etherꢀethyl acetate, 8:2); Yield: 0.176 g, 70% over two
25
J
steps; MP: 81ꢀ84 °C, lit37 81ꢀ84 °C; [α] +38.5 (
D
c 1, CHCl3)
J
25
D
NMR (50 MHz, CDCl3+CCl4): 14.2, 52.6, 60.3, 61.3, 64.1,
70.1, 122.7, 127.5, 128.2, 128.4, 138.9, 145.2, 165.7, 171.6;
MS (ESI):m/z: 344.18 (M+Na)+; HRMS: Calculated for
C17H24O5Nꢀ322.1649, foundꢀ322.1640.
{For ent
ꢀ
15 Lit5 [α] −40.5 (
c
1, CHCl3)}; IR (CHCl3, cmꢀ1):
1
νmax 3443, 2940, 2890, 1655, 1280; H NMR (200 MHz,
CDCl3+CCl4):
1H), 2.87 (t,
1H), 3.79 (dd,
δ
1.46 (s, 9H), 1.60ꢀ1.65 (m, 6H), 2.11 (br s,
= 13.0 Hz, 1H), 3.59 (dd, = 5.9 & 11.0 Hz,
= 9.0 & 11.0 Hz, 1H), 3.93 (br d, = 13.5 Hz,
J
J
(4
R
,5
R,
E)-Diethyl
5-(benzylamino)-4-((tert-
J
J
butyldimethylsilyl)oxy)hex-2-enedioate (23): To a stirred
solution of hydroxyl amino ester 16 (0.7 g, 2.18 mmol),
imidazole (0.3 g, 4.36 mmol) and DMAP (0.027 g, 0.22 mmol)
in CH2Cl2 (20 mL) was added TBSCl (0.6 g, 4.36 mmol)
dissolved in CH2Cl2 (5 mL) slowly at 0 ºC after which reaction
was heated to reflux for 6 h until completion of reaction.
Reaction mass was concentrated under reduced pressure
followed by column chromatography using ethyl acetateꢀpet
ether (5:95) to yield 0.8 g of hydroxy amino TBS ether 23 as
1H), 4.25ꢀ4.29 (m, 1H); 13C NMR (100 MHz, CDCl3+CCl4):
δ
19.3, 24.8, 25.1, 28.3, 39.7, 52.0, 60.6, 79.4, 155.8; MS (ESI):
m/z: 238 (M+Na)+; HRMS: Calculated for C11H22O3Nꢀ
216.1954, foundꢀ216.1600; HPLC detail for racemic hydroxy
compound (15): HPLC Kromacil 5ꢀAmycoat column (250×4.6
mm). Isopropanol/nꢀHexane = 4:96; flow rate 0.5 ml/min, λ =
210 nm) retention time (min): rt1 = 22.18; rt2 = 24.05 (1:1).
Enantiomerically pure hydroxy compound
(
15
)
HPLC
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 7 of 12
Journal Name
RSC Advances
View ArticAle ROnTliInCeLE
DOI: 10.1039/C5RA06429E
thick colorless liquid. Rf: 0.5 (pet. etherꢀethyl acetate, 8:2); CDCl3+CCl4):
25
δ
–5.3, –4.2, 13.9, 17.8, 23.1, 25.5, 32.2, 52.2,
61.8, 70.2, 70.5, 170.8; MS (ESI): m/z: 288.23 (M+H)+, 310.14
(M+Na)+; HRMS: Calculated for C14H30O3NSiꢀ 288.1989,
foundꢀ 288.1979.
Yield: 85% over two steps. [α]
−7.69 (c 1, CHCl3); IR
D
1
(CHCl3, cmꢀ1): νmax 2980, 1720, 1620; H NMR (500 MHz,
CDCl3+CCl4): 0.01 (s, 3H), 0.03 (s, 3H), 0.87 (s, 9H), 1.24ꢀ
(2
R
,3
R
)-3-Hydroxypiperidine-2-carboxylic acid (3):
A
1.31 (m, 6H), 2.17 (br s, 1H), 3.28 (d,
= 13 Hz, 1H), 3.84 (d, = 13.0 Hz, 1H), 4.12ꢀ4.20 (m, 5H),
4.47ꢀ4.48 (m, 1H), 5.95 (dd, = 1.5 & 15.5 Hz, 1H), 6.95 (dd,
J = 5.5 Hz, 1H), 3.65 (d,
mixture of amine 25 (100 mg, 0.35 mmol) and 6 N HCl (10
mL) was kept at 120 ºC for 3 h. The solvent was removed under
reduced pressure and the residue was dissolved in H2O (50
mL). The mixture was loaded on an ionꢀexchange column
(DOWEX 50W X8) and eluted with H2O and then with aq. NH3
solution. The eluate of aq. NH3 was concentrated to dryness
J
J
J
J
= 5.2 & 15.5 Hz, 1H), 7.21ꢀ7.28 (m, 5H); 13C NMR (125 MHz,
CDCl3+CCl4): −4.6, −4.4, 14.3, 18.1, 25.7, 52.2, 60.3, 60.7,
65.7, 73.7, 121.7, 127.1, 128.2, 128.3, 139.4, 147.5, 166.0,
172.0; MS (ESI): m/z: 436.68 (M+H)+; HRMS: Calculated for
C23H38ON5Siꢀ436.2514, foundꢀ436.2505.
under reduced pressure to give
3 (46 mg, 91%) as a crystalline
solid. Rf: 0.3 (CH2Cl2ꢀMeOHꢀNH4OH, 9:1:1%); Yield: 91%;
25
(2
R
,3
R)-Methyl
3-((tert-butyldimethylsilyl)oxy)-6-
MP: 238–243 ºC (dec.), lit.39 230ꢀ238 °C; [α] –13.8 (
D
c 1.0, aq.
oxopiperidine-2-carboxylate (24): The amino ester 23 (0.8 g,
2.2 mmol) was dissolved in ethanol (10 mL) and to that was
added catalytic amount of palladium hydroxide over carbon
(10%, 20 mg). The resulting reaction mixture was stirred under
hydrogen atmosphere using balloon for 2 h. The reaction
mixture was filtered through Celite and the filtrate was
concentrated in vacuo. The crude product was purified by flash
chromatography using silica gel (pet etherꢀethyl acetate, 7:3) to
20
D
HCl 10%), {lit.7 [α] –14 (
c 0.5, aq. HC1 10%)}; IR (CHCl3,
cmꢀ1): νmax 3287, 2920, 1625, 1405 cm–1; 1H NMR (400 MHz,
D2O): δ 1.64ꢀ1.80 (m, 2H), 2.02ꢀ2.08 (m, 2H), 2.22 (s, 1H),
3.07ꢀ3.12 (m, 1H), 3.40ꢀ3.36 (m, 1H), 3.83 (d,
J = 7.8 Hz, 1H),
4.17ꢀ4.13 (m, 1H); 13CꢀNMR (100 MHz, D2O): δ 18.5, 28.7,
42.5, 60.8, 65.5, 170.0; MS (ESI): m/z: 146 (M+H)+.
(2S,3R)-tert-Butyl 3-hydroxy-2-(hydroxymethyl)piperidine-
1-carboxylate (26): To stirred suspension of LAH (0.152 g, 4
mmol) in anhydrous THF (3 mL) was added the lactam 24 (240
provide amide 24 (0.52 g) as a colorless thick oil. Rf: 0.4 (pet.
25
D
etherꢀethyl acetate, 8:2); Yield: 85%; [α] −26 (c 1.5, CHCl3);
IR (CHCl3, cm–1): νmax 3399, 2955, 2857, 1732, 1643, 1215; mg, 0.8 mmol) dissolved in anhydrous THF (3 mL) and the
1H NMR (200 MHz, CDCl3):
(t, = 7.2 Hz, 3H), 1.68 (br s, 1H), 1.79ꢀ1.88 (m, 2H), 2.26ꢀ (10 mL) was added to the reaction mixture and extracted with
2.40 (m, 1H), 2.54ꢀ2.72 (m, 1H), 3.99ꢀ4.02 (m, 1H), 4.23 (q, ethyl acetate (3 × 25 mL). The organic layer was dried over
= 7.2 Hz, 2H), 4.35ꢀ4.39 (m, 1H), 5.96 (br s, 1H); 13CꢀNMR anhydrous Na2SO4, filtered and concentrated under reduced
δ 0.12 (s, 6H), 0.90 (s, 9H), 1.30 reaction mixture was stirred for 8 h at room temperature. Water
J
J
(50 MHz, CDCl3):
δ –5.1, –4.9, 14.1, 17.9, 25.6, 26.4, 26.5, pressure. The residue thus obtained was purified by flash
61.8, 62.3, 65.4, 170.1, 171.4. MS (ESI): m/z: 302.2 (M+H)+; chromatography (pet ether–ethyl acetate 10:90) to afford diol
HRMS: Calculated for C14H28O4NSiꢀ302.1782, foundꢀ 26 (138 mg) as a white crystalline solid. Rf: 0.5 (pet. etherꢀethyl
302.1777.
(2 ,3 )-Ethyl 3-((tert-butyldimethylsilyl)oxy)piperidine-2-
acetate, 2:8); Yield: 75%; MP: 126ꢀ128 ºC, lit.8 124ꢀ126 °C;
25 25
[α] +27 (c 1.0, MeOH), {lit.40 [α] +29.8 (
c 0.99, MeOH)};
R
R
D
D
carboxylate (25): To the amide 24 (0.2 g, 0.7 mmol) in
anhydrous THF (5 mL) was added BH3ꢁDMS (0.2 mL, 2 mmol)
dropwise at 0 ºC. The resulting reaction mixture was further
stirred at 5 ºC for 20 h. Methanol (excess) was added to the
reaction mixture, stirred for 4 h and concentrated under reduced
pressure. Water (10 mL) was added and the reaction mixture
was extracted using dichloromethane (3 × 10 mL). The
collected organics were dried over anhydrous Na2SO4, filtered
and concentrated under reduced pressure to give the crude
product which was purified using flash chromatography over
silica gel (70:30, EtOAc: pet ether) to furnish amine 25 (0.147
IR (CHCl3, cmꢀ1) : υmax 3448, 3025, 2945, 1674, 1215, 1120,
838 cm–1; H NMR (200 MHz, CDCl3+CCl4+DMSOꢀd6): δ
1
1.15ꢀ1.29 (m, 1H), 1.39 (s, 9H), 1.61ꢀ1.82 (m, 3H), 2.69ꢀ2.82
(m, 1H), 3.45ꢀ3.61 (m, 2H), 3.89ꢀ3.92 (m, 2H), 4.08ꢀ4.16 (m,
1H); 13C (125 MHz, CDCl3+CCl4+DMSOꢀd6): δ 18.8, 26.3,
28.0, 39.6, 59.1, 59.8, 63.8, 79.1, 155.9; MS(ESI): m/z: 232
(M+H)+, 254 (M+Na)+; HRMS: Calculated for C11H21NNaO4ꢀ
254.1368, foundꢀ254.1369. HPLC detail for racemic dihydroxy
compound (26) HPLC chiracel OJꢀH column (250×4.6 mm).
Isopropanol/pet ether = 5:95 flow rate 0.5 ml/min, λ = 210 nm)
retention time (min): rt1 = 13.39; rt2 = 14.98 (1:1).
g, 78%) as a colorless dense liquid. Rf: 0.5 (pet. etherꢀethyl
25
Enantiomerically pure dihydroxy compound
chiracel OJꢀH column (250 × 4.6 mm) isopropanol/pet ether =
(26) HPLC
acetate, 2:8); Yield: 78%; [α] –27 (
c
1.0, CHCl3); IR (CHCl3,
D
cmꢀ1): νmax 3436, 3020, 2931, 2400, 1731, 1215 cm–1; H 5:95 flow rate 0.5 ml/min, λ = 210 nm) retention time (min): rt1
1
NMR (200 MHz, CDCl3+CCl4): δ 0.00 (s, 3H), 0.06 (s, 3H), = 13.18 (major); rt2 = 15.05 (>97% ee).
0.86 (s, 9H), 1.36 (t,
J = 7.3 Hz, 3H), 1.41ꢀ1.51 (m, 2H), 1.58ꢀ
(
E)-Ethyl
3-((2S,3R)-1-benzyl-3-((S)-2,2-dimethyl-1,3-
1.68 (m, 2H), 1.84ꢀ1.87 (m, 1H), 2.01ꢀ2.05 (m, 1H), 2.53ꢀ2.64 dioxolan-4-yl)aziridin-2-yl)acrylate (17): To a stirred solution
(m, 1H), 3.11 (dd,
Hz, 1H), 3.78 (dt,
J
J
= 1.1 & 10.1 Hz, 1H), 3.32 (d,
= 5.4 & 10.5 Hz, 1H), 3.98 (m, 1H), 4.10ꢀ CH2Cl2 (30 mL) was added DIBALꢀH (3.6 mL, 3.6 mmol, 1 M
J = 13.5 of trans aziridineꢀ2ꢀcarboxylate 13 (1 g, 3.27 mmol) in dry
4.18 (m, 1H), 4.31ꢀ4.39 (m, 1H); 13CꢀNMR (100 MHz, solution in toluene) at −78 °C slowly over period of 15 min and
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VJieowuArrtnicalelONnlainme e
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DOI: 10.1039/C5RA06429E
stirred for another 15 min. TLC showed complete convertion of MS (ESI):m/z: 372.14 [M+Na]+. HRMS: Calculated for
ester to aldehyde. Reaction was quenched by addition of MeOH C19H28O5Nꢀ350.1962, found 350.1967.
(0.3 mL) and allowed to warm to 0 °C. Saturated aqueous
NH4Cl (10 mL) was added and stirred for 0.25 h after which
(4
R
,5
S
,
E
)-Ethyl
5-(benzylamino)-4-((tert-
)-2,2-dimethyl-1,3-dioxolan-4-
butyldimethylsilyl)oxy)-5-((
S
organic layer was separated and aqueous layer was washed with yl)pent-2-enoate (28): To a stirred solution of hydroxyl amino
CH2Cl2 (3 × 20 mL). Combined organic layers were washed ester 27 (1 g, 2.86 mmol), imidazole (0.4 g, 6 mmol) and
with brine, dried over anhydrous Na2SO4, filtered, concentrated DMAP ( 0.0.24 g, 0.2 mmol) in CH2Cl2 (20 mL) was added
in vacuo and used as such for next reaction. To a stirred TBSCl (1.27 g, 8.44 mmol) dissolved in CH2Cl2 (5 mL) slowly
o
solution NaH (0.09 g, 3.6 mmol, prewashed with dry
n
ꢀhexane) at C after which reaction was heated to reflux for 6 h until
dissolved in THF (10 mL) was added triethyl phosphonoacetate completion of reaction. Reaction mass was concentrated under
(0.71 mL, 3.6 mmol) slowly at 0 °C and stirred for 10 minutes. reduced pressure followed by column chromatography using
The aldehyde from above reaction dissolved in 5 ml of dry THF ethyl acetate: pet ether (5:95) to yield 1.18 g of ꢀOTBS
was added and stirring continued for another 2 h at same protected aminoꢀalcohol 28 as thick colourless liquid. Rf: 0.5
temperature until completion of reaction. The reaction was (pet. etherꢀethyl acetate, 8:2); Yield: 90%; IR (CHCl3, cmꢀ1):
quenched with saturated aqueous NH4Cl (10 mL) and extracted νmax 2984, 2931, 1721, 1657, 1472, 1369, 1260, 1160, 1059.
25
D
2.7, CHCl3); 1HNMR (200 MHz,
0.04 (s, 3H), 0.09 (s, 3H), 0.91 (s, 9H), 1.31 (t,
3H), 1.35 (s, 3H), 1.40 (s, 3H), 2.72 (br s, 1H), 3.70 (t, = 7.7
Hz, 1H), 3.84ꢀ4.04 (m, 1H), 4.22 (q, 2H), 4.29ꢀ4.46 (m, 2H),
6.08 (dd, = 1.4 & 15.6 Hz, 1H), 7.1 (dd, = 5.2 & 15.6 Hz,
1H), 7.25ꢀ7.36 (m, 5H); 13C NMR(50 MHz, CDCl3):
−4.9,
−4.5, 14.1, 18.1, 25.2, 25.8, 26.8, 53.1, 60.3, 63.7, 66.9, 73.3,
with ethyl acetate (3 × 20 mL). The combined organic layers
were then washed with brine (15 mL), dried over anhydrous
Na2SO4, filtered and concentrated in vacuo. Purification on
flash column chromatography (pet. ether: ethyl acetate, 1:9)
furnished compound 17 (0.75 g) as thick colorless oil. Rf: 0.5
(pet etherꢀethyl acetate, 8:2); Yield: 75%, over two steps; IR
(CHCl3, cmꢀ1): νmax 2984, 2932, 1716, 1644, 1370, 1265;
[α]
+11.11
(c
CDCl3+CCl4):
δ
J
J
J
δ
25
D
1
[α] −34 (
c
1, CHCl3); H NMR (200 MHz, CDCl3+CCl4):
δ
75.5, 108.8, 121.4, 126.9, 128.2, 149.0, 166.2; MS (ESI): m/z:
1.30 (t,
J
= 7.0 Hz, 3H), 1.33 (s, 3H), 1.40 (s, 3H), 2.12 (dd,
J
=
486.27 [M+Na]+; HRMS: Calculated for C25H42O5NSiꢀ
464.2827, foundꢀ464.2847.
2.6 & 4.9 Hz, 1H), 2.72 (dd,
J
= 2.4 & 9.9 Hz, 1H), 3.61 (dd,
J
= 5.5 & 7.9 Hz, 1H), 3.72ꢀ3.85 (m, 2H), 3.91ꢀ4.09 ( m, 2H),
4.20 (q, = 7.0 Hz, 2H), 6.13 (d, = 15.2 Hz, 1H), 6.89 ( dd,
= 9.9 & 15.2 Hz, 1H), 7.26ꢀ7.35 (m, 5H); 13C NMR (100 MHz, suspension of 28 (0.9 g, 1.94 mmol) and 10% Pd(OH)2/C (60
CDCl3+CCl4): 14.2, 25.5, 26.7, 40.1, 49.6, 57.0, 60.3, 66.24, mg) in MeOH (20 mL) was stirred under a H2 atmosphere at
(5
R,6
S
)-5-((tert-Butyldimethylsilyl)oxy)-6-((
S
)-2,2-
J
J
J
dimethyl-1,3-dioxolan-4-yl)piperidin-2-one
(29):
A
δ
76.1, 109.5, 125.1, 127.1, 127.9, 128.2, 138.6, 142.9, 165.3; room temperature for 2.5 h, filtered through Celite and
MS (ESI): m/z: 354.15 [M+Na]+; HRMS: Calculated for concentrated under reduced pressure. The residue was purified
C19H26O4Nꢀ332.1856, foundꢀ332.1858.
(4 ,5 )-Ethyl 5-(benzylamino)-5-((S)-2,2-dimethyl-1,3-
by silica gel flash column chromatography (EtOAc/pet. ether =
1:3) to afford amide 29 (0.59 g) as a colorless thick liquid. Rf:
R
R,
E
dioxolan-4-yl)-4-hydroxypent-2-enoate (27): To a stirred 0.5 (pet. etherꢀethyl acetate, 1:1); Yield: 92%; IR (CHCl3, cmꢀ
25
D
1): νmax 3408, 2927, 1670, 1457, 1380, 1216; [α] –22.9 (
c
solution of ester 17 (1.4 g, 4.2 mmol) in CH3CN: water (9:1, 25
mL) was added TFA (0.64 mL, 8.4 mmol) dropwise at 0 ºC.
The reaction mixture was slowly warmed to room temperature
and stirred until complete disappearance of starting material (~
5ꢀ6 h). Reaction was quenched by addition of excess NaHCO3,
water (10 mL) was added and organic mass was extracted with
ethyl acetate (3 × 20 mL). Combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure followed by column
chromatographic purification using ethyl acetateꢀpet. ether
(15:85) to yield 1.11 g of aminoꢀalcohol 27 as thick liquid. Rf:
0.5 (pet. etherꢀethyl acetate, 7:3); Yield: 80%; IR (CHCl3, cmꢀ
1
1.15, CHCl3). HNMR (400 MHz, CDCl3+CCl4):
δ 0.1 (s, 3H),
0.11 (s, 3H), 0.91 (s, 9H), 1.34 (s, 3H), 1.41 (s, 3H), 1.78ꢀ1.87
(m, 1H), 1.94ꢀ2.01 (m, 1H), 2.29ꢀ2.38 (m, 1H), 2.47ꢀ2.85 (m,
1H), 3.20 (t,
& 8 Hz, 1H), 4.00ꢀ4.1 (m, 2H), 6.02 (br s, 1H); 13C NMR (100
MHz, CDCl3+CCl4): –4.5, –4.1, 17.9, 25.2, 25.8, 26.6, 28.5,
J = 7 Hz, 1H), 3.72ꢀ3.77 (m, 1H), 3.84 (dd, J = 5
δ
29.1, 61.7, 67.2, 68.1, 76.3, 109.3, 170.6; MS (ESI): m/z
:
352.18 [M+Na]+; HRMS: Calculated for C16H32O4NSiꢀ
330.2101, foundꢀ330.2095.
(5
dimethyl-1,3-dioxolan-4-yl)piperidin-2-one (30): To the NaH
(0.044 g, 1.8 mmol, prewashed with dry ꢀhexane) in DMF (2
R,6S)-1-Allyl-5-((tert-butyldimethylsilyl)oxy)-6-((S)-2,2-
1): νmax 3453, 2985, 1717, 1656, 1455, 1370, 1263, 1175;
25
n
[α] −50 (
c
1.8, CHCl3); 1H NMR (200 MHz, CDCl3+CCl4):
δ
D
mL) was added amide 29 (0.4 gm, 1.21 mmol) in DMF (2 mL)
1.29 (t,
J
= 7.0 Hz, 3H), 1.32 (s, 3H), 1.39 (s,3H), 2.74 (dd,
J
=
dropwise at 0 ºC and stirred for 1 h at room temperature. Allyl
3.6 & 5.4 Hz, 1H), 3.77ꢀ4.03 (m, 4H), 4.1ꢀ4.26 (m, 3H), 4.55 bromide (0.154 mL, 1.8 mmol) was added dropwise at 0 ºC.
(dd,
dd,
MHz, CDCl3):
J
J
= 3.6 & 5.4Hz, 1H), 6.2 (dd,
= 3.7 & 15.6 Hz, 1H), 7.26ꢀ7.34 (m, 5H); 13C NMR (50 temperature. Reaction mixture was then quenched using water
14.1, 25.1, 26.3, 51.0, 60.3, 61.3, 67.3, 69.0, (20 mL) and extracted with ethyl acetate (3 × 15 mL). The
74.9, 109.0, 121.3, 127.1, 128.1, 128.4, 139.5, 147.0, 166.1; combined organics washed with brine, dried over anhydrous
J = 2 & 15.6 Hz, 1H), 6.9 ( The resulting reaction mixture stirred for 3ꢀ4 h at room
δ
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

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DOI: 10.1039/C5RA06429E
Na2SO4, filtered and concentrated in vacuo. The crude product CDCl3+CCl4):
was column purified on flash chromatography (pet. etherꢀethyl
acetate, 7:3) to afford the allylated product 30 as colorless 1H), 2.59ꢀ2.68 (m, 1H), 2.99 (dd,
liquid. Rf: 0.5 (pet. etherꢀethyl acetate, 2:1); Yield: 0.357 g, 1H), 4.19 (q, Hz, 2H), 5.84 (dt,
5.18 (m, 1H), 5.62ꢀ5.72 (m, 1H), 5.88 (dd,
6.73 (dd,
= 6 & 16 Hz, 1H); 13C NMR (50 MHz,
CDCl3+CCl4): ꢀ4.8, 14.2, 24.8, 25.6, 26.7, 47.3, 60.7, 64.3,
δ
0.06 (s, 3H), 0.08 (s, 3H), 0.87 (s, 9H), 1.30 (t,
J
=
7
Hz, 3H), 1.73ꢀ1.75 (m, 1H), 1.86ꢀ1.93 (m, 1H), ), 2.35 (m,
= 7 & 16 Hz, 1H), 3.99 (m,
= 2 & 16 Hz, 1H), 5.11ꢀ
= 1 & 16 Hz, 1H),
J
J
=
7
J
25
D
0.07
85%; IR (CHCl3, cmꢀ1): νmax 2986, 1630, 1420, 1107. [α]
J
J
– 83.4 (
c
1, CHCl3); 1H NMR (200 MHz, CDCl3+CCl4):
δ
δ
(s, 3H), 0.08 (s, 3H), 0.88 (s, 9H), 1.35 (s, 3H), 1.43 (s, 3H),
1.88ꢀ1.92 (m, 4H), 2.33ꢀ2.44 (m, 1H), ), 2.53ꢀ2.67 (m, 1H),
3.33ꢀ3.37 (m, 1H), 3.54ꢀ3.75 (m, 3H), 4.03ꢀ4.05 (m, 2H), 4.9
(m, 1H), 5.11ꢀ5.24 (m, 2H), 5.61ꢀ5.81 (m, 1H); 13C NMR (50
MHz, CDCl3+CCl4):δ –4.9, 17.8, 25.4, 25.5, 25.6, 26.3, 26.5,
48.4, 64.4, 65.4, 66.7, 78.5, 109.6, 117.1, 133.4, 168.8; MS
(ESI): m/z: 356.41 [M+H]+.
67.0, 117.3, 123.9, 132.3, 144.5, 165.4, 169.1; MS (ESI) m/z
:
390.12 [M+Na]+; HRMS: Calculated for C19H34O4NSiꢀ
368.2252, foundꢀ368.2247.
(8R,8aS)-8-((tert-Butyldimethylsilyl)oxy)-6,7,8,8a-
tetrahydroindolizin-5(3H)-one (18): The olefinic compound
32 (0.075 g, 0.2 mmol) and Grubbs’ 2nd generation catalyst (5
mg, 2 mol%) in anhydrous CH2Cl2 (50 mL) was refluxed for 5
h. The reaction mixture was filtered through Celite and
((5R,6S)-1-Allyl-5-((tert-butyldimethylsilyl)oxy)-6-((S)-1,2-
dihydroxyethyl)piperidin-2-one (31): Protected lactam 30
(0.2 g, 0.56 mmol) was treated with 80% aqueous acetic acid (2
mL), and the resulting mixture was allowed to react at 80 °C.
The reaction was monitored by TLC and was judged to be
complete after 3 h. The solution was then diluted with H2O (8
mL) and extracted with EtOAc (3 × 10 mL). The extracts were
treated with saturated NaHCO3 solution, and the combined
concentrated in vacuo to provide crude 3. The crude product
was purified using column chromatography (pet. etherꢀethyl
acetate, 1:1) to provide the ring closed product 18 (0.044 g,
80%) as a colorless sticky liquid. Rf: 0.3 (pet. etherꢀethyl
acetate, 1:1); Yield: 80%; IR (CHCl3, cmꢀ1): νmax 1640, 1620;
25
D
25
D
[α] +53 (
c
1, CHCl3); lit41 {for entꢀ[α] –53.73 (
c
1.10,
1
organic layers were dried over anhydrous Na2SO4, filtered and CHCl3)}; HNMR (400 MHz, CDCl3+CCl4):
δ 0.08 (s, 6H),
concentrated to give a crude residue that was purified by flash 0.90 (s, 9H), 1.79ꢀ1.81 (m, 1H), 2.02ꢀ2.03 (m, 1H), 2.39ꢀ2.46
chromatography (pet. etherꢀethyl acetate, 1:9). Pure terminal (m, 1H), 2.60ꢀ2.62 (m, 1H), 3.53ꢀ3.55 (m, 1H), 4.02ꢀ4.06 (m,
diol 31 (0.14 g) was obtained as a thick gummy liquid. Rf: 0.4 1H), 4.15ꢀ4.16 (m, 1H), 4.45ꢀ4.50 (m, 1H), 5.92ꢀ5.94 (m, 2H);
(ethyl acetate); Yield: 75%; IR (CHCl3, cmꢀ1): νmax 3554, 13C NMR(100 MHz, CDCl3+CCl4):
δ −4.6, −4.1, 18.0, 25.7,
25
D
29.7,30.2, 53.3, 69.1, 71.1, 126.8, 128.5, 168.2. MS (ESI): m/z
:
3340, 2986, 1627, 1423, 1107; [α]
1HNMR (200 MHz, CDCl3+CCl4):
–34.9 (c 1, CHCl3);
268.02 [M+H]+. HRMS: Calculated for C14H26NO2Siꢀ
268.1733; foundꢀ268.1741.
δ
0.06 (s, 3H), 0.07 (s, 3H),
0.88 (s, 9H), 1.99ꢀ2.11 (m, 2H), 2.14ꢀ2.33 (m, 1H), 2.53ꢀ2.63
(m, 1H), 3.35ꢀ3.37 (m, 1H), 3.54ꢀ3.69 (m, 4H), 3.94 (s, 1H),
4.71ꢀ4.77 (m, 2H), 5.26ꢀ5.58 (m, 2H), 5.72ꢀ5.88 (m, 1H); 13C
NMR(100 MHz, CDCl3+CCl4): –4.8, –4.7, 18.0, 25.3, 25.8,
26.9, 50.3, 64.1, 64.7, 66.1, 73.6, 117.5, 132.8, 171.0; MS
(ESI): m/z: 352.23 [M+Na]+.
R
)-6-((
S
)-2,2-Dimethyl-1,3-dioxolan-4-yl)piperidin-2-one
(0.66 g, 1.99
(33): To a stirred solution of aziridine ester 1
7
mmol) in methanol (10 mL) was added ammonium formate
(1.24 g, 19.9 mmol) and 10% Pd/C (100 mg), and the mixture
was refluxed for 3 h. The reaction mixture was filtered through
Celite, concentrated and purified by column chromatography
(pet etherꢀethyl acetate, 2:8) to afford 33 as a thick yellowish
(E)-Ethyl 3-((2S,3R)-1-allyl-3-((tert-butyldimethylsilyl)oxy)-
6-oxopiperidin-2-yl)acrylate (32): Diol 31 (0.2 g, 0.607
mmol) was dissolved in acetone–water (3 mL, 2:1) at 0 ºC,
treated with sodium metaperiodate (0.2 g, 0.9 mmol) and stirred
at 15 ºC for 15 min. The reaction was quenched using ethylene
glycol (0.01 mL), extracted with CH2Cl2 (3 ×10 mL), washed
with brine, dried over anhydrous Na2SO4 and filtered. The
combined organics were concentrated under reduced pressure
to afford crude aldehyde which was used as such for next
reaction.
25
D
liquid. Rf: 0.4 (ethyl acetate); Yield: 0.37 g, 95%; [α] −17.5
25
D
(
c
1.1, CHCl3); {lit.42 [α] –14.4, (
c
0.5, CHCl3)}; IR (CHCl3,
cmꢀ1): νmax 3402, 2985, 2936, 1664, 1457, 1371, 1072; H
1
NMR (400 MHz, CDCl3+CCl4):
3H), 1.40 (s, 3H), 1.63ꢀ1.83 (m, 2H), 1.85ꢀ2.01 (m, 1H), 2.17ꢀ
2.49 (m, 2H), 3.31 (td, = 5.4 & 8.7 Hz, 1H), 3.66 (dd, = 5.4
& 8.2 Hz, 1H), 3.86ꢀ3.88 (m, 1H), 4.03 (dd, = 6.0 & 8.2 Hz,
1H), 6.21 (br s, 1H); 13C NMR (100 MHz, CDCl3+CCl4):
19.7, 24.8, 25.3, 26.8, 31.3, 56.2, 66.2, 79.1, 109.79, 171.2; MS
(ESI): m/z
200.11 (M+H)+, 222.10 (M+Na)+; HRMS:
δ 1.20ꢀ1.28 (m, 1H), 1.33 (s,
J
J
J
δ
To a solution of aldehyde from above reaction in CH2Cl2
(15
mL)
was
added
(carboethoxymethylene)
:
triphenylphosphorane (0.4 g, 1.2 mmol) and the reaction
mixture was stirred for 6 h. Solvent was evaporated and the
reaction mixture was adsorbed on silica. Purification by column
chromatography (pet. ether–ethyl acetate, 8:2) gave 32 as a
thick liquid (0.167 g). Rf: 0.5 (pet. etherꢀethyl acetate, 1:1);
Calculated for C7H18NO3ꢀ200.1281, foundꢀ200.1277.
Aknowledgement
LBK, KPP, PNC and SK thank CSIR, New Delhi, India for
fellowship. We also thank Dr. U R Kalkote, Dr. H B Borate,
Dr. N. B. Dumare and D. B. Kalbhor for helpful discussion.
The authors thank CSIR, New Delhi for financial support as of
Yield: 75%; IR (CHCl3, cmꢀ1): νmax 2986, 1723, 1656, 1630,
25
1107; [α]
–45 (c
1, CHCl3) 1HNMR (200 MHz, XII year plan programme under title ORIGIN (CSCꢀ0108) and
D
ACT (CSCꢀ0301)
.
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J. Name., 2012, 00, 1-3 | 9

RSC Advances
Page 10 of 12
ARTICLE
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C5RA06429E
Notes and references
a
CSIRꢀNational Chemical Laboratory, Dr. Homi Bhabha Road, Puneꢀ
411008, Maharashtra, India.
Ratle, X. Monseur and R. Goutarel, Bull. Soc. Chim. Belg., 1972, 81
,
425; (
Bull. Soc. Chim. Belg., 1972, 81, 443; (
Quevauviller, Compt. Rend. Soc. Biol., 1968, 162, 1138 [CA 70:
95233k]; ( ) P. Bourinet and A. Quevauviller, Ann. Phar. Fr., 1968,
c
) Q. KhuongꢀHuu, G. Ratle, X. Monseur and R. Goutarel,
Email: sp.chavan@ncl.res.in
d
) P. Bourinet and A.
†
Electronic Supplementary Information (ESI) is available at
DOI: 10.1039/b000000x/
e
26, 787 [CA 71: 29012g].
13. J. D. Scott, T. N. Tippie and R. M. Williams, Tetrahedron Lett., 1998,
39,3659.
14. (
1989, 19, 3485; (
) S. A. Hermitage and M. G. Moloney, Tetrahedron:Asymmetry,
1994, , 1463; ( ) T. J. Hodgkinson and M. Shipman, Synthesis,
) P. K. Upadhyay and P. Kumar, Synthesis, 2010, 15
a
) S.ꢀB. Huang, J. S. Nelson and D. D. Weller, Synth. Commun.,
b
) A. Sadiq and N. Sewald, ARKIVOC, 2012, , 28;
5
1. Review articles: (
a
) M. He, J. Ind. Microbiol. Biotechnol., 2006, 33
,
(c
401;( ) H. P. Broquist, Annu. Rev. Nutr., 1991, 11, 435; (
b
c
) V.
5
d
Vranova, L. Lojkova, K. Rejsek, and P. Formanek, Chirality, 2013,
25, 823.
1998, 1141; (
e
,
2512.
2.
3.
(
a
) D. C. N. Swindells, P. S. White and J. A. Findlay, Can. J. Chem.,
1978, 56, 2491; ( ) A. B. Smith III, K. J. Hale, L. M. Laakso, K.
Chen and A. Riéra, Tetrahedron Lett., 1989, 30, 6963; ( ) A. B.
15. For reviews, see: (
Lombart and W. D. Lubell, Tetrahedron, 1997, 53, 12789; (
Cowell, Y. S. Lee, J. P. Cain and V. J. Hruby, Curr. Med. Chem.,
2004, 11, 2785; ( ) T. D. Copeland, E. M. Wondrak, J. Toszer, M.
M. Roberts and S. Oraszan, Biochem. Biophys. Res. Commun., 1990
169, 310; ( ) M. Quibell, A. Benn, N. Flinn, T. Monk, M. Ramjee, Y.
Wang and J. Watts, Bioꢀorg. Med. Chem., 2004, 12, 5689.
16. ( ) P. H.ꢀY. Cheoug, H. Zhang, R. Thayumanavan, F. Tanaka, K. N.
Houk and C. F. Barbas III, Org. Lett., 2006, , 811; ( ) C. E.;
Aroyan, M. M. Vasbinder and S. Miller, Org. Lett., 2005, , 3849; (
a
) S. Hanessian, G. McNaughtonꢀSmith, H.ꢀG.;
b
b
) S. M.
c
Smith III, S. M. Condon, J. A. McCauley, J. L. Leazer Jr., J. W.
c
Leahy and R. E. Maleczka Jr., J. Am. Chem. Soc., 1997, 119, 962l;
,
(
d
a
) A. B. Smith III, C. M. Adams, Acc. Chem. Res., 2004, 37, 365.
d
(
) H. Tanaka, A. Kuroda, H. Marusawa, H. Hatanaka, T. Kino, T.
Goto, M. Hashimoto and T. Taga, J. Am. Chem. Soc., 1987, 109
5031; ( ) D. Romo, S. D. Meyer, D. D. Johnson and S. L. Schreiber,
J. Am. Chem. Soc., 1993, 115, 7906; ( ) R. E. Ireland, J. L. Gleason,
,
a
b
8
b
c
7
c)
L. D. Gregnas and T. K. A. Highsmith, J. Org. Chem., 1996, 61
,
X. Liu, L. Lin and X. Feng, Acc. Chem. Res., 2011, 44, 574 and
references cited therein.
6856.
4. D. L. Boger, J.ꢀH. Chen and K. W. Saionz, J. Am. Chem. Soc., 1996,
118, 1629.
17. For recent syntheses of pipeclic acid: (a) A. Sadiq and N. Sewald, J.
Amino Acids, 2013, 8; (b) R. A. Fernandes and J. L. Nallasivam, Org.
Biomol. Chem., 2012, 10, 7789; (c) T. K. Beng and R. E. Gawley, J.
Am. Chem. Soc., 2010, 132, 12216; (d) B. V. S. Reddy, D. N. Chaya,
J. S. Yadav and R. Gree, Synthesis, 2012, 297. For reviews on
syntheses of pipecolic acid and derivatives, see: (e) C. Agami, F.
Couty and C. PuchotꢀKadouri, Synlett, 1998, 449; (f) F. Couty,
Amino Acids, 1999, 16, 297; (g) F. P. J. T. Rutjes, L. B. Wolf and H.
E. J. Schoemaker, Chem. Soc., Perkin Trans. 1, 2000, 4197; (h) K.ꢀH.
Park and M. J. Kurth, Tetrahedron, 2002, 58, 8629; (i) C. Kadouriꢀ
Puchot, S. Comesse, Amino Acids, 2005, 29, 101; (j) A. A. Cant and
A. Sutheland, Synthesis, 2012, 1935; (k) S. Mohapatra, S. Bhakta, N.
Baral and S. Nayak, Res. Chem. Intermed., 2014, 1ꢀ9. For some
recent synthesis of 3ꢀhydroxypipecolic acid: (l) O. K. Karjalainen and
A. M. P. Koskinen, Tetrahedron, 2014, 70, 2444; (m) S. V. Pansare
and E. K. Paul, Org. Biomol. Chem., 2012, 10, 2119; (n) S.
Begliomini, L. Sernissi, D. Scarpi and E. G. Occhiato, Eur. J. Org.
Chem., 2014, ASAP. For review on synthesis of 3ꢀhydroxypipecolic
acid: (o) A. Cochi, D. Gomez Pardo and J. Cossy, Eur. J. Org.
Chem., 2013, 809.
5. J. B. Rangisetty, M. R. Pullagurla, R. J. J. Muthiah and C. N.
Jobdevairakkam, US patent 7683175, 2008.
6.
(a
) T. Fujii, M. Mukaihara, H. Agematu and H. Tsunekawa, Biosci.
Biotechnol. Biochem., 2002, 66, 622; ( ) S. B. Singh, D. L. Zink, J.
b
M. Liesch, R. T. Mosley, A. W. Dombrowski, G. F. Bills, S. J.
DarkinꢀRattray, D. M. Schmatz and M. A. Goetz, J. Org. Chem.,
2002, 67, 815; (c) A. V. Bieliauskas and M. K. H. Pflum, Chem. Soc.
Rev., 2008, 37, 1402.
7. I. Pastuszak, R. J. Molyneux, L. F. James and A. D. Elbein,
Biochemistry, 1990, 29, 1886.
8. M. A. Wijdeven, J. Willemsen and F. P. J. T. Rutjes, Eur. J. Org.
Chem., 2010, 2831.
9. F. Ferreira, C. Greck and J. P. Genet, Bull. Soc. Chim. Fr., 1997, 134
,
615.
10. (
K. Olden, Cancer Res. 1988, 48, 1410; (
Res., 1986, 46, 5131; ( ) C. Galustian, S. Foulds, J. F. Dye and P. J.
Guillou, Immunopharmacology, 1994, 27, 165; ( ) P. C. Das, J. D.
Roberts, S. L. White and K. Olden, Oncol. Res. 1995, , 425; (e) H.
Motohiro, N. Kunio, T. Hiroshi, H. Junji, K. Masanobu, A. Hatsuo
and I. Hiroshi, Patent EP 104826 Chem. Abstr 1984, 101, 28283x.
11. ( ) F. A., Jr., Kuehl, C. F. Spencer and K. Folkers, J. Am. Chem.
Soc., 1948, 70, 2091; ( ) Sh. Kobayashi, M. Ueno and R. Suzuki,
Tetrahedron Lett., 1999, 40, 2175.
12. ( ) G. Ratle, X. Monseur, B. C. Das, J. Yassi, Q. KhuongꢀHuu and R.
a
) M. J. Humphries, K. Matsumoto, S. L. White, R. J. Molyneux and
b
) J. W. Dennis, Cancer
c
d
7
18. For recent syntheses of lentiginosine, see: (
Soorukram, C. Kuhakarn, P. Tuchinda, V. Reutrakul, M. Pohmakotr,
Eur. J. Org. Chem., 2014, 1708; ( ) S. V. Kauloorkar, V. Jha, G.
Jogdand and P. Kumar, Org. Bio. Chem., 2014, 12, 4454; ( ) G.ꢀW.
Kim, T. Jin, J.ꢀS. Kim, S.ꢀH. Park, K.ꢀH. Lee, S.ꢀS. Kim, I.ꢀS.
Myeong and W.ꢀH. Ham, Tetrahedron: Asymmetry, 2014, 25, 87; (
a) S. Duꢀaꢀman, D.
;
.,
b
a
c
b
d
)
a
M. Lingamurthy, A. Rajender and B. V. Rao, Tetrahedron:
Goutarel, Bull. Soc. Chim. Fr., 1966, 2945; (b) Q. KhuongꢀHuu, G.
10 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 11 of 12
Journal Name
RSC Advances
View ArticAle ROnTliInCeLE
DOI: 10.1039/C5RA06429E
Asymmetry, 2014, 25, 860; (
Tetrahedron: Asymmetry, 2014, 25, 497; (
Zhang and A. Chen, RSC Adv., 2013, , 20298; (
Yang, J. Org. Chem., 2012, 77, 7891; ( ) S.ꢀW. Liu, H.ꢀC. Hsu, C.ꢀ
H. Chang, H.ꢀH. G. Tsai and D.ꢀR. Hou, Eur. J. Org. Chem., 2010,
4771; ( ) R. Lahiri, H. P. Kokatla and Y. D. Vankar, Tetrahedron
Lett., 2011, 52, 781; ( ) I. S. Kim, Q. R. Li, G. R. Dong, Y. C. Kim,
Y. J. Hong, M. Lee, K.ꢀW. Chi, J. S. Oh and Y. H. Jung, Eur. J. Org.
e
) H. Yoon, K. S. Cho and T. Sim,
) J. Zeng, Q. Zhang, H.ꢀK.
) J. Shao and J.ꢀS.
Tetrahedron: Asymmetry, 1997,
Davis, Synthesis, 2000, 1347; (
Yudin, Acc. Chem. Res., 2006, 39, 194; (
ARKIVOC, 2006, , 6; ( ) D. S. Tsang, S. Yang, F. A. Alphonse and
A. K. Yudin, Chem. Eur. J., 2008, 14, 886; ( ) G. S. Singh, S. M.
D’hooghe and N. De Kimpe, Chem. Rev., 2007, 107, 2080; ( ) C.
Schneider, Angew. Chem. Int. Ed., 2009, 48, 2082; ( ) S. Stanković,
S. D’hooghe, M. Catak, H. Eum, M. Waroquier, V. Van Speybroeck,
N. De Kimpe and H.ꢀJ. Ha, Chem. Soc. Rev., 2012, 41, 643; ( ) P.
Lu, Tetrahedron, 2010, 66, 2549; (o) T. Ishikawa, Heterocycles,
2012, 85, 2837. p) H. Ohno, Chem. Rev. 2014, ASAP
8
, 1693; (
) I. D. G. Watson, L. Yu and A. K.
) A. Padwa, S. S. Murphree,
g) W. M. McCoull, F. A.
f
h
3
g
i
h
3
j
k
i
l
j
m
Chem., 2010, 1569; (
k
) M.ꢀJ. Chen and Y.ꢀM. Tsai, Tetrahedron
n
Lett., 2007, 48, 6271; (
l
) S. R. Angle, D. Bensa and D. S. Belanger, J.
Org. Chem., 2007, 72, 5592; and references cited therein. For a
review on lentiginosine, see: ( ) F. Cardona, A. Goti and A.Brandi, 22. (
.
m
a
) T. M. Shaikh and A. Sudalai, Tetrahedron: Asymmetry, 2009, 20
,
Eur. J. Org. Chem., 2007, 1551; (n) F. M. Cordero, D. Giomi and A.
Brandi, Curr. Top. Med. Chem., 2014, 14, 1294.
2287; (b) A. S. Kamal and R. Vangala, Tetrahedron, 2011, 67, 1341;
(c
)
M. K. Gurjar, L. Ghosh, M. Syamala and V. Jayasree,
Tetrahedron Lett., 1994, 35, 8871.
and G. Panda, Tetrahedron, 2014, 70, 1363; (b) X.ꢀG. Wang, A.ꢀE. 23. ( ) T. Oishi, T. Iwakuma, M. Hirama and S. Itô, Synlett, 1995, 404;
Wang and P.ꢀQ. Huang, Chin. Chem. Lett. 2014, 25, 193; ( ) Q. R. ) S. Chooprayoon, C. Kuhakarn, P. Tuchinda, V. Reutrakul and M.
Li, G. R. Dong, S. J. Park, Y. R. Hong, I. S. Kim and Y. H. Jung, Pohmakotr, Org. Biomol. Chem., 2011, , 531.
Eur. J. Org. Chem., 2013, 4427; ( ) V. Dhand, J. A. Draper, J. Moore 24. D. B. Denny and S. T. Ross, J. Org. Chem., 1961, 27, 998.
and R. Britton, Org. Lett., 2013, 15, 1914; ( ) G. Archibald, C. Lin, 25. ( ) H.ꢀD. Ambrosi, W. Duczek, E. Gründemann, M. Ramm and K.
P. Boyd, D. Barker and V. J. Caprio, J. Org. Chem., 2012, 77, 7968; Jähnisch, Liebigs Ann. Chem., 1994, 1013; ( ) K. S. Ajish Kumar, V.
) M.ꢀJ. Chen and Y.ꢀM. Tsai, Tetrahedron, 2011, 67, 1564; ( ) H. D. Chaudhari and D. D. Dhavale, Org. Biomol. Chem., 2008, , 703.
G. Choi, J. H. Kwon, J. C. Kim, W. K. Lee, H. Eum and H.ꢀJ. Ha, 26. K. W. C. Poon, K. M. Lovell, K. N. Dresner and A. Datta, J. Org.
Tetrahedron Lett., 2010, 51, 3284; ( ) D. J. Wardrop and E. G. Chem., 2008, 73, 752.
Bowen, Org. Lett., 2011, 13, 2376; ( ) Y.ꢀS. Tian, J.ꢀE. Joo, B.ꢀS. 27. a) T. Bieg and W. Szeja, Synthesis 1985, 76; For Pd catalyzed
Kong, V.ꢀT. Pham, K.ꢀY. Lee and W.ꢀH. Ham, J. Org. Chem., 2009,
74, 3962; ( ) J. Louvel, F. Chemla, E. Demont, F. Ferreira, A. Perezꢀ
Luna, Org. Lett., 2011, 13, 6452; ( ) H. K. Zhang, S. Q. Xu, J.
Zhuang, J. Ye and P. Q. Huang, Tetrahedron, 2012, 68, 6656; ( ) R.
W. Bates and M. R. Dewey, Org. Lett., 2009, 11, 3706; ( ) S. J.
Oxenford, S. P. Moore, G. Carbone, G. Barker, P. O’Brien, M. R.
19. For recent syntheses of swainsonine, see: (a) P. Singh, S. K. Manna
a
c
(b
9
d
e
a
b
(f
g
6
h
i
regioselective cleavage of vinyl aziridines please see: b) Ref. 25b; c)
G. W. Spears, K. Nakanishi and Y Ohfune. Synlett, 1991. 91; d) K.
Fugami. K. Miura. Y. Morizawa, K. Oshima, K. Utimoto and H.
j
k
l
Nozaki, Tetrahedron, 1989, 45, 3089; For hydrogenation of ester
m
aziridines and C(2)ꢀN, C(3)ꢀN bond cleavage, Please see: e) Y. Lim
and W. K. Lee Tetrahedron Lett., 1995, 36, 8431.
Shipton, J. Gilday and K. R. Campos, Tetrahedron: Asymmetry, 28. C. Greck, F. Ferreira and J. P. Genêt, Tetrahedron Lett., 1996, 37
2010, 21, 1563; ( ) S. N. Murthy and Y. V. D. Nageswar, Synthesis, 2031.
2011, 755. For a review of swainsonine syntheses, see: ( ) L. Nin, H. 29. G. Rassu, L. Auzzas, V. Zambrano, P. Burreddu, L. Pinna, L.
Ba and A. Haji, Chin. J. Org. Chem., 2009, 29, 1354; (
Curr. Org. Synth., 2005, , 39; ( ) A. E. Nemr, Tetrahedron, 2000,
,
n
o
p
) S. G. Pyne,
Battistini, F. Zanardi and G. Casiraghi, J. Org. Chem., 2004, 69,
2
q
1625.
56, 8579; (q) B. K. Lee, H. G. Choi, E. J. Roh, W. K. Lee and T. Sim, 30. (a) P. J. Garegg and B. Samulesson, Synthesis, 1979, 469; (b) H. B.
Tetrahedron Lett. 2013, 54, 553.
Mereyala, P. M. Goud, R. R. Gadikota and K. R. Reddy, J.
Carbohydr. Chem., 2000, 19, 1211.
20. (
Tetrahedron: Asymmetry, 2011, 22, 587; (
Dumare and K. R. Harale and U. R. Kalkote, Tetrahedron Lett.,
2011, 52, 404; ( ) S. P. Chavan, K. R. Harale and K. P. Pawar,
Tetrahedron Lett., 2013, 54, 4851; (
Tetrahedron Lett., 2004, 45, 421; ( ) S.P. Chavan, N. B. Dumare and
K. P. Pawar, RSC Adv., 2014, , 32594; (
a
) S. P. Chavan, K. R. Harale, N. B. Dumare and U. R. Kalkote,
b
) S. P. Chavan, N. B. 31. (a) R. H. Grubbs, Handbook of Metathesis. In Applications in
Organic Synthesis; WILEYꢀVCH, 2003; Vol. 2; (b) G. C. Fu, R. H.
c
Grubbs, J. Am. Chem. Soc., 1992, 114, 7324.
d
) S. P. Chavan and C. Praveen, 32. S. C. Deshmukh, A. Roy and P. Talukdar, Org. Biomol. Chem., 2012,
e
10, 7536.
4
f
) S. P. Chavan, L. B. 33. H.ꢀD. Ambrosi, W. Duczek, E. Gründemann. M. Ramm and K.
Khairnar, P. C. Chavan and D. B. Kalbhor, Tetrahedron: Asymmetry
2014, 25, 1246; (g) S. P. Chavan, L. B. Khairnar, P. C. Chavan, N. B. 34. D. B. Denny and S. T. Ross, J. Org. Chem., 1961, 27, 998.
Dumare and D. B. Kalbhor Tetrahedron Lett. 2014, 55, 6423. 35. K. Jähnisch, Liebigs Ann./Recueil, 1997, 757.
21. For reviews, see: ( ) U. M. Lindström, P. Somfai, Synthesis, 1998, 36. S.ꢀB. Huang, J. S. Nelson and D. D. Weller, Synth. Commun., 1989,
109; ( ) B. Zwanenburg and P. ten Holte, Top. Curr. Chem., 2001, 19, 3485.
216, 93; ( ) J. B. Sweeney, Chem. Soc. Rev., 2002, 31, 247; ( ) X. E. 37. F. SánchezꢀSancho and B. Herradón, Tetrahedron: Asymmetry, 1998,
Hu, Tetrahedron, 2004, 60, 2701; ( ) D. Tanner, Angew. Chem., Int. , 1951.
Ed. Engl., 1994, 33, 599; ( ) H. M. I. Osborn and J. Sweeney,
,
Jähnisch, Liebigs Ann. Chem., 1994, 1013.
a
b
c
d
e
9
f
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 11

RSC Advances
Page 12 of 12
ARTICLE
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C5RA06429E
38. (a) DꢀR. Hou, SꢀY. Hung and CꢀC. Hu, Tetrahedton: Asymmetry
,
2005, 16, 3858, (b) L.ꢀA. Watanabe, S. Haranaka, B. Jose, M.
Yoshida, T. Kato, M. Moriguchi, K. Soda and N. Nishino,
Tetrahedron: Asymmetry, 2005, 16, 903.
39. L. Battistini, F. Zanardi, G. Rassu, P. Spanu, G. Pelosi, G. G. Fava,
M. B. Ferrari and G. Casiraghi, Tetrahedron: Asymmetry 1997
,
8
,
2975.
40. W. H. Chiou, G. H.; Lin and C. W. Liang, J. Org. Chem., 2010, 75
,
174.
41. (a) T. Oishi, T. Iwakuma, M. Hirama and S. Itô, Synlett, 1995, 404;
(b) S. Chooprayoon, C. Kuhakarn, P. Tuchinda, V. Reutrakul and M.
Pohmakotr, Org. Biomol. Chem., 2011, 9, 531.
42. Deshmukh, S. C.; Roy, A.; Talukdar, P. Org. Biomol. Chem. 2012
,
10, 7536.
12 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012