Synthesis of 4-hydroxy-2-methylproline derivatives via pyrrolidine ring assembly: chromatographic resolution and diastereoselective synthesis approaches

Article abstract of DOI:10.1016/j.tetasy.2016.07.001

4-Hydroxy-2-methylproline diastereomers are successfully prepared without the use of an external chiral auxiliary. Dihydroxylation of the key intermediate 2 resulted in lactone 4 as a mixture of diastereomers in good yield. Mesylation, hydrogenation and c

Full text of DOI:10.1016/j.tetasy.2016.07.001

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of 4-hydroxy-2-methylproline derivatives via pyrrolidine
ring assembly: chromatographic resolution and diastereoselective
synthesis approaches
Vinay Shankar Tiwari a,b, Raghavendra Murugula a, Shyam Raj Yadav a, Wahajul Haq a,b,
⇑
a MPC Division, CSIR-Central Drug Research Institute, Lucknow 220031, India
b Academy of Scientific and Innovative Research, New Delhi 110001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
4-Hydroxy-2-methylproline diastereomers are successfully prepared without the use of an external
chiral auxiliary. Dihydroxylation of the key intermediate 2 resulted in lactone 4 as a mixture of
diastereomers in good yield. Mesylation, hydrogenation and concomitant intramolecular cyclization of
4 led to the formation of both (2R,4R)- and (2R,4S)-4-hydroxy-2-methylprolines as a mixture of
diastereomers. Appropriate protection followed by chromatographic separation resulted in
isolation of both cis- and trans-diastereomers in enantiomerically pure form and in equal quantity. In
subsequent experiments, the synthesis of the more challenging diastereomers (2R,4R)- and
(2S,4S)-4-hydroxy-2-methylproline was achieved by diastereoselective iodolactonization of (R)- or
(S)-allylalanine obtained after hydrolysis of intermediate 2, followed by pyrrolidine ring closer under
Received 21 June 2016
Accepted 8 July 2016
Available online xxxx
mild alkaline conditions. After selective protection and deprotection, Fmoc-(2R,4R)-
14, a building block suitable for solid phase peptide synthesis was obtained.
a
-Me-Hyp(tBu)-OH
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
methylprolines is generally carried out starting from 4-hydrox-
yproline as a starting material. The stereoselective synthesis
reported for 4-hydroxy-2-methylprolines generally yield products
with 70–98% ee using chiral auxiliary in one way or the other. It is
important to note that the enantiomeric purity of these amino
acids is crucial for the biological activity of peptides. Therefore,
these interesting monomers can be used for peptide engineering
only when a facile synthesis is available to obtain these quaternary
amino acids in enantiomerically pure forms. The synthesis of trans-
4-hydroxy-2-methylprolines by the resolution of racemic or
enantioenriched diastereomeric mixtures has already been reported
with success starting from trans-4-hydroxyproline.5 However, the
other cis-diastereomers remain inaccessible by these methods due
to the fact that 4-hydroxyproline is readily available only in its
trans-form while the cis-4-hydroxyproline is highly expensive.6 An
interesting stereoselective synthesis of 4-hydroxy-2-methylprolines,
that excludes the use of 4-hydroxyproline as a starting material, was
reported by Kolaczkowski and Barnes.7 Starting from (S)-alanine,
Modification of native peptides by incorporation of structurally
rigid amino acid surrogates into their sequences leads to several
beneficial effects such as conformational stability, stability against
proteolytic degradation, selectivity and potency.1 The use of
enantiomerically pure quaternary amino acids has gained
significant attention due to their unique properties for designing
peptides with interesting structural features and biological
activity.2 Quaternary cyclic amino acids, such as proline and
hydroxyproline are of special interest due to their exceptional con-
formational rigidity, which induces helicity upon incorporation into
peptides.3 In spite of their potential advantages, the use of
quaternary amino acids is limited as these amino acids are not com-
mercially available. In recent years, efforts were made to develop
methodologies for the synthesis of these specialized amino acids
for further use. The synthetic procedures for quaternary proline
derivatives remain challenging as reported by Calaza and Cativiela.4
4-Hydroxy-2-methylprolines are interesting structural variants
of cyclic quaternary amino acids but remain underutilized due to
limited synthetic methodology. The preparation of 4-hydroxy-2-
both cis-
a trans-isomers of 4-hydroxy-2-methylprolines were
obtained in high yields and enantioselectivity.
Herein we deal with the synthesis of 4-hydroxy-2-methylpro-
line diastereomers via pyrrolidine ring assembly using
(2R,4S)-allyloxazolidinone 2 as a key intermediate. Compound 2
can be easily obtained starting from (2S,4S)-oxazolidinone 1, a
⇑
Corresponding author. Tel.: +91 522 2772470.
E-mail address: w_haq@cdri.res.in (W. Haq).
http://dx.doi.org/10.1016/j.tetasy.2016.07.001
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Tiwari, V. S.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.07.001

2
V. S. Tiwari et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
versatile synthon, by enantioretentive allylation.8 We report the
synthesis of enantiopure 4-hydroxy-2-methylprolines starting
from alanine via intermediate 1 by a resolution approach using
column chromatography. In subsequent experiments, the
diastereoselective synthesis of (2R,4R)- and (2S,4S)-4-hydroxy-2-
methylprolines, the more rare forms, were achieved using 1 as a
starting material. In both approaches, diastereomerically pure
products were obtained without the use of an external chiral
auxiliary.
Based on the retrosynthesis, the preparation of 4-hydroxy-2-
methylprolines by chromatographic resolution approach is shown
in Scheme 1. Compound 1 (Karady oxazolidinone) was prepared by
BF3ꢀEt2O catalysed oxazolidinone formation with Cbz-
L-alanine and
benzaldehyde dimethyl acetal. Enantioretentive alkylation of 1
using LiHMDS and allyl bromide was optimized at this stage to
improve the yield of allyloxazolidinone 2. It was found that the
slow addition of 1.2 equiv of LiHMDS in a pre-cooled mixture of
oxazolidinone 1 and 1.2 equiv of allyl bromide gave compound 2
in 75–80% yield. The terminal dihydroxylation of compound 2
was attempted using K2OsO4ꢀ2H2O according to the literature.9
We did not obtain the expected dihydroxylated product 3, instead
compound 4 was isolated as nearly a 1:1 mixture of diastereomers
as evident from NMR-spectroscopy. The reaction product after the
usual work-up showed two spots on TLC, where one spot was
characterized as lactone 4 and the other was characterized as ben-
zaldehyde. Interestingly, the formation of benzaldehyde indicated
in situ lactonization via intermediate 3 (Fig. 2).10
2. Results and discussion
Quaternary 4-hydroxyprolines are generally prepared from
commercially available trans-4-hydroxyproline. These procedures
are limited to accessing only the (2S,4R)-configuration starting
from trans 4-hydroxyproline. The corresponding cis-4-hydroxypro-
line is highly expensive. Therefore, a versatile synthetic route
starting from commercially available and cost effective starting
material which allows access to both (2S,4R) and (2R,4R) is highly
desirable. The retrosynthetic analysis for 4-hydroxy-2-methylpro-
line is presented in Figure 1. Our initial strategy was based on the
enantioselective dihydroxylation of 2, obtained by the alkylation of
1 with allyl bromide. Contrary to our expected dihydroxylation
product 3, we isolated lactone 4. Mesylation of the primary alcohol
of 4 resulted in compound 5, which upon Cbz-deprotection and
hydrolysis furnished 4-hydroxy-2-methylproline diastereomers 6
via intramolecular cyclization.
Ph
O
O
Z-N
OH
OH
3
Figure 2. Mechanism for in situ lactonization.
O
HO
O
We made several attempts for asymmetric dihydroxylation of
the compound 2 with AD mix-a and AD mix-b in order to improve
OH
O
OMs
Z-HN
N
H
O
the stereoselectivity but were unsuccessful. Compound 4 was trea-
ted with mesyl chloride in the presence of triethylamine to obtain
the corresponding methylsulfonate ester 5. Compound 5 was sub-
jected to catalytic hydrogenation in methanol and 2 equiv of DIEA
for 3 h. The crude amino lactones obtained were readily converted
into 4-hydroxy-2-methylprolines 6 by treatment with LiOH at room
temperature. We did not isolate the free amino acid and the crude
product was treated with di-tert-butyl-dicarbonate followed by
treatment with diazomethane to give the corresponding N-Boc
protected 4-hydroxy-2-methylproline methylester 7, which was
characterized as mixture of diastereomers (2R,4S)- and
(2R,4R)-4-hydroxy-2-methylproline. We speculated that after the
lactone was opened by LiOH, a successive ring-closure reaction
would have occurred immediately resulting in 6. The diastere-
omeric mixture of 7 was not resolvable on TLC. Therefore, hydroxyl
group was masked with TBDMS-Cl/imidazole to form 8 as a mixture
of diastereomers which were very well separated on TLC. Thus the
5
4
6
O
Ph
O
Z-N
HO
O
OH
Z-HN
Ph
3
HO
O
O
Ph
O
O
Z-N
Z-N
1
2
Figure 1. Retrosynthetic analysis of 4-hydroxy 2-methylprolines.
Ph
Z-N
Ph
Z-N
O
O
HO
O
O
a
b
d
c
O
O
O
O
e
OH
OMs
OH
Z-HN
O
Z-HN
N
H
benzaldehyde
O
4
2
1
5
6
TBDMS
TBDMS
TBDMS
HO
O
O
g
f
O
O
+
O
N
O
N
N
N
O
Boc
O
O
Boc
Boc
O
Boc
7
8
8a
8b
Scheme 1. Synthesis of protected diastereomers of 4-hydroxy-2-methylproline. Reagents and conditions: (a) LiHMDS, allyl bromide, THF, ꢁ78 °C, 3 h, 75–80%; (b) NMO,
K2OsO4ꢀ2H2O, acetone, 18 h, 85%; (c) MsCl, Et3N, THF, 0 °C, 1/2 h, 85%; (d) (i) H2, Pd/C, DIEA, methanol, 3 h, (ii) LiOH, methanol/water 9:1 (v/v), 2 h; (e) (i) (Boc)2O,
dioxane/water 1:1, 0 °C to rt, 3 h (ii) CH2N2, diethyl ether, 0 °C to rt, 3 h, (75% over four steps) (f) TBDMS-Cl, imidazole, DMF, rt, 12 h; (g) Chromatography.
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V. S. Tiwari et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
diastereomers 8a and 8b were easily separated by column chro-
matography over silica gel eluting with ethyl acetate–hexane
(1:9). The fast moving isomer was characterized as 8b (2R,4R) and
the slow moving isomer was found to be 8a (2R,4S). In the 1H
NMR spectrum, diastereomer 8a (2R,4S) has two multiples at
1.87–1.94 and 2.25–2.34 ppm (trans-isomer) whereas the
diastereomer 8b (2R,4R) had two multiplets at 2.04–2.09 and
2.14–2.23 ppm (cis-isomer) for the two diastereotopic protons at
C3 carbon, which were in agreement with the values reported in
the literature.6a,11
methylproline, we modified our initial strategy as illustrated in
Scheme 2. Allyloxazolidinone 2 was hydrolysed and the resultant
Cbz-(R)-allylalanine was subjected to iodolactonization with
N-iodosuccinimide. The iodolactonization proceeded smoothly to
predominantly give the cis-diastereomer in a ratio of 83:17
(cis-9a/trans-9b) as evident by NMR and reported by Pattarozzi
et al.12 The mixture of iodolactone diastereomers was then heated
with a base, which enabled the cis-diastereomer 9a to form bicyclic
pyrrolidine lactone 10, while the trans-iodolactone 9b remained
unreacted due to unfavorable geometry.
The stereochemistry of compounds 8a and 8b at the newly
generated C4 stereocenter was assigned using 2D NOE
NMR-spectroscopy with respect to C2. i.e. (2R), as illustrated in
Figure 3. We did not observe an NOE between C2CH3 M C4H in
compound 8a, which is characteristic of a trans-configuration, i.e.
(2R,4S), and is further supported by the strong NOE correlation
between C3H0 M C4H and C5H0 M C4H. However, in compound
8b we observed strong NOE between C2CH3 M C4H, thus indicat-
ing a cis-configuration, i.e. (2R,4R) and is further supported by
the strong NOE correlation C3H M C4H and C5H M C4H.
The intramolecular cyclization reaction of cis-iodolactone 9a to
bicyclic pyrrolidine lactone 10 was further optimized by screening
with different polar solvents and organic and inorganic bases. The
results of the optimization reaction are summarized in Table 1. The
best conditions for intramolecular cyclization were found to be
DMF as the solvent with 3 equiv of K2CO3 as the base at 80 °C,
which provided 76% of the bicyclic pyrrolidine lactone 10 after
5 h (entry 6, Table 1). The bicyclic pyrrolidine lactone 10 was easily
purified by column chromatography and hydrolysed to give
(2R,4R)-N-Cbz-4-hydroxy-2-methylproline 11 exclusively. The acid
group of compound 11 was converted into the corresponding
benzyl ester 12 using benzyl bromide and triethyl amine. The
In order to develop a stereoselective method for the synthesis of
a more challenging cis-diastereomer, i.e. (2R,4R)-4-hydroxy-2-
Figure 3. (a) 2D NOESY spectra of compound 8a showing no NOE contact between C2CH3 M C4H and strong NOE correlation between C3H0MC4H and C5H0 M C4H. (b) 2D
NOESY spectra of compound 8b showing strong NOE contact between C2CH3 M C4H, C3H M C4H and C5H M C4H.
O
O
O
Ph
O
a
b
O
O
O
c
Z-N
I
I
O
N
Z-HN
cis-9a/trans-9b (83/17)
Z-HN
Z
minor unreacted
2
10
trans-9b
O
HO
HO
O
f
e
d
OH
OH
OBn
OBn
N
N
Z
N
Z
N
Z
O
O
O
O
Fmoc
11
12
14
13
Scheme 2. Diastereoselective synthesis of (2R,4R)-4-hydroxy-2-methylproline from L-alanine. Reagents and conditions: (a) (i) NaOH, methanol/water 9:1 (v/v), 5–6 h, (ii)
NIS, CHCl3, rt, 2 h, 80% (over two steps); (b) K2CO3, DMF, 80 °C, 5 h, 76%; (c) LiOH, MeOH/THF/water (2:2:3, v/v), rt, overnight, 95%; (d) benzyl bromide, Et3N, THF, overnight,
78%; (e) tertiary butyl 2,2,2-trichloroacetamidate, DCM/hexane 1:2 (v/v), 48 h, 55%; (f) (i) H2, Pd/C, methanol, 2 h, (ii) Fmoc-OSu, K2CO3, dioxane/water (1:1, v/v), 0 °C to rt,
overnight, 86% (over two steps).
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4
V. S. Tiwari et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Table 1
(2S,4S)- and (2R,4R)-4-hydroxy-2-methylproline starting with
- and -alanine, respectively, in high yields. These cis-isomers of
Reaction optimization table for cyclization reaction
L
D
4-hydroxy-2-methylproline are difficult to synthesize in enan-
tiomerically pure form due to the limited scope of starting material
and poor yield. The main advantage of this protocol is that it does
not require any external chiral reagent. We have also prepared an
orthogonally protected monomer compatible for solid phase pep-
tide synthesis. These methodologies are useful for the multi gram
scale synthesis of all of the 4-hydroxy-2-methylproline
diastereomers.
O
O
O
O
base
solvent
O
O
I
temprature
time
I
N
Z-HN
cis-9a/trans-9b (83/17)
Z-HN
Z
minor unreacted
10
trans-9b
Entry
Solvent
Base
Time (h)
% Yielda
1
2
3
4
5
6
ACN
ACN
DMF
DMF
DMF
DMF
DIEA (1 equiv)
24
12
24
5
12
5
NRb
30c
NRb
23d
38d
76d
K2CO3 (2 equiv)
DIEA (1 equiv)
DIEA (3 equiv)
K2CO3 (1 equiv)
K2CO3 (3 equiv)
4. Experimental
4.1. General
All chemicals and reagents were purchased from Sigma Aldrich
(St. Louis, MO). The progress of the reaction was monitored by
thin-layer chromatography (TLC) on ready-made silica gel plates
(Merck, Darmstadt, Germany; UV active). The plates were either
developed under iodine vapour or seen directly under UV-light
(254 nm). Wherever required, compounds were also detected by
spraying the TLC plates with 2 N HBr/AcOH followed by 0.2%
ninhydrin solution in acetone and heating the plates at ꢂ110 °C in
a hot air oven for 45 min. Column chromatography was performed
over silica gel (60–120 mesh size). 1H NMR spectra were recorded
at 300 MHz or 400 MHz and 13C NMR spectra were recorded at
75 MHz or 100 MHz using a Bruker (Billerica, MA) DRX-300 or
Bruker DRX-400 spectrophotometer, respectively, and reported in
parts per million (ppm) on the d scale relative to tetramethylsilane
as an internal standard. Coupling constants (J) are reported in Hz.
Melting points are reported uncorrected and were determined on
melting point apparatus containing silicon oil. IR spectra were
recorded using Agilent (Palo Alto, CA) Cary 630 FTIR spectropho-
tometer. Mass spectra were obtained using JEOL (Tokyo, Japan)
SX-102 (ESI), Agilent 6520 Q-TOF (ESI-HRMS) instruments. Optical
rotations were measured on an AUTOPOL III digital polarimeter.
Bold entry signify the optimum reaction condition for cyclization reaction.
a
Isolated yield of bicyclic lactone 10.
No reaction at room temperature.
Reaction was performed at reflux.
Reaction was performed at 80 °C.
b
c
d
hydroxy group of compound 12 was protected with a tertiary butyl
group using tertiary butyl 2,2,2-trichloroacetamidate and
a
catalytic amount of BF3ꢀEt2O to give compound 13. The concomi-
tant removal of Cbz-protection and benzyl ester protection by
hydrogenation and Fmoc-protection to the resultant amine,
yielded the suitably protected (2R,4R)-4-hydroxy-2-methylproline
14 ready for solid phase peptide synthesis.
In order to extend and validate the applicability of this method-
ology, we synthesized the other enantiomer (2S,4S)-4-hydroxy-2-
methylproline starting from Cbz-protected D-alanine as illustrated
in Scheme 3. The intermediate compound 15 which is an enan-
tiomer of allyloxazolidinone 2, was subjected to similar reaction
sequence as described in Scheme 2 to give (2S,4S)-4-hydroxy-2-
methylproline 18, which is the other enantiomer of compound 11.
O
4.1.1. (2S,4S)-Benzyl-4-methyl-5-oxo-2-phenyloxazolidine-carbo-
xylate 1
Ph
O
O
a
O
Properly dried Z-(S)-alanine (22.3 g, 100 mmol) and benzalde-
hyde dimethyl acetal (14.4 mL, 95.9 mmol) in diethyl ether
(500 mL) were cooled to ꢁ78 °C followed by the dropwise addition
of BF3ꢀEt2O (60.2 mL, 489 mmol) under a nitrogen atmosphere. The
reaction mixture was then allowed to warm to room temperature
and stirred until completion of the reaction as monitored by TLC.
The reaction mixture was treated with saturated aqueous NaHCO3
at 0 °C, initially in small portions until strong bubbling ceased, and
then the mixture was extracted with Et2O (3 ꢃ 150 mL). The com-
bined organic phase was washed with brine and dried over anhy-
drous sodium sulfate. The solvent was removed under vacuum
and the predominant cis-isomer was obtained from the crude mix-
ture by silica gel column chromatography using ethyl acetate in
hexane (1:4) as the eluent. The compound was further crystallised
from diethyl ether/hexane to yield compound 1 (18.66 g, 60% yield)
as white crystalline solid: mp 53–54 °C; 1H NMR (400 MHz, CDCl3)
d = 1.56 (d, J = 6.9 Hz, 3H), 4.45 (q, J = 6.9 Hz, 1H), 5.11–5.21 (m,
2H), 6.64 (s, 1H), 7.25–7.40 (m, 10H); 13C NMR (100 MHz, CDCl3)
d = 18.2, 52.2, 67.9, 89.1, 126.3, 126.6, 128.1, 128.5, 128.6, 128.8,
I
Z-N
Z-HN
cis-16a/trans-16b
(83:17)
15
b
unreacted 16b
HO
O
OH
c
O
O
N
Z
N
Z
18
17
Scheme 3. Synthesis of (2S,4S)-4-hydroxy-2-methylproline from
D-alanine.
Reagents and conditions: (a) (i) NaOH, methanol/water 9:1 (v/v), 5–6 h, (ii) NIS,
CHCl3, rt, 2 h, 77% (over two steps); (b) K2CO3, DMF, 80 °C, 5 h, 63%; (c) LiOH, MeOH/
THF/water (2:2:3, v/v), rt, overnight, 94%.
3. Conclusion
129.8, 135.4, 136.9, 153.4, 172.5; FTIR (KBr):
m = 3352, 1800,
1717, 763 cmꢁ1; HRMS (ESI-TOF) calculated for [C18H17NO4+H]+
312.1230, found 312.1229.
We have developed a facile method to access all of the
diastereomers of the 4-hydroxy-2-methylprolines in enantiomeri-
cally pure form. Herein we have demonstrated the preparation of
(2R,4R)- and (2R,4S)-4-hydroxy-2-methylproline diastereomers
starting with inexpensive L-alanine by chromatographic resolution
of the diastereomers. We have also developed diastereoselective
synthesis for the preparation of the cis-isomers namely
4.1.2. (2S,4R)-Benzyl-4-allyl-4-methyl-5-oxo-2-phenyloxazoli-
dine-3-carboxylate 2
A solution of compound 1 (7.78 g, 25 mmol) and allyl bromide
(2.6 mL, 30 mmol) in dry THF (30 mL) was cooled to ꢁ78 °C under
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V. S. Tiwari et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
stirring. To this solution LiHMDS (30 mL, 1 M in THF) was added at
ꢁ78 °C under a nitrogen atmosphere. The reaction mixture was
further stirred at ꢁ78 °C for 3 h. The reaction mixture was then
quenched with saturated ammonium chloride and extracted with
ethyl acetate (3 ꢃ 150 mL). The combined organic layer was
washed with brine, dried over sodium sulfate and evaporated.
The crude product obtained was purified by column chromatogra-
phy using ethyl acetate in hexane (1:5) as eluent to obtain com-
1350 cmꢁ1 HRMS (ESI-TOF) calculated for [C15H20NO7S+H]+
;
358.0955, found 358.0956.
4.1.5. (2R,4S)-1-tert-Butyl-2-methyl-4-hydroxy-2-methylpyrroli-
dine-1,2-dicarboxylate and (2R,4R)-1-tert-butyl-2-methyl-4-
hydroxy-2-methylpyrrolidine-1,2-dicarboxylate 7
Compound 5 (715 mg, 2 mmol) was dissolved in methanol
(20 mL) and DIEA (0.85 mL, 5 mmol) was added. To this solution
10% Pd/C (0.2 g) was added then the reaction mixture was
subjected to hydrogenation at 30 psi for 3 h. The crude product
obtained after evaporation of methanol was hydrolyzed using
aqueous LiOH (168 mg, 2 mmol) in methanol:water (9:1, 20 mL)
for 2 h. After completion of the hydrolysis, methanol was evapo-
rated and dioxane (10 mL) was added followed by the addition of
Boc2O (0.7 mL, 3 mmol) at 0 °C. The reaction mixture was stirred
for 3 h and then dioxane was evaporated under reduced pressure.
The aqueous phase was acidified with citric acid up to pH 3 and
extracted with ethyl acetate (15 mL ꢃ 3). The organic phase was
washed with brine, dried over sodium sulfate and evaporated in
vacuo. To a solution of the crude product in methanol (15 mL)
was added diazomethane dissolved in diethyl ether (20 mL) at
0 °C until the reaction mixture became yellow. After completion
of the esterification, the solvents were evaporated under reduced
pound 2 (7.02 g, 80%) as a colorless oil: [
a
]
D
21 = ꢁ63.4 (c 0.73,
CHCl3): 1H NMR (400 MHz, CDCl3), (major rotamer) d = 1.81(s,
3H), 2.52 (dd, J = 13.7, 6.4 Hz, 1H), 3.24–3.30 (m, 1H), 4.91–4.97
(m, 2H) 5.05–5.26 (m, 2H), 5.61–5.69 (m, 1H), 6.28 (s, 1H), 6.87
(d, J = 6.3 Hz, 1H), 7.20–7.41 (m, 9H); (minor rotamer) d = 1.72(s,
3H), 2.52 (dd, J = 13.7, 6.4 Hz, 1H), 2.89–2.91 (m, 1H), 4.91–4.97
(m, 2H) 5.05–5.26 (m, 2H), 5.61–5.69 (m, 1H), 6.35 (s, 1H), 6.87
(d J = 6.3 Hz, 1H), 7.20–7.41 (m, 9H); 13C NMR (100 MHz, CDCl3)
(major rotamer only) d = 23.7, 39.5, 63.2, 67.3, 89.5, 121.4, 126.8,
128.7, 129.9, 131.6, 135.3, 137.1, 151.7, 174.2; FTIR(neat)
m
= 3535, 1795, 1711, 1216 cmꢁ1; HRMS (ESI-TOF) calculated for
[C21H22NO4+H]+ 352.1543, found 352.1549.
4.1.3. Benzyl-N-[(3R,5S)-5-(hydroxymethyl)-3-methyl-2-oxote-
trahydrofuran-3-yl]carbamate and benzyl-N-[(3R,5R)-5-(hydro-
xymethyl)-3-methyl-2-oxotetrahydrofuran-3-yl]carbamate 4
Potassium osmate dihydrate (0.74 g, 2 mmol) was added to a
stirred solution of compound 2 (3.51 g, 10 mmol) and N-methyl-
morpholine N-oxide (2.43 g, 20 mmol) in acetone (160 mL) and
water (20 mL). The reaction mixture was stirred for 12 h, then
potassium osmate dihydrate (0.37 g, 1 mmol) was further added
and stirring was continued for another 6 h. The reaction mixture
was quenched with sodium sulfite (0.8 g), diluted with water and
extracted with ethyl acetate. After concentration in vacuo, the
inseparable almost (1:1) mixture of both diastereomers of com-
pound 4 (2.37 g, 85%) was obtained as a colorless oil: 1H NMR
(300 MHz, CDCl3): d = 1.51–1.53 (m, 3H), 2.22–2.32 (m, 1.5H),
2.53–2.67 (m, 0.5H), 2.67–2.69 (m, 1H), 3.57 (m, 0.5H), 3.60(m,
0.5H), 3.72–3.92 (m, 1H), 4.55 (s, 0.5H), 4.85 (s, 0.5H), 5.08 (s,
2H), 5.26 (s, 0.5H), 5.35 (s, 0.5H), 7.34 (s, 5H) ppm; 13C NMR
(75 MHz, CDCl3): d = 22.9, 25.3, 35.6, 35.9, 56.9, 57.5, 63.5, 63.6,
67.1, 128.2, 128.3, 128.6, 135.8, 155, 155.2, 176.9, 178 ppm; FTIR
pressure to yield compound
(395 mg, 75%, over four steps) as
7
as
a
a
diastereomeric mixture
colorless oil: 1H NMR
(300 MHz, CDCl3): d = 1.43 and 1.46 (2 ꢃ s, Boc-rotamers, 9H total),
1.54 and 1.58 (2 ꢃ s, 2-methyl-rotomers, 3H total), 2.03–2.14 (m,
1H), 2.25–2.37 (m, 1H), 3.53–3.58 (m, 1H), 3.71 (s, 1H),
3.76–3.80 (m, 4H), 4.26 (m, 1H), 4.48 (m, 1H) ppm; 13C NMR
(75 MHz, CDCl3): d = 22.8, 23.9, 28.3, 47.3, 48.3, 52.2, 52.8, 53.0,
55.8, 56.0, 56.4, 64.1, 64.4, 68.9 69.4, 70.1, 80.3, 80.6, 153.4,
153.9, 176.2, 176.8 ppm; HRMS (ESI-TOF) calculated for
[C12H22NO5+Na]+ 282.1312, found 282.1311.
4.1.6. (2R,4S)-1-tert-Butyl-2-methyl-4-(tert-butyldimethylsily-
loxy)-2-methylpyrrolidine-1,2-dicarboxylate 8a and (2R,4R)-1-
tert-butyl-2-methyl-4-(tert-butyldimethylsilyloxy)-2-methyl-
pyrrolidine-1,2-dicarboxylate 8b
To a stirred solution of Compound 7 (390 mg, 1.5 mmol) in DMF
(15 mL) was added TBDMS-Cl (906 mg, 6 mmol) and imidazole
(306 mg, 4.5 mmol) at room temperature and stirred for 12 h at
room temperature. The reaction mixture was quenched with water
and extracted in ethyl acetate. The solvent was evaporated to
obtain a crude product, which was purified by column chromatog-
raphy using ethyl acetate–hexane (1:10) as eluent to obtain chro-
matographically homogeneous 8a (218 mg, 39%) and 8b (201 mg,
35%) as colourless oil.
(neat)
m
= 3366, 1769, 1708, 1519, 1217 cmꢁ1; HRMS (ESI-TOF) cal-
culated for [C14H18NO5+H]+ 280.1179, found 280.1185.
4.1.4. Benzyl-N-[(3R,5S)-5-(hydroxymethylmethanesulfonate)-
3-methyl-2-oxotetrahydrofuran-3-yl]carbamate and benzyl-N-
[(3R,5R)-5-(hydroxymethylmethanesulfonate)-3-methyl-2-oxo-
tetrahydrofuran-3-yl]carbamate 5
To a stirred solution of a diastereomeric mixture of compound 4
(1.4 g, 5 mmol) in THF (30 mL) were added mesyl chloride
(1.16 mL, 15 mmol) and Et3N (2.1 mL, 15 mmol) at 0 °C. The reac-
tion mixture was stirred at 0 °C for 30 min, then saturated sodium
bicarbonate was added and the aqueous layer was extracted with
ethyl acetate (3 ꢃ 50 mL). The combined organic layer was washed
with brine, dried over sodium sulfate and evaporated under
reduced pressure to obtain a crude inseparable mixture of diastere-
omers of compound 5, which was purified by column chromatog-
raphy using methanol in chloroform (1:20) as eluent to obtain
diastereomers of compound 5 (1.52 g, 85%) as a colorless oil: 1H
NMR (300 MHz, CDCl3): d = 1.51–1.54 (m, 3H), 2.21–2.39 (m, 1H),
2.55–2.79 (m, 1H), 3.07 (s, 3H), 4.0–4.15 (m, 0.5H), 4.26–4.28 (m,
0.5H), 4.40–4.49 (m, 1H), 4.68 (s, 0.5H), 5.09 (s, 2H), 5.25–5.27
(m, 0.5H), 7.34 (s, 5 H) ppm; 13C NMR (75 MHz, CDCl3) d = 14.2,
22.8, 25.4, 35.9, 37.8, 37.9, 42.6, 43.2, 56.4, 56.9, 67.2, 67.5, 68.2,
69.2, 73.7, 74.1, 76.7, 77.3, 128.2, 128.4, 128.6, 135.7, 154.9,
trans-Isomer 8a: 1H NMR (300 MHz, CDCl3): d = 0.07 (s, 6H), 0.88
(s, 9H), 1.41 and 1.45 (2 ꢃ s, Boc-rotamers, 9H total), 1.65 and 1.68
(2 ꢃ s, 2-methyl-rotamers, 3H total), 1.87–1.94 (m, 1H), 2.25–2.34
(dd, J = 13.3, 5.7 Hz, 1H), 3.32–3.35 (ddd, J = 11.3, 3.0, 1.3 Hz, 0.7H),
3.41–3.45 (ddd, J = 11.2, 3.2, 1.2 Hz, 0.3H), 3.69–3.76 (m, 4H), 4.38–
4.40 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3): d = ꢁ4.9, 17.9, 23.2,
24.1, 25.7, 28.3, 47.3, 48.2, 52.1, 54.6, 54.9 63.9, 64.2, 68.1, 68.8,
79.7, 80.1, 153.5, 153.9, 174.5, 174.7 ppm; HRMS (ESI-TOF) calcu-
lated for [C18H36NO5Si+H]+ 374.2357, found 374.2358.
cis-Isomer 8b: 1H NMR (300 MHz, CDCl3): d = 0.06 (s, 6H), 0.87
(s, 9H), 1.41 and 1.45 (2 ꢃ s, Boc-rotamers, 9H total), 1.52 and
1.57 (2 ꢃ s, 2-methyl-rotamers, 3H total), 2.04–2.09 (m, 1H),
2.14–2.23 (m, 1H), 3.24–3.33 (m, 1H), 3.70–3.78 (m, 4H),
4.34–4.38 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3): d = ꢁ 4.9,
17.9, 22.6, 23.4, 25.7, 28.3, 47.4, 48.2, 52.1, 55.9, 56.1, 64.8, 65.1,
69.3, 69.9, 79.7, 80.1, 153.5, 153.9, 175.1, 175.2 ppm; HRMS
(ESI-TOF) calculated for [C18H36NO5Si+H]+ 374.2357, found
374.2355.
155.3, 175.8, 176.8 ppm; FTIR (neat)
m = 3430, 1780, 1710, 1515,
Please cite this article in press as: Tiwari, V. S.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.07.001

6
V. S. Tiwari et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
4.1.7. Benzyl-N-[(3R,5R)-5-(iodomethyl)-3-methyl-2-oxotetrahy-
drofuran-3-yl]carbamate 9a and benzyl-N-[(3R,5S)-5-(iodo-
methyl)-3-methyl-2-oxotetrahydrofuran-3-yl]carbamate 9b
To the stirred solution of compound 2 (2.11 g, 6 mmol) in
methanol (100 mL) was added NaOH (2 M, 10 mL) and reaction
mixture was stirred at room temperature for 5–6 h. The solvent
was removed under reduced pressure and the resulting residue
was acidified with citric acid up to pH 3. This mixture was
extracted with ethyl acetate (3 ꢃ 50 mL) and the combined organic
layer was washed with brine, dried over sodium sulfate and
concentrated under vacuum. The crude product thus obtained
was dissolved in dry CHCl3 (60 mL) and N-iodosuccinimide
(1.62 g, 7.2 mmol) was added at room temperature under an inert
atmosphere. The reaction mixture was allowed to stir for 2 h at
room temperature so that the starting material disappeared from
reaction mixture. After completion, the reaction mixture was
quenched with saturated aqueous solution of Na2S2O5 until the
colour of the reaction mixture changed from dark red to yellow.
This mixture was then extracted with ethyl acetate (3 ꢃ 120 mL)
and the combined organic layer was washed with brine, dried over
sodium sulfate and concentrated under vacuum. The crude product
was purified over silica gel using ethyl acetate–hexane (1:4) as the
eluent to afford mixture of diastereomers 9a and 9b (ratio cis-9a/
trans-9b 83:17 as evident from NMR spectroscopy) as a dark yel-
low oil (1.87 g, 80% after two steps). 1H NMR (400 MHz, CDCl3):
d = 1.50 (s, 2.57H), 1.57 (s, 0.69H), 2.08–2.11 (m, 0.23H), 2.43–
2.49 (m, 0.90H), 2.59–2.66 (m, 0.91H), 2.78–2.79 (m, 0.25H),
3.31–3.49 (m, 2H), 4.55 (br s, 0.83H), 4.78 (br s, 0.17H), 5.09 (m,
2.1H), 5.20 (br s, 0.27H), 5.29 (br s, 0.77H), 7.31–7.39 (m, 4.99H);
13C NMR (100 MHz, CDCl3): d = 5.4, 23.0, 25.8, 41.2, 41.5, 51.1,
58.2, 67.2, 75.6, 76.0, 128.2, 128.4, 128.6, 135.8, 140.3, 154.8,
column chromatography using methanol–chloroform (1:20) as
eluent to give compound 11 as a light yellow oil (660 mg, 95%);
[a]
21 = +6.0 (c 0.22, CH3OH); 1H NMR (400 MHz, CDCl3): d = 1.54
D
(s, 1H), 1.63 (s, 2H), 2.01–2.11 (m, 1H), 2.42–2.52 (m, 1H), 3.52–
3.59 (m, 1H), 3.77–3.88 (m, 1H), 4.31 (br s, 1H), 5.07–5.19 (m,
2H), 5.70 (br s, 3H), 7.31–7.35 (m, 5H); 13C NMR (100 MHz, CDCl3
d): 22.8, 23.9, 46.8, 47.7, 56.1, 56.2, 64.4, 65.2, 67.5, 67.8, 69.2, 69.6,
127.9, 128.0, 128.2, 128.5, 128.6, 135.9, 136.1, 154.8, 155.2, 176.7,
177.3; FTIR (neat)
m
= 3399, 3019, 2925, 1650, 1216 cmꢁ1; HRMS
(ESI-TOF) calculated for [C14H17NO5+H]+ 280.1179, found
280.1176.
4.1.10. (2R,4R)-Dibenzyl-4-hydroxy-2-methylpyrrolidine-1,2-
dicarboxylate 12
To a stirred solution of compound 11 (628 mg, 2.25 mmol) in
THF (25 mL) were added Et3N (376
lL, 2.7 mmol) and benzyl bro-
mide (330 L, 2.7 mmol). The reaction mixture was stirred at room
l
temperature overnight. After completion of the reaction, the reac-
tion mixture was diluted by the addition of ethyl acetate (50 mL)
and washed with water (50 mL) followed by brine (50 mL). The
organic phase was dried over anhydrous sodium sulphate, filtered
and concentrated to give a crude product, which was purified by
silica gel column chromatography to give compound 12 as a color-
less oil (648 mg, 78%). 1H NMR (400 MHz, CDCl3): d = 1.54 (s, 1.2H),
1.65 (s, 2.5H), 2.10–2.15 (m, 1H), 2.28–2.33 (m, 1H), 3.51–3.53 (m,
0.4H), 3.58–3.66 (m, 1.5H), 3.81–3.92 (m, 1H), 4.26 (br s, 1H),
4.90–5.29 (m, 4H), 7.19–7.36 (m, 10H); 13C NMR (100 MHz, CDCl3):
d = 22.8, 23.9, 47.2, 48.4, 56.2, 56.7, 64.4, 65.1, 67.1, 67.4, 67.7, 67.8,
69.5, 70.1, 127.8, 128.0, 128.1, 128.2, 128.4, 128.5, 128.6, 135.0,
135.2, 136.0, 136.1, 154.2, 155.4, 175.3, 175.6; FTIR (neat)
m
= 3415, 3019, 1710, cmꢁ1
; HRMS (ESI-TOF) calculated for
176.2; FTIR (neat)
m
= 3352, 3020, 1795, 1711, 1215 cmꢁ1; HRMS
[C21H23NO5+H]+ 370.1649, found 370.1647.
(ESI-TOF) calculated for [C14H16INO4+H]+ 390.0197, found
390.0200.
4.1.11. (2R,4R)-Dibenzyl 4-tert-butoxy-2-methylpyrrolidine-1,2-
dicarboxylate 13
4.1.8. (1R,4R)-Benzyl 4-methyl-3-oxo-2-oxa-5-azabicyclo[2.2.1]
heptane-5-carboxylate 10
Tertiary butyl 2,2,2-trichloroacetamidate (714 mg, 3.26 mmol)
was added to a solution of compound 12 (600 mg, 1.63 mmol) in
dry dichloromethane:hexane (1:2, 6 mL) followed by the addition
To a solution containing a mixture of diastereomers 9a and 9b
(1.46 g, 4 mmol) in DMF (10 mL), K2CO3 (1.66 g, 12 mmol) was
added and the reaction mixture was allowed to stir at 80 °C for
5 h. After completion of the reaction as evident from TLC, cold
water (20 mL) was added and the reaction mixture was extracted
with ethyl acetate (50 mL ꢃ 3). The combined organic layer was
washed with brine, dried over sodium sulfate and concentrated
under vacuum. The crude product, which contained the unreacted
trans-iodolactone 9b and the bicyclic lactone 10, was purified over
silica gel using ethyl acetate–hexane (1:3) as eluent to give a light
of catalytic amount of BF3ꢀEt2O (33
lL, 20 lL/mmol). The mixture
was stirred at room temperature for 48 h. The reaction mixture
was quenched by the addition of solid sodium bicarbonate and fil-
tered through a small bed of silica gel eluting with ethyl acetate–
hexane (1:10) to give compound 13 as a colorless oil (380 mg,
55%). 1H NMR (400 MHz, CDCl3): d = 1.19 (s, 4H), 1.20 (s, 5H),
1.59 (s, 1.5H), 1.67 (s, 1.7H), 2.10–2.14 (m, 1H), 2.20–2.27 (m,
1H), 3.34–3.43 (m, 1H), 3.80–3.89 (m, 1H), 4.23–4.28 (m, 1H),
4.85–5.22 (m, 4H), 7.24–7.35 (m, 10H); 13C NMR (100 MHz, CDCl3):
d = 22.9, 24.0, 28.3, 46.2, 47.2, 53.7, 54.3, 63.8, 64.5, 66.7, 66.8, 66.9,
67.0, 67.3, 68.0, 73.9, 74.0, 127.8, 127.9, 128.0, 128.1, 128.4, 128.5,
135.7, 136.0, 136.3, 136.8, 154.1, 155.2, 173.5, 173.7; FTIR (neat)
yellow oil (790 mg, 76%). [
a
]
21 = ꢁ18.8 (c 0.13, CH3OH); 1H NMR
D
(400 MHz, CDCl3): d = 1.84 (s, 3H), 2.11 (m, 2H), 3.60–3.70 (dd,
2H, J = 31, 11 Hz), 4.94 (br s, 1H), 5.09–5.19 (m, 2H), 7.32–7.35
(m, 5H); 13C NMR (100 MHz, CDCl3): d = 13.7, 46.1, 53.2, 64.5,
67.5, 75.1, 128.1, 128.2, 128.6, 135.9, 155.3, 172.3; FTIR (neat)
m
= 3399, 3019, 1644, cmꢁ1
; HRMS (ESI-TOF) calculated for
[C25H31NO5+H]+ 426.2275, found 426.2275.
m
= 3399, 3019, 1644, 1215 cmꢁ1; HRMS (ESI-TOF) calculated for
[C14H15NO4+H]+ 262.1074, found 262.1075.
4.1.12. (2R,4R)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-4-tert-
butoxy-2-methylpyrrolidine-2-carboxylic acid 14
4.1.9. (2R,4R)-1-(Benzyloxycarbonyl)-4-hydroxy-2-methylpyrro-
lidine-2-carboxylic acid 11
To a solution of compound 13 (300 mg, 0.7 mmol) in methanol
(20 mL) was added Pd/C (10%, 30 mg). This reaction mixture was
then subjected to hydrogenation at 30 psi for 2 h. The catalyst
was removed by filtration and the filtrate was evaporated under
reduced pressure to obtain the amine as a gummy residue. The
amine was dissolved in dioxane:water (1:1, 20 mL) and the pH of
the mixture was adjusted to ꢂ9 by the addition of potassium car-
bonate at 0 °C. Next, Fmoc-OSu (283 mg, 0.84 mmol) was added at
this stage and the reaction mixture was allowed to stir overnight at
room temperature. Dioxane was removed under vacuum and the
pH of the reaction mixture was adjusted to ꢂ3 by adding aqueous
At first, LiOHꢀH2O (315 mg, 7.5 mmol) was added to a solution
of lactone 10 (650 mg, 2.5 mmol) in MeOH:THF:water (2:2:3,
14 mL), and the mixture was stirred overnight. The solvent was
removed under vacuum and the pH of the reaction mixture was
adjusted to ꢂ2 by the addition of aq. KHSO4. The solution was then
extracted with ethyl acetate (3 ꢃ 50 mL) and the combined organic
layers were washed with water (50 mL) and brine (50 mL). The
organic layer was then dried over sodium sulfate and concentrated
under vacuum to give a crude product, which was then purified by
Please cite this article in press as: Tiwari, V. S.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.07.001

V. S. Tiwari et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
citric acid. The reaction mixture was then extracted with ethyl
acetate (3 ꢃ 25 mL). The combined organic phase was washed with
brine, dried over sodium sulfate and evaporated to give crude pro-
duct, which was purified by silica gel column chromatography
using methanol–chloroform (1:20) as the eluent to give compound
mixture 16a and 16b in this case. Yield (1.65 g, 63%) as colorless
oil. [
21 = +40.7 (c 0.15, CH3OH); 1H NMR (400 MHz, CDCl3):
d = 1.84 (s, 3H), 2.10–2.13 (m, 2H), 3.60–3.71 (dd, 2H, J = 31,
11 Hz), 4.94 (br s, 1H), 5.09–5.16 (m, 2H), 7.30–7.38 (m, 5H); 13C
NMR (100 MHz, CDCl3): d = 13.7, 46.1, 53.2, 64.5, 67.5, 75.1,
a
]
D
14 as a light yellow oil (253 mg, 86% after two steps). [
a]
21 = +2.6
128.1, 128.2, 128.6, 135.9, 155.3, 172.3; FTIR (neat) m = 3399,
D
(c 0.08, CH3OH); 1H NMR (400 MHz, CDCl3): d = 1.23 (s, 9H), 1.42
(s, 1H), 1.58 (s, 2H), 1.98–2.12 (m, 1H), 2.30–2.40 (m, 1H),
3.48–3.74 (m, 2H), 4.20–4.28 (m, 2H), 4.31–4.46 (m, 1H),
4.50–4.55 (m, 1H), 7.29–7.41 (m, 4H), 7.56–7.59 (m, 2H),
7.72–7.76 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 22.8, 23.7,
27.9, 28.1, 45.9, 47.3, 54.3, 55.1, 63.7, 64.6, 67.3, 68.6, 75.5, 76.3,
119.9, 125.1, 127.1, 127.7, 141.3, 143.8, 143.9, 154.4, 174.7; FTIR
3019, 1644, 1215 cmꢁ1
;
HRMS (ESI-TOF) calculated for
[C14H15NO4+H]+ 262.1074, found 262.1075.
4.1.16. (2S,4S)-1-(Benzyloxycarbonyl)-4-hydroxy-2-methylpyr-
rolidine-2-carboxylic acid 18
The method for this synthesis was the same as reported for
compound 11 while the starting material used was bicyclic lactone
(neat)
m
= 3341, 3019, 1672, cmꢁ1; HRMS (ESI-TOF) calculated for
17 in this case. Yield (1.64 g, 94%) colorless oil; [
a
]
21 = ꢁ6.7 (c 0.10,
D
[C25H29NO5+H]+ 424.2118, found 424.2102.
CH3OH); 1H NMR (400 MHz, CDCl3): d = 1.57 (s, 1H), 1.67 (s, 2H),
2.01–2.11 (m, 1H), 2.42–2.52 (m, 1H), 3.52–3.59 (m, 1H),
3.77–3.88 (m, 1H), 4.35 (br s, 1H), 5.12–5.22 (m, 3H), 7.32–7.37
(m, 5H); 13C NMR (100 MHz, CDCl3 d): 22.8, 23.9, 46.8, 47.7,
56.1, 56.2, 64.4, 65.2, 67.6, 67.8, 69.2, 69.6, 127.9, 128.0, 128.2,
128.5, 128.6, 135.9, 136.1, 154.8, 155.2, 176.7, 177.3; FTIR (neat)
4.1.13. (2R,4S)-Benzyl-4-allyl-4-methyl-5-oxo-2-phenyloxazoli-
dine-3-carboxylate 15
The method fort this synthesis was the same as reported for
compound 2, but the starting amino acid used was Cbz-D-alanine
in this case. Yield (5.13 g, 80%) as colorless oil: 1H NMR
(400 MHz, CDCl3), (major rotamer) d = 1.81(s, 3H), 2.52 (dd,
J = 13.7, 6.4 Hz, 1H), 3.24–3.30 (m, 1H), 4.91–4.97 (m, 2H)
5.10–5.26 (m, 2H), 5.63–5.73 (m, 1H), 6.28 (s, 1H), 6.87 (d,
J = 6.3 Hz, 1H), 7.20–7.41 (m, 9H); (minor rotamer) d = 1.72 (s,
3H), 2.52 (dd, J = 13.7, 6.4 Hz, 1H), 2.89–2.94 (m, 1H), 4.91–4.97
(m, 2H) 5.10–5.26 (m, 2H), 5.57–5.61 (m, 1H), 6.35 (s, 1H), 6.87
(d J = 6.3 Hz, 1H), 7.20–7.41 (m, 9H); 13C NMR (100 MHz, CDCl3)
(major rotamer only) d = 23.6, 39.5, 63.2, 67.3, 89.5, 121.4, 126.8,
m
= 3399, 3019, 2925, 1650, 1216 cmꢁ1; HRMS (ESI-TOF) calculated
for [C14H17NO5+H]+ 280.1179, found 280.1176.
Acknowledgements
The financial assistance form CDRI is gratefully acknowledged
CSIR – India (Grant # BSC0108). V.S.T. is thankful to UGC – India,
and R.M and S.R.Y. are thankful to CSIR – India for financial assis-
tance in the form of fellowship. The authors also acknowledge
SAIF-CDRI for providing the spectral data. CDRI Communication
Number 9271.
128.4, 128.7, 131.0, 135.3, 151.7, 174.2; FTIR(neat)
m = 3535,
1795, 1711, 1216 cmꢁ1
;
HRMS (ESI-TOF) calculated for
[C21H22NO4+H]+ 352.1543, found 352.1549.
References
4.1.14. Benzyl-N-[(3S,5S)-5-(iodomethyl)-3-methyl-2-oxotetra-
hydrofuran-3-yl]carbamate 16a and benzyl-N-[(3S,5R)-5-(iodo-
methyl)-3-methyl-2-oxotetrahydrofuran-3-yl]carbamate 16b
The method for this synthesis was the same as reported for
compound 9a and 9b, but the starting compound used was
compound 15 in this case. Yield (4.38 g, 77%, after two steps, ratio
cis 16a/trans 16b 83:17 as evident from NMR-spectroscopy) as
dark yellow oil. 1H NMR (400 MHz, CDCl3): d = 1.52 (s, 2.62H),
1.59 (s, 0.78H), 2.07–2.14 (m, 0.21H), 2.46–2.51 (m, 0.87H),
2.64–2.67 (m, 0.87H), 2.79–2.84 (m, 0.19H), 3.34–3.52 (m, 2H),
4.58 (br s, 0.83H), 4.82 (br s, 0.16H), 5.12 (m, 2.1H), 5.22 (br s,
0.25H), 5.32 (br s, 0.76H), 7.34–7.39 (m, 5H); 13C NMR (100 MHz,
CDCl3): d = 5.4, 23.0, 41.5, 58.2, 67.2, 76.0, 128.2, 128.4, 128.6,
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Gentilucci, L.; De Marco, R.; Cerisoli, L. Curr. Pharm. Des. 2010, 16, 3185–3203;
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135.8, 154.8, 176.2; FTIR (neat)
m = 3352, 3020, 1795, 1711,
1215 cmꢁ1 HRMS (ESI-TOF) calculated for [C14H16INO4+H]+
;
390.0197, found 390.0200.
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4.1.15. (1S,4S)-Benzyl 4-methyl-3-oxo-2-oxa-5-azabicyclo[2.2.1]
heptane-5-carboxylate 17
The method for this synthesis was the same as reported for
compound 10 while the starting material used was diastereomeric
Please cite this article in press as: Tiwari, V. S.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.07.001