Improved synthesis of cyclic α -hydrazino acids of five- to nine-membered rings and optical resolution of 5,6,7-membered ring hydrazino acids

Article abstract of DOI:10.1080/00397911.2014.905601

GRAPHICAL ABSTRACT Synthesis of cyclic α-hydrazino acids of five- to nine-membered rings has been described. Di-tert-butyl or dibenzyl malonate was used as starting materials instead of diethyl malonate, which was used in our first report. Deprotection of

Full text of DOI:10.1080/00397911.2014.905601

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Improved Synthesis of Cyclic α-
Hydrazino Acids of Five- to Nine-
Membered Rings and Optical Resolution
of 5,6,7-Membered Ring Hydrazino Acids
Indranil Duttagupta a , Koushik Goswami a , Prathyusha Chatla a &
Surajit Sinha a
a Department of Organic Chemistry , Indian Association for the
Cultivation of Science , Kolkata , India
Accepted author version posted online: 30 Apr 2014.Published
online: 01 Jul 2014.
To cite this article: Indranil Duttagupta , Koushik Goswami , Prathyusha Chatla & Surajit Sinha
(2014) Improved Synthesis of Cyclic α-Hydrazino Acids of Five- to Nine-Membered Rings and
Optical Resolution of 5,6,7-Membered Ring Hydrazino Acids, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:17, 2510-2519,
DOI: 10.1080/00397911.2014.905601
To link to this article: http://dx.doi.org/10.1080/00397911.2014.905601
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Synthetic Communications1, 44: 2510–2519, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.905601
IMPROVED SYNTHESIS OF CYCLIC a-HYDRAZINO
ACIDS OF FIVE- TO NINE-MEMBERED RINGS
AND OPTICAL RESOLUTION OF 5,6,7-MEMBERED
RING HYDRAZINO ACIDS
Indranil Duttagupta, Koushik Goswami, Prathyusha Chatla,
and Surajit Sinha
Department of Organic Chemistry, Indian Association for the Cultivation of
Science, Kolkata, India
GRAPHICAL ABSTRACT
Abstract Synthesis of cyclic a-hydrazino acids of five- to nine-membered rings has been
described. Di-tert-butyl or dibenzyl malonate was used as starting materials instead of
diethyl malonate, which was used in our first report. Deprotection of tert-butyl or benzyl
ester of the final compounds was much easier than that of ethyl or methyl esters. Overall
yield of these acids were 39, 50, 47, 52, and 51%, respectively. These acids were then
converted to the diastereomers either via the formation of peptides with L-phenylalanine
methyl ester or via the formation of esters (for five- to seven-membered rings) with L-2-
-phenylalaninol. All diastereomers were separated except the nine-membered ring by
flash chromatography. Hydrolysis of diastereomeric esters generated the optically
pure five-, six- and seven-membered cyclic a-hydrazino acids. In this process, both the
Received November 28, 2013.
Address correspondence to Surajit Sinha, Department of Organic Chemistry, Indian Association
for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 700 032, India.
E-mail: ocss5@iacs.res.in
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
2510

SYNTHESIS OF CYCLIC a-HYDRAZINO ACIDS
2511
enantiomers have been isolated and the chiral auxiliary L-2-phenylalaninol was recovered.
Absolute stereochemistry was determined from x-ray crystallographic analysis.
Keywords Cyclic a-hydrazino acids; malonates; (S)=(R)-d-aza proline; (S)=(R)-1,
2-diazepane-3-carboxylic acid; (S)=(R)-piperazic acid
INTRODUCTION
In our efforts toward the synthesis of cyclic a-hydrazino acids (Fig. 1) from
diethyl malonate as one of the starting materials, we encountered problems associa-
ted with the hydrolysis of methyl or ethyl esters of eight- and nine-membered rings to
generate free acids, which was eventually achieved under harsh conditions using
BBr3.[1] Though there are several methods reported on the synthesis of piperazic
acid,[2] there are only few synthetic routes to delta aza-proline 1[3] or substituted
aza-prolines[4] and no reports on the synthesis of eight- and nine-membered rings.
Rutjes et al.[5] has reported the synthesis of cyclic a-hydrazino acid derivatives, where
mostly five- and six-membered rings along with one example of seven-membered ring
having a chloro group at the 5-position has been discussed. However, no reports
described the synthesis of unsubstituted seven-membered cyclic amino acid 3. As a
part of our chemical biology program, we require cyclic a-hydrazino acids, which
will be used to prepare peptide inhibitors, and the presence of N and N0 will help
us to design them accordingly.
In this article, we report an improved procedure for the synthesis of cyclic
a-hydrazino acids of five- to nine-membered rings. Diastereomeric separation of five-
to eight-membered rings after the formation of peptides with L-phenylalanine
methyl ester and optical resolution of five- to seven-memebered ring hydrazino acids
via the hydrolysis of their diastereomeric esters using L-2-phenylalaninol as a chiral
auxiliary have been reported.
RESULTS AND DISCUSSION
To address the problem of ester hydrolysis at the last step and to improve the
yields of five- to nine-membered cyclic hydrazino acids, we used di-tert-butyl or
dibenzyl malonate as one of the starting materials. The retrosynthetic route is shown
in Scheme 1.
The synthesis of five- (1), six- (2), and seven- (3) membered rings proceeded as
expected following our previously reported protocol[1] from common intermediate 7.
The experimental details are provided in the supporting information.
Figure 1. Cyclic a-hydrazino acids.

2512
I. DUTTAGUPTA ET AL.
Scheme 1. Retrosynthetic analysis.
Synthesis of Eight- and Nine-Membered Cyclic a-Hydrazino Acids
The intermediate 7 was subjected to N-allylation=homoallylation followed by
RCM with Grubbs’s second-generation catalyst[6] in toluene to obtain the eight-
and nine-membered rings 8a=b and 9a=b, respectively. The protected compounds
were then subjected to hydrogenation condition during which the reduction of the
double bond of 8/9 and debenzylation of the esters 8b and 9b occurred smoothly.
The free acids 4 and 5 were generated in quantitative yields from 10a=b, 11, and
12 on treatment with trifluoroacetic acid (TFA) in dichloromethane (DCM)
(Scheme 2).
Chiral Resolution
The amino acids need to be enantiopure to be used as building blocks for the
synthesis of bioactive peptides. Accordingly, we tried to separate the enantiomers
through the formation of diastereomers with Evans’s chiral auxiliary; unfortunately,
the acid coupling reaction with the auxiliary did not take place under various con-
ditions (acid chloride, AgCN=C6H6, LDA=THF, BuLi=THF). We then had to
employ a different strategy using a chiral auxiliary with different functionality, a
rather primitive form of chiral auxiliary (Scheme 3).
Scheme 2. Synthesis of eight- and nine-membered a-hydrazino acids.

SYNTHESIS OF CYCLIC a-HYDRAZINO ACIDS
2513
Scheme 3. Chiral resolution.
The five-, six-, and seven-membered NBoc protected cyclic a-hydrazino acids
underwent 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) coupling[7a] with
2-amino-3-phenylpropan-1-ol (L-2-phenylalaninol, chiral auxiliary) to form diastereo-
meric esters (16, 17, and 18), which were then separated by flash chromatography.
The separated esters were hydrolyzed (K2CO3 in MeOH=H2O) back to the respective
free NBoc-protected acids and the chiral auxiliary was recovered. TFA-mediated
deprotection of the NBoc protected acids yielded the pure enantiomeric mono-TFA
salts[2a] of five-, six-, and seven-membered cyclic a-hydrazino acids. The eight- and
nine-membered NBoc-protected cyclic a-hydrazino acids were avoided because of the
inability of the ester bonds to undergo hydrolysis under usual conditions.[1] The efficacy
of the method was justified by comparing the specific rotation values (ꢀ10.9 and þ10.5)
of piperazic acid 2, with the literature reports (ꢀ10.5 and þ11.1) for the R and S enan-
tiomers, respectively.[2c,d] This is the fourth asymmetric synthesis of d-aza proline and
first asymmetric synthesis of seven-membered cyclic hydrazino acids. In the case of
piperazic acid, few syntheses have been reported. Among these syntheses, the Evans
auxiliary-mediated synthesis was widely used by several groups during the piperazic
acid–containing natural product synthesis. Though fewer number of steps were involved
in their syntheses, yields were variable, strong organometallic reagents (nBuLi, LDA)
were involved, and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) was
used in excess amount (26 equivalent) to minimize the formation of side products. Hale
et al.[2i] then standardized the reaction conditions where DMPU was used as 16.5
equivalents and also reported a better method using alternative oxazolidinone. In their
method 3R isomer was obtained in 96% ee whereas 3S-isomer was obtained in 90% ee.
After the successful separation of diastereomeric esters, we then became
interested to see their separation through peptide coupling with a standard amino
acid, L-phenylalanine. Accordingly, the NBoc-protected cyclic a-hydrazino acids
(13 to 20) were subjected to an EDC coupling[7b] with L-phenylalanine methyl ester
to obtain a diasteriomeric mixture of dipeptides (Scheme 4). The dipeptides were
separated by flash chromatography.

2514
I. DUTTAGUPTA ET AL.
Scheme 4. Peptide coupling.
Figure 2. (A) X-ray crystal structure of 22a. (B) X-ray crystal structure of 23a (thermal ellipsoids are
drawn at the 30% probablity level).[8]
Assigning the absolute stereochemistry of the diastereomers poised itself as a
major challenge but fortunately the compounds 22a and 23a could be crystallized.
The crystal structure (Fig. 2) revealed that the upper spots (in TLC) corresponds
to the L-isomer as the (hydrogen marked in black) chiral centers are both (S) and
accordingly the lower spot corresponds to D isomer of the a-hydrazoic acids in both
the cases and hence by analogy we may conclude that the same is true for 21a, 24a,
25a and 21b, 24b, 25b in five-, eight-, and nine-membered rings, respectively.
CONCLUSION
We have developed a simple method for the synthesis of cyclic a-hydrazino
acids from easily available starting materials and reagents. Overall yields of five-
to nine-membered rings have been improved from 26, 16, 34, 13.5, and 13.33% to
39, 50, 47, 52, and 51%, respectively, by changing diethylmalonate to di-tert-butyl
or dibenzyl malonates. Reactions were very clean, isolated the products in very pure
form without any contamination of reagents or starting materials. The optical resol-
ution of both the enantiomers of five-, six-, and seven-membered rings were achieved
using phenylalaninol as a simple chiral auxiliary and obtained both the isomers in

SYNTHESIS OF CYCLIC a-HYDRAZINO ACIDS
2515
100% optically pure form. Chiral auxiliary was recovered just by simple acid=base
workup method. Absolute configuration was determined by x-ray crystallographic
analysis.
EXPERIMENTAL
All reagents were purchased from commercial sources and used without further
purification, unless otherwise stated. Petroleum ether (PE) refers to the fraction of
petroleum boiling between 60 and 80 ꢁC. THF is the abbreviation for tetrahydro-
furan, TFA for trifluoroacetic acid, and EA stands for ethyl acetate. All reactions
were carried out in oven-dried glassware under an argon atmosphere using anhy-
drous solvents, standard syringe, and septum techniques unless otherwise indicated.
Organic extracts were dried over anhydrous Na2SO4 and then filtered prior to
removal of all volatiles under reduced pressure on rotary evaporator. Chromato-
graphic purification of products was accomplished using column chromatography
on silica gels (mesh 100–200). Thin-layer chromatography (TLC) was carried out
on aluminum sheets, silica gel 60 F254 (Merck; layer thickness 0.25 mm). Visualiza-
tion of the developed chromatogram was performed by ceric ammonium molybdate
(CAM) stains. 1H and 13C NMR spectra were recorded at 300 or 500 MHz and 75 or
125 MHz, respectively, using CDCl3 or CD3OD as solvent. Chemical shifts (d) are
given in parts per million relative to the solvent residual peak or TMS as internal
standard. The following abbreviations are used for multiplicity of NMR signals:
s ¼ singlet, d ¼ doublet, t ¼ triplet, m ¼ multiplet, and br ¼ broad. DBAD indicates
di-tert-butylazodicarboxylate. The presence of extra signals in 13C of compounds
11, 17, 18, 24, 25, and 29 can be attributed to the presence of multiple conformers
of the hydrazino rings.
General Procedure for N-Allylation and RCM (8a): 1,2-Di-tert-buty-l-
3,3-di-tert-butyl-1,2-diazocane-1,2,3,3-tetracarboxylate, 8a
NaH (67 mg, 2.79 mmol) was added to a solution of 7c (0.583 g, 1.16 mmol) in
dry DMF (10 ml) at 0 ꢁC under argon atmosphere and stirred for 10 min, after which
allyl bromide (0.28 mg, 2.79 mmol, 0.2 ml) was added. The reaction mixture was then
allowed to stir for 30 min. Aqueous saturated NH4Cl solution (1 ml) was added to
the reaction mixture followed by removal of DMF under reduced pressure; it was
then extracted with EtOAc (30 ml) and washed with water (3 ꢂ 10 ml) and brine.
The organic layer was dried over anhydrous Na2SO4. Removal of organic solvent
in vacuo quantitatively yielded the N-allylated product as a colorless oil.
Grubbs’s second-generation catalyst (47 mg, 0.055 mmol, 5 mol%) was added
to a solution of the previous compound in 90 ml dry toluene. The mixture was then
heated at 80 ꢁC for 4 h followed by the addition of another 47 mg (0.055 mmol,
5 mol%) of the catalyst, and stirring continued for another 2 h. After completion
of the reaction (as indicated by TLC), toluene was removed in vacuo. The crude
product was column purified (15% EA in PE) to obtain the product in 74%
(0.44 g, 0.86 mmol, 2 steps) yield.
1H NMR (500 MHz, CDCl3) d 5.72–5.74 (m, 0.32H), 5.59–5.64 (m, 0.68H),
5.44–5.46 (m, 0.29H), 5.38–5.40 (d, 0.71H), 4.63 (d, 0.71H, J ¼ 17.5 Hz), 4.34

2516
I. DUTTAGUPTA ET AL.
(brm, 0.29H), 3.80 (dd, 0.29H, J ¼ 16.5,5 Hz), 3.72 (dd, 0.71H, J ¼ 17.5, 4 Hz),
2.46–2.60 (m, 2H), 2.28–2.33 (m, 1H), 2.13–2.21 (m, 1H), 1.20–1.51 (m, 36H); 13C
NMR (125 MHz, CDCl3) d 167.4, 167.2, 166.8, 166.6, 155.6, 153.7, 153.1, 129.4,
127.4, 127.0, 82.1, 82.0, 81.8, 81.6, 81.1, 80.9, 80.1, 49.0, 47.9, 32.2, 32.0, 29.8,
29.4, 28.7, 28.5, 28.4, 28.1, 27.9, 22.1; HRMS (ESI) (M þ Na)þ calculated for
C26H44N2O8Naþ ¼ 535.2995 found 535.2993.
General Procedure for Hydrogenolysis (10a): Tetra-tert-butyl
1,2-Diazocane-1,2,3,3-tetracarboxylate, 10a
To a solution of 8a (0.41 g, 0.8 mmol) in methanol (10 ml), 10% Pd=C (20 mg)
was added, and the resulting mixture was then stirred under hydrogen atmosphere
(1 atm) for 4 h. The reaction was monitored by TLC. Methanol was removed
followed by celite filtration with DCM provided the pure compound (0.407 g,
0.79 mmol) in almost quantitative yield.
1H NMR (500 MHz, CDCl3) d 3.98 (br s, 0.50H), 3.70–3.78 (br m, 0.50H),
3.08–3.30 (br m, 1H), 2.26–2.29 (m, 1H), 1.88–2.02 (m, 1H), 1.62–1.71 (m, 5H),
1.25–1.67 (m, 43H); 13C NMR (125 MHz, CDCl3) d 167.7, 167.2, 166.7, 155.3,
153.3, 82.2, 82.0, 81.4, 81.1, 80.6, 73.5, 50.6, 48.6, 34.4, 33.1, 28.4, 28.4, 28.3, 28.3,
28.2, 28.0, 26.5, 25.8, 25.4, 25.1; HRMS (ESI) (M þ Na)þ calculated for
C26H46N2O8Naþ 537.3152; found 537.3152.
General Procedure for tert-Butyl Group Deprotection (4):
1,2-Diazocane-3-carboxylic Acid, 4[1]
A solution of 10a (0.35 g, 0.68 mmol) in 30% TFA in DCM (8 ml) was stirred at
0 ꢁC for 6 h. Removal of TFA and DCM gave eight-membered free acid 4 (0.257 g,
0.66 mmol) in 97% yield.
1H NMR (500 MHz, CD3OD) d 3.702–3.734 (q, 1H, J ¼ 6.5), 3.053–3.112 (m,
2H), 2.187 (s, 1H), 1.893–1.957 (brm, 3H), 1.812 (brs, 2H), 1.643 (s, 2H), 1.264–1.313
(m, 1H); 13C NMR (125 MHz, CD3OD) d 174.6, 59.4, 49.4, 48.1, 48.0, 47.8, 47.6,
47.5, 47.3, 47.1, 26.1, 24.9, 24.4, 22.2 ; HRMS (ESI) (M þ H)þ calculated for
C7H15N2Oþ2 159.1134; found 159.1127.
General Procedure for Diasterioisomer Formation (Esterification
with L-Phenylalaninol) (16)
(2-(tert-Butoxycarbonylamino)-3-phenylpropyl)-1,2-di-tert-butyl-pyra-
zolidine-1,2,3-tricarboxylate, 16. A mixture of 13 (0.03 g, 0.095 mmol), NBoc-L-
phenylalaninol (0.026 g, 0.10 mmol), EDC (0.02 g, 0.10 mmol), and DMAP (2 mg,
0.01 mmol) in dry DCM (3 ml) was stirred for 4 h at 4 ꢁC. The resulting dicyclohex-
ylurea was removed by filtration, and the filtrate was concentrated under
reduced pressure. The residue was purified by flash chromatography to separate
the two diastereoisomers 16a and 16b (overall yield 87%, 6.7 mg, 0.007 mmol,
mixture). Compound 16a: Yield 38% (0.02 g, 0.036 mmol of 16a) from 0.03 g,
0.09 mmol of 13.

SYNTHESIS OF CYCLIC a-HYDRAZINO ACIDS
2517
25
½aꢃD ꢀ 4:13 (c 0.96, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.18–7.31 (m, 5H),
5.39–5.41 (m, 1H), 4.74 (dd, 1H, J ¼ 8.1, 6.9 Hz), 4.02–4.16 (m, 4H), 3.19–3.28 (m,
1H), 2.80–2.95 (m, 2H), 2.37–2.48 (m, 1H), 2.19–2.31 (m, 1H), 1.39–1.50 (m,
27H); 13C NMR (75 MHz, CDCl3) d 171.0, 156.1, 155.6, 154.6, 137.8, 129.5,
128.6, 126.6, 82.1, 81.8, 79.4, 65.8, 59.2, 51.3, 47.2, 37.8, 30.6, 28.5, 28.3; HRMS
(ESI) (M þ Na)þ calculated for C28H43N3O8Naþ 572.2948; found 572.2947.
2-(tert-Butoxycarbonylamino)-3-phenylpropyl)-1,2-di-tert-butylpyrazo-
lidine-1,2,3-tricarboxylate 16b. Yield 36% (0.019 g, 0.034 mmol of 16b) from
0.03 g, 0.095 mmol of 13.
25
½aꢃD ꢀ 1:42 (c 0.84, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.18–7.31 (m, 5H),
5.17 (brs, 1H), 4.67–4.72 (m, 1H), 4.08–4.16 (m, 4H), 3.19–3.29 (m, 1H), 2.75–2.92
(m, 2H), 2.38–2.47 (m, 1H), 2.18–2.30 (m, 1H), 1.39–1.50 (m, 27H); 13C (75 MHz,
CDCl3) d 170.9, 156.0, 155.5, 154.9, 137.5, 129.6, 129.5, 128.7, 126.7, 82.1, 81.8,
79.5, 65.6, 59.5, 50.9, 46.9, 38.0, 30.7, 28.5, 28.3, 28.3; HRMS (ESI) (M þ Na)þ
calculated for C28H43N3O8Naþ 572.2948; found 572.2946.
General Procedure for Preparation of Chiral a-Hydrazino Acid (1)
Pyrazolidine-3-carboxylic acid mono-TFA salt, 1a. K2CO3 (0.02 g,
0.14 mmol) was added to a solution of 16a (0.02 g, 0.036 mmol) in 2 ml MeOH=
H2O (2:1) and the mixture was stirred for 2 h followed by removal of MeOH in
vacuo. The reaction mixture was then washed with diethylether (3 ꢂ 2 ml) to recover
the chiral auxiliary. The residue was acidified with cold 1 N HCl and extracted with
EtOAc (10 ml). The organic layer was washed with water and brine. Removal of the
organic solvent furnished the free acid in 88% (10 mg, 0.032 mmol) yield.
The free acid was redissolved in 2 ml dry DCM. It was then cooled to 0 ꢁC, fol-
lowed by the addition of 0.4 ml TFA. The reaction mixture was then allowed to stir
for 4 h. Removal of the organic solvent yielded the TFA salt of completely depro-
25
tected 1a (6.87 mg, 0.03 mmol), ½aꢃD 1:46 (c 1.00, CH3OH).
25
Pyrazolidine-3-carboxylic acid mono-TFA salt, 1b[1]. ½aꢃD ꢀ 1:42 (c 0.90,
CH3OH). Yield, 76% over two steps (5.73 mg, 0.025 mmol) from 0.018 g, 0.033 mmol
of 16b.
General Procedure for Peptide Coupling with Methyl Ester of
L-Phenylalanine (21)
(S)-Di-tert-butyl-3-((S)-1-methoxy-1-oxo-3-phenylpropan-2-yl-carbamoyl)
pyrazolidine-1,2-dicarboxylate, 21a. Diisopropylethylamine (0.45 g, 0.6 ml,
3.5 mmol) was added dropwise to a stirred suspension of L-phenylalanine methyl
ester hydrochloride (0.35 g, 1.6 mmol) in dichloromethane (15 ml) at room tempera-
ture under an atmosphere of nitrogen. The solution was cooled to 0 ꢁC and then 13
(0.551 g, 1.74 mmol) and 1-hydroxybenzotriazole (0.26 g, 1.9 mmol) were added suc-
cessively, each in one portion. The suspension was stirred at 0 ꢁC for a further 15 min
and then EDC (0.37 g, 1.9 mmol) was added in one portion. The mixture was allowed
to warm to room temperature over the course of 18 h. The reaction mixture was then
evaporated in vacuo. The residue was taken up in EtOAc (100 ml) and washed with

2518
I. DUTTAGUPTA ET AL.
0.1 N HCl, water, and brine. The organic layer was dried over anhydrous Na2SO4.
Removal of organic solvent in vacuo followed by flash chromatography separated
the diastereomers, and yields of 21a and 21b were 40% and 21%, respectively.
Mixture of diastereomers was obtained in 12% yield (0.10 g, 0.21 mmol).
Yield 40% (0.33 g, 0.69 mmol of 21a) from 0.551 g, 1.74 mmol, of 13.
25
½aꢃD ꢀ 2:51 (c 8.19, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.62 (brs, 1H),
7.13–7.31 (m, 5H), 4.82 (td, 1H, J ¼ 8.4, 6 Hz), 4.52 (dd, 1H, J ¼ 8.7, 6.6 Hz), 3.89
(ddd, 1H, J ¼ 11.1, 8.4, 3 Hz), 3.69 (s, 3H), 3.12–3.23 (m, 2H), 2.89 (dd, 1H,
J ¼ 10.8, 8.7 Hz), 2.32–2.43 (m, 1H), 1.78–1.90 (m, 1H), 1.51 (s, 9H), 1.48 (s, 9H).
13C NMR (75 MHz, CDCl3) d 171.39, 170.31, 155.9, 154.9, 136.2, 129.2, 128.3,
126.9, 82.5, 82.3, 61.5, 53.1, 52.1, 46.7, 38.5, 31.2, 28.1, 28.0; HRMS (ESI)
(M þ Na)þ calculated for C24H35N3O7Naþ 500.2373; found 500.2372.
(R)-Di-tert-butyl-3-((S)-1-methoxy-1-oxo-3-phenylpropan-2-ylcarbam-oyl)
pyrazolidine-1,2-dicarboxylate, 21b. Yield 21% (0.175 g, 0.37 mmol of 21b) from
0.551 g, 1.74 mmol, of 13.
25
½aꢃD 12:51 (c 8.39, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.84 (brs, 1H),
7.19–7.31 (m, 5H), 4.69–4.71 (brm, 1H), 4.57 (dd, 1H, J ¼ 9, 5.7 Hz), 3.93 (ddd,
1H, J ¼ 15, 8.4, 4.2 Hz), 3.66 (s, 3H), 3.13–3.28 (m, 2H), 2.92 (dd, 1H, J ¼ 8.3,
5 Hz), 2.40–2.51 (m, 1H), 2.22–2.31 (m, 1H), 1.48 (s, 9H), 1.44 (s, 9H) 13C NMR
(75 MHz, CDCl3) d 171.4, 171.2, 156.7, 155.0, 136.2, 129.2, 129.1, 128.5, 126.9,
82.3, 61.3, 53.8, 52.1, 47.1, 47.1, 37.6, 31.3, 28.0; HRMS (ESI) (M þ Na)þ calculated
for C24H35N3O7Naþ 500.2373; found 500.2372.
ACKNOWLEDGMENT
We are thankful to the Inorganic Chemistry Department of IACS for their help
in crystal structure determination.
FUNDING
S. S. thanks the Department of Science and Technology, India, for financial
support by Grant SR=S1=OC=0087=2012. I. D. G. is thankful to the Council of
Scientific and Industrial Research, K. G. is thankful to Indian Association for the
Cultivation of Science (IACS), and P. C. is thankful to Indian Institute of Chemical
Biology (IICB) for their fellowships.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
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