Straightforward and facile approach toward the n-derivatization of pyroglutamates through mitsunobu reaction: Synthesis of N-alkyl/N-acyl pyroglutamates

Article abstract of DOI:10.1080/00397911.2010.519844

Pyroglutamates have been acknowledged as useful chiral synthons for the synthesis of many bioactive natural products, ACE inhibitors, and conformationally constrained peptides. Though the reactivity differences between two differential carbonyl groups have been well exploited, there is still a dearth of publications on the N-alkylation/acylation of native pyroglutamate as such, due to the relatively low reactivity of NH of pyroglutamates. In the present communication, we report for the first time a simple and efficient methodology for the N-alkylation/acylation of pyroglutamate via Mitsunobu reaction. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.519844

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Straightforward and Facile Approach
Toward the N-Derivatization of
Pyroglutamates Through Mitsunobu
Reaction: Synthesis of N-Alkyl/N-Acyl
Pyroglutamates
a
a
Sharad Kumar Panday , Jagdish Prasad & Manoher Bhushan Pathak
a
a
Department of Chemistry, Faculty of Engineering and Technology,
M. J. P. Rohilkhand University, Bareilly, India
Accepted author version posted online: 30 Jun 2011.Published
online: 08 Jun 2011.
To cite this article: Sharad Kumar Panday , Jagdish Prasad & Manoher Bhushan Pathak (2011)
Straightforward and Facile Approach Toward the N-Derivatization of Pyroglutamates Through
Mitsunobu Reaction: Synthesis of N-Alkyl/N-Acyl Pyroglutamates, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:24, 3654-3661,
DOI: 10.1080/00397911.2010.519844
To link to this article: http://dx.doi.org/10.1080/00397911.2010.519844
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1
Synthetic Communications , 41: 3654–3661, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.519844
STRAIGHTFORWARD AND FACILE APPROACH
TOWARD THE N-DERIVATIZATION OF
PYROGLUTAMATES THROUGH MITSUNOBU
REACTION: SYNTHESIS OF N-ALKYL/N-ACYL
PYROGLUTAMATES
Sharad Kumar Panday, Jagdish Prasad, and
Manoher Bhushan Pathak
Department of Chemistry, Faculty of Engineering and Technology,
M. J. P. Rohilkhand University, Bareilly, India
GRAPHICAL ABSTRACT
Abstract Pyroglutamates have been acknowledged as useful chiral synthons for the synthesis
of many bioactive natural products, ACE inhibitors, and conformationally constrained
peptides. Though the reactivity differences between two differential carbonyl groups have
been well exploited, there is still a dearth of publications on the N-alkylation/acylation of
native pyroglutamate as such, due to the relatively low reactivity of NH of pyroglutamates.
In the present communication, we report for the first time a simple and efficient methodology
for the N-alkylation/acylation of pyroglutamate via Mitsunobu reaction.
Keywords Acylation; alkylation; lactam NH; Mitsunobu reaction; pyroglutamates
INTRODUCTION
Pyroglutamates=N-substituted pyroglutamates have emerged as useful chiral
[
1]
synthons for the synthesis of many bioactive natural products such as anatoxin,
[4,5]
[
bulgecinine, salinosporamide, ACE inhibitors,
2]
[3]
and conformationally con-
Pyroglutamic acid has two differential carbonyl groups, a
[6,7]
strained peptides.
carboxyl and a lactam carbonyl, and the reactivity differences between these two
differential carbonyl groups have been well investigated. Although good synthetic
[
8,9]
[10]
[11,12]
[13–15]
procedure are available for the synthesis of 2,
tuted pyroglutamates, the same is not true for the N-alkylation=acylation of
3,
4,
or 5
substi-
Received December 18, 2009.
Address correspondence to Sharad Kumar Panday, Department of Chemistry, Faculty of
Engineering and Technology, M. J. P. Rohilkhand University, Bareilly, U. P., India. E-mail:
skpandey@mjpru.ac.in; drsharadpandey@yahoo.com
3
654

N-DERIVATIZATION OF PYROGLUTAMATES
3655
[16]
pyroglutamates.
components of many bioactive products, such as fosinopril,
Even though N-acylated=alkylated pyroglutamates are essential
[
17–20]
and have been used
pertaining to the synthesis of variety of natural=
[21]
efficiently as chiral auxiallaries
bioactive compounds, yet a facile synthetic route for the N-acylation=alkylation
of lactam NH of pyroglutamate is still in demand. That prompted us to study the
Mitsunobu reaction of pyroglutamates with acids and alcohols with the objective of
exploring the possibility of developing an efficient procedure for the N-acylation=
alkylation of pyroglutamates.
In our ongoing program toward the synthesis of bioactive molecules from
pyroglutamates, we were interested in investigating a simple strategy for the
N-derivatization of pyroglutamates, especially so when earlier literature procedures
[
22]
for N-acylation of pyroglutamates were not very encouraging in our case.
Further, because racemization at C-2 of pyroglutamate or other centers in substi-
tuted pyroglutamates was also a distinct possibility under the usual basic conditions,
it was truly demanding to develop a procedure for N-alkylation=acylation of pyro-
glutamates that would give satisfactory results at room temperature and not require
drastic basic conditions, thereby eliminating the possibility of any racemization.
Based on these presumptions, we attempted N-alkylation=acylation of pyrogluta-
mate through the Mitsunobu reaction.
The Mitsunobu reaction offers a unique methodology for the condensation of
various nucleophiles with alcohols in the presence of diethylazodicarboxylate
(DEAD) and triphenyl phosphine (Ph P), leading to esters, phenyl ethers, and
various other compounds, and it has been well documented.
3
[
23–26]
However, to the
best of our knowledge, there has been no report describing this reaction between
lactam NH of pyroglutamate and alcohol or carboxylic acids under Mitsunobu con-
[
27]
ditions,
which prompted us to explore the possibility of alkylation=acylation of
lactam NH of pyroglutamate where the amine part was replaced by pyroglutamate.
In the present communication, we describe our attempts at the N-alkylation=
acylation of pyroglutamates, taking advantage of Mitsunobu reaction, where we
modified the reactants by replacing the amine component in the usual Mitsunobu
reaction with pyroglutamates. Thus, pyroglutamate, was allowed to react with
alcohols=acids in the presence of DEAD and Ph P using tetrahydrofuran (THF)
3
as a solvent. To check the feasibility of the reaction, methyl (2S)-pyroglutamate
(
(
(
2) (1 eq) was allowed to react with benzyl alcohol (1.2 eq) in the presence of DEAD
1.4 eq) and Ph P (1.4 eq) using THF as a solvent, and N-benzyl-methyl
3
2S)-pyroglutamate (4) was obtained in 52% yield. The structural assignment was
1
[28]
made on the basis of HNMR, which was in consonance with the reported values.
1
The absence of a signal for NH proton and the presence of peaks in H NMR at d
.0 ppm and d 5.03 ppm respectively for benzylic protons was clear evidence for the
4
successful replacement of the NH proton of pyroglutamate by a benzylic moiety
under Mitsunobu conditions. Comparison of optical rotation with the reported
value excluded the possibility of any racemization during the reaction. To ascertain
further that no racemization=epimerization had occurred during the reaction, chiral
high-performance liquid chromatography (HPLC) was also performed for com-
pound (4), which showed the presence of exclusively one enantiomer with more than
90% overall purity. This eliminated the possibility of any racemization=epimeriza-
tion during the reaction.

3656
S. K. PANDAY, J. PRASAD, AND M. B. PATHAK
Scheme 1. Reactions and reagents: 1, SOCl , THF and M
2
1
THF, and R -OH.
e
OH for 2 or menthol for 3; 2, DEAD, Ph
3
P,
Table 1. Various N-alkyl=acyl pyroglutamates
1
R
Compound
R
4
5
6
7
Methy1
Methy1
Menthy1
Menthy1
-CH
-COCH
-CH Ph
2
Ph
2
Ph
2
8
9
Menthy1
Menthy1
Menthy1
3 3
-C(CH )
2
-COCH Ph
-COPh
1
0
To standardize the methodology and explore the scope of this reaction, various
N-alkylation=acylations using different alcohol=acids were attempted, where the
desired N-alkyl=acyl derivatives were obtained in reasonable yields. The results
of different N-alkylation=acylations attempted on pyroglutamates have been
summarized in Scheme 1 and Table 1.
These results demonstrate the simple and efficient approach for the
N-alkylation=acylation of pyroglutamates for which not many reports are available
in literature because of the relatively low reactivity of NH of pyroglutamate toward
further reactions. Further studies on the development of bioactive molecules taking
advantage of this N-alkylation=acylation procedure are in progress and shall be
reported in due course.
EXPERIMENTAL
Spectral data were recorded as follows: Perkin-Elmer (FTIR), Jeol SX-102
1
13
FAB) (MS), Bruker Advance 400 ( H NMR and C), Rudolf Autopol III polar-
(
imeter (optical rotation), Elementar Vario EL III. Dry THF was used wherever
required. Chiral HPLC was performed on a D-7000 HPLC manager report system-
using column chiral 1C and hexane as solvent.
Methyl (2S) Pyroglutamate (2)
Methyl (2S)-pyroglutamate (2) was prepared from pyroglutamic acid (1)
6.45 g, 0.05 mol, 1.0 equivalent) according to procedure described in literature
(
and was obtained as a colorless oil. Yield: 5.75 g (80%). Data of this compound were
[28]
identical with the reported values.

N-DERIVATIZATION OF PYROGLUTAMATES
3657
Menthyl (2S)-Pyroglutamate (3)
Pyroglutamic acid (6.45 g, 0.05 mol, 1.0 equivalent) was dissolved in dry THF
15 mL), and thionyl chloride (4 mL, 0.55 mol, 1.1 equivalent) was added dropwise at
(
ꢀ
0
C while stirring the reaction mixture. When addition was complete, the mixture
was stirred at room temperature for 2 h, and the solvent was evaporated under
vacuum to get crude pyroglutamoyl chloride (7.35 g), which was used as such for
esterification. In another flask, menthol (8.2 g, 0.053 mol, 1.1 eq) was dissolved in
dry THF (10 mL), and triethylamine was added to it, followed by dropwise addition
of a solution of pyroglutamoyl chloride (7.35 g, 0.048 mol, 1.0 equivalent) in THF at
ꢀ
0
C. When the addition was complete, the mixture was stirred at room temperature
for 2 h. Progress of the reaction was monitored by thin-layer chromatography
TLC). At the completion of reaction, the solvent was evaporated under vacuum
(
and the reaction was quenched with water (10 mL). The reaction mixture was
extracted twice with ethyl acetate (2 ꢁ 25 mL). The combined ethyl acetate layer
was washed with saturated NaCl solution (15 mL), dried over Na SO , concentrated,
2
4
and purified by column chromatography using 20% EtOAc–hexane as eluent to
afford the pure compound 3 as a colorless oil, Yield: 9.0 g (70%); IR (KBr): 1695,
ꢂ1
1
1
705, 2985, 3018 cm ; H NMR (CDCl ): d 0.78 (3H, d, J ¼ 7.5 Hz,CH ), 0.93
3
3
(6H, m, CH ), 1.0–1.97 (9H, m, menthyl), 2.08–2.12 (1H, m, H-3), 2.26–2.43 (1H,
m, H-3 ), 3.28–3.36 (1H, m, H-4), 3.48–3.58 (1H, m, H-4 ), 4.00–4.18 (1H, m, H-2),
3
0
0
4
.66 (1H, m, OCH) 6.90 (br s, NH); MS (m=z): 268 (M þ 1), 221, 154, 130 128.
General Procedure for N-Acylation/Alkylation of Pyroglutamates
Methyl (2S)-pyroglutamate (2) or menthyl (2S)-pyroglutamate (3) (1.0 equiva-
lent) was dissolved in dry THF (5 mL), DEAD (1.4 equivalent), and Ph P (1.4
3
equivalent) and then added to the solution of 2 or 3 and stirred for 30 min at room
temperature. After 30 min alcohol or acid (1.2 equivalent) in THF (5 mL) was added
to it, and the reaction mixture was stirred at room temperature for 7 h. Progress of
the reaction was monitored by TLC. At the completion of the reaction, the solvent
was evaporated under vacuum, poured into water (15 mL), and extracted twice with
ethyl acetate (2 ꢁ 20 mL). The combined ethyl acetate layer was washed with satu-
rated NaCl solution (10 mL), dried over Na SO , concentrated and purified by
2
4
column chromatography on silica using 20% EtOAc–hexane as eluent to afford
the pure compounds 4–10. Chiral purity of the reaction product was ascertained
by performing chiral HPLC experiment for compounds 4 and 6 using column chiral
1
C where only one single prominent peak was observed in the spectrum. That was
enough evidence to ascertain the desired stereochemistry without any racemization
or epimerization.
Methyl (2S)-N-Benzyl Pyroglutamate (4)
Compound 4 was prepared from methyl (2S)-pyroglutamate (2) (1.0 g, 7.0 mmol)
and benzyl alcohol (0.910 g, 8.43 mmol) and was obtained as an oil. Yield: 830 mg
2
D
5
25
D
[28]
(
1
52%); ½aꢃ þ 2:85 (c 0.1, CHCl ), reported ½aꢃ þ 3:5 (c 1, MeOH);
IR (KBr):
3
ꢂ1
1
680, 1745, 2920 and 3450cm ; H NMR (CDCl ): d 2.02–2.12 (1H, m, H-3),
3

3658
S. K. PANDAY, J. PRASAD, AND M. B. PATHAK
0
0
2
.19–2.32 (1H, m, H-3 ), 2.37–2.45 (1H, m, H-4), 2.52–2.63(1H, m, H-4 ), 3.63 (3H, s,
0
OCH ), 3.95–4.05 (2H, m, H-2 þ PhCH ), 5.03 (1H, d, J ¼ 16.0Hz, PhCH )
3
2
2
þ
.16–7.35 (5H, m, ArH); MS: m=z 233 (M ) Analysis for C H O N, calculated: C,
13 15 3
7
6
6.95; H, 6.44; N, 6.00. Found: C, 66.73; H, 6.28; N, 6.24.
Methyl (2S)-N-Phenyl Acetyl Pyroglutamate (5)
Compound 5 was prepared from methyl (2S)-pyroglutamate (2) (1.0 g,
.0 mmol) and phenyl acetic acid (1.141 g, 8.38 mmol) and was obtained as an oil.
7
25
ꢂ1
Yield: 445 mg (39%); ½aꢃ ꢂ 3:34 (c 0.1, CHCl ); IR (KBr): 1687, 1732, 2957 cm
;
D
3
1
0
H NMR (CDCl ): d 2.02–2.12 (1H, m, H-3), 2.19–2.32 (1H, m, H-3 ), 2.37–2.45
3
0
(
1H, m, H-4), 2.52–2.63 (1H, m, H-4 ), 3.64 (3H, s, OCH ), 4.18–4.31 (2H, m,
0
3
H-2 þ PhCH ), 4.38–4.43 (1H, d, J ¼ 16.5, PhCH ), 7.24–7.36 (5H, m, ArH); MS:
2
2
m=z 267 (Mþ), 221, 207, 118. Analysis for C H O N, calculated: C, 64.37; H,
1
4
15
4
5
.75; N, 5.36. Found: C, 64.55; H, 5.91; N, 5.29.
Menthyl (2S)-N-Benzyl Pyroglutamate (6)
Compound 6 was prepared from menthyl (2S)-pyroglutamate (3) (1.0 g,
.75 mmol) and benzyl alcohol (0.487 g, 4.50 mmol) as described perviously and
3
2
5
was obtained as an oil. Yield: 775 mg (58%); ½aꢃ ꢂ 18:91 (c 0.1 CHCl ); IR (KBr):
D
3
ꢂ1
1
1
1
710, 2985, 3018 cm ; H NMR (CDCl ): H NMR (CDCl ): d 0.78 (3H, d,
3 3
J ¼ 7.5 Hz,CH ), 0.82 (6H, m,CH ), 1.0–1.91 (9H, m, menthyl), 1.97–2.05 (1H, m,
3
3
0
0
H-3), 2.19–2.30 (1H, m, H-3 ), 2.35–2.45 (1H, m, H-4), 2.51–2.57 (1H, m, H-4 ),
.84–3.87 (1H, d, J ¼ 16.5 Hz, PhCH ), 3.89–3.92 (1H, m, H-2) 4.70–4.78 (1H,m,
3
2
0
13
OCH) 5.13–5.17 (1H, d, J ¼ 16.5 Hz, PhCH ), 7.18–7.37 (5H, m, ArH); C NMR
2
(
CDCl ): d 16.19, 20.69, 21.93, 22.84, 23.23, 26.31, 29.62, 31.34, 34.05, 40.58, 45.49,
3
4
6.85, 58.68, 75.43, 127.79, 128.35, 128.72, 135.79, 171.33, 175.01; MS (m=z): 358
(
7
M þ 1), 356 (Mꢂ1) 220, 218, 174, 91. Analysis for C H O N, calculated: C,
2
2
31
3
3.95; H, 8.68; N, 3.92. Found: C, 74.02; H, 8.76; N, 4.13.
Menthyl (2S)-N-[N’-Benzyl-meth-5’-yl-pyrrolidine-2’-one]
Pyroglutamate (7)
Compound 7 was prepared from menthyl (2S)-pyroglutamate (3) (1.0 g,
.75 mmol) and N-benzyl pyroglutaminol (0.922 g, 4.5 mmol) and was obtained as
3
25
an oil. Yield: 700 mg, (41%); ½aꢃ ꢂ 111:32 (c 0.1, CHCl ); IR(KBr): 1702, 1732,
D
3
ꢂ1
1
2
1
958, 3017 cm ; H NMR (CDCl ): d 0.73–0.79(3H, d, J ¼ 7.5 Hz, CH ), 0.84–
3
3
.14 (9H, m, CH þmenthyl), 1.23–1.56 (6H, m, menthyl), 1.65–2.05 (4H, m, H-3
3
0
0
0
and H-3 of menthyl pyroglutamate as well as H-4 and H-4 of N-benzyl meth-5 -yl
pyrrolidine-2-one), 2.13–2.24 (1H, m, H-5 of N-benzyl pyrrolidine-2-one), 2.34–
0
2.40 (2H, m, H-4 of menthyl pyroglutamate H-3 of N-benzyl meth-5 -yl pyrroli-
0
dine-2-one), 2.43–2.54 (2H, m, H-4 of menthyl pyroglutamate as well as H-3 of
0
0
N-benzyl meth-5 -yl pyrrolidine-2-one), 3.97–4.04 (2H, m, H-2 þ PhCH ), 4.18–4.26
2
0
(
2H, m, N-CH ), 4.71–4.78 (1H, m, OCH), 4.97–5.04(1H, d, J ¼ 16.5, PhCH );
2
2
7.18–7.35 (5H, m, ArH); MS (m=z): 536, 268, 266, 207, 130, 128, 91. Analysis for
C H O N , calculated: C,71.37; H, 8.37; N, 6.17. Found: C, 71.21; H, 8.47; N, 6.10.
2
7
38
4
2

N-DERIVATIZATION OF PYROGLUTAMATES
3659
Menthyl (2S)-N-t-Butyl Pyroglutamate (8)
Compound 8 was prepared from menthyl (2S)-pyroglutamate (3) (1.0 g,
.75 mmol.) and t-butyl alcohal (0.335 g, 4.50 mmol) as described previously and was
3
2
5
obtained as an oil. Yield: 581 mg (48%); ½aꢃ ꢂ 134:24 (c 0.1 CHCl ); IR (KBr):
D
3
ꢂ1
1
1
734, 2959, 3022 cm ; H NMR (CDCl ): d 0.78 (3H, d, J ¼ 7.5 Hz,CH ), 0.82 (6H,
3
3
m,CH ), 1.0–1.89, (18H, m, menthyl þ t-butyl), 1.92–2.08 (2H, m, H-3), 2.31–2.47
3
0
(
1H, m, H-4), 2.51–2.64 (1H, m, H-4 ), 4.63–4.67 (1H,m, H-2) 4.73–4.82 (1H, m,
OCH); MS (m=z): 340 (M þ H O), 324 (Mþ), 278, 267, 202. Analysis for
2
C H O N, calculated: C, 70.58; H, 10.21; N, 4.33. Found: C, 70.70; H, 10.11; N, 4.50.
1
9
33
3
Menthyl (2S)-N-Phenyl Acetyl Pyroglutamate (9)
Compound 9 was prepared from menthyl (2S)-pyroglutamate (3) (1.0 g,
.75 mmol) and phenyl acetic acid (0.622 g, 4.50 mmol) and was obtained as an oil.
3
25
ꢂ1
Yield: 950 mg (66%); ½aꢃ ꢂ 33:74 (c 0.1 CHCl ); IR (KBr): 1720, 1754, 3023 cm
;
D
3
1
H NMR (CDCl ): d 0.78 (3H, d, J ¼ 7.5 Hz,CH ), 0.93(6H, m, CH ), 1.0–1.91,
3
3
3
0
(
9H, m, menthyl), 1.97–2.05 (1H, m, H-3), 2.19–2.30 (1H, m, H-3 ), 2.35–2.45 (1H,
0
m, H-4), 2.51–2.57 (1H, m, H-4 ), 3.62–3.68 (1H, d, J ¼ 24 Hz, PhCH ), 4.17–4.24
2
0
(
2H,m, H-2, OCH), 4.38–4.42(1H, d, J ¼ 16.5, PhCH ); 7.23–7.35 (5H, m, ArH);
2
MS (m=z): 413, 295, 118, 91. Analysis for C H O N, calculated: C, 71.68; H,
31
2
3
4
8
.05; N, 3.74, Found: C, 71.90; H, 7.91; N, 3.89.
Menthyl (2S)-N-Phenyl Carbonyl Pyroglutamate (10)
Compound 10 was prepared from menthyl (2S)-pyroglutamate (3) (1.0 g,
.75 mmol) and benzoic acid (0.550 g, 4.50 mmol) as described previously and was
3
2
5
obtained as an oil. Yield: 723 mg (52%); ½aꢃ ꢂ 109:37 (c 0.1 CHCl ); IR (KBr):
D
3
ꢂ1
; H NMR (CDCl ): H NMR (CDCl ): d 0.85 (3H, d,
3 3
1
1
1
710, 2985, 3018 cm
J ¼ 7.5 Hz,CH ), 0.91 (6H, m,CH ), 1.0–1.86, (9H, m, menthyl), 2.06–2.12 (2H, m,
3
3
0
H-3), 2.33–2.45 (1H, m, H-4), 2.52–2.56 (1H, m, H-4 ), 4.15–4.22 (2H, m, H-2 þ OCH);
.41–8.06 (5H, m, ArH); MS (m=z): 385, 383, 356, 327, 251, 237, 207, 191, 105.
Analysis for C H O N, calculated: C, 71.16; H, 7.82; N, 3.77. Found: C, 71.35; H,
7
2
2
29
4
8
.00; N, 3.67.
ACKNOWLEDGMENTS
We are extremely thankful to the University Grants Commission for financial
assistance in form of a major research project and to SAIF, Central Drug Research
Institute, Lucknow, for providing all the spectral data.
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3660
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