Efficient synthesis of N-protected amino/peptide Weinreb amides from T3P and DBU

Article abstract of DOI:10.1016/j.tetlet.2012.11.064

The reaction of N^α-protected amino/peptide acid with N,O-dimethylhydroxylamine hydrochloride in the presence of T3P and DBU to obtain enantiomerically pure N^α-protected amino/peptidyl Weinreb amides in high yields has been described. Fmoc-Ala-Weinreb amide 2a is obtained as single crystal, and its structure was determined through X-ray crystallography.

Full text of DOI:10.1016/j.tetlet.2012.11.064

Tetrahedron Letters 54 (2013) 478–482
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthesis of N-protected amino/peptide Weinreb amides
from T3P and DBU
⇑
K. M. Sharnabai, G. Nagendra, T. M. Vishwanatha, Vommina V. Sureshbabu
#109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi, Bangalore 560 001, India
a r t i c l e i n f o
a b s t r a c t
a
Article history:
The reaction of N -protected amino/peptide acid with N,O-dimethylhydroxylamine hydrochloride in the
a
Received 1 October 2012
Revised 13 November 2012
Accepted 17 November 2012
Available online 24 November 2012
presence of T3P and DBU to obtain enantiomerically pure N -protected amino/peptidyl Weinreb amides
in high yields has been described. Fmoc-Ala-Weinreb amide 2a is obtained as single crystal, and its
structure was determined through X-ray crystallography.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Weinreb amides
T3P
DBU
a
N -protected amino/peptide acids
Weinreb amides1 have been employed as efficient and useful
compounds for the preparation of ketones,2 aldehydes,3 acetylenes,4
heterocycles,5 natural products6 and also as a prolific moiety in Birch
reductions and Wittig reactions as well.7,8 Recently Weinreb amides
development of mild and efficient synthetic reagents. In this re-
spect from past decade the use of T3P (1-propanephosphonic acid
cyclic anhydride) has experienced an exponential growth. The dis-
tinctive environmental benefits of T3P over other conventional re-
agents are due to its less toxicity, mild reaction conditions, broad
functional group tolerance, high yields, less cost, low epimeriza-
tion, and commercial availability. In addition, the formation of
water soluble byproducts makes the isolation of the desired prod-
uct simple and circumvents the use of volatile organic compounds
(VOCs) during work-up. More importantly, T3P22 has experienced a
renaissance as eco-friendly coupling reagent, which has been fre-
quently described as most effective coupling reagent in the field
of peptide chemistry.23 The advantages of T3P have been utilized
in organic synthesis not only as coupling reagent but also as dehy-
drating agent and for various functional group interconversions
that is, for the synthesis of nitriles, isonitriles, oxadiazoles, and thi-
adiazoles.24 Recently, T3P has been used as catalyst for the prepa-
ration of polysubstituted quinolines25 and for the synthesis of
fused heterocycles.26 Our group has reported the Curtius27a and
Lossen rearrangements mediated by T3P.27b Also, T3P has been
have been utilized in the synthesis of trifluoromethylketones.9
A
specific class is the N-protected amino/peptide Weinreb amides,
which are the key constituents for the preparation of unnatural ami-
no acids and peptidomimetics.10 Classically, these derivatives have
been synthesized by the treatment of N,O-dimethylhydroxylamine
with an activated carboxylic group. Several peptide coupling re-
agents have been employed in this transformation which include
BOP,11 DCC,12 DCC/HOBt,13 CBr4/PPh3,14 EDC/HOBt,15 and CDMT.16
Additionally, mixed anhydride,17 acid chloride,18 acid fluoride19
,
and acyl benzotriazole20 methods have also been used under varied
reaction conditions.
Some of these procedures are reported to be efficient, neverthe-
less, several limitations like poor yields, long coupling duration,
harsh conditions, and tedious product isolation have evoked the
search of efficient reagent system. Recently, 1-[(1-cyano-2-eth-
oxy-2oxoethylideneaminooxy)-dimethylaminomorpholinomethyl
ene)]methanaminiumhexafluoro phosphate (COMU)21 was em-
ployed to convert N-Boc-protected amino acids into the corre-
sponding Weinreb amides in good yield and purity. As COMU is
very expensive, it is less attractive for large scale preparations.
The recent demand for efficient and environmentally benign
syntheses of fine chemicals and pharmaceuticals has lead to the
a
employed for the synthesis of N -protected aminothio acids27c
and b- and
on the utility of T3P, we herein describe the synthesis of enantio-
merically enriched N-protected -amino/peptide pure Weinreb
c
-amino alcohols.27d In continuation of our interest
a
amides mediated by T3P under mild conditions and the results
are summarized herein.
A thorough literature survey on the T3P mediated Weinreb
amide preparations revealed that, side chain
Glu-OMe was converted into respective Weinreb amide by the
treatment of T3P and N-ethylmorpholine (NEM). Initially, we
c-COOH of N-Boc-
⇑
Corresponding author. Tel.: +91 80 2296 1339, mobile: +91 09986312937.
E-mail addresses: sureshbabuvommina@rediffmail.com, hariccb@hotmail.com,
hariccb@gmail.com (V.V. Sureshbabu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.064

K. M. Sharnabai et al. / Tetrahedron Letters 54 (2013) 478–482
479
Table 1
sought to reinvestigate the synthesis of Weinreb amide 2a derived
from Fmoc-Ala-OH 1a following this literature protocol.28 The
same reaction conditions failed to give good yield of 2a (Table 1,
entry 1) in 30 min. Consequently, we examined the ability of vari-
ous bases to promote the reaction of 1a with T3P and N,O-dim-
ethylhydroxylamine at 0 °C. The reaction progress was monitored
by the TLC. DMAP and imidazole failed to give the expected prod-
uct in 40 min (Table 1, entries 2 and 3). The use of TEA, NMM, and
pyridine (Table 1, entries 4–6) gave satisfactory yields of 2a after
35 min. However, isolation of the pure product required column
purification which precludes the choice of base. The amidine type
base DBU has been found to be more effective than traditional ter-
tiary organic bases in several organic reactions.29 Its high basicity
is attributed by the resonance-stabilized cations. Because of the Le-
wis basic properties (non-nucleophillic) DBU has also been used as
efficient catalyst in organic synthesis.29 Recently, we have demon-
strated the efficacy of DBU for the synthesis of ureas.30 To test the
scope of DBU in the present reaction, we carried out the reaction of
1a and N,O-dimethylhydroxylamine at 0 °C in the presence of T3P
and DBU (Table 1, entry 7). After 30 min, TLC examination con-
firmed that the reaction was found to be complete. A simple aque-
ous work-up of the reaction mixture resulted in the isolation of the
product 2a in high yield and purity (>98% conversion as confirmed
by HPLC analysis). Similar study was undertaken to determine if
solvent played a significant role in the reaction outcome. It was
found that CH3CN provided best result in terms of yield and purity
to other solvents including THF, DMF, DMSO, toluene, and CH2Cl2
(Table 1, entries 8–12). Additionally, we carried out the reaction
of 1a with T3P and N,O-dimethylhydroxylamine in the presence
of NEM as a base in CH3CN (Table 1, entry 13). Comparison of
the results obtained in entries 1 and 13 suggested that yields were
also influenced by the solvent and the good yield was obtained in
CH3CN.
Optimization of reaction conditions for the synthesis of 2a
T3P, base
solvent
N
OH
FmocHN
O
FmocHN
(MeO)MeNH.HCl
O
O
1a
2a
Entrya
Base
Solvent
Yield (%)
Time (min)
1
2
3
4
5
6
7
8
NEM
DMAP
THFb
71c
—
—
30
40
40
35
35
35
30
40
40
35
40
35
30
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
DMF
Imidazole
NMM
TEA
Pyridine
DBU
79c
81c
83c
97d
75c
80d
69c
71c
78c
80c
DBU
DBU
DBU
DBU
DBU
NEM
9
10
11
12
13
THF
Toluene
CH2Cl2
CH3CNc
a
b
c
1.1 equiv of NHMe(OMe)ꢀHCl in 1.1 equiv of TEA was used.
Reported reaction conditions were maintained.
Isolated yield after column purification.
d
Yields of the crude product after work-up followed by triturating with ether.
R
T3P, DBU
CH3CN
R
N
OH
PgHN
O
PgHN
(MeO)MeNH.HCl,
0°C, 30 min
O
O
1a-p
2a-p
Pg = Fmoc, Boc or Cbz group
R = amino acid side chain
a
Exploring the scope of the optimized reaction conditions, we
Scheme 1. Synthesis of N -protected amino acid derived Weinreb amides.
further synthesized a series of compounds 2b–p (Scheme 1).31
Table 2
a
List of N -Fmoc/Boc/Cbz-protected amino acid Weinreb amides
a 2D5
ꢁ
½ ꢁ
a 2D5
b
b
Entry
Product 2
Yielda (%)
97
Entry
i
Product 2
Yielda (%)
91
½
BnS
N
N
FmocHN
O
O
N
a
ꢂ12.4
+18.2
ꢂ18.3
ꢂ15.6
ꢂ19.1
ꢂ20.2
ꢂ28.2
ꢂ26.2
BocHN
ButO
O
O
O
O
FmocHN
b
c
98
91
90
j
89
99
91
N
N
CbzHN
O
O
O
O
Ph
FmocHN
BocHN
N
N
N
k
l
CbzHN
O
O
O
O
O
O
4
N
d
FmocHN
O
O
BocHN
FmocN
COOMe
N
O
FmocHN
e
ꢂ25.1
92
m
ꢂ38.1
94
O
O
O
(continued on next page)

480
K. M. Sharnabai et al. / Tetrahedron Letters 54 (2013) 478–482
Table 2 (continued)
a 2D5
ꢁ
½ ꢁ
a 2D5
b
b
Entry
Product 2
Yielda (%)
89
Entry
n
Product 2
Yielda (%)
89
½
HO
N
ꢂ37.116
N
N
f
ꢂ14.5
ꢂ16.7
BocN
O
FmocHN
O
O
O
O
O
MeS
N
FmocHN
HO
O
N
g
90
94
o
p
—
75
93
FmocHN
O
BnOOC
N
BocHN
O
h
ꢂ13.9
ꢂ25.6
O
CbzHN
O
O
a
Isolated yield.
(c 1, CH2Cl2).
b
(a) Chiral HPLC profile of 2a
(b) Chiral HPLC profile of 2b
Rt = 15.50 min
Rt = 11.01 min
(d) RP-HPLC of crude product 2c
(c) Chiral HPLC of racemic mixture of 2a and
2b. Rt = 11.3 and 15.1 min
Rt = 16.0 min
Figure 1. (a) Chiral HPLC profile of 2a. (b) Chiral HPLC profile of 2b. (c) Chiral HPLC of racemic mixture of 2a and 2b. (d) RP-HPLC RP-HPLC of crude product 2c.
The products were isolated by a simple work-up followed by trit-
urating with ether. As furnished in Table 2, yields are good in all
cases (89–99%). The method is compatible with commonly used
N-urethane protecting groups, different side chain functionalized
amino acids (Ser, Tyr, Thr, Lys, and Glu) and sterically hindered
amino acids (Ile and Aib) as well. The RP-HPLC32 analysis of crude
2c (>98% purity) revealed the good purity of the products (Fig. 1d).
Further, several N-protected di and tri-peptide derived Weinreb
amides 4a–g were also synthesized (Scheme 2) and have been ob-
tained in good yields (Table 3). The structural assignment of the
Weinreb amides 2 and 4 was made on the basis of 1H, 13C NMR,
and mass spectral data.33
Fmoc-D-Ala-Weinreb amide 2b and intentionally prepared D, L mix-
ture. The samples 2a (Fig. 1a) and 2b (Fig. 1b) had single distinct
peak with retention values at Rt 11.01 and 15.50, respectively. Also
an intentionally made equimolar mixture of 2a and 2b showed a
significant difference in the retention times between
D and L amino
acid derivatives (Fig. 1c, retention times for the racemic amides de-
rived from 2a and 2b were Rt 11.3 and 15.1 min). These studies con-
firmed that the present protocol is free from racemization.
During the course of this study Fmoc-Ala-Weinreb amide 2a
(CCDC No. 900995) was obtained as single crystal and the molecu-
lar structure was determined through X-ray crystallography. Two
literature precedents were found on the crystal structure analysis
of amino acid derived Weinreb amides. Zheng et al.,35 reported
The optical rotational data obtained for all samples showed that
no racemization of the chiral center on the
a-carbon atom occurred
the crystal structure of racemic Boc-L-phenylalanyl N-methoxy-
during the synthesis. Also, these values are in consistent to the re-
N-methylamide. Thomas Kolter has reported the crystal structure
of aminobutyric acid derived Weinreb amide.36 In the present
study, the crystals of Weinreb amide 2a suitable for X-ray analysis
ported ones in the literature. The chiral HPLC34 analysis was carried
out for enantiomeric pair of Fmoc-L-Ala-Weinreb amide 2a and

K. M. Sharnabai et al. / Tetrahedron Letters 54 (2013) 478–482
481
R1
O
R1
O
T3P, DBU,
CH3CN
H
N
H
N
O
PgHN
N
PgHN
OH
O
R2
(MeO)MeNH.HCl,
50-90 min
O
R2
3a-g
Pg = Fmoc/Boc or Cbz group
R1, R2= amino acid side chains
4a-g
a
Scheme 2. Synthesis of N -protected peptidyl Weinreb amides.
Table 3
a
List of N -Fmoc/Boc/Cbz-protected amino peptidyl Weinreb amides
a 2D5
ꢁ
(c l, CHCl3)
Entry
Peptidyl Weinreb amide 4
Yield (%)
HRMS [M+Na]+ Obsd/calcd
½
a
b
c
d
e
f
Fmoc-Phe-Lue-N(OMe)Me
Fmoc-Ala-Phe-N(OMe)Me
Boc-Val-Ala-N(OMe)Me
+58.9
ꢂ116.3
+17.8
ꢂ97.1
ꢂ22.5
ꢂ75.13
+112.3
88
90
87
92
91
90
95
566.2622/566.2631
524.2145/524.2161
354.2001/354.2005
444.2459/444.2474
432.2107/432.2111
376.2145/376.2236
595.2511/595.2533
Boc-Phe-Leu-N(OMe)Me
Cbz-Ala-Ser(OtBu)-N(OMe)Me
Cbz-Phe-Lue-Ala-N(OMe)Me
Fmoc-Phg-Val-Gly-N(OMe)Me
g
Supplementary data
Supplementary data (crystallographic data for compound Fmoc-
Ala-Weinreb amide 2a (CCDC No.900995)) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.11.064.
References and notes
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Figure 2. ORTEP diagram with 30% probability ellipsoid with atom numbering.
were grown by layering of a THF solution with hexane. The crystal
structure reveals that orthorhombic non-centrosymmetric space
group P212121 with Z = 4. The crystal structure is mainly stabilized
by strong N–Hꢀ ꢀ ꢀO bonds along with weak C–Hꢀ ꢀ ꢀO bonds. An OR-
TEP diagram depicted in Figure 2 shows the molecular structure,
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angle values for compound 2a are given in Supplementary data.37
In conclusion a simple and modular procedure has been de-
scribed for the preparation of a series of N-protected a-amino/pep-
tide Weinreb amides by employing combination of T3P and DBU.
The use of mild conditions enables the isolation of the products
without racemization. The Weinreb amide 2a was obtained as sin-
gle crystal and the molecular structure has been confirmed
through X-ray crystallography.
Acknowledgments
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We gratefully acknowledge the Board of Research in Nuclear
Sciences (Grant No. 2011/37C/35/BRNS), Govt. of India for the
financial assistance. M.S.K. Thanks the DST Govt. of India for the
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32. HPLC particulars: Agilent 1100 series having G1311A VWD at k = 254 nm, flow
0.5 mL/min,
Column:
Agilent
Eclipse
XDB-C18,
pore
size-5 lm,
diameter ꢃ length = 4.6 ꢃ 150 mm; Method: gradient 0.1% TFA water–
acetonitrile; acetonitrile 30–100% in 30 min.
a
33. Spectroscopic data: N -Fmoc-Ala-N(OMe)Me (2a): White solid (86%); mp 113 °C;
IR (KBr): 1725, 1662 cmꢂ1 1H NMR (300 MHz, CDCl3) d 1.23 (d, J = 7.2 Hz, 3H),
;
3.13 (s, 3H), 3.65 (s, 3H), 4.21 (t, J = 5.8 Hz, 1H), 4.48 (d, J = 9.1 Hz, 2H), 4.59 (m,
1H), 5.51 (d, J = 5.2 Hz, 1H), 7.25–7.77 (m, 8H); 13C NMR (75 MHz, CDCl3) d
17.2, 32.0, 43.1, 46.2, 60.6, 66.5, 125.8, 127.1, 127.6, 128.1, 139.5, 140.9, 153.6,
155.8; HRMS: m/z [M+Na]+ calcd for C20H22N2O4: 377.1477; found: 377.1471.
a
N -Fmoc-Phe-Leu-N(OMe)Me (4a): White solid (81%); mp 118 °C; IR (KBr):
1706, 1665 cmꢂ1 1H NMR (300 MHz, CDCl3) d 0.98 (d, J = 6.9 Hz, 6H), 1.42 (m,
;
2H), 1.78 (m, 1H), 2.98 (m, 1H), 3.11 (m, 1H), 3.16 (s, 3H), 3.58 (s, 3H), 4.18 (t,
J = 7.5 Hz, 1H), 4.45 (d, J = 12.5, 2H), 4.54 (d, J = 3.9 Hz, 2H), 4.71 (m, 1H), 5.51
(d, J = 5.5 Hz, 1H), 6.11 (s, br, 1H), 7.11–7.59 (m, 13H); 13C NMR (75 MHz,
CDCl3) d 20.8, 21.4, 30.8, 36.3, 39.2, 43.5, 45.9, 53.6, 59.8, 65.1, 120.1, 125.2,
125.8, 127.0, 127.6, 128.2, 128.5, 138.6, 139.8, 140.9, 155.5, 155.9, 170.6;
HRMS: m/z [M+Na]+ calcd for C32H37N3O5: 566.2631; found 566.2622.
a
N -Cbz-Val-N(OMe)Me (2k): Isolated as white solid (99%); mp IR (KBr): 1715,
25. Jida, M.; Deprez, B. New J. Chem. 2012, 36, 869.
26. Wen, X.; Bakali, J. E.; Deprez-Poulain, R.; Deprez, B. Tetrahedron Lett. 2012, 53,
2440.
1650 cmꢂ1 1H NMR (300 MHz, CDCl3) d 0.99 (d, J = 10.6 Hz, 6H), 2.25 (m, 1H),
3.19 (s, 3H), 3.58 (s, 3H), 4.21 (d, J = 7.9 Hz, 1H), 5.43 (s, 2H), 7.12 (s, 5H); 13C
NMR (75 MHz, CDCl3) d 17.8, 30.2, 32.0, 53.6, 60.1, 64.6, 127.0, 128.1, 128.4,
139.5, 153.4, 155.2; HRMS: m/z [M+Na]+ calcd for C15H22N2O4: 317.1477;
27. (a) Basavaprabhu; Narendra, N.; Lamani, R. S.; Sureshbabu, V. V. Tetrahedron
Lett. 2010, 51, 3002; (b) Vasantha, B.; Hemantha, H. P.; Sureshbabu, V. V.
Synthesis 2010, 2990; (c) Madhu, C.; Basavaprabhu; Vishwanatha, T. M.;
Sureshbabu, V. V. Tetrahedron Lett. 2012, 53, 1406; (d) Nagendra, G.; Madhu, C.;
Vishwanatha, T. M. Tetrahedron Lett. 2012, 53, 5059.
28. Burkhart, F.; Hoffmann, M.; Kessler, H. Angew. Chem., Int. Ed. 1997, 36, 1191.
29. (a) Cota, I.; Chimentao, R.; Sueiras, J.; Medina, F. Cat. Commun. 2008, 9, 2090;
(b) Yeom, C.-E.; Kim, M. J.; Kin, B. M. Tetrahedron 2007, 63, 904; (c) Galliani, G.;
Rindone, B.; Saliu, F. Tetrahedron Lett. 2009, 50, 5123; (d) Wang, F.; Cai, S.;
Wang, S.; Xi, C. Org. Lett. 2011, 13, 3202.
found: 317.1468.
a
N -Boc-Asp-(
a
-OMe)-N(OMe)Me (2l): Isolated as colorless oil (94%); IR (neat):
1722, 1753 cmꢂ1 1H NMR (300 MHz, CDCl3) d 1.32 (s, 9H), 3.21 (s, 3H), 2.61–
;
2.75 (m, 2H), 3.18 (s, 3H),3.51 (s, 3H), 4.36 (m, 1H), 4.72 (s, br, 1H), 13C NMR
(75 MHz, CDCl3) d 28.3, 28.5, 32.2, 49.4, 50.9, 60.8, 78.4, 155.2, 170.3, 173.4;
HRMS: m/z [M+Na]+ calcd for found C12H22N2NaO6: 313.1478; found:
313.1462.
34. Chiral HPLC particulars: Agilent 1100 series having G1311A VWD at k = 254 nm,
flow 1.0 mL/min, Column: Phenominex made Lux, pore size-5 l, Cellusole-1,
30. Sureshbabu, V. V.; Basavaprabhu Synlett 2011, 1160.
31. General procedure for the synthesis of N-Fmoc/Boc/Cbz-a-amino/peptidyl Weinreb
diameter ꢃ length = 250 ꢃ 4.6 mm; Method: 80:20 n-hexane-isopropanol in
isocratic mode in 40 min.
amides 2 and 4: To a solution of N-protected amino/peptide acid (1.0 mmol) in
CH3CN (2.0 mL), DBU (1.1 mmol, 0.16 mL), and T3P (50% in EtOAc, 1.02 mL,
3.2 mmol) were added at 0 °C and the solution was stirred for about 10 min.
Then, N,O-dimethylhydroxylamine (1.1 mmol, 0.11 g, hydrochloride salt was
neutralized by the addition of 1.1 mmol, 0.12 mL TEA) was added to the
reaction mixture and the reaction was allowed to stir till the completion of the
35. Zheng, X.; Isaac, O. D.; Miller, D. D.; Charles, R. R. Chirality 2000, 12, 2.
36. Peter, S.; Thomas, M.; Martin, N.; Heike, H.; Thomas, K. Acta Crystallogr. 2002,
58, 1415.
37. CCDC No. 900995 contains the supplementary crystallographic data for
compound 2a. These data can be obtained free of charge from the Cambridge
Crystallographic Data Center via http://www.ccdc.cam.ac.uk/datarequest/cif.