Efficient synthesis of N-fmoc-aminoalkoxy pentafluorophenyl carbonates: Application for the synthesis of oligopeptidyl carbamates

Article abstract of DOI:10.1080/00397910902790378

N-Fmoc-Aminoalkoxy pentafluorophenyl carbonates have been synthesized through the reaction of N-Fmoc-aminoalkoxy carbonyl chloride with pentafluorophenol. The reaction was clean and high yielding, and the products have been fully characterized using infra

Full text of DOI:10.1080/00397910902790378

Synthetic Communications1, 39: 3555–3566, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902790378
Efficient Synthesis of N-Fmoc-Aminoalkoxy
Pentafluorophenyl Carbonates: Application
for the Synthesis of Oligopeptidyl Carbamates
Vommina V. Sureshbabu and H. P. Hemantha
Peptide Research Laboratory, Department of Studies in Chemistry,
Central College Campus, Bangalore University, Bangalore, India
Abstract: N-Fmoc-b-Aminoalkoxy pentafluorophenyl carbonates have been
synthesized through the reaction of N-Fmoc-b-aminoalkoxy carbonyl chloride
with pentafluorophenol. The reaction was clean and high yielding, and the pro-
ducts have been fully characterized using infrared, NMR, and mass spectroscopy.
Their utility as efficient building blocks for the preparation of N-
Fmoc-oligopeptidyl carbamate esters and acids has been demonstrated. The
method exemplifies a simple protocol for the efficient preparation of oligopepti-
dyl carbamates in solution phase.
Keywords: N-Fmoc-b-Aminoalkoxy carbonyl chlorides, carbonates, oligopepti-
dyl carbamates, pentafluorophenol
INTRODUCTION
The urethane moiety (Fig. 1)[1,2] has vital roles in several bioactive
molecules, and the synthetic peptidyl carbamates are under various
clinical and therapeutical studies.[3–10] Among the various reports on
the synthesis of oligopeptides, Cho et al. have employed[4] the stepwise
solid-phase synthesis of linear and cyclic peptidyl carbamates using the
active p-nitrophenyl carbonates as building blocks.
Received October 31, 2008.
Address correspondence to Vommina V. Sureshbabu, Peptide Research
Laboratory, Department of Studies in Chemistry, Central College Campus,
Bangalore University, Dr. B. R. Ambedkar Veedhi, Bangalore 560 001, India.
E-mail: hariccb@rediffmail.com
3555

3556
V. V. Sureshbabu and H. P. Hemantha
Figure 1. Insertion of carbamate bond as peptide bond isostere.
These carbonates were prepared by the reaction of Fmoc-b-amino
alcohol with p-nitrophenyl chloroformate. A similar strategy was
reported by Warrass et al. utilizing benzotriazolyl carbonate monomers
prepared by using dibenzotriazolyl carbonates (DBTC).[6] Alsina et al.
used the succinimidyl carbonates synthesized by treating b-amino alcohol
with disuccinimidyl carbonate (DSC).[11] Some of these active carbonates
were not isolated but prepared and used in situ, whereas some others were
found to be stable only up to a limited period of time and hence cannot
be stored for longer times. In addition, some of these protocols are less
attractive from the synthetic standpoint because of the use of excess
reagent, longer reaction time (24 h), and lower yields. Recently, our group
reported the synthesis of N-Fmoc aminoalkoxy pentachlorophenyl car-
bonates and demonstrated their utility as monomers for the synthesis
of the oligocarbamate esters.[12] To improve the reactivity and applica-
tions of such active carbonate monomers, we proceeded with synthesizing
highly reactive pentafluorophenyl carbonates as oligocarbamate building
blocks. Accordingly, we herein describe the synthesis of N-Fmoc-
b-aminoalkoxy pentafluorophenyl carbonates and their utility as efficient
building blocks for the oligopeptidyl carbamate synthesis.
RESULTS AND DISCUSSION
The N-Fmoc-b-amino alcohols were prepared by the reduction of the
in situ–generated amino acid–derived mixed anhydride using NaBH4.
The conversion of the N-protected amino alcohols into their amino-
alkoxy carbonyl chlorides was brought out by the reaction with
phosgene.[12,13] When phosgene was bubbled into a solution of N-Fmoc-
b-amino alcohol at ꢀ20ꢁC, the corresponding N-Fmoc-aminoalkoxy
carbonyl chloride 1 was formed in about 1.5 h, which was isolated as a
solid powder (Scheme 1).
These intermediates were further utilized for the preparation of pep-
tidyl carbamate. Hence, a reaction of Fmoc-b-aminoalkoxy carbonyl
chloride 1 with the amino acid ester in the presence of N-methylmorpho-
line (NMM) yielded dipeptides 3 possessing carbamate linkages in place

N-Fmoc-b-Aminoalkoxy Carbonyl Chlorides
3557
Scheme 1. Synthesis of Fmoc-amino alkoxy carbonyl chloride from amino acid.
of the amide bond within 2 h. In spite of the good reactivity of
N-Fmoc-aminoalkoxy carbonyl chlorides with the nucleophiles, their
poor shelf stability and moisture sensitivity put a barrier on their hand-
ling. Their conversion into stable compounds with retention of the reactiv-
ity can be achieved by treating with a substituted phenol, resulting in active
carbonates. Among the various choices, pentafluorophenol (Pfp) was
selected because it has been considered as the best auxiliary in routine
peptide synthesis. Compared to the contemporary reagents—pentachloro-
phenol, p-nitrophenol, trichlorophenol, N-hydroxysuccinimide—the Pfp is
advantageous because of its high reactivity. The pentafluorophenyl carbo-
nates
2 were prepared by the reaction of Pfp with N-Fmoc-
b-aminoalkoxy carbonyl chloride 1 in the presence of NMM (Scheme 2).
The N-Fmoc-b-aminoalkoxy pentafluorophenyl carbonates 2 were
also utilized for the synthesis of N-Fmoc-dipeptidyl carbamate esters 3.
For this, 2 was treated with an amino acid methyl ester hydrochloride salt
neutralized with NMM at 0ꢁC (Scheme 2). The reaction was complete
Scheme 2. Synthesis of active carbonate 2 and its utility in making di- and
oligopeptidyl carbamates.

3558
V. V. Sureshbabu and H. P. Hemantha
Table 1. List of N-Fmoc-peptidyl carbamate esters 3, 4, 5 and acids 7
Yield M.p.
(ꢁC)
HRMS (MþNa)
Entry
Dipeptidyl carbamates
(%)
(obsd.=calcd.)
3a
3b
3c
4a
4b
5a
5b
7a
7b
N-Fmoc-Alac-Val-OMe
88
94
86
78
77
63
58
76
75
112
113
109
88
118
112
132
—
477.2009 (477.2002)
509.1728 (509.1722)
533.2620 (533.2628)
592.2633 (592.2635)
728.2986 (728.2982)
679.2949 (679.2955)
755.3272 (755.3268)
477.2008 (477.2002)
505.2310 (505.2315)
N-Fmoc-Metc-Ala-OMe
N-Fmoc-Ilec-Leu-OMe
N-Fmoc-Alac-Leuc-Ala-OMe
N-Fmoc-Metc-Ilec-Phe-OMe
N-Fmoc-Alac-Glyc-Ilec-Ala-OMe
N-Fmoc-Ilec-Phec-Glyc-Ala-OMe
N-Fmoc-Alac-Leu-OH
N-Fmoc-Valc-Ile-OH
—
within 20–25 min. No column purification was required, and all the
N-Fmoc-peptidyl carbamate esters 3a–c were obtained as white solid
powders after precipitation from hexane–ethyl acetate (8:2) in about
85–96% yield and were found to be more than 99% pure as analyzed
by (HPLC) high-performance liquid chromatography.
The utility of the active carbonates 2 was further demonstrated for
the synthesis of several N-Fmoc-oligopeptidylcarbamates. The Fmoc
group from the dipeptidyl carbamate ester 3 was removed using 20%
DEA=CH2Cl2 in 0.5 h, and the resulting free amino peptidyl carbamate
ester was reacted with 2 (Scheme 2) to obtain the tripeptidyl carbamate
esters (4a and b) in good yield and purity. Similarly, a few tetrapeptidyl
carbamate esters were also prepared (5a and b, Table 1).
Finally, 2 was also employed for the synthesis of peptidyl carbamate
acids 7. This would readily give free terminal carboxylic acid end in the
peptidyl carbamates so that the further chain extension=modification
could be easily accomplished (Scheme 3). An amino acid was converted
to its bis-TMS derivative[14] by refluxing it in CH2Cl2 with trimethylsilyl
chloride (TMS-Cl) and N-ethyldiisopropylamine (DIEA) and was reacted
with 2 at 0ꢁC. The resulting N-Fmoc-peptidyl carbamate acids 7a and b
were isolated as pure ones after a workup, and the yields were more
Scheme 3. Preparation of dipeptidyl carbamate acids 7.

N-Fmoc-b-Aminoalkoxy Carbonyl Chlorides
3559
than 70% (Table 1). All the synthesized compounds were free from
racemization as evident by HPLC analysis. Our attempt to prepare
dipeptidyl carbamate acids 7 from 1 was not satisfactory, giving rise to
only about 10% conversion into the desired products. In these cases,
much of the alcohol was recovered.
CONCLUSION
In summery, we have demonstrated a simple and efficient route for the
synthesis of shelf-stable N-Fmoc-b-aminoalkoxy pentafluorophenyl
carbonates starting from the corresponding aminoalkoxy carbonyl
chlorides and pentafluorophenol. They have been employed as efficient
monomeric building blocks for the synthesis of oligopeptidyl carbamate
esters=acids. The reactions were clean and high yielding, and all the
compounds were isolated and fully characterized.
EXPERIMENTAL
Melting points were determined using the capillary method and are
uncorrected. Infrared (IR) spectra were recorded on a Nicolet model
impact 300D Fourier Transform (FT)–IR spectrometer (KBr pellets,
3 cmꢀ1 resolution). 1H and 13C NMR spectra were recorded on a Bruker
AMX 400-MHz spectrometer. Mass spectra were recorded on HRMS.
All solvents were freshly distilled prior to use. Amino acid methyl ester
hydrochlorides were prepared by using methanol and thionyl chloride.
Unless or otherwise mentioned, all amino acids used have an
L-configuration. Thin-layer chromatographic (TLC) analysis was carried
out using the precoated silica-gel G254 plates.
General Procedure for the Synthesis of N-Fmoc-b-Aminoalkoxy
Pentafluorophenyl Carbonates 2
A solution of pentafluorophenol (1.2mmol) in dry CH2Cl2 (10 mL) was
added to a stirred solution of N-Fmoc-b-aminoalkoxy carbonyl chloride
1 (1 mmol) at 0ꢁC in dry CH2Cl2 followed by NMM (1.5mmol). After
the completion of the reaction, citric acid (10%, 10mL) was added, and
the resulting layers were separated. The organic layer was washed with
aqueous sodium carbonate solution (10%, 10mLꢂ 2), water (10 mL ꢂ 3),
and brine (10 mL). Finally, it was dried over anhydrous sodium sulfate

3560
V. V. Sureshbabu and H. P. Hemantha
and concentrated under vacuum to obtain the desired compound as a white
solid.
Data
N-Fmoc-Ala-w(CH2–O–CO–O)-Pfp 2a
1
Mp: 99ꢁC; H NMR (CDCl3, 300 MHz): d 1.31 (d, 3H, J ¼ 6.6 Hz), 3.60
(m, 1H), 4.19 (t, 1H), 4.31 (m, 2H), 4.40 (d, 2H, J ¼ 7.0 Hz), 5.10 (d, 1H,
J ¼ 6.6 Hz), 7.3–7.7 (m, 8H); 13C NMR (CDCl3, 200 MHz): d 17.2,
46.0, 47.2, 66.8, 72.1, 120.0, 124.9, 127.0, 127.7, 131.1, 132.1, 141.3,
143.8, 155.5, 170.1; IR (KBr) 1710, 1782 cmꢀ1. HRMS calcd. for C25H18
F5NNaO5: 530.1003; found 530.1009 [M þ Na]þ.
N-Fmoc-Val-w(CH2–O–CO–O)-Pfp 2b
Mp: 101ꢁC; 1H NMR (CDCl3, 300 MHz): d 0.96 (d, 6H, J ¼ 4.4 Hz), 1.87
(m, 1H), 3.86 (m, 1H), 4.19–4.51 (m, 5H), 4.92 (d, 1H, J ¼ 7.1 Hz),
7.31–7.79 (m, 8H); 13C NMR (CDCl3, 200 MHz): d 18.3, 31.7, 47.0,
52.9, 66.8, 70.5, 120.0, 124.9, 127.0, 127.7, 131.1, 132.7, 141.3, 142.4,
143.8, 150.9, 155.5, 171.5; IR (KBr) 1705, 1782 cmꢀ1. HRMS calcd. for
C27H22F5NNaO5: 558.1316; found 558.1314 [M þ Na]þ.
N-Fmoc-Ile-w(CH2–O–CO–O)-Pfp 2c
Mp: 92ꢁC; 1H NMR (CDCl3, 300 MHz): d 0.77 (t, 3H), 0.85 (d, 3H), 1.33
(m, 2H), 1.52 (m, 1H), 3.74 (m, 1H), 4.21 (t, 1H), 4.36 (d, 2H J ¼ 3.1 Hz),
4.42 (d, 2H, J ¼ 8 Hz), 4.9 (d, 1H, J ¼ 9.3 Hz), 7.29 (m, 2H), 7.4–7.7 (m,
6H); 13C NMR (CDCl3, 200 MHz): d 11.1, 14.0, 15.3, 25.2, 35.8, 36.9,
47.3, 54.1, 54.6, 66.7, 70.3, 119.9, 124.9, 125.6, 127.0, 127.6, 136.5,
138.5, 139.1, 141.3, 142.5, 143.8, 151.3, 156.0, 170.2; IR (KBr): 1698,
1787 cmꢀ1
. HRMS calcd. for C28H24F5NNaO5: 572.1472; found
572.1465 [M þ Na]þ.
N-Fmoc-Leu-w(CH2–O–CO–O)-Pfp 2d
Mp: 103ꢁC; 1H NMR (CDCl3, 300 MHz): d 0.91 (d, 6H, J ¼ 7.2 Hz), 1.63
(m, 3H), 2.75 (m, 1H), 4.19 (t, 1H, J ¼ 6.9 Hz), 4.34 (m, 2H), 4.40 (m,
2H), 4.91(d, 1H, J ¼ 7.1 Hz), 7.25–7.80 (m, 8H); 13C NMR (CDCl3,

N-Fmoc-b-Aminoalkoxy Carbonyl Chlorides
3561
200 MHz): d 11.3, 15.1, 25.2, 38.8, 47.3, 57.3, 66.7, 71.2, 119.9, 124.9,
127.0, 127.7, 131.0, 132.0, 132.7, 141.3, 143.6, 150.5, 155.6, 168.9; IR
(KBr) 1710, 1783 cmꢀ1. HRMS calcd. for C28H24F5NNaO5: 572.1472;
found 572.1479 [M þ Na]þ.
N-Fmoc-Phe-w(CH2–O–CO–O)-Pfp 2e
Mp: 110ꢁC; 1H NMR (CDCl3, 300 MHz): d 2.90 (d, 2H, J ¼ 5.0 Hz), 3.71
(m, 1H), 4.19 (t, 1H, J ¼ 13.5 Hz), 4.30 (m, 2H), 4.40 (d, 2H, J ¼ 7.0 Hz),
5.41 (d, 1H), 7.20–7.80 (m. 13H); 13C NMR (CDCl3, 200 MHz): d 37.3,
47.2, 51.1, 66.8, 70.4, 119.9, 124.9, 127.0, 127.7, 127.8, 129.1, 131.1, 132.1,
136.2, 138.6, 142.4, 143.7, 151.1, 155.6, 172.1; IR (KBr) 1705, 1782cmꢀ1
.
HRMS calcd. for C31H22F5NNaO5: 606.1316; found 606.1320 [M þ Na]þ.
N-Fmoc-Gly-w(CH2–O–CO–O)-Pfp 2f
1
Mp: 114ꢁC; H NMR (CDCl3, 300 MHz): 3.20 (m, 2H), 4.19 (t, 1H,
J ¼ 13.0 Hz), 4.30 (m, 2H), 4.39 (d, 2H, J ¼ 6.9 Hz), 4.91 (br, 1H),
7.30–7.80 (m, 8H); 13C NMR (CDCl3, 200 MHz): d 39.5, 47.1, 66.8,
71.8, 120.0, 124.9, 127.0, 127.7, 132.1, 132.2, 132.3, 143.8, 150.9, 155.6,
169.8; IR (KBr) 1715, 1780 cmꢀ1. HRMS calcd. for C24H16F5NNaO5:
516.0846; found 516.0852 [M þ Na]þ.
N-Fmoc-Met-w(CH2–O–CO–O)-Pfp 2 g
1
Mp: 107ꢁC; H NMR (CDCl3, 300 MHz): d 1.82 (m, 2H), 1.95 (s, 3H),
2.21 (t, 2H, J ¼ 12.9 Hz), 2.70 (m, 1H), 3.81 (m, 1H), 4.18 (t, 1H,
J ¼ 14.0 Hz), 4.32 (d, 2H), 4.41 (d, 2H, J ¼ 7.2 Hz), 7.21–7.80 (m, 8H);
13C NMR (CDCl3, 200 MHz): d 15.0, 29.3, 32.7, 47.2, 54.1, 66.7, 70.5,
119.8, 124.0, 124.8, 127.7, 131.6, 132.1, 132.7, 141.3, 142.4, 150.7,
155.6, 171.1; IR (KBr) 1705, 1785 cmꢀ1
.
HRMS calcd. for
C27H22F5NNaO5S: 590.1037; found 590.1031 [M þ Na]þ.
N-Fmoc-Asp(OBzl)-w(CH2–O–CO–O)-Pfp 2h
1
Mp: 129ꢁC; H NMR (CDCl3, 300 MHz): d 2.97 (m, 3H), 4.12–4.45 (m,
5H), 4.91 (d, 2H, J ¼ 6.0 Hz), 5.01(s, 1H), 7.01–7.80 (m, 13H); 13C NMR
(CDCl3, 200 MHz): d 40.6, 47.3, 52.0, 63.2, 66.4, 71.0, 119.8, 124.9, 127.0,
127.7, 128.8, 129.1, 131.1, 132.1, 132.7, 135.2, 137.0, 141.3, 142.4, 151.2,
155.6, 171.2, 171.8; IR (KBr) 1710, 1779 cmꢀ1. HRMS calcd. for
C33H24F5NNaO7: 664.1371; found 664.1380 [M þ Na]þ.

3562
V. V. Sureshbabu and H. P. Hemantha
N-Fmoc-LPhg-w(CH2–O–CO–O)-Pfp 2i
Mp: 106ꢁC; 1H NMR (CDCl3, 300 MHz): d 4.19 (t, 1H, J ¼ 13.0 Hz), 4.40
(m, 5H), 4.92 (d, 1H, J ¼ 7.2 Hz), 7.11–7.80 (m, 13H); 13C NMR (CDCl3,
200 MHz): 47.2, 54.4, 66.8, 70.4, 119.9, 124.9, 127.0, 127.7, 128.8, 129.1,
131.6, 132.1, 132.4, 136.2, 141.3, 142.4, 143.7, 151.2, 155.8, 169; IR (KBr)
1705, 1780 cmꢀ1. HRMS calcd. for C30H20F5NNaO5: 592.1159; found
592.1157 [M þ Na]þ.
Synthesis of N-Fmoc Peptidyl Carbamate Ester 3
A solution of amino acid methyl ester hydrochloride (1.2 mmol)
neutralized with NMM (1.5 mmol) was added to a solution of 2 (1 mmol)
in dry CH2Cl2 (12 mL) at 0ꢁC, and the reaction mixture was stirred at
same temperature for 30 min. Citric acid (10%, 10 mL) was added, and
the layers were separated. The organic layer was washed with sodium
carbonate solution (10%, 10 mL ꢂ 2), water (10 mL ꢂ 2), and brine
(10 mL) and dried over anhydrous sodium sulfate. The crude was purified
by column chromatography using 30% EtOAc in hexane.
Data
N-Fmoc-Ala-w(CH2–O–CO–NH)-Val-OMe 3a
1H NMR (CDCl3, 300MHz): d 0.81 (d, 6H, J ¼ 6.1 Hz), 1.17 (d, 3H,
J¼ 6.9 Hz), 1.75 (m, 1H, J ¼ 6.8 Hz), 2.52 (m, 1H), 3.53 (br, 1H), 3.74
(s, 3H), 4.11 (m, 2H), 4.19 (t, 1H), 4.34 (d, 2H, J¼ 6.2 Hz), 4.89 (d, 1H,
J¼ 6.1 Hz), 5.33 (s, 1H), 7.30–7.77 (m, 8H); 13C NMR (CDCl3,
200 MHz): d 17.3, 18.2, 42.1, 42.7, 47.4, 49.1, 52.3, 66.7, 67.9, 120.0, 125.1,
127.1, 127.8, 141.4, 144.0, 155.6, 156.7, 173.4; IR (KBr) 1715, 1777 cmꢀ1
.
N-Fmoc-Met-w(CH2–O–CO–NH)-Ala-OMe 3b
1H NMR (CDCl3, 300 MHz): d 1.2 (d, 3H, J ¼ 5.8 Hz), 1.47 (d, 3H,
J ¼ 6.9 Hz), 1.94–2.75 (m, 6H), 3.71 (s, 3H), 4.10–4.41 (m, 5H),
5.13–5.2 (br, 2H), 7.13–7.79 (m, 8H); 13C NMR (CDCl3, 200 MHz): d
14.6, 18.7, 26.1, 30.9, 35.2, 47.2, 52.1, 54.2, 63.9, 66.8, 120.0, 125.0,
127.1, 127.2, 141.3, 144.0, 155.6, 156.4, 172.7; IR (KBr) 1698, 1789 cmꢀ1
.

N-Fmoc-b-Aminoalkoxy Carbonyl Chlorides
3563
N-Fmoc-Ile-w(CH2–O–CO–NH)-Leu-OMe 3c
1H NMR (CDCl3, 300 MHz): d 0.81–0.98 (m, 14H), 1.51 (m, 4H), 3.21
(br, 2H), 3.72 (s, 3H), 4.12–4.39 (m, 5H), 5.14–5.28 (br, 2H), 7.1–7.79
(m, 8H); 13C NMR (CDCl3, 200 MHz): d 18.5, 22.4, 24.8, 32.4, 38.2,
41.2, 47.4, 48.8, 52.4, 54.9, 55.8, 64.2, 66.8, 120.0, 125.0, 127.2, 127.2,
141.3, 144.0, 155.6, 156.4, 172.9; IR (KBr) 1715, 1781 cmꢀ1
.
General Procedure for the Synthesis of Oligopeptidyl Carbamates 4, 5
A solution of 3 (1 mmol) in a mixture of DEA=CH2Cl2 (1:1, 10 mL) was
stirred for 30 min, and the reaction mixture was concentrated under
reduced pressure to remove DEA completely. The resulting free amino
peptidyl carbamate was isolated after trituration of the residue with ether
(15 mL). It was dissolved in dry CH2Cl2 (10 mL) and cooled to 0ꢁC. A
solution of 2 in dry CH2Cl2 was added followed by NMM (1.2 mmol).
After the completion of the reaction (TLC), the reaction mixture was
washed with 10% citric acid solution, water (10 mL ꢂ 2), and brine. The
crude was purified by column chromatography using 35% hexane–EtOAc
to get the tripeptidyl carbamate ester as a solid. Similar steps were
repeated to obtain the tetrapeptidyl carbamates.
Data
N-Fmoc-Ala-w(CH2–O–CO–NH)-Leu-w(CH2-O-CO-NH)-Ala-OMe 4a
1H NMR (CDCl3, 300 MHz): d 0.87 (d, 6H, J ¼ 7.3 Hz), 1.26 (m, 6H,
J ¼ 6.8 Hz), 1.42 (m, 3H), 2.42 (m, 1H), 3.53 (br, 1H), 3.72 (s, 3H),
4.11 (m, 2H), 4.20–4.35 (m, 6H), 5.33–5.68 (m, 3H), 7.30–7.79 (m, 8H);
13C NMR (CDCl3, 200 MHz): d 17.3, 18.2, 18.5, 25.3, 35.6, 46.7, 46.9,
49.1, 51.2, 60.8, 62.7, 66.7, 68.2, 119.9, 125.1, 127.1, 127.8, 141.4,
144.0, 155.6, 156.3, 156.7, 172.8; IR (KBr) 1710, 1778, 1780 cmꢀ1
.
N-Fmoc-Met-w(CH2–O–CO–NH)-Ile-w(CH2–O–CO–NH)-Phe-OMe 4b
1H NMR (CDCl3, 300 MHz): d 0.90 (d, 6H, J ¼ 7 Hz), 1.97–2.2 (m, 7H),
1.44 (m, 3H), 2.51 (m, 1H), 3.1 (br, 2H), 3.35 (m, 1H), 3.70 (s, 3H), 4.12
(m, 1H), 4.3–4.6 (m, 7H), 5.6–5.8 (m, 3H), 7.1–7.7 (m, 13H): 13C NMR
(CDCl3, 200 MHz): 14.8, 17.4, 19.2, 22.3, 24.5, 32.1, 41.1, 47.3, 48.8,
52.3, 54.8, 59.2, 64.5, 66.8, 68.2, 72.1, 120.0, 125.0, 127.1, 127.2, 127.7,

3564
V. V. Sureshbabu and H. P. Hemantha
128.6, 129.6, 135.7, 141.2, 144.7, 155.6, 156.1, 157.2, 172.0; IR (KBr)
1705, 1768, 1778 cmꢀ1
.
N-Fmoc-Ala-w(CH2–O–CO–NH)-Gly-w(CH2–O–CO–NH)-Ile-w
(CH2–O–CO–NH)-Ala-OMe 5a
1H NMR (CDCl3, 300 MHz): 0.87 (d, 6H, J ¼ 7.3 Hz), 1.26 (m, 6H,
J ¼ 6.8 Hz), 1.42 (m, 3H), 2.42 (m, 1H), 3.14–3.38 (m, 4H), 3.53 (br,
1H), 3.72 (s, 3H), 4.11 (m, 2H), 4.20–4.35 (m, 7H), 5.33 (br, 3H),
7.30–7.79 (m, 8H); 13C NMR (CDCl3, 200 MHz): d 17.3, 18.2, 18.5,
22.1, 25.3, 35.6, 42.6, 46.7, 46.9, 49.1, 51.2, 60.8, 62.7, 66.7, 68.2, 119.9,
125.1, 127.1, 127.8, 141.4, 144.0, 155.6, 156.3, 156.7, 168.2, 172.8; IR
(KBr) 1710, 1777, 1780 cmꢀ1
.
N-Fmoc-Ile-w(CH2–O–CO–NH)-Phe-w(CH2–O–CO–NH)-Gly-w
(CH2–O–CO–NH)-Ala-OMe 5b
1H NMR (CDCl3, 300 MHz): 0.95 (d, 6H, J ¼ 6.8 Hz), 1.15 (d, 3H,
J ¼ 5.8 Hz), 1.50–1.81 (m, 3H), 3.12–3.32 (m, 8H), 3.71 (s, 3H), 4.11
(m, 2H), 4.41–4.62 (m, 6H), 5.25 (br, 3H), 6.1 (s, 1H), 7.30–7.80 (m,
13H); 13C NMR (CDCl3, 200 MHz): d 14.7, 18.6, 20.8, 22.3, 22.5, 35.6,
37.3, 46.7, 47.0, 49.1, 52.3, 54.0, 66.7, 67.9, 70.1, 120.0, 125.1, 127.1,
127.8, 128.5, 128.6, 138.0, 141.4, 144.0, 155.4, 155.5, 156.9, 167.2,
171.2, 173.9; IR (KBr) 1700, 1778, 1785 cmꢀ1
.
Synthesis of N-Fmoc-Peptidyl Carbamate Acid 7
Initially, an amino acid was converted to its Bis TMS derivative 6.
TMS-Cl (2.5 mmol), followed by TEA (2.5 mmol), and was added to a
suspension of amino acid (1 mmol) in CH2Cl2 refluxed for 3 h. The mix-
ture was cooled to rt and was added to a stirred solution of 2 in CH2Cl2
at 0ꢁC. After 1 h, the reaction mixture was concentrated, and the residue
was taken into a solution of sodium carbonate. The aqueous layer was
washed with ether (10 mL ꢂ 2), followed by acidification using dilute
HCl. The precipitate was extracted into ethyl acetate (15 mL), and the
organic layer was washed with water (10 mL ꢂ 3), followed by brine wash
(15 mL). The solvent was removed under reduced pressure to afford the
desired compound as gummy solids.

N-Fmoc-b-Aminoalkoxy Carbonyl Chlorides
3565
Data
N-Fmoc-Ala-w(CH2–O–CO–NH)-Leu-OH 7a
1H NMR (CDCl3, 300 MHz): d 0.85 (d, 6H, J ¼ 6.4 Hz), 1.2 (d, 3H,
J ¼ 5.8 Hz), 1.45 (m, 3H), 3.68–3.7 (m, 4H), 4.20–4.42 (m, 4H),
5.10–5.2 (br, 2H), 7.10–7.80 (m, 8H); 13C NMR (CDCl3, 200 MHz): d
22.3, 22.9, 38.3, 41.1, 47.4, 48.8, 49.7, 52.3, 64.7, 66.7, 120.0, 125.0,
127.0, 127.3, 127.9, 128.6, 129.2, 135.7, 141.4, 144.0, 155.6, 156.4,
172.8; IR 1707, 1778 cmꢀ1
.
N-Fmoc-Val-w(CH2–O–CO–NH)-Ile-OH 7b
1H NMR (CDCl3, 300 MHz): d 0.8–0.9 (m, 12H), 1.58 (m, 4H), 3.31 (br,
1H), 4.12–4.39 (m, 5H), 5.2 (m, 2H), 5.32 (br, 1H), 7.5–7.79 (m, 8H); 13
C
NMR (CDCl3, 200 MHz): d 18.5, 22.4, 24.8, 32.4, 41.2, 48.8, 54.9, 64.2,
66.8, 120.0, 125.0, 127.2, 141.3, 144.0, 155.6, 156.4, 168.9, 172.9; IR
1710, 1780 cmꢀ1
.
ACKNOWLEDGMENT
We thank the Council of Scientific and Industrial Research (CSIR),
New Delhi [Grant No. 01(2034)=06=EMR-II] for the financial support.
REFERENCES
1. Cho, C. Y.; Moran, E. J.; Cherry, S. R.; Stephans, J. C.; Fodor, S. P. A.;
Adams, C. L.; Sundaram, A.; Jacobs, J. W.; Schultz, P. G. An unnatural
biopolymer. Science 1993, 261, 1303–1305.
2. Wilson, M. E.; Nowick, J. S. In Methods of Organic Chemistry: Synthesis of
Peptides and Peptidomimetics; Houben-Weyl: New York, 2003, vol. E22c,
pp. 590–605.
3. Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A.
Applications of combinatorial technologies to drug discovery, 2: Combina-
torial organic synthesis, library screening strategies, and future directions.
J. Med. Chem. 1994, 37, 1385–1401.
4. Cho, C. Y.; Youngquist, R. S.; Paikoff, S. J.; Beresini, M. H.; Hebert, A. R.;
Berleau, L. T.; Liu, C. W.; Wemmer, D. E.; Keough, T.; Schultz, P. G. Synth-
esis and screening of linear and cyclic oligocarbamate libraries: Discovery of
high affinity ligands for GPIIb=IIIa. J. Am. Chem. Soc. 1998, 120, 7706–7718.

3566
V. V. Sureshbabu and H. P. Hemantha
5. Digenis, G. A.; Agha, B. J.; Tsuji, K.; Kato, M.; Shinogi, M. Peptidyl
carbamates incorporating amino acid isosteres as novel elastase inhibitors.
J. Med. Chem. 1986, 29, 1468–1476.
6. Warras, R.; Walden, P.; Wiesmuller, K. H.; Jung, G. Oligocarbamates as
MHC class I ligands. Lett. Pept. Sci. 1998, 5, 125–128.
7. Cho, C. Y.; Liu, C. W.; Wemmer, D. E.; Schultz, P. G. Cyclic and linear oligo-
carbamate ligands for human thrombin. Bioorg. Med. Chem. 1999, 7, 1171–1179.
8. Owens, R. A.; Gesellchen, P. D.; Houchins, B. J.; Dimarchi, R. D. The rapid
identification of HIV protease inhibitors through the synthesis and screening of
defined peptide mixtures. Biochem. Biophys. Res. Commun. 1991, 181, 402–408.
9. Campbell, D. A.; Bermak, L. C.; Burkoth, T. S.; Patel, D. V. A transition
state analog inhibitor combinatorial library. J. Am. Chem. Soc. 1995, 117,
5381–5382.
10. Wang, X.; Huq, I.; Rana, T. M. HIV-I TAR RNA recognition by an
unnatural biopolymer. J. Am. Chem. Soc. 1997, 119, 6444–6445.
11. Alsina, J.; Rabanal, F.; Chiva, C.; Giralt, E.; Albericio, F. Active carbonate
resins: Application to the solid phase synthesis of alcohol, carbamate and
cyclic peptides. Tetrahedron 1998, 54, 10125–10152.
12. Sureshbabu, V. V.; Sudarshan, N.; Venkataramanarao, R. Peptidyl
carbamates: Efficient synthes using N-Fmoc-b-amino alkoxy carbonyl
chlorides=active pentachlorophenyl carbonates as monomeric building
blocks. Int. J. Pept. Res. Ther. 2008, 14, 149–156.
13. Eckert, H.; Forster, B. Triphosgene, a crystalline phosgene substitute. Angew.
Chem. Int. Ed. Engl. 1987, 26, 894–895.
14. Tantry, S. J.; Sureshbabu, V. V. Synthesis of Na-protected peptide acids by
the N-C chain extension employing O, N-bis-trimethylsilyl-amino acids using
the mixed anhydride method. Indian J. Chem. 2004, 43B, 1282–1287.