An efficient conversion of the carboxylic group of N-Fmoc α-amino acids/peptide acids into N-formamides employing isocyanates as key intermediates

Article abstract of DOI:10.1021/jo701371k

(Chemical Equation Presented) Reaction of 96% formic acid with isocyanates derived from N-Fmoc α-amino acids/peptide acids catalyzed by DMAP has yielded a new class of stable formamides as crystalline solids which have been characterized by IR, ¹

Full text of DOI:10.1021/jo701371k

hydroxyl protection in peptide synthesis.10-12 N-Formyl amino
acid esters can be dehydrated to the corresponding isonitriles13
which are versatile starting materials for the synthesis of various
bioactive compounds14 and important components in Passeri-
ni’s15 as well as Ugi’s multicomponent reactions.16
An Efficient Conversion of the Carboxylic Group
of N-Fmoc r-Amino Acids/Peptide Acids into
N-Formamides Employing Isocyanates as Key
Intermediates
There are a large number of reports on formylation of the
amino group including that of R-amino acid esters. These
include the direct reaction with formic acid17 or along with a
catalyst like ZnO,18 KF-Al2O3,19 formylation with acetic formic
anhydride,20 chloral,21 carbodiimide activated formic acid,22 and
ammonium formate.23 In peptide chemistry, the reported formy-
lation procedures24 have targeted the conversion of the amino
group of amino acid esters into N-formamides (Figure 1).
N. S. Sudarshan, N. Narendra, H. P. Hemantha, and
Vommina V. Sureshbabu*
Department of Studies in Chemistry, Central College Campus,
Bangalore UniVersity, Bangalore 560001, India
hariccb@rediffmail.com
ReceiVed July 7, 2007
FIGURE 1. N-Formyl R-amino acid ester.
However, there has not been any report on the transformation
of the carboxylic acid function of the N-protected amino acid
into a formamide moiety. A reaction of such sort would lead to
the generation of a novel class of formamides as shown in Figure
2. These form a new type of synthons to carry out the chemical
transformations analogous to the existing reactions of the
N-formyl group but over the C terminus of NR-protected amino
acids/peptide acids. Retrosynthetic analysis of the target for-
mamide leads to a reaction of monoprotected N-Fmoc alkyl gem-
diamine with a suitable existing formylating agent. But, since
such a gem-diamine synthon is neither stable under acidic or
Reaction of 96% formic acid with isocyanates derived from
N-Fmoc R-amino acids/peptide acids catalyzed by DMAP
has yielded a new class of stable formamides as crystalline
1
solids which have been characterized by IR, H NMR, 13C
NMR, and mass spectroscopy. Conversion of the side chain
carboxylic acid of N-Fmoc-5-oxazolidinones of Asp/Glu into
the N-formyl group also has been accomplished. The reaction
is simple, mild, and high yielding.
(10) Luca, L. D.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2002,
67, 5152.
(11) (a) Martinez, J.; Laur, J. Synthesis 1982, 979. (b) Floresheimer, A.;
Kula, M. R. Monatsh. Chem. 1988, 119, 1323.
N-Formamides represent a valuable class of compounds by
virtue of their widespread applications in medicinal and organic
chemistry. They are extensively used in the pharmaceuticals to
make medically useful compounds like fluoroquinones,1 imi-
dazoles,2 nitrogen bridged heterocycles,3 etc. Formamides are
the important entities in organic synthesis as they are starting
materials for a variety of products such as formamidines,4
monomethylated amines,5 and isocyanides.6 They also serve as
useful reagents in the Vilsmeier formylation reactions,7 asym-
metric allylation,8 and hydrosilylation of carbonyl compounds.9
Further, the formyl group finds utility as both amino and
(12) For use of the formyl group as the amino protecting group in the
synthesis of partially modified retroinverso peptides see: Chorev, M.;
Goodman, M. Int. J. Peptide Protein Res. 1983, 21, 258.
(13) (a) Walborsky, H. M.; Niznik, G. K. J. Org. Chem. 1972, 37, 187.
(b) Skorna, G.; Ugi, I. Angew. Chem., Int. Ed. Engl. 1977, 16, 259. (c)
Kim, M.; Euler, W. B.; Rosen, W. J. Org. Chem. 1997, 62, 3766. (d)
Porcheddu, A.; Giacomelli, G.; Salaris, M. J. Org Chem. 2005, 70, 2361.
(e) Katritzky, A. R.; Xie, L.; Fan, W. Q. Synnthesis 1993, 45.
(14) (a) Rigby, J. H.; Laurent, S. J. Org. Chem. 1998, 63, 6742. (b)
Howard, N.; Abell, C.; Blakemore, W.; Chessari, G.; Congreve, M.; Howard,
S.; Jhoti, H.; Murry, C. W.; Seavers, L. C. A.; Montfort, L. M. J. Med.
Chem. 2006, 49, 1346.
(15) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126. (b). Andreana, P.
R.; Liu, C. C.; Schreiber, S. L. Org. Lett. 2004, 6, 4231.
(16) (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
(b) Brahmachary, E.; Ling, F. H.; Svec, F.; Frechet, J. M. J. J. Comb. Chem.
2003, 5, 441.
(17) Jung, S. H.; Ahn, J. H.; Park, S. K.; Choi, J.-K. Bull. Korean Chem.
Soc. 2002, 23, 149.
(1) Jackson, A.; Meth-Cohn, O. J. Chem. Soc., Chem. Commun. 1995,
1319.
(2) Chen, B-C.; Bednarz, M. S.; Zhao, R.; Sundeen, J. E.; Chen, P.; Shen,
Z.; Skoumboudris, A. P.; Barrish, J. C. Tetrahedron Lett. 2000, 41, 5453.
(3) Kakehi, A.; Ito, S.; Hayeshi, S.; Fujii, T. Bull. Chem. Soc. Jpn. 1995,
68, 3753.
(4) Han, Y.; Cai, L. Tetrahedron Lett. 1997, 38, 5423.
(5) (a) Effenberger, F.; Eichhorn, J. Tetrahedron: Asymmetry 1997, 8,
469. (b) Humber, L. G. J. Med. Chem. 1971, 14, 982.
(6) (a) Waki, J.; Meienhofer, J. J. Org. Chem. 1977, 42, 2019. (b) Ugi,
I. Angew. Chem., Int. Ed. Engl. 1982, 21, 810. (c) Schollkopf, U. Angew.
Chem., Int. Ed. Engl. 1977, 16, 339.
(7) Downie, I. M.; Earle, M. J.; Heaney, H.; Shuhaiber, K. F. Tetrahedron
1993, 49, 4015.
(8) Iseki, K.; Mizuno, S.; Kuroki, Y.; Kobayashi, Y. Tetrahedron 1999,
55, 977.
(18) Hosseini-Sarvari, M.; Sharghi, H. J. Org. Chem. 2006, 71, 6652.
(19) Mihara, M.; Ishino, Y.; Minakata, S.; Komatsu, M. Synthesis 2003,
15, 2317.
(20) (a) Sheehan, J. C.; Yang, D. D. H. J. Am. Chem. Soc. 1958, 80,
1154. (b) Strazzolini, P.; Giumani, A. G.; Cauci, S. Tetrahedron 1990, 46,
1081.
(21) Blicke, F. F.; Lu, C.-J. J Am. Chem Soc. 1952, 74, 3933.
(22) (a) Waki, J.; Meienhofer, J. J. Org. Chem. 1977, 42, 2019. (b) Chen,
F. M. F.; Benotoin, N. L. Synthesis 1979, 709.
(23) Reddy, P. G.; Kumar, G. D. K.; Baskaran, S. Tetrahedron 2000,
41, 9149.
(9) (a) Kobayashi, S.; Yasuda, M.; Hachiya, I. Chem. Lett. 1996, 407.
(b) Iseki, K.; Mizuno, S.; Kuroki, Y.; Kobayashi, Y. Tetrahedron 1999,
55, 977.
(24) (a) Duczek, W.; Deutsch, J.; Vieth, S.; Niclas, H. J. Synthesis 1996,
37. (b) Kotha, S.; Behera, M.; Khedar, P. Tetrahedron Lett. 2004, 45, 7589.
10.1021/jo701371k CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/14/2007
9804
J. Org. Chem. 2007, 72, 9804-9807

TABLE 1. Yield of N-Fmoc-gPhe-CO-H over Different Bases
reaction
time (h)
equiv
added
yield
(%)
entry
1
base
NMM
10
1.0
2.0
1.0
1.0
1.0
0.5
0.3
0.2
35
45
45
30
85
84
84
70
FIGURE 2. N-(1-(Fmoc amino)alkyl) formamide.
2
3
4
pyridine
TEA
DMAP
10
10
4
4
4
SCHEME 1. Synthesis of N-Fmoc r-Amino Acid Derived
N-Formamides
4
SCHEME 2. Conversion of N-Fmoc Peptide Acids into
Formamides
FIGURE 3. Formamides of NR-Fmoc-Asp/Glu-5-oxazolidinone.
SCHEME 3. Synthesis of N-(1-Amino alkyl)formamides and
Their Acylation
alkaline conditions25 nor can be easily isolated,26 this approach
offers its own difficulties. Hence we envisaged an alternate route
of employing stable N-Fmoc R-amino isocyanates as starting
materials and directly formylating them under Goldsmith-Wick-
type conditions.27 Accordingly, we herein report a simple and
efficient protocol for the conversion of N-Fmoc R-amino acids/
peptide acids to the N-Fmoc R-amino formamides through the
formolysis of the corresponding isocyanates (Scheme 1). The
reaction is also an example for the transformation of the
carboxylic acid group into the N-formyl functionality.
Our group has recently reported the preparation of N-Fmoc
R-amino isocyanates and their application to the synthesis of
dipeptidylureas28 and oligo R-peptidyl ureas.29 In another recent
report, Guichard and co-workers also have employed the
succinimidyl carbamate derivatives of N-Boc/Z/Fmoc protected
R-amino acids in the synthesis of ureidopeptides and urea-
peptide hybrids.30 In the persistence of our efforts to explore
newer applications of N-Fmoc R-amino isocyanates, we carried
out the acidolysis reaction of the isocyanates with formic acid
in the presence of 4-(dimethylamino)pyridine (DMAP) leading
to the formation of the title formamides.
was then treated with nearly twice an equivalent of 96% formic
acid with CH2Cl2 as solvent at -10 °C to yield the formamide
3c. The reaction was run in both the absence and the presence
of DMAP. As expected, there was a tremendous surge up to
90% in the yield for catalyzed reaction as against the uncatalyzed
one. This observation was consistent with the proven mechanism
of activation of isocyanates toward nucleophillic attack upon
complexation with DMAP.27 Parallel reactions were also run
with other tertiary amino bases like N-methylmorpholine
(NMM), pyridine, and triethylamine (TEA) as replacements to
DMAP. But the yields in these cases were only up to 30-40%
even with higher equivalents of base and longer reaction times
(Table 1). The overall course of the DMAP-catalyzed formy-
lation reaction starting from the corresponding isocyanate was
complete within 2-3 h.
Also, the elevation in reaction temperature from -10 to
25 °C produced unsatisfactory yields with mixture of impurities.
After having optimized the reaction conditions, the reaction was
repeated for other N-Fmoc R-amino acids and in all the cases,
corresponding N-formyl compounds 3a-l were obtained in good
yields. Further, the extrusion of the products from the reaction
mixtures as stable solids allowed for a simple workup procedure
and product isolation with near purity. Final purification was
done through recrystallization with the DMSO-water system.
Studies on the reaction were initiated with Fmoc-phenylala-
nine 1c as starting material. The required isocyanate precursor
was prepared as an isolable solid through the Curtius rearrange-
ment of the corresponding acid azide.31,32 The isocyanate 2c
(25) (a) Louden, G. M.; Almond, M. R.; Jacob, J. N. J. Am. Chem. Soc.
1981, 103, 4508. (b) Parham, M. E.; Louden, G. M. Biochem. Biophys.
Res. Commun. 1978, 80, 1.
(26) (a) Fletcher, M. D.; Campbell, M. M. Chem. ReV. 1998, 98, 763.
(b) Fuller, W. P.; Goodman, M.; Verlander, M. S. J. Am. Chem. Soc. 1985,
107, 5821.
(27) (a) Schuemacher, A. C.; Hoffmann, R. W. Synthesis 2001, 243. (b)
For application of the Goldsmith-Wick-type reaction to the synthesis of
retroinverso peptides see: Venkataramanarao, R.; Sureshbabu, V. V.
Tetrahedron Lett. 2006, 47, 9139.
(28) Patil, B. S.; Vasanthakumar, G. R.; Sureshbabu, V. V. J. Org. Chem.
2003, 68, 7274.
(31) For preparation of N-Fmoc R-amino acid azides, see: Sureshbabu,
V. V.; Ananda, K.; Vasanthakumar, G. R. J. Chem. Soc., Perkin Trans. 1
2000, 4328.
(29) Sureshbabu, V. V.; Patil, B. S.; Venkataramanarao, R. J. Org. Chem.
2006, 71, 7700.
(30) Fischer, L.; Semetey, V.; Lozano, J.-M.; Schaffner, A.-P.; Briand,
J.-P.; Didierjean, C.; Guichard, G. Eur. J. Org. Chem. 2007, 2511.
(32) The isocyanates were prepared either by refluxing the N-Fmoc
R-amino acid azides in toluene for 30 min or by exposing the toluene
solution of azides to microwave irradiation for 45 s at 600 MHz power.
For experimental details and properties of these isocyanates see ref 28.
J. Org. Chem, Vol. 72, No. 25, 2007 9805

TABLE 2. List of Formamides Derived from N-Fmoc r-Amino Acids/peptide Acids
HRMS (M + Na+)
yielda
(%)
mp
(°C)
entry
formamidesb
Fmoc-gGly-CO-H 3a
Fmoc-gAla-CO-H 3b
Fmoc-gPhe-CO-H 3c
Fmoc-gVal-CO-H 3d
Fmoc-gLeu-CO-H 3e
Fmoc-gIle-CO-H 3f
Fmoc-gMet-CO-H 3g
Fmoc-L-gPhg-CO-H 3h
Fmoc-D-gPhg-CO-H 3i
Fmoc-gAsp(OMe)-CO-H 3j
Fmoc-gCys(Bn)-CO-H 3k
Fmoc-gPro-CO-H 3l
Fmoc-Val-gVal-CO-H 6a
Fmoc-Ala-gVal-CO-H 6b
Fmoc-L-Phg-gAla-CO-H 6c
Fmoc-D-Phg-gAla -CO-H 6d
Fmoc-Val-D-gPhe-CO-H 6e
Fmoc-Phe-Ala-gLeu-CO-H 7
Fmoc-Asp(â-NH-CHO)-5-oxazolidinone 8a
Fmoc-Glu(γ-NH-CHO)-5-oxazolidinone 8b
calcd
obsd
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
79
90
89
89
86
80
79
82
83
78
82
75
86
82
83
80
79
78
81
79
168
178
192
183
156
140
165
186
185
138
174
gum
93
210
183
179
150
152
152
157
319.1059
333.1215
409.1528
361.1528
375.1685
375.1685
393.1249
395.1372
395.1372
391.1270
455.1405
359.1372
460.2212
432.1899
466.1743
466.1743
508.2212
593.2740
389.1113
403.1270
319.1058
333.1211
409.1512
361.1526
375.1687
375.1686
393.1233
395.1368
395.1368
391.1266
455.1402
359.1370
460.2207
432.1895
466.1737
466.1737
508.2207
593.2733
389.1108
403.1265
a Yields correspond to isolated formamides starting from isocyanates. b The “g” notation in Fmoc-gXaa-CO-H represents the gem-diamine derivative (see
ref 30).
TABLE 3. List of N-Fmoc-Dipeptidyl N-Formamides Synthesized
The generality of the reaction was demonstrated by the
synthesis of Fmoc-protected di- and tripeptide acid derived
N-formamides (Scheme 2). The required isocyanates were
prepared through the rearrangement of the corresponding
N-Fmoc dipeptide and tripeptide acid azides and reacted with
96% formic acid under similar reaction conditions to obtain the
formamides 6a-e and 7 in 78-86% yield and were fully
characterized.
Finally the reaction was extended to the conversion of the
side chain carboxylic acid of N-Fmoc-Asp/Glu derived 5-ox-
azolidinones into the N-formyl derivatives (Figure 3, 8a and
8b). In these preparations, the required products were isolated
in 80% yield but the product isolation required workup
procedures and column purification.
Although mild conditions were maintained throughout the
reaction, the optical purity of the formamide products was
verified by conducting studies using 1H NMR spectroscopy. The
1H NMR spectra of both MPLC purified Fmoc-D-Phg-L-gAla-
CO-H and Fmoc-L-Phg-L-gAla-CO-H showed distinct methyl
group doublets at δ 1.16, 1.18 and δ 1.25, 1.26, respectively,
while the mixture of epimers had two doublets at δ1.17, 1.18
and δ 1.24, 1.28. This clearly showed the absence of the
formation of the other isomer due to epimerization during the
reaction course.
We then undertook the deprotection of the Fmoc group form
the N-formamides 3 to demonstrate their application in the
synthesis of Fmoc-protected dipepidylformamides. Deprotection
was carried out by stirring 3 in 20% diethylamine in CH2Cl2
solution for 20 min until the completion of the reaction as
evident by TLC. The resulting amine-free N-(1-amino alkyl)-
formamides were coupled directly with the mixed anhydride
of Fmoc-amino acid to obtain Fmoc-dipeptidyl N-formamides
6d and 9a-f (Scheme 3, Table 3). All the peptide formamides
thus prepared were adequately characterized.
via Scheme 3
HRMS (M + Na)+
yielda
(%)
mp
(°C)
compd
calcd
obsd
9a
9b
9c
9d
9e
9f
79
78
83
71
77
74
128
190
192
203
217
137
432.1899
492.1933
474.2369
464.1620
474.2369
522.2369
432.1890
492.1923
474.2367
464.1628
474.2366
522.2364
a Isolated yield from 3.
dipeptides and tripeptides and also to the insertion of the
N-formyl group in the side chains of Fmoc-Asp/Glu-derived
5-oxazolidinones. The reaction is simple, mild, high yielding,
and racemization free.
Experimental Section
Typical Procedure for the Synthesis of N-Formamides. To a
stirred solution of Fmoc-R amino acid/peptide acid (10 mmol) in
THF were added 1.2 mL (11.0 mmol) of N-methylmorpholine and
1.05 mL (11.0 mmol) of ethyl chloroformate at -20 °C. The
mixture was stirred for 5 min and 0.98 g (15 mmol) of sodium
azide in a minimum amount of water was added. The stirring was
continued for 20 min or until completion of the reaction. THF was
then evaporated under vacuum and the residue was dissolved in
CH2Cl2. The organic extract was washed with 5% Na2CO3, 10%
citric acid, water, and brine and dried over anhydrous sodium
sulfate. CH2Cl2 was removed under reduced pressure and the residue
dissolved in 15.0 mL of toluene. The solution was refluxed for 30
min or irradiated with microwaves for 45 s at 600 MHz power.
Complete conversion of acid azide (IR peak at 2145 cm-1) to
isocyanate (IR peak at 2225 cm-1) was confirmed and toluene was
removed in vacuo. The resulting isocyanate was dissolved in 15
mL of dry CH2Cl2. To this solution was added 0.79 mL of 96%
formic acid (2.0 mmol) and 0.37 g of DMAP (0.3 mmol) at
-10 °C with stirring for 4 h when a white precipitate appears. The
solvent was evaporated, hexane was added, and the resulting solid
was filtered. The solid product was washed with 10% citric acid
(20 mL), 5% Na2CO3 (20 mL), and water and recrystallized with
the DMSO-water system.
In conclusion, we have synthesized a novel class of N-(1-
Fmoc-amino alkyl)formamides employing the isocyanates de-
rived from N-Fmoc R-amino acids/peptides. The formolysis
reaction of the isocyanates has yielded the title compounds in
excellent yields. The protocol has been extended to Fmoc
9806 J. Org. Chem., Vol. 72, No. 25, 2007

(S)-(9H-Fluren-9-yl)methyl 1-formamido-2-phenylethylcar-
bamate (Fmoc-gPhe-CO-H, 3c): yield 3.09 g (8.02 mmol, 80%)
product obtained was filtered, washed with aqueous 5% Na2CO3
(10 mL), 5% citric acid (10 mL), and water, dried, and recrystallized
with DMSO-water.
of white solid; mp 192 °C; Rf (10% MeOH/CHCl3) 0.33; [R]24
D
1
3.36 (c 1.1, DMSO); H NMR (d6-DMSO) δ 2.91 (br, 2H), 4.18
(9H-Fluoren-9-yl)methyl 1-(1-formamido-3-methylbutylamino)-
1-oxo-3-phenylpropan-2-ylcarbamate (Fmoc-Phe-gLeu-CO-H,
9f): yield 3.60 g (7.21 mmol, 72%) of off-white solid; mp 137 °C;
Rf (10% MeOH/CHCl3) 0.27; [R]24D 9.00 (c 1.0, DMSO); 1H NMR
(d6-DMSO) δ 0.95 (d, J ) 5.6 Hz, 6H), 1.52 (m, 3H), 3.01 (m,
2H), 4.11 (t, J ) 11.3 Hz, 1H), 4.24 (d, J ) 7.2 Hz, 2H), 4.51 (m,
1H), 5.32 (m, 1H), 6.12 (m, 1H), 7.10-7.90 (m, 13H), 8.12 (m,
1H), 8.24 (m, 1H); 13C NMR (d6-DMSO) δ 21.6, 25.3, 37.3, 46.7,
46.9, 51.3, 61.8, 65.7, 119.9, 125.3, 126.2, 127.2, 127.3, 127.6,
128.8, 130.4, 132.3, 138.1, 140.6, 143.7, 155.6, 164.1, 173.9.
(br, m, 1H), 4.30 (d, J ) 7.6 Hz, 2H), 5.11 (d, J ) 6.8 Hz, 2H),
5.49 (d, J ) 6.6 Hz, 1H), 7.07-7.31 (m, 7H), 7.37-7.48 (t, J )
14.1 Hz, 2H), 7.58 (d, J ) 6.7 Hz, 2H), 7.72 (d, J ) 7.1 Hz, 2H),
8.01 (d, J ) 3.4 Hz, 1H), 8.12 (br, 1H); 13C NMR (d6-DMSO) δ
37.3, 47.2, 54.5, 66.5, 120.0, 124.8, 126.8, 127.1, 127.7, 127.9,
128.5, 129.4, 137.6, 141.5, 144.1, 156.6, 164.2.
(S)-(9H-Fluoren-9-yl)methyl 4-(2-formamidoethyl)-5-oxoox-
azolidine-3-carboxylate (Fmoc-Glu (γ-NHCHO)-oxazolidinone,
8b): yield: 2.67 g (7.12 mmol, 71%) of white solid; mp 157 °C;
Rf (10% MeOH/CHCl3) 0.31; [R]24D 75.6 (c 1.2, DMSO); 1H NMR
(d6-DMSO) δ 1.84 (m, 2H), 3.31 (m, 2H), 4.21-4.34 (m, 3H),
4.71 (t, J ) 12.9 Hz, 1H), 5.72 (s, 2H), 7.30-7.43 (m, 4H), 7.71-
7.89 (m, 4H), 8.01 (m, 1H), 8.17 (s, 1H); 13C NMR (d6-DMSO) δ
26.2, 46.2, 46.5, 59.5, 65.4, 71.2, 119.8, 124.0, 127.0, 127.5, 141.0,
144.0, 160.0, 163.4, 168.0.
General Procedure for the Deprotection of the Fmoc Group
from 3 and Acylation to Fmoc-Protected Peptidyl N-Forma-
mides 9. To 18 mL of 20% diethylamine in CH2Cl2 was added
N-Fmoc-amino-N-formamide 3 (1 mmol) and the mixture was
stirred for 20 min at rt. After completion of the reaction (TLC),
the solvent and an excess of diethylamine were removed completely
under reduced pressure. The resulting N-(1-amino alkyl)formamide
was dissolved in dry THF (5.0 mL) and maintained at 0 °C. To
this was added the THF solution containing 1.1 mmol of Fmoc
amino acid mixed anhydride and the resulting mixture was stirred
for 2-3 h until completion of the coupling. The reaction mixture
was then evaporated and triturated with water and ether. The solid
Acknowledgment. We thank the Department of Science and
Technology, New Delhi, India for financial support. We also
thank S.I.F. and the Department of Organic Chemistry at Indian
Institute of Science, Bangalore for the NMR and mass spectral
facility and Professor Fred Naider of CUNY, New York for
useful discussions. We acknowledge an unknown referee for
valuable suggestions on the application of the N-formamides
for peptide chain extension.
Supporting Information Available: Characterization data of
all the compounds, 1H NMR spectra of compounds 3c,f,g,j, 6a,c,d,
and 7, 13C NMR spectra of the compounds 3b,d,f,g,j and 7, HRMS
of 3a-e,g,h,j, 6a,c,e, 7, 8b, and 9b,c, LCMS of 3a,d,l and 8a,
ESMS of 3e, 6b,c, and 8b, and MALDITOF of 7. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO701371K
J. Org. Chem, Vol. 72, No. 25, 2007 9807