Iodine-Mediated Oxidative Coupling of Hydroxamic Acids with Amines towards a New Peptide-Bond Formation

Article abstract of DOI:10.1055/s-0035-1560266

An efficient and straightforward approach for the coupling of N^α-protected hydroxamic acids with an amino component in the presence of iodine is delineated. The reaction is mediated by the formation of unstable but reactive acyl nitroso intermediates. The peptide hydroxamic acids were found to be useful substrates in coupling reactions.

Full text of DOI:10.1055/s-0035-1560266

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2565–2569
letter
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M. Krishnamurthy et al.
Letter
Synlett
Iodine-Mediated Oxidative Coupling of Hydroxamic Acids with
Amines towards a New Peptide-Bond Formation
Muniyappa Krishnamurthy
T. M. Vishwanatha
R3
R4
O
R3
H2N
O
Nageswara Rao Panguluri
V. Panduranga
H
O
H
I2, DMSO
N
R4
H
O
N
R1
N
R1
N
O
N
R1
NHOH
H
Vommina V. Sureshbabu*
R2
O
one-pot
5–30 min
R2
R2
# 109, Peptide Research Laboratory, Department of Studies
in Chemistry, Central College Campus, Bangalore University,
Dr. B. R. AmbedkarVeedhi, Bangalore 560 001, India
hariccb@gmail.com
hariccb@hotmail.com
sureshbabuvommina@rediffmail.com
R1 = protecting group
R2, R3 = amino acid side chain
R4 = amino acid ester
Received: 10.04.2015
Accepted after revision: 18.08.2015
Published online: 15.10.2015
amine with loss of volatile HNO (Scheme 1).17 The reaction
between hydroxamic acid and amine has also been applied
to the synthesis of di- and tripeptide esters. However, with-
out the presence of an oxidant in this reported case, poor
yields and prolonged reaction times were obtained.18 We
now report promising results of an oxidative coupling of
N-protected α-amino hydroxamic acids with amines, with
loss of nitrous oxide leading to the formation of peptides in
short duration. The central feature of this reaction rep-
resents a novel traceless and fast synthesis of peptides. Ad-
ditionally, we hope that peptide hydroxamic acids can be
used for oxidative coupling reactions of polypeptides and
protein synthesis. Research interest in hydroxamic acids
derived from amino and peptide acids has experienced a re-
naissance since their initial utility in Lossen rearrangement
for the identification of the parent structure.19
DOI: 10.1055/s-0035-1560266; Art ID: st-2015-b0263-l
Abstract An efficient and straightforward approach for the coupling
of Nα-protected hydroxamic acids with an amino component in the
presence of iodine is delineated. The reaction is mediated by the forma-
tion of unstable but reactive acyl nitroso intermediates. The peptide hy-
droxamic acids were found to be useful substrates in coupling reac-
tions.
Key words Nα-protected amino hydroxamic acids, amino acid esters,
oxidative acylation, acyl nitroso intermediate, iodine
The amide bond1 is a key backbone of many organic and
biological molecules including pharmaceuticals,2 natural
products,3 peptides,4 and proteins.5 Development of a new
amide-bond-forming reaction is one of the most important
synthetic transformations for which improved methods are
sought.6 A protocol for the coupling of peptide fragments
constitutes an important step in the total chemical synthe-
sis of proteins.7 In this context, there has been an impres-
sive growth in the past two decades in native chemical liga-
tion (NCL)8 and an alternative to NCL9,10 such as Staudinger
ligation,11 oxo-ester ligation,12 peptide hydrazide ligation,13
various oxidative activation ligation methods using peptide
thioacids,14 and ligation of C-terminal α-keto acid with
N-terminal hydroxyl amine.15 Although the application of
each of these methods is fully demonstrated in unprotected
peptide-fragment coupling, the difficulty in the preparation
of desired starting substrates has necessitated the search for
alternative and easily synthesizable peptide substrates.
Thus our attention was caught by a little known reac-
tion involving oxidative coupling of hydroxamic acids with
amines,16 which results in the formation of amides. The
proposed mechanism confirms the formation of a reactive
acyl nitroso intermediate followed by trapping with an
I
O
O
O
R1-NH2
R2
I2
O
H
H
R1
N
R1
N
O
R1
N
H
2HI
HNO
••
H2N
I
R2
Scheme 1 General reaction mechanism for the amide bond formation
Our group has described the synthesis of ureidopep-
tides through in situ generation of isocyanate from amino
and peptide hydroxamic acids followed by trapping with an
amine under mild conditions.20 Recently, there is a wide
range of methods developed for the synthesis of ureas and
carbamates from Lossen rearrangement of hydroxamic ac-
ids.21 Meanwhile, oxidative activation of hydroxamic acids
for the production of an acyl nitroso intermediate has been
studied and confirmed since the 1960’s.22 For example, the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2565–2569

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M. Krishnamurthy et al.
Letter
Synlett
acyl nitroso intermediate has been used as a reactive dieno-
phile in Diels–Alder-type reactions23 and it is a current top-
ic of interest in natural product synthesis.24
In an attempt to improve the yield of 3a, various oxi-
dants and solvents were screened at room temperature (Ta-
ble 1, entries 4–13). The oxidants H2O2 and NaIO4 were
found to be inefficient for this transformation (Table 1, en-
tries 4–7). Solvent also played an important role, and the
reaction in toluene, DMF, THF, MeOH, H2O, and MeOH–H2O
led to lower yield and requires long reaction duration.
When I2 was used in the presence of DMSO, the desired
product 3a was formed in 95% yield (Table 1, entry 8). Thus,
the optimized protocol was selected to be hydroxamic acid
(1.0 equiv), amine (1.2 equiv), I2 (0.3 equiv) in DMSO, at
room temperature for 5–30 minutes.
With the optimized conditions in hand, various amino
acid esters 6 were employed to couple with Nα-protected
hydroxamic acids 5, and the results are furnished in Table 2.
Both simple and sterically hindered amino acids performed
well to produce the dipeptide esters 7 in good to excellent
yields. The question of epimerization during the course of
coupling is also addressed using chiral HPLC. The diastereo-
meric products Fmoc-(L)-Phg-Phe-OMe (7l), Fmoc-(D)-Phg-
Phe-OMe (7l*) obtained from the Fmoc-protected L-Phg-
NHOH (5l) and D-Phg-NHOH (5l*) were analyzed. Both 7l
and 7l* showed peaks at tR = 14.82 min and tR = 18.47 min,
respectively. Also, an intentionally prepared equimolar
mixture of 7l and 7l* showed distinct peaks at tR = 15.69
min and tR = 18.45 min. From these observations, it was
proved that the present protocol is free from racemization.
In the course of our investigation on the epimerization-
free synthesis of amides and peptides by novel reagents and
substrates,25 we envisioned that hydroxamic acid could be
used to couple with amines for the production of peptides.
The reaction conditions were optimized using optically
pure Fmoc-Ala-NHOH (1a) with benzyl amine (2a) as our
model reaction, and the results are summarized in Table
1.26 When the direct reaction of 1a with 2a was conducted
in toluene by following the reported protocol18 only 15% of
the desired product 3a was obtained (Table 1, entry 1).
However, when the reaction was studied at 70 °C for eight
hours, the formation of the two products was observed.
One of these products was the expected amide 3a, and the
other product was identified as urea derivative 4a which
was obtained by the thermal Lossen rearrangement of hy-
droxamic acid (Table 1, entry 2).27
The Danishefsky group reported that DMSO could act as
an oxidant for the direct ligation of peptide thioacids with
amines without additives.28 Thus, the reaction of 1a and 2a
was carried out in DMSO at room temperature and yielded
51% of 3a (Table 1, entry 3). Interestingly, ureido compound
4a was not present. These observations highlight the re-
quirement of room temperature for the selective formation
of an amide.
Table 1 Synthesis of Nα-Protected Aryl Amide 3a: Optimization of Reaction Conditions
O
H
conditions
N
Ph
NHOH
+
H2N
Ph
+
FmocHN
FmocHN
N
N
Ph
FmocHN
H
H
O
O
1a
2a
3a
4a
Entry
Solvent
Oxidant (equiv)
Temp (°C)
Time
Yield of 3a (%)a
Yield of 4a (%)a
1
2
toluene
toluene
DMSO
DMF
–
r.t.
70
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
16 h
8 h
15
35
51
54
61
80
62
95
60
75
68
–
–
21
–
–
–
–
–
–
–
–
–
–
–
–
3
–
6 h
4
H2O2 (1.0)
H2O2 (1.0)
NaIO4 (0.5)
NaIO4 (0.5)
I2 (0.3)
I2 (0.3)
I2 (0.3)
I2 (0.3)
I2 (0.3)
I2 (0.3)
3h
5
DMSO
DMSO
THF
3 h
6
40 min
1 h
7
8
DMSO
THF
30 min
1 h
9
10
11
12
13
MeOH
DMF
1 h
1 h
H2O
1 h
MeOH–H2O
1 h
45
a Yields corresponding to the isolated pure product 3a.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2565–2569

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Table 2 Synthesis of Dipeptide Esters 728–32
R1
R2
I2 (0.3 equiv)
DMSO
R1
H
N
PG
COOX
+
PG
NHOH
N
H2N
COOX
N
H
r.t., 5–30 min
R2
H
O
O
6
5
7a–l
Entry
1
Product 7
Yield (%)a
93
Fmoc-Ala-Phe-Ome
7a
2
3
Fmoc-Val-Ala-Ome
7b
91
85
96
90
71
89
65
90
92
94
88
85
Fmoc-Leu-Phe-Obn
7c
4
Fmoc-Phe-Gly-Ome
7d
5
Cbz-Leu-Phe-Ome
7e
6
Cbz- Phe-Aib-Ome
7f
7
Cbz-Ile-Gly-Ome
7g
8
Boc-Aib-Aib-Ome
7h
9
Boc-Phe-Val-Ome
7i
10
11
12
13
Boc-Leu-Phe-Ome
7j
Boc-Pro-Phe-Ome
7k
Fmoc-(L)-Phg-Phe-Ome
7l
Fmoc-(D)-Phg-Phe-Ome
7l*
a Yields corresponding to the isolated pure dipeptide esters 7.
Much work remains to be done to develop hydoxamic
acid mediated peptide ligation. In particular, the reaction in
aqueous buffer is currently under investigation. We have
(nevertheless) presented here a peptide-bond strategy from
simple Nα-protected hydroxamic acid and amines. This pro-
cess was mediated by the formation of known acyl nitroso
intermediate. The optimized reaction for coupling of hy-
droxamic acids and amines took place under mild condi-
tions and in short duration of time. The chemistry can be
easily operated, and the isolation of the product is simple.
The reaction showed tolerance towards Fmoc, Boc, and Cbz
protecting groups.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560266.
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References and Notes
(1) Pattabiraman, V. R.; Bode, J. W. Nature (London, U.K.) 2011, 480,
471.
(2) (a) Allen, C. L.; Chhatwal, R.; Williams, J. M. J. Chem. Commun.
2012, 666. (b) Roy, S.; Roy, S.; Gribble, G. W. Tetrahedron 2012,
68, 9867. (c) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.;
Humphrey, G. R.; Leazer, J. L. Jr.; Linderman, R. J.; Lorenz, K.;
Manley, J.; Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green
Chem. 2007, 9, 411. (d) Carey, J. S.; Laffan, D.; Thomson, C.;
Williams, M. T. Org. Biomol. Chem. 2006, 4, 2337.
(3) (a) Lanigan, R. M.; Sheppard, T. D. Eur. J. Org. Chem. 2013, 33,
7453. (b) Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606.
(c) Allen, C. L.; Williams, J. M. J. Chem. Soc. Rev. 2011, 40, 3405.
(d) Basavaprabhu; Vishwanatha, T. M.; Nageswarao, P.;
Acknowledgment
We sincerely thankful to Council of Scientific and Industrial Research
(CSIR) Grant No. 02(0149)/13/EMR-II Government of India, New Delhi
for financial support. T.M.V., N.P. and V.P. are thankful to CSIR for SRF
fellowship.
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Sureshbabu, V. V. Synthesis 2013, 45, 1569. (e) Joullie, M. M.;
Lassen, K. M. ARKIVOC 2010, (viii), 189. (f) Gernigon, N.; Al-
Zoubi, R. M.; Hall, D. G. J. Org. Chem. 2012, 77, 8386.
F.; Ermolenko, M.; Ollivier, N.; Sasaki, K.; Crich, D.; Delpech, B.;
Melnyk, O. Bioorg. Med. Chem. 2013, 21, 3479. (k) Crich, D.;
Sasaki, K. Org. Lett. 2009, 11, 3514. (l) Chen, W.; Shao, J.; Hu, M.;
Yu, W.; Giulianotti, M. A.; Houghten, R. A.; Yu, Y. Chem. Sci.
2013, 4, 970. (m) Wu, X.; Stockdill, J. L.; Wang, P.; Danishefsky,
S. J. J. Am. Chem. Soc. 2010, 132, 4098. (n) Yamashiro, D.; Blake, J.
F. Int. J. Pept. Prot. Chem. 1981, 18, 383. (o) Dyer, F. B.; Park, C.
M.; Joseph, R.; Garner, P. J. Am. Chem. Soc. 2011, 133, 20033.
(p) Joseph, R.; Dyer, F. B.; Garner, P. Org. Lett. 2013, 15, 732.
(q) Pan, J.; Devarie-Baez, N. O.; Xian, M. Org. Lett. 2011, 11, 1092.
(r) Wu, W.; Zhang, Z.; Liebeskind, L. S. J. Am. Chem. Soc. 2011,
133, 14256. (s) Mali, S. M.; Jadhav, S. V.; Gopi, H. N. Chem.
Commun. 2012, 48, 7085. (t) Wang, P.; Danishefsky, S. J. J. Am.
Chem. Soc. 2010, 132, 17045. (u) Wang, P.; Li, X.; Zhu, J.; Chen, J.;
Yuan, Y.; Wu, X.; Danishefsky, S. J. J. Am. Chem. Soc. 2011, 133,
1597.
(4) (a) El-Faham, A.; Albericio, F. Chem. Rev. 2011, 111, 6557.
(b) Lippert, J. W. III. ARKIVOC 2005, (xiv), 87. (c) Montalbetti, C.
A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827. (d) Han, S. Y.;
Kim, Y. A. Tetrahedron 2004, 60, 2447. (e) Wilson, R. M.;
Stockdill, J. L.; Wu, X.; Li, X.; Vadola, P. A.; Park, P. K.; Wang, P.;
Danishefsky, S. J. Angew. Chem. Int. Ed. 2012, 51, 2834. (f) Bode,
J. W. Curr. Opin. Drug Discovery Dev. 2006, 9, 765.
(5) (a) Kent, S. B. H. Chem. Soc. Rev. 2009, 38, 338. (b) Spasser, L.;
Brik, A. Angew. Chem. Int. Ed. 2012, 51, 6840. (c) Chalker, J. M.
Chem. Biol. Drug. Des. 2013, 81, 122.
(6) (a) Shen, B.; Makley, D. M.; Johnston, J. N. Nature (London, U.K.)
2010, 465, 1027. (b) Gunanathan, C.; Ben-David, Y.; Milstein, D.
Science 2007, 317, 790. (c) Watson, A. J. A.; Maxwell, A. C.;
Williams, J. M. J. Org. Lett. 2009, 11, 2667. (d) Yoo, W.-J.; Li, C.-J. J.
Am. Chem. Soc. 2006, 128, 13064. (e) Cadoni, R.; Porcheddu, A.;
Giomelli, G.; Luca, L. D. Org. Lett. 2012, 14, 5014. (f) Orliac, A.;
Pardo, D. G.; Bombrun, A.; Cossy, J. Org. Lett. 2013, 15, 902.
(g) Tian, J.; Gao, W. C.; Zhou, D. M.; Zhang, C. Org. Lett. 2012, 14,
3020.
(7) (a) Pellois, J. P.; Muir, T. W. Curr. Opin. Chem. Biol. 2006, 10, 487.
(b) Aimoto, S. Biopolymers 1999, 51, 247. (c) Rademann, J.
Angew. Chem. Int. Ed. 2004, 43, 4554. (d) Hemantha, H. P.;
Narendra, N.; Sureshbabu, V. V. Tetrahedron 2012, 68, 9491.
(e) Payne, R. J.; Wong, C. H. Chem. Commun. 2010, 46, 21.
(f) Sletten, E. M.; Bertozzi, C. R. Angew. Chem. Int. Ed. 2009, 48,
6974.
(8) (a) Dawson, P. E.; Muir, T. W.; Clark-Lewis, I.; Kent, S. B. H.
Science 1994, 266, 776. (b) Sohma, Y.; Hua, Q. X.; Whittaker, J.;
Weiss, M. A.; Kent, S. B. H. Angew. Chem. Int. Ed. 2010, 49, 5489.
(9) (a) Dirksen, A.; Dawson, P. E. Curr. Opin. Chem. Biol. 2008, 12,
760. (b) Hackenberger, C. P. R.; Schwarzer, D. Angew. Chem. Int.
Ed. 2008, 47, 10030. (c) Dawson, P. E.; Kent, S. B. H. Annu. Rev.
Biochem. 2000, 69, 923. (d) Kent, S. B. H. J. Pept. Sci. 2003, 9, 574.
For a review on ligation of noncysteine amino acids, see:
(e) Wong, C. T. T.; Tung, C. L.; Li, X. Mol. BioSyst. 2013, 9, 826.
(10) Mende, F.; Beisswenger, M.; Seitz, O. J. Am. Chem. Soc. 2010, 132,
11110.
(15) (a) Bode, J. W.; Fox, R. M.; Baucom, K. D. Angew. Chem. Int. Ed.
2006, 45, 1248. (b) Wu, J.; Ruiz-Rudriguez, J.; Comstock, J. M.;
Dong, J. Z.; Bode, J. W. Chem. Sci. 2011, 2, 1976. (c) Carrillo, N.;
Davalos, E. A.; Russak, J. A.; Bode, J. W. J. Am. Chem. Soc. 2006,
128, 1452. (d) Ju, L.; Lippert, A. R.; Bode, J. W. J. Am. Chem. Soc.
2008, 130, 4253. (e) Ju, L.; Bode, J. W. Org. Biomol. Chem. 2009, 7,
2259. (f) Pattabiraman, V. R.; Ogunkoya, A. O.; Bode, J. W.
Angew. Chem. Int. Ed. 2012, 51, 5114.
(16) (a) Sklarz, B.; Al-Sayab, A. F. J. Chem. Soc. 1964, 1318. (b) Ozaki,
S.; Masui, M. Chem. Pharm. Bull. 1977, 25, 1179.
(17) Atkinson, R. N.; Storey, B. M.; King, S. B. Tetrahedron Lett. 1996,
37, 9287.
(18) Hoffmann, E.; Faiferman, I. J. Org. Chem. 1964, 29, 748.
(19) (a) Seifter, S.; Gallop, P. M.; Michaels, S.; Meilman, E. J. Biol.
Chem. 1960, 235, 2613. (b) Gallop, P. M.; Seifter, S.; Lukin, M.;
Meilman, E. J. Biol. Chem. 1960, 235, 2619. (c) Wieland, T.; Fritz,
H. Chem. Ber. 1953, 86, 1186.
(20) (a) Narendra, N.; Chennakrishnareddy, G.; Sureshbabu, V. V.
Org. Biomol. Chem. 2009, 7, 3520. (b) Vasantha, B.; Hemantha, H.
P.; Sureshbabu, V. V. Synthesis 2010, 2990.
(21) (a) Yoganathan, S.; Miller, S. J. Org. Lett. 2013, 15, 602; and refer-
ences cited therein. (b) Dube, P.; Nathel, N. F. F.; Vetelino, M.;
Couturier, M.; Aboussafy, L.; Pichette, S.; Jorgensen, M. L.;
Hardink, M. Org. Lett. 2009, 11, 5622.
(11) (a) Nilsson, B. L.; Kiessling, L. L.; Raines, R. T. Org. Lett. 2000, 13,
1939. (b) Van Berkel, S. S.; Van Eldijk, M. B.; van Hest, J. C. M.
Angew. Chem. Int. Ed. 2011, 50, 8806.
(12) (a) Wan, Q.; Chen, J.; Yuan, Y.; Danifshesky, S. J. J. Am. Chem. Soc.
2008, 130, 15814. (b) Strehin, I.; Gourevitch, D.; Zhang, Y.;
Heber Katz, E.; Messersmith, P. B. Biomater. Sci. 2013, 1, 603.
(c) Warren, J. D.; Miller, J. S.; Keding, S. J.; Danishefsky, S. J. J. Am.
Chem. Soc. 2004, 126, 6576.
(13) (a) Fang, G. M.; Li, Y. M.; Shen, F.; Huang, Y. C.; Li, J.-B.; Lin, Y.;
Cui, H.-K.; Liu, L. Angew. Chem. Int. Ed. 2011, 50, 7645. (b) Zheng,
J. S.; Tang, S.; Huang, Y. C.; Liu, L. Acc. Chem. Res. 2013, 46, 2475.
(14) (a) McKervey, M. A.; O’Sullivan, M. B.; Myers, P. L.; Green, R. H.
J. Chem. Soc., Chem. Commun. 1993, 94. (b) Merkx, R.; Brouwer,
A.; Rijkers, D. T. S.; Liskamp, R. M. J. Org. Lett. 2005, 7, 1125.
(c) Merkx, R.; Van Haren, M. J.; Rijkers, D. T. S.; Liskamp, R. M. J. J.
Org. Chem. 2007, 72, 4574. (d) Raz, R.; Rademann, J. Org. Lett.
2012, 14, 5038. (e) Mhidia, R.; Beziere, N.; Blanpain, A.;
Pommery, N.; Melnyk, O. Org. Lett. 2010, 12, 3982. (f) Crich, D.;
Sana, K.; Guo, S. Org. Lett. 2007, 9, 4423. (g) Crich, D.; Sharma, I.
Angew. Chem. Int. Ed. 2009, 48, 2355. (h) Sasaki, K.; Crich, D. Org.
Lett. 2010, 12, 3254. (i) Talan, R. S.; Sanki, A. K.; Sucheck, S. J.
Carbohydr. Res. 2009, 344, 2048. (j) Mhidia, R.; Boll, E.; Fecourt,
(22) (a) Boyland, E.; Nery, R. J. Chem. Soc. 1966, 354. (b) Kobashi, K.;
Sakaguchi, K.; Takebe, S.; Hosaka, K. Anal. Biochem. 1985, 146, 7.
(23) (a) Miller, T. W.; Isenberg, J. S.; Roberts, D. D. Chem. Rev. 2009,
109, 3099. (b) Keck, G. E.; Webb, R. R.; Yates, J. B. Tetrahedron
1981, 37, 4007. (c) Kirby, G. W. Chem. Soc. Rev. 1978, 6, 1.
(d) Corrie, J. E. T.; Kirby, G. W.; Mackinnon, J. W. M. J. Chem. Soc.,
Perkin Trans. 1 1985, 883. (e) Kirby, G. W.; Mcguigan, H.;
Mackinnon, J. W. M. McLean D.; Sharma, R. P. J. Chem. Soc.,
Perkin Trans. 1 1985, 1437. (f) Iwasa, S.; Tajima, K.; Tsushima, S.;
Nishiyama, H. Tetrahedron Lett. 2001, 42, 5897.
(24) (a) Streith, J.; Defoin, A. Synthesis 1994, 1107. (b) Keck, G. E.;
Webb, R. R. II. J. Org. Chem. 1982, 47, 1302. (c) Chaiyaveij, D.;
Cleary, L.; Batsanov, A. S.; Marder, T. B.; Shea, K. J.; Whiting, A.
Org. Lett. 2011, 13, 3442.
(25) (a) Tantry, S. J.; Venkataramanarao, R.; Chennakrishnareddy, G.;
Sureshbabu, V. V. J. Org. Chem. 2007, 73, 9360. (b) Madhu, C.;
Vishwanatha, T. M.; Sureshbabu, V. V. Synthesis 2013, 45, 2727.
(c) Gopi, H. N.; Sureshbabu, V. V. Tetrahedron Lett. 1998, 39,
9769.
(26) Enantiopurehydroximate of α-amino acids and peptides were
synthesized through reported protocol, see: Giacomelli, G.;
Porcheddu, A.; Salaris, M. Org. Lett. 2003, 5, 2715.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2565–2569

2569
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Letter
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(27) (a) Anilkumar, R.; Chandrasekhar, S.; Sridhar, M. Tetrahedron
Lett. 2000, 41, 5291. (b) Dube, P.; Nathel, N. F. F.; Vetelino, M.;
Couturier, M.; Aboussafy, C. L.; Pichette, S.; Jorgensen, M. L.;
Hardink, M. Org. Lett. 2009, 11, 5622.
(28) Wang, P.; Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132, 17045.
(29) General Procedure for the Preparation of Dipeptide Esters
7a–l*
5.32 (br d, J = 6 Hz, 1 H, NH, Fmoc), 6.46 (br d, J = 6 Hz, 1 H, NH,
amide), 7.06–7.76 (m, 13 H, 5 CH, Ph, 8 CH, Fmoc). 13C NMR (75
MHz, CDCl3): δ = 18.6 (CβAla), 37.9 (CβPhe), 47.2 (CαFmoc),
50.2 (CαAla), 52.5 (Me), 53.3 (CαPhe), 67.2 (CβFmoc), 120.1,
125.1, 127.3, 127.8, 128.6, 128.7, 129.3 (CH, Ar), 135.7 (C, Ar),
141.4 and 143.9 (C, Fmoc), 156.4 (C=O, Fmoc), 171.7 and 171.8
(C=O). HRMS: m/z [M + H]+ calcd for C28H29N2O5: 473.2076;
found: 473.2062.
To a solution of Nα-protected amino hydroxamic acid 5 (1.0
equiv) in DMSO (5 mL), I2 (0.3 equiv), and amino acid ester 6
(1.2 equiv) were added at r.t. and stirred. After completion of
the reaction, as monitored by TLC analysis (5–30 min), the
solvent was removed under reduced pressure, and the crude
residue was diluted with EtOAc (20 mL). The organic layer was
washed with 10% Na2CO3 (15 mL), 10% citric acid (15 mL), H2O
(10 mL) and brine solution (10 mL), dried over anhydrous
Na2SO4, and evaporated in vacuo. The crude residue was puri-
fied through silica gel column chromatography (100–200
mesh), EtOAc–hexane (40:60) as eluent to obtain dipeptide
esters.
(31) Methyl
2-[2-({[(4aH-Fluoren-9-yl)methoxy]carbonyl}-
amino)methylbutanamido]propanoate [Fmoc-Val-Ala-OMe
(7b)]
1H NMR (300 MHz, CDCl3): δ = 0.95 [d, J = 5 Hz, 6 H,
CHCH(CH3)2], 1.26 (d, J = 5 Hz, 3 H, CHCH3), 2.04–2.10 [m, 1 H,
CHCH(CH3)2], 3.69 (s, 3 H, OCH3), 4.18–4.25 (m, 2 H, δCH,
NHCHCH, Val, αCH, NHCHCH3, Ala), 4.35 (t, J = 3 Hz, 1 H, CH2CH,
Fmoc), 4.42 (d, J = 5 Hz, 2 H, CH2CH, Fmoc), 5.28 (br d, J = 6 Hz,
1 H, NH, Fmoc), 6.42 (br d, J = 5 Hz, 1 H, NH, amide), 7.26–7.77
(m, 8 H, 8 CH, Fmoc). 13C NMR (75 MHz, CDCl3): δ = 17.5 (CβAla),
19.1 (CγVal), 31.1 (CβVal), 47.3 (CαFmoc), 50.1 (CαAla), 52.3
(Me), 59.0 (CαVal), 67.2 (CβFmoc), 120.1, 125.1, 127.2, 127.8
(CH, Fmoc), 141.4 and 143.8 (C, Fmoc), 156.4 (C=O, Fmoc), 172.2
and 172.3 (C=O). HRMS: m/z [M + H]+ calcd for C24H29N2O5:
425.2076; found: 425.2082.
(30) Methyl
2-[2-({[(4aH-Fluoren-9-yl)methoxy]carbonyl}-
amino)propanamido]-3-phenylpropanoate [Fmoc-Ala-Phe-
OMe, 7a].
1H NMR (300 MHz, CDCl3): δ = 1.33 (d, J = 3 Hz, 3H , CH3), 3.12–
3.17 (m, 2 H, CH2Ph), 3.70 (s, 3 H, OCH3), 4.05–4.09 (m, 1 H, δCH,
NHCHCH3, Ala), 4.17–4.20 (m, 1 H, αCH,-NHCHCH2, Phe), 4.31 (t,
J = 9 Hz, 1 H, CH2CH, Fmoc), 4.34 (d, J = 9 Hz, 2 H, CH2CH, Fmoc),
(32) Optical purity of products 7b,c was determined by HPLC. See
Supporting Information for the HPLC chromatograms.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2565–2569