Efficient preparation of aminoxyacyl amides, aminoxy hybrid peptides, and α-aminoxy peptides

Article abstract of DOI:10.1021/jo901612j

(Chemical Equation Presented) N-(Pg-α-aminoxy acids) 1a-g are converted to N-(Pg-α-aminoxyacyl)benzotriazoles 2a-g, which react under mild conditions with amines, α-amino acids/α-dipeptides, and α-aminoxy acids to give aminoxyacyl amides 3a-g, (3e+3e′), and (3g+3g′), aminoxy hybrid peptides 4a-h, (4a+4a′), 6a-d, 9a-e, (9a+9a′), and (9b+9b′), and α-aminoxy peptides 10a,b in good yields without racemization. 2009 American Chemical Society.

Full text of DOI:10.1021/jo901612j

pubs.acs.org/joc
Efficient Preparation of Aminoxyacyl Amides, Aminoxy Hybrid Peptides,
and r-Aminoxy Peptides
Alan R. Katritzky,*,‡ Ilker Avan,‡,§ and Srinivasa R. Tala‡
‡Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville,
Florida 32611-7200, and Department of Chemistry, Anadolu University, 26470, Eskis-ehir, Turkey
§
katritzky@chem.ufl.edu
Received July 24, 2009
N-(Pg-R-aminoxy acids) 1a-g are converted to N-(Pg-R-aminoxyacyl)benzotriazoles 2a-g, which
react under mild conditions with amines, R-amino acids/R-dipeptides, and R-aminoxy acids to give
aminoxyacyl amides 3a-g, (3e+3e0), and (3g+3g0), aminoxy hybrid peptides 4a-h, (4a+4a0), 6a-d,
9a-e, (9a+9a0), and (9b+9b0), and R-aminoxy peptides 10a,b in good yields without racemization.
Introduction
amide bonds are resistant to enzymatic degradation;
therefore, R-aminoxy acids have been explored as peptido-
mimetics.3b
In peptidomimetic foldamer chemistry, β-peptides have been
applied widely in biomolecular design.1 Unlike R-peptides,
short β-peptides can fold into well-defined secondary struc-
tures, such as helices, sheets, and turns. Since β-peptides have
excellent stability toward proteases,2 they are widely used as
backbone-modified amino acids in drug design. R-Aminoxy
acids are analogues of β-amino acids in which the β-carbon
atom is replaced by an oxygen atom. An R-aminoxy acid is
more rigid than its corresponding β-amino acid,3a and aminoxy
R-Aminoxy peptides have attracted considerable interest
as novel foldamers4 because of their unusual conformations
and interesting bioactivities.5 Aminoxy peptides may feature
strong intramolecular hydrogen bonds between adjacent
residues in peptidomimetic foldamers.6 For example, pep-
tides consisting of R-aminoxy acids can possess eight-mem-
bered-ring intramolecular hydrogen bonds (R N-O turns),7
and peptides consisting of β-aminoxy acids can possess nine-
membered-ring intramolecular hydrogen bonds (β N-O
turns).5e Oligomers of homochiral R- or β-aminoxy acids
can form helical structures consisting of consecutive N-O
turns (1.88 and 1.79 helices, respectively).8 β-Sugar ami-
noxy peptides exhibited rigid ribbon-like secondary struc-
tures composed of 5/7 bifurcated intramolecular hydrogen
bonds.6a Hybrid peptides of an R-aminoxy acid provided
robust 12/10-mixed helices.9
(1) (a) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev. 2001,
101, 3219–3232. (b) Seebach, D.; Matthews, J. L. Chem. Commun. 1997,
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2003, 68, 8853–8858. (d) Vanderesse, R.; Thevenet, L.; Marraud, M.;
Boggetto, N.; Reboud, M.; Corbier, C. J. Peptide Sci. 2003, 9, 282–299. (e)
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8690 J. Org. Chem. 2009, 74, 8690–8694
Published on Web 10/15/2009
DOI: 10.1021/jo901612j
r
2009 American Chemical Society

Katritzky et al.
JOCArticle
Peptides containing R-aminoxy acids are good recep-
tors for anions because of the acidity of their aminoxy
amide protons.10 A compound derived from an R-aminoxy
acid has been used as an effective chemical shift reagent
for measuring the ee of carboxylic acids;11a another compound
derived from an R-aminoxy acid forms chloride channels to
mediate chloride ion transportation across cell membranes.11b
Published methods for the preparation of aminoxy acid
derivatives and aminoxy peptides include (i) combinations of
coupling reagents such as Bop-HOBt-NEM, HBTU-HOBt-
NEM, DIC-HOAt;12 EDCl-HOBt, EDCl-HOAt;6a TBTU/
HOBt/DIEA;13 HOBt, BOP, DIEA;14 iBuOCOCl/NMM;5d
DIC/HOBt;15 (ii) activated esters;16,17 and (iii) R-amino
diazoketone.18 These methods often involve longer reaction
times13 and N-diacylation products16 and give low yields.15
Hence, there is a need for a mild and efficient general method
to prepare aminoxyacyl amides, aminoxy hybrid peptides,
and aminoxy peptides.
Results and Discussion
Preparation of N-Pg(r-aminoxyacyl)benzotriazole 2a-g.
N-Protected (R-aminoxy) acids 1b-g were synthesized from
either corresponding R-bromocarboxylic acids or R-hydro-
xycarboxylic acids and were well characterized by 1H NMR,
13C NMR, and elemental analysis. The complete reaction
procedure and the characterization data of N-protected (R-
aminoxy)acids 1b-g are given in the Supporting Informa-
tion. N-Pg(R-aminoxy) acid 1a was obtained from a com-
mercial source. N-Pg(R-aminoxyacyl)benzotriazoles 2a-g
have been prepared by treatment of N-Pg(R-aminoxy) acids
1a-g with 4 equiv of 1H-benzotriazole and 1 equiv of thionyl
chloride in THF at room temperature in 56-89% yields
(Scheme 1, Table 1). Products 2a-g were characterized by
1H NMR, 13C NMR, and elemental analysis.
SCHEME 1. Preparation of N-Pg(R-aminoxyacyl)benzotriazo-
les 2a-g
N-Acylbenzotriazoles are stable, mostly crystalline com-
pounds and easy to handle. These N-acylbenzotriazoles are
advantageous for N-, O-, C-, and S-acylation,19 especially where
the corresponding acid chlorides are unstable or difficult to
prepare.19l,m N-Fmoc-(R-aminoacyl)benzotriazoles and their
Boc- and Cbz- analogues enabled the preparation of chiral di-,
tri-, and tetrapeptides in good yields from natural amino acids in
solution phase with complete retention of chirality.19b,20 Re-
cently, we have also prepared peptide alcohols in good yields
using N-protected (R-aminoacyl)benzotriazoles and N-protected
(R-dipeptidoyl)benzotriazoles.21 Herein, we describe a new
method for the preparation of aminoxyacyl amides, aminoxy
hybrid peptides, and aminoxy peptides by using N-protected
(R-aminoxyacyl)benzotriazoles 2.
TABLE 1. Preparation of N-Pg(R-aminoxyacyl)benzotriazoles 2a-g
entry
Pg: protecting group
R
2, yielda (%) mp (°C)
1
2
3
4
5
6
7
tert-butoxycarbonyl (Boc)
phthalimide (Phth)
phthalimide (Phth)
benzyloxycarbonyl (Cbz)
Cbz
H
H
2a, 67
2b, 75
2c, 56
2d, 66
2e, 58
2f, 89
2g, 77
114-115
155-157
145-147
86-87
oil
Me
H
Me
CH(CH3)2
Ph
Cbz
Cbz
oil
oil
aIsolated yield.
(10) Yang, D.; Li, X.; Sha, Y.; Wu, Y.-D. Chem.;Eur. J. 2005, 11, 3005–
3009.
(11) (a) Yang, D.; Li, X.; Fan, Y.-F.; Zhang, D.-W. J. Am. Chem. Soc.
2005, 127, 7996–7997. (b) Li, X.; Shen, B.; Yao, X.-Q.; Yang, D. J. Am. Soc.
Chem. 2007, 129, 7264–7265.
(12) Lee, M.; Lee, J.; Baek, B.; Shin, I. Synlett 2003, 325–328.
(13) Thevenet, L.; Vanderesse, R.; Marraud, M.; Didierjean, C.; Aubry,
A. Tetrahedron Lett. 2000, 41, 2361–2364.
(14) Baek, B.; Lee, M.; Kim, K.-Y.; Cho, U.-I.; Boo, D. W.; Shin, I. Org.
Lett. 2003, 5, 971–974.
(15) Shin, I.; Park, K. Org. Lett. 2002, 4, 869–872.
(16) Dulery, V.; Renaudet, O.; Dumy, P. Tetrahedron 2007, 63, 11952–
11958.
(17) Foillard, S.; Rasmussen, M. O.; Razkin, J.; Boturyn, D.; Dumy, P. J.
Org. Chem. 2008, 73, 983–991.
(18) Yang, D.; Zhang, Y.-H.; Li, B.; Zhang, D.-W. J. Org. Chem. 2004,
69, 7577–7581.
(19) (a) Katritzky, A. R.; Angrish, P.; Hur, D.; Suzuki, K. Synthesis 2005,
397–402. (b) Katritzky, A. R.; Angrish, P.; Suzuki, K. Synthesis 2006, 411–
424. (c) Katritzky, A. R.; Suzuki, K.; Singh, S. K.; He, H.-Y. J. Org. Chem.
2003, 68, 5720–5723. (d) Katritzky, A. R.; He, H.-Y.; Suzuki, K. J. Org.
Chem. 2000, 65, 8210–8213. (e) Katritzky, A. R.; Wang, M. Y.; Yang, H. F.;
Zhang, S. M.; Akhmedov, N. G. ARKIVOC 2002, viii, 134–142;. (f)
Katritzky, A. R.; Shestopalov, A. A.; Suzuki, K. ARKIVOC 2005, vii, 36–
55;. (g) Katritzky, A. R.; Tala, S. R.; Singh, S. K. Synthesis 2006, 3231–3237.
(h) Katritzky, A. R.; Chen, Q.-Y.; Tala, S. R. Org. Biomol. Chem. 2008, 6,
2400–2404. (i) Katritzky, A. R.; Singh, A.; Haase, D. N.; Yoshioka, M.
Arkivoc 2009, viii, 47–56;. (j) Katritzky, A. R.; Tala, S. R.; Abo-Dya, N. E.;
Abdel-Samii, Z. K. Synthesis 2009, 1708–1714. (k) Katritzky, A. R.; Tala, S.
R.; Abo-Dya, N. E.; Gyanda, K.; El-Gendy, B.; E-D, M.; Abdel-Samii, Z.
K.; Steel, P. J. J. Org. Chem. 2009, 74, 7165–7167. (l) Katritzky, A. R.;
Belyakov, S. A. Aldrichim. Acta 1998, 31, 35–46. (m) Katritzky, A. R.; Li, J.;
Xie, J. Tetrahedron 1999, 55, 8263–8293. (n) Katritzky, A. R.; Angrish, P.;
Todadze, E. Synlett 2009, 2392–2411.
Preparation of N-Pg(r-aminoxyacyl)amides 3a-g,
(3e+3e0), and (3g+3g0). R-Aminoxyacylamides also exhibit
intramolecular hydrogen bonds between adjacent residues
(R N-O turns) in peptidomimetic foldamers.6b,7a N-Pg(R-
aminoxyacyl) amides 3a-g, (3eþ3e0), and (3gþ3g0) were ob-
tained by reaction between N-Pg(R-aminoxyacyl)benzotri-
azoles 2a,b,d-f and the corresponding amines in THF at
room temperature in the presence of triethylamine in 38-
78% yields (Scheme 2, Table 2). Products 3a-g, (3eþ3e0),
1
and (3gþ3g0) were characterized by H NMR, 13C NMR,
and elemental analysis. Retention of enantiopurity of pro-
duct 3g was confirmed by chiral HPLC using a Whelk-O1
column (with detection at 254 nm, a flow rate of 1.0 mL/min,
and MeOH as the eluting solvent). The diastereomer 3g
showed a single retention-time peak in chiral HPLC at
3.46, while its corresponding diastereomeric mixture
(3gþ3g0) showed two peaks at 3.46 and 5.68.
SCHEME 2. Preparation of N-Pg(R-aminoxyacyl)amides
3a-g, (3eþ3e0), and (3gþ3g0)
(20) (a) Katritzky, A. R.; Kazuyuki, S.; Singh, S. K. Synthesis 2004, 2645–
2652. (b) Katritzky, A. R.; Chen, Q.-Y.; Tala, S. R. Chem. Biol. Drug. Des.
2009, 73, 611–617.
(21) Katritzky, A. R.; Abo-Dya, N. E.; Tala, S. R.; Gyanda, K.; Abdel-
Samii, Z. K. Org. Biomol. Chem. 2009, DOI: 10.1039/b905730g.
Synthesis of r-Aminoxy Hybrid Peptides. R-Aminoxy
hybrid peptides are defined as including at least one
J. Org. Chem. Vol. 74, No. 22, 2009 8691

Katritzky et al.
JOCArticle
TABLE 2. Preparation of N-(Pg)-aminoxy Acid Amides 3a-g, (3eþ3e0), and (3gþ3g0)
entry
2
amine
3, yielda (%)
mp (°C)
1
2
3
4
5
6
7
8
9
Boc-AOGly-Bt, 2a
Boc-AOGly-Bt, 2a
Cbz-AOGly-Bt, 2d
Phth-AOGly-Bt, 2b
Cbz-AOGly-Bt, 2d
Cbz-AOGly-Bt, 2d
Cbz-L-AOAla-Bt, 2e
Cbz-L-AOVal-Bt, 2f
Cbz-L-AOVal-Bt, 2f
isopropylamine
c-hexylamine
c-hexylamine
p-methoxyaniline
L-2-methylbenzylamine
DL-2-methylbenzylamine
p-methoxyaniline
L-2-methylbenzylamine
DL-2-methylbenzylamine
3a, 74
3b, 62
3c,78
3d, 38
67-68
137-139
69-70
210-211
oil
3e, 67
(3eþ3e0), 73
oil
3f, 56
3g, 67
31-32
96-97
oil
(3gþ3g0), 58
aIsolated yield. bAO stands for aminoxy in the nomenclature for aminoxy compounds throughout the paper.
TABLE 3. R-AO-R-hybrid Dipeptides 4a-h and (4aþ4a0)
entry
2
amino acid
product 4, yielda (%)
mp (°C)
1
2
3
4
5
6
7
8
9
Cbz-AOGly-Bt, 2d
Cbz-AOGly-Bt, 2d
Cbz-L-AOAla-Bt, 2e
Cbz-L-AOAla-Bt, 2e
Cbz-L-AOAla-Bt, 2e
Cbz-L-AOVal-Bt, 2f
Cbz-L-AOVal-Bt, 2f
Cbz-AOGly-Bt, 2d
Cbz-L-AOAla-Bt, 2e
L-Phe-OH
DL-Phe-OH
L-Phe-OH
L-Trp-OH
L-Leu-OH
L-Phe-OH
L-Trp-OH
L-Cys-OH
L-Cys-OH
Cbz-AOGly-L-Phe-OH, 4a, 51
Cbz-AOGly-DL-Phe-OH, (4aþ4a0), 56
Cbz-L-AOAla-L-Phe-OH, 4b, 61
Cbz-L-AOAla-L-Trp-OH, 4c, 72
Cbz-L-AOAla-L-Leu-OH, 4d, 78
Cbz-L-AOVal-L-Phe-OH, 4e, 69
Cbz-L-AOVal-L-Trp-OH, 4f, 66
Cbz-AOGly-L-Cys-OH, 4g, 66
Cbz-L-AOVal-L-Cys-OH, 4h, 61
oil
oil
33-34
128-130
oil
126-127
26-27
oil
oil
aIsolated yield.
TABLE 4. Preparation of R-AO-R,R-hybrid Tripeptides 6a-d
entry
2
dipeptide, 5
product 6, yielda (%)
mp (°C)
1
2
3
4
Cbz-AOGly-Bt, 2d
Cbz-AOGly-Bt, 2d
Cbz-L-AOAla-Bt, 2e
Cbz-L-AOVal-Bt, 2f
Gly-L-Phe-OH
Gly-L-Leu-OH
Gly-L-Phe-OH
Gly-L-Phe-OH
Cbz-AOGly-Gly-L-Phe-OH, 6a, 81
Cbz-AOGly-Gly-L-Leu-OH, 6b, 70
Cbz-L-AOAla-Gly-L-Phe-OH, 6c, 50
Cbz-L-AOVal-Gly-L-Phe-OH, 6d, 67
oil
oil
63-64
123-124
aIsolated yield.
R-aminoxy acid residue and at least one natural amino acid
residue. We have prepared R-AO-R-hybrid dipeptides 4a-h
and (4aþ4a0), R-AO-R,R-hybrid tripeptides 6a-d, and R,R-
AO-hybrid dipeptides 9a-d and (9aþ9a0).
dipeptides 5a,b in CH3CN-H2O in the presence of triethy-
lamine in 50-81% yields (Scheme 4, Table 4).
SCHEME 4. Preparation of R-AO-R,R-hybrid Tripeptides
6a-d
Preparation of r-AO-r-hybrid dipeptides 4a-h and
(4aþ4a0). R-AO-R-Hybrid dipeptides 4a-h and (4aþ4a0)
were prepared by treatment of N-(Pg-aminoxyacyl)benzo-
triazoles 2d-f and the corresponding amino acids in CH3-
CN-H2O in the presence of triethylamine at room tempera-
ture in 51-78% yields (Scheme 3, Table 3). Products 4a-h
1
were characterized by H NMR, 13C NMR, and elemental
analysis. Retention of enantiopurity of R-AO-R-hybrid di-
peptides 4a and (4aþ4a0) was supported by chiral HPLC
analysis using a Chirobiotic T column (detection at 254 nm,
flow rate 1.0 mL/min, and MeOH as eluent). R-AO-R-hybrid
dipeptide 4a showed a single retention-time peak in chiral
HPLC analysis at 3.15, while the corresponding enantio-
meric mixture (4aþ4a0) showed two peaks at 2.89 and 3.69.
Preparation of r,r-AO-hybrid Dipeptides 9a-e, (9aþ9a0),
and (9bþ9b0). R,R-AO-hybrid dipeptides 9a-e, (9aþ9a0),
and (9bþ9b0) were obtained by treatment of N-Pg(R-amino-
acyl)benzotriazole 7a-c and the corresponding aminoxy
acids 8a,b (details about preparation of compounds 8a,b
are given in the Supporting Information) in CH3CN-H2O
(3:1) in the presence of triethylamine at room temperature in
44-90% yields (Scheme 5, Table 5). All products 9a-e,
(9aþ9a0), and (9bþ9b0) were characterized by 1H NMR, 13C
NMR, and elemental analysis. The enantiomeric purity of
SCHEME 3. R-AO-R-hybrid Dipeptides 4a-h and (4aþ4a0)
SCHEME 5. Preparation of R,R-AO-hybrid Dipeptides 9a-e,
(9aþ9a0), and (9bþ9b0)
Preparation of r-AO-R,R-hybrid tripeptides 6a-d. R-AO-
R,R-hybrid tripeptides 6a-d were prepared by treatment of
N-Pg(R-aminoxyacyl)benzotriazoles 2d-f with unprotected
8692 J. Org. Chem. Vol. 74, No. 22, 2009

Katritzky et al.
JOCArticle
TABLE 5. Preparation of R,R-AO-hybrid Dipeptides 9a-e, (9aþ9a0), and (9bþb0)
entry
7
8
product 9
yielda (%)
mp (°C)
1
2
3
4
5
6
7
Cbz-L-Ala-Bt, 7a
Cbz-DL-Ala-Bt, (7aþ7a0)
Cbz-DL-Phe-Bt, (7bþ7b0)
Cbz-L-Met-Bt, 7c
Cbz-L-Phe-Bt, 7b
AOGly-OH, 8a
AOGly-OH, 8a
AOGly-OH, 8a
AOGly-OH, 8a
AOGly-OH, 8a
L-AOAla-OH, 8b
L-AOAla-OH, 8b
Cbz-L-Ala-AOGly-OH, 9a
Cbz-DL-Ala-AOGly-OH, (9aþ9a0)
Cbz-DL-Phe-AOGly-OH, (9bþ9b0)
Cbz-L-Met-AOGly-OH, 9c
Cbz-L-Phe-L-AOAla-OH, 9d
Cbz-L-Met-L-AOAla-OH, 9e
61
71
90
72
81
44
73
24-25
24-25
Cbz-L-Phe-Bt, 7b
Cbz-L-Phe-AOGly-OH, 9b
121-122
145-146
87-88
38-39
127-128
Cbz-L-Met-Bt, 7c
aIsolated yield.
TABLE 6. Preparation of R-Aminoxy Dipeptides 10a and 10b
entry
2
8
product 10, yielda (%)
1
2
Cbz-L-AOVal-Bt, 2f
Cbz-L-AOMan-Bt, 2g
AOGly-OH, 8a
L-AOAla-OH, 8b
Cbz-L-AOVal-AOGly-OH, 10a, 58
Cbz-L-AOMan-L-AOAla-OH, 10b, 52
aIsolated yield.
R,R-AO-hybrid dipeptides 9b and (9bþ9b0) was supported by
chiral HPLC analysis using a Chirobiotic T column (detec-
tion at 254 nm, flow rate 0.6 mL/min, and MeOH-H2O (7:3)
as eluent). R,R-AO-hybrid dipeptide 9b showed a single peak
in HPLC analysis at 4.74, while the corresponding enantio-
meric mixture (9bþ9b0) showed two peaks at 4.10 and 5.32.
Preparation of r-Aminoxy Dipeptides 10a,b. R-Aminoxy
dipeptides 10a,b were prepared in 55-58% yields by reaction
of N-(Pg-aminoxyacyl)benzotriazoles 2f,g with the corre-
sponding aminoxy acids 8a,b in CH3CN-H2O (3:1) in the
presence of triethylamine at ambient temperature (Scheme 6,
(ppm, δ units) and spin-spin coupling J (Hz). DMF was dried
and distilled over CaH2, whereas THF was used after distillation
over Na/benzophenone.
General Preparation of N-(Pg-aminoxyacyl)benzotriazole (2).
Thionyl chloride (1.2 mmol) was added to a solution of benzo-
triazole (4.16 mmol) in anhydrous THF (5 mL) at 0 °C, and the
reaction mixture was stirred for 20 min at same temperature.
N-(Pg)-aminoxyacetic acid (1.0 mol) dissolved in anhydrous
THF (3 mL) was added dropwise to the mixture. After being
stirred for 4 h at 0 °C, the reaction mixture was allowed to warm
to room temperature. After 1 h, the white precipitate was filtered
off, and the filtrate was concentrated under reduced pressure.
The residue was diluted with CH2Cl2 (25 mL), and the solution
washed with saturated Na2CO3 solution (3 ꢀ 10 mL) and then
saturated brine solution and finally dried over anhydrous
Na2SO4. The solvent was evaporated under reduced pressure
to afford N-(Pg-aminoxyacyl)benzotriazoles (2).
Table 6). Products 10a,b were characterized by 1H NMR, 13
C
NMR, and elemental analysis.
SCHEME 6. Preparation of R-Aminoxy Dipeptides 10a and 10b
Boc-AOGly-Bt (2a): White microcrystals (67%); mp 115-
116 °C; 1H NMR (CDCl3) δ 1.50 (s, 9H), 5.54 (s, 2H), 7.54 (t,
J = 7.5 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.96 (s, 1H), 8.14 (d,
J = 8.1 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H); 13C NMR (CDCl3) δ
28.3, 74.6, 82.7, 114.1, 120.6, 126.8, 130.9, 131.0, 146.0, 156.4,
168.3. Anal. Calcd for C13H16N4O4: C, 53.42; H, 5.52; N, 19.17.
Found: C, 53.07; H, 5.69; N, 18.59.
General Preparation of N-(Pg)-aminoxy Acid Amides (3).
Amine (1 equiv) and triethylamine (1 molar equiv) in THF
(2 mL) were added to a stirred solution of N-(Pg-aminoxy-
acyl)benzotriazole (2) (1 molar equiv) in THF (4 mL) dropwise
at 0 °C, and the mixture was stirred for 2 h at room temperature.
After evaporation of THF, EtOAc (20 mL) was added to the
solution, which was washed with saturated Na2CO3 solution
(3 ꢀ 10 mL) and brine (10 mL) and dried over anhydrous
Na2SO4. Evaporation of the solvent under reduced pressure
gave the crude amides.
In comparison with literature methods, our method has
the following advantages: (i) utilization of milder reaction
conditions, (ii) shorter reaction times, (iii) better yields, (iv)
use of inexpensive, easily synthesizable N-(Pg-R-aminoxy-
acyl)benzotriazole reagents for peptide coupling, (v) cou-
pling without protecting the carboxylic acid group, (vi) no
N-diacylation products, and (vii) avoids racemization.
Conclusions
tert-Butyl 2-(Isopropylamino)-2-oxoethoxycarbamate (3a)13.
The crude product was recrystallized from diethyl ether-
hexanes to give white microcrystals (74%): mp 67-68 °C;
1H NMR (CDCl3) δ 1.19 (d, J = 6.6 Hz, 6H), 1.49 (s, 9H), 4.00-
4.20 (m, 1H), 4.27 (s, 2H), 7.51 (s, 1H), 8.00 (s, 1H); 13C NMR
(CDCl3) δ 22.5, 28.1, 41.0, 76.1, 83.0, 157.8, 167.8. Anal. Calcd
for C10H20N2O4: C, 51.71; H, 8.68; N, 12.06. Found: C, 52.09;
H, 8.90; N, 12.12.
General Preparation of r-AO-r-hybrid Dipeptides 4 and
R-AO-R,R-hybrid Tripeptides 6. The unprotected amino acids
(1.5 mmol) and triethylamine (2.0 mmol) were dissolved in a
minimum amount of water. Acetonitrile (3 mL) was added, and
the solution was cooled to 0 °C. A solution of N-(Pg-aminooxya-
cyl)benzotriazole (2) (1 mmol) in acetonitrile (4 mL) was added
dropwise over 10 min at 0 °C and the resulting solution stirred
for 4 h at 10 °C. After evaporation of THF, EtOAc (20 mL) was
In conclusion, a mild and an efficient general method for
the preparation of R-aminoxyacylamides, R-aminoxy hybrid
peptides, and R-aminoxy peptides has been developed by
reacting N-(Pg-R-aminoxyacyl)benzotriazoles with amines,
R-amino acids, peptides, and R-aminoxy acids. All of the
R-aminoxy derivatives were obtained under mild reaction
conditions in good yields and with no racemization.
Experimental Section
Melting points are uncorrected. 1H (300 MHz) and 13C
(75 MHz) NMR spectra were recorded on a 300 MHz apparatus
in CDCl3 or DMSO-d6 with TMS as internal standard. The
data are reported as follows: chemical shift in parts per million
J. Org. Chem. Vol. 74, No. 22, 2009 8693

Katritzky et al.
JOCArticle
added, and the mixture was washed with 4 N HCl solution (3 ꢀ
15 mL) and brine (15 mL) and dried over anhydrous Na2SO4.
The solvent was evaporated under reduced pressure to give
crude product 4 or 6.
4.51 (s, 2H), 5.06 (d, J = 12.3 Hz, 1H), 5.13 (d, J = 12 Hz, 1H),
C
NMR (CDCl3) δ 18.3, 48.0, 68.0, 73.3, 128.3, 128.7, 128.8, 135.6,
156.7, 171.2, 171.9. Anal. Calcd for C13H16N2O6: C, 52.70; H,
5.44; N, 9.46. Found: C, 53.08; H, 5.72; N, 9.19.
General Preparation of r-Aminoxy Dipeptides 10. R-Aminoxy
acid hydrochloric acid salts (8) (1.5 mmol) and triethylamine
(3.5 mmol) were dissolved in a minimum amount of water.
Acetonitrile (3 mL) was added, and the solution was cooled
to 0 °C. A solution of N-(Pg-aminoxyoacyl)benzotriazole (2)
(1 mmol) in acetonitrile (3 mL) was added dropwise over 10 min
at 0 °C, and the resulting solution was stirred for 4 h at 10 °C.
After the solvent was evaporated under vacuum, EtOAc (20 mL)
was added, and the mixture was washed with 3 N HCl solution
(3 ꢀ 15 mL) and brine (15 mL) and dried over anhydrous
Na2SO4. The solvent was evaporated under reduced pressure
to give crude product 10.
5.59 (d, J = 8.4 Hz, 1H), 7.26-7.45 (m, 6H), 10.42 (br s 1H); 13
Cbz-AOGly-L-Phe-OH (4a). The residue was purified by
column chromatography [EtOAc-hexanes (from 1:3 to 1:1)]
to give an oil (51%): [R]2D3 = -9.0 (c 1.00, CH3OH); 1H NMR
(CDCl3) δ 3.02 (dd, J = 14.0 Hz, 8.3 Hz, 1H), 3.25 (dd, J = 14.0
Hz, 4.9 Hz, 1H), 4.28 (s, 2H), 4.76-4.89 (m, 1H), 5.11 (s, 2H),
7.14-7.30 (m, 5H), 7.33 (s, 5H), 7.72 (br s, 1H), 8.08 (s, 1H), 8.23
(br s, 1H); 13C NMR (CDCl3) δ 37.3, 53.6, 68.5, 75.8, 127.2,
128.6, 128.8, 128.9, 129.4, 135.1, 136.2, 158.5, 169.8, 174.5.
Anal. Calcd for C19H20N2O6.H2O: C, 58.46; H, 5.16; N, 7.18.
Found: C, 58.76; H, 5.42; N, 7.38.
Cbz-AOGly-Gly-L-Phe-OH (6a). The residue was recrystal-
lized from diethyl ether-hexanes to give white hydroscopic
microcrystals, (81%): mp 29-31 °C; [R]2D3 = þ7.1 (c 1.00, CH3-
OH); 1H NMR (CDCl3) δ 2.92 (br s, 1H), 3.04 (br s, 1H), 3.76 (br
s, 1H), 3.83 (br s, 1H), 4.22 (br s, 2H), 4.67 (br s, 1H), 5.00 (br s,
2H), 6.92-7.36 (m, 12H), 8.04 (s, 1H), 8.73 (s, 1H); 13C NMR
(CDCl3) δ 37.4, 42.8, 53.8, 68.4, 75.9, 127.3, 128.3, 128.6, 128.8,
128.9, 129.6, 135.3, 136.1, 158.6, 169.8, 170.5, 173.8. Anal. Calcd
for C21H23N3O7: C, 58.74; H, 5.40; N, 9.79. Found: C, 58.57; H,
5.28; N, 9.60.
General Preparation of r,r-AO-hybrid Dipeptides 9. R-Ami-
noxy acid hydrochloric acid salts 8 (1.5 mmol) and triethylamine
(3.5 mmol) were dissolved in minimum amount of water. Acet-
onitrile (3 mL) was added, and the solution was cooled to 0 °C.
A solution of N-(Pg-aminoacyl)benzotriazole (7) (1 mmol) in
acetonitrile (3 mL) was added dropwise over 10 min at 0 °C, and
the resulting solutionwas stirredfor 4 h at 10 °C. The reactionwas
monitored by TLC [EtOAc-hexanes (1:1)]. The solvent was
evaporated under vacuum. The mixture was diluted with EtOAc
(20 mL), washed with 4 N HCl solution (3 ꢀ 15 mL) and brine
(15 mL), and dried over anhydrous Na2SO4. The solvent was
evaporated under reduced pressure to give crude product 9.
Cbz-L-Ala-AOGly-OH (9a). The residue was purified by
column chromatography [EtOAc-hexanes (from 1:3 to 1:1)]
to obtain a sticky oil (61%): [R]2D3 = -27.8 (c 1.00, CH3OH); 1H
NMR (CDCl3) δ 1.39 (d, J = 6.9 Hz, 3H), 4.31-4.51 (m, 1H),
Cbz-L-AOVal-AOGly-OH (10a). The residue was an oily
mixture of 10a (80%) and 1f (20%): [R]2D3 = -56.0 (c 1.00,
CH3OH); (data from the mixture) 1H NMR (CDCl3) δ 0.91 (d,
J = 6.9 Hz, 3H), 1.04 (d, J = 6.9 Hz, 3H), 2.18-2.30 (m, 1H),
4.19 (d, J = 4.2 Hz, 1H), 4.43 (d, J = 17.4 Hz, 1H), 4.54 (d, J =
17.4 Hz, 1H), 5.17 (d, J = 11.7 Hz, 1H), 5.24 (d, J = 12.0 Hz,
1H), 7.32-7.42 (m, 5H), 8.17 (s, 1H), 11.64 (br s, 1H); 13C
NMR (CDCl3) δ 16.7, 18.9, 30.9, 69.0, 75.1, 91.2, 128.6,
128.7, 128.8, 128.9, 129.0, 134.7, 159.5, 171.1, 172.0; HRMS
[M þ Na]þ found 363.1175, theoretical for C15H20N2O7 Naþ
3
363.1163.
Acknowledgment. We thank Dr. C. D. Hall for helpful
discussions.
Supporting Information Available: Materials and methods;
general procedure for preparation of N-protected aminoxy acids
1b-g and their characterization data; characterization data of
2b-2g, 3b-g, (3gþ3g0), (4aþ4a0)-4h, 6b-d, (9aþ9a0)-9e, and
10b, 1H NMR, 13C NMR spectra of compounds and chiral
HPLC chromatograms. This material is available free of charge
via the Internet at http://pubs.acs.org.
8694 J. Org. Chem. Vol. 74, No. 22, 2009