Synthesis and characterization of chiral N-O turns induced by α-aminoxy acids

Article abstract of DOI:10.1021/jo010376a

Chiral α-aminoxy acids of various side chains were synthesized with high optical purity starting from chiral α-amino acids. The conformations of diamides 13a-e, 15, and 16 were probed by using NMR, FT-IR, and CD spectroscopic methods as well as X-ray crystallography. The right-handed turns with eight-membered-ring intramolecular hydrogen bonds between adjacent residues (called the N-O turns) were found to be preferred for D-aminoxy acid residues, and they were independent of the side chains. The rigid chiral N-O turns should have great potential in molecular design.

Full text of DOI:10.1021/jo010376a

J . Org. Chem. 2001, 66, 7303-7312
7303
Syn th esis a n d Ch a r a cter iza tion of Ch ir a l N-O Tu r n s In d u ced by
r-Am in oxy Acid s
Dan Yang,*,† Bing Li,† Fei-Fu Ng,† Yi-Long Yan,† J in Qu,† and Yun-Dong Wu‡
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, and Department of
Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong
yangdan@hku.hk
Received April 13, 2001
Chiral R-aminoxy acids of various side chains were synthesized with high optical purity starting
from chiral R-amino acids. The conformations of diamides 13a -e, 15, and 16 were probed by using
NMR, FT-IR, and CD spectroscopic methods as well as X-ray crystallography. The right-handed
turns with eight-membered-ring intramolecular hydrogen bonds between adjacent residues (called
the N-O turns) were found to be preferred for D-aminoxy acid residues, and they were independent
of the side chains. The rigid chiral N-O turns should have great potential in molecular design.
In tr od u ction
In biological systems, turn structures play critical roles
in the recognition of receptors, enzymes, and antibodies.1
As â-turns are one of the three major classes of peptide
and protein secondary structures, significant effort has
been made to design and synthesize â-turn mimetics for
elucidation of molecular recognition and drug discovery.2-11
In contrast, γ-turns, which involve a seven-membered-
ring hydrogen bond, are much less common in proteins
and peptides.12-15
F igu r e 1. HF/6-31G**-optimized structures of compound 1
(only the four lowest-energy conformations are shown).
and acceptor properties of adjacent amide groups. We
previously reported that R-aminoxyacetic acid induced a
strong eight-membered-ring hydrogen bond between
adjacent amino acid residues (the N-O turn),17 which
can be considered as an extended γ-turn.18,19
For peptides of R-amino acids, the propensity of turn
formation depends on the nature, position, and relative
configuration of amino acid residues. Therefore, it is
Due to the repulsion of lone-pair electrons of nitrogen
and oxygen atoms, R-aminoxy acids should have rigid
conformations16 and modulate the hydrogen bond donor
† The University of Hong Kong.
‡ The Hong Kong University of Science and Technology.
(1) (a) Creighton, T. E. Proteins: Structures and Molecular Prin-
ciples, 2nd ed.; Freeman: New York, 1993. (b) Rose, G. D.; Gierash,
L. m.; Smith, J . A. Adv. Protein Chem. 1985, 37, 1-109.
(2) Kahn, M. Synlett 1993, 821-826.
(12) Khaled, M. A.; Urry, D. W.; Okamoto, K. Biochem. Biophys.
Res. Commun. 1976, 72, 162-169.
(13) Pavone, V.; Lombardi, A.; D’Auria, G.; Saviano, M.; Nastri, F.;
Paolillo, L.; Di Blasio, B.; Pedone, C. Biopolymers 1992, 32, 173-183.
(14) Burgess, K.; Ho, K.-K.; Pettitt, B. M. J . Am. Chem. Soc. 1994,
116, 799-800.
(3) Bach, A. C., II; Espina, J . R.; J ackson, S. A.; Stouten, P. F. W.;
Duke, J . L.; Mousa, S. A.; DeGrado, W. F. J . Am. Chem. Soc. 1996,
118, 293-294.
(4) Eguchi, M.; Lee, M. S.; Nakanishi, H.; Stasiak, M.; Lovell, S.;
Kahn, M. J . Am. Chem. Soc. 1999, 121, 12204-12205.
(5) Gardner, R. R.; Liang, G.-B.; Gellman, S. H. J . Am. Chem. Soc.
1999, 121, 1806-1816.
(15) J ime´nez, A. I.; Cativiela, C.; Marraud, M. Tetrahedron Lett.
2000, 41, 5353-5356.
(16) (a) Riddell, F. G. Tetrahedron 1981, 37, 849. (b) Raban, M.; Kost,
D. Tetrahedron 1984, 40, 3345. (c) For an insightful discussion of the
conformational preference of the N-O bond in relation to calicheami-
cin-DNA interactions, see: Walker, S.; Gange, D.; Gupta, V.; Kahne,
D. J . Am. Chem. Soc. 1994, 116, 3197-3206.
(6) Gallo, E. A.; Gellman, S. H. J . Am. Chem. Soc. 1993, 115, 9774-
9788.
(7) Virgilio, A. A.; Bray, A. A.; Zhang, W.; Trinh, L.; Snyder, M.;
Morrissey, M. M.; Ellman, J . A. Tetrahedron 1997, 53, 6635-6644.
(8) Souers, A. J .; Virgilio, A. A.; Rosenquist, Å.; Fenuik, W.; Ellman,
J . A. J . Am. Chem. Soc. 1999, 121, 1817-1825.
(9) Feng, Y.-B.; Wang, Z.-C.; J in, S.; Burgess, K. J . Am. Chem. Soc.
1998, 120, 10768-10769.
(10) Feng, Y.-B.; Pattarawarapan, M.; Wang, Z.-C.; Burgess, K. J .
Org. Chem. 1999, 64, 9175-9177.
(11) Mu¨ller, G.; Hessler, G.; Decornez, H. Y. Angew. Chem., Int. Ed.
2000, 39, 894-896.
(17) Yang, D.; Ng, F.-F.; Li, Z.-J .; Wu, Y.-D.; Chan, K. W.-K.; Wang,
D.-P. J . Am. Chem. Soc. 1996, 118, 9794-9795.
(18) A similar extended γ-turn reported by Marraud involves an
eight-membered-ring hydrogen bond between an amide carbonyl group
and the hydroxyl group of N-hydroxy amides: Dupont, V.; Lecoq, A.;
Mangeot, J .-P.; Aubry, A.; Boussard, G.; Marraud, M. J . Am. Chem.
Soc. 1993, 115, 8898-8906.
(19) The´venet, L.; Vanderesse, R.; Marraud, M.; Didierjean, C.;
Aubry, A. Tetrahedron Lett. 2000, 41, 2361-2364.
10.1021/jo010376a CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/11/2001

7304 J . Org. Chem., Vol. 66, No. 22, 2001
Yang et al.
Sch em e 1a
a
(i) NaNO2, KBr, H2SO4 at 0-5 °C; (ii) CH3OH, SOCl2, rt; (iii) CbzNHOH, NaH, DMF at 0-5 °C.
Sch em e 2a
interesting to probe whether or not the eight-membered-
ring hydrogen-bonded N-O turns are still favored when
side chains are introduced to R-aminoxyacetic acid.
According to the ab initio molecular orbital calculations,19
the four lowest-energy conformers (1A-D) of L-R-ami-
noxypropionic acid diamide 1 were found to contain eight-
membered-ring hydrogen bonds (Figure 1). The NOCRCO
angles were negative for 1A and 1B but positive for 1C
and 1D. Thus, the hydrogen bonding pattern of 1A or
1B allowed a left-handed turn, while that of 1C or 1D
resulted in a right-handed turn. The ab initio calculation
results suggested that chiral R-aminoxy acids of L-
configuration should prefer a left-handed chiral N-O
turn (1A or 1B). Furthermore, the R-methyl group was
anti to the N-O bond in 1A but gauche in 1B, which
made 1A the most stable conformation. In this paper, we
report our experimental work on the synthesis and
characterization of chiral N-O turns induced by R-ami-
noxy acids.21
a
(i) NaNO2, H2SO4, H2O, 80-95%; (ii) AcCl, reflux, 95%; (iii)
DCC, t-BuOH, DMAP, CH2Cl2, 75-90%; (iv) K2CO3, MeOH, H2O,
85-98%; (v) N-hydroxyphthalimide, DEAD, PPh3, THF, 69-83%.
Resu lts a n d Discu ssion
R-aminoxy esters 6a -c were found to be in the range of
92-94% as determined by HPLC analysis.
The Cbz protecting group of R-aminoxy acids was
difficult to remove under mild conditions. For example,
the hydrogenation method cannot be used because the
free R-aminoxy acids obtained can be further hydroge-
nated to give R-hydroxy acids.23
We developed a general method for the synthesis of
chiral R-aminoxy acids as shown in Scheme 2. The
diazotization of L-R-amino acids gave R-hydroxy acids
7a -e with retention of configuration at the R-carbon due
to the neighboring-group participation.24 Acetylation,
DCC coupling, and deacetylation yielded 10a -e with
retention of configuration. The Mitsunobu reaction25 of
the tert-butyl esters 10a -e afforded the protected R-ami-
noxy acids 11a -e with inversion of configuration at the
R-carbon. The overall yields for syntheses of R-aminoxy
Syn th esis of Ch ir a l r-Am in oxy Acid s. Testa22 re-
ported a method for synthesizing chiral R-aminoxy acids,
but the optical purities of the R-aminoxy acids were not
reported in the literature.23 We used this method to
synthesize several D-R-aminoxy acids from natural L-R-
amino acids (2a -c) with overall yields of R-aminoxy
esters 6a -c in the range of 36-55% (Scheme 1). While
the conversion of L-R-amino acids to R-bromo acids
proceeded with high retention at the R-carbon, nucleo-
philic displacement of R-bromo acids with CbzNHOH
followed an SN2 mechanism with inversion of configura-
tion to afford D-R-aminoxy acids. The optical purities of
(20) Wu, Y.-D.; Wang, D.-P.; Chan, K. W. K.; Yang, D. J . Am. Chem.
Soc. 1999, 121, 11189-11196.
(21) For preliminary results, see: Yang, D.; Qu, J .; Li, B.; Ng, F.-
F.; Wang, X.-C.; Cheung, K.-K.; Wang, D.-P.; Wu, Y.-D. J . Am. Chem.
Soc. 1999, 121, 589-590.
(22) Testa, E.; Nicolaus, B. J . R.; Mariani, L.; Pagani, G. Helv. Chim.
Acta 1963, 46, 766.
(24) Brewster, P.; Hiron, F.; Hugers, E. D.; Ingold, C. K,; Rao, P. A.
D. S. Nature 1950, 166, 179-180.
(25) Mitsunobu, O. Synthesis 1981, 1-28.
(23) Briggs, M. T.; Morley, J . S. J . Chem. Soc., Perkin Trans. 1 1979,
2138-2143.

Chiral N-O Turns Induced by R-Aminoxy Acids
J . Org. Chem., Vol. 66, No. 22, 2001 7305
Sch em e 3a
Ta ble 1. UV a n d CD Da ta of Com p ou n d s 13a , 15, a n d 16
in MeOH
13a
15
16
UV 246 nm (ꢀ ) 10 466) 250 nm (ꢀ ) 6433) 240 nm (ꢀ ) 6067)
261 nm (∆ꢀ ) +10.1) 251 nm (∆ꢀ ) +2.6) no strong Cotton
CD
effect above
230 nm was found
235 nm (∆ꢀ ) -4.5) 224 nm (∆ꢀ ) -1.6)
DMSO-d6 titration studies of 13a -e, 15, and 16 (2 mM
in CDCl3) (Figure 3) showed that the chemical shift of
Ha at the N-terminus had a dramatic downfield shift,
whereas Hb at the C-terminus showed little change upon
addition of DMSO-d6.
a
1
(i) NH2NH2‚H2O, MeOH; (ii) 4-chlorobenzoic acid, EDCI,
These H NMR studies suggest that the N-terminus
HOBt, CH2Cl2, 61-95%; (iii) TFA, CH2Cl2; (iv) 4-chloroaniline,
EDCI, HOBt, CH2Cl2, 65-84%.
protons (Ha’s) of diamides 13a -e, 15, and 16 are solvent
accessible, whereas C-terminus ones (Hb’s) are intra-
molecularly hydrogen bonded. That is, the N-O turn is
maintained when a side chain is introduced to R-ami-
noxyacetic acids.
acids were in the range of 36-56%, and no purification
was needed for most of the steps. The optical purities of
chiral R-aminoxy acids 11a , 11c, and 11d were found to
be 95-99% by HPLC analysis, which indicates that very
little or no racemization occurred in the synthesis of
chiral R-aminoxy acids. Furthermore, the phthaloyl group
can be cleaved with hydrazine hydrate, whereas the tert-
butyl group can be easily removed with trifluoroacetic
acid. The orthogonal conditions for deprotection of ph-
thaloyl and tert-butyl groups make R-aminoxy acids
11a -e ideal building blocks for peptide synthesis.26
Design a n d Syn th esis of r-Am in oxy Dia m id es for
Cir cu la r Dich r oism Exciton Cou p lin g Stu d y. The
circular dichroism (CD) exciton coupling method27 was
used to determine the handedness of the chiral N-O
turns. Compounds 13a -e were designed with two p-
chlorophenyl chromophores of similar π f π* absorptions
at both termini. They were expected to exhibit a strong
Cotton effect due to the exciton coupling. Compounds
13a -e were synthesized starting from bisprotected D-R-
aminoxy acids 11a -e (Scheme 3). Deprotection of the
phthaloyl group using hydrazine hydrate in methanol
gave the free aminoxy group, which was then coupled
with 4-chlorobenzoic acid using standard peptide coupling
methods to provide compounds 12a -e. Treatment of
compounds 12a -e with trifluoroacetic acid in CH2Cl2
followed by coupling with 4-chloroaniline using 1-[3-
F T-IR Stu d ies of Ch ir a l D-r-Am in oxy Dia m id es
13a , 15, a n d 16.29 FT-IR spectra of the N-H stretch
region of compounds 13a , 15, and 16 at a 1 mM
concentration in CH2Cl2 are shown in Figure 4. For
compound 13a , the peak at 3345 cm-1 corresponded to
the non-hydrogen-bonded amide N-H at the N-terminus.
The peaks in the region of 3300-3100 cm-1 were assigned
to the stretching bands of the hydrogen-bonded amide
N-H at the C-terminus, and the multiplicity was prob-
ably due to the vibrational coupling of the C-terminal
amide N-H with its adjacent aryl group. For compound
15, the peak at 3379 cm-1 corresponded to the non-
hydrogen-bonded N-terminal amide N-H, whereas ab-
sorptions in the region of 3300-3100 cm-1 were assigned
to an intramolecular hydrogen-bonded amide N-H at the
C-terminus, the pattern of which was complicated again
by the vibrational coupling of the C-terminal amide N-H
with its adjacent aryl group. The spectrum of compound
16 showed a broad peak at 3341 cm-1, assigned as the
stretching band of the hydrogen-bonded N-isobutyl amide
N-H overlapped with that of the non-hydrogen-bonded
N-oxy amide N-H. The small peak at 3433 cm-1 cor-
responded to the non-hydrogen-bonded isobutyl amide
N-H.
(dimethylamino)propyl]-3-ethylcarbodiimide
iodide (EDCI)/1-hydroxybenzotriazole (HOBt) afforded
the D-R-aminoxy diamides 13a -e.
methyl-
The FT-IR studies revealed that the R-aminoxy dia-
mides 13a , 15, and 16 adopted predominantly the intra-
molecular eight-membered-ring hydrogen-bonded con-
formations.
CD Stu d ies for Dia m id es 13a -e, 15, a n d 16.27 The
UV and CD data of compounds 13a , 15, and 16 in MeOH
are shown in Table 1. Due to the presence of two
chromophores, the UV spectrum of compound 13a ex-
hibited the charge-transfer transition band at λmax ) 246
nm, and its molar extinction coefficient (ꢀ ) 10 466) was
almost twice of that for compound 15 or 16.
Diamides 15 and 16 containing only one p-chlorophenyl
chromophore were also designed and synthesized (Scheme
4). In contrast to 13a -e, these monochromophoric com-
pounds should give a weak Cotton effect as no exciton
coupling would occur.
1H NMR Stu d ies of Ch ir a l D-r-Am in oxy Dia m id es
13a -e, 15, a n d 16.6,21,28 1H NMR dilution studies of
diamides 13a -e, 15, and 16 (Figure 2) showed that the
chemical shifts of NHb’s changed very little upon dilution
with CD2Cl2, whereas the chemical shifts of NHa’s ap-
parently moved upfield.
The CD spectrum of compound 15 revealed a relatively
weak positive Cotton effect (∆ꢀ ) +2.6) in the region of
the electronic charge-transfer band at λmax ) 251 nm,
while no strong Cotton effect above 230 nm was found
for compound 16 (Figure 5a). In contrast, the CD spec-
trum of compound 13a showed two very strong Cotton
effects of opposite signs: the first Cotton effect at the
longer wavelength (261 nm) had a value of ∆ꢀ ) +10.1,
(26) While the manuscript was in preparation, Shin et al. reported
the synthesis of chiral phthaloyl D-R-aminoxy acid monomers with
benzyl ester as the C-terminal protecting group. See: Shin, I.; Lee,
M.; Lee, J .; J ung, M.; Lee, W.; Yoon, J . J . Org. Chem. 2000, 65, 7667-
7675.
(27) Harada, N.; Nakanishi, K. In Circular Dichroic Spectroscopy:
Exciton Coupling in Organic Stereochemistry; University Science
Books: Mill Valley, CA, 1983.
(28) Gellman, S. H.; Dado, G. P.; Liang, G. B.; Adams, B. R. J . Am.
Chem. Soc. 1991, 113, 1164-1173.
(29) For a review of IR studies of intramolecular hydrogen bonds in
small molecules, see: Aaron, H. S. Top. Stereochem. 1980, 11, 1.

7306 J . Org. Chem., Vol. 66, No. 22, 2001
Yang et al.
Sch em e 4a
a
(i) TFA, CH2Cl2; (ii) 4-chloroaniline, EDCI, HOBt, CH2Cl2, 80%; (iii) NH2NH2‚H2O, MeOH; (iv) pivaloyl chloride, NaHCO3, CH2Cl2,
H2O, 93%; (v) isobutylamine, EDCI, HOBt, CH2Cl2, 78%.
F igu r e 2. 1H NMR chemical shifts of amide protons of 13a -e, 15, and 16 in CD2Cl2 at 25 °C as a function of the logarithm of
concentration.
while the second Cotton effect at the shorter wavelength
(235 nm) had a value of ∆ꢀ ) -4.5. Thus, a positive
exciton coupling was observed for compound 13a .
For compound 13a , the chirality between the long axes
of the two chromophores is approximated by that between
the N-O bond and the CR-CO bond due to the favorable

Chiral N-O Turns Induced by R-Aminoxy Acids
J . Org. Chem., Vol. 66, No. 22, 2001 7307
F igu r e 3. 1H NMR chemical shifts of amide protons of 13a -e, 15, and 16 (2 mM in 0.5 mL of CDCl3) at 25 °C when increasing
amounts of DMSO-d6 were added.
The solvent effects on the conformations of D-R-ami-
noxy acid diamides were examined by CD spectroscopy.
The CD spectra of compound 13a at 0.75 mM in cyclo-
hexane, dichloromethane, dioxane, acetonitrile, and metha-
nol are shown in Figure 6a. Similar curves were observed
in different solvents, but the Cotton effects (originating
from dipole-dipole interactions between the two chro-
mophores) showed greatly enhanced amplitudes going
from polar solvents to nonpolar solvents: ∆ꢀ261 ) +10.1
and ∆ꢀ235 ) -4.5 in MeOH, whereas ∆ꢀ261 ) +16 and
∆ꢀ239 ) -13.6 in cyclohexane. This is because the long
axis transitions of the p-chlorophenyl chromophores
coupled much more efficiently in nonpolar solvents.
F igu r e 4. N-H stretch region of FT-IR spectra for compounds
13a , 15, and 16 at 1 mM in CH2Cl2 at room temperature.
planar s-trans conformation of amide bonds (Figure 5b).
In other words, the absolute chirality of the N-O and
CR-CO bonds, which is the dihedral angle NOCRCO, can
be determined by the signs of Cotton effects. The positive
exciton coupling observed for compound 13a indicated a
positive dihedral angle NOCRCO and thus a right-
handed turn conformation. This result correlates well
with the ab initio calculation,20 which predicted the
mirror images of 1A and 1B as the most stable conforma-
tions.
The effect of side chains on the chiral N-O turn
structure was also probed by CD methods. The CD
spectra of diamides 13a -e (Figure 6b) showed strong
positive exciton coupling with maximum peaks around
260 nm and minimum peaks around 235 nm, indicating
that all five diamides of D-configurations adopted the
right-handed N-O turn structures though the side chains
were different. Therefore, we conclude that the conforma-
tion of the chiral N-O turn is determined by the chirality

7308 J . Org. Chem., Vol. 66, No. 22, 2001
Yang et al.
F igu r e 5. (a) Circular dichroism (CD) spectra of compounds 13a (s), 15 (- - -), and 16 (‚‚‚) taken at 25 °C at 0.75 mM concentration
in MeOH. (b) Diagram showing a conformation of the right-handed screwness with a positive dihedral angle NOCRCO.
F igu r e 6. (a) Diamide 13a at 0.75 mM in the following
solvents: cyclohexane (- - s), CH2Cl2 (- ‚‚ -), CH3CN (s),
dioxane (- s -), CH3OH (- - -). (b) CD data of diamides 13a -e
at 0.75 mM in CH2Cl2: 13a (s ‚‚ s), 13b (- - s), 13c (- s
-), 13d (s), 13e (- - -).
F igu r e 8. ORTEP view of compound 13a .
in the solid state as revealed by X-ray structural analysis.
Single crystals of compound 13a were grown in dichlo-
romethane solution, and its X-ray structure is shown in
Figure 8.
As noted below, good agreements were found between
the X-ray structure of compound 13a and the calculated
structure 1A.20
F igu r e 7. 2D ROESY spectrum of compound 13a (5 mM in
An intramolecular eight-membered-ring hydrogen bond
CDCl3 at 10 °C).
N(1)H(1)‚‚‚O(3)dC(13) was identified in the X-ray struc-
ture by the short H(1)‚‚‚O(3) distance (2.12 Å), correlating
of the R-aminoxy acid residue but not by the nature of
quite well with the calculation result (2.10 Å). Statistical
the side chains.
surveys of crystallography data suggest that the optimum
2D ROESY30 Stu d y of Com p ou n d 13a . Two-dimen-
hydrogen bond distance is approximately 1.9 Å for H‚‚‚
sional rotating-frame Overhauser effect spectroscopy (2D
O.31
ROESY) of compound 13a (5 mM in CDCl3) at 10 °C
showed a strong nuclear Overhauser effect (NOE) be-
tween NHa and CRH but a weak NOE between NHb and
CRH, indicating that compound 13a adopted a folded
The p-chlorophenyl group and the adjacent amide
group were found to be coplanar. Besides, the amide
bonds were in the s-trans conformation.
The dihedral angle N(2)O(1)C(1)C(6) was +78.5° in
the X-ray structure, comparable to the calculation result
of +78.4°, which suggests that the diamide 13a adopted
a right-handed turn conformation.
structure (Figure 7). According to the calculation re-
sults,20 in conformation 1A, the distance between NHa
and CRH was 2.7 Å, whereas that between CRH and NHb
was 3.4 Å. But for conformation 1B, the distance between
The dihedral angle N(2)O(1)C(1)C(2) was -163.5° in
the X-ray structure, showing that the isobutyl group was
almost anti to the N-O bond. Both the ab initio calcula-
tion and 2D ROESY study indicated that such a structure
was the most stable conformation.
NHa and CRH was similar to that between NHb and CRH.
The observed NOE pattern indicated that compound 13a
should adopt the mirror image conformation of 1A in
solution.
Hyd r ogen Bon d in g Geom etr y Stu d ied by X-r a y
Cr ysta llogr a p h y. D-R-Aminoxy acid diamides adopted
a right-handed N-O turn structure in solution as deter-
mined by 1D and 2D NMR, FT-IR, and CD spectroscopic
methods. Such a novel turn structure was also observed
(30) Bothner-by, A. A.; Stephens, R. L.; Lee, J .; Warren, C. D.;
J eanloz, R. W. J . Am. Chem. Soc. 1984, 106, 811-813.
(31) Baker, E. N.; Hubbard, R. E. Prog. Biophys. Mol. Biol. 1984,
44, 97.

Chiral N-O Turns Induced by R-Aminoxy Acids
J . Org. Chem., Vol. 66, No. 22, 2001 7309
Ta ble 2. Up field Ch em ica l Sh ift Va lu es (p p m ) of Am id e
P r oton s in Com p ou n d s 17-19 a t Room Tem p er a tu r e (1
m M in CD2Cl2)
ent with that formed from R-aminoxyacetic acids, dia-
mides 17-19 with identical N- and C-terminal groups
were prepared. 1H NMR dilution studies of diamides 17-
19 in CD2Cl2 revealed similar upfield chemical shift
values (δ 8.06-8.36) of the amide proton Hb in all three
compounds (Table 2). In addition, the FT-IR spectra of
the N-H stretch region of compounds 17-19 showed
similar absorption patterns (Figure 9). Therefore, we
concluded that N-O turns, with or without an R-sub-
stituent, have comparable stabilities in non-hydrogen-
bonding solvents. This is mainly due to the conforma-
tional constraint of the N-O bond.
diamide
δH (ppm)
δH (ppm)
a
b
17
18
19
8.51
7.94
8.24
8.36
8.32
8.06
Con clu sion
In this paper, chiral R-aminoxy acids of various side
chains were synthesized in high optical purity starting
from chiral R-amino acids. A novel N-O turn with an
intramolecular eight-membered-ring hydrogen bond was
formed in peptides containing chiral R-aminoxy acids.
The hydrogen bonding geometry of the chiral N-O turn
was established by NMR, FT-IR, and CD methods as well
as by X-ray crystallography and is consistent with ab
initio calculation results. Right-handed N-O turns were
preferred for D-aminoxy acid residues and were indepen-
dent of side chains. The rigid chiral N-O turns should
have great potential as foldamers in molecular design.
Exp er im en ta l Section
Ch a r a cter iza tion Da ta for D-Meth yl 2-N-Ben zyloxy-
ca r bon yl-a m in oxy-3-m eth yl Bu ta n oa te (6a ): colorless oil;
[R]20D ) +98.5° (c 1.00, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ
7.72 (s, 1H), 7.35 (m, 5H), 5.17 (d, J ) 3.4 Hz, 2H), 4.25 (d, J
) 4.8 Hz, 1H), 3.76 (s, 3H), 2.09-2.20 (m, 1H), 1.03 (d, J )
6.9 Hz, 3H), 0.98 (d, J ) 7.0 Hz, 3H); 13C NMR (75.47 MHz,
CDCl3) δ 171.6, 156.9, 135.5, 128.6, 128.5, 128.3, 88.7, 67.6,
51.9, 30.4, 18.6, 17.4; IR (CH2Cl2) 3380 (N-H), 1746 (CdO)
cm-1; FABMS m/z 282 (M+ + 1).
Ch a r a cter iza tion Da ta for D-Meth yl 2-N-Ben zyloxy-
ca r bon yl-a m in oxy-3-m eth yl P en ta n oa te (6b): colorless oil;
[R]20D ) +90.2° (c 1.00, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ
7.78 (s, 1H), 7.35 (m, 5H), 5.17 (d, J ) 3.4 Hz, 2H), 4.46 (dd,
J ) 3.8, 9.7 Hz, 1H), 3.75 (s, 3H), 1.86-1.97 (m, 1H), 1.65-
1.75 (m, 1H), 1.48-1.55 (m, 1H), 0.95 (d, J ) 5.7 Hz, 3H), 0.93
(d, J ) 6.5 Hz, 3H); 13C NMR (75.47 MHz, CDCl3) δ 172.6,
156.9, 135.4, 128.6, 128.5, 128.4, 82.6, 67.7, 52.1, 39.8, 24.5,
23.1, 21.5; IR (CH2Cl2) 3383 (N-H), 1747 (CdO) cm-1; LRMS
(EI, 20 eV) m/z 295 (M+); HRMS (EI, 20 eV) calcd for C15H21
-
NO5 (M+) 295.1240, found 295.1241.
Ch a r a cter iza tion Da ta for D-Meth yl 2-N-Ben zyloxy-
ca r bon yl-a m in oxy-3-p h en yl P r op a n oa te (6c): white solid;
1
mp 74-75 °C; [R]20 ) +49.0° (c 1.00, CH2Cl2); H NMR (300
D
MHz, CDCl3) δ 7.78 (s, 1H), 7.20-7.39 (m, 10H), 5.12 (d, J )
1.9 Hz, 2H), 4.68 (dd, J ) 5.3, 7.0 Hz, 1H), 3.70 (s, 3H), 3.12
(dd, J ) 4.0, 7.0 Hz, 2H); 13C NMR (75.47 MHz, CDCl3) δ 171.3,
156.9, 135.7, 135.4, 129.3, 128.6, 128.5, 128.4, 128.3, 127.0,
84.4, 67.6, 52.1, 37.1; IR (CH2Cl2) 3379 (N-H), 1751 (CdO)
cm-1; LRMS (EI, 20 eV) m/z 329 (M+); HRMS (EI, 20 eV) calcd
for C18H19NO5 (M+) 329.1263, found 329.1274.
L-2-Hyd r oxy-3-p h en ylp r op ion ic Acid (7c). L-Phenylala-
nine (5 g, 0.03 mol) was dissolved in dilute hydrochloric acid
(130 mL, 0.5 N) at 0 °C. Sodium nitrite (6.2 g, 0.09 mol) was
added. The mixture was allowed to stir at 0 °C for 6 h. The
solution was transferred into a separating funnel and extracted
with diethyl ether. The combined organic layer was dried over
anhydrous sodium sulfate, concentrated in vacuo, and then
azeotroped with toluene twice to yield a yellow syrup. After
removal of residual toluene under high vacuum, the residue
was washed with hexane and filtered to give a white solid (2.93
F igu r e 9. N-H stretch region of FT-IR spectra for compounds
17-19 (1 mM in CH2Cl2 at room temperature).
Com p a r ison of th e Sta bility of N-O Tu r n s w ith
or w ith ou t a n r-Su bstitu en t. To compare the relative
stability of the chiral N-O turns carrying an R-substitu-

7310 J . Org. Chem., Vol. 66, No. 22, 2001
Yang et al.
g, 58%): mp 126-127 °C (lit.32 124.5 °C); 1H NMR (270 MHz,
CD3OD) δ 7.25 (m, 5H), 4.33 (dd, J ) 4.4, 8.0 Hz, 1H), 3.10
lytical TLC (silica gel 60), 20% EtOAc in n-hexane, Rf ) 0.20;
69% yield; white solid; mp 97-98 °C; [R]20 ) +58.3° (c 1.80,
D
(dd, J ) 4.4, 13.8 Hz, 1H), 2.91 (dd, J ) 8.0, 13.8 Hz, 1H); 13
C
CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 7.85-7.77 (m, 4H), 4.83
NMR (75 MHz, CDCl3) δ 178.0, 135.8, 129.5, 129.3, 128.7,
128.5, 127.2, 71.0, 40.2.
(q, J ) 6.7 Hz, 1H), 1.61 (d, J ) 6.7 Hz, 3H), 1.47 (s, 9H); 13
C
NMR (75.47 MHz, CDCl3) δ 168.76, 163.22, 134.49, 128.78,
123.52, 82.43, 81.68, 27.77, 16.39; IR (CH2Cl2) 1794 (CdO),
1739 (CdO) cm-1; LRMS (EI, 20 eV) m/z 291 (M+, 3), 111 (49),
L-ter t-Bu tyl 2-Acetyloxy-3-p h en ylp r op a n oa te (9c). To
compound 7c (2 g, 12.1 mmol) was added acetyl chloride (10
mL) at 0 °C. The reaction mixture was then refluxed at 60 °C
for 4 h. Excess acetyl chloride was removed under vacuum.
Diethyl ether was added, and the solution was washed with
water. The organic layer was dried and evaporated under
vacuum to give compound 8c (2.43 g) as a crude oil. The
product was used in the next step without further purification.
Compound 8c and tert-butyl alcohol (1.97 g, 26.6 mmol) were
dissolved in CH2Cl2 (30 mL), and DMAP (486 mg, 4.0 mmol)
was added. Then, DCC (3.29 g, 16.0 mmol) in CH2Cl2 (10 mL)
was added at 0 °C. The reaction mixture was stirred at room
temperature (rt) for 12 h. Then, the urea was filtered and the
organic layer was washed with water. The organic layer was
dried and evaporated under reduced pressure. The crude
residue was purified by flash column chromatography (15%
EtOAc in n-hexane) to give compound 9c as a yellow oil (2.53
g, 81%): 1H NMR (300 MHz, CDCl3) δ 7.32-7.20 (m, 5H), 5.09
(dd, J ) 5.2, 8.2 Hz, 1H), 3.09 (m, 2H), 2.05 (s, 3H), 1.39 (s,
9H); 13C NMR (75.47 MHz, CDCl3) δ 170.27, 168.69, 136.18,
129.38, 128.34, 126.88, 82.13, 73.37, 37.31, 27.84, 20.59.
L-ter t-Bu tyl 2-Hyd r oxy-3-p h en ylp r op a n oa te (10c). To
a solution of potassium carbonate (5.04 g, 36.5 mmol) in
methanol (14 mL) and water (20 mL) was added compound
9c (3.21 g, 12.2 mmol). The resulting solution was stirred
vigorously at rt for 12 h. Methanol was removed under
vacuum, and the resulting aqueous solution was extracted with
CH2Cl2 twice. The organic layer was then dried over anhydrous
sodium sulfate and concentrated under vacuum to provide
compound 10c as a yellow oil (2.40 g, 89%): 1H NMR (300
MHz, CDCl3) δ 7.31-7.19 (m, 5H), 4.31 (m, 1H), 3.08 (dd, J )
4.8, 13.9 Hz, 1H), 2.93 (dd, J ) 7.1, 13.6 Hz, 2H), 1.43 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 173.8, 137.1, 129.6, 128.6, 127.0,
82.8, 71.7, 40.9, 28.3; LRMS (EI, 20 eV) m/z 222 (M+); HRMS
(EI, 20 eV) calcd for C13H18O3 (M+) 222.1256, found 222.1246.
97 (70), 89 (54), 77 (100); HRMS (EI, 20 eV) calcd for C15H17
-
NO5 (M+) 291.1107, found 291.1112.
D-ter t-Bu tyl 2-P h th alim idoxy-3-m eth ylbu tan oate (11d):
prepared following the same procedure for compound 11c;
analytical TLC (silica gel 60), 20% EtOAc in n-hexane, Rf )
0.23; 75% yield; white solid; mp 79-80 °C; [R]20 ) +64.3° (c
D
1.10, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 7.85-7.75 (m, 4H),
4.34 (d, J ) 7.4 Hz, 1H), 2.31-2.28 (m, 1H), 1.49 (s, 9H), 1.23
(d, J ) 6.9 Hz, 3H), 1.08 (d, J ) 6.9 Hz, 3H); 13C NMR (67.94
MHz, CDCl3) δ 168.41, 163.13, 134.55, 128.84, 123.50, 91.43,
82.29, 30.35, 27.89, 18.39, 18.07; IR (CH2Cl2) 1793 (CdO), 1739
(CdO) cm-1; LRMS (EI, 20 eV) m/z 319 (M+, 3), 111 (41), 77
(100); FABMS m/z 320 (M+ + 1); HRMS (EI, 20 eV) calcd for
C
17H23NO5 (M+) 319.1420, found 319.1420.
D-ter t-Bu tyl 2-P h th alim idoxy-3-m eth ylpen tan oate (11e):
prepared following the same procedure for compound 11c;
analytical TLC (silica gel 60), 20% EtOAc in n-hexane, Rf )
0.38; 83% yield; white solid; mp 85-87 °C; [R]20 ) +43.5° (c
D
1.05, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.84-7.75 (m, 4H),
4.53 (d, J ) 6.1 Hz, 1H), 2.08-2.01 (m, 1H), 1.72-1.65 (m,
1H), 1.49 (s, 9H), 1.40-1.27 (m, 1H), 1.18 (d, J ) 6.8 Hz, 3H),
1.01 (t, J ) 7.3 Hz, 3H); 13C NMR (75.47 MHz, CDCl3) δ 168.43,
163.01, 134.36, 128.72, 123.31, 89.21, 82.09, 36.83, 27.76,
25.01, 14.34, 11.19; IR (CH2Cl2) 1793 (CdO), 1739 (CdO) cm-1
;
FABMS m/z 334 (M+ + 1); HRMS (EI, 20 eV) calcd for C18H23
-
NO5 (M+) 333.1576, found 333.1555.
D-ter t-Bu t yl 2-p -Ch lor op h en ylca r b on yl-a m in oxy-4-
m eth ylp en ta n oa te (12a ). To a solution of 11a (1 g, 3.00
mmol) in anhydrous methanol (10 mL) was added hydrazine
hydrate (0.62 mL, 9 mmol), and the resulting mixture was
stirred at rt for 1 h. The mixture was concentrated under
vacuum, and 3% sodium carbonate solution (10 mL) was
added. After the mixture was extracted with ether, the
combined organic layer was dried over anhydrous sodium
sulfate and concentrated to provide 533 mg of oil. Then,
4-chlorobenzoic acid (469 mg, 3 mmol) was added together with
CH2Cl2 (10 mL). To this mixture were added HOBt (608 mg,
4.50 mmol) and EDCI (891 mg, 3 mmol). The reaction mixture
was stirred overnight. The organic layer was washed with
saturated sodium hydrogen carbonate and dilute hydrochloric
acid solution. It was then dried and evaporated, and the
residue was then purified by flash column chromatography
(10% EtOAc in n-hexane) to provide compound 12a as a white
D-ter t-Bu tyl 2-P h th alim idoxy-3-ph en ylpr opan oate (11c).
To a solution of compound 10c (2.57 g, 11.6 mmol), N-
hydroxyphthalimide (1.89 g, 11.6 mmol), and triphenylphos-
phine (3.04 g, 11.6 mmol) in anhydrous THF (30 mL) at 0 °C
under nitrogen was added diethylazodicarboxylate (2 mL, 12.7
mmol) via a syringe. The mixture was stirred overnight, and
the solvent was removed in vacuo. The residue was taken up
with CH2Cl2 and water. The organic layer was dried over
anhydrous sodium sulfate and evaporated off under vacuum.
The resulting residue was purified by flash column chroma-
tography (10% EtOAc in n-hexane) to provide compound 11c
as a white solid (3.8 g, 89%): mp 68-70 °C; analytical TLC
solid (780 mg, 76%): mp 105-107 °C; [R]20 ) +51.4° (c 1.50,
D
EtOH); 1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 7.65 (d, J )
8.6 Hz, 2H), 7.41 (d, J ) 8.6 Hz, 2H), 4.52 (dd, J ) 4.1, 9.2 Hz,
1H), 2.03 (m, 1H), 1.80 (m, 2H), 1.50 (s, 9H), 1.05 (d, J ) 6.6
Hz, 3H), 0.99 (d, J ) 6.7 Hz, 3H); 13C NMR (67.94 MHz, CDCl3)
δ 171.88, 164.81, 138.41, 130.29, 129.02, 128.50, 127.43, 82.56,
82.33, 39.87, 28.08, 24.69, 23.13, 21.76; IR (CH2Cl2) 3393 (N-
H) cm-1; MS (APCI) m/z 341.9 (M+); HRMS (EI, 20 eV) calcd
for C17H24NO4Cl (M+) 341.1394, found 341.1386.
(silica gel 60), 20% EtOAc in n-hexane, Rf ) 0.34; [R]20
)
D
1
+26.4° (c 1.00, CH2Cl2); H NMR (300 MHz, CDCl3) δ 7.71-
7.83 (m, 4H), 7.23-7.36 (m, 5H), 4.93 (t, J ) 7.1 Hz, 1H), 3.31
(m, 2H), 1.35 (s, 9H); 13C NMR (75.47 MHz, CDCl3) δ 168.2,
163.5, 135.5, 134.9, 129.9, 129.2, 128.8, 127.4, 124.0, 86.6, 83.1,
37.5, 28.1; MS (APCI) m/z 367 (M+).
D-ter t-Bu tyl 2-P h th alim idoxy-4-m eth ylpen tan oate (11a):
prepared following the same procedure for compound 11c;
analytical TLC (silica gel 60), 20% EtOAc in n-hexane, Rf )
D-ter t-Bu tyl 2-p-Ch lor op h en ylca r bon yl-a m in oxy-p r o-
p a n oa t e (12b ): prepared following the same procedure for
compound 12a ; 76% yield; white solid; mp 69-70 °C; [R]20
)
D
0.30; 70% yield; white solid; mp 76-78 °C; [R]20 ) +77.0° (c
D
1
+68.6° (c 1.00, EtOH); H NMR (300 MHz, CDCl3) δ 9.62 (s,
1H), 7.68 (dd, J ) 1.9, 7.7 Hz, 2H), 7.40 (dd, J ) 1.9, 7.7 Hz,
2H), 4.56 (q, J ) 7.0 Hz, 1H), 1.50 (d, J ) 7.0 Hz, 3H), 1.49 (s,
9H); 13C NMR (75.47 MHz, CDCl3) δ 171.97, 165.07, 138.44,
130.25, 129.02, 128.66, 82.70, 79.67, 28.09, 16.35; IR (CH2Cl2)
1733 (CdO), 1690 (CdO) cm-1; LRMS (EI, 20 eV) m/z 299 (M+,
3), 243 (42), 141 (31), 139 (100); FABMS m/z 300 (M+ + 1);
HRMS (EI, 20 eV) calcd for C14H18NClO4 (M+) 299.0924, found
299.0938.
1.00, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 7.72-7.78 (m, 4H),
4.74 (dd, J ) 5.1, 9.0 Hz, 1H), 1.98 (m, 2H), 1.66 (m, 1H), 1.45
(s, 9H), 1.06 (d, J ) 6.5 Hz, 3H), 1.00 (d, J ) 6.5 Hz, 1H); 13
C
NMR (75.47 MHz, CDCl3) δ 169.2, 163.2, 134.5, 128.9, 123.6,
84.8, 82.4, 39.9, 27.9, 24.5, 22.9, 22.0; MS (APCI) m/z 333.9
(M+ + 1); HRMS (EI, 20 eV) calcd for C18H23NO5 (M+)
333.1576, found 333.1573.
D-ter t-Bu tyl 2-P h th a lim id oxy-p r op a n oa te (11b): pre-
pared following the same procedure for compound 11c; ana-
D-ter t-Bu t yl 2-p -Ch lor op h en ylca r b on yl-a m in oxy-3-
p h en ylp r op a n oa te (12c): prepared following the same pro-
cedure for compound 12a ; 67% yield; white solid; mp 95-96
°C; [R]20D ) +29.7° (c 1.02, EtOH); 1H NMR (300 MHz, CDCl3)
(32) Weast, R. C. Handbook of Chemistry and Physics, 67th ed.; CRC
Press: Boca Raton, FL, 1986-1987.

Chiral N-O Turns Induced by R-Aminoxy Acids
J . Org. Chem., Vol. 66, No. 22, 2001 7311
δ 10.22 (br, 1H), 7.66 (d, J ) 8.4 Hz, 2H), 7.32 (d, J ) 8.5 Hz,
2H), 7.26-7.16 (m, 5H), 4.80 (t, J ) 6.2 Hz, 1H), 3.18 (dd, J )
6.4, 14.4 Hz, 1H), 3.09 (dd, J ) 6.2, 14.4 Hz, 1H), 1.32 (s, 9H);
13C NMR (75.47 MHz, CDCl3) δ 170.80, 165.31, 138.10, 135.35,
130.18, 129.55, 128.74, 128.24, 126.88, 83.69, 82.69, 37.19,
27.85; IR (CH2Cl2) 1733 (CdO), 1693 (CdO) cm-1; LRMS (EI,
20 eV) m/z 375 (M+, 2), 319 (14), 171 (11), 149 (100); FABMS
m/z 376 (M+ + 1); HRMS (EI, 20 eV) calcd for C20H22NClO4
(M+) 375.1237, found 375.1258.
D-ter t-Bu t yl 2-p -Ch lor op h en ylca r b on yl-a m in oxy-3-
m eth ylbu ta n oa te (12d ): prepared following the same pro-
cedure for compound 12a ; 95% yield; white solid; mp 99-101
°C; [R]20D ) +55.4° (c 1.02, EtOH); 1H NMR (270 MHz, CDCl3)
δ 10.12 (s, 1H), 7.71 (d, J ) 8.5 Hz, 2H), 7.36 (d, J ) 8.5 Hz,
2H), 4.34 (d, J ) 4.6 Hz, 1H), 2.18-2.11 (m, 1H), 1.48 (s, 9H),
1.06 (d, J ) 6.8 Hz, 3H), 0.97 (d, J ) 6.8 Hz, 3H); 13C NMR
(67.92 MHz, CDCl3) δ 171.20, 165.21, 138.08, 130.51, 128.75,
88.00, 82.42, 30.53, 28.07, 18.38, 17.45; IR (CH2Cl2) 1730 (Cd
O), 1690 (CdO) cm-1; LRMS (EI, 20 eV) m/z 327 (M+, 1), 271
(29), 155 (11), 141 (30), 139 (100); FABMS m/z 328 (M+ + 1);
HRMS (EI, 20 eV) calcd for C16H22NClO4 (M+) 327.1237, found
327.1241.
D-p-Ch lor oph en yl 2-p-Ch lor oph en ylcar bon yl-am in oxy-
3-p h en ylp r op a n oa m id e (13c): prepared following the same
procedure for compound 13b; analytical TLC (silica gel 60),
20% EtOAc in n-hexane, Rf ) 0.15; 65% yield; white solid; mp
56-57 °C; [R]20 ) +150.1° (c 1.00, CH2Cl2); 1H NMR (300
D
MHz, CDCl3) δ 10.56 (s, 1H), 8.82 (s, 1H), 7.67 (d, J ) 8.9 Hz,
2H), 7.50 (d, J ) 8.6 Hz, 2H), 7.38-7.26 (m, 4H), 4.55 (dd, J
) 3.0, 10.5 Hz, 1H), 3.45 (dd, J ) 3.0, 14.6 Hz, 1H), 3.05 (dd,
J ) 10.5, 14.6 Hz, 1H); 13C NMR (67.94 MHz, CDCl3) δ 168.06,
167.45, 139.41, 137.17, 136.37, 129.47, 129.31, 129.22, 128.93,
128.83, 128.46, 128.43, 127.14, 121.14, 89.45, 38.06; IR (CH2-
Cl2) 3339 (br, N-H), 3302 (br, N-H), 3272 (br, N-H), 1686
(CdO) cm-1; LRMS (EI, 20 eV) m/z 428 (M+, 28), 260 (31), 258
(100); FABMS m/z 429 (M+ + 1); HRMS (EI, 20 eV) calcd for
C22H18N2Cl2O3 (M+) 428.0694, found 428.0694.
D-p-Ch lor oph en yl 2-p-Ch lor oph en ylcar bon yl-am in oxy-
3-m eth ylbu ta n oa m id e (13d ): prepared following the same
procedure for compound 13b; analytical TLC (silica gel 60),
20% EtOAc in n-hexane, Rf ) 0.18; 82% yield; white solid; mp
1
186-187 °C; [R]20 ) +170.0° (c 1.04, CH2Cl2); H NMR (300
D
MHz, CDCl3) δ 10.39 (s, 1H), 9.13 (s, 1H), 7.69 (d, J ) 8.8 Hz,
2H), 7.67 (d, J ) 8.5 Hz, 2H), 7.41 (d, J ) 8.5 Hz, 2H), 7.28 (d,
J ) 9.1 Hz, 2H), 4.24 (d, J ) 4.7 Hz, 1H), 2.47-2.37 (m, 1H),
1.16 (d, J ) 6.9 Hz, 3H); 13C NMR (75.47 MHz, CDCl3) δ
168.80, 167.96, 139.35, 136.39, 129.23, 128.89, 128.81, 128.67,
121.23, 92.32, 31.06, 19.41, 16.50; IR (CH2Cl2) 3376 (br, N-H),
3345 (br, N-H), 3301 (br, N-H), 3270 (br, N-H), 1687 (Cd
O) cm-1; LRMS (EI, 20 eV) m/z 380 (M+, 37), 139 (100); FABMS
m/z 381 (M+ + 1); HRMS (EI, 20 eV) calcd for C18H18N2Cl2O3
(M+) 380.0694, found 380.0698.
D-ter t-Bu t yl 2-p -Ch lor op h en ylca r b on yl-a m in oxy-3-
m eth ylp en ta n oa te (12e): prepared following the same pro-
cedure for compound 12a ; 61% yield; white solid; mp 87-88
°C; [R]20D ) +48.8° (c 1.10, EtOH); 1H NMR (300 MHz, CDCl3)
δ 9.46 (s, 1H), 7.64 (d, J ) 8.5 Hz, 2H), 7.39 (d, J ) 8.5 Hz,
2H), 4.45 (d, J ) 3.4 Hz, 1H), 2.04-1.88 (m, 1H), 1.80-1.58
(m, 1H), 1.50 (s, 9H), 1.47-1.34 (m, 1H), 1.01 (t, J ) 7.5 Hz,
3H), 0.96 (d, J ) 7.0 Hz, 3H); 13C NMR (75.47 MHz, CDCl3) δ
171.19, 164.67, 138.33, 130.38, 129.00, 128.49, 86.19, 82.49,
D-p-Ch lor oph en yl 2-p-Ch lor oph en ylcar bon yl-am in oxy-
3-m eth ylp en ta n oa m id e (13e): prepared following the same
procedure for compound 13b; analytical TLC (silica gel 60),
20% EtOAc in n-hexane, Rf ) 0.35; 66% yield; white solid; mp
40-42 °C; [R]20D ) +53.4° (c 1.02, CH2Cl2); 1H NMR (300 MHz,
CDCl3) δ 10.55 (s, 1H), 9.85 (s, 1H), 7.68 (d, J ) 6.6 Hz, 2H),
7.65 (d, J ) 6.6 Hz, 2H), 7.35 (d, J ) 8.5 Hz, 2H), 7.26 (d, J )
8.8 Hz, 2H), 4.35 (d, J ) 3.0 Hz, 1H), 2.13-1.98 (m, 1H), 1.62-
1.52 (m, 1H), 1.47-1.33 (m, 1H), 0.97-0.90 (m, 6H); 13C NMR
(75.47 MHz, CDCl3) δ 169.52, 167.93, 139.26, 136.20, 129.47,
129.14, 128.92, 128.68, 121.36, 90.62, 37.76, 26.42, 13.52,
11.89; IR (CH2Cl2) 3445 (br, N-H), 3410 (br, N-H), 3370 (br,
N-H), 3345 (br, N-H), 1727 (CdO), 1687 (CdO) cm-1; LRMS
(EI, 20 eV) m/z 394 (M+, 28), 224 (26), 154 (35), 139 (100);
FABMS m/z 395 (M+ + 1); HRMS (EI, 20 eV) calcd for
37.27, 28.12, 25.81; IR (CH2Cl2) 1730 (CdO), 1691 (CdO) cm-1
;
LRMS (EI, 20 eV) m/z 341 (M+, 3), 285 (20), 182 (28), 139 (100);
FABMS m/z 342 (M+ + 1); HRMS (EI, 20 eV) calcd for C17H24
-
NO4Cl (M+) 341.1394, found 341.1404.
D-p-Ch lor oph en yl 2-p-Ch lor oph en ylcar bon yl-am in oxy-
p r op a n oa m id e (13b). A solution of compound 12b (589 mg,
1.73 mmol) in dichloromethane (5 mL) in an ice bath was
treated with trifluoroacetic acid (5 mL). After being stirred at
room temperature for 1 h, the reaction mixture was concen-
trated under vacuum and azeotroped with toluene. Then,
4-chloroaniline (220 mg, 1.73 mmol) was added together with
dichloromethane (10 mL). To this mixture were added HOBt
(351 mg, 2.60 mmol) and EDCI (668 mg, 2.25 mmol). The
reaction mixture was stirred overnight. The organic layer was
washed with a solution of saturated sodium hydrogen carbon-
ate and dilute hydrochloric acid. It was then dried over
anhydrous sodium sulfate, evaporated under vacuum, and
purified by flash column chromatography (20% EtOAc in
n-hexane) to provide compound 13b (512 mg, 84%) as a white
crystalline solid: mp 84-86 °C; analytical TLC (silica gel 60),
C
19H20N2Cl2O3 (M+) 394.0851, found 394.0854.
D-p-Ch lor oph en yl 2-P h th alim idoxy-4-m eth ylpen tan oa-
m id e (14). A solution of 11a (1.5 g, 4.5 mmol) in dichlo-
romethane (5 mL) in an ice bath was treated with trifluoro-
acetic acid (5 mL). After being stirred at room temperature
for 1 h, the reaction mixture was concentrated under vacuum
and azeotroped with toluene. Then, 4-chloroaniline (574 mg,
4.5 mmol) was added together with dichloromethane (10 mL).
To this mixture were added HOBt (790 mg, 5.85 mmol) and
EDCI (1.35 g, 4.55 mmol). The reaction mixture was stirred
overnight. The organic layer was washed with a solution of
saturated sodium hydrogen carbonate and dilute hydrochloric
acid. It was then dried over anhydrous sodium sulfate,
evaporated under vacuum, and purified by flash column
chromatography (20% EtOAc in n-hexane) to provide com-
pound 14 as a white solid (1.29 g, 74%): mp 118-120 °C;
analytical TLC (silica gel 60), 30% EtOAc in n-hexane, Rf )
20% EtOAc in n-hexane, Rf ) 0.14; [R]20 ) +116.4° (c 1.10,
D
CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 10.51 (s, 1H), 10.22 (s,
1H), 7.71 (dd, J ) 8.6, 1.8 Hz, 2H), 7.63 (dd, J ) 2.0, 8.8 Hz,
2H), 7.36 (dd, J ) 2.0, 8.6 Hz, 2H), 7.26 (d, J ) 8.8 Hz, 2H),
4.52 (q, J ) 7.0 Hz, 1H), 1.56 (d, J ) 7.0 Hz, 3H); 13C NMR
(75.47 MHz, CDCl3) δ 170.14, 167.61, 139.34, 136.14, 129.58,
129.17, 128.97, 128.69, 128.64, 121.32, 83.83, 17.38; IR (CH2-
Cl2) 1690 (CdO) cm-1; LRMS (EI, 20 eV) m/z 352 (M+, 26),
141 (32), 139 (100); FABMS m/z 353 (M+ + 1); HRMS (EI, 20
eV) calcd for C16H14N2Cl2O3 (M+) 352.0381, found 352.0377.
0.32; [R]20 ) +174.6° (c 1.30, EtOH); 1H NMR (300 MHz,
D-p-Ch lor oph en yl 2-p-Ch lor oph en ylcar bon yl-am in oxy-
4-m eth ylp en ta n oa m id e (13a ): prepared following the same
procedure for compound 13b; 53% yield; white solid; mp 92-
D
CDCl3) δ 9.51 (s, 1H), 7.78 (m, 4H), 7.76 (d, J ) 8.9 Hz, 2H),
7.26 (d, J ) 8.9 Hz, 2H), 4.85 (dd, J ) 3.8, 9.0 Hz, 1H), 2.18
(m, 1H), 2.84 (m, 2H), 1.12 (d, J ) 6.6 Hz, 3H), 1.01 (d, J )
6.7 Hz, 3H); 13C NMR (75.47 MHz, CDCl3) δ 168.96, 164.40,
136.23, 135.29, 129.55, 129.08, 128.72, 124.17, 121.23, 87.12,
41.93, 24.94, 23.39, 21.84; IR (CH2Cl2) 3353 (N-H), 1792 (Cd
O), 1736 (CdO), 1686 (CdO) cm-1; LRMS (EI, 20 eV) m/z 386
(M+, 3), 153 (55), 136 (53), 77 (100); HRMS (EI, 20 eV) calcd
for C20H19N2O4Cl (M+) 386.1033, found 386.1031.
95 °C; [R]20 ) +119.6° (c 2.70, EtOH); 1H NMR (300 MHz,
D
CDCl3) δ 10.28 (s, 1H), 8.88 (s, 1H), 7.70 (d, J ) 7.7 Hz, 4H),
7.44 (d, J ) 7.4 Hz, 2H), 7.28 (d, J ) 9.6 Hz, 2H), 4.46 (t, J )
6.6 Hz, 1H), 1.93 (m, 1H), 1.84 (t, J ) 6.8 Hz, 2H), 1.03 (d, J
) 7.9 Hz, 3H), 1.01 (d, J ) 6.5 Hz, 3H); 13C NMR (67.94 MHz,
CDCl3) δ 169.53, 168.17, 139.55, 136.48, 129.34, 129.16, 128.90,
128.61, 121.09, 86.76, 40.83, 24.95, 23.24, 21.77; IR (CH2Cl2)
3339, 3313, 3303, 3193 cm-1; MS (APCI) 395.2 (M+ + 1);
HRMS (EI, 20 eV) calcd for C19H20N2O3Cl2 (M+) 394.0851,
found 394.0851.
D-p -Ch lor op h en yl 2-ter t-Bu t ylca r b on yl-a m in oxy-4-
m eth ylp en ta n oa m id e (15). To a solution of 14 (472 mg, 1.22
mmol) in anhydrous methanol (5 mL) was added hydrazine

7312 J . Org. Chem., Vol. 66, No. 22, 2001
Yang et al.
1
hydrate (0.25 mL, 3.66 mmol), and the resulting mixture was
stirred at rt for 1 h. The mixture was concentrated under
vacuum, and 3% sodium carbonate solution was added. The
mixture was extracted with ether. The combined organic layer
was dried over anhydrous sodium sulfate and concentrated to
provide a white solid 14a (225 mg). Compound 14a was used
in the next step without further purification. To a solution of
compound 14a in dichloromethane (10 mL) were added pyri-
dine (0.133 mL, 1.59 mmol) and trimethylacetyl chloride (0.104
mL, 1.22 mmol) at 0 °C. The mixture was then allowed to stir
at rt for 5 h. The mixture was washed with dilute hydrochloric
acid. The organic layer was dried over anhydrous sodium
sulfate and concentrated. The residue was purified by flash
column chromatography to provide compound 15 (280 mg,
Com p ou n d 17: white crystalline solid; mp 62-65 °C; H
NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 8.50 (br s, 1H), 4.34 (s,
2H), 3.12 (t, J ) 6.4 Hz, 2H), 1.85-1.80 (m, 1H), 1.21 (s, 9H),
0.93 (d, J ) 6.7 Hz, 6H); 13C NMR (75.47 MHz, CDCl3) δ
178.48, 168.80, 75.89, 46.61, 37.98, 28.37, 27.07, 20.14; IR
(CH2Cl2) 3383 (br), 3303 (br), 2966, 1687, 1679 cm-1; LRMS
(CI) m/z 231 (M+ + 1); HRMS (CI) calcd for C11H22N2O3 (M+)
230.1630, found 230.1630.
Com p ou n d 18: white crystalline solid; mp 97-100 °C;
[R]20 +64.4° (c 1.09, CH2Cl2); H NMR (300 MHz, CDCl3) δ
1
D
8.31 (br s, 1H), 7.96 (s, 1H), 7.38-7.25 (m, 5H), 4.33 (dd, J )
10.4, 3.0 Hz, 1H), 3.39 (dd, J ) 14.5, 3.0 Hz, 1H), 3.18-3.00
(m, 2H), 2.94 (dd, J ) 10.4, 14.5 Hz, 1H), 1.84-1.75 (m, 1H),
1.05 (s, 9H), 0.92 (d, J ) 3.9 Hz, 3H), 0.89 (d, J ) 3.9 Hz, 3H);
13C NMR (75.47 MHz, CDCl3) δ 177.65, 169.79, 137.53, 129.46,
128.61, 126.85, 88.35, 46.66, 38.10, 37.84, 28.37, 26.89, 20.13;
IR (CH2Cl2) 3416 (br), 3376 (br), 3312 (br), 2969, 1684, 1611
cm-1; LRMS (EI, 20 eV) m/z 320 (M+, 1), 248 (2), 204 (100);
HRMS (EI) calcd for C18H28N2O3 (M+) 320.2100, found 320.2101.
67%) as a white solid: mp 165-167 °C; [R]20 ) +127.7° (c
D
1.80, EtOH); 1H NMR (300 MHz, CDCl3) δ 10.33 (s, 1H), 8.41
(s, 1H), 7.66 (d, J ) 8.9 Hz, 2H), 7.28 (d, J ) 8.7 Hz, 2H), 4.33
(t, J ) 6.6 Hz, 1H), 1.89 (m, 1H), 1.79 (t, J ) 6.6 Hz, 2H), 1.21
(s, 9H), 1.01 (d, J ) 6.5 Hz, 3H), 0.99 (d, J ) 6.5 Hz, 3H); 13
C
NMR (67.94 MHz, CDCl3) δ 179.55, 169.64, 136.62, 128.98,
128.84, 121.11, 86.32, 40.78, 38.25, 27.06, 24.88, 23.26, 21.77;
IR (CH2Cl2) 3378, 3293, 3264, 3191 cm-1; MS (APCI) 341.2
(M+ + 1); HRMS (EI, 20 eV) calcd for C17H25N2O3Cl (M+)
340.1554, found 340.1548.
Com p ou n d 19: white crystalline solid; mp 112-114 °C;
[R]20 +64.2° (c 0.89, CH2Cl2); H NMR (300 MHz, CDCl3) δ
1
D
8.60 (s, 1H), 8.12 (br s, 1H), 4.26 (dd, J ) 7.7, 5.5 Hz, 1H),
3.14-3.09 (m, 1H), 3.04-2.99 (m, 1H), 1.89-1.77 (m, 2H),
1.70-1.68 (m, 2H), 1.20 (s, 9H), 0.98 (d, J ) 6.6 Hz, 3H), 0.95
(d, J ) 6.6 Hz, 3H), 0.91 (d, J ) 5.6 Hz, 3H), 0.92 (d, J ) 5.6
Hz, 3H); 13C NMR (75.47 MHz, CDCl3) δ 178.40, 171.56, 85.47,
46.55, 41.01, 38.11, 28.45, 27.12, 24.78, 23.30, 21.81, 20.18,
20.15; IR (CH2Cl2) 3431 (br), 3385 (br), 3322 (br), 2964, 1687,
1659 cm-1; LRMS (EI, 20 eV) m/z 286 (M+, 20), 214 (18), 131
(100); HRMS (EI) for C15H30N2O3 (M+) calcd 286.2256, found
286.2182.
D-Isob u t yl
2-p -Ch lor op h en ylca r b on yl-a m in oxy-4-
m eth ylp en ta n oa m id e (16). A solution of 12a (580 mg, 1.7
mmol) in dichloromethane (5 mL) at 0 °C was treated with
trifluoroacetic acid (5 mL). After being stirred at rt for 1 h,
the reaction mixture was concentrated under vacuum and
azeotroped with toluene. It was then dissolved in dichloro-
methane (10 mL), followed by addition of isobutylamine (0.34
mL, 3.4 mmol). To this mixture were added HOBt (344 mg,
2.55 mmol) and EDCI (555 mg, 1.87 mmol). The reaction
mixture was stirred overnight. The organic layer was dried
over anhydrous sodium sulfate and concentrated. The residue
was purified by flash column chromatography to provide
Ack n ow led gm en t. This work was supported by The
University of Hong Kong, The Hong Kong University
of Science and Technology, and Hong Kong Research
Grants Council.
compound 16 (460 mg, 80%) as a white solid: mp 99-102 °C;
1
[R]20 ) +31.2° (c 1.80, EtOH); H NMR (300 MHz, CDCl3) δ
D
10.95 (s, 1H), 8.22 (t, J ) 5.7 Hz, 1H), 7.66 (d, J ) 8.5 Hz,
2H), 7.28 (d, J ) 8.5 Hz, 2H), 4.31 (dd, J ) 3.6, 9.1 Hz, 1H),
2.82 (m, 2H), 1.76 (m, 1H), 1.70 (m, 2H), 0.77 (m, 6H); 13C NMR
(75.47 MHz, CDCl3) δ 172.49, 166.94, 139.10, 129.79, 129.40,
129.27, 129.23, 128.59, 85.61, 47.08, 41.41, 28.69, 25.04, 23.57,
21.99, 20.43; IR (CH2Cl2) 3433, 3380, 3341 cm-1; MS (APCI)
341.2 (M+); HRMS (EI, 20 eV) calcd for C17H26N2O3Cl (M+)
341.1632, found 341.1646.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal data; HPLC analysis of chiral R-aminoxy acids 6a -c, 11a ,
1
11c, and 11d ; H NMR dilution study of compounds 17-19;
1
and H and 13C NMR spectra of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O010376A