Determination of the absolute configuration of amines and α-amino acids by 1H NMR of (R)-O-aryllactic acid amides

Article abstract of DOI:10.1021/jo9604191

(R)-O-Aryllactic acid (ROAL) amides derived from α-chiral primary amines and α-amino acid esters show different chemical shifts in ¹H NMR spectroscopy (300 MHz) depending on their configuration. Molecular mechanics, semiempirical calculations, and ¹H NMR studies suggest that, in solution, these amides prefer an ap-Z conformation with the C_αOAr and C=O groups close to anti-periplanar as in the case of mandelic acid amides. The proposed conformational preference is different from that of the ROAL esters (C_αH and C=O groups in a syn-periplanar conformation). The conformational model for ROAL amides allows the absolute configuration assignment of primary amines and α-amino acid esters according to the relative position of the aryl group and the substituents on the amine moiety, and also their enantiomeric composition.

Full text of DOI:10.1021/jo9604191

J . Org. Chem. 1996, 61, 7285-7290
7285
Deter m in a tion of th e Absolu te Con figu r a tion of Am in es a n d
1
r-Am in o Acid s by H NMR of (R)-O-Ar ylla ctic Acid Am id es†
Rafael Chinchilla,‡ Larry R. Falvello,§,| and Carmen Na´jera*,‡
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99,
03080 Alicante, Spain, and Departamento de Qu´ımica Inorga´nica, Instituto de Ciencias de los Materiales
de Arago´n, Facultad de Ciencias, Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain
Received February 29, 1996X
(R)-O-Aryllactic acid (ROAL) amides derived from R-chiral primary amines and R-amino acid esters
1
show different chemical shifts in H NMR spectroscopy (300 MHz) depending on their configuration.
1
Molecular mechanics, semiempirical calculations, and H NMR studies suggest that, in solution,
these amides prefer an ap-Z conformation with the CROAr and CdO groups close to anti-periplanar
as in the case of mandelic acid amides. The proposed conformational preference is different from
that of the ROAL esters (CRH and CdO groups in a syn-periplanar conformation). The conforma-
tional model for ROAL amides allows the absolute configuration assignment of primary amines
and R-amino acid esters according to the relative position of the aryl group and the substituents
on the amine moiety, and also their enantiomeric composition.
Sch em e 1
In tr od u ction
One of the most classical and widely used methods to
determine the absolute configuration of organic molecules
is based on NMR studies of the different chemical shifts
of diastereomers prepared from chiral derivatizing agents.
This method is based on the anisotropy of aromatic rings
in chiral auxiliaries (Scheme 1) derived from: (a) man-
delic acid, such as (R)- or (S)-R-methoxy-R-(trifluoro-
methyl)phenylacetic acid (MTPA, 1),1 R-methoxy-R-
phenylacetic acid (MPA, 2),2 or R-methoxy-R-arylacetic
acids (AMAAs, 3),3 (b) axially chiral compounds such as
2′-methoxy-1,1′-binaphthyl-2′-carboxylic acid (MBNC, 4),4
(c) diazaphosphamidic chlorides such as 5, derived from
(R)-2-(anilinomethyl)pyrrolidine,5 and (d) (R)-O-aryllactic
acids (ROAL, 6).6 These reagents have been used for the
configurational determination of alcohols and amines via
their esters1a,b,d,2a,3a,b,d,4-6 and amides,1b,c,e,2b,3a,c,5 respec-
and the low cost of the starting lactic esters. They are
obtained by reaction of ethyl (S)-lactate with phenols
under Mitsunobu conditions followed by hydrolysis of the
ester functionality.7 These reagents have been used
previously as (a) chiral derivatizing agents in the deter-
mination of enantiomeric purity of alcohols and amines
by 19F NMR analysis of their esters and amides respec-
tively,8 (b) in the determination of the absolute configu-
ration of alcohols as ester derivatives,6a and (c) in the
kinetic resolution of alcohols using esterification re-
agents.9 We have recently used these ROAL acids as
chiral solvating agents for the direct 1H NMR determi-
nation of the enantiomeric purity of amines and amino
alcohols.10 The magnitude of the nonequivalent chemical
shifts for the diastereomeric ROAL salts of racemic chiral
amines and amino alcohols has, in general, a higher value
than with the use of other acids such as MTPA11 or (R)-
O-acetylmandelic (ROAM) acids.12 We report here the
determination of the absolute configuration of amines
1
tively, using H or 19F NMR spectroscopy.
(R)-O-Aryllactic acids (ROAL, 6) are especially conve-
nient chiral auxiliaries because of their easy preparation
† This paper is dedicated to Prof. Antonino Fava on his 73rd
birthday.
‡ Universidad de Alicante.
§ To whom the correspondence on X-ray structure should be ad-
dressed.
| Universidad de Zaragoza-CSIC.
X Abstract published in Advance ACS Abstracts, October 1, 1996.
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519. (b) Sullivan, G. R.; Dale, J . A.; Mosher, H. S. J . Org. Chem. 1973,
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H. Tetrahedron Lett. 1991, 32, 2939-2942. (d) Ohtani, I.; Kusumi, T.;
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Asymmetry 1995, 6, 1877-1880.
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S0022-3263(96)00419-7 CCC: $12.00 © 1996 American Chemical Society

7286 J . Org. Chem., Vol. 61, No. 21, 1996
Chinchilla et al.
Ta ble 1. Selected Ch em ica l Sh ifts of ROAL Am id esa (300
MHz, CDCl3)
Sch em e 2
amideb
acid amine
entry no.
no.
no.
Ha
Hb
Hc
Hd
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
6a (R)-7a (R,R)-8a a 1.15
6a (S)-7a (R,S)-8a a 1.06
6c (R)-7a (R,R)-8ca 1.13
6c (S)-7a (R,S)-8ca 1.02
6d (R)-7a (R,R)-8d a 1.13
6d (S)-7a (R,S)-8d a 0.99
6a (R)-7b (R,R)-8a b 1.09
6a (S)-7b (R,S)-8a b 1.01
6a (R)-7c (R,R)-8a c 1.51
6a (S)-7c (R,S)-8a c 1.43
6b (R)-7c (R,R)-8bc 1.52
6b (S)-7c (R,S)-8bc 1.45
6c (R)-7c (R,R)-8cc 1.48
6c (S)-7c (R,S)-8cc 1.38
6d (R)-7c (R,R)-8d c 1.47
6d (S)-7c (R,S)-8d c 1.36
6a (R)-7d (R,R)-8a d 1.61
6a (S)-7d (R,S)-8a d 1.51
6a (R)-7e (R,R)-8a e 3.72 1.46
6a (S)-7e (R,S)-8a e 3.77 1.38
6a (R)-7f (R,R)-8a f 3.68 2.23
6a (S)-7f (R,S)-8a f 3.76 2.14
6c (R)-7f (R,R)-8cf 3.62 2.20
6c (S)-7f (R,S)-8cf 3.73 2.10
6a (R)-7g (R,R)-8a g 3.68 3.11, 3.22
6a (S)-7g (R,S)-8a g 3.74 3.05
0.77
0.92
0.70
0.91
0.66
0.91
Sch em e 3
0.93
0.97
0.80
0.96
0.74
0.75
0.92
0.68
6a (R)-7h (R,R)-8a h 0.92 3.29, 3.45 4.26, 4.32
6a (S)-7h (R,S)-8a h 0.79 3.47, 3.52 4.51
a
b
From the diastereomeric mixture. Assignments referred to
notation in Scheme 3.
1
and R-amino acid esters by H NMR spectroscopy using
Sch em e 4
ROAL acids as chiral derivatizing agents.
Resu lts a n d Discu ssion
In the present study, four representative ROAL acids
(6a -d , Scheme 2) were employed for the preparation of
a series of diastereomeric amides by combination with
R-chiral primary amines (7a -d ), R-amino acid esters
(7e-g), and even an O-benzyl-protected â-amino alcohol13
(7h ) (Scheme 3). The oxalyl chloride method was used
for the amidation reactions because it proved to afford
higher yield of amides and also cleaner and faster
reactions compared to the DCC methodology.2b Under
these reaction conditions, no kinetic resolution was
observed when the amidation was carried out with
racemic amines, yielding 1:1 mixtures of diastereomeric
amides.
methoxy group (Table 1, entries 19-26). All these results
must agree with a preferred conformation for these ROAL
amides, which would explain the differences obtained and
give us an adequate model for predicting the absolute
configuration of any R-chiral primary amine using ROAL
acids.
1
In Table 1 the H NMR chemical shifts for each set of
the prepared amides 8 (Scheme 3) are summarized. Once
the two diastereomeric amides were obtained from a
ROAL acid 6 and a racemic amine 7, their chemical shifts
were assigned to a particular starting (R)- or (S)-amine
by comparison with the corresponding shifts in the single-
diastereomer amide prepared from an enantiomerically
pure amine of known configuration. A series of consis-
tent results can be observed in the chemical shifts given
in Table 1. For example, for amides derived from (S)-
amines 7a -d the signal corresponding to the methyl
group at CR on the amine moiety always appears at a
higher field (shielding effect) than that for amides from
the corresponding (R)-amines (Table 1, entries 1-18). On
the other hand, for amides derived from (R)-R-amino acid
methyl esters 7e-g, a shielding effect is observed on the
The proposed conformational models for MTPA,1a
MPA,2a or AMAAs3d esters show that the methine proton,
O-CO, and CF3 (for MTPA) or OMe moieties (for MPA
or AMAAs) lie roughly in a common plane and that the
CRCF3 or CROMe groups remain syn-periplanar to the
CdO group (9 and 10, Scheme 4). In the case of the
corresponding amides the conformational model differs
because all the recent experimental2b,3c and theoretical3c
studies on the conformation of MPA and AMAA amides
in solution indicate a conformational preference for CR-
OMe and CdO groups in an anti-periplanar position
(ap-Z conformation, 11, Scheme 4). An intramolecular
hydrogen bond2b,14 between the amide hydrogen and the
methoxy substituent and the lower dipole moment3d have
been suggested as conformational stabilization factors.
(13) Prepared by deprotonation of (R/ S)- and (S)-2-aminobutanol
with sodium hydride in refluxing THF and subsequent reaction with
benzyl bromide.
(14) Helmchen, G.; Ott, R.; Sauber, K. Tetrahedron Lett. 1972,
3873-3878.

1H NMR of (R)-O-Aryllactic Acid Amides
J . Org. Chem., Vol. 61, No. 21, 1996 7287
Sch em e 5
F igu r e 1. Thermal ellipsoid plot of one molecule of (R,S)-8a a
showing the atom naming scheme. Non-hydrogen atoms are
represented by their 50% probability ellipsoids.
tions we obtained a conformation ap-Z for ROAL amides,
as represented in Scheme 5 by 8B (together with its
extended Newman projection), which shows a lower
conformational energy by more than 2 kcal/mol compared
to any of the other possible conformers created by
rotation of the single CRsCdO bond. Using the AM1
semiempirical method we obtained similar and, in some
cases, larger energy differences. For example, the ap-Z
conformer shows a conformational energy 5 kcal/mol
lower than the sp-Z conformer (CROPh and CdO groups
in a syn-periplanar position), the latter closely related
to the conformer obtained by X-ray analysis for (R,S)-
8a a . From the molecular mechanics modeling it was
easy to see how the ap-Z conformer was also stabilized
by the formation of an intramolecular hydrogen bond
between the amide hydrogen and the phenoxy substitu-
ent, something similar to what has been previously
suggested for the case of MPA amides.2b Moreover, this
fact was supported by the absence of displacement of the
1H NMR signal corresponding to the amide proton for
samples of different concentration, and also by the
presence of a sharp band at 3420 cm-1 in the IR spectrum
of amide 8a d (2% solution in CCl4).14
X-ray analysis has supported the notion that the more
stable conformation of ROAL esters is that with the CRH
and CdO groups occupying syn-periplanar positions5 (12,
Scheme 4). Apparently, an extension of the ROAL-ester
conformational model to amides 8 would explain the
different observed chemical shifts for amides from (R)-
or (S)-amines as represented in conformer 8A (Scheme
4). The stereodifferentiation of R1 and R2 would depend
on the relative position of the aryl ring anisotropically
inducing high-field shifts for protons in the R1 group
facing the aromatic system. With this background in
mind, and in order to check if the conformational prefer-
ence for ROAL amides in the solid state would also be
accommodated in solution, suitable crystals of amide
(R,S)-8a a were subjected to X-ray analysis. The struc-
ture, shown in Figure 1, revealed a conformation with
CROAr and CdO groups close to a syn-periplanar ar-
rangement (sp-Z) with a torsion angle O(1)-O(2) ) 27°,
and with the aromatic ring facing the ethyl group on the
(S)-amine moiety. A conformer like this in solution would
produce a shielding effect on the ethyl group in question,
1
and therefore the H NMR would show a displacement
Once this conformational preference for ROAL amides
was established, it was necessary to determine the
orientation of the aryl group in the ap-Z rotamer, that
is, the relative stability of the two possible ap-Z conform-
ers 8C and 8D (Scheme 5), which would shield one group
or the other (R1 or R2) in the amine fragment. This was
investigated for ROAL amides from isopropylamine and
acids 6a -d , again using molecular mechanics calcula-
tions, with the result that conformer 8C was 1.1 kcal/
mol lower in energy than 8D for amides from all of the
ROAL acid used. The same energy difference was
obtained using the AM1 semiempirical calculation
method16 for the case of the ROAL amide from isopro-
pylamine and 6c. It was also shown that the aromatic
ring was preferentially located close to coplanarity with
the CR-H bond. Moreover, differential NOE experiments
on amide (R,S)-8a d (Table 1, entry 18) showed incre-
ments only in the signals of protons CRH (12%) and Hortho
(14%) after irradiation on Hortho and CRH respectively,
whereas after irradiation on the aromatic methyl group
no enhancement was observed at the methyl on CR
(Scheme 5).
of the signals toward higher fields compared to those
corresponding to the amide from the (R)-amine. This is
totally opposite to the results obtained for (R,R)- and
(R,S)-8a a in CDCl3 solution (Table 1, entries 1 and 2)
which reveal that the aromatic ring is shielding the
methyl group on the amine moiety of (R,S)-8a a . This
result shows that in this case it is not possible to extend
conformational assignments from the solid state to
compounds in solution in a reliable way. In the case of
amide (R,S)-8a a , the X-ray studies revealed favorable
crystal packing through intermolecular hydrogen bonds
between N(1)-H(1) from one molecule and O(2) from
another one, thus forcing the observed solid state con-
formation.
Due to the change in the conformational preference for
MPA and AMAAs amides compared with the correspond-
ing esters (see above), it seemed logical that an ap-Z
conformation could also be the most stable one in solution
for the case of ROAL amides. The anti conformation
between the amide proton and the methine proton of the
amine moiety in the ROAL amides can be established
1
because of the coupling constant of ∼7-9 Hz in the H
All these results suggest that the preferred conformer
of ROAL amides 8 should be close to the one represented
NMR spectra, a characteristic that is general to amides
from primary amines.2b,3c These facts prompted us to
study the relative energies for the different rotamers of
an example amide, created from the simplest ROAL acid
6c and isopropylamine, using molecular mechanics15 and
semiempirical16 calculations. From the former calcula-
(15) PCMODEL for Windows from Serena Software was used for
these calculations (MMX force field).
(16) AM1 as implemented in MOPAC 6.00; J . P. S. J ames, Franck
J . Seiler Research Laboratory, United States Air Force Academy, CO
80840.

7288 J . Org. Chem., Vol. 61, No. 21, 1996
Chinchilla et al.
Sch em e 6
and SOAL amides from the same amine and application
of the described above conformational model would allow
the determination of the absolute configuration of the
available amine.
Con clu sion s
In summary, we report that cheap and easily prepared
(R)-O-aryllactic (ROAL) acids can be used for the deter-
mination of the absolute configuration of R-chiral primary
amines and R-amino acid esters via the differences in the
1H NMR shifts of their corresponding diastereomeric
amides. The ap-Z conformational model proposed for
these ROAL amides is consistent with those recently
proposed for MPA and AMAA amides and different from
that previously suggested for ROAL esters. As the
in Scheme 6 (together with its extended Newman projec-
tion), in which is shown the position of the aryl group
shielding the R1 group in the amine fragment, which
suffers downfield chemical shifts compared to the un-
shielded R2 group. With this proposed model it would
be possible to predict the absolute configuration of any
R-chiral primary amine, as confirmed by the results
shown in Table 1.
1
difference in H NMR chemical shifts is larger for ROAL
amides than for MTPA amides and, at least, of a similar
magnitude to that for MPA or AMAA amides, these acids
turn out to be an interesting alternative to the use of
other chiral derivatizing agents.
With regard to the chemical shift values presented in
Table 1, some points are worth noting. First, it can be
deduced from the analysis of the conformational model
for 8, shown in Scheme 6, that the shielding effect should
be more noticeable if the affected group is far from the
chiral center in the amine moiety. That is shown, for
example, in amides (R,R)- and (R,S)-8a a (Table 1, entries
1 and 2) derived from sec-butylamine 7a where the
difference in chemical shifts is 0.09 ppm for the methyl
group (protons a) bonded directly to the chiral center
whereas the difference is 0.15 ppm for the methyl in the
ethyl substituent. The same effect can be observed in
amides (R,R)- and (R,S)-8a f, derived from (R)- and (S)-
valine methyl ester respectively, where ∆δ ) 0.09 ppm
for the methine protons, whereas ∆δ ) 0.18 and ∆δ )
0.17 ppm for the isopropyl methyls. Another fact is the
observed loss of stereodifferentiation when the aryl
system in the ROAL acid bears electron-withdrawing
groups, thus decreasing the intensity of the induced ring
current and therefore the anisotropic aromatic shielding
effect. Thus, when two chlorine groups are present in
the aromatic ring of the acid moiety (6b) as in amides
(R,R)- and (R,S)-8bc (Table 1, entries 11 and 12), the
difference in chemical shifts is 0.07 ppm for the methyl
groups in the amine fragment, whereas in amides (R,R)-
and (R,S)-8cc (Table 1, entries 13 and 14) from ROAL
acid 6c the difference is 0.10 ppm and for amides (R,R)-
and (R,S)-8d c from acid 6d the difference is 0.11 ppm
(Table 1, entries 15 and 16). In general, the difference
in 1H NMR chemical shifts is larger for ROAL amides
than for MTPA amides and, at least, their values are
similar in magnitude to those of MPA or AMAA amides.
In all cases it was possible to determine the enantio-
meric purity of the amines by integration of the signal
corresponding to the residual diastereomer in the reac-
tion crude. Thus, for amide (R,S)-8a c (Table 1, entry 10)
from (S)-1-phenylethylamine (Aldrich 96%), 2% of the
(R,R)-8a c amide was detected.
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. Optical rotations
were measured in CH2Cl2. FT-IR spectra were obtained from
KBr pellets unless otherwise stated. NMR spectra were
1
determined at 300 MHz for H and 75 MHz for 13C using CDCl3
as solvent and TMS as internal standard. Mass spectra (EI)
were obtained at 70 eV. Elemental analyses were performed
by the Microanalyses Service of the University of Alicante.
High resolution mass spectra (EI) were determined by the
corresponding Service at the University of Zaragoza. X-ray
data were collected using Mo KR radiation (graphite crystal
monochromator, λ ) 0.71073 Å), µ ) 0.72 cm-1, T ) 22-25 (
1 °C. The atomic coordinates and other data for compound
(R,S)-8a a were deposited in the Cambridge Crystallographic
Data Centre. Benzene and toluene were dried over sodium
wire. All starting materials were commercially available of
the best grade and were used without further purification.
P r ep a r a tion of Am id es. Gen er a l P r oced u r e. The
corresponding ROAL acid (0.5 mmol) was dissolved in benzene
or toluene (3 mL) under an argon atmosphere, and then oxalyl
chloride (0.84 mmol, 80 µL) was added at 0 °C followed by DMF
(ca. 2 µL). The reaction mixture was stirred for 30 min at 0
°C and 2 h at room temperature, with the solvent then being
evaporated (15 Torr), and benzene or toluene was added (3
mL). To this mixture was added dropwise a solution of amine
(0.5 mmol) and pyridine (1 mmol, 80 µL) in benzene or toluene
(2 mL). The resulting suspension was stirred for 2 h at room
temperature, and then 2 N HCl was added (10 mL) and the
mixture was extracted with ether (2 × 10 mL). The combined
organic layers were washed with saturated aqueous NaHCO3
(2 × 10 mL), dried over anhydrous Na2SO4, and evaporated
in vacuo (15 Torr) affording crude amides 7 with yields ranging
between 80-90%. The crude amides were pure enough for
1H NMR analysis (>90% by GC), but those obtained from
enantiomerically pure amines were purified by crystallization
or column chromatography on silica gel for analytical purposes.
(S)-N-sec-Bu tyl-(R)-2-(4-ch lor o-2-m eth ylp h en oxy)p r o-
p ion a m id e ((R,S)-8a a ). Yield: 79%. Mp 126-127 °C (hex-
ane/ether); [R]27D +13.6° (c ) 1.0); IR ν 3272, 3088, 1655, 1560,
1244, 873, 800 cm-1; 1H NMR δ 0.92 (t, J ) 7.3 Hz, 3H), 1.06
(d, J ) 6.4 Hz, 3H), 1.43-1.54 (m, 2H), 1.57 (d, J ) 6.7 Hz,
3H), 2.25 (s, 3H), 3.94 (m, 1H), 4.57 (q, J ) 6.7 Hz, 1H), 6.16
(br d, J ) 7.6 Hz, 1H), 6.68 (d, J ) 8.6 Hz, 1H), 7.07-7.15 (m,
2H); 13C NMR δ 10.21, 16.29, 18.93, 20.30, 29.62, 46.15, 75.92,
114.00, 126.50, 126.69, 129.00, 130.84, 153.77, 171.24; MS m/ z
269 (M+, 31), 169 (45), 128 (44), 100 (61), 72 (46), 57 (82), 44
(100). Anal. Calcd for C14H20ClNO2: C, 62.33; H, 7.47; N, 5.19.
Found: C, 62.33; H, 7.52; N, 4.87.
It is worthy of note that, since both enantiomers of
lactate esters are commercially available, it is possible
to prepare the corresponding enantiomeric (S)-O-aryl-
lactic (SOAL) acids and therefore to obtain two diaster-
eomeric amides by combination of a single amine of
unknown configuration with ROAL and SOAL acids.
That would allow the absolute configuration of R-chiral
primary amines to be established when just one of the
enantiomers is available, because the amide from the
SOAL acid and the available amine will be enantiomeric
to the amide from the ROAL acid with the nonavailable
one. Comparison of the chemical shifts of both ROAL
(S)-N-sec-Bu t yl-(R)-2-p h en oxyp r op ion a m id e ((R,S)-
8ca ). Yield: 80%. Mp 69-70 °C (hexane); [R]25 +35.6° (c )
D

1H NMR of (R)-O-Aryllactic Acid Amides
J . Org. Chem., Vol. 61, No. 21, 1996 7289
1.1); IR ν 3309, 3072, 1647, 1530, 1232, 695, 756 cm-1; 1H NMR
δ 0.91 (t, J ) 7.3 Hz, 3H), 1.02 (d, J ) 6.7 Hz, 3H), 1.47 (m,
2H), 1.57 (d, J ) 6.7 Hz, 3H), 3.93 (m, 1H), 4.66 (q, J ) 6.7
Hz, 1H), 6.22 (br d, J ) 7.2 Hz, 1H), 6.88-7.03 (m, 3H), 7.30
(m, 2H); 13C NMR δ 10.26, 18.95, 20.23, 29.58, 46.19, 75.12,
115.49, 122.00, 129.69, 156.88, 171.75; MS m/ z 221 (M+, 17),
121 (100), 77 (39), 57 (45). HRMS m/ z calcd for C13H19NO2
221.1416, found 221.1414.
(S)-N-sec-Bu t yl-(R)-2-(2-n a p h t h yloxy)p r op ion a m id e
((R,S)-8d a ). Yield: 78%. Mp 107-108 °C (hexane/EtOAc);
[R]25D +66.9° (c ) 1.6); IR ν 3363, 3055, 1655, 1521, 1521, 1509,
1216, 843 cm-1; 1H NMR δ 0.92 (t, J ) 7.3 Hz, 3H), 0.99 (d, J
) 6.4 Hz, 3H), 1.47 (m, 2H), 1.64 (d, J ) 6.7 Hz, 3H), 3.95 (m,
1H), 4.79 (q, J ) 6.7 Hz, 1H), 6.20 (br d, J ) 7.6, 1H), 7.16 (m,
1H), 7.41 (m, 3H), 7.76 (m, 3H); 13C NMR δ 10.30, 19.06, 20.30,
29.62, 46.20, 75.37, 108.84, 118.49, 124.27, 126.65, 126.95,
127.58, 129.43, 129.80, 134.31, 154.75, 171.49; MS m/ z 271
(M+, 59), 171 (80), 144 (79), 128 (52), 127 (54), 72 (53), 57 (52),
44 (100). Anal. Calcd for C17H21NO2: C, 75.25; H, 7.80; N,
5.16. Found: C, 75.66; H, 7.87; N, 4.95.
for C21H21NO2: C, 78.97; H, 6.63; N, 4.39. Found: 78.66; H,
6.63; N, 4.01.
(S)-N-(1-Na p h th yleth yl)-(R)-2-(4-ch lor o-2-m eth ylp h e-
n oxy)p r op ion a m id e ((R,S)-8a d ). Yield: 82%. Mp 174-175
°C (hexane/EtOAc); [R]25 +65.7° (c ) 1.0); IR ν 3253, 3075,
D
3047, 1648, 1558, 1491, 1243, 1191, 1144, 875, 746 cm-1; H
1
NMR δ 1.52 (d, J ) 6.7 Hz, 3H), 1.60 (d, J ) 6.7 Hz, 3H), 2.13
(s, 3H), 4.62 (q, J ) 6.7 Hz, 1H), 5.94 (quintet, J ) 6.7 Hz,
1H), 6.59 (br d, J ) 7.2 Hz, 1H), 6.72 (d, J ) 8.2 Hz, 1H), 7.13
(m, 2H), 7.47 (m, 4H), 7.85 (m, 2H), 8.05 (m, 1H); 13C NMR δ
16.26, 18.83, 20.62, 44.47, 76.03, 113.92, 122.56, 123.27,
125.19, 125.94, 126.54, 126.59, 126.68, 128.53, 128.86, 129.06,
130.89, 131.05, 133.96, 137.74, 153.80, 170.89; MS m/ z 367
(M+, 12), 226 (56), 155 (100). Anal. Calcd for C22H22ClNO2:
C, 71.83; H, 6.03; N, 3.81. Found: C, 71.92; H, 6.05; N, 3.45.
(S)-N-[(R)-2-(4-Ch lor o-2-m eth ylp h en oxy)p r op a n oyl]a -
la n in e Met h yl E st er ((R,S)-8a e). Yield: 68%. Mp 107-
108 °C (hexane); [R]25 +5.1° (c ) 1.0); IR ν 3420, 3279, 1740,
D
1662, 1247, 802, 660 cm-1; 1H NMR δ 1.37 (d, J ) 7.0 Hz, 3H),
1.58 (d, J ) 6.7 Hz, 3H), 2.29 (s, 3H), 3.77 (s, 3H), 4.61 (quintet,
J ) 7.0 Hz, 1H), 4.64 (q, J ) 6.7 Hz, 1H), 6.68 (d, J ) 8.5 Hz,
1H), 7.02 (br d, J ) 7.2 Hz, 1H), 7.15 (m, 2H); 13C NMR δ
13.33, 18.30, 18.45, 47.67, 52.56, 75.32, 113.56, 126.49, 126.60,
129.20, 130.94, 153.60, 171.41, 173.07; MS m/ z 299 (M+, 26),
169 (50), 130 (38), 70 (32), 55 (38), 44 (100). HRMS m/ z calcd
for C14H18ClNO4 299.0924, found 299.0919.
(S)-N-(1-Cycloh exyleth yl)-(R)-2-(4-ch lor o-2-m eth ylp h e-
n oxy)p r op ion a m id e ((R,S)-8a b). Yield: 79%. Mp 135-136
°C (hexane/ether); [R]25 +17.4° (c ) 1.4); IR ν 3256, 3088,
D
1654, 1563, 1247, 870, 799 cm-1; 1H NMR δ 0.94-1.25 (m, 6H),
1.01 (d, J ) 6.7 Hz, 3H), 1.58 (d, J ) 6.7 Hz, 3H), 1.65-1.74
(m, 5H), 2.25 (2, 3H), 3.87 (m, 1H), 4.58 (q, J ) 6.7 Hz), 1H),
6.22 (br d, J ) 8.2 Hz, 1H), 6.69 (d, J ) 8.5 Hz, 1H), 7.07-
7.15 (m, 2H); 13C NMR δ 16.33, 17.90, 18.97, 26.10, 26.36,
28.77, 29.18, 43.07, 48.89, 75.88, 113.93, 126.47, 126.69,
128.95, 130.85, 153.72, 171.06; MS m/ z 323 (M+, 7), 169 (24),
69 (20), 55 (27), 44 (100). Anal. Calcd for C18H26ClNO2: C,
66.76; H, 8.09; N, 4.32. Found: C, 66.79; H, 8.14; N, 3.97.
(S)-N-(1-P h en yleth yl)-(R)-2-(4-ch lor o-2-m eth ylp h en ox-
y)p r op ion a m id e ((R,S)-8a c). Yield: 83%. Mp 127-128 °C
(S)-N-[(R)-2-(4-Ch lor o-2-m et h ylp h en oxy)p r op a n oyl]-
va lin e Meth yl Ester ((R,S)-8a f). Yield: 79%. [R]25D +10.0°
(c ) 1.4); IR (film) ν 3283, 3086, 1748, 1666, 1242, 873, 803,
660 cm-1; 1H NMR δ 0.75 (d, J ) 7.0 Hz, 3H), 0.80 (d, J ) 7.0
Hz, 3H), 1.60 (d, J ) 6.7 Hz, 3H), 2.14 (m, 1H), 2.29 (s, 3H),
3.76 (s, 3H), 4.55 (dd, J ) 9.1, 4.6 Hz, 1H), 4.69 (q, J ) 6.7
Hz, 1H), 6.70 (d, J ) 8.5 Hz, 1H), 6.86 (br d, J ) 9.0 Hz, 1H),
7.16 (m, 2H); 13C NMR δ 16.24, 17.32, 18.48, 18.77, 31.09,
52.16, 56.47, 75.08, 113.32, 126.40, 126.54, 128.89, 130.90,
153.53, 171.62, 171.95; MS m/ z 327 (M+, 30), 169 (53), 158
(44), 72 (100), 55 (50); HRMS m/ z calcd for C16H22ClNO4
327.1237, found 327.1229.
(hexane/ether); [R]25 +6.7° (c ) 2.0); IR ν 3262, 3082, 1652,
D
1558, 1243, 1252, 804, 696 cm-1; H NMR δ 1.43 (d, J ) 7.0
1
Hz, 3H), 1.55 (d, J ) 6.7 Hz, 3H), 2.23 (s, 3H), 4.62 (q, J ) 6.7
Hz, 1H), 5.15 (quintet, J ) 7.0 Hz, 1H), 6.62 (br d, J ) 7.5 Hz,
1H), 6.72 (d, J ) 8.8 Hz, 1H), 7.10-7.36 (m, 7H); 13C NMR δ
16.31, 18.68, 21.75, 48.26, 75.86, 113.98, 125.91, 126.60,
126.72, 127.47, 128.77, 129.05, 130.91, 142.73, 153.73, 170.96;
MS m/ z 317 (M+, 3), 105 (47), 44 (100). Anal. Calcd for
C18H20ClNO2: C, 68.03; H, 6.34; N, 4.41. Found: C, 68.33; H,
6.41; N, 4.41.
(S)-N-[(R)-2-P h en oxyp r op a n oyl]va lin e Met h yl E st er
((R,S)-8cf). Yield: 77%. [R]25 +19.5° (c ) 1.5); IR (film) ν
D
3426, 3064, 1743, 1687, 1226, 755, 692 cm-1; H NMR δ 0.68
1
(d, J ) 6.7 Hz, 3H), 0.74 (d, J ) 7.0 Hz, 3H), 1.59 (d, J ) 6.7
Hz, 3H), 2.10 (m, 1H), 3.74 (s, 3H), 4.54 (dd, J ) 9.0, 4.9 Hz,
1H), 4.75 (q, J ) 6.7 Hz, 1H), 6.82 (br d, J ) 8.9 Hz, 1H), 6.92
(m, 3H), 7.30 (m, 2H); 13C NMR δ 17.26, 18.70, 18.75, 31.04,
52.12, 56.49, 74.68, 115.25, 122.02, 129.72, 156.88, 171.96,
172.13; MS m/ z 279 (M+, 6), 165 (30), 121 (100), 77 (41), 72
(51), 55 (32); HRMS m/ z calcd for C15H21NO4 279.1471, found
279.1467.
(S)-N-[(R)-2-(4-Ch lor o-2-m et h ylp h en oxy)p r op a n oyl]-
p h en yla la n in e Meth yl Ester ((R,S)-8a g). Yield: 76%.
[R]27D +37.7° (c ) 2.1); IR (film) ν 3416, 3064, 3030, 1745, 1672,
1242, 874, 806, 702 cm-1; 1H NMR δ 1.55 (d, J ) 6.7 Hz, 3H),
2.13 (s, 3H), 3.05 (d, J ) 5.8 Hz, 2H), 3.75 (s, 3H), 4.59 (q, J
) 6.7 Hz, 1H), 4.90 (dt, J ) 8.2 Hz, 5.8 Hz, 1H), 6.55 (d, J )
8.5 Hz, 1H), 6.74 (br d, J ) 8.2 Hz, 1H), 6.82 (m, 1H), 7.02-
7.14 (m, 6H); 13C NMR δ 16.19, 18.69, 37.71, 52.33, 52.39,
75.09, 113.18, 126.38, 126.61, 127.11, 128.56, 128.92, 130.85,
135.20, 153.60, 171.53, 171.64; MS m/ z 375 (M+, 30), 213 (85),
169 (100), 146 (55), 120 (60), 91 (55), 55 (43), 44 (68); HRMS
m/ z calcd for C20H22ClNO4 375.1237, found 375.1227.
(S)-N-(1-P h en yleth yl)-(R)-2-(2,4-d ich lor op h en oxy)p r o-
p ion a m id e ((R,S)-8bc). Yield: 84%. Mp 127-128 °C (hex-
ane/EtOAc); [R]22 -16.9° (c ) 1.7); IR ν 3268, 3094, 1663,
D
1563, 1288, 807, 697 cm-1; 1H NMR δ 1.46 (d, J ) 7.0 Hz, 3H),
1.59 (d, J ) 6.7 Hz, 3H), 4.70 (q, J ) 6.7 Hz, 1H), 5.13 (quintet,
J ) 7.0 Hz, 1H), 6.89 (d, J ) 8.5 Hz, 1H), 7.03 (br d, J ) 7.3
Hz, 1H), 7.19-7.42 (m, 7H); 13C NMR δ 18.33, 22.04, 48.47,
76.80, 116.07, 124.43, 125.85, 127.41, 127.95, 128.72, 130.22,
142.75, 151.32, 169.96; MS m/ z 337 (M+, 1), 176 (49), 105
(100). Anal. Calcd for C17H17Cl2NO2: C, 60.37; H, 5.07; N,
4.14. Found: C, 60.48; H, 5.07; N, 3.80.
(S )-N -(1-P h e n yle t h yl)-(R )-2-p h e n oxyp r op ion a m id e
((R,S)-8cc). Yield: 81%. Mp 151-152 °C (hexane/EtOAc);
[R]25D +1.2° (c ) 1.9); IR ν 3343, 3062, 3042, 1653, 1525, 1230,
1
755, 704 cm-1; H NMR δ 1.39 (d, J ) 7.0 Hz, 3H), 1.55 (d, J
) 6.7 Hz, 3H), 4.70 (q, J ) 6.7 Hz, 1H), 5.15 (quintet, J ) 7.0
Hz, 1H), 6.65 (br d, J ) 7.0 Hz, 1H), 6.90-7.05 (m, 3H), 7.30
(m, 5H); 13C NMR δ 18.70, 21.60, 48.16, 75.12, 115.52, 122.08,
125.99, 127.40, 128.70, 129.75, 142.77, 156.88, 171.23; MS m/ z
269 (M+, 12), 176 (42), 121 (100), 105 (69), 77 (57). Anal. Calcd
for C17H19NO2: C, 75.81; H, 7.11; N, 5.20. Found: C, 75.76;
H, 7.27; N, 4.79.
(S)-N-2-[1-(Ben zyloxy)b u t yl]-(R)-2-(4-ch lor o-2-m et h -
ylp h en oxy)p r op ion a m id e ((R,S)-8a h ). Yield: 82%. Mp
98-99 °C (hexane/ether); [R]25 -10.2° (c ) 1.7); IR ν 3267,
D
3091, 1657, 1559, 1249, 1191, 696, 661 cm-1; H NMR δ 0.79
1
(S)-N-(1-P h en ylet h yl)-(R)-2-(2-n a p h t h yloxy)p r op ion -
a m id e ((R,S)-8d c). Yield: 80%. Mp 161-162 °C (hexane/
(t, J ) 7.3 Hz, 3H), 1.40-1.62 (m, 2H), 1.55 (d, J ) 6.7 Hz,
3H), 2.20 (s, 3H), 3.47 (dd, J ) 9.5, 4.0 Hz, 1H), 3.52 (dd, J )
9.5, 3.7 Hz, 1H), 4.01 (m, 1H), 4.52 (s, 2H), 4.61 (q, J ) 6.7
Hz, 1H), 6.60 (br d, J ) 7.9 Hz, 1H), 6.69 (d, J ) 8.8 Hz, 1H),
7.08 (m, 2H), 7.31 (m, 5H); 13C NMR δ 10.36, 16.24, 18.83,
24.70, 50.05, 70.90, 73.14, 75.57, 113.66, 126.37, 126.60,
127.51, 127.71, 128.39, 128.98, 130.84, 138.03, 153.75, 171.50;
MS m/ z 375 (M+, 1), 91 (100), 58 (65). Anal. Calcd for
C21H26ClNO3: C, 67.10; H, 6.97; N, 3.73. Found: C, 66.92; H,
6.99; N, 3.35.
EtOAc); [R]25 +81.1° (c ) 1.3); IR ν 3373, 3061, 3030, 1658,
D
1507, 1216, 844, 699 cm-1; 1H NMR δ 1.36 (d, J ) 7.0 Hz, 3H),
1.62 (d, J ) 6.7 Hz, 3H), 4.85 (q, J ) 6.7 Hz, 1H), 5.16 (quintet,
J ) 7.0 Hz, 1H), 6.67 (br d, J ) 7.5 Hz, 1H), 7.16-7.47 (m,
9H), 7.76 (m, 3H); 13C NMR δ 18.78, 21.59, 48.22, 75.22,
108.82, 118.50, 124.33, 126.01, 126.69, 126.96, 127.43, 127.61,
128.72, 129.46, 129.87, 134.30, 142.74, 154.67, 171.20; MS m/ z
319 (M+, 44), 171 (65), 144 (63), (45), 105 (100). Anal. Calcd

7290 J . Org. Chem., Vol. 61, No. 21, 1996
Chinchilla et al.
X-r a y Str u ctu r e Deter m in a tion . Samples suitable for
use in X-ray diffraction analysis were obtained by crystalliza-
tion of (R,S)-8a a in hexane/EtOAc. Crystal data and a
summary of data collection parameters and refinement results
have been deposited with the Cambridge Crystallographic
Data Centre.17 A colorless crystal was mounted on a glass fiber
and covered with a thin layer of epoxy. The unit-cell param-
eters were refined18 to the zero-corrected positions of 25
reflections in the 2θ range 20.2-28.7°. The crystal is mono-
clinic, space group P21, with a ) 10.075(1), b ) 4.7537(4), c )
(H(14C)) attached to C(14) had their isotropic displacement
parameters set to 1.2 times the equivalent isotropic displace-
ment parameters of their respective parent carbon atoms, and
a similarity restraint was used for the three C-H distances
of the methyl group at C(14); otherwise, all hydrogens were
refined freely, each with its own isotropic displacement
parameter. In all, 242 parameters were refined to 2304 data
and 4 restraints. The latter included an origin-fixing re-
straint21 for the polar axis. The enantiomorph, established
by the value of the Flack parameter,22 -0.12(12), is in
agreement with the absolute configuration established spec-
troscopically. The refinement converged (max, mean shift/esd
) 0.199, 0.024) with wR2 ) 0.1080, R1 ) 0.0455, GOF ) 1.060
and restrained GOF ) 1.059. The final difference map had
maximum and minimum densities of 0.14 and -0.14 e/Å3.
15.860(2) Å, â ) 106.78(1)°, V ) 727.2(2) Å3, Z ) 2.
A
hemisphere of data was collected, from 4.0 to 48.0° in 2θ.
During data collection, three monitor reflections were remea-
sured after each hour of X-ray exposure, and three reflections
were used to check crystal orientation after every 400 mea-
surements. An empirical absorption correction19 was based
on the presence of two symmetry-equivalent quadrants of data
and gave maximum and minimum correction factors of 0.93
and 0.84. The structure was solved by direct methods and
Ack n ow led gm en t. This work was financially sup-
ported by the DGICYT (Projects PB92-0360 and PB94-
1515) from the Spanish Ministerio de Educacio´n y
Ciencia (MEC). We thank Dr. Andreas Heumann for a
generous gift of acids 6a and 6b, and Prof. Ricardo
Riguera and Dr. Shamil Latypov for semiempirical
calculations. We also thank Mr. Diego Alonso for
running NOE experiments.
2
refined to F0 by full-matrix least-squares, using all unique
data.20 Non-hydrogen atoms were refined anisotropically.
Hydrogen atoms were located in difference Fourier maps. The
hydrogen atom attached to C(8) and one of the hydrogen atoms
(17) The author has deposited atomic coordinates for (R,S)-8a a with
the Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(18) Diffractometer control program: CAD4-PC Version 1.5c, 1994,
Delft Instruments X-ray Diffraction bv, Delft, The Netherlands.
(19) Data were processed on a Local Area VAXcluster (VMS V5.5-
2), with the program XCAD4B (K. Harms, Philipps Universita¨t
Marburg) and with the commercial package SHELXTL-PLUS Release
4.21/V: 1990, Siemens Analytical X-ray Instruments, Inc., Madison,
WI.
(20) (a) Least-squares calculations were done on a Hewlett-Packard
9000 715/50 (HP-UX V9.01), with the program Shelxl-93. (b) G. M.
Sheldrick, Shelxl-93: FORTRAN-77 program for the refinement of
crystal structures from diffraction data. University of Go¨ttingen, 1993.
(c) Sheldrick, G. M. Manuscript in preparation.
Su p p or tin g In for m a tion Ava ila ble: Crystal packing
diagram for compound (R,S)-8a a (1 page). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O9604191
(21) Flack, H. D.; Schwarzenbach, D. Acta Crystallogr. Sect. A 1988,
A44, 499-506.
(22) (a) Flack, H. D. Acta Crystallogr. Sect. A 1983, A39, 876-881.
(b) Bernardinelli, G.; Flack, H. D. Acta Crystallogr. Sect. A 1985, A41,
500-511.