Synthetic studies on L-proline and (4R)-hydroxy-L-proline derivatives

Article abstract of DOI:10.1055/s-2004-822384

The preparation of a number of L-proline and (4R)-hydroxy-L-proline derivatives to assess their enantioselectivity when applied to several techniques and experimental conditions is described. All the derivatives prepared incorporated at least one 3,5-disubstituted aromatic ring that contained nitro, chloro or methyl groups and were obtained by classical methods. In spite of the difficulties that arise from the presence of rotational isomers in most cases, the compounds studied are fully described by their ¹H and ¹³C NMR spectra.

Full text of DOI:10.1055/s-2004-822384

PAPER
1171
Synthetic Studies on L-Proline and (4R)-Hydroxy-L-proline Derivatives
S
ynthetic Studie
e
s
on
L
-Pro
r
e
4
R
)-Hydro
s
xy-
L
-prol
a
ine
D
erivative
s
González,a Olga Abad,a M. Carmen Santano,a Cristina Minguillón*a,b
a
Laboratori de Química Farmacèutica, Facultat de Farmàcia, Universitat de Barcelona, Avda. Diagonal s/n, 08028 Barcelona, Spain
b
Institut de Recerca Biomèdica de Barcelona-Parc Científic de Barcelona (IRBB-PCB), Josep Samitier 1-5, 08028 Barcelona, Spain
Fax +34(93)4037104; E-mail: cminguillon@pcb.ub.es
Received 4 February 2004; revised 17 March 2004
the other hand, the establishment of a second p-p interac-
tion was considered to reinforce the association between
chiral selector and enantiomers. Thus, two aromatic rings
were introduced in a number of selectors (Figure 1). The
Abstract: The preparation of a number of L-proline and (4R)-hy-
droxy-L-proline derivatives to assess their enantioselectivity when
applied to several techniques and experimental conditions is de-
scribed. All the derivatives prepared incorporated at least one 3,5-
disubstituted aromatic ring that contained nitro, chloro or methyl presence of aromatic rings of distinct character (p-donor/
groups and were obtained by classical methods. In spite of the dif-
p-acceptor) in the same selector was also considered in or-
ficulties that arise from the presence of rotational isomers in most
der to enlarge their application domain.
cases, the compounds studied are fully described by their 1H and 13
NMR spectra.
C
A third reacting point is required on the chiral selector to
fix it on the chromatographic matrix and to test its enanti-
oselectivity in CSPs for HPLC. (4R)-Hydroxy-L-proline
was then used as the basic scaffold. The three functions of
this hydroxy amino acid allow the introduction of the two
aromatic rings previously mentioned and the fixation of
the selector through the third function (Figure 2).
Key words: amino acids, enantiomeric resolution, chirality, L-pro-
line derivatives, chiral selectors
Introduction
The enantioselectivity of doubly derivatized chiral selec-
tors can also be studied in solution (CCC14 or NMR).
Some selectors derivatized in the three functions have also
been prepared for this purpose. Here we address the syn-
thesis and spectroscopic characterization of these L-pro-
line derivatives (Figure 1).
Natural and synthetic enantiomerically pure a-amino ac-
ids have been extensively used as chiral moieties in the
preparation of chiral selectors for the separation of enan-
tiomers. In particular, multiple interaction chiral station-
ary phases (CSPs) for HPLC, also known as brush-type
phases or ‘Pirkle phases’, have chiral selectors of this
kind.1,2 The structural simplicity of these chiral selectors
facilitates their modification in order to assess the effect
of structural changes on enantioselectivity.
Results and Discussion
L-Proline derivatives have been mostly used as chiral moi-
ety in the so-called ‘ligand-exchange’ CSPs.3 However,
their applications as multiple interaction CSPs in chiral
liquid chromatography are few,4–9 although high enanti-
oselectivity is sometimes attained for certain enantiomer-
ic mixtures.7 L-Proline derivatives have also been used as
chiral selectors for chiral gas chromatography,10 chiral
countercurrent chromatography (CCC),11 capillary
electrophoresis12 or as chiral ligands for enantioselective
catalytic reactions.13 In this context, in our laboratory, the
preparation of chiral selectors derived from L-proline to
be used not only in CSPs for HPLC but also in CCC, enan-
tioselective liquid membranes or as chiral solvating
agents in NMR has been undertaken.
N-Acyl Derivatives of L-Proline and (4R)-Hydroxy-L-
proline
General methods were applied to prepare the L-proline
and (4R)-hydroxy-L-proline derivatives. The acylation of
the amino group of amino acids with the corresponding
acyl chloride in basic aqueous media was first described
by Saunders15,16 for the preparation of 3,5-dinitrobenzoyl
derivatives of amino acids. The same method has been
used as a general procedure for the preparation of N-acyl
derivatives of L-proline3,9 and other amino acids.17,18 The
N-acyl derivatives of L-proline and (4R)-hydroxy-L-pro-
line were obtained in moderate yields by this method
(Scheme 1). The use of an excess of the acyl chloride in
the reaction with (4R)-hydroxy-L-proline to obtain N,O-
diacylated derivatives yielded only the corresponding N-
acyl derivative. The formation of the O-acyl derivative
was not observed in any case.
Structural modifications on the chiral selectors have been
proposed either to adapt them to the intrinsic characteris-
tics of the technique or to improve enantioselectivity.
Thus, on the one hand, to tune lipophilicity while simulta-
neously maintaining the same chiral structure, several se-
lectors have been prepared from the same chiral entity. On
The reaction of N-acyl-L-proline derivatives with the ap-
propriate amine in the presence of 1-ethoxycarbonyl-2-
ethoxy-1,2-dihydroquinoline (EEDQ) as a coupling
agent19 yielded the corresponding N-acyl-L-prolinamides
(Scheme 1). The standard procedure (Method A) was
used in most cases. However, the characteristics of some
SYNTHESIS 2004, No. 8, pp 1171–1182
x
x
.
x
x
.2
0
0
4
Advanced online publication: 19.05.2004
DOI: 10.1055/s-2004-822384; Art ID: Z02304SS
© Georg Thieme Verlag Stuttgart · New York

1172
T. González et al.
PAPER
Figure 1 L-Proline and (4R)-hydroxy-L-proline derivatives.
ginning of the reaction prevented the formation of the de-
sired amide 14 when methanol was not added.
As usual in N-acylproline derivatives,20 the rotation of the
N-acyl bond is restricted in all the compounds prepared.
This restriction resulted either in the duplicity of peaks
1
both in H and 13C NMR spectra or in the broadening of
Figure 2 Possibilities to graft chiral selectors derived from (4R)-hy-
droxy-L-proline onto the chromatographic matrix.
signals in which coupling constants were hardly measur-
able for most of these compounds. Two-dimensional 1H-
1
1H and H-13C correlation spectra were recorded when
compounds led us to modify the reaction conditions.
Thus, the lack of reactivity of 11 in dichloromethane was
attributed to the low solubility of this compound in the
solvent. The use of DMF as a solvent allowed us to obtain
the amide 12. Nevertheless, the yield was low (27%) after
17 hours of reaction and only after 70 hours of reaction
was a maximum yield of 72% attained. The preparation of
14 required the addition of methanol as a cosolvent in the
reaction. In this case, the lack of solubility of the salt
formed between the acid 13 and n-butylamine at the be-
necessary to correctly assign signals to the two rotational
isomers. The relative population of rotational isomers de-
pends on substitution. Thus, while the rotamer assigned as
s-cis was hardly detectable for certain N-(3,5-dimethyl-
benzoyl), N-(3,5-dichlorobenzoyl) and N-docecanoyl de-
1
rivatives (up to 10–15%, calculated on H NMR spectra
using deuterated chloroform as solvent), N-(3,5-dini-
trobenzoyl) derivatives showed populations up to 30% of
this minor rotational isomer either in chloroform or in
R2
O
COOH
COOH
N
H
NH2-R2
O
ClCOR1
O
R1
N
N
NH
(a)
EEDQ / (b)
R1
R
R
R
R: H Pro
R: OH HPro
N-acyl-L-proline derivatives
(1, 5, 9, 11, 13, 17 and 19)
N-acyl-L-prolinamide derivatives
(2-4, 6-8, 10, 12, 14, 15, 18 and 20)
Scheme 1 Conditions: (a) 1 N NaOH, 0 °C; (b) CH2Cl2 (DMF for 12 and CH2Cl2–MeOH for 14).
Synthesis 2004, No. 8, 1171–1182 © Thieme Stuttgart · New York

PAPER
Synthetic Studies on L-Proline and (4R)-Hydroxy-L-proline Derivatives
1173
methanol. In compounds containing a N-boc group, two (Scheme 2). The O-acylation of derivative 16 was then at-
singlets (relative integration: 1:1.4) were usually observed tempted in biphasic Schotten–Baumann conditions or in
when spectra were acquired at room temperature. These refluxing pyridine, but without success. The starting prod-
singlets collapsed into a single signal when the tempera- uct was recovered in all assays. At this point, taking into
ture increased to 70 °C.
account the chemical stability required for a compound
used as a chiral selector, the carbamate function was con-
sidered in the derivatization of the hydroxyl group.
The lipophilicity of compounds 2–4 and 6–8 was compar-
atively estimated on the basis of a TLC essay on silica gel.
When eluting with ethyl acetate, the Rf for these com-
pounds were almost homogeneously distributed within
the range from 0.60 to 0.40, and provided an interesting
series of chiral selectors with the same chiral scaffold and
distinct lipophilicity. The N¢-(3,5-dimethylphenyl)-L-pro-
linamides 4 and 8 were the most lipophilic and the N¢-bu-
tyl-L-prolinamides 2 and 6 were the most polar
compounds in that group. In all cases, the N-(3,5-dini-
trobenzoyl) derivatives were more lipophilic than their N-
(3,5-dimethylbenzoyl) counterparts.
O-(3,5-Dimethylphenylaminocarbonyl) Derivatives of
(4R)-Hydroxy-L-proline
The direct double derivatization of (4R)-hydroxy-L-pro-
line with 3,5-dimethylphenyl isocyanate was carried out
in anhydrous pyridine (Scheme 2). Compound 32 was ob-
tained in 78% yield after purification by crystallization.
Most of the (4R)-hydroxy-L-proline derivatives prepared
showed six separate signals for the six protons of the pyr-
rolidine ring. However, usually it was not possible to mea-
sure the complete set of coupling constants. In this
context, compound 32 was an exception. The clear cou-
pling pattern for the cycloaliphatic protons of this com-
pound allowed the unequivocal direct assignment of each
Attempts to Obtain O-Acyl Derivatives of (4R)-Hy-
droxy-L-proline
The preparation of N-acetyl-O-benzoyl-L-hydroxyproline
and its O-debenzoylated analogue has been described.21
The lability of O-acyl derivatives of hydroxyl amino ac-
1
signal in the monodimensional H NMR spectrum (200
MHz) (Figure 3).
ids, such as hydroxyproline and serine under mild basic Compounds mono-derivatized with 3,5-dimethylphenyl
conditions, can be deducted from this study. The absence isocyanate were obtained from the N-protected amino
of O-acyl derivative in the direct acylation of hydroxypro- acid (Scheme 3). Thus, compound 26 is a key intermedi-
line with acyl halides can be attributed to this lability, ate in the synthesis of chiral selectors that have either the
which may be related to the presence of the free carboxy- carboxy (28, 30) or the amino groups (34) free to be bond-
lic acid. Thus, to obtain chiral selectors with the carboxyl ed to the chromatographic matrix. Compound 26 was first
group free to be grafted onto the chromatographic matrix, obtained from commercially available dicyclohexylam-
the phthalimidomethyl group was chosen as a protecting monium N-tert-butoxycarbonyl-(4R)-hydroxy-L-proli-
group removable in mild acidic conditions. Although the nate. Because of the interference of dicyclohexylamine
protection of carboxylic acids with this group in free ami- present in the reaction as a counter-ion in the starting
no acids has been reported,22 the direct protection of (4R)- product, an excess of 3.5 equivalents of 3,5-dimethylphe-
hydroxy-L-proline by the reaction with phthalimidometh- nyl isocyanate was determined as the optimum ratio of re-
yl chloride was not possible. However, a moderate yield agents for the reaction. In these conditions, 26 was
of 16 was obtained from the N-acyl derivative 13 obtained in 45% yield. The reaction was not improved ei-
O
O
O
N
O
N
COOH
O
O
Cl
O
N
O
N
HO
(a)
HO
CH3
CH3
16
13
H3C
H3C
CH3
CH3
COOH
N
COOH
NH
O
CH3
CH3
O
H3C
N C O
HN
H3C
N
O
(b)
H
HO
32
Scheme 2 Conditions: (a) DMSO, 70 °C; (b) pyridine, 115 °C.
Synthesis 2004, No. 8, 1171–1182 © Thieme Stuttgart · New York

1174
T. González et al.
PAPER
Figure 3 Full assignment of pyrrolidine proton signals in the 1H NMR spectra of 32.
ther by using DMF as a nonbasic polar solvent or by add- used was reduced to 1.5 equivalents with respect to the
ing dibutyltin dilaurate, a catalyst in the preparation of amino acid and the yield in 26 increased up to 90%.
carbamates.23,24 Only N,N¢-bis(3,5-dimethylphenyl)urea
The derivatization of the carboxy group of 26 by reaction
from the decomposition of the isocyanate during the
with 3,5-dimethylaniline in the presence of EEDQ yielded
workup procedure, and N-(3,5-dimethylphenyl)-N¢,N¢-di-
27. In the same reaction, ethyl N-(3,5-dimethylphe-
cyclohexylurea, from the reaction of the latter with dicy-
nyl)carbamate was isolated. The detection of ethyl N-(2-
clohexylamine were obtained when DMF was used. No
thiazolyl)carbamate as a by-product in the formation of an
increase in the yield of 26 was detected when using the
amide link has been reported when using EEDQ.25 How-
ever, although these authors propose a direct reaction be-
catalyst. The commercialization of the free N-boc-protect-
ed amino acid allowed us to use it as starting material. In
tween the amine and the coupling agent, we suggest that
this case, the amount of 3,5-dimethylphenyl isocyanate
in our case this product results from the reaction of the
H3C
H3C
COOH
CH3
CH3
N
BOC
O
O
CH3
CH3
NH
BOC
NH
NH
(c)
HO
(a)
O
O
O
N
(b)
CH3
COOH
34
H3C
N
O
H3C
N
O
27
H
H
N
BOC
H3C
N
H
O
26
O
(c)
CH3
CH3
COOH
N
NHBu
O
CH3
COOH
NH
O
O
O
N
(d)
(b)
O
H3C
N
O
H3C
N
O
H
H
R
R
H3C
N
O
H
35
R: NO2 28
R: CH3 30
R: NO2 29
R: CH3 31
R
R
Scheme 3 Reagents and conditions: (a) 3,5-Me2C6H3NCO, pyridine, 115 °C; (b) RNH2, EEDQ, CH2Cl2, r.t.; (c) TFA/CH2Cl2 (30:70), r.t.;
(d) 3,5-R2C6H3COCl, 1 N NaOH, 0 °C.
Synthesis 2004, No. 8, 1171–1182 © Thieme Stuttgart · New York

PAPER
Synthetic Studies on L-Proline and (4R)-Hydroxy-L-proline Derivatives
1175
aniline on the carbonate intermediate when EEDQ is used The removal of the protecting group on 26, followed by
as coupling agent (Scheme 4). The steric hindrance the reaction with the appropriate acyl chloride, yielded the
caused by the tert-butoxycarbonyl group promotes the acids 28 and 30, but only in moderate to low yields. Alter-
formation of this by-product. This mechanism explains natively, 30 was obtained from 13 by reaction with 3,5-
the absence of the same by-product when using 3,5-dime- dimethylphenyl isocyanate (Scheme 5). This alternative
thylaniline and EEDQ on other substrates. The steric hin- route allowed the preparation of 30 from (4R)-hydroxy-L-
drance between the tert-butoxycarbonyl group and the proline with a higher global yield (39% versus 10%).
1
dimethylphenyl group in 27 can also be seen in the H However, it was not possible to obtain 28 from 11 by the
NMR spectrum, which particularly lacked resolution for analogous reaction. Compound 28 was not detectable in
this compound in CDCl3 at room temperature. When py- the complex mixture resulting from the treatment of 11
ridine-d5 was used as solvent instead of CDCl3 all signals with 3,5-dimethylphenyl isocyanate. Compounds 28 and
in the 1H NMR spectrum were duplicated. The same spec- 30 were further derivatized by the reaction with n-butyl-
trum recorded at 70 °C showed single broad absorptions. amine. Amides 29 and 31, respectively, were obtained in
The removal of the N-tert-butoxycarbonyl group with moderate yields.
TFA produced 34 in a high yield.
O
OEt
O
O
b
CH3
CH3
COOH
BOC
N
OEt
OEt
O
O
O
N
BOC
N
H3C
N
O
H3C
N
O
H
H
26
a
a
H3C
NH2
b
H3C
CH3
H3C
CH3
H
O
N
OEt
CH3
NH
BOC
O
O
N
CH3
H3C
N
O
27
H
Scheme 4
CH3
(a)
COOH
N
CH3
COOH
N
O
O
O
H3C
N C O
HO
CH3
H3C
N
O
H
CH3
13
H3C
30
H3C
O
R2
NH
O
R2
NH
O
O
O
ClCOR
(b)
N
N
R
O
HO
CH3
CH3
H3C
R: 3,5-(CH3)2C6H3 23
R2: 3,5-(CH3)2C6H3 R: 3,5-(CH3)2C6H3 24
R2: C4H9
R: 3,5-(NO2)2C6H3 25
H3C
R2: C4H9
R2: C4H9
14
R2: 3,5-(CH3)2C6H3 15
Scheme 5 Conditions: (a) pyridine, 115 °C; (b) 2 N NaOH/CHCl3 (20:80), r.t.
Synthesis 2004, No. 8, 1171–1182 © Thieme Stuttgart · New York

1176
T. González et al.
PAPER
N-Acyl Derivatives of L-Proline and (4R)-Hydroxy-L-proline;
General Procedure (Scheme 1)
O-Acyl Derivatives of (4R)-Hydroxy-L-proline
Following the method described,16 the corresponding amino acid L-
proline or (4R)-hydroxy-L-proline (8.7 mmol) was dissolved in aq 1
N NaOH (10 mL) and cooled in an ice-bath. The appropriate acyl
chloride (9.6 mmol) and aq 1 N NaOH (15 mL) were added sepa-
rately and simultaneously over 20 min. The solution was stirred at
r.t. for 90 min and acidified with conc. HCl (pH 2–3).
Further derivatization can be introduced on compounds
which still have a free hydroxyl group. Thus, the reaction
of 14 and 15 with the appropriate acyl chloride under bi-
phasic Schotten–Baumann conditions yielded 23, 24, and
25 (Scheme 5). The preparation of 23 or 24 from 14 con-
firms the involvement of the free acid in the lability of the
ester function on position 4, since the reversal order of de-
rivatization does not allow to obtain the doubly acylated
N-(3,5-Dinitrobenzoyl)-L-proline (1)
The precipitate obtained was collected by filtration and crystallized
compounds. However, in spite of the several reaction con- from 96% EtOH; yield: 83%; mp 176–177 °C (Lit.4 mp 177 °C);
[a]D20 –89.4 (c = 1, abs EtOH) [Lit.4 [a]D25 –91.0 (c = 1, abs
ditions tested, it was not possible to obtain the correspond-
ing O-acyl derivatives from 20.
EtOH)].
1H NMR (500 MHz, CDCl3/CD3OD): d = 1.94 (m, 1 H, C4Ha), 2.03
The preparation of O-acyl derivatives was also possible
(m, C4H2, s-cis), 2.07 (m, 1 H, C4Hb), 2.12 (m, 1 H, C3Ha), 2.20 (m,
from N-boc-(4R)-hydroxy-L-proline by the reversal of de-
rivatization order relating to the preparation of 34
(Scheme 6). Thus, 21 was successfully obtained in a high
yield by coupling of 3,5-dimethylaniline on the amino ac-
id. The formation of ethyl 3,5-dimethylphenylcarbamate
as a by-product in this reaction was also detected. The es-
ter 22 was prepared satisfactorily by the O-acylation of
21. However, it was not possible to obtain the 3,5-dini-
trobenzoyl derivative of 21 when using 3,5-dinitroben-
zoyl chloride, in spite of the diverse reaction conditions
tested. As in the case of 27, the slow molecular mobility
in the NMR time scale for 22 resulted in spectra that
lacked resolution at room temperature. The removal of the
N-protecting group of this compound with TFA under the
same conditions used for 26 and 27 allowed us to obtain
the amine 33 in a high yield.
C3Ha, s-cis), 2.25 (m, C3Hb, s-cis), 2.34 (m, 1 H, C3Hb), 3.47 (m, 1
H, C5Ha), 3.62 (m, 1 H, C5Hb), 3.85 (m, C5H2, s-cis), 4.38 (dd, C2H,
s-cis), 4.62 (dd, 1 H, J = 5, 8.5 Hz, C2H), 8.56 (d, C2¢,6¢H, s-cis), 8.72
(d, 2 H, C2¢,6¢H), 8.99 (t, C4¢H, s-cis), 9.05 (t, 1 H, C4¢H).
13C NMR (75.5 MHz, CDCl3/CD3OD): d = 22.3 (C4H2, s-cis), 25.1
(C4H2), 29.1 (C3H2), 31.1 (C3H2, s-cis), 47.0 (C5H2, s-cis), 49.9
(C5H2), 59.5 (C2H), 61.3 (C2H, s-cis), 119.5 (C4¢H, s-cis), 119.9
(C4¢H), 127.0 (C2¢,6¢H, s-cis), 127.4 (C2¢,6¢H), 139.0 (C1¢), 139.9 (C1¢,
s-cis), 148.2 (C3¢,5¢), 164.9 (CON), 173.1 (CO2H).
N-(3,5-Dimethylbenzoyl)-L-proline (5)
The mixture obtained was extracted with EtOAc. The organic ex-
tracts were washed with H2O, dried, filtered and the solvent was re-
moved under reduced pressure. The resulting solid was crystallized
from EtOH–H2O; yield: 69%; mp 143–144 °C; [a]D20 +74.1 (c = 1,
96% EtOH).
1H NMR (200 MHz, CDCl3): d = 1.92 (m, 1 H, C4Ha), 1.99 (m, 1 H,
C4Hb), 2.10–2.50 (m, 2 H, C3H2), 2.34 (s, 6 H, 2 ArCH3), 3.57 (t, 2
H, C5H2), 3.75 (t, C5H2, s-cis), 4.35 (dd, C2H, s-cis), 4.74 (dd, 1 H,
J = 5, 8 Hz, C2H), 7.09 (s, 1 H, C4¢H), 7.15 (s, 2 H, C2¢,6¢H), 7.95 (br
s, 1 H, CO2H).
13C NMR (50.3 MHz, CDCl3): d = 21.1 (2 CH3Ar), 22.1 (C4H2,
s-cis), 25.0 (C4H2), 28.7 (C3H2), 30.8 (C3H2, s-cis), 46.1 (C5H2,
s-cis), 50.2 (C5H2), 59.3 (C2H), 61.4 (C2H, s-cis), 124.0 (C2¢,6¢H,
s-cis), 124.6 (C2¢,6¢H), 131.3 (C4¢H, s-cis), 131.8 (C4¢H), 135.3 (C1¢),
137.8 (C3¢,5¢), 171.2 (CON), 174.8 (CO2H), 175,6 (CO2H, s-cis).
1
All organic solutions were dried over Na2SO4. H and 13C NMR
spectra were recorded either on a Varian Gemini-200 instrument, a
Varian Gemini-300, a Varian Mercury 400 or a Varian VXR500.
The field of the instrument used is indicated in each case. Chemical
shifts are quoted in d values downfield from TMS, and J values are
given in Hz. All melting points are uncorrected. Optical rotation
values were determined in a Perkin-Elmer 241 polarimeter. Ele-
mental analyses were performed on a CE Instruments apparatus
Mod. EA 1108 (Carlo Erba Instruments, Milan, Italy) using stan-
dard conditions by the Serveis Científico-Tècnics de la Universitat
de Barcelona (Spain).
N-(3,5-Dichlorobenzoyl)-L-proline (9)
The resulting mixture was extracted with EtOAc. The solid ob-
tained from the organic extracts was crystallized from EtOH–H2O;
yield: 80%; mp 108–111 °C; [a]D20 –75.6 (c = 1, abs EtOH).
H3C
H3C
H3C
COOH
BOC
CH3
CH3
CH3
O
O
O
N
NH
BOC
NH
NH
NH
(a)
(b)
(c)
HO
O
O
N
N
BOC
H3C
H3C
HO
O
O
21
22
33
CH3
CH3
Scheme 6 Reagents and Conditions: (a) 3,5-Me2C6H3NH2, EEDQ, CH2Cl2, r.t.; (b) 3,5-Me2C6H3COCl, 2 N NaOH/CHCl3 (25:75), r.t.;
(c) TFA/CH2Cl2 (30:70), r.t.
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Synthetic Studies on L-Proline and (4R)-Hydroxy-L-proline Derivatives
1177
1H NMR (400 MHz, CDCl3): d = 1.95 (m, 1 H, C4Ha), 2.07 (m, 1 H,
C3Ha), 2.18 (m, 1 H, C4Hb), 2.33 (m, 1 H, C3Hb), 3.53 (m, 1 H,
C5Ha), 3.60 (m, 1 H, C5Hb), 3.76 (m, C5H2, s-cis), 4.32 (d, C2H,
s-cis), 4.69 (dd, 1 H, C2H), 7.29 (s, C2¢,6¢H, s-cis), 7.38 (s, C4¢H,
s-cis), 7.44 (s, 3 H, C2¢,6¢H and C4¢H).
13C NMR (100.6 MHz, CDCl3): d = 22.2 (C4H2, s-cis), 25.1 (C4H2),
29.3 (C3H2), 30.1 (C3H2, s-cis), 46.6 (C5H2, s-cis), 50.1 (C5H2), 59.4
(C2H), 61.0 (C2H, s-cis), 125.7 (C2¢,6¢H), 128.6 (C2¢,6¢H, s-cis), 130.4
(C4¢H), 133.4 (C4¢H, s-cis), 135.2 (C3¢,5¢), 138.3 (C1¢), 167.4
(CONH), 175.6 (CO2H).
Anal. Calcd for C12H11Cl2NO4: C, 47.39; H, 3.65; Cl, 23.31; N,
4.61. Found: C, 47.50; H, 3.75; Cl, 23.10; N, 4.45.
N-Dodecanoyl-(4R)-hydroxy-L-proline (19)
The solid obtained was collected by filtration and crystallized from
Et2O–hexane; yield: 74%; mp 86–87 °C; [a]D20 –39.3 (c = 1, 96%
EtOH).
1H NMR (200 MHz, CDCl3): d = 0.86 (t, 3 H, C12¢H3), 1.24 (m, 16
H, C4¢–11¢H2), 1.62 (m, 2 H, C3¢H2), 2.20 (m, 1 H, J3a,3b = 13.2 Hz,
J2,3a = 8 Hz, J4,3a = 4.4 Hz, C3Ha), 2.34 (t, 2 H, CH2CO), 2.43 (m,
1 H, J2,3b = 8 Hz, J4,3b = 4.4 Hz, C3Hb), 3.52 (dd, 1 H, J5a,5b = 11 Hz,
Anal. Calcd for C12H11Cl2NO3: C, 50.02; H, 3.85; Cl, 24.61; N,
4.86. Found: C, 50.10; H, 4.05; Cl, 24.31; N, 4.65.
J
4,5a = 2.6 Hz, C5Ha), 3.65 (dd, 1 H, J4,5b = 4.4 Hz, C5Hb), 4.57 (m,
1 H, C4H), 4.65 (dd, 1 H, C2H), 5.45 (br s, 2 H, OH and CO2H).
N-(3,5-Dinitrobenzoyl)-(4R)-hydroxy-L-proline (11)
The solid obtained was collected by filtration and crystallized from
Et2O–hexane; yield: 40%; mp 116–117 °C; (Lit.4 mp 100 °C);
[a]D20 –154.5 (c = 1, 96% EtOH) [Lit.4 [a]D25 –129.5 (c = 1, abs
EtOH)].
13C NMR (75.5 MHz, CDCl3): d = 14.1 (C12¢H3), 22.6 (C11¢H2), 24.6
(C3¢H2), 29.5 (C4¢–9¢H2), 31.9 (C10¢H2), 34.5 (C2¢H2), 37.0 (C3H2),
55.1 (C5H2), 58.0 (C4H), 69.7 (C2H), 174.3 and 174.4 (CO2H and
CON).
N-Acyl-L-prolinamide Derivatives; General Procedure
Method A, Scheme 1: The appropriate amine (1.1 mmol) was added
to a solution of the corresponding N-acyl derivative (1, 5, 9, 17 or
19) and EEDQ (1.1 equiv) in CH2Cl2 (20 mL). The mixture was
stirred at r.t. for 24 h. The resulting solution was washed with 2 N
HCl, 5% NaHCO3 and H2O. The solid obtained from the organic ex-
tracts was crystallized from the appropriate solvent.
1H NMR (200 MHz, CD3OD): d = 2.27 (m, 1 H, C3Ha), 2.39 (m, 1
H, C3Ha, s-cis), 2.54 (m, 1 H, J3a,3b = 12 Hz, C3Hb), 2.73 (m, C3Hb,
s-cis), 3.52 (dd, 1 H, C5Ha), 3.83 (dd, C5Ha, s-cis), 3.93 (m, C5Hb,
s-cis), 3.99 (dd, 1 H, J5a,5b = 12 Hz, J4,5b = 3.6 Hz, C5Hb), 4.55 (m, 1
H, C4H), 4.62 (m, C4H, s-cis), 4.72 (dd, C2H, s-cis), 4.86 (dd, 1 H,
J
2,3a = J2,3b = 8 Hz, C2H), 8.84 (d, C2¢,6¢H, s-cis), 8.92 (d, 2 H, C2¢,6¢H),
9.16 (t, C4¢H, s-cis), 9.19 (t, 1 H, C4¢H).
13C NMR (50.3 MHz, CD3OD): d = 38.8 (C3H2), 40.7 (C3H2, s-cis),
56.3 (C5H2, s-cis), 58.9 (C5H2), 59.6 (C2H), 61.1 (C2H, s-cis), 69.4
(C4H, s-cis), 71.1 (C4H), 120.9 (C4¢H, s-cis), 121.3 (C4¢H), 128.5
(C2¢,6¢H, s-cis), 128.8 (C2¢,6¢H), 140.0 (C3¢,5¢), 140.6 (C3¢,5¢, s-cis),
149.9 (C1¢), 167.6 (CON), 174.7 (CO2H, s-cis), 175.2 (CO2H).
N-(3,5-Dinitrobenzoyl)-N¢-(butyl)-L-prolinamide (2)
Yield: 68%; mp 139–140 °C (EtOH–H2O); [a]D20 –87.0 (c = 1, 96%
EtOH).
1H NMR (500 MHz, CDCl3): d = 0.92 (t, 3 H, C4¢¢H3), 1.36 (m, 2 H,
C3¢¢H2), 1.52 (m, 2 H, C2¢¢H2), 1.92 (m, 1 H, C4Ha), 2.05 (m, C4H2,
s-cis), 2.15 (m, 1 H, C3Ha), 2.21 (m, 1 H, C4Hb), 2.40 (m, 1 H, C3Hb),
3.13 (m, C1¢¢H2, s-cis), 3.29 (m, 2 H, C1¢¢H2), 3.48 (m, 1 H, C5Ha),
3.69 (m, 1 H, C5Hb), 3.85 (m, C5H2, s-cis), 4.16 (m, C2H, s-cis), 4.64
(dd, 1 H, C2H), 5.72 (br s, NH, s-cis), 6.48 (br s, 1 H, NH), 8.60 (d,
N-(3,5-Dimethylbenzoyl)-(4R)-hydroxy-L-proline (13)
The resulting mixture was extracted with EtOAc. The solid ob-
tained from the evaporation of the organic extracts was crystallized
from EtOH–H2O; yield: 50%; mp 194–195 °C; [a]D20 –121.0 (c = 1,
96% EtOH).
1H NMR (200 MHz, CDCl3/CD3OD): d = 2.16 (m, 1 H, C3Hb), 2.33
(s, 6 H, 2 CH3Ar), 2.41 (m, 1 H, C3Ha), 3.48 (m, 1 H, C5Ha), 3.77
(dd, 1 H, J5a,5b = 11.5 Hz, J4,5b = 4 Hz, C5Hb), 4.20 (br s, 1 H, OH),
4.42 (m, 1 H, C4H), 4.52 (m and m, C2H and C4H, s-cis), 4.75 (dd,
1 H, J2,3a = J 2,3b = 8.8 Hz, C2H), 7.04 (s, ArH, s-cis), 7.09 (s, 1 H,
C4¢H), 7.15 (s, 2 H, C2¢,6¢H).
13C NMR (75.5 MHz, CDCl3/CD3OD): d = 21.0 (CH3Ar), 37.4
(C3H2), 39.4 (C3H2, s-cis), 54.8 (C5H2, s-cis), 57.8 (C5H2 and C2H),
60.6 (C2H, s-cis), 68.1 (C4H, s-cis), 69.6 (C4H), 124.2 (C2¢,6¢H,
s-cis), 124.8 (C2¢,6¢H), 131.0 (C4¢H, s-cis), 132.0 (C4¢H), 135.2 (C1¢),
137.9 (C3¢,5¢), 171.5 (CON), 174.0 (CO2H).
C
2¢,6¢H, s-cis), 8.72 (m, 2 H, C2¢,6¢H), 9.04 (d, C4¢H, s-cis), 9.10 (m, 1
H, C4¢H).
13C NMR (50.3 MHz, CDCl3): d = 13.6 (C4¢¢H3), 19.9 (C3¢¢H2), 22.3
(C4H2, s-cis), 25.5 (C4H2), 28.3 (C2¢¢H2), 31.4 (C3H2), 32.1 (C3H2,
s-cis), 39.4 (C1¢¢H2), 48.0 (C5H2, s-cis), 50.4 (C5H2), 60.7 (C2H),
63.3 (C2H, s-cis), 119.5 (C4¢H, s-cis), 120.0 (C4¢H), 127.2
(C2¢,6¢H, s-cis), 127.6 (C2¢,6¢H), 139.3 (C1¢), 148.3 (C3¢,5¢), 165.3
(CON), 170.2 (CONH).
Anal. Calcd for C16H20N4O6: C, 52.74; H, 5.53; N, 15.38. Found: C,
52.61; H, 5.52; N, 15.08.
N-(3,5-Dinitrobenzoyl)-N¢-(octadecyl)-L-prolinamide (3)
Yield: 62%; mp 132–133 °C (96% EtOH); [a]D20 –32.8 (c = 1, py-
ridine).
1H NMR (200 MHz, CDCl3/CD3OD): d = 0.88 (t, 3 H, CH3), 1.25
(m, 30 H, C3¢¢–17¢¢H2), 1.54 (m, 1 H, C2¢¢H2), 1.95 (m, 1 H, C4Ha), 2.21
(m, 3 H, C4Hb and C3H2), 3.06 (t, C1¢¢H2, s-cis), 3.27 (t, 2 H, C1¢¢H2),
3.47 (m, 1 H, C5Ha), 3.76 (m, 1 H, C5Hb), 4.18 (m, C2H, s-cis), 4.57
(dd, 1 H, C2H), 8.63 (m, C2¢,6¢H, s-cis), 8.83 (m, 2 H, C2¢,6¢H), 9.06
(m, C4¢H, s-cis), 9.12 (m, 1 H, C4¢H).
13C NMR (50.3 MHz, CDCl3/CD3OD): d = 14.1 (C18¢¢H3), 22.7
(C17¢¢H2), 25.6 (C4H2), 26.9 and 28.0 (C3H2 and C3¢¢H2), 29.2–30.8
(C4¢¢–16¢¢H2), 31.9 (C2¢¢H2), 39.9 (C1¢¢H2), 50.3 (C5H2), 60.7 (C2H),
120.1 (C4¢H), 127.6 (C2¢,6¢H), 139.4 (C1¢), 148.5 (C3¢,5¢), 165.2
(CON), 169.7 (CONH).
Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C,
63.51; H, 6.20; N, 5.38.
N-(3,5-Dichlorobenzoyl)-(4R)-hydroxy-L-proline (17)
The solid obtained was crystallized from EtOH–H2O; yield: 70%;
mp 223–225 °C; [a]D20 –116.4 (c = 1, abs EtOH).
1H NMR (400 MHz, CDCl3): d = 2.16 (m, 1 H, C3Ha), 2.20 (m,
C3Ha, s-cis), 2.40 (m, 1 H, C3Hb), 3.44 (d, 1 H, C5Ha), 3.69 (m, C5Ha,
s-cis), 3.75 (dd, 1 H, C5Hb), 3.85 (m, C5Hb, s-cis), 4.33 (m and br s,
2 H, C4H and OH), 4.44 (m, C4H, s-cis), 4.54 (dd, C2H, s-cis), 4.75
(dd, 1 H, C2H), 7.37 (s, C2¢,6¢H, s-cis), 7.41 (s, C4¢H, s-cis), 7.45 (s,
3 H, C2¢,6¢H and C4¢H).
13C NMR (100.6 MHz, CDCl3/CD3OD): d = 37.4 (C3H2), 39.0
(C3H2, s-cis), 55.0 (C5H2, s-cis), 57.6 (C5H2), 57.9 (C2H), 59.8
(C2H, s-cis), 67.8 (C4H, s-cis), 69.5 (C4H), 125.4 (C2¢,6¢H, s-cis),
125.6 (C2¢,6¢H), 128.2 (C4¢H, s-cis), 130.2 (C4¢H), 135.0 (C3¢,5¢), 138.2
(C1¢), 167.7 (CON), 173.8 (CO2H).
Anal. Calcd for C30H48N4O6: C, 64.26; H, 8.63; N, 9.99. Found: C,
64.29; H, 8.63; N, 9.94.
Synthesis 2004, No. 8, 1171–1182 © Thieme Stuttgart · New York

1178
T. González et al.
PAPER
N-(3,5-Dinitrobenzoyl)-N¢-(3,5-dimethylphenyl)-L-prolina-
13C NMR (50.3 MHz, CDCl3): d = 21.1 and 21.2 (2 CH3Ar¢ and 2
CH3Ar¢¢), 25.2 (C4H2), 26.7 (C3H2), 50.5 (C5H2), 60.5 (C2H), 117.3
(C2¢¢,6¢¢H), 124.6 (C2¢,6¢H), 125.4 (C4¢¢H), 131.8 (C4¢H), 135.8 (C1¢),
138.0 and 138.3 (C3¢,5¢ and C3¢¢,5¢¢) 138.1 (C1¢¢), 168.9 (CON), 172.0
(CONH).
mide (4)
Yield: 41%; mp 230–231 °C (acetone–hexane); [a]D20 –49.4 (c = 1,
96% EtOH).
1H NMR (200 MHz, CDCl3/CD3OD): d = 2.00 (m, 1 H, C4Ha), 2.28
(m, 3 H, C4Hb and C3H2), 2.30 (s, 6 H, 2 CH3Ar), 3.57 (m, 1 H,
C5Ha), 3.80 (m, 1 H, C5Hb), 4.35 (dd, C2H, s-cis), 4.76 (dd, 1 H,
C2H), 6.70 (s, C4¢¢H, s-cis), 6.77 (s, 1 H, C4¢¢H), 6.86 (s, C2¢¢,6¢¢H,
s-cis), 7.22 (s, 2 H, C2¢¢,6¢¢H), 8.64 (d, C2¢,6¢H, s-cis), 8.87 (d, 2 H,
Anal. Calcd for C22H26N2O2: C, 75.40; H, 7.48; N, 7.99. Found: C,
75.20; H, 7.37; N, 7.97.
N-(3,5-Dichlorobenzoyl)-N¢-(3,5-dimethylphenyl)-L-prolin-
C
2¢,6¢H), 8.91 (m, C4¢H, s-cis), 9.13 (m, 1 H, C4¢H).
amide (10)
Yield: 50%; mp 249–250 °C (96% EtOH); [a]D20 +178.7 (c = 1,
13C NMR (75.5 MHz, DMSO-d6): d = 21.0 (2 CH3Ar), 22.7 (C4H2,
s-cis), 24.8 (C4H2), 29.8 (C3H2), 31.6 (C3H2, s-cis), 47.2 (C5H2,
s-cis), 49.9 (C5H2), 61.1 (C2H), 62.0 (C2H, s-cis), 117.3 (C2¢¢,6¢¢H),
118.8 (C4¢H, s-cis), 119.6 (C4¢H), 124.9 (C4¢¢H), 125.2 (C4¢¢H, s-cis),
127.0 (C2¢,6¢H, s-cis), 127.4 (C2¢,6¢H), 137.6 (C3¢¢,5¢¢), 138.6, 139.1 and
140.0 (C1¢¢, C1¢ and C1¢, s-cis), 147.8 (C3¢,5¢, s-cis) , 148.0 (C3¢,5¢),
164.4 (CON), 164.9 (CON, s-cis), 169.6 (CONH), 170.0
(CONH, s-cis).
CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.93 (m, 1 H, C4Ha), 2.09 (m, 1 H,
C3Ha), 2.14 (m, 1 H, C4Hb), 2.24 (s, 6 H, 2 CH3Ar), 2.53 (m, 1 H,
C3Hb), 3.48 (m, 1 H, C5Ha), 3.59 (m, 1 H, C5Hb), 4.89 (dd, 1 H,
C2H), 6.69 (s, 1 H, C4¢¢H), 7.14 (s, 2 H, C2¢,6¢H), 7.41 (d, 2 H,
C
2¢¢,6¢¢H), 7.44 (d, 1 H, C4¢¢H); 9.14 (br s, 1 H, NH).
13C NMR (100.6 MHz, CDCl3): d = 21.2 (2 CH3Ar), 25.3 (C4H2),
27.2 (C3H2), 50.5 (C5H2), 61.0 (C2H), 117.4 (C2¢¢,6¢¢H), 125.6
(C2¢,6¢H), 125.8 (C4¢¢H), 130.3 (C4¢H), 135.3 (C3¢,5¢), 137.8 (C1¢¢),
138.4 (C3¢¢,5¢¢), 138.6 (C1¢), 168.4 (2 CON).
Anal. Calcd for C20H20N4O6: C, 58.25; H, 4.89; N, 13.59. Found: C,
58.26; H, 4.95; N, 13.43.
N-(3,5-Dimethylbenzoyl)-N¢-(butyl)-L-prolinamide (6)
Yield: 40%; mp 82–83 °C (Et2O–hexane); [a]D20 –76.2 (c = 1, 96%
EtOH).
Anal. Calcd for C20H20Cl2N2O2: C, 61.39; H, 5.15; Cl, 18.12; N,
7.16. Found: C, 61.60; H, 5.45; Cl, 17.80; N, 7.05.
1H NMR (200 MHz, CDCl3): d = 0.91 (t, 3 H, C4¢¢H3), 1.34 (m, 2 H,
C3¢¢H2), 1.48 (m, 2 H, C2¢¢H2), 1.78 (m, 1 H, C4Ha), 2.01 (m, 2 H,
C3Ha and C4Hb), 2.33 (s, 6 H, 2 CH3Ar), 2.47 (m, 1 H, C3Hb), 3.26
(m, 2 H, C1¢¢H2), 3.50 (m, 2 H, C5H2), 4.75 (dd, 1 H, C2H), 7.09 (m,
3 H, ArH), 7.12 (br s, 1 H, NH).
13C NMR (50.3 MHz, CDCl3): d = 13.6 (C4¢¢H3), 19.9 (C3¢¢H2), 21.1
(2 CH3Ar), 22.3 (C4H2, s-cis), 25.3 (C4H2), 26.9 (C2¢¢H2), 28.3
(C3H2, s-cis), 31.4 (C3H2), 39.2 (C1¢¢H2), 46.6 (C5H2, s-cis), 50.4
(C5H2), 59.6 (C2H), 63.2 (C2H, s-cis), 123.9 (C2¢,6¢H, s-cis), 124.5
(C2¢,6¢H), 131.7 (C4¢H), 136.1 (C1¢), 137.9 (C3¢,5¢), 170.9 and 171.5 (2
CON).
N-(3,5-Dichlorobenzoyl)-N¢-(3,5-dimethylphenyl)-(4R)-hy-
droxy-L-prolinamide (18)
Yield: 55%; mp 273–274 °C (EtOH–H2O); [a]D20 –100.0 (c = 1, abs
EtOH).
1H NMR (400 MHz, CD3OD): d = 2.10 (m, 1 H, C3Ha), 2.15 (s, 6 H,
2 CH3Ar), 2.38 (m, 1 H, C3Hb), 3.42 (d, 1 H, C5Ha), 3.79 (m, C5H2,
s-cis), 3.86 (m, 1 H, C5Hb), 4.46 (dd, 1 H, C4H), 4.54 (m, C4H,
s-cis), 4.60 (dd, C2H, s-cis), 4.70 (br s, 1 H, OH), 4.80 (dd, 1 H,
C2H), 6.74 (s, C4¢¢H, s-cis), 6.78 (s, 1 H, C4¢¢H), 6.85 (s, C2¢¢,6¢¢H,
s-cis), 7.24 (s, 2 H, C2¢¢,6¢¢H), 7.42 (s, C2¢,6¢H and C4¢H, s-cis), 7.62
(s, 3 H, C2¢,6¢H and C4¢H).
Anal. Calcd for C18H26N2O2: C, 71.49; H, 8.67; N, 9.26. Found: C,
71.10; H, 8.96; N, 9.43.
13C NMR (100.6 MHz, CDCl3): d = 20.4 (2 CH3Ar), 38.2 (C3H2),
40.3 (C3H2, s-cis), 56.0 (C5H2, s-cis), 58.7 (C5H2), 60.5 (C2H), 62.2
(C2H, s-cis), 68.1 (C4H, s-cis), 69.9 (C4H), 118.0 (C2¢¢,6¢¢H), 118.3
(C2¢¢,6¢¢H, s-cis), 125.7 (C2¢,6¢H, s-cis), 125.9 (C4¢¢H2), 126.1 (C2¢,6¢H),
126.3 (C4¢¢H, s-cis), 129.6 (C4¢H, s-cis), 130.2 (C4¢H), 135.2 (C3¢,5¢),
138.4 (C1¢), 138.5 (C3¢¢,5¢¢), 139.4 (C1¢¢), 167.5 (CON), 171.1
(CONH).
N-(3,5-Dimethylbenzoyl)-N¢-(octadecyl)-L-prolinamide (7)
Yield: 42%; mp 93–94 °C (96% EtOH); [a]D20 –51.3 (c = 1, 96%
EtOH).
1H NMR (200 MHz, CDCl3): d = 0.88 (t, 3 H, CH3), 1.25 (m, 30 H,
C
3¢¢–17¢¢H2), 1.52 (m, 1 H, C2¢¢Ha), 1.80 (m, 1 H, C4Ha), 2.00 (m, 2 H,
Anal. Calcd for C20H20Cl2N2O3: C, 58.98; H, 4.95; Cl, 17.41; N,
6.88. Found: C, 59.30; H, 5.05; Cl, 17.15; N, 6.63.
C4Hb and C3Ha), 2.33 (s, 6 H, 2 CH3Ar), 2.50 (m, 1 H, C3Hb), 3.25
(m, 2 H, C1¢¢H2), 3.50 (m, 2 H, C5H2), 4.28 (m, C2H, s-cis), 4.75 (m,
1 H, C2H), 7.09 (m, 3 H, ArH), 7.10 (br s, 1 H, NH).
N¢-(3,5-Dimethylphenyl)-N-dodecanoyl-(4R)-hydroxy-L-pro-
linamide (20)
13C NMR (50.3 MHz, CDCl3): d = 14.1 (C18¢¢H3), 21.2 (2 CH3Ar),
22.6 (C17¢¢H2), 25.3 (C4H2), 26.9 (C3H2 and C3¢¢H2), 29.2–29.6 (C4¢¢–
16¢¢H2), 31.9 (C2¢¢H2), 39.5 (C1¢¢H2), 50.4 (C5H2), 59.6 (C2H), 124.6
(C2¢,6¢H), 131.7 (C4¢H), 136.0 (C1¢), 138.0 (C3¢,5¢), 170.8 and 171.6 (2
CON).
Yield: 45%; mp 132–133 °C (EtOH–H2O); [a]D20 –49.2 (c = 1, 96%
EtOH).
1H NMR (200 MHz, CDCl3): d = 0.88 (t, 3 H, C12¢H3), 1.25 (m, 16
H, C4¢–11¢H2), 1.68 (m, 3 H, C3¢H2 and OH), 1.98 (m, 1 H, J3a,3b = 13
Hz, J2,3a = 8 Hz, C3Ha), 2.26 (s, 6 H, 2 CH3Ar), 2.28–2.45 (m, 2 H,
C2¢H2), 2.77 (dt, 1 H, J2,3b = 4.8 Hz, C3Hb), 3.45 (dd, 1 H, J5a,5b = 10.6
Hz, J4,5a = 4.4 Hz, C5Ha), 3.68 (dd, 1 H, J4,5b = 5.4 Hz, C5Hb), 4.70
(m, 1 H, C4H), 4.88 (dd, 1 H, C2H), 6.71 (s, 1 H, C4¢¢H), 7.15 (s, 2
H, C2¢¢,6¢¢H), 9.46 (br s, 1 H, NH).
13C NMR (50.3 MHz, CDCl3): d = 14.0 (C12¢H3), 21.2 (2 CH3Ar),
22.6 (C11¢H2), 24.7 (C3¢H2), 29.2–29.5 (C4¢–9¢H2), 31.8 (C10¢H2), 34.7
(C2¢H2), 35.9 (C3H2), 54.9 (C5H2), 59.3 (C4H), 70.0 (C2H), 117.4
(C2¢¢,6¢¢H), 125.8 (C4¢¢H), 137.8 (C1¢¢), 138.4 (C3¢¢,5¢¢), 169.3 (CONH),
174.2 (CON).
Anal. Calcd for C32H54N2O: C, 77.06; H, 10.91; N, 5.62. Found: C,
77.40; H, 10.91; N, 5.62.
N-(3,5-Dimethylbenzoyl)-N¢-(3,5-dimethylphenyl)-L-prolin-
amide (8)
Yield: 66%; mp 204–205 °C (96% EtOH); [a]D20 –129.0 (c = 1,
96% EtOH).
1H NMR (200 MHz, CDCl3): d = 1.86 (m, 1 H, C4Ha), 2.05 (m, 2 H,
C4Hb and C3Ha), 2.27 (s, 6 H, 2 CH3Ar¢¢), 2.33 (s, 6 H, 2 CH3Ar¢),
2.66 (m, 1 H, C3Hb), 3.51 (m, 2 H, C5H2), 4.99 (dd, 1 H, C2H), 6.72
(s, 1 H, C4¢¢H), 7.08 (s, 1 H, C4¢H), 7.10 (s, 2 H, C2¢¢,6¢¢H), 7.22 (s, 2
H, C2¢,6¢H), 9.53 (br s, 1 H, NH).
Anal. Calcd for C25H40N2O3: C, 72.08; H, 9.68; N, 6.72. Found: C,
71.88; H, 9.25; N, 6.72.
Synthesis 2004, No. 8, 1171–1182 © Thieme Stuttgart · New York

PAPER
Synthetic Studies on L-Proline and (4R)-Hydroxy-L-proline Derivatives
1179
N-Acyl-(4R)-hydroxy-L-prolinamide Derivatives; General Pro-
cedure
13C NMR (50.3 MHz, CDCl3): d = 21.0 and 21.1 (4 CH3Ar), 36.9
(C3H2), 58.6 (C5H2), 59.5 (C2H), 70.0 (C4H), 117.4 (C2¢¢,6¢¢H), 124.9
(C2¢,6¢H), 125.7 (C4¢¢H), 132.0 (C4¢H), 135.3 (C1¢), 137.7 (C1¢¢), 137.9
and 138.3 (C3¢,5¢ and C3¢¢,5¢¢), 169.5 (CON), 172.1 (CONH).
Method B, Scheme 1: Analogous to Method A, the appropriate
amine (2.5 equiv) was added to a solution of the N-acyl derivative
11 or 13 and EEDQ (2.5 equiv) in DMF (15 mL) for 11 and CH2Cl2
(15 mL) for 13. The mixture was stirred at r.t. and the course of the
reaction was controlled by TLC. The workup procedure was the
same as in Method A.
Anal. Calcd for C22H26N2O3: C, 72.11; H, 7.15; N, 7.64. Found: C,
72.25; H, 7.44; N, 7.68.
Phthalimidomethyl N-(3,5-Dimethylbenzoyl)-(4R)-hydroxy-L-
prolinate (16) (Scheme 2)
N-(3,5-Dinitrobenzoyl)-N¢-(3,5-dimethylphenyl)-(4R)-hydroxy-
L-prolinamide (12)
After a reaction time of 60 h, CH2Cl2 was added and the workup
procedure was followed in the usual way. Compound 12 was crys-
tallized from abs EtOH; yield: 72%; mp 215–216 °C; [a]D20 –155.9
(c = 1, 96% EtOH).
Following the procedure described,22 the previously prepared22 N-
chloromethylphthalimide (3.9 mmol) was added to a solution of 13
(3.8 mmol) and dicyclohexylamine (3.8 mmol), in DMSO (40 mL).
The mixture was stirred at 70 °C for 5 h. After extraction with
CH2Cl2, the solid obtained was crystallized from Et2O–hexane;
yield: 52%; mp 100–101 °C; [a]D20 –64.2 (c = 1, CHCl3).
1H NMR (200 MHz, CD3OD): d = 2.16 (m, 1 H, C3Ha), 2.20 (s, 6 H,
2 CH3Ar), 2.36 (m, 1 H, C3Hb), 3.38 (dd, 1 H, C5Ha), 3.76 (m, C5H2,
s-cis), 3.87 (dd, 1 H, J5a,5b = 12 Hz, J4,5b = 4 Hz, C5Hb), 4.45 (m, 1
1H NMR (200 MHz, CDCl3): d = 2.11 (m, 1 H, C3Ha), 2.27 (s, 6 H,
2 CH3Ar), 2.35 (m, 1 H, C3Hb), 2.73 (br s, 1 H, OH), 3.47 (dd, 1 H,
J
5a,5b = 10 Hz, C5Ha), 3.74 (dd, 1 H, J4,5b = 4 Hz, C5Hb), 4.45 (m, 1
H, C4H), 4.53 (m, C4H, s-cis), 4.84 (dd and br s, 2 H, J2,3a = J2,3b
=
H, C4H), 4.79 (dd, 1 H, J2,3a = J2,3b = 8 Hz, C2H), 5.83 (dd, 2 H,
8 Hz, C2H and OH), 6.60 (s, C4¢¢H, s-cis), 6.64 (s, C2¢¢,6¢¢H, s-cis),
6.70 (s, 1 H, C4¢¢H); 7.15 (s, 2 H, C2¢¢,6¢¢H), 8.60 (m, C2¢,6¢H, s-cis),
8.72 (m, C4¢H, s-cis), 8.82 (m, 2 H, C2¢,6¢H), 9.01 (m, 2 H, C4¢H).
CH2), 7.00 (s, 1 H, C4¢H), 7.09 (s, 2 H, C2¢,6¢H), 7.80 (m, 2 H,
C
5¢¢,6¢¢H), 7.91 (m, 2 H, C4¢¢,7¢¢H).
13C NMR (50.3 MHz, CDCl3): d = 21.1 (2 CH3Ar), 37.5 (C3H2),
57.6 (C5H2 and C2H), 61.0 (CH2), 70.1 (C4H), 123.8 (C4¢¢,7¢¢H), 124.9
(C2¢,6¢H), 131.6 and 131.8 (C4¢H and C4a¢¢,7a¢¢), 134.5 (C5¢¢,6¢¢H), 135.5
(C1¢), 137.7 (C3¢,5¢), 165.5 (CON), 170.4 (COO), 170.8 (CONCO).
13C NMR (50.3 MHz, CD3OD): d = 21.3 (2 CH3Ar, s-cis), 21.5 (2
CH3Ar), 39.5 (C3H2), 41.3 (C3H2, s-cis), 57.6 (C5H2, s-cis), 59.4
(C5H2), 61.7 (C2H), 62.8 (C2H, s-cis), 69.6 (C4H, s-cis), 71.2 (C4H),
118.4 (C2¢¢,6¢¢H, s-cis), 119.2 (C2¢¢,6¢¢H), 120.4 (C4¢H, s-cis), 121.2
(C4¢H), 127.1 (C2¢,6¢H), 127.4 (C2¢,6¢H, s-cis), 128.4 (C4¢¢H, s-cis),
128.9 (C4¢¢H), 139.2, 139.7 and 140.1 (C3¢¢,5¢¢, C1¢ and C1¢¢), 150.0
(C3¢,5¢), 167.7 (CON), 172.2 (CONH).
Anal. Calcd for C23H22N2O6: C, 65.40; H, 5.25; N, 6.63. Found: C,
65.16; H, 5.32; N, 6.58.
N,O-Bis(3,5-dimethylphenylaminocarbonyl)-(4R)-hydroxy-L-
proline (32) (Scheme 32)
Anal. Calcd for C20H20N4O7: C, 56.07; H, 4.71; N, 13.08. Found: C,
55.92; H, 4.52; N, 13.19.
The title compound was obtained by the reaction of (4R)-hydroxy-
L-proline (500 mg, 3.8 mmol) in anhyd pyridine (15 mL) with 3,5-
dimethylphenyl isocyanate (1.24 g, 8.4 mmol). After heating at re-
flux temperature for 5 h, the mixture was poured into ice/water and
extracted with EtOAc. The organic extracts were washed with 2 N
HCl and H2O. The resulting solid was crystallized from EtOH–H2O;
yield: 78%; mp 217–218 °C; [a]D20 +10.2 (c = 1, MeOH).
N¢-(Butyl)-N-(3,5-dimethylbenzoyl)-(4R)-hydroxy-L-prolin-
amide (14)
MeOH was added to the reaction mixture until the complete disso-
lution of the precipitate formed on the addition of the amine. After
4 days of reaction, the solid obtained was purified by crystallization
from acetone–hexane; yield: 57%; mp 152–153 °C; [a]D20 –90.3
(c = 1, 96% EtOH).
1H NMR (200 MHz, CDCl3): d = 0.89 (t, 3 H, C4¢¢H3), 1.34 (m, 2 H,
C3¢¢H2), 1.49 (m, 2 H, C2¢¢H2), 1.68 (br s, 1 H, OH), 2.07 (m, 1 H,
C3Ha), 2.32 (s, 6 H, 2 CH3Ar), 2.74 (m, 1 H, C3Hb), 3.25 (q, 2 H,
C1¢H2), 3.53 (dd, 1 H, C5Ha), 3.67 (dd, 1 H, J5a,5b = 10 Hz, J4,5b = 3.6
Hz, C5Hb), 4.48 (m, 1 H, C4H), 4.92 (dd, 1 H, J2,3a = J2,3b = 8.6 Hz,
C2H), 7.07 (s, 1 H, C4¢H), 7.10 (s, 2 H, C2¢,6¢H), 7.21 (br s, 1 H, NH).
1H NMR (200 MHz, CDCl3): d = 2.06 (m, 1 H, J2,3a = 11.4 Hz,
J
3a,3b = 14.0 Hz, J4,3a = 5.2 Hz, C3Ha), 2.30 (s, 6 H, 2 CH3Ar), 2.34
(s, 6 H, 2 CH3Ar), 2.59 (dd, 1 H, J2,3b = 6.2 Hz, C3Hb), 3.47 (d, 1 H,
J
5a,5b = 13.2, C5Ha), 4.15 (dd, 1 H, J4,5b = 5.6 Hz, C5Hb), 4.49 (dd, 1
H, C2H), 5.59 (m, 1 H, C4H), 6.59 (br s, 1 H, NH), 6.76 (s, 1 H,
C4¢H), 6.96 and 7.01 (s and s, 5 H, C4¢¢H, C2¢,6¢H and C2¢¢,6¢¢H).
13C NMR (50.3 MHz, CDCl3/CD3OD): d = 20.9 and 21.1 (CH3Ar),
34.5 (C3H2), 52.1 (C5H2), 61.9 (C2H), 76.0 (C4H), 116.4 (C2¢,6¢H),
123.6 (C2¢¢,6¢¢H), 125.2 (C4¢H), 130.2 (C4¢¢H), 131.0 (C1¢¢), 137.2 (C1¢),
138.5 and 138.8 (C3¢,5¢ and C3¢¢,5¢¢), 152.1 (HNCOO), 159.1
(NCONH), 172.1 (CO2H).
13C NMR (75.5 MHz, CDCl3): d = 13.7 (C4¢¢H3), 20.0 (C3¢¢H2), 21.1
(CH3Ar), 31.4 (C2¢¢H2), 36.4 (C3H2), 39.3 (C1¢¢H2), 58.5 (C5H2 and
C2H), 70.1 (C4H), 125.0 (C2¢,6¢H), 132.0 (C4¢H), 135.6 (C1¢), 137.9
(C3¢,5¢), 171.0 (CON), 172.1 (CONH).
Anal. Calcd. for C23H27N3O5: C, 64.92; H, 6.39; N, 9.87. Found: C,
64.96; H, 6.32; N, 9.98.
Anal. Calcd for C18H26N2O3: C, 67.90; H, 8.23; N, 8.80. Found: C,
67.53; H, 8.13; N, 8.99.
O-(3,5-Dimethylphenylaminocarbonyl)-(4R)-hydroxy-L-pro-
line Derivatives; General Procedures
N-(3,5-Dimethylbenzoyl)-N¢-(3,5-dimethylphenyl)-(4R)-hy-
droxy-L-prolinamide (15)
Method A: 3,5-Dimethylphenyl isocyanate (1.25 g, 8.5 mmol) was
added to dicyclohexylammonium N-(tert-butoxycarbonyl)-(4R)-
hydroxy-L-prolinate (1 g, 2.4 mmol) in anhyd pyridine (30 mL).
The solution was refluxed for 22 h. EtOAc and 2 N HCl were added
to the cooled mixture. The organic solution was washed with 2 N
HCl and extracted with 50% ammonia. The basic extracts were
acidified with 2 N HCl and extracted with EtOAc. The solid result-
ing from the evaporation of the acidic organic extracts was crystal-
lized from EtOH–H2O to afford 412 mg (45%) of 26. N-(3,5-
Dimethylphenyl)-N¢,N¢-dicyclohexylurea (570 mg) and N,N¢-
bis(3,5-dimethylphenyl)urea (760 mg) were isolated from the neu-
tral organic extracts by chromatography on silica gel.
After a reaction time of 17 h, the solid obtained was purified by
crystallization from EtOH–H2O; yield: 64%; mp 225–226 °C;
[a]D20 –153.8 (c = 1.5, CHCl3); [a]D20 –8.7 (c = 1, 96% EtOH).
1H NMR (200 MHz, CDCl3): d = 2.17 (m, 1 H, C3Ha), 2.26 (m, 6 H,
2 CH3Ar¢¢), 2.32 (s, 6 H, 2 CH3Ar¢), 2.86 (m, 1 H, C3Hb), 3.56 (dd,
1 H, C5Ha), 3.65 (dd, 1 H, J5a,5b = 10 Hz, J4,5b = 3.4 Hz, C5Hb), 4.52
(m, 1 H, C4H), 5.13 (dd, 1 H, J2,3a = J2,3b = 8 Hz, C2H), 6.72 (s, 1 H,
C4¢¢H), 7.08 (s, 1 H, C4¢H), 7.12 (s, 2 H, C2¢,6¢H), 7.21 (s, 2 H,
C
2¢¢,6¢¢H), 9.50 (br s, 1 H, NH).
Synthesis 2004, No. 8, 1171–1182 © Thieme Stuttgart · New York

1180
T. González et al.
PAPER
N-(3,5-Dimethylphenyl)-N¢,N¢-dicyclohexylurea
3.3 mmol for 26) in CH2Cl2 (20 mL) the appropriate amine (1.7
mmol, 3.3 mmol for 26) was added. The solution was stirred at r.t.
for 24 h (60 h for 26). The organic solution was washed with 2 N
HCl and aq 5% NaHCO3.
The solid was crystallized from EtOH–H2O; mp 262–263 °C.
1H NMR (200 MHz, CDCl3): d = 1.00 (m, 20 H, CH2cycl.), 2.27 (s,
6 H, 2 CH3Ar), 3.49 (m, 2 H, 2 CH), 6.18 (br s, 1 H, NH), 6.63 (s, 1
H, C4H), 7.01 (s, 2 H, C2,6H).
13C NMR (50.3 MHz, CDCl3): d = 21.3 (2 CH3Ar), 25.4 (C4H2),
26.3 (C3H2 and C5H2), 31.8 (C2H2 and C6H2), 55.3 (CHN), 117.1
(C2¢,6¢H), 124.2 (C4¢H), 138.4 (C3¢,5¢), 139.1 (C1¢), 154.5 (CO).
N-(tert-Butoxycarbonyl)-N¢-(3,5-dimethylphenyl)-(4R)-hy-
droxy-L-prolinamide (21) (Scheme 6)
The solid obtained was purified by chromatography on silica gel;
yield: 86%; mp 77–79 °C; [a]D20 –66.8 (c = 1, CHCl3).
1H NMR (300 MHz, DMSO-d6, 70 ºC): d = 1.31 [br s, 9 H,
C(CH3)3], 1.95 (m, 2 H, C3Ha), 2.15 (m, 1 H, C3Hb), 2.22 (s, 6 H, 2
CH3Ar), 3.17 (d, 1 H, C5Ha), 3.45 (dd, 1 H, C5Hb), 4.30 (m, 2 H, C2H
and OH), 4.85 (m, 1 H, C4H), 6.63 (s, 1 H, C4¢H), 7.21 (s, 2 H,
N,N¢-Bis(3,5-dimethylphenyl)urea
The solid was crystallized from 96% EtOH; mp 278–280 °C.
1H NMR (200 MHz, DMSO-d6): d = 2.22 (s, 12 H, 4 CH3Ar), 6.60
(s, 2 H, 2 C4H), 7.07 (s, 4 H, 2 C2,6H), 8.46 (s, 2 H, 2 NH).
C
2¢,6¢H), 9.60 (br s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 21.3 (ArCH3), 116.0 (C2,6H),
13C NMR (75.5 MHz, DMSO-d6, 70 °C): d = 20.9 (2 CH3Ar), 27.9
[C(CH3)3], 39.7 (C3H2), 54.9 (C5H2), 59.4 (C2H), 68.0 (C4H), 78.4
[(C(CH3)3], 117.0 (C2¢,6¢H), 124.5 (C4¢H), 137.3 (C3¢,5¢), 138.7 (C1¢),
153.4 (NCO2t-Bu), 170.9 (CONH).
123.6 (C4H), 137.9 (C3,5), 139.8 (C1), 152.6 (CO).
Method B: 3,5-Dimethylphenyl isocyanate (970 mg, 6.5 mmol) was
added to N-(tert-butoxycarbonyl)-(4R)-hydroxy-L-proline (1 g, 4.2
mmol) in anhyd pyridine (30 mL). The solution was refluxed during
22 h. The workup procedure was the same described in Method A.
Following this procedure 1.44 g of 26 (90% yield) was obtained af-
ter crystallization from EtOH–H2O.
Anal. Calcd for C18H26N2O3: C, 67.90; H, 8.23; N, 8.80. Found: C,
67.93; H, 8.30; N, 8.60.
N-(tert-Butoxycarbonyl)-N¢-(3,5-dimethylphenyl)-(4R)-(3,5-
dimethylphenylaminocarbonyloxy)-L-prolinamide (27)
(Scheme 3)
N-(tert-Butoxycarbonyl)-(4R)-(3,5-dimethylphenylaminocarbo-
nyloxy)-L-proline (26) (Scheme 3)
The solid obtained was crystallized from Et2O–hexane; yield: 65%;
Mp 185–186 °C; [a]D20 –40.2 (c = 1, 96% EtOH).
mp 115 °C; [a]D20 –51.1 (c = 1, CHCl3).
1H NMR (200 MHz, CDCl3): d = 1.45 and 1.48 (s and s, 9 H, 3 CH3),
2.29 (s, 6 H, 2 CH3Ar), 2.47 (m, 2 H, C3H2), 3.72 (m, 2 H, C5H2),
4.40 (dd, C2H, s-cis), 4.50 (dd, 1 H, J2,3a = J2,3b = 8 Hz, C2H), 5.32
(m, 1 H, C4H), 6.64 (br s, 1 H, NH), 6.74 (s, 1 H, C4¢H), 6.99 (s, 1
H, C2¢,6¢H).
1H NMR (200 MHz, CDCl3): d = 1.47 [s, 9 H, C(CH3)3], 2.29 (s, 12
H, 4 CH3Ar), 2.80 (m, 2 H, C3H2), 3.67 (m, 2 H, C5H2), 4.58 (m, 1
H, C2H), 5.32 (m, 1 H, C4H), 6.60 (s, 1 H, C4¢¢H), 6.73 (s, 2 H, C4¢H
and NHCOO), 7.00 (s, 2 H, C2¢¢,6¢¢H), 7.15 (s, 2 H, C2¢,6¢H), 9.15 (br
s, 1 H, CONH).
13C NMR (50.3 MHz, CDCl3): d = 21.3 (CH3Ar), 28.2 [C(CH3)3,
s-cis], 28.3 [C(CH3)3], 35.2 (C3H2), 36.7 (C3H2, s-cis), 52.0
(C5H2, s-cis), 52.7 (C5H2), 57.6 (C2H), 57.8 (C2H, s-cis), 72.7 (C4H,
s-cis), 73.2 (C4H), 81.0 [C(CH3)3, s-cis], 81.4 [C(CH3)3], 116.4
(C2¢,6¢H), 125.4 (C4¢H), 137.2 (C1¢), 138.7 (C3¢,5¢, s-cis), 138.8 (C3¢,5¢),
152.6 (NCO2t-Bu), 153.8 (HNCOO, s-cis), 155.3 (HNCOO), 175.2
(CO2H, s-cis), 177.6 (CO2H).
13C NMR (50.3 MHz, CDCl3): d = 21.2 (2 CH3Ar), 21.3 (2 CH3Ar),
28.2 [C(CH3)3], 33.6 (C3H2), 52.8 (C5H2), 59.1 (C2H), 73.5 (C4H),
81.3 [C(CH3)3], 116.5 and 117.4 (C2¢,6¢H and C2¢¢,6¢¢H), 125.4 and
125.8 (C4¢H and C4¢¢H), 137.3 and 137.7 (C1¢ and C1¢¢), 138.5 and
138.7 (C3¢,5¢ and C3¢¢,5¢¢), 152.7 and 156.1 (HNCOO and NCO2t-Bu),
168.8 (CONH).
Anal. Calcd for C27H35N3O5: C, 67.34; H, 7.32; N, 8.73. Found: C,
67.60; H, 7.65; N, 8.53.
Anal. Calcd for C19H26N2O6: C, 60.30; H, 6.92; N, 7.40. Found: C,
60.25; H, 6.98; N 7.42.
N-(3,5-Dinitrobenzoyl)-N¢-(butyl)-(4R)-(3,5-dimethylphenyl-
aminocarbonyloxy)-L-prolinamide (29) (Scheme 3)
The solid obtained was crystallized from 96% EtOH; yield: 60%;
mp 108–110 °C; [a]D20 +123.5 (c = 1, CHCl3).
1H NMR (200 MHz, CDCl3): d = 0.92 (t, 3 H, C4¢¢H3), 1.35 (m, 2 H,
C3¢¢H2), 1.51 (m, 2 H, C2¢¢H2), 2.25 (m, 6 H, 2 CH3Ar), 2.44 (m, 1 H,
C3Ha), 2.84 (m, 1 H, C3Hb), 3.32 (m, 2 H, C1¢¢H2), 3.67 (d, 1 H,
C5Ha), 4.03 (dd, 1 H, C5Hb), 4.84 (dd, 1 H, C2H), 5.38 (m, 1 H, C4H),
6.61 (br s, 2 H, 2 NH), 6.71 (s, 1 H, C4¢H), 6.90 (s, 2 H, C2¢,6¢H), 8.72
(d, 2 H, C2¢¢,6¢¢H), 8.96 (d, C2¢¢,6¢¢H, s-cis), 9.12 (t, 1 H, C4¢¢H).
13C NMR (100.6 MHz, CDCl3): d = 13.7 (C4¢¢¢H2), 20.0 (C3¢¢¢H2),
21.3 (2 CH3Ar), 31.4 (C2¢¢¢H2), 33.7 (C3H2), 39.7 (C1¢¢¢H2), 56.2
(C5H2), 59.3 (C2H), 73.9 (C4H), 116.4 (C2¢¢,6¢¢H2), 120.6 (C4¢H),
125.8 (C4¢¢H), 127.8 (C2¢,6¢H), 136.7 (C1¢¢), 138.4 (C1¢), 138.9 (C3¢¢,5¢¢),
148.5 (C3¢,5¢), 152.4 (OCONH), 166.0 (CON), 169.2 (CONH).
N-(3,5-Dimethylbenzoyl)-(4R)-(3,5-dimethylphenylaminocar-
bonyloxy)-L-proline (30) (Scheme 5)
Following Method B, 30 was obtained from 13 and purified by
chromatography on silica gel; yield: 95%; mp 128–129 °C; [a]D
–123.1 (c = 1, CHCl3).
20
1H NMR (300 MHz, CDCl3): d = 2.25 (s, 6 H, 2 CH3Ar), 2.28 (s, 6
H, 2 CH3Ar), 2.58 (m, 1 H, C3Ha), 2.79 (m, 1 H, C3Hb), 3.79 (d, 1
H, J5a,5b = 11.8 Hz, C5Ha), 3.89 (dd, 1 H, J4,5b = 4 Hz, C5Hb), 4.94
(dd, 1 H, J2,3a = J2,3b = 8 Hz, C2H), 5.28 (m, 1 H, C4H), 6.69 (s, 1 H,
C4¢¢H), 6.93 (s, 2 H, C2¢¢,6¢¢H), 7.03 (s, 1 H, C4¢H), 7.12 (s, 1 H,
C
2¢,6¢H), 7.40 (br s, 1 H, NH), 9.60 (br s, 1 H, CO2H).
13C NMR (75.5 MHz, CDCl3): d = 21.1 and 21.3 (CH3Ar), 34.5
(C3H2), 56.2 (C5H2), 58.2 (C2H), 73.1 (C4H), 116.4 (C2¢¢,6¢¢H), 125.1
(C2¢,6¢H), 125.2 (C4¢¢H), 132.6 (C4¢H), 134.4 (C1¢), 137.7 (C1¢¢), 138.1
and 138.6 (C3¢,5¢ and C3¢¢,5¢¢), 152.6 (HNCOO), 172.0 (CON), 174.0
(CO2H).
Anal. Calcd for C25H29N5O8: C, 56.92; H, 5.54; N, 13.28. Found: C,
57.10; H, 5.60; N, 12.95.
Anal. Calcd for C23N26N2O2: C, 67.30; H, 6.38; N, 6.82. Found: C,
66.98; H, 6.22; N, 6.91.
N-(3,5-Dimethylbenzoyl)-N¢-(butyl)-(4R)-(3,5-dimethylphenyl-
aminocarbonyloxy)-L-prolinamide (31) (Scheme 3)
(4R)-(3,5-Dimethylphenylaminocarbonyloxy) and (4R)-Hy-
droxy-L-prolinamide Derivatives; General Procedure
To a solution of the appropriate acid N-(tert-butoxycarbonyl)-(4R)-
hydroxy-L-proline, 26, 28 or 30 (1.3 mmol) and EEDQ (1.7 mmol,
The product obtained was crystallized from Et2O–hexane; yield:
53%; mp 90–91 °C; [a]D20 –11.7 (c = 1, 96% EtOH).
Synthesis 2004, No. 8, 1171–1182 © Thieme Stuttgart · New York

PAPER
Synthetic Studies on L-Proline and (4R)-Hydroxy-L-proline Derivatives
1181
+
1H NMR (200 MHz, CDCl3): d = 0.87 (t, 3 H, C4¢¢H3), 1.31 (m, 2 H,
C3¢¢H2), 1.45 (m, 2 H, C2¢¢H2), 2.21 (s, 6 H, 2 CH3Ar), 2.23 (s, 6 H,
2 CH3Ar), 2.34 (m, 1 H, C3Ha), 2.79 (m, 1 H, C3Hb), 3.27 (m, 2 H,
C1¢¢H2), 3.80 (m, 2 H, C5H2), 4,97 (dd, 1 H, C2H), 5.31 (s, 1 H, C4H),
6.67 (s, 1 H, C4¢H), 6.87 (s, 2 H, C2,6H), 7.05 (s, 1 H, C4¢H), 7.08 (s,
2 H, C2¢,6¢H), 7.23 (t, 1 H, NH), 7.31 (br s, 1 H, NH).
H, NH2 ), 3.52 (dd, 1 H, C5Hb), 3.93 (dd, 1 H, J2,3a = J2,3b = 8.5 Hz,
C2H), 5.15 (m, 1 H, C4H), 6.63 (s, 1 H, C4¢H), 7.07 (s, 2 H, C2¢,6¢H),
9.70 (br s, 1 H, HNCOO).
13C NMR (50.3 Mz, DMSO-d6): d = 21.3 (CH3), 35.4 (C3H2), 50.4
(C5H2), 59.9 (C2H), 73.7 (C4H), 116.4 (C2¢,6¢H), 124.5 (C4¢H), 138.0
(C3¢,5¢), 138.9 (C1¢), 152.9 (HNCOO), 170.3 (CO2H).
13C NMR (50.3 MHz, CDCl3): d = 13.7 (C4¢¢¢H3), 20.0 (C3¢¢¢H2), 21.1
and 21.2 (2 CH3Ar and 2 CH3Ar), 31.4 (C2¢¢¢H2), 33.3 (C3H2), 39.4
(C1¢¢¢H2), 56.5 (C5H2), 58.3 (C2H), 73.6 (C4H), 116.4 (C2¢¢,6¢¢H),
125.0 (C2¢,6¢H), 125.1 (C4¢¢H), 132.5 (C4¢H), 135.0 and 137.3 (C1¢ and
C1¢¢), 138.2 and 138.6 (C3¢,5¢ and C3¢¢,5¢¢), 152.6 (OCONH), 170.1
(CON), 172.2 (CONH).
Anal. Calcd. for C14H18N2O4: C, 60.42; H, 6.52; N, 10.07. Found :
C, 60.15; H, 6.45; N, 9.83.
N-Benzoyl Derivatives of (4R)-(3,5-dimethylphenylaminocar-
bonyloxy)-L-proline (Scheme 3)
Following the procedure above described for 1 and 5, compounds
28 and 30 were obtained from 35 and the appropriate acyl chloride.
Anal. Calcd for C27H34N3O4: C, 69.82; H, 7.32; N, 9.05. Found: C,
69.70; H, 7.30; N, 8.99.
N-(3,5-Dinitrobenzoyl)-4(R)-(3,5-dimethylphenylaminocarbon-
yloxy)-L-proline (28)
The solid resulting from the workup procedure was chromato-
graphed on silica gel (CHCl3–MeOH, 97:3); yield: 65%; mp 149–
150 °C; [a]D20 –99.4 (c = 1, 96% EtOH).
Deprotection of N-tert-Butoxycarbonyl Derivatives; General
Procedure
A solution of either 22, 27 or 26 (0.8 mmol) in trifluoroacetic acid
and CH2Cl2 (20 mL, 30:70) was stirred at r.t. for 30 min. The mix-
ture was basified with NH4OH and extracted with CH2Cl2. The sol-
vent was evaporated and the residual solid collected.
1H NMR (200 MHz, acetone-d6): d = 2.26 (s, 6 H, 2 CH3Ar), 2.48
(m, 1 H, C3Ha), 2.68 (m, 1 H, C3Hb), 3.85 (d, 1 H, J5a,5b = 12 Hz,
C5Ha), 4.24 (dd, 1 H, J4,5b = 4 Hz, C5Hb), 4.84 (dd, 1 H, J2,3a
=
N¢-(3,5-Dimethylphenyl)-(4R)-(3,5-dimethylbenzoyloxy)-L-pro-
linamide (33) (Scheme 6)
From 22 (1.22 mmol), 402 mg of a white oil that crystallized on
standing was obtained; yield: 92%; mp 106–109 °C; [a]D20 +1.39
(c = 1, CHCl3).
1H NMR (400 MHz, CDCl3): d = 2.25 (m, 1 H, C3Ha), 2.30 (s, 6 H,
2 CH3Ar¢), 2.36 (s, 6 H, 2 CH3Ar¢¢), 2.60 (m, 1 H, C3Hb), 3.00 (br s,
1 H, NH), 3.15 (m, 1 H, C5Ha), 3.39 (m, 1 H, C5Hb), 4.19 (dd, 1 H,
C2H), 5.45 (m, 1 H, C4H), 6.75 (s, 1 H, C4¢H), 7.20 (s, 1 H, C4¢¢H),
7.24 (s, 2 H, C2¢,6¢H), 7.62 (s, 2 H, C2¢¢,6¢¢H), 9.55 (br s, 1 H, NH).
13C NMR (100.6 MHz, CDCl3): d = 20.9 (2 CH3Ar¢ and 2 CH3Ar¢¢),
37.5 (C3H2), 53.9 (C5H2), 60.9 (C2H), 78.2 (C4H), 118.0 (C2¢,6¢H),
127.0 (C4¢H), 127.5 (C2¢¢,6¢¢H), 130.0 (C1¢¢), 135.5 (C4¢¢H), 137.9 (C1¢),
138.5 (C3¢,5¢ and C3¢¢,5¢¢), 166.5 (COO), 172.5 (CONH).
J2,3b = 8 Hz, C2H), 5.46 (m, 1 H, C4H), 6.70 (s, 1 H, C4¢¢H), 6.73
(s, C4¢¢H, s-cis), 7.15 (s, 2 H, C2¢¢,6¢¢H), 7.25 (s, C2¢¢,6¢¢H, s-cis), 8.64
(br s, 1 H, NH), 8.79 (d, 2 H, C2¢,6¢H), 9.09 (m, 1 H, C4¢H), 9.14 (d,
C
2¢,6¢H, s-cis), 9.22 (m, C4¢H, s-cis).
13C NMR (50.3 MHz, acetone-d6): d = 21.8 (CH3Ar), 36.1 (C3H2),
56.8 (C5H2), 60.0 (C2H), 74.4 (C4H), 117.2 (C2¢¢,6¢¢H), 121.2 (C4¢H),
125.6 (C4¢¢H), 128.9 (C2¢,6¢H), 139.4 (C3¢,5¢), 139.8 and 140.0 (C1¢¢ and
C
3¢¢,5¢¢), 149.8 (C1¢), 153.7 (HNCOO), 166.4 and 166.8 (CON and
CO2H).
Anal. Calcd for C21H20N4O9: C, 53.40; H, 4.27; N, 11.86. Found: C,
53.56; H, 4.44; N, 11.36.
N-(3,5-Dimethylbenzoyl)-(4R)-(3,5-dimethylphenylaminocar-
bonyloxy)-L-proline (30)
Anal. Calcd for C22H26N2O3: C, 72.11; H, 7.15; N, 7.64. Found: C,
71.85; H, 6.93; N, 7.58.
The title compound was obtained in 30% yield after purification by
chromatography on silica gel (CHCl3–MeOH, 99:1). Alternatively,
compound 30 was obtained from 13 (Scheme 5).
N¢-(3,5-Dimethylphenyl)-(4R)-(3,5-dimethylphenylaminocar-
bonyloxy)-L-prolinamide (34) (Scheme 3)
The solid was chromatographed on silica gel (hexane–EtOAc,
50:50) and crystallized from EtOH–H2O; yield: 91%; mp 159–160
°C; [a]D20 –0.7 (c = 1, CHCl3); [a]D20 +9.1 (c = 1, 96% EtOH).
(4R)-Acyloxy-L-prolinamide Derivatives; General Procedure
The appropriate acyl chloride (0.8 mmol) and aq 2 N NaOH (1.6
mL) were added separately to a solution of either 14, 15 or 21 (0.8
mmol) in CHCl3 (8 mL). The mixture was stirred at r.t. and the
course of the reaction was controlled by TLC. The mixture was
poured into H2O, and the organic extracts were washed with aq 2 N
NaOH. After drying the organic solution (Na2SO4), the solvent was
removed under reduced pressure.
1H NMR (400 MHz, CDCl3): d = 2.18 (m, 1 H, C3Ha), 2.29 (s, 12 H,
4 CH3Ar), 2.56 (dd, 1 H, J3a,3b = 16 Hz, J2,3b = 8 Hz, C3Hb), 3.02 (dd,
1 H, J5a,5b = 12 Hz, J4,5a = 3.4 Hz, C5Ha), 3.30 (dd, 1 H, J4,5b = 1.8
Hz, C5Hb), 4.12 (dd, 1 H, J2,3a = J2,3b = 8 Hz, C2H), 5.30 (m, 1 H,
C4H), 6.72 and 6.76 (s and s, 1 H and 1 H, C4¢H and C4¢¢H), 6.90 (br
s, 1 H, NHCOO), 7.05 and 7.25 (s and s, 2 H and 2 H, C2¢,6¢H and
N-(tert-Butoxycarbonyl)-N¢-(3,5-dimethylphenyl)-(4R)-(3,5-
dimethylbenzoyloxy)-L-prolinamide (22) (Scheme 6)
After a reaction period of 24 h, the product obtained was chromato-
graphed on silica gel using hexane–EtOAc mixtures as eluent;
yield: 60%; yellowish oil; [a]D20 –99.4 (c = 1, 96% EtOH).
1H NMR (300 MHz, DMSO-d6, 60 ºC): d = 1.19 [s, 9 H, C(CH3)3],
2.23 (s, 6 H, 2 CH3Ar), 2.45 (m, 1 H, C3Ha), 3.45 (m, 1 H, C3Hb),
3.60 (m, 1 H, C5Ha), 3.70 (m, 1 H, C5Hb), 4.45 (m, 1 H, C2H), 5.43
(m, 1 H, C4H), 6.70 (s, 1 H, C4¢H), 7.23 (s, 2 H, C2¢,6¢H), 7.33 (s, 1
H, C4¢¢H), 7.56 (s, 2 H, C2¢¢,6¢¢H), 9.79 (s, 1 H, CONH).
13C NMR (100.6 MHz, CDCl3): d = 20.9 (4 CH3Ar), 29.2
[C(CH3)3], 33.1 (C3H2), 53.6 (C5H2), 59.9 (C2H), 73.9 (C4H), 81.0
[C(CH3)3], 118.9 (C2¢,6¢H), 126.0 (C4¢H), 128.5 (C2¢¢,6¢¢H), 130.0
(C1¢¢), 135.9 (C4¢¢H), 136.1 (C1¢), 138.5 (C3¢,5¢), 139.0 (C3¢¢,5¢¢), 156.5
(NCOO), 166.5 (COO), 169.5 (CONH).
C
2¢¢,6¢¢H), 9.58 (br s, 1 H, NHCO).
13C NMR (100.6 MHz, CDCl3): d = 21.3 (4 CH3Ar), 36.8 (C3H2),
53.3 (C5H2), 60.6 (C2H), 76.9 (C4H), 116.4 and 117.0 (C2¢,6¢H and
C
2¢¢,6¢¢H), 125.0 and 125.9 (C4¢H and C4¢¢H), 137.2 and 138.0 (C1¢ and
C1¢¢), 138.6 (C3¢,5¢ and C3¢¢,5¢¢), 153.1 (NHCOO), 172.7 (CONH).
Anal. Calcd for C22H27N3O3: C, 69.27; H, 7.13, N, 11.01. Found: C,
68.94; H, 7.13; N, 11.24.
(4R)-(3,5-Dimethylphenylaminocarbonyloxy)-L-proline (35)
(Scheme 3)
The solid obtained was crystallized from EtOH; yield: 73%; mp
220–221 °C; [a]D20 +14.4 (c = 1, DMSO).
1H NMR (300 MHz, DMSO-d6): d = 2.11 (m, 1 H, C3Ha), 2.19 (s, 6
H, 2 CH3Ar), 2.24 (m, 1 H, C3Hb), 3.20 (d, 1 H, C5Ha), 3.40 (br s, 2
Synthesis 2004, No. 8, 1171–1182 © Thieme Stuttgart · New York

1182
T. González et al.
PAPER
Anal. Calcd for C27H34N2O5: C, 69.51; H, 7.34; N, 6.00. Found: C,
69.73; H, 7.77; N, 5.78.
57.6 (C2H), 76.2 (C4H), 122.6 (C4¢¢¢H), 124.8 (C2¢,6¢H), 129.2
(C2¢¢¢,6¢¢¢H), 132.5 (C4¢H), 133.0 (C1¢¢¢), 134.8 (C1¢), 138.4 (C3¢,5¢),
148.5 (C3¢¢¢,5¢¢¢), 161.7 (COO), 169.4 (CON), 172.0 (CONH).
N¢-(Butyl)-N-(3,5-dimethylbenzoyl)-(4R)-(3,5-dimethylbenzoyl-
oxy)-L-prolinamide (23) (Scheme 5)
After a reaction period of 24 h, the solid obtained was crystallized
from EtOH–H2O; yield: 58%; mp 131–132 °C; [a]D20 –104.8 (c = 1,
96% EtOH).
Anal. Calcd for C25H28N4O8: C, 58.59; H, 5.51; N, 10.93. Found: C,
58.51; H, 5.87; N, 10.54.
Acknowledgments
1H NMR (200 MHz, CDCl3): d = 0.91 (t, 3 H, C4¢¢H3), 1.36 (m, 2 H,
C3¢¢H2), 1.50 (m, 2 H, C2¢¢H2), 2.28 (s, 6 H, 2 CH3Ar), 2.35 (s, 6 H,
2 CH3Ar), 2.39 (m, 1 H, C3Ha), 2.99 (m, 1 H, C3Hb), 3.30 (q, 2 H,
C1¢¢H2), 3.80 (m, 2 H, C5H2), 5.03 (dd, 1 H, C2H), 5.49 (m, 1 H,
C4H), 7.06 (s, 3 H, C2¢,6¢H and C4¢H), 7.20 (s and br s, 2 H, C4¢¢¢H and
NH), 7.54 (s, 1 H, C2¢¢¢,6¢¢¢H).
Financial support from the Ministerio de Ciencia y Tecnología of
Spain (projects: BQU2000-0235, BQU2001-3228) is gratefully
acknowledged. We wish to thank Nuria Rubio and Biotza Gutierrez
for experimental contributions.
13C NMR (50.3 MHz, CDCl3): d = 13.6 (C4¢¢H3), 20.0 (C3¢¢H2), 21.0
(4 CH3Ar), 31.4 (C2¢¢H2), 32.6 (C3H2), 39.4 (C1¢¢H2), 56.0 (C5H2),
58.0 (C2H), 73.5 (C4H), 124.7 (C2¢,6¢H), 127.2 (C2¢¢¢,6¢¢¢H), 129.3
(C1¢¢¢), 132.2 (C4¢H), 135.0 (C4¢¢¢H), 135.2 (C1¢), 138.0 (C3¢,5¢), 138.2
(C3¢¢¢,5¢¢¢), 166.0 (COO), 170.0 (CON), 172.3 (CONH).
References
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Anal. Calcd for C27H34N2O4: C, 71.97; H, 7.60; N, 6.22. Found: C,
71.69; H, 7.30; N, 6.29.
(5) Ohwa, M.; Akiyoshi, M.; Hitamura, S. J. Chromatogr. 1990,
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N-(3,5-Dimethylbenzoyl)-(4R)-(3,5-dimethylbenzoyloxy)-N¢-
(3,5-dimethylphenyl)-L-prolinamide (24) (Scheme 5)
After 68 h, the solid resulting from the workup procedure was crys-
tallized from EtOH–H2O; yield: 91%; mp 202–203 °C; [a]D
–211.7 (c = 1,5, CHCl3).
20
1H NMR (200 MHz, CDCl3): d = 2.27 (s, 6 H, 2 CH3Ar), 2.28 (s, 6
H, 2 CH3Ar), 2.37 (s, 6 H, 2 CH3Ar), 2.46 (m, 1 H, C3Ha), 3.14 (m,
1 H, C3Hb), 3.82 (m, 2 H, C5H2), 5.24 (dd, 1 H, J2,3a = J2,3b = 8 Hz,
C2H), 5.54 (m, 1 H, C4H), 6.75 (s, 1 H, C4¢¢H), 7.07 (s, 3 H, C2¢,6¢H
and C4¢H), 7.20 (s, 1 H, C4¢¢¢H), 7.22 (s, 2 H, C2¢¢,6¢¢H), 7.55 (s, 2 H,
C
2¢¢¢,6¢¢¢H), 9.46 (br s, 1 H, NH).
13C NMR (50.3 MHz, CDCl3): d = 21.1 (4 CH3Ar), 21.2 (2 CH3Ar),
32.0 (C3H2), 56.0 (C5H2), 59.0 (C2H), 73.4 (C4H), 117.4 (C2¢¢,6¢¢H),
124.8 (C2¢,6¢H), 125.8 (C4¢¢H), 127.2 (C2¢¢¢,6¢¢¢H), 129.2 (C1¢¢¢), 132.4
(C4¢H), 134.9 (C1¢), 135.0 (C4¢¢¢H), 137.8 (C1¢¢), 138.1, 138.3 and
138.5 (C3¢,5¢, C3¢¢,5¢¢and C3¢¢¢,5¢¢¢), 166.0 (COO), 167.5 (CON), 172.9
(CONH).
Anal. Calcd for C31H34N2O4: C, 74.67; H, 6.87; N, 5.62. Found: C,
74.30; H, 6.95; N, 5.28.
N¢-(Butyl)-N-(3,5-dimethylbenzoyl)-(4R)-(3,5-dinitrobenzoyl-
oxy)-L-prolinamide (25) (Scheme 5)
(18) Oliveros, L.; Minguillón, C.; González, T. J. Chromatogr. A
1994, 672, 59.
(19) Belleau, B.; Malek, G. J. Am. Chem. Soc. 1968, 90, 1651.
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1232.
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(22) Nefkens, G. H. L.; Tesser, G. I.; Nivard, R. J. F. Recl. Trav.
Chim. Pays-Bas 1963, 82, 941.
(23) Francis, T.; Thorne, M. P. Can. J. Chem. 1976, 54, 24.
(24) Lämmerhofer, M.; Lindner, W. J. Chromatogr. A 1996, 741,
33.
After 48 h of reaction, the resulting solid was chromatographed on
silica gel (hexane–EtOAc, 60:40); yield: 40%; mp 123–124 °C;
[a]D20 –87.5 (c = 1, 96% EtOH).
1H NMR (200 MHz, CDCl3): d = 0.91 (t, 3 H, C4¢¢H3), 1.35 (m, 2 H,
C3¢¢H2), 1.50 (m, 2 H, C2¢¢H2), 2.34 (s, 6 H, 2 CH3Ar), 2.47 (m, 1 H,
J3a,3b = 15 Hz, J2,3a = 7.5 Hz, J3a,4 = 5 Hz, C3Ha), 3.12 (m, 1 H,
J3b,4 = 4 Hz, J2,3b = 7.5 Hz, C3Hb), 3.28 (q, 2 H, C1¢¢H2), 3.87 (m, 2
H, J5a,5b = 12.5 Hz, C5Ha), 3.96 (dd, J4,5b = 3.7 Hz, C5Hb), 5.05 (dd,
1 H, J2,3a = J2,3b = 7.5 Hz, C2H), 5.61 (m, 1 H, C4H), 7.11 (s, 1 H,
C4¢H), 7.14 (s, 2 H, C2¢,6¢H), 9.03 (dd, 1 H, C2¢¢¢,6¢¢¢H), 9.25 (t, 1 H,
C4¢¢¢H).
(25) Lombardino, J. G.; Anderson, S. L.; Norris, C. P. J.
Heterocycl. Chem. 1978, 15, 655.
13C NMR (50.3 MHz, CDCl3): d = 13.6 (C4¢¢H3), 19.9 (C3¢¢H2), 21.1
(2 CH3Ar), 31.3 (C2¢H2), 32.5 (C3H2), 39.5 (C1¢¢H2), 55.5 (C5H2),
Synthesis 2004, No. 8, 1171–1182 © Thieme Stuttgart · New York