Design of potential new HIV protease inhibitors: Enantioconvergent synthesis of new pyrrolidin-3-ol, and pyrrolidin-3-one peptide conjugates

Article abstract of DOI:10.1039/b101584m

Novel potential HIV protease inhibitors are obtained by an enantioconvergent synthesis of mimicking Phe-Pro dipeptides, achieved through the coupling between Boc(L)Phe or Boc(L)Tyr and both enantiomers of syn-2-benzylpyrrolidin-3-ol and their correspondin

Full text of DOI:10.1039/b101584m

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Design of potential new HIV protease inhibitors:
enantioconvergent synthesis of new pyrrolidin-3-ol,
and pyrrolidin-3-one peptide conjugates
1
Jérôme Courcambeck, Frédéric Bihel, Céline De Michelis, Gilles Quéléver and
Jean Louis Kraus*
Laboratoire de Chimie Biomoléculaire, Parc Scientifique de Luminy, Case 901,
Université de la Méditerranée, 70 route Léon Lachamp, F-13288 Marseille Cedex 9, France.
E.mail: kraus@luminy.univ-mrs.fr; Fax: 33 (0) 4 91 82 94 16; Tel.: 33 (0) 4 91 82 91 41
Received (in Cambridge, UK) 16th February 2001, Accepted 23rd April 2001
First published as an Advance Article on the web 30th May 2001
Novel potential HIV protease inhibitors are obtained by an enantioconvergent synthesis of mimicking
Phe-Pro dipeptides, achieved through the coupling between Boc()Phe or Boc()Tyr and both enantiomers
of syn-2-benzylpyrrolidin-3-ol and their corresponding pyrrolidin-3-one analogs. The stereochemistry and
enantiopurity of intermediate 3-hydroxypyrrolidines 5a and 5b are determined through 1H NMR analysis,
and through the synthesis and 19F NMR assignments of the corresponding Mosher’s esters 13a and 13b.
The enantiopure compounds 5a and 5b are obtained with 100% diastereoselectivity using specific experimental
reductive conditions upon Meldrum’s acid derivatives of activated aromatic amino acids.
Introduction
Chiral 2-substituted pyrrolidin-3-ols or pyrrolidin-3-ones have
been widely used in the design of pseudopeptides as aspartyl,1–3
serine,4 cysteine5,6 proteinase inhibitors, or non-peptidic
neuraminidase inhibitors.7 In the course of our studies directed
towards the synthesis of new anti-HIV protease derivatives, we
investigated the possibility of using the pyrrolidin-3-one and
pyrrolidin-3-ol synthons as proline-mimicking moieties. Indeed
it has been observed that HIV protease shows a preference for
Tyr-Pro and Phe-Pro primary cleavages8–12 at P1-P1Ј residues
(notation according to Schechter and Berger).13 A represen-
tation of the interactions of one natural substrate with the
native HIV-1 protease is given in Fig. 1.10,12 These Tyr-Pro and
Phe-Pro preferences are particularly interesting, because it
is unusual for mammalian endopeptidases to cleave at the N-
terminal proline residue position.12,14 This cleavage specificity
suggests that these new peptidomimicking derivatives will
exhibit a high enzymatic selectivity against the HIV-1 protease.
These enzymatic observations are the basis for the design of
Fig. 1 Representation of one specific substrate of the HIV-1 protease
(PR), situated between PR-RT in the pol polyprotein.10,12
new HIV protease inhibitors. For this purpose, the proline
moiety is replaced by a substituted pyrrolidine ring, which
is also capable of interacting with both S1Ј and S2Ј enzyme
pockets (Fig. 2). This new family of compounds interacts with
the four hydrophobic pockets, which are surrounded by the
enzyme catalytic site.
substituted pyrrolidin-3-ols respectively, 1a,b and 2a,b and
N-tyrosinyl- (or phenylalanyl)-2-substituted pyrrolidin-3-ones
respectively, 3a,b and 4a,b.
The tyrosinyl or phenylalanyl moieties interact with the S1
pocket (Ile 50, Ile 84, Leu 23) through the side chain of the
aromatic amino acid and with the S2 pocket (Ile 47, Val 32)
through the tert-butyl group. The substituted pyrrolidine ring,
which replaces the proline residue in the substrates including
Phe-Pro or Tyr-Pro sequences, interacts with the S1Ј pocket (Ile
50Ј, Ile 84Ј, Leu 23Ј) and with the S2Ј pocket (Ile 47Ј, Val 32Ј):
the S1Ј pocket through the methylene groups of the pyrrolidine
ring, and the S2Ј pocket through the benzyl substituent on the
pyrrolidine ring. These new modified dipeptides mimicking 1, 2
and 3, 4 (Fig. 2) are also capable of maintaining a tight inter-
action with the two aspartic acid residues (25 and 25Ј) of the
HIV protease active site through a water molecule.
The versatile pyrrolidinol chiral building blocks 5a and
5b were first synthesised through an enantioconvergent
strategy.
In this paper, we report the total enantioconvergent synthesis
of the target molecules: N-tyrosinyl- (or N-phenylalanyl)-2-
DOI: 10.1039/b101584m
J. Chem. Soc., Perkin Trans. 1, 2001, 1421–1430
This journal is © The Royal Society of Chemistry 2001
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Fig. 2 Representation of the binding of the target molecules 1a,b;
2a,b and 3a,b; 4a,b within the different S1, S1Ј and S2, S2Ј pockets of
the HIV protease active site.
Scheme 1 Reagents, conditions: i) DCC, DMAP, CH2Cl2, 0 ЊC to RT;
ii) EtOAc, reflux; iii) NaBH4, AcOH, CH2Cl2, Ϫ15 to Ϫ5 ЊC; iv) BH3–
DMS, THF, reflux; v) TPAP (5 mol%), NMO, CH2Cl2, 0 ЊC to RT.
adduct was used as a suitable precursor for the synthesis of the
chiral N-substituted tetramic acids 7a and 7b (Scheme 1), which
afforded the corresponding 4-hydroxypyrrolidin-2-ones 8a and
8b after stereoselective reduction. However, it should be under-
lined that the methodology described by Jouin et al.15,16 did not
lead to 100% diastereoselectivity, as claimed by the authors, for
the synthesis of compounds 8a and 8b. Considering these con-
tradictory results, we modified the experimental procedure in
order to prepare 5a, 5b as diastereo- and enantio-pure com-
pounds, and to increase the diastereoselectivity of the tetramic
Compounds 5a and 5b were then coupled to various aromatic
amino acids (Phe and Tyr) using peptidic synthesis methods,
which led to the final target molecules 1a,b and 2a,b. The
N-tyrosinyl- (or phenylalanyl)-2-substituted pyrrolidin-3-ones,
respectively 3a,b and 4a,b, were obtained from the correspond-
ing pyrrolidin-3-ones 6a and 6b.
1
acid reduction step. Their purity was demonstrated by a H
NMR study of the 5-hydroxypyrrolidin-2-ones 8a, 8b and
by a 19F NMR study of the Mosher’s esters 13a, 13b of
the key synthons, syn-2-benzylpyrrolidin-3-ols 5a and 5b
(Scheme 2).
Synthesis of pyrrolidin-3-ols and pyrrolidin-3-ones
Results and discussion
In earlier studies, Jouin et al.15,16 and more recently Peet et al.6
described a total stereoselective synthesis of 5-alkylpyrrolidine-
2,4-diones and 5-alkyl-4-hydroxypyrrolidin-2-ones. Other
synthetic routes have also been described. For example, the
pyrrolidin-2-one moiety was accessible via a 5-exo-cyclisation
pathway described by Parsons and co-workers.17 Unfortunately
this synthetic strategy led to a mixture of stereoisomers. Reddy
et al.18 described a method allowing the synthesis of 5-alkyl-4-
hydroxypyrrolidin-2-one intermediates, through a Wittig reac-
tion on various oxazolidinones, coming from various α-amino
acids. The olefination was followed by a rearrangement carried
on under strongly acidic conditions, which led to N-substituted
5-alkylpyrrolidine-2,4-diones. These compounds were later
reduced to their corresponding pyrrolidin-3-ols using sodium
borohydride as reductive agent.
Addition of Meldrum’s acid to Boc()PheOH 9a or Boc()-
PheOH 9b in the presence of DCC–DMAP (respectively, 1.18
and 1.5 equiv.) led to the corresponding adducts 10a and 10b,
in excellent yields (Scheme 1). These results were inconsistent
with previous observations reported by Jouin et al.15,16 and by
Joullié and co-workers,19 who found that the DCC–DMAP
activation system was not suitable for this reaction. Those
authors recommended the use of isopropenyl chloroformate as
activating agent for this reaction. The corresponding adducts
10a and 10b, when refluxed for 10 minutes in EtOAc, under-
went a cyclisation reaction. After spontaneous decarboxyla-
tion, this step produced the corresponding tetramic acids 7a
and 7b, which were directly purified by recrystallisation in
ethanol–hexane. The next step was their diastereoselective
reduction using sodium borohydride. Following the reduction
conditions (NaBH4 in a mixture of acetic acid–methylene
dichloride) reported by Jouin et al.,15,16 we found that the dia-
stereoselectivity excess was not 100% but only 63% as measured
by 1H NMR (Fig. 3). Finally we found that the optimal reduc-
tion conditions leading to 100% diastereoisomeric excess for 1
equiv. of tetramic acid 7a or 7b were: NaBH4 (4 equiv.), AcOH
Among the proposed synthetic routes leading to enantiopure
pyrrolidin-3-ol synthons, we selected the procedure described
by Jouin et al.,15,16 which involved tetramic acids 7a and 7b as
intermediates, and which appeared to be a very efficient
method. The first step required the addition of Meldrum’s
acid to selected activated amino acids 9a,b. The resulting
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Fig. 3 1H NMR spectra of the pyrrolidin-3-ol 8a.
Fig. 4 19F NMR spectra of Mosher’s esters 13a and 13b.
in 93% yield. This method led to better yields than did classical
Swern oxidation conditions.23
In order to confirm the enantiopurity of the 4-hydroxy-
pyrrolidin-2-ones 8a and 8b obtained from this enantio-
convergent strategy, we attempted to synthesise their
corresponding Mosher’s esters24 11a and 11b using experi-
mental conditions described in Scheme 2. Unfortunately only
the β-elimination enelactam products 12a and 12b were
obtained. These results led us to synthesise the Mosher’s esters
13a and 13b, starting from the key synthons 5a and 5b. The
Mosher’s esters 13a and 13b were obtained in 95% yields using
the following experimental conditions: (R)-(ϩ)-Mosher’s acid
chloride reagent (1.1 equiv.), DMAP (2 equiv.), in methylene
dichloride, at temperatures ranging from 0 ЊC to RT.
NMR studies
The diastereoisomeric excess of 4-hydroxypyrrolidin-2-ones
8a and 8b (Scheme 2) resulting from the reductive step was
determined through 1H NMR studies. The chemical shifts
of the hydroxy proton were found respectively at δ 5.46 for
the syn isomer, and at δ 5.56 for the anti isomer, in DMSO-d6
(Fig. 3). These NMR measurements allowed us to confirm the
diastereoselectivity of the reduction step of the tetramic acids
7a and 7b, and therefore the diastereoisomeric purity of the
syn-5-benzyl-4-hydroxypyrrolidin-2-ones 8a and 8b.
Scheme 2 Reagents, conditions: i) (R)-(ϩ)-Mosher’s acid chloride,
DMAP, CH2Cl2, 0 ЊC to RT.
(16 equiv.), at temperatures ranging from Ϫ15 to Ϫ5 ЊC. Under
these conditions, compounds 8a and 8b were obtained in 92%
yield. Reduction of lactams 8a and 8b using BH3–DMS in
THF20,21 led to the enantio- and diastereo-pure key synthons
pyrrolidin-3-ols 5a and 5b. These synthons were oxidised into
their corresponding pyrrolidin-3-ones 6a and 6b, using Ley–
Mardsen methodology22 [TPAP 5 mol%, NMO (1.5 equiv.), in
methylene dichloride, at temperatures ranging from 0 ЊC to RT]
The 19F NMR study performed on the Mosher’s esters 13a
and 13b allowed us to evaluate the enantiomeric purity of key
synthons 5a and 5b. 19F NMR spectra represented in Fig. 4
showed respectively only one single peak for fluorine signals of
compounds 13a and 13b, while two peaks were found for the
1
mixture of compounds 13a and 13b. This H and 19F NMR
study clearly demonstrated the diastereo- and enantio-purity of
compounds 13a, 13b and 5a, 5b.
J. Chem. Soc., Perkin Trans. 1, 2001, 1421–1430
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Synthesis of peptide conjugates
Starting from the key synthons, viz. the pyrrolidin-3-ols 5a, 5b
and their counterparts 6a and 6b containing the pyrrolidin-3-
one scaffold, two series of derivatives were synthesised follow-
ing the sequences represented in Schemes 3 and 4. The synthesis
of the first series containing the pyrrolidinol motif (Scheme 3)
Scheme 4 Reagents, conditions: i) TFA–CH2Cl2; ii) PyBOP, Et3N,
CH2Cl2, 0 ЊC to RT; iii) H2 (1 atm.), 10% Pd–C (4 mol%), EtOH, 25 ЊC.
Conclusions
We report the total enantioconvergent synthesis of new poten-
tial HIV protease inhibitors, which are based on proline substi-
tution by mimicking pyrrolidinol or pyrrolidinone moieties in
specific Phe-Pro or Tyr-Pro sequences found in various HIV
protease substrates. Key synthon pyrrolidin-3-ols 5a, 5b and
pyrrolidin-3-ones 6a, 6b were synthesised through an enantio-
convergent synthesis, which led to the target compounds in
diastereo- and enantio-pure forms, as demonstrated by 1H
NMR and 19F NMR studies.
Scheme 3 Reagents, conditions: i) NaH, TBAI (5 mol%), BnBr, THF,
0 ЊC to RT; ii) TFA–CH2Cl2; iii) PyBOP, Et3N, CH2Cl2, 0 ЊC to RT; iv)
H2 (1 atm.), 20% Pd(OH)2–C (10 mol%), EtOH, 25 ЊC.
Experimental
General procedures
involved the protection of the hydroxy function of pyrrolidin-
3-ols 5a and 5b by a benzyl group. The resulting ethers 14a
and 14b were isolated in quantitative yields. After N-Boc
deprotection, the salts 15a and 15b were coupled to various
N-Boc-protected aromatic amino acids, i.e. Boc()PheOH 9a,
and Boc()Tyr(OBn)OH 9c using (benzotriazol-1-yloxy)-
tripyrrolidinophosphonium hexafluorophosphate (PyBOP)25 in
methylene dichloride, in the presence of Et3N. The resulting
compounds 16a, 16b and 17a, 17b were isolated in excellent
yields. The last step was the deprotection of the benzyloxy
group, achieved by hydrogenolysis in the presence of
Pearlman’s catalyst [20% Pd(OH)2 on charcoal; 10 mol%]
leading to the final compounds 1a, 1b and 2a, 2b.
The last series of final compounds 3a,3b and 4a,4b were
isolated respectively from pyrrolidin-3-ones 6a and 6b, using a
similar procedure (Scheme 4). After N-Boc deprotection, the
corresponding salts 18a, 18b were coupled with N-Boc-protected
aromatic amino acids, i.e. Boc()PheOH 9a and Boc()Tyr-
(OBn)OH 9c. The pyrrolidinone–aromatic amino acid conju-
gates 3a, 3b and 4a, 4b were obtained in 98, 97% and 98, 99%
yields, respectively. The tyrosinyl derivatives 19a and 19b were
deprotected by classical hydrogenation with black palladium
(Pd–C 10%, 4 mol%) leading to the tyrosinylpyrrolidin-3-ones
4a and 4b in quantitative yields. The two series of compounds,
which have been fully characterised, will be later tested as
HIV-1 protease inhibitors.
Unless otherwise noted, starting materials and reagents were
obtained from commercial suppliers and were used without
purification. All the protected amino acids, and peptide-
coupling reagents, were purchased from BACHEM. Tetra-
hydrofuran was distilled over sodium benzophenone ketyl
immediately prior to use. Methylene dichloride was distilled
over P2O5 and stored over molecular sieves 4 Å at ϩ4 ЊC. Ethyl
acetate was stored on molecular sieves 4 Å. NMR spectra were
recorded at 250 MHz for 1H, and 63 MHz for 13C with a Brüker
AC-250 apparatus. In some cases, the spectra are of poor reso-
lution because of the presence of different conformers and
rotamers. One drop of TFA was then added to the solution in
the NMR tube to decrease the conformational flexibility of the
molecules and to increase the resolution. 19F NMR spectra were
recorded at 282.4 MHz on a Brüker Avance 300. J-Values are
given in Hz. IR spectra were recorded with an FT-IR appar-
atus. Optical rotations were measured at 25 ЊC using a Perkin-
Elmer 241 polarimeter with a path length of 1.0 dm, at the
sodium -ray. All mps are uncorrected. Flash column chrom-
atography was carried out on Merck 60F254 silica gel (230–400
mesh). Centrifugal radial chromatography was carried out with
a Chromatotron,TM Model No 7924T, using plates coated with
silica gel Merck 60 PF254. Reactions were monitored by TLC
using Merck 60F254 TLC plates. Mass spectra were recorded
using fast atom bombardment (FAB > 0) in positive mode
(Dr Astier, Laboratoire de Mesures Physiques-RMN, USTL,
1424
J. Chem. Soc., Perkin Trans. 1, 2001, 1421–1430

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Montpellier, France) on a JEOL DX-100 using a caesium ion
source and glycerol–thioglycerol (1 : 1, GT) or m-nitrobenzyl
alcohol (NOBA) as matrix.
81.01, 59.82, 34.27, 27.87; m/z (FAB > 0, GT) 579 ([2M ϩ H]ϩ,
11%), 290 ([M ϩ H]ϩ, 24), 234 (100), 190 (7) (Found: C, 66.32;
H, 6.81; N, 4.72. C16H19NO4 requires C, 66.42; H, 6.62; N,
4.84%).
5-[(2S)-2-(tert-Butoxycarbonylamino)-1-hydroxy-3-phenyl-
propylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione 10a
(4S,5S)-2-Benzyl-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidin-
2-one 8a
To a stirred solution of Boc()PheOH 9a (3.00 g, 11.3 mmol),
Meldrum’s acid (1.79 g, 12.4 mmol), and DMAP (2.07 g, 17.0
mmol) in CH2Cl2 (30 mL) under nitrogen at 0 ЊC was added
dropwise a solution of DCC (2.75 g, 13.3 mmol) in CH2Cl2 (15
mL) via a syringe over a period of 15 minutes. The resulting
solution was then allowed to warm up to room temperature and
was stirred during 4 hours. The slurry mixture was then poured
rapidly into cold EtOAc (250 mL) according to the procedure
described by Jouin et al.15,16 and filtered. The layers were separ-
ated, and the organic layer was successively washed with cold
5% aq. citric acid (150 mL, 2×), cold water (150 mL, 2×), and
cold brine (150 mL). The organic layer was dried over
anhydrous MgSO4, and concentrated to yield 10a (4.43 g, quan-
titative yield) as a white powder; mp 119 ЊC (lit.,15 120 ЊC); Rf
0.73 (EtOAc–cyclohexane–AcOH 7 : 3 : 1); δH (250 MHz;
DMSO-d6) 7.29–7.07 (6H, m), 5.41 (1H, br s), 2.91–2.61 (2H,
m), 1.52 (6H, s), 1.16 (9H, s); m/z (FAB > 0, GT) 392 ([M ϩ H]ϩ,
10%), 336 (30), 292 (28), 148 (18), 120 (21), 103 (10), 91 (28)
(Found: C, 60.58; H, 6.55; N, 3.47. C20H25NO7 requires C,
60.47; H, 6.46; N, 3.59%).
To a stirred solution of 7a (2.60 g, 8.99 mmol) in CH2Cl2 (54
mL) was added acetic acid (8.2 mL, 144 mmol) at Ϫ5 ЊC, then
NaBH4 (1.36 g, 35.9 mmol) at Ϫ15 ЊC over a period of 30 min-
utes. The resulting mixture was stirred during 45 minutes, and
then warmed to Ϫ5 ЊC during 9 hours. 150 mL of 5% aq. citric
acid was then added at 0 ЊC, and the layers were separated. The
aqueous phase was extracted with CH2Cl2 (50 mL, 3×), and
the combined organic layers were successively washed with 5%
aq. citric acid (67 mL), water (67 mL, 2×) and brine (67 mL),
dried over anhydrous MgSO4, and concentrated under reduced
pressure. Flash chromatographic purification (EtOAc–DCM
6 : 4) gave 8a (2.41 g, 92%) as a white powder; mp 119 (lit.,15
120–124 ЊC); Rf 0.42 (DCM–EtOAc 6 : 4); [α]D25 43.2 (c 1.15,
MeOH) {lit.,15 [α]D25 43 (c 1, MeOH)}; νmax(CHCl3)/cmϪ1 3403,
3062, 2982, 2930, 1779, 1685, 1627, 1577, 1455, 1366, 1246,
1172, 1114, 1020, 751; δH (250 MHz; DMSO-d6) 7.22–7.13 (5H,
m), 5.46 (1H, d, J 4.0 Hz), 4.27–4.17 (2H, m), 3.03 (1H, dd,
J 13.6, 6.5 Hz), 2.86 (1H, dd, J 13.5, 4.8 Hz), 2.41 (1H, dd,
J 16.6, 7.0 Hz), 2.18 (1H, dd, J 16.5, 7.5 Hz), 1.29 (9H, s);
δC (62.9 MHz; DMSO-d6) 172.35, 150.22, 139.31, 130.77,
129.03, 126.97, 82.49, 64.88, 63.42, 40.92, 34.12, 28.42; m/z
(FAB > 0, GT) 314 ([M ϩ Na]ϩ, 41%), 292 ([M ϩ H]ϩ, 16), 236
(100), 218 (9), 214 (31), 192 (9) (Found: C, 65.78; H, 7.16; N,
4.94. C16H21NO4 requires C, 65.96; H, 7.27; N, 4.81%).
5-[(2R)-2-(tert-Butoxycarbonylamino)-1-hydroxy-3-phenyl-
propylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione 10b
A similar procedure, as used for the preparation of 10a, led to
10b (quantitative) as a white powder; mp 119 ЊC (lit.,15 120 ЊC);
Rf 0.73 (EtOAc–cyclohexane–AcOH 7 : 3 : 1); νmax(KBr)/cmϪ1
3049; δH (250 MHz; DMSO-d6) 7.44–7.26 (6H, m), 5.62 (1H, br
s), 3.03–2.81 (2H, m), 1.71 (6H, s), 1.36 (9H, s); m/z (FAB > 0,
GT) 414 ([M ϩ Na]ϩ, 22), 392 ([M ϩ H]ϩ, 21), 336 (57), 292 (7),
148 (7), 120 (19), 103 (8), 91 (31) (Found: C, 61.51; H, 6.52; N,
3.46. C20H25NO7 requires C, 61.37; H, 6.44; N, 3.58%).
(4R,5R)-5-Benzyl-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-
2-one 8b
A similar procedure, as used for the preparation of 8a, led to 8b
(92%) as a white powder; mp 119 ЊC (lit.,15 119–120 ЊC); Rf 0.42
(DCM–EtOAc 6 : 4); [α]D25 Ϫ43.1 (c 1.00, MeOH) {lit.,15 [α]D25
Ϫ43.5 (c 1, MeOH)}; νmax(CHCl3)/cmϪ1 3064, 2984, 2933,
1781, 1684, 1647, 1627, 1579, 1506, 1457, 1364, 1249, 1154,
1088,1019, 761, 706; δH (250 MHz; CDCl3) 7.24–7.12 (5H, m),
5.47 (1H, d, J 4.0 Hz), 4.28–4.16 (2H, m), 3.01 (1H, dd, J 13.5,
6.4 Hz), 2.88 (1H, dd, J 13.5, 4.7 Hz), 2.40 (1H, dd, J 16.6, 6.9
Hz), 2.19 (1H, dd, J 16.6, 7.4 Hz), 1.32 (s, 9H); δC (62.9 MHz;
DMSO-d6) 172.22, 149.71, 137.83, 129.92, 128.48, 126.53,
83.25, 65.47, 62.76, 40.02, 33.95, 27.90; m/z (FAB > 0, GT) 314
([M ϩ Na]ϩ, 11%), 292 ([M ϩ H]ϩ, 7), 236 (100), 218 (11), 214
(15), 192 (13) (Found: C, 65.81; H, 7.34; N, 4.72. C16H21NO4
requires C, 65.96; H, 7.27; N, 4.81%).
(5S)-5-Benzyl-1-tert-butyloxycarbonyl-4-hydroxy-1,5-dihydro-
pyrrol-2-one 7a
A stirred solution of 10a (4.43 g, 11.31 mmol) in dry nitrogen-
bubbled EtOAc (300 mL) was refluxed for 10 minutes. The solu-
tion was concentrated under reduced pressure to yield 4.49 g of
a yellowish powder which was then recrystallised in ethanol–
hexane to provide 7a (3.08 g, 94%) as a white powder; mp
141 ЊC (lit.,15 141 ЊC); Rf 0.48 (EtOAc–cyclohexane–AcOH
7 : 3 : 1); [α]D25 ϩ231.4 (c 1.02, MeOH) {lit.,15 [α]D25 ϩ230 (c 1,
MeOH)}; νmax(KBr)/cmϪ1 3327, 3031, 2988, 2928, 1761, 1649,
1629, 1573, 1478, 1362, 1310, 1155, 1085, 761, 704; δH (250
MHz; DMSO-d6) 7.04 (3H, m), 6.80 (2H, m), 4.47 (1H, s), 4.43
(1H, br d, J 2.8 Hz), 3.17 (1H, dd, J 13.8, 5.1 Hz), 2.98–2.84
(1H, m), 1.31 (9H, s); δC (62.9 MHz; DMSO-d6) 175.62, 168.81,
149.06, 134.58, 129.58, 127.98, 126.74, 94.87, 81.05, 59.80,
34.25, 27.91; m/z (FAB > 0, GT) 579 ([2M ϩ H]ϩ, 8%), 290
([M ϩ H]ϩ, 36), 234 (100), 190 (12) (Found: C, 66.53; H, 6.47;
N, 4.75. C16H19NO4 requires C, 66.42; H, 6.62; N, 4.84%).
(2S,3S)-2-Benzyl-1-(tert-butoxycarbonyl)pyrrolidin-3-ol 5a
To a stirred solution of 8a (1.86 g, 6.39 mmol) in THF (48 mL)
under nitrogen was added a solution of BH3–DMS (1.96 mL,
19.2 mmol) dropwise via a syringe at room temperature. The
solution was refluxed for 35 minutes. The reaction mixture was
then cooled and poured into diethyl ether (300 mL). The borane
reagent excess was neutralised with saturated aq. NH4Cl (55
mL). The layers were separated, and the organic layer was suc-
cessively washed with 5% aq. citric acid solution (100 mL),
water (100 mL, 2×), and brine (100 mL). The resulting slurry
mixture was then dried over anhydrous MgSO4 and concen-
trated under reduced pressure. Flash chromatographic purifi-
cation (DCM–EtOAc 9 : 1, then 8 : 2) gave 5a (1.70 g, 96%) as a
white powder; mp 71 ЊC; Rf 0.47 (DCM–EtOAc 8 : 2); [α]D25
Ϫ6.00 (c 1.00, CHCl3); νmax(CHCl3)/cmϪ1 3435, 3030, 2979,
2933, 1794, 1682, 1603, 1477, 1454, 1404, 1367, 1169, 1108;
δH (250 MHz; CDCl3 ϩ TFA) 7.25–7.12 (5H, m), 4.29 (1H, dd,
J 12.7, 6.2 Hz), 4.04 (1H, br dd, J 13.9, 5.7 Hz), 3.48–3.31 (2H,
m), 3.01 (1H, dd, J 13.6, 5.2 Hz), 2.85 (1H, dd, J 13.57, 8.4 Hz),
(5R)-5-Benzyl-1-(tert-butoxycarbonyl)-4-hydroxy-1,5-dihydro-
pyrrol-2-one 7b
A similar procedure, as used for the preparation of 7a, led to 7b
(92%) as a white powder; mp 142 ЊC (lit.,15 148 ЊC); Rf 0.48
(EtOAc–cyclohexane–AcOH 7 : 3 : 1); [α]D25 Ϫ231.1 (c 1.04,
MeOH) {lit.,15 [α]D25 Ϫ230 (c 1, MeOH)}; νmax(KBr)/cmϪ1 3327,
3028, 2932, 1757, 1644, 1577, 1477, 1367, 1297, 1154, 1083, 758,
703; δH (250 MHz; DMSO-d6) 7.09 (3H, m), 6.84 (2H, m), 4.52
(1H, s), 4.47 (1H, br d, J 2.8 Hz), 3.20 (1H, dd, J 13.9, 5.3 Hz),
2.92 (1H, br d, J 13.7 Hz), 1.35 (9H, s); δC (62.9 MHz; DMSO-
d6) 175.67, 168.78, 149.06, 134.58, 129.55, 127.92, 126.67, 94.77,
J. Chem. Soc., Perkin Trans. 1, 2001, 1421–1430
1425

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2.02–1.60 (2H, m), 1.35 (9H, s); δC (62.9 MHz; DMSO-d6)
154.95, 139.58, 129.72, 128.32, 126.03, 79.57, 71.59, 61.92,
43.46, 34.60, 31.29, 28.45; m/z (FAB > 0, GT) 555 ([2M ϩ H]ϩ,
2%), 300 ([M ϩ Na]ϩ, 3), 278 ([MϩH]ϩ, 24), 222 (100), 204
(12), 186 (24), 178 (5), 160 (11) (Found: C, 69.37; H, 8.44; N,
5.18. C16H23NO3 requires C, 69.29; H, 8.36; N, 5.05%).
washed with 5% aq. NaHCO3 (4 mL), water (4 mL, 2×), and
brine (4 mL), dried over anhydrous MgSO4, and concentrated
under reduced pressure. Chromatotron purification (cyclo-
hexane–EtOAc 8.5 : 1.5) gave 13a (0.104 g, 95%) as a colourless
oil; Rf 0.44 (cyclohexane–EtOAc 8.5 : 1.5); [α]D25 Ϫ26.5 (c 0.59,
CHCl3); νmax(CHCl3)/cmϪ1 3065, 2980, 2931, 1749, 1685, 1496,
1453, 1402, 1367, 1346, 1255, 1171, 1123, 1082, 1049, 980, 945,
858, 765, 699, 650; δH (250 MHz; CDCl3) 7.44 (2H, m), 7.37
(3H, m), 7.06 (3H, m), 6.89 (2H, m), 5.22 (1H, q, J 6.5 Hz), 4.20
(1H, q, J 6.3 Hz), 3.41 (4H, br s), 3.24–2.71 (3H, m), 2.05 (1H,
m), 1.66–1.51 (1H, m), 1.35 (9H, s); δC (62.9 MHz; CDCl3)
166.09, 154.48, 138.01, 131.78, 129.91, 129.60, 128.71, 128.31,
127.50, 126.26, 121.14, 84.77 (q, J 26.6 Hz), 79.99, 75.80, 59.78,
55.45, 43.02, 34.62, 29.42, 28.41; δF (282.4 MHz; CDCl3)
Ϫ71.62 (3F, s); m/z (FAB > 0, GT) 508 ([M ϩ H]ϩ, 10%), 430
(45) (Found: C, 63.44; H, 6.26; N, 2.71. C26H30F3NO5 requires
C, 63.28; H, 6.13; N, 2.84%).
(2R,3R)-2-Benzyl-1-(tert-butoxycarbonyl)pyrrolidin-3-ol 5b
A similar procedure, as used for the preparation of 5a, led to 5b
(94%) as a white powder; mp 71 ЊC; Rf 0.40 (DCM–EtOAc
8 : 2); [α]D25 6.00 (c 1.00, CHCl3); νmax(CHCl3)/cmϪ1 3437, 3064,
2979, 2932, 1792, 1684, 1603, 1539, 1465, 1405, 1368, 1168,
1110, 1051, 651; δH (250 MHz; CDCl3 ϩ TFA) 7.11–7.01
(5H, m), 4.10 (1H, dd, J 12.7, 6.3 Hz), 3.90 (1H, br dd, J 13.9,
5.7 Hz), 3.27–3.15 (2H, m), 2.75 (1H, dd, J 13.5, 8.4 Hz),
1.86 (1H, m), 1.63–1.51 (2H, m), 1.25 (9H, s); δC (62.9 MHz;
CDCl3) 154.95, 139.58, 129.69, 128.32, 126.03, 79.55, 71.61,
61.94, 43.42, 34.59, 31.31, 28.45; m/z (FAB > 0, GT) 555
([2M ϩ H]ϩ, 3%), 300 ([M ϩ Na]ϩ, 3), 278 ([M ϩ H]ϩ, 22), 222
(100), 204 (10), 186 (19), 178 (8), 160 (8) (Found: C, 69.46;
H, 8.27; N, 5.16. C16H23NO3 requires C, 69.29; H, 8.36; N,
5.05%).
(4R,5R)-2-Benzyl-1-(tert-butoxycarbonyl)-3-[(R)-ꢀ-methoxy-ꢀ-
(trifluoromethyl)phenylacetoxy]pyrrolidine 13b
A similar procedure, as used for the preparation of 13a, led to
13b (95%) as a colourless oil; Rf 0.46 (cyclohexane–EtOAc
8.5 : 1.5); [α]D25 Ϫ67.9 (c 0.59, CHCl3); νmax(CHCl3)/cmϪ1 3064,
3030, 2979, 2898, 1747, 1684, 1496, 1478, 1454, 1399, 1367,
1254, 1169, 1124, 1082, 1047, 1018, 994, 946, 858, 766, 700, 650;
δH (250 MHz; CDCl3) 7.49 (2H, m), 7.37 (3H, m), 7.05 (3H, m),
6.85 (2H, m), 5.22 (1H, q, J 6.4 Hz), 4.16 (1H, q, J 6.1 Hz), 3.50
(4H, s), 3.18 (1H, m), 2.58–2.98 (2H, m), 2.02 (1H, m), 1.67
(1H, m), 1.29 (9H, s); δC (62.9 MHz; CDCl3) 166.09, 154.60,
138.10, 132.09, 129.94, 129.64, 128.67, 128.34, 127.35, 126.30,
125.73, 84.48 (q, J 26.8 Hz), 80.06, 75.73, 60.47, 53.58, 43.06,
34.15, 29.32, 27.01; δF (282.4 MHz; CDCl3) Ϫ71.37 (3F, s); m/z
(FAB > 0, GT) 530 ([M ϩ Na]ϩ, 100%), 475 (8), 430 (9)
(Found: C, 62.44; H, 6.31; N, 2.69. C26H30F3NO5 requires C,
62.32; H, 6.13; N, 2.84%).
(2S)-2-Benzyl-1-(tert-butoxycarbonyl)pyrrolidin-3-one 6a
To a stirred solution of 5a (0.200 g, 0.721 mmol), NMO (0.127
g, 1.08 mmol), and powdered 4 Å molecular sieves in CH2Cl2
(2 mL) was added continuously TPAP (12.7 mg, 5 mol%) at
0 ЊC, under nitrogen. The solution was then allowed to warm to
room temperature and was stirred during 20 minutes. The
slurry mixture was filtered on a short silica column and washed
with EtOAc. The product was concentrated under reduced
pressure, and chromatotron purification (cyclohexane–EtOAc
7 : 3) gave 6a (0.185 g, 93%) as a colourless oil; Rf 0.43 (cyclo-
hexane–EtOAc 8 : 2); [α]D25 199.9 (c 1.00, MeOH); νmax(CHCl3)/
cmϪ1 3019, 2980, 2931, 1757, 1701, 1691, 1478, 1454, 1406,
1215, 1148, 1116; δH (250 MHz; CDCl3) 7.16–7.02 (3H, m),
6.88–6.84 (2H, m), 3.96 (1H, br s), 3.54–3.00 (2H, m), 2.93–2.82
(1H, m), 2.69–2.48 (1H, m), 2.27–2.07 (1H, m), 1.77–1.58 (1H,
m), 1.33 (9H, s); δC (62.9 MHz; CDCl3) 213.68, 154.13, 136.18,
129.75, 128.41, 126.81, 80.18, 63.23, 41.47, 36.21, 36.11, 28.41;
m/z (FAB > 0, GT) 551 ([2M ϩ H]ϩ, 5%), 288 ([M ϩ Na]ϩ, 7),
276 ([M ϩ H]ϩ, 15), 220 (100), 202 (23), 176 (11), 91 (39)
(Found: C, 69.63; H, 7.78; N, 4.93. C16H21NO3 requires C,
69.79; H, 7.69; N, 5.09%).
(2S,3S)-2-Benzyl-3-benzyloxy-1-(tert-butoxycarbonyl)-
pyrrolidine 14a
To a stirred solution of 5a (0.500 g, 1.80 mmol) in THF (7.5
mL), under nitrogen, were added successively tetrabutyl-
ammonium iodide (TBAI) (53.3 mg, 5 mol%) and benzyl
bromide (653 µL, 5.41 mmol) via a syringe. The solution was
cooled to 0 ЊC, and NaH (95%; 50.0 mg, 1.98 mmol) was added.
After 10 minutes, the solution was allowed to warm to
room temperature, and was stirred for 6 hours. 5% Aq. citric
acid (30 mL) was then added, and the solution was extracted
with EtOAc (12 mL, 3×). The layers were separated, and the
organic layer was successively washed with water (12 mL, 2×)
and brine (12 mL), dried over anhydrous MgSO4, and concen-
trated under reduced pressure. Chromatotron purification
(cyclohexane, then cyclohexane–EtOAc 8 : 2) gave 14a (0.656 g,
99%) as a clear yellow oil; Rf 0.41 (cyclohexane–EtOAc 9 : 1);
[α]D25 17.7 (c 1.34, MeOH); νmax(CHCl3)/cmϪ1 3029, 2980, 1684,
1497, 1402, 1168, 1085; δH (250 MHz; CDCl3 ϩ TFA) 7.31–7.21
(5H, m), 7.19–7.10 (5H, m), 4.38 (1H, m, J 11.7 Hz), 4.32 (1H,
d, J 11.8 Hz), 4.12 (1H, br dd, J 12.7, 6.4 Hz), 3.97 (1H, br dd,
J 14.9, 6.4 Hz), 3.34–3.28 (2H, m), 2.89 (1H, dd, J 13.5, 6.8 Hz),
2.78 (1H, dd, J 13.4, 5.8 Hz), 2.00–1.93 (1H, m), 1.87–1.72 (1H,
m), 1.27 (9H, m); δC (62.9 MHz; CDCl3) 154.68, 139.61, 138.22,
129.98, 128.44, 128.13, 127.70, 127.58, 125.88, 79.39, 78.74,
71.94, 60.24, 42.77, 35.05, 28.46, 26.97; m/z (FAB > 0, GT) 735
([2M ϩ H]ϩ, 3%), 390 ([M ϩ Na]ϩ, 4), 368 ([M ϩ H]ϩ, 25), 312
(81), 294 (6), 268 (11), 220 (20), 176 (27), 91 (96) (Found: C,
74.29; H, 7.88; N, 3.92. C23H29NO3 requires C, 74.17; H, 7.95;
N, 3.81%).
(2R)-2-Benzyl-1-(tert-butoxycarbonyl)pyrrolidin-3-one 6b
A similar procedure, as used for the preparation of 6a, led to 6b
(90%) as a colourless oil; Rf 0.43 (cyclohexane–EtOAc 8 : 2);
[α]D25 Ϫ198.4 (c 1.02, MeOH); νmax(CHCl3)/cmϪ1 3019, 2980,
2931, 1757, 1691, 1406, 1215, 1148, 1116; δH (250 MHz;
CDCl3) 7.40 (3H, m), 7.20 (2H, m), 4.35 (1H, br s), 3.91 (1H,
m), 3.35 (1H, m), 3.29–3.20 (1H, m), 3.02–2.82 (1H, m),
2.70–2.48 (1H, m), 2.20–2.03 (1H, m), 1.70 (9H, s); δC (62.9
MHz; CDCl3) 213.80, 154.25, 136.28, 129.84, 128.51, 126.92,
80.30, 63.35, 41.71, 36.27, 36.14, 28.52; m/z (FAB > 0, GT)
551 ([2M ϩ H]ϩ, 3%), 288 ([M ϩ Na]ϩ, 7), 276 ([M ϩ H]ϩ,
18), 220 (100), 202 (23), 176 (11), 91 (35) (Found: C, 69.61;
H, 7.81; N, 5.00. C16H21NO3 requires C, 69.79; H, 7.69; N,
5.09%).
(4S,5S)-2-Benzyl-1-(tert-butoxycarbonyl)-3-[(R)-ꢀ-methoxy-ꢀ-
trifluoromethyl)phenylacetoxy]pyrrolidine 13a
To a stirred solution of 5a (0.130 g, 0.469 mmol) and DMAP
(0.116 mg, 0.442 mmol) in CH2Cl2 (4 mL) was added (R)-(ϩ)-
Mosher’s acid chloride (98 µL, 0.516 mmol) dropwise at 0 ЊC,
under nitrogen. The solution was then allowed to warm to
room temperature and was stirred for 1.5 h. The slurry mixture
was then diluted with 12 mL of diethyl ether and successively
(2R,3R)-2-Benzyl-3-benzyloxy-1-(tert-butoxycarbonyl)-
pyrrolidine 14b
A similar procedure, as used for the preparation of 14a, led to
1426
J. Chem. Soc., Perkin Trans. 1, 2001, 1421–1430

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14b (99%), as a colourless oil; Rf 0.43 (cyclohexane–EtOAc
9 : 1); [α]D25 Ϫ18.90 (c 1.17, MeOH); νmax(CHCl3)/cmϪ1 3065,
2979, 1682, 1497, 1454, 1403, 1171, 1130, 1088; δH (250 MHz;
CDCl3 ϩ TFA) 7.27–7.15 (10H, m), 4.30 (1H, d, J 11.8 Hz),
4.10 (1H, d, J 11.8 Hz), 4.11 (1H, br dd, J 12.7, 6.4 Hz), 3.92
(1H, br dd, J 14.8, 6.4 Hz), 3.38–3.22 (2H, m), 2.91 (1H, dd,
J 13.5, 6.9 Hz), 2.80 (1H, dd, J 13.5, 5.8 Hz), 1.97–1.89 (1H, m),
1.82–1.71 (1H, m), 1.28 (9H, s); δC (62.9 MHz; CDCl3) 154.75,
139.67, 138.29, 130.03, 128.48, 128.20, 127.74, 127.66, 125.95,
79.48, 78.82, 71.92, 60.28, 42.84, 35.12, 28.53, 27.02; m/z
(FAB > 0, GT) 735 ([2M ϩ H]ϩ, 2%), 390 ([M ϩ Na]ϩ, 5), 368
([M ϩ H]ϩ, 17), 312 (100), 294 (10), 268 (16), 220 (13), 176 (18),
91 (45) (Found: C, 74.98; H, 7.81; N, 3.93. C23H29NO3 requires
C, 75.17; H, 7.95; N, 3.81%).
28.45, 26.97; m/z (FAB > 0, NBA) 537 ([M ϩ Na]ϩ, 11%), 515
([M ϩ H]ϩ, 91), 459 (46), 415 (100), 307 (11), 268 (43), 176 (24),
164 (11), 176 (24), 120 (28), 91 (55) (Found: C, 74.87; H, 7.51;
N, 5.37. C32H38N2O4 requires C, 74.68; H, 7.44; N, 5.44%).
(2R,3R)-2-Benzyl-3-benzyloxy-1-[N-(tert-butoxycarbonyl)-L-
phenylalanyl]pyrrolidine 16b
A similar procedure, as used for the preparation of 16a, led to
16b (93%) as a colourless oil; Rf 0.46 (DCM–EtOAc 9 : 1); [α]D25
Ϫ5.8 (c 1.00, MeOH); νmax(CHCl3)/cmϪ1 3293, 3053, 2981,
2931, 1703, 1634, 1495, 1455, 1368, 1248, 1170, 1117, 1029;
δH (250 MHz; CDCl3) 7.30–6.98 (15H, m), 5.23 (1H, d, J 8.6
Hz), 4.57 (1H, m), 4.29–4.15 (2H, m), 4.04 (1H, m), 3.78 (1H,
m), 3.48–3.37 (1H, m), 3.21–3.05 (1H, m), 2.98–2.88 (2H, m),
2.76 (1H, m), 2.65–2.45 (1H, m), 1.76 (2H, m), 1.36 (9H, s);
δC (62.9 MHz; CDCl3) 170.82, 155.18, 139.49, 138.06, 136.98,
129.83, 129.50, 128.44, 128.32, 128.09, 127.82, 127.62, 126.90,
125.94, 79.57, 78.29, 71.49, 59.58, 53.13, 44.23, 39.95, 33.18,
28.44, 26.59; m/z (FAB > 0, NBA) 537 ([M ϩ Na]ϩ, 11%), 515
([M ϩ H]ϩ, 91), 459 (46), 415 (100), 307 (11), 268 (43), 176
(24), 164 (11), 176 (24), 120 (28), 91 (55) (Found: C, 74.81;
H, 7.35; N, 5.39. C32H38N2O4 requires C, 74.68; H, 7.44; N,
5.44%).
(2S,3S)-2-Benzyl-3-(benzyloxy)pyrrolidinium trifluoroacetate
15a
To a stirred solution of 14a (0.414 g, 1.13 mmol) in CH2Cl2 (1.7
mL) was added TFA (1.7 mL, 22.6 mmol) under nitrogen at
0 ЊC. The solution was then allowed to warm to room temper-
ature and was stirred for 30 minutes. Coevaporation with tolu-
ene (12 mL) and concentration under reduced pressure gave the
resulting salt 15a (0.432 g, quantitative yield) as a colourless
oil; δH (250 MHz; CD3OD) 7.56–7.44 (10H, m), 4.85 (1H, d,
J 11.5 Hz), 4.61 (1H, d, J 11.5 Hz), 4.26 (1H, br s), 3.93 (1H,
br s), 3.78–3.46 (2H, m), 3.42–3.33 (1H, m), 3.26–3.13 (1H,
m), 2.61–2.47 (1H, m), 2.29–2.17 (1H, m); δC (62.9 MHz;
CDCl3) 139.69, 138.64, 130.82, 130.72, 130.30, 129.98, 129.78,
128.98, 78.94, 72.74, 67.51, 44.98, 34.05, 30.54; m/z (FAB > 0,
NBA) 535 ([2M ϩ H]ϩ, 4%), 268 ([M ϩ H]ϩ, 55), 176 (31), 91
(100).
(2S,3S)-2-Benzyl-1-O-benzyl-[N-(tert-butoxycarbonyl)-L-
tyrosinyl]-3-benzyloxypyrrolidine 17a
To a stirred solution of TFA salt 15a (0.236 g, 0.619 mmol),
Boc()Tyr(Bn)OH 9c (0.230 g, 0.619 mmol), and PyBOP (0.386
g, 0.743 mmol) in CH2Cl2 (6 mL) was added Et3N (216 µL, 1.55
mmol) dropwise at 0 ЊC under nitrogen. The solution was then
allowed to warm to room temperature and was stirred for
3 hours. After concentration under reduced pressure, the result-
ing slurry was diluted in EtOAc (12 mL) and successively
washed with 5% aq. NaHCO3 (4 mL), water (4 mL), 5% citric
acid (4 mL), water (4 mL, 2×), and brine (4 mL), dried over
anhydrous MgSO4, and concentrated under reduced pressure.
Chromatotron purification (cyclohexane–EtOAc 7 : 3) gave 17a
(0.365 g, 95%) as a colourless oil; Rf 0.52 (cyclohexane–EtOAc
7 : 3); [α]D25 30.63 (c 1.02, MeOH); νmax(CHCl3)/cmϪ1 3434, 3065,
3031, 2979, 2931, 1749, 1701, 1636, 1511, 1497, 1454, 1367,
1289, 1241, 1175, 1111, 1026, 699; δH (250 MHz; CDCl3)
7.31–7.12 (15H, m), 7.09–6.99 (2H, m), 6.86–6.70 (2H, m),
5.23 (1H, d, J 8.4 Hz), 4.93 (3H, m), 4.43 (1H, m), 4.25 (1H,
m), 4.20 (2H, m), 3.63–3.52 (1H, m), 3.28–3.16 (1H, m), 2.93
(1H, m), 2.82 (1H, m), 2.59–2.37 (1H, m), 1.58–1.47 (3H, m),
1.35 (9H, s); δC (62.9 MHz; CDCl3) 170.90, 157.74, 155.19,
139.39, 137.95, 137.05, 130.52, 130.04, 129.01, 128.71, 128.53,
128.44, 128.09, 127.97, 127.77, 127.58, 126.03, 114.93, 79.69,
77.32, 71.84, 69.98, 60.16, 53.33, 43.58, 39.20, 33.53, 28.44,
26.97; m/z (FAB > 0, NBA) 1241 ([2M ϩ H]ϩ, 3%), 643
([M ϩ Na]ϩ, 11), 621 ([M ϩ H]ϩ, 95), 565 (58), 521 (49), 413
(20), 294 (6), 268 (59), 226 (25), 197 (7), 91 (100) (Found: C,
75.59; H, 7.20; N, 4.41. C39H44N2O5 requires C, 75.46; H,
7.14; N, 4.51%).
(2R,3R)-2-Benzyl-3-(benzyloxy)pyrrolidinium trifluoroacetate
15b
A similar procedure, as used in the preparation of 15a, led to
15b (quantitatively) as a colourless oil; δH (250 MHz; CD3OD)
7.59–7.32 (10H, m), 4.88 (1H, d, J 11.5 Hz), 4.64 (1H, d,
J 11.5 Hz), 4.30 (1H, m), 3.94 (1H, m), 3.65–3.57 (1H, m), 3.50
(1H, m), 3.40 (1H, dd, J 13.8, 7.3 Hz), 3.24 (1H, dd, J 13.9, 7.8
Hz), 2.65–2.49 (1H, m), 2.34–2.19 (1H, m); δC (62.9 MHz;
CDCl3) 139.67, 138.62, 130.83, 130.75, 130.27, 129.95, 129.79,
128.95, 78.96, 72.74, 67.50, 44.99, 34.08, 30.57; m/z (FAB > 0,
NBA) 535 ([2M ϩ H]ϩ, 3%), 268 ([M ϩ H]ϩ, 46), 176 (37), 91
(100).
(2S,3S)-2-Benzyl-3-benzyloxy-1-[N-(tert-butoxycarbonyl)-L-
phenylalanyl]pyrrolidine 16a
To a stirred solution of TFA salt 15a (0.190 g, 0.498 mmol),
Boc()PheOH 9a (0.132 g, 0.498 mmol), and PyBOP (0.311 g,
0.598 mmol) in CH2Cl2 (5 mL) was added Et3N (174 µL, 1.25
mmol) dropwise at 0 ЊC under nitrogen. The solution was then
allowed to warm to room temperature and was stirred for 3
hours. After concentration under reduced pressure, the result-
ing slurry was diluted in EtOAc (12 mL) and successively
washed with 5% aq. NaHCO3 (4 mL), water (4 mL), 5% aq.
citric acid (4 mL), water (4 mL, 2×), and brine (4 mL), dried
over anhydrous MgSO4, and concentrated under reduced pres-
sure. Chromatotron purification (cyclohexane–EtOAc 7 : 3)
gave 16a (0.243 g, 95%) as a colourless oil; Rf 0.45 (cyclo-
hexane–EtOAc 7 : 3); [α]D25 26.4 (c 1.01, MeOH); νmax(CHCl3)/
cmϪ1 3290, 3051, 3028, 2975, 2929, 1702, 1635, 1496, 1454,
1365, 1250, 1169, 1114, 1019, 922; δH (250 MHz; CDCl3) 7.13–
6.77 (15H, m), 5.12 (1H, d, J 9.3 Hz), 4.41–4.29 (1H, m), 4.11–
4.05 (3H, m), 3.52–3.35 (1H, m), 3.14–3.02 (1H, m), 2.90–2.67
(4H, m), 2.45–2.24 (1H, m), 1.51–1.30 (2H, m), 1.23 (9H, s);
δC (62.9 MHz; CDCl3) 170.81, 155.19, 139.39, 137.98, 136.66,
130.07, 129.52, 128.46, 128.24, 128.10, 127.78, 127.65, 126.96,
126.04, 79.76, 78.59, 71.84, 60.08, 53.21, 43.54, 40.13, 33.57,
(2R,3R)-2-Benzyl-1-O-benzyl-[N-(tert-butoxycarbonyl)-L-
tyrosinyl]-3-benzyloxypyrrolidine 17b
A similar procedure, as used for the preparation of 17a, led to
17b (96%) as a white powder; mp 37–38 ЊC; Rf 0.38 (DCM–
EtOAc 7 : 3); [α]D25 Ϫ5.00 (c 1.00, MeOH); νmax(KBr)/cmϪ1 3433,
3065, 3032, 2980, 2932, 1748, 1701, 1636, 1510, 1497, 1455,
1368, 1288, 1240, 1173, 1115, 1027, 700; δH (250 MHz; CDCl3)
7.25–6.91 (17H, m), 6.74 (2H, m), 5.20 (1H, d, J 8.8 Hz), 4.85
(2H, m), 4.45 (1H, br d, J 8.8 Hz), 4.21 (1H, m), 4.10 (2H, m),
3.73 (1H, m), 3.38 (1H, m), 3.17 (1H, m), 3.01–2.85 (2H, m),
2.75–2.67 (1H, m), 2.55–2.39 (1H, m), 1.70 (2H, m), 1.26 (9H,
s); δC (62.9 MHz; CDCl3) 170.90, 157.74, 155.19, 139.39,
138.07, 137.99, 137.05, 130.52, 130.04, 129.01, 128.71, 128.59,
J. Chem. Soc., Perkin Trans. 1, 2001, 1421–1430
1427

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128.53, 128.44, 128.09, 127.97, 127.77, 127.58, 127.35, 126.03,
114.93, 79.69, 77.32, 71.84, 69.98, 60.16, 53.33, 43.58, 39.20,
33.53, 28.68, 26.82; m/z (FAB > 0, NBA) 1241 ([2M ϩ H]ϩ,
2%), 643 ([M ϩ Na]ϩ, 4), 621 ([M ϩ H]ϩ, 29), 565 (8), 521 (17),
413 (8), 294 (3), 268 (12), 226 (9), 197 (5), 91 (58) (Found: C,
75.30; H, 7.03; N, 4.62. C39H44N2O5 requires C, 75.46; H, 7.14;
N, 4.51%).
J 8.2 Hz), 6.52 (2H, d, J 8.2 Hz), 5.21 (1H, d, J 8.9 Hz), 4.31
(1H, m), 3.90 (1H, m), 3.74 (1H, m), 3.13 (1H, m), 2.97 (1H, m),
2.76–2.63 (2H, m), 2.41 (1H, m), 2.21 (1H, m), 1.85 (1H, m),
1.34 (1H, m), 1.24 (9H, s); δC (62.9 MHz; CDCl3) 171.38, 155.71,
155.53, 139.34, 130.65, 129.79, 128.48, 127.67, 126.34, 115.62,
80.26, 70.68, 61.91, 53.66, 44.13, 39.09, 33.34 28.50, 28.36; m/z
(FAB > 0, NBA) 463 ([M ϩ Na]ϩ, 4%), 441 ([M ϩ H]ϩ, 13), 385
(6), 341 (4), 204 (5), 178 (5), 136 (60), 107 (16), 91 (14) (Found:
C, 68.23; H, 7.41; N, 6.25. C25H32N2O5 requires C, 68.16; H,
7.32; N, 6.36%).
(2S,3S)-2-Benzyl-1-[N-(tert-butoxycarbonyl)-L-phenylalanyl]-
pyrrolidin-3-ol 1a
A stirred solution of 16a (0.170 g, 0.330 mmol) in ethanol
(2 mL) was bubbled with dry nitrogen during 10 minutes.
Pearlman’s catalyst (20% Pd(OH)2/C) (57.9 mg, 10 mol%) was
then added, and the slurry was again nitrogen bubbled during
5 minutes. The reaction mixture was stirred for 50 minutes
under a flux of hydrogen (atmospheric pressure) at room tem-
perature. The resulting slurry was then filtered over Celite,
concentrated under reduced pressure and chromatotron puri-
fied (cyclohexane–EtOAc 6 : 4) to obtain 1a (0.138 g, 99%) as a
white powder; mp 51 ЊC; Rf 0.30 (cyclohexane–EtOAc 6 : 4);
[α]D25 21.6 (c 1.00, MeOH); νmax(CHCl3)/cmϪ1 3631, 3434, 3051,
2975, 2932, 1766, 1733, 1700, 1630, 1558, 1509, 1493, 1433,
1389, 1247, 1165, 1050, 677; δH (250 MHz; CDCl3) 7.17–7.00
(10H, m), 5.16 (1H, d, J 8.6 Hz), 4.40 (1H, m), 4.20 (1H, m),
3.81 (1H, m), 3.26–3.07 (2H, m), 2.82–2.65 (3H, m), 2.43–2.35
(1H, m), 1.47 (2H, br s), 1.27 (9H, s); δC (62.9 MHz; CDCl3)
170.90, 155.21, 139.46, 136.59, 129.71, 129.48, 128.52, 128.39,
127.00, 126.19, 79.81, 70.52, 61.97, 53.45, 44.05, 40.07, 33.24,
30.97, 28.41; m/z (FAB > 0, NBA) 447 ([M ϩ Na]ϩ, 10%), 425
([M ϩ H]ϩ, 100), 369 (92), 351 (7), 325 (62), 307 (8), 248 (7), 204
(11), 178 (78), 160 (17), 120 (72), 91 (57) (Found: C, 70.88;
H, 7.69; N, 6.48. C25H32N2O4 requires C, 70.73; H, 7.60; N,
6.60%).
(2R,3R)-2-Benzyl-1-[N-(tert-butoxycarbonyl)-L-tyrosinyl]-
pyrrolidin-3-ol 2b
A similar procedure, as used for the preparation of 2a, led to 2b
(96%) as a colourless oil; Rf 0.31 (cyclohexane–EtOAc 6 : 4);
[α]D25 8.36 (c 1.35, MeOH); νmax(CHCl3)/cmϪ1 3428, 3051, 2982,
2932, 1705, 1628, 1515, 1494, 1455, 1363, 1294, 1249, 1152,
1110, 1052, 705; δH (250 MHz; CDCl3) 7.40–7.24 (6H, m), 7.08
(2H, m), 6.76 (2H, m), 5.40 (1H, d, J 8.6 Hz), 4.64 (1H, m), 4.28
(1H, m), 3.89 (1H, m), 3.60 (1H, m), 3.33 (1H, m), 3.19 (1H, m),
3.04 (1H, m), 2.91 (1H, m), 2.65 (1H, m), 1.86–1.71 (2H, m),
1.47 (9H, s); δC (62.9 MHz; CDCl3) 171.37, 155.63, 155.53,
139.26, 130.78, 129.48, 128.59, 127.54, 126.41, 115.56, 80.24,
70.48, 63.11, 53.63, 45.10, 38.88, 32.95, 28.51, 28.45; m/z
(FAB > 0, NBA) 463 ([M ϩ Na]ϩ, 3%), 441 ([M ϩ H]ϩ, 8), 385
(5), 341 (7), 204 (6), 178 (12), 136 (71), 107 (22), 91 (16) (Found:
C, 68.33; H, 7.41; N, 6.28. C25H32N2O5 requires C, 68.16; H,
7.32; N, 6.36%).
(2S)-2-Benzyl-3-oxopyrrolidinium trifluoroacetate 18a
The same procedure as previously described for the synthesis of
15a, led, when applied to 6a, quantitatively to 18a, as a colour-
less oil; δH (250 MHz; CD3OD) 7.30–7.21 (5H, m), 3.97
(1H, dd, J 10.7, 4.0 Hz), 3.71–3.60 (1H, m), 3.49–3.36 (1H,
m), 3.29–3.20 (2H, m), 2.83–2.59 (2H, m); δC (62.9 MHz;
CD3OD) 207.49, 136.63, 129.98, 129.44, 128.62, 67.45, 41.89,
34.55, 31.90; m/z (FAB > 0, GT) 351 ([2M ϩ H]ϩ, 3%), 176
([M ϩ H]ϩ, 58).
(2R,3R)-2-Benzyl-1-[N-(tert-butoxycarbonyl)-L-phenylalanyl]-
pyrrolidin-3-ol 1b
A similar procedure, as used for the preparation of 1a, led to
1b (99%) as a colourless oil; Rf 0.29 (cyclohexane–EtOAc
6 : 4); [α]D25 9.83 (c 0.54, MeOH); νmax(CHCl3)/cmϪ1 3431, 3052,
2978, 2931, 1762, 1732, 1703, 1634, 1561, 1507, 1491, 1432,
1391, 1245, 1169, 1051, 678; δH (250 MHz; CDCl3) 7.11–6.93
(10H, m), 5.23 (1H, d, J 8.5 Hz), 4.48 (1H, m), 3.99 (2H, m),
3.44 (1H, m), 3.15 (2H, m), 2.87–2.76 (2H, m), 2.54–2.38
(1H, m), 1.64 (1H, m), 1.46 (2H, m), 1.23 (9H, s); δC (62.9
MHz; CDCl3) 171.03, 155.33, 139.42, 136.90, 129.72, 129.52,
128.75, 128.59, 127.03, 126.35, 79.79, 70.60, 61.33, 53.40,
45.02, 40.14, 32.93, 28.52, 27.01; m/z (FAB > 0, GT) 447
([M ϩ Na]ϩ, 11%), 425 ([M ϩ H]ϩ, 63), 369 (43), 351 (12),
325 (100), 307 (6), 204 (7), 178 (46), 160 (16), 91 (32) (Found:
C, 70.94; H, 7.49; N, 6.66. C25H32N2O4 requires C, 70.73; H,
7.60; N, 6.60%).
(2R)-2-Benzyl-3-oxopyrrolidinium trifluoroacetate 18b
A similar procedure, as used for the preparation of 15a, led to
18b quantitatively, as a colourless oil; δH (250 MHz; CD3OD)
7.62–7.48 (5H, m), 4.26 (1H, dd, J 10.4, 3.9 Hz), 4.01–3.88
(1H, m), 3.82–3.70 (1H, m), 3.63–3.54 (1H, m), 3.48 (1H,
m), 3.13–3.07 (1H, m), 2.96–2.88 (1H, m); δC (62.9 MHz;
CD3OD) 207.51, 136.65, 130.01, 129.42, 128.64, 67.41, 41.93,
34.51, 31.87; m/z (FAB > 0, GT) 351 ([2M ϩ H]ϩ, 4%), 176
([M ϩ H]ϩ, 53).
(2S)-2-Benzyl-1-[N-(tert-butoxycarbonyl)-L-phenylalanyl]-
pyrrolidin-3-one 3a
To a stirred solution of the TFA salt 18a (0.105 g, 0.363 mmol),
Boc()PheOH 9a (97.3 mg, 0.363 mmol), and PyBOP (0.234 g,
0.436 mmol) in CH2Cl2 (4 mL) was added Et3N (127 µL, 0.908
mmol) dropwise at 0 ЊC under nitrogen. The solution was then
allowed to warm to room temperature and was stirred during
1.5 h. After concentration under reduced pressure, the resulting
slurry was diluted in EtOAc (12 mL) and successively washed
with 5% aq. NaHCO3 (4 mL), water (4 mL), 5% aq. citric acid
(4 mL), water (4 mL, 2×), and brine (4 mL), dried over
anhydrous MgSO4, and concentrated under reduced pressure.
Chromatotron purification (cyclohexane–EtOAc 7 : 3) gave 3a
(0.332 g, 98%) as a yellowish oil; Rf 0.40 (cyclohexane–EtOAc
7 : 3); [α]D25 115.2 (c 1, MeOH); νmax(KBr)/cmϪ1 3305, 3065, 3030,
2980, 2930, 1759, 1705, 1644, 1495, 1455, 1368, 1247, 1168,
1080, 1055, 1030, 704; δH (250 MHz; CDCl3) 7.19–7.00 (8H, m),
6.81 (2H, m), 5.27 (1H, d, J 8.7 Hz), 4.48 (1H, m), 4.12 (1H, m),
3.25 (1H, dd, J 13.4, 5.8 Hz), 2.96–2.69 (5H, m), 2.33 (1H, br
(2S,3S)-2-Benzyl-1-[N-(tert-butoxycarbonyl)-L-tyrosinyl]-
pyrrolidin-3-ol 2a
A stirred solution of 17a (0.100 g, 0.161 mmol) in ethanol
(2 mL) was nitrogen bubbled during 10 minutes. Pearlman’s
catalyst [Pd(OH)2/C 20%, moisture ≈ 60% (28.3 mg wet, 10
mol%)] was then added, and the slurry solution was again
nitrogen bubbled during 5 minutes. The reaction mixture was
stirred for 45 minutes under a flux of hydrogen (under atmos-
pheric pressure) at room temperature. The resulting slurry was
then filtered over Celite, concentrated under reduced pressure,
and purified by chromatotron (cyclohexane–EtOAc 6 : 4) to
obtain 2a (69.8 mg, 98%) as a white solid; mp 87–88 ЊC; Rf
0.45 (EtOAc–cyclohexane 6 : 4); [α]D25 33.2 (c 1.00, MeOH);
νmax(KBr)/cmϪ1 3429, 3052, 2981, 2932, 1700, 1629, 1516, 1508,
1497, 1453, 1369, 1289, 1249, 1170, 1103, 1048, 705; δH (250
MHz; CDCl3) 7.28 (1H, br s), 7.11–6.94 (5H, m), 6.81 (2H, d,
1428
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dd, J 18.9, 8.8 Hz), 1.47 (1H, m), 1.34 (9H, s); δC (62.9 MHz;
CDCl3) 212.31, 171.21, 155.18, 136.32, 135.74, 129.95, 129.75,
129.35, 128.67, 128.48, 127.01, 79.80, 63.30, 52.27, 42.61, 39.87,
36.21, 35.08, 28.34; m/z (FAB > 0, GT) 845 ([2M ϩ H]ϩ, 3%),
445 ([M ϩ Na]ϩ, 5), 423 ([M ϩ H]ϩ, 27), 376 (28), 323 (16), 202
(4), 176 (15), 120 (24), 91 (23) (Found: C, 70.28; H, 7.21; N,
6.52. C25H30N2O4 requires C, 70.37; H, 7.16; N, 6.63%).
(24) (Found: C, 72.62; H, 6.92; N, 5.19. C32H36N2O5 requires C,
72.70; H, 6.86; N, 5.30%).
(2S)-2-Benzyl-1-[N-(tert-butoxycarbonyl)-L-tyrosinyl]-
pyrrolidin-3-one 4a
A stirred solution of 19a (0.150 g, 0.284 mmol) in ethanol
(2 mL) was nitrogen bubbled during 10 minutes. 10% Pd–C
(12.1 mg, 4 mol%) was then added, and the slurry was
again nitrogen bubbled during 5 minutes. The reaction mixture
was stirred for 8 hours under a flux of hydrogen (under atmos-
pheric pressure) at room temperature. The resulting slurry was
then filtered over Celite, concentrated under reduced pressure,
and chromatotron purified (cyclohexane–EtOAc 6 : 4) to
obtain 4a (0.122 g, 98%) as a white powder; mp 71 ЊC; Rf 0.33
(cyclohexane–EtOAc 6 : 4); [α]D25 107.9 (c 1.00, MeOH);
νmax(KBr)/cmϪ1 3428, 3331, 3064, 2982, 2932, 1759, 1701, 1641,
1614, 1594, 1516, 1499, 1455, 1369, 1248, 1170, 1103, 1046;
δH (250 MHz; CDCl3) 7.56 (1H, br s), 7.21–6.99 (4H, m), 7.00–
6.89 (3H, m), 6.73 (1H, d, J 8.2 Hz), 6.65 (1H, d, J 8.3 Hz),
5.50 (1H, d, J 8.9 Hz), 4.51 (1H, m), 4.36 (1H, br s), 3.30 (1H,
dd, J 13.4, 5.8 Hz), 3.01–2.76 (5H, m), 2.54–2.37 (1H, m),
1.76–1.53 (1H, m), 1.41 (9H, s); δC (62.9 MHz; CDCl3)
212.51, 171.80, 155.80, 155.47, 135.66, 130.53, 129.79, 128.63,
127.24, 127.16, 115.59, 80.31, 63.15, 52.55, 42.79, 39.01, 36.32,
35.20, 28.41; m/z (FAB > 0, NBA) 877 ([2M ϩ H]ϩ, 3%), 461
([M ϩ Na]ϩ, 4), 439 ([M ϩ H]ϩ, 15), 383 (12), 339 (11), 202 (4),
176 (11), 136 (11), 107 (23) (Found: C, 68.29; H, 7.02; N, 6.47.
C25H30N2O5 requires C, 68.47; H, 6.90; N, 6.39%).
(2R)-2-Benzyl-1-[N-(tert-butoxycarbonyl)-L-phenylalanyl]-
pyrrolidin-3-one 3b
A similar procedure, as used for the preparation of 3a, led to 3b
(97%) as a colourless oil; Rf 0.40 (cyclohexane–EtOAc 7 : 3);
[α]D25 Ϫ24.01 (c 1.11, MeOH); νmax(CHCl3)/cmϪ1 3433, 3058,
3031, 2981, 2930, 1760, 1705, 1647, 1496, 1456, 1369, 1246,
1167, 1095; δH (250 MHz; CDCl3) 7.15–7.01 (8H, m), 6.81 (2H,
m), 5.29 (1H, d, J 8.6 Hz), 4.58–4.47 (1H, m), 4.12 (1H, m),
3.27–3.07 (1H, m), 2.99–2.61 (5H, m), 2.34 (1H, m), 1.28 (9H,
s); δC (62.9 MHz; CDCl3) 212.43, 171.45, 155.29, 136.67,
135.84, 129.87, 129.80, 129.33, 128.74, 128.60, 127.12, 80.11,
63.07, 52.39, 42.77, 40.98, 36.78, 35.21, 28.34; m/z (FAB > 0,
GT) 445 ([M ϩ Na]ϩ, 4%), 423 ([M ϩ H]ϩ, 26), 376 (27), 323
(25), 202 (4), 176 (12), 120 (18), 91 (22) (Found: C, 71.26; H,
7.09; N, 6.55. C25H30N2O4 requires C, 71.07; H, 7.16; N, 6.63%).
(2S)-2-Benzyl-1-O-benzyl-[N-(tert-butoxycarbonyl)-L-
tyrosinyl]pyrrolidin-3-one 19a
To a stirred solution of the TFA salt 18a (0.210 g, 0.726 mmol),
Boc()Tyr(Bn)OH 9c (0.270 g, 0.726 mmol), and PyBOP (0.454
g, 0.872 mmol) in CH2Cl2 (5 mL) was added Et3N (253 µL, 1.82
mmol) dropwise at 0 ЊC under nitrogen. The solution was then
allowed to warm to room temperature and was stirred during 2
hours. After concentration under reduced pressure, the result-
ing slurry was diluted in EtOAc (12 mL) and successively
washed with 5% aq. NaHCO3 (4 mL), water (4 mL), 5% aq.
citric acid (4 mL), water (4 mL, 2×), and brine (4 mL), dried
over anhydrous MgSO4, and concentrated under reduced pres-
sure. Chromatotron purification (cyclohexane–EtOAc 7 : 3)
gave 19a (0.369 g, 96%) as a colourless oil; Rf 0.35 (cyclo-
hexane–EtOAc 7 : 3); [α]D25 89.8 (c 1.00, MeOH); νmax(CHCl3)/
cmϪ1 3434, 3338, 3065, 3032, 2981, 2931, 1758, 1705, 1643,
1611, 1541, 1498, 1455, 1240, 1174, 1094, 1017; δH (250 MHz;
CDCl3) 7.31–7.25 (4H, m), 7.19–7.01 (6H, m), 6.90 (2H, m),
6.77 (2H, d, J 8.6 Hz), 5.33 (1H, d, J 8.8 Hz), 4.95 (2H, m), 4.52
(1H, m), 4.20 (1H, m), 3.37 (1H, dd, J 13.43, 5.9 Hz), 3.02–2.78
(5H, m), 2.46 (1H, br dd, J 19.2, 9.0 Hz), 1.59 (1H, m), 1.43
(9H, s); δC (62.9 MHz; CDCl3) 212.40, 171.44, 157.86, 155.25,
136.86, 135.85, 130.47, 129.84, 128.67, 128.59, 128.09, 127.49,
127.39, 127.11, 115.05, 80.00, 69.98, 63.04, 52.47, 42.69, 39.20,
36.36, 35.19, 28.45; m/z (FAB > 0, GT) 551 ([M ϩ Na]ϩ, 4), 529
([M ϩ H]ϩ, 38), 473 (33), 429 (21), 226 (19), 202 (7), 176 (18), 91
(63) (Found: C, 72.58; H, 6.79; N, 5.39. C32H36N2O5 requires C,
72.70; H, 6.86; N, 5.30%).
(2R)-2-Benzyl-1-[N-(tert-butoxycarbonyl)-L-tyrosinyl]-
pyrrolidin-3-one 4b
A similar procedure to that used for the preparation of 4a, led
to 4b (99%) as a white powder; mp 84 ЊC; Rf 0.41 (DCM–
EtOAc 7 : 3); [α]D25 Ϫ81.8 (c 1.00, MeOH); νmax(KBr)/cmϪ1 3430,
3058, 2982, 2931, 1759, 1704, 1641, 1614, 1593, 1498, 1455,
1370, 1169,1103, 1045; δH (250 MHz; CDCl3) 7.06 (1H, br s),
6.94–6.84 (4H, m), 6.75 (3H, m), 6.57 (1H, d, J 8.3 Hz), 6.46
(1H, d, J 8.3 Hz), 5.30 (1H, d, J 8.8 Hz), 4.40 (1H, m), 4.36
(1H, m), 3.14 (1H, m), 2.90 (1H, m), 2.79–2.54 (4H, m),
2.36–2.09 (1H, m), 1.91 (1H, m), 1.23 (9H, s); δC (62.9 MHz;
CDCl3) 212.35, 171.60, 155.67, 155.42, 135.01, 130.63, 129.83,
128.64, 127.89, 127.19, 115.73, 80.42, 63.38, 54.06, 41.53,
38.23, 36.72, 35.70, 28.45; m/z (FAB > 0, NBA) 877
([2M ϩ H]ϩ, 2%), 461 ([M ϩ Na]ϩ, 3), 439 ([M ϩ H]ϩ, 15),
383 (12), 339 (11), 202 (4), 176 (11), 136 (71), 107 (23) (Found:
C, 68.66; H, 6.82; N, 6.28. C25H30N2O5 requires C, 68.47; H,
6.90; N, 6.39%).
Acknowledgements
This work received financial support from the ANRS (Agence
Nationale de Recherche contre le SIDA). We are grateful to
Miss Caroline Parandier for excellent technical assistance. The
authors gratefully acknowledge Dr Toni Williamson for
English language correction.
(2R)-2-Benzyl-1-O-benzyl-[N-(tert-butoxycarbonyl)-L-
tyrosinyl]pyrrolidin-3-one 19b
A similar procedure, as used for the preparation of 19a, led to
19b (96%) as a white powder; mp 43 ЊC; Rf 0.37 (cyclohexane–
EtOAc 7 : 3); [α]D25 Ϫ72.9 (c 1.00, MeOH); νmax(KBr)/cmϪ1 3435,
3064, 3030, 2982, 2928, 1759, 1705, 1645, 1540, 1497, 1455,
1241, 1174, 1093, 1017, 651; δH (250 MHz; CDCl3) 7.64–7.51
(4H, m), 7.46–7.17 (6H, m), 7.11 (4H, m), 6.36 (1H, d, J 8.6
Hz), 5.27 (2H, m), 4.78 (1H, m), 4.32 (1H, m), 3.84 (1H, m),
3.32–3.01 (5H, m), 2.78 (1H, m), 1.77 (1H, m), 1.52 (9H, s); δC
(62.9 MHz; CDCl3) 212.32, 171.56, 158.17, 155.33, 136.90,
135.81, 130.57, 129.83, 128.94, 128.66, 128.33, 127.46, 127.39,
127.19, 115.04, 80.06, 69.94, 63.26, 52.28, 42.80, 39.98, 36.71,
35.66, 28.41; m/z (FAB > 0, GT) 551 ([M ϩ Na]ϩ, 3%), 529
([M ϩ H]ϩ, 18), 473 (10), 429 (13), 226 (11), 202 (4), 176 (9), 91
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