Preparation of β-amino-α-mercapto acids and amides: Stereocontrolled syntheses of 2′-sulfur analogues of the taxol C-13 side chain, both syn and anti S-acetyl-N-benzoyl-3-phenylisocysteine

Article abstract of DOI:10.1016/S0040-4020(02)00175-8

Stereoselective syntheses of both syn and anti S-acetyl-N-benzoyl-3-phenylisocysteine as coupling-ready reagents via the ring-opening reactions of trans- and cis-oxazoline-5-carboxylates with thiolacetic acid were demonstrated. In addition, we report upon ring-opening reactions of oxazoline-5-carboxamides. Ab initio molecular calculations were used to explain the different reactivities of these oxazolines with respect to the ring-opening reaction.

Full text of DOI:10.1016/S0040-4020(02)00175-8

TETRAHEDRON
Pergamon
Tetrahedron 58 32002) 2777±2787
Preparation of b-amino-a-mercapto acids and amides:
stereocontrolled syntheses of 20-sulfur analogues of the taxol C-13
side chain, both syn and anti S-acetyl-N-benzoyl-3-phenylisocysteine
Sang-Hyeup Lee,a Xin Qi,b Juyoung Yoon,c,p Kensuke Nakamurad and Yoon-Sik Leea,p
aSchool of Chemical Engineering, College of Enginering, Seoul National University, Kwanak-Gu, Shinlim-Dong, San 56-1,
Seoul 151-742, South Korea
bSchool of Chemical Engineering, Dalian University of Technology, Dalian 116012, People's Republic of China
cDepartment of New Materials Chemistry and Bio-functional Materials Research Center, Silla University, Pusan 617-736, South Korea
dInstitute of Medicinal Molecular Design, Bunkyo-ku, Tokyo 113-0033, Japan
Received 28 September 2001; accepted 18 February 2002
AbstractÐStereoselective syntheses of both syn and anti S-acetyl-N-benzoyl-3-phenylisocysteine as coupling-ready reagents via the
ring-opening reactions of trans- and cis-oxazoline-5-carboxylates with thiolacetic acid were demonstrated. In addition, we report upon
ring-opening reactions of oxazoline-5-carboxamides. Ab initio molecular calculations were used to explain the different reactivities of these
oxazolines with respect to the ring-opening reaction. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
which play a crucial role in the activation or inactivation
of regulatory peptides.
Paclitaxel 3taxol), a complex natural product currently
considered to be one of the most promising anticancer
agent, bears the 32R,3S)-N-benzoyl-3-phenylisoserine unit
3see Fig. 1) in its C-13 side chain. Although the speci®c
roles of its functional group in microtubule binding are
poorly understood, numerous efforts have been made to
modify this side chain and to determine its structure±
activity relationships. These studies have shown that
20-hydroxyl functionality is crucial for microtubule bind-
ing,1±3 perhaps acting as a hydrogen bond donor.2a,c±e,g,3 In
light of this hypothesis, the synthesis of analogues con-
taining the 20-thiol functionality, which is more acidic
than the hydroxyl group, would be of considerable interest
to those attempting to understand the features of paclitaxel
binding site on microtubules and to the development of new
compounds with more desirable properties than paclitaxel.
As far as we are aware, no attempts have been previously
made to synthesize this thiol derivative.
Common used methods for the synthesis of b-amino-a-mer-
capto acids include the electrophilic sulfenylation of
N-protected b-amino esters which can be available via the
Arndt±Eistert homologation of the corresponding a-amino
acids,5 or of the aspartic acid derivatives6b±d,12 in which the
a-ester moiety is used for the introduction of the side chain
using a regioselective tandem reduction-Wittig Horner
reaction.13
As reported by the Roques6b±d and Baldwin groups,12 the
preferential attack of the sulfenylating agent on the least
hindered face of the dianion is a key point in the sulfenylation
step. Even though this approach must be an ef®cient way of
preparing b-amino-a-mercapto acids, optically active
b-amino acids are required as a starting material and further-
more, only anti isomers of b-amino-a-mercapto esters are
accessible from these optically active b-amino acids.
In addition, peptidomimetics4 bearing a thiol moiety as zinc
chelating group are of great interest in the development of
potent inhibitors for numerous zinc-metalloproteases
having exopeptidase5,6 or endopeptidase activities,7±11
The synthesis of dl-isocysteine from dl-thiomalic acid was
also reported.14 Although stereochemical integrity should in
principle be maintained, since the literature methods do not
involve any functional group transformation at the chiral
center of isocysteine, literature methods are extremely
limited in terms of the availability of optically active start-
ing materials, and therefore this methodology cannot be
easily extended to the substituted analogues.
Keywords: 3-amino-2-mercapto acid; oxazoline; taxol; sharpless asym-
metric aminohydroxylation.
p
Corresponding authors. Tel.: 182-51-309-5618; fax: 182-51-309-5176;
e-mail: jyoon@silla.ac.kr; Tel.:182-2-880-7073; fax: 182-2-888-1604;
e-mail: yslee@snu.ac.kr
Along with the aziridine-2-carboxylates,15±17 oxazoline-5-
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020302)00175-8

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S.-H. Lee et al. / Tetrahedron 58 62002) 2777±2787
calculations were used to explain the different reactivities of
these oxazolines. In addition, we describe stereoselective
syntheses of both syn and anti 2-acetylthio-3-benzoyl-
amino-3-phenylpropanoic acids as coupling-ready reagents
for the synthesis of 20-sulfur analogues of taxol via the ring-
opening reactions of trans- and cis-oxazoline-5-carboxyl-
ates with thiolacetic acid.
2. Results and discussion
Figure 1. Structure of Paclitaxel 3taxol).
Our ®rst objective was the synthesis of anti and syn
b-amino-a-mercapto acids that can be directly used for
coupling. In our earlier report,18 we demonstrated the poten-
tial utility of oxazoline-5-carboxylates as the synthetic
equivalentof an a-cation for the preparation of a-substi-
tuted b-amino esters. For the synthesis of both syn and anti
b-amino-a-mercapto esters, a combination of protecting
groups, namely, the S-acetyl group19 and the methyl ester
group were used. However, the methyl ester group cannot be
carboxylates can be useful intermediates as synthetic
equivalents of an a-cation for the preparation of
a-substituted b-amino esters. In our earlier report,18 we
demonstrated the potential utility of these intermediates
for the synthesis of a-substituted b-amino esters. In a conti-
nuation of this work, we report here upon ring-opening
reactions of oxazoline-5-carboxamides. Ab initio molecular
Scheme 1. Preparation of anti b-amino-a-mercapto acid.

S.-H. Lee et al. / Tetrahedron 58 62002) 2777±2787
2779
Scheme 2. Preparation of syn b-amino-a-mercapto acid.

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S.-H. Lee et al. / Tetrahedron 58 62002) 2777±2787
Scheme 3. Ring-opening reaction of oxazoline-5-carboxamide.
selectively removed by saponi®cation without affecting the
S-acetyl group because of the greater susceptibility of the
latter. Moreover, in its ester form, the b-amino-a-mercapto
acid is susceptible to epimerization at the a-center in basic
condition.6c,d,12 To avoid this, we chose another type of
carboxylic acid protecting group, which can be removed
under neutral or acidic conditions.
functionalized to the syn acetylamino alcohol 2, using
3DHQ)2PHAL and N-bromoacetamide following
a
published procedure.20 The N-protecting acetyl group was
changed with a benzoyl group for the possible utility of
these oxazoline-5-caboxylate as an intermediate for the
synthesis of a modi®ed taxol side chain. In this step, con-
comitant transesteri®cation of the isopropyl ester to the
methyl ester also occurred. Benzoylamino alcohol 3 was
converted to its methanesulfonate 5 in 93% yield, treatment
of methanesufonate 5 with DBU afforded both trans-6 and
cis-oxazoline 4 in the ratio 25:1, which was con®rmed by
The synthesis of anti S-acetyl-N-benzoyl-3-phenyliso-
cysteine 39) was relatively straightforward 3Scheme 1).
In our synthetic scheme, isopropyl cinnamate 1 was ®rst

S.-H. Lee et al. / Tetrahedron 58 62002) 2777±2787
2781
Figure 2. Transition states and their activation energies for ring-opening reactions of oxazoline esters 34, 6) and amides 317, 18).
1H NMR. As explained in our earlier report,18 the DBU-
induced cyclization proceeds via initial epimerization,
prior to cyclization. However, we failed to isolate trans-
oxazoline methyl ester 6 by column chromatography,
but after transprotecting the carboxylic acid with the
p-methoxybenzyl 3PMB) group,19 the trans-oxazoline
PMB ester 7 was isolated with a yield of 76%. Ring-opening
reaction with thiolacetic acid gave anti acetylthio ester 8 in
89% yield, which was then reacted with tri¯uoroacetic acid
3TFA) and anisole to give 32S,3S)-2-acetylthio-3-benzoyl-
amino-3-phenylpropanoic acid 39). This anti 3-phenyl-
isocysteine derivative 9 has a coupling ready, free
carboxylic acid group and an acetyl group, which can be
easily cleaved, on its thiol moiety, and this was synthesized
from isopropyl cinnamate 31) wit h an overall yield of
40%.
duced as a N-protecting group to give the amino alcohol
benzyl ester 11. Again, treatment of 11 with Tf2O afforded
the cis-oxazoline 12 in 90% yield. When this cis-oxazoline
12 was reacted with neat thiolacetic acid, syn acetylthio
ester 16 32R,3S) was obtained in 77% yield after heating
for 12 h at80 8C and additional heating for 1 day at 908C.
Because of the lower reactivity of cis-oxazoline, compared
to the trans isomer, the ring-opening reaction needed a
higher reaction temperature and longer reaction time.
However, we failed to deprotect the benzyl group to give
its free acid under various hydrogenation conditions, which
included both catalytic hydrogenation, and catalytic transfer
hydrogenation that are known to be effective for some
compounds that contains divalent sulfur, a poison for the
hydrogenolysis catalyst.19
Finally, cis-oxazoline benzyl ester 12 was transformed to its
PMB ester 13. The ring-opening reaction of 13 with thiol-
acetic acid led to syn acetylthio PMB ester 14 378% yield),
which was then reacted with TFA±anisole to give 32R,3S)-
2-acetylthio-3-benzoylamino-3-phenylpropanoic acid 315),
i.e. a coupling-ready syn 3-phenylisocysteine derivative, in
an overall yield of 34% from isopropyl cinnamate 31).
On the other hand, the preparation of syn S-acetyl-N-
benzoyl-3-phenylisocysteine 315) was rather complex and
the choice of protecting group was essential throughout the
synthesis. For the synthesis of the syn isomer, we ®rst
started from the amino alcohol methyl ester 3. As shown
in Scheme 1, treatment of 3 with tri¯uoromethanesulfonic
anhydride 3Tf2O) afforded the cis-oxazoline methyl ester 4
with a yield of 85%. However, hydrolysis of the methyl
ester using either lithium hydroxide or potassium carbonate
to make free acid led epimerization at the a-center.
To prepare dipeptide containing the b-amino-a-mercapto
acid group, we examined the ring-opening reactions of
oxazoline-5-carboxamides with thiolacetic acid. Both cis-
and trans-oxazoline-5-carboxylates 34, 6) were transformed
to their carboxamides 317, 18) 3Scheme 3). Treatment of
trans-oxazoline-5-carboxamide 18 with thiolacetic acid
led to the anti acetylthio amide 19 in 79% yield. Removal
of the acetyl group using lithium hydroxide gave the anti thiol
amide 20. On the other hand, cis-oxazoline-5-carboxamide
Our nextchoice was the benzyl ester 3Scheme 2), which can
be removed under typical hydrogenation conditions. The
N-acetyl group and the isopropyl ester of 2 were removed
by acid hydrolysis,20 and the free acid generated was
converted to the benzyl ester.21 A benzoyl group was intro-

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S.-H. Lee et al. / Tetrahedron 58 62002) 2777±2787
ring-opening reaction with thiolacetic acid compared from
other substrates.
To demonstrate the possible utility of this method, trans-
oxazoline-5-carboxylate 6 was coupled with l-alanine
t-butyl ester after 6 was hydrolyzed to its free acid 3Scheme
4). Again, ring-opening reaction with thiolacetic acid gave
the model dipeptide 22 in 91% yield. This dipeptide
contains the acetylthio and t-butyl ester groups which can
be easily manipulated for further use. In principle, other
amino acids or dipeptides can be used for the coupling
reaction, and ring-opening reagents other than thiolacetic
acid, such as trimethylsilyl azide or thiophenol, can be
used.18
3. Conclusions
In conclusion, we have stereoselectively synthesized both
anti and syn S-acetyl-N-benzoyl-3-phenylisocysteine 39, 15)
as coupling-ready reagents for dipepetide or 20-sulfur ana-
logues of the taxol C-13 side chain. In our synthesis, the
stereoselective ring-opening reactions of trans- and cis-
oxazoline-5-carboxylates with thiolacetic acid were utilized
as a key step. These compounds contain a coupling-ready
free carboxylic acid and labile acetyl group on their thiol
moiety. In addition, we have developed steroselective ring-
opening reactions of trans-oxazoline-5-carboxamides with
thiolacetic acid. Basically, these methods can be further
utilized with any amino acid and other ring-opening
reagents such as trimethylsilyl azide or thiophenol to pre-
pare di- or tri-peptide containing a-substituted b-amino
acid. Ab initio molecular calculations were used to explain
the different reactivities of these cis- and trans-oxazolines
with respect to the ring-opening reaction.
4. Experimental
4.1. General methods
Scheme 4. Preparation of anti b-amino-a-mercapto acid containing
dipeptide.
17 was not ring-opened to give the desired syn acetylthio
amide even at higher temperature and longer reaction time.
NMR spectra were recorded using a JEOL JNM-LA 300
spectrometer at 300 MHz 3for H NMR) and at75 MHz
1
3for 13C NMR). Chemical shifts were obtained in ppm,
using TMS as an internal standard. Mass spectra were
obtained using a JEOL JMS AX505WA spectrometer.
Infrared spectra were recorded with a JASCO FTIR-200
Spectrometer. Melting points were determined in open
capillaries, and are uncorrected. Optical rotations were
determined using a JASCO DIP 1000 polarimeter. Ele-
mental analyses were performed using Elementar Vario
EL at Korea Basic Science Institute. Flash chromatography
was carried outusing Merck silica gel 60 3230±400 mesh).
Thin layer chromatography was carried out using Merck 60
F254 plates with a 0.25 mm thickness. The CHCl3, CH2Cl2,
and MeOH were distilled from CaH2. THF and ether were
distilled from sodium-benzophenone ketyl.
In order to explain the poor reactivity of cis-oxazoline-5-
carboxamide 17, we carried out ab initio molecular orbital
calculations 3Fig. 2). All the calculations were carried out
using Gaussian 94.22 At the transition state of ring-opening
upon thiolacetic acid attacks, cis-oxazoline-5-carboxylate 4
was found to be less reactive than the trans isomer 6 by
8.3 kcal/mol ahtte RHF/6-31G
p
level. cis-Oxazoline-5-
carboxamide 17 was also found to be less reactive than
trans-oxazoline-5-carboxamide 18 by 5.5 kcal/mol athte
same theory level. This activation energy difference is
equivalent to more than a 100-fold difference of the relative
reaction rate at room temperature. At the transition state, the
ester or amide group takes a perpendicular orientation to the
forming and breaking bonds, to maximize the resonance
between the p-orbitals of the carbonyl and the reaction
center carbons. This makes the steric repulsion between
the phenyl and the ester or amide groups in the cis-orien-
tation at the transition state more severe compared to the
reactant. These results clearly explain the reason why cis-
oxazoline-5-carboxamide 17 is so unreactive toward the
4.1.1. -2R,3S)-3-Acetylamino-2-hydroxy-3-phenylpropa-
noic acid isopropyl ester -2). This compound was prepared
in 81% yield, according to the reported acetamide-based
Sharpless aminohydroxylation protocol:20 mp 111±1128C;
18
[a]D ˆ128.38 3cˆ1, CHCl3); 1H NMR 3CDCl3, 300 MHz)

S.-H. Lee et al. / Tetrahedron 58 62002) 2777±2787
2783
d 1.29 3d, Jˆ6.2 Hz, 3H), 1.31 3d, Jˆ6.2 Hz, 3H), 2.01 3s,
3H), 3.26 3d, Jˆ3.8 Hz, 1H), 4.48 3dd, Jˆ2.0, 3.8 Hz, 1H),
5.11 3sept, Jˆ6.2 Hz, 1H), 5.56 3dd, Jˆ2.0, 9.2 Hz, 1H),
6.30 3br d, Jˆ9.2 Hz, 1H), 7.20±7.45 3m, 5H); 13C NMR
3CDCl3, 75 MHz) d 21.48, 21.65, 23.14, 54.31, 70.79,
73.25, 126.86, 127.74, 128.58, 138.88, 169.28, 172.40;
HRMS 3CI) m/zˆ266.1400 3M1H)1, calcd for
C14H20N1O4ˆ266.1392.
4.00 mmol) in THF 325 mL) at0 8C under N2. After being
stirred for 30 min at 08C, the reaction mixture was stirred for
an additional 1 h at room temperature. After removal of the
solventunder reduced pressure, ht e residue was suspended
in EtOAc 320 mL) and then passed through a short silica gel
plug 3,10 cm3) and further eluted with EtOAc 3100 mL).
The combined ®ltrate was concentrated under reduced
pressure, and the crude product was crystallized from
EtOAc±hexane to afford 5 3700 mg, 1.85 mmol, 93%) as
a white solid: mp 127.5±128.58C; 1H NMR 3CDCl3,
300 MHz) d 2.81 3s, 3H), 3.83 3s, 3H), 5.35 3d, Jˆ2.7 Hz,
1H), 5.99 3dd, Jˆ2.7, 9.2 Hz, 1H), 6.90 3br d, Jˆ9.2 Hz,
1H), 7.25±7.60 3m, 8H), 7.75±7.90 3m, 2H); 13C NMR
3CDCl3, 75 MHz) d 38.67, 53.30, 54.02, 80.22, 126.57,
127.13, 128.58, 128.75, 129.03, 132.07, 133.57, 136.62,
166.92, 167.38; HRMS 3FAB) m/zˆ378.1022 3M1H)1,
calcd for C18H20N1O6S1ˆ378.1011.
4.1.2. -2R,3S)-3-Benzoylamino-2-hydroxy-3-phenylpropa-
noic acid methyl ester -3). Compound 2 31000 mg,
3.77 mmol) was treated with 0.5 M HCl in MeOH
3100 mL), and heated under re¯ux for 10 h. After removal
of the solvent under reduced pressure, the residue was again
treated with 0.5 M HCl in MeOH 3100 mL) and heated
under re¯ux for an additional 10 h. After removal of the
solventunder reduced pressure, the residue was re-dissolved
in fresh MeOH 32£60 mL) and re-evaporated. To this resi-
due, dry CH2Cl2 380 mL) was added and itwas then cooled
t o 08C. To this suspension, Et3N 32.63 mL, 18.9 mmol) in
CH2Cl2 35 mL) was added, followed by BzCl 3530 mg,
3.77 mmol) in CH2Cl2 33 mL), and the reaction mixture
was stirred for 1 h at 08C and then for 1 h at room tempera-
ture. The reaction mixture was then passed through a short
silica gel plug 3,20 cm3) and further eluted with EtOAc
3200 mL). The combined ®ltrate was then concentrated
under reduced pressure, and the residue was crystallized
from EtOAc±hexane to afford 3 3990 mg, 3.31 mmol,
88%) as a off-white solid. An analytical sample was
obtained by re-crystallization 3CHCl3±hexane): mp 178±
4.1.5. -4S,5R)-2,4-Diphenyl-2-oxazoline-5-carboxylic acid
methyl ester -6). DBU 3357 mg, 2.34 mmol) was added to a
stirred solution of compound 5 3590 mg, 1.56 mmol) in dry
CHCl3 330 mL) at room temperature, and the resulting solu-
tion was heated under re¯ux for 2 h. After being cooled to
room temperature, the reaction mixture was then passed
through a short silica gel plug 3,10 cm3) and further eluted
with EtOAc 3100 mL). The combined ®ltrate was then
concentrated under reduced pressure, and puri®cation of
the residue by ¯ash chromatography 3hexane±EtOAc, 6:1)
afforded 6 3400 mg, 1.42 mmol, 91%) as a colorless oil
3trans-oxazoline 6/cis-oxazoline 4ˆ25:1 by 1H NMR analy-
1
1
1818C; H NMR 3CDCl3, 300 MHz) d 3.30 3d, Jˆ3.9 Hz,
sis): H NMR 3CDCl3, 300 MHz) d 3.87 3s, 3H), 4.92 3d,
1H), 3.85 3s, 3H), 4.64 3dd, Jˆ2.0, 3.9 Hz, 1H), 5.75 3dd,
Jˆ2.0, 9.0 Hz, 1H), 6.99 3br d, Jˆ9.0 Hz, 1H), 7.20±7.60
3m, 8H), 7.70±7.85 3m, 2H); 13C NMR 3CDCl3, 75 MHz) d
53.28, 54.80, 73.20, 126.88, 127.04, 127.94, 128.63, 128.73,
131.76, 134.03, 138.66, 166.85, 173.38; HRMS 3FAB)
m/zˆ300.1240 3M1H)1, calcd for C17H18N1O4ˆ300.1236.
Jˆ6.4 Hz, 1H), 5.45 3d, Jˆ6.4 Hz, 1H), 7.20±7.60 3m, 8H),
8.05±8.15 3m, 2H); 13C NMR 3CDCl3, 75 MHz) d 52.74,
74.62, 83.13, 126.46, 126.76, 128.04, 128.45, 128.71,
128.85, 131.93, 141.09, 163.99, 170.63; HRMS 3FAB)
m/zˆ282.1125 3M1H)1, calcd for C17H16N1O3ˆ282.1130.
4.1.6. -4S,5R)-2,4-Diphenyl-2-oxazoline-5-carboxylic acid
p-methoxybenzyl ester -7). 1 M LiOH solution 3990 mL,
0.990 mmol) was added dropwise to a stirred solution of 6
3252 mg, 0.896 mmol) in a MeOH±water mixture 38 mL,
3:1) at0 8C. After being stirred for 30 min at 08C, the reac-
tion mixture was stirred for an additional 2 h at 458C. The
resulting solution was then poured to a mixture of EtOAc
330 mL)Ð5% aqueous citric acid 330 mL), and the organic
phase was separated. The aqueous phase was extracted with
EtOAc 35£30 mL), and the combined organic extract was
dried over MgSO4 and evaporated. To this residue, DMAP
311 mg, 0.09 mmol) and p-methoxybenzylalcohol 3149 mg,
1.08 mmol) was added, followed by a THF±CH2Cl2 mixture
330 mL, 1:1), and the resulting solution was then cooled
t o 08C. To this solution, DCC 3203 mg, 0.986 mmol) in
CH2Cl2 31 mL) was added dropwise. The reaction mixture
was stirred for 3 h at 08C and for an additional 3 h at room
temperature. The reaction mixture was then ®ltered to
remove the solid precipitated during the reaction period.
The ®ltrate was concentrated under reduced pressure, and
puri®cation of the residue by ¯ash chromatography
3hexane±EtOAc, 6:1) afforded 7 3264 mg, 0.681 mmol,
76%) as a sticky oil, which slowly solidi®ed on standing:
mp 73.5±75.58C; 1H NMR 3CDCl3, 300 MHz) d 3.81
3s, 3H), 4.90 3d, Jˆ6.6 Hz, 1H), 5.18 3d, Jˆ11.9 Hz,
1H), 5.29 3d, Jˆ11.9 Hz, 1H), 5.37 3d, Jˆ6.6 Hz, 1H),
4.1.3. -4S,5S)-2,4-Diphenyl-2-oxazoline-5-carboxylic acid
methyl ester -4): procedure A. Tf2O 3423 mg, 1.50 mmol)
in CH2Cl2 32 mL) was added dropwise to a stirred solution
of 3 3299 mg, 1.00 mmol) and DMAP 3367 mg, 3.00 mmol)
in CH2Cl2 330 mL) at 2308C under N2. After being stirred
for 1 h at 2308C, the reaction mixture was warmed to room
temperature. The reaction mixture was then passed through
a shortsilica gel plug 3 ,10 cm3) and further eluted with
EtOAc±hexane 360 mL, 1:1). The combined ®ltrate was
then concentrated under reduced pressure, and puri®cation
of the residue by ¯ash chromatography 3hexane±EtOAc,
6:1) afforded 4 as a white solid. This was further puri®ed
by re-crystallization 3hexane) yielding 4 3240 mg, 0.853
1
mmol, 85%) as white needles: mp 92.5±93.58C; H NMR
3CDCl3, 300 MHz) d 3.21 3s, 3H), 5.39 3d, Jˆ10.8 Hz, 1H),
5.75 3d, Jˆ10.8 Hz, 1H), 7.20±7.60 3m, 8H), 8.05±8.20 3m,
2H); 13C NMR 3CDCl3, 75 MHz) d 51.57, 73.51, 81.10,
126.75, 127.76, 128.11, 128.16, 128.46, 128.72, 131.96,
136.90, 164.78, 168.49; HRMS 3FAB) m/zˆ282.1126
3M1H)1, calcd for C17H16N1O3ˆ282.1130.
4.1.4. -2R,3S)-3-Benzoylamino-2-methanesulfonyloxy-3-
phenylpropanoic acid methyl ester -5). MsCl 3342 mg,
3.00 mmol) in THF 32 mL) was added dropwise to a stirred
solution of 3 3599 mg, 2.00 mmol) and Et3N 3558 mL,

2784
S.-H. Lee et al. / Tetrahedron 58 62002) 2777±2787
6.80±7.00 3m, 2H), 7.20±7.65 3m, 10H), 8.00±8.20 3m,
2H); 13C NMR 3CDCl3, 75 MHz) d 55.30, 67.25, 74.62,
83.20, 114.07, 126.52, 126.82, 127.28, 128.02, 128.46,
128.76, 128.84, 130.31, 131.94, 141.10, 159.92, 164.11,
169.99; HRMS 3FAB) m/zˆ388.1544 3M1H)1, calcd for
C24H22N1O4ˆ388.1549.
was added, and the resulting suspension was then evapo-
rated using rotary evaporator under water aspirator vacuum
for 1 h at75 8C to give clear solution. To this solution, ben-
zene 320 mL) was added, and the resulting solution was
re¯uxed using dean-stark apparatus for 10 h. After removal
of the solvent under reduced pressure, dry ether 330 mL)
was added to the resulting residue. The crude precipitate
was collected and re-crystallized from MeOH±ether to
afford 10 31600 mg, 3.61 mmol, 96%) as white crystalline
4.1.7.
-2S,3S)-2-Acetylthio-3-benzoylamino-3-phenyl-
propanoic acid p-methoxybenzyl ester -8): procedure
B. Thiolacetic acid 31 mL) was added to compound 7
3244 mg, 0.630 mmol) in a 6 mL vial at room temperature.
The vial was then closed tightly with a te¯on disk lid, and
the reaction mixture was heated to 708C for 14 h with
occasional swirling. After removal of the solvent under
reduced pressure, the residue was puri®ed by ¯ash chroma-
tography 3hexane±EtOAc, 3:1) to afford 8 as a white solid.
This was further puri®ed by re-crystallization 3EtOAc±
hexane) yielding 8 3260 mg, 0.561 mmol, 89%) as white
19
solid: mp 188±1908C; [a]D ˆ213.78 3cˆ1, MeOH); IR
3KBr) 3221±26313b), 1758, 1511 cm21
;
1H NMR
3CD3OD, 300 MHz) d 2.36 3s, 3H), 4.47 3d, Jˆ7.7 Hz,
1H), 4.51 3d, Jˆ7.7 Hz, 1H), 4.99 3d, Jˆ12.1 Hz, 1H),
5.05 3d, Jˆ12.1 Hz, 1H), 7.05±7.50 3m, 12H), 7.65±7.75
3m, 2H); 13C NMR 3CD3OD, 75 MHz) d 21.31, 58.81,
68.19, 73.71, 126.96, 129.08, 129.38, 129.49, 129.81,
130.29, 130.81, 134.71, 136.49, 141.69, 143.47, 171.87;
HRMS 3FAB) m/zˆ272.1277 3M1H)1, calcd for
C16H18N1O3ˆ272.1287; Anal. calcd for C16H18N1O3: C,
62.14; H, 5.90; N, 3.15; S, 7.21. Found: C, 62.00; H, 6.03;
N, 3.14; S, 7.42.
19
needles: mp 117±1188C; [a]D ˆ287.28 3cˆ1, CHCl3);
1
IR 3KBr) 3374, 1736, 1700, 1653 cm21; H NMR 3CDCl3,
300 MHz) d 2.37 3s, 3H), 3.80 3s, 3H), 4.82 3d, Jˆ4.2 Hz,
1H), 4.96 3d, Jˆ11.9 Hz, 1H), 5.01 3d, Jˆ11.9 Hz, 1H), 5.64
3dd, Jˆ4.2, 9.2 Hz, 1H), 6.75±6.90 3m, 2H), 7.00±7.15 3m,
2H), 7.20±7.60 3m, 8H), 7.75±7.90 3m, 2H), 8.00 3br d, Jˆ
9.2 Hz, 1H); 13C NMR 3CDCl3, 75 MHz) d 30.21, 49.58,
54.79, 55.24, 67.51, 113.92, 126.28, 126.67, 127.07, 127.95,
128.61, 128.70, 129.99, 131.72, 133.88, 138.38, 159.77,
166.65, 170.74, 192.44; HRMS 3FAB) m/zˆ464.1515
3M1H)1, calcd for C26H26N1O5S1ˆ464.1532; Anal. calcd
for C26H26N1O5S1: C, 67.22; H, 5.64; N, 3.02; S, 6.90.
Found: C, 67.22; H, 5.80; N, 2.95; S, 6.70.
4.1.10. -2R,3S)-3-Benzoylamino-2-hydroxy-3-phenylpro-
panoic acid benzyl ester -11). Benzoyl chloride 3430 mg,
3.06 mmol) in CH2Cl2 35 mL) was added dropwise to a
stirred solution of compound 10 31331 mg, 3.00 mmol)
and Et3N 31.254 mL, 9.00 mmol) in CH2Cl2 360 mL) at
08C. The reaction mixture was then stirred for 1 h at 08C,
and for a further hour at room temperature. After removal of
the solvent under reduced pressure, the residue was treated
with EtOAc 35£50 mL) and passed through a short silica gel
plug 3,15 cm3). The combined ®ltrate was concentrated
under reduced pressure, and the residue was re-crystallized
from EtOAc±hexane to afford 11 31050 mg, 2.80 mmol,
4.1.8.
-2S,3S)-2-Acetylthio-3-benzoylamino-3-phenyl-
propanoic acid -9): procedure C. Compound 8 3150 mg,
0.324 mmol) in a 6 mL vial was treated with a mixture of
TFA±anisole 33 mL, 5:1). The vial was then closed tightly
with a te¯on disk lid, and the reaction mixture was stirred
for 20 min at room temperature. After removal of the
solventunder reduced pressure, the residue was re-dissolved
in fresh CH2Cl2 33£30 mL) and re-evaporated, and ®nally
dried in high vacuum to give viscous oil. This residue was
treated with a mixture of CH2Cl2±hexane 35 mL, 1:4) to
give white precipitates, and this was washed several times
with hot hexane to afford 9 3109 mg, 0.317 mmol, 98%) as
20
93%) as white needles: mp 145±146.58C; [a]D ˆ12.548
3cˆ1, CHCl3); IR 3KBr) 3458, 3363, 3031, 2952, 1732,
1
1642 cm21; H NMR 3CDCl3, 300 MHz) d 3.31 3d, Jˆ
4.0 Hz, 1H), 4.66 3dd, Jˆ2.4, 4.0 Hz, 1H), 5.20 3d, Jˆ
11.9 Hz, 1H), 5.27 3d, Jˆ11.9 Hz, 1H), 5.77 3dd, Jˆ2.2,
9.0 Hz, 1H), 6.99 3br d, Jˆ9.0 Hz, 1H), 7.20±7.60 3m,
13H), 7.65±7.75 3m, 2H); 13C NMR 3CDCl3, 75 MHz) d
54.89, 68.32, 73.27, 126.88, 127.02, 127.86, 128.52,
128.64, 128.66, 131.65, 133.95, 134.61, 138.38, 166.77,
172.69; HRMS 3FAB) m/zˆ376.1543 3M1H)1, calcd for
C23H22N1O4ˆ376.1549; Anal. calcd for C23H22N1O4: C,
73.39; H, 5.89; N, 3.72. Found: C, 73.02; H, 5.93; N, 3.66.
19
white solid: mp 161±1638C; [a]D ˆ234.48 3cˆ1, MeOH);
IR 3KBr) 3374, 3058±24643b), 1710, 1642 cm21; 1H NMR
3CDCl3, 300 MHz) d 2.37 3s, 3H), 4.81 3d, Jˆ4.2 Hz, 1H),
5.64 3dd, Jˆ4.2, 9.3 Hz, 1H), 6.91 3br s, 1H), 7.20±7.65 3m,
8H), 7.75±7.90 3m, 2H), 8.08 3br d, Jˆ9.2 Hz, 1H); 13C
NMR 3CDCl3, 75 MHz) d 30.19, 48.91, 54.92, 126.45,
127.21, 128.11, 128.76, 128.79, 132.09, 133.44, 138.12,
167.84, 173.44, 192.85; HRMS 3FAB) m/zˆ344.0963
3M1H)1, calcd for C18H18N1O4S1ˆ344.0957; Anal. calcd
for C18H18N1O4S1: C, 62.77; H, 5.27; N, 4.07; S, 9.31.
Found: C, 62.67; H, 5.11; N, 3.81; S, 9.17.
4.1.11.
-4S,5S)-2,4-Diphenyl-2-oxazoline-5-carboxylic
acid benzyl ester -12). Application of procedure A to
1000 mg of 11 32.66 mmol), 1127 mg of Tf2O 33.99
mmol) and 976 mg of DMAP 37.99 mmol) gave 860 mg
of 12 32.41 mmol, 90%) as white needles after ¯ash
chromatography 3hexane±EtOAc, 8:1) followed by
re-crystallization 3hexane): mp 104±1058C; [a]D
21
ˆ
268.28 3cˆ1, CHCl3); IR 3KBr) 3063, 3031, 2937, 1747,
1674 cm21 1H NMR 3DMSO-d6, 300 MHz) d 4.29 3d,
;
4.1.9. -2R,3S)-3-Amino-2-hydroxy-3-phenylpropanoic
acid p-toluenesulfonate -10). Compound 2 31000 mg,
3.77 mmol) was treated with 10% aqueous HCl 320 mL),
and heated under re¯ux for 4 h. After being cooled to
room temperature, the solvent was then evaporated to
dryness to afford white crystalline residue. To this residue,
TsOH´H2O 3753 mg, 3.96 mmol) and benzyl alcohol 38 mL)
Jˆ12.3 Hz, 1H), 4.73 3d, Jˆ12.3 Hz, 1H), 5.66 3d, Jˆ
10.8 Hz, 1H), 5.84 3d, Jˆ10.8 Hz, 1H), 6.95±7.40 3m,
10H), 7.50±7.70 3m, 3H), 7.95±8.10 3m, 2H); 13C NMR
3DMSO-d6, 75 MHz) d 66.57, 72.96, 80.96, 127.00,
128.18, 128.38, 128.46, 128.58, 128.74, 129.26, 132.56,
135.20, 137.77, 163.82, 168.34; HRMS 3FAB) m/zˆ
358.1449 3M1H)1, calcd for C23H20N1O3ˆ358.1443;

S.-H. Lee et al. / Tetrahedron 58 62002) 2777±2787
2785
Anal. calcd for C23H20N1O3: C, 77.08; H, 5.62; N, 3.91.
Found: C, 77.01; H, 5.75; N, 3.85.
1H), 7.20±7.90 3m, 10H), 8.95 3br d, Jˆ9.3 Hz, 1H),
12.84 3br s, 1H); 13C NMR 3DMSO-d6, 75 MHz) d 30.21,
50.95, 52.90, 127.39, 127.75, 127.82, 128.25, 128.31,
131.40, 134.13, 139.53, 165.98, 170.45, 193.49;
HRMS 3FAB) m/zˆ344.0955 3M1H)1, calcd for
C18H18N1O4S1ˆ344.0957.
4.1.12.
-4S,5S)-2,4-Diphenyl-2-oxazoline-5-carboxylic
acid p-methoxybenzyl ester -13). A 10% Pd/C catalyst
3164 mg) was added to a stirred solution of 12 3822 mg,
2.30 mmol) in EtOAc 335 mL). The mixture was then
hydrogenated under atmospheric H2 3balloon) atroom
temperature for 30 h, and ®ltered through a short Celitew
pad 3,5 cm3), and further eluted with EtOAc 3150 mL).
The combined ®ltrate was concentrated under reduced
pressure, and dried in high vacuum. The resulting slightly
yellow solid was dissolved in a THF±CH2Cl2 mixture
330 mL, 1:2), and p-methoxybenzyl alcohol 3381 mg,
2.76 mmol) and DMAP 328 mg, 0.23 mmol) was added.
To this solution, DCC 3498 mg, 2.41 mmol) in CH2Cl2
35 mL) was added dropwise at0 8C. The reaction mixture
was stirred for 12 h at room temperature, and then ®ltered to
remove the solid precipitated during the reaction period.
The ®ltrate was concentrated under reduced pressure, and
puri®cation of the residue by ¯ash chromatography
3hexane±EtOAc, 6:1) afforded 13 as a white solid. This
was further puri®ed by re-crystallization 3hexane) yielding
13 3612 mg, 1.58 mmol, 69%) as white needles: mp 101.5±
4.1.15. -2R,3S)-2-Acetylthio-3-benzoylamino-3-phenyl-
propanoic acid benzyl ester -16). Application of procedure
B to 140 mg of 12 30.392 mmol) and 0.8 mL of thiolacetic
acid at80 8C for 12 h and 908C for 1 d gave 131 mg of 16
30.302 mmol, 77%) as white needles after ¯ash chromato-
graphy 3hexane±EtOAc, 7:2) followed by re-crystallization
21
3EtOAc±hexane): mp 128±1298C; [a]D ˆ190.28 3cˆ
0.70, CHCl31); IR 3KBr), 3374, 3047, 2937, 1731, 1708,
1653 cm21; H NMR 3CDCl3, 300 MHz) d 2.37 3s, 3H),
4.78 3d, Jˆ9.3 Hz, 1H), 5.02 3s, 2H), 5.69 3dd, Jˆ9.0,
9.2 Hz, 1H), 7.01 3br d, Jˆ8.4 Hz, 1H), 7.10±7.55 3m,
13H), 7.65±7.80 3m, 2H); 13C NMR 3CDCl3, 75 MHz) d
30.37, 51.32, 55.52, 67.74, 126.97, 127.17, 128.33,
128.37, 128.46, 128.56, 128.60, 128.80, 131.71, 133.68,
134.68, 138.50, 166.31, 168.38, 195.52; HRMS 3FAB)
m/zˆ434.1423 3M1H)1, calcd for C25H24N1O4S1ˆ
434.1426; Anal. calcd for C25H24N1O4S1: C, 69.10; H,
5.57; N, 3.22; S, 7.38. Found: C, 69.14; H, 5.51; N, 3.19;
S, 7.62.
21
102.58C; [a]D ˆ264.98 3cˆ1, CHCl3); IR 3KBr) 3058,
3031, 2926, 1742, 1668 cm21
;
1H NMR 3DMSO-d6,
300 MHz) d 3.74 3s, 3H), 4.19 3d, Jˆ11.9 Hz, 1H), 4.66
3d, Jˆ11.9 Hz, 1H), 5.62 3d, Jˆ10.8 Hz, 1H), 5.81 3d,
Jˆ10.8 Hz, 1H), 6.80±7.05 3m, 4H), 7.10±7.40 3m, 5H),
7.50±7.70 3m, 3H), 7.95±8.05 3m, 2H); 13C NMR
3DMSO-d6, 75 MHz) d 55.03, 65.94, 72.43, 80.39,
113.65, 126.50, 126.57, 127.66, 127.83, 127.92, 128.06,
128.73, 130.03, 132.02, 137.25, 159.20, 163.30, 167.83;
HRMS 3FAB) m/zˆ388.1563 3M1H)1, calcd for
C24H22N1O4ˆ388.1549; Anal. calcd for C24H22N1O4: C,
74.21; H, 5.71; N, 3.60. Found: C, 74.23; H, 5.75; N, 3.59.
4.1.16.
-4S,5S)-2,4-Diphenyl-2-oxazoline-5-carboxylic
acid methylamide -17). Compound 4 3150 mg, 0.533
mmol) in a 6 mL vial was treated with 33% MeNH2/EtOH
solution 31.5 mL). The vial was then closed tightly with a
te¯on disk lid, and the reaction mixture was stirred for 1 d at
room temperature. After removal of the solvent under
reduced pressure, the residue was puri®ed by ¯ash chroma-
tography 3hexane±EtOAc, 4:5) to afford 18 38 mg,
0.029 mmol, 5%) and 17 3140 mg, 0.499 mmol, 94%) as a
21
white solid: mp 137±1398C; [a]D ˆ22278 3cˆ1, CHCl3);
1
4.1.13. -2R,3S)-2-Acetylthio-3-benzoylamino-3-phenyl-
propanoic acid p-methoxybenzyl ester -14). Application
of procedure B to 378 mg of 13 31.00 mmol) and 1.2 mL of
thiolacetic acid at 908C for 36 h gave 360 mg of 14
30.777 mmol, 78%) after ¯ash chromatography 3hexane±
EtOAc, 3:1); IR 3neat) 3293, 3060, 2924, 1737, 1703,
IR 3KBr) 3410, 3279, 3105, 3031, 1668, 1653 cm21; H
NMR 3CDCl3, 300 MHz) d 2.45 3d, Jˆ5.0 Hz, 3H), 5.30
3d, Jˆ10.4 Hz, 1H), 5.73 3d, Jˆ10.4 Hz, 1H), 6.07 3br d,
Jˆ5.0 Hz, 1H), 7.10±7.65 3m, 8H), 8.05±8.20 3m, 2H); 13C
NMR 3CDCl3, 75 MHz) d 25.32, 72.84, 82.87, 126.62,
127.63, 128.00, 128.10, 128.59, 128.65, 132.22, 136.62,
163.59, 167.69; HRMS 3FAB) m/zˆ281.1294 3M1H)1,
calcd for C17H17N2O2ˆ281.1290; Anal. calcd for
C17H17N2O2: C, 72.58; H, 6.09; N, 9.96. Found: C, 72.13;
H, 6.08; N, 9.77.
1
1640 cm21; H NMR 3CDCl3, 300 MHz) d 2.33 3s, 3H),
3.79 3s, 3H), 4.75 3d, Jˆ9.2 Hz, 1H), 4.94 3s, 2H), 5.67
3dd, Jˆ9.0, 9.2 Hz, 1H), 6.75±6.90 3m, 2H), 7.00±7.15
3m, 3H), 7.20±7.55 3m, 8H), 7.60±7.75 3m, 2H); 13C
NMR 3CDCl3, 75 MHz) d 30.29, 51.36, 55.21, 55.46,
67.58, 113.86, 126.77, 126.91, 127.11, 128.24, 128.51,
128.69, 130.22, 131.62, 133.65, 138.46, 159.73, 166.23,
168.33, 195.41; HRMS 3FAB) m/zˆ464.1532 3M1H)1,
calcd for C26H26N1O5S1ˆ464.1532.
4.1.17. -4S,5R)-2,4-Diphenyl-2-oxazoline-5-carboxylic
acid methylamide -18). Compound 6 3205 mg, 0.729
mmol) in a 6 mL vial was treated with 33% MeNH2/EtOH
solution 32 mL). The vial was then closed tightly with a
te¯on disk lid, and the reaction mixture was stirred for 4 h
at room temperature. After removal of the solvent under
reduced pressure, the residue was puri®ed by ¯ash chroma-
tography 3hexane±EtOAc, 3:2) to afford 18 3197 mg,
0.703 mmol, 96%) as a sticky oil; IR 3neat) 3303, 3059,
4.1.14. -2R,3S)-2-Acetylthio-3-benzoylamino-3-phenyl-
propanoic acid -15). Application of procedure C to
90 mg of 14 30.194 mmol) and TFA±anisole 32 mL, 5:1)
gave 65 mg of 15 30.189 mmol, 98%). Treatment with a
mixture of CH2Cl2±hexane 35 mL, 1:4) appeared in pro-
2923, 1657, 1544 cm21; H NMR 3CDCl3, 300 MHz) d
1
cedure C was unnecessary since a white solid was obtained
upon drying in high vacuum: mp 166±1688C; [a]D
2.91 3d, Jˆ5.0 Hz, 3H), 4.85 3d, Jˆ6.6 Hz, 1H), 5.52 3d,
Jˆ6.6 Hz, 1H), 6.41 3br d, Jˆ5.0 Hz, 1H), 7.20±7.75 3m,
8H), 8.05±8.20 3m, 2H); 13C NMR 3CDCl3, 75 MHz) d
25.92, 74.62, 84.42, 126.56, 126.79, 127.79, 128.48,
128.67, 128.79, 132.13, 141.66, 162.49, 170.69; HRMS
19
ˆ
186.78 3cˆ1, MeOH); IR 3KBr) 3368±25003b), 1710,
1653 cm21 1H NMR 3DMSO-d6, 300 MHz) d 2.34 3s,
3H), 4.61 3d, Jˆ11.2 Hz, 1H), 5.45 3dd, Jˆ9.3, 11.2 Hz,
;

2786
S.-H. Lee et al. / Tetrahedron 58 62002) 2777±2787
3FAB) m/zˆ281.1296 3M1H)1, calcd for C17H17N2O2ˆ
08C. To this stirred solution, a mixture of EDCI´HCl salt
3327 mg, 1.706 mmol) and DIEA 3310 mL, 1.780 mmol) in
CH2Cl2 35 mL) was added dropwise. The reaction mixture
was stirred for 30 min at 08C and for an additional 18 h at
room temperature. After removal of the solvent under
reduced pressure, the residue was treated with CH2Cl2
310 mL) and then passed through a short silica gel plug
3,10 cm3) and further eluted with EtOAc 350 mL). The
combined ®ltrate was concentrated under reduced pressure,
and puri®cation of the residue by ¯ash chromatography
3hexane±EtOAc, 9:2) afforded 21 as a white solid. This
was further puri®ed by re-crystallization 3hexane) to afford
21 3480 mg, 1.217 mmol, 86%) as a white crystalline solid:
281.1290.
4.1.18. -2S,3S)-2-Acetylthio-3-benzoylamino-3-phenyl-
propanoic acid methylamide -19). Application of pro-
cedure B to 176 mg of 18 30.628 mmol) and 1 mL of
thiolacetic acid at 708C for 12 h gave 178 mg of 19
30.499 mmol, 79%) as white needles after ¯ash chroma-
tography 3hexane±EtOAc, 5:3) followed by re-crystalli-
20
zation 3EtOAc±hexane): mp 187±1908C; [a]D ˆ21378
3cˆ1, CHCl3); IR 3KBr) 3337, 3279, 3110, 2937, 1695,
1
1653 cm21; H NMR 3CDCl3, 300 MHz) d 2.39 3s, 3H),
2.65 3d, Jˆ4.8 Hz, 3H), 4.39 3d, Jˆ3.3 Hz, 1H), 5.60 3dd,
Jˆ3.3, 8.8 Hz, 1H), 6.04 3br d, Jˆ4.8 Hz, 1H), 7.10±7.70
3m, 8H), 7.85±8.10 3m, 2H), 9.21 3br d, Jˆ8.8 Hz, 1H); 13C
NMR 3CDCl3, 75 MHz) d 26.36, 30.42, 49.50, 55.67,
126.41, 127.25, 127.93, 128.61, 128.72, 131.71, 133.86,
139.17, 166.52, 171.20, 195.82; HRMS 3FAB) m/zˆ
357.1282 3M1H)1, calcd for C19H21N2O3S1ˆ357.1273;
Anal. calcd for C19H21N2O3S1: C, 63.84; H, 5.92; N, 7.78;
S, 8.97. Found: C, 63.84; H, 6.12; N, 7.80; S, 9.14.
19
mp 108±1108C; [a]D ˆ196.48 3cˆ1, CHCl3); IR 3KBr)
3421, 3063, 2989, 1737, 1689, 1663 cm21 1H NMR
;
3CDCl3, 300 MHz) d 1.42 3s, 9H), 1.46 3d, Jˆ7.0 Hz,
3H), 4.51 3dq, Jˆ7.0, 7.1 Hz, 1H), 4.84 3d, Jˆ6.8 Hz,
1H), 5.54 3d, Jˆ6.8 Hz, 1H), 7.06 3br d, Jˆ7.1 Hz, 1H),
7.20±7.65 3m, 8H), 8.05±8.20 3m, 2H); 13C NMR 3CDCl3,
75 MHz) d 19.20, 28.56, 49.27, 75.03, 83.03, 85.02, 127.25,
127.48, 128.42, 129.18, 129.29, 129.43, 132.67, 142.35,
163.31, 170.12, 172.00; HRMS 3FAB) m/zˆ395.1974
3M1H)1, calcd for C23H27N2O4ˆ395.1970; Anal. calcd
for C23H27N2O4: C, 69.85; H, 6.88; N, 7.08. Found: C,
70.06; H, 6.91; N, 6.90.
4.1.19. -2S,3S)-3-Benzoylamino-2-mercapto-3-phenyl-
propanoic acid methylamide -20). 1 M LiOH solution
3315 mL, 0.315 mmol) was added dropwise to a stirred
solution of 19 3107 mg, 0.300 mmol) in a MeOH±water
mixture 3degassed, 4 mL, 3:1) at room temperature under
N2. After being stirred for 30 min at room temperature, the
reaction mixture was concentrated 3,2 mL) under reduced
pressure, and then poured to a mixture of H2O 320 mL)±
CHCl3 320 mL). The pH of the aqueous phase was adjusted
to 2±3 using 1N HCl, and the organic phase was separated.
The aqueous phase was extracted with CHCl3 34£20 mL),
and the combined organic extract was dried over MgSO4
and evaporated. The residue was puri®ed by ¯ash chroma-
tography 3CHCl3±MeOH, 20:1) to afford 20 392 mg,
0.293 mmol, 98%) as a white solid: mp 219±2228C;
4.1.21. N-[-2S,3S)-2-Acetylthio-3-benzoylamino-3-phenyl-
propionyl]-alanine tert-butyl ester -22). Application of
procedure B to 395 mg of 21 31.00 mmol) and 1.5 mL of
thiolacetic acid at 708C for 6 h gave 430 mg of 22
30.914 mmol, 91%) a off-white solid after ¯ash chroma-
ˆ
19
tography 3benzene±EtOAc, 7:1): mp 168±1708C; [a]D
21158 3cˆ1, CHCl3); IR 3KBr) 3321, 3247, 3058, 2979,
1753, 1732, 1700, 1657 cm21 1H NMR 3CDCl3, 300
;
MHz) d 1.27 3d, Jˆ7.0 Hz, 3H), 1.39 3s, 9H), 2.41 3s,
3H), 4.22 3dq, Jˆ7.0, 7.0 Hz, 1H), 4.49 3d, Jˆ3.5 Hz,
1H), 5.65 3dd, Jˆ3.5, 8.8 Hz, 1H), 6.45 3br d, Jˆ7.0 Hz,
1H), 7.15±7.65 3m, 8H), 7.85±8.05 3m, 2H), 8.94 3br d, Jˆ
8.8 Hz, 1H); 13C NMR 3CDCl3, 75 MHz) d 17.76, 27.80,
30.35, 48.92, 49.82, 55.45, 82.20, 126.42, 127.22, 127.85,
128.55, 128.67, 131.63, 133.89, 138.94, 166.54, 169.70,
170.90, 195.21; HRMS 3FAB) m/zˆ471.1954 3M1H)1,
calcd for C25H31N2O5S1ˆ471.1954.
19
[a]D ˆ248.08 3cˆ0.93, CHCl3); IR 3KBr) 3310, 3058,
1
2921, 25553HS), 1658, 1642 cm21; H NMR 3CDCl3, 300
MHz) d 2.49 3d, Jˆ10.3 Hz, 1H), 2.68 3d, Jˆ5.0 Hz, 3H),
3.60 3dd, Jˆ3.7, 10.2 Hz, 1H), 5.53 3dd, Jˆ3.7, 8.4 Hz, 1H),
5.89 3br d, Jˆ5.0 Hz, 1H), 7.15±7.65 3m, 8H), 7.85±8.00
3m, 2H), 8.81 3br d, Jˆ8.4 Hz, 1H); 13C NMR 3CDCl3,
75 MHz) d 26.38, 45.51, 58.26, 126.28, 127.12, 127.95,
128.67, 128.72, 131.79, 133.81, 139.62, 167.12, 172.48;
HRMS 3FAB) m/zˆ315.1168 3M1H)1, calcd for
C17H19N2O2S1ˆ315.1168.
Acknowledgements
Financial support from the Korean Research Foundation
32000-042-D00044) is gratefully acknowledged.
4.1.20.
N-[-4S,5R)-2,4-Diphenyl-2-oxazoline-5-carbo-
nyl]-alanine tert-butyl ester -21). 1 M LiOH solution
31.564 mL, 1.564 mmol) was added dropwise to a stirred
solution of 6 3400 mg, 1.422 mmol) in a MeOH±water
mixture 312 mL, 3:1) at 08C. After being stirred for
30 min at0 8C, the reaction mixture was stirred for an
additional 2 h at 458C. The reaction mixture was then
poured to a mixture of EtOAc 350 mL)Ð5% aqueous citric
acid 350 mL), and the organic phase was separated. The
aqueous phase was extracted with EtOAc 35£50 mL), and
the combined organic extract was dried over MgSO4 and
evaporated. To this residue, l-alanine t-butyl ester´HCl salt
3310 mg, 1.706 mmol), HOBt´H2O 3261 mg, 1.706 mmol),
and DIEA 3310 mL, 1.780 mmol) was added, followed by
THF 330 mL), and the resulting solution was then cooled to
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