Stereochemical control in the preparation of α-amino N-methylthiazolidine masked aldehydes used for peptide aldehydes synthesis

Article abstract of DOI:10.1016/S0040-4020(02)00115-1

Chiral N-methyl thiazolidines masked α-amino aldehydes are used for solid phase peptide aldehyde elongation. Contrary to N-Boc-protected α-amino aldehydes, N-trityl protection secures the chiral integrity of the incoming aldehyde chiral C1′ carbon atom du

Full text of DOI:10.1016/S0040-4020(02)00115-1

TETRAHEDRON
Pergamon
Tetrahedron 58 :2002) 2673±2680
Stereochemical control in the preparation of a-amino
N-methylthiazolidine masked aldehydes used for peptide
aldehydes synthesis
p
Christel Gros, Cyril Boulegue, Nathalie Galeotti, Gilles Niel and Patrick Jouin
Á
UPR9023, CNRS, CCIPE, 141, rue de la Cardonille, 34094 Montpellier Cedex 5, France
Received 14 September 2001; revised 30 November 2001; accepted 29 January 2002
AbstractÐChiral N-methyl thiazolidines masked a-amino aldehydes are used for solid phase peptide aldehyde elongation. Contrary to
N-Boc-protected a-amino aldehydes, N-trityl protection secures the chiral integrity of the incoming aldehyde chiral C10 carbon atom during
condensation of the amino aldehydes with l-cysteinyl residues. The Ac-Tyr-Val-Ala-Asp-H caspase inhibitor was prepared on a solid
support starting from the N-trityl-amino thiazolidine masked aspartinal as a validation of this process. q 2002 Elsevier Science Ltd. All
rights reserved.
1. Introduction
mediate target. Previous related studies involving Boc- or
Z-N-protected a-amino aldehydes favor this pathway since
no or little racemization at the C10 carbon atom has ever
been observed or reported.9±11
Owing to the biological importance of peptide aldehydes as
mechanism-based enzyme inhibitors,1,2 and to their chemi-
cal utility for fragments ligation,3 several C-terminal linkers
have been introduced as masked aldehyde templates to
perform peptide aldehyde elongation on a solid support.4,5
As part of our investigations into the preparation of peptide
aldehydes,6 we previously showed that the N-methyl
thiazolidine ring was a very ef®cient masked aldehyde
precursor.7 The N-methyl thiazolidine ring can be ef®ciently
hydrolyzed under neutral conditions, a known deprotection
method used for N-methyl thiazoles,8 and subsequently the
target peptide can be recovered from the resin while
maintaining both chemical and stereochemical integrity.
We reinvestigate herein the preparation of the requisite
a-amino acid derived N-methyl thiazolidines.6
In a ®rst set of experiments we reinvestigated the condensa-
tion of N-Boc-:S)-phenylalaninal12 with :R)-Cys,HCl free
acid :Table 1). We observed that this condensation was
incomplete under Wyslouch's reaction conditions :i.e.
2 equiv. of pyridine in MeOH, 24 h).10 Under different
reaction conditions :KHCO3 in DMF, 1 h), the starting
1
aldehyde was completely consumed, but H NMR analysis
of the formed thiazolidine 1 revealed the presence of two
C10 epimeric thiazolidines in a 90:10 ratio. The con®gura-
tion of both the major :10S,2R,4R)-1a isomer and the minor
1
:10R,2S,4R)-1c isomers was assigned from the H NMR
literature data.10 We also con®rmed that the :10R,2S,4R)
isomer 1c was obtained predominantly when starting from
N-Boc-:R)-phenylalaninal. Otherwise, as mentioned by
Wyslouch et al.,11 additional epimerization of C2 occurred
when the mixture 1a and 1c, obtained from N-Boc-:S)- or
N-Boc-:R)-phenylalaninal, was allowed to stand several
hours or was heated a few minutes in [D6]DMSO solution.
Besides the signals at 4.53 and 4.65 ppm :Table 1), which
were attributed to :10S,2R,4R)-1a and :10R,2S,4R)-1c,
respectively, by 2D COSY and TOCSY NMR experiments,
two signi®cant new signals appeared at 4.57 and 4.50 ppm
and might be attributed to 1b and 1c, respectively. However
a complete interpretation of the spectrum was complicated
by the presence of BocNH rotamers.
2. Results and discussion
The previously developed synthesis of the head amino
thiazolidine residue A involved a rather tedious synthetic
pathway :route 2, Scheme 1), including the reduction of an
intermediate iminium B which was constructed via the
Mitsunobu cyclization of a thioamide precursor D.6 Though
epimerization free, this process is not suitable for large-
scale preparations. Therefore we chose the straightforward
condensation of an N-protected a-amino aldehyde E with a
cysteinyl derivative F :route 1) to construct this inter-
In order to verify these preliminary results we performed the
condensation reaction between N-Boc-:S)- or N-Boc-:R)-
phenylalaninal and :R)-Cys-OMe,HCl :Table 2, entries 1
Keywords: N-trityl; thiazolidine; peptide aldehyde; solid phase; ligation.
Corresponding author. Tel.: 133-467-14-29-70; fax: 133-467-14-29-24;
e-mail: niel@ccipe.montp.inserm.fr
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020:02)00115-1

2674
C. Gros et al. / Tetrahedron 58 ,2002) 2673±2680
Scheme 1.
Table 1. Selected 1H NMR :d, ppm) of compounds 1a, 1d in [D6]DMSO solution
1a
10:S), 2:R), 4:R)
1ba
1c
10:R), 2:S), 4:R)
1da
10:S), 2:S), 4:R)
10:R), 2:R), 4:R)
0
BocNH :JNH,1
0
H2 :J1 ,2
)
6.79 :9.0)
4.53 :6.0)
7.00 :7.5)
4.57 :7.8)
6.70 :9.4)
4.65 :7.8)
6.70 :9.2)
4.50 :5.8)
)
a
After gentle heating for 5 min in the NMR tube.
Table 2. Thiazolidines obtained by condensation of various aldehydes with :R)-Cys-OMe,HCl
a: 10:S), 2:R), 4:R); b: 10:S), 2:S), 4:R); c: 10:R), 2:S), 4:R); d: 10:R), 2:R), 4:R)
Entry
Aldehyde
Yield :%)a
Diastereoisomers :relative percentages)b,c
1
2
3
4
5
6
7
Boc-:S)-Phe-H
86
84
88
92
89
91
85
2a :53)
2a :27)
3a :100)
2b :11)
2b :8)
3b :0)
2c :23)
2c :38)
2d :13)
2d :27)
Boc-:R)-Phe-H
Trt-:S)-Phe-H
Trt-:R)-Phe-H
Trt-:S)-Leu-H
Trt-:S)-Asp:OtBu)-H
Trt-:S)-Ser:OSEM)-H
d
d
±
3c :29)
±
3d :71)
d
d
±
±
d
d
4a :80)
5a :55)
6a :71)
4b :20)
5b :45)
6b :29)
±
±
±
±
±
±
d
d
d
d
a
Reaction conditions: 1.5 equiv. :R)-Cys-OMe,HCl, 1.5 equiv. KHCO3 :DMF), 1 h, rt.
Ratios were estimated by HPLC :entries 1, 2).
Ratios were estimated by 1H NMR :entries 3±7).
Not observed.
b
c
d
and 2). Here the obtained thiazolidines 2a±d were a mixture
:Scheme 2).14 Consequently, we assigned the respective
:10S,2S,4R) and :10R,2S,4R) con®gurations to thiazolidines
2a and 2d. Therefore, we attempted the synthesis of these
target thiazolidines starting from less epimerizable amino
aldehydes.
of four diastereoisomers including both C2-epimers, from
an equilibrium already observed for such thiazolidines,13
and undesirable C10-epimers. This latter epimerization
could have occurred prior to or during the condensation
step, at both the aldehyde and the imine level and was accu-
rately assessed by HPLC analysis. The cis-relation between
C2 and C4 in thiazolidines 2a and 2d was proven by their
conversion to the corresponding bicyclic lactams 8 and 9
To this end we chose the trityl-protecting amino group
since this protecting group prevents partial racemization
of N-protected a-amino aldehydes,15,16 possibly by

C. Gros et al. / Tetrahedron 58 ,2002) 2673±2680
2675
above conditions. All the N-trityl-a-amino aldehydes we
tested led cleanly and with good yields to the desired thia-
zolidines without observable C10 epimerization. This was
demonstrated in the case of N-trityl-:S)- or :R)-phenyl-
alaninal :entries 3, 4) since each individual condensation
with :R)-Cys-OMe,HCl led to fully distinct diastereo-
isomers. Condensation of N-trityl-:S)-phenylalaninal
appears to be a marginal case, leading to a single isomer
:10S,2R,4R)-3a, :probably due to a favorable matched pair
of reactants), whereas the N-trityl-:R)-phenylalaninal
produced a pair of C2 epimers :10R,2S,4R)-3c and
:10R,2R,4R)-3d in a 29:71 ratio. Thus, contrary to what
Wyslouch et al. observed with the Boc protection,11 the
predominant :R) con®guration at C2 was introduced inde-
pendently of the incoming N-trityl-protected aldehyde chir-
ality. In addition, on storage in [D6]DMSO solution or after
rapid heating in the NMR tube, we did not observe any
evolution of the pure compound 3a or of the mixture of
compounds 3c and 3d. Condensation of Trt-:S)-Leu-H,
Trt-:S)-Asp:OtBu)-H and Trt-:S)-Ser:OSEM)-H under the
same conditions as for N-Trt-:S)-Phe-H also favored the
formation of the major :2R)-epimer, though in variable
proportions :entries 5±7). We veri®ed that compounds 4a,
5a and 6a possessed a cis-con®gurated thiazolidine ring
since strong H2±H4 correlations were observed by
NOESY experiments.
Scheme 2. Reagents and conditions: :i) HCHO, NaBH3CN, AcOH cat.;
:ii) TFA, MeOH; :iii) KHCO3, MeOH.
As for thiazolidines 2a and 2d, we ascertained the absolute
con®guration at the C2 position by performing the internal
cyclization of the N-methyl compounds 10 and 11c, d
resulting from 3a and 3d, respectively.18 After TFA-assisted
removal of the C10 trityl protecting group of 3a and
cyclization of the resulting primary amine, the bicyclic
thiazolidinyl lactam 8 was obtained in 95% yield as the
sole product. A similar reaction sequence starting from
the mixture of compounds 3c, d led exclusively to the
transformation of 3d into the bicyclic lactam 9 since only
the C2 and C4 substituents, possessing a cis relationship,
suppressing the deprotonation of the a-center, like the
phenyl¯uorenyl protecting group.17 In addition, the selec-
tive cleavage of the trityl protection under mild acidic
conditions is of great value for peptide elongation when
the head thiazolidine residue is linked to the resin. Amino
aldehydes were prepared by oxidation of their correspond-
ing alcohols according to the procedure described by
Albeck16 and condensed with :R)-Cys-OMe,HCl under the
Scheme 3. Reagents and conditions: :i) HCHO, NaBH3CN, AcOH cat.; :ii) NaOH 1N, dioxane/water :73% over two steps); :iii) 1-Ahx-Met-Expansinw resin,
BOP, HOBt, DIEA, DCM; :iv) 1% TFA in MeOH; :v) TFA/water :95:5); :vi) CuO :14 equiv.), CuCl2 :9 equiv.), CH3CN/water/DMF :1:1:2) :54% from 13).

2676
C. Gros et al. / Tetrahedron 58 ,2002) 2673±2680
allowed a bicyclic topology. We also observed by NMR
analysis that the free amine intermediate derived from
the detritylation of 3c did not evolve even after standing
48 h at room temperature in [D5]pyridine. This further
demonstrated that there was no observable C2 equilibration
of the unprotected amino thiazolidine under these
conditions.
phase synthesis of a model peptide and offers a viable
alternative to the preparation of peptide aldehydes.
3. Experimental
3.1. General
1H NMR spectra were recorded at 200 MHz on a Bruker
Avance-DPX and chemical shifts are reported in ppm.
Mass spectra were performed either in the FAB1 mode,
unless otherwise noted, by the Department of Physical
Measurements of the University of Montpellier II or using
MALDI-TOF mass spectrometry, in the positive mode, on a
Bruker Bi¯ex III and DHB as a matrix. Optical rotations
were run at 208C. Column chromatography was conducted
by using silica gel :70±230 or 240±400 mesh) as the
stationary layer. Analytical TLC was performed on silica
gel 60F254 aluminum sheets. Analytical HPLC was carried
out with a Kromasil C8 column :5 mm; 4.6£150 mm) using
a linear gradient of acetonitrile10.1% TFA :solvent B) in
water10.1% TFA :solvent A) at a ¯ow rate of 1.5 mL/min
:conditions A). Usual work-up A consisted in :i) dissolving
the residue in AcOEt, :ii) several successive washings of the
organic phase with NaHCO3 :5% aqueous solution), KHSO4
:5% aqueous solution) and brine, :iii) drying the organic
phase over sodium sulfate, :iv) evaporation of the solvent
under reduced pressure. Usual work-up B is similar to work-
up A except that the order of treatment with NaHCO3 and
KHSO4 was reversed.
To evaluate the ability of these N-trityl-amino thiazolidines
to serve as precursors for the synthesis of peptide aldehydes
on solid support, we prepared the Ac-Tyr-Val-Ala-Asp-H
caspase inhibitor.2,19,20 Prepared from BocAsp:OtBu)H, the
mixture of thiazolidines 5a, b was N-methylated18 to 12a, b
:Scheme 3) which was then saponi®ed to give the N-methyl
thiazolidine 13a, b :overall yield: 72%). Coupling of
compound 13a, b to the Met-Expansinw resin was
performed through 6-amino-hexanoic acid as a spacer.7
Deprotection of the tritylamino group was performed
under mild acid conditions. Fmoc-strategy was chosen for
elongation to the masked tetrapeptide aldehyde. The ®nal
cleavage step was successfully performed as previously
described6,8 using a mixture of copper salts which enabled
the isolation of Ac-Tyr-Val-Ala-Asp-H in a 54% overall
yield from 13a, b. The crude product was estimated to be
1
90% pure by analytical HPLC and its H NMR data were
favorably compared to literature data.19 Slow epimerization
of the ®nal product in [D4]MeOH was only observed after
standing at room temperature for one day. MALDI-TOF
mass spectrometry, in the positive mode, revealed two
major signals corresponding to [M1Na]1 and
[M±H12£Na]1, the latter of which was presumably related
to the presence of a carboxylate sodium salt.
3.2. Preparation of the N-protected amino aldehydes
In conclusion, the preparation of N-methyl-thiazolidinyl-
derived amino aldehydes was improved by direct condensa-
tion of N-protected amino aldehydes with l-cysteinyl
residues.6 We have shown that whereas the straightforward
condensation of Boc-protected amino aldehydes with
:R)-cysteinyl residues gives an uncontrollable level of
epimerization of the incoming aldehyde chiral center, the
use of N-tritylamino aldehydes dramatically secures the
stereochemical integrity of the ®nal thiazolidine derivatives.
This methodology was successfully applied to the solid
N-Boc-:S)-, N-Boc-:R)-phenylalaninal were prepared by
reduction of their respective esters according to Fehrentz's
procedure.12 All N-Boc protected a-amino aldehydes were
used without puri®cation and condensed immediately with
the appropriate cysteinyl residue.
N-Trityl-,S)-phenylalaninal, N-trityl-,R)-phenylalaninal,
N-trityl-,S)-leucinal. These compounds were prepared
according to Albeck16 and could be stored at 08C for three
months without loss of optical purity.
Scheme 4. Reagents and conditions: :i) ClCO2iBu, NMM, DME then NaBH4, water; :ii) H2, Pd/C, abs. EtOH :73% over two steps); :iii) TrtCl, NEt3, DCM;
:iv) Swern's oxidation; :v) SEMCl, DIEA, DCM; :vi) Dibal, toluene.

C. Gros et al. / Tetrahedron 58 ,2002) 2673±2680
2677
N-Trityl-,S)-aspartinal 4-tert-butyl ester ,20). This alde-
hyde was prepared in four steps starting from N-Z-aspartinol
4-tert-butyl ester 17 :Scheme 4), itself obtained by
reduction of 16 according to the procedure of Rodriguez
et al.21
15 mmol) was stirred overnight at rt in CH2Cl2. The solvent
was evaporated under reduced pressure. Work-up B
furnished compound 23 as an oil which was suf®ciently
1
pure for the next step. Yield: 97%; H NMR :[D6]DMSO)
dˆ7.44±7.40 :m, 6H), 7.32±7.16 :m, 9H), 4.52 :s, 2H),
3.60±3.43 :m, 3H), 3.35 :m, 2H), 3.17 :s, 3H), 2.91 :d,
Jˆ9.8 Hz, 3H), 2.80 :d, 1H), 0.83 :t, Jˆ7.4 Hz, 2H),
20.01 :s, 9H); MS :FAB1); m/z :%): 491 :13), 459 :6),
3.2.1. -S)-Aspartinol 4-tert-butyl ester -18). Hydrogena-
tion of compound 17 :4.2 g, 13.6 mmol) was performed
using palladium on charcoal :0.42 g) under a hydrogen
atmosphere in abs EtOH :110 mL) for 4 h. Evaporation of
the solvent furnished the amino alcohol 18 as an oil. This
product was used in the next step without further puri®ca-
tion. Yield: 99%; 1H NMR :[D6]DMSO) dˆ3.27±3.12 :m,
2H), 2.97 :m, 1H), 2.31 :dd, Jˆ15.0, 4.8 Hz), 2.01 :dd,
Jˆ15.0, 8.4 Hz), 1.41 :s, 9H).
20
398 :9), 369 :5), 243 :100); [a]D ˆ29.6 :cˆ1.05, MeOH).
3.2.6. N-Trityl--S)-serinal 3-[2--trimethylsilyl)-ethoxy-
methyl ether] -24). To a solution of ester 23 :4.61 g,
9.4 mmol) in dry toluene :100 mL) cooled at 2758C was
added Dibal :20.6 mL; 1 M/toluene) over a 30-minute
period. The temperature was allowed to reach 2458C,
then MeOH :5 mL) was added dropwise. After room
temperature had been reached, the solvent was evaporated
under reduced pressure. Diethyl ether :80 mL) was added to
the residue, and the organic phase was washed twice succes-
sively with cold 1N HCl :40 mL), a 5% aqueous solution of
NaHCO3 :40 mL) and brine :40 mL) and was dried over
sodium sulfate. The oily residue was puri®ed by ¯ash
column chromatography :AcOEt/cyclohexane 90:10) to
give aldehyde 24 :2.46 g, 5.33 mmol) and alcohol 25
:1.23 g, 2.65 mmol); this latter compound could be oxidized
to aldehyde 24 in the same way as were the tritylamino
aldehydes. Yield: 57%; 1H NMR :CDCl3) dˆ9.31 :d,
Jˆ0.8 Hz, 1H), 7.56±7.49 :m, 6H), 7.33±7.16 :m, 9H),
4.52 :q, AB system, Jˆ6.8 Hz, 2H), 3.70 :dd, Jˆ9.6,
3.6 Hz, 1H), 3.52 :dd, Jˆ11.8, 10.0 Hz, 2H), 3.41 :m,
1H), 3.06 :dd, Jˆ9.6, 5.2 Hz, 1H), 0.89 :m, 2H), 0.01 :s,
9H); MS :FAB1); m/z :%): 463 :9), 433 :5), 370 :12), 341
:7), 243 :100).
3.2.2. N-Trityl--S)-aspartinol 4-tert-butyl ester -19).
Amino alcohol 18 :2.15 g, 12.3 mmol) and NEt3 were
dissolved in dry CH2Cl2 :60 mL). To the ice-bath cooled
preceding solution, trityl chloride :3.43 g, 12.3 mmol)
dissolved in CH2Cl2 :20 mL) was added dropwise over
15 min. After stirring 1 h at rt the solvent was evaporated
and the residue dissolved in AcOEt :100 mL). Work-up B
followed by a ¯ash column chromatography puri®cation
:AcOEt/cyclohexane 80:20) furnished alcohol 19 as an
1
oil. Yield: 83%; H NMR :CDCl3) dˆ7.59±7.54 :m, 6H),
7.30±7.17 :m, 9H), 3.42 :dd, Jˆ11.0, 4.0 Hz, 1H), 3.14 :dd,
Jˆ11.0, 6.0 Hz, 1H), 2.99 :m, 1H), 2.58 :bs, 1H), 1.88 :dd,
Jˆ15.7, 3.5 Hz, 1H), 1.78 :dd, Jˆ15.7, 6.3 Hz, 1H), 1.39 :s,
9H); MS :FAB1); m/z :%): 418 :6), 360 :4), 340 :4), 307 :5),
20
277 :13), 243 :36), 185 :100); [a]D ˆ17.6 :cˆ1, MeOH);
Anal. calcd for C27H29NO3: C, 78.03; H, 7.04; N, 3.37.
Found: C, 78.25; H, 7.20; N, 3.43.
3.3. Preparation of thiazolidines -2±6)
3.2.3. N-Trityl--S)-aspartinal 4-tert-butyl ester -20).
Swern's procedure22 was used to perform the oxidation of
1
To a stirred solution of protected aldehyde :1 mmol) in
DMF, was added a freshly prepared aqueous solution of
H-Cys-OMe,HCl :1.5 mmol) and KHCO3 :1.5 mmol) at
58C. The reaction mixture was further stirred for 1 h at rt
and diluted with brine. The aqueous phase was extracted
three times with diethyl ether or AcOEt. The combined
organic extracts were dried over sodium sulfate and the
solvent was evaporated. The residue was puri®ed by ¯ash
column chromatography :AcOEt/cyclohexane).
compound 19. Yield: 98%; H NMR :CDCl3) dˆ9.19 :s,
1H), 7.60±7.55 :m, 6H), 7.37±7.21 :m, 9H), 3.41 :dd,
Jˆ6.0, 3.2 Hz, 1H), 2.63 :dd, Jˆ16.4, 3.2 Hz, 1H), 2.16
:dd, Jˆ16.4, 6.0 Hz, 1H), 1.77 :bs, 1H), 1.46 :s, 9H); MS
:FAB1); m/z :%): 416 :8), 358 :6), 338 :5), 243 :100), 57
:42).N-Trityl-,S)-serinal 3-[2-,trimethylsilyl)-ethoxymethyl
ether] ,24). This aldehyde was prepared from serine methyl
ester hydrochloride 21 in three steps :Scheme 4).
3.2.4. N-Trityl--S)-serine methyl ester -22). The trityl
group was introduced similarly as for compound 18. The
resulting trityl amino derivative 22 was obtained as a solid
after work-up B and puri®cation by ¯ash column chromato-
3.3.1. Thiazolidines -2a±d). These compounds were not
separable by ¯ash column chromatography. The crude
condensation mixtures obtained from N-Boc-:S)-,
respectively, N-Boc-:R)-phenylalaninal were studied by
1
graphy :AcOEt/cyclohexane 80:20). Yield: 92%; H NMR
1
HPLC and H NMR spectrometry :Table 3).
:[D6]DMSO) dˆ7.44±7.35 :m, 6H), 7.32±7.15 :m, 9H),
4.94 :t, Jˆ6.0 Hz, 1H), 3.50 :dd, Jˆ10.6, 3.0 Hz, 1H),
3.42 :dd, Jˆ10.6, 6.6 Hz, 1H), 3.21 :m, 1H), 3.12 :s, 3H),
2.80 :d, Jˆ10.0 Hz, 1H); MS :FAB1); m/z :%): 362 :15),
344 :6), 330 :5), 243 :100); mp 1478C :lit. mp 1468C);23
Table 3. Selected 1H NMR and HPLC data of compounds 2a±d
2a
2b
2c
2d
1H NMR, d OCH3 :ppm)a
HPLC, tR :min)b
3.69
5.91
3.70
5.61
3.66
5.41
3.64
5.10
20
[a]D ˆ112.3 :cˆ1.2, MeOH); Anal. calcd for
C23H23NO3: C, 76.42; H, 6.42; N, 3.88. Found: C, 76.22;
H, 6.28; N, 3.75.
a
Recorded in [D6]DMSO.
Gradient: 50±70% solvent B in 10 min.
b
3.2.5. N-Trityl--S)-serine 3-[2--trimethylsilyl)-ethoxy-
methyl ether] methyl ester -23). A mixture of compound
22 :3.61 g, 10 mmol), DIEA :5.2 mL, 30 mmol) and
1
3.3.2. Thiazolidine -3a). Yield: 88%; H NMR :CDCl3)
dˆ7.60±7.55 :m, 6H, Ar), 7.38±7.14 :m, 12H, Ar), 6.91
2-:trimethylsilyl)-ethoxy)-methyl
chloride
:2.66 mL,

2678
C. Gros et al. / Tetrahedron 58 ,2002) 2673±2680
0
epimers 6a and 6b except those assigned to H2, H3 and
:m, 2H, Ar), 4.32 :d, Jˆ9.8 Hz, 1H, H2), 3.80 :s, 3H,
1
OCH3), 3.72±3.53 :m, 2H, H4, NHcycle), 3.36 :m, 1H,
0
OCH3; H NMR :[D6]DMSO) for 6a, dˆ7.50 :m, 6H,
H1 ), 3.27 :dd, Jˆ10.6, 5.8 Hz, 1H, H5), 2.91 :d,
Ar), 7.34±7.18 :m, 12H, Ar), 4.63 :dd, Jˆ12.1, 2.4 Hz,
0
Jˆ9.2 Hz, 1H, NHTrt), 2.82 :dd, Jˆ10.6, 6.2 Hz, H5),
1H, H2), 4.35 :d, Jˆ6.6 Hz, 1H, H3 ), 4.11 :d, Jˆ6.6 Hz,
0
0
0
1H, H3 ), 3.71 :m, 1H, H4 ), 3.70 :s, 3H, OCH3), 3.43±3.31
2.45 :dd, Jˆ13.2, 4.0 Hz, 1H, H2 ), 2.15 :dd, Jˆ13.2,
1
10.8 Hz, 1H, H2 ); MS :FAB ); m/z :%): 509 :16), 461
:4), 431 :4), 307 :10), 277 :42), 243 :100); mp 1498C;
0
0
:m, 3H, NHcycle/H4 ), 3.24±3.15 :m, 2H, H2 /H5), 2.99 :m,
0
0
1H, H1 ), 2.74±2.62 :m, 1H, H5), 2.34 :dd, Jˆ9.2, 6.2 Hz,
20
0
0
[a]D ˆ212.1 :cˆ1.9, CHCl3); Anal. calcd for
1H, H2 ), 0.76 :m, 2H, H5 ), 20.05 :s, 9H, SiMe3); MS
C32H32N2O2S: C, 75.56; H, 6.34; N, 5.51. Found: C,
75.45; H, 6.20; N, 5.42.
:FAB1); m/z :%): 547 :3), 469 :7), 386 :9), 315 :9), 243
1
:100). H NMR :[D6]DMSO) for 6b, dˆ7.50 :m, 6H, Ar),
7.34±7.18 :m, 12H, Ar), 4.90 :dd, Jˆ8.0, 8.0 Hz, 1H, H2),
0
0
3.3.3. Thiazolidines -3c, d). The mixture of these
unseparated oily compounds was obtained in a combined
yield of 92%; 1H NMR :CDCl3) for 3d, dˆ7.62 :m, 6H, Ar),
7.35±7.17 :m, 12H, Ar), 6.72 :m, 2H, Ar), 4.49 :m, 1H, H2),
3.86 :s, 3H, OCH3), 3.69 :dd, Jˆ9.8, 6.4 Hz, 1H, H4), 3.23
4.46 :d, Jˆ6.4 Hz, 1H, H3 ), 4.21 :d, Jˆ6.4 Hz, 1H, H3 ),
3.67 :s, 3H, OCH3), 3.55 :m, 1H, NHcycle), 3.43±3.31 :m,
0
0
1H, H4 ), 3.24±3.15 :m, 1H, H2 ), 2.99±2.91 :m, 1H, H5),
0
2.81 :m, 1H, H2 ), 2.74±2.62 :m, 1H, H5), 2.09 :m, 1H, H1 ),
0
0
0.76 :m, 2H, H5 ), 20.03 :s, 9H, SiMe3).
0
:m, 1H, H1 ), 3.21 :dd, Jˆ10.0, 6.4 Hz, 1H, H5), 2.75 :dd,
1
0
Jˆ10.0, 9.8 Hz, 1H, H5), 2.67 :m, 2H, H2 ); MS :FAB );
3.4. Preparation of N-methyl thiazolidines -7a±d), -10),
-11c±d) and -12a, b)
m/z :%): 509 :8), 491 :2), 461 :7), 431 :6), 369 :14), 277
:33), 243 :100).
To a stirred solution of the thiazolidine 2a±d, 3a, 3c, d or
5a, b :1 mmol) in CH3CN/CH2Cl2 :3:1, 2 mL) was added
successively an aqueous solution of formaldehyde :6 mmol)
and sodium cyanoborohydride :1.6 mmol) in one portion at
rt. Acetic acid :50 mL) was added four times to the mixture
until disappearance in about 30 min of the starting material
as determined by TLC. The solvent was evaporated and
work-up A led to the title compounds after puri®cation by
¯ash column chromatography.
3.3.4. Thiazolidines -4a, b). The mixture of these
unseparated compounds was obtained in a combined yield
of 89%. Some of the 1H NMR signals were common to both
0
epimers 6a and 6b except those assigned to H2, H4, H4 and
OCH3, 1H NMR :[D6]DMSO) for 4a, dˆ7.48±7.41 :m, 6H,
Ar), 7.30±7.10 :m, 12H, Ar), 4.59 :dd, Jˆ12.1, 2.6 Hz, 1H,
H2), 3.81 :m, 1H, H4), 3.71 :s, 3H, OCH3), 3.57 :m,
1H, NHcycle), 3.17 :dd, Jˆ10.2, 7.3 Hz, 1H, H5), 2.99 :m,
0
1H, H1 ), 2.72 :dd, Jˆ10.2, 9.4 Hz, 1H, H5), 2.55 :d,
0
Jˆ10.1 Hz, 1H, NHCPh3), 1.42±1.20 :m, 1H, H3 ), 1.11±
3.4.1. Thiazolidine -7a±d). Obtained from 2a±d as a
mixture of four diastereoisomers which was directly used
for the preparation of bicyclic lactams 8 and 9 :see below).
Yield: 89%.
0
0
0.79 :m, 1H, H2 ), 0.46 :d, Jˆ6.3 Hz, 3H, H4 ), 0.45 :m,
1
0
0
1H, H2 ), 0.44 :d, Jˆ6.5 Hz, 3H, H4 ); MS :FAB ); m/z
:%): 475 :3), 429 :7), 381 :6), 349 :9), 307 :19), 243
1
:100). H NMR :[D6]DMSO) for 4b, dˆ7.48±7.41 :m,
6H, Ar), 7.30±7.10 :m, 12H, Ar), 4.75 :dd, Jˆ10.9,
3.6 Hz, 1H, H2), 4.30 :m, 1H, H4), 3.57 :s, 3H, OCH3),
3.57 :m, 1H, NHcycle), 3.49 :m, 1H, H5), 2.99 :d,
Jˆ5.1 Hz, 1H, H5), 2.83 :s, 1H, NHCPh3), 2.21 :m, 1H,
3.4.2. Thiazolidine -10). Solid, obtained from 3a as a single
diastereoisomer. Yield: 94%; 1H NMR :CDCl3) dˆ7.73 :m,
6H), 7.36±7.09 :m, 12H), 6.74 :m, 2H), 3.58 :s, 3H), 3.51
:d, Jˆ2.4 Hz, 1H, NH), 3.50±3.37 :m, 2 H, H4/H5), 3.29 :d,
Jˆ5.2 Hz, 1H, H2), 3.11 :dd, Jˆ8.2, 3.4 Hz, 1H, H5), 2.65
0
0
0
0
H1 ), 1.42±1.20 :m, 2H, H2 /H3 ), 1.11±0.79 :m, 1H, H2 ),
0
0
0.51 :d, Jˆ6.0 Hz, 3H, H4 ), 0.31 :d, Jˆ6.3 Hz, 3H, H4 ).
0
0
:m, 1H, H1 ), 2.55 :dd, Jˆ13.6, 3.6 Hz, 1H, H2 ), 2.29 :dd,
1
0
Jˆ13.6, 11.2 Hz, 1H, H2 ), 1.91 :s, 3 H); MS :FAB ); m/z
20
3.3.5. Thiazolidines -5a, b). The mixture of these
unseparated compounds was obtained in a combined yield
of 91% Some of the 1H NMR signals were common to both
epimers 6a and 6b except those assigned to H2, H4 and
:%): 523 :7), 445 :5), 307 :39), 289 :21), 243 :100); mp
169±1708C; [a]D ˆ195 :cˆ2.01, CHCl3); Anal. calcd for
C33H34N2O2S: C, 75.83; H, 6.56; N, 5.36. Found: C, 75.63;
H, 6.46; N, 5.28.
1
OCH3; H NMR :[D5]Pyridine) for 5a, dˆ7.78 :m, 6H,
Ar), 7.34±7.13 :m, 12H, Ar), 5.58 :d, Jˆ5.6 Hz, 1H, H2),
4.22 :dd, Jˆ6.1, 6.1 Hz, 1H, H4), 3.64 :s, 3H, OCH3), 3.34
3.4.3. Thiazolidines -11c, d). Oil, obtained from 3c, d as a
mixture of inseparable diastereoisomers. Yield: 92%; most
1H NMR signals were common to both epimers 11c and 11d
except those assigned to H2, OCH3 and NCH3. 1H NMR for
11c :CDCl3) dˆ7.76±7.64 :m, 6H), 7.39±7.12 :m, 12H),
6.79 :m, 2H), 3.99 :d, Jˆ1.6 Hz, 1H, H2), 3.71 :s, 3H), 3.46
:dd, Jˆ8.2, 6.4 Hz, 1H, H4), 3.37 :dd, Jˆ10.5, 6.4 Hz, 1H,
0
:m, 1H, H1 ), 3.21 :dd, Jˆ10.4, 6.1 Hz, 1H, H5), 3.03 :dd,
0
Jˆ10.4, 6.1 Hz, 1H, H5), 2.17 :dd, Jˆ15.9, 7.7 Hz, 1H, H2 ),
0
2.17 :dd, Jˆ15.9, 2.7 Hz, 1H, H2 ), 1.38 :s, 9H, tBu); MS
:FAB2); m/z :%): 533 :4), 461 :7), 369 :9), 307 :8), 277
:18), 243 :25), 185 :100), 93 :46). 1H NMR :[D5]Pyridine)
for 5b, dˆ7.78 :m, 6H, Ar), 7.34±7.13 :m, 12H, Ar), 4.88
:d, Jˆ4.8 Hz, 1H, H2), 3.95 :dd, Jˆ8.5, 6.2 Hz, 1H, H4),
0
H5), 3.18 :dd, Jˆ10.5, 8.2 Hz, 1H, H5), 3.07 :m, 1H, H1 ),
2.68 :d, Jˆ9.2 Hz, 1H, NH), 2.34 :dd, Jˆ12.6, 2.4 Hz, 1H,
0
3.81 :m, 1H, H1 ), 3.61 :s, 3H, OCH3), 3.41 :dd, Jˆ9.7,
0
0
H2 ), 2.29 :dd, Jˆ12.6, 7.8 Hz, 1H, H2 ), 2.08 :s, 3H); MS
:FAB1); m/z :%): 523 :5), 445 :6), 307 :35), 289 :15) 243
:100).
8.5 Hz, 1H, H5), 2.96 :dd, Jˆ9.7, 6.1 Hz, 1H, H5), 2.23
0
:m, 2H, H2 ), 1.37 :s, 9H, tBu).
3.3.6. Thiazolidines -6a, b). The mixture of these
unseparated compounds was obtained in a combined yield
of 91%. Some of the 1H NMR signals were common to both
3.4.4. Thiazolidines -12a, b). Oil, obtained from 5a, b as a
mixture of inseparable diastereoisomers. Yield: 88%; only
aromatic and NCH3 1H NMR signals were common to both

C. Gros et al. / Tetrahedron 58 ,2002) 2673±2680
2679
1
epimers 12a and 12b; H NMR for 12a :CDCl3) dˆ7.83±
7.65 :m, 6H), 7.35±6.94 :m, 14H), 4.62 :d, Jˆ3.4 Hz, 1H,
H2), 3.99 :d, Jˆ4.8 Hz, 1H, H4), 3.82 :s, 3H), 3.60 :m, 1H,
3.6. Preparation of Ac-Tyr-Val-Ala-Asp-H
3.6.1. Thiazolidine -13a, b). Thiazolidine 12a, b :874 mg,
1.6 mmol) in dioxane :10 mL) was saponi®ed for 3 h at
1108C by 1N NaOH :8 mL, 8 mmol). The reaction mixture
was acidi®ed with a 5% aqueous solution of KHSO4 and the
dioxane was evaporated. The residue was extracted three
times with AcOEt and the organic phases were dried over
sodium sulfate. Filtration of the dessicant and evaporation
of the solvent gave the expected product as oil and a mixture
of diastereoisomers in a 1:1 ratio. Yield: 63% Aromatic,
0
H1 ), 3.22 :dd, Jˆ10.6, 4.8 Hz, 1H, H5), 2.95 :d, Jˆ10.6 Hz,
1H, H5), 2.40 :s, 3H, NCH3), 2.27 :dd, Jˆ15.2, 9.6 Hz, 1H,
0
0
H2 ), 1.41 :s, 9H), 1.20 :dd, Jˆ15.2, 1.8 Hz, 1H, H2 ); MS
:FAB2); m/z :%): 547 :4), 469 :7), 386 :12), 243 :100),
1
57 :9). H NMR for 12b :CDCl3) dˆ7.83±7.65 :m, 6H),
7.35±6.94 :m, 14H), 4.15 :d, Jˆ2.8 Hz, 1H, H2), 3.75 :m,
1H, H4), 3.72 :s, 3H), 3.48 :dd, Jˆ10.2, 9.8 Hz, 1H, H5),
0
3.02 :m, 2H, H1 /H5), 2.40 :s, 3H, NCH3), 1.83 :d,
1
0
Jˆ6.2 Hz, 2H, H2 ), 1.40 :s, 9H).
NCH3 and OtBu H NMR signals were common to both
epimers 13a and 13b; 1H NMR :[D6]DMSO) for 13a
dˆ7.54±7.42 :m, 6H), 7.37±7.10 :m, 10H), 3.90 :d,
Jˆ3.0 Hz, 1H, H2), 3.60 :m, 2H, H4/H5), 3.22 :d,
3.5. Preparation of bicyclic lactams -8) and -9)
0
Jˆ6.8 Hz, 1H, H5), 2.88 :m, 1H, H1 ), 2.47 :d, Jˆ8.8 Hz,
0
3.5.1. Lactams -8) and -9). Compounds 7a±d :380 mg,
1 mmol) were stirred in tri¯uoroacetic acid :0.7 mL,
10 mmol) for 40 min. After evaporation of the acid,
MeOH :2 mL) and KHCO3 :10 mg, 1 mmol) were added
to the reaction mixture which was stirred for 4 h at rt. The
solvent was evaporated and the residue dissolved in AcOEt.
The organic phase was washed three times with brine then
dried over sodium sulfate. The solvent was evaporated and
the residue was puri®ed by ¯ash column chromatography
:CH2Cl2/MeOH 98:2), affording pure compounds 12 and 13
in a ratio of 9:1. Yield: 54%. Analytical data are given
below.
1H, NH), 1.35 :dd, Jˆ10.4, 7.6 Hz, 1H, H2 ), 1.23 :s, 9H),
1
0
1.16 :dd, Jˆ10.4, 7.0 Hz, 1H, H2 ); MS :FAB ); m/z :%):
533 :10), 489 :8), 477 :15), 433 :25), 271 :33), 243 :100), 57
:45). 1H NMR :[D6]DMSO) for 13b dˆ7.54±7.42 :m, 6H),
7.37±7.10 :m, 10H), 4.37 :d, Jˆ3.4 Hz, 1H, H2), 3.78 :d,
0
Jˆ6.8 Hz, 1H, H4), 3.31 :m, 1H, H1 ), 2.92 :m, 2H, H5), 2.33
0
:d, Jˆ10.4 Hz, 1H, NH), 2.25 :dd, Jˆ14.2, 8.0 Hz, 1H, H2 ),
0
1.96 :dd, Jˆ14.2, 5.6 Hz, 1H, H2 ), 1.23 :s, 9H).
3.6.2. Peptide elongation. Starting from a Met-Expansinw
resin :300 mg, 0.216 mmol), Fmoc-Ahx-OH :252 mg,
0.71 mmol) was ®rst introduced using the BOP reagent
:288 mg, 0.65 mmol) and DIEA :0.169 mL, 0.99 mmol) in
DMF. After removal of the Fmoc group with a solution of
3.5.2. Lactam -8). To compound 10 :330 mg, 0.63 mmol)
dissolved in CH2Cl2/methanol :1:1, 1.5 mL) was added
tri¯uoroacetic acid :15 mL, 0.22 mmol). After 15 min
solid KHCO3 :10 mg, 1 mmol) was added and the mixture
was stirred for 2 h at rt. The solvent was evaporated and the
residue was dissolved in AcOEt. The organic phase was
washed three times with brine then dried over sodium
sulfate. The solvent was evaporated leaving the expected
product as a solid residue. Yield: 75%; 1H NMR
:[D6]DMSO) dˆ7.60 :s, 1H, NH), 7.37±7.13 :m, 5H),
4.17 :dd, Jˆ1.6, 1.6 Hz, 1H, H5), 3.88 :m, 1H, H4),
3.83 :d, Jˆ5.0 Hz, 1H, H1), 3.08 :dd, Jˆ12.5, 5.6 Hz,
1H, H8), 2.92 :d, Jˆ5.0 Hz, 1H, H8), 2.83 :dd, Jˆ12.0,
piperidine in DMF, thiazolidine 13a,
b
:176 mg,
0.33 mmol) was introduced using the BOP reagent
:144 mg, 0.33 mmol), HOBt :50 mg, 0.33 mmol) and
DIEA :0.113 mL, 0.65 mmol). Deprotection of the trityl
group was performed using a 1% TFA solution in MeOH
and this cycle was repeated twice until the optical density of
the ®ltrate was constant. All the other amino acids :3 equiv.)
were introduced using the Fmoc strategy :Diisopropyl-
carbodiimide, 3 equiv., HOBt, 3 equiv., DIEA, 1.5 equiv.).
Completion of the coupling steps was checked by the
ninhydrin test of Kaiser.24 After N-terminal acetylation,
side chain protecting groups were removed by successive
treatment with TFA/water :95:5). Cleavage from the resin
followed our previously described procedure7 leading to the
0
0
4.8 Hz, 1H, H1 ), 2.70 :dd, Jˆ12.0, 11.0 Hz, 1H, H1 ),
2.10 :s, 3 H); MS :FAB1); m/z :%): 249 :100), 203 :20),
201 :25), 158 :3), 111 :23), 91 :15); mp 150±1518C;
caspase inhibitor Ac-Tyr-Val-Ala-Asp-H as
a white
20
powder. Yield: 54% :starting from 13a, b). 1H NMR
:[D4]MeOH) mixture of diastereoisomeric hemiacetals
dˆ7.04 :d, Jˆ8.5 Hz, 2H, Tyr), 6.67 :d, Jˆ8.5 Hz, 2H,
Tyr), 4.55 :m, 2H, Asp), 4.33 :m, 1H, Tyr), 4.24 :m, 1H,
Val), 4.13 :d, Jˆ7.2 Hz, 1H, Ala), 3.01 :dd, Jˆ14.0, 5.7 Hz,
1H, Tyr), 2.77 :dd, Jˆ14.0, 9.3 Hz, 1H, Tyr), 2.69±2.60 :m,
1H, Asp), 2.52±2.45 :m, 1H, Asp), 2.05 :m, 1H, Val), 1.90
:s, 3H, Ac), 1.33 :d, Jˆ7.2 Hz, 3H, Ala), 0.94 :d, Jˆ6.6 Hz,
3H, Val), 0.92 :d, Jˆ6.6 Hz, 3H, Val); MS :MALDI-TOF);
m/z :%): 515 :M1Na1), 537 :M12Na121). HPLC
tRˆ3.20 min using A/B 80:20 to A/B 50:50 in 10 min.
[a]D ˆ252.4 :cˆ2.12, CHCl3); Anal. calcd for
C13H16N2OS: C, 62.87; H, 6.49; N, 11.28. Found: C,
62.79; H, 6.48; N, 11.35.
3.5.3. Lactam -9). The above procedure was repeated
starting from the mixture of thiazolidines 11c, d,
furnishing lactam 9 as a white solid after puri®cation by
¯ash column chromatography :CH2Cl2/MeOH 98:2).
1
Yield: 63%; H NMR :[D6]DMSO) dˆ7.62 :s, 1H, NH),
7.38±7.17 :m, 5H), 4.40 :d, Jˆ1.0 Hz, 1H, H5), 3.86 :dd,
Jˆ5.3, 0.8 Hz, 1H, H1), 3.29 :m, 1H, H4), 3.11 :dd, Jˆ10.6,
5.3 Hz, 1H, H8), 3.01 :dd, Jˆ10.6, 0.7 Hz, 1H, H8), 2.88 :dd,
0
Jˆ13.1, 5.9 Hz, 1H, H1 ), 2.81 :dd, Jˆ13.1, 8.3 Hz, 1H,
1
0
H1 ), 2.16 :s, 3H); MS :FAB ); m/z :%): 249 :100), 203
:14), 201 :32), 158 :4), 111 :26), 91 :25); mp 138±1398C;
Acknowledgements
20
[a]D ˆ225.6 :cˆ1.02, CHCl3); Anal. calcd for
C13H16N2OS: C, 62.87; H, 6.49; N, 11.28. Found: C,
62.75; H, 6.36; N, 11.18.
We are grateful to Dr S. L. Salhi for revising the manuscript
and Ms E. Demey for mass spectrometry measurements.

2680
C. Gros et al. / Tetrahedron 58 ,2002) 2673±2680
10. Wyslouch, A.; Lisowski, M.; Pedyczak, A.; Siemion, I. Z.
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