Ni(II)-catalyzed Michael additions. Part 2: Dynamic kinetic resolution in the reduction of chiral α-hydrazino-β-ketoacid derivatives

Article abstract of DOI:10.1016/S0040-4020(02)00538-0

Relative syn 1,2-hydrazinoalcohols have been prepared through diastereoselective Ni(II)-catalyzed Michael addition of chiral derivatives of acetoacetic acid and of 3-oxostearic acid to dialkyl azodicarboxylates, followed by stereoselective reduction of the keto function.

Full text of DOI:10.1016/S0040-4020(02)00538-0

TETRAHEDRON
Pergamon
Tetrahedron 58 &2002) 5699±5708
NiꢀII)-catalyzed Michael additions.
Part 2: Dynamic kinetic resolution in the reduction of chiral
a-hydrazino-b-ketoacid derivativesq
Caroline Marchi,a Elisenda Trepat,a Marcial Moreno-ManÄas,a Adelina Vallriberaa,p
and Elies Molinsb
a
Á
Department of Chemistry, Universitat Autonoma de Barcelona, Cerdanyola, 08193 Barcelona, Spain
Á
Institut de Ciencia de Materials de Barcelona "CSIC), Campus de la UAB, E-08193 Cerdanyola, 08193 Barcelona, Spain
b
Received 12 February 2002;revised 22 April 2002;accepted 17 May 2002
AbstractÐRelative syn 1,2-hydrazinoalcohols have been prepared through diastereoselective Ni&II)-catalyzed Michael addition of chiral
derivatives of acetoacetic acid and of 3-oxostearic acid to dialkyl azodicarboxylates, followed by stereoselective reduction of the keto
function. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
in diastereoselective metal-catalyzed Michael reactions
using chiral 1,3-dicarbonyl compounds as nucleophiles.
Related signi®cant works are the ones by d'Angelo9 who
has reported the use of chiral enamines prepared from b-oxo
esters and Christoffers10 who uses chiral enamino esters
which undergo copper-catalyzed asymmetric reactions.
Our approximation is based on the use of chiral derivatives
of b-ketoacids as nucleophiles &Scheme 1).
The Michael reaction is one of the most common
methods for the formation of C±C bonds. However, the
limitations of conjugate additions caused by basic catalysts
are well known. The use of transition metals under
essentially neutral conditions normally offer advantages.2
Furthermore, this approach allows the use of chiral
ligands in asymmetric Michael reactions.3 Of particular
signi®cance is the work of Shibasaki4 based on the use of
BINOL and heterobimetallic catalysts, containing two metal
centers where one is a lanthanide capable of activating the
acceptor, while lithium coordinates to the enolate. Other
combinations have been used like Ni&II) and a chiral
diamine,5 Co&II) and a chiral bis&dihydroxazolylphenyl)-
oxalamide,6 and Mg&II) and an aminoindanol derived
bis&oxazoline).7
We have previously reported that Ni&salicylaldehydate)2 is
an ef®cient catalyst for reactions of a series of Michael
acceptors and 3-methyl-2,4-pentanedione and ethyl
2-methyl-3-oxobutanoate with generation of quaternary
centers.1 Moreover, some of these reactions have been
performed under organic-per¯uorinated biphasic condi-
tions. Reactions were carried out four consecutive times
with high yields using the same per¯uorinated phase
where the catalyst was dissolved. In this case, a Ni&II)
complex of the Schiff base of salicylaldehide and
4-per¯uorodecylaniline was used.11
An alternative approach relies on the use of a chiral
auxiliary in the nucleophile.8 We are particularly interested
Scheme 1.
q For part 1, see Ref. 1.
Keywords: nickel catalysis;conjugate addition;chiral induction; syn-1,2-hydrazinoalcohol;kinetic resolution; b-ketoacid derivatives.
Corresponding author. Fax: 134-9358-11265;e-mail: adelina.vallribera@uab.es
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020&02)00538-0

5700
C. Marchi et al. / Tetrahedron 58 "2002) 5699±5708
Scheme 2.
Our group has also explored Ni&II)-catalyzed diastereo-
selective Michael additions of N-acetoacetyl derivative of
enantiomerically pure Evans oxazolidinone to a broad list of
electrophiles. Useful diastereoselectivities have been
achieved.1
to different dialkyl azodicarboxylates gave excellent chemi-
cal yields and moderate diastereomeric excesses &Scheme 2
and Table 1). For the reaction of dibenzyl azodicarboxylate,
an increase in diastereomeric excesses is observed along
time, indicating that an equilibration occurs till it reaches
a thermodynamic control which corresponds to a 78% of de
&entries 1±4 and entries 5±8 of Table 1). The best result was
obtained in the case of diethyl azodicarboxylate affording
2b in 84% de.
The aim of this work is to establish a new practical method-
ology to prepare enantiopure 1,2-hydrazynoalcohols based
on a diastereoselective Ni&II)-catalyzed Michael addition
step followed by stereoselective reduction of the keto
function &Scheme 1).
The major diastereoisomers 2 were separated by column
chromatography and no epimerization was observed. The
reaction of 1 with dibenzyl azodicarboxylate afforded
diastereoisomer &R)-2a with a 77% yield &entry 7 of Table
1). This compound has been previously prepared by our
group through a ruthenium-catalyzed Michael addition of
1 and dibenzyl azodicarboxylate.13 Furthermore, we have
noticed that the stereochemical preference using Ni&saly-
cilaldehyate)2 or RuH2&PPh3)4 is the same if the chiral
auxiliary is identical. In addition, it is also the same as
that previously described for the Oppolzer's sultam in
conventional alkylations.14 Consequently, we assume the
same &R) con®guration for all major diastereoisomers 2b,
2c, and 2d. In related cases where Evans oxazolidinone was
used as chiral auxiliary, no isolation was possible without
epimerization.1
2. Results
Preliminary experiments showed that Oppolzer's sultam
was the chiral auxiliary of choice when using chiral deriva-
tives of acetoacetic acid. N-Acetoacetyl-&R)-bornane-10,2-
sultam,
1 &Scheme 2) was prepared as described
previously.12 In adducts 2, the diastereomeric integrity is
compromised by the remaining intercarbonilic active
proton, hence we use Ni&salicylaldehyate)2´H2O as catalyst
in neutral medium. Ni&II)-catalyzed conjugate additions of 1
Table 1. Conjugate additions of acetoacetyl derivatives of Oppolzer's
sultam to different dialkyl azodicarboxylates promoted by Ni&II) &Scheme
2)
Other chiral b-ketoamides were also studied. Chiral deriva-
tives of 3-oxostearic acid 3 and 5 &Scheme 3) were obtained
in 61 and 51% yields, respectively, through acylation of
Meldrum's acid with palmitoyl choride and then reaction
with the chiral auxiliary &Scheme 3). This methodology has
been previously applied only to more simple alcohols and
amines.15 Best yields were obtained by adding a catalytic
amount of DMAP &10%) under nitrogen atmosphere in the
formation of the acylated Meldrum's acid.
Entry
R
T &8C)
t &h)
2
Yield 2 &%)a
deb 2 &%)
1
2
3
4
5
6
7
8
Bzl
Bzl
Bzl
Bzl
Bzl
Bzl
Bzl
Bzl
Et
Rt
Rt
Rt
Rt
35
35
35
35
35
35
35
17
48
72
144
7
17
48
120
48
48
17
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2dd
100c
100c
46
56
68
77
30
74
76
78
84
80
55
100c
100c
100c
100c
&77)
100c
9
10
11
67 &60)
75 &66)
100c
t-Bu
iPr
Michael additions of 3 and 5 were carried out with different
dialkyl azodicarboxylates. Ni&salycilaldehyate)2 was used
as catalyst &Scheme 4). Diastereomeric excesses were only
moderate &Table 2). On one hand, we have observed an
increase in de with time for compound 4 until thermo-
dynamic equilibrium &entries 2 and 3 of Table 2) has been
reached, on the other hand, con®gurational stability is
a
Overall yield and, in parentheses, yield of isolated major diastereoisomer
&R)-2.
b
Diastereomeric excesses were determined by 1H NMR integration of well
separated signals.
c
Conversion yields were determined by 1H NMR.
Not isolated.
d

C. Marchi et al. / Tetrahedron 58 "2002) 5699±5708
5701
Scheme 3.
Scheme 4.
noticed for 6b &entries 5 and 6 of Table 2). Thereby the
stereochemical stability depends on the chiral auxiliary
present at the compound.
Table 2. Conjugate additions of 3-oxostearic acid derivatives of Oppolzer's
sultam to different dialkyl azodicarboxylates promoted by Ni&II) &Scheme
4)
Entry
R
T &8C)
t
dea &%) 4±6
Conjugate addition diastereoisomers 2, 4 and 6 were
normally not separated and reduction of the keto function
was performed in a stereoselective manner. We have
initially studied the reduction of a diastereomeric mixture
of 2a &Scheme 5). The use of Zn&BH4)2 as reductor for chiral
b-ketoamides has been reported in the literature.16 In our
group we have previously used it successfully, to reduce the
keto group of a similar compound but having Evans' oxa-
zolidinone as chiral auxiliary.1 Nevertheless, reduction of
2a failed. Then, we turned our attention to BH3´SMe2 as
reducing agent in the presence of TiCl4 as a chelator
Lewis acid.17 It is worth remarking that under these condi-
tions, practically only one of the four possible stereoisomers
b
1
2
3
4
5
6
7
8
9
3
3
3
5
5
5
5
5
5
Bzl
Bzl
Bzl
Bzl
Et
0
24 h
17 h
14 days
18 h
17 h
6 days
72 h
48 h
4
4
4
6a
6b
6b
6c
6c
6d
±
Rt
Rt
r.t
Rt
Rt
Rt
50
Rt
60
76
20
64
60
Et
t-Bu
t-Bu
CH2CCl3
b
±
0
c
18 h
±
a
Diastereomeric excesses were determined by 1H NMR integration of well
separated signals.
No reaction under these conditions.
Not determined.
b
c

5702
C. Marchi et al. / Tetrahedron 58 "2002) 5699±5708
Scheme 5.
Table 3. Reduction of the keto function of Michael adducts from acetoacetyl derivatives of Oppolzer's sultam with BH3 and TiCl4 &Scheme 5)
Entry
2
R
T &8C)
t &min)
7
dea 2 &%)
dea 7 &%)
Yieldb 7 &%)
1
2
3
4
5
6
7
8
2a
2a
2a
2b
2b
2c
2d
2d
Bzl
Bzl
Bzl
Et
223
223
223
223
0
223
223
0
15
20
60
10
10
20
10
10
7a
7a
7a
7b
7b
7c
76
40
±
56
56
74
52
52
95
95
95
78
97
60
70
94
67c
64
d
55
65
Et
100e
32
t-Bu
iPr
iPr
7df
7df
100e
100e
Diastereomeric excesses were determined by 1H NMR integration of well separated signals.
Yield corresponding to the two consecutive steps &Michael addition and reduction).
Yield corresponding to the reduction step.
Not determined.
Conversion yield determined by 1H NMR.
Not isolated.
a
b
c
d
e
f
is obtained with a high de of 94±97% &Table 3) in the
when applied to b-ketoesters and b-ketosulfones gives a
high diastereoselectivity in favor of the corresponding syn
stereoisomer. In our case, we suppose that the same syn
stereochemistry is obtained in all cases. This was con®rmed
for 7c &20S,30R) and 7b &20S,30R) from X-ray diffraction
analysis.18 The con®guration of C-2 for the major dia-
stereoisomer has changed from compounds 2 &R) to
compounds 7 &S). A dynamic kinetic resolution process
could explain these results &Scheme 6). If epimerization of
diastereoisomers &R)-2 and &S)-2 is rapid enough with
respect to the reduction step and their rates of the reduction
are substantially different, the reduction would afford only
one stereoisomer. In our case, under the reaction conditions,
the major diastereoisomer &R) of Michael reaction
epimerises to the minor &S) which is reduced to afford an
unique stereoisomer &20S,30R)-7. Consequently, from differ-
ent diasteromeric mixtures of 2a the same unique alcohol is
obtained &entries 1 and 2 of Table 3).
reduction of 2a, 2b and 2d. For compound 7c, breaking of
one of the amide groups has been observed &Scheme 5). It
has been extensively described that this reduction protocol
Other reductants such as LiBH4 and DIBAL-H gave worst
results.
Concerning the reduction of Michael adducts derived from
Scheme 6.

C. Marchi et al. / Tetrahedron 58 "2002) 5699±5708
5703
Scheme 7.
Table 4. Reduction of the keto function of Michael adducts from chiral 3-oxostearic acid with BH3 and TiCl4 &Scheme 7)
Entry
T &8C)
t
dea 4±6 &%)
dea 8 and 9 &%)
Yieldb 8 and 9 &%)
c
1
2
3
4
5
6
7
4
4
4
4
6a
6b
6d
223
223
223
0
223
223
223
10 min
20 min
25 min
15 min
3 h
8
8
8
8
9a
9b
9d
16
0
74
74
97
0
60
60
20
±
c
±
&47)
76
±
d
c
±
60
60
39 &36)
60 &47)
64 &43)
1.5 h
2 h
d
±
a
1
Diastereomeric excesses were determined by H NMR integration of well separated signals.
Overall reaction yield and, in parentheses, yield of major diastereoisomer.
Not isolated.
Not determined.
b
c
d
Scheme 8.
2-oxostearic acid &Scheme 7) we have applied the best
conditions found for 2. Isolation of major alcohols in good
yields has been possible. It has to be considered that yields
given in Table 4 correspond to the two steps &Michael
addition and reduction). In addition, we have observed
that the diastereomeric excesses of hydrazinoalcohol 8
&Xop) obtained at different reaction times are much higher
than the ones of starting ketone, 4 &entries 1±3 of Table 4),
and that the major alcohol comes from the minor ketone.
This indicates that at 2238C, a kinetic resolution has taken
place.
The absolute con®guration of the hydrazinoalcohol 8
&20S,30R) was assigned by comparison of the stereo-
chemistry previously assigned to the hydrazinoalcohols 7
which have the same chiral auxiliary &Xop). This is reason-
able because all these compounds have been obtained
through the same reactions. In addition, comparison of the
molar rotation of 8 and &R)-2a &similar substances with
unequal molecular weights) show a great coincidence &for
2a [M]ˆ258 &CHCl3) and for 8 [M]ˆ209 &CHCl3)).
Reduction of Michael adducts from N-acetoacetyl-4-
benzyloxazolidin-2-one using Zn&BH4)2 allowed the
formation of an unique alcohol with a stereochemistry
20R,30S &X-ray diffraction analysis of 11).1 Now, we report
that when the reduction is carried out with TiCl4/BH3´SMe2,
the same major alcohol is obtained, consequently
exhibiting identical speci®c rotation &Scheme 8). We
assume the same chirality for the major diastereoisomers
9a,b,d as for 11. Molar rotations of 11 &[M]ˆ139
&CHCl3)) and &20R,30S)-9b &[M]ˆ144 &CHCl3)) were very
similar as expected.
We have observed that selectivity does not increase mono-
tonically with decreasing temperature &entries 4 vs 5 and 7
vs 8 of Table 3, and entries 3 vs 4 of Table 4). This is not
unexceptional since there are many examples of such a
behavior satisfactorily explained by the isoinversion
principle. They are either due to variations in the nature of
the rate determining step with temperature, or due to
changes in mechanism. An indepth study on this phenom-
enon has been published.19

5704
C. Marchi et al. / Tetrahedron 58 "2002) 5699±5708
3. Conclusion
4.2.2. ꢀ2R)-N-ꢀ3-Oxooctadecanoyl)bornane-10,2-sultam
ꢀ3). The title compound was prepared as an oil &61%
20
Nickel&salycilaldehydate)2 catalyses useful Michael addi-
tions of enantiomerically pure acetoacetic and 3-oxostearic
acid derivatives of common chiral auxiliaries &Xop and Xev).
The reduction of the corresponding chiral b-ketoamides can
be carried out in a stereoselective manner using BH3 in the
presence of TiCl4. When using Xop, a dynamic kinetic reso-
lution is observed in this reduction step. Con®gurationally
opposite enantiopure syn-1,2-hydrazinoalcohols have been
obtained using Oppolzer sultam &20S,30R) or Evans oxazo-
lidinone &20R,30S).
yield) following the same procedure as for 5: [a]D ˆ250
&cˆ1.08, CHCl3). IR &®lm) 2924, 2854, 1729, 1694, 1630,
1
1462, 1335 cm21. H NMR &CDCl3, 250 MHz) d 0.88 &t,
Jˆ6.5 Hz, 3H), 0.96 &s, 3H), 0.97 &s, 3H enol), 1.16 &s, 3H),
1.17 &s, 3H enol), 1.26 &s broad, 24H), 1.56 &m, 2H), 1.89±
2.34 &m, 7H), 2.50 &t, Jˆ7.3 Hz, 2H), 3.37 &center AB
system, Jˆ13.8 Hz, 1H), 3.50 &center AB system,
Jˆ13.8 Hz, 1H), 3.64 &d, Jˆ16.8 Hz, 1H), 3.88 &q,
Jˆ4.0 Hz, 1H), 4.01 &d, Jˆ16.8 Hz, 1H), 5.63 &s, enol),
8.73 &s, enol). 13C NMR &CDCl3, 250 MHz) d 14.0, 19.8,
20.8, 22.8, 23.3, 26.4, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.6
&4C), 29.4, 31.8, 32.6, 37.9, 43.1, 44.8, 47.7, 48.5, 49.9,
52.6, 64.9, 164.8, 202.3. Anal. calcd for C28H49NO4S: C,
67.84;H, 9.96;N, 2.83;S, 6.47. Found: C, 67.93;H,
10.07;N, 2.76;S, 5.17.
4. Experimental
4.1. General
4.3. General method for preparation of compounds 2b
and c, 4, 6a±d
Melting points were determined with a Ko¯er apparatus and
are uncorrected. IR spectra were recorded with a Nicolet
FT-IR 510 ZDX. NMR spectra were recorded with a Bruker
AC 250 or a Bruker AM 244. 1H NMR chemicals shifts are
reported relative to tetramethylsilane at dˆ0.0. 13C NMR
chemical shifts are expressed relative to tetramethylsilane at
dˆ0.0. Mass spectra were obtained with a Hewlett±Packard
5989A spectrometer and determined at an ionizing voltage
of 70 eV. Elemental analyses were performed at the `Servei
4.3.1. ꢀ2R,20R)-N-{20-[N,N0-Bisꢀethyloxycarbonyl)hydra-
zino]-30-oxobutanoyl}bornane-10,2-sultam
ꢀꢀR)-2b).
Ethylazodicarboxylate &0.418 g, 2.40 mmol) was added to
a mixture of 1 &0.600 g, 2.00 mmol) and Ni&salicylalde-
hyde)2±2H2O &0.067 g, 0.20 mmol, 0.06 M) in 1,2-dichloro-
ethane &3.3 ml) at 358C under magnetic stirring during 48 h.
The resulting solution was washed with 1 M hydrochloric
acid and water. The organic layer was dried and evaporated.
The resulting oil was a diastereomeric mixture of &R)-2b and
&S)-2b in a ratio 92:8 &84% de). The residue was puri®ed by
chromatography through silica-gel using hexanes/diethyl-
ether &50:50) as eluent to give 0.567 g &60%) of the major
diastereoisomer of &R)-2b as a solid, mp 58±608C:
Á
 Á
d'Analisi Quõmica de la Universitat Autonoma de
Barcelona'.
4.2. General method for preparation of compounds 3
and 5
20
4.2.1. ꢀ4S)-N-ꢀ3-Oxooctadecanoyl}-4-benzyloxazolidin-
2-one ꢀ5). Meldrum's acid &2.00 g, 13.8 mmol), dimethyl-
aminopyridine &0.34 g, 2.7 mmol) and anhydrous pyridine
&2.23 ml, 27.6 mmol) were dissolved in anhydrous dichloro-
methane &50 ml) with stirring under nitrogen atmosphere.
The solution was cooled to 08C and palmitoyl chloride
&3.53 ml, 20.7 mmol) was then added to the mixture. The
mixture was stirred for 2 h at 08C and for 15 h at room
temperature. The solvent was evaporated off and &4S)-4-
benzyl-2-oxazolidinone &3.67 g, 20.7 mmol) was added to
the residue. The mixture was dissolved in anhydrous toluene
and was re¯uxed with stirring for 5 h. The solvent was
evaporated and the residue was chromatographed through
silica-gel. Compound 5 was eluted with hexanes/ethyl
acetate &80:20) and obtained as an orange solid &3.51 g,
[a]D ˆ61.2 &cˆ0.85, CHCl3). IR &KBr) 3446, 1738,
1700, 1331, 1223 cm21 1H NMR &d6-benzene, 336 K,
.
250 MHz) d 0.46 &s, 3H), 0.68±0.87 &m, 2H), 0.91 &t,
Jˆ7.3 Hz, 3H), 1.02 &t, Jˆ7.3 Hz, 3H), 1.06 &s, 3H),
1.24±1.41 &m, 3H), 1.81 &dd, Jˆ13.9, 8.0 Hz, 1H), 2.26
&dq, Jˆ13.9, 5.1 Hz, 1H), 2.50 &s, 3H), 2.77 &center of AB
system, 2H), 3.56 &dd, Jˆ8.0, 5.1 Hz, 1H), 3.92 &dt, Jˆ7.3,
5.1 Hz, 2H), 4.03 &dd, Jˆ9.5, 7.3 Hz, 2H), 6.51 &s, 1H);MS-
NH3 &m/z, %): 474 &4) [M111], 249 &71), 233 &100), 216
&93). 13C NMR &d6-benzene, 336 K, 62.5 MHz) mixture of
conformational isomers d 14.7, 14.8, 20.3, 20.4, 20.7, 20.8,
27.2, 33.1, 38.3, 38.5, 38.7, 45.5, 48.5, 49.6, 52.8, 52.9,
53.1, 62.3, 62.5, 62.7, 63.9, 64.2, 65.4, 65.5, 71.0, 71.1,
156.6, 157.0, 168.2, 198.4. Anal. calcd for C20H31N3O8S:
C, 50.71;H, 6.60;N, 8.91;S, 6.78. Found: C, 50.78;H, 6.56;
N, 8.72;S 6.05.
20
51% yield), mp 50±518C: [a]D ˆ37 &cˆ0.98, CHCl3). IR
&KBr) 2925, 2854, 1792, 1715, 1694, 1398, 1356, 1328,
1
1229, 1187 cm21. H NMR &d6-benzene, 400 MHz) d 0.89
4.3.2. ꢀ2R,20R)-N-{20-[N,N0-Bisꢀtert-butyloxycarbonyl)-
hydrazino]-30-oxobutanoyl}bornane-10,2-sultam ꢀꢀR)-
2c). The title compound was prepared as a solid &66%
yield), mp 66±698C, following the same procedure as for
&t, Jˆ7.0 Hz, 3H), 1.22±1.32 &m, 24H), 1.57 &t, Jˆ7.0 Hz,
2H), 2.25 &dt, Jˆ7.0, 1.2 Hz, 2H), 2.44 &dd, Jˆ11.4, 9.4 Hz,
1H), 3.14 &dd, Jˆ13.7, 3.2 Hz, 1H), 3.25 &t, Jˆ8.5 Hz, 1H),
3.46 &dd, Jˆ9.1, 1.8 Hz, 1H), 3.82 &s, 2H), 4.21±4.26 &m,
1H), 6.87 &d, Jˆ6.7 Hz, 2H), 6.98±7.06 &m, 3H). 13C NMR
&CDCl3, 62.5 MHz) d 14.1, 22.6, 23.3, 29.0, 29.3, 29.4, 29.6
&7C), 31.9, 37.7, 42.9, 50.5, 54.9, 66.3, 127.3, 128.9 &2C),
129.4 &2C), 135.1, 153.6, 166.7, 203.4. ESI-MS &m/z):
458.53 &M11)1, 480.49 &M1Na)1, 496.46 &M1K)1.
Anal. calcd for C28H43O4N: C, 73.48;H, 9.47;N, 3.06.
Found: C, 73.58;H, 9.57;N, 3.10.
20
2b: [a]D ˆ56.1 &cˆ0.82, CHCl3). IR &KBr) 3412, 1738,
1705, 1334, 1157 cm21 1H NMR &d6-benzene, 336 K,
.
250 MHz) d 0.46 &s, 3H), 0.68±0.84 &m, 2H), 1.06 &s,
3H), 1.31 &s, 9H), 1.23±1.38 &m, 3H), 1.43 &s, 9H), 1.80
&dd, Jˆ13.9, 7.3 Hz, 1H), 2.25 &dq, Jˆ13.9, 3.7 Hz, 1H),
2.49 &s, 3H), 2.76 &center of AB system, Jˆ13.9, 2.77 Hz,
2H), 3.53 &dd, Jˆ7.3, 4.4 Hz, 1H), 6.44 &s, 1H). 13C NMR
&d6-benzene, 336 K, 250 MHz) mixture of conformational

C. Marchi et al. / Tetrahedron 58 "2002) 5699±5708
5705
isomers d 20.3, 20.5, 20.8, 20.9, 27.2, 28.8, 33.1, 38.3, 38.5,
38.7, 45.5, 48.5, 49.6, 52.8, 53.0, 53.2, 65.5, 65.7, 71.2,
71.5, 81.5, 83.5, 155.7, 155.8, 168.4, 198.6. Anal. calcd
for C24H39N3O8S: C, 54.41;H, 7.42;N, 7.97;S, 6.05.
Found: C, 54.69;H, 7.49;N, 7.78;S, 5.36.
stirring during 17 h. No puri®cation was required before
performing the next reaction. An aliquot was puri®ed by
chromatography through silica-gel using mixtures of
hexanes/ethylacetate as eluent to obtain a mixture of dia-
stereoisomers: IR &®lm) 3289, 2924, 2853, 1785, 1750,
1714, 1693, 1384, 1328, 1215 cm21. 1H NMR &d6-benzene,
360 K, 250 MHz) d 0.89 &t, Jˆ7 Hz, 3H), 0.95±1.06 &m,
6H), 1.29 &s broad, 24H), 1.75±1.91 &m, 2H), 2.38±2.52
&m, 1H), 2.81±3.06 &m, 2H), 3.21±3.51 &m, 3H), 3.92±
4.07 &m, 4H), 4.09±4.28 &m, 1H), 6.83±6.91 &m, 2H),
6.99±7.07 &m, 3H), 7.24 &s broad, 1H). 13C NMR &d6-ben-
zene, 336 K, 62.5 MHz) d 14.7 &2C), 14.8, 14 9, 23.5 &2C),
24.3 &2C), 30.0 &2C), 30.3 &2C), 30.4 &2C), 30.5 &2C), 30.6
&2C), 30.7 &2C), 32.9 &2C), 38.3, 38.4, 41.7, 41.8, 55.8 &2C),
62.6 &2C), 64.2 &2C), 67.5, 67.6, 70.8, 71.8, 127.8, 128.0,
129.6, 129.7, 130.2 &2C), 135.9, 136.5, 154.2, 154.4, 156.5,
157.5, 169.6, 169.8, 201.9, 202.1. ESI-MS &m/z): 632.57
[M11]1, 654.54 [M1Na]1, 670.48 [M1K]1. Anal. calcd
for C34H53N3O8: C, 64.64;H, 8.45;N, 6.65. Found: C,
64.72;H, 8.34;N, 6.47.
4.3.3. ꢀ2R,20R)-N-{20-[N,N0-Bisꢀbenzyloxycarbonyl)hydra-
zino]-30-oxooctadecanoyl}bornane-10,2-sultam ꢀꢀ20R)-
4). The title compound was prepared as a liquid following
the same procedure as for 2b, but in this case the reaction
was carried out at room temperature and under stirring
during 18 h. No puri®cation was required before performing
the next reaction. Only an aliquot was puri®ed. IR &®lm)
3330, 2924, 2854, 1734, 1699, 1332, 1218, 1157, 739,
1
697 cm21. H NMR &CDCl3, 336 K, 250 MHz) d 0.46 &s,
3H), 0.72±0.79 &m, 3H), 0.83 &t, Jˆ7.3 Hz, 3H), 1.06 &s,
3H), 1.27±1.38 &m, 28H), 1.65±175 &m, 2H), 1.81 &dd,
Jˆ13.9, 8.0 Hz, 1H), 2.27 &dq, Jˆ13.9, 3.7 Hz, 1H), 2.49
&s, 3H), 2.72 &part B of AB system, Jˆ13.9 Hz, 1H), 2.82
&part A of AB system, Jˆ13.9 Hz, 1H), 3.53 &dd, Jˆ8.0,
5.1 Hz, 1H), 4.94±5.13 &m, 4H), 6.57 &s, 1H), 7.04±7.23 &m,
10H), 7.35 &s, 1H). 13C NMR &CDCl3, 336 K, 62.5 MHz)
mixture of conformers 20.2 and 20.4, 20.8, 20.9, 23.5, 27.1,
29.9, 30.3, 30.4, 30.5, 30.6, 30.7, 32.9, 36.7, 42.0, 45.5,
48.5, 49.6, 53.0, 65.5 and 65.7, 68.2 and 68.3, 68.4, 68.5,
69.8 and 69.9, 70.0, 128.0, 128.2, 128.6, 128.9, 129.0,
129.2, 136.5, 137.2, 156.5 and 157.0, 168.3, 201.0. Anal.
calcd for C44H63N3O8S: C, 66.55;H, 8.00;N, 5.29;S, 4.04.
Found: C, 66.99;H, 8.14;N, 5.04, S, 3.63.
4.3.6. ꢀ4S)-N-{20-[N,N0-Bisꢀtert-butyloxycarbonyl)hydra-
zino]-30-oxooctadecanoyl}-4-benzyloxazolidin-2-one
ꢀꢀ20R)-6c and ꢀ20S)-6c). The title compound was prepared
as an oil following the same procedure as for 2b, but in this
case the reaction was carried out at 508C and under stirring
during 48 h. The crude was puri®ed by chromatography
through silica-gel using mixtures of hexanes/ethylacetate
as eluent to obtain a mixture of diastereoisomers &63%
yield). Pure ®rst eluted diastereoisomer: IR &®lm) 3368,
2925, 2854, 1785, 1740, 1723, 1703, 1392, 1368,
4.3.4. ꢀ4S)-N-{20-[N,N0-Bisꢀbenzyloxycarbonyl) hydra-
zino]-30-oxooctadecanoyl}-4-benzyloxazolidin-2-one
ꢀꢀ20R)-6a and ꢀ20S)-6a). The title compounds were prepared
as oils following the same procedure as for 2b, but in this
case, the reaction was carried out at room temperature and
under stirring during 18 h. No puri®cation was required
before performing the next reaction. An aliquot was puri®ed
by chromatography through silica-gel using mixtures of
hexanes/ethylacetate as eluent to obtain a mixture of dia-
stereoisomers: IR &®lm) 3332, 2924, 2854, 1785, 1757,
1153 cm21 1H NMR &d6-benzene, 360 K, 250 MHz) d
.
0.88 &t, Jˆ6.8 Hz, 3H), 1.29 &s broad, 24H), 1.37 &s, 9H),
1.43 &s, 9H), 1.68±1.88 &m, 2H), 2.43 &dd, Jˆ13.6, 8.8 Hz,
1H), 2.84±2.97 &m, 2H), 3.25±3.33 &m, 1H), 3.37 &t,
Jˆ8.8 Hz, 1H), 3.48 &dd, Jˆ8.9, 3.0 Hz, 1H), 4.20±4.29
&m, 1H), 6.84±6.87 &m, 2H), 6.97±7.10 &m, 3H), 7.11 &s,
1H). 13C NMR &d6-benzene, 336 K, 250 MHz) d 14.7, 23.6,
24.3, 28.7 &3C), 28.9 &3C), 30.0, 30.3, 30.4, 30.5, 30.6, 30.7
&5C), 32.9, 38.4, 41.6, 55.9, 67.5, 72.1, 81.5, 83.3, 128.0,
129.6 &2C), 130.2 &2C), 136.1, 154.4, 155.6, 156.4, 170.0,
202.5. Anal. calcd for C38H61N3O8: C, 66.35;H, 8.94;N,
6.11. Found: C, 65.94;H 9.08;N, 5.98. Pure second dia-
stereoisomer: IR &®lm) 3369, 2925, 2853, 1785, 1744, 1727,
1703, 1393, 1368, 1153 cm21. 1H NMR &d6-benzene, 360 K,
250 MHz) d 0.88 &t, Jˆ6.8 Hz, 3H), 1.29 &s broad, 24H),
1.37 &s, 9H), 1.44 &s, 9H), 1.68±1.93 &m, 2H), 2.47 &dd,
Jˆ13.8, 10 Hz, 1H), 2.88±3.01 &m, 2H), 3.22±3.40 &m,
2H), 3.48 &dd, Jˆ8.6, 2.7 Hz, 1H), 4.09±4.12 &m, 1H),
6.16 &s broad, 1H), 6.88 &d, Jˆ7.0 Hz, 2H), 6.98±7.07 &m,
3H), 7.11 &s, 1H). 13C NMR &d6-benzene, 336 K, 250 MHz)
d 14.7, 23.6, 24.3, 28.7 &3C), 28.9 &3C), 30.0, 30.3, 30.4,
30.5, 30.6, 30.7 &5C), 32.9, 38.4, 41.6, 55.8, 67.4, 72.2, 81.5,
83.3, 128.0, 129.6 &2C), 130.2 &2C), 136.6, 154.2, 155.6,
156.4, 170.0, 202.3.
1722, 1701, 1215 cm21 1H NMR &d6-benzene, 360 K,
.
250 MHz) d 0.89 &t, Jˆ6.9 Hz, 3H13H), 1.29 &s broad,
24H124H), 1.67±1.87 &m, 2H12H), 2.30±2.35 &m, 1H),
2.44 &dd, Jˆ13.8, 9.5 Hz, 1H), 2.79 &dd, Jˆ13.2, 2.7 Hz,
1H), 2.86±3.03 &m, 1H11H), 3.18±3.49 &m, 3H13H),
4.03±4.13 &m, 1H), 4.17±4.24 &m, 1H), 4.89±5.15 &m,
4H14H), 6.18±7.08 &m, 15H115H), 7.37 &s broad,
1H11H). 13C NMR &d6-benzene, 336 K, 62.5 MHz) d
14.7 &2C), 23.5 &2C), 24.2 &2C), 29.9 &2C), 30.2 &2C), 30.4
&2C), 30.4 &2C), 30.5 &2C), 30.6 &2C), 30.7 &2C), 32.8 &2C),
38.3, 38.4, 41.8 &2C), 55.8 &2C), 67.6 &2C), 68.4 &2C), 69.8
&2C), 70.9, 71.8, 127.9±130.3 &30C), 136.0, 136.4, 136.7,
136.8, 137.0 &2C), 154.3, 154.4, 156.6 &2C), 157.4 &2C),
169.3, 169.5, 201.7, 201.9. ESI-MS: 756.37 [M11]1,
778.40 [M1Na]1, 794.38 [M1K]1. Anal. calcd for
C44H57N3O8: C, 69.91;H, 7.59;N, 5.56. Found: C, 69.73;
H, 7.57;N, 5.36.
4.3.7. ꢀ4S)-N-{20-[N,N0-Bisꢀtri¯uoroethyloxycarbonyl)-
hydrazino]-30-oxooctadecanoyl}-4-benzyloxazolidin-2-
one ꢀꢀ20R)-6d and ꢀ20S)-6d). The title compounds were
prepared as oils following the same procedure as for 2b,
but in this case the reaction was carried out at room tempera-
ture and under stirring during 18 h. No puri®cation was
required before performing the next reaction. An aliquot
4.3.5. ꢀ4S)-N-{20-[N,N0-Bisꢀethyloxycarbonyl)hydrazino]-
30-oxooctadecanoyl}-4-benzyloxazolidin-2-one ꢀꢀ20R)-6b
and ꢀ20S)-6b). The title compounds were prepared as oils
following the same procedure as for 2b, but in this case the
reaction was carried out at room temperature and under

5706
C. Marchi et al. / Tetrahedron 58 "2002) 5699±5708
was puri®ed by chromatography through silica-gel using
mixtures of hexanes/ethylacetate as eluent to obtain a
mixture of diastereoisomers: IR &®lm) 3306, 2921, 2853,
Jˆ13.9, 8.0 Hz, 1H), 2.00 &dq, Jˆ13.9, 3.7 Hz, 1H), 2.78
&center of AB system, Jˆ24.9, 13.9 Hz, 2H), 3.64 &dd,
Jˆ8.0, 5.1 Hz, 1H), 4.46 &broad s, 1H), 4.64 &sext,
Jˆ5.9 Hz, 1H), 4.94 &center of AB system, Jˆ17.5,
12.4 Hz, 2H), 5.15 &center of AB system, Jˆ18.3,
12.4 Hz, 2H), 5.63 &d, Jˆ7.3 Hz, 1H), 7.03±7.30 &m,
10H); 13C NMR &d6-benzene, 336 K, 250 MHz) d &mixture
of conformers) 20.2 and 20.3, 21.2 and 21.3, 27.1, 33.2, 38.6
and 38.8, 39.0, 45.6, 48.5, 49.3, 53.6, 65.9, 66.1, 67.5 and
67.8, 68.7 and 68.8, 68.9, 69.5, 128.8, 129.1, 129.2, 136.9,
137.2, 156.9, 158.5, 169.8. Calcd for C30H37N3O8S: C,
60.08;H, 6.22;N, 7.01;S, 5.35. Found: C, 60.43;H, 6.13;
N, 6.97;S, 5.14.
1
1784, 1752, 1728, 1702, 1395, 1275, 1210 cm21. H NMR
&d6-benzene, 360 K, 250 MHz) d 0.94 &t, Jˆ6.8 Hz, 3H),
1.33 &s broad, 24H), 1.71±1.93 &m, 2H), 2.46±2.58 &m,
1H), 2.93±3.09 &m, 1H), 3.21±3.33 &m, 3H), 3.45±3.63
&m, 1H), 4.27±4.35 &m, 1H), 4.54±4.63 &m, H), 6.86±7.22
&m, 5H), 7.72 &broad s, 1H). 13C NMR &d6-benzene, 336 K,
250 MHz) d 14.7 &2C), 23.5 &2C), 24.2 &2C), 30.0 &2C), 30.3
&2C), 30.4 &2C), 30.6 &2C), 32.8 &2C), 38.3 &2C), 41.9 &2C),
55.9 &2C), 67.7, 67.9, 70.7, 71.5, 76.1 &2C), 77.1 &2C), 95.7,
95.9, 128.0 &2C), 129.6 &2C), 129.7 &2C), 130.1 &2C), 130.2
&2C), 135.8, 136.2, 154.2, 154.4, 154.7, 155.6, 168.7, 168.9,
200.8, 201.1. Anal. calcd for C34H47N3O8Cl6: C, 48.70;H,
5.65;N, 5.01;Cl, 25.37. Found: C, 48.80;H, 5.81;N, 4.81;
Cl, 25.74.
4.4.3. ꢀ2R,20S,30R)-N-{2-[N-tert-Butyloxycarbonylhydra-
zino]-3-hydroxybutanoyl}bornane-10,2-sultam ꢀꢀ20S,
30R)-7c). The title compound was prepared following the
same procedure as for 7b, but in this case was puri®ed by
chromatography through silica-gel using mixtures of
hexanes/diethylether &2:3). The unique alcohol was
obtained as a white solid in 32% yield &yield corresponding
to the two consecutive steps, Michael addition and reduc-
4.4. General method for preparation of compounds 7a±c
4.4.1. ꢀ2R,20S,30R)-N-{2-[N,N0-Bisꢀethyloxycarbonyl)hy-
drazino]-3-hydroxybutanoyl}bornane-10,2-sultam ꢀꢀ20S,
20
30R)-7b).
A diasteromeric mixture of 2b &0.476 g,
tion), mp 180±1828C: [a]D ˆ251.7 &cˆ0.58, CHCl3). IR
&KBr) 3400, 3306, 3268, 2976, 1728, 1686, 1334, 1277,
1.00 mmol) was dissolved in anhydrous dichloromethane
with stirring and under nitrogen atmosphere. The solution
was cooled to 2238C and a 1 M solution of TiCl4 in CH2Cl2
&1.2 ml, 1.2 mmol) was added. Followed by an immediate
slow addition of a 10 M solution of BH3±Me2S in CH2Cl2
&100 ml, 1 mmol). The resulting mixture was stirred at
2238C during 10 min. Then 1 M HCl was added and the
organic layer was washed with a saturated solution of NaCl
in H2O. The organic layer was then dried, evaporated and
puri®ed by chromatography on silica-gel, eluting with
hexanes/diethylether &3:7). The unique alcohol &20S,30R)-
7b was obtained a solid in 65% yield, mp 103±1058C:
1
1139, 1111 cm21. H NMR &d6-benzene, 336 K, 250 MHz)
d 0.48 &s, 3H), 0.73±0.91 &m, 2H), 0.98 &s, 3H), 1.19±1.38
&m, 3H), 1.31 &d, Jˆ5.9 Hz, 3H), 1.41 &s, 9H), 1.85 &dd,
Jˆ13.9, 8.0 Hz, 1H), 2.00 &dq, Jˆ13.9, 5.1 Hz, 1H), 2.81
&center of AB system, Jˆ24.1, 13.9 Hz, 2H), 3.67 &dd,
Jˆ8.0, 5.1 Hz, 1H), 4.19±4.23 &m, 2H), 4.65 &broad s,
1H), 6.02 &broad s, 1H)). 13C NMR &d6-benzene, 336 K,
62.5 MHz) d &mixture of conformers) 20.1 and 20.2, 20.3,
21.2, 21.4, 27.1, 29.0, 33.4, 39.1, 45.7, 48.3, 49.0, 53.6,
53.7, 66.0, 66.1, 68.2, 68.5, 70.6, 70.9, 80.9, 157.6, 172.3.
Calcd for C19H33N3O6S: C, 52.88;H, 7.71;N, 9.74;S, 7.43.
Found: C, 53.12;H, 7.47;N, 9.42;S, 7.00.
20
[a]D ˆ263.5 &cˆ0.63, CHCl3). IR &KBr) 3415, 3378,
3295, 2980, 2962, 2933, 1733, 1710, 1686, 1333,
4.4.4. ꢀ2R,20S,30R)-N-{2-[N,N0-Bisꢀbenzyloxycarbonyl)-
hydrazino]-3-hydroxyoctadecanoyl}bornane-10,2-sultam
ꢀꢀ20S,30R)-8). The title compound was prepared as an oil
following the same procedure as for 7b but in this case
the reaction was stirred at 2238C during 25 min. The resi-
due was puri®ed by chromatography through silica-gel
using dichloromethane and an unique alcohol was obtained
1219 cm21 1H NMR &d6-benzene, 336 K, 250 MHz) d
.
0.56 &s, 3H), 0.90±1.50 &m, 5H), 1.07 &s, 3H), 1.21 &t,
Jˆ7.3 Hz, 3H), 1.56 &t, Jˆ7.3 Hz, 3H), 1.96 &dd, Jˆ13.9,
8.0 Hz, 1H), 2.09 &dq, Jˆ13.9, 3.7 Hz, 1H), 2.91 &center of
AB system, Jˆ25.6, 13.2 Hz, 2H), 3.76 &dd, Jˆ7.3, 5.1 Hz,
1H), 4.03 &m, 2H), 4.19 &m, 2H), 4.62±4.85 &m, 2H), 5.69
&d, Jˆ6.6 Hz, 1H). 13C NMR &d6-benzene, 336 K,
62.5 MHz) d 14.7, 14.8, 20.2, 20.3, 21.0, 21.1, 27.1, 33.2,
38.7, 38.8, 39.0, 45.5, 48.4, 49.1, 53.4, 53.5, 53.6, 62.8,
63.1, 63.3, 63.9, 64.2, 65.9, 66.1, 67.6, 68.6, 157.0, 158.7,
170.3. MS-NH3 &m/z, %): 476 &4) [M111], 4), 432 &68), 271
&100), 233 &95).
20
in 47% yield: [a]D ˆ226.4 &cˆ1.06, CHCl3). IR &®lm)
3446, 3304, 2926, 2853, 1785, 1718, 1703, 1407, 1388,
1217 cm21 1H NMR &d6-benzene, 343 K, 250 MHz) d
.
0.47 &s, 3H), 0.79±0.90 &m, 3H), 0.81 &t, Jˆ6.8 Hz, 3H),
1.00 &s, 3H), 1.22±1.32 &m, 28H), 1.40±2.02 &m, 4H), 2.81
&part A, AB system, Jˆ13.8 Hz, 1H), 2.87 &part B, AB
system, Jˆ13.8 Hz, 1H), 3.68 &dd, Jˆ7.5, 5.0 Hz, 1H),
4.42±4.47 &m, 1H), 4.85 &part A, AB system, Jˆ12.5 Hz,
1H), 4.93 &part B, AB system, Jˆ12.5 Hz, 1H),), 5.04 &part
A, AB system, Jˆ12.3 Hz, 1H), 5.13 &part B, AB system,
Jˆ12.3 Hz, 1H), 5.63 &d, Jˆ6.6 Hz, 1H), 6.95±7.27 &m,
10H). 13C NMR &d6-benzene, 343 K, 250 MHz) d 14.7,
20.3, 21.2, 23.6, 26.8, 27.1, 30.3, 30.5, 30.6 &2C), 30.7
&7C), 32.8, 33.2, 34.7, 38.8, 45.6, 48.5, 49.2, 53.6, 66.0,
68.0, 68.7, 69.6, 71.7, 128.8 &4C), 129.1 &4C), 129.2 &2C),
137.0, 137.2, 157.1, 158.3, 170.1. MALDI-TOF MS &m/z):
820.1 [M1Na]1, 836.1 [M1K]1. Calcd for C44H65N3O8S:
C, 66.39;H, 8.23;N, 5.28;S, 4.03. Found: C, 66.41;H, 8.13;
N, 5.53;S, 4.16.
4.4.2. ꢀ2R,20S,30R)-N-{2-[N,N0-Bisꢀbenzyloxycarbonyl)-
hydrazino]-3-hydroxybutanoyl}bornane-10,2-sultam
ꢀꢀ20S,30R)-7a). The title compound was prepared following
the same procedure as for 7b, but in this case was puri®ed by
chromatography through silica-gel using mixtures of
hexanes/ethylacetate &2:3). The unique alcohol was
obtained as a white solid in 67% yield &yield corresponding
to the two consecutive steps, Michael addition and reduc-
20
tion), mp 177±1788C: [a]D ˆ243.1 &cˆ1.00, CHCl3). IR
&KBr) 3435, 3321, 2961, 1735, 1728, 1723, 1691, 1335,
1217, 748, 700 cm21
;
1H NMR &d6-benzene, 336 K,
250 MHz) d 0.46 &s, 3H), 0.75±0.91 &m, 2H), 0.97 &s,
3H), 1.15±1.36 &m, 3H), 1.44 &d, Jˆ5.9 Hz, 3H), 1.84 &dd,

C. Marchi et al. / Tetrahedron 58 "2002) 5699±5708
5707
4.4.5. ꢀ2R,20S,30R)-N-{2-[N,N0-Bisꢀbenzyloxycarbonyl)-
hydrazino]-3-hydroxyoctadecanoyl}bornane-10,2-sultam
ꢀꢀ20R,30S)-8)). The title compound was isolated as the minor
diastereoisomer from reduction of compound 4:
case the reaction was stirred at 2238C during 3 h. The resi-
due was puri®ed by chromatography through silica-gel
using dichloromethane. The major diastereoisomer
20
&20R,30S)-9a was obtained in 36% yield: [a]D ˆ21.4
20
[a]D ˆ211 &cˆ1.01, CHCl3). IR &®lm) 3437, 3318,
&cˆ1.15, CHCl3). IR &®lm) 3446, 3304, 2926, 2853, 1785,
1718, 1703, 1407, 1388, 1217 cm21. 1H NMR &d6-benzene,
343 K, 250 MHz) d 0.99 &t, Jˆ6.8 Hz, 3H), 1.40 &broad s,
24H), 1.54±2.02 &m, 4H), 2.57 &dd, Jˆ13.4, 9.6 Hz, 1H),
3.20 &dd, Jˆ13.4, 3.2 Hz, 1H), 3.57±3.82 &m, 2H), 4.32±
4.40 &m, 1H), 4.53±4.55 &m, 1H), 5.02±5.24 &m, 4H), 6.43
&d, Jˆ6.1 Hz, 1H), 7.03±7.35 &m, 15H), 7.51 &broad s, 1H).
13C NMR &d6-benzene, 343 K, 62.5 MHz) d 14.2, 23.0,
26.4, 29.7, 30.0, 30.1 &8C), 32.3, 34.1, 38.2, 55.7, 64.8,
66.6, 68.1, 69.0, 71.1, 127.4, 128.3 &2C), 128.5 &2C),
128.7 &2C), 128.8 &2C), 129.1 &2C), 129.7 &2C), 135.9,
136.5, 153.0, 156.9, 157.3, 171.1. Calcd for C44H59N3O8:
C, 69.91;H, 7.59;N, 5.56. Found: C, 69.73;H, 7.57;N,
5.36. The minor diastereoisomer &4S,20S,30R)-N-{20-[N,N0-
bis&benzyloxycarbonyl)hydrazino]-30-hydroxyoctadecanoyl}-
4-benzyloxazolidin-2-one, &20S,30R)-9a was obtained in 3%
1
2924, 2853, 1734, 1719, 1691, 1335, 1215 cm21. H NMR
&d6-benzene, 343 K, 250 MHz) d 0.44 &s, 3H), 0.69±0.82
&m, 3H), 0.80 &t, Jˆ6.6 Hz, 3H), 0.94 &s, 3H), 1.21±1.34
&m, 28H), 1.43±2.08 &m, 4H), 2.72 &part A, AB system,
Jˆ13.6 Hz, 1H), 2.81 &part B, AB system, Jˆ13.6 Hz,
1H), 3.69 &dd, Jˆ7.3, 4.7 Hz, 1H), 4.40±4.50 &m, 1H),
4.87 &broad s, 2H), 4.98 &part A, AB system, Jˆ12.5 Hz,
1H), 5.05 &part B, AB system, Jˆ12.5 Hz, 1H),), 5.20 &d,
Jˆ7.5 Hz, 1H), 6.94±7.19 &m, 10H), 7.18 &broad s, 1H). 13C
NMR &d6-benzene, 343 K, 250 MHz) d 14.7, 20.3, 21.7,
23.6, 26.8, 27.0, 30.3, 30.6, 30.7 &8C), 32.8, 33.7, 35.2,
39.2, 46.1, 48.3, 49.0, 53.7, 66.6, 67.9, 68.8, 69.5, 70.4,
128.8 &4C), 128.9 &4C), 129.2 &2C), 136.9, 137.1, 156.5,
158.4, 18.8.
20
4.4.6. ꢀ4S,20R,30S)-N-{20-[N,N0-Bisꢀethyloxycarbonyl)hy-
drazino]-30-hydroxyoctadecanoyl}-4-benzyloxazolidin-
2-one ꢀꢀ20R,30S)-9b). The title compound was prepared as
an oil following the same procedure as for 7b but in this case
the reaction was stirred at 2238C during 1.30 h. The residue
was puri®ed by chromatography through silica-gel using
dichloromethane. The major diastereoisomer &20R,30S)-9b
yield: [a]D ˆ6.6 &cˆ0.91, CHCl3). IR &®lm) 3451, 2926,
1
2853, 1785, 1718, 1386, 1216, 1113 cm21. H NMR &d6-
benzene, 343 K, 250 MHz) d 0.88 &t, Jˆ6.8 Hz, 3H), 1.30
&broad s, 24H), 1.56±1.90 &m, 4H), 2.26 &dd, Jˆ13.4,
9.6 Hz, 1H), 3.02 &dd, Jˆ13.4, 3.5 Hz, 1H), 3.32±3.39 &m,
1H), 3.51 &dd, Jˆ8.9, 3.5 Hz, 1H), 4.16±4.25 &m, 1H),
4.40±4.42 &m, 1H), 4.98±5.14 &m, 4H), 6.25 &d,
Jˆ6.3 Hz, 1H), 6.85±7.24 &m, 16H). 13C NMR &d6-benzene,
343 K, 62.5 MHz) d 14.7, 23.6, 27.1, 30.3, 30.6, 30.7 &8C),
32.9, 34.6, 38.4, 56.3, 66.3, 67.1, 68.8, 69.5, 71.3, 127.9±
130.1 &15C), 136.6, 136.9, 137.1, 153.5, 157.3, 157.9, 171.4.
20
was obtained in 47% yield: [a]D ˆ22.8 &cˆ1.05, CHCl3).
IR &®lm) 3416, 3303, 2924, 2853, 1785, 1700, 1384,
1
1229 cm21. H NMR &d6-benzene, 400 MHz) d 0.89 &t,
Jˆ6.8 Hz, 3H), 0.96 &t, Jˆ7.2 Hz, 3H), 1.00 &t, Jˆ7.2 Hz,
3H), 1.29 &broad s, 24H), 1.55±1.69 &m, 1H), 1.75±1.88 &m,
2H), 1.96±2.03 &m, 1H), 2.41 &dd, Jˆ11.5, 9.6 Hz, 1H), 3.11
&dd, Jˆ13.4, 3.6 Hz, 1H), 3.39 &t, Jˆ8.6 Hz, 1H), 3.52 &dd,
Jˆ8.9, 3.4 Hz, 1H), 3.91±4.08 &m, 4H), 4.20±4.30 &m, 1H),
4.47±4.52 &m, 1H), 6.38 &d, Jˆ6.1 Hz, 1H), 6.90 &dd, Jˆ7.9,
1.9 Hz, 2H), 7.00±7.10 &m, 3H). 13C NMR &CDCl3,
62.5 MHz) d 14.7, 14.8, 14.9, 23.6, 27.0, 30.3, 30.6 &8C),
30.7, 32.9, 34.6, 38.7, 56.2, 62.9, 63.9, 65.4, 66.9, 71.6,
128.0, 129.6 &2C), 130.2 &2C), 136.4, 153.5, 157.6, 158.0,
172.0. Calcd for C34H55N3O8: C, 64.43;H, 8.75;N, 6.63.
Found: C, 64.41;H, 8.72;N, 6.51. The minor diastereo-
isomer &4S,20S,30R)-N-{20-[N,N0-bis&ethyloxycarbonyl)hy-
drazino]-30-hydroxyoctadecanoyl}-4-benzyloxazolidin-2-
4.4.8. ꢀ4S,20R,30S)-N-{20-[N,N0-Bisꢀtrichloroethyloxycar-
bonyl)hydrazino]-30-hydroxyoyl}-4-benzyloxazolidin-2-
one ꢀꢀ20S,30R)-9d). The title compound was prepared as an
oil following the same procedure as for 7b but in this case
the reaction was stirred at 2238C during 2 h. The residue
was puri®ed by chromatography through silica-gel using
dichloromethane. The major diastereoisomer &20S,30R)-9d
20
was obtained in 43% yield: [a]D ˆ16.0 &cˆ0.95, CHCl3).
IR &®lm) 3481, 3255, 2922, 2852, 1788, 1770, 1746, 1703,
1520, 1378, 1332, 1213, 1109 cm21; 1H NMR &d6-benzene,
343 K, 250 MHz) d 0.99 &t, Jˆ6.9 Hz, 3H), 1.39 &broad s,
24H), 1.64±2.08 &m, 4H), 2.61 &dd, Jˆ13.6, 9.5 Hz, 1H),
3.20 &dd, Jˆ13.6, 3.4 Hz, 1H), 3.75±3.77 &m, 2H), 4.43±
4.53 &m, 2H), 4.60±4.79 &m, 2H), 4.60±4.79 &m, 4H), 6.41
&d, Jˆ5.4 Hz, 1H), 7.07 &d, Jˆ6.4 Hz, 2H), 7.51±7.26 &m,
3H), 7.75 &broad s, 1H). 13C NMR &d6-benzene, 343 K,
62.5 MHz) d 15.0, 23.5, 26.9, 30.2, 30.5, 30.6 &8C), 32.8,
34.7, 38.8, 56.2, 65.5, 67.3, 71.8, 76.1, 77.0, 96.0 &2C),
128.2 &2C), 130.2 &2C), 136.2, 153.6, 155.8 &2C), 171.2.
Calcd for C34H49N3O8Cl6: C, 48.58;H, 5.87;N, 5.00;Cl,
25.31. Found: C, 48.83;H, 5.89;N, 4.89, Cl, 25.28. The
minor diastereoisomer &4S,20S,30R)-N-{20-[N,N0-bis&tri-
chloroethyloxycarbonyl)hydrazino]-30-hydroxyoyl}-4-
benzyloxazolidin-2-one, &20R,30S)-9d was obtained in 21%
20
one, &20S,30R)-9b, was obtained in 13% yield: [a]D ˆ23.3
&cˆ1.20, CHCl3). IR &®lm) 3409, 3310, 2924, 2853, 1785,
1708, 1391, 1215 cm21. 1H NMR &d6-benzene, 400 MHz) d
0.89 &t, Jˆ8.0 Hz, 3H), 0.94 &t, Jˆ7.0 Hz, 3H), 1.00 &t,
Jˆ7.2 Hz, 3H), 1.30 &broad s, 24H), 1.59±1.65 &m, 1H),
1.78±1.80 &m, 2H), 1.93±1.97 &m, 1H), 2.36 &dd, Jˆ13.5,
9.4 Hz, 1H), 3.11 &broad dd, Jˆ13.5 Hz, 1H), 3.28 &t,
Jˆ8.5 Hz, 1H), 3.48 &dd, Jˆ8.8, 2.9 Hz, 1H), 3.93±4.08
&m, 4H), 4.09±4.22 &m, 1H), 4.47±4.49 &m, 1H), 6.30
&broad s, 1H), 7.04 &d, Jˆ7.04 Hz, 2H), 6.99±7.09 &m,
3H). 13C NMR &CDCl3, 62.5 MHz) d 14.7, 14.8, 14.9,
23.6, 27.1, 30.3, 30.6 &8C), 30.7, 32.9, 34.6, 38.6, 56.3,
63.0, 63.9, 66.0, 67.1, 71.1, 128.0, 129.7 &2C), 130.2 &2C),
136.6, 153.5, 157.5, 158.2, 171.5.
20
yield: [a]D ˆ12.0 &cˆ0.97, CHCl3). IR &®lm) 3488, 3391,
1
2925, 2854, 1784, 1736, 1702, 1211, 1109 cm21; H NMR
&d6-benzene, 343 K, 250 MHz) d 0.95 &t, Jˆ6.8 Hz, 3H),
1.36 &broad s, 24H), 1.49±2.09 &m, 4H), 2.53 &dd, Jˆ13.6,
9.7 Hz, 1H), 3.23 &dd, Jˆ13.6, 3.6 Hz, 1H), 3.44±3.73 &m,
2H), 4.26±4.32 &m, 1H), 4.33±4.51 &m, 1H), 4.55±4.75 &m,
4H), 6.37 &d, Jˆ5.4 Hz, 1H), 6.99±7.21 &m, 5H), 7.57
4.4.7. ꢀ4S,20R,30S)-N-{20-[N,N0-Bisꢀbenzyloxycarbonyl)-
hydrazino]-30-hydroxyoctadecanoyl}-4-benzyloxazoli-
din-2-one ꢀꢀ20R,30S)-9a). The title compound was prepared
as an oil following the same procedure as for 7b but in this

5708
C. Marchi et al. / Tetrahedron 58 "2002) 5699±5708
&broad s, 1H). 13C NMR &d6-benzene, 343 K, 62.5 MHz) d
14.7, 23.5, 27.0, 30.2, 30.3, 30.5, 30.6 &7C), 32.8, 34.6, 38.6,
56.4, 66.0, 67.3, 71.5, 76.2, 77.0, 96.0 &2C), 128.1, 129.7
&2C), 130.1 &2C), 136.4, 153.5, 155.8 &2C), 171.0.
Â
1995, 6, 9705±9708. &b) Tan, K.;Alvarez, R.;Nour, M.;Cave ,
C.;Chiaroni, A.;Riche, C.;d'Angelo, J.
2001, 42, 5021±5023.
Tetrahedron Lett.
10. Christoffers, J.;Mann, A. Angew. Chem. Int. Ed. 2000, 39,
2752±2754.
11. Meseguer, M.;Moreno-Man Äas, M.;Vallribera, A.
Tetrahedron Lett. 2000, 41, 4093±4095.
Acknowledgements
  Â
12. Galvez, N.;Moreno-ManÄas, M.;Padro s, I.;Sebastia n, R. M.;
Serra, N.;Vallribera, A. Polyhedron 1995, 14, 1397±1399.
Â
13. Lumbierres, M.;Marchi, C.;Moreno-Man Äas, M.;Sebastia n,
R. M.;Vallribera, A.;Lago, E.;Molins, E. Eur. J. Org. Chem.
2001, 2321±2328.
We acknowledge ®nancial support from MEC of Spain
&project PB98-0902 and predoctoral grant to E. T.), and
CIRIT &Generalitat de Catalunya, projects SGR98-0056
and SGR2000-0062 and postdoctoral grant to C. M.). We
are indebted to Dr Anna Roglans from Universitat de Girona
for performing the ESI-MS experiments.
Â
14. &a) Moreno-ManÄas, M.;Sebastia n, R. M.;Vallribera, A.;
Â
Molins, A. Tetrahedron 1995, 51, 10795±10800. &b) Galvez,
Â
N.;Molins, E.;Moreno-Man Äas, M.;Sebastia n, R. M.;Serra,
N.;Trepat, E.;Vallribera, A. J. Heterocycl. Chem. 2000, 37,
895±905.
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