Synthetic studies of carzinophilin. Part 2: Synthesis of 3,4-dibenzyloxy-2-methylidene-1-azabicyclo[3.1.0]hexane systems corresponding to the C1-C17 fragment of carzinophilin

Article abstract of DOI:10.1016/S0040-4020(03)00378-8

A model compound bearing the C1-C17 fragment of carzinophilin was synthesized. The synthesis involved coupling reaction of a cyclic thioimidate with the 4H-oxazol-5-one derivative, ring-opening of the 4H-oxazol-5-one to furnish a dehydropeptide system, elaboration of the C1-C6 enolamide, and construction of the aziridine ring as key steps.

Full text of DOI:10.1016/S0040-4020(03)00378-8

Tetrahedron 59 (2003) 3041–3062
Synthetic studies of carzinophilin. Part 2: Synthesis of 3,4-
dibenzyloxy-2-methylidene-1-azabicyclo[3.1.0]hexane systems
corresponding to the C1–C17 fragment of carzinophilinq
†
Masaru Hashimoto, Miyoko Matsumoto and Shiro Terashima
,
*
*
Sagami Chemical Research Center, 2743-1, Hayakawa, Ayase, Kanagawa 252-1193, Japan
Received 30 January 2003; accepted 6 March 2003
Abstract—A model compound bearing the C1–C17 fragment of carzinophilin was synthesized. The synthesis involved coupling reaction of
a cyclic thioimidate with the 4H-oxazol-5-one derivative, ring-opening of the 4H-oxazol-5-one to furnish a dehydropeptide system,
elaboration of the C1–C6 enolamide, and construction of the aziridine ring as key steps. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
system (the C1–C6 unit), has not been accomplished
yet. In the course of our synthetic studies on 1, we have
developed a synthetic method providing a (1-aza-
bicyclo[3.1.0]hex-2-ylidene)glycine system.1a,b We have
also reported an efficient and stereoselective synthetic
route to the C6–C13 pyrrolidine framework1c as well as a
synthetic scheme giving the unique C1–C6 enamide
system.1c,d Applying the knowledge accumulated in these
studies, syntheses of the C1–C17 fragment of carzino-
philin (3,4) have been achieved and disclosed in
communication forms.1c,d In the second part of this
series of papers, we would like to report full details of
these studies.
Carzinophilin (1) is an antitumor antibiotic isolated
from Streptomyces sahachiroi by Hata et al. in 1954.3
After the structure elucidation and revisions were repeated
several times, 1 was proved to have the same structure as
azinomycin B,4 which was isolated by Yokoi et al. in 1986
and disclosed to bear a characteristic (1-azabicyclo[3.1.0]-
hex-2-ylidene)glycine system.5 The unique structure as
well as potent bioactivity of 1 attracted chemists to study
its total synthesis.6,7 Recently, Coleman et al. reported
successful total synthesis of 2.8 However, synthesis of 1
carrying another unique 1-acetyl-2-hydroxyenamide
q See refs 1 and 2.
Keywords: carzinophilin; azinomycin; pyrrolidin; (1-azabicyclo[3.1.0.]hex-2-ylidene) glycine; azalactone.
*
Corresponding authors. Tel./fax: þ81-172-35-0869; e-mail: hmasaru@cc.hirosaki-u.ac.jp; terashima@sagami.or.jp
†
Present address: Department of Agriculture and Life Science, Hirosaki University, 3 Bunkyo-Cho, Hirosaki, 036-8561, Japan.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00378-8

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M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
2. Results and discussion
one in a stereoselective manner.9 Considering a selective
deprotection at the later synthetic stages, the (4-methoxy-
phenyl)methyl (MPM) group was selected for protecting the
nitrogen moiety instead of the benzyl group employed by
them. Refluxing commercially available 2,3,5-tri-O-benzyl-
b-D-arabinofuranose (5) with MPMNH2 in toluene under
azeotropic conditions produced the unstable adduct.
Characteristic signals at 4.77 (minor) and 4.85 (major)
ppm in the 1H NMR spectrum of the crude product indicated
that the crude material consists of a mixture of isomeric
N-glycosides 6 but not of the corresponding imines.
According to Nicotra’s procedure,9 crude 6 was directly
reacted with vinylmagnesium bromide to afford an insepar-
able diastereomeric mixture of the adduct 7 in 71% yield in
two steps. The addition of a vinyl group proceeded
stereoselectively (ca. 25:1), but the stereochemistry of the
major product was not assigned at this stage. The
diastereomeric mixture 7 was subjected to PCC oxidation
in the presence of powdered molecular sieves 4A,9 giving
lactam 8 in 71% yield and epi-8 (3%). These isomers were
separated by silica gel column chromatography. The vinyl
group of the major product 8 was transformed into a
2.1. Synthetic strategy
As described in the preceding paper, we have succeeded in
preparing the N-acyl-(1-azabicyclo[3.1.0]hexan-2-ylidene)-
glycine ester system. So, a model compound involving the
C1–C16 fragment I was set as our next synthetic target. Our
basic synthetic strategy is outlined in Scheme 1. Since the
1-azabicyclo[3.1.0]hexane system has been revealed to be
labile, the aziridine ring should be constructed at the final
stage of the synthesis.1a,b Accordingly, (5-hydroxymethyl)-
pyrrolidin-2-ylidene derivative II was anticipated to be a
precursor to the target molecule I. The pyrrolidin-2-ylidene
amino acid moiety was planned to be furnished by coupling
reaction of an anionic species of glycine derivative III with
pyrrolidin-2-one IV. Although we have already accom-
plished the preparation of (pyrrolinylidene)malonate esters
and N-acyl-(pyrrolidin-2-ylidene)glycine esters in our
previous studies,1a,b development of synthetic methodology
for the N-acyl-(pyrrolidin-2-ylidene)glycine amide system
was required in this study. There were no reports about the
procedures for this framework except for studies aiming at
the synthesis of azinomycins (¼carzinophilin) carried out
by Coleman et al. and Armstrong et al.6 The peptide unit III
might be prepared by a coupling of the glycine unit with
1-acetyl-2-hydroxyethenyl amine V or its synthetic
equivalent. It was also necessary to establish a route to V
bearing a structure unprecedented in natural products. The
core pyrrolidine part IV was planned to be synthesized
stereoselectively from D-arabinose applying the protocol
developed by Nicotra et al.9,10
Scheme 1. Synthetic strategy of the C1–C17 fragment of carzinophilin (1).
2.2. Synthesis of the 3,4-dihydroxypyrrolidin-2-one
corresponding to the C8–C13 unit1c
Scheme 2. Synthesis of C8–C13 unit 13. Reagents and conditions:
(a) MPMNH2, toluene. reflux, 12 h. (b) CH2vCHMgBr, THF, 08C!rt,
12 h, 71% 2 steps. (c) PCC, MS4A, CH2Cl2, rt, 4 h, 71%. (d) O3, EtOH,
2258C, 20 min, then NaBH4, 08C 20 min, 98%. (d) TBDMSCl, imidazile,
DMF, rt, 12 h 89%. (e) Lawesson reagent, toluene, 608C, 20 min, 83%.
(f) (EtO2C)CHBr, CH2Cl2, rt, 5 h then DBU, PPh3, 4 h 82%. (g) TBAF,
THF, rt, 1.5 h, 88%. (h) MsCl, Et3N, CH2Cl2, 2788C, 2 h, 88%. (i) KHMDS
THF 608C, 40 min, 63%.
First, synthesis of the 3,4-dihydroxypyrrolidin-2-one corre-
sponding to the C8–C13 unit was investigated. We applied
the protocol disclosed by Nicotra et al. providing
(3S,4R,5S)-1-benzyl-3,4-dibenzyloxy-5-vinylpyrrolidin-2-

M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
3043
alcoholic function was protected in the form of a TBDMS
group to afford silyl ether 11 in 96% yield.
With the C8–C13 central domain of 1 in hand, synthesis of
the model compound 3 was examined according to our
reported methodology.1a These studies were carried out
with the aim to demonstrate the utility of 11 for the synthesis
of the C1–C17 fragment of 1 as well as 1 itself. The amide
moiety of 11 was converted into thiolactam by heating with
the Lawesson reagent,12 giving 12 in 83% yield. On
successive treatment of 12 with diethyl bromomalonate
and DBU, the Eschenmoser coupling, took place yielding
pyrrolidin-2-ylidenemalonate 13a. The reaction employing
KHCO3 in place of DBU could not complete the reaction
and gave only S-malonyl thioimidate 15. This result is in
contrast to our precedent synthesis of the model compound
16 lacking two alkoxy functions at the C12 and C13
positions (carzinophilin numbering). The adduct 13a was
converted into mesylate 13c by the usual methods through
alcohol 13b in good overall yield. Heating 13c with
KHMDS was found to effect the aziridine ring closure to
give the desired 3 in 63% yield after silica gel column
chromatography. Interestingly, the dibenzyloxy compound
3 seemed to be more stable than 16 by considering the
reaction conditions and isolation yield. This was useful
information for our further studies (Fig. 2).
Figure 1. Observed NOEs in epi-8 and 9.
hydroxymethyl group by O3 oxidation and following
reduction of the ozonide with NaBH4 affording alcohol 9
in 98% overall yield without isomerization (Scheme 2). The
1
stereochemistries of these products were established by H
NMR experiments employing NOE technique. Irradiation of
the signal due to the C5 proton (3.53 ppm) of epi-8 induced
NOEs at the signals of C3H (3.81 ppm) and one of the exo-
methylene protons (4.92 ppm) as shown in Figure 1. Signal
intensity of C4H (3.50 ppm) in epi-8 was increased by
another irradiation of C5CH signal (6.05 ppm). On the other
hand, an NOE was observed between C4H (4.22 ppm) and
C5H (3.53 ppm) in the case of 9. These observations
revealed the stereochemistry of the newly introduced C5
positions of epi-8 and 9 to be R- and S-configuration,
respectively. The X-ray crystallographic analysis of 9
supported these assignments (data not shown).
Next, the MPM group of 9 attached to the nitrogen was
selectively removed. The results are summarized in Table 1.
When 9 was treated with 10 equiv. of ammonium cerium
(IV) nitrate (CAN) in a 1:1 mixture of CH3CN and H2O,11
over-oxidation occurred to afford a considerable amount of
imide 14 (35% yield) along with the desired compound 10
(51% yield) (run 1). The selectivity could not be improved
by reducing the amount of CAN employed (run 2). The
reaction in dry CH3CN was very slow (run 3) suggesting
that this oxidation requires H2O. Addition of a small amount
of H2O was found to accelerate the oxidation (run 4).
Selective removal of the MPM group was finally achieved
efficiently by treating 9 with five equivalents of CAN in 19:1
mixture of CH3CN and H2O at 08C, giving 10 in 99% yield
(run 5). The reaction completed within 30 min. The
Figure 2. Structures of thioimidate 15 and the previous model compound
16.
2.3. Development of a synthetic route to N-acyl-
(pyrrolidin-2-ylidene)glycine amide systems1d
Our next focus was the construction of a N-acyl-(pyrrolidin-
2-ylidene)glycine amide systems. Although it was disclosed
that the Herdeis protocol was applicable to N-acyl-
(pyrrolidin-2-ylidene)glycine esters,1b we could not apply
this methodology to preparation of N-acyl-(pyrrolidin-2-
ylidene)glycine amide systems in spite of intensive
experimentation. Conversion of the (pyrrolidin-2-ylidene)-
malonate 13 into the N-acyl-(pyrrolidin-2-ylidene)glycine
amide system was also unsuccessful. After much effort, the
4H-oxazol-5-one (azlactone) method finally provided us
fruitful results as described below.
Table 1. Selective deprotection of the N-MPM group of 9
It was found that O-methyl imidate 17 and S-methyl
thioimidate 18 readily couple with azlactones 19–21. Prior
to the coupling reaction, 17 was prepared from 11 in 95%
Run
Amount of CAN
(mol equiv.)
Ratio of
CH3CN/H2O
Time
(hr)
Yield
(%)
13
yield by treating with Me3OBF4 and 18 was produced in
96% yield by treating 12 with methyl iodide in CH2Cl2.
Azlactone 19–21 were prepared from the corresponding
N-acyl glycines in almost quantitative yields by
1-cyclohexyl-3-(2-morphorinoethyl)carbodiimide metho-p-
toluenesulfonate in THF.14 As shown in Table 2, heating 17
with three equivalents of 1914 at 808C in toluene afforded
the adduct 22 in 33% yield (run 1). Using pyridine as a
9
10
14
1
2
3
4
5
10
2
3
2
5
1:1
1:1
1:0
9:1
19:1
2
0
51
45
53
66
99
35
15
0
0.6
0
0.7
12
12
0.5
15
36
28
0

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M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
Table 2. Coupling reaction of imidates 17 and 18 with azlactones 19–21
C6D6), 70:30 (in CDCl3), 50:50 (in CD3OD)]. This implies
that tautomerism occurs between these isomers by way of
the imine–enamine isomerization. The stereochemistry of
1
these tautomers was determined using 22 based on its H
NMR spectra to reveal that the major and minor isomer have
E- and Z-configuration, respectively, as described below
(Fig. 4). Comparing the chemical shifts of C13H signals
(carzinophilin numbering) disclosed that the signals of the
minor Z-isomer appeared at 5.35 ppm in CDCl3 which is
0.23 ppm lower field than that of the major E-isomer due to
magnetic deshielding by the carbonyl group on the
azlactone ring. A signal corresponding to the N9H
(carzinophilin numbering) of the E-isomer (7.82 ppm) was
observed at 1.04 ppm lower field than that of the minor
Z-isomer (6.78 ppm). This observation suggested existence
ofstronghydrogenbondingbetweentheN9Handthecarbonyl
group of the azlactone moiety in the case of the major isomer.
Hydrogen bonding is also possible in the case of the Z-isomer
between N9H and the nitrogen atom of the azlactone ring.
However, molecular modeling of those compounds showed
Run Imidate
Azlactone
Conditions
Product Yield (%)
1
2
3
4
5
6
7
8
17
17
18
18
17
18
17
18
19 (3 equiv.) Toluene, 808C
19 (3 equiv.) Pyridine, 508C
19 (4 equiv.) Toluene, 808C
19 (3 equiv.) Toluene, rt
20 (3 equiv.) Toluene, 808C
20 (4 equiv.) Toluene, 808C
21 (1 equiv.) CHCl3, 408C
21 (1 equiv.) Benzene, 508C
22
22
22
22
23
23
24
24
33
0
82
0
0
1.7
2.7
7.2
˚
that the hydrogen bonding of the Z-isomer (ca. 2.6 A length)
might be geometrically less favorable than that of the major
solvent, the reaction did not occur at all (run 2). When four
equivalents of 18 was employed instead of 17, the reaction
proceeded more efficiently to give 22 in 82% yield (run 3).
The reaction required heating around 808C (run 4), but
higher temperature only accelerated decomposition of both
substrates. From the viewpoint of application to the total
synthesis of 1, the scope and limitation of this coupling
reaction were also examined employing azlactones bearing
different substituents. It was found that 2-t-butyl-4H-
oxazol-5-one (20) gave no adduct 23 when 17 was
employed. However, 20 afforded a trace amount of the
adduct 23 (1.7%) by treating with 18 (run 6). Azlactone 21
substituted with a 2-methylpropenyl group gave the adduct
24 in 2.7 and 7.2% yield by treatment with 17 or 18,
respectively (run 7, 8). Since those conditions were
accompanied with decomposition of the azlactones 19–
21, excess amounts of 19,20 were used for the reaction.
However, we could employ only one equivalent of 21
because of supply difficulty. Taking into account the later
elaboration steps for left hand moiety as disclosed in the
preceding paper, the coupling with azlactones bearing
similar substituents to 21 was anticipated to be promising
for the total synthesis. An aryl or a vinyl group is expected
to stabilize an anionic species of 4H-oxazol-5-one
(azlactone) by mesomeric effect as shown in Figure 3. In
fact, the coupling reaction with azlactones 19,21 carrying
anion-stabilizing substituents, gave better results than that
with 20, an azlactone without an anion-stabilizing group.
Accordingly, a substituent that stabilizes the anion should
be incorporated into the azlactone which will be employed
in the total synthesis.
15
˚
E-isomer (ca. 2.3 A length).
Figure 4. Chemical shifts (N9H and C13H) of the major tautomer E-22 and
the minor tautomer Z-22 (minor) in CDCl3.
Transformation of the azlactone ring into the dehydropep-
tide system was next examined. Contrary to our assumption,
the azlactone ring of 22 was found to be quite stable. For
example, no reaction occurred by heating 22 with
isopropylamine in a sealed tube at 1008C. Simple desilyl-
ation was only observed by heating with a highly reactive
isopropylchloroalminum amide, the Weinreb amide,15 in
benzene. However, it was found that the azlactone ring can
be activated by acylation of the amino group of the
pyrrolidine ring in 22. Thus, reaction of 22 with Boc2O or
Alloc2O in the presence of DMAP16 cleanly yielded
unstable carbamates 25a or 25b and the following additions
of isopropylamine into the reaction mixtures effected the
aziridine ring-openings, affording a diastereomeric mixture
of dehydropeptides 26a,b, respectively (E-26a: 5.5%,
Z-26a: 55%, E-26b: 45%, Z-26b: 20% yields each in 2
steps) (Scheme 3). These isomers were easily separated by
column chromatography. It was also found that these isomers
undergo no isomerization under the usual conditions. It is
worth noting that neither benzoyl chloride nor TrocCl reacts
with 22 under similar conditions to those described above.
Figure 3. The anion of azlactone stabilized by the substituent.
The 1H NMR spectra of the adducts 22–24 showed that they
exist as mixtures of isomers about the C7–C8 double bonds
(carzinophilin numbering). It was found that the isomeric
ratio of 22 changed by the solvents employed [80:20 (in
The stereochemistries of E- and Z-26 were determined
based on their 1H NMR spectra. The C13H signals of
E-25a,b shifted higher field than those of Z-26. Probably,
the C13H of the E-isomer is magnetically shielded by the

M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
3045
energy. These geometries were then re-optimized based on
6-31Gp base set.18 Figure 6 shows the conformer with
minimum steric energy found by those calculations. This
suggests that the pyrrolidine ring is twisted due to repulsion
between the C6 side chain and the carbamate group attached
to N9. The distance between C13H and the amide proton at
˚
N16 was estimated to be 2.54 A. Accordingly, the NOEs
between them can be expected in the cases of E-26a,b.
Scheme 3. Opening of the azlactone rings to provide dehydropeptide
systems. Reagents and conditions: (a) (for 25a): Boc2O, cat. DMAP, THF,
rt, 30 min (for 25b): Alloc2O, cat. DMAP, THF, rt, 30 min then,
(b) isopropylamine, rt 30 min, 5.5% (E-26a), 65% (Z-26a), 45% (E-26b),
20% (Z-26b). (c) Pd(PPh3)4, dimedone, THF, rt, 10–30 min, 87% (from
E-26b), 92% (from Z-26b). (d) TMSOTf, 2,6-Lu, CH2Cl2, rt 30 min, 68%.
Figure 6. Conformation of VI with lowest steric energy obtained by the
calculations.
Interestingly, the locked C7–C8 double bond was unlocked
again by deprotection of the carbamoyl group. For example,
treatment of E-26b with dimedone and a catalytic amount of
Figure 5. Observed NOEs in each isomer 26 and their chemical shifts of the
C13H signal in CDCl3.
19
Pd(PPh3)4 in THF effected smooth cleavage of the Alloc
C17 carbonyl group. In the cases of E-26a,b characteristic
NOEs were observed at the C13H [carzinophilin number-
ing, 4.68 ppm (E-26a) and 4.69 ppm (E-26b)] by irradiation
of the N16H signal [7.86 ppm (E-26a) and 7.96 ppm
(E-26b)]. On the other hand, NOEs were detected between
C13H (5.23 ppm) and N5 proton signals (9.97 ppm) in the
1H NMR spectra of Z-26a. NOE experiments were not
performed for Z-26b because of signal overlapping. The
signals of N5H and N16H could be readily distinguished by
their signal patterns (N5H¼doublet, N16H¼singlet).
group providing 28 in 92% yield as an inseparable mixture
consisted of three isomers. Deprotection of the Alloc group
of Z-26b was also achieved in 87% yield under the same
conditions giving the deprotected pyrrolidine, which was
identical with 28 prepared from E-26b. The isomers in 28
might include not only tautomers about the C7–C8 double
bond but also rotamers about the amide bonds. As described,
removal of the Alloc group of E and Z-26b resumes these
tautomerism. No informative NOEs were obtained for the
C7–C8 double bond in the major isomer of 28, however, the
stereochemistry for that olefin moiety in 28 was assigned to
be E-configuration by observing a signal of the C13H
(carzinophilin numbering) in the major isomer of 28 at
4.71 ppm which corresponds well to those of E-26a,b and
not to those of Z-26a,b. Deprotection of the Boc group of E-
26a with TMSOTf in the presence of 2,6-lutidine brought
about dehydration to give imidazolinone 27.
Conformations of E-26 were further examined by computer-
assisted molecular modeling studies.17 Dehydropeptides
E-26 involve complicated conjugation of p-electrons in the
molecules. Thus, it was necessary to employ molecular
orbital calculations to obtain reliable conformations. We
chose a model compound VI in Figure 6 in order to save the
time required for computations. Conformation search by an
ab initio method for VI was not still practical due to
abundant numbers of atoms existing in the molecule. Thus,
stable conformations of VI were obtained by the following
protocol. First, a conformational search in the PC Spartan
Pro17 was performed for VI employing semiempirical AM1
method to give 100 stable conformers. Twenty-six con-
formers were found within 3.0 kcal/mol from the minimum
2.4. Conversion into the analogue 4a, the C6–C13
fragment1d
Dehydropeptides E-26b, Z-26b, and 28 were successfully
converted into 4a as shown in Scheme 4 by applying the
procedures we had developed. The TBDMS group in E-26b

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M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
Scheme 5. Preliminary trials for preparing the C1–C6 fragment.
We were able to achieve a preparation of this enamide
system by a novel synthetic scheme employing non-
oxidative conditions in the key step. Thus, N-benzyl-
oxycarbonyl-L-threonine was reduced with a borane
dimethylsulfide complex in THF. Selective protection of
the primary alcohol with TBDPSCl–Et3N–CH2Cl2 gave
alcohol 34. After oxidation of 34 using SO3·Py-DMSO, the
ketone moiety was protected in the form of dimethyl acetal
by the usual method to afford acetal 35. After removal of the
TBDPS group, the alcoholic function of 35 was oxidized
with PDC in the presence of molecular sieves 4A to give
unstable aldehyde 36 in a moderate yield (Scheme 6).
Scheme 4. Transformation of E-26b, Z-26b, and 28 into 4b. Reagents and
conditions: (a) HCl, MeOH rt, 20 min–1 h, 98% (E-29), 93% (Z-29), 77%
(31). (b) MsCl, Et3N, CH2Cl2, 2788C 30 min–2 h, 88% (E-30), 96%
(E-30), 68% (32). (c) Pd(PPh3)4, dimedone, rt, THF, 10 min–30 min, 97%
(from E-30), 82% (from Z-30). (d) KHMDS, THF rt, 5 min, 64%.
was cleaved with HCl in MeOH to give alcohol E-29 in 98%
yield. This was further converted into mesylate E-30 by the
usual conditions. In these two steps, we observed no
isomerization about the C7–C8 double bond. Deprotection
of the Alloc group with Pd(PPh3)4 in the presence of
dimedone accompanied isomerization giving rise to N-
unprotected mesylate 32 in 97% yield which consists of
1
more than three isomers according to its H NMR spectra.
The other isomer Z-26b was also subjected to the series of
three reactions to afford 32 which was identical to the
sample prepared from E-26b in all respects. Thus, the Alloc
group was found to lock the configuration of the C7–C8
double bond. The mesylate 32 was also synthesized from 28
by desilylation and subsequent mesylation. As expected, the
aziridine ring closure was found to be achieved by treating
32 with KHMDS in THF for 5 min to afford 4a in 64% as a
single isomer. The stereochemistry of 4a will be discussed
later in this report.
Scheme 6. Preparation of the C1–C6 fragment. Reagents and conditions:
(a) BH3·SMe2, THF, 08C!rt, 16 h, 75%. (b) TBDPSCl, Et3N, CH2Cl2,
08C!rt, 16 h, 56%. (c) SO3·Py, DMSO, Et3N, rt, 2.5 h, 92%.
(d) (CH3O)3CH, p-TsOH, MeOH, rt, 2.5 h, 97%. (e) TBAF, THF, 08C,
1.5 h, 94%. (f) PDC, MS4A, CH2Cl2, rt, 1.5 h, 65%. (g) p-TsOH, THF,
H2O, rt, 71%. (h) CH2N2, Et2O, rt, 10 h, 33%. (i) H2, 10% Pd/C, MeOH, rt,
14 h, 93%.
2.5. Development of the synthetic scheme for b-hydroxy-
enamide system corresponding to the C1–C6 unit1d
Next, we examined a synthetic method for the b-hydroxy
enamide system 33b corresponding to the C1–N6 unit of 1.
Since this system 33b is synthetically equivalent to the
ketoaldehyde 33a, it was expected that it can be furnished
by oxidation of the corresponding 1,3-diol 31a, 3-hydroxy-
ketone 31b, or 3-hydroxyaldehyde 31c. However, we could
not obtain 33b (¼33a) by oxidation of 31a–c. Most cases of
the oxidation of 31a–c we examined, such as TPAP-
NMO,20 TEMPO,21 PCC,22 PDC,23 SO3·Py-DMSO,24
Dess–Martin,25 and Swern oxidations26 resulted in complex
mixtures of products. Oxidation of 31a with SO3·Py-DMSO
gave only a certain product but it was a,b-unsaturated
aldehyde 33c. These results suggested that the desired b-
hydroxy enamide system 33b is unstable under oxidative
conditions (Scheme 5).
On deprotection of the dimethyl acetal in 36 the construc-
tion of a b-hydroxy enamide system took place to produce
32c, which was obtained in an almost pure form in 75%
yield after aqueous work up. The 1H NMR spectrum of 32c
showed a signal at 11.65 ppm (doublet, J¼11.0 Hz) as an
exchangeable proton with D2O, disclosing that 32c takes an
enol form. The E-configuration of the C3–C4 double bond
(carzinophilin numbering) was ascertained by observing a
strong NOE at the C1H3 (2.28 ppm) on irradiating the
olefinic C4H (7.23 ppm). Notably, 32c appeared as a broad
spot on its silica gel TLC and was extracted with AcOEt
only under acidic conditions like a carboxylic acid. Thus,
32c was treated with CH2N2 to give methyl enol ether 37

M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
3047
which could be purified by preparative TLC. It was
anticipated that the C1–C6 b-hydroxy enamide system
can not survive under the conditions required for the total
synthesis. Accordingly, we decided to introduce the C1–N5
unit into the trunk framework in a protected form and to trim
functions in the later synthetic stages. Thus, amine 38
derived from 35 by catalytic hydrogenolysis, was employed
as the C1–N5 unit.
2.6. Synthesis of the C1–C17 fragment 4b
Based on the information accumulated in the studies
mentioned above, the C1–C17 fragment 4b was attempted
in order to verify our strategy (Scheme 7). Taking into
account the later synthetic stages, the TBDMS group of 22
was replaced with a mesyl group in a good overall yield by
sequential deprotection and mesylation prior to introduction
of the C1–C5 fragment. Right after purification by column
chromatography, the mesylate 39 was obtained as a mixture
of E- and Z-isomers about the C7–C8 double bond (60:40
1
isomeric ratio based on the H NMR spectrum). Interest-
ingly, recrystallization of 39 from AcOEt–hexane under-
went the isomerization, giving the pure E-isomer with
.90% recovery.27 The E-configuration of 39 was assigned
by comparing the chemical shifts for the N9H and C13H of
39 (7.78 and 5.10 ppm, respectively) with those of the
isomers E-22 and Z-22 shown in Figure 4. Incorporation of
the amine 38 into 39 was attempted after activation of the
azlactone ring by N9-acylation. Thus, treatment of 39 with
Alloc2O in the presence of DMAP took place N-carbamoyl-
ation which was accompanied by isomerization of the C7–
C8 double bond giving a mixture of E- and Z-N-Alloc
derivatives E-40 and Z-40 in 27 and 61% yield, respectively.
These isomers could be separated by silica gel preparative
TLC. It was found that heating pure E-40 with 38 at 508C in
high concentration resulted in the azlactone ring-opening as
well as isomerization of the double bond to afford a mixture
of dehydropeptides E-41 and Z-41 in 75 and 15% yield,
respectively. The same treatment of Z-40 also provided a
mixture E-41 and Z-41 in 68% and 20% yield, respectively.
The stereochemistries of E- and Z-41 were established by
comparison of their 1H NMR spectra with those of isomeric
pairs of 26b, which were assigned by NOE experiments as
shown in Figure 5.
Next, elaboration of the C1–N6 moiety was studied. The
TBDPS group of E-41 was removed selectively in 93%
yield by using HF·Py in pyridine and subsequent oxidation
of the obtained alcohol with PDC in the presence of
molecular sieves 4A in CH2Cl2 provided alcohol E-42 in
66% yield. As expected, treatment of E-42 with p-TsOH in
aqueous THF at room temperature smoothly took place
formation of the b-hydroxy enamide system. Since the silica
gel TLC of the product gave a broad spot as mentioned,
purification was performed after conversion into methyl
ether E-43 by methylation of the enol moiety with CH2N2.
Similar chemical shifts for the C4H and the N5H to those of
model compound 37 suggested the E-configuration of the
newly furnished C3–C4 double bond. The Alloc group of
E-43 could be removed by Pd(PPh3)4-catalyzed reaction
employing AcOH as a nucleophile,28 giving E-44 in 57%
yield. Isomerization of the C7–C8 double bonds was not
observed in the series of these transformations. The
Scheme 7. Synthesis of the C1–C17 fragment 4b of carzinophilin.
Reagents and conditions: (a) TBAF, THF, rt, 2.5 h, 90%. (b) MsCl, Et3N,
CH2Cl2, 2788C, 1 h, 90%. (c) recrystallization, .90% recovery. (d) Alloc2O,
DMAP, THF, rt, 10 min. (e) 38, DMAP, 508C, 1 h, yields are shown in
the Scheme. (f) HF·Py, pyridine, 08C!rt, 93% (from E-41), 79% (from
Z-41). (g) PDC, MS4A, CH2Cl2, rt, 68% (for E-42), 83% (for Z-42).
(h) p-TsOH, aq. THF, rt. (i) CH2N2, THF–Et2O rt, 12 h, 67% in 2 steps
(E-43). (j) CH2N2 AcOEt–Et2O, rt, 12 h, 78% 2 steps (Z-43). (k) cat.
Pd(PPh3)4, PPh3, AcOH, THF, rt, 57% (from E-43), 88% (from Z-43).
(l) TBAF, MS4A, THF, rt, 10 min, 73%.

3048
M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
1
Z-isomer Z-41 was also subjected to a series of these
transformations. Desilylation of Z-41 proceeded in 79%
yield and subsequent oxidation provided Z-42 in 78% yield.
Construction of the b-hydroxy enamide system in a similar
manner to that described above gave Z-43 in 78% yield in
two steps. Interestingly, removal of the Alloc group of Z-43
by the same treatment as above resulted in the isomerization
of the C7C8 double bond giving E-44 as a single isomer.
The 1H NMR spectrum of this sample was identical to that
of E-44 prepared from E-43. The intermediate Z-44 could be
obtained by quick purification. Isomerization of Z-44 into
E-44 was found to be completed within 6 hours by standing
in CDCl3 at room temperature.
comparison of the H NMR spectral data of azinomycin B
4-O-methyl ether (AZB-4-O-Mevcarzinophilin-4-O-Me),5
4a,b, and Armstrong’s Z-isomer analogue29 gave us
considerable information. As shown in Table 3, the coupling
constants between C12–H and C13–H in 4a,b were
observed both as 4.1 Hz, which resembles that of AZB-4-
OMe (3.9 Hz). On the contrary, that observed in
Armstrong’s Z-isomer is clearly different (1.0 Hz). Taking
these considerations into account, the stereochemistries at
the C7–C8 double bond of 4a,b were assigned to have the
same E-configuration as that of 1.
Table 3. Chemical shifts (ppm), signal patterns (parenthesized), and
coupling constants (italic, Hz) in the AZB-4-OMe, 4a,b, and the
Armstrong’s Z-isomer
In those transformations, the chemical yields of the
Z-isomers were always slightly better than those for the
E-isomers. This would be explained by the fact that those
reactions with the E-isomers accompany formation of uracil
derivative VII by an attack of the N5 atom to the carbamoyl
group as shown in Scheme 8. Actually, the reaction of E-41
with TBAF gave pyrimidin-2,4-dione derivative 45 in good
yield.
Proton
AZB-4-OMe
4a
4b
Armstrong’s
Z-isomer
1
4
2.24 (s)
7.19 (s)
3.90 (s)
10.89 (s)
–
–
–
2.23 (s)
7.16 (s)
3.89 (s)
11.03 (s)
4-O-Me
5
9.47 (br d)
7.5
6.95 (dd)
4.8, 4.8
2.18 (d)
3.6
2.40 (dd)
1, 5.3
3.03 (ddd)
3.6, 4.9, 5.3
4.42 (dd)
1.0, 4.9
5.012 (dd)
1, 1
10a
10b
11
2.25 (d)
3.9
2.51 (d)
5.4
3.22 (ddd)
3.9, 5.4, 5.8
4.63 (dd)
3.9, 5.8
5.55 (d)
3.9
2.23 (d)
4.1
2.35 (d)
5.4
3.06 (ddd)
4.1, 5.4, 5.4
4.55 (dd)
4.1, 5.4
5.01 (dd)
0.9, 4.1
8.43 (s)
2.30 (d)
4.1
2.44 (d)
4.8
3.10 (ddd)
4.1, 4.7, 4.8
4.59 (dd)
4.1, 4.7
5.01 (dd)
1.0, 4.1
8.28 (s)
Scheme 8. Undesired formation of uracil ring from E-dehydropeptides.
Synthesis of the C1–C17 model compound 4b was
accomplished by the aziridine ring formation. Treatments
of E-44 with KH or KHMDS in THF, which provided
preferable results in the previous model studies, resulted in
decomposition of the starting material. After further
experimentation, it was found that a combined use of
TBAF and finely powdered molecular sieves 4A in THF
achieved the aziridine ring closure, providing 4b as a single
isomer in 73% yield. The product 4b was readily purified by
silica gel column chromatography.
12
13
16
8.50 (s)
7.89 (s)
Molecular modeling was also studied by the method similar
to that as described for the conformation analysis of model
compound VI. A model compound VII was chosen for these
calculations. Since the bulky C13 O-benzyloxy group and
C18 carbons of 4a,b was replaced to methyl groups in
model VII, the amide bonds N5–C6 and N16–C17 were
fixed on Z-geometry in the conformation search.
Conformer A in Figure 7 is the most stable conformation
found by those calculations. The distance between C13H
and the amide proton attached to N16 of this conformer is
Finally, assignment of the stereochemistry of 4b was
attempted. Stereochemistry of the C3–C4 double bond
(carzinophilin numbering) and the pyrrolidine moiety could
be established rigorously by observing NOEs for C1–
H$C4–H, C4–H$C4–OCH3, C10a–H$C11–H,
C10b–H$C13–H, and C11–H$C12–H by differential
NOE experiments in CDCl3. However, no useful infor-
mation was obtained by the NOE technique concerning the
C7–C8 double bond. Similar experiments employing 4a
also did not give an NOE between N16–H and C13–H.
Incidentally, the NOE between the signals of N16–H and
C13–H was not described by Yokoi et al. in their report on
the structure determination of azinomycins.5 However,
˚
4.29 A. The most stable conformer in which the distance
˚
C13H$N16H is within 3.0 A found by those calculations
has 6.9 kcal/mol higher steric energy. Accordingly, it might
be reasonable about the absence of NOE between C13H and
N16H in the cases of 4a,b. Our calculations for model
compounds VI and VII suggested that stable conformations
of the C1–C6 and N16–C18 side chains depend on
functions attached to their N9 positions.

M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
3049
1.16, CHCl3). IR (film): 3300, 2900, 2850, 1605, 1505,
1450, 1240, 990, 730, 690 cm21 1H NMR (400 MHz,
.
CDCl3): d 3.45 (1H, dd, J¼2.2, 8.7 Hz, C5H), 3.53 (1H, d,
J¼12.4 Hz, ArCHHN), 3.65 (3H, m, C1H2, C4H), 3.72 (1H,
d, J¼12.4 Hz, ArCHHN), 3.78 (3H, s, CH3O), 3.84 (1H, dd,
J¼4.3, 6.4 Hz, C3H), 3.95 (1H, dd, J¼4.6, 6.4 Hz, C2H),
4.41 (1H, d, J¼11.5 Hz, PhCHHO), 4.50 (1H, d, J¼11.7 Hz,
PhCHHO), 4.51 (1H, d, J¼12.1 Hz, PhCHHO), 4.54 (1H, d,
J¼11.7 Hz, PhCHHO), 4.55 (1H, d, J¼12.1 Hz, PhCHHO),
4.66 (1H, d, J¼11.5 Hz, PhCHHO), 5.16 (1H, dd, J¼1.5,
17.2 Hz, C7HH), 5.23 (1H, dd, J¼1.5, 10.2 Hz, C7HH),
5.77 (1H, ddd, J¼8.7, 10.2, 17.2 Hz, C6H), 6.83 (2H, dt,
J¼8.7, 2.0 Hz, aromatic protons for MPM), 7.20–7.34
(17H, m, aromatic protons), EI-MS (rel. int.%): m/z¼568
(0.05, MHþ), 476 (1.7, [M2Bn]þ), 460 (0.35, [M2BnO]þ),
446 (1.1, [M2MPM]þ), 121 (100, MeOPhCHþ2 ), 91 (53,
Bnþ). CI-MS (isobutene): m/z 568 (MHþ). EI-HIMS: calcd
for C36H42NO5 (Mþ): m/z¼568.3064. Found m/z¼
568.3046.
4.3. (3S,4R,5S)-3,4-Disbenzyloxy-1-(4-methoxyphenyl-
methyl)-5-vinylpyrrolidin-2-one (8) and its (3S,4R,5R)-
diastereomer (epi-8)
Figure 7. Two conformers of model compound VII.
4.3.1. Reaction procedure. A mixture of 7 (7.30 g,
12.9 mmol), PCC (11.0 g, 51.2 mmol), and powdered
molecular sieves 4A (10 g) in CH2Cl2 (100 mL) was stirred
for 4 h. To the solution, Et2O (300 mL) and Celitew (10 g)
were added successively and the mixture was further stirred
for 1 h. The mixture was filtered through a pad of Celitew,
and the filtrate was concentrated in vacuo. Purification of the
residue by silica gel column chromatography (Et2O/
hexane¼50:50) gave 8 (4.05 g, 71%) and epi-8 (170 mg,
3.0%), and recovered 7 (391 mg, 5.3%).
3. Conclusion
As described above, we have succeeded in developing a
novel synthetic methodology for 1. Applying the knowledge
accumulated in these studies, we attempted the total
synthesis of 1 which will be the subject of the following
paper.30
4. Experimental
4.1. General
4.3.2. Data of 8. [a]2D0¼21388 (c 2.35, CHCl3). IR (film):
3010, 2900, 1710, 1610, 1510, 1240, 1100, 1030, 730,
1
690 cm21. H NMR (400 MHz, CDCl3): d 3.68 (1H, d,
See General in the experimental part for Part 1 of this series
of papers. Compounds with large molecular weight
(MW.750) could not be subjected to high-resolution mass
spectroscopy.
J¼14.5 Hz, ArCHHN), 3.81 (3H, s, OCH3), 3.96 (1H, dd,
J¼8.7, 7.5 Hz, C5H), 4.11 (1H, t, J¼7.5 Hz, C4H), 4.34
(1H, ddd, J¼0.7, 7.5 Hz, C3H), 4.46, 4.54 (each 1H, d,
J¼11.6 Hz, PhCH2O), 4.84 (1H, d, J¼11.7 Hz, PhCHHO),
5.07 (1H, d, J¼14.5 Hz, ArCHHN), 5.13 (1H, d, J¼11.7 Hz,
PhCHHO), 5.24 (1H, d, J¼17.0 Hz, C5CHvCHH), 5.39
(1H, d, J¼10.1 Hz, 5CHvCHH), 5.75 (1H, ddd, J¼8.7,
10.1, 17.0 Hz, C5CHvCH2), 6.88, 7.16 (each 2H, dt,
J¼8.7, 2.9 Hz, aromatic protons for MPM), 7.24–7.36 (8H,
m, aromatic protons), 7.43 (2H, m, aromatic protons). EI-
MS (rel. int.%): m/z¼444 (0.50, MHþ), 337 (9.7,
[M2BnO]þ), 121 (63, MeOPhCH2þ), 91 (100, PhCHþ2 ).
EI-HIMS: calcd for C28H30NO4 (MHþ): m/z¼444.2176.
Found: m/z¼444.2161.
4.2. (2R,3S,4R,5S)-1,3,4-Tribenzyloxy-5-(4-methoxy-
phenyl)methylamino-6-hepten-2-ol (7)
A solution of 2,3,5-tri-O-benzyl-b-D-arabinofuranose (5)
(25.0 g, 59.5 mmol) and 4-methoxybenzylamine (8.90 g,
64.9 mmol) in toluene (200 mL) was stirred under reflux
using a Dean–Stark condenser to remove the H2O
produced. After stirring for 12 h, the solvent was removed
in vacuo to give crude 6 as a viscous oil. After 6 was
dissolved in THF (200 mL), vinylmagnesium bromide
(0.87 M in THF, 180 mL, 156 mmol) was added at 08C
over 30 min. After the cooling bath was removed, the
mixture was stirred at room temperature for 12 h. The
mixture was cooled to 2788C, then the reaction was
quenched by adding saturated aqueous NH4Cl solution and
the THF was removed in vacuo. The mixture was poured
into water, and extracted with Et2O. The combined extracts
were washed with brine, dried over Na2SO4, and concen-
trated in vacuo. Purification of the residue by silica gel
column chromatography (hexane/AcOEt¼90:10) gave 7 in
almost pure form (23.7 g, 71%) as a syrup. [a]2D0¼24.498 (c
4.3.3. Data of epi-8. IR (nujor) 2920, 1680, 1510, 1460,
1
1240 cm21. H NMR (400 MHz, CDCl3): d 3.27 (3H, s,
CH3O), 3.50 (1H, dd, J¼5.3, 5.9 Hz, C4H), 3.53 (1H, dd,
J¼5.9, 9.1 Hz, C5H), 3.69 (1H, d, J¼14.6 Hz, ArCHHN),
3.81 (1H, d, J¼5.3 Hz, C3H), 4.23, 4.42 (each 1H, d,
J¼11.7 Hz, PhCH2O), 4.91 (1H, d, J¼12.2 Hz, PhCHHO),
4.92 (1H, dd, J¼1.7, 19.1 Hz, C5CHvCHH), 5.01 (1H, dd,
J¼1.7, 9.9 Hz, C5CHvCHH), 5.03 (1H, d, J¼14.6 Hz,
ArCHHN), 5.13 (1H, d, J¼12.2 Hz, PhCHHO), 6.05 (1H,
ddd, J¼9.1, 9.9, 19.1 Hz, C5CHvCH2), 6.72 (2H, br d,

3050
M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
J¼8.7 Hz, aromatic protons for MPM), 7.02–7.16 (8H, m,
aromatic protons), 7.25 (2H, br d, J¼7.2 Hz, aromatic
protons), 7.43 (2H, br t, J¼7.1 Hz, aromatic protons). EI-
MS (rel. int.%): m/z¼444 (0.50, MHþ), 337 (6.2,
[M2BnO]þ), 121 (65, MeOPhCH2þ), 91 (100, PhCHþ2 ).
EI-HIMS: calcd for C28H30NO4 (MHþ): m/z¼444.2176.
Found: m/z¼444.2183. Anal. calcd for C28H29NO4: C,
75.82%; H, 6.59%; N, 3.16%. Found C, 75.76%; H, 6.59%;
N, 3.11%.
recrystallization from hexane/EtOAc to give colorless
needles. Mp: 109.5–111.08C. [a]2D0¼293.78 (c 1.11,
CHCl3). IR (nujor): 3500, 3280, 1720, 1460, 1380, 1270,
1120, 1100, 750 cm21. 1H NMR (400 MHz, CDCl3): d 2.51
(1H, br t, J¼6.1 Hz, alcoholic proton), 3.63–3.79 (3H, m,
C5H, C5CH2O), 4.33 (1H, t, J¼6.9 Hz, C4H), 4.37 (1H, d,
J¼6.9 Hz, C3H), 4.58, 4.64 (each 1H, d, J¼11.7 Hz,
PhCH2O), 4.79, 5.10 (each 1H, d, J¼11.8 Hz, PhCH2O),
6.49 (1H, br, amide proton), 7.25–7.43 (10H, m, aromatic
protons), EI-MS (rel. int.%): m/z¼328 (0.2, MHþ), 221 (1.2,
[MH2BnO]þ), 91 (100, PhCHþ2 ), EI-HIMS: calcd for
C19H22NO4 (MHþ): m/z¼328.1550. Found: m/z¼328.1555.
Anal. calcd for C19H21NO4: C, 69.71%; H, 6.47%; N,
4.28%. Found: C, 69.31%; H, 6.41%; N, 4.20%.
4.4. (3S,4R,5S)-3,4-Dibenzyloxy-5-hydroxymethyl-1-(4-
methoxyphenyl)methyl-pyrrolidin-2-one (9)
Ozone gas (O3/O2) generated by an ozonizer was bubbled
through a solution of 8 (1.07 g, 2.41 mmol) in EtOH
(20 mL) at 2258C for 20 min. After TLC showed
consumption of the starting material, O2 gas was further
bubbled for 10 min to remove the excess ozone. NaBH4
(300 mg, 7.9 mmol) was added to the ethanolic solution,
and the cooling bath was removed. The mixture was stirred
at room temperature for 20 min, and neutralized by adding
concentrated hydrochloric acid until litmus paper indicated
slightly acidic. The mixture was filtered through a pad of
Celitew, and the filtrate was concentrated in vacuo.
Purification of the residue by silica gel column chromato-
graphy (CHCl3/acetone¼90:10) gave 9 (1.06 g, 98%) as a
white solid. Analytical sample was prepared by recrystal-
lization from hexane-EtOAc to give colorless needles. Mp:
94.5–96.08C. [a]2D0¼21428 (c 0.940, CHCl3). IR (nujor)
3450, 2920, 1690, 1510, 1450, 1350, 1240, 1120, 1090,
1040, 740 cm21. 1H NMR (400 MHz, CDCl3): d 2.04 (1H,
dd, J¼6.4, 7.3 Hz, alcoholic proton), 3.53 (1H, ddd, J¼2.0,
4.0, 7.9 Hz, C5H), 3.67 (1H, ddd, J¼4.0, 7.3, 12.4 Hz,
C5CHHO), 3.74 (1H, ddd, J¼2.0, 6.4, 12.4 Hz, C5CHHO),
4.04 (1H, d, J¼14.8 Hz, ArCHHN), 4.22 (1H, dd, J¼6.9,
7.9 Hz, C4H), 4.42 (1H, dd, J¼0.7, 6.9 Hz, C3H), 4.55, 4.65
(each 1H, d, J¼11.7 Hz, PhCH2O), 4.86 (1H, d, J¼11.5 Hz,
PhCHHO), 4.90 (1H, d, J¼14.8 Hz, ArCHHN), 5.22 (1H, d,
J¼11.5 Hz, PhCHHO), 6.85, 6.78 (each 2H, dt, J¼8.7,
2.9 Hz, aromatic protons for MPM), 7.21–7.45 (10H, m,
aromatic protons). EI-MS (rel. int.%) m/z¼429 (0.40,
[M2H2O]þ), 341 (4.3, [M2BnO]þ), 121 (100,
MeOPHCHþ2 ), 91 (68, PhCHþ2 ). CI-MS (isobutene):
m/z¼448 (MHþ). Anal. calcd for C27H29NO5: C, 72.46%;
H, 6.53%; N, 3.13%. Found: C, 72.36%; H, 6.39%; N,
3.18%.
4.5.2. Treatment of 9 in a 1:1 mixture of CH3CN–H2O
(Table 1, run 2). A solution of 9 (30.1 mg, 67.0 mmol) and
CAN (73.4 g, 135 mmol) in a mixture of CH3CN (500 mL)
and H2O (500 mL) was stirred at room temperature for
40 min. Similar work up to that described above gave the
crude product. Purification of the residue by silica gel
column chromatography (CH2Cl2/acetone¼99:1, 90:10, and
AcOEt/MeOH¼97:3) gave 14 (4.60 mg, 15%), recovered 9
(4.5 mg, 15%), and 10 (9.8 mg, 45%).
4.5.3. Data of 14. IR (film): 3450, 2920, 1730, 1670, 1600,
1
1510, 1290, 1250, 1110, 1020, 760, 730, 690 cm21. H
NMR (400 MHz, CDCl3): d 2.23 (1H, dd, J¼5.4, 7.6 Hz,
alcoholic proton), 3.86 (3H, s, CH3O), 3.97 (1H, ddd,
J¼2.9, 7.6, 12.3 Hz, C5CHHO), 4.00 (1H, ddd, J¼2.7, 5.4,
12.3 Hz, C5CHHO), 4.39 (1H, t, J¼8.0 Hz, C4H), 4.63 (1H,
d, J¼8.0 Hz, C3H), 4.63 (1H, ddd, J¼2.7, 2.9, 8.0 Hz,
C5H), 4.69, 4.73 (each 1H, d, J¼11.8 Hz, PhCH2O), 4.74,
5.11 (each 1H, d, J¼11.5 Hz, PhCH2O), 6.91 (2H, br d,
J¼8.9 Hz, aromatic protons), 7.27–7.40 (10H, m, aromatic
protons), 7.64 (2H, br d, J¼8.9 Hz, aromatic protons). EI-
MS (rel int.%) m/z¼462 (0.5, Mþ), 355 (1.0,
[M2BnOþH]þ), 91 (100, PhCHþ2 ).
4.6. (3S,4R,5S)-3,4-Dibenzyloxy-5-(t-butyldimethyl-
siloxy)methylpyrrolidin-2-one (11)
A solution of 10 (8.57 g, 26.2 mmol), TBDMSCl (5.25 g,
35.0 mmol) and imidazole (7.13 g, 104 mmol) in DMF
(1.0 mL) was stirred at room temperature for 1 h. The
mixture was poured into water and extracted with Et2O. The
combined extracts were washed with brine, dried over
MgSO4, then concentrated in vacuo. Purification of the
residue by silica gel column chromatography (CH2Cl2/
acetone¼95:5) gave 11 (10.3 g, 89%) as an oil.
[a]2D0¼21068 (c 1.07, CHCl3). IR (film): 3200, 2950,
2920, 2850, 1710, 1250, 1110, 830, 770, 730, 690 cm21. 1H
NMR (400 MHz, C6D6): d 20.01, 0.01 (each 3H, s
(CH3)2Si), 0.92 (9H, s, (CH3)3CSi), 3.11 (1H, dddd,
J¼1.5, 3.0, 4.0, 7.5 Hz, C5H), 3.33 (1H, dd, J¼3.0,
10.5 Hz, C5CHHO), 3.57 (1H, dd, J¼4.0, 10.5 Hz,
C5CHHO), 4.12 (1H, t, J¼7.5 Hz, C4H), 4.36 (1H, d,
J¼12.0 Hz, PhCHHO), 4.45 (1H, d, J¼7.5 Hz, C3H), 4.48
(1H, d, J¼12.0 Hz, PhCHHO), 4.96, 5.35 (each 1H, d,
J¼11.8 Hz, PhCH2O), 6.88 (1H, br, amide proton), 7.05–
7.24 (8H, m, aromatic protons), 7.44 (2H, br d, J¼7.0 Hz,
aromatic protons). EI-MS (rel. int.%): m/z¼442 (0.01,
MHþ), 384 (1.0, [M2tBu]þ), 91 (100, PhCHþ2 ). EI-HIMS:
4.5. (3S,4R,5S)-3,4-Dibenzyloxy-5-hydroxymethyl-
pyrrolidin-2-one (10)
4.5.1. Preparation of 10 (Table 1, run 5). A solution of 9
(3.00 g, 6.70 mmol) and ammonium cerium (IV) nitrate
(CAN, 18.3 g, 33 mmol) in a mixture of CH3CN (15 mL)
and H2O (750 mL) was stirred at room temperature for 1 h.
The mixture was neutralized by addition of saturated
NaHCO3 solution. The resulting suspension was filtered
through a pad of Celitew and the filtrate was concentrated in
vacuo. The resulting aqueous suspension was extracted with
AcOEt and the combined ethyl acetate extracts were washed
with brine, dried over MgSO4 then concentrated in vacuo.
Purification of the residue by silica gel column chromato-
graphy (AcOEt/MeOH¼97:3) gave 10 (2.18 g, 6.67 mmol,
99%) as a white solid. Analytical sample was prepared by

M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
3051
calcd for C25H36NO4Si: (MHþ) m/z¼442.2415. Found:
m/z¼ 442.2406.
concentrated in vacuo. Purification of the residue by silica
gel column chromatography (CH2Cl2/acetone¼97:3) gave
13b (85.1 mg, 88%) as an oil. [a]2D0¼31.88 (c 1.01, CHCl3).
IR (film): 3450, 3320, 2950, 2850, 1660, 1590, 1380, 1250,
4.7. (3S,4R,5S)-3,4-Dibenzyloxy-5-(t-butyldiphenyl-
siloxy)methylpyrrolidin-2-thione (12)
1
1090, 1050, 1020 cm21. H NMR (400 MHz, CDCl3): d
1.25, 1.28 (each 3H, t, J¼7.1 Hz, OCH2CH3£2), 2.14 (1H,
br t, J¼5.5 Hz, alcoholic proto), 3.83 (2H, m, C5CHHO),
4.05–4.25 (6H, C4H, C5H, OCH2CH3£2), 4.44, 4.63 (each
1H, J¼11.7 Hz, PhCH2O), 4.62, 4.69 (each 1H, d,
J¼11.0 Hz, PhCH2O), 5.37 (1H, d, J¼2.8 Hz, C3H),
7.25–7.37 (10H, aromatic protons), 9.12 (1H, br, NH). EI-
MS (rel. int.%): m/z¼470 (0.40, MHþ), 424 (2.2,
[M2EtO]þ), 378 (1.3, [M2Bn]þ), 363 (2.4, [M2BnO]þ),
91 (100, PhCHþ2 ). EI-HIMS: calcd for C26H32NO7 (Mþ):
m/z¼470.2196. Found: m/z¼470.2180.
A mixture of 11 (501 mg, 1.13 mmol) and Lawesson’s
reagent (460 mg, 1.13 mmol) in toluene (5.0 mL) was
heated at 608C for 40 min. After cooling, the mixture was
filtered and the filtrate was concentrated in vacuo.
Purification of the residue by silica gel column chromato-
graphy (hexane/Et2O¼70:30) gave 12 (500 mg, 97%) as an
oil. [a]2D0¼21238 (c 2.16, CHCl3). IR (film): 3300, 2800,
1
1530, 1500, 1380, 1250, 1110 cm21. H NMR (400 MHz,
CDCl3): d 0.04 (6H, s, (CH3)2Si), 0.87 (9H, s, (CH3)3CSi),
3.73 (1H, dd, J¼3.5, 10.6 Hz, C5CHHO), 3.76 (1H, dd,
J¼6.8, 10.6 Hz, C5CHHO), 3.89 (1H, ddt, J¼1.3, 3.8,
6.8 Hz, C5H), 4.23 (1H, dd, J¼5.5, 6.8 Hz, C4H), 4.42 (1H,
d, J¼5.5 Hz, C3H), 4.47, 4.58 (each 1H, d, J¼11.9 Hz,
PhCH2O), 4.89, 5.26 (each 1H, d, J¼11.6 Hz, PhCH2O),
7.20–7.46 (10H, m, aromatic protons), 7.90 (1H, br, amide
proton). EI-MS (rel. int.%): m/z¼458 (0.10, MHþ), 442 (1.1,
[M2Me]þ), 400 (3.2, [M2tBu]þ), 351 (5.8, [MH2BnO]þ),
91 (100, PhCH2þ). EI-HIMS: calcd for C25H36NO3SSi (Mþ):
m/z¼458.2187. Found m/z¼ 458.2714.
4.10. Diethyl (3R,4R,5S)-2-[3,4-dibenzyloxy-5-(methane-
sulfoxy)methylpyrrolidin-2-ylidene]malonate (13c)
A mixture of 13b (84.0 mg, 179 mmol), methanesulfonyl
chloride (17.0 mL, 24.7 mg, 215 mmol), and Et3N
(42.0 mL, 30.5 mg, 300 mmol) in CH2Cl2 (2.5 mL) was
stirred at 2788C. After stirring for 2 h, MeOH (100 mL) was
added to the mixture to decompose excess reagent. The
mixture was poured into water and extracted with Et2O. The
combined extracts were washed with brine, dried over
MgSO4, then concentrated in vacuo. Purification of the
residue by silica gel column chromatography (CH2Cl2/
acetone¼97:3) gave 13c (86.5 mg, 88%) as an oil.
[a]2D0¼2.838 (c 1.13, CHCl3). IR (film): 3350, 2980, 2920,
1720, 1660, 1590, 1360, 1250, 1180, 1100, 1010, 740 cm21
.
1H NMR (400 MHz, CDCl3): d 1.25 (3H, t, J¼7.2 Hz,
OCH2CH3), 1.28 (3H, t, J¼7.1 Hz, OCH2CH3), 3.02 (3H, s,
CH3SO3), 4.09–4.46 (9H, C4H, C5H, C5CHHO,
OCH2CH3£2, PhCHHO), 4.59 (1H, J¼11.7 Hz, PhCHHO),
4.60, 4.68 (each 1H, d, J¼11.1 Hz, PhCH2O), 5.34 (1H, d,
J¼2.0 Hz, C3H), 7.25–7.37 (10H, aromatic protons), 9.18
(1H, br, NH). EI-MS (rel. int.%): m/z¼502 (1.2, MHþ), 456
(0.7, [M2Bn]þ), 441 (0.6, [M2BnO]þ), 91 (100, PhCHþ2 ).
EI-HIMS: calcd for C27H34NO9S (Mþ): m/z¼548.1955.
Found: m/z¼548.1955.
4.8. Diethyl (3R,4R,5S)-2-[3,4-dibenzyloxy-5-(t-butyl-
dimethylsiloxy)methylpyrrolidin-2-ylidene]malonate
(13a)
A mixture of 12 (135 mg, 295 mmol) and diethyl bromo-
malonate (300 mg, 1.26 mmol) was stirred at room
temperature for 5 h. 1,8-Diazabicyclo[5.4.0]undec-7-ene
(500 mL, 509 mg, 3.3 mmol) was added to the mixture,
then the stirring was continued for 3 h. Triphenylphosphine
(100 mg, 381 mmol) was added, and the mixture was stirred
at room temperature for 5 h. The whole mixture was poured
into water and extracted with Et2O. The combined ethereal
extracts were washed with brine, dried over MgSO4, then
concentrated in vacuo. Purification of the residue by silica
gel column chromatography (hexane/Et2O¼65:35) gave
13a (142 mg, 82%) as an oil. [a]2D0¼þ10.48 (c 0.845,
CHCl3). IR (film): 3350, 2920, 1720, 1660, 1590, 1390,
4.11. Diethyl (3R,4R,5S)-2-[1-aza-3,4-dibenzyloxy-
bicyclo[3.1.0]hex-2-ylidene]malonate (3)
1
1250, 1100, 1010 cm21. H NMR (400 MHz, CDCl3): d
0.05, 0.06 (each 3H, s, (CH3)2Si), 0.90 (9H, s, (CH3)3CSi),
1.23, 1.27 (each 3H, t, J¼7.1 Hz, OCH2CH3£2), 3.75 (1H,
dd, J¼6.6, 10.4 Hz, C5CHHO), 3.77 (1H, dd, J¼4.8,
10.4 Hz, C5CHHO), 4.04 (1H, br q, J¼ca. 6 Hz, C5H),
3.90–4.26 (H, C4H, OCH2CH3£2), 4.47, 4.57 (each 1H,
J¼10.3 Hz, PhCH2O), 4.60, 4.65 (each 1H, d, J¼11.2 Hz,
PhCH2O), 5.30 (1H, d, J¼2.8 Hz, C3H), 7.26–7.38 (10H,
aromatic protons), 9.03 (1H, br, NH). EI-MS (rel. int.%):
m/z¼584 (0.10, MHþ), 564 (0.4, [M2Me]þ), 538 (1.7,
[M2EtO]þ), 526 (1.4, [M2tBu]þ), 480 (2.4, [M2tBu–
EtOH]þ), 91 (100, PhCHþ2 ). EI-HIMS: calcd for
C32H46NO7Si (Mþ): m/z¼584.3045. Found m/z¼584.3021.
A mixture of 13c (19.0 mg, 34.0 mmol) and potassium
bis(trimethylsilylamide) (0.5 M in toluene, 85 mL) was
stirred at 608C for 40 min. The mixture was poured into
water and extracted with AcOEt. The combined extracts
were washed with brine, dried over MgSO4, then concen-
trated in vacuo. Purification of the residue by silica gel
column chromatography (benzene/AcOEt¼90:10) gave 3
(9.6 mg, 63%) as an oil. IR (film): 2970, 2920, 1720, 1650,
1
1300, 1360, 1340, 1320, 1100, 1080, 750, 700 cm21. H
NMR (400 MHz, CDCl3): d 1.26, 1.34 (each 3H, t,
J¼7.1 Hz, OCH2CH3£2), 2.51 (1H, d, J¼3.8 Hz, C6H),
2.71 (1H, dd, J¼1.7, 5.1 Hz, C6H), 3.14 (1H, ddd, J¼3.8,
4.4, 5.1 Hz, C5H), 4.18, 4.22 (each 1H, dq, J¼10.8, 7.1 Hz,
OCH2CH3), 4.32 (1H, dd, J¼0.6, 4.4 Hz, C4H), 4.29, 4.37
(each 1H, dq, J¼10.1, 7.1 Hz, OCH2CH3), 4.41, 4.49 (each
1H, d, J¼11.7 Hz, PhCH2O), 4.63, 4.69 (1H, d, J¼11.3 Hz,
PhCH2O) 5.24 (1H, d, J¼0.6, 1.7 Hz). EI-MS (rel. int.%):
m/z¼406 (0.1, [M2EtO]þ), 360 (0.7, [M2Bn]þ), 91 (100,
4.9. Diethyl (3R,4R,5S)-2-(3,4-dibenzyloxy-5-hydroxy-
methylpyrrolidin-2-ylidene)malonate (13b)
A mixture of 13a (120 mg, 205 mmol) and TBAF (1.0 M in
THF, 250 mL) in THF (3.0 mL) was stirred at room
temperature. After stirring for 1.5 h, the mixture was

3052
M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
PhCHþ2 ). EI-HIMS: calcd for C19H22NO6 ([M2Bn]þ):
m/z¼360.1477 Found: m/z¼360.1477.
4.15. 2-(2-Methyl-2-propenyl)-4H-oxazol-5-one (21)
Treatments of N-3-methylbut-2-enoyl glycine (41.5 mg,
264 mmol) in the same manner as described in Section 4.14
gave crude 21 (36.5 mg, quantitative yield). IR (film): 2930,
1820, 1740, 1120, 910 cm21. 1H NMR (200 MHz, CDCl3):
d 1.95, 2.14 (each 3H, s), 4.22 (2H, s), 5.76 (1H, s). This
sample gradually colored by being kept at room temperature
in high concentration. Thus, it was immediately subjected to
the next step.
4.12. (2S,3R,4S)-3,4-Dibenzyloxy-2-(t-butyldimethyl-
siloxy)methyl-5-methoxy-3,4-dihydro-2H-pyrrole (17)
A mixture of 11 (116 mg, 259 mmol) and Me3OBF4 (70 mg,
473 mmol) in CH2Cl2 (3.0 mL) was stirred at room
temperature for 40 min. The mixture was poured into
saturated NaHCO3 aqueous solution and extracted with
Et2O. The combined extracts were washed with brine, dried
over K2CO3, then concentrated in vacuo to give 17 in almost
pure form (110 mg, 95%) as an oil. IR (film): 2920, 1640,
1450, 1350, 1250, 1110, 1020, 830, 770, 730, 690 cm21. 1H
NMR (200 MHz, CDCl3): d 0.01 (6H, s, (CH3)2Si), 0.86
(9H, s, (CH3)3CSi), 3.72 (1H, dd, J¼4.1, 10.5 Hz,
C2CHHO), 3.86 (3H, s, CH3O), 3.87 (2H, m, C2H,
C2CHHO), 4.30 (1H, t, J¼6.5 Hz, C3H), 4.59 (1H, d,
J¼11.7 Hz, PhCHHO), 4.60 (2H, s, PhCH2O), 4.66 (1H, d,
J¼6.5 Hz, C4H), 4.80 (1H, d, J¼11.7 Hz, PhCHHO), 7.33
(10H, m, aromatic protons). This sample was immediately
subjected to the next step.
4.16. 4-[(3R,4R,5S)-3,4-Dibenzyloxy-5-(t-butyldimethyl-
siloxymethyl)pyrrolidin-2-ylidene]-2-phenyl-4H-oxazol-
5-one (22)
4.16.1. Preparation from 17 (Table 2, run 1). A mixture of
17 (25.6 mg, 56.3 mmol) and 1914 (36.3 mg, 225 mmol) in
toluene (100 mL) was stirred at 808C for 12 h, then
concentrated in vacuo. Purification of the residue by silica
gel column chromatography (hexane/AcOEt¼80:20) gave
22 (11.0 mg, 33%) as an oil. IR (film): 3300, 2920, 1720,
1
1650, 1120, 1100, 840, 700 cm21. H NMR spectra of this
1
sample showed that it consists of the two tautomers. H
4.13. (2S,3R,4S)-3,4-Dibenzyloxy-2-(t-butyldimethyl-
siloxy)methyl-5-methylthio-3,4-dihydro-2H-pyrrole (18)
NMR (400 MHz, CDCl3, a¼0.75, b¼0.25): d 20.05
[3H£aþ6£b, s, Si(CH3)(E-isomer), Si(CH3)£2(Z-isomer)],
20.01 [3H£a, s, Si(CH3)(E-isomer)], 0.89 [9H£a, s,
A solution of 12 (500 mg, 1.13 mmol) was stirred in a
mixture of methyl iodide (500 mL, 1.14 g, 8.0 mmol) and
CH2Cl2 (5.0 mL) at room temperature in the dark. After
stirring for 12 h, the mixture was poured into a mixture of
aqueous saturated NaHCO3 solution (10 mL) and aqueous
10% Na2S2O3 solution (10 mL), then extracted with
Et2O. The combined extracts were washed with brine,
dried over MgSO4, then concentrated in vacuo to give an
almost pure sample of 18 (500 mg, 1.09 mmol, 97%) as an
oil. IR (film) 2920, 1580, 1250, 1110, 1020, 830, 780, 730,
(CH3)3CSi(E-isomer)],
0.91
[9H£b,
s,
(CH3)3-
CSi(Z-isomer)], 3.51 [1H£a, dd, J¼4.7, 10.2 Hz,
C5CHH(E-isomer)], 3.60 [1H£b, dd, J¼8.0, 10.1 Hz,
C5CHH(Z-isomer)], 3.63 [1H£a, dd, J¼6.8, 10.2 Hz,
C5CHH(E-isomer)], 3.64 [1H£b, dd, C5CHHO(Z-isomer)],
3.81 [1H£a, ddd, J¼4.7, 5.1, 6.8 Hz, C5H(E-isomer)], 3.89
[1H£b, br d, J¼4.1 Hz, C4H(Z-isomer)], 3.98 [1H£a, dd,
J¼2.4,
5.1 Hz,
C4H(E-isomer)],
3.99
[1H£b,
C5H(Z-isomer)], 4.01 [1H£a, br d, J¼12.0 Hz,
PhCHHO(Z-isomer)], 4.09, 4.25 [each 1H£a, d, J¼
12.0 Hz, PhCH2O (E-isomer)], 4.27 [1H£b, J¼12.0 Hz,
PhCHHO(Z-isomer)], 4.95 [1H£a, d, J¼11.8 Hz,
PhHHO(E-isomer)], 4.99, 5.02 [each 1H£b, d, J¼11.3 Hz,
PhCH2O(Z-isomer)], 5.10 [1H£a, d, J¼11.8 Hz,
1
700 cm21. H NMR (400 MHz, CDCl3): d 0.05 (6H, s,
(CH3)2Si), 0.96 (9H, s, (CH3)3CSi), 2.30 (3H, s, CH3S), 3.88
(1H, dd, J¼3.9, 10.1 Hz, C2CHHO), 3.92 (1H, dd, J¼2.9,
10.1 Hz, C2CHHO), 4.15 (1H, dddd, J¼0.6, 2.9, 3.9,
6.5 Hz, C2H), 4.25 (1H, dd, J¼5.6, 6.5 Hz, C3H), 4.34
(2H, s, PhCH2O), 4.58, 4.70 (each 1H, d, J¼11.8 Hz,
PhCH2O), 4.90 (1H, dd, J¼0.6, 5.6 Hz, C4H), 7.05–7.45
(10H, m, aromatic protons). EI-MS: (rel. int.%) m/z¼456
(1.3 [M2Me]þ), 414 (56, [M2tBu]þ), 91 (100, Bnþ).
CI-MS (isobutene): m/z¼472 (Mþ). This sample was
immediately subjected to the next step.
PhHHO(E-isomer)],
5.22
[1H£a,
d,
J¼2.4 Hz,
C3H(E-isomer)], 5.60 [1H£b br s, C3H(Z-isomer)], 5.98
[1H£b, br, amine proton(Z-isomer)], 7.00–7.20 (11H, m,
aromatic protons), 7.41 [2H£b, m, aromatic protons
(Z-isomer)], 7.50 [2H£a, m, aromatic protons(E-isomer)],
7.90 [1H£a, br, amine proton(E-isomer)], 8.00 (2H, m,
aromatic protons). EI-MS (rel. int.%): m/z¼584 (9.9, Mþ),
527 (1.0, [M2tBu]þ), 91 (100, PhCHþ2 ). EI-HIMS: calcd
for C34H40N2O5Si (Mþ): m/z¼584.2708. Found: m/z¼
584.2688.
4.14. 2-(1,1-Dimethylethyl)-4H-oxazol-5-one (20)
A suspension of N-pivaloyl glycine (160 mg, 1.0 mmol) and
1-cyclohexyl-3-(2-morphorinoethyl)carbodiimide metho-p-
toluenesulfonate14 (500 mg, 1.18 mmol) in THF (2.0 mL)
was stirred at room temperature. After stirring for 3 h, Et2O
was added. The resulting suspension was filtered and the
filtrate was concentrated in vacuo to give almost pure 20
(140 mg, quantitative yield) as a colorless oil. IR (film):
4.16.2. Preparation from 18 (Table 2, run 3). Treatments
of 18 (15.0 mg, 31.8 mmol) with 19 (20 mg, 124 mmol) in a
similar manner to those described in Section 4.16.1 gave 22
(15.3 mg, 82%) after silica gel column chromatography.
The 1H NMR spectrum of this sample was identical to that
described in Section 4.16.1.
1820, 1770, 1190, 1110, 890, 730 cm21 1H NMR
.
(200 MHz, CDCl3): d 1.28 (9H, s), 4.17 (2H, s). EI-MS
(rel int.%) m/z¼141 (1.2, Mþ), 126 (32, [M2Me]þ), 57
(100, tBuþ). This sample gradually colored by being kept at
room temperature in high concentration. Thus, it was
immediately subjected to the next step.
4.17. 4-[(3R,4R,5S)-3,4-Dibenzyloxy-5-(t-butyldimethyl-
siloxymethyl)pyrrolidin-2-ylidene]-2-(1,1-dimethyl-
ethyl)-4H-oxazol-5-one (23) (Table 2, run 6)
Treatments of 18 (15.0 mg, 31.8 mmol) with 20 (20 mg,

M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
3053
141 mmol) in the same manner as described in Section
4.16.1 gave 23 (300 mg, 0.5 mmol, 1.7%) as an oil, after
washed with brine, dried over MgSO4, then concentrated in
vacuo. Purification of the residue by silica gel column
chromatography (Et2O/hexane¼50:50!80:20) gave Z-26a
(19.0 mg, 65%) and E-26a (1.50 mg, 5.5%) both as an
oil.
1
silica gel column chromatography. The H NMR spectrum
of this sample showed that it consists of the two tautomers
1
arising from the enamine moiety (E/Z¼77:23). H NMR
(200 MHz, CDCl3, a¼0.77, b¼0.23, some signals of the
minor isomer could not be assigned). d 0.03, 0.58 [each
3H£a, s, (CH3)Si£2(E-isomer)], 0.88 [9H£a, s, (CH3)3CSi
(E-isomer)], 0.90 [9H£b, s, (CH3)3CSi(Z-isomer)], 1.29
[9H£b, s, (CH3)3C(Z-isomer)], 1.31 [9H£a, s, (CH3)3C(E-
isomer)], 3.78 (2H, m, C5CH2O), 4.11 (2H, m, C5H, C4H),
4.53, 4.48 (each 1H, d, J¼11.0 Hz, PhCH2O), 4.83, 4.95
(each 1H, d, J¼10.6 Hz, PhCH2O), 4.98 [1H£a, s, C3H(E-
isomer)], 5.24 [1H£b, s, C3H(E-isomer)], 6.63 [1H£b, br,
amine proton(Z-isomer)], 7.10–7.45 (10H, m, aromatic
protons), 7.60 [1H£a, br, amine proton(E-isomer)]. EI-MS
(rel int.%) m/z¼564 (6.9, Mþ), 507 (1.3, [M2tBu]þ), 91
(100, PhCHþ2 ). EI-HIMS: calcd for C32H44N2O5Si (Mþ):
m/z¼ 564.3021. Found: m/z¼564.3027.
4.19.2. Data of E-26a. IR (film): 3270, 2950, 2920, 1690,
1670, 1510, 1470, 1370, 1370, 1250, 1150, 1110, 1060, 830,
700 cm21 1H NMR (400 MHz, CDCl3, carzinophilin
.
numbering): d 0.007, 0.014 (each 3H, s, (CH3)Si £2), 0.86
(9H, s, (CH3)3CSi), 1.16, 1.13 (each 3H, d, J¼6.5 Hz,
(CH3)2CH–), 3.85 (1H, dd, J¼8.9, 9.8 Hz, C11CHHO),
3.92 (1H, dd, J¼6.5, 9.8 Hz, C11CHHO), 4.11 (1H, dd,
J¼1.3, 5.1 Hz, C12H), 4.14 (1H, m, (CH3)2CH–), 4.26 (1H,
ddd, J¼5.0, 6.5, 9.8 Hz, C11H), 4.41, 4.55 (each 1H, d,
J¼11.3 Hz, PhCH2O), 4.65, 4.69 (each 1H, d, J¼11.7 Hz,
PhCH2O), 5.23 (1H, br s, C13H), 6.59 (1H, br d, J¼8.0 Hz,
N5H), 7.20–7.35 (10H, aromatic protons), 7.44 (2H, m,
aromatic protons), 7.51 (1H, br t, J¼7.3 Hz, aromatic
proton), 7.93 (2H, br d, J¼7.3 Hz, aromatic protons), 9.97
(1H, br s, N16H). EI-MS (rel int.%) m/z¼743 (1.5, Mþ), 686
(0.5, [M2tBu]þ), 643 (3.2, [M2tBuCOOþH]þ), 91 (100,
PhCHþ2 ).
4.18. 4-[(3R,4R,5S)-3,4-Dibenzyloxy-5-(t-butyldimethyl-
siloxymethyl)pyrrolidin-2-ylidene]-2-(2-methyl-propen-
1-yl)-4H-oxazol-5-one (24) (Table 2, run 8)
Treatments of 18 (124 mg, 271 mmol) with 21 (36.5 mg,
264 mmol) in the same manner as described for Section
4.16.1 gave 24 (10.8 mg 7.2%) as an oil after silica gel
4.19.3. Data of Z-26a. IR (film) 3420, 3350, 1730, 1650,
1520, 1470, 1380, 1280, 1250, 1100, 840, 780, 750, 730,
700 cm21 1H NMR (400 MHz, CDCl3, carzinophilin
.
1
column chromatography. The H NMR spectrum of this
numbering): d 0.05, 0.08 (each 3H, s, (CH3)Si£2), 0.88
(9H, s, (CH3)3CSi), 1.15 (each 3H, d, J¼6.7 Hz,
(CH3)2CH–), 1.25 (each 3H, d, J¼6.3 Hz, (CH3)2CH–),
3.91 (1H, dd, J¼4.8, 10.3 Hz, C11CHHO), 3.93 (1H, dd,
J¼3.4, 10.3 Hz, C11CHHO), 4.11 (1H, m, (CH3)2CH–),
4.20 (1H, dd, J¼4.6, 7.1 Hz, C12H), 4.42 (1H, d,
J¼11.4 Hz, PhCHHO), 4.44 (1H, m, C11H), 4.51 (1H, d,
J¼11.4 Hz, PhCHHO), 4.61, 4.66 (each 1H, d, J¼11.3 Hz,
PhCH2O), 4.68 (1H, d, J¼4.8 Hz, C13H), 6.03 (1H, br d,
J¼8.1 Hz, N5H), 7.16–7.39 (12H, aromatic protons), 7.45
(1H, br t, J¼7.5 Hz, aromatic proton), 7.58 (2H, br dd,
J¼1.3, 7.5 Hz, aromatic protons), 7.86 (1H, br s, N16H). EI-
MS (rel int.%) m/z¼743 (1.0, Mþ), 686 (1.0, [M2tBu]þ),
643 (3.1, [M2tBuCOOþH]þ), 91 (100, PhCH2þ).
sample showed that it consists of the two tautomers arising
from its enamine moiety (E/Z¼78:22). 1H NMR (400 MHz,
CDCl3, a¼0.78, b¼0.22, some signals of the minor isomer
could not be assigned). d 0.45 [3H£a, s, (CH3)Si(E-
isomer)], 0.70 [6H£bþ3H£a, s, (CH3)Si£2(Z-isomer)],
(CH3)Si(Z-isomer)], 1.94, 2.17 (each 3H, br s,
CvC(CH3)2), 3.78 [2H£a, d, J¼5.6 Hz, C5CH2O(major)],
3.97 [2H£b, d, J¼4.2 Hz, C5CH2O(major)], 4.13 (2H, m,
C5H, C4i), 4.32 [1H£b, d, J¼12.0 Hz, PhCHHO(Z-
isomer)], 4.40 [1H£a, d, J¼12.0 Hz, PhCHHO(E-isomer)],
4.44 (1H, d, J¼12.0 Hz, PhCHHO), 4.77 [1H£b, d,
J¼11.0 Hz, PhCHHO(Z-isomer)], 4.78 [1H£a, d, J¼
11.8 Hz, PhCHHO(Z-isomer)], 4.83 [1H£a, d, J¼11.8 Hz,
PhCHHO(Z-isomer)], 4.85 [1H£a, d, J¼11.8 Hz,
PhCHHO(Z-isomer)], 5.03 [1H£a, d, J¼1.3 Hz, C3H(E-
isomer)], 5.28 (1H£a, s, C3H(E-isomer)), 5.80 [1H, quint,
J¼1.2 Hz, CHvC(CH3)2(Z-isomer)], 5.82 [1H, quint,
J¼1.2 Hz, CHvC(CH3)2(E-isomer)], 6.65 [1H£b, br,
amine proton(Z-isomer)], 7.15–7.42 (10H, m, aromatic
protons), 7.75 [1H, br s, amine proton(E-isomer)]. EI-MS
(rel int.%) m/z¼562 (9.4, Mþ), 414 (30, [M2Bn–
isobutene]þ), 91 (100, PhCHþ2 ).
4.20. (3R,4R,5S)-2-[(E)-1-Benzoylamino-1-[N-(1-methyl-
ethyl)carbamoyl]methylidene]-3,4-dibenzyloxy-1-(2-
propenyloxy)carbonyl-5-(t-butyldimethylsiloxy)methyl-
pyrrolidine (E-26b) and its Z-isomer (Z-26b)
4.20.1. Reaction procedure. Treatments of 22 (520 mg,
890 mmol) with DMAP (1.0 g, 8.3 mmol) and Alloc2O
(202 mg, 1.08 mmol) in THF (1.0 mL) and following
addition of isopropyl amine (200 mL) in a similar manner
to that described in 4.19.1 gave Z-26b (127 mg, 20%) and
E-26b (296 mg, 45%) both as an oil, after silica gel column
chromatography.
4.19. (3R,4R,5S)-2-[(E)-1-Benzoylamino-1-[N-(1-methyl-
ethyl)carbamoyl]methylidene]-3,4-dibenzyloxy-1-(1,1,-
dimethylethoxyl)carbonyl-5-(t-butyldimethylsiloxy)-
methylpyrrolidine (E-26a) and its Z-isomer (Z-26a)
4.20.2. Data of E-26b. [a]2D0¼þ1478 (c 1.06, CHCl3). IR
4.19.1. Reaction procedure. A mixture of 22 (23.0 mg,
39.4 mmol), DMAP (7.20 mg, 59.0 mmol), and Boc2O
(12.7 mg, 58.0 mmol) in THF (1.0 mL) was stirred at
room temperature for 30 min. Isopropyl amine (100 mL,
excess) was added to the mixture and stirring was continued
for additional 30 min. The mixture was poured into water
and extracted with Et2O. The combined extracts were
(film): 3400, 3270, 2920, 2850, 1720, 1660, 1470, 1380,
1280, 1250, 1100, 830, 780, 730, 700 cm21 1H NMR
.
(400 MHz, CDCl3, carzinophilin numbering): d 0.04, 0.08
(each 3H, s, (CH3)Si£2), 0.88 (9H, s, (CH3)3CSi), 1.11 (3H,
d, J¼6.6 Hz, (CH3)2CH–), 1.22 (3H, d, J¼6.5 Hz,
(CH3)2CH–), 3.93 (2H, d, J¼3.5 Hz, C11CH2O), 4.12
(1H, m, (CH3)2CH–), 4.25 (1H, dd, J¼5.0, 7.4 Hz, C12H),

3054
M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
4.40 (1H, d, J¼11.4 Hz, PhCHHO), 4.49 (1H, dt, J¼3.5,
7.4 Hz, C11H), 4.55 (1H, d, J¼11.4 Hz, PhCHHO), 4.59
(1H, d, J¼9.6 Hz, PhCHHO), 4.59 (1H, m, CH2
vCHCHHO), 4.65 (1H, d, J¼9.6 Hz, PhCHHO), 4.65
(1H, m, CH2vCHCHHO), 4.69 (1H, d, J¼5.0 Hz, C13H),
5.24 (1H, dq, J¼10.4, 1.2 Hz, CHHvCHCH2O), 5.32 (1H,
dq, J¼17.0, 1.2 Hz, CHHvCHCH2O), 5.91 (1H, br d,
J¼8.3 Hz, N5H), 5.98 (1H, ddt, J¼10.4, 17.0, 6.1 Hz,
CH2vCHCH2O), 7.15–7.37 (12H, aromatic protons),
7.40 (1H, tat, J¼7.4, 1.2 Hz, aromatic protons), 7.59 (2H,
dq, J¼7.4, 1.2 Hz, aromatic protons), 7.98 (1H, br s, N16H).
EI-MS (rel. int.%): m/z¼727 (0.7, Mþ), 670 (2.1, [M2tBu]þ),
612 (3.0, [M2tBu–Me2CHNH]þ), 105 (69, PhCH2Oþ), 91
(100, PhCH2þ). EI-HIMS: calcd for C41H53N3O7Si (Mþ):
m/z¼727.3654. Found: m/z¼ 727.3619.
4.22. (3R,4R,5S)-2-[(E)-1-Benzoylamino-1-[N-(1-methyl-
ethyl)carbamoyl]methylidene]-3,4-dibenzyloxy-5-(t-
butyldimethylsiloxymethyl)pyrrolidine (28)
4.22.1. From E-26b. A mixture of E-26b (15.0 mg,
20.6 mmol), PPh3 (2.0 mg, 7.6 mmol), and dimedone
(4.0 mg, 28.6 mmol) in THF (1.0 mL) was stirred with
Pd(PPh3)4 (1.7 mg, 1.4 mmol) at room temperature for
10 min. The mixture was poured into water and extracted
with Et2O. The combined extracts were washed with brine,
dried over MgSO4, then concentrated in vacuo. Purification
of the residue by silica gel column chromatography (hexane/
Et2O¼75:25) gave 28 (11.6 mg, 87%) as an oil. Since the 1H
NMR spectrum of this sample was found to be complicated
due to the existence of tautomers arising from the C7–C8
double bond as well as the rotamers due to the carbamoyl
groups, assignment of all signals could not be performed.
Accordingly, signals of the major isomer (ca. 90%) are
4.20.3. Data of Z-26b. [a]2D0¼219.18 (c 1.76, CHCl3). IR
(film): 3400, 3270, 2950, 2920, 2850, 1700, 1670, 1510,
1460, 1380, 1310, 1250, 1110, 1060, 830, 770, 730,
1
described. H NMR (CDCl3): d 0.06, 0.07 (each 3H, s,
690 cm21
.
1H NMR (400 MHz, CDCl3, carzinophilin
(CH3)Si£2), 0.89 (9H, s, (CH3)3CSi), 1.11, 1.14 (each 3H,
d, J¼6.5 Hz, (CH3)2CH–), 3.67 (1H, dd, J¼6.4, 10.1 Hz,
C11CHHO), 3.79 (1H, dd, J¼4.7, 10.4 Hz, C11CHHO),
3.39 (1H, m, C11H), 4.07 (1H, m, (CH3)2CH–), 4.25 (1 h, d,
J¼11.4 Hz, PhCHHO), 4.27 (1H, dd, J¼4.6, 6.3 Hz, C12H),
4.52 (1H, d, J¼11.4 Hz, PhCHHO), 4.57 (1H, d, PhCHHO),
4.61 (1H, d, PhCHHO), 4.71 (1H, d, J¼4.6 Hz, C13H), 5.60
(1H, br d, J¼7.8 Hz), 7.05 (2H, m, aromatic protons), 7.20–
7.52 (10H, aromatic protons), 7.68 (2H, br d, J¼7.5 Hz,
aromatic protons), 8.42 (1H, br s, N16H). EI-MS (rel.
int.%): m/z¼643 (0.1, Mþ), 586 (1.7, [M2tBu]þ), 481 (9.2,
[M2tBu–PhCO]þ), 91 (100, PhCHþ2 ). EI-HIMS: calcd for
C37H49N3O5Si (Mþ): m/z¼634.3441. Found m/z¼
643.3459.
numbering): d 0.020, 0.024 (each 3H, s, (CH3)Si£2), 0.87
(9H, s, (CH3)3CSi), 1.01 (3H, d, J¼6.6 Hz, (CH3)2CH–),
1.13 (3H, d, J¼6.5 Hz, (CH3)2CH–), 3.88 (1H, t, J¼9.4 Hz,
C11CHHO), 3.95 (1H, dd, J¼4.6, 9.4 Hz, C11CHHO), 4.12
(1H, dd, J¼1.3, 4.7 Hz, C12H), 4.12 (1H, m, (CH3)2CH–),
4.33 (1H, dt, J¼9.4, 4.7 Hz, C11H), 4.42, 4.56 (each 1H, d,
J¼11.8 Hz, PhCHHO), 4.66, 4.69 (each 1H, d, J¼11.8 Hz,
PhCHHO), 4.71 (2H, dd, J¼1.1, 5.8 Hz, CH2vCHCH2O),
5.17 (1H, br s, C13H), 5.23 (1H, dq, J¼10.4, 1.1 Hz,
CHHvCHCH2O), 5.36 (1H, dq, J¼17.2, 1.1 Hz,
CHHvCHCH2O), 5.92 (1H, ddt, J¼10.4, 17.2, 4.7 Hz,
CH2vCHCH2O), 5.99 (1H, br d, J¼7.3 Hz, N5H), 7.23–
7.36 (10H, aromatic protons), 7.45 (2H, br t, J¼7.5 Hz,
aromatic protons), 7.52 (1H, br t, J¼7.5 Hz, aromatic
protons), 7.91 (2H, br d, J¼7.5 Hz, aromatic protons), 9.79
(1H, br s, N16H). EI-MS (rel. int.%) m/z¼727 (1.0, Mþ),
670 (1.7, [M2tBu]þ), 105 (80, BnOþ), 91 (100, Bnþ). EI-
HIMS: calcd for C41H53N3O7Si (Mþ): m/z¼727.3654.
Found m/z¼727.3636.
4.22.2. From Z-26b. The same treatments of Z-26b
(210 mg, 28.8 mmol) as described in Section 4.22.1 gave
1
28 (17.1 mg, 92%) as an oil. H NMR spectrum of this
sample was identical with that described in Section 4.22.1.
4.23. (3R,4R,5S)-2-[(E)-1-Benzoylamino-1-[N-(1-methyl-
ethyl)carbamoyl]methylidene]-3,4-dibenzyloxy-1-(2-
propenyloxy)carbonyl-5-hydroxymethylpyrrolidine (E-
29)
4.21. 4-[(3R,4R,5S)-3,4-Dibenzyloxy-5-(t-butyldimethyl-
siloxy)methylpyrrolidin-2-ylidene]-1-(1-methyl)ethyl-2-
phenyl-2-imidazol-5-one (27)
A mixture of E-26a (12.0 mg, 16.1 mmol), 2,6-di-t-butyl
pyridine (5.0 mL, 4.03 mg, 22.0 mmol), and TMSOTf
(4.2 mL, 4.83 mg, 22.0 mmol) in CH2Cl2 (1.0 mL) was
stirred at 08C for 30 min. The mixture was poured into water
and extracted with Et2O. The combined ethereal extracts
were washed with brine, dried over MgSO4, then concen-
trated in vacuo. Purification of the residue by silica gel
column chromatography (hexane/AcOEt¼80:20) gave 27
(8.0 mg, 68%) as an oil. IR (film), 2950, 2920, 1710, 1700,
1650, 1380, 1360, 1300, 1280, 1250, 1130, 1090, 835, 775,
A solution of E-26b (108 mg, 148 mmol) and conc. HCl
(12 M, 20 mL) in MeOH (3.0 mL) was stirred at room
temperature for 30 min. The mixture was poured into a
mixture of brine and saturated aqueous NaHCO3 solution
(1:1) and extracted with AcOEt. The combined extracts
were dried over MgSO4 and concentrated in vacuo.
Purification of the residue by silica gel column chromato-
graphy (CH2Cl2/acetone¼85:15) gave E-29 (89 mg, 98%)
as an oil. [a]2D0¼þ1268 (c 1.30, CHCl3). IR (film): 3500,
3200, 2970, 2920, 1720, 1640, 1480, 1380, 1100, 1020, 730,
690 cm21
.
1H NMR (200 MHz, CDCl3, carzinophilin
700 cm21 1H NMR (200 MHz, CDCl3, carzinophilin
.
numbering): d 0.02, 0.04 (each 3H, s, (CH3)Si2), 1.43
(3H, d, J¼6.5 Hz, (CH3)2CH–), 1.47 (9H, s, (CH3)3C–),
1.52 (3H, d, J¼ 6.5 Hz, (CH3)2CH–), 3.96 (1H, t,
J¼10.0 Hz, C11CHH), 4.05–4.35 (4H, C11H, C12H,
C11CHH, (CH3)2CH), 4.51–4.3.78 (4H, PhCH2O£2),
5.59 (1H, s, C13H), 7.28–7.63 (20H, aromatic protons).
EI-MS (rel. int.%): m/z¼726 (0.1, MHþ), 626 (1.7,
[M2Boc]þ), 91 (100, PhCHþ2 ).
numbering): d 1.12, 1.14 (each 3H, d, J¼7.2 Hz,
(CH3)2CH–), 3.07 (1H, br t, J¼7.2 Hz, alcoholic proton),
4.06 (3H, C11CH2O, (CH3)2CH–), 4.42 (1H, m, C11H),
4.44 (1H, d, J¼11.7 Hz, PhCHHO), 4.55 (1H, d, J¼11.7 Hz,
PhCHHO), 4.57 (1H, d, J¼11.7 Hz, PhCHHO), 4.59 (1H, br
dd, J¼5.8, 12.9 Hz, CH2vCHCHHO), 4.68 (1H, br dd,
J¼5.8, 12.9 Hz, CH2vCHCHHO), 4.83 (1H, d, J¼11.7 Hz,
PhCHHO), 4.84 (1H, br s, C3H), 5.23 (1H, dq, J¼10.5,

M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
3055
1.3 Hz, CHHvCHCH2O), 5.34 (1H, dq, J¼17.2, 1.3 Hz,
CHHvCHCH2O), 5.91 (1H, ddt, J¼10.5, 17.2, 5.8 Hz,
CH2vCHCH2O), 7.20–7.60 (13H, aromatic protons),
7.72–7.75 (4H, aromatic protons, NH£2), EI-MS (rel.
int.%): m/z¼613 (2.0, Mþ), 528 (5.6, [M2(CH3)2-
CHNHCOþH]þ), 105 (84, PhCH2Oþ), 91 (100, PhCH2þ).
EI-HIMS: calcd for C35H39N3O7 (Mþ): m/z¼613.2790.
Found: m/z¼613.2792.
J¼1.1 Hz, 7.4 Hz, aromatic protons), 7.61 (2H, br d,
J¼7.4 Hz, aromatic protons), 7.94 (1H, br s, N16H). EI-
MS (rel. int.%): m/z¼691 (0.05, Mþ), 105 (75, PhCH2Oþ),
91 (100, PhCH2þ).
4.26. (3R,4R,5S)-2-[(Z)-1-Benzoylamino-1-[N-(1-methyl-
ethyl)carbamoyl]methylidene]-3,4-dibenzyloxy-1-(2-
propenyloxy)carbonyl-5-methansulfoxymethyl-
pyrrolidine (Z-30)
4.24. (3R,4R,5S)-2-[(Z)-1-Benzoylamino-1-[N-(1-methyl-
ethyl)carbamoyl]methylidene]-3,4-dibenzyloxy-1-(2-
propenyloxy)carbonyl-5-hydroxymethylpyrrolidine (Z-
29)
Treatments of Z-29 (103 mg, 168 mmol) in the same manner
as described in Section 4.25 gave Z-30 (111 mg, 96%) as an
oil, after silica gel column chromatography. [a]2D0¼23.548
(c 1.30, CHCl3). IR (film): 3380, 3270, 2970, 2930, 1700,
1670, 1650, 1510, 1460, 1360, 1170, 1060, 980, 960, 730,
Treatments of Z-26b (13.0 mg, 17.9 mmol) in the same
manner as described in Section 4.23 gave Z-29 (10.2 mg,
93%) as an oil, after silica gel column chromatography.
[a]2D0¼þ23.48 (c 1.41, CHCl3). IR (film): 3400, 3300, 2970,
700 cm21 1H NMR (400 MHz, CDCl3, carzinophilin
.
numbering): d 1.09, 1.17 (each 3H, d, J¼6.6 Hz,
(CH3)2CH–), 2.79 (3H, s, CH3SO3), 4.36 (1H, t,
C11CHHO), 4.46 (1H, dd, J¼1.2, 5.7 Hz, C12H), 4.47
(1H, m, (CH3)2CH–), 4.50 (3H, C5CHHO, PhCHHO£2),
4.57 (1H, d, J¼11.1 Hz, PhCHHO), 4.62 (1H, ddd, J¼4.7,
5.7, 9.1 Hz, C11H), 4.71 (2H, br d, J¼5.7 Hz, CH2
vCHCH2O), 4.77 (1H, d, J¼11.5 Hz, PhCHHO), 5.24
(1H, dq, J¼10.5, 1.1 Hz, CHHvCHCH2O), 5.33 (1H, dq,
J¼17.3, 1.1 Hz, CHHvCHCH2O), 5.51 (1H, br s, C3H),
5.91 (1H, ddt, J¼10.5, 17.3, 5.7 Hz, CH2vCHCH2O), 6.13
(1H, br d, J¼8.1 Hz, N5H), 7.17 (2H, br dd, J¼1.6, 7.3 Hz,
aromatic protons), 7.24–7.38 (10H, aromatic protons),
7.46–7.92 (5H, m, aromatic protons), 9.54 (1H, br,
N16H). CI-MS (isobutane): m/z¼732 ([MþC4H7]þ), 692
(MHþ), 633 ([MH2isopropylamine]þ).
1700, 1670, 1510, 1470, 1390, 1310, 1070, 730, 700 cm21
.
1H NMR (400 MHz, CDCl3, carzinophilin numbering): d
1.12, 1.18 (each 3H, d, J¼6.5 Hz, (CH3)2CH–), 2.51 (1H,
br, alcoholic proton), 4.16 (1H, m, (CH3)2CH–), 4.17 (1H,
dd, J¼1.0, 6.0 Hz, C12H), 4.37 (1H, J¼3.2, 6.0 Hz, C11H),
4.48 (1H, d, J¼11.9 Hz, PhCHHO), 4.52, 4.59 (each 1H, d,
J¼11.6 Hz, PhCH2O), 4.67 (2H, br d, J¼5.6 Hz, CH2
vCHCH2O), 4.82 (1H, d, J¼11.9 Hz, PhCHHO), 5.19 (1H,
dq, J¼10.5, 1.5 Hz, CHHvCHCH2O), 5.28 (1H, dq,
J¼17.3, 1.5 Hz, CHHvCHCH2O), 5.56 (1H, br s, C3H),
5.87 (1H, ddt, J¼10.5, 17.3, 5.6 Hz, CH2vCHCH2O), 6.24
(1H, br d, J¼8.1 Hz, N5H), 7.25–7.40 (10H, aromatic
protons), 7.46–7.92 (5H, m, aromatic protons), 9.56 (1H, br,
N16H). EI-MS (rel. int.%): m/z¼613 (4.3, Mþ), 570 (0.5,
[M2isopropyl]þ), 555 (0.8, [M2ally alcohol]þ), 528 (0.7,
[M2(CH3)2CHNHCOþH]þ), 105 (83, PhCH2Oþ), 91 (100,
PhCH2þ). EI-HIMS: calcd for C35H39N3O7 (Mþ):
m/z¼613.2790. Found: m/z¼613.2765.
4.27. (3R,4R,5S)-2-[(E)-1-Benzoylamino-1-[N-(1-methyl-
ethyl)carbamoyl]methylidene]-3,4-dibenzyloxy-5-
hydroxymethylpyrrolidine (31)
Treatments of 28 (14.0 mg, 21.7 mmol) in the same manner
as described in Section 4.23 gave 31 (9.0 mg, 77%) as an oil,
after silica gel column chromatography. The 1H NMR
spectrum of this sample showed that it consists of the four
isomers arising from tautomers and rotamers (isomer
4.25. (3R,4R,5S)-2-[(E)-1-Benzoylamino-1-[N-(1-methyl-
ethyl)carbamoyl]methylidene]-3,4-dibenzyloxy-1-(2-
propenyloxy)carbonyl-5-methansulfoxymethyl-
pyrrolidine (E-30)
1
ratio¼5:2:2:1). H NMR (400 MHz, some signals of the
A mixture of E-29 (87.0 mg, 142 mmol), Et3N (40 mL,
29 mg, 285 mmol), and MsCl (15 mL, 22.0 mg, 193 mmol)
in CH2Cl2 (3.0 mL) was stirred at 2788C for 2 h. After
excess reagent was decomposed by MeOH (100 mL), the
mixture was poured into water and extracted with AcOEt.
The combined extracts were washed with brine, dried over
MgSO4 and concentrated in vacuo. Purification of the
residue by silica gel column chromatography (CH2Cl2/
acetone 85:15) gave E-30 (86.5 mg, 88%) as an oil.
[a]2D0¼þ1478 (c 1.01, CHCl3). IR (film): 3370, 2970,
minor isomer could not be assigned.): d 0.78, 0.80 [each
3H£0.2, d, J¼6.6 Hz, (CH3)2CH–(the second isomer)],
1.11, 1.13 [each 3H£0.5, d, J¼6.6 Hz, (CH3)2CH–(major
isomer)], 1.12, 1.14 [each 3H£0.2, d, J¼6.6 Hz,
(CH3)2CH–(another second isomer)], 2.72–3.00 (1H, br,
OH), 3.19 [1H£0.2, dd, J¼3.9, 10.7 Hz, C5CHHO–(the
second isomer)], 3.73 [2H£0.5, m, C5CH2O(major iso-
mer)], 4.06 (1H, m, (CH3)2CH–), 4.25 (1H, m, C5CHHO)],
3.38 [1H£0.5, dd, J¼5.2, 6.7 Hz, C12H(major)], 4.55–4.72
(2H, PhCH2O), 4.67 [1H£0.2, d, J¼11.2 Hz, PhCHHO(the
second isomer)], 4.77 [[1H£0.2, d, J¼11.2 Hz, PhCHHO
(the second isomer)], 4.78 [1H£0.2, d, J¼11.2 Hz,
PhCHHO (the second isomer)], 4.82 [1H£0.5, d,
J¼5.2 Hz, C12H(major isomer)], 4.95 [1H£0.2, dd,
J¼3.9, 2.7 Hz, C12H(the second isomer)], 5.08 [1H£0.2,
d, J¼4.2 Hz, C13H(the second isomer)], 5.40 [1H£0.2, br d,
J¼5.5 Hz, NH(the second isomer)], 5.53 [1H£0.5, br d,
J¼7.8 Hz, NH (major isomer)], 6.78 [1H£0.2, br d,
J¼7.8 Hz, NH (the second isomer)], 6.98–7.90 (15H,
aromatic protons), 8.12, 8.13 [each 1H£0.2, br NH(the
second isomer)£2], 8.48[1H£0.5, br s, NH (major isomer)].
2920, 1720, 1655, 1645, 1380, 1280, 1170, 750, 700 cm21
.
1H NMR (400 MHz, CDCl3, carzinophilin numbering): d
1.12, 1.14 (each 3H, d, J¼6.6 Hz, (CH3)2CH–), 3.08 (3H, s,
CH3SO3–), 4.11 (1H, (CH3)2CH–), 4.29 (1H, dd, J¼4.2,
7.4 Hz, C12H), 4.40–4.71 (9H, C11H, C11CH2O,
PhCH2O£2, CH2vCHCH2O), 4.73 (1H, d, J¼1.2 Hz,
C13H), 5.26 (1H, dq, J¼10.4, 1.3 Hz, CHHvCHCH2O),
5.32 (1H, dq, J¼17.2, 1.3 Hz, CHHvCHCH2O), 5.91 (1H,
ddt, J¼10.4, 17.2, 5.8 Hz, CH2vCHCH2O), 6.36 (1H, br d,
J¼8.1 Hz, N5H), 7.17 (1H, br d, J¼7.2 Hz, aromatic
protons) 7.24–7.38 (10H, aromatic protons), 7.50 (1H, tt,

3056
M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
EI-MS (rel int.%) m/z¼529 (1.1, Mþ), 444 (13, [M2(CH3)2-
CHCO]þ), 105 (85, PhCH2Oþ), 91 (100, PhCHþ2 ). EI-
HIMS: calcd for C31H35N3O5 (Mþ): m/z¼529.2563. Found:
m/z¼529.2579.
over MgSO4, then concentrated in vacuo. Purification of the
residue by silica gel column chromatography (AcOEt/
hexane¼50:50) gave 4a (8.2 mg, 64%) as an oil.
[a]2D0¼51.68 (c 0.760, CHCl3). IR (film): 3280, 1720,
1650, 1640, 1540, 1520, 1480, 1380, 1250, 1100, 1070,
1020, 730, 700 cm21. 1H NMR (400 MHz, CDCl3): d 1.17,
1.19 (each 3H, d, J¼6.5 Hz, (CH3)2CH–), 2.23 (1H, d,
J¼4.1 Hz, C10Hb), 2.35 (1H, d, J¼5.4 Hz, C10Ha), 3.06
(1H, dt, J¼4.1, 5.4 Hz, C11H), 4.08 (1H, m, (CH3)2CH–),
4.31, 4.49 (each 1H, d, J¼10.8 Hz, PhCH2O), 4.55 (1H, dd,
J¼4.1, 5.4 Hz, C12H), 4.64, 4.67 (each 1H, d, J¼12.0 Hz,
PhCH2O), 5.01 (1H, dd, J¼0.9, 4.1 Hz, C13H), 6.99 (2H, br
dd, J¼1.5, 7.0 Hz, aromatic protons), 7.07 (2H, br dd,
J¼1.5, 7.0 Hz, aromatic protons), 7.12 (1H, tt, J¼1.5,
7.0 Hz, aromatic protons), 7.30–7.42 (7H, aromatic pro-
tons), 7.47 (1H, tt, J¼1.5, 7.0 Hz, aromatic protons), 7.75
(2H, br dd, J¼1.5, 7.0 Hz, aromatic protons), 8.43 (1H, br s,
N16H), 9.47 (1H, br d, J¼7.5 Hz, N5H). EI-MS (rel int.%);
m/z¼511 (2.7, Mþ), 420 (13, [M2Bn]þ), 105 (97,
PhCH2Oþ), 91 (100, PhCHþ2 ). EI-HIMS: calcd for
C31H33N3O4 (Mþ): m/z¼511.2485. Found: m/z¼511.2479.
4.28. (3R,4R,5S)-2-[(E)-1-Benzoylamino-1-[N-(1-methyl-
ethyl)carbamoyl]methylidene]-3,4-dibenzyloxy-5-
methansulfoxymethylpyrrolidine (32)
4.28.1. Preparation from E-30. A mixture of E-30
(36.0 mg, 52.1 mmol), PPh3 (4.0 mg, 15.3 mmol), and
dimedone (8.0 mg, 57.0 mmol) in THF (1.0 mL) was stirred
with Pd(PPh3)4 (4.0 mg, 3.6 mmol) at room temperature.
After stirring for 10 min, the mixture was filtered through a
pad of silica gel, and filtrate was concentrated in vacuo.
Purification of the residue by silica gel column chromato-
graphy (CH2Cl2/acetone¼90:10) gave 28 (31.0 mg, 97%) as
1
an oil. Since the H NMR spectrum of this sample was
found to be complicated due to the existence of more than
three isomers, signals of the major isomer are mainly
assigned. IR (film): 3370, 3320, 2920, 1720, 1650, 1510,
1
1350, 1250, 1170, 1120, 1100, 730, 700 cm21. H NMR
(400 MHz, CDCl3): d 1.11, 1.12 (each 3H, d, J¼6.5 Hz,
(CH3)2CH), 2.91 (3H£0.04, s, CH3SO3), 2.98 (3H£0.02,
CH3SO3), 3.00 (3H£0.04, s, CH3SO3), 3.09 (1H£0.9, s,
CH3SO3), 4.06 (1H, m, (CH3)2CH), 4.10–4.66 (8H, C11H,
C11CH2O, C13H, PhCH2O£2), 4.69 (1H, d, J¼4.6 Hz,
C13H), 5.55 (1H, br d, J¼7.7 Hz, N5H), 7.00–7.85 (15H,
aromatic protons), 8.60 (1H, br, N16H). EI-MS (rel. int.%):
m/z¼607 (0.08, Mþ), 522 (7.8, [M2(CH3)2CHCO]þ), 105
(69, PhCH2Oþ), 91 (100, PhCHþ2 ). EI-HIMS: calcd for
C32H37N3O7S (Mþ): m/z¼607.2358. Found: m/z¼
607.2352.
4.30. (2R,3R)-3-(Benzyloxycarbonyl)amino-4-t-butyl-
diphenylsiloxy-2-butanol (34)
4.30.1. Reduction of N-Z-L-threonine. A solution of
N-benzyloxycarbonyl-L-threonine (10.2 g, 40.3 mmol) and
added borane methylsulfide complex (10 M, 15 mL) in THF
(80 mL) was stirred at 08C. The mixture was allowed to
warm to room temperature. After stirring for 16 h, the
mixture was cooled to 08C again, and water was added to
decompose the excess reagent. The mixture was poured into
water and extracted with AcOEt. The combined extracts
were washed with brine, dried over MgSO4, then concen-
trated in vacuo. Purification by silica gel column chroma-
tography (CH2Cl2/acetone¼60:40) gave (2R,3R)-2-
(benzyloxycarbonyl)amino-1,3-butanediol (7.27 g, 75%)
as an oil. The 1H NMR spectral data were identical to
those reported in the literature.31
4.28.2. Preparation from Z-30. Treatments of Z-30
(30.2 mg, 43.6 mmol) in the same manner as described in
Section 4.28.1 gave 32 (21.8 mg, 82%) as an oil, after silica
gel column chromatography. The 1H NMR spectrum of this
sample was almost identical to that of an authentic sample
except for small differences in the isomeric ratio.
4.30.2. Protection with TBDPS group giving 34. A
mixture of (2R,3R)-2-(benzyloxycarbonyl)amino-1,3-
butanediol (2.10 g, 8.78 mmol), TBDPSCl (4.50 g,
16.4 mmol), and Et3N (2.60 g, 25.7 mmol) in CH2Cl2
(18 mL) was stirred at 08C. The mixture was allowed to
warm to room temperature. After stirring for 12 h, the
mixture was poured into water and extracted with Et2O. The
combined extracts were washed with brine, dried over
MgSO4, and concentrated in vacuo. Purification of the
residue by silica gel column chromatography (benzene/
AcOEt¼85:15) gave 34 (2.35 g, 56%) as a white solid.
Analytical sample was prepared by recrystallization from
ether–hexane to give needles. Mp: 88–898C. [a]2D0¼0.008
(c 1.13, CHCl3). IR (nujor): 3520, 3300, 1680, 1550, 1460,
4.28.3. Preparation from 31. A mixture of 31 (9.0 mg,
16.0 mmol), Et3N (6.0 mL, 4.3 mg, 42 mmol), and MsCl
(1.5 mL, 2.2 mg, 19.3 mmol) in CH2Cl2 (1.0 mL) was stirred
at 2788C for 1 h. After excess reagent was decomposed by
MeOH (100 mL), the mixture was poured into water and
extracted with AcOEt. Combined extracts were washed with
brine, dried over MgSO4 and concentrated in vacuo.
Purification of the residue by silica gel column chromato-
graphy (CH2Cl2/acetone¼90:10) gave 32 (6.6 mg, 68%) as
1
an oil. The H NMR spectrum of this sample was almost
identical to that of an authentic sample except for small
differences in the isomeric ratio.
4.29. (3R,4R,5S)-2-[1-Benzoylamino-2-[N-(1-methyl-
ethyl)carbamoyl]methylene]-3,4-dibenzyloxy-1-
azabicyclo[3.1.0]hexane (4a)
1270, 1130, 1110, 1070, 700, 500 cm21 1H NMR
.
(200 MHz, CDCl3): d 1.06 (9H, s, (CH3)3CSi), 1.18 (3H,
d, J¼6.4 Hz, C1H3), 2.87 (1H, br, alcoholic proton), 3.58
(1H, br m, C3H), 3.83 (2H, br d, J¼3.7 Hz, C4H2O), 4.21
(1H, br q, J¼6.4 Hz, C2H), 5.10 (2H, s, PhCH2O), 5.40 (1H,
br, amide proton), 7.30 (11H, m, aromatic protons), 7.62
(4H, m, aromatic protons). Anal. calcd for C28H35NO4Si: C,
70.41%; H, 7.39%; N, 2.92%. Found C, 70.21%; H, 7.44%;
N, 2.78%.
A mixture of 32 (14.9 mg, 24.5 mmol) and potassium
bis(trimethylsilylamide) (0.5 M in hexane, 50 mL, 25 mmol)
in THF (1.5 mL) was stirred at room temperature for 5 min.
The mixture was poured into water and extracted with
AcOEt. Combined extracts were washed with brine, dried

M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
3057
4.31. (3R)-3-(Benzyloxycarbonyl)amino-4-t-butyl-
diphenylsiloxy-2,2-dimethoxybutane (35)
4.32.2. Oxidation giving 36. A suspension of (2R)-3-
(benzyloxycarbonyl)amino-3,3-dimethoxybutanol (97.0 mg,
343 mmol), PDC (645 mg, 1.72 mmol), and powdered
molecular sieves 4A (450 mg) in CH2Cl2 (3.0 mL) was stirred
at room temperature for 1.5 h. Celitew (2.0 g) and Et2O
(20 mL)wereaddedtothemixture, andthewholemixturewas
further stirred at room temperature for 20 min. The mixture
was filtered through a pad of Celitew, and the filtrate was
concentrated in vacuo. Purification of the residue by silica gel
column chromatography (benzene/AcOEt¼93:7) gave 36
(68.5 mg, 71%). IR (film) 3330, 2940, 1720, 1530, 1240,
1170, 1150 cm21. 1H NMR (200 MHz, CDCl3): d 1.23 (3H, s,
C1H3), 3.27(3H, s, CH3O), 3.34(3H, brs, CH3O), 4.66 (1H, br
d, J¼8.2 Hz, C2H), 5.12 (2H, s, PhCH2O), 5.37 (1H, br d,
J¼8.2 Hz, amideproton),7.36(5H,m,aromaticprotons), 9.77
(1H, s, C1HO).
4.31.1. Oxidation of the alcohol in 34. Sulfur trioxide
pyridine complex (3.60 g, 22.0 mmol) was added to a
mixture of 34 (2.70 g, 5.66 mmol) and Et3N (4.0 mL,
2.88 g, 28.5 mmol) in DMSO (12.0 mL) at room tempera-
ture. After stirring for 2.5 h, the mixture was poured into
water and extracted with Et2O. The combined extracts were
washed with brine, dried over MgSO4, then concentrated in
vacuo. Purification of the residue by silica gel column
chromatography (benzene/AcOEt¼96:4) gave (3R)-3-
(benzyloxycarbonyl)amino-4-t-butyldiphenylsiloxy-2-buta-
none (2.49 g, 5.24 mmol, 92%) as a white solid. Analytical
sample was prepared by recrystallization from ether-hexane
to give needles. Mp: 63–648C. IR (nujor): 3280, 1720,
1
1700, 1270, 1130, 1110, 710 cm21. H NMR (400 MHz,
CDCl3): d 1.01 (9H, s, (CH3)3CSi), 2.21 (3H, s, C1H3), 3.93,
4.11 (each 1H, dd, J¼3.3, 10.8 Hz, C4H2O), 4.48 (1H, dt,
J¼7.3, 3.3 Hz, C3H), 5.09 (2H, s, PhCH2O), 5.80 (1H, br d,
J¼7.3 Hz, amide proton), 7.38 (11H, m, aromatic protons),
7.63 (4H, m, aromatic protons). EI-MS (rel. int.%) m/z¼432
(1.0, [M2MeCvO]þ), 418 (3.2, [M2tBu]þ), 91 (100,
Bnþ).
4.33. (Z)-3-(Benzyloxycarbonyl)amino-4-hydroxybut-3-
ene-2-one (32c)
A mixture of 36 (17.0 mg, 64.9 mmol) and p-TsOH·H2O
(3.0 mg, 15.7 mmol) in a mixture of THF (700 mL) and H2O
(300 mL) was stirred at room temperature for 2 h. The
mixture was poured into sat. NaHCO3 solution, and the
aqueous solution was washed with Et2O. The aqueous
solution was acidified with conc. HCl and extracted with
AcOEt. The combined extracts were washed with brine,
dried over MgSO4, then concentrated in vacuo to give 32c
4.31.2. Dimethyl acetal formation giving 35. A solution of
the (2R,3R)-3-(benzyloxycarbonyl)amino-4-t-butyldiphe-
nylsiloxy-2-butanone (38.0 mg, 80.0 mmol) in a mixture
of MeOH (1.0 mL) and trimethyl orthoformate (1.0 mL)
was stirred in the presence of p-TsOH·H2O (3.0 mg,
15 mmol) at room temperature. After neutralization with
Et3N, the mixture was concentrated in vacuo. Purification of
the residue by silica gel column chromatography (benzene/
Et2O¼95:5) gave 35 as an oil. [a]2D0¼þ11.38 (c 1.04,
CHCl3). IR (film): 3350, 2950, 2930, 1730, 1510, 1110,
1050, 700 cm21. 1H NMR (200 MHz, CDCl3): d 1.03 (9H,
s, (CH3)3CSi), 1.28 (3H, s, C1H3), 3.15 (3H, s, CH3O), 3.19
(3H, br s, CH3O), 3.75 (1H, dd, J¼4.8, 10.5 Hz, C4HHO),
3.81 (1H, dd, J¼4.0, 10.5 Hz, C4HHO), 4.05 (1H, m, C3H),
4.96 (1H, br d, J¼10.5 Hz, amide proton), 5.08, 5.15 (each
1H, d, J¼7.42 Hz, PhCH2O), 7.42 (11H, m, aromatic
protons), 7.65 (4H, m, aromatic protons). EI-MS (rel int.%):
m/z¼490 (0.1, [M2MeO]þ), 464 (0.6, [M2tBu]þ), 432
(1.0, [M2MeC(OMe)2]þ), 91 (88, Bnþ), 89 (100, MeCþ-
(OMe)2). EI-HIMS: calcd for C29H36NO4Si ([M2MeO]þ):
m/z¼490.2415. Found m/z¼490.2401.
1
(11.4 mg, 75%) as an oil. H NMR (200 MHz, CDCl3): d
2.28 (3H, s, C1H3), 5.17 (2H, s, PhCH2O), 7.22 (1H, dd,
J¼1.2, 12.2 Hz, C4H), 7.38 (5H, m, aromatic protons), 7.60
(1H, br s, amide proton), 11.55 (1H, d, J¼12.2 Hz, OH). EI-
MS (rel int.%) m/z¼236 (1.6, MHþ), 235 (1.7, Mþ), 91
(100, Bnþ).
4.34. (Z)-3-(Benzyloxycarbonyl)amino-4-methoxybut-3-
ene-2-one (37)
An ethereal solution of CH2N2 (excess amount) was added
to a solution of 32c (11.4 mg, 48.5 mmol) in Et2O (3.0 mL)
at room temperature. After stirring for 10 h, the mixture was
concentrated in vacuo. Purification of the residue by
preparative silica gel TLC (CH2Cl2/acetone¼90:10) gave
37 (4.0 mg, 33%) as an oil. IR (film): 3300, 1720, 1640,
1500, 1250, 1120, 1050 cm21. 1H NMR (200 MHz, CDCl3):
d 2.24 (3H, s, C1H3), 3.93 (3H, s, CH3O), 5.14 (2H, s,
PhCH2O), 6.03 (1H, br s, NH), 7.14 (1H, s, C4H), 7.35 (5H,
m, aromatic protons). EI-MS (rel int.%): m/z¼249 (0.5,
Mþ), 206 (3.4, [M2MeCO]þ), 91 (100, Bnþ). Anal. calcd
for C13H15NO4: C, 62.64%; H, 6.07%; N, 5.61%. Found: C,
62.41%; H, 6.05%; N, 5.50%.
4.32. (2R)-2-(Benzyloxycarbonyl)amino-3,3-dimethoxy-
butanal (36)
4.32.1. Removal of the TBDPS group in 35. A mixture of
35 (1.40 g, 2.68 mmol) and TBAF (1.0 M in THF, 2.7 mL)
in THF (10 mL) was stirred at room temperature for 1.5 h.
The mixture was poured into water and extracted with
Et2O. The combined extracts were washed with brine, dried
over MgSO4, and concentrated in vacuo. Purification of the
residue by silica gel column chromatography (CH2Cl2/
acetone¼93:7) gave (2R)-3-(benzyloxycarbonyl)amino-
4.35. (3R)-3-Amino-4-(t-butyldiphenylsilyl)oxy-2-
butanone dimethyl acetal (38)
A suspension of 35 (2.61 g, 5.01 mmol) and 10% Pd/C
(300 mg) in MeOH (40 mL) was stirred vigorously at room
temperature under H2 atmosphere (1 atm) for 14 h. The
catalyst was removed by short Celitew column to give 38
(1.80 g, 93%) as an oil. [a]2D0¼þ13.08 (c 1.16, CHCl3). IR
(film): 330, 2930, 1430, 1110, 1060, 1040, 820, 700,
1
3,3-dimethoxybutanol (716 mg, 94%) as an oil. H NMR
(200 MHz, CDCl3): d 1.27 (3H, s, C1H3), 3.23, 3.26 (each
3H, s, CH3O£2), 3.75 (2H, br, C4H2O), 3.89 (1H, dt, J¼7.1,
4.8 Hz, C3i), 5.12 (2H, s, PhCH2O), 5.24 (1H, br d,
J¼7.1 Hz, amide proton), 7.35 (5H, m, aromatic protons).
1
500 cm21. H NMR (200 MHz, CDCl3): d 1.06 (9H, s,
(CH3)3CSi), 1.19 (3H, s, C1H3), 3.03, 3.14 (each 3H, s,

3058
M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
CH3O£2), 3.14 (1H, dd, J¼3.4, 7.5 Hz, C3H), 3.57 (1H, dd,
J¼7.5, 9.8 Hz, C4HHO), 3.77 (1H, dd, J¼3.4, 9.8 Hz,
C4HHO), 7.37, 7.65 (6H, H, respectively, m, aromatic
protons). EI-MS (rel int.%) m/z¼355 (1.5, [M2MeOH]þ),
330 (1.3, [M2tBu]þ), 298 (17, [M2tBu–MeOH], 89 (100,
MeCþ(OMe)2). EI-HIMS: calcd for C21H30NO2Si
([M2MeO]þ): m/z¼356.2047. Found: m/z¼356.2036.
amine proton(Z-isomer)], 7.78 [1H£a, br, amine proton(E-
isomer)].
4.36.3. Recrystallization of 39. A tautomeric mixture
(E/Z¼60:40) of 39 (630 mg) was dissolved in a mixture of
hexane/AcOEt (ca. 3:1). Standing the solution at room
temperature gave E-isomer of 39 (570 mg) as needles. Mp:
126–1298C. [a]2D0¼274.68 (c 1.08, CHCl3). IR (nujor):
3280, 1720, 1640, 1360, 1360, 1340, 1100, 950, 730,
4.36. 4-[(3R,4R,5S)-3,4-Dibenzyloxy-5-(methane-
sulfoxy)methylpyrrolidin-2-ylidene]-2-phenyl-4H-
oxazol-5-one (39)
1
690 cm21. H NMR (400 MHz, CDCl3): d 3.04 (3H, s,
CH3SO3), 4.21 (1H, dd, J¼1.8, 4.7 Hz, C4H), 4.35 (1H, d,
J¼11.8 Hz, PhCHHO), 4.36 (1H, dd, J¼7.6, 10.0 Hz,
C5CHHO), 4.42–4.52 (2H, C5H, PhCHHO), 4.56 (1H, d,
J¼11.8 Hz, PhCHHO), 4.90, 4.96 (each 1H, d, J¼11.7 Hz,
PhCH2O), 5.10 (1H, d, J¼1.8 Hz, C3H), 7.21 (2H, br dd,
J¼2.0, 7.9 Hz, aromatic protons), 7.32–7.50 (11H, aro-
matic protons), 7.78 (1H, br, amine proton), 7.99 (2H, m,
aromatic protons). Anal. calcd for C29H28N2O7S: C,
63.49%; H, 5.14%; N, 5.11%; S, 5.84%. Found: C,
63.57%; H, 5.08%; N, 5.07%; S, 5.81%.
4.36.1. Removal of the TBDMS ether in 25b. A mixture of
25b (170 mg, 291 mmol) and TBAF (1.0 M in THF,
500 mL) in THF (2.0 mL) was stirred at room temperature
for 2.5 h. The mixture was poured into water and extracted
with AcOEt. The combined extracts were washed with
brine, dried over MgSO4, then concentrated in vacuo.
Purification of the residue by silica gel column chromato-
graphy (hexane/AcOEt¼55:45) gave 4-[(3R,4R,5S)-3,4-
dibenzyloxy-5-hydroxymethylpyrrolidin-2-ylidene]-2-
phenyl-4H-oxazol-5-one (123 mg, 90%) as an oil. IR (film):
3300, 2920, 1720, 1640, 1600, 1580, 1320, 1300, 1090,
4.37. (E)-4-[(3R,4R,5S)-1-allyoxycarbonyl-3,4-dibenzyl-
oxy-5-(methanesulfoxy)methylpyrrolidin-2-ylidene]-2-
phenyl-4H-oxazol-5-one (E-40) and its Z-isomer (Z-40)
1
1070, 890, 740, 690 cm21. The H NMR spectrum of this
sample showed that it consists of the two tautomers arising
from its enamine moiety (E/Z¼60:40). 1H NMR (400 MHz,
CDCl3, a¼0.60, b¼0.40, some signals of the minor isomer
could not be assigned). d 2.36 [1H£a, br dd, J¼6.6, 5.2 Hz,
alcoholic proton (Z-isomer)], 3.83–4.03 [2Hþ1H£b,
C5CH2O, alcoholic proton (Z-isomer)], 4.10 [1H£b, d,
J¼4.3 Hz, C4H(Z-isomer)], 4.20–4.29 [1Hþ1H£a, C5H,
C4H(E-isomer)], 4.30 [1H£b, d, J¼11.9 Hz, PhCHHO(Z-
isomer)], 4.39, 4.59, [each 1H£a, d, J¼11.8 Hz,
PhCHHO(E-isomer)], 4.60 [1H£b, d, J¼11.9 Hz,
PhCHHO(Z-isomer)], 4.84, 4.91 [each 1H£b, PhCHHO],
(Z-isomer)), 4.92, 5.03 [each 1H£a, d, J¼11.6 Hz, PhCH2-
O(E-isomer)], 5.13 [1H£a, d, J¼2.2 Hz, C3H(E-isomer)],
5.37 [1H£b, s, C3H(Z-isomer)], 7.22 (2H, m, aromatic
protons), 7.30–7.50 (11H, m, aromatic protons), 7.59
[1H£b, br, amine proton (Z-isomer)], 7.82 [1H£a, br,
amine proton(E-isomer)], 7.91–8.00 (2H, m, aromatic
protons). EI-MS (rel. int.%): m/z¼470 (12, Mþ), 91 (100,
Bnþ). EI-HIMS: calcd for C28H26N2O5 (Mþ): m/z¼
470.1842. Found: m/z¼470.1839.
4.37.1. The reaction procedure. A mixture of 39 (20.0 mg,
36.5 mmol), DMAP (10 mg, 82.0 mmol), and Alloc2O
(13.5 mg, 72.3 mmol) in THF (1.0 mL) was stirred at
room temperature for 10 min. The mixture was poured
into water, and extracted with Et2O. The combined extracts
were washed with brine, dried over MgSO4, then concentrated
in vacuo. Purification of the residue by preparative silica gel
TLC (benzene/AcOEt¼90:10) gave E-40 (Rf¼0.77, 6.3 mg,
27%) and Z-39 (Rf¼0.73, 14.0 mg, 61%) as oils.
4.37.2. Data of E-40. [a]2D0¼þ1088 (c 0.461, CHCl3). IR
(film): 3420, 1790, 1720, 1570, 1360, 1255, 1170, 1110,
1
1055, 990, 960, 690 cm21. H NMR (400 MHz, CDCl3): d
2.92 (3H, s, CH3SO3), 4.23 (1H, dd, J¼1.0, 5.3 Hz, C3H),
4.53 (1H, t, J¼9.2 Hz, C5CHHO), 4.55, 4.62 (each 1H, d,
J¼11.7 Hz, PhCH2O), 4.66–4.74 (4H, C5H, CH2
vCHCHHO, PhCH2O), 4.77 (1H, ddt, J¼5.6, 13.0,
1.5 Hz, CH2vCHCHHO), 4.85 (1H, dd, J¼4.0, 9.3 Hz,
C5CHHO), 5.08 (1H, br s, C3H), 5.25 (1H, dq, J¼10.4,
1.5 Hz, CHHvCHCH2O), 5.32 (1H, dq, J¼17.2, 1.5 Hz,
CHHvCHCH2O), 5.93 (1H, ddt, J¼10.4, 17.2, 5.6 Hz,
CH2vCHCH2O), 7.23–7.40 (10H, aromatic protons), 7.51
(2H, br t, J¼7.7 Hz, aromatic protons), 7.57 (1H, br t,
J¼7.7 Hz, aromatic proton), 8.05 (2H, br t, J¼7.7 Hz,
aromatic protons). EI-MS (rel int.%): m/z¼632 (trace, Mþ),
496 (3.8, [M2CH2vCHCH2OMs]þ), 105 (66, PhCOþ), 91
(100, PhCHþ2 ). CI-MS (isobutane): m/z¼633 (MHþ). EI-
HIMS: calcd for C33H32N2O9S (Mþ): m/z¼632.1828.
Found: m/z¼632.1831.
4.36.2. Mesylation giving 39. A mixture of 4-[(3R,4R,5S)-
3,4-dibenzyloxy-5-hydroxy-methylpyrrolidin-2-ylidene]-2-
phenyl-4H-oxazol-5-one (590 mg, 1.26 mmol), MsCl
(281 mg, 2.45 mmol), and Et3N (377 mg, 3.74 mmol) in
CH2Cl2 (6.0 mL) was stirred at 2788C for 1 h. After MeOH
(300 mL) was added to decompose excess MsCl, the
mixture was poured into water and extracted with AcOEt.
The combined extracts were washed with brine, dried over
MgSO4, then concentrated in vacuo. Purification of the
residue by silica gel column chromatography (hexane/
1
AcOEt¼60:40) gave 39 (630 mg, 95%) as an oil. The H
4.37.3. Data of Z-40. [a]2D0¼þ1938 (c 1.39, CHCl3). IR
NMR spectrum of this sample showed that it consists of the
two tautomers arising from its enamine moiety
(E/Z¼60:40). 1H NMR (400 MHz, CDCl3, a¼0.60,
b¼0.40, some signals assignable are only described.): d
3.04 [3H£a, s, CH3SO3(E-isomer)], 3.07 [3H£b, s,
CH3SO3(Z-isomer)], 5.10 [1H£a, d, J¼1.8 Hz, C3H(E-
isomer)], 5.36 [1H£b, s, C3H(Z-isomer)], 7.03 [1H£b, br,
(film): 3400, 1770, 1620, 1570, 1360, 1280, 1170, 990, 960,
1
695 cm21. H NMR (400 MHz, CDCl3): d 2.92 (3H, s,
CH3SO3), 4.21 (1H, dd, J¼1.0, 4.8 Hz, C3H), 4.50–4.65
(5H, PhCHHO£3, C5H, C5CHHO), 4.68 (1H, ddt, J¼5.8,
13.0, 1.4 Hz, CH2vCHCHHO), 4.72 (1H, d, J¼11.4 Hz,
PhCHHO), 4.78 (1H, ddt, J¼5.8, 13.0, 1.4 Hz, CH2
vCHCHHO), 4.97 (1H, dd, J¼3.8, 8.8 Hz, C5CHH), 5.20

M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
3059
(1H, dq, J¼10.4, 1.4 Hz, CHHvCHCH2O), 5.33 (1H, dq,
J¼17.2, 1.4 Hz, CHHvCHCH2O), 5.46 (1H, br s, C3H),
5.91 (1H, ddt, J¼10.4, 17.2, 5.8 Hz, CH2vCHCH2O),
7.25–7.35 (10H, aromatic protons), 7.49 (2H, br t,
J¼7.5 Hz, aromatic protons), 7.57 (1H, br t, J¼7.5 Hz,
aromatic proton), 8.05 (2H, br t, J¼7.5 Hz, aromatic protons).
EI-MS (rel. int.%) m/z¼632 (0.05, Mþ), 526 (0.70, [M2PH
CHO]þ), 496 (2.5, [M2CH2vCHCH2OMs]þ), 105 (89,
PhCOþ), 91 (100, PhCHþ2 ). EI-HIMS: calcd for
C33H32N2O9S (Mþ): m/z¼632.1828. Found: m/z¼ 632.1803.
m, C3H), 4.47 (1H, dd, J¼4.5, 9.3 Hz, C11CHHO), 4.57
(2H, s, PhCH2O), 4.59 (1H, m, C11H), 4.69 (2H, br d,
J¼5.7 Hz, CH2vCHCH2O), 4.82 (1H, d, J¼11.4 Hz,
PhCHHO), 5.21 (1H, dq, J¼10.4, 1.4 Hz, CHHvCHCH2-
O), 5.30 (1H, dq, J¼17.2, 1.4 Hz, CHHvCHCH2O), 5.71
(1H, br s, C13H), 5.88 (1H, ddt, J¼10.4, 17.2, 5.7 Hz,
CH2vCHCH2O), 7.18–7.56 (15H, m, aromatic protons,
N5H), 7.63 (4H, m, aromatic protons), 7.88 (2H, br d,
J¼7.2 Hz, aromatic protons), 9.25 (1H, br s, NH). EI-MS
(rel. int.%): m/z¼872 (1.3, [M2tBu–CH3C(OCH3)2–H]þ),
851 (2.5, [M2CH3C(OCH3)2–H–PhH]þ), 794 (5.1, [872-
PhH]þ and/or [8512tBu]þ), 105 (83, PhCOþ), 91 (100,
4.38. (3R,4R,5S)-2-[(E)-1-Benzoylamino-1-[1-(t-butyl-
diphenylsiloxy)methyl-2,2-dimethoxypropyl]-car-
bamoyl]methylidene-3,4-dibenzyloxy-1-(prop-2-en-1-
yloxy)carbonyl-5-(methanesulfoxy)methylpyrrolidine
(E-41) and its Z-isomer (Z-41)
PhCHþ2 ).
SI-MS
(3-nitrobenzylalcohol):
m/z¼988
([M2CH3O]þ); SI-MS (3-nitrobenzylalcoholþNaCl):
m/z¼1042 ([MþNa]þ).
4.39. (3R,4R,5S)-2-[(E)-1-Benzoylamino-1-(1-formyl-
2,2-dimethoxypropyl)carbamoyl]methylidene-3,4-
dibenzyloxy-1-(prop-2-en-1-yloxy)carbonyl-5-(methane-
sulfoxy)methylpyrrolidine (E-42)
4.38.1. Preparation employing E-40. A mixture of E-40
(4.30 mg, 6.80 mmol), 38 (4.0 mg, 10.3 mmol), and DMAP
(1.0 mg, 8.2 mmol) in toluene (2.0 mL) was concentrated by
a rotary evaporator. The mixture was heated at 508C for 2 h.
Purification of the mixture by silica gel column chroma-
tography (benzene/AcOEt¼90:10!80:20) gave Z-41
(1.1 mg, 15%) and E-41 (5.2 mg, 75%) both as an oil.
4.39.1. Removal of the TBDPS group in E-41. A mixture
of E-41 (135 mg, 132 mmol) and HF–pyridine complex
(Aldrich, 300 mL) in pyridine (3.0 mL) was stirred at 08C
for 30 min. After the mixture was further stirred for 1 h at
room temperature, the mixture was poured into sat.
NaHCO3 solution and extracted with AcOEt. The combined
extracts were washed with brine, dried over MgSO4, then
concentrated in vacuo. Purification of the residue by silica
gel column chromatography (benzene/AcOEt¼60:40) gave
(3R,4R,5S)-2-[(E)-1-benzoylamino-1-(1-hydroxymethyl-
2,2-dimethoxypropyl)-carbamoyl]methyllidene-3,4-diben-
zyloxy-1-(prop-2-en-1-yloxycarbonyl-5-(methanesulfoxy)-
methylpyrrolidine (95.8 mg, 93%) as an oil. [a]2D0¼þ1398
(c 0.745, CHCl3). IR (film): 3400, 2930, 1720, 1660, 1510,
4.38.2. Preparation employing Z-40. Treatments of Z-40
(13.5 mg, 21.4 mmol) in the same manner as described in
Section 4.38.1 gave Z-41 (4.3 mg, 4.3 mmol, 20%), and
E-41 (15.0 mg, 14.7 mmol, 68%) both as oils.
4.38.3. Data of E-41. [a]2D0¼þ93.88 (c 1.06, CHCl3). IR
(film) 3370, 2920, 1715, 1670, 1500, 1470, 1355, 1270,
1170, 1110, 700 cm21
.
1H NMR (400 MHz, CDCl3,
carzinophilin numbering): d 0.90 (9H, s, (CH3)3CSi), 1.40
(3H, s, C1H3), 3.04 (3H, s, CH3SO3), 3.15, 3.21 (each 3H, s,
CH3O£2), 3.70 (1H, dd, J¼5.3, 10.3 Hz, C4HHO), 3.86
(1H, dd, J¼3.5, 10.3 Hz, C4HHO), 4.23 (1H, dd, J¼3.6,
6.7 Hz, C12H), 4.31 (1H, m, C3H), 4.35–4.66 (10H, m,
C13H, C11H, C11CH2O, PhCH2O£2, CH2vCHCH2O),
5.14 (1H, dq, J¼10.4, 1.4 Hz, CHHvCHCH2O), 5.21 (1H,
dq, J¼17.2, 1.4 Hz, CHHvCHCH2O), 5.81 (1H, ddt,
J¼10.4, 17.2, 5.7 Hz, CH2vCHCH2O), 6.90 (1H, br d,
J¼8.8 Hz, N5H), 7.12 (2H, m, aromatic protons), 7.23–7.40
(11H, m, aromatic protons), 7.49 (1H, br t, J¼7.9 Hz,
aromatic proton), 7.57 (4H, m, aromatic protons), 7.63 (2H,
br dd, J¼1.6, 7.9 Hz, aromatic protons), 7.73 (1H, br s,
N16H). EI-MS (rel int.%) m/z¼914 (0.04, [M2PhCO]þ),
872 (3.6, [M2tBu–CH3C(OCH3)2–H]þ), 851 (1.6,
[M2CH3C(OCH3)2–H–PhH]þ), 794 (3.7, [8722PhH]þ
and/or [8512tBu]þ), 105 (84, PhCOþ), 91 (100, Bnþ).
SI-MS (3-nitrobenzylalcohol): m/z¼988 ([M2CH3O]þ).
1
1470, 1370, 1280, 1170, 1040, 730, 700 cm21. H NMR
(400 MHz, CDCl3, carzinophilin numbering): d 1.26 (3H, s,
C1H3), 3.09 (3H, s, CH3SO3), 3.21, 3.23 (each 3H, s,
CH3O£2), 3.68–3.83 (3H, m, C4H2O, alcoholic proton),
4.09 (1H, m, C3H), 4.30 (1H, dd, J¼4.3, 7.1 Hz, C12H),
4.43 (1H, d, J¼11.5 Hz, PhCHHO), 4.46 (1H, dd, J¼4.0,
10.3 Hz, C11CHHO), 4.52 (1H, d, J¼4.8, 10.3 Hz,
C11CHHO), 4.61 (1H, d, J¼11.7 Hz, PhCHHO), 4.62–
4.69 (4H, m, C13H, C11H, CH2vCHCHHO, PhCHHO),
4.72 (1H, ddt, J¼5.8, 13.0, 1.4 Hz, CH2vCHCHHO), 5.27
(1H, dq, J¼10.4, 1.4 Hz, CHHvCHCH2O), 5.34 (1H, dq,
J¼17.2, 1.4 Hz, CHHvCHCH2O), 5.95 (1H, ddt, J¼10.4,
17.2, 5.8 Hz, CH2vCHCH2O), 6.45 (1H, br d, J¼6.7 Hz,
N5H), 7.17 (2H, m, aromatic protons), 7.26–7.58 (10H, m,
aromatic protons), 7.50–7.58 (3H, m, aromatic protons),
7.91 (1H, br, N16H). EI-MS (rel. int.%): m/z¼673 (0.3,
[M2BnOH]þ), 105 (75, PhCOþ), 91 (100, PhCHþ2 ). SI-MS
(3-nitrobenzylalcoholþKCl): m/z¼820 ([MþK]þ), 750
([M2CH3O]þ).
SI-MS (3-nitrobenzylalcoholþNaCl):
([MþNa]þ).
m/z¼1042
4.38.4. Data of Z-41. [a]2D0¼þ33.888 (c 0.96, CHCl3). IR
(film): 3400, 3270, 2950, 2920, 1700, 1670, 1380, 1360,
4.39.2. Oxidation giving E-42. A mixture of (3R,4R,5S)-2-
[(E)-1-benzoylamino-1-(1-hydroxymethyl-2,2-dimethoxy-
propyl)carbamoyl]methylidene-3,4-dibenzyloxy-1-(prop-2-
en-1-yloxy)carbonyl-5-(methanesulfoxy)methylpyrrolidine
(93.5 mg, 120 mmol), powdered molecular sieves 4A
(100 mg), and PDC (220 mg, 568 mmol) in CH2Cl2
(3.0 mL) was stirred at room temperature for 2 h. Celitew
(300 mg) and Et2O (15 mL), were added to the mixture
1
1300, 1170, 1110, 1060, 700 cm21. H NMR (400 MHz,
CDCl3, carzinophilin numbering):
d
0.93 (9H, s,
(CH3)3CSi), 1.37 (3H, s, C1H3), 2.70 (3H, s, CH3SO3),
3.15, 3.18 (each 3H, s, CH3O£2), 3.81 (1H, dd, J¼4.3,
10.5 Hz, C4HHO), 3.89 (1H, dd, J¼4.0, 10.5 Hz, C4HHO),
4.14 (1H, br d, J¼6.3 Hz, C12H), 4.31 (1H, t, J¼9.3 Hz,
C11CHHO), 4.43 (1H, d, J¼11.4 Hz, PhCHHO), 4.44 (1H,

3060
M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
successively, and the whole mixture was further stirred for
20 min at room temperature. After filtration, the filtrate was
concentrated in vacuo. Purification of the residue by silica
gel column chromatography (benzene/AcOEt¼60:40) gave
E-42 (63.8 mg, 68%). [a]2D0¼þ1918 (c 1.07, CHCl3). IR
(film): 3400, 2930, 1720, 1650, 1380, 1270, 1170, 1020,
1000, 700 cm21. 1H NMR (400 MHz, CDCl3, carzinophilin
numbering): d 1.34 (3H, s, C1H3), 3.08 (3H, s, CH3SO3),
3.26, 3.36 (each 3H, s, CH3O£2), 4.30 (1H, dd, J¼4.0,
7.0 Hz, C12H), 4.42 (1H, d, J¼11.5 Hz, PhCHHO), 4.50–
4.69 (8H, m, C13H, C11CH2O, PhCHHO£3, CH2vCH2O),
4.79 (1H, m, C11H), 4.89 (1H, d, J¼8.1 Hz, C3H), 5.24
(1H, dq, J¼1.4, 10.4 Hz, CHHvCH2O), 5.30 (1H, dq,
J¼1.4, 17.2 Hz, CHHvCH2O), 5.93 (1H, ddt, J¼10.4,
17.2, 5.9 Hz, OCH2CHvCH2), 6.81 (1H, br d, J¼8.1 Hz,
N5H), 7.15 (2H, br dd, J¼1.5, 7.5 Hz, aromatic
protons), 7.25–7.38, (10H, m, aromatic protons), 7.50
(1H, tt, J¼1.2, 8.0 Hz, aromatic proton), 7.56 (2H, bb,
J¼1.2, 8.0 Hz, aromatic protons), 7.81 (1H, br, N16H), 9.77
(1H, s, C4HO). EI-MS (rel. int.%): m/z¼593 (0.70,
[M2BnOH–CH3C(CH3)2þ], 105 (82, PhCOþ), 91 (100,
Bnþ). SI-MS (3-nitrobenzylalcoholþNaCl): m/z¼818
([MþK]þ).
(40.0 mg, 120 mmol) in the same manner as described in
Section 4.39.2 gave Z-41 (33.2 mg, 83%) as an oil after
silica gel column chromatography. [a]2D0¼þ42.68 (c 1.04,
CHCl3) IR (film): 3400, 2920, 2850, 1730, 1710, 1700,
1
1670, 1650, 1380, 1260, 1170, 1120, 730, 700 cm21. H
NMR (200 MHz, CDCl3, carzinophilin numbering): d 1.27
(3H, s, C1H3), 2.75 (3H, s, CH3SO3), 3.19, 3.27 (each 3H, s,
CH3O£2), 4.17 (1H, dd, J¼1.2, 5.6 Hz, C12H), 4.36 (1H, t,
J¼9.0 Hz, C11CHHO), 4.45 (1H, d, J¼11.4 Hz, PhCHHO),
4.52 (2H, m, C11CHHO, PhCHHO), 4.60 (1H, d,
J¼11.5 Hz, PhCHHO), 4.63 (1H, m, C11H), 4.73 (2H, dt,
J¼5.7, 1.2 Hz, CH2vCHCH2O), 4.83 (1H, d, J¼11.4 Hz,
PhCHHO), 4.83 (1H, d, J¼6.8 Hz, C3H), 5.25 (1H, dq,
J¼10.4, 1.2 Hz, CHHvCHCH2O), 5.34 (1H, dq, J¼17.2,
1.2 Hz, CHHvCHCH2O), 5.69 (1H, s, C13H), 5.92 (1H,
ddt, J¼10.4, 17.2, 5.7 Hz, CH2vCHCH2O), 6.77 (1H, br d,
J¼6.8 Hz, N5H), 7.26–7.38 (10H, m, aromatic protons),
7.46 (2H, br t, J¼7.3 Hz, aromatic protons), 7.55 (1H, br t,
J¼7.3 Hz, aromatic proton), 7.90 (12H, br d, J¼7.3 Hz,
aromatic protons), 9.61 (1H, br, N16H), 9.76 (1H, s, C4HO).
EI-MS (rel int.%): m/z¼593 (0.20, [M2BnOH –
CH3C(CH3)þ2 ], 105 (86, PhCOþ), 91 (100, Bnþ). SI-MS
(3-nitrobenzylalcoholþNaCl): m/z¼802 ([MþNa]þ), 741
([M2MeO]þ).
4.40. (3R,4R,5S)-2-[(Z)-1-Benzoylamino-1-(1-formyl-2,2-
dimethoxypropyl)carbamoyl]methylidene-3,4-dibenzyl-
oxy-1-(prop-2-en-1-yloxycarbonyl-5-(methanesulfoxy)-
methylpyrrolidine (Z-42)
4.41. (3R,4R,5S)-2-[(E)-1-benzoylamino-1-((Z)-4-
methoxybut-3-en-2-on-3-ylcarbamoyl)methylidene-3,4-
dibenzyloxy-1-(prop-2-en-1-yloxy)carbonyl-5-(methane-
sulfoxy)methylpyrrolidine (E-43)
4.40.1. Removal of TBDPS group in E-41. Treatments of
Z-41 (25 mg, 24.5 mmol) in the same manner as described in
Section 4.39.1 gave (3R,4R,5S)-2-[(Z)-1-benzoylamino-1-
(1-hydroxymethyl-2,2-dimethoxypropyl)-carbamoyl]-
methylidene-3,4-dibenzyloxy-1-(prop-2-en-1-yloxy)car-
bonyl-5-(methanesulfoxy)methylpyrrolidine (15.3 mg,
79%) as an oil after silica gel column chromatography.
[a]2D0¼27.748 (c 1.11, CHCl3). IR (film): 3480, 3250, 2920,
1700, 1660, 1510, 1475, 1390, 1355, 1310, 1170, 1060, 960,
A solution of E-42 (9.30 mg, 11.3 mmol) in a mixture of
THF (1.0 mL) and H2O (0.5 mL) was stirred with
p-TsOH·H2O (1.0 mg, 5.3 mmol) at room temperature for
30 min. The mixture was poured into water, extracted with
AcOEt. The combined extracts were washed with
brine, dried over MgSO4, then concentrated in vacuo to
give a crude (3R,4R,5S)-2-[(E)-1-benzoylamino-1-((Z)-4-
hydroxybut-3-en-2-on-3-ylcarbamoyl)methylidene-3,4-
dibenzyloxy-1-(prop-2-en-1-yloxy)carbonyl-5-(methane-
sulfoxy)methylpyrrolidine as an oil. IR (film): 3400, 3030,
2930, 1720, 1670, 1630, 1360, 2280, 1170, 960, 730,
700 cm21, 1H NMR (200 MHz, CDCl3): d¼2.23, 3.11 (each
3H, s, C1H3, CH3SO3, respectively), 4.32 (1H, dd, J¼4.5,
6.9 Hz, C12H), 4.36 (1H, d, J¼12.1 Hz, PhCHHO), 4.40–
4.77 (9H, m, C13H, C11H, C11CH2O, PhCHHO£3,
CH2vCHCH2O), 5.24 (1H, dq, J¼10.3, 1.2 Hz,
CHHvCHCH2O), 5.31 (1H, dd, J¼17.1, 1.2 Hz,
CHHvCHCH2O), 5.88 (1H, ddt, J¼10.3, 17.1, 6.1 Hz,
CH2vCHCH2O), 7.10–7.18 (2H, m, aromatic protons),
7.26 (1H, s, C4HOH), 7.27–7.48 (10H, m, aromatic
protons), 7.50–7.55 (3H, m, aromatic protons), 7.89, 8.65
(each 1H, br s, N5H, N16H), 12.48 (1H, br, C4HOH). This
sample was dissolved in a mixture of THF (1.0 mL) and
Et2O (2.0 mL). An excess amount of ethereal CH2N2 was
added, and the mixture was stood at room temperature for
12 h. After concentration in vacuo, purification of the
residue by silica gel column chromatography (AcOEt/
benzene¼70:30) gave E-43 (5.7 mg, 67% for 2 steps) as an
oil. [a]2D0¼þ90.08 (c 0.620, CHCl3). IR (film): 3370, 2930,
1720, 1660, 1355, 1280, 1260, 1170, 1100, 960, 730,
1
730, 700 cm21. H NMR (400 MHz, CDCl3, carzinophilin
numbering): d 1.22 (3H, s, C1H3), 2.80 (3H, s, CH3SO3),
3.12, 3.20 (each 3H, s, CH3O£2), 3.69 (1H, ddd, J¼4.6, 5.9,
11.6 Hz, C4HHO), 3.91 (1H, ddd, J¼3.5, 9.2, 11.6 Hz,
C4HHO), 4.12 (1H, br dd, J¼4.6, 9.2 Hz, OH), 4.18 (1H,
dd, J¼1.2, 5.6 Hz, C12H), 4.37 (1H, t, J¼8.9, Hz,
C11CHHO), 4.45 (1H, d, J¼11.4 Hz, PhCHHO), 4.51–
4.64 (4H, C5H, C5CHHO, PhCHHO£2), 4.73 (2H, br d,
J¼5.8 Hz, CH2vCHCH2O), 4.83 (1H, d, J¼11.7 Hz,
PhCHHO), 5.25 (1H, dq, J¼10.4, 1.4 Hz, CHHvCHCH2-
O), 5.34 (1H, dq, J¼17.2, 1.4 Hz, CHHvCHCH2O), 5.35
(1H, 1H, br s, C13H), 5.92 (1H, ddt, J¼10.4, 17.2, 5.8 Hz,
CH2vCHCH2O), 6.40 (1H, br d, J¼8.5 Hz, N5H), 7.23–
7.29 (10H, aromatic protons), 7.46 (2H, br t, J¼7.8 Hz,
aromatic protons), 7.55 (1H, br t, J¼7.8 Hz, aromatic
protons), 7.91 (1H, br t, J¼7.8 Hz, aromatic protons). EI-
MS (rel. int.%): m/z¼673 (0.2, [M2BnOH]þ), 105 (72,
PhCOþ), 91 (100, PhCHþ2 ). SI-MS (3-nitrobenzylalcohol):
m/z¼750 ([M2CH3O]þ). SIMS (3-nitrobenzylalcoholþ
NaCl): m/z¼804 ([MþNa]þ).
4.40.2. Oxidation giving Z-42. Treatments of (3R,4R,5S)-2-
[(Z)-1-benzoylamino-1-(1-hydroxymethyl-2,2-dimethoxy-
propyl)carbamoyl]methylidene-3,4-dibenzyloxy-1-(prop-2-
en-1-yloxy)carbonyl-5-(methanesulfoxy)methylpyrrolidine
700 cm21 1H NMR (400 MHz, CDCl3, carzinophilin
.
numbering): d 2.28, 3.06, 3.86 (each 3H, s, C1H3,
CH3SO3, CH3O, respectively), 4.29 (1H, dd, J¼3.7,

M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
3061
7.0 Hz, C12H), 4.42 (1H, d, J¼11.6 Hz, PhCHHO), 4.46–
4.43. (3R,4R,5S)-2-[(E)-1-benzoylamino-1-((Z)-4-
4.55 (3H, m, C11CH2O, PhCHHO), 4.61 (2H, m, CH2
vCHCH2O), 4.65 (2H, br s, PhCH2O), 4.67 (1H, d,
J¼3.7 Hz, C13H), 4.76 (1H, m, C11H), 5.21 (1H, dq,
J¼10.4, 1.2 Hz, CHHvCHCH2O), 5.27 (1H, dq, J¼17.2,
1.2 Hz, CHHvCHCH2O), 5.89 (1H, ddt, J¼10.4, 17.2,
6.0 Hz, CH2vCHCH2O), 7.02 (1H, s, C4H), 7.14–7.27
(1H, m, aromatic protons), 7.27–7.42 (10H, m, aromatic
protons), 7.51 (1H, dt, J¼7.4, 1.3 Hz, aromatic proton), 7.58
(2H, br dd, J¼1.3, 7.4 Hz, aromatic protons), 7.62, 7.76
(each 1H, br s, N5H, N16H). EI-MS (rel. int.%): m/z¼689
(0.1, [M2allyl alcohol]þ), 651 (0.2, [M2MsOH]þ), 105
(82, PhCOþ), 91 (100, PhCHþ2 ). CI-MS (isobutane):
m/z¼748 (Mþ).
methoxybut-3-en-2-on-3-ylcarbamoyl)methylidene-3,4-
dibenzyloxy-5-(methanesulfoxy)methylpyrrolidine
(E-44)
4.43.1. Preparation from E-43. A mixture of E-43 (5.7 mg,
7.63 mmol), Ph3P (1.0 mg, 3.8 mmol), AcOH (1.0 mL), and
Pd(Ph3P)4 (1.0 mg, 1.0 mmol) in THF (1.0 mL) was stirred
at room temperature for 10 min. After benzene (5.0 mL)
was added, the mixture was concentrated in vacuo.
Purification of the residue by silica gel column chromato-
graphy (CH2Cl2/acetone¼70:30) gave E-44 (2.90 mg, 57%)
as an oil. [a]2D0¼þ47.28 (c 1.14, CHCl3). IR (film) 3400,
3320, 3030, 3000, 2930, 1650, 1480, 1350, 1250, 1170,
1100, 960, 750, 700, 525 cm21 1H NMR (400 MHz,
.
4.42. (3R,4R,5S)-2-[(Z)-1-benzoylamino-1-((Z)-4-
methoxybut-3-en-2-on-3-ylcarbamoyl)methylidene-3,4-
dibenzyloxy-1-(prop-2-en-1-yloxycarbonyl-5-
(methanesulfoxy)methylpyrrolidine (Z-43)
CDCl3, carzinophilin numbering): d 2.22 (3H, s, C1H3),
3.09 (3H, s, CH3SO3), 3.87 (3.H, s, CH3O), 4.17 (1H, m,
C11H), 4.20 (1H, m, C11CHHO), 4.29 (1H, d, J¼11.1 Hz,
PhCHHO), 4.33 (1H, dd, J¼4.8, 6.8 Hz, C12H), 4.39 (1H,
m, C11CHHO), 4.56, 4.57 (each 1H, d, J¼11.9 Hz,
PhCH2O), 4.58 (1H, d, J¼11.1 Hz, PhCHHO), 4.74 (1H,
d, J¼4.8 Hz, C13H), 7.02 (2H, m, aromatic protons), 7.21–
7.39 (10H, aromatic protons), 7.42 (1H, br s, NH), 7.53 (1H,
br t, J¼7.3 Hz, aromatic proton), 7.72 (2H, br d, J¼7.3 Hz,
aromatic protons), 8.59 (1H, br s, NH). EI-MS (rel. int.%)
m/z¼631 (0.02, [M2MeOH]þ), 105 (79, PhCOþ), 91 (100,
PhCHþ2 ). CI-MS (isobutane): m/z¼664 (MHþ).
Similar treatments of Z-42 (33.2 mg, 42.6 mmol) to those
described in Section 4.41 gave crude (3R,4R,5S)-2-[(Z)-1-
benzoylamino-1-((Z)-4-hydroxybut-3-en-2-on-3-ylcarba-
moyl)methylidene-3,4-dibenzyloxy-1-(prop-2-en-1-yloxy)-
carbonyl-5-(methanesulfoxy)methylpyrrolidine. IR (film):
3310, 3020, 2930, 1700, 1670, 1630, 1520, 1510, 1380,
1
1360, 1300, 1245, 1170, 1065, 960, 730, 700 cm21, H
NMR (200 MHz, CDCl3, carzinophilin numbering): d 2.27
(3H, s, C1H3), 2.80 (3H, s, CH3SO3), 4.17 (1H, dd, J¼1.3,
5.7 Hz, C12H), 4.36 (1H, dd, J¼8.5, 9.2 Hz, C11CHHO),
4.41–4.58 (4H, m, C11CHHO, PhCHHO£3), 4.62 (1H, m,
C11H), 4.69 (2H, br d, J¼5.7 Hz, CH2vCHCH2O), 4.80
(1H, d, J¼11.5 Hz, PhCHHO), 5.25 (1H, dq, J¼10.4,
1.2 Hz, CHHvCHCH2O), 5.31 (1H, dq, J¼17.1, 1.2 Hz,
CHHvCHCH2O), 5.57 (1H, d, J¼1.3 Hz, C13H), 5.93 (1H,
ddt, J¼10.4, 17.1, 5.7 Hz, CH2vCHCH2O), 7.20–7.25
(2H, aromatic protons), 7.26 (1H, s, C4HOH), 7.26–7.60
(8H, aromatic protons), 7.43–7.60 (3H, m, aromatic
protons), 7.90 (2H, aromatic protons), 8.80, 9.57 (each
1H, br s, N5H, N16H), 12.37 (1H, br, C4HOH). The same
treatments as described in Section 4.42 gave Z-43 (24.9 mg,
78% in 2 steps) as an oil after silica gel column
chromatography. [a]D20¼þ5.108 (c 0.980, CHCl3). IR
(film): 3270, 2920, 1700, 1670, 1500, 1470, 1380, 1360,
4.43.2. Preparation from Z-43. The same treatments of
Z-43 (24.9 mg, 33.0 mmol) as described in Section 4.43.1
gave Z-44 (19.3 mg, 88%) after silica gel column chroma-
tography. 1H NMR (200 MHz, CDCl3): d 2.21 (3H, s,
C1H3), 2.97 (3H, s, CH3SO3), 3.77 (3H, s, CH3O), 4.20–
4.75 (8H, m, C12H, C11H, C11CH2O, PhCH2O£2), 5.31
(1H, s, C13H), 6.37 (1H, br s, NH), 7.12 (1H, s,
CC4HOMe), 7.20–7.52 (13H, m, aromatic protons), 7.85
(3H, m, NH, aromatic protons), 8.45 (1H, br s, NH). The 1H
NMR spectrum of this sample changed to one identical to
that of Z-44 after standing its CDCl3 solution at room
temperature for 12 h.
4.44. (3R,4R,5S)-2-[(E)-1-Benzoylamino-1-(4-methoxy-
3-buten-2-on-3-ylcarbamoyl)]methylidene-3,4-dibenzyl-
oxy-1-azabicyclo[3.1.0]hexane (4b)
1
1255, 1170, 1065, 730, 700 cm21. H NMR (400 MHz,
CDCl3, carzinophilin numbering): d 2.30 (3H, s, C1H3),
2.78 (3H, s, CH3SO3), 3.84 (3H, s, CH3O), 4.16 (1H, dd,
J¼1.1, 5.6 Hz, C12H), 4.36 (1H, t, J¼9.0 Hz, C11CHHO),
4.49 (1H, d, J¼11.3 Hz, PhCHHO), 4.50 (1H, dd, J¼2.4,
9.0 Hz, C11CHHO), 4.51 (1H, d, J¼11.3 Hz, PhCHHO),
4.56 (1H, d, J¼11.3 Hz, PhCHHO), 4.62 (1H, m, C11H),
4.71 (2H, br d, J¼5.7 Hz, CH2vCHCH2O), 4.80 (1H, d,
J¼11.3 Hz, PhCHHO), 5.23 (1H, dq, J¼10.4, 1.1 Hz,
CHHvCHCH2O), 5.32 (1H, dq, J¼17.2, 1.1 Hz,
CHHvCHCH2O), 5.69 (1H, br s, JvC13H), 5.91 (1H,
ddt, J¼10.4, 17.2, 5.7 Hz, CH2vCHCH2O), 7.18 (1H, s,
C4H), 7.21–7.39 (10H, m, aromatic protons), 7.47 (2H, br t,
J¼7.7 Hz, aromatic protons), 7.55 (1H, br t, J¼7.7 Hz,
aromatic proton), 7.61 (1H, br s, NH), 7.93 (2H, br d,
J¼7.3 Hz, aromatic protons), 9.55 (1H, br s, NH). SI-MS
(3-nitrobenzylalcoholþNaCl) m/z¼770 (MþNa). EI-MS
spectrum of this sample provided no useful information
about its structure.
Tetrabutylammonium fluoride (1 M in THF, 10 mL) was
added to a suspension of E-44 (5.2 mg, 8.4 mmol) and
powdered molecular sieves 4A (10 mg) in THF (1.0 mL).
After stirring at room temperature for 10 min, the mixture
was poured into water and extracted with AcOEt. The
combined extracts were washed with brine, dried over
MgSO4, then concentrated in vacuo. Purification of the
residue by preparative silica gel TLC (AcOEt) gave 4b
(Rf¼0.4, 3.5 mg, 73%) as an oil. [a]2D0¼þ43.58 (c 0.630,
CHCl3). IR (film): 3270, 3060, 3030, 2970, 2920, 1650,
1510, 1480, 1250, 1100, 730, 700 cm21 1H NMR
.
(200 MHz, CDCl3, carzinophilin numbering): d 2.23 (1H,
s, C1H3), 2.30 (1H, d, J¼4.1 Hz, C10Hb), 2.44 (1H, d,
J¼4.8 Hz, C10Ha), 3.10 (1H, ddd, J¼4.1, 4.1, 4.8 Hz,
C11H), 3.89 (3H, s, CH3O), 4.31 (1H, d, J¼10.7 Hz,
PhCHHO), 4.52 (1H, d, J¼10.7 Hz, PhCHHO), 4.59 (1H,
dd, J¼4.1, 4.7 Hz, C12H), 4.65, 4.69 (each 1H, d, J¼1.8 Hz,
PhCH2O), 5.01 (1H, dd, J¼1.0, 4.1 Hz, C13H), 6.97 (2H, br

3062
M. Hashimoto et al. / Tetrahedron 59 (2003) 3041–3062
10. Carcano, M.; Nicotra, F.; Panza, L.; Russo, G. J. Chem. Soc,
Chem. Commun. 1989, 297.
d, J¼7.3 Hz, aromatic protons), 7.07 (2H, tt, J¼1.2, 7.3 Hz,
aromatic protons), 7.14 (1H, tt, J¼1.2, 7.3 Hz, aromatic
proton), 7.16 (s, C4HOMe), 7.48 (1H, tt, J¼1.5, 5.7 Hz,
aromatic protons), 7.74 (2H, tt, J¼1.5, 5.7 Hz, aromatic
proton), 8.28 (1H, br s, N16H), 11.03 (1H, br s, N5H). EI-
MS (rel. int.%): m/z¼567 (0.43, Mþ), 550 (0.30,
[M2OH]þ), 536 (0.30, [M2CH3O]þ), 524 (0.40,
[M2CH3CO]þ), 476 (1.1, [M2BnOH]þ), 105 (84,
PhCOþ), 91 (100, PhCH2þ). CI-MS (isobutane): m/z¼568
(MHþ), 550 ([M2OH]þ), 536 ([M2CH3O]þ).
11. Guanti, G.; Banfi, L.; Narisano, E.; Scolastico, C.; Bossone, E.
Synthesis 1985, 609.
12. Pedersen, B. S.; Lawesson, S.-O. Tetrahedron 1979, 35, 2433.
13. Weintraub, L.; Oles, S. R.; Kalish, N. J. Org. Chem. 1968, 33,
1679.
14. Hoyng, C. F.; McKenna, M.; Novak, K. Syn. Commun. 1980,
10, 761.
15. Levin, J. I.; Turos, E.; Weinreb, S. M. Syn. Commun. 1982, 12,
989.
16. Ohfune, Y.; Tomita, M. J. Am. Chem. Soc. 1982, 104, 3511.
17. PC Spartan Pro Ver.1.08 (Wavefunction Inc.) was employed
for calculations.
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