Synthetic studies of carzinophilin. Part 3: Synthetic approach toward carzinophilin and successful synthesis of 13-O-desacetyl-12,13-di-O-benzyl-4-O-methylcarzinophilin

Article abstract of DOI:10.1016/S0040-4020(03)00379-X

The synthetic procedures of the title compound (2), a protected form of carzinophilin (1), were developed. While efforts toward the total synthesis of 1 failed, comparison of the ¹H NMR spectra of 2 and some other related compounds with that of

Full text of DOI:10.1016/S0040-4020(03)00379-X

Tetrahedron 59 (2003) 3063–3087
Synthetic studies of carzinophilin. Part 3: Synthetic approach
toward carzinophilin and successful synthesis of
13-O-desacetyl-12,13-di-O-benzyl-4-O-methylcarzinophilinq
†
Masaru Hashimoto, Masaharu Sugiura and Shiro Terashima
,
*
*
Sagami Chemical Research Center, 2743-1, Hayakawa, Ayase, Kanagawa, 252-1193, Japan
Received 30 January 2003; accepted 6 March 2003
Abstract—The synthetic procedures of the title compound (2), a protected form of carzinophilin (1), were developed. While efforts toward
the total synthesis of 1 failed, comparison of the 1H NMR spectra of 2 and some other related compounds with that of 1 provided definite
support for the absolute stereochemistry of 1 which has a complicated history regarding its structure. q 2003 Elsevier Science Ltd. All rights
reserved.
1. Introduction
achieving the preparation of 13-O-desacetyl-12,13-di-O-
benzyl-4-O-methylcarzinophilin (2), the protected form of
1. Spectral comparisons of natural product 1 with synthetic
2 as well as some related analogues definitely established
the structure of carzinophilin, which had been revised
several times, as shown.1e Now we would like to disclose
full details of these studies.
Carzinophilin (1) is an antitumor antibiotic isolated from
Streptomyces sahachiroi by Hata et al. in 1954.3 It was
proved that 1 has 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 attracted chemists to study total synthesis of this
compounds.4,6,7 Recently, Coleman et al. reported their
successful total synthesis of azinomycin A lacking the
C4-hydroxymethylene group of 1.8 However, synthesis of 1,
more functionalized on the right-hand C1–C6 unit, has not
been accomplished yet. In the course of our synthetic studies
on 1, we have developed a series of synthetic methods for (i)
an aziridine formation reaction giving 1-azabicyclo[3.1.0]-
hexan-2-ylidene system,1a (ii) a protocol which provides the
C8–C13 pyrrolidine ring stereoselectively,1c (iii) an
efficient method giving the pyrrolidin-2-ylidene system by
a coupling reaction between a 4H-oxazol-5-one (azlactone)
and a methyl thioimidate followed by azlactone ring-
opening,1d and (iv) a protocol preparing the C1–C6
b-hydroxy enamide system constituting another structural
characteristic of 1.1d We have succeeded in the synthesis of
various analogues of 1 by employing these method-
ologies.1a–d Although our further efforts have not culmi-
nated in a complete total synthesis of 1, we succeeded in
q See refs 1 and 2.
2. Results and discussion
2.1. Synthetic plan
Keywords: azlactone; pyrrolidine unit; dehydropeptide; 13-O-desacetyl-
12,13-di-O-benzyl-4-O-methylcarzinophilin.
*
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.
†
We have reported that N-benzoyl protected dehydropeptide
I can be readily prepared by employing a phenylazlactone
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00379-X

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M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
(2-phenyl-4H-oxazol-5-one) prepared from hippuric acid.
However, it was found the N-benzoyl group cannot be
replaced with a C17–C21 unit in spite of many efforts.
Accordingly, we decided to introduce the C17–C21 frame-
work into the azlactone ring prior to the coupling with
methylthioimidate IV. We have also disclosed that the
azlactone ring is required to carry a substituent, which
stabilizes the anionic species IX for the coupling reaction
with pyrrolidine moiety IV. Therefore, an azlactone III
carrying the 2-alkoxymethylpropen-1-yl group was antici-
pated to be promising as the coupling unit. The C18–C21
moiety was expected to be functionalized stereoselectively
after the coupling reaction with IV. Taking our previous
studies into account, Alloc protection of the N9 position of
the (pyrrolidin-2-ylidene)azlactone VI might activate the
azlactone ring to receive the amine of the C1–N5
equivalent, the right segment of 1, and the b-hydroxy
enamide system could be constructed by the procedure
recently developed.1d It was expected that a basic treatment
might effect the aziridine ring closure to provide
azinomycin 1 after deprotection (Scheme 1).
carzinophilin 1) was achieved by treating with AcCl
(1.1 equiv.) and pyridine (0.82 equiv.) in the presence of
DMAP (0.15 equiv.), affording acetate 5 in 89% yield. After
protection of the remaining alcohol as a TES ether, the
lactam moiety was converted into thiolactam by treating
with Lawesson’s reagent9 (!6). Methyl thioimidate 7 was
obtained in a good yield by treating 6 with excess methyl
iodide in CH2Cl2. The crude 7 was subjected to the next
coupling reaction without purification (Scheme 2).
Scheme 2. Synthesis of the C7–C13 unit. Reagents and conditions: (a) H2,
20% Pd(OH)2/C, MeOH, rt, 12 h. (b) TBDPSCl, ImH, DMF, rt, 85% 2
steps. (c) AcCl, cat. DMAP, pyridine, CH2Cl2, 2208C!rt, 12 h, 89%. (d)
TESCl, ImH, DMF, 08c!rt, 90%. (e) Lawesson reagent, toluene, 608C,
30 min 99%. (f) MeI, CH2Cl2, rt, in the dark, 3 h, 99%.
2.3. Preparation of the azlactone bearing C6–C7–N16–
C21 unit
As described, our preliminary experiments revealed that
(E)-4-(2-alkoxymethylpropenyl)azlactones (11E) or its
Z-isomer 11Z might be promising for the C6–C7–N16–
C21 unit. As shown in Scheme 3, the alcoholic function of
ethyl (E)-3-hydroxymethyl-2-butenoate (8), prepared
according to the procedure reported by Garner et al.,10
was protected with a BOM group, and subsequent
saponification provided carboxylic acid 9. Condensation
of 9 with glycine benzyl ester using 1-[3-(dimethylamino)-
propyl]-3-ethylcarbodiimide hydrochloride (WSCI·HCl),
Scheme 1. Synthetic plan based on the preceding studies.
2.2. Preparation of the C8–C13 pyrrolidine unit
Scheme 3. Synthesis of the C6–C7–N16–C21 azlactones 11E and 11Z.
Reagents and conditions: (a) BOMCl, i-PrNEt2, CH2Cl2, rt, 12 h. (b) NaOH,
H2O, THF, 608C, 12 h. (c) Gly-OBn·p-TsOH WSCI·HCl, Et3N, CH2Cl2, rt.
12 h, 85% 3 steps. (d) NaOH, H2O, THF, rt, 99% (for both 11E and 11Z).
(e) CMCD (see text), THF, rt, 99%, (for both 11E and 11Z). (f) Gly-OBn·p-
TsOH, Et3N, 2108C, 40 min, 97%. (g) i-PrO2CCl, Et3N, THF, 08C, 10 min
then NaBH4 10 min, 63%. (h) BOMCl, i-PrNEt2, CH2Cl2, rt, 12 h,
57%.
Preparation of the C8–C13 pyrrolidine commenced with
3,4-dibenzyloxy-5-hydroxymethylpyrrolidin-2-one (3).1c
After the benzyl groups of 3 were removed by catalytic
reduction, the primary alcohol was protected as a TBDPS
ether to give 4 in 85% yield for two steps. Selective
acetylation of the C3-hydroxyl group (the C13 position of

M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
3065
gave benzyl N-acylglycinate 10E in 85% for three steps.
After saponification, dehydration employing 1-cyclohexyl-
3-(2-morphorinoethyl)carbodiimide metho-p-toluene-
sulfonate (CMCD)11 in THF at room temperature effected
the azlactone ring formation producing 11E in a quantitative
yield. Another Z-isomer 11Z was also prepared in a
stereoselective manner as follows. On treatment of com-
mercial citraconic anhydride with glycine benzyl ester
p-toluene sulfonate in the presence of Et3N, the addition
reaction at the C4-position proceeded regioselectively
(selectivity¼87:13), affording a mixture of carboxylic
acids 90. The carboxylic acid moiety of 90 was reduced
selectively by way of a mixed anhydride, and the newly
produced hydroxyl group was protected as a BOM ether.
Following saponification of the ester moiety gave the
corresponding glycine derivative in a pure form after
recrystallization. Similar dehydration with CMCD to that
described above gave 11Z also in quantitative yield without
isomerization of the Z-geometry about the olefin moiety.
C18–C19 double bond did not isomerize under standard
TLC conditions, although tautomerism about the C7–C8
double bond was observed (12E: RF¼0.50 and 0.58, 12Z:
RF¼0.54 and 0.62; developed with hexane–AcOEt¼70:30).
Interestingly, these isomers could be separated by careful
silica gel column chromatography.
2.5. Elaboration of the C17–C21 functionalities
Contrary to our expectation, hydrogenolysis of the BOM
ether in 12E employing Pd/C–H2 failed, and those
conditions selectively reduced the C7–C8 double bound.
The BOM group of 12E was found to be removed smoothly
by DDQ oxidation12 giving aldehyde 13 in 72% yield as an
87:13 mixture of tautomers concerning to the C7–C8
double bond (carzinophilin numbering). Interestingly, the
same reaction with 12Z effected complete isomerization of
the C18–C19 double bond, providing 13 in 85% yield. This
sample was identical to that prepared from 12E in all
respects. The stereochemistry of the C18–C19 double bond
was determined by observing cross-peaks between the
protons for aldehyde and the C18H of both tautomers in
their phase-sensitive NOESY spectra. In a preparative scale,
crude 13 was directly reduced with NaBH4 without
purification to provide alcohol 14 as a mixture of the two
tautomers concerning to the C7–C8 double bonds in 82%
yield for two steps. As described, we could obtain only
E-isomer 14.
2.4. Coupling the azlactones 11E and 11Z with the
C8–C13 pyrrolidine unit 7
With 11E and 11Z in hand, the coupling reaction with
S-methyl thioimidate 7, the C8–C13 pyrrolidine unit was
examined (Scheme 4). It was found that coupling product
12E was obtained in 47% yield based on the amount of 7
employed, by heating with 5.9 equiv. of 11E in a mixture of
toluene and pyridine with bubbling of argon gas during the
reaction. The starting 7 (41%) was recovered under these
conditions. The adduct 12E was found to be an 87:13
tautomeric mixture about the C7–C8 double bond (carzino-
According to the E-stereochemistry of the C18–C19 double
bond, two oxygens should be introduced in an anti-
relationship. Specifically, the Sharpless asymmetric epoxi-
dation13 is plausible for this purpose. However, the epoxide
obtained by the epoxidation of 14 suffered epoxide ring
opening under the standard Sharpless’s conditions (TBHP,
Ti(OiPr)4, DIPT) giving the tartarate and isopropanol
adducts probably due to the electron-donating azlactone
ring.14 Next, Sharpless asymmetric dihydroxylation15 of 14
was investigated as an alternative route. It was found that
oxidation of 14 with a stoichiometric amount of (DHQ)2-
PHAL (1.3 equiv.) and OsO4 (1.1 equiv.) in CH2Cl2 and
subsequent degradation of the osmate ester with H2S gas
gave b-triol 15 in 69% yield with nice stereoselectivity
(a/b¼90:10). Catalytic conditions (AD-mixa, CH3SO2-
NH2) for 14 provided only a trace amount of the product.
The reaction using (DHQ)CLB in place of (DHQ)2PHAL
reduced the desired a-selectivity. When dihydroxylation of
14 was performed with a stoichiometric amount of
(DHQD)2PHAL, the corresponding diastereomer was
obtained with complete stereoselectivity. These results
suggested that a-selective dihydroxylation of 14 is a so-
called ‘miss-match’ reaction from the viewpoint of double
asymmetric induction. The stereochemistry of this dihy-
droxylation reaction was assigned based on the Sharpless
rule (Scheme 5).15
1
philin numbering) based on its H NMR spectrum. On the
other hand, the same treatments employing 11Z brought
about isomerization of the C18–C19 double bond to
produce 12Z in 9.3% yield as a tautomeric mixture about
the C7–C8 double bond (E/Z¼90:10) along with 12E (32%)
and recovered 7 (50%). Two-dimensional silica gel TLC
analysis of the mixture of 12E and 12Z revealed that the
The primary hydroxyl group of 15 was mesylated
selectively with MsCl in the presence of g-collidine, and
subsequent treatment with DBU took place formation of an
exo-epoxide to give 16 in 75% yield for two steps. Since the
stereochemistry of a hydroxyl group at the C18 in 16 was
different from that of 1, the C18 hydroxyl group was
inverted. Mitsunobu inversion16 for 16 employing the
Scheme 4. Coupling of methylthioimidate 7 with azlactones 11E and 11Z.

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M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
Esterification of 18 with the naphthoic acid 1920 was
performed employing WSCI·HCl and DMAP in CH2Cl2, to
afford epoxy ester 20 in 96% yield. Both the TBDPS and
TES groups of 20 were removed with TBAF in the presence
of AcOH, giving diol 21 in 98% yield. The reaction without
using AcOH gave rise to sequential elimination of the
naphthoate moiety by 1,6-elimination (between the N9H
and the C18OCOAr) and hydration to produce a mixture of
16 and 18 along with their desilylated compounds. Selective
mesylation of the primary hydroxy group in 21 using MsCl
and g-collidine and subsequent protection of the C12OH
with a TES group furnished the C6–C22 unit 22. Similarly
to 12E and 12Z, all the (pyrrolidin-2-ylidene)azlactones
13–16, 18, and 20–22 except for 17 were found to be
obtained as mixtures of the two tautomers arising from their
C7–C8 double bonds. The ratio of these tautomers changed
from 50:50 to 80:20 in favor of the E-isomers.
2.6. Preparation of the novel C1–N5 unit
Although we had developed amine 23 as the C1–N5 unit
which brought us successful preparation of the C1–C17
model compounds,1c our preliminary experiments revealed
that the acetal moiety of 23 was not stable enough to be
utilized for preparing carzinophilin (1). Thus, we designed
the alternative C1–N5 unit 28, which was expected to be
more stable under acidic conditions. Commercial L-threo-
nine methyl ester hydrochloride (24) was first converted into
the 9-fluorenylmethoxycarbonyl (Fmoc) derivative 25 in a
quantitative yield by using FmocCl21 and NaHCO3 under
aqueous conditions. After the hydroxyl group in 25 was
converted into a MPM ether employing Yonemitsu’s
imidate,22 the ester moiety was reduced with Zn(BH4)2 in
Et2O to provide alcohol 26 in 58% yield for two steps.
Oxidation of 26 with Dess–Martin reagent and subsequent
treatment with TBDMSCN in CH3CN at 808C resulted in
the formation of O-silyl cyanohydrin, 27 in 92% yield for
two steps as a mixture of the diastereomers about the
cyanohydrin moiety. Removal of the Fmoc groups of 27 was
achieved by treating with piperidine to afford 28 as a
diastereomeric mixture in 90% yield. While these dia-
stereomers were separated by silica gel column chromato-
graphy, only the major polar isomer was used for the
next step in consideration of operational simplicity
(Scheme 6).
Scheme 5. Elaboration of the C17–C21 functionalities. Reagents and
conditions: (a) DDQ, CH2Cl2, H2O, 30 min, 85% (from 12E), 85% (from
12Z). (b) NaBH4, MeOH, 30 min, 82% 2 steps. (c) (DHQ)2PHAL
(1.4 equiv.), OsO4 (1.1 equiv.), CH2Cl2, 08C, 15 min, 69% (80% de).
(d) MsCl, g-collidine, CH2Cl2, 08C, 2 h. (e) DBU, THF, rt, 1 h, 75% 2 steps.
(f) Dess–Martin reagent, CH2Cl2, rt, 2 h, 84%. (g) CeCl3·7H2O, NaBH4,
MeOH, 2158C, 10 min, 95%, 80% de. (h) 19, WSCI·HCl, DMAP, CH2Cl2,
rt, 97%. (i) TBAF, AcOH, THF, rt, 3 h, 98%. (j) MsCl, g-collidine, CH2Cl2,
08C, 2 h, 67% (14% recovery of 21). (k) TESCl, ImH, DMF, rt, 10 min,
97%.
naphthoic acid 19 was found to be fruitless, then sequential
oxidation–reduction protocol was examined next. Oxi-
dation of 15 with Dess–Martin reagent17 gave ketone 17 in
84% yield. Fortunately, 17 was obtained as needles so that
recrystallization of 17 removed the minor diastereomer
derived in the dihydroxylation step. b-Stereoselective
reduction of 17 was achieved by the combined use of
CeCl3·7H2O and NaBH4 in MeOH18 at 158C providing 18 in
95% yield with 80% de. When the reduction was performed
with Zn(BH4)2 in Et2O,19 the diastereoselectivity was
60% de. The stereochemistry of 18 was determined by
Scheme 6. Preparation of the improved C1–N5 unit. Reagents and
conditions: (a) FmocCl, NaHCO3, dioxane, H2O, rt, 1 h, 99%.
(b) MPMC(vNH)CCl3, cat. TfOH, Et2O, rt, 3 h. (c) Zn(BH4)2, Et2O, rt,
12 h, 58% 2 steps. (d) Dess–Martin reagent, CH2Cl2, rt, 30 min.
(e) TBDMSCN, CH3CN, 808C, 3 h, 92% 2 steps. (f) Piperidine, DMF, rt,
1 h (90%), then separation of the major polar isomer.
1
comparing its H NMR spectra with that of a-alcohol 16.

M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
3067
2.7. Opening the azlactone ring to furnish the
dihydropeptide system and attempts toward completing
the total synthesis of carzinophilin1
29E in 69% yield along with its Z-isomer 29Z as a minor
product (3.3% yield). These isomers were readily separated
by silica gel column chromatography. When a larger
amount of DMAP was employed for the reaction, yields
of products decreased considerably due to production of
polar materials. Comparison of the 1H NMR spectra of 29E
and 29Z with those of the model compounds previously
synthesized made it possible to assign their stereo-
chemistries at the C7–C8 double bond. Specifically, the
signal for C13H of 29E was observed at 5.12 ppm, while
According to the information accumulated, the azlactone
rings of 22 (a 73:27 mixture of the two tautomers) was
activated by carbamoylation of the N9 position (carzino-
philin numbering) with an Alloc group by treating with
Alloc2O in the presence of a catalytic amount of DMAP
(5 mol%). Successively, amine 28 was added to the reaction
mixture without work-up, and the whole mixture was heated
at 408C in high concentration. These operations effected the
opening of the azlactone ring providing E-dehydropeptide
1
that of 29Z was at 6.41 ppm in their H NMR spectra. We
have already established that signals for the C13H of the
E-isomers appear around 1 ppm higher field than those of
the Z-isomers and this phenomena was confirmed by NOE
experiments using some model compounds. Accordingly,
the stereochemistry of the C7-C8 moiety of 29E and 29Z
was established to be E- and Z-configuration, respectively
(Scheme 7).
Elaboration of the C1–N5 moiety was next studied. After
removing the MPM group of 29E by DDQ oxidation, the
reproduced alcoholic moiety was further oxidized with
Dess–Martin reagent to give b-keto cyanohydrin 30 in 94%
yield for two steps. The N-Alloc group of 30 was cleaved by
employing Pd(PPh3)4-catalyzed reaction in the presence of
AcOH,23 giving the pyrrolidine 31 in a quantitative yield.
Contrary to the precedent model compounds, removal of the
Alloc group did not give rise to the tautomerism of the
C7–C8 double bond, so that 31 was obtained as a single
E-isomer. The protected cyanhydrin moiety of 31 was
deassembled by cleaving the TBDMS ether and subsequent
basic treatment. These operations also cleave the TES
group. The product was isolated after converting it into the
corresponding methyl enol ether with CH2N2 affording 32 in
82% yield for two steps.
With the dehydropeptide systems 31 and 32 in hand,
construction of the aziridine ring was next attempted. All
the conditions so far examined (DBU, KHMDS, TBAF, and
phosphazene base P4–tBu etc.) gave fruitless results, and
complex mixtures were obtained, in spite of the fact that
some of those conditions brought us successful aziridine
formation in the previous model synthesis. This aziridine
ring formation was further investigated by employing model
36a (Scheme 8). However, all the attempts also did not
achieve the aziridine formation giving 37a. In contrast, we
have already proved that the model compound 36b, bearing
two benzyloxy groups at the C12 and C13 positions, is
Scheme 7. Construction of the right hand moiety and attempts for
completion of the total synthesis. Reagents and conditions: (a) cat. DMAP,
Alloc2O, THF, rt, 10 min, then 28, concentration on rotary evaporator at
408C for 15 min, 69% (29E), 3.3% (29Z). (b) DDQ, CH2Cl2, H2O, 1 h,
97%. (c) Dess–Martin reagent, CH2Cl2, rt, 40 min, 97%. (d) Pd(PPh3)4,
PPh3, AcOH, THF, rt, 10 min, 100%. (e) TBAF, AcOH, THF, 3 h, then aq.
NaHCO3, 10 min. (f) CH2N2, Et2O, 1 h, 82% 2 steps. (g) DBU, CH2Cl2, rt,
4 h, low yield.
Scheme 8. Aziridine ring formation using the model compounds.

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M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
gradually appeared after standing the solution at room
temperature for 3 h (E/Z¼93:7) and this isomerization
attained an equilibrium after 18 h (E/Z¼88:12). Other
compounds 40–43,45–47 carrying the azlactone rings
were observed as mixtures of the two tautomers
(E/Z¼56:44–80:20). Epoxy ketone 44 was insoluble in
MeOH which was a preferable solvent for NaBH4–CeCl3
reduction of 17. Ethanol dissolved 44 well, but the reduction
in EtOH gave a complex mixture. Thus, the C10 function of
44 was converted into mesylate 45 prior to the reduction. It
was found that mesylate 45 was soluble in MeOH and
cerium (III) assisted NaBH4 reduction of 45 in MeOH
proceeded stereoselectively (80% de) to provide 46 in 90%
yield. The minor a-isomer was removed at the stage of 48.
After the naphthoic acid 1920 was attached, the dehydro-
peptide chain was furnished by sequential N9-carbamoyl-
ation and azlactone opening with amine 28, giving rise to
48E and 48Z. Similar operations to those described for the
preparation of 32 from 29E elaborated the C1–C4
functionalities giving 38. As expected, treatment of 38
with TBAF in the presence of powdered molecular sieves
4A in THF took place the aziridine ring formation
furnishing 4-O-methyl-13-desacetyl-12,13-di-O-benzyl-
carzinophilin (2) in 47% yield. The product was found to
be stable enough to be isolated in a pure state by preparative
Scheme 9. Proposed pathway for decomposition of 31, 32a,b, and 36a.
cleanly cyclized to give 37b by employing KHMDS as the
base.
Taking these results into account, 31, 32 and 36a might be
explained by the base-induced 1,4-elimination of the
C13-acetate, producing imine XI, which decomposes or
polymerizes under the reaction conditions as shown in
Scheme 9. Notably, treatment of 31 with DBU in CH2Cl2
gave amide 33 in a low yield. Amide 33 might be derived
from XI, and is known to be isolated from the culture broth
along with AZs.5 Since the leaving ability of an acetate
function in 36a is obviously higher than that of the
benzyloxy group in 36b, we expected that the aziridine
constructing reaction employing the mesylate 38, which
bears the same two benzyl groups as 36b, can proceed to
furnish the whole carbon framework of carzinophilin (1)
albeit in a protected form (Fig. 1).
1
silica gel TLC. The H NMR spectral data of 2 closely
resembled that reported for AZB-4-O-Me (54) by Yokoi
et al.5 except for the chemical shift of C13–H where an
acetoxy group is replaced with a benzyloxy group as shown
in Table 1. Needless to say, the 1H NMR spectrum of 2 was
also closely coincident with that of our model compounds
53 about the C1–N16 proton signals and not with that of
Armstrong’s Z-isomer 55. This spectral feature is antici-
pated to definitely support Yokoi’s structure of 1.
Figure 1. Structure of 38.
Expecting to further advance the synthetic scheme to 1, we
next examined removal of the two benzyl groups, which
protect the two hydroxy groups at the C12 and C13
positions. However, all the attempts met with failure. For
example, the hydrogenolytic condition using Pd/C in AcOEt
resulted in selective aziridine ring-opening to give
2-methylpyrrolidine 52 in 47% yield with recovery of 2
(24%). Formation of diol 51 was not observed at all. These
results led us to conclude that it is impossible to obtain 1
from 2.
2.8. Successful preparation of 4-O-methyl-13-desacetyl-
12,13-di-O-benzylcarzinophilin 2
As shown in Scheme 10, mesylate 38 was synthesized by a
synthetic route similar to that employed for the preparation
of 32 with small modifications. Coupling reaction of
azlactone 11E with methyl thioimidate 39 proceeded in
the absence of pyridine, affording the adduct 40 in 58%
yield with 17% recovery of 39. Sequential oxidative
cleavage of the BOM ether by DDQ and reduction of the
produced aldehyde gave the alcohol 41 in slightly better
yield than that of 14 from 12E. Being different from the case
of 14, the dihydroxylation of 41 with a stoichiometric
amount of OsO4–(DHQ)2PHAL was found to proceed in a
highly diastereoselective manner, giving triol 42 in 65%
yield. The minor diastereomer was not observed in its
400 MHz 1H NMR spectrum. Thus, the enantiomeric purity
of this sample was estimated to be .96% de. After
mesylation of the primary alcohol in 42, the C19–C21
epoxide was introduced by treating with DBU, to provide
epoxy alcohol 43. Then, 43 was converted into epoxy
ketone 44 by Dess–Martin oxidation. The ketone 44 was
obtained as prisms after recrystallization (mp 145–1478C).
The 1H NMR spectrum measured right after dissolving
crystalline 44 with CDCl3 indicated the sole existence of the
E-isomer about the C7–C8 double bonds (carzinophilin
numbering), however, signals of corresponding Z-isomer
2.9. Relationship of the stereochemistry between the C18
and those of the pyrrolidine moiety
The relative stereochemistry about the C11, C12, and C13
positions of azinomycin B (¼carzinophilin 1) has been
established as 11S p,12R p, and 13R p by detailed NOE
experiments in the Yokoi’s report.5 On the other hand, the
absolute stereochemistry of C18 has been proposed as S
configuration based on amide 33 isolated from the same
culture broth as that producing 1 (Fig. 2). However, the
stereochemical relationship between C18 and the pyrroli-
dine moiety has not been discussed well. Although Coleman
et al. reported the total synthesis of azinomycin A, the
natural analogue of 1 lacking C4 enol system, they did not
mention the stereochemical relationships between them.
Accordingly, four diastereomers of the model compounds
57SE, 57SZ, 57RE, and 57RZ were synthesized as shown in

M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
3069
Scheme 10. Successful preparation of 4-O-methyl-13-desacetyl-12,13-di-O-benzylcarzinophilin. Reagents and conditions: (a) toluene, 608C, Ar gas bubbling,
12 h, 58% (17% recovery of 39). (b), DDQ, CH2Cl2, H2O, rt, 30 min. (c) NaBH4, MeOH, 08C, 30 min, 97% 2 steps. (d) (DHQ)2PHAL (1.2 equiv.), OsO4
(0.99 equiv.), CH2Cl2, 2108C, 15 min, then H2S, 65% (96% de). (e) MsCl, g-collidine, CH2Cl2, 08C, 4 h, 81%. (f) DBU, THF, 08C, 30 min, 84%. (g) Dess–
Martin reagent, CH2Cl2, 40 min, 92%. (h) TBAF, THF, rt, 12 h. (i) MsCl, g-collidine CH2Cl2, rt, 1 h, 83% 2 steps. (j) NaBH4, CeCl3·7H2O, MeOH, 94% (80%
de). (k) WSCI·HCl, DMAP, CH2Cl2, rt, 12 h, 91%. (l) Alloc2O, DMAP (0.11 equiv.), 15 min, then 28, concentration on rotary evaporator at 508C, 40 min. 78%
(48E), 2% (48Z). (m) DDQ, CH2Cl2, H2O, rt, 1 h, 94%. (n) Dess–Martin reagent CH2Cl2, rt, 1 h, 98%. (o) Pd(PPh3)4, PPh3, AcOH, THF, 89%. (p) TBAF,
THF, 2 h, then aq. NaHCO3, 20 min. (q) CH2N2, Et2O, rt, 12 h, 54% 2 steps. (r) TBAF, MS4A, THF, rt, 15 min, 47%. (s) H2, 10% Pd/C, AcOEt, 3 h, 47%,
(24% recovery of 2).
Scheme 11. Ester 56, the diastereomer of 20 at C18 position
was prepared by acylation of the intermediate 16 with
naphthoic acid 19 under the usual conditions. Both 20 and
56 were subjected to the azlactone ring opening reaction
with isopropylamine to give stereoisomeric pairs of
dehydropeptides 57SE and 57SZ, and 57RE and 57RZ,
respectively.
between C12-O-TES ether 29 and C12 alcohols 32 and 58
suggested that introduction of a TES group at C12 alcohol
shifts the C13H signal around 0.2 ppm lower field, however,
that small shifting might be disregarded in the discussions.
Although isomerization about the C7–C8 double bond of 58
might be possible based on our results obtained in this series
of studies, the C7–C8 stereochemistry could be assigned as
E-geometry, because there is only a small difference of
C13H chemical shift between that of 1 and 58, and we had
already disclosed that the C7–C8 stereochemistry affects
the chemical shift of C13H. Stereochemistries of the C7–C8
double bonds in four diastereomers of 57 were established
by comparing their 1H NMR spectra with those of our
precedent model compounds, the stereochemistries of
which had been confirmed based on NOE experiments.
With those dehydropeptides in hand, we next studied the 1H
NMR spectral relationship between C18 and the pyrrolidine
ring moiety employing four isomers of 57, carzinophilin (1),
our synthetic intermediate 32, and methyl pyrrolidine
derivative 58 (Fig. 3). Methylpyrrolidine 58 was derived
from 1 by Yokoi et al. in their structure determining
studies.5 First, comparing the chemical shift for C13H

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M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
Table 1. Chemical shifts (ppm), signal patterns (parenthesized), and
coupling constants (italic, Hz) of 2, our precedent model compound 53,
AZB-4-OMe 54 (derived from 1), and Armstrong’s Z-isomer 55
Proton
2
53
54
55
1
4
2.22 (s)
7.14 (s)
3.89 (s)
10.58 (s)
2.23 (s)
7.16 (s)
3.89 (s)
11.03 (s)
2.24 (s)
7.19 (s)
3.90 (s)
10.89 (s)
–
–
–
4-OMe
5
6.95 (dd)
4.8, 4.8
2.18 (d)
3.6
10
2.27 (d)
4.1
2.30 (d)
4.1
2.25 (d)
3.9
2.48 (d)
5.1
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)
–
–
–
–
–
–
2.51 (d)
5.4
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
7.89 (s)
–
–
–
–
11
12
13
3.12 (ddd)
4.1, 4.8, 5.1
4.49 (dd)
3.6, 4.8
4.94 (dd)
1.0, 3.6
8.50 (s)
5.15 (s)
1.53 (s)
2.60 (d)
4.6
3.22 (ddd)
3.9, 5.4, 5.8
4.63 (dd)
3.9, 5.8
5.55 (d)
3.9
8.50 (s)
5.08 (s)
1.51 (s)
2.80 (d)
4.3
16
18
20
21
Scheme 11. Synthesis of four diastereomers 57SE, 57SZ, 57RE, and 57RZ.
2.90 (d)
4.6
2.99 (s)
4.3
–
–
1
Similarly to the discussion described in 2.7, the H NMR
signals of C13Hs in 29Z, 57SZ, and 57RZ (6.41, 6.41,
6.27 ppm. respectively) appeared around 1.3 ppm lower
field than those of the corresponding E-isomers 29E, 57SE,
and 57RE (5.12, 5.17, 4.84 ppm) due to deshielding by the
carbonyl group at C17. Accordingly, comparison of the
C13H signals obviously suggested E-configurations about
the C7–C8 enamine moiety of 1, methylpyrrolidine
derivatives 58, and 32 (Table 2).
Figure 3. Structure of the methylpyrrolidine derivative 58.
There is a significant difference in the C18H signal between
1 and 58. However, the stereochemistry of the C18 in 58
must be identical with that of 1, since 58 was derived from
1. Thus, it is presumed that the aziridine ring of 1 affects the
C18H chemical shift for some reasons. The C18H signals of
Table 2. 1H NMR chemical shifts for C13H, C15H, and C18H of 1 and its
analogues in CDCl3
C13H
C15H
C18H
C7C8 double bond
E
C15 position
S
C18 position
S
Z
R
R
1
58
32
29E
29Z
57SE
57SZ
57RE
57RZ
5.53
5.36
5.37
5.12
2.19
2.16
2.21
2.06
2.00
2.04
2.01
5.01
5.42
5.32
5.53
5.43
5.39
5.45
6.41
6.41
6.27
5.17
4.84
1.59
2.17
5.12
5.02
Figure 2. Structure of 33 and planaer structure of 1.

M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
3071
18S isomers 32, 29E, 29Z, 57SE, and 57SZ were observed at
5.32–5.53 ppm, while those of 18R isomers 57RE and 57RZ
appeared at 5.12 and 5.02 ppm, respectively. These
observations disclosed that 1 and 58 carry the same relative
stereochemistry about the C13 and the C19 positions as
those of 32, 29E, 29Z, 57SE, and 57SZ. The acetyl protons
corresponding to C15H3 of them showed normal chemical
shifts at 2.0–2.2 ppm. In contrast, that of 57RE, carrying
another stereochemical relationship between C13 and C18,
appeared at 1.59 ppm. This unusual chemical shift might be
explained by a shielding effect due to the naphthalene ring
in the molecule, although the geometrical relationship
between the naphthalene group and C13H is unclear.
catalyst was removed through a short Celitew column, the
eluent was concentrated below 258C in vacuo. A mixture of
the residue, TBDPSCl (11.0 g, 40.1 mmol), and imidazole
(6.00 g, 88.1 mmol) in DMF (40 mL) was stirred at room
temperature for 12 h. 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–acetone¼50:50) gave 4 (10.2 g,
85% in two steps) as a white powder. Analytical sample was
prepared by recrystallization from CH2Cl2–hexane to give
needles. Mp 142–1438C. [a]2D0¼272.38 (c 1.00, CHCl3). IR
(nujor): 3300, 3220, 1680, 1120, 710 cm21 1H NMR
.
(200 MHz, CDCl3) d 1.04 (9H, s, (CH3)3CSi), 3.74 (2H,
C5CHHO, C5H), 3.90 (1H, dd, J¼5.3, 11.7 Hz, C5CHHO),
4.45 (2H, m, C3H, C4H), 6.06 (1H, br, amide proton),
7.40–7.50 (6H, aromatic protons), 7.55–7.65 (4H,
aromatic protons). EI-MS (rel int.%): m/z¼386 (trace,
MHþ). 328 (6.0, [M2tBu]þ). 250 (100, [M2tBu–
benzene]þ). CI-MS (isobutene) m/z¼386 (MHþ).
EI-HRMS: Calcd for C21H28NO4Si (MHþ): m/z¼
386.1788. Found: m/z¼386.1786. Anal. calcd for
C21H27NO4Si: C, 65.42%; H, 7.06%; N, 3.63%. Found: C,
65.3%; H, 7.13%; N, 3.66%.
On the other hand, the absolute stereochemistries for the
C18 and C19 positions of 1 can be identical to those of 33,
being 18S, 19S, respectively, by taking into account the fact
that amide 33 was isolated along with 1 from the same
culture broth. Accordingly, stereochemical relationship
between C13 and C18 is only required for assigning the
absolute stereochemistry for C13 of carzinophilin (1). The
configuration of C13 of our analogues is incontestably R
because it comes from the C3 carbon of D-arabinose. By
putting these results and considerations together, the
stereochemistry of the C13 function of 1 is concluded to
be 13R, identical to that of 2 which we had synthesized from
D-arabinose. Accordingly, these studies might be the first to
reveal the absolute stereochemistry of the pyrrolidine ring
moiety of 1 as C11S, C12R, and C13R.
4.3. (3S,4R,5S)-3-Acetoxy-5-(tert-butyldiphenylsiloxy)-
methyl-4-hydroxypyrrolidin-2-one (5)
A mixture of 4 (10.1 g, 26.3 mmol), AcCl (2.27 g,
28.9 mmol), DMAP (480 mg, 3.93 mmol), and pyridine
(1.87 g, 23.7 mmol) in CH2Cl2 (180 mL) was stirred at
2238C The mixture was allowed to warm gradually to room
temperature and stirred for 12 h. 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 –acetone¼80:20)
3. Conclusion
Although the total synthesis of 1 turned out to be
unsuccessful, our synthetic studies culminated in providing
13-O-desacetyl-12,13-di-O-benzyl-4-O-methylcarzino-
philin (2), the protected form of 1. Spectral comparisons of 2
with that of 1 confirmed the structure of the natural
carzinophilin (1) that has had a complicated history
regarding its structure. Total synthesis of 1 is still required
for final confirmation of its structure, although Coleman has
achieved the total synthesis of azinomycin A,8 the natural
analogue of 1 lacking the C4 enol function. Our studies also
provided various structural types of azinomycin derivatives.
These were subjected to biological assays, which will be the
subject of the following report.24
gave
5
(10.1 g, 89%) as an amorphous solid.
[a]2D0¼231.48 (c 1.31, CHCl3). IR (film): 3400, 2950,
1720, 1240, 1120, 1090, 740, 710 cm21 1H NMR
.
(200 MHz, CDCl3): d 1.06 (9H, s, (CH3)3CSi), 2.22 (3H,
s, CH3COO), 3.63 (1H, d, J¼3.9 Hz, alcoholic proton), 3.75
(2H, C5H, C5CHHO), 3.96 (1H, dd, J¼3.7, 10.7 Hz,
C5CHHO), 4.49 (1H, dt, J¼3.9, 7.7 Hz, C4H), 5.45 (1H,
d, J¼7.7 Hz, C3H), 6.10 (1H, br s, amide proton), 7.40–
7.50 (6H, aromatic protons), 7.55–7.65 (4H, aromatic
protons). EI-MS (rel int.%): m/z¼428 (trace, Mþ), 412 (3.6,
[M2Me]þ), 370 (63, [M2t-Bu]þ), 43 (100, CH3COþ).
CI-MS (isobutane): m/z¼428 (MHþ). EI-HRMS calcd
for C23H30NO5Si (MHþ): m/z¼428.1894. Found:
m/z¼428.1872.
4. Experimental
4.1. General
4.4. (3S,4R,5S)-3-Acetoxy-5-(tert-butyldiphenylsiloxy)-
methyl-4-(triethylsiloxy)pyrrolidin-2-thione (6)
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.
4.4.1. TES ether formation of 5. A solution of 5 (12.5 g,
29.3 mmol), TESCl (5.70 g, 37.9 mmol), and imidazole
(8.00 g, 117 mmol) in DMF (30 mL) was stirred at room
temperature for 30 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 to give (3S,4R,5R)-3-acetoxy-5-(tert-butyldiphenyl-
siloxy)methyl-4-(trimethylsiloxy)pyrrolidin-2-one (14.2 g,
4.2. (3S,4R,5S)-5-(tert-Butyldiphenylsiloxy)methyl-3,4-
dihydroxypyrrolidin-2-one (4)
A suspension of 3 (10.2 g, 31.2 mmol) and 20% Pd(OH)2/C
(900 mg) in MeOH (150 mL) was stirred vigorously under
H2 atmosphere at room temperature for 12 h. After the

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M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
90%) as a white solid. Analytical sample was prepared by
recrystallization from hexane–AcOEt (75:25) to give
needles. Mp 172–1748C. [a]2D0¼270.98 (c 1.15, CHCl3).
IR (nujor): 3300, 1720, 2700, 1230, 1140, 1110, 1070,
4.6. (E)-3-(Benzyloxymethoxy)methyl-2-butenoic acid
(9)
A solution of methyl (E)-3-hydroxymethyl-2-butenoate
(8)10 (2.50 g, 19.2 mmol), i-Pr2NEt (10 mL, 7.42 g,
57.4 mmol), and BOMCl (5.96 g, 47.4 mmol) in CH2Cl2
(20 mL) was stirred at 08C for 12 h. The mixture was poured
into dil. HCl solution and extracted with Et2O. The
combined extracts were washed with brine, dried over
MgSO4 then concentrated in vacuo. The residue was diluted
with THF (50 mL), and the solution was stirred vigorously
with aqueous 1.0 M NaOH solution (70 mL) at 608C for
12 h. After cooling, THF was removed in vacuo. The
residual aqueous solution was washed with Et2O. The
aqueous layer was acidified by the addition of aqueous 2 M
HCl solution, then extracted with AcOEt. The combined
extracts were washed with brine, dried over MgSO4, then
concentrated in vacuo to give crude 8 (4.5 g). The yield was
1
830, 750, 720, 710 cm21. H NMR (200 MHz, CDCl3): d
0.53 (6H, m, (CH3CH2)3Si), 0.88 (9H, t, J¼7.4 Hz,
(CH3CH2)3Si), 1.06 (9H, s, (CH3)3CSi), 2.17 (3H, s,
CH3COO), 3.62 (2H, m, C5H, C5CHHO), 3.87 (1H, dd,
J¼6.07, 11.4 Hz, C5CHHO), 4.58 (1H, t, J¼7.7 Hz, C4H),
5.66 (1H, d, J¼7.7 Hz, C3H), 5.87 (1H, br, amide proton),
7.40–7.50 (6H, aromatic protons), 7.55–7.65 (4H,
aromatic protons). Anal. calcd for C29H43NO5Si2: C,
64.28%; H, 7.80%; N, 2.59%. Found: C, 64.30%; H,
7.99%; N, 2.57%.
4.4.2. Treatment with Lawesson reagent to give 6. A
mixture of (3S,4R,5S)-3-acetoxy-5-(tert-butyldiphenyl-
siloxy)methyl-4-(triethylsiloxy)pyrrolidin-2-one (14.2 g,
26.3 mmol) and Lawesson’s reagent (10.7 g, 26.4 mmol)
in toluene (200 mL) was stirred at 608C for 40 min. After
cooling, the precipitate was removed by filtration and the
filtrate was concentrated in vacuo. Purification of the
residue by silica gel column chromatography (hexane–
AcOEt¼85:15) gave 6 (14.2 g, 97%) as a white solid.
Analytical sample was prepared by recrystallization from
hexane to give needles. Mp 126–126.58C. [a]2D0¼þ1058 (c
1.10, CHCl3). IR (nujor): 3360, 1740, 1520, 1240, 1120,
740, 710 cm21. 1H NMR (200 MHz, CDCl3): d 0.55 (6H, m,
(CH3CH2)3Si), 0.87 (9H, t, J¼7.4 Hz, (CH3CH2)3Si), 1.06
(9H, s, (CH3)3CSi), 2.19 (3H, s, CH3COO), 3.66 (1H, dd,
J¼3.0, 10.4 Hz, C5CHHO), 3.73 (1H, m, C5H), 3.92 (1H,
dd, J¼5.4, 10.4 Hz, C5CHHO), 4.55 (1H, t, J¼7.4 Hz,
C4H), 5.66 (1H, d, J¼7.4 Hz, C3H), 7.40–7.50 (6H,
aromatic protons), 7.55–7.65 (4H, aromatic protons), 7.79
(1H, br, thioamide proton). Anal. calcd for C29H43NO4Si2S:
C, 62.43%; H, 7.77%; N, 2.51%; S, 5.75%. Found: C,
62.38%; H, 7.86%; N, 2.53%; S, 5.75%.
1
not calculated because the product was crude material. H
NMR (200 MHz, CDCl3) d 2.12 (3H, d, J¼1.0 Hz, C4H3),
4.13 (2H, d, J¼1.0 Hz, C3CH2O), 4.64, 4.81 (each 2H, s,
OCH2O, PhCH2O), 6.03 (1H, hex, J¼1.0 Hz, C2H), 7.35
(5H, m, aromatic protons). This sample was immediately
subjected to the next step.
4.7. Benzyl N-[(E)-3-(benzyloxymethoxy)methyl-2-
butenoyl]glycinate (10E)
A mixture of crude 8 (4.5 g), benzyl glycinate p-toluene-
sulfonic acid salt (11.0 g, 32.6 mmol), WSCI·HCl (7.60 g,
40.0 mmol), and Et3N (3.60 g, 35.6 mmol) in CH2Cl2
(40 mL) was stirred at room temperature for 12 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 (hexane–
AcOEt¼60:40) gave 10E (6.29 g, 85% in three steps) as a
white solid. Analytical sample was prepared by recrystalli-
zation from hexane–AcOEt to give needles. Mp 62–648C.
IR (nujor) 3270, 2920, 2760, 1760, 1670, 1530, 1520, 1460,
4.5. (2S,3R,4S)-4-Acetoxy-2-(tert-butyldiphenylsiloxy)-
methyl-3,4-dihydro-5-methylthio-3-triethylsiloxy-2H-
pyrrole (7)
1
1390, 1360, 1190, 1120, 1080, 1060, 750 cm21. H NMR
(200 MHz, CDCl3): d 2.11 (3H, s, C40H3), 4.06 (2H, s,
C30CH2O), 4.12 (2H, d, J¼5.3 Hz, C2H2), 4.62, 4.78, 5.20
(each 2H, s, PhCH2O£2, OCH2O), 5.92 (1H, br s, C20H),
5.93 (1H, br, amide proton), 7.35 (10H, aromatic protons).
EI-MS (rel int.%) m/z¼384 (0.1, Mþ), 276 (3.2,
[M2BnO]þ), 276 (4.3, [M2BnOH]þ), 247 (13,
[M2BnOCO]þ), 91 (100, Bnþ). EI-HRMS calcd for
C22H26NO5 (Mþ): 384.1812. Found: m/z¼384.1821. Anal.
calcd for C22H26NO5: C, 68.91%; H, 6.57%; N, 3.65%.
Found: 68.88%; H, 6.58%; N, 3.58%.
A mixture of 6 (2.06 g, 3.69 mmol) and methyl iodide
(5.0 mL, excess) in CH2Cl2 (5.0 mL) was stirred at room
temperature in the dark for 3 h. The mixture was poured into
a mixture of aq. NaHCO3 and aq. Na2S2O3 solution, then
extracted with Et2O. The combined extracts were washed
with brine, dried over MgSO4, then concentrated in vacuo to
give almost pure 7 (2.10 g, 99%) as a solid. Analytical
sample was prepared by recrystallization from hexane to
give needles. Mp 82–838C. [a]2D0¼21098 (c 1.03, CHCl3).
IR (nujor): 1750, 1560, 1240, 1220, 1110, 1090, 1090, 1050,
1
850, 740, 730, 710, 620, 500 cm21. H NMR (200 MHz,
4.8. 2-[(E)-2-(Benzyloxymethoxy)methyl-1-propenyl]-
4H-oxazol-5-one (11E)
CDCl3): d 0.63 (6H, dq, J¼1.1, 7.5 Hz, (CH3CH2)3Si), 0.97
(9H, t, J¼7.5 Hz, (CH3CH2)3Si), 1.03 (9H, s, (CH3)3CSi),
2.16 (3H, s, CH3COO), 2.46 (3H, s, CH3S), 3.76 (1H, dd,
J¼3.2, 10.8 Hz, C2CHHO), 4.00 (2H, m, C2H, C2CHHO),
4.61 (1H, t, J¼6.9 Hz, C3H), 6.21 (1H, d, J¼6.9 Hz, C4H),
7.40–7.50 (6H, aromatic protons), 7.55–7.65 (4H, aromatic
protons), 7.79 (1H, br, thioamide proton). EI-MS (rel int.%)
m/z¼542 (2.6, [M2Et]þ), 514 (100, [M2tBu]þ). Anal.
calcd for C30H45NO4SSi2: C, 63.00%; H, 7.93%; N, 2.45%.
Found: C, 62.09%; H, 8.00%; N, 2.44%.
4.8.1. Saponification of 10E. A suspension of 10E (250 mg,
653 mmol) in a mixture of THF (3.0 mL) and aqueous 1.0 M
NaOH solution (2.0 mL) was stirred vigorously at room
temperature for 2 h. After the THF was removed in vacuo,
the resulting aqueous solution was washed with Et2O. The
residual aqueous solution was acidified by the addition of
aqueous 2.0 M HCl solution, then extracted with AcOEt.
The combined extracts were washed with brine, dried over

M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
3073
MgSO4, then concentrated in vacuo to give N-[(E)-3-
(benzyloxymethoxy)methyl-2-butenoyl]glycine (190 mg,
99%) as a white solid. Analytical sample was prepared by
recrystallization from hexane–AcOEt to give needles. Mp
residue by silica gel column chromatography (CH2Cl2–
acetone¼90:10) gave a mixture of benzyl N-[(Z)-3-hydro-
xymethyl-2-butenoylglycinate and its (E)-isomer (87:13
ratio, 120 mg, 63%). (200 MHz, CDCl3, a¼0.87, b¼0.13):
d 1.91 (3H£a, d, J¼1.3 Hz, C40H3 for desired), 2.04 (3H£b,
d, J¼1.6 Hz, C30H3 for undesired), 4.10 (2H, d, J¼5.3 Hz,
C2H2), 4.24 (2H, s, CH2O), 5.15 (2H£b, s, PhCH2O for
undesired), 5.19 (2H£a, s, PhCH2O for desired), 5.74
(1H£a, m, C30H for desired), 5.83 (1H£b, m, C30H for
undesired), 6.42 (1H£a, br, amide proton for desired), 7.39
(6H, m, aromatic protons, amide proton).
90.5–918C. IR (nujor): 3330, 1750, 1630, 1220, 1040 cm21
.
1H NMR (200 MHz, CDCl3): d 2.13 (3H, d, J¼0.6 Hz,
C40H3), 4.11 (2H, br s, C30CH2O), 4.13 (2H, d, J¼5.3 Hz,
C2H2), 4.66, 4.82 (each 2H, s, PhCH2O, OCH2O), 5.99 (1H,
br s, C20H), 6.30 (1H, br t, J¼5.3 Hz, amide proton), 7.37
(5H, aromatic protons). EI-MS (rel int.%) m/z¼172 (4.8,
[M2BnOCH2]þ), 91 (100, Bnþ). CI-MS (isobutene)
m/z¼294 (Mþ), 276 ([M2H2O]þ). Anal. calcd for
C15H19NO5: C, 61.42%; H, 6.53%; N, 4.78%. Found C,
61.34%; H, 6.51%; N, 4.73%.
4.10.2. BOM ether formation, giving 10Z. A mixture of
benzyl N-[(Z)-3-hydroxymethyl-2-butenoylglycinate con-
taining its (E)-isomer (900 mg, 3.42 mmol), BOMCl
(2.0 g, 12.8 mmol), and i-Pr2NEt (2.5 g, 19.3 mmol) in
CH2Cl2 (5.0 mL) was stirred at room temperature for 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 (CH2Cl2–
acetone¼96:4) gave 10Z (600 mg, 45%) as an oil. 1H NMR
(200 MHz, CDCl3): d 1.93 (3H, d, J¼1.2 Hz, C40H3), 4.00
(2H, d, J¼5.4 Hz, C2H2), 4.61, 4.62, 4.79, 5.16 (each 2H, s,
C30CH2O, PhCH2O£2, OCH2O), 5.77 (1H, br s, C20H), 6.43
(1H, br, amide proton), 7.35 (10H, m, aromatic protons).
4.8.2. Dehydration giving 11E. A mixture of N-[(E)-3-
(benzyloxymethoxy)methyl-2-but-enoyl]glycine (306 mg,
1.04 mmol) and 1-cyclohexyl-3-(2-morphorinoethyl)carbo-
diimide metho-p-toluenesulfonate (CMCD)11 (650 mg,
1.54 mmol) in THF (5.0 mL) was stirred at room tempera-
ture for 4 h. The mixture was filtered, and the filtrate was
concentrated in vacuo below 308C to provide almost pure
11E (295 mg, quantitative yield) as an oil. 1H NMR
(200 MHz, CDCl3) d 2.10 (3H, s, C30H3), 4.14, 4.27, 4.63,
4.81 (each 2H, s, C4H2, C20CH2O, PhCH2O, OCH2O), 6.14
(1H, br s, C10H), 7.34 (5H, m, aromatic protons). This
sample was immediately used for the next step without
further purification.
4.11. 2-[(Z)-2-(Benzyloxymethoxy)methylpropenyl]-4H-
oxazol-5-one (11Z)
4.9. Benzyl N-[(Z)-3-carboxy-2-butenoyl]glycinate (13)
4.11.1. Basic saponification of 10E. The same treatment of
10Z (4.90 g, 12.79 mmol) as described in Section 4.8.1
(Saponification of 10E) gave N-[(Z)-3-(benzyloxymethoxy)-
methyl-2-butenoyl]glycine (3.70 g, 99%) as an oil. IR (film):
A mixture of citraconic anhydride (12) (3.75 g, 33.3 mmol)
benzyl glycinate p-toluenesulfonic acid salt (12.0 g,
35.6 mmol), and Et3N (3.67 g, 36.3 mmol) in CH2Cl2
(60 mL) was stirred at 08C for 40 min. The mixture was
poured into saturated NaHCO3 and washed with Et2O. After
acidification by the addition of aqueous HCl solution, the
aqueous solution was extracted with AcOEt. The combined
extracts were washed with brine, dried over MgSO4, then
concentrated to give 90 which was contaminated with a
small amount of the regioisomer (87:13 ratio, 9.00 g, 97%).
1H NMR (200 MHz, CDCl3, a¼0.87, b¼0.13) d 2.13
(3H£a, d, J¼1.3 Hz, C40H3 for desired), 2.20 (3H£b, d,
J¼1.7 Hz, C30H3 for undesired), 4.15 (2H, d, J¼5.2 Hz,
C2H2), 5.19 (2H£b, s, PhCH2O for undesired), 5.21 (2H£a,
s, PhCH2O for desired), 6.11 (1H£b, m, C30H for
undesired), 6.41 (1H£a, m, C30H for desired), 7.39 (6H,
aromatic protons, amide proton). This sample was subjected
to the next step without further purification.
1
3330, 1740, 1620, 1220, 1110, 1070, 1050, 1030 cm210. H
NMR (200 MHz, CDCl3): d 1.94 (3H, d, J¼1.3 Hz, C4 H3),
3.94 (d, J¼5.3 Hz, C2H2), 4.60, 4.62, 4.79 (each 2H, s,
C3CH2O, PhCH2O, OCH2O), 5.77 (1H, br s, C20H), 6.68 (1H,
br t, J¼5.3 Hz, amide proton), 7.32 (5H, m, aromatic protons).
CI-MS (isobutene): m/z¼294 (Mþ), 276 ([M2H2O]þ).
4.11.2. Dehydration giving 11Z. Treatments of 10Z
(52.0 mg, 177 mmol) in the same manner as described in
Section 4.8.2 (Dehydration giving 11E) gave 11Z (48.7 mg,
quantitative yield) as an oil. IR (film) 1830, 1650, 1150,
1
1130 cm21. H NMR (200 MHz, CDCl3) d 2.06 (3H, s,
C30H3), 4.22, 4.63, 4.65, 4.81 (each 2H, s, C4H2, C20CH2O,
PhCH2O, OCH2O), 5.87 (1H, br s, C10H), 7.34 (5H, m,
aromatic protons). CI-MS m/z¼276 (MHþ). This sample
was immediately used for the next step without further
purification.
4.10. Benzyl N-[(Z)-3-(benzyloxymethoxy)methyl-2-
butenoyl]glycinate (10Z)
4.12. 4-[(3R,4R,5S)-3-Acetoxy-5-(tert-butyldiphenyl-
siloxy)methyl-4-(triethylsiloxy)pyrrolidin-2-ylidene]-2-
[2-(E)-(benzyloxymethoxy)methyl-1-propenyl]-4H-
oxazol-5-one (12E) and its (2Z)-isomer (12Z)
4.10.1. Reduction of the carboxylic acid moiety in 13. A
solution of crude 13 (200 mg, 722 mmol), Et3N (216 mg,
2.13 mmol), and isopropyl chloroformate (164 mg,
1.34 mmol) in THF (5.0 mL) was stirred at 08C for
10 min. Aqueous NaBH4 solution (100 mg in 1.0 mL,
2.63 mmol) was added to the reaction mixture at 08C, and
the mixture was stirred for additional 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
4.12.1. Reaction with 11E. A mixture of 11E (2.90 g,
10.6 mmol) and 7 (1.02 g, 1.79 mmol) in toluene (3.0 mL)
and pyridine (3.0 mL) was stirred at 608C for 12 h with Ar
gas bubbling. After concentration in vacuo, the residue was
purified by silica gel column chromatography (hexane–
AcOEt¼90:10!20:80) to give recovered 7 (423 mg, 41%)

3074
M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
as a solid and 12E (676 mg, 47%) as an oil. The produced
12E was obtained as an 87:13 mixture of tautomers arising
from its enamine moiety.
741 (4.1, [M2t-Bu]þ). EIMS of this sample gave no useful
information. Accordingly EI-HRMS was not measured.
4.13. 4-[(3R,4R,5S)-3-Acetoxy-5-(tert-butyldiphenyl-
siloxy)methyl-4-(triethylsiloxy)pyrrolidin-2-ylidene]-2-
(2-formyl-1-propenyl)-4H-oxazol-5-one (13)
4.12.2. Reaction with 11Z. The Z-isomer 11Z (2.82 g,
10.2 mmol) was treated with 7 (700 mg, 1.23 mmol) in a
similar manner to that described previously. Silica gel
column chromatography of the residue (AcOEt–
hexane¼87:13) gave recovered 7 (350 mg, 50%) as an oil,
12Z (91.4 mg, 9.3%) as an oil, and 12E (312 mg, 32%) as an
4.13.1. Preparation from 12E. A mixture of 12E (14.0 mg,
17.5 mmol) and DDQ (6.0 mg, 264 mmol) in a mixture of
CH2Cl2 (1.0 mL) and H2O (100 mL) was stirred at room
temperature for 30 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 preparative
TLC (hexane–AcOEt¼70:30) gave 13 (RF¼0.55, 8.2 mg,
85%) as a yellow oil. IR (film): 3300, 2960, 2870, 1770,
1720, 1690, 1650, 1620, 1610, 1520, 121, 1170, 1150, 1110,
1
oil. The H NMR spectrum of 12E was identical to that of
the sample prepared from 11E. The product 12E was
obtained as a 90:10 mixture of tautomers arising from the
enamine moiety.
4.12.3. Physical data of 12E. IR (film): 3320, 2960, 2930,
1760, 1720, 1640, 1230, 1210, 1140, 1110, 1060, 740,
1
1
700 cm21. The H NMR spectrum of this sample showed
that it consists of the two tautomers arising from its enamine
1020, 830, 730, 700, 500 cm21. The H NMR spectrum of
this sample showed that it consists of the two tautomers
arising from its enamine moiety (E/Z¼90:10). Assignments
of signals for the main isomer and some for the minor
isomer are described. 1H NMR (400 MHz, CDCl3, a¼0.90,
b¼0.10, carzinophilin numbering): d 0.58 [6H£a, m,
(CH3CH2)3Si (Z-isomer)], 0.62 [6H£a, q, J¼8.0 Hz, (CH3-
CH2)3Si (E-isomer)], 0.86 [9H£b, t, J¼7.2 Hz, (CH3CH2)3-
Si (Z-isomer)], 0.92 [9H£a, t, J¼7.2 Hz, (CH3CH2)3Si
(E-isomer)], 2.13 [3H£b, CH3COO (Z-isomer)], 2.17
[3H£a, s, CH3COO (E-isomer)], 2.19 [3H£a, d,
J¼1.3 Hz, C20H3 (E-isomer)], 2.22 [3H£b, d, J¼1.3 Hz,
C20H3 (Z-isomer)], 3.67 [1H£a, dd, J¼2.3, 10.1 Hz,
C11CHHO (E-isomer)], 3.79 [1H£b, dd, J¼3.7, 10.9 Hz,
C11CHHO (Z-isomer)], 3.88–4.00 (2H, C11H, C5CHHO),
4.40 [1H£b, dd, J¼3.1, 5.4 Hz, C12H (Z-isomer)], 4.63
[1H£a, t, J¼6.4 Hz, C12H (E-isomer)], 6.18 [1H, d,
J¼3.1 Hz, C13H (Z-isomer)], 6.51 [1H£a, d, J¼6.4 Hz,
C13H (E-isomer)], 6.69 (1H, hext, J¼1.3 Hz, C18H), 7.00
[1H£b, br s, amine proton (Z-isomer)], 7.35–7.47 (6H,
aromatic protons), 7.58–7.70 (4H, aromatic protons), 8.13
[1H£a, br s, amine proton(E-isomer)], 9.54 [1H£a, s, C21H
(E-isomer)], 9.58 [1H£b, s, C21H (Z-isomer)]. NOE cross
peaks were observed between the signals at d 9.54$d 6.51,
d 9.58$d 6.51 by phase sensitive NOESY spectrum. EI-MS
(rel int.%) m/z¼676 (0.2, Mþ), 647 (0.1, [M2Et]þ), 277
moiety (E/Z¼87:13). Assignments of signals for the main
1
isomer and some for the minor isomer are described. H
NMR (200 MHz, CDCl3, a¼0.87, b¼0.13): d 0.58 (6H, m,
(CH3CH2)3Si), 0.90 (9H, t, J¼8.2 Hz, (CH3CH2)3Si), 1.03
[9H£a, s, (CH3)3CSi (E-isomer)], 1.03 [9H£b, s, (CH3)3CSi
(Z-isomer)], 2.05 (3H, s, C30H3), 2.15 (3H, s, CH3COO),
3.65 [1H£a, dd, J¼5.1, 12.8 Hz, C5CHHO (E-isomer)],
3.88 (2H, m, C5H, C5CHHO), 4.13 (2H, br s, C20CH2O),
4.60 [1H£a, t, J¼6.2 Hz, C4H], 4.63 (2H, s, OCH2O or
PhCH2O), 4.80 [2H£a, s, OCH2O (E-isomer) or PhCH2O
(E-isomer)], 4.82 [2H£b, s, OCH2O (Z-isomer) or PhCH2O
(Z-0isomer)], 6.10 (1H, hext, J¼1.3 Hz, C10H), 6.15 [2H£b,
C2 H (Z-isomer), C3H (Z-isomer)], 6.43 [1H£a, d,
J¼6.2 Hz, C3H (E-isomer)], 6.62 [1H£b, br, amine proton
(Z-isomer)], 7.40 (11H, m, aromatic protons), 7.67 (4H,
aromatic protons), 7.77 [1H, br s, amine proton (E-isomer)].
EI-MS (rel int.%) m/z¼798 (99, Mþ), 769 (6.0, [M2Et]þ),
741 (4.1, [M2tBu]þ), 199 (100, Ph2SiþvO), 91 (68, Bnþ).
EI-HRMS calcd for C44H58N2O8Si2 (Mþ): m/z¼798.3733.
Found: m/z¼798.3740.
4.12.4. Physical data of 12Z. IR (film): 3330, 2970, 2940,
1770, 1740, 1650, 1220, 1150, 1110, 1060, 1045, 1030, 740,
1
710 cm21. The H NMR spectrum of this sample showed
that it consists of the two tautomers arising from its enamine
(100,
[M2HOC(Me)vCH–AcOH–TBDPSOCH3]þ).
moiety (E/Z¼90:10). Assignments of signals for the main
CI-MS (isobutene): m/z¼677 (MHþ). EI-HIMS: calcd for
1
isomer and some for the minor isomer are described. H
C36H48N2O7Si2
(Mþ):
m/z¼676.3001.
Found:
NMR (200 MHz, CDCl3, a¼0.90, b¼0.10, carzinophilin
numbering): d 0.59 (6H, m, (CH3CH2)3Si), 0.89 (9H, t,
J¼8.2 Hz, (CH3CH2)3Si), 1.02 [9H£a, s, (CH3)3CSi
(E-isomer)], 1.04 [9H£b, s, (CH3)3CSi (Z-isomer)], 2.00
[3H£a, s, C20H3 (E-isomer)], 2.03 [3H£b, s, C20H3
(Z-isomer)], 2.11 [3H£b, s, CH3COO (Z-isomer)], 2.15
[3H£a, s, CH3COO (E-isomer)], 3.64 [1H£a, dd, J¼5.1,
12.8 Hz, C11CHHO (E-isomer)], 3.88 (2H, m, C5H,
C11CHHO), 4.57 [1H£a, t, J¼6.2 Hz, C12H(E-isomer)],
4.63 (2H, s, PhCH2O), 4.63–4.84 (4H, m, C21CH2O,
OCH2O), 5.88 [1H£a, hext, J¼1.3 Hz, C18H (E-isomer)],
5.60 (1H, m, C18H (Z-isomer)), 6.18 [1H£b, d, J¼3.5 Hz,
C13H (Z-isomer)], 6.41 [1H£a, d, J¼6.2 Hz, C13H
(E-isomer)], 6.77 [1H£b, br, amine proton (Z-isomer)],
7.25–7.52 (11H, aromatic protons), 7.57–7.70 (4H,
aromatic protons), 7.76 [1H£a, br s, amine proton(major)].
CI-MS (isobutene) m/z¼798 (99, Mþ), 769 (6.0, [M2Et]þ),
m/z¼676.2994. In a preparative scale, the crude sample
was not purified and directly subjected to the next step.
4.13.2. Preparation from 12Z. Treatments of 12Z (6.0 mg,
8.9 mmol) similarly to those described previously gave 13
(4.2 mg, 86%) as an oil after preparative TLC. The 1H NMR
spectrum of this sample was identical to that of an authentic
sample prepared from 12E.
4.14. 4-[(3R,4R,5S)-3-Acetoxy-5-(tert-butyldiphenyl-
siloxy)methyl-4-(triethylsiloxy)pyrrolidin-2-ylidene]-2-
(2-hydroxymethyl-1-propenyl)-4H-oxazol-5-one (14)
A mixture of 12E (2.60 g, 3.25 mmol) and DDQ (890 mg,
3.92 mmol) in a mixture of CH2Cl2 (25 mL), and H2O
(250 mL) was stirred at room temperature for 30 min. The
mixture was poured into water and extracted with Et2O. The

M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
3075
combined extracts were washed with brine, dried over
1750, 1650, 1590, 1230, 1140, 1115, 1060, 740, 705 cm21
.
MgSO4, then concentrated in vacuo. A mixture of the
residue, and NaBH4 (150 mg, 3.97 mmol) in MeOH
(15 mL) was stirred at 08C for 30 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–AcOEt¼60:40) gave
14 (1.81 g, 82% in two steps) as an oil. IR (film): 3400,
2970, 2950, 1740, 1720, 1640, 1460, 1370, 1230, 1120,
1080, 740, 710 cm21. The 1H NMR spectrum of this sample
showed that it consists of the two tautomers arising from its
enamine moiety (E/Z¼75:25). Assignments of signals for
the main isomer and some for the minor isomer are
The 1H NMR spectrum of this sample was complicated due
to existence of the two tautomers arising from its enamine
moiety (E/Z¼75:25) as well as the two diastereomers at the
C18 position. Assignments of signals for the main 7E18R-
isomer and some of the second major 7Z,18R-isomer are
described. 1H NMR (200 MHz, CDCl3, a¼0.75, b¼0.25) d
0.58 (6H, m, (CH3CH2)3Si), 0.85, [9H£b, (CH3CH2)3Si
(7Z,18R-isomer)], 0.89 [9H£a, (CH3CH2)3Si (7E,18R-
isomer)], 1.00 [9H£a, (CH3)3CSi (7E,18R-isomer)], 1.05
[9H£b, (CH3)3CSi (7Z,18R-isomer)], 2.04 [3H£trace, s,
(7Z,18S isomer)], 2.11 [3H£a, s, (7Z,18R isomer)], 2.15
[3H£a, s, (7E,18R isomer)], and 2.16 [3H£trace, s, (7E,18S
isomer)], 2.95, 3.33 [each 1H£a, alcoholic protons (7E18R-
isomer)], 3.47–4.00 (6H m, C11H, C11CH2O, C21H2O,
C18H), 4.35 [1H£b, dd, J¼3.4, 4.8 Hz, C13H (7Z,18R-
isomer)], 4.59 [1H£aþ1H, C12H (7E,18R-isomer),
alcoholic proton], 6.13 [1H£a, d, J¼3.4 Hz, C13H
(7Z,18R-isomer)], 6.44 [1H£a, d, J¼6.4 Hz, C13H
(7E,18R-isomer)], 6.45 [1H£trace, d, J¼6.4 Hz, C13H
(7E,18S-isomer)], 7.40 (6H, aromatic protons), 7.62
(4H, m, aromatic protons), 7.74 [1H£a, amine proton
(7E,18R-isomer)]. CI-MS m/z¼713 (MHþ), 695
([M2H2O]þ). EI-MS of this sample provided no useful
information.
1
described. H NMR (400 MHz, CDCl3, a¼0.75, b¼0.25,
carzinophilin numbering): d 0.65 (6H, m, (CH3CH2)3Si),
0.85 [9H£b, t, J¼7.8 Hz, (CH3CH2)3Si (Z-isomer)], 0.90
[9H£a, t, J¼7.8 Hz, (CH3CH2)3Si (E-isomer)], 1.02 [9H£b,
s, (CH3)3CSi (Z-isomer)] 1.07 [9H£a, s, (CH3)3CSi
(E-isomer)], 1.90 [1H£a, br t, J¼6.1 Hz, alcoholic proton
(E-isomer)], 2.09 [3H£a, s, C20H3 (E-isomer)], 2.11
[3H£b, s, CH3COO (Z-isomer)], 2.15 [3H£a, s, CH3COO
(E-isomer)], 2.70 [1H£b, br t, J¼6.1 Hz, alcoholic proton
(Z-isomer)], 3.65 [1H£a, m, C11CHHO (E-isomer)], 3.78
[1H£b, dd, J¼3.7, 10.8 Hz, C11CHHO (Z-isomer)], 3.85
[1H£b, dd, J¼7.6, 10.8 Hz, C11CHHO (Z-isomer)], 3.86–
3.93 [2H£a, m, C11H (E-isomer), C11CHHO (E-isomer)],
3.98 [1H£b, m, C11H (Z-isomer)], 4. 16 (2H, br d,
J¼6.1 Hz, C21H), 4.34 [1H£b, dd, J¼3.0, 5.1 Hz, C4H
(Z-isomer)], 4.59 [1H£a, t, J¼6.4 Hz, C12H (E-isomer)]
6.11 [1H£a, hext, J¼1.4 Hz, C18H (E-isomer)], 6.12
[1H£a, J¼3.0 Hz, C13H (Z-isomer)], 6.16 [1H£b,
J¼1.4 Hz, C18H (Z-isomer)], 7.05 [1H£b, br, amine proton
(Z-isomer)], 7.35–7.46 (6H, aromatic protons), 7.59–7.68
(4H, aromatic protons), 7.77 [1H£a, br, amine proton
(E-isomer)]. EI-MS (rel int.%) m/z¼678 (1.1, Mþ), 649
(1.1, [M2Et]þ), 87 (100, [M2AcOH–OH]þ). EI-HRMS:
calcd for C36H50N2O7Si2 (Mþ): m/z¼678.3158. Found:
m/z¼678.3149.
4.16. 4-[(3R,4R,5S)-3-Acetoxy-5-(tert-butyldiphenyl-
siloxy)methyl-4-(triethylsiloxy)pyrrolidin-2-ylidene]-2-
[(1R,2S)-2,3-epoxy-1-hydroxy-2-methylpropyl]-4H-
oxazol-5-one (16)
A mixture of 15 (1.10 g, 1.54 mmol), g-collidine (431 mg,
3.56 mmol), and MsCl (266 mg, 2.32 mmol) in CH2Cl2
(10 mL) was stirred at room temperature for 2 h. After
MeOH (100 mL) was added in order to decompose excess
MsCl, the mixture was poured into water and extracted with
Et2O. The combined extracts were washed with brine, dried
over MgSO4, then concentrated in vacuo to give the crude
mesylate containing g-collidine. A mixture of the crude
mesylate, and DBU (250 mg, 1.67 mmol) in CH2Cl2
(10 mL) was stirred with 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 (hexane–
AcOEt¼65:35) gave 16 (802 mg, 75%) as an oil. Separation
of the minor diastereomer was not attempted. IR (film): 330,
2960, 2930, 2870, 1760, 1650, 1590, 1370, 1230, 1220,
1150, 1120, 1060, 1010, 910, 840, 740, 710, 510 cm21. The
1H NMR spectrum of this sample showed that it consists of
the two tautomers arising from its enamine moiety (E/Z
¼65:35). Assignments of signals for the main isomer and
some for the minor isomer are described. 1H NMR
(400 MHz, CDCl3, a¼0.65, b¼0.35, carzinophilin number-
ing): d 0.51–0.61 (6H, m, (CH3CH2)3Si), 0.85 [9H£b, t,
J¼7.8 Hz, (CH3CH2)3Si (Z-isomer)], 0.91 [9H£a, t,
J¼7.8 Hz, (CH3CH2)3Si (E-isomer)], 1.02 (9H£a, s,
(CH3)3CSi (E-isomer)), 1.07 [9H£b, s, (CH3)3CSi (Z-
isomer)], 1.32 [3H£a, s, C20H3 (E-isomer)], l.37 [3H£b,
s, C20H3 (Z-isomer)], 2.11 [3H£b, s, CH3COO (Z-isomer)],
2.16 [3H£b, s, CH3COO (E-isomer)], 2.68 [1H£a, d,
J¼4.6 Hz, C21H (E-isomer)], 2.72 [1H£b, d, J¼4.5 Hz,
C21H (Z-isomer)], 2.93 [1H£a, br d, J¼6.8 Hz, alcoholic
4.15. 4-[(3R,4R,5S)-3-Acetoxy-5-(tert-butyldiphenyl-
siloxy)methyl-4-(triethylsiloxy)pyrrolidin-2-ylidene]-2-
[(1R,2S)-1,2,3-trihydroxy-2-methylpropyl]-4H-oxazol-5-
one (15)
In a hood, a solution of 13 (1.00 g, 1.47 mmol) in CH2Cl2
(3.0 mL) was added to a mixture of OsO4 (374 mg,
1.47 mmol) and (DHQ)2PHAL15 (1.38 g, 1.77 mmol) in
CH2Cl2 (20 mL) at 08C with stirring. After stirring for
15 min, H2S gas was bubbled through the mixture to give a
black suspension. Celitew (3 g) and AcOEt (50 mL) were
added to the suspension, and the whole mixture was stirred
at room temperature for additional 30 min with H2S
bubbling. After filtration through a pad of Celitew, the
filtrate was concentrated in vacuo. Purification of the
residue by silica gel column chromatography (hexane–
AcOEt¼60:40!10:90) gave recovered 14 (70 mg, 7%) and
15 (730 mg, 69%) both as oil. The 1H NMR spectrum of 15
indicated that diastereomeric excess of this sample about the
C18 position (carzinophilin numbering) was 80% de based
on the signal intensity for C15H3 observed at 2.04 (7Z,18S
isomer), 2.11 (7Z,18R isomer), 2.15 (7E18R isomer), and
2.16 (7E18S isomer). IR (film): 3380, 2960, 2950, 2880,

3076
M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
proton (E-isomer)], 2.96 [1H£a, d, J¼4.6 Hz, C21H
(E-isomer)], 2.99 [1H£b, d, J¼4.5 Hz, C21H (Z-isomer)],
3.09 [1H£b, br d, J¼6.4 Hz, alcoholic proton (Z-isomer)],
3.62–3.98 (3H, C11H, C11CH2O), 4.29 [1H£a, br d,
J¼6.8 Hz, C18H (E-isomer)], 4.30 [1H£b, br d, J¼6.4 Hz,
C18H (Z-isomer)], 4.37 [1H£b, dd, J¼3.4, 5.2 Hz, C12H
(Z-isomer)], 4.60 [1H£a, t, J¼6.4 Hz, C12H (E-isomer)],
6.16 [1H£b, d, J¼3.4 Hz, C13H (Z-isomer)], 6.43 [1H£a, d,
J¼6.4 Hz, C13H (E-isomer)], 6.82 [1H£b, br, amine proton
(Z-isomer)], 7.36–7.47 (6H, m, aromatic protons), 7.56–
7.69 (4H, m, aromatic protons), 7.71 [1H£a, br, amine
proton (E-isomer)]. EI-MS (rel. int.%): m/z¼694 (2.4, Mþ),
676 (0.8, [M2H2O]þ), 665 (1.0, [M2Et]þ), 653 (1.3,
[M2Ac]þ), 637 (4.0, [M2tBu]þ and/or [M2CH3-
COCH2]þ), 199 (100, Ph2SiþvO) CI-MS (isobutene):
m/z¼695 (MHþ), EI-HRMS calcd for C36H50N2O8Si2
(Mþ): m/z¼694.3107. Found: m/z¼694.3079.
AcOEt. The combined extracts were washed with brine,
dried over MgSO4, then concentrated in vacuo. The residue
was purified by silica gel column chromatography (AcOEt–
hexane¼40:60) gave 18 (594 mg, 95%) as an oil. IR (film):
3320, 2960, 2940, 2880, 1760, 1740, 1655, 1590, 1370,
1210, 1215, 1150, 1110, 1070, 1060, 1015, 910, 830, 730,
705, 500 cm21. The 1H NMR spectrum of this sample
showed that it consists of the two tautomers arising from its
enamine moiety (E/Z¼80:20). Assignments of signals for
the main isomer and some for the minor isomer are
1
described. H NMR (400 MHz, CDCl3, a¼0.80, b¼0.20,
carzinophilin numbering): d 0.60 (6H, m, (CH3CH2)3Si), 5
[9H£b, t, J¼7.8 Hz, (CH3CH2)3Si (Z-isomer)], 0.91 [9H£a,
t, J¼7.8 Hz, (CH3CH2)3Si (E-isomer)], 1.01 [9H£a, s,
(CH3)3CSi (E-isomer)], 1.07 [9H£b, s, (CH3)3CSi
(Z-isomer)], 1.36 [3H£a, s, C20H3 (E-isomer)], 1.41
[3H£b, s, C20H3 (Z-isomer)], 2.12 [3H£b, s, CH3COO
(Z-isomer)], 2.14 [3H£a, s, CH3COO (Z-isomer)], 2.69 (1H,
m, C21HH), 2.87 [1H£a, br d, J¼3.3 Hz, alcoholic proton
(E-isomer)], 2.95 [1H£b, br d, J¼3.3 Hz, alcoholic proton
(Z-isomer)], 3.06 (1H, m, C21HH), 3.63 [1H£a, m,
C11CHHO (E-isomer)], 3.76 [1H£b, dd, J¼3.5, 10.9 Hz,
C11CHHO (Z-isomer)], 3.82–4.00 (H, C11H, C11CHHO),
4.36 [1H£b, dd, J¼3.3, 5.1 Hz, C12H (Z-isomer)], 4.46
[1H£a, br d, J¼3.3 Hz, C18H (E-isomer)], 4.54 [1H£b, br
d, J¼3.3 Hz, C18H (Z-isomer)], 4.61 [1H£a, t, J¼6.5 Hz,
C12H (E-isomer)], 6.16 [1H£b, d, J¼3.3 Hz, C13H(Z-
isomer)], 6.45 [1H£a, d, J¼6.5 Hz, C13H (E-isomer)], 7.41
(6H, m, aromatic protons), 7.58–7.65 (4H, m, aromatic
protons), 7.75 [1H£a, br, amine proton(E-isomer)]. EI-MS
(rel. int.): m/z¼694 (7.6, Mþ), 676 (1.7, [M2H2O]þ), 637
(14, [M2tBu]þ), 199 (100, Ph2SiþvO). CI-MS
(isobutene): m/z¼695 (MHþ), 637 (14, [M2t-Bu]þ). EI-
HRMS: calcd for C36H50N2O8Si2 (Mþ): m/z¼694.3107.
Found: m/z¼694.3093.
4.17. 4-[(3R,4R,5S)-3-Acetoxy-5-(tert-butyldiphenyl-
siloxy)methyl-4-(triethylsiloxy)pyrrolidin-2-ylidene]-2-
[(S)-2,3-epoxy-2-methylpropionyl]-4H-oxazol-5-one (17)
A mixture of 16 (700 mg, 1.01 mmol) and Dess–Martin
reagent (535 mg, 1.30 mmol) in CH2Cl2 (10 mL) was stirred
at room temperature for 2 h. The mixture was poured into a
1:1 mixture of aqueous 10% Na2S2O3 solution and aqueous
saturated NaHCO3 solution, then 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–
AcOEt¼70:30) gave 17 (587 mg, 84%) as a yellow solid.
Analytical sample was prepared by recrystallization from
hexane–Et2O to give yellow needles. Mp 97–1028C. IR
(nujor): 3350, 2970, 2930, 1760, 1720, 1640, 1520, 1210,
1
1140, 1110, cm21. H NMR (400 MHz, CDCl3, carzino-
philin numbering): d 0.62 (6H, q, J¼7.7 Hz, (CH3CH2)3Si),
0.93 (9H, t, J¼7.7 Hz, (CH3CH2)3Si), 1.00 (9H, s,
(CH3)3CSi), 1.65 (3H, s, C20H3), 2.23 (3H, s, CH3COO),
2.89 (1H, d, J¼5.9 Hz, C21HH), 3.58 (1H, d, J¼5.9 Hz,
C21HH), 3.64 (1H, dd, J¼2.6, 10.8 Hz, C11CHHO), 3.96
(1H, m, C11H), 3.98 (1H, dd, J¼3.8, 10.8 Hz, C11CHHO),
4.69 (1H, t, J¼7.1 Hz, C12H), 6.66 (1H, d, J¼7.1 Hz,
C13H), 7.35–7.35 (6H, aromatic protons), 7.56 (2H,
aromatic protons), 7.68 (2H, m, aromatic protons), 8.34
(1H, br s, amine proton). EI-MS (rel. int.%): m/z¼692 (4.5,
Mþ), 676 (1.5, [M2H2O]þ), 663 (1.5, [M2Et]þ), 635 (36,
[M2tBu]þ), 199 (100, Ph2SiþvO). CI-MS (isobutane):
m/z¼693 (MHþ), 677 ([M2H2O]þ). EI-HRMS: calcd for
4.19. 4-[(3R,4R,5S)-3-Acetoxy-5-(tert-butyldiphenyl-
siloxy)methyl-4-(triethylsiloxy)pyrrolidin-2-ylidene]-2-
[(1S,2S)-2,3-epoxy-1-(3-methoxy-5-methyl-1-
naphthoxy)-2-methylpropyl]-4H-oxazol-5-one (20)
A mixture of 18 (594 mg, 856 mmol), and the naphthoic
acid 19 (370 mg, 1.71 mmol), DMAP (335 mg, 2.74 mmol),
and WSCI·HCl (320 mg, 1.66 mmol) in CH2Cl2 (10 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 (hexane–AcOEt¼80:20) gave
20 (741 mg, 97%) as an oil. IR (film): 3320, 2950, 2930,
C36H48N2O8Si2
(Mþ):
m/z¼692.2950.
Found:
m/z¼692.2955. Anal. calcd for C36H50N2O9Si2 (MþH2O):
C, 60.64%; H, 7.35%; N, 3.93%. Found C, 60.67%; H,
6.99%; N, 3.81%.
1760, 1730, 1650, 1590, 1230, 1210, 1070, 750, 700 cm21
.
The 1H NMR spectrum of this sample showed that it
consists of the two tautomers arising from its enamine
moiety (E/Z¼75:25). Assignments of signals for the main
4.18. 4-[(3R,4R,5S)-3-Acetoxy-5-(tert-butyldiphenyl-
siloxy)methyl-4-(triethylsiloxy)pyrrolidin-2-ylidene]-2-
[(1S,2S)-2,3-epoxy-1-hydroxy-3-methylpropyl]-4H-
oxazol-5-one (18)
1
isomer and some for the minor isomer are described. H
NMR (200 MHz, CDCl3, a¼0.75, b¼0.25, carzinophilin
numbering): d 0.59 (6H, m, (CH3CH2)3Si), 0.84 [9H£b, t,
J¼ 7.7 Hz, (CH3CH2)3Si (Z-isomer)], 0.89 [9H£a, t,
J¼7.7 Hz, (CH3CH2)3Si (E-isomer)], 1.02 [9H£a, s,
(CH3)3CSi (E-isomer)], 1.04 [9H£b, s, (CH3)3CSi
(Z-isomer)], 1.51 [3H£a, C20H3 (E-isomer)], 1.55 [3H£b,
C20H3 (Z-isomer)], 1.99 [3H£a, s, CH3COO (E-isomer)],
2.04 [3H£b, s, CH3COO (Z-isomer)], 2.67 (3H, s, CH3Ar),
Sodium borohydride (41.0 mg, 1.08 mmol) was added to a
mixture of 17 (625 mg, 903 mmol) and CeCl3·7H2O
(165 mg, 430 mmol) in MeOH (50 mL) at 2158C with
stirring. After stirring for 10 min, the mixture was poured
into aqueous. 5% citric acid solution and extracted with

M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
3077
2.70 [1H£a, d, J¼5.0 Hz, C21HH (E-isomer)], 2.74 [1H£b,
d, J¼4.6 Hz, C21HH (Z-isomer)], 3.05 [1H£a, d, J¼5.0 Hz,
C21HH (E-isomer)], 3.11 [1H£b, d, J¼4.6 Hz, C21HH
(Z-isomer)], 3.58–3.98 (3H, m, C11H, C11H2O), 3.98 (3H,
s, CH3OAr), 4.34 [1H£b, dd, J¼3.1, 4.5 Hz, C12H
(Z-isomer)], 4.59 [1H£a, t, J¼6.4 Hz, C12H (E-isomer)],
5.82 [1H£b, s, C18H (Z-isomer)], 5.86 [1H£a, s, C18H
(E-isomer)], 6.15 [1H£b, d, J¼3.1 Hz, C13H (Z-isomer)],
6.43 [1H£a, d, J¼6.4 Hz, C13H (E-isomer)], 6.99 [1H£b,
br s, amine proton (Z-isomer)], 7.33–7.77 (13H, aromatic
protons), 7.80 [1H£a, br s, amine proton (E-isomer)], 7.84
[1H£a, d, J¼02.6 Hz, C20H (E-isomer)], 7.890 [1H£b, d,
J¼2.6 Hz, C2 H (Z-isomer)], 8.62 (1H, m, C8 H). SI-MS
(3-nitrobenzylalcohol): m/z¼893 (MHþ), 863 ([M2Et]þ),
835 ([MH–isobutene]þ). Neither EI- nor CI-MS of this
sample gave informative peaks. So, EI-HRMS was not
measured.
further stirred for 10 h at room temperature. The mixture
was poured into aqueous 5% citric acid 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 chromatog-
raphy (CH2Cl2–acetone 70:30!50:50) gave the mesylate
(69.0 mg, 67%) and recovered 21 (13.5 mg, 14%), both as
an oil.
4.21.2. Physical data of the mesylate. IR (film) 3350, 2940,
1735, 1855, 1600, 1360, 1235, 1220, 1175, 1070, 960, 910,
730, 530 cm21. The 1H NMR spectrum of this sample
showed that it consists of the two tautomers arising from its
enamine moiety (E/Z¼50:50). Assignments of signals for
the main isomer and some for the minor isomer are
described. 1H NMR (200 MHz, CDCl3, carzinophilin
numbering): d 1.54 [3H£0.5, s, C20H3 (one isomer)], 1.56
[3H£0.5, s, C20H3 (another isomer)], 1.97 [3H£0.5, s,
CH3COO (one isomer)], 2.13 [3H£0.5, s, CH3COO
(another isomer)], 2.67 (3H, s, CH3Ar), 2.72 [1H£0.5, d,
J¼4.7 Hz, C21HH (one isomer)], 2.76 [1H£0.5, d,
J¼4.9 Hz, C21HH (another isomer)], 3.05 [3H£0.5, s,
CH3SO3 (one isomer)], 3.07 [3H£0.5, s, (another isomer)],
3.57 [1H£0.5, br, alcoholic proton (one isomer)], 3.69
[1H£0.5, br, alcoholic proton (another isomer)], 3.97 (3H, s,
CH3OAr), 4.30–4.45 (2H, C11H, C11CHHO), 4.46–4.63
(2H, C12H, C11CHHO), 5.77 [1H£0.5, s, C18H (one
isomer)], 5.79 [1H£0.5, s, C18H (one isomer)], 5.98 (1H,
C3H) 7.11 [1H£0.5, br, amine proton(Z-isomer)], 07.36 (2H,
m, C60H, C70H), 7.47 (1H, d, J¼2.4 Hz, C4 H), 7.78
[1H£0.5, br, amine proton (E-isomer)], 7.88 (1H, m, C20H),
8.62 (1H, m, C80H). SI-MS (3-nitrobenzylalcohol):
m/z¼619 (MHþ). Neither EI- nor CI-MS of this sample
gave useful signals. So, EI-HRMS was not measured.
4.20. 4-[(3R,4R,5S)-3-Acetoxy-4-hydroxy-5-hydroxy-
methylpyrrolidin-2-ylidene]-2-[(1S,2S)-2,3-epoxy-2-
methyl-1-(3-methoxy-5-methyl-1-naphthoxy)propyl]-
4H-oxazol-5-one (21)
A mixture of 20 (24.5 mg, 27.4 mmol), AcOH (50 mL),
TBAF (1.0 M in THF, 80 mL) in THF (1.0 mL) was stirred
at room temperature for 3 h. 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 (hexane–AcOEt¼60:40) gave 21
(14.5 mg, 98%) as an oil. IR (film): 3370, 2850, 1730, 1650,
1490, 1240, 1070, 1040, 910, 730 cm21. The 1H NMR
spectrum of this sample showed that it consists of the two
tautomers arising from its enamine moiety (E/Z¼55:45).
Assignments of signals for the main isomer and some for the
1
minor isomer are described. H NMR (200 MHz, CDCl3,
4.21.3. Formation of the TES ether giving 22. A mixture
of the mesylate (140 mg, 226 mmol), imidazole (160 mg,
2.35 mmol, 10 equiv.), and TESCl (150 mg, 1.0 mmol,
4.5 equiv.) in DMF (5.0 mL) was stirred at room tempera-
ture 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 silica gel column chromato-
graphy (hexane–AcOEt¼1:1) gave 22 (160 mg, 97%) as an
oil. IR (film): 3350, 2950, 2880, 1740, 1750, 1650, 1600,
a¼0.55, b¼0.45, carzinophilin numbering): d 1.52 [3H£a,
s, C20H3 (E-isomer)], 1.59 [3H£b, s, C20H3 (Z-isomer)],
1.92[3H£a, s, CH3COO (E-isomer)], 2.11 [3H£b, s,
CH3COO (Z-isomer)], 2.66 (3H, s, CH3Ar), 2.73 (1H, m,
C21HH), 3.08 (1H, m, C21H), 3.96 [3H£b, s, CH3OAr
(Z-isomer)], 3.97 [3H£a, s, CH3OAr (E-isomer)], 3.65–
4.15 (3H, m, C11H, C11CH2O), 4.38 [1H£b, dd, J¼3.5,
6.1 Hz, C12H (Z-isomer)], 4.53 [1H£a, dd, J¼5.4, 7.3 Hz,
C12H (E-isomer)], 5.77 [1H£b, s, C18H (Z-isomer)], 5.82
[1H£a, s, C18H (E-isomer)], 6.03 [1H£b, d, J¼3.1 Hz, C13H
(E-isomer)], 06.10 [1H£a, d, J¼5.4 Hz, C13H (Z-isomer)],
7.36 (2H, C6 H, C70H), 7.46 [1H£a, br s, C40H], 7.87 (1H, m,
C20H), 8.61 (1H, m, C80H). SI-MS (3-nitrobenzylalcohol)
m/z¼541 (MHþ). Neither EI- nor CI-MS of this sample
gave informative signals. So, EI-HRMS was not
measured.
1
1360, 1280, 1220, 1240, 1180, 1080, 735 cm21. The H
NMR spectrum of this sample showed that it consists of the
two tautomers arising from its enamine moiety
(E/Z¼60:40). Assignments of signals for the main isomer
1
and some for the minor isomer are described. H NMR
(200 MHz, CDCl3, a¼0.60, b¼0.40, carzinophilin number-
ing): d 0.68 (6H, m, (CH3CH2)3Si), 0.91 (9H, t, J¼7.7 Hz,
(CH3CH2)3Si), 1.52 [3H£a, s, C20H3 (E-isomer)], 1.52
[3H£b, s, C20H3 (Z-isomer)], 2.00 [3H£a, s, CH3COO
(E-isomer)], 2.10 [3H£b, s, CH3COO (Z-isomer)], 2.67 (3H,
s, CH3Ar), 2.70 [1H£a, d, J¼4.9 Hz, C21HH (E-isomer)],
2.74 [1H£b, d, J¼4.7 Hz, C21HH (Z-isomer)], 3.076
[3H£a, s, CH3SO3 (E-isomer)], 3.083 [3H£b, s, CH3SO3
(Z-isomer)]. 3.07 (1H, m, C21HH), 3.97 (3H, s, CH3OAr),
4.25–4.50 (3Hþ1H£b, m, C11H, C11CH2O, C12H
(Z-isomer)), 4.62 [1H£a, t, J¼5.3 Hz, C12H (E-isomer)],
5.76 [1H£b, s, C18H (Z-isomer)], 5.81 [1H£a, s, C18H
(E-isomer)], 6.03 [1H£b, d, J¼1.9 Hz, C13H (Z-isomer)],
4.21. 4-[(3R,4R,5S)-3-Acetoxy-5-metanesulfoxymethyl-
4-(triethylsiloxy)pyrrolidin-2-ylidene]-2-[(1S,2S)-2,3-
epoxy-2-methyl-1-(3-methoxy-5-methyl-1-naphthoxy)-
propyl]-4H-oxazol-5-one (22)
4.21.1. Selective mesylation of 21. Methanesulfonyl
chloride (20.7 mg, 181 mmol) was added to a mixture of
21 (90.0 mg, 167 mmol) and g-collidine (37.0 mg,
303 mmol) in CH2Cl2 (2.0 mL) at 08C with stirring. The
cooling bath was removed after 30 min and the mixture was

3078
M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
6.13 [1H£a, J¼5.3 Hz, C13H (E-isomer)], 6.93 [1H£b, br,
amine p0roton (Z-isomer)], 7.37 (2H, C60H, C70H), 7.48 (1H,
br s, C4 H), 7.77 [1H£a, b0r, amine proton (E-isomer)], 7.85
[1H£a, d, J¼02.6 Hz, C2 H (E-isomer)], 7.900 [1H£b, d,
J¼2.6 Hz, C2 H (Z-isomer)], 8.63 (1H, m, C8 H). CI-MS
(isobutane): m/z¼733 (MHþ), 675 ([M2MeC(O)CH2]þ)þ).
EI-MS of this sample gave no informative peaks. EI-HRMS
was not measured.
solution (100 mL), then 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–
AcOEt¼50:50) gave 26 (2.40 g, 58% in two steps) as an oil.
[a]2D0¼217.58 (c 1.26, CHCl3). IR (film): 3430, 2980, 2960,
2950, 1710, 1520, 1450, 1250, 1110, 1080, 1040, 830, 760,
740 cm21 1H NMR (200 MHz, CDCl3) d 1.24 (3H, d,
.
J¼6.3 Hz, C4H3), 2.45 (1H, br, alcoholic proton), 3.77 (2H,
m, C1H2), 3.81 (3H, s, CH3O), 3.81 (1H, m, C2H), 4.22 (1H,
t, J¼6.9 Hz, methyne proton of Fmoc), 4.28 (1H, d,
J¼11.1 Hz, ArCHHO), 4.42 (2H, methylene proton of
Fmoc), 4.58 (1H, d, J¼11.1 Hz, ArCHHO), 5.32 (1H, br,
amide proton), 6.89 (2H, br d, J¼8.6 Hz, aromatic protons),
7.20 (2H, br d, J¼8.6 Hz, aromatic protons), 7.33 (4H, m,
aromatic protons), 6.63 (2H, d, J¼7.2 Hz, aromatic
protons), 7.76 (2H, d, J¼7.0 Hz, aromatic protons). CI-
MS (isobutene): m/z¼448 (MHþ), 429 (M2H2Oþ). No
useful information was obtained by EI-MS. So, EI-HRMS
could not be measured.
4.22. N-(9-Fluorenylmethoxycarbonyl)-L-threonine
methyl ester (25)
A suspension of L-threonine methyl ester hydrochloride 24
(3.30 mg, 19.3 mmol) and FmocCl (5.00 g, 19.3 mmol) in a
mixture of dioxane (10 mL) and aqueous NaHCO3 solution
(4.0 g in 20 mL) was stirred vigorously for 1 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 to give a crude solid.
Recrystallization from Et2O gave 25 (6.80 g, 99%) as fine
needles. [a]2D0¼213.68 (c 1.01, CHCl3). Mp 126–1278C. IR
(nujor): 3470, 3300, 2950, 2930, 1720, 1700, 1540, 1450,
4.24. (2RS,3S,4R)-2-(tert-Butyldiphenylsiloxy-3-(9-
fluorenylmethoxycarbonyl)amino-4-(4-methoxyphenyl)-
methoxypentanonitrile (27)
1380, 1280, 1255, 1090, 1060, 1020, 1000, 760, 740 cm21
.
1H NMR (200 MHz CDCl3, amino acid numbering) d 1.24
(3H, d, J¼6.2 Hz, C4H3), 2.05 (1H, d, J¼4.8 Hz, alcoholic
proton), 3.78 (3H, s, CH3O), 4.20–4.46 (5H, m, C2H, C3H,
two methylenes and a methyne protons for Fmoc), 5.58 (1H,
br d, J¼8.7 Hz, amide proton), 7.35 (4H, m, aromatic
protons), 7.61 (2H, br d, J¼7.1 Hz, aromatic protons), 7.76
(2H, d, J¼6.9 Hz, aromatic protons). Anal. calcd for
C20H21NO5: C, 67.59%; H, 5.96%; N, 3.94%. Found: C,
67.65%; H, 5.98%; N, 3.83%.
A mixture of 26 (86.0 mg, 192 mmol) and Dess–Martin
reagent (150 mg, 364 mmol) in CH2Cl2 (3.0 mL) was stirred
at room temperature for 30 min. The mixture was poured
into 5:2:10 mixture of aqueous 5% Na2S2O3 solution,
aqueous saturated NaHCO3, and water, then extracted with
AcOEt. The combined ethyl acetate extracts were washed
with brine, dried with MgSO4, then concentrated in vacuo.
After the residue was dissolved in CH3CN (3.0 mL),
TBDMSCN (150 mg, 1.06 mmol) was added to the solution.
The mixture was stirred at 808C for 3 h, and concentrated in
vacuo. The residue was purified by silica gel column
chromatography (hexane–AcOEt¼80:20) to give 27
(103 mg, 92%) as a 75:25 mixture of the diastereomers.
IR (film): 3440, 3350, 2860, 2840, 2250 (weak) 1730, 1615,
1515, 1250, 1110, 1040, 840, 780, 760, 740 cm21; 1H NMR
(200 MHz, CDCl3, a¼0.75, b¼0.25): d 0.13 (3H, s,
(CH3)Si), 0.20 [3H£a, s, (CH3)Si (major)], 0.22 [3H£b, s,
(CH3)Si (minor)], 0.89 [9H£a, s, (CH3)3CSi (major)], 0.91
[3H£b, s, (CH3)3CSi (minor)], 1.22 [3H£a, d, J¼6.3 Hz,
C5H3 (major)], 1.24 [3H£a, d, J¼7.1 Hz, C5H3 (minor)],
3.81 (3H£a, s), 3.82 [3H£b, s, CH3O (major)], 3.90–4.60
(8H, m), 5.27 [1H£b, br d, J¼8.7 Hz, amide proton
(minor)], 5.38 [1H£a, br d, J¼9.1 Hz, amide proton
(major)], 6.90 (2H, br d, J¼8.6 Hz, aromatic protons),
7.20–7.45 (4H, m, aromatic protons) 7.59 (2H, d, J¼7.3 Hz,
aromatic protons), 7.76 (2H, d, J¼7.3 Hz, aromatic
protons). CI-MS m/z¼588 (MHþ), 587 (Mþ). EIMS did
not provide informative peaks. So, EI-HRMS was not
measured.
4.23. (2R,3R)- 2-(9-Fluorenylmethoxycarbonylamino)-3-
(4-methoxyphenyl)methoxybutanol (26)
Trifluoromethanesulfonic acid (20 mL, 3.38 mg, 20 mmol)
was added to a mixture of 25 (3.30 g, 9.24 mmol) and
4-methoxyphenylmethyl trichloroacetoimidate (3.00 g,
10.6 mmol) in a mixture of THF (20 mL) and Et2O
(40 mL) at room temperature with stirring. After 3 h, the
mixture was concentrated in vacuo. Purification of the
residue by silica gel column chromatography (hexane–
AcOEt¼80:20) gave the MPM ether containing trichloro-
acetoamide. Analytical sample was obtained as an oil by
purification with preparative silica gel preparative TLC
(hexane–AcOEt¼80:20). IR (film) 3440, 3360, 2950, 1750,
1730, 1520, 1250, 1215, 1080, 1030, 760, 740 cm21. H
1
NMR (200 MHz, CDCl3): d 1.24 (3H, d, J¼6.3 Hz, C4H3),
3.81 (3H, s, CH3O), 4.11 (3H, s, CH3O), 4.00–4.46 (6H, m,
C2H, C3H, ArCHHO, two methylenes and a methyne
protons for Fmoc), 4.53 (1H, d, J¼11.5 Hz, ArCHHO), 5.58
(1H, br d, J¼9.6 Hz, amide proton), 6.89 (2H, br d,
J¼6.8 Hz, aromatic protons), 7.20 (2H, br d, J¼6.8 Hz,
aromatic protons), 7.33 (4H, aromatic protons), 7.63 (2H,
dd, J¼5.2, 8.7 Hz, aromatic protons), 7.76 (2H, d,
J¼6.0 Hz, aromatic protons). CI-MS (isobutene) m/z¼476
(MHþ). The crude MPM ether thus obtained was diluted
with Et2O (10 mL). The solution was mixed with Zn(BH4)2
(ca. 4 M in Et2O, 20 mL, 8.0 mmol) and the mixture was
stirred at room temperature for 12 h. After methanol was
added to the mixture in order to decompose excess reagent,
the mixture was poured into aqueous 10% citric acid
4.25. (2R or 2S, 3S,4R)-2-tert-Butyldiphenylsiloxy-3-
amino-4-(4-methoxyphenyl)methoxypentanenitrile (28)
4.25.1. Reaction procedure. A solution of 27 (2.60 g,
4.44 mmol) in a mixture of DMF (20 mL) and piperidine
(4.0 mL) was stirred at room temperature for 1 h. The
mixture was concentrated in vacuo. Purification of the
residue by silica gel column chromatography

M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
3079
(hexane–AcOEt¼90:10) gave 28 (1.04 g, 64%) and its
d J¼4.5 Hz, CH2vCHCH2O), 4.72 (1H, dd, J¼3.2, 10.2 Hz,
C11CHHO), 5.12 (1H, s, C13H), 5.25 (1H, br d J¼10.1 Hz,
diastereomer (453 mg, 27%).
CHHvCHCH2O), 5.34 (1H, br
d
J¼16.4 Hz,
4.25.2. Physical data of 28. RF¼0.35 (silica gel, hexane–
AcOEt¼70:30). [a]2D0¼29.108 (c 1.23, CHCl3). IR (film):
3400, 2970, 2940, 2870, 1610, 1515, 1465, 1250, 1110,
1070, 1035, 840, 780 cm21; 1H NMR (200 MHz, CDCl3): d
0.13, 0.21 (each 3H, s, (CH3)Si£2), 0.91 (9H, s, (CH3)3CSi),
1.30 (3H, d, J¼6.2 Hz, C5H3), 2.80 (1H, dd, J¼3.0, 7.1 Hz,
C3H), 3.80 (3H, s, CH3O), 3.82 (1H, m, C4H), 4.33 (1H, d,
J¼7.2 Hz, C2H), 4.35 (1H, d, J¼11.3 Hz, ArCHHO), 4.57
(1H, d, J¼11.3 Hz, ArCHHO), 6.88 (2H, br t, J¼8.7 Hz,
aromatic protons), 7.21 (2H, br d, J¼8.7 Hz, aromatic
protons); CI-MS (isobutene): m/z¼365 (MHþ), 338
([M2HCN]þ). EIMS provided no informative peaks. So,
EI-HRMS was not measured.
CHHvCHCH2O), 5.53 (1H, s, C18H), 5.97 (1H, DDT,
J¼10.1, 16.4, 5.9 Hz, CH2vCHCH2O), 6.33 (1H, br d,
J¼7.9 Hz, N5H), 6.83 (2H, br d J¼8.7 Hz, aromatic protons
for0 MPM), 7.30–7.37 (4H, m, aromatic protons for MPM,
C6 H, C70H),0 7.47 (1H, d, J¼2.6 Hz, C40H), 8.14 (1H, d,
J¼2.6 Hz, C2 H), 8.70 (1H, m, C80H), 9.32 (1H, br s, N16H).
SI-MS (3-tirobenzylalcohol) m/z¼1181 (MHþ). Neither
EI-MS nor CI-MS of this sample gave informative signals.
So, EI-HRMS was not measured.
4.26.3. Physical data of 29Z. IR (film): 3430, 3350, 2260,
1720, 1620, 1510, 1470, 1360, 1230, 1180, 1115, 1090,
.
1030, 960, 840, 730 cm21 1H NMR (200 MHz CDCl3,
carzinophilin numbering): d 0.19, 0.21 (each 3H, s,
(CH3)2Si), 0.69 (6H, m, (CH3CH2)3Si), 0.88 (9H, s,
(CH3)3CSi), 0.95 (9H, t, J¼7.1 Hz, (CH3CH2)3Si), 1.18
(3H, d, J¼6.2 Hz, C1H3), 1.43 (3H, s, C20H3), 2.00 (3H, s,
CH3COO), 2.29 (3H, d, J¼4.1 Hz, C21HH), 2.67 (3H, s,
CH3Ar), 2.95 (3H, s, CH3SO3), 2.97 (3H, d, J¼4.1 Hz,
C21HH), 3.54 (1H, br dd, J¼5.5, 12.9 Hz, C11CHHO), 3.79
(3H, s, CH3OAr), 3.98 (3H, s, MeOAr), 4.00–4.57 (9H, m,
C2H, C3H, C11H, C12H, C11CHHO, CH2vCHCH2O,
ArCH2O), 4.73 (1H, d, J¼7.0 Hz, C11H), 4.88 (1H, dq,
J¼17.0, 1.4 Hz, CHHvCHCH2O), 4.98 (1H, dq, J¼10.4,
1.4 Hz, CHHvCHCH2O), 5.43 (1H, s, C18H), 5.44 (1H, m,
CH2vCHCH2O), 6.41 (1H, s, C13H), 6.83 (2H. br d
J¼8.7 Hz, aromatic protons for MPM). 6.97 (1H, br d
J¼8.9 Hz, N5H), 7.33 (4H, m, aromatic protons for MPM,
C60H, C70H), 07.50 (1H, d, J¼2.5 Hz, C40H), 8.07 (1H, d,
J¼2.5 Hz, C1 H), 8.74 (1H, dd, J¼3.0, 6.7 Hz, C80H), 8.99
(br s, N16H). SI-MS (3-nitrobenzylalcohol): m/z¼1181
(MHþ), 1121 (M2AcOþ); SI-MS (3-nitrobenzylalcoholþ
KCl): m/z¼1219 ([MþK]þ). Neither EI- nor CI-MS of this
sample gave informative signals. So, EI-HRMS was not
measured.
4.25.3. Physical data of the diastereomer of 28. RF¼0.45
(silica gel, hexane–AcOEt¼70:30). [a]2D0¼251.38 (c 1.16,
CHCl3). IR (film): 3420, 2970, 2940, 2870, 1610, 1515,
1470, 1250, 1100, 1040, 840, 780 cm21
.
1H NMR
(200 MHz, CDCl3): d 0.12, 0.21 (each 3H, s, (CH3)Si£2),
0.91 (9H, s, (CH3)3CSi), 1.31 (3H, d, J¼6.2 Hz, C5H3), 2.83
(1H, dd, J¼2.9, 7.7 Hz, C3H), 3.76 (1H, m, C4H), 3.80 (3H,
s, CH3O), 4.27 (1H, d, J¼10.9 Hz, ArCHHO), 4.40 (1H, d,
J¼7.6 Hz, C2H), 4.55 (1H, d, J¼10.9 Hz, ArCHHO), 6.87
(2H, br d, J¼8.7 Hz, aromatic protons), 7.21 (2H, br d,
J¼8.7 Hz, aromatic protons); CI-MS m/z¼365 (MHþ), 338
([M2HCN]þ). EIMS provided no informative peaks. So,
EI-HRMS was not measured.
4.26. (3R,4R,5S)-3-Acetoxy-2-[(E)-1-[(2S,3S)-3,4-epoxy-
2-(3-methoxy-5-methylnaphthoxy)-3-methyl-butyryl-
amino]-1-[N-[(1R or 1S,3R)-[1-tert-butyldimethylsiloxy-
1-cyano-3-(4-methoxyphenylmethoxy)but-2-yl]-
carbamoyl]]methylidene-4-triethylsiloxy-5-(methane-
sulfonyl)oxymethyl-1-(2-propenyloxycarbonyl)-
pyrrolidine (29E) and its Z-isomer (29Z)
4.26.1. Reaction procedure. A mixture of 22 (130 mg,
177 mmol), DMAP (1.0 mg, 8.2 mmol), and Alloc2O
(49.0 mg, 265 mmol) in THF (5.0 mL) was stirred at room
temperature. After 10 min, a solution of 28 (90 mg,
247 mmol) in THF (4.0 mL) was added to the mixture.
The whole mixture was concentrated in vacuo at 408C over
15 min. Purification of the residue by silica gel column
chromatography (hexane–AcOEt¼80:20!60:40) gave 29Z
(7.0 mg, 3.3%) and 29E (144 mg, 69%) both as an oil.
4.27. (3R,4R,5S)-3-Acetoxy-2-[(E)-1-[(2S,3S)-3,4-epoxy-
3-methyl-2-(3-methoxy-5-methyl-1-naphthoxy)butyryl-
amino]-1-[N-[(1R or 1S,3R)-[1-tert-butyldimethylsiloxy-
1-cyano-3-oxobut-2-yl]carbamoyl]]methylidene-4-tri-
ethylsiloxy-5-(methanesulfoxymethyl-1-(2-propenyl-
oxycarbonyl)pyrrolidine (30)
4.27.1. Removal of the MPM group in 29E. A mixture of
the 29E (40.0 mg, 33.8 mmol) and DDQ (30.0 mg,
132 mmol) in a mixture of CH2Cl2 (2.0 mL) and H2O
(200 mL) was stirred at room temperature for 1 h. The
mixture was poured into a 1:1 mixture of aqueous 5%
Na2S2O3 and saturated aqueous NaHCO3 solutions, then
extracted with AcOEt. The organic extracts were washed
with brine, dried over MgSO4, then concentrated in vacuo.
Purification of the residue by silica gel column chromato-
graphy (hexane–AcOEt¼50:50) afforded the corresponding
alcohol (35 mg, 97%) as a colorless caramel. [a]2D0¼þ91.68
(c 1.11, CHCl3). IR (film): 3430, 1730, 1690, 1510, 1360,
4.26.2. Physical data of 29E. [a]2D0¼þ62.08 (c 1.21,
CHCl3). IR (film): 3420, 3320, 2860, 2840, 1730, 1690,
1620, 1510, 1360, 1280, 1240, 1180, 1090, 850, 810,
750 cm21 1H NMR (400 MHz, CDCl3, carzinophilin
.
numbering): d 0.14, 0.19 (each 3H, s, (CH3)2Si), 0.58 (6H,
m, (CH3CH2)3Si), 0.88 (9H, t, J¼7.9 Hz, (CH3CH2)3Si),
0.89 (9H, s, (CH3)3CSi), 1.29 (3H, d, J¼6.4 Hz, C1H3), 1.57
(3H, s, C20H3), 2.06 (3H, s, CH3COO), 2.67 (3H, s,
CH3Ar), 2.70 (1H, d, J¼4.7 Hz, C21HH), 2.95, (3H, s,
CH3SO3), 3.08 (1H, d, J¼4.7 Hz, C21HH), 3.96 (3H, s,
CH3OAr), 4.05 (2H, m, C3H, C11H), 4.13 (1H, br q,
J¼6.4 Hz, C2H), 4.43 (1H, m, C11CHHO), 4.44 (1H, d,
J¼4.1 Hz, C12H), 4.47, 4.50 (each 1H, d, J¼10.5 Hz,
OCH2CHvCH2), 4.61 (1H, d, J¼5.4 Hz, C4H), 4.66 (2H, br
1
1280, 1235, 1180, 1080, 840, 810, 750 cm21. H NMR
(200 MHz, CDCl3, carzinophilin numbering): d 0.16, 0.21
(each 3H, s, (CH3)2Si), 0.70 (6H, m, (CH3CH2)3Si), 0.90
(9H, s, (CH3)3CSi), 0.94 (9H, t, J¼8.2 Hz, (CH3CH2)3Si),
1.30 (3H, d, J¼6.4 Hz, C1H3), 1.58 (3H, s, C20H3), 2.06

3080
M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
(3H, s, CH3COO), 2.44 (1H, br, alcoholic proton), 2.67 (3H,
s, CH3Ar), 2.72 (1H, d, J¼4.6 Hz, C21HH), 3.00 (3H, s,
CH3SO3), 3.07 (1H, d, J¼4.6 Hz, C21HH), 3.96 (3H, s,
CH3OAr), 3.97 (1H, m, C3H), 4.37 (1H, br, C2H), 4.40–
4.55 (3H, C11H, C12H, C11CHHO), 4.63 (3H, CH2
vCHCH2O, C11CHHO), 4.80 (1H, d, J¼6.6 Hz, C4H),
5.18 (1H, s, C18H), 5.20 (1H, dq, J¼10.3, 1.0 Hz,
CHHvCHCH2O), 5.32 (1H, dq, J¼17.0, 1.0 Hz,
CHHvCHCH2O), 5.50 (1H, s, C13H), 5.94 (1H, ddt,
J¼10.3, 17.0, 5.9 Hz, CH2vCHCH2O), 6.44 (1H, br d
J¼8.5 Hz, N5H), 7.34 (2H, C60H, C70H), 0 7.48 (1H, d,
J¼2.5 0Hz, C40H), 8.13 (1H, d, J¼2.5 Hz, C2 H), 8.68 (1H,
m, C8 H), 9.35 (1H, br s, N16H). SI-MS (3-nitrobenzyl-
alcohol): m/z¼1061 (MHþ), 1003 ([M2CH2vCHCH2-
O]þ), 817 ([M2CH3CH(OH)CH(CH(CN)(OTBS))NH]þ).
Neither EI-MS nor CI-MS of this sample gave informative
peaks. So, EI-HRMS was not measured.
1420, 1360, 1280, 1235, 1215, 1180, 1100, 1070, 1050,
1000, 960, 840, 810, 750 cm21 1H NMR (200 MHz,
.
CDCl3, carzinophilin numbering): d 0.16, 0.23 (each 3H,
s, (CH3)2Si), 0.45 (6H, m, (CH3CH2)3Si), 0.70 (9H, t,
J¼7.2 Hz, (CH3CH2)3Si), 0.91 (9H, s, (CH3)3CSi), 1.53,
2.11, 2.22, 2.69 (each 3H, s, C20H3, CH3COO, C1H3,
CH3Ar, respectively), 2.76 (1H, d, J¼4.4 Hz, C21HH), 3.03
(3H, s, CH3SO3), 3.37 (1H, d, J¼4.4 Hz, C21HH), 4.00 (3H,
s, CH3OAr), 4.20 (3H, C11H, C12H, C11CHHO), 4.18 (1H,
m, C11CHHO), 4.94 (1H, dd, J¼3.4, 9.0 Hz, C3H), 5.11
(1H, d, J¼3.4 Hz, C4H), 5.39, 5.68 (each 1H, s, C13H,
C18H, respectively), 7.13 (1H, br 0s, N9H), 7.22 (1H, br d
J¼9.0 Hz N5H). 7.37 (2H, C6 H, C70H), 7.50, 8.02
(each 1H, d, J¼2.5 Hz, C40H, C20H, respectively), 8.64
(1H, br s, N16H), 8.73 (1H, m, C80H). SI-MS (3-nitro-
benzylalcohol): m/z¼975 (MHþ). Neither EI- nor CI-MS of
this sample gave useful peaks. So, EI-HRMS was not
measured.
4.27.2. Oxidation giving 30. A mixture of the alcohol
(148 mg, 139 mmol) and Dess–Martin reagent (120 mg,
291 mmol) in CH2Cl2 (10 mL) was stirred at room
temperature for 40 min. The mixture was poured into a
1:1 mixture of aqueous 5% Na2S2O3 and saturated aqueous
NaHCO3 solution, then 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–
AcOEt¼60:40) gave 30 (144 mg, 98%) as a colorless
caramel. [a]2D0¼þ72.98 (c 1.13, CHCl3). IR (film): 3440,
3410, 330, 2960, 2260 (weak), 1730, 1690, 1500, 1370,
4.29. (3R,4R,5S)-3-Acetoxy-2-[(E)-1-[(2S,3S)-3,4-epoxy-
3-methyl-2-(3-methoxy-5-methylnaphthoxy)butyryl-
amino]-1-[N-[(3R)-(Z)-1-methoxymethylene-2-oxo-
propyl1-[1-hydroxy-1-cyano-3-oxobutan-2-yl]-
carbamoyl]]methylidene-4-triethylsilyloxy-5-(methane-
sulfonyl)oxymethyl-carbonylpyrrolidine (32)
A mixture of 31 (11.0 mg, 11.3 mmol) and TBAF (1.0 M in
THF, 34 mL) in a mixture of THF (1.5 mL) and
AcOH(25 mL) was stirred at room temperature for 3 h.
After saturated aqueous NaHCO3 solution (200 mL) was
added to the mixture, the mixture was stirred at room
temperature for 10 min. The mixture was poured into
aqueous 10% citric acid solution, and extracted with AcOEt.
The combined extracts were washed with brine, dried over
MgSO4, then concentrated in vacuo. After the residue was
dissolved in CH2Cl2 (1.0 mL), an ethereal CH2N2 (1.0 mL,
excess) was added to the solution. The mixture was kept
standing at room temperature for 1 h. After concentration,
the residue was purified by silica gel column chromato-
graphy (CH2Cl2–acetone¼50:50) to give 32 (6.8 mg, in
82% two steps) as a colorless caramel. [a]2D0¼29.18 (c 0.31,
CHCl3). IR (film): 3370, 2950, 1740, 1730, 1710, 1690,
1680, 1640, 1620, 1605, 1510, 1500, 1360, 1240, 1220,
1280, 1240, 1180, 900, 840, 810, 735 cm21 1H NMR
.
(200 MHz, CDCl3, carzinophilin numbering): d 0.21, 0.23
(each 3H, s, (CH3)2Si), 0.68 (6H, m, (CH3CH2)3Si), 0.92
(9H, s, (CH3)3CSi), 0.94 (9H, t, J¼8.3, (CH3CH2)3Si), 1.53,
2.06, 2.34, 2.67 (each 3H, s, C20H3, CH3COO, C1H3,
CH3Ar, respectively), 2.71 (1H, d, J¼4.7 Hz, C21HH), 3.02
(3H, s, CH3SO3), 3.07 (1H, d, J¼4.7 Hz, C21HH), 3.96 (3H,
s, CH3OAr), 4.40–4.80 (7H, C3H, C11H, C12H, C11CH2O,
CH2vCHCH2O), 5.03 (1H, d, J¼4.0 Hz, C4H), 5.17 (1H, s,
C13H), 5.27 (2H, m, CH2vCHCH2O), 5.44 (1H, s, C18H),
5.92 (1H, ddt, J¼10.4, 17.1, 5.8 Hz, CH2vCHCH2O), 6.70
(1H, br d J¼6.3 Hz, N5H), 7.34 (2H, m, C60H, C70H), 7.47
(1H, d, J¼2.5 Hz, 0C40H), 8.11 (1H, d, J¼2.5 Hz, C20H),
8.68 (1H, m, C8 H), 9.36 (1H, br s, N16H). SI-MS
(3-nitrobenzylalcoholþNaCl): m/z¼1081 ([MþNa]þ),
1059 (MHþ). Neither EI-MS nor CI-MS of this sample
gave useful information. So, EI-HRMS was not measured.
1180, 1080, 1050, 970, 735 cm21 1H NMR (200 MHz,
.
CDCl3, carzinophilin numbering, 2.0 mg/mL; The spectral
pattern of this sample changed depending upon the
concentration): d 1.58, 2.207, 2.213, 2.69 (each 3H, s,
C20H3, C1H3, CH3COO, CH3Ar, respectively), 2.81 (1H, d,
J¼4.3 Hz, C21HH), 3.80 (1H, d, J¼3.6 Hz, alcoholic
proton), 3.83 (1H, d, J¼4.3 Hz, C21HH), 3.83, 4,00 (each
3H, s, CH3O£2), 4.27–4.34 (3H, m, C11H, C12H,
C11CHHO), 4.42 (1H, d, J¼3.8, 10.3 Hz, C11CHHO),
5.32 (1H, s, C18H), 5.37 (1H, d, J¼3.2 Hz, C13H), 7.21
(1H, s, C4H), 7.220, 7.33 (each 1H, br s, N5H, N9H), 7.33
(2H, m, C60H, C7 H), 7.54, 8.00 (each 1H, d, J¼2.6 Hz,
C400H, C20H, respectively), 8.57 (1H, s, N16H), 8.63 (1H, m,
C8 H). SI-MS (3-nitrobenzylalcohol): m/z¼734 (MHþ), 634
([M2(CH3C(O)C(vCHOMe))þ], 619 ([M2(CH3-
C(O)C(v CHOMe)NH)]þ). SI-MS (3-nitrobenzylalcoholþ
NaCl): m/z¼756 ([MþNa]þ), 734 (MHþ), 634 ([M2(CH3-
C(O)C(vCHOMe))þ], 619 ([M2(CH3C(O(vCHOMe)-
NH))þ]. Neither EI- nor CI-MS of this sample gave useful
peaks. So, EI-HRMS was not measured.
4.28. (3R,4R,5S)-3-Acetoxy-2-[(E)-1-[(2S,3S)-3,4-epoxy-
3-methyl-2-(3-methoxy-5-methylnaphthoxy)butyryl-
amino]-1-[N-[1R or 1S, (3R)-[1-tert-butyldimethylsiloxy-
1-cyano-3-oxobutan-2-yl]carbamoyl]]methylidene-4-
triethylsilyloxy-5-(methanesulfoxymethylpyrrolidine
(31)
A mixture of 30 (16.3 mg, 15.4 mmol), AcOH (3.0 mL),
PPh3 (800 mg, 3.0 mmol), and Pd(PPh3)4 (1.3 mg, 1.2 mmol)
in THF (1.0 mL) was stirred at room temperature for
10 min. After the mixture was concentrated in vacuo, the
residue was purified by silica gel column chromatography
(AcOEt–hexane¼60:40) to give 31 (15.0 mg, 100%) as a
colorless caramel. [a]D20¼238.98 (c 1.11, CHCl3). IR (film):
3350, 2960, 1750, 1720, 1660, 1629, 1600, 1510, 1500,

M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
3081
4.30. 4-[(3R,4R,5S)-3,4-Dibenzyloxy-5-(tert-butyl-
dimethylsiloxy)methylpyrrolidin-2-ylidene]-2-[2-(E)-
(benzyloxymethoxy)methyl-1-propenyl]-4H-oxazol-5-
one (40)
IR (film) 3370, 2930, 2860, 1720, 1660, 1635, 1455, 130,
1
1210, 1110, 1070, 1030, 910, 740, 700, 505 cm21. The H
NMR spectrum of this sample showed that it consists of the
two tautomers arising from its enamine moiety
(E/Z¼70:303). Assignments of signals for the main isomer
1
4.30.1. Reaction procedure. A mixture of 11E (610 mg,
1.02 mmol) and 7 (1.88 g, 6.82 mmol) in toluene (2.0 mL)
was stirred at 608C for 12 h under Ar gas bubbling. After
concentration, the residue was purified by silica gel column
chromatography (hexane–AcOEt¼90:10!30:70) to give
recovered 7 (105 mg, 17%) and 40 (489 mg, 58%) both as
an oil.
and some for the minor isomer are described. H NMR
(200 MHz, CDCl3, a¼0.70, b¼0.30, carzinophilin number-
ing) d 0.96 [9H£a, s, (CH3)3CSi (E-isomer)], 1.00 [9H£a, s,
(CH3)3CSi (Z-isomer)], 1.96 [3H£b, s, C30H3 (Z-isomer)],
2.04 [3H£a, s, C20H3 (E-isomer)], 2.38 [1H£a, br,
alcoholic proton (E-isomer)], 3.71 [1H£a, dd, J¼4.3,
10.5 Hz, C11CHHO (E-isomer)], 3.78 [1H£b, dd, J¼4.9,
10.3 Hz, C11CHHO (Z-isomer)], 3.80 [1H, dd, J¼6.2,
10.5 Hz, C11CHHO (E-isomer)], 3.82 [1H£b, dd, J¼8.2,
10.3 Hz, C11CHHO (Z-isomer)], 3.99 [2H£b, br s,
C20CH2O (Z-isomer)], 4.08–4.20 [2Hþ1H£b, C11H,
C12H, PhCHHO (E-isomer)], 4.31 [1H£a, d, J¼11.8 Hz,
PhCHHO (E-isomer)], 4.41 [1H£b, d, J¼12.0 Hz,
PhCHHO (E-isomer)], 4.45 [1H£a, d, J¼11.8 Hz,
PhCHHO (E-isomer)], 4.70 [1H£a, d, J¼9.6 Hz, PhCHHO
(Z-isomer)], 4.75 [1H£a, d, J¼10.9 Hz PhCHHO
(E-isomer)], 4.79 [1H£b, d, J¼9.6 Hz, PhCHHO
(Z-isomer)], 5.55 [1H£a, d, J¼2.6 Hz, C13H(E-isomer)],
5.20 [1H£b, s, C13H (Z-isomer)], 6.09 [1H£b, m, C18H
(Z-isomer)], 6.13 [1H, hext, J¼1.3 Hz, C18H (E-isomer)],
7.01 [2H£b, aromatic protons (Z-isomer)], 7.15–7.40 [14H,
aromatic protons], 7.53–7.62 (4H, aromatic protons), 7.83
[1H£a, br s, amine proton(E-isomer)]. CI-MS (isobutene)
m/z¼703 (MHþ), 687 ([M2Me]þ). EI-MS provided gave
only a fragmented signal [m/z¼199, (Ph2SiþvO)].
EI-HRMS was not measured.
4.30.2. Physical data of 40. IR (film): 3400, 3030, 3010,
2930, 2860, 1720, 1635, 1455, 1110, 1060, 910, 735, 700,
610, 500 cm21. The 1H NMR spectrum of this sample
showed that it consists of the two tautomers arising from its
enamine moiety (E/Z¼80:20). Assignments of signals for
the main isomer and some for the minor isomer are
1
described. H NMR (400 MHz, CDCl3, a¼0.80, b¼0.20,
carzinophilin numbering): d 1.03 [9H£a, s, (CH3)3CSi
(E-isomer)], 1.07 [9H£b, s, (CH3)3CSi (Z-isomer)], 2.15
[3H£b, s, C20H3 (Z-isomer)], 2.16 [3H£a, s, C20H3
(E-isomer)], 3.76 [1H£a, dd, J¼4.1, 10.6 Hz, C11CHHO
(E-isomer)], 3.85 [1H£a, dd, J¼6.0, 10.6 Hz, C11CHHO
(E-isomer)], 3.86 [2H£b, m, C11CH2O (Z-isomer)], 4.16
(3H, m, C11H, C21CH2O), 4.37 [1H£a, d, J¼11.8 Hz,
PhCHHO (E-isomer)], 4.49 [1H£b, PhCHHO (Z-isomer)],
4.52 [1H£a, d, J¼11.8 Hz, PhCHHO (E-isomer)], 4.64
[2H£b, s, PhCH2O (Z-isomer)], 4.65 [1H£a, s, PhCH2O
(E-isomer)], 4.81 [2H£b, s, OCH2O (Z-isomer)], 4.82
[2H£a, s, OCH2O (E-isomer)], 4.83 [1H£a, d, J¼11.6 Hz
PhCHHO (E-isomer)], 5.00 [1H£a, d, J¼11.6 Hz PhCHHO
(E-isomer)], 5.10 [1H£a, d, J¼2.3 Hz, C13H (E-isomer)],
5.26 [1H£b, s, C13H (Z-isomer)], 6.15 [1H£b, hext,
J¼1.3 Hz, C18H (Z-isomer)], 6.18 [1H£a, hext,
J¼1.3 Hz, C18H (E-isomer)], 6.74 [1H£b, br s, amine
proton (Z-isomer)], 7.08 [2H£b, m, aromatic protons
(Z-isomer)], 7.12 [2H£a, aromatic protons (E-isomer)],
7.22–7.45 (14H, aromatic protons), 7.63 (4H, m, aromatic
protons), 7.90 (1H£a, br s, amine proton). EI-MS (rel.
int.%): m/z¼822 (trace, Mþ), 765 (trace, [M2tBu]þ), 687
(trace, [M2tBu–PhH]þ), 91 (100, Bnþ). CI-MS (isobutene):
m/z¼823 (MHþ). EI-HRMS calcd for C50H54N2O7Si (Mþ):
m/z¼822.3702. Found: m/z¼822.3706.
4.32. 4-[(3R,4R,5S)-3,4-Dibenzyloxy-5-(tert-butyl-
dimethylsiloxy)methylpyrrolidin-2-ylidene]-2-[(1R,2S)-
1,2,3-trihydroxy-2-methylpropyl]-4H-oxazol-5-one (42)
In a hood, a solution of 41 (1.75 g, 2.49 mmol) in CH2Cl2
(3.0 mL) was added to a mixture of OsO4 (624 mg,
2.46 mmol) and (DHQ)2PHAL15 (2.40 g, 3.08 mmol) in
CH2Cl2 (20 mL) at 08C with stirring. After stirring for
15 min, H2S gas was bubbled into the mixture to give a
black suspension. Celitew (3 g) and AcOEt (50 mL) were
added to the suspension, and the whole mixture was stirred
at room temperature for additional 30 min with H2S
bubbling. After filtration through a pad of Celitew, the
filtrate was concentrated in vacuo. Purification of the
residue by silica gel column chromatography (AcOEt–
hexane¼90:10) gave 42 (1.19 g, 65%) as an oil. The signals
due to 18S isomer (carzinophilin numbering) was not
4.31. 4-[(3R,4R,5S)-3,4-Dibenzyloxy-5-(tert-butyl-
dimethylsiloxy)methylpyrrolidin-2-ylidene]-2-[2-(E)-
hydroxymethyl-1-propenyl]-4H-oxazol-5-one (41)
1
observed by 400 MHz H NMR spectrum of this sample.
Thus, the diastereomeric purity was estimated to be .96%
A mixture of 40 (1.10 g, 1.33 mmol) and DDQ (400 mg,
1.76 mmol) in a mixture of CH2Cl2 (15 mL) and H2O
(1.5 mL) was stirred at room temperature for 30 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. After the residue was
dissolved in MeOH (5.0 mL), NaBH4 (100 mg, 2.63 mmol)
was added at 08C. The mixture was stirred at the same
temperature for 30 min, poured into water, then extracted
with AcOEt. The combined ethyl acetate extracts were
washed with brine, dried over MgSO4, then concentrated in
vacuo. Purification of the residue by silica gel column
chromatography (hexane–AcOEt¼70:30) gave 41 as an oil.
de. IR (film) 3360, 2940, 2860, 1720, 1650, 1590, 1455,
1
1430, 1380, 1110, 1065, 910, 730, 700, 505 cm21. The H
NMR spectrum of this sample showed that it consists of the
two tautomers arising from its enamine moiety
(E/Z¼56:44). Assignments of signals for the main isomer
1
and some for the minor isomer are described. H NMR
(400 MHz, CDCl3, a¼0.56, b¼0.44, carzinophilin number-
ing) d 1.03 [9H£a, s, (CH3)3CSi (E-isomer)], 1.06 [9H£b,
(CH3)3CSi (Z-isomer)], 1.15 [3H£b, C20H3 (Z-isomer)],
1.18 [3H£a, C20H3 (E-isomer)], 2.70 [1H£a, br, alcoholic
proton (E-isomer)], 3.02 [1H£b, br, alcoholic proton
(Z-isomer)], 3.30 (1H, br, alcoholic proton), 3.57 (2H, m,

3082
M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
C11CHHO, alcoholic proton), 3.75 (1H, m, C11CHHO),
8.88 [1Hþ1H£a, C11H, C12H (E-isomer)], 3.96 [1H£b, d,
J¼4.1 Hz, C12H (Z-isomer)], 4.18 (2H, br s, C21H2O), 4.27
[1H£b, d, J¼11.9 Hz, PhCHHO (Z-isomer)], 4.41 [1H£a, d,
J¼11.8 Hz, PhCHHO (E-isomer)], 4.49 [1H£b, d,
J¼11.9 Hz, PhCHHO (Z-isomer)], 4.55 [1H£a, d,
J¼11.8 Hz, PhCHHO (E-isomer)], 4.57 (1H, br, C18H),
4.74 [1H£b, d, J¼11.0 Hz, PhCHHO (Z-isomer)], 4.76
[1H£a, d, J¼11.6 Hz, PhCHHO (E-isomer)], 4.84 [1H£b,
d, J¼11.0 Hz, PhCHHO (Z-isomer)], 4.89 [1H£a, d,
J¼11.6 Hz, PhCHHO (E-isomer)], 5.09 [1H£a, d,
J¼2.3 Hz, C13H (E-isomer)], 5.23 [1H£b, s, C13H
(Z-isomer)], 7.08–7.16 (2H, aromatic protons), 7.23–7.50
(14H, aromatic protons), 7.62 (4H, aromatic protons), 7.87
[1H£a, br s, amine proton(E-isomer)]. CI-MS (isobutane)
m/z¼737 (MHþ), 675 ([M2HOCH2CMe]þ). EI-MS of this
sample provided no structural information. So, EI-HRMS
was not measured.
C(OH)Me]þ), 199 (100, Ph2Siþ¼O). EI-HRMS: calcd for
C42H46N2O7Si ([M2MsOH]þ): m/z¼718.3076. Found
m/z¼718.3071.
4.33.2. The epoxide cyclization giving 43. A mixture of the
mesylate (990 mg, 1.22 mmol) and DBU (220 mg,
1.44 mmol) in CH2Cl2 (10 mL) was stirred at 08C for
30 min. 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
(hexane–AcOEt¼65:35) gave 43 (738 mg, 84%) as an oil.
IR (film) 3420, 2940, 2860, 1730, 1650, 1490, 1460, 1430,
1280, 1210, 1110, 1070, 910, 735, 700, 610, 505 cm21. The
1H NMR spectrum of this sample showed that it consists of
the two tautomers arising from its enamine moiety
(E/Z¼68:32). Assignments of signals for the main isomer
1
and some for the minor isomer are described. H NMR
(200 MHz, CDCl3, a¼0.68, b¼0.32, carzinophilin number-
ing) d 1.04 [9H£a, s, (CH3)3CSi (E-isomer)], 1.07 [9H£b, s,
(CH3)3CSi (Z-isomer)], 1.37 (3H, s, C20H3), 2.70 [1H£a, d,
J¼4.6 Hz, C21HH (E-isomer)], 2.71 [1H£b, d, J¼4.6 Hz,
C21HH (Z-isomer)], 2.98 (1H, d, J¼4.6 Hz, C21HH),
3.01[1H£a, d, J¼6.7 Hz, alcoholic proton (E-isomer)],
3.40 [1H£b, d, J¼6.4 Hz, alcoholic proton (Z-isomer)], 3.77
[1H£a, dd, J¼3.7, 10.3 Hz, C11CHHO (E-isomer)], 3.86
[2H£bþ1H£a, C11CHHO (E-isomer), C11CH2O], 3.99
[1H£b, d, J¼4.3 Hz, C12H (Z-isomer)], 4.19 [2H£a, C12H
(E-isomer), C11H (E-isomer)], 4.27 [1H£b, J¼6.4 Hz,
C18H (Z-isomer)], 4.33 [1H£a, d, J¼6.7 Hz, C18H
(E-isomer)], 4.42, 4.56 [each 1H£a, d, J¼11.8 Hz,
PhCH2O (E-isomer)], 4.74 [1H£b, J¼11.1 Hz, PhCHHO
(Z-isomer)], 4.81 [1H£a, J¼11.5 Hz, PhCHHO
(E-isomer)], 4.86 [1H£b, J¼11.1 Hz, PhCHHO
(Z-isomer)], 4.97 [1H£a, J¼11.5 Hz, PhCHHO
(E-isomer)], 5.10 [1H£a, d, J¼2.0 Hz, C13H (E-isomer)],
5.22 [1H£a, s, C13H (Z-isomer)], 6.94 [1H£b, br, amine
proton (Z-isomer)], 7.12 (2H, aromatic protons), 7.2–7.45
(11H, aromatic protons), 7.63 (4H, aromatic protons), 7.85
[1H£a, br s, amine proton (E-isomer)]. EI-MS (rel. int.%):
m/z¼718 (1.0, Mþ), 700 (0.5, [M2H2O]þ), 199 (68,
Ph2SiþvO), 91 (100, Bnþ). EI-HRMS calcd for
4.33. 4-[(3R,4R,5S)-3,4-Dibenzyloxy-5-(tert-butyl-
dimethylsiloxy)methylpyrrolidin-2-ylidene]-2-[(1R,2S)-
2,3-epoxy-1-hydroxy-2-methylpropyl]-4H-oxazol-5-one
(43)
4.33.1. Selective mesylation of 42. A mixture of 42
(624 mg, 774 mmol), MsCl (130 mg, 1.14 mmol), and g-
collidine (187 mg, 1.50 mmol), in CH2Cl2 (3.0 mL) was
stirred at room temperature for 4 h. After MeOH (100 mL)
was added in order to decompose excess MsCl, 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–
AcOEt¼60:40) gave the mesylate (514 mg, 81%). IR (film):
3350, 2930, 2860, 1760, 1650, 1480, 1360, 1175, 1110,
1
1070, 1000, 970, 910, 740, 700, 505 cm21. The H NMR
spectrum of this sample showed that it consists of the two
tautomers arising from its enamine moiety (E/Z¼56:44).
Assignments of signals for the main isomer and some for the
1
minor isomer are described. H NMR (400 MHz, CDCl3,
a¼0.56, b¼0.44, carzinophilin numbering) d 1.02 [9H£a, s,
(CH3)3CSi (E-isomer)], 1.07 [9H£b, s, (CH3)3CSi (E-
isomer)], 1.30 [3H£b, C20H3 (Z-isomer)], 1.31 [3H£a, s,
C20H3 (E-isomer)], 3.00 [3H£b, s, CH3SO3 (Z-isomer)],
3.02 [3H£a, s, CH3SO3 (Z-isomer)], 3.17 [1H£a, C19OH
(E-isomer)], 3.23 [1H£a, br d, J¼6.5 Hz, C18OH
(E-isomer)], 3.53 [1H£b, br, C19OH (Z-isomer)], 3.75
[1H£a, dd, J¼4.0, 10.9 Hz, C11CHHO (E-isomer)], 3.87
[2H£a, alcoholic proton, C11CHHO (E-isomer)], 3.97
[1H£b, C12H (Z-isomer)], 4.19 [3H£a, C12H (E-isomer),
C18H (E-isomer), C11H (E-isomer)], 4.25, 4.29 [each
1H£a, d, J¼10.2 Hz, C21H2O (E-isomer)], 4.41, 4.53 [each
1H£a, d, J¼11.9 Hz, PhCH2O (E-isomer)], 4.74 [1H£b,
J¼11.0 Hz, PhCHHO (Z-isomer)], 4.76 [1H£a, J¼11.5 Hz,
PhCHHO (E-isomer)], 4.85 [1H£b, J¼11.0 Hz, PhCHHO
(Z-isomer)], 4.89 [1H£a, J¼11.5 Hz, PhCHHO (Z-isomer)],
5.08 [1H£a, d, J¼2.7 Hz, C13H (E-isomer)], 5.21 [1H£b, s,
C13H (Z-isomer)], 6.91 [1H£a, br, amine proton
(Z-isomer)], 7.08 [2H£b, aromatic protons (Z-isomer)],
7.14 [2H£a, aromatic protons (E-isomer)], 7.21–7.48 (14H,
aromatic protons), 7.62 (4H, aromatic protons), 7.89 [1H£a,
amine proton (E-isomer)]. EI-MS (rel int.%): m/z¼718
(trace, [M2MsOH]þ), 661 (trace, [M2MsOCH2-
C42H46N2O7Si
m/z¼718.3064.
(Mþ):
m/z¼718.3076.
Found:
4.34. 4-[(3R,4R,5S)-3,4-Dibenzyloxy-5-(tert-butyl-
dimethylsiloxy)methylpyrrolidin-2-ylidene]-2-[(2S)-2,3-
epoxy-2-methylpropionyl]-4H-oxazol-5-one (44)
A mixture of 43 (738 mg, 1.03 mmol) and Dess–Martin
reagent (550 mg, 1.33 mmol) in CH2Cl2 (10 mL) was stirred
at room temperature for 40 min. The mixture was poured
into aqueous 10% Na2S2O3 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–
AcOEt¼65:35) gave 44 (676 mg, 92%) as a yellow solid.
Analytical sample was prepared by recrystallization from
hexane–Et2O to give yellow needles. Mp 145–1478C.
[a]2D0¼þ10.78 (c 1.07, CHCl3). IR (nujor): 3280, 1720,
1
1690, 1620, 1510, 1320, 1110 cm21. H NMR (200 MHz,
CDCl3, measured right after dissolved, carzinophilin
numbering): d 1.02 (9H, s, (CH3)3CSi), 1.73 (3H, s,

M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
3083
C20H3), 2.83, 3.33 (each 1H, d, J¼5.6 Hz, C21H2), 3.72
(1H, dd, J¼3.7, 11.0 Hz, C11CHHO), 3.90 (1H, dd, J¼5.4,
11.0 Hz, C11CHHO), 4.22 (2H, m, C12H, C11H), 4.37,
4.51 (each 1H, d, J¼11.8 Hz, PhCH2O), 4.85, 5.06 (each
1H, d, J¼11.8 Hz, PhCH2O), 5.14 (1H, d, J¼3.1 Hz,
C13H), 7.14 (2H, m, aromatic protons), 7.20–7.50 (14H,
aromatic protons), 7.60 (4H, aromatic protons), 8.56 (1H, br
[1H£b, d, J¼5.6 Hz, C21HH (Z-isomer)], 3.37 [1H£a, d,
J¼5.7 Hz, C21HH (E-isomer)], 4.01 [1H£b, d, J¼3.5 Hz,
C4H (Z-isomer)], 4.13–4.50 [5Hþ1H£a, C11H, C11CH2O,
PhCH2O, C12H (E-isomer)], 4.72 [1H£b, d, J¼11.6 Hz,
PhCHH (Z-isomer)], 4.74 [1H£a, d, J¼11.8 Hz, PhCHH
(E-isomer)], 4.78 [1H£b, d, J¼11.6 Hz, PhCHH
(Z-isomer)], 4.85 [1H£a, d, J¼11.8 Hz, PhCHH
(E-isomer)], 4.96 [1H£a, d, J¼1.9 Hz, C13H (E-isomer)],
5.26 [1H£b, s, C13H (Z-isomer)], 7.25 (2H, m, aromatic
protons), 7.44 (8H, m, aromatic protons), 8.55 [1H£a, br s,
amine proton (E-isomer)]. EI-MS (rel. int.%): m/z¼556
(1.0, Mþ), 540 (trace, [M2O]þ), 91 (100, Bnþ). EI-HIMS
calcd for C27H28N2O9S (Mþ): m/z¼556.1516. Found
m/z¼556.1524.
1
s, amine proton). H NMR (200 MHz, CDCl3, measured
kept standing for 10 h after dissolved, a¼0.90, b¼0.10,
assignment of the main isomer and some for the minor
isomer are described): d 1.02 [9H£a, s, (CH3)3CSi
(E-isomer)], 1.09 [9H£b, s, (CH3)3CSi (Z-isomer)], 1.72
[3H£b, s, C20H3 (Z-isomer)], 1.73 [3H£a, s, C20H3
(E-isomer)], 2.83 [1H£a, d, J¼5.6 Hz, C21HH (E-isomer)],
2.91 [1H£b, d, J¼5.7 Hz, C21HH (Z-isomer)], 3.33 [1H£a,
d, J¼5.6 Hz, C21HH (E-isomer)], 3.40 [1H£b, d, J¼5.7 Hz,
C21HH (Z-isomer)], 3.72 [1H£a, dd, J¼3.7, 11.0 Hz,
C11CHHO (E-isomer)], 3.90 [1H£a, dd, J¼5.4, 11.0 Hz,
C11CHHO (E-isomer)], 4.22 (2H, m, C12H, C11H), 4.37,
4.51 [each 1H£a, d, J¼11.8 Hz, PhCH2O (E-isomer)], 4.85,
5.06 [each 1H£a, d, J¼11.8 Hz, PhCH2O (E-isomer)], 5.14
[1H£a, d, J¼3.1 Hz, C13H (E-isomer)], 5.29 [1H£b, s,
C13H (Z-isomer)], 7.14 (2H, aromatic protons), 7.20–7.50
(14H, aromatic protons), 7.60 (4H, aromatic protons), 8.56
[1H£a, br s, amine proton (E-isomer)]. EI-MS (rel. int.%):
m/z¼716 (1.0, Mþ), 659 (3.6, [M2tBu]þ), 199 (100.
Ph2SiþvO), 91 (62, Bnþ). CI-MS (isobutene): m/z¼717
(MHþ), 701 ([M2O]þ). EI-HIMS calcd for C42H44N2O7Si
(Mþ): m/z¼716.2919. Found: m/z¼716.2890. Anal. calcd
for C42H44N2O7Si: C, 70.37%; H, 6.19%; N, 3.91%. Found:
C, 70.16%; H, 6.23%; N, 3.85%.
4.36. 4-[(3R,4R,5S)-3,4-Dibenzyloxy-5-(methane-
sulfoxy)methylpyrrolidin-2-ylidene]-2-[(1S,2S)-2,3-
epoxy-1-hydroxy-2-methylpropyl]-4H-oxazol-5-one (46)
Sodium borohydride (8.0 mg, 212 mmol) was added to a
mixture of 45 (130 mg, 188 mmol) and CeCl3·7H2O
(30.0 mg, 80.0 mmol) in MeOH (10 mL) at 2158C with
stirring. After stirring for 10 min, the mixture was poured
into aqueous. 5% citric acid solution, then extracted with
AcOEt. The combined extracts were washed with brine,
dried over MgSO4, then concentrated in vacuo. The residue
was purified by silica gel column chromatography (hexane–
AcOEt¼65:35) gave 46 (123 mg, 94%) as an oil. IR (film)
3330, 2930, 1740, 1660, 1490, 1360, 1175, 1070, 960 cm21
.
The 1H NMR spectrum of this sample showed that it
consists of the two tautomers arising from its enamine
moiety (E/Z¼65:35). Assignments of signals for the main
1
4.35. 4-[(3R,4R,5S)-3,4-Dibenzyloxy-5-(methane-
sulfoxy)methylpyrrolidin-2-ylidene]-2-[(2S)-2,3-epoxy-
2-methylpropionyl]-4H-oxazol-5-one (45)
isomer and some for the minor isomer are described. H
NMR (200 MHz, CDCl3, a¼0.65, b¼0.35, carzinophilin
numbering): d 1.43 [3H£a, C20H3 (E-isomer)], 1.46 [3H£b,
C20H3 (E-isomer)], 2.72 (1H, d, J¼4.5 Hz, C21HH), 2.90
[1H£a, d, J¼3.1 Hz, alcoholic proton (E-isomer)], 3.03
[3H£a, s, CH3SO3 (E-isomer)], 3.05 [3H£b, s, CH3SO3
(Z-isomer)], 3.01 [1H£a, d, J¼4.5 Hz, C21HH (E-isomer)],
3.12 [1H£b, d, J¼3.5 Hz, alcoholic proton (Z-isomer)],
4.43–4.58 (6H, C12H, C11H, C11CH2O, PhCH2O), 4.74
[1H£b, d, J¼11.7 Hz, PhCHHO (Z-isomer)], 4.75 [1H£a, d,
J¼11.7 Hz, PhCHHO (E-isomer)], 4.86 (1H, d, J¼11.7 Hz,
PhCHHO), 5.00 [1H£a, d, J¼1.6 Hz, C13H (E-isomer)],
5.28 [1H£b, s, C13H (Z-isomer)], 7.09 [1H£b, br s, amine
proton (Z-isomer)], 7.20 (2H, aromatic protons), 7.35 (8H,
aromatic protons), 7.78 [1H£a, amine proton (E-isomer)].
EI-MS (rel. int.%) m/z¼558 (1.0, Mþ), 91 (100, Bnþ).
CI-MS (isobutene) m/z¼559 (MHþ), 541 ([M2H2O]þ).
EI-HIMS calcd for C27H30N2O9S (Mþ): m/z¼558.1673.
Found m/z¼558.1675.
A mixture of 44 (crystalline, 50.0 mg, 69.8 mmol) and
TBAF (1.0 M in THF, 100 mL) in THF (1.5 mL) was stirred
at room temperature for 12 h. The mixture was poured into
aqueous 1 M H3PO4 solution and extracted with AcOEt.
The combined extracts were washed with brine, dried over
MgSO4, and concentrated in vacuo. After the residue was
dissolved in CH2Cl2 (1.5 mL), MsCl (10.5 mg, 129 mmol),
and g-collidine (30 mg, 248 mmol) were added to the
solution at room temperature and the mixture was stirred for
10 h. After addition of MeOH (100 mL) in order to
decompose excess MsCl, the mixture was poured into
aqueous 1 M H3PO4 solution and extracted with AcOEt.
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 (CH2Cl2–acetone¼93:7) gave 45 (32.5 mg, 83% in
two steps) as an oil IR (film) 3450, 3300, 1720, 1680, 1630,
1510, 1320, 1100, 1070, 750, 700 cm21. The 1H NMR
spectrum of this sample showed that it consists of the two
tautomers arising from its enamine moiety (E/Z¼77:23).
Assignments of signals for the main isomer and some for the
4.37. 4-[(3R,4R,5S)-3,4-Dibenzyloxy-5-(methane-
sulfoxy)methylpyrrolidin-2-ylidene]-2-[(1S,2S)-2,3-
epoxy-1–(3-methoxy-5-methyl-1-naphthoxy)-2-methyl-
propyl]-4H-oxazol-5-one (47)
1
minor isomer are described. H NMR (200 MHz, CDCl3,
A mixture of 46 (35.0 mg, 62.7 mmol), and the naphthoic
acid 19 (20 mg, 92.6 mmol), DMAP (11 mg, 90 mmol), and
WSCI·HCl (17 mg, 89 mmol) in CH2Cl2 (2 mL) was stirred
at room temperature for 12 h. The mixture was poured into
water and extracted with Et2O. The combined extracts were
washed with brine, dried over MgSO4, then concentrated in
a¼0.77, b¼0.23, carzinophilin numbering): d 1.72 [3H£b,
s, C20H3 (Z-isomer)], 1.75 [3H£a, s, C20H3 (E-isomer)],
2.81 [1H£a, d, J¼5.7 Hz, C21HH (E-isomer)], 2.87 [1H£b,
d, J¼5.6 Hz, C21HH (Z-isomer)], 2.98 [3H£a, s, CH3SO3
(E-isomer)], 3.01 [3H£b, s, CH3SO3 (Z-isomer)], 3.33

3084
M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
vacuo. Purification of the residue by silica gel column
chromatography (hexane–AcOEt¼60:40) gave 47
(43.0 mg, 91%) as an oil. IR (film) 3330, 2940, 1730,
1660, 1600, 1360, 1280, 1240, 1210, 1180, 1070 cm21. The
1H NMR spectrum of this sample showed that it consists of
the two tautomers arising from its enamine moiety
(E/Z¼58:42). Assignments of signals for the main isomer
numbering). d 0.15, 0.20 (each 3H, s, (CH3)2Si), 0.89 (9H, s,
(CH3)3CSi), 1.25 (3H, d, J¼6.3 Hz, C1H3), 1.50, 2.66 (each
3H, s, C20H3, CH3Ar, respectively), 2.69 (1H, d, J¼4.5 Hz,
C21HH), 2.77 (3H, s, CH3SO3), 2.98 (1H, d, J¼4.5 Hz,
C21HH), 3.73, 3.90 (each 3H, s, CH3OAr£2), 4.01–4.18
(4H, m, C2H, C12H, C11CH2O), 4.41 (1H, d, J¼10.9 Hz,
ArCHHO), 4.44–4.61 (8H, m, C3H, C4H, C11H,
ArCH2O£2, ArCHHO), 4.63, 4.69 (each 1H, br dd,
J¼5.9, 13.1 Hz, CH2vCHCH2O), 4.73 (1H, d, J¼2.1 Hz,
C13H), 5.03 (1H, s, C18H), 5.22 (1H. br d, J¼10.6 Hz,
CHHvCHCH2O), 5.32 (1H, dq, J¼17.0, 1.2 Hz,
CHHvCHCH2O), 5.94 (1H, ddt, J¼10.6, 17.0, 5.9 Hz,
CH2vCHCH2O), 6.53 (1H, br d, J¼8.7 Hz, N5H), 6.72,
7.18 (each 2H, br d, J¼8.6 Hz, aromatic protons for MP0M),
7.22–7.36 (12H, m, aromat0ic protons for Bn, C60H, C7 H),
7.44 (1H, dd, J¼2.6 Hz,0C4 H), 7.47 (1H, br s, N16H), 8.57
(1H, br d, J¼8.4 Hz, C8 H). SI-MS (3-nitrobenzylalcoholþ
NaCl): m/z¼1227 ([MþNa]þ), 1204 (MHþ). Neither EI-MS
nor CI-MS of this sample gave structural information. So,
EI-HRMS was not measured.
1
and some for the minor isomer are described. H NMR
(400 MHz, CDCl3, a¼0.58, b¼0.42, carzinophilin number-
ing): d 1.57 [9H£a, s, C20H (E-isomer)], 1.58 [9H£b, s,
C20H (Z-isomer)], 2.66 [3H£a, s, CH3Ar (E-isomer)], 2.67
[3H£b, s, CH3Ar (Z-isomer)], 2.75 [1H£a, d, J¼4.8 Hz,
C21HH (E-isomer)], 2.77 [1H£b, d, J¼4.8 Hz, C21HH
(Z-isomer)], 3.02 [3H£b, s, CH3SO3 (Z-isomer)], 3.03
[3H£a, s, CH3SO3 (E-isomer)], 3.12 [1H£a, d, J¼4.8 Hz,
C21HH (E-isomer)], 3.13 [1H£b, d, J¼4.8 Hz, C21HH
(Z-isomer)], 3.94 [3H£a, s, CH3OAr (E-isomer)], 3.98
[3H£b, s, CH3OAr (Z-isomer)], 4.07 [1H£b, br d,
J¼3.2 Hz, C12H (Z-isomer)], 4.15 [1H£b, br d, J¼4.8 Hz,
C12H (E-isomer)], 4.26 [1H£b, d, J¼11.7 Hz, PhCHHO
(Z-isomer)], 4.30 [1H£a, d, J¼11.8 Hz, PhCHHO
(E-isomer)], 4.30–4.49 (3H, C11H, C11CH2O), 4.52
[1H£b, d, J¼11.8 Hz, PhCHHO (E-isomer)], 4.54 [1H£b,
d, J¼11.7 Hz, PhCHHO (Z-isomer)], 4.71 [1H£b, d,
J¼11.6 Hz, PhCHHO (E-isomer)], 4.79 [1H£b, d, J¼
11.1 Hz, PhCHHO (Z-isomer)], 4.80 [1H£b, d, J¼
11.6 Hz, PhCHHO (E-isomer)], 4.86 [1H£b, d, J¼
11.1 Hz, PhCHHO (Z-isomer)], 5.03 [1H£a, d, J¼1.2 Hz,
C13H (E-isomer)], 5.28 [1H£b, s, C13H (Z-isomer)], 5.81
[1H£b, s, C18H (Z-isomer)], 5.90 [1H£a, s, C18H
(E-isomer)], 7.18 (2H, aromatic protons), 7.26–7.40 (10H,
aromatic protons), 7.45 [1H£a, br d, J¼002.5 Hz, C400H
(E-isomer)], 7.49 [1H£b, br d, J0¼0 2.7 Hz, C4 H (Z-isomer)],
7.90 [1H£b, br d, J¼2.7 Hz, C2 H (Z-isomer)], 7.9100[1H£a,
br d, J¼2.5 Hz, C200H (E-isomer)], 8.65 (1H, m, C8 H). SI-
MS (3-nitrobenzylalcoholþNaCl): m/z¼779 ([MþNa]þ),
757 (MHþ). Neither EI- nor CI-MS of this sample gave
structural information. EI-HRMS was not measured.
4.38.3. Physical data of 48Z. IR (film) 3420, 3340, 2930,
1710, 1510, 1470, 1380, 1360, 1300, 1280, 1250, 1170,
1070, 840 cm21. 1H NMR (200 MHz, CDCl3, carzinophilin
numbering) d 0.17, 0.20 (each 3H, s, (CH3)2Si), 0.90 (9H, s,
(CH3)3CSi), 1.46 (3H, s, C20H3), 1.17 (3H, d, J¼6.3 Hz),
2.36 (1H, d, J¼4.2 Hz, C21CHH), 2.66 (3H, s, CH3Ar), 2.72
(3H, s, CH3SO3), 3.04 (1H, d, J¼4.2 Hz, C21CHH), 3.53
(1H, br dd, J¼5.2, 10.3 Hz, C11CHHO), 3.76 (3H, s,
CH3OAr), 3.98 (3H, s, CH3OAr), 4.02 (1H, m, CH2
vCHCHHO), 4.05 (1H, dd, J¼0.8, 4.9 Hz, C12H), 4.10
(1H, dq, J¼1.7, 6.3 Hz, C2H), 4.19 (1H, m, CH2
vCHCHHO), 4.25 (1H, t, J¼10.3 Hz, C11CHHO), 4.36
(1H, d, J¼11.6 Hz, ArCHHO), 4.42 (2H, m, C3H, C11H),
4.20 (1H, d, J¼10.9 Hz, ArCHHO), 4.44, 4.48 (each 1H, d,
J¼11.4 Hz, ArCH2O), 4.49 (1H, d, J¼10.9 Hz, ArCHHO),
4.68 (1H, d, J¼11.6 Hz, ArCHHO), 4.76 (1H, d, J¼7.0 Hz,
C4H), 4.90 (1H, dq, J¼17.2, 1.4 Hz, CHHvCHCH2O),
4.97 (1H, dq, J¼10.4, 1.4 Hz, CHHvCHCH2O), 5.42 (1H,
ddd, J¼5.8, 10.4, 17.2 Hz, CH2vCHCH2O), 5.43 (1H, s,
C10H), 5.30 (1H, br s, C13H), 6.81 (2H, br d, J¼8.7 Hz,
aromatic protons for MPM), 7.08 (1H, br d, J¼9.1 Hz,
N5H), 7.48–7.42 (14H, m, aromatic protons), 7.51 (1H, d,
J¼2.5 Hz, C40H), 8.07 (1H, d, J¼2.5 Hz, C20H), 8.74 (1H,
br d, J¼7.9 Hz, C80H), 8.96 (1H, br s, N16H).
4.38. (3R,4R,5S)-3,4-Dibenzyloxy-2-[(E)-1-((2S,3S)-3,4-
epoxy-2-(3-methoxy-5-methyl-1-naphthoxy)-3-methyl-
butyrylamino)-1-[(1R, or S,3R)-(1-tert-butyldimethyl-
siloxy-1-cyano-3-(4-methoxyphenylmethyloxy)but-2-
yl)carbamoyl]]methylidene-5-(methanesulfoxy)methyl-
1-(2-propenyloxycarbonyl)pyrrolidine (48E) and its (Z)-
isomer (48Z)
4.39. (3R,4R,5S)-3,4-Dibenzyloxy-2-[(E)-1-((2S,3S)-3,4-
epoxy-2-(3-methoxy-5-methyl-1-naphthoxy)-3-methyl-
butyrylamino)-1-[N-(1R, or S,3R)-(1-tert-butyldimethyl-
siloxy-1-cyano-3-oxobut-2-yl)carbamoyl]]methylidene-
5-(methanesulfoxy)methyl-1-(2-propenyloxycarbonyl)-
pyrrolidine (49)
4.38.1. Reaction procedure. A mixture of 47 (28.0 mg,
37.1 mmol), DMAP (500 mg, 4.1 mmol), and Alloc2O
(10.3 mg, 55.4 mmol) in THF (1.0 mL) was stirred at
room temperature for 10 min. A solution of 28 (50 mg,
137 mmol) in THF (4.0 mL) was added into the mixture.
The mixture was concentrated in vacuo by a rotary
evaporator at 408C over 15 min. Purification of the residue
by silica gel column chromatography (hexane–
AcOEt¼70:30!60:40) gave 48Z (1.0 mg, 2%) and 48E
(35.0 mg, 78%) as oils.
4.39.1. Removal of MPM group in 48E. A mixture of 48E
(31.0 mg, 25.7 mmol) and DDQ (11.3 mg, 49.8 mmol) in a
mixture of CH2Cl2 (2.0 mL) and H2O (200 mL) was stirred
at room temperature for 1 h. The mixture was poured into a
1:1 mixture of aqueous 5% Na2S2O3 and saturated aqueous
NaHCO3 solutions, then 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–
AcOEt¼50:50) afforded the corresponding alcohol
4.38.2. Physical data of 48E. [a]2D0¼þ80.18 (c 0.824,
CHCl3). IR (film): 3430, 3370, 2960, 2930, 1730, 1715,
1690, 1620, 1600, 1510, 1470, 1360, 1300, 1280, 1250,
1240, 1210, 1175, 1090, 1050, 990, 960, 910, 850, 810, 780,
1
730, 700 cm21. H NMR (400 MHz, CDCl3, carzinophilin

M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
3085
(26.2 mg, 94%) as a colorless caramel. [a]2D0¼þ85.38 (1.08,
CHCl3). IR (film): 3500, 3400, 2960, 2930, 1730, 1590,
1500, 1495, 1470, 1390, 1360, 1280, 1235, 1210, 1175,
THF (2.0 mL) was stirred at room temperature for 10 min.
After the mixture was concentrated in vacuo, the residue
was purified by silica gel column chromatography (AcOEt–
hexane¼60:40) to give 50 (18.0 mg, 89%) as a colorless
caramel. [a]2D0¼þ22.58 (c 1.00, CHCl3). IR (film): 3400,
3360, 2930, 2860, 1720, 1710, 1660, 1620, 1600 1510,
1500, 1420, 1360, 1280, 1260, 1240, 1215, 1175, 1090,
1050, 845 cm21. 1H NMR (400 MHz, CDCl3, carzinophilin
numbering): d 0.20 0.22 (each 3H, s, (CH3)2Si), 0.92 (9H, s,
(CH3)3CSi), 1.56, 2.30, 2.67 (each 3H, s, C20H3, C1H3,
CH3Ar, respectively), 2.87 (1H, d, J¼4.5 Hz, C21HH), 2.99
(3H, s, CH3SO3), 3.02 (1H, d, J¼4.5 Hz, C21HH), 3.97 (3H,
s, CH3OAr), 4.05 (1H, br d, J¼2.5 Hz, C12H), 4.25 (3H, m,
C11CHH2O, PhCHHO), 4.38 (1H, m, C11H), 4.44 (1H, d,
J¼11.7 Hz, PhCHHO), 4.66 (1H, d, J¼11.3 Hz, PhCHHO),
4.73 (1H, d, J¼1.8 Hz, C13H), 4.78 (1H, dd, J¼4.0, 7.7 Hz,
C3H), 4.80 (1H, d, J¼11.3 Hz, PhCHHO), 4.86 (1H, s,
C18H), 5.00 (1H, d, J¼4.0 Hz, C4H) 6.90 (1H, br s, N9H),
6.91 (1H, br d, J¼7.7 Hz, N5H), 7.10 (2H, m, aromatic
protons), 7.19 (3H, m, aromatic protons), 7.26–7.38 (7H,
aromatic protons), 7.49 (1H, d, J¼2.6 Hz, C40H), 7.95 (1H,
d, J¼2.6 Hz, C20H), 8.46 (1H, br s, N16H), 8.69 (1H, br d,
7.8 Hz, C80H). SI-MS (3-nitrobenzylalcoholþNaCl): m/z¼
1021 ([MþNa]þ), 999 (MHþ). Neither EI-MS nor CI-MS of
this sample gave informative peaks. So, EI-HRMS was not
measured.
1
1090, 1050, 990, 960, 850, 810, 780, 750, 700 cm21. H
NMR (400 MHz, CDCl3, carzinophilin numbering): d 0.16,
0.20 (each 3H, s, (CH3)2Si), 0.90 (9H, s, (CH3)3CSi), 1.28
(3H, d, J¼6.5 Hz, C1H3), 1.53 (3H, s, C20H3), 2.55 (1H, d,
J¼5.6 Hz, alcoholic proton), 2.66 (3H, s, CH3Ar), 2.76,
2.98 (each 1H, d, J¼4.5 Hz, C21H2), 3.92 (3H, s, CH3SO3),
4.01 (1H, ddd, J¼2.9, 4.8, 8.5 Hz, C11H), 4.20 (1H, dd,
J¼3.1, 6.6 Hz, C12H), 4.34 (1H, m, C2H), 4.47–4.73 (10H,
m, C3H, C4H, C11CH2O, CH2vCHCH2O, PhCH2O£2),
4.75 (1H, d, J¼3.1 Hz, C13H), 4.95 (1H, s, C18H), 5.23
(1H, dq, J¼10.4, 1.2 Hz, CHHvCHCH2O), 5.31 (1H, dq,
J¼17.2, 1.4 Hz, CHHvCHCH2O), 5.93 (1H, ddt, J¼10.4,
17.2, 5.9 Hz, CH2vCHCH2O), 6.70 (1H, br d, J¼8.8 Hz,
N5H), 7.24–7.36 (12H, aromatic protons), 7.45 (1H, d,
J¼2.5 Hz, C40H), 7.68 (1H, br s, N16H), 7.88 (1H, d,
J¼2.5 Hz, C20H), 8.60 (1H, dd, J¼1.7, 7.8 Hz, C80H). SI-
MS (3-nitrobenzylalcoholþNaCl): m/z¼1107 ([MþNa]þ),
1084 (MHþ). Neither EI-MS nor CI-MS of this sample gave
structural information. So, EI-HRMS was not measured.
4.39.2. Oxidation giving 49. A mixture of the alcohol
(240 mg, 221 mmol) and Dess–Martin reagent (180 mg,
437 mmol) in CH2Cl2 (4.0 mL) was stirred at room
temperature for 1 h. The mixture was poured into a 50:50
mixture of aqueous 5% Na2S2O3 and saturated aqueous
NaHCO3 solutions, then 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–
AcOEt¼60:40) gave 49 (234 mg, 98%) as a colorless
caramel. [a]2D0¼þ758 (c 0.82, CHCl3). IR (film): 3370,
2860, 2830, 1720, 1690, 1500, 1360, 1280, 1240, 1215,
4.41. (3R,4R,5S)-3,4-Dibenzyloxy-2-[(E)-1-((2S,3S)-3,4-
epoxy-2-(3-methoxy-5-methylnaphthoxy)-3-methyl-
butyrylamino)-1-(N-(Z)-1-methoxymethylene-2-oxo-
propyl)carbamoyl]]methylidene-5-methanesulfoxy-
methylpyrrolidine (38)
A mixture of 50 (28.0 mg, 28.0 mmol) and TBAF (1.0 M in
THF, 50 mL) in a mixture of THF (1.0 mL) and
AcOH(30 mL) was stirred at room temperature for 3 h.
After saturated aqueous NaHCO3 solution (200 mL) was
added to the mixture, the mixture was stirred at room
temperature for 10 min, poured into aqueous 10% citric acid
solution, then extracted with AcOEt. The combined extracts
were washed with brine, dried over MgSO4, then concen-
trated in vacuo. After the residue was dissolved in CH2Cl2
(1.0 mL), ethereal CH2N2 (1.0 mL, excess) was added to the
solution. The mixture was kept standing for 1 h at room
temperature. After concentration, the obtained residue was
purified by silica gel column chromatography (CH2Cl2–
acetone¼70:30) to give 38 (13.2 mg, 54%) as a colorless
caramel. [a]2D0¼þ178 (c 0.44, CH3CN). IR (film): 3370,
2940, 1700, 1665, 1640, 1620, 1600, 1500, 1420, 1355,
1180, 1090, 1050, 990, 960, 840, 810, 780, 740, 700 cm21
.
1H NMR (400 MHz, CDCl3, carzinophilin numbering): d
0.19, 0.21 (each 3H, s, (CH3)2Si), 0.90 (9H, s, (CH3)3CSi),
1.55, 2.37, 2.66 (each 3H, s, C20H3, C1H3, CH3Ar,
respectively), 2.76 (1H, d, J¼4.5 Hz, C21HH), 2.98 (3H,
s, CH3SO3), 2.98 (1H, d, J¼4.5 Hz, C21HH), 3.93 (3H, s,
CH3OAr), 4.19 (1H, dd, J¼3.0, 6.2 Hz, C12H), 4.48–4.72
(10H, m, C4H, C11H, C11CH2O, CH2vCHCH2O,
PhCH2O£2), 4.74 (1H, d, J¼3.0 Hz, C13H) 4.91 (1H, s,
C18H), 5.00 (1H, d, J¼3.7 Hz, C3H), 5.20 (1H, dq, J¼10.4,
1.1 Hz, CHHvCHCH2O), 5.28 (1H, dq, J¼17.2, 1.1 Hz,
CHHvCHCH2O), 5.90 (1H, ddt, J¼10.4, 17.2, 5.4 Hz,
CH2vCHCH2O), 6.99 (1H, br d, J¼6.7 Hz, N5H), 7.22–
7.35 (12H, m, aromatic protons), 7.46 (1H, d, J¼2.50Hz,
C40H), 7.61 (1H, br s, N16H), 7.87 (1H, d, J¼2.5 Hz, C2 H),
8.61 (1H, dd, J¼2.4, 7.5 Hz, C80H). SI-MS (3-nitrobenzyl-
alcoholþNaCl): m/z¼1105 ([MþNa]þ), 1083 (MHþ).
Neither EI-MS nor CI-MS of this sample gave informative
peaks. So, EI-HRMS was not measured.
1240, 1175, 1090, 1050, 960, 740 cm21 1H NMR
.
(400 MHz, CDCl3, carzinophilin numbering): d 1.59, 2.22,
2.68 (each 3H, s, C20H3, C1H3, CH3Ar, respectively), 2.84
(1H, d, J¼4.4 Hz, C21HH), 2.98 (3H, s, CH3SO3), 3.07 (1H,
d, J¼4.4 Hz, C21HH), 3.83 3.98 (each 3H, s, CH3O£2),
4.45 (1H, dd, J¼1.9, 4.6 Hz, C12H), 4.23 (2H, m, C11H,
C11CHHO), 4.29 (1H, d, J¼11.7 Hz, PhCHHO), 4.40 (1H,
dd, J¼2.7, 9.0 Hz, C5CHHO), 4.45 (1H, d, J¼11.7 Hz,
PhCHHO), 4.63 (1H, d, J¼11.1 Hz, PhCHHO), 4.73 (1H, d,
J¼1.9 Hz, C13H), 4.83 (1H, d, J¼11.1 Hz, PhCHHO), 7.01
(1H, br s, NH), 7.13 (2H, m, aromatic protons), 7.15 (1H, s,
C4H), 7.17 (1H, br s, NH), 7.18–7.37 (7H, aromatic
protons), 7.51 (1H, d, J¼2.6 Hz, C40H), 7.97 (1H, d,
J¼2.6 Hz, C20H), 8.47 (1H, br s, N16H), 8.68 (1H, br d,
4.40. (3R,4R,5S)-3,4-Dibenzyloxy-2-[(E)-1-((2S,3S)-3,4-
epoxy-2-(3-methoxy-5-methyl-1-naphthoxy)-3-methyl-
butyrylamino)-1-[N-(1R or S,3R)-(1-tert-butyldimethyl-
siloxy-1-cyano-3-oxobut-2-yl)carbamoyl]]methylidene-
5-(methanesulfoxy)methylpyrrolidine (50)
A mixture of the 49 (22.0 mg, 20.3 mmol), AcOH (3.0 mL),
PPh3 (1.5 mg, 5.7 mmol), Pd(PPh3)4 (0.3 mg, 0.27 mmol) in

3086
M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
8.2 Hz, C80H). SI-MS (3-nitrobenzylalcoholþNaCl):
m/z¼894 ([MþNa]þ), 872 (MHþ). Neither EI-MS nor
CI-MS of this sample gave informative peaks. So,
EI-HRMS was not measured.
4.44. (3R,4R,5S)-3-Acetoxy-5-(tert-butyldiphenylsiloxy)-
methyl-4-(triethylsiloxy)pyrrolidin-2-ylidene]-2-
[(1R,2S)-2,3-epoxy-1-(3-methoxy-5-methyl-1-
naphthoxy)-2-methylpropyl]-4H-oxazol-5-one (56)
4.42. 13-Desacetyl-12,13-di-O-benzyloxy-4-O-methyl-
carzinophilin (2)
Treatment of 16 (31.0 mg, 43.2 mmol) and 19 (14.0 mg,
64.8 mmol) in the same manner as described in Section 4.19
gave 56 (31.0 mg, 78%) as an oil after silica gel column
chromatography. IR (film): 3320, 2940, 1730, 1650, 1590,
A mixture of 38 (3.7 mg, 4.9 mmol), powdered molecular
sieves 4A (10 mg), and TBAF (1.0 M in THF, 6.0 mL) in
THF (1.0 mL) was stirred at room temperature for 15 min.
After filtration, the filtrate was poured into water and
extracted with AcOEt. The combined extracts were washed
with brine, dried over Na2SO4, then concentrated in vacuo.
Purification by preparative silica gel TLC (CH2Cl2–
acetone¼70:30) gave 2 (1.8 mg, 47%) as a colorless
caramel. [a]2D0¼þ8.58 (c 0.082, CH3CN). IR (film): 3360,
2930, 1705, 1640, 1620, 1600, 1510, 1500, 1280, 1235,
1280, 1240, 1210, 1190, 1110, 1080, 910, 740, 700 cm21
.
The 1H NMR spectrum of this sample showed that it
consists of the two tautomers arising from its enamine
moiety (E/Z¼ 80:20). Assignments of signals for the main
1
isomer and some for the minor isomer are described. H
NMR (200 MHz, CDCl3, a¼0.80, b¼0.20, carzinophilin
numbering) d 1.00 (9H, s, (CH3)3CSi), 1.56 [3H£a, s,
C2CH3 (E-isomer)], 1.57 [1H£b, C2CH3 (Z-isomer)], 2.67
(3H, s, CH3Ar), 2.80, 3.07 (each 1H, d, J¼4.3 Hz, C12H2),
3.70 (1H, m, C13H), 3.89 (1H, m, C11CHHO), 3.91 (3H, s,
CH3OAr), 4.15 (2H, m, C11H, C11CHHO), 4.31, 4.45 [each
1H£a, d, J¼11.9 Hz, PhCH2O (E-isomer)], 4.70 [1H£a, d,
J¼11.4 Hz, PhCHHO (E-isomer)], 4.75, 4.85 [each 1H£b,
d, J¼10.9 Hz, PhCH2O (Z-isomer)], 4.93 [1H£a, d, J¼
11.4 Hz, PhCHHO (E-isomer)], 5.00 [1H£a, d, J¼2.7 Hz,
C13H (E-isomer)], 5.20 [1H£b, s, C3H (Z-isomer)], 5.50
(1H, s, C10H), 6.61 [1H£b, br s, amine proton (Z-isomer)],
7.10 (2H, m, aromatic protons), 7.18–7.48 (17H, aromatic
protons), 7.60 (4H, m, aromatic protons), 7.64 [1H£a, br s,
amine proton (E-isomer)], 7.99 (1H, d, J¼2.6 Hz, C200H),
8.69 (1H, dd, J¼2.5, 7.3 Hz, C800H). SI-MS (nitro-
benzylalcoholþNaCl) m/z¼939 ([MþNa]þ), 917 (MHþ).
Neither EI-MS nor CI-MS of this sample gave useful
structural information.
1
1210, 1190, 1170, 1085, 1045 cm21. H NMR (400 MHz,
CDCl3, carzinophilin numbering) d 1.53 (3H, s, C20H3),
2.22 (3H, s, C1H3), 2.27 (1H, d, J¼4.1 Hz, C10H), 2.48
(1H, d, J¼5.1 Hz, C10H), 2.60 (1H, d, J¼4.6 Hz, C21HH),
2.66 (3H, s, CH3Ar), 2.90 (1H, d, J¼4.6 Hz, C21HH), 3.12
(1H, ddd, J¼4.1, 4.8, 5.1 Hz, C11H), 3.89 3.96 (each 3H, s,
CH3O£2), 4.49 (1H, dd, J¼3.6, 4.8 Hz, C12H), 4.53 (2H, br
s, PhCH2O), 4.54, 4.60 (each 1H, d, J¼11.5 Hz, PhCH2O),
4.94 (1H, dd, J¼1.0 3.6 Hz, C13H), 5.16 (1H, s, C18H),
7.14 (1H, s, C4H), 7.20–7.40 (12H, aromatic protons), 7.48
(1H, d, J¼2.6 Hz, C40H), 7.96 (1H, d, J¼2.6 Hz, C200H),
8.21 (1H, br s, C16H), 8.60 (1H, dd, J¼2.4, 7.4 Hz, C8 H),
10.58 (1H, br s, N5H). SI-MS (3-nitrobenzylalcoholþ
NaCl): m/z¼798 ([MþNa]þ), 776 (MHþ). Neither EI-MS
nor CI-MS of this sample gave informative peaks, so EI-
HRMS was not measured.
4.45. (3R,4R,5S)-3-Acetoxy-5-(tert-butyldiphenyl-
siloxy)methyl-2-[(E)-1-[(2S,3S)-3,4-epoxy-2-(3-methoxy-
5-methyl-1-naphthoxy)-3-methylbutyrylamino]-1-(N-
isopropylcarbamoyl)]methylidene-4-triethylsiloxy-1-(2-
propenyloxylcarbony)pyrrolidine (57SE) and its Z-
isomer (57SZ) and those diastereomers (57RE) and
(57RZ)
4.43. (3R,4R,5S)-3,4-Dibenzyloxy-2-[(E)-1-((2S,3S)-3,4-
epoxy-2-(3-methoxy-5-methyl-1-naphthoxy)-3-methyl-
butanoylamino)-1-N-((Z)-1-methocymethylidene-2-
oxypropyl)carbamoyl-5-methypyrrolidine (52)
4.43.1. Reaction procedure. A suspension of 2 (4.2 mg,
5.4 mmol) and 10% Pd/C (1.0 mg) in AcOEt (1.0 mL) was
stirred vigorously for 3 h under H2 atmosphere. After
filtration, the mixture was concentrated in vacuo. The
residue was purified by preparative silica gel TLC
(CH2Cl2–acetone 70:30) to give 52 (2.0 mg, 47%) and
recovered 2 (1.0 mg, 24%). The 1H NMR spectrum of
recovered 2 was identical with that of an authentic
sample.
4.45.1. Reaction procedure for 57SE and 57SZ. A mixture
of 20 (7.3 mg, 8.2 mmol), Alloc2O (2.0 mL, 12 mmol), and
DMAP (1.0 mg, 8.1 mmol) in THF (1.0 mL) was stirred at
room temperature for 10 min. Isopropyl amine (100 mL)
was added to the mixture and the mixture was stirred for
30 min at room temperature. After concentration in vacuo,
purification of the residue by preparative silica gel column
TLC (CH2Cl2–acetone¼90:10) gave 57SZ (4.0 mg,
3.0 mmol, 47%) and 57SE (3.0 mg, 35%) both as an oil.
4.43.2. Physical data of 52. (IR (film) 3380, 2930, 1700,
1650, 1640, 1620, 1600, 1490, 1280, 1230, 1180 cm21. 1H
NMR (400 MHz, CDCl3, carzinophilin numbering): d 1.21
(3H, d, J¼6.6 Hz, C11CH3), 1.61, 2.23, 2.69 (each 3H, s,
C20H3, C1H3, CH3Ar, respectively), 2.81, 3.10 (each 1H, d,
J¼4.5 Hz, C20H2), 3.80 (1H, C12H), 3.80, 3.98 (each 3H, s,
CH3O£2), 4.08 (1H, dq, J¼4.9, 6.6 Hz, C11H), 4.31, 4.43
(each 1H, d, J¼12.0 Hz, PhCH2O), 4.60 (1H, d, J¼11.1 Hz,
PhCHHO) 4.65 (1I, d, J¼1.5 Hz, C13H), 4.81 (1H, d,
J¼11.1 Hz, PhCHHO), 5.13 (1H, s, C18H), 7.03 (1H, br s,
NH), 7.12–7.40 (13H, NH, aro0matic protons), 7.51, 7.97
(each 1H, d, J¼2.5 Hz, C20H, C5 H, respectively), 8.26 (1H,
br s, NH), 8.69 (1H, br d, J¼10.9 Hz).
1
4.45.2. NMR data of 57SE. H NMR (400 MHz, CDCl3,
carzinophilin numbering): d 0.59 (6H, m, (CH3CH2)3Si),
0.88 (9H, t, J¼7.9 Hz, (CH3CH2)3Si), 1.02 (3H, d,
J¼6.5 Hz, C4CH3), 1.07 (9H, s, (CH3)3CSi), 1.08 (3H, d,
J¼6.5 Hz, C4CH3), 1.59 (3H, s, C20H3), 2.04 (3H, s,
CH3COO), 2.67 (3H, s, CH3Ar), 2.73 (1H, d, J¼5.6 Hz,
C21HH), 3.09 (1H, d, J¼5.6 Hz, C21HH), 3.97 (3H, s,
CH3OAr), 4.00 (1H, m, C4H), 4.19 (3H, m, C11H,
C11CH2), 4.49 (1H, dd, J¼1.5, 4.5 Hz, C12H), 4.66 (2H,
br d J¼4.5 Hz, CH2vCHCH2O), 5.06 (1H, dd J¼1.4,
10.5 Hz, CHHvCHCH2O), 5.09 (1H, dd J¼1.5, 15.4 Hz,

M. Hashimoto et al. / Tetrahedron 59 (2003) 3063–3087
3087
CHHvCHCH2O), 5.17 (1H, d, J¼ 1.5 Hz, C13H), 5.39
(1H, s, C18H), 5.59 (1H, bd, J¼8.6 Hz, N5H), 5.68 (1H,
ddt, J¼10.5, 15.4, 5.5 Hz, CH2vCHCH2O), 7.30–7.50
(12H, m, aromatic protons C60H, C70H), 7.49 (1H, d,
J¼2.40Hz, C40H), 8.03 (1H, d, J¼2.4 Hz, C20H), 8.69 (1H,
m, C8 H), 9.06 (1H, br s, N16H).
(1H, d, J¼2.5 Hz, C13H), 6.45 (1H, br 0d, J¼7.8 Hz, N5H),
7.30–7.50 (12H, m, aromatic protons C6 H, C700H), 7.48 (1H,
d, J¼2.6 Hz, C40H), 8.11 (1H, d, J¼2.6 Hz, C2 H), 8.65 (1H,
dd, J¼8.2 Hz, C80H), 9.26 (1H, br s, N16H).
1
4.45.3. NMR data of 57SZ. H NMR (400 MHz, CDCl3,
References
carzinophilin numbering): d 0.68 (6H, m, (CH3CH2)3Si),
0.92 (9H, t, J¼7.8 Hz, (CH3CH2)3Si), 1.13 (3H, d,
J¼6.5 Hz, C4CH3), 1.07 (9H, s, (CH3)3CSi), 1.16 (3H, d,
J¼6.5 Hz, C4CH3), 1.43 (3H, s, C20H3), 2.01 (3H, s,
CH3COO), 2.66 (3H, s, CH3Ar), 2.67 (1H, d, J¼4.7 Hz,
C21HH), 3.17 (1H, d, J¼4.7 Hz, C21HH), 3.39 (1H, ddt,
J¼5.5, 13.6, 1.3 Hz, OCHHCHvCH2), 3.82 (1H, ddt,
J¼5.8, 13.6, 1.3 Hz, OCHHCHvCH2), 3.98 (3H, s,
CH3OAr), 3.8–4.2 (4H, C11H, C11CH2, C4H), 4.40 (1H,
dd, J¼2.5, 5.2 Hz, C12H), 6.41 (1H, s, C13H), 4.86 (1H, dq
J¼10.5, 1.4 Hz, CHHvCHCH2O), 4.75 (1H, dq J¼17.2,
1.5 Hz, CHHvCHCH2O), 5.45 (1H, s, C18H), 6.70 (1H, bd,
J¼ 7.9 Hz, N5H), 5.25 (1H, ddt, J¼10.5, 17.2, 5.6 Hz, CH2
vCHCH2O), 7.30–7.50 (12H, m, aromatic protons C60H,
C700H), 7.49 (1H, d, J¼2.6 Hz, C40H), 8.15 (1H, d, J¼2.6 Hz,
C2 H), 8.68 (1H, dd, J¼8.7 Hz, C80H), 9.17 (1H, br s, N16H).
1. Parts of this series of papers have been the subject of five
preliminary communications: (a) Hashimoto, M.; Yamada, K.;
Terashima, S. Chem. Lett. 1992, 975. (b) Hashimoto, M.;
Matsumoto, M.; Yamada, K.; Terashima, S. Tetrahedron Lett.
1994, 35, 2207. (c) Hashimoto, M.; Terashima, S. Chem. Lett.
1994, 1001. (d) Hashimoto, M.; Terashima, S. Tetrahedron
Lett. 1994, 35, 9409. (e) Hashimoto, M.; Terashima, S.
Heterocycles 1998, 47, 59.
2. For preliminary communications, see Ref. 1e.
3. Hata, T.; Koga, F.; Sano, Y.; Kanamori, K.; Matsumae, A.;
Sunagawa, R.; Hoshi, T.; Shima, T.; Ito, S.; Tomizawa, S.
Antibiot. Ser. A 1954, 7, 107.
4. Moran, E. J.; Armstrong, R. W. Tetrahedron Lett. 1991, 32,
3807.
5. Yokoi, K.; Nagaoka, K.; Nakashima, T. Chem. Phram. Bull.
1986, 34, 4554.
4.45.4. Reaction procedure for 57SE and 57SZ. Treat-
ment of 56 (3.0 mg, 3.3 mmol) in the same manner as
described previously gave 57RZ (1.4 m, 42%) and 57RE
(1.3 mg, 39%) as oils.
6. (a) Coleman, R. S. Synlett 1998, 1031. For reviews on the
chemical synthesis of carzinophilins A and B see: (a).
(b) Hodgkinson, T. J.; Coleman, R. S. Tetrahedron 2001, 57,
4467.
7. See references in Part 1 of this series of papers: Hashimoto,
M.; Matsumoto, M.; Terashima, S. Tetrahedron 2003, 59,
3019.
1
4.45.5. NMR data of 57SE. H NMR (400 MHz, CDCl3,
carzinophilin numbering): d 0.62 (6H, m, (CH3CH2)3Si),
0.89 (9H, t, J¼7.7 Hz, (CH3CH2)3Si), 0.93 (3H, d, J¼
6.5 Hz, C4CH3), 1.07 (9H, s, (CH3)3CSi), 1.56 (3H, d, J¼
6.5 Hz, C4CH3), 1.59 (3H, s, CH3COO), 1.66 (3H, s,
C20H3), 2.69 (3H, s, CH3Ar), 2.83 (1H, d, J¼4.4 Hz,
C21HH), 3.15 (1H, d, J¼4.4 Hz, C21HH), 3.97 (3H, s,
CH3OAr), 3.97 (1H, m, C4H), 4.19 (3H, m, C11H,
C11CH2), 4.38 (2H, m, OCH2CHvCH2), 4.46 (1H, dd,
J¼1.3, 4.3 Hz, C12H), 4.84 (1H, s, C13H), 5.06 (1H, dd
J¼1.4, 10.5 Hz, CHHvCHCH2O), 5.07 (1H, dd J¼1.5,
15.4 Hz, CHHvCHCH2O), 5.12 (1H, s, C18H), 5.50 (1H, bd,
J¼8.0 Hz, N5H), 5.65 (1H, ddt, J¼10.6, 17.0, 5.8 Hz,
CH2vCHCH2O), 7.30–7.50 (12H, m, aromatic protons
C60H, C70H), 07.51 (1H, d, J¼2.6 Hz, C40H), 8.12 (1H, d,
J¼2.4 Hz, C2 H), 8.69 (1H, dd, J¼2.3, 7.4 Hz, C80H), 9.28
(1H, br s, N16H).
8. Coleman, R. S.; Li, J.; Navarro, A. Angew. Chem. Int. Ed.
2001, 40, 1736.
9. Pedersen, B. S.; Lawesson, S.-O. Tetrahedron 1979, 35, 2433.
10. Garner, P.; Ramakanth, S. J. Org. Chem. 1987, 52, 2629.
11. Hoyng, C. F.; McKenna, M.; Novak, K. Synth. Commun. 1980,
10, 761.
12. Ward, R. S.; Satyanarayana, P.; Rao, B. V. G. Tetrahedron
Lett. 1981, 22, 3021.
13. Katsuki, T.; Sharpless, K. B. J. Org. Chem. 1980, 102, 5974.
14. Lu, L. D.-L.; Johnson, R. A.; Finn, M. G.; Sharpless, K. B.
J. Org. Chem. 1984, 49, 731.
15. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
16. Mitsunobu, O. Synthesis 1981, 1.
17. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
18. Rucker, G.; Horster, H.; Gajwski, W. Synth. Commun. 1980,
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1
4.45.6. NMR data of 57RZ. H NMR (400 MHz, CDCl3,
carzinophilin numbering): d 0.65 (6H, m, (CH3CH2)3Si),
0.91 (9H, t, J¼7.7 Hz, (CH3CH2)3Si), 1.11 (3H, d,
J¼6.5 Hz, C4CH3), 1.03 (9H, s, (CH3)3CSi), 1.17 (3H, d,
J¼6.5 Hz, C4CH3), 1.32 (3H, s, C20H3), 2.17 (3H, s,
CH3COO), 2.67 (3H, s, CH3Ar), 2.67 (1H, d, J¼4.4 Hz,
C21HH), 3.11 (1H, d, J¼4.4 Hz, C21HH), 3.96 (3H, s,
CH3OAr), 4.40 (2H, m, OCH2CHvCH2), 3.95 (2H, m,
C11CH2O), 4.05 (1H, m, C18H), 4.16 (1H, m, C11H), 4.40
(2H, m, C11H2), 5.02 (1H, s, C18H), 5.08 (1H, dq, J¼10.3,
1.4 Hz, CHHvCHCH2O), 5.10 (1H, dq, J¼17.2, 1.4 Hz,
CHHvCHCH2O), 5.60 (1H, ddt, J¼10.3, 17.2, 5.8 Hz), 6.27
19. Nakata, T.; Tanaka, T.; Oishi, T. Tetrahedron Lett. 1981, 22,
4723.
20. Shibuya, M. Tetrahedron Lett. 1983, 24, 1175.
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Tetrahedron 2003, 59, 3089.