Synthetic studies on antascomicin A: Construction of the C18-C34 fragment

Article abstract of DOI:10.1016/j.tet.2004.04.072

Stereoselective synthesis of the C18-C34 fragment of antascomicin A is described. Construction of the C27-C34 carbocycle moiety was achieved via catalytic Ferrier carbocylization and Johnson-Claisen rearrangement, which was converted to iodide 2 by use of

Full text of DOI:10.1016/j.tet.2004.04.072

Tetrahedron 60 (2004) 5341–5352
Synthetic studies on antascomicin A: construction of the
C18–C34 fragment
*
Haruhiko Fuwa, Yumiko Okamura and Hideaki Natsugari
*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 6 April 2004; revised 26 April 2004; accepted 28 April 2004
Abstract—Stereoselective synthesis of the C18–C34 fragment of antascomicin A is described. Construction of the C27–C34 carbocycle
moiety was achieved via catalytic Ferrier carbocylization and Johnson–Claisen rearrangement, which was converted to iodide 2 by use of
asymmetric alkylation and Sharpless epoxidation as key transformations. Coupling of iodide 2 and sulfone 3 furnished the C18–C34
fragment.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
fermentation broth of a strain of Micromonospora, which
was isolated from a soil sample collected in China (Fig. 1).7
The molecular architecture of antascomicin A was deter-
mined by extensive NMR studies and X-ray crystal-
lographic analysis. Antascomicin A exhibits potent
binding affinity to FKBP12 (IC50 2.0 nM) and antagonize
the immunosuppressive effect of FK506 and rapamycin but
interestingly it does not show immunosuppressive activity.
Given its intriguing biological activity, we became inter-
ested in the potential utility of antascomicin A as a lead
compound for the generation of novel class of non-
immunosuppressive neurotrophic molecules. Here, we
describe a stereoselective synthesis of the C18–C348
fragment of antascomicin A that is an important key
intermediate toward the total synthesis.
FK506 (tacrolimus)1 and rapamycin (sirolimus)2 are potent
immunosuppressive agents in human clinical organ trans-
plantation. The biological mode of action of these promising
natural products have been extensively investigated over the
past decade.3 For example, FK506 is known to form an
active complex with the cytosolic immunophilin FKBP12,
which subsequently binds to the secondary proteinous target
calcineurin. The latter interaction is responsible for potent
immunosuppressive activity of FK506. On the other hand, it
has recently been discovered that FKBP is present in the
brain at levels 10–40 times higher than in the immune
system, suggesting the possibility of nervous system roles
for immunophilins.3b,4 Subsequently, FK506 has been
reported to elicit neurite outgrowth and neuroprotective
effects in neuronal cultures at picomolar concentrations.5
Although the mechanism of neuronal activity of FKBP has
not yet been clarified, it has been shown that the
neurotrophic properties of FKBP ligands are independent
of calcineurin-mediated effects.3b,6 Thus, FKBP ligands are
now considered as potential lead compounds for the
development of drugs for treatment and cure of neuro-
degenerative disorders such as Alzheimer’s and Parkinson’s
diseases. With regard to clinical use, efforts have been
devoted to the design of neurotrophic FKBP ligands that are
non-immunosuppressive.5,6
Macrolide antibiotics antascomicin A–E were found in a
Keywords: Ferrier carbocyclization; Johnson–Claisen rearrangement;
Asymmetric alkylation; Sulfone anion coupling.
*
Corresponding authors. Tel./fax: þ81-3-5841-4775;
e-mail addresses: hfuwa@mol.f.u-tokyo.ac.jp;
natsu@mol.f.u-tokyo.ac.jp
Figure 1. Structures of antascomicin A–E.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.072

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H. Fuwa et al. / Tetrahedron 60 (2004) 5341–5352
2. Results and discussions
2.1. Synthetic planning
Our synthetic planning for the synthesis of the C18–C34
fragment 1 is outlined in Scheme 1. We divided 1 into
iodide 2 and sulfone 3 by retro-sulfone anion coupling. The
former segment was traced back to ester 4, which could be
obtained from allylic alcohol 5 by Johnson–Claisen
rearrangement.9 In turn, 5 should be available from
exocyclic enol ether 6 via Ferrier carbocyclization.10
Scheme 2. Reagents and conditions: (a) Ph3P·HBr, MeOH, MeCN, rt, 89%;
(b) NaOMe, MeOH, rt; (c) TrCl, pyridine, CH2Cl2, rt, 81% (two steps);
(d) BnBr, NaH, DMF, 50 8C; (e) p-TsOH·H2O, MeOH/CHCl3 (5:1), rt, 91%
(two steps); (f) I2, PPh3, imidazole, benzene, rt, 84%; (g) NaH, DMF, rt,
94%; (h) Hg(OCOCF3)2, acetone/H2O (2:1), rt, 95%; (i) MsCl, Et3N,
CH2Cl2, rt, quant.; (j) LiBH4, CeCl·7H2O, THF/MeOH (1:1), 0 8C, 98% (dr
5.3:1); (k) n-EtCO2H, CH3C(OEt)3, 140 8C, 76%.
Employing other bases such as KOt-Bu (THF, 0 8C) and
DBU (toluene, 100 8C), 6 was obtained in only moderate
yield. Catalytic Ferrier carbocyclization11 was smoothly
carried out by exposure of 6 to Hg(OCOCF3)2 (10 mol%) in
acetone/H2O, leading to hydroxyketone 12 in 95% yield as a
10:1 mixture of diastereomers. Treatment of 12 with MsCl
in the presence of Et3N gave enone 13. Stereoselective 1,2-
reduction of 13 turned out to be rather problematic than
anticipated. The results of several attempts to optimize the
reaction are summarized in Table 1. Under the standard
Luche reduction conditions,12 we obtained an inseparable
mixture of 5 and its epimer in a ratio of 3.7:1 in 88%
combined yield (entry 1). Use of THF as a co-solvent
slightly improved the stereochemical outcome (entry 2). We
found that the use of much reactive LiBH4 in MeOH/THF at
0 8C resulted in an improved 5.3:1 diastereomer ratio (entry
3). An attempt to conduct the reaction at low temperature
caused a significant decrease in the stereoselectivity (entry
4). We have also examined several aluminum hydride
reagents such as LiAlH4, LiAlH(Ot-Bu)3 and DIBALH, but
these reductants were found to be uniformly ineffective for
the present case (entries 5–7). With satisfactory reaction
conditions established, we then conducted Johnson–Claisen
rearrangement of 5. Thus, treatment of 5 with a catalytic
amount of n-propionic acid in CH3CH(OEt)3 at 140 8C
cleanly delivered ester 4. For the major isomer, the
Scheme 1. Synthetic planning toward the C18–C34 fragment 1.
2.2. Synthesis of the C29–C34 carbocycle
Synthesis of the C18–C34 fragment was commenced with
tri-O-acetyl-D-glucal 7 (Scheme 2). Treatment of 7 with
methanol in the presence of a catalytic amount of
triphenylphosphine hydrogen bromide complex (Ph3P·HBr)
gave methyl glucoside 8 in 89% yield (a/b¼ca. 9:1).
Deacetylation of 8 followed by selective protection of the
primary alcohol led to trityl ether 9 (81% yield for two
steps). Benzylation of the remaining hydroxyls and
deprotection of the trityl group delivered alcohol 10 in
91% yield (two steps). Iodination of 10 under the standard
conditions delivered 11 in 84% yield. Conversion of 11 to 6
was best achieved by treatment of 11 with sodium hydride in
DMF, affording exocyclic enol ether 6 in high yield.
Table 1. Reduction of 13 under a variety of conditions
Entry
Reagents and conditions
dr (5/epi-5)a
Yield (%)
1
2
3
4
5
6
7
NaBH4, CeCl3·7H2O, MeOH, 0 8C
NaBH4, CeCl3·7H2O, MeOH/THF (1:1), 0 8C
LiBH4, CeCl3·7H2O, MeOH/THF (1:1), 278 8C
LiBH4, CeCl3·7H2O, MeOH/THF (1:1), 0 8C
LiAlH4, THF 0 8C
3.7:1
4.0:1
2.8:1
5.3:1
1:1
97
88
86
98
Quant.
84
96
LiAlH(Ot-Bu)3 THF, 0 8C
DiBALH, CH2Cl2, 278 8C
1:1
1:1.1
a
1
Estimated by H NMR (400 MHz).

H. Fuwa et al. / Tetrahedron 60 (2004) 5341–5352
5343
subjected to Sharpless asymmetric epoxidation using (þ)-
diethyl tartarate as a chiral auxiliary to afford hydroxyl
epoxide 15. The minor C29 epimer was readily separated
during these transformations. To install the C27 methyl
group, hydroxyl epoxide 15 was exposed to trimethyl-
aluminum (AlMe3) in hexane/CH2Cl2.13 Surprisingly,
however, the only isolatable product was strained
bicyclic compound 16, whose structure was confirmed by
1H NMR analysis and NOE experiments on the correspond-
ing bis(acetate) 17 (Fig. 3). This outcome can be explained
by an intramolecular SN2 attack of the C31 benzyloxy
group to the oxirane activated by AlMe3. Although such
reaction is undesirable in this case, it is interesting that the
strained bicycle 16 was constructed in a relatively simple
manner.
Figure 2. Stereochemical confirmation of 4 based on 1H NMR analysis.
The benzyl groups were replaced with methyl groups for clarity.
stereochemistry at C29 was unambiguously confirmed by
1H NMR analysis (Fig. 2).
2.4. Elaboration of the C26 and C27 stereocenters via
asymmetric reactions
2.3. Initial attempt to construct the C26 and C27
stereocenters
With the above result in mind, we intended to elaborate the
C26 and C27 stereocenters using asymmetric alkylation and
epoxidation. To this end, ester 4 was reduced with LiAlH4
and the double bond was saturated by diimde reduction
using p-toluenesulfonyl hydrazide (p-TsNHNH2) and
aqueous sodium acetate to afford alcohol 18 (Scheme 4).
At this stage, the undesired C29 epimer was easily separated
by flash chromatography. Tosylation, displacement with
sodium cyanide, and hydrolysis under basic conditions led
to carboxylic acid 19 in 84% overall yield from 18
(Scheme 4). Coupling14 of 19 with (R)-(þ)-4-benzyl-2-
oxazolidinone furnished oxazolidinone 20 in 92% yield.
The C27 methyl group was successfully incorporated by
asymmetric alkylation15 of 20 under the standard conditions
(NaHMDS, MeI, THF, 278 8C), affording 21 in 93% yield as
a single isomer by 1H NMR (400 MHz). The chiral auxiliary
was reductively removed with LiAlH4 to give alcohol 22.
Oxidation, Wittig reaction of the derived aldehyde, and
subsequent DIBALH reduction gave allylic alcohol 23 (98%
yield for the three steps). Sharpless epoxidation of 23 afforded
hydroxyl epoxide 24 as a single stereoisomer, which was
iodinated and reduced with zinc, giving rise to allylic alcohol
25, therebyestablishingtheC26stereocenter. Protectionofthe
resultant hydroxyl group with t-butyldimethylsilyl trifluoro-
methanesulfonate (TBSOTf) and Et3N, oxidative cleavage of
the double bond, and subsequent reduction of the derived
aldehyde led to alcohol 26 (83% yield for the four steps).
Finally, iodination of 26 under standard conditions furnished
iodide 2 in 97% yield.
Stereoselective incorporation of the C26 hydroxyl and C27
methyl groups is seemingly challenging because they locate
remote from other stereocenters. Our initial strategy toward
the construction of the C26 and C27 stereocenters is
summarized in Scheme 3. Reduction of ester 4 with
DIBALH followed by Wittig reaction gave enoate 14.
After reduction of 14, the resultant allylic alcohol was
Scheme 3. Reagents and conditions: (a) DIBALH, CH2Cl2, 278 8C;
(b) Ph3PvCHCO2Et, benzene, rt, 80% (two steps); (c) DIBALH, CH2Cl2,
˚
278 8C, 93%; (d) Ti(Oi-Pr)4, (þ)-DET, t-BuOOH, 4 A molecular sieves,
CH2Cl2, 220 8C, 65%; (e) AlMe3, hexane/CH2Cl2 (2:1), 278 to 0 8C;
(f) Ac2O, Et3N, DMAP, CH2Cl2, 0 8C to rt, 67% (two steps).
2.5. Synthesis of the C18–C24 sulfone
Synthesis of the C18–C24 sulfone 3 was performed based
on Julia coupling as a key step, which is delineated in
Scheme 5. Iodination of alcohol 27 followed by treatment
with PhSO2Na gave sulfone 28 in 75% yield for the two
steps. Coupling of sulfone anion derived from 28 with
known aldehyde 291b (89% yield), acylation and the ensuing
exposure to Na(Hg) in buffered methanol afforded olefin 30
(E/Z¼ca. 8:1) in 83% yield for the two steps. Deprotection
of the silyl group with TBAF gave alcohol 31. Treatment of
31 with PhSSPh in the presence of n-Bu3P followed by
mCPBA oxidation of the resultant phenyl sulfide afforded
sulfone 3 in 75% yield for the two steps.
Figure 3. Confirmation of the structure of 17. The benzyl group was
replaced with a methyl group for clarity.

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H. Fuwa et al. / Tetrahedron 60 (2004) 5341–5352
Scheme 4. Reagents and conditions: (a) LiAlH4, THF, 0 8C, quant.; (b) p-TsNHNH2, aq. NaOAc, DME, 95 8C, 80%; (c) p-TsCl, Et3N, DMAP, CH2Cl2, rt,
92%; (d) NaCN, DMSO, 60 8C, 91%; (e) KOH, aq. EtOH, reflux, quant.; (f) PivCl, Et3N, THF, 278 to 0 8C; LiCl, (R)-(2)-4-benzyl-2-oxazolidinone, rt, 92%;
(g) NaHMDS, MeI, THF, 278 8C, 93%; (h) LiAlH4, THF, 0 8C, 91%; (i) (COCl)2, DMSO, Et3N, CH2Cl2, 278 8C to rt; (j) Ph3PvCHCO2Et, toluene, 80 8C;
˚
(k) DIBALH, CH2Cl2, 278 8C, 98% (three steps); (l) Ti(Oi-Pr)4, (2)-DET, t-BuOOH, 4 A molecular sieves, CH2Cl2, 220 8C, 99%; (m) I2, PPh3, imidazole,
THF, rt; (n) Zn, AcOH, EtOH/CH2Cl2, rt, 97% (two steps); (o) TBSOTf, Et3N, CH2Cl2, 0 8C; (p) OsO4, NMO, THF/H2O, rt; (q) NaIO4, THF/pH 7 buffer, rt;
(r) NaBH4, MeOH, 0 8C, 83% (four steps); (s) I2, PPh3, imidazole, benzene, rt, 97%.
2.6. Completion of the synthesis
With requisite segments in hand, we then turned our
attention to the crucial coupling stage. Gratifyingly, union
of iodide 2 and sulfone 3 could be efficiently and
conveniently achieved (Scheme 6). Thus, sulfone 3 with
LiHMDS followed by addition of HMPA and iodide 2
delivered coupling product 32 in 90% yield. The resultant
phenylsulfonyl group was removed by treatment with
Na(Hg) in buffered methanol, leading to 1 in 71% yield.
Scheme 5. Reagents and conditions: (a) I2, PPh3, imidazole, THF, rt;
(b) PhSO2Na, DMF, rt, 75% (two steps); (c) 28 (2 equiv.), n-BuLi, THF,
3. Conclusion
278 8C; 29, 278 8C, 89%; (d) Ac2O, Et3N, DMAP, CH2Cl2, 0 8C to rt;
(e) 5% Na(Hg), Na2HPO4, MeOH, 0 8C, 83% (two steps), E/Z¼ca. 8:1;
We have completed the stereoselective synthesis of the
C18–C34 fragment of antascomicin A. The key features of
the present synthesis are (i) an efficient and stereoselective
(f) TBAF, THF, rt, quant.; (g) PhSSPh, n-Bu3P, DMF, rt; (h) mCPBA,
NaHCO3, CH2Cl2, 0 8C to rt, 75% (two steps).
construction of the C29–C34 cyclohexyl moiety based on
catalytic Ferrier carbocyclization and Johnson–Claisen
rearrangement and (ii) a convergent assembly of the C25–
C34 and C18–C24 segments via sulfone anion coupling.
Further efforts toward the total synthesis of antascomicin A
are currently underway and will be reported in due course.
4. Experimental
4.1. General methods
Scheme 6. Reagents and conditions: (a) 3, LiHMDS, THF, 278 to 0 8C; 2,
HMPA, rt, 90%; (b) 5% Na(Hg), Na2HPO4, THF/MeOH, 0 8C to rt, 71%.
All reactions sensitive to air and/or moisture were carried

H. Fuwa et al. / Tetrahedron 60 (2004) 5341–5352
5345
out under an atmosphere of argon in oven-dried glassware
with anhydrous solvents. All anhydrous solvents were
purchased from Wako Pure Chemicals Co. Inc. and used
without further drying. Triethylamine were distilled from
calcium hydride under argon atmosphere. Lithium chloride
was dried with heating under high vacuum prior to use. All
other reagents purchased were of the highest commercial
quality and used as received unless otherwise stated.
Analytical thin layer chromatography was carried out
using E. Merck silica gel 60 F254 plates (0.25 mm
thickness). Column chromatography was performed on
Kanto Chemical silica gel 60N (spherical, neutral). Flash
chromatography was carried out using Fuji Silysia silica gel
BW300 (200–400 mesh). Optical rotations were recorded
on a JASCO DIP-1000 digital polarimeter. Infrared spectra
spectra were recorded on a JASCO FT/IR-420 spectrometer.
1H and 13C NMR spectra were recorded on a JEOL JNM-
LA400 or JNM-LA500 spectrometer. Chemical shifts are
reported in ppm and tetramethylsilane was used as the
internal standard. Coupling constants (J) are reported in
hertz (Hz). The following abbreviations are used to
designate the multipilicities: s¼singlet, d¼doublet, t¼
triplet, m¼multiplet, br¼broad. Low- and high-resolution
mass spectra were recorded on a JEOL SX-102A mass
spectrometer under fast atom bombardment (FAB) contions
using m-nitrobenzyl alcohol (NBA) as a matrix.
NMR (400 MHz, CDCl3) d 7.47–7.26 (m, 15H), 4.77 (br s,
1H), 3.92 (m, 1H), 3.61 (m, 1H), 3.44–3.37 (m, 3H), 3.31 (s,
3H), 2.76 (br, 1H), 2.50 (br, 1H), 2.11 (m, 1H), 1.66 (m,
1H); 13C NMR (100 MHz, CDCl3) d 143.6, 128.6, 128.3,
128.0, 127.2, 98.5, 87.3, 74.9, 69.4, 68.9, 64.9, 54.7, 36.7;
HRMS (FAB) calcd for C26H28O5Na [(MþNa)þ] 443.1834,
found 443.1791.
4.1.2. Primary alcohol 10. To a solution of trityl ether 9
(11.82 g, 28.14 mmol) in DMF (100 mL) was added NaH
(60% in oil, 5.30 g, 132.5 mmol). The mixture was heated at
50 8C for 20 min and then treated with BnBr (11.8 mL,
99.2 mmol). After being stirred at 50 8C for 50 min, the
reaction was cooled to 0 8C and quenched with methanol.
The resultant mixture was diluted with ethyl acetate, washed
with water, saturated aqueous ammonium chloride and
brine, dried (Na2SO4), filtered, and concentrated under
reduced pressure to give crude bis(benzyl)ether, which was
used in the next step without further purification.
To a solution of the above bis(benzyl)ether in MeOH/CHCl3
(5:1, 180 mL) was added p-TsOH·H2O (1.61 g, 8.46 mmol).
After being stirred at room temperature overnight, the
reaction was quenched with triethylamine and the mixture
concentrated under reduced pressure. Purification of the
residue by column chromatography (silica gel, 20!40%
ethyl acetate/hexane) gave primary alcohol 10 (9.55 g, 95%
for the two steps) as a colorless clear oil. 10: [a]3D0¼þ69 (c
0.43, CHCl3); IR (film) 3446, 2925, 1453, 1365, 1206, 1097,
1049, 738, 698 cm21; 1H NMR (400 MHz, CDCl3) d 7.34–
7.26 (m, 10H), 4.95 (d, J¼10.7 Hz, 1H), 4.81 (br s, 1H),
4.71–4.62 (m, 3H), 3.99 (ddd, J¼11.7, 8.8, 4.9 Hz, 1H),
3.85–3.72 (m, 2H), 3.64 (m, 1H), 3.50 (m, 1H), 3.30 (s, 3H),
2.29 (ddd, J¼14.6, 4.9, ,1 Hz, 1H), 1.80 (br, 1H), 1.66
(ddd, J¼14.6, 11.7, 3.9 Hz, 1H); HRMS (FAB) calcd for
C21H26O5Na [(MþNa)þ] 381.1678, found 381.1659.
4.1.1. Trityl ether 9. To a stirred solution of tri-O-acetyl-D-
glucal 7 (10.0 g, 36.7 mmol) in acetonitrile (90 mL) were
added MeOH (2.30 mL, 56.8 mmol) and Ph3P·HBr (2.53 g,
7.37 mmol). After being stirred at room temperature
overnight, the reaction mixture was concentrated under
reduced pressure. Purification of the residue by column
chromatography (silica gel, 25!40% ethyl acetate/hexane)
gave methyl glucoside 8 (10.05 g, 90%) as a 10:1 mixture of
anomers. Data for major anomer: 1H NMR (400 MHz,
CDCl3) d 5.31 (ddd, J¼11.8, 9.8, 5.9 Hz, 1H), 5.02 (dd,
J¼10.7, 9.8 Hz, 1H), 4.85 (br s, 1H), 4.32 (dd, J¼12.7,
4.9 Hz, 1H), 4.08 (dd, J¼12.7, 1.9 Hz, 1H), 3.95 (ddd,
J¼10.7, 4.9, 1.9 Hz, 1H), 3.35 (s, 3H), 2.25 (ddd, J¼12.7,
5.9, ,1 Hz, 1H), 2.10 (s, 3H), 2.04 (s, 3H), 2.01 (s, 3H),
1.82 (ddd, J¼12.7, 11.8, 3.9 Hz, 1H).
4.1.3. Iodide 11. To a solution of primary alcohol 10
(9.50 g, 26.5 mmol) in THF (150 mL) were added imidazole
(3.61 g,
53.0 mmol),
triphenylphosphine
(12.5 g,
47.7 mmol) and iodine (12.8 g, 50.4 mmol). After being
stirred at room temperature for 30 min, the reaction was
quenched with saturated aqueous Na2SO3. The resultant
mixture was diluted with ethyl acetate, washed with water
and brine, dried (Na2SO4), filtered, and concentrated under
reduced pressure. Purification of the residue by column
chromatography (silica gel, 10% ethyl acetate/hexane) gave
iodide 11 (11.39 g, 92%) as a colorless clear oil. 11:
[a]3D0¼þ49 (c 1.12, CHCl3); IR (film) 2930, 2901, 1452,
To a solution of the above methyl glucoside 8 (10.05 g,
33.1 mmol) in MeOH (100 mL) was added NaOMe (1 M in
MeOH, 3.30 mL, 0.330 mmol). After being stirred at room
temperature for 1 h, the reaction was quenched by addition
of Amberlystw and the mixture was filtered and concen-
trated under reduced pressure to give crude triol, which was
used in the next reaction without further purification.
1
1366, 1213, 1131, 1108, 1048, 738, 695 cm21; H NMR
(400 MHz, CDCl3) d 7.36–7.27 (m, 10H), 5.00 (d,
J¼10.7 Hz, 1H), 4.82 (br s, 1H), 4.72 (d, J¼10.7 Hz, 1H),
4.63 (d, J¼11.7 Hz, 1H), 4.60 (d, J¼11.7 Hz, 1H), 4.00
(ddd, J¼11.7, 8.8, 4.9 Hz, 1H), 3.53 (m, 1H), 3.46–3.30 (m,
6H), 2.31 (ddd, J¼12.7, 4.9, ,1 Hz, 1H), 1.69 (ddd,
J¼12.7, 11.7, 3.9 Hz, 1H); HRMS (FAB) calcd for
C21H25IO4Na [(MþNa)þ] 491.0695, found 491.0728.
To a solution of the above triol in CH2Cl2/pyridine (4:1, v/v,
100 mL) were added DMAP (0.40 g, 3.27 mmol) and
triphenylmethyl chloride (11.06 g, 39.7 mmol). After
being stirred at room temperature overnight, the reaction
mixture was diluted with ethyl acetate and washed with
water and brine. The organic layer was dried (Na2SO4),
filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by column chromatography (silica gel,
40!50% ethyl acetate/hexane) gave trityl ether 9 (11.82 g,
85% for the two steps) as a colorless clear oil. 9: [a]3D0¼þ79
(c 0.42, CHCl3); IR (film) 3411, 2931, 1490, 1446, 1209,
4.1.4. Exocyclic enol ether 6. To a solution of iodide 11
(4.96 g, 10.6 mmol) in DMF (100 mL) at 0 8C was added
NaH (60% in oil, 2.12 g, 53.0 mmol). After being stirred at
room temperature overnight, the reaction was quenched
with water at 0 8C. The resultant mixture was diluted with
1
1128, 1050, 986, 955, 900, 764, 747, 705, 679 cm21; H

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H. Fuwa et al. / Tetrahedron 60 (2004) 5341–5352
ethyl acetate, washed with water and brine, dried (Na2SO4),
filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by column chromatography (silica gel,
10% ethyl acetate/hexane) gave exocylic enol ether 6
(3.41 g, 94%) as a colorless clear oil. 6: [a]2D5¼þ24 (c 2.63,
CHCl3); IR (film) 2931, 2857, 1657, 1452, 1361, 1211,
6.82 mmol) in THF/MeOH (1:1, v/v, 70 mL) at 0 8C were
added CeCl3·7H2O (5.08 g, 13.6 mmol) and LiBH4
(594 mg, 27.3 mmol). After being stirred at 0 8C for 1 h,
the reaction was quenched with saturated NH4Cl. The
resultant mixture was diluted with ethyl acetate, washed
with water and brine. The combined aqueous layer was back
extracted with ethyl acetate. The organic layers were
combined, dried (Na2SO4), filtered, and concentrated
under reduced pressure. Purification of the residue by
column chromatography (silica gel, 20% ethyl acetate/
hexane) gave an inseparable 5.3:1 mixture of allylic alcohol
5 and its epimer (2.07 g, 98%) as a colorless clear oil. 5:
[a]3D0¼þ18 (c 0.55, CHCl3); IR (film) 3437, 2919, 2864,
1
1111, 1039, 734, 697 cm21; H NMR (400 MHz, C6D6) d
7.32 (d, J¼6.8 Hz, 1H), 7.22 (d, J¼8.0 Hz, 1H), 7.17–7.05
(m, 8H), 4.95 (apparently s, 1H), 4.86 (apparently s, 1H),
4.68 (d, J¼11.8 Hz, 1H), 4.65–4.60 (m, 3H), 4.51 (d,
J¼12.7 Hz, 1H), 4.38 (d, J¼12.7 Hz, 1H), 4.03 (ddd, J¼9.7,
7.8, 3.9 Hz, 1H), 3.90 (d, J¼7.8 Hz, 1H), 3.19 (s, 3H), 2.20
(ddd, J¼13.6, 4.8, 3.9 Hz, 1H), 1.73 (ddd, J¼13.6, 9.7,
3.9 Hz, 1H); 13C NMR (100 MHz, C6D6) d 155.7, 139.3,
139.1, 128.6, 128.5, 128.3, 127.9, 127.8, 127.7, 127.6,
100.1, 96.7, 79.9, 76.4, 73.3, 72.2, 55.0, 35.6; HRMS (FAB)
calcd for C21H24O4Na [(MþNa)þ] 363.1572, found
363.1530.
1
1453, 1383, 1362, 1101, 1041, 737, 696 cm21; H NMR
(400 MHz, CDCl3, major isomer) d 7.36–7.27 (m, 10H),
5.69–5.65 (m, 2H), 4.92 (d, J¼11.8 Hz, 1H), 4.71 (d,
J¼11.8 Hz, 1H), 4.67 (d, J¼11.7 Hz, 1H), 4.63 (d,
J¼11.7 Hz, 1H), 4.17 (m, 1H), 3.80 (dd, J¼8.0, 6.0 Hz,
1H), 3.65 (m, 1H), 2.52 (m, 1H), 2.40 (d, J¼5.9 Hz, 1H),
2.25 (m, 1H); HRMS (FAB) calcd for C20H22O3Na
[(MþNa)þ] 333.1467, found 333.1501.
4.1.5. Hydroxy ketone 12. To a solution of exocyclic enol
ether 6 (507.7 mg, 1.493 mmol) in acetone/water (2:1, v/v,
15 mL) was added Hg(OCOCF3)2 (64 mg, 0.15 mmol).
After being stirred at room temperature overnight, the
reaction mixture was concentrated under reduced pressure
to remove acetone. The resultant mixture was diluted with
water and extracted with ethyl acetate. The organic layer
was dried (Na2SO4), filtered, and concentrated under
reduced pressure. Purification of the residue by flash
chromatography (silica gel, 50% ethyl acetate/hexane)
gave hydroxy ketone 12 (460.1 mg, 95%) as a 10:1 mixture
of diastereomers. 12: [a]3D0¼222 (c 0.61, CHCl3); IR (film)
3439, 2926, 1727, 1453, 1359, 1207, 1107, 1026, 740,
4.1.8. Ester 4. To a solution of allylic alcohol (6.16 g,
19.9 mmol) in CH3C(OEt)3 (200 mL) was added n-pro-
pionic acid (0.200 mL) and the resultant mixture was heated
at 140 8C for 1 day. After cooling, the mixture was
concentrated under reduced pressure. Purification of the
residue by column chromatography (silica gel, 5!8% ethyl
acetate/hexane) gave an inseparable mixture of ester 4 and
its C29 epimer (5.78 g, 76%) as a colorless clear oil. 4:
[a]3D0¼266 (c 0.57, CHCl3); IR (film) 2924, 2871, 1732,
1
1453, 1371, 1159, 1094, 1028, 736, 697 cm21; H NMR
1
698 cm21; H NMR (400 MHz, CDCl3, major isomer) d
(400 MHz, CDCl3, major isomer) d 7.37–7.25 (m, 10H),
5.67 (dt, J¼10.3, 2.3 Hz, 1H), 5.61 (dd, J¼10.3, 1.4 Hz,
1H), 4.76–4.66 (m, 4H), 4.18–4.08 (m, 3H), 3.70 (ddd,
J¼11.9, 7.3, 3.7 Hz, 1H), 2.75 (m, 1H), 2.36 (dd, J¼15.3,
7.1 Hz, 1H), 2.27 (dd, 1H, J¼15.3, 7.8 Hz), 2.20 (ddd,
J¼12.8, 3.7, 3.7 Hz, 1H), 1.56 (ddd, J¼12.8, 11.9, 11.9 Hz,
1H), 1.26 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3,
major isomer) d 172.1, 138.8 (£2), 132.1, 128.4 (£2), 128.3,
127.8, 127.73, 127.70, 127.67, 127.5, 127.3, 79.2, 79.0,
72.0, 71.8, 60.5, 40.5, 33.3, 33.0, 14.3; HRMS (FAB) calcd
for C24H28O4Na [(MþNa)þ] 403.1885, found 403.1882.
7.39–7.25 (m, 10H), 4.82 (d, J¼11.7 Hz, 1H), 4.74 (d,
J¼11.7 Hz, 1H), 4.61 (d, J¼11.7 Hz, 1H), 4.54 (d,
J¼11.7 Hz, 1H), 4.33 (br, 1H), 4.04 (m, 1H), 3.98 (m,
1H), 2.68–2.53 (m, 2H), 2.32 (m, 1H), 2.02 (m, 1H), 1.74
(m, 1H); 13C NMR (100 MHz, CDCl3, major isomer) d
206.1, 138.2, 137.6, 128.41, 128.39, 128.0, 127.8, 127.7,
85.7, 77.3, 76.7, 72.9, 65.9, 47.7, 36.5; HRMS (FAB) calcd
for C20H22O4Na [(MþNa)þ] 349.1416, found 349.1454.
4.1.6. Enone 13. To a solution of hydroxy ketone 12 (7.87 g,
24.1 mmol) in CH2Cl2 (200 mL) at 0 8C were added Et3N
(20.0 mL, 143.5 mmol) and MsCl (5.60 mL, 72.4 mmol).
After being stirred at room temperature for 90 min, the
reaction mixture was diluted with ethyl acetate, washed with
1 M aqueous HCl, saturated aqueous NaHCO3 and brine,
dried (Na2SO4), filtered, and concentrated under reduced
pressure. Purification of the residue by column chromatog-
raphy (silica gel, 20!30% ethyl acetate/hexane) gave
enone 13 (7.42 g, quantitative) as a colorless clear oil. 13:
IR (film) 3032, 2930, 2870, 1688, 1621, 1496, 1453, 1387,
4.1.9. Enoate 14. To a solution of ester 4 (1.37 g,
3.61 mmol) in CH2Cl2 (36 mL) at 278 8C was added
DIBALH (1.01 M solution in hexane, 3.93 mL, 3.97 mL).
After being stirred at 278 8C for 30 min, the reaction was
quenched with saturated aqueous potassium sodium tartrate.
The resultant mixture was diluted with ethyl acetate and
stirred vigorously at room temperature until the layers
became clear. The organic layer was separated and washed
with brine, dried (Na2SO4), filtered, and concentrated under
reduced pressure. The residue was passed through a pad of
silica gel to give aldehyde (0.97 g) as a colorless clear oil,
which was used in the next step without further purification.
1
1360, 1115, 1025, 739, 697 cm21; H NMR (400 MHz,
CDCl3) d 7.44–7.27 (m, 10H), 6.83 (ddd, J¼9.7, 5.8,
2.9 Hz, 1H), 6.04 (d, J¼9.7 Hz, 1H), 5.02 (d, J¼11.7 Hz,
1H), 4.80 (d, J¼11.7 Hz, 1H), 4.73 (d, J¼11.7 Hz, 1H), 4.65
(d, J¼11.7 Hz, 1H), 4.05 (d, J¼8.8 Hz, 1H), 3.94 (m, 1H),
2.78 (ddd, J¼18.5, 5.8, 4.9 Hz, 1H), 2.51 (ddd, J¼18.5, 7.8,
2.9 Hz, 1H); HRMS (FAB) calcd for C20H20O3Na
[(MþNa)þ] 331.1310, found 331.1336.
To a solution of the above aldehyde (0.97 g) in benzene
(30 mL) was added Ph3PvCHCO2Et (1.51 g, 4.33 mmol).
After being stirred at room temperature overnight, the
reaction mixture was concentrated under reduced pressure.
Purification of the residue by flash chromatography (silica
gel, 10% ethyl acetate/hexane) gave enoate 14 (1.17 g, 80%
4.1.7. Allylic alcohol 5. To a solution of enone 13 (2.10 g,

H. Fuwa et al. / Tetrahedron 60 (2004) 5341–5352
5347
for the two steps) as a colorless clear oil. 14: [a]2D6¼2100 (c
;
1267, 1202, 1158, 1094, 736, 698 cm21 1H NMR
v/v, 30 mL) at 278 8C was added AlMe3 (1.00 M solution
in hexane, 5.34 mL, 5.34 mmol). The reaction mixture was
allowed to warm to 0 8C over 3 h and the reaction was
quenched with saturated aqueous potassium sodium tartrate.
The resultant mixture was diluted with ethyl acetate and
stirred vigorously at room temperature until layers became
clear. The organic layer was separated and the aqueous layer
was extracted with ethyl acetate three times. The organic
layers were combined, dried (Na2SO4), filtered, and
concentrated under reduced pressure. Purification of the
residue by flash chromatography (silica gel, 60!75% ethyl
acetate/hexane) gave bicyclic compound 16 (491.2 mg,
95%) as a pale yellow oil. 16: [a]2D6¼2127 (c 0.79, CHCl3);
IR (film) 3423, 2925, 2877, 1452, 1398, 1059, 738,
0.46, CHCl3); IR (film) 2861, 1717, 1654, 1452, 1365, 1310,
(400 MHz, CDCl3) d 7.37–7.26 (m, 10H), 6.90 (dt,
J¼15.6, 7.8 Hz, 1H), 5.85 (d, J¼15.6 Hz, 1H), 5.64 (d,
J¼9.8 Hz, 1H), 5.60 (d, J¼9.8 Hz, 1H), 4.77–4.62 (m, 4H),
4.19 (q, J¼6.8 Hz, 2H), 4.11 (m, 1H), 3.67 (ddd, J¼11.7,
7.8, 3.9 Hz, 1H), 2.40 (m, 1H), 2.28–2.11 (m, 3H), 1.36–
1.27 (m, 4H); 13C NMR (100 MHz, CDCl3) d 166.3, 146.1,
138.8 (£2), 132.1, 128.40, 128.37, 128.35, 127.8, 127.7,
127.52, 127.47, 123.4, 79.6, 79.3, 72.1, 71.8, 60.3, 38.5,
35.3, 33.6, 14.3; HRMS (FAB) calcd for C26H30O4Na
[(MþNa)þ] 429.2042, found 429.2036.
1
4.1.10. Hydroxy epoxide 15. To a solution of enoate 14
(1.28 g, 3.15 mmol) in CH2Cl2 (30 mL) at 278 8C was
added DIBALH (1.01 M solution in hexane, 8.75 mL,
8.84 mmol). After being stirred at 278 8C for 2 h, the
reaction was quenched with saturated aqueous potassium
sodium tartrate. The resultant mixture was diluted with ethyl
acetate and stirred vigorously at room temperature until
layers became clear. The organic layer was separated and
washed with brine, dried (Na2SO4), filtered, and concen-
trated under reduced pressure. Purification of the residue by
flash chromatography (silica gel, 30!40% ethyl acetate/
hexane) gave allylic alcohol (1.07 g, 93%) as a colorless
clear oil: [a]2D6¼2101 (c 0.62, CHCl3); IR (film) 3435,
698 cm21; H NMR (400 MHz, CDCl3) d 7.36–7.26 (m,
5H), 6.08–6.06 (m, 2H), 4.66 (d, J¼11.7 Hz, 1H), 4.58 (d,
J¼11.7 Hz, 1H), 4.17 (br s, 1H), 3.80–3.55 (m, 5H), 2.62
(d, J¼4.9 Hz, 1H), 2.55 (br s, 1H), 2.35 (m, 1H), 1.83–1.73
(m, 2H), 1.64 (ddd, J¼12.7, 11.7, 3.9 Hz, 1H), 1.42 (m, 1H);
13C NMR (100 MHz, CDCl3) d 138.3, 133.9, 128.8, 128.4,
128.3, 127.7, 127.6, 73.9, 73.7, 71.5, 70.9, 70.6, 63.4, 29.3,
27.8, 26.7; HRMS (FAB) calcd for C17H22O4Na
[(MþNa)þ] 313.1416, found 313.1381.
4.1.12. Bis(acetate) 17. To a solution of bicyclic compound
16 (491.2 mg, 1.69 mmol) in CH2Cl2 (15 mL) 0 8C were
added Et3N (1.90 mL, 13.6 mmol), DMAP (62 mg,
0.507 mmol) and Ac2O (1.00 mL, 10.6 mmol). After being
stirred at room temperature for 2 h 15 min, the reaction was
quenched with MeOH at 0 8C. The resultant mixture was
diluted with ethyl acetate, washed with 1 M aqueous HCl,
saturated aqueous NaHCO3 and brine, dried (Na2SO4),
filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by flash chromatography (silica gel,
20!30% ethyl acetate/hexane) gave bis(acetate) 17
(421.4 mg, 67%) as a colorless clear oil. 17: [a]2D5¼2139
(c 0.61, CHCl3); IR (film) 2927, 2850, 1743, 1451, 1370,
1225, 1059, 738, 699 cm21; 1H NMR (400 MHz, CDCl3) d
7.37–7.26 (m, 5H), 6.07–6.05 (m, 2H), 5.00 (ddd, J¼7.1,
6.0, 2.5 Hz, 1H), 4.68 (d, J¼12.1 Hz, 1H), 4.56 (d,
J¼12.1 Hz, 1H), 4.41 (dd, J¼12.1, 2.5 Hz, 1H), 4.15 (br,
1H), 4.14 (ddd, J¼12.1, 7.1 Hz, 1H), 3.78 (ddd, J¼11.7, 6.0,
3.2 Hz, 1H), 3.69 (br, 1H), 2.55 (br, 1H), 2.07 (s, 3H), 2.02
(s, 3H), 1.76 (br, 2H), 1.58 (ddd, J¼12.6, 12.1, 3.7 Hz, 1H),
1.45 (m, 1H); 13C NMR (100 MHz, CDCl3) d 170.8, 170.3,
138.4, 133.6, 129.0, 128.4, 127.7, 127.64, 127.60, 73.75,
73.70, 71.5, 70.5, 67.7, 62.9, 30.0, 27.5, 26.8, 21.0, 20.8;
HRMS (FAB) calcd for C21H26O6Na [(MþNa)þ] 397.1627,
found 397.1613.
1
2917, 2858, 1452, 1094, 1028, 972, 737, 697 cm21; H
NMR (400 MHz, CDCl3) d 7.38–7.26 (m, 10H), 5.70–5.61
(m, 4H), 4.77–4.68 (m, 4H), 4.12–4.08 (m, 3H), 3.67 (ddd,
J¼11.7, 7.8, 3.9 Hz, 1H), 2.32 (m, 1H), 2.16–2.03 (m, 3H),
1.35–1.24 (m, 2H); 13C NMR (100 MHz, CDCl3) d 138.9,
138.8, 132.9, 131.4, 129.8, 128.4, 128.3, 127.8, 127.7,
127.5, 127.0, 79.9, 79.6, 72.0, 71.8, 63.6, 38.6, 36.0, 33.6;
HRMS (FAB) calcd for C24H28O3Na [(MþNa)þ] 387.1936,
found 387.1966.
To a solution of allylic alcohol (1.00 g, 2.75 mmol) in
˚
CH2Cl2 (30 mL) were added 4 A molecular sieves (1.00 g)
and (þ)-diethyl tartrate (0.100 mL, 0.584 mmol). The
mixture was cooled to 220 8C and treated with titanium
isopropoxide (0.120 mL, 0.407 mmol). After being stirred
at 220 8C for 30 min, t-butyl hydroperoxide (5 M solution
in decane, 0.830, 4.15 mL) was introduced. After being
stirred at 220 8C overnight, the reaction was quenched with
saturated aqueous Na2SO4. The resultant mixture was
filtered through Celitew and the filtrate was extracted with
ethyl acetate. The organic layers were combined, dried
(Na2SO4), filtered, and concentrated under reduced
pressure. Purification of the residue by flash chromato-
graphy (silica gel, 40!50% ethyl acetate/hexane) gave
hydroxy epoxide 15 (674.8 mg, 65%) as a colorless clear oil.
4.1.13. Alcohol 18. To a solution of ester 4 (5.78 g,
15.2 mmol) in THF (120 mL) at 0 8C was added LiAlH4
(692 mg, 18.2 mmol). After being stirred at 0 8C for 1 h, the
mixture was successively treated with 15% aqueous NaOH
and water, and the precipitate formed was removed by
filtration. The filtrate was concentrated under reduced
pressure. Purification of the residue by column chromato-
graphy (silica gel, 40% ethyl acetate/hexane) gave an
inseparable mixture of alcohol and its C29 epimer (5.13 g,
quantitative) as a colorless clear oil: [a]3D0¼282 (c 0.35,
CHCl3); IR (film) 3436, 2924, 2862, 1452, 1072, 736,
1
15: H NMR (400 MHz, CDCl3) d 7.38–7.26 (m, 10H),
5.69–5.67 (m, 2H), 4.77–4.67 (m, 2H), 4.12 (dd, J¼7.8,
2.9 Hz, 1H), 3.91 (ddd, J¼12.7, 4.9, 2.0 Hz, 1H), 3.72–3.61
(m, 2H), 3.02 (m, 1H), 2.91 (m, 1H), 2.49 (m, 1H), 2.01 (ddd,
J¼12.6, 4.0, 3.9 Hz, 1H), 1.73 (m, 1H), 1.69–1.51 (m, 2H),
1.41 (ddd, J¼12.6, 11.7, 10.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 138.8 (£2), 132.2, 128.4, 127.8, 127.7, 127.5, 127.3,
79.5, 79.3, 72.1, 71.7, 61.4, 58.4, 53.9, 37.9, 34.3, 33.9.
1
4.1.11. Bicyclic compound 16. To a solution of hydroxy
epoxide 15 (674.8 mg, 1.78 mmol) in CH2Cl2/hexane (1:2,
697 cm21; H NMR (400 MHz, CDCl3, major isomer) d
7.37–7.26 (m, 10H), 5.64 (br, 2H), 4.77–4.68 (m, 4H), 4.12

5348
H. Fuwa et al. / Tetrahedron 60 (2004) 5341–5352
1
(m, 1H), 3.78–3.65 (m, 3H), 2.43 (m, 1H), 2.17 (ddd,
J¼11.9, 4.6, 3.7 Hz, 1H), 1.72–1.63 (m, 2H), 1.53 (m, 1H),
1.31 (ddd, J¼11.9, 11.9, 10.1 Hz, 1H); 13C NMR
(100 MHz, CDCl3, major isomer) d 138.9 (£2), 133.3,
128.38, 128.36, 128.34, 127.77, 127.75, 127.69, 127.5,
126.6, 79.8, 79.6, 72.0, 71.8, 60.3, 40.3, 33.7, 32.8; HRMS
(FAB) calcd for C22H26O3Na [(MþNa)þ] 361.1780, found
361.1738.
698 cm21; H NMR (400 MHz, CDCl3) d 7.37–7.26 (m,
10H), 4.79–4.67 (m, 4H), 3.44–3.36 (m, 2H), 2.35 (t,
J¼7.3 Hz, 2H), 2.14–2.07 (m, 2H), 1.74 (m, 1H), 1.60 (q,
J¼7.3 Hz, 2H), 1.51 (m, 1H), 1.34 (m, 1H), 1.03 (ddd,
J¼12.6, 12.1, 11.2 Hz, 1H), 0.94 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 139.04, 138.99, 128.34, 128.32, 127.7,
127.6, 127.5, 127.4, 119.6, 82.2, 81.4, 72.6, 72.3, 37.0, 34.8,
31.6, 29.9, 29.8, 15.0; HRMS (FAB) calcd for
C23H27NO2Na [(MþNa)þ] 372.1939, found 372.1942.
A solution of the above alcohol (5.13 g, 15.2 mmol) and
p-toluenesulfonyl hydrazide (28.3 g, 152 mmol) in DME
(80 mL) was heated at 95 8C. To this solution was added
dropwise aqueous NaOAc (19.9 g, 243 mmol) in water
(80 mL) over a period of 4 h, and the resultant mixture was
heated at 95 8C for further 1 h. After cooling, the resultant
mixture was diluted with ethyl acetate, washed with water
and brine, dried (Na2SO4), filtered, and concentrated under
reduced pressure. Purification of the residue by column
chromatography (silica gel, 35!40% ethyl acetate/hexane)
gave alcohol 18 (4.10 g, 80%) as a colorless clear oil. 18: IR
(film) 3435, 2925, 2863, 1453, 1100, 1070, 1027, 736,
To a solution of the above nitrile (3.40 g, 9.74 mmol) in
EtOH/water (1:1, v/v, 100 mL) was added KOH (5.47 g,
97.5 mmol) and the resultant mixture was heated under
reflux overnight. After cooling to room temperature, the
resultant mixture was acidified with 1 M aqueous HCl and
extracted with CHCl3. The combined organic layer was
dried (Na2SO4), filtered, and concentrated under reduced
pressure. Purification of the residue by column chromato-
graphy (silica gel, 5% methanol/chloroform) gave car-
boxylic acid 19 (3.58 g, quantitative) as a colorless clear oil.
19: [a]2D9¼213 (c 0.36, CHCl3); IR (film) 3446, 2927, 2863,
1707, 1453, 1100, 1071, 737, 698 cm21 1H NMR
;
1
697 cm21; H NMR (400 MHz, CDCl3) d 7.38–7.25 (m,
10H), 4.77–4.68 (m, 4H), 3.69–3.67 (m, 2H), 3.43–3.36
(m, 2H), 2.13–2.07 (m, 2H), 1.73 (m, 1H), 1.62–1.42 (m,
5H), 1.32 (m, 1H), 1.05 (ddd, J¼11.7, 11.4, 11.4 Hz, 1H),
0.94 (m, 1H); 13C NMR (100 MHz, CDCl3) d 139.2 (£2),
128.3 (£2), 127.7 (£2), 127.4 (£2), 82.5, 81.9, 72.4, 72.3,
60.7, 39.2, 37.7, 32.5, 30.6, 30.3; HRMS (FAB) calcd for
C22H28O3Na [(MþNa)þ] 363.1936, found 363.1890.
(400 MHz, CDCl3) d 7.37–7.25 (m, 10H), 4.77–4.67 (m,
4H), 3.42–3.35 (m, 2H), 2.38 (t, J¼7.6 Hz, 2H), 2.12–2.08
(m, 2H), 1.73 (m, 1H), 1.59 (q, J¼7.6 Hz, 2H), 1.42–1.24
(m, 2H), 1.02 (ddd, J¼12.4, 12.4, 11.0 Hz, 1H), 0.92 (m,
1H); 13C NMR (100 MHz, CDCl3) d 179.2, 139.1 (£2),
128.3 (£2), 127.7 (£2), 127.4 (£2), 82.4, 81.7, 72.4, 72.3,
37.3, 35.3, 31.6, 31.0, 30.20, 30.18.
4.1.14. Carboxylic acid 19. To a solution of alcohol 18
(4.10 g, 12.1 mmol) in CH2Cl2 (120 mL) were added Et3N
(6.75 mL, 48.4 mmol), DMAP (0.44 g, 3.60 mmol) and
p-toluenesulfonyl chloride (5.77 g, 30.3 mmol). After being
stirred at room temperature for 4 h, the reaction mixture was
diluted with ethyl acetate, washed with 1 M aqueous HCl,
saturated aqueous NaHCO3 and brine, dried (Na2SO4),
filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by column chromatography (silica gel,
10!20% ethyl acetate/hexane) gave tosylate (5.46 g, 92%)
as a colorless clear oil: [a]2D8¼29 (c 0.45, CHCl3); IR (film)
1H NMR (400 MHz, CDCl3) d 7.78 (d, J¼8.4 Hz, 2H),
7.36–7.26 (m, 12H), 4.73–4.62 (m, 4H), 4.05 (t,
J¼6.41 Hz, 2H), 3.35–3.30 (m, 2H), 2.43 (s, 3H), 2.06–
1.97 (m, 2H), 1.59–1.55 (m, 3H), 1.43 (m, 1H), 1.24 (m,
1H), 0.96 (ddd, J¼12.1, 12.1, 11.0 Hz, 1H), 0.85 (m, 1H);
13C NMR (100 MHz, CDCl3) d 144.8, 139.1, 139.0, 133.0,
129.9, 128.3, 127.9, 127.6, 127.43, 127.40, 82.2, 81.6, 72.4,
72.3, 68.4, 37.2, 35.1, 32.1, 30.1, 30.0, 21.6; HRMS (FAB)
calcd for C29H34O5SNa [(MþNa)þ] 517.2025, found
517.2017.
4.1.15. Oxazolidinone 20. To a solution of carboxylic acid
19 (1.30 g, 3.53 mmol) in THF (30 mL) was added Et3N
(0.980 mL, 7.03 mmol) and cooled to 278 8C. The reaction
mixture was treated with pivaloyl chloride (0.520 mL,
4.22 mmol) and gradually warmed to 0 8C over 90 min. The
reaction mixture was then treated with (R)-4-benzyl-2-
oxazolidinone (626 mg, 3.53 mmol) and LiCl (450 mg,
10.6 mmol) and stirred at room temperature overnight. The
resultant mixture was diluted with ethyl acetate, washed
with water and brine, dried (Na2SO4), filtered, and
concentrated under reduced pressure. Purification of the
residue by column chromatography (silica gel, 20!30%
ethyl acetate/hexane) gave oxazolidinone 20 (1.68 g, 92%)
as a colorless clear oil. 20: [a]2D7¼243 (c 0.36, CHCl3); IR
(film) 2925, 2861, 1780, 1699, 1452, 1386, 1354, 1211,
1098, 738, 699 cm21; 1H NMR (400 MHz, CDCl3) d 7.38–
7.20 (m, 15H), 4.77–4.66 (m, 5H), 4.20–4.16 (m, 2H),
3.42–3.38 (m, 2H), 3.29 (dd, J¼13.4, 3.4 Hz, 1H), 3.02–
2.87 (m, 2H), 2.76 (dd, J¼13.4, 9.4 Hz, 1H), 2.18–2.09 (m,
2H), 1.77 (m, 1H), 1.66–1.61 (m, 2H), 1.41 (m, 1H), 1.32
(m, 1H), 1.07 (ddd, J¼12.5, 12.5, 11.0 Hz, 1H), 0.96 (m,
1H); 13C NMR (100 MHz, CDCl3) d 173.2, 153.5, 139.2
(£2), 135.3, 129.4, 129.0, 128.34, 128.30, 127.68, 127.66,
127.39, 127.36, 82.5, 81.9, 72.34, 72.28, 66.2, 55.2, 37.9,
37.6, 35.4, 33.3, 30.7, 30.4, 30.3; HRMS (FAB) calcd for
C33H37NO5Na [(MþNa)þ] 550.2569, found 550.2576.
2925, 2864, 1452, 1360, 1175, 1097, 738, 697, 662 cm21
;
To a solution of the above tosylate (5.28 g, 10.7 mmol) in
DMSO (100 mL) was added NaCN (2.62 g, 53.5 mmol).
After being stirred at 60 8C for 4 h, the reaction mixture was
cooled to room temperature and diluted with ethyl acetate.
The organic layer was washed with water and brine, dried
(Na2SO4), filtered, and concentrated under reduced
pressure. Purification of the residue by column chromato-
graphy (silica gel, 25% ethyl acetate/hexane) gave nitrile
(3.40 g, 91%) as a colorless clear oil: [a]2D8¼29 (c 0.51,
CHCl3); IR (film) 2925, 2862, 1452, 1100, 1068, 1028, 737,
4.1.16. Alkylated product 21. To a solution of oxazolidi-
none 20 (4.54 g, 8.82 mmol) in THF (80 mL) at 278 8C was
added NaHMDS (1.0 M solution in THF, 12.3 mL,
12.3 mmol). The reaction mixture was stirred at 278 8C
for 1 h before methyl iodide (1.21 mL, 19.4 mmol) was
introduced. The resultant mixture was stirred at 278 8C for

H. Fuwa et al. / Tetrahedron 60 (2004) 5341–5352
5349
6 h and the reaction was quenched with saturated aqueous
NH4Cl at 240 8C. The resultant mixture was diluted with
ethyl acetate, washed with saturated aqueous NH4Cl and
brine, dried (Na2SO4), filtered, and concentrated under
reduced pressure. Purification of the residue by flash
chromatography (silica gel, 20% ethyl acetate/hexane)
gave alkylated product 21 (4.38 g, 94%) as a colorless
clear oil. 21: [a]2D9¼251 (c 1.15, CHCl3); IR (film) 2926,
2864, 1780, 1697, 1453, 1386, 1351, 1235, 1210, 1099, 738,
oil, which was used in the next reaction without further
1
purification. H NMR (400 MHz, CDCl3) d 7.38–7.26 (m,
10H), 6.81 (dd, J¼15.6, 8.4 Hz, 1H), 5.77 (d, J¼15.6 Hz,
1H), 4.77–4.68 (m, 4H), 4.19 (q, J¼7.3 Hz, 2H), 3.42–3.32
(m, 2H), 2.39 (m, 1H), 2.11–2.00 (m, 2H), 1.71 (m, 1H),
1.38–1.19 (m, 7H), 1.07–0.94 (m, 4H), 0.85 (m, 1H).
To a solution of the above enoate (1.059 g) in CH2Cl2
(20 mL) at 278 8C was added DIBALH (0.95 M solution in
hexane, 7.13 mL, 7.51 mmol). After being stirred at 278 8C
for 1 h, the reaction was quenched with saturated aqueous
potassium sodium tartrate. The resultant mixture was
diluted with ethyl acetate and stirred vigorously at room
temperature until layers became clear. The organic layer
was separated, washed with brine, dried (Na2SO4), filtered,
and concentrated under reduced pressure. Purification of the
residue by flash chromatography (silica gel, 30% ethyl
acetate/hexane) gave allylic alcohol 23 (872.1 mg, 98% for
the three steps) as a colorless clear oil. 23: [a]2D5¼238 (c
0.20, CHCl3); IR (film) 3436, 2924, 2864, 1452, 1370, 1098,
1
698 cm21; H NMR (400 MHz, CDCl3) d 7.36–7.20 (m,
15H), 4.75–4.66 (m, 5H), 4.22–4.16 (m, 2H), 3.82 (m, 1H),
3.42–3.32 (m, 2H), 3.26 (dd, J¼13.3, 2.7 Hz, 1H), 2.77 (dd,
J¼13.3, 9.6 Hz, 1H), 2.15–2.06 (m, 2H), 1.83–1.69 (m,
2H), 1.31–1.21 (m, 6H), 1.08–0.85 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 177.1, 153.0, 139.2 (£2), 135.2, 129.4,
128.9, 128.32, 128.27, 127.64, 127.59, 127.4, 127.34,
127.32, 82.4, 81.8, 72.3, 72.2, 66.1, 55.3, 39.8, 37.9, 37.7,
35.3, 33.7, 30.7, 30.3, 18.3; HRMS (FAB) calcd for
C34H39NO5Na [(MþNa)þ] 564.2726, found 564.2744.
1
4.1.17. Primary alcohol 22. To a solution of alkylated
product 21 (1.35 g, 2.55 mmol) in THF (30 mL) at 0 8C was
added LiAlH4 (116 mg, 3.06 mmol). After being stirred at
0 8C, the reaction was quenched with saturated aqueous
potassium sodium tartrate. The resultant mixture was
diluted with ethyl acetate and stirred at room temperature
until the layers became clear. The organic layer was washed
with brine, dried (Na2SO4), filtered, and concentrated under
reduced pressure. Purification of the residue by flash
chromatography (silica gel, 30% ethyl acetate/hexane)
gave primary alcohol 22 (858.4 mg, 91%) as a colorless
clear oil. 22: [a]2D5¼24 (c 0.85, CHCl3); IR (film) 3437,
2924, 2864, 1452, 1383, 1367, 1101, 1068, 1028, 736,
1075, 971, 736, 697 cm21; H NMR (400 MHz, CDCl3) d
7.38–7.25 (m, 10H), 5.59 (dt, J¼15.3, 5.3 Hz, 1H), 5.52
(dd, J¼15.3, 7.3 Hz, 1H), 4.77–4.68 (m, 4H), 4.09 (dd,
J¼5.5, 5.3 Hz, 2H), 3.42–3.32 (m, 2H), 2.23 (m, 1H),
2.12–2.02 (m, 2H), 1.73 (m, 1H), 1.40–1.10 (m, 5H), 1.04–
0.92 (m, 4H), 0.84 (m, 1H); 13C NMR (100 MHz, CDCl3) d
139.3, 138.7, 128.3, 127.64, 127.62, 127.33, 127.27, 82.7,
81.9, 72.3, 72.2, 63.8, 43.7, 38.1, 33.7, 33.4, 30.4, 30.3,
20.9; HRMS (FAB) calcd for C26H34O3Na [(MþNa)þ]
417.2406, found 417.2399.
4.1.19. Hydroxy epoxide 24. To a solution of allylic
alcohol 23 (842.1 mg, 2.137 mmol) in CH2Cl2 (20 mL)
1
697 cm21; H NMR (500 MHz, CDCl3) d 7.37–7.26 (m,
were added 4 A molecular sieves (1.00 g) and (2)-diethyl
˚
10H), 4.77–4.68 (m, 4H), 3.49–3.36 (m, 4H), 2.13–2.07
(m, 2H), 1.75–1.65 (m, 2H), 1.41 (m, 1H), 1.37–1.23 (m,
3H), 1.06 (ddd, J¼13.7, 8.2, 5.5 Hz, 1H), 0.99–0.87 (m,
5H); 13C NMR (125 MHz, CDCl3) d 139.3 (£2), 128.3 (£2),
127.7 (£2), 127.4, 82.6, 82.0, 72.32, 72.26, 68.5, 40.1, 37.4,
33.2, 33.0, 31.5, 30.4, 16.9; HRMS (FAB) calcd for
C24H32O3Na [(MþNa)þ] 391.2249, found 391.2249.
tartrate (0.550 mL, 3.21 mmol). The reaction mixture was
cooled to 220 8C and treated with titanium isopropoxide
(0.760 mL, 2.57 mmol). After being stirred at 220 8C for
30 min, t-butyl hydroperoxide (5 M solution in decane,
1.28 mL, 6.40 mmol) was introduced. After being stirred at
220 8C for 4 h, the reaction mixture was treated with 0.5 M
tartaric acid and stirred at room temperature for 1 h. The
resultant mixture was diluted with ethyl acetate, washed
with water and brine, dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue was
taken up in ether (30 mL) and treated with 1 M aqueous
NaOH (20 mL) at 0 8C. After being stirred at 0 8C for
30 min, the reaction mixture was diluted with ether, washed
with water and brine, dried (Na2SO4), filtered, and
concentrated under reduced pressure. Purification of the
residue by flash chromatography (silica gel, 40% ethyl
acetate/hexane) gave hydroxy epoxide 24 (870.5 mg, 99%)
as a colorless clear oil. 24: [a]2D6¼26 (c 0.21, CHCl3); IR
(film) 3438, 2924, 2864, 1616, 1453, 1383, 1102, 1070,
4.1.18. Allylic alcohol 23. To a solution of oxalyl chloride
(0.400 mL, 4.59 mmol) in CH2Cl2 (15 mL) at 278 8C was
added DMSO (0.480 mL, 6.76 mmol). After being stirred at
278 8C for 15 min, a solution of primary alcohol 22
(830.4 mg, 2.257 mmol) in CH2Cl2 (10 mLþ5 mL rinse)
was introduced. After being stirred at 278 8C for further
15 min, the reaction mixture was treated with Et3N
(1.26 mL, 9.04 mmol) and allowed to warm to room
temperature over 30 min. The resultant mixture was diluted
with ethyl acetate, washed with saturated aqueous NH4Cl
and brine, dried (Na2SO4), filtered, and concentrated under
reduced pressure to give crude aldehyde, which was
immediately used in the next reaction without further
purification.
1
1028, 902, 737, 698 cm21; H NMR (500 MHz, CDCl3) d
7.37–7.26 (m, 10H), 4.77–4.68 (m, 4H), 3.91 (ddd, J¼12.5,
5.5, 2.4 Hz, 1H), 3.62 (ddd, J¼12.5, 7.3, 4.3 Hz, 1H), 3.45–
3.34 (m, 2H), 2.92 (m, 1H), 2.73 (dd, J¼7.4, 2.2 Hz, 1H),
2.12–2.05 (m, 2H), 1.74 (m, 1H), 1.63–1.39 (m, 3H), 1.33
(m, 1H), 1.23 (m, 1H), 1.02–0.85 (m, 5H); 13C NMR
(125 MHz, CDCl3) d 139.3 (£2), 128.3, 127.7, 127.6, 127.3,
82.6, 81.9, 72.3, 72.2, 61.8, 60.7, 56.8, 41.7, 37.7, 33.3,
32.8, 31.1, 30.4, 16.5; HRMS (FAB) calcd for C26H34O4Na
[(MþNa)þ] 433.2355, found 433.2400.
To a solution of the above aldehyde in CH2Cl2 (30 mL) was
added Ph3PvCHCO2Et (1.10 g, 3.16 mmol). After being
stirred at room temperature overnight, the resultant mixture
was concentrated under reduced pressure. Purification of the
residue by flash chromatography (silica gel, 10% ethyl
acetate/hexane) gave enoate (1.059 g) as a colorless clear

5350
H. Fuwa et al. / Tetrahedron 60 (2004) 5341–5352
4.1.20. Secondary allylic alcohol 25. To a solution of
hydroxy epoxide 24 (756.1 mg, 1.844 mmol) in THF
(20 mL) were added imidazole (377 mg, 5.538 mmol),
triphenylphosphine (1.45 g, 5.528 mmol) and iodine
(937 mg, 3.689 mmol). After being stirred at room tem-
perature for 90 min, the reaction was quenched with
saturated aqueous Na2SO3. The resultant solution was
diluted with ethyl acetate, washed with saturated aqueous
Na2SO3 and brine, dried (Na2SO4), filtered, and concen-
trated under reduced pressure to give iodoepoxide,
which was used in the next reaction without further
purification.
which was used in the next reaction without further
purification.
To a solution of the above crude aldehyde in MeOH (6 mL)
at 0 8C was added NaBH4 (15 mg, 0.397 mmol). After being
stirred at 0 8C for 30 min, the reaction was quenched with
saturated aqueous NH4Cl. The resultant mixture was diluted
with ethyl acetate, washed with water and brine, dried
(Na2SO4), filtered, and concentrated under reduced
pressure. Purification of the residue by flash chromato-
graphy (silica gel, 10!20% ethyl acetate/hexane) gave
primary alcohol 26 (138.2 mg, 83% for the four steps) as a
colorless clear oil. 26: [a]2D9¼29 (c 0.43, CHCl3); IR (film)
3446, 2928, 2856, 1455, 1383, 1362, 1252, 1097, 835, 775,
To a solution of the above crude iodoepoxide in EtOH/CH2-
Cl2 (2:1, v/v, 24 mL) were added zinc dust (1.21 g,
18.5 mmol) and acetic acid (0.210 mL, 3.67 mmol). After
being stirred at room temperature for 2 h, the reaction
mixture was filtered through Celitew, and the filtrate was
concentrated under reduced pressure. The residue was
diluted with ethyl acetate, washed with saturated aqueous
NaHCO3 and brine, dried (Na2SO4), filtered, and concen-
trated under reduced pressure. Purification of the residue by
flash chromatography (silica gel, 15!30% ethyl acetate/
hexane) gave secondary allylic alcohol 25 (706.8 mg, 97%
for the two steps) as a colorless clear oil. 25: [a]2D6¼219 (c
1.32, CHCl3); IR (film) 3442, 2925, 2868, 1453, 1373, 1100,
1
736, 697 cm21; H NMR (400 MHz, CDCl3) d 7.38–7.24
(m, 10H), 4.78–4.67 (m, 4H), 3.60–3.49 (m, 3H), 3.42–
3.33 (m, 2H), 2.11–2.07 (m, 2H), 1.80–1.70 (m, 2H), 1.65
(m, 1H), 1.42–1.24 (m, 3H), 1.06–0.83 (m, 15H), 0.08 (s,
3H), 0.07 (s, 3H); 13C NMR (100 MHz, CDCl3) d 139.22,
139.20, 128.3, 127.64, 127.62, 127.34, 127.32, 82.6, 82.0,
76.8, 72.4, 72.2, 63.4, 39.5, 37.0, 33.7, 33.4, 31.9, 30.4,
25.9, 18.1, 15.2, 24.4, 24.5; HRMS (FAB) calcd for
C31H48O4SiNa [(MþNa)þ] 535.3220, found 535.3235.
4.1.22. Iodide 2. To a solution of primary alcohol 26
(644.7 mg, 1.259 mmol) in benzene (20 mL) were added
imidazole (257 mg, 3.775 mmol), triphenylphosphine
(826 mg, 3.149 mmol) and iodine (640 mg, 2.520 mmol).
After being stirred at room temperature for 30 min, the
reaction was quenched with saturated aqueous Na2SO3. The
resultant mixture was diluted with ethyl acetate, washed
with saturated aqueous Na2SO3 and brine, dried (Na2SO4),
filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by flash chromatography (silica gel, 5%
ethyl acetate/hexane) gave iodide 2 (741.5 mg, 96%) as a
colorless clear oil. 2: [a]2D9¼21 (c 0.40, CHCl3); IR (film)
2926, 2855, 1453, 1384, 1254, 1101, 1071, 836, 775, 734,
1027, 993, 920, 736, 697 cm21 1H NMR (500 MHz,
;
CDCl3) d 7.38–7.25 (m, 10H), 5.84 (ddd, J¼17.1, 10.4,
6.4 Hz, 1H), 5.22 (dd, J¼17.1, ,1 Hz, 1H), 5.18 (dd,
J¼10.4, ,1 Hz, 1H), 4.76–4.67 (m, 4H), 3.93 (m, 1H),
3.42–3.33 (m, 2H), 2.15–2.07 (m, 2H), 1.75–1.63 (m, 2H),
1.50 (m, 1H), 1.47–1.28 (m, 3H), 1.06 (m, 1H), 1.02–0.86
(m, 5H); 13C NMR (125 MHz, CDCl3) d 139.3, 139.0,
128.3, 127.6, 127.3, 115.9, 82.6, 82.1, 80.5, 72.3, 72.2, 38.9,
37.0, 35.8, 33.3, 31.9, 30.5, 15.2; HRMS (FAB) calcd for
C26H34O3Na [(MþNa)þ] 417.2406, found 417.2399.
1
4.1.21. Primary alcohol 26. To a solution of secondary
allylic alcohol 25 (127.9 mg, 0.3246 mmol) in CH2Cl2
(6 mL) at 0 8C were added Et3N (0.180 mL, 1.29 mmol) and
TBSOTf (0.220 mL, 0.958 mmol). After being stirred at
0 8C for 40 min, the reaction was quenched with MeOH.
The resultant mixture was diluted with ethyl acetate, washed
with saturated aqueous NH4Cl and brine, dried (Na2SO4),
filtered, and concentrated under reduced pressure to give
crude silyl ether, which was used in the next reaction
without further purification.
696 cm21; H NMR (400 MHz, CDCl3) d 7.39–7.25 (m,
10H), 4.78–4.68 (m, 4H), 3.42–3.36 (m, 3H), 3.18–3.26
(m, 2H), 2.15–2.08 (m, 2H), 1.86 (m, 1H), 1.65 (m, 1H),
1.37–1.30 (m, 2H), 1.25 (ddd, J¼13.4, 9.7, 3.7 Hz, 1H),
1.06 (m, 1H), 1.00–0.86 (m, 11H), 0.82 (d, J¼7.0 Hz, 3H),
0.11 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) d
139.3 (£2), 128.30 (£2), 128.29 (£2), 127.69 (£2), 127.65
(£2), 127.3 (£2), 82.6, 82.0, 76.1, 72.3, 72.2, 38.1, 37.0,
35.4, 33.5, 32.1, 30.5, 25.9, 18.1, 15.7, 11.2, 24.1, 24.6;
HRMS (FAB) calcd for C31H47IO3SiNa [(MþNa)þ]
645.2237, found 645.2272.
To a solution of the above crude silyl ether in THF/water
(1:1, v/v, 6 mL) were added NMO (190 mg, 1.622 mmol)
and a small crystal of OsO4. After being stirred at room
temperature for 3.5 h, the reaction mixture was diluted with
ethyl acetate, washed with saturated aqueous Na2SO3 and
brine, dried (Na2SO4), filtered, and concentrated under
reduced pressure to give crude diol, which was used in the
next reaction without further purification.
4.1.23. Sulfone 28. To a solution of alcohol 27 (4.17 g,
19.9 mmol) in toluene (100 mL) were added imidazole
(4.06 g, 59.6 mmol), triphenylphosphine (10.4 g, 39.7 mol)
and iodine (10.1 g, 39.8 mmol). After being stirred at room
temperature for 25 min, the reaction was quenched with
saturated aqueous Na2SO3. The resultant mixture was
diluted with ethyl acetate, washed with water and brine,
dried (Na2SO4), filtered, and concentrated under reduced
pressure. Purification of the residue by column chromato-
graphy (silica gel, 5% ethyl acetate/hexane) gave iodide
(6.00 g, 94%) as a colorless clear oil.
To a solution of the above crude diol in THF/pH 7 buffer
(1:1, v/v, 6 mL) at 0 8C was added NaIO4 (208 mg,
0.972 mmol). After being stirred at room temperature for
1.5 h, the reaction mixture was diluted with ethyl acetate,
washed with water and brine, dried (Na2SO4), filtered, and
concentrated under reduced pressure to give crude aldehyde,
To a solution of the above iodide (6.00 g, 18.8 mmol) in
DMF (100 mL) was added PhSO2Na (15.5 g, 94.4 mmol).

H. Fuwa et al. / Tetrahedron 60 (2004) 5341–5352
5351
After being stirred at room temperature for 4 h, the resultant
mixture was diluted with ethyl acetate, washed with water
(£2) and brine, dried (Na2SO4), filtered, and concentrated
under reduced pressure. Purification of the residue by
column chromatography (silica gel, 30% ethyl acetate/hex-
ane) gave sulfone 28 (4.99 g, 80%) as a colorless clear oil.
28: 1H NMR (400 MHz, CDCl3) d 7.89 (d, J¼7.6 Hz, 2H),
7.67–7.54 (m, 3H), 7.19 (d, J¼7.6 Hz, 2H), 6.86 (d,
J¼8.8 Hz, 2H), 4.40 (s, 2H), 3.81 (s, 3H), 3.41 (t, J¼6.8 Hz,
2H), 3.11 (t, J¼8.0 Hz, 2H), 1.86–1.78 (m, 2H), 1.69–1.63
(m, 2H); 13C NMR (100 MHz, CDCl3) d 159.2, 139.1,
133.6, 130.3, 129.2, 128.1, 113.8, 72.6, 68.9, 56.0, 55.3,
28.2, 20.0.
4.1.25. Alcohol 31. To a solution of (E)-olefin 30 (1.94 g,
5.13 mmol) in THF (40 mL) was added TBAF (1.0 M
solution in THF, 15.4 mL, 15.4 mmol). After being stirred at
room temperature for 1 h, the reaction mixture was diluted
with ethyl acetate, washed with saturated aqueous NH4Cl
and brine, dried (Na2SO4), filtered, and concentrated under
reduced pressure. Purification of the residue by flash
chromatography (silica gel, 20!40% ethyl acetate/hexane)
gave alcohol 31 (1.35 g, quant.) as a colorless clear oil. 31:
IR (film) 3436, 2929, 2860, 1612, 1513, 1460, 1247, 1175,
1097, 1035, 971, 821 cm21; 1H NMR (400 MHz, CDCl3) d
7.27–7.25 (m, 2H), 6.89–6.87 (m, 2H), 5.53 (dt, J¼15.5,
6.7 Hz, 1H), 5.37 (dd, J¼15.5, 7.9 Hz, 1H), 4.43 (s, 2H),
3.80 (s, 3H), 3.47 (m, 1H), 3.38 (t, J¼6.3 Hz, 2H), 3.33
(ddd, J¼10.3, 7.9, 4.2 Hz, 1H), 2.29 (m, 1H), 2.13–2.08 (m,
2H), 1.70–1.65 (m, 2H), 1.45 (dd, J¼7.9, 4.2 Hz, 1H), 0.97
(d, J¼6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 159.1,
132.8, 131.6, 130.7, 129.3, 113.8, 72.5, 69.3, 67.3, 55.3,
39.7, 29.5, 29.3, 16.6; HRMS (FAB) calcd for C16H24O3Na
[(MþNa)þ] 287.1623, found 287.1642.
4.1.24. (E)-Olefin 30. To a solution of sulfone 28 (4.55 g,
13.8 mmol) in THF (40 mL) at 278 8C was added n-BuLi
(1.58 M solution in hexane, 7.30 mL, 11.5 mmol). After
being stirred at 278 8C for 30 min, a solution of aldehyde
29 (1.73 g, 8.56 mmol) in THF (40 mL) was introduced.
Stirring was continued for 1 h at 278 8C before the reaction
was quenched with saturated aqueous NH4Cl. The resultant
mixture was diluted with ethyl acetate, washed with water
and brine, dried (Na2SO4), filtered, and concentrated
under reduced pressure. Purification of the residue by
column chromatography (silica gel, 20!40% ethyl acetate/
hexane) gave coupling product (3.93 g, 89%) as a colorless
clear oil.
4.1.26. Sulfone 3. To a solution of alcohol 31 (1.80 g,
6.82 mmol) in DMF (50 mL) were added diphenyl disulfide
(2.98 g, 13.6 mmol) and n-Bu3P (3.40 mL, 13.6 mmol).
After being stirred at room temperature overnight, the
reaction mixture was diluted with ethyl acetate, washed with
water and brine, dried (Na2SO4), filtered, and concentrated
under reduced pressure. Purification of the residue by
column chromatography (silica gel, 5!10% ethyl acetate/
hexane) gave phenyl sulfide (2.23 g, 92%) as a colorless
clear oil: [a]2D8¼þ22 (c 0.43, CHCl3); IR (film) 2927, 2853,
1612, 1585, 1513, 1480, 1456, 1439, 1364, 1301, 1247,
To a solution of the above coupling product (3.93 g) in
CH2Cl2 (80 mL) at 0 8C were added Et3N (2.00 mL,
14.3 mmol), DMAP (88 mg, 0.720 mmol) and Ac2O
(10.7 mmol). The reaction mixture was allowed to warm
to room temperature over 90 min. The reaction was
quenched with MeOH at 0 8C and the resultant mixture
was diluted with ethyl acetate, washed with water and brine,
dried (Na2SO4), filtered, and concentrated under reduced
pressure. Purification of the residue by column chromato-
graphy (silica gel, 20!30% ethyl acetate/hexane) gave
acetate (4.08 g, 96%) as a colorless clear oil.
1173, 1097, 1037, 969, 820, 739, 690 cm21 1H NMR
;
(400 MHz, CDCl3) d 7.32–7.24 (m, 6H), 7.15 (m, 1H),
6.88–6.86 (m, 2H), 5.43 (dt, J¼15.3, 6.0 Hz, 1H), 5.35 (dd,
J¼15.3, 7.1 Hz, 1H), 4.42 (s, 2H), 3.79 (s, 3H), 3.44 (t,
J¼6.4 Hz, 2H), 2.91 (dd, J¼12.4, 6.9 Hz, 1H), 2.80 (dd,
J¼12.4, 7.1 Hz, 1H), 2.38 (m, 1H), 2.10–2.05 (m, 2H),
1.69–1.61 (m, 2H), 1.09 (d, J¼6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 159.1, 138.9, 137.3, 134.4, 130.8,
129.6, 129.5, 129.3, 128.9, 128.8, 125.6, 113.8, 103.1, 72.5,
69.3, 55.3, 40.9, 36.4, 29.4, 29.0, 20.0; HRMS (FAB) calcd
for C22H28O2SNa [(MþNa)þ] 379.1708, found 379.1730.
To a solution of the above acetate (4.08 g) in MeOH
(70 mL) at 0 8C were added Na2HPO4 (19.6 g, 138 mmol)
and Na(Hg) (5%, 31.8 g, 69.0 mmol). After being stirred at
room temperature overnight, the reaction mixture was
filtered through Celitew and the filtrate was concentrated
under reduced pressure. The residue was diluted with ethyl
acetate, washed with saturated aqueous NH4Cl and brine,
dried (Na2SO4), filtered, and concentrated under reduced
pressure. Purification of the residue by column chromato-
graphy (silica gel, 5!10% ethyl acetate/hexane) gave (E)-
olefin 30 (2.21 g, 83% for the two steps) as a colorless clear
oil. 30: [a]2D8¼21 (c 0.36, CHCl3); IR (film) 2954, 2929,
To a solution of the above phenyl sulfide (1.90 g,
5.34 mmol) in CH2Cl2 (50 mL) at 0 8C were added
NaHCO3 (2.24 g, 26.7 mmol) and mCPBA (75% purity,
3.07 g, 13.3 mmol). After being stirred at room temperature
for 45 min, the reaction mixture was cooled to 0 8C and the
reaction was quenched with saturated aqueous Na2S2O3/
saturated aqueous NaHCO3 (1:1, v/v). The resultant mixture
was diluted with ethyl acetate, washed with brine, dried
(Na2SO4), filtered, and concentrated under reduced
pressure. Purification of the residue by column chromato-
graphy (silica gel, 20!25% ethyl acetate/hexane) gave
sulfone 3 (1.67 g, 81%) as a colorless clear oil. 3: [a]3D0¼þ2
(c 1.15, CHCl3); IR (film) 2929, 2854, 1611, 1512, 1446,
2855, 1613, 1513, 1464, 1249, 1101, 1038, 837, 776 cm21
;
1H NMR (400 MHz, CDCl3) d 7.27–7.25 (m, 2H), 6.89–
6.86 (m, 2H), 5.42 (dt, J¼15.6, 6.8 Hz, 1H), 5.32 (dd,
J¼15.6, 6.8 Hz, 1H), 4.42 (s, 2H), 3.80 (s, 3H), 3.48–3.42
(m, 3H), 3.34 (dd, J¼9.7, 6.8 Hz, 1H), 2.26 (m, 1H), 2.10–
2.03 (m, 2H), 1.70–1.62 (m, 2H), 0.95 (d, J¼6.8 Hz, 3H),
0.89 (s, 9H), 0.03 (s, 6H); 13C NMR (100 MHz, CDCl3) d
159.1, 133.3, 130.8, 129.3, 129.2, 113.8, 72.5, 69.5, 68.3,
55.3, 39.3, 29.6, 29.3, 26.0, 18.4, 16.8, 25.27, 25.31;
HRMS (FAB) calcd for C22H38O3SiNa [(MþNa)þ]
401.2488, found 401.2472.
1
1301, 1246, 1146, 1087, 1033, 821, 745, 688 cm21; H
NMR (400 MHz, CDCl3) d 7.90–7.88 (m, 2H), 7.63–7.53
(m, 3H), 7.26–7.24 (m, 2H), 6.90–6.86 (m, 2H), 5.38 (dt,
J¼15.2, 6.7 Hz, 1H), 5.22 (dd, J¼15.2, 7.3 Hz, 1H), 4.40 (s,
2H), 3.80 (s, 3H), 3.39 (t, J¼6.7 Hz, 2H), 3.10 (dd, J¼14.0,
6.1 Hz, 1H), 3.01 (dd, J¼14.0, 6.7 Hz, 1H), 2.74 (m, 1H),

5352
H. Fuwa et al. / Tetrahedron 60 (2004) 5341–5352
728. Total syntheses: (c) Nicolaou, K. C.; Piscopio, A. D.;
Bertinato, P.; Chakraborty, T. K.; Minowa, N.; Koide, K.
Chem. Eur. J. 1995, 1, 318. (d) Romo, D.; Meyer, S. D.;
Johnson, D. D.; Schreiber, S. L. J. Am. Chem. Soc. 1993, 115,
7906. (e) Hayward, C. M.; Yohannes, D.; Danishefsky, S. J.
J. Am. Chem. Soc. 1993, 115, 9345. (f) Smith, A. B., III;
Condon, S. M.; McCauley, J. A.; Leazer, J. L., Jr.; Leahy,
J. W.; Maleczka, R. E., Jr. J. Am. Chem. Soc. 1997, 119, 947.
(g) Smith, A. B., III; Condon, S. M.; McCauley, J. A.; Leazer,
J. L., Jr.; Leahy, J. W.; Maleczka, R. E., Jr. J. Am. Chem. Soc.
1997, 119, 962.
2.00–1.96 (m, 2H), 1.63–1.56 (m, 2H), 1.12 (d, J¼7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 159.1, 140.1, 133.5,
132.8, 130.7, 130.1, 129.24, 129.18, 128.0, 113.8, 113.7,
72.5, 69.2, 62.4, 55.3, 32.0, 29.2, 28.9, 20.7; HRMS (FAB)
calcd for C22H28O4SNa [(MþNa)þ] 411.1606, found
411.1599.
4.1.27. C18–C34 fragment 1. To a solution of sulfone 3
(216.1 mg, 0.5570 mmol) in THF (2 mL) at 278 8C was
added LiHMDS (1.0 M solution in THF, 0.480 mL,
0.480 mmol). After being stirred at 278 8C for 25 min,
the reaction mixture was warmed to 0 8C and treated with
HMPA (0.400 mL) and iodide 2 (141.5 mg, 0.2312 mmol)
in THF (2 mL). After being stirred at room temperature for
2 h, the reaction was quenched with saturated aqueous
NH4Cl at 0 8C. The resultant mixture was diluted with ethyl
acetate, washed with water and brine, dried (Na2SO4),
filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by flash chromatography (silica gel,
5!10% ether/hexane) gave coupling product (184.2 mg,
90%) as a colorless clear oil.
3. For reviews, see: (a) Schreiber, S. L. Science 1991, 251, 283.
(b) Hamilton, G. S.; Steiner, J. P. J. Med. Chem. 1998, 41,
5119.
4. Steiner, J. P.; Dawson, T. M.; Fotuhi, M.; Glatt, C. E.;
Snowman, A. M.; Cohen, N.; Snyder, S. H. Nature 1992, 358,
584.
5. For reviews, see: (a) Guo, X.; Dillman, J. F.; Dawson, V. L.;
Dawson, T. M. Ann. Neurol. 2001, 50, 6. (b) Gold, B. G.;
Villafranca, J. E. Curr. Top. Med. Chem. 2003, 3, 1368.
6. (a) Steiner, J. P.; Hamilton, G. S.; Ross, D. T.; Valentine, H. L.;
Guo, H.; Connolly, M. A.; Liang, S.; Ramsey, C.; Li, J.-H.;
Huang, W.; Howorth, P.; Soni, R.; Fuller, M.; Sauer, H.;
Nowotnick, A.; Suzdak, P. D. Proc. Natl. Acad. Sci. U.S.A.
1997, 94, 2019. (b) Hamilton, G. S.; Huang, W.; Connolly,
M. A.; Ross, D. T.; Guo, H.; Valentine, H. L.; Suzdak, P. D.;
Steiner, J. P. Bioorg. Med. Chem. Lett. 1997, 7, 1785.
(c) Hamilton, G. S.; Wu, Y. Q.; Limburg, D.; Wilkinson, D.;
Vaal, M.; Li, J.-H.; Thomas, C.; Huang, W.; Sauer, H.; Ross,
D. T.; Soni, R.; Chen, Y.; Guo, H.; Howorth, P.; Valentine, H.;
Liang, S.; Spicer, D.; Fuller, M.; Steiner, J. P. J. Med. Chem.
2002, 45, 3549. (d) Wu, Y. Q.; Wilkinson, D.; Limburg, D.; Li,
J.-H.; Sauer, H.; Ross, D. T.; Liang, S.; Spicer, D.; Valentine,
H.; Fuller, M.; Guo, H.; Howorth, P.; Soni, R.; Chen, Y.;
Steiner, J. P. J. Med. Chem. 2002, 45, 3550.
To a solution of the above coupling product (184.2 mg,
0.2088 mmol) in MeOH/THF (4:1, v/v, 5 mL) at 0 8C were
added Na2HPO4 (593 mg, 4.177 mmol) and Na(Hg) (5%,
1.00 g, 2.17 mmol). After being stirred at room temperature
overnight, the reaction mixture was filtered through Celitew.
The filtrate was diluted with ethyl acetate, washed with
saturated aqueous NH4Cl and brine, dried (Na2SO4),
filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by flash chromatography (silica gel,
10% ether/hexane) gave C18–C34 fragment 1 (110.5 mg,
71%) as a colorless clear oil. 1: [a]2D9¼29 (c 0.36, CHCl3);
IR (film) 2928, 2855, 1613, 1513, 1456, 1383, 1363, 1249,
1099, 1068, 1035, 835, 773, 736, 697 cm21 1H NMR
;
(400 MHz, CDCl3) d 7.38–7.24 (m, 12H), 6.86 (d,
J¼8.8 Hz, 2H), 5.38–5.22 (m, 2H), 4.80–4.65 (m, 4H),
4.42 (s, 2H), 3.79 (s, 3H), 3.46–3.30 (m, 5H), 2.20–1.95
(m, 5H), 1.70–1.57 (m, 4H), 1.40–0.72 (m, 25H), 0.02 (s,
6H); 13C NMR (100 MHz, CDCl3) d 159.1, 139.3, 136.9,
130.8, 129.2, 128.32, 128.28, 127.8, 127.64, 127.62, 127.3,
113.7, 82.7, 82.1, 76.5, 72.5, 72.4, 72.2, 69.5, 55.2, 39.1,
37.1, 36.9, 35.3, 33.5, 33.0, 32.1, 30.5, 30.1, 29.7, 29.1,
26.0, 20.9, 18.1, 15.1, 24.2, 24.4; HRMS (FAB) calcd for
C47H70O5SiNa [(MþNa)þ] 765.4890, found 765.4857.
7. Fehr, T.; Sanglier, J.-J.; Schuler, W.; Gschwind, L.; Ponelle,
M.; Schilling, W.; Wioland, C. J. Antibiot. 1996, 49, 230.
8. The carbon numbering in this paper corresponds to that of
antascomicin A.
9. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom,
T. J.; Li, T.-T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem.
Soc. 1970, 92, 741. Nicolaou and co-workers have success-
fully utilized Johnson–Claisen rearrangement in their total
synthesis of rapamycin (Ref. 2e). On the other hand, Ireland
ester enolate rearrangement has been employed by
Danishefsky and his colleagues in their rapamycin synthesis.
See: Fisher, M. J.; Myers, C. D.; Joglar, J.; Chen, S.-H.;
Danishefsky, S. J. J. Org. Chem. 1991, 56, 5826.
References and notes
10. For reviews, see: (a) Ferrier, R. J. Top. Curr. Chem. 2001, 215,
153. (b) Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93,
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1. Isolation and structure determination: (a) Tanaka, H.; Kuroda,
A.; Marusawa, H.; Hatanaka, H.; Kino, T.; Goto, T.;
Hashimoto, M.; Taga, T. J. Am. Chem. Soc. 1987, 109,
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Desmond, R.; Mills, S. G. J. Am. Chem. Soc. 1990, 112, 2998.
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H. Tetrahedron Lett. 1982, 23, 3597.
14. Chakraborty, T. K.; Suresh, V. R. Tetrahedron Lett. 1998, 39,
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´
2. Isolation and structure determination: (a) Vezina, C.;
Kudelski, A.; Sehgal, S. N. J. Antibiot. 1975, 28, 721.
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´
(b) Sehgal, S. N.; Baker, H.; Vezina, C. J. Antibiot. 1975, 28,