Total synthesis of (-)-hennoxazole A

Article abstract of DOI:10.1016/S0040-4020(01)00593-2

The antiviral marine natural product (-)-hennoxazole A was efficiently synthesized by a convergent approach. The stereoselective synthesis of the functionalized tetrahydropyran fragment was accomplished by the Mukaiyama aldol reaction, chelation-controlle

Full text of DOI:10.1016/S0040-4020(01)00593-2

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 6311±6327
Total synthesis of (2)-hennoxazole A
Fumiaki Yokokawa,p Toshinobu Asano and Takayuki Shioiri
Faculty of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Received 21 March 2001; revised 3 May 2001; accepted 24 May 2001
AbstractÐThe antiviral marine natural product (2)-hennoxazole A was ef®ciently synthesized by a convergent approach. The stereoselec-
tive synthesis of the functionalized tetrahydropyran fragment was accomplished by the Mukaiyama aldol reaction, chelation-controlled
1,3-syn reduction, Wacker oxidation, and acid catalyzed intramolecular ketalization. The nonconjugated triene fragment was synthesized by
SN2 displacement of an allylic bromide with vinyllithium and the CrCl2-mediated iodoole®nation followed by palladium-catalyzed cross
coupling with MeMgBr. The ®nal steps include the fragment coupling using DEPC and oxazole synthesis via an oxidation/cyclodehydration
process. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
polycyclic marine alkaloid diazonamide A±B (5±6),2
cyanobacterium-derived muscoride
(7),3 and the
A
hennoxazole family.4 Other unique structural features of
hennoxazole A are a highly functionalized tetrahydro-
pyranyl ring moiety, and a nonconjugated triene unit. The
unique structural features and interesting biological activity
of hennoxazole A have attracted the attention of several
synthetic research groups. Wipf and Lim have accomplished
the total synthesis of the antipode of 1, and their synthesis
has elucidated the absolute con®guration of 1 and relative
Hennoxazoles A±D (1±4) are marine natural products,
isolated by Scheuer, Higa, and co-workers from the marine
sponge Poly®brospongia sp. near Miyako island, Okinawa,
Japan.1 Hennoxazole A (1) is active against herpes simplex
virus type 1 (IC50ˆ0.6 mg mL21) and displays peripheral
analgesic activity comparable with that of indomethacin.
The most unique feature of its structure is a directly linked
bisoxazole core, (Fig. 1) which is only found in the complex
Figure 1. Bisoxazole based natural products.
Keywords: hennoxazole A; total synthesis; aldol reaction; Wacker oxidation.
Corresponding author. Tel.: 181-52-836-3440; fax: 181-52-834-9309; e-mail: yokokawa@phar.nagoya-cu.ac.jp
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00593-2

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F. Yokokawa et al. / Tetrahedron 57 (2001) 6311±6327
Scheme 1. Retrosynthetic analysis of (2)-hennoxazole A.
stereochemistries at C8 and C22.5 Recently, the total syn-
thesis of hennoxazole A (1) having the natural con®guration
has been reported by Williams and co-workers.6 Our interest
in the total synthesis of oxazole/oxazoline/thiazole/thiazo-
line based marine natural products7 led us to hennoxazole
A (1) as a challenging synthetic target.8,9 Here, we report
the details of our synthetic work on (2)-hennoxazole
A (1).10
2. Results and discussions
2.1. Synthetic plan
Our initial synthetic plan called for disconnection at C14 to
provide the C14±C25 triene fragment 8 and the C1±C13 tetra-
hydropyran fragment 9. The triene fragment 8 was further
divided into the C19±C23 allylic bromide 11, the C2 unit, and
Scheme 2. Synthesis of C14±C25 fragment (a) DPSCl, imidazole, DMF, 95%; (b) DIBAL, Et2O, 2788C; (c) (method A) (CF3CH2O)2P(O)CH(CH3)CO2CH3
(17), KHMDS, 18-crown-6, THF, 2788C, 48%; (method B) (PhO)2P(O)CH(CH3)CO2CH3 (18), NaI, DBU, THF, 2788C±08C, 82%; (d) DIBAL, Et2O,
2788C, 94%; (e) CBr4, Ph3P, CH3CN, 99%; (f) 21, Pd(CH3CN)2Cl2, NMP, 76% (E/Zˆ1:1); (g) 23, t-BuLi, HMPA, THF, 2788C, 53%; (h) TBAF, THF, 90%;
(i) Py´SO3, DMSO, Et3N, CH2Cl2; (j) CrCl2, CHI3, THF, 68%; (k) MeMgBr, Pd(Ph3P)4, THF, quant., (l) aq. HCl, MeOH, THF, 83%; (m) PDC, DMF, 72%.

F. Yokokawa et al. / Tetrahedron 57 (2001) 6311±6327
6313
skipped diene 24 in 53% yield. The (Z)-con®guration of
the C20±C21 double bond in 24 was con®rmed by the
existence of 7% NOE enhancement between the ole®nic
proton and the ole®nic methyl protons. After deprotection
of the DPS group, the resulting primary alcohol 25 was
oxidized by the Parikh±Doering oxidation17 to furnish the
corresponding aldehyde, which was immediately subjected
to the Takai's CrCl2-mediated iodoole®nation process18 to
give the (E)-vinyl iodide 26 in 61% yield. Cross coupling of
the vinyl iodide 26 with MeMgBr in the presence of palla-
dium catalyst19 constructed the nonconjugated triene unit 27
in quantitative yield. Finally, deprotection of the methoxy-
methyl group (MOM) followed by oxidation using pyridi-
nium dichromate (PDC) gave the C14±C25 triene fragment 8
in 60% yield (Scheme 2).
Scheme 3. Synthesis of C1±C6 fragment (a) n-BuLi, 1,3-dithiane, THF;
(b) vinylmagnesium bromide, CuI, THF, 63%; (c) KH, PMBCl, n-Bu4NI,
THF, 86%; (d) MeI, CaCO3, aq. CH3CN, 74%.
the C14±C18 vinyl metal 10. The linear precursor 12 of the
tetrahydropyran fragment was disconnected at the C6±C7
bond to lead to the C1±C6 aldehyde 13 and the C7±C13
oxazole methyl ketone 14 (Scheme 1).
2.3. Synthesis of the C1±C14 tetrahydropyran fragment
2.2. Synthesis of the C14±C25 triene fragment
The synthesis of the C1±C6 aldehyde 13 was started by
treatment of commercially available (R)-glycidyl tosylate
(29) with lithiated 1,3-dithiane followed by copper-cata-
lyzed Grignard addition to afford the alcohol 30 in 63%
yield. Protection of the alcohol 30 as its p-methoxybenzyl
(PMB) ether 31 and removal of the 1,3-dithiane provided
the aldehyde 13 in 64% yield (Scheme 3).
The synthesis of the C14±C25 triene unit was initiated by
protection of methyl (S)-3-hydroxy-2-methylpropionate
(15) as its DPS (tert-butyldiphenylsilyl)ether to give 16 in
95% yield. Diisobutylaluminum hydride (DIBAL) reduc-
tion of 16 afforded the corresponding aldehyde, which
was directly treated with the phosphonate 17 under (Z)-
selective Still±Horner ole®nation conditions11 to provide
the (Z)-ester 19 in 48% yield as a single isomer. We also
found that (Z)-selective ole®nation using the Ando's phos-
phonate 1812 in the presence of NaI-1,8-diazabicyclo[5.4.0]-
7-undecene (DBU) gave the (Z)-ester 19 in much better
yield (82%) as a single isomer. Reduction of the methyl
ester 19 with DIBAL followed by bromination of the result-
ing allylic alcohol 20 using CBr4 and Ph3P gave the allylic
bromide 11 in 93% yield.13 Although we initially attempted
the Stille coupling14 of the allylic bromide 11 with the vinyl
stannane 21,15 this coupling reaction caused the loss of the
C20±C21 double bond stereochemistry to give the insepa-
rable E/Z mixture 22 in 76% yield due to the p±s±p
isomerization of the p-allyl intermediate derived from 11.
In spite of an extensive variation of reaction parameters, we
were unable to suppress the isomerization of the C20±C21
double bond. However, we were able to solve this problem
by SN2 displacement of the allylic bromide 11 with the vinyl
lithium derived from the vinyl iodide 2316 to afford the
The C7±C14 oxazole methyl ketone 14 was synthesized from
the ester 3220 via the Weinreb amide formation21 followed
by the Grignard addition. The BF3´OEt2 mediated
Mukaiyama aldol reaction between the trimethylsilyl enol
ether 33 derived from the oxazole methyl ketone 14 and the
aldehyde 13 to provide the aldol adduct 34 in 75% yield
with good diastereoselectivity (90:10 anti/syn).22 This trans-
formation established the C6 stereocenter with a good level
of 1,3-anti induction.24 Subsequent chelation-controlled
reduction25 of the C8 ketone from the aldol adduct 34
afforded the syn diol 35 in 91% yield, which was protected
as an acetonide to give 36 in 90% yield.26 In spite of the
stereoselective formation of the linear precursor of the tetra-
hydropyran unit, we were unable to convert the terminal
ole®n of 36 to the methyl ketone 37 using Wacker oxi-
dation27 or oxymercuration protocols.28 We speculated
that the chelation of two valent metal between the oxazole
nitrogen and C8 oxygen would prevent the oxidation of the
Scheme 4. Synthesis of C1±C13 fragment (a) HCl´HNMe(OMe), Me3Al, CH2Cl2; (b) MeMgBr, THF, 59%; (c) TMSOTf, Et3N, CH2Cl2; (d) 13, BF3´OEt2,
CH2Cl2, 2788C, 75% (90:10); (e) Et2BOMe, NaBH4, THF, 91%; (f) 2,2-dimethoxy propane, p-TsOH, 90%.

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F. Yokokawa et al. / Tetrahedron 57 (2001) 6311±6327
Scheme 5. Revised retrosynthetic analysis of (2)-hennoxazole A.
terminal ole®n.29 Therefore, we had to revise the initial
synthetic plan for the tetrahydropyran fragment (Scheme 4).
the C1±C10 tetrahydropyran fragment 39 and the C11±C25
triene±oxazole fragment 38 in our revised synthetic
strategy. The linear precursor 40 of the C1±C10 tetrahydro-
pyran fragment 39 would be obtained by aldol reaction of
the C1±C6 aldehyde 13 with benzalacetone (41). The C11±
C25 triene±oxazole fragment 38 would be synthesized from
the C14±C25 triene unit 8 and serine methyl ester (Scheme
5).
2.4. Revised synthetic plan
The sluggish oxidation of the terminal ole®n of the C1±C14
segment 36 led us to shift the position of disconnection from
C14 to C11. Accordingly, hennoxazole A (1) was divided into
Scheme 6. Synthesis of C1±C10 fragment (a) TMSOTf, Et3N, CH2Cl2, 96%; (b) 13, BF3´OEt2, CH2Cl2, 2788C, 89% (88:12); (c) Et2BOMe, NaBH4, THF; (d)
2,2-dimethoxy propane, PPTs; (e) silica gel column chromatography, 44; 59%, 45; 9%; (f) PdCl2, Cu(OAc)2´H2O, AcNMe2/H2O (7:1), 77%; (g) PPTs, MeOH,
85%; (h) NaH, MeI, THF, 98%; (i) OsO4, NMO, aq. acetone; (j) NaIO4, pH 7 phosphate buffer, THF; (k) Cp2TiCH2AlClMe2, THF, 72%; (l) OsO4, NMO, aq.
acetone; (m) DPSCl, Et3N, DMAP, CH2Cl2, 94%; (n) MsCl, Et3N, DMAP, CH2Cl2; (o) n-Bu4NN3, DMF, 1008C, 68%; (p) Ph3P, aq. THF, 558C, 68%.

F. Yokokawa et al. / Tetrahedron 57 (2001) 6311±6327
6315
Scheme 7. Synthesis of C11±C25 fragment (a) DEPC, HCl´H-(S)-Ser-OMe, Et3N, DMF, 91%; (b) Deoxo-¯uor, CH2Cl2, 220 to 2308C; (c) BrCCl3, DBU,
CH2Cl2, 80%: (d) aq. LiOH, THF, quant.
2.5. Synthesis of the C1±C10 tetrahydropyran fragment
and C11±C25 triene±oxazole fragment
For the preparation of the C11±C25 triene±oxazole fragment
38, coupling of the C14±C25 triene unit 8 with (S)-serine
methyl ester hydrochloride using diethyl phosphorocyani-
date (DEPC)32 afforded the amide 51 in 91% yield. Accord-
ing to the Wipf and Williams' methodology,33 dehydrative
cyclization of the b-hydroxy amide 51 with bis(2-methoxy-
ethyl)aminosulfur tri¯uoride (Deoxo-¯uor) to the oxazoline
followed by oxidation with BrCCl3 and DBU provided the
oxazole 52 in 80% yield. Saponi®cation of the methyl ester
52 in quantitative yield completed the construction of the
C11±C25 triene±oxazole fragment 38 (Scheme 7).
The synthesis of the C1±C10 tetrahydropyran fragment 39
was started by the BF3´OEt2 mediated aldol reaction
between the trimethylsilyl enol ether 42 derived from
benzalacetone (41) and the C1±C6 aldehyde 13 afforded
the aldol adduct 43 in 89% yield with similar diastereoselec-
tivity (88:12 anti/syn).22 Subsequent chelation-controlled
reduction of the C8 ketone, protection of the corresponding
syn-diols as acetonides followed by separation on silica gel
gave the desired isomer 44 (59%),26 the minor isomer 45
(9%),26 and recovered starting diol (31%). In contrast to the
failure of the Wacker oxidation of 36, the modi®ed Wacker
oxidation30 of the terminal ole®n of 44 proceeded smoothly
to give the methyl ketone 40 in 77% yield. Mild acidic
treatment of 40 simultaneously caused the cleavage of the
acetonide and the intramolecular ketalization to produce the
tetrahydropyran 46 in 85% yield. O-Methylation of 46,
oxidative cleavage of the styryl group in 47 and Tebbe
ole®nation31 afforded 48 in 72% yield. Dihydroxylation of
the terminal ole®n 48 with osmium tetroxide and N-methyl-
morpholine-N-oxide (NMO), and selective protection of the
primary alcohol led to the mono-tert-butyldiphenylsilyl
(DPS) ether 49 in 94% yield as mixture of diastereoisomers
(3.2:1). Treatment of the resulting alcohol with methane-
sulfonyl chloride (MsCl) and then displacement with
n-Bu4NN3 provided the azide 50 in 68% yield. Mild reduc-
tion of the azide 50 with Ph3P/H2O completed the formation
of the C1±C10 tetrahydropyran segment 39 in 68% yield
(Scheme 6).
2.6. Synthesis of hennoxazole A
The ®nal steps of the synthesis began with the condensation
of 39 and 38 using DEPC32 and removal of the DPS group
provided the amido alcohol 53 in 86% yield. Oxazole syn-
thesis via an oxidation/cyclodehydration process5,34 was
performed through intermediary bromo-oxazoline under
Wipf's conditions to afford the bisoxazole 54 in 60%
yield. The ®nal oxidative removal of the C4-PMB group
with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)35 pro-
vided (2)-hennoxazole A (1) in 36% yield. The spectral
data recorded on synthetic hennoxazole A were identical
in all respects with spectra provided for the natural product
(Scheme 8).
In summary, we have developed an ef®cient, convergent
strategy for the preparation of the structurally and bio-
logically attractive marine natural product hennoxazole A.
Scheme 8. Synthesis of (2)-hennoxazole A (a) DEPC, Et3N, DMF; (b) TBAF, THF, 86%; (c) Dess±Martin periodinane, CH2Cl2; (d) BrCCl2CCl2Br, Ph3P,
2,6-di-tert-butylpyridine, CH2Cl2, 08C; (e) DBU, CH3CN, 60%; (f) DDQ, pH 7 phosphate buffer, CH2Cl2, 36%.

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F. Yokokawa et al. / Tetrahedron 57 (2001) 6311±6327
3. Experimental
1H NMR (270 MHz, CDCl3) d 1.03 (9H, s, (CH3)3C), 1.15
(3H, d, Jˆ6.9 Hz, C26±CH3), 2.68±2.76 (1H, m, C22±CH),
3.68 (3H, s, CH3 ester), 3.72 (1H, dd, Jˆ9.6, 5.6 Hz, CH2),
3.83 (1H, dd, Jˆ9.6, 6.9 Hz, CH2), 7.34±7.42 (6H, m, ArH),
7.64±7.67 (4H, m, ArH); 13C NMR (67.8 MHz, CDCl3) d
13.4, 19.2, 26.7, 42.3, 51.5, 65.9, 127.6, 129.6, 133.5, 135.5,
175.3. Anal. Calcd for C21H28O3Si: C, 70.74; H, 7.92.
Found: C, 70.68; H, 8.00.
3.1. General information
Melting points were measured on a YANACO melting point
apparatus and are uncorrected. Infrared spectra were
recorded on a SHIMADZU FT IR-8100 spectrometer. Opti-
cal rotations were measured on a DIP-1000 digital polari-
meters with a sodium lamp (lˆ589 nm, D line) and are
reported as follows: [a]T (c g/100 mL, solvent).
3.1.2. Methyl (2Z,4R)-5-(tert-butyldiphenylsiloxy)-2,4-
dimethyl-2-pentenoate (19). (Method A): To a stirred
solution of 16 (2.1 g, 5.89 mmol) in ether (20 mL) was
added DIBAL (0.95 M in hexane, 6.2 mL, 5.89 mmol) at
2788C. After being stirred at 2788C for 20 min, the
reaction mixture was quenched by the addition of 1 M
aqueous KHSO4. The mixture was extracted with CHCl3
(£3). The organic extracts were washed with water,
saturated aqueous NaHCO3, and brine. The organic layer
was dried (Na2SO4), ®ltered, and concentrated to afford
the aldehyde.
D
1H NMR spectra were recorded on a JEOL EX-270
(270 MHz) or ALPHA 500 (500 MHz) or LAMBDA
(500 MHz) spectrometer. Chemical shifts are reported in
ppm from tetramethylsilane as the internal standard. Data
are reported as follows: chemical shift, integration, multi-
plicity (sˆsinglet, dˆdoublet, tˆtriplet, qˆquartet, brˆ
broad, mˆmultiplet), coupling constants (Hz), and assign-
ment. Hennoxazole A numbering is used for assignments on
all intermediates. 13C NMR spectra were recorded on a
JEOL EX-270 (67.8 MHz) spectrometer with complete
proton decoupling. Chemical shifts are reported in ppm
from tetramethylsilane with the solvent as the internal
standard (chloroform: d 77.0 ppm).
A solution of (CF3CH2O)2P(O)CH(CH3)CO2CH3 (17)
(2.3 g, 6.92 mmol) and 18-crown-6 (6.6 g, 25.0 mmol) in
THF (50 mL) was cooled to 2788C and treated with
KHMDS (0.5 M in toluene, 13.8 mL, 6.9 mmol). After the
mixture was stirred for 15 min, a solution of the aldehyde in
THF (10 mL, plus 5 mL of rinse) was added by cannula. The
resulting mixture was stirred at 2788C for 2.5 h and then at
2108C for 30 min. The reaction mixture was quenched by
the addition of saturated aqueous NH4Cl and the bulk of
THF was removed. The residue was extracted with ether
(£1), and the organic extracts were washed with brine,
dried (MgSO4), ®ltered, and concentrated. The residue
was puri®ed by ¯ash chromatography (BW-200, hexane/
etherˆ30:1) to afford the desired product 19 as a colorless
oil (1.13 g, 2.85 mmol, 48%).
Analytical thin layer chromatography were performed on
Merck Art. 5715, Kieselgel 60F254/0.25 mm thickness
plates. Visualization was accomplished with UV light,
phosphomolybdic acid, or ninhydrin solution followed by
heating. Preparative thin layer chromatography were
performed on Merck Art. 5744, Kiselgel 60F254/0.5 mm
thickness plates. Elementary analysis (Anal) and high
resolution mass spectra (HRMS) were performed at the
Analytical Facility at Nagoya City University.
Solvents for extraction and chromatography were reagent
grade. Liquid chromatography was performed with forced
¯ow (¯ash chromatography of the indicated solvent mixture
on silica gel BW-820 MH or BW-200 (Fuji Silysia Co.)).
Tetrahydrofuran (THF) was distilled from sodium metal/
benzophenone ketyl. Diethyl ether was distilled from
lithium aluminum hydride. Dichloromethane (CH2Cl2),
methanol and hexamethylphosphoramide (HMPA) were
distilled from calcium hydride. Toluene, acetonitrile
(CH3CN), dimethylsulfoxide (DMSO) and N,N-dimethyl-
(Method B): To a stirred solution of 16 (271 mg, 0.76 mmol)
in ether (3 mL) was added DIBAL (1.5 M in toluene,
0.54 mL, 0.81 mmol) at 2788C. After being stirred at
2788C for 20 min, the reaction mixture was quenched by
the addition of 1 M aqueous KHSO4. The mixture was
extracted with CHCl3 (£3). The organic extracts were
washed with water, saturated aqueous NaHCO3, and brine.
The organic layer was dried (Na2SO4), ®ltered, and concen-
trated to afford the aldehyde.
Ê
formamide (DMF) were dried over 4 A molecular sieves.
Triethylamine and N,N-diisopropylethylamine were dried
over potassium hydroxide. All other commercially available
reagents were used as received.
A solution of (PhO)2P(O)CH(CH3)CO2CH3 (18) (305 mg,
0.952 mmol) in THF (2.4 mL) was treated with NaI
(171 mg, 1.14 mmol) and DBU (0.14 mL, 0.94 mmol) at
08C for 10 min. After the mixture was cooled to 2788C, a
solution of the aldehyde in THF (1 mL, plus 0.7 mL of
rinse) was added by cannula. The resulting mixture was
stirred at 2788C for 30 min and then at 08C for 30 min.
The reaction mixture was quenched by the addition of satu-
rated aqueous NH4Cl and extracted with ether (£1), and the
organic extracts were washed with brine, dried (MgSO4),
®ltered, and concentrated. The residue was puri®ed by
¯ash chromatography (BW-200, hexane/etherˆ30:1) to
afford the desired product 19 as a colorless oil (247 mg,
3.1.1. (S)-Methyl 3-tert-butyldiphenylsiloxy-2-methyl-
propionate (16). To a stirred solution of 15 (3 g,
25.4 mmol) in DMF (50 mL) at 08C was added imidazole
(3.63 g, 53.3 mmol) and DPSCl (7 mL, 26.9 mmol). The
reaction mixture was stirred at 08C for 30 min and then at
room temperature for 7.5 h. After dilution with ether, the
mixture was washed with 1 M aqueous KHSO4, water,
saturated aqueous NaHCO3, water, and brine. The organic
layer was dried (MgSO4), ®ltered, and concentrated. The
residue was puri®ed by ¯ash chromatography (BW-820
MH, hexane/etherˆ10:1) to afford the desired product 16
0.62 mmol, 82%): [a]25 ˆ241.9 (c 1.2, CHCl3); IR nmax
-
D
1
(neat) cm21 1721, 1429, 1225, 1113; H NMR (270 MHz,
as a colorless oil (8.62 g, 24.2 mmol, 95%): [a]26 ˆ216.5
D
(c 1.1, CHCl3); IR nmax(neat) cm21 1742, 1429, 1200, 1113;
CDCl3) d 1.02 (3H, d, Jˆ5.9 Hz, C26±CH3), 1.04 (9H, s,

F. Yokokawa et al. / Tetrahedron 57 (2001) 6311±6327
6317
(CH3)3C), 1.89 (3H, d, Jˆ1.3 Hz, C27±CH3), 3.33±3.44
(1H, m, C22±CH), 3.54 (2H, d, Jˆ5.9 Hz, CH2), 3.68 (3H,
s, CH3 ester), 5.78 (1H, dd, Jˆ9.6, 1.3 Hz, C21±CH), 7.34±
7.44 (6H, m, ArH), 7.62±7.67 (4H, m, ArH); 13C NMR
(67.8 MHz, CDCl3) d 16.8, 19.3, 20.8, 26.8, 36.2, 51.2,
68.3, 126.9, 127.5, 129.5, 133.9, 135.6, 145.7, 168.3.
HRMS (EI) m/z Calcd for C24H32O3Si: 396.2121. Found:
396.2111.
(0.47 mL, 5.86 mmol). The reaction mixture was stirred at
08C for 30 min and then at room temperature for 15 h. After
the bulk of CH2Cl2 was removed, the residue was diluted
with ether and washed with 1 M aqueous KHSO4, water,
saturated aqueous NaHCO3, water, and brine. The organic
layer was dried (MgSO4), ®ltered, and concentrated. The
residue was puri®ed by ¯ash chromatography (BW-820
MH, hexane/EtOAcˆ20:1), followed by vacuum distillation
(Kugelrohr, bp 1108C/9 mmHg) to afford the desired
product 23 as a colorless oil (819 mg, 3.20 mmol, 80%):
IR nma1x(neat) cm21 1607, 1441, 1385, 1210, 1146, 1111,
1042; H NMR (270 MHz, CDCl3) d 1.64±1.74 (2H, m,
C15±CH2), 2.16 (2H, apparent q, Jˆ7.3 Hz, C16±CH2),
3.35 (3H, d, Jˆ1.0 Hz, OCH2OCH3), 3.52 (2H, t, Jˆ
6.3 Hz, C14±CH2), 4.61 (2H, d, Jˆ0.7 Hz, OCH2OCH3),
6.03 (1H, dd, Jˆ14.2, 1.3 Hz, C18±CH), 6.52 (1H, dt, Jˆ
14.2, 7.3 Hz, C17±CH); 13C NMR (67.8 MHz, CDCl3) d
28.4, 32.7, 55.1, 66.6, 75.0, 96.4, 145.7. Anal. Calcd for
C7H13IO2: C, 32.83; H, 5.12. Found: C, 32.56; H, 5.04.
3.1.3. (2Z,4R)-5-(tert-Butyldiphenylsiloxy)-2,4-dimethyl-
2-pentenol (20). To a stirred solution of 19 (2.15 g,
5.40 mmol) in ether (19 mL) was added DIBAL (0.95 M
in hexane, 15 mL, 14.3 mmol) at 2788C. After being stirred
at 2788C for 30 min, the reaction mixture was quenched by
the addition of 10% aqueous potassium sodium tartrate. The
mixture was extracted with CHCl3 (£3). The organic
extracts were washed with water, saturated aqueous
NaHCO3, and brine. The organic layer was dried
(Na2SO4), ®ltered, and concentrated. The residue was puri-
®ed by ¯ash chromatography (BW-820 MH, hexane/
EtOAcˆ5:1) to afford the desired product 20 as a colorless
3.1.6. (2R,3Z,6E)-1-(tert-Butyldiphenylsiloxy)-10-(meth-
oxymethyloxy)-2,4-dimethyl-3,6-decadiene (24). To a
stirred solution of 23 (161 mg, 0.63 mmol) in THF (2 mL)
was added t-BuLi (1.47 M in pentane, 0.86 mL, 1.3 mmol)
at 2788C. After 5 min, HMPA (0.2 mL) was added and then
a solution of 11 (163 mg, 0.38 mmol) in THF (0.5 mL, plus
0.5 mL of rinse) was added via cannula. The reaction
mixture was stirred at 2788C for 30 min, then quenched
by the addition of saturated aqueous NH4Cl. The mixture
was extracted with ether (£1), and the organic extracts were
washed with brine, dried (MgSO4), ®ltered, and concen-
trated. The residue was puri®ed by ¯ash chromatography
(BW-820 MH, hexane/etherˆ50:1±20:1) to afford the
desired product 24 as a colorless oil (96 mg, 0.20 mmol,
oil (1.87 g, 5.06 mmol, 94%): [a]24 ˆ214.8 (c 1.0,
D
CHCl3); IR nmax(neat) cm21 3368, 1428, 1113, 1084,
1007; 1H NMR (270 MHz, CDCl3) d 0.89 (3H, d, Jˆ
6.6 Hz, C26±CH3), 1.04 (9H, s, (CH3)3C), 1.81 (3H, d,
Jˆ1.3 Hz, C27±CH3), 1.92 (1H, br, OH), 2.74±2.81 (1H,
m, C22±CH), 3.30 (1H, dd, Jˆ9.6, 8.2 Hz, CH2), 3.49
(1H, dd, Jˆ9.6, 5.6 Hz, CH2), 3.94 (1H, dd, Jˆ11.9,
6.9 Hz, C19±CH2), 4.16 (1H, dd, Jˆ11.9, 4.0 Hz, C19±
CH2), 5.03 (1H, d, Jˆ9.9 Hz, C21±CH), 7.35±7.46 (6H,
m, ArH), 7.63±7.68 (4H, m, ArH); 13C NMR (67.8 MHz,
CDCl3) d 17.4, 19.1, 21.9, 26.8, 35.0, 62.1, 68.8, 127.6,
129.7, 131.7, 133.4, 135.5, 135.6. HRMS (EI) m/z Calcd
for C19H23O2Si: 311.1467 (M12t-Bu). Found: 311.1461.
53%): [a]25 ˆ234.7 (c 1.2, CHCl3); IR nmax(neat) cm21
D
3.1.4. (2Z,4R)-5-(tert-Butyldiphenylsiloxy)-2,4-dimethyl-
2-pentenyl bromide (11). To a stirred solution of 20
(611 mg, 1.66 mmol) and Ph3P (522 mg, 1.99 mmol) in
CH3CN (5.6 mL) at 08C was added CBr4 (660 mg,
1.99 mmol). The reaction mixture was stirred at 08C for
5 min and then at room temperature for 15 min. The
reaction mixture was ®ltered through silica gel (hexane/
etherˆ10:1 wash) and the combined ®ltrate was concen-
trated. The residue was puri®ed by ¯ash chromatography
(BW-820 MH, hexane/etherˆ100:1±50:1) to afford the
desired product 11 as a colorless oil (706 mg, 1.64 mmol,
1428, 1150, 1113, 1082, 1044; 1H NMR (270 MHz,
CDCl3) d 0.98 (3H, d, Jˆ6.6 Hz, C26±CH3), 1.05 (9H, s,
(CH3)3C), 1.59±1.67 (2H, m, C15±CH2), 1.62 (3H, d, Jˆ
1.7 Hz, C27±CH3), 2.00±2.07 (2H, m, C16±CH2), 2.53±
2.73 (3H, m, C19±CH2 and C22±CH), 3.35 (3H, s,
OCH2OCH3), 3.40±3.53 (4H, m, C23±CH2 and C14±CH2),
4.61 (2H, s, OCH2OCH3), 4.92 (1H, d, Jˆ8.6 Hz, C21±CH),
5.25±5.40 (2H, m, C17 and C18±CH), 7.33±7.42 (6H, m,
ArH), 7.65±7.68 (4H, m, ArH); 13C NMR (67.8 MHz,
CDCl3) d 17.7, 19.2, 23.3, 26.8, 29.0, 29.5, 35.2, 35.5,
55.0, 67.1, 68.8, 96.3, 127.5, 128.4, 128.5, 129.4, 130.3,
134.0, 134.1, 135.6. HRMS (EI) m/z Calcd for
C30H44O3Si: 480.3060. Found: 480.3042.
99%): [a]24 ˆ297.3 (c 1.2, CHCl3); IR nmax(neat) cm21
D
1
1428, 1206, 1113, 1084; H NMR (270 MHz, CDCl3) d
0.99 (3H, d, Jˆ6.6 Hz, C26±CH3), 1.04 (9H, s, (CH3)3C),
1.81 (3H, d, Jˆ1.3 Hz, C27±CH3), 2.60±2.70 (1H, m, C22±
CH), 3.45±3.50 (2H, m, CH2), 3.79 (1H, A of AB,
Jˆ9.6 Hz, C19±CH2), 4.01 (1H, B of AB, Jˆ9.6 Hz, C19±
CH2), 5.15 (1H, dd, Jˆ9.9, 1.3 Hz, C21±CH), 7.34±7.45
(6H, m, ArH), 7.63±7.67 (4H, m, ArH); 13C NMR
(67.8 MHz, CDCl3) d 17.0, 19.2, 22.0, 26.8, 32.6, 35.7,
68.1, 127.6, 129.6, 131.9, 133.8, 134.4, 135.6. HRMS (EI)
m/z Calcd for C19H2279BrOSi: 373.0623 (M12t-Bu). Found:
373.0622.
3.1.7. (2R,3Z,6E)-10-(Methoxymethyloxy)-2,4-dimethyl-
3,6-decadien-1-ol (25). To a stirred solution of 24 (86 mg,
0.18 mmol) in THF (1 mL) was added TBAF (140 mg,
0.54 mmol) at 08C. The reaction mixture was stirred at
08C for 30 min and then at room temperature for 1.5 h.
After dilution with ether, the organic layer was washed
with water and brine, dried (MgSO4), ®ltered, and concen-
trated. The residue was puri®ed by ¯ash chromatography
(BW-820 MH, hexane/EtOAcˆ5:1) to afford the desired
product 25 as a colorless oil (39 mg, 0.16 mmol, 90%):
3.1.5. (1E)-5-(Methoxymethyloxy)-1-pentenyl iodide
(23). To a stirred solution of (4E)-5-iodo-4-penten-1-ol16
(844 mg, 3.98 mmol) in CH2Cl2 (13 mL) at 08C was
added i-Pr2NEt (1.4 mL, 8.04 mmol) and MOMCl
[a]26 ˆ15.3 (c 1.0, CHCl3); IR nmax(neat) cm21 3432,
D
1
1443, 1150, 1113, 1040; H NMR (270 MHz, CDCl3) d
0.93 (3H, d, Jˆ6.6 Hz, C26±CH3), 1.45 (1H, br, OH),
1.63±1.69 (2H, m, C15±CH2), 1.71 (3H, d, Jˆ1.0 Hz,

6318
F. Yokokawa et al. / Tetrahedron 57 (2001) 6311±6327
C27±CH3), 2.05±2.13 (2H, m, C16±CH2), 2.55±2.70 (1H, m,
C22±CH), 2.75 (2H, m, C19±CH2), 3.28±3.35 (1H, m, C23±
CH2), 3.36 (3H, s, OCH2OCH3), 3.43±3.45 (1H, m, C23±
CH2), 3.52 (2H, t, Jˆ6.6 Hz, C14±CH2), 4.61 (2H, s,
OCH2OCH3), 4.93 (1H, d, Jˆ9.9 Hz, C21±CH), 5.33±5.52
(2H, m, C17 and C18±CH); 13C NMR (67.8 MHz, CDCl3) d
17.3, 23.5, 29.0, 29.5, 35.3, 35.5, 55.0, 67.1, 67.8, 96.3,
128.0, 128.1, 130.6, 136.4. Anal. Calcd for C14H26O3: C,
69.38; H, 10.81. Found: C, 69.14; H, 10.83.
(2H, m, C19±CH2), 2.99±3.09 (1H, m, C22±CH), 3.36 (3H,
s, OCH2OCH3), 3.52 (2H, t, Jˆ6.6 Hz, C14±CH2), 4.61 (2H,
s, OCH2OCH3), 5.00 (1H, d, Jˆ8.9 Hz, C21±CH), 5.30±
5.49 (4H, m, C17 and C18 and C23 and C24±CH); 13C NMR
(67.8 MHz, CDCl3) d 17.9, 21.4, 23.3, 29.1, 29.5, 35.2,
35.3, 55.1, 67.1, 96.4, 122.5, 128.2, 130.2, 130.4, 132.4,
136.2. HRMS (EI) m/z Calcd for C16H28O2: 252.2089.
Found: 252.2087.
3.1.10. (4E,7Z,9S,10E)-7,9-Dimethyl-4,7,10-dodecatri-
enol (28). To a stirred solution of 27 (66 mg, 0.26 mmol)
in THF (0.8 mL) was added 20% aqueous HCl (0.8 mL).
The reaction mixture was stirred at room temperature for
6 h, and then MeOH (0.1 mL) was added. After 3.5 h, the
reaction mixture was quenched by the addition of saturated
aqueous NaHCO3, and extracted with ether (£1). The
organic extracts were washed with water and brine, dried
(MgSO4), ®ltered, and concentrated. The residue was puri-
®ed by ¯ash chromatography (BW-820 MH, hexane/
etherˆ5:1) to afford the desired product 28 as a colorless
3.1.8. (1E,3R,4Z,7E)-11-(Methoxymethyloxy)-3,5-dimethyl-
1,4,7-undecatrienyl iodide (26). To a stirred solution of 25
(138 mg, 0.57 mmol) and triethylamine (0.24 mL,
1.73 mmol) in CH2Cl2 (1.3 mL)-DMSO (1.3 mL) was
added Py´SO3 (272 mg, 1.71 mmol) at 08C. The reaction
mixture was allowed to warm to room temperature and
stirred for 15 min. The mixture was poured into saturated
aqueous NaHCO3 and extracted with ether (£1). The
organic extracts were washed with 1 M aqueous KHSO4,
water and brine, dried (MgSO4), ®ltered, and concentrated
to afford the aldehyde.
oil (45 mg, 0.22 mmol, 83%): [a]25 ˆ257.2 (c 0.8,
D
CHCl3); IR nmax(neat) cm21 3346, 1449, 1375, 1057; H
1
To a suspension of CrCl2 (420 mg, 3.42 mmol) in THF
(3 mL) was added a solution of the aldehyde and iodoform
(449 mg, 1.14 mmol) in THF (1 mL, plus 0.5 mL of rinse)
via cannula at 08C. The reaction mixture was allowed to
warm to room temperature and stirred for 50 min. The
mixture was poured into water, and extracted with ether
(£2). The organic extracts were washed with brine, dried
(MgSO4), ®ltered, and concentrated. The residue was puri-
®ed by ¯ash chromatography (BW-820 MH, hexane only,
hexane/etherˆ40:1±30:1) to afford the desired product 26
NMR (270 MHz, CDCl3) d 0.99 (3H, d, Jˆ6.9 Hz, C26±
CH3), 1.43 (1H, br, OH), 1.61±1.69 (8H, m, C25 and C27±
CH3 and C15±CH2), 2.05±2.13 (2H, m, C16±CH2), 2.69±
2.75 (2H, m, C19±CH2), 3.01 (1H, m, C22±CH), 3.65 (2H,
t, Jˆ6.6 Hz, C14±CH2), 5.00 (1H, d, Jˆ9.2 Hz, C21±CH),
5.36±5.48 (4H, m, C17 and C18 and C23 and C24±CH); 13C
NMR (67.8 MHz, CDCl3) d 17.9, 21.4, 23.3, 28.8, 32.4,
35.2, 35.3, 62.4, 122.5, 128.3, 130.2, 130.4, 132.3, 136.2.
HRMS (EI) m/z Calcd for C14H24O: 208.1827. Found:
208.1827.
as a pale yellow oil (142 mg, 0.39 mmol, 68%): [a]25
ˆ
D
2118.5 (c 1.1, CHCl3); IR nmax(neat) cm21 1453, 1150,
3.1.11. (4E,7Z,9S,10E)-7,9-Dimethyl-4,7,10-dodecatri-
enoic acid (8). To a stirred solution of 28 (62 mg,
0.30 mmol) in DMF (2.7 mL) was added PDC (784 mg,
2.08 mmol). The reaction mixture was stirred at room
temperature for 3.5 h, and then poured into water. The
mixture was extracted with ether (£2), and the organic
extracts were washed with 1 M aqueous KHSO4 and
brine, dried (MgSO4), ®ltered, and concentrated. The resi-
due was puri®ed by ¯ash chromatography (BW-820 MH,
hexane/EtOAcˆ4:1) to afford the desired product 8 as a
1
1113, 1044; H NMR (270 MHz, CDCl3) d 1.04 (3H, d,
Jˆ6.9 Hz, C26±CH3), 1.61±1.71 (2H, m, C15±CH2), 1.66
(3H, d, Jˆ1.3 Hz, C27±CH3), 2.05±2.13 (2H, m,
C16±CH2), 2.68 (2H, d, Jˆ5.9 Hz, C19±CH2), 3.07±3.15
(1H, m, C22±CH), 3.36 (3H, s, OCH2OCH3), 3.52 (2H, t,
Jˆ6.6 Hz, C14±CH2), 4.62 (2H, s, OCH2OCH3), 4.96 (1H,
d, Jˆ8.9 Hz, C21±CH), 5.28±5.48 (2H, m, C17 and C18±
CH), 5.96 (1H, dd, Jˆ14.5, 1.7 Hz, C24±CH), 6.45 (1H,
dd, Jˆ14.5, 6.6 Hz, C23±CH); 13C NMR (67.8 MHz,
CDCl3) d 20.4, 23.4, 29.0, 29.5, 35.4, 39.0, 55.1, 67.1,
73.8, 96.4, 127.4, 127.6, 130.8, 134.5, 150.5. Anal. Calcd
for C15H25IO2: C, 49.46; H, 6.92. Found: C, 49.56; H, 6.91.
colorless oil (48 mg, 0.22 mmol, 72%): [a]25 ˆ278.1 (c
D
0.6, CHCl3); IR nmax(neat) cm21 3500±2500, 1713, 1441,
1
1412, 1283; H NMR (270 MHz, CDCl3) d 0.99 (3H, d,
Jˆ6.9 Hz, C26±CH3), 1.63 (6H, m, C25 and C27±CH3),
2.29±2.45 (4H, m, C16 and C19±CH2), 2.69±2.71 (2H, m,
C15±CH2), 2.99 (1H, m, C22±CH), 5.00 (1H, d, Jˆ9.6 Hz,
C21±CH), 5.35±5.45 (4H, m, C17 and C18 and C23 and C24±
CH), 11.22 (1H, br, OH); 13C NMR (67.8 MHz, CDCl3) d
17.9, 21.4, 23.3, 27.5, 34.1, 35.3, 35.4, 122.5, 128.6, 129.3,
130.4, 132.1, 136.2, 179.7. HRMS (EI) m/z Calcd for
C14H22O2: 222.1620. Found: 222.1618.
3.1.9.
(4E,7Z,9R,10E)-1-(Methoxymethyloxy)-7,9-di-
methyl-4,7,10-dodecatriene (27). To a solution of 26
(62 mg, 0.17 mmol) in THF (1 mL) was added Pd(Ph3P)4
(20 mg, 0.017 mmol) and MeMgBr (0.93 M in THF,
1.1 mL, 1 mmol). The reaction mixture was stirred at
room temperature for 1.5 h, and then quenched by the
addition of saturated aqueous NH4Cl, and extracted with
ether (£1). The organic extracts were washed with brine,
dried (MgSO4), ®ltered, and concentrated. The residue was
puri®ed by ¯ash chromatography (BW-820 MH, hexane/
etherˆ100:1±50:1) to afford the desired product 27 as a
3.1.12. 2-[(2S)-2-Hydroxy-4-pentenyl]-1,3-dithiane (30).
1,3-Dithiane (2.765 g, 23.0 mmol) was dissolved in THF
(31 mL) and cooled to 2108C. n-Butyllithium (1.5 M in
hexane, 16 mL, 24.0 mmol) was added and the solution
was stirred at 2108C for 2 h, and then cooled to 2788C.
A solution of (R)-glycidyl tosylate (29) (5 g, 21.9 mmol) in
THF (8 mL, plus 3 mL £2 of rinse) was added by cannula,
and the solution was maintained at 2788C for 3.5 h and
colorless oil (46 mg, 0.17 mmol, 100%): [a]25 ˆ260.1 (c
D
0.9, CHCl3); IR nmax(neat) cm21 1453, 1385, 1377, 1150,
1
1113, 1044; H NMR (270 MHz, CDCl3) d 1.00 (3H, d,
Jˆ6.6 Hz, C26±CH3), 1.61±1.71 (8H, m, C25 and C27±CH3
and C15±CH2), 2.05±2.12 (2H, m, C16±CH2), 2.68±2.72

F. Yokokawa et al. / Tetrahedron 57 (2001) 6311±6327
6319
allowed to warm to room temperature over 2 h. Saturated
aqueous NaHCO3 was added, and the mixture was extracted
with ether (£1). The organic layer was washed with brine,
dried (MgSO4), ®ltered, and concentrated. The residue was
puri®ed by ¯ash chromatography (BW-820 MH, hexane/
EtOAcˆ10:1±4:1) to afford the epoxide as a colorless oil
(2.625 g, 14.9 mmol), which was directly employed for the
next step.
129.2, 130.5, 133.9, 158.8. HRMS (EI) m/z Calcd for
C17H24O2S2: 324.1218. Found: 324.1216.
3.1.14. (3S)-3-p-Methoxybenzyloxy-5-hexenal (13). To a
stirred solution of 31 in CH3CN/H2O (9:1, 20 mL) was
added CaCO3 (6 g, 59.9 mmol) and MeI (3.4 mL,
54.6 mmol). The resulting mixture was stirred at 408C for
11 h, then ®ltered through a pad of celite, and the ®ltrate was
concentrated. The residue was puri®ed by ¯ash chroma-
tography (BW-820 MH, hexane/EtOAcˆ8:1) to afford the
desired product 13 as a colorless oil (939 mg, 4.01 mmol,
To a stirred suspension of CuI (425 mg, 2.23 mmol) in THF
(70 mL) was added vinylmagnesium bromide (0.95 M in
THF, 23.5 mL, 22.3 mmol) at 2508C. After the mixture
was stirred for 30 min, a solution of the epoxide (2.625 g,
14.9 mmol) in THF (10 mL, plus 2 mL of rinse) was added
by cannula. The resulting mixture was stirred at 2408C for
40 min, and then allowed to warm to 2108C over 30 min.
The reaction mixture was quenched by the addition of satu-
rated aqueous NH4Cl and the bulk of THF was removed.
The residue was extracted with ether (£1), and the organic
extracts were washed with brine, dried (MgSO4), ®ltered,
and concentrated. The residue was puri®ed by ¯ash
chromatography (BW-820 MH, hexane/EtOAcˆ6:1±4:1)
to afford the desired product 30 as a colorless oil (2.803 g,
74%): [a]26 ˆ139.6 (c 1.0, CHCl3); IR nmax(neat) cm21
D
1725, 1642, 1613, 1586, 1514, 1466, 1443, 1248; 1H
NMR (270 MHz, CDCl3)
d
2.31±2.52 (2H, m,
CH2CHvCH2), 2.57±2.72 (2H, m, C5±CH2), 3.80 (3H, s,
OCH3), 3.97±4.06 (1H, m, C4±CH), 4.45 (1H, d, Jˆ
11.0 Hz, CH2Ar), 4.56 (1H, d, Jˆ11.0 Hz, CH2Ar), 5.10±
5.15 (2H, m, CH2CHvCH2), 5.73±5.88 (1H, m,
CH2CHvCH2), 6.87 (2H, d, Jˆ8.6 Hz, ArH), 7.24 (2H,
Jˆ8.9 Hz, ArH), 9.76 (1H, s, CHO); 13C NMR
(67.8 MHz, CDCl3) d 38.3, 48.0, 55.2, 70.8, 73.2, 113.7,
118.0, 129.2, 130.0, 133.4, 159.1, 201.1. HRMS (EI) m/z
Calcd for C14H18O3: 234.1256. Found: 234.1257.
13.7 mmol, 63%): [a]26 ˆ124.2 (c 1.0, CHCl3); IR nmax
-
D
(neat) cm21 3432, 1640, 1422, 1275, 1244; 1H
NMR (270 MHz, CDCl3) d 1.89 (2H, t, Jˆ6.8 Hz,
±SCH2CH2CH2S±), 2.03 (1H, br, OH), 2.10±2.18 (2H, m,
C5±CH2), 2.20±2.33 (2H, m, CH2CHvCH2), 2.81±2.97
(4H, m, ±SCH2CH2CH2S±), 3.99 (1H, br, C4±CH), 4.27
(1H, t, Jˆ7.3 Hz, C6±CH), 5.14 (2H, d, Jˆ12.9 Hz,
CH2CHvCH2), 5.74±5.89 (1H, m, CH2CHvCH2); 13C
NMR (67.8 MHz, CDCl3) d 25.9, 30.0, 30.3, 41.9, 42.1,
44.4, 67.4, 118.2, 133.9. HRMS (EI) m/z Calcd for
C9H16OS2: 204.0643. Found: 204.0651.
3.1.15. 4-Acetyl-2-((E)-2-phenylethenyl)oxazole (14). To
a slurry of the N,O-dimethyl hydroxylamine hydrochloride
(130 mg, 1.33 mmol) in CH2Cl2 (3 mL) was added dropwise
trimethylaluminum (1.02 M in hexane, 1.3 mL, 1.33 mmol)
at 08C. After 30 min, a solution of the ester 3220 in CH2Cl2
(2 mL plus 1 mL £2 of rinse) was added by cannula. The
reaction mixture was stirred at 08C for 1 h, then warmed to
room temperature, and stirred for 40 h. Aqueous KHSO4
(1 M) was added and then the mixture was diluted with
water. The aqueous layer was extracted with CHCl3 (£3)
and washed with brine. The organic layer was dried
(Na2SO4), ®ltered, and concentrated to give the crude
Weinreb amide. This intermediate was used in the next
reaction without further puri®cation.
3.1.13. 2-[(2S)-2-p-Methoxybenzyloxy-4-pentenyl]-1,3-
dithiane (31). KH (35% oil dispersion, 1.2 g, 10.5 mmol)
was suspended in THF (15 mL) and cooled to 2158C. A
solution of the alcohol 30 (1.482 g, 7.25 mmol) in THF
(5 mL, plus 312 mL of rinse) was added by cannula, and
the solution was stirred for 5 min. To the resulting solution
was added PMBCl (1.2 mL, 8.85 mmol) and Bu4NI (1.3 g,
3.52 mmol). The reaction mixture was stirred at 2108C for
30 min, and then allowed to warm to room temperature over
1 h. The excess KH was quenched by the addition of metha-
nol, followed by 1 M aqueous KHSO4. The resulting
mixture was extracted with ether (£1), and the organic
layer was washed with water and brine, dried (MgSO4),
®ltered, and concentrated. The residue was puri®ed by
¯ash chromatography (BW-820 MH, hexane/etherˆ10:1)
to afford the desired product 31 as a pale yellow oil
To a solution of the above amide in THF (5 mL) was added
MeMgBr (0.93 M in THF, 1.3 mL, 1.15 mmol) at 2788C.
After 15 min, the mixture was warmed to 2208C and stirred
at this temperature for 30 min. After addition of 1 M
aqueous KHSO4, the mixture was diluted with EtOAc, and
washed with 1 M aqueous KHSO4, water, and brine. The
organic layer was dried (Na2SO4), ®ltered, and concen-
trated. The residue was puri®ed by silica gel column chro-
matography (BW-200, hexane/EtOAcˆ4:1±2:1) to afford
the desired product 14 as a pale yellow solid (111 mg,
0.520 mmol, 59%): mp 153±1548C (hexane/EtOAc); IR
n
max(CHCl3) cm21 3021, 1690, 1559, 1474, 1217, 1113;
(2.022 g, 6.23 mmol, 86%): [a]25 ˆ135.9 (c 1.0, CHCl3);
1H NMR (270 MHz, CDCl3) d 2.57 (3H, s, CH3CO), 6.95
(1H, d, Jˆ16.4 Hz, Ph±CHv), 7.34±7.44 (3H, m, ArH),
7.53±7.57 (2H, m, ArH), 7.61 (1H, d, Jˆ16.4 Hz, Ph±
CHvCH), 8.18 (1H, s, oxazole-5-H); 13C NMR
(67.8 MHz, CDCl3) d 27.5, 112.8, 127.3, 128.9, 129.6,
134.8, 138.2, 141.6, 141.8, 161.6, 192.5. HRMS (EI) m/z
Calcd for C13H11NO2: 213.0790. Found: 213.0780.
D
IR nma1x(neat) cm21 1640, 1613, 1586, 1514, 1464, 1422,
1248; H NMR (270 MHz, CDCl3) d 1.87±2.02 (3H, m,
±SCH2CH2CH2S±, C5±CH2), 2.08±2.13 (1H, m, C5±
CH2), 2.31±2.34 (2H, m, CH2CHvCH2), 2.74±2.92 (4H,
m, ±SCH2CH2CH2S±), 3.74 (1H, m, C4±CH), 3.81 (3H, s,
OCH3), 4.16 (1H, dd, Jˆ9.4, 5.1 Hz, C6±CH), 4.44 (1H, d,
Jˆ11.0 Hz, CH2Ar), 4.57 (1H, d, Jˆ11.0 Hz, CH2Ar),
5.07±5.14 (2H, m, CH2CHvCH2), 5.74±5.90 (1H, m,
CH2CHvCH2), 6.88 (2H, d, Jˆ8.4 Hz, ArH), 7.28 (2H,
Jˆ8.6 Hz, ArH); 13C NMR (67.8 MHz, CDCl3) d 25.9,
29.8, 30.2, 38.4, 40.0, 43.8, 55.1, 71.0, 74.5, 113.5, 117.4,
3.1.16. 4-[(3R,5R)-3-Hydroxy-5-(p-methoxybenzyloxy)-
7-octenoyl]-2-((E)-2-phenylethenyl)oxazole (34). To a
solution of the methyl ketone 14 (32.2 mg, 0.151 mmol)
in CH2Cl2 (1 mL) was added triethylamine (52 mL,

6320
F. Yokokawa et al. / Tetrahedron 57 (2001) 6311±6327
Figure 2.
0.378 mmol) and trimethylsilyl tri¯ate (41 mL, 0.227 mmol)
at 08C. After 30 min, saturated aqueous NaHCO3 was added
to the mixture, which was diluted with water. The aqueous
layer was extracted with CH2Cl2 and washed with brine. The
organic layer was dried (Na2SO4), ®ltered, and concen-
trated. This intermediate was used in the next reaction
without further puri®cation.
dried (MgSO4), ®ltered, and concentrated. The residue
was puri®ed by silica gel column chromatography (BW-
200, hexane/EtOAcˆ4:1) to afford the desired cyclic
p-methoxybenzylidene acetal (Fig. 2) as a pale yellow
solid (21.7 mg, 48.7 mmol, 77%): mp 108±1108C (hexane/
21
EtOAc); [a]D ˆ216.5 (c 0.49, CHCl3); IR nmax(CHCl3)
cm21 2942, 1688, 1646, 1617, 1559, 1516, 1248, 1171,
1117, 1038; H NMR (270 MHz, CDCl3) d 1.63 (1H, br±
1
To a solution of the above silyl ether 33 in CH2Cl2 (0.3 mL)
was added a solution of the aldehyde 13 (37.1 mg,
0.158 mmol) in CH2Cl2 (0.3 mL plus 0.2 mL £2 of rinse)
via cannula at 2788C. Successively BF3´Et2O (21 mL,
0.166 mmol) was added dropwise. After 30 min, pH 7 phos-
phate buffer was added and the mixture was warmed to
room temperature. The mixture was diluted with EtOAc,
and washed with water and brine. The organic layer was
dried (Na2SO4), ®ltered, and concentrated. The residue
was puri®ed by silica gel column chromatography
(BW-200, hexane/EtOAcˆ2:1) to afford the desired product
34 as a white powder (50.6 mg, 0.113 mmol, 75%): mp
s, C5±CH2), 2.02±2.14 (1H, m, C5±CH2), 2.23±2.34 (1H,
m, C3±CH2), 2.37±2.52 (1H, m, C3±CH2), 3.35 (1H, dd,
Jˆ7.1, 15.0 Hz, C7±CH2), 3.68±3.76 (1H, m, C7±CH2),
3.76 (3H, s, Ar±OCH3), 4.08±4.19 (1H, m, C4±CH),
4.92±5.01 (1H, m, C6±CH), 5.07±5.16 (2H, m,
CHvCH2), 5.80±5.95 (1H, m, CHvCH2), 5.92 (1H, s,
PMP±CH), 6.82±6.96 (3H, m, ArH, Ph±CHvCH), 7.35±
7.43 (5H, m, ArH), 7.51±7.63 (3H, m, ArH, Ph±CHvCH),
8.19 (1H, s, C10±H); 13C NMR (67.8 MHz, CDCl3) d 33.3,
40.5, 41.5, 55.3, 69.3, 71.8, 94.7, 112.7, 113.5, 117.4, 127.3
(CH £2), 128.9 (CH £2), 129.6, 131.1, 133.6, 134.8, 138.2,
141.5, 159.6, 161.5, 192.8. Anal. Calcd for C27H27NO5: C,
72.79; H, 6.11; N, 3.14. Found: C, 72.46; H, 6.18; N, 3.26.
25
104±1068C (hexane/EtOAc); [a]D ˆ110.7 (c 0.70,
CHCl3); IR nmax(CHCl3) cm21 3544 (br), 3013, 1684,
1646, 1612, 1559, 1514, 1302, 1248, 1217, 1075; 1H
NMR (270 MHz, CDCl3) d 1.68±1.79 (2H, m, C5±CH2),
2.33±2.43 (2H, m, C3±CH2), 3.05±3.08 (2H, m, C7±CH2),
3.39 (1H, d, Jˆ3.3 Hz, C6±OH), 3.78 (3H, s, Ar±OCH3),
3.76±3.82 (1H, m, C4±CH), 4.38±4.54 (1H, m, C6±CH),
4.45 (1H, d, Jˆ11.0 Hz, Ar±CH2), 4.60 (1H, d, Jˆ
11.0 Hz, Ar±CH2), 5.07±5.14 (2H, m, CHvCH2), 5.76±
5.91 (1H, m, CHvCH2), 6.83±6.96 (3H, m, ArH,
Ph±CHvCH), 7.24±7.33 (2H, m, ArH), 7.34±7.43 (3H,
m, ArH), 7.45±7.62 (3H, m, ArH, Ph±CHvCH), 8.15
(1H, s, C10±H); 13C NMR (67.8 MHz, CDCl3) d 38.5
(38.0), 40.7 (40.5), 47.2, 55.3, 64.8 (67.0), 71.2 (70.4),
75.2, 112.7, 113.8, 117.4, 127.3, 128.9, 129.4, 129.6,
130.4, 134.3, 134.8, 138.3, 141.5, 141.8, 159.1, 161.6,
194.7. Figures in parentheses show signals of the minor
diastereomer. Anal. Calcd for C27H29NO5: C, 72.46; H,
6.53; N, 3.13. Found: C, 72.59; H, 6.52; N, 3.10.
3.2. Stereochemical proof of 34
The NOE analysis of the above cyclic p-methoxybenzyl-
idene acetal established the 1,3-anti dioxygen relationship
of the acetal, thereby securing the stereochemical assign-
ment of the aldol adduct 34.
3.2.1. 2-((E)-Phenylethenyl)-4-{(4R,6R)-2,2-dimethyl-4-
[(2S)-2-(p-methoxybenzoloxy)-4-pentenyl]-1,3-dioxan-6-
yl}oxazole (36). To a solution of the aldol adduct 34
(21.8 mg, 48.7 mmol) in THF (0.5 mL) was added diethyl-
methoxyborane (1.0 M in THF, 97 mL, 97.4 mmol) at
2788C. After 40 min, NaBH4 (5 mg, 0.122 mmol) was
added and the reaction mixture was stirred at this tempera-
ture for 4 h. After addition of pH 7 phosphate buffer
(0.5 mL), MeOH (0.3 mL) and 30% aqueous H2O2
(0.4 mL) were added at 08C. The mixture was stirred at
08C for 15 min and then warmed to room temperature
over 30 min. After dilution with water, the aqueous layer
was extracted with EtOAc (£3) and washed with brine. The
organic layer was dried (Na2SO4), ®ltered, and concen-
trated. The residue was puri®ed by silica gel column
chromatography (BW-200, hexane/EtOAcˆ2:1±1:1) to
afford the desired syn-diol 35 as a white powder (19.9 mg,
44.3 mmol, 91%), which was directly used for the next step.
3.1.17. 2-((E)-2-Phenylethenyl)-4-{[(2S,4R,6R)-2-(p-meth-
oxyphenyl)-6-(2-methyl-1,3-dioxolan-2-yl)methyl]-1,3-
dioxan-4-yl}acetyloxazole. To a solution of the aldol
adduct 34 (28.4 mg, 63.4 mmol) in CH2Cl2 (1 mL) was
Ê
added molecular sieves 4 A powder (60 mg) and DDQ
(16 mg, 69.8 mmol). After 30 min, the reaction mixture
was diluted with Et2O, and then washed with saturated
aqueous NaHCO3 (£3) and brine. The organic layer was

F. Yokokawa et al. / Tetrahedron 57 (2001) 6311±6327
6321
Figure 3.
The above syn-diol (13.7 mg, 30.5 mmol) was dissolved in
2,2-dimethoxypropane (0.8 mL), and then p-toluenesulfonic
acid (1 mg) was added. After 1 h, saturated aqueous
NaHCO3 was added and then the mixture was diluted with
water. The aqueous layer was extracted with EtOAc and
washed with brine. The organic layer was dried (Na2SO4),
®ltered, and concentrated. The residue was puri®ed by silica
gel column chromatography (BW-200, hexane/EtOAcˆ4:1)
to afford the desired product as a colorless oil (13.4 mg,
resulting solution was stirred at 2788C for 2 h and then
quenched by the addition of saturated aqueous NaHCO3.
The mixture was extracted with CHCl3 (£3), and the
combined organic extracts were dried (Na2SO4), ®ltered,
and concentrated. The residue was puri®ed by ¯ash
chromatography (BW-820 MH, hexane/EtOAcˆ6:1±4:1±
3:1) to afford the desired product 43 as a colorless oil
(1.178 g, 3.10 mmol, 89%) in an inseparable 88:12 mixture
of diastereomers, which were directly used for the next step:
[a]26 ˆ125.9 (c 1.4, MeOH); IR nmax(neat) cm21 1684,
25
27.4 mmol, 90%): [a]D ˆ122.8 (c 0.79, CHCl3); IR
D
1
1651, 1611, 1514, 1451, 1339, 1248; H NMR (500 MHz,
n
max(CHCl3) cm21 2914, 1644, 1613, 1514, 1381, 1250,
1
1165, 1094; H NMR (270 MHz, CDCl3) d 1.46 (3H, s,
CH3), 1.53 (3H, s, CH3), 1.58±1.70 (3H, m, C5±CH2,
C7±CH2), 1.79±1.85 (1H, m, C7±CH2), 2.32±2.40 (2H, m,
C3±CH2), 3.72±3.79 (1H, m, C4±CH), 3.80 (3H, s,
Ar±OCH3), 4.18±4.29 (1H, m, C6±CH), 4.40 (1H, d, Jˆ
10.9 Hz, Ar±CH2), 4.57 (1H, d, Jˆ10.9 Hz, Ar±CH2),
4.93±4.99 (1H, m, C8±CH), 5.06±5.13 (2H, m,
CHvCH2), 5.78±5.93 (1H, m, CHvCH2), 6.86±6.95
(3H, m, ArH, Ph±CHvCH), 7.29±7.53 (9H, m, ArH,
Ph±CHvCH, C10±H); 13C NMR (67.8 MHz, CDCl3) d
19.9 (19.8), 30.3, 36.6, 38.9 (38.3), 41.8, 55.3, 65.3 (65.4),
65.5 (66.0), 71.3 (70.3), 73.9, 99.1, 113.7, 113.8, 117.2,
127.0, 128.7, 129.1, 129.3, 129.5, 134.39, 134.42, 135.3,
136.1, 143.2, 159.0, 161.4. Figures in parentheses show
signals of the minor diastereomer. HRMS (EI) m/z Calcd
for C30H35NO5: 489.2515. Found: 489.2503.
CDCl3) d 1.61±1.66 (1H, m, C5±CH2), 1.70±1.75 (1H, m,
C5±CH2), 2.33±2.45 (2H, m, CH2CHvCH2), 2.78 (1H, dd,
Jˆ17.1, 8.2 Hz, C7±CH2) (2.69, dd, Jˆ16.4, 4.6 Hz), 2.86
(1H, dd, Jˆ17.1, 3.7 Hz, C7±CH2), 3.43 (1H, d, Jˆ3.0 Hz,
OH), 3.77 (3H, s, OCH3) (3.75, s), 3.79±3.85 (1H, m,
C4±CH), 4.32±4.43 (1H, m, C6±CH), 4.45 (1H, d, Jˆ
11.0 Hz, CH2Ar), 4.60 (1H, d, Jˆ11.0 Hz, CH2Ar) (4.61,
d, Jˆ11.0 Hz), 5.08±5.14 (2H, m, CH2CHvCH2), 5.80±
5.89 (1H, m, CH2CHvCH2), 6.67 (1H, d, Jˆ16.4 Hz,
CHvCHPh) (6.72, d, Jˆ16.4 Hz), 6.86 (2H, d, Jˆ8.8 Hz,
ArH), 7.27 (2H, d, Jˆ8.6 Hz, ArH), 7.39±7.42 (3H, m,
CHvCHPh and ArH), 7.50±7.55 (3H, m, ArH); 13C NMR
(67.8 MHz, CDCl3) d 37.5 (37.9), 40.8 (40.4), 47.3, 55.2
(55.15), 65.1 (67.1), 71.2 (70.3), 76.5, 113.7 (113.8), 117.3
(117.6), 126.2 (126.4), 128.2 (128.4), 128.8 (128.6), 129.4
(129.9), 130.4, 130.5, 134.1 (133.8), 134.3 (134.2), 143.2
(143.0), 159.0 (159.2), 200.2 (199.5). Figures in parentheses
show signals of the minor diastereomer. Anal. Calcd for
C24H28O4: C, 75.76; H, 7.42. Found: C, 75.60; H, 7.43.
3.2.2. 2-Trimethylsiloxy-4-phenyl-1,3-butadiene (42). To
a solution of benzalacetone (41) (1.08 g, 7.39 mmol) and
triethylamine (1.54 mL, 11.1 mmol) in CH2Cl2 (25 mL) at
2108C was added dropwise TMSOTf (1.8 mL, 9.95 mmol).
After 15 min, the solution was poured into saturated
aqueous NaHCO3 and extracted with CHCl3 (£3). The
organic layer was dried (Na2SO4), ®ltered, and concen-
trated. The residue was puri®ed by ¯ash chromatography
(BW-820 MH, hexane/EtOAcˆ5:1) to afford the labile
silyl enol ether 42 as a colorless oil (1.554 g, 7.12 mmol,
3.2.4.
4-[(2S,4S,6R)-2-p-Methoxybenzyloxy-4-(2-pro-
penyl)-1,3-dioxan-6-yl]-1-phenyl-2-buten-3-one. A sus-
pension of the aldol adduct 43 (48 mg, 0.126 mmol) and
Ê
powdered 4 A molecular sieves in CH2Cl2 (1.3 mL) was
stirred for 15 min prior to the addition of DDQ (40 mg,
0.176 mmol). After 20 min, the mixture was diluted with
ether and ®ltered through a pad of celite. The ®ltrate was
washed with saturated aqueous NaHCO3, water, and brine,
dried (MgSO4), ®ltered, and concentrated. The residue was
puri®ed by ¯ash chromatography (BW-820 MH, hexane/
EtOAcˆ7:1) to afford the cyclic p-methoxybenzylidene
acetal (Fig. 3) product as a colorless oil (31 mg,
96%), which was directly used for the next step: IR nmax
-
(neat) cm21 1634, 1599, 1589, 1495, 1449, 1329, 1312,
1287, 1254; H NMR (270 MHz, CDCl3) d 0.20 (9H, s,
1
Si(CH3)3), 4.43 (1H, s, C7±CH2), 4.47 (1H, s, C7±CH2),
6.58 (1H, d, Jˆ15.7 Hz, CHvCHPh), 6.80 (1H, d, Jˆ
15.7 Hz, CHvCHPh), 7.20±7.25 (1H, m, ArH), 7.29±
7.34 (2H, m, ArH), 7.40±7.43 (2H, m, ArH); 13C NMR
(67.8 MHz, CDCl3) d 0.20, 96.9, 126.3, 126.7, 127.5,
128.4, 129.1, 136.7, 154.9.
0.082 mmol, 65%): [a]26 ˆ232.2 (c 1.0, CHCl3); IR
D
1
n
max(neat) cm21 1688, 1659, 1613, 1576, 1518, 1248; H
NMR (270 MHz, C6D6) d 1.31±1.36 (1H, m, C5±CH2), 1.90
(1H, td, Jˆ12.7, 6.1 Hz, C5±CH2), 2.09±2.17 (1H, m,
CH2CHvCH2), 2.29±2.40 (1H, m, CH2CHvCH2), 2.66
(1H, dd, Jˆ15.2, 7.9 Hz, C7±CH2), 3.00 (1H, dd, Jˆ15.2,
6.6 Hz, C7±CH2), 3.24 (3H, s, OCH3), 3.81 (1H, m,
C4±CH), 4.80±4.85 (1H, m, C6±CH), 5.02±5.09 (2H, m,
CH2CHvCH2), 5.80 (1H, s, CHMP), 5.80±5.93 (1H, m,
CH2CHvCH2), 6.59 (1H, d, Jˆ16.2 Hz, CHvCHPh),
3.2.3. (1E,5R,7S)-1-Phenyl-5-hydroxy-7-p-methoxybenzyl-
oxy-1,9-decadiene-3-one (43). To a solution of the alde-
hyde 13 (818 mg, 3.49 mmol) and the silyl enol ether 42
(948 mg, 4.34 mmol) in CH2Cl2 (20 mL) at 2788C was
added dropwise BF3´OEt2 (0.55 mL, 4.34 mmol). The

6322
F. Yokokawa et al. / Tetrahedron 57 (2001) 6311±6327
6.81 (2H, d, Jˆ8.7 Hz, ArH), 7.01 (3H, m, ArH), 7.19 (2H,
m, ArH), 7.52 (1H, d, Jˆ16.2 Hz, CHvCHPh), 7.65 (2H, d,
Jˆ8.6 Hz, ArH); 13C NMR (67.8 MHz, CDCl3) d 33.1,
40.5, 42.6, 55.3, 69.2, 71.9, 94.8, 113.5, 117.4, 125.9,
127.3, 128.3, 128.9, 130.6, 131.1, 133.6, 134.1, 143.2,
159.7, 197.2. HRMS (EI) m/z Calcd for C24H26O4:
378.1831. Found: 378.1837.
159.1. Anal. Calcd for C27H34O4: C, 76.74; H, 8.11.
Found: C, 76.59; H, 8.22.
Data for the minor diastereomer 45: mp 87±898C (ether/
n-pentane); [a]25 ˆ129.3 (c 0.7, CHCl3); IR nmax(KBr)
D
1
cm21 1640, 1611, 1584, 1512, 1464, 1375, 1250; H NMR
(270 MHz, CDCl3) d 1.20±1.27 (2H, m, C5±CH2), 1.43
(3H, s, CH3), 1.49 (3H, s, CH3), 1.53±1.58 (1H, m,
C7±CH2), 1.80±1.91 (1H, m, C7±CH2), 2.33±2.38 (2H, m,
CH2CHvCH2), 3.52±3.56 (1H, m, C4±CH), 3.75 (3H, s,
OCH3), 4.00 (1H, m, C6±CH), 4.36 (1H, d, Jˆ11.5 Hz,
CH2Ar), 4.34±4.38 (1H, m, C8±CH), 4.55 (1H, d, Jˆ
11.5 Hz, CH2Ar), 5.06±5.13 (2H, m, CH2CHvCH2),
5.76±5.92 (1H, m, CH2CHvCH2), 6.08 (1H, dd, Jˆ16.0,
6.3 Hz, CHvCHPh), 6.53 (1H, d, Jˆ16.0 Hz, CHvCHPh),
6.88 (2H, d, Jˆ8.4 Hz, ArH), 7.19±7.38 (7H, m, ArH); 13C
NMR (67.8 MHz, CDCl3) d 20.0, 30.3, 36.8, 38.3, 40.5,
55.3, 65.9, 70.1, 70.2, 73.5, 98.6, 113.7, 117.3, 126.4,
127.5, 128.3, 129.7, 129.8, 130.4, 130.6, 134.4, 136.6,
159.1. Anal. Calcd for C27H34O4: C, 76.74; H, 8.11.
Found: C, 76.48; H, 7.94.
3.3. Stereochemical proof of 43
The NOE analysis of the above cyclic p-methoxybenzyl-
idene acetal established the 1,3-anti dioxygen relationship
of the acetal, thereby securing the stereochemical assign-
ment of the aldol adduct 43.
3.3.1.
(4S)-5-[(4R,6R)-4-((E)-2-Phenylethenyl)-2,2-di-
methyl-1,3-dioxan-6-yl]-4-p-methoxybenzyloxy-2-pen-
tene (44). To a stirred solution of the aldol adduct 43
(660 mg, 1.73 mmol) in THF (7 mL) at 2788C was added
Et2BOMe (1.0 M in THF, 1.9 mL, 1.9 mmol). After 30 min,
NaBH4 (66 mg, 1.74 mmol) was added, and the mixture was
stirred at 2788C for 1 h. The reaction mixture was quenched
by the addition of pH 7 phosphate buffer (1.1 mL) and
methanol (3.1 mL), then allowed to warm to 08C. To this
was added 2:1 methanol/30% aqueous H2O2 (3 mL) care-
fully. The mixture was stirred at 08C for 1.5 h, and then
allowed to warm to room temperature over 1.5 h. The
mixture was extracted with CHCl3 (£3), and the combined
organic extracts were washed with 1 M aqueous KHSO4 and
brine, dried (Na2SO4), ®ltered, and concentrated. The
residue was puri®ed by ¯ash chromatography (BW-820
MH, hexane/EtOAcˆ3:1±2:1) to afford the syn-diol as a
colorless oil (690 mg, 1.80 mmol), which was directly
used for the next step.
3.3.2.
(4R)-5-[(4R,6R)-4-((E)-2-Phenylethenyl)-2,2-di-
methyl-1,3-dioxan-6-yl]-4-p-methoxybenzyloxy-2-penta-
none (40). A suspension of 44 (286 mg, 0.677 mmol), PdCl2
(12 mg, 0.068 mmol), and Cu(OAc)2´H2O (27 mg, 0.135
mmol) in AcNMe2/H2O (7:1, 6 mL) was placed under O2
(balloon) and stirred at room temperature for 19.5 h. The
reaction mixture was diluted with ether, and washed with
water (£2) and brine, dried (MgSO4), ®ltered, and concen-
trated. The residue was puri®ed by ¯ash chromatography
(BW-820 MH, hexane/etherˆ2:1±1:1) to afford the desired
product 40 as a colorless oil (230 mg, 0.525 mmol, 77%):
[a]26 ˆ17.6 (c 1.0, CHCl3); IR nmax(neat) cm21 1713,
D
1
1613, 1586, 1514, 1379, 1360, 1248; H NMR (270 MHz,
CDCl3) d 1.37±1.70 (4H, m, C5 and C7±CH2), 1.46 (3H, s,
CH3), 1.50 (3H, s, CH3), 2.17 (3H, s, C1±CH3), 2.59 (1H, dd,
Jˆ15.8, 4.9 Hz, C3±CH2), 2.75 (1H, dd, Jˆ15.8, 6.9 Hz,
C3±CH2), 3.80 (3H, s, OCH3), 4.11±4.18 (2H, m, C4 and
C6±CH), 4.45 (1H, d, Jˆ10.7 Hz, CH2Ar), 4.53 (1H, d,
Jˆ10.9 Hz, CH2Ar), 4.44±4.55 (1H, m, C8±CH), 6.15
(1H, dd, Jˆ16.0, 6.3 Hz, CHvCHPh), 6.59 (1H, d, Jˆ
16.0 Hz, CHvCHPh), 6.88 (2H, d, Jˆ8.2 Hz, ArH),
7.23±7.39 (7H, m, ArH); 13C NMR (67.8 MHz, CDCl3) d
20.0, 30.3, 31.3, 37.6, 42.5, 49.5, 55.3, 65.3, 70.1, 71.8,
72.1, 98.7, 113.8, 126.4, 127.5, 128.4, 129.3, 129.7, 130.4,
130.6, 136.5, 159.1, 207.2. Anal. Calcd for C27H34O5: C,
73.94; H, 7.81. Found: C, 74.30; H, 8.12.
syn-Diol (690 mg, 1.80 mmol) was dissolved in 2,2-di-
methoxypropane (6 mL), and then PPTs (270 mg) was
added. After 26 h, an additional PPTs (270 mg) was added
and the mixture was stirred for 10 h. An additional PPTs
(270 mg) was added and the mixture was stirred for
additional 11 h. The mixture was diluted with ether, washed
with saturated aqueous NaHCO3, water, and brine, dried
(MgSO4), ®ltered, and concentrated. The residue was puri-
®ed by ¯ash chromatography (BW-200, hexane/etherˆ10:1,
hexane/EtOAcˆ5:1±2:1) to afford the desired product 44 as
a colorless oil (430 mg, 1.02 mmol, 59%), the minor
diastereomer 45 as white crystals (64 mg, 0.15 mmol,
9%), and the starting material (208 mg, 0.54 mmol, 31%).
Data for the desired product 44: [a]26 ˆ131.1 (c 1.0,
D
CHCl3); IR nmax(neat) cm21 1640, 1613, 1586, 1514,
1379, 1248; 1H NMR (270 MHz, CDCl3) d 1.27±1.41
(1H, m, C5±CH2), 1.46 (3H, s, CH3), 1.50 (3H, s, CH3),
1.56±1.63 (3H, m, C5 and C7±CH2), 2.33±2.37 (2H, m,
CH2CHvCH2), 3.73±3.78 (1H, m, C4±CH), 3.81 (3H, s,
OCH3), 4.16±4.20 (1H, m, C6±CH), 4.40 (1H, d, Jˆ
10.9 Hz, CH2Ar), 4.50±4.53 (1H, m, C8±CH), 4.58 (1H,
d, Jˆ10.9 Hz, CH2Ar), 5.07±5.15 (2H, m, CH2CHvCH2),
5.79±5.95 (1H, m, CH2CHvCH2), 6.16 (1H, dd, Jˆ16.0,
6.3 Hz, CHvCHPh), 6.58 (1H, d, Jˆ16.0 Hz, CHvCHPh),
6.89 (2H, d, Jˆ8.7 Hz, ArH), 7.19±7.39 (7H, m, ArH); 13C
NMR (67.8 MHz, CDCl3) d 20.1, 30.4, 37.7, 38.9, 41.9,
55.3, 65.3, 70.2, 71.4, 74.0, 98.7, 113.8, 117.2, 126.4,
127.5, 128.4, 129.3, 129.9, 130.5, 130.8, 134.5, 136.6,
3.3.3. (1E,3R)-4-[(2R,4R,6R)-4-p-Methoxybenzyloxy-2-
methoxy-2-methyl
tetrahydropyran-6-yl]-1-phenyl-3-
hydroxy-1-butene (46). Methyl ketone 40 (230 mg,
0.525 mmol) was dissolved in anhydrous methanol (5 mL)
and PPTS (10 mg, 0.040 mmol) was added in one portion.
After 6.5 h, NaHCO3 was added, and the mixture was
®ltered. The ®ltrate was concentrated. The residue was puri-
®ed by ¯ash chromatography (BW-820 MH, hexane/
EtOAcˆ2:1) to afford the desired product 46 as a colorless
oil (183 mg, 0.444 mmol, 85%): [a]26 ˆ250.3 (c 1.0,
D
CHCl3); IR nmax(neat) cm21 3475, 1613, 1586, 1514,
1
1495, 1383, 1362, 1248; H NMR (270 MHz, CDCl3) d
1.19±1.45 (2H, m, C3 and C5±CH2), 1.39 (3H, s,
C1±CH3), 1.73±1.93 (2H, m, C7±CH2), 2.02 (1H, d,

F. Yokokawa et al. / Tetrahedron 57 (2001) 6311±6327
6323
Jˆ12.4 Hz, C5±CH2), 2.26 (1H, dd, Jˆ12.7, 3.5 Hz,
C3±CH2), 3.23 (3H, s, C29±OCH3), 3.72 (1H, s, OH), 3.80
(3H, s, OCH3), 3.83±3.92 (2H, m, C4 and C6±CH), 4.47
(2H, s, CH2Ar), 4.54 (1H, br, C8±CH), 6.20 (1H, dd, Jˆ
15.8, 6.1 Hz, CHvCHPh), 6.64 (1H, d, Jˆ15.8 Hz,
CHvCHPh), 6.86 (2H, d, Jˆ8.4 Hz, ArH), 7.23±7.39
(7H, m, ArH); 13C NMR (67.8 MHz, CDCl3) d 23.8, 38.0,
41.9, 43.1, 48.0, 55.3, 69.7, 70.0, 70.9, 72.4, 100.1, 113.8,
126.3, 127.4, 128.4, 129.0, 129.6, 130.6, 131.6, 136.8,
159.0. Anal. Calcd for C25H32O5: C, 72.79; H, 7.82.
Found: C, 72.58; H, 8.01.
®ltered, and concentrated to afford the aldehyde (194 mg),
which was used for the next step without further
puri®cation.
To a solution of the aldehyde in THF (1.9 mL) at 2788C
was added dropwise Tebbe reagent (Cp2TiCH2AlClMe2)
(0.5 M in toluene, 1.85 mL, 0.93 mmol). The reaction
mixture was stirred at 2788C for 4 min, and then allowed
to warm to 08C over 8 min, and quenched by the addition of
0.1N aqueous NaOH. The mixture was stirred at room
temperature, and then ®ltered through a pad of celite by
washing with ether. The ®ltrate was separated and the
organic layer was washed with brine, dried (MgSO4),
®ltered, and concentrated. The residue was puri®ed by
¯ash chromatography (BW-820 MH, hexane/etherˆ5:1) to
afford the desired product 48 as a colorless oil (134 mg,
3.3.4. (1E,3R)-4-[(2R,4R,6R)-4-p-Methoxybenzyloxy-2-
methoxy-2-methyl
tetrahydropyran-6-yl]-1-phenyl-3-
methoxy-1-butene (47). To a solution of the alcohol 46
(108 mg, 0.262 mmol) in THF (2.5 mL) at 08C was added
NaH (60% oil dispersion, 26 mg, 0.650 mmol) in one
portion. After 30 min, to this mixture was added dropwise
MeI (0.033 mL, 0.530 mmol). The reaction mixture was
stirred at 08C for 40 min and then at room temperature for
14 h. The excess hydride was quenched by dropwise
addition of saturated aqueous NaHCO3. Ether was added,
the layers were separated, and the organic layer was washed
with 1 M aqueous KHSO4, water, and brine, dried (MgSO4),
®ltered, and concentrated. The residue was puri®ed by ¯ash
chromatography (BW-820 MH, hexane/EtOAcˆ7:1±5:1)
to afford the desired product 47 as a colorless oil (109 mg,
0.382 mmol, 72%): [a]26 ˆ251.4 (c 1.0, CHCl3); IR
D
n
max(neat) cm21 1615, 1588, 1514, 1248; 1H NMR
(270 MHz, CDCl3) d 1.20 (1H, q, Jˆ11.7 Hz, C5±CH2),
1.34 (3H, s, C1±CH3), 1.38 (1H, d, Jˆ11.9 Hz, C3±CH2),
1.53±1.62 (1H, m, C5±CH2), 1.89±1.92 (1H, m, C3±CH2),
1.94±2.04 (1H, m, C7±CH2), 2.22 (1H, dd, Jˆ12.5, 3.1 Hz,
C7±CH2), 3.15 (3H, s, C29±OCH3), 3.26 (3H, s, C28±OCH3),
3.61±3.66 (1H, br, C6±CH), 3.68±3.76 (1H, m, C4±CH),
3.80 (3H, s, OCH3), 3.83±3.90 (1H, m, C8±CH), 4.47 (2H, s,
CH2Ar), 5.19±5.27 (2H, m, CHvCH2), 5.60±5.73 (1H, m,
CHvCH2), 6.86 (2H, d, Jˆ8.6 Hz, ArH), 7.25 (2H, d,
Jˆ7.9 Hz, ArH); 13C NMR (67.8 MHz, CDCl3) d 23.8,
37.7, 41.8, 42.0, 47.8, 55.2, 55.8, 65.7, 69.4, 71.4, 79.6,
99.5, 113.6, 117.9, 128.9, 130.7, 138.2, 158.8. Anal. Calcd
for C20H30O5: C, 68.54; H, 8.63. Found: C, 68.32; H, 8.72.
0.256 mmol, 98%): [a]26 ˆ237.8 (c 1.3, CHCl3); IR
D
1
n
max(neat) cm21 1613, 1588, 1514, 1495, 1248; H NMR
(270 MHz, CDCl3) d 1.22 (1H, q, Jˆ11.4 Hz, C5±CH2),
1.34 (3H, s, C1±CH3), 1.35 (1H, dd, Jˆ12.4, 11.4 Hz,
C3±CH2), 1.64±1.72 (1H, m, C5±CH2), 1.99±2.04 (2H, m,
C3 and C7±CH2), 2.21 (1H, d, Jˆ12.4 Hz, C7±CH2), 3.14
(3H, s, C29±OCH3), 3.30 (3H, s, C28±OCH3), 3.65 (1H, br,
C6±CH), 3.78 (3H, s, OCH3), 3.83 (1H, m, C4±CH), 3.88±
3.95 (1H, m, C8±CH), 4.45 (2H, s, CH2Ar), 6.04 (1H, dd,
Jˆ16.0, 8.2 Hz, CHvCHPh), 6.55 (1H, d, Jˆ15.9 Hz,
CHvCHPh), 6.85 (2H, d, Jˆ8.4 Hz, ArH), 7.22±7.39
(7H, m, ArH); 13C NMR (67.8 MHz, CDCl3) d 23.9, 37.9,
42.1, 42.2, 47.9, 55.3, 56.0, 65.8, 69.6, 71.4, 79.3, 99.6,
113.7, 126.3, 127.7, 128.5, 129.0, 129.6, 130.8, 133.3,
136.3, 158.9. Anal. Calcd for C26H34O5: C, 73.21; H, 8.03.
Found: C, 72.96; H, 8.14.
3.3.6. (3R)-4-[(2R,4R,6R)-4-p-Methoxybenzyloxy-2-meth-
oxy-2-methyl tetrahydropyran-6-yl]-3-methoxy-1-tert-
butyldiphenylsiloxy-2-butanol (49). To a solution of 48
(77 mg, 0.220 mmol) and NMO (52 mg, 0.444 mmol) in
acetone/water (8:1, 1.8 mL) at room temperature was
added OsO4 (0.1 M in tert-butanol, 0.22 mL, 0.022 mmol).
The mixture was stirred for 4.5 h, and then quenched by the
addition of saturated aqueous Na2SO3. The resulting
mixture was extracted with EtOAc (£1), and the organic
layer was washed with water and brine, dried (Na2SO4),
®ltered and concentrated. The residue was puri®ed by
¯ash chromatography (BW-820 MH, hexane/EtOAcˆ1:2,
EtOAc/EtOHˆ10:1) to afford the diol (83 mg), which was
directly used for the next step.
3.3.5. (3R)-4-[(2R,4R,6R)-4-p-Methoxybenzyloxy-2-meth-
oxy-2-methyl tetrahydropyran-6-yl]-3-methoxy-1-butene
(48). To a solution of 47 (228 mg, 0.534 mmol) and NMO
(125 mg, 1.07 mmol) in acetone/water (8:1, 3.94 mL) at
room temperature was added OsO4 (0.1 M in tert-butanol,
0.54 mL, 0.054 mmol). The mixture was stirred for 5 h, and
then quenched by the addition of saturated aqueous Na2SO3.
The resulting mixture was extracted with EtOAc (£1), and
the organic layer was washed with water and brine, dried
(Na2SO4), ®ltered and concentrated to afford the diol
(250 mg), which was used for the next step without further
puri®cation.
To a stirred solution of the diol (83 mg) in CH2Cl2 (1.2 mL)
at 08C was added triethylamine (0.063 mL, 0.432 mmol),
DMAP (4 mg, 0.033 mmol), and DPSCl (0.084 mL,
0.323 mmol). The reaction mixture was stirred at 08C for
50 min and then at room temperature for 13 h. After dilution
with ether, the mixture was washed with 1 M aqueous
KHSO4, water, saturated aqueous NaHCO3, water, and
brine. The organic layer was dried (MgSO4), ®ltered, and
concentrated. The residue was puri®ed by ¯ash chroma-
tography (BW-820 MH, hexane/EtOAcˆ3:1) to afford the
desired product 49 as a colorless oil (129 mg, 0.207 mmol,
To a solution of the diol in THF/pH 7 phosphate buffer (1:1,
4.6 mL) at 08C was added NaIO4 (171 mg, 0.80 mmol) in
one portion. The reaction mixture was stirred at 08C for
5 min, and then at room temperature for 20 min. Ether and
water were added, and the layers were separated. The
organic layer was washed with brine, dried (MgSO4),
94%, 3.2:1 mixture of diastereoisomers): [a]26 ˆ233.6 (c
D
1.0, CHCl3); IR nmax(neat) cm21 3475, 1615, 1588, 1514,
1248; 1H NMR (270 MHz, CDCl3) d 1.07 (9H, s, (CH3)3C),
1.17±1.41 (2H, m, C3 and C5±CH2), 1.33 (3H, s, C1±CH3)
(1.30, s), 1.69±1.84 (2H, m, C3 and C5±CH2), 1.89±2.02

6324
F. Yokokawa et al. / Tetrahedron 57 (2001) 6311±6327
(1H, m, C7±CH2), 2.20±2.24 (1H, m, C7±CH2), 2.96 (1H,
br, OH) (2.59, d, Jˆ5.4 Hz), 3.15 (3H, s, C29±OCH3) (3.10,
s), 3.31 (3H, s, C28±OCH3) (3.37, s), 3.46±3.50 (1H, m,
C6±CH), 3.63±3.90 (5H, m, C4, C8, C9±CH and
C10±CH2), 3.80 (3H, s, OCH3) (3.77, s), 4.47 (2H, s,
CH2Ar), 6.87 (2H, d, Jˆ8.4 Hz, ArH), 7.25 (2H, d, Jˆ
6.8 Hz, ArH), 7.38±7.43 (6H, m, ArH), 7.66±7.69 (4H, m,
ArH); 13C NMR (67.8 MHz, CDCl3) d 19.3, 23.7, 26.9, 35.5
(35.7), 37.7 (37.9), 42.0, 48.0 (47.9), 55.2, 57.2 (57.6), 64.7
(64.4), 65.7 (65.5), 69.5, 71.3, 72.9 (72.6), 78.1, 99.7 (99.6),
113.7, 127.6, 129.0, 129.6, 130.7, 133.1, 135.4 (135.3),
158.9. Figures in parentheses show signals of the minor
diastereomer. Anal. Calcd for C36H50O7Si: C, 69.42; H,
8.09. Found: C, 69.21; H, 8.07.
added Ph3P (49 mg, 0.187 mmol) and water (0.011 mL,
0.611 mmol). The resulting solution was heated to 558C
for 70 min before it was cooled to room temperature. The
solvent was removed and the residue was puri®ed by ¯ash
chromatography (BW-200, CHCl3/methanolˆ200:1) to
afford the desired product 39 as a colorless oil (26 mg,
0.042 mmol, 68%), which was directly used for the next
step.
3.3.9. Methyl [2S,2(4E,7Z,9S,10E)]-2-[7,9-dimethyl-
4,7,10-dodecatrienyl-1-carbonyl(amino)]-3-hydroxypro-
panoate (51). To a stirred solution of the carboxylic acid 8
(44 mg, 0.198 mmol) and (S)-serine methyl ester hydro-
chloride (34 mg, 0.219 mmol) in DMF (0.8 mL) at 08C
was successively added dropwise DEPC (0.036 mL,
0.221 mmol) and triethylamine (0.060 mL, 0.432 mmol).
After being stirred at 08C for 1 h and then at room tempera-
ture for 2.5 h, the reaction mixture was diluted with ether
and washed with 1 M aqueous KHSO4, water, saturated
aqueous NaHCO3, water, and brine. The organic layer was
dried (MgSO4), ®ltered, and concentrated. The residue was
puri®ed by ¯ash chromatography (BW-820 MH, hexane/
EtOAcˆ1:1±1:2) to afford the desired product 51 as a
3.3.7. (3R)-4-[(2R,4R,6R)-4-p-Methoxybenzyloxy-2-meth-
oxy-2-methyl tetrahydropyran-6-yl]-3-methoxy-1-tert-
butyldiphenylsiloxy-2-butylazide (50). To a stirred solu-
tion of the alcohol 49 (105 mg, 0.169 mmol) in CH2Cl2
(1 mL) at 08C was added triethylamine (0.24 mL,
1.73 mmol), DMAP (2 mg, 0.016 mmol), and MsCl
(0.078 mL, 1.01 mmol). The reaction mixture was stirred
at 08C for 15 min and then at room temperature for 2 h.
After dilution with ether, the mixture was washed with
1 M aqueous KHSO4, water, saturated aqueous NaHCO3,
water, and brine. The organic layer was dried (MgSO4),
®ltered, and concentrated to afford the mesylate (117 mg),
which was used for the next step without further
puri®cation.
colorless oil (58 mg, 0.179 mmol, 91%): [a]26 ˆ227.3 (c
D
0.8, CHCl3); IR nmax(neat) cm21 3368, 1748, 1651, 1538,
1
1439, 1211; H NMR (270 MHz, CDCl3) d 0.99 (3H, d,
Jˆ6.8 Hz, C26±CH3), 1.64 (6H, m, C25 and C27±CH3),
2.04 (1H, br, OH), 2.34 (4H, m, C16 and C19±CH2), 2.64±
2.70 (2H, m, C15±CH2), 3.01 (1H, br, C22±CH), 3.78 (3H, s,
OCH3), 3.92 (2H, qd, Jˆ11.0, 3.1 Hz, C13±CH2), 4.65±4.67
(1H, m, C12±CH), 4.99 (1H, d, Jˆ9.4 Hz, C21±CH), 5.35±
5.43 (4H, m, C17 and C18 and C23 and C24±CH), 6.55 (1H, d,
Jˆ6.8 Hz, NH); 13C NMR (67.8 MHz, CDCl3) d 18.0, 21.5,
23.4, 28.4, 35.27, 35.32, 36.3, 52.7, 54.7, 63.4, 122.4, 128.9,
129.2, 130.3, 131.9, 136.0, 170.8, 172.9. HRMS (EI) m/z
Calcd for C18H29NO4: 323.2097. Found: 323.2086.
To a solution of the mesylate (117 mg) in DMF (0.2 mL)
was added a solution of Bu4NN3 (480 mg, 1.69 mmol) in
THF (0.8 mL). The reaction mixture was stirred at 1008C for
4 h. After dilution with ether, the mixture was washed with
water (£2) and brine. The organic layer was dried (MgSO4),
®ltered, and concentrated. The residue was puri®ed by ¯ash
chromatography (BW-820 MH, hexane/EtOAcˆ6:1) to
afford the desired product 50 as a colorless oil (75 mg,
0.116 mmol, 68%, 3.8:1 mixture of diastereoisomers):
3.3.10. Methyl (3E,6Z,8S,9E)-2-(6,8-dimethyl-3,6,9-
undecatrienyl)-oxazole-4-carboxylate (52). To a stirred
solution of the amido alcohol 51 (28 mg, 0.087 mmol) in
CH2Cl2 (0.9 mL) at 2208C was added dropwise Deoxo-
¯uor (0.032 mL, 0.174 mmol). The reaction mixture was
stirred at 2208C for 25 min, and then quenched by the
addition of saturated aqueous NaHCO3. The mixture was
extracted with CHCl3 (£3), and the combined organic
extracts were washed with brine, dried (Na2SO4), ®ltered,
and concentrated to afford the oxazoline (48 mg), which was
used for the next step without further puri®cation.
[a]25 ˆ235.9 (c 0.6, CHCl3); IR nmax(neat) cm21 2101,
D
1
1613, 1588, 1514, 1248; H NMR (270 MHz, CDCl3) d
1.08 (9H, s, (CH3)3C), 1.16±1.44 (2H, m, C3 and
C5±CH2), 1.29 (3H, s, C1±CH3) (1.27, s), 1.76 (2H, t, Jˆ
6.2 Hz, C7±CH2), 1.99±2.03 (1H, m, C5±CH2), 2.20±2.24
(1H, m, C3±CH2), 3.10 (3H, s, C29±OCH3) (3.14, s), 3.32
(3H, s, C28±OCH3) (3.29, s), 3.56±3.66 (3H, m, C4, C6, and
C8±CH), 3.80 (3H, s, OCH3), 3.84 (1H, m, C9±CH), 3.88
(2H, d, Jˆ5.8 Hz, C10±CH2), 4.48 (2H, s, CH2Ar), 6.88 (2H,
d, Jˆ8.6 Hz, ArH), 7.25 (2H, d, Jˆ6.3 Hz, ArH), 7.40±7.45
(6H, m, ArH), 7.66±7.69 (4H, m, ArH); 13C NMR
(67.8 MHz, CDCl3) d 19.2, 23.7, 26.8, 35.9 (36.2), 37.6
(37.7), 42.0, 47.9 (47.9), 55.3, 57.6 (57.3), 63.7 (63.9),
65.2 (65.7), 65.6 (65.8), 69.6, 71.3 (71.4), 76.9 (77.3),
99.6, 113.7, 127.6 (127.7), 129.0, 129.7, 130.7 (132.8),
132.9 (132.9), 135.4 (135.4), 158.9. Figures in parentheses
show signals of the minor diastereomer. Anal. Calcd for
C36H49N3O6Si: C, 66.74; H, 7.62; N, 6.49. Found: C,
66.65; H, 7.67; N, 6.38.
To a solution of the oxazoline (48 mg) in CH2Cl2 (0.9 mL)
at 08C was successively added BrCCl3 (0.026 mL,
0.256 mmol) and DBU (0.040 mL, 0.268 mmol). The reac-
tion mixture was stirred at 08C for 2 h, and then allowed to
warm to room temperature over 12 h. The mixture was
diluted with ether, washed with saturated aqueous NH4Cl,
water, and brine, dried (MgSO4), ®ltered, and concentrated.
The residue was puri®ed by ¯ash chromatography (BW-820
MH, hexane/etherˆ5:1) to afford the desired product 52 as a
colorless oil (21 mg, 0.069 mmol, 80%): [a]26 ˆ247.2 (c
D
3.3.8. (3R)-4-[(2R,4R,6R)-4-p-Methoxybenzyloxy-2-meth-
oxy-2-methyl tetrahydropyran-6-yl]-3-methoxy-1-tert-
butyldiphenylsiloxy-2-butylamine (39). To a solution of
the azide 50 (40 mg, 0.062 mmol) in THF (0.6 mL) was
0.9, CHCl3); IR nmax(neat) cm21 1752, 1588, 1439, 1377,
1323; 1H NMR (270 MHz, CDCl3) d 0.99 (3H, d, Jˆ6.8 Hz,
C26±CH3), 1.61 (3H, s, C27±CH3), 1.62 (3H, d, Jˆ4.0 Hz,
C25±CH3), 2.48 (2H, m, C16±CH2), 2.68 (2H, m, C19±CH2),

F. Yokokawa et al. / Tetrahedron 57 (2001) 6311±6327
6325
2.87 (2H, t, Jˆ7.3 Hz, C15±CH2), 3.00 (1H, m, C22±CH),
3.90 (3H, s, OCH3), 4.98 (1H, d, Jˆ9.4 Hz, C21±CH), 5.34±
5.36 (2H, m, C23 and C24±CH), 5.41±5.42 (2H, m, C17 and
C18±CH), 8.13 (1H, s, C13±CH); 13C NMR (67.8 MHz,
CDCl3) d 18.0, 21.5, 23.3, 28.3, 29.9, 35.3£2, 52.1, 122.4,
128.2, 129.6, 130.3, 131.8, 133.0, 136.0, 143.5, 161.6,
165.2. HRMS (EI) m/z Calcd for C18H25NO3: 303.1834.
Found: 303.1827.
C5±CH2), 1.34 (3H, s, C1±CH3) (1.26, s), 1.62 (3H, s,
C27±CH3), 1.65 (4H, m, C5±CH2 and C25±CH3), 1.71 (1H,
br, OH), 1.81±1.90 (1H, m, C3±CH2), 1.95±2.05 (1H, m,
C7±CH2), 2.20±2.25 (1H, m, C7±CH2), 2.49 (2H, m,
C19±CH2), 2.69 (2H, m, C16±CH2), 2.83 (2H, t, Jˆ7.7 Hz,
C15±CH2), 3.00 (1H, m, C22±CH), 3.19 (3H, s, C29±OCH3),
3.43 (3H, s, C28±OCH3), 3.64±3.91 (5H, m, C4, C6, C8±CH
and C10±CH2), 3.79 (3H, s, OCH3), 4.28 (1H, m, C9±CH),
4.45 (2H, s, CH2Ar) (4.47, s), 4.99 (1H, d, Jˆ9.2 Hz,
C21±CH), 5.36 (2H, m, C23 and C24±CH), 5.44 (2H, m,
C17 and C18±CH), 6.86 (2H, d, Jˆ8.6 Hz, ArH), 7.23 (2H,
d, Jˆ8.4 Hz, ArH), 7.32 (1H, d, Jˆ8.9 Hz, NH) (7.61, d,
Jˆ7.9 Hz), 8.08 (1H, s, C13±CH) (The peaks of n-hexane
were observed.); 13C NMR (67.8 MHz, CDCl3) d 18.0, 21.5,
23.4, 23.8, 28.3, 29.8 (30.4), 35.3 (35.3), 36.3 (36.7), 38.0
(37.7), 42.1, 47.9 (48.2), 52.3 (52.6), 55.3, 57.4 (58.0), 64.3,
65.5 (65.8), 69.7, 71.4 (71.3), 77.2, 77.6, 99.6 (99.7), 113.7,
122.4, 128.3, 129.0, 129.6, 130.4, 130.7, 131.8, 135.6,
136.0, 140.7, 158.9, 161.5, 164.2. Anal. Calcd for
C37H54N2O8´1/2n-hexane: C, 68.84; H, 8.81; N, 4.01.
Found: C, 68.84; H, 8.49; N, 4.01.
3.3.11. (3E,6Z,8S,9E)-2-(6,8-dimethyl-3,6,9-undecatri-
enyl)-oxazole-4-carboxylic acid (38). To a solution of the
ester 52 (45 mg, 0.148 mmol) in THF (0.6 mL) at 08C was
added 0.5N aqueous LiOH (0.5 mL, 0.25 mmol). After
10 min, the reaction mixture was stirred at room tempera-
ture for 70 min. After the reaction mixture was acidi®ed by
the addition of 1 M aqueous KHSO4, the mixture was
extracted with ether (£3). The combined organic extracts
were dried (MgSO4), ®ltered, and concentrated to afford the
desired product 38 as a white wax (42 mg, 100%):
[a]27 ˆ242.8 (c 0.5, CHCl3); IR nmax(neat) cm21 3500±
D
2500, 1682, 1592, 1439, 1113; 1H NMR (270 MHz, CDCl3)
d 0.98 (3H, d, Jˆ6.8 Hz, C26±CH3), 1.61 (3H, s, C27±CH3),
1.63 (3H, d, Jˆ4.0 Hz, C25±CH3), 2.49±2.54 (2H, m,
C16±CH2), 2.67 (2H, m, C19±CH2), 2.92 (2H, t, Jˆ7.4 Hz,
C15±CH2), 2.95 (1H, m, C22±CH), 4.99 (1H, d, Jˆ9.2 Hz,
C21±CH), 5.35±5.40 (2H, m, C23 and C24±CH), 5.41±5.51
(2H, m, C17 and C18±CH), 8.23 (1H, s, C13±CH), 8.62 (1H,
br, OH); 13C NMR (67.8 MHz, CDCl3) d 18.0, 21.5, 23.3,
28.2, 29.8, 35.3 £2, 122.4, 128.1, 129.8, 130.3, 131.8, 132.5,
136.0, 144.6, 165.0, 165.7. HRMS (EI) m/z Calcd for
C17H23NO3: 289.1678. Found: 289.1700.
3.3.13. Protected hennoxazole A (54). To a stirred solution
of the alcohol 53 (27 mg, 0.041 mmol) in CH2Cl2 (0.3 mL)
at 08C was added Dess±Martin periodinane (52 mg,
0.123 mmol). The reaction mixture was stirred at room
temperature for 15 min, and then diluted with ether. The
mixture was washed with aqueous NaHCO3/Na2S2O3 (1:1)
and brine, dried (MgSO4), ®ltered, and concentrated to
afford the aldehyde. The aldehyde was then immediately
dissolved in CH2Cl2 (1.9 mL) cooled to 08C, and treated
with Ph3P (53 mg, 0.202 mmol) and 2,6-di-tert-butyl
pyridine (0.23 mL, 1.02 mmol). Then, BrCCl2CCl2Br
(66 mg, 0.203 mmol) was added. After 30 min, DBU
(0.16 mL, 1.07 mmol) in CH3CN (1.9 mL) was added by
cannula. The reaction mixture was then warmed to room
temperature for 1 h and concentrated. The residue was puri-
®ed by ¯ash chromatography (BW-820 MH, hexane/
EtOAcˆ3:1±2:1) to afford the desired product 54 as a color-
3.3.12. (3R)-4-[(2R,4R,6R)-4-p-Methoxybenzyloxy-2-meth-
oxy-2-methyl tetrahydropyran-6-yl]-2-[(3E,6Z,8S,9E)-2-
(6,8-dimethyl-3,6,9-undecatrienyl)-oxazole-4-carbonyl]-
amino-3-methoxy-1-butanol (53). To a stirred solution of
the carboxylic acid 38(14 mg, 0.048 mmol) and the amine
39 (32 mg, 0.052 mmol) in DMF (0.3 mL) at 08C was
successively added dropwise DEPC (0.010 mL,
0.061 mmol) and triethylamine (0.014 mL, 0.101 mmol).
After being stirred at 08C for 2 h and then at room tempera-
ture for 7.5 h, the reaction mixture was diluted with ether
and washed with 1 M aqueous KHSO4, water, saturated
aqueous NaHCO3, water, and brine. The organic layer was
dried (MgSO4), ®ltered, and concentrated. The residue was
puri®ed by ¯ash chromatography (BW-820 MH, hexane/
EtOAcˆ5:1±4:1±2:1) to afford the coupling product as a
colorless oil (39 mg), which was directly used for the next
step.
less oil (16 mg, 0.024 mmol, 60%): [a]26 ˆ231.5 (c 0.7,
D
CHCl3); IR nmax(neat) cm211 1615, 1584, 1514, 1449, 1375,
1248; 1H NMR (270 MHz, CDCl3) d 0.98 (3H, d, Jˆ6.8 Hz,
C26±CH3), 1.22±1.43 (2H, m, C3 and C5±CH2), 1.32 (3H, s,
C1±CH3), 1.62 (3H, s, C27±CH3), 1.64 (3H, m, C25±CH3),
2.05±2.21 (4H, m, C3, C5 and C7±CH2), 2.50±2.55 (2H, m,
C16±CH2), 2.68 (2H, m, C19±CH2), 2.90 (2H, t, Jˆ7.4 Hz,
C15±CH2), 2.98 (1H, m, C22±CH), 3.07 (3H, s, C29±OCH3),
3.31 (3H, s, C28±OCH3), 3.54 (1H, m, C6±CH), 3.79 (3H, s,
OCH3), 3.79 (1H, m, C4±CH), 4.42 (1H, m, C8±CH), 4.45
(2H, s, CH2Ar), 4.99 (1H, d, Jˆ9.2 Hz, C21±CH), 5.35 (2H,
m, C23 and C24±CH), 5.41±5.45 (2H, m, C17 and C18±CH),
6.86 (2H, d, Jˆ8.6 Hz, ArH), 7.23 (2H, d, Jˆ8.6 Hz, ArH),
7.62 (1H, s, C10±CH), 8.13 (1H, s, C13±CH) (The peaks of
n-hexane were observed.); 13C NMR (67.8 MHz, CDCl3) d
18.0, 21.5, 23.3, 23.8, 28.3, 29.9, 35.3, 37.5, 40.7, 42.1,
47.7, 55.3, 56.5, 65.8, 69.5, 71.4, 72.8, 77.2, 99.6, 113.7,
122.4, 128.3, 129.0, 129.6, 130.2, 130.3, 130.8, 131.9,
135.7, 136.0, 138.0, 141.6, 155.4, 158.9, 165.4. Anal.
Calcd for C37H50N2O7´1/2n-hexane: C, 70.87; H, 8.47; N,
4.13. Found: C, 71.09; H, 8.19; N, 4.19.
To a stirred solution of the coupling product (39 mg) in THF
(0.4 mL) was added TBAF (29 mg, 0.111 mmol) at 08C.
The reaction mixture was stirred at 08C for 30 min and
then at room temperature for 40 min. After dilution with
EtOAc, the organic layer was washed with water (£2) and
brine, dried (Na2SO4), ®ltered, and concentrated. The resi-
due was puri®ed by ¯ash chromatography (BW-820 MH,
hexane/EtOAcˆ1:1±1:2±1:5) to afford the desired product
53 as a colorless oil (27 mg, 0.041 mmol, 86%, 3.7:1
mixture of diastereoisomers): [a]26 ˆ279.8 (c 0.7,
D
CHCl3); IR nmax(neat) cm21 3407, 1661, 1599, 1514,
1451, 1375, 1248; H NMR (270 MHz, CDCl3) d 0.99
1
3.3.14. (2)-Hennoxazole A (1). To a solution of 54 (10 mg,
0.016 mmol) in CH2Cl2 (0.2 mL) was added pH 7 phosphate
(3H, d, Jˆ6.8 Hz, C26±CH3), 1.11±1.43 (2H, m, C3 and

6326
F. Yokokawa et al. / Tetrahedron 57 (2001) 6311±6327
Chem. 1988, 53, 5014±5020. (c) kabiramides, A±E: Matsu-
naga, S.; Fusetani, N.; Hashimoto, K.; Koseki, K.; Noma, M.;
Noguchi, H.; Sankawa, U. J. Org. Chem. 1989, 54, 1360±
1363. (d) jaspisamides, A±C: Kobayashi, J.; Murata, O.;
Shigemori, H. J. Nat. Prod. 1993, 56, 787±791. (e) mycalo-
lides: Matsunaga, S.; Sugawara, T.; Fusetani, N. J. Nat. Prod.
1998, 61, 1164±1167 and references cited therein.
5. (a) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558±559.
(b) Wipf, P.; Lim, S. Chimia 1996, 50, 157±167.
6. Williams, D. R.; Brooks, D. A.; Berliner, M. A. J. Am. Chem.
Soc. 1999, 121, 4924±4925.
buffer (0.011 mL). DDQ (4 mg, 0.018 mmol) was added to
the mixture at 08C. After 5 min, the mixture was allowed to
warm to room temperature for 15 min. An additional DDQ
(1 mg, 0.004 mmol) was added at 08C, and then the mixture
was stirred at room temperature for 10 min. The reaction
mixture was quenched by the addition of saturated aqueous
NaHCO3 and the resulting mixture was extracted with
CHCl3 (£3). The combined organic extracts were washed
with water, dried (Na2SO4), ®ltered, and concentrated. The
residue was puri®ed by preparative thin layer chromato-
graphy plate (10 cm£20 cm, 0.5 mm, hexane/EtOAcˆ1:4)
to afford the synthetic (2)-hennoxazole A (1) as a colorless
7. (a) Yokokawa, F.; Hamada, Y.; Shioiri, T. J. Chem. Soc.,
Chem. Commun. 1996, 871±872. (b) Sugiyama, H.; Yoko-
kawa, F.; Shioiri, T. Org. Lett. 2000, 2, 2149±2152. (c) Wu,
M.; Okino, T.; Nogle, L. M.; Marquez, B. L.; Williamson,
R. T.; Sitachitta, N.; Berman, F. W.; Murray, T. F.; McGough,
K.; Jacobs, R.; Colsen, K.; Asano, T.; Yokokawa, F.; Shioiri,
T.; Gerwick, W. H. J. Am. Chem. Soc. 2000, 122, 12041±
12042. (d) Yokokawa, F.; Sameshima, H.; Shioiri, T. Synlett
2001, 986±988.
oil (3.0 mg, 0.006 mmol, 36%): [a]26 ˆ242.7 (c 0.12,
D
CHCl3) (Ref. 1 [a]Dˆ247 (c 3.1, CHCl3)); IR nmax(neat)
cm21 3432, 1634, 1580, 1451, 1375, 1231; 1H NMR
(500 MHz, CDCl3) d 0.95 (3H, d, Jˆ7.0 Hz, C26±CH3),
1.10 (1H, q, Jˆ11.6 Hz, C5±CH2), 1.21 (1H, dd, Jˆ12.2,
11.0 Hz, C3±CH2), 1.24 (3H, s, C1±CH3), 1.58 (3H, dd,
Jˆ3.7, 1.2 Hz, C25±CH3), 1.59 (3H, d, Jˆ1.5 Hz, C27±
CH3), 1.88 (1H, ddt, Jˆ12.2, 4.6, 2.4 Hz, C5±CH2), 1.97
(1H, ddd, Jˆ12.5, 4.6, 1.8 Hz, C7±CH2), 2.05 (2H, m, C3
and C7±CH2), 2.50 (2H, q, Jˆ6.7 Hz, C16±CH2), 2.69 (2H,
m, C19±CH2), 2.89 (2H, t, Jˆ7.3 Hz, C15±CH2), 3.01 (1H,
m, C22±CH), 3.03 (3H, s, C29±OCH3), 3.22 (3H, s, C28±
OCH3), 3.52 (1H, m, C6±CH), 3.61 (1H, d, Jˆ5.2 Hz,
OH), 3.89 (1H, m, C4±CH), 4.46 (1H, dd, Jˆ7.9, 6.1 Hz,
C8±CH), 4.95 (1H, dd, Jˆ9.8, 0.9 Hz, C21±CH), 5.34 (2H,
m, C23 and C24±CH), 5.41±5.56 (2H, m, C17 and C18±CH),
7.98 (1H, s, C10±CH), 8.40 (1H, s, C13±CH); 13C NMR
(67.8 MHz, CDCl3) d 18.0, 21.8, 23.5, 24.0, 28.6, 30.4,
35.8, 35.9, 41.5, 41.7, 46.0, 47.8, 56.1, 64.2, 66.5, 73.2,
100.0, 122.8, 129.5, 130.0, 130.9, 131.3, 132.5, 136.8,
137.5, 139.4, 142.1, 156.2, 165.9. HRMS (EI) m/z Calcd
for C29H42N2O6: 514.3043. Found: 514.3053.
8. For our preliminary synthetic studies on hennoxazole A, see:
(a) Cheng, Z.; Hamada, Y.; Shioiri, T. Synlett 1997, 109±110.
(b) Shioiri, T.; McFarlane, N.; Hamada Heterocycles 1998, 47,
73±76.
9. For other synthetic studies on hennoxazole A, see: (a) Barrett,
A. G. M.; Kohrt, J. T. Synlett 1995, 415±415. (b) Vakalopou-
los, A.; Hoffmann, H. M. R. Org. Lett. 2001, 3, 177±180.
10. For a preliminary account of the total synthesis of (2)-
hennoxazole A, see: Yokokawa, F.; Asano, T.; Shioiri, T.
Org. Lett. 2000, 2, 4169±4172.
11. (a) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405±
4408. (b) Hensel, M. J.; Fuchs, P. L. Synth. Commun. 1986,
1285±1295. (c) Rathke, M. W.; Bouhlel, E. Synth. Commun.
1990, 20, 869±875.
12. (a) Ando, K. J. Synth. Org. Chem., Jpn 2000, 58, 869±876.
(b) Ando, K.; Oishi, T.; Hirama, M.; Ohno, H.; Ibuka, T.
J. Org. Chem. 2000, 65, 4745±4749.
Acknowledgements
13. Cheng, Z.; Nakao, R.; Hamada, Y.; Shioiri, T., unpublished
results. We thank Dr Z. Cheng and Mr R. Nakao for their
preliminary studies on the preparation of the triene unit.
14. Sheffy, F. K.; Godschalx, J. P.; Stille, J. K. J. Am. Chem. Soc.
1984, 106, 4833±4840.
This work was ®nancially supported in part by Grant-in-Aid
for Research in Nagoya City University (to F. Y.), Uehara
Memorial Foundation (to F. Y.), and Grant-in-Aids from the
Ministry of Education, Science, Sports and Culture, Japan.
We would like to thank Professor P. Wipf (University of
Pittsburgh) for physical data of the enantiomer of 52 and
helpful discussions. Helpful comments by Professor Y.
Hamada (Chiba University) at the early stage of this work
are also acknowledged.
15. Valle, L. D.; Stille, J. K.; Hegedus, L. S. J. Org. Chem. 1990,
55, 3019±3023.
16. MOM ether 23 was prepared from the known alcohol by treat-
ment with MOMCl and i-Pr2NEt in CH2Cl2, see Yamada, H.;
Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1991, 65, 4569±
4574.
17. Parikh, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89,
5505±5507.
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