Synthesis of the JKLM-ring fragment of ciguatoxin

Article abstract of DOI:10.1016/S0040-4020(03)00873-1

A stereoselective synthesis of the LM-ring fragment has been achieved starting from a sugar derivative. A stereoselective synthesis of the JKLM-ring fragment has been achieved through a coupling between two segments via heteroconjugate addition, seven-membered ether ring formation mediated by an acetylene cobalt complex, and spiroketalization reaction.

Full text of DOI:10.1016/S0040-4020(03)00873-1

Tetrahedron 59 (2003) 6851–6872
Synthesis of the JKLM-ring fragment of ciguatoxin
*
Takayuki Baba, Guobin Huang and Minoru Isobe
Laboratory of Organic Chemistry, Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
Received 25 March 2003; revised 9 May 2003; accepted 13 May 2003
Abstract—A stereoselective synthesis of the LM-ring fragment has been achieved starting from a sugar derivative. A stereoselective
synthesis of the JKLM-ring fragment has been achieved through a coupling between two segments via heteroconjugate addition, seven-
membered ether ring formation mediated by an acetylene cobalt complex, and spiroketalization reaction.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Several synthetic groups have been studying the total
synthesis of CTX over last decade.8 Recently, Hirama’s
group reported the first total synthesis of CTX3C, a member
of the CTX family.9 We also have endeavored to develop
effective methodologies, and established valid method-
ologies for the construction of medium-sized ether rings via
cobalt complex-mediated cyclization during the course of
our studies toward the synthesis of CTX.10 We have already
achieved the syntheses of the ABC rings with the side
chain,11 the BCDE,12 the D0EF,13 the E0FGH14 rings15 using
acetylene cobalt complex strategy. With regard to right part
of CTX, we previously report0ed a model study of
stereoselective synthesis of the H IJK-ring fragment.16 In
this paper, we provide full detail of the synthesis of the LM-
and the JKLM-ring fragments as the right end of CTX.
Ciguatoxin (CTX) is a principal toxin of ciguatera, which is
known as the most widespread seafood poisoning.1 The
causative toxins of this poisoning produced by the epiphytic
dinoflagellate, Gambierdiscus toxicus,2 are accumulated in
carnivorous fish of many species through the food chain
among coral biota, and finally causing human intoxication.
The poisoning symptom does crisis to more than 20000
people annually in the world.1 It is a serious problem
especially in the societies of tropical and subtropical
regions. CTX was first isolated from moray eel, Gym-
nothorax javanicus, by Scheuer and co-workers at the
University of Hawaii and characterized as a polyether
compound in 1980.3 Thus far, more than 23 congeners of
CTX have been identified to date.1 Ciguatoxins (CTXs) and
another structurally related marine toxin, brevetoxins
(BTXs), are selective sodium channel activators, which
bind quasi-irreversibly to site 5 on the voltage-sensitive
sodium channels (VSSC) in nerves, heart and muscle.4,5 In
spite of structural similarity to BTXs, the binding affinity of
CTX was shown to be some ten times more potent than that
of BTXs.4 CTX remains the most potent neurotoxin known
with a mouse lethality LD50 of 0.35 mg/kg (i.p.).4
2. Synthesis of the LM-ring fragment
Firstly, we set about the synthesis of the LM-ring fragment
of CTX.17 Its retrosynthetic analysis is shown in Scheme 1.
We anticipated that LM-ring system could be derived from
hemiacetal 3 by asymmetric dihydroxylation reaction and
then cyclization. Hemiacetal 3 could be prepared from a,b-
unsaturated lactone 4 through a stereocontrolled conjugate
addition and enolate trapping reaction. Lactone 4 would be
synthesized starting from tri-O-acetyl-D-galactal 5.
Since Yasumoto and co-workers determined the gross
structure of CTX in 1989,6 its complicated structure has
been in the foreground of attention among the scientists. The
chemical construction of CTX is a trans-fused polycyclic
system composed of a single carbon chain that winds the
length of the molecule and linking by ether oxygens into a
series of five- to nine-membered oxacycles. Its absolute
configuration was successfully elucidated by Yasumoto and
co-workers in 1997 as shown in Figure 1.7
The synthesis of the initial target 1 is outlined in Scheme 2.
Tri-O-acetyl-D-galactal 5 was deacetylated under the
condition of NaOMe/MeOH to afford D-galactal 6 in 87%
yield. The primary hydroxyl group of 6 was selectively
silylated, and the allylic hydroxyl group was then
selectively protected by benzoylation with benzoyl chloride
and pyridine under 2358C. The remaining hydroxyl group
was protected as the benzyl ether to afford 9. After
desilylation with TBAF and protection with TBDPS, the
protected D-galactal was oxidized by PCC at 808C to give
Keywords: ciguatoxin; lactone; spiroketalization.
*
Corresponding author. Tel.: þ81-52-789-4109; fax: þ81-52-789-4111;
e-mail: isobem@agr.nagoya-u.ac.jp
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00873-1

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T. Baba et al. / Tetrahedron 59 (2003) 6851–6872
Figure 1.
lactone 12,18 which was treated with DBU to give the
desired enlactone 13 in 98% yield.19 With the key enlactone
13 in hand, it was treated with Me2CuLi to give mono-
methylated lactone in 91% yields. After the mono-
methylated lactone was treated with LiHMDS for 30 min
at 2788C, MeI was added to the reaction mixture at this
temperature to give dimethyllactone 14 and its C51-epimer
with the ratio of 7:1 in 93% combined yield. Addition of
allylmagnesium bromide to dimethyllactone 14 provided
hemiacetal 15. Asymmetric dihydroxylation and spiroketal-
ization were conducted under Sharpless condition20 to
afford a mixture of four isomers 16a–d with the ratio of
4:4:1:1 in 75% combined yield, which were easily separated
by preparative TLC.
The stereochemistry of compounds 16c and d was also
determined through careful analysis of their NMR spectra,
shown in Figure 2. The stereochemistry at C54 in 16c and d
could be easily inverted into 16b and 1a by Mitsunobu
reaction,21 respectively. The mixture of 16c and d were
treated with DEAD, PPh3 and p-nitrobenzoic acid, then
treated with K2CO3/MeOH to provide a mixture of 16c and
b in 95% yield (Scheme 3).
3. Synthesis of the JKLM-ring fragment
3.1. Retrosynthetic analysis
Having accomplished the synthesis of the LM-ring
fragment, we now could consider the synthesis of the
JKLM-ring fragment of CTX. According to our plan, the
synthesis of CTX could be achieved via the coupling of two
large segment, acetylene in the Segment L 17 with aldehyde
in Segment R 18 (Scheme 4). This would be followed by the
construction of central part (FG-ring), and finally A-ring
cyclization. We have already reported the synthesis of
Segment L 17.12b The retrosynthetic analysis for the right
part of CTX is illustrated in Scheme 5. Segment R 18 could
be derived from acetylene 19, representing C30–C38
portion of CTX, and the JKLM-ring fragment 2. Opening
of the terminal spiroketal in 2 provides 20 as a synthetic
equivalent. The seven-membered ring in 20 would be
constructed via acetylene cobalt complex 21. Opening of the
seven-membered ring K in 21 gives 22, which further leads
us to the two segments vinyl sulfone 23 and acetylene 24 to
be coupled between the C46 and C47 positions on the basis
of a heteroconjugate addition.10j–l
The stereochemistry of 16a–d was determined through
careful analysis of their 1H NMR and NOESY spectra,
shown as following. The important data of compound 16a
are the coupling constants J50,51¼11.0 Hz, J49,50¼11.0 Hz,
and the observation of the cross peaks between H-53a and
H-54, H-53b and C60–Me on its NOESY experiment. These
data indicate that the conformation of the pyranose-nucleus
and the stereochemistry of C54 are as depicted in Figure 2.
For 16b, the coupling constants J50,51¼2.0 Hz,
J49,50¼1.5 Hz and the observation of the cross peak between
H-48 and C59–Me on its NOESY experiment suggested that
C59-Me and C60-Me are axial. The observation of the cross
peaks between H-53b and H-54, H-53b and C60–Me
indicated that the stereochemistry of its C54 is S
configuration.
3.2. Synthesis of the acetylene subsegment
We attempted to transform the LM-ring system of 16 into
acetylene 24 (Scheme 6). The C54 hydroxyl groups of 16a
and b were protected by benzyl group, and then treated with
TBAF to afford a mixture of alcohols 25 in 92% yield. The
primary alcohol of 25 was successfully converted into
chloride and iodide under ordinary conditions to provide 26
and 27. Both of the attempts for the transformation of 26 and
27 into acetylene under basic conditions were, however,
unsuccessful.22 We have also tried direct opening of
Scheme 1. Retrosynthetic analysis of the LM-ring fragment 1.

T. Baba et al. / Tetrahedron 59 (2003) 6851–6872
6853
Scheme 2. Reagents, conditions and yields: (a) NaOMe, MeOH, 87%; (b) TBSCl, Py, DMF, room temperature, 68%; (c) BzCl, Py, DMAP, 2358C, 93%; (d)
BnBr, NaH, DMF, 92%; (e) TBAF, THF, 95%; (f) TBDPSCl, imidazole, DMF, 100%; (g) PCC, (CH2Cl)2, 51%; (h) DBU, CH2Cl2, 98%; (i) Me2CuLi, Et2O
98%; (j) LiHMDS, MeI, THF, 2788C (14–C51-epimer¼7:1); (k) CH2vCHCH2MgBr, Et2O, 2788C 87%; (l) AD-mix-a, t-BuOH, H2O, 75%.
spiroketal in 25 with 1,3-propanedithiol catalyzed with
BF3·OEt2 to afford dithiane product,23 but it could not afford
the desired product. To our regret, it would seem no other
efficient way to derive the acetylene compound 24 from
LM-ring system 16, though we explored every avenue.
Faced with this impasse, we were forced to abandon this
line, and seek out another way. An alternative strategy for
construction of the acetylene segment 24 is shown in
Scheme 7. Thus, tri-O-acetyl-D-glucal was converted to the
enone 31 by a four-step sequence; O-glycosidation with
Scheme 3. Reagents, conditions and yields: (i) p-NO2C6H4CO2H, DEAD,
PPh3, toluene; (ii) K2CO3, MeOH, 95% in 2 steps.
Figure 2.

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T. Baba et al. / Tetrahedron 59 (2003) 6851–6872
Scheme 4.
2-propanol catalyzed by BF3·OEt2, saponification with basic
MeOH, silylation under the condition of TBSCl/imidazole
and oxidation by DMSO/Ac2O. These steps were amenable
to a large-scale operation. 1,4-Addition of lithium dimethyl
cuprate to a,b-unsaturated carbonyl of 31, followed by
enolate trapping with MeI in the presence of N,N-
dimethylacetamide as a co-solvent provided 32 as an
exclusive diastereomer. The stereochemistry of 32 was
confirmed by the analysis of its data of 1H NMR and
NOESY experiment (Fig. 3). The carbonyl group was
condition25 and afforded an alcohol, which was protected
with benzyl group together with the primary alcohol after
desilylation. Subsequent acidic hydrolysis of the isopropy-
lidene group afforded 41. Oxidative cleavage of the 1,2-diol
41 by Pb(OAc)4 provided the corresponding aldehyde 42.
The aldehyde was treated with lithium TMS acetylide and
MeI, and then desilylated with TBAF to give the acetylene
44. Finally, removal of the dithiane group was performed by
brief treatment of 44 with N-chlorosuccinimide and AgNO3
in wet acetonitrile containing 2,4,6-collidine.26 The yield of
this reaction was moderate probably due to the instability of
acetylene moiety under the reaction condition, though this
was the most suitable method for unmasking of the ketone
group of 44. Several other procedures were also tested for this
conversion (e.g. CuCl2 and CuO in wet acetone,27 [bis(tri-
fluoroacetoxy)iodo]-benzene28 or MeI29 in wet acetonitrile),
but they produced substantial amount of inseparable by-
product. The unmasked ketone was reduced to an alcohol 46
(diastereomeric mixture at C49; ca. 2:1) which was protected
by TBS group to afford the targeted compound 47.
24
stereoselectively reduced to the alcohol by NaBH(OAc)3
after the removal of the TBS group of 32 to afford the diol
34. Opening of the pyranose ring of 34 with 1,3-
propanedithiol was unsuccessful under BF3·OEt2 catalyzed
condition. On the other hand, concentrated hydrochloric
acid in chloroform provided open-chain triol compound in
nearly quantitative yield, which was subsequently protected
with TBS and isopropylidene group to give 37. Coupling
reaction of the lithio derivative of dithiane 37 with glycidyl
methoxybenzyl ether proceeded uneventfully under mild
Scheme 5. Retrosynthetic analysis of right part of ciguatoxin.

T. Baba et al. / Tetrahedron 59 (2003) 6851–6872
6855
Figure 3.
compound 51. The protective groups in 51 were manipu-
lated to provide 55 in 4 steps under standard conditions. The
acetal 55 was transformed to lactone 58 via acetolysis with
sulfuric acid in acetic anhydride, hydrolysis with aqueous
hydrochloric acid in ethylene glycol dimethyl ether and
oxidation of the anomeric position. Addition of allylmag-
nesium bromide to the lactone 58, followed by Kishi’s
silane reduction,32 provided hydropyran system 59 as an
exclusive diastereomer. Removal of the pivaloyl group from
59 led to diol 60 which was converted to 62 through
disilylation and selective removal of the silyl group attached
to the primary hydroxyl group.33 Oxidation of the primary
alcohol followed by dibromo-olefination of the resulting
aldehyde 63 gave the vinyl dibromide 64,34 which was
converted to the thiophenylacetylene 65 by further treat-
ment with n-BuLi and PhSSO2Ph. Then the TBS group was
exchanged to acetyl group to give 66. Concordant with our
previous work, this thiophenylacetylene underwent highly
regioselective hydrosilylation in the presence of a catalytic
amount of cobalt complex to afford the corresponding
vinylsilane 67,35 albeit minor amount of an inseparable
isomer (later determined to be the inner olefin isomer of
allyl group) could be detected by 1H NMR. In this reaction,
stoichiometric use of the cobalt complex caused increase of
isomerization of terminal olefin into inner olefin. And we
found that the isomerization is due to the activity of
Co2(CO)6 species liberated from the catalyst. However, to
our delight, the minor isomer gradually filtered out over the
course of the remainder of the synthesis. Finally, removal of
Scheme 6. Reagents, conditions and yields: (a) (i) BnBr, NaH, DMF, 88%,
(ii) TBAF, THF, 92%; (b) CCl4, PPh3, 79%; (c) I2, imidazole, PPh3, 82%;
(d) LDA, THF, 2788C; (e) DBU, THF, reflux; (f) HS(CH2)3SH, BF3·OEt2,
2408C to room temperature.
3.3. Synthesis of the vinyl sulfone subsegment
The construction of the other requisite subsegment for the
JKLM-ring system bearing vinyl sulfonyl group is illus-
trated in Scheme 8. Synthesis of the vinyl sulfone 69 began
from methyl a-D-glucopyranoside derivative 48.12 Thus, the
hydroxyl group of the C42 position in 48 was selectively
protected by pivaloyl group.30 The remaining free hydroxyl
group in 49 was converted to the thiocarbamate by treating
with in situ generated thiocarbonyldiimidazole, and
removed under modified Barton conditions31 to afford
Scheme 7. Reagents, conditions and yields: (a) i-PrOH, BF3·OEt2, CH2Cl2; (b) Et3N, MeOH, H2O, 84% in 2 steps; (c) TBSCl, imidazole, DMF; (d) Ac2O,
DMSO, 97% in 2 steps; (e) CuI, MeLi, Et2O, 08C, then MeI, DMA, 92%; (f) TBAF, THF, 82%; (g) NaBH(OAc)3, CH3CN, AcOH, 93%; (h) 1,3-propanedithiol,
HCl, CHCl3; (i) TBSCl, Et3N, DMAP, CH2Cl2, 89% in 2 steps; (j) 2,2-dimethoxypropane, PPTS, CH2Cl2, quant.; (k) t-BuLi, (2S)-glycidylmethoxybenzyl
ether, THF, HMPA, 96%; (l) TBAF, THF; (m) NaH, BnBr, DMF; (n) 80% AcOH, 70% in 3 steps; (o) Pb(OAc)4, CH2Cl2, 99%; (p) n-BuLi, TMS–acetylene,
THF, then MeI; (q) TBAF, THF, 86% in 2 steps; (r) NCS, AgNO3, 2,4,6-collidine, CH3CN, H2O; (s) NaBH4, MeOH; (t) TBSOTf, Py, CH3CN, 54% in 3 steps.

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T. Baba et al. / Tetrahedron 59 (2003) 6851–6872
Scheme 8. Reagents, conditions and yields: (a) PivCl, Py, CH2Cl2, 68%; (b) thiophosgene, imidazole, CHCl3, toluene, 908C; (c) AIBN, NaH2PO2, 2-methoxy-
ethanol, reflux, 87% in 2 steps; (d) NaOMe, MeOH, 80%; (e) KOH, BnCl; (f) Amberlyst 15Ew, MeOH, 86% in 2 steps; (g) PivCl, Py, CH2Cl2; (h) H2SO4,
Ac2O, 96% in 2 steps; (i) HCl, DME, H2O, 63%; (j) Ac2O, DMSO, 98%; (k) (i) CH2vCHCH2MgBr, THF, 2788C, (ii) Et3SiH, BF3·OEt2, CH3CN, 2108C,
66% in 2 steps; (l) NaOMe, MeOH, 93%; (m) TBSCl, imidazole, DMF; (n) CSA, MeOH, 88% in 2 steps; (o) (ClCO)2, DMSO, CH2Cl2; (p) CBr4, PPh3,
CH2Cl2, 91% in 2 steps; (q) n-BuLi, THF, 278 to 08C, then PhSSO2Ph; (r) (i) TBAF, THF, (ii) Ac2O, Py, 77% in 3 steps; (s) Et3SiH, biscobalthexacarbonyl-2-
methyl-but-3-yn-2-ol (cat.), 608C, (CH2Cl)2; (t) K2CO3, MeOH; (u) mCPBA, Na2HPO4,CH2Cl2, 85% in 3 steps.
the acetyl group, followed by treatment with mCPBA in the
presence of sodium hydrogen phosphate provided the vinyl
sulfone 69.
10 times stronger) as compared with homologous medium
sized ring formation we previously conducted using
acetylene cobalt complex.11–15 In addition, functional
group at C52 turned to be a dominant factor in this reaction;
attempted formation of the K ring from 1,3-dithiane
derivative or TIPS ether at C52, for example, failed due to
competing nucleophilic participation of the heteroatom on
the functional group at C52. Therefore, the C52 TBS group,
having served its role in the coupling reaction, was now
replaced by an acetyl group for the purpose of diminishing
the nucleophilicity at the fifth position from the cationic
center. Application of the usual methods for exchange of
protective groups to the above adduct 70 delivered the
expected acetate 72, which could be readily converted into
corresponding acetylene cobalt complex 73 by simply
mixing with Co2(CO)8 in CH2Cl2. Upon treatment of 73
with BF3·OEt2, the K ring cyclization took place with
attendant loss of the PMB group attached to the primary
hydroxyl group to afford the bicyclic compound 74.
Reductive decomplexation of 74 was conducted with an
excess amount of Bu3SnH under heating in toluene.36 This
reaction provided the corresponding endocyclic olefin
together with an inseparable mixture of the inner olefin
isomers of allyl group, similar to hydrosilylation of
thiophenylacetylene 66 in Scheme 8, but this time the
amount of the undesired olefin isomer was considerable.
3.4. Heteroconjugate addition and K ring cyclization
Having accomplished the preparation of both subsegments
46 and 47 for the elaboration of the JKLM-ring system, our
attention turned to the coupling of these two compounds.
The coupling between 47 and 69 and subsequent K ring
cyclization are depicted in Scheme 9. To our temporary
delight, application of the condition employed in our
previous model studies produced a coupling compound in
good yield.16a,b Thus, generation of the lithium acetylide of
47 with n-BuLi in THF, followed by addition of 69, gave
diastereomeric mixture of 70 in 80% yield. However, NMR
studies with 70 were ambiguous, and our empirical method
for determination of the stereochemistry of adduct estab-
lished through related heteroconjugate additions was not
sufficiently consistent to allow us to assign with confidence
the C46 configuration of 70. While the stereochemical
assignments were tentative at this point, the crucial
cyclization reaction of the K ring was studied.
We are aware that some attempts for the cyclization of the K
ring need rather concentrated Lewis acid condition (around

T. Baba et al. / Tetrahedron 59 (2003) 6851–6872
6857
Scheme 9. Reagents, conditions and yields: (a) (i) n-BuLi, THF, (ii) TBAF, THF, 87% in 2 steps; (b) ethyl vinyl ether, PPTS, CH2Cl2, quant.; (c) (i) TBAF,
THF, 88%, (ii) Ac2O, DMAP, Py, (iii) CSA, MeOH, quant. in 2 steps; (d) Co2(CO)8, CH2Cl2; (e) BF3·OEt2, CH2Cl2, 93% in 2 steps; (f) bis-
(trimethylsilyl)acetylene, Bu3SnH, toluene, 87% (75: 68%, 76: 19%).
Working with closely related model systems, a reliable
protocol was developed for evasion from encumbering
isomerization during the reductive decomplexation with
hydrosilylation. By simply adding an excess amount of bis-
(trimethylsilyl)acetylene in the decomplexation reaction,
the formation of the side product, which stems most likely
from the activity of Co2(CO)6 species liberated from the
substrate, could completely suppressed.37 Application of
this procedure to the problem at hand was quite successful
and cleanly afforded the desired endocyclic olefin 75 and its
C46-epimer 76, both having syn stereochemistry between
H44 and H49, as chromatographically separable products in
87% combined yield (75–76¼3.6:1). Thus, it seemed to
indicate unequivocally that the stereochemical problem lay
simply at C46.
differentiation from endocyclic olefin to give methyl ketone
80. The stereoselective dihydroxylation of the endocyclic
olefin in 80 was achieved under Sharpless condition39 to
afford 81 and 82 as an equilibrium mixture, which
underwent desilylation and spiroketalization in the expected
sense by treatment with HF·pyridine in acetonitrile to afford
the tetracyclic compound 83 as a major product with a
minor spiro-isomer. Finally, reduction with sodium-amal-
gam in methanol gave the desulfonylation product 84. The
stereochemistry of 84 was confirmed through the NOE
experiments. The results are shown in Figure 4 with arrows.
4. Conclusion
We have achieved an efficient synthesis of the JKLM ring
fragment in 16 steps from acetylene 47 and vinyl sulfone 69
based on the convergent strategy. It proceeds with modest
stereochemical control at C46, but virtually complete
On the basis of our previous work,16a,b it appeared that the
heteroconjugate addition reaction of lithium acetylide of 47
(R¼Li) toward vinyl sulfone 69 with non-protected b-
hydroxyl group, which would be well-positioned to direct
the addition of nucleophile to the same face of the vinyl
sulfone, might proceed with extremely high stereoselectiv-
ity under adequate condition. The model studies also
showed that the stereoselectivity of heteroconjugate
addition is highly dependent on solvent and coordination
ability of metal. What was puzzling, however, was that
solvent modification had surprisingly little effect on the
stereoselectivity in this particular system (Table 1).
Table 1. Stereoselectivity at C46 position in coupling between 47 and 69
Entry
Conditions
Yielda
(%)
Ratiob
75:76
1
2
3
4
5
6
7
8
9
10
n-BuLi, THF, 08C, 30 min
80
74
94
74
90
85
D
D
NR
NR
3.6:1
3.4:1
3.1:1
2.0:1
1.9:1
1.9:1
–
–
–
–
n-BuLi, Et2O/hexane, 0 to 158C, 5 h
n-BuLi, THF/hexane (1/4), 08C, 2 h
MeLi·LiBr, THF, 278 to 2308C, 2 days
n-BuLi, Et2O, 0 to 258C, 11 h
3.5. Spiroketalization
n-BuLi, THF, 2208C, 4 h
n-BuLi, LiBr, THF, 278 to 258C, 3 h
NaH, n-BuLi, THF, 278 to 08C, 30 h
EtMgBr, THF, 278 to 258C, 15 h
EtMgBr, Et2O, 278 to 258C, 15 h
With the requisite bicyclic compound 75 available, the only
issue that remained was the crucial spiroketalization. The
final stage of the synthesis of the JKLM-ring fragment is
illustrated in Scheme 10. Removal of the acetyl group in 75,
followed by selective protection of the primary alcohol by
TBS group and oxidation with IBX,38 furnished ketone 79.
The terminal olefin in 79 was oxidized for the purpose of
D—decomposed; NR—no reaction.
a
Yield of adduct 70.
b
The ratios of the stereoisomers at C46 position were indirectly established
from the ratios of 75 and 76, which were transformed by 5 steps from the
coupling product 70.

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T. Baba et al. / Tetrahedron 59 (2003) 6851–6872
Scheme 10. Reagents, conditions and yields: (a) K2CO3, MeOH, THF; (b) TBSCl, Et3N, DMAP, CH2CH2, 95% in 2 steps; (c) IBX, DMSO, 97%; (d) PdCl2,
CuCl, DMF, H2O, O2, 85%; (e) AD-mix-b, CH3SO2NH2, t-BuOH, H2O; (f) HF·Py, CH3CN, 72% in 2 steps; (g) Na–Hg, Na2HPO4, MeOH, 82%.
performed with a Bruker ARX-400 (400 MHz) or a JEOL
L500 (500 MHz). Carbon NMR spectra (13C NMR) were
recorded on a Varian Gemini 2000 (75.4 MHz), a Bruker
ARX-400 (100 MHz) or a JEOL L500 (125 MHz) with
proton decoupling. Chemical shift values are reported as d
in parts per million (ppm) with CDCl3 (d 77.0) as an internal
standard. Optical rotations were measured on a JASCO DIP-
370 digital polarimeter or a JASCO P-1010-TG polarimeter.
High-resolution or low-resolution mass spectra were
recorded on a Micromass Q-TOF (ESI) or a JEOL JMS-
700 spectrometer (FAB and EI), and are reported in m/z.
Elemental analyses were performed by Analytical Labora-
Figure 4.
tory at School of Bioagricultural Sciences, Nagoya
University. Reactions were monitored by thin-layer chro-
control at all other positions including thermodynamically
driven adjustment of syn selective K ring cyclization and
final spiroketalization. Further studies toward the synthesis
of the right part of CTX along this line are now in progress.
matography carried out on 0.25 mm silica gel coated glass
plates 60F254 (Cica Merck, Art 1.05715) using UV light as
visualizing agent and 7% ethanolic phosphomolybdic acid,
or p-anisaldehyde solution as developing agents. Cica
Merck silica gel 60 (particle size 0.063–0.2 mm ASTM)
was used for open-column chromatography. Unless other-
wise noted, non-aqueous reactions were conducted in oven-
dried (2008C) or flame-dried glassware under inert atmos-
phere. Dry THF was distilled from potassium metal with
benzophenone. Anhydrous Et2O was purchased from Kanto
Chemical Co., Inc. in a bottle as Ethyl Ether Anhydrous.
Dry CH2Cl2 was distilled from CaH2 under nitrogen
atmosphere. BF3·OEt2 were distilled from CaH2. All other
commercially available reagents were used as received.
Hyflo-Super-Celw (nacalai tesque) was used as filter aid.
5. Experimental
5.1. General
Infrared (IR) spectra were recorded on a JASCO FT/IR-
8300 spectrophotometer or a Paragon 1000 FT-IR spec-
trometer and are reported in wave number (cm21). Proton
NMR spectra (1H NMR) were recorded on a Varian Gemini
2000 (300 MHz), a Bruker ARX-400 (400 MHz) or a JEOL
L500 (500 MHz). All samples were dissolved in CDCl3, and
chemical shift values are reported in parts per million (ppm)
with tetramethylsilane (TMS, d 0.00) as an internal
standard. Data are reported as follows: chemical shift
[integrated intensity, multiplicity (s¼singlet, d¼doublet,
t¼triplet, q¼quartet, qn¼quintet, sep¼septet, br¼
broadened, m¼multiplet), coupling constant(s) in Hertz,
assignment]. The assignment of NMR spectra was largely
achieved from COSY spectra. NOESY experiments were
5.1.1. D-Galactal 6. To a solution of tri-O-acetyl-D-galactal
5 (16.1 g, 59 mmol) in dry MeOH was added NaOMe
(54 mg), the mixture was stirred for 3 days, then evaporated
under reduced pressure to give a crude product (10.0 g). The
residue was filtered through a silica gel column to give a
syrup (9.00 g). This syrup was crystallized from AcOEt to
give a white solid of D-galactal 6 (7.50 g, 87%). 6: mp 99–
1008C, [a]1D6¼220.68 (c 1.350, MeOH).

T. Baba et al. / Tetrahedron 59 (2003) 6851–6872
6859
5.1.2. TBS-D-galactal 7. To a mixture of D-galactal 6
(7.30 g, 50.0 mmol), pyridine (7.90 g, 100 mmol) and
DMAP (0.30 g) in dry DMF (150 mL) was added TBSCl
(7.90 g, 52.5 mmol) in three portions over 1 h at 08C. After
stirring for 1 h at 08C, the mixture was stirred overnight at
room temperature, then poured into 5% NaHCO3 solution
and extracted with AcOEt (£3). The combined organic layer
was dried over Na2SO4, filtered and evaporated under
reduced pressure to provide crude oil product. The residue
was purified by silica gel chromatography (AcOEt–
hexane¼1:1) to give TBS-D-galactal 7 (8.90 g, 68%) as
colorless oil. Compound 7. [a]1D6¼þ3.948 (c 0.815, CHCl3).
1H NMR (CDCl3, 500 MHz) d 0.12 (6H, s, –Si(CH3)2), 0.91
(9H, s, –SiC(CH3)3), 2.73 (1H, br s, –OH), 3.18 (1H, br s, –
OH), 3.88 (1H, m, H-48), 3.90–3.99 (2H, ddd, J¼10.5, 5.0,
4.0 Hz, H-47a, 47b), 4.10 (1H, m, H-49), 4.31 (1H, m, H-
50), 4.72 (1H, dt, J¼6.5, 2.0 Hz, H-51), 6.38 (1H, dd,
J¼6.5, 1.5 Hz, H-50). 13C NMR (CDCl3, 125 MHz) d
25.48, 25.46, 18.3, 25.8, 63.4, 64.2, 66.1, 75.7, 103.1,
144.5.
d, J¼12.0 Hz, –CH2Ph), 4.86 (1H, dd, J¼6.5, 3.5 Hz, H-
51), 5.76 (1H, t, J¼3.5 Hz, H-50), 6.46 (1H, dd, J¼6.5,
1.0 Hz, H-50), 7.21–7.58 (8H, m, aromatic), 8.03 (2H, d,
J¼7.3 Hz, aromatic). 13C NMR (CDCl3, 125 MHz) d
25.35, 25.26, 18.4, 25.9, 60.9, 65.7, 70.8, 73.4, 77.4,
98.5, 127.7, 127.8, 127.9, 128.3, 128.4, 129.7, 133.1, 137.9,
145.8, 166.2. FAB-MS 477 [MþþNa]þ.
5.1.5. Bz-Bn-D-galactal 10. To a solution of TBS-Bz-Bn-D-
galactal 9 (3.24 g, 7.14 mmol) in dry THF (20.0 mL) was
added dropwise TBAF (1 M solution in THF, 7.20 mL,
7.20 mmol) at room temperature under Ar atmosphere.
After stirring for 3 h, the mixture was concentrated to
dryness under reduced pressure. The residue was purified by
silica gel (Et2O–hexane¼1:4) to give Bz-Bn-D-galactal 10
a colorless oil. Compound 10.
(2.30 g, 95%) as
[a]1D6¼2170.28 (c 1.00, CHCl3). 1H NMR (CDCl3,
500 MHz) d 1.88 (1H, br s, –OH), 3.88 (1H, dd, J¼10.5,
5.0 Hz, H-47a), 4.04 (1H, dd, J¼10.5, 8.0 Hz, H-47b), 4.15
(1H, t, J¼4.0 Hz, H-49), 4.27 (1H, m, H-48), 4.55 (1H, d,
J¼12.0 Hz, –CH2Ph), 4.79 (1H, d, J¼12.0 Hz, –CH2Ph),
4.93 (1H, dd, J¼6.5, 4.0 Hz, H-51), 5.77 (1H, dt, J¼3.5,
1.5 Hz, H-50), 6.48 (1H, dd, J¼6.5, 1.0 Hz, H-50), 7.25–
7.60 (8H, m, aromatic), 8.05 (2H, d, J¼7.5 Hz, aromatic).
13C NMR (CDCl3, 125 MHz) d 60.8, 64.8, 71.1, 72.9, 76.1,
98.3, 128.0, 128.1, 128.8 129.7, 129.9, 133.2, 137.3, 145.7,
166.2.
5.1.3. TBS-Bz-D-Galactal 8. To a solution of TBS-D-
galactal 7 (6.50 g, 25.0 mmol) in dry pyridine (60.0 mL)
was added dropwise benzoyl chloride (3.69 g, 26.3 mmol)
over 30 min at 2358C under Ar atmosphere. After stirring
for 1.5 h at this temperature, the mixture was warmed to 08C
over 15 min, then poured into saturated NaHCO3 solution
and extracted with AcOEt (£3). The combined organic layer
was washed with brine, dried over Na2SO4, filtered and
evaporated under reduced pressure to provide a crude oil
product (10.0 g). The residue was purified by silica gel
chromatography (AcOEt–hexane¼1:4) to give TBS-Bz-D-
galactal 8 (8.50 g, 93%) as a colorless oil. 8: [a]2D0¼63.88 (c
0.890, CHCl3) 1H NMR (CDCl3, 500 MHz) d 0.11 (6H, s, –
Si(CH3)2), 0.91 (9H, s, –SiC(CH3)3), 2.94 (1H, br s, –OH),
3.92 (1H, dd, J¼11.0, 4.0 Hz, H-47a), 4.04 (1H, dd, J¼11.0,
6.0 Hz, H-47b), 4.06 (1H, dd, J¼6.0, 4.0 Hz, H-48), 4.42
(1H, br s, H-49), 4.81 (1H, dt, J¼6.5, 2.0 Hz, H-51), 5.68
(1H, dd, J¼4.5, 2.0 Hz, H-50), 6.53 (1H, dd, J¼6.5, 1.5 Hz,
H-50), 7.40–7.60 (3H, m, aromatic), 8.10 (2H, d, J¼7.3 Hz,
aromatic). 13C NMR (CDCl3, 125 MHz) d 25.46, 18.3, 25.8
62.9, 64.1, 68.1, 75.9, 98.6, 128.4, 129.8, 129.9, 133.2,
146.1, 166.2.
5.1.6. TBDPS-Bz-Bn-D-galactal 11. To a mixture of Bz-
Bn-D-galactal 10 (1.44 g, 4.24 mmol) and TBDPSCl
(1.40 g, 5.09 mmol) imidazole (634 mg, 9.32 mmol) in dry
DMF (20.0 mL) was added dropwise at room temperature.
After stirring for 2 h, the mixture was poured into saturated
NaHCO3 solution and extracted with AcOEt (£3). The
combined organic layer was washed with saturated
NaHCO3 solution and brine, dried over Na2SO4, filtered
and evaporated under reduced pressure to give a crude oil.
The residue was purified by silica gel chromatography
(Et2O–hexane¼1:10) to provide TBDPS-Bz-Bn-D-galactal
11 (2.44 g, 100%). Compound 11: [a]1D6¼255.38 (c 0.560,
CHCl3). 1H NMR (CDCl3, 500 MHz) d 1.09 (9H, s,
–SiC(CH3)3), 4.01 (1H, dd, J¼11.0, 5.0 Hz, H-47a), 4.12
(1H, dd, J¼11.0, 7.5 Hz, H-47b), 4.18 (1H, t, J¼3.5 Hz, H-
49), 4.31 (1H, m, H-48), 4.56 (1H, d, J¼12.0 Hz, –CH2Ph),
4.74 (1H, d, J¼12.0 Hz, –CH2Ph), 4.81 (1H, dd, J¼6.0,
3.5 Hz, H-51), 5.73 (1H, t, J¼4.0 Hz, H-50), 6.34 (1H, d,
J¼6.0 Hz, H-50), 7.22–7.74 (18H, m, aromatic), 8.03 (2H,
d, J¼7.5 Hz, aromatic). 13C NMR (CDCl3, 125 MHz) d
19.2, 26.5, 26.9, 61.4, 65.5, 7.0, 73.2, 77.2, 98.4, 127.66,
127.68, 127.71, 128.3, 128.4, 129.6, 129.68, 129.69, 129.98,
132.9, 133.4, 133.5, 134.8, 135.59, 135.65, 137.8, 145.7,
166.2.
5.1.4. TBS-Bz-Bn-D-galactal 9. A slurry of 60% NaH
(1.25 g) was placed in a 500 mL round bottom flask, and it
was washed with hexane (£2). The residual powder was
suspended in dry DMF (100 mL). To this suspension were
added at 08C a solution of TBS-Bz-D-galactal 8 (7.77 g,
21.3 mmol) in dry DMF (140 mL) and benzyl bromide
(4.00 g, 23.4 mmol) at 08C under Ar atmosphere. After
stirring for 6 h, the mixture was poured into 5% NaHCO3
solution, extracted with Et2O (£3). The combined organic
layer was washed with 5% NaHCO3 solution, dried over
Na2SO4, filtered and evaporated under reduced pressure to
provide the oil product (10.0 g). The residue was purified by
silica gel chromatography (Et2O–hexane¼1:10) to give a
colorless oil of TBS-Bz-Bn-D-galactal 9 (8.90 g, 92%). 9:
[a]1D6¼298.98 (c 1.23, CHCl3) 1H NMR (CDCl3, 500 MHz)
d 0.07 (6H, s, –Si(CH3)2), 0.91 (9H, s, –SiC(CH3)3), 3.89
(1H, dd, J¼10.5, 5.0 Hz, H-47a), 4.01 (1H, dd, J¼10.5,
7.5 Hz, H-47b), 4.16 (1H, dd, J¼4.0, 3.5 Hz, H-49), 4.20
(1H, m, H-48), 4.60 (1H, d, J¼12.0 Hz, –CH2Ph), 4.78 (1H,
5.1.7. Lactone 12. The mixture of TBDPS-Bz-Bn-D-
galactal 11 (2.17 g, 3.75 mmol) and PCC (2.82 g) in
30 mL 1,2-dichloroethane was heated at 808C for 6 h
under Ar atmosphere. After the reaction was completed,
the mixture was poured onto a silica gel column and eluted
with hexane–Et2O¼4:1 to provide lactone 12 (1.13 g, 51%)
as colorless oil. 12: 1H NMR (CDCl3, 500 MHz) d 1.05 (9H,
s, –SiC(CH3)3), 3.05 (2H, ddd, J¼17.5, 11.0, 8.0 Hz, H-51),
3.86 (1H, dd, J¼10.5, 5.5 Hz, H-47a), 3.96 (1H, dd, J¼10.5,
9.0 Hz, H-47b), 4.40 (1H, m, H-48), 4.42 (1H, m, H-49),

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T. Baba et al. / Tetrahedron 59 (2003) 6851–6872
4.73 (1H, d, J¼11.0 Hz, –CH2Ph), 4.80 (1H, d, J¼11.0 Hz,
–CH2Ph), 5.42 (1H, ddd, J¼11.0, 8.0, 2.0 Hz, H-50), 7.22–
7.62 (18H, m, aromatic), 7.98 (2H, dd, J¼7.8, 1.0 Hz,
aromatic). 13C NMR (CDCl3, 125 MHz) d 19.2, 26.9, 32.2,
61.2, 65.8, 69.7, 71.3, 75.1, 79.0, 127.6, 127.8, 127.9, 128.4,
128.6, 129.2, 129.8, 129.9, 130.1, 132.6, 132.7, 133.6,
135.4, 135.5, 137.5, 165.6, 167.8. FAB-MS 617 [MþNa]þ,
578 [MþH]þ.
–CH2Ph), 7.18–7.60 (15H, m, aromatic). 13C NMR (CDCl3
125 MHz) d 14.7, 19.2, 19.3, 26.8, 38.6, 40.1, 61.5, 71.1,
77.1, 77.2, 127.5, 127.7, 127.8, 127.8, 128.4, 129.8, 129.9,
132.9, 135.5, 135.5, 137.8, 174.4. FAB-MS 525 [MþNa]þ,
0
503 [MþH]þ, 14 (C51-epimer of 14): H NMR (CDCl3,
500 MHz) d 0.96 (3H, d, J¼7.5 Hz, CH3-60), 1.04 (9H, s,
–SiC(CH3)3), 1.18 (3H, d, J¼7.0 Hz, CH3-59), 2.37 (1H, m,
H-50), 3.05 (1H, dq, J¼7.5, 5.0 Hz, H-51), 3.73 (1H, t,
J¼3.0 Hz, H-49), 3.82 (1H, dd, J¼10.0, 5.5 Hz, H-47a),
4.03 (1H, dd, J¼10.0, 8.5 Hz, H-47b), 4.47 (1H, ddd, J¼8.5,
5.5, 3.0 Hz, H-48), 4.57 (1H, d, J¼11.4 Hz, –CH2Ph), 4.68
(1H, d, J¼11.4 Hz, –CH2Ph), 7.24–7.62 (15H, m aromatic).
13C NMR (CDCl3, 125 MHz) d 13.0, 13.1, 19.2, 26.8, 34.2,
34.7, 61.7, 71.7, 75.3, 78.6, 127.4, 127.7, 127.8, 128.4,
129.8, 129.9, 132.9, 133.1, 135.5, 135.6, 137.9, 173.5. FAB-
MS 525 [MþNa]þ, 503 [MþH]þ.
1
5.1.8. Enlactone 13. To a solution of lactone 12 (1.13 g,
1.9 mmol) in dry CH2Cl2 (20.0 mL) was added DBU
(380 mg, 2.47 mmol) at room temperature under Ar
atmosphere. After stirring for 2 h, the mixture was
evaporated under reduced pressure and the residue was
purified by silica gel chromatography (Et2O–hexane¼1:2)
to give enlactone 13 (889 mg, 98%) as a colorless oil.
Compound 13: [a]1D6¼293.18 (c 1.030, CHCl3). H NMR
1
(CDCl3, 500 MHz) d 1.04 (9H, s, –SiC(CH3)3), 3.91 (1H,
dd, J¼10.5, 5.5 Hz, H-47a), 4.12 (1H, dd, J¼10.3, 8.5 Hz,
H-47b), 4.19 (1H, dd, J¼5.5, 3.5 Hz, H-49), 4.44 (1H, ddd,
J¼8.5, 5.5, 3.5 Hz, H-48), 4.60 (2H, s, –CH2Ph), 6.09 (1H,
d, J¼10.0 Hz, H-51), 6.88 (1H, dd, J¼10.0, 5.5 Hz, H-50),
7.22–7.63 (15H, m, aromatic). 13C NMR (CDCl3, 125 MHz)
d 19.2, 26.8, 61.0, 65.8, 71.9, 79.7, 123.9, 127.7, 127.81,
127.83, 128.0, 128.5, 129.8, 129.9, 132.7, 132.9, 135.4,
135.5, 137.5, 142.8, 162.6. FAB-MS 495 [MþNa]þ, 473
[MþH]þ.
5.1.10. LM-Ring fragment 16a–d. To a solution of
dimethyllactone 14 (330 mg, 0.66 mmol) in dry Et2O
(10 mL) was added allylmagnesium bromide (1 M in
THF, 1.00 mL) at 2788C under Ar atmosphere. After
stirring for 3 h, the mixture was added saturated NH4Cl
solution, then warmed to room temperature, extracted with
Et2O (£3). The combined organic layer was washed with
brine, dried over Na2SO4, filtered and evaporated under
reduced pressure to give a crude oil. The residue was
purified by silica gel chromatography (Et2O–hexane¼1:10)
to give hemiacetal 15 as a colorless oil mixture (270 mg,
87% based on recovering starting material) and recover
starting material (42 mg).
5.1.9. Dimethyllactone 14. A solution of MeLi (1.14 M in
Et2O, 11.8 mL, 13.5 mmol) was added dropwise to a slurry
solution of CuI (1.28 g, 6.75 mmol) in dry Et2O (20 mL) at
08C under Ar atmosphere. After the mixture was stirred for
10 min, the copper reagent was treated with TMSCl
(2.2 mL, 16.9 mmol). After the mixture was cooled at
2208C, a solution of enlactone 13 (795 mg, 1.69 mmol) in
dry Et2O (10 mL) was added, the mixture was stirred
overnight at this temperature. After the reaction was
completed, the mixture was poured into NH3/NH4Cl
solution (pH¼8) and extracted with Et2O. The combined
organic layer was washed with saturated NaHCO3 solution
and brine, dried over Na2SO4, filtered and evaporated under
reduced pressure to provide crude oil product. The residue
was purified by silica gel chromatography (Et2O–
hexane¼1:2) to give a colorless oil (748 mg, 91%). To a
solution of LiHMDS (1 M in THF, 4.00 mL, 4.00 mmol) in
dry THF (20 mL) was added dropwise a solution of the oil
(1.48 g, 3.03 mmol) in dry THF (25 mL) at 2788C under Ar
atmosphere. After stirring for 30 min, methyl iodide (1 mL,
15.16 mmol) was added dropwise. After stirring for 30 min,
the mixture was quenched by saturated NH4Cl, then warmed
to room temperature and extracted with AcOEt. The
combined organic layer was washed with brine, dried over
Na2SO4, filtered and evaporated under reduced pressure to
provide the crude oil. This crude oil was purified by silica
gel chromatography (Et2O–hexane¼1:5) to give dimethyl-
lactone 14 (1.25 g) and its C51-epimer 140 (170 mg) in 93%
combined yield. Compound 14: 1H NMR (CDCl3,
500 MHz) d 1.01 (9H, s, –SiC(CH3)3), 1.08 (3H, d,
J¼7.0 Hz, CH3-59), 1.21 (3H, d, J¼6.5 Hz, CH3-60), 1.83
(1H, m, H-50), 2.02 (1H, dq, J¼9.0, 7.0 Hz, H-51), 3.53
(1H, dt, J¼2.0, 2.0 Hz, H-49), 3.88–3.97 (2H, ddd, J¼10.5,
7.5, 5.5 Hz, H-47a), 4.42 (1H, td, J¼7.5, 2.0 Hz, H-48), 4.39
(1H, d, J¼12.0 Hz, –CH2Ph), 4.57 (1H, d, J¼12.0 Hz,
To a mixture of AD-mix-a (280 mg) in 50% aqueous t-
BuOH (5.00 mL) was added hemiacetal 15 (90 mg) at 08C,
then the mixture was stirred for 2 days at this temperature.
After starting material disappeared, the reaction was
quenched by Na2SO3 (100 mg), then the mixture was stirred
for 30 min, extracted with AcOEt (£3). The combined
organic layer was washed by brine, dried over Na2SO4,
filtered and evaporated under reduced pressure to provide a
crude oil. The residue was purified by preparative TLC
(Et2O–hexane¼1:1) to give LM-ring fragment 16a
(Rf¼0.38, 28 mg), 16b (Rf¼0.0.38, 27 mg), 16c
(Rf¼0.0.66, 7 mg) and 16d (Rf¼0.0.66, 8 mg) in 75%
combined yield. Compound 16a: 1H NMR (CDCl3,
500 MHz) d 0.96 (3H, d, J¼6.0 Hz, CH3-59), 0.97 (3H, d,
J¼6.5 Hz, CH3-60), 1.05 (9H, s, –SiC(CH3)3), 1.49 (1H, dq,
J¼11.0, 6.5 Hz, H-51), 1.54 (1H, br s, OH-54), 1.72 (1H, m,
H-50), 1.94 (1H, ddd, J¼14.0, 2.5, 1.0 Hz, H-53a), 2.21
(1H, dd, J¼14.0, 7.0 Hz, H-53b), 3.22 (1H, dd, J¼11.0,
6.0 Hz, H-49), 3.70 (1H, d, J¼10.0 Hz, H-55a), 3.88 (1H,
dd, J¼11.0, 4.0 Hz, H-47a), 4.10 (1H, d, J¼11.5 Hz,
–CH2Ph), 4.11 (1H, ddd, J¼8.0, 6.0, 4.0 Hz, H-48), 4.25
(1H, dd, J¼10.0, 4.0 Hz, H-55b), 4.26 (1H, d, J¼11.5 Hz,
–CH2Ph), 4.31 (1H, dd, J¼11.0, 8.5 Hz, H-47b), 7.05–7.70
(15H, m aromatic). 13C NMR (CDCl3, 125 MHz) d 13.4,
15.5, 19.2, 26.9, 34.4, 42.5, 47.0, 63.2, 71.4, 71.9, 75.2,
79.7, 109.0, 127.5, 127.59, 127.61, 127.9, 128.2, 129.5,
129.6, 133.9, 134.1, 135.7, 135.7. FAB-MS 583 [MþNa]þ,
561 [MþH]þ. Compound 16b. 1H NMR (CDCl3, 500 MHz)
d 1.05 (9H, s, –SiC(CH3)3), 1.18 (3H, d, J¼7.5 Hz,
CH3-59), 1.21 (3H, d, J¼7.5 Hz, CH3-60), 1.52 (1H, br s,
OH-54), 1.73 (1H, m, H-51), 1.73 (1H, dd, J¼13.5, 4.0 Hz,
H-53), 2.09 (1H, qt, J¼7.5, 2.0 Hz, H-50), 2.39 (1H, dd,

T. Baba et al. / Tetrahedron 59 (2003) 6851–6872
6861
J¼13.5, 7.5 Hz, H-53), 3.21 (1H, t, J¼1.5 Hz, H-49), 3.73
(1H, dd, J¼10.0, 2.0 Hz, H-55), 3.76 (1H, dd, J¼10.0,
6.5 Hz, H-47), 3.84 (1H, dd, J¼10.0, 6.5 Hz, H-47), 4.00
(1H, td, J¼6.5, 2.0 Hz, H-48), 4.37 (1H, d, J¼11.5 Hz,
–CH2Ph), 4.53 (1H, m, H-2), 4.65 (1H, d, J¼11.5 Hz,
–CH2Ph), 7.23–7.69 (15H, m, aromatic). 13C NMR (CDCl3,
125 MHz) d 18.9, 19.2, 19.8, 26.9, 35.6, 39.2, 46.9, 63.8,
69.0, 70.1, 71.0, 74.1, 110.3, 127.3, 127.6, 127.6, 127.6,
127.9, 128.2, 129.6, 133.7, 135.5, 135.6, 138.8. FAB-MS
d 13.5, 15.4, 19.3, 27.0, 34.5, 42.6, 44.2, 63.2, 71.5,
72.1, 75.3, 76.6, 79.6, 108.9, 123.6, 127.6, 127.7, 127.7,
128.2, 129.6, 129.7, 130.6, 133.8, 134.1, 135.5, 135.7,
135.7, 137.9, 150.7, 164.4. Compound 16b0 (p-nitrobenzo-
1
ate of 16b): H NMR (CDCl3, 500 MHz) d 1.04 (9H, s,
–SiC(CH3)3), 1.16 (3H, d, J¼7.5 Hz, CH3), 1.21 (3H, d,
J¼7.5 Hz, CH3), 1.74 (1H, qd, J¼7.5, 1.5 Hz, H-51), 1.95
(1H, dd, J¼14.0, 4.5 Hz, H-53a), 2.09 (1H, qt J¼7.5,
2.0 Hz, H-50), 2.57 (1H, dd, J¼14.0, 7.5 Hz, H-53b), 3.21
(1H, br s., H-49), 3.78 (1H, dd, J¼10.5, 6.5 Hz, H-47), 3.84
(1H, dd, J¼10.5, 6.0 Hz, H-47), 3.96–4.0 (2H, m, H-48,
55a), 4.09 (1H, dd, J¼10.5, 5.5 Hz, H-55b), 4.36 (1H, d,
J¼12.0 Hz, –CH2Ph), 4.63 (1H, d, J¼12.0 Hz, –CH2Ph),
5.50 (1H, m, H-54), 7.21–8.28 (19H, m, aromatic). 13C
NMR (CDCl3, 125 MHz) d 18.8, 19.2, 19.7, 26.9, 35.6,
38.9, 43.6, 63.8, 69.3, 71.1, 71.2, 75.7, 76.6, 110.1, 123.5,
127.4, 127.6, 128.2, 129.6, 129.7, 130.6, 130.7, 133.7,
133.8, 135.5, 135.7, 138.7, 150.6, 164.6.
1
583 [MþNa]þ, 561 [MþH]þ. Compound 16c. H NMR
(CDCl3, 500 MHz) d 1.02 (9H, s, –SiC(CH3)3), 1.12 (3H, d,
J¼7.5 Hz, CH3-59), 1.20 (3H, d, J¼7.5 Hz, CH3-60), 1.53
(br s, 1H, OH-55), 1.59 (1H, qd, J¼7.5, 1.0 Hz, H-51), 1.78
(1H, dd, J¼13.5, 6.0 Hz, H-53a), 2.05 (1H, qt, J¼7.5,
2.0 Hz, H-50), 2.17 (1H, d, J¼13.5, 2.0 Hz, H-48), 3.05
(1H, dd, J¼2.0, 1.5 Hz, H-49), 3.62 (1H, dd, J¼10.5,
4.5 Hz, H-47), 3.87 (1H, dd, J¼10.5, 8.0 Hz, H-47), 3.89
(1H, dd, J¼10.0, 1.0 Hz, H-55a), 4.12 (1H, ddd, J¼8.0, 4.5,
2.0 Hz, H-48), 4.16 (1H, dd, J¼10.0, 5.5 Hz, H-55b), 4.24
(1H, m, H-54), 4.26 (1H, d, J¼12.0 Hz, –CH2Ph), 4.58 (1H,
To a solution of p-nitrobenzoate 16a0 and 16b0 (1.00 g,
1.41 mmol) in MeOH (20 mL) was added K2CO3 (195 mg,
1.41 mmol) at room temperature under Ar atmosphere.
After stirring for 2 h, the mixture was evaporated under
reduced pressure. The residue was dissolved in distilled
water and extracted with AcOEt (£3). The combined
organic layer was dried over Na2SO4 and filtered,
evaporated under reduced pressure. The residue was
purified by silica gel chromatography (Et2O–hexane¼1:5)
to give the mixture of 16a and b (785 mg, 99%).
d, J¼12.0 Hz, –CH2Ph), 7.14–7.64 (15H, m, aromatic). 13
C
NMR (CDCl3, 125 MHz) d 19.0, 19.1, 19.8, 26.8, 35.1,
38.9, 45.0, 64.3, 69.2, 70.9, 71.0, 76.7, 77.5, 110.4, 127.4,
127.7, 127.7, 127.9, 128.2, 129.6, 129.7, 133.4, 133.5,
135.6, 135.6, 135.8, 138.4. FAB-MS 583 (MþþNa, 5), 561
(MþþH, 14), 543 (Mþ2OH, 6). Compound 16d. 1H NMR
(CDCl3, 500 MHz) d 0.80 (3H, d, J¼6.5 Hz, CH3-60), 0.88
(3H, d, J¼6.5 Hz, CH3-59), 1.01 (9H, s, –SiC(CH3)3), 1.45
(1H, br s, OH-54), 1.52 (1H, dq, J¼10.0, 6.5 Hz, H-51),
1.68 (1H, m, H-50), 1.86 (1H, d, J¼13.5 Hz, H-53a), 2.02
(1H, dd, J¼13.5, 5.5 Hz, H-53b), 3.14 (1H, dd, J¼10.5,
6.0 Hz, H-49), 3.71 (1H, dd, J¼11.5, 4.0 Hz, H-47), 3.94
(1H, d, J¼11.5 Hz, –CH2Ph), 3.98 (1H, dd, J¼10.0, 5.0 Hz,
H-55a), 4.03 (1H, d, J¼11.5 Hz, –CH2Ph), 4.10 (1H, ddd,
J¼10.0, 6.0, 4.0 Hz, H-48), 4.22 (1H, d, J¼10.0 Hz,
H-55b), 4.26 (1H, m, H-54), 4.27 (1H, dd, J¼11.5,
10.0 Hz, H-47), 6.70–7.66 (15H, m, aromatic) 13C NMR
(CDCl3, 125 MHz) d 13.3, 15.4, 19.1, 26.9, 34.2, 41.8, 43.6,
62.9, 71.4, 72.2, 74.9, 78.2, 79.4, 109.7, 127.6, 127.7, 127.9,
128.2, 129.6, 129.7, 133.6, 133.9, 135.7, 135.8, 137.8.
FAB-MS 583 [MþNa]þ, 561 [MþH]þ.
5.1.12. Alcohol 25. To a solution of spiroketals 16a and b
(292 mg, 0.521 mmol) in DMF (3.00 mL) was added
47.1 mg of 60% NaH (47.1 mg) at 08C under Ar
atmosphere. After stirring for 30 min, the mixture was
added BnBr (269 mg, 1.56 mmol), then stirred for 5 h. The
mixture was added ice-water (0.50 mL), subsequently added
saturated NaHCO3 solution, and extracted with AcOEt (£3).
The combined organic layer was washed with NaHCO3
solution and brine, dried over Na2SO4, filtered and
evaporated to give a crude oil. The residue was purified
by silica gel column (Et2O–hexane¼1:20) to give a mixture
of benzyl ether (227 mg, 88% based on recovered starting
material) and recovered starting material (70 mg). To a
solution of the mixture of benzyl ether (200 mg,
0.308 mmol) in THF (5.00 mL) was added TBAF
(1.20 mL, 1 M in THF, 1.20 mmol) at room temperature
under Ar atmosphere, then the mixture was stirred for 6 h.
The mixture was evaporated under reduced pressure to give
a crude oil. The residue was purified by silica gel
chromatography (Et2O–hexane¼1:2) to give alcohol 25
5.1.11. Inversion of stereogenic center at C54 of 16c and
d. To a mixture of spiroketal 16c and d (67.4 mg,
0.120 mmol), p-nitrobenzoic acid (90.0 mg, 0.602 mmol)
and PPh3 (158 mg, 0.602 mmol) in dry toluene (5.00 mL)
was added DEAD (0.100 mL, 0.602 mmol) at room
temperature under Ar atmosphere, then the mixture was
stirred for 1 h. After the reaction was completed, the mixture
was evaporated under reduced pressure and purified by
preparative TLC (Et2O–hexane¼1:1) to give p-nitrobenzo-
ate 16a0 (Rf¼0.0.68, 26.0 mg) and 16b0 (Rf¼0.0.74, 35 mg)
in 95% combined yield. Compound 16a0 (p-nitrobenzoate of
16a) 1H NMR (CDCl3, 500 MHz) d 0.97 (3H, d, J¼7.5 Hz,
CH3), 1.07 (3H, d, J¼6.5 Hz, CH3), 1.07 (9H, s,
–SiC(CH3)3), 1.55 (1H, m, H-51), 1.75 (1H, dq, J¼11.0,
6.5 Hz, H-51), 2.18 (1H, d, J¼15.0 Hz, H-53a), 2.45 (1H,
dd, J¼15.0, 7.5 Hz, H-53b), 3.24 (1H, dd, J¼11.0, 6.0 Hz,
H-49), 3.88 (1H, dd, J¼11.0, 4.0 Hz, H-47), 4.0 (1H, d,
J¼11.0 Hz, H-55a), 4.09 (1H, d, J¼11.5 Hz, –CH2Ph), 4.14
(1H, m, H-48), 4.23 (1H, d, J¼11.5 Hz, –CH2Ph), 4.48 (1H,
dd, J¼11.0, 4.5 Hz, H-55b), 5.59 (1H, br s, H-54), 7.04–
8.28 (19H, m, aromatic). 13C NMR (CDCl3, 125 MHz)
1
(117 mg, 92%) as colorless oil. Compound 25. H NMR
(CDCl3, 500 MHz) d 0.92 (3H, d, J¼6.5 Hz, CH3), 0.96
(3H, d, J¼6.5 Hz, CH3), 1.43 (1H, m, H-51), 1.92 (1H, m,
H-50), 2.06 (2H, ddd, J¼14.0, 7.0, 4.0 Hz, H-53a), 3.76
(1H, m, H-49), 3.93 (4H, m, H-47, 48, 55a, 55b), 4.21 (1H,
m, H-54), 4.38 (2H, d, J¼12.0 Hz, –CH2Ph), 4.47 (1H, d,
J¼12.0 Hz, –CH2Ph), 4.56 (1H, d, J¼12.0 Hz, –CH2Ph),
7.24–7.34 (10H, m, aromatic). 13C NMR (CDCl3, 125 MHz)
d 13.4, 15.5, 26.5, 34.6, 42.8, 43.7, 63.1, 71.1, 72.4, 73.2,
78.2, 80.8, 109.2, 127.5, 127.7, 127.7, 128.0, 128.1, 128.4,
128.5, 134.8.
5.1.13. Chloride 26. A solution of alcohol 25 (44.2 mg,

6862
T. Baba et al. / Tetrahedron 59 (2003) 6851–6872
0.107 mmol) and PPh3 (113 mg, 0.429 mmol) in CCl4
(10 mL) was refluxed overnight under Ar atmosphere. After
the reaction was completed, the mixture was evaporated
under reduced pressure and the residue was purified by
preparative TLC (Et2O–hexane¼1:3) to give chloride 26
(36.6 mg, 79%). Compound 26. 1H NMR (CDCl3,
125 MHz) d 1.17 (3H, d, J¼7.5 Hz, CH3), 1.20 (3H, d,
J¼7.0 Hz, CH3), 1.72 (1H, dq, J¼7.5, 2.0 Hz, H-51), 1.85
(1H, dd, J¼13.0, 5.0 Hz, H-53a), 2.13 (1H, tq, J¼7.5,
2.0 Hz, H-50), 2.38 (1H, dd, J¼13.0, 7.5 Hz, H-53b), 3.20
(1H, br s, H-49), 3.58 (2H, ddd, J¼11.0, 7.5, 6.0 Hz, H-47a,
47b), 3.92 (1H, dd, J¼10.0, 2.5 Hz, H-55a), 4.01 (1H, dd,
J¼10.0, 6.0 Hz, H-55b), 4.04 (1H, ddd, J¼7.5, 6.0, 2.0 Hz,
H-48), 4.33, (1H, m, H-53), 4.36 (1H, d, J¼11.5 Hz,
–CH2Ph), 4.44 (1H, d, J¼11.5 Hz, –CH2Ph), 4.67 (2H, d,
J¼11.5 Hz, –CH2Ph), 7.24–7.34 (10H, m, aromatic). 13C
NMR (CDCl3, 125 MHz) d 18.8, 19.7, 35.4, 38.8, 43.9,
44.3, 69.1, 71.1, 71.5, 71.6, 77.6, 110.5, 127.6, 127.6, 127.7,
127.8, 128.3, 128.4, 138.1, 138.3. FAB-MS 431 [MþH]þ.
and extracted with CH2Cl2. The extracts were washed with
brine, dried over Na2SO2, and concentrated under reduced
pressure to give acetal 28 as a crude oil, which was used in
the next step without further purification.
To a solution of the crude oil of acetal 28 in MeOH (1.50 L)
were added H2O (300 mL) and Et3N (300 mL) at room
temperature. After stirring for 5.5 h at room temperature, the
reaction mixture was concentrated under reduced pressure,
and recrystallized (hexane/ether) to give diol 29 (117 g,
84% in 2 steps). Compound 29. Mp 98–1008C. IR (KBr)
n
max 3392, 2970, 2937, 2900, 1439, 1386, 1326, 1096, 1029,
947, 819, 794 cm21. H NMR (300 MHz, CDCl3) d 1.18
(3H, d, J¼6.0 Hz, –CH(CH3)2), 1.24 (3H, d, J¼6.0 Hz,
–CH(CH3)2), 2.23 (1H, br s, –OH), 2.40 (1H, br s, –OH),
3.75 (1H, dt, J¼9.0, 4.5 Hz, H-480), 3.86 (2H, m, H-470a,
470b), 3.98 (1H, sep, J¼6.0 Hz, –CH(CH3)2), 4.21 (1H, t,
J¼4.5 Hz, H-49), 5.09 (1H, br s, H-52), 5.73 (1H, dt, J¼10,
2.5 Hz, H-50), 5.96 (1H, br-d, J¼10 Hz, H-51). 13C NMR
(CDCl3, 75 MHz) d 21.8, 23.6, 62.8, 64.3, 70.4, 71.2, 92.5,
127.0, 133.2. Anal. calcd for C9H16O4: C, 57.43; H, 8.57.
Found: C, 57.26; H, 8.48.
1
5.1.14. Iodide 27. To a mixture of alcohol 25 (54 mg,
0.129 mmol), PPh3 (67.5 mg, 0.257 mmol) and imidazole
(18 mg, 0.257 mmol) in dry toluene (5.00 mL) was added
iodine (65.3 mg, 0.257 mmol) at room temperature under
Ar atmosphere, then the mixture was stirred for 6 h. After
the reaction was quenched by adding saturated NaHCO3
solution, the mixture was extracted with Et2O. The
combined organic layer was washed with saturated
NaHCO3 solution and brine, dried over Na2SO4, filtered
and evaporated under reduced pressure to give a crude
oil. The crude oil was purified by preparative TLC to
give a mixture of iodide 27 (55 mg, 82%). Compound 27.
1H NMR (CDCl3, 500 MHz) d 0.94 (3H, d, J¼7.0 Hz,
CH3), 0.97 (3H, d, J¼7.5 Hz, CH3), 2.02 (2H, m, H-51a,
53a), 2.16 (1H, dd, J¼13.5, 7.5 Hz, H-53b), 2.23 (1H, m,
H-50), 3.06 (1H, dd, J¼10.0, 5.5 Hz, H-47a), 3.19 (1H,
dd, J¼10.0, 8.5 Hz, H-47b), 3.89 (2H, m, H-48, 55a),
4.00 (1H, dd, J¼9.5, 5.0 Hz, H-55b), 4.22 (1H, m H-54),
4.35 (1H, d, J¼12.0 Hz, –CH2Ph), 4.38 (2H, dd,
J¼12.0 Hz, –CH2Ph), 4.61 (1H, d, J¼12.0 Hz,
–CH2Ph), 7.18–7.28 (10H, m, aromatic). 13C NMR
(CDCl3, 125 MHz) d 6.3, 13.2, 13.3, 32.2, 34.6, 42.8,
68.9, 71.2, 71.3, 72.1, 78.1, 78.4, 110.5, 127.6, 127.6,
127.9, 128.1, 128.4, 128.4, 138.3. FAB-MS 523 [MþH]þ,
5.1.16. Alcohol 30. To a solution of diol 29 (20.4 g,
0.108 mol) and imidazole (22.1 g, 0.324 mol, 3 equiv.) in
DMF (1.00 L) was added TBSCl (19.6 g, 0.13 mol) at 08C.
After stirring for 30 min at 08C, the reaction mixture was
poured into cold saturated NaHCO3 solution and extracted
with Et2O (£3). The extracts were washed with brine, dried
over Na2SO4, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(AcOEt–hexane¼1:9) to give alcohol 30 (32.8 g, 100%).
Compound 30. IR (KBr) nmax 3448, 2959, 2931, 2887, 2859,
1
1473, 1385, 1256, 1131, 1087, 1031, 837, 778 cm21. H
NMR (300 MHz, CDCl3) d 0.10 (6H, s, –Si(CH3)2), 0.90
(9H, s, –SiC(CH3)3), 1.16 (3H, d, J¼6.0 Hz, –CH(CH3)2),
1.23 (3H, d, J¼6.0 Hz, –CH(CH3)2), 2.80 (1H, d, J¼4.0 Hz,
–OH), 3.77 (2H, m, H-470a, 470b), 3.88 (1H, m, H-480), 3.95
(1H, sep, J¼6.0 Hz, –CH(CH3)2), 4.16 (1H, m, H-49), 5.04
(1H, m, H-52), 5.73 (1H, dt, J¼10.5, 2.5 Hz, H-50), 5.96
(1H, dt, J¼10.5, 1.0 Hz, H-51). 13C NMR (CDCl3, 75 MHz)
d 25.7, 25.6, 18.2, 21.9, 23.7, 25.8, 65.5, 67.2, 69.9, 70.1,
92.4, 126.5, 132.6. Anal. calcd for C15H30O4Si: C, 59.56; H,
10.00. Found: C, 59.57; H, 9.98.
0
1
395. Compound 27 (anomeric isomer of iodide 27): H
NMR (CDCl3, 500 MHz) d 1.18 (3H, d, J¼7.5 Hz, CH3),
1.22 (3H, d, J¼7.5 Hz, CH3), 1.71 (1H, qd, J¼7.5,
1.5 Hz, H-51), 1.84 (1H, dd, J¼13.0, 5.5 Hz, H-53a),
2.12 (1H, qt, J¼7.5, 2.0 Hz, H-50), 2.40 (1H, dd, J¼13.0,
7.5 Hz, H-53b), 3.27 (1H, t, J¼2.0 Hz, H-49), 3.35 (1H,
dd, J¼10.0, 9.0 Hz, H-47a), 3.94 (1H, dd, J¼9.5, 2.5 Hz,
H-55a), 4.06 (1H, ddd, J¼9.0, 5.0, 2.0 Hz, H-48), 4.17
(1H, dd, J¼9.5, 6.0 Hz, H-55b), 4.34 (1H, d, J¼11.5 Hz,
–CH2Ph), 4.41 (1H, m, H-55b), 4.47 (1H, dd, J¼11.5 Hz,
–CH2Ph), 4.70 (1H, d, J¼11.5 Hz, –CH2Ph), 7.24–7.34
(10H, m, aromatic). FAB-MS 523 [MþH]þ.
5.1.17. Enone 31. The alcohol 30 (32.8 g, 0.108 mol) was
dissolved in DMSO (600 mL) and acetic anhydride
(400 mL). After stirring for 12 h at room temperature, the
reaction mixture was poured into cold H2O and extracted
with Et2O (£3). The extracts were washed with brine, dried
over Na2SO4, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(AcOEt–hexane¼1:19) to give enone 31 (31.6 g, 97%).
Compound 31. IR (KBr) nmax 2958, 2931, 2885, 2859, 1698,
1473, 1384, 1319, 1255, 1135, 1091, 1065, 1035, 917, 837,
778 cm21 1H NMR (CDCl3, 300 MHz) d 0.05 (3H, s,
.
–Si(CH3)2), 0.07 (3H, s, –Si(CH3)2), 0.87 (9H, s,
–SiC(CH3)3), 1.21 (3H, d, J¼6.0 Hz, –CH(CH3)2), 1.26
(3H, d, J¼6.0 Hz, –CH(CH3)2), 3.98 (1H, dd, J¼11.5,
5.5 Hz, H-470a), 4.07 (1H, sep, J¼6.0 Hz, –CH(CH3)2), 4.08
(1H, dd, J¼11.5, 2.5 Hz, H-470b), 4.49 (1H, dd, J¼5.5,
2.5 Hz, H-480), 5.40 (1H, d, J¼3.5 Hz, H-36), 6.08 (1H, d,
J¼10.5 Hz, H-50), 6.84 (1H, dt, J¼10.5, 3.5 Hz, H-51). 13C
5.1.15. Diol 29. To a solution of tri-O-acetyl-D-glucal
(200 g, 0.735 mol) and 2-propanol (112 mL, 1.47 mol,
2 equiv.) in dry CH2Cl2 (2.00 L) was added dropwise
BF3·OEt2 (46.4 mL, 0.367 mol, 0.5 equiv.) at 08C. After
stirring for 50 min at room temperature, the reaction
mixture was poured into cold saturated NaHCO3 solution

T. Baba et al. / Tetrahedron 59 (2003) 6851–6872
6863
NMR (CDCl3, 75 MHz) d 25.5, 25.5, 18.2, 21.8, 23.2,
25.7, 62.5, 71.0, 76.0, 91.4, 127.9, 144.7, 195.2.
[a]2D9¼210.328 (c 0.990, CHCl3). Anal. calcd for
C15H28O4Si: C, 59.96; H, 9.39. Found: C, 59.96; H, 9.53.
5.1.20. Dithiane 37. To a solution of diol 34 (9.01 g,
41.3 mmol) and 1,3-propanedithiol (8.59 mL, 82.6 mmol)
in CHCl3 (30.6 mL) was slowly added 12N HCl
(183 mL) at 08C. After stirring for 10 min at 08C, the
reaction mixture was poured into a cold saturated NaOH
and NaHCO3 solution slowly and extracted with AcOEt
(£10). The extracts were dried over Na2SO4 and
concentrated under reduced pressure. The remaining
residue was chromatographed on a silica gel short
column (100% AcOEt) to provide triol 35 as a dark
green crude oil (15.3 g) that was used directly without
further purification.
5.1.18. Dimethylketol 33. To a stirred solution containing
CuI (6.82 g, 35.8 mmol) in dry Et2O (236 mL) was added
methyl lithium (1.14 M solution in Et2O, 62.8 mL,
71.6 mmol) at 08C. After stirring for 15 min, the reaction
mixture was mixed with enone 31 (10.7 g, 35.4 mmol) with
dry Et2O (118 mL). After stirring for further 30 min, to the
reaction mixture were slowly added iodomethane (11.1 mL,
177 mmol) and N,N-dimethylacetamide (138 mL). The
resulting mixture was gradually warmed to room tempera-
ture. After stirring 2.5 h the reaction mixture was poured
into a cold 1.2N HCl solution. The resulting mixture was
filtered through a Hyflo-Super-Celw and extracted with
Et2O (£3). The extracts were dried over Na2SO4, and
concentrated under reduced pressure. The remaining crude
oil was chromatographed on a silica gel column (AcOEt–
hexane¼1:19) to give dimethylketone 32 (11.5 g, 98%).
To a solution of the crude oil (15.3 g) in CH2Cl2 (413 mL)
were added Et3N (17.3 mL, 124 mmol), DMAP (5.04 g,
41.3 mmol) and TBSCl (7.47 g, 49.5 mmol) at room
temperature. After stirring for 4 h at room temperature,
the reaction mixture was poured into a cold saturated NH4Cl
solution and extracted with AcOEt (£3). The extracts were
dried over Na2SO4 and concentrated under reduced pressure
to provide a crude oil containing diol 36 (21.5 g) that was
used directly without further purification.
To a solution of dimethylketone 32 (10.8 g, 32.8 mmol) in
THF (164 mL) was added TBAF (1.0 M solution in THF,
164 mL, 164 mmol) at 08C. After stirring for 40 min at room
temperature, the reaction mixture was pouring into cold
saturated NH4Cl solution, and extracted with Et2O (£3), the
organic layer was dried over Na2SO4 and concentrated
under reduced pressure. The remaining crude oil was
chromatographed on a silica gel column (AcOEt–
hexane¼1:4) to provide dimethylketol 33 (6.31 g, 89%).
Compound 33. IR (KBr) nmax 3436, 2974, 2367, 1729, 1637,
1457, 1381, 1071, 1011 cm21. 1H NMR (CDCl3, 300 MHz),
d 1.03 (3H, d, J¼6.5 Hz, CH3-59), 1.11 (3H, d, J¼6.5 Hz,
CH3), 1.15 (3H, d, J¼6.0 Hz, –CH(CH3)2), 1.18 (3H, d,
J¼6.0 Hz, –CH(CH3)2), 1.58 (1H, dq, J¼12.5, 6.5 Hz,
H-51), 2.25 (1H, br, –OH), 2.32 (1H, dq,0 J¼12.5, 6.5 Hz,
H-50), 3.82 (1H, dd, J¼12.0, 4.0 Hz, H-47 a), 3.91 (1H, dd,
J¼12.0, 4.0 Hz, H-470b), 3.93 (1H, s0ep, J¼6.0 Hz,
–CH(CH3)2), 4.17 (1H, t, J¼4.0 Hz, H-48 ), 4.73 (1H, d,
J¼6.0 Hz, H-52). 13C NMR (CDCl3, 75 MHz), d 10.2, 16.4,
21.4, 23.4, 39.9, 44.3, 62.0, 69.3, 74.5, 102.2. HRMS (FAB)
calcd for C11H21O4 [MþH]þ 217.1440, found 217.1463.
To a solution of the crude oil (21.5 g) in CH2Cl2 (413 mL)
were added 2,2-dimethoxypropane (101 mL, 825 mmol)
and p-toluenesulfonic acid monohydrate (3.53 g,
18.6 mmol). After stirring 5 days at room temperature, the
reaction mixture was poured into a cold saturated NaHCO3
solution and extracted with Et2O (£3). The extracts were
dried over Na2SO4 and concentrated under reduced
pressure. The remaining residue was chromatographed on
a silica gel column (AcOEt–hexane¼1:9) to provide
dithiane 37 (15.7 g, 90% in 3 steps) as a colorless oil.
Compound 37. IR (KBr) nmax 2934, 2360, 1464, 1380, 1250,
1220, 1102, 1073, 838, 777, 669, 517 cm21 1H NMR
.
(CDCl3, 300 MHz) d 0.07 (6H, s, –Si(CH3)2), 0.87 (3H, d,
J¼6.5 Hz, CH3), 0.89 (9H, s, –SiC(CH3)3), 1.03 (3H, d,
J¼6.5 Hz, CH3), 1.31 (3H, s, CH3), 1.37 (3H, s, CH3), 1.80–
1.95 (1H, m, –SCH2CH2CH2S–), 2.04–2.15 (1H, m,
–SCH2CH2CH2S–), 2.29–2.46 (2H, m, H-50, 51), 2.77–
2.92 (4H, m, –SCH2CH2CH2S–), 3.48 (1H, dd, J¼10.5,
4.5 Hz, H-470a), 3.73 (1H, dd, J¼10.5, 7.5 Hz, H-470b), 3.91
(1H, dd, J¼10.5, 4.5 Hz, H-49), 3.94 (1H, d, J¼9.5 Hz, H-
52), 4.07 (1H, dt, J¼7.5, 4.5 Hz, H-480). 13C NMR (CDCl3,
75 MHz), d 25.6, 25.5, 10.7, 10.9, 18.2, 25.5, 25.9,
26.1, 28.4, 30.2, 30.3, 31.9, 37.2, 52.9, 62.4, 78.2,
79.5, 107.3. [a]2D9¼þ13.768 (c 1.015, CHCl3). Anal. calcd
for C20H40O3S2Si: C, 57.09; H, 9.58. Found: C, 56.98; H,
9.82.
5.1.19. Diol 34. To a solution of dimethylketol 33 (4.89 g,
22.6 mmol) in CH3CN (113 mL) and AcOH (113 mL) was
added NaBH(OAc)3 (16.8 g, 67.8 mmol) at 2108C. After
stirring for 30 min, the reaction mixture was pouring into
cold NaOH and NaHCO3 solution, and extracted with Et2O
(£3). The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The remaining crude
oil was chromatographed on a silica gel column (AcOEt–
hexane¼1:1) to provide diol 34 (4.75 g, 96%). Compound
34. IR (KBr) nmax 3405, 2971, 2932, 1457, 1381, 1340,
5.1.21. Dibenzyl ether 40. A solution of dithiane 37 (1.22 g,
2.90 mmol) in 10% HMPA/THF (19.0 mL) was treated with
t-BuLi (1.48 M in pentane, 2.35 mL, 3.48 mmol) at 2788C.
Immediately thereafter a precooled (2788C) solution of
(2S)-glycidylmethoxybenzyl ether (676 mg, 3.48 mmol) in
10 % HMPA/THF (9.51 mL) was added. The reaction
mixture was rapidly warmed to 2458C and then quenched
with saturated aqueous NH4Cl. At ambient temperature the
mixture was partitioned between Et2O and water. The
organic layer was dried over Na2SO4 and concentrated
under reduced pressure. The remaining residue was
1
1101, 1073, 1045, 1013. H NMR (CDCl3, 300 MHz), d
1.00 (3H, d, J¼7.0 Hz, CH3), 1.07 (3H, d, J¼7.0 Hz, CH3),
1.13 (3H, d, J¼6.0 Hz, –CH(CH3)2), 1.20 (3H, d, J¼6.0 Hz,
–CH(CH3)2), 1.51–1.69 (2H, m, H-51, 50), 2.19 (1H, br,
–OH), 2.44 (1H, br, –OH), 3.67–3.83 (4H, m, H-49, 480,
470a, 470b), 3.88 (1H, sep, J¼6.0 Hz, –CH(CH3)2), 4.50 (1H,
d, J¼3.5 Hz, H-52). [a]D29¼þ110.38 (c 1.030, CHCl3). Anal.
calcd for C11H22O4: C, 60.52; H, 10.16. Found: C, 60.41; H,
10.35.
chromatographed on
a silica gel column (AcOEt–
hexane¼1:4) to provide alcohol 38 (1.71 g, 96%).

6864
T. Baba et al. / Tetrahedron 59 (2003) 6851–6872
To a solution of the alcohol 38 (1.71 g, 2.78 mmol) in THF
(23.6 mL) was added tetrabutylammonium fluoride (1.0 M
solution in THF, 4.17 mL, 4.17 mmol) at 08C. After stirring
for 10 min at room temperature, the reaction mixture was
poured into cold saturated NH4Cl solution and extracted
with Et2O (£3). The organic phase was dried over Na2SO4
and concentrated under reduced pressure. The remaining
crude oil was used directly without further purification. A
one-necked flask was charged with NaH (60% dispersed in
mineral oil, 455 mg, 11.4 mmol). After most of the mineral
oil has been removed by washing with hexane, DMF
(9.11 mL) was added to the flask, followed by a solution of
the crude oil in DMF at 08C. After stirring 1 h at room
temperature, the reaction mixture was cooled to 08C again.
Benzyl bromide (0.81 mL, 6.83 mmol) and a solution of
tetrabutylammonium iodide (84.0 mg, 0.278 mmol) in DMF
(4.55 mL) were added to the mixture. After the addition has
been complete, the mixture was allowed to room tempera-
ture and stirred for 4 h. The reaction mixture was poured
into a cold saturated NH4Cl solution and extracted with
Et2O (£3). The extracts were dried over Na2SO4 and
concentrated under reduced pressure. The remaining residue
was chromatographed on a silica gel column (AcOEt–
hexane¼1:9) to provide dibenzyl ether 40 (1.67 g, 88% in 2
steps). Compound 40. IR (KBr) nmax 2933, 2361, 1616,
1514, 1457, 1379, 1248, 1074, 909, 821, 735, 698, 576,
Na2SO4 and concentrated under reduced pressure. The
remaining residue was chromatographed on a silica gel
column (AcOEt–hexane¼1:4) to provide aldehyde 42
(7.43 g, 99%) as a colorless oil. Compound 42. IR (KBr)
n
1302, 1302, 1248, 1174, 1090, 1035, 909, 821, 738, 699,
max 2907, 2860, 2712, 2367, 1721, 1613, 1513, 1455, 1364,
1
581, 522, 460 cm21. H NMR (CDCl3, 300 MHz), d 1.03
(3H, d, J¼7.0 Hz, CH3), 1.14 (3H, d, J¼7.0 Hz, CH3), 1.90
(2H, br m, –SCH2CH2CH2S–), 2.13 (1H, dd, J¼15.5,
6.0 Hz, H-53a), 2.19 (1H, dd, J¼15.5, 3.0 Hz, H-53b), 2.71–
2.76 (4H, m, –SCH2CH2CH2S–), 2.90 (1H, qd, 7.0, 4.0 Hz,
H-51), 3.05 (1H, qdd, J¼7.0, 4.0, 1.0 Hz, H-50), 3.51 (1H,
dd, J¼10.0, 6.0 Hz, H-55a), 3.58 (1H, dd, J¼10.0, 4.5 Hz,
H-55b), 3.80 (3H, s, –C6H4OCH3), 4.03–4.09 (1H, m, H-
54), 4.49 (1H, d, J¼12.0 Hz, –CH2C6H4OCH3), 4.52 (1H, d,
J¼12.0 Hz, –CH2C6H4OCH3), 4.63 (1H, d, J¼11.5 Hz,
–OCH2Ph), 4.66 (1H, d, J¼11.5 Hz, –CH2Ph), 6.85–6.90
(2H, m, aromatic), 7.23–7.38 (7H, m, aromatic), 9.56 (1H,
d, J¼1.0 Hz, H-49). 13C NMR (CDCl3, 75 MHz), d 11.2,
11.6, 24.6, 25.6, 26.0, 37.3, 38.6, 47.1, 55.2, 58.4, 71.7,
71.9, 72.8, 76.0, 113.8, 127.5, 128.1, 128.3, 129.3, 130.4,
138.7, 159.3, 203.4. [a]2D8¼233.878 (c 0.555, CHCl3).
HRMS (FAB) calcd for C27H37O4S2 [MþH]þ 489.2133,
found 489.2133.
5.1.23. Acetylene 47. To a solution of (trimethylsilyl)ace-
tylene (3.22 mL, 22.8 mmol) in dry THF (76.0 mL) was
slowly added t-BuLi (1.59 M in n-hexane, 13.4 mL,
21.3 mmol) at 2788C. After stirring for 15 min at 08C, the
reaction mixture was added the solution of aldehyde 42
(7.43 g, 15.2 mmol) in dry THF (76.0 mL). After stirring for
20 min at 08C, the reaction mixture was added iodomethane
(9.46 mL, 152 mmol). After stirring for 2.5 h at room
temperature, the reaction mixture was poured into a cold
saturated NH4Cl solution and extracted with Et2O (£4). The
extracts were dried over Na2SO4 and concentrated under
reduced pressure. The remaining residue was chromato-
graphed on a silica gel column (AcOEt–hexane¼1:9) to
provide a colorless oil (8.14 g, 89%) containing the
propargyl ether 43.
1
516 cm21. H NMR (CDCl3, 300 MHz), d 0.98 (3H, d,
J¼6.5 Hz, –CH3), 1.10 (3H, d, J¼6.5 Hz, CH3), 1.24 (3H, s,
–OC(CH3)2O–), 1.31 (3H, s, –OC(CH3)2O–), 1.89 (2H, m,
–SCH2CH2CH2S–), 2.15–2.30 (2H, m, H-53a, 53b), 2.58–
2.89 (6H, m, H-50, 51, –SCH2CH2CH2S–), 3.47 (1H, dd,
J¼9.5, 6.5 Hz, H-470a), 3.50 (1H, dd, J¼9.5, 5.5 Hz, H-
55a), 3.55 (1H, dd, J¼9.5, 5.0 Hz, H-55b), 3.64 (1H, dd,
J¼9.5, 5.5 Hz, H-470b), 3.79 (3H, s, –C6H4OCH3), 3.90
(1H, dd, J¼10.5, 5.0 Hz, H-49), 4.04 (1H, m, H-54), 4.24
(1H, ddd, J¼6.5, 5.5, 5.0 Hz, H-480), 4.47 (1H, d,
J¼11.5 Hz, –CH2C6H4OCH3), 4.51 (1H, d, J¼11.5 Hz,
–CH2C6H4OCH3), 4.54 (1H, d, J¼11.0 Hz, –OCH2Ph),
4.60 (2H, d, J¼11.0 Hz, –OCH2Ph), 4.69 (1H, d,
J¼11.0 Hz, –OCH2Ph), 6.83–6.89 (2H, m, aromatic),
7.21–7.40 (12H, m, aromatic). 13C NMR (CDCl3,
100 MHz), d 8.5, 13.3, 25.2, 25.8, 25.9, 28.4, 31.8, 37.3,
39.2, 55.3, 59.2, 69.8, 72.0, 72.3, 72.9, 73.5, 76.3, 76.6,
80.0, 107.6, 113.8, 127.3, 127.5, 127.8, 127.9, 128.2, 128.3,
129.2, 130.5, 138.3, 139.0, 159.2. [a]2D9¼24.008 (c 0.580,
CHCl3). Anal. calcd for C39H52O6S2: C, 68.79; H, 7.70.
Found: C, 68.67; H, 7.82.
To a solution of the propargyl ether 43 (8.01 g, 13.3 mmol)
in THF (119 mL) was added TBAF (1.0 M solution in THF,
14.7 mL, 14.7 mmol) at 08C. After stirring for 10 min at
room temperature, the reaction mixture was poured into
cold saturated NH4Cl solution and extracted with Et2O (£3).
The organic layer was dried over Na2SO4 and concentrated
under reduced pressure. The remaining crude oil was
chromatographed on a silica gel column (AcOEt–
hexane¼1:4) to provide the acetylene 44 (6.99 g, 99%).
5.1.22. Aldehyde 42. A solution of dibenzyl ether 40
(11.4 g, 16.7 mmol) in 80% acetic acid (167 mL) was stirred
at 408C for 1 day. The reaction mixture was poured into a
cold NaOH and NaHCO3 solution and extracted with AcOEt
(£4). The resulting extract was dried over Na2SO4, and
concentrated under reduced pressure to give a crude oil that
was chromatographed on a silica gel column (AcOEt–
hexane¼1:2) to provide diol 41 (9.89 g, 81%).
To a solution of N-chlorosuccinimide (2.70 g, 20.2 mmol),
silver nitrate (3.86 g, 22.7 mmol), and 2,4,6-collidine
(8.01 mL, 60.7 mmol) in CH3CN (20.2 mL) and H2O
(10.1 mL) was added a solution of the acetylene 44
(2.54 g, 4.80 mmol), in CH3CN (20.2 mL) at 2108C.
After stirring for 5 min, the reaction mixture was treated
successively at 1 min intervals with saturated aqueous
Na2SO3, saturated aqueous NaHCO3, and brine (10 mL
each). The mixture was filtered through Hyflo-Super-Celw.
After the filter cake was washed thoroughly with 1:1
hexane–CH2Cl2, the organic layer of the filtrate was dried
over Na2SO4 and concentrated under reduced pressure. The
To a solution of diol 41 (9.89 g, 15.4 mmol) in dry CH2Cl2
(51.4 mL) was slowly added lead(IV) acetate (8.21 g,
18.5 mmol) with dry CH2Cl2 (103 mL) at 08C. After stirring
for 1 h at room temperature, the reaction mixture was
poured into a cold saturated NaHCO3 and Na2SO3 solution
and extracted with Et2O (£3). The extracts were dried over

T. Baba et al. / Tetrahedron 59 (2003) 6851–6872
6865
remaining crude oil was chromatographed on a silica gel
column (AcOEt–hexane¼1:4) to provide the a colorless oil
(4.39 g) containing ketone 45 and 2,4,6-collidine.
s, –CCH3), 1.52 (3H, s, –CCH3), 2.92 (1H, br-d, –OH), 3.43
(3H, s, –OCH3), 3.46–3.92 (6H, m, H-42, 43, 44, 45, 46a,
46b), 4.77 (1H, d, J¼4.0 Hz, H-41). 13C NMR (CDCl3,
75 MHz) d 18.9, 26.8, 28.9, 38.6, 55.2, 62.1, 62.7, 68.7,
73.3, 74.1, 97.5, 99.7, 178.1. [a]2D5¼þ124.18 (c 1.00,
CHCl3). Anal. calcd for C15H26O7: C, 56.59; H, 8.23.
Found: C, 56.59; H, 8.46.
To a solution of ketone 45 (4.39 g) in MeOH (48.0 mL) was
added NaBH4 (728 mg, 19.2 mmol) at 08C. After stirring for
30 min at 08C, the reaction mixture was poured into cold
1.2N HCl and extracted with AcOEt (£5). The organic layer
was dried over Na2SO4 and concentrated under reduced
pressure. The remaining crude oil was chromatographed on
a silica gel column (AcOEt–hexane¼1:9) to provide alcohol
46 (1.78 g, 51% in 2 steps).
5.1.25. Diol 54. To a solution of imidazole (17.1 g,
0.251 mol) in CHCl3 (170 mL) was gradually added
thiophosgene (4.80 mL, 62.8 mmol) as a solution of
toluene (60.0 mL) while cooling so that temperature
may not go up too much by the exothermic reaction.
After the reaction mixture was stirred for 1 h at room
temperature, a solution of pivaloate 49 (10.0 g) in toluene
(86 mL) and CH3Cl (20 mL) was added, and stirring the
resulting mixture was continued for further 2 days at
refluxing temperature. The resulting mixture was concen-
trated under reduced pressure to give a crude oil. The
remaining oil was chromatographed on a silica gel short
column (Et2O–hexane¼3:7) to provide a yellow oil
containing the thiocarbamate 50 (13.1 g). NaH2PO2·H2O
(18.0 g, 170 mmol) and small amount of toluene were
placed in a flask. After the azeotropic operation with
toluene was repeated 3 times, the flask was charged with
2-methoxyethanol. (212 mL). The flask was maintained
under a dry Ar atmosphere and heated at 1058C in an oil
bath. The mixture was stirred vigorously and AIBN
(4.18 g, 25.0 mmol) was added as a solution of 2-
methoxyethanol (63.8 mL) by portions. Immediately
after adding the solution of AIBN, the thiocarbamate 50
(7.28 g, 17.0 mmol) was added as a solution of 2-
methoxyethanol (63.8 mL) slowly. After stirring for
10 min, the solution was poured into iced water, and the
mixture was extracted with AcOEt (£3). The extracts
were combined and dried over Na2SO4, and the solvent
was removed by evaporation on a rotary evaporator to
give a yellow crude oil. The oil was chromatographed on
a silica gel column (Et2O–hexane¼2:1) to provide color-
less oil containing the deoxygenated compound 51
(5.32 g).
To a solution of the alcohol 46 (525 mg, 1.19 mmol) in
CH3CN (11.9 mL) were added pyridine (0.96 mL,
11.9 mmol) and TBSOTf (0.55 mL, 2.38 mmol) at 08C.
After stirring for 5 h at room temperature, the reaction
mixture was poured into cold saturated aqueous NH4Cl and
extracted with Et2O (£3). The extracts were washed with
brine, dried over Na2SO4, and concentrated under reduced
pressure. The remaining residue was chromatographed on a
silica gel column (AcOEt–hexane¼1:19) to provide acety-
lene 47 (648 mg, 98%). Compound 47. IR (KBr) nmax 3307,
2930, 2361, 1614, 1514, 1464, 1362, 1250, 1096, 836, 774,
1
697, 668 cm21. H NMR (CDCl3, 300 MHz), d 0.00–0.08
(6H, m, –Si(CH3)2), 0.86–1.03 (15H, m, –SiC(CH3)3, CH3-59,
CH3-60), 1.62–1.99 (4H, m, H-50, 51, 53a, 53b), 2.36–2.45
(1H, m, H-47), 3.32–3.40 (3H, m, –OCH3), 3.48–4.06 (5H, m,
H-49, 52, 54, 55a, 55b), 3.83 (3H, s, –OCH2C6H4OCH3),
4.49–4.76 (4H, m, –OCH2Ar), 6.90 (2H, br-d, J¼8.0 Hz,
aromatic), 7.27–7.39 (7H, m, aromatic). 13C NMR (CDCl3,
75 MHz), d 24.5, 24.4, 24.3, 24.0, 23.9, 10.7, 10.9, 11.1,
11.5, 12.1, 12.4, 12.7, 18.0, 25.9, 34.6, 34.7, 37.5, 37.7,
38.1, 38.5, 38.6, 38.8, 38.9, 55.3, 56.5, 56.7, 71.4, 71.6,
71.9, 72.0, 72.4, 73.0, 74.1, 74.6, 74.7, 75.6, 75.8, 76.1,
81.7, 82.2, 113.8, 127.3, 127.4, 127.5, 127.7, 128.2, 129.2,
130.5, 130.6, 139.0, 139.1, 159.2. Anal. calcd for
C33H50O5Si: C, 71.44; H, 9.08. Found: C, 71.30; H, 9.11.
5.1.24. Pivalate 49. To a solution of methyl-a-D-glucopy-
ranoside (1.19 kg, 6.13 mol) in N,N-dimethylformamide
(6.00 L) were added 2,2-dimethoxypropane (1.88 L,
15.3 mol) and Amberlyst 15Ew (6.00 g) at room tempera-
ture. After stirring for 3 days at room temperature, the
reaction mixture was filtered and concentrated under
reduced pressure to give the diol as gummy paste
(1.43 kg). To the solution of the paste (100.0 g, ca.
0.42 mol) in CH2Cl2 (2.00 L) and pyridine (200 mL) at
08C under N2 atmosphere was added pivaloyl chloride
(52.6 mL, 0.427 mol) dropwise. After stirring for 2 days at
room temperature, the reaction mixture was poured into a
cold saturated NH4Cl solution and extracted with Et2O (£3).
The resulting extract was dried over Na2SO4 and concen-
trated in vacuo to leave a viscous oil. The oil was dissolved
in Et2O containing small amount of hexane and stand still
for crystallization. The mother liquors were decanted and
the crystals were collected by filtration and then dried at
high vacuum. The recrystallization procedure was repeated
twice. A total of 92.0 g of pivaloate 49 (68%) was obtained
in three crops. Compound 49. IR (KBr) nmax 3476, 2990,
2917, 2880, 2840, 2361, 1736, 1482, 1374, 1270, 1198,
To a solution of the colorless oil of 51 (32.6 g, 108 mmol) in
MeOH and THF (720 mL, MeOH–THF¼1:1) was added
NaOMe (17.5 g, 323 mmol) at room temperature. After
stirring for 45 min, the reaction mixture was poured into a
cold saturated NH4Cl solution and extracted with Et2O (£3).
The extracts were dried over Na2SO4, and concentrated
under reduced pressure to give a crude oil that was
chromatographed on
a silica gel column (Et2O–
hexane¼1:1) to provide the alcohol 52 (21.8 g, 93%).
To a solution of alcohol 52 (15.1 g, 69.2 mmol) in benzyl
chloride (553 mL) was added potassium hydroxide (166 g)
at room temperature. After stirring for 1 h at 1108C, the
reaction mixture was cooled to room temperature and
poured into a cooled saturated ammonium chloride solution.
The resulting mixture was extracted with Et2O (£3). The
extracts were dried over Na2SO4, and concentrated under
reduced pressure. The remaining residue was chromato-
graphed on a silica gel short column to remove the large
quantities of non-volatile benzyl alcohol generated from
benzyl chloride by the aqueous work up. A yellow oil
1
1167, 1042, 990, 945, 850, 750, 666, 521 cm21. H NMR
(CDCl3, 300 MHz) d 1.20 (9H, s, –COC(CH3)3), 1.43 (3H,

6866
T. Baba et al. / Tetrahedron 59 (2003) 6851–6872
containing the benzyl ether 53 (22.4 g) was obtained in the
end, and that was used in the next step without further
purification.
was dried over Na2SO4 and concentrated under reduced
pressure. The remaining oil was chromatographed on a short
silica gel column (AcOEt–hexane¼1:9) to give lactone 58
(7.75 g, 93%). Compound 58. IR (KBr) nmax 2976, 2875,
To a solution of the benzyl ether 53 (37.1 g, 0.12 mol) in
MeOH (1150 mL) was added Amberlyst 15Ew (11.5 g) at
room temperature. After stirring for 40 min at room
temperature, the reaction mixture was filtered and concen-
trated under reduced pressure to leave a viscous oil. The
remaining oil was chromatographed on a silica gel short
column (Et2O–hexane¼4:1) to provide diol 54 (32.0 g, 99%
in 2 steps). Compound 54. IR (KBr) nmax 3324, 2907, 2361,
1734, 1456, 1378, 1330, 1237, 1182, 1106, 1052, 909, 842,
2361, 1735, 1457, 1364, 1282, 1150, 1040, 742, 698 cm21
.
1H NMR (CDCl3, 300 MHz), d 1.20 (18H, s, –COC(CH3)3),
2.03 (1H, ddd, J¼14.5, 7.0, 6.5 Hz, H-43a), 2.60 (1H, ddd,
J¼14.5, 7.0, 6.0 Hz, H-43b), 4.10 (1H, dd, J¼6.0, 6.5 Hz,
H-42), 4.23 (1H, dd, J¼12.5, 4.0 Hz, H-46a), 4.28 (1H, dd,
J¼12.5, 2.5 Hz, H-46b), 4.65 (1H, d, J¼12.0 Hz,
–OCH2Ph), 4.83 (1H, ddd, J¼9.0, 4.0, 2.5 Hz, H-45), 4.87
(1H, d, J¼12.0 Hz, –OCH2Ph), 5.04 (1H, dt, J¼9.0, 7.0 Hz,
H-44), 7.25–7.38 (5H, m, aromatic). 13C NMR (CDCl3,
75 MHz), d 26.8, 27.0, 32.7, 38.7, 38.8, 61.9, 64.0, 71.9,
72.6, 77.5, 128.1, 128.3, 128.6, 136.8, 168.8, 177.3, 178.0.
[a]2D8¼þ77.98 (c 1.005, CHCl3). Anal. calcd for C23H32O7:
C, 65.70; H, 7.67. Found: C, 65.84; H, 7.80.
1
739, 697, 600, 520 cm21. H NMR (CDCl3, 300 MHz), d
1.84 (1H, q, J¼11.5 Hz, H-43a), 2.16 (1H, dt, J¼11.5,
4.5 Hz, H-43b), 3.06 (2H, br s, –OH), 3.39 (3H, s, –OCH3),
3.42–3.63 (3H, m, H-42, 44, 45), 3.72 (1H, d, J¼15.0 Hz,
H-46a), 3.78 (1H, d, J¼15.0 Hz, H-46b), 4.54 (1H, d,
J¼12.0 Hz, –OCH2Ph), 4.62 (1H, d, J¼12.0 Hz,
–OCH2Ph), 7.24–7.38 (5H, m, aromatic). 13C NMR
(CDCl3, 75 MHz), d 32.9, 54.8, 62.2, 65.6, 70.9, 72.0,
73.6, 97.0, 127.8, 127.8, 128.4, 137.9. [a]2D8¼þ65.78 (c
0.99, CHCl3). Anal. calcd for C14H20O5: C, 62.67; H, 7.51.
Found: C, 62.67; H, 7.53.
5.1.27. Allylhydropyrane 59. To a solution of lactone 58
(14.1 g, 0.33 mmol) in THF (334 mL) was added allylmag-
nesium bromide (1.0 M solution in Et2O, 38.5 mL,
0.38 mmol) at 2788C. After stirring for 30 min, the reaction
mixture was quenched by addition of AcOEt and poured
into a cold saturated NH4Cl solution. The resulting mixture
was extracted with Et2O (£3) and dried over Na2SO4.
Removal of the volatiles in vacuo gave crude product that
was chromatographed on silica gel (AcOEt–hexane¼3:17)
to give hemiacetal (15.2 g) as a mixture of anomers. It was
used directly in the next step without further purification. To
a solution of the crude product (15.2 g, 32.9 mmol) in
CH3CN (334 mL) were added Et3SiH (16.1 mL,
98.6 mmol) and BF3·OEt2 (6.37 mL, 49.3 mmol) at
2108C. After stirring for 20 min, the reaction mixture was
poured into a cold saturated NaHCO3 solution. The resulting
mixture was extracted with Et2O (£3) and dried over
Na2SO4. Removal of the volatiles in vacuo gave crude
product that was chromatographed on silica gel (AcOEt–
hexane¼1:19) to give allylhydropyrane 59 (8.02 g, 54% in 2
steps). Compound 59. IR (KBr) nmax 3448, 3068, 2976,
2874, 2362, 1732, 1644, 1481, 1364, 1285, 1150, 1110,
1035, 990, 914, 838, 739, 699, 596 cm21. 1H NMR (CDCl3,
300 MHz), d 1.20 (18H, s, –COC(CH3)3), 1.44 (1H, q,
J¼11.5 Hz, H-43a), 2.24 (1H, m, H-40a), 2.61 (1H, m, H-
40b), 2.72 (1H, ddd, J¼11.5, 5.0, 4.0 Hz, H-43b), 3.24–3.38
(total 2H, m, H-41, 42), 3.57 (1H, ddd, J¼10.0, 6.0, 2.0 Hz,
H-45), 4.06 (1H, dd, J¼12.0, 6.0 Hz, H-46a), 4.21 (1H, dd,
J¼12.0, 2.0 Hz, H-46b), 4.43 (1H, d, J¼11.5 Hz, –
OCH2Ph), 4.62 (1H, d, J¼11.5 Hz, –OCH2Ph), 4.66 (1H,
ddd, J¼11.5, 10.0, 5.0 Hz, H-44), 4.98–5.13 (2H, m, H-57),
5.79–5.95 (1H, m, H-39), 7.25–7.38 (5H, m, aromatic). 13C
NMR (CDCl3, 75 MHz), d 26.9, 27.0, 34.6, 35.7, 38.6, 38.7,
62.9, 66.8, 71.0, 75.0, 77.2, 80.1, 116.8, 127.8, 127.8, 128.4,
134.6, 137.9, 177.3, 178.2. [a]3D0¼þ7.248 (c 0.990, CHCl3).
Anal. calcd for C26H38O6: C, 69.93; H, 8.58. Found: C,
69.98; H, 8.60.
5.1.26. Lactone 58. To a solution of diol 54 (30.7 g,
0.11 mol) in CH2Cl2 (1150 mL) were added pivaloyl
chloride (42.3 mL, 0.34 mol) and DMAP (41.9 g,
0.34 mol) at 08C. After stirring for 1 h at room temperature,
the reaction mixture was poured into a cold saturated NH4Cl
solution and extracted with Et2O (£3). The extracts were
dried over Na2SO4 and concentrated under reduced
pressure. The remaining oil was chromatographed on a
silica gel short column (Et2O–hexane¼1:4) to provide the
dipivaloate 55 (48.2 g, 97% in 2 steps) that was used
directly in the next step without further purification.
To a solution of dipivaloate 55 (24.5 g, 56.1 mmol) in acetic
anhydride (561 mL) was slowly added conc. H2SO4
(1.12 mL) at 08C. After stirring for 15 min at 08C, the reaction
mixture was poured into a cold saturated NaHCO3 solution
and extracted with Et2O (£3). The extracts were dried over
Na2SO4 and concentrated under reduced pressure. The
remaining oil was chromatographed on a silica gel column
(AcOEt–hexane¼1:9) to provide the acetate 56 (22.7 g, 87%).
The acetate 56 existed as a mixture of anomers.
A mixture of the acetate 56 (21.2 g, 45.6 mmol) in 1,2-
dimethoxyethane (414 mL), H2O (20.7 mL) and conc. HCl
(20.7 mL) was stirred vigorously and heated to 558C for
14 h. After the reaction mixture was cooled to room
temperature, it was poured into a cold saturated NaHCO3
solution and extracted with Et2O (£3). The extracts were
dried over Na2SO4 and concentrated under reduced
pressure. The remaining oil was chromatographed on a
silica gel column (AcOEt–hexane¼1:4) to give the hemi-
acetal 57 (12.6 g, 66%) as a mixture of anomers.
5.1.28. Alcohol 62. To a solution of allylhydropyrane 59
(8.02 g, 18.0 mmol) in MeOH (180 mL) was added NaOMe
(5.82 g, 108 mmol) at room temperature. After stirring for
4 h, the reaction mixture was poured into a cold saturated
NH4Cl solution. The resulting mixture was extracted with
Et2O (£7) and dried over Na2SO4. Removal of the volatiles
in vacuo gave crude product that was chromatographed on
The oil of the hemiacetal 57 (8.40 g, 19.9 mmol) was
dissolved in DMSO (119 mL) and acetic anhydride
(79.5 mL). After magnetically stirring for 14 h at room
temperature, the reaction mixture was added Et2O and
washed with saturated NaHCO3 solution. The organic layer

T. Baba et al. / Tetrahedron 59 (2003) 6851–6872
6867
silica gel column (AcOEt–hexane¼2:1) to give diol 60
(£3). The extracts were dried over Na2SO4, and concen-
trated under reduced pressure. The remaining crude oil was
chromatographed on a silica gel column (AcOEt–
hexane¼1:19) to give the dibromo-olefin 64 (8.76 g, 91%).
(4.65 g, 93%).
To a solution of diol 60 (6.24 g, 22.4 mmol) in DMF
(149 mL) were added imidazole (7.63 g, 112 mmol) and
TBSCl (10.1 g, 67.3 mmol) at 08C. After stirring for 8 h at
room temperature, the reaction mixture was poured into a
cold saturated NH4Cl solution and extracted with Et2O (£3).
The resulting extracts were washed with H2O (£2), dried
over Na2SO4 and concentrated under reduced pressure to
give a crude oil that was chromatographed on a silica gel
short column (AcOEt–hexane¼1:19) to provide colorless
oil containing disilylether 61 (13.0 g).
To a stirred solution containing the dibromo-olefin 64
(8.26 g, 15.1 mmol) in THF (158 mL) was added a solution
of n-BuLi (21.2 mL, 33.2 mmol, 1.57 M in n-hexane) at
2788C. The reaction mixture was gradually warmed to 08C
for 1.5 h. After that, the reaction mixture was added
PhSSO2Ph (7.92 g, 31.6 mmol) with THF (63.2 mL). After
stirring for 1 h, the reaction mixture was poured into cold
saturated NH4Cl solution. The resulting mixture was
extracted with Et2O (£3). The extracts were dried over
Na2SO4, and concentrated under reduced pressure. The
remaining crude oil was chromatographed on a silica gel
column (AcOEt–hexane¼1:19) to give thiophenylacetylene
65 (6.71 g, 98%). Compound 65. IR (KBr) nmax 3228, 3065,
2929, 2857, 2366, 2175, 1642, 1584, 1473, 1328, 1252,
The oil of disilylether 61 was dissolved in 257 mL of
methanol and treated with CSA (1.04 g, 4.48 mmol) at
2108C for 1 h. The reaction mixture was poured into a cold
saturated NaHCO3 solution. The resulting mixture was
extracted with Et2O (£3) and dried over Na2SO4. Removal
of the volatiles in vacuo gave a crude product that was
chromatographed on silica gel column (AcOEt–
hexane¼1:9) to give alcohol 62 (7.72 g, 88% in 2 steps).
Compound 62. IR (KBr) nmax 3496, 3074, 3032, 2930, 2859,
1642, 1473, 1456, 1362, 1253, 1096, 1005, 912, 861, 837,
1
1087, 1025, 915, 838, 778, 739, 688, 595, 538 cm21. H
NMR (CDCl3, 300 MHz), d 0.06 (6H, s, –Si(CH3)2), 0.86
(9H, s, –SiC(CH3)3), 1.48 (1H, dt, J¼12.0, 10.5 Hz, H-43a),
2.30 (1H, br-dt, J¼14.0, 7.0 Hz, H-40a), 2.44 (1H, dt,
J¼12.0, 4.0 Hz, H-43b), 2.63 (1H, m, H-40b), 3.21–3.35
(2H, m, H-41, 42), 3.64 (1H, ddd, J¼11.0, 9.0, 4.5 Hz, H-
44), 4.05 (1H, d, J¼9.0 Hz, H-45), 4.48 (1H, d, J¼11.5 Hz,
–OCH2Ph), 4.61 (1H, d, J¼11.5 Hz, –OCH2Ph), 5.04–5.15
(2H, m, H-57), 5.86–6.01 (1H, m, H-39), 7.18–7.44
(10H, m, aromatic). 13C NMR (CDCl3, 75 MHz), d 24.7,
4.6, 17.9, 25.6, 35.9, 39.4, 70.0, 71.1, 72.6, 74.1, 74.9,
80.2, 96.9, 117.1, 126.6, 127.9, 128.5, 129.2, 132.2,
134.7, 138.1. [a]2D9¼þ0.638 (c 1.050, CHCl3). Anal. calcd
for C29H38O3SSi: C, 70.40; H, 7.74./ Found: C, 70.41; H,
7.47.
1
777, 737, 698, 670 cm21. H NMR (CDCl3, 300 MHz), d
0.06 (6H, s, –Si(CH3)2), 0.88 (9H, s, –SiC(CH3)3), 1.46 (1H,
q, J¼11.5 Hz, H-43a), 2.00 (1H, br, –OH), 2.22 (1H, m,
H-40a), 2.39 (1H, dt, J¼11.5, 4.5 Hz, H-43b), 2.63 (1H, m,
H-40b), 3.13–3.23 (2H, m, H-42, 45), 3.31 (1H, ddd, J¼9.0,
7.5, 3.0 Hz, H-41), 3.58 (1H, ddd, J¼11.0, 9.0, 4.5 Hz,
H-44), 3.58 (1H, br, H-46a), 3.80 (1H, br, H-46b), 4.48 (1H,
d, J¼11.5 Hz, –OCH2Ph), 4.61 (1H, d, J¼11.5 Hz,
–OCH2Ph), 5.00–5.13 (2H, m, H-57), 5.79–5.93 (1H, m,
H-39), 7.24–7.39 (5H, m, aromatic). 13C NMR (CDCl3,
75 MHz), d 25.1, 24.3, 17.8, 25.6, 36.0, 38.9, 62.7, 66.8,
71.1, 75.5, 79.5, 81.6, 117.0, 127.9, 127.9, 128.5, 134.8,
138.2. [a]2D9¼þ1.598 (c 1.015, CHCl3). Anal. calcd for
C22H36O4Si: C, 67.30; H, 9.24. Found: C, 67.26; H, 9.35.
5.1.30. Vinyl sulfone 69. To a solution of thiophenylace-
tylene 65 (6.71 g, 14.8 mmol) in THF (103 mL) was added
TBAF (1.0 M solution in THF, 30.9 mL, 44.4 mmol) at 08C.
After stirring for 3 h at room temperature, the reaction
mixture was poured into cold saturated NH4Cl solution. The
resulting mixture was extracted with Et2O (£3). The
extracts were dried over Na2SO4, and concentrated under
reduced pressure. The remaining crude oil was chromato-
graphed on a silica gel column (AcOEt–hexane¼1:4) to
give an alcohol (4.66 g, 83%).
5.1.29. Thiophenylacetylene 65. To a magnetically stirred
solution containing oxalyl chloride (3.06 mL, 35.0 mmol) in
CH2Cl2 (250 mL) was added a mixture of DMSO (4.97 mL,
70.1 mmol) and CH2Cl2 (16.7 mL) at 2788C. After stirring
for 20 min, to the reaction mixture was added alcohol 62
(6.88 g, 17.5 mmol) with CH2Cl2 (83.5 mL). After stirring
for 1 h, to the reaction mixture was slowly added Et3N
(14.7 mL, 105 mmol), which was gradually warmed to
2308C. After stirring 1 h, the reaction mixture was poured
into a cooled saturated NH4Cl solution. The resulting
mixture was extracted with Et2O (£3). The extracts were
concentrated under reduced pressure. The remaining residue
was passed through a silica gel and Na2SO4 short column
(100% AcOEt) to provide a colorless oil containing the
aldehyde 63.
To a solution of the alcohol (3.43 g, 9.01 mmol) in 90.1 mL
of CH2Cl2 were added acetic anhydride (1.27 mL,
13.5 mmol) and DMAP (1.21 g, 9.92 mmol) at 08C. After
stirring for 10 min at room temperature, the reaction
mixture was poured into a cold saturated NH4Cl solution
and extracted with Et2O (£3). The resulting extracts were
dried over Na2SO4 and concentrated under reduced
pressure. The remaining crude oil was chromatographed
on a silica gel column (AcOEt–hexane¼1:9) to give acetate
66 (3.66 g, 96%).
To a magnetically stirred solution containing carbon
tetrabromide (23.2 g, 70.1 mmol) in CH2Cl2 (58.4 mL)
was added a solution of Ph3P (4.46 g, 140 mmol) in CH2Cl2
(58.4 mL) at 08C. After stirring for 10 min at 08C, the
reaction mixture was added the oil of aldehyde 63 with
CH2Cl2 (58.4 mL). After stirring for 20 min, the reaction
mixture was poured into a cooled saturated NaHCO3
solution. The resulting mixture was extracted with CH2Cl2
To a stirred solution containing the acetate 66 (3.66 g,
8.66 mmol) in 1,2-dichloroethane (86.6 mL) were added
Et3SiH (13.8, 86.6 mmol) and biscobalthexacarbonyl-2-
methyl-but-3-yn-2-ol (467 mg, 1.30 mmol) at room tem-
perature. After stirring for 1.5 h at 608C, the reaction
mixture was concentrated under reduced pressure. The

6868
T. Baba et al. / Tetrahedron 59 (2003) 6851–6872
remaining crude oil was chromatographed on a silica gel
column (AcOEt–hexane¼1:9) to give the vinyl sulfide 67
(4.30 g, 100%).
527 cm21. Anal. calcd for C56H76O10SSi: C, 69.39 H, 7.90.
Found: C, 69.39; H, 7.97.
5.1.32. Alcohol 72. To a solution of heteroconjugate adduct
70 (169 mg, 0.174 mmol) in CH2Cl2 (1.43 mL) was added
ethyl vinyl ether (0.27 mL) and PPTS (3.0 mg) at room
temperature. After stirring for 1.5 h, the reaction mixture
was poured into a cold saturated NaHCO3 solution and
extracted with Et2O (£3). The organic layer was washed
with brine, dried over Na2SO4 and concentrated under
reduced pressure. The remaining crude oil was chromato-
graphed on a silica gel column (AcOEt–hexane¼1:4) to
give the ethoxyethyl ether 71 (181 mg, 100%).
To a solution of vinyl sulfide 67 (4.30 g, 8.66 mmol) in
MeOH (86.6 mL) was added K2CO3 (1.20 g, 8.66 mmol) at
08C. After stirring for 1.5 h at room temperature, the
reaction mixture was poured into a cold saturated NH4Cl
solution and extracted with Et2O (£3). The resulting
extracts were dried over Na2SO4 and concentrated under
reduced pressure. The remaining crude oil was chromato-
graphed on a silica gel column (AcOEt–hexane¼3:17) to
give alcohol 68 (4.17 g, 97%).
To a solution of alcohol 68 (3.77 g, 7.59 mmol) and
Na2HPO4 (7.54 g, 53.1 mmol) in CH2Cl2 (75.8 mL) was
added mCPBA (70%, 4.12 g, 167 mmol) at 08C. After
stirring for 1 h, the reaction mixture was poured into a cold
NaHCO3 and Na2SO3 solution. The resulting mixture was
extracted with Et2O and dried over Na2SO4, and concen-
trated under reduced pressure. The remaining crude oil was
chromatographed on a silica gel column (AcOEt–
hexane¼1:4) to give vinyl sulfone 69 (3.68 g, 85%).
Compound 69. IR (KBr) nmax 3484, 3067, 2956, 2876,
1603, 1447, 1298, 1237, 1140, 1082, 1004, 912, 843, 742,
To the solution of the ethoxyethyl ether 71 (127 mg,
0.122 mmol) in THF (1.22 mL) was added TBAF (1.0 M
solution in THF, 1.22 mL, 1.22 mmol) at room temperature.
After magnetically stirring for 6 days at 508C, the reaction
mixture was pouring into cold saturated NH4Cl solution,
and extracted with Et2O (£3). The organic layer was washed
with brine, dried over Na2SO4, and concentrated under
reduced pressure. The remaining crude oil was chromato-
graphed on a silica gel column (AcOEt–hexane¼1:3) to
provide an alcohol (99.7 mg, 88%).
1
699, 575 cm21. H NMR (CDCl3, 300 MHz), d 0.58–0.88
To the solution of the alcohol (246 mg, 0.265 mmol) in
CH2Cl2 (2.65 mL) were added pyridine (107 mL,
1.33 mmol), acetic anhydride (75 mL, 0.796 mmol) and
DMAP (32.0 mg, 0.265 mmol) at room temperature. After
stirring for 1 h, the reaction mixture was poured into cold
saturated NH4Cl solution, extracted with Et2O (£3) and
washed with brine. The organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The
remaining crude oil was chromatographed on a silica gel
column (AcOEt–hexane¼1:4) to provide the acetate
(257 mg, 100%). To the solution of the acetate (257 mg,
0.265 mmol) in MeOH (2.65 mL) was added camphorsul-
fonic acid (6 mg, 0.027 mmol) at room temperature. After
stirring for 5 min, the reaction mixture was pouring into
cold saturated NaHCO3 solution, extracted with Et2O (£3)
and washed with brine. The organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The
remaining crude oil was chromatographed on a silica gel
column (AcOEt–hexane¼1:3) to provide alcohol 72
(218 mg, 91%). Compound 72. IR (KBr) nmax 3447, 2935,
2361, 1732, 1613, 1514, 1455, 1373, 1306, 1247, 1087, 820,
749, 699, 560 cm21. Anal. calcd for C52H64O11S: C, 69.62
H, 7.19. Found: C, 69.49; H, 7.29.
(15H, m, Si(CH2CH3)3), 1.47 (1H, q, J¼11.5 Hz, H-43a),
2.16 (1H, m, H-40a), 2.55 (1H, m, H-40b), 2.73 (1H, dt,
J¼12.0, 4.5 Hz, H-43b), 3.01 (1H, d, J¼9.0 Hz, –OH),
3.11–3.27 (2H, m, H-41, 42), 3.34 (1H, m, H-44), 4.45 (1H,
d, J¼11.5 Hz, –OCH2Ph), 4.63 (1H, d, J¼11.5 Hz,
–OCH2Ph), 4.76 (1H, t, J¼9.0 Hz, H-45), 4.97–5.05 (2H,
m, H-57), 5.68–5.83 (1H, m, H-39), 6.40 (1H, d, J¼9.0 Hz,
H-46), 7.26–7.40 (5H, m, aromatic), 7.48–7.63 (3H, m,
aromatic), 7.83–7.90 (2H, m, aromatic). 13C NMR (CDCl3,
75 MHz), d 3.1, 6.9, 35.6, 39.4, 68.8, 70.8, 75.2, 78.5, 79.8,
116.7, 126.7, 127.9, 128.0, 128.5, 129.2, 133.2, 134.7,
138.1, 145.8, 154.3. [a]2D9¼21168 (c 0.355, CHCl3). Anal.
calcd for C29H40O5SSi: C, 65.87; H, 7.62. Found: C, 65.87;
H, 7.73.
5.1.31. Heteroconjugate adduct 70. To a stirred solution
containing acetylene 47 (2.40 g, 4.32 mmol) in dry THF
(43.2 mL) was added n-BuLi (1.59 M solution in hexane,
2.72 mL, 4.32 mmol) at 08C. After stirring for 30 min, the
reaction mixture was added vinyl sulfone 69 (722 mg,
1.37 mmol) with dry THF (14.4 mL). After stirring 2.5 h the
reaction mixture was poured into a cooled saturated NH4Cl
solution. The resulting mixture was extracted with Et2O
(£3). The organic layer was washed with brine, dried over
Na2SO4, and concentrated under reduced pressure to give
the crude oil (3.28 g). To a solution of the crude oil (3.28 g)
in THF (14.4 mL) was added TBAF fluoride (1.0 M solution
in THF, 2.73 mL, 2.73 mmol) at 08C. After stirring for
5 min at 08C, the reaction mixture was quenched by pouring
into cold saturated NH4Cl solution, and extracted with Et2O
(£3). The organic layer was washed with brine, dried over
Na2SO4 and concentrated under reduced pressure. The
remaining crude oil that was chromatographed on a silica
gel column (AcOEt–hexane¼1:3) to provide heteroconju-
gate adduct 70 (1.05 g, 80% in 2 steps) and excess acetylene
47 (1.56 g, 65%). Compound 70. IR (KBr) nmax 3448, 2930,
1613, 1514, 1455, 1306, 1250, 1087, 836, 775, 748, 698,
5.1.33. Endocyclic olefin 75 and 76. To the solution of
alcohol 72 (167 mg, 0.172 mmol) in CH2Cl2 (0.86 mL) was
added di-cobaltoctacarbonyl (295 mg, 0.862 mmol) with
CH2Cl2 (0.86 mL) at 08C. After stirring for 2 h at room
temperature, the reaction mixture was concentrated under
reduced pressure. The remaining residue was chromato-
graphed on a silica gel short column (AcOEt–hexane¼1:1)
to provide a crude oil (218 mg) that was used directly in the
next step without further purification. To the solution of the
crude oil (218 mg,) in CH2Cl2 (17.2 mL) was added
BF3·OEt2 (0.22 mL, 1.72 mmol) at 08C. After stirring for
30 min at 08C, the reaction mixture was poured into a cold
saturated NaHCO3 solution, extracted with Et2O (£3), and
washed with brine. The extracts were dried over Na2SO4

T. Baba et al. / Tetrahedron 59 (2003) 6851–6872
6869
and concentrated under reduced pressure. The remaining oil
was chromatographed on a silica gel column (AcOEt–
hexane¼1:4) to give the bicyclic product 74 (165 mg, 93%).
d 11.0, 11.6, 21.2, 30.3, 35.9, 36.1, 37.3, 38.2, 39.5, 56.4,
62.8, 70.6, 71.1, 72.5, 75.1, 75.8, 78.3, 79.5, 116.8, 127.7,
127.8, 128.0, 128.1, 128.2, 128.4, 128.5, 129.2, 130.5,
133.5, 134.5, 136.0, 138.1, 138.2, 139.4, 170.4. Anal. calcd
for C43H54O9S: C, 69.14 H, 7.29. Found: C, 69.11; H, 7.25.
To the solution of 74 (165 mg, 0.160 mmol) in toluene
(7.99 mL) was added bis(trimethylsilyl)acetylene (1.09 mL,
4.79 mmol) and n-Bu3SnH (0.43 mL, 1.60 mmol). After
stirring 30 min at 608C, the reaction mixture was concen-
trated under reduced pressure. The remaining residue was
chromatographed on a silica gel column (AcOEt–
hexane¼9:41) to provide the endocyclic olefin 75
(81.0 mg, 68%) and its C46-epimer 76 (22.0 mg, 19%).
Compound 75. IR (KBr) nmax 3447, 2929, 2876, 2343, 1729,
1455, 1373, 1306, 1245, 1147, 1086, 1028, 915, 748, 699,
607, 532 cm21. 1H NMR (CDCl3, 400 MHz), d 0.87 (3H, d,
J¼7.0 Hz, CH3), 0.88 (3H, d, J¼7.0 Hz, CH3), 1.43 (1H,
ddd, J¼12.0, 11.5, 11.0 Hz, H-43a), 1.55–1.60 (1H, m,
H-50), 1.79–1.93 (4H, m, –OH, H-51, 53a, 53b), 1.98 (3H, s,
–OCOCH3), 2.00–2.08 (1H, m, H-40a), 2.53–2.56 (1H, m,
H-40b), 2.59 (1H, dt, J¼12.0, 4.0 Hz, H-43b), 2.75 (1H, dd,
J¼9.0, 8.5 Hz, H-45), 3.05 (1H, m, H-41), 3.08 (1H, td,
J¼9.0, 2.5 Hz, H-46), 3.10 (1H, dd, J¼13.5, 10.5 Hz,
H-58a), 3.18 (1H, ddd, J¼11.0, 9.0, 4.5 Hz, H-42), 3.34
(1H, ddd, J¼11.5, 8.5, 4.5 Hz, H-44), 3.54 (1H, m, H-54),
3.59 (1H, ddd, J¼11.5, 6.5, 4.5 Hz, H-55a), 3.79 (1H, ddd,
J¼11.5, 6.5, 4.5 Hz, H-55b), 3.84 (1H, dd, J¼13.5, 1.5 Hz,
H-58b), 3.90 (1H, br, H-49), 4.42 (1H, d, J¼11.5 Hz,
–OCH2Ph), 4.54 (1H, d, J¼11.5 Hz, –OCH2Ph), 4.58 (1H,
d, J¼11.5 Hz, –OCH2Ph), 4.62 (1H, d, J¼11.5 Hz,
–OCH2Ph), 4.92–5.04 (3H, m, H-52, 57), 5.62–5.73 (1H,
m, H-39), 5.83 (1H, ddd, J¼11.5, 4.5, 3.5 Hz, H-48), 5.93
(1H, ddd, J¼11.5, 3.5, 2.0 Hz, H-47), 7.20–7.38 (10H, m,
aromatic), 7.52–7.56 (2H, m, aromatic), 7.62–7.66 (1H, m,
aromatic), 7.88–7.91 (2H, m, aromatic). 13C NMR (CDCl3,
100 MHz), d 36.7, 37.0, 37.6, 37.9, 38.4, 38.5, 39.1, 39.4,
39.6, 39.7, 57.0, 57.2, 63.3, 64.2, 70.7, 70.8, 70.9, 70.9,
71.2, 72.3, 72.9, 73.0, 75.8, 75.8, 76.8, 77.1, 77.2, 77.5,
77.8, 78.9, 79.1, 79.4, 79.5, 79.6, 80.5, 81.3, 116.8, 116.9,
127.7, 127.8, 127.9, 127.9, 128.0, 128.0, 128.1, 128.2,
128.4, 128.5, 128.6, 128.9, 129.1, 131.0, 131.9, 133.6,
135.1, 135.6, 135.8, 138.1, 138.1, 138.1, 138.2, 140.1,
170.4, 170.8. Anal. calcd for C43H54O9S: C, 69.14 H, 7.29.
Found: C, 69.11; H, 7.25. Compound 76. 1H NMR (CDCl3,
400 MHz), d 0.89 (3H, d, J¼7.0 Hz, CH3), 0.90 (3H, d,
J¼6.5 Hz, CH3), 1.38 (1H, q, J¼11.0 Hz, H-43a), 1.43–1.51
(1H, m, H-50), 1.77–2.00 (4H, m, –OH, H-51, 53a, 53b),
2.00 (3H, s, –OCOCH3), 2.03–2.12 (1H, m, H-40a), 2.43
(1H, m, H-40b), 2.66 (1H, dt, J¼11.5, 4.0 Hz, H-43b), 3.05
(1H, dddd, J¼11.0, 8.0, 4.5, 2.0 Hz, H-46), 3.09–3.16 (2H,
m, H-41, 42), 3.16 (1H, dd, J¼9.5, 4.5 Hz, H-45), 3.34 (1H,
ddd, J¼11.5, 9.0, 4.5 Hz, H-44), 3.40 (1H, dd, J¼14.0,
11.0 Hz, H-58a), 3.48 (1H, dq, J¼8.0, 4.0 Hz, H-54), 3.60
(1H, dd, J¼14.0, 2.0 Hz, H-58b), 3.62 (1H, ddd, J¼12.0,
7.5, 4.0 Hz, H-55a), 3.81 (1H, ddd, J¼12.0, 5.0, 4.0 Hz, H-
55b), 4.04 (1H, td, J¼4.0, 2.5 Hz, H-49), 4.42 (1H, d,
J¼11.5 Hz, –OCH2Ph), 4.55 (1H, d, J¼11.5 Hz,
–OCH2Ph), 4.58 (1H, d, J¼11.5 Hz, –OCH2Ph), 4.62 (1H,
d, J¼11.5 Hz, –OCH2Ph), 4.92–4.98 (2H, m, H-57), 5.08
(1H, ddd, J¼10..0, 5.5, 2.5 Hz, H-52), 5.54–5.64 (1H, m,
H-39), 5.70 (1H, dd, J¼11.5, 4.0 Hz, H-48), 5.91 (1H, ddd,
J¼11.5, 8.0, 2.0 Hz, H-47), 7.25–7.38 (10H, m, aromatic),
7.51–7.58 (2H, m, aromatic), 7.61–7.65 (1H, m, aromatic),
7.88–7.91 (2H, m, aromatic). 13C NMR (CDCl3, 100 MHz),
5.1.34. Ketone 79. To a solution of endocyclic olefin 75
(118 mg, 0.16 mmol) in THF (1.58 mL) and MeOH
(1.58 mL) was treated with K2CO3 (39 mg, 0.28 mmol)
overnight at room temperature. The reaction mixture was
poured into saturated NH4Cl solution and extracted with
AcOEt (£3). The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The remaining residue
was chromatographed on a silica gel column (AcOEt–
hexane¼2:3) to provide diol 77 (104 mg, 93%).
To a solution of the diol 77 (104 mg, 0.15 mmol) in CH2Cl2
(1.48 mL) were added Et3N (206 mL, 1.48 mmol), DMAP
(18 mg, 0.15 mmol), and TBSCl (111 mg, 0.74 mmol) at
08C. After stirring for 3 h at room temperature, the reaction
mixture was poured into cold saturated NH4Cl solution,
extracted with Et2O (£3), and washed with brine. The
organic layer was dried over Na2SO4 and concentrated
under reduced pressure. The remaining crude oil was
chromatographed on a silica gel column (AcOEt–
hexane¼1:4) to provide silyl ether 78 (114 mg, 94%).
To a solution of silyl ether 78 (114 mg, 0.14 mmol) in
DMSO (1.39 mL) was added IBX (78 mg, 0.28 mmol) at
room temperature. After stirring for 4 h, the reaction
mixture was added H2O and filtered through Hyflo-Super-
Celw. After the filter cake was washed with Et2O, the
organic phase of the filtrate was dried over Na2SO4 and
concentrated under reduced pressure. The remaining crude
oil was chromatographed on a silica gel column (AcOEt–
hexane¼1:4) to provide ketone 79 (111 mg, 98%). Com-
pound 79. IR (KBr) nmax 3066, 2929, 2858, 1712, 1455,
1307, 1252, 1087, 837, 748, 698, 565, 533 cm21. 1H NMR
(CDCl3, 400 MHz), d 0.05 (3H, s, –Si(CH3)2), 0.06 (3H, s,
–Si(CH3)2), 0.86 (3H, d, J¼7.0 Hz, CH3-59), 0.89 (9H, s,
–SiC(CH3)3), 1.02 (3H, d, J¼7.0 Hz, CH3-60), 1.38 (1H, dt,
J¼12.0, 11.0 Hz, H-43a), 1.92–2.05 (2H, m, H-40a, 50),
2.45 (1H, dt, J¼12.0, 4.5 Hz, H-43b), 2.49–2.56 (1H, m,
H-40b), 2.63–2.81 (5H, m, H-45, 46, 51, 53a, 53b), 2.96–
3.09 (3H, m, H-41, 42, 44), 3.10 (1H, dd, J¼14.0, 10.0 Hz,
H-58a), 3.59 (1H, dd, J¼10.5, 5.5 Hz, H-55a), 3.70 (1H, dd,
J¼10.5, 5.0 Hz, H-55b), 3.76 (1H, dd, J¼14.0, 2.0 Hz,
H-58b), 3.81 (1H, ddd, J¼6.0, 4.0, 2.0 Hz, H-49), 4.06 (1H,
dt, J¼7.5, 4.5 Hz, H-54), 4.34 (1H, d, J¼11.5 Hz,
–OCH2Ph), 4.55 (1H, d, J¼11.5 Hz, –OCH2Ph), 4.56 (1H,
d, J¼11.0 Hz, –OCH2Ph), 4.65 (1H, d, J¼11.0 Hz,
–OCH2Ph), 4.94–5.03 (2H, m, H-57), 5.61–5.74 (2H, m,
H-39, 47), 5.90 (1H, ddd, J¼11.5, 3.0, 2.5 Hz, H-48), 7.20–
7.36 (10H, m, aromatic), 7.52–7.57 (2H, m, aromatic),
7.61–7.66 (1H, m, aromatic), 7.84–7.91 (2H, m, aromatic).
13C NMR (CDCl3, 100 MHz), d 10.9, 13.7, 18.3, 25.9, 36.1,
36.8, 39.6, 44.6, 48.5, 57.3, 64.7, 70.9, 72.9, 75.0, 76.0, 78.0,
78.7, 79.3, 79.7, 116.8, 127.6, 127.7, 128.0, 128.3, 129.1,
130.6, 133.5, 134.9, 135.1, 138.1, 138.7, 140.0. Anal. calcd for
C47H64O8SSi: C, 69.08 H, 7.89. Found: C, 69.07; H, 7.87.
5.1.35. Diketone 80. To a solution of ketone 79 (71 mg,
0.087 mmol) in DMF (1.58 mL) and H2O (158 mL) was

6870
T. Baba et al. / Tetrahedron 59 (2003) 6851–6872
added PdCl2 (1.5 mg, 8.7 mmol) and CuCl (4.3 mg,
0.043 mmol) at room temperature. After stirring overnight
under O2 atmosphere, the reaction mixture was filtered
through Hyflo-Super-Celw. After the filter cake was washed
with Et2O, the organic layer of the filtrate was washed with
brine, dried over Na2SO4, and concentrated under reduced
pressure. The remaining crude oil was chromatographed on
a silica gel column (AcOEt–hexane¼3:17) to provide
diketone 80 (62 mg, 85%). Compound 80. IR (KBr) nmax
2929, 2858, 2359, 1714, 1456, 1362, 1307, 1252, 1087, 837,
(2.36 mL) was added large excess amount of Na2HPO4
(ca. 100 mg) and Hg-Na (ca. 100 mg). After stirring for
4.5 h, the reaction mixture was filtered through Hyflo-
Super-Celw. After the filter cake was washed with Et2O, the
organic phase of the filtrate was dried over Na2SO4 and
concentrated under reduced pressure. The remaining crude
oil was purified by preparative TLC (AcOEt–hexane¼1:1)
to give JKLM-ring fragment 84 (2.3 mg, 82%). Compound
84. IR (KBr) nmax 3447, 2926, 1717, 1636, 1456, 1355,
1077, 1025, 938, 739, 698 cm21 1H NMR (CDCl3,
.
1
749, 699, 535, 419 cm21. H NMR (CDCl3, 400 MHz), d
400 MHz) d 1.01 (3H, d, J¼6.5 Hz, CH3-60), 1.06 (3H, d,
J¼6.5 Hz, CH3-59), 1.01 (3H, d, J¼7.5 Hz, CH3-58), 1.40
(1H, q, J¼11.5 Hz, H-43a), 1.48 (1H, dq, J¼11.0, 6.5 Hz,
H-51), 1.61 (1H, ddq, J¼11.0, 10.0, 6.5 Hz, H-50), 2.00
(1H, qdd, J¼7.5, 5.0, 3.5 Hz, H-46), 2.08 (1H, dd, J¼14.0,
4.0 Hz, H-53a), 2.13 (1H, dd, J¼14.0, 6.5 Hz, H-53b), 2.14
(3H, s, –COCH3), 2.45 (1H, dd, J¼15.5, 9.0 Hz, H-40a),
2.54 (1H, dt, J¼12.0, 4.5 Hz, H-43), 2.79 (1H, dd, J¼15.5,
3.5 Hz, H-40b), 2.95 (1H, dd, J¼9.5, 5.0 Hz, H-45), 3.15
(1H, ddd, J¼11.5, 9.0, 4.5 Hz, H-42), 3.26 (1H, t, J¼9.5 Hz,
H-49), 3.59 (1H, td, J¼9.0, 3.5 Hz, H-41), 3.62 (1H, dd,
J¼9.5, 2.0 Hz, H-48), 3.65 (1H, dd, J¼3.5, 2.0 Hz, H-47),
3.69 (1H, ddd, J¼11.5, 9.5, 4.5 Hz, H-44), 3.85 (1H, dd,
J¼9.5, 5.0 Hz, H-55a), 3.96 (1H, dd, J¼9.5, 2.0 Hz, H-55b),
4.26 (1H, dddd, J¼6.5, 5.0, 4.0, 2.0 Hz, H-54), 4.39 (1H, d,
J¼11.5 Hz, –OCH2Ph), 4.45 (1H, d, J¼12.0 Hz,
–OCH2Ph), 4.47 (1H, d, J¼12.0 Hz, –OCH2Ph), 4.63 (1H,
d, J¼11.5 Hz, –OCH2Ph), 7.20–7.37 (10H, m, aromatic).
13C NMR (CDCl3, 100 MHz) d 13.5, 15.8, 19.7, 29.7, 30.6,
36.8, 38.4, 42.0, 42.5, 46.5, 70.6, 71.1, 71.6, 71.9, 75.1,
75.8, 78.1, 78.4, 86.6, 109.3, 127.6, 127.7, 127.8, 127.8,
128.4, 138.0, 138.1, 207.2. HRMS (FAB) calcd for
C35H47O8 [MþH]þ 595.3271, found 595.3262.
0.05 (3H, s, –Si(CH3)2), 0.06 (3H, s, –Si(CH3)2), 0.85 (3H,
d, J¼7.0 Hz, CH3-59), 0.89 (9H, s, –Si(CH3)3), 1.03 (3H, d,
J¼7.0 Hz, CH3-60), 1.40 (1H, dt, J¼12.0, 11.0 Hz, H-43a),
1.96 (1H, qnd, J¼7.0, 4.0 Hz, H-50), 2.10 (3H, s, –COCH3),
2.32 (1H, dd, J¼16.0, 9.5 Hz, H-40a), 2.48 (1H, dt, J¼12.0,
4.5 Hz, H-43b), 2.66 (1H, q, J¼7.0 Hz, H-51), 2.67 (1H, dd,
J¼17.0, 8.0 Hz, H-53a), 2.68 (1H, t, J¼8.0 Hz, H-45), 2.76
(1H, dd, J¼16.0, 3.0 Hz, H-40b), 2.78 (1H, dd, J¼17.0,
4.0 Hz, H-53b), 2.80–2.83 (1H, m, H-46), 2.97 (1H, ddd,
J¼11.0, 9.0, 4.5 Hz, H-42), 3.05 (1H, ddd, J¼11.0, 8.5,
4.5 Hz, H-44), 3.09 (1H, dd, J¼14.0, 9.5 Hz, –CH2SO2Ph),
3.51 (1H, dt, J¼9.5, 3.0 Hz, H-41), 3.57 (1H, dd, J¼14.0,
1.5 Hz, –CH2SO2Ph), 3.59 (1H, dd, J¼10.5, 5.5 Hz, H-55a),
3.71 (1H, dd, J¼10.5, 5.0 Hz, H-55b), 3.82 (1H, ddd, J¼5.5,
3.5, 1.5 Hz, H-49), 4.07 (1H, dtd, J¼7.5, 5.5, 4.5 Hz,
H-54), 4.30 (1H, d, J¼11.5 Hz, –OCH2Ph), 4.56 (1H, d,
J¼11.5 Hz, –OCH2Ph), 4.57 (1H, d, J¼11.0 Hz,
–OCH2Ph), 4.66 (1H, d, J¼11.0 Hz, –OCH2Ph), 5.67 (1H,
ddd, J¼12.0, 3.5, 2.0 Hz, H-55a), 5.81 (1H, dt, J¼12.0,
2.5 Hz, H-47), 7.20–7.36 (10H, m, aromatic), 7.52–7.57
(2H, m, aromatic), 7.61–7.66 (1H, m, aromatic), 7.85–7.89
(2H, m, aromatic). 13C NMR (CDCl3, 100 MHz), d 25.4,
10.9, 13.9, 18.2, 25.9, 30.8, 36.7, 39.5, 39.7, 44.7, 45.8,
48.5, 57.5, 64.7, 70.6, 72.9, 75.5, 76.0, 76.2, 78.6, 78.7,
79.0, 127.6, 127.7, 127.9, 128.0, 128.3, 128.4, 129.1, 130.2,
133.5, 134.6, 137.9, 138.7, 140.1, 206.3, 212.8. HRMS
(FAB) calcd for C47H65O9SSi [MþH]þ 833.4119, found
833.4105.
Acknowledgements
This work was supported by a grant-in-aid from the Ministry
of Education, Science and Technology. Dr B. Kirshbaum
contributed to this study in earlier stage. We are grateful to
Mr Kitamura (analytical laboratory in this school) for
elemental analyses.
5.1.36. JKLM-ring fragment 84. To the oil of diketone 80
(8.9 mg, 0.011 mmol) were added a mixture of AD-mix-a
(299 mg) and methylsulfonamide (1.0 mg, 0.011 mmol) in
50% aqueous t-BuOH (2.14 mL) in 08C. After stirring
overnight, the reaction mixture was quenched by adding
Na2SO3 (320 mg), extracted with AcOEt (£3) and washed
with saturated NaHCO3 solution. The organic layer was
concentrated under reduced pressure. The remaining crude
oil was chromatographed on a silica gel short column (100%
AcOEt) to provide an equilibrium mixture of 81 and 82
(7.7 mg, 83%).
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