Studies directed toward the total synthesis of pinnatoxin A: Synthesis of the 6,5,6-dispiroketal (BCD ring) system by double hemiketal formation/hetero-Michael addition strategy

Article abstract of DOI:10.1016/S0040-4020(02)01379-0

An efficient, highly stereoselective synthesis of the C10-C26 portion of pinnatoxin A has been achieved, wherein the key step is a highly stereoselective construction of the 6,5,6-dispiroketal (BCD ring) system by an intramolecular hetero-Michael addition of a hemiketal alkoxide reversibly formed under the influence of lithium methoxide.

Full text of DOI:10.1016/S0040-4020(02)01379-0

Tetrahedron 58 (2002) 10353–10374
Studies directed toward the total synthesis of pinnatoxin A:
synthesis of the 6,5,6-dispiroketal (BCD ring) system by double
hemiketal formation/hetero-Michael addition strategy
Seiichi Nakamura, Jun Inagaki, Masashi Kudo, Tomohiro Sugimoto, Kohei Obara,
*
Makoto Nakajima and Shunichi Hashimoto
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Received 19 September 2002; accepted 30 October 2002
Abstract—An efficient, highly stereoselective synthesis of the C10–C26 portion of pinnatoxin A has been achieved, wherein the key step is
a highly stereoselective construction of the 6,5,6-dispiroketal (BCD ring) system by an intramolecular hetero-Michael addition of a
hemiketal alkoxide reversibly formed under the influence of lithium methoxide. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
molecular architecture, coupled with the associated biologi-
cal activity and scarcity of natural supply, renders them
worthy targets for total synthesis.6–8
Recently, novel marine-derived polyether macrocycles such
as pinnatoxins,1 spirolides,2 gymnodimine,3 and spiro-
prorocentrimine4 containing a spiro-linked cyclic imine
moiety have been isolated. These natural products have
been considered as culprits in shellfish poisoning, and the
majority of them have also been found to be Ca2þ channel
activators.2a,5 Pinnatoxins, the first and most prominent
members of this class, were isolated from the shellfish Pinna
muricata and characterized by Uemura and co-workers in
1995.1a Very recently, pteriatoxins have been isolated from
the Okinawan bivalve Pteria penguin and characterized by
the same group.1e Structurally, pinnatoxins and pteriatoxins
share a unique 27-membered carbocyclic backbone which is
composed of an unusual 6,7-spiro-linked imine moiety (AG
ring), a 5,6-bicycloketal (EF ring), and a 6,5,6-dispiroketal
(BCD ring), and represent variations in the substitution
pattern at C21, C22, C28 and C33. Their unprecedented
With respect to a presumed biosynthetic pathway to these
molecules, Uemura proposed that the 6,7-azaspirocyclic
(AG ring) system would arise from a sequence of
intramolecular Diels–Alder reaction and imine formation
events or vice versa, which would lead to the concurrent
assembly of a polyether macrocycle. In this context, a
macrocyclization strategy via a biomimetic intramolecular
Diels–Alder reaction, while its application remains to be
explored, would provide one of the most concise and elegant
solutions to the challenge posed by their molecular
architecture. By employing this bold macrocyclization
strategy followed by an ingenious imine formation, Kishi
and co-workers accomplished the first total synthesis of
(2)-pinnatoxin A in 1998, which also established the
absolute stereochemistry of the natural (þ)-pinnatoxin A, as
shown in 1.6 The crucial biomimetic intramolecular Diels–
Alder reaction in Kishi’s landmark synthesis of (2)-1
produced a 1.0:0.9:0.4 mixture of three out of the eight
possible adducts, with the desired exo product favored. It is
of interest to note that all three products possessed the
correct regiochemistry, while there is room for improve-
ment in the stereoselectivity.
In planning our synthesis of pinnatoxin A (1), we also were
greatly intrigued by Uemura’s biosynthetic proposal.1a Our
synthetic strategy is outlined in Scheme 1. Standard
retrosynthetic manipulation of 1 based on an intramolecular
Diels–Alder transform dictated disconnections at the C9–
C10, C5–C31, and C35–C39 linkages to reveal diene 2 as
an advanced intermediate. We envisioned installation of the
C31–C35 diene moiety exploiting Wittig olefination or a
Keywords: dispiroketal; hemiketal formation; hetero-Michael addition.
*
Corresponding author. Tel.: þ81-11-706-3236; fax: þ81-11-706-4981;
e-mail: hsmt@pharm.hokudai.ac.jp
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01379-0

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S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
like process, which led back to the C10–C31 fragment 3.
The bicycloketal (EF) ring system in 3 could be constructed
readily from ketone 4 by an intramolecular ketalization via
C29,C30-diol. Consequently, the C10–C31 ketone frag-
ment 4 became the first important target for our synthetic
venture, wherein a strategic point lay in the construction of
the 6,5,6-dispiroketal (BCD ring) system.
Apart from the construction of the azaspirocyclic (AG ring)
system, a stereocontrolled construction of the 6,5,6-
dispiroketal (BCD ring) system presents a major challenge
in the synthesis of 1 as mentioned by the Kishi,6 Murai,7 and
Hirama8 groups.9 Although a number of methods have been
developed to synthesize bicyclic spiroketal subunits,10 the
Scheme 2. Kishi’s synthesis of the dispiroketal portion of (2)-pinnatoxin
A.
formation of tricyclic dispiroketals has been less thoroughly
investigated.11,12 The majority of reported synthetic strat-
egies in either case rely on acid-catalyzed cyclization of
open-chain hydroxyketones. An important consideration for
dispiroketalization here is that the BCD ring system with a
cisoid relationship about the spirocyclic centers benefits
from two anomeric effects but experiences the dipole-dipole
repulsion arising from the C16–O12 and C19–O23 bonds.
Hence, it is uncertain whether the classic dispiroketalization
strategy will result in high selectivity for the desired ketal
configurations. In this context, Kishi and co-workers
demonstrated that treatment of an appropriate tetrahydroxy
diketone with CSA led to the formation of a 2:3 mixture of
C19 epimeric dispiroketals, and the unwanted transoid
isomer epimerized exclusively to the desired cisoid isomer
under standard silylation conditions (Scheme 2).6 In the
same context, Hirama and co-workers found that the
equilibrium ratio of C19 epimeric dispiroketals under
thermodynamically controlled ketalization was greatly
improved by use of toluene as a solvent, wherein it was
suggested that an intramolecular hydrogen bond between
the terminal C10,C24-dihydroxy groups might play an
important role in the stereoselective formation of the desired
isomer (Eq. (1)).8a On the other hand, Murai and Ishihara
and co-workers reported that treatment of 1,12-bis(silyl-
oxy)-4,5,8-triketone with aqueous HF in CH3CN led to the
preferential formation of the desired 6,5,6-dispiroketal out
of the eight possible isomers in 76% yield, and suggested
that the anomeric effect would be enhanced by a ketone
carbonyl group adjacent to the spirocenter (Eq. (2)).7a,b
ð1Þ
Scheme 1. Retrosynthetic analysis of pinnatoxin A.

S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
10355
with Bu4NF (Eq. (3)).
ð3Þ
ð2Þ
To this end, the synthesis of the C14–C23 ketone fragment
10 commenced with alkylation of dithiane 2215 with iodide
2116 (Scheme 3). Lithiation of 22 followed by addition of
iodide 21 furnished 2,2-disubstituted dithiane 23 in 95%
yield. Exposure of 23 to TsOH in aqueous MeOH resulted in
concurrent removal of the pentylidene ketal and the THP
ether to give triol 24 (98%), which upon treatment with
4-methoxybenzaldehyde dimethyl acetal in the presence of
a catalytic amount of PPTS provided alcohol 25 in 75%
An alternative approach to spiroketals involves the hetero-
Michael addition of a hemiketal alkoxide to an internal
enone,13 which has the advantage of generating a chiral
center from an enone in the conjugate addition step as well
as a chiral spirocenter. This elegant approach, however, has
not yet been applied to the synthesis of dispiroketals. On
inspection of a ketone carbonyl group at C25 of 4, it was
readily apparent that a strategy based on this approach
would not only benefit from the construction of the BCD
ring system but also from the direct assembly of the EF ring
system. Some concern, however, arose over the formation of
the C19,C23 epimeric dispiroketal with a transoid arrange-
ment, which is not only stabilized by two anomeric effects
like the desired cisoid isomer but also relieved of the dipole
repulsion. Despite no clear thermodynamic preference for
the desired isomer, we envisaged that the dispiroketal
fragment 4 would be favorably derived from the tandem
hemiketal formation/hetero-Michael reaction sequence
shown in 5 by judicious choice of conditions. As a result,
the C10–C31 enone fragment 6 was chosen as a precursor
to 4. After appropriate functional group manipulations, 6
could be disconnected at the C23–C24 double bond to give
aldehyde 7 and b-ketophosphonate 8. In turn the aldehyde 7
was envisioned to be obtained by aldol fragment coupling of
aldehyde 9 and methyl ketone 10 followed by installation of
the C15 methyl group.
In our initial studies directed toward the total synthesis of 1,
we felt it was prudent to test the viability of the key
hemiketal formation/hetero-Michael reaction process to
construct the BCD ring system. Herein, we describe the
details of our model study and offer a mechanistic
explanation for the stereochemical outcome observed in
the present reaction.14
2. Results and discussions
2.1. Synthesis of the dispiroketalization precursor
With the synthesis of halichondrin Bs, Kishi and co-workers
achieved the novel construction of the fully functionalized
6,6-spiroketal system by exploiting tandem Bu4NF-induced
in situ desilylation/hemiketal formation/intramolecular
hetero-Michael addition.13d Based on this precedent,
triketone 19 corresponding to the C10–C26 portion of
pinnatoxin A was chosen as a model substrate for the
dispiroketalization studies. At this juncture, we envisaged
that the assembly of the dispiroketal 20 would be triggered
by selective desilylation of the C12 TES group in 19
Scheme 3. Reagents and conditions: (a) BuLi, THF/HMPA (10:1), 2788C,
1 h, 95%; (b) TsOH, MeOH/H2O, 35 h, 98%; (c) anisaldehyde dimethyl
acetal, PPTS, CH2Cl2, 6 h, 75%; (d) TESCl, imidazole, CH2Cl2, 2 h, 98%;
(e) DIBAL-H, CH2Cl2, 278 to 2208C, 2 h, 87%; (f) SO3·pyridine, Et3N,
DMSO, 1 h, 92%; (g) MeMgI, THF–Et2O, 278 to 2508C, 2 h, 92%;
(h) SO3·pyridine, Et3N, DMSO, 1 h, 93%.

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S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
furnished alcohol 38 as a single diastereomer in 81% yield
(Scheme 5). The resultant hydroxyl group was protected as
its TES ether to give 39 in 89% yield. Reductive removal of
the oxazolidinone auxiliary22 proceeded without incident
to afford optically pure (R)-alcohol 36 in 81% yield,
accompanied by an 84% recovery of the auxiliary. This
more practical sequence furnished aldehyde 9 in 52% yield
over five steps from the reusable oxazolidinone auxiliary.
With the C10–C13 aldehyde fragment 9 and the C14–C23
ketone fragment 10 in hand, the stage was now set for
elaboration of the C10–C23 aldehyde 7 (Scheme 6). Aldol
fragment coupling of 9 and 10 using LiHMDS–ZnCl2 in
THF furnished aldol adduct 40 in 98% yield. The super-
fluous C13 hydroxyl group was then removed by the
elimination–hydrogenation sequence. Acetylation of
alcohol 40 was followed by exposure to DBU to give
enone 41 in 88% yield. Of various conditions
surveyed,23 conjugate reduction with the Stryker
reagent24 proved to be the optimal choice, affording
ketone 42 in 91% yield. Stereoselective creation of the
quaternary carbon center at C15 was well performed
by chelation-controlled addition of MeMgI to ketone 42
in 95% yield. The resultant hydroxyl group in 43 was
Scheme 4. Reagents and conditions: (a) NaH, BnBr, THF/HMPA (5:1),
10 h; (b) TsOH, THF/H2O (10:1), 608C, 5 h, 91% (two steps); (c) PivCl,
pyridine, CH2Cl2, 08C, 1 h, then rt, 1 h, 90%; (d) TESCl, Et3N, CH2Cl2, 1 h,
97%; (e) DIBAL-H, CH2Cl2, 2788C, 1 h, 94%; (f) SO3·pyridine, Et3N,
DMSO, 1 h, 97%.
yield. Silylation of the C23 hydroxyl group with TESCl was
followed by reductive cleavage of the 4-methoxybenzyl-
idene (MP) acetal with DIBAL-H17 to afford primary
alcohol 27 in 85% yield, along with 7% of its isomer 28.
Transformation of alcohol 27 to methyl ketone 10 was
effected by sequential Parikh–Doering oxidation,18 addition
of MeMgI, and re-oxidation in 79% yield for the three-step
process.
The synthesis of the C10–C13 aldehyde fragment 9 was
initiated with benzylation of the known alcohol 31, readily
obtained from D-malic acid,19 to provide benzyl ether 32,
which upon exposure to TsOH in aqueous THF afforded diol
33 in 91% yield (Scheme 4). Selective protection of the
primary hydroxyl group with PivCl was followed by
silylation with TESCl to give 35 in 87% yield. Deprotection
of the C13 pivaloate ester with DIBAL-H provided alcohol
36 in 94% yield, which underwent Parikh–Doering
oxidation to afford aldehyde 9 in 72% yield over six steps
from alcohol 31.
Although this route is amenable to a large supply of the
aldehyde 9, the overall length of this sequence from D-malic
acid (11 steps, 47% overall yield) as well as the use of an
expensive starting material prompted us to explore an
alternative route to 9. Since the length of the sequence was
due to tedious protecting group interchanges, we turned our
attention to the feasibility of Evans’ diastereoselective
a-hydroxylation methodology.20 Reaction of the sodium
enolate derived from the known carboximide 3721 with
2-(phenylsulfonyl)-3-phenyloxaziridine in THF at 2908C
Scheme 6. Reagents and conditions: (a) LiHMDS, ZnCl2, THF, 2788C,
then 9, 278 to 2508C, 1.5 h, 98%; (b) Ac2O, pyridine, DMAP, 20 h;
(c) DBU, CH2Cl2, 08C, 1 h, 88% (two steps); (d) [(Ph3P)CuH]6, benzene,
10 h, 91%; (e) MeMgI, Et2O, 2788C, 1 h, 95%; (f) TBSOTf, 2,6-lutidine,
CH2Cl2, 4 h, 93%; (g) Bu4NF (1.05 equiv.), THF/AcOH (10:1), 08C, 1 h,
88%; (h) SO3·pyridine, Et3N, DMSO, 1 h, 94%.
Scheme 5. Reagents and conditions: (a) NaHMDS, 2-(phenylsulfonyl)-3-
phenyloxaziridine, THF, 2908C, 80%; (b) TESCl, imidazole, CH2Cl2, 1 h,
89%; (c) LiBH4, H2O, THF, 08C, 1 h, 81%; (d) see Scheme 4.

S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
10357
conditions27 furnished the target triketone 19 in 93%
yield.
2.2. Dispiroketalization via double hemiketal
formation/hetero-Michael addition process
With a viable route to the dispiroketal precursor 19 secured,
the stage was now set for the tandem hemiketal formatio-
n/intramolecular hetero-Michael addition. As mentioned
above, we initially explored a direct conversion of 19 to
dispiroketals triggered by selective desilylation of the C12
TES group with Bu4NF in THF. The reaction, however, met
with failure (Eq. (4)). Therefore, we examined a stepwise
procedure as follows (Scheme 8). Upon exposure of 19 to
1N aqueous HCl in THF, selective desilylation of the C12
TES ether provided an equilibrium mixture of products.
While the NMR and mass spectra revealed the absence of a
TES group, the complexity of the spectrum prevented the
characterization of their components. In the infrared
spectrum of the mixture, absorptions at 1713 and
1676 cm21 indicated the presence of a nonconjugated
ketone carbonyl and the preservation of an enone moiety,
respectively. On the basis of these spectral characteristics,
we eventually conjectured that hydroxytriketone 49
and stereoisomers of hemiketals 50 and 51 might be
involved in the mixture under equilibrium. Aside from the
structural confirmation, our attention was next focused on
the base-promoted cyclization process.
Scheme 7. Reagents and conditions: (a) Ph3PvCHCOMe, benzene, reflux,
10 h, 98%; (b) DDQ, CH2Cl2/pH7 phosphate buffer (10:1), 20 min, 94%;
(c) Dess–Martin periodinane, CH2Cl2/pyridine, 08C, 1 h, 96%; (d) NCS,
AgNO3, g-collidine, CH3CN/H2O (4:1), 93%.
protected as its TBS ether to give 44 in 93% yield. Selective
deprotection of the primary TES ether was accomplished
by treatment of 44 with Bu4NF in THF/AcOH, providing
alcohol 45 in 88% yield. Subsequent Parikh–Doering
oxidation completed the synthesis of the C10–C23
aldehyde 7, a key intermediate for the actual C10–C31
enone fragment 6 as well as for a model triketone 19, in 94%
yield.
ð4Þ
The enone functionality was readily installed by
Wittig olefination with Ph3PvCHCOMe to give 46 in
98% yield (Scheme 7). Deprotection of the MPM ether
with DDQ25 followed by Dess–Martin oxidation26
provided diketone 48 in 90% yield. Oxidative removal of
the dithiane protective group under standard Corey
Submission of the equilibrium mixture to NaOMe
(1.0 equiv.) in THF/MeOH (10:1) at 08C resulted in the
formation of four dispiroketal diastereomers out of the eight
Scheme 8. Reagents and conditions: (a) 1N aqueous HCl/THF, 08C, 1 h; (b) NaOMe (1 equiv.), THF/MeOH (10:1), 08C, 1 h, 91% (20/52/53/54¼77:8:10:5).

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S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
possible stereoisomers in a 77:8:10:5 ratio in a total yield of
91% for the two-step sequence from triketone 19. The
dispiroketal isomers were readily separated by chromato-
graphy. Gratifyingly, the major product proved to be the
desired dispiroketal 20 as follows. Stereochemical assign-
1
ments of the four diastereomers followed from H NOE
experiments as shown in Fig. 1, which deserve some
comments. Since the steric bulk of the C12 side-chain and
the C15 TBS ether directs both C15–O and C12–C11 bonds
to equatorial positions on the tetrahydropyran ring, the B
ring of each isomer is presumed to adopt a chair
conformation. On the other hand, homonuclear decoupling
experiments established the vicinal coupling constants
between the protons at C22 and C23 (20: 2.1, 11.2 Hz, 52:
2.0, 11.2 Hz, 53: 2.4, 11.2 Hz, 54: 1.8, 10.8 Hz), the
magnitude of which indicated that the D ring of each
isomer would also adopt the chair conformation where
C23–H was axially disposed. Based on these conformation-
al analysis, the stereochemistry of the desired
(16R,19R,23R)-dispiroketal 20 was verified by the
diagnostic 1H NOE correlation between C12–H and
C23–H. This NOE is only possible in the desired
dispiroketal with a cisoid arrangement as previously
Figure 2. X-Ray crystal structure of anti 59, rendered in Chem3D. For the
purpose of clarity, only protons attached to stereogenic centers are shown.
1
observed by the Murai7a,c and Hirama8a groups. The H
NOE between C17–H and C12–H allowed for the
establishment of 16S configuration of 52, whereas C17–H
1
exhibited a significant H NOE interaction with C15–CH3
in dispiroketals 53 and 54 with 16R configuration. The 19S
and 23S configurations of 52 were confirmed by the absence
of an NOE between C23–H and C18–H in conjunction with
an NOE between SiC(CH3)3 and C20–H. Thus, the
stereochemistry of the newly formed chiral centers in 52
was established as 16S,19S,23S, which were totally opposite
to those in 20. Of the three possible isomers with 16R
configuration, significant NOE interactions of SiC(CH3)3
with C23–H and C24–H in 53 and the absence of an NOE
Scheme 9. Reagents and conditions: (a) NaBH4, CH2Cl2/MeOH (4:1), 08C,
2 h, 93%; (b) Bu4NF, THF, reflux, 12 h, 91%; (c) SO3·pyridine, Et3N,
DMSO, 2 h, 90%; (d) H2, 20% Pd(OH)2/C, AcOEt, 13 h, 92%; (e)
H2NNHCONH2·HCl, NaOAc, EtOH/H2O (5:1), 8 h, 98% (syn/anti¼1:1.6).
between SiC(CH3)3 and the C23 side-chain of 54 in
conjunction with an NOE between C23–H and C18–H
allowed us to assign the stereochemistries of 53 and 54 as
16R,19S,23S, and 16R,19R,23S, respectively.28 Finally, the
stereochemistry of all the stereogenic centers in the
dispiroketal 20 was unambiguously established by X-ray
crystallography of the derived semicarbazone anti 59 as
shown in Fig. 2. The dispiroketal 20 was derivatized by the
following five-step sequence of reactions to give anti 59
(Scheme 9): (1) reduction of the C25 carbonyl group with
NaBH4; (2) desilylation of the C15 hydroxyl group with
Bu4NF under reflux; (3) oxidation of the C25 hydroxyl
group with SO3·pyridine in DMSO; (4) debenzylation of the
C10 hydroxyl group with Pd(OH)2 under hydrogen; (5)
semicarbazone formation.
Encouraged by these results, we next studied the effects of
base to determine the optimal conditions for highest yield
and stereoselectivity (Table 1). Of the alkaline metal
methoxides screened, LiOMe was found to be the base of
choice for this cyclization, providing the desired dis-
piroketal 20 in high yield and with the highest level of
diastereoselectivity. The use of NaOMe or KOMe slightly
decreased the diastereoselectivity as the formation of 53
increased, though similar ratios of 52 and 54 were observed
as with the case of LiOMe. Addition of 12-crown-4 did not
affect the outcome of the reaction with LiOMe (entry 4),
suggesting that the stereoselectivity observed here would
Figure 1. Selected NOE interactions observed in the dispiroketals.

S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
10359
Table 1. Double hemiketal formation/intramolecular hetero-Michael
addition
was the optimal solvent for the tandem hemiketal
formation/intramolecular hetero-Michael addition process.
While the reaction of 19 under the influence of LiOMe in
THF proceeded smoothly at room temperature to give a
mixture of 20 and 52, it took 48 h to provide nearly the
identical ratio of products observed with the reaction (4 h) in
THF/MeOH (10:1). It was therefore suggested that MeOH
as a co-solvent contributed not only to the dissolution of
metal methoxides but also to the apparent accelaration of the
isomerization reaction of 52 to 20. This result might be
ascribed to the nature of the enolate intermediates capable of
internal chelation with the dispiroketal oxygen atoms.
Somewhat surprisingly, the use of MeOH as the solvent
resulted in a complex mixture of products.
Entry
Base
Temperature
Time
Yield (%)
20/52/53/54a
1
2
NaOMe
KOMe
LiOMe
LiOMe
Triton B
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
NaOMe
KOMe
08C
08C
08C
08C
08C
rt
rt
rt
rt
rt
1 h
2 h
24 h
24 h
5 h
10 s
5 min
1 h
4 h
48 h
8 h
1.5 h
1.5 h
91
90
87
91
86
73
88
87
92
80
89
88
91
77:8:10:5
74:9:12:5
85:8:2:5
3
4b
5
83:8:3:6
2.3. Stereochemical models
77:7:11:5
33:64:0:3
50:46:0:4
77:15:2:6
84:8:3:5
6
7
8
9
10
11
12
13
2.3.1. Thermodynamic stability of the dispiroketals. In
order to understand the observed stereochemical outcome
of the reaction, we attempted to gain a mechanistic insight
into the double hemiketal formation/hetero-Michael
addition. Since the preferential formation of the desired
isomer 20 was the result of some thermodynamic control,
the thermodynamic stability of the dispiroketals was
examined.
82:8:6:4
2508C
2508C
2508C
20:80:0:0
24:76:0:0
24:76:0:0
a
Determined by HPLC analysis (column, Zorbaxw Sil, 4.6£250 mm;
eluent, 9% AcOEt in hexane; flow rate 1.0 mL/min).
In the presence of 3 equiv. of 12-crown-4.
b
In general, three factors have been suggested to influence
the thermodynamic stability of 1,7-dioxaspiro[5.5]unde-
canes, i.e. anomeric effects, steric influences, and intra-
molecular hydrogen bonding or other chelation effects.10 To
predict the stability of the dispiroketals, an additional factor,
dipole–dipole interaction, should be taken into consider-
ation. In this context, McGarvey and co-workers reported
the stability of the transoid and cisoid isomers of 1,7,9-
trioxadispiro[5.1.5.3]hexadecanes (Eq. (5)).29 On the
assumption that it has the all-chair conformations, the
cisoid isomer 60, wherein both O1 and O9 are axially
disposed about the central ring, incorporates four stabilizing
anomeric effects. On the other hand, the transoid isomer 61
embodies a maximum of three anomeric effects. However,
60 is estimated to be less stable by 0.3–0.7 kcal/mol than 61
because of the dipole–dipole repulsion of the two axial
C–O bonds in 60.
not arise from the chelation effect of the lithium cation.
Ammonium hydroxide such as triton B also promoted the
cyclization but was less effective in terms of diastereo-
selectivity (entry 5). While LiOMe-promoted cyclization of
19 at 08C required a significantly longer time to reach
completion compared with the cases of NaOMe and KOMe
(entries 1 and 2 vs 3), the reaction at room temperature
greatly shortened the reaction time to 4 h without affecting
the product yield and diastereoselectivity (entry 9).
Monitoring of this reaction by TLC and HPLC analyses
showed that the intramolecular hetero-Michael addition
took place immediately to predominantly form the unde-
sired stereoisomer 52, which was then slowly consumed to
give the desired isomer 20 as a major product (entries 6–9).
When the reaction time was prolonged (48 h), the ratio of 20
slightly diminished while the proportion of transoid isomer
53 doubled (entry 10). A similar process to form 20 as a
major product via 52 was also observed with the use of
NaOMe or KOMe (vide infra). At this point, we examined
the effects of temperature on the isomerization process. We
found that the reaction at 2508C proceeded smoothly to
give an approximately 1:3 mixture of 20 and 52 regardless
of the nature of metal methoxides employed, without any
detection of the formation of 53 and 54 (entries 11–13). No
isomerization was observed at this temperature. From these
results, it is clear that the isomers 20 and 52 obtained here
are the kinetically formed products. As expected, a 1:4
mixture of 20 and 52 formed with the use of LiOMe was
smoothly isomerized at room temperature to give nearly the
same ratio of products as that originally observed at room
temperature. A similar isomerization process was also
ascertained at 08C with the case of NaOMe or KOMe (vide
infra).
ð5Þ
With these considerations in mind, we turned our attention
to the actual dispiroketals (Fig. 3). Of the four dispiroketals
obtained, isomers 20 and 53 appear to be more stable from
two stabilizing anomeric effects compared to the other
isomers 52 and 54 that benefit from only a single
anomeric effect. While dispiroketal 20 is destabilized by
the dipole–dipole repulsion between C16–O12 and C19–
O23 bonds, dispiroketal 53 is relieved of the dipole-dipole
destabilization, but suffered from the severe steric inter-
action between the C15 TBS ether and the C23 side-chain.
Finally, it should be noted that THF/MeOH (100:1–5:1)

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S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
Table 2. The relative steric energy calculated by MacroModelw MM2p
Figure 3. Steric and stereoelectronic effects that influence the thermo-
dynamic stabilities of the four dispiroketals.
As a consequence, no clear thermodynamic preference for
either of 20 and 53 was given.
To further examine this analysis, molecular mechanics
calculations were carried out using the MM2p force field
with Monte Carlo method on MacroModel 6.0.30 The steric
energies of the eight possible isomers relative to 20 are
shown in Table 2. The calculations revealed that 53 was
slightly more stable than 20 by 0.27 kcal/mol. While
other isomers are less stable than 20, it should be noted
that the difference in energy between 52 and 20 is only
2.04 kcal/mol.
On the basis of these results, it is strongly suggested that
interconversion of the dispiroketal isomers might not attain
equilibrium under our dispiroketalization conditions
(Table 1, entries 1–3, 9 and 10) where the second most
stable, desired dispiroketal 20 was the major product, and
the most stable isomer 53 was obtained as one of the minor
products. In an effort to attain the equilibrium between these
isomers, we separately submitted both isomers 20 and 53 to
more harshly basic conditions (Eqs. (6) and (7)). We found
that treatment of each isomer with NaOMe in THF/MeOH
(10:1) at room temperature provided nearly identical ratios
of the dispiroketal isomers 20, 52, and 53 at equilibrium
(5 h). In the equilibrium mixture roughly equimolar
amounts of 20 and 53 were formed as major products,
though the combined yields of dispiroketals were less than
50% due to the formation of C-Michael product 66 and
many decomposition products. These results are in good
accordance with the foregoing speculation on the thermo-
dynamic stability of the products. At this juncture,
reasonable questions came to mind as to why 52 kinetically
formed at an early stage isomerized smoothly to give the
desired isomer 20 in preference to the most stable isomer 53,
and why the isomerization of 20 to 53 was so slow,
particularly under the conditions with the use of LiOMe.
Clearly, the diastereoselection observed in the present
system is the result of both kinetic and thermodynamic
control (vide infra).
ð6Þ

S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
10361
ð7Þ
2.3.2. Origin of the kinetic preference for the formation
of the isomer 52. We have already mentioned that two
isomers 20 and 52 in a ratio of 1:4–1:3 were predominantly
obtained at 2508C regardless of the nature of metal
methoxides, indicating that both isomers are the result of
some kinetic control. Given the thermodynamic stability of
the dispiroketal isomers, further discussions are required to
account for the origin of the preference for the formation of
the undesired isomer 52 as well as for that of the desired
isomer 20. To explain these results, not only the
composition of the hemiketal mixture but also their
stereochemistry should be taken into consideration. Judging
from IR spectrum and 13C NMR spectroscopy, it is
conceivable that seven stereoisomers, i.e. 49, two of 50,
and four of 51, are involved in the mixture at equilibrium.
However, assuming that equilibration of these isomers is
rapid enough to interconvert each other, the problem could
be reduced to the proportion of the four possible stereo-
Scheme 11. Transition state models for the hetero-Michael addition of 51A
and 51B.
isomers of hemiketal 51 and the facility of cyclization of
each isomer.
The proportion of the four stereoisomers of 51, labeled as
51a–d, depends on the thermodynamic stabilities of
themselves. The most stable conformations of 51a–d are
presumed as presented in Scheme 10. On the assumption
that the bulk of the C15 TBS ether and the C19 side-chain
directs both C15–C16 and C19–C20 bonds to pseudo-
equatorial positions on the tetrahydrofuran ring, the cisoid
isomers 51a and 51c would benefit from the envelope
geometry in the five-membered ring, wherein hydrogen
bond between the hemiketal hydroxyl group and the B ring
oxygen might function as a structure-stabilizing element.
On the other hand, the transoid isomers 51b and 51d would
adopt the half-chair geometry, wherein they suffer from the
steric repulsion between the C15 TBS ether and the
hemiketal hydroxyl group. These considerations suggest
that the equilibrium between these isomers might heavily lie
to 51a and 51c, wherein 51a benefits from an anomeric
stabilization. It is also suggested that the hindered nature of
the hemiketal hydroxyl group in 51b and 51d would prevent
the enone functionality from undergoing hetero-Michael
addition.
The formation of 20 and 52 from 51A and 51C, metalated
derivatives of 51a and 51c, respectively, is well explained
by invoking transition state models A and C rather than B
and D as shown in Scheme 11. Of these models, B and D are
Scheme 10. Most stable conformations presumed for the four stereoisomers
of hemiketal 51.

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S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
Scheme 13. Transition state models for the formation of 20 and 53.
which would prevent the enone functionality from under-
going hetero-Michael addition (vide supra), whereas 20 can
be smoothly formed from 51A (Scheme 13). While the pKb
of LiOMe is unknown, the choice of this base, which is
weaker than NaOMe or KOMe, is crucial to the success of
the present tandem double hemiketal formation/hetero-
Michael addition process simply because its basicity is weak
enough to prevent the desired isomer 20 from undergoing
retro-Michael reaction even at room temperature.
Scheme 12. Pathway for the isomerization of the dispiroketals.
disfavored by the severe repulsion between the hydrogens at
C18 and C23. Compared with model C, model A seems
energetically disadvantageous due to the weak steric
interaction between the C12 and C23 side-chains. Provided
that the system is under Curtin–Hammett control, this
process leads to the predominant formation of 52 as
observed early in the course of the dispiroketalization
reaction.
3. Conclusion
We have developed an efficient, highly stereoselective
method for the construction of the 6,5,6-dispiroketal (BCD)
ring system of pinnatoxin A, which is based on an
intramolecular hetero-Michael addition of a hemiketal
alkoxide reversibly formed under the influence of lithium
methoxide. We have also offered a mechanistic explanation
for the observed stereochemical outcome. This novel
process should be useful in the construction of other
dispiroketals. In the following article, we describe the
stereoselective synthesis of the C10–C31 (BCDEF ring)
portion of pinnatoxin A utilizing this methodology.
2.3.3. Rationalization for the predominant formation of
the desired isomer 20. With an explanation for the
significant kinetic preference for the formation of 52
offered, we now address a rationalization for a high level
of stereoselectivity for the desired isomer 20 under LiOMe-
mediated dispiroketalization conditions. Since the stereo-
chemistries of the newly formed chiral centers in 20 were
totally opposite to those in 52, it is obvious that the
isomerization of 52 to 20 proceeded via the reaction
sequence of retro-Michael reaction, dissociation to 49A,
double hemiketalization, and hetero-Michael addition
(Scheme 12). As shown in Table 2, the dispiroketal 52 is
the most stable isomer of the six isomers other than two
isomers 20 and 53 with little difference in energy.
Theoretically, 54 and the four possible isomers 62–65
could equilibrate with the more stable isomers 20 and 53
under the conditions where 52 undergoes isomerization.
Since 20 and 53 have the same configuration at C16, a prime
requirement for the preferential formation of 20 over 53
would be a much more facile hetero-Michael reaction of
51A relative to that of 51B as well as an energy barrier high
enough to suppress the retro-Michael reaction from 20 to
51A. This explanation can be rationalized by considering
that the formation of 53 from 51B is particularly disfavored
by the hindered nature of the hemiketal alkoxide in 51B
4. Experimental
4.1. General
Melting points were determined on a Bu¨chi 535 digital
melting point apparatus and were uncorrected. Optical
rotations were recorded on a JASCO P-1030 digital
polarimeter. Infrared (IR) spectra were recorded on a
JASCO FT/IR-5300 spectrophotometer and absorbance
bands were reported in wavenumber (cm21). Proton nuclear
magnetic resonance (1H NMR) spectra were recorded on
JEOL EX270 (270 MHz), JEOL AL400 (400 MHz) or
Bruker ARX500 (500 MHz) spectrometers, with tetra-
methylsilane (dH 0.00) or C6H6 (dH 7.20) as an internal
standard. Coupling constants (J) are reported in hertz (Hz).
Abbreviations of multiplicity are as follows: s, singlet; d,

S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
10363
doublet; t, triplet; q, quartet; m, multiplet; br, broad. Data
are presented as follows: chemical shift, multiplicity,
coupling constants, integration, and assignment. Carbon
nuclear magnetic resonance (13C NMR) spectra were
recorded on JEOL EX270 (67.8 MHz), JEOL AL400
(100.6 MHz) or Bruker ARX500 (125.8 MHz) spec-
trometers, with CDCl3 (dC 77.0) or C6D6 (dC 128.0) as an
internal standard. Electron ionization (EI) mass spectra were
recorded on JEOL JMS-DX303 or JEOL FABmate
spectrometer, operating with an ionization energy of
70 eV. Fast atom bombardment (FAB) mass spectra were
recorded on a JEOL JMS HX110 spectrometer.
23 (26.1 g, 60.3 mmol) in MeOH (120 mL)–H2O (10 mL)
at room temperature. After stirring for 35 h, the reaction was
quenched with Et3N (4.1 mL). The solvent was removed in
vacuo, and the residual yellow oil (26.3 g) was purified by
column chromatography (silica gel 100 g, 1:1
n-hexane/AcOEt!1:4 AcOEt/acetone) to give triol 24
(16.6 g, 98%) as a colorless syrup: [a]2D5¼24.94 (c 1.11,
CHCl3); IR (neat) 3385, 2938, 1422, 1275, 1069, 909, 868,
1
752 cm21; H NMR (500 MHz, CDCl3) d 1.51–1.66 (m,
6H, C17–H2, C21–H2, C22–H2), 1.85–2.00 (m, 8H,
OH£3, C18–H, C20–H2, SCH2CH2), 2.16 (m, 1H, C18–
H), 2.77–2.88 (m, 4H, SCH2£2), 3.49 (dd, J¼7.2, 11.0 Hz,
1H, C15–H), 3.66–3.72 (m, 4H, C15–H, C16–H, C23–
H2); 13C NMR (125 MHz, CDCl3) d 20.1, 25.4, 25.9, 27.6,
32.3, 33.8, 37.7, 52.8, 61.8, 66.4, 72.1; FAB-HRMS m/z
calcd for C12H24O3S2Na (MþþNa) 303.1064, found
303.1068.
Column chromatography was carried out on Merck
Kieselgel 60 (63–200 mm or 40–63 mm), Wakogel C-200
(75–150 mm) or Kanto Silica gel 60 N (63–210 mm).
Analytical thin layer chromatography (TLC) was carried out
on Merck Kieselgel 60 F254 plates. HPLC analyses were
performed on a JASCO PU-980 and UV-970 (detector,
l¼254 nm). Retention times (tR) and peak ratios were
determined with a Shimadzu Chromatopac C-R6A. Hexane
was of HPLC grade, and filtered and degassed before use.
4.1.3. (S)-4-(2-{2-[2-(4-Methoxyphenyl)-1,3-dioxolan-4-
yl]ethyl}-1,3-dithian-2-yl)-1-butanol (25). Pyridinium
p-toluenesulfonate (1.0 g, 3.98 mmol) was added to a stirred
solution of triol 24 (20.3 g, 72.4 mmol) and p-anisaldehyde
dimethyl acetal (19.7 g, 108.1 mmol) in CH2Cl2 (150 mL)
at room temperature under an argon atmosphere. After
stirring for 6 h, Et3N (3 mL) was added to the reaction
mixture. The solvent was removed in vacuo, and the
residual yellow oil (40.6 g) was purified by column
chromatography (silica gel 150 g, 4:1!2:1 n-hexane/
AcOEt) to give acetal 25 (21.7 g, 75%) as a colorless
syrup: [a]2D5¼29.25 (c 1.15, CHCl3); IR (neat) 3445, 2938,
1615, 1516, 1454, 1304, 1284, 1173, 1076, 909, 831 cm21
;
1H NMR (500 MHz, CDCl3) d 1.43 (brs, 1H, OH), 1.49–
1.67 (m, 4H, C21–H2, C22–H2), 1.69–1.98 (m, 7H, C17–
H2, C18–H, C20–H2, SCH2CH2), 2.19 (m, 1H, C18–H),
2.73–2.87 (m, 4H, SCH2£2), 3.62–3.65 (m, 2.5H, C15–H,
C23–H2), 3.73 (m, 0.5H, C15–H), 3.81 (s, 3H,
C6H4OCH3), 4.10 (m, 0.5H, C15–H), 4.18–4.29 (m,
1.5H, C15–H, C16–H), 5.76 (s, 0.5H, ArCH), 5.88 (s,
0.5H, ArCH), 6.90 (m, 2H, ArH), 7.39–7.43 (m, 2H, ArH);
13C NMR (125 MHz, CDCl3) d 20.1, 20.2, 25.1, 25.7, 28.1,
28.6, 32.5, 33.8, 38.05, 38.10, 52.6, 52.7, 55.1, 62.03, 62.04,
69.7, 70.4, 76.0, 76.5, 102.7, 103.7, 113.38, 113.41, 127.5,
127.8, 129.4, 130.0, 159.9, 160.0; FAB-HRMS m/z calcd for
C20H30O4S2 (Mþ) 398.1586, found 398.1563.
Reagents and solvents were purified by standard means or
used as received otherwise noted. Dehydrated stabilizer
free THF was purchased from Kanto Chemical Co., Inc.
2-(Phenylsulfonyl)-3-phenyloxaziridine,31
Stryker
reagent32 and Dess–Martin periodinane33 were prepared
according to literature procedures.
4.1.1. (S)-2,2-Diethyl-5-(2-{2-[4-(tetrahydropyran-2-
yloxy)butyl]-1,3-dithian-2-yl}ethyl)-1,3-dioxolane (23).
Butyllithium in n-hexane (2.6 M, 16.6 mL, 43.2 mmol)
was added to a solution of dithiane 22 (12.4 g, 44.9 mmol)
in THF (100 mL)–HMPA (10 mL) at 2788C under an
argon atmosphere. After 30 min, a solution of iodide 21
(10.2 g, 35.9 mmol) in THF (12 mL) was added, and the
mixture was stirred at 2788C for 1 h. The reaction was
quenched with saturated aqueous NH4Cl (50 mL), and the
whole was extracted with AcOEt (2£80 mL). The organic
extract was washed with brine (2£50 mL), and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product (21.5 g, yellow oil), which was
purified by column chromatography (silica gel 200 g, 8:1
n-hexane/AcOEt) to give dithiane 23 (14.7 g, 95%) as a
colorless oil: [a]2D3¼23.61 (c 2.32, EtOH); IR (neat) 2942,
4.1.4. (S)-2-{2-[2-(4-Methoxyphenyl)-1,3-dioxolan-4-yl]-
ethyl-2-[4-(triethylsilyloxy)butyl]-1,3-dithiane
2872, 1454, 1354, 1275, 1173, 1123, 1078, 1034, 920 cm21
;
(26).
1H NMR (500 MHz, CDCl3) d 0.88–0.92 (m, 6H,
pentylidene CH3£2), 1.52–1.96 (m, 21H, C17–H2, C18–
H, C20–H2, C21–H2, C22–H2, SCH2CH2, pentylidene
CH2£2, THP CH2£3), 2.12 (m, 1H, C18–H), 2.79–2.83 (m,
4H, SCH2£2), 3.40 (m, 1H, THP OCH), 3.49–3.53 (m, 2H,
C15–H, C23–H), 3.76 (m, 1H, THP OCH), 3.87 (m, 1H,
C23–H), 4.05–4.10 (m, 2H, C15–H, C16–H), 4.58 (m, 1H,
THP OCHO); 13C NMR (125 MHz, CDCl3) d 7.7, 7.9, 19.3,
20.4, 25.1, 25.2, 25.6, 25.7, 28.3, 29.3, 29.5, 29.6, 30.4,
33.8, 37.9, 52.6, 61.9, 66.8, 69.7, 75.8, 98.45, 98.46, 112.4;
FAB-HRMS m/z calcd for C22H40O4S2 (Mþ) 432.2368,
found 432.2375.
TESCl (3.27 mL, 19.5 mmol) was added to a stirred solution
of alcohol 25 (7.02 g, 17.6 mmol) and imidazole (3.00 g,
44.0 mmol) in CH2Cl2 (60 mL) at 08C under an argon
atmosphere. After stirring at room temperature for 2 h, the
reaction was quenched by addition of ice, and the whole
mixture was partitioned between AcOEt (100 mL) and
saturated aqueous NH4Cl (40 mL). The organic layer was
washed with brine (40 mL), and dried over Na2SO4.
Filtration and evaporation in vacuo furnished the crude
product (10.5 g), which was purified by column chroma-
tography (silica gel 80 g, 10:1 n-hexane/AcOEt) to give
TES ether 26 (8.83 g, 98%) as a colorless oil: [a]2D4¼27.12
(c 2.21, CHCl3); IR (neat) 2951, 2876, 1615, 1516, 1458,
4.1.2. (S)-4-[2-(4-Hydroxybutyl)-1,3-dithian-2-yl]-
butane-1,2-diol (24). p-Toluenesulfonic acid monohydrate
(1.00 g, 5.3 mmol) was added to a stirred solution of acetal
1379, 1304, 1248, 1171, 1092, 1036, 1011, 829, 743 cm21
;
1H NMR (500 MHz, CDCl3) d 0.57–0.62 (m, 6H, Si(CH2-
CH3)3), 0.94–0.99 (m, 9H, Si(CH2CH3)3), 1.47–1.54 (m,

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S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
4H, C21–H2, C22–H2), 1.68–1.96 (m, 7H, C17–H2,
C18–H, C20–H2, SCH2CH2), 2.20 (m, 1H, C18–H),
2.73–2.87 (m, 4H, SCH2£2), 3.60–3.64 (m, 2.5H, C15–
H, C23–H2), 3.73 (m, 0.5H, C15–H), 3.81 (s, 3H,
C6H4OCH3), 4.10 (m, 0.5H, C15–H), 4.18–4.28 (m,
1.5H, C15–H, C16–H), 5.76 (s, 0.5H, ArCH), 5.87 (s,
0.5H, ArCH), 6.90 (m, 2H, ArH), 7.39–7.43 (m, 2H, ArH);
13C NMR (100 MHz, CDCl3) d 4.4, 6.7, 20.3, 25.3, 25.9,
28.3, 28.7, 32.9, 33.9, 34.1, 38.3, 52.8, 55.2, 62.5, 69.9,
70.6, 76.2, 76.8, 102.9, 103.0, 103.97, 104.03, 113.6, 127.7,
128.0, 129.8, 130.4, 160.2, 160.3; EI-LRMS m/z 512
(Mþ), 241 (bp); EI-HRMS m/z calcd for C26H44O4S2Si
(Mþ) 512.2450, found 512.2455; Anal calcd for
C26H44O4S2Si: C, 60.89; H, 8.65; S, 12.50, found C,
60.66; H, 8.70; S, 12.64.
(Mþ), 121 (bp); EI-HRMS m/z calcd for C26H46O4S2Si
(Mþ) 514.2607, found 514.2604.
4.1.6. (S)-2-(4-Methoxybenzyl)oxy-4-{2-[4-(triethylsilyl-
oxy)butyl]-1,3-dithian-2-yl}butyraldehyde (29). Sulfur
trioxide pyridine complex (4.64 g, 29.2 mmol) was added
over 15 min to a stirred solution of alcohol 27 (5.03 g,
9.77 mmol) and Et3N (8.1 mL, 58.1 mmol) in DMSO
(60 mL) under an argon atmosphere. After stirring at room
temperature for 1 h, the mixture was diluted with Et2O
(50 mL) and poured into saturated aqueous NH4Cl (50 mL)
and H2O (20 mL) at 08C. The whole was extracted with
AcOEt (2£80 mL), and the organic layer was washed
successively with saturated aqueous NH4Cl (40 mL) and
brine (2£30 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo furnished the crude
product (6 g, orange oil), which was purified by column
chromatography (silica gel 60 g, 8:1 n-hexane/AcOEt) to
give aldehyde 29 (4.62 g, 92%) as a colorless oil:
[a]2D2¼226.3 (c 2.01, CHCl3); IR (neat) 2951, 1732,
4.1.5. (S)-2-(4-Methoxybenzyl)oxy-4-{2-[4-(triethylsilyl-
oxy)butyl]-1,3-dithian-2-yl}-1-butanol (27). Diisobutyl-
aluminum hydride in n-hexane (1.01 M, 93.9 mL,
94.8 mmol) was added to a stirred solution of p-methoxy-
benzylidene acetal 26 (19.4 g, 37.9 mmol) in CH2Cl2
(250 mL) at 2788C under an argon atmosphere. After
stirring at 2208C for 2 h, the reaction was quenched with
methanol (5 mL), and 1 M aqueous sodium potassium
tartrate (400 mL) was added to the solution. The mixture
was stirred vigorously at room temperature for 3 h, and
extracted with AcOEt (2£400 mL). The combined organic
extracts were washed with brine (200 mL), and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product (23.2 g), which was purified by
column chromatography (silica gel 400 g, 8:1!6:1
n-hexane/AcOEt) to give alcohol 27 (17.1 g, 87%) as a
colorless oil, along with isomer 28 (1.40 g, 7%) as a
colorless oil: [a]2D2¼þ12.9 (c 2.23, CHCl3); IR (neat) 3447,
1
1613, 1514, 1284, 1098, 743 cm21; H NMR (500 MHz,
CDCl3) d 0.59 (q, J¼8.0 Hz, 6H, Si(CH2CH3)3), 0.96 (t,
J¼8.0 Hz, 9H, Si(CH2CH3)3), 1.47–1.55 (m, 4H, C21–H2,
C22–H2), 1.80–1.95 (m, 8H, C17–H2, C18–H2, C20–H2,
SCH2CH2), 2.74–2.81 (m, 4H, SCH2£2), 3.61 (m, 2H,
C23–H2), 3.75 (m, 1H C16–H), 3.81 (s, 3H, C6H4OCH3),
4.53 (d, J¼11.5 Hz, 1H, OCHAr), 4.58 (d, J¼11.5 Hz, 1H,
OCHAr), 6.89 (d, J¼8.5 Hz, 2H, ArH), 7.28 (d, J¼8.5 Hz,
2H, ArH), 9.62 (d, J¼2.0 Hz, 1H, CHO); 13C NMR
(100 MHz, CDCl3) d 4.4, 6.7, 20.2, 25.0, 25.16, 25.23,
25.9, 32.6, 32.9, 38.4, 52.8, 55.2, 62.5, 72.1, 82.7, 113.9,
129.2, 129.6, 159.5, 203.2; EI-LRMS m/z 512 (Mþ), 121
(bp); EI-HRMS m/z calcd for C26H44O4S2Si (Mþ)
512.2450, found 512.2471; Anal calcd for C26H44O4S2Si:
C, 60.89; H, 8.65; S, 12.50, found C, 60.86; H, 8.62; S,
12.70.
1
2951, 1514, 1284, 1096, 743 cm21; H NMR (500 MHz,
CDCl3) d 0.59 (q, J¼8.0 Hz, 6H, Si(CH2CH3)3), 0.96 (t,
J¼8.0 Hz, 9H, Si(CH2CH3)3), 1.45–1.56 (m, 4H, C21–H2,
C22–H2), 1.71 (m, 2H, C17–H2), 1.84–2.00 (m, 7H, OH,
C18–H2, C20–H2, SCH2CH2), 2.77–2.80 (m, 4H,
SCH2£2), 3.49–3.56 (m, 2H, C15–H, C16–H), 3.62 (m,
2H, C23–H2), 3.66 (m, 1H, C15–H), 3.81 (s, 3H,
C6H4OCH3), 4.49 (d, J¼11.3 Hz, 1H, OCHAr), 4.58 (d,
J¼11.3 Hz, 1H, OCHAr), 6.89 (d, J¼8.6 Hz, 2H, ArH),
7.28 (d, J¼8.6 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3)
d 4.2, 6.5, 20.2, 25.2, 25.3, 25.7, 38.0, 52.9, 54.9, 55.0, 62.3,
63.9, 70.9, 78.9, 113.5, 129.1, 130.2, 159.0; EI-LRMS m/z
514 (Mþ), 121 (bp); EI-HRMS m/z calcd for C26H46O4S2Si
(Mþ) 514.2607, found 514.2608; Anal calcd for
C26H46O4S2Si: C, 60.65; H, 9.01; S, 12.46, found C,
60.52; H, 8.99; S, 12.50.
4.1.7. (3S)-3-(4-Methoxybenzyl)oxy-5-{2-[4-(triethyl-
silyl)oxybutyl]-1,3-dithian-2-yl}-2-pentanol (30). MeI
(1.25 mL, 20.0 mmol) in Et2O (2 mL) was added over
30 min to a suspension of magnesium tuning (510.3 mg,
21.0 mmol) in Et2O (4 mL) under an argon atmosphere.
After refluxing for 30 min, the solution was cooled to room
temperature, and diluted with THF (15 mL). The mixture
was cooled to 2788C, and a solution of aldehyde 29 (2.05 g,
4.00 mmol) in THF (3 mL) was added. After stirring at
2788C for 1 h and at 2508C for 1 h, the reaction was
quenched with saturated aqueous NH4Cl (40 mL), and the
whole was extracted with AcOEt (80 mL and 40 mL). The
combined organic extracts were washed successively with
saturated aqueous NH4Cl (40 mL) and brine (2£30 mL),
and dried over anhydrous Na2SO4. Filtration and evapor-
ation in vacuo furnished the crude product (2.4 g), which
was purified by column chromatography (silica gel 20 g, 4:1
n-hexane/ AcOEt) to give alcohol 30 (1.94 g, 92%) as a
colorless oil: [a]2D2¼þ18.8 (c 2.06, CHCl3); IR (neat) 3461,
Data for 28: [a]2D1¼21.48 (c 2.3, CHCl3); IR (neat) 3455,
1
2951, 1613, 1514, 1458, 1248, 1096, 743 cm21; H NMR
(400 MHz, CDCl3) d 0.59 (q, J¼8.0 Hz, 6H, Si(CH2CH3)3),
0.95 (t, J¼8.0 Hz, 9H, Si(CH2CH3)3), 1.48–1.60 (m, 6H),
1.82–1.94 (m, 5H), 2.10 (m, 1H), 2.35 (brs, 1H, OH), 2.74–
2.87 (m, 4H), 3.31 (dd, J¼8.0, 9.2 Hz, 1H, C15–H), 3.49
(dd, J¼3.2, 9.2 Hz, 1H, C15–H), 3.61 (m, 2H, C23–H2),
3.78–3.81 (m, 4H, C16–H, C6H4OCH3), 4.48 (s, 2H,
OCH2Ar), 6.89 (d, J¼8.8 Hz, 2H, ArH), 7.26 (d, J¼8.8 Hz,
2H, ArH); 13C NMR (68 MHz, CDCl3) d 4.4, 6.7, 20.3,
25.4, 25.9, 28.0, 33.0, 33.8, 38.3, 53.1, 55.2, 62.6, 70.4,
73.0, 74.2, 113.8, 129.4, 130.0, 159.3; EI-LRMS m/z 514
1
2951, 1613, 1514, 1456, 1248, 1094, 820, 743 cm21; H
NMR (500 MHz, CDCl3) d 0.59 (q, J¼8.0 Hz, 6H, Si(CH2-
CH3)3), 0.95 (t, J¼8.0 Hz, 9H, Si(CH2CH3)3), 1.17 (d,
J¼6.3 Hz, 3H, C14–H3), 1.47–1.65 (m, 4H, C21–H2,
C22–H2), 1.81–2.05 (m, 8H, C17–H2, C18–H2, C20–H2,
SCH2CH2), 2.47 (d, J¼3.0 Hz, 1H, OH), 2.74–2.84 (m, 4H,
SCH2£2), 3.23–3.32 (m, 1H, C15–H), 3.60–3.63 (m, 2H,

S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
10365
C23–H2), 3.75 (m, 1H, C16–H), 3.81 (s, 3H, C6H4OCH3),
4.48 (d, J¼10.9 Hz, 0.5H, OCHAr), 4.53 (s, 1H, OCHAr),
4.63 (d, J¼11.5 Hz, 0.5H, OCHAr), 6.89 (d, J¼8.5 Hz, 2H,
ArH), 7.28 (d, J¼8.5 Hz, 2H, ArH); 13C NMR (100 MHz,
CDCl3) d 4.4, 6.8, 18.1, 18.7, 20.37, 20.41, 23.6, 24.1, 25.4,
25.86, 25.91, 32.2, 32.95, 32.98, 33.7, 38.15, 38.18, 53.1,
53.2, 55.1, 62.47, 62.54, 67.9, 68.5, 71.5, 71.7, 82.2, 83.2,
113.6, 113.7, 129.3, 129.4, 130.0, 130.3, 159.0, 159.1; FAB-
HRMS m/z calcd for C27H48O4S2Si (Mþ) 528.2764, found
528.2778.
vacuo. The yellow residue was purified by column
chromatography (silica gel 80 g, 1:1 n-hexane/AcOEt) to
give diol 33 (4.20 g, 91%) as a colorless syrup:
[a]2D3¼24.81 (c 1.33, CHCl3); IR (neat) 3387, 2934,
1
2866, 1454, 1366, 1096, 737 cm21; H NMR (500 MHz,
CDCl3) d 1.73 (m, 1H, C11–H), 1.84 (m, 1H, C11–H), 2.34
(brs, 1H, OH), 3.15 (brs, 1H, OH), 3.50 (m, 1H, C13–H),
3.63 (m, 1H, C13–H), 3.65–3.74 (m, 2H, C10–H), 3.92 (m,
1H, C12–H), 4.53 (s, 2H, OCH2Ph), 7.29–7.37 (m, 5H,
ArH); 13C NMR (100 MHz, CDCl3) d 32.6, 66.0, 67.0, 69.7,
72.5, 127.1, 127.8, 137.6; EI-LRMS m/z 196 (Mþ), 91 (bp);
EI-HRMS m/z calcd for C11H16O3 (Mþ) 196.1099, found
196.1089.
4.1.8. (S)-3-(4-Methoxybenzyl)oxy-5-{2-[4-(triethylsilyl)-
oxybutyl]-1,3-dithian-2-yl}pentan-2-one (10). Sulfur tri-
oxide pyridine complex (3.17 g, 19.9 mmol) was added over
15 min to a stirred solution of alcohol 30 (3.50 g,
6.62 mmol) and Et3N (5.5 mL, 39.7 mmol) in DMSO
(30 mL) at room temperature under an argon atmosphere.
After stirring at room temperature for 1 h, the mixture was
diluted with Et2O (60 mL) and poured into saturated
aqueous NH4Cl (60 mL) at 08C. The whole was extracted
with AcOEt (2£50 mL), and the organic extract was washed
with H2O (2£30 mL), and brine (2£30 mL), and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product (3.6 g, orange oil), which was
purified by column chromatography (silica gel 40 g, 10:1
n-hexane/AcOEt) to give ketone 10 (3.25 g, 93%) as a
colorless oil: [a]2D5¼224.1 (c 0.98, CHCl3); IR (neat) 2951,
1715, 1613, 1514, 1458, 1418, 1354, 1302, 1248, 1284,
4.1.10. (R)-4-Benzyloxy-1-(pivaloyl)oxy-2-butanol (34).
Trimethylacetyl chloride (3.19 mL, 25.9 mmol) was added
to a stirred solution of diol 33 (4.85 g, 24.7 mmol) in
CH2Cl2 (20 mL)–pyridine (20 mL) at 08C under an argon
atmosphere. After stirring at 08C for 1 h and at room
temperature for 1 h, the reaction was quenched with crushed
ice, and the whole was partitioned between AcOEt
(100 mL) and 10% aqueous HCl (40 mL). The aqueous
layer was extracted with AcOEt (80 mL), and the combined
organic extracts were washed successively with H2O
(40 mL), saturated aqueous NaHCO3 (2£40 mL) and brine
(2£30 mL), and dried over anhydrous Na2SO4. Filtration
and evaporation in vacuo furnished the crude product
(8.2 g), which was purified by column chromatography
(silica gel 100 g, 6:1!4:1 n-hexane/AcOEt) to give ester 34
(6.25 g, 90%) as a colorless oil: [a]2D5¼22.37 (c 3.35,
CHCl3); IR (neat) 3472, 2971, 2872, 1728, 1481, 1456,
1
1175, 1098, 1036, 822, 743 cm21; H NMR (500 MHz,
CDCl3) d 0.59 (q, J¼8.0 Hz, 6H, Si(CH2CH3)3), 0.95 (t,
J¼8.0 Hz, 9H, Si(CH2CH3)3), 1.44–1.56 (m, 4H, C21–H2,
C22–H2), 1.79–2.05 (m, 8H, C17–H2, C18–H2, C20–H2,
SCH2CH2), 2.18 (s, 3H, C14–H3), 2.70–2.84 (m, 4H,
SCH2£2), 3.59–3.62 (m, 2H, C23–H2), 3.75 (m, 1H, C16–
H), 3.81 (s, 3H, C6H4OCH3), 4.40 (d, J¼11.5 Hz, 1H,
OCHAr), 4.52 (d, J¼11.5 Hz, 1H, OCHAr), 6.89 (d,
J¼8.5 Hz, 2H, ArH), 7.27 (d, J¼8.5 Hz, 2H, ArH); 13C
NMR (100 MHz, CDCl3) d 4.4, 6.8, 20.3, 25.3, 25.5, 25.87,
25.90, 26.7, 33.0, 38.5, 52.8, 55.2, 62.5, 71.9, 84.1, 113.7,
129.3, 129.4, 159.2, 210.6; FAB-HRMS m/z calcd for
C27H46O4S2Si (Mþ) 526.2607, found 526.2623; Anal calcd
for C27H46O4S2Si: C, 61.55; H, 8.80; S, 12.17, found C,
61.27; H, 8.76; S, 12.41.
1
1366, 1285, 1163, 1001, 1032, 739, 698 cm21; H NMR
(500 MHz, CDCl3) d 1.22 (s, 9H, C(CH3)3), 1.79–1.82 (m,
2H, C11–H), 2.98 (brs, 1H, OH), 3.66 (m, 1H, C10–H),
3.73 (m, 1H, C10–H), 4.03–4.12 (m, 3H, C12–H, C13–
H2), 4.53 (s, 2H, OCH2Ph), 7.28–7.37 (m, 5H, ArH); 13C
NMR (100 MHz, CDCl3) d 26.8, 32.9, 38.4, 67.2, 67.70,
67.74, 72.7, 127.1, 127.2, 127.9, 137.6, 177.9; FAB-HRMS
m/z calcd for C16H25O4 (MþþH) 281.1796, found
281.1736.
4.1.11. (R)-4-Benzyloxy-1-(pivaloyl)oxy-2-(triethylsilyl)-
oxybutane (35). TESCl (4.13 mL, 24.3 mmol) was added to
a stirred solution of alcohol 34 (6.20 g, 22.1 mmol) and
imidazole (3.76 g, 55.3 mmol) in CH2Cl2 (50 mL) at 08C
under an argon atmosphere. After stirring at room
temperature for 1 h, the reaction was quenched with crushed
ice, and the mixture was partitioned between AcOEt
(100 mL) and H2O (80 mL). The aqueous layer was
extracted with AcOEt (80 mL), and the combined organic
extracts were washed successively with H2O (40 mL), and
brine (2£30 mL), and dried over Na2SO4. Filtration and
evaporation in vacuo furnished the crude product (9.2 g, a
colorless oil), which was purified by column chromato-
graphy (silica gel 100 g, 10:1!8:1 n-hexane/AcOEt) to
give TES ether 35 (8.46 g, 97%) as a colorless oil:
[a]2D3¼þ8.29 (c 3.29, CHCl3); IR (neat) 2957, 2878, 1732,
4.1.9. (R)-4-(Benzyloxy)butane-1,2-diol (33). To
a
solution of alcohol 31 (4.11 g, 23.5 mmol) in THF
(50 mL)–HMPA (10 mL) at 08C was added NaH
(620 mg, 25.8 mmol), followed by addition of BnBr
(3.4 mL, 28.2 mmol). After stirring at room temperature
for 10 h, the reaction was quenched with MeOH (3 mL), and
the whole was partitioned between AcOEt (100 mL) and
saturated aqueous NH4Cl (30 mL). The aqueous layer was
extracted with AcOEt (50 mL), and the combined organic
extracts were washed with brine (2£40 mL), and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product, which was used without further
purification.
1480, 1456, 1366, 1283, 1238, 1161, 1123, 1009, 737 cm21
;
p-Toluenesulfonic acid monohydrate (500 mg, 2.63 mmol)
was added to a stirred solution of the crude acetal in THF
(60 mL)-H2O (6 mL) at room temperature, and the mixture
was stirred at 608C for 5 h. After cooling, the reaction was
quenched with Et3N (3 mL), and the solvent was removed in
1H NMR (500 MHz, CDCl3) d 0.69 (q, J¼8.1 Hz, 6H,
Si(CH2CH3)3), 0.95 (t, J¼8.1 Hz, 9H, Si(CH2CH3)3), 1.20
(s, 9H, C(CH3)3), 1.77 (m, 1H, C11–H), 1.85 (m, 1H,
C11–H), 3.54–3.61 (m, 2H, C10–H2), 3.99–4.00 (m, 2H,
C13–H2), 4.07 (m, 1H, C12–H), 4.48 (d, J¼11.9 Hz, 1H,

10366
S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
OCHPh), 4.51 (d, J¼11.9 Hz, 1H, OCHPh), 7.29 (m, 1H,
ArH), 7.32–7.35 (m, 4H, ArH); FAB-HRMS m/z calcd for
C22H39O4Si (MþþH) 395.2618, found 395.2608.
solution of 2-(phenylsulfonyl)-3-phenyloxaziridine (16.8 g,
63.6 mmol) in THF (50 mL) was added. Upon completion
of the addition, the reaction was quenched by addition of
AcOH (15 mL) in THF (30 mL), and the mixture was
partitioned between AcOEt (150 mL) and saturated aqueous
NaHCO3 (50 mL). The aqueous layer was extracted with
AcOEt (100 mL), and the combined organic extracts were
washed successively with saturated aqueous Na2SO3
(100 mL), 1 M aqueous NaHSO4 (100 mL), saturated
aqueous NaHCO3 (100 mL), and brine (100 mL), and
dried over anhydrous Na2SO4. Filtration and evaporation
in vacuo furnished the crude product (33.6 g, a yellow oil),
which was purified by column chromatography (silica gel
500 g, 4:1 n-hexane/AcOEt) to give alcohol 38 (12.6 g,
80%) as a colorless oil: [a]2D6¼280.4 (c 2.16, CHCl3); IR
(neat) 3493, 3030, 2926, 2865, 1780, 1696, 1497, 1454,
4.1.12. (R)-4-Benzyloxy-2-(triethylsilyl)oxy-1-butanol
(36). Diisobutylaluminum hydride in n-hexane (1.01 M,
41.8 mL, 42.2 mmol) was added to a stirred solution of ester
35 (8.34 g, 21.13 mmol) in CH2Cl2 (120 mL) at 2788C
under an argon atmosphere. After stirring at 2788C for 1 h,
the reaction was quenched with MeOH (10 mL), and 10%
aqueous potassium sodium tartrate (100 mL) was added.
The mixture was stirred vigorously at room temperature for
2 h, and the whole was extracted with AcOEt (2£150 mL).
The combined organic extracts were washed with brine
(60 mL) and dried over anhydrous Na2SO4. Filtration and
evaporation in vacuo furnished the crude product, which
was purified by column chromatography (silica gel 100 g,
6:1 n-hexane/AcOEt) to give alcohol 36 (6.15 g, 94%) as a
colorless oil: [a]2D3¼þ4.49 (c 3.08, C6H6); IR (neat) 3445,
1
1391, 1354, 1292, 1213, 1121, 1014, 737 cm21; H NMR
(500 MHz, CDCl3) d 2.12 (m, 1H, C11–H), 2.20 (m, 1H,
C11–H), 2.74 (dd, J¼9.6, 13.6 Hz, 1H, CHPh), 3.25 (dd,
J¼3.2, 13.6 Hz, 1H, CHPh), 3.64–3.72 (m, 2H, C10–H2),
3.79 (dd, J¼7.8, 8.9 Hz, 1H, CHO), 4.00 (dd, J¼2.3, 8.9 Hz,
1H, CHO), 4.24 (dddd, J¼2.3, 3.2, 7.8, 9.6 Hz, 1H, NCH),
4.38 (d, J¼11.1 Hz, 1H, OCHPh), 4.44 (d, J¼11.1 Hz, 1H,
OCHPh), 5.18 (t, J¼4.9 Hz, 1H, C12–H), 7.13 (m, 2H,
ArH), 7.22 (m, 1H, ArH), 7.26–7.34 (m, 7H, ArH); 13C
NMR (67.8 MHz, CDCl3) d 33.7, 37.3, 55.4, 65.6, 66.6,
68.1, 73.1, 127.2, 127.6, 127.9, 128.1, 128.7, 129.2, 134.9,
138.1, 153.2, 174.6; FAB-HRMS m/z calcd for C21H24NO5
(MþþH) 370.1655, found 370.1652; Anal. calcd for
C21H23NO5: C, 68.28; H, 6.28; N, 3.79, found: C, 68.28;
H, 6.40; N, 3.81.
2955, 2876, 1456, 1414, 1364, 1238, 1096, 1007, 741 cm21
;
1H NMR (500 MHz, CDCl3) d 0.61 (q, J¼8.0 Hz, 6H,
Si(CH2CH3)3), 0.96 (t, J¼8.0 Hz, 9H, Si(CH2CH3)3), 1.80–
1.88 (m, 2H, C11–H2), 2.29 (brs, 1H, OH), 3.47–3.59 (m,
4H, C10–H2, C13–H2), 3.95 (m, 1H, C12–H), 4.48 (d,
J¼11.8 Hz, 1H, OCHPh), 4.51 (d, J¼11.8 Hz, 1H, OCHPh),
7.27–7.36 (m, 5H, ArH); 13C NMR (125 MHz, CDCl3) d
4.9, 6.8, 34.3, 66.4, 66.5, 70.2, 73.0, 127.55, 127.62, 128.3,
138.1; FAB-HRMS m/z calcd for C17H31O3Si (MþþH)
311.2043, found 311.2035; Anal. calcd for C17H30O3Si: C,
65.76; H, 9.74, found: C, 65.51; H, 9.68.
4.1.13. (R)-4-Benzyloxy-2-(triethylsilyl)oxybutanal (9).
Sulfur trioxide pyridine complex (3.59 g, 22.5 mmol) was
added over 15 min to a stirred solution of alcohol 36 (3.50 g,
11.27 mmol) and Et3N (9.4 mL, 67.6 mmol) in DMSO
(20 mL) under an argon atmosphere. After stirring for 1 h,
the mixture was diluted with Et2O (50 mL), and poured into
saturated aqueous NH4Cl (40 mL) and H2O (20 mL) at 08C.
The whole was extracted with AcOEt (2£80 mL), and the
combined organic extracts were washed with saturated
aqueous NH4Cl (2£40 mL) and brine (2£30 mL), and dried
over anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product (4.9 g, orange oil), which was
purified by column chromatography (silica gel 50 g, 8:1
n-hexane/AcOEt) to give aldehyde 9 (3.39 g, 97%) as a
colorless oil: [a]2D3¼þ2.25 (c 3.11, CHCl3); IR (neat) 2957,
1H NMR (500 MHz, CDCl3) d 0.62 (q, J¼7.8 Hz, 6H,
Si(CH2CH3)3), 0.95 (t, J¼7.8 Hz, 9H, Si(CH2CH3)3), 1.96
(m, 2H, C11–H2), 3.56 (m, 1H, C10–H), 3.65 (m, 1H,
C10–H), 4.19 (m, 1H, C12–H), 4.46 (d, J¼11.9 Hz, 1H,
OCHPh), 4.49 (d, J¼11.9 Hz, 1H, OCHPh), 7.27–7.36 (m,
5H, ArH), 9.63 (d, J¼1.1 Hz, 1H, CHO); 13C NMR
(125 MHz, CDCl3) d 4.7, 6.6, 33.4, 64.8, 72.8, 74.7,
127.4, 127.5, 128.2, 138.1, 203.5; FAB-HRMS m/z calcd for
C17H29O3Si (MþþH) 309.1886, found 309.1877.
4.1.15. [3(2R),4R]-4-Benzyl-3-[4-benzyloxy-2-(triethyl-
silyl)oxybutyryl]-2-oxazolidinone (39). TESCl (6.6 mL,
39.3 mmol) was added to a solution of alcohol 38 (13.2 g,
35.7 mmol) and imidazole (6.1 g, 89.4 mmol) in CH2Cl2
(100 mL) at 08C under an argon atmosphere. After stirring
at room temperature for 1 h, the reaction was quenched with
H2O (50 mL), and the whole was extracted with AcOEt
(200 mL). The organic extract was washed with brine
(100 mL), and dried over anhydrous Na2SO4. Filtration and
evaporation in vacuo furnished the crude product (17.5 g),
which was purified by column chromatography (silica gel
150 g, 8:1 n-hexane/AcOEt) to give TES ether 39 (15.4 g,
89%) as a colorless oil; [a]2D1¼243.4 (c 0.99, CHCl3): IR
(neat) 2955, 2876, 1780, 1715, 1454, 1389, 1350, 1211,
1136, 1103, 1015, 972, 733, 700 cm21; 1H NMR (500 MHz,
CDCl3) d 0.65 (q, J¼8.0 Hz, 6H, Si(CH2CH3)3), 0.97 (t,
J¼8.0 Hz, 9H, Si(CH2CH3)3), 2.09 (q, J¼5.3 Hz, 2H, C11–
H2), 2.64 (dd, J¼10.3, 13.3 Hz, 1H, CHPh), 3.31 (dd,
J¼3.1, 13.3 Hz, 1H, CHPh), 3.64–3.72 (m, 3H, C10–H2,
CHO), 3.94 (dd, J¼2.3, 8.9 Hz, 1H, CHO), 4.25 (m, 1H,
NCH), 4.41 (s, 2H, OCH2Ph), 5.55 (t, J¼5.3 Hz, 1H, C12–
H), 7.15 (m, 2H, ArH), 7.20 (m, 1H, ArH), 7.25–7.33 (m,
7H, ArH); 13C NMR (67.8 MHz, CDCl3) d 4.6, 6.7, 35.6,
37.7, 55.6, 65.9, 66.3, 68.3, 72.9, 127.1, 127.5, 127.8, 128.1,
128.8, 129.3, 135.4, 138.4, 153.3, 173.7; FAB-HRMS m/z
calcd for C27H38NO5Si (MþþH) 484.2519, found
484.2538; Anal. calcd for C27H37NO5Si: C, 67.05; H,
7.71; N, 2.89, found: C, 67.09; H, 7.75; N, 2.88.
2878, 1736, 1456, 1416, 1240, 1117, 1015, 835, 735 cm21
;
4.1.14. [3(2R),4R]-4-Benzyl-3-(4-benzyloxy-2-hydroxy-
butyryl)-2-oxazolidinone (38). A solution of imide 37
(15.0 g, 42.4 mmol) in THF (75 mL) was added to a solution
of NaHMDS (1.0 M in THF, 50.9 mL, 50.9 mmol) at
2788C under an argon atmosphere. After stirring at 2788C
for 30 min, the solution was cooled to 2908C, and a
4.1.16. (R)-4-Benzyloxy-2-(triethylsilyl)oxy-1-butanol
(36). Lithium borohydride in THF (0.65 M, 16.9 mL,

S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
10367
11.0 mmol) was added to a stirred solution of oxazolidinone
39 (4.07 g, 8.41 mmol) in THF (40 mL)–H2O (0.22 mL,
12.2 mmol) at 08C under an argon atmosphere. After stirring
at 08C for 1 h, the reaction was quenched with saturated
aqueous NH4Cl (40 mL), and the whole was extracted with
AcOEt (2£50 mL). The organic extract was washed with
brine (30 mL), and dried over anhydrous Na2SO4. Filtration
and evaporation in vacuo furnished the crude product
(4.34 g), which was purified by column chromatography
(silica gel 80 g, 6:1!1:1 n-hexane/AcOEt) to give alcohol
36 (2.10 g, 81%) as a colorless oil, along with recovered
auxiliary (1.25 g, 84%) as a colorless solid. The spectral
data of this material were identical with those of a sample
obtained from 31 as described above.
alcohol 40 (2.32 g, 2.78 mmol) and DMAP (20.4 mg,
0.16 mmol) in pyridine (20 mL) under an argon atmosphere.
After stirring at room temperature for 20 h, the reaction was
quenched by addition of H2O (20 mL), and the whole was
extracted with AcOEt (2£60 mL). The combined organic
extracts were washed successively with 0.1% aqueous HCl
(2£50 mL), H2O (40 mL), saturated aqueous NaHCO3
(40 mL) and brine (2£20 mL), and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the
crude product (3.7 g, yellow oil), which was used without
further purification.
DBU (0.50 mL, 3.34 mmol) was added to a stirred solution
of the crude acetate (3.7 g) in CH2Cl2 (15 mL) at 08C under
an argon atmosphere. After stirring at 08C for 1 h, the
reaction was quenched with saturated aqueous NH4Cl
(20 mL), and the mixture was extracted with AcOEt
(60 mL). The organic layer was washed successively with
saturated aqueous NH4Cl (20 mL) and brine (2£20 mL),
and dried over anhydrous Na2SO4. Filtration and evapor-
ation in vacuo furnished the crude product (2.8 g), which
was purified by column chromatography (silica gel 20 g,
10:1!8:1 n-hexane/AcOEt) to give enone 41 (2.01 g, 88%
(two steps)) as a colorless oil: [a]2D8¼227.8 (c 2.17,
CHCl3); IR (neat) 2953, 2876, 1694, 1630, 1514, 1456,
4.1.17. (3S,7R)-9-Benzyloxy-6-hydroxy-3-(4-methoxy-
benzyl)oxy-7-(triethylsilyl)oxy-1-{2-[4-(triethylsilyl)oxy-
butyl]-1,3-dithian-2-yl}nonan-4-one (40). Butyllithium in
n-hexane (1.56 M, 11.1 mL, 17.32 mmol) was added to a
solution of HMDS (3.7 mL, 17.54 mmol) in THF (40 mL) at
08C under an argon atmosphere. After 10 min at 08C, the
solution was cooled to 2788C, and a solution of ketone 10
(6.96 g, 13.23 mmol) in THF (20 mL) was added dropwise
over 30 min. After stirring at 2788C for 30 min, a solution
of ZnCl2 (4.72 g, 34.62 mmol) in THF (20 mL) was added,
and the mixture was stirred for 30 min. A solution of
aldehyde 9 (3.49 g, 11.31 mmol) in THF (10 mL) was added
to the mixture at 2788C. After stirring at 2788C for 1 h and
then at 2508C for 30 min, the mixture was quenched with
saturated aqueous NH4Cl (100 mL), and the whole was
extracted with AcOEt (2£150 mL). The combined organic
extracts were washed successively with saturated aqueous
NH4Cl (100 mL) and brine (2£50 mL), and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product (11.9 g, slightly yellow oil),
which was purified by column chromatography (silica gel
100 g, 6:1 n-hexane/AcOEt) to give b-hydroxy ketone 40
(9.26 g, 98%) as a colorless oil: [a]2D6¼221.4 (c 1.19,
CHCl3); IR (neat) 3493, 2953, 2876, 1715, 1612, 1514,
1
1416, 1302, 1248, 1096, 1038, 1011, 820, 741 cm21; H
NMR (500 MHz, CDCl3) d 0.56–0.61 (m, 12H, Si(CH2-
CH3)3£2), 0.92–0.97 (m, 18H, Si(CH2CH3)3£2),
1.44–1.55 (m, 4H, C21–H2, C22–H2), 1.75–1.96 (m, 9H,
C11–H2, C17–H2, C18–H, C20–H2, SCH2CH2), 2.06 (m,
1H, C18–H), 2.66–2.83 (m, 4H, SCH2£2), 3.51 (m, 1H,
C10–H), 3.58–3.62 (m, 3H, C10–H, C23–H2), 3.80 (s, 3H,
C6H4OCH3), 3.89 (m, 1H, C16–H), 4.31 (d, J¼11.5 Hz,
1H, OCHAr), 4.46 (d, J¼11.8 Hz, 1H, OCHPh), 4.50 (d,
J¼11.8 Hz, 1H, OCHPh) 4.52–4.57 (m, 2H, C12–H,
OCHAr), 6.68 (dd, J¼1.3, 15.6 Hz, 1H, C14–H), 6.85–
6.88 (m, 2H, ArH), 7.04 (dd, J¼4.7, 15.6 Hz, 1H, C13–H),
7.23–7.30 (m, 3H, ArH), 7.31–7.36 (m, 4H, ArH); 13C
NMR (100 MHz, CDCl3) d 4.4, 4.7, 6.7, 6.8, 20.2,
25.2, 25.8, 27.2, 33.0, 33.1, 37.5, 38.4, 52.8, 55.0, 62.5,
65.9, 68.9, 71.4, 72.8, 83.3, 113.6, 122.4, 127.3, 127.4,
128.1, 129.1, 129.4, 138.1, 150.4, 159.1, 200.4; FAB-
HRMS m/z calcd for C44H72O6S2Si2Na (MþþNa)
839.4207, found 839.4216; Anal. calcd for
C44H72O6S2Si2: C, 64.66; H, 8.88; S, 7.85, found: C,
64.59; H, 8.86; S, 7.97.
1
1456, 1416, 1248, 1096, 1011, 822, 741 cm21; H NMR
(500 MHz, CDCl3) d 0.57–0.63 (m, 12H, Si(CH2CH3)3£2),
0.93–0.97 (m, 18H, Si(CH2CH3)3£2), 1.44–1.55 (m, 4H,
C21–H2, C22–H2), 1.68–2.05 (m, 10H, C11–H2, C17–H2,
C18–H2, C20–H2, SCH2CH2), 2.58–2.88 (m, 6H, C14–
H2, SCH2£2), 3.04 (d, J¼3.5 Hz, 1H, OH), 3.53–3.65 (m,
4H, C10–H2, C23–H2), 3.79–3.85 (m, 5H, C12–H, C16–
H, C6H4OCH3), 4.07 (m, 1H, C13–H), 4.35–4.39 (m, 1H,
OCHAr), 4.50 (s, 2H, OCH2Ph), 4.56 (m, 1H, OCHAr), 6.87
(d, J¼8.5 Hz, 2H, ArH), 7.24–7.31 (m, 3H, ArH), 7.33–
7.35 (m, 4H, ArH); 13C NMR (125 MHz, CDCl3) d 4.3, 4.9,
6.7, 6.8, 20.2, 25.2, 25.77, 25.80, 26.4, 26.5, 32.9, 33.0,
33.3, 38.5, 40.3, 41.3, 52.9, 55.1, 62.5, 66.2, 66.5, 69.6,
70.4, 71.7, 72.0, 72.4, 72.9, 73.0, 83.8, 84.1, 113.7, 127.4,
127.56, 127.60, 128.20, 128.22, 129.4, 129.5, 138.0,
138.1, 159.3, 212.1, 212.5; FAB-HRMS m/z calcd for
C44H75O7S2Si2 (MþþH) 835.4493, found 835.4485; Anal.
calcd for C44H74O7S2Si2: C, 63.26; H, 8.93; S, 7.68, found:
C, 63.29; H, 8.91; S, 7.86.
4.1.19. (3S,7S)-9-Benzyloxy-3-(4-methoxybenzyl)oxy-7-
(triethylsilyl)oxy-1-{2-[4-(triethylsilyl)oxybutyl]-1,3-
dithian-2-yl}nonan-4-one (42). Stryker reagent (3.89 g,
1.98 mmol) was added to a solution of enone 41 (2.03 g,
2.48 mmol) in wet benzene (21 mL) at room temperature
under an argon atmosphere. After stirring of the dark brown
solution at room temperature for 10 h, the solvent was
removed in vacuo. The crude product (6.1 g) was purified by
column chromatography (silica gel 30 g, 20:1!8:1
n-hexane/AcOEt) to give ketone 42 (1.85 g, 91%) as a
colorless oil: [a]2D5¼216.4 (c 1.10, CHCl3); IR (neat) 2953,
2876, 1715, 1613, 1514, 1456, 1416, 1302, 1248, 1175,
1
4.1.18. (3S,7R)-9-Benzyloxy-3-(4-methoxybenzyl)oxy-7-
(triethylsilyl)oxy-1-{2-[4-(triethylsilyl)oxybutyl]-1,3-
dithian-2-yl}-5-nonen-4-one (41). Acetic anhydride
(0.52 mL, 5.56 mmol) was added to a stirred solution of
1098, 1038, 1011, 820, 741 cm21; H NMR (500 MHz,
CDCl3) d 0.56–0.61 (m, 12H, Si(CH2CH3)3£2), 0.92–0.97
(m, 18H, Si(CH2CH3)3£2), 1.44–1.55 (m, 4H, C21–H2,
C22–H2), 1.66–2.02 (m, 12H, C11–H2, C13–H2, C17–H2,

10368
S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
C18–H2, C20–H2, SCH2CH2), 2.58–2.83 (m, 6H, C14–
H2, SCH2£2), 3.49–3.56 (m, 2H, C10–H2), 3.58–3.61 (m,
2H, C23–H2), 3.77 (m, 1H, C16–H), 3.80 (s, 3H,
C6H4OCH3), 3.91 (m, 1H, C12–H), 4.37 (d, J¼11.4 Hz,
1H, OCHAr), 4.45–4.51 (m, 3H, OCHAr, OCH2Ph), 6.87
(d, J¼8.5 Hz, 2H, ArH), 7.25–7.30 (m, 3H, ArH), 7.32–
7.36 (m, 4H, ArH); 13C NMR (100 MHz, CDCl3) d 4.5, 5.0,
6.8, 6.9, 20.3, 25.3, 25.86, 25.91, 26.8, 30.5, 33.0, 33.1,
33.6, 37.0, 38.5, 52.9, 62.5, 66.9, 68.5, 71.8, 72.9, 83.9,
113.7, 127.3, 127.5, 128.1, 129.3, 129.4, 138.3, 159.2,
212.2; FAB-HRMS m/z calcd for C44H73O6S2Si2 (Mþ2H)
817.4387, found 817.4401; Anal. calcd for C44H74O6S2Si2:
C, 64.50; H, 9.10; S, 7.83, found: C, 64.74; H, 8.94; S,
7.82.
organic layer was washed successively with 0.1% aqueous
HCl (2£40 mL), H2O (10 mL), saturated aqueous NaHCO3
(2£10 mL) and brine (2£10 mL), and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the
crude product (818 mg, yellow oil), which was purified by
column chromatography (silica gel 10 g, 16:1 n-hexane/
AcOEt) to give silyl ether 44 (626.3 mg, 93%) as a colorless
oil: [a]2D4¼24.09 (c 2.25, CHCl3); IR (neat) 2953, 2876,
1613, 1514, 1460, 1416, 1372, 1250, 1096, 1007, 835, 774,
741 cm21 1H NMR (500 MHz, CDCl3) d 0.09 (s, 3H,
;
SiCH3), 0.10 (s, 3H, SiCH3), 0.56–0.61 (m, 12H, Si(CH2-
CH3)3£2), 0.87 (s, 9H, SiC(CH3)3), 0.92–0.97 (m, 18H,
Si(CH2CH3)3£2), 1.21 (s, 3H, C37–H3), 1.46–1.64 (m, 9H,
C13–H2, C14–H2, C17–H, C21–H2, C22–H2), 1.69–1.90
(m, 8H, C11–H2, C17–H, C18–H, C20–H2, SCH2CH2),
2.15 (m, 1H, C18–H), 2.67–2.78 (m, 4H, SCH2£2), 3.17
(dd, J¼2.0, 9.1 Hz, 1H, C16–H), 3.49–3.56 (m, 2H,
C10–H2), 3.57–3.60 (m, 2H, C23–H2), 3.78–3.79 (m,
4H, C12–H, C6H4OCH3), 4.43–4.52 (m, 3H, OCHAr,
OCH2Ph), 4.57 (d, J¼10.9 Hz, 1H, OCHAr), 6.85 (m, 2H,
ArH), 7.24–7.28 (m, 3H, ArH), 7.31–7.33 (m, 4H, ArH);
13C NMR (125 MHz, CDCl3) d 21.8, 21.7, 4.4, 5.1, 6.8,
6.9, 18.4, 20.4, 23.4, 25.3, 25.5, 25.88, 25.93, 26.1, 31.6,
33.1, 35.5, 36.6, 37.4, 38.3, 53.5, 55.2, 62.7, 67.1, 70.1,
72.9, 73.9, 78.2, 85.0, 113.6, 127.4, 127.6, 128.2, 128.9,
131.3, 138.5, 158.9; FAB-HRMS m/z calcd for
C51H91O6S2Si3 (Mþ2H) 947.5565, found 947.5565; Anal.
calcd for C51H92O6S2Si3: C, 64.50; H, 9.76; S, 6.75, found:
C, 64.48; H, 9.61; S, 6.71.
4.1.20. (3S,4R,7S)-9-Benzyloxy-3-(4-methoxybenzyl)oxy-
4-methyl-7-(triethylsilyl)oxy-1-{2-[4-(triethylsilyl)oxy-
butyl]-1,3-dithian-2-yl}nonan-4-ol (43). A solution of
ketone 42 (630.7 mg, 0.77 mmol) in Et2O (2 mL) was
added to a solution of MeMgI (prepared from MeI
(0.24 mL, 3.86 mmol) and magnesium tuning (93.4 mg,
3.84 mmol)) in Et2O (8 mL) at 2788C under an argon
atmosphere. After stirring at 2788C for 1 h, the reaction was
quenched with saturated aqueous NH4Cl (20 mL), and the
whole was extracted with AcOEt (50 mL). The organic
layer was washed with brine (20 mL), and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product, which was purified by column
chromatography (silica gel 10 g, 6:1 n-hexane/AcOEt) to
give alcohol 43 (611.6 mg, 95%) as a colorless oil:
[a]2D5¼þ1.25 (c 1.12, C6H6); IR (neat) 3486, 2953, 2876,
1613, 1514, 1456, 1416, 1372, 1248, 1094, 1011, 822,
4.1.22. 4-{2-[(3S,4R,7S)-9-Benzyloxy-4-(tert-butyldi-
methylsilyl)oxy-3-(4-methoxybenzyl)oxy-4-methyl-7-
(triethylsilyl)oxynonyl]-1,3-dithian-2-yl}butan-1-ol (45).
Bu4NF in THF (1.0 M, 7.76 mL, 7.76 mmol) was added to a
stirred solution of tris-silyl ether 44 (7.02 g, 7.39 mmol) in
THF (70 mL)–AcOH (7 mL) at 08C. After stirring at 08C
for 1 h, saturated aqueous NaHCO3 (20 mL) was added, and
the whole was extracted with AcOEt (2£150 mL). The
combined organic extracts were washed successively with
saturated aqueous NaHCO3 (2£40 mL), H2O (40 mL) and
brine (2£40 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo furnished the crude
product (7.1 g, colorless oil), which was purified by column
chromatography (silica gel 150 g, 6:1!4:1!1:2 n-hexane/
AcOEt) to give alcohol 45 (5.44 g, 88%) as a colorless oil,
along with diol (506.7 mg, 9%) as a colorless syrup:
[a]2D5¼26.02 (c 1.19, CHCl3); IR (neat) 3463, 2953, 2876,
1613, 1514, 1460, 1370, 1250, 1092, 1036, 835, 774,
1
739 cm21; H NMR (500 MHz, CDCl3) d 0.57–0.62 (m,
12H, Si(CH2CH3)3£2), 0.93–0.97 (m, 18H, Si(CH2-
CH3)3£2), 1.14 (s, 3H, C37–H3), 1.42–1.68 (m, 9H,
C13–H2, C14–H2, C17–H, C21–H2, C22–H2), 1.70–
1.91 (m, 8H, C11–H2, C17–H, C18–H, C20–H2,
SCH2CH2), 2.17 (m, 1H, C18–H), 2.26 (brs, 1H, OH),
2.70–2.80 (m, 4H, SCH2£2), 3.20 (dd, J¼3.0, 8.0 Hz, 1H,
C16–H), 3.51–3.55 (m, 2H, C10–H2), 3.59–3.62 (m, 2H,
C23–H2), 3.80 (s, 3H, C6H4OCH3), 3.86 (m, 1H, C12–H),
4.46 (d, J¼11.9 Hz, 1H, OCHPh), 4.50 (d, J¼11.9 Hz, 1H,
OCHPh), 4.55 (d, J¼11.0 Hz, 1H, OCHAr), 4.63 (d,
J¼11.0 Hz, 1H, OCHAr), 6.87 (d, J¼8.6 Hz, 2H, ArH),
7.26–7.33 (m, 7H, ArH); 13C NMR (100 MHz, CDCl3) d
4.4, 5.0, 6.8, 7.0, 20.5, 23.6, 25.4, 25.5, 25.9, 30.8, 32.2,
33.0, 35.3, 37.1, 38.2, 53.3, 55.1, 62.6, 66.9, 69.8, 72.8,
74.2, 74.8, 86.8, 113.6, 127.3, 127.4, 128.1, 129.1, 130.5,
138.3, 159.0; FAB-HRMS m/z calcd for C45H78O6S2Si2Na
(MþþNa) 857.4676, found 857.4702; Anal. calcd for
C45H78O6S2Si2: C, 64.70; H, 9.41; S, 7.68, found: C,
64.73; H, 9.24; S, 7.78.
741 cm21 1H NMR (500 MHz, CDCl3) d 0.09 (s, 3H,
;
SiCH3), 0.10 (s, 3H, SiCH3), 0.58 (q, J¼8.1 Hz, 6H,
Si(CH2CH3)3), 0.87 (s, 9H, SiC(CH3)3), 0.94 (t, J¼8.1 Hz,
9H, Si(CH2CH3)3), 1.22 (s, 3H, C37–H3), 1.46–1.62 (m,
10H, C13–H2, C14–H2, C17–H, C21–H2, C22–H2, OH),
1.69–1.90 (m, 8H, C11–H2, C17–H, C18–H, C20–H2,
SCH2CH2), 2.16 (m, 1H, C18–H), 2.67–2.79 (m, 4H,
SCH2£2), 3.16 (dd, J¼2.0, 9.2 Hz, 1H, C16–H), 3.50–3.56
(m, 2H, C10–H2), 3.59–3.61 (m, 2H, C23–H2), 3.79 (m,
4H, C12–H, C6H4OCH3), 4.44–4.50 (m, 3H, OCHAr,
OCH2Ph), 4.59 (d, J¼10.8 Hz, 1H, OCHAr), 6.84–6.87 (m,
2H, ArH), 7.24–7.30 (m, 3H, ArH), 7.31–7.33 (m, 4H,
ArH); 13C NMR (125 MHz, CDCl3) d 21.9, 21.8, 5.1, 6.9,
18.3, 20.2, 23.5, 25.2, 25.4, 25.85, 25.88, 26.1, 31.7, 32.7,
35.3, 36.6, 37.3, 38.1, 53.4, 55.2, 62.4, 67.1, 70.1, 72.9,
4.1.21. 2-[(3S,4R,7S)-9-Benzyloxy-4-(tert-butyldimethyl-
silyl)oxy-3-(4-methoxybenzyl)oxy-4-methyl-7-(triethyl-
silyl)oxynonyl]-2-[4-(triethylsilyl)oxybutyl]-1,3-dithiane
(44). TBSOTf (0.25 mL, 1.09 mmol) was added to a stirred
solution of alcohol 43 (590.6 mg, 0.707 mmol) and 2,6-
lutidine (0.41 mL, 3.54 mmol) in CH2Cl2 (5 mL) at 08C
under an argon atmosphere. After stirring at room
temperature for 4 h, the reaction was quenched with H2O
(10 mL), and the whole mixture was partitioned between
AcOEt (50 mL) and 0.1% aqueous HCl (40 mL). The

S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
10369
74.0, 78.2, 85.0, 113.6, 127.4, 127.6, 128.2, 128.9, 131.2,
138.4, 158.9; FAB-HRMS m/z calcd for C45H78O6S2Si2Na
(MþþNa) 857.4676, found 857.4689; Anal. calcd for
C45H78O6S2Si2: C, 64.70; H, 9.41; S, 7.68, found: C,
64.68; H, 9.54; S, 7.63.
(m, 9H, C11–H2, C18–H, C20–H2, C21–H2, SCH2CH2),
2.24 (m, 1H, C18–H), 2.19–2.22 (m, 5H, C22–H2, C26–
H3), 2.67–2.79 (m, 4H, SCH2£2), 3.17 (dd, J¼1.6, 8.7 Hz,
1H, C16–H), 3.51–3.56 (m, 2H, C10–H2), 3.78–3.79 (m,
4H, C12–H, C6H4OCH3), 4.46–4.50 (m, 3H, OCHAr,
OCH2Ph), 4.59 (d, J¼10.9 Hz, 1H, OCHAr), 6.09 (d,
J¼16.0 Hz, 1H, C24–H), 6.75 (m, 1H, C23–H), 6.85 (d,
J¼8.5 Hz, 2H, ArH), 7.23–7.26 (m, 3H, ArH), 7.32–7.33
(m, 4H, ArH); 13C NMR (100 MHz, CDCl3) d 21.9, 21.7,
5.0, 6.9, 18.3, 22.6, 23.3, 25.2, 25.3, 25.8, 26.0, 26.7, 31.6,
32.4, 35.4, 36.5, 37.3, 37.8, 53.1, 55.0, 66.9, 69.9, 72.8,
73.9, 78.0, 84.7, 113.4, 127.2, 127.4, 128.0, 128.7, 130.9,
131.4, 138.2, 147.2, 158.7, 198.0; FAB-HRMS m/z calcd for
C48H80O6S2Si2Na (MþþNa) 895.4832, found 895.4851;
Anal. calcd for C48H80O6S2Si2: C, 66.01; H, 9.23; S, 7.34,
found: C, 65.86; H, 9.30; S, 7.44.
4.1.23. 4-{2-[(3S,4R,7S)-9-Benzyloxy-4-(tert-butyldi-
methylsilyl)oxy-3-(4-methoxybenzyl)oxy-4-methyl-7-
(triethylsilyl)oxynonyl]-1,3-dithian-2-yl}butyraldehyde
(7). Sulfur trioxide pyridine complex (1.26 g, 7.94 mmol)
was added over 30 min to a stirred solution of alcohol 45
(2.21 g, 2.65 mmol) and Et3N (2.2 mL, 15.9 mmol) in
DMSO (25 mL) under an argon atmosphere. After stirring
at room temperature for 1 h, the mixture was diluted with
Et2O (30 mL), and poured into saturated aqueous NH4Cl
(50 mL) at 08C. The whole mixture was extracted with
AcOEt (2£80 mL). The combined organic extracts were
washed successively with 0.5 M aqueous NaHSO4
(2£30 mL), saturated aqueous NaHCO3 (30 mL) and brine
(2£30 mL), and dried over anhydrous Na2SO4. Filtration
and evaporation in vacuo furnished the crude product
(2.25 g, slightly yellow oil), which was purified by column
chromatography (silica gel 50 g, 10:1!8:1 n-hexane/
AcOEt) to give aldehyde 7 (2.07 g, 94%) as a colorless
oil: [a]2D5¼26.15 (c 1.04, CHCl3); IR (neat) 2953, 2878,
1726, 1613, 1514, 1458, 1370, 1250, 1094, 1007, 835, 774,
4.1.25. 1-[2-[(3S,4R,7S)-9-Benzyloxy-4-(tert-butyldi-
methylsilyl)oxy-3-hydroxy-4-methyl-7-(triethylsilyl)-
oxy]nonyl-1,3-dithian-2-yl]-4-hepten-6-one (47). To a
solution of MPM ether 46 (571.2 mg, 0.649 mmol) in
CH2Cl2 (10 mL)–pH 7 phosphate buffer (1 mL) was added
2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(176.9 mg,
0.779 mmol) at room temperature. After stirring for
20 min, saturated aqueous NaHCO3 (10 mL) was added,
and the whole was extracted with AcOEt (2£50 mL). The
combined organic extracts were washed successively with
saturated aqueous NaHCO3 (2£20 mL), H2O (20 mL) and
brine (2£20 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo furnished the crude
product, which was purified by column chromatography
(silica gel 30 g, 4:1 n-hexane/Et2O) to give alcohol 47
(459.4 mg, 94%) as a colorless oil: [a]2D1¼27.81 (c 2.01,
CHCl3); IR (neat) 3480, 2953, 2878, 1676, 1628, 1456,
741 cm21 1H NMR (500 MHz, CDCl3) d 0.09 (s, 3H,
;
SiCH3), 0.10 (s, 3H, SiCH3), 0.58 (q, J¼8.0 Hz, 6H,
Si(CH2CH3)3), 0.86 (s, 9H, SiC(CH3)3), 0.94 (t, J¼8.0 Hz,
9H, Si(CH2CH3)3), 1.22 (s, 3H, C37–H3), 1.53–1.64 (m,
5H, C13–H2, C14–H2, C17–H), 1.69–1.91 (m, 10H, C11–
H2, C17–H, C18–H, C20–H2, C21–H2, SCH2CH2), 2.12
(m, 1H, C18–H), 2.40–2.43 (m, 2H, C22–H2), 2.73–2.75
(m, 4H, SCH2£2), 3.17 (m, 1H, C16–H), 3.49–3.58 (m, 2H,
C10–H2), 3.78 (m, 4H, C12–H, C6H4OCH3), 4.44–4.50
(m, 3H, OCHAr, OCH2Ph), 4.59 (d, J¼10.9 Hz, 1H,
OCHAr), 6.84–6.86 (m, 2H, ArH), 7.24–7.29 (m, 3H,
ArH), 7.31–7.33 (m, 4H, ArH), 9.73 (t, J¼1.3 Hz, 1H,
CHO); 13C NMR (125 MHz, CDCl3) d 21.8, 21.7, 5.1, 6.9,
17.0, 18.4, 23.4, 25.2, 25.3, 25.9, 26.1, 31.7, 35.6, 36.6,
37.4, 37.6, 43.6, 53.2, 55.2, 67.1, 70.1, 72.9, 74.0, 78.3,
84.9, 113.6, 127.4, 127.6, 128.2, 128.9, 131.2, 138.5, 159.0,
201.7; FAB-HRMS m/z calcd for C45H76O6S2Si2Na
(MþþNa) 855.4519, found 855.4564; Anal. calcd for
C45H76O6S2Si2: C, 64.85; H, 9.19; S, 7.70, found: C,
64.69; H, 9.00; S, 7.63.
1
1418, 1362, 1254, 1091, 1007, 835, 774, 741 cm21; H
NMR (500 MHz, CDCl3) d 0.11 (s, 3H, SiCH3), 0.12 (s, 3H,
SiCH3), 0.59 (q, J¼7.9 Hz, 6H, Si(CH2CH3)3), 0.87 (s, 9H,
SiC(CH3)3), 0.95 (t, J¼7.9 Hz, 9H, Si(CH2CH3)3), 1.21 (s,
3H, C37–H3), 1.39–1.48 (m, 3H, C13–H, C17–H2), 1.54–
1.73 (m, 5H, C13–H, C14–H2, C21–H2), 1.75–1.78 (m,
2H, C11–H2), 1.88–2.00 (m, 5H, C18–H, C20–H2,
SCH2CH2), 2.21–2.26 (m, 5H, C22–H2, C26–H3), 2.31
(m, 1H, C18–H), 2.44 (d, J¼4.8 Hz, 1H, OH), 2.72–2.77
(m, 2H, SCH2), 2.83–2.89 (m, 2H, SCH2), 3.30 (m, 1H,
C16–H), 3.52–3.55 (m, 2H, C10–H2), 3.83 (m, 1H, C12–
H), 4.47 (m, J¼11.9 Hz, 1H, OCHPh), 4.50 (m, J¼11.9 Hz,
1H, OCHPh), 6.09 (dd, J¼16.0 Hz, 1H, C24–H), 6.78 (m,
1H, C23–H), 7.28 (m, 1H, ArH), 7.32–7.36 (m, 4H, ArH);
13C NMR (100 MHz, CDCl3) d 22.23, 22.18, 4.9, 6.8,
18.1, 22.5, 23.6, 25.2, 25.6, 25.7, 26.6, 31.1, 32.3, 33.3,
35.3, 36.8, 37.9, 52.9, 66.7, 69.7, 72.8, 78.2, 127.3, 127.4,
128.1, 131.4, 138.2, 147.2, 198.0; FAB-HRMS m/z calcd for
C40H72O5S2Si2Na (MþþNa) 775.4257, found 775.4194;
Anal. calcd for C40H72O5S2Si2: C, 63.78; H, 9.63; S, 8.51,
found: C, 63.69; H, 9.51; S, 8.64.
4.1.24. 1-[2-[(3S,4R,7S)-9-Benzyloxy-4-(tert-butyldi-
methylsilyl)oxy-3-(4-methoxybenzyl)oxy-4-methyl-7-
(triethylsilyl)oxy]nonyl-1,3-dithian-2-yl]-4-hepten-6-one
(46). To a solution of aldehyde 7 (592.2 mg, 0.71 mmol) in
benzene (10 mL) was added 1-triphenylphosphoranylidene-
2-propanone (407.0 mg, 1.28 mmol), and the mixture was
refluxed for 10 h. After cooling, the solvent was removed in
vacuo, and the residue (1.42 g, yellow solid) was purified by
column chromatography (silica gel 20 g, 8:1 n-hexane/
AcOEt) to give enone 46 (611.2 mg, 98%) as a colorless oil:
[a]2D1¼25.89 (c 2.04, CHCl3); IR (neat) 3485, 2953, 1678,
4.1.26. 1-[2-[(4R,7S)-9-Benzyl-4-(tert-butyldimethyl-
silyl)oxy-4-methyl-3-oxo-7-(triethylsilyl)oxy]nonyl-1,3-
dithian-2-yl]-4-hepten-6-one (48). Dess–Martin periodi-
nane (338.2 mg, 0.797 mmol) was added over 10 min to a
solution of alcohol 47 (241.0 mg, 0.319 mmol) in CH2Cl2
(100 mL)–pyridine (5 mL) at 08C under an argon atmos-
phere. After stirring at 08C for 1 h, the reaction was
1
1615, 1514, 1460, 1362, 1252, 1094, 835, 741 cm21; H
NMR (500 MHz, CDCl3) d 0.09 (s, 6H, Si(CH3)2), 0.58 (q,
J¼7.9 Hz, 6H, Si(CH2CH3)3), 0.86 (s, 9H, SiC(CH3)3), 0.94
(t, J¼7.9 Hz, 9H, Si(CH2CH3)3), 1.22 (s, 3H, C37–H3),
1.56–1.65 (m, 6H, C13–H2, C14–H2, C17–H2), 1.72–1.90

10370
S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
quenched with saturated aqueous NaHCO3 (25 mL) and
1 M Na2S2O3 (25 mL), and the whole was extracted with
Et2O (2£80 mL). The combined organic extracts were
washed with brine (2£40 mL), and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the
crude product (272.0 mg, yellow oil), which was purified by
column chromatography (silica gel 15 g, 8:1 n-hexane/
AcOEt) to give ketone 48 (230.2 mg, 96%) as a colorless
oil: [a]2D2¼þ10.3 (c 2.27, CHCl3); IR (neat) 2953, 2878,
1715, 1678, 1628, 1456, 1418, 1362, 1254, 1096, 1007, 835,
775, 741 cm21; 1H NMR (500 MHz, CDCl3) d 0.13 (s, 6H,
Si(CH3)2), 0.57 (q, J¼8.0 Hz, 6H, Si(CH2CH3)3),
0.92–0.95 (m, 18H, Si(CH2CH3)3, SiC(CH3)3), 1.24 (m,
1H, C13–H), 1.33 (s, 3H, C37–H3), 1.50–1.80 (m, 9H,
C11–H2, C13–H, C14–H2, C20–H2, C21–H2), 1.86–1.97
(m, 2H, SCH2CH2), 2.14–2.24 (m, 7H, C18–H2, C22–H2,
C26–H3), 2.68–2.78 (m, 3H, C17–H, SCH2), 2.80–2.90
(m, 3H, C17–H, SCH2), 3.47–3.55 (m, 2H, C10–H2), 3.79
(m, 1H, C12–H), 4.45 (d, J¼11.9 Hz, 1H, OCHPh), 4.49 (d,
J¼11.9 Hz, 1H, OCHPh), 6.09 (d, J¼15.8 Hz, 1H, C24–H),
6.77 (m, 1H, C23–H), 7.28 (m, 1H, ArH), 7.32–7.34
(m, 4H, ArH); 13C NMR (100 MHz, CDCl3) d 22.4, 22.3,
4.8, 6.8, 18.2, 22.5, 25.0, 25.7, 25.8, 26.6, 31.0, 31.5, 32.3,
33.3, 36.8, 36.9, 38.7, 52.5, 66.7, 68.9, 72.8, 82.5, 127.3,
127.4, 128.1, 131.5, 138.2, 147.0, 198.0, 214.6; FAB-
HRMS m/z calcd for C40H70O5S2Si2Na (MþþNa)
25.8, 26.0, 26.7, 31.3, 31.5, 32.2, 35.7, 36.7, 36.9, 41.6,
66.8, 69.0, 72.8, 82.5, 127.3, 127.4, 128.1, 131.5, 138.3,
147.1, 198.2, 208.3, 214.3; FAB-HRMS m/z calcd for
C37H64O6Si2Na (MþþNa) 683.4139, found 683.4113;
Anal. calcd for C37H64O6Si2: C, 67.22; H, 9.74, found: C,
67.10; H, 9.84.
4.1.28. Double hemiketal formation/intramolecular
hetero-Michael addition. To a solution of TES ether 19
(100.6 mg, 0.15 mmol) in THF (1 mL) at 08C was added 1N
aqueous HCl (0.1 mL). After stirring at 08C for 1 h, the
reaction was quenched with saturated aqueous NaHCO3
(3 mL), and the mixture was partitioned between AcOEt
(20 mL) and H2O (5 mL). The organic extract was washed
with brine (2£10 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo furnished the crude
product, which was used without further purification.
NaOMe (1 M in MeOH, 0.15 mL, 0.15 mmol) was added to
a stirred solution of the equilibrium mixture in THF
(1.5 mL) at 08C under an argon atmosphere. After stirring
at 08C for 1 h, the reaction was quenched by addition of
saturated aqueous NH4Cl (5 mL), and the whole was
extracted with AcOEt (2£20 mL). The combined organic
extracts were washed with brine (10 mL), and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product (93.5 mg), which was purified
by column chromatography (silica gel 5 g, 12:1!8:1
n-hexane/AcOEt) to give a mixture of dispiroketals
(75.6 mg, 91%, 20/52/53/54¼77:8:10:5) as a colorless oil.
The ratio of isomers was determined by HPLC analysis
(column, Zorbaxw sil, 4.6£250 mm; eluent, 10:1 n-hexane/
AcOEt; flow rate, 1.0 mL/min; detection, 254 nm, tR
(53)¼11.6 min, tR (20)¼22.3 min, tR (52)¼34.5 min, tR
(54)¼38.4 min). The isomers could be readily separated by
column chromatography (silica gel 20 g, 12:1!8:1
n-hexane/AcOEt) to afford 20 (53.3 mg, 64%), along with
isomers 52 (5.8 mg, 7%), 53 (7.3 mg, 9%) and 54 (3.6 mg,
4%).
773.4101,
found
773.4061;
Anal.
calcd
for
C40H70O5S2Si2: C, 63.95; H, 9.39; S, 8.54, found: C,
63.75; H, 9.42; S, 8.66.
4.1.27. (3E,12R,15S)-17-Benzyloxy-12-(tert-butyldi-
methylsilyl)oxy-8,11-dioxo-12-methyl-15-(triethylsilyl)-
oxy-3-heptadecen-2-one (19). A solution of dithioacetal 48
(258.0 mg, 0.343 mmol) in Et2O (3 mL) was added to a
solution of AgNO3 (350 mg, 2.06 mmol), N-chlorosuccini-
mide (297.7 mg, 2.23 mmol) and 2,4,6-collidine (0.4 mL) in
80% aqueous CH3CN (10 mL) at room temperature. After
stirring for 20 min, saturated aqueous Na2SO3 (5 mL),
saturated aqueous NaHCO3 (5 mL) and brine (5 mL) were
added. The mixture was filtered through a Celite pad and the
filtrate was extracted with AcOEt (2£50 mL). The com-
bined organic extracts were washed successively with 0.3%
aqueous HCl (5£30 mL), H2O (30 mL), saturated aqueous
NaHCO3 (30 mL) and brine (30 mL), and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product (280.4 mg), which was
purified by column chromatography (silica gel 15 g, 4:1
n-hexane/AcOEt) to give triketone 19 (209.9 mg, 93%) as a
colorless oil: [a]2D5¼þ9.33 (c 1.07, CHCl3); IR (neat) 2955,
2878, 1715, 1678, 1630, 1454, 1362, 1254, 1094, 1007, 835,
775, 737 cm21; 1H NMR (500 MHz, CDCl3) d 0.11 (s, 6H,
Si(CH3)2), 0.55 (q, J¼7.5 Hz, 6H, Si(CH2CH3)3),
0.90–0.94 (m, 18H, Si(CH2CH3)3, SiC(CH3)3), 1.23 (m,
1H, C13–H), 1.31 (s, 3H, C37–H3), 1.49–1.61 (m, 2H,
C13–H, C14–H), 1.67–1.78 (m, 5H, C11–H2, C14–H,
C21–H2), 2.18–2.22 (m, 5H, C22–H2, C26–H3),
2.47–2.50 (m, 2H, C20–H2), 2.53–2.57 (m, 2H,
C18–H2), 2.79 (m, 1H, C17–H), 2.92 (m, 1H, C17–H),
3.48–3.52 (m, 2H, C10–H2), 3.77 (m, 1H, C12–H), 4.43
(d, J¼11.2 Hz, 1H, OCHPh), 4.47 (d, J¼11.2 Hz, 1H,
OCHPh), 6.05 (d, J¼16.2 Hz, 1H, C24–H), 6.73 (m, 1H,
C23–H), 7.25 (m, 1H, ArH), 7.30–7.31 (m, 4H, ArH); 13C
NMR (125 MHz, CDCl3) d 22.4, 22.3, 4.8, 6.8, 18.2, 21.7,
4.1.29. 1-[(2R,6R,8R,10S,13R)-10-(2-Benzyloxy)ethyl-13-
(tert-butyldimethylsilyloxy)-13-methyl-1,7,9-trioxadi-
spiro[5.1.5.2]pentadec-2-yl]-2-propanone (20). [a]2D3¼
24.70 (c 1.02, CHCl3); IR (neat) 2953, 2857, 1717, 1456,
1
1364, 1252, 1225, 1103, 1042, 870, 774, 698 cm21; H
NMR (500 MHz, CDCl3) d 0.07 (s, 3H, SiCH3), 0.09 (s, 3H,
SiCH3), 0.85 (s, 9H, SiC(CH3)3), 1.17 (m, 1H, C22–H),
1.29 (s, 3H, C37–H3), 1.40–1.49 (m, 2H, C13–H, C20–H),
1.58–1.87 (m, 9H, C11–H2, C13–H, C14–H, C17–H,
C18–H, C20–H, C21–H, C22–H), 1.91 (m, 1H, C21–H),
2.04 (m, 1H, C18–H), 2.09–2.19 (m, 5H, C14–H, C17–H,
C26–H3), 2.41 (dd, J¼6.9, 15.2 Hz, 1H, C24–H), 2.56 (dd,
J¼6.1, 15.2 Hz, 1H, C24–H), 3.51 (m, 1H, C10–H), 3.59
(m, 1H, C10–H), 3.94 (m, 1H, C12–H), 4.28 (m, 1H, C23–
H), 4.48 (s, 2H, OCH2Ph), 7.26 (m, 1H, ArH), 7.32–7.33
(m, 4H, ArH); 13C NMR (125 MHz, CDCl3) d 21.93,
21.91, 18.0, 19.4, 24.4, 25.9, 30.1, 30.6, 30.8, 31.3,
34.1, 34.3, 35.9, 37.5, 50.3, 67.6, 67.9, 69.2, 72.7, 73.5,
107.9, 110.5, 127.3, 127.5, 128.3, 138.7, 207.6; TLC
Rf¼0.51 (3:1 n-hexane/AcOEt); FAB-HRMS m/z calcd for
C31H50O6SiNa (MþþNa) 569.3274, found 569.3267; Anal.
calcd for C31H50O6Si: C, 68.09; H, 9.22, found: C, 68.22; H,
9.17.

S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
10371
4.1.30. 1-[(2S,6S,8S,10S,13R)-10-(2-Benzyloxy)ethyl-13-
(tert-butyldimethylsilyloxy)-13-methyl-1,7,9-trioxadi-
spiro[5.1.5.2]pentadec-2-yl]-2-propanone (52). [a]2D9¼
þ38.6 (c 1.06, CHCl3); IR (neat) 2930, 2857, 1715, 1456,
(3:1 n-hexane/AcOEt); FAB-HRMS m/z calcd for C31H50-
O6SiNa (MþþNa) 569.3274, found 569.3299.
4.1.33. 1-[(2R,6R,8R,10S,13R)-10-(2-Benzyloxyethyl)-13-
hydroxy-13-(tert-butyldimethylsilyl)oxy-1,7,9-trioxadi-
spiro[5.1.5.2]pentadec-2-yl]-2-propanol (55). A solution
of ketone 20 (50.5 mg, 0.092 mmol) in CH2Cl2 (8 mL) was
added to a solution of NaBH4 (7.0 mg, 0.18 mmol) in
MeOH (2 mL) at 08C. After stirring at 08C for 2 h, the
mixture was poured into saturated aqueous NH4Cl (4 mL),
and the whole was extracted with AcOEt (2£15 mL). The
combined organic extracts were washed with brine (10 mL),
and dried over anhydrous Na2SO4. Filtration and evapor-
ation in vacuo furnished the crude product, which was
purified by column chromatography (silica gel 5 g, 8:1
n-hexane/AcOEt) to give alcohol 55 (47.0 mg, 93%) as a
colorless oil: [a]2D2¼26.27 (c 1.11, CHCl3); IR (neat) 3520,
2934, 2859, 1456, 1370, 1252, 1225, 1175, 1140, 1036, 970,
870, 835, 774 cm21; 1H NMR (500 MHz, CHCl3) d 0.08 (s,
3H, SiCH3), 0.09 (s, 3H, SiCH3), 0.85 (s, 9H, SiC(CH3)3),
1.09 (d, J¼6.2 Hz, 1.5H, C26–H3), 1.11 (d, J¼6.2 Hz,
1.5H, C26–H3), 1.22–1.30 (m, 4H, C22–H, C37–H3), 1.35
(m, 1H, C13–H), 1.46–2.09 (m, 14H, C11–H2, C13–H,
C14–H, C17–H, C18–H2, C20–H2, C21–H2, C22–H,
C24–H2), 2.12–2.22 (m, 2H, C14–H, C17–H), 3.47–3.64
(m, 2.5H, C10–H, OH), 3.82 (brs, 0.5H, OH), 3.98–4.23
(m, 3H, C12–H, C23–H, C25–H), 4.49 (s, 1H, OCHPh),
4.51 (s, 1H, OCHPh), 7.29 (m, 1H, ArH), 7.33–7.35 (m, 4H,
ArH); 13C NMR (125 MHz, CDCl3) d 21.93, 21.92, 18.0,
19.5, 19.7, 23.4, 24.0, 24.37, 24.40, 25.9, 29.5, 29.6, 30.69,
30.73, 30.8, 31.4, 33.8, 33.9, 34.1, 34.4, 35.6, 35.8, 37.6,
37.8, 44.5, 44.8, 63.5, 66.8, 67.2, 67.7, 67.8, 68.5, 69.8,
72.7, 72.8, 73.6, 73.7, 107.7, 107.8, 110.4, 110.9, 127.3,
127.4, 127.5, 127.8, 128.2, 128.3, 138.2, 138.7; FAB-
HRMS m/z calcd for C31H52O6SiNa (MþþNa) 571.3431,
found 571.3408.
1
1362, 1252, 1176, 1138, 1098, 1049, 835, 774 cm21; H
NMR (500 MHz, CDCl3) d 0.08 (s, 3H, SiCH3), 0.09 (s, 3H,
SiCH3), 0.86 (s, 9H, SiC(CH3)3), 1.21 (m, 1H, C22–H),
1.35–1.43 (m, 4H, C13–H, C37–H3), 1.49–1.55 (m, 2H,
C13–H, C20–H), 1.63–1.73 (m, 5H, C11–H, C14–H,
C20–H, C21–H, C22–H), 1.75–1.81 (m, 2H, C11–H,
C14–H), 1.84–1.98 (m, 3H, C17–H, C18–H, C21–H),
2.02 (m, 1H, C17–H), 2.19 (s, 3H, C26–H3), 2.29 (ddd,
J¼7.1, 8.9, 12.5 Hz, 1H, C18–H), 2.42 (dd, J¼5.7, 14.6 Hz,
1H, C24–H), 2.47 (dd, J¼7.6, 14.6 Hz, 1H, C24–H), 3.50–
3.58 (m, 2H, C10–H2), 3.62 (m, 1H, C12–H), 4.35 (m, 1H,
C23–H), 4.49 (s, 2H, OCH2Ph), 7.27 (m, 1H, ArH), 7.33–
7.34 (m, 4H, ArH); 13C NMR (125 MHz, C6D6) d -1.7,
18.4, 20.3, 21.7, 26.2, 28.6, 29.9, 30.2, 31.2, 34.1,
36.4, 37.8, 38.6, 51.1, 67.2, 68.3, 70.8, 73.2, 75.2, 107.1,
112.5, 127.6, 127.8, 128.6, 139.5, 205.4; TLC Rf¼0.45
(3:1 n-hexane/ AcOEt); FAB-HRMS m/z calcd for
C31H50O6SiNa (MþþNa) 569.3274, found 569.3278;
Anal. calcd for C31H50O6Si: C, 68.09; H, 9.22, found: C,
68.06; H, 9.19.
4.1.31. 1-[(2S,6S,8R,10S,13R)-10-(2-Benzyloxy)ethyl-13-
(tert-butyldimethylsilyloxy)-13-methyl-1,7,9-trioxadi-
spiro[5.1.5.2]pentadec-2-yl]-2-propanone (53). [a]2D4¼
þ28.5 (c 0.45, CHCl3); IR (neat) 2949, 2857, 1721, 1454,
1
1362, 1252, 1184, 1146, 1049, 868, 835, 773 cm21; H
NMR (500 MHz, CDCl3) d 0.07 (s, 3H, SiCH3), 0.10 (s, 3H,
SiCH3), 0.86 (s, 9H, SiC(CH3)3), 1.09 (m, 1H, C22–H),
1.30 (s, 3H, C37–H3), 1.43 (m, 1H, C13–H), 1.50–1.65 (m,
6H, C13–H, C14–H, C18–H, C20–H2, C21–H), 1.66–
1.76 (m, 3H, C11–H2, C22–H), 1.84–2.00 (m, 3H, C17–H,
C18–H, C21–H), 2.12 (m, 3H, C26–H3), 2.19 (m, 1H,
C14–H), 2.27 (m, 1H, C17–H), 2.53 (dd, J¼9.3, 16.2 Hz,
1H, C24–H), 2.62 (dd, J¼3.3, 16.2 Hz, 1H, C24–H), 3.49–
3.57 (m, 2H, C10–H2), 3.97 (m, 1H, C12–H), 4.28 (m, 1H,
C23–H), 4.43 (d, J¼11.8 Hz, 1H, OCHPh), 4.48 (d,
J¼11.8 Hz, 1H, OCHPh), 7.28 (m, 1H, ArH), 7.30–7.35
(m, 4H, ArH); 13C NMR (125 MHz, CDCl3) d 22.0, 18.1,
20.0, 24.6, 25.9, 29.3, 30.5, 30.6, 31.0, 34.4, 36.1, 36.2,
37.0, 50.5, 66.2, 67.1, 67.5, 72.8, 72.9, 107.5, 110.6, 127.5,
127.6, 128.3, 138.5, 207.0; TLC Rf¼0.59 (3:1 n-hexane/
AcOEt); FAB-HRMS m/z calcd for C31H50O6SiNa
(MþþNa) 569.3274, found 569.3256; Anal. calcd for
C31H50O6Si: C, 68.09; H, 9.22, found: C, 68.17; H, 9.19.
4.1.34. 1-[(2R,6R,8R,10S,13R)-10-(2-Benzyloxyethyl)-13-
hydroxy-13-methyl-1,7,9-trioxadispiro[5.1.5.2]penta-
dec-2-yl]-2-propanol (56). Bu4NF in THF (1 M, 0.55 mL,
0.55 mmol) was added to a solution of TBS ether 55
(60.3 mg, 0.11 mmol) in THF (1 mL), and the mixture was
refluxed for 12 h. The reaction was quenched with saturated
aqueous NH4Cl (3 mL), and the whole was extracted with
AcOEt (2£10 mL). The combined organic extracts were
washed successively with water (5 mL) and brine (5 mL),
and dried over anhydrous Na2SO4. Filtration and concen-
tration in vacuo furnished the crude product, which was
purified by column chromatography (silica gel 8 g, 2:1
n-hexane/AcOEt) to give alcohol 56 (43.2 mg, 91%) as a
colorless oil: [a]2D4¼26.93 (c 0.75, CHCl3); IR (neat) 3505,
4.1.32. 1-[(2S,6R,8R,10S,13R)-10-(2-Benzyloxy)ethyl-13-
(tert-butyldimethylsilyloxy)-13-methyl-1,7,9-trioxadi-
spiro[5.1.5.2]pentadec-2-yl]-2-propanone (54). [a]2D1¼
þ33.7 (c 0.49, CHCl3); IR (neat) 2928, 2855, 1721, 1462,
2938, 2868, 1454, 1227, 1086, 1028, 968, 868, 737 cm21
;
1H NMR (500 MHz, CHCl3) d 1.09–1.11 (m, 3H, C26–
H3), 1.22 (s, 1.5H, C37–H3), 1.24 (s, 1.5H, C37–H3), 1.30
(m, 1H, C22–H), 1.45–2.05 (m, 16H, C11–H2, C13–H2,
C14–H2, C17–H, C18–H, C20–H2, C21–H2, C22–H,
C24–H2, OH), 2.10–2.24 (m, 2H, C17–H, C18–H), 3.44–
3.62 (m, 3H, C10–H2, OH), 3.96–4.23 (m, 3H, C12–H,
C23–H, C25–H), 4.50 (s, 1H, OCHPh), 4.52 (s, 1H,
OCHPh), 7.28 (m, 1H, ArH), 7.32–7.35 (m, 4H, ArH); 13C
NMR (125 MHz, CHCl3) d 19.5, 19.8, 21.0, 21.2, 23.4,
24.2, 29.5, 29.7, 30.70, 30.74, 30.8, 31.2, 34.4, 34.7, 35.4,
35.6, 35.7, 35.8, 37.6, 37.9, 44.6, 44.7, 63.2, 66.5, 67.1,
1
1370, 1256, 1041, 835, 774 cm21; H NMR (500 MHz,
CDCl3) d 0.07 (s, 6H, SiCH3), 0.84 (s, 9H, SiC(CH3)3),
1.26–1.28 (m, 4H, C22–H, C37–H3), 1.45 (m, 1H, C13–
H), 1.53–1.83 (m, 11H, C11–H, C13–H, C14–H, C17–H,
C18–H, C20–H, C21–H, C22–H), 2.01–2.21 (m, 6H,
C14–H, C17–H, C18–H, C26–H3), 2.43 (dd, J¼5.4,
16.0 Hz, 1H, C24–H), 2.68 (dd, J¼7.3, 16.0 Hz, 1H,
C24–H), 3.50–3.58 (m, 2H, C10–H2), 3.91 (m, 1H,
C23–H), 4.00 (m, 1H, C12–H), 4.48 (s, 2H, OCH2Ph),
7.26 (m, 1H, ArH), 7.32–7.33 (m, 4H, ArH); TLC Rf¼0.43

10372
S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
67.7, 67.9, 69.0, 69.7, 69.9, 70.0, 72.8, 72.9, 73.9, 107.8,
108.0, 110.6, 111.2, 127.4, 127.5, 127.7, 127.9, 128.2,
128.3, 137.9, 138.6; FAB-HRMS m/z calcd for C25H39O6
(MþþH) 435.2747, found 435.2725.
4.1.37. 1-[(2R,6R,8R,10S,13R)-13-Hydroxy-10-(2-hydro-
xy)ethyl-13-methyl-1,7,9-trioxadispiro[5.1.5.2]pentadec-
2-yl]-2-propanone Semicarbazone (59). A solution of
semicarbazide hydrochloride (23.7 mg, 0.21 mmol) and
sodium acetate (24.5 mg, 0.42 mmol) in H2O (0.1 mL)
was added to a stirred solution of ketone 58 (14.6 mg,
42.63 mmol) in EtOH (0.5 mL) at room temperature. After
stirring for 8 h, the mixture was partitioned between Et2O
(2 mL) and H2O (2 mL), and the aqueous layer was
extracted with AcOEt (2£10 mL). The combined organic
extracts were washed with brine (5 mL), and dried over
anhydrous Na2SO4. Filtration and concentration in vacuo
furnished the crude product, which was purified by column
chromatography (silica gel 5 g, 20:1!10:1 CH2Cl2/MeOH)
to give semicarbazone 59 (16.6 mg, 98%) as a white solid.
The isomers could be separated by column chromatography
(silica gel 5 g, 1:4 acetone/AcOEt) to afford anti 59 (8.8 mg,
52%), along with syn 59 (5.7 mg, 33%): data for anti
isomer; mp 139–1408C (hexane/Et2O); IR (nujol) 3478,
3345, 2942, 1682, 1580, 1441, 1379, 1227, 1136, 1020, 868,
4.1.35. 1-[(2R,6R,8R,10S,13R)-10-(2-Benzyloxyethyl)-13-
hydroxy-13-methyl-1,7,9-trioxadispiro[5.1.5.2]penta-
dec-2-yl]-2-propanone (57). Sulfur trioxide pyridine
complex (46.3 mg, 0.291 mmol) was added to a solution
of alcohol 56 (42.2 mg, 97.1 mmol) and Et3N (0.1 mL,
0.71 mmol) in DMSO (3 mL) under an argon atmosphere.
After stirring for 2 h, saturated aqueous NH4Cl (2 mL) was
added, and the resulting mixture was partitioned between
water (5 mL) and AcOEt (15 mL). The aqueous layer was
extracted with AcOEt (5 mL), and the combined organic
extracts were washed with brine (5 mL), and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product (43.5 mg, slightly yellow oil),
which was purified by column chromatography (silica gel
5 g, 6:1!4:1 n-hexane/AcOEt) to give ketone 57 (37.6 mg,
90%) as a colorless oil: [a]2D3¼26.69 (c 1.21, CHCl3); IR
(neat) 3571, 2940, 2866, 1715, 1454, 1362, 1076, 1001, 953,
1
756 cm21; H NMR (500 MHz, CDCl3) d 1.24–1.31 (m,
4H, C22–H, C37–H3), 1.47–1.59 (m, 2H, C13–H,
C20–H), 1.60–1.95 (m, 11H, C11–H2, C13–H, C14–H2,
C17–H, C18–H, C20–H, C21–H2, C22–H), 1.90 (s, 3H,
C26–H3), 2.10–2.23 (m, 2H, C17–H, C18–H), 2.41
(dd, J¼6.2, 14.0 Hz, 1H, C24–H), 2.49 (dd, J¼5.8,
14.0 Hz, 1H, C24–H), 2.63 (s, 1H, OH), 2.89 (brs, 1H,
OH), 3.64 (m, 1H, C10–H), 3.77 (m, 1H, C10–H), 3.99 (m,
1H, C12–H), 4.14 (m, 1H, C23–H), 7.90 (s, 1H, NH); FAB-
HRMS m/z calcd for C19H34N3O6 (MþþH) 400.2448, found
400.2422.
1
868, 739, 698 cm21; H NMR (500 MHz, CDCl3) d 1.19–
1.21 (m, 4H, C22–H, C37–H3), 1.45–1.55 (m, 2H, C13–H,
C20–H), 1.62–1.75 (m, 6H, C11–H, C13–H, C14–H,
C20–H, C21–H, C22–H), 1.77–1.90 (m, 6H, OH, C11–H,
C14–H, C17–H, C18–H, C21–H), 2.09 (s, 3H, C26–H3),
2.11–2.19 (m, 2H, C17–H, C18–H), 2.42 (dd, J¼6.6,
15.3 Hz, 1H, C24–H), 2.58 (dd, J¼6.2, 15.3 Hz, 1H,
C24–H), 3.53 (m, 1H, C10–H), 3.59 (m, 1H, C10–H),
3.88 (m, 1H, C12–H), 4.29 (m, 1H, C23–H), 4.49 (s, 2H,
OCH2Ph), 7.27 (m, 1H, ArH), 7.32–7.33 (m, 4H, ArH); 13
C
NMR (125 MHz, CDCl3) d 19.4, 21.0, 30.2, 30.6, 30.7,
31.3, 34.5, 35.7, 35.9, 37.5, 50.1, 67.4, 68.4, 69.5, 69.7,
108.1, 110.7, 127.4, 127.5, 128.3, 138.7, 207.3; FAB-
HRMS m/z calcd for C25H37O6 (MþþH) 433.2590, found
433.2583.
4.1.38. Typical procedure for the double hemiketal
formation/intramolecular hetero-Michael addition
(Table 1, entry 3). To a solution of TES ether 19
(20.0 mg, 30 mmol) in THF (0.3 mL) at 08C was added
1N aqueous HCl (0.03 mL). After stirring at 08C for 1 h, the
reaction was quenched with saturated aqueous NaHCO3
(1 mL), and the mixture was poured into a two-layer
mixture of Et2O (5 mL) and H2O (5 mL). The whole was
extracted with AcOEt (2£10 mL), and the combined
organic extracts were washed with brine (2£5 mL), and
dried over anhydrous Na2SO4. Filtration and evaporation in
vacuo furnished the crude product, which was used without
further purification.
4.1.36. 1-[(2R,6R,8R,10S,13R)-13-Hydroxy-10-(2-hydroxy-
ethyl)-13-methyl-1,7,9-trioxadispiro[5.1.5.2]pentadec-2-
yl]-2-propanone (58). Palladium hydroxide on carbon
(20%, 5.6 mg) was added to a solution of benzyl ether 57
(34.6 mg, 80 mmol) in AcOEt (0.5 mL), and the flask was
fitted with a hydrogen balloon and purged with hydrogen.
After stirring for 13 h, the catalyst was filtered through a
Celite pad, and the filtrate was evaporated in vacuo. The
crude product (30.2 mg) was purified by column chroma-
tography (silica gel 5 g, 1:2 n-hexane/AcOEt) to give
alcohol 58 (25.2 mg, 92%) as a colorless oil: [a]2D4¼27.68
(c 0.50, CHCl3); IR (neat) 3482, 2940, 1713, 1439, 1362,
LiOMe (1 M in MeOH, 30 mL, 30 mmol) was added to a
stirred solution of the equilibrium mixture in THF (0.3 mL)
at room temperature under an argon atmosphere. After
stirring at room temperature for 4 h, the reaction was
quenched by addition of saturated aqueous NH4Cl (5 mL),
and the whole was extracted with AcOEt (2£10 mL). The
combined organic extracts were washed with brine (5 mL),
and dried over anhydrous Na2SO4. Filtration and evapor-
ation in vacuo furnished the crude product (18.5 mg), which
was purified by column chromatography (silica gel 5 g,
12:1!8:1 n-hexane/AcOEt) to give a mixture of dispiro-
ketals (15.2 mg, 92%, 20/52/53/54¼84:8:3:5) as a colorless
oil. The ratio of isomers was determined by HPLC analysis
(column, Zorbaxw sil, 4.6£250 mm; eluent, 10:1 hexane/
AcOEt; flow rate, 1.0 mL/min; detection, 254 nm, tR
(53)¼11.6 min, tR (20)¼22.3 min, tR (52)¼34.5 min, tR
(54)¼38.4 min).
1227, 1140, 1074, 1022, 955, 868 cm21
;
1H NMR
(500 MHz, CDCl3) d 1.21–1.25 (m, 4H, C22–H, C37–
H3), 1.46–1.58 (m, 2H, C13–H, C20–H), 1.63–1.76 (m,
7H, OH, C11–H, C13–H, C14–H, C20–H, C21–H, C22–
H), 1.79–1.92 (m, 5H, C11–H, C14–H, C17–H, C18–H,
C21–H), 2.08–2.23 (m, 5H, C17–H, C18–H, C26–H3),
2.49 (dd, J¼6.8, 16.0 Hz, 1H, C24–H), 2.82 (dd, J¼5.9,
16.0 Hz, 1H, C24–H), 3.03 (brs, 1H, OH), 3.62 (m, 1H,
C10–H), 3.77 (m, 1H, C10–H), 4.07 (m, 1H, C12–H), 4.38
(m, 1H, C23–H); 13C NMR (125 MHz, C6D6) d 19.8, 21.8,
30.7, 31.15, 31.21, 31.3, 34.8, 36.5, 38.2, 38.4, 49.8, 60.4,
69.8, 69.9, 108.3, 111.3, 206.3; FAB-HRMS m/z calcd for
C18H31O6 (MþþH) 343.2121, found 343.2137.

S. Nakamura et al. / Tetrahedron 58 (2002) 10353–10374
10373
4.1.39. Equilibration under basic conditions. (i) Reaction
of 20 with NaOMe. NaOMe (1 M in MeOH, 45 mL,
45 mmol) was added to a stirred solution of 20 (24.5 mg,
44.8 mmol) in THF (0.5 mL) under an argon atmosphere.
After stirring for 5 h, the reaction was quenched by addition
of saturated aqueous NH4Cl (5 mL), and the whole was
extracted with AcOEt (2£10 mL). The combined organic
extracts were washed with brine (5 mL), and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product, which was purified by column
chromatography (silica gel 5 g, 12:1!8:1 n-hexane/AcOEt)
to give a mixture of dispiroketals (11.0 mg, 45%,
20/52/53/54¼53:5:42:,1) as a colorless oil, along with
C-Michael product 66 (2.7 mg, 11%): data for C-Michael
product 66: [a]2D2¼þ30.7 (c 0.68, CHCl3); IR (neat) 3466,
2928, 2857, 1717, 1460, 1362, 1258, 1134, 1096, 1026, 953,
Na2SO4. Filtration and evaporation in vacuo furnished the
crude product, which was purified by column chroma-
tography (silica gel 5 g, 10:1!8:1 n-hexane/AcOEt) to give
a mixture of dispiroketals (12.3 mg, 95%, 52/53/54¼
22:64:14) as a colorless oil.
Acknowledgements
This research was supported in part by a Grant-in-Aid for
Scientific Research on Priority Areas (A) ‘Exploitation of
Multi-Element Cyclic Molecules’ from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
We are grateful to Mses H. Matsumoto, A. Maeda, S. Oka,
and M. Kiuchi of Center for Instrumental Analysis,
Hokkaido University, for technical assistance with NMR,
MS, and elemental analysis.
835 cm21 1H NMR (500 MHz, CDCl3) d 0.15 (s, 3H,
;
SiCH3), 0.19 (s, 3H, SiCH3), 0.90 (s, 9H, SiC(CH3)3), 1.36
(s, 3H, C37–H3), 1.43 (m, 2H), 1.54–1.73 (m, 10H), 2.02–
2.36 (m, 7H), 2.47 (dd, J¼2.2, 15.7 Hz, 1H), 2.52 (dd,
J¼6.9, 13.3 Hz, 1H), 3.59 (m, 1H, C10–H), 3.66 (m, 1H,
C10–H), 4.05 (brs, 1H, OH), 4.17 (m, 1H, C12–H), 4.52 (d,
J¼11.9 Hz, 1H, OCHPh), 4.58 (d, J¼11.9 Hz, 1H, OCHPh),
7.27 (m, 1H, ArH), 7.31–7.37 (m, 4H, ArH); FAB-HRMS
m/z calcd for C31H50O6SiNa (MþþNa) 569.3274, found
569.3264.
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established by the following experiments (Eqs. (8) and (9)).
Upon treatment of either 52 or 53 with CSA in CH2Cl2, nearly
identical ratios of dispiroketal isomers 52–54 at equilibrium in
favor of 53 were obtained, with no trace of the desired isomer
20. It was therefore concluded that the C23 configurations of
52–54 should be the same but opposite to that of 20
15. McGarvey, G. J.; Stepanian, M. W. Tetrahedron Lett. 1996,
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ð8Þ
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ð9Þ
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(a) DIBAL-H, MeCu, THF–HMPA (5:1), 2508C, 61%
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