A highly stereoselective synthesis of the C10-C31 (BCDEF ring) portion of pinnatoxin A

Article abstract of DOI:10.1016/S0040-4020(02)01380-7

An efficient, highly stereoselective synthesis of the C10-C31 (BCDEF ring) portion of pinnatoxin A has been achieved utilizing tandem double hemiketal formation/intramolecular hetero-Michael addition to construct the 6,5,6-dispiroketal (BCD ring) system a

Full text of DOI:10.1016/S0040-4020(02)01380-7

Tetrahedron 58 (2002) 10375–10386
A highly stereoselective synthesis of the C10–C31 (BCDEF ring)
portion of pinnatoxin A
*
Seiichi Nakamura, Jun Inagaki, Tomohiro Sugimoto, Yasuyuki Ura 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–C31 (BCDEF ring) portion of pinnatoxin A has been achieved utilizing
tandem double hemiketal formation/intramolecular hetero-Michael addition to construct the 6,5,6-dispiroketal (BCD ring) system and
subsequent intramolecular ketalization to form the 5,6-bicycloketal (EF ring) system as key steps. q 2002 Elsevier Science Ltd. All rights
reserved.
1. Introduction
was centered on the construction of the 6,5,6-dispiroketal
(BCD ring) system. We investigated the viability of the
desired dispiroketalization via a tandem double hemiketal
formation/intramolecular hetero-Michael addition process
(Eq. (1)). Armed with positive results, we now embarked on
the synthesis of the C10–C31 (BCDEF ring) portion of
pinnatoxin A.2
In the preceding article,1 a retrosynthetic analysis of
pinnatoxin A was outlined, wherein the C10–C31 ketone
fragment 1 became the first important target for our
synthetic venture. In the synthesis of 1, our strategic interest
2. Results and discussions
2.1. Synthesis of the dispiroketalization precursor
According to the retrosynthetic analysis shown in the
preceding paper, b-ketophosphonate 5 was initially chosen
as the C24–C31 fragment (Eq. (2)). The synthesis of 5 was
implemented as shown in Scheme 1. Protection of the
known alcohol 63 with TBSCl gave silyl ether 7 in 97%
yield (Scheme 1). The benzyl group in 7 was removed by
ð1Þ
ð2Þ
Keywords: dispiroketal; hemiketal formation; hetero-Michael addition;
internal ketalization.
*
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)01380-7

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S. Nakamura et al. / Tetrahedron 58 (2002) 10375–10386
Scheme 2. Reagents and conditions: (a) Ph3PvCHCON(OMe)Me,
benzene, reflux, 39 h, 90%; (b) TBDPSCl, imidazole, DMF, 12 h, 94%;
(c) MeMgI, Et2O, 08C, 5 h, 94%.
required a large (10-fold) excess of Me2CuLi. Furthermore,
this step involved a tedious chromatographic separation of
anti isomer 11 from syn isomer 12 due to modest
diastereoselectivity. Thus, we felt compelled to improve
the efficiency of this step. We surmised that by replacing a
less reactive enoate with a more reactive enone, a diversity
of reaction conditions available would overcome these
problems. In this scenario, the construction of the C23–C24
linkage relied on a fragment assembly aldol reaction.
Toward this end, we initiated the synthesis of (E) enone
16 with lactol 8 as shown in Scheme 2. An initial attempt
to elaborate an enone moiety directly from 8 with
Ph3PvCHCOMe proved to be unrewarding because of
the propensity of the product to undergo an intramolecular
hetero-Michael addition under Wittig conditions. We
therefore adopted a stepwise approach. By treatment with
a phosphorane carrying Weinreb’s amide,8 the lactol 8 was
first converted to a,b-unsaturated amide 14 in 90% yield.
Protection of the primary hydroxyl group as its TBDPS
Scheme 1. Reagents and conditions: (a) TBSCl, imidazole, DMF, 16 h,
97%; (b) H2, 20% Pd(OH)2, EtOH, 48 h, 83%; (c) Ph3PvCHCO2Et,
benzene, reflux, 32 h, 98%; (d) TBDPSCl, imidazole, DMF, 13 h, 95%;
(e) Me2CuLi (10 equiv.), TMSCl (10 equiv.), THF, 2208C, 16 h, 71% of 11
and 15% of 12; (f) (MeO)2P(O)CH2Li, THF, 2788C, 1 h, 80%; (g) LiCl,
i-Pr2NEt, CH3CN, 20 h, 96%.
Table 1. Conjugate addition of organocopper reagents to 16
hydrogenolysis to afford the lactol 8, which upon treatment
with Ph3PvCHCO2Et in refluxing benzene furnished (E)
enoate 9 as a single stereoisomer in 81% yield. The resultant
hydroxyl group was protected as its TBDPS ether (95%) to
set up conjugate addition of methylcopper reagents to create
the stereogenic center at C27. According to the Hanessian
protocol4 originally developed by Corey,5 the crucial
conjugate addition of Me2CuLi to enoate 10 was achieved
in the presence of TMSCl to provide a 4.5:1 mixture of
adducts favoring the desired anti isomer 11 in 86%
combined yield. After separation of the isomers, anti isomer
11 was converted to b-ketophosphonate 5 in 80% yield.6
Horner–Wadsworth–Emmons olefination of the C10–C23
aldehyde fragment 41 with 5 under Masamune conditions7
proceeded uneventfully to furnish (E) enone 13 in 96%
yield.
Entry
Organocopper
reagents
Additive
Temperature
(8C)
Yield
(%)
17:18a
1
2
3
4
5
Me2CuLi
Me2CuLi
Me2CuLi
MeCu(CN)Li
MeCu(CN)Li
–
0
83
83
54b
80
74:26
95:5
99:1
99:1
TMSCl
BF3·OEt2
BF3·OEt2
TMSCl
278
278
278
278
Although the synthesis of the C10–C31 enone fragment 13
was realized by the above route, this synthesis was far from
optimal. The major drawback lay in the conjugate addition
step. While the Hanessian conditions proved to be the only
choice for this process, the conjugate addition to enoate 10
SM recovery
a
Determined by HPLC analysis (column, Zorbaxw Sil, 4.6£250 mm;
eluent, 9% AcOEt in hexane; flow rate 1.0 mL/min).
1,2-Adduct was obtained in 21% yield.
b

S. Nakamura et al. / Tetrahedron 58 (2002) 10375–10386
10377
ether was followed by treatment with MeMgI9 to afford the
desired enone 16 in 88% yield.
favoring antiisomer 17 in 83% yield (entry 2). The use of
BF3·OEt2 exhibited much higher anti-selectivity (99:1), but
the product yield was only 54% due to the formation of a
1,2-adduct (entry 3). We next examined the reaction with
MeCu(CN)Li instead of Me2CuLi. We found that conjugate
addition of MeCu(CN)Li to 16 in the presence of BF3·OEt2
at 2788C led to the virtually exclusive formation of anti
adduct 17 in 80% yield (entry 4). On the other hand, the
reaction with MeCu(CN)Li/TMSCl did not work (entry 5).
Although anti-selective conjugate addition reactions of
methylcopper or dimethylcuprate reagents to g-alkoxy-a,b-
unsaturated esters have been extensively studied,10 a limited
number of examples for g-alkoxy-a,b-enone system have
been reported.11 – 13 We initially examined conjugate
addition of Me2CuLi to the enone 16 (Table 1). It was
found that the reaction with 4 equiv. of Me2CuLi proceeded
at 08C to give a readily separable mixture of adducts in 83%
yield with modest anti-selectivity (entry 1). It is well
documented that an additive such as TMSCl or BF3·OEt2
has a remarkable effect on the rate as well as the
stereochemical outcome of conjugate addition of organo-
copper reagents to a,b-unsaturated carbonyl compounds.14
Indeed the reaction of 16 with Me2CuLi in the presence of
TMSCl proceeded at 2788C to completion within an hour to
afford, after acid hydrolysis, a 95:5 mixture of adducts
The stereochemistry at C27 of anti adduct 17 was
1
established by H NOE experiment of the bicycloketal 19
derived from 17 upon exposure to TFA in CH2Cl2 (Eq. (3)).
C27–H showed significant NOE interactions with C28–H
and C31–H, suggesting that C27–H was axially disposed.
ð3Þ
With the efficient synthesis of the C24–C31 ketone
fragment 17 realized, the stage was now set for the aldol
fragment coupling to construct the C23–C24 bond and the
elaboration of the dispiroketalization precursor 23
(Scheme 3). The lithium enolate derived from methyl
ketone 17 was allowed to react with the C10–C23 aldehyde
fragment 4, providing a mixture of diastereomeric aldol
Scheme 3. Reagents and conditions: (a) LiHMDS, THF, 2788C, then 4,
278 to 2508C, 1.5 h, 88%; (b) Ac2O, pyridine, DMAP, 16 h; (c) DBU,
CH2Cl2, 1 h, 89% (two steps); (d) DDQ, CH2Cl2/pH 7 phosphate buffer
(10:1), 1 h, 93%; (e) Dess–Martin periodinane, CH2Cl2/pyridine (5:1), 08C,
1 h, 84%; (f) NCS, AgNO3, g-collidine, CH3CN/H2O (4:1), 87%.
Scheme 4. Reagents and conditions: (a) 1N aqueous HCl/THF (1:10), 08C,
1 h; (b) LiOMe (1 equiv.), THF/MeOH (10:1), 4 h, 77% of 1 and 14% of
other isomers (two steps); (c) CSA, CH2Cl2, 5 h, 62%.

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S. Nakamura et al. / Tetrahedron 58 (2002) 10375–10386
adducts 20 in 88% yield. Acetylation of the hydroxyl group
in 20 was followed by exposure to DBU to furnish enone 13
in 89% yield. Finally, the target triketone 23 was obtained
by oxidative deprotection of MPM ether15 followed by
Dess–Martin oxidation16 and oxidative hydrolysis of
dithiane under standard Corey conditions17 in 68% yield
over three steps from 13.
(40 mL). The organic layer was washed with brine
(2£30 mL), and dried over anhydrous Na2SO4. Filtration
and evaporation in vacuo furnished the crude product (8.0 g,
colorless oil), which was purified by column chromato-
graphy (silica gel 80 g, 20:1!16:1 n-hexane/acetone) to
give silyl ether 7 (6.44 g, 97%) as a colorless oil:
[a]2D4¼þ97.2 (c 1.19, CHCl3); IR (neat) 2930, 1458, 1372,
;
1H NMR
1246, 1215, 1119, 1036, 839, 777 cm21
2.2. Construction of BCDEF ring system
(500 MHz, CDCl3) d 0.08 (s, 3H, SiCH3), 0.11 (s, 3H,
SiCH3), 0.90 (s, 9H, SiC (CH3)3), 1.35 (s, 3H, acetonide
CH3), 1.53 (s, 3H, acetonide CH3), 3.57 (dd, J¼3.8,
13.7 Hz, 1H, C31–H), 3.73–3.76 (m, 2H, C28–H, C31–
H), 4.24 (m, 1H, C30–H), 4.41 (dd, J¼3.1, 7.0 Hz, 1H,
C29–H), 4.55 (d, J¼11.2 Hz, 1H, CHPh), 4.79–4.82 (m,
2H, C27–H, CHPh), 7.27 (m, 1H, ArH), 7.31–7.36 (m, 4H,
ArH); 13C NMR (100 MHz, CDCl3) d 24.8, 24.4, 18.3,
25.2, 25.8, 26.8, 62.8, 69.7, 70.7, 73.8, 75.2, 100.0, 109.7,
127.3, 127.7, 128.1, 137.8; FAB-HRMS m/z calcd for
C21H33O5Si (Mþ2H) 393.2097, found 393.2086; Anal.
calcd for C21H34O5Si: C, 63.92; H, 8.69, found: C, 63.77; H,
8.57.
Having successfully arrived at 23, we were now ready for
the key dispiroketalization via a tandem double hemiketal
formation/hetero-Michael addition process (Scheme 4).
Following the protocol developed in model studies,1 we
first submitted triketone 23 to 1N aqueous HCl. Gratify-
ingly, selective liberation of the C12 hydroxyl group
resulted in the formation of an equilibrium mixture of
hydroxytriketone 24 and hemiketals, which upon treatment
with LiOMe in THF/MeOH (10:1) at room temperature
afforded the desired dispiroketal 1 in 77% isolated yield,
accompanied by 14% of other diastereomers. Finally,
removal of the acetonide group in 1 with CSA in CH2Cl2
with concomitant bicycloketalization gave the C10–C31
fragment 25, containing the BCDEF ring system of
pinnatoxin A, as a single isomer in 62% yield.18 The
stereochemistries of 1 and 25 were verified by the
diagnostic 1H NOE correlation between C12–H and
C23–H.20
4.1.2. Ethyl (2E,4R,5S,6S)-4-(tert-butyldimethylsilyl)-
oxy-5,6-(dimethylmethylenedioxy)-7-hydroxy-2-hep-
tenoate (9). To a solution of benzyl acetal 7 (3.45 g,
8.7 mmol) in EtOH (30 mL) was added 20% Pd(OH)2
(246 mg), and the mixture was vigorously stirred for 2 days
under a hydrogen atmosphere. The catalyst was filtered
through a Celite pad, and the filtrate was evaporated in
vacuo to furnish the crude product (2.7 g, colorless oil),
which was purified by column chromatography (silica gel
80 g, 4:1 n-hexane/AcOEt) to give lactol 8 (2.22 g, 83%) as
3. Conclusion
1
a colorless oil: H NMR (500 MHz, CDCl3) d 0.14 (s, 3H,
We have achieved an efficient, highly stereoselective
synthesis of the C10–C31 (BCDEF ring) portion of
pinnatoxin A, wherein the key features involve (a) a
stereocontrolled conjugate addition of MeCu(CN)Li in the
presence of BF3·OEt2 to establish the C27 stereogenic
center, (b) a fragment assembly aldol reaction to join the
C23–C24 bond, (c) a tandem double hemiketal formation/
intramolecular hetero-Michael addition2 to construct the
6,5,6-dispiroketal (BCD ring) system, and (d) an intra-
molecular ketalization to form the 5,6-bicycloketal (EF
ring) system. Further efforts toward a total synthesis of
pinnatoxin A are currently underway.
SiCH3), 0.15 (s, 3H, SiCH3), 0.93 (s, 9H, SiC(CH3)3), 1.34
(s, 3H, acetonide CH3), 1.52 (s, 3H, acetonide CH3), 3.00 (d,
J¼3.0 Hz, 1H, OH), 3.56 (dd, J¼4.0, 12.6 Hz, 1H, C31–H),
3.66 (dd, J¼3.2, 6.6 Hz, 1H, C28–H), 3.80 (dd, J¼3.6,
12.6 Hz, 1H, C31–H), 4.25 (m, 1H, C30–H), 4.40 (dd,
J¼3.2, 6.6 Hz, 1H, C29–H), 5.01 (dd, J¼3.0, 6.6 Hz, 1H,
C27–H).
A solution of ethyl (triphenylphosphoranylidene)acetate
(1.04 g, 2.97 mmol) and hemiacetal (603.2 mg, 1.98 mmol)
in benzene (40 mL) was heated at reflux for 32 h. The
solvent was evaporated in vacuo and the residue was
purified by column chromatography (silica gel 50 g,
8:1!4:1 n-hexane/AcOEt) to give enoate 9 (727 mg,
98%) as a colorless syrup: [a]2D2¼222.6 (c 1.03, CHCl3);
IR (neat) 3499, 2934, 2861, 1723, 1471, 1369, 1258, 1167,
1078, 1040, 839 cm21; 1H NMR (500 MHz, CDCl3) d 0.08
(s, 3H, SiCH3), 0.13 (s, 3H, SiCH3), 0.92 (s, 9H,
SiC(CH3)3), 1.30 (t, J¼7.3 Hz, 3H, OCH2CH3), 1.35 (s,
3H, acetonide CH3), 1.47 (s, 3H, acetonide CH3), 2.49 (dd,
J¼6.4, 7.1 Hz, 1H, OH), 3.68 (m, 2H, C31–H), 4.12 (m,
1H, C29–H), 4.19–4.23 (m, 3H, C30–H, OCH2CH3), 4.64
(m, 1H, C28–H), 6.04 (d, J¼15.7 Hz, 1H, C26–H), 6.89
(dd, J¼5.7, 15.7 Hz, 1H, C27–H); 13C NMR (100 MHz,
CDCl3) d 24.7, 24.1, 14.2, 18.1, 25.4, 25.8, 27.6, 60.5,
61.5, 70.8, 77.7, 78.5, 108.2, 122.8, 146.1, 165.6; EI-LRMS
m/z 359 (Mþ2CH3), 75 (bp); EI-HRMS m/z calcd for
C17H31O6Si (Mþ2CH3) 359.1890, found 359.1893; Anal.
calcd for C18H34O6Si: C, 57.72; H, 9.15, found: C, 57.54; H,
9.13.
4. Experimental
4.1. General
For a description of general information, see the preceding
paper.1 N-Methoxy-N-methyl-2-(triphenylphosphoranyl-
idene)acetamide was prepared according to the literature
procedure.8
4.1.1. (3aS,6S,7S,7aS)-6-Benzyloxy-2,2-dimethyl-7-(tert-
butyldimethylsilyl)oxy-tetrahydro-1,3-dioxolo[4,5-
c]pyran (7). TBSCl (2.80 g, 18.6 mmol) was added to a
stirred solution of alcohol 6 (4.73 g, 16.9 mmol) and
imidazole (2.87 g, 42.2 mmol) in DMF (60 mL) at 08C
under an argon atmosphere. After stirring for 16 h, the
reaction was quenched with three pieces of ice, and the
mixture was partitioned between AcOEt (100 mL) and H2O

S. Nakamura et al. / Tetrahedron 58 (2002) 10375–10386
10379
4.1.3. Ethyl (2E,4R,5S,6S)-4-(tert-Butyldimethylsilyl)-
oxy-7-(tert-butyldiphenylsilyl)oxy-5,6-(dimethylmethyl-
ene-dioxy)-2-heptenoate (10). TBDPSCl (0.54 mL,
2.10 mmol) was added to a stirred solution of alcohol 9
(654.0 mg, 1.75 mmol) and imidazole (297.6 mg,
4.38 mmol) in DMF (20 mL) at 08C under an argon
atmosphere. After stirring at room temperature for 13 h,
the reaction was quenched by addition of crushed ice, and
the whole was partitioned between AcOEt (50 mL) and H2O
(30 mL). The aqueous layer was extracted with AcOEt
(50 mL), and the combined organic extracts were washed
with brine (2£30 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo furnished the crude
product (1.3 g), which was purified by column chromato-
graphy (silica gel 30 g, 20:1 n-hexane/acetone) to give
TBDPS ether 10 (1.02 g, 95%) as a colorless syrup:
[a]2D2¼26.70 (c 1.27, CHCl3); IR (neat) 2934, 2859,
H), 3.64 (dd, J¼7.9, 10.8 Hz, 1H, C31–H), 3.71 (dd, J¼2.3,
7.3 Hz, 1H, C28–H), 3.80 (dd, J¼2.6, 10.8 Hz, 1H, C31–
H), 4.06–4.11 (m, 3H, C29–H, OCH2CH3), 4.25 (m, 1H,
C30–H), 7.34–7.42 (m, 6H, ArH), 7.68–7.73 (m, 4H,
ArH); FAB-HRMS m/z calcd for C35H56O6Si2Na (MþþNa)
651.3513, found 651.3516.
Data for 12: [a]2D4¼230.9 (c 1.01, CHCl3); IR (neat) 2934,
2859, 1736, 1464, 1427, 1370, 1254, 1179, 1111, 835,
1
702 cm21; H NMR (500 MHz, CDCl3) d 20.17 (s, 3H,
SiCH3), 20.06 (s, 3H, SiCH3), 0.77 (s, 9H, SiC(CH3)3),
0.94 (d, J¼6.8 Hz, 3H, C36–H3), 1.06 (s, 9H, SiC(CH3)3),
1.23 (t, J¼7.0 Hz, 3H, OCH2CH3), 1.32 (s, 3H, acetonide
CH3), 1.41 (s, 3H, acetonide CH3), 2.14 (dd, J¼10.3,
14.6 Hz, 1H, C26–H), 2.22 (m, 1H, C27–H), 2.43 (dd,
J¼3.8, 14.6 Hz, 1H, C26–H), 3.64 (dd, J¼8.0, 10.9 Hz, 1H,
C31–H), 3.72 (dd, J¼2.6, 7.9 Hz, 1H, C28–H), 3.79 (dd,
J¼1.9, 10.9 Hz, 1H, C31–H), 3.99 (m, 1H, C29–H), 4.11
(q, J¼7.0 Hz, 2H, OCH2CH3), 4.25 (m, 1H, C30–H), 7.34–
7.42 (m, 6H, ArH), 7.68–7.74 (m, 4H, ArH); FAB-HRMS
m/z calcd for C35H56O6Si2Na (MþþNa) 651.3513, found
651.3520.
1
1728, 1661, 1472, 1370, 1258, 1169, 980 cm21; H NMR
(500 MHz, CDCl3) d 20.13 (s, 3H, SiCH3), 20.06 (s, 3H,
SiCH3), 0.75 (s, 9H, SiC(CH3)3), 1.06 (s, 9H, SiC(CH3)3),
1.29 (t, J¼7.1 Hz, 3H, OCH2CH3), 1.34 (s, 3H, acetonide
CH3), 1.42 (s, 3H, acetonide CH3), 3.77 (dd, J¼7.8,
11.2 Hz, 1H, C31–H), 3.90 (dd, J¼3.3, 11.2 Hz, 1H,
C31–H), 4.06 (m, 1H, C29–H), 4.19 (q, J¼7.1 Hz, 3H,
OCH2CH3), 4.30 (m, 1H, C30–H), 4.45 (m, 1H, C28–H),
5.91 (dd, J¼1.1, 15.6 Hz, 1H, C26–H), 6.85 (dd, J¼5.8,
15.6 Hz, 1H, C27–H), 7.35–7.43 (m, 6H, ArH), 7.67–7.72
(m, 4H, ArH); 13C NMR (100 MHz, CDCl3) d 24.8, 24.0,
14.3, 18.0, 19.3, 25.4, 25.8, 26.9, 27.5, 60.4, 63.7, 70.9,
78.6, 79.1, 108.4, 122.6, 127.46, 127.53, 129,48, 129.49,
133.3, 133.5, 135.5, 135.7, 147.0, 165.8; FAB-HRMS m/z
calcd for C34H52O6Si2Na (MþþNa) 635.3200, found
635.3218.
4.1.5. Dimethyl (4R,5R,6S,7S)-5-(tert-butyldimethyl-
silyl)oxy-8-(tert-butyldiphenylsilyl)oxy-6,7-(dimethyl-
methylenedioxy)-4-methyl-2-oxopentylphosphonate (5).
Butyllithium in n-hexane (1.54 M, 0.31 mL, 0.477 mmol)
was added to a solution of dimethyl methylphosphonate
(59.4 mg, 0.479 mmol) in THF (5 mL) at 2788C under an
argon atmosphere. After stirring for 50 min, a solution of
ester 11 (100.0 mg, 0.159 mmol) in THF (2 mL) was added,
and the mixture was stirred at 2788C for 1 h. The reaction
was quenched with saturated aqueous NH4Cl (10 mL), and
the whole was extracted with AcOEt (2£25 mL). The
combined organic extracts were washed successively with
brine (2£10 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, 1:4 n-hexane/AcOEt) to give phosphonate 5
(89.7 mg, 80%) as a colorless syrup: [a]2D2¼234.5 (c 1.20,
CHCl3); IR (neat) 2955, 2857, 1715, 1472, 1372, 1260,
4.1.4. Ethyl (3R,4R,5S,6S)-4-(tert-butyldimethylsilyl)-
oxy-7-(tert-butyldiphenylsilyl)oxy-5,6-(dimethylmethyl-
enedioxy)-3-methylheptanoate (11). Methyllithium in
Et2O (1.14 M, 19.0 mL, 21.7 mmol) was added to a
suspension of CuI (2.06 g, 10.85 mmol) in THF (35 mL)
at 2788C under an argon atmosphere, and the resulting
mixture was stirred at 08C for 20 min to form a clear,
colorless solution. After cooling to 2788C, TMSCl
(1.38 mL, 10.85 mmol) was added, and the mixture was
stirred at this temperature for 5 min. A solution of enoate 10
(665.0 mg, 1.08 mmol) in THF (5.0 mL) was added, and the
mixture was stirred at 2208C for 16 h. The reaction was
quenched by addition of saturated aqueous NH4Cl (50 mL),
and the mixture was stirred at room temperature for 1 h. The
whole mixture was extracted with AcOEt (2£50 mL), and
the combined organic extracts were washed with brine
(2£20 mL), and dried over anhydrous Na2SO4. Filtration
and evaporation in vacuo furnished the crude product
(yellow oil), which was purified by column chromatography
(silica gel 50 g, 16:1 n-hexane/AcOEt) to give anti adduct
11 (479.2 mg, 71%) as a colorless syrup, along with its
stereoisomer 12 (105.2 mg, 15%); [a]2D4¼233.5 (c 1.04,
CHCl3); IR (neat) 2934, 2859, 1736, 1460, 1377, 1254,
1181, 1090, 837, 704 cm21; 1H NMR (500 MHz, CDCl3) d
20.16 (s, 3H, SiCH3), 20.02 (s, 3H, SiCH3), 0.77 (s, 9H,
SiC(CH3)3), 0.96 (d, J¼6.4 Hz, 3H, C36–H3), 1.06 (s, 9H,
SiC(CH3)3), 1.21 (t, J¼7.3 Hz, 3H, OCH2CH3), 1.35 (s, 3H,
acetonide CH3), 1.40 (s, 3H, acetonide CH3), 2.17–2.24 (m,
2H, C26–H, C27–H), 2.54 (dd, J¼9.6, 20.4 Hz, 1H, C26–
1
1032, 897, 835, 706 cm21; H NMR (500 MHz, CDCl3) d
20.15 (s, 3H, SiCH3), 20.01 (s, 3H, SiCH3), 0.79 (s, 9H,
SiC(CH3)3), 0.92 (d, J¼7.0 Hz, 3H, C36–H3), 1.06 (s, 9H,
SiC(CH3)3), 1.35 (s, 3H, acetonide CH3), 1.38 (s, 3H,
acetonide CH3), 2.31 (m, 1H, C27–H), 2.52 (dd, J¼8.3,
18.0 Hz, 1H, C26–H), 2.83 (dd, J¼4.8, 18.0 Hz, 1H, C26–
H), 2.97 (dd, J¼13.9, 22.6 Hz, 1H, C24–H), 3.08 (dd,
J¼13.9, 22.7 Hz, 1H, C24–H), 3.61 (dd, J¼7.7, 10.8 Hz,
1H, C31–H), 3.67 (dd, J¼2.9, 7.4 Hz, 1H, C28–H), 3.73 (d,
J¼11.2 Hz, 3H, POCH3), 3.74 (d, J¼11.2 Hz, 3H, POCH3),
3.78 (dd, J¼2.8, 10.8 Hz, 1H, C31–H), 4.07 (dd, J¼6.3,
7.4 Hz, 1H, C29–H), 4.25 (m, 1H, C30–H), 7.34–7.42 (m,
6H, ArH), 7.67–7.72 (m, 4H, ArH); FAB-HRMS m/z calcd
for C36H59O8PSi2Na (MþþNa) 729.3384, found 729.3378.
4.1.6. [1R,1(4S,5S),2R,5E,9(3S,4R,7S)]-9-{2-[9-Benzyl-
oxy-4-(tert-butyldimethylsilyl)oxy-3-(4-methoxybenzyl)-
oxy-4-methyl-7-(triethylsilyl)oxynonyl]-1,3-dithian-2-
yl}-1-(tert-butyldimethylsilyl)oxy-1-[5-(tert-butyldiphe-
nylsilyl)oxymethyl-2,2-dimethyl-1,3-dioxolan-4-yl]-2-
methyl-5-nonen-4-one (13). To a solution of phosphonate 5
(242.1 mg, 0.34 mmol) and LiCl (42.0 mg, 0.99 mmol) in

10380
S. Nakamura et al. / Tetrahedron 58 (2002) 10375–10386
CH3CN (5 mL) was added i-Pr2NEt (0.34 mL, 1.95 mmol),
followed by addition of a solution of aldehyde 4 (274.1 mg,
0.33 mmol) in CH3CN (1 mL) under an argon atmosphere.
After stirring for 37 h, the reaction was quenched with
saturated aqueous NH4Cl (10 mL), and the whole was
extracted with AcOEt (40 mL). The organic extract was
washed with brine (10 mL), and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the
crude product, which was purified by column chromato-
graphy (silica gel 50 g, 12:1 n-hexane/AcOEt) to give enone
13 (444.4 mg, 96%) as a colorless syrup: [a]2D5¼217.5 (c
1.17, CHCl3); IR (neat) 2953, 1698, 1671, 1615, 1514,
1462, 1370, 1250, 1092, 835, 775, 739, 704 cm21; 1H NMR
(500 MHz, CDCl3) d 20.17 (s, 3H, SiCH3), 20.01 (s, 3H,
SiCH3), 0.08 (s, 6H, SiCH3£2), 0.58 (q, J¼7.9 Hz, 6H,
Si(CH2CH3)3), 0.77 (s, 9H, SiC(CH3)3), 0.85 (s, 9H,
SiC(CH3)3), 0.91 (d, J¼7.0 Hz, 3H, C36–H3), 0.92 (t,
J¼7.9 Hz, 9H, Si(CH2CH3)3), 1.05 (s, 9H, SiC(CH3)3), 1.21
(s, 3H, C37–H3), 1.35 (s, 3H, acetonide CH3), 1.40 (s, 3H,
acetonide CH3), 1.53–1.61 (m, 6H, C13–H2, C14–H2,
C17–H2), 1.71–1.88 (m, 9H, C11–H2, C18–H, C20–H2,
C21–H2, SCH2CH2), 2.10–2.17 (m, 3H, C18–H, C22–
H2), 2.33 (m, 1H, C27–H), 2.39 (dd, J¼8.7, 16.1 Hz, 1H,
C26–H), 2.64–2.74 (m, 5H, C26–H, SCH2£2), 3.16 (brd,
J¼7.9 Hz, 1H, C16–H), 3.49–3.57 (m, 2H, C10–H2), 3.60
(dd, J¼7.9, 10.8 Hz, 1H, C31–H), 3.66 (dd, J¼2.7, 7.6 Hz,
1H, C28–H), 3.76–3.79 (m, 5H, C12–H, C31–H,
C6H4OCH3), 4.08 (m, 1H, C29–H), 4.25 (m, 1H, C30–
H), 4.43–4.50 (m, 3H, OCHAr, OCH2Ph), 4.58 (d,
J¼11.0 Hz, 1H, OCHAr), 6.05 (d, J¼15.9 Hz, 1H, C24–
H), 6.76 (m, 1H, C23–H), 6.84 (d, J¼8.5 Hz, 2H, ArH),
7.23–7.28 (m, 3H, ArH), 7.31–7.42 (m, 10H, ArH), 7.67–
7.72 (m, 4H, ArH); 13C NMR (100 MHz, CDCl3) d 25.1,
24.1, 22.1, 21.9, 4.9, 6.8, 14.4, 17.8, 18.1, 18.8, 22.4,
23.2, 25.0, 25.1, 25.5, 25.6, 25.7, 25.9, 26.7, 27.7, 31.4,
32.1, 33.9, 35.4, 36.4, 37.2, 37.8, 42.8, 53.0, 54.7, 63.7,
66.7, 69.8, 72.4, 72.6, 73.8, 77.2, 78.0, 78.6, 84.5, 107.7,
113.4, 127.1, 127.2, 127.3, 127.9, 128.6, 129.25, 129.29,
130.8, 133.1, 133.3, 135.4, 135.6, 138.3, 145.5, 158.8,
199.2; FAB-HRMS m/z calcd for C79H128O10S2Si4Na
(MþþNa) 1435.7923, found 1435.7960.
390.2312, found 390.2282; Anal. calcd for C18H35NO6Si:
C, 55.50; H, 9.06; N, 3.60, found: C, 55.42; H, 8.92; N, 3.62.
4.1.8. (2E,4R,5S,6S)-N-Methoxy-N-methyl-4-(tert-butyl-
dimethylsilyl)oxy-7-(tert-butyldiphenylsilyl)oxy-5,6-
(dimethylmethylenedioxy)-2-heptenamide (15). TBDPSCl
(1.70 mL, 6.53 mmol) was added to a stirred solution of
alcohol 14 (2.32 g, 5.94 mmol) and imidazole (1.01 g,
14.9 mmol) in DMF (20 mL) at 08C under an argon
atmosphere. After stirring at room temperature for 12 h,
the reaction was quenched by addition of crushed ice, and
the whole was partitioned between AcOEt (80 mL) and H2O
(30 mL). The organic layer was washed with brine
(2£30 mL), and dried over anhydrous Na2SO4. Filtration
and evaporation in vacuo furnished the crude product,
which was purified by column chromatography (silica gel
50 g, 6:1!4:1 n-hexane/AcOEt) to give TBDPS ether 15
(3.49 g, 94%) as a colorless syrup: [a]2D5¼211.5 (c 1.12,
CHCl3); IR (neat) 2932, 1669, 1634, 1470, 1427, 1385,
1256, 1107, 837, 704 cm21; 1H NMR (500 MHz, CDCl3) d
20.11 (s, 3H, SiCH3), 20.05 (s, 3H, SiCH3), 0.76 (s, 9H,
SiC(CH3)3), 1.05 (s, 9H, SiC(CH3)3), 1.34 (s, 3H, acetonide
CH3), 1.42 (s, 3H, acetonide CH3), 3.23 (s, 3H, NCH3), 3.55
(s, 3H, NOCH3), 3.81 (dd, J¼8.0, 11.2 Hz, 1H, C31–H),
3.91 (dd, J¼2.7, 11.2 Hz, 1H, C31–H), 4.12 (m, 1H, C29–
H), 4.30 (m, 1H, C30–H), 4.56 (m, 1H, C28–H), 6.55 (d,
J¼15.4 Hz, 1H, C26–H), 6.88 (dd, J¼5.1, 15.4 Hz, 1H,
C27–H), 7.34–7.41 (m, 6H, ArH), 7.66–7.71 (m, 4H,
ArH); 13C NMR (100 MHz, CDCl3) d 24.9, 24.5, 17.8,
19.0, 25.2, 25.5, 26.7, 27.3, 31.9, 61.3, 63.8, 71.0, 78.6,
107.8, 119.7, 127.2, 127.3, 129.15, 129.17, 133.2, 133.3,
135.2, 135.4, 144.9, 165.5; FAB-HRMS m/z calcd for
C34H54NO6Si2 (MþþH) 628.3490, found 628.3442; Anal.
calcd for C34H53NO6Si2: C, 65.03; H, 8.51; N, 2.23, found:
C, 64.72; H, 8.51; N, 2.12.
4.1.9. (3E,5R,6S,7S)-5-(tert-Butyldimethylsilyl)oxy-8-
(tert-butyldiphenylsilyl)oxy-5,6-(dimethylmethylene-
dioxy)-3-octen-2-one (16). A solution of MeI (2.25 mL,
36.1 mmol) in Et2O (10 mL) was added over 30 min to a
suspension of magnesium tuning (877.5 mg, 36.1 mmol) in
Et2O (11 mL) under an argon atmosphere. After refluxing
for 30 min, the solution was cooled to room temperature,
and added to a stirred solution of amide 15 (4.53 g,
7.21 mmol) in Et2O (60 mL) at 08C under an argon
atmosphere. After stirring at 08C for 5 h, the mixture was
poured into saturated aqueous NH4Cl (60 mL), and the
whole was extracted with AcOEt (2£50 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 (5 g), which was purified
by column chromatography (silica gel 100 g, 12:1!8:1
n-hexane/AcOEt) to give enone 16 (3.94 g, 94%) as a
colorless oil: [a]2D3¼þ3.1 (c 1.06, C6H6); IR (neat) 2932,
2859, 1682, 1634, 1472, 1427, 1362, 1256, 1111, 984, 837,
4.1.7. (2E,4R,5S,6S)-N-Methoxy-N-methyl-4-(tert-butyl-
dimethylsilyl)oxy-5,6-(dimethylmethylenedioxy)-7-
hydroxy-2-heptenamide (14). A solution of N-methoxy-N-
methyl-2-(triphenylphosphoranylidene)acetamide (17.9 g,
68.0 mmol) and lactol 8 (11.6 g, 38.1 mmol) in benzene
(120 mL) was refluxed for 39 h. The solvent was evaporated
in vacuo and the residue (31 g, brown solid) was purified
by column chromatography (silica gel 300 g, 8:1!4:1
n-hexane/acetone) to give amide 14 (13.3 g, 90%) as a
colorless syrup: [a]2D2¼231.8 (c 1.30, CHCl3); IR (neat)
3463, 2934, 1667, 1636, 1464, 1418, 1383, 1254, 1217,
1171, 1078, 837, 704 cm21; 1H NMR (500 MHz, CDCl3) d
0.10 (s, 3H, SiCH3), 0.16 (s, 3H, SiCH3), 0.95 (s, 9H,
SiC(CH3)3), 1.35 (s, 3H, acetonide CH3), 1.48 (s, 3H,
acetonide CH3), 2.59 (m, 1H, OH), 3.26 (s, 3H, NCH3), 3.70
(m, 5H, C31–H2, NOCH3), 4.17–4.19 (m, 2H, C29–H,
C30–H), 4.75 (m, 1H, C28–H), 6.71 (d, J¼15.5 Hz, 1H,
C26–H), 6.93 (dd, J¼4.7, 15.5 Hz, 1H, C27–H); 13C NMR
(100 MHz, CDCl3) d 24.8, 24.6, 18.0, 25.2, 25.6, 27.4,
32.1, 61.4, 61.6, 70.9, 77.7, 78.3, 107.8, 119.8, 144.3, 165.5;
FAB-HRMS m/z calcd for C18H36NO6Si (MþþH)
1
779, 704 cm21; H NMR (500 MHz, CDCl3) d 20.14 (s,
3H, SiCH3), 20.07 (s, 3H, SiCH3), 0.76 (s, 9H, SiC(CH3)3),
1.06 (s, 9H, SiC(CH3)3), 1.33 (s, 3H, acetonide CH3), 1.42
(s, 3H, acetonide CH3), 2.20 (s, 3H, C24–H3), 3.78 (dd,
J¼7.6, 11.2 Hz, 1H, C31–H), 3.89 (dd, J¼3.5, 11.2 Hz, 1H,
C31–H), 4.06 (m, 1H, C29–H), 4.30 (m, 1H, C30–H), 4.44
(m, 1H, C28–H), 6.13 (d, J¼16.0 Hz, 1H, C26–H), 6.44
(dd, J¼6.0, 16.0 Hz, 1H, C27–H), 7.35–7.47 (m, 6H, ArH),

S. Nakamura et al. / Tetrahedron 58 (2002) 10375–10386
10381
7.67–7.71 (m, 4H, ArH); 13C NMR (100 MHz, CDCl3) d
24.9, 23.9, 18.0, 19.2, 25.3, 25.8, 26.9, 27.3, 27.5, 63.5,
71.1, 78.5, 79.2, 108.4, 127.48, 127.54, 129.5, 129.6, 131.4,
133.1, 133.4, 135.5, 135.7, 145.9, 197.7; FAB-HRMS m/z
calcd for C33H50O5Si2Na (MþþNa) 605.3094, found
605.3076.
(neat) 3455, 2932, 2859, 1472, 1427, 1372, 1252, 1219,
1
1111, 835, 777, 704 cm21; H NMR (500 MHz, CDCl3) d
20.15 (s, 3H, SiCH3), 20.08 (s, 3H, SiCH3), 0.73 (s, 9H,
SiC(CH3)3), 1.07 (s, 9H, SiC(CH3)3), 1.246 (s, 3H,
C(CH3)2), 1.254 (s, 3H, C(CH3)2), 1.34 (s, 3H, acetonide
CH3), 1.41 (s, 3H, acetonide CH3), 3.79 (dd, J¼8.2,
11.1 Hz, 1H, C31–H), 3.94 (dd, J¼2.9, 11.1 Hz, 1H,
C31–H), 3.97 (t, J¼6.2 Hz, 1H, C29–H), 4.24 (dd,
J¼6.2, 7.0 Hz, 1H, C28–H), 4.30 (m, 1H, C30–H), 5.53
(dd, J¼7.0, 15.7 Hz, 1H, C27–H), 5.68 (d, J¼15.7 Hz, 1H,
C26–H), 7.34–7.42 (m, 6H, ArH), 7.68–7.74 (m, 4H,
ArH); 13C NMR (100 MHz, CDCl3) d 24.7, 23.5, 17.9,
19.2, 25.5, 25.8, 26.9, 27.7, 29.2, 29.5, 63.8, 70.3, 72.0,
79.0, 79.6, 108.1, 126.6, 127.5, 127.6, 129.5, 133.5, 133.9,
135.7, 135.8, 140.7; FAB-HRMS m/z calcd for C34H54O5-
Si2Na (MþþNa) 621.3408, found 621.3412.
4.1.10. (4R,5R,6S,7S)-5-(tert-Butyldimethylsilyl)oxy-8-
(tert-butyldiphenylsilyl)oxy-5,6-(dimethylmethylene-
dioxy)-4-methylocten-2-one (17). Methyllithium in Et2O
(1.14 M, 3.6 mL, 4.12 mmol) was added to a suspension of
CuCN (369.1 mg, 4.12 mmol) in THF (15 mL) at 2788C
under an argon atmosphere, and the resulting mixture was
stirred at 08C for 10 min to form a clear, colorless solution.
After cooling to 2788C, BF3·OEt2 (0.52 mL, 4.12 mmol)
was added, and the mixture was stirred at this temperature
for 5 min. A solution of enone 16 (600.0 mg, 1.03 mmol) in
THF (3 mL) was added, and the mixture was stirred at
2788C for 1 h. The reaction was quenched by addition of
saturated aqueous NH4Cl (9 mL) and 28% aqueous NH3
(3 mL), and the mixture was diluted with Et2O (10 mL).
After stirring at room temperature for 20 min, the whole was
extracted with AcOEt (50 mL). The organic extract was
washed successively with 3% aqueous HCl (2£20 mL),
H2O (20 mL), saturated aqueous NaHCO3 (2£20 mL) and
brine (2£20 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo furnished the crude
product (603.8 mg, slightly yellow oil), which was purified
by column chromatography (silica gel 15 g, 20:1 n-hexane/
AcOEt) to give ketone 17 (490.8 mg, 80%) as a colorless
syrup: [a]2D5¼239.0 (c 1.06, CHCl3); IR (neat) 2934, 2859,
1719, 1472, 1427, 1370, 1254, 1217, 1088, 897, 837, 777,
4.1.11. (1S,2R,3R,5S,7S)-2-(tert-Butyldimethylsilyl)oxy-
7-(tert-butyldiphenylsilyloxy)methyl-3,5-dimethyl-6,8-
dioxabicyclo[3.2.1]octane
(19).
TFA
(0.05 mL,
0.65 mmol) was added to a stirred solution of ketone 17
(165.1 mg, 0.28 mmol) in CH2Cl2 (5 mL) at room tempera-
ture. After stirring for 1 h, Et3N (0.5 mL) was added to the
slightly pink solution. The resultant solution was poured
into a two-layer mixture of Et2O (10 mL) and saturated
aqueous NaHCO3 (20 mL), and the layers were separated.
The aqueous layer was extracted with AcOEt (2£20 mL),
and the combined organic extracts were washed with brine
(2£10 mL), and dried over anhydrous Na2SO4. Filtration
and evaporation in vacuo furnished the crude product
(176.9 mg, slightly yellow oil), which was purified by
column chromatography (silica gel 10 g, 20:1 n-hexane/
AcOEt) to give acetal 19 (123.1 mg, 83%) as a colorless oil:
[a]2D5¼þ38.8 (c 1.01, CHCl3); IR (neat) 2957, 2859, 1471,
1429, 1385, 1252, 1206, 1107, 1069, 1007, 835, 775, 739,
1
704 cm21; H NMR (500 MHz, CDCl3) d 20.13 (s, 3H,
SiCH3), 0.04 (s, 3H, SiCH3), 0.79 (s, 9H, SiC(CH3)3), 0.92
(d, J¼6.4 Hz, 3H, C36–H3), 1.07 (s, 9H, SiC(CH3)3), 1.35
(s, 3H, acetonide CH3), 1.40 (s, 3H, acetonide CH3), 2.06 (s,
3H, C24–H3), 2.26–2.31 (m, 2H, C26–H2), 2.72 (m, 1H,
C27–H), 3.63 (dd, J¼7.7, 10.8 Hz, 1H, C31–H), 3.69 (dd,
J¼2.4, 7.4 Hz, 1H, C28–H), 3.80 (dd, J¼2.7, 10.8 Hz, 1H,
C31–H), 4.08 (m, 1H, C29–H), 4.25 (m, 1H, C30–H),
7.35–7.42 (m, 6H, ArH), 7.69–7.74 (m, 4H, ArH); 13C
NMR (100 MHz, CDCl3) d 24.8, 23.9, 14.8, 18.1, 19.1,
25.7, 25.9, 26.9, 27.9, 30.3, 33.6, 46.6, 63.8, 72.5, 77.4,
78.8, 108.0, 127.4, 127.5, 129.39, 129.43, 133.3, 133.4,
135.6, 135.7, 208.0; FAB-HRMS m/z calcd for C34H54O5-
Si2Na (MþþNa) 621.3408, found 621.3379; Anal. calcd for
C34H54O5Si2: C, 68.07; H, 9.09, found: C, 68.18; H, 9.00.
702 cm21 1H NMR (500 MHz, CDCl3) d 0.06 (s, 3H,
;
SiCH3), 0.09 (s, 3H, SiCH3), 0.83 (d, J¼6.8 Hz, 3H, C36–
H3), 0.93 (s, 9H, SiC(CH3)3), 1.06 (s, 9H, SiC(CH3)3), 1.42
(s, 3H, C24–H3), 1.47–1.51 (m, 2H, C26–H2), 1.95 (m, 1H,
C27–H), 3.65 (dd, J¼1.8, 3.9 Hz, 1H, C28–H), 3.80 (m,
1H, C31–H), 3.96 (dd, J¼5.7, 10.4 Hz, 1H, C31–H), 4.19
(m, 1H, C30–H), 4.36 (dd, J¼1.8, 4.5 Hz, 1H, C29–H),
7.36–7.46 (m, 6H, ArH), 7.63–7.66 (m, 4H, ArH); 13C
NMR (100 MHz, CDCl3) d 24.8, 24.4, 16.8, 18.2, 19.1,
24.4, 25.9, 26.8, 29.8, 40.3, 61.4, 67.6, 80.9, 107.3, 127.7,
127.7, 129.81, 129.83, 132.8, 133.1, 135.4, 135.6; FAB-
HRMS m/z calcd for C31H49O4Si2 (MþþH) 541.3170,
found 541.3163.
Data for syn-isomer 18: [a]2D4¼230.4 (c 0.82, CHCl3); IR
(neat) 2932, 2859, 1719, 1472, 1427, 1368, 1254, 1217,
4.1.12. [1R,1(4S,5S),2R,9(3S,4R,7S)]-9-{2-[9-Benzyloxy-
4-(tert-butyldimethylsilyl)oxy-3-(4-methoxybenzyl)oxy-
4-methyl-7-(triethylsilyl)oxynonyl]-1,3-dithian-2-yl}-1-
(tert-butyldimethylsilyl)oxy-1-[5-(tert-butyldiphenyl-
silyl)oxymethyl-2,2-dimethyl-1,3-dioxolan-4-yl]-6-
hydroxy-2-methylnonan-4-one (20). Butyllithium in
n-hexane (1.56 M, 0.47 mL, 0.73 mmol) was added to a
solution of HMDS (0.16 mL, 0.76 mmol) in THF (2 mL) at
08C under an argon atmosphere. After 10 min at 08C, the
solution was cooled to 2788C, and a solution of ketone 17
(323.0 mg, 0.606 mmol) in THF (1 mL) was added. After
30 min, a solution of aldehyde 4 (336.5 mg, 0.404 mmol) in
THF (1 mL) was added, and the mixture was stirred at
2788C for 1 h and at 2508C for 30 min. The reaction was
1
1111, 835, 777, 704 cm21; H NMR (500 MHz, CDCl3) d
20.16 (s, 3H, SiCH3), 20.07 (s, 3H, SiCH3), 0.76 (s, 9H,
SiC(CH3)3), 0.89 (d, J¼6.7 Hz, 3H, C36–H3), 1.07 (s, 9H,
SiC(CH3)3), 1.36 (s, 3H, acetonide CH3), 1.41 (s, 3H,
acetonide CH3), 2.10 (s, 3H, C24–H3), 2.24–2.29 (m, 2H,
C26–H, C27–H), 2.50 (m, 1H, C26–H), 3.65 (dd, J¼7.8,
11.0 Hz, 1H, C31–H), 3.70 (dd, J¼2.5, 7.5 Hz, 1H, C28–
H), 3.80 (dd, J¼2.3, 11.0 Hz, 1H, C31–H), 3.99 (m, 1H,
C29–H), 4.24 (m, 1H, C30–H), 7.34–7.42 (m, 6H, ArH),
7.68–7.74 (m, 4H, ArH); FAB-HRMS m/z calcd for
C34H55O5Si2 (MþþH) 599.3588, found 599.3581.
Data for 1,2-adduct: [a]2D2¼25.91 (c 2.10, CHCl3); IR

10382
S. Nakamura et al. / Tetrahedron 58 (2002) 10375–10386
quenched with saturated aqueous NH4Cl (15 mL), and the
whole was extracted with AcOEt (2£40 mL). The combined
organic extracts were washed successively with saturated
aqueous NH4Cl (20 mL) and brine (2£20 mL), and dried
over anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product (748.0 mg, slightly yellow oil),
which was purified by column chromatography (silica gel
15 g, 4:1!3:1 n-hexane/Et2O) to give b-hydroxyketone 20
(508.9 mg, 88%) as a colorless oil: [a]2D5¼217.7 (c 1.10,
CHCl3); IR (neat) 3509, 2955, 1707, 1613, 1514, 1462,
1427, 1370, 1250, 1090, 835, 775, 741, 704 cm21; 1H NMR
(500 MHz, CDCl3) d 20.16 to 20.15 (m, 3H, SiCH3),
20.01 (m, 3H, SiCH3), 0.09 (s, 6H, SiCH3£2), 0.58 (q,
J¼7.9 Hz, 6H, Si(CH2CH3)3), 0.78 (s, 9H, SiC(CH3)3), 0.86
(s, 9H, SiC(CH3)3), 0.90 (d, J¼6.2 Hz, 3H, C36–H3), 0.94
(t, J¼7.9 Hz, 9H, Si(CH2CH3)3), 1.06 (s, 9H, SiC(CH3)3),
1.21 (s, 3H, C37–H3), 1.31–1.34 (m, 4H, C22–H,
acetonide CH3), 1.39 (s, 3H, acetonide CH3), 1.42–1.47
(m, 2H, C22–H, C14–H), 1.53–1.64 (m, 6H, C13–H2,
C14–H, C17–H, C21–H2), 1.69–1.89 (m, 8H, C11–H2,
C17–H, C18–H, C20–H2, SCH2CH2), 2.15 (m, 1H, C18–
H), 2.27–2.33 (m, 2H, C26–H, C27–H), 2.37–2.43 (m,
1H, C24–H), 2.47–2.52 (m, 1H, C24–H), 2.63–2.77 (m,
5H, C26–H, SCH2£2), 2.98 (d, J¼3.0 Hz, 0.5H, OH), 3.03
(d, J¼3.0 Hz, 0.5H, OH), 3.16 (m, 1H, C16–H), 3.47–3.57
(m, 2H, C10–H2), 3.62 (m, 1H, C31–H), 3.66 (dd, J¼2.3,
7.4 Hz, 1H, C28–H), 3.77–3.79 (m, 5H, C12–H, C31–H,
C6H4OCH3), 3.98 (m, 1H, C23–H), 4.06 (m, 1H, C29–H),
4.24 (m, 1H, C30–H), 4.43–4.51 (m, 3H, OCHAr,
OCH2Ph), 4.58 (d, J¼11.0 Hz, 1H, OCHAr), 6.83–6.85
(m, 2H, ArH), 7.23–7.27 (m, 3H, ArH), 7.32–7.41 (m, 10H,
ArH), 7.68–7.72 (m, 4H, ArH); FAB-HRMS m/z calcd for
12:1!10:1 n-hexane/AcOEt) to give enone 13 (375.4 mg,
89% (two steps)) as a colorless syrup. The spectral data of
this material were identical with those of a sample obtained
from aldehyde 4 and b-ketophosphonate 5 as described
above.
4.1.14. [1R,1(4S,5S),2R,5E,9(3S,4R,7S)]-9-{2-[9-Benzyl-
oxy-4-(tert-butyldimethylsilyl)oxy-3-hydroxy-4-methyl-
7-(triethylsilyl)oxynonyl]-1,3-dithian-2-yl}-1-(tert-butyl-
dimethylsilyl)oxy-1-[5-(tert-butyldiphenylsilyl)oxy-
methyl-2,2-dimethyl-1,3-dioxolan-4-yl]-2-methyl-5-
nonen-4-one (21). To a solution of MPM ether 13
(601.0 mg, 0.425 mmol) in CH2Cl2 (8 mL)-pH 7 phosphate
buffer (0.8 mL) was added 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (115.6 mg, 0.509 mmol) at room tempera-
ture. After stirring for 1 h, saturated aqueous NaHCO3
(20 mL) was added, and the whole was extracted with
AcOEt (2£40 mL). The combined organic extracts were
washed successively with saturated aqueous NaHCO3
(3£30 mL), H2O (30 mL) and brine (2£30 mL), and dried
over anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product (626.1 mg), which was purified
by column chromatography (silica gel 10 g, 10:1 n-hexane/
AcOEt) to give alcohol 21 (512.7 mg, 93%) as a colorless
oil: [a]2D5¼219.1 (c 1.15, CHCl3); IR (neat) 3491, 2932,
1696, 1669, 1632, 1462, 1427, 1372, 1254, 1101, 837, 775,
1
741, 704 cm21; H NMR (500 MHz, CDCl3) d 20.15 (s,
3H, SiCH3), 0.00 (s, 3H, SiCH3), 0.11 (s, 6H, SiCH3£2),
0.59 (q, J¼8.0 Hz, 6H, Si(CH2CH3)3), 0.78 (s, 9H,
SiC(CH3)3), 0.87 (s, 9H, SiC(CH3)3), 0.91 (d, J¼6.8 Hz,
3H, C36–H3), 0.95 (t, J¼8.0 Hz, 9H, Si(CH2CH3)3), 1.06
(s, 9H, SiC(CH3)3), 1.21 (s, 3H, C37–H3), 1.36 (s, 3H,
acetonide CH3), 1.40 (s, 3H, acetonide CH3), 1.43–1.48 (m,
3H, C13–H, C17–H2), 1.56–1.63 (m, 5H, C13–H, C14–
H2, C21–H2), 1.72–1.95 (m, 7H, C11–H2, C18–H, C20–
H2, SCH2CH2), 2.15–2.17 (m, 2H, C22–H2), 2.27–2.42
(m, 4H, C18–H, C26–H, C27–H, OH), 2.71–2.86 (m, 5H,
C26–H, SCH2£2), 3.30 (dd, J¼3.6, 10.2 Hz, 1H, C16–H),
3.52–3.55 (m, 2H, C10–H2), 3.62 (dd, J¼7.9, 10.9 Hz, 1H,
C31–H), 3.68 (dd, J¼2.8, 7.5 Hz, 1H, C28–H), 3.78–3.83
(m, 2H, C12–H, C31–H), 4.09 (m, 1H, C29–H), 4.26 (m,
1H, C30–H), 4.47 (d, J¼11.9 Hz, 1H, OCHPh), 4.50 (d,
J¼11.9 Hz, 1H, OCHPh), 6.06 (d, J¼15.7 Hz, 1H, C24–H),
6.77 (m, 1H, C23–H), 7.27 (m, 1H, ArH), 7.32–7.42 (m,
10H, ArH), 7.68–7.73 (m, 4H, ArH); 13C NMR (125 MHz,
CDCl3) d 25.0, 24.0, 22.2, 22.1, 4.9, 6.8, 14.6, 17.9, 18.1,
19.0, 22.6, 23.7, 25.2, 25.6, 25.8, 26.8, 27.8, 31.1, 32.3,
33.4, 33.9, 35.4, 36.9, 38.1, 42.9, 53.0, 63.8, 66.7, 69.7,
72.7, 72.8, 77.2, 77.3, 77.4, 78.2, 78.8, 107.9, 127.31,
127.33, 127.4, 127.5, 128.1, 129.35, 129.39, 130.9, 133.3,
133.4, 135.5, 135.7, 138.2, 145.8, 199.6; FAB-HRMS m/z
calcd for C71H120O9S2Si4Na (MþþNa) 1315.7348, found
1315.7340.
C79H130O11S2Si4Na
1453.8100.
(MþþNa)
1453.8028,
found
4.1.13. [1R,1(4S,5S),2R,5E,9(3S,4R,7S)]-9-{2-[9-Benzyl-
oxy-4-(tert-butyldimethylsilyl)oxy-3-(4-methoxybenzyl)-
oxy-4-methyl-7-(triethylsilyl)oxynonyl]-1,3-dithian-2-
yl}-1-(tert-butyldimethylsilyl)oxy-1-[5-(tert-butyldiphe-
nylsilyl)oxymethyl-2,2-dimethyl-1,3-dioxolan-4-yl]-2-
methyl-5-nonen-4-one (13). Acetic anhydride (0.05 mL,
0.538 mmol) was added to a stirred solution of alcohol 20
(428.8 mg, 0.299 mmol) and DMAP (3.6 mg, 29 mmol) in
pyridine (1.5 mL) under an argon atmosphere. After stirring
at room temperature for 16 h, H2O (10 mL) was added, and
the whole was extracted with AcOEt (2£40 mL). The
combined organic extracts were washed successively with
1% aqueous HCl (2£20 mL), H2O (20 mL), saturated
aqueous NaHCO3 (20 mL) and brine (2£20 mL), and
dried over anhydrous Na2SO4. Filtration and evaporation
in vacuo furnished the crude product (504.4 mg, yellow oil),
which was used without further purification.
DBU (75 mL, 0.449 mmol) was added to a stirred solution
of the crude acetate (504.4 mg) in CH2Cl2 (1.5 mL) at room
temperature. After stirring for 1 h, the reaction was
quenched with saturated aqueous NH4Cl (10 mL), and the
whole was extracted with AcOEt (2£40 mL). The combined
organic extracts were washed successively with saturated
aqueous NH4Cl (20 mL) and brine (2£20 mL), and dried
over anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product (534.4 mg, yellow oil), which
was purified by column chromatography (silica gel 10 g,
4.1.15. [1R,1(4S,5S),2R,5E,9(4R,7S)]-9-{2-[9-Benzyloxy-
4-(tert-butyldimethylsilyl)oxy-4-methyl-3-oxo-7-
(triethylsilyl)oxynonyl]-1,3-dithian-2-yl}-1-(tert-butyldi-
methylsilyl)oxy-1-[5-(tert-butyldiphenylsilyl)oxymethyl-
2,2-dimethyl-1,3-dioxolan-4-yl]-2-methyl-5-nonen-4-one
(22). Dess–Martin periodinane (607 mg, 1.43 mmol) was
added to a solution of alcohol 21 (1.03 g, 0.795 mmol) in
CH2Cl2 (10 mL)–pyridine (2 mL) at 08C under an argon
atmosphere. After stirring at 08C for 1 h, the reaction was

S. Nakamura et al. / Tetrahedron 58 (2002) 10375–10386
10383
quenched with saturated aqueous NaHCO3 (5 mL) and 1 M
Na2S2O3 (5 mL), and the whole was extracted with AcOEt
(2£50 mL). The combined organic extracts were washed
successively with 0.5% aqueous HCl (3£20 mL), saturated
aqueous NaHCO3 (2£20 mL) and brine (2£20 mL), and
dried over anhydrous Na2SO4. Filtration and evaporation in
vacuo furnished the crude product (1.14 g, slightly yellow
oil), which was purified by column chromatography (silica
gel 20 g, 16:1!12:1 n-hexane/AcOEt) to give ketone 22
(867.5 mg, 84%) as a colorless oil: [a]2D4¼210.1 (c 1.02,
CHCl3); IR (neat) 2953, 1715, 1672, 1630, 1462, 1427,
1368, 1254, 1215, 1090, 1007, 835, 775, 739, 702 cm21; 1H
NMR (500 MHz, CDCl3) d 20.15 (s, 3H, SiCH3), 0.00 (s,
3H, SiCH3), 0.13 (s, 6H, SiCH3£2), 0.57 (q, J¼7.9 Hz, 6H,
Si(CH2CH3)3), 0.78 (s, 9H, SiC(CH3)3), 0.91–0.95 (m,
21H, C36–H3, Si(CH2CH3)3, SiC(CH3)3), 1.06 (s, 9H,
SiC(CH3)3), 1.23 (m, 1H, 13–H), 1.33 (s, 3H, C37–H3),
1.36 (s, 3H, acetonide CH3), 1.40 (s, 3H, acetonide CH3),
1.49–1.79 (m, 9H, C11–H2, C13–H, C14–H2, C20–H2,
C21–H2), 1.83–1.97 (m, 2H, SCH2CH2), 2.15–2.17 (m,
4H, C18–H2, C22–H2), 2.34 (m, 1H, C27–H), 2.40 (dd,
J¼8.7, 16.1 Hz, 1H, C26–H), 2.66–2.89 (m, 7H, C17–H2,
C26–H, SCH2£2), 3.47–3.55 (m, 2H, C10–H2), 3.62 (dd,
J¼7.8, 10.8 Hz, 1H, C31–H), 3.68 (dd, J¼2.8, 7.5 Hz, 1H,
C28–H), 3.78–3.82 (m, 2H, C12–H, C31–H), 4.09 (m, 1H,
C29–H), 4.26 (m, 1H, C30–H), 4.45 (d, J¼11.9 Hz, 1H,
OCHPh), 4.49 (d, J¼11.9 Hz, 1H, OCHPh), 6.06 (d,
J¼15.7 Hz, 1H, C24–H), 6.76 (m, 1H, C23–H), 7.27 (m,
1H, ArH), 7.31–7.42 (m, 10H, ArH), 7.68–7.73 (m, 4H,
ArH); 13C NMR (100 MHz, CDCl3) d 24.9, 23.9, 22.19,
22.17, 5.0, 6.9, 14.7, 18.0, 19.1, 22.7, 25.1, 25.7, 25.86,
25.93, 26.9, 27.9, 31.3, 31.7, 32.4, 33.4, 34.0, 36.9, 37.1,
39.0, 43.0, 52.7, 63.9, 66.9, 69.2, 72.8, 72.9, 77.2, 77.5,
78.2, 78.9, 82.7, 108.0, 127.38, 127.43, 127.52, 127.54,
128.2, 129.4, 129.5, 131.1, 133.4, 133.5, 135.7, 135.8,
138.4, 145.7, 199.8, 214.6; FAB-HRMS m/z calcd for
C71H118O9S2Si4Na (MþþNa) 1313.7191, found 1313.7170.
3H, SiCH3), 0.58 (q, J¼7.9 Hz, 6H, Si(CH2CH3)3), 0.77 (s,
9H, SiC(CH3)3), 0.91–0.96 (m, 21H, C36–H3, Si(CH2-
CH3)3, SiC(CH3)3), 1.05 (s, 9H, SiC(CH3)3), 1.23 (m, 1H,
C13–H), 1.33 (s, 3H, C37–H3), 1.36 (s, 3H, acetonide
CH3), 1.40 (s, 3H, acetonide CH3), 1.47–1.64 (m, 2H, C13–
H, C14–H), 1.67–1.78 (m, 5H, C11–H2, C14–H, C21–
H2), 2.13–2.17 (m, 2H, C22–H2), 2.32 (m, 1H, C27–H),
2.39 (dd, J¼8.5, 16.1 Hz, 1H, C26–H), 2.46–2.62 (m, 4H,
C18–H2, C20–H2), 2.76–2.82 (m, 2H, C17–H, C26–H),
2.97 (ddd, J¼5.1, 7.4, 19.4 Hz, 1H, C17–H), 3.48–3.56 (m,
2H, C10–H2), 3.61 (dd, J¼7.7, 10.8 Hz, 1H, C31–H), 3.67
(dd, J¼2.7, 7.5 Hz, 1H, C28–H), 3.76–3.82 (m, 2H, C12–
H, C31–H), 4.09 (dd, J¼6.2, 7.5 Hz, 1H, C29–H), 4.25 (m,
1H, C30–H), 4.45 (d, J¼11.8 Hz, 1H, OCHPh), 4.49 (d,
J¼11.8 Hz, 1H, OCHPh), 6.05 (d, J¼16.0 Hz, 1H, C24–H),
6.74 (m, 1H, C23–H), 7.27 (m, 1H, ArH), 7.31–7.42 (m,
10H, ArH), 7.67–7.73 (m, 4H, ArH); 13C NMR (100 MHz,
CDCl3) d 24.9, 23.9, 22.22, 22.15, 5.0, 6.9, 14.7, 18.0,
18.3, 19.1, 22.0, 25.7, 25.86, 25.93, 26.1, 26.9, 27.9, 31.47,
31.54, 32.2, 34.0, 35.8, 36.8, 37.0, 41.8, 43.0, 63.9, 66.9,
69.2, 72.7, 72.9, 77.5, 78.9, 82.7, 108.0, 127.35, 127.43,
127.5, 128.2, 129.45, 129.50, 131.1, 133.4, 133.5, 135.7,
135.8, 138.5, 145.7, 199.9, 208.3, 214.2; FAB-HRMS m/z
calcd for C68H112O10Si4Na (MþþNa) 1223.7230, found
1223.7270.
4.1.17. [1(2R,6R,8R,10S,13R),4R,5R,5(4S,5S)]-1-[10-(2-
Benzyloxy)ethyl-13-(tert-butyldimethylsilyl)oxy-13-
methyl-1,7,9-trioxadispiro[5.1.5.2]pentadec-2-yl]-5-(tert-
butyldimethylsilyl)oxy-5-[5-(tert-butyldiphenylsilyl)oxy-
methyl-2,2-dimethyl-1,3-dioxolan-4-yl]-4-methylpentan-
2-one (1). To a solution of TES ether 23 (554.2 mg,
0.46 mmol) in THF (7 mL) at 08C was added 1N aqueous
HCl (0.7 mL). After stirring at 08C for 1 h, the reaction was
quenched with saturated aqueous NaHCO3 (10 mL), and the
whole was extracted with AcOEt (50 mL). The organic
extract was washed with brine (10 mL), and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product (539.8 mg), which was used
without further purification.
4.1.16. [1R,1(4S,5S),2R,5E,14R,17S]-19-Benzyloxy-1,14-
bis(tert-butyldimethylsilyl)oxy-1-[5-(tert-butyldiphenyl-
silyl)oxymethyl-2,2-dimethyl-1,3-dioxolan-4-yl]-2,14-
dimethyl-17-(triethylsilyl)oxy-5-nonadecene-4,10,13-
trione (23). A solution of dithioacetal 22 (181.9 mg,
0.140 mmol) in Et2O (0.5 mL) was added to a solution of
AgNO3 (143.5 mg, 0.845 mmol), N-chlorosuccinimide
(121.5 mg, 0.91 mmol) and 2,4,6-collidine (0.1 mL,
0.757 mmol) in 80% aqueous CH3CN (3 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 to the mixture. The mixture was
filtered through a Celite pad, and the filtrate was extracted
with AcOEt (2£40 mL). The combined organic extracts
were washed successively with 0.5% aqueous HCl
(2£30 mL), H2O (20 mL), saturated aqueous NaHCO3
(2£30 mL) and brine (2£20 mL), and dried over Na2SO4.
Filtration and evaporation in vacuo furnished the crude
product (229.6 mg), which was purified by column
chromatography (silica gel 10 g, 16:1 n-hexane/AcOEt) to
give triketone 23 (145.8 mg, 87%) as a colorless oil:
[a]2D5¼213.1 (c 1.05, CHCl3); IR (neat) 2955, 1715, 1672,
1630, 1462, 1370, 1254, 1215, 1090, 1007, 837, 777, 739,
LiOMe (17.6 mg, 0.46 mmol) was added to a stirred
solution of the equilibrium mixture (539.8 mg) in THF
(5 mL)–MeOH (0.5 mL) at 08C under an argon atmosphere.
After stirring at room temperature for 4 h, the reaction was
quenched by addition of saturated aqueous NH4Cl (10 mL),
and the mixture was partitioned between AcOEt (50 mL)
and H2O (10 mL). The organic extract was washed with
brine (10 mL), and dried over anhydrous Na2SO4. Filtration
and evaporation in vacuo furnished the crude product
(524.2 mg, yellow oil), which was purified by flash column
chromatography (silica gel 30 g, 12:1!8:1 n-hexane/Et2O)
to give dispiroketal 1 (387.3 mg, 77%) as a colorless oil,
along with isomers (one less polar isomer (29.4 mg, 6%)
and two more polar isomers (40.8 mg, 8%)) as a colorless
oil: [a]2D4¼222.9 (c 0.46, CHCl3); IR (neat) 2934, 2859,
1713, 1462, 1370, 1254, 1223, 1088, 976, 835, 775, 737,
1
702 cm21; H NMR (500 MHz, CDCl3) d 20.17 (s, 3H,
SiCH3), 20.02 (s, 3H, SiCH3), 0.07 (s, 3H, SiCH3), 0.08 (s,
3H, SiCH3), 0.76 (s, 9H, SiC(CH3)3), 0.85 (s, 9H,
SiC(CH3)3), 0.87 (d, J¼6.7 Hz, 3H, C36–H3), 1.01 (m,
1H, C22–H), 1.06 (s, 9H, SiC(CH3)3), 1.28 (s, 3H, C37–
H3), 1.33 (s, 3H, acetonide CH3), 1.37 (s, 3H, acetonide
1
704 cm21; H NMR (500 MHz, CDCl3) d 21.64 (s, 3H,
SiCH3), 20.01 (s, 3H, SiCH3), 0.13 (s, 3H, SiCH3), 0.14 (s,

10384
S. Nakamura et al. / Tetrahedron 58 (2002) 10375–10386
CH3), 1.39–1.51 (m, 3H, C13–H, C20–H, C21–H), 1.59–
1.61 (m, 3H, C13–H, C14–H, C22–H), 1.67–1.83 (m, 5H,
C11–H2, C17–H, C18–H, C20–H), 1.88 (m, 1H, C21–H),
2.02 (m, 1H, C18–H), 2.08–2.29 (m, 4H, C14–H, C17–H,
C26–H, C27–H), 2.38 (dd, J¼8.2, 16.0 Hz, 1H, C24–H),
2.50 (dd, J¼5.1, 16.0 Hz, 1H, C24–H), 2.66 (dd, J¼5.0,
16.7 Hz, 1H, C26–H), 3.48 (m, 1H, C10–H), 3.56–3.61
(m, 3H, C10–H, C28–H, C31–H), 3.76 (dd, J¼2.4,
10.8 Hz, 1H, C31–H) 3.94 (m, 1H, C12–H), 4.04 (dd,
J¼6.2, 7.5 Hz, 1H, C29–H), 4.23–4.30 (m, 2H, C23–H,
C30–H), 4.44 (s, 2H, OCH2Ph), 7.23 (m, 1H, ArH), 7.29–
7.41 (m, 10H, ArH), 7.67–7.72 (m, 4H, ArH); 13C NMR
(125 MHz, CDCl3) d 25.0, 23.8, 21.93, 21.90, 14.4, 18.1,
19.1, 19.4, 24.4, 25.8, 25.9, 28.1, 30.2, 30.6, 30.8, 33.5, 34.2,
34.5, 35.8, 37.5, 47.3, 49.8, 63.9, 67.8, 68.0, 68.9, 72.2, 72.7,
73.4, 77.3, 79.0, 107.9, 108.1, 110.5, 127.3, 127.4, 127.5,
127.6, 128.2, 129.5, 129.6, 133.5, 133.6, 135.7, 135.9,
138.7, 208.7; FAB-HRMS m/z calcd for C62H98O10Si3Na
(MþþNa) 1109.6365, found 1109.6440; Anal. calcd for
C62H98O10Si3: C, 68.46; H, 9.08, found: C, 68.06; H, 9.00.
4.1.19. (2R,3S,4S)-2-(tert-Butyldimethylsilyl)oxy-5-(tert-
butyldiphenylsilyl)oxy-3,4-(dimethylmethylene)dioxy-
pentanal (26). Ozone gas was bubbled through a stirred
solution of enoate 10 (100.4 mg, 0.164 mmol) in CH2Cl2
(20 mL) at 2788C until the solution turned pale blue. After
stirring at 2788C for 15 min, Me2S (5 mL) was added, and
the mixture was stirred at room temperature for 10 h.
Evaporation in vacuo furnished the crude product (108 mg,
slightly yellow oil), which was purified by column
chromatography (silica gel 15 g, 20:1 n-hexane/AcOEt) to
give aldehyde 26 (74.3 mg, 83%) as a colorless oil:
[a]2D6¼24.7 (c 1.13, CHCl3); IR (neat) 2932, 2859, 1738,
1
1472, 1427, 1383, 1256, 1111, 837, 781, 704 cm21; H
NMR (270 MHz, CHCl3) d 20.08 (s, 3H, SiCH3), 0.00 (s,
3H, SiCH3), 0.81 (s, 9H, SiC(CH3)3), 1.06 (s, 9H,
SiC(CH3)3), 1.33 (s, 3H, acetonide CH3), 1.42 (s, 3H,
acetonide CH3), 3.77 (dd, J¼5.9, 10.5 Hz, 1H, C31–H),
3.97 (dd, J¼4.6, 10.5 Hz, 1H, C31–H), 4.25–4.31 (m, 3H,
C28–H, C29–H, C30–H), 7.37–7.44 (m, 6H, ArH), 7.67–
7.70 (m, 6H, ArH), 9.58 (d, J¼2.0 Hz, 1H, CHO); 13C NMR
(100 MHz, CDCl3) d 25.0, 24.5, 18.0, 19.2, 24.9, 25.7,
26.9, 27.1, 63.3, 76.6, 77.4, 77.9, 108.7, 127.6, 127.7,
129.65, 129.67, 133.2, 133.4, 135.6, 135.7, 201.4; FAB-
HRMS m/z calcd for C48H80O6S2Si2Na (MþþNa)
895.4832, found 895.4851.
4.1.18. [2S,5R,6R,8R,10R,10(1S,2R,3R,5R,7S)]-2-[2-
(Benzyloxy)ethyl]-5-(tert-butyldimethylsilyl)oxy-10-[2-
(tert-butyldimethylsilyl)oxy-7-(tert-butyldiphenylsilyl)-
oxymethyl-3-methyl-6,8-dioxabicyclo[3.2.1]oct-5-
ylmethyl]-5-methyl-1,7,9-trioxadispiro[5.1.5.2]penta-
decane (25). To a solution of ketone 1 (48.0 mg, 44.1 mmol)
in CH2Cl2 (0.5 mL) was added CSA (10.3 mg, 44.1 mmol),
and the solution was stirred for 5 h. The mixture was poured
into a two-layer mixture of saturated aqueous NaHCO3
(5 mL) and Et2O (5 mL), and the whole was extracted with
AcOEt (2£15 mL). The combined organic extracts were
washed with brine (2£10 mL), and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the
crude product (slightly yellow oil), which was purified by
column chromatography (silica gel 15 g, 16:1 n-hexane/
AcOEt) and preparative thin layer chromatography (20:1
CH2Cl2/AcOEt) to give bicycloketal 25 (28.1 mg, 62%) as a
colorless oil: [a]2D1¼þ9.81 (c 1.65, CHCl3); IR (neat) 2953,
2859, 1462, 1364, 1252, 1138, 1103, 1049, 1005, 976, 835,
4.1.20. [1(2R,6R,8R,10S,13R),5R,5(4S,5S)]-1-[10-(2-Ben-
zyloxy)ethyl-13-(tert-butyldimethylsilyl)oxy-13-methyl-
1,7,9-trioxadispiro[5.1.5.2]pentadec-2-yl]-5-(tert-butyl-
dimethylsilyl)oxy-5-[5-(tert-butyldiphenylsilyl)oxy-
methyl-2,2-dimethyl-1,3-dioxolan-4-yl]-3-penten-2-one
(28). To a solution of LiHMDS (prepared from HMDS
(10 mL, 47.4 mmol) and butyllithium in n-hexane (1.56 M,
28 mL, 43.7 mmol)) in THF (0.25 mL) was added a solution
of methyl ketone 3 (20.0 mg, 36.6 mmol) in THF (0.1 mL)
at 2788C under an argon atmosphere. After stirring at this
temperature for 1 h, aldehyde 26 (23.8 mg, 43.9 mmol) in
THF (0.15 mL) was added, and the resulting mixture was
stirred at 2788C for 2 h. The reaction was quenched with
saturated aqueous NH4Cl (1 mL), and the mixture was
partitioned between Et2O (3 mL) and H2O (3 mL). The
aqueous layer was extracted with AcOEt (2£10 mL), and
the combined organic extracts were washed with brine
(10 mL), and dried over anhydrous Na2SO4. Filtration and
evaporation in vacuo furnished the crude product (46.1 mg),
which was used without further purification.
1
774, 702 cm21; H NMR (500 MHz, C6D6) d 0.13 (s, 6H,
SiCH3), 0.17 (s, 3H, SiCH3), 0.18 (s, 3H, SiCH3), 0.94 (d,
J¼6.7 Hz, 3H, C36–H3), 1.01 (s, 9H, SiC(CH3)3), 1.07 (s,
9H, SiC(CH3)3), 1.19 (s, 9H, SiC(CH3)3), 1.34 (s, 3H, C37–
H3), 1.37 (m, 1H, C22–H), 1.46–1.53 (m, 3H), 1.57 (m,
1H), 1.64 (m, 1H), 1.72 (t, J¼12.5 Hz, 1H, C26–H), 1.81–
1.87 (m, 2H), 1.89–2.00 (m, 3H), 2.02–2.21 (m, 6H), 2.27–
2.38 (m, 3H), 3.75 (m, 1H, C10–H), 3.79 (t, J¼1.5 Hz, 1H,
C28–H), 3.83 (m, 1H, C10–H), 4.00 (dd, J¼9.3, 10.4 Hz,
1H, C31–H), 4.21 (dd, J¼5.5, 10.4 Hz, 1H, C31–H), 4.27
(m, 1H, C12–H), 4.43 (m, 1H, C30–H), 4.43 (d,
J¼12.3 Hz, 1H, OCHPh), 4.47 (d, J¼12.3 Hz, 1H,
OCHPh), 4.50 (m, 1H, C23–H), 4.56 (dd, J¼1.5, 4.3 Hz,
1H, C29–H), 7.13 (m, 1H, ArH), 7.18–7.23 (m, 2H, ArH),
7.26–7.29 (m, 6H, ArH), 7.35–7.38 (m, 2H, ArH), 7.76–
7.78 (m, 4H, ArH); 13C NMR (125 MHz, CDCl3) d 24.7,
24.3, 21.88, 21.86, 16.9, 18.1, 18.3, 19.2, 19.7, 24.4,
25.89, 25.92, 26.8, 29.6, 30.1, 30.6, 32.3, 34.3, 34.6, 35.7,
37.6, 39.4, 44.7, 61.5, 67.8, 67.9, 68.0, 68.8, 72.7, 73.5,
78.0, 80.2, 107.9, 108.0, 110.3, 127.2, 127.4, 127.7, 127.8,
128.2, 129.8, 133.0, 133.2, 135.5, 135.6, 138.8; FAB-
HRMS m/z calcd for C59H92O9Si3Na (MþþNa) 1051.5946,
found 1051.5980.
Ac2O (10 mL, 0.11 mmol) was added to a stirred solution of
the aldol adduct (46.1 mg) in pyridine (0.3 mL) under an
argon atmosphere. After stirring for 5 h, the solution was
poured into a two-layer mixture of AcOEt (5 mL) and H2O
(1 mL), and the whole was extracted with AcOEt (5 mL).
The organic extract was washed successively with 3%
aqueous HCl (3£3 mL), H2O (3 mL), saturated aqueous
NaHCO3 (3 mL) and brine (2£3 mL), and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product (48.4 mg), which was used
without further purification.
DBU (10 mL, 66.9 mmol) was added to a solution of the
acetate (48.4 mg) in CH2Cl2 (0.3 mL) at 08C under an argon
atmosphere. After stirring for 2 h, the reaction was
quenched with saturated aqueous NH4Cl (0.5 mL), and the

S. Nakamura et al. / Tetrahedron 58 (2002) 10375–10386
10385
whole was partitioned between AcOEt (5 mL) and H2O
Acknowledgements
(1 mL). The organic extract was washed with brine
(2£2 mL), and dried over anhydrous Na2SO4. Filtration
and evaporation in vacuo furnished the crude product
(47.3 mg), which was purified by column chromatography
(silica gel 15 g, 60:1 benzene/acetone) to give enone 28
(9.6 mg, 24%) as a colorless oil, along with recovered
ketone 3 (10.9 mg, 56%): [a]2D1¼23.8 (c 0.25, C6H6); IR
(neat) 2932, 2857, 1698, 1674, 1634, 1462, 1370, 1254,
1223, 1111, 978, 835, 775, 702 cm21; 1H NMR (500 MHz,
CDCl3) d 20.18 (s, 3H, SiCH3), 20.10 (s, 3H, SiCH3), 0.07
(s, 3H, SiCH3), 0.08 (s, 3H, SiCH3), 0.73 (s, 9H,
SiC(CH3)3), 0.85 (s, 9H, SiC(CH3)3), 1.06 (9H,
SiC(CH3)3), 1.09–1.18 (m, 1H, C22–H), 1.28 (s, 3H,
C37–H3), 1.30 (s, 3H, acetonide CH3), 1.39 (s, 3H,
acetonide CH3), 1.41–1.49 (m, 2H, C13–H, C20–H),
1.56–1.86 (m, 9H, C11–H2, C13–H, C14–H, C17–H,
C18–H, C20–H, C21–H, C22–H), 1.90 (m, 1H, C21–H),
1.99–2.18 (m, 3H, C14–H, C17–H, C18–H), 2.59 (dd,
J¼7.9, 15.5 Hz, 1H, C24–H), 2.64 (dd, J¼5.1, 15.5 Hz, 1H,
C24–H), 3.49 (m, 1H, C10–H), 3.59 (m, 1H, C10–H), 3.75
(dd, J¼8.0, 11.2 Hz, 1H, C31–H), 3.87 (dd, J¼3.0, 11.2 Hz,
1H, C31–H), 3.96 (m, 1H, C12–H), 4.00 (m, 1H, C29–H),
4.28 (m, 1H, C30–H), 4.34–4.39 (m, 2H, C23–H, C28–H),
4.43 (s, 2H, OCH2Ph), 6.16 (d, J¼15.7 Hz, 1H, C26–H),
6.66 (dd, J¼6.0, 15.7 Hz, 1H, C27–H), 7.23 (m, 1H, ArH),
7.28–7.42 (m, 10H, ArH), 7.67–7.71 (m, 4H, ArH); 13C
NMR (125 MHz, CDCl3) d 24.9, 23.8, 21.92, 21.88,
17.9, 18.7, 19.2, 19.5, 24.4, 25.4, 25.7, 25.9, 26.9, 27.6,
29.7, 30.2, 30.5, 30.6, 34.2, 34.5, 35.9, 37.5, 47.3, 63.7,
67.8, 68.0, 69.4, 71.1, 72.8, 73.4, 78.7, 79.3, 108.0, 108.5,
110.5, 127.3, 127.6, 127.7, 128.2, 129.59, 129.63, 131.3,
133.4 133.6, 135.6, 135.7, 135.8, 138.7, 145.4, 198.0; FAB-
HRMS m/z calcd for C61H94O10Si3Na (MþþNa)
1093.6052, found 1093.6040.
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.
References
1. Nakamura, S.; Inagaki, J.; Kudo, M.; Sugimoto, T.; Obara, K.;
Nakajima, M.; Hashimoto, S. Tetrahedron 2002, 58, 10353.
2. For a preliminary communication, see: Nakamura, S.; Inagaki,
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3. Schmidt, R. R.; Gohl, A. Chem. Ber. 1979, 112, 1689–1704.
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4.1.21. [1(2R,6R,8R,10S,13R),4R,5R,5(4S,5S)]-1-[10-(2-
Benzyloxy)ethyl-13-(tert-butyldimethylsilyl)oxy-13-
methyl-1,7,9-trioxadispiro[5.1.5.2]pentadec-2-yl]-5-(tert-
butyldimethylsilyl)oxy-5-[5-(tert-butyldiphenylsilyl)-
oxymethyl-2,2-dimethyl-1,3-dioxolan-4-yl]-4-methyl-
pentan-2-one (1). Methyllithium in Et2O (1.14 M, 0.16 mL,
0.18 mmol) was added to a suspension of CuCN (16.0 mg,
0.18 mmol) in THF (1 mL) at 2788C under an argon
atmosphere, and the resulting mixture was stirred at 08C for
10 min to form a clear, colorless solution. After cooling to
2788C, BF3·OEt2 (24 mL, 0.19 mmol) was added, and the
mixture was stirred at this temperature for 5 min. A solution
of enone 28 (12.0 mg, 11.2 mmol) in THF (0.5 mL) was
added, and the mixture was stirred at 2788C for 2 h. The
reaction was quenched by addition of saturated aqueous
NH4Cl (2 mL) and 28% aqueous NH3 (1 mL), and the
mixture was diluted with Et2O (5 mL). After stirring at room
temperature for 20 min, the whole was extracted with
AcOEt (15 mL). The organic extract was washed succes-
sively with 3% aqueous HCl (5 mL), H2O (10 mL),
saturated aqueous NaHCO3 (5 mL) and 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 n-hexane/A-
cOEt) to give ketone 1 (8.9 mg, 73%) as a colorless syrup.
The spectral data of this material were identical with those
of a sample obtained from triketone 23 as described above.
11. anti-Selective conjugate addition reactions of methylcopper or
dimethylcuprate reagents to g-alkoxy-a,b-enone, see: (a) Me2-
Cu(CN)Li2/TMSCl: DiFranco, E.; Ravikumar, V. T.;
Salomon, R. G. Tetrahedron Lett. 1993, 34, 3247–3250.
(b) Me2CuLi: Horita, K.; Hachiya, S.; Ogihara, K.; Yoshida,
Y.; Nagasawa, M.; Yonemitsu, O. Heterocycles 1996, 42,
99–104. (c) MeCu(CN)Li: Amigoni, S.; Schulz, J.; Martin, L.;
Le Floc’h, Y. Tetrahedron: Asymmetry 1997, 8, 1515–1518.
12. Raczko reported copper-catalyzed conjugate addition reac-
tions of Grignard reagents to g-alkoxy-a,b-enones: Raczko, J.
Tetrahedron: Asymmetry 1997, 8, 3821–3828.
13. For conjugate addition reactions of other organocopper
reagents to g-alkoxy-a,b-enones, see: (a) Roush, W. R.;
Lesur, B. M. Tetrahedron Lett. 1983, 24, 2231–2234.
(b) Leonard, J.; Ryan, G. Tetrahedron Lett. 1987, 28,
2525–2528.
14. For reviews on organocopper-Lewis acid reagents, see:
(a) Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1986, 25,
947–959. (b) Lipshutz, B. H. In Organometallics in Synthesis
A Manual; Schlosser, M., Ed.; Wiley: West Sessex, 2002;
pp 665–815.
15. (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron
Lett. 1982, 23, 885–888. (b) Horita, K.; Yoshioka, T.; Tanaka,
T.; Oikawa, Y.; Yonemitsu, O. Tetrahedron 1986, 42,
3021–3028.
16. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48,

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1991, 113, 7277–7287.
17. Corey, E. J.; Erickson, B. W. J. Org. Chem. 1971, 36,
3553–3560.
18. The isomerization of 25 to its C19 epimer, if any, could not be
found under the ketalization conditions (CSA in CH2Cl2). In
this respect, Murai and co-workers reported that the C19
epimer of the closely related dispiroketal compound isomer-
ized under the similar conditions to give a 4.3:1 equilibrium
mixture of C19 epimeric dispiroketals, with the undesired
configuration favored.19 However, they did not mention the
result of epimerization of the desired isomer.
19. Sugimoto, T.; Ishihara, J.; Murai, A. Synlett 1999, 541–544.
20. To further ascertain the stereochemical assignment of the
products, an alternative route to the dispiroketal 1 from 3, the
stereochemistry of which was unambiguously established by a
single-crystal X-ray analysis,1 was explored (Scheme 5). The
reaction of the lithium enolate derived from methyl ketone 3
with aldehyde 26, which was obtained by the ozonolysis of
enoate 10 in 83% yield, stopped at ca. 40% conversion of 3 to
afford an inseparable mixture of aldol adduct 27 and unreacted
ketone 3. Treatment of the mixture with Ac2O followed by
exposure to DBU gave enone 28 in 24% overall yield for the
three steps, along with 56% recovery of ketone 3. Installation
of the C27 methyl group under the foregoing conditions
furnished 1 in 73% yield, which was identical in all respects
with the material derived from an equilibrium mixture of
hydroxytriketone 24 and hemiketals.
Scheme 5. Reagents and conditions: (a) O3, CH2Cl2, 2788C, 15 min, then
Me2S, rt, 10 h, 83%; (b) LiHMDS, THF, 2788C, 1 h, then 26, 2788C, 2 h;
(c) Ac2O, pyridine, 5 h; (d) DBU, CH2Cl2, 08C, 2 h, 24% (three steps);
(e) MeCu(CN)Li, BF3·OEt2, THF/Et2O (11:1), 2788C, 2 h, 73%.