A stereoselective route to multi-substituted tetrahydropyrans by vinyl radical cyclization

Article abstract of DOI:10.1016/j.tet.2005.07.007

The tin-mediated 6-exo-trig radical cyclization of the acetylenic β-alkoxy acrylates proceeded smoothly to give fully substituted tetrahydropyrans in good yields with high equatorial selectivity irrespective of the stereochemistry of the propargylic posit

Full text of DOI:10.1016/j.tet.2005.07.007

Tetrahedron 61 (2005) 8589–8597
A stereoselective route to multi-substituted tetrahydropyrans by
vinyl radical cyclization
Naoki Hiramatsu,a Natsuko Takahashi,a Ryoji Noyorib,† and Yuji Moria,
*
aFaculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku, Nagoya 468-8503, Japan
bDepartment of Chemistry and Research Center for Materials Science, Nagoya University, Chikusa, Nagoya 464-8606, Japan
Received 13 June 2005; accepted 6 July 2005
Available online 21 July 2005
Abstract—The tin-mediated 6-exo-trig radical cyclization of the acetylenic b-alkoxy acrylates proceeded smoothly to give fully substituted
tetrahydropyrans in good yields with high equatorial selectivity irrespective of the stereochemistry of the propargylic position.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The tetrahydropyran nucleus is an integral structural
component of an increasing number of biologically
significant marine polycyclic ether toxins.1 The synthesis
of such a fused ring system is receiving a great deal of
attention, and a variety of approaches have been developed.2
Among them, radical cyclization methods developed for the
stereoselective synthesis of trans-fused tetrahydropyrans
include the intramolecular addition of acyl,3 ketyl,4 and
vinyl radicals5 to b-alkoxy acrylates. However, these
methods were limited to the construction of the general
structure I, and the formation of fully substituted tetra-
hydropyrans such as structure II has not been studied
(Fig. 1). The ring system II would serve as a potent
precursor of 4-hydroxy-3-methyl-tetrahydropyrans III and
IV,6 which correspond to the I ring of yessotoxin7 and
Figure 1.
adriatoxin8 and the H ring of gambieric acids,9 respectively.
mediated radical reaction of propargyl alcohol derivatives
to construct multi-substituted tetrahydropyrans.
An efficient and straightforward construction of II is
envisioned by the 6-exo-trig cyclization of vinyl radical V
generated from a propargyl alcohol derivative.
2. Results and discussion
Of particular concern is the influence of the alkoxy group
adjacent to the vinyl radical on the cyclization. The
stereochemistry and the protecting group of the hydroxy
group might influence the reaction course of the radical
reaction, such as cyclization, premature reduction (hydro-
stannation), and elimination.10 We report here a tin-
The synthesis of radical cyclization precursors is summar-
ized in Scheme 1. Treatment of (2S,3S)-3-(tert-butyl-
dimethylsilyloxy)tetrahydropyran-2-carboxaldehyde11 with
ethynylmagnesium bromide gave a separable mixture of
propargyl alcohols 1 and 2 in 63 and 33% yield,
respectively. The protection of each alcohol with methoxy-
methyl or p-methoxybenzyl groups, desilylation, and the
hetero-Michael reaction with methyl propiolate in the
presence of N-methylmorpholine afforded (E)-alkoxy
acrylates 3 and 4.
Keywords: Radical cyclization; Tetrahydropyrans; Polycyclic ethers;
Alkoxy acrylates.
*
Corresponding author. Tel.: C81 52 832 1781; fax: C81 52 834 8090;
e-mail: mori@ccmfs.meijo-u.ac.jp
† Nagoya University. Visiting Professor at Meijo University.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.007

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N. Hiramatsu et al. / Tetrahedron 61 (2005) 8589–8597
cyclization to be completed within 60 min. The reported
radical cyclizations of b-alkoxy acrylates were carried out
by the slow addition of a benzene solution of Bu3SnH and
AIBN over a period of hours by a syringe pump (80 8C,
w12 h).3,5
The high stereoselectivity and good yields of the radical
cyclization prompted us to extend this study to more
functionalized precursors. The synthesis started with the
known bicyclic alcohol 9,12 which was prepared in five steps
according to our oxiranyl anion strategy.13 Protection of the
alcohol with the triethylsilyl group, hydrogenolysis of the
benzyl ether, and oxidation with Dess–Martin periodinane
afforded aldehyde 10 (Scheme 2).
Scheme 1. Reagents and conditions: (a) MOM–Cl, NaH, DMF or PMB–Cl,
NaH, DMF; (b) Bu4NF, THF, rt; (c) methyl propiolate, NMM, CH2Cl2, rt.
Reaction of the acetylenic b-alkoxy acrylates 3 with
Bu3SnH and AIBN in toluene at a concentration of
0.05 M and at 110 8C for 40 min and the subsequent acidic
destannylation of the products gave the 6,6-bicyclic ethers 6
having equatorial CH2CO2Me and OR groups in good yields
(Table 1). The radical cyclization of the other isomers 4 also
proceeded under the same reaction conditions to provide the
bicyclic products 8, which have equatorial CH2CO2Me and
axial OR substituents (Table 2). The stereochemistry of the
cyclization products was determined by an NOE interaction
between the axial Ha and Hb protons of the newly formed
tetrahydropyran ring (9% NOE for 6a, 10% NOE for 8a).
Interestingly, the 6-exo-trig radical cyclization reaction of
both isomers 3 and 4 proceeded with high diastereo-
selectivity and in good yields in such a way as to give
products with an equatorial CH2CO2Me, irrespective of the
stereochemistry of the alkoxy group at the propargylic
position. It is worthwhile noting that the present reaction
conditions (a 0.05 M solution in toluene at 110 8C) led the
Table 1. Radical cyclization of 3
Scheme 2.
The reaction with ethynylmagnesium bromide gave a
mixture of diastereoisomers 11 and 12, which were easily
separated by flash chromatography. The stereochemistry of
both isomers was determined by the 1H NMR analysis of the
corresponding acetonide derivatives. After protection of the
propargyl alcohol with an acetyl group, the triethylsilyl
group was removed and then an acrylate moiety was
introduced with methyl propiolate to give acetylenic
b-alkoxy acrylates 13a and 14 in 60 and 85% yield,
respectively. A partial 1,3-migration of the acetyl group was
observed during the hetero-Michael reaction with methyl-
propiolate: the extent of the migration was 1:3.5 for 13a and
1:9 for 14. The p-methoxybenzylation of 11 resulted in a
low yield of the product due to the 1,3-migration of the
triethylsilyl group and the partial decomposition of the
silylene group under the reaction conditions.
Substrate
5/Yield (%)a
6/Yield (%)a
dsb
3a RZMOM
3b RZPMB
5a/90
5b/75
6a/91
6b/72
95:5
94:6
a Isolated yield after flash chromatography.
b Determined by 1H NMR analysis.
Table 2. Radical cyclization of 4
Treatment of 13 and 14 with Bu3SnH and AIBN in refluxing
toluene furnished the tricyclic ethers 15 and 16 in good
yields with high stereoselectivity (Table 3). The stereo-
chemistry of 15a and 16 was determined by the NOE
experiments. An 11.6% NOE was observed between the Ha
and Hb of 15a, and in the case of 16, 10.2 and 5.1% NOEs
were detected between Ha and Hb and between Hb and Hc,
respectively. The results showed again that the
Substrate
7/Yield (%)a
8/Yield (%)a
dsb
4a RZMOM
4b RZPMB
7a/87
7b/90
8a/92c
8b/69
95:5
94:6
a Isolated yield after flash chromatography.
b Determined by 1H NMR analysis.
c Isolated as RZH.

N. Hiramatsu et al. / Tetrahedron 61 (2005) 8589–8597
8591
Table 3. Radical cyclization of 13 and 14
The following hydrolysis of the b-alkoxy acrylate group of
18 in the presence of the silylene group was carried out
effectively with p-TsOH in the presence of n-dodecanthiol14
in acetonitrile at 80 8C, giving the desired tetrahydropyran
19 in 82% yield. The principle of the group-selective radical
cyclization also applied to the other isomer 20 and the
functionalized tetrahyropyran 21 was constructed in good
yield.
Substrate
Product
Yield (%)a
dsb
3. Conclusion
13a
13b
14
15a
15b
16
78c
82
92:8
96:4
93:7
81
In summary, we developed a straightforward approach
towards multi-substituted tetrahydropyrans via a vinyl
radical generated from an acetylenic b-alkoxy acrylate
moiety. We also demonstrated interesting group-selective
radical cyclizations and the efficient thiol-mediated depro-
tection of b-alkoxy acrylate group. The tetrahydropyran ring
constructed contains methoxycarbonylmethyl, hydroxy, and
exocyclic methylene groups, which are useful for the partial
and total synthesis of the related structurally and biologi-
cally interesting class of polycyclic ethers.
a Isolated yield after flash chromatography.
1
b Determined by H NMR analysis.
c Corrected yield based on pure 13a.
stereochemistry of the substituent at the propargylic
position did not affect the radical cyclization.
We next examined the protecting group of a propargyl
alcohol to prevent the 1,3-migration of the acetyl and
triethylsilyl groups in the synthesis of 13 and 14. As the
hetero-Michael reaction of an alcohol with methyl
propiolate proceeded in an excellent yield, we decided to
introduce two acrylate groups, one for a protecting group of
a propargyl alcohol and the other for a radical acceptor.
Removal of the triethylsilyl group of 11 followed by the
reaction of the resulting diol with methyl propiolate in the
presence of N-methylmorpholine gave bis(b-alkoxy
acrylate) 17 in 94% yield (Scheme 3).
4. Experimental
4.1. General
IR spectra were recorded in CHCl3 solution on a JASCO
FTIR-420 spectrometer. 1H and 13C NMR spectra were
recorded on a JEOL A-400 or A-600 spectrometer in CDCl3
solution using TMS and CDCl3 (77.00 ppm) as internal
standards, respectively. EI and FAB mass spectra were
obtained on JEOL JMS-700 and HX-110 mass spec-
trometers, respectively. Optical rotations were determined
on a JASCO DIP-370 digital polarimeter. All air- and
moisture-sensitive reactions were carried out under an argon
atmosphere in dry, freshly distilled solvents under
anhydrous conditions. Flash chromatography was carried
out with E. Merck silica gel 60 (230–400 mesh). The term
‘dried’ refers to the drying of an organic solution over
MgSO4 followed by filtration.
4.1.1. (S)-1-[(2R,3S)-3-(tert-Butyldimethylsilyloxy)tetra-
hydropyran-2-yl]prop-2-yn-1-ol (1) and (R)-1-[(2R,3S)-
3-(tert-butyldimethylsilyloxy)tetrahydropyran-2-yl]-
prop-2-yn-1-ol (2). To a stirred solution of 0.5 M
ethynylmagnesium bromide in Et2O (14.5 mL, 10.5 mmol)
at 0 8C was added a solution of (2S,3S)-3-(tert-butyl-
dimethylsilyloxy)tetrahydropyran-2-carboxaldehyde11
(857 mg, 3.51 mmol) in THF (18 mL), and the reaction
mixture was stirred for 1 h. The reaction was quenched with
saturated aqueous NH4Cl and the mixture was extracted
with EtOAc. The extract was washed with water and brine,
dried, and concentrated. Purification by flash chromato-
graphy (20% EtOAc in hexane) gave alcohols 1 (599 mg,
63%) and 2 (313 mg, 33%). Compound 1: colorless oil;
[a]2D5C25.4 (c 1.0, CHCl3); IR (CHCl3) 3564, 3306, 1472,
1234, 1162, 837 cmK1; 1H NMR (400 MHz, CDCl3) d 0.10
(3H, s), 0.12 (3H, s), 0.89 (9H, s), 1.49 (1H, m), 1.62–1.71
(2H, m), 2.07 (1H, m), 2.45 (1H, d, JZ2.0 Hz), 2.76 (1H, d,
JZ10.2 Hz, OH), 3.19 (1H, dd, JZ8.8, 1.9 Hz), 3.45 (1H,
m), 3.77 (1H, ddd, JZ10.7, 8.8, 4.4 Hz), 4.00 (1H, m), 4.58
Scheme 3.
Although 17 could suffer radical cyclization in 4-exo and
6-exo fashions, leading to an oxetane and a tetrahydropyran,
respectively, we anticipated that a group-selective cycliza-
tion via a 6-exo pathway would occur for an obvious steric
reason. Indeed, the treatment of 17 with Bu3SnH and AIBN
in refluxing toluene followed by acidic destannylation
furnished the desired tetrahydropyran 18 in good yields with
high diastereoselectivity.

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N. Hiramatsu et al. / Tetrahedron 61 (2005) 8589–8597
(1H, ddd, JZ10.7, 1.9, 1.9 Hz); 13C NMR (100 MHz,
CDCl3) dK4.8, K4.0, 17.8, 25.2, 25.6, 25.7 (2!C), 33.0,
61.5, 67.3, 68.2, 72.6, 83.2, 83.6; HREIMS m/z calcd for
C14H26O3Si 270.1650, found 270.1692. Compound 2:
colorless oil; [a]D25C65.2 (c 1.0, CHCl3); IR (CHCl3)
Purification by flash chromatography (40% EtOAc in
hexane) gave 3 (58 mg, 96%) as a colorless oil; [a]2D5C
114.5 (c 1.0, CHCl3); IR (CHCl3) 3306, 1705, 1645, 1623,
1
1438, 1335, 1147, 1070, 1022 cmK1; H NMR (400 MHz,
CDCl3) d 1.56 (1H, dddd, JZ17.6, 12.7, 11.2, 5.4 Hz),
1.73–1.85 (2H, m), 2.32 (1H, m), 2.49 (1H, d, JZ2.0 Hz,),
3.34 (3H, s,), 3.47 (1H, ddd, JZ11.2, 11.2, 3.4 Hz), 3.48
(1H, dd, JZ5.4, 2.0 Hz), 3.69 (3H, s), 4.10 (1H, m), 4.16
(1H, ddd, JZ10.7, 9.3, 4.9 Hz), 4.61 and 5.01 (each 1H, d,
JZ6.8 Hz), 4.67 (1H, t, JZ2.2 Hz), 5.32 and 7.51 (each 1H,
d, JZ12.2 Hz); 13C NMR (100 MHz, CDCl3) d 24.6, 29.1,
51.1, 56.2, 63.4, 68.4, 74.9, 75.6, 79.3, 80.8, 94.3, 98.1,
160.8, 167.9; HREIMS m/z calcd for C14H20O6 284.1259,
found 284.1265.
3563, 3306, 1472, 1254, 1104, 861 cmK1 1H NMR
;
(400 MHz, CDCl3) d 0.08 (3H, s), 0.10 (3H, s), 0.87 (9H,
s), 1.47 (1H, dddd, JZ13.2, 13.2, 10.7, 4.4 Hz), 1.62–1.79
(2H, m), 2.05 (1H, m), 2.49 (1H, d, JZ2.4 Hz), 2.87 (1H, d,
JZ10.2 Hz, OH), 3.26 (1H, dd, JZ9.3, 3.4 Hz), 3.37 (1H,
ddd, JZ11.7, 11.7, 2.9 Hz), 3.64 (1H, ddd, JZ10.7, 9.3,
4.9 Hz), 4.02 (1H, m), 4.65 (1H, ddd, JZ10.2, 3.4, 2.4 Hz);
13C NMR (100 MHz, CDCl3) dK4.9, K4.0, 17.8, 25.0, 25.7
(3!C), 33.1, 62.8, 68.0, 68.4, 74.1, 81.7, 83.7; HREIMS
m/z calcd for C14H26O3Si 270.1650, found 270.1269.
4.1.3. (E)-3-{(2S,3S)-2-[(S)-1-(p-Methoxybenzyloxy)
acid
prop-2-ynyl]tetrahydropyran-3-yloxy}acrylic
4.1.2. (E)-3-{(2S,3S)-2-[(S)-1-(Methoxymethoxy)prop-2-
ynyl]tetrahydropyran-3-yloxy}acrylic acid methyl ester
(3a). (i) O-Methoxymethylation. To a stirred solution of 1
(76 mg, 0.281 mmol) in THF were added NaH (60% in
mineral oil, 79 mg, 1.976 mmol) and MOM–Cl (0.28 mL,
3.670 mmol), and the reaction mixture was refluxed for 1 h.
After cooling to rt, the mixture was extracted with EtOAc.
The extract was washed with water and brine, dried, and
concentrated. Purification by flash chromatography (20%
EtOAc in hexane) gave methoxymethyl ether (72 mg, 81%)
as a colorless oil; [a]D25C101.6 (c 1.0, CHCl3); IR (CHCl3)
methyl ester (3b). To a solution of alcohol 1 (100 mg,
0.37 mmol) in DMF (1.8 mL) were added NaH (60% in
mineral oil, 45 mg, 1.85 mmol) and PMB–Cl (0.15 mL,
1.11 mmol), and the reaction mixture was stirred at 0 8C for
17 h. The reaction was quenched with saturated aqueous
NH4Cl and the mixture was extracted with Et2O. The extract
was washed with water and brine, dried, and concentrated.
Purification by flash chromatography (30% EtOAc in
hexane) gave PMB ether (95 mg, 65%). The desilylation
of the PMB ether and the reaction with methyl propiolate
were carried out in the same manner as described for 3a to
give 3b (82 mg, 95% for two steps) as a colorless oil;
[a]2D5C124.2 (c 1.0, CHCl3); IR (CHCl3) 3306, 1705, 1643,
1622, 1514, 1157, 1076 cmK1; 1H NMR (400 MHz, CDCl3)
d 1.49 (1H, dddd, JZ12.7, 12.7, 12.7, 5.4 Hz), 1.62–1.81
(2H, m), 2.02 (1H, m), 2.53 (1H, d, JZ2.4 Hz), 3.37 (1H,
dd, JZ8.8, 2.4 Hz), 3.41 (1H, ddd, JZ11.2, 11.2, 3.4 Hz),
3.72 (3H, s), 3.78 (3H, s), 4.05–4.18 (2H, m), 4.26 (1H, t,
JZ2.4 Hz), 4.44 and 5.77 (each 1H, d, JZ11.7 Hz), 5.16
and 7.33 (each 1H, d, JZ12.2 Hz), 6.83 and 7.24 (each 2H,
d, JZ8.8 Hz); 13C NMR (100 MHz, CDCl3) d 24.7, 29.2,
51.1, 55.1, 65.0, 68.4, 70.4, 74.9, 75.8, 79.8, 80.9, 97.7,
113.7 (2!C), 128.6, 130.5 (2!C), 159.5, 161.2, 168.0;
HREIMS m/z calcd for C20H24O6 360.1571, found
360.1554.
3306, 1464, 1253, 1104, 1029, 838 cmK1 1H NMR
;
(400 MHz, CDCl3) d 0.087 (3H, s), 0.094 (3H, s), 0.89
(9H, s), 1.45 (1H, dddd, JZ13.2, 13.2, 10.7, 4.4 Hz), 1.62–
1.79 (2H, m), 2.12 (1H, m), 2.45 (1H, d, JZ2.0 Hz), 3.24
(1H, dd, JZ8.8, 1.5 Hz), 3.42 (1H, ddd, JZ11.7, 11.7,
2.4 Hz), 3.43 (3H, s), 3.80 (1H, ddd, JZ10.7, 8.8, 4.4 Hz),
4.06 (1H, m), 4.71 and 4.97 (each 1H, d, JZ6.8 Hz), 4.75
(1H, t, JZ2.0 Hz); 13C NMR (100 MHz, CDCl3) dK4.7,
K3.3, 17.9, 25.0, 25.8 (3!C), 33.5, 56.4, 64.5, 66.4, 68.5,
73.6, 81.3, 84.3, 95.3; EIMS m/z 314 (MC).
(ii) Desilylation. The product obtained above (72 mg,
0.228 mmol) was dissolved in THF (2.3 mL), and 1.0 M
TBAF in THF (0.3 mL, 0.300 mmol) was added at 0 8C. The
reaction mixture was stirred at rt for 1.5 h and then
concentrated. Purification by flash chromatography (50–
60% EtOAc in hexane) gave alcohol (42.3 mg, 93%) as a
colorless oil; [a]D25C157.1 (c 1.0, CHCl3); IR (CHCl3)
3536, 3306, 1465, 1348, 1153, 1099, 1026 cmK1; 1H NMR
(400 MHz, CDCl3) d 1.47 (1H, dddd, JZ12.7, 12.7, 10.7,
4.4 Hz), 1.63–1.81 (2H, m), 2.17 (1H, m), 2.52 (1H, d, JZ
2.0 Hz), 2.63 (1H, br, OH), 3.27 (1H, dd, JZ9.3, 3.4 Hz),
3.40 (1H, ddd, JZ11.7, 11.7, 3.0 Hz), 3.42 (3H, s), 3.89
(1H, ddd, JZ10.7, 9.3, 4.9 Hz), 4.02 (1H, dddd, JZ11.2,
4.4, 1.5, 1.5 Hz), 4.67 and 4.98 (each 1H, d, JZ6.8 Hz,),
4.75 (1H, dd, JZ3.4, 2.0 Hz); 13C NMR (100 MHz, CDCl3)
d 24.9, 31.8, 56.0, 66.5, 66.7, 68.2, 75.3, 79.6, 81.7, 94.4;
EIMS m/z 201 (MHC).
4.1.4. (E)-3-{(2S,3S)-2-[(R)-1-(Methoxymethoxy)prop-2-
ynyl]tetrahydropyran-3-yloxy}acrylic acid methyl ester
(4a). The procedure used for the preparation of 3a was
employed. An experiment starting with alcohol 2 (102 mg,
0.378 mmol) provided 4a (72 mg, 67%) as a colorless oil;
[a]2D5K56.0 (c 1.0, CHCl3); IR (CHCl3) 3305, 1701, 1645,
1623, 1438, 1150, 1028 cmK1; 1H NMR (400 MHz, CDCl3)
d 1.59 (1H, dddd, JZ17.5, 12.2, 10.7, 5.4 Hz), 1.73–1.85
(2H, m), 2.30 (1H, m), 2.53 (1H, d, JZ2.4 Hz), 3.40 (3H, s),
3.45 (1H, m), 3.57 (1H, dd, JZ9.3, 2.4 Hz), 3.70 (3H, s),
4.04 (1H, ddd, JZ10.6, 9.3, 4.9 Hz), 4.08 (1H, m), 4.64
(1H, t, JZ2.4 Hz), 4.68 and 5.98 (each 1H, d, JZ6.8 Hz),
5.33 and 7.50 (each 1H, d, JZ12.7 Hz); 13C NMR
(100 MHz, CDCl3) d 24.5, 29.2, 51.1, 55.8, 65.1, 67.8,
76.0, 77.1, 78.0, 80.4, 94.4, 98.3, 160.9, 168.0; HREIMS
m/z calcd for C14H20O6 284.1259, found 284.1231.
(iii) Reaction with methyl propiolate. To a stirred solution of
the alcohol obtained above (42.3 mg, 0.212 mmol) in
CH2Cl2 (2.1 mL) were added methyl propiolate (76 mL,
0.846 mmol) and N-methylmorpholine (NMM) (47 mL,
0.423 mmol). After stirring at rt for 4 h, the reaction
mixture was extracted with EtOAc and the extract was
washed with water and brine, dried, and concentrated.
4.1.5. (E)-3-{(2S,3S)-2-[(R)-1-(p-Methoxybenzyloxy)
prop-2-ynyl]tetrahydropyran-3-yloxy}acrylic acid
methyl ester (4b). The procedure used for the preparation

N. Hiramatsu et al. / Tetrahedron 61 (2005) 8589–8597
8593
of 3b was employed. An experiment starting with alcohol 2
(100 mg, 0.37 mmol) provided 4b (80 mg, 60%) as a
colorless oil; [a]D25K79.8 (c 1.0, CHCl3); IR (CHCl3)
3305, 1705, 1644, 1623, 1438, 1148, 1073 cmK1; 1H NMR
(400 MHz, CDCl3) d 1.55 (1H, dddd, JZ18.0, 12.3, 10.7,
5.8 Hz), 1.70–1.81 (2H, m), 2.23 (1H, m), 2.57 (1H, d, JZ
2.0 Hz), 3.41 (1H, m), 3.54 (1H, dd, JZ9.3, 2.4 Hz), 3.70
(3H, s), 3.81 (3H, s), 3.98–4.07 (2H, m), 4.33 (1H, t, JZ
2.4 Hz), 4.51 and 4.81 (each 1H, d, JZ11.2 Hz, OCH2Ph),
5.25 and 7.45 (each 1H, d, JZ12.2 Hz), 6.87 and 7.28 (each
2H, d, JZ8.8 Hz); 13C NMR (100 MHz, CDCl3) d 24.7,
29.4, 51.4, 55.5, 67.9, 68.0, 71.0, 77.5, 77.6, 78.8, 80.9,
98.4, 114.1, 128.5, 130.3 (2!C), 159.7, 161.4 (2!C),
168.4; HREIMS m/z calcd for C20H24O6 360.1571, found
360.1538.
4.95 (1H, s), 5.38 (1H, d, JZ2.0 Hz), 6.87 and 7.32 (each
2H, d, JZ8.8 Hz); 13C NMR (100 MHz, CDCl3) d 25.3,
29.3, 36.9, 51.8, 55.2, 67.7, 73.2, 74.2, 76.0, 80.3, 84.6,
107.7, 113.7 (2!C), 129.2 (2!C), 130.6, 144.3, 159.1,
171.5; HREIMS m/z calcd for C20H26O6 362.1727, found
362.1768.
4.2.3. (2R,4R,4aR,8aS)-(4-Hydroxy-3-methyleneocta-
hydropyrano[3,2-b]pyran-2-yl)acetic acid methyl ester
(8a). A colorless oil; [a]2D5C75.1 (c 1.0, CHCl3); IR
(CHCl3) 3567, 1738, 1438, 1099, 960 cmK1 1H NMR
;
(400 MHz, CDCl3) d 1.43 (1H, dddd, JZ12.2, 12.2, 12.2,
5.4 Hz), 1.65–1.78 (2H, m), 2.09 (1H, m), 2.42 (1H, s, OH),
2.63 (1H, dd, JZ15.1, 8.8 Hz), 2.73 (1H, dd, JZ15.1,
4.9 Hz), 3.06 (1H, dd, JZ9.3, 2.9 Hz), 3.46 (1H, m), 3.71
(3H, s), 3.74 (1H, ddd, JZ11.2, 9.3, 4.4 Hz), 3.92 (1H, m),
4.41 (1H, d, JZ2.9 Hz), 4.71 (1H, dd, JZ8.8, 4.9 Hz), 4.91
(1H, d, JZ1.5 Hz), 5.16 (1H, s); 13C NMR (100 MHz,
CDCl3) d 25.3, 29.2, 36.8, 51.8, 68.1, 70.8, 72.5, 81.0,
113.1, 145.3, 171.4, 187.0; HREIMS m/z calcd for
C12H18O5 242.1153, found 242.1178.
4.2. General procedure for radical cyclization and
destannylation
(i) Radical cyclization. A solution of an alkynyl b-alkoxy
acrylate (0.30 mmol, 1.0 equiv), Bu3SnH (0.9 mmol,
1.3 equiv), and AIBN (5 mg, catalytic amount) in toluene
(6 mL, 0.05 M solution) was heated at 110 8C for 30–
60 min. After cooling to rt, the reaction mixture was
concentrated under reduced pressure. The residue was
purified by silica gel flash chromatography (EtOAc/hexane)
to give cyclization product.
4.2.4. (2R,4R,4aS,8aS)-{4-(p-Methoxybenzyloxy)-3-
methyleneoctahydropyrano[3,2-b]pyran-2-yl}acetic
acid methyl ester (8b). A colorless oil; [a]2D5C40.8 (c 1.0,
CHCl3); IR (CHCl3) 1736, 1612, 1514, 1439, 1247,
1099 cmK1 1H NMR (400 MHz, CDCl3) d 1.37 (1H,
;
dddd, JZ12.7, 12.2, 12.2, 4.4 Hz), 1.64 (1H, m), 1.79 (1H,
m), 2.08 (1H, m), 2.67 (1H, dd, JZ15.6, 8.8 Hz), 2.72 (1H,
dd, JZ15.6, 3.4 Hz), 3.06 (1H, dd, JZ9.3, 3.4 Hz), 3.37
(1H, ddd, JZ11.7, 11.7, 2.4 Hz), 3.72 (3H, s), 3.80 (3H, s),
3.87 (1H, ddd, JZ11.2, 9.3, 4.4 Hz), 4.01 (1H, m), 4.14
(1H, d, JZ2.9), 4.37 and 4.59 (each 1H, d, JZ12.2 Hz),
4.62 (1H, t, JZ6.8 Hz), 5.03 (1H, d, JZ2.0 Hz), 5.21 (1H,
s), 6.86 and 7.27 (each 2H, d, JZ8.8 Hz); 13C NMR
(100 MHz, CDCl3) d 25.0, 29.7, 36.6, 51.8, 55.2, 68.4, 69.0,
70.5, 71.2, 78.2, 81.5, 113.1, 113.7 (2!C), 129.3 (2!C),
130.1, 143.8, 159.0, 171.4; HREIMS m/z calcd for
C20H26O6 362.1727, found 362.1751.
(ii) Destannylation. The cyclization product (0.2 mmol,
1.0 equiv) was dissolved in CH2Cl2 (2 mL) or MeOH
(2 mL) and p-TsOH$H2O (0.3 mmol, 1.5 equiv) was added.
The reaction mixture was stirred at rt for 1 h and the reaction
was quenched with Et3N (0.2 mL). The mixture was
concentrated and purified by flash chromatography
(EtOAc/hexane) to give a product.
4.2.1. (2R,4S,4aS,8aS)-(4-Methoxymethoxy-3-methylene-
octahydropyrano[3,2-b]pyran-2-yl)acetic acid methyl
ester (6a). A colorless oil; [a]2D5C83.2 (c 1.0, CHCl3); IR
(CHCl3) 1737, 1439, 1103, 1039 cmK1
;
1H NMR
(400 MHz, CDCl3) d 1.45 (1H, dddd, JZ12.2, 12.2, 12.2,
5.4 Hz), 1.65–1.80 (2H, m), 2.06 (1H, m), 2.71 (1H, dd, JZ
15.1, 8.3 Hz), 2.78 (1H, dd, JZ15.1, 5.4 Hz), 2.95 (1H, t,
JZ9.3 Hz), 3.30 (1H, ddd, JZ11.2, 9.3, 4.4 Hz), 3.36 (1H,
ddd, JZ11.2, 11.2, 3.4 Hz), 3.43 (3H, s), 3.71 (3H, s), 3.95
(1H, m), 4.16 (1H, br d, JZ9.3 Hz), 4.29 (1H, dd, JZ8.3,
5.4 Hz), 4.74 and 4.88 (each 1H, d, JZ6.8 Hz), 4.96 (1H,
s,), 5.32 (1H, d, JZ2.0 Hz); 13C NMR (100 MHz, CDCl3) d
25.2, 29.3, 36.9, 51.9, 55.8, 67.7, 74.2, 76.0, 77.3, 84.1,
96.4, 107.4, 144.4, 171.4; HREIMS m/z calcd for C14H22O6
286.1415, found 286.1453.
4.2.5. (4aR,6R,7R,8aS)-2,2-Di(tert-butyl)-7-(triethylsilyl-
oxy)hexahydro-1,3,5-trioxa-2-silanaphthalene-6-carbal-
dehyde (10). (i) Triethylsilylation. To a stirred solution of
alcohol 9 (1.95 g, 4.79 mmol) and 2,6-lutidine (1.4 mL,
12.0 mmol) in CH2Cl2 (32 mL) was added TESOTf
(1.30 mL, 5.75 mmol) at 0 8C, and the reaction mixture
was stirred for 1 h. The reaction was quenched with
saturated aqueous NaHCO3 and the mixture was extracted
with EtOAc. The extract was washed with water and brine,
dried, and concentrated. Purification by flash chromato-
graphy (5% EtOAc in hexane) gave triethylsilyl ether
(2.35 g, 94%) as a colorless oil; [a]2D5K31.1 (c 1.0, CHCl3);
4.2.2. (2R,4S,4aS,8aS)-[4-(p-Methoxybenzyloxy)-3-
methyleneoctahydropyrano[3,2-b]pyran-2-yl]acetic acid
methyl ester (6b). A colorless oil; [a]2D5C34.6 (c 0.82,
CH3Cl); IR (CHCl3) 1735, 1613, 1514, 1439, 1248,
IR (CHCl3) 1473, 1365, 1091, 826 cmK1 1H NMR
;
(400 MHz, CDCl3) d 0.56 (6H, m), 0.91 (9H, t, JZ
6.7 Hz,), 0.98 (9H, s), 1.04 (9H, s), 1.53 (1H, q, JZ
11.2 Hz,), 2.38 (1H, ddd, JZ11.2, 4.4, 4.4 Hz), 3.31 (1H,
ddd, JZ10.2, 10.2, 4.9 Hz), 3.35 (1H, ddd, JZ9.3, 5.9,
2.0 Hz), 3.51 (1H, dd, JZ10.3, 5.9 Hz), 3.61 (1H, ddd, JZ
11.2, 9.3, 4.9 Hz), 3.70 (1H, dd, JZ10.3, 2.0 Hz), 3.75 (1H,
ddd, JZ11.2, 8.8, 4.4 Hz), 3.83 (1H, t, JZ10.2 Hz), 4.19
(1H, dd, JZ10.2, 4.9 Hz), 4.51 and 4.61 (each 1H, d, JZ
12.2 Hz), 7.23–7.34 (5H, m); 13C NMR (100 MHz, CDCl3)
d 4.9 (3!C), 6.8 (3!C), 19.9, 22.6, 27.0 (3!C), 27.4
1102 cmK1 1H NMR (400 MHz, CDCl3) d 1.45 (1H,
;
dddd, JZ12.2, 12.2, 12.2, 5.4 Hz), 1.66–1.79 (2H, m), 2.05
(1H, m), 2.71 (1H, dd, JZ15.6, 8.3 Hz), 2.77 (1H, dd, JZ
15.6, 5.4 Hz), 3.03 (1H, t, JZ9.3 Hz), 3.28 (1H, ddd, JZ
11.2, 9.3, 4.4 Hz), 3.38 (1H, ddd, JZ11.7, 11.7, 3.4 Hz),
3.71 (3H, s), 3.80 (3H, s), 3.93–4.01 (2H, m), 4.22 (1H, dd,
JZ8.3, 5.4 Hz), 4.65 and 4.71 (each 1H, d, JZ11.7 Hz),

8594
N. Hiramatsu et al. / Tetrahedron 61 (2005) 8589–8597
(3!C), 42.5, 66.3, 66.9, 69.5, 72.0, 73.4, 77.1, 82.0, 127.5,
127.8 (2!C), 128.3 (2!C), 138.1; HREIMS m/z calcd for
C28H50O5Si2 522.3197, found 522.3210.
t, JZ10.2 Hz), 4.17 (1H, dd, JZ10.2, 4.9 Hz), 4.63 (1H,
ddd, JZ10.2, 2.4, 2.4 Hz); 13C NMR (100 MHz, CDCl3) d
5.0 (3!C), 6.8 (3!C), 20.0, 22.6, 27.0 (3!C), 27.4 (3!
C), 42.2, 42.9, 62.6, 66.6, 67.3, 71.9, 74.5, 77.1, 83.3;
HREIMS m/z calcd for C23H44O5Si2 456.2727, found
456.2749. Compound 12: colorless oil; [a]2D5K42.3 (c 1.0,
(ii) Hydrogenolysis. A mixture of the product (2.35 g,
4.51 mmol) and Pd(OH)2/C (259 mg) in EtOAc (30 mL)
was stirred under a hydrogen atmosphere for 1 h. The
reaction mixture was filtered through a short column of
Celite and the filtrate was concentrated. Purification by flash
chromatography (10–30% EtOAc in hexane) gave the
alcohol (1.77 g, 91%) as a colorless oil; [a]2D5K45.9 (c
1.0, CHCl3); IR (CHCl3) 3596, 1473, 1098 cmK1; 1H NMR
(400 MHz, CDCl3) d 0.63 (6H, q, JZ7.8 Hz), 0.97 (9H, t,
JZ7.8 Hz), 0.99 (9H, s), 1.04 (9H, s), 1.56 (1H, q, JZ
11.7 Hz), 1.91 (1H, t, JZ6.3 Hz, OH), 2.39 (1H, ddd, JZ
12.2, 4.4, 4.4 Hz), 3.25 (1H, ddd, JZ8.8, 5.4, 2.9 Hz), 3.33
(1H, ddd, JZ10.3, 9.3, 4.9 Hz,), 3.58–3.67 (2H, m), 3.73
(1H, ddd, JZ11.2, 9.3, 4.4 Hz), 3.78 (1H, t, JZ10.3 Hz),
3.83 (1H, m), 4.14 (1H, dd, JZ10.2, 4.9 Hz); 13C NMR
(100 MHz, CDCl3) d 4.9 (3!C), 6.8 (3!C), 19.9, 22.6,
27.0 (3!C), 27.4 (3!C), 42.3, 62.4, 66.4, 66.8, 72.2, 76.9,
82.1; HREIMS m/z calcd for C21H44O5Si2 432.2727, found
432.2656.
CHCl3); IR (CHCl3) 3570, 3307, 1473, 1095, 1063 cmK1
;
1H NMR (400 MHz, CDCl3) d 0.66 (6H, q, JZ8.3 Hz), 0.98
(9H, t, JZ8.3 Hz), 0.99 (9H, s), 1.05 (9H, s), 1.57 (1H, q,
JZ11.2 Hz), 2.43 (1H, d, JZ2.0 Hz), 2.44 (1H, m), 2.58
(1H, d, JZ10.7 Hz, OH), 3.28 (1H, dd, JZ9.3, 2.0 Hz),
3.39 (1H, ddd, JZ9.3, 9.3, 4.9 Hz), 3.74 (1H, ddd, JZ11.2,
9.3, 4.4 Hz), 3.81 (1H, t, JZ10.2 Hz), 3.89 (1H, ddd, JZ
11.2, 6.3, 4.9 Hz), 4.18 (1H, dd, JZ10.2, 4.9 Hz), 4.56 (1H,
ddd, JZ10.7, 2.0, 2.0 Hz); 13C NMR (100 MHz, CDCl3) d
5.0 (3!C), 6.7 (3!C), 19.9, 22.6, 27.0 (3!C), 27.4 (3!
C), 42.0, 61.1, 66.0, 66.7, 71.9, 72.9, 77.3, 82.8, 83.1;
HREIMS m/z calcd for C23H44O5Si2 456.2727, found
456.2758.
4.2.7. (E)-(4aR,6R,7R,8aS)-3-{6-[(1S)-1-(Acetoxy)pro-
pynyl]-2,2-di(tert-butyl)hexahydro-1,3,5-trioxa-2-sila-
naphthalen-7-yloxy}acrylic acid methyl ester (13a). (i)
Acetylation. To a stirred solution of alcohol 11 (294 mg,
0.645 mmol) in CH2Cl2 (3.0 mL) were added pyridine
(0.2 mL) and acetic anhydride (0.2 mL), and the reaction
mixture was stirred at rt for 3 h. The solvent was evaporated
azeotropically with heptane three times. The residue was
purified by flash chromatography (7% EtOAc in hexane) to
give acetate (274 mg, 85%) as a colorless oil; [a]2D5K21.4 (c
1.0, CHCl3); IR (CHCl3) 3307, 1743, 1473, 1366, 1237,
1099, 1070 cmK1; 1H NMR (400 MHz, CDCl3) d 0.66 (6H,
q, JZ7.8 Hz), 0.99 (9H, t, JZ7.8 Hz), 0.99 (9H, s), 1.05
(9H, s), 1.57 (1H, q, JZ11.7 Hz), 2.13 (3H, s), 2.43 (1H,
ddd, JZ11.7, 4.4, 4.4 Hz), 2.47 (1H, d, JZ2.4 Hz), 3.33
(1H, ddd, JZ10.2, 10.2, 4.9 Hz), 3.39 (1H, dd, JZ9.3,
2.4 Hz), 3.73–3.81 (2H, m), 3.86 (1H, t, JZ10.2 Hz), 4.22
(1H, dd, JZ10.2, 4.9 Hz), 5.77 (1H, t, JZ2.4 Hz); 13C
NMR (100 MHz, CDCl3) d 5.0 (3!C), 6.8 (3!C), 19.9,
21.0, 22.6, 27.1 (3!C), 27.4 (3!C), 42.2, 60.1, 63.6, 66.6,
66.7, 71.8, 75.4, 77.1, 82.2, 169.6; EIMS m/z 498 (MC).
(iii) Oxidation. To a solution of the alcohol (1.94 g,
4.49 mmol) in CH2Cl2 (45 mL) was added Dess–Martin
periodinane (2.10 g, 4.94 mmol) at 0 8C, and the reaction
mixture was stirred at rt for 1.5 h. The reaction was
quenched with saturated aqueous Na2S2O3 and the mixture
was extracted with CH2Cl2. The extract was washed with
saturated aqueous NaHCO3, water, and brine, dried, and
concentrated. Purification by flash chromatography (30%
EtOAc in hexane) gave aldehyde 10 (1.76 g, 91%) as a
colorless oil; [a]2D5K42.58 (c 1.0, CHCl3); IR (CHCl3) 1737,
1473, 1100 cmK1; 1H NMR (400 MHz, CDCl3) d 0.62 (6H,
q, JZ7.8 Hz), 0.96 (9H, t, JZ7.8 Hz), 0.99 (9H, s), 1.04
(9H, s), 1.65 (1H, q, JZ11.7 Hz), 2.47 (1H, ddd, JZ12.2,
4.4, 4.4 Hz), 3.33 (1H, ddd, JZ10.3, 10.3, 4.4 Hz), 3.77
(1H, dd, JZ9.3, 1.0 Hz,), 3.78–3.87 (2H, m), 3.88 (1H, t,
JZ10.3 Hz), 4.19 (1H, dd, JZ10.3, 4.4 Hz), 9.71 (1H, d,
JZ1.0 Hz); 13C NMR (100 MHz, CDCl3) d 4.9 (3!C), 6.7
(3!C), 19.9, 22.6, 27.0 (3!C), 27.4 (3!C), 42.9, 66.5,
66.9, 71.4, 76.6, 84.8, 198.1; HREIMS m/z calcd for
C21H42O5Si2 430.2568, found 362.2561.
(ii) Detriethylsilylation. A solution of the acetate (281 mg,
0.565 mmol) in THF (3.0 mL) and 80% acetic acid (7.5 mL)
was stirred for 5.5 h. The solution was neutralized with 15%
NH4OH to pH 8.0 and extracted with EtOAc. The extract
was washed with water and brine, dried, and concentrated.
Purification by flash chromatography (30% EtOAc in
hexane) gave the alcohol (216 mg, 100%) as a colorless
oil; [a]2D5C2.4 (c 1.0, CHCl3); IR (CHCl3) 3601, 3306,
4.2.6. (1S)-1-[(4aR,6S,7R,8aS)-2,2-Di(tert-butyl)-7-(tri-
ethylsilyloxy)hexahydro-1,3,5-trioxa-2-silanaphthalen-
6-yl]prop-2-yn-1-ol (11) and (1R)-1-[(4aR,6S,7R,8aS)-
2,2-Di(tert-butyl)-7-(triethylsilyloxy)hexahydro-1,3,5-
trioxa-2-silanaphthalen-6-yl]prop-2-yn-1-ol (12). The
procedure used for the preparation of 1 was employed. An
experiment starting with aldehyde 10 (988 mg, 2.29 mmol)
provided the crude products, which were purified by flash
chromatography (15–30% EtOAc in hexane). The first
eluate gave alcohol 12 (454 mg, 44%) and the second eluate
gave alcohol 11 (552 mg, 53%). Compound 11: colorless
oil; [a]2D5K53.1 (c 1.0, CHCl3); IR (CHCl3) 3567, 3307,
1473, 1098, 1067, 1006 cmK1; 1H NMR (400 MHz, CDCl3)
d 0.64 (6H, q, JZ8.3 Hz), 0.97 (9H, t, JZ8.3 Hz), 0.99 (9H,
s), 1.05 (9H, s), 1.57 (1H, q, JZ11.7 Hz,), 2.41 (1H, ddd,
JZ11.7, 4.4, 4.4 Hz), 2.45 (1H, d, JZ2.4 Hz), 2.65 (1H, d,
JZ10.2 Hz, OH), 3.33 (1H, ddd, JZ10.2, 10.2, 4.9 Hz),
3.36 (1H, dd, JZ9.3, 3.4 Hz), 3.73–3.81 (2H, m), 3.85 (1H,
1
1741, 1473, 1366, 1235, 1104 cmK1; H NMR (400 MHz,
CDCl3) d 0.99 (9H, s), 1.05 (9H, s), 1.56 (1H, q, JZ
11.4 Hz), 1.87 (1H, d, JZ5.5 Hz, OH), 2.14 (3H, s), 2.51
(1H, d, JZ2.2 Hz), 2.53 (1H, ddd, JZ11.4, 4.8, 4.8 Hz),
3.34 (1H, ddd, JZ10.3, 9.2, 4.8 Hz), 3.44 (1H, dd, JZ9.5,
2.6 Hz), 3.80 (1H, ddd, JZ11.4, 9.2, 4.4 Hz), 3.83 (1H, m),
3.85 (1H, t, JZ10.3 Hz), 4.20 (1H, dd, JZ10.3, 4.8 Hz),
5.79 (1H, t, JZ2.2 Hz); 13C NMR (100 MHz, CDCl3) d 19.9,
20.9, 22.6, 27.0 (3!C), 27.4 (3!C), 41.6, 63.7, 66.1, 66.6,
71.7, 75.8, 77.1, 77.2, 81.6, 169.8; EIMS m/z 384 (MC).
(iii) Reaction with methyl propiolate. The procedure used
for the preparation of 3a was employed. An experiment

N. Hiramatsu et al. / Tetrahedron 61 (2005) 8589–8597
8595
starting with the above alcohol (216 mg, 0.563 mmol)
provided acetate (237 mg, 90%), which was assigned to be a
78:22 mixture of 13a and its regioisomer by 1H NMR
analysis; IR (CHCl3) 3306, 1741, 1706, 1645, 1235,
subjected to the radical cyclization and destannylation to
give 15a (155 mg, 61% as a 92:8 mixture of diastereo-
isomers, 78% corrected yield based on pure 13a) as a
colorless oil; [a]D25K27.5 (c 0.34, CHCl3); IR (CHCl3)
1741, 1473, 1439, 1371, 1236, 1107, 1047 cmK1; 1H NMR
(400 MHz, CDCl3) d 0.96 (9H, s), 1.04 (9H, s), 1.49 (1H, q,
JZ11.7 Hz), 2.08 (3H, s), 2.47 (1H, ddd, JZ11.7, 4.4,
4.4 Hz), 2.61 (1H, dd, JZ15.1, 9.3 Hz), 2.70 (1H, dd, JZ
15.1, 4.4 Hz), 3.22 (1H, dd, JZ9.8, 3.4 Hz), 3.33 (1H, ddd,
JZ10.3, 10.3, 4.9 Hz), 3.72 (3H, s), 3.79 (1H, t, JZ
10.3 Hz), 3.80 (2H, m), 4.11 (1H, dd, JZ10.3, 4.9 Hz), 4.54
(1H, dd, JZ8.8, 4.9 Hz), 5.03 (1H, d, JZ1.5 Hz), 5.29 (1H,
s), 5.63 (1H, d, JZ3.4 Hz); 13C NMR (100 MHz, CDCl3) d
19.9, 21.3, 22.6, 27.0 (3!C), 27.4 (3!C), 36.7, 38.5, 51.9,
66.7, 67.0, 71.3, 72.2, 72.6, 77.8, 79.1, 115.3, 141.7, 169.9,
171.4; HREIMS m/z calcd for C23H38O8Si 470.2335, found
470.2312.
1
1104 cmK1; H NMR (400 MHz, CDCl3) (signals of the
major isomer 13a) d 0.98 (9H, s), 1.05 (9H, s), 1.63 (1H, q,
JZ11.4 Hz), 2.14 (3H, s), 2.50 (1H, d, JZ1.8 Hz), 2.68
(1H, ddd, JZ12.1, 4.8, 4.8 Hz), 3.38 (1H, ddd, JZ9.9, 9.9,
4.1 Hz), 3.65 (1H, dd, JZ9.5, 2.2 Hz), 3.71 (3H, s), 3.83
(1H, m), 3.86 (1H, t, JZ10.2 Hz), 4.10 (1H, ddd, JZ11.4,
9.5, 4.8 Hz), 4.23 (1H, dd, JZ10.2, 5.1 Hz), 5.37 and 7.48
(each 1H, d, JZ12.5 Hz, CH]CH), 5.63 (1H, t, JZ
2.2 Hz); HREIMS m/z calcd for C23H36O8Si 468.2179,
found 456.2184.
4.2.8. (E)-(4aR,6R,7R,8aS)-3-{2,2-Di(tert-butyl)-6-[(1S)-
1-(p-methoxybenzyloxy)-2-propynyl]hexahydro-1,3,5-
trioxa-2-silanaphthalen-7-yloxy}acrylic acid methyl
ester (13b). The procedures of 3b (i) and 13a (ii and iii)
were employed. An experiment starting with alcohol 11
(18 mg, 0.039 mmol) provided 13b (6.7 mg, 31%) as a
colorless oil; [a]D25K60.6 (c 0.55, CHCl3); IR (CHCl3)
3307, 1705, 1644, 1622, 1516, 1235, 1100 cmK1; 1H NMR
(400 MHz, CDCl3) d 0.97 (9H, s), 1.04 (9H, s), 1.61 (1H, q,
JZ11.7 Hz), 2.53 (1H, d, JZ2.0 Hz), 2.62 (1H, ddd, JZ
11.7, 4.4, 4.4 Hz), 3.36 (1H, ddd, JZ10.3, 10.3, 4.9 Hz),
3.62 (1H, dd, JZ9.8, 2.0 Hz), 3.70 and 3.81 (each 3H, s),
3.80 (1H, m), 3.86 (1H, t, JZ10.3 Hz), 4.09 (1H, ddd, JZ
11.2, 9.8, 4.9 Hz), 4.23 (1H, dd, JZ10.3, 4.9 Hz), 4.30 (1H,
t, JZ2.0 Hz), 4.47 and 4.80 (each 1H, d, JZ11.7 Hz), 5.27
and 7.42 (each 1H, d, JZ12.2 Hz), 6.87 and 7.27 (each 2H,
d, JZ9.3 Hz); 13C NMR (100 MHz, CDCl3) d 19.9, 22.6,
27.0 (3!C), 27.4 (3!C), 38.2, 51.2, 55.2, 66.6, 67.3, 70.8,
71.4, 75.7, 76.6, 77.2, 78.1, 80.5, 98.5, 113.8 (2!C), 129.0,
129.9 (2!C), 159.6, 160.7, 178.1; HREIMS m/z calcd for
C29H42O8Si 546.2646, found 546.2684.
4.2.11. (4aR,5S,7S,8aR,9aS,10aR)-[2,2-Di(tert-butyl)-5-
(p-methoxybenzyloxy)-6-methylenetetradecahydro-1,3,
8,10-tetraoxa-2-silaanthracen-7-yl]acetic acid methyl
ester (15b). According to the general procedure, 13b
(6.7 mg, 0.012 mmol) was subjected to the radical cycliza-
tion and destannylation to give 15b (5.6 mg, 82% as a 96:4
mixture of diastereoisomers) as a colorless oil; [a]2D5K30.6
(c 1.0, CHCl3); IR (CHCl3) 1738, 1513, 1102, 1054 cmK1
;
1H NMR (400 MHz, CDCl3) d 0.96 (9H, s), 1.03 (9H, s),
1.46 (1H, q, JZ11.7 Hz), 2.45 (1H, ddd, JZ11.7, 4.4,
4.4 Hz), 2.66 (1H, dd, JZ15.1, 5.8 Hz), 2.72 (1H, dd, JZ
15.1, 5.8 Hz), 3.17 (1H, dd, JZ9.8, 2.9 Hz), 3.31 (1H, ddd,
JZ9.8, 9.8, 4.4 Hz), 3.71 (3H, s), 3.84 (3H, s), 3.72–3.95
(2H, m), 3.92 (1H, t, JZ10.3 Hz), 4.14 (1H, dd, JZ10.3,
4.9 Hz), 4.15 (1H, d, JZ2.9 Hz), 4.34 and 4.56 (each 1H, d,
JZ12.2 Hz), 4.60 (1H, br t, JZ7.3 Hz), 5.00 (1H, s), 5.02
(1H, d, JZ1.5 Hz), 6.86 and 7.24 (each 2H, d, JZ8.8 Hz);
13C NMR (100 MHz, CDCl3) d 19.9, 22.5, 27.0 (3!C),
27.4 (3!C), 36.6, 38.7, 51.8, 55.2, 66.7, 69.2, 69.6, 70.6,
72.1, 77.9, 78.0, 81.2, 113.3, 113.7 (2!C), 129.2 (2!C),
130.1, 143.5, 159.1, 171.4; HREIMS m/z calcd for
C29H44O8Si 548.2802, found 548.2857.
4.2.9. (E)-(4aR,6R,7R,8aS)-3-{6-[(1R)-1-(Acetoxy)prop-
2-ynyl]-2,2-di(tert-butyl)hexahydro-1,3,5-trioxa-2-sila-
naphthalen-7-yloxy}acrylic acid methyl ester (14). The
procedure used for the preparation of 13a was employed. An
experiment starting with alcohol 12 (106 mg, 0.232 mmol)
provided acetate 14 (92 mg, 85% as a 9:1 mixture of
regioisomers) as a colorless oil; [a]2D5K49.8 (c 1.0, CHCl3);
IR (CHCl3) 3307, 1745, 1707, 1645, 1625, 1220, 1137,
4.2.12. (4aR,5R,7S,8aR,9aS,10aR)-[5-Acetoxy-2,2-di(tert-
butyl)-6-methylenetetradecahydro-1,3,8,10-tetraoxa-2-
silaanthracen-7-yl]acetic acid methyl ester (16). Accord-
ing to the general procedure, 14 (90 mg, 0.192 mmol, a 9:1
mixture of regioisomers) was subjected to the radical
cyclization and destannylation to give 16 (73 mg, 81% as a
93:7 mixture of diastereoisomers) as a colorless oil; [a]2D5K
27.5 (c 0.25, CH3Cl); IR (CHCl3) 1741, 1238, 1104,
1
1105 cmK1; H NMR (400 MHz, CDCl3) d 0.99 (9H, s),
1.05 (9H, s), 1.63 (1H, q, JZ11.7 Hz), 2.10 (3H, s), 2.50
(1H, d, JZ2.4 Hz), 2.66 (1H, ddd, JZ11.7, 4.9, 4.9 Hz),
3.39 (1H, ddd, JZ10.2, 9.8, 4.9 Hz), 3.61 (1H, dd, JZ9.3,
2.4 Hz), 3.70 (3H, s), 3.84 (1H, ddd, JZ11.7, 9.3, 4.4 Hz),
3.90 (1H, t, JZ10.2 Hz), 4.05 (1H, ddd, JZ11.7, 9.8,
4.9 Hz), 4.21 (1H, dd, JZ10.2, 4.9 Hz), 5.31 and 7.43 (each
1H, d, JZ12.2 Hz), 5.58 (1H, t, JZ2.4 Hz); 13C NMR
(100 MHz, CDCl3) d 19.9, 20.7, 22.6, 27.0 (3!C), 27.4
(3!C), 38.0, 51.2, 62.0, 66.4, 71.4, 74.5, 75.2, 77.7, 77.8,
79.0, 98.5, 160.3, 167.7, 169.3; HREIMS m/z calcd for
C23H36O8Si 468.2179, found 468.2202.
1
1054 cmK1; H NMR (400 MHz, CDCl3) d 0.97 (9H, s),
1.02 (9H, s), 1.55 (1H, q, JZ11.7 Hz), 2.17 (3H, s), 2.47
(1H, ddd, JZ11.7, 4.4, 4.4 Hz), 2.70 (1H, dd, JZ15.1,
9.3 Hz), 2.77 (1H, dd, JZ15.1, 4.9 Hz), 3.13 (1H, t, JZ
9.8 Hz), 3.29 (1H, ddd, JZ10.2, 10.2, 4.9 Hz), 3.41 (1H,
ddd, JZ11.7, 9.3, 4.4 Hz), 3.71 (3H, s), 3.81 (1H, t, JZ
10.2 Hz), 3.84 (1H, ddd, JZ11.7, 10.2, 4.4 Hz), 4.11 (1H,
dd, JZ10.2, 4.9 Hz), 4.35 (1H, dd, JZ9.3, 4.9 Hz), 4.94
(1H, d, JZ2.0 Hz), 5.00 (1H, d, JZ2.0 Hz), 5.40 (1H, d,
JZ9.8 Hz); 13C NMR (100 MHz, CDCl3) d 19.9, 20.8, 22.6,
27.0 (3!C), 27.4 (3!C), 36.9, 38.3, 51.9, 66.6, 72.2, 73.3,
74.30, 74.33, 77.4, 81.2, 107.7, 141.9, 169.9, 170.9;
HREIMS m/z calcd for C23H38O8Si 470.2336, found
470.2345.
4.2.10. (4aR,5S,7S,8aR,9aS,10aR)-[5-Acetoxy-2,2-di(tert-
butyl)-6-methylenetetradecahydro-1,3,8,10-tetraoxa-2-
silaanthracen-7-yl]acetic acid methyl ester (15a).
According to the general procedure, a 78:22 mixture of
13a and its regioisomer (257 mg, 0.550 mmol) was

8596
N. Hiramatsu et al. / Tetrahedron 61 (2005) 8589–8597
4.2.13. (E,E)-(4aR,6R,7R,8aS)-3-{2,2-Di(tert-butyl)-6-
[(1S)-1-(2-methoxycarbonylvinyloxy)-2-propynyl]-hexa-
hydro-1,3,5-trioxa-2-silanaphthalen-7-yloxy}acrylic acid
methyl ester (17). (i) Detriethylsilylation. A solution of 11
(240 mg, 0.527 mmol) and p-TsOH$H2O (5.0 mg,
0.026 mmol) in MeOH (5.3 mL) was stirred at rt for 1 h.
The reaction was quenched with Et3N (0.2 mL) and the
reaction mixture was concentrated. Purification by flash
chromatography (40% EtOAc in hexane) gave diol (169 mg,
94%) as a solid. Mp 190–191 8C; [a]2D5K31.4 (c 1.0,
51.1, 51.9, 66.5, 69.4, 70.8, 71.9, 72.9, 77.9, 79.9, 82.3,
98.9, 115.2, 141.9, 160.0, 170.1; HREIMS m/z calcd for
C25H40O9Si 512.2442, found 512.2425.
4.2.15. (4aR,5S,7S,8aR,9aS,10aS)-[2,2-Di(tert-butyl)-5-
hydroxy-6-methylenetetradecahydro-1,3,8,10-tetraoxa-
2-silaanthracen-7-yl]acetic acid methyl ester (19). A
solution of 18 (479 mg, 0.936 mmol, a 94:6 mixture of
diastereoisomers), n-dodecanethiol (0.90 mL, 3.743 mmol),
and TsOH$H2O (53 mg, 0.281 mmol) in CH3CN (9.4 mL)
was heated at 80 8C for 1.5 h. After cooling to rt, Et3N
(0.2 mL) was added to the solution and the reaction mixture
was concentrated. Purification by flash chromatography
(30% EtOAc in hexane) gave pure 19 (322 mg, 82%) as a
solid. Mp 155–156 8C; [a]2D5K47.5 (c 0.28, CHCl3); IR
1
CH3Cl); H NMR (400 MHz, acetone-d6) d 1.00 (9H, s),
1.42 (9H, s), 1.56 (1H, q, JZ11.7 Hz), 2.44 (1H, ddd, JZ
11.7, 4.9, 4.9 Hz), 2.80 (1H, d, JZ2.4 Hz), 3.33 (1H, dd,
JZ9.3, 3.4 Hz), 3.35 (1H, ddd, JZ10.3, 10.3, 4.9 Hz), 3.70
(1H, m), 3.78 (1H, t, JZ10.3 Hz), 3.80 (1H, ddd, JZ11.2,
9.3, 4.9 Hz), 4.11 (1H, dd, JZ10.3, 4.9 Hz), 4.25 (1H, d,
JZ5.4 Hz, OH), 4.54 (1H, d, JZ8.3 Hz, OH), 4.62 (1H,
ddd, JZ8.3, 3.4, 2.4 Hz); 13C NMR (100 MHz, acetone-d6)
d 20.4, 23.1, 27.4 (3!C), 27.7 (3!C), 42.5, 63.3, 67.5,
73.2, 74.7, 77.7, 79.1, 83.1, 84.8; HREIMS m/z calcd for
C17H30O5Si 342.1863, found 342.1852.
1
(CHCl3) 3574, 1738, 1473, 1438, 1100, 1048 cmK1; H
NMR (400 MHz, CDCl3) d 0.97 (9H, s), 1.04 (9H, s), 1.52
(1H, q, JZ11.7 Hz), 2.16 (1H, s, OH), 2.47 (1H, ddd, JZ
11.7, 4.4, 4.4 Hz), 2.63 (1H, dd, JZ15.1, 8.8 Hz), 2.73 (1H,
dd, JZ15.1, 4.9 Hz), 3.18 (1H, dd, JZ9.3, 2.9 Hz), 3.41
(1H, ddd, JZ10.3, 10.3, 4.9 Hz), 3.71 (3H, s), 3.82 (2H,
ddd, JZ9.3, 9.3, 4.4 Hz), 3.85 (1H, t, JZ10.3 Hz), 4.14
(1H, dd, JZ10.3, 4.9 Hz), 4.46 (1H, d, JZ2.9 Hz), 4.68
(1H, dd, JZ8.8, 4.9 Hz), 4.98 (1H, d, JZ1.5 Hz), 5.17 (1H,
s); 13C NMR (100 MHz, CDCl3) d 19.9, 22.6, 27.0 (3!C),
27.4 (3!C), 36.8, 38.3, 51.9, 66.7, 69.0, 70.9, 72.2, 72.4,
77.8, 80.7, 113.7, 144.8, 171.4; HREIMS m/z calcd for
C21H36O7 428.2230, found 428.2238.
(ii) Reaction with methyl propiolate. The diol (507 mg,
1.48 mmol) dissolved in THF (10 mL), and treated with
methyl propiolate (0.53 mL, 5.94 mmol) and NMM
(0.65 mL, 5.94 mmol). The reaction mixture was stirred at
rt for 17 h and extracted with EtOAc. The extract was
washed with water and brine, dried, and concentrated.
Purification by flash chromatography (20% EtOAc in
hexane) gave 17 (756 mg, 100%) as a colorless oil;
[a]2D5K3.3 (c 1.0, CHCl3); IR (CHCl3) 3305, 1710, 1645,
4.2.16. (E,E)-(4aR,6R,7R,8aS)-3-{2,2-Di(tert-butyl)-6-
[(1R)-1-(2-methoxycarbonylvinyloxy)-2-propynyl]-hexa-
hydro-1,3,5-trioxa-2-silanaphthalen-7-yloxy}acrylic acid
methyl ester (20). The procedure used for the preparation of
17 was employed. An experiment starting with alcohol 12
(111 mg, 0.243 mmol) provided acetate 20 (123 mg, 97%)
as a colorless oil; [a]D25K97.4 (c 1.0, CHCl3); IR (CHCl3)
1
1625, 1438, 1137 cmK1; H NMR (400 MHz, CDCl3) d
0.98 (9H, s), 1.05 (9H, s), 1.65 (1H, q, JZ11.7 Hz), 2.66
(1H, d, JZ2.4 Hz), 2.69 (1H, ddd, JZ11.7, 4.4, 4.4 Hz),
3.39 (1H, ddd, JZ10.2, 9.8, 4.9 Hz), 3.71 and 3.72 (each
3H, s), 3.74 (1H, dd, JZ9.8, 2.0 Hz), 3.83 (1H, ddd, JZ
11.2, 9.8, 4.4 Hz), 3.86 (1H, t, JZ10.2 Hz), 4.10 (1H, ddd,
JZ11.2, 9.8, 4.9 Hz), 4.20 (1H, dd, JZ10.2, 4.9 Hz), 4.81
(1H, t, JZ2.4 Hz), 5.37 and 7.46 (each 1H, d, JZ12.7 Hz),
5.41 and 7.61 (each 1H, d, JZ12.7 Hz); 13C NMR
(100 MHz, CDCl3) d 19.9, 22.6, 26.9 (3!C), 27.4 (3!
C), 38.0, 51.2, 51.3, 66.3, 70.1, 71.2, 75.1, 75.3, 77.2, 78.9,
79.5, 99.1, 99.3, 159.8, 159.9, 167.5, 167.6; HREIMS m/z
calcd for C25H38O9Si 510.2285, found 510.2297.
3305, 1711, 1646, 1626, 1483, 1137 cmK1 1H NMR
;
(400 MHz, CDCl3) d 0.98 (9H, s), 1.04 (9H, s), 1.63 (1H,
q, JZ11.7 Hz, H4ax), 2.65 (1H, d, JZ2.4 Hz), 2.68 (1H,
ddd, JZ11.7, 4.4, 4.4 Hz), 3.39 (1H, ddd, JZ10.3, 9.3,
4.9 Hz), 3.60 (1H, dd, JZ9.3, 2.0 Hz), 3.69 and 3.70 (each
3H, s), 3.84 (1H, ddd, JZ11.2, 9.3, 4.4 Hz), 3.89 (1H, t, JZ
10.3 Hz), 4.11 (1H, ddd, JZ11.2, 9.3, 4.9 Hz), 4.21 (1H, dd,
JZ10.3, 4.9 Hz), 4.79 (1H, t, JZ2.2 Hz), 5.33 and 7.41
(each 1H, d, JZ12.2 Hz), 5.41 and 7.57 (each 1H, d, JZ
12.7 Hz); 13C NMR (100 MHz, CDCl3) d 19.9, 22.6, 27.0
(3!C), 27.4 (3!C), 38.0, 51.2 (2!C), 66.3, 68.4, 71.3,
73.9, 76.5, 77.2, 77.9, 79.9, 99.1, 99.5, 159.5, 160.0, 167.4,
167.5; HREIMS m/z calcd for C25H38O9Si 510.2285, found
510.2296.
4.2.14. (E)-(4aR,5S,7S,8aR,9aS,10aR)-[2,2-Di(tert-butyl)-
5-(2-methoxycarbonylvinyloxy)-6-methylenetetradeca-
hydro-1,3,8,10-tetraoxa-2-silaanthracen-7-yl]acetic acid
methyl ester (18). According to the general procedure, 17
(756 mg, 1.48 mmol) was subjected to the radical cycliza-
tion and destannylation to give 18 (577 mg, 76% as a 94:6
mixture of diastereoisomers) as a colorless oil; [a]2D5K35.7
(c 1.0, CHCl3); IR (CHCl3) 1739, 1707, 1473, 1438, 1139,
1107, 1047 cmK1; 1H NMR (400 MHz, CDCl3) d 0.97 (9H,
s), 1.03 (9H, s), 1.48 (1H, q, JZ11.7 Hz), 2.48 (1H, ddd, JZ
11.7, 4.4, 4.4 Hz), 2.63 (1H, dd, JZ15.1, 8.8 Hz), 2.71 (1H,
dd, JZ15.1, 4.9 Hz), 3.26 (1H, dd, JZ9.8, 2.9 Hz), 3.34
(1H, ddd, JZ10.2, 10.2, 4.9 Hz), 3.68 and 3.71 (each 3H, s),
3.79–3.86 (2H, m), 3.85 (1H, t, JZ10.2 Hz), 4.12 (1H, dd,
JZ10.2, 4.9 Hz), 4.50 (1H, dd, JZ8.8, 4.9 Hz), 4.63 (1H, d,
JZ2.9 Hz), 5.11 (1H, d, JZ1.5 Hz), 5.24 (1H, s), 5.35 and
7.45 (each 1H, d, JZ12.2 Hz); 13C NMR (100 MHz,
CDCl3) d 19.9, 22.5, 27.0 (3!C), 27.4 (3!C), 36.6, 38.4,
4.2.17.
(E)-(4aR,5R,7S,8aR,9aS,10aR)-[2,2-Di(tert-
butyl)-5-(2-methoxycarbonylvinyloxy)-6-methylene-
tetradecahydro-1,3,8,10-tetraoxa-2-silaanthracen-7-yl]
acetic acid methyl ester (21). According to the general
procedure, 20 (121 mg, 0.238 mmol) was subjected to the
radical cyclization and destannylation to give 21 (90 mg,
74% as a 94:6 mixture of diastereoisomers) as a colorless
oil; [a]2D5K18.1 (c 1.0, CHCl3); IR (CHCl3) 1734, 1706,
1
1473, 1438, 1139, 1104, 1054 cmK1; H NMR (400 MHz,
CDCl3) d 0.96 (9H, s), 1.03 (9H, s), 1.55 (1H, q, JZ
11.7 Hz), 2.48 (1H, ddd, JZ11.7, 4.4, 4.4 Hz), 2.72 (1H, dd,
JZ15.1, 4.4 Hz), 2.78 (1H, dd, JZ15.1, 5.4 Hz), 3.18 (1H,

N. Hiramatsu et al. / Tetrahedron 61 (2005) 8589–8597
8597
4. (a) Lee, E.; Tae, J. S.; Chong, T. H.; Park, Y. C. Tetrahedron
Lett. 1994, 35, 129–132. (b) Sakamoto, Y.; Matsuo, G.;
Matsukura, H.; Nakata, T. Org. Lett. 2001, 3, 2749–2752. (c)
Hori, N.; Matsukura, H.; Nakata, T. Org. Lett. 1999, 1,
1099–1101. (d) Matsuo, G.; Hori, N.; Nakata, T. Tetrahedron
Lett. 1999, 40, 8859–8862.
t, JZ9.3 Hz), 3.29–3.38 (2H, m), 3.69 and 3.72 (each 3H,
s), 3.80 (1H, t, JZ10.2 Hz), 3.83 (1H, m), 4.15 (1H, dd, JZ
10.2, 5.4 Hz), 4.29–4.35 (2H, m), 5.03 (1H, t, JZ2.0 Hz),
5.20 (1H, d, JZ2.0 Hz), 5.37 and 7.53 (each 1H, d, JZ
12.2 Hz); 13C NMR (100 MHz, CDCl3) d 19.9, 22.6, 27.0
(3!C), 27.4 (3!C), 36.7, 38.1, 51.1, 52.0, 66.5, 72.2, 74.2,
74.3, 77.2, 81.7, 83.3, 98.2, 109.5, 141.3, 162.6, 168.0,
170.1; HREIMS m/z calcd for C25H40O9Si 512.2442, found
512.2473.
´
5. Leeuwenburgh, M. A.; Litjens, R. E. J. N.; Codee, J. D. C.;
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Acknowledgements
This work was supported by the Uehara Memorial
Foundation and by a Grant-in Aid for Creative Scientific
Research (No. 14GS0214) from the Japan Society for the
Promotion of Science.
8. Ciminiello, P.; Fattorusso, E.; Forino, M.; Magno, S.; Poletti,
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