Synthesis of dioxabicyclo[3.2.1]octane core of the zaragozic acids

Article abstract of DOI:10.3987/COM-05-S(T)71

Synthesis of the bicyclic core of zaragozic acids employing chiral furylglycerol (6) is described. Key steps are stereoselective construction of the C4 to C6 carbon centers by syn-dihydroxylation of alkene followed by reduction of carbonyl group in pyrano

Full text of DOI:10.3987/COM-05-S(T)71

HETEROCYCLES, Vol. 67, No. 2, 2006
731
HETEROCYCLES, Vol. 67, No. 2, 2006, pp. 731 - 748. © The Japan Institute of Heterocyclic Chemistry
Received, 15th August, 2005, Accepted, 15th September, 2005, Published online, 16th September, 2005. COM-05-S(T)71
SYNTHESIS OF DIOXABICYCLO[3.2.1]OCTANE CORE OF THE
ZARAGOZIC ACIDS
Masayoshi Tsubuki,* Hiroyuki Okita, and Toshio Honda*
Faculty of Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara,
Shinagawa, Tokyo 142-8501, Japan
e-mail:tsubuki@hoshi.ac.jp
Abstract – Synthesis of the bicyclic core of zaragozic acids employing chiral
furylglycerol (6) is described. Key steps are stereoselective construction of the C4
to C6 carbon centers by syn-dihydroxylation of alkene followed by reduction of
carbonyl group in pyranone (8), introduction of ethynyl moiety as a carboxylic
acid synthon at C3 by nucleophilic addition of lithium trimethylsilylacetylide to
aldehyde (19), and bicyclic formation of dihydroxy ketone by ketalization,
providing the 2,8-dioxabicyclo[3.2.1]octane core of zaragozic acids.
INTRODUCTION
The zaragozic acids and squalestatins, (Figure 1) fungal metabolites isolated independently by three
groups,1-3 are potent inhibitors of squalene synthase (EC 2.5.1.21), that catalyzes the first committed
enzyme of sterol biosynthesis. These compounds were shown to be not only inhibitors of mammalian
squalene synthase,4 but also antifungal agents2a and ras-farnesyl-protein transferase inhibitors.1,5 Since
inhibition of squalene synthase would be ideal from a therapeutic point of view, they are the most
promising lead compounds for the development of new cholesterol-lowering drugs. These acids possess
unusual and characteristic 4,6,7-trihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid core
with six contiguous stereogenic centers. The core system is common to all members of the family with
the only differences arising at C1 alkyl and C6 fatty acid side chains. This combination of potent
biological activity and the complexity of their structures has stimulated a large number of synthetic
R1O
5
OH
R1=
OAc
R=
7
3
O
1
HO2C
Ph
O
R
HO2C
O
CO2H
OH
Figure 1. Zaragozic acid A (Squalestatin S1)

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HETEROCYCLES, Vol. 67, No. 2, 2006
studies6 toward the core system and several total syntheses.7 As part of our continuing studies directed to
the synthesis of physiologically active natural products using chiral furylcarbinols,8 we describe in detail
a synthesis of the bicyclic core of zaragozic acids.9
RESULTS AND DISCUSSION
The common core of zaragozic acids bears six contiguous stereogenic centers with citric acid unit, whose
stereoselective construction seems to be a critical issue of the synthesis. The strategy for the synthesis of a
model core (1) was envisaged to employ pyranone (3), readily accessible from chiral furylglycerol (4) by
oxidative transformation. (Scheme 1) syn-Dihydroxylation of 3 followed by reduction of ketone would
occur from less hindered side to provide the corresponding 4,5,6-trihydroxypyran with the desired
stereochemistries, and C1 unit as carboxylic acid synthon can be introduced by stereoselective
nucleophilic addition. Intramolecular ketalization of 2 would lead to the bicyclic core of zaragozic acids.
syn dihydroxylation
OH
OR
PO
HO
C1 unit
PO
HO
7 OH
6
PO OP
3 C1 unit
4
5
HO
HO
5
1
3
6
O
7
4
5
OH
7
OH
4
5
O
1
O
1
O
3 C1 unit
HO
PO
OH
4
O
7
6
3
O
6
1
OH
O
O
PO
O
OH
O
3
OH
4
1
2
reduction
Scheme 1. Retrosynthetic analysis of zaragozic acid core system
Synthesis of the key intermediate, highly oxygenated pyran (14) was carried out as follows. (Scheme 2)
Chelation controlled addition reaction10 of 2-lithio-3,4-bis(methoxymethyloxymethyl)furan, prepared by
treatment of 5 with BuLi, to (S)-2,3-O-isopropylideneglyceraldehyde11 in the presence of ZnBr2 afforded
a mixture of (2S, 3S)-glycerol (6) and its epimer in a ratio of 91:9, respectively. Ring enlargement of 6 by
reaction with NBS12 in aq. THF gave lactol (7), which was treated with TBSCl in the presence of Ag2O to
afford α-silyl ether (8) and β-ether in a ratio of 86:14, respectively. The stereochemistry at the anomeric
position in 8 was deduced by the basis on our previous result.8b Dihydroxylation of 8 with OsO4 in the
presence of pyridine occurred from the opposite side of adjacent silyl moiety to provide diol (9)
quantitatively. Acid treatment of 9 in acetone brought about removal of MOM group followed by
bis-ketalization to afford 10 in 63.9% yield. Reduction of ketone (10) at C6 (zaragozic acid numbering)
with NaBH4 in MeOH at -78 ºC gave the desired (6R)-alcohol (11) and its epimer in 90.9 and 9.0% yields,
respectively. Since the stereochemistries at C6 in both alcohols could not be deduced from their 1H NMR
spectral analyses, the stereostructure of 11 was unambiguously determined by the X-Ray crystallographic
analysis of desilylated compound (12). Protection of alcohol (11) as benzyl ether gave 13, which was

HETEROCYCLES, Vol. 67, No. 2, 2006
733
R1 R2
PO OP
PO OP
OTBS
O
OTBS
O
PO
PO
PO
HO
4
O
O
O
4
O
v
iv
i
6
ii
6
O
O
O
5
HO
PO
O
O
O
O
P=MOM
5
O
O
O
O
O
O
O
OH
7 R1, R2=H, OH
8 R1=H, R2=OTBS
6
9
10
iii
OR
O
OR
O
3
O
O
O
O
O
vi
viii
6
O
O
O
O
O
OH
OBn
O
O
11 R=TBS
12 R=H
13 R=TBS
14 R=H
vii
ix
X Ray crystal structure of 12
Scheme 2. i, n-BuLi, ZnBr2, THF, (S)-2,3-O-isopropylideneglyceraldehyde, 81.6 %; ii, NBS, aq. THF, 89.5 %;
iii, TBSCl, Ag2O, DMF, 73.7 %; iv, OsO4, pyridine, Et2O, 99.2 %; v, p-TsOH, acetone, 63.9 %; vi, NaBH4, MeOH,
90.9 %; vii, TBAF, THF, 91.7 %; viii, NaH, BnBr, DMF, 93.8 %; ix, TBAF, THF, 84.7 %.
treated with TBAF to afford lactol (14). The observed stereoselectivity in the reduction of 10 at C6
position is rationalized that equatorial approach of hydride would favor over axial approach which
generates the severe steric repulsion between hydride and bulky dioxolane ring at C4 position.
We first examined nucleophilic addition of C1 equivalent synthon, such as vinylmagnesium halide,
ethynylmagnesium halide, trimethylsilyl cyanide etc, to lactol at C3 position in 14. In most cases
formation of unidentified polar products together with starting material was found probably due to the
lower reactivity of lactol with quaternary carbon at α position. Therefore, introduction of C1 unit to
aldehyde followed by its transformation into the bicyclic core of zaragozic acids was devised as shown in
Scheme 3. Lactol (14) was reduced with LiAlH4 to the open-chain diol (15). Compound (15) was
converted to aldehyde (19) by sequential acetylation of the primary hydroxyl group in 15, silylation of the
secondary hydroxyl group in 16, hydrolysis of acetate in 17, and oxidation of the primary hydroxyl group
in 18 with Dess-Martin reagent13 in 75% overall yield.
Addition of C1 synthon to aldehyde (19) was carried out using several reagents under various conditions,
and the selected results are shown in Table 1. More than 5 equiv. of reagent was used for the reaction
because a stoichiometric amount of reagent gave only the recovery of starting material. The addition of
vinylmagnesium bromide and lithium acetylide·ethylenediamine complex to 19 gave a mixture of
isomers in low yields with moderate selectivities (entries 1 and 3), whereas the reaction with
ethynylmagnesium bromide and trimethylsilyl cyanide gave none of the desired adducts (entries 2 and 4).
Pleasingly, the addition of lithium trimethylsilylacetylide gave a good yield of the adducts with moderate
selectivity (entry 5). The best selectivity was recorded by lowering temperature. Highly diastereoselective

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HETEROCYCLES, Vol. 67, No. 2, 2006
Table 1. Nucleophilic addition to aldehyde (19)
O
OR1
OR2
O
selectivitya
reagent (equivalent)
H2C=CHMgBr (10)
HC≡CMgBr (6)
entry
yield (%)
38.6
condition
R
OTBS
O
O
85:15
-
1
2
THF, 0°C, 0.5 h
THF, rt, 10 h
iv
i
O
O
14
O
O
NR
O
O
OBn
OBn
O
O
(10)
H2NCH2CH2NH2
HC≡CLi
23.8b
3
73:27
THF, 0°C, 0.5 h
15 R1=R2=H
18 R=CH2OH
19 R=CHO
TMSCN
(10)c
ii
v
16 R1=Ac, R2=H
-
0
CH2Cl2, 0°C, 0.5 h
THF, -10°C, 0.5 h
THF, -78°C, 0.5 h
4
5
6
iii
17 R1=Ac, R2=TBS
88.8
94.4
86:14
>99:1
(9)
TMSC≡CLi
TMSC≡CLi
(7)
Scheme 3. i, LiAlH4, THF, 93.6 %; ii, Ac2O, DMAP,
pyridine, CH2Cl2, 95.5 %; iii, TBSOTf, Et3N, CH2Cl2,
92.6 %; iv, 1M LiOH, MeOH, 91.3 %; v, Dess-Martin
oxid., 99.6 %.
a The ratio of the (3R) to (3S) products was determined by 270 MHz
1H NMR spectral analysis. b Together with the recovery of starting
material. c A catalytic amount of ZnI2 was also used.
addition of lithium trimethylsilylacetylide in THF at -78 °C proceeded to afford propargylic alcohol (20)
as a sole product in 94.4% (entry 6). Usage of additives did not give any improvement of both yield and
selectivity.
Although the stereochemistry at C3 position in 20 could not be determined at this stage, its conversion to
the bicyclic core of zaragozic acids was carried out (Scheme 4). Desilylation of terminal silyl moiety in
20 with K2CO3 followed by acetylation of newly created alcohol in 21 gave acetate (22) quantitatively.
14
Selective removal of less hindered acetonide in 22 with FeCl3·SiO2 afforded diol (23), which was then
converted into ketone (25) by sequential acetylation of the primary alcohol in 23 and Dess-Martin
oxidation of the secondary alcohol in 24 in 54% overall yield. Alkaline hydrolysis of diacetate (25)
disappointingly gave a trace amount of the corresponding dihydroxyketone. In this regard, protecting
OH
OR
OR1
OR
O
O
O
O
R
OTBS
3
O
O
O
O
OTBS
O
OTBS
OTBS
iv
iii
vi
i
O
O
O
O
19
O
O
OR2
OAc
O
OH
O
OBn
OBn
OBn
OBn
O
O
O
O
23 R1=Ac, R2=H
24 R1=R2=Ac
25 R=Ac
29 R=MOM
20 R=TMS
21 R=H
22 R=Ac
v
v
ii
26 R=MOM
27 R1=MOM, R2=H
28 R1=MOM, R2=Ac
H
H
BnO
OAc
BnO
OAc
6
7
6
7
AcO
AcO
AcO
H
H
OAc
OAc
vii
O
O
HO
+
O
O
3
H
3
OH
H
AcO
31
indicates nOe enhancement
30
Scheme 4. i, lithium trimethylsilylacetylide, THF, 94.4 %; ii, K2CO3, MeOH, 99.8 %; iii, Ac2O, DMAP, pyridine, CH2Cl2,
99.4 % for 22; MOMCl, i-Pr2NEt, CH2Cl2, 97.4 % for 26; iv, FeCl3-SiO2, CHCl3, 86.1 % for 23, 68.1 % for 27; v, Ac2O,
DMAP, pyridine, CH2Cl2, 99.3 % for 24, 96.7 % for 28; vi, Dess-Martin oxid., 62.7 % for 25, 75.4 % for 29; vii, HCl,
MeOH; then Ac2O, DMAP, pyridine, CH2Cl2, 32.5 % for 30, 20.7 % for 31 (2 steps).

HETEROCYCLES, Vol. 67, No. 2, 2006
735
group in 21 was changed from acetyl to methoxymethyl group, which could be readily removed by acid
treatment. Methoxymethylation of alcohol (21) gave quantitatively 26, which was further converted into
29 by the same sequences as above via diol (27) and monoacetate (28) in 50% overall yield. The stage
was set for construction of the bicyclic core of zaragozic acids by ketalization. Although several bicyclic
ketals could be formed upon acid cyclization of ketone (29), we hoped that acid-mediated cyclization
would proceed under kinetic control to provide the desired 2,8-dioxabicyclo[3.2.1]octane system
according to the useful observation by Myles.15 Treatment of 29 with a trace amount of conc. HCl in
MeOH gave two unstable ketals in a ratio of ca. 3:2, which without purification were isolated by
peracetylation to furnish the desired bicyclic compound (30) and its isomer (31) in 32.5 and 20.7% yields,
respectively. The 3:2 ratio of the two ketal products did not change over 2 days time period. No other
ketals were detected under this condition, even more prolonged reaction time. Assignment of the
stereostructures of both bicyclic systems (30) and (31) was based on NMR experiments including HMQC,
HMBC, and NOEDIFF. Diagnostic nOe enhancements for both 30 and 31 and also the coupling constants
of J6-7=2.4Hz for 30 and J6-7=3.1Hz for 31 were observed, respectively. These NMR spectroscopic study
provides strong evidence for the stereochemical confirmation and thus for the sense of diastereoselectivity
of the nucleophilic addition process. Both bicyclic ketals (30) and (31) possess
2,8-dioxabicyclo[3.2.1]octane systems, however 31 has an incorrect substitution arrangement. The
formation of product (31) is quite different from product distribution upon ketalization of similar polyoxy
ketones reported by Myles15 and Armstrong.7g We supposed that initial hydrolysis of the acetonide at C5
position followed by ring closure of the hydroxyl at C5 onto the carbonyl at C1 might lead to a
five-membered intermediate, whose second acetonide at C4 may be removed and subsequently
competitive ring closure of each the hydroxyl at C3 and the hydroxyl attached at C4 might result in the
formation of 30 or 31 based on the informative results in acid-mediated ketalization by Hashimoto7f and
Armstrong.7g Although this discrepancy in product distribution would not be rationally explained, the
relatively higher nucleophilicity of hydroxyl attached at C4 than that of hydroxyl at C3 owing to the
inductive effect of ethynyl moiety16 could play a significant role in the second ring closure.
For purposes of higher synthetic efficiency, introduction of C1 unit to lactol (14) was reexamined.
(Scheme 5) Treatment of 20 equiv. of lithium trimethylsilylacetylide in THF at rt for 10 h gave
propargylic alcohol (32) in 32.3% together with the recovery of starting material. To our delight, addition
of 40 equiv. of trimethylsilylethynylmagnesium chloride proceeded diastereoselectively to afford
propargylic alcohol (32) in 84.5% yield and none of its epimer was found. The stereochemistry at C3
position in 32 was elucidated by comparison of the acetate (22) obtained above. Desilylation of silyl
moiety in 32 gave diol (33), whose selective acetylation of alcohol at C3 position followed by silylation
of alcohol in 34 afforded silyl ether (35). Since 35 was found to be an epimer of 22 at C3 position by

736
HETEROCYCLES, Vol. 67, No. 2, 2006
TMS
O
O
OR1
OR1
HO
O
O
OH
O
R
OR2
OR2
O
3
O
O
O
O
OH
i
iii
v
vi
O
O
O
O
14
32
O
O
O
O
O
O
OBn
O
OBn
36
O
OBn
O
OBn
O
O
37 R1=R2=H
34 R1=Ac, R2=H
35 R1=Ac, R2=TBS
32 R=TMS
33 R=H
vii
viii
iv
ii
38 R1=Ac, R2=H
22 R1=Ac, R2=TBS
O
O
3
O
O
ix
x
36
19
O
O
O
OBn
O
39
Scheme 5. i, trimethylsilylethynylmagnesium chloride, THF, 84.5 %; ii, K2CO3, MeOH, 65.3 %; iii, Ac2O, DMAP,
pyridine, CH2Cl2, 91.1 %; iv, TBSOTf, Et3N, CH2Cl2, 62.5 %; v, Dess-Martin oxid., 97.0 %; vi, NaBH4, aq. EtOH,
THF, 31.4 %; vii, Ac2O, DMAP, pyridine, CH2Cl2, 97.4 %; viii, TBSOTf, Et3N, CH2Cl2, 88.9 %; ix, PCC, NaOAc,
Celite, CH2Cl2, 71.5 %; x, lithium trimethylsilylacetylide, THF, 73.5 %.
their NMR spectral analyses, thus confirming that the stereostructure of 32 should be 3S. Inversion at C3
position in 32 was also carried out as follows. Attempts to directly invert the stereochemistry at C3
position by Mitsunobu reaction failed. Dess-Martin oxidation of 32 gave an inseparable mixture of
hemiketals (36), in a ratio of 78:22, which was reduced with NaBH4 to afford a mixture of the desired
alcohol (37) and its epimer (33) in a ratio of 9:1 together with an unidentified product which might be
deoxygenated compound. A mixture of 37 and 33 was converted into acetate (22) and its epimer (35) by
the same procedure as above. Interestingly, hemiketals (36) was also prepared by the addition of lithium
trimethylsilylacetylide (5 equiv.) to lactone (39), obtained by oxidation of lactol (14) with PCC, in THF at
-78 °C in 73.5%.
The opposite diastereoselectivity observed in the nucleophilic addition reactions to aldehyde (19) and
lactol (14) is of interest from a mechanistic point of view. Although several highly diastereoselective
nucleophilic additions to open-chain α,β-dialkoxy aldehydes17 and higher carbohydrates18 are known, the
stereochemical outcome of the reactions to polyalkoxy carbonyl compounds with quaternary carbons at α
positions such as 19 and 14 is hardly predictable. These results can be explained by assuming an
α-chelation transition state (A), which could be formed under relatively kinetic condition, in the addition
to aldehyde (19) and either a δ-chelation19 transition state (B) or a Felkin-Anh transition state (C) in the
addition to lactol (14). (Figure 2) The diastereoselectivity observed in the reduction of hemiketals (36)
would be also rationalized by a Felkin-Anh transition state.
We have disclosed a new method for the construction of 2,8-dioxabicyclo[3.2.1]octane core of zaragozic
acids employing the stereocontrolled modifications of chiral pyranone (8), accessible from (2S,3S)-

HETEROCYCLES, Vol. 67, No. 2, 2006
737
Li+
O
BnO
H
O
O
O
H
A
O
H
O
O
O
H
Mg
Br
O
O
B
C
Figure 2.
furylglycerol (6), and the diastereoselective introduction of ethynyl moiety as a carboxylic acid synthon to
aldehyde (19) as key steps. Acid treatment of ketone (29) followed by peracetylation led to the formation
of bicyclic core (30) together with incorrect substituted isomer (31). Application of 30 to the natural
product would be possible by oxidation of the core substituents and introduction of side chains.
EXPERIMENTAL
1
13
IR spectra were obtained using a JASCO FT/IR-200 spectrophotometer. H and C NMR spectra were
obtained on a JEOL JNM-LA270 (1H NMR: 270 MHz, 13C-NMR: 67.8 MHz) for solutions in CDCl3, and
1
chemical shifts are reported on the scale using TMS as an internal standard of 0.00 for H NMR spectra
13
and CDCl3 as an internal standard of 77.00 for C NMR spectra, respectively. JEOL JNM-LA500 (1H
NMR: 500 MHz, 13C NMR: 125 MHz) instrument was used only for the measurement of compounds (30)
and (31). MS spectra were measured with a JEOL JMS-D300 spectrometer. Optical rotations were taken
with a JASCO DIP-360 polarimeter. Elemental analyses were performed on a Yanaco-MT5. X-Ray
measurement was carried out on a Rigaku AFC 7R diffractometer.
(2S,3S)-3-{2'-[3',4'-Bis(methoxymethyloxymethyl)furyl]}-1,2-O-isopropylideneglycerol (6). To a
solution of 3,4-bis(methoxymethyloxymethyl)furan (5) (19.9 g, 92 mmol) in THF (300 mL) was added
dropwise n-BuLi (1.69 M in hexane; 65.5 mL, 110 mmol) at –50 °C. The reaction mixture was stirred for
1 h at 0 °C, and ZnBr2 (25 g, 110 mmol) was added portionwise. After being stirred for 30 min, a solution
of (S)-2,3-O-isopropylideneglyceraldehyde (8.0 g, 61.5 mmol) in THF (50 mL) was added dropwise at
0°C. The reaction was allowed to warm to rt and stirred for 10 h. The reaction was carefully quenched
with saturated aqueous NH4Cl solution in ice bath. The reaction mixture was concentrated, and a residue
was extracted with AcOEt, and the combined organic layer was washed with brine. The organic layer was
dried over Na2SO4 and evaporated to give a residue, which was chromatographed on silica gel
(hexane/AcOEt=3:2) to afford a mixture of (2S, 3S)-glycerol (6) and (2S, 3R)-glycerol (91:9) as a
colorless oil (11.3 g, 81.6 %). A small sample of mixture was purified carefully to give pure (2S,
1
3S)-glycerol (6). IRνcm-1: 3450 (OH). H NMR:δ1.36 and 1.43 (each 3H, each s, CMe2), 3.07 (1H, d,
J=3.7 Hz, 3-OH), 3.38 and 3.40 (each 3H, each s, OMe), 4.12 and 4.20 (each 1H, each dd, J=9.2, 6.1 Hz,
1-H2), 4.43 (1H, distorted q, J=6.1 Hz, 2-H), 4.48 (2H, s, 4'-CH2), 4.54 and 4.61 (each 1H, each d, J=12.2
Hz, 3'-CH2), 4.63 and 4.66 (each 2H, each s, OCH2OMe), 4.83 (1H, dd, J=6.1, 3.7 Hz, 3-H), 7.39 (1H, s,
5'-H). HRMS m/z: Calcd for C16H26O8 (M+): 346.1627. Found: 346.1630. [α]D25 +2.73° (c=1.01, CHCl3).
(2S)-6-Hydroxy-2-[(4'S)-2',2'-dimethyl-1',3'-dioxolan-4'-yl]-4,5-bis(methoxymethyloxymethyl)-6H-
pyran-3(2H)-one (7). To a stirred solution of the above mixture of glycerol (6.0 g, 17.3 mmol) and
sodium acetate (1.85 g, 22.5 mmol) in aqueous THF (150 mL, THF/H2O=4:1) was added portionwise
NBS (4.0 g, 22.5 mmol) at 0 °C, and the resulting mixture was stirred for 30 min at the same temperature.
The reaction mixture was successively treated with an excess of 10% KI solution and with saturated

738
HETEROCYCLES, Vol. 67, No. 2, 2006
Na2S2O3 solution. After removal of the solvent, the aqueous solution was extracted with AcOEt, and the
combined organic layer was washed with brine. The organic layer was dried over Na2SO4 and evaporated
to give a residue, which was chromatographed on silica gel (hexane/AcOEt=3:2) to afford lactol (7) (5.6 g,
89.5 %) as a colorless oil. IRνcm-1: 3400 (OH), 1690 (CO). 1H NMR:δ1.38 and 1.44 (each 3H, each s,
CMe2), 3.36 and 3.39 (each 3H, each s, OMe), 3.98 (2H, dt, J=15.3, 6.7Hz, 5'-H2), 4.28 and 4.37 (each
1H, each d, J=11.0 Hz, 4-CH2), 4.39 and 4.57 (each 1H, each d, J=14.0 Hz, 5-CH2), 4.45 (1H, d, J=4.9
Hz, 6-OH), 4.61 and 4.68 (each 2H, each s, OCH2OMe), 4.71 (1H, ddd, J=6.7, 6.7, 3.1 Hz, 4'-H), 4.86
(1H, d, J=3.1 Hz, 2-H), 5.87 (1H, d, J=4.9 Hz, 6-H). HRMS m/z: Calcd for C15H23O9 (M+-15): 347.1342.
24
Found: 347.1342. Anal. Calcd for C16H26O9: C, 53.03; H, 7.53. Found: C, 53.05; H, 7.33. [α]D +4.66°
(c=0.72, CHCl3).
(2S,6S)-6-tert-Butyldimethylsiloxy-2-[(4'S)-2',2'-dimethyl-1',3'-dioxolan-4'-yl]-4,5-bis-(methoxy-
methyloxymethyl)-6H-pyran-3(2H)-one (8). A mixture of lactol (7) (6.78 g, 18.8 mmol), Ag2O (30.5 g,
131 mmol), and TBSCl (19.7 g, 131 mmol) in DMF (250 mL) was stirred for 2 days at -30 °C. After
insoluble material was filtered off through a Celite pad, the filtrate was concentrated to leave a residue,
which was chromatographed on silica gel (hexane/AcOEt=9:1) to afford α-silyl ether (8) and β-silyl ether
(86:14) as a colorless oil (6.59 g, 73. 7 %). A mixture was purified carefully to give pure α-silyl ether (8),
1
however pure β-silyl ether could not be separated. α-Silyl ether (8): IRνcm-1: 1690 (CO). H NMR:δ
0.19 and 0.20 (each 3H, each s, SiMe2), 0.92 (9H, s, CMe3), 1.37 and 1.43 (each 3H, each s, CMe2), 3.35
and 3.38 (each 3H, each s, OMe), 3.97 (2H, m, 5'-H2), 4.22 and 4.60 (each 1H, each d, J=13.4 Hz, 5-CH2),
4.25 and 4.36 (each 1H, each d, J=11.0 Hz, 4-CH2), 4.61 and 4.64 (each 2H, each s, 2×OCH2OMe),
4.67-4.74 (2H, m, 2-H, 4'-H), 5.81 (1H, s, 6-H). HRMS m/z: Calcd for C21H37O9Si (M+-15): 461.2207.
Found: 461.2209. Anal. Calcd for C22H40O9Si: C, 55.44; H, 8.46. Found: C, 55.30; H, 8.41. [α]D29 +12.5°
(c=1.0, CHCl3).
(2S,4S,5R,6S)-6-tert-Butyldimethylsiloxy-4,5-dihydroxy-4,5-bis(methoxymethyloxymethyl)-2-
[(4'S)-2',2'-dimethyl-1',3'-dioxolan-4'-yl]-3,4,5,6-tetrahydro-2H-pyran-3-one (9). To a stirred solution
of enone (8) (3.2 g, 6.72 mmol) in Et2O (150 mL) was added pyridine (2.2 mL, 26.9 mmol) and OsO4
(2.2 g, 8.75 mmol) at 0 °C and the resulting mixture was further stirred for 12 h at rt. After removal of the
solvent, the residue was dissolved in pyridine (100 mL). To this solution was added a solution of NaHSO3
(9.1 g, 87.5 mmol) in H2O (100 mL), and the mixture was stirred for 12 h at rt. Evaporation of the solvent
gave a residue, which was chromatographed on silica gel (hexane/AcOEt=3:2) to afford diol (9) (3.4 g,
99.2 %) as a colorless oil. IRνcm-1: 1730 (CO), 3540 (OH). 1H NMR:δ0.19 and 0.26 (each 3H, each s,
SiMe2), 0.98 (9H, s, CMe3), 1.38 and 1.39 (each 3H, each s, CMe2), 3.30 and 3.38 (each 3H, each s,
OMe), 3.30 and 4.21 (each 1H, each s, 4, 5-OH), 3.56 and 4.75 (each 1H, each d, J=10.4 Hz, 4-CH2),
3.68 (2H, s, 5-CH2), 4.01 (1H, dd, J=8.6, 6.1 Hz, 5'-HH), 4.13 (1H, dd, J=8.6, 6.7 Hz, 5'-HH), 4.53 and
4.58 (each 1H, each d, J=6.7 Hz, OCH2OMe), 4.58 (1H, ddd, J=6.7, 6.1, 4.3 Hz, 4'-H), 4.62 and 4.66
(each 1H, each d, J=6.7 Hz, OCH2OMe), 4.66 (1H, d, J=4.3 Hz, 2-H), 5.25 (1H, s, 6-H). HRMS m/z:
Calcd for C22H42O11Si (M+): 510.2494. Found: 510.2492. Anal. Calcd for C22H42O11Si: C, 51.75; H, 8.29.
Found: C, 51.67; H, 8.46. [α]D22 -79.8° (c=1.03, CHCl3).
(2S,4S,5R,6S)-6-tert-Butyldimethylsiloxy-2-[(4'S)-2',2'-dimethyl-1',3'-dioxolan-4'-yl]-3,4,5,6-tetra-
hydro-2H-pyran-3-one-4,5-bis[spiro-4''-(2'',2''-dimethyl-1'',3''-dioxolane)] (10). A solution of diol (9)
(1.0 g, 1.96 mmol) and p-TsOH·H2O (1.86 g, 9.8 mmol) in acetone (50 mL) was refluxed for 5 h. To the
mixture was added saturated NaHCO3 solution in ice-bath. After removal of the solvent, the aqueous
solution was extracted with hexane-Et2O (1:1), and the combined organic layer was washed with brine.
The organic layer was dried over Na2SO4 and evaporated to give a residue, which was chromatographed
on silica gel (hexane/AcOEt=9:1) to afford triacetonide (10) (629 mg, 63.9 %) as a colorless oil. IRν
cm-1: 1740 (CO). 1H NMR:δ0.21 and 0.23 (each 3H, each s, SiMe2), 0.96 (9H, s, CMe3), 1.36 and 1.41
(each 3H, each s, CMe2), 1.41 (6H, s, CMe2), 1.47 and 1.55 (each 3H, each s, CMe2), 3.98-4.15 (6H, m, 4,
5-CH2, 5'-H2), 4.52 (1H, d, J=3.7 Hz, 2-H), 4.67 (1H, m, 4'-H), 5.06 (1H, s, 6-H). HRMS m/z: Calcd for

HETEROCYCLES, Vol. 67, No. 2, 2006
739
C24H42O9Si (M+): 502.2597. Found: 502.2597. Anal. Calcd for C24H42O9Si: C, 57.35; H, 8.42. Found: C,
57.11; H, 8.36. [α]D24 -85.4° (c=1.27, CHCl3).
(2S,3R,4R,5R,6S)-6-tert-Butyldimethylsiloxy-3-hydroxy-2-[(4'S)-2',2'-dimethyl-1',3'-dioxolan-4'-
yl]-3,4,5,6-tetrahydro-2H-pyran-4,5-bis[spiro-4''-(2'',2''-dimethyl-1'',3''-dioxolane)] (11). To
a
stirred solution of ketone (10) (629 mg, 1.25 mmol) in MeOH (30 mL) was added portionwise NaBH4 (71
mg, 1.88 mmol) at -78 °C. The reaction mixture was allowed to warm to 0 °C over 3 h. To the mixture
was added saturated NH4Cl solution and the solvent was concentrated to give a residue, which was
extracted with AcOEt. The combined organic layer was washed with brine. The organic layer was dried
over Na2SO4 and evaporated to give a residue, which was chromatographed on silica gel
(hexane/AcOEt=17:3) to afford (3R)-alcohol (11) (574 mg, 90.9 %) as a colorless oil. IRνcm-1: 3500
1
(OH). H NMR:δ0.16 and 0.18 (each 3H, each s, SiMe2), 0.93 (9H, s, CMe3), 1.36 and 1.40 (each 3H,
each s, CMe2), 1.46 (6H, s, CMe2), 1.47 and 1.51 (each 3H, each s, CMe2), 3.48 (1H, d, J=9.2 Hz, 3-OH),
3.73 (1H, br d, J=9.2 Hz, 3-H), 3.74 (1H, br d, J=6.1 Hz, 2-H), 3.86 and 3.91 (each 1H, each d, J=9.8 Hz,
4 or 5-CH2), 3.93 and 4.16 (each 1H, each d, J=9.2 Hz, 4 or 5-CH2), 4.00 (1H, dd, J=8.5, 5.5 Hz, 5'-HH),
4.08 (1H, dd, J=8.5, 6.1 Hz, 5'-HH), 4.46 (1H, distorted q, J=6.1, 5.5 Hz, 4'-H), 4.94 (1H, s, 6-H). HRMS
23
m/z: Calcd for C23H41O9Si (M+-15): 489.2520. Found: 489.2521. [α]D -49.7° (c=0.84, CHCl3). Further
1
elution gave (3S)-alcohol (57 mg, 9.0 %) as a colorless oil. IRνcm-1: 3530 (OH). H NMR:δ0.16 and
0.17 (each 3H, each s, SiMe2), 0.92 (9H, s, CMe3), 1.46, 1.47 and 1.51 (18H, each s, CMe2), 3.53 (1H, d,
J=9.2 Hz, 3-OH), 3.76 (1H, br d, J=9.2 Hz, 3-H), 3.76 (1H, br d, J=6.1 Hz, 2-H), 3.86 and 3.91 (each 1H,
each d, J=9.6 Hz, 4 or 5-CH2), 3.94 and 4.16 (each 1H, each d, J=9.2 Hz, 4 or 5-CH2), 3.96 and 3.98
(each 1H, each dd, J=10.4, 6.1 Hz, 5'-H2), 4.40 (1H, distorted q, J=6.1 Hz, 4'-H), 5.00 (1H, s, 6-H).
HRMS m/z: Calcd for C23H41O9Si (M+-15): 489.2520. Found: 489.2521. [α]D24 -49.5° (c=1.08, CHCl3).
(2S,3R,4R,5R,6R)-3,6-Dihydroxy-2-[(4'S)-2',2'-dimethyl-1',3'-dioxolan-4'-yl]-3,4,5,6-tetrahydro-2H-
pyran-4,5-bis[spiro-4''-(2'',2''-dimethyl-1'',3''-dioxolane)] (12). To a stirred solution of silyl ether (11)
(46.5 mg, 0.092 mmol) in THF (2 mL) was added dropwise TBAF (1.0 M in hexane, 0.14 mL, 0.14
mmol) at 0 °C and the mixture was stirred for 1 h at the same temperature. After the mixture was
quenched with saturated NH4Cl solution, the solvent was removed to give a residue, which was extracted
with AcOEt. The combined organic layer was washed with brine. The organic layer was dried over
Na2SO4 and evaporated to give a residue, which was chromatographed on silica gel (hexane/AcOEt=7:3)
to afford lactol (12) (33 mg, 91.7 %). Colorless prisms. mp 200-201°C (Et2O). IRνcm-1: 3500 (OH). 1H
NMR:δ1.36 and 1.43 (each 3H, each s, CMe2), 1.45 and 1.47 (each 3H, each s, CMe2), 1.48 and 1.51
(each 3H, each s, CMe2), 2.82 (1H, d, J=3.7 Hz, 6-OH), 3.49 (1H, d, J=8.5 Hz, 3-OH), 3.76 (1H, br d,
J=8.5 Hz, 3-H), 3.80 (1H, br d, J=8.5 Hz, 2-H), 3.87 and 3.97 (each 1H, each d, J=9.8 Hz, 4 or 5-CH2),
3.96 and 4.10 (each 1H, each dd, J=8.6, 6.1 Hz, 5'-H2), 4.12 and 4.19 (each 1H, each d, J=9.2 Hz, 5 or
6-CH2), 4.46 (1H, distorted q, J=6.1 Hz, 4'-H), 5.07 (1H, d, J=3.7 Hz, 6-H). 13C NMR:δ -5.9, -4.6, 17.7,
25.2, 25.5, 26.1, 55.4, 55.5, 64.7, 67.8, 69.0, 69.9, 73.0, 80.9, 81.5, 94.7, 96.7, 97.2, 109.1, 203.8. HRMS
m/z: Calcd for C18H30O9 (M+): 390.1890. Found: 390.1890. Anal. Calcd for C18H30O9: C, 55.37; H, 7.75.
25
Found: C, 55.49; H, 7.84. [α]D -43.6° (c=1.15, CHCl3). Crystal data of 12: C18H30O9, FW=390.43,
orthorhombic, P 2 2 2 , a=12.928(9) Å, b=16.65(1) Å, c=9.364(9) Å, V=2016(2) Å3, Z=4,
1 1 1
µ(CuKα)=8.71 cm-1, D(calc)=1.286 g/cm3; 1229 reflections with 2θmax=163.6° were recorded on a
Rigaku AFC7R diffractometer with graphite monochromated Cu-Kα radiation. Of those, 1203 with
I>3.00σ(I) were judged as observed. The structure was solved using SHELXS-86. R=0.088, Rw=0.090.
(2S,3R,4R,5R,6S)-3-Benzyloxy-6-tert-butyldimethylsiloxy-2-[(4'S)-2',2'-dimethyl-1',3'-dioxolan-4'-yl]-
3,4,5,6-tetrahydro-2H-pyran-4,5-bis[spiro-4''-(2'',2''-dimethyl-1'',3''-dioxolane)] (13). To a stirred
solution of alcohol (11) (330 mg, 066 mmol) and benzyl bromide (0.16 mL, 1.31 mmol) in DMF (15 mL)
was added portionwise NaH (ca. 60% purity, 52.3 mg, 1.31 mmol) at 0 °C and the reaction mixture was
stirred for 30 min at the same temperature. After the mixture was quenched with saturated NH4Cl solution,
the solvent was removed to give a residue, which was extracted with hexane-Et2O (1:1). The combined

740
HETEROCYCLES, Vol. 67, No. 2, 2006
organic layer was washed with brine. The organic layer was dried over Na2SO4 and evaporated to give a
residue, which was chromatographed on silica gel (hexane/AcOEt=9:1) to afford benzyl ether (13) (365
mg, 93.8 %) as a colorless oil. 1H NMR: δ 0.13 (6H, s, SiMe2), 0.92 (9H, s, CMe3), 1.41 (6H, s, CMe2),
1.43 and 1.54 (each 3H, each s, CMe2), 1.55 (6H, s, CMe2), 3.59 (1H, br d, J=8.5 Hz, 2-H), 3.66 (1H, d,
J=1.2 Hz, 3-H), 3.74 and 4.36 (each 1H, each d, J=9.8 Hz, 4-CH2), 3.84 and 4.26 (each 1H, each d,
J=9.8 Hz, 5-CH2), 3.86 and 4.01 (each 1H, each dd, J=8.5, 6.1 Hz, 5'-H2), 4.53 (1H, dt, J=8.5, 6.1 Hz,
4'-H), 4.80 and 5.05 (each 1H, each d, J=11.6 Hz, PhCH2), 5.07 (1H, s, 6-H), 7.20-7.32 (3H, m, Ar-H),
7.43 (2H, dd, J=7.9, 1.8 Hz, m-Ar-H). 13C NMR: δ -5.7, -4.6, 17.7, 25.5, 25.8, 26.2, 26.6, 26.8, 26.9, 66.9,
67.0, 69.9, 71.1, 72.9, 74.6, 79.8, 81.6, 83.4, 98.2, 108.9, 109.4, 111.2, 126.9, 127.7, 128.0, 139.1. HRMS
m/z: Calcd for C30H47O9Si (M+-15): 579.2989. Found: 579.2992. [α]D26 -22.3° (c=0.93, CHCl3).
(2S,3R,4R,5R,6R)-3-Benzyloxy-6-hydroxy-2-[(4'S)-2',2'-dimethyl-1',3'-dioxolan-4'-yl]-3,4,5,6-tetra-
hydro-2H-pyran-4,5-bis[spiro-4''-(2'',2''-dimethyl-1'',3''-dioxolane)] (14). To a stirred solution of
silyl ether (13) (760 mg, 1.28 mmol) in THF (20 mL) was added dropwise TBAF (1.0M in hexane, 1.92
mL, 1.92 mmol) at 0 °C and the mixture was stirred for 30 min at the same temperature. After the mixture
was quenched with saturated NH4Cl solution, the solvent was removed to give a residue, which was
extracted with AcOEt. The combined organic layer was washed with brine. The organic layer was dried
over Na2SO4 and evaporated to give a residue, which was chromatographed on silica gel
1
(hexane/AcOEt=7:3) to afford lactol (14) (520 mg, 84.7 %) as a colorless oil. IRνcm-1: 3600 (OH). H
NMR:δ1.36 and 1.41 (each 3H, each s, CMe2), 1.42 (6H, s, CMe2), 1.55 and 1.57 (each 3H, each s,
CMe2), 2.67 (1H, br s, 6-OH), 3.67 (1H, d, J=8.5 Hz, 2-H), 3.68 (1H, br s, 3-H), 3.73 and 4.37 (each 1H,
each d, J=9.8 Hz, 4-CH2), 3.83 and 4.04 (each 1H, each dd, J=8.6, 6.1 Hz, 5'-H2), 4.01 and 4.31 (each 1H,
each d, J=9.2 Hz, 5-CH2), 4.54 (1H, dt, J=8.5, 6.1 Hz, 4'-H), 4.74 and 5.03 (each 1H, each d, J=11.6 Hz,
PhCH2), 5.15 (1H, br s, 6-H), 7.23-7.32 (3H, m, Ar-H), 7.44 (2H, dd, J=7.9, 1.8 Hz, m-Ar-H). HRMS
m/z: Calcd for C24H33O9 (M+-15): 465.2122. Found: 465.2119. [α]D26 -7.47° (c=1.06, CHCl3).
(2R,3R,4R,5S,6S)-4-Benzyloxy-6,7-O-isopropylidenedioxy-1,5-heptanediol-2,3-bis[spiro-4'-(2',2'-
dimethyl-1',3'-dioxolane)] (15). To a stirred suspension of LiAlH4 (79 mg, 2.08 mmol) in THF (5 mL)
was added a solution of lactol (14) (200 mg, 2.08 mmol) in THF (2 mL) at 0 °C and the reaction mixture
was stirred for 1 h at rt. After quenching with 30% NaOH, insoluble material was filtered off through a
Celite pad. The filtrate was extracted with AcOEt and the combined organic layer was washed with brine.
The organic layer was dried over Na2SO4 and evaporated to give a residue, which was chromatographed
on silica gel (hexane/AcOEt=2:1) to afford diol (15) (188 mg, 93.6 %) as a colorless oil. IRνcm-1: 3500
1
(OH). H NMR: δ1.35 and 1.44 (each 3H, each s, CMe2), 1.44 and 1.45 (each 3H, each s, CMe2), 1.52
and 1.53 (each 3H, each s, CMe2), 2.59 (1H, t, J=5.5 Hz, 1-OH), 3.48 (1H, d, J=4.9 Hz, 5-OH), 3.70 and
3.83 (each 1H, each dd, J=11.6, 5.5 Hz, 1-H2), 3.86 and 4.00 (each 1H, each d, J=9.2 Hz, 2 or 3-CH2),
3.96-4.17 (3H, m, 4, 5, 6-H), 4.06 and 4.25 (each 1H, each d, J=9.2 Hz, 2 or 3-CH2), 4.73 and 4.83 (each
1H, each d, J=11.6 Hz, PhCH2), 7.26-7.39 (5H, m, Ar-H). HRMS m/z: Calcd for C24H35O9 (M+-15):
467.2281. Found: 467.2283. Anal. Calcd for C25H38O9: C, 62.22; H, 7.94. Found: C, 62.02; H, 7.95.
[α]D22 +6.55° (c=1.08, CHCl3).
(2S,3R,4R,5S,6S)-1-Acetoxy-4-benzyloxy-6,7-O-isopropylidenedioxy-1,5-heptanol-2,3-bis[spiro-4'-
(2',2'-dimethyl-1',3'-dioxolane)] (16). A solution of diol (15) (258 mg, 0.54 mmol), Ac2O (0.2 mL, 2.14
mmol), a catalytic amount of DMAP, and pyridine (0.22 mL, 2.68 mmol) in CH2Cl2 (15 mL) was stirred
for 1 h at rt. After quenching with saturated NH4Cl solution, the mixture was extracted with AcOEt. The
combined organic layer was washed with brine. The organic layer was dried over Na2SO4 and evaporated
to give a residue, which was chromatographed on silica gel (hexane/AcOEt=3:1) to afford acetate (16)
1
(268 mg, 95.5 %) as a colorless oil. IRνcm-1: 1740 (CO), 3500 (OH). H NMR: δ1.26 and 1.35 (each
3H, each s, CMe2), 1.42 and 1.44 (each 3H, each s, CMe2), 1.45 and 1.50 (each 3H, each s, CMe2), 2.10
(3H, s, COCH3), 3.50 (1H, d, J=2.5 Hz, 5-OH), 3.95-4.26 (11H, m), 4.70 and 4.85 (each 1H, each d,
J=11.6 Hz, PhCH2), 7.29-7.40 (5H, m, Ar-H). HRMS m/z: Calcd for C26H37O10 (M+-15): 509.2386.

HETEROCYCLES, Vol. 67, No. 2, 2006
741
25
Found: 509.2386. Anal. Calcd for C27H40O10: C, 61.81; H, 7.69. Found: C, 61.52; H, 7.82. [α]D -6.54°
(c=1.64, CHCl3).
(2S,3R,4R,5S,6S)-1-Acetoxy-4-benzyloxy-5-tert-butyldimethylsiloxy-6,7-O-isopropylidenedioxy-
heptane-2,3-bis[spiro-4'-(2',2'-dimethyl-1',3'-dioxolane)] (17). To a stirred solution of alcohol (16)
(310 mg, 0.59 mmol) and Et3N (0.49 mL, 3.55 mmol) in CH2Cl2 (15 mL) was added TBSOTf (0.54 mL,
2.37mmol) at 0 °C and the mixture was stirred for 2 h at rt. After quenching with saturated NH4Cl
solution, the mixture was extracted with AcOEt. The combined organic layer was washed with brine. The
organic layer was dried over Na2SO4 and evaporated to give a residue, which was chromatographed on
silica gel (hexane/AcOEt=9:1) to afford silyl ether (17) (350 mg, 92.7 %) as a colorless oil. IRνcm-1:
1730 (CO). 1H NMR: δ0.09 and 0.15 (each 3H, each s, SiMe2), 0.86 (9H, s, CMe3), 1.32 and 1.39 (each
3H, each s, CMe2), 1.44 and 1.45 (each 3H, each s, CMe2), 1.49 (6H, s, CMe2), 2.07 (3H, s, COCH3),
3.61 (1H, d, J=7.3 Hz, 4-H), 3.72 and 3.78 (each 1H, each d, J=10.4 Hz, 2 or 3-CH2), 3.98 (2H, d, J=7.3
Hz, 7-H2), 4.21 and 4.40 (each 1H, each d, J=9.2 Hz, 2 or 3-CH2), 4.23 (2H, br s, 1-H2), 4.25 and 5.11
(each 1H, each d, J=11.6 Hz, PhCH2), 4.30 (1H, dt, J=7.3, 2.4 Hz, 6-H), 4.53 (1H, dd, J=7.3, 2.4 Hz,
5-H), 7.23-7.34 (5H, m, Ar-H). HRMS m/z: Calcd for C32H51O10Si (M+-15): 623.3252. Found: 623.3252.
[α]D25 -20.4° (c=1.03, CHCl3).
(2R,3R,4R,5S,6S)-4-Benzyloxy-5-tert-butyldimethylsiloxy-6,7-O-isopropylidenedioxy-1-heptanol-
2,3-bis[spiro-4'-(2',2'-dimethyl-1',3'-dioxolane)] (18). To a stirred solution of acetate (17) (300 mg,
0.47 mmol) in MeOH (10 mL) was added dropwise 1M LiOH (1.0 mL, 0.94 mmol) at 0 °C and the
mixture was stirred for 1 h at rt. After the mixture was neutralized with 1M HCl, the solvent was removed
to give a residue, which was extracted with AcOEt. The combined organic layer was washed with brine.
The organic layer was dried over Na2SO4 and evaporated to give a residue, which was chromatographed
on silica gel (hexane/AcOEt=4:1) to afford lactol (18) (256 mg, 91.3 %) as a colorless oil. IRνcm-1:
3525 (OH). 1H NMR: δ0.12 and 0.16 (each 3H, each s, SiMe2), 0.87 (9H, s, CMe3), 1.33 and 1.41 (each
3H, each s, CMe2), 1.43 and 1.46 (each 3H, each s, CMe2), 1.52 (6H, s, CMe2), 2.74 (1H, t, J=4.3 Hz,
1-OH), 3.45 and 3.67 (each 1H, each d, J=9.8 Hz, 2 or 3-CH2), 3.67 (1H, d, J=6.1 Hz, 4-H), 3.67 and
3.76 (each 1H, each dd, J=11.6, 4.3 Hz, 1-H2), 3.97 and 4.05 (each 1H, each dd, J=7.9, 6.1 Hz, 7-H2),
4.21 and 4.39 (each 1H, each d, J=9.2 Hz, 2 or 3-CH2), 4.21 and 5.09 (each 1H, each d, J=11.0 Hz,
PhCH2), 4.28 (1H, ddd, J=7.9, 6.1, 3.1 Hz, 6-H), 4.54 (1H, dd, J=6.1, 3.1 Hz, 5-H), 7.23-7.34 (5H, m,
25
Ar-H). HRMS m/z: Calcd for C30H49O9Si (M+-15): 581.3144. Found: 581.3144. [α]D -10.5° (c=1.39,
CHCl3).
(2R,3R,4R,5S,6S)-4-Benzyloxy-5-tert-butyldimethylsiloxy-6,7-O-isopropylidenedioxypentanal-2,3-
bis[spiro-4'-(2',2'-dimethyl-1',3'-dioxolane)] (19). To a stirred solution of alcohol (18) (284 mg, 0.48
mmol) in CH2Cl2 (10 mL) was added portionwise Dess-Martin periodinane (1.62 g, 3.81 mmol) at 0 °C
and the mixture was stirred for 1 h at rt. After dilution with Et2O, insoluble material was filtered off. The
filtrate was successively washed with saturated NaHCO3 solution, saturated Na2S2O3 solution, and brine.
The organic layer was dried over Na2SO4 and evaporated to give a residue, which was chromatographed
on silica gel (hexane/AcOEt=9:1) to afford aldehyde (19) (282 mg, 99.6 %) as a colorless oil. IRνcm-1:
1
1725 (CHO). H NMR: δ0.05 and 0.12 (each 3H, each s, SiMe2), 0.83 (9H, s, CMe3), 1.31 and 1.37
(each 3H, each s, CMe2), 1.43 and 1.44 (each 3H, each s, CMe2), 1.51 (6H, s, CMe2), 3.52 (1H, d, J=6.7
Hz, 4-H), 3.85 and 4.20 (each 1H, each dd, J=9.8, 1.2 Hz, 2-CH2), 3.92-4.01 (2H, m, 7-H2), 4.09 and 4.35
(each 1H, each d, J=9.2 Hz, 3-CH2), 4.20 (1H, m, 6-H), 4.33 and 5.04 (each 1H, each d, J=11.6 Hz,
13
PhCH2), 4.46 (1H, dd, J=6.7, 2.4 Hz, 5-H), 7.21-7.34 (5H, m, Ar-H), 9.49 (1H, d, J=1.2 Hz, CHO). C
NMR:δ -4.4, -3.8, 18.1, 24.9, 25.6, 25.7, 25.9, 26.1, 26.2, 27.1, 63.8, 65.8, 67.7, 68.8, 74.1, 76.4, 76.5,
78.3, 86.0, 89.3, 108.5, 109.9, 111.4, 126.5, 127.0, 128.0, 137.4, 203.1. HRMS m/z: Calcd for C30H47O9Si
(M+-15): 579.2988. Found: 579.2993. [α]D22 -7.37° (c=1.59, CHCl3).
(2S,3S,4R,5R,6S,7R)-4-Benzyloxy-3-tert-butyldimethylsiloxy-1,2-O-isopropylidenedioxy-9-trimeth-

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HETEROCYCLES, Vol. 67, No. 2, 2006
ylsilyl-8-nonyn-7-ol-5,6-bis[spiro-4'-(2',2'-dimethyl-1',3'-dioxolane)] (20). To a stirred solution of
lithium trimethylsilylacetylide [prepared from trimethylsilylacetylene (0.55 mL, 3.91 mmol) and n-BuLi
(1.56 M in hexane, 2.28 mL, 3.55 mmol) in THF (5 mL)] was added dropwise a solution of aldehyde (19)
(290 mg, 0.488 mmol) in THF (2 mL) at -78 °C and the mixture was stirred for 30 min at the same
temperature. After the mixture was quenched with saturated NH4Cl solution, the solvent was removed to
give a residue, which was extracted with AcOEt. The combined organic layer was washed with brine. The
organic layer was dried over Na2SO4 and evaporated to give a residue, which was chromatographed on
silica gel (hexane/AcOEt=9:1) to afford propargyl alcohol (20) (319 mg, 94.4 %) as a colorless oil. IRν
cm-1: 3450 (OH). 1H NMR: δ0.02 and 0.14 (each 3H, each s, SiMe2), 0.18 (9H, s, SiMe3), 0.87 (9H, s,
CMe3), 1.32 and 1.46 (each 3H, each s, CMe2), 1.51 (6H, s, CMe2), 1.51 and 1.53 (each 3H, each s,
CMe2), 3.06 (1H, br s, 7-OH), 3.75 (1H, d, J=7.9 Hz, 4-H), 4.02 and 4.06 (each 1H, each d, J=10.4 Hz, 5
or 6-CH2), 4.03 and 4.19 (each 1H, each d, J=8.5 Hz, 1-H2), 4.32-4.41 (1H, m, 2-H), 4.37 and 5.09 (each
1H, each d, J=11.6 Hz, PhCH2), 4.39 and 4.51 (each 1H, each d, J=9.8 Hz, 5 or 6-CH2), 4.48 (1H, dd,
13
J=7.9, 2.5 Hz, 3-H), 4.61 (1H, br s, 7-H), 7.22-7.35 (5H, m, Ar-H). C NMR:δ -4.4, -3.7, -0.4, 18.1,
24.8, 26.0, 26.1, 26.2, 26.3, 26.5, 26.6, 63.5, 63.8, 66.8, 67.8, 70.1, 73.6, 77.7, 77.8, 87.7, 92.1, 104.2,
108.5, 110.9, 111.3, 126.4, 127.1, 128.1, 137.8. HRMS m/z: Calcd for C35H57O9Si2 (M+-15): 677.3539.
Found: 677.3534. [α]D23 -14.1° (c=1.27, CHCl3).
(2S,3S,4R,5R,6S,7R)-4-Benzyloxy-3-tert-butyldimethylsiloxy-1,2-O-isopropylidenedioxy-8-nonyn-7-
ol-5,6-bis[spiro-4'-(2',2'-dimethyl-1',3'-dioxolane)] (21). A mixture of trimethylsilylacetylene (20) (218
mg, 0.315 mmol) and K2CO3 (57 mg, 0.410 mmol) in MeOH (10 mL) was stirred for 2 h at rt. After
insoluble material was filtered off, the filtrate was condensed to give a residue, which was
chromatographed on silica gel (hexane/AcOEt=17:3) to afford acetylene (21) (195 mg, 99.8 %) as a
1
colorless oil. IRνcm-1: 3300 (acetylene), 3500 (OH). H NMR: δ0.06 and 0.15 (each 3H, each s,
SiMe2), 0.87 (9H, s, CMe3), 1.33 and 1.46 (each 3H, each s, CMe2), 1.49 and 1.51 (each 3H, each s,
CMe2), 1.52 (6H, s, CMe2), 2.51 (1H, d, J=1.8 Hz, 9-H), 3.18 (1H, d, J=3.1 Hz, 7-OH), 3.75 (1H, d,
J=7.3 Hz, 4-H), 3.96-4.10 (2H, m, 1-H2), 4.01 and 4.07 (each 1H, each d, J=9.8 Hz, 5 or 6-CH2), 4.31
and 5.09 (each 1H, each d, J=11.6 Hz, PhCH2), 4.28-4.35 (1H, m, 2-H), 4.39 and 4.44 (each 1H, each d,
J=9.8 Hz, 5 or 6-CH2), 4.49 (1H, dd, J=7.3, 2.4 Hz, 3-H), 4.66 (1H, dd, J=3.1, 1.8 Hz, 7-H), 7.25-7.35
20
(5H, m, Ar-H). HRMS m/z: Calcd for C32H49O9Si (M+-15): 605.3144. Found: 605.3133. [α]D -15.2°
(c=1.36, CHCl3).
(2S,3S,4R,5R,6S,7R)-7-Acetoxy-4-benzyloxy-3-tert-butyldimethylsiloxy-1,2-O-isopropylidenedioxy-
8-nonyne-5,6-bis[spiro-4'-(2',2'-dimethyl-1',3'-dioxolane)] (22). A solution of alcohol (21) (130 mg,
0.21 mmol), Ac2O (79.3 µL, 0.84 mmol), a catalytic amount of DMAP, and pyridine (85 µL, 1.05 mmol)
in CH2Cl2 (2.5 mL) was stirred for 12 h at rt. After quenching with saturated NH4Cl solution, the mixture
was extracted with AcOEt. The combined organic layer was washed with brine. The organic layer was
dried over Na2SO4 and evaporated to give a residue, which was chromatographed on silica gel
(hexane/AcOEt=9:1) to afford acetate (22) (138 mg, 99.4 %) as a colorless oil. IRνcm-1: 1750 (CO),
3300 (acetylene). 1H NMR: δ0.02 and 0.14 (each 3H, each s, SiMe2), 0.87 (9H, s, CMe3), 1.29 and 1.42
(each 3H, each s, CMe2), 1.45 and 1.47 (each 3H, each s, CMe2), 1.51 and 1.54 (each 3H, each s, CMe2),
2.10 (3H, s, COCH3), 2.47 (1H, d, J=2.5 Hz, 9-H), 3.75 (1H, d, J=8.6 Hz, 4-H), 3.96-4.07 (2H, m, 1-H2),
4.08 and 4.38 (each 1H, each d, J=9.8 Hz, 5 or 6-CH2), 4.36-4.45 (1H, m, 2-H), 4.40 and 4.62 (each 1H,
each d, J=10.4 Hz, 5 or 6-CH2), 4.50 (1H, dd, J=8.6, 1.2 Hz, 3-H), 4.54 and 5.23 (each 1H, each d,
J=12.2 Hz, PhCH2), 5.78 (1H, d, J=2.5 Hz, 7-H), 7.19-7.29 (5H, m, Ar-H). HRMS m/z: Calcd for
C34H51O10Si (M+-15): 647.3252. Found: 647.3252. [α]D24 -33.5° (c=1.42, CHCl3).
(2S,3S,4R,5R,6S,7R)-7-Acetoxy-4-benzyloxy-3-tert-butyldimethylsiloxy-8-nonyn-1,2-diol-5,6-bis-
[spiro-4'-(2',2'-dimethyl-1',3'-dioxolane)] (23). A mixture of triacetonide (22) (194 mg, 0.29 mmol) and
FeCl3-SiO2 complex (20 mg) in CHCl3 (10 mL) was stirred for 2 h at rt. After insoluble material was
filtered off through a Celite pad, the filtrate was concentrated to leave a residue, which was

HETEROCYCLES, Vol. 67, No. 2, 2006
743
chromatographed on silica gel (hexane/AcOEt=7:3) to afford diol (23) (157 mg, 86.1 %) as a colorless oil.
IRνcm-1: 1740 (CO), 3300 (acetylene), 3500 (OH). 1H NMR: δ0.03 and 0.18 (each 3H, each s, SiMe2),
0.88 (9H, s, CMe3), 1.43 and 1.45 (each 3H, each s, CMe2), 1.54 and 1.55 (each 3H, each s, CMe2), 2.11
(3H, s, COCH3), 2.50-2.65 (2H, br s, 1, 2-OH), 2.50 (1H, d, J=2.4 Hz, 9-H), 3.86-4.97 (3H, m, 1-H2, 2-H),
4.09 and 4.38 (each 1H, each d, J=9.8 Hz, 5 or 6-CH2), 4.16 (1H, d, J=8.6 Hz, 4-H), 4.37 and 4.64 (each
1H, each d, J=10.4 Hz, 5 or 6-CH2), 4.35 and 4.40 (1H, m, 3-H), 4.64 and 5.17 (each 1H, each d, J=12.2
Hz, PhCH2), 5.83 (1H, d, J=2.4 Hz, 7-H), 7.25-7.34 (5H, m, Ar-H). HRMS m/z: Calcd for C31H47O10Si
(M+-15): 607.2937. Found: 607.2935. [α]D24 -24.7° (c=0.86, CHCl3).
(2S,3S,4R,5R,6S,7R)-1,7-Diacetoxy-4-benzyloxy-3-tert-butyldimethylsiloxy-8-nonyn-2-ol-5,6-bis-
[spiro-4'-(2',2'-dimethyl-1',3'-dioxolane)] (24). A solution of diol (23) (34 mg, 0.055 mmol), Ac2O (7.7
µL, 0.082 mmol), a catalytic amount of DMAP, and pyridine (6.6 µL, 0.082 mmol) in CH2Cl2 (5 mL) was
stirred for 1 h at rt. After quenching with saturated NH4Cl solution, the mixture was extracted with AcOEt.
The combined organic layer was washed with brine. The organic layer was dried over Na2SO4 and
evaporated to give a residue, which was chromatographed on silica gel (hexane/AcOEt=4:1) to afford
1
acetate (24) (36 mg, 99.3 %) as a colorless oil. IRνcm-1: 1740 (CO), 3300 (acetylene) 3500 (OH). H
NMR: δ0.00 and 0.07 (each 3H, each s, SiMe2), 0.86 (9H, s, CMe3), 1.42 and 1.45 (each 3H, each s,
CMe2), 1.55 (6H, s, CMe2), 2.10 (6H, s, 2×COCH3), 2.45 (1H, br s, 2-OH), 2.51 (1H, d, J=2.4 Hz, 9-H),
4.03 (1H, m, 2-H), 4.10 (1H, d, J=9.8 Hz, 5 or 6-CHH), 4.14 (1H, d, J=8.6 Hz, 4-H), 4.25-4.44 (4H, m,
1-H2, 3-H, 5 or 6-CHH), 4.35 and 4.63 (each 1H, each d, J=9.8 Hz, 5 or 6-CH2), 4.59 and 5.19 (each 1H,
each d, J=12.2 Hz, PhCH2), 5.84 (1H, d, J=2.4 Hz, 7-H), 7.26-7.30 (5H, m, Ar-H). HRMS m/z: Calcd for
C33H49O11Si (M+-15): 649.3043. Found: 649.3012. [α]D25 -28.8° (c=0.75, CHCl3).
(3R,4R,5R,6S,7R)-1,7-Diacetoxy-4-benzyloxy-3-tert-butyldimethylsiloxy-8-nonyn-2-one-5,6-bis-
[spiro-4'-(2',2'-dimethyl-1',3'-dioxolane)] (25). A mixture of alcohol (24) (32 mg, 0.048 mmol) and
Dess-Martin periodinane (102 mg, 0.241 mmol) in CH2Cl2 (2 mL) was stirred for 6 h at rt. After dilution
with hexane-Et2O (5 mL, 1/1), the mixture was filtered through a Celite pad. The filtrate was successively
washed with saturated NaHCO3 solution, saturated Na2S2O3 solution, and brine. The organic layer was
dried over Na2SO4 and evaporated to give a residue, which was chromatographed on silica gel
(hexane/AcOEt=9:1) to afford ketone (25) (20 mg, 62.7 %) as a colorless oil. IRνcm-1: 1740 (CO), 3300
(acetylene). 1H NMR: δ0.06 and 0.11 (each 3H, each s, SiMe2), 0.92 (9H, s, CMe3), 1.41 and 1.44 (each
3H, each s, CMe2), 1.50 and 1.51 (each 3H, each s, CMe2), 2.13 and 2.17 (each 3H, each s, COCH3), 2.44
(1H, d, J=2.4 Hz, 9-H), 4.10 and 4.30 (each 1H, each d, J=9.8 Hz, 1-H2), 4.36 and 4.52 (each 1H, each d,
J=9.8 Hz, 5 or 6-CH2), 4.36 (1H, d, J=6.1 Hz, 4-H), 4.56 and 5.12 (each 1H, each d, J=11.6 Hz, 5 or
6-CH2), 4.72 (1H, d, J=6.1 Hz, 3-H), 4.84 and 5.17 (each 1H, each d, J=16.5 Hz, PhCH2), 5.83 (1H, d,
J=2.4 Hz, 7-H), 7.24-7.31 (5H, m, Ar-H). HRMS m/z: Calcd for C33H47O11Si (M+-15): 647.2886. Found:
647.2886. [α]D21 -15.4° (c=0.4, CHCl3).
(2S,3S,4R,5R,6S,7R)-4-Benzyloxy-3-tert-butyldimethylsiloxy-1,2-O-isopropylidenedioxy-7-methoxy-
methyloxy-8-nonyne-5,6-bis[spiro-4'-(2',2'-dimethyl-1',3'-dioxolane)] (26). A solution of alcohol (21)
(252 mg, 0.41 mmol), MOMCl (0.46 mL, 6.1 mmol), and i-Pr2NEt (1.63 mL, 9.3 mmol) in CH2Cl2 (2.5
mL) was refluxed for 6 h. After quenching with saturated NH4Cl solution, the mixture was extracted with
AcOEt. The combined organic layer was washed with brine. The organic layer was dried over Na2SO4
and evaporated to give a residue, which was chromatographed on silica gel (hexane/AcOEt=9:1) to afford
1
ether (26) (263 mg, 97.4 %) as a colorless oil. IRνcm-1: 3300 (acetylene). H NMR: δ0.04 and 0.15
(each 3H, each s, SiMe2), 0.86 (9H, s, CMe3), 1.31 and 1.44 (each 3H, each s, CMe2), 1.45 (6H, s, CMe2),
1.51 and 1.53 (each 3H, each s, CMe2), 2.47 (1H, d, J=2.5 Hz, 9-H), 3.33 (3H, s, OCH3), 3.95 (1H, d,
J=6.7 Hz, 4-H), 3.93-4.10 (4H, m, 1-H2, 5 or 6-CH2), 4.31 and 5.14 (each 1H, each d, J=12.2 Hz, PhCH2),
4.43 (2H, s, OCH2O), 4.46-4.56 (3H, m, 2-H, 3-H, 7-H), 4.62 and 4.90 (each 1H, each d, J=6.7 Hz, 5 or
6-CH2), 7.20-7.32 (5H, m, Ar-H). HRMS m/z: Calcd for C34H53O10Si (M+-15): 649.3407. Found:
649.3407. [α]D24 -33.9° (c=1.28, CHCl3).

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HETEROCYCLES, Vol. 67, No. 2, 2006
(2S,3S,4R,5R,6S,7R)-4-Benzyloxy-3-tert-butyldimethylsiloxy-7-methoxymethyloxy-8-nonyne-1,2-
diol-5,6-bis[spiro-4'-(2',2'-dimethyl-1',3'-dioxolane)] (27). The same procedure as for the alcohol (22)
was applied to compound (26) to afford diol (27) (68.1 %) as a colorless oil. IRνcm-1: 3310 (acetylene),
3490 (OH). 1H NMR: δ0.05 and 0.18 (each 3H, each s, SiMe2), 0.86 (9H, s, CMe3), 1.43 and 1.46 (each
3H, each s, CMe2), 1.56 (6H, s, CMe2), 2.49 (1H, d, J=1.8 Hz, 9-H), 2.60 and 2.80 (each 3H, each br s,
1-OH, 2-OH), 3.33 (3H, s, OCH3), 3.87-4.08 (5H, m, 1-H2, 2-H, 5 or 6-CH2), 4.34-4.45 (5H, m, 3-H, 4-H,
OCH2O, PhCHH), 4.58 (1H, d, J=1.8 Hz, 7-H), 4.64 and 4.94 (each 1H, each d, J=6.7 Hz, 5 or 6-CH2),
5.08 (1H, d, J=12.2 Hz, PhCHH), 7.23-7.34 (5H, m, Ar-H). 13C NMR:δ -4.7, -3.7, 18.1, 25.9, 26.0, 26.3,
26.7, 27.0, 55.9, 62.8, 66.5, 67.2, 68.0, 73.5, 74.0, 74.1, 76.4, 76.8, 80.6, 86.7, 87.5, 94.2, 110.3, 111.6,
126.2, 127.0, 128.0, 138.2. HRMS m/z: Calcd for C31H49O10Si (M+-15): 609.3095. Found: 609.3097.
[α]D24 -24.7° (c=0.86, CHCl3).
(2S,3S,4R,5R,6S,7R)-1-Acetoxy-4-benzyloxy-3-tert-butyldimethylsiloxy-7-methoxymethyloxy-8-
nonyn-2-ol-5,6-bis[spiro-4'-(2',2'-dimethyl-1',3'-dioxolane)] (28). The same procedure as for the
alcohol (23) was applied to compound (27) to afford acetate (28) (96.7 %) as a colorless oil. IRνcm-1:
1740 (CO), 3300 (acetylene) 3500 (OH). 1H NMR: δ0.03 and 0.14 (each 3H, each s, SiMe2), 0.85 (9H,
s, CMe3), 1.43 and 1.46 (each 3H, each s, CMe2), 1.56 and 1.57 (each 3H, each s, CMe2), 2.11 (3H, s,
COCH3), 2.50 (1H, d, J=2.4 Hz, 9-H), 2.66 (1H, br s, 2-OH), 3.32 (3H, s, OCH3), 3.99-4.10 (3H, m, 2-H,
5 or 6-CHH), 4.23 (1H, dd, J=11.6, 7.9 Hz, 1-HH), 4.31-4.49 (6H, m, 1-HH, 3-H, 4-H, PhCHH, OCH2O),
4.60 (1H, d, J=2.4 Hz, 7-H), 4.62 and 4.93 (each 1H, each d, J=6.7 Hz, 5 or 6-CH2), 5.10 (1H, d, J=11.6
Hz, PhCHH), 7.23-7.34 (5H, m, Ar-H). HRMS m/z: Calcd for C33H51O11Si (M+-15): 651.3196. Found:
651.3197. [α]D22 -32.3° (c=0.37, CHCl3).
(3R,4R,5R,6S,7R)-1-Acetoxy-4-benzyloxy-3-tert-butyldimethylsiloxy-7-methoxymethyloxy-8-nonyn-
2-one-5,6-bis[spiro-4'-(2',2'-dimethyl-1',3'-dioxolane)] (29). The same procedure as for the alcohol
(24) was applied to compound (28) to afford ketone (29) (75.4 %) as a colorless oil. IRνcm-1: 1740 (CO),
3280 (acetylene). 1H NMR: δ0.05 and 0.11 (each 3H, each s, SiMe2), 0.92 (9H, s, CMe3), 1.39 and 1.46
(each 3H, each s, CMe2), 1.53 (6H, s, CMe2), 2.18 (3H, s, COCH3), 2.48 (1H, d, J=2.4 Hz, 9-H), 3.36
(3H, s, OCH3), 3.99 and 4.09 (each 1H, each d, J=9.8 Hz, 1-H2), 4.30 and 4.38 (each 1H, each d, J=9.2
Hz, OCH2O or 5-CH2 or 6-CH2), 4.32 and 4.93 (each 1H, each d, J=11.0 Hz, OCH2O or 5-CH2 or 6-CH2),
4.50 (1H, d, J=5.5 Hz, 4-H), 4.61 (1H, d, J=2.4 Hz, 7-H), 4.64 and 4.95 (each 1H, each d, J=6.7 Hz,
OCH2O or 5-CH2 or 6-CH2), 4.81 (1H, d, J=5.5 Hz, 3-H), 4.85 and 5.12 (each 1H, each d, J=16.5 Hz,
13
PhCH2), 7.24-7.31 (5H, m, Ar-H). C NMR:δ -4.6, -4.5, 18.2, 20.5, 25.8, 25.9, 26.3, 26.9, 27.1, 56.0,
65.6, 66.9, 67.2, 68.2, 73.2, 75.4, 76.7, 77.7, 80.4, 86.8, 86.9, 94.2, 111.0, 127.2, 128.1, 138.0, 170.0,
23
201.7. HRMS m/z: Calcd for C33H49O11Si (M+-15): 649.3042. Found: 649.3042. [α]D -30.4° (c=0.18,
CHCl3).
Intramolecular ketalization of 29. A solution of ketone (29) (18 mg, 0.027 mmol) and a trace amount of
conc. HCl in MeOH (2 mL) was heated at 50 ºC for 2 days. After neutralization with saturated NaHCO3
solution, the mixture was extracted with CHCl3. The organic layer was dried over Na2SO4 and evaporated
to give a residue, which was used for the next reaction without any purification. A solution of the above
crude product, Ac2O (12.8 µL, 0.136 mmol), a catalytic amount of DMAP, and pyridine (13.2 µL, 0.163
mmol) in CH2Cl2 (2 mL) was stirred for 10 h at rt. After quenching with saturated NH4Cl solution, the
mixture was extracted with AcOEt. The combined organic layer was washed with brine. The organic
layer was dried over Na2SO4 and evaporated to give a residue, which was chromatographed on silica gel
(CH2Cl2/AcOEt=9:1) to afford (4R,6R,7R)-7-acetoxy-4-(1R-1-acetoxypropynyl)-6-benzyloxy-4-
hydroxy-1,4,5-tris(acetoxymethyl)-2,8-dioxabicyclo[3.2.1]octane (31) (3.0 mg, 20.7 %) as a colorless
1
oil. IRνcm-1: 1750 (CO), 3280 (OH); H NMR (500 MHz) δ 2.07, 2.08, 2.090 and 2.092 (each 3H,
each s, 4 x CH3CO), 2.59 (1H, d, J=2.4 Hz, -C≡CH), 3.21 (1H, br s, OH), 3.80 and 4.41 (each 1H, each d,
J=12.8 Hz, 3-H2), 4.07 and 4.17 (each 1H, each d, J=12.2 Hz, CH2OAc), 4.18 and 4.52 (each 1H, each d,
J=11.3 Hz, CH2OAc), 4.51 (1H, d, J=3.1 Hz, H-6), 4.55 and 4.66 (each 1H, each d, J=11.9 Hz, PhCH2),

HETEROCYCLES, Vol. 67, No. 2, 2006
745
13
5.44 (1H, d, J=3.1 Hz, H-7), 5.97 (1H, d, J=2.4 Hz, CHOAc), 7.23-7.38 (5H, m, ArH); C NMR (125
MHz) δ 20.68, 20.70, 20.76, 22.82, 62.31, 63.07, 65.60, 66.35, 70.58, 72.50, 76.47, 77.73, 78.83, 81.76,
84.14, 102.82, 127.69, 128.07, 128.52, 137.13, 168.89, 169.06, 169.17, 170.05. HRMS m/z: Calcd for
28
C25H27O12 (M+-15): 519.1500. Found: 519.1492. [α]D -6.6° (c=0.2, CHCl3). Further elution with
CH2Cl2/AcOEt (4/1) afforded (3R,4S,6R,7R)-7-acetoxy-6-benzyloxy-3-ethynyl-4-hydroxy-1,4,5-tris-
(acetoxymethyl)-2,8-dioxabicyclo[3.2.1]octane (30) (4.7 mg, 32.5 %) as a colorless oil. IRνcm-1: 1750
(CO), 3280 (OH); 1H NMR (500 MHz) δ 1.91, 1.98, 2.10 and 2.17 (each 3H, each s, 4 x CH3CO), 2.61
(1H, d, J=2.1 Hz, -C≡CH), 3.42 (1H, s, OH), 4.13 and 4.30 (each 1H, each d, J=12.2 Hz, CH2OAc), 4.14
and 4.44 (each 1H, each d, J=12.2 Hz, CH2OAc), 4.35 (1H, d, J=2.4 Hz, H-6), 4.38 and 4.50 (each 1H,
each d, J=11.3 Hz, CH2OAc), 4.45 and 4.68 (each 1H, each d, J=12.2 Hz, PhCH2), 4.87 (1H, d, J=2.1 Hz,
H-3), 5.50 (1H, d, J=2.4 Hz, H-7), 7.25-7.38 (5H, m, ArH); 13C NMR (125 MHz) δ 20.68, 20.71, 20.87,
22.70, 60.62, 63.08, 63.57, 67.97, 70.76, 71.93, 76.58, 76.83, 78.24, 82.00, 86.70, 103.17, 127.86, 128.34,
128.67, 136.69, 168.99, 169.37, 169.57, 169.95. EIMS m/z: 480 (M+-54). [α]D24 +15.8° (c=0.1, CHCl3).
(2S,3S,4R,5R,6S,7S)-4-Benzyloxy-1,2-O-isopropylidenedioxy-9-trimethylsilyl-8-nonyn-3,7-diol-5,6-
bis[spiro-4'-(2',2'-dimethyl-1',3'-dioxolane)] (32). To a stirred solution of trimethylsilylethynyl-
magnesium chloride [prepared from trimethylsilylacetylene (2.65 mL, 18.7 mmol) and EtMgCl (2 M in
THF, 9.37 mL, 18.7 mmol) in THF (20 mL)] was added dropwise a solution of lactol (14) (222 mg, 0.46
mmol) in THF (6 mL) at 0 °C and the mixture was stirred for 40 h at rt. After the mixture was quenched
with saturated NH4Cl solution, the solvent was removed to give a residue, which was extracted with
AcOEt. The combined organic layer was washed with brine. The organic layer was dried over Na2SO4
and evaporated to give a residue, which was chromatographed on silica gel (hexane/AcOEt=7:1) to afford
propargyl alcohol (32) (226 mg, 84.5 %) as a colorless oil. IRνcm-1: 3450 (OH). 1H NMR: δ 0.19 (9H,
s, SiMe3), 1.33 and 1.50 (each 3H, each s, CMe2), 1.45 (6H, s, CMe2), 1.52 and 1.53 (each 3H, each s,
CMe2), 2.80 (1H, br s, 7-OH), 3.72 (1H, d, J=3.1 Hz, 3-OH), 3.97-4.36 (9H, m,1-H2, 2-H, 3-H, 4-H,
5-CH2, 6-CH2), 4.60 (1H, br s, 7-H), 4.78 and 4.83 (each 1H, each d, J=11.6 Hz, PhCH2), 7.25-7.40 (5H,
13
m, Ar-H). C NMR:δ -0.4, 25.3, 26.0, 26.3, 26.7, 27.8, 66.5, 67.9, 68.1, 68.9, 74.0, 75.2, 75.7, 76.9,
26
87.3, 89.2, 93.4, 103.3, 109.1, 110.7, 111.8, 127.7, 128.3, 137.8. [α]D -8.2° (c=0.85, CHCl3). Further
elution with hexane/AcOEt (6/4) gave the recovery of the starting material (14) (17.4 mg, 7.8%).
Conversion of 32 into (2S,3S,4R,5R,6S,7S)-7-acetoxy-4-benzyloxy-3-tert-butyldimethylsiloxy-1,2-
O-isopropylidenedioxy-8-nonyne-5,6-bis[spiro-4'-(2',2'-dimethyl-1',3'-dioxolane)] (35). The same
procedure as for the trimethylsilylacetylene (20) was applied to compound (32) to afford
(2S,3S,4R,5R,6S,7S)-4-benzyloxy-1,2-O-isopropylidenedioxy-8-nonyn-3,7-diol-5,6-bis[spiro-4'-(2',2'-
dimethyl-1',3'-dioxolane)] (33) (65.3 %) as a colorless oil. 1H NMR: δ 1.25 and 1.34 (each 3H, each s,
CMe2), 1.45 (6H, s, CMe2), 1.52 and 1.53 (each 3H, each s, CMe2), 2.61 (1H, d, J=1.8 Hz, 9-H), 2.80 (1H,
br s, 7-OH), 3.70 (1H, d, J=2.4 Hz, 3-OH), 3.85-4.35 (9H, m, 1-H2, 2-H, 3-H, 4-H, 5-CH2, 6-CH2), 4.60
(1H, br s, 7-H), 4.76 and 4.84 (each 1H, each d, J=11.0 Hz, PhCH2), 7.26-7.42 (5H, m, Ar-H). The same
procedure as for the above propargylic alcohol (21) was applied to compound (33) to afford
(2S,3S,4R,5R,6S,7S)-7-acetoxy-4-benzyloxy-1,2-O-isopropylidenedioxy-8-nonyn-3-ol-5,6-bis[spiro-4'-
(2',2'-dimethyl-1',3'-dioxolane)] (34) (91.1 %) as a colorless oil. 1H NMR: δ 1.35 and 1.45 (each 3H,
each s, CMe2), 1.49 and 1.51 (each 3H, each s, CMe2), 1.53 and 1.55 (each 3H, each s, CMe2), 2.13 (3H, s,
COCH3), 2.51 (1H, d, J=1.8 Hz, 9-H), 2.80 (1H, br s, 7-OH), 3.69 (1H, d, J=1.8 Hz, 3-OH), 3.88-4.35
(9H, m, 1-H2, 2-H, 3-H, 4-H, 5-CH2, 6-CH2), 4.67 and 4.84 (each 1H, each d, J=11.0 Hz, PhCH2), 5.63
(1H, d, J=2.4 Hz, 7-H), 7.26-7.42 (5H, m, Ar-H). The same procedure as for the above alcohol (16) was
applied to compound (34) to afford silyl ether (35) (62.5 %) as a colorless oil. IRνcm-1: 1750 (CO), 3300
(acetylene). 1H NMR: δ0.07 and 0.14 (each 3H, each s, SiMe2), 0.85 (9H, s, CMe3), 1.25 and 1.33 (each
3H, each s, CMe2), 1.43 and 1.47 (each 3H, each s, CMe2), 1.50 and 1.54 (each 3H, each s, CMe2), 2.05
(3H, s, COCH3), 2.49 (1H, d, J=2.4 Hz, 9-H), 3.78 (1H, d, J=6.7 Hz, 4-H), 3.87 (2H, br s, 5 or 6-CH2),
3.98-4.07 (2H, m, 1-H2), 4.25 and 4.37 (each 1H, each d, J=9.8 Hz, 5 or 6-CH2), 4.35-4.45 (1H, m, 2-H),
4.42 and 5.12 (each 1H, each d, J=11.6 Hz, PhCH2), 4.51 (1H, dd, J=7.3, 2.4 Hz, 3-H), 5.87 (1H, d,

746
HETEROCYCLES, Vol. 67, No. 2, 2006
J=2.4 Hz, 7-H), 7.22-7.29 (5H, m, Ar-H). HRMS m/z: Calcd for C34H51O10Si (M+-15): 647.3252. Found:
647.3233.
(2S,3S,4R,5R,6S,7R)-4-Benzyloxy-1,2-O-isopropylidenedioxy-8-nonyn-3,7-diol-5,6-bis[spiro-4'-
(2',2'-dimethyl-1',3'-dioxolane)] (37). The same procedure as for the above propargylic alcohol (18) was
applied to compound (32) to afford an inseparable diastereomixture (2:1) of (2S,3R,4R,5R)-3-benzyloxy-
6-hydroxy-2-[(4'S)-2',2'-dimethyl-1',3'-dioxolan-4'-yl]-6-trimethylsilylethynyl-3,4,5,6-tetrahydro-
2H-pyran-4,5-bis[spiro-4''-(2'',2''-dimethyl-1'',3''-dioxolane)] (36) (97.0 %) as a colorless oil. IRν
1
cm-1: 3360 (OH). H NMR:δ0.15 and 0.23 (total 9H, each s, SiMe3), 1.26, 1.36, 1.37, 1.42, 1.49, 1.53,
1.58, 1.61, and 1.67 (total 18H, each s, 3xCMe2), 3.20 (1H, br s, OH), 3.40-5.05 (total 11H, m, 1-H, 2-H,
CHOCH2, 3xCH2O, PhCH2), 7.23-7.32 (3H, m, Ar-H), 7.44 (2H, dd, J=7.9, 1.8 Hz, m-Ar-H). HRMS
m/z: Calcd for C29H41O9Si (M+-15): 561.2519. Found: 561.2519. To a stirred solution of lactol (36) (9 mg,
0.016 mmol) in 20% aqueous EtOH (1 mL) and THF (1 mL) was added portionwise NaBH4 (2 mg, 0.053
mmol) at 0 °C. The reaction mixture was stirred for 4 h at rt. To the mixture was added saturated NH4Cl
solution and the solvent was concentrated to give a residue, which was extracted with AcOEt. The
combined organic layer was washed with brine. The organic layer was dried over Na2SO4 and evaporated
to give a residue, which was chromatographed on silica gel (hexane/AcOEt=7:3) to afford a mixture of
alcohol (37) and its epimer (33) (9:1) as a colorless oil (2.5 mg, 31.4 %). For 37: 1H NMR: δ 1.35 and
1.45 (each 3H, each s, CMe2), 1.50 and 1.52 (each 3H, each s, CMe2), 1.53 and 1.54 (each 3H, each s,
CMe2), 2.57 (1H, d, J=2.3 Hz, 9-H), 3.05 (1H, d, J=3.9 Hz, 7-OH), 3.47 (1H, d, J=2.9 Hz, 3-OH),
3.98-4.28 (9H, m,1-H2, 2-H, 3-H, 4-H, 5-CH2, 6-CH2), 4.63 (1H, dd, J=2.3, 3.9 Hz, 7-H), 4.76 and 4.83
(each 1H, each d, J=11.4 Hz, PhCH2), 7.26-7.42 (5H, m, Ar-H).
Conversion of 37 into 22. The same procedure as for the alcohol (21) was applied to compound (37) to
afford
a
mixture of (2S,3S,4R,5R,6S,7R)-7-acetoxy-4-benzyloxy-1,2-O-isopropylidenedioxy-8-
nonyn-7-ol-5,6-bis[spiro-4'-(2',2'-dimethyl-1',3'-dioxolane)] (38) and its epimer (9:1) as a colorless oil
1
(97.4 %). For 38: H NMR: δ 1.37 and 1.41 (each 3H, each s, CMe2), 1.47 and 1.48 (each 3H, each s,
CMe2), 1.51 and 1.53 (each 3H, each s, CMe2), 2.55 (1H, d, J=2.3 Hz, 9-H), 3.64 (1H, d, J=2.0 Hz,
3-OH), 3.96-4.42 (9H, m, 1-H2, 2-H, 3-H, 4-H, 5-CH2, 6-CH2), 4.72 and 4.91 (each 1H, each d, J=11.4
Hz, PhCH2), 5.61 (1H, d, J=2.3 Hz, 7-H), 7.26-7.42 (5H, m, Ar-H). The same procedure as for the
alcohol (16) was applied to compound (38) to afford a mixture of acetate (22) and its epimer (35) (9:1) as
a colorless oil (88.9 %) .
(2S,3R,4R,5R)-3-Benzyloxy-2-[(4'S)-2',2'-dimethyl-1',3'-dioxolan-4'-yl]-3,4,5,6-tetrahydro-2H-
pyran-6-one-4,5-bis[spiro-4''-(2'',2''-dimethyl-1'',3''-dioxolane)] (39). To a stirred suspension of PCC
(112 mg, 0.52 mmol), anhydrous NaOAc (68 mg, 0.83 mmol), and Celite (112 mg) in CH2Cl2 (2 mL) was
added a solution of lactol (14) (50 mg, 0.104 mmol) in CH2Cl2 (2 mL) at rt. The reaction mixture was
stirred for 2 h at rt. After dilution with Et2O, insoluble material was filtered off through a Celite pad. The
filtrate was extracted with AcOEt. The combined organic layer was washed with brine. The organic layer
was dried over Na2SO4 and evaporated to give a residue, which was chromatographed on silica gel
(hexane/AcOEt=3:1) to afford lactone (39) (35.6 mg, 71.5 %) as a colorless oil. IRνcm-1: 1740 (CO). 1H
NMR:δ1.36, 1.39, 1.42, 1.52, 1.55, and 1.58 (each 3H, each s, 3 x CMe2), 3.80 and 3.85 (each 1H, each
d, J=9.8 Hz, 4-CH2), 3.84 (1H, d, J=2.4 Hz,, 3-H), 3.96 (1H, dd, J=7.3, 2.4 Hz, 2-H), 4.01 and 4.09 (each
1H, each dd, J=9.2, 6.1 Hz, 5'-H2), 4.32 and 4.45 (each 1H, each d, J=8.6 Hz, 5-CH2), 4.52 (1H, m, 4'-H),
4.72 and 5.04 (each 1H, each d, J=11.6 Hz, PhCH2), 7.26-7.41 (5H, m, Ar-H). HRMS m/z: Calcd for
C25H34O9: 478.2201. Found: 478.2200. [α]D24 +21.03° (c=0.71, CHCl3).
Addition of lithium trimethylsilylacetylide to 39. The same procedure as for the above aldehyde (19)
was applied to compound (39) to afford an inseparable diastereomixture (2:1) of 36 (73.5 %) as a
colorless oil.

HETEROCYCLES, Vol. 67, No. 2, 2006
747
ACKNOWLEDGEMENTS
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology of Japan.
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