Synthetic study of tautomycin. Part 2: Synthesis of Ichihara's fragment based on regioselective enzymatic acetylation of complex molecule

Article abstract of DOI:10.1016/j.tet.2005.10.013

Formal synthesis of tautomycin, which inhibits type 1 and type 2A protein phosphatases, was achieved. Spiroketal diol 21 was synthesized from alcohol 2 or 11. The regioselective enzymatic acetylation of 21 with the lipase 'Amano PS' gave monoacetate 23 in

Full text of DOI:10.1016/j.tet.2005.10.013

Tetrahedron 62 (2006) 716–725
Synthetic study of tautomycin. Part 2: Synthesis of Ichihara’s
fragment based on regioselective enzymatic acetylation
of complex molecule
c
a
Yusuke Ishii,a Shinji Nagumo,b, Takayuki Arai, Masami Akuzawa,
*
Norio Kawaharaa and Hiroyuki Akitac
aHokkaido College of Pharmacy, Katuraoka 7-1, Otaru 047-02, Japan
bDepartment of Applied Chemistry, Kogakuin University, Nishi-shinjuku 1-24-2, Shinjuku, Tokyo 163-8677, Japan
cSchool of Pharmaceutical Science, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan
Received 31 May 2005; accepted 3 October 2005
Available online 8 November 2005
Abstract—Formal synthesis of tautomycin, which inhibits type 1 and type 2A protein phosphatases, was achieved. Spiroketal diol 21 was
synthesized from alcohol 2 or 11. The regioselective enzymatic acetylation of 21 with the lipase ‘Amano PS’ gave monoacetate 23 in 90%
yield, which was converted into Ichihara’s intermediate 31 based on Julia coupling and Wittig homologation.
q 2005 Published by Elsevier Ltd.
1. Introduction
C5–C16. This plan requires selective functionalization
between different primary hydroxy groups at the C5 and
C16 positions of B. Enzymatic esterification with lipase was
expected to be an efficient approach for controlling the
regiochemistry, since lipase exhibited potential molecular
recognition in many cases of chiral resolution of racemic
alcohols.6 Although regioselective enzymatic esterification
has been reported, most of them are examples for limited
types of substrates.7 Selective acetylation between different
primary hydroxy groups in a highly complex molecule had
not been reported when we started this study. Compound B
should be stereoselectively prepared by transacetalization of
ketone C with five stereocenters. Compound C can be
retrosynthetically divided into segment C9–C16 D and
sulfone E, which would be easily prepared from (C)-malic
acid.8
Tautomycin was isolated by Isono et al. from a culture of
Streptomyces spiroverticillatus.1 The structure contains
spiroketal and maleic anhydride moieties and 13 chiral
centers. The absolute configuration of the compound
was determined by spectroscopic analysis of chemical
degradation products and conformational calculations.2
Tautomycin is
a
representative tumor promoter
and specifically inhibits type 1 and type 2A protein
phosphatases.3 Total syntheses have been achieved by
several groups.4 The structural complexity and unique
biological activity stimulated us to carry out a synthetic
study of tautomycin on the basis of the original strategy. We
herein report the formal synthesis of tautomycin based on
regioselective enzymatic protection of a spiroketal
compound with two primary hydroxy groups.5
1.2. Synthesis of segment C9–C16
1.1. Synthetic strategy
We previously reported highly enantioselective esterifi-
cation of meso-diol 1 with lipase from Porcine pancreas
‘PPL’ (Scheme 2).9 At first, we therefore selected (K)-2 as
a starting material for our synthesis of segment C9–C16.
Sulfinylation of (K)-2 (95% ee) with PhSSPh and Bu3P10
followed by oxidation of the sulfur atom with MCPBA gave
sulfone 4 in excellent yield. Removal of acetyl and benzyl
groups in 4 and the subsequent acetalization provided 7
efficiently. Treatment of 7 with tert-BuLi and allyl bromide
Scheme 1 shows our retrosynthesis. We chose compound A,
which is a synthetic intermediate of tautomycin reported by
Ichihara et al. as a target molecule.4a This molecule should
be obtainable by successive installation of two kinds of
alkyl chains to compound B corresponding to segment
Keywords: Tautomycin; Regioselective; Enzymatic acetylation.
*
Corresponding author. Tel.: C81 3 3340 2683; fax: C81 3 3340 0147;
e-mail: bt13071@ns.kogakuin.ac.jp
afforded the alkylated product 8 in 82% yield.
0040–4020/$ - see front matter q 2005 Published by Elsevier Ltd.
doi:10.1016/j.tet.2005.10.013

Y. Ishii et al. / Tetrahedron 62 (2006) 716–725
717
Scheme 1.
Desulfurization11 of 8 with Na(Hg) resulted in the formation
of 9 corresponding to segment C9–C16 of tautomycin.
Treatment of 9 with MCPBA gave epoxide 10 as an
epimeric mixture.
column chromatography with silica gel. Diol 14 was
coverted into 15 upon treatment with 2,2-dimethoxypropane
in the presence of TsOH$H2O. Reduction of 15 with LiAlH4
followed by TPAP oxidation produced aldehyde 17, which
was finally converted into 9 by Wittig homologation.
We also developed an alternative route for the synthesis of
optically active 9 based on palladium-catalyzed hydro-
genolysis of vinyloxirane with HCOOH (Scheme 3).12
Epoxyalcohol 11, which was synthesized according to
Meyers’s method,13 was converted into vinyloxirane 12 by
oxidation and subsequent Wittig homologation. Reductive
C–O bond cleavage of 12 with HCOOH in the presence of
Pd(dba)2 afforded alcohol 13 along with a small amount of
inseparable stereo isomer. The ratio was found to be ca. 7:1
based on the 1H NMR spectroscopic data. Catalytic
hydrogenation of 13 with Pd(OH)2–C gave diol 14, which
could be separated from a small amount of isomer by
1.3. Synthesis of spiroketaldiol corresponding to segment
C5–C16 and enzymatic regioselective acetylation
of the diol
Next, coupling of the segment C5–C8 and the segment
C9–C16 was carried out (Scheme 4). Without separation, 10
was subjected to the coupling with an anion generated from
18. BF3$Et2O was essential for the smooth conversion to
give the hydroxysulfone 19 in 68% yield.4h,14 Treatment of
19 with Na(Hg) followed by Swern oxidation afforded
ketone 20 corresponding to the segment C5–C16.
Scheme 2. (a) Lipase PPL, vinyl acetate, 33 8C, 2 day; (b) PhSSPh, n-Bu3P, pyridine; (c) MCPBA, CH2Cl2; (d) K2CO3, MeOH (e) H2, Pd(OH)2–C, MeOH;
(f) (MeO)2CMe2, 10-camphorsulfonic acid, benzene; (g) allyl bromide, tert-BuLi, THF; (h) 5% Na(Hg), MeOH, reflux; (i) MCPBA, CH2Cl2.

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Y. Ishii et al. / Tetrahedron 62 (2006) 716–725
Scheme 3. (a) (i) Dess–Martin oxidn (ii) Ph3P]CHCOOMe, DMSO; (b) Pd(dba), Ph3P, HCOOH, Et3N, dioxane; (c) H2, Pd(OH)2–C, MeOH;
(d) (MeO)2CMe2, TsOH$H2O; (e) DIBAL-H, toluene, K78 8C; (f) TPAP, NMO, CH2Cl2; (g) Ph3PMeC$BrK, n-BuLi, THF.
Scheme 4. (a) tert-BuLi, BF3$Et2O, THF; (b) (i) 5% Na(Hg), MeOH, reflux (ii) TPAP, NMO, CH2Cl2; (c) 10-camphorsulfonic acid, MeOH.
Transformation of 20 into the spiroketal 21 proceeded
stereoselectively upon treament with camphorsulfonic acid
in MeOH to give 21 in 99% yield. The structure of 21 was
assigned on the basis of spectroscopic data. The stereo-
chemistry of the newly introduced asymmetric center at the
C10 position was determined by observed NOEs between
C6–H and C14–H or C15–Me proton.
assigned on the basis of spectroscopic data. A decoupling
experiment of the H NMR spectrum showed a correlation
between two protons at the C16 position (d 4.06, dd, JZ
11.0, 4.2 Hz: d 3.86, dd, JZ11.0, 6.4 Hz) and C15–H.
1
1.4. Conversion of 24 into 31 corresponding to C1–C18
of tautomycin
The most important issue in our synthetic study of
tautomycin is enzymatic differentiation of two primary
hydroxy groups in 21. Based on the results of a screening
experiment, the lipase ‘Amano PS’ from Pseudomonas sp.
was selected as a catalyst of regioselective acetylation of 21.
The enzyme preferentially accelerated the acetylation of a
hydroxy group at the C16 position to provide 23 in 90%
yield (Table 1). On the other hand, chemical acetylation of
21 with an equivalent of acetic anhydride in pyridine did not
show a satisfactory selectivity. The structure of 23 was
Finally, the conversion of monoacetate 23 into Ichihara’s
intermediate of tautomycin was attempted through Julia
coupling15 and Wittig homologation (Scheme 5). Oxidation
of 23 with Dess–Martin periodinane gave the aldehyde 25,
which was coupled with the sulfone 26 upon treatment with
n-BuLi at K50 8C to afford b-hydroxysulfone. After
acetylation of the crude b-hydroxysulfone, reductive
elimination of the acetylated product accompanied
deprotection of the terminal acetyl group to give 27.
Dess–Martin oxidation of 27 followed by Wittig
Table 1.
22 (%)
23 (%)
24 (%)
21 (Recovered) (%)
Amano PS, vinyl acetate
Ac2O, pyridine
5
11
90
36
2
16
3
31

Y. Ishii et al. / Tetrahedron 62 (2006) 716–725
719
Scheme 5. (a) Dess–Martin oxidn; (b) (i) n-BuLi, THF, K50 8C (ii) Ac2O, DMAP, pyridine (iii) 5% Na(Hg), MeOH, 50 8C; (c) (i) Dess–Martin oxidn (ii)
Ph3P]CHCOOMe, CH2Cl2 (d) H2, Pd(OH)2–C,MeOH; (e) (i) Dess–Martin oxidn (ii) Ph3PMeC$BrK, n-BuLi, THF, 0 8C; (f) LiAlH4, THF, 0 8C.
homologation provided a,b-unsaturated ester 28, which was
converted into 29 in high yield upon treatment with
Pd(OH)2–C under H2. Dess–Martin oxidation of 29
followed by treatment with Ph3P]CH2 gave the terminal
alkene 30. Finally, reduction of 30 with LiAlH4 afforded
alcohol 31, whose spectroscopic data were identical with
those reported by Ichihara et al.
rotations were measured on a JASCO DIP-370. IR spectra
were recorded on a JASCO A-3, JASCO IRA-102 or a
JASCO FT-IR-7000 spectrometer. NMR spectra were
recorded on a JEOL GX-270, a JEOL EX-400, or a JEOL
AL-400 spectrometer using tetramethylsilane as an internal
standard. Chemical shifts are given in ppm. The following
abbreviations are used: s, singlet; d, doublet; t, triplet; q,
quartet; br, broad. MS spectra were measured on a Hitachi
M-2000 (EI-MS, SIMS), a JEOL JMA-DX303 or a JEOL
JMA-DA5000 (FAB-MS) instrument. Column chromato-
graphy was carried out on Merck’s Silica gel 60 (70–230
mesh ASTM).
2. Conclusion
In conclusion, we achieved the formal synthesis of
tautomycin based on regioselective enzymatic acetylation
of spiroketal diol 21. Compound 21 was prepared from
optically active monoacetate 2 (12 steps, 16.5% overall
yield). The intermediate 10 in the synthetic route of 21
was alternatively made based on pallaium-catalyzed
hydrogenolysis of vinyloxirane with HCOOH. Regio-
selective enzymatic acetylation of 21 with the lipase
‘Amano PS’ proceeded with high selectivity to give the
desired monoacetate 23 in 90% yield. An efficient molecular
recognition by using the lipase ‘Amano PS’ would be
applicable to the differentiation of complex compounds
having plural primary alcohols. Finally, conversion of 23
into Ichihara’s intermediate 31 based on Julia coupling and
Wittig homologation was achieved.
3.1.1. (2R,3S,4R)-3-Benzyloxy-2,4-dimethyl-5-(phenyl-
thio)pentyl acetate (3). To a mixture of 2 (19.2 g,
68.6 mmol), diphenyl disulfide (19.4 g, 89.0 mmol) and
pyridine (100 ml) was added tri-n-butylphosphine (28 ml,
113 mmol) at room temperature. The mixture was stirred for
30 h at room temperature, then quenched with brine and
extracted with Et2O. The organic layer was washed with 2 N
HCl and brine, dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by column
chromatography on silica gel eluted with hexane–AcOEt
(19/1) to give 3 (24.3 g, 65.3 mmol, 95%) as a colorless oil:
[a]D25 C9.1 (c 1.38, CHCl3); IR (neat) 1740 cmK1; 1H NMR
(400 MHz, CDCl3) d 7.36–7.15 (10H, m), 4.57 (2H, s),
4.00–3.91 (2H, m), 3.55 (1H, t, JZ4.9 Hz), 3.05 (1H, dd,
JZ12.7, 6.4 Hz), 2.80 (1H, dd, JZ12.7, 7.3 Hz), 2.14–1.97
(2H, m), 2.01 (3H, s), 1.11 (3H, d, JZ6.8 Hz), 1.01 (3H, d,
JZ6.8 Hz); 13C NMR (68 MHz, CDCl3) d 171.0, 138.6,
136.7, 129.3, 128.9, 128.3, 127.5, 127.5, 126.0, 81.6, 74.6,
67.1, 38.4, 35.7, 35.4, 20.9, 15.0, 12.9; FAB-MS m/z 373
(MCC1). Anal. Calcd for C22H28O3S: C, 70.93; H, 7.58.
Found: C, 70.64; H, 7.69.
3. Experimental
3.1. General methods
The melting points were determined on a Yanaco micro
melting point apparatus and were uncorrected. Optical

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Y. Ishii et al. / Tetrahedron 62 (2006) 716–725
3.1.2. (2R,3S,4R)-3-Benzyloxy-2,4-dimethyl-5-(phenyl-
sulfonyl)pentyl acetate (4). To a solution of 3 (1.09 g,
2.93 mmol) in CH2Cl2 (15 ml) was added MCPBA (70%
purity, 2.20 g, 8.92 mmol) at 0 8C. The mixture was stirred
at room temperature for 24 h, then quenched with 10%
aqueous Na2SO3 and extracted with CH2Cl2. The extract
was washed with saturated aqueous NaHCO3 and brine,
dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by column chroma-
tography on silica gel eluted with hexane–AcOEt (4/1) to
give 5 (1.14 g, 2.82 mmol, 96%) as as a colorless oil: [a]D24
3.1.5. (2R,3S,4R)-1,3-Isopropylidenedioxy-2,4-dimethyl-
5-(phenylsulfonyl)pentane (7). To a solution of 6 (11.8 g,
43.4 mmol) and 2,2-dimethoxypropane (25 ml) in benzene
(100 ml) was added 10-camphorsulfonic acid (1.00 g,
4.31 mmol) at room temperature. The mixture was stirred
at room temperature for 24 h, then quenched with saturated
aqueous NaHCO3 and extracted with Et2O. The extract was
dried over MgSO4 and concentrated under reduced pressure
to give 7 (11.8 g, 37.8 mmol, 87%) as a white crystal: mp
64–65 8C; [a]2D4 K23.0 (c 1.30, CHCl3); IR (neat)
1
2990 cmK1; H NMR (400 MHz, CDCl3) d 7.92 (2H, d,
1
K27.3 (c 1.37, CHCl3); IR (neat) 1740 cmK1; H NMR
JZ7.3 Hz), 7.67 (1H, t, JZ7.3 Hz), 7.58 (2H, t, JZ7.3 Hz),
4.00 (1H, dd, JZ11.7, 2.9 Hz), 3.60 (1H, dd, JZ8.8,
2.4 Hz), 3.54 (1H, dd, JZ11.7, 1.5 Hz), 3.16 (1H, dd, JZ
14.2, 2.0 Hz), 2.83 (1H, dd, JZ14.2, 9.8 Hz), 2.06 (1H, m),
1.47 (1H, m), 1.36 (3H, s), 1.34 (3H, s), 1.13 (3H, d, JZ
6.4 Hz), 0.83 (3H, d, JZ6.8 Hz); 13C NMR (68 MHz,
CDCl3) d 139.7, 133.7, 129.3, 128.0, 99.0, 74.0, 66.9, 58.2,
31.1, 29.9, 29.5, 18.9, 16.2, 10.4; FAB-MS m/z 313 (MCC
1). Anal. Calcd for C16H24O4S: C, 61.51; H, 7.74. Found: C,
61.71; H, 7.96.
(270 MHz, CDCl3) d 7.88 (2H, d, JZ7.3 Hz), 7.64 (1H, t,
JZ7.3 Hz), 7.54 (2H, t, JZ7.9 Hz), 7.37–7.22 (5H, m),
4.47 (2H, s), 4.01–3.87 (2H, m), 3.52 (1H, t, JZ4.9 Hz),
3.34 (1H, dd, JZ14.2, 3.9 Hz), 2.90 (1H, dd, JZ14.2,
7.8 Hz), 2.58–2.44 (1H, m), 2.13–1.98 (1H, m), 2.03 (3H, s),
1.11 (3H, d, JZ6.8 Hz), 0.93 (3H, d, JZ6.8 Hz); 13C NMR
(68 MHz, CDCl3) d 170.9, 139.8, 138.2, 133.6, 129.3,
128.4, 127.9, 127.7, 127.6, 80.7, 73.3, 67.0, 59.3, 34.6, 30.7,
20.9, 15.6, 12.6; FAB-MS m/z 405 (MCC1). Anal. Calcd
for C22H28O5S: C, 65.32; H, 6.98. Found: C, 64.98; H, 7.18.
3.1.6. (5R,6S,7R)-6,8-Isopropylidenedioxy-5,7-dimethyl-
4-phenylsulfonyl-1-octene (8). To a solution of tert-BuLi
(1.7 M in pentane, 6.0 ml, 10.2 mmol) in THF (10 ml) was
added dropwise 7 (2.07 g, 6.63 mmol) in THF (10 ml) at
K78 8C under an argon atmosphere. The reaction mixture
was stirred at K78 8C for 1 h and then K20 8C for 15 min.
After the mixture was recooled to K78 8C, allyl bromide
(1.20 g, 9.92 mmol) in THF (5 ml) was added dropwise.
After being stirred at K78 8C for 30 min, the mixture was
quenched with saturated aqueous NaHCO3 and extracted
with Et2O. The extract was dried over MgSO4 and
concentrated under reduced pressure to give 8 (1.92 g,
5.45 mmol, 82%) as a colorless oil: [a]2D0 C13.1 (c 1.31,
CHCl3); IR (neat) 2988 cmK1; 1H NMR (400 MHz, CDCl3)
d 7.90–7.85 (2H, m), 7.69–7.65 (1H, m), 7.60–7.55 (2H, m),
5.70–5.61 (0.5H, m), 5.53–5.42 (0.5H, m), 5.11–5.03 (2H,
m), 4.45 (0.5H, dd, JZ9.8, 2.4 Hz), 4.17 (0.5H, dd, JZ11.7,
2.4 Hz), 3.95 (0.5H, dd, JZ11.7, 2.4 Hz), 3.71 (0.5H, dd,
JZ9.8, 2.4 Hz), 3.61 (0.5H, dd, JZ11.7, 1.5 Hz), 3.52
(0.5H, dd, JZ11.7, 1.5 Hz), 3.05–2.99 (1H, m), 2.80 (0.5H,
dt, JZ15.1, 5.9 Hz), 2.58–2.39 (2H, m), 2.34–2.27 (0.5H,
m), 2.10–2.00 (0.5H, m), 1.80–1.75 (0.5H, m), 1.46 (1.5H,
s), 1.39 (1.5H, s), 1.34 (3H, s), 1.26 (1.5H, d, JZ7.3 Hz),
1.06 (1.5H, d, JZ6.8 Hz), 0.99 (1.5H, d, JZ6.8 Hz), 0.80
(1.5H, d, JZ6.8 Hz); 13C NMR (68 MHz, CDCl3) d 139.9,
138.4, 135.2, 133.8, 133.7, 129.3, 128.9, 128.4, 119.3,
117.7, 99.0, 73.6, 73.0, 67.1, 66.7, 63.7, 35.7, 33.3, 32.1,
30.1, 29.8, 29.7, 29.5, 28.3, 19.2, 18.8, 11.1, 10.7, 10.5, 9.7;
FAB-MS m/z 353 (MCC1). Anal. Calcd for C19H28O4S: C,
64.74; H, 8.01. Found: C, 64.51; H, 8.28.
3.1.3. (2R,3S,4R)-3-Benzyloxy-2,4-dimethyl-5-phenyl-
sulfonyl-1-pentanol (5). To a solution of 4 (1.14 g,
2.82 mmol) in methanol (10 ml) was added K2CO3
(0.800 g, 5.80 mmol) at room temperature. After being
stirred for 30 min, the mixture was poured into brine. The
mixture was extracted with Et2O. The extract was dried over
MgSO4 and concentrated under reduced pressure. The
residue was purified by column chromatography on silica
gel eluted with hexane–AcOEt (2/1) to give 5 (1.02 g,
2.82 mmol, 100%) as a colorless oil: [a]2D3 K22.2 (c 1.07,
CHCl3); IR (neat) 3527 cmK1; 1H NMR (270 MHz, CDCl3)
d 7.92–7.83 (2H, m), 7.68–7.49 (3H, m), 7.38–7.22 (5H, m),
4.47 (2H, s), 3.61 (1H, t, JZ4.6 Hz), 3.53 (2H, d,
JZ5.9 Hz), 3.34 (1H, dd, JZ14.2, 4.0 Hz), 2.92 (1H, dd,
JZ14.2, 8.2 Hz), 2.57 (1H, m), 1.98–1.78 (2H, m), 1.12
(3H, d, JZ6.9 Hz), 0.91 (3H, d, JZ6.9 Hz); 13C NMR
(68 MHz, CDCl3) d 139.8, 138.2, 133.6, 129.3, 128.4,
127.9, 127.7, 81.4, 73.0, 66.2, 59.5, 37.1, 30.4, 15.8, 12.2;
FAB-MS m/z 363 (MCC1). Anal. Calcd for C20H26O4S: C,
66.27; H, 7.23. Found: C, 65.99; H, 7.35.
3.1.4. (2R,3S,4R)-2,4-Dimethyl-5-(phenylsulfonyl)pentane-
1,3-diol (6). A mixture of 5 (19.4 g, 53.6 mmol), 20%
Pd(OH)2–C (1.00 g) and methanol (150 ml) was stirred
under H2 atmosphere at room temperature for 2 h. The
reaction mixture was filtered, and the filtrate was
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel eluted with
hexane–AcOEt (1/2) to give 6 (13.9 g, 51.1 mmol, 95%) as
a colorless oil: [a]D24 K5.5 (c 1.09, CHCl3); IR (neat)
1
3464 cmK1; H NMR (400 MHz, CDCl3) d 7.92 (2H, d,
3.1.7. (5S,6S,7R)-6,8-Isopropylidenedioxy-5,7-dimethyl-
1-octene (9). A solution of 8 (6.02 g, 17.1 mmol) and 5%
Na(Hg) (12.0 g) in methanol (60 ml) was refluxed for 4 h.
The reaction mixture was quenched with saturated aqueous
NaHCO3 and extracted with Et2O. The extract was dried
over MgSO4 and concentrated under reduced pressure.
The residue was purified by column chromatography on
silica gel eluted with hexane–AcOEt (19/1) to give 9
(2.86 g, 13.5 mmol, 79%) as a colorless oil: [a]2D0 K13.6
JZ7.3 Hz), 7.66 (1H, t, JZ7.3 Hz), 7.58 (2H, t, JZ7.3 Hz),
3.73 (1H, t, JZ4.9 Hz), 3.61 (2H, d, JZ4.9 Hz), 3.32 (1H,
dd, JZ14.4, 4.9 Hz), 2.96 (1H, dd, JZ14.4, 7.3 Hz),
2.46–2.32 (3H, m), 1.76 (1H, m), 1.08 (3H, d, JZ6.8 Hz),
0.93 (3H, d, JZ6.8 Hz); 13C NMR (68 MHz, CDCl3) d
139.8, 133.7, 129.3, 127.8, 75.0, 66.2, 59.9, 37.3, 31.8, 14.7,
11.8; FAB-MS m/z 273 (MCC1). Anal. Calcd for
C13H20O4S: C, 57.32; H, 7.40. Found: C, 57.09; H, 7.72.

Y. Ishii et al. / Tetrahedron 62 (2006) 716–725
721
(c 1.49, CHCl3); IR (neat) 2935 cmK1; 1H NMR (270 MHz,
CDCl3) d 5.80 (1H, ddt, JZ16.8, 10.2, 6.9 Hz), 5.02 (1H,
dd, JZ16.8, 1.5 Hz), 4.95 (1H, dd, JZ10.2, 1.5 Hz), 4.06
(1H, dd, JZ11.7, 2.9 Hz), 3.59 (1H, dd, JZ11.7, 2.0 Hz),
3.48 (1H, dd, JZ9.8, 2.4 Hz), 2.25–2.09 (1H, m), 2.08–1.92
(1H, m), 1.65–1.40 (2H, m), 1.41 (3H, s), 1.40 (3H, s), 1.04
(3H, d, JZ6.9 Hz), 1.03–0.94 (2H, m), 0.92 (3H, d, JZ
6.3 Hz); 13C NMR (68 MHz, CDCl3) d 138.5, 114.5, 98.5,
76.0, 67.1, 33.5, 30.6, 30.1, 29.8, 29.7, 18.9, 15.4, 10.4;
FAB-MS m/z 213 (MCC1). Anal. Calcd for C13H24O2: C,
73.53; H, 11.39. Found: C, 73.81; H, 11.79.
temperature under an argon atmosphere. After being stirred
for 5 min, a solution of 12 (186 mg, 0.641 mmol) in THF
(3 ml) was added to the reaction mixture. After being stirred
for 4 h, the reaction mixture was filtered. The filtrate was
concentrated under reduced pressure extracted with Et2O.
The extract was dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by column
chromatography on silica gel eluted with hexane–AcOEt
(19/1) to give 13 (160 mg, 0.548 mmol, 85%) as a colorless
oil. Compound 13 contained small amounts of any stereo
isomer (ca. 7:1): [a]D20 K19.6 (c 1.35, CHCl3); IR (neat)
3508, 1723, 1655 cmK1 1H NMR (270 MHz, CDCl3)
;
d 7.40–7.23 (5H, m), 6.80 (1H, dd, JZ15.8, 9.2 Hz), 5.85
(1H, d, JZ15.8 Hz), 4.53 (1H, d, JZ11.9 Hz), 4.47 (1H, d,
JZ11.9 Hz), 3.72 (3H, s), 3.65 (1H, d, JZ8.9 Hz), 3.56
(1H, dd, JZ8.9, 4.0 Hz), 3.50 (1H, dd, JZ8.9, 5.0 Hz), 2.83
(1H, br), 2.55–2.37 (1H, m), 1.87–1.73 (1H, m), 1.15 (3H, d,
JZ6.6 Hz), 0.96 (3H, d, JZ6.9 Hz). For minor isomer, 7.04
(1/7H, dd, JZ15.6, 8.4 Hz), 5.88 (1/7H, dd, JZ15.6,
1.0 Hz), 1.01 (3/7H, d, JZ6.8 Hz), 0.98 (3/7H, JZ7.1 Hz);
13C NMR (68 MHz, CDCl3) d 167.0, 151.0, 137.8, 128.4,
127.7, 127.5, 120.8, 76.8, 75.5, 73.5, 51.5, 40.8, 35.9, 16.7,
9.7; SIMS m/z 293 (MCC1); HR-MS m/z 293.1780 (Calcd
for C17H25O4: 293.1751).
3.1.8. (5S,6S,7R)-1,2-Epoxy-6,8-isopropylidenedioxy-
5,7-dimethyloctane (10). According to the preparation of
4, 9 (3.01 g, 14.2 mmol) was converted into 10 (2.27 g,
9.96 mmol, 70%) as a colorless oil: [a]2D0 K9.4 (c 1.04,
1
CHCl3); IR (neat) 3048, 1199 cmK1; H NMR (400 MHz,
CDCl3) d 4.07 (1H, dd, JZ11.5, 2.4 Hz), 3.60 (1H, dd, JZ
11.5, 1.8 Hz), 3.48 (1H, dd, JZ9.7, 2.4 Hz), 2.90 (1H, m),
2.76 (1H, m), 2.48 (1H, m), 1.71–1.35 (11H, m), 1.16–0.98
(4H, m), 0.93 (3H, d, JZ6.6 Hz), 0.92 (3H, d, JZ6.4 Hz);
13C NMR (68 MHz, CDCl3) d 98.4, 75.7, 66.8, 52.2, 51.9,
47.0, 46.6, 33.8, 33.6, 29.7, 29.6, 29.5, 29.4, 29.1, 27.0,
26.7, 18.7, 15.34, 15.31, 10.31, 10.28; EI-MS m/z 213
(MCKCH3), 197, 171, 129; HR-MS m/z 213.1491 (Calcd
for C12H21O3: 213.1491).
3.1.11. Methyl (4S,5R,6R)-5,7-dihydroxy-4,6-dimethyl-
heptanoate (14). According to the preparation of 6, 13
(286 mg, 0.979 mmol) was converted into 14 (144 mg,
0.706 mmol, 72%) as a colorless oil: [a]2D0 K19.4 (c 1.25,
3.1.9. Methyl (2E,4S,5S,6R)-7-benzyloxy-4,5-epoxy-4,
6-dimethyl-2-heptenoate (12). To a solution of 1117
(1.21 g, 5.13 mmol) in CH2Cl2 (30 ml) was added Dess–
Martin periodinane (3.26 g, 7.07 mmol) at room tempera-
ture. The mixture was stirred at room temperature for
40 min, then quenched with 1 N NaOH solution and
extracted with Et2O. The extract was dried over MgSO4
and concentrated under reduced pressure to give crude
aldehyde compound, which was dissolved in DMSO
(15 ml). To the solution was added methyl (triphenylpho-
sphoraniliden)acetate (2.57 g, 7.70 mmol) at room tempera-
ture under an argon atmosphere. The mixture was stirred at
room temperature for 30 min, then quenched with H2O and
extracted with Et2O. The extract was dried over MgSO4 and
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel eluted with
hexane–AcOEt (100/3) to give 12 (1.28 g, 4.41 mmol, 86%)
as a colorless oil: [a]D20 C4.0 (c 1.21, CHCl3); IR (neat)
1725, 1657 cmK1; 1H NMR (270 MHz, CDCl3) d 7.37–7.24
(5H, m), 6.77 (1H, d, JZ15.8 Hz), 6.00 (1H, d, JZ
15.8 Hz), 4.47 (2H, s), 3.75 (3H, s), 3.45 (1H, dd, JZ9.2,
4.9 Hz), 3.33 (1H, dd, JZ9.2, 8.2 Hz), 2.65 (1H, d, JZ
9.2 Hz), 1.93–1.75 (1H, m), 1.43 (3H, s), 1.10 (3H, d, JZ
6.6 Hz); 13C NMR (68 MHz, CDCl3) d 166.5, 150.3, 138.2,
128.3, 127.5, 127.3, 120.8, 73.1, 72.5, 69.5, 59.5, 51.6, 33.8,
15.9, 14.4; EI-MS m/z 290 (MC), 259, 169; HR-MS m/z
290.1500 (Calcd for C17H22O4: 290.1517).
1
CHCl3); IR (neat) 3402, 1734 cmK1; H NMR (270 MHz,
CDCl3) d 3.69 (2H, dd, JZ4.6, 1.3 Hz), 3.67 (3H, s), 3.51
(1H, dd, JZ7.6, 3.6 Hz), 2.52 (2H, br), 2.41 (1H, ddd, JZ
15.8, 8.9, 5.9), 2.31 (1H, ddd, JZ15.8, 8.6, 6.9 Hz),
1.94–1.71 (1H, m), 1.70–1.54 (1H, m), 1.45–1.30 (1H, m),
0.98 (3H, d, JZ6.6 Hz), 0.97 (3H, d, JZ6.9 Hz); 13C NMR
(68 MHz, CDCl3) d 174.3, 77.2, 67.4, 51.6, 36.6, 35.5, 31.4,
28.0, 14.8, 10.0; SIMS m/z 205 (MCC1); HR-MS m/z
205.1431 (Calcd for C10H21O4: 205.1439).
3.1.12. Methyl (4S,5R,6R)-5,7-isopropylidenedioxy-4,
6-dimethylheptanoate (15). According to the preparation
of 7, 14 (15.5 mg, 0.0760 mmol) was converted into 15
(17.6 mg, 0.0721 mmol, 95%) as a colorless oil: [a]D20
1
K15.0 (c 1.68, CHCl3); IR (neat) 1742 cmK1; H NMR
(270 MHz, CDCl3) d 4.06 (1H, dd, JZ11.5, 2.6 Hz), 3.67
(3H, s), 3.60 (1H, dd, JZ11.5, 1.6 Hz), 3.47 (1H, dd, JZ
8.6, 2.3 Hz), 2.48–2.22 (2H, m), 1.86–1.71 (1H, m),
1.67–1.45 (2H, m), 1.41 (3H, s), 1.39 (3H, s), 1.28–1.11
(1H, m), 1.07 (3H, d, JZ6.9 Hz), 0.92 (3H, d, JZ6.3 Hz);
13C NMR (68 MHz, CDCl3) d 174.1, 98.7, 75.9, 67.1, 51.6,
33.8, 31.3, 29.9, 29.7, 26.7, 26.1, 19.0, 15.3, 10.4; EI-MS
m/z 229 (MCKCH3); HR-MS m/z 229.1442 (Calcd for
C12H21O4: 229.1439).
3.1.13. (4S,5R,6R)-5,7-Isopropylidenedioxy-4,6-dimethyl-
1-heptanol (16). To a solution of 15 (133 mg, 0.545 mmol)
in toluene (3 ml) was added dropwise diisobutylaluminium
hydride (DIBAH, 1.0 M toluene sol., 1.36 ml, 1.36 mmol) at
K78 8C under an argon atmosphere. The mixture was
stirred at K78 8C for 20 min and then quenched with a small
amount of H2O. The precipitate was removed by filtration.
3.1.10. Methyl (2E,4S,5R,6R)-7-benzyloxy-4,6-dimethyl-
5-hydroxy-2-heptenoate (13). To a solution of tris-
(dibenzylideneacetone)dipalladium(0)–chloroform adduct
(66 mg, 0.064 mmol) in THF (3 ml) was added HCOOH
(0.106 ml, 2.81 mmol), triethylamine (0.178 ml, 1.28 mmol)
and triphenylphosphine (16.8 mg, 0.064 mmol) at room

722
Y. Ishii et al. / Tetrahedron 62 (2006) 716–725
The filtrate was dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by column
chromatography on silica gel eluted with hexane–AcOEt
(4/1) to give 16 (108 mg, 0.500 mmol, 92%) as a colorless
oil: [a]2D0 K10.8 (c 0.83, CHCl3); IR (neat) 3410 cmK1; 1H
NMR (270 MHz, CDCl3) d 4.06 (1H, dd, JZ11.5, 3.0 Hz),
3.72–3.55 (3H, m), 3.48 (1H, dd, JZ9.9, 2.3 Hz), 1.78–1.30
(7H, m), 1.41 (3H, s), 1.40 (3H, s), 1.35 (3H, d, JZ6.9 Hz),
1.10–0.90 (1H, m), 0.93 (3H, d, JZ6.3 Hz); 13C NMR
(68 MHz, CDCl3) d 98.7, 76.1, 67.2, 63.1, 33.9, 29.9, 29.7,
29.6, 26.9, 19.0, 15.7, 10.5; EI-MS m/z 201 (MCKCH3);
HR-MS m/z 201.1501 (Calcd for C11H21O3: 201.1489).
37.1, 26.6, 25.6, 15.1; EI-MS m/z 252 (MC), 237; HR-MS
m/z 252.1174 (Calcd for C14H20O2S1: 252.1183). According
to the preparation of 4, this thiophenylated compound
(980 mg, 3.89 mmol) was converted into 18 (733 mg,
2.85 mmol, 66%) as a colorless oil: [a]2D2 C16.4 (c 1.00,
CHCl3); IR (neat) 2988, 1307, 1149 cmK1 1H NMR
;
(400 MHz, CDCl3) d 7.93 (2H, dt, JZ7.6, 2.0 Hz), 7.65
(1H, tt, JZ7.6, 2.0 Hz), 7.57 (2H, t, JZ7.6 Hz), 4.02
(1H, dd, JZ8.3, 6.0 Hz), 3.82 (1H, q, JZ6.0 Hz), 3.60 (1H,
dd, JZ8.3, 6.0 Hz), 3.49 (1H, dd, JZ14.0, 2.0 Hz), 2.90
(1H, dd, JZ14.0, 9.8 Hz), 2.21–2.09 (1H, m), 1.27 (3H, s),
1.23 (3H, s), 1.13 (3H, d, JZ6.8 Hz); 13C NMR (100 MHz,
CDCl3) d 139.9, 133.6, 129.3, 127.9, 109.3, 78.7, 67.6, 58.6,
33.1, 26.4, 25.2, 16.5; EI-MS m/z 269 (MCKMe), 101;
HR-MS m/z 269.0875 (Calcd for C13H17O4S1: 269.0847).
3.1.14. (4S,5R,6R)-5,7-Isopropylidenedioxy-4,6-dimethyl-
heptanal (17). To a solution of 16 (43.0 mg, 0.199 mmol) in
CH2Cl2 (3 ml) was added N-methylmorpholine N-oxide
(NMO, 35 mg, 0.299 mmol) and tetrapropylammonium
perruthenate (TPAP, trace) at 0 8C under an argon
atmosphere. After being stirred for 1.5 h, the reaction
mixture was diluted with ether and filtered through a Celite
pad. The filtrate was concentrated under reduced pressure.
The residue was purified by column chromatography on
silica gel eluted with hexane–AcOEt (1/1) to give 17
(28.0 mg, 0.131 mmol, 66%) as a colorless oil: [a]2D0 K13.9
(c 0.59, CHCl3); IR (neat) 1723 cmK1; 1H NMR (270 MHz,
CDCl3) d 9.80 (1H, t, JZ1.6 Hz), 4.07 (1H, dd, JZ11.5,
2.6 Hz), 3.60 (1H, dd, JZ11.5, 1.6 Hz), 3.48 (1H, dd, JZ
9.6, 2.3 Hz), 2.61–2.35 (2H, m), 1.85–1.70 (1H, m),
1.67–1.45 (2H, m), 1.41 (3H, s), 1.40 (3H, s), 1.25–1.10
(1H, m), 1.07 (3H, d, JZ6.9 Hz), 0.92 (3H, d, JZ6.3 Hz);
13C NMR (68 MHz, CDCl3) d 202.2, 98.7, 75.9, 67.1, 41.2,
33.8, 29.9, 29.7, 23.0, 19.0, 15.4, 10.5; EI-MS m/z 199
(MCKCH3); HR-MS m/z 199.1346 (Calcd for C11H19O3:
199.1333).
3.1.17. (2R,3R,9S,10R,11R)-1,2:10,12-Diisopropylidene-
dioxy-3,9,11-trimethyl-6-dodecanone (20). To a solution
of tert-BuLi (1.7 M in pentane, 0.30 ml, 0.510 mmol) in
THF (1.6 ml) was added dropwise a solution of 18 (77.9 mg,
0.274 mmol) in THF (0.5 ml) at K78 8C under an argon
atmosphere. After being stirred for 1 h, a solution of 10
(60.5 mg, 0.265 mmol) in THF (0.5 ml) and boron
trifluoride etherate (BF3$Et2O, 0.1 ml, 0.380 mmol) was
added to this solution. After being stirred at K78 8C for
30 min, the mixture was quenched with saturated aqueous
NaHCO3 and extracted with Et2O. The extract was dried
over MgSO4 and concentrated under reduced pressure. The
residue was purified by column chromatography on silica
gel eluted with hexane–AcOEt (2/1) to give 19 (92.3 mg,
0.180 mmol, 68%) as a colorless oil: [a]2D2 K6.2 (c 0.93,
CHCl3); IR (neat) 3506 cmK1; SIMS m/z 513 (MCC1);
HR-MS m/z 513.2893 (Calcd for C27H45O7S: 513.2883).
Anal. Calcd for C27H44O7S: C, 62.93; H, 8.93. Found: C,
63.25; H, 8.65. A solution of 19 (555 mg, 1.08 mmol) and
5% Na(Hg) (4.7 g) in methanol (18 ml) was refluxed for
1.5 h. The reaction mixture was quenched with H2O and
extracted with Et2O. The extract was dried over MgSO4 and
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel eluted with
hexane–AcOEt (2/1) to give alcohol (397 mg) as a colorless
oil. To a solution of this alcohol in CH2Cl2 (8 ml) was added
NMO (188 mg, 1.61 mmol) and TPAP (19 mg, 0. 054 mg)
at 0 8C under an argon atmosphere. After being stirred for
1.5 h, the solvent was removed under reduced pressure. The
residue was purified by column chromatography on silica
gel eluted with Et2O to give 20 (375 mg, 1.01 mmol, 94%)
as a colorless oil: [a]D19 K15.9 (c 1.39, CHCl3); IR (neat)
3.1.15. Conversion of 17 into 9. To a suspension of
(356 mg,
methyltriphenylphosphonium
bromide
0.997 mmol) in THF (2 ml) was added dropwise n-BuLi
(1.56 M in toluene, 0.617 ml, 0.963 mmol) at 0 8C under an
argon atmosphere. After being stirred for 10 min, a solution
of 17 (71.0 mg, 0.332 mmol) in THF (2 ml) was added to
the mixture at K20 8C. After being stirred for 1 h at
K20 8C, the reaction mixture was quenched with H2O at
0 8C and extracted with Et2O. The extract was dried over
MgSO4 and concentrated under reduced pressure. The
residue was purified by column chromatography on silica
gel eluted with hexane–AcOEt (9/1) to give 9 (63.7 mg,
0.300 mmol, 90%) as a colorless oil.
1
1714 cmK1; H NMR (400 MHz, CDCl3) d 4.06 (1H, dd,
3.1.16. (2R,3S)-1,2-Isopropylidenedioxy-3-methyl-4-
(phenylsulfonyl)butane (18). According to the preparation
of 3, (2R,3R)-(K)-erythro-3-methylbutane-1,2,4-triol 1,
2-acetonide12 (1.1 g, 6.88 mmol) was converted into thio-
phenylated compound (971 mg, 3.85 mmol, 56%) as a color-
JZ11.2, 2.4 Hz), 4.00 (1H, dd, JZ7.8, 6.4 Hz), 3.82 (1H,
dd, JZ13.7, 7.3 Hz), 3.62–3.54 (2H, m), 3.46 (1H, dd, JZ
9.8, 2.4 Hz), 2.59–2.33 (4H, m), 1.91–1.81 (1H, m),
1.77–1.67 (1H, m), 1.66–1.32 (4H, m), 1.40 (3H, s), 1.39
(6H, s), 1.34 (3H, s), 1.19–1.07 (1H, m), 1.06 (3H, d, JZ
6.8 Hz), 0.90 (3H, d, JZ6.4 Hz), 0.83 (3H, d, JZ6.4 Hz);
13C NMR (100 MHz, CDCl3) d 210.8, 108.8, 98.6, 80.2,
76.0, 67.8, 67.1, 40.5, 39.8, 36.2, 33.8, 29.9, 29.8, 27.7,
26.7, 25.6, 24.8, 19.0, 15.5, 15.3, 10.5; SIMS m/z 371
(MCC1); HR-MS m/z 371.2811 (Calcd for C21H39O5:
371.2795). Anal. Calcd for C21H38O5: C, 68.07; H, 10.34.
Found: C, 68.29; H, 10.95.
less oil: [a]2D2 C23.4 (c 1.05, CHCl3); IR (neat) 2988 cmK1
;
1H NMR (270 MHz, CDCl3) d 7.39–7.33 (2H, m),
7.30–7.22 (2H, m), 7.18–7.10 (1H, m), 4.03 (1H, dd, JZ
7.6, 6.9 Hz), 3.93 (1H, dt, JZ7.6, 6.9 Hz), 3.61 (1H, t, JZ
7.6 Hz), 3.37 (1H, dd, JZ13.0, 3.6 Hz), 2.68 (1H, dd,
JZ13.0, 9.2 Hz), 1.97–1.80 (1H, m), 1.39 (3H, s), 1.34
(3H, m), 0.99 (3H, d, JZ6.6 Hz); 13C NMR (68 MHz,
CDCl3) d 136.9, 128.8, 128.7, 125.6, 109.0, 79.2, 67.9, 37.3,

Y. Ishii et al. / Tetrahedron 62 (2006) 716–725
723
3.1.18. (2R,3R,6R,8R,8(1R),9S)-2-Hydroxymethyl-8-
(2-hydroxy-1-methylethyl)-3,9-dimethyl-1,7-dioxaspiro[5.5]-
undecane (21). To a solution of 20 (334 mg, 0.903 mmol)
in methanol (3 ml) was added CSA (20 mg, 0.0862 mmol)
at room temperature. The mixture was stirred for 1 h, then
quenched with saturated aqueous NaHCO3 and extracted
with Et2O. The extract was dried over MgSO4 and
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel eluted with
hexane–AcOEt (1/1) to give 21 (244 mg, 0.897 mmol, 99%)
as a colorless oil: [a]D19 K66.1 (c 1.03, CHCl3); IR (neat)
3379 cmK1; 1H NMR (400 MHz, CDCl3) d 3.74 (1H, d, JZ
10.6 Hz), 3.64 (1H, dd, JZ10.9, 4.3 Hz), 3.58–3.43 (3H,
m), 3.35 (1H, ddd, JZ9.9, 6.9, 3.0 Hz), 2.20–1.97 (2H, m),
1.88–1.73 (2H, m), 1.72–1.37 (9H, m), 1.09 (3H, d, JZ
6.8 Hz), 0.96 (3H, d, JZ7.3 Hz), 0.85 (3H, d, JZ6.4 Hz);
13C NMR (100 MHz, CDCl3) d 95.9, 75.1, 72.4, 64.7, 64.0,
37.5, 36.0, 30.9, 29.9, 28.1, 27.7, 26.7, 17.4, 14.3, 11.4;
SIMS m/z 273 (MCC1); HR-MS m/z 273.2082 (Calcd for
C15H29O4: 273.2064). Anal. Calcd for C15H28O4: C, 66.14;
H, 10.36. Found: C, 65.76; H, 11.02.
4.25 (1H, dd, JZ11.2, 2.4 Hz), 4.09 (1H, dd, JZ11.2,
6.8 Hz), 3.64 (1H, dd, JZ10.7, 3.9 Hz), 3.57–3.44 (3H, m),
2.13–2.00 (1H, m), 2.08 (3H, s), 1.87–1.20 (11H, m), 1.08
(3H, d, JZ6.3 Hz), 0.95 (3H, d, JZ6.8 Hz), 0.88 (3H, d,
JZ6.3 Hz); 13C NMR (100 MHz, CDCl3) d 171.2 (s), 96.0
(s), 72.8 (d), 72.4 (d), 65.6 (t), 64.9 (t), 37.4 (d), 35.6 (t),
31.4 (d), 29.8 (t), 28.1 (d), 28.0 (t), 26.7 (t), 20.9 (q), 17.5
(q), 14.3 (q), 11.3 (q); SIMS m/z 315 (MCC1); HR-MS m/z
315.2167 (Calcd for C17H31O5: 315.2170).
3.1.20. (2R,2(1R),3S,6R,8R,9R)-2-(2-Acetoxy-1-methyl-
ethyl)-8-formyl-3,9-dimethyl-1,7-dioxaspiro
[5.5]-
undecane (25). To solution of 23 (95.0 mg,
a
0.303 mmol) in CH2Cl2 (2 ml) was added Dess–Martin
periodinane (193 mg, 0.455 mmol) at 0 8C under an argon
atmosphere. The mixture was stirred at 0 8C for 1 h, then
quenched with saturated aqueous NaHCO3 and extracted
with Et2O. The extract was dried over MgSO4 and
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel eluted with
hexane–AcOEt (9/1) to give 25 (80.0 mg, 0.256 mmol,
84%) as a colorless oil: [a]2D2 K45.6 (c 1.22, CHCl3); IR
(neat) 1742 cmK1; 1H NMR (400 MHz, CDCl3) d 9.58 (1H,
d, JZ2.4 Hz), 4.05 (1H, dd, JZ11.2, 4.4 Hz), 3.85 (1H, dd,
JZ11.2, 6.3 Hz), 3.59 (1H, d, JZ10.0 Hz), 3.42 (1H, d, JZ
10.0 Hz), 2.06 (3H, s), 2.02–1.37 (11H, m), 1.07 (3H, d, JZ
6.8 Hz), 0.95 (6H, d, JZ6.8 Hz); 13C NMR (100 MHz,
CDCl3) d 201.3, 171.2, 95.8, 79.4, 73.1, 66.0, 35.3, 34.7,
30.1, 29.5, 28.0, 27.3, 26.3, 20.9, 16.6, 14.8, 11.0; SIMS m/z
313 (MCC1); HR-MS m/z 313.2013 (Calcd for C17H29O5:
312.2013).
3.1.19. (2R,3R,6R,8R,8(1R),9S)-2-Acetoxymethyl-8-2-
acetoxy-1-methylethyl)-3,9-dimethyl-1,7-dioxaspiro-
[5.5]undecane (22), (2R,3S,3(1R),6R,8R,9R)-2-(2-
acetoxy-1-methylethyl)-8-hydroxymethyl-3,9-dimethyl-
1,7-dioxaspiro[5.5]undecane (23) and (2R,3R,6R,8R,
8(1R),9S)-2-acetoxymethyl-8-(2-hydroxy-1-methylethyl)-
3,9-dimethyl-1,7-dioxaspiro[5.5]undecane (24). A mixture
of spirodiol 1 (94.6 mg, 0.348 mmol), lipase Amano PS
(100 mg) and vinylacetate (20 ml) was incubated at 33 8C
for 39 h. The reaction mixture was filtered and the filtrate
was concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel eluted with
hexane–AcOEt (9/1/1/1) to give 22 (6.0 mg, 0.017 mmol,
5%), 23 (98.0 mg, 0.312 mmol, 90%), 24 (2.0 mg,
0.0064 mmol, 2%) and 21 (3.0 mg, 0.011 mmol, 3%) as
colorless oils. 22: [a]D22 K54.3 (c 1.06, CHCl3); IR (neat)
3.1.21. (2R)-1-Benzyloxy-2-methyl-3-phenylsulfonyl-
propane (26). According to the preparation of 3, (S)-(K)-
3-benzyloxy-2-methylpropanol17 (231 mg, 1.28 mmol) was
converted into the thiophenylated compound (334 mg,
1.23 mmol, 96%) as a colorless oil: [a]2D2 C10.3 (c 1.07,
CHCl3); IR (neat) 2962 cmK1; 1H NMR (400 MHz, CDCl3)
d 7.37–7.22 (9H, m), 7.14 (1H, tt, JZ7.3, 2.0 Hz), 4.47 (2H,
s), 3.46–3.38 (2H, m), 3.15 (1H, dd, JZ13.2, 6.0 Hz), 2.79
(1H, dd, JZ13.2, 7.3 Hz), 2.07 (1H, octet, JZ6.8 Hz), 1.06
(3H, d, JZ6.8 Hz); 13C NMR (100 MHz, CDCl3) d 138.5,
137.2, 128.82, 128.80, 128.3, 127.5, 125.6, 74.0, 73.0, 37.5,
33.8, 16.8; EI-MS m/z 272 (MC); HR-MS m/z 272.1238
(Calcd for C17H20O1S1: 272.1234). According to the
preparation of 4, this thiophenylated compound (300 mg,
1.10 mmol) was converted into 26 (317 mg, 1.04 mmol,
95%) as a colorless oil: [a]2D2 K4.6 (c 1.09, CHCl3); IR
1
1742 cmK1; H NMR (400 MHz, CDCl3) d 4.22 (1H, dd,
JZ11.7, 2.4 Hz), 4.12 (1H, dd, JZ11.7, 6.8 Hz), 4.06 (1H,
dd, JZ11.2, 4.4 Hz), 3.85 (1H, dd, JZ11.2, 6.3 Hz),
3.49–3.43 (2H, m), 2.08 (3H, s), 2.06 (3H, s), 2.10–1.99
(1H, m), 1.98–1.86 (1H, m), 1.81–1.71 (1H, m), 1.70–1.36
(8H, m), 1.07 (3H, d, JZ6.3 Hz), 0.94 (3H, d, JZ6.8 Hz),
0.88 (3H, d, JZ6.3 Hz); 13C NMR (100 MHz, CDCl3) d
171.1, 171.0, 95.9, 73.0, 72.7, 66.3, 65.5, 35.7, 34.7, 31.2,
29.7, 28.1, 27.9, 26.5, 21.0, 20.9, 17.6, 14.9, 11.0; SIMS m/z
357 (MCC1); HR-MS m/z 357.2262 (Calcd for C19H33O6:
357.2275). 23: [a]2D2 K68.9 (c 0.99, CHCl3); IR (neat) 3480,
1
(neat) 1586, 1305 cmK1; H NMR (400 MHz, CDCl3) d
1
1741 cmK1; H NMR (400 MHz, CDCl3) d 4.06 (1H, dd,
7.94–7.89 (2H, m), 7.64 (1H, tt, JZ7.3, 1.5 Hz), 7.55 (2H, t,
JZ6.8 Hz), 7.36–7.23 (5H, m), 4.43 (1H, d, JZ12.2 Hz),
4.40 (1H, d, JZ12.2 Hz), 3.45–3.38 (2H, m), 3.31(1H, dd,
JZ9.3, 6.0 Hz), 2.93 (1H, dd, JZ14.2, 7.8 Hz), 2.46–2.33
(1H, m), 1.12 (3H, d, JZ6.8 Hz); 13C NMR (100 MHz,
CDCl3) d 140.1, 138.1, 133.5, 129.2, 128.4, 127.8, 127.6,
127.5, 73.5, 72.9, 59.3, 29.4, 17.2; EI-MS m/z 304 (MC);
HR-MS m/z 304.1105 (Calcd for C17H20O3S1: 304.1132).
JZ11.0, 4.2 Hz), 3.86 (1H, dd, JZ11.0, 6.2 Hz), 3.73 (1H,
br d, JZ10.7 Hz), 3.59–3.52 (1H, m), 3.45 (1H, dd, JZ
10.1, 2.4 Hz), 3.34 (1H, ddd, JZ10.1, 6.8, 2.9 Hz), 2.06
(3H, s), 2.06–1.89 (2H, m), 1.82–1.73 (1H, m), 1.70–1.39
(9H, m), 1.08 (3H, d, JZ6.6 Hz), 0.95 (3H, d, JZ7.0 Hz),
0.85 (3H, d, JZ6.4 Hz); 13C NMR (100 MHz, CDCl3) d
171.2, 95.9, 75.0, 72.7, 66.1, 64.0, 36.0, 34.8, 30.8, 29.8,
28.1, 27.6, 26.6, 20.9, 17.4, 14.8, 11.1; SIMS m/z 315
(MCC1); HR-MS m/z 315.2170 (Calcd for C17H31O5:
315.2170). Anal. Calcd for C17H30O5: C, 64.94; H, 9.62.
Found: C, 64.99; H, 10.15. 24: [a]2D2 K64.3 (c 1.36, CHCl3);
IR (neat) 3422, 1734 cmK1; 1H NMR (400 MHz, CDCl3) d
3.1.22. (2R,2(3S),3R,6R,8R,8(1R),9S)-2-(4-Benzyloxy-3-
methyl-1-butenyl)-8-(2-hydroxy-1-methylethyl)-3,
9-dimethyl-1,7-dioxaspiro[5.5]undecane (27). To a solution
of 26 (112 mg, 0.368 mmol) in THF (1.7 ml) was added

724
Y. Ishii et al. / Tetrahedron 62 (2006) 716–725
dropwise n-BuLi (1.58 M in hexane, 0.442 mmol, 280 ml) at
K50 8C. After being stirred for 15 min, a solution of 25
(76.5 mg, 0.245 mmol) in THF (400 ml) was slowly added
to the reaction mixture. The mixture was stirred for 30 min,
then quenched with saturated aqueous NH4Cl and extracted
with ethylacetate. The extract was dried over MgSO4 and
concentrated to give crude b-hydroxysulfone as a mixture of
four diastereomers. To a solution of the b-hydroxysulfone in
pyridine (3 ml) were added 4-dimethylaminopyridine
(0.170 mmol, 21 mg) and acetic anhyride (0.681 mmol,
64 ml) at room temperature. The mixture was stirred for 1 h,
then quenched with H2O and extracted with ethylacetate.
The combined organic layers were washed with 2 N
aqueous HCl and saturated aqueous NaHCO3, dried
(MgSO4), and concentrated to give crude b-acetoxysulfone.
To a solution of this b-acetooxysulfone in methanol (4 ml)
was added sodium–mercury amalgam (5% Na–Hg, 656 mg,
2.94 mmol) at room temperature. After being stirred for 1 h
at 50 8C, the reaction mixture was quenched with H2O at
room temperature and extracted with ethylacetate. The
extract was dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by column
chromatography on silica gel eluted with hexane–AcOEt
(9/1) to give 27 (29.1 mg, 0.0700 mmol, 29% from 25) as a
colorless oil: [a]2D2 K30.0 (c 1.25, CHCl3); IR (neat) 3470,
1715 cmK1; 1H NMR (400 MHz, CDCl3) d 7.38–7.27 (5H,
m), 5.58 (1H, dd, JZ15.1, 6.8 Hz), 5.44 (1H, ddd, JZ15.1,
7.8, 1.0 Hz), 4.51 (2H, s), 3.65 (1H, dd, JZ10.2, 4.4 Hz),
3.61 (1H, dd, JZ10.2, 7.8 Hz), 3.51 (1H, dd, JZ10.0,
2.4 Hz), 3.45 (1H, dd, JZ10.0, 6.3 Hz), 3.40 (1H, dd, JZ
9.3, 6.8 Hz), 3.32 (1H, dd, JZ9.3, 6.8 Hz), 2.53 (1H, heptet,
JZ6.8 Hz), 2.08 (1H, tt, JZ13.1, 4.4 Hz), 1.88–1.72 (2H,
m), 1.71–1.22 (9H, m), 1.12 (3H, d, JZ6.8 Hz), 1.06 (3H, d,
JZ6.3 Hz), 0.95 (3H, d, JZ6.8 Hz), 0.77 (3H, d, JZ
6.3 Hz); 13C NMR (100 MHz, CDCl3) d 138.7, 136.1,
129.8, 128.3, 127.5, 127.4, 96.0, 76.7, 75.4, 72.9, 72.6, 65.0,
37.6, 36.7, 36.0, 34.7, 30.1, 28.2, 27.8, 26.6, 18.1, 17.0,
14.5, 11.4; SIMS m/z 417 (MCC1); HR-MS m/z 417.2997
(Calcd for C26H41O4: 417.3003).
(56 mg, 0.168 mmol) at 0 8C under an argon atmosphere.
The mixture was stirred at room temperature for 3 h, then
quenched with H2O and extracted with Et2O. The extract
was dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by column chromatog-
raphy on silica gel eluted with hexane–AcOEt (9/1) to give
28 (22.3 mg, 0.0474 mmol, 85%) as a colorless oil: [a]D22
1
K54.6 (c 0.74, CHCl3); IR (neat) 1727 cmK1; H NMR
(400 MHz, CDCl3) d 7.36–7.22 (5H, m), 6.80 (1H, dd,
JZ15.8, 9.2 Hz), 5.89 (1H, dd, JZ15.8, 0.7 Hz), 5.56 (1H,
dd, JZ15.8, 6.6 Hz), 5.43 (1H, dd, JZ15.8, 7.6 Hz), 4.52
(2H, s), 3.73 (3H, s), 3.58 (1H, dd, JZ10.0, 7.6 Hz), 3.45
(1H, dd, JZ10.0, 2.0 Hz), 3.41 (1H, dd, JZ9.2, 6.6 Hz),
3.32 (1H, dd, JZ9.2, 7.2 Hz), 2.62–2.38 (2H, m), 2.04 (1H,
tt, JZ13.2, 4.3 Hz), 1.70–1.24 (9H, m), 1.17 (3H, d, JZ
6.3 Hz), 1.08 (3H, d, JZ6.9 Hz), 0.90 (3H, d, JZ6.9 Hz),
0.77 (3H, d, JZ6.6 Hz); 13C NMR (100 MHz, CDCl3) d
167.1, 150.7, 138.7, 136.2, 129.8, 128.3, 127.53, 127.45,
120.9, 96.2, 76.8, 75.3, 73.8, 73.0, 51.5, 39.6, 36.8, 35.9,
34.7, 30.0, 28.7, 27.7, 26.4, 18.1, 17.7, 17.1, 10.8; SIMS m/z
471 (MCC1); HR-MS m/z 471.3102 (Calcd for C29H43O5:
471.3108).
3.1.24. (2S,2(3S),3R,6R,8R,8(1R),9S)-2-(4-Hydroxy-3-
methylbutyl)-8-(3-methoxycarbonyl-1-methylpropyl)-
3,9-dimethyl-1,7-dioxaspiro[5.5]undecane (29). According
to the preparation of 6, 28 (12.3 mg, 0.0262 mmol) was
converted into 29 (9.4 mg, 0.024 mmol, 90%) as a
colorless oil: [a]2D2 K70.8 (c 0.37, CHCl3); IR (neat)
3468, 1744 cmK1; 1H NMR (400 MHz, CDCl3) d 3.67 (3H,
s), 3.51 (1H, dd, JZ10.7, 6.3 Hz), 3.46 (1H, dd, JZ10.7,
6.3 Hz), 3.30 (1H, dd, JZ10.3, 2.4 Hz), 3.22–3.15 (1H, m),
2.44–2.25 (2H, m), 2.09–1.97 (1H, m), 1.89–1.74 (2H, m),
1.72–1.24 (16H, m), 1.00 (3H, d, JZ6.8 Hz), 0.93 (3H, d,
JZ6.3 Hz), 0.90 (3H, d, JZ6.8 Hz), 0.82 (3H, d, JZ
6.3 Hz); 13C NMR (100 MHz, CDCl3) d 174.4, 95.8, 74.6,
74.5, 68.2, 51.6, 36.1, 35.7, 34.9, 34.0, 31.0, 30.2, 30.0,
28.9, 28.1, 27.5, 26.9, 26.7, 18.1, 16.5, 16.0, 10.8; SIMS m/z
385 (MCC1); HR-MS m/z 385.2981 (Calcd for C22H41O5:
385.2952).
3.1.23. (2R,2(3S),3R,6R,8R,8(1R),9S)-2-(4-Benzyloxy-3-
methyl-1-butenyl)-8-(3-methoxycarbonyl-1-methyl-2-
propenyl)-3,9-dimethyl-1,7-dioxaspiro[5.5]undecane
(28). According to the preparation of 25, 27 (26.0 mg,
0.0625 mmol) was converted into the corresponding
aldehyde (24.0 mg, 0.0580 mmol, 93%) as a colorless oil:
3.1.25. (2R,2(1R),3S,6R,8S,8(3S),9R)-2-(3-Methoxy-
carbonyl-1-methylpropyl)-8-(3-methyl-4-pentenyl)-3,
9-dimethyl-1,7-dioxaspiro[5.5]undecane (30). To a solution
of 29 (3.7 mg, 0.0096 mmol) in CH2Cl2 (74 ml) was added
Dess–Martin periodinane (6.1 mg, 0.016 mmol) and
NaHCO3 (8.1 mg, 0.096 mmol) at 0 8C. The mixture was
stirred at room temperature for 2 h, then quenched with
saturated aqueous NaHCO3 and extracted with Et2O. The
extract was dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by column
chromatography on silica gel eluted with hexane–AcOEt
(6/1) to give aldehyde compound (3.2 mg) as a colorless oil.
To a suspension of methyltriphenylphosphonium bromide
(9.0 mg, 0.025 mmol) in THF (90 ml) was added potassium
t-butoxide (2.6 mg, 0.024 mmol) at 0 8C under an argon
atmosphere. After being stirred for 30 min, a solution of the
aldehyde compound (9.7 mg) in THF (30 ml) was added to
the mixture at 0 8C. After 2 h, the reaction mixture was
quenched with H2O at 0 8C and extracted with ethylacetate.
The extract was dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by column
1
[a]D22 K58.8 (c 1.02, CHCl3); IR (neat) 1725 cmK1; H
NMR (400 MHz, CDCl3) d 9.67 (1H, d, JZ2.9 Hz),
7.36–7.24 (5H, m), 5.57 (1H, dd, JZ15.1, 6.8 Hz), 5.44
(1H, dd, JZ15.1, 7.8 Hz), 4.51 (2H, s), 3.83 (1H, dd, JZ
9.8, 2.4 Hz), 3.56 (1H, dd, JZ9.8, 7.8 Hz), 3.40 (1H, dd,
JZ9.3, 6.8 Hz), 3.32 (1H, dd, JZ9.3, 6.8 Hz), 2.66–2.47
(2H, m), 2.11 (1H, tt, JZ13.2, 4.4 Hz), 1.83–1.73 (1H, m),
1.71–1.27 (8H, m), 1.20 (3H, d, JZ6.8 Hz), 1.07 (3H, d, JZ
6.8 Hz), 0.96 (3H, d, JZ6.8 Hz), 0.78 (3H, d, JZ6.3 Hz);
13C NMR (100 MHz, CDCl3) d 203.5, 138.6, 136.2, 129.7,
128.3, 127.5, 127.4, 96.2, 76.7, 75.3, 72.9, 70.9, 49.3, 36.8,
35.8, 34.7, 30.0, 29.0, 27.6, 26.3, 18.0, 17.0, 11.6, 11.5;
SIMS m/z 415 (MCC1); HR-MS m/z 415.2856 (Calcd for
C26H39O4: 415.2846). To a solution of the aldehyde
compound (23.2 mg, 0.0560 mmol) in CH2Cl2 (0.350 ml)
was added methyl (triphenylphosphoraniliden)acetate

Y. Ishii et al. / Tetrahedron 62 (2006) 716–725
725
chromatography on silica gel eluted with hexane–AcOEt
(20/1) to give 30 (2.3 mg, 0.0061 mmol, 60%) as a colorless
oil: [a]2D2 K62.7 (c 0.15, CHCl3); IR (neat) 1744 cmK1
References and notes
;
1. Cheng, X.-C.; Kihara, T.; Kusakabe, H.; Magae, J.; Kobayashi,
Y.; Fang, R.-P.; Ni, Z.-F.; Shen, Y.-C.; Ko, K.; Yamaguchi, I.;
Isono, K. J. Antibiot. 1987, 40, 907.
1H NMR (400 MHz, CDCl3) d 5.72 (1H, ddd, JZ17.6, 10.3,
7.3 Hz), 5.00–4.89 (2H, m), 3.67 (3H, s), 3.28 (1H, dd, JZ
9.8, 2.4 Hz), 3.14 (1H, t, JZ9.8 Hz), 2.40 (1H, ddd, JZ
15.6, 9.8, 5.4 Hz), 2.29 (1H, ddd, JZ15.6, 9.8, 7.3 Hz),
2.18–1.98 (2H, m), 1.89–1.76 (2H, m), 1.71–1.35 (9H, m),
1.34–1.18 (5H, m), 1.01 (3H, d, JZ6.8 Hz), 1.00 (3H, d, JZ
6.3 Hz), 0.91 (3H, d, JZ6.8 Hz), 0.81 (3H, d, JZ6.8 Hz);
13C NMR (100 MHz, CDCl3) d 174.3, 145.0, 112.4, 95.6,
74.7, 74.6, 51.5, 37.9, 36.1, 35.0, 34.1, 32.9, 31.2, 30.9,
30.2, 28.2, 27.6, 27.0, 26.7, 20.1, 18.0, 16.1, 10.8; SIMS m/z
381 (MCC1); HR-MS m/z 381.3015 (Calcd for C23H41O4:
381.3003).
2. (a) Ubukata, M.; Cheng, X.-C.; Isono, K. J. Chem. Soc., Chem.
Commun. 1990, 244. (b) Cheng, X.-C.; Ubukata, M.; Isono, K.
J. Antibiot. 1990, 43, 809. (c) Ubukata, M.; Cheng, X.-C.;
Isobe, M.; Isono, K. J. Chem. Soc., Perkin Trans. 1 1993, 617.
3. Magae, J.; Osada, H.; Cheng, X.-C.; Isono, K. J. Antibiot.
1992, 45, 252.
4. For total syntheses, see: (a) Oikawa, H.; Oikawa, M.; Ueno, T.;
Ichihara, A. Tetrahedron Lett. 1994, 35, 4809. (b) Oikawa, M.;
Ueno, T.; Oikawa, H.; Ichihara, A. J. Org. Chem. 1995, 60,
5048. (c) Ichikawa, Y.; Tsuboi, K.; Jiang, Y.; Naganawa, A.;
Isobe, M. Tetrahedron Lett. 1995, 36, 7101. (d) Shimizu, S.;
Nakamura, S.; Nakada, M.; Shibasaki, M. Tetrahedron 1996,
52, 13363. (e) Sheppeck, J.; Liu, W.; Chamberlin, R. J. Org.
Chem. 1997, 62, 387. (f) Tsuboi, K.; Ichikawa, Y.; Naganawa,
A.; Isobe, M.; Ubukata, M.; Isono, K. Tetrahedron 1997, 53,
5083. (g) Jiang, Y.; Ichikawa, Y.; Isobe, M. Tetrahedron 1997,
53, 5103. (h) Tsuboi, K.;Ichikawa, Y.; Jiang, Y.;Naganawa, A.;
Isobe, M. Tetrahedron 1997, 53, 5123. For formal synthesis,
see: (i) Marshall, J. A.; Yanik, M. M. J. Org. Chem. 2001, 66,
1373. For synthetic studies, see: (j) Oikawa, M.; Oikawa, H.;
Ichihara, A. Tetrahedron Lett. 1993, 34, 4797. (k) Nakamura,
S.; Shibasaki, M. Tetrahedron Lett. 1994, 35, 4145. (l) Ueno, T.;
Oikawa, M.; Oikawa, H.; Ichihara, A. Biosci. Biotechnol.
Biochem. 1995, 59, 2104. (m) Maurer, K. W.; Armstrong, R. W.
J. Org. Chem. 1996, 61, 3106.
3.1.26. (2S,2(1R),3S,6R,8S,8(3S),9R)-2-(4-Hydroxy-1-
methylbutyl)-8-(3-methyl-4-pentenyl)-3,9-dimethyl-1,
7-dioxaspiro[5.5]undecane (31). To a solution of 30 (2.0 mg,
0.0053 mmol) in THF (30 ml) was added LiAlH4 (0.4 mg) at
0 8C. The mixture was stirred at 0 8C for 10 min, then
quenched with a small amount of H2O. The precipitate was
removed by filtration. The filtrate was dried over MgSO4
and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel eluted with
hexane–AcOEt (4/1) to give 31 (1.6 mg, 0.0045 mmol,
80%) as a colorless oil: [a]2D2 K60.0 (c 0.16, CHCl3); IR
(neat) 3350 cmK1; 1H NMR (270 MHz, CDCl3) d 5.72 (1H,
ddd, JZ17.5, 10.2, 7.6 Hz), 4.96 (1H, d, JZ17.5 Hz), 4.91
(1H, d, JZ10.2 Hz), 3.72–3.57 (2H, br), 3.30 (1H, dd, JZ
10.2, 2.3 Hz), 3.16 (1H, t, JZ9.0 Hz), 2.19–1.95 (2H, m),
1.90–1.77 (1H, m), 1.74–1.16 (18H, m), 1.02 (3H, d, JZ
6.3 Hz), 1.00 (3H, d, JZ6.9 Hz), 0.90 (3H, d, JZ6.9 Hz),
0.82 (3H, d, JZ6.6 Hz); [Ichihara’s data: d 5.73 (1H, ddd,
JZ17.2, 9.9, 7.3 Hz), 4.96 (1H, dt, JZ17.2, 1.6 Hz), 4.92
(1H, dd, JZ9.9, 1.6 Hz), 3.65 (2H, td, JZ6.6, 2.6 Hz), 3.30
(1H, dd, JZ10.3, 2.3 Hz), 3.16 (1H, td, JZ9.0, 1.6 Hz),
2.17–1.97 (2H, m), 1.85 (1H, m), 1.73–1.20 (17H, m), 1.02
(3H, d, JZ5.9 Hz), 1.00 (3H, d, JZ6.6 Hz), 0.90 (3H, d,
JZ6.9 Hz), 0.82 (3H, d, JZ6.6 Hz)]; 13C NMR (67.8 MHz,
CDCl3) d 145.0, 112.3, 95.6, 74.74, 74.67, 63.3, 37.9, 36.1,
35.1, 34.3, 32.9, 30.9, 30.3, 29.5, 28.3, 27.8, 27.5, 26.7,
20.1, 18.1, 16.5, 10.9; SIMS m/z 353 (MCC1); HR-MS m/z
353.3064 (Calcd for C22H41O3: 353.3054).
5. A part of this work has been reported: Nagumo, S.; Arai, T.;
Akita, H. Tetrahedron Lett. 1997, 38, 5165.
6. Wong, C.-H.; Whitesides, G. M. Enzymes in Synthetic Organic
Chemistry; Pergamon: Oxford, 1994.
7. (a) Palmer, D. C.; Terradas, F. Tetrahedron Lett. 1994, 35,
1673. (b) Morimoto, T.; Murakami, N.; Nagata, A.;
Sakakibara, J. Chem. Pharm. Bull. 1994, 42, 751. (c)
Danieli, B.; Luisetti, M.; Riva, S.; Bertinotti, A.; Ragg, E.;
Scaglioni, L.; Bombaredelli, E. J. Org. Chem. 1995, 60, 3637.
8. Mori, K.; Iwasawa, H. Tetrahedron 1980, 36, 87.
9. Nagumo, S.; Arai, T.; Akita, H. Chem. Pharm. Bull., 1996, 44,
1391.
10. Mitsunobu, O. Synthesis 1981, 1.
11. Dabby, R. E.; Kenyson, J.; Mason, R. F. J. Chem. Soc. 1952,
4881.
12. (a) Nagasawa, K.; Shimizu, I.; Nakata, T. Tetrahedron Lett.
1996, 37, 6881. (b) Oshima, M.; Yamazaki, H.; Shimizu, I.;
Nisar, M.; Tsuji, J. J. Am. Chem. Soc. 1989, 111, 6280.
13. Meyers, A. I.; Babiak, K. A.; Campbell, C. A.; Comins, D. L.;
Fleming, M. P.; Henning, R.; Heuschmann, M.; Hudspeth,
J. P.; Kane, J. M. J. Am. Chem. Soc. 1983, 105, 5015.
14. (a) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(b) Eis, M. J.; Wrobel, J. E.; Ganem, B. J. Am. Chem. Soc.
1984, 106, 3693.
Acknowledgements
A Grant-in Aid for Encouragement of Young Scientists
(10771254 to S.N.) from the Ministry of Education, Science
and Culture of Japan is gratefully acknowledged. We are
also grateful to the Akiyama Foundation (to S.N.) for its
support to this project. We also thank Dr. Yoshihiko Hirose
(Amano Pharmaceutical Co., Ltd) for the generous gift of
Amano PS.
15. Julia, M.; Paris, J.-M. Tetrahedron Lett. 1973, 4833.