First total synthesis of modiolide A, based on the whole-cell yeast-catalyzed asymmetric reduction of a propargyl ketone

Article abstract of DOI:10.1016/j.tet.2007.06.038

While the first total synthesis of modiolide A (1a), a 10-membered ring lactone with a marine-origin was achieved, an important chiral building block for constructing the chirality at C-4 in 1a, (S)-6-[(4-methoxybenzyl)oxy]-1-trimethylsilyl-1-hexyn-3-ol (

Full text of DOI:10.1016/j.tet.2007.06.038

Tetrahedron 63 (2007) 8752–8760
First total synthesis of modiolide A, based on the whole-cell
yeast-catalyzed asymmetric reduction of a propargyl ketone
*
Masaaki Matsuda, Takahiro Yamazaki, Ken-ichi Fuhshuku and Takeshi Sugai
Department of Chemistry, Keio University, 3-14-1 Hiyoshi, Yokohama, Kanagawa 223-8522, Japan
Received 24 May 2007; revised 12 June 2007; accepted 13 June 2007
Available online 16 June 2007
Abstract—While the first total synthesis of modiolide A (1a), a 10-membered ring lactone with a marine-origin was achieved, an important
chiral building block for constructing the chirality at C-4 in 1a, (S)-6-[(4-methoxybenzyl)oxy]-1-trimethylsilyl-1-hexyn-3-ol (3a) was
obtained in as high as 96.1% ee. Asymmetric reduction of a silylated propargyl ketone (5) mediated by whole-cell of Pichia minuta IAM
12215 was established. This yeast-mediated reduction was also applicable to provide stereochemically pure (3S,5R)-5-[(4-methoxybenzyl)-
oxy]-1-trimethylsilyl-1-hexyn-3-ol (15), a synthetic intermediate for the related 10-membered lactone, tuckolide (16).
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
center at C-4 and an acetal alcohol (R)-4a5,6 with the chiral
center at C-9. We chose the whole-cell yeast-mediated
reduction7 of the corresponding propargyl ketone 5. There
are a number of methods for preparation of enantiomerically
enriched forms of propargyl alcohols, for example, chirally
modified boranes8 or transition metal complex-mediated re-
duction9 of propargyl ketones, and the addition of acetylides
on aldehydes, in the presence of chiral Lewis bases.10,11
Compared with them, the whole-cell yeast-catalyzed reduc-
tion has an advantage that the chiral catalyst is supplied in
a large quantity and self-reproducible manner, by a simple
incubation from a seed culture.
Naturally occurring 10-membered ring lactones from fungal
metabolites present a wide variety of bioactive substances.
Among them, modiolide A (1a) was isolated by Kobayashi
and co-workers1 as antibacterial and antifungal substance
from marine-origin microorganisms.
Inspired by Pilli’s approach to construct 10-membered ring
lactones,2,3 the synthesis of modiolide A (1a) was designed
based on the intramolecular Nozaki–Hiyama–Kishi cou-
pling reaction4 of the intermediate 2 with the concomitant
establishment of the C-7 stereogenic center (Scheme 1).
The precursor 2 was further divided into two segments,
a propargyl alcohol (S)-3a, which constitutes the chiral
2. Results and discussion
2.1. Preparation of propargyl alcohol (S)-3a by whole-
cell yeast-catalyzed reduction
O
O
9
O
O
7
The first task is the preparation of an propargylic synthon
(S)-3a involving the C-4 chiral center. Toward this end, an
aldehyde 612 was treated with TMSCCLi and subsequent
Dess–Martin periodinane oxidation provided the substrate
5 in 93% yield (Scheme 2). Then, cultured cells of four re-
cently developed yeast strains, Pichia minuta IAM 12215,
Pichia angusta IAM 12895, Trichosporon cutaneum
IAM12206, Candida floricola IAM 13115, which were
screened as the ones capable of reducing hydrophobic, bulky
carbonyl compounds,13 were applied. Among the above four
strains, only P. minuta accepted the ketone 5 as the substrate.
HOC
I
HO
4
OH
2
OTBS
modiolide A 1a
OPMB
OPMB
O
(9)
TMS
TMS
OH
MeO
OMe
(4)
OH
(R)-4a
(S)-3a
5
Scheme 1.
The incubation conditions were summarized in Table 1. The
reduction smoothly proceeded only under the following
* Corresponding author. Tel.: +81 45 566 1709; fax: +81 45 566 1697;
e-mail: sugai@chem.keio.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.038

M. Matsuda et al. / Tetrahedron 63 (2007) 8752–8760
8753
the known (S)-3c,18 by comparison of the sign of rotation
(Scheme 2, see Section 4.4.1).
O
(a),(b)
OH
PMBO
(c)
CHO
PMBO
TMS
6
5
The acetylenic TMS group of (S)-3a was removed and the
free hydroxyl group was then protected as TBS ether to
give 7b (99%, Scheme 3). The (E)-alkenyl iodide structure
in 8a was provided (74%) by way of an alkenylstannane.
At this stage, the PMB protective group was removed
(97%), and the subsequent oxidation of primary alcohol
yielded the requisite carboxylic acid 9 (95%, Scheme 3).
(d)
PMBO
(S)-3a
TMS
96.1% ee
OH
OAc
PMBO
PMBO
+
(S)-3a
3b
TMS
TMS
>99.9% ee
OR
(a),(b)
(S)-3a
PMBO
OH
(e),(f)
7a R = H
TBDPSO
(S)-3a
b
TBS
(S)-3c
TMS
OTBS
(c),(d)
(e)
Scheme 2. (a) TMSCCLi, THF; (b) Dess–Martin periodinane, CH2Cl2 93%;
(c) P. minuta IAM 12215, 88%; (d) P. cepacia lipase (Amano PS-C), vinyl
acetate, i-Pr2O, 94% recovery for 3a; (e) DDQ, CH2Cl2–H2O, 54%; (f)
TBDPSCl, imidazole, DMF, quantitative.
PMBO
OTBS
I
8a
OTBS
(f),(g)
HO
HO2C
I
Table 1. Picha minuta-mediated reduction of 5
I
9
8b
Entry
Pre-incubation time (h)
Yield (3a, %)
ee (3a, %)
Scheme 3. (a) K2CO3, MeOH; (b) TBSCl, imidazole, DMF, 99%; (c)
n-Bu3SnH (1.2 equiv), AIBN (0.04 equiv), benzene; (d) I2, CH2Cl2, 74%;
(e) DDQ (1.2 equiv), CH2Cl2–H2O, 97%; (f) SO3–pyridine, i-Pr2NEt,
DMSO, CH2Cl2; (g) NaClO2, 2-methyl-2-butene, NaH2PO4, aq tert-
BuOH, 95%.
1
2
3
4
5
6
24
26
29
30
35
42
89
92
88
91
94.0
93.0
96.1
91.0
88.0
NA
78
No reaction
2.2. Combination with another chiral starting material
(R)-4a toward acyclic precursor 2
condition, due to the substantially inhibitory property of 5.
The substrate was directly introduced into the fermentation
broth at low substrate concentration (0.2%). With a fixed
charge of whole-cell yeast-enzyme catalysts [w/wcw (wet
cell weight), 0.05], the period of pre-incubation was exam-
ined. Better rate of the reduction as well as the
enantioselectivity were observed in yeast cells in the rela-
tively younger stage, with the pre-incubation of 24–30 h (en-
tries 1–4). (S)-Alcohol 3a with 96.1% ee became available in
88% yield (entry 3). Along with the prolonged pre-incuba-
tion, the enantioselectivity decreased; finally, there was no
reaction after 42 h pre-incubation (entry 6). It was notewor-
thy that the pre-incubation required plentiful oxygen supply
(see Section 4.3), otherwise, there was observed almost no
reduction.
The second task is the synthesis of another four-carbon syn-
thon involving the chirality at C-9 in the lactones. Toward
this end, an acetal alcohol (R)-4a of 92.6% ee was prepared
(76%) by Yamadazyma farinosa NBRC 10896-mediated
asymmetric reduction5,6 of commercially available ketone
10 in a large scale (Scheme 4). Enantioselective enrichment
OH OMe
O
OMe
OMe
(a)
(c)
(b)
OMe
(R)-4a
10
92.6% ee
OAc OMe
OMe
(R)-4a
>99.9% ee
(R)-4b
The chiral starting materials with a supply in certain quantity
as well as the consistent enantiomeric purity only deserve
the chiral pool for natural product synthesis. For this pur-
pose, integrated combination of asymmetric synthesis and
enzyme-mediated kinetic resolution have so far been devel-
oped.14–16 In this particular case, the ee of (S)-3a was further
enhanced to be over 99.9% by the treatment with Pseudomo-
nas cepacia lipase (Amano PS-C)17 in the presence of vinyl
acetate in 94% as the recovery even from the starting mate-
rial with 92.4% ee (for detail, see Section 4.5), via the re-
moval of contaminating (R)-3a as the acetate (R)-3b. The
(S)-absolute configuration of the above-mentioned 3a was
confirmed by the derivatization to 3c. The oxidative depro-
tection of PMB with DDQ (54%) and the subsequent regio-
selective protection on the primary hydroxyl group provided
OMe
O
(d),(e)
MeO
O
O
9 + 4a
I
OTBS
11
(f)
O
HOC
I
2
OTBS
Scheme 4. (a) Y. farinosa NBRC 10896, 76%; (b) P. cepacia lipase (Amano
PS-C), vinyl acetate, 58%; (c) K2CO3, MeOH, 98%; (d) 2,4,6-trichloroben-
zoyl chloride, Et3N, THF; (e) DMAP, benzene, quantitative; (f) p-TsOH–
H2O, acetone.

8754
M. Matsuda et al. / Tetrahedron 63 (2007) 8752–8760
was performed by treatment with lipase6,19 in the presence of
vinyl acetate to give an acetate (R)-4b (69% conversion,
58% yield, Scheme 4). This acetate was hydrolyzed to
give the alcohol (R)-4a of >99.9% ee (98%). Then the
acid 9 was condensed with alcohol (R)-4a to give an ester
11 (quantitative) by activating via Yamaguchi’s mixed an-
hydride intermediate in the presence of DMAP.20
intermediate for Pilli’s synthesis of 10-membered lactone,
while that in (4S,7R,9R)-12a (d¼4.45, J6,7¼1.8 Hz) was
far from 13.
The final task was the introduction of a double bond at C-2
(Scheme 5). Toward the end, first, the free hydroxyl group at
C-7 was protected by TBS ether (95%), and the resulted bis-
TBS ether 12b was phenylselenylated with phenylselenenyl
chloride21 to give 14 in 75% yield. Its 1H NMR suggested the
single isomer, we however, did not pursue the detail of its
stereochemistry. Immediately, it was treated with H2O2 to
promote oxidation to the corresponding selenoxide and the
subsequent syn-elimination to give the requisite cis-double
bond to afford (4R,7S,9R)-1b in 75% yield. Finally, two
TBS ethers were deprotected (91%) with HF–pyridine,22
to give (+)-modiolide A (1a, Scheme 5); mp 187–188 ꢀC
[lit.23 mp 189–191 ꢀC]; [a]2D1.8 +34.7 (c 0.250, MeOH)
[lit.1 [a]1D8 +42 (c 0.25, MeOH)]; whose spectral data coin-
cided with those reported for the natural product.1
2.3. Stereoselective cyclization and derivation to
modiolide A (1a)
After the cleavage of the dimethyl acetal in the above-
mentioned 11 under acidic conditions, the resulted aldehyde
2 was submitted to the key-step, the intramolecular Nozaki–
Hiyama–Kishi coupling. The reaction proceeded in a
stereoselective manner, to give the desired (4S,7S,9R)-12a
(52%) as the major product along with diastereomeric
(4S,7R,9R)-12a (9%) as in Scheme 5. The control of the
stereogenic center at C-7 was well understandable by the
previous results for which the stereochemistry at C-7 was
dominated by that at C-9, regardless of the stereochemistry
2.4. Application of the whole-cell reduction to another
propargyl ketone 17
1
at the C-4 chiral center.2,3 The H signal at C-7 (d: 4.06,
J6,7¼8.8 Hz) in (4S,7S,9R)-12a coincided well with those
at C-7 (d: 4.21, J6,7¼10.8 Hz) in 13,2 which is a key
In the course of the present study, we became interested
in the whole-cell yeast-mediated reduction of propargyl
ketones. A propargyl alcohol (3S,5R)-15 (Scheme 6) was
selected as the next target. This alcohol is the key
intermediate24 for another naturally occurring 10-membered
O
O
O
(a)
O
O
O
+
HOC
I
HO
HO
O
OTBS
(4S,7S,9R)-12a
OTBS
(4S,7R,9R)-12a
2
OTBS
(9)
9
PMBO
O
O
OPMB
TMS
7
(7)
HO
HO
OH
1.8
TMS
H
H
O
OH
tuckolide 16
(decarestrictine D)
(R)-17
O
HO
HO
H
(3S,5R)-15
O
O
OTBS
OTBS
8.8
H
OH
OH OMe
PMBO
OMe
OMe
(4S,7R,9R)-12a
(4S,7S,9R)-12a
OTBS
(a)
OMe
H
(R)-4a
O
(R)-4c
>99.9% ee
O
10.8
13
H
OTBS
PMBO
PMBO
(b)
CO2Me
CHO
O
(R)-18b
(R)-18a
(b)
(c)
O
(4S,7S,9R)-12a
TBSO
PMBO
OH
PMBO
OH
(c)
OTBS
+
(R)-18a
(4S,7S,9R)-12b
TMS
TMS
O
O
(3R,5R)-15
(3S,5R)-15
SePh
O
O
(d)
TBSO
TBSO
(e)
N
N
(d)
N
N
OTBS
(4R,7S,9R)-1b
(3RS,5R)-15
(R)-17
OTBS
Me
Me
14
HO
HO
(2R,2'R)-19
(2S,2'S)-19
O
O
PMBO
O
HO
PMBO
OH
(e)
OH
(4R,7S,9R)-1a
TMS
TMS
(R)-17
(3S,5R)-15
Scheme 5. (a) CrCl2 (12 equiv), NiCl2, (0.5 mol %), DMF, 52% for
(4S,7S,9R)-12a and 9% for (4S,7R,9R)-12a; (b) TBSCl, imidazole, DMF,
95%; (c) LDA (2.1 equiv), PhSeCl (2.2 equiv), HMPA (1.5 equiv), THF,
75%; (d) H2O2, NaHCO3, THF, 75%; (e) HF–pyridine, THF, pyridine, 91%.
Scheme 6. (a) PMBCl, NaH, DMF, quantitative; (b) AcOH–H2O, 94%;
(c) TMSCCLi, THF, 82%; (d) Dess–Martin periodinane, CH2Cl2 87%;
(e) P. minuta IAM 12215, 61%.

M. Matsuda et al. / Tetrahedron 63 (2007) 8752–8760
8755
ring lactone, tuckolide (decarestrictine D, 16),25,26 which
had been isolated as the substance with inhibitory activity
on cholesterol biosynthesis and synthesized by several
groups.12,24,27–29
100–210 mm, 37560-79) from Kanto Chemical Co. were
used for preparative thin-layer chromatography and column
chromatography, respectively. Peptone and yeast extract
were purchased from Kyokuto Pharmaceutical Co., for the
cultivation of microorganism. Yeast strains are available
from Institute of Applied Microbiology Culture Collection;
Institute of Molecular and Cellular Biosciences, University
of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
The substrate (R)-17 for yeast-catalyzed reduction was pre-
pared as in Scheme 6, and we have some comments on the
route to its precursor 18a. First, the hydroxyl group of the
starting material, (R)-4a synthesized as above was protected
in a conventional manner (quantitative), by treatment with
p-methoxybenzyl chloride and NaH, and the subsequent
hydrolysis of the dimethyl acetal in (R)-4c (94%) provided
b-PMBoxy aldehyde 18a.24 The choice of (R)-4c as the inter-
mediate enabled avoiding the use of p-methoxybenzyl
trichloroacetimidate, which had been necessary for the prep-
aration of the so far reported starting material, (R)-18b, a b-
PMBoxy ester. Second, as Andrus had stated before,24 in the
course of the addition of TMS acetylide on aldehyde (R)-18a,
the undesired (3R,5R)-15 predominated over (3S,5R)-isomer
(2.6:1). The addition proceeded strongly in substrate-
controlled manner, influenced by the chelation between
pre-existing PMBoxy group. Attempts to change this situa-
tion into ‘reagent control’ were in vain. Even the addition
of either enantiomer of diamines (2R,20R)-19 or (2S,20S)-
1930 only slightly changed the ratio of the resulting both di-
astereomers, (3R,5R)-15 and (3S,5R)-15 in 4.0:1 or 3.0:1.
In our hand, a mixture of diastereomers (3RS,5R)-15 without
separation was directly oxidized to the substrate (R)-17.
4.2. Analytical methods
All mps are uncorrected. IR spectra were measured as films
for oils or KBr disks of solids on a Jasco FT/IR-410 spec-
trometer. 1H NMR spectra were measured in CDCl3 at
400 MHz on a Jeol JNM GX-400 spectrometer, and 13C
NMR spectra were measured in CDCl3 at 100 MHz on
a Jeol GX-400 spectometer, unless otherwise stated. HPLC
data were recorded on Jasco PU-2080 and MD-2010 liquid
chromatographs. Optical rotation values were recorded on
a Jasco DIP 360 and P-1010 polarimeter.
4.3. Pre-incubation of P. minuta IAM 1221513
A small portion of yeast cells of P. minuta IAM 12215 grown
on the agar-plate culture was aseptically inoculated to a glu-
cose medium [containing glucose (20 g), peptone (8.0 g),
yeast extract (2.0 g), KH2PO4 (1.2 g), K2HPO4 (0.8 g), at
pH 6.5, total volume of 400 mL] in four 500-mL baffled
Erlenmeyer cultivating flasks. The flask was loosely capped
with sterilized filter paper, instead of conventional foamed
polyurethane plug, for a plenty of oxygen supply, and then
shaken on a gyratory shaker (180 rpm) for 29 h at 30 ꢀC.
The OD (660 nm) reached 1.37.
As in the same manner for ynone 5 (Scheme 2), only P. min-
uta accepted 17 as the substrate, among the aforementioned
four yeast strains under pH-controlled (6.0) conditions. This
substrate 17 was less toxic compared with 5, then the reduc-
tion proceeded more smoothly. The desired alcohol (3S,5R)-
15 was obtained as a single isomer in 61% yield with the re-
covery of 17 (9%, Table 2, entry 1). Increase of the cell mass
applied (¼lower substrate/cell catalysts) and prolonged re-
action time (entry 2) lowered the yield of the desired product
as well as the recovery of the unreacted substrate.
4.4. Reduction of propargyl ketones with whole cells of
P. minuta IAM 12215
4.4.1. (S)-(D)-6-[(4-Methoxybenzyl)oxy]-1-trimethyl-
silyl-1-hexyn-3-ol 3a. To a 100 mL of grown broth as above
was directly added 5 (210 mg, 0.690 mmol), and the mixture
was stirred at 30 ꢀC for 22 h. Then the reaction mixture was
saturated with sodium chloride and mixed with ethyl acetate
(100 mL). The mixture was stirred for 1 h and filtered
through a pad of Celite. The organic layer of the filtrate
was separated and the aqueous layer was further extracted
with ethyl acetate. The combined organic extracts were
washed with brine, dried over anhydrous sodium sulfate,
and concentrated in vacuo. The residue was purified by silica
gel column chromatography (15 g). Elution with hexane–
ethyl acetate (2:1) afforded 3a (185.2 mg, 88%); [a]D25.5
Table 2. Picha minuta-mediated reduction of 17
Entry Sub/WCW Time (h) Yield [(3S,5R)-15, %] Recovery (17, %)
1
2
0.02
0.01
28
52
61
57
9
3
WCW¼wet cell weight; for detail, see Section 4.4.2.
3. Conclusion
1
We established a first total synthesis of (+)-modiolide A,
based on the whole-cell yeast-catalyzed reduction of carbonyl
precursor for providing the key-intermediates. Especially,
newly developed conditions for asymmetric reduction of
propargyl ketones worked very well in a preparative scale.
+0.85 (c 2.69, EtOH); H NMR d: 0.17 (s, 9H), 1.70–1.92
(m, 4H), 2.88 (d, J¼5.9 Hz, 1H), 3.51 (m, 2H), 3.81 (s,
3H), 4.41 (ddd, J¼5.6, 5.6, 5.9 Hz, 1H), 4.43 (d,
J¼11.6 Hz, 1H), 4.48 (d, J¼11.6 Hz, 1H), 6.88 (d,
J¼8.7 Hz, 2H), 7.63 (d, J¼8.7 Hz, 2H); 13C NMR d: 0.0,
25.5, 35.2, 55.3, 62.5, 69.8, 72.6, 89.1, 106.7, 113.8,
129.3, 130.0, 159.1; IR nmax 3404, 2956, 2861, 2170,
1613, 1514, 1456, 1362, 1250, 844 cmꢁ1. Anal. Calcd for
C17H26O3Si: C 66.62, H 8.55. Found: C 66.43, H 8.54.
HPLC analysis [column, Daicel Chiralcel OD–H,
0.46 cmꢂ25 cm; hexane–i-PrOH (20:1); flow rate 0.5 mL/
min]: tR (min)¼20.4 [1.9%, (R)-3a]; 24.0 [98.0%, (S)-3a];
96.1% ee.
4. Experimental
4.1. Materials and methods
Merck silica gel 60 F254 thin-layer plates (1.05744,
0.5 mm thickness) and silica gel 60 (spherical and neutral;

8756
M. Matsuda et al. / Tetrahedron 63 (2007) 8752–8760
This was converted to (S)-3c in conventional two steps. (S)-
3c: [a]2D3.0 +5.9 (c 0.570, CHCl3) [lit.18 [a]2D2 ꢁ5.7 (c 0.525,
hexane–ethyl acetate (4:1 to 2:1). First, less polar acetate 3b
[Rf¼0.57 (hexane–ethyl acetate¼2:1)] was eluted, and fur-
ther elution afforded 3a (987.2 mg, 98%) as a pale yellow
oil. Rf¼0.40 (hexane–ethyl acetate¼2:1); [a]2D9.2 +0.57 (c
2.66, EtOH); HPLC analysis [column, Daicel Chiralcel
OD–H, 0.46 cmꢂ25 cm; hexane–i-PrOH (20:1); flow rate
0.5 mL/min]: tR(min)¼23.6 [single peak, (S)-3a]. Its IR
and NMR spectra were identical with those as above.
1
CHCl3) for (R)-isomer]; H NMR d: 0.18 (s, 9H), 1.06 (s,
9H), 1.66–1.91 (m, 4H), 2.75 (d, J¼5.9 Hz, 1H), 3.70 (m,
2H), 4.44 (ddd, J¼5.7, 5.7, 5.9 Hz, 1H), 7.41 (m, 4H),
7.68 (m, 6H); 13C NMR d: 0.01, 19.2, 26.9, 28.3, 35.1,
62.6, 63.9, 89.2, 106.7, 127.6, 129.6, 133.4, 135.5; IR nmax
3387, 2957, 2931, 2858, 2170, 1428, 1251, 1112, 1009,
844, 702, 614 cmꢁ1
.
4.6. Preparation of substrates 5 and (R)-17
4.4.2. (3S,5R)-(L)-5-[(4-Methoxybenzyl)oxy]-1-trime-
thylsilyl-1-hexyn-3-ol 15. Pre-incubation of P. minuta was
carried out as above for 36 h at 30 ꢀC. The wet cells were
harvested by centrifugation (3000 rpm) and washed with
phosphate buffer (0.1 M, pH 6.0). The weight of combined
wet cells was ca. 5.1 g from 100 mL of the broth. Harvested
cells of P. minuta (9.5 g) were applied for the reduction of 17
(199.6 mg, 0.656 mmol) at 30 ꢀC for 28 h. During the reac-
tion, its pH was occasionally adjusted to 6.0 by the addition
of aqueous sodium hydroxide solution with an automatic pH
controller. The product was extracted in the same manner as
described before, and the residue was purified by silica gel
column chromatography (12.5 g). Elution with hexane–
ethyl acetate (15:1 to 6:1) afforded (3S,5R)-15 (121.6 mg,
4.6.1. 6-[(4-Methoxybenzyl)oxy]-1-trimethylsilyl-1-
hexyn-3-one 5. To a solution of trimethylsilylacetylene
(3.9 mL, 28.2 mmol) in anhydrous THF (20.2 mL) was
added dropwise n-BuLi (2.46 M in hexane, 10.5 mL,
25.9 mmol) at 0 ꢀC for 30 min. To a stirred solution of an al-
dehyde 612 (4.9 g, 23.5 mmol) in anhydrous THF (20.2 mL)
at ꢁ78 ꢀC was added the pre-formed solution of lithium tri-
methylsilylacetylide via a cannula. After the mixture had
been stirred at ꢁ78 ꢀC for 40 min, the reaction was gradually
warmed to room temperature. After stirring at room temper-
ature for 30 min, the reaction was quenched by addition of
saturated aqueous ammonium chloride solution. The mix-
ture was extracted with ethyl acetate. The organic layer
was washed with brine, dried over anhydrous sodium sulfate,
and concentrated in vacuo. The residue was charged on a
silica gel column (360 g), and eluted with hexane–ethyl ace-
tate (4:1 to 2:1) afforded racemic 3a (6.85 g, 95%) as a pale
yellow oil.
1
61%); [a]2D3.2 ꢁ86.5 (c 1.12, CHCl3); H NMR d: 0.19 (s,
9H), 1.26 (d, J¼6.3 Hz, 3H), 1.83 (ddd, J¼2.9, 6.1, 14.4 Hz,
1H), 1.95 (ddd, J¼1.6, 9.3, 14.4 Hz, 1H), 3.58 (d, J¼7.9 Hz,
1H), 3.80 (s, 3H), 4.10 (ddq, J¼2.9, 9.3, 6.3 Hz, 1H), 4.40 (d,
J¼10.7 Hz, 1H), 4.56 (d, J¼10.7 Hz, 1H), 4.56 (ddd, J¼1.6,
6.1, 7.9 Hz, 1H), 6.87 (d, J¼8.6 Hz, 2H), 7.29 (d, J¼8.6 Hz,
2H); 13C NMR d: 0.0, 19.4, 43.1, 55.3, 61.1, 70.6, 73.3, 89.1,
106.7, 113.8, 129.5, 130.1, 159.2; IR nmax 3423, 2962, 2837,
2170, 1614, 1587, 1514, 1464, 1421, 1375, 1342, 1302,
1250, 1174, 1142, 1111, 1036, 941, 845, 760 cmꢁ1. Anal.
Calcd for C17H26O3Si: C 66.62, H 8.55. Found: C 66.67,
H 8.42. Its NMR spectra were identical with those reported
previously.24 The crude product of yeast reduction contained
only (3S,5R)-15 [Rf 0.64, hexane–AcOEt (2:1)], and no
diastereomeric (3R,5R)-15 [Rf 0.54, hexane–ethyl acetate
(2:1)] was observed. 1H NMR spectrum of the crude sample
showed no signals assigned for (3R,5R)-15, for example,
d: 3.83 [ddq, J¼6.1, 3.5, 9.5 Hz, 1H (H-5)]. Moreover,
no (3R,5R)-15 isomer was observed by 13C NMR. 13C
NMR spectrum for authentic (3R,5R)-15, d: 0.0, 19.6,
44.7, 55.3, 62.0, 70.2, 74.0, 88.9, 106.3, 113.8, 129.3,
130.1, 159.1. As the 100% of stereochemical purity at C-5
had already been confirmed in the course of preparation of
the substrate (R)-17, the results show the present sample is
a single stereoisomer.
To a solution of racemic 3a (1.17 g, 3.83 mmol) in dichloro-
methane (38 mL) was added Dess–Martin periodinane
(2.21 g, 5.22 mmol), and the mixture was stirred for 6 h at
room temperature. The workup as before and the purification
with silica gel column (75 g) afforded 5 (1.14 g, 98%) as
a pale yellow oil. 1H NMR d: 0.00 (s, 9H), 1.72 (tt, J¼6.4,
7.3 Hz, 2H), 2.44 (t, J¼7.3 Hz, 2H), 3.23 (t, J¼6.4 Hz,
2H), 3.57 (s, 3H), 4.18 (s, 2H), 6.64 (d, J¼8.5 Hz, 2H),
7.02 (d, J¼8.5 Hz, 2H); 13C NMR d: ꢁ0.68, 24.1, 42.1,
55.3, 68.7, 72.5, 97.7, 101.9, 113.7, 129.1, 130.3, 159.0,
187.2; IR nmax 2958, 2900, 2859, 2149, 2091, 1678, 1613,
1514, 1360, 1303, 1250, 1098, 1037, 847, 762 cmꢁ1. Anal.
Calcd for C17H24O3Si: C 67.06, H 7.95. Found: C 67.23,
H 8.00.
4.6.2. (R)-4,4-Dimethoxy-2-butanol 4a. According to the
reported procedure,5,6 4,4-dimethoxy-2-butanone (10) was
incubated with the harvested cells of Y. farinosa NBRC
10896 to give (R)-4a (76%); [a]2D0.0 +12.0 (c 1.00, CHCl3).
The ee of 4a was determined by HPLC analysis of the cor-
responding benzoate 4d. HPLC [column, Daicel Chiralcel
OJ, 0.46 cmꢂ25 cm; hexane–i-PrOH (9:1); flow rate
0.5 mL/min]: tR (min)¼11.9 (96.3%), 12.8 (3.7%); 92.6%
ee. This was treated with P. cepacia lipase (Amano PS-C)
and vinyl acetate to give the corresponding acetate (R)-4b
(58%). To the solution of 4b (3.1 g, 17.5 mmol) in methanol
(43 mL) was added potassium carbonate (2.4 g, 17.4 mmol)
and the mixture was stirred at 0 ꢀC for 3 h. Then the reaction
mixture was poured into 40 mL of saturated aqueous ammo-
nium chloride solution and evaporated. The mixture was
extracted with ethyl acetate and organic layer was washed
with brine, dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo. Bulb-to-bulb distillation afforded
4.5. Lipase-catalyzed enantiomeric enhancement of 3a
To a solution of 3a (92.4% ee, 1.05 g, 3.43 mmol) in diiso-
propyl ether (12.3 mL) was added vinyl acetate (6.1 mL)
and lipase (Amano PS-C, 1.06 g), and stirred at room tem-
perature for 32.5 h. Then to the mixture was further added
Amano PS-C (527.7 mg) and stirring was continued at
room temperature. After stirring for 36 h, an additional
amount of Amano PS-C (530.7 mg) was added, and stirring
was further continued for 47 h, so that the total reaction time
reached 115.5 h. The mixture was passed through a pad of
Celite and the filtrate was concentrated in vacuo. The residue
was charged on a silica gel column (125 g), and eluted with

M. Matsuda et al. / Tetrahedron 63 (2007) 8752–8760
8757
(R)-4a (2.3 g, 98%) as a pale yellow oil. This was over
99.9% ee, judged by the HPLC analysis of 4d as described
above.
was washed with brine, dried over anhydrous sodium sulfate,
and concentrated in vacuo. The residue was charged on a sil-
ica gel column (18 g), and eluted with hexane–ethyl acetate
(15:1 to 10:1) to afford (R)-17 (283.5 mg, 87%) as a pale yel-
low oil; [a]2D2.7 ꢁ9.52 (c 1.35, CHCl3); 1H NMR d: 0.23 (s,
9H), 1.25 (d, J¼6.3 Hz, 3H), 2.62 (dd, J¼5.4, 15.9 Hz,
1H), 2.91 (dd, J¼7.5, 15.9 Hz, 1H), 3.79 (s, 3H), 4.12
(ddq, J¼5.4, 7.5, 6.3 Hz, 1H), 4.43 (d, J¼11.0 Hz, 1H),
4.50 (d, J¼11.0 Hz, 1H), 6.86 (d, J¼8.3 Hz, 2H), 7.25 (d,
J¼8.8 Hz, 2H); 13C NMR d: ꢁ0.7, 19.9, 52.4, 55.3, 70.6,
71.0, 98.1, 102.1, 113.7, 129.2, 130.4, 159.0, 185.4; IR
nmax 2964, 2933, 2902, 2837, 1678, 1614, 1514, 1464,
1375, 1338, 1302, 1250, 1174, 1128, 1066, 866, 847,
762 cmꢁ1. Anal. Calcd for C17H24O3Si: C 67.06, H 7.95.
Found: C 67.42, H 7.98.
4.6.3. (R)-1,1-Dimethoxy-3-[(4-methoxybenzyl)oxy]bu-
tane 4c. To a dispersion of sodium hydride (55% in paraffin,
240 mg, 5.5 mmol) in anhydrous N,N-dimethylformamide
(DMF, 3.5 mL) was added dropwise a solution of 4a
(399 mg, 3.0 mmol) in anhydrous DMF (0.7 mL). The mix-
ture was stirred at room temperature for 20 min, and 4-
methoxybenzyl chloride (564 mg, 3.6 mmol) was added
dropwise. After stirring at room temperature overnight, the
reaction was quenched by addition of water (5 mL). The
mixture was extracted with ethyl acetate. The organic layer
was washed with brine, dried over anhydrous sodium sulfate,
and concentrated in vacuo. The residue was charged on a sil-
ica gel column (38 g), and eluted with hexane–ethyl acetate
(4:1 to 3:1) to afford 4c (748.5 mg, 99%) as a pale yellow oil;
4.7. Total synthesis of modiolide A (1a)
1
[a]2D0.0 ꢁ50.7 (c 0.975, CHCl3); H NMR (Jeol JNM-270,
4.7.1. (S)-3-[(tert-Butyldimethylsilyl)oxy]-6-[(4-methoxy-
benzyl)oxy]-1-hexyne 7b. To a solution of 3a (100% ee,
934.0 mg, 3.05 mmol) in methanol (30.5 mL) was added po-
tassium carbonate (425.9 mg, 3.08 mmol) and the mixture
was stirred at 0 ꢀC for 5 h. Then the mixture was poured
into 35 mL of saturated aqueous ammonium chloride solu-
tion and concentrated in vacuo. The mixture was extracted
with ethyl acetate and organic layer was washed with brine,
dried over anhydrous sodium sulfate, filtered and concen-
trated in vacuo. The residue was charged on a silica gel col-
umn (50 g) and eluted with hexane–ethyl acetate (1:1) to
afford 7a (704.9 mg, 99%) as a pale yellow oil; [a]D22.9
270 MHz, CDCl3) d: 1.21 (d, J¼6.1 Hz, 3H), 1.70 (ddd,
J¼4.4, 7.5, 14.0 Hz, 1H), 1.87 (ddd, J¼4.4, 8.5, 14.0 Hz,
1H), 3.29 (s, 3H), 3.30 (s, 3H), 3.64 (m, 1H), 3.80 (s, 3H),
4.36 (d, J¼11.0 Hz, 1H), 4.51 (d, J¼11.0 Hz, 1H), 4.54
(dd, J¼4.4, 7.5 Hz, 1H), 6.87 (d, J¼8.6 Hz, 2H), 7.26 (d,
J¼8.8 Hz, 2H); 13C NMR d: 19.8, 40.1, 52.6, 53.2, 55.2,
70.1, 71.2, 102.2, 113.7, 129.2, 130.9, 159.0; IR nmax
2933, 2834, 2061, 1613, 1586, 1514, 1465, 1375, 1347,
1302, 1249, 1173, 1122, 1054, 960, 910, 872, 822, 754,
708 cmꢁ1. Anal. Calcd for C14H22O4: C 66.12, H 8.72.
Found: C 66.17, H 8.58.
1
ꢁ3.6 (c 1.52, EtOH); H NMR d: 1.74–1.95 (m, 4H), 2.46
4.6.4. (R)-3-[(4-Methoxybenzyl)oxy]butanal 18a. Acetal
4c (555.3 mg, 2.18 mmol) was stirred in 20 mL of a mixed
solvent of acetic acid and water (1:1) at room temperature
overnight. To the resulting solution was added dropwise
a cooled aqueous sodium hydrogen carbonate solution.
The mixture was extracted with ethyl acetate. The organic
layer was washed with brine, dried over anhydrous sodium
sulfate, and concentrated in vacuo. The residue was charged
on a silica gel column (25 g), and eluted with hexane–ethyl
acetate (3:1) to afford 18a (427.1 mg, 94%) as a pale yellow
(d, J¼2.0 Hz, 1H), 3.52 (m, 2H), 3.81 (s, 3H), 4.42 (ddd,
J¼2.0, 5.9, 5.9 Hz, 1H), 4.45 (d, J¼11.5 Hz, 1H), 4.49 (d,
J¼11.5 Hz, 1H), 6.89 (d, J¼8.8 Hz, 2H), 7.27 (d, J¼
8.8 Hz, 2H); 13C NMR d: 25.4, 35.2, 55.3, 61.8, 69.7,
72.6, 84.9, 113.7, 129.3, 129.9, 159.1; IR nmax 3396, 3288,
2955, 2932, 2863, 1612, 1586, 1514, 1456, 1361, 1248,
1175, 1033, 821, 638 cmꢁ1. Anal. Calcd for C14H18O3: C
71.77, H 7.74. Found: C 71.55, H 7.77.
To a solution of 7a (597.4 mg, 2.55 mmol) in N,N-dimethyl-
formamide (DMF, 7.3 mL) was added imidazole (349.5 mg,
5.13 mmol) and tert-butyldimethylsilyl chloride (TBSCl,
469.2 mg, 3.11 mmol). After stirring at room temperature
overnight, the reaction was quenched by addition of water
(20 mL). The mixture was extracted with ethyl acetate.
The organic layer was washed with brine, dried over anhy-
drous sodium sulfate, and concentrated in vacuo. The residue
was charged on a silica gel column (75 g), and eluted with
hexane–ethyl acetate (8:1) to afford 7b (887.9 mg, quantita-
tive) as a pale yellow oil; [a]2D6.4 ꢁ27.3 (c 1.76, EtOH); 1H
NMR d: 0.10 (s, 3H), 0.14 (s, 3H), 0.90 (s, 9H), 1.76 (m,
4H), 2.38 (d, J¼2.0 Hz, 1H), 3.48 (m, 2H), 3.81 (s, 3H),
4.38 (ddd, J¼2.0, 5.6, 5.6 Hz, 1H), 4.44 (s, 2H), 6.88 (d,
J¼8.8 Hz, 2H), 7.27 (d, J¼8.8 Hz, 2H); 13C NMR d:
ꢁ5.0, ꢁ4.5, 18.2, 25.5, 25.8, 35.3, 55.3, 62.5, 69.7, 72.1,
72.4, 85.4, 113.7, 129.1, 130.6, 159.0; IR nmax 3307, 2954,
2857, 1613, 1514, 1464, 1361, 1302, 1249, 1173, 1096,
1038, 1005, 838, 778, 666 cmꢁ1. Anal. Calcd for
C20H32O3Si: C 68.92, H 9.25. Found: C 68.57, H 9.10.
1
oil; [a]1D9.0 ꢁ40.2 (c 0.975, CHCl3); H NMR d: 1.28 (d,
J¼6.1 Hz, 3H), 2.50 (ddd, J¼2.2, 5.0, 16.0 Hz, 1H), 2.68
(ddd, J¼2.2, 7.4, 16.0 Hz, 1H), 3.80 (s, 3H), 4.06 (m, 1H),
4.41 (d, J¼11.0 Hz, 1H), 4.54 (d, J¼11.0 Hz, 1H), 6.87 (d,
J¼8.8 Hz, 2H), 7.24 (d, J¼8.8 Hz, 2H), 9.77 (t, J¼2.2 Hz,
1H); 13C NMR d: 19.7, 50.4, 55.2, 69.8, 70.2, 113.8,
129.2, 130.2, 159.2, 201.5; IR nmax 2971, 2934, 2905,
2837, 2727, 2547, 2058, 1887, 1724, 1613, 1586, 1514,
1465, 1377, 1338, 1302, 1248, 1174, 1110, 1035, 954,
822, 756, 708 cmꢁ1; Anal. Calcd for C12H16O3: C 69.21,
H 7.74. Found: C 69.00, H 7.68. Its NMR spectra were iden-
tical with that reported previously.24
4.6.5. (R)-5-[(4-Methoxybenzyl)oxy]-1-trimethylsilyl-1-
hexyn-3-one 17. To a solution of (3RS,5R)-15 [328.7 mg,
1.07 mmol, prepared from (R)-18a according to the previous
report24] in dichloromethane (11.9 mL) was added Dess–
Martin periodinane (687.3 mg, 1.62 mmol) at 0 ꢀC. The re-
sulting mixture was stirred at 0 ꢀC for 4 h, and quenched
with a mixture of saturated aqueous sodium thiosulfate
and sodium hydrogen carbonate solution (3:1). The reaction
mixture was extracted with chloroform. The organic layer
4.7.2. (1E,3S)-3-[(tert-Butyldimethylsilyl)oxy]-1-iodo-6-
[(4-methoxybenzyl)oxy]-1-hexene 8a. To a stirred solution

8758
M. Matsuda et al. / Tetrahedron 63 (2007) 8752–8760
of 7b (887.9 mg, 2.55 mmol) in anhydrous benzene
(50.9 mL) under an argon atmosphere were added tri-n-
butylstannyl hydride (279.0 mg, 1.08 mmol) and azobisiso-
butyronitrile (AIBN, 16.5 mg, 0.10 mmol). The reaction
mixture was refluxed for 12 h and then concentrated in
vacuo. The residue was charged on a silica gel column
(200 g) and eluted with hexane–ethyl acetate (30:1 to
20:1) to afford an alkenylstannane (1.21 g, 74%) as a pale
yellow oil. This was dissolved in dichloromethane
(18.9 mL), and to this was added iodine (482.9 mg,
1.90 mmol) at 0 ꢀC. After the mixture was stirred at 0 ꢀC
for 30 min, the reaction was quenched by addition of satu-
rated aqueous sodium thiosulfate solution. The mixture
was extracted with chloroform. The organic layer was
washed with brine, dried over anhydrous sodium sulfate,
and concentrated in vacuo. The residue was charged on a
silica gel column (100 g) and eluted with hexane–ethyl
acetate (30:1) to afford 8a (937.2 mg, quantitative) as
solution and brine, dried over anhydrous sodium sulfate,
and concentrated in vacuo. The residue was charged on a sil-
ica gel column (20 g) and eluted with hexane–ethyl acetate
(16:1 to 8:1) to afford an aldehyde (204.3 mg, 95%) as
a pale yellow oil.
This was dissolved in a mixture of tert-butyl alcohol and
water [3.3:5 (v/v), 7.3 mL], and to the solution were added
2-methyl-2-butene (970.2 mg, 13.8 mmol) and sodium
dihydrogen phosphate (557.4 mg, 4.65 mmol) at room tem-
perature. Then sodium chlorite (653 mg, ca. 80% purity,
5.77 mmol) was added and the mixture was stirred at room
temperature overnight. The reaction was quenched by addi-
tion of saturated aqueous ammonium chloride solution
(10 mL) and the mixture was extracted with diethyl ether.
The organic layer was washed with brine, dried over anhy-
drous sodium sulfate, and concentrated invacuo. The residue
was charged on a silica gel column (15 g) and eluted with
hexane–ethyl acetate (2: 1) to afford 9 (214.2 mg, quantita-
tive) as a pale yellow oil; [a]2D4.7 ꢁ30.8 (c 1.11, EtOH); 1H
NMR d: 0.03 (s, 3H), 0.05 (s, 3H), 0.88 (s, 9H), 1.75–1.97
(m, 2H), 2.34–2.48 (m, 2H), 4.20 (dt, J¼5.9, 5.4 Hz, 1H),
6.27 (d, J¼14.4 Hz, 1H), 6.49 (dd, J¼5.9, 14.4 Hz, 1H);
13C NMR d: ꢁ4.9, ꢁ4.5, 18.2, 25.8, 29.0, 31.8, 73.7, 76.7,
147.9, 179.5; IR nmax 3045, 2954, 2929, 2895, 2857, 2674,
1710, 1607, 1471, 1463, 1414, 1362, 1256, 1102, 946,
837, 777 cmꢁ1. Anal. Calcd for C12H23IO3Si: C 38.92, H
6.26. Found: C 38.86, H 6.34.
1
a pale yellow oil; [a]2D3.4 ꢁ16.3 (c 1.60, EtOH); H NMR
d: 0.02 (s, 3H), 0.03 (s, 3H), 0.88 (s, 9H), 1.53–1.67
(m, 4H), 3.43 (t, J¼6.1 Hz, 1H), 3.81 (s, 3H), 4.10 (dt,
J¼6.1, 4.9 Hz, 1H), 4.42 (s, 2H), 6.19 (d, J¼14.3 Hz, 1H),
6.50 (dd, J¼6.1, 14.3 Hz, 1H), 6.88 (d, J¼8.3 Hz, 2H),
7.25 (d, J¼8.3 Hz, 2H); 13C NMR d: ꢁ4.8, ꢁ4.5, 18.2,
25.2, 25.9, 34.1, 55.3, 69.8, 72.5, 74.9, 75.8, 113.7, 129.2,
130.5, 148.9, 159.0; IR nmax 2952, 2929, 2855, 1611,
1463, 1361, 1249, 1361, 1096, 1038, 836, 776 cmꢁ1. Anal.
Calcd for C20H33IO3Si: C 50.42, H 6.98. Found: C 50.52,
H 7.05.
4.7.5. (4S,5E,10R)-30,30-Dimethoxy-1-methylpropyl 4-
[(tert-butyldimethylsilyl)oxy]-6-iodo-5-hexenoate 11. To
4.7.3. (5E,4S)-4-[(tert-Butyldimethylsilyl)oxy]-6-iodo-5-
hexen-1-ol 8b. To a stirred solution of 8a (291.1 mg,
0.611 mmol) in dichloromethane (5.8 mL) were added water
(0.29 mL) and DDQ (166.6 mg, 0.734 mmol) at 0 ꢀC. After
stirring at 0 ꢀC for 3 h, the reaction was quenched by addi-
tion of saturated aqueous sodium hydrogen carbonate solu-
tion. The mixture was extracted with chloroform. The
organic layer was washed with brine, dried over anhydrous
sodium sulfate, and concentrated in vacuo. The residue
was charged on a silica gel column (25 g) and eluted with
toluene–ethyl acetate (12:1) to afford 8b (210.6 mg, 97%)
as a pale yellow oil; [a]2D4.8 ꢁ33.4 (c 1.49, EtOH); 1H
NMR d: 0.04 (s, 3H), 0.05 (s, 3H), 0.89 (s, 9H), 1.53–1.65
(m, 4H), 1.75 (s, 1H), 3.59–3.66 (m, 2H), 4.17 (dt, J¼6.1,
5.1 Hz, 1H), 6.22 (d, J¼14.3 Hz, 1H), 6.52 (dd, J¼6.1,
14.3 Hz, 1H); 13C NMR d: ꢁ4.8, ꢁ4.5, 18.2, 25.8, 27.9,
33.9, 62.8, 74.8, 76.0, 148.6; IR nmax 3330, 2952, 2929,
2857, 1607, 1471, 1361, 1255, 1096, 1062, 944, 837,
776 cmꢁ1. Anal. Calcd for C12H25IO2Si: C 40.45, H 7.07.
Found: C 40.63, H 7.15.
a
mixture of 9 (549.8 mg, 1.485 mmol) and Et3N
(165.3 mg, 1.633 mmol) in THF (26.5 mL) was added
2,4,6-trichlorobenzoyl chloride (398.3 mg, 1.633 mmol).
The mixture was stirred at room temperature for 5 h. The
white precipitate was removed by filtration with a sintered
glass funnel under N2, and the precipitate was washed with
dry THF. The combined filtrate and washings were concen-
trated in vacuo by a stream of Ar. The residue was diluted
with dry benzene (36.9 mL). To this mixture were added
alcohol (R)-4a (265.4 mg, 1.978 mmol) and DMAP
(390.0 mg, 3.192 mmol) in dry benzene (16.1 mL). The re-
action mixture was stirred at room temperature for 8.5 h.
Then the reaction was quenched by addition of saturated
aqueous sodium hydrogen carbonate solution (50 mL). The
mixture was extracted with ethyl acetate. The organic layer
was washed with brine, dried over anhydrous sodium sulfate,
and concentrated in vacuo. The residue was charged on a sil-
ica gel column (75 g) and eluted with hexane–ethyl acetate
(5:1) to afford 11 (720.3 mg, quantitative) as a pale yellow
oil; [a]2D2.6 ꢁ34.3 (c 1.49, EtOH); 1H NMR d: 0.03 (s, 3H),
0.04 (s, 3H), 0.88 (s, 9H), 1.24 (d, J¼6.4 Hz, 3H), 1.78
(ddd, J¼4.8, 5.0, 14.3 Hz, 1H; dd, J¼5.5, 7.7 Hz, 2H),
1.92 (ddd, J¼4.7, 7.8, 14.3 Hz, 1H), 2.31 (t, J¼7.7 Hz,
1H), 2.32 (t, J¼7.7 Hz, 1H), 3.30 (s, 6H), 4.18 (ddt,
J¼1.0, 5.9, 5.5 Hz, 1H), 4.42 (dd, J¼4.7, 4.8 Hz, 1H),
5.00 (ddq, J¼7.8, 5.0, 6.4 Hz, 1H), 6.24 (dd, J¼1.0,
14.2 Hz, 1H), 6.49 (dd, J¼5.9, 14.2 Hz, 1H); 13C NMR d:
ꢁ4.9, ꢁ4.5, 18.2, 20.5, 25.8, 29.5, 32.2, 39.0, 52.4, 53.2,
67.9, 73.8, 76.4, 101.6, 148.2, 172.6; IR nmax 2955, 2930,
2857, 1732, 1607, 1463, 1362, 1256, 1185, 1096, 947,
838, 778 cmꢁ1. Anal. Calcd for C18H35IO5Si: C 44.44,
H 7.25. Found: C 44.59, H 7.34.
4.7.4. (4S,5E)-4-[(tert-Butyldimethylsilyl)oxy]-6-iodo-5-
hexenoic acid 9. To a stirred solution of 8b (215.6 mg,
0.605 mmol) in dichloromethane (5.1 mL) was added diiso-
propylethylamine (0.72 mL, 4.24 mmol) and the resulting
mixture was stirred at 0 ꢀC for 5 min. Then, dimethyl sulfox-
ide (0.43 mL, 6.51 mmol) was added and the mixture stirred
at 0 ꢀC for another 10 min. At this time, SO3–pyridine
(387.9 mg, 2.44 mmol) was added and the mixture stirred
at 0 ꢀC for 20 min. The reaction was quenched by addition
of water (10 mL) and the mixture was extracted with chloro-
form. The organic layer was washed with saturated aqueous
ammonium chloride solution, sodium hydrogen carbonate

M. Matsuda et al. / Tetrahedron 63 (2007) 8752–8760
8759
4.7.6. (4S,5E,7S,9R)-4-[(tert-Butyldimethylsilyl)oxy]-7-
hydroxy-9-methyl-5-nonen-9-olide 12a and its
(4S,7R,9R)-isomer. To a stirred solution of 11 (227.8 mg,
0.468 mmol) in acetone (35.5 mL) was added p-toluenesul-
fonic acid monohydrate (20.2 mg, 0.106 mmol). The reac-
tion mixture was stirred at room temperature for 3 h. Then
the mixture was poured into phosphate buffer solution
(0.5 M, pH 7.0, 30 mL) and concentrated in vacuo. The mix-
ture was extracted with chloroform and the organic layer was
washed with brine, dried over anhydrous sodium sulfate, and
concentrated in vacuo. The very unstable aldehyde 2 was
employed for the next step immediately without further
purification.
the reaction was quenched by addition of water (10 mL).
The mixture was extracted with Et2O. The organic layer
was washed with brine, dried over anhydrous sodium sulfate,
and concentrated in vacuo. The residue was charged on a sil-
ica gel column (10 g) and eluted with hexane–ethyl acetate
(10:1) to afford 12b (206.7 mg, 95%) as a colorless oil;
1
[a]2D6.2 +16.0 (c 1.88, EtOH); H NMR d: 0.02 (s, 6H),
0.04 (s, 6H), 0.85 (s, 9H), 0.86 (s, 9H), 1.19 (d, J¼6.3 Hz,
3H), 1.77 (m, 2H), 1.89 (m, 1H), 2.02 (m, 2H), 2.24 (m,
1H), 4.02 (m, 2H), 5.09 (ddq, J¼2.8, 9.9, 6.3 Hz, 1H),
5.30 (dd, J¼8.8, 15.6 Hz, 1H), 5.45 (dd, J¼9.3, 15.6 Hz,
1H); 13C NMR d: ꢁ4.67, ꢁ4.65, ꢁ4.4, ꢁ4.2, 18.2, 21.5,
25.8, 31.6, 35.6, 44.9, 67.5, 73.0, 75.3, 132.3, 135.1,
174.3; IR nmax 2959, 2930, 2857, 1731, 1472, 1362, 1252,
1162, 1113, 1082, 837, 776 cmꢁ1. Anal. Calcd for
C22H44O4Si2: C 61.63, H 10.34. Found: C 61.01, H 10.43.
To a stirred solution of chromium(II) chloride (696.9 mg,
5.67 mmol) and nickel(II) chloride (3.6 mg, 0.028 mmol) in
degassed DMF (78.9 mL) at 0 ꢀC was added the above-men-
tioned crude aldehyde in degassed DMF (14.8 mL) via a can-
nula. The reaction mixture was gradually warmed to room
temperature and stirred for 11 h. Then the mixture was con-
centrated in vacuo and poured into water (50 mL). The mix-
ture was extracted with diethyl ether. The organic layer was
washed with brine, dried over anhydrous sodium sulfate,
andconcentratedinvacuo. Theresiduewaschargedonasilica
gel column (15 g) and eluted with hexane–ethyl acetate (3:1).
Some contaminated fractions were further purified with
preparative TLC with hexane–ethyl acetate (3:1, developed
twice). Pure (4S,7S,9R)-12a (77.0 mg, 52%) and (4S,7R,9R)-
12a (13.3 mg, 9%) were totally obtained through the above-
mentioned column chromatography and preparative TLC.
These were recrystallized from diethyl ether–hexane to give
analytical samples as colorless needles, respectively.
4.7.8. (2Z,4S,5E,7S,9R)-4,7-Bis[(tert-butyldimethylsilyl)-
oxy]-9-methyl-2,5-nonadien-9-olide 1b. To a solution of
diisopropylamine (113.5 mg, 1.11 mmol) in dry THF
(2.6 mL) was added dropwise n-BuLi (2.46 M in hexane,
0.411 mL, 1.01 mmol) at 0 ꢀC. After stirring at 0 ꢀC for
30 min, the mixture was cooled to ꢁ78 ꢀC. Then a solution
of 12b (206.7 mg, 0.482 mmol) in dry THF (9.7 mL) was
added to the cooled reaction mixture. After stirring at
ꢁ78 ꢀC for 1 h, a solution of phenylselenenyl chloride
(206.0 mg, 1.08 mmol) and hexamethylphosphoric triamide
(HMPA, 129.6 mg, 0.723 mmol) in dry THF (6.5 mL) were
added dropwise. The reaction mixture was stirred at ꢁ78 ꢀC
for 45 min, then further at ꢁ40 ꢀC for 45 min. Then the reac-
tion was quenched by addition of saturated aqueous ammo-
nium chloride solution (20 mL). The mixture was extracted
with ethyl acetate. The organic layer was washed with brine,
dried over anhydrous sodium sulfate, and concentrated in
vacuo. The residue was charged on a silica gel column (30 g)
and eluted with toluene–ethyl acetate (100:1) to afford a-phe-
nylselenylated lactone 14 (209.6 mg, 75%) as colorless solid.
(4S,7S,9R)-12a: Rf¼0.40 (hexane–ethyl acetate¼3:1, devel-
oped twice). Mp 64.5–65.5 ꢀC; [a]D24.5 +28.2 (c 1.49, EtOH);
1H NMR d: 0.02 (s, 3H), 0.04 (s, 3H), 0.86 (s, 9H), 1.21 (d,
J¼6.4 Hz, 3H), 1.75 (ddd, J¼11.0, 11.2, 13.9 Hz, 1H), 1.92
(m, 2H), 2.05 (m, 2H), 2.25 (m, 1H), 4.06 (m, 2H), 5.14 (ddq,
J¼1.5, 11.2, 6.4 Hz, 1H), 5.42 (dd, J¼8.3, 15.6 Hz, 1H),
5.49 (dd, J¼8.8, 15.6 Hz, 1H); 13C NMR d: ꢁ4.6, ꢁ4.2,
18.2, 21.4, 25.8, 31.5, 35.6, 43.4, 67.4, 72.3, 75.2, 133.8,
134.5, 174.2; IR nmax 3469, 2954, 2930, 2857, 1728, 1365,
To a solution of above 14 (209.6 mg, 0.359 mmol) in dry
THF (3.8 mL) were added sodium hydrogen carbonate
(86.6 mg, 1.03 mmol) and aqueous hydrogen peroxide solu-
tion (30%, 0.132 mL, 1.29 mmol) at 0 ꢀC. The reaction mix-
ture was gradually warmed to room temperature and stirred
for 16 h. Then the reaction mixture was refluxed for 42 h,
and the reaction was quenched by addition of saturated aque-
ous sodium hydrogen carbonate solution (10 mL). The mix-
ture was extracted with ethyl acetate. The organic layer was
washed with brine, dried over anhydrous sodium sulfate, and
concentrated in vacuo. The residue was charged on a silica
gel column (15 g) and eluted with hexane–ethyl acetate
(10:1) and some contaminated fractions were further puri-
fied with preparative TLC with hexane–ethyl acetate
(10:1). Bis-TBS ether 1b (115.3 mg, 75%) was totally
obtained through the above-mentioned column chromato-
graphy and preparative TLC as colorless solid. Mp 49.5–
1336, 1249, 1158, 1119, 994, 978, 892, 837, 776 cmꢁ1
.
Anal. Calcd for C16H30O4Si: C 61.11, H 9.61. Found: C
60.89, H 9.41.
(4S,7R,9R)-12a: Rf¼0.47 (hexane–ethyl acetate¼3:1, devel-
oped twice). Mp 95–96 ꢀC; [a]2D4.4 ꢁ13.6 (c 1.02, EtOH); 1H
NMR d: 0.01 (s, 3H), 0.03 (s, 3H), 0.86 (s, 9H), 1.21 (d, J¼
6.4 Hz, 3H), 1.77 (ddd, J¼2.2, 11.0, 14.6 Hz, 1H), 1.87 (m,
1H; ddd, J¼2.1, 5.1, 14.6 Hz, 1H), 1.94–2.11 (m, 2H), 2.25
(m, 1H), 4.06 (ddd, J¼4.2, 8.6, 9.5 Hz, 1H), 4.45 (ddd, J¼
1.8, 2.2, 5.1 Hz, 1H), 5.38 (ddq, J¼2.1, 11.0, 6.4 Hz, 1H),
5.45 (dd, J¼8.6, 16.1 Hz, 1H), 5.65 (dd, J¼1.8, 16.1 Hz,
1H); 13C NMR d: ꢁ4.6, ꢁ4.2, 18.2, 21.1, 25.9, 31.8, 35.1,
42.4, 64.7, 67.6, 75.5, 129.5, 132.8, 175.2. Anal. Calcd for
C16H30O4Si: C 61.11, H 9.61. Found: C 60.95, H 9.50.
1
51.0 ꢀC; [a]2D2.9 +35.1 (c 1.22, EtOH); H NMR d: 0.03 (s,
3H), 0.05 (s, 6H), 0.07 (s, 3H), 0.87 (s, 18H), 1.23 (d,
J¼6.3 Hz, 3H), 1.77 (ddd, J¼3.6, 4.4, 14.2 Hz, 1H), 1.83
(ddd, J¼9.0, 9.5, 14.2 Hz, 1H), 4.18 (ddd, J¼4.4, 8.3,
9.0 Hz, 1H), 4.73 (dd, J¼2.0, 7.8 Hz, 1H), 5.28 (ddq,
J¼3.6, 9.5, 6.3 Hz, 1H), 5.54 (dd, J¼8.3, 16.1 Hz, 1H),
5.61 (dd, J¼7.8, 16.1 Hz, 1H), 5.74 (dd, J¼2.0, 12.7 Hz,
1H), 5.78 (d, J¼12.7 Hz, 1H); 13C NMR d: ꢁ4.73, ꢁ4.66,
4.7.7. (4S,5E,7S,9R)-4,7-Bis[(tert-butyldimethylsilyl)-
oxy]-9-methyl-5-nonen-9-olide 12b. To a solution of
12a (158.9 mg, 0.505 mmol) in DMF (1.4 mL) were added
imidazole (68.9 mg, 1.01 mmol) and TBSCl (92.1 mg,
0.611 mmol). After stirring at room temperature for 15 h,

8760
M. Matsuda et al. / Tetrahedron 63 (2007) 8752–8760
2. Pilli, R. A.; Victor, M. M. J. Braz. Chem. Soc. 2001, 12,
373–385.
3. Pilli, R. A.; Victor, M. M. Tetrahedron Lett. 2002, 43, 2815–
2818.
ꢁ4.3, ꢁ4.2, 18.2, 21.5, 25.8, 44.1, 68.6, 72.5, 72.7, 120.8,
129.5, 137.8, 168.1; IR nmax 2959, 2930, 2887, 2857,
1723, 1472, 1389, 1253, 1212, 1107, 1079, 1006, 978,
954, 887, 861, 836, 777, 670 cmꢁ1. Anal. Calcd for
C22H42O4Si2: C 61.92, H 9.92. Found: C 61.51, H 9.80.
4. F€urstner, A. Chem. Rev. 1999, 99, 991–1045.
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Sugai, T. Synth. Commun. 2000, 30, 3061–3072.
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8. Midland, M. M.; Tramontano, A.; Kazubski, A.; Richard, S.;
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1984, 40, 1371–1380.
4.7.9. (2Z,4S,5E,7S,9R)-4,7-Dihydroxy-9-methyl-2,5-non-
adien-9-olide [(D)-modiolide A] 1a. In a polypropylene-
made vessel, bis-TBS ether 1b (120.1 mg, 0.2814 mmol)
was dissolved in dry THF (0.10 mL) and pyridine
(0.01 mL) and treated with a stock solution of HF–pyri-
dine–THF22 (1.28 M, 1.77 mL, 2.27 mmol) at room temper-
ature for 27 h. At the intervals of 25.5 h, the above-
mentioned HF–pyridine–THF solution (1.0 mL, 1.28 mmol)
was added twice and the stirring was continued totally for
82.5 h. The workup as above and the purification by prepar-
ative TLC, which was developed with ethyl acetate, afforded
1a (50.8 mg, 91%). This was recrystallized from ethyl ace-
tate–diethyl ether to give an analytical sample as colorless
needles. Mp 187–188 ꢀC [lit.23 189–191 ꢀC; [a]2D1.8 +34.7
(c 0.250, MeOH) [lit.1 [a]D18 +42 (c 0.25, MeOH)]; 1H
NMR (400 MHz, CD3OD) d: 1.22 (d, J¼6.4 Hz, 3H), 1.71
(ddd, J¼11.2, 11.2, 14.0 Hz, 1H), 1.87 (ddd, J¼1.8, 3.5,
14.0 Hz, 1H), 4.12 (ddd, J¼3.5, 8.5, 11.2 Hz, 1H), 4.68
(ddd, J¼1.5, 2.9, 7.6 Hz, 1H), 5.25 (ddq, J¼1.8, 11.2,
6.4 Hz, 1H), 5.55 (dd, J¼8.5, 15.9 Hz, 1H), 5.62 (dd,
J¼7.6, 15.9 Hz, 1H), 5.82 (dd, J¼2.9, 12.7 Hz, 1H), 5.87
(dd, J¼1.5, 12.7 Hz, 1H); 13C NMR (100 MHz, CD3OD)
d: 21.6, 44.0, 70.0, 72.2, 72.8, 122.8, 130.9, 137.7, 138.6,
170.0; IR nmax 3279, 2976, 2915, 2885, 1713, 1398, 1236,
1220, 1113, 1049, 1028, 947 cmꢁ1. Anal. Calcd for
C10H14O4: C 60.59, H 7.12. Found: C 60.43, H 7.13. Its
NMR spectra were in good accordance with those reported
for isolated natural product.1
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The authors thank Professor Jun-ichi Kobayashi of Hok-
kaido University for information on modiolide A, Professor
Masatoshi Asami of Yokohama National University and Pro-
fessor Keisuke Suzuki of Tokyo Institute of Technology for
their valuable suggestions on the addition of TMS acetylide.
Amano Enzyme Inc. is acknowledged with thanks for the
gift of lipase PS-C. This work was supported both by
a Grant-in-Aid for Scientific Research (no.18580106) and
‘High-Tech Research Center’ Project for Private Universi-
ties: matching fund subsidy 2006–2011 from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan, and acknowledged with thanks.
€
€
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