Synthetic studies on macrolactin A by using a (diene)Fe(CO)3 complex

Article abstract of DOI:10.1016/j.tet.2003.09.092

The stereoselective synthesis of the two segments 3 and 4 of macrolactin A 1 is described. Macrolactin A is a 24-membered polyene macrolide antibiotic, which is of interest due to a strong activity against B16-F10 murine tumor cell and HIV-1 virus. The ke

Full text of DOI:10.1016/j.tet.2003.09.092

Tetrahedron 59 (2003) 9305–9313
Synthetic studies on macrolactin A by using a
(diene)Fe(CO)3 complex
Akihiro Fukuda,a Yusuke Kobayashi,a Tetsutaro Kimachib and Yoshiji Takemotoa
,
*
aGraduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
bFaculty of Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 Koshien Kyuban-cho, Nishinomiya 663-8179, Japan
Received 11 September 2003; revised 30 September 2003; accepted 30 September 2003
Abstract—The stereoselective synthesis of the two segments 3 and 4 of macrolactin A 1 is described. Macrolactin A is a 24-membered
polyene macrolide antibiotic, which is of interest due to a strong activity against B16–F10 murine tumor cell and HIV-1 virus. The key step
of the synthesis is the 1,2-migration reaction of a (diene)Fe(CO)3 complex with a introduction of the thiol group to construct the unstable
(E,Z)-conjugated dienic moiety (C8–C11).
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Macrolactin A 1 was isolated from a deep sea marine
bacterium in 1989 as a 24-membered polyene macrolide
antibiotic.1 This compound possesses three sets of (E,E) and
(E,Z) conjugated dienes and four stereogenic centers in the
molecule, and exhibits a broad spectrum of activity with
significant antiviral and cancer cell cytotoxic properties
including inhibition of B16–F10 murine melanoma cell
replication.2,3 Because of unreliable supply from cell culture
as well as its structural uniqueness and broad therapeutic
potential, macrolactin A has been an attractive target for
asymmetric synthesis. Although, thus far, three total
synthesis4 and novel synthetic studies5 have been
developed, systematic examination of the structure–activity
relationship of macrolactins such as 1 and 2 have not yet
been carried out to reveal the mechanism of their biological
activities. With an expectation of preparing macrolactin
A–M and other analogues, we have started to develop a
flexible synthetic strategy for synthesizing structural
analogues bearing the (8E,10E)- and (16E,18Z)-dienic
moieties (Scheme 1). We report herein a novel synthetic
strategy of key subunit 3 for macrolactin A that utilize the
(diene)Fe(CO)3 complex as a mobile chiral auxiliary for
constructing C7–C13 fragment.
2. Results and discussion
The synthetic plan of total synthesis of macrolactin A
Scheme 1. Macrolactin A and its retrosynthetic analysis.
Keywords: macrolactin; iron–tricarbonyl complex; antibiotics; antivirus;
synthesis.
*
Corresponding author. Tel.: þ81-75-753-4528; fax: þ81-75-753-4569;
e-mail: takemoto@pharm.kyoto-u.ac.jp
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.092

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A. Fukuda et al. / Tetrahedron 59 (2003) 9305–9313
involves assembly of two fragments 3 and 4 by dia-
stereoselective alkenylation6 and macrolactonization7
(Scheme 1). The (diene)Fe(CO)3 complex in 3 plays a
central role in our strategy, serving not only as a chiral
auxiliary for constructing the two chiral centers (C7 and
C13), but also as a protecting group of the unstable (E,Z)-
conjugated dienic moiety (C8–C11).8 We have already
reported that treatment of (E,E)-cyanophosphate complex A
with Lewis acid such as BF3·etherate and LiClO4 in the
presence of a nucleophile gave the (E,Z)-nitrile complex D
as a major isomer via the intermediates B and C
(Scheme 2).9 In this way, the 1,2-migration reaction
provided the protected (E,Z)-dienic product stereo-
selectively. We anticipated that this compound 3 could be
prepared from meso-dialdehyde Fe(CO)3 complex 710 by
aldol condensation of achiral or chiral acetate (7!6), 1,2-
migration of the Fe(CO)3 complex along with a hydride
introduction (6!5), and subsequent diastereoselective
alkylation, followed by Pd-catalyzed cross-coupling
reaction (5!3). On the other hand, 4 could be derived
from enyne 8, which would be synthesized from aldehyde 9
in two steps, by hydrozirconation with Cp2ZrHCl and
subsequent transmetallation with dimethylzinc.6
Scheme 3. (a) AcOEt, LDA, 60% (6a/6b¼1/4); (b) TBSOTf, 95%; (c)
(EtO)2P(O)CN, LiCN; (d) NuH, Acid, Solvent (see Table 1).
several acidic catalysts and solvents in the presence of
4-fluorobenzenethiol, a weaker nucleophile than ethyl thiol
(Table 1). These results indicate that the solvent employed
have a significant effect on the ratio of the products
12b–15b. Although use of THF as a solvent gave
(alkenediyl)iron complex 13b as a major product, the
same reaction of 11 in CH2Cl2 at 2408C provided non-
migrated product 14b predominantly. In contrast, the
desired product 12b was obtained in moderate yield by
the same treatment of 11 in dioxane. Furthermore, employ-
ing HBF4 as an acid in dioxane at room temperature led to
the best yield of 12b together with the (E,E)-migrated
product 15b. We have no reasonable explanation of the
solvent effect that determined the predominant product at
this stage.
Table 1. 1,2-Migration of phosphate 11 in the presence of 4-fluorobenzene
thiol
Entry
Acid
Solvent
Yield (%)
Scheme 2. 1,2-Migration of phosphate A for synthesis of (E,Z)-diene
Fe(CO)3 complex D.
12
13
14
15
a
a
1
2
3
4
BF3·OEt2
BF3·OEt2
BF3·OEt2
HBF4
THF
CH2Cl2
1,4-Dioxane
1,4-Dioxane
10
18
27
46
35
a
–
46
–
–
–
a
Synthesis of the fragment 3 commenced from aldehyde 7.
Aldol condensation of 7 with the lithium enolate of ethyl
acetate gave the desired alcohol 6b in 60% yield as a major
product (6a/6b¼1/4) (Scheme 3). After protecting the
hydroxyl group of 6b (10, 95% yield), cyanophosphate 11
was obtained as a mixture of diastereoisomers by the usual
manner.11 Having the desired starting material at hand, we
first investigated the key 1,2-migration of 11 in the presence
of several hydride reagents such as triethylsilane and
sodium cyanoborohydride.12 Although we have tried the
reaction of 11 under various reaction conditions, unfortu-
nately, the aimed migration product could not be obtained at
all. Our focus was then directed to the 1,2-migration in the
presence of thiol as a nucleophile. Unexpectedly, subjection
of 11 to a typical 1,2-migration reaction (5 equiv. of EtSH
and 0.1 equiv. of BF3·Et2O in THF at room temperature)
only furnished the undesired (alkenediyl)iron complex
13a13 in 58% yield and we could not identified the desired
product 12a in the reaction mixture. We next examined
–
a
a
–
16
8
a
a
–
–
a
The product was not identified.
Having established the synthesis of the desired (E,Z)-dienyl
sulfide Fe(CO)3 complex 12b, we next investigated an
efficient introduction of the (2Z,4E)-hexadienoic acid
moiety into 12b (Scheme 4). This nitrile 12b was first
subjected to hydride-reduction using an excess of DIBAL-H
(16, 77% yield), and the desired acetate 17 was obtained in
98% yield after protection with acetic anhydride in pyridine.
Although we expected the subsequent Reformatsky reaction
of 17 proceeded diastereoselectively by utilizing the
chirality of the (diene)Fe(CO)3 moiety, the propargylation
of the resulting aldehyde 17 with propargyl bromide and
zinc in the presence of NH4Cl14 furnished secondary
alcohols 18a and 18b as a 1/1 mixture. Several experiments
with indium (0) and aluminum (0) could not improve the

A. Fukuda et al. / Tetrahedron 59 (2003) 9305–9313
9307
Table 2. Asymmetric methylation of aldehyde 9 in the presence of several
chiral ligands to synthesize 23
Entry
Ligand Me2Zn
(equiv.) (equiv.)
Ti(O-i-Pr)4
(equiv.)
Temperature Yield
(8C)
ee
(%)
(%)
1
2
3
E (0.06) 1.5
1.5
1.2
2.2
225
0
225
27
22
99
68
22
96
F (0.1)
G (0.2)
3.0
2.0
(Table 2). The reactions with bis-sulfonamide E18a and (S)-
BINOL F18b gave rise to the desired alcohol 23 in low to
moderate enantioselectivity. However, 23 was obtained in
99% yield with high enantioselectivity (96% ee) under
Seebach’s conditions [Me2Zn and Ti(O-i-Pr)4 in the
presence of (þ)-TADDOL G (20 mol%)].18c The resulting
alcohol 23 was protected as a TBS ether before removal of
the terminal PMB ether to furnish primary alcohol 24.
Oxidation of 24 to an aldehyde, followed by exposure to
Corey’s reagent,19 produced (E)-enyne 26 as a major
product [E/Z¼6/1]. After separation of undesired (Z)-
enyne by column chromatography, deprotection of the
TMS group in 26 gave the desired product 8.
Scheme 4. (a) DIBAL-H, 77%; (b) Ac2O, 98%; (c) propargyl bromide, Zn,
NH4Cl, 88% (12a/12b¼1/1); (d) TBSOTf, 50%; (e) pinacolborane, Rh
(CO)(PPh3)2Cl, 27%; (f) Ethyl (Z)-3-iodopropenate, Pd(PPh3)4, 10%
TIOH, 43% (21), 24% (22); (g) K2CO3, EtOH, 85%.
diastereoselectivity of 18a and 18b. Configuration of the
products 18a and 18b was elucidated by comparison of their
Rf values according to the literature.15 Fortunately, protec-
tion of a mixture of 18a and 18b with TBSOTf only gave the
desired product 19 in 50% yield along with recovery of
undesired diastereomer 18a. Hydroboration of 19 with
pinacolborane (27% yield),16 followed by Pd-catalyzed
cross-coupling reaction with ethyl (Z)-3-iodopropenoate,17
produced a mixture of acetate 21 and alcohol 22 in 46 and
20% yields, respectively. The acetate 21 was easily
transformed into 22 by the hydrolysis with K2CO3 in EtOH.
Finally, treatment of alcohol 22 with IBX20 gave rise to the
desired product 3 (Scheme 6). Therefore, we next examined
the coupling reaction of aldehyde 3 and enyne 8 using the
Wipf’s protocol6 [hydrozirconation and Me2Zn-mediated
nucleophilic addition]. Although the coupling reaction of 3
and 4 was carried out under various reaction conditions
(even in the presence of chiral amino alcohol as a promoter),
we could obtained no desired product 27 at all. To secure the
formation of alkenylzinc species 4 from 8, the reaction of 4
with benzaldehyde was conducted, giving the corresponding
alcohol 28 in 50% yield. From these results, the failure of
coupling of 3 with 4 seems to be attributed to the poor
reactivity of the aldehyde 3.
With the half building block now accessible, we undertook
the synthesis of the other fragment 8, which involved the
catalytic asymmetric methylation of 9 with dimethylzinc.
Synthesis of 8 began with PMB aldehyde 9 derived from
1,5-pentanediol in two steps (Scheme 5). The asymmetric
18
methylation of 9 with Me2Zn and Ti(O-i-Pr)4 was first
examined in the presence of several chiral ligands E–G
Scheme 6. (a) IBX; (b) Cp2Zr(H)Cl; Me2Zn; (c) benzaldehyde, 50%.
3. Conclusion
We have succeeded in the synthesis of (Z,E,E,Z)-tetraene
complex 22 by the 1,2-migration reaction of the Fe(CO)3
group and also chiral enyne 8 by the catalytic asymmetric
methylation with Me2Zn, while the final coupling reaction
Scheme 5. (a) Me2Zn Ti(O-i-Pr)4, (þ)-TADDOL, 99% (95% ee);
(b) TBSCI, imidazole, 93%; (c) DDQ; NaBH4, quant; (d) IBX, 76%;
(e) TMSCCCHvPPh3, 84%; (f) TBAF, 94%.

9308
A. Fukuda et al. / Tetrahedron 59 (2003) 9305–9313
of 3 and 8 has not yet been achieved. We are now
investigating alternative strategy for total synthesis of
macrolactin A.
(dd, 1H, J¼5.2, 8.2 Hz), 9.32 (d, 1H, J¼4.0 Hz); 13C NMR
(CDCl3) d: 14.1, 43.6, 54.4, 61.1, 68.2, 68.2, 81.4, 85.0,
172.0, 196.1; IR (CHCl3): 3539, 2065, 2004, 1717,
1678 cm21; MS (FAB) m/z 339 (MHþ, 37), 321 (8), 254
(96), 237 (100). Anal. calcd for C13H14FeO7: C, 46.18; H,
4.17. Found: C, 46.00; H, 4.18.
4. Experimental
4.1.2. Ethyl (3RS,4RS,4E,6E)-tricarbonyliron[(h4-4-7)-
3-(tert-butyldimethylsilyloxy)-7-formylhepta-4,6-dieno-
ate] (10). To a stirred solution of 6b (150 mg, 0.444 mmol)
in THF (14 ml) were successively added 2,6-lutidine
(0.16 ml, 1.33 mmol) and TBSOTf (tert-butyldimethylsilyl
trifluoromethanesulfonate) (0.15 ml, 0.666 mmol) at
2408C. The mixtures was stirred at 2408C for 1 h, before
being quenched with aqueous ammonium chloride solution.
The aqueous layer was extracted with AcOEt. The
combined organic layers were washed with brine, dried
over MgSO4, and concentrated in vacuo. The crude residue
was purified by column chromatography (SiO2, hexane/
4.1. General information
Melting points are uncorrected. IR spectra were obtained
using a JASCO FTIR-410 spectrometer. 1H NMR
(500 MHz) and 13C NMR (125.7 MHz) spectra were
obtained using a JEOL JNM-LA-500 spectrometer using
TMS as an internal standard. Optical rotations were
measured with a JASCO DIP-360 polarimeter. Nominal
(MS) and high-resolution (HRMS) mass spectra were
measured with a JEOL JMS-01SG-2 or JMS-HX/HX
110A mass spectrometer. Column chromatography was
carried out using Merck Kieselgel 60. Enantiomeric excess
was determined by chiral HPLC using a Shimadzu SPD-
10A with Daicel Chiralpak AD (0.46 cm£25 cm), Chiralpak
1
AcOEt¼10/1) to give 10 (190 mg, 95%). a yellow oil; H
NMR (CDCl3) d: 0.09 (s, 3H), 0.13 (s, 3H), 0.86 (s, 9H),
1.27 (t, 3H, J¼7.0 Hz), 1.40 (dd, 1H, J¼3.4, 7.9 Hz), 1.69
(dd, 1H, J¼8.2, 8.5 Hz), 2.61 (dd, 1H, J¼4.0, 15.0 Hz), 2.68
(dd, 1H, J¼7.6, 15.0 Hz), 3.97 (ddd, 1H, J¼4.0, 7.6,
8.5 Hz), 4.12–4.17 (m, 2H), 5.42 (dd, 1H, J¼5.2, 8.2 Hz),
5.83 (dd, 1H, J¼5.2, 7.9 Hz), 9.35 (d, 1H, J¼3.4 Hz); 13C
NMR (CDCl3) d: 24.6, 24.0, 14.1, 18.0, 25.6, 44.5, 55.2,
60.6, 66.7, 71.9, 82.2, 87.4, 170.2, 195.7; IR (CHCl3): 2956,
2858, 2065, 2007, 1731, 1679 cm21; MS (FAB) m/z 452
(Mþ, 82), 424 (96), 368 (53), 236 (81), 153 (100); HRMS
(FAB) m/z calcd for C19H28FeO7Si (Mþ) 452.0954. Found:
452.0956.
OD
(0.46 cm£25 cm),
or
Chiralpak
OD-H
(0.46 cm£25 cm). Dry solvents purchased from Kanto
Chemicals were used in all reactions.
4.1.1. Ethyl (3RS,4RS,4E,6E)-tricarbonyliron[(h4-4-7)-
7-formyl-3-hydroxyhepta-4,6-dienoate] (6b). A solution
of AcOEt (352 mg, 4.00 mmol) in 4.0 ml THF was added to
a LDA solution, which was prepared with n-BuLi (1.59 M
in hexane, 3.0 ml, 4.80 mmol) and i-Pr2NH (0.67 ml,
4.80 mmol) in THF (5.6 ml), at 2788C under an argon
atmosphere. After 30 min, the resulting solution was slowly
added to a stirred solution of 7 (1.00 g, 4.00 mmol) in THF
(25 ml) at 2788C. The mixture was stirred for 30 min at
2788C and a saturated NaHCO3 solution was added to the
whole mixture. The resulting mixture was allowed to warm
up to room temperature, and extracted with AcOEt. The
combined organic layers were washed with brine, dried over
MgSO4, and concentrated in vacuo. The crude residue was
purified by column chromatography (SiO2, hexane/
AcOEt¼2/1) to give 6a (201 mg, 15%) and 6b (812 mg,
60%).
4.1.3. Ethyl (3RS,4SR,5SR,5Z,7E)-tricarbonyliron[(h4-5-
8)-3-(tert-butyldimethylsilyloxy)-8-cyano-4-(4-fluoro-
phenysulphanyl)octa-5,7-dienoate] (12). To a stirred
solution of 10 (490 mg, 1.08 mmol) in THF (11 ml) were
added diethyl phosphorocyanidate (0.18 ml, 1.2 mmol) and
LiCN (11 mg, 0.32 mmol) at 08C under an argon
atmosphere. After 30 min, a saturated NaHCO3 solution
was added to the mixture, and the resulting mixture was
extracted with AcOEt. The extracts were washed with brine,
dried over MgSO4, and then concentrated in vacuo to give
11 (757 mg, 100%) as a crude product, which was used
without further purification for next reaction [entry 1 in
Table 1]. To a stirred solution of 11 (25 mg, 0.038 mmol) in
THF (0.38 ml) were added 4-fluorobenzenethiol (0.082 ml,
0.77 mmol) and BF3·OEt2 (0.010 ml, 0.079 mmol) at 08C
under an argon atmosphere. After 1 h, a saturated NaHCO3
solution was added to the reaction mixture, and the resulting
mixture was extracted with AcOEt. The extract was washed
with brine, dried over MgSO4, and concentrated in vacuo.
The crude residue was purified by column chromatography
(SiO2, hexane/AcOEt¼12/1) to give 12 (2.3 mg, 10%) and
13 (7.7 mg, 35%) [entry 2 in Table 1]. To a stirred solution
of 11 (25 mg, 0.038 mmol) in CH2Cl2 (0.38 ml) were added
4-fluorobenzenethiol (0.082 ml, 0.77 mmol) and BF3·OEt2
(0.010 ml, 0.079 mmol) at 2408C under an argon
atmosphere. After 1 h, a saturated NaHCO3 solution was
added to the reaction mixture, and the resulting mixture was
extracted with AcOEt. The extract was washed with brine,
dried over MgSO4, and concentrated in vacuo. The crude
residue was purified by column chromatography (SiO2,
Compound 6b. Yellow crystals: mp 151.5–1528C (AcOEt);
1
Rf¼0.50 (hexane/AcOEt¼1/1); H NMR (CDCl3) d: 1.30
(dd, 1H, J¼4.0, 7.6 Hz), 1.30 (t, 3H, J¼7.0 Hz), 1.50 (dd,
1H, J¼7.0, 8.5 Hz), 2.59 (dd, 1H, J¼8.5, 16.8 Hz), 2.71 (dd,
1H, J¼3.1, 16.8 Hz), 3.50 (d, 1H, J¼4.3 Hz), 4.00 (dddd,
1H J¼3.1, 4.3, 7.0, 8.5 Hz), 4.21 (q, 2H, J¼7.0 Hz), 5.65
(dd, 1H, J¼5.2, 8.5 Hz), 5.86 (dd, 1H, J¼5.2, 7.6 Hz), 9.33
(d, 1H, J¼4.0 Hz); 13C NMR (CDCl3) d: 14.2, 42.3, 54.9,
61.2, 65.2, 69.1, 82.5, 86.3, 172.3, 196.1; IR (CHCl3): 3528,
2065, 2006, 1716, 1680 cm21; MS (FAB) m/z 339 (MHþ,
37), 321 (40), 283 (21), 254 (90), 237 (95), 154 (100). Anal.
calcd for C13H14FeO7: C, 46.18; H, 4.17. Found: C, 46.24;
H, 4.26.
Compound 6a. Yellow crystals: mp 68–698C (CHCl3/
hexane); Rf¼0.40 (hexane/AcOEt¼1/1); 1H NMR (CDCl3)
d: 1.22 (dd, 1H, J¼4.0, 8.2 Hz), 1.30 (t, 3H, J¼7.0 Hz), 1.52
(dd, 1H, J¼5.8, 8.9 Hz), 2.53 (dd, 1H, J¼9.5, 16.8 Hz), 2.69
(dd, 1H, J¼3.1, 16.8 Hz), 3.31 (s, 1H), 4.18–4.23 (m, 1H),
4.20 (t, 2H, J¼7.0 Hz), 5.58 (dd, 1H, J¼5.2, 8.9 Hz), 5.83

A. Fukuda et al. / Tetrahedron 59 (2003) 9305–9313
9309
hexane/AcOEt¼12:1) to give 12 (4.0 mg, 18%) and 14
(8.4 mg, 46%, 2/1 diastereomixture) [entry 3 in Table 1]. To
a stirred solution of 11 (18 mg, 0.028 mmol) in 1,4-dioxane
(0.28 ml) were added 4-fluorobenzenethiol (0.061 ml,
0.57 mmol) and BF3·OEt2 (0.010 ml, 0.079 mmol) at room
temperature under an argon atmosphere. After 1 h, another
BF3·OEt2 (0.010 ml, 0.079 mmol) was added to the reaction
mixture at room temperature. After 1 h, a saturated NaHCO3
solution was added to the reaction mixture, and the resulting
mixture was extracted with AcOEt. The extract was washed
with brine, dried over MgSO4, and concentrated in vacuo.
The crude residue was purified by column chromatography
(SiO2, hexane/AcOEt¼12/1) to give 12 (4.5 mg, 27%) and
15 (2.7 mg, 16%) [entry 4 in Table 1]. To a stirred solution
of 11 (88.0 mg, 0.132 mmol) in 1,4-dioxane (1.3 ml) were
added 4-fluorobenzenethiol (0.14 ml, 1.3 mmol) and HBF4
(54% ether solution, 0.022 ml, 0.16 mmol) at 208C under an
argon atmosphere. After 1 h, a saturated NaHCO3 solution
was added to the reaction mixture, and the resulting mixture
was extracted with AcOEt. The extract was washed with
brine, dried over MgSO4, and concentrated in vacuo. The
crude residue was purified by column chromatography
(SiO2, hexane/AcOEt¼12/1) to give 12 (35.8 mg, 46%) and
15 (6.2 mg, 8%).
isomer: 0.94 (dd, 1H, J¼7.0, 7.9 Hz), 1.17 (dd, 1H, J¼8.9,
10.1 Hz), 1.31 (t, 3H, J¼7.0 Hz), 2.59–2.64 (m, 1H), 2.71–
2.75 (m, 1H), 3.09–3.15 (m, 1H), 3.64 (d, 1H, J¼7.0 Hz),
4.22 (q, 2H, J¼7.0 Hz), 4.73 (dd, 1H, J¼5.2, 8.9 Hz), 5.02
(dd, 1H, J¼5.2, 7.9 Hz), 7.06–7.10 (m, 2H), 7.48 (dd, 2H,
J¼5.5, 8.2 Hz); IR (CHCl3): 3540, 2058, 1996, 1731,
1490 cm21; MS (FAB) m/z 475 (Mþ, 2.8), 458 (8), 374
(100); HRMS (FAB) m/z calcd for C20H17FFeNO5S
(M2OHþ) 458.0161. Found: 458.0142.
1
Compound 15. A yellow oil; H NMR (CDCl3) d: 0.08 (s,
3H), 0.12 (s, 3H), 0.43 (d, 1H, J¼7.9 Hz), 0.90 (s, 9H), 1.09
(dd, 1H, J¼8.5, 10.1 Hz), 1.28 (dd, 3H, J¼7.0, 7.3 Hz), 2.61
(dd, 1H, J¼4.0, 15.9 Hz), 2.71 (dd, 1H, J¼8.5, 15.9 Hz),
3.02 (dd, 1H, J¼2.1, 10.1 Hz), 4.10–4.19 (m, 2H), 4.45
(ddd, 1H, J¼2.1, 4.0, 8.5 Hz), 4.58 (dd, 1H, J¼4.9, 8.5 Hz),
5.41 (dd, 1H, J¼4.9, 7.9 Hz), 7.08 (dd, 2H, J¼8.2, 8.5 Hz),
7.43 (dd, 2H, J¼5.5, 8.2 Hz); 13C NMR (CDCl3) d: 25.0,
24.7, 14.1, 18.0, 24.8, 25.7, 38.7, 60.8, 61.4, 61.8, 72.2,
81.5, 86.8, 116.6 (J¼21.7 Hz), 120.8, 128.7 (J¼3.1 Hz),
137.3 (J¼8.3 Hz), 163.1 (J¼249.0 Hz), 170.7; IR (CHCl3):
2955, 2932, 2858, 2223, 2068, 2011, 1731, 1489 cm21; MS
(FAB) m/z: 590 (MHþ, 1.3), 307 (39), 154 (100); HRMS
(FAB) m/z calcd for C26H33FFeNO6SSi (MHþ) 590.1131.
Found: 590.1110.
1
Compound 12. A yellow oil; H NMR (CDCl3) d: 0.16 (s,
3H), 0.19 (s, 3H), 0.93 (s, 9H), 1.30 (dd, 3H, J¼7.0, 7.3 Hz),
1.38 (d, 1H, J¼7.6 Hz), 2.58 (dd, 1H, J¼3.7, 16.2 Hz), 2.61
(d, 1H, J¼11.9 Hz), 3.11 (dd, 1H, J¼10.1, 16.2 Hz), 3.30
(dd, 1H, J¼7.9, 11.9 Hz), 4.14–4.20 (m, 2H), 4.44 (dd, 1H,
J¼3.7, 10.1 Hz), 4.98 (dd, 1H, J¼5.2, 7.9 Hz), 5.31 (dd, 1H,
J¼5.2, 7.6 Hz), 7.00–7.04 (m, 2H), 7.26–7.29 (m, 2H); 13C
NMR (CDCl3) d: 4.8, 24.2, 14.2, 18.0, 25.2, 25.6, 40.1,
58.5, 60.9, 63.2, 71.5, 82.8, 92.0, 116.3 (J¼21.7 Hz), 121.4,
129.7, 136.6 (J¼8.3 Hz), 162.8 (J¼248.2 Hz), 171.1; IR
(CHCl3): 2956, 2931, 2858, 2223, 2066, 2005, 1721,
1490 cm21; MS (FAB) m/z 590 (MHþ, 4.7), 561 (3.3),
379 (26), 378 (100). Anal. calcd for C26H32FFeNO6SSi: C,
52.97; H, 5.47; N, 2.38. Found: C, 52.68; H, 5.54; N, 2.37.
4.1.4. (2SR,6SR,7RS,2E,4Z)-Tricarbonyliron[(h4-2-5)-7-
(tert-butyldimethylsilyloxy)-6-(4-fluorophenysulphanyl)-
9-hydroxynona-2,4-dienal] (16). To a stirred solution of 12
(88.0 mg, 0.149 mmol) in toluene (1.5 ml) were added
DIBAL-H (1.0 M in toluene, 0.89 ml, 0.89 mmol) at 2788C
under an argon atmosphere. The mixture was stirred at 08C
for 2 h and then quenched with aqueous ammonium
chloride solution. The resulting mixture was filtrated
through a pad of Celite and washed with AcOEt. The
combined filtrates were washed with brine, dried over
MgSO4, and concentrated in vacuo. The crude residue was
purified by column chromatography (SiO2, hexane/
1
AcOEt¼5/1) to give 16 (63.5 mg, 77%). A yellow oil; H
NMR (CDCl3) d: 0.15 (s, 3H), 0.18 (s, 3H), 0.95 (s,
9H),1.70–1.80 (s, 1H), 1.83–1.87 (m, 1H), 2.12 (dd, 1H,
J¼4.3, 8.9 Hz), 2.27–2.34 (m, 1H), 2.86 (d, 1H,
J¼11.9 Hz), 3.44 (dd, 1H, J¼7.9, 11.9 Hz), 3.78–3.89 (m,
2H), 4.33 (dd, 1H, J¼4.0, 8.9 Hz), 5.00 (dd, 1H, J¼5.5,
7.9 Hz), 5.53 (dd, 1H, J¼5.5, 8.9 Hz), 6.97 (dd, 2H, J¼8.5,
8.5 Hz), 7.33–7.36 (m, 2H), 9.12 (d, 1H, J¼4.3 Hz); 13C
NMR (CDCl3) d: 24.7, 23.9, 18.2, 25.8, 37.7, 54.8, 59.6,
59.9, 65.5, 74.5, 82.9, 91.7, 116.0 (J¼21.7 Hz), 130.2, 136.6
(J¼8.3 Hz), 162.7 (J¼248.0 Hz), 197.0; IR (CHCl3): 3427,
2955, 2931, 2858, 2061, 1998, 1678, 1489 cm21; MS (FAB)
m/z 551 (MHþ, 1.9), 522 (3.0), 423 (15), 339 (27), 73 (100);
HRMS (FAB) m/z calcd for C24H32FFeO6SSi (MHþ)
551.1022. Found: 551.1035.
1
Compound 13. A yellow oil; H NMR (CDCl3) d: 0.16 (s,
3H), 0.16 (s, 3H), 0.15 (d, 1H, J¼8.2 Hz), 0.92 (s, 9H), 1.30
(dd, 3H, J¼7.0, 7.0 Hz), 2.74 (dd, 1H, J¼6.1, 15.3 Hz), 2.90
(dd, 1H, J¼5.8, 15.3 Hz), 3.51 (dd, 1H, J¼5.8, 11.3 Hz),
4.02 (dd, 1H, J¼7.6, 8.2 Hz), 4.17–4.23 (m, 2H), 4.44 (ddd,
1H, J¼5.8, 5.8, 6.1 Hz), 4.46 (dd, 1H, J¼7.0, 7.6 Hz), 4.73
(dd, 1H, J¼7.0, 11.3 Hz), 7.03 (dd, 2H, J¼8.5, 8.5 Hz),
7.39–7.42 (m, 2H); 13C NMR (CDCl3) d: 24.9, 24.5,
23.9, 14.2, 18.1, 25.8, 44.9, 50.0, 57.7, 60.9, 71.9, 82.5,
97.4, 116.5 (J¼21.7 Hz), 126.6, 127.3 (J¼3.0 Hz), 135.7
(J¼8.3 Hz), 163.0 (J¼249.0 Hz), 170.2, 202.5, 208.5,
209.5; IR (CHCl3): 2956, 2932, 2859, 2205, 2074, 2018,
1729, 1489 cm21; MS (FAB) m/z 590 (MHþ, 1.1), 462 (26),
378 (100); HRMS (FAB) m/z calcd for C26H33FFeNO6SSi
(MHþ) 590.1131. Found: 590.1151.
4.1.5. (2SR,6SR,7RS,2E,4Z)-Tricarbonyliron[(h4-2-5)-9-
acetoxy-7-(tert-butyldimethylsilyloxy)-6-(4-fluoropheny-
sulphanyl)nona-2,4-dienal] (17). To a stirred solution of
16 (88.7 mg, 0.161 mmol) in pyridine (1.6 ml) were added
Ac2O (23 ml, 0.24 mmol) and (dimethylamino)pyridine
(2.0 mg, 0.016 mmol) at 08C. The mixture was stirred at
room temperature for 2 h, and then quenched with a
saturated NaHCO3 solution. The resulting mixture was
extracted with AcOEt. The extract was washed with brine,
1
Compound 14. A yellow oil; H NMR (CDCl3) d: Major
isomer: 0.87 (dd, 1H, J¼7.6, 9.8 Hz), 1.11 (dd, 1H, J¼8.9,
9.5 Hz), 1.29 (t, 3H, J¼7.0 Hz), 2.60 (dd, 1H, J¼9.2,
15.9 Hz), 2.70 (dd, 1H, J¼4.0, 15.9 Hz), 3.09–3.15 (m,
1H), 3.53 (d, 1H, J¼9.8 Hz), 4.21 (q, 2H, J¼7.0 Hz), 4.84
(dd, 1H, J¼5.2, 8.9 Hz), 5.11 (dd, 1H, J¼5.2, 7.6 Hz),
7.06–7.10 (m, 2H), 7.48 (dd, 2H, J¼5.5, 8.2 Hz), Minor

9310
A. Fukuda et al. / Tetrahedron 59 (2003) 9305–9313
dried over MgSO4, and concentrated in vacuo. The crude
residue was purified by column chromatography (SiO2,
hexane/AcOEt¼7/1) to give 17 (93.6 mg, 98%). A yellow
oil; 1H NMR (CDCl3) d: 0.16 (s, 3H), 0.18 (s, 3H), 0.95 (s,
9H), 1.93 (dd, 1H, J¼3.7, 8.5 Hz), 2.08–2.12 (m, 1H), 2.10
(s, 3H), 2.22–2.30 (m, 1H), 2.57 (d, 1H, J¼11.6 Hz), 3.40
(dd, 1H, J¼8.2, 11.6 Hz), 4.13–4.17 (m, 1H), 4.23–4.30
(m, 2H), 5.04 (dd, 1H, J¼5.2, 8.2 Hz), 5.56 (dd, 1H, J¼5.2,
8.5 Hz), 7.00 (dd, 2H, J¼8.2, 8.5 Hz), 7.32–7.35 (m, 2H),
9.17 (d, 1H, J¼3.7 Hz); 13C NMR (CDCl3) d: 24.6, 24.0,
18.2, 20.9, 25.8, 35.0, 54.6, 58.9, 61.1, 64.3, 72.4, 82.9,
91.4, 116.2 (J¼21.7 Hz), 129.7, 137.0 (J¼8.3 Hz), 162.9
(J¼249.0 Hz), 171.1, 196.1; IR (CHCl3): 2956, 2932, 2858,
2062, 1998, 1736, 1684, 1489 cm21; MS (FAB) m/z 593
(MHþ, 16), 508 (26), 381 (100); HRMS (FAB) m/z calcd for
C26H34FFeO7SSi (MHþ) 593.1128. Found: 593.1119.
4.1.7. (4SR,5SR,9SR,10RS,5E,7Z)-Tricarbonyliron[(h4-
5-8)-12-acetoxy-4,10-bis(tert-butyldimethylsilyloxy)-9-
(4-fluorophenysulphanyl)dodeca-5,7-dieneyne] (19). To a
stirred solution of a mixture of 18a and 18b (117 mg,
0.185 mmol) in pyridine (0.67 ml) was added TBSOTf
(0.085 ml, 0.37 mmol) at 08C under an argon atmosphere.
The mixture was stirred for 30 min, before being quenched
with aqueous saturated sodium chloride solution. The
mixture was extracted with AcOEt. The combined extracts
were washed with brine, dried over MgSO4, and concen-
trated in vacuo. The crude residue was purified by column
chromatography (SiO2, hexane/AcOEt¼20/1) to give 19
(68.9 mg, 50%) and 18a (55.6 mg, 48%).
1
Compound 19. A yellow oil; H NMR (CDCl3) d: 0.01 (s,
3H), 0.06 (s, 3H), 0.16 (s, 3H), 0.20 (s, 3H), 0.88 (s, 9H),
0.95 (s, 9H), 2.06 (s, 3H), 1.97–2.09 (m, 2H), 2.19 (dd, 1H,
J¼2.4, 2.7 Hz), 2.23–2.30 (m, 1H), 2.33 (ddd, 1H, J¼2.7,
5.5, 16.8 Hz), 2.40–2.45 (m, 1H), 2.56 (d, 1H, J¼11.9 Hz),
3.17 (dd, 1H, J¼7.9, 11.9 Hz), 3.47 (m, 1H), 4.07–4.16 (m,
2H), 4.29 (dd, 1H, J¼5.2, 7.6 Hz), 4.87 (dd, 1H, J¼5.2,
7.9 Hz), 5.07 (dd, 1H, J¼5.2, 8.9 Hz), 6.98 (dd, 2H, J¼8.5,
8.5 Hz), 7.34–7.37 (m, 2H); 13C NMR (CDCl3) d: 24.5,
24.4, 24.3, 24.0, 18.1, 18.2, 21.0, 25.8, 25.9, 29.1, 35.5,
59.0, 61.2, 63.5, 64.2, 71.6, 72.8, 73.1, 79.5, 80.1, 92.6,
116.0 (J¼21.6 Hz), 130.1, 136.7 (J¼8.3 Hz), 162.6
(J¼248.0 Hz), 171.1; IR (CHCl3): 3306, 2956, 2932,
2891, 2858, 2046, 1980, 1734, 1489 cm21; MS (CI) m/z
(relative intensity) 747 (MHþ, 0.49), 289 (73), 157 (100),
133 (100); HRMS (CI) m/z calcd for C35H52FFeO7SSi2
(MHþ) 747.2305. Found: 747.2269.
4.1.6. (4SR,5SR,9SR,10RS,5E,7Z)-Tricarbonyliron[(h4-
5-8)-12-acetoxy-10-(tert-butyldimethylsilyloxy)-9-(4-
fluorophenysulphanyl)dodeca-5,7-dieneyne-4-ol] (18b).
To a mixture of 17 (435 mg, 0.734 mmol), NH4Cl (47 mg,
0.88 mmol), and zinc dust (58 mg, 0.88 mmol) in THF
(7.3 ml) was added propargyl bromide (0.083 ml,
1.10 mmol) at room temperature under an argon
atmosphere. The resulting mixture was stirred for 1 h and
then quenched with an aqueous ammonium chloride
solution. The mixture was extracted with ether and the
combined extracts were washed with aqueous ammonium
chloride solution and brine, dried over MgSO4, and
concentrated in vacuo. The crude residue was purified by
column chromatography (SiO2, hexane/AcOEt¼7/1) to give
a mixture of 18a and 18b (18a/18b¼1/1.2) (409 mg, 88%).
4.1.8. Ethyl (7SR,8SR,12SR,13RS,2Z,4E,8E,10Z)-tri-
carbonyliron[(h4-8-11)-7,13-bis(tert-butyldimethylsilyl-
oxy)-12-(4-fluorophenylsulphanyl)-15-hydroxypenta-
Compound 18a. A yellow oil; Rf¼0.30 (hexane/AcOEt¼
5/1); 1H NMR (CDCl3) d: 0.16 (s, 3H), 0.20 (s, 3H), 0.95 (s,
9H), 1.86 (dd, 1H, J¼8.2, 9.2 Hz), 2.01–2.09 (m, 1H), 2.09
(s, 3H), 2.16 (dd, 1H, J¼2.4, 2.4 Hz), 2.21–2.29 (m, 1H),
2.36–2.39 (m, 2H), 2.60 (d, 1H, J¼11.9 Hz), 3.14 (dd, 1H,
J¼7.9, 11.9 Hz), 3.34–3.39 (m, 1H), 3.97–4.01 (m, 1H),
4.21 (dd, 1H, J¼4.6, 9.2 Hz), 4.31–4.36 (m, 1H), 4.83 (dd,
1H, J¼5.5, 7.9 Hz), 4.99 (dd, 1H, J¼5.5, 9.2 Hz), 6.99–
7.03 (m, 2H), 7.32–7.37 (m, 2H).
deca-2,4,8,10-tetraenoate]
(22).
A
solution
of
pinacolborane (0.230 ml, 0.230 mmol), freshly prepared
according to the literature,16 was slowly added to a stirred
solution of 19 (85.2 mg, 0.114 mmol) and Rh(CO)(PPh3)2Cl
(4.8 mg, 0.0072 mmol) in CH2Cl2 (0.60 ml) at 08C under an
argon atmosphere. After being stirred at room temperature
for 1 h, the reaction mixture was quenched with water and
extracted with ether. The extract was washed with brine,
dried over MgSO4, and concentrated in vacuo. The crude
residue was purified by column chromatography (SiO2,
hexane/AcOEt¼20/1) to give 19 (17.7 mg, 21%) and 20
(26.8 mg, 27%). In a flask, a solution of ethyl (Z)-3-
iodopropenoate (27.6 mg, 0.122 mmol) and tetrakis(triphe-
nylphosphine)palladium (28.2 mg, 0.0244 mmol) in THF
(0.67 ml) was stirred for 30 min under an argon atmosphere.
In a second flask, to a stirred solution of 20 (26.8 mg,
0.0306 mmol) in THF (0.67 ml) was added 10% thallium
hydroxide solution (0.27 ml) at 08C under an argon
atmosphere. The mixture was stirred at room temperature
for 2 min, and the content of the first flask (0.34 ml) was
then transferred into this boronate solution at 08C. After
being stirred at room temperature for 1 h, the mixture was
quenched with water and extracted with ether. The extract
was washed with brine, dried over MgSO4, and concentrated
in vacuo. The crude residue was purified by column
chromatography (SiO2, hexane/AcOEt¼15/1) to give 21
(11.0 mg, 43%) and 22 (5.8 mg, 24%). To a stirred solution
of 21 (11.0 mg, 0.0130 mmol) in ethanol (0.5 ml) was added
Compound 18b. A yellow oil; Rf¼0.25 (hexane/AcOEt¼
5/1); 1H NMR (CDCl3) d: 0.16 (s, 3H), 0.19 (s, 3H), 0.94 (s,
9H), 1.70 (dd, 1H, J¼7.9, 8.9 Hz), 2.01–2.09 (m, 1H), 2.06
(s, 3H), 2.23–2.29 (m, 1H), 2.29 (dd, 1H, J¼2.4, 2.4 Hz),
2.33–2.39 (m, 1H), 2.46–2.53 (m, 1H), 2.52 (d, 1H,
J¼11.6 Hz), 3.22 (dd, 1H, J¼7.9, 11.6 Hz), 3.46–3.51 (m,
1H), 4.12 (dd, 2H, J¼6.1, 7.0 Hz), 4.25 (dd, 1H, J¼5.2,
8.9 Hz), 4.87 (dd, 1H, J¼5.2, 7.9 Hz), 5.13 (dd, 1H, J¼5.2,
8.9 Hz), 6.99–7.03 (m, 2H), 7.32–7.37 (m, 2H); 13C NMR
(CDCl3) d: 24.7, 24.6, 24.0, 24.0, 18.1, 18.2, 20.9, 21.1,
25.8, 25.8, 28.7, 29.9, 35.4, 35.5, 57.8, 59.0, 60.7, 61.0,
62.5, 63.5, 66.3, 71.6, 71.7, 71.8, 72.1, 72.4, 72.6, 78.8,
79.6, 79.8, 80.0, 90.7, 91.6, 115.9 (J¼21.7 Hz), 116.0
(J¼21.7 Hz), 130.2 (J¼4.1 Hz), 130.3 (J¼3.0 Hz), 136.7
(J¼8.2 Hz), 137.1 (J¼8.3 Hz), 162.7 (J¼248.0 Hz), 162.8
(J¼249.2 Hz), 171.2, 171.9; IR (CHCl3): 3567, 3305, 2956,
2932, 2893, 2858, 2047, 1982, 1732, 1489 cm21; MS (FAB)
m/z 631 (M2Hþ, 15), 604 (27), 547 (68), 267 (82), 127
(100); HRMS (FAB) m/z calcd for C29H36FFeO7SSi
(M2Hþ) 631.1284. Found: 631.1322.

A. Fukuda et al. / Tetrahedron 59 (2003) 9305–9313
9311
1
K2CO3 (10 mg, 0.072 mmol) at 08C. After being stirred
at room temperature for 6 h, the mixture was evaporated
and extracted with AcOEt. The extract was washed
with brine, dried over MgSO4, and concentrated in
vacuo. The crude residue was purified by column chroma-
tography (SiO2, hexane/AcOEt¼15/1) to give 22 (8.9 mg,
85%).
AcOEt¼5/1) to give 9 (2.7 g, 90%) as a colorless oil; H
NMR (CDCl3) d: 1.60–1.66 (m, 2H), 1.70–1.76 (m, 2H),
2.45 (dt, 2H, J¼1.8, 7.2 Hz), 3.46 (t, 2H, J¼6.1 Hz), 3.80 (s,
3H), 4.42 (s, 2H), 6.88 (d, 2H, J¼8.5 Hz), 7.25 (d, 2H,
J¼8.5 Hz), 9.76 (t, 1H, J¼1.8 Hz); 13C NMR (CDCl3) d:
18.9, 29.1, 43.5, 55.2, 69.3, 72.5, 113.7, 129.2, 130.5, 159.1,
202.5; IR (CHCl3): 1722, 1612, 1513, 1464 cm21; MS (EI)
m/z (relative intensity) 222 (Mþ, 6.8), 137 (20), 121 (100);
HRMS (EI) calcud. for C13H18O3 (Mþ) 222.1256. Found
222.1251.
1
Compound 22. A yellow oil; H NMR (CDCl3) d: 0.00 (s,
3H), 0.02 (s, 3H), 0.14 (s, 3H), 0.18 (s, 3H), 0.88 (s, 9H),
0.93 (s, 9H), 1.30 (t, 3H, J¼7.0 Hz), 1.79 (dd, 1H, J¼8.2,
8.9 Hz), 1.80–1.86 (m, 1H), 2.04–2.14 (m, 2H), 2.46 (ddd,
1H, J¼3.7, 8.5, 14.6 Hz), 2.48 (ddd, 1H, J¼4.9, 5.2,
14.6 Hz), 2.59 (d, 1H, J¼11.9 Hz), 3.19 (dd, 1H, J¼7.9,
11.9 Hz), 3.51 (ddd, 1H, J¼3.7, 4.9, 8.2 Hz), 3.58–3.66 (m,
2H), 4.19 (q, 2H, J¼7.0 Hz), 4.29 (dd, 1H, J¼4.6, 7.9 Hz),
4.83 (dd, 1H, J¼5.2, 7.9 Hz), 5.06 (dd, 1H, J¼5.2, 8.9 Hz),
5.65 (d, 1H, J¼11.3 Hz), 6.12 (ddd, 1H, J¼5.2, 8.5,
15.0 Hz), 6.60 (dd, 1H, J¼11.3, 11.9 Hz), 6.94 (dd, 2H,
J¼8.5, 8.5 Hz), 7.28–7.31 (m, 2H), 7.45 (dd, 1H, J¼11.9,
15.0 Hz); 13C NMR (CDCl3) d: 24.6, 24.4, 24.2, 23.9,
14.3, 18.1, 18.2, 25.8, 25.9, 38.6, 41.5, 59.4, 59.5, 60.2,
64.8, 65.0, 73.8, 74.2, 80.0, 93.5, 115.9 (J¼21.6 Hz), 116.4,
129.3, 130.4 (J¼3.1 Hz), 136.4 (J¼8.3 Hz), 140.5, 144.9,
162.5 (J¼246.9 Hz), 166.9; IR (CHCl3): 3514, 2955, 2931,
2890, 2858, 2044, 1976, 1702, 1637, 1595, 1489 cm21; MS
(FAB) m/z 805 (MHþ, 0.31), 677 (10), 431 (100), 73 (100);
HRMS (CI) m/z calcd for C32H53FeO8Si2 (M2C6H4FSþ)
677.2628. Found: 677.2647.
4.1.10. (2R)-6-(4-Methoxybenzyloxy)hexan-2-ol (23).
Entry 1 in Table 2. A catalyst E (8.17 mg, 0.022 mmol)
was placed in a dried round-bottom flask under an argon
atmosphere. To this, were added degassed toluene (1.0 ml)
and Ti(O-i-Pr)4 (0.16 ml, 0.54 mmol), and the mixture was
stirred at 2408C for 20 min. After being cooled to 2788C, a
1.0 M solution of Me2Zn (0.54 ml, 0.54 mmol) in hexane
was added to the mixture. To the whole mixture was added a
solution of 9 (80 mg, 0.36 mmol) in toluene (1 ml). The
mixture was warmed to 2258C, and stirring was continued
at that temperature for 2 h. The mixture was quenched with
2N HCl and extracted with ether. The extract was washed
with water and brine, dried over MgSO4, and concentrated
in vacuo. The crude residue was purified by column
chromatography (SiO2, hexane/AcOEt¼2/1) to furnish 23
(34.2 mg, 27%, 68%ee). Entry 2 in Table 2: (S)-BINOL F
(10.2 mg, 0.0356 mmol) was placed in a dry flask under an
argon atmosphere. To this were added degassed toluene
(0.8 ml) and Ti(O-i-Pr)4 (0.12 ml, 0.42 mmol), and the
mixture was stirred at room temperature for 60 min. A
solution of 9 (80 mg, 0.36 mmol) in toluene (0.8 ml) and a
1.0 M solution of Me2Zn (1.07 ml, 1.07 mmol) were added
to the mixture at 08C. After being stirred at 08C for 2 h, the
reaction mixture was quenched with 1N HCl. The mixture
was treated by the same procedure described above to give
23 (18.5 mg, 22%, 22% ee). Entry 3 in Table 2: (þ)-
TADDOL G (1.18 g, 2.52 mmol) was placed in a dry
Schlenk tube under an argon atmosphere. To this were
added Ti(O-i-Pr)4 (0.89 ml, 3.02 mmol) and toluene
(19 ml). After being stirred at room temperature for 5 h,
toluene and 2-propanol was removed in vacuo. A solution of
Ti(O-i-Pr)4 (7.4 ml, 25 mmol) in toluene (9.4 ml) was added
to the yellow solid residue at room temperature, and the
mixture was cooled to 2258C. To the reaction mixture was
successively added a solution of 9 (2.80 g, 12.6 mmol) in
toluene (28 ml) and then Me2Zn (25.2 ml, 1.0 M solution in
n-hexane, 25.2 mmol). After being quenched with a NH4Cl
solution, the mixture was filtrated through a pad of Celite
and washed with ether. The organic phase was washed with
brine, dried over MgSO4, and concentrated in vacuo. The
crude residue was purified by column chromatography
(SiO2, hexane/AcOEt¼2/1) to furnish 23 (2.96 g, 99%, 96%
ee). The enantiomeric excess of 23 was determined by chiral
HPLC analysis (DAICEL Chiralcel OD, 3% 2-propanol in
hexane, 1.2 ml/min, retention times: (R) (major) 20.9 min,
(S) (minor) 22.1 min.
4.1.9. 5-(4-Methoxybenzyloxy)pentanal (9). To a suspen-
sion of sodium hydride (1.9 g, 48 mmol) in DMF (100 ml)
was added 1,5-pentandiol (5.0 g, 48 mmol) at 08C under an
argon atmosphere, and the mixture was stirred at room
temperature for 30 min. To the mixture was slowly added a
solution of 4-methoxybenzyl chloride (6.5 ml, 48 mmol) at
2208C, and the whole was stirred at 08C for 12 h. After
being quenched with water, the mixture was extracted with
ether. The extract was washed with brine, dried over
MgSO4, and concentrated in vacuo. The crude residue was
purified by column chromatography (SiO2, hexane/
AcOEt¼2/1) to give the PMB ether (5.2 g, 48%) as a
colorless oil; 1H NMR (CDCl3) d: 1.37 (br, 1H), 1.41–1.47
(m, 2H), 1.55–1.66 (m, 4H), 3.45 (t, 2H, J¼6.4 Hz), 3.64 (t,
2H, J¼6.1 Hz), 3.80 (s, 3H), 4.43 (s, 2H), 6.88 (d, 2H,
J¼8.5 Hz), 7.26 (d, 2H, J¼8.5 Hz); 13C NMR (CDCl3) d:
22.3, 29.3, 32.3, 55.1, 62.4, 69.9, 72.5, 113.6, 129.2, 130.5,
159.0; IR (CHCl3): 3430, 1612, 1513, 1464 cm21; MS (EI)
m/z (relative intensity) 224 (Mþ, 8.4), 223 (6.0), 137 (56),
121 (100); HRMS (EI) m/z calcd for C13H20O3 (Mþ)
224.1412. Found 224.1413. To a solution of oxalyl chloride
(1.7 ml, 20 mmol) in CH2Cl2 (45 ml) was added a solution
of DMSO (1.5 ml, 21 mmol) in CH2Cl2 (10 ml) at 2608C.
The mixture was stirred for 2 min, and then cooled to
2788C. To the mixture was added dropwise a solution of the
PMB ether (3.0 g, 13 mmol) in CH2Cl2 (14 ml) and the
resulting mixture was stirred at 2788C for 1.5 h. After
triethylamine (9.3 ml) was added to the mixture at 2788C,
the resulting mixture was warmed to 08C. The mixture was
quenched with water at 08C and extracted with ethyl acetate.
The extracts were washed with water and brine, dried over
MgSO4, and concentrated in vacuo. The crude residue was
purified by column chromatography (SiO2, hexane/
Compound 23. A colorless oil; [a]2D0¼22.75 (c¼1.40,
CHCl3); 1H NMR (CDCl3) d: 1.18 (d, 3H, J¼6.1 Hz), 1.36
(br, 1H), 1.39–1.52 (m, 4H), 1.59–1.67 (m, 2H), 3.45 (t,
2H, J¼6.4 Hz), 3.80 (s, 3H), 3.80 (m, 1H), 4.43 (s, 2H), 6.88
(d, 2H, J¼8.5 Hz), 7.26 (d, 2H, J¼8.5 Hz); 13C NMR

9312
A. Fukuda et al. / Tetrahedron 59 (2003) 9305–9313
(CDCl3) d: 22.4, 23.4, 29.6, 39.0, 55.2, 67.9, 69.9, 72.5,
113.7, 129.2, 130.6, 159.1; IR (CHCl3): 3445, 1612, 1513,
1464 cm21; MS (EI) m/z (relative intensity) 238 (Mþ, 6.8),
137 (47), 121 (100); HRMS (EI) calcd for C14H22O3 (Mþ)
238.1569. Found 238.1576.
4.1.13. (5R)-5-(tert-Butyldimethylsilyloxy)hexanal (25).
To a solution of 24 (455 mg, 1.91 mmol) in 19 ml of a
mixture of DMSO and THF (2/1) was added IBX (697 mg,
2.49 mmol), and the mixture was stirred at room tempera-
ture for 30 min. After being poured into a saturated
NaHCO3 solution, the aqueous layer was extracted with
diethyl ether, and combined organic layers were washed
with brine, dried over MgSO4, and concentrated in vacuo.
The crude residue was purified by column chromatography
(SiO2, hexane/AcOEt¼5/1) to give 25 (335 mg, 76%) as a
colorless oil; [a]D22¼28.90 (c¼1.28, CHCl3); 1H NMR
(CDCl3) d: 0.05 (s, 3H), 0.05 (s, 3H), 0.89 (s, 9H), 1.13 (d,
3H, J¼6.1 Hz), 1.38–1.49 (m, 2H), 1.58–1.66 (m, 1H),
1.68–1.77 (m, 1H), 2.43 (m, 2H), 3.78–3.84 (m, 1H), 9.76
(t, 1H, J¼1.8 Hz); 13C NMR (CDCl3) d: 24.8, 24.4, 18.1,
18.3, 23.7, 25.8, 38.9, 43.9, 68.1, 202.6; IR (CHCl3): 1722,
1255 cm21; MS (CI) m/z (relative intensity) 231 (MHþ,
9.1), 99 (100); HRMS (CI) calcd for C12H27O2Si (MHþ)
231.1780. Found 231.1785.
4.1.11. Determination of the absolute configuration of 23.
Absolute configuration was determined by 1H NMR
methods previously described by Mosher et al.21 1H NMR
of (þ) or (2)-MTPA esters of 23 are as follows: (þ)-MTPA
1
ester: H NMR (CDCl3) d: 1.32 (d, 3H, J¼6.1 Hz), 1.48–
1.67 (m, 6H), 3.35 (t, 2H, J¼6.4 Hz), 3.56 (s, 3H), 3.80 (s,
3H), 4.40 (s, 2H), 5.14 (m, 1H), 6.87 (d, 2H, J¼8.5 Hz),
7.23 (d, 2H, J¼8.5 Hz), 7.37 (m, 3H), 7.53 (m, 2H). (2)-
1
MTPA ester: H NMR (CDCl3) d: 1.24 (d, 3H, J¼6.1 Hz),
1.33–1.48 (m, 6H), 3.42 (t, 2H, J¼6.4 Hz), 3.53 (s, 3H),
3.80 (s, 3H), 4.41 (s, 2H), 5.14 (m, 1H), 6.87 (d, 2H,
J¼8.5 Hz), 7.23 (d, 2H, J¼8.5 Hz), 7.37 (m, 3H), 7.53 (m,
2H).
4.1.12. (5R)-5-(tert-Butyldimethylsilyloxy)hexan-1-ol
(24). To a solution of alcohol 23 (1.00 g, 4.20 mmol) in
DMF (20 ml) was successively added imidazole (857 mg,
12.6 mmol) and TBSCl (1260 mg, 8.40 mmol) at room
temperature. The whole was stirred at room temperature for
2 h, before quenching with a saturated NaHCO3 solution.
The mixture was extracted with ether and the extract was
washed with water and brine, dried over MgSO4, and
concentrated in vacuo. The crude residue was purified by
column chromatography (SiO2, hexane/AcOEt¼20/1) to
give the TBS ether (1.38 g, 93%) as a colorless oil;
4.1.14. (8R,3E)-8-(tert-Butyldimethylsilyloxy)-1-(tri-
methylsilyl)non-3-en-1-yne (27). To a suspension of
triphenyl-(3-trimethylsilylprop-2-ynyl)phosphonium bromide
(400 mg, 0.882 mmol) in 4.4 ml of THF was added a 1.58 M
solution of n-butyllithum (0.56 ml, 0.882 mmol) at 2788C,
and the mixture was stirred at 2408C for 30 min. A solution
of 25 (135 mg, 0.588 mmol) in THF (1 ml) was added to the
mixture at 2788C. The whole was stirred at 2788C for 1 h
and then allowed to warm to ambient temperature. After
being stirred for 4 h, the mixture was quenched with water
and extracted with ether. The combined extracts were
washed with brine, dried over MgSO4, and concentrated in
vacuo. The crude residue was purified by column chroma-
tography (SiO2, hexane/AcOEt¼200/1) to furnish 27
(161 mg, 84%) and Z-isomer (26 mg, 14%). 27: a colorless
1
[a]2D0¼24.83 (c¼1.35, CHCl3); H NMR (CDCl3) d: 0.04
(s, 3H), 0.04 (s, 3H), 0.88 (s, 9H), 1.18 (d, 3H, J¼5.8 Hz),
1.33–1.45 (m, 4H), 1.55–1.62 (m, 2H), 3.45 (t, 2H,
J¼6.4 Hz), 3.74–3.79 (m, 1H), 3.80 (s, 3H), 4.43 (s, 2H),
6.88 (d, 2H, J¼8.5 Hz), 7.26 (d, 2H, J¼8.5 Hz); 13C NMR
(CDCl3) d: 24.8, 24.5, 18.1, 22.3, 23.7, 25.9, 30.0, 39.5,
55.1, 68.5, 70.0, 72.4, 113.7, 129.1, 130.1, 159.0; IR
(CHCl3): 1612, 1513, 1464, 1250 cm21; MS (CI) m/z
(relative intensity) 353 (MHþ, 1.7), 351 (1.2), 121 (100);
HRMS (CI) calcd for C20H37O3Si (MHþ) 353.2519. Found
353.2502. To a solution of the TBS ether (1.2 g, 3.4 mmol)
in a mixture of CH2Cl2 (34 ml) and H2O (2 ml) was added
DDQ (85 mg, 3.7 mmol) at 08C. The mixture was stirred at
room temperature for 60 min, before being addition of
methanol (30 ml). To reduce p-anisaldehyde produced in
the reaction, several portions of NaBH4 were added to the
mixture at 08C until p-anisaldehyde had disappeared on the
TLC. After being quenched with saturated NaHCO3
solution, the mixture was diluted with ether and filtered
through a pad of Celite. The combined filtrates were washed
with water and brine, dried over MgSO4, and concentrated
in vacuo. The crude residue was purified by column
chromatography (SiO2, hexane/AcOEt¼5/1) to furnish 24
(790 mg, quant.) as a colorless oil; [a]2D2¼26.87 (c¼1.53,
CHCl3); 1H NMR (CDCl3) d: 0.05 (s, 3H), 0.05 (s, 3H), 0.89
(s, 9H), 1.12 (d, 3H, J¼6.1 Hz), 1.26 (br, 1H), 1.32–1.50
(m, 4H), 1.54–1.60 (m, 2H), 3.62–3.67 (m, 2H), 3.76–3.83
(m, 1H); 13C NMR (CDCl3) d: 24.7, 24.4, 18.1, 21.8, 23.8,
oil; [a]2D0¼25.75 (c¼1.57, CHCl3); H NMR (CDCl3) d:
1
0.04 (s, 3H), 0.04 (s, 3H), 0.18 (s, 9H), 0.88 (s, 9H), 1.11 (d,
3H, J¼6.1 Hz), 1.32–1.52 (m, 4H), 2.07–2.11 (m, 2H),
3.73–3.80 (m, 1H), 5.50 (d, 1H, J¼15.9 Hz), 6.18–6.24 (m,
1H); 13C NMR (CDCl3) d: 24.7, 24.4, 0.0, 18.1, 23.9, 24.8,
25.9, 33.1, 39.1, 68.3, 92.4, 104.2, 109.7, 146.2; IR
(CHCl3): 2958, 2931, 2858, 2131, 1626, 1254, 844 cm21
;
MS (CI) m/z (relative intensity) 325 (MHþ, 11), 309 (100),
267 (27), 193 (70); HRMS (CI) calcd for C18H37OSi2
(MHþ) 325.2383. Found 325.2375.
4.1.15. (8R,3E)-8-(tert-Butyldimethylsilylloxy)non-3-en-
1-yne (8). To a stirred solution of 27 (52 mg, 0.16 mmol)
in THF (0.87 ml) was added a 1.0 M solution of tetra-n-
butylammonium fluoride (0.23 ml, 0.23 mmol) in THF at
08C. After 1 h, the mixture was quenched with brine and
extracted with diethyl ether. The extracts were washed with
brine, dried over MgSO4, and concentrated in vacuo. The
crude residue was purified by column chromatography
(SiO2, hexane/AcOEt¼100/1) to give 8 (38 mg, 94%) as a
colorless oil; [a]D21¼27.56 (c¼1.59, CHCl3); 1H NMR
(CDCl3) d: 0.04 (s, 3H), 0.05 (s, 3H), 0.88 (s, 9H), 1.11 (d,
3H, J¼5.8 Hz), 1.35–1.53 (m, 4H), 2.09–2.13 (m, 2H),
2.78 (d, 1H, J¼1.8 Hz), 3.75–3.80 (m, 1H), 5.46 (dd, 1H,
J¼1.8, 15.9 Hz), 6.24 (dt, 1H, J¼7.0, 15.9 Hz); 13C NMR
(CDCl3) d: 24.7, 24.4, 18.1, 23.8, 24.7, 25.9, 33.0, 39.0,
68.3, 75.6, 82.5, 108.5, 146.8; IR (CHCl3): 3306, 2954,
2931, 2858, 2102, 1629, 1255, 835 cm21; MS (CI) m/z
25.9, 32.8, 39.4, 63.0, 68.5; IR (CHCl3): 3442, 1255 cm21
;
MS (CI) m/z (relative intensity) 233 (MHþ, 22), 101 (13), 57
(100); HRMS (CI) calcd for C12H29O2Si (MHþ) 233.1937.
Found 233.1933.

A. Fukuda et al. / Tetrahedron 59 (2003) 9305–9313
9313
(relative intensity) 253 (MHþ,43), 237 (30), 195 (37), 121
(51), 19 (100); HRMS (CI) calcd for C15H29OSi (MHþ)
253.1988. Found 253.1992.
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Acknowledgements
This research was supported by grants from the Japan
Health Sciences.
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