Synthesis of (S)-imperanene by using allylic substitution

Article abstract of DOI:10.1021/jo900854p

(Chemical Equation Presented) Synthesis of (S)-imperanene (1) was studied by using copper-assisted allylic substitution of ArCH=CHCH(L)CH₂Ar (L: leaving group) and (i-PrO)Me₂SiCH₂MgCl. Preliminary substitution between PhCH=CHCH(L)Me (L = AcO, PivO, MeOCO₂, (2-Py)CO₂) and Bu copper reagents derived from BuMgX (X = Br, Cl) and CuBr·Me₂S or CuCl in 1:1-40:1 ratios suggested acetate 28 as the best substrate. To prepare 28, kinetic resolution of racemic (E)-TMSCH=CHCH(OH)CH₂Ar² (Ar² = (p-TBSO)(m-MeO)C₆H₃) carried out by using the asymmetric epoxidation with (-)-DIPT afforded the corresponding epoxy alcohol and (S)-allylic alcohol. After separation by chromatography, these products were converted to (S,E)-Bu₃SnCH=CHCH(OH)CH₂Ar², which upon palladium-catalyzed coupling with Ar²-I followed by acetylation gave 28 (95-98% ee). Substitution of 28 with (i-PrO)Me ₂SiCH₂MgCl and CuBr·Me₂S in a 4:1 ratio at 0°C proceeded cleanly to produce 29 with 100% inversion in 92% yield. Finally, Tamao oxidation furnished 1.

Full text of DOI:10.1021/jo900854p

pubs.acs.org/joc
Synthesis of (S)-Imperanene by Using Allylic Substitution
Yuji Takashima and Yuichi Kobayashi*
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku,
Yokohama 226-8501, Japan
ykobayas@bio.titech.ac.jp
Received April 24, 2009
Synthesis of (S)-imperanene (1) was studied by using copper-assisted allylic substitution of
ArCHdCHCH(L)CH2Ar (L: leaving group) and (i-PrO)Me2SiCH2MgCl. Preliminary substitution
between PhCHdCHCH(L)Me (L=AcO, PivO, MeOCO2, (2-Py)CO2) and Bu copper reagents deri-
ved from BuMgX (X=Br, Cl) and CuBr Me2S or CuCl in 1:1-40:1 ratios suggested acetate 28 as the
3
best substrate. To prepare 28, kinetic resolution of racemic (E)-TMSCHdCHCH(OH)CH2Ar2
(Ar2=(p-TBSO)(m-MeO)C6H3) carried out by using the asymmetric epoxidation with (-)-DIPT
afforded the corresponding epoxy alcohol and (S)-allylic alcohol. After separation by chromatog-
raphy, these products were converted to (S,E)-Bu3SnCHdCHCH(OH)CH2Ar2, which upon palla-
dium-catalyzed coupling with Ar2-I followed by acetylation gave 28 (95-98% ee). Substitution of 28
with (i-PrO)Me2SiCH2MgCl and CuBr Me2S in a 4:1 ratio at 0 °C proceeded cleanly to produce 29
3
with 100% inversion in 92% yield. Finally, Tamao oxidation furnished 1.
Introduction
SN2-type product observed with alkyl copper reagent is another
problem to be solved.
In the past decade allylic substitution of secondary (optically
active) allylic alcohol derivatives with copper reagents has
much progressed with the finding of reactive leaving groups
such as C6F5CO2, o-(Ph2P)C6H4CO2, o-(Ph2PO)C6H4CO2,
(RO)2P(O)O, and (2-Py)CO2. With these groups a wide range
of allylic substrates have been shown to undergo γ-substitution
with high efficiency in yield and in regio- and stereoselectiv-
ities.1 However, there are a class of substrates that suffer from
low regioselectivity by steric and/or electronic reason. For
example, the γ-aryl allylic alcohol derivatives afford a mixture
of regioisomers in varying ratios depending on copper reagents
and reaction conditions.2 Somewhat low percent inversion3 for
To advance in this area, we have become interested in the
synthesis of (S)-imperanene (1) by using γ- and R-selective
allylic substitutions of esters 2 and 3 with masked “HOCH2”
copper reagents derived from (i-PrO)Me2SiCH2MgCl4 and
CuX to give 4, which would furnish alcohol 5 by oxidation
(Scheme 1). This target, isolated from Imperata cylindrica by
Ohizumi,5 inhibit platelet aggregation. Recently, inhibition
(1) (a) Negishi, E.; Liu, F. In Metal-catalyzed Cross-coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; Chapter
1.(b) Kar, A.; Argade, N. P. Synthesis 2005, 2995–3022.
(2) (a) Goering, H. L.; Tseng, C. C. J. Org. Chem. 1983, 48, 3986–3990.
(b) Tseng, C. C.; Yen, S.-J.; Goering, H. L. J. Org. Chem. 1986, 51, 2892–
ꢀ
2895. (c) Norinder, J.; Bogar, K.; Kanupp, L.; Backvall, J.-E. Org. Lett. 2007,
€
9, 5095–5098.
(3) We define “% inversion” as (% ee of product/% ee of substrate) ꢀ
(4) Tamao, K.; Ishida, N. Tetrahedron Lett. 1984, 25, 4245–4248.
(5) Matsunaga, K.; Shibuya, M.; Ohizumi, Y. J. Nat. Prod. 1995, 58,
138–139.
100.
5920 J. Org. Chem. 2009, 74, 5920–5926
Published on Web 07/06/2009
DOI: 10.1021/jo900854p
r
2009 American Chemical Society

Takashima and Kobayashi
JOCArticle
SCHEME 2. Investigation of the Anti SN20 Approacha
SCHEME 1. Two Approaches to Imperanenea
aAr = (m-MeO)(p-R2O)C6H3 (R2 = PMB, TBS, TBDPS, Ts).
of tyrosinase activity was newly reported.6 Four syntheses7
of 1 and one synthesis8 of the enantiomer have been reported
to date. The key to the success in these syntheses was the
proper control of the reactive oxygen-containing functional
groups and suppression of side reactions induced by these
groups. Herein, we report a different approach to 1 using
allylic substitution.
Results and Discussion
The first approach to 4 from 2 was examined by using
our protocol,9 in which a cis allylic picolinate is required
for high γ-selectivity. Thus, picolinate 9 with (m-MeO)(p-
PMBO)C6H3 (abbreviated to Ar1) was chosen as 2, and
synthesized in a racemic form by the method summarized
in Scheme 2. Coupling of acetylene 6 and Ar1CH2Cl was
accomplished with the Pd/XPhos catalyst to afford 7 in 94%
aXPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.
attempted with DDQ in wet CH2Cl2,12 CF3CO2H in
11
yield.10 Other attempts by using catalysts such as Co(acac)3
CH2Cl2,13 NaB(CN)H3/BF3 Et2O in THF at 80 °C,14
3
Ph3CBF4 in CH2Cl2,15 and Dowex in MeOH/THF.16 How-
ever, these reagents unfortunately gave a mixture of uni-
dentified products. Another attempt on acetate 12 derived
and CuCN and by conducting the reaction in HMPA did
not afford the product. Conversion of 7 to picolinate 9
proceeded well. Allylic substitution of picolinate 9 with ((i-
PrO)Me2SiCH2)2CuMgCl, synthesized from (i-PrO)Me2-
13
from 11 with CF3CO2H in CH2Cl2 and ClSO2NCO in
17
CH2Cl2 produced a mixture. Next, the transformation of
SiCH2MgCl (2 equiv) and CuBr Me2S (1 equiv) at 0 °C
3
(30 min), proceeded smoothly to afford the γ-substitution
product 10 regioselectively in good yield. Oxidation of 10
under the reported conditions successfully produced alcohol
11 in 61% yield. Finally, removal of the PMB group was
Scheme 2 was examined with compounds possessing the
TBS, TBDPS, or Ts protective group in place of the PMB
group. However, Pd/XPhos-catalyzed coupling of these
acetylenes with ArCH2Cl was unsuccessful, yielding
<26% of the desired product or a mixture of unidentified
products.
The second approach of Scheme 1 through the SN2-type
substitution (i.e., 3 to 4) was investigated next. Allylic
substitution of racemic ArCHdCHCH(L)R, which has the
same structural type as 3, has been well documented,1
whereas reactions of the optically active substrates have been
reported a little.2 Unfortunately, percent inversion is at the
90% level with varying regioselectivity depending on the
(6) Takara, K.; Iwasaki, H.; Ujihara, K.; Wada, K. J. Oleo Sci. 2008, 57,
191–196.
(7) (a) Shattuck, J. C.; Shreve, C. M.; Solomon, S. E. Org. Lett. 2001, 3,
3021–3023. (b) Doyle, M. P.; Hu, W.; Valenzuela, M. V. J. Org. Chem. 2002,
67, 2954–2959. (c) Davies, H. M. L.; Jin, Q. Tetrahedron: Asymmetry 2003,
14, 941–949. (d) Carr, J. A.; Bisht, K. S. Org. Lett. 2004, 6, 3297–3300.
€
(8) Eklund, P. C.; Riska, A. I.; Sjoholm, R. E. J. Org. Chem. 2002, 67,
7544–7546.
(9) (a) Kiyotsuka, Y.; Acharya, H. P.; Katayama, Y.; Hyodo, T.;
Kobayashi, Y. Org. Lett. 2008, 10, 1719–1722. (b) Kiyotsuka, Y.; Kobaya-
shi, Y. Tetrahedron Lett. 2008, 49, 7256–7259. (c) Kiyotsuka, Y.; Katayama,
Y.; Acharya, H. P.; Hyodo, T.; Kobayashi, Y. J. Org. Chem. 2009, 74, 1939–
1951.
(10) Larsen, C. H.; Anderson, K. W.; Tundel, R. E.; Buchwald, S. L.
Synlett 2006, 18, 2941–2946.
(13) Fellows, I. M.; Kaelin, D. E., Jr.; Martin, S. F. J. Am. Chem. Soc.
2000, 122, 10781–10787.
(11) Kuno, A.; Saino, N.; Kamachi, T.; Okamoto, S. Tetrahedron Lett.
2006, 47, 2591–2594.
(14) Srikrishna, A.; Viswajanani, R.; Sattigeri, J. A.; Vijaykmar, D.
J. Org. Chem. 1995, 60, 5961–5962.
(12) (a) Vig, O. P.; Bari, S. S.; Sharma, A.; Sattar, M. A. Indian J. Chem.,
Sect. B: Org. Chem. Incl. Med. Chem. 1990, 29B, 284–286. (b) Oikawa, Y.;
Tanaka, T.; Horita, K.; Yonemitsu, O. Tetrahedron Lett. 1984, 25, 5397–
5400. (c) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885–888.
(15) Barton, D. H. R.; Magnus, P. D.; Streckert, G.; Zurr, D. J. Chem.
Commun. 1971, 1109–1111.
(16) Pletcher, J. M.; McDonald, F. E. Org. Lett. 2005, 7, 4749–4752.
(17) Kim, J. D.; Han, G.; Jeong, L. S.; Park, H.; Zee, O. P.; Jung, Y. H.
Tetrahedron 2002, 58, 4395–4402.
J. Org. Chem. Vol. 74, No. 16, 2009 5921

Takashima and Kobayashi
JOCArticle
reagents and reaction conditions as summarized in eq 1.18
Due to this reason, we explored substitution between
PhCHdCHCH(L)Me (L=AcO, PivO, MeOCO2, (2-Py)-
CO2) and Bu copper reagents derived from BuMgX
TABLE 1. Preliminary Study of Allylic Substitutiona
BuMgX
entry substrate
L
X equiv CuBr Me2S equiv 15:16:17:SMb
3
1
2
3
4
5
6
7
8
rac-14a AcO
rac-14a AcO
Cl 2.0 2.2
Br 2.0 2.3
Cl 4.0 1.0
Br 4.0 1.0
Cl 4.0 0.4
Cl 4.0 0.1
0:18c:0:82
0:29c:0:71
92:<1:7:0
94:<2:4:0
92:<1:7:0
94:<1:6:0
98:<2:0:0
97:<2:<1:0
(X = Cl, Br) and CuBr Me2S or CuCl in 1:1-40:1 ratios
3
(eq 2). As summarized in Table 1, the reaction of rac-14a-c
with the copper reagents in >4:1 ratios in THF at 0 °C for 1 h
was highly R-selective irrespective of the leaving groups
(entries 3-8, 10, and 14), whereas substitution with the 1:1
reagent was γ-selective, but proceeded slowly (entries 1, 2,
11, and 12). Both BuMgBr and BuMgCl showed essentially
the same regioselectivity and reactivity in reactions with
acetate rac-14a. On the other hand, picolinate rac-14d was
highly reactive with the 1:1 reagent, and gave the γ-product
efficiently (entries 15 and 16).
rac-14a AcO
rac-14a AcO
rac-14a AcO
rac-14a AcO
rac-14a AcO
rac-14a AcO
Cl 1.4 CuCl,d 0.2
Br 1.4 CuCl,d 0.2
9 rac-14b PivO
10 rac-14b PivO
Cl 2.0 2.3
Cl 4.0 1.0
0:0:0:100
91:9:0:0
11 rac-14c MeOCO2 Cl 2.0 2.3
12 rac-14c MeOCO2 Br 2.0 2.3
13 rac-14c MeOCO2 Cl 4.0 1.0
14 rac-14c MeOCO2 Br 4.0 1.0
0:15e:0:85
2:64e:0:34
89:11e:7:0
99:<1:0:0
15 rac-14d (2-Py)CO2 Cl 2.0 2.3
16 rac-14d (2-Py)CO2 Br 2.0 2.2
17 rac-14d (2-Py)CO2 Cl 4.0 1.0
18 rac-14d (2-Py)CO2 Br 4.0 1.0
4:96e:0:0
4:96e:0:0
64:29e:7:0
53:41e:6:0
aReactions were carried out at 0 °C for 1 h unless otherwise noted.
c
bStarting material. Cis:trans=ca. 1:2 by 1H NMR spectroscopy. dAt
-20 °C for 2 h. eCis:trans=ca. 2:1 by 1H NMR spectroscopy.
With the above results in hand, we prepared optically
active esters (S)-14a (>99% ee) and (S)-14c (81% ee) from
the corresponding alcohol19 of >99% ee (for (S)-14a,
Ac2O, DMAP, pyridine, CH2Cl2, rt, 100%; for (S)-14c,
ClCO2Me, pyridine, CH2Cl2, 0 °C-rt, 85%), though sub-
stantial drop in ee was observed with (S)-14c. These
esters upon reaction with BuMgBr/CuBr Me2S (>4:1)
3
under the optimized conditions produced (S)-15 in good
yields with high percent inversion and regioselectivity
(eq 3). Similarly, reactions with (i-PrO)Me2SiCH2MgCl/
CuBr Me2S (4:1) proceeded well to produce 18 quite
3
efficiently (eq 4). On the basis of these results and the
ee of (S)-14a and (S)-14c mentioned above, we decided
to use acetate 28 with (p-TBSO)(m-MeO)C6H3 as Ar2
in the real synthesis of imperanene (1) as shown in
Scheme 3. In addition, we are pleased to conclude
that highly efficient allylic substitution of ArCHd
CHCH(OAc)R with R0MgBr/CuBr Me2S is now estab-
3
lished.20
Successful synthesis of 1 and unsuccessful attempts for the
preparation of intermediates are summarized in Schemes 3
and 4. TBS ether 20 was converted to homologue 21 and Ar2-
CCH (31) through the Wittig reaction and the Corey-Fuchs
reaction, respectively, in good yields. An attempted asym-
metric addition of 31 to 21 according to the literature
(19) Itoh, T.; Matsushita, Y.; Abe, Y.; Han, S.-H.; Wada, S.; Hayase, S.;
Kawatsura, M.; Takai, S.; Morimoto, M.; Hirose, Y. Chem.;Eur. J. 2006,
12, 9228–9237.
(20) Additional example of successful substitution:
(18) The copper catalyst used in ref 2c (CuX) is uncertain because of
inconsistent description (Table 3, entry 2 and SI, CuCl vs. CuBr Me2S). As
3
shown in Table 1 of the present MS, we confirmed essentially no difference
between CuCl and CuBr Me2S.
3
5922 J. Org. Chem. Vol. 74, No. 16, 2009

Takashima and Kobayashi
JOCArticle
SCHEME 3. Synthesis of (S )-Imperanene
methods21 was, however, unsuccessful, giving unidentified
products (Scheme 4, attempt 1) probably due to the enoliz-
able methylene moiety as suggested by Trost in his similar
case.22,23 In contrast, addition of the lithium anion of 31 to
aldehyde 21 proceeded cleanly to produce racemic alcohol
rac-32, which was subjected to oxidation in order to obtain
ketone 33 for asymmetric hydrogen transfer reaction. How-
reduction of 34 was quite slow, affording alcohol (S)-22 in
24% yield after 24 h (attempt 3).24,25
Next, kinetic resolution of racemic allylic alcohol rac-23 by
asymmetric epoxidation26 was investigated to create the asym-
metric center for the allylic substitution. Under the reported
conditions,27 asymmetric epoxidation of rac-23, synthesized
from rac-22 by Red-Al reduction, afforded (S)-23 and epoxide
24 in reasonable yields. Both of the products were separated by
chromatography on silica gel, and converted to alcohol 27
separately. Epoxidation of (S)-23 was followed by Mitsunobu
inversion to afford 25 in 88% yield. Peterson reaction of 25 with
Bu3SnLi (prepared from Bu3SnH and LDA) proceeded well to
furnish γ-stannyl alcohol 26 stereoselectively in good yield.
Palladium-catalyzed Stille coupling of 26 with (p-TBSO)(m-
MeO)C6H3I (27, abbreviated to Ar2-I)28 was successful under
ever, oxidations with PCC, Dess-Martin, TPAP, SO3 Py
3
resulted in formation of complex mixtures (attempt 2). In
contrast, oxidation of racemic alcohol rac-22 derived from
21 and TMS acetylene successfully afforded ketone 34
(attempt 3). Unfortunately, asymmetric hydrogen transfer
(21) (a) Gao, G.; Moore, D.; Xie, R.-G.; Pu, L. Org. Lett. 2002, 4, 4143–
4146. (b) Gao, G.; Wang, Q.; Yu, X.-Q.; Xie, R.; Pu, L. Angew. Chem., Int.
Ed. 2006, 45, 122–125.
(22) Trost, B. M.; Ameriks, M. K. Org. Lett. 2004, 6, 1745–1748. Cf.:
Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687–9688.
(23) In contrast, the following reaction was successfully executed by the
authors to produce ii, which was converted to (S)-6 for the first approach
(Scheme 2).
modified conditions of Farina29 with use of Pd2dba3 CHCl3
3
(5mol%), AsPPh3 (20mol%), andLiCl(4equiv) inNMPatrt
to afford alcohol 28 (99% ee) in 78% yield.30 In a similar
manner, epoxide 24 was converted to 28 (98% ee) via vinyl-
stannane 26 in two steps. Finally, acetylation of alcohol 28 with
(26) (a) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda,
M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237–6240. (b) Gao, Y.;
Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B.
J. Am. Chem. Soc. 1987, 109, 5765–5780.
(27) Kinetic resolution of γ-silylallylic alcohols: Kitano, Y.; Matsumoto,
T.; Sato, F. Tetrahedron 1988, 44, 4073–4086.
(28) Prepared as presented below. See the Experimental Section.
(24) Reaction at 35 °C produced a mixture of (S)-22 and unidentified
products.
(25) In contrast, asymmetric hydrogen transfer reduction of ketones iii
and iv executed by the authors gave alcohols v (90%, 98% ee) and vi (86%),
respectively.
(29) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585–9595.
(30) Other conditions (Pd2dba3 CHCl3/AsPPh3 in THF at 50 °C, Pd-
3
(PPh3)4/CuI/CsF in DMF at 50 °C, and Pd(PPh3)4/LiCl in refluxing toluene)
were unsuccessful, in our hand.
J. Org. Chem. Vol. 74, No. 16, 2009 5923

Takashima and Kobayashi
JOCArticle
SCHEME 4. Attempted Preparation of Intermediatesa
an argon atmosphere. After 20 min at 0 °C, a solution of 20
(2.04 g, 7.66 mmol) in THF (10 mL) was added to the reaction
mixture. The mixture was allowed to warm slowly to ambient
temperature, stirred for 14 h, and poured into saturated NH4Cl.
The product was extracted with EtOAc twice. The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated in vacuo to afford a residual oil, which was
chromatographed on silica gel with hexane/EtOAc (from 1:0
to 20:1) to afford the corresponding enol ether (2.14 g, 95%) as a
1
65:35 mixture of trans and cis isomers: H NMR (300 MHz,
CDCl3) δ 0.14 (s, 6 H), 0.99 (s, 9 H), 3.66 (s, 2 H), and 3.77 (s,
1 H), 3.80 (s, 3 H), 5.16 (d, J=7 Hz, 0.35 H), and 5.76 (d, J=
13 Hz, 0.65 H), 6.05 (d, J=7 Hz, 0.35 H), and 6.94 (d, J=13 Hz,
0.65 H), 6.66-6.78 (m, 3 H).
To a solution of the above enol ether (114 mg, 0.387 mmol)
and NaI (63 mg, 0.42 mmol) in MeCN (7 mL) was added TMSCl
(0.043 mL, 0.34 mmol) at -18 °C under an argon atmosphere.
After 30 min at -18 °C, the reaction mixture was poured into
aqueous Na2S2O3. The product was extracted with EtOAc
twice. The combined organic layers were washed with brine,
dried over MgSO4, and concentrated in vacuo to afford a
residual oil, which was chromatographed on silica gel with
hexane/EtOAc (from 1:0 to 20:1) to afford aldehyde 21 (78
mg, 72%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 0.15
(s, 6 H), 0.99 (s, 9 H), 3.60 (d, J=2.5 Hz, 2 H), 3.80 (s, 3 H), 6.63-
6.70 (m, 2 H), 6.84 (d, J=8 Hz, 1 H), 9.71 (t, J=2.5 Hz, 1 H).
To a solution of trimethylsilylacetylene (0.62 mL, 4.39 mmol)
in THF (12 mL) was added n-BuLi (2.73 mL, 1.55 M in THF,
4.23 mmol) at -78 °C under an argon atmosphere. After 0.5 h of
stirring at -78 °C, a solution of aldehyde 21 (948 mg, 3.38 mmol)
in THF (8 mL) was added to the solution. After 2 h of stirring at
-50 °C, the mixture was poured into saturated NH4Cl. The
product was extracted with EtOAc twice. The combined organic
layers were washed with brine, dried over MgSO4, and concen-
trated in vacuo to afford a residual oil, which was purified by
chromatography on silica gel with hexane/EtOAc (from 1:0 to
20:1) to afford propargyl alcohol rac-22 (931 mg, 73%) as a
aAr2 = (p-TBSO)(m-MeO)C6H3. Ru cat. = Ru[(S,S )-TsDPEN](p-cymene).
Ac2O and DMAP in CH2Cl2 afforded allylic acetate 29 in 95%
yield, which was 95% ee by chiral HPLC. The coupling reaction
of 29 with (i-PrO)Me2SiCH2MgCl/CuBr Me2S (4:1) at 0 °C
3
completed within 1 h to furnish the R-substitution product 30
regioselectively in 92% yield. Finally, oxidation of 30 under the
given conditions proceeded with concomitant desilylation of
the TBS ether to produce (S)-imperanene (1) in 73% yield: 95%
ee by chiral HPLC, [R]25D þ98 (c 0.70, CHCl3); lit. [R]25D þ97
(c 0.68, CHCl3) and [R]25D þ103 (c 1.7, CHCl3).7b
1
colorless oil: IR (neat) 3393, 1516, 1251, 1041, 841 cm-1; H
NMR (300 MHz, CDCl3) δ 0.15 (s, 6 H), 0.16 (s, 9 H), 0.99 (s, 9
H), 2.91 (dd, J=13, 6 Hz, 1 H), 2.94 (dd, J=13, 6 Hz, 1 H), 3.79
(s, 3 H), 4.53 (t, J=6 Hz, 3 H), 6.69-6.73 (m, 1 H), 6.71-6.80 (m,
2 H); 13C NMR (75 MHz, CDCl3) δ -4.5 (-), -0.08 (-), 18.5
(þ), 25.8 (-), 43.8 (þ), 55.5 (-), 63.7 (-), 90.3 (þ), 106.1 (þ),
113.8 (-), 120.8 (-), 122.2 (-), 129.8 (þ), 144.1 (þ), 150.8 (þ);
HRMS (FAB) calcd for C20H34O3Si2Na [(M þ Na)þ] 401.1944,
found 401.1943.
Conclusions
In summary, we have achieved the synthesis of (S)-imper-
anene (1) through R-selective allylic substitution of acetate
29 with the copper reagent derived from (i-PrO)Me2
SiCH2MgCl/CuBr Me2S (4:1) under the reaction conditions
3
established herein. Furthermore, several results unexpect-
edly encountered during the synthesis are disclosed as useful
information for future study of transforming highly oxyge-
nated aromatic compounds.
(E)-1-(4-(tert-Butyldimethylsilyloxy)-3-methoxyphenyl)-4-
(trimethylsilyl)but-3-en-2-ol (rac-23). To an ice-cold solution of
propargyl alcohol rac-22 (1.30 g, 3.43 mmol) in Et2O (35 mL)
was added Red-Al (1.91 mL, 70% toluene solution, 6.85 mmol)
under an argon atmosphere. After 1 h of stirring at room tem-
perature, the mixture was poured into saturated 1 N HCl with
vigorous stirring. The product was extracted with EtOAc twice.
The combined organic layers were washed with brine, dried over
MgSO4, and concentrated in vacuo to afford a residual oil, which
was chromatographed on silica gel with hexane/EtOAc (from 1:0
to 10:1) to afford allylic alcohol rac-23 (1.21 g, 92%) as a
Experimental Section
1-(4-(tert-Butyldimethylsilyloxy)-3-methoxyphenyl)-4-(trime-
thylsilyl)but-3-yn-2-ol (rac-22). To a solution of vanillin (5.01 g,
32.9 mmol) and imidazole (4.52 g, 66.4 mmol) in CH2Cl2
(70 mL) was added TBSCl (7.58 g, 50.3 mmol). The mixture
was stirred at room temperature for 1 h and poured into
saturated NH4Cl. The product was extracted with CH2Cl2
twice. The combined organic layers were washed with brine,
dried over MgSO4, and concentrated in vacuo to afford a
residual oil, which was chromatographed on silica gel with
hexane/EtOAc (from 1:0 to 20:1) to afford the known silyl ether
2031 (8.25 g, 94%) as a colorless oil.
1
colorless oil: IR (neat) 3393, 1517, 1281, 1125, 839 cm-1; H
NMR (300 MHz, CDCl3) δ 0.06 (s, 9 H), 0.15 (s, 6 H), 0.99 (s,
9H),1.71(brs,1H),2.68(dd,J=13.5, 8 Hz, 1 H), 2.82 (dd, J=13.5,
5 Hz, 1 H), 3.79 (s, 3 H), 4.24-4.34 (m, 1 H), 5.85 (dd, J=19,
1 Hz, 1 H), 6.09 (dd, J=19, 5 Hz, 1 H), 6.65 (dd, J=8, 2 Hz, 1 H),
6.70 (d, J = 2 Hz, 1 H), 6.79 (d, J = 8 Hz, 1 H); 13C NMR
(75 MHz, CDCl3) δ -4.5 (-), -1.2 (-), 18.5 (þ), 25.8 (-),
43.5 (þ), 55.5 (-), 75.0 (-), 113.5 (-), 120.9 (-), 121.8 (-),
129.6 (-), 131.0 (þ), 143.8 (þ), 147.5 (-), 150.9 (þ); HRMS
(FAB) calcd for C20H36O3Si2Na [(M þ Na)þ] 403.2101, found
403.2097.
To an ice-cold solution of (methoxymethyl)triphenylpho-
sphonium chloride (3.12 g, 9.10 mmol) in THF (40 mL) was
added NaN(TMS)2 (9.00 mL, 1.0 M in THF, 9.00 mmol) under
(31) Rao, P. N. P.; Chen, Q.-H.; Knaus, E. E. J. Med. Chem. 2006, 49,
1668–1683.
5924 J. Org. Chem. Vol. 74, No. 16, 2009

Takashima and Kobayashi
JOCArticle
(R)-2-(4-(tert-Butyldimethylsilyloxy)-3-methoxyphenyl)-1-
((2R,3R)-3-(trimethylsilyl)oxiran-2-yl)ethanol (24) and (E,R)-1-
(4-(tert-Butyldimethylsilyloxy)-3-methoxyphenyl)-4-(trimethylsilyl)-
but-3-en-2-ol ((S)-23). To a solution of Ti(O-i-Pr)4 (0.88 mL,
2.97 mmol) in CH2Cl2 (22 mL) was added (-)-DIPT (0.74 mL,
3.53 mmol) at -10 °C under an argon atmosphere. After 50 min
of stirring at -10 °C, a solution of allylic alcohol rac-23 (1.13 g,
2.97 mmol) in CH2Cl2 (8 mL) was added to the solution. After
50 min of stirring at -10 °C, the solution was cooled to -40 °C,
and t-BuOOH (0.56 mL, 5.86 M in CH2Cl2, 3.28 mmol) was
added. The solution was stirred at -20 °C for 7 h, and Me2S
(0.24 mL, 3.27 mmol) was added. The solution was stirred
at room temperature for 0.5 h, and 10% aqueous tartaric acid
(0.5 mL) and NaF (174 mg, 4.14 mmol) were added. The
resulting mixture was stirred for 30 min and filtered through a
pad of Celite. The filtrate was concentrated in vacuo to afford a
residual oil, which was chromatographed on silica gel with
hexane/EtOAc (from 100:1 to 4:1) to afford allylic alcohol (S)-
23 (572 mg, 51%) and epoxy alcohol 24 (525 mg, 44%) as a
colorless oil. Epoxy alcohol 24: [R]27D -3.7 (c 0.22, CHCl3); IR
(neat) 3447, 1516, 1282, 1250, 841 cm-1; 1H NMR (300 MHz,
CDCl3) δ 0.06 (s, 9 H), 0.14 (s, 6 H), 0.99 (s, 9 H), 1.95 (d, J=
2 Hz, 1 H), 2.36 (d, J=4 Hz, 1 H), 2.77-2.81 (m, 2H), 2.85 (t, J=
4 Hz, 1 H), 3.79 (s, 3 H), 3.96-4.04 (m, 1 H), 6.67 (dd, J=8, 2 Hz,
1 H), 6.74 (d, J=2 Hz, 1 H), 6.78 (d, J=8 Hz, 1 H); 13C NMR
(75 MHz, CDCl3) δ -4.6 (-), -3.6 (-), 18.5 (þ), 25.8 (-), 40.2
(þ), 48.0 (-), 55.5 (-), 57.9 (-), 70.6 (-), 113.3 (-), 120.9 (-),
121.6 (-), 130.6 (þ), 143.8 (þ), 151.0 (þ); HRMS (FAB) calcd
for C20H36O4Si2Na [(M þ Na)þ] 419.2050, found 419.2045.
Allylic alcohol (S)-23: [R]23D -9.3 (c 0.56, CHCl3).
(S)-2-(4-(tert-Butyldimethylsilyloxy)-3-methoxyphenyl)-1-
((2S,3S)-3-(trimethylsilyl)-oxiran-2-yl)ethanol (ent-24). To a solu-
tion of Ti(O-i-Pr)4 (0.45 mL, 1.52 mmol) in CH2Cl2 (10 mL) was
added (þ)-DIPT (0.38 mL, 1.82 mmol) at -10 °C under an argon
atmosphere. After 30 min of stirring at -10 °C, a solution of
allylic alcohol (S)-23 (577 mg, 1.52 mmol) in CH2Cl2 (5 mL) was
added to the solution. After 45 min of stirring at -20 °C, the
solution was cooled to -30 °C, and t-BuOOH (0.29 mL, 5.86 M
in CH2Cl2, 1.70 mmol) was added. The solution was stirred at
-20 °C for 13 h, and Me2S (0.12 mL, 1.63 mmol) was added. The
solution was stirred at room temperature for 0.5 h, and 10%
aqueoustartaricacid(0.3 mL) andNaF(0.114 g, 2.74mmol) were
added. The resulting mixture was stirred for 30 min and filtered
through a pad of Celite. The filtrate was concentrated in vacuo to
afford a residual oil, which was chromatographed on silica gel with
hexane/EtOAc (from 100:1 to 4:1) to afford epoxy alcohol ent-24
(0.505 g, 84%) as a colorless oil: [R]25D þ3.5 (c 0.63, CHCl3).
(R)-2-(4-(tert-Butyldimethylsilyloxy)-3-methoxyphenyl)-1-
((2S,3S)-3-(trimethylsilyl)-oxiran-2-yl)ethanol (25). To an ice-cold
solution of epoxy alcohol ent-24 (99 mg, 0.25 mmol), PPh3 (104 mg,
0.397 mmol), and ClCH2COOH (31 mg, 0.31 mmol) in THF
(1.5 mL) was added DIAD (0.15 mL, 0.305 mmol) dropwise. After
3 h of stirring at 0 °C, the mixture was allowed to warm to room
temperature over 13 h. The reaction mixture was concentrated in
vacuo to afford a residual oil, which was chromatographed on silica
gel with hexane/EtOAc (from 1:0 to 20:1) to afford the correspond-
ing chloroacetate (106 mg, 90%) as a colorless oil: 1H NMR
(300 MHz, CDCl3) δ 0.00 (s, 9 H), 0.14 (s, 6 H), 0.99 (s, 9 H),
1.95 (d, J=3 Hz, 1 H), 2.89 (dd, J=14, 8 Hz, 1 H), 2.94 (dd, J=
6, 3 Hz, 1 H), 3.01 (dd, J=14, 6 Hz, 1 H), 3.79 (s, 3 H), 4.05 (d, J=
15 Hz, 1 H), 4.10 (d, J=15 Hz, 1 H), 4.84 (dt, J=6, 8 Hz, 1 H), 6.63
(dd, J=8, 2 Hz, 1 H), 6.72 (d, J=2 Hz, 1 H), 6.77 (d, J=8 Hz, 1 H);
13C NMR (75 MHz, CDCl3) δ -4.6 (-), -3.7 (-), 18.5 (þ), 25.8
(-), 37.7 (þ), 41.0 (þ), 49.8 (-), 55.5 (-), 56.2 (-), 79.4 (-), 113.0
(-), 121.0 (-), 121.7 (-), 129.2 (þ), 144.1 (þ), 151.0 (þ), 166.7 (þ).
To an ice-cold solution of the above chloroacetate (327 mg,
0.691 mmol) in MeOH (3 mL) was added n-PrNH2 (0.06 mL,
0.73 mmol). After 1.5 h of stirring at 0 °C, the mixture was
poured into saturated NH4Cl. The product was extracted with
EtOAc twice. The combined organic layers were washed with
brine, dried over MgSO4, and concentrated in vacuo to afford a
residual oil, which was chromatographed on silica gel with
hexane/EtOAc (from 10:1 to 4:1) to afford epoxy alcohol 25
(269 mg, 98%) as a colorless oil: [R]24D -29 (c 0.18, CHCl3); IR
(neat) 3394, 1513, 1281, 1250, 841 cm-1; 1H NMR (300 MHz,
CDCl3) δ 0.02 (s, 9 H), 0.14 (s, 6 H), 0.99 (s, 9 H), 2.00 (d, J=
5 Hz, 1 H), 2.13 (d, J=4 Hz, 1 H), 2.79 (dd, J=13, 7 Hz, 1 H),
2.84-2.96 (m, 2 H), 3.59-3.69 (m, 1 H), 3.79 (s, 3 H), 6.66 (dd,
J=8, 2 Hz, 1 H), 6.72 (d, J=2 Hz, 1 H), 6.78 (d, J=8 Hz, 1 H);
13C NMR (75 MHz, CDCl3) δ -4.6 (-), -3.6 (-), 18.5 (þ), 25.8
(-), 40.7 (þ), 49.7 (-), 55.6 (-), 58.7 (-), 74.3 (-), 113.3 (-),
120.9 (-), 121.6 (-), 130.7 (þ), 143.8 (þ), 151.0 (þ); HRMS
(FAB) calcd for C20H36O4Si2Na [(M þ Na)þ] 419.2050, found
419.2061.
(R,E)-1-(4-(tert-Butyldimethylsilyloxy)-3-methoxyphenyl-
4-(tributylstannyl)but-3-en-2-ol (26). From 25:. To an ice-cold
solution of i-Pr2NH (0.32 mL, 2.28 mmol) in THF (4 mL) was
added n-BuLi (1.14 mL, 1.55 M in THF, 1.77 mmol) under an
argon atmosphere. After 0.5 h of stirring at 0 °C, Bu3SnH
(0.20 mL, 0.744 mmol) and, after 0.5 h at 0 °C, a solution of
epoxy alcohol 25 (260 mg, 0.655 mmol) in THF (2.5 mL) were
added to the solution. Stirring was continued at 0 °C for 1 h
and at room temperature for 4 h. The solution was poured
into saturated NH4Cl. The product was extracted with EtOAc
twice. The combined organic layers were washed with brine,
dried over MgSO4, and concentrated in vacuo to afford a
residual oil, which was chromatographed on silica gel with
hexane/EtOAc (from 1:0 to 20:1) to afford γ-stannyl alcohol
26 (330 mg, 84%) as an yellow oil: [R]23D1-8.7 (c 0.62, CHCl3);
IR (neat) 3360, 1515, 1282, 840 cm-1; H NMR (300 MHz,
CDCl3) δ 0.15 (s, 6 H), 0.84-0.94 (m, 15 H), 0.99 (s, 9 H),
1.23-1.37 (m, 6 H), 1.43-1.53 (m, 6 H), 1.67 (d, J=4 Hz, 1 H),
2.70 (dd, J=14, 8 Hz, 1 H), 2.82 (dd, J=14, 5 Hz, 1 H), 3.79
(s, 3 H), 4.23-4.32 (m, 1 H), 6.05 (dd, J = 19, 5 Hz, 1 H;
J
Sn-H(cis)=65 Hz), 6.17 (dd, J=19, 0.6 Hz, 1 H; JSn-H(gem)=
71 Hz), 6.65 (dd, J=8, 2.5 Hz, 1 H), 6.70-6.73 (m, 1 H), 6.75-
6.81 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ -4.6 (-), 9.5 (þ),
13.8 (-), 18.5 (þ), 25.8 (-), 27.4 (þ), 29.1 (þ), 43.7 (þ), 55.5
(-), 75.9 (-), 113.5 (-), 120.9 (-), 121.8 (-), 128.1 (-), 131.3
(þ), 143.7 (þ), 149.8 (-), 150.9 (þ). From 24: To an ice-cold
solution of i-Pr2NH (0.70 mL, 4.99 mmol) in THF (5 mL) was
added n-BuLi (2.51 mL, 1.55 M in THF, 3.89 mmol) under an
argon atmosphere. After 0.5 h of stirring at 0 °C, Bu3SnH
(0.43 mL, 1.60 mmol) and, after 0.5 h at 0 °C, a solution of
epoxy alcohol 24 (572 mg, 1.44 mmol) in THF (3 mL) were
added to the solution. Stirring was continued at 0 °C for 1 h
and at room temperature for 4 h. The solution was poured
into saturated NH4Cl. The product was extracted with EtOAc
twice and purified as above to afford alcohol 26 (646 mg,
75%) as an yellow oil.
1-(tert-Butyldimethylsilyloxy)-4-iodo-2-methoxybenzene (27).
To a solution of phenol 2-methoxyphenol (103 mg, 0.83 mmol)
and NaOH (61 mg, 1.53 mmol) in MeOH (2 mL) was added I2
(215 mg, 0.847 mmol) at -4 °C. The mixture was stirred at -4 °C
for 1 h and poured into H2O. The product was extracted with
EtOAc twice. The combined organic layers were washed with
aqueous Na2S2O and brine, dried over MgSO4, and concen-
trated in vacuo to afford a residual oil, which was chromato-
graphed on silica gel with hexane/EtOAc (from 1:0 to 10:1) to
afford 4-iodo-2-methoxyphenol (120 mg, 70%) as a colorless oil:
1H NMR (300 MHz, CDCl3) δ 3.88 (s, 3 H), 5.57 (s, 1 H), 6.68 (d,
J=8 Hz, 1 H), 7.13 (d, J=2 Hz, 1 H), 7.18 (dd, J=8, 2 Hz, 1 H).
The 1H NMR spectrum was identified with that reported.32
(32) Fryatt, T.; Botting, N. P. J. Labelled Compd. Radiopharm. 2005, 48,
951–969.
J. Org. Chem. Vol. 74, No. 16, 2009 5925

Takashima and Kobayashi
JOCArticle
A solution of the above iodide (404 mg, 1.84 mmol), TBSCl
(369 mg, 2.45 mmol), and imidazole (203 mg, 2.98 mmol) in
CH2Cl2 (10 mL) was stirred at room temperature for 12 h and
poured into saturated NH4Cl. The product was extracted with
CH2Cl2 twice. The combined organic layers were washed with
brine, dried over MgSO4, and concentrated in vacuo to afford a
residual oil, which was chromatographed on silica gel with
hexane to afford 27 (454 mg, 74%) as a colorless oil: IR (neat)
1581, 1496, 1256, 1224, 831 cm-1; 1H NMR (300 MHz, CDCl3)
δ 0.14 (s, 6 H), 0.98 (s, 9 H), 3.78 (s, 3 H), 6.59 (d, J=8 Hz, 1 H),
7.10 (d, J=2.5 Hz, 1 H), 7.12 (dd, J=8, 2.5 Hz, 1 H); 13C NMR
(75 MHz, CDCl3) δ -4.6 (-), 18.5 (þ), 25.7 (-), 55.7 (-), 83.4
(þ), 121.2 (-), 122.9 (-), 130.0 (-), 145.3 (þ), 152.0 (þ).
(R,E)-1,4-Bis(4-(tert-butyldimethylsilyloxy)-3-methoxyphe-
nyl)but-3-en-2-ol (28). To a solution of the above iodide (224
mg, 0.615 mmol), LiCl (69 mg, 1.63 mmol), Ph3As (26 mg,
145.3 (þ), 150.7 (þ), 151.0 (þ), 170.2 (þ); HRMS (FAB)
calcd for C32H50O6Si2Na [(M þ Na)þ] 609.3044, found
609.3045.
(R,E)-1,4-Bis(4-(tert-butyldimethylsilyloxy)-3-methoxyphen-
yl)-3-(isopropyloxydimethylsilyl)methylbut-3-en (30). To an
ice-cold suspension of CuBr Me2S (32 mg, 0.156 mmol) in
3
THF (2.4 mL) was added (i-PrO)Me2SiCH2MgCl (0.75 mL,
0.85 M in THF, 0.64 mmol) dropwise. After 0.5 h of stirring
at 0 °C, a solution of acetate 29 (94 mg, 0.16 mmol) in THF
(1.6 mL) was added to the mixture dropwise. After 1 h of
stirring at 0 °C, the mixture was diluted with EtOAc and
saturated NH4Cl with vigorous stirring. The layers were
separated and the aqueous layer was extracted with EtOAc
twice. The combined organic layers were washed with brine,
dried over MgSO4, and concentrated in vacuo to afford a
residual oil, which was chromatographed on silica gel with
hexane/EtOAc (from 1:0 to 30:1) to afford olefin 30 (97.5 mg,
92%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 0.01-
0.19 (m, 2H), 0.09 (s, 6 H), 0.12 (s, 6 H), 0.14 (s, 6 H), 0.98 (s,
9 H), 0.99 (s, 9 H), 1.10 (d, J=6 Hz, 1 H), 1.12 (d, J=6 Hz, 1 H),
2.48-2.72 (m, 3 H), 3.70 (s, 3 H), 3.79 (s, 3 H), 3.88-4.00 (m,
1 H), 5.86 (dd, J=16, 8 Hz, 1 H), 6.09 (d, J=16 Hz, 1 H),
6.56-6.63 (m, 2 H), 6.72-6.79 (m, 4 H); 13C NMR (75 MHz,
CDCl3) δ -4.60 (-), -4.57 (-), -0.58 (-), -0.08 (-), 18.52
(þ), 18.54 (þ), 22.8 (þ), 25.8 (-), 25.9 (-), 40.9 (-), 45.4 (þ),
55.5 (-), 64.8 (-), 109.7 (-), 113.7 (-), 118.8 (-), 120.5 (-),
120.9 (-), 121.7 (-), 128.6 (-), 131.9 (þ), 133.8 (-), 134.2
(þ), 134.3 (-), 143.0 (þ), 144.3 (þ), 150.4 (þ), 150.9 (þ).
(S)-Imperanene (1). To a solution of olefin 30 (97.5 mg, 0.148
mmol), KF (65.5 mg, 1.13 mmol), and KHCO3 (95,6 mg, 0.955
mmol) in THF/MeOH (1:1, 4 mL) was added 35% H2O2 (0.43
mL, 4.94 mmol) dropwise at 60 °C. After 2 h of stirring at
60 °C, the reaction mixture was poured into aqueous Na2S2O3.
The product was extracted with EtOAc twice. The combined
organic layers were washed with brine, dried over MgSO4,
and concentrated in vacuo to afford a residual oil, which was
chromatographed on silica gel with hexane/EtOAc (from 20:1
to 1:1) to afford (S)-imperanene (1) (35.7 mg, 73%) as a
colorless oil: 95% ee by HPLC analysis (Chiralcel OD-H,
hexane/i-PrOH = 70/30, 0.3 mL/min, rt; tR/min = 51.8 (R),
60.6 (S)); [R]25D þ97.7 (c 0.70, CHCl3); [R]25D þ104 (c 0. 010,
CHCl3), [R]25D þ97 (c 0. 68, CHCl3);7b,7d 1H NMR (300 MHz,
CDCl3) δ 1.77 (br s, 1 H), 2.56-2.78 (m, 3 H), 3.55 (dd, J=11,
7 Hz, 1 H), 3.66 (dd, J=11, 4 Hz, 1 H), 3.81 (s, 3 H), 3.87 (s, 3
H), 5.62 (s, 1 H), 5.78 (s, 1 H), 5.92 (dd, J=16, 8 Hz, 1 H), 6.34
(d, J=16 Hz, 1 H), 6.65-6.69 (m, 2 H), 6.78-6.86 (m, 4 H);
13C NMR (75 MHz, CDCl3) δ 37.7 (þ), 47.6 (-), 55.9 (-), 65.3
(þ), 108.3 (-), 111.8 (-), 114.2 (-), 114.5 (-), 119.7 (-), 121.9
(-), 128.4 (-), 129.7 (þ), 131.6 (-), 132.2 (-), 143.9 (þ), 145.3
(þ), 146.4 (þ), 146.7 (þ). These 1H and 13C MMR spectra
were identical with those reported.7b,7d
0.085 mmol), and Pd2(dba)3 CHCl3 (21 mg, 0.020 mmol) in
3
NMP (1 mL) was added a solution of γ-stannyl alcohol 26
(250 mg, 0.418 mmol) in NMP (3 mL) under an argon
atmosphere. After 11 h of stirring at room temperature,
the mixture was poured into saturated NH4Cl. The product
was extracted with EtOAc twice. The combined organic
layers were washed with brine, dried over MgSO4, and
concentrated in vacuo to afford a residual oil, which was
purified by chromatography on silica gel with hexane/
EtOAc (from 1:0 to 10:1) to afford allylic alcohol 28 (207
mg, 91%) as an yellow oil: >99% ee by HPLC analysis
(Chiralcel OD-H, hexane/i-PrOH=98/2, 0.3 mL/min, 40 °C;
tR/min=51.7 (S), 55.2 (R)); [R]23D -22.7 (c 1.09, CHCl3); IR
(neat) 3373, 1513, 1281, 1125, 903 cm-1; 1H NMR (300 MHz,
CDCl3) δ 0.146 (s, 6 H), 0.152 (s, 6 H), 0.99 (s, 18 H), 2.78 (dd,
J=14, 8 Hz, 1 H), 2.90 (dd, J=14, 5 Hz, 1 H), 3.77 (s, 3 H),
3.81 (s, 3 H), 4.41-4.50 (m, 1 H), 6.13 (dd, J=16, 7 Hz, 1 H),
6.50 (d, J=16 Hz, 1 H), 6.68-6.90 (m, 6 H); 13C NMR (75
MHz, CDCl3) δ -4.6 (-), 18.6 (þ), 25.8 (-), 44.1 (þ), 55.50
(-), 55.53 (-), 73.7 (-), 109.9 (-), 113.6 (-), 119.6 (-),
120.96 (-), 121.01 (-), 121.8 (-), 129.6 (-), 130.4 (-), 130.7
(þ), 131.1 (þ), 143.9 (þ), 145.0 (þ),150.9 (þ), 151.1 (þ); HRMS
(FAB) calcd for C30H48O5Si2Na [(MþNa)þ] 567.2938, found
567.2940.
(R,E)-1,4-Bis(4-(tert-butyldimethylsilyloxy)-3-methoxyphe-
nyl)but-3-en-2-yl Acetate (29). To a solution of allylic alco-
hol 28 (55 mg, 0.0937 mmol) and DMAP (14.5 mg, 0.119
mmol) in CH2Cl2 (0.5 mL) was added a solution of Ac2O
(0.011 mL, 0.12 mmol) in CH2Cl2 (0.7 mL) at -18 °C under
an argon atmosphere. After 2 h of stirring at -18 °C, the
mixture was poured into saturated NaHCO3. The product
was extracted with CH2Cl2 twice. The combined organic
layers were washed with brine, dried over MgSO4, and
concentrated in vacuo to afford a residual oil, which was
purified by chromatography on silica gel with hexane/
EtOAc (from 1:0 to 30:1) to afford acetate 29 (52 mg, 95%)
as an yellow oil: 95% ee by HPLC analysis (Chiralcel OD-H,
hexane/i-PrOH=99/1, 0.3 mL/min, 40 °C; tR/min=24.1 (R),
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Science, Sports, and Culture, Japan. The alcoholic
precursor of (S)-14a,c was kindly provided by Professor
Toshiyuki Itoh at the Department of Chemistry and Bio-
technology, Tottori University.
38.7 (S)); [R]25 -12 (c 0.93, CHCl3); IR (neat) 1735, 1508,
D
1281, 1235, 903 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.13 (s,
6 H), 0.14 (s, 6 H), 0.98 (s, 9 H), 0.99 (s, 9 H), 2.02 (s, 3 H), 2.88
(dd, J = 14, 6 Hz, 1 H), 2.97 (dd, J = 14, 7 Hz, 1 H), 3.75
(s, 3 H), 3.80 (s, 3 H), 5.56 (q, J=7 Hz, 1 H), 5.99 (dd, J=16, 7 Hz,
1 H), 6.46 (d, J = 16 Hz, 1 H), 6.64-6.85 (m, 6 H); 13C
NMR (75 MHz, CDCl3) δ -4.6 (-), 18.52 (þ), 18.54 (þ),
21.4 (-), 25.79 (-), 25.80 (-), 41.1 (þ), 55.50 (-), 55.51 (-),
73.5 (-), 110.1 (-), 113.6 (-), 119.7 (-), 120.8 (-), 121.0 (-),
121.9 (-), 125.1 (-), 130.3 (þ), 130.5 (þ), 132.7 (-), 143.7 (þ),
Supporting Information Available: Experimental proce-
dures and spectral data of compounds described herein. This
material is available free of charge via the Internet at http://
pubs.acs.org.
5926 J. Org. Chem. Vol. 74, No. 16, 2009