Concise synthesis of cyclic ethers via the palladium-catalyzed coupling of ketene acetal triflates and organozinc reagents. Application to the iterative synthesis of polycyclic ethers

Article abstract of DOI:10.1021/jo025566f

The reaction of the ketene acetal triflates 9a-e and a zinc homoenolate 10 in the presence of a catalytic amount of Pd(PPh₃)₄ gave the enol ethers 11a-e in good yields. The products were converted to the corresponding cyclic ethers 1

Full text of DOI:10.1021/jo025566f

3494
J . Org. Chem. 2002, 67, 3494-3498
Con cise Syn th esis of Cyclic Eth er s via th e P a lla d iu m -Ca ta lyzed
Cou p lin g of Keten e Aceta l Tr ifla tes a n d Or ga n ozin c Rea gen ts.
Ap p lica tion to th e Iter a tive Syn th esis of P olycyclic Eth er s
Isao Kadota,† Hiroyoshi Takamura, Kumi Sato, and Yoshinori Yamamoto*
Research Center for Sustainable Materials Engineering, Institute of Multidisciplinary Research for
Advanced Materials, and Department of Chemistry, Graduate School of Science, Tohoku University,
Sendai 980-8578, J apan
yoshi@yamamoto1.chem.tohoku.ac.jp
Received J anuary 30, 2002
The reaction of the ketene acetal triflates 9a -e and a zinc homoenolate 10 in the presence of a
catalytic amount of Pd(PPh3)4 gave the enol ethers 11a -e in good yields. The products were
converted to the corresponding cyclic ethers 14a and 14b by hydroboration and lactonization. The
present methodology allowed us to synthesize the DE and GH ring segment of gambierol in a concise
manner. Iterative syntheses of the polycyclic ethers 26 and 32 are also described.
Sch em e 1. Retr osyn th etic An a lysis of Ga m bier ol
(1)
In tr od u ction
In recent years there has been an explosion of interest
in biologically active natural products of marine origin.1
Because of their structural novelty and toxicity, polycyclic
ethers are particularly attractive targets for synthetic
chemists.2 Gambierol (1), a potent neurotoxin isolated
from the cultured cells of Gambierdiscus toxicus, has 8
ether rings and 18 stereogenic centers.3 The compound
shows toxicity against mice (LD50 50 µg/kg), and the
symptoms resemble those caused by ciguatoxins, infer-
ring the possibility that it is also implicated in ciguatera
poisoning.1 The unique structural features have attracted
the attention of synthetic chemists, and a number of
strategies have been investigated.4 Scheme 1 illustrates
our initial synthetic approach toward 1. Retrosynthetic
disassembly of the target molecule 1 based on the
vinyllithium-aldehyde condensation followed by Barton
deoxygenation afforded 2 and 3.5 The ABCDE ring
segment 2 would be synthesized from 4 and 5 by the
† Institute of Multidisciplinary Research for Advanced Materials.
(1) For recent reviews, see: (a) Shimizu, Y. Chem. Rev. 1993, 93,
1685-1698. (b) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897-
1909.
(2) For recent reviews, see: (a) Alvarez, E.; Candenas, M.-L.; Pe´rez,
R.; Ravelo, J . L.; Mart´ın, J . D. Chem. Rev. 1995, 95, 1953-1980. (b)
Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1996, 35, 589-607. (c)
Mori, Y. Chem. Eur. J . 1997, 3, 849-852. Also see: (d) Hoberg, J . O.
Tetrahedron 1998, 54, 12630-12670.
(3) (a) Satake, M.; Murata, M.; Yasumoto, T. J . Am. Chem. Soc.
1993, 115, 361-362. (b) Morohashi, A.; Satake, M.; Yasumoto, T.
Tetrahedron Lett. 1999, 39, 97-100.
(4) (a) Kadota, I.; Park, C.-H.; Ohtaka, M.; Oguro, N. Yamamoto,
Y. Tetrahedron Lett. 1998, 39, 6365-6368. (b) Kadota, I.; Kadowaki,
C.; Yoshida, N. Yamamoto, Y. Tetrahedron Lett. 1998, 39, 6369-6372.
(c) Kadota, I.; Ohno, A.; Matsukawa, Y.; Yamamoto, Y. Tetrahedron
Lett. 1998, 39, 6373-6376. (d) Kadowaki, C.; Philip, W. H. C.; Kadota,
I.; Yamamoto, Y. Tetrahedron Lett. 2000, 41, 5769-5772. (e) Fuwa,
H.; Sasaki, M.; Tachibana, K. Tetrahedron Lett. 2000, 41, 8371-8375.
(f) Kadota, I.; Takamura, H.; Sato, K.; Yamamoto, Y. Tetrahedron Lett.
2001, 42, 4729-4731. (g) Kadota, I.; Ohno, A.; Matsuda, K.; Yamamoto,
Y. J . Am. Chem. Soc. 2001, 123, 6702-6703. (h) Sakamoto, Y.; Matsuo,
G.; Matukura, H.; Nakata, T. Org. Lett. 2001, 3, 2749-2752. (i) Cox,
J . M.; Rainier, J . D. Org. Lett. 2001, 3, 2919-2922. (j) Fuwa, H.; Sasaki,
M.; Tachibana, K. Tetrahedron 2001, 57, 3019-3033. (k) Fuwa, H.;
Sasaki, M.; Tachibana, K. Org. Lett. 2001, 3, 3549-3552. (l) Kadota,
I.; Kadowaki, C.; Park, C.-H.; Takamura, H.; Sato, K.; ChanP. W. H.;
Thorand, S.; Yamamoto, Y. Tetrahedron, 2002, 58, 1799-1816.
same methodology. On the basis of this analysis, we
synthesized the GH ring segment 8, precursor of 3, as
shown in Scheme 2. The intramolecular reaction of 6,
prepared from 2-deoxy-D-ribose in 12 steps, mediated by
BF3‚OEt2 gave 7 as the sole product in quantitative
yield.4c The product 7 was converted to 8 by a four-step
sequence including ozonolysis, Wittig reaction, hydroge-
nation, and lactonization.4l Although the GH ring seg-
ment 8 was obtained in a highly stereoselective manner,
the synthesis was not particularly efficient because of the
relatively long synthetic schemes (total 17 steps). This
problem prompted us to develop a new synthetic route.
Here we report an efficient and concise synthesis of
medium sized cyclic ethers via the palladium-catalyzed
coupling of ketene acetal triflates and organozinc re-
agents.6,7
(5) Nicolaou, K. C.; Theodorakis, E. A.; Rutjes, F. P. J . T.; Sato, M.;
Tiebes, J .; Xiao, X.-Y.; Hwang, C.-K.; Duggan, M. E.; Yang, Z.;
Couladouros, E. A.; Sato, F.; Shin, J .; He, H.-M.; Bleckman, T. J . Am.
Chem. Soc. 1995, 117, 10239-10251.
10.1021/jo025566f CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/25/2002

Iterative Synthesis of Polycyclic Ethers
J . Org. Chem., Vol. 67, No. 10, 2002 3495
Ta ble 1. P a lla d iu m -Ca ta lyzed Cou p lin g of Keten e Aceta l
Tr ifla tes 9 a n d Zin c Hom oen ola te 10a
Sch em e 2
Sch em e 3
Resu lts a n d Discu ssion
Our new synthetic strategy is illustrated in Scheme 3.
Since the palladium-catalyzed coupling of alkylzinc re-
agents and aryl halides was reported by Negishi in 1977,8
a number of modified reactions have been developed.9 In
1986, Tamaru reported the palladium-catalyzed coupling
of alkenyl triflates, derived from ketones, and zinc
homoenolates.10 It was thought that the coupling of the
ketene acetal triflate 9, derived from lactones, and the
zinc homoenolate 1011 would give the cyclic enol ether
11, and the subsequent hydroboration of the double bond
of 11 followed by lactonization would provide the desired
cyclic ether 12.
a
Reactions were carried out with 10 (2 equiv) in the presence
b
of Pd(PPh3)4 (5 mol %) in benzene at room temperature. Ketene
acetal triflates were prepared from the corresponding lactones by
the standard procedure and used without purification. c Isolated
yields.
Sch em e 4a
The results of the coupling of 9 and 10 are summarized
in Table 1. Treatment of 9a , prepared from the corre-
sponding lactone by the standard procedure,7e with 2
equiv of the zinc homoenolate 10 in the presence of
Pd(PPh3)4 at room temperature gave the enol ether 11a
in 74% yield (entry 1). Similarly, the reaction of the six-
membered ketene acetal triflates 9b and 9c with 10
under the same reaction conditions gave the correspond-
ing cyclic enol ethers 11b and 11c, respectively, in good
yields (entries 2 and 3). To synthesize the DE and GH
rings of gambierol, it was necessary to know whether the
palladium-catalyzed coupling methodology is applicable
(6) For a preliminary communication, see ref 4f.
(7) For the synthesis of cyclic ethers via the coupling of ketene acetal
triflates derived from lactones, see: (a) Tsushima, K.; Araki, K.; Murai,
A. Chem. Lett. 1989, 1313-1316. (b) Tsushima, K.; Murai, A. Chem.
Lett. 1990, 761-764. (c) Feng, F.; Murai, A. Chem. Lett. 1992, 1587-
1590. (d) Feng, F.; Murai, A. Synlett 1995, 863-865. (e) Fujiwara, K.;
Tsunashima, M.; Awakura, D.; Murai, A. Tetrahedron Lett. 1995, 36,
8263-8266. (f) Nicolaou, K. C.; Theodorakis, E. A.; Rutjes, F. P. J . T.;
Tiebes, J .; Sato, M.; Untersteller, E.; Xiao, X.-Y. J . Am. Chem. Soc.
1995, 117, 1171-1172. (g) Nicolaou, K. C.; Theodorakis, E. A.; Rutjes,
F. P. J . T.; Sato, M.; Tiebes, J .; Xiao, X.-Y.; Hwang, C.-K.; Duggan, M.
E.; Yang, Z.; Couladouros, E. A.; Sato, F.; Shin, J .; He, H.-M.;
Bleckman, T. J . Am. Chem. Soc. 1995, 117, 10239-10251. (h) Nicolaou,
K. C.; Sato, M.; Miller, N. D.; Gunzner, J . L.; Renaud, J .; Untersteller,
E. Angew. Chem., Int. Ed. Engl. 1996, 35, 889-891. (i) Sasaki, M.;
Fuwa, H.; Inoue, M.; Tachibana, K. Tetrahedron Lett. 1998, 39, 9027-
9030.
(8) Negishi, E.; King, A. O.; Okukado, N. J . Org. Chem. 1977, 42,
1821-1823.
(9) For recent reviews, see: (a) Erdik, E. Tetrahedron 1992, 48,
9577-9648. (b) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117-
2188. (c) Knochel, P.; Perea, J . J . A.; J ones, P. Tetrahedron 1998, 54,
8275-8391.
(10) Tamaru, Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z. Tetrahedron
Lett. 1986, 27, 955-958.
(11) Tamaru, Y.; Ochiai, H.; Nakamura, T.; Tsubaki, K.; Yoshida,
Z. Tetrahedron Lett. 1985, 26, 5559-5562.
a
Reagents and conditions: (a) BH3‚SMe2. THF, 0 °C to rt, then
30% H2O2, 3 N NaOH, rt; (b) TEMPO, NaClO, KBr, CH2CH2/H2O,
0 °C.
to seven-membered ketene acetal triflates. The reaction
of 9d with 10 under the same reaction conditions afforded
the desired cyclic enol ether 11d in 82% yield (entry 4).
Also, 9e gave 11e in 76% yield (entry 5).
Scheme 4 describes the conversion of the enol ethers
obtained to the corresponding bicyclic ethers. Hydro-
boration of 11a with BH3‚SMe2 followed by oxidative
workup gave a 7:3 mixture of the diols 12a and 13a in
87% combined yield.12 Although attempts to effect
(12) The similar hydroboration-reduction of unsaturated esters with
diborane giving the corresponding diols has been reported; see: Brown,
H. C.; Keblys, K. A. J . Am. Chem. Soc. 1964, 86, 1795-1801.

3496 J . Org. Chem., Vol. 67, No. 10, 2002
Kadota et al.
Sch em e 5a
Sch em e 7a
a
Reagents and conditions: (a) BH3‚SMe2. THF, 0 °C to rt, then
30% H2O2, 3 N NaOH, rt; (b) TEMPO, NaClO, KBr, CH2CH2/H2O,
0 °C, 79% (2 steps).
Sch em e 6a
a
Reagents and conditions: (a) (i) PhNTf2, KHMDS, DMPU,
THF, -78 °C; (ii) 10, Pd(PPh3)4, benzene, rt, 73% (2 steps); (b)
BH3‚SMe2, THF, 0 °C to rt, then 30% H2O2, 3 N NaOH, rt, 92%;
(c) TEMPO, NaClO, KBr, CH2CH2/H2O, 0 °C, 87 %; (d) same as a,
80%; (e) same as b, 81%; (f) same as c, 82%.
a
Reagents and conditions: (a) (i) thexylborane, THF, 0 °C to
rt, then 30% H2O2, 3 N NaOH, rt; (ii) LiAlH4, ether, 0 °C; (b)
TEMPO, NaClO, KBr, CH2CH2/H2O, 0 °C, 68% (3 steps).
Hydroboration of 20 with BH3‚SMe2 followed by oxidative
workup afforded the diol 21 as the sole product in 92%
yield. TEMPO oxidation of 21 provided 22 in 87% yield.
The similar transformation as above produced the tet-
racyclic compound 26 in an allowable yield (36% in four
steps), although the stereoselectivity in the hydroboration
of 23 was moderate.
Scheme 8 demonstrates the synthesis of the poly-
oxepane 32. Triflation of 27 followed by palladium-
catalyzed coupling with zinc bishomoenolate 28 gave the
seven-membered cyclic enol ether 29 in 78% yield.
Hydroboration of 29 with thexylborane afforded the
corresponding â-hydroxy cyclic ether having an unreacted
ester group, which was then saponified and subjected to
Yamaguchi lactonization to give 30 as a sigle stereo-
isomer in 71% overall yield.16 Iteration of this five-step
sequnce starting from 30 provided the 7,7,7-tricyclic
lactone 32 in 34% overall yield.
chemoselective hydroboration of the double bond in the
presence of an ester group giving the corresponding
δ-hydroxy ester resulted in failure, the diol 12a could be
converted directly to the desired lactone 14a by TEMPO
oxidation. The treatment of 12a with aqueous NaClO in
the presence of catalytic amounts of TEMPO and KBr
afforded 14a in 89% yield.13 Similarly, the bicyclic lactone
14b was obtained from 11b in reasonable yield (45% in
two steps).
On the basis of these results, we next investigated the
synthesis of the DE and GH ring segment of 1. Treatment
of 11d with BH3‚SMe2 followed by oxidative work up gave
the diol 15 as a mixture of diastereomers (Scheme 5).
TEMPO oxidation of 15 gave a 43:57 mixture of the DE
ring segment 16 and its stereoisomer 17 in 79% yield
from 11d . Although several attempts such as the use of
bulky borane reagents were made to improve the stereo-
selectivity, the diastereomer ratio remained about 1:1.
Scheme 6 describes the synthesis of the GH ring
segment. Hydroboration of 11e with thexylborane gave
a mixture of the diol 18 and unidentified compounds
having ester and aldehyde groups. Treatment of this
mixture with LiAlH4 gave pure 18 as a single stereo-
isomer. Oxidation of 18 gave the GH ring segment 8 in
68% yield in three steps from 11e.
(14) For examples of the iterative synthesis of polycyclic ethers,
see: (a) Kozikowski, A. P.; Ghosh, A. K. J . Org. Chem. 1985, 50, 3017-
3019. (b) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-
K. J . Am. Chem. Soc. 1989, 111, 5330-5334. (c) Yamamoto, Y.;
Yamada, J .; Kadota, I. Tetrahedron Lett. 1991, 32, 7069-7072. (d)
Palazo´n, J . M.; Soler, M. A.; Ram´ırez, M. A.; Mart´ın, V. S. Tetrahedron
Lett. 1993, 34, 5467-5470. (e) Lee. E.; Tae, J . S.; Chong, Y. H.; Park,
Y. C.; Yun, M.; Kim, S. Tetrahedron Lett. 1994, 35, 129-132. (f)
Hoffmann, R. W.; Mu¨nster, I. Tetrahedron Lett. 1995, 36, 1431-1434.
(g) Evans, P. A.; Roseman, J . D.; Garber, L. T. J . Org. Chem. 1996,
61, 4880-4881. (h) Hayashi, N.; Fujiwara, K.; Murai, A. Tetrahedron
Lett. 1996, 37, 6173-6176. (i) Mori, Y.; Yaegashi, K.; Furukawa, H. J .
Am. Chem. Soc. 1996, 118, 8158-8159. (j) Bowman, J . L.; McDonald,
F. E. J . Org. Chem. 1998, 63, 3680-3682. (k) Rainier, J . D.; Allwein,
S. P. Tetrahedron Lett. 1998, 39, 9601-9604. (l) Hori, N.; Matsukura,
H.; Matsuo, G.; Nakata, T. Tetrahedron Lett. 1999, 40, 2811-2814.
(m) Marmsa¨ter, F. P.; West, F. G. J . Am. Chem. Soc. 2001, 123, 5144-
5145.
Encouraged by the performance of the present meth-
odology described above, we attempted to carry out the
iterative synthesis of polycyclic ethers.14,15 Treatment of
the lactone 19 with KHMDS and PhNTf2 gave the
corresponding ketene acetal triflate, which was directly
subjected to the palladium-catalyzed coupling with 10 to
give the cyclic enol ether 20 in 73% yield (Scheme 7).
(15) For examples of biomimetic synthesis of polycyclic ethers by
the cascade reaction of polyepoxides, see: (a) Tokiwano, T.; Fujiwara,
K.; Murai, A. Synlett 2000, 335-338. (b) McDonald, F. E.; Wang, X.;
Do, B.; Hardcastle, K. I. Org. Lett. 2000, 2, 2917-2919.
(16) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989-1993.
(13) Anelli, P. L.; Banfi, S.; Montanari, F.; Quici, S. J . Org. Chem.
1989, 54, 2970-2972.

Iterative Synthesis of Polycyclic Ethers
J . Org. Chem., Vol. 67, No. 10, 2002 3497
Sch em e 8a
Hyd r obor a tion of 11a . To a mixture of 11a (101 mg, 0.33
mmol) in THF (3 mL) at 0 °C was added BH3‚SMe2 (130 µL,
1.33 mmol), and the mixture was allowed to warm to room
temperature with stirring. After 2 h, 1 N NaOH (2 mL) and
30% H2O2 (1 mL) were added at 0 °C, and the resulting
mixture was vigorously stirred for 0.5 h at room temperature.
The mixture was diluted with EtAOc, then washed with
saturated Na2SO3 and brine. Concentration and chromatog-
raphy gave 12a (60 mg, 61%) and 13a (25 mg, 26%).
12a : colorless needle; mp 173 °C (EtOAc); Rf ) 0.35 (EtOAc);
1
[R]20 -28.8° (c 1.00, MeOH); IR (KBr) 3600-3200 cm-1; H
D
NMR (300 MHz, CDCl3) δ 7.51-7.35 (m, 5 H), 5.52 (s, 1 H),
4.31 (dd, J ) 10.5, 4.8 Hz, 1 H), 3.71-3.64 (m, 3 H), 3.59-
3.49 (m, 2 H), 3.41-3.33 (m, 1 H), 3.24 (ddd, J ) 8.8, 8.8, 2.6
Hz, 1 H), 2.48 (ddd, J ) 11.4, 4.4, 4.4 Hz, 1 H), 2.05-1.98 (m,
2 H), 1.79-1.53 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ 137.3,
129.1, 128.3, 126.2, 101.7, 82.4, 76.6, 73.1, 69.5, 69.2, 62.8, 38.3,
28.4, 28.2. Anal. Calcd for C16H22O5: C, 65.29; H, 7.53.
Found: C, 65.09; H, 7.71.
13a : colorless needle; mp 157-158 °C (EtOAc); Rf ) 0.21
(EtOAc); [R]21 +20.6° (c 1.00, MeOH); IR (KBr) 3500-3000
D
a
cm-1; H NMR (300 MHz, CDCl3) δ 7.50-7.35 (m, 5 H), 5.59
1
Reagents and conditions: (a) (i) PhNTf2, KHMDS, DMPU,
THF, -78 °C; (ii) 28, Pd(PPh3)4, benzene, rt, 78% (2 steps); (b) (i)
thexylborane, THF, 0 °C to rt, then H2O2, 3 N NaOH, 0 °C; (ii)
LiOH, THF-H2O, 40 °C; (iii) 2,4,6-trichlorobenzoyl chloride, Et3N,
THF, 0 °C to rt, the DMAP, benzene, rt, 71% (3 steps); (c) same
as a, 71%; (d) same as b, 48%.
(s, 1 H), 4.22 (dd, J ) 10.1, 4.6 Hz, 1 H), 4.07-3.98 (m, 2 H),
3.87 (dd, J ) 10.5, 4.6 Hz, 1 H), 3.80-3.60 (m, 4 H), 2.19 (ddd,
J ) 13.2, 3.8, 3.8 Hz, 1 H), 2.02-1.93 (m, 3 H), 1.77-1.54 (m,
4 H); 13C NMR (75 MHz, CDCl3) δ 129.1, 128.3, 126.1, 102.1,
79.2, 74.5, 69.9, 69.6, 66.1, 62.3, 46.8, 32.2, 28.8, 25.3. Anal.
Calcd for C16H22O5: C, 65.29; H, 7.53. Found: C, 65.10; H, 7.71.
TEMP O Oxid a tion of 12a . To a solution of 12a (30 mg,
0.1 mmol) in 3 mL of CH2Cl2 at 0 °C were added aqueous KBr
(1.0 M, 10 µL) and a catalytic amount of TEMPO. While
vigorously stirring, a freshly prepared NaClO solution (ca. 0.3
M, 1:1 mixture of comercial bleach solution and saturated
NaHCO3, 1.2 mL, 0.37 mmol) was added dropwise. After 1 h,
the mixture was quenched with Na2SO3 and extracted with
EtOAc. The organic layer was washed with brine and concen-
trated. The residue was purified by chromatography (hexane/
EtOAc, 1:1) to give 14a (26 mg, 89%): colorless needle; mp
Con clu sion
We have developed a novel method for the concise
synthesis of trans-fused cyclic ethers via the palladium-
catalyzed coupling of ketene acetal triflates and orga-
nozinc reagents. We are now in a position to synthesize
the DE and GH ring segments of gambierol efficiently
with a shorter number of steps (11 and 10 steps from
2-deoxy-D-ribose, respectively) in comparison with the
previous methods.4c,l Furthermore, the present methodol-
ogy was successfully applied to the iterative synthesis of
polycyclic ethers.
317 °C (hexane/CH2Cl2); Rf ) 0.38 (hexane/EtOAc, 1:1); [R]21
D
+63.1° (c 0.75, CHCl3); IR (KBr) 1742 cm-1
;
1H NMR (300
MHz, CDCl3) δ 7.49-7.36 (m, 5 H), 5.55 (s, 1 H), 4.33 (dd, J )
10.5, 4.8 Hz, 1 H), 4.16-4.08 (m, 1 H), 3.75-3.46 (m, 4 H),
2.83 (ddd, J ) 18.1, 9.1, 4.7 Hz, 1 H), 2.72-2.60 (m, 2 H), 2.27-
2.16 (m, 1 H), 1.96-1.81 (m, 2 H); 13C NMR (75 MHz, CDCl3)
δ 169.8, 136.9, 129.2, 128.4, 126.1, 101.9, 76.1, 75.8, 74.9, 73.6,
68.9, 34.8, 27.8, 24.3. Anal. Calcd for C16H18O5: C, 66.19; H,
6.25. Found: C, 65.89; H, 6.12.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions involving air- and/or
moisture-sensitive materials were carried out under argon
with dry solvents. On workup, extracts were dried over MgSO4.
Reactions were monitored by thin-layer chromatography car-
ried out on 0.25 mm silica gel plates (60F-254). Column
chromatography was performed with silicagel (60N, spherical,
neutral, particle size 0.100-0.210 mm). Yields refer to chro-
matographically and spectroscopically homogeneous materials.
Syn th esis of 8. To a solution of 2,3-dimethyl-2-butene (29
µL, 0.24 mmol) in THF (1 mL) at 0 °C was added BH3‚SMe2
(23 µL, 0.24 mmol). The mixture was stirred at 0 °C for 1 h.
To the resulting thexylborane solution at 0 °C was added a
solution of 11e (65 mg, 0.20 mmol) in THF (1 mL), and the
mixture was stirred at room temperature. After 2 h, 1 N NaOH
(0.4 mL) and 30% H2O2 (0.2 mL) were added at 0 °C, and the
mixture was vigorously stirred at room temperature for 0.5
h. The mixture was quenched with saturated Na2SO3 at 0 °C
and extracted with EtOAc. The organic layer was washed with
brine, concentrated, and dissolved in ether (2 mL). To the
mixture at 0 °C was added LiAlH4 (16 mg, 0.41 mmol). After
1 h, the reaction was quenched with brine, and the resulting
white precipitate was removed by filteration through a Celite
pad. The filtrate was concentrated to give the cr ude diol 18,
which was subjected directly to TEMPO oxidation to give 8
(42 mg, 68%): colorless prism; mp 189 °C (hexane/CH2Cl2); Rf
Typ ica l P r oced u r e for th e P a lla d iu m -Ca ta lyzed Cou -
p lin g of Keten e Aceta l Tr ifla tes 9 a n d Zin c Hom oen ola te
10. Syn th esis of 11a . To a suspension of Zn-Cu couple (367
mg, 5.5 mmol) in benzene (4 mL) and DMA (0.5 mL) was added
methyl 3-iodopropionate (330 µL, 2.8 mmol). The mixture was
refluxed for 2 h and then cooled to room temperature. A
solution of 9a (510 mg, 1.4 mmol) in benzene (5 mL) and a
solution of Pd(PPh3)4 (80 mg, 0.07 mmol) in benzene (5 mL)
were added to the resulting mixture, successively. After
stirring for 3 h, the mixture was quenched with Et3N, filtered
through a silica gel pad, and concentrated. The residue was
purified by silica gel chromatography (hexane/EtOAc, 4:1
containing 0.5% Et3N) to give 11a (313 mg, 73%): colorless
needle; mp 122 °C (hexane/CH2Cl2); Rf ) 0.31 (hexane/EtOAc,
) 0.18 (hexane/EtOAc, 1:1); [R]23 +62.2° (c 1.00, CHCl3); IR
D
(KBr) 1740 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.46-7.33 (m,
5 H), 5.42 (s, 1 H), 4.32-4.23 (m, 1 H), 4.16-4.09 (m, 1 H),
3.70-3.55 (m, 4 H), 2.70 (ddd, J ) 16.3, 8.2, 8.2 Hz, 1 H), 2.55
(ddd, J ) 17.2, 7.0, 7.0 Hz, 1 H), 2.21-1.97 (m, 5 H), 1.94-
1.81 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ 171.3, 137.3, 129.0,
128.3, 126.0, 101.1, 81.0, 80.8, 77.4, 75.2, 69.3, 28.5, 28.2, 27.6,
26.0. Anal. Calcd for C17H20O5: C, 67.09; H, 6.62. Found: C,
66.90; H, 6.60.
4:1); [R]23 +58.2° (c 1.00, CHCl3); IR (KBr) 1726, 1674 cm-1
;
D
1H NMR (300 MHz, CDCl3) δ 7.52-7.36 (m, 5H), 5.61 (s, 1 H),
4.56 (dd, J ) 5.0, 2.3 Hz, 1 H), 4.39 (dd, J ) 8.4, 2.9 Hz, 1 H),
3.88-3.82 (m, 1 H), 3.79-3.75 (m, 2 H), 3.69 (s, 3 H), 2.51-
2.46 (m, 2 H), 2.38-2.24 (m, 4 H); 13C NMR (75 MHz, CDCl3)
δ 173.2, 152.2, 137.4, 129.0, 128.2, 126.1, 101.5, 94.0, 74.9, 69.8,
68.9, 51.5, 31.7, 28.8, 26.6. Anal. Calcd for C17H20O5: C, 67.09;
H, 6.62. Found: C, 66.84; H, 6.59.
Syn th esis of 30. Hydroboration of 29 (53 mg, 0.15 mmol)
with thexylborane followed by the usual oxidative workup gave

3498 J . Org. Chem., Vol. 67, No. 10, 2002
Kadota et al.
the corresponding hydroxy ester, which was used directly for
the next reaction. To a mixture of the ester in THF (0.4 mL)
and H2O (0.2 mL) was added LiOH‚H2O (10 mg, 0.23 mmol),
and the mixture was stirred at 40 °C for 3.5 h. The mixture
was acidified carefully by 1 N HCl to pH 3-4 at 0 °C and
extracted with EtOAc. The organic layer was washed with
brine and concentrated. The residure was dissolved in THF
(1 mL) and then treated with Et3N (32 µL, 0.23 mmol) and
2,4,6-trichlorobenzoyl chloride (40 µL, 0.24 mmol) at 0 °C. After
stirring for 3 h at room temperature, the mixture was diluted
with benzene (7 mL) and introduced to a mixture of DMAP
(37 mg, 0.30 mmol) in benzene (3 mL). After stirring at room
temperature for 11 h, the mixture was diluted with EtOAc,
and the insoluble material was filtered off. The filtrate was
concentrated and purified by chromatography (hexane/EtOAc,
1:1) to give 30 (24 mg, 71%): colorless prism; mp 208 °C
(hexane/CH2Cl2); Rf ) 0.29 (hexane/EtOAc, 1:1); [R]23D +24.4°
H), 4.23 (dd, J ) 10.6, 3.6 Hz, 1 H), 3.61 (t, J ) 9.9 Hz, 1 H),
3.50-3.38 (m, 3 H), 2.65-2.57 (m, 2 H), 2.19-1.97 (m, 6 H),
1.77-1.62 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 174.4, 137.4,
129.0, 128.3, 126.1, 101.4, 84.0, 83.1, 82.1, 80.6, 69.7, 35.7, 33.5,
29.1, 27.4, 21.1. Anal. Calcd for C18H22O5: C, 67.91; H, 6.97.
Found: C, 67.41; H, 7.13.
Ack n ow led gm en t. This work was financially sup-
ported by a Grant-in-Aid for Scientific Research from
the Ministry of Education, Science and Culture of
J apan.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for 11b-e, 12b, 13b, 14b, 16, 17, 20-26, 29, 31, and 32
and copies of 1H and 13C NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(c 1.00, CHCl3); IR (KBr) 1724 cm-1
;
1H NMR (300 MHz,
CDCl3) δ 7.47-7.32 (m, 5 H), 5.43 (s, 1 H), 4.42-4.40 (m, 1
J O025566F