Short synthesis of tert-butyl-hydroxylated 3,5-di-tert-butyl-4-hydroxybenzaldehyde: Synthesis of tert-butyl-hydroxylated S-2474

Article abstract of DOI:10.1021/jo020587v

We have developed a very short synthesis of tertbutyl-hydroxylated di-tert-butyl-4-hydroxybenzaldehyde in which the HBr-DMSO system is used as an effective oxidant (overall yield of 45% for the entire four-step process from 2-tert-butyl-p-cresol). We also accomplished the synthesis of a major metabolite of the antiarthritic drug candidate S-2474.

Full text of DOI:10.1021/jo020587v

Sh or t Syn th esis of ter t-Bu tyl-Hyd r oxyla ted
3,5-Di-ter t-bu tyl-4-h yd r oxyben za ld eh yd e:
Syn th esis of ter t-Bu tyl-Hyd r oxyla ted S-2474
Masanao Inagaki,* Saichi Matsumoto, and Tatsuo Tsuri
Discovery Research Laboratories, Shionogi & Company,
Ltd., Fukushima-ku, Osaka 553-0002, J apan
masanao.inagaki@shionogi.co.jp
Received September 6, 2002
F IGURE 1.
Abstr a ct: We have developed a very short synthesis of tert-
butyl-hydroxylated di-tert-butyl-4-hydroxybenzaldehyde in
which the HBr-DMSO system is used as an effective oxidant
(overall yield of 45% for the entire four-step process from
2-tert-butyl-p-cresol). We also accomplished the synthesis of
a major metabolite of the antiarthritic drug candidate
S-2474.
The enzymatic hydroxylation (oxidation) of a tert-butyl
group in the food antioxidant BHT (butylated hydroxy-
toluene, 1 in Figure 1) to produce the tert-butyl-hydroxy-
lated metabolite 2 occurs in hepatic and pulmonary
microsomes of rats and mice and has been found to be
an important step in both BHT bioactivation and the
resulting toxicity in these species.1 A similar hydroxyla-
tion reaction has also been found to be a metabolic
pathway in in vitro rat or human microsomes for our di-
tert-butylphenol derivative, (E)-(5)-(3,5-di-tert-butyl-4-
hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-diox-
ide (S-2474; 4), which has been identified as a new type
of antiarthritic drug candidate having both NSAID
(nonsteroidal antiinflammatory drug) and cytokine modu-
lating properties.2 Among several synthetic methods3 of
F IGURE 2.
the tert-butyl-hydroxylated di-tert-butylphenols involving
direct microbial oxidation,3b only one example is clear and
feasible.3a However, while this method3a is suitable for
the preparation of the unsubstituted derivative at the
4-position of phenol (R1 ) OH, R2 ) H in Figure 1), it
cannot be applied for the preparation of aldehyde 3b, a
key intermediate for the synthesis of a major metabolite
of S-2474, without any modifications or multistep func-
tional group transformations. Since not only our com-
pound but also several known antiinflammatory drug
candidates, such as KME-4,4 E-5110,5 BF-389,6 and CI-
10047 (Figure 2), having the common structure of a 3,5-
di-tert-butyl-4-hydroxybenzylidene moiety are prepared
from 3,5-di-tert-butyl-4-hydroxybenzaldehyde (3a ), pre-
dicted metabolites can be easily prepared from the
common key intermediate, tert-butyl-hydroxylated 3,5-
di-tert-butyl-4-hydroxybenzaldehyde (3b). A widely ap-
(1) (a) Thompson, J . A.; Malkinson, A. M.; Wand, M. D.; Mastovich,
S. L.; Mead, E. W.; Schullek, K. M.; Laudenschlager, W. G. Drug Metab.
Dispos. 1987, 15, 833 and references cites therein. (b) Thompson, J .
A.; Schullek, K. M.; Fernandez, C. A.; Malkinson, A. M. Carcinogenesis
1989, 10, 773. (c) Malkinson, A. M.; Thaete, L. G.; Blumenthal, E. J .;
Thompson, J . A. Toxicol. Appl. Pharacol. 1989, 101, 196. (d) Bolton, J .
L.; Sevestre, H.; Ibe, B. O.; Thompson, J . A. Chem. Res. Toxicol. 1990,
3, 65. (e) Bolton, J . L.; Thompson, J . A. Drug Metab. Dispos. 1991, 19,
467. (f) Bolton, J . L.; Valerio, L. G., J r.; Thompson, J . A. Chem. Res.
Toxicol. 1992, 5, 816. (g) Bolton, J . L.; Thompson, J . A.; Allentoff, A.
J .; Miley, F. B.; Malkinson, A. M. Toxicol. Appl. Pharmacol. 1993, 123,
43. (h) Guan, X.; Hardenbrook, J .; Fernstrom, M. J .; Chaudhuri, R.;
Malkinson, A. M.; Ruch, R. J . Carcinogenesis 1995, 16, 2575. (i) Dwyer-
Nield, L. D.; Thompson, J . A.; Peljak, G.; Squier, M. K. T.; Barker, T.
D.; Parkinson, A.; Cohen, J . J .; Dinsdale, D.; Malkinson, A. M.
Toxicology 1998, 130, 115.
(2) (a) Inagaki, M.; Tsuri, T.; J yoyama, H.; Ono, T.; Yamada, K.;
Kobayashi, M.; Hori, Y.; Arimura, A.; Yasui, K.; Ohno, K.; Kakudo,
S.; Koizumi, K.; Suzuki, R.; Kato, M.; Kawai,S.; Matsumoto, S. J . Med.
Chem. 2000, 43, 2040. (b) Inagaki, M.; Haga, N.; Kobayashi, M.; Ohta,
N.; Kamata, S.; Tsuri, T. J . Org. Chem. 2002, 67, 125.
(3) (a) Miller, J . A.; Matthews, R. S. J . Org. Chem. 1992, 57, 2514.
(b) Yano, Y.; Ishii, K.; Hidaka, T.; Kondou, H.; Kawaharada, H.
J apanese Patent Application 258173, 1985. (c) Ikuta, H.; Yamagishi,
Y.; Akasaka, M.; Yamatsu, I.; Kobayashi, S.; Yoda, H.; Katayama, K.
J apanese Patent Application 115860, 1988. (d) Kawashima, Y.; Ota,
A.; Mibu, H. J apanese Patent Application 507042, 1994; WO 5647,
1994. (e) Goto, K.; Hashimoto, K.; Kanai, K. WO 9985, 1990.
(4) Hidaka, T.; Hosoe, K.; Ariki, Y.; Takeo, K.; Yamashita, T.;
Katsumi, I.; Kondo, H.; Yamashita, K.; Watanabe, K. J pn. J . Phar-
macol. 1984, 36, 77.
(5) Ikuta, H.; Shirota, H.; Kobayashi, S.; Yamagishi, Y.; Yamada,
K.; Yamatsu, I.; Katayama, K. J . Med. Chem. 1987, 30, 1995.
(6) Wong, S.; Lee, S. J .; Frierson, M. R., III; Proch, J .; Miskowski,
T. A.; Rigby, B. S.; Schmolka, S. J .; Naismith, R. W.; Kreutzer, D. C.;
Lindquist, R. Agents Actions 1992, 37, 90.
(7) Unangst, P. C.; Connor, D. T.; Cetenko, W. A.; Sorenson, R. J .;
Kostlan, C. R.; Sircar, J . C.; Wright, C. D.; Schrier, D. J .; Dyer, R. D.
J . Med. Chem. 1994, 37, 322.
10.1021/jo020587v CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/01/2003
1128
J . Org. Chem. 2003, 68, 1128-1131

SCHEME 1
SCHEME 2 a
SCHEME 3
a
Reagents: (a) glyoxal, conc HCl, AcOH (79%); (b) Mel, t-BuOK
(84%); (c) (1) NBS, AlBN; (2) KOAc, AcOH then aq HCl (87%); (d)
ethylene glycol, PPTS (88%); (e) LiAlH4 then H3O+ (86%).
plicable and efficient synthetic method for 3b is reported
here and was used to synthesize a major metabolite of
S-2474.
TABLE 1. Oxid a tion of 2 in DMSO u n d er Va r iou s
Con d ition s
reagents
(mol %)
temp
(°C)
time
(h)
yields (%)
of 3b, 10, and 11
entry
Two approaches were considered initially to convert
2-tert-butyl-p-cresol (6) into 3b through the benzofura-
none derivative 7 as described in Scheme 1. The first
approach via compound 8 proceeded via oxidation of the
benzylic methyl group of 7, followed by reduction of the
lactone moiety. The second pathway is reduction of 7 to
phenol 2, followed by selective oxidation of the benzylic
methyl group.
1
2
3
4
5
6
NBS (120)
NBS (20)
47% HBr (50)
47% HBr (50)
47% HBr (120)
47% HBr (240)
120
120
100
100
100
100
1
1
1
4
2
1
59 (10)
41 (3b), 31 (10)
60 (3b), 10 (11)
67 (3b)
65 (3b)
72 (3b)
bromine in aqueous acetic acid or tert-butyl alcohol in
good yield.10h Recently, Baik and co-workers have re-
ported that NBS promotion of DMSO oxidation is very
effective for this class of cresols and the oxidation could
remarkably proceed smoothly even with a catalytic
amount of NBS.10i
Phenol 2 was obtained from 7 by NaBH4 reduction in
DME-MeOH in almost quantitative yield (Scheme 3). We
first tried the oxidation of phenol 2 to aldehyde 3b under
the conditions (Br2/aq AcOH or aq t-BuOH) that gave
complex mixtures containing only a trace amount of 3b.
The other conditions (1.2 equiv of NBS in DMSO at 120
°C for 1 h) gave an exclusively over-oxidation product,
the lactol 10 (59% yield, entry 1 in Table 1). Oxidation
with NBS (0.2 equiv in DMSO at 120 °C for 1 h) gave 3b
The details of the first approach are as follows. A
commercially available 2-tert-butyl-p-cresol (6) was con-
verted to 7-tert-butyl-5-methyl-3H-benzofuran-2-one with
glyoxal in acetic acid,8,9 and then directly converted to 7
by geminal dimethylation with MeI and t-BuOK in 66%
yield in 2 steps. Oxidation of 7 to the lactone-aldehyde 8
could be achieved via geminal dibromination and hy-
drolysis in 87% yield. The formyl group of 8 was protected
with ethylene acetal to give 9 in 88% yield. Reduction of
9 with LiAlH4 and subsequent acidic workup provided
the desired key-intermediate 3b in 86% yield, with an
overall yield of 44% for the entire six-step process
summarized in Scheme 2.
This route was shown to be effective, but a shorter
synthesis would be even better. Next, we attempted direct
oxidation of phenol 2 to aldehyde 3b. Some methods of
oxidation of 2,6-di-tert-butyl-p-cresol (1) to 3,5-di-tert-
butyl-4-hydroxybenzaldehyde (3a ) were reported.10 In
general, symmetrically hindered cresols are oxidized by
(10) (a) Kajigaeshi, S.; Morikawa, Y.; Fujisaki, S.; Kakinami, T.;
Nishihira, K. Bull. Chem. Soc. J pn. 1991, 64, 1060. (b) Hirano, M.;
Ishii, T.; Morimoto, T. Bull. Chem. Soc. J pn. 1991, 64, 1434. (c)
Takehira, K.; Shimizu, M.; Watanabe, Y.; Orita, H.; Hayakawa, T.
Tetrahedron Lett. 1990, 31, 2607. (d) Becker, H.-D. J . Org. Chem. 1965,
30, 982. (e) Nishinaga, A.; Itahara, T.; Matsuura, T. Angew. Chem.,
Int. Ed. Engl. 1975, 14, 356. (f) Itahara, T.; Sakakibara, T. Bull. Chem.
Soc. J pn. 1979, 52, 631. (g) Cohen, L. A. J . Org. Chem. 1957, 22, 1333.
(h) Coppinger, G. M.; Campbell, T. W. J . Am. Chem. Soc. 1953, 75,
734. (i) Baik, W.; Lee, H. J .; J ang, J . M.; Koo, S.; Kim, B. H. J . Org.
Chem. 2000, 65, 108. (j) Fujibayashi, S.; Nakayama, K.; Nishiyama,
Y.; Ishii, Y. Chem. Lett. 1994, 1345. (k) Vidyasagar, A.; Nalawala, K.
J .; Varshney, A. K. Indian J . Chem., Sect. B 1993, 32, 872.
(8) Layer, R. W. J . Heterocycl. Chem. 1975, 12, 1067.
(9) Using 4-bromo-2-tert-butylphenol or 2-tert-butylphenol as start-
ing materials, this synthetic method of 2(3H)-benzofuranones could
not proceed cleanly, and only trace amounts of benzofuranone deriva-
tives (6% and 5% yield, respectively) were obtained. We thus decided
that the benzaldehyde derivative 3b would be led by oxidation of a
benzylic methyl group.
J . Org. Chem, Vol. 68, No. 3, 2003 1129

SCHEME 4
in 41% and the lactol 10 in 31% yield, respectively (entry
2 in Table 1). In the NBS-DMSO oxidation, production
of the lactol 10 could not be avoided and it tended to
increase as the reaction time became longer. According
to Baik’s report,10i “the reaction mechanism (1 f 3a )
could involve a phenoxy radical or a hypobromite, in
either case p-benzoquinone methide (QM) derivative and
hydrogen bromide were formed, and bromodimethylsul-
fonium bromide (12)11 would be generated in situ from
HBr and DMSO (eq 1 in Scheme 4).” Moreover, this
reaction (1 f 3a ) also proceeded with a catalytic amount
of NBS, and we thought it to be more reasonable that 12
is the only active species, because the first step of
formation of the QM derivative via either phenoxy radical
or hypobromite is not a catalytic cycle. On the other hand,
12 is a useful synthetic reagent,12-14 especially for elec-
trophilic aromatic bromination.15 We attempted to in-
vestigate whether this reaction occurred with HBr-DMSO
as an oxidant. As expected, HBr-DMSO was revealed to
be a very effective reagent for oxidation of phenol 2,
giving 3b in moderate to good yield (entries 3, 4, 5, and
6 in Table 1). Under the conditions of 0.5 equiv of
concentrated HBr (47% aqueous) and DMSO at 100 °C,
a reaction time over 3 h was needed for a complete
reaction because an intermediate benzyl alcohol 11
remained under shorter reaction time (entry 3). Using a
larger amount of HBr shortened the reaction time but
did not have any effect on the yield of 3b (entries 4, 5,
and 6). From these experiments, the oxidation of phenol
2 to aldehyde 3b by HBr-DMSO gave much better
results, especially in over-oxidation, and was revealed to
be more reproducible than NBS-DMSO oxidation. HBr-
DMSO oxidation has some advantages in handling,
safety, and cost compared to NBS-DMSO oxidation.
The reaction mechanism initiated by an ionic bromi-
nation on the 4-position of the phenol 2 and the HBr
catalytic cycle are summarized in Scheme 4.10h We have
accomplished the synthesis of the widely applicable key
intermediate 3b from 2-tert-butyl-p-cresol (6) with an
overall yield of 45% for the entire four-step process.
As mentioned above, we also tried to obtain an au-
thentic sample of the tert-butyl-hydroxylated S-2474
derivative 5 to be prepared from 3b. Aldehyde 3b was
converted to THP ether 17 almost quantitatively by
selective protection of the primary alcohol. Ether 17 was
treated with N-ethyl-γ-sultam (18) in the presence of
LDA to provide an aldol-type adduct 19 as diastereoiso-
meric mixtures. A crude adduct 19 was treated with MsCl
and triethylamine following deprotection of the THP
ether to afford tert-butyl-hydroxylated S-2474 (5) in 86%
yield in three steps (Scheme 5).
In summary, we have demonstrated two approaches
and developed an efficient and widely applicable synthe-
sis of tert-butyl-hydroxylated 3,5-di-tert-butyl-4-hydroxy-
benzaldehyde (3b) from 2-tert-butyl-p-cresol (6). The key
compound 3b could be obtained from 2 in one step by
HBr-DMSO oxidation, which is the first example, to our
knowledge, of HBr-DMSO being used as an oxidant of
hindered p-cresol to the corresponding p-hydroxybenzal-
dehyde. Using this convenient method, we have ac-
complished the synthesis of the major metabolite, tert-
butyl-hydroxylated S-2474 (5). This new preparative
sequence should be very important in metabolic studies
of this class of compounds and should be adaptable in
(11) (a) Majetich, G.; Hicks, R.; Reister, S. J . Org. Chem. 1997, 62,
4321. (b) Mislow, K.; Simmons, T.; Melillo, J .; Ternay, A. J . Am. Chem.
Soc. 1964, 86, 1452.
(12) Olah, G.; Arvanaghi, M.; Vankar, Y. Synthesis 1979, 721.
(13) Chow, Y.; Bakkar, B. Synthesis 1982, 648.
(14) Floyd, M.; Du, M.; Fabio, P.; J acob, L.; J ohnson, B. J . Org.
Chem. 1985, 50, 5022.
(15) (a) Megyeri, G.; Keve, T. Synth. Commun. 1989, 19, 3415. (b)
Fletcher, T.; Pan, H. J . Am. Chem. Soc. 1956, 78, 4812. (c) Reference
11a.
1130 J . Org. Chem., Vol. 68, No. 3, 2003

SCHEME 5 a
combined organic layer was washed with dil. HCl and brine,
dried, and evaporated. A crude solid was obtained, which was
crystallized from n-hexane to afford the pure title compound as
colorless crystals (33.6 g, 95%). Mp 114-116°C. 1H NMR
(CDCl3): δ 1.41 (s, 9H), 1.43 (s, 6H), 2.27 (s, 3H), 2.47 (br s,
1H), 3.79 (s, 2H), 6.93 (d, J ) 1.8 Hz, 1H), 7.01 (d, J ) 1.8 Hz,
1H), 8.92 (br s, 1H). 13C NMR (CDCl3): δ 21.13, 25.48, 29.92,
34.87, 39.60, 74.32, 125.53, 126.11, 127.20, 132.70, 137.83,
152.69. IR (Nujol): 3521, 3407, 3230, 2855, 1462, 1425, 1378,
1234, 1211 cm-1. Anal. Calcd for C15H24O2: C, 76.23; H, 10.24.
Found: C, 76.11; H, 10.09.
3-ter t-Bu tyl-4-h yd r oxy-5-(2-h yd r oxy-1,1-d im eth yleth yl)-
ben za ld eh yd e (3b). (a ) A Stoich iom etr ic Rea ction . Phenol
2 (236 mg, 1.00 mmol) was dissolved with DMSO (4.7 mL) and
47% HBr (0.28 mL, 2.4 mmol) was added at 23 °C. The reaction
was heated at 100 °C for 1 h. After being cooled to 23 °C, the
reaction was quenched with water. A product was extracted with
n-hexane-AcOEt (1:1) and the organic layer was washed with
water twice, followed by brine, dried, and evaporated. The crude
residue was subjected to column chromatography on silica gel
(n-hexane:AcOEt 85:15) to afford the title compound as a pale
a
Reagents: (a) dihydropyran, PPTS (97%); (b) LDA; (c) MsCl,
Et3N; (d) p-TsOH, MeOH (86% for 3 steps).
the future to the preparation of important derivatives
possessing this functionality.
1
pink solid (181 mg, 72%). Mp 119-121 °C. H NMR (CDCl3): δ
1.44 (s, 9H), 1.47 (s, 6H), 3.02 (br s, 1H), 3.85 (br s, 2H), 7.69 (d,
J ) 2.1 Hz, 1H), 7.73 (d, J ) 2.1 Hz, 1H), 9.81 (s, 1H), 10.42 (s,
1H). 13C NMR (CDCl3): δ 24.81, 29.24, 34.62, 39.67, 71.56,
126.80, 127.15, 127.86, 134.56, 137.74, 161.76, 191.51. IR
(KBr): 3249, 2960, 1658, 1595, 1581, 1387, 1296, 1271, 1207
cm-1. Anal. Calcd for C15H22O3: C, 71.97; H, 8.86. Found: C,
71.91; H, 8.95. (b) A Ca ta lytic Rea ction . Phenol 2 (4.73 g, 20.0
mmol) was dissolved with DMSO (95 mL) and 47% HBr (1.16
mL, 10 mmol) was added at 23 °C. The reaction was heated at
100 °C for 4 h. The title compound was obtained in a similar
manner as described above. Yield 3.35 g (67%). The data for
byproducts 10 and 11 are described in the Supporting Informa-
tion.
3-ter t-Bu tyl-5-[1,1-dim eth yl-2-(tetr ah ydr opyr an -2-yloxy)-
eth yl]-4-h yd r oxyben za ld eh yd e (17). A mixture of 3b (1.09
g, 4.35 mmol), dihydropyran (1.6 mL, 17.4 mmol), PPTS (100
mg, 0.44 mmol), and CH2Cl2 (10 mL) was stirred for 40 min at
room temperature. To the reaction were added sat. NaHCO3 and
AcOEt. The organic layer was separated and washed with brine,
dried, and evaporated. The residue was purified by chromatog-
raphy on silica gel (n-hexane:AcOEt 4:1) to give the title
compound (1.40 g, 97%) as a colorless oil. 1H NMR (CDCl3): δ
1.44 (s, 9H), 1.49 (s, 3H), 1.52 (s, 3H), 1.52-1.90 (m, 6H), 3.47
(d, J ) 9.0 Hz, 1H), 3.51-3.72 (m, 2H), 3.92 (d, J ) 9.0 Hz, 1H),
7.70 (d, J ) 2.1 Hz, 1H), 7.74 (d, J ) 2.1 Hz, 1H), 9.83 (s, 1H),
10.09 (s, 1H). IR (CHCl3): 3195, 2952, 1680, 1585, 1429, 1385,
1277, 1263, 1225, 1215, 1203, 1190, 1122, 1036 cm-1. Anal. Calcd
for C20H30O4: C, 71.82; H, 9.04. Found: C, 71.64; H, 9.12.
Exp er im en ta l Section
1
Melting points are uncorrected. H NMR spectra were deter-
mined at 200 or 300 MHz. 13C NMR spectra were determined
at 75.5 MHz. Unless otherwise stated, all reactions were carried
out under a nitrogen atmosphere with guaranteed grade solvents
that had been dried over type 4A or 3A molecular sieves. Drying
of organic extracts over anhydrous sodium sulfate is simply
indicated by the word “dried”. Column chromatography using
Merck Silica gel 60 (70-230 or 230-400 mesh) is referred to as
“chromatography on silica gel”.
7-ter t-Bu tyl-3,3,5-tr im eth yl-3H-ben zofu r a n -2-on e (7). A
mixture of 2-tert-butyl-p-cresol (6) (82 g, 0.50 mol), 40 wt %
glyoxal (87 g, 0.60 mol), concentrated HCl (5.5 mL), and AcOH
(375 mL) was heated at reflux for 3 h.8 The reaction mixture
was cooled to room temperature and a precipitate was collected
and washed with water and MeOH. Yield 80.6 g (79%). The
precipitate was used for the next reaction without further
purification. The above benzofuran-2-one intermediate (80 g,
0.39 mol) and MeI (69 mL, 1.11 mol) were dissolved with THF
(1000 mL) and t-BuOK (110 g, 0.98 mol) was added in small
portions with ice-cooling. The reaction was stirred for 1 h at 5
°C. The reaction mixture was poured into 0.1 N HCl and a
product was extracted with AcOEt. The organic layer was
washed with 5% NaHCO3 followed by brine and dried. Removal
of the solvent gave a crystalline residue that was crystallized
from MeOH-H2O (1:4) to give the title compound (76.4 g, 84%)
as yellow solids. Mp 77-79 °C. 1H NMR (CDCl3): δ 1.39 (s, 9H),
1.48 (s, 6H), 2.35 (s, 3H), 6.86 (d, J ) 1.2 Hz, 1H), 7.01 (d, J )
1.2 Hz, 1H). 13C NMR (CDCl3): δ 21.36, 25.38, 29.55, 34.08,
42.22, 120.41, 125.97, 133.29, 133.65, 133.79, 147.68, 181.18. IR
(KBr): 2970, 1799, 1458, 1273, 1059, 1028 cm-1. Anal. Calcd
for C15H20O2: C, 77.55; H, 8.68. Found: C, 77.31; H, 8.61.
2-ter t-Bu tyl-6-(2-h ydr oxy-1,1-dim eth yleth yl)-4-m eth ylph e-
n ol (2). To a mixture of the lactone 7 (35 g, 0.151 mol), NaBH4
(20 g, 0.528 mol), and DME (200 mL) was added slowly MeOH
(105 mL) at 65-75 °C over 1 h. The reaction was stirred for an
additional 0.5 h at 70 °C and then allowed to cool to 23 °C and
quenched with AcOEt and water. The organic layer was sepa-
rated and an aqueous layer was back-washed with AcOEt. The
Ack n ow led gm en t. The authors thank Drs. Mit-
suaki Ohtani, Kenji Kawada, Norihiko Tanimoto, and
Takeshi Shiota for their encouragement and helpful
discussions throughout this study.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the synthesis of 8, 9, 3b, and 5, and data for 8, 9,
5, 10, and 11. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O020587V
J . Org. Chem, Vol. 68, No. 3, 2003 1131