Asymmetric Oxidative Cyclization of o-Phenolic Oxime-Esters: First Synthesis of Enantiomerically Enriched Spiroisoxazoline Methyl Esters

Article abstract of DOI:10.1021/jo970082i

A new method for the synthesis of enantiomerically enriched cyclohexadienone spiroisoxazoline (-)-2a has been described. Asymmetric intramolecular oxidative cyclization of the o-phenolic oximeester 1c using a novel optically active tertiary alcohol (-)-3 as a chiral auxiliary proceeded smoothly to afford cyclohexadienone spiroisoxazoline 2c in 83% yield. Opitcally active tertiary alcohol (-)-3 was synthesizied from racemic (1S*,8R*,9R*,10R*)-8-phenyl-1-decalol (4) by optical resolution. Removal of the chiral auxiliary in 2c with CF₃COOH followed by methylation gave methyl ester (-)-2a in 74% ee (71% chemical yield) having S-configuration. The absolute configuration of 2a was determined by the synthesis of the marine natural product (+)-aerothionin.

Full text of DOI:10.1021/jo970082i

4428
J . Org. Chem. 1997, 62, 4428-4433
Asym m etr ic Oxid a tive Cycliza tion of o-P h en olic Oxim e-Ester s:
F ir st Syn th esis of En a n tiom er ica lly En r ich ed Sp ir oisoxa zolin e
Meth yl Ester s
Masatoshi Murakata, Masafumi Tamura, and Osamu Hoshino*
Faculty of Pharmaceutical Sciences, Science University of Tokyo, Shinjuku-ku, Tokyo 162, J apan
Received J anuary 15, 1997X
A new method for the synthesis of enantiomerically enriched cyclohexadienone spiroisoxazoline
(-)-2a has been described. Asymmetric intramolecular oxidative cyclization of the o-phenolic oxime-
ester 1c using a novel optically active tertiary alcohol (-)-3 as a chiral auxiliary proceeded smoothly
to afford cyclohexadienone spiroisoxazoline 2c in 83% yield. Opitcally active tertiary alcohol (-)-3
was synthesizied from racemic (1S*,8R*,9R*,10R*)-8-phenyl-1-decalol (4) by optical resolution.
Removal of the chiral auxiliary in 2c with CF3COOH followed by methylation gave methyl ester
(-)-2a in 74% ee (71% chemical yield) having S-configuration. The absolute configuration of 2a
was determined by the synthesis of the marine natural product (+)-aerothionin.
In tr od u ction
The isolation and structure determination of several
bromotyrosine-derived natural marine metabolites con-
taining the spirocyclohexadienylisoxazoline moiety1 have
been reported. The oxidative cyclization of o-phenolic
oxime-acid derivatives serves a powerful method2 for the
construction of the spiroisoxazoline ring system in these
natural products. Successful oxidations employ manga-
nese(III) tris(acetylacetonate),3 2,4,4,6-tetrabromocyclo-
hexa-2,5-dienone,2c,d thallium(III) nitrate,2e,f thallium(III)
trifluoroacetate [Tl(OCOCF3)3],2f,g and anodic oxidation
conditions.2e Recently, hypervalent iodine compounds
were found to be very efficient agents for the oxidation
of a variety of phenolic oximes to give the corresponding
spiroisoxazolines under mild conditions.2h-j
The racemic syntheses of aerothionin, homoaerothio-
nin, and aerophobin-1, which are isolated from sponges
of Aplysia aerophoba, Aplysia fistularis, and Verongia
thiona, by the oxidative cyclization of o-phenolic oxime-
ester 1a using Tl(OCOCF3)3 as oxidant have been re-
ported (Scheme 1),2g,4 showing that spiroisoxazoline
methyl ester 2a is a key compound in the synthesis of
these marine natural products. However, asymmetric
F igu r e 1.
Sch em e 1
X Abstract published in Advance ACS Abstracts, J une 1, 1997.
(1) (a) Aerothionin, homoaerothionin: Moody, K.; Thomson, R. H.;
Fattorusso, E.; Minale, L.; Sodano, G. J . Chem. Soc., Perkin Trans. 1
1972, 18. (b) Aerophobin-1: Cimino, G.; De Rosa, S.; De Stefano, S.;
Self, R.; Sodano, G. Tetrahedron Lett. 1983, 24, 3029. (c) Recent reports
on other natural marine products: Gopichand, Y.; Schmitz, F. J .
Tetrahedron Lett. 1979, 3921. Nakamura, H.; Wu, H.; Kobayashi, J .
Tetrahedron Lett. 1985, 26, 4517. Morris, S. A.; Andersen, R. J . Can.
J . Chem. 1989, 67, 677. Longeon, A.; Guyot, M.; Vacelet, J . Experientia
1990, 46, 548. Kernan, M. R.; Cambie, R. C.; Bergquist, P. R. J . Nat.
Prod. 1990, 53, 615. Gunasekera, S. P.; Cross, S. S. J . Nat. Prod. 1992,
55, 509. Ko¨nig, G. M.; Wright, A. D. Heterocycles 1993, 36, 1351.
Mancini, I.; Guella, G.; Laboute, P.; Debitus, C.; Pietra, F. J . Chem.
Soc., Perkin Trans. 1 1993, 3121.
(2) (a) Forrester, A. R.; Thomson, R. H.; Woo, S.-O. J . Chem. Soc.,
Chem. Commun. 1973, 604. (b) Forrester, A. R.; Thomson, R. H.; Woo,
S.-O. J . Chem. Soc., Perkin Trans. 1 1975, 2340. (c) Forrester, A. R.;
Thomson, R. H.; Woo, S.-O. J . Chem. Soc., Perkin Trans. 1 1975, 2348.
(d) Forrester, A. R.; Thomson, R. H.; Woo, S.-O. J ustus Liebigs Ann.
Chem. 1978, 66. (e) Noda, H.; Niwa, M.; Yamamura, S. Tetrahedron
Lett. 1981, 22, 3247. (f) Nishiyama, S.; Yamamura, S. Tetrahedron Lett.
1982, 23, 1281. (g) Nishiyama, S.; Yamamura, S. Tetrahedron Lett.
1983, 24, 3351; Nishiyama, S.; Yamamura, S. Bull. Chem. Soc. J pn.
1985, 58, 3453. (h) Kac¸an, M.; Koyuncu, D.; McKillop, A. J . Chem.
Soc., Perkin Trans. 1 1993, 1771. (i) Murakata, M.; Yamada, K.;
Hoshino, O. J . Chem. Soc., Chem. Commun. 1994, 443. (j) Murakata,
M.; Yamada, K.; Hoshino, O. Tetrahedron 1996, 47, 14713.
synthesis of these natural products is not known.3
Therefore, we planned to develop a method for the
preparation of optically active 2a , which should be useful
for the asymmetric synthesis of these compounds.
Recently, the asymmetric oxidative cyclization of o-
phenolic oxime-ester 1b using iodosylbenzene (PhIO) to
give an optically active spiroisoxazoline 2b has been
achieved in our laboratory (Scheme 1).2i However, the
8-phenylmenthyl ester in 2b could not be hydrolyzed
under various conditions, including treatment of 2b with
K2CO3-MeOH (0 °C), aqueous HCl (reflux), TfOH (0 °C),5
(4) Biomimetic synthesis of aerothionin, see: Okamoto, K. T.;
Clardy, J . Tetrahedron Lett. 1987, 28, 4969.
(5) The cleavage of cyclohexyl esters by TfOH has been reported:
Tam, J . P.; Wong, T.-Wai; Riemen, M. W.; Tjoeng, F.-S.; Merrifield, R.
B. Tetrahedron Lett. 1979, 4033.
(3) As to their absolute configuration, only (+)-aerothionin has been
determined by its X ray crystallographic analysis; see, ref 12.
S0022-3263(97)00082-0 CCC: $14.00 © 1997 American Chemical Society

Asymmetric Oxidative Cyclization of o-Phenolic Oxime-Esters
J . Org. Chem., Vol. 62, No. 13, 1997 4429
Sch em e 2
Sch em e 3
olefin 8, which was prepared by olefination of enantio-
merically pure ketone 7.
(8R,9R,10R)-8-Phenyl-1-decalone (7) {[R]28 +41.3 (c
D
0.47, CHCl3)} was obtained in four steps from racemic
(1S*,8R*,9R*,10R*)-8-phenyl-1-decalol (4).9 Treatment
of 4 with phthalic anhydride in pyridine under reflux for
4 h gave the ester-acid 5 in 74% yield. Amidation with
(S)-1-phenylethylamine provided diastereomers 6a (35%)
and 6b (41%), which were separated by silica gel column
chromatography. Hydrolysis of 6a gave enantiomerically
pure (-)-4 in 89% yield, J ones oxidation of which
produced optically active ketone 7 in 91% yield. The
absolute configuration of 7 was determined to be
8R,9R,10R by circular dichroism measurement {[θ]295
+6847 (c 0.049, MeOH)}.10
With enantiomerically pure ketone 7 in hand, we
focussed our attention on the direct introduction of a
methyl group into 7. However, as shown in Scheme 3,
methyl group addition to the carbonyl group of 7 by
Me3Al or MeLi gave the undesired axial alcohol 10
predominantly. The stereochemistry of 10 was deduced
1
by an examination of the H NMR spectrum: a peak due
to a methyl group appeared at δ 0.46 as a result of the
anisotropic effect of the benzene ring at the C8-position.
On the other hand, the reaction of 8 (prepared from 7
using the Wittig reaction) with m-CPBA gave epoxide 11
in 87% yield, reduction of which again gave the axial
alcohol 10. This result showed the epoxide to be R-ori-
ented. These findings suggest that the π-facial selectivity
of an electrophile (m-CPBA) to olefin 8 was R, whereas
nucleophiles (Me3Al and MeLi) approach the ketone 7
from the â-face.
TMSI-MeCN (reflux),6 or (Bu3Sn)2O-Et2O (rt to reflux).7
All of these reactions gave intractable mixtures, perhaps
as a result of the instability of the cyclohexadienone
spiroisoxazoline moiety under these vigorous conditions.8
These results suggest that chiral auxiliaries which
require hydrolytic conditions for their cleavage are
unsuitable for the synthesis of 2a . For the purpose of
the synthesis of optically active 2a , it seemed necessary
to prepare a new chiral auxiliary. Therefore, we designed
the tertiary alcohol (-)-3 as an auxiliary, because it was
expected to be easily removed by acid-assisted elimina-
tion under mild conditions. The present paper deals with
the preparation of optically active 3 and the synthesis of
enantiomerically enriched spiroisoxazoline methyl esters
(-)-2a .
On the basis of the results mentioned above, in order
to obtain the equatorial alcohol (-)-3, the â-epoxide was
prepared via the bromohydrin obtained from 8 (Scheme
2). The Wittig olefination of 7 provided 8 in 90% yield.
Treatment of 8 with N-bromosuccimide in DME-H2O
followed by ring closure afforded 9 in 67% yield. As
expected, the equatorial alcohol (-)-3 was obtained in
79% yield by reduction of 9 with LiAlH4. The stereo-
chemistry of the methyl group in (-)-3 was determined
Resu lts a n d Discu ssion
1
on the basis of the H NMR spectrum, which displayed a
The synthesis of optically active tertiary alcohol (-)-3
{[R]31D -19.8 (c 1.32, CHCl3)} is shown in Scheme 2. The
key intermediate compound was optically active exo
methyl singlet at δ 1.22.
(9) The racemic bicyclic secondary alcohol as a chiral auxiliary has
been reported: Whitesell, J . K.; Lawrence, R. M.; Chen, H.-H. J . Org.
Chem. 1986, 51, 4779.
(10) Cf. For circular dichroism spectrum of (8S,9R,10S)-(+)-
8-methyl-trans-1-decalone: Hagishita, S.; Kuriyama, K. J . Chem. Soc.,
Perkin Trans. 1 1980, 950.
(6) J ung, M. E.; Lyster, M. A. J . Am. Chem. Soc. 1977, 99, 968.
(7) Mata, E. G.; Mascaretti, O. A. Tetrahedron Lett. 1988, 29, 6893.
(8) For example, decomposition of the cyclohexadienone spiro-
isoxazoline with pyridine has been reported; see, ref 2d.

4430 J . Org. Chem., Vol. 62, No. 13, 1997
Murakata et al.
Sch em e 4
Sch em e 5
Sch em e 6
o-Phenolic oxime-ester 1c was easily prepared in three
steps from 2-[(benzyloxy)imino]-3-[2-(benzyloxy)-3,5-di-
bromo-4-methoxyphenyl]propionic acid (12)1a (Scheme 4).
Treatment of 12 with p-nitrophenol afforded a p-nitro-
phenyl ester 13 in 91% yield, and transesterification of
13 with lithiated (-)-3 produced 1-methyl-1-decalyl ester
14 in 85% yield. Hydrogenolysis of 14 gave o-phenolic
oxime-ester 1c {[R]30D +38.1 (c 1.13, CHCl3)} in 91% yield.
As shown in Scheme 5, the reaction of o-phenolic
oxime-ester 1c with PhIO in the presence of camphor-
sulfonic acid (CSA)2i in CH2Cl2 at -78 °C proceeded
smoothly to afford spiroisoxazoline 2c in 83% yield. The
500 MHz 1H NMR spectrum showed insufficiently re-
solved signals to enable accurate measurement of the
diastereomeric excess (de). Therefore, the de (∼70 to
80%) was estimated on the basis of the relatively resolved
methylene proton signals of the isoxazoline ring.
The chiral auxiliary in 2c, as well as the phenyl-
menthyloxy group in 2b, could not be cleaved successfully
by acid- or base-catalyzed hydrolysis. Therefore, we tried
to remove the chiral auxiliary under acidic conditions.
As expected, removal of the chiral auxiliary of spiroisox-
azoline 2c was achieved by treatment with CF3COOH
at rt for 1 h. Methylation using DCC and MeOH gave
methyl ester (-)-2a {[R]29D -56.4 (c 1.0, benzene)} in 74%
ee (71% chemical yield) having the S-configuration. The
enantiomeric excess (ee) was determined by HPLC using
a chiral column. It is reasonable to assume that epimer-
ization of 2c and racemization of 2a did not occur in
removal of the chiral auxiliary and at the methylation
stage, because the degree of the ee of (-)-2a was in the
range of the de of 2c (∼70 to 80% de). Furthermore, it
was found that optically active methyl ester 2a was stable
enough to keep its optical purity for at least 1 month at
0 °C. To the best of our knowledge, this is the first
example of a synthesis of enantiomerically enriched
cyclohexadienone spiroisoxazoline methyl esters. On the
other hand, the chiral auxiliary in 2c was converted into
a mixture of products by acid-assisted elimination at the
cleavage stage. Purification of this mixture gave exo
olefin 8 in 52% yield, the spectral data and the specific
rotation of which were identical with those for the exo
olefin obtained by olefination (Scheme 2) of 7. Thus, at
least a partial recycling of the chiral auxiliary (-)-3 was
found to be possible. Other products could not be
characterized, because they were inseparable by chro-
matography (silica gel, hexane).
A possible asymmetric induction mechanism is de-
picted in Scheme 6. Two hypervalent iodine complexes
A and B would be generated in the oxidation of 1c with
CSA-PhIO. Complex A would suffer from steric repul-
sion between the phenyl group of the chiral auxiliary and
the ligand of the hypervalent iodine reagent. The ap-
parently more stable complex B would lead to isomer 2c,
the observed major product.
Following recrystallization, the absolute configuration
of (-)-2a (84% ee)11 was determined by the synthesis of
the marine natural product (+)-aerothionin,12 as shown
in Scheme 7. According to Yamamura’s method (for
racemic aerothionin),2g optically active spiroisoxazoline
methyl ester (-)-2a was reduced with Zn(BH4)2 to give
cyclohexadienylisoxazoline (+)-15, amidation of which
with butanediamine afforded (+)-aerothionin {[R]28
D
(11) The ee of 2a could be increased by recrystallization from
MeOH-petroleum ether. Methyl esters 2a having 84% ee were
obtained from the mother liquid.
(12) For the optical rotation {[R]D +210 (c 1.7, MeOH)} and the
absolute configuration (S-configuration) of (+)-aerothionin, see: Mc-
Millan J . A.; Paul, I. C.; Goo, Y. M.; Rinehart, J r., K. L.; Krueger, W.
C.; Pschigoda, L. M. Tetrahedron Lett. 1981, 22, 39.

Asymmetric Oxidative Cyclization of o-Phenolic Oxime-Esters
J . Org. Chem., Vol. 62, No. 13, 1997 4431
481.2633. Anal. Calcd for C32H35NO3: C, 79.80; H, 7.33; N,
Sch em e 7
2.91. Found: C, 79.64; H, 7.38; N, 2.82. 6b: mp 152-154 °C
1
(AcOEt); [R]30 -75.7 (c, 1.03, CHCl3); H NMR δ 1.11-2.04
D
(13H, m), 1.68 (3H, d, J ) 6.9 Hz), 1.85-1.98 (1H, m), 2.30
(1H, dt, J ) 3.5, 10.9 Hz), 4.89 (1H, dt, J ) 4.4, 10.3 Hz), 5.31
(1H, m), 5.85 (1H, d, J ) 7.6 Hz), 6.47 (1H, m), 6.76 (2H, m),
6.91 (2H, m), 7.03 (1H, m), 7.13-7.48 (8H, m); 13C NMR δ 21.4,
23.8, 26.2, 32.8, 33.7 (CH2 × 2), 37.7, 42.0, 49.1, 49.3, 50.7,
77.9, 124.6, 126.6, 126.9, 127.2, 127.5, 127.6, 128.3, 128.4,
128.7, 130.5, 131.2, 138.0, 142.9, 147.8, 165.1, 168.5; IR (KBr)
3420, 3070, 2960, 2900, 1740, 1660, 1520, 1460 cm-1; MS m/ z
481 (M+); HRMS calcd for C32H35NO3 481.2615, found 481.2607.
Anal. Calcd for C32H35NO3: C, 79.80; H, 7.33; N, 2.91.
Found: C, 79.68; H, 7.34; N, 2.84.
+166 (c, 0.26, MeOH)} having S-configuration. Spectral
data of the synthetic sample were identical to those
reported in the literature.1a,2g
In conclusion, we have developed a method for the
synthesis of enantiomerically enriched spiroisoxazolines
by use of the novel optically active tertiary alcohol (-)-3
as a chiral auxiliary. The optically active spiroisoxazoline
methyl ester 2a should be useful as a synthon for the
synthesis of other bromotyrosine-derived natural marine
metabolites.
(1S,8R,9R,10R)-8-P h en yl-1-d eca lol [(-)-4]. A solution of
amide 6a (800 mg, 1.66 mmol) in 20% KOH (4 mL) and EtOH
(15 mL) was refluxed for 7 h. The solvent was removed under
reduced pressure. After addition of water (50 mL), the mixture
was extracted with Et2O (50 mL × 3). The organic extracts
were washed with saturated NaCl and dried over Na2SO4. The
solvent was removed under reduced pressure to afford (-)-4
(340 mg, 89%): mp 61-63 °C; [R]30 -6.9 (c, 1.07, CHCl3); 1H
D
NMR δ 1.0-1.86 (14H, m), 2.39 (1H, dt, J ) 3.1, 11.1 Hz),
3.46 (1H, dt, J ) 4.6, 9.3 Hz), 7.18-7.35 (5H, m); 13C NMR δ
23.8, 26.4, 33.8 (CH2 × 2), 35.0, 37.0, 41.8, 50.4, 54.7, 75.6,
126.9, 127.5, 129.2, 147.0; IR (KBr) 3590, 3020, 2925, 2875,
1610 cm-1; MS m/ z 230 (M+); HRMS calcd for C16H22
O
Exp er im en ta l Section
230.1670, found 230.1673.
Gen er a l. Melting points are uncorrected. 1H NMR (270
MHz or 500 MHz) and 13C NMR (67.5 MHz) spectra were
recorded in CDCl3 solution using TMS as an internal standard,
unless otherwise noted. Column chromatography was per-
formed on silica gel.
(8R,9R,10R)-8-P h en yl-1-d eca lon e (7). To a solution of
alcohol (-)-4 (340 mg, 1.48 mmol) in acetone (4 mL) was added
dropwise J ones reagent (1.1 g, 6.6 mmol) at 0 °C, until the
solution turned brown. The reaction mixture was stirred for
1 h. The mixture was quenched with i-PrOH and filtered.
After addition of water (4 mL), the filtrate was extracted with
AcOEt (50 mL × 3). The organic extracts were washed with
saturated NaCl and dried over MgSO4. The solvent was
removed under reduced pressure to afford 7 (308 mg, 91%):
(1S*,8R*,9R*,10R*)-8-P h en yl-1-d eca lyl
H yd r ogen
P h th a la te (5). A solution of racemic (1S*,8R*,9R*,10R*)-8-
phenyl-1-decalol (4)9 (2.4 g, 10.4 mmol) and phthalic anhydride
(1.5 g, 10.4 mmol) in pyridine (15 mL) was refluxed for 4 h.
The reaction mixture was cooled to 0 °C and then diluted with
10% HCl. The solution was extracted with Et2O (100 mL ×
3). The organic extracts were washed with saturated NaCl
and dried over MgSO4. The solvent was removed under
reduced pressure to afford 5 (2.9 g, 74%) as colorless crystals:
mp 139-143 °C (Et2O-petroleum ether); 1H NMR δ 1.15-
1.85 (13H, m), 1.89-2.15 (1H, m), 2.36-2.44 (1H m), 4.96 (1H,
dt, J ) 4.6, 10.2 Hz), 6.55 (1H, t, J ) 7.3 Hz), 6.85-7.05 (5H,
m), 7.24-7.47 (2H, m), 7.74 (1H, dd, J ) 1.2, 7.8 Hz); 13C NMR
δ 23.8, 26.2, 32.4, 33.6, 33.7, 38.0, 42.1, 49.6, 50.2, 79.0, 124.8,
126.8, 128.0, 129.4, 130.2, 130.4, 130.5, 131.0, 131.6, 147.5,
167.0, 171.8; IR (KBr) 2940, 2890, 1720, 1600 cm-1; MS m/ z
378 (M+); HRMS calcd for C24H26O4 378.1831, found 378.1831.
Anal. Calcd for C24H26O4: C, 76.16; H, 6.93. Found: C, 75.93;
H, 6.82.
mp 121-123 °C (hexane); [R]28 +41.3 (c, 0.47, CHCl3); [θ]295
D
1
+6847 (c 0.049, MeOH); H NMR δ 1.22-2.38 (13H, m), 2.60
(1H, t, J ) 11.0 Hz), 2.84 (1H, dt, J ) 4.3, 11.0 Hz), 7.09-7.27
(5H, m); 13C NMR δ 25.7, 27.9, 33.7, 34.1, 35.6, 42.6, 42.9, 46.2,
60.0, 125.7, 127.2, 128.1, 146.6, 211.6; IR (KBr) 3400, 2950,
1710 cm-1; MS m/ z 228 (M+); HRMS calcd for C16H20
O
228.1514, found 228.1511. Anal. Calcd for C16H20O: C, 84.16;
H, 8.83. Found: C, 84.15; H, 9.06.
(8R,9R,10R)-8-P h en yl-1-m eth ylen ed eca lin (8). Under
argon atmosphere, a suspension of KOt-Bu (281 mg, 2.5 mmol)
and methyltriphenylphosphonium bromide (893 mg, 2.5 mmol)
in Et2O (8 mL) was stirred at rt for 1 h. To this mixture was
added a solution of 7 (280 mg, 1.23 mmol) in Et2O (2.5 mL)
and CH2Cl2 (2.5 mL) at 0 °C. The resulting mixture was
stirred at rt for 8 h. After addition of water, this solution was
extracted with Et2O (50 mL × 3). The organic extracts were
washed with saturated NaCl and dried over Na2SO4. The
solvent was removed under reduced pressure, and the crude
product was purified by column chromatography (benzene)
followed by bulb-to-bulb distillation to afford 8 (250 mg, 90%)
(1S,8R,9R,10R)- a n d (1R,8S,9S,10S)-8-P h en yl-1-d eca lyl
(S)-[(1-P h en yleth yl)ca r ba m oyl]p h th a la te (6a a n d 6b). To
a solution of 5 (2.5 g, 6.6 mmol) and (S)-1-phenylethylamine
(0.8 g, 6.6 mmol) in DMF (16 mL) were added diethyl
cyanophosphonate (1.1 g, 6.6 mmol) and Et3N (0.7 g, 6.9 mmol)
at 0 °C, and the mixture was stirred at 0 °C for 30 min. After
being stirred at rt for 5 h, the reaction mixture was diluted
with water (40 mL). The product was taken up in AcOEt (40
mL)-benzene (20 mL). The organic layer was washed suc-
cessively with water, saturated NaHCO3, and saturated NaCl
and dried over MgSO4. The solvent was removed under
reduced pressure, and the crude product was purified by
column chromatography (hexane:AcOEt ) 2:1) to afford 6a (1.1
g, the second eluate, 35%) and 6b (1.3 g, the first eluate,
as an oil: bp 130 °C/4 mmHg; [R]28 +29.0 (c, 1.67, CHCl3);
D
1H NMR δ 1.09-2.24 (14H, m), 2.73 (1H, dt, J ) 3.6, 11.2 Hz),
4.29, 4.57 (each 1H, s), 7.09-7.38 (5H, m); 13C NMR δ 26.3,
29.1, 34.7, 35.1, 38.3, 38.4, 45.1, 45.7, 50.8, 107.7, 125.4, 127.0,
128.3, 147.5, 151.0; IR (CHCl3): 3350, 2900, 2840, 1610 cm-1
;
MS m/ z 226 (M+); HRMS calcd for C17H22 226.1721, found
226.1726.
(1S,8R,9R,10R)-8-P h en yl-1-m eth ylen edecalin Oxide (9).
To a solution of 8 (250 mg, 1.11 mmol) in DME (3 mL) and
H2O (5 mL) was added N-bromosuccinimide (229 mg, 1.29
mmol), and the mixture was stirred at rt for 3 h. After
addition of water, the product was taken up in Et2O (50 mL ×
3). The organic layer was washed with saturated NaCl and
dried over Na2SO4. The solvent was removed under reduced
pressure, and the product thus obtained was dissolved in
MeOH (3 mL). To this solution was added a solution of KOH
(600 mg) in H2O (1 mL) at 0 °C. The resulting mixture was
stirred at rt for 10 min. After addition of water, the mixture
was extracted with CH2Cl2 (50 mL × 3). The organic extracts
41%): 6a : mp 148-150 °C (AcOEt); [R]29 +7.1 (c, 1.06,
D
1
CHCl3); H NMR δ 1.05-1.78 (13H, m), 1.64 (3H, d, J ) 6.6
Hz), 1.89-1.94 (1H, m), 2.27 (1H, dt, J ) 3.3, 11.1 Hz), 4.85
(1H, dt, J ) 4.5, 10.4 Hz), 5.27 (1H, m), 5.84 (1H, d, J ) 7.6
Hz), 6.42 (1H, m), 6.67-6.76 (4H, m), 7.10-7.52 (9H, m); 13C
NMR δ 22.1, 23.7, 26.2, 32.5, 33.6 (CH2 × 2), 37.5, 41.9, 49.4,
49.6, 50.1, 77.8, 124.6, 126.7, 126.9, 127.0, 127.5, 127.7, 128.4,
128.6, 128.9, 130.7, 131.2, 138.0, 143.2, 147.8, 165.3, 168.6;
IR (KBr) 3350, 2950, 2900, 1730, 1660, 1545, 1470 cm-1; MS
m/ z 481 (M+); HRMS calcd for C32H35NO3 481.2615, found

4432 J . Org. Chem., Vol. 62, No. 13, 1997
Murakata et al.
were washed with saturated NaCl and dried over MgSO4. The
solvent was removed under reduced pressure, and the crude
product was purified by column chromatography (benzene) to
afford 9 (180 mg, 67%): mp 104-109 °C; [R]30D -21.6 (c, 1.01,
stirred at 0 °C for 30 min. After the mixture was stirred at rt
for 4 h, the solvent was removed under reduced pressure. After
being diluted with AcOEt, the mixture was filtered, and the
filtrate was washed with saturated NaHCO3 and saturated
NaCl and dried over MgSO4. The solvent was removed under
reduced pressure, and the crude product was purified by
column chromatography (hexane:AcOEt ) 3:2) to afford 13
(14.3 g, 91%): mp 132-134 °C (AcOEt-Et2O); 1H NMR δ 3.89
(3H, s), 3.95 (2H, s), 4.95 (1H, s), 5.29 (2H, s), 7.07 (2H, d, J )
9.2 Hz), 7.25-7.37 (11H, m), 8.17 (2H, d, J ) 9.2 Hz); 13C NMR
δ 27.0, 60.7, 74.6, 78.6, 112.8, 114.6, 122.5, 125.1, 128.1, 128.3,
128.4, 128.5, 128.6 (CH × 2), 132.8, 135.7, 136.4, 145.4, 148.9,
154.2, 155.1, 161.1, due to overlap (quarternary C × 2), not
all carbons resonances were visible; IR (KBr) 3300, 1730, 1580,
1520, 1450 cm-1; MS m/ z 686 (M+ + 4), 684 (M+ + 2), 682
(M+); HRMS calcd for C30H24O7N281Br2 685.9891, found
685.9889, calcd for C30H24O7N281Br79Br 683.9930, found
683.9938, calcd for C30H24O7N279Br2 681.9950, found 681.9940.
Anal. Calcd for C30H24N2O7Br2: C, 52.65; H, 3.53; N, 4.09.
Found: C, 52.65; H, 3.75; N, 4.04.
1
CHCl3); H NMR δ 1.10-2.20 (15H, m), 2.18 (1H, d, J ) 4.6
Hz), 2.70 (1H, dd, J ) 2.0, 4.6 Hz), 7.07-7.26 (5H, m); 13C
NMR δ 25.0, 26.1, 34.0, 34.3, 36.9, 38.2, 42.6, 44.8, 47.8, 48.4,
61.7, 125.2, 126.0, 127.9, 147.5; IR (KBr): 3450, 3050, 2960,
2900, 1510, 1230, 750 cm-1; MS m/ z 242 (M+); HRMS calcd
for C17H22O 242.1669, found 242.1669.
(1S,8R,9R,10R)-1-Meth yl-8-p h en yl-1-d eca lol (3). To a
suspension of LiAlH4 (216 mg, 5.68 mmol) in Et2O (10 mL)
was added a solution of 9 (437 mg, 1.8 mmol) in Et2O (5 mL)
at 0 °C, and the mixture was refluxed for 1 h. After successive
addition of water (0.21 mL), 15% NaOH (0.21 mL), and water
(0.63 mL), the mixture was filtered and dried over K2CO3. The
solvent was removed under reduced pressure, and the crude
product was purified by flash column chromatography (hexane:
AcOEt ) 10:1) followed by bulb-to-bulb distillation to afford 3
(367.7 mg, 84%) as an oil: bp 220-235 °C/3 mmHg; [R]31
D
-19.8 (c, 1.32, CHCl3); 1H NMR δ 1.22 (3H, s), 0.88-1.79 (14H,
m), 2.50 (1H, dt, J ) 3.3, 11.2 Hz), 7.16-7.34 (5H, m); 13C NMR
δ 22.7, 22.8, 26.3, 34.7 (CH2 × 2), 37.7, 40.2, 42.0, 46.4, 56.6,
74.2, 126.6, 128.0, 129.0, 146.5; IR (CHCl3) 3600, 2950, 2860,
(1S,8R,9R,10R)-1-Meth yl-8-p h en yl-1-d eca lyl 2-[(Ben z-
yloxy)im in o]-3-[2-(b en zyloxy)-3,5-d ib r om o-4-m et h oxy-
p h en yl]p r op ion a te (14). Under argon atmosphere, to a
solution of optically active tertiary alcohol 3 (1.6 g, 6.6 mmol)
in toluene (30 mL) was added a solution of MeLi in Et2O (6.7
mL, 6.63 mmol, 0.99 M) at 0 °C, and the mixture was stirred
for 30 min. Then HMPA (3.5 mL, 19.8 mmol) was added at 0
°C. The mixture was stirred at rt for 30 min and heated at
80 °C for 3 h. The resulting mixture was cooled to 0 °C and
added to a solution of nitrophenyl ester 13 (4.5 g, 6.6 mmol)
in toluene (30 mL) at 0 °C. The reaction mixture was stirred
at 0 °C for 3 h and then at rt for 5 h. After addition of water
at 0 °C, the mixture was extracted with Et2O (100 mL × 3).
The organic extracts were washed with saturated NaHCO3 and
saturated NaCl and dried over Na2SO4. The solvent was
removed under reduced pressure, and the crude product was
purified by column chromatography (benzene) to afford 1.9 g
of 14 along with 0.9 g of recovered alcohol 3. The recovered
alcohol was resubjected to the same reaction to afford ad-
1610 cm-1; MS m/ z 244 (M+); HRMS calcd for C17H24
O
244.1825, found 244.1818.
(1R*,8R*,9R*,10R*)-1-Meth yl-8-p h en yl-1-d eca lol (10).
This compound was prepared from racemic ketone 7 using
Me3Al (method A) or MeLi (method B). Method A: Under
argon atmosphere, to a solution of racemic ketone 7 (50 mg,
0.22 mmol) in toluene (2 mL) was added a solution of Me3Al
in toluene (0.5 mL, 1 mmol, 2 M) at 0 °C. The mixture was
stirred at rt for 30 min and refluxed for 12 h. After the
mixture was cooled to 0 °C, 0.5 N NaOH was added. The
product was taken up in Et2O (20 mL × 3). The organic layer
was washed with saturated NaCl and dried over Na2SO4. The
solvent was removed under reduced pressure, and the crude
product was purified by column chromatography (CHCl3:
AcOEt ) 30:1) to afford 10 (43.5 mg, 81%) as an oil. Method
B: Under argon atmosphere, to a solution of racemic ketone
7 (50 mg, 0.22 mmol) in THF (2 mL) was added a solution of
MeLi in Et2O (0.3 mL, 0.3 mmol, 0.99 M) at -78 °C. The
mixture was stirred at -78 °C for 1 h and quenched with
saturated NH4Cl. Workup as above gave 10 (47.8 mg, 89%)
as an oil: 1H NMR δ 0.46 (3H, s), 1.01-1.84 (14H, m,), 2.60-
2.74 (1H, m), 7.1-7.30 (5H, m); 13C NMR δ 21.6, 26.2, 32.3,
34.8 (CH2 × 2), 38.1, 39.0, 43.1, 45.5, 54.2, 72.4, 125.6, 127.7,
128.3, 149.3; IR (CHCl3) 3350, 2900, 2850, 1610 cm-1; MS m/ z
244 (M+); HRMS calcd for C17H24O 244.1825, found 244.1835.
(1R*,8R*,9R*,10R*)-8-P h en yl-1-m eth ylen ed eca lin Ox-
id e (11). This compound was prepared from racemic meth-
ylenedecalin 8. To a solution of racemic methylenedecalin 8
(80.5 mg, 0.36 mmol) in CH2Cl2 (2 mL) was added 80%
m-CPBA (98.4 mg, 0.57 mmol) at 0 °C. The mixture was
stirred at 0 °C for 2 h. After addition of Ca(OH)2 (120 mg),
the resulting mixture was stirred at rt for 1 h, and then the
mixture was filtered. After the filtrate was diluted with
CH2Cl2, the organic layer was washed with saturated NaHCO3
and saturated NaCl, and dried over MgSO4. The solvent was
removed under reduced pressure, and the crude product was
purified by column chromatography (benzene) to afford 11
(75.7 mg, 87%) as an oil: 1H NMR δ 1.03-2.05 (14H, m), 2.14,
2.39 (each 1H, d, J ) 4.3 Hz), 2.32-2.42 (1H, m), 7.12-7.36
(5H, m); 13C NMR δ 23.7, 25.8, 34.2, 34.6, 36.2, 39.0, 40.0, 42.0,
46.2, 55.2, 60.5, 125.6, 126.7, 128.7, 148.3; IR (KBr): 3400,
3050, 2950, 2900, 1510, 1230, 750 cm-1; MS m/ z 242 (M+);
HRMS calcd for C17H22O 242.1669, found 242.1667. In a
fashion similar to that described for 3, this compound 11 was
subjected to the same reduction (77%). The spectral properties
of the product were identical with those obtained for axial
alcohol 10.
ditional 14 as an oil (4.4 g, total 85%): [R]32 +44.8 (c, 1.17,
D
CHCl3); 1H NMR δ 1.05-1.75 (12H, m), 1.37 (3H, s), 2.18-
2.29 (1H, m), 2.40-2.50 (1H, m), 2.56-2.63 (1H, m), 3.84 (3H,
s), 2.87, 3.42 (each 1H, d, J ) 15.5 Hz), 4.83, 4.85 (each 1H, d,
J ) 10.9 Hz), 5.12, 5.17 (each 1H, d, J ) 11.9 Hz), 6.8-7.52
(16H, m); 13C NMR δ 20.8, 22.8, 25.4, 26.3, 33.9, 34.6, 36.9,
37.5, 40.5, 46.4, 50.5, 60.6, 74.4, 77.5, 89.0, 112.6, 114.2, 125.1,
127.6, 127.8, 127.9, 128.1, 128.2, 128.4, 129.3, 131.5, 136.7 (C
× 2), 146.8, 150.6, 153.4, 154.1, 161.0, due to overlap (CH ×
2), not all carbons resonances were visible; IR (CHCl3) 3320,
2900, 1710, 1600, 1460, 1420 cm-1; MS (EI+) m/ z 791 (M+
+
4), 789 (M+ + 2), 787 (M+); MS (FAB+) m/ z 790 (M+ + 4 -
H), 788 (M+ + 2 - H), 786 (M+ - H); HRMS (FAB+) calcd for
C41H42NO581Br2 790.1389, found 790.1381, calcd for C41H42
NO579Br2 786.1430, found 786.1433.
-
(1S,8R,9R,10R)-1-Meth yl-8-ph en yl-1-decalyl 2-(Hydr oxy-
im in o)-3-(2-h yd r oxy-3,5-d ibr om o-4-m eth oxyp h en yl)p r o-
p ion a te (1c). A solution of benzyl ether 14 (4.4 g, 5.58 mmol)
in AcOH (40 mL) and dioxane (40 mL) was hydrogenated over
Pd-black (960 mg) under H2 at rt for 7 h. After filtration, the
filtrate was basified with saturated NaHCO3 and then ex-
tracted with AcOEt (200 mL × 3). The organic extracts were
washed with saturated NaCl and dried over MgSO4. The
solvent was removed under reduced pressure, and the crude
product was purified by column chromatography (CHCl3:
MeOH ) 20:1) to afford 1c (3.1 g, 91%) as an oil: [R]30 +38.1
D
1
(c, 1.13, CHCl3); H NMR δ 1.05-1.77 (12H, m), 1.56 (3H, s),
2.49-2.69 (2H, m), 2.72-2.76 (1H, m), 3.29, 3.48 (each 1H, d,
J ) 13.9 Hz), 3.86 (3H, s), 6.82-7.4 (6H, m), 8.48 (1H, br); 13
C
NMR δ 21.3, 23.0, 25.2, 26.2, 33.9, 34.5, 37.1 (CH2 × 2), 40.7,
46.0, 50.4, 60.5, 91.8, 107.1, 108.0, 119.6, 125.3, 127.5, 128.2,
134.2, 146.7, 148.3, 152.5, 154.1, 163.2; IR (CHCl3) 3350, 2930,
1720, 1670, 1460, 1410 cm-1; MS (FAB+) m/ z 612 (M+ + 4 +
H), 610 (M+ + 2 + H), 608 (M+ + H); HRMS (FAB+) calcd for
p-Nitr op h en yl 2-[(Ben zyloxy)im in o]-3-[2-(ben zyloxy)-
3,5-d ibr om o-4-m eth oxyp h en yl]p r op ion a te (13). To a so-
lution of benzyloxime-acid 121a (13 g, 23.1 mmol) in CH2Cl2
(130 mL) were added DCC (5.24 g, 25.4 mmol) and p-
nitrophenol (3.9 g, 28.1 mmol) at 0 °C, and the mixture was
C27H32NO581Br2 612.0606, found 612.0635, calcd for C27H32
NO581Br79Br 610.0627, found 610.0641, calcd for C27H32
NO579Br2 608.0648, found 608.0626.
-
-

Asymmetric Oxidative Cyclization of o-Phenolic Oxime-Esters
J . Org. Chem., Vol. 62, No. 13, 1997 4433
Oxid a tive Cycliza tion of 1c. CSA (1.28 g, 5.5 mmol) was
added to a suspension of PhIO (1.22 g, 5.5 mmol) in CH2Cl2
(60 mL) at rt, and the mixure was stirred for 2 h. The
resulting clear solution was cooled to -78 °C. A solution of
o-phenolic oxime-ester 1c (3.06 g, 5 mmol) in CH2Cl2 (60 mL)
was added to the solution above, and the mixure was warmed
to 0 °C. After addition of water, the mixture was stirred at rt
for 30 min. Extractive workup followed by column chroma-
tography (benzene) afforded spirocyclohexadienone isoxazoline
2c (2.53 g, 83%). The de (70-80%) was estimated on the basis
of methylene proton signals of the isoxazoline ring in the 500
62.2, 86.9, 106.7, 120.9, 136.0, 150.0, 159.7, 163.2, 188.7; IR
(CHCl3) 1720, 1675, 1595, 1540, 1440 cm-1; MS m/ z 397 (M+
+ 4), 395 (M+ + 2), 393 (M+).
(5S,6R)-Meth yl 7,9-Dibr om o-6-h yd r oxy-8-m eth oxy-1-
oxa -2-a za sp ir o[4.5]d eca -2,7,9-tr ien e-3-ca r boxyla te [(+)-
15]. Compound (+)-15 was prepared from (-)-2a (84% ee)
according to Yamamura’s method:2g [R]28 +181 (c, 0.86,
D
1
benzene); H NMR (acetone-d6) δ 3.22 (1H, d, J ) 18.2 Hz),
3.73, 3.83 (each 3H, s), 3.85 (1H, d, J ) 18.2 Hz), 4.22, 5.43
(each 1H, d, J ) 8.3 Hz), 6.52 (1H, s); 13C NMR (acetone-d6) δ
39.8, 52.8, 60.2, 75.1, 92.4, 113.8, 122.1, 132.0, 148.7, 152.4,
161.1; IR (CHCl3) 3400, 2930, 1720, 1580, 1440 cm-1; MS m/ z
1
MHz H NMR spectrum.
(1S,8R,9R,10R)-1-Meth yl-8-p h en yl-1-d eca lyl 7,9-d ibr o-
399 (M+ + 4), 397 (M+ + 2), 395 (M+); HRMS calcd for C11H11
-
m o-8-m eth oxy-6-oxo-1-oxa-2-azaspir o[4.5]deca-2,7,9-tr ien e-
NO581Br2 398.8963, found 398.8955, calcd for C11H11NO581Br79Br
396.8983, found 396.8961, calcd for C11H11NO579Br2 394.9004,
found 394.8992.
1
3-ca r boxyla te (2c): 500 MHz H NMR δ 1.46 (3H, s), 1.21-
1.80 (12H, m), 2.10-2.94 (3H, m), 2.17 (major product) (1H,
d, J ) 17.6 Hz), 3.00 (major product) (1H, d, J ) 17.6 Hz),
2.72 (minor product) (1H, d, J ) 17.7 Hz), 2.86 (minor product)
(1H, d, J ) 17.7 Hz), 4.15 (3H, s), 6.65 (major product) (1H,
s), 6.66 (minor product) (1H, s), 7.1-7.3 (5H, m); 13C NMR
(major product) δ 21.2, 22.9, 26.3, 33.8, 34.5, 37.1, 37.7, 40.7,
44.4, 46.5, 49.6, 62.0, 86.7, 90.4, 107.2, 119.1, 125.6, 127.8,
128.4, 137.1, 147.3, 150.9, 157.2, 163.1, 188.9; IR (CHCl3) 3370,
2590, 1710, 1600, 1580, 1550, 1450 cm-1; MS (FAB-) m/ z 609
(M- + 4), 607 (M- + 2), 605 (M-); HRMS (FAB-) calcd for
C27H29NO581Br79Br 607.0392, found 607.0362.
(+)-Aer oth ion in . (+)-Aerothionin was synthesized from
(+)-15 according to Yamamura’s method:2g [R]28D +166 (c, 0.26,
MeOH); lit.:12 [R]D +210 (c, 1.7, MeOH); 1H NMR (acetone-d6)
δ 1.62 (4H, m), 3.18 (2H, d, J ) 18.2 Hz), 3.30-3.45 (4H, m),
3.73 (6H, s), 3.84 (2H, d, J ) 18.2 Hz), 4.17 (2H, d, J ) 7.4
Hz), 5.44 (2H, d, J ) 7.4 Hz, OH), 6.52 (2H, s), 7.65 (2H, m,
NH); 13C NMR (acetone-d6) δ 27.4, 39.5, 40.2, 60.2, 75.2, 91.5,
113.8, 122.0, 132.3, 148.7, 155.3, 160.0; IR (CHCl3) 3350, 1660,
1600, 1580, 1530, 1100 cm-1; MS (FAB+) m/ z 819 (M+ + 4 +
H), 815 (M+ + H); HRMS (FAB+) calcd for C24H27N4-
O881Br279Br2 818.8521, found 818.8496, calcd for C24H27N4-
O879Br4 814.8562, found 814.8536.
Syn th esis of (5S)-Meth yl 7,9-Dibr om o-8-m eth oxy-6-
oxo-1-oxa -2-a za sp ir o[4.5]d e ca -2,7,9-t r ie n e -3-ca r b ox-
yla te [(-)-2a ]. To a solution of 2c (2.1 g, 3.46 mmol) in CH2Cl2
(15 mL) was added TFA (15 mL) at 0 °C, and the mixture was
stirred at rt for 1 h. The solvent was removed under reduced
pressure, and the resulting rersidue was dissolved in CH2Cl2
(35 mL). To this solution was added MeOH (179 mg, 5.6
mmol), DCC (1.21 g, 5.9 mmol), and DMAP (68 mg, 0.56 mmol)
in this order. The mixture was stirred at rt for 30 min. After
filtration, the solvent was removed under reduced pressure,
and the crude product was purified by column chromatography
(benzene) to afford (-)-2a (racemic 2a 2g) in 74% ee (970.4 mg,
71%). The ee was determined by HPLC analysis (hexane:
Ack n ow led gm en t. We are grateful to Dr. T. Nakata
and Dr T. Suenaga (RIKEN) for the circular dichroism
measurements.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of all new compounds and HPLC chromatograms of
(-)-2a using a chiral column (18 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
EtOH ) 9:1) using chiralcel-OA (DAICEL): [R]29 -56.4 (c,
D
1.0, benzene); 1H NMR δ 3.31, 3.61 (each 1H, d, J ) 17.8 Hz),
3.91 (3H, s), 4.18 (3H, s), 6.79 (1H, s); 13C NMR δ 44.4, 53.2,
J O970082I