Opening of aryl-substituted epoxides to form quaternary stereogenic centers: Synthesis of (-)-mesembrine

Article abstract of DOI:10.1021/jo0511039

Cycloalkanones are easily converted into aryl-substituted cyclic alkenes by the addition of an aryl Grignard reagent followed by dehydration. These alkenes are good substrates for asymmetric epoxidation. We have found that the addition of allylic and benzylic Grignard reagents can occur preferentially at the benzylic position of the derived epoxides to give the quaternary stereogenic center. This approach led to a short synthesis of the nanomolar serotonin re-uptake inhibitor (-)-mesembrine.

Full text of DOI:10.1021/jo0511039

Opening of Aryl-Substituted Epoxides To Form Quaternary
Stereogenic Centers: Synthesis of (-)-Mesembrine
Douglass F. Taber* and Yigang He
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716
Taberdf@udel.edu
Received June 1, 2005
Cycloalkanones are easily converted into aryl-substituted cyclic alkenes by the addition of an aryl
Grignard reagent followed by dehydration. These alkenes are good substrates for asymmetric
epoxidation. We have found that the addition of allylic and benzylic Grignard reagents can occur
preferentially at the benzylic position of the derived epoxides to give the quaternary stereogenic
center. This approach led to a short synthesis of the nanomolar serotonin re-uptake inhibitor (-)-
mesembrine.
Introduction
Alicyclic rings containing quaternary stereogenic cen-
ters1 with attached aromatic rings are a common motif
both among physiologically active alkaloids, including
mesembrine 1 and morphine 2, and in medicinal chem-
istry. We report what promises to be a general enantio-
selective method for the construction of such stereogenic
centers. We have illustrated the power of this approach
with a short synthesis of (-)-mesembrine 1.2-4
(-)-Mesembrine 1 was isolated as the major alkaloid
component of Sceletium tortuosum, chewed for its stimu-
lant properties by the indigenous population of the
Kalahari. In a limited trial,5 the dried and powdered
plant preparation, a mild stimulant, was shown to have
marked anxiolytic properties. This crude preparation was
also shown to be a powerful anti-addictive. The pure
alkaloid 1 was recently shown6 to be a nanomolar
inhibitor of serotonin re-uptake, with efficacy being
observed at a once-a-day oral dose of 100 µg.
(1) For reviews on the enantioselective construction of quaternary
stereogenic centers, see: (a) Martin, S. F. Tetrahedron 1980, 36, 419.
(b) Fuji, K. Chem. Rev. 1993, 93, 2037. (c) Corey, E. J.; Guzman-Perez,
A. Angew. Chem., Int. Ed. 1998, 37, 388. (d) Christoffers, J.; Mann, A.
Angew. Chem., Int. Ed. 2001, 40, 4591. (e) Dennisova, I.; Barriault, L.
Tetrahedron 2003, 59, 10105. (f) Douglas, C. J.; Overman, L. E. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5363.
(2) For the isolation and structural determination of (-)-mesem-
brine, see: (a) Popelak, A.; Haack, E.; Lettenbauer, G.; Spingler, H.
Naturwissenschaften 1960, 47, 156. (b) Smith, E.; Hosansky, N.;
Shamma, M.; Moss, J. B. Chem. Ind. 1961, 402.
(3) For leading references to previous enantioselective syntheses of
(-)-mesembrine, see: (a) Takano, S.; Imamura, Y.; Ogasawara, K.
Tetrahedron Lett. 1981, 22, 4479. (b) Takano, S.; Samizu, K.; Ogasawara,
K. Chem. Lett. 1990, 1239. (c) Fukumoto, K.; Tanabe, T.; Nemoto, H.
J. Org. Chem. 1995, 60, 6785. (d) Mori, M.; Kuroda, S.; Zhang, C.; Sato,
Y. J. Org. Chem. 1997, 62, 3263. (e) Denmark, S. E.; Marcin, L. R. J.
Org. Chem. 1997, 62, 1675. (f) Langlois, Y.; Dalko, P. I.; Brun, V.
Tetrahedron Lett. 1998, 39, 8979. (g) Ogasawara, K.; Yamada, O.
Tetrahedron Lett. 1998, 39, 7747. (h) Taber, D. F.; Neubert, T. D. J.
Org. Chem. 2001, 66, 143. For leading references to previous enanti-
oselective syntheses of (+)-mesembrine, see: (i) Meyers, A. I.; Hanreich,
R.; Wanner, K. T. J. Am. Chem. Soc. 1985, 107, 7776. (j) Kosugi, H.;
Miura, Y.; Kanna, H.; Uda, H. Tetrahedron: Asymmetry 1993, 4, 1409.
(4) For leading references to the synthesis of racemic mesembrine,
see: (a) Chavan, S. P.; Khobragade, D. A.; Pathak, A. B.; Kalkote, U.
R. Tetrahedron Lett. 2004, 45, 5263. (b) Kulkarni, M. G.; Rasne, R.
M.; Davawala, S. I.; Doke, A. K. Tetrahedron Lett. 2002, 43, 2297. (c)
Rigby, J. H.; Dong, W. Org. Lett. 2000, 2, 1673.
(5) For cultural background and some limited activity trials of
Sceletium tortuosum, see: Smith, M. T.; Crouch, N.; Gericke, N.; Hirst,
M. J. Ethnopharmacol. 1996, 50, 119.
(6) For the in vitro and in vivo activity of (-)-mesembrine, see:
Gericke, N. P.; VanWyk, B.-E. PCT Int. Appl., WO 9746234 CAN 128:
80030, 1997.
10.1021/jo0511039 CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/17/2005
J. Org. Chem. 2005, 70, 7711-7714
7711

Taber and He
TABLE 1. Opening of Arene-Substituted Cyclic
SCHEME 1
Epoxides
Results and Discussion
We recently observed (Scheme 1)7 that allylic and
benzylic Grignard reagents would open epoxides such as
3 to give selectively the product 4. We envisioned that
an epoxide such as 5, with an attached arene,8 might be
similarly activated.
In the event (Table 1), we were not disappointed. Even
a simple nonactivating arene9-11 (entry 1) gave a sub-
stantial portion of the desired product. An activating
p-methyl (entry 2) increased the fraction of the desired
secondary alcohol. With the still more activating p-
methoxy (entry 3), the cyclic quaternary stereogenic
center was formed smoothly.
We also explored alternative nucleophiles with the
epoxide 5d10 (Table 1). We found that allylic and benzylic
Grignard reagents gave the desired ring-opening prod-
ucts. It was striking that, although the alkyne-activated
epoxide (Scheme 1) gave the branched product 4 with
crotylmagnesium chloride, the arene-activated epoxide
gave only the complementary linear product 6g. The less
reactive and more basic alkyl, phenyl, and vinyl Grignard
reagents gave primarily undesired side products. This
difference is attributable at least in part to the lack of
reactivity of these nucleophiles toward the trisubstituted
cyclic expoxide. Et3Al8d gave rearrangement to the cy-
clohexanone followed by hydride reduction, while Et2-
AlCN12 gave only rearrangement to the ketone.
The beauty of this approach is that it allows the
construction of a quaternary stereogenic center on an
existing ring. It is particularly exciting that, using the
Shi epoxidation,13 one can convert a prochiral cyclic
a Ratio of two isomers was determined by 1H NMR. b Combined
yields of two isomers. c Isolated yield of 6b.
(7) Taber, D. F.; He, Y.; Xu, M. J. Am. Chem. Soc. 2004, 126, 13900.
(8) For reports of the opening of arene-activated trisubstituted
epoxides at the more substituted carbon to establish a quaternary
center, see: (a) Gerteisen, T. J.; Kleinfelter, D. C. J. Org. Chem. 1971,
36, 3255. (b) Krause, N.; Seebach, D. Chem. Ber. 1988, 121, 1315. (c)
Kauffmann, T.; Neiteler, C.; Robbe, S. Chem. Ber. 1992, 125, 2409. (d)
Jansen, J.; Knopp, M.; Amberg, W.; Bernard, H.; Koser, S.; Mu¨ller, S.;
Mu¨nster, I.; Pfeiffer, T.; Riechers, H. Org. Process Res. Dev. 2001, 5,
16.
(9) (a) For the preparation of the alkenes corresponding to 5a and
5c, see: Balsamo, A.; Crotti, P.; Macchia, B.; Macchia, F. Tetrahedron
1973, 29, 2183. (b) For the preparation of the alkenes corresponding
to 5b and 5c, see: Doan, L.; Bradley, K.; Gerdes, S.; Whalen, D. L. J.
Org. Chem. 1999, 64, 6227.
(10) For the preparation of 5d, see: Hoshino, O.; Sawaki, S.;
Shimamura, N.; Onodera, A.; Umezawa, B. Chem. Pharm. Bull. 1987,
35, 2734.
alkene to the enantiomerically defined product. To es-
tablish the viability of this approach and to confirm the
sense of absolute stereocontrol of the process, we con-
verted the monoprotected cyclohexanone 6d (Scheme 2)
to (-)-mesembrine (1).
The cyclohexanone 8 reacted with the aromatic Grig-
nard reagent 9 to give the known10 alkene 10, after
dehydration using PTSA in the presence of excess eth-
ylene glycol. Shi expoxidation13 of 10 followed by ring-
opening of the resulting crude epoxide by allylmagnesium
chloride gave the enantiomerically enriched secondary
alcohol 6d.10 The enantiomers of 6d were well-resolved
by chiral HPLC (Chiralcel OD, 15% 2-propanol/hexane,
1 mL/min, retention time: 17.6 min for the minor
enantiomer and 34.2 min for the major enantiomer). The
alcohol 6d derived from Shi epoxidation had 96% ee.
(11) We found that the sensitive epoxides could be prepared ef-
ficiently from the alkenes with dimethyl dioxirane: Murray, R. W.;
Singh, M. Org. Synth. 1997, 74, 91.
(12) Newbold, R. C.; Shih, T. L.; Mrozik, H.; Fisher, M. H. Tetra-
hedron Lett. 1993, 34, 3825.
(13) Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.
7712 J. Org. Chem., Vol. 70, No. 19, 2005

Synthesis of (-)-Mesembrine
SCHEME 2a
Experimental Section
Epoxide (5c). A solution of 1-(4-methoxyphenyl)-cyclohex-
ene (0.752 g, 3.68 mmol) in 2 mL of acetone was added to a
solution of dimethyldioxirane4 (50 mL, ∼0.07 M) in acetone
at room temperature. The yellow color of dimethyldioxirane
disappeared immediately. After evaporation of acetone, the
residue was treated immediately with 10 mL of 2.0 M
allylmagnesium chloride as described below.
Typical Procedure for the Ring Opening of Epoxides
with Grignard Reagents. To a solution of epoxide (2 mmol)
in anhydrous THF (15 mL) was added dropwise a solution of
Grignard reagent (10 mmol, 5 equiv) over 2 min at 0 °C. The
reaction mixture was warmed slowly to room temperature and
then stirred overnight. The reaction mixture was partitioned
between saturated aqueous NH4Cl and ether. The combined
organic extract was dried (Na2SO4) and concentrated, and the
residue was chromatographed.
Alcohol (6b): Clear oil (58% yield), TLC Rf ) 0.46 (PE/
acetone, 3:1), Rf ) 0.43 for the minor isomer 5f. IR (neat, cm-1):
3456 (s), 2935 (s), 2863 (s), 1638 (w), 1514 (m), 1454 (m), 1239
1
(m); H NMR (400 MHz, CDCl3) δ: 7.15-7.30 (m, 4H), 5.23
(m, 1H), 4.92 (d, J ) 30.4 Hz, 1H), 4.89 (d, J ) 23.2 Hz, 1H),
4.02 (t, J ) 3.2 Hz, 1H), 2.34-2.64 (m, 2H), 2.34 (s, 3H), 1.45-
2.10 (m, 9H); 13C NMR (CDCl3, 100 MHz) δ u: 141.9, 135.9,
117.1, 45.2, 41.3, 28.3, 27.0, 21.2, 20.1; d: 134.7, 129.5, 127.0,
74.1, 21.1; HRMS calcd for C16H21 (M + H - H2O) 213.1643,
found 213.1644.
Alkene (10). To a Grignard reagent prepared from Mg (1.82
g, 75.0 mmol) and 4-bromoveratrole (13.0 g, 60.0 mmol) in 40
mL of anhydrous THF at 0 °C was added 1,4-dioxaspiro[4,5]-
decan-8-one 8 (7.80 g, 50.0 mmol) in 20 mL of anhydrous THF
over 5 min under nitrogen. After being stirred at 0 °C for 30
min, then ambient temperature for 2 h, the reaction mixture
was partitioned between ether and saturated aqueous NH4-
Cl. The combined organic extract was dried (Na2SO4) and
concentrated. To the residue was added benzene (200 mL),
ethylene glycol (30 mL), and p-toluenesulfonic acid (10 mg). A
Dean-Stark water separation apparatus was set up, and the
solution was heated to reflux until about 0.9 mL of water had
been collected. The reaction mixture was partitioned between
ether and saturated aqueous NaHCO3. The organic extract was
dried (Na2SO4) and evaporated, and the residue was chro-
matographed to give 8.86 g of alkene 10 (64% yield from 8) as
white solid: mp 76-78 °C (lit.10 ) 77.5-78 °C). 1H NMR (400
MHz, CDCl3) δ: 6.80-6.95 (m, 3H), 5.91 (m, 1H), 4.01 (s, 4H),
3.88 (s, 3H), 3.87 (s, 3H), 2.64 (m, 2H), 2.46 (br, 2H), 1.90 (t,
J ) 6.4 Hz, 2H).
Alcohol (6d). To a 500-mL three-necked flask was added
alkene 10 (2.31 g, 8.37 mmol), 85 mL of a 2:1 mixture of
dimethoxymethane and acetonitrile, 50 mL of potassium
carbonate-acetic acid buffer solution, tetrabutylammonium
hydrogen sulfate (63 mg), and Shi’s chiral ketone (0.756 g, 2.93
mmol). The flask was connected to two dropping funnels, one
charged with a solution of oxone (7.72 g, 12.6 mmol) in 30 mL
of aqueous 4 × 10-4 Na2EDTA and the other charged with 30
mL of 1.47 M aqueous KOH. The two solutions were added
dropwise at the same rate over 65 min to the cold reaction
mixture which was stirred vigorously at 0 °C. After 3 h, ether
(100 mL) was added. The biphasic mixture was partitioned
between ether and, sequentially, water and brine. The organic
extract was dried (Na2SO4) and concentrated. The residue was
dissolved in 50 mL of anhydrous THF. To this solution
allylmagnesium chloride (21 mL, 2.0 M) was added dropwise
over 5 min at 0 °C under N2. The reaction solution was warmed
slowly from 0 °C to room temperature, then maintained at
ambient temperature overnight. The reaction mixture was
partitioned between saturated aqueous NH4Cl and ether. The
combined organic extract was dried over Na2SO4 and concen-
trated in vacuo. The residue was chromatographed to give 2.04
g of alcohol 6d (73% yield from 10) as a colorless oil. TLC Rf
) 0.56 (ether), [R]22D +37.3 (c 1.6, THF); IR (neat, cm-1): 3514
(s), 2954 (s), 1637 (w), 1587 (w), 1518 (s), 1464 (m), 1256 (s),
a (a) THF, 0-20 °C, overnight; (b) benzene, PTSA (cat.), ethylene
glycol (excess), reflux; (c) Shi’s catalyst, DME-acetonitrile-H2O,
0 °C, 4 h; (d) allylmagnesium chloride, THF, 0-20 °C, overnight;
(e) 10% aqueous HCl, THF, reflux, 1 h; (f) O3, MeOH, -78 °C;
CeCl3‚7H2O (1.0 equiv), NaBH4 (8.0 equiv), 0 °C; (g) TsCl (1 equiv),
Et3N, CH2Cl2, 20 °C, overnight; (h) 40% aqueous CH3NH2, THF,
65 °C, 1 h; (i) MnO2, CH2Cl2, 20 °C, 3 h.
Exposure of 6d to 10% aqueous HCl in THF gave the
enone 11.4b Selective ozonolysis of the terminal double
bond in 11 followed by treatment14 of the resulting
15
ozonide in situ with NaBH4 in the presence of CeCl3
furnished the diol 113h as a 4:1 mixture of diastereomers.
The primary hydroxyl group in 11 was selectively con-
verted into the corresponding tosylate 12, which on
heating with 40% aqueous methylamine followed by
3h
oxidation using activated MnO2 gave (-)-mesembrine
(1), ([R]22D -55.4, lit. ) -62.8,3a -63.3,3d -53.0,3e -59.33h),
identical (1H, 13C NMR) with authentic material.
Conclusion
We believe that the approach outlined here will be a
useful strategy for the enantioselective assembly of cyclic
quaternary stereogenic centers having attached aromatic
rings, complementary to such recently developed methods
as enantioselective allylation16 and enantioselective aryl-
ation.17
(14) Sousa, J. A.; Bluhm, A. C. J. Org. Chem. 1960, 25, 108.
(15) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
(16) (a) Trost, B. M.; Pissot-Soldermann, C.; Chen, I.; Schroeder,
G. M. J. Am. Chem. Soc. 2004, 126, 4480. (b) Trost, B. M.; Xu, J. J.
Am. Chem. Soc. 2005, 127, 2846.
(17) (a) Aahman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.;
Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918. (b) Hamada, T.;
Chieffi, A.; Ahman, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
1261.
J. Org. Chem, Vol. 70, No. 19, 2005 7713

Taber and He
1150 (m), 1028 (m); 1H NMR (400 MHz, CDCl3) δ: 6.83-6.95
(m, 3H), 5.28 (m, 1H), 4.96 (d, J ) 23.6 Hz, 1H), 4.93 (d, J )
17.2 Hz, 1H), 4.16 (t, J ) 3.6 Hz, 1H), 3.97 (m, 4H), 3.88 (s,
3H), 3.86 (s, 3H), 3.08 (d, J ) 8.0 Hz, 1H), 1.65-2.50 (m, 8H);
13C NMR (CDCl3, 100 MHz) δ u: 148.6, 147.1, 137.2, 117.3,
108.7, 64.6, 64.1, 44.6, 41.6, 36.7, 30.5, 25.2; d: 134.3, 119.1,
110.8, 110.3, 74.3, 55.8, 55.7; HRMS calcd for C19H26O5 (M+)
334.1780, found 334.1774.
Tosylate (13). To a solution of diol 12 (major isomer, 133
mg, 0.478 mmol) in 5 mL of anhydrous CH2Cl2 was added
triethylamine (145 mg, 1.44 mmol) and tosyl chloride (91.2 mg,
0.478 mmol). After being stirred under N2 at ambient tem-
perature for 16 h, the reaction mixture was partitioned
between saturated aqueous Na2CO3 and CH2Cl2. The combined
organic extract was dried (Na2SO4) and concentrated. The
crude product was chromatographed to give 0.186 g of tosylate
13 (90% yield) as a clear oil. TLC Rf ) 0.34 (ether), [R]22D -11.4
(c 0.35, THF); IR (neat, cm-1): 3390 (b), 2938 (s), 1598 (s), 1464
(m), 1359 (s), 1252 (s), 1176 (s); 1H NMR (400 MHz, CDCl3) δ:
7.69 (d, J ) 8.0 Hz, 2H), 7.30 (d, J ) 8.0 Hz, 2H), 6.75 (br,
3H), 5.90 (dd, J ) 10.0 Hz, 1.2 Hz, 1H), 5.78 (d, J ) 10.0 Hz,
1H), 4.19 (br, 1H), 3.81-3.98 (m, 2H), 3.85 (s, 3H), 3.84 (s,
3H), 2.44 (s, 3H), 1.67-2.17 (m, 7H); 13C NMR (CDCl3, 100
MHz) δ u: 149.0, 147.7, 144.9, 137.8, 133.2, 67.8, 41.8, 40.9,
35.0, 28.8; d: 133.7, 132.5, 129.9, 127.9, 119.4, 111.1, 110.3,
67.0, 56.1, 56.0, 21.8; HRMS calcd for C23H28O6S (M+) 432.1607,
found 432.1605.
Enone (11). To a solution of alcohol 6d (0.90 g, 2.7 mmol)
in 10 mL of THF was added 10% aqueous HCl (4 mL). After
heating to reflux for 1 h, the reaction mixture was partitioned
between saturated aqueous Na2CO3 and CH2Cl2. The combined
CH2Cl2 extract was dried (Na2SO4) and concentrated in vacuo.
The residue was chromatographed to give 0.67 g of enone 11
(92% yield) as a colorless oil, TLC Rf ) 0.69 (PE/EtOAc, 1:1),
[R]22 -107.6 (c 0.8, THF); IR (neat, cm-1): 2935 (m), 1682
D
(s), 1639 (w), 1603 (w), 1518 (s), 1464 (m), 1255 (s), 1148 (m),
1027 (m); 1H NMR (400 MHz, CDCl3) δ: 7.07 (d, J ) 10.0 Hz,
1H), 6.86 (s, 3H), 6.17 (d, J ) 10.0 Hz, 1H), 5.56 (m, 1H), 5.11
(d, J ) 15.2 Hz, 1H), 5.08 (d, J ) 8.4 Hz, 1H), 3.88 (s, 3H),
3.87 (s, 3H), 2.15-2.73 (m, 6H); 13C NMR (CDCl3, 90 MHz) δ
u: 199.6, 149.1, 148.0, 135.4, 119.0, 46.3, 43.6, 36.1, 34.5; d:
155.3, 133.6, 129.5, 119.4, 111.1, 110.2, 56.1, 55.9; HRMS calcd
for C17H21O3 (M + H) 273.1491, found 273.1490.
(-)-Mesembrine (1). To a sealed thick-walled reaction
flask was added tosylate 13 (144 mg, 0.33 mmol), methylamine
(2.0 mL, 40% in water), and THF (4.0 mL). The reaction
mixture was heated at 65 °C for 1 h and then concentrated in
vacuo, and the residual oil was dissolved in CH2Cl2 (15 mL).
To this solution activated MnO2 (220 mg, 2.53 mmol) was
added, and the mixture was stirred at room temperature for
3 h. After filtration through a thin layer of Celite, the filtrate
was concentrated and the residue was chromatographed to
give 58.8 mg of (-)-mesembrine (61% yield) as a colorless oil.
Diol (12). To a solution of enone 11 (0.663 g, 2.43 mmol) in
HPLC-grade methanol (20 mL) was added an indicator amount
of Sudan III. After being purged with O2 at -78 °C for 2 min,
O3 was bubbled through the solution until the red color of
Sudan III disappeared. The reaction was purged with N2 for
5 min, and then CeCl3‚7H2O8 (1.00 g, 2.68 mmol) was added.
The reaction mixture was cooled with an ice-water bath, and
then NaBH4 (554 mg, 14.6 mmol) was added in three portions
over 5 min. After an additional 30 min, NaBH4 (92 mg, 2.43
mmol) was added followed by stirring for another 30 min. The
latter procedure was repeated once more. The reaction mixture
was partitioned between water and CH2Cl2. The combined
organic extract was dried (Na2SO4) and concentrated, and the
residue was chromatographed to give 0.474 g of diol 11 (4:1
mixture of two diasteromers, 73% yield) as a colorless oil. TLC
TLC Rf ) 0.21(wet ether), [R]22 -55.4 (c 0.54, MeOH); IR
D
(neat, cm-1): 2944 (m), 1716 (s), 1520 (s), 1454 (m), 1253 (s),
1148 (m), 1027 (m); 1H NMR (400 MHz, CDCl3) δ: 6.93 (dd, J
) 8.4, 2.4 Hz, 1H), 6.90 (d, J ) 2.0 Hz, 1H), 6.84 (d, J ) 8.4
Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.13-3.17 (m, 1H), 2.96 (t,
J ) 3.6 Hz, 1H), 2.61 (m, 2H), 2.35-2.46 (m, 2H), 2.33 (s, 3H),
2.04-2.26 (m, 5H); 13C NMR (CDCl3, 90 MHz) δ u: 211.5,
149.3, 147.8, 140.4, 55.1, 47.8, 40.8, 39.1, 36.4, 35.5; d: 118.2,
111.3, 110.3, 70.6, 56.2, 56.1, 40.3; HRMS calcd for C17H23-
NO3 (M+) 289.1678, found 289.1671.
Rf ) 0.18 (wet ether), [R]22 -23.5 (c 0.55, THF); IR (neat,
D
cm-1): 3390 (b), 2941 (s), 1715 (m), 1520 (s), 1260 (s), 1026
(s); 1H NMR (400 MHz, major isomer, CDCl3) δ: 6.78-6.82
(m, 3H), 5.86-5.95 (m, 2H), 4.21 (m, 1H), 3.86 (s, 3H), 3.85 (s,
3H), 3.47-3.58 (m, 2H), 1.62-2.07 (m, 7H); 13C NMR (CDCl3,
major isomer, 90 MHz) δ u: 148.8, 147.4, 139.1, 59.7, 45.0,
41.8, 35.0, 28.9; d: 134.9, 131.7, 119.4, 110.9, 110.5, 67.2, 56.1,
56.0; 1H NMR (400 MHz, minor isomer, CDCl3) δ: 6.80-6.82
(m, 3H), 5.60-6.06 (m, 2H), 4.13 (m, 1H), 3.87 (s, 3H), 3.85 (s,
3H), 3.55-3.65 (m, 2H), 1.62-2.10 (m, 7H); 13C NMR (CDCl3,
minor isomer, 90 MHz) δ u: 148.9, 147.5, 139.0, 59.7, 44.7,
41.9, 32.6, 28.5; d: 136.5, 130.0, 119.0, 111.1, 110.3, 64.6, 56.1,
56.0; HRMS calcd for C16H22O4Na (M + Na) 301.1416, found
301.1412.
Acknowledgment. We thank the NIH (GM60287)
for financial support of this study, and DSM for a gift
of Shi ketone. This work is dedicated to the memory of
Conrad J. Kowalski, a master of the science and art of
organic synthesis.
Supporting Information Available: General experimen-
tal details, characterization of the products from Table 1, and
spectra for all new compounds and for 1. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0511039
7714 J. Org. Chem., Vol. 70, No. 19, 2005