Enantioselective construction of cyclic quaternary centers: (-)-mesembrine

Article abstract of DOI:10.1021/jo001237g

The preparation of the crystalline amide 2 is reported. Conjugate addition to 2 proceeded with the expected high diastereocontrol to give 3. This set the stage for subsequent intramolecular alkylidene C-H insertion to give, after ozonolysis and aldol condensation, (-)-mesembrine 1. Amide 2 should be a useful chiron for the enantioselective construction of cyclic quaternary centers.

Full text of DOI:10.1021/jo001237g

J . Org. Chem. 2001, 66, 143-147
143
En a n tioselective Con str u ction of Cyclic Qu a ter n a r y Cen ter s:
(-)-Mesem br in e
Douglass F. Taber* and Timothy D. Neubert
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716
Taberdf@udel.edu
Received August 14, 2000
The preparation of the crystalline amide 2 is reported. Conjugate addition to 2 proceeded with the
expected high diastereocontrol to give 3. This set the stage for subsequent intramolecular alkylidene
C-H insertion to give, after ozonolysis and aldol condensation, (-)-mesembrine 1. Amide 2 should
be a useful chiron for the enantioselective construction of cyclic quaternary centers.
In tr od u ction
In cor p or a tion of th e Alk en yl Ch lor id e. The first
challenge in this strategy was the incorporation of the
alkenyl chloride. In previous approaches7c we had pre-
pared chloroalkenes by homologation by Wittig reaction
of a ketone with (chloromethylene)triphenylphosphorane.
We hypothesized that the direct introduction of an
alkylating agent incorporating the alkenyl chloride would
offer a more efficient solution to this problem. In fact, it
was known that 3-bromo-1-chloro-2-methylpropene 4
(Scheme 1) could easily be prepared by NBS bromination
of the inexpensive 1-chloro-2-methylpropene.9 With the
alkylating agent 4 in hand, we effected alkylation of the
acetoacetate dianion10 to give the ketoester 5 in good
yield. Reduction then gave the secondary alcohol 6.
The Sceletium alkaloid (-)-mesembrine (1), a naturally
occurring serotonin uptake inhibitor1 isolated from the
Mesembryanthemaceae family (Sceletium tortuosum),
has become an interesting lead compound for the prepa-
ration of antidepressants. The central challenge in the
synthesis of mesembrine2,3 and its analogues is the
enantioselective construction of the chiral quaternary
center.4 We hypothesized that it might be possible to
accomplish such a construction by carrying an alkenyl
chloride such as 2 through several preparative steps.
These steps would include the enantioselective establish-
ment of a chiral ternary center based on stereoselective
conjugate addition5 followed by intramolecular cyclization
of 3 via intramolecular alkylidene C-H insertion.6 This
C-H insertion would proceed with retention of absolute
configuration7,8 to convert the ternary center of 3 to the
quaternary center of 1.
We next needed a dehydration method that would
give predominantly the (E)-R,â-unsaturated ester from
the secondary alcohol 6.11 In fact, mesylation followed by
in situ elimination gave exclusively (13C NMR) the
(4) For an overview of methods for the enantioselective construction
of quaternary centers, see: (a) Posner, G. H.; Kogan, T. P.; Hulce, M.
Tetrahedron Lett. 1984, 25, 383. (b) Pfau, M.; Revial, G.; Guingant,
A.; d’Angelo, J . J . Am. Chem. Soc. 1985, 107, 273. (c) Koga, K.;
Tomioka, K.; Cho, Y. S.; Sato, F. J . Org. Chem. 1988, 53, 4094. (d)
Fukumoto, K.; Ihara, M.; Takahashi, M.; Niitsuma, H.; Taniguchi, N.;
Yasui, K. J . Org. Chem. 1989, 54, 5413. (e) Lee, E.; Shin, I. J .; Kim, T.
S. J . Am. Chem. Soc. 1990, 112, 260. (f) Overman, L. E.; Ashimori, A.;
Matsuura, T.; Poon, D. J . J . Org. Chem. 1993, 58, 6949. (g) Gilbert, J .
C.; Selliah, R. D. Tetrahedron 1994, 50, 1651. (h) Watanabe, N.;
Ohtake, Y.; Hashimoto, S.; Shiro, M.; Ikegami, S. Tetrahedron Lett.
1995, 36, 1491. (i) Overman, L. E.; Ashimori, A.; Bachand, B.; Calter,
M. A.; Govek, S. P.; Poon, D. J . J . Am. Chem. Soc. 1998, 120, 6488. (j)
Overman, L. E.; Paone, D. V.; Stearns, B. A. J . Am. Chem. Soc. 1999,
121, 7702. (k) Rife, J .; Ortuno, R. M. Tetrahedron: Asymmetry 1999,
10, 4245.
(5) (a) Evans, D. A.; Bartroli, J .; Shih, T. L. J . Am. Chem. Soc. 1981,
103, 2127. (b) Hruby, V. J .; Nicolas, E.; Russell, K. C. J . Org. Chem.
1993, 58, 766. (c) Hruby, V. J .; Qian, X.; Russell, K. C.; Boteju, L. W.
Tetrahedron 1995, 51, 1033. For an alternative approach to â-aryl acids
with high enantiomeric purity, see: (d) Buchwald, S. L.; Appella, D.
H.; Moritani, Y.; Shintani, R.; Ferreira, E. M. J . Am. Chem. Soc. 1999,
121, 9473.
(1) Gericke, N. P.; Van Wyk, B. E. World Patent 9746234, 1997.
(2) 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. For leading references to previous
enantioselective syntheses of (+)-mesembrine see: (h) Meyers, A. I.;
Hanreich, R.; Wanner, K. T. J . Am. Chem. Soc. 1985, 107, 7776. (i)
Kosugi, H.; Miura, Y.; Kanna, H.; Uda, H. Tetrahedron: Asymmetry
1993, 4, 1409.
(3) For leading references to syntheses of racemic mesembrine,
see: (a) Gramain, J .; Remuson, R. Tetrahedron Lett. 1985, 26, 4083.
(b) Shono, T.; Terauchi, J .; Matsumura, Y. Chem. Lett. 1989, 11, 1963.
(c) Parkinson, C. J .; Pinhey, J . T. J . Chem. Soc., Perkin Trans. 1 1991,
1053. (d) Michael, J . P.; Howard, A. S.; Katz, R. B.; Zwane, M. I.
Tetrahedron Lett. 1992, 33, 6023. (e) Rajagopalan, P. Tetrahedron Lett.
1997, 38, 1893. (f) Rigby, J . H.; Dong, W. Org. Lett. 2000, 2, 1673.
(6) Taber, D. F.; Sahli, A.; Yu, H.; Meagley, R. P. J . Org. Chem. 1995,
60, 6571.
(7) (a) Gilbert, J . C.; Blackburn, B. K. J . Org. Chem. 1986, 51, 3656.
(b) Gilbert, J . C.; Giamalva, D. H. J . Org. Chem. 1992, 557, 4185. (c)
Taber, D. F.; Meagley, R. P.; Doren, D. J . J . Org. Chem. 1996, 61, 5723.
(8) For a related approach based on Rh-mediated intramolecular
C-H insertion, see: Wee, A. G. H.; Yu, Q. Tetrahedron Lett. 2000, 41,
587.
(9) Banthorpe, D. V.; Christou, P. N. J . Chem. Soc., Perkin Trans.
1 1981, 105.
(10) Nozaki, H.; Maruoka, K.; Hashimoto, S.; Kitagawa, Y.; Yama-
moto, H. Bull. Chem. Soc. J pn. 1980, 53, 3301.
10.1021/jo001237g CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/06/2000

144 J . Org. Chem., Vol. 66, No. 1, 2001
Taber and Neubert
Sch em e 1
Sch em e 2
(E)-R,â-unsaturated ester 7. Hydrolysis converted 7 to
the (E)-R,â-unsaturated acid 8, the (E,E)-isomer of which
was nicely crystalline. It could be isolated in 64% yield
from 7 by trituration of the crude acid with Et2O.
The (E,E)-material was employed in the subsequent
Sch em e 3
1
synthetic steps to minimize the complexity of the H and
13C NMR spectra. However, it should be noted that the
initial E/ Z-alkenyl chloride isomeric mixture produced
the same yield for each of those steps, including the
intramolecular alkylidene carbene C-H insertion.
Con ju ga te Ad d ition : Esta blish m en t of th e Ter -
n a r y Cen ter . The second challenge in this approach was
the establishment of the ternary center with high enan-
tiomeric purity. We envisioned that this could be ac-
complished by conjugate addition to an (E)-4-phenyl-2-
oxazolidinone R,â-unsaturated amide, following the
precedent of Hruby.5b,c Introduction of the chiral auxiliary
was accomplished by the reaction of lithiated (S)-(+)-4-
phenyl-2-oxazolidinone 9 with the mixed pivalic acid
anhydride derivative of 8 (Scheme 2). Conjugate addition
to the derived acyl oxazolidinone 2 proceeded with high
stereoselectivity5b,c to give 3. We were unable to detect
the alternative diastereomer by 13C NMR of the crude
reaction mixture, and X-ray crystallography showed that
the desired diastereomer of 3 had indeed been obtained.
Hydrolysis of the oxazolidinone amide 3 then gave the
acid 11. An attractive feature of this approach is that
the chiral auxiliary 9 can easily be recovered in almost
quantitative yield following the hydrolysis.
In tr a m olecu la r Alk ylid en e In ser tion : In cor p or a -
tion of th e Qu a ter n a r y Cen ter . With 11 in hand, we
proceeded to investigate intramolecular alkylidene C-H
insertion (Scheme 3).6,7 As we had expected, the strongly
basic conditions of the cyclization were not compatible
with the acyl oxazolidinone 3, nor with the unprotected
primary alcohol 12. The derived benzyl ether 13, how-
ever, cyclized smoothly to give the desired cyclopentene
14. As expected, the C-H insertion proceeded with
retention of absolute configuration.
induced cyclization of these with KOH/methanol,7c we
found in this case that the intramolecular aldol reaction
and subsequent dehydration to give the cyclohexenone
15 proceeded more efficiently under acid catalysis. The
cyclohexenone 15 was reduced to the secondary alcohol
16 to avoid Michael-type addition with the formed
primary alcohol upon removal of the benzyl protecting
group. Debenzylation of 16 gave the primary alcohol 17,
which was then converted selectively to the mesylate 18.
Amination, oxidation, and cyclization then gave (-)-
mesembrine 1. The synthetic material so prepared gave
1H and 13C NMR, IR, MS, and optical rotation results
identical with the literature values.2a,d,e
Con clu sion
The strategy outlined here for the enantioselective
construction of quaternary centers will have many ap-
plications in target-directed organic synthesis. The acyl
oxazolidinone 2 in particular should be a useful chiron
for the enantioselective construction of physiologically
active natural products, due to its ease of use and
exceptional ability to impart stereocontrol.
Ozon olysis/Ald ol Con d en sa tion : Syn th esis of (-)-
Mesem b r in e. Ozonolysis of 14 gave the intermediate
keto aldehyde (Scheme 4). Although in the past we have
(11) (a) Katzenellenbogen, J .A.; Utawanit, T. J . Am. Chem. Soc.
1974, 96, 6153. (b) Huckin, S. N.; Weiler, L. J . Am. Chem. Soc. 1974,
96, 1082.

(-)-Mesembrine
J . Org. Chem., Vol. 66, No. 1, 2001 145
ethanol (100 mL) at 0 °C, under N2, was added portionwise
sodium borohydride (2.1 g, 54.8 mmol) over a 10 min period.
Saturated NH4Cl aqueous solution (100 mL) was added, and
the solution was then neutralized with 1 N HCl. The reaction
mixture was concentrated in vacuo and then partitioned
between Et2O and H2O. The combined organic extract was
dried (MgSO4) and concentrated in vacuo. The residue was
chromatographed to give 6 (8.1 g, 36.6 mmol, 80% yield) as a
clear oil: TLC Rf ) 0.47, 30% EtOAc/hexane; 1H NMR δ 1.28
(t, J ) 7.1 Hz, 3H), 1.59-1.76 (m, 2H), 1.77-1.79 (m, 3H),
2.09-2.59 (m, 4H), 3.05-3.07 (m, 1H), 3.91-4.04 (m, 1H), 4.18
(q, J ) 7.1 Hz, 2H), 5.85 (d, J ) 14.2 Hz, 1H); 13C NMR δ
(major isomer) C 177.2, 136.6, CH 110.4, 65.6, CH2 58.8, 39.8,
32.7,31.5, CH3 19.3, 12.6; 13C NMR δ (minor isomer) C 177.2,
136.5, CH 110.9, 66.1, CH2 59.2, 39.7, 31.9, 26.4, CH3 19.3,
14.8; IR cm-1 3464 (b), 2982 (m), 1738 (s), 1640 (w), 1244 (m).
(2E,6E)-7-Ch lor o-6-m et h ylh ep t a -2,6-d ien oic Acid (8).
To a stirring mixture of 7 (2.0 g, 9.9 mmol), lithium hydroxide
monohydrate (457 mg, 10.9 mmol), and p-dioxane (40 mL) at
room temperature was added H2O until a clear solution
formed. The solution was stirred at ambient temperature for
17 h. The solution was acidified to pH ) 1 by addition of
aqueous sodium hydrogen sulfate solution (10%). The reaction
mixture was partitioned between EtOAc and H2O. The com-
bined organic extract was dried (MgSO4) and concentrated in
vacuo. The residue was chromatographed to give 8 (1.7 g, 9.7
mmol, 98% yield) as a clear oil. The major isomer was isolated
as a white solid (1.1 g, 6.3 mmol, 64% yield) by recrystallization
from 20:1 Et2O/hexane (0.1 g/mL): mp ) 45-46 °C; TLC Rf )
0.19, 30% EtOAc/hexane; 1H NMR δ 1.79 (s, 3H), 2.43 (t, J )
7.5 Hz, 2H), 2.38 (q, J ) 7.1 Hz, 2H), 5.82-5.87 (m, 2H), 6.98-
7.27(m, 1H); 13C NMR δ C 170.5, 1355, CH 148.9, 119.9, 111.7,
CH2 33.7, 28.7, CH3 14.8; IR cm-1 2919 (s), 2200-3000 (b),
1691 (s), 1642 (m), 1314 (m). Anal. Calcd for C8H11NO2Cl: C,
55.02; H, 6.35. Found: C, 55.06; H, 6.22.
Sch em e 4
(2E,6E)-(4S)-3-(7-Ch lor o-6-m eth ylh ep ta -2,6-d ien oyl)-4-
p h en yloxa zolid in -2-on e (2). To a stirring solution of 8 (1.3
g, 7.4 mmol) and anhydrous THF (150 mL) at -78 °C under
N2, was added triethylamine (890 mg, 8.9 mmol) followed by
the dropwise addition of pivaloyl chloride (990 mg, 8.2 mmol)
over a 5 min period. The formed suspension was stirred at
-78 °C for 15 min and then at 0 °C for 45 min followed by
cooling to -78 °C. This suspension was transferred dropwise
via cannula at -78 °C to a preformed suspension of (4S)-(+)-
4-phenyl-2-oxazolidinone (1.2 g, 7.4 mmol), n-butyllithium (3.0
mL, 7.4 mmol, 2.5 M in hexanes), and anhydrous THF (30 mL)
(n-butyllithium added to (S)-(+)-4-phenyl-2-oxazolidinone and
THF at -78 °C, stirred 20 min). The resulting suspension was
stirred at -78 °C for 20 min and then at room temperature
for 2 h. The reaction mixture was partitioned between EtOAc
and H2O. The combined organic extract was dried (MgSO4)
and concentrated in vacuo. The residue was chromatographed
to give 2 (1.6 g, 5.0 mmol, 68% yield) as a white solid: mp )
55-56 °C; TLC Rf ) 0.22, 20% EtOAc/hexane; 1H NMR δ 1.73
(s, 3H), 2.21-2.27 (m, 2H), 2.31-2.42 (m, 2H), 4.17 (dd, J )
8.8 Hz, J ) 3.8 Hz, 1H), 4.76 (t, J ) 8.7 Hz, 1H), 5.50 (dd, J
) 8.4 Hz, J ) 3.8 Hz, 1H), 6.07 (s, 1H), 6.81-6.97 (m, 1H),
7.16-7.41 (m, 6H); 13C NMR δ C 162.8, 152.2, 137.6, 135.5,
CH 148.4, 127.6, 127.3, 124.4, 119.4, 111.6, 56.2, CH2 68.5,
33.9, 29.1, CH3 14.9; IR cm-1 2917 (w), 1779 (s), 1688 (s), 1635
(m), 1199 (m). Anal. Calcd for C17H18NO3Cl: C, 63.85; H, 5.67;
N, 4.38. Found: C, 63.90; H, 5.54; N, 4.19.
(6E)-(3(3S),4S)-3-[7-Ch lor o-3-(3,4-d im eth oxyp h en yl)-6-
m eth ylh ep t-6-en oyl]-4-p h en yloxa zolid in -2-on e (3). To a
stirring suspension of magnesium (472 mg, 19.4 mmol) and
anhydrous THF (10 mL) heated at reflux, under N2, was added
dropwise a solution of 4-bromoveratrole (4.1 g, 18.9 mmol) in
anhydrous THF (3 mL), over a 1 h period. The formed solution
was cooled to room temperature and added dropwise via
cannula to a stirring solution of copper(I) bromide-dimethyl
sulfide complex (1.9 g, 9.5 mmol), anhydrous THF (20 mL),
and dimethyl sulfide (20 mL) at -40 °C. The resulting
suspension was stirred at -40 °C for 10 min followed by the
dropwise addition of 2 (2.0 g, 6.3 mmol) in THF (10 mL) at
-15 °C over a 20 min period. The mixture was stirred at -15
Exp er im en ta l Section
Gen er a l. The general experimental method was identical
to that previously published12 except for combustion analysis,
which was carried out by Quantitative Technologies Inc., P.O.
Box 389, Chimney Rock Road, Bldg. 29E, Bound Brook, NJ
08805.
7-Ch lor o-6-m eth yl-3-oxoh ep t-6-en oic Acid Eth yl Ester
(5). To a stirring suspension of sodium hydride (3.9 g, 97 mmol,
60% in mineral oil) and anhydrous THF (350 mL) at 0 °C,
under N2, was added dropwise a solution of ethyl acetoacetate
(11.5 g, 97 mmol) and anhydrous THF (10 mL). The clear
solution was stirred at 0 °C for 10 min. A solution of 2.5 M
n-butyllithium in hexanes (37 mL, 93 mmol) was added
dropwise at 0 °C followed by stirring for 10 min. Next, 3-bromo-
1-chloro-2-methyl-1-propene (15.0 g, 88.4 mmol) was added
dropwise at 0 °C, and the solution was then allowed to warm
to room temperature over 1 h. Water (20 mL) was added and
the solution was neutralized with 1 N HCl. The reaction
mixture was partitioned between Et2O and H2O. The combined
organic extract was dried (MgSO4) and concentrated in vacuo.
The residue was chromatographed to give 5 (14.1 g, 64.5 mmol,
73% yield) as a clear oil: TLC Rf ) 0.35, 10% EtOAc/hexane;
1H NMR δ (major isomer) 1.28 (t, J ) 7.2 Hz, 3H), 1.75 (s,
3H), 2.38 (t, J ) 6.7 Hz, 2H), 2.68 (t, J ) 7.8 Hz, 2H), 3.43 (s,
1
2H), 4.19 (q, J ) 7.2 Hz, 2H), 5.82 (s, 1H); H NMR δ (minor
isomer) 1.28 (t, J ) 7.2 Hz, 3H), 1.78 (s, 3H), 2.44 (t, J ) 6.7
Hz, 2H), 2.68 (t, J ) 7.8 Hz, 2H), 3.44 (s, 2H), 4.19 (q, J ) 7.2
Hz, 2H), 5.80 (s, 1H); 13C NMR δ (major isomer) C 199.9, 165.4,
135.3, CH 111.7, CH2 59.9, 47.5, 39.3, 30.0, CH3 19.3, 14.7;
13C NMR δ (minor isomer) C 200.3, 165.5, 135.5, CH 111.2,
CH2 59.8, 47.7, 38.4, 24.3, CH3 19.3, 12.7; IR cm-1 2983 (m),
1743 (s), 1718 (s), 1641 (m), 1318 (m).
7-Ch lor o-3-h yd r oxy-6-m eth ylh ep t-6-en oic Acid Eth yl
Ester (6). To a stirring solution of 5 (10.0 g, 45.7 mmol) and
(12) Taber, D. F.; Christos, T. E.; Neubert, T. D.; Batra, D. J . Org.
Chem. 1999, 64, 9673.

146 J . Org. Chem., Vol. 66, No. 1, 2001
Taber and Neubert
°C for 10 min. The reaction mixture was partitioned between
EtOAc and H2O. The combined organic extract was dried
(MgSO4) and concentrated in vacuo. The residue was chro-
matographed to give 3 (2.7 g, 5.9 mmol, 94% yield) as a white
solid: mp ) 95-97 °C; TLC Rf ) 0.29, 30% EtOAc/hexane; 1H
NMR δ 1.61-1.67 (m, 1H), 1.68 (s, 3H), 1.69-1.81 (m, 3H),
2.93 (dd, J ) 14.8, 6.2 Hz, 1H), 2.99-3.08 (m, 1H), 3.63 (dd, J
) 14.8, 7.7 Hz, 1H), 3.77 (s, 3H), 3.88 (s, 3H), 4.15 (dd,J )
8.6, 3.8 Hz, 1H), 4.62 (t, J ) 8.9 Hz, 1H), 5.36 (dd, J ) 8.6, 3.8
Hz, 1H), 5.61 (s, 1H), 6.62 (s, 1H), 6.63-6.78 (m, 2H), 6.91-
6.93 (m, 2H), 7.21-7.24 (m, 3H); 13C NMR δ C 169.9, 152.1,
147.2, 146.1, 137.1, 136.5, CH 127.5, 126.9, 123.9, 117.9, 110.7,
109.6, 109.5, 56.0, 39.7, CH2 68.2, 40.1, 33.2, 32.3, CH3 54.3,
54.2, 14.8; IR cm-1 2934 (m), 1780 (s), 1736 (m), 1704 (m),
1518 (m).
66.8, 35.5, 33.4, 32.9, CH3 54.3, 54.2, 14.9; IR cm-1 3398(m),
2934 (s), 1591 (w), 1517 (s), 1259 (s), 1029 (s).
(3S)-3-(3,4-Dim et h oxyp h en yl)-1-m et h yl-3-[(2-p h en yl-
m eth oxy)eth yl]cyclop en ten e (14). To a stirring solution of
13 (9.0 g, 23.2 mmol) and anhydrous Et2O (180 mL), under
N2, was added KHMDS (116 mL, 57.9 mmol, 0.5 M in toluene)
dropwise over a 10 min period. The resulting solution was
stirred at ambient temp for 17 h. The reaction mixture was
partitioned between Et2O and H2O. The combined organic
extract was dried (MgSO4) and concentrated in vacuo. The
residue was chromatographed to give 14 (6.9 g, 19.7 mmol,
85% yield) as a clear oil: TLC Rf ) 0.72, 30% EtOAc/hexane;
1H NMR δ 1.79 (s, 3H), 2.01-2.19 (m, 4H), 2.20-2.33 (m, 2H),
3.23-3.42 (m, 2H), 3.83 (s, 3H), 3.84 (s, 3H), 4.39 (s, 2H), 5.54
(s, 1H), 6.73-6.82 (m, 3H), 7.21-7.36 (m, 5H); 13C NMR δ C
147.1, 145.4, 140.1, 139.2, 137.1, 53.2, CH 128.9, 126.8, 126.0,
125.9, 116.4, 109.3, 108.3, CH2 71.4, 66.7, 40.0, 38.9, 34.3, CH3
54.4, 54.3, 15.4; IR cm-1 2931 (m), 1516 (m), 1452 (w), 1256
(m), 1029 (m).
(4S)-4-(3,4-Dim et h oxyp h en yl)-4-[2-(p h en ylm et h oxy)-
eth yl]cycloh ex-2-en on e (15). To a stirring solution of 14 (975
mg, 2.8 mmol) and anhydrous CH2Cl2 (30 mL), under N2, at
-78 °C, was bubbled a gentle stream of O3/O2 until the
observed exotherm ceased (∼10 min). Excess O3 was subse-
quently purged with a dry stream of N2, and then triph-
enylphosphine (800 mg, 3.1 mmol) was added. The resulting
solution was allowed to warm to room temperature over a 17
h period. The solvent was removed in vacuo, and the residue
was dissolved in benzene (80 mL) followed by the addition of
p-toluenesulfonic acid monohydrate (33 mg, 0.17 mmol). The
solution was heated at reflux for 4 h using a Dean-Stark trap
to remove H2O. The reaction mixture was partitioned between
EtOAc and H2O. The combined organic extract was dried
(MgSO4) and concentrated in vacuo. The residue was chro-
matographed to give 15 (840 mg, 2.3 mmol, 83% yield) as a
clear oil: TLC Rf ) 0.46, 30% EtOAc/hexane; 1H NMR δ 2.13-
2.39 (m, 6H), 3.44 (t, J ) 6.2 Hz, 2H), 3.84 (s, 3H), 3.87 (s,
3H), 6.13 (d, J ) 10.1 Hz, 1H), 6.76-6.81 (m, 3H), 7.20-7.38
(m, 5H); 13C NMR δ C 197.8, 147.5, 146.3, 136.5, 133.9, 41.5,
CH 154.2, 127.6, 126.8, 126.1, 126.0, 117.7, 109.5, 108.4, CH2
71.6, 65.4, 39.6, 35.0, 33.0, CH3 54.4, 54.3; IR cm-1 2935 (m),
1680 (s), 1517 (s), 1453 (w), 1259 (s), 1027 (m).
(6E)-(3S)-7-Ch lor o-3-(3,4-d im eth oxyp h en yl)-6-m eth yl-
h ep t-6-en oic Acid (11). To a stirring solution of 3 (1.2 g, 2.6
mmol), H2O (3 mL), and THF (12 mL), at -5 °C, was added
hydrogen peroxide (1.14 mL, 10.4 mmol, 30%) dropwise over
a 10 min period. A solution of lithium hydroxide monohydrate
(174 mg, 4.2 mmol) and H2O (5 mL) was added dropwise, at
-5 °C, over a 15 min period. The resulting mixture was stirred
at 0 °C for 2 h followed by the addition of sodium sulfite
solution (10.4 mmol) in H2O (10 mL). The reaction mixture
was partitioned between EtOAc and H2O. The combined
organic extract was dried (MgSO4) and concentrated in vacuo.
The residue was triturated with Et2O to give recovered (4S)-
(+)-4-phenyl-2-oxazolidinone (390 mg, 2.4 mmol, 92% yield).
The aqueous portion was acidified to pH ) 2 using 1 N HCl.
The reaction mixture was partitioned between CH2Cl2 and
H2O. The combined organics were dried (MgSO4) and concen-
trated in vacuo. The residue was chromatographed to give 11
(780 mg, 2.5 mmol, 96% yield) as a clear oil: TLC Rf ) 0.52,
10% MeOH/CH2Cl2; 1H NMR δ 1.62-1.67 (m, 1H), 1.68 (s, 3H),
1.69-1.91 (m, 3H), 2.61 (d, J ) 7.4 Hz, 2H), 2.91-3.02 (m,
1H), 3.86 (s, 3H), 3.87 (s, 3H), 5.68 (s, 1H), 6.63-6.82 (m, 3H);
13C NMR δ C 176.9, 147.3, 146.2, 136.4, 133.9, CH 117.7, 110.8,
109.8, 109.2, 39.2, CH2 40.3, 33.1, 32.0, CH3 54.3, 54.2, 14.7;
IR cm-1 2800-3400 (b), 1708 (s), 1592 (w), 1518 (s), 1260 (m).
(3S)-7-Ch lor o-3-(3,4-d im eth oxyp h en yl)-6-m eth ylh ep t-
6-en -1-ol (12). To a stirring solution of 11 (2.0 g, 6.4 mmol)
and anhydrous THF (50 mL), at 0 °C, was added lithium
aluminum hydride (270 mg, 7.1 mmol) portionwise over a 5
min period. The resulting solution was heated at reflux for 1
h. H2O (0.27 mL) was added at 0 °C, followed by 15% NaOH
(0.27 mL) and H2O (0.81 mL). The mixture was filtered
through a bed of Celite with EtOAc, and the filtrate was
partitioned between EtOAc and H2O. The combined organic
extract was dried (MgSO4) and concentrated in vacuo. The
residue was chromatographed to give 12 (1.7 g, 5.7 mmol, 89%
(4S)-4-(3,4-Dim et h oxyp h en yl)-4-[2-(p h en ym et h oxy)-
eth yl]cycloh ex-2-en ol (16). To a stirring suspension of
lithium aluminum hydride (21 mg, 0.55 mmol) and anhydrous
THF (10 mL), under N2, at 0 °C, was added dropwise over a 2
min period a solution of 15 (200 mg, 0.55 mmol) and THF (1
mL). The resulting solution was stirred at room temperature
for 20 min. H2O (0.02 mL) was added at 0 °C, followed by 15%
NaOH (0.02 mL) and H2O (0.06 mL). The mixture was filtered
through a bed of Celite with EtOAc and then partitioned
between EtOAc and H2O. The combined organic extract was
dried (MgSO4) and concentrated in vacuo. The residue was
chromatographed to give 16 (176 mg, 0.48 mmol, 87% yield)
1
yield) as a clear oil: TLC Rf ) 0.56, 10% MeOH/CH2Cl2; H
NMR δ 1.09-1.17 (m, 1H), 1.61-1.71 (m, 2H), 1.73 (s, 3H),
1.74-1.97 (m, 4H), 2.52-2.66 (m, 1H), 3.41-3.58 (m, 2H), 3.87
(s, 3H), 3.88 (s, 3H), 5.68 (s, 1H), 6.63-6.82 (m, 3H); 13C NMR
δ C 147.4, 145.9, 136.9, 135.2, CH 118.1, 110.5, 109.7, 109.1,
40.0, CH2 59.5, 38.1, 33.4, 33.0, CH3 54.3, 54.2, 14.8; IR cm-1
3398 (m), 2934 (s), 1591 (w), 1517 (s), 1259 (s).
1
as a clear oil: TLC Rf ) 0.32, 50% EtOAc/hexane; H NMR δ
1.23-2.16 (m, 6H), 3.28-3.47 (m, 2H), 3.84 (s, 3H), 3.86 (s,
3H), 4.08-4.29 (m, 1H), 5.00 (s, 3H), 5.83-6.13 (m, 2H), 6.76-
6.85 (m, 3H), 7.22-7.38 (m, 5H); 13C NMR δ (major isomer) C
147.1, 145.7, 137.2, 136.8, 40.4, CH 133.3, 129.9, 126.5, 126.0,
117.9, 109.3, 108.8, 65.7, CH2 71.4, 65.7, 40.2, 33.5, 27.3, CH3
54.4, 54.3; 13C NMR δ (minor isomer) C 147.2, 145.7, 137.5,
136.8, 40.4, CH 134.9, 128.2, 126.8, 125.9, 117.5, 109.2, 108.6,
62.8, CH2 71.4, 65.6, 39.8, 31.2, 26.8, CH3 54.4, 54.3; IR cm-1
3410 (b), 2935 (s), 2861 (m), 1580 (w), 1517 (s), 1260 (s). HRMS
calcd for C23H27O3 (M + H - H2O), 351.19602; found, 351.1954.
(4S)-4-(3,4-Dim et h oxyp h en yl)-4-(2-h yd r oxyet h yl)cy-
cloh ex-2-en ol (17). To a solution of liquid ammonia (20 mL)
and anhydrous THF (10 mL) at -78 °C was added sodium
metal (24 mg, 1.1 mmol) in small portions. Alcohol 16 (100
mg, 0.27 mmol) in THF (1 mL) was added to the above dark
blue solution. The mixture was stirred at -78 °C for 30 min,
and then solid NH4Cl (500 mg) was added to quench the
reaction. The mixture was warmed to room temperature over
1 h, then partitioned between EtOAc and H2O. The combined
organic was dried (MgSO4) and concentrated in vacuo. The
(5S)-1-Ch lor o-5-(3,4-dim eth oxyph en yl)-2-m eth yl-7-(ph e-
n ylm eth oxy)h ep t-1-en e (13). To a stirring solution of 12 (1.0
g, 3.4 mmol) and anhydrous DMF (0.2 mL), at -0 °C, was
added sodium hydride (82 mg, 3.4 mmol, 60%) portionwise over
a 10 min period. The resulting solution was stirred at ambient
temp for 30 min. Benzyl bromide (580 mg, 3.4 mmol) was
added at 0 °C, dropwise over a 2 min period. The mixture was
stirred at ambient temp for 17 h. The reaction mixture was
partitioned between CH2Cl2 and H2O. The combined organic
extract was dried (MgSO4) and concentrated in vacuo. The
residue was chromatographed to give 13 (1.1 g, 2.9 mmol, 84%
1
yield) as a clear oil: TLC Rf ) 0.72, 30% EtOAc/hexane; H
NMR δ 1.50-1.70 (m, 2H), 1.71 (s, 3H), 1.72-1.99 (m, 4H),
2.49-2.66 (m, 1H), 3.20-3.39 (m, 2H), 3.84 (s, 3H), 3.87 (s,
3H), 4.41 (s, 2H), 5.65 (s, 1H), 6.61-6.82 (m, 3H), 7.23-7.38
(m, 5H); 13C NMR δ C 147.3, 145.8, 137.0, 136.9, 135.4, CH
126.8, 126.0, 118.2, 110.5, 109.9, 109.6, 109.2, 40.0, CH2 71.4,

(-)-Mesembrine
J . Org. Chem., Vol. 66, No. 1, 2001 147
residue was chromatographed to give 17 (65 mg, 0.23 mmol,
86% yield) as a clear oil: TLC Rf ) 0.13, 50% EtOAc/hexane;
1H NMR δ 1.22-1.40 (m, 1H), 1.73-2.09 (m, 7H), 3.48-3.64
(m, 2H), 3.86 (s, 3H), 3.89 (s, 3H), 4.21-4.29 (m, 1H), 5.89-
5.99 (m, 2H), 6.79-6.86 (m, 3H); 13C NMR δ C 148.7, 147.4,
138.9, 44.8, CH 134.8, 131.5, 119.3, 110.8, 110.4, 67.0, CH2
59.6, 41.7, 34.8, 28.8, CH3 56.0, 55.8; IR cm-1 3352 (b), 2937
(s), 1708 (w), 1517 (s), 1261 (s), 1025 (s). HRMS calcd for
dissolved in CH2Cl2 (15 mL). Activated manganese(IV) oxide
(460 mg) was added, and the mixture was stirred at room
temperature for 3 h. The mixture was filtered through a bed
of Celite, and the filtrate was concentrated in vacuo. The
residue was chromatographed to give (-)-mesembrine 1 (138
mg, 0.48 mmol, 68% yield) as a clear oil: TLC Rf ) 0.52, 10%
MeOH/CH2Cl2; [R]20 ) -59.3 (c ) 3.0, MeOH) [lit.2a [R]D
)
D
-62.8 (c ) 1.4, MeOH), lit.2d [R]30 ) -53.0 (c ) 0.24, MeOH)
D
1
C
16H21O3 (M + H - H2O), 261.14907; found, 261.1499.
(4S)-4-(3,4-Dim eth oxyp h en yl)-4-(2-m eth a n su lfon yloxy-
lit.2e [R]24 ) -63.3 (c ) 1.13, MeOH)]; H NMR δ 2.04-2.26
D
(m, 5H), 2.32 (s, 3H), 2.34-2.46 (m, 2H), 2.59-2.61 (m, 2H),
2.95 (t, J ) 3.6 Hz, 1H), 3.08-3.17 (m, 3H), 3.88 (s, 3H), 3.90
(s, 3H), 6.84 (d, J ) 8.2 Hz, 1H), 6.91 (dd, J ) 5.9 Hz, J ) 2.2
Hz, 1H), 6.95 (d, J ) 2.3 Hz, 1H); 13C NMR δ C 209.8, 147.5,
146.0, 138.7, 46.0, CH 116.4, 109.5, 108.5, 68.9, CH2 53.3, 39.0,
37.3, 34.7, 33.7, CH3 54.5, 54.3, 38.5; IR cm-1 2940 (m), 1717
(s), 1519 (s), 1453 (m), 1254 (s), 1026 (m). Anal. Calcd for
eth yl)cycloh ex-2-en ol (18). To a stirring solution of 17 (1.3
g, 4.7 mmol) and anhydrous Et2O (100 mL), under N2, at 0 °C
was added dropwise methanesulfonyl chloride (570 mg, 5.0
mmol) over a 3 min period. The mixture was stirred at 0 °C
for 1 h. The mixture was partitioned between EtOAc and H2O.
The combined organic extract was dried (MgSO4) and concen-
trated in vacuo. The residue was chromatographed to give 18
(1.4 g, 1.1 mmol, 84% yield) as a clear oil: TLC Rf ) 0.51,
50% EtOAc/hexane; 1H NMR δ 1.29-1.42 (m, 1H), 1.61-2.28
(m, 6H), 2.92 (s, 3H), 3.86-3.89 (m, 6H), 4.02-4.31 (m, 3H),
5.84-6.08 (m, 2H), 6.79-6.87 (m, 3H); 13C NMR δ (major
isomer) C 147.4, 146.0, 136.1, 40.1, CH 131.8, 131.1, 117.8,
109.5, 108.6, 65.3, CH2 65.6, 39.4, 33.4, 27.0, CH3 54.5, 54.3,
35.8; 13C NMR δ (minor isomer) C 147.3, 146.0, 135.9, 40.0,
CH 133.4, 129.3, 117.4, 109.4, 108.5, 62.4, CH2 65.6, 39.1, 30.8,
26,7, CH3 54.4, 54.3, 35.9; IR cm-1 3384 (b), 2937 (s), 1588
(w), 1517 (s), 1351 (s), 1172 (s).
C
17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C, 70.20; H,
7.80; N, 4.60.
Ack n ow led gm en t. We thank Dupont Agricultural
Products and the NIH (GM60287) for financial support
of this work. We express our appreciation to J ohn Groce
and Gina Blankenship for NMR spectroscopy and to
William J . Marshall for X-ray crystallography.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
for compounds 1-8 and 11-18 and X-ray data for compound
3. This material is available free of charge via the Internet at
http://pubs.acs.org.
(-)-Mesem br in e. A stirring solution of 18 (250 mg, 0.70
mmol), methylamine (5 mL, 40% in H2O), and THF (10 mL),
under N2, was heated at 65 °C in a sealed tube for 1 h. The
mixture was concentrated in vacuo, and the residual oil was
J O001237G