Enantioselective total synthesis of (-)-(S)-stepholidine

Article abstract of DOI:10.1021/jo9020826

(Chemical Equation Presented) Enantioselective total synthesis of (-)-(S)-stepholidine, a drug candidate for the treatment of schizophrenia and/or drug abuse, is described. Asymmetric transfer hydrogenation of imines with use of Noyori's catalyst was used

Full text of DOI:10.1021/jo9020826

pubs.acs.org/joc
Enantioselective Total Synthesis of (-)-(S)-
Stepholidine
Jian-Jun Cheng and Yu-She Yang*
State Key Laboratory of Drug Research, Shanghai Institute of
Materia Medica, Chinese Academy of Sciences, Shanghai
201203, China
FIGURE 1. Structure of (-)-(S)-stepholidine.
potential role in the treatment of drug abuse,4 which would
reduce drug abuse liability with diminished potential to
induce extrapyramidal motor deficits. So far, clinical trial
and animal studies have demonstrated that l-SPD is a
potential candidate for the treatment of schizophrenia and/
or drug abuse.5
ysyang@mail.shcnc.ac.cn
Received September 27, 2009
Chemically, l-SPD is a prototypical member of the tetra-
hydroprotoberberines, characterized by a tetracyclic ring
skeleton, an isoquinoline core, and a chiral carbon at C(14).
Although several asymmetric syntheses of tetrahydroproto-
berberines have been reported,6 the substitution pattern of
stepholidine, which ischaracterizedby 9,10-substitution atthe
D ring and the presence of two phenol groups, makes it a
special target. Moreover, the extremely low content (∼0.1%)
of this compound in natural sources and the need for large
amounts of the compound for clinical research necessitate its
total synthesis. Racemic synthesis of stepholidine has already
been reported by Chiang and Brochmann-Hassen,7,8 but the
enantioselective preparation has not been reported yet. Here-
in, we present the first enantioselective synthesis of l-SPD via
enantioselective reduction of imine.
Enantioselective total synthesis of (-)-(S)-stepholidine, a
drug candidate for the treatment of schizophrenia and/or
drug abuse, is described. Asymmetric transfer hydroge-
nation of imines with use of Noyori’s catalyst was used as
the key step and (-)-(S)-stepholidine was synthesized in 6
steps, with 42% overall yield and >99% ee.
Asymmetric transfer hydrogenation of imines with formic
acid/triethylamine catalyzed by suitably designed chiral Ru-
(II) complexes has been developed by Noyori et al.,9 and
since then it has become the method of choice in enantiose-
lective reduction of cyclic imines. Several asymmetric synth-
eses of tetrahydroisoquinolines have been reported with use
of this protocol.10 As outlined retrosynthetically in Scheme
1, our approach relies on the enantioselective reduction of
cyclic imine 4, using the method described by Noyori et al., in
the hope of achieving high ee. This cyclic imine could be
prepared from the corresponding amide 5 via Bisch-
ler-Napieralski cyclization.
Tetrahydroprotoberberines(THPBs), a series of alkaloids
isolated from the Chinese herb Corydalis ambigua and
various species of Stephania,1 was reported to possess a wide
range of biological activities.2 It was recently reported that
they elicit profound effects on the dopaminergic pathway in
the central nervous system. Among them, (-)-(S)-stepholi-
dine (l-SPD, 1, Figure 1), which is extracted from Stephanie
intermedi, has attracted a great deal of attention since it was
reported to display a unique pharmacological profile toward
dopamine (DA) receptors. l-SPD acts as a D1 DA receptor
agonist while it elicits antagonistic activity at the D2 DA
receptor,3 which accords perfectly with the acknowledged
pathogenesis of schizophrenia, thus acting as a promising
antipsychotic drug candidate with a novel mechanism.
Besides, this compound was also described to possess a
The requisite amide 10 was prepared with Chiang’s
method.8 Thus, phenylacetic acid 6 was subjected to a
(5) (a) Mao, J.; Guo, Y.; Yang, Y.-S.; Shen, J.-S.; Jin, G.-Z.; Zhen, X.-C.
Curr. Med. Chem. 2007, 14, 2996–3002. (b) Chu, H.-Y.; Jin, G.-Z.; Friedman,
E.; Zhen, X.-C. Cell. Mol. Neurobiol. 2008, 28, 491–499.
(6) (a) Matulenko, M. A.; Meyers, A. I. J. Org. Chem. 1996, 61, 573–580.
(b) Cutter, P. S.; Miller, R. B.; Schore, N. E. Tetrahedron 2002, 58, 1471–
1478. (c) Davis, F. A.; Mohanty, P. K. J. Org. Chem. 2002, 67, 1290–1296. (d)
Boudou, M.; Enders, D. J. Org. Chem. 2005, 70, 9486–9494. (e) Grajewska,
A.; Rozwadowska, M. D. Tetrahedron: Asymmetry 2007, 18, 2910–2914.
(7) Chiang, H.-C.; Brochmann-Hanssen, E. J. Org. Chem. 1977, 42, 3190–
3194.
(8) Chiang, H.-C. Taiwan Yaoxue Zazhi 1977, 28, 111–120.
(9) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1996, 118, 4916–4917.
(10) For examples, see: (a) Vedejs, E.; Trapencieris, P.; Suna, E. J. Org.
Chem. 1999, 64, 6724–6729. (b) Tietze, L. F.; Rackelmann, N.; Sekar, G.
Angew. Chem., Int. Ed. 2003, 42, 4254–4257. (c) Mujahidin, D.; Sven Doye, S.
Eur. J. Org. Chem. 2005, 2689–2693. (d) Werner, F.; Blank, N.; Opatz, T.
Eur. J. Org. Chem. 2007, 3911–3915.
(1) Hsu, B.; Kin, K. C. Arch. Int. Pharmcodyn. 1962, 89, 318–327.
(2) (a) Bhakuni, D. S.; Jain, S. In The Alkaloids: Chemistry and Pharmacol-
ogy; Brossi, A., Ed.; Academic Press: New York, 1986; Vol. 28, p 95. (b)
Memetzidis, G.; Stambach, J. F.; Jung, L.; Schott, C.; Heitz, C.; Stoclet, J. C.
Eur. J. Med. Chem. 1991, 26, 605–611. (c) Suffnees, M.; Cordell, A. C. In The
Alkaloids; Brossi, A., Ed.; Academic Press: Orlando, FL, 1985; Vol. 25, p 3. (d)
Cushman, M.; Dekow, F. W.; Jacobsen, L. B. J. Med. Chem. 1979, 22, 331–333.
(3) (a) Jin, G.-Z.; Huang, K.; Sun, B.-C. Neurochem. Int. 1992, 20
(Suppl.), 175S–178S. (b) Jin, G.-Z.; Sun, B.-C. Adv. Exp. Med. Biol. 1995,
363, 27–28. (c) Jin, G.-Z.; Zhu, Z.-T.; Fu, Y. Trends. Pharmacol. Sci. 2002,
23, 4–7.
(4) Wang, W.; Zhou, Y.-Q.; Sun, J.; Pan, L.-F.; Kang, L.; Dai, Z.-Z.; Yu,
R.; Jin, G.-Z.; Ma, L. Neuropharmacology 2007, 52, 355–361.
DOI: 10.1021/jo9020826
r
Published on Web 10/30/2009
J. Org. Chem. 2009, 74, 9225–9228 9225
2009 American Chemical Society

Cheng and Yang
JOCNote
SCHEME 1. Retrosynthesis of (-)-(S)-Stepholidine
SCHEME 2. Preparation of Amide 11
SCHEME 3. Synthesis of (-)-(S)-Stepholidine from Amide 11
hydroxymethylation directed by phenylboronic acid in
the presence of paraformaldehyde (Scheme 2).11,12 The
phenol group of 7 was methylated with Me2SO4 to yield
the lactone 8, and aminolysis of 8 with phenethylamine
9 afforded 10 in high yield. The benzyl alcohol group
was converted to its acetate 11 under the condition of
Ac2O/Et3N.
Bischler-Napieralski reaction13,14 proceeded smoothly
under the promotion of POCl3 in CH3CN (Scheme 3), to
give the imine 12 in excellent yield. However, this compound
was found to be unstable even at room temperature. For
example, the purity of the freshly prepared sample dropped
from 95% to about 70% after standing at 25 °C for 24 h.
Therefore, freshly prepared 12 without further purification
was used for the following reduction. Asymmetric transfer
(11) Nagata, W.; Itazaki, H.; Okada, K.; Wakabayashi, T.; Shibata, K.;
Tokutake, N. Chem. Pharm. Bull. 1975, 23, 2867–2877.
(12) Cushman, M.; Dekow, F. W. J. Org. Chem. 1979, 44, 407–409.
(13) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030–2036.
(14) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797–1842.
9226 J. Org. Chem. Vol. 74, No. 23, 2009

Cheng and Yang
JOCNote
TABLE 1. Debenzylation of Substrate 2
(ꢀ2), 128.5 (ꢀ2), 128.2, 128.0, 127.8, 127.7, 127.2 (ꢀ3), 126.2,
120.5, 114.6, 113.9, 112.1, 70.9, 70.6, 61.4, 58.4, 55.9, 40.7, 40.4,
35.0, 20.9. MS (EI) m/z (%): 583 (Mþ, 9), 523 (5), 433 (7), 241
(15), 240 (79), 150 (8), 149 (34), 91 (100). HRMS (EI) calcd for
method
conditions
ee (%)
yield
A
B
H2, MeOH, Pd/C
37% HCl, reflux
70.4
99.6
95
74
C
35H37NO7 583.2570, found 583.2542.
3-(Benzyloxy)-6-((7-(benzyloxy)-3,4-dihydro-6-methoxyiso-
quinolin-1-yl)methyl)-2-methoxybenzyl Acetate (12). To a solu-
tion of the amido ester 11 (5.02 g, 8.6 mmol) in dry acetonitrile
(200 mL) was added POCl3 (5 mL) then the mixture was refluxed
for 2 h under nitrogen. The reaction mixture was cooled to room
temperature and concentrated under vacuum. The residue was
dissolved in CH2Cl2, washed with sat. NaHCO3 and brine, dried
over Na2SO4, and concentrated to yield a yellow solid (4.80 g),
which was characterized as imine 12 but unstable at room
temperature. 1H NMR (CDCl3, 300 MHz): δ 7.44-7.28 (m,
10 H), 6.96 (s, 1 H), 6.83 (d, J = 8.6 Hz, 1 H), 6.72 (d, J = 8.6 Hz,
1 H), 6.70 (s, 1 H), 5.24 (s, 2 H), 5.08 (s, 2 H), 5.00 (s, 2 H), 3.98
(s, 2 H), 3.92 (s, 3 H), 3.90 (s, 3 H), 3.69 (t, J = 7.5 Hz, 2 H), 2.66
(t, J = 7.5 Hz, 2 H), 2.03 (s, 3 H). 13C NMR (CDCl3, 100 MHz):
δ 174.7, 171.0, 156.9, 151.2, 149.5, 147.5, 136.4, 135.4, 133.9,
128.6 (ꢀ3), 128.2, 128.0, 127.6, 127.2 (ꢀ4), 126.8, 123.9, 117.3,
115.1, 114.9, 111.0, 71.2, 70.6, 61.5, 58.4, 56.5, 56.0, 41.1, 35.2,
25.4, 21.0. MS (ESI) m/z 566.2 [M þ H]þ.
hydrogenation was carried out under argon in DMF, in the
presence of Noyori’s catalyst (13) and formic acid/triethyla-
mine (v/v = 5/2) as the hydrogen source. Tetrahydroisoqui-
noline 14 was obtained in 84% chemical yield from the amide
11. Because the ee value of this compound was difficult to
determine using chiral HPLC analysis, we convert 14 to the
corresponding free hydroxyl derivative 15, and the enantios-
electivity of 15 was determined as 95.6% ee.
Closure of ring C was accomplished by chlorination of the
benzyl alcohol group in 15 under the condition of SOCl2/
CH2Cl2 at 0 °C, giving the intermediate 16, which trans-
formed directly to 2 under the basifying of the CH2Cl2
solution with aqueous NaHCO3.
Debenzylation of the benzyl ethers of 2 was first tried with
Pd/C catalytic hydrogenation; however, the ee value of the
product 1 was determined to be 70.4%, based on 99.8% ee of
the substrate 2 (Method A, Table 1). It is presumed that a
reversible process of dehydrogenation and hydrogenation in
the presence of Pd/C and H2 led to the oxidation of benzylic
amine 2 to a doubly conjugated enamine (by dehydrogena-
tion), which was hydrogenated to yield racemic product, thus
leading to the partial racemization.15 Therefore, the depro-
tection was carried out via refluxing 2 in 37% hydrochloric
acid (Method B, Table 1), and (-)-(S)-stepholidine was
isolated in 99.6% ee and 74% isolated yield. Spectral char-
acteristics of the isolated sample in our laboratory are
consistent with those reported in the literature.16
3-(Benzyloxy)-6-(((S)-7-(benzyloxy)-1,2,3,4-tetrahydro-6-me-
thoxyisoquinolin-1-yl)methyl)-2-methoxybenzyl Acetate (14).
A freshly prepared imine 12 (4.80 g, 8.5 mmol) was dissolved
in anhydrous DMF (50 mL), and the solution was degassed for
5 min with argon. RuCl[(R,R)-TsDPEN(P-cymene)] (13, CAS:
192139-92-7) (54 mg, 1 mol %) was added followed by formic
acid/triethylamine (v/v = 5/2, 5.0 mL), and the reaction mixture
was stirred at room temperature for 8 h under argon. The reaction
was quenched with sat. NaHCO3 (100 mL) and extracted with
ethyl acetate. The combined organic layer was washed with brine,
dried over Na2SO4, filtered, and concentrated. The crude product
was purified by column chromatography (CH2Cl2/CH3OH/
Et3N = 100/1/1) to give 14 as light brown oil (4.06 g, 84%).
1
[R]23 -51.9 (c 0.85, CHCl3). H NMR (CDCl3, 300 MHz): δ
D
In conclusion, the first enantioselective total synthesis of
(-)-(S)-stepholidine was accomplished with use of Noyori’s
protocol of enantioselective reduction of cyclic imine. The
target alkaloid was prepared in 6 steps and 42% overall yield
from the amide 10, with an ee value over 99%.
7.48-7.28(m, 10H), 6.96(d, J= 8.5 Hz, 1 H), 6.91 (d, J= 8.5Hz,
1 H), 6.64 (s, 1 H), 6.61 (s, 1 H), 5.35 (d, J = 11.4 Hz, 2 H), 5.20 (d,
J = 11.4 Hz, 2 H), 5.12 (s, 2 H), 5.08 (s, 2 H), 3.99-3.93 (m, 1 H),
3.92 (s, 3 H), 3.86 (s, 3 H), 3.24-3.16 (m, 1 H), 3.12-2.87 (m, 3 H),
2.82-2.70 (m, 2 H), 2.03 (s, 3 H). 13C NMR (CDCl3, 100 MHz): δ
170.9, 150.5, 149.3, 148.1, 145.9, 137.1, 136.7, 131.8, 128.8, 128.5
(ꢀ2), 128.4, 128.4, 127.9, 127.7, 127.3 (ꢀ2), 127.1 (ꢀ2), 126.8,
126.2, 114.6, 112.2, 111.9, 70.7, 70.6, 61.4, 58.2, 56.2, 55.8, 39.5,
38.6, 29.6, 28.6, 21.1. MS (EI) m/z (%): 507 (5), 492 (8), 476 (4),
417 (8), 416 (28), 414 (7), 269 (20), 268 (100), 177 (14), 149 (8), 148
(7), 91 (23). HRMS (EI) calcd for C35H37NO6 567.2621, found
567.2616.
Experimental Section
6-((4-(Benzyloxy)-3-methoxyphenethylcarbamoyl)methyl)-3-
(benzyloxy)-2-methoxybenzyl Acetate (11). To a solution of
compound 10 (3.00 g, 5.54 mmol) in CH2Cl2 (50 mL) was added
Et3N (3.8 mL, 27.7 mmol). The mixture was cooled to 0 °C, and
acetic anhydride (1.6 mL, 16.6 mmol) was added dropwise.
After being stirred overnight at room temperature, the reaction
mixture was diluted with CH2Cl2 (50 mL), washed with water
and brine, dried over Na2SO4, filtered, and concentrated. The
residue was purified by recrystallization from toluene to afford
a white solid 11 (2.37 g, 79%). Mp 95 - 97 °C. 1H NMR
(CDCl3, 300 MHz): δ 7.46-7.28 (m, 10 H), 6.90 (d, J = 8.3 Hz,
1 H), 6.84 (d, J = 8.3 Hz, 1 H), 6.73 (d, J = 8.2 Hz, 1 H), 6.64 (d,
J = 1.9 Hz, 1 H), 6.46 (dd, J = 8.2, 1.9 Hz, 1 H), 5.46 (br, 1 H),
5.15 (s, 2 H), 5.12 (s, 2 H), 5.10 (s, 2 H), 3.88 (s, 3 H), 3.83 (s, 3
H), 3.53 (s, 2 H), 3.42 (q, J = 7.0 Hz, 2 H), 2.65 (t, J = 7.0 Hz, 2
H), 2.00 (s, 3 H). 13C NMR (CDCl3, 100 MHz): δ 170.8, 170.7,
151.1, 150.1, 149.1, 146.7, 137.1, 136.6, 131.6, 129.0, 128.6
(3-(Benzyloxy)-6-(((S)-7-(benzyloxy)-1,2,3,4-tetrahydro-6-me-
thoxyisoquinolin-1-yl)-methyl)-2-methoxyphenyl)methanol (15).
To a solution of 14 (2.00 g, 3.5 mmol) in ethanol (50 mL) was
added 10% NaOH (50 mL) then the mixture was refluxed for
1 h. The mixture was cooled and ethanol was removed in vacuo.
The residue was extracted with CH2Cl2 and the combined
organic layer was washed with brine, dried over Na2SO4, and
concentrated to yield 15 as light yellow solid (1.76 g, 95%, chiral
HPLC: 95.6% ee). Mp 139-141 °C. [R]23 -16.7 (c 0.52,
D
CHCl3). 1H NMR (CDCl3, 300 MHz): δ 7.48-7.27 (m, 10 H),
6.89 (d, J = 8.4 Hz, 1 H), 6.83(d, J = 8.4 Hz, 1 H), 6.78 (s, 1 H),
6.60 (s, 1 H), 5.17 (s, 2 H), 5.13 (s, 2 H), 4.83 (d, J = 11.6 Hz, 1
H), 4.45 (d, J = 11.6 Hz, 1 H), 4.02-3.95 (m, 1 H), 3.94 (s, 3 H),
3.88 (s, 3 H), 3.06-2.96 (m, 2 H), 2.92-2.81 (m, 2 H), 2.80-2.69
(m, 1 H), 2.62-2.54 (m, 1 H). 13C NMR (CDCl3, 100 MHz): δ
150.4, 148.3, 148.1, 146.3, 137.2, 137.2, 135.5, 131.8, 129.7, 128.5
(ꢀ4), 128.0, 127.9, 127.8, 127.3 (ꢀ2), 127.2 (ꢀ2), 125.2, 114.1,
112.9, 112.0, 71.5, 70.8, 61.8, 56.3, 55.9, 55.1, 40.6, 40.0, 29.1.
MS (EI) m/z (%): 507 (6), 492 (13), 432 (9), 417 (7), 416 (25), 269
(15) For examples, see: (a) Parvulescu, A. N.; De Vos, D. E.; Jacobs, P. A.
Chem. Commun. 2005, 42, 5307–5309. (b) Parvulescu, A. N.; Jacobs, P. A.;
De Vos, D. E. Chem.;Eur. J. 2007, 13, 2034–2043. (c) Parvulescu, A. N.;
Van der Eycken, E.; Jacobs, P. A.; De Vos, D. E. J. Catal. 2008, 255, 206–212.
(16) Ichikawa, K.; Kinoshita, T.; Ital, A.; litaka, Y.; Sankawa, U.
Heterocycles 1984, 22, 2071–2077.
J. Org. Chem. Vol. 74, No. 23, 2009 9227

Cheng and Yang
JOCNote
(18), 268 (100), 177 (13), 176 (5), 149 (9), 148 (6), 91 (26). HRMS
calcd for C33H35NO5 525.2515, found 525.2500.
Method B. Compound 2 (0.60 g, 1.2 mmol) was refluxed in a
mixture of concentrated hydrochloric acid (30 mL) and EtOH
(10 mL) for 2 h. The reaction mixture was cooled to 0 °C and
basified with concentrated ammonia solution (50 mL). The
mixture was extracted with CH2Cl2. The combined organic
layer was washed with brine, dried over Na2SO4, filtered, and
concentrated to give the crude product, which was purified as
described in Method A to give 1 (0.29 g, 74%, 99.6% ee). Mp
14-(S)-3,9-Dimethoxyl-2,10-dibenzyloxytetrahydroprotober-
berine (2). A solution of 15 (1.50 g, 2.8 mmol) in CH2Cl2 (100 mL)
was cooled to 0 °C, and thionyl chloride (3 mL) was added
dropwise. The reaction mixture was stirred at room temperature
for 1 h before it was cooled to 0 °C and sat. NaHCO3 (100 mL) was
added slowly. After being stirred for another 1 h, the reaction was
stopped and the organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated to yield a thick yellow oil,
which was recrystallized from ethyl acetate-petroleum ether to
128-129 °C [lit.16 mp 125-126 °C]. [R]23 -281.7 (c 1.0,
D
1
CH3OH). H NMR (CD3OD, 300 MHz): δ 6.78-6.66 (m, 3
H), 6.63 (s, 1 H), 4.15 (d, J = 15.7 Hz, 1 H), 3.79 (s, 3 H), 3.77
(s, 3 H), 3.50-3.38 (m, 2 H), 3.32-2.98 (m, 3 H), 2.74-2.52 (m,
3 H). 13C NMR (CD3OD, 100 MHz): δ 149.3, 148.3, 146.5,
145.5, 131.2, 129.2, 127.7, 126.7, 125.9, 116.9, 113.6, 113.0, 61.1,
60.9, 56.8, 55.3, 53.3, 37.0, 29.7. MS (EI) m/z (%): 327 (Mþ, 84),
325 (62), 296 (16), 178 (100), 176 (21), 150 (18), 135 (20). Anal.
Calcd for C19H23NO5 (1 þ H2O): C, 66.07; H, 6.71; N, 4.06.
Found: C, 65.85; H, 6.64; N, 3.97.
give yellow solid 2(1.28 g, 90%, 99.8% ee). Mp 104-106 °C. [R]23
D
-198.4 (c0.89, CHCl3). 1HNMR(CDCl3, 300 MHz): δ7.48-7.27
(m, 10 H), 6.83 (d, J = 8.5 Hz, 2 H), 6.79 (d, J = 8.5 Hz, 2 H), 6.74
(s, 1 H), 6.65 (s, 1 H), 5.14 (s, 2 H), 5.11 (s, 2 H), 4.24 (d, J = 15.8
Hz, 1 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.56-3.46 (m, 2 H), 3.23-3.05
(m, 3 H), 2.77-2.60 (m, 3 H). 13C NMR (CDCl3, 100 MHz): δ
149.2, 148.2, 146.4, 145.6, 137.2 (ꢀ2), 129.6, 128.7 (ꢀ4), 128.5,
128.2, 127.8 (ꢀ2), 127.5, 127.4 (ꢀ2), 127.2 (ꢀ2), 123.7, 113.0,
112.0, 111.8, 71.5, 70.9, 60.2, 59.1, 55.9, 53.9, 51.4, 36.2, 29.0. MS
(EI) m/z (%): 507 (Mþ, 14), 416 (100), 149 (78), 91 (71). HRMS
(EI) calcd for C33H33NO4 507.2410, found 507.2409.
Acknowledgment. We thank Shanghai institute of organic
chemistry, Chinese academy of sciences, for the ee determi-
nation of the chiral compounds in this paper.
(-)-(S)-Stepholidine (1). Method A. A mixture of compound
2 (0.60 g, 1.2 mmol) and 10% Pd-C (60 mg) in CH3OH (30 mL)
was stirred under hydrogen atmosphere for 2 h. After the Pd-C
catalyst was filtered off, the solvent was removed under reduced
pressure and the residue was purified by column chromatogra-
phy (CH2Cl2/CH3OH = 50/1) to yield the title compound 1
(0.36 g, 95%, 70.4% ee).
Supporting Information Available: Synthetic procedures
1
and characterizing data for compounds 6-10, H, 13C spectra
for all new compounds, and details of ee determination of
compounds 15, 2, and 1. This material is available free of charge
via the Internet at http://pubs.acs.org.
9228 J. Org. Chem. Vol. 74, No. 23, 2009