Stereoselective synthesis of (R)-(-)-denopamine, (R)-(-)-tembamide and (R)-(-)-aegeline via asymmetric reduction of azidoketones by Daucus carota in aqueous medium

Article abstract of DOI:10.1016/S0957-4166(02)00024-1

A simple and efficient stereoselective synthesis of (R)-denopamine and other naturally occurring hydroxy amides from optically active (R)-2-azido-1-arylethanols, is described for the first time via reduction of the corresponding α-azidoarylketones with en

Full text of DOI:10.1016/S0957-4166(02)00024-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3381–3385
Stereoselective synthesis of (R)-(−)-denopamine,
(R)-(−)-tembamide and (R)-(−)-aegeline via asymmetric reduction
of azidoketones by Daucus carota in aqueous medium
J. S. Yadav,* P. Thirupathi Reddy, S. Nanda and A. Bhaskar Rao
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 8 December 2001; accepted 15 January 2002
Abstract—A simple and efficient stereoselective synthesis of (R)-denopamine and other naturally occurring hydroxy amides from
optically active (R)-2-azido-1-arylethanols, is described for the first time via reduction of the corresponding a-azidoarylketones
with enzymes from Daucus Carota root, under mild and environmentally friendly conditions. The products are formed with high
degrees of enantioselectivity. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
low overall yields.9 Recently, the asymmetric reduction
of substituted a-amino ketones to b-amino alcohol
derivatives10 with high enantioselectivity using the Ru–
BINAP complex has been reported.
Many chiral b-amino aryl ethanols are found to be
potential synthetic precursors of pharmaceutically
important molecules.1 Recent studies have demon-
strated that the two enantiomers of a chiral drug usu-
ally display different biological activities2 and in most
of the aryl ethanolamine drugs, the biological activity
resides mainly in the (R)-enantiomer.3 The increasing
demand and interest in the stereoselective synthesis of
these biologically useful molecules prompted us to take
up their synthesis. The synthesis of (R)-denopamine 1,
a new selective b-antagonist for the treatment of con-
gestive heart failure4 and other naturally occurring
biologically active molecules such as (R)-tembamide 2
and (R)-aegeline 3, which are used in traditional Indian
medicines and have been shown to have good hypo-
glycemic activity,5 has now been achieved.
Our continuous investigations on the development of
new environmentally favorable bioreduction processes
for the synthesis of chiral azido alcohols,11 which are
potential intermediates for aryl ethanolamine drugs12
and our keen interest in the utility of such strategies for
the total synthesis of enantiopure pharmaceutically
important molecules led us to complete the study
reported herein. Recently, plant cell cultures13 and
whole plant cells14 have been considered as suitable
biochemical systems for the stereoselective reduction of
prochiral ketones. More recently, we have investigated
the reduction of a variety of prochiral ketones with
Daucus carota root in aqueous medium provided the
corresponding alcohols15 with good to excellent enan-
tioselectivity and in high yield. Accordingly, we have
focused our attention to extend this methodology to the
preparation of key intermediates, i.e. (R)-chiral azido
alcohols 5a and 5b from the corresponding a-azido aryl
ketones 4a and 4b.
To date few methods have been reported for the synthe-
sis of optically active (R)-denopamine 1,6 (R)-tem-
bamide 2 and (R)-aegeline 3,7 these include either
tedious chemical and biological methods8 or require the
use of expensive reagents with multi-step syntheses and
* Corresponding author. Fax: +91-40-7160512; e-mail: yadav@iict.ap.nic.in
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00024-1

3382
J. S. Yada6 et al. / Tetrahedron: Asymmetry 12 (2001) 3381–3385
2. Results and discussion
Next, the azido alcohols 5a and 5b were reduced by
hydrogenation over palladium on charcoal (5%) in
methanol at room temperature for 2 h, which afforded
the corresponding amino alcohols 6a and 6b in quantita-
tive yields. We also investigated the reduction of 5a with
lithium aluminum hydride, which gave 6a in good yield,
whereas in the reduction of 5b unwanted cleavage of the
silyl protecting group was observed and 4-hydroxy-
phenylethanolamine was formed.
Initially, we investigated the reduction of a-azidoaryl
ketones 4a and 4b with baker’s yeast and Daucus carota,
interestingly both of them gave the required azido
alcohols 5a and 5b with high enantioselectivity and the
results obtained with both biocatalysts are shown in
Table 1. Based on the results shown in Table 1, we chose
Daucus carota as the biocatalyst for the asymmetric
reduction of azido ketones to optically active azido
alcohols due to its operational simplicity, the easy
isolation of the reaction products, the inexpensive and
readily available biomaterial, the mild conditions and the
high yield and enantioselectivity.
Acylation of 6a with benzoyl chloride in the presence of
50% aqueous NaOH then gave 2 in 92% yield. Similarly
amino alcohol 6a was treated with cinnamoyl chloride to
afford 3 in 90% yield. The specific rotation values of 2
and 3 were in good agreement with those reported in the
literature (Scheme 2).7
The first step of our present strategy involved the
stereoselective reduction of 2-azido-1-aryl ketones 4a and
4b (Scheme 1) with Daucus carota, which provided the
respective (R)-2-azido-1-aryl ethanols 5a and 5b with
excellent enantiomeric excess (99–100%) and in high yield
(85–92%). The enantiomeric excess of these azido alco-
hols was determined by chiral HPLC analysis and in this
reduction; the observed stereochemistry could be
explained on the basis of Prelog’s rule16 and the absolute
configuration was confirmed by comparing their specific
rotations with those of authentic samples.11b,17
In a similar manner, the reaction of 6b and 3,4-
dimethoxyphenylacetyl chloride under similar conditions
provided the required hydroxyamide 7 in 88% yield. The
amide group was then reduced to an amino group using
borane in THF at 50°C, followed by deprotection of the
silyl group with KF/MeOH, as described by Corey et al.,7
to give (R)-(−)-denopamine 1 in good yield (75%)
(Scheme 3).
Table 1. Reduction of azido ketones in aqueous media at room temperature
Ketone
Product
Biocatalyst
Additive
Sucrose
Sucrose
Time (days)
Yieldc
E.e. (%)d
Abs. conf.e
4a
4a
4b
4b
5a
5a
5b
5b
Baker’s yeasta
Daucus carotab
Baker’s yeast
Daucus carota
2
2
3
3
88
92
78
85
98
99
\99
100
R
R
R
R
a Baker’s yeast-mediated reactions were performed as reported in the literature.11b
b Daucus carota-mediated reactions were performed as reported in Section 4.
c Isolated yields after chromatographic purification.
d Determined by HPLC analysis using a Daicel chiral OD column: hexane/isopropanol=8.5/1.5.
e The absolute configuration was assigned by analogy Ref. 11b.
Scheme 1.
Scheme 2.

J. S. Yada6 et al. / Tetrahedron: Asymmetry 12 (2001) 3381–3385
3383
Scheme 3.
3. Conclusion
mL) and an ethanolic solution of azido ketones 4a and
4b (1 g, 1.5 mL EtOH] was added to the suspension.
The reaction mixture was then incubated in an orbital
shaker (150 rpm) for 2 to 3 days at room temperature.
The progress of the reaction was monitored by TLC
and GC analysis. Finally, the suspensions were
removed by filtration and washed with ether (2×20
mL). The combined filtrate was extracted with ether
(2×30 mL), washed with brine and dried over Na2SO4.
The solvent was removed in vacuo and the residue was
chromatographed on silica gel (60–120 mesh) using
n-hexane:ethyl acetate (95:5) affording the pure azido
alcohols 5a and 5b in good yield. The structure of these
compounds was confirmed by spectral analysis and the
enantiomeric excess was determined by the chiral
HPLC.
In summary, we have established a convenient and
simple procedure for the preparation of chiral azido
alcohols from a-azido ketones with Daucus carota root
reduction process, under milder conditions. We have
also explained the importance of these optically active
azido alcohols as precursors for the synthesis of a
variety of pharmaceutically important molecules. Since
this is a novel and alternative methodology to classical
biochemical methods, it has wide scope and enables the
synthesis of an analogous series of compounds. Further
work is in progress and will appear in due course.
4. Experimental
4.1. General
4.2.1. (R)-(−)-2-Azido-1-(4-methoxyphenyl)ethanol 5a.
Yield=0.929 g (92%), colourless liquid; [h]2D5=−40.1 (c
1
1.02, CHCl3); H NMR (CDCl3, 200 MHz): l 2.10 (br
Melting points were recorded on a Buchi R-535 appara-
tus. IR spectra were recorded on a Nicolet-740 FT-IR
spectrophotometer. 1H and 13C NMR spectra were
recorded in CDCl3 and DMSO-d6 solutions on Varian
Gemini 200 and 50 MHz spectrometers and chemical
shifts were reported in ppm. Mass spectra were
recorded on VG micromass-7070H (70 eV). C,H,N
analysis was performed on a Vario EL analyzer. Opti-
cal rotations were recorded on a Jasco Dip 360 digital
polarimeter. HPLC analysis was performed on a Schi-
madzu liquid chromatography LC-6A, equipped with a
SCE-6A, system controller, SPD-6A fixed wave length
UV monitor detector and Chromatopac C-R4A data
processor as integrator. The column was 4.6×250 mm
chiralcel OD column (Daicel). The eluents were hex-
ane–isopropanol (HPLC grade, 85:15) at a flow rate of
0.5 mL min−1 and monitored at 254 nm wavelength.
Baker’s yeast type-1 was obtained from Sigma Chemi-
cals Co. All starting materials were prepared according
to the literature procedure. The fresh carrot roots were
obtained from a local market.
s, 1H), 3.40 (m, 2H), 3.78 (s, 3H), 4.80 (dd, 1H, J=7.2,
4.0 Hz), 6.85 (d, 2H, J=7.8 Hz) 7.25 (d, 2H, J=7.8
Hz); 13C NMR (CDCl3, 50 MHz): l 55.5, 58.2, 114.4,
127.5, 132.5, 159.8. MS (CI): m/z 193 (M+); IR (CHCl3,
cm−1): 3426, 2100, 1024. Anal. calcd for C9H11N3O2: C,
55.95; H, 5.74; N, 21.75. Found: C, 55.97; H, 5.68; N,
21.73%.
4.2.2.
(R)-(−)-2-Azido-1-(4-tert-butyldimethylsilyloxy-
phenyl)ethanol 5b. Oil; yield=0.879 g (85%); [h]2D5=
1
−59.5 (c 1.00, CHCl3); H NMR (CDCl3, 200 MHz): l
0.20 (s, 6H), 1.00 (s, 9H), 2.35 (br s, 1H), 3.40 (m, 2H),
4.80 (m, 1H), 6.85 (d, 2H, J=7.4 Hz), 7.25 (d, 2H,
J=7.4 Hz). 13C NMR (CDCl3, 50 MHz) l: −4.46,
13.92, 25.62, 58.10, 73.09, 120.24, 127.00, 127.12,
133.14. MS (CI): m/z 293 (M+); IR (CHCl3, cm−1):
3422, 2086, 1026. Anal. calcd for C14H23SiN3O2: C,
57.30; H, 7.90; N, 14.32; Si, 9.57. Found: C, 57.38; H,
7.94; N, 14.38; Si, 9.63%.
4.2.3. Synthesis of (R)-(−)-tembamide 2. The azido alco-
hol 5a (0.772 g, 4 mmol) was dissolved in MeOH (5
mL) and stirred under a hydrogen atmosphere (1 atm)
in the presence of 5% Pd–C (20 mg) at room tempera-
ture for 2 h. The catalyst was removed by filtration and
the filtrate was concentrated to give amino alcohol 6a.
The residue was dissolved in DCM (5 mL), a solution
4.2. General procedure for the reduction of 2-azido-1-
aryl ketones 4a and 4b with Daucus carota
In a 1000 mL Erlenmeyer flask, freshly cut carrot root
pieces (100 g, 1×1.5 cm) were suspended in water (400

3384
J. S. Yada6 et al. / Tetrahedron: Asymmetry 12 (2001) 3381–3385
of 50% aqueous NaOH (1.10 g, 12 mmol) in water (6.5
mL) was added at 0–5°C and vigorously stirred for 10
min. To the resulting solution of 6a, a solution of
benzoyl chloride (5 mmol) in anhydrous toluene (3 mL)
was added dropwise through a syringe over a period of
5 min. After the addition was complete, the reaction
mixture was stirred for a further 20 min. The solvent
was evaporated in vacuo and the residue was diluted
with cold water. The precipitate was filtered and
washed with water, dried in air and then recrystallized
from ethanol:water (80:20) to afford pure (R)-(−)-tem-
bamide 2. Yield=1.08 (92%), white crystalline solid;
mp 154–155°C; [h]D25=−59.6 (c 0.52, CHCl3) [lit.7
[h]2D4=−59.8 (c 0.4, CHCl3)]; 1H NMR (CDCl3, 200
MHz) l: 2.85 (br s, OH), 3.36–3.48 (m, 1H), 3.78 (s,
3H), 3.82–3.95 (m, 1H), 4.65 (dd, 1H, J=7.6, 4.2 Hz),
6.52 (m, 1H), 6.85 (d, 2H, J=8.2 Hz), 7.30 (d, 2H,
J=8.2 Hz), 7.38–7.45 (m, 3H), 7.75 (d, 2H, J=8.2 Hz).
13C NMR (DMSO-d6, 50 MHz) l: 47.02, 54.44, 71.57,
112.87, 120.87, 126.87, 127.99, 128.63, 134.31, 139.17,
148.21, 165.83. MS: m/z 271 (M+), IR (KBr, cm−1):
3492, 3385, 1628, 1042. Anal. calcd for C16H17NO3: C,
70.84; H, 6.26; N, 5.18. Found: C, 70.88; H, 6.28; N,
5.12%.
148.91, 157.08, 169.80; MS (CI): m/z 445 (M+); IR
(KBr, cm−1): 3475, 3362, 1638, 1035. Anal. calcd for
C24H35SiNO5: C, 66.68; H, 7.94; N, 3.14; Si, 6.30.
Found: C, 66.74; H, 7.98; N, 3.12; Si, 6.36%.
4.3. Synthesis of (R)-(−)-denopamine 1
To a solution of hydroxy amide 7 (0.890 g, 2 mmol) in
dry THF (5 mL), a solution of BH3·THF (1 M, 3 mL,
3 mmol) was added. The resulting mixture was stirred
at 50°C for 2 h under an N2 atmosphere and then
cooled to room temperature and cautiously quenched
with methanol (0.3 mL). The solvent was evaporated
and the residue was dissolved in dry methanol (4 mL),
cooled to 0°C and KF (2 mmol) in methanol (1 mL)
was added. Anhydrous methanolic HCl (1 M, 2.5 mL,
2.5 mmol) was added and the mixture was stirred for 4
h at room temperature. The solvent was removed and
the residue was diluted with ethyl acetate (20 mL),
washed with 10% aqueous NaCl (3 mL), and dried over
Na2SO4. The solvent was removed under reduced pres-
sure and the solid obtained was recrystallized from
n-hexane:ethyl acetate (70:30) to afford pure (R)-
denopamine 1. Yield=0.477 g (75%), mp 164–165°C.
[h]D25=−27.8 (c 1.02, MeOH) [lit.6a [h]2D4=−27.5 (c 0.95,
1
4.2.4. Synthesis of (R)-(−)-aegeline 3. The reduction of
5a followed by treatment with cinnamoyl chloride
under similar conditions gave (R)-(−)-aegeline 3.
Yield=1.18 g (90%), white crystalline solid; mp 195–
196°C (lit: 196–197). [h]2D5=−36.1 (c 0.45, CHCl3) [lit.7
[h]2D4=−35.6 (c 0.4, CHCl3)]; 1H NMR (CDCl3, 200
MHz) l: 3.18–3.35 (m, 1H), 3.57–3.70 (m, 1H), 3.80 (s,
3H), 4.72 (m, 1H), 5.12 (d, 1H, J=3.3 Hz), 6.60 (d, 1H,
J=15.8 Hz), 6.85 (d, 2H, J=8.4 Hz), 7.25–7.38 (m,
5H), 7.42–7.55 (m, 3H), 7.68 (m, 1H); 13C NMR
(DMSO-d6, 50 MHz) l: 47.02, 54.44, 71.57, 112.87,
120.78, 126.39, 126.87, 127.99, 128.63, 134.31 and
139.17, 158.01, 165.83; MS(CI): m/z 297 (M+). IR
(KBr, cm−1): 3458, 3328, 1632, 1039. Anal. calcd for
C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found: C,
72.88; H, 6.38; N, 4.83%.
MeOH)]; H NMR (CDCl3, 200 MHz): l 3.02–3.38 (m,
6H), 3.79 (s, 3H), 3.81 (s, 3H), 5.18 (dd, 1H, J=3.6, 1.8
Hz), 6.68–6.88 (m, 5H), 7.21 (d, 2H, J=8.2 Hz); 13C
NMR (CDCl3, 50 MHz): l 34.88, 50.95, 52.76, 56.10,
72.52, 111.32, 114.46, 119.85, 126.98, 132.10, 134.30,
147.88, 149.20, 158.42, 159.33; MS (CI): m/z 318 (M+);
IR (KBr, cm−1): 2938, 1622, 1585. HRMS calcd for
C18H23NO4: 318.1704; Found: 318.1658.
Acknowledgements
P.T.R. and S.N. thank CSIR New Delhi for the award
of fellowships.
4.2.5. Preparation of hydroxyamide 7. To a stirred solu-
tion of amino alcohol 6b (3 mmol) in DCM (5 mL) and
50% aq. NaOH (0.825 g, 9 mmol) in water (4.8 mL)
was added a solution of 3,4-dimethoxyphenylacetyl
chloride (4 mmol) in anhydrous toluene (3 mL) over a
period of 5 min at 0–5°C and the reaction mixture was
stirred for a further 20 min. The solvent was removed
in vacuo and the residue was diluted with cold water
and then extracted with ethyl acetate (2×20 mL) and
dried over Na2SO4. The solvent was evaporated and the
residue was chromatographed on silica gel (60–120
mesh) eluting with n-hexane:ethyl acetate (70:30)
afforded the corresponding hydroxyamine 7 in pure
form. Yield=1.17 g, (88%); mp 37–38°C. [h]2D5=−32.2
References
1. (a) Roth, H. J.; Kleeman, A. Pharmaceutical Chemistry,
Drug Synthesis; Ellis Harwood: UK, 1988; Vol. 1, p. 144;
(b) Hong, Y.; Gao, Y.; Nie, X.; Zepp, C. M. Tetrahedron
Lett. 1994, 31, 5551; (c) Hieble, J. P.; Bondinell, W.;
Ruffolo, R. R., Jr. J. Med. Chem. 1995, 38, 3415; (d)
Hieble, J. P.; Bondinell, W.; Ruffolo, R. R., Jr. J. Med.
Chem. 1995, 38, 3681; (e) Ramachandran, P. V.; Gong,
B.; Brown, H. C. Chirality 1995, 7, 103.
2. (a) Millership, J. S.; Fitzpatrick, A. Chirality 1993, 5, 573
and references cited therein; (b) Brittain, R. T.; Farmer,
J. B.; Marshall, R. J. Br. J. Pharmacol. 1973, 48, 144; (c)
Chapman, I. D.; Buchheit, K. H.; Manley, P.; Morley, J.
Trends J. Pharmacol. Sci. 1992, 13, 231; (d) Stinson, S. C.
Chem. Eng. News 2000, 78, 59.
1
(c 1.02, CHCl3); H NMR (CDCl3, 200 MHz): l 0.18
(s, 6H), 0.98 (s, 9H), 3.16–3.30 (m, 1H), 3.48 (s, 2H),
3.52–3.66 (m, 1H), 3.82 (s, 3H), 3.84 (s, 3H), 4.69 (dd,
1H, J=7.2, 4.0 Hz), 5.79 (t, 1H, J=6.8 Hz), 6.75 (m,
5H), 7.10 (d, 2H, J=8.6 Hz); 13C NMR (DMSO-d6, 50
MHz) l: −4.82, 13.96, 42.60, 46.10, 55.30, 70.98,
111.10, 112.50, 117.88, 126.98, 128.12, 132.94, 147.75,
3. (a) Ruffolo, R. R., Jr. Tetrahedron 1991, 47, 9953; (b)
Lunts, L. H. C.; Main, B. G.; Tucker, H. In Medicinal
Chemistry, The Role of Organic Chemistry in Drug
Research; Roberts, S. M.; Price, B. J., Ed.; Academic
Press: New York, 1985; pp. 49–92.

J. S. Yada6 et al. / Tetrahedron: Asymmetry 12 (2001) 3381–3385
4. (a) Yokoyama, H.; Yanagisawa, T.; Taira, N. J. Cardio- Am. Chem. Soc. 1998, 120, 13529.
3385
vasc. Pharmacol. 1988, 12, 323; (b) Bristow, M. R.;
Hershberger, R. E.; Port, J. D.; Minobe, W.; Rasmussen,
R. Mol. Pharmacol. 1989, 35, 295.
11. (a) Yadav, J. S.; Reddy, P. T.; Hashim, S. R. Synlett
2000, 1469; (b) Yadav, J. S.; Reddy, P. T.; Nanda, S.;
Rao, A. B. Tetrahedron: Asymmetry 2001, 12, 63 and
references cited therein.
12. (a) Lu, S. F.; Herbet, B.; Haufe, G.; Laue, K. W.;
Padgett, W. L.; Oshunleti, O.; Daly, J. W.; Kirk, K. L. J.
Med. Chem. 2000, 43, 1611; (b) Procopiou, P. A.; Mer-
ton, G. E.; Todd, M.; Webb, G. Tetrahedron: Asymmetry
2001, 12, 2005.
13. (a) Naoshima, Y.; Akakabe, Y. J. Org. Chem. 1989, 54,
4237; (b) Naoshima, Y.; Akakabe, Y. Phytochemistry
1991, 30, 3595; (c) Akakabe, Y.; Takahashi, M.;
Kamazawa, M.; Kikuchi, K.; Tachibana, H.; Obtani, H.;
Noashima, Y. J. Chem. Soc., Perkin Trans. 1 1995, 1295.
14. (a) Chadha, A.; Manohar, M.; Soundrarajan, T.;
Lokeswari, T. S. Tetrahedron: Asymmetry 1996, 7, 1571;
(b) Baldassarre, F.; Bertoni, G.; Chiappe, C.; Marioni, F.
J. Mol. Catal.-B Enzym. 2000, 11, 55.
5. Shoeb, A.; Kapil, R. S.; Popli, S. P. Phytochemistry 1973,
12, 2071.
6. (a) Corey, E. J.; Link, J. O. J. Org. Chem. 1991, 56, 442;
(b) Kawagucki, T.; Saito, K.; Matsuki, K.; Iwakuma, T.;
Takeda, M. Chem. Pharm. Bull. 1993, 4, 639.
7. Brown, R. F. C.; Jackson, W. R.; Mc Carthy, T. D.
Tetrahedron: Asymmetry 1993, 4, 205.
8. (a) Ikezaki, M.; Umino, N.; Gaino, M.; Aoe, K.;
Iwakuma, T.; Ohishi, T. Yakugaku. Zasshi 1986, 106, 80;
(b) Noguchi, K.; Irie, K, Japan Patent 79 70, 233, 1979,
Chem. Abstr. 1979, 91 630; (c) Kuck, A. M.; Albonico, S.
M.; Deulofeu, V. J. Chem. Soc., Section C 1967, 1327; (d)
Gu, J.-X.; Zu-Yi, L.; Guo-Qiang, L. Tetrahedron 1993,
49, 5803.
9. Senuma, M.; Yamato, E.; Koumato, T.; Gaino, M.;
Kawaguchi, T.; Iwakuma, T. Chem. Expt. 1989, 4, 245.
10. (a) Ohkuma, T.; Ishii, D.; Takeno, H.; Noyori, R. J. Am.
Chem. Soc. 2000, 122, 6510; (b) Doucet, H.; Ohkuma, T.;
Murata, K.; Yokozawa, T.; Kozawa, M.; Katayama, E.;
England, A. F.; Ikariya, T.; Noyori, R. Angew. Chem.,
Int. Ed. 1998, 37, 1703; (c) Ohkuma, T.; Koizumi, M.;
Doucet, H.; Pham, T.; Kozawa, M.; Murata, K.;
Katayama, E.; Yokozawa, T.; Ikariya, T.; Noyori, R. J.
15. Yadav, J. S.; Nanda, S.; Reddy, P. T.; Rao, A. B. J. Org.
Chem. 2001, in press.
16. (a) Prelog, V. Helv. Pure Appl. Chem. 1964, 9, 119; (b)
Sih, C.-J.; Chen, C.-S. Angew. Chem., Int. Ed. Engl. 1984,
23, 570.
17. Guy, A.; Dubffet, T.; Doussot, J.; Falguieres, A. G.
Synlett 1991, 403.