Stereoselective hydrocoupling of [(1R)-exo]-3-exo-(diphenylmethyl)bornyl cinnamates by electroreduction

Article abstract of DOI:10.1021/ol016566p

Equation presented The chiral auxiliary [(1R)-exo]-3-exo-(diphenylmethyl)borneol, synthesized from (1R)-(+)-camphor in three steps, was highly effective for the stereoselective hydrocoupling of its cinnamates by electroreduction. From the resulting hydrod

Full text of DOI:10.1021/ol016566p

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3241-3244
Stereoselective Hydrocoupling of
[(1R)-exo]-3-exo-(Diphenylmethyl)bornyl
Cinnamates by Electroreduction
Naoki Kise,* Keisuke Iwasaki, Naohiko Tokieda, and Nasuo Ueda
Department of Biotechnology, Faculty of Engineering, Tottori UniVersity,
Tottori 680-8552, Japan.
kise@bio.tottori-u.ac.jp
Received August 13, 2001
ABSTRACT
The chiral auxiliary [(1R)-exo]-3-exo-(diphenylmethyl)borneol, synthesized from (1R)-(+)-camphor in three steps, was highly effective for the
stereoselective hydrocoupling of its cinnamates by electroreduction. From the resulting hydrodimers, (3R,4R)-3,4-diaryladipic acid esters and
(3R,4R)-3,4-diarylhexane-1,6-diols were synthesized in 87−95% ee.
Electroreduction of R,â-unsaturated compounds in aqueous
solution is a well-recognized method to obtain the corre-
sponding hydrodimers.1 In addition, the electroreduction of
cinnamic acid esters in an aprotic solvent affords cyclized
products of hydrodimers2 as all-trans isomers stereospecifi-
cally (Scheme 1).2a-c,e These results prompted us to inves-
tigate enantioselective hydrocoupling of cinnamic acid
derivatives, because the obtained hydrodimers can be con-
verted into several C2-symmetric compounds as shown in
Scheme 1. We have started our study using readily available
and well-known chiral auxiliaries such as optically active
alcohols, oxazolines,3 and oxazolidinones.3b,4 We have
already reported that (S)-4-isobutyloxazolidinone was the
most effective chiral auxiliary among them.5 The best
selectivity for the dl-hydrodimer, however, was R,R/S,S )
85:15. Therefore, a more effective chiral auxiliary is desir-
able. Although the electroreduction of cinnamates derived
Scheme 1
(1) (a) Baizer, M. M. J. Electrochem. Soc. 1964, 111, 215-222. (b)
Baizer, M. M.; Anderson, J. D. J. Electrochem. Soc. 1964, 111, 223-226.
(c) Rifi, M. R. Technique of Electroorganic Synthesis, Part II; Weinberg,
N. L., Ed.; Wiley: New York, 1975; pp 192-215.
(2) (a) Klemm, L. H.; Olson, D. R. J. Org. Chem. 1973, 58, 3390-
3394. (b) Kanetsuna, H.; Nonaka, T. Denki Kagaku 1981, 49, 526-531.
(c) Smith, C. Z.; Utley, H. P. J. Chem. Soc., Chem. Commun. 1981, 492-
494. (d) Nishiguchi, I.; Hirashima, T. Angew. Chem., Int. Ed. Engl. 1983,
22, 52-53. (e) Utley, J. H. P.; Gu¨llu¨, M.; Motevalli, M. J. Chem. Soc.,
Perkin Trans. 1 1995, 1961-1970.
(3) (a) Lutomski, K. A.; Meyers, A. I. Asymmetric Synthesis; Academic
Press: New York, 1984; Vol. III, pp 213-274. (b) Ager, D. J.; Prakash, I.;
Schaad, D. R. Chem. ReV. 1996, 96, 835-875.
(4) (a) Evans, D. A. Asymmetric Synthesis; Academic Press: New York,
1984; Vol. III, pp 87-90. (b) Heathcock, C. H. Asymmetric Synthesis;
Academic Press: New York, 1984; Vol. III, pp 184-188.
(5) (a) Kise, N.; Echigo, M.; Shono, T. Tetrahedron Lett. 1994, 35,
1897-1900. (b) Kise, N.; Mashiba, S.; Ueda, N. J. Org. Chem. 1998, 63,
7931-7938.
10.1021/ol016566p CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/12/2001

from (-)-menthol, (-)-8-phenylmenthol, and (-)-endo-
borneol gave poor results,5b we investigated effective chiral
auxiliaries based on a modification of (1R)-(+)-camphor,
since it is readily available and inexpensive. We report herein
that [(1R)-exo]-3-exo-(diphenylmethyl)borneol6 (1) is a highly
effective chiral auxiliary for the electroreductive hydro-
coupling of its cinnamates.
steric hindrance.6b Consequently, the cinnamate of 1 was pre-
pared in three steps (Scheme 3): acetylation of 1, condensa-
Scheme 3
The synthesis of 1 from (+)-camphor was carried out in
three steps as shown in Scheme 2. To improve the total yield
Scheme 2
tion of the acetate 3 with benzaldehyde, and dehydration of
the resulting hydroxy ester 4a (Ar ) Ph) gave trans-
cinnamate 5a in 79% overall yield. Several aryl-substituted
trans-cinnamate 5b-h were prepared similarly (Table 1).
Table 1. Synthesis of trans-Cinnamates 5 from 1
Ar
% yield of 4a
% yield of 5a
of 1, we modified the reported methods.6,7 The trimethylsilyl
enol ether of (+)-camphor was prepared in 93% yield by
the successive treatment of (+)-camphor with n-BuLi and
TMSCl in Et2O. The reaction of the silyl enol ether with
chlorodiphenylmethane in the presence of TiCl4 at -50 °C
for 1 h gave (1R)-3-exo-(diphenylmethyl)camphor (2) in 98%
yield with a small amount of its stereoisomer. The 3-exo-
Ph
4a 98
4b 81
4c 82
4d 98
4e 95
4f 83
4g 98
4h 87
5a 90
5b 86
5c 85
5d 79
5e 86
5f 75
5g 64
5h 85
o-MeOC6H4
m-MeOC6H4
p-MeOC6H4
p-FC6H4
2-naphthyl
1-furyl
1
3,4-methylenedioxyphenyl
a Isolated yields.
ketone 2 was identified by its H NMR spectrum, which
showed the C3 endo proton as a doublet at δ 2.91 ppm
coupled to the C11 proton (J ) 12.1 Hz). If the C3 proton
was exo, it should also couple to the C4 proton (J ) 4-5
Hz) and C5 exo proton (J ) 1-2 Hz).8 The following LAH
reduction of 2 in THF gave 1 with a small amount of its
stereoisomer. Recrystallization of the crude product afforded
isomerically pure [(1R)-exo]-3-exo-(diphenylmethyl)borneol
(1) in 86% yield. The 2-exo-3-exo configuration of 1 has
been suggested by Pearson6b and was also confirmed by its
1H NMR analysis. Namely, the C2 endo proton (δ 3.83 ppm)
gave a double doublet coupled to the C3 endo proton (J )
7.5 Hz) and the OH proton (J ) 3.2 Hz), and the C3 endo
proton gave a double doublet (δ 2.70 ppm) coupled to the
C2 endo proton (J ) 7.5 Hz) and the C11 proton (J ) 13.0
Hz). In addition, NOE observed between the C2 and C3
protons shows that these protons are located on the same
side (Scheme 2).
Electroreduction of 5a was carried out at a constant current
of 75 mA in 0.33 M Et4NOTs/acetonitrile using an undivided
cell and a Pb cathode, according to the reported method.5b
The noncyclized hydrodimer 6a was obtained in 68% yield
along with 7a (Scheme 4). It is noted that the cyclized hy-
Scheme 4
Unfortunately, all attempts for direct cinnamoylation of 1
failed. Pearson has reported that ester formation and hy-
drolysis of 1 was very difficult to accomplish because of
(6) (a) Oppolzer, W.; Kurth, M.; Reichlin, D.; Chapuis, C.; Mohnhaupt,
M.; Moffatt, F. HelV. Chem. Acta 1981, 64, 2802-2807. (b) Pearson, A.
J.; Gontcharov, A. V. J. Org. Chem. 1998, 63, 152-162.
3242
Org. Lett., Vol. 3, No. 21, 2001

drodimer could not be detected, since Dieckmann condensa-
tion of 6a is inhibited by the steric hindrance as mentioned
above. The diastereomeric excess (de) of the hydrodimer 6a
Table 3. Transformation of 6 to 9 and 8
Ar
% yield of 9a % yield of 8a (% ee)b
1
seemed to be more than 90% by its H NMR spectrum.9
Ph
9a 88
9c 84
9d 90
9e 90
8a 80 (92)
8c 75 (92)
8d 78 (92)
8e 80 (87)
8f 52 (95)
To confirm the selectivity and stereochemistry, the dimer
6a was transformed to known dimethyl ester 8a5 (Scheme
5). Hydrolysis of 6a by normal methods failed owing to the
m-MeOC6H4
p-MeOC6H4
p-FC6H4
2-naphthyl
9f 68
1-furyl
3,4-methylenedioxyphenyl
9g 56 (87)c
9h 70 (89)c
Scheme 5
a Isolated yields. b Determined by 1H NMR analysis with Eu(hfc)3.
1
c Determined from the corresponding diacetate by H NMR analysis with
Eu(hfc)3.
(entry 6). The enantioselectivities of diesters 8c-f and the
diacetates of diols 9g,h were determined to be 87-95% ee
by 1H NMR spectra with Eu(hfc)3. The 3R,4R configuration
1
was confirmed for 8c-e by H NMR and chiral HPLC
1
analyses5b and was assumed for 8f and 9g,h by H NMR
correlation of 6f-h with 6a.
The reaction mechanism of the hydrocoupling of 5 can
be speculated to be similar to that reported previously for
cinnamic acid esters.2a,b,10 An anion radical is produced by
one-electron transfer to 5 and couples with another anion
radical. Semiempirical (UHF/AM1) and DFT (UB3LYP
3-21G* and 6-31G*) calculations11 of anion radical of 5a
gave two optimized structures A and B (Figure 1). From
the results described above, it seems that the coupling occurs
steric hindrance. Alternatively, LAH reduction of 6a afforded
diol 9a in 88% yield together with 1 in 95% yield. Oxidation
of 9a followed by esterification in methanol gave dimethyl
ester 8a, which consisted of only the dl-isomer; the meso-
isomer was not detected by 1H NMR analysis. The absolute
stereochemistry and enantiomeric excess of 8a were deter-
1
mined to be 3R,4R and 92% ee by H NMR spectrum with
Eu(hfc)3 and chiral HPLC analysis.5b This result showed that
the hydrodimer 6a was obtained as a mixture of two
stereoisomers, R,R-form (major) and S,S-form (minor), in
92% de.
The electroreduction of aryl-substituted cinnamate 5b-h
and the subsequent transformation of the dimers 6c-h were
carried out by the same procedures as above, and the results
are summarized in Tables 2 and 3. Although ortho substitu-
tion inhibited the electroreductive hydrocoupling significantly
(Table 2, entry 2), para and meta substitution (entries 3-5,
7, and 8) did not hinder it except for the â-naphthyl group
Table 2. Electroreduction of trans-Cinnamates 5
entry
Ar
% yield of 6a % yield of 7a
1
2
3
4
5
6
7
8
Ph
6a 68
6b 3
7a 30
7b 77
7c 28
7d 35
7e 24
7f 57
7g 31
7h 22
o-MeOC6H4
m-MeOC6H4
p-MeOC6H4
p-FC6H4
2-naphthyl
1-furyl
6c 54
6d 54
6e 62
6f 18
6g 52
6h 64
3,4-methylenedioxyphenyl
a Isolated yields.
Figure 1. Minimized structures of anion radical of 5a.
Org. Lett., Vol. 3, No. 21, 2001
3243

from the more stable A at the less hindered Si face (â-side)
and gives the R,R-dimer selectively (Scheme 6).
hydrocoupling of cinnamates. From the resulting hydrodimers
5, the R,R-enantiomers of C2-symmetric 3,4-diaryladipic acid
diesters 8 and 3,4-diarylhexane-1,6-diols 9 were obtained in
87-95% ee. The utility of 1 as a chiral auxiliary in other
reactions is now being investigated.
Scheme 6
Acknowledgment. (N.K. is grateful to the Electric
Technology Research Foundation of Chugoku for financial
support.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL016566P
(10) Fussing, I.; Gu¨llu¨, M.; Hammerich, O.; Hussain, A.; Nielsen, M.
F.; Utley, J. H. P. J. Chem. Soc., Perkin Trans. 2 1996, 649-658.
(11) The calculations were carried out using the Gaussian 98W pro-
gram: Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P.
M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.;
Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98W, Revision
A.9; Gaussian, Inc.: Pittsburgh, PA, 1998.
At present [(1R)-exo]-3-exo-(diphenylmethyl)borneol (1)
is the most effective chiral auxiliary for the electroreductive
(7) Full details of the modifications are in Supporting Information.
(8) (a) Coxon, J. M.; Hartshorn, M. P.; Lewis, A. J. Aust. J. Chem. 1971,
24, 1017-1026. (b) Taber, D. T.; Raman, K.; Gaul, M. D. J. Org. Chem.
1987, 52, 28-34.
1
(9) The H NMR spectrum of 6a showed major (>90%) three singlets
for methyl protons at 0.19, 0.67, and 1.20 ppm with minor (<10%) three
singlets at 0.11, 0.65, and 1.14 ppm.
3244
Org. Lett., Vol. 3, No. 21, 2001