Enantioselective addition of diethylzinc to aldehydes catalyzed by a β-amino alcohol derived from (+)-3-carene

Article abstract of DOI:10.1016/S0957-4166(03)00347-1

A (+)-3-carene derived aminoalcohol was successfully used as a chiral ligand in the catalytic enantioselective diethylzinc addition to various aldehydes. Very high enantiomeric excess (up 98% in 1-(2-methoxyphenyl)-1-propanol) was obtained. A plausible mechanism has been suggested for the observed enantioselectivity.

Full text of DOI:10.1016/S0957-4166(03)00347-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1763–1766
Enantioselective addition of diethylzinc to aldehydes catalyzed by
a b-amino alcohol derived from (+)-3-carene
†
Sudhir N. Joshi and Sanjay V. Malhotra*
Department of Chemistry and Environmental Science, New Jersey Institute of Technology, University Heights, Newark, NJ, USA
Received 24 January 2003; accepted 25 March 2003
Dedicated to Professor Robert L. Augustine on his 70th birthday
Abstract—A (+)-3-carene derived aminoalcohol was successfully used as a chiral ligand in the catalytic enantioselective diethylzinc
addition to various aldehydes. Very high enantiomeric excess (up 98% in 1-(2-methoxyphenyl)-1-propanol) was obtained. A
plausible mechanism has been suggested for the observed enantioselectivity. © 2003 Elsevier Science Ltd. All rights reserved.
The enantioselective CꢀC bond formation is among the
With our earlier work on the synthesis of terpene based
6a,b
most fundamental and important synthetic construc-
compounds,
and in particular the success seen in the
1
tions in chemistry. Catalytic asymmetric addition reac-
application of isopinocampheyl based ligands in catalytic
2
d
6c
tions have attracted major attention in this regard and
today it is one of most active areas of research in
organic chemistry. The enantioselective addition of
diethylzinc to aldehydes in the presence of catalytic
amounts of chiral aminoalcohols as effective chiral
ligand for this reaction was first discovered by Oguni et
asymmetric deprotonation, we were inspired by the
7
recent reports by Nugent et al. A (+)-3-carene derived
amino alcohol was successfully used as a chiral auxiliary
in the addition of lithium cyclopropyl acetylide to an
unprotected N-acylketimine in very high enantiomeric
excess. While there are reports on the successful use of
3
8
9
10
al. However, the first report of very high enantioselec-
pinene, nopinone, fenchone-camphor
and very
11
tivity in the catalytic addition of Et Zn was reported by
recently limonene derived amino alcohols in the enan-
tioselective addition of diethylzinc, to the best of our
knowledge there is no report on (+)-3-carene derived
amino alcohols. Herein we report the first study on the
use of (1S,3R,4S,6R)-4-amino-3-caranol, a (+)-3-carene
derived aminoalcohol as chiral catalyst in the enantiose-
lective addition of diethylzinc to aldehydes.
2
4
Noyori et al., who achieved 98% ee using DAIB
(
N,N-dimethylamino isoborneol), a terpene based chiral
ligand. Since then various catalysts derived from terpene
based chiral amino alcohols have been used to
catalyze this type of reaction with varied asymmetric
5
inductions.
Scheme 1.
*
Corresponding author. Fax: 973-596-3586; e-mail: sanjay.malhotra@njit.edu
Postdoctoral research associate.
†
0
957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00347-1

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S. N. Joshi, S. V. Malhotra / Tetrahedron: Asymmetry 14 (2003) 1763–1766
Table 2. Enantioselective addition of diethylzinc to alde-
hydes catalyzed by b-amino alcohol 2
Entry Aldehyde
Yield (%)a Ee (%) Config.b
1
2
3
4
5
6
7
8
Benzaldehyde 3a
68
68
66
76
77
60
69
81
73
33
98
73
72
75
93
–
(R)-(+)
(R)-(+)
(R)-(+)
(R)-(+)
(R)-(+)
(R)-(+)
(R)-(+)
(R)-(+)
–
o-Chlorobenzaldehyde 3b
p-Chlorobenzaldehyde 3c
o-Methoxybenzaldehyde 3d
p-Methoxybenzaldehyde 3e
o-Methylbenzaldehyde 3f
(E)-Cinnamaldehyde 3g
Cyclohexanecarboxaldehyde 3h 55
p-Nitrobenzaldehyde 3i
Pyridine carboxaldehyde 3j
c
Scheme 2.
9
10
NR
d
The b-amino alcohol was synthesized in two simple
60
–
–
7a
steps following the literature procedure. (+)-3-Carene
on epoxidation with MCPBA yielded the corresponding
carane epoxide 1 in 80% yield (Scheme 1). Epoxide 1,
a
Isolated yield.
b
c
Determined by comparison of specific rotation with literature value.
Based on recovered starting material.
Could not be separated from the catalyst.
on MgBr induced, diastereoselective, nucleophilic ring
2
d
opening with morpholine was converted to the corre-
sponding b-amino alcohol derivative 2 in 60% yield.
react under the experimental conditions and a sluggish
reaction was seen with 2-pyridine carboxaldehyde.
This amino alcohol 2, (1S,3S,4S,6R)-3,7,7-trimethyl-4-
morpholino-4-yl-bicyclo(4.1.0)heptano-3-ol, was used
as a chiral auxiliary for the enantioselective addition of
diethylzinc to aldehydes (Scheme 2). Initial studies with
the catalyst loading suggested that maximum ee was
obtained with 15% catalyst (Table 1).
In all the examples studied the R absolute configuration
for the resulting alcohols was noted. Based on our
results a plausible mechanism for the diethylzinc addi-
tion is proposed (Fig. 1) which can be explained with
2a,13
Noyori type tricyclic transition state model.
Also, in our preliminary experiments it was noted that
temperature has a detrimental effect on the ee. A high
ee and yield was obtained at room temperature. Inter-
estingly, however, low conversion and low ee were
observed at lower temperature, which is advantageous
from the practical viewpoint. To generalize the reac-
tion, various aldehydes were reacted with diethylzinc
under optimum reaction conditions, i.e. toluene as a
The diethylzinc coordinates with tertiary hydroxy
group of amino alcohol 2 to form a pentacyclic amino
alcohol–zinc complex (Fig. 1). The stereochemical dis-
position of gem dimethyl groups, tertiary methyl group
as well as the bulkier amine moiety makes the attach-
ment of the aldehyde from the top b face highly hin-
dered. Among the two diastereomeric anti transition
states, the anti (R)-TS, (4-anti R, Fig. 1), where the
aldehyde approaches with ‘re face attack’ suffers no
unfavorable steric interactions with the Ph and the
1
2
solvent, 20°C, 15% chiral catalyst. The results are
summarized in Table 2.
The efficiency of the chiral catalyst to activate the
diethylzinc was reasonably high, as the GC analysis
showed conversion >98% within 4 h. The results show
Zn –Et group and is energetically more favorable. The
A
steric interaction between Zn –Et and the N-alkyl
A
14
substituent is responsible for the further energy differ-
ence between the two transition states anti-(R) and
anti-(S) and is responsible for higher ee with bulkier
N-alkyl derivatives.
(
Table 2) that overall moderate to good yields (55–77%)
were obtained. Also, for most of the aldehydes studied
a moderate to excellent enantioselectivity (72–98%) was
obtained. However, with the exception of p-chloroben-
zaldehyde where the reaction was extremely sluggish
and did not go to completion a low selectivity (entry 3,
ee 33%) was seen. A moderate selectivity was obtained
with an a,b-unsaturated aldehyde (E-cinnamaldehyde,
ee 75%) while reaction with an aliphatic aldehyde
To summarize, we have demonstrated the effective use
of a sterically hindered, bicyclic aminoalcohol as a
chiral catalyst, in the enantioselective addition of
diethylzinc to various aldehydes. The results illustrate
the stereochemical efficacy of a conformationally con-
strained b-amino alcohol with rare trans disposed
aminoalkyl and alcohol groups significantly deviated
from the usual coplanarity. A plausible mechanism has
(
cyclohexanecarboxaldehyde, ee 93%) gave product
with high ee. In a notable observation very high enan-
tioselectivity (ee >98%) was obtained in the case of
o-anisaldehyde. While p-nitrobenzaldehyde did not
Table 1. Effect of catalyst loading on the ee in the diethylzinc addition to benzaldehyde
Entry
Catalyst mol (%)
Yield (%)
[h]D
Ee
Configuration
1
2
3
5
10
15
62
65
69
+22.0
+37.4
+39.0
46.6
77.9
81.2
R
R
R

S. N. Joshi, S. V. Malhotra / Tetrahedron: Asymmetry 14 (2003) 1763–1766
1765
Figure 1. Proposed transition states.
been proposed to account for the effective facial enan-
tioselection in a sterically demanding framework. The
studies regarding theoretical calculations for the pro-
posed transition states are currently underway.
Asymmetry 2002, 13, 1–4; (h) Garc ´ı a Mart ´ı nez, A.; Teso
Vilar, E.; Garc ´ı a Fraile, A.; de la Moya Cerero, S.;
Mart ´ı nez Ruiz, P. Tetrahedron: Asymmetry 1998, 9,
1737–1745; (i) Garc ´ı a Mart ´ı nez, A.; Teso Vilar, E.; Gar-
c ´ı a Fraile, A.; de la Moya Cerero, S.; Mart ´ı nez Ruiz, P.;
Subramanian, L. R. Tetrahedron: Asymmetry 1996, 7,
1
257–1260.
Acknowledgements
6
7
. (a) Brown, H. C.; Malhotra, S. V.; Ramachandran, P. V.
Tetrahedron: Asymmetry 1996, 7, 3527; (b) Joshi, S. N.;
Deshmukh, A. R. A. S.; Bhawal, B. M. Tetrahedron:
Asymmetry 2000, 11, 1477; (c) Malhotra, S. V. Chem. Ind.
S.V.M. gratefully acknowledges the SBR grant
(
c421120) from the New Jersey Institute of Technol-
(
Dekker) 82 (Catal. Org. React.) 2000, 415.
ogy for this work. Also, we would like to thank Dr.
Clementine Reyes for help in NMR analysis during this
work.
. (a) Kauffman, G. S.; Harris, G. D.; Dorow, R. L.; Stone,
B. R. P.; Parsons, R. L., Jr.; Pesti, J. A.; Magnus, N. A.;
Fortunak, J. M.; Confalone, P. N.; Nugent, W. A. Org.
Lett. 2000, 2, 3119–3121; (b) Parsons, R. L.; Fortunak, J.
M.; Dorow, R. L.; Harris, G. D.; Kauffman, G. S.;
Nugent, W. A.; Winemiller, M. D.; Briggs, T. F.; Xiang,
B.; Collum, D. B. J. Am. Chem. Soc. 2001, 123, 9135–
References
1
2
. Methods of Organic Chemistry (Houben-Weyl); Helm-
chen, G.; Hoffmann, R. W.; Mulzer, J.; Schanumann, E.;
Eds.; Thieme: Stuttgart, 1996; Vol. E21.
. (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed.
Engl. 1991, 30, 49–69; (b) Soai, K.; Niwa, S. Chem. Rev.
992, 92, 833–856; (c) Pu, L.; Yu, H. B. Chem. Rev. 2001,
01, 757–824; (d) Asymmetric Catalysis in Organic Syn-
thesis; Noyori, R., Ed.; John Wiley & Sons: New York,
NY, 1995.
. (a) Oguni, N.; Omi, T.; Yamamoto, Y.; Nakamura, A.
Chem. Lett. 1983, 841–842; (b) Oguni, N.; Omi, T. Tetra-
hedron Lett. 1984, 25, 2823–2824.
. Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am.
Chem. Soc. 1986, 108, 6071.
9
143.
. (a) Cherng, Y.-J.; Fang, J.-M.; Lu, T.-J. J. Org. Chem.
999, 64, 3207–3212; (b) Nugent, W. A. J. Chem. Soc.,
8
1
Chem. Commun. 1999, 1369–1370; (c) Posner, T.; Sears,
P. T.; Nugent, W. A.; Blackmond, D. G. Org. Lett. 2000,
1
1
2
, 2511–2513.
9
. Goralski, C. T.; Chrisman, W.; Hasha, D. L.; Nicholson,
L. W.; Rudolf, P. R.; Zakett, D.; Singaram, B. Tetra-
hedron: Asymmetry 1997, 8, 3863–3871.
3
1
0. (a) Goldfuss, B.; Houk, K. N. J. Org. Chem. 1998, 63,
8998–9006; (b) Goldfuss, B.; Steigelmann, M.; Khan, S.
I.; Houk, K. N. J. Org. Chem. 2000, 65, 77–82; (c)
Goldfuss, B.; Steigelmann, M.; Rominger, F. Eur. J. Org.
Chem. 2000, 1785–1792; (d) Knollmuller, M.; Ferencic,
M.; Gartner, P.; Mereiter, K.; Noe, C. R. Tetrahedron:
Asymmetry 1998, 9, 4009–4020; (e) Knollmuller, M.; Fer-
encic, M.; Gartner, P. Tetrahedron: Asymmetry 1999, 10,
3969–3975.
4
5
. (a) Blaser, H.-U. Chem. Rev. 1992, 92, 935–952; (b)
Genov, M.; Kostova, K.; Dimitrov, V. Tetrahedron:
Asymmetry 1997, 8, 1869–1876; (c) Suzuki, Y.; Ogata, Y.;
Hiroi, K. Tetrahedron: Asymmetry 1999, 10, 1219–1222;
(
d) Hanyu, N.; Mino, T.; Sakamoto, M.; Fujita, T.
11. (a) Chrisman, W.; Camara, J. N.; Marcellini, K.; Sin-
garam, B.; Goralski, C. T.; Hasha, D. L.; Rudolf, P. R.;
Nicholson, L. W.; Borodychuk, K. Tetrahedron Lett.
2001, 42, 5805–5807; (b) Steiner, D.; Sethofer, S. D.;
Goralski, C. T.; Singaram, B. Tetrahedron: Asymmetry
2002, 13, 1477–1483.
Tetrahedron Lett. 2000, 41, 4587; (e) Hanyu, N.; Aoki,
T.; Mino, T.; Sakamoto, M.; Fujita, T. Tetrahedron:
Asymmetry 2000, 11, 2971–2979; (f) Hanyu, N.; Aoki, T.;
Mino, T.; Sakamoto, M.; Fujita, T. Tetrahedron: Asym-
metry 2000, 11, 4127–4136; (g) Garc ´ı a Mart ´ı nez, A.; Teso
Vilar, E.; Garc ´ı a Fraile, A.; de la Moya Cereo, S.;
Mart ´ı nez-Ruiz, P.; Chicharro Villas, P. Tetrahedron:
12. Typical experimental procedure: To a solution of 2 (36
mg, 0.15 mmol) in toluene (2 mL) was added 2 M Et Zn
2

1
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S. N. Joshi, S. V. Malhotra / Tetrahedron: Asymmetry 14 (2003) 1763–1766
toluene solution (1.0 mL, 2 mmol) under argon at room
give the purified alcohols (yield 68%). The enantiomeric
excess and absolute configuration was determined from
the specific rotation of the purified product.
temperature. The reaction was allowed to stir for 30 min
at room temperature and then benzaldehyde (1 mmol) in
toluene (2 mL) was added to it over 2 min. The reaction
mixture turned yellow upon addition of aldehyde and was
allowed to stir at room temperature for 20 h. Reaction
was quenched with 2N HCl (4 mL), the organic layer
separated and aqueous layer extracted with diethyl ether
13. (a) Yamakawa, M.; Noyori, R. J. Am. Chem. Soc. 1995,
117, 6327–6335; (b) Yamakawa, M.; Noyori, R.
Organometallics 1999, 18, 128–133.
14. To study the effect of bulk of the N-alkyl substituent on
enantioselectivity, (1S,3R,4S,6R)-4-allylamino-3-caranol,
a chiral catalyst with less bulkier N-allyl group was
synthesized. When used as a chiral catalyst in the enan-
tioselective alkylation of benzaldehyde, (R)-1-phenyl-1-
propanol was obtained with 60% ee which is considerably
less for the same reaction with chiral catalyst 2 (ee 81%
with benzaldehyde).
(3×5 mL). The combined organic extracts were washed
with saturated sodium hydrogen carbonate (5 mL) fol-
lowed by water (5 mL) and finally brine (5 mL). Drying
over Na SO4 and evaporation under reduced pressure
2
yielded a crude alcohol, which was further purified by
flash column chromatography (acetone/pet ether 1:25) to