Highly enantioselective addition of dialkylzinc reagents to ketones promoted by titanium tetraisopropoxide

Article abstract of DOI:10.1016/S0957-4166(02)00572-4

The preparation of several 1,2-bis(hydroxycamphorsulfonamido)cyclohexenes from the corresponding 1,2-cyclohexenediamine and camphorsulfonyl chloride is described. The use of these ligands to promote the enantioselective addition of dialkylzinc to ketones

Full text of DOI:10.1016/S0957-4166(02)00572-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2291–2293
Highly enantioselective addition of dialkylzinc reagents to
ketones promoted by titanium tetraisopropoxide
Miguel Yus,* Diego J. Ramo´n and Oscar Prieto
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, E-03080 Alicante, Spain
Received 11 September 2002; accepted 12 September 2002
Abstract—The preparation of several 1,2-bis(hydroxycamphorsulfonamido)cyclohexenes from the corresponding 1,2-cyclohexene-
diamine and camphorsulfonyl chloride is described. The use of these ligands to promote the enantioselective addition of
dialkylzinc to ketones in the presence of titanium tetraisopropoxide gives the expected tertiary alcohols with very high
enantiomeric excess (>99%). © 2002 Elsevier Science Ltd. All rights reserved.
The synthesis of chiral building blocks containing a
stereogenic quaternary carbon centre is a considerable
challenge in organic synthesis.1 The simplest approach to
the construction of the corresponding heteroatom-substi-
tuted quaternary carbon stereocentres is the enantioselec-
tive addition of organometallic reagents to carbonylic
derivatives.2 Among other organometallics, dialkylzinc
Investigation into the use of hydroxysulfonamides as
reagents are ideal alkyl nucleophile synthons since it is
chiral ligands in the enantioselective addition of dialkyl-
very easy to obtain many different functionalised
reagents.3 However, their low reactivity towards elec-
trophilic compounds represents a significant drawback.
This drawback has been transformed into an advantage
by the use of several promoters in order to perform
different types of additions: A plethora of chiral ligands
has been used in the enantioselective addition of dialkyl-
zinc to aldehydes,4 this reaction being the typical reaction
to prove the efficiency of different type of ligands.
zinc reagents to aldehydes promoted by titanium
tetraalkoxides9 has been an ongoing concern in our
laboratory for some time.10 We have reported the first
sulfonamide-type chiral ligand 2, which is able to pro-
mote the enantioselective addition of dialkylzinc reagents
to ketones in the presence of titanium tetraisopropoxide.8
A further evolution of this ligand was introduced by the
use of different C2-symmetric derivatives, the bis sulfon-
amide 3 being the best among the corresponding C2-sym-
metric ligands, giving better enantioselection under
milder conditions than ligand 2.11
On the other hand, the reaction of dialkylzinc reagents
with ketones does not yield the addition product (tert-
alcohol),5 giving instead the corresponding secondary
alcohol, arising from a reduction process.6 Only very
recently, have the first examples of chiral ligands that
enable the addition of organozinc reagents to ketones
been described independently and simultaneously.7,8
The addition of diphenylzinc to phenones has been
reported, using a mixture of aminoalcohol 1 and
methanol as promoter. The success of the addition was
ascribed to the higher reactivity of the zinc reagent, as
well as the higher acidic character of the system due to
the presence of methoxy groups.7
* Corresponding author. Tel.: +34-965 903548; fax: +34-965 903549;
e-mail: yus@ua.es
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00572-4

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M. Yus et al. / Tetrahedron: Asymmetry 13 (2002) 2291–2293
After being informed of the preliminary results
obtained by Walsh using the ligand 4a, we report herein
our independent work with ligands 4a–c in the enan-
tioselective addition of dialkylzinc reagents to ketones
promoted by titanium tetraisopropoxide.12
sponding tert-alcohol was obtained in both poor yield
as well as enantiomeric excess (compare entries 1–3).
Having established that ligand 4a was the appropriate
system, the influence of different ketones, as well as
dialkylzinc reagent, on the enantioselection was studied
(Table 1, entries 4–10). The first observation is that the
enantioselectivity of the reaction is not influenced by
the alkylzinc reagent used. Thus, the same level of
enantioselectivity was obtained using dimethylzinc
instead of diethylzinc (compare entries 1 and 4).
The synthesis of ligands 4 was performed by reaction of
the corresponding commercially available 1,2-cyclohex-
anediamines and chiral camphorsulfonyl chloride to
give the expected 1,2-bis(camphorsulfonamido)-cyclo-
hexane,13 which were subsequently reduced using
DIBAL-H to give a mixture from which it was easy to
isolate the expected ligands 4a, b and c in 58, 55 and
46% yield, respectively.
The influence of different para-substituted acetophe-
none derivatives on the enantioselectivity was also stud-
ied. Thus, we used 4-methylacetophenone and 4-(trifl-
uoromethyl)acetophenone as electrophiles. The enan-
tiomeric excess found in these cases was similar to that
found for acetophenone (compare entries 1, 5 and 6).
We can conclude that there is no relationship between
the enantiomeric excess found and the electronic char-
acter of the group placed at the para-position.
Once ligands 4 were prepared, the next aim was to find
the best one for the enantioselective addition of
diethylzinc to acetophenone in the presence of titanium
tetraisopropoxide to give the expected tert-alcohol (see
Table 1). The reaction using 10% of chiral ligand 4a at
room temperature in toluene gave, after only 8 h, the
expected 1-phenyl-2-butanol with an excellent enan-
tiomeric excess. However, when the ligands 4b or c were
used under the same reaction conditions, the corre-
It is interesting to note that the reaction using a more
Table 1.
Ketone
tert-Alcohol
Entry
R1
R2
R3
Ligand
t (h)
Yield (%)a
E.e.b
Absolute configuration
1
2
3
4
5
6
7
8
9
Me
Me
Me
Et
Me
Me
Me
BrCH2
Me
Me
Ph
Ph
Ph
Ph
Et
Et
Et
Me
Et
Et
Et
Et
Et
Et
4a
4b
4c
4a
4a
4a
4a
4a
4a
4a
8
120
72
8
8
8
8
0.2
8
8
80
20c
98
36
24
97.5
95
93
86
50
\99
\99
S
R
R
R
–
–
–
S
–
–
16d
\95
90
4-MeC6H4
4-CF3C6H4
2-C10H8
Ph
(E)-PhCHꢀCH
PhCꢁC
90
\95
70
90
\95
10
a Isolated yields after bulb-to-bulb distillation.
b Determined by GLC analysis using a g-CD column.
c Starting ketone was recovered in 8% yield.
d Starting ketone was recovered in 40% yield.

M. Yus et al. / Tetrahedron: Asymmetry 13 (2002) 2291–2293
2293
crowded ketone such as 2-acetylnaphthalene gave sig-
nificantly lower enantioselectivity (entry 7). However, in
the case of using a ketone with a chelating functionality
close to the carbonyl group, such as 2-bromoacetophe-
none, the enantiomeric excess fell to 50%, the reaction
time being only 15 min (entry 8).
F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; pp.
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Finally, when the addition was performed using a,b-
unsaturated ketones, the enantioselection was higher
than 99%, the minor of the enantiomers being unde-
tectable by chiral GLC analysis.
In summary, we can conclude that trans-1,2-bis-
(hydroxy-camphorsulfonamide)cyclohexane 4a is an
extraordinary ligand for promotion of the enantioselec-
tive addition of dialkylzinc reagents to ketones in the
presence of titanium tetraisopropoxide. In most cases,
the otherwise difficult to obtain tert-alcohol was
formed in good chemical yields and with excellent levels
of enantioselection.
5. (a) Watanabe, M.; Soai, K. J. Chem. Soc., Perkin Trans.
1 1994, 3125–3128; (b) Noyori, R.; Suga, S.; Kawai, K.;
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In Comprehensive Organometallic Chemistry; Wilkinson,
G., Ed.; Pergamon Press: Oxford, 1982; Vol. 2, pp.
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C.R. Acad. Sci., Ser. C 1967, 264, 527–530; (d) Coates,
G. E.; Ridley, D. J. Chem. Soc. (A) 1966, 1064–1069.
7. Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120,
445–446.
The scope and the mechanism of catalytic species
described herein is currently under further
investigation.
8. (a) Ramo´n, D. J.; Yus, M. Tetrahedron 1998, 54, 5651–
5666; (b) Ramo´n, D. J.; Yus, M. Tetrahedron Lett. 1998,
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Acknowledgements
9. For a review on enantioselective reactions promoted by
titanium derivatives, see: Ramo´n, D. J.; Yus, M. Recent
Res. Devel. Org. Chem. 1998, 2, 498–523.
10. (a) Ramo´n, D. J.; Yus, M. Tetrahedron: Asymmetry 1997,
8, 2479–2496; (b) Prieto, O.; Ramo´n, D. J.; Yus, M.
Tetrahedron: Asymmetry 2000, 11, 1629–1644; (c) Yus,
M.; Ramo´n, D. J.; Prieto, O. Tetrahedron: Asymmetry
2002, 13, 1573–1579.
This work was financially supported by the DGICYT
(Project PB97-0133) and DGI (Project BQU2001-0538)
from the Spanish Ministerio de Educacio´n, Cultura y
Deporte.
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