Chiral tertiary alcohols from a trans-1-arenesulfonyl-amino-2- isoborneolsulfonylaminocyclohexane-catalyzed addition of organozincs to ketones

Article abstract of DOI:10.1016/j.tetasy.2005.08.031

The catalytic enantioselective addition of different organozinc reagents, such as alkyl, or in situ generated aryl, allyl, alkenyl and alkynyl derivatives to simple aryl ketones, was accomplished using titanium tetraisopropoxide and chiral ligands derived from 1-arenesulfonylamino-2- isoborneolsulfonylamidocyclohexane, giving the corresponding tertiary alcohols with enantioselectivities up to ≥99%. A simple and efficient procedure for the synthesis of the disulfonamide ligands used is described.

Full text of DOI:10.1016/j.tetasy.2005.08.031

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3341–3344
Chiral tertiary alcohols from a trans-1-arenesulfonyl-amino-
2-isoborneolsulfonylaminocyclohexane-catalyzed
addition of organozincs to ketones
*
*
´
Vicente J. Forrat, Diego J. Ramon and Miguel Yus
Instituto de Sı´ntesis Orga´nica (ISO) and Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Alicante,
Apdo. 99, E-03080 Alicante, Spain
Received 23 August 2005;accepted 30 August 2005
Available online 29 September 2005
Dedicated to Professor Josep Castells on the occasion of his 80th birthday
Abstract—The catalytic enantioselective addition of different organozinc reagents, such as alkyl, or in situ generated aryl, allyl, alkenyl
and alkynyl derivatives to simple aryl ketones, was accomplished using titanium tetraisopropoxide and chiral ligands derived from
1-arenesulfonylamino-2-isoborneolsulfonylamidocyclohexane, giving the corresponding tertiary alcohols with enantioselectivities
up to >99%. A simple and efficient procedure for the synthesis of the disulfonamide ligands used is described.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
cationic titanium center bearing the chiral ligand12
favoring a possible p-staking effect between aryl moie-
ties, and showing a hydrogen bond between the a-pro-
ton of the ketone and the oxygen atom of the chiral
ligand.13
Nowadays the catalytic enantioselective generation of
compounds with stereogenic tertiary carbon atoms can
be easily achieved in most cases.1 However, the related
approach to compounds bearing quaternary stereocen-
ters is still an enormous challenge for synthetic organic
chemistry. Thus, every new enantioselective procedure
for the construction of a fully substituted carbon center
is of great value,2 the simplest approach for the prepara-
tion of chiral tertiary alcohols being the enantioselective
1,2-addition of organometallic reagents3 to ketones.4
Pri
OPri
OPri
OPri
OH
NH
O
O
Ti
Ti
S
S
N
O
Pri
O2
O2
H
R2
O
R1
H
Recently, we have introduced isoborneolsulfonamide5 1
as the first chiral ligand6 able to promote the catalytic
enantioselective addition of dialkylzinc reagents to sim-
ple ketones7 in the presence of titanium isopropoxide.8
Simple initial mechanistic studies suggested that the cat-
alytic cycle could be similar to that proposed for the
classical enantioselective addition of dialkylzinc reagents
to aldehydes,9 by only changing the corresponding elec-
trophile.10 The stereochemical outcome of the reaction
was rationalized by the formation of a catalytic bimetal-
lic11 species 2, in which the ketone was coordinated to a
Ar
1
2
The possible participation of a catalytic bimetallic spe-
cies 2 suggested the synthesis of chiral ligands 314 and
4 (HOCSAC)15 able to accommodate two titanium
atoms at the same time. In this way, the previous results
could be improved depending on the length and angles
between the isoborneolsulfonamide moieties;this con-
cept was also applicable to aldehydes.16 The ligand
HOCSAC gave the best enantiomeric excess (only one
enantiomer detected) for the alkylation of a,b-unsatu-
rated ketones, being used as the asymmetric key step
*
Corresponding authors. Tel.: +34 965 90 35 48;fax: +34 965 90 35
49;e-mail addresses: djramon@ua.es; yus@ua.es
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.031

3342
V. J. Forrat et al. / Tetrahedron: Asymmetry 16 (2005) 3341–3344
in the synthesis of (À)-frontalin.17 HOCSAC 4 is also an
excellent ligand for the arylation of ketones using boro-
nic acids as the starting nucleophile source.18
O
i, 4-X-C6H4SO2Cl (7)
CH2Cl2 / NaOH (2 M)
0 oC / 5 h
SO2
NH
NH2
NH2
S
NH
NH
HN
SO2
O2
6
SO2
ii,
OH
OH
3a: ortho
3b: meta
3c: para
O
SO2Cl
8
X
DMAP / Et3N
CH3CN
0 oC / 24 h
9a: X = Me (59 %)
9b: X = MeO (55 %)
S
NH HN SO2
O2
X
OH
HO
HOCSAC
4
NaBH4
O2S NH HN SO2
EtOH
0 oC / 24 h
Following our ongoing project on the development of
new chiral ligands based on isoborneolsulfonamide
structures, we herein report the first synthesis of chiral
trans-1-arenesulfonylamino-2-isoborneolsulfonylamino-
cyclohexane derivatives 5 and the preliminary results on
their use as chiral promoters in the catalytic enantiose-
lective addition of different zinc reagents to aryl ketones.
OH
5a (82 %)
5b (79 %)
Scheme 1.
Ti(OPri)4
(110 mol %)
R1 OH
O
2. Results and discussion
+ R22Zn
R1
R2
Ligand 5
(5 mol %)
PhMe / 25 oC
120 h
Chiral ligands 5 were prepared from the corresponding
chiral (1R,2R)-trans-1,2-diaminocyclohexane 6 by reac-
tion with the corresponding arenesulfonyl chloride 7 in
a biphasic media at 0 °C, followed by the standard cou-
pling reaction of the in situ prepared amine with
(1S)-(+)-10-camforsulfonyl chloride 8 to yield the
corresponding ketones 9 with good chemical yields.
These ketones were diastereoselectively reduced to the
expected tridentate ligands 5 with good chemical yields
and diastereoselectivities higher than 80% (Scheme 1).
The major diastereoisomer 5 was easily isolated in pure
form (>99%) by column chromatography.
12
10
11
Ligand 5a
Ligand 5b
R2
Et
Yield (%)
R1
Me
Et
R2
Et
R1
Me
Et
ee (%)
>99
Yield (%)
ee (%)
>99
55
25
65
29
>99
>99
Me
Me
Scheme 2.
Once ligands 5 were prepared, they were first tested in
the enantioselective addition of commercially available
dialkylzincs 11 to simple phenyl alkyl ketones, in the
presence of Ti(OPri)4. The reaction gave the expected
tertiary alcohols 12 after 5 days at room temperature
(Scheme 2). Although the reaction rate was slow, the
enantioselectivity was excellent for all the tested cases,
the minor enantiomer not being detected by chiral col-
umn GC analysis. The reaction using dimethylzinc 11a
as the initial source of the nucleophile gave a lower yield
than for diethylzinc 11b independent of the ligand used,
5a or 5b.
O
O
+
Pd(PPh3)4
+
Et2Zn
Ph
14
11b
13
Ligand 5
(5 mol %)
Ti(OPri)4
(110 mol %)
PhMe / 25 oC PhCOMe
48 h
(10a)
OH
OH
Ph
Ph
+
Ph
Ph
After the success was found for the enantioselective
alkylation of simple ketones, we turned our attention
to the zinc reagent. The first example studied was the
allylation process, which was accomplished by reaction
of cinnamyl acetate 13 with diethylzinc 11b catalyzed
by palladium(0)tetrakistriphenylphosphine to yield the
corresponding allyl zinc reagent (Scheme 3).19 The
syn-15
anti-15
32%, ee 12%
25%, ee 14%
5a
5b
32%, ee 26%
25%, ee 20%
Scheme 3.

V. J. Forrat et al. / Tetrahedron: Asymmetry 16 (2005) 3341–3344
3343
Ti(OPri)4
(10 mol %)
O
Ph
H
OH
O
+
Et2Zn +
+
+
Et2Zn
BPh3
Ph
Ligand 5
(5 mol %)
PhMe / 25 oC
Br
Ph
16
Ph
17
11b
10a
10c
20
11b
5a
5b
77%, ee 20%
19%, ee 36%
48 h
96 h
Ligand 5
(5 mol %)
PhMe / 25 oC
Ti(OPri)4
(110 mol %)
Scheme 4.
in situ formed cinnamyl zinc derivative was trapped by
reaction with acetophenone 10a in the presence of tita-
nium tetraisopropoxide to yield, after hydrolysis with
an aqueous saturated solution of ammonium chloride,
equimolar amounts of both diastereoisomers 15.20 The
ee values were poor and similarly independent of ligand
5 used.
OH
Ph
Br
21
5a 120 h 90%, ee >99%
5b 24 h 96%, ee >99%
The next process studied was the alkynylation process
performed by deprotonation of phenylacetylene 16 to
yield the corresponding alkynyl zinc reagent, which
was trapped by reaction with acetophenone 10a in the
presence of substoichiometric amounts of chiral ligand
5 and titanium tetraisopropoxide21 to yield the propar-
gylic alcohol 17 (Scheme 4). Although the results
obtained are modest, they show that typical transmetal-
lation processes can be used in the addition of ketones
just by a fine tuning of the ligand choice.
Scheme 6.
diate was obtained starting from commercially available
triphenylboron 20 by transmetallation with dimethyl-
zinc 11b by heating in toluene at 70 °C.23 This interme-
diate was reacted in situ with para-bromoacetophenone
10c in the presence of substoichiometric amounts of
ligands 5 and a small excess of titanium tetraisopropox-
ide giving the expected diaryl ethanol derivative 21 with
excellent enantioselectivities. The minor enantiomer was
not detected by chiral column HPLC analysis. Surpris-
ingly, the reaction rate seemed to be quite different for
both chiral ligands, with 5b catalyzing the enantioselec-
tive more efficiently. We currently do not have any
explanation for this behavior (Scheme 6).
The alkenylation process was far more successful. The
hydrozirconation of phenylacetylene to yield the corre-
sponding terminal alkenylzirconium derivative followed
by transmetallation with dimethylzinc 11a gave the
expected alkenylzinc reagent,22 which was trapped as
above by the reaction with acetophenone in the presence
of an excess of titanium tetraisopropoxide and substoi-
chiometric amounts of chiral ligands 5 (Scheme 5), both
ligands rendering similar results.
3. Conclusion
In conclusion, we have described herein an easy and
simple synthesis of different chiral trans-1-arenesulfonyl-
amino-2-isoborneolsulfonylaminocyclohexane deriva-
tives, which permits the highly modular preparation of
this type of compound. These ligands have shown to
be excellent promoters for the catalytic enantioselective
alkylation and arylation of ketones (only one enantio-
mer being detected), very good for the alkenylation pro-
cess and modest for the allylation and alkynylation
reactions. This strategy sheds light on the possibility of
using any known transmetallation process to obtain
in situ the starting zinc derivatives for this unusual addi-
tion to ketones. Work is currently in progress in order to
the fine tune the properties of the chiral ligands by
changes on the substitution of the arenesulfonyl moiety
and improving the results for the allylation and alkynyl-
ation reactions.
We finally studied the catalytic enantioselective aryla-
tion of ketones. The corresponding phenyl zinc interme-
H
+
Me2Zn
+
Cp2ZrHCl
Ph
11a
16
18
Ligand 5
Ti(OPri)4
(5 mol %)
(110 mol %)
PhMe / 25 oC PhCOMe
72 h
(10a)
OH
Ph
Ph
19
Acknowledgements
5a 85%, ee 76%
5b 77%, ee 78%
This work was generously supported by the current
Scheme 5.
Spanish Ministerio de Educacion y Ciencia (project
´

3344
V. J. Forrat et al. / Tetrahedron: Asymmetry 16 (2005) 3341–3344
(e) Wu, K.-H.;Gau, H.-M. Organometallics 2004, 23, 580–
588.
CTQ2004-01261), the Generalitat Valenciana (projects
GV05/157 and CTIDB/2002/318) and University of
Alicante (UA). V.J.F. thanks the UA for a fellowship.
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11. For a review, see: Ma, J.-A.;Cahard, D. Angew. Chem.,
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