Synthesis of new C2-symmetrical bis(hydroxycamphorsulfonamide) ligands and their application in the enantioselective addition of dialkylzinc reagents to aldehydes and ketones

Article abstract of DOI:10.1016/S0957-4166(03)00045-4

The preparation of several C₂-symmetric disulfonamides derived from chiral camphorsulfonyl chloride and different diamines (with or without stereogenic elements) is described. Their use in the titanium tetraisopropoxide-promoted enantioselective addition of dialkylzinc reagents to aldehydes has been tested, the best enantiomeric excess being up to 76%. Moreover, the unusual addition of dialkylzinc reagents to ketones can also be achieved with excellent enantioselectivity (up to 92% e.e.) using this type of ligand. When using para-substituted phenones as electrophiles, the enantiomeric excess of the resulting tert-alcohol is independent of the electronic properties of the group attached to the aromatic ring of the phenone. In the case of using more hindered ketones the enantioselectivity is lower, so indicating a steric influence in the reaction.

Full text of DOI:10.1016/S0957-4166(03)00045-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1103–1114
Synthesis of new C2-symmetrical
bis(hydroxycamphorsulfonamide) ligands and their application in
the enantioselective addition of dialkylzinc reagents to aldehydes
and ketones
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 9 December 2002; revised 24 December 2002; accepted 9 January 2003
This paper is warmly dedicated to Professor Dr. Gerard van Koten on the occasion of his 60th birthday
Abstract—The preparation of several C2-symmetric disulfonamides derived from chiral camphorsulfonyl chloride and different
diamines (with or without stereogenic elements) is described. Their use in the titanium tetraisopropoxide-promoted enantioselec-
tive addition of dialkylzinc reagents to aldehydes has been tested, the best enantiomeric excess being up to 76%. Moreover, the
unusual addition of dialkylzinc reagents to ketones can also be achieved with excellent enantioselectivity (up to 92% e.e.) using
this type of ligand. When using para-substituted phenones as electrophiles, the enantiomeric excess of the resulting tert-alcohol
is independent of the electronic properties of the group attached to the aromatic ring of the phenone. In the case of using more
hindered ketones the enantioselectivity is lower, so indicating a steric influence in the reaction. © 2003 Elsevier Science Ltd. All
rights reserved.
1. Intoduction
substituted quaternary carbon stereocenters may be
obtained by different methods such as enantioselective
epoxidation,4 dihydroxylation,5 desymmetrization of
meso-compounds,6 bacterial hydrolysis,7 as well as the
use of a-functionalised configurationally stable8
organolithium compounds.9 The construction of qua-
ternary stereogenic centers that allows the connection
of two simple synthons by formation of one or more
carbonꢀcarbon bonds is strategically the most desirable
option, since this generally maximises the overall
efficiency of the reaction sequence required for the
construction of the molecular framework. In addition,
the enantioselective 1,2-addition of organometallic
reagents to carbonylic derivatives is probably the most
straightforward and useful method for achieving this
goal.10 Among non-stabilised organometallic com-
pounds,11,12 dialkylzinc reagents13 are ideal alkyl nucleo-
phile synthons as it is possible to prepare many differ-
ent functionalised organometallic reagents due to their
low reactivity. At the same time, this is also a draw-
back, since they do not react with simple carbonyl
compounds. This has been turned into an advantage by
the development of several promoters to allow different
types of addition processes. Thus, a plethora of chiral
The invention and development of new methods for the
synthesis of complex molecules of both natural and
unnatural origin remains an enduring challenge in
organic chemistry. Over the past decades one of the
major efforts in this arena has been directed towards
the controlled enantioselective construction of open
chain systems with different stereogenic centers or ele-
ments.1 Among methods for the generation of different
stereogenic elements of a molecule, the synthesis of
chiral building blocks containing a quaternary stereo-
genic carbon center2 is a considerable challenge within
organic synthesis, mainly as a result of steric factors.
Biocatalytic approaches to the synthesis of such chiral
building blocks are limited and, for example, the kinetic
resolution of carboxylic esters containing fully substi-
tuted stereogenic carbon centers with proteases and
carboxyl estereases is generally impeded by steric repul-
sion, being feasible only in special cases.3 Heteroatom-
* Corresponding author. Tel.: +34-965-903548; fax: +34-965-903549;
e-mail: yus@ua.es
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00045-4

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M. Yus et al. / Tetrahedron: Asymmetry 14 (2003) 1103–1114
two alkyl moieties.24 In both cases, the two metal atoms
are bonded by bridging-alkoxides. For ketones,19a we
assumed a catalytic cycle and catalytic species similar to
those reported for aldehydes (dititanium species). Since
the non-linear effect was not observed when an excess
of titanium isopropoxide was used, and the enantiose-
lectivity was independent of chemical yield (no autoin-
duction effect was detected), as well as the fact that the
enantioselectivity found when methyltitanium triisopro-
poxide was used as the source of the nucleophile was
zero. This fact indicates that the uncatalysed reaction is
very fast and the role of the dialkylzinc reagent is to
transfer the alkyl moiety to the titanium center, thereby
keeping its concentration very low.19a All these facts
were previously outlined for the nucleophilic alkylation
of aldehydes.22 A similar synergistic effect occurring in
the proximal metal centers has already been described
for different reactions.25 Usually, one metal center acts
to activate the carbonyl derivative (acidic center) while
the other metal center activates the nucleophile for
attack.26 However, the possibility of forming a double
coordination complex between the carbonyl compound
and both acidic metal centers cannot be ruled out.25f,27
With these factors in mind, we report herein the synthe-
sis of different C2-symmetrical ligands28 bearing two
camphorsulfonamide29 or hydroxycamphorsulfonamide
moieties30 connected by different diamines with or with-
out stereogenic elements, and their use in the enantiose-
lective addition of dialkylzinc reagents to aldehydes
and, more interestingly and unusually, to ketones.31
Where we hoped that the chiral ligand would force the
binuclear metal complex into a more rigid and determi-
nate form, with both metallic centers in closer proxim-
ity, thus improving the enantioselectivity of the
reaction.
Figure 1. Chiral promoters for the addition of dialkylzinc
reagents to ketones.
ligands has been introduced to carry out the enantiose-
lective addition to aldehydes.14 However, dialkylzinc
reagents do not add to ketones, even at high tempera-
tures, yielding only products arising from the reduction
of ketones.15 The lack of reactivity in the addition of
dialkylzinc reagents to ketones has been used in the
chemo- and enantioselective addition to keto-aldehyde
derivatives promoted by a,b-amino alcohols.16 Only
very recently, the enantioselective addition of
diphenylzinc to phenones using the amino alcohol 1
(Fig. 1) as a ligand has been reported.17 In addition,
simultaneously and independently we introduced
hydroxycamphorsulfonamide derivatives 218 as chiral
ligands for the enantioselective addition of dialkylzinc
reagents to ketones19 in the presence of titanium tetra-
isopropoxide.20 The enantioselective addition of
diethylzinc to acetophenone under similar conditions
using other common chiral ligands such as TADDol,
binaphthol, 1,2-bistriflamidocyclohexane, as well as 1,2-
hydroxysulfonamide derivatives failed.19a Therefore, the
study of this type of addition using any structure
derived from 2 is of great interest. In the particular case
of the enantioselective addition of dialkylzinc reagents
to aldehydes promoted by chiral amino alcohols, a
general mechanism, involving a dimetallic aggregate as
the catalytic species, has been widely accepted.21 In the
case of the related addition using titanium tetra-
alkoxides, neither the catalytic cycle nor the catalytic
species is clearly defined. There are two possible struc-
tures for the catalyst, both being dimetallics (see Fig.
2): (a) An aggregate with two titanium atoms, one of
them bearing the chiral ligand and the other bearing the
alkyl group,22 in this case the catalytic species seems to
be a pentacoordinate positively charged titanium center
and a octahedral hexacoordinate negatively charged
titanium center;23 and (b) an aggregate with a titanium
atom bearing the chiral ligand and a zinc atom bearing
2. Results and discussion
2.1. Synthesis of chiral disulfonamide ligands
Disulfonamide ligands 5 were easily prepared from the
corresponding commercially available (+)-10-camphor-
sulfonyl chloride 3 by reaction with the corresponding
xylylenediamine (or xylylenediammonium dichloride32)
4 in the presence of triethylamine and a substoichiomet-
ric amount of 4-(dimethylamino)pyridine (DMPA) at
0°C giving, after basic work-up, the expected disulfon-
amides 5 in excellent yields (Scheme 1). In a similar
manner (Fig. 3), the reaction of (+)-2,2%-diamino-1,1%-
binaphthyl with the corresponding enantiomer of cam-
phorsulfonyl chloride (3 or ent-3) or methanesulfonyl
chloride gave the corresponding disulfonamides 6, 7
and 8,33 respectively, in low yield (25, 29 and 32%,
respectively). The subsequent reduction of diketones
5–7 using an excess of diisobutylaluminium hydride
gave the expected tetradentate hydroxycamphorsulfon-
amide ligands as a mixture of all possible exo/endo
isomers. In all cases, the main product was the corre-
sponding exo/exo diastereoisomer 9–11, which was eas-
ily isolated by flash column chromatography (see Fig. 4
and Table 1). In some cases, the second most abundant
diastereoisomer exo/endo could also be isolated (12 and
Figure 2. Postulated dimetallic catalytic species in the enan-
tioselective addition of diethylzinc to aldehydes in the pres-
ence of titanium tetraisopropoxide.

M. Yus et al. / Tetrahedron: Asymmetry 14 (2003) 1103–1114
1105
order to establish whether this low enantiomeric excess
was a consequence of a mismatched pair of chiral
elements,34 the same reaction was performed with the
diastereomeric ketone 7, again obtaining a racemic
mixture of the secondary alcohol 14a (Table 2, entry 5).
Moreover, when the reaction was carried out using
ligand 8, where the only chiral element is due to the
binaphthyl moiety, a racemic mixture was also obtained
(Table 2, entry 6). These results may be interpreted
considering that the steric hindrance in the catalytic
specie is quite different using xylyl derivatives 5 or
binaphthyl derivatives 6–8. In the case of using bis(hy-
droxycamphorsulfonamide) ligands 9, the obtained
results depend on the relative position of the hydroxy-
camphorsulfonamide moieties: While the enantioselec-
tivity for 1,3-35 (9b) and 1,4- (9c) derivatives was the
same, the enantiomeric ratio for the 1,2-isomer (9a)
decreased. This may be attributed to steric interaction
between both metals attached to each hydroxycam-
phorsulfonamide moiety (Table 2, entries 7–9). Surpris-
ingly, when the reaction was performed using the chiral
ligand 12, which contains a hydroxy group in the endo
position and the relative position of both hydroxycam-
phorsulfonamide moieties is meta, the enantiomeric
Scheme 1. Reagents and conditions: i, DMAP (0.2 equiv.),
MeCN, 0°C, 24 h. ii, NaOH (3 M); then 1 M HCl.
Figure 3. Chiral ligands derived from (+)-2,2%-diamino-1,1%-
binaphthyl.
13). However, all attempts to purify the corresponding
minor endo/endo diastereoisomer failed.
2.2. Enantioselective addition of diethylzinc to
aldehydes
Once ligands 5 and 9–13 were prepared, they were
tested in the standard enantioselective addition of
diethylzinc to benzaldehyde, in the presence of titanium
tetraisopropoxide and using 10 mol% of the corre-
sponding chiral ligand (see Scheme 2 and Table 2,
entries 1–15). The reaction using diketones 5 as chiral
ligands gave in all cases modest enantioselectivity under
the conditions assayed, irrespective of the relative posi-
tion of the camphorsulfonyl moiety in the benzene ring
(Table 2, entries 1–3). When the reaction was per-
formed using the binaphthylamine derivative 6 the
enantiomeric excess decreased, so near-racemic sec-
ondary alcohol 14a was isolated (Table 2, entry 4). In
Figure 4. Chiral tetradentate ligands.

1106
M. Yus et al. / Tetrahedron: Asymmetry 14 (2003) 1103–1114
Table 1. Synthesis of tetradentate ligands 9–13 by reduction
Entry
Starting diketone
Diastereomeric ratioa
Ligand
Yield (%)b
exo/exo
exo/endo
endo/endo
No.
1
2
3
4
5
6
7
5a
5b
90
95
7
4
3
1
9a
9b
12
9c
10
11
13
76c
72
5
58
50
56
4
5c
6
7
85
85
95
10
10
4
5
5
1
a Determined by 1H NMR (300 MHz) of the crude mixture.
b Isolated yield after flash column chromatography based on starting diketone.
c Isolated yield after recrystallization from CHCl3.
3). When the ortho-xylylenediamine derivative 9a was
used as promoter in the previously mentioned addition,
the starting acetophenone was consumed after 3 days at
room temperature. Although the enantiomeric excess
obtained was promising (Table 3, entry 1), the yield of
the expected alcohol 15 was modest36 due to other
side-reactions of the starting ketone but not to any
process which involves decomposition of the formed
tert-alcoholate. In fact, the tert-alcoholate is stable
under the reaction conditions for 1 week. When the
same reaction was performed using the corresponding
meta-derivative 9b, the yield increased in a shorter
reaction time, as well as the enantiomeric excess (Table
3, entry 2). However, when the most remote para-
derivative 9c was used, both the chemical yield and
enantioselectivity decreased again (Table 3, entry 5). In
the case of the binaphthyl derivative 11, the reaction
was slower and after 10 days the chemical yield was
miserable, the enantioselectivity being similar to that
obtained with ligand 9b (compare entries 1, 2, 5 and 6
in Table 3). These results show that ligand 9b is the best
promoter.35 It must be pointed out that the absolute
configuration of the tert-alcohol 15 can be correlated
with the starting camphorsulfonyl chloride used. Thus,
Scheme 2. Reagents and conditions: i, chiral ligand 9–13
(10%), PhMe. ii, MeOH; then saturated NH4Cl.
ratio obtained was the same as for ligand 9c (both
hydroxy groups are exo). Previously, we reported that
the relative position of the hydroxy group is crucial in
order to induce good enantioselectivity, the enantiose-
lection with ligands of the type endo-2 was nearly
zero.18 The enantiomeric excesses obtained using
binaphthyl derivatives 10 and 11 as chiral ligands were
lower than those obtained with the corresponding xylyl
derivatives 9 (Table 2, entries 11–14), a change in the
temperature having no effect on the enantioselectivity.
When the reaction was performed using chiral ligand 13
(one of the hydroxy groups is placed in the endo-posi-
tion), benzyl alcohol was the only reaction product
isolated (94% yield). Finally, different aldehydes were
submitted to the aforementioned enantioselective addi-
tion using the best chiral ligand 9b. In all cases tested,
the enantioselectivity was lower than for benzaldehyde
(Table 2, compare entries 8 and 16–18).
when the starting chloride is the
D
-(+)-10-camphorsul-
fonyl derivative, as in the cases of ligands 9 and 12, the
main enantiomer is S. Meanwhile, when the starting
chloride is the opposite enantiomer, as for ligands 11
and ent-2b, the tert-alcohol 15 presents R configura-
tion. In order to improve either the yield or the enan-
tioselectivity, other reaction conditions, including
temperature as well as the use of deprotonating bases,37
were tested. However, in all cases the yield was lower
but the enantiomeric excess of the alcohol 15 was
similar (Table 3, entries 3 and 4). On the other hand,
the reaction promoted by the tetradentate C1-symmetric
ligand 12 was slower than that promoted by the related
C2-system 9b, giving both lower chemical yield and
enantioselectivity (Table 3, compare entries 2 and 7). In
ligand 12, one of the hydroxy groups is placed at the
exo-position (yielding high enantioselectivity) and the
other hydroxy group is placed at the endo-position (low
enantioselectivity), which could explain these poor
results. To study a possible synergistic effect, the same
reaction was carried out using a 1:1 mixture of
exo:endo ligand ent-2b (Table 3, entry 8). As result,
there is the same amount of chiral grouping in the
2.3. Enantioselective addition of dialkylzinc to ketones
The enantioselective addition of dialkylzinc reagents to
ketones is a considerable challenge and only chiral
ligands of the type 2 are known to promote this pro-
cess. We anticipated that the use of dimetallic chelating
ligands may lead to better enantioselectivity or
improved reaction conditions, since the proximity and
the spatial order around both metal centers could be
controlled by the ligand. Therefore, we tested different
chiral tetradentate C2-symmetric ligands, as well as the
corresponding related C1-symmetric systems, in the
enantioselective addition of diethylzinc to acetophenone
to give the corresponding tert-alcohol 15, using in all
cases 10 mol% of the chiral ligand (Scheme 3 and Table

M. Yus et al. / Tetrahedron: Asymmetry 14 (2003) 1103–1114
Table 2. Enantioselective addition of diethylzinc to aldehydes
1107
Entry
R
Ligand
Temp. (°C)
Time (h)
sec-Alcohol
No.
Yield (%)a
e.e.b,c
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5a
5b
5c
6
7
8
9a
9b
9c
12
10
10
11
11
13
9b
9b
9b
−20
−20
−20
−20
−20
−20
25
25
25
25
0
25
−20
25
25
25
16
16
16
16
16
16
3
3
3
3
3
3
72
3
48
16
16
16
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14b
14c
14d
\95
\95
\95
\95
\95
\95
\95
\95
\95
\95
\95
\95
60c
40d
38d
36d
6d
2d
2d
50
76
74
74
30
9
10
11
12
13
14
15
16
17
18
26
20d
95
40d
0e
–
f
Ph(CH2)2
80g
50h
i
–
25
25
65j
32h,k
26h,k
PhCꢁC
52l
a Isolated yield after bulb-to-bulb distillation.
b Determined by GLC using a b-CD column.
c Absolute configuration: S.
d Absolute configuration: R.
e The starting aldehyde was recovered in 30% yield.
f The only product isolated was benzyl alcohol.
g The starting aldehyde was recovered in 15% yield.
h Determined as the corresponding trifluoroacetate by GLC using a g-CD column (see Ref. 30).
i R=(E)-PhCHꢂCH.
j The starting aldehyde was recovered in 10% yield.
k Determined after being transformed into compound 14b by hydrogenolysis under Pd/C catalysis (see Ref. 30).
l The starting aldehyde was recovered in 5% yield.
The reaction took longer when dimethylzinc was used
as the nucleophile source instead of diethylzinc, but the
enantiomeric ratio was the same in both cases (Table 3,
entry 2 and Table 4, entry 1). If we suppose a similar
catalytic cycle is in operation for the enantioselective
addition of dialkylzinc reagents to ketones19a as that
reported for aldehydes,22 the relationship between the
product enantiomeric ratio and the electronic character
of the group at the para position of the phenone ring
could enlighten us about the rate-determining step. In
the standard case of enantioselective addition of
diethylzinc to different aromatic aldehydes, the plot of
log(enantiomeric ratio) versus Hammett | values38 pre-
sents three types of tangents: (a) a positive tangent39
(the greater the electron-withdrawing group character,
the higher the enantiomeric ratio); (b) a negative tan-
gent,40 in both cases the rate-determining step is inter-
preted to be transfer of the alkyl group to the
carbonylic moiety; and (c) the tangent is zero, so in this
case the rate-determining step is believed to be the
removal of the final alkoxide from the catalytic spe-
cies.24 Moreover, when there is a relationship between
the enantiomeric ratio and the basic character of group
at the para position18 (instead of its electronic charac-
ter), the rate-determining step seems to be the complex-
ation between the titanium catalytic species and the
carbonyl moiety, because the basic group attached to
the aldehyde competes with the carbonyl group in the
Scheme 3. Reagents and conditions: i, chiral ligand 9, 11, 12
or ent-2b (10%), PhMe. ii, MeOH; then saturated NH4Cl.
reaction, but the chiral elements are not linked together
covalently. For a better comparison of results for sys-
tems 12 and ent-2b, the reaction was quenched at the
same chemical yield so as to get the same influence of
the chiral tert-alcoholate product over the reaction.19a
Although, the enantiomeric excess of the alcohol 15
was the same for both systems (compare entries 7 and
8 in Table 3), the reaction with ligand ent-2b was
slower than that for system 12. Apparently, there is
only a slight synergistic effect using ligand 12, account-
able for the chemical yield. However, this effect is
higher and is reflected in both the yield and the enan-
tioselectivity when the results using ligand 9b are com-
pared with those previously reported for ligands of the
type 2.19a Once the enantioselective addition of
diethylzinc to acetophenone was optimised, other
ketones and dialkylzinc reagents were submitted to the
same reaction using chiral ligand 9b in order to obtain
the expected tertiary alcohols (Scheme 4 and Table 4).

1108
M. Yus et al. / Tetrahedron: Asymmetry 14 (2003) 1103–1114
Table 3. Enantioselective addition of diethylzinc to acetophenone promoted by titanium tetraisopropoxide
Entry
Ligand
Time (days)
Temp. (°C)
tert-Alcohol 15
e.e. (S)b
Yield (%)a
1
2
3
4
5
6
7
8
9a
9b
3
2
10
10
2
10
3
4
25
25
0
45
78
86
81
78
76
82f
70
68f
75
9b
35c
9bd
9c
0
5e
25
25
25
25
60
11
15c
45g
45i
12
ent-2bh
a Isolated yield after bulb-to-bulb distillation.
b Determined by GLC using b-CD column.
c The starting ketone was recovered in 60% yield.
d CaH2 was used as base to deprotonate the chiral ligand.
e The starting ketone was recovered in 90% yield.
f Absolute configuration: R.
g The starting ketone was recovered in 20% yield.
h A 1:1 mixture of exo:endo alcohol ent-2b was used as chiral ligand (20% total amount).
i The starting ketone was recovered in 10% yield.
Scheme 4. Reagents and conditions: i, PhMe, 25°C. ii, MeOH; then saturated NH4Cl.
basicity of the organotitanium derivative formed in
situ, which may deprotonate the starting ketone, thus
preventing the addition process.41 The reaction with a
ketone containing a large aromatic moiety, such as
2-acetylnaphthalene, gave lower enantiomeric excess
than that with simple phenyl ketones (Table 4, entry 6),
indicating that the catalyst is sensitive to steric hin-
drance effects. The enantioselectivity found when the
reaction was performed using an alkenylketone deriva-
tive gave similar results to the corresponding phenones
(Table 4, entry 7). However, for a more conformation-
ally restricted alkynylketone derivative, the enan-
tiomeric excess was zero (Table 4, entry 8). It must be
pointed out that when a heteroaromatic ketone deriva-
tive was used, such as 2-acetylthiophene, the enan-
aforementioned complexation. In the case presented
herein, the enantiomeric excess found for an electron-
donating (methyl; Table 4, entry 2), neutral (hydrogen,
Table 3, entry 2) and an electron-withdrawing group
(trifluoromethyl; Table 4, entry 3) was the same within
experimental error, which may be interpreted by con-
sidering that the rate-determining step is removal of the
final tert-alkoxide from the catalytic titanium species.
The presence of a bromine atom at the a-position to the
carbonylic center in the ketone derivative changed nei-
ther the enantiomeric excess nor the yield (Table 4,
entry 4). However, the use of a cyclic phenone, such as
a-tetralone, led to decreased yield and enantiomeric
ratio, giving nearly racemic product 19 (Table 4, entry
5). This unusually low yield may be attributed to the

M. Yus et al. / Tetrahedron: Asymmetry 14 (2003) 1103–1114
1109
Table 4. Enantioselective addition of dialkylzinc reagents to ketones promoted by titanium tetraisopropoxide
Entry
Ketone
R3
Time (days)
tert-Alcohol
No.
Yield (%)a
e.e.b
1
2
3
4
5
6
7
8
9
PhCOEt
Me
Et
Et
Et
Et
Et
Et
Et
Et
3
2
2
2
6
2
4
1
2
15
16
17
18
19
20
21
22
23
\95
\95
\95
95e
90c
92d
92d
92d,f
16
4-MeC6H4COMe
4-CF3C6H4COMe
PhCOCH2Br
a-Tetralone
42g
2-Acetylnaphthalene
(E)-4-Phenyl-3-buten-2-one
4-Phenyl-3-butyn-2-one
2-Acetylthiophene
85h
58
89h
86
\95
2d
95e
40
a Isolated yield after bulb-to-bulb distillation.
b The e.e.s were determined by GLC using b-CD column and are given following the elution order.
c Absolute configuration: R.
d Determined by GLC using g-CD column.
e The starting ketone was recovered in 5% yield.
f Absolute configuration: S.
g The starting ketone was recovered in 50% yield.
h The starting ketone was recovered in 10% yield.
tiomeric excess of the corresponding tert-alcohol
decreased (Table 4, entry 9). Finally, when the reaction
4. Experimental
was performed using more electrophilic ketones, such
as 2,2,2-trifluoroacetophenone or ethyl pyruvate, the
4.1. General
only products isolated were the corresponding racemic
Full general statements were described elsewhere.30 All
reactions using dialkylzinc or diisobutylaluminium
hydride were carried out under an argon atmosphere.
o-Xylylenediammonium dichloride was prepared in a
two-step process according to the reported procedure,32
starting from the corresponding dibrominated material,
subsequent reaction with potassium phthalimide,
hydrazine and final hydrolysis with hydrochloric acid
gave the expected product in 45% overall yield. b-CD
stands for 50 m WCOT fused silica capillary column
(0.25 mm diam, 0.25 mm film thickness, CP-cyclodex-
trin-b-2,3,6-M-19). g-CD stands for 50 m WCOT fused
silica capillary column (0.25 mm diam, 0.25 mm film
thickness, FS-Lipodex-E). MS samples were inserted in
the modality of Direct Insertion Probed (DIP).
1-phenyl-2,2,2-trifluoroethanol (8 h) or isopropyl pyru-
vate (15 days), respectively. These products arise from a
reduction process (typical reaction between ketones and
dialkylzinc reagents) or a transesterification process
(typically reaction between carboxylic esters and tita-
nium alkoxides), respectively.
3. Conclusion
We have described new C2-symmetric chiral disulfon-
amide ligands, which can be prepared easily from chiral
camphorsulfonyl chloride and diamines (with or with-
out stereogenic elements). These ligands have been suc-
cessfully used in the enantioselective addition of
dialkylzinc reagents to aldehydes and ketones in the
presence of titanium isopropoxide. The relative position
of both hydroxycamphorsulfonamide moieties in the
chiral ligand has some effect on both the enantioselec-
tivity and the yield of the reaction, as well as the
reaction time, which may be interpreted in terms of
some synergistic effects between both metal centers in
the chiral ligand. There is no variation in the enantiose-
lectivity of the reaction when para-substituted phenones
bearing electron-donating or withdrawing groups are
used. The ligands described show a higher enantioselec-
tivity in the addition of dialkylzinc reagents to ketones
than previously reported ligands, even using milder
reaction conditions, which may indicate that the idea of
covalently-linked groupings of chiral ligands could be
useful for a further improvement in the enantioselectiv-
ity of this addition, as well as other reactions.
4.2. Preparation of disulfonamides 5–8
To a solution of the corresponding diamine 4 or (+)-
2,2%-diamino-1,1%-binaphthalyl (12 mmol) in acetonitrile
(25 mL) and 4-(dimethylamino)pyridine (DMPA, 0.66
g, 5.4 mmol) was added a solution of the corresponding
sulfonyl chloride (25 mmol) in acetonitrile (25 mL) at
0°C. The resulting mixture was stirred during 24 h,
allowing the temperature to rise to 25°C. Then, the
reaction mixture was quenched with 3 M NaOH (25
mL) and extracted with ethyl acetate (3×20 mL). The
combined organic layers were washed with 1 M HCl
(25 mL), dried over MgSO4 and evaporated (15 Torr)
to afford the crude pure title product. Yields are
included in Scheme 1 and text. Spectroscopic, physical
and analytical data follow.

1110
M. Yus et al. / Tetrahedron: Asymmetry 14 (2003) 1103–1114
4.2.1. (1S,4S,1%S,4%S)-N-{2-(7%,7%-Dimethyl-2%-oxobicy-
clo[2.2.1]hept-1%-ylmethylsulfonamidomethyl)benzyl}-7,7-
dimethyl-2-oxobicyclo[2.2.1]hept-1-ylmethanesulfonamide,
5a. White solid, Rf 0.50 (hexane/ethyl acetate: 2/3);
mp 50–52°C (CHCl3); [h]2D5=+24.4 (c 1.6, EtOH); w
(melted) 3289 (OH, NH), 3090 (CꢂCH), 1734 (CꢂO),
1329 cm−1 (SO2); lH (CDCl3) 0.78, 0.97 [6 and 6H,
respectively, 2s, 2×C(CH3)2], 1.20–2.40 [14H, m, 2×
(CH2)2CHCH2], 2.86, 3.33 (2, 2H, respectively, 2d,
J=14.6, 2×CH2S), 4.45 (4H, d, J=5.4, CH2N), 6.12
(2H, s, 2×NH), 7.25–7.30, 7.40–7.45 (2, and 2H,
respectively, 2m, ArH); lC (CDCl3) 19.0 (2C), 19.3
(2C), 25.7 (2C), 26.55 (2C), 42.2 (2C), 42.35 (2C),
44.2 (2C), 48.15 (2C), 49.35 (2C), 58.5 (2C), 127.85
(2C), 129.8 (2C), 135.15 (2C), 216.15 (2C); m/z (DIP)
564 (M+, 1%), 349 (28), 333 (21), 332 (27), 119 (100),
118 (70), 109 (47), 95 (11). Anal. calcd for
C28H40N2O6S2: C, 59.55; H, 7.14; N, 4.96; S, 11.35.
Found: C, 59.56; H, 7.21; N, 4.88; S, 11.33%.
(32), 105 (78), 95 (30), 93 (41), 91 (30), 81 (48), 79
(27), 67 (71), 55 (43). Anal. calcd for C28H40N2O6S2:
C, 59.55; H, 7.14; N, 4.96; S, 11.35. Found: C, 59.51;
H, 7.12; N, 4.88; S, 11.23%.
4.2.4. (M,1S,4S,1%S,4%S)-N-{1-[2-(7%,7%-Dimethyl-2%-oxo-
bicyclo[2.2.1]hept-1%-ylmethylsulfonamido)-1-naphthyl]-2-
naphthyl} - 7,7 - dimethyl - 2 - oxobicyclo[2.2.1]hept - 1 - yl-
methanesulfonamide, 6. Pale yellow solid, Rf 0.26 (hex-
ane/ethyl acetate: 3/2); mp 119–121°C (ethyl acetate/
hexane); [h]2D5=+19.6 (c 2.5, CHCl3); w (melted) 3331,
3268 (OH, NH), 3050, 1610 (CꢂCH), 1740 (CꢂO),
1156 cm−1 (SO2); lH (CDCl3) 0.55, 0.91 [6 and 6H,
respectively, 2s, 2×C(CH3)2], 1.20–2.20 [14H, m, 2×
(CH2)2CHCH2], 2.95, 3.38 (2, 2H, respectively, 2d,
J=14.7, 2×CH2S), 7.01 (2H, s, 2×NH), 6.97, 7.20-
7.30, 7.35–7.45, 7.90, 8.19 (2, 2, 2, 2, 2 and 2H,
respectively, d, m, m, d, d and d, respectively, J=7.9,
8.5, 9.1, 9.1, ArH); lC (CDCl3) 19.35 (2C), 19.4 (2C),
25.6 (2C), 26.8 (2C), 42.35 (2C), 42.55 (2C), 48.2
(2C), 51.25 (2C), 58.6 (2C), 118.65 (2C), 119.25 (2C),
125.0 (2C), 125.35 (2C), 127.5 (2C), 128.3 (2C),
130.75 (2C), 130.95 (2C), 132.9 (2C), 134.9 (2C),
214.8 (2C); m/z (DIP) 712 (M+, <1%), 124 (22), 122
(26), 121 (39), 110 (27), 109 (60), 108 (47), 107 (77),
95 (46), 94 (16), 93 (82), 91 (70), 82 (21), 81 (45), 79
(100), 77 (65), 69 (57), 67 (85), 66 (28), 65 (29), 55
(78), 53 (45). Anal. calcd for C40H44N2O6S2: C, 67.39;
H, 6.22; N, 3.93. Found: C, 67.42; H, 6.15; N, 3.86%.
4.2.2. (1S,4S,1%S,4%S)-N-{3-(7%,7%-Dimethyl-2%-oxobicy-
clo[2.2.1]hept-1%-ylmethylsulfonamidomethyl)benzyl}-7,7-
dimethyl-2-oxobicyclo[2.2.1]hept-1-ylmethanesulfonamide,
5b. White solid, Rf 0.52 (hexane/ethyl acetate: 2/3);
mp 118–120°C (ethyl acetate/hexane); [h]2D5=+9.05 (c
1.7, CHCl3); w (melted): 3229, 3264 (OH, NH), 3030
(CꢂCH), 1730 (CꢂO), 1331 cm−1 (SO2); lH (CDCl3)
0.77, 0.97 [6 and 6H, respectively, 2s, 2×C(CH3)2],
1.35–2.45 [14H, m, 2×(CH2)2CHCH2], 2.86, 3.23 (2,
2H, respectively, 2d, J=14.6, 2×CH2S), 3.25 (4H, d,
J=5.4, 2×CH2N), 5.85 (2H, s, 2×NH), 7.30–7.40, 7.40
(3, and 1H, respectively, m and s respectively, ArH);
lC (CDCl3) 19.3 (2C), 19.6 (2C), 26.3 (2C), 26.8 (2C),
42.55 (2C), 42.7 (2C), 47.3 (2C), 48.55 (2C), 50.1
(2C), 59.0 (2C), 127.55 (2C), 128.0, 128.95 (2C),
137.55, 216.85 (2C); m/z (DIP) 564 (M+, <1%), 351
(43), 350 (48), 349 (100), 325 (44), 215 (32), 161 (32),
151 (29), 148 (32), 134 (24), 133 (23), 123 (31), 119
(42), 118 (57), 109 (85), 107 (35), 106 (29), 105 (41),
104 (29), 93 (28), 91 (27), 81 (59), 79 (48), 77 (41), 67
(42), 55 (42). Anal. calcd for C28H40N2O6S2: C, 59.55;
H, 7.14; N, 4.96; S, 11.35. Found: C, 59.57; H, 7. 14;
N, 4.95; S, 11.32%.
4.2.5.
(M,1R,4R,1%R,4%R)-N-{1-[2-(7%,7%-Dimethyl-2%-
oxobicyclo[2.2.1]hept - 1% - ylmethylsulfonamido) - 1 - naph-
thyl]-2-naphthyl}-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-
ylmethanesulfonamide, 7. Brown solid, Rf 0.54 (hex-
ane/ethyl acetate: 1/1); mp 84–86°C (ethyl acetate/
hexane); [h]2D5=+23.9 (c 1.48, CHCl3); w (melted):
3340, 3251 (OH, NH), 3050, 1619 (CꢂCH), 1740
(CꢂO), 1153 cm−1 (SO2); lH (CDCl3) 0.71, 0.91 [6 and
6H, respectively, 2s, 2×C(CH3)2], 1.20–2.30 [14H, m,
2×(CH2)2CHCH2], 2.79, 3.52 (2, 2H, respectively, 2d,
J=14.9, 2×CH2S), 6.91 (2H, s, 2×NH), 7.04, 7.25–
7.30, 7.40–7.45, 7.91, 8.06, 8.18 (2,2,2,2,2, and 2H,
respectively, d, m, m, d, d, d, J=8.5, 7.9, 9.1, 9.1,
ArH); lC (CDCl3) 19.35 (2C), 19.5 (2C), 25.15 (2C),
27.0 (2C), 42.15 (2C), 42.4 (2C), 48.1 (2C), 50.65
(2C), 58.4 (2C), 118.25 (2C), 118.9 (2C), 124.7 (2C),
125.35 (2C), 127.5, (2C), 128.3 (2C), 130.75 (2C),
130.9 (2C), 132.5 (2C), 135.0 (2C), 215.15 (2C); m/z
(DIP) 712 (M+, 100%), 81 (10), 69 (12). Anal. calcd
for C40H44N2O6S2: C, 67.39; H, 6.22; N, 3.93. Found:
C, 67.31; H, 6.17; N, 3.87%.
4.2.3. (1S,4S,1%S,4%S)-N-{4-(7%,7%-Dimethyl-2%-oxobicy-
clo[2.2.1]hept-1%-ylmethylsulfonamidomethyl)benzyl}-7,7-
dimethyl-2-oxobicyclo[2.2.1]hept-1-ylmethanesulfonamide,
5c. White solid, Rf 0.42 (hexane/ethyl acetate: 2/3);
mp 155–157°C (ethyl acetate/hexane); [h]2D5=+6.3 (c
1.2, CHCl3); w (melted) 3300, 3273 (OH, NH), 3055
(CꢂCH), 1742 (CꢂO), 1323 cm−1 (SO2); lH (CDCl3)
0.78, 0.96 [6 and 6H, respectively, 2s, 2×C(CH3)2],
1.40–2.40 [14H, m, 2×(CH2)2CHCH2], 2.86, 3.20 (2,
2H, respectively, 2d, J=15.2, 2×CH2S), 4.31 (4H, d,
J=6.7, 2×CH2N), 5.82 (2H, t, J=6.7, 2×NH), 7.30–
7.40 (4H, m, ArH); lC (CDCl3) 19.25 (2C), 19.65
(2C), 26.6 (2C), 26.85 (2C), 42.55 (2C), 43.7 (2C),
47.15 (2C), 48.6 (2C), 50.25 (2C), 59.1 (2C), 128.5
(4C), 136.6 (2C), 216.9 (2C); m/z (DIP) 564 (M+,
<1%), 351 (48), 349 (100), 325 (29), 215 (52), 161
(90), 152 (25), 151 (45), 135 (61), 134 (65), 133 (89),
132 (20), 123 (34), 119 (35), 118 (71), 109 (75), 108
4.2.6. (M)-N-{1-[(2-Methylsulfonamido)-1-naphthyl]-2-
naphthyl}methanesulfonamide, 8.33 Pale yellow solid, Rf
0.64 (hexane/ethyl acetate: 2/3); mp 100–102°C (ethyl
acetate/hexane); [h]D=+92.65 (c 1.6, CHCl3);
w
(melted) 3331, 3268 (OH, NH), 3050 (CꢂCH), 1356
cm−1 (SO2); lH (CDCl3) 2.86 (6H, s, 2×CH3), 6.18
(2H, s, 2×NH), 6.96, 7.25–7.30, 7.40–7.50, 7.90–8.10
(2, 2, 2 and 6H, respectively, d, m, m and m, respec-
tively J=8.5, ArH); lC (CDCl3) 40.70 (2C), 118.35
(2C), 118.65 (2C), 124.45 (2C), 125.85 (2C), 127.9

M. Yus et al. / Tetrahedron: Asymmetry 14 (2003) 1103–1114
1111
(2C), 128.55 (2C), 131.0 (2C), 131.25 (2C), 132.5 (2C),
134.3 (2C); m/z (GC) 440 (M+, 38%), 283 (24), 282
(100), 281 (31), 280 (15), 279 (19), 267 (30), 266 (13),
265 (17), 264 (15), 207 (10), 141 (11), 140 (28).
129.3 (2C), 137.6 (2C); m/z (DIP) 568 (M+, <1%), 353
(43), 351 (45), 335 (63), 333 (38), 166 (70), 137 (60), 136
(80), 135 (100), 134 (91), 121 (34), 120 (46), 119 (80),
118 (69), 109 (34), 108 (78), 107 (35), 106 (37), 105 (37),
93 (46), 91 (34), 81 (39), 79 (57), 67 (43). Anal. calcd for
C28H44N2O6S2: C, 59.13; H, 7.80; N, 4.93; S, 11.27.
Found: C, 59.19; H, 7.75; N, 4.97; S, 11.31%.
4.3. Preparation of bis(hydroxycamphorsulfonamides)
ligands 9–13
4.3.3.
(1S,2R,4S,1%S,2%R,4%S)-N-{4-(2%-Hydroxy-7%,7%-
To a solution of the corresponding diketone 5–7 (10
mmol) in THF (50 mL) was added a solution of
diisobutylaluminium hydride (1 M in hexane 25 mL, 25
mmol) at −78°C under an argon atmosphere. The
resulting mixture was stirred during 24 h, allowing the
temperature to rise to 25°C. Then, the reaction mixture
was quenched with 2 M HCl (25 mL) and extracted
with CH2Cl2 (3×20 mL). The combined organic layers
were washed with brine (30 mL), dried over MgSO4 and
evaporated (15 Torr) yielding a residue, which was
purified by flash chromatography (silica gel, hexane/
ethyl acetate) to afford the expected title alcohols.
Yields are included in Table 1. Spectroscopic, physical
and analytical data follow.
dimethylbicyclo[2.2.1]hept - 1% - ylmethylsulfonamido-
methyl)benzyl}-2-hydroxy-7,7-dimethylbicyclo[2.2.1]hept-
1-ylmethanesulfonamide, 9c. White solid, Rf 0.63 (hex-
ane/ethyl acetate: 2/3); mp 147–149°C (ethyl
acetate/hexane); [h]D25=−1.4 (c 1.5, CHCl3); w (melted)
3430, 3302 (OH, NH), 3042 (CꢂCH), 1322 (SO2), 1142
cm−1 (CO); lH (CDCl3) 0.76, 1.00 [6 and 6H, respec-
tively, 2s, 2×C(CH3)2], 1.05–2.15 [14H, m, 2×
(CH2)2CHCH2], 2.79, 3.35 (2, 2H, respectively, 2d,
J=13.4, 2×CH2S), 3.14 (2H, s, 2×OH), 4.05–4.10 (2H,
m, 2×CHO), 4.30 (4H, d, J=6.1, 2×CHN), 4.97 (2H, t,
J=5.5, 2×NH), 7.30–7.40 (4H, m, ArH); lC (CDCl3)
19.8 (2C), 20.5 (2C), 27.3 (2C), 30.45 (2C), 39.0 (2C),
44.3 (2C), 46.95 (2C), 48.7 (2C), 50.35 (2C), 52.9 (2C),
76.35 (2C), 128.55 (4C), 136.75 (2C); m/z (DIP) 568
(M+, <1%), 335 (55), 334 (49), 333 (90), 136 (39), 135
(85), 134 (54), 133 (95), 121 (45), 120 (62), 119 (43), 118
(52), 109 (38), 108 (51), 107 (73), 106 (72), 105 (46), 93
(57), 91 (52), 81 (30), 79 (100), 77 (33). Anal. calcd for
C28H44N2O6S2: C, 59.13; H, 7.80; N, 4.93; S, 11.27.
Found: C, 59.09; H, 7.71; N, 4.84; S, 11.16%.
4.3.1.
(1S,2R,4S,1%S,2%R,4%S)-N-{2-(2%-Hydroxy-7%,7%-
dimethylbicyclo[2.2.1]hept - 1% - ylmethylsulfonamido-
methyl)benzyl}-2-hydroxy-7,7-dimethylbicyclo[2.2.1]hept-
1-ylmethanesulfonamide, 9a. White solid, Rf 0.69 (hex-
ane/ethyl acetate: 3/2); mp 79–81°C (ethyl
acetate/hexane); [h]D25=−46.2 (c 2.0, CHCl3); w (melted)
3522, 3247 (OH, NH), 3092 (CꢂCH), 1320 (SO2), 1144
cm−1 (CO); lH (CDCl3) 0.78, 1.01 [6 and 6H, respec-
tively, 2s, 2×C(CH3)2], 1.05–1.85 [14H, m, 2×
(CH2)2CHCH2], 2.82, 3.41 (2, 2H, respectively, 2d,
J=13.4, 2×CH2S), 3.13 (2H, s, 2×OH), 4.00–4.10 (2H,
m, 2×CHO), 4.43 (4H, d, J=6.1, 2×CHN), 5.06 (2H, s,
2×NH), 7.30–7.45 (4H, m, ArH); lC (CDCl3) 19.75
(2C), 20.35 (2C), 27.25 (2C), 30.25 (2C), 40.0 (2C),
44.25 (2C), 44.55 (2C), 48.65 (2C), 50.25 (2C), 52.2
(2C), 76.2 (2C), 128.7 (2C), 130.45 (2C), 135.1 (2C);
m/z (DIP) 568 (M+, <1%), 334 (50), 33 (64), 316 (100),
135 (81), 133 (32), 117 (59), 108 (49), 95 (36), 93 (36), 79
(51), 77 (32), 67 (40). Anal. calcd for C28H44N2O6S2: C,
59.13; H, 7.80; N, 4.93; S, 11.27. Found: C, 59.14; H,
7.85; N, 4.87; S, 11.33%.
4.3.4. (M,1S,2R,4S,1%S,2%R,4%S)-N-{1-[2-(2%-Hydroxy-
7%,7%-dimethylbicyclo[2.2.1]hept-1%-ylmethylsulfonamido)-
1-naphthyl]-2-naphthyl}-2-hydroxy-7,7-dimethylbicyclo-
[2.2.1]hept-1-ylmethanesulfonamide, 10. Pale brown
solid, Rf 0.52 (hexane/ethyl acetate: 3/2); mp 133–135°C
(ethyl acetate/hexane); [h]2D5=+24.05 (c 1.7, CHCl3); w
(melted) 3521, 3402 (OH, NH), 3062, 1610 (CꢂCH),
1152 cm−1 (CO); lH (CDCl3) 0.73, 0.89 [6 and 6H,
respectively, 2s, 2×C(CH3)2], 1.00–1.75 [14H, m, 2×
(CH2)2CHCH2], 2.74 (2H, s, 2×OH),2.86, 3.24, (2, 2H,
respectively, 2d, J=13.7, 2×CH2S), 3.90–3.95 (2H, m,
2×CHO), 6.31 (2H, s, 2×NH), 7.04, 7.30–7.40, 7.45–
7.55, 7.95–8.05, 8.01 (2, 2, 2, 4 and 2H, respectively, d,
m, m and d, respectively, J=8.5, 9.1, respectively,
ArH); lC (CDCl3) 18.6 (2C), 19.6 (2C), 27.25 (2C),
28.05 (2C), 38.35 (2C), 43.85 (2C), 48.85 (2C), 50.5
(2C), 53.65 (2C), 74.8 (2C), 119.15 (2C), 119.5 (2C),
125.0 (2C), 125.95 (2C), 127.95 (2C), 128.05 (2C),
128.65 (2C), 131.15 (2C), 132.75 (2C), 134.5 (2C); m/z
(DIP) 716 (M+, 56%), 499 (20), 482 (100), 284 (81), 283
(99), 282 (22), 281 (63), 268 (35), 267 (69), 266 (75), 265
(54), 135 (29), 107 (20), 79 (22), 67 (22). Anal. calcd for
C40H48N2O6S2: C, 67.01; H, 6.75; N, 3.91. Found: C,
67.07; H, 6.76; N, 3.88%.
4.3.2.
(1S,2R,4S,1%S,2%R,4%S)-N-{3-(2%-Hydroxy-7%,7%-
dimethylbicyclo[2.2.1]hept - 1% - ylmethylsulfonamido-
methyl)benzyl}-2-hydroxy-7,7-dimethylbicyclo[2.2.1]hept-
1-ylmethanesulfonamide, 9b. White solid, Rf 0.61 (hex-
ane/ethyl acetate: 2/3); mp 66–68°C (ethyl
acetate/hexane); [h]2D5=−46.2 (c 1.8, EtOH); w (melted)
3530, 3286 (OH, NH), 3085, 1316 (CꢂCH), 1138 cm−1
(CO); lH (CDCl3) 0.75, 0.96 [6 and 6H, respectively, 2s,
2×C(CH3)2], 1.05–1.75 [14H, m, 2×(CH2)2CHCH2], 2.15
(2H, s, 2×OH), 2.75, 3.24 (2, 2H, respectively, 2d,
J=14.0, 2×CH2S), 4.00–4.05 (2H, m, 2×CHO), 4.26
(4H, d, J=5.5 2×CHN), 5.56 (2H, t, J=5.7, 2×NH),
7.25–7.35, 7.36 (3 and 1H, respectively, m and s, respec-
tively, ArH); lC (CDCl3) 19.75 (2C), 20.45 (2C), 27.25
(2C), 30.35 (2C), 39.0 (2C), 44.25 (2C), 47.0 (2C), 48.65
(2C), 50.3 (2C), 52.75 (2C), 76.35 (2C), 127.85 (2C),
4.3.5. (M,1R,2S,4R,1%R,2%S,4%R)-N-{1-[2-(2%-Hydroxy-
7%,7%-dimethylbicyclo[2.2.1]hept-1%-ylmethylsulfonamido)-
1-naphthyl]-2-naphthyl}-2-hydroxy-7,7-dimethylbicyclo-
[2.2.1]hept-1-ylmethanesulfonamide, 11. Pale brown
solid, Rf 0.62 (hexane/ethyl acetate: 3/2); mp 111–113°C
(ethyl acetate/hexane); [h]2D5=+25.5 (c 1.3, CHCl3); w

1112
M. Yus et al. / Tetrahedron: Asymmetry 14 (2003) 1103–1114
(melted) 3545, 3346 (OH, NH), 3040, 1598 (CꢂCH),
1145 cm−1 (CO); lH (CDCl3) 0.65, 0.97 [6 and 6H,
respectively, 2s, 2×C(CH3)2], 1.25–1.85 [14H, m, 2×
(CH2)2CHCH2], 2.66, 3.48 (2, 2H, respectively, 2d, J=
13.4, 2×CH2S), 3.74 (2H, s, 2×OH), 3.95–4.00 (2H, m,
2×CHO), 6.21 (2H, s, 2×NH), 7.01, 7.25–7.35, 7.35–
7.50, 7.50–8.05, 8.10 (2, 2, 2, 4 and 2 H, respectively, d,
3m and d, respectively, J=8.5, 9.1, ArH); lC (CDCl3)
19.35 (2C), 19.85 (2C), 26.75 (2C), 29.8 (2C), 38.75
(2C), 43.85 (2C), 48.4 (2C), 50.0 (2C), 53.05 (2C), 75.65
(2C), 118.55 (2C), 118.95 (2C), 124.4 (2C), 125.5 (2C),
127.65 (2C), 128.3 (2C), 130.75 (2C), 131.05 (2C),
132.15 (2C), 133.95 (2C); m/z (DIP) 716 (M+, 100%),
501 (16), 500 (47), 482 (15), 285 (15), 284 (19), 283 (44),
282 (51), 281 (34), 268 (11), 267 (45), 93 (15). Anal.
calcd for C40H48N2O6S2: C, 67.01; H, 6.75; N, 3.91.
Found: C, 67.01; H, 6.69; N, 3.86%.
130.8, 130.85, 130.95, 132.15, 132.2, 133.8, 134.05; m/z
(DIP) 716 (M+, <1%), 351 (59), 349 (37), 136 (47), 135
(100), 134 (43), 133 (33), 118 (50), 109 (32), 107 (38),
106 (31), 104 (33), 91 (38), 81 (52), 79 (46), 67 (30).
Anal. calcd for C40H48N2O6S2: C, 67.01; H, 6.75; N,
3.91. Found: C, 67.10; H, 6.70; N, 3.97%.
4.4. Enantioselective addition of dialkylzinc to alde-
hydes or ketones in the presence of titanium
isopropoxide
To a solution of corresponding ligand 5–13 (0.5 mmol)
in toluene (5 mL) was added a ca. 2 M solution in
toluene of the corresponding dialkylzinc reagent (9
mmol, 4.5 mL) at temperatures ranging from −20°C to
rt (see Tables 2–4) under an argon atmosphere (see
Schemes 2–4). After 10 min stirring, titanium tetra-
isopropoxide (6.5 mmol, 2 mL) was added to the
resulting solution and, after 10 additional min, the
corresponding aldehyde or ketone (5 mmol) was added.
The resulting mixture was stirred at the same tempera-
ture during several hours to days (see Tables 2–4).
Then, methanol (1 mL) and a saturated NH4Cl solution
(20 mL) were successively added, the mixture was
filtered through celite, extracted with ethyl acetate (3×
50 mL) and the organic layer dried over MgSO4. The
solvents were removed under reduced pressure (15
Torr) and the residue was distillate bulb-to-bulb to
yield the expected alcohols. Yields and enantiomeric
excess (e.e.) are included in Tables 2–4. Compounds
14a,18 14b–d,30 as well as 15, 18–21 and 23,19a were
already described by us and were characterised by
comparison of their physical and spectroscopic data
with those reported in the literature. Spectroscopic and
physical data, as well as literature references follow.
4.3.6.
(1S,2R,4S,1%S,2%S,4%S)-N-{3-(2%-Hydroxy-
7%,7%-dimethylbicyclo[2.2.1]hept-1%-ylmethylsulfonamido-
methyl)benzyl}-2-hydroxy-7,7-dimethylbicyclo[2.2.1]hept-
1-ylmethanesulfonamide, 12. White solid, Rf 0.71 (hex-
ane/ethyl acetate: 2/3); mp 57–59°C (ethyl
acetate/hexane); [h]2D5=−9.6 (c 1.9, EtOH); w (melted)
3532, 3285 (OH, NH), 3045 (CꢂCH), 1317 (SO2), 1141
cm−1 (CO); lH (CDCl3) 0.74, 0.95, 0.82 [3, 3 and 3H,
respectively, 3s, 2×C(CH3)2], 1.00–2.40 [14H, m, 2×
(CH2)2CHCH2], 2.75, 2.96, 3.02, 3.24 (1, 1, 1 and 1H,
respectively, 2d and 2d, respectively, J=13.7, 14.3,
2×CH2S), 3.28, 3.61 (1 and 1H, respectively, 2s, 2×OH),
4.00–4.05, 4.15–4.20 (1 and 1H, respectively, 2m, 2×
CHO), 4.24, 4.27 (2, 2H, respectively, 2d, J=6.1, 2×
CHN), 5.63, 5.97 (1, 1H, respectively, 2t, J=6.1,
2×NH), 7.25–7.40 (4H, m, ArH); lC (CDCl3) 18.7, 19.7,
20.25, 20.4, 23.6, 27.2, 28.1, 30.35, 38.4, 38.9, 43.85,
44.2, 46.9, 47.0, 48.6, 50.25, 50.8, 51.35, 52.8, 56.0,
75.05, 76.3, 127.6, 127.65, 127.7, 129.15, 137.6, 137.7;
m/z (DIP) 566 (M+−2, <1%), 353 (43), 352 (17), 351
(24), 335 (30), 333 (39), 166 (32), 137 (33), 136 (86), 135
(82), 134 (34), 133 (19), 120 (46), 119 (100), 109 (17),
108 (31), 107 (21), 106 (10), 93 (25), 91 (21). Anal. calcd
for C28H44N2O6S2: C, 59.13; H, 7.80; N, 4.93; S, 11.27.
Found: C, 59.17; H, 7.84; N, 4.91; S, 11.27%.
4.4.1. 2-(4-Methylphenyl)-2-butanol, 16.42 Colourless oil,
bp 150–155°C (0.1 Torr); Rf 0.65 (hexane/ethyl acetate:
7/3); [h]D=−2.89 (c 1.9, EtOH; e.e. 92%); w (film) 3428
(OH), 3024, 1649 (CꢂCH), 1127 cm−1 (CO); lH (CDCl3)
0.78 (3H, t, J=7.4, CH2CH3), 1.51 (3H, s, CH3), 1.81
(2H, q, J=7.4, CH2CH3), 1.87 (1H, s OH), 2.32 (3H, s
ArCH3), 7.13, 7.29 (2, 2H, respectively, 2d, J=8.0,
ArH); lC (CDCl3) 8.3, 20.85, 29.5, 36.55, 74.75, 124.75
(2C), 128.7 (2C), 135.9, 144.8; m/z (GC) 164 (M+, 2%),
135 (100), 131 (13), 91 (21), 57 (12).
4.3.7. (M,1R,2S,4R,1%R,2%R,4%R)-N-{1-[2-(2%-Hydroxy-
7%,7%-dimethylbicyclo[2.2.1]hept-1%-ylmethylsulfonamido)-
1-naphthyl]-2-naphthyl}-2-hydroxy-7,7-dimethylbicyclo-
[2.2.1]hept-1-ylmethanesulfonamide, 13. White solid, Rf
0.69 (hexane/ethyl acetate: 1/1); mp 58–60°C (ethyl
acetate/hexane); [h]D25=+8.3 (c 1.05, CHCl3); w (melted)
3450, 3364 (OH, NH), 3034, 1624 (CꢂCH), 1159 cm−1
(CO); lH (CDCl3) 0.63, 0.72, 0.78 and 0.96 [3, 3, 3 and
3H, respectively, 4s, 2×C(CH3)2], 1.15–2.60 [14H, m,
2×(CH2)2CHCH2], 2.67, 2.86, 3.02, 3.50 (1, 1, 1 and 1H,
respectively, 2d and 2d, respectively, J=13.4, 13.7,
2×CH2S), 3.90–3.95, 4.05–4.10 (1 and 1H, respectively,
2m, 2×CHO), 6.21, 6.49 (1 and 1H, respectively, 2s,
2×NH), 7.00–7.05, 7.25–7.35, 7.45–7.50, 7.95–8.15 (2,
2,2 and 6H, respectively, 4m, ArH); lC (CDCl3) 18.25,
19.3, 19.7, 18.8, 23.15, 26.75, 27.55, 29.75, 37.75, 38.8,
43.45, 43.8, 48.35, 50.65, 51.15, 52.45, 53.05, 56.75,
74.45, 75.55, 118.4, 118.9, 119.05, 119.1, 119.25, 124.25,
124.35, 124.4, 124.65, 125.5, 127.5, 128.25, 130.75,
4.4.2. 2-(4-Trifluoromethylphenyl)-2-butanol, 17.42 Colour-
less oil, bp 150–155°C (0.1 Torr); Rf 0.60 (hexane/ethyl
acetate: 7/3); [h]D=−10.6 (c 2.5, EtOH; e.e. 92%); w
(film): 3406 (OH), 3060, 1618 (CꢂCH), 1327 (CF), 1125
cm−1 (CO); lH (CDCl3) 0.79 (3H, t, J=7.4, CH2CH3),
1.55 (3H, s, CH3), 1.84 (2H, q, J=7.4, CH2CH3), 1.89
(1H, s, OH), 7.53, 7.58 (2, 2H, respectively, 2d, J=8.6,
ArH); lC (CDCl3) 8.05, 29.6, 36.6, 74.85, 120.7 (q,
2JCF=271.1), 125.0 (q, 3JCF=10.95), 125.35 (2C),
127.85 (q, 1JCF=815.0), 151.5; m/z (GC) 218 (M+,
<1%), 189 (100), 145 (10).
4.4.3. 3-Methyl-1-phenyl-1-pentyn-3-ol, 22.43 Colourless
oil, bp 155–160°C (0.1 Torr); Rf 0.85 (hexane/ethyl
acetate: 7/3); [h]D=+3.2 (c 2.1, EtOH; e.e. 2%); w (film)
3404 (OH), 3049, 1636 (CꢂCH), 2196 (CꢁC), 1118 cm−1

M. Yus et al. / Tetrahedron: Asymmetry 14 (2003) 1103–1114
1113
(CO); lH (CDCl3) 1.10 (3H, t, J=7.4, CH2CH3), 1.56
(3H, s, CH3), 1.78 (2H, q, J=7.4, CH2CH3), 2.10 (1H,
s, OH), 7.25–7.30, 7.40–7.45 (3, 2H, respectively, 2m,
ArH); lC (CDCl3) 9.05, 29.25, 36.6, 69.05, 83.3, 92.7,
122.8, 128.15, 128.2 (2C), 131.6 (2C); m/z (GC) 174
(M+, 5%), 146 (10), 145 (100), 129 (10), 115 (10).
M. C.; Tregay, S. W. J. Am. Chem. Soc. 1999, 121,
686–699.
12. For
reviews
on
functionalised
non-stabilised
organometallic compounds and their use in organic syn-
thesis, see: (a) Yus, M.; Ramo´n, D. J. Latv. Kim. Z. 2002,
79–92; (b) Boudier, A.; Bromm, L. O.; Lotz, M.;
Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 4414–4435;
(c) Na´jera, C.; Yus, M. Recent Res. Devel. Org. Chem.
1997, 1, 67–96; (d) Na´jera, C.; Yus, M. Trends Org.
Chem. 1991, 2, 155–181.
Acknowledgements
13. For reviews on the use of dialkylzinc reagents in synthe-
sis, see: (a) Knochel, P.; Almena Perea, J. J.; Jones, P.
Tetrahedron 1998, 54, 8275–8319; (b) Knochel, P. In
Metal-Catalysed Cross-Coupling Reactions; Diederich,
F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; pp.
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Synlett 1995, 393–403; (e) Knochel, P.; Singer, R. D.
Chem. Rev. 1993, 93, 2117–2188.
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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