Trans-1-sulfonylamino-2-isoborneolsulfonylaminocyclohexane derivatives: Excellent chiral ligands for the catalytic enantioselective addition of organozinc reagents to ketones

Article abstract of DOI:10.1002/chem.200501397

The catalytic enantioselective addition of different organozinc reagents (such as alkyl and aryl derivatives or in situ generated aryl, allyl alkenyl, and alkynyl derivatives obtained through different transmetallation processes) to simple ketones has bee

Full text of DOI:10.1002/chem.200501397

FULL PAPER
DOI: 10.1002/chem.200501397
trans-1-Sulfonylamino-2-isoborneolsulfonylaminocyclohexane Derivatives:
Excellent Chiral Ligands for the Catalytic Enantioselective Addition of
Organozinc Reagents to Ketones
Vicente J. Forrat, Oscar Prieto, Diego J. Ramón,* and Miguel Yus*[a]
Abstract: The catalytic enantioselective
addition of different organozinc re-
agents (such as alkyl and aryl deriva-
tives or in situ generated aryl, allyl al-
kenyl, and alkynyl derivatives obtained
isopropoxide and chiral ligands derived
from substituted trans-1-sulfonylamino-
2-isoborneolsulfonylaminocyclohexane,
producing the corresponding tertiary
alcohols with enantiomeric excesses
(ee) up to >99%. A simple and effi-
cient procedure for the synthesis of the
chiral ligands used in these reactions is
described.
Keywords: alcohols
· asymmetric
through
different
transmetallation
À
catalysis
enantioselectivity · titanium
·
C C coupling
·
processes) to simple ketones has been
accomplished by using titanium tetra-
Introduction
Among the different enantioselective approaches to the
synthesis of this kind of molecule,[5] those which imply the
formation of a carbon–carbon bond are more powerful than
those that use simple functionalization. In this case the sim-
plest approach for the preparation of chiral tertiary alcohols
is the enantioselective 1,2-addition of organometallics[6] to
the corresponding carbonyl compounds.[7] Although there
are several examples of addition of organolithium or
Grignard reagents to ketones, at least one equivalent of an
often expensive and difficult to prepare chiral ligand is com-
pulsory in all cases. To reduce the amount of the chiral
ligand required, an organometallic reagent with lower nucle-
ophilic character is usually considered. However, under
these new conditions, and to guarantee the success of the re-
action, the chiral system must determine not only the topol-
The preparation of chiral molecules bearing a quaternary
stereocenter is still a very important challenge in synthetic
organic chemistry, with the diastereoselective approach
being the most commonly used.[1] However, the enantiose-
lective version of these reactions have, in general, some ad-
vantages over the diastereoselective ones, such as for the re-
peated preparation of a compound, the need for the attach-
ment and deattachment of a chiral auxiliary at the beginning
and end of the synthetic process is avoided. Nevertheless,
there are some elegant diastereoselective approaches which
do not need the first step. Thus, the asymmetric multi-
component Sakurai reaction,[2] which utilizes aliphatic meth-
yl ketones, allyl silanes, and chiral norpseudoephedrine
derivatives, yielded the expected benzyl ether with excel-
lent diastereoselectivity;[3] the final reductive deprotection
with lithium and substoichiometric amounts of an arene[4]
liberates the corresponding homoallylic tertiary alcohol
(Scheme 1).
[a] V. J. Forrat, Dr. O. Prieto, Dr. D. J. Ramón, Prof. Dr. M. Yus
Instituto de Síntesis Orgµnica (ISO) and Departamento de Química
Orgµnica. Facultad de Ciencias
Universidad de Alicante, Apdo. 99, 03080 Alicante (Spain)
Fax : (+34)965-90-35.49
E-mail: djramon@ua.es
yus@ua.es
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Scheme 1. Diastereoselective approach to the synthesis of tertiary alco-
hols. OTf=trifluoromethanesulfonate; de=diastereomeric excess.
Chem. Eur. J. 2006, 12, 4431 – 4445
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4431

ogy of the reaction, but also the chemical reaction itself.
This new role of the catalyst may be achieved by either acti-
vating the organometallic reagent or, in the most classical
sense, by activating the carbonyl compound. Some catalysts
are able to activate both the nucleophile and the carbonyl
compound at the same time.[8]
Organozinc reagents are the ideal candidates for this type
of addition as their nucleophilicity is very low. In fact, it is
well known that they do not add to aldehydes in noncoordi-
nating solvents or to ketones.[9] Only recently, and in the
framework of our ongoing project for the development of
new chiral sulfonamides and their use in enantioselective
catalytic synthesis,[10] the introduction of the isoborneolsulfo-
namide ligand 1[11] permitted the first enantioselective cata-
lytic addition of commercially available dialkylzinc reagents
to simple ketones[12] in the presence of titanium alkoxides[13]
(Scheme 2). The role of the titanium alkoxide is not only to
agents to aldehydes in the presence of titanium tetraisoprop-
oxide.[15] In this proposal, it is assumed that the bimetallic
species[16] has both a highly electrophilic, pentacoordinated,
positively charged titanium center and a highly nucleophilic,
hexacoordinated, negatively charged titanium center.[17] The
idea was to remove the flexible alkoxide bridge ligands gen-
erating a more rigid structure in which, playing with the dia-
mine used, the length and angles between both guest titani-
um centers could be clearly controlled and therefore the
synergistic effect of both metallic centers and the enantiose-
lectivity could be improved.
Results and Discussion
In this paper, we present our results on the development of
new chiral isoborneolsulfonamide ligands and their uses as
chiral promoters for the catalytic enantioselective addition
of different organozinc reagents to simple ketones to give
tertiary alcohols, the driving force of the design being that
closer 1,2-etylendiamine linkers might favor the aforemen-
tioned synergistic effect of the two guest titanium metals.
Synthesis of the isoborneolsulfonamide ligands: The sym-
metrical chiral bis(isoborneolsulfonamide) ligands 6a–c
(Scheme 3) were prepared by reaction of the corresponding
Scheme 2. First enantioselective catalytic addition of dialkylzinc reagents
to simple ketones.
form the active chiral catalytic species, but also the removal
of the tertiary alcohol generated during the catalytic cycle.
In a further effort to improve the enantioselectivity, li-
gands derived from aryl or benzyl diamines containing two
isoborneolsulfonamide moieties were prepared. Among the
tested systems, ligand 2 was the best, improving the enantio-
selectivity and the reaction conditions.[14] The design of this
type of ligand was governed by the hypothetical existence of
the bimetallic catalytic species 3,[11b] which is similar to that
described for the enantioselective addition of dialkylzinc re-
Scheme 3. Synthesis of chiral tetradentate ligands 6a–c. DMAP=4(dime-
thylamino)pyridine.
ethylendiamine 4 with two equivalents of commercially
available (1S)-(+)-10-camphorsulfonyl chloride (5) to give,
after successive basic and acidic treatment, the correspond-
ing ketones with yields ꢀ90%.[18] These crude ketone prod-
ucts were directly reduced with sodium borohydride to yield
a mixture of all possible diastereomeric alcohols (Table 1),
with the exo–exo diastereoisomer as the main product,
easily isolated in all cases by flash chromatography. Alterna-
tively, the final reduction can be performed by using an
excess of diisobutylaluminium hydride at low temperature,
rendering after hydrolysis the expected diols with similar
chemical yields and diastereomeric ratios. The crystal struc-
ture of the exo-diol 6c (HOCSAC), derived from the corre-
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À
C C Coupling
FULL PAPER
Table 1. Synthesis of tetradentate ligands 6a–c.
Entry
Diastereomeric ratio[a]
Yield [%][b]
exo–exo
exo–endo
endo–endo
1
2
3
90
98
97
7
1
2
3
1
1
6a
6b
6c
53
45
66
1
[a] Determined by H NMR spectroscopy (300 MHz) from the crude mix-
ture. [b] Yield of the main diastereoisomer after flash chromatography.
sponding trans-1,2-bis(camphorsulfonylamido)cyclohexane
was obtained by recrystallization of the pure ligand (see
below).
In a similar way, the diastereomeric partners 6d,e were
prepared with moderate chemical yields for the overall
process; this was achieved by substituting the starting chiral
Scheme 4. Synthesis of chiral ligands 10a–c. DIBAL=diisobutylalumi-
num hydride.
standard conditions, followed
by reduction of the in situ gen-
erated ketone to the corre-
sponding exo-derivative 11 with
69% overall yield. This biden-
tate ligand was the reference
for the rest of the tri- and tetra-
dentate ligands 6 and 10 to
check our ligand design hypoth-
esis.
sulfonyl chloride with its enantiomer (1R)-(À)-10-camphor-
sulfonyl chloride (ent-5). The use of the achiral 1,2-cis-dia-
minocyclohexane as the starting amine led to the prepara-
tion of the ligand 6 f.
In addition to the symmetrical bis(isoborneol)sulfona-
mides (6), the unsymmetrical compounds 10 were prepared.
In this case two different reaction pathways should be fol-
lowed depending on the substituents (Scheme 4). In the case
of aryl-substituted compounds 10a,b, the only way to obtain
them was by reaction of equivalent amounts of the chiral
amine 4 and the corresponding arylsulfonyl chloride deriva-
tive 7 in a biphasic media of aqueous NaOH and methylene
chloride. Then, subsequent reaction with the chiral (1S)-(+)-
10-camphorsulfonyl chloride (5) and final basic and acidic
treatment gave the expected ketones 8.[19] Reduction with
sodium borohydride under standard conditions produced a
mixture of two possible diastereomeric alcohols, the major
exo-derivatives 10a,b were easily isolated after flash chro-
matography. However, the best procedure to obtain the me-
sylamide 10c was firstly to introduce the camphorsulfonyl
moiety and then the mesyl group, the final reduction pro-
ducing the ligand 10c in 45% overall yield.
Catalytic enantioselective addition of zinc reagents to
simple ketones: Once the ethylenic ligands were prepared,
they were first tested in the enantioselective addition of
commercially available diethylzinc (13a) to ketones 12,[20] in
the presence of a slight excess of titanium tetraisopropoxide
(Table 2). As a reference (entry 1), the ethylation of aceto-
phenone with 10 mol% of ligand 11 gave the expected alco-
hol 14a in a practically quantitative yield after 8 h, the ee
determined as only 66% with S configuration. To our de-
light, the same reaction with the simple ethylene derivative
6a rendered the alcohol 14a with
a notable 92% ee
(entry 2). It should be pointed out that the amount of ligand
was reduced to keep the total amount of isoborneolsulfona-
mide unit constant and, despite this decrease, the result was
significantly higher for the ligand able to bind to two titani-
um atoms compared to the one (used in a double amount)
able to bind only one titanium atom, indirectly confirming
our initial hypothesis of the presence of bimetallic species.
Finally, the isoborneolsulfonamide 11 was prepared by the
reaction of the commercially available chiral (1S)-(+)-10-
camphorsulfonyl chloride (5) with cyclohexylamine under
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M. Yus, D. J. Ramón et al.
Table 2. Ligand optimization for the catalytic enantioselective ethylation of ketones.
very close results to those ob-
tained by using a stoichiometric
amount (compare entries 4, 7,
and 8). It should be pointed out
that when the reaction was per-
formed with triethylaluminium
instead of standard diethylzinc,
the alcohol 14a was isolated as
a racemic mixture. The diaster-
eomeric ligands 6d,e were
tested to determine if both
chiral starting materials (dia-
mines and sulfonyl chloride)
produced the matched or mis-
matched couples. The results in-
dicated that both the ligands
6d,e were the mismatched dia-
stereoisomers as the reaction
took a very long time, produc-
ing very modest enantioselec-
tivities. From these results, and
comparing with those of en-
tries 3 and 4, the outcome of
the reaction seems to be con-
trolled by the isoborneol motif
and not by the amine. However,
when the reaction was conduct-
ed by using ligand 6 f (entry 11)
Entry
Ligand
t [h]
Product
R
X
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
11[c]
6a
6b
8
96
48
8
72
3
216
15
120
120
72
120
120
8
14a
14a
14a
14a
14a
14a
14a
14a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
Br
H
H
>95
60
15
80
20
90
90
90
25
20
16
55
65
83
79
70
80
90
66 (S)
92 (S)
23 (S)
98 (S)
97 (S)
90 (S)
90 (S)
96 (S)
33 (R)
36 (R)
24 (R)
>99[h] (S)
>99[h] (S)
96 (S)
49 (R)
50 (R)
16 (À)
>99[h] (À)
6c
6c[d]
6c[e]
6c[f]
6c[g]
6d
9
ent-14a
ent-14a
ent-14a
14a
10
11
12
13
14
15
16
17
18
6e
6 f
10a
10b
10c
6a
6c
6a
6c
14a
14a
14b
14b
14c
14c
22
0.2
17
8
(E)-PhCH=CH
(E)-PhCH=CH
[a] Isolated yields after bulb-to-bulb distillation. [b] Determined by using GLC with a cyclodextrin column, the
absolute configuration or the sign of the predominant enantiomer is indicated in parentheses. [c] 10 mol% of
ligand used. [d] The addition was performed at 08C. [e] The addition was performed at 608C. [f] Only
10 mol% of titanium tetraisopropoxide was used. [g] Only 40 mol% of titanium tetraisopropoxide was used.
[h] Only one enantiomer was detected.
However, it is also worth noting that the reaction with the
tetradentate ligand 6a was slower than for the bidentate
ligand 11. This result encouraged us to try the ligand 6b, as
in our previous experience N-benzyl isoborneolsulfonamides
yielded the best results.[11,14] However, the enantioselectivity
for the ethylation of acetophenone with 6b was very modest
(entry 3), thus we reasoned that the phenyl substituents on
the ligand 6b make it more difficult to achieve the appropri-
ate arrangement in the catalyst. To ensure the favorable syn-
ergistic effect of both metallic centers we turned our atten-
tion to the exo-diol derived from trans-1,2-bis(camphorsulfo-
nylamido)cyclohexane (6c, HOCSAC) in which the rotation
around the carbon–carbon bond of the 1,2-diamine subunit
was restricted. After only 8 h, the starting acetophenone was
consumed producing the expected alcohol with excellent re-
sults (entry 4). The effect of temperature on the ethylation
of acetophenone (12a) was studied by using the HOCSAC
ligand (6c) as model. From this study, we found that despite
the enantioselectivity remaining practically unchanged when
the temperature was decreased to 08C, the chemical yield
decreased and the reaction time was longer. When the same
ethylation was performed at 608C, the enantioselectivity de-
creased to some extent (entry 6). The fact that the amount
of titanium tetraisopropoxide played an important role in
these results was demonstrated by the long reaction time
and lower enantioselectivity observed for the addition of di-
ethylzinc to acetophenone by using 5 mol% of 6c and only
10 mol% of the titanium alkoxide. However, an increase in
the amount of titanium complex up to 40 mol% yielded
(prepared from the achiral cis-1,2-diaminoyclohexane and
the chiral (1S)-(+)-10-camphorsulfonyl chloride (5)), the ab-
solute configuration of the alcohol ent-1a produced was R
instead of S as expected when using ligands of the series de-
rived from 5. All these results point out the inherent diffi-
culties involved in proposing any transition-step model.
Once we ascertained that ligands with two isoborneol moiet-
ies gave better results than the ligand with only one group
(compare entries 1 and 4), we wondered if the second iso-
borneol group was actually necessary or whether it could be
replaced by another achiral group. Thus, the enantioselec-
tive addition of diethylzinc to acetophenone in the presence
of titanium tetraisopropoxide was carried out by using li-
gands 10. Surprisingly, the enantioselectivity was unbeatable
for the arylsulfonyl derivatives 10a,b, with only one enan-
tiomer of alcohol 14a detected by CG analysis, although the
reaction time was sensibly increased (entries 12 and 13). The
reaction with the less hindered ligand 10c derived from
mesyl gave a slightly worse result compared to previous li-
gands, but it was practically the same as for the HOCSAC
ligand (compare entries 14 and 4). If the reaction time is in-
cluded in the comparison, the HOCSAC ligand (6c) gave
the best results, this tendency was also observed for other
ketones, such as bromoacetophenone and benzylidenace-
tone, for the last case the alcohol 14c was detected as only
one enantiomer (entry 18).
Once ligands 6c and 10a,b were determined as the best
promoters for the ethylation of simple ketones, we studied
the scope of the reaction by changing starting ketones 12
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C C Coupling
FULL PAPER
and organozinc reagents 13 (Table 3). The reaction worked
nicely when dimethylzinc (13b) was used as the source of
nucleophile, giving excellent results for the reaction promot-
ed by HOCSAC (6c) and only one enantiomer for ligands
Table 3), the same addition giving the racemic alcohol 14i
when the simple ligand 1 was used.[11b] This example is illus-
trative of the scope of the reaction as the promoter differen-
tiates between two rather similar alkyl substituents on the
ketone, this ketone being less
reactive than the related aryl
alkyl ketones. Finally, it should
Table 3. Catalytic enantioselective addition of zinc reagents to ketones.
be pointed out that the reaction
can be performed by using
commercially available diphe-
nylzinc[23] to yield the corre-
sponding diarylalkanol deriva-
tives[24] 15 with good enantiose-
lectivities.[25]
The
arylation
process was insensitive to the
presence of either electron-do-
nating or -withdrawing groups
at the 4-position on the aromat-
ic ring of ketone,[26] while the
Entry
Ligand
R1
R2
R3
Product
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
6c
10a
10b
6c
6c
6c
6c
6c
6c
6c
Ph
Ph
Ph
Et
Et
Et
Me
Me
Me
Et
Et
Et
ent-14a
ent-14a
ent-14a
14d
>95
25[c]
98 (R)
>99[d] (R)
>99[d] (R)
95 (À)
29[c]
enantioselectivity
decreased
4-MeC6H4
4-F3CC6H4
2-naphthyl
(E)-PhCH=CH
PhC C
cC6H11
4-MeC6H4
4-BrC6H4
4-F3CC6H4
4-BrC6H4
Me
Me
Me
nBu
Me
nBu
Me
Me
Me
Et
90
90
>95
80
>95
70[e]
>95[f]
>95[f]
>95[f]
>95[f]
when the bulkiness of alkyl
group was increased (en-
tries 10–13), as was previously
found when using diethylzinc.
Despite the potential high in-
terest of the above mentioned
type of chiral diarylalkanols 15
with electronically and sterical-
ly similar aryl rings, the use of
very expensive diphenylzinc
(13c) makes this approach less
attractive for their enantioselec-
tive syntheses. To avoid this in-
convenience, other alternative
14e
14 f
14g
14h
14i
15a
15b
15c
93 (À)
86 (À)
Et
Et
85 (+)
>99[d] (+)
65 (À)
ꢁ
9
Me
Ph
Ph
Ph
Ph
10
11
12
13
92[g] (À)
96[g] (+)
91[g] (+)
80[g] (+)
6c
6c
6c
15d
[a] Isolated yields after bulb-to-bulb distillation or column chromatography. [b] Determined by using GLC
with a cyclodextrin column, the absolute configuration or the sign of the predominant enantiomer is indicated
in parentheses. [c] Yield after 120 h. [d] Only one enantiomer was detected. [e] Yield after 240 h. [f] Yield after
24 h. [g] Determined by using HPLC with Chiracel AD column.
10a,b; however, the reaction times and the chemical yields
were accountably more inferior for ligands 10 than for 6c
(compare entries 1–3). The presence of either electron-do-
nating or -withdrawing groups at the 4-position of the aro-
matic ring of the ketone did not have any impact on the re-
sults (compare entries 4 and 5 in Table 3 and entry 4 in
Table 2). However, the size of both the aromatic group and
the corresponding alkyl substituent of the ketones had an
important impact on the results. Thus, the increase in size of
the aryl substituent from phenyl to naphthyl (entries 4 and 6
in Tables 2 and 3, respectively) or the alkyl substituent from
methyl to n-butyl (entries 18 and 7 in Tables 2 and 3, respec-
tively) decreased the enantioselectivity from 98, >99% to
86, 85%, respectively. The ethylation process also worked
nicely for a,b-unsaturated ketones, independent of the mul-
tiple bonds, with only one enantiomer detected. These excel-
lent results with HOCSAC as the promoter ligand have
been applied to the synthesis of (À)-frontatlin through the
catalytic enantioselective addition of dimethylzinc to a func-
tionalized a,b-unsaturated ketone,[21] and to other tertiary
alcohols.[22] It is worth noting that the enantioselective addi-
tion of dimethylzinc (13b) to cyclohexyl butyl ketone took
place, for the first time, with a meritorious 65% ee (entry 9,
preparations of organozinc reagents were evaluated.[27] Our
first choice was the use of arylboronic acids as a viable
phenyl source,[28] as they avoid the use of the aryllithium or
the related magnesium derivative and overcomes the intrin-
sic problem of the presence of achiral lithium or magnesium
salts, which could compete with the chiral catalysts in the
addition step.[29] Thus, the reaction of different boronic acids
16 with an excess of diethylzinc at 708C gave the corre-
sponding arylzinc derivatives 17, which were in situ trapped
by reaction with different ketones 12 to yield the expected
diarylalkanols 15 or the related alcohols 14 after hydrolysis
(Table 4). In fact, the reaction of phenyl boronic acid and 4-
bromoacetophenone produced the expected alcohol 15b
with a slightly worse result than when pure diphenylzinc was
used (compare entries 11 and 1 in Tables 3 and 4, respective-
ly), with byproducts resulting from the ethylation of the
ketone and the auto-aldol condensation process detected.
To minimize the formation of these byproducts, several reac-
tion condition parameters were changed, such as the addi-
tion temperature, amount of titanium tetraisopropoxide, and
solvent, and in all cases the chemical yields were significant-
ly inferior and the enantioselectivity similar. We then stud-
ied the influence of the nature of the ketone on the enantio-
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4435

M. Yus, D. J. Ramón et al.
Table 4. Catalytic enantioselective arylation of ketones by using boronic
acids as source of nucleophile.
dropped (entry 10) and the reaction time was increased to
three days producing chemical yield of only 31% (40% of
starting ketone was recovered).
The reaction performed by using 3-pyridylboronic acid or
diethyl(3-pyridyl)borane merits a separate comment, as in
both cases the expected tertiary alcohol could not be detect-
ed, the starting acetophenone being consumed in reduction,
auto-aldol, and ethylation processes.
One of the drawbacks of the aforementioned protocol
was the use of a large excess of diethylzinc due to the pres-
ence of two acidic protons from the boronic acid, which are
partially removed[30] prior to the exchange to form the hypo-
thetical species 17. The difficulty in adjusting this excess
meant that one of the byproducts was the corresponding
ethylated tertiary alcohol, the amount of which was always
lower than 10%. To overcome this problem, we turned our
attention to triarylborane as an initial source of nucleophile,
as three aryl moieties of borane compound are exchangea-
ble in principle.[31] Thus, the overnight reaction of triphenyl-
borane (18) and diethylzinc (13a) at 708C under an argon
atmosphere, hypothetically, produced the corresponding
ethyl phenyl zinc intermediated of type 17, which was in situ
trapped by standard catalytic enantioselective addition to 4-
bromoacetophenone, by using HOCSAC (6c) as chiral pro-
moter, to yield the expected diaryl alkanol 15b with excel-
lent results after a 16 h reaction (Table 5, entry 1). The
enantioselectivity obtained for this reaction was similar to
that obtained when using either the pure diphenylzinc or
the boronic/zinc exchange strategy. The previous transmetal-
lation step could be avoided and the alcohol 15b obtained
by simply mixing all reagents at the same time, which im-
plies that the transmetallation step is faster than the further
Entry
X
R1
R2
Product
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
Me
Br
CF3
H
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
Et
nBu
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
15b
15b[c]
79
81 (+)
73 (+)
n.d.[f]
45[d]
15b[e]
2
40
35
25
65
58
65
15b[g]
72 (+)
75 (+)
6[i] (R)
30[i] (R)
84 (+)
93 (À)
64[l] (À)
68 (+)
15b[h]
ent-14a
ent-14j
ent-15a
ent-15b
ent-15c
15d
9
10
11
31[j] (52)[k]
41[j] (91)[k]
Ph
[a] Isolated yields after column chromatography. [b] Determined by
HPLC using a Chiracel columns, the absolute configuration or the sign of
the predominant enantiomer is indicated in parentheses. [c] The tempera-
ture for the addition step was 08C. [d] Isolated yield after 10 d. [e] The
temperature for the addition step was 608C. [f] n.d.=not detected.
[g] Only 10 mol% of Ti(OiPr)4 was used. [h] CH2Cl2 was used as the sol-
A
vent. [i] Determined by using GLC with a cyclodextrin column. [j] Isolat-
ed yield after 3 d. [k] Yield based on the amount of starting ketone con-
sumed. [l] Isolated yield after 3 d.
selectivity, finding that the results for simple small dialkyl
ketones were very low, increasing as the difference between
both alkyl groups increased (en-
tries 6 and 7, Table 4). For aryl
Table 5. Catalytic enantioselective phenylation of ketones by using triphenylborane as source of nucleophile.
alkyl ketones the results were
good, decreasing as the alkyl
group became more hindered
(compare entries 1 and 11). The
effect of the substitutents on the
arylboronic acid was also
checked, and the enantioselec-
tivity obtained for systems bear-
ing either a weak electron-do-
nating group or a slightly elec-
tron-withdrawing group gave re-
sults in the range of those ob-
Entry
Ligand
t [h]
R1
R2
Product
Yield [%][a]
ee [%][b]
tained
by
using
pure
1
2
3
4
5
6
7
8
6c
6c
10a
10b
6c
6c
6c
6c
16
60[c]
120
24
16
16
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-MeC6H4
4-F3CC6H4
4-BrC6H4
nBu
Me
Me
Me
Me
Me
Me
Et
15b
15b
15b
15b
15a
96
81
90
96
98
83
63
50
90 (+)
82 (+)
diphenylzinc (entries 8 and 9),
which could lead one to believe
that the electronic character of
arylboronic acid did not have
any influence on the results.
However, when the reaction
was performed with 4-trifluoro-
methylphenylboronic acid as a
nucleophilic aryl source, the
>99[d] (+)
>99[d] (+)
93 (À)
15c
15d
78 (+)
40
70
79 (+)
Me
ent-14j
25[e] (R)
[a] Isolated yields after column chromatography. [b] Determined by using HPLC with a Chiracel column, the
absolute configuration or the sign of the predominant enantiomer is indicated in parentheses. [c] The previous
transmetallation process was not performed. [d] Only one enantiomer was detected. [e] Determined by using
enantioselectivity substantially GLC with a cyclodextrin column.
4436
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 4431 – 4445

À
C C Coupling
FULL PAPER
catalytic enantioselective one (entry 2). However, in this
case, the enantioselectivity and chemical yield were slightly
lower, while the reaction time was greatly increased. Sur-
prisingly, when the reaction was performed with the triden-
tate chiral systems 10a,b, only one enantiomer of product
could be detected, although the reaction time suffered an
important increase. The presence of a weak electron-donat-
ing group on the aryl moiety of the ketone had a beneficial
effect as far as the enantioselectivity was concerned; howev-
er, the presence of electron-withdrawing groups on the aryl
moiety or the presence of a more hindered alkyl moiety in
the ketone decreased these results (entries 5–7). The use of
2-pentanone gave the expected alcohol ent-14j with similar
results to those obtained when phenylboronic acid was used
as a nuleophilic source (compare entries 7 and 8 in Tables 4
and 5, respectively) and significantly lower than those ob-
tained for aryl alkyl ketones.
Surprisingly, the reaction failed when other commercially
available triarylborane derivatives were used as a source of
nucleophile. We rationalized these results by proposing that
amine derivatives present in the reaction mixture were
acting as stabilizating agents for the borane, which could in-
terfere in either the transmetallation or the addition step. In
fact, very recently, the kinetics of the transmetallation reac-
tions between different phenylborane complexes and dieth-
ylzinc has been studied, showing that the presence of
amines retarded this equilibrium and that even the phenyl-
zinc reagent generated from ammonia complex was signifi-
cantly less reactive.[30g] To prove this hypothesis, we pre-
pared the corresponding substituted triarylborane by direct
reaction of the corresponding arylmagnesium bromide 19
with trifluoro boron ether complex,[32] followed by precipita-
tion of magnesium salts to avoid the possible competition of
this Lewis acid with the chiral titanium one. The salt-free
triarylborane was then transmetallated with diethylzinc and
the arylzinc reagent of type 17 was trapped in the catalytic
enantioselective addition to acetophenone (12a) in the pres-
ence of chiral promoter HOCSAC (6c) to yield, after hy-
drolysis, the expected diarylalkanols 15 (Table 6). The re-
sults were excellent for 4-methylphenylmagnesium bromide
(entry 1) and practically independent of the electronic char-
acter of substituents (compare entries 2 and 4). It should be
pointed out that in the cases where chloro- and methoxy-
phenylmagnesium bromide derivatives were used (entries 3
and 5), the typical elimination of magnesium salts failed.
These results point out the great importance of the presence
of any hypothetical “inert” salt additives to obtain good re-
sults.
After the great success in the arylation of ketones after
the boron/zinc-transmetallation process, we focused on the
use of alternative zinc reagents obtained by transmetallation
in the catalytic enantioselective addition, the first trial being
an allylation process.[33] The idea was to employ allyl esters
as a source of nucleophile through p-allyl palladium umpo-
lung processes. It is well known that their reaction with pal-
ladium(0) renders the corresponding allyl palladium com-
plex, which in turn can be transmetallated with diethylzinc
to generate in situ allylzinc derivatives.[34] The final catalytic
enantioselective reaction with ketones would give the corre-
sponding chiral tertiary homoallylic alcohol. Thus, when the
reaction was performed by using diallyl carbonate (21a)
with acetophenone (12a) as the electrophilic partner and
HOCSAC (6c) as the chiral promoter, the expected alcohol
22a was obtained with an excellent chemical yield, but with
a very low enantioselectivity (Scheme 5), the absolute con-
figuration of alcohol being S,[35] as was expected for this
ligand. The same reaction with cinnamyl acetate (21b) gave
an equimolecular mixture of the two diastereoisomers syn-
and anti-22b, the enantioselectivity depending on the chiral
promoter used. When the promoter HOCSAC (6c) was
used, the diastereoisomer syn-22b showed the highest ee of
the series (Scheme 5). Independently of the promoter used
(6c, 10a, or 10c), the diastereoisomer syn-22b produced
higher ee than the related anti-22b, the value for the former
isomer being double that of the previous one. The results
are indeed not very good, so the transmetallation strategy is
not a good one to use for the allylation processes.
The next process studied was the alkynylation process,[36]
performed by deprotonation of phenylacetylene (23a) with
diethylzinc to yield the corresponding alkynyl zinc re-
Table 6. Catalytic enantioselective arylation of ketones by using
Grignard reagents as source of nucleophile.
Entry
t [h]
R
Product
Yield [%][a]
ee [%][b]
1
2
3
4
5
5
23
97
23
100
4-Me
3-Me
4-Cl
4-F
4-MeO
ent-15a
15e
95
30
15
70
0
96 (+)
86 (À)
12 (À)
84 (À)
–
15 f
15g
15h
[a] Isolated yields after column chromatography. [b] Determined by using
HPLC with a Chiracel column, the sign of the predominant enantiomer
is indicated in parentheses.
Scheme 5. Allylation of acetophenone (12a): a) [Pd
ACHTREUNG
Et2Zn (900 mol%), PhMe, 708C, 16 h; b) Ti
(5 mol%), PhCOMe (12a, 100 mol%), 258C.
ACHTREUNG
Chem. Eur. J. 2006, 12, 4431 – 4445
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4437

M. Yus, D. J. Ramón et al.
agent,[37] which was trapped by subsequent reaction with
acetophenone (12a) in the presence of substoichiometric
amounts of a chiral ligand and titanium tetraisopropoxide
(Scheme 6). The results when HOCSAC (6c) was used
6c gave slightly lower enantioselection than ligand 10b in
the alkenylation of acetophenone by using trimethylsilyl-
substituted alkynes to yield alcohol 26a (compare entries 1
and 2); this functionalized tertiary alcohol had extra value
due to its possible utilization as starting material in further
coupling reactions.[41] As in previous addition processes, the
alkenylation by using phenylacetylene (23a) gave practically
the same results for ligands 10a,b (entries 3 and 4). Con-
cerning the scope of the reaction, the best results were ob-
tained by using aliphatic alkynes (with or without function-
alization). The nature of the ketone was more important
than the bulkiness of the substitutents, thus the a,b-unsatu-
rated ketones produced a worse result (entry 6).
Scheme 6. Alkynylation of acetophenone (12a): a) PhMe, 258C, 3 h;
b) Ti(OiPr)4 (10 mol%), ligand (5 mol%), PhCOMe (12a, 100 mol%),
258C.
N
Spectroscopic studies on the possible catalyst: Once we
found that the ligands reported in this study (tri- and tetra-
dentate isoborneolsulfonamide derivatives) produced better
enantioselectivity than the related bidentate isoborneolsul-
fonamide derivatives (indirect proof of our hypothesis that
the catalytic species was a bimetallic titanium complex), we
then tried to confirm it spectroscopically. We initiated the
study with the crystal structure of chiral ligand HOCSAC
(6c, Figure 1), which showed a typical C2 symmetry, in con-
cordance with the 1H NMR spectrum obtained. However,
all our attempts to obtain suitable crystals of the related
HOCSAC–titanium complexes failed, producing powdered
materials.
(53% ee) were better than those obtained when tridentate
ligands 10a,b were used (20 and 36% ee, respectively). This
level of enantioselectivity could not be improved by either
the addition of 2.5 mol% of the polyethyleneglicol deriva-
tive[38] (DiMPEG: polyethylene glycol dimethyl ether Mn
2000, after 62 h: 24%, 32% ee) or by performing the previ-
ous preparation of phenylethynyltitanium triisopropoxide[39]
and final addition to acetophenone (after 48 h: 60%,
8% ee), protocols which have been successfully applied for
other enantioselective additions to carbonyl compounds.
Finally, we studied the catalytic enantioselective alkenyla-
tion of ketones through a hydrozirconation process of termi-
nal alkynes,[40] followed by a transmetallation with dimethyl-
zinc (13b) and addition to ketones, which was far more suc-
cessful (Table 7). Firstly, we studied the influence of the
chiral promoter on the enantioselectivity, finding that ligand
After this failure, we turned our attention to the possibili-
ty of detecting the bimetallic HOCSAC-titanium complex
1
by other spectroscopic techniques. Thus, H NMR spectra of
mixtures of different ratios of ligand HOCSAC (6c) and ti-
tanium tetraisopropoxide were recorded at room tempera-
ture (Figure 2). Previously, we applied this strategy with the
simple ligand 1, obtaining com-
Table 7. Catalytic enantioselective alkenylation of ketones.
plicated spectra in which the
structure of the main complex
depended strongly on the initial
amount of titanium tetraiso-
propoxide added.[11b] In the case
studied here, when a equimo-
lecular amount of HOCSAC
was mixed with titanium tetrai-
sopropoxide in toluene at room
temperature, after removing all
volatiles, the spectrum showed
mainly two compounds: the
starting unchanged ligand and
another complex. Surprisingly,
Entry
Ligand
R1
R2
R3
t [h]
Product
Yield [%][a]
ee [%][b]
when the reagents ratio in-
creased from 1:1 to 1:2, only
one complex appeared, the
same compound detected in the
previous spectrum. This com-
plex was also the main product
of the mixture obtained by
using a large excess of titanium
tetraisopropoxide, which indi-
1
2
3
4
5
6
7
6c
10b
10a
10b
10b
10b
10b
SiMe3
SiMe3
Ph
Ph
Ph
Ph
Ph
Ph
PhC=C
Ph
Me
Me
Me
Me
Me
Me
Et
108
60
72
72
60
26a
26a
26b
26b
26c
26d
26e
55
75
85
77
57
98
45
85 (À)
94 (À)
76 (S)
78 (S)
94 (S)
74 (À)
90 (S)
Ph
nBu
nBu
nBu
16
132
[a] Isolated yields after column chromatography. [b] Determined by using HPLC with a Chiracel column, the
absolute configuration or the sign of the predominant enantiomer is indicated in parentheses.
4438
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 4431 – 4445

À
C C Coupling
FULL PAPER
Conclusion
We describe here the preparation of different trans-1-sulfo-
nylamino-2-isoborneolaminocyclohexane derivatives able to
chelate two titanium atoms at the same time. These ligands
have been successfully used in the uncommon catalytic
enantioselective addition of organozinc reagents to ketones.
The procedures permitted not only the use of commercially
available dialkylzinc reagents but also of other zinc reagents
obtained through different transmetallation processes from
arylboronic acids, arylboranes, arylmagnesiums, allylesters,
and alkenylzirconiums. The enantioselectivity found for ter-
tiary alcohols obtained after an alkylation or an arylation
process was unsurpassable (only one enantiomer detected).
Enantioselectivity was excellent for the alkenylation process
(up to 94% ee), whereas the enantiomeric excesses for relat-
ed alcohols obtained through an alkynylation or allylation
process were modest. Some evidence for the presence of a
complex bearing two titanium atoms and a ligand molecule
in the mechanistic pathway were found through 1H N MR
spectroscopic studies, this being the driving force behind our
ligand design.
Figure 1. ORTEP drawing of HOCSAC ligand (6c).
cates its high stability, providing indirect proof of the possi-
ble existence of bimetallic complexes as the truly catalytic
active species and validated our proposal for ligand design.
Experimental Section
Chemicals and instrumentation: Melt-
ing points were obtained with a Reich-
ert Thermovar apparatus. Distillation
for purification of the alcohol products
was performed in a Büchi GKR-51
bulb-to-bulb distillation apparatus,
boiling points correspond to the air
bath temperature. [a]D were recorded
at room temperature (ca. 258C) in a
DIP-1000 JASCO polarimeter (p.a.
solvents, Panreac). FTIR spectra were
obtained on a Nicolet Impact 400D
spectrophotometer. NMR spectra
were recorded on a Bruker AC-300
(300 MHz for 1H and 75 MHz for 13C
spectra) by using CDCl3 as the solvent
and TMS as the internal standard;
chemical sifts are given in d (ppm)
and coupling constants (J) in Hz. Mass
spectra (EI) were obtained at 70 eV
on a Shimazdu QP-5000 spectrometer,
giving fragment ions in m/z with rela-
tive intensities (%) in parentheses.
High resolution mass spectra and X-
ray experiments were performed by
the corresponding Mass Spectrometry
and Crystallographic Service at the
University of Alicante. The purity of
volatile products and the chromato-
graphic analyses (GLC) were deter-
mined with a Hewlett Packard HP-
5890 instrument equipped with
a
flame ionization detector and 12 m
HP-1 capillary column (0.2 mm diame-
ter, 0.33 mm film thickness, OV-1 sta-
tionary phase), by using nitrogen
Figure 2. 1H NMR spectra in CDCl3 at room temperature of HOCSAC/Ti
A
(2 mLminÀ1
)
as the carrier gas
Chem. Eur. J. 2006, 12, 4431 – 4445
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4439

M. Yus, D. J. Ramón et al.
(Tinjector =2758C,
T
detector =3008C,
T
column =808C (3 min) and 60–2708C
13.7 Hz, 2H each; 2”CH2S), 3.45 (s, 2H; 2”OH), 4.00–4.50 (m, 2H; 2”
CHO), 4.85–4.86 (m, 2H; 2”CHN), 6.42 (s, 2H; 2”NH), 7.20–7.25 ppm
(m, 10H; 2”Ph); 13C NMR: d=19.6 (2C), 20.10 (2C), 27.3 (2C), 29.9
(2C), 39.2 (2C), 44.1 (2C), 48.4 (2C), 50.2 (2C), 53.85 (2C), 62.3 (2C),
75.95 (2C), 128.3 (4C), 128.4 (2C), 128.7 (4C), 138.0 (2C); IR (KBr):
(158CminÀ1), p=40 kPa; tr values are given in min under these condi-
tions). The enantiomeric ratios (er) for the calculation of the enantiomer-
ic excess of tertiary alcohols were determined with the aforementioned
apparatus by using either a 50 m WCOT fused silica capillary column
(0.25 mm diameter, 0.25 mm film thickness, CP-cyclodextrin-b-2,3,6M-
19) with nitrogen as the carrier gas (Tinjector =2508C, Tdetector =2608C; A
n˜ =3562, 3416, 3259 (NH, OH), 3030 (C=CH), 1334, 1146 (SO2N),
+
1074 cmÀ1 (C O); MS (EI): m/z (%): 642 (<1) [MÀ2H] , 106 (100);
À
T
column =1008C (20 min) and 2208C (0.38CminÀ1), P=
HRMS: m/z: calcd for C34H48N2O6S2·C10H7N2O3S: 427.2055; found:
conditions:
120 kPa) or a 50 WCOT fused silica capillary column (0.25 mm diameter,
0.25 mm film thickness, FS-Lipodex-E, g-CD, Tinjector =2508C, Tdetector
427.2055.
=
(1S,2R,4S,1’R,2’R,1’’S,2’’R,4’’S)-N-{trans-2’-[2’’-Hydroxy-7’’,7’’-
2608C; B conditions: Tcolumn =908C (5 min) and 1808C (0.18CminÀ1), P=
120 kPa). Alternatively, the enantiomeric ratios were determined by
HPLC analyses in a HP-1100 or Jasco P-1030 apparatus by using hexane/
2-propanol mixtures as solvents, and as chiral columns: Chiralcel OD-H
(ODH), Chiralpak AD (AD), Chiralpak AS (AS), and Chiralcel OJ
(OJ), indicating in each case the column and solvent ratio used. The tr(R)
and tr(S) values are given in min under these conditions. TLC was carried
out on Schleicher & Schuell F1400/LS 254 plates coated with a 0.2 mm
layer of silica gel; detection by UV254 light, staining with phosphomolyb-
dimethylbicyclo
droxy-7,7-dimethylbicyclo
ACHTREUNG
AHCTREUNG
White crystals; Rf =0.51 (hexane/AcOEt 1:1); m.p. 175–1778C (AcOEt/
hexane); [a]D =À37.19 (c=2.1 in CHCl3); 1H NMR: d=0.83, 1.06 (2s,
6H each; 4”CH3), 1.10–2.15 (m, 24H; CH(CH2)4CH, 2”(CH2)2CHCH2),
G
2.89, 3.47 (2d, J=13.6 Hz, 2H each; 2”CH2S), 3.05 (brs, 2H; 2”OH),
4.05–4.10 (m, 2H; 2”CHO), 5.50–5.55 ppm (m, 2H; 2”NH); 13C NMR:
d=19.8 (2C), 20.45 (2C), 24.65 (2C), 27.25 (2C), 30.5 (2C), 34.6 (2C),
38.95 (2C), 44.35 (2C), 48.7 (2C), 50.5 (2C), 53.85 (2C), 57.65 (2C),
76.55 ppm (2C); IR (KBr): n˜ =3529, 3214, (OH), 1140, 1073 cmÀ1 (CO);
MS (EI): m/z (%): 528 (<1) [MÀH2O]+, 93 (100); HRMS: m/z: calcd
for C26H46N2O6S2-H2O: 528.2691; found: 528.2673; crystal data:
C26H46N2O6S2, M=546.77; orthorhombic, a=12.903(2), b=20.813(4), c=
dic acid (25 g phosphomolybdic acid, 10 g Ce(SO4)2·4H2O, 60 mL concen-
A
trated H2SO4 and 940 mL H2O) or with I2; Rf values are given under
these conditions. Column chromatography was carried out by using silica
gel 60 of 35–70 mesh. (E)-1-Phenylhept-1-en-3-one[42] and cyclohexyl but-
1-yl ketone[43] were prepared by reaction of the corresponding acyl chlor-
ide with morpholine, followed by addition of n-butyllithium. All reagents
were commercially available (Acros, Aldrich, Strem) and were used as
received. Solvents were dried by standard procedures.[44]
23.066(4) Š; V=6194(4) Š3; space group P2(1)2(1)2; Z=8; 1calcd
1.173 MgmÀ3; l=0.71073 Š; m=0.210 mmÀ1; F
(000)=2368; T=À100Æ
=
AHCTREUNG
18C. Data collection based on three w-scan runs (starting with w=À348)
at values of f=0, 120, 2408 with the detector at 2q=À328. An additional
run of 100 frames at 2q=À32, w=À34, and f=08 was acquired to im-
prove redundancy. For each of these runs, 606 frames were collected at
0.38 intervals and 30 s per frame. The diffraction frames were integrated
by using the program SAINT and the integrated intensities were correct-
ed for Lorentz-polarization effects with SADABS. The structure was
solved by direct methods[3] and refined to all 10802 unique Fo2 by full
matrix least squares. All of the hydrogen atoms were placed at idealized
positions and refined as rigid atoms. Final wR2=0.1260 for all data and
705 parameters; R1=0.0704 for 5413 Fo >4s(Fo).
General procedure for the synthesis of isoborneol sulfonamide deriva-
tives 6 and 11: A solution of DMAP (0.66 g, 5.4 mmol, 0.45 equiv), Et3N
(3.5 mL, 25 mmol, 2.1 equiv), and the corresponding ethylendiamine 4
(12 mmol, 1 equiv) or cyclohexylamine (24 mmol, 2 equiv) in CH3CN(25
mLmmolÀ1) was added to a solution of (1S)-(+)-10-camphorsulfonyl
chloride (5) or its enantiomer (1R)-(À)-10-camphorsulfonyl chloride (ent-
5) (6.25 g, 25 mmol, 2.1 equiv) in CH3CN(25 mL) at 0 8C. The mixture
was stirred for 24 h and the temperature allowed to rise to 258C. Then,
the mixture was quenched by the addition of an aqueous solution of
NaOH (3m, 25 mL) and extracted with EtOAc (3”30 mL). The com-
bined organic layers were washed with a HCl solution (2m, 50 mL), dried
over Na2SO4, and concentrated. Finally, the crude residue was dissolved
in ethanol (60 mL) and treated with NaBH4 (1.82 g, 6 equiv) at 08C. The
reaction mixture was warmed up to room temperature and stirred for
24 h. After this time, ethanol was removed under reduced pressure
(15 Torr) and the resulting residue was dissolved in a saturated solution
of NH4Cl (50 mL) and extracted with EtOAc (3”30 mL). The combined
organic layers were washed with brine, dried over anhydrous Na2SO4, fil-
tered, and then concentrated. The residue was purified by flash chroma-
tography on silica gel (hexane/EtOAc) to give isoborneolsulfonamides
6a–f and 11. Yields are included in Table 1 and in the Results and Dis-
cussion section.
(1S,2R,4S,1’S,2’S,1’’S,2’’R,4’’S)-N-{trans-2’-[2’’-Hydroxy-7’’,7’’-
dimethylbicyclo
2-hydroxy-7,7-dimethylbicyclo
White solid; Rf =0.8 (hexane/AcOEt 1:1); m.p. 181–1838C (AcOEt/
ACHTREUNG
AHCTREUNG
1
hexane); [a]D =À97.7 (c=1.9 in CHCl3); H NMR: d=0.55, 0.71 (2s, 6H
each; 4”CH3), 0.80–1.50 (m, 14H; 2”(CH2)2CHCH2), 2.46, 2.88 (2d, J=
13.7 Hz, 2H each; 2”CH2S), 2.97 (s, 2H; 2”OH), 3.95–4.50 (m, 2H; 2”
CHO), 4.70–4.85 (m, 2H; 2”CHN), 5.70 (s, 2H; 2”NH), 7.10–7.30 ppm
(m, 10H; 2”Ph); 13C NMR: d=19.4 (2C), 21.05
(2C), 27.3 (2C), 30.10
G
(2C), 39.05 (2C), 44.15 (2C), 48.5 (2C), 50.2 (2C), 53.8 (2C), 62.4 (2C),
75.95 (2C), 127.8 (4C), 128.5 (2C), 128.8 (4C), 137.6 ppm (2C); IR
(KBr): n˜ =3513, 3431, 3278 (NH, OH), 3060 (C=CH), 1142, 1077 cmÀ1
+
À
(C O); MS (EI): m/z (%): 626 (<1) [MÀH2O] , 106 (100); HRMS: m/
z: calcd for C34H48N2O6S2·C17H24NO3S: 322.1471; found: 322.1432.
(1S,2R,4S,1’’S,2’’R,4’’S)-N-{trans-2’-[2’’-Hydroxy-7’’,7’’-dimethylbicyclo-
ACHTREUNG
(1R,2S,4R,1’R,2’R,1’’R,2’’S,4’’R)-N-{trans-2’-[2’’-Hydroxy-7’’,7’’-
ACHTREUNG
dimethylbicyclo
ACHTREUNG
(hexane/AcOEt 1:1); m.p. 134–1368C (AcOEt/hexane); [a]D =À95.3 (c=
droxy-7,7-dimethylbicyclo
White solid; Rf =0.59 (hexane/AcOEt 1:1); m.p. 209–2118C (AcOEt/
AHCTREUNG
1
1.04 in CHCl3); H NMR: d=0.84, 1.07 (2s, 6H each; 4”CH3), 1.45–1.80
1
(m, 14H; 2” CH2CH(CH2)2), 2.94, 3.50 (2d, J=13.9 Hz, 2H each; 2”
A
hexane); [a]D =À54.7 (c=1.7 in CHCl3); H NMR: d=0.83, 1.07 (2s, 6H
CH2S), 3.36 (brs, 2H; 2”OH), 3.30–3.40 (m, 4H; 2”CH2N), 4.05–4.10
(m, 2H; 2”CHO), 5.55–5.65 ppm (m, 2H; 2”NH); 13C NMR: d=19.8
(2C), 20.5 (2C), 27.3 (2C), 30.3 (2C), 39.2 (2C), 43.5 (2C), 44.3 (2C),
48.8 (2C), 50.3 (2C), 52.1 (2C), 76.2 ppm (2C); IR (KBr): n˜ =3530, 3284
each; 4”CH3), 1.10–2.20 (m, 24H; CH(CH2)4CH, 2”(CH2)2CHCH2),
A
2.96, 3.49 (2d, J=13.7 Hz, 2H each; 2”CH2S), 3.10–3.25 (m, 2H; 2”
OH), 4.05–4.10 (m, 2H; 2”CHO), 4.90–4.95 ppm (m, 2H; 2”NH);
13C NMR: d=19.85 (2C), 20.5 (2C), 24.5 (2C), 27.35 (2C), 30.45 (2C),
34.2 (2C), 39.05 (2C), 44.35 (2C), 48.75 (2C), 50.45 (2C), 54.15 (2C),
(NH, OH), 1148, 1066 cmÀ1 (C O); MS (EI): m/z (%): 492 (<1)
À
[MÀH2O]+, 183 (100); HRMS: m/z: calcd for C22H40N2O6S2·H2O:
57.45 (2C), 76.25 ppm (2C); IR (KBr): n˜ =3466, 3212 (NH, OH), 1142,
1072 cmÀ1 (C O); MS (EI): m/z (%): 545 (<1) [MÀH] , 135 (100);
+
À
474.2209; found: 474.2222.
HRMS: m/z: calcd for C26H46N2O6S2: 528.2797; found: 528.2758.
(1S,2R,4S,1’R,2’R,1’’S,2’’R,4’’S)-N-{trans-2’-[2’’-Hydroxy-7’’,7’’-
dimethylbicyclo
ACHTREUNG
(1S,2R,4S,1’R,2’R,1’’S,2’’R,4’’S)-N-{cis-2’-[2’’-Hydroxy-7’’,7’’-
2-hydroxy-7,7-dimethylbicyclo
A
dimethylbicyclo
ACHTREUNG
White solid; Rf =0.72 (hexane/AcOEt 1:1); m.p. 181–1838C (AcOEt/
droxy-7,7-dimethylbicyclo
ACHTREUNG
1
hexane); [a]D =À11.5 (c=1.9 in CHCl3); H NMR: d=0.40, 0.78 (2s, 6H
White solid; Rf =0.5 (hexane/AcOEt 1:1); m.p. 170–1728C (AcOEt/
hexane); [a]D =À40.5 (c=1.44 in CHCl3); 1H NMR: d=0.83, 1.06, 1.07
each; 4”CH3), 0.95–1.70 (m, 14H; 2”CH2CH(CH2)2), 1.94, 2.94 (2d, J=
A
4440
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 4431 – 4445

À
C C Coupling
FULL PAPER
(3s, 6H, 3H, 6H; 4”CH3), 1.15–2.1 (m, 24H; CH
A
m/z (%): 327 (16), 96 (100); HRMS: m/z: calcd for C23H34N2O6S2:
498.1858; found: 498.1845.
(CH2)2CHCH2), 2.90, 3.03, 3.47, 3.52 (4d, J=13.7 Hz, 1H each; 2”
CH2S), 3.19, 3.63 (2s, 1H each; 2”OH), 4.05–4.10 (m, 2H; 2”CHO),
5.50–5.70 ppm (m, 2H; 2”NH); 13C NMR: d=19.75, 19.8, 20.35, 20.45,
20.95, 21.95, 27.25, 29.6, 30.05, 30.3, 30.45, 39.0, 40.0, 44.3, 44.35, 48.65,
48.7, 50.35, 50.45, 53.2, 53.5, 54.0, 54.15, 60.3, 76.25, 76.35 ppm; IR (KBr):
General procedure for the synthesis of isoborneol derivatives 10a,b:
NaBH4 (2.27 g, 60 mmol, 6 equiv) was added to a solution of the corre-
sponding pure ketone 8 (10 mmol, 1.0 equiv) in ethanol (50 mL) at 08C.
The reaction temperature was then allowed to rise to 258C and the reac-
tion mixture was stirred for 24 h. After this time, the reaction was
quenched with saturated NH4Cl and extracted with EtOAc (4”40 mL).
The combined organic layers were washed with brine, dried over anhy-
drous Na2SO4, filtered, and then concentrated. The residue was purified
by flash chromatography on silica gel (hexane/EtOAc) to give isobor-
neolsulfonamides 10a,b. Yields are included in Scheme 4.
n˜ =3533, 3300 (NH, OH), 1144 cmÀ1 (C O); MS (EI): m/z (%): 528 (<1)
À
[MÀH2O]+, 135 (99), 114 (98), 93 (100); HRMS: m/z: calcd for
C26H46N2O6S2·H2O: 528.2691; found: 528.2695.
A
N
yl)methanesulfonamide (11): Pale yelow oil; Rf =0.70 (hexane/AcOEt
3:2); [a]D =À46.4 (c=1.68 in CHCl3); 1H NMR: d=0.82, 1.07 (2s, 3H
each; 2”CH3), 1.10–2.05 (m, 18H; (CH2)5CH, (CH2)2CHCH2), 2.86, 3.43
(2d, J=13.7 Hz, 1H each; CH2S), 3.30 (s, 1H; OH), 4.10–4.15 (m, 1H;
CHO), 4.76 ppm (d, J=7.4 Hz, 1H; NH); 13C NMR: d=19.8, 20.45, 24.7,
24.8, 25.05, 27.25, 30.5, 34.45, 34.5, 38.85, 44.3, 48.5, 50.4, 52.8, 53.85,
(1S,2R,4S,1’R,2’R)-N-{trans-2’-[2-Hydroxy-7,7-dimethylbicyclo-
A
mide (10a): White solid; Rf =0.63 (hexane/AcOEt 1:1); m.p. 90–928C
(AcOEt/hexane); [a]D =+7.8 (c=2.1 in CHCl3); 1H NMR: d=0.87, 1.10
76.3 ppm; IR (KBr): n˜ =3541, 3281 (NH, OH), 1137, 1175 cmÀ1 (C O);
À
(2s, 3H each;
C
A
G
MS (EI): m/z (%): 314 (<1) [MÀH]+, 99 (100); HRMS: m/z: calcd for
(CH2)2CHCH2), 2.43 (s, 3H; CH3Ar), 2.82–2.86, 3.08–3.12 (2m, 1H each;
2”CHN), 2.99, 3.59 (2d, J=13.7 Hz, 1H each; CH2S), 3.40 (d, J=3.8 Hz,
1H; CHO), 4.10 (s, 1H; OH), 4.97 (d, J=7.2 Hz, 1H; NH), 5.18 (d, J=
7.8 Hz, 1H; NH), 7.31, 7.75 ppm (2d, J=8.1 Hz, 2H each; Ar);
13C NMR: d=19.9, 21.45, 21.5, 24.4, 24.6, 27.3, 30.6, 33.2, 35.0, 39.0, 44.4,
48.8, 50.5, 53.7, 57.0, 57.7, 60.4, 126.9 (2C), 129.8 (2C), 137.6, 143.6 ppm;
C16H29NO3S: 315.1868; found: 315.1878.
General procedure for the synthesis of canforsulfonamide derivatives 8:
An aqueous solution of NaOH (2m, 15 mL) was added to a solution of
(1R,2R)-trans-(+)diaminocyclohexane (1.37 g, 12 mmol, 1 equiv) in
CH2Cl2 (15 mL) at 08C. A solution of the corresponding arenesulfonyl
chloride 7 (12 mmol, 1.0 equiv) in CH2Cl2 (15 mL) was then slowly added
to the resulting biphasic mixture (this mixture was stirred strongly) and
the temperature was allowed to rise to 258C over 6 h. After this time, the
reaction was quenched by the addition of HCl (2m) until the mixture
reached an acidic pH. The organic layer was then decanted and discard-
ed. The acid aqueous layer was basified by the addition of an aqueous
solution of NaOH (3m) and extracted with CH2Cl2 (4”50 mL). The re-
sulting organic layers were dried over anhydrous Na2SO4, filtered, and
then concentrated. DMAP (0.73 mg, 0.5 equiv) and Et3N(7.6 mL,
4.5 equiv) were added to a solution of the resulting crude residue in
IR (KBr): n˜ =3535, 3290 (NH, OH), 1088 cmÀ1 (C O); MS (EI): m/z
À
(%): 483 (<1) [MÀH]+, 96 (100); HRMS: m/z: calcd for C23H36N2O5S2:
484.2066; found: 484.2054.
(1S,2R,4S,1’R,2’R)-N-{trans-2’-[2-Hydroxy-7,7-dimethylbicyclo-
A
namide (10b): White solid; Rf =0.29 (hexane/AcOEt 1:1); m.p. 85–878C
(AcOEt/hexane); [a]D =+9.2 (c=0.77 in CHCl3); 1H N MR: d=0.86,
1.10 (2s, 3H each;
C
A
U
(CH2)2CHCH2), 2.80–2.85, 3.10–3.15 (2m, 1H each; 2”CHN), 2.97, 3.59
(2d, J=13.7 Hz, 1H each; CH2S), 3.45 (brs, 1H; OH), 3.87 (s, 3H;
CH3O), 5.10 (d, J=7.2 Hz, 1H; NH), 5.33 (d, J=7.8 Hz, 1H; NH), 6.98,
7.81 ppm (2d, J=8.9 Hz, 2H each; Ar); 13C N MR: d=19.9, 20.4, 24.4,
24.6, 27.3, 30.55, 33.1, 34.85, 39.0, 44.4, 48.75, 50.5, 53.7, 55.6, 56.9, 57.6,
CH3CN(25 mL) at
0 8C. A solution of (1S)-(+)-10-camphorsulfonyl
chloride (5, 4.51 g, 18 mmol, 1.5 equiv) in CH3CN(25 mL) was slowly
added to the above solution at 08C. After 24 h, the temperature of the
mixture was allowed to rise to 258C and the reaction mixture was then
quenched by the addition of an aqueous solution of NaOH (3m, 50 mL).
This mixture was extracted with EtOAc (4”40 mL) and the resulting or-
ganic layers were washed with HCl (2m), dried over anhydrous Na2SO4,
filtered, and then concentrated. The residue was purified by flash chro-
matography on silica gel (hexane/EtOAc) to give ketones 8. Yields are
included in Scheme 4.
76.6, 114.3 (2C), 129.1 (2C), 132.2, 162.9 ppm; IR (KBr): n˜ =3529, 3286
(NH, OH), 1164 cmÀ1 (C O); MS (EI): m/z (%): 500 (<1) [M] , 96
+
À
(100); HRMS: m/z: calcd for C23H36N2O6S2·H: 499.1931; found: 499.1931.
(1S,2R,4S,1’R,2’R)-N-{trans-2’-[2-Hydroxy-7,7-dimethylbicyclo-
A
(10c): A solution of (1S)-(+)-10-camphorsulfonyl chloride (5, 3.10 g,
12.5 mmol, 1.05 equiv) in CH3CN(25 mL) was added to a solution of
(1R,2R)-trans-(+)diaminocyclohexane (4c, 1.37 g, 12 mmol, 1 equiv),
DMAP (0.66 g, 0.5 equiv), and Et3N(7.6 mL, 4.5 equiv) in CH 3CN
(25 mL) at 08C. The reaction mixture stirred for 24 h and the reaction
temperature allowed to rise to 258C. After this time, the reaction was
quenched by the addition of an aqueous solution of NaOH (3m, 25 mL)
and was extracted with EtOAc (4”40 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered, and then
concentrated. The resulting crude residue was dissolved in THF (25 mL)
and Et3N(1.8 mL, 13 mmol, 1.1 equiv) was added at 0 8C. Then, methane-
sulfonyl chloride (9, 1.01 mL, 13.0 mmol, 1.1 equiv) was slowly added at
the same temperature. The reaction temperature was allowed to rise to
258C and the mixture was stirred for 24 h. After this time, the reaction
mixture was quenched by the addition of an aqueous solution of NaOH
(3m) and was extracted with EtOAc. The combined organic layers were
washed with HCl (1m), dried over anhydrous Na2SO4, filtered, and then
concentrated. DIBAL (1m in hexane, 35 mL, 35 mmol, 3.5 equiv) was
added to a solution of the resulting residue in anhydrous THF (50 mL)
under an argon atmosphere at À788C. The reaction mixture was then
warmed to room temperature and after 24 h stirring, was quenched with
HCl (2m) and extracted with CH2Cl2 (3”25 mL). The organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered, and then
concentrated. The residue was purified by flash chromatography on silica
gel (hexane/EtOAc) to give the title compound 10c. The yield of the re-
action is included in Scheme 4. White solid; Rf =0.24 (hexane/AcOEt
1:1); m.p. 185–1878C (AcOEt/hexane); [a]D =À29.8 (c=1.24 in CHCl3);
(1S,4S,1’R,2’R)-N-{trans-2’-[7,7-Dimethyl-2-oxobicyclo
ACHTREUNG
methylsulfonamino]cyclohexyl}-4’’-methylbenzenesulfonamide
White solid; Rf =0.41 (hexane/AcOEt 1:1); m.p. 67–698C (AcOEt/
1
hexane); [a]D =++23.3 (c=1.2 in CHCl3); H NMR: d=0.97, 1.11 (2s, 3H
each; C
N
N
(s, 3H; CH3Ar), 2.75–2.85, 3.10–3.20 (2m, 1H each; 2”CHN), 3.01, 3.42
(2d, J=15.1 Hz, 1H each; CH2S), 5.19 (d, J=7.0 Hz, 1H; NH), 5.55 (d,
J=5.8 Hz, 1H; NH), 7.28, 7.78 ppm (2d, J=8.1 Hz, 2H each; Ar);
13C NMR: d=19.50, 19.80, 21.5, 24.1, 24.5, 27.0, 33.6, 42.65, 42.9, 48.7,
51.2, 56.9, 57.3, 59.3, 60.35, 127.2 (2C), 129.6 (2C), 137.3, 143.2,
216.7 ppm; IR (KBr): n˜ =3273 (NH, OH), 1744 cmÀ1 (C=O); MS (EI):
m/z (%): 482 (<1) [M]+, 96 (100); HRMS: m/z: calcd for C23H34N2O5S2:
482.1909; found: 482.1899.
(1S,4S,1’R,2’R)-N-{trans-2’-[7,7-Dimethyl-2-oxobicyclo
ACHTREUNG
methylsulfonamino]cyclohexyl}-4’’-methoxybenzenesulfonamide
White solid; Rf =0.43 (hexane/AcOEt 1:1); m.p. 67–698C (AcOEt/
1
hexane); [a]D =+22.4 (c=1.2 in CHCl3); H NMR: d=090, 1.04 (2s, 3H
each; C
N
N
2.80, 3.10–3.15 (2m, 1H each; 2”CHN), 3.02, 3.44 (2d, J=15.0 Hz, 1H
each; CH2S), 3.86 (s, 3H; CH3O), 5.24 (d, J=7.0 Hz, 1H; NH), 5.58 (d,
J=5.8 Hz, 1H; NH), 6.97, 7.83 ppm (2d, J=8.9 Hz, 2H each; Ar);
13C NMR: d=19.50, 19.80, 24.1, 24.4, 26.4, 27.0, 33.55, 42.6, 42.8, 48.7,
51.2, 55.5, 56.9, 57.2, 59.2, 114.15 (2C), 129.3 (2C), 131.85, 162.7,
216.7 ppm; IR (KBr): n˜ =3290 (NH, OH), 1744 cmÀ1 (C=O); MS (EI):
Chem. Eur. J. 2006, 12, 4431 – 4445
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4441

M. Yus, D. J. Ramón et al.
1H NMR: d=0.84, 1.07 (2s, 3H each; C
(CH2)4CH, (CH2)2CHCH2), 2.90, 3.54 (2d, J=13.7 Hz, 1H each; CH2S),
A
49.9 min; [a]D =+9.6 (c=2.0 in CH2Cl2); er 1st/2nd >99:<1; 1H NMR:
d=1.92 (s, 3H; CH3), 2.55 (s, 1H; OH), 7.25–7.40 ppm (m, 9H; ArH);
13C NMR: d=30.7, 75.85, 120.85, 125.7 (2C), 127.2 (2C), 127.65, 128.3
ACHTREUNG
3.30 (s, 3H; CH3S), 3.08 (s, 1H; OH), 4.05–4.10 (m, 1H; CHO), 5.45–
5.50 ppm (m, 2H; 2”NH); 13C NMR: d=19.85, 20.4, 24.55, 24.6, 27.25
30.45, 34.2, 34.5 39.0, 41.7, 44.35, 48.65, 50.55, 53.95, 57.45, 57.55,
(2C), 131.1 (2C), 147.05, 147.3 ppm; IR (film): n˜ =3437 (OH), 1678 (C=
+
CH), 1011 cmÀ1 (C O); MS (EI): m/z (%): 278 (7) [M+H] , 277 (1)
À
76.55 ppm; IR (KBr): n˜ =3527, 3292 (NH, OH), 1150, 1075 cmÀ1 (C O);
[M]+, 261 (100).
À
MS (EI): m/z (%): 329 (<1) [MÀCH3SO2]+, 96 (100); HRMS: m/z:
1-(4’-Trifluoromethylphenyl)-1-phenylethanol (15c):[51] Pale yellow oil;
Rf =0.48 (hexane/AcOEt 4:1); tr (GC)=10.33 min; HPLC (AD, UV
225 nm, hexane/2-propanol 99:1, flow 1 mLminÀ1): tr (1st)=13.1, tr
(2nd)=15.4 min; [a]D =+19.9 (c=1.37 in CH2Cl2); er 1st/2nd 4:96;
1H NMR: d=1.91 (s, 3H; CH3), 2.44 (s, 1H; OH), 7.20–7.40, 7.50,
7.53 ppm (m, 2d, J=8.8 Hz, 9H; ArH); 13C NMR: d=30.15, 75.54,
calcd for C17H32N2O5S2: 408.1753; found: 408.1769.
General procedure for the enantioselective addition of commercially
available diorganozinc reagents to ketones: A solution of the diorgano-
zinc reagent (13, 12 mmol, 2.4 equiv) in toluene (4.5–20 mL, depending
on the commercial source) was added to a solution of corresponding
chiral ligand 6, 10, or 11 (0.5 mmol, 0.05 equiv) in toluene (10 mL) under
an argon atmosphere. After 5 min stirring at 258C, a new solution of Ti-
124.25 (q, 1J
126.1 (2C), 127.35, 128.35, 129.0 (q, 2J
(film): n˜ =3453 (OH), 1366 (C=CH), 1126 (C F), 1071 cm (C O); MS
(EI): m/z (%): 268 (<1) [M+2H]+, 267 (<1) [M+H]+, 266 (2) [M]+,
251 (100).
A
G
AHCTREUNG
A
sponding ketone (12, 5 mmol, 1.0 equiv). The reaction mixture was stir-
red for several hours/days (see Tables 2, 3, and the Results and Discus-
sion section) at the same temperature and finally quenched by the suc-
cessive addition of methanol (1 mL) and a saturated solution of NH4Cl
(15 mL). The mixture was filtered through Celite and the resulting solu-
tion was extracted with EtOAc (3”50 mL). The organic layers were
dried over anhydrous Na2SO4, filtered, and then concentrated. The resi-
due was purified by bulb-to-bulb distillation or flash chromatography
(hexane/EtOAc) to give chiral tertiary alcohols 14a–i and 15a–d. Yields
and ee values are included in Tables 2, 3, and the Results and Discussion.
Compounds 14a–c,f[11b] and 14d,e,[14] which have been previously fully de-
scribed by us, were characterized by comparison of their spectroscopic
(1H and 13C NMR, IR, and mass spectra) and chromatographic data with
those of the reported alcohols. For the other cases, physical and spectro-
scopic data, including literature references for known compounds follow.
1-(4’-Bromophenyl)-1-phenyl-1-propanol (15d):[52] Pale yellow oil; Rf =
0.57 (hexane/AcOEt 4:1); tr (GC)=13.15 min; HPLC (AD, UV 225 nm,
hexane/2-propanol 97:3, flow 1 mLminÀ1): tr (1st)=10.1, tr (2nd)=
11.7 min; [a]D =+9.9 (c=1.65 in CH2Cl2); er 1st/2nd 10:90; 1H NMR:
d=0.85 (t, J=7.3 Hz, 3H; CH3), 2.04 (s, 1H; OH), 2.26 (q, J=7.2 Hz,
2H; CH2), 7.15–7.40 ppm (m, 9H; ArH); 13C NMR: d=8.0, 34.25, 78.15,
120.65, 125.95 (2C), 127.0, 127.95, 128.25, 131 (2C), 145.85 (2C),
146.4 ppm (2C); IR (film): n˜ =3583 (OH), 1483 (C=CH), 1005 cmÀ1 (C
À
O); MS (EI): m/z (%): 293 (<1) [M+2H]+, 292 (<1) [M+H]+, 291 (<
1) [M]+, 260 (100).
General procedure for the enantioselective addition of organozinc re-
agents prepared from arylboronic acids to ketones: A solution of Et2Zn
(1.1m in toluene, 6.5 mL, 7.2 mmol, 7.2 equiv) was slowly added to a
pressure tube charged with the corresponding arylboronic acid (16,
2.4 mmol, 2.4 equiv) at 08C under argon atmosphere. The resulting solu-
tion was warmed to 708C and stirred for 16 h. Then, the mixture was
cooled to 08C, and HOCSAC ligand (6c) (0.027 g, 0.05 mmol, 0.05 equiv)
(E)-3-Ethyl-1-phenylhept-1-en-3-ol (14g):[46] Pale yellow oil; Rf =0.67
(hexane/AcOEt 7:3); tr (GC)=11.2 min; HPLC (ODH, UV 225 nm,
hexane/2-propanol 98:2, flow 1 mLminÀ1): tr (1st)=12.8, tr (2nd)=
13.8 min; [a]D =+7.6 (c=1.84 in CHCl3); er 1st/2nd 92.5:7.5; 1H NMR:
d=0.85–1.70 (m, 15H; CH3CH2C(OH)(CH2)3CH3), 6.18 (d, J=16.1 Hz,
U
and Ti(OiPr)4 (0.39 mL, 1.3 mmol, 1.3 equiv) were successively added.
A
1H; CHCPh), 6.57 (d, J=16.1 Hz, 1H; CHPh), 7.15–7.40 ppm (m, 5H;
Ph); 13C NMR: d=7.8, 14.0, 23.15, 25.75, 33.7, 40.65, 75.55, 126.25 (2C),
127.15, 127.75, 128.45 (2C), 135.6, 137.15 ppm; IR (film): n˜ =3444 (OH),
1449 cmÀ1 (C=CH); MS (EI): m/z (%): 219 (<1) [M]+, 129 (100).
After 15 min stirring allowing the temperature to rise to 258C, the corre-
sponding ketone (12, 1 mmol, 1 equiv) was added. The reaction mixture
was stirred at the same temperature for 24 h, and was then quenched by
the successive addition of methanol (1 mL) and a saturated solution of
NH4Cl (15 mL). The mixture was filtered through Celite and the result-
ing solution was extracted with EtOAc (3”15 mL). The organic layers
were dried over anhydrous Na2SO4, filtered, and then concentrated. The
residue was purified by bulb-to-bulb distillation or flash chromatography
(hexane/EtOAc) to give chiral tertiary alcohols 14a,j and 15a–d. Yields
and ee values are included in Table 4. Compounds 14a,j[11b] have been
previously fully described by us, and were characterized by the compari-
son of their spectroscopic (1H and 13C NMR, IR, and mass spectra) and
chromatographic data with those of the reported alcohols. Alcohols 15a–
d have already been described in the previous section.
3-Methyl-1-phenyl-1-pentyn-3-ol (14h):[47] Pale yellow oil; Rf =0.85
(hexane/AcOEt 7:3); b.p. 155–1608C (0.1 Torr); tr (GC)=10.47 min; GC
(B conditions): tr (1st)=175.2, tr (2nd)=176.1 min; [a]D =+160.0 (c=1.9
in EtOH); er 1st/2nd >99:<1; 1H NMR: d=1.10 (t, J=7.4 Hz, 3H;
CH2CH3), 1.56 (s, 3H; CCH3), 1.78 (q, J=7.4 Hz, 2H; CH2), 2.10 (s, 1H;
OH), 7.25–7.30, 7.40–7.45 ppm (2m, 3H, 2H; Ph); 13C NMR: d=9.05,
29.25, 36.6, 69.05, 83.3, 92.7, 122.8, 128.15, 128.2 (2C), 131.6 ppm (2C);
IR (film): n˜ =3404 (OH), 3049, 1636 (C=CH), 2196 (C=C), 1118 cmÀ1
+
À
(C O); MS (EI): m/z (%): 174 (5) [M] , 145 (100).
2-Cyclohexyl-2-hexanol (14i):[48] Rf =0.74 (hexane/AcOEt 7:3); b.p. 130–
1358C (0.1 Torr); tr (GC)=10.18 min; GC (A conditions): tr (1st)=94.91,
tr (2nd)=95.81 min; [a]D =À7.0 (c=0.37 in CHCl3); er 1st/2nd 82.5:17.5;
1H NMR: d=0.91 (t, J=6.7 Hz, 3H; CH2CH3), 0.96–1.90 ppm (m, 21H;
General procedure for the enantioselective addition of organozinc re-
agents prepared from triphenylborane (18) to ketones: As in the previous
general procedure, but charging the pressure tube with triphenylborane
(18, 0.387 g, 1.6 mmol, 4.8 equiv) and a solution of Et2Zn (1.1m in tol-
uene, 6.5 mL, 7.2 mmol, 7.2 equiv). Yields and ee values are included in
Table 5. Compound 14j[11b] has been previously fully described by us, and
was characterized by the comparison of its spectroscopic (1H and
13C NMR, IR, and mass spectra) and chromatographic data with those of
the reported alcohol. Alcohols 15a–d have been already described in the
previous section.
(CH2)5CHCCH3(OH)
(CH2)3); 13C NMR: d=14.1, 23.35, 23.95, 25.45,
A
26.55, 26.75, 26’8, 26.85, 27.5, 39.6, 47.2, 74.35 ppm; IR (film): n˜ =3434
+
(OH), 1143 cmÀ1 (C O); MS (EI): m/z (%): 169 (15) [MÀCH3] , 101
À
(100), 71 (100).
1-(4’-Methylphenyl)-1-phenylethanol (ent-15a):[49] Pale yellow oil; Rf =
0.44 (hexane/AcOEt 4:1); tr (GC)=10.74 min; HPLC (AD, UV 225 nm,
hexane/2-propanol 97:3, flow 1 mLminÀ1): tr (1st)=12.7, tr (2nd)=
13.5 min; [a]D =+16.0 (c=1.2 in CH2Cl2); er 1st/2nd 98:2; 1H NMR: d=
1.92 (s, 3H; CH3CO), 2.18 (brs, 1H; OH), 2.32 (s, 3H; CH3Ar), 7.20–
7.40 ppm (m, 9H; ArH); 13C NMR: d=20.95, 30.8, 76.05, 125.8 (4C),
126.8, 128.1 (2C), 128.8 (2C), 136.6, 145.1, 148.2 ppm; IR (film): n˜ =3437
General procedure for the enantioselective addition of organozinc re-
agents prepared from arylmagnesium derivatives (19) to ketones: The
corresponding arylmagnesium halide (19, 7.75 mmol, 3.1 equiv) was
added to a solution of BF3OEt2 (20, 0.314 mL, 2.5 mmol, 1 equiv) in
Et2O (7.5 mL) at 258C under an argon atmosphere, and the resulting
mixture was stirred at the same temperature for 24 h. After this time, the
solution was filtered off and the solvent in the clear solution was re-
moved in vacuo. This crude residue was dissolved in toluene (7.5 mL),
stirred at room temperature for 24 h, and filtered off again under an
(OH), 1518 (C=CH), 1075 cmÀ1 (C O); MS (EI): m/z (%): 213 (1)
À
[M+H]+, 212 (6) [M]+, 197 (100).
1-(4’-Bromophenyl)-1-phenylethanol (15b):[50] Pale green oil; Rf =0.5
(hexane/AcOEt 4:1); tr (GC)=15.10 min; HPLC (ODH, UV 235 nm,
hexane/2-propanol 99:1, flow 1 mLminÀ1): tr (1st)=41.8, tr (2nd)=
4442
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 4431 – 4445

À
C C Coupling
FULL PAPER
argon atmosphere. Finally, the removal of toluene in vacuo produced the
corresponding triarylborane, which was treated with a solution of Et2Zn
(1.1m in toluene, 6.5 mL, 7.2 mmol, 7.2 equiv), following the same proto-
col as in the previous procedure to obtain the diarylalkanols 15a,e–g.
Yields and ee values are included in Table 6. Alcohol 15a has been al-
ready described in the previous section. For other cases, physical and
spectroscopic data, including literature references for known compounds
follow.
13C NMR: d=25.3, 60.3, 74.1, 117.75, 125.6, 126.1 (2C), 127.2, 128.3
(2C), 128.5 (2C), 129.2 (2C), 133.55, 137.6, 141.0 ppm; IR (film): n˜ =
3456 (OH), 1606 cmÀ1 (C=CH); MS (EI): m/z (%): 239 (<1) [M+2H]+,
117 (100).
2,3-Diphenyl-4-penten-2-ol (anti-22b):[55] Pale yellow oil. Rf =0.22
(hexane/AcOEt: 4/1); tr (GC)=13.10 min; HPLC (AD, UV 254 nm,
hexane/2-propanol 98:2, flow 1 mLminÀ1): tr (1st)=15.1, tr (2nd)=
28.9 min; [a]D =+0.5 (c=3.44, CHCl3); er 1st/2nd 61:39; 1H N MR d=
1.11 (s, 3H; CH3), 3.36 (d, J=9.5 Hz, 1H; CHPh), 5.13–5.25 (m, 2H;
CH=CH2), 6.24–6.45 (m, 1H; CH=CH2), 7.18–7.38 ppm (m, 10H; 2”Ph);
13C NMR: d=25.15, 60.3, 74.0, 117.7, 125.6, 126.1 (2C), 127.15, 128.3
(2C), 128.5 (2C), 129.4 (2C), 133.5, 137.6, 140.8 ppm; IR (film): n˜ =3465
(OH), 1606 cmÀ1 (C=CH); MS (EI): m/z (%): 239 (<1) [M+2H]+, 117
(100).
1-(3’-Methylphenyl)-1-phenylethanol (15e):[53] Pale yellow oil; Rf =0.61
(hexane/AcOEt 7:3); tr (GC)=11.03 min; HPLC (AD, UV 225 nm,
hexane/2-propanol 99:1, flow 1 mLminÀ1): tr (1st)=27.7, tr (2nd)=
31.3 min; [a]D =À14.3 (c=1.2 in CH2Cl2); er 1st/2nd 7:93; 1H NMR: d=
1.89 (s, 3H; CH3CO), 2.30 (s, 3H; ArCH3), 2.32 (brs 1H; OH), 7.10–
7.40 ppm (m, 9H; ArH); 13C NMR: d=21.5, 30.7, 76.1, 122.85, 125.75
(2C), 126.45, 127.6, 127.95, 128.05 (2C), 137.6, 147.85, 148.0 ppm; IR
Preparation of 2,4-diphenyl-3-butyn-2-ol (24) by enantioselective alkyny-
(film): n˜ =3435 (OH), 1606 (C=CH), 1379 cmÀ1 (C O); MS (EI): m/z
À
lation of acetophenone (12a):
A solution of phenylacetylene (23a,
(%): 213 (2) [M+H]+, 212 (7) [M]+, 197 (100).
0.33 mL, 3 mmol, 3 equiv) and diethylzinc (1.1m in toluene, 2.7 mL,
3 mmol, 3 equiv) in toluene (0.5 mL) was stirred at room temperature for
3 h under an argon atmosphere. After this time, the corresponding chiral
1-(4’-Chlorophenyl)-1-phenylethanol (15 f):[52] Pale yellow oil; Rf =0.59
(hexane/AcOEt 7:3); tr (GC)=11.02 min; HPLC (AD, UV 225 nm,
hexane/2-propanol 99:1, flow 1 mLminÀ1): tr (1st)=35.7, tr (2nd)=
40.6 min; [a]D =À5.3 (c=0.2, CHCl3); er 1st/2nd 44:56; 1H NMR: d=
1.90 (s, 3H; CH3), 2.28 (s, 1H; OH), 7.20–7.40 ppm (m, 9H; ArH);
13C NMR: d=30.7, 30.8, 75.8, 125.7 (2C), 127.15, 127.3 (2C), 128.2 (2C),
128.25 (2C), 132.65, 146.5, 147.4 ppm; IR (film): n˜ =3416 (OH),
1502 cmÀ1 (C=CH); MS (EI): m/z (%): 233 (1) [M+H]+, 232 (7) [M]+,
217 (100).
ligand 6c, 10a, or 10b (0.05 mmol, 0.05 equiv), Ti(OiPr)4 (0.03 mL,
R
0.1 mmol, 0.1 equiv), and toluene (2 mL) were successively added. The
resulting solution was stirred for 1 h and acetophenone (12a, 0.12 mL,
1 mmol, 1 equiv) was added. The reaction mixture was stirred at the
same temperature for several hours, before being quenched by the suc-
cessive addition of methanol (1 mL) and a saturated solution of NH4Cl
(15 mL). The mixture was filtered through Celite and the resulting solu-
tion was extracted with EtOAc (3”15 mL). The organic layers were
dried over anhydrous Na2SO4, filtered, and then concentrated. The resi-
due was purified by flash chromatography (hexane/EtOAc) to give the
title alcohol 24.[56] Yields and ee values are included in Scheme 6. Pale
yellow oil; Rf =0.41 (hexane/AcOEt 4:1); tr (GC)=12.3 min; HPLC
(AD, UV 235 nm, hexane/2-propanol 99:1, flow 1 mLminÀ1): tr (1st)=
36.7, tr (2nd)=44.4 min; [a]D =À4.0 (c=1.85 in CHCl3); er 1st/2nd
1-(4’-Fluorophenyl)-1-phenylethanol (15g):[52] Pale yellow oil; Rf =0.57
(hexane/AcOEt 7:3); tr (GC)=9.29 min; HPLC (AD, UV 217 nm,
hexane/2-propanol 99:1, flow 0.8 mLminÀ1): tr (1st)=37.9, tr (2nd)=
1
39.4 min; [a]D =À4.9 (c=1.06, CHCl3; er 1st/2nd 92:8; H NMR: d=1.92
(s, 3H; CH3), 2.15 (s, 1H; OH), 6.95–7.0, 7.20–7.40 ppm (2m, 5H, 4H;
ArH); 13C NMR: d=31.0, 75.8, 114.8 (d, 2J
ACHTREUNG
127.1 (2C), 127.6 (d, 3J
A
ACHTREUNG
1
3.3 Hz), 147.7, 161.7 ppm (d, 1J
C
76.5:23.5; H NMR: d=1.87 (s, 3H; CH3), 2.50 (brs, 1H; OH), 7.25–7.50,
7.70–7.75 ppm (2m, 5H each; 2”Ph); 13C NMR: d=33.3, 70.4, 84.9, 92.4,
122.5, 124.9 (2C), 127.7, 128.3, 128.35 (2C), 128.5 (2C), 131.7 (2C),
145.6 ppm; IR (film): n˜ =3380 (OH), 3388 (C=C), 1493 cmÀ1 (C=CH);
MS (EI): m/z (%): 222 (31) [M]+, 207 (100).
General procedure for the enantioselective allylation of acetophenone
(12a): A solution of [Pd(PPh3)4] (11.5 mg, 0.01 mmol, 0.01 equiv), either
U
allyl carbonate (21a, 0.43 mL, 3 mmol, 3 equiv) or cynnamyl acetate
(21b, 1.0 mL, 6 mmol, 6 equiv), and diethylzinc (1.1m in toluene, 8.2 mL,
9 mmol, 9 equiv) was stirred at 708C for 16 h in a pressure tube under an
argon atmosphere. After this time, the mixture was cooled to 08C, and
the corresponding chiral ligand 6c, 10a, or b (0.05 mmol, 0.05 equiv) and
General procedure for the enantioselective alkenylation of ketones: The
corresponding alkyne 23 (1.2 mmol, 1.2 equiv) was added to a suspension
of Cp2ZrHCl (25, 309 mg, 1.2 mmol, 1.2 equiv), in CH2Cl2 (4 mL) under
an argon atmosphere. The reaction mixture was stirred for 20 min at
room temperature, and then the solvent was removed in vacuo. The re-
sulting residue was dissolved in toluene (5 mL), cooled to À788C, and
treated with Me2Zn (2.0m in toluene, 0.600 mL, 1.2 mmol, 1.2 equiv) for
30 min. The corresponding chiral ligand 6c, 10a, or 10b (0.05 mmol,
Ti(OiPr)4 (0.35 mL, 1.1 mmol, 1.1 equiv) were successively added. After
E
15 min stirring allowing the temperature to rise to 258C, acetophenone
(12a, 0.12 mL, 1 mmol, 1 equiv) was added. The reaction mixture was
stirred at the same temperature for several hours, and then quenched by
the successive addition of methanol (1 mL) and a saturated solution of
NH4Cl (15 mL). The mixture was filtered through Celite and the result-
ing solution was extracted with EtOAc (3”15 mL). The organic layers
were dried over anhydrous Na2SO4, filtered, and then concentrated. The
residue was purified by flash chromatography (hexane/EtOAc) to give
chiral tertiary alcohols 22. Yields and ee values are included in Scheme 5.
2-Phenyl-4-penten-2-ol (22a):[54] Pale yellow oil; Rf =0.54 (hexane/
AcOEt 7:3); tr (GC)=9.27 min; HPLC (AS, UV 208 nm, hexane/2-prop-
anol 99.5:0.5, flow 0.6 mLminÀ1): tr ((R)-22a)=12.29, tr ((S)-22a)=
13.22 min; [a]D =À2.6 (c=0.85 in CHCl3) er R/S 48:52; 1H N MR: d=
1.55 (s, 3H; CH3), 2.05 (s, 1H; OH), 2.50, 2.69 (2dd, J=8.3, 13.7 Hz, J=
6.4, 13.7 Hz; 1H each; CH2CO), 5.10–5.15 (m, 2H; CH2=CH), 5.55–5.70
(m, 1H; CH2=CH), 7.40–7.45 ppm (m, 5H; Ph); 13C NMR: d=29.9, 48.4,
73.6, 119.4, 124.7 (2C), 126.6, 128.13 (2C), 133.6, 147.6 ppm; IR (film):
0.05 equiv) and Ti(OiPr)4 (0.33 mL, 1.10 mmol, 1.1 equiv) were mixed in
N
toluene (2 mL) at room temperature in another Schlenk flask for 15 min
under argon atmosphere. This solution was then added to the previous
Schlenk flask containing the dimethylzinc at À788C. After the addition,
the solution was warmed to 08C and added the corresponding ketone
(12, 1 mmol, 1 equiv). The reaction mixture was then warmed to room
temperature and stirred for several hours, followed by the successive ad-
dition of methanol (1 mL) and a saturated solution of NH4Cl (15 mL) to
quench the reaction. The mixture was filtered through Celite and the re-
sulting solution was extracted with EtOAc (3”15 mL). The organic
layers were dried over anhydrous Na2SO4, filtered, and then concentrat-
ed. The residue was purified by flash chromatography (hexane/EtOAc)
to give chiral tertiary alcohols 26. Yields and ee values are included in
Table 7.
n˜ =3415 (OH), 1684 (C=CH), 1208 cmÀ1 (C O); MS (EI): m/z (%): 160
À
2-Phenyl-4-trimethylsilyl-3-buten-2-ol (26a): Pale yellow oil; Rf =0.6
(hexane/AcOEt 7:3); tr (GC)=7.14 min; HPLC (OJ, UV 231 nm,
hexane/2-propanol 99:1, flow 0.5 mLminÀ1): tr (1st)=12.4, tr (2nd)=
19.3 min; [a]D =À13.4 (c=0.55 in CHCl3); er 1st/2nd 3:97; 1H NMR: d=
(<1) [MÀ2H]+, 121 (100).
2,3-Diphenyl-4-penten-2-ol (syn-22b):[55] Pale yellow oil; Rf =0.22
(hexane/AcOEt 4:1); tr (GC)=13.16 min; HPLC (AD, UV 254 nm,
hexane/2-propanol 98:2, flow 1 mLminÀ1): tr (1st)=15.7, tr (2nd)=
21.5 min; [a]D =À1.1 (c=1.22, CHCl3); er 1st/2nd 79:21; 1H NMR: d=
1.23 (s, 3H; CH3), 3.37 (d, J=9.5 Hz, 1H; CHPh), 5.05–5.25 (m, 2H;
CH=CH2), 6.20–6.45 (m, 1H; CH=CH2), 7.20–7.35 ppm (m, 10H; 2”Ph);
0.13 (s, 9H; Si(CH3)3), 1.67 (s, 3H; CH3CO), 2.05 (s, 1H; OH), 5.98 (d,
R
J=8.8 Hz, 1H; CH=CHSi), 6.36 (d, J=8.8 Hz, 1H; CH=CHSi), 7.25–
7.50 ppm (m, 5H; Ph); 13C NMR: d=À1.3 (3C), 29.3, 75.5, 125.2 (2C),
126.2, 126.85, 128.2 (2C), 146.5, 151.6 ppm; IR (film): n˜ =3388 (OH),
Chem. Eur. J. 2006, 12, 4431 – 4445
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4443

M. Yus, D. J. Ramón et al.
1606 (C=CH), 840, 765 cmÀ1 (Si
C
[2] D. J. Ramón, M. Yus, Angew. Chem. 2005, 117, 1628–1661; Angew.
Chem. Int. Ed. 2005, 44, 1602–1634.
calcd for C13H20OSi: 220.1283; found: 220.1269.
[3] a) L. F. Tietze, K. Schiemann, C. Wegner, J. Am. Chem. Soc. 1995,
117, 5851–5852; b) L. F. Tietze, C. Wegner, C. Wulff, Synlett 1996,
471–472; c) L. F. Tietze, K. Schiemann, C. Wegner, C. Wulff, Chem.
Eur. J. 1998, 4, 1862–1869; d) L. F. Tietze, C. Wegner, C. Wulff, Eur.
J. Org. Chem. 1998, 1639–1644; e) L. F. Tietze, B. Weigand, L.
Vçlkel, C. Wulff, C. Bittner, Chem. Eur. J. 2001, 7, 161–168; f) L. F.
Tietze, L. Vçlkel, C. Wulff, B. Weigand, C. Bittner, P. McGrath, K.
Johnson, M. Schäfer, Chem. Eur. J. 2001, 7, 1304–1308; g) L. F.
Tietze, S. Hçlskeen, J. Adrio, T. Kinzel, C. Wegner, Synthesis 2004,
2236–2239.
[4] For reviews on different aspects of this methodology see: a) M. Yus,
Chem. Soc. Rev. 1996, 25, 155–161; b) D. J. Ramón, M. Yus, Eur. J.
Org. Chem. 2000, 225–237; c) M. Yus, Synlett 2001, 1197–1205;
d) D. J. Ramón, M. Yus, Rev. Cubana Quim. 2002, 14, 76–115; e) M.
Yus, D. J. Ramón, Latv. J. Chem. 2002, 79–92; f) M. Yus in The
Chemistry of Organolithium Compounds (Eds.: Z. Rapopport, I.
Marek), Wiley, Chichester, 2004, Chapter 11, pp. 647–747.
[5] a) K. Fuji, Chem. Rev. 1993, 93, 2037–2066; b) E. J. Corey, A.
Guzmµn-PØrez, Angew. Chem. 1998, 110, 402–415; Angew. Chem.
Int. Ed. 1998, 37, 388–401; c) J. Christoffers, A. Mann, Angew.
Chem. 2001, 113, 4725–4732; Angew. Chem. Int. Ed. 2001, 40, 4591–
4597; d) J. Christoffers, A. Baro, Angew. Chem. 2003, 115, 1726–
1728; Angew. Chem. Int. Ed. 2003, 42, 1688–1690; e) D. J. Ramón,
M. Yus, Curr. Org. Chem. 2004, 8, 149–183.
[6] M. Yus, D. J. Ramón, Recent Res. Dev. Org. Chem. 2002, 6, 297–378.
[7] D. J. Ramón in Quaternary Stereocenters: Challenges and Solutions
for Organic Synthesis (Eds.: J. Christoffers, A. Baro), Wiley-VCH,
Weinheim, Chapter 8, pp. 207–241.
[8] a) H. Grçger, Chem. Eur. J. 2001, 7, 5246–5251; b) G. J. Rowlands,
Tetrahedron 2001, 57, 1865–1882; c) S. Woodward, Tetrahedron
2002, 58, 1017–1050; d) M. Shibasaki, M. Kanai, K. Funabashi,
Chem. Commun. 2002, 1989–1999; e) M. Kanai, N. Kato, E. Ichika-
wa, M. Shibasaki, Synlett 2005, 1491–1508.
[9] a) J. Boersma in Comprehensive Organometallic Chemistry, Vol. 2
(Ed.: G. Wilkinson), Pergamon Press, Oxford, 1982, pp. 823–862;
b) R. Noyori, S. Suga, K. Kawai, S. Okada, M. Kitamura, N. Oguni,
T. Kanedo, Y. Matsuda, J. Organomet. Chem. 1990, 382, 19–37;
c) M. Watanabe, K. Soai, J. Chem. Soc. Perkin Trans. 1 1994, 3125–
3128; d) P. Knochel in Encyclopedia of Reagents for Organic Synthe-
sis, Vol. 3 (Ed.: L. A. Paquette), Wiley, Chichester, 1995, pp. 1861–
1866.
[10] a) D. J. Ramón, M. Yus, Tetrahedron: Asymmetry 1997, 8, 2479–
2496; b) O. Prieto, D. J. Ramón, M. Yus, Tetrahedron: Asymmetry
2000, 11, 1629–1644; c) M. Yus, D. J. Ramón, O. Prieto, Tetrahe-
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2,4-Diphenyl-3-buten-2-ol (26b):[40d] Pale yellow oil; Rf =0.5 (hexane/
AcOEt 7:3); tr (GC)=10.28 min; HPLC (ODH, UV 254 nm, hexane/2-
propanol 92:8, flow 0.8 mLminÀ1): tr ((R)-26b)=14.1, tr ((S)-26b)=
1
17.1 min; [a]D =++6.0 (c=0.44 in CHCl3); er R/S 11.0:89.0; H NMR: d=
1.76 (s, 3H; CH3), 2.03 (s, 1H; OH), 6.58 (d, J=16.0 Hz, 1H; CH=
CHCO), 6.65 (d, J=16.0 Hz, 1H; CH=CHCO), 7.20–7.40, 7.52 ppm (m,
d, J=7.2 Hz, 8H, 2H; 2”Ph); 13C N MRd=29.8, 74.7, 125.2 (2C), 126.5
(2C), 127.1, 127.6, 127.65, 128.3 (2C), 128.55 (2C), 136.3, 136.65,
146.5 ppm; IR (film): n˜ =3388 (OH), 3028, 1499 cmÀ1 (C=CH); MS (EI):
m/z (%): 225 (2) [M+H]+, 224 (12) [M]+, 181 (100).
2-Phenyl-3-octen-2-ol (26c):[40d] Pale yellow oil; Rf =0.64 (hexane/AcOEt
7:3); tr (GC)=7.82 min; HPLC (OJ, UV 220 nm, hexane/2-propanol 97:3,
flow 1 mLminÀ1): tr ((R)-26c)=5.8, tr ((S)-26c)=7.2 min; [a]D =À2.9
(c=1.3 in CHCl3); er R/S 3.0:97.0; 1H NMR: d=0.89 (t, J=6.7 Hz, 3H;
CH3CH2), 1.25–1.40 (m, 4H; (CH2)2CH3), 1.63 (s, 3H; CH3CO), 1.85 (s,
1H; OH), 2.05–2.10 (m, 2H; CH2CH=CH), 5.60–5.70 (m, 1H; CH=
CHCO), 5.77 (d, J=15.6 Hz, 1H; CH=CHCO), 7.20–7.25, 7.25–7.35,
7.46 ppm (2m, d, J=7.2 Hz, 1H, 2H, 2H; Ph); 13C NMR: d=13.9, 22.25,
29.9, 31.4, 31.9, 74.4, 125.2 (2C), 126.7, 128.1 (2C), 129.2, 136.8,
147.3 ppm; IR (film): n˜ =3403 (OH), 3034, 1499 cmÀ1 (C=CH); MS (EI):
m/z (%): 204 (<1) [M]+, 147 (100).
3-Methyl-1-phenylnon-4-en-1-yn-3-ol (26d):[40d] Pale yellow oil; Rf =0.58
(hexane/AcOEt 7:3); tr (GC)=9.64 min; HPLC (ODH, UV 251 nm,
hexane/2-propanol 97:3, flow 0.5 mLminÀ1): tr (1st)=14.7, tr (2nd)=
19.1 min; [a]D =À7.6 (c=4.5 in CHCl3); er 1st/2nd 13:87; 1H NMR: d=
0.91 (t, J=7.2 Hz, 3H; CH3CH2), 1.30–1.45 (m, 4H; (CH2)2CH3), 1.64 (s,
3H; CH3CO), 2.05–2.10 (m, 2H; CH2CH=CH), 2.21 (brs, 1H; OH), 5.66
(d, J=15.5 Hz, 1H; CH=CHCO), 6.04 (dt, J=15.5 Hz, 1H; CH=
CHCO), 7.25–7.35, 7.40–7.45 ppm (2m, 3H, 2H; Ph); 13C NMR: d=13.9,
22.2, 30.45, 31.1, 31.5, 68.3, 84.4, 91.6, 122.7, 128.2 (2C), 130.7, 131.6
(2C), 133.9 ppm; IR (film): n˜ =3376 (OH), 1494 (C=CH), 1106,
1077 cmÀ1 (C O); MS (EI): m/z (%): 230 (<1) [M+2H] , 229 (<1)
+
À
[M+H]+, 228 (2) [M]+, 227 (3) [MÀH]+, 171 (100).
3-Phenylnon-4-en-3-ol (26e):[40d] Pale yellow oil; Rf =0.74 (hexane/
AcOEt 7:3); tr (GC)=12.70 min; HPLC (OJ, UV 217 nm, hexane/2-prop-
anol 97:3, flow 1 mLminÀ1): tr ((R)-26e)=5.7, tr ((S)-26e)=7.4 min;
[a]D =À10.3 (c=1.1 in CHCl3) er R/S 5.0:95.0; 1H NMR: d=0.85, 0.91
(2t, J=7.3, 6.9 Hz, 3H each; 2”CH3), 1.30–1.40 (m, 4H; (CH2)2CH3),
1.79 (s, 1H; OH), 1.85–2.0 (m, 2H; CH2CO), 2.05–2.10 (m, 2H; CH2CH=
CH), 5.65–5.70 (m, 1H; CH=CHCO), 5.82 (d, J=15.5 Hz, 1H; CH=
CHCO), 7.25, 7.36, 7.45 ppm (2t, d, J=7.2, 7.5, 7.6 Hz, 1H, 2H, 2H;
Ph); 13C NMR: d=8.0, 13.9, 22.2, 31.4, 32.0, 35.1, 76.75, 125.5 (2C),
126.5, 128.0 (2C), 129.4, 136.05, 146.2 ppm; IR (film): n˜ =3471 (OH),
1499 cmÀ1 (C=CH); MS (EI): m/z (%): 218 (<1) [M]+, 217 (<1)
[MÀH]+, 189 (100).
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CCDC-289391 contains the supplementary crystallographic data for this
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Acknowledgements
This work was generously supported by the current Spanish Ministerio
de Educación y Ciencia (project CTQ2004-01261), the Generalitat Va-
lenciana (projects GV05/157 and CTIDB/2002/318), and University of
Alicante (UA). We thank Dr. T. Soler for X-ray analysis of ligand
HOCSAC (6c), who should be contacted for any communication about
crystal structure (Tatiana.Soler@ua.es). V.J.F. and O.P. thank the UA for
the corresponding fellowships.
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Received: November 9, 2005
Published online: March 31, 2006
Chem. Eur. J. 2006, 12, 4431 – 4445
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4445