New ligands and structural insights into the catalytic asymmetric addition of organozinc reagents to ketones

Article abstract of DOI:10.1016/j.tet.2011.04.022

The catalytic asymmetric addition of alkyl groups to ketones has received considerable attention. Outlined herein is the synthesis of two new ligands based on the C₂-symmetric 11,12-diamino-9,10-dihydro-9,10- ethanoanthracene. The scope of the new ligands has been evaluated in the catalytic asymmetric addition of diethylzinc to a variety of ketones. Enantioselectivities as high as 99% have been achieved. The structures of two of these ligands have been determined by X-ray crystallography and are compared with related structures. Additionally, the structure of a titanium complex bound to a bis(sulfonamide) diol ligand is reported.

Full text of DOI:10.1016/j.tet.2011.04.022

Tetrahedron 67 (2011) 4467e4474
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New ligands and structural insights into the catalytic asymmetric addition of
organozinc reagents to ketones
a
c
a
c
b
ꢀ
Gabriela Huelgas , Lynne K. LaRochelle , Lucrecia Rivas , Yekaterina Luchinina , Ruben A. Toscano ,
Patrick J. Carroll c, Patrick J. Walsh c, Cecilia Anaya de Parrodi a
Departamento de Ciencias Químico Biologicas, Universidad de las Americas Puebla, Santa Catarina Martir s/n, Cholula, 72820 Puebla, Mexico
,
*
a
ꢀ
ꢀ
ꢀ
b
ꢀ
ꢀ
ꢀ
ꢀ
Instituto de Química, Universidad Nacional Autonoma de Mexico, Ciudad Universitaria, Mexico D.F. 04510, Mexico
c Department of Chemistry, University of Pennsylvania, 231 S. 34th St, Philadelphia, PA 19104, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The catalytic asymmetric addition of alkyl groups to ketones has received considerable attention. Out-
lined herein is the synthesis of two new ligands based on the C2-symmetric 11,12-diamino-9,10-dihydro-
9,10-ethanoanthracene. The scope of the new ligands has been evaluated in the catalytic asymmetric
addition of diethylzinc to a variety of ketones. Enantioselectivities as high as 99% have been achieved. The
structures of two of these ligands have been determined by X-ray crystallography and are compared with
related structures. Additionally, the structure of a titanium complex bound to a bis(sulfonamide) diol
ligand is reported.
Received 28 March 2011
Received in revised form 6 April 2011
Accepted 7 April 2011
Available online 14 April 2011
Keywords:
Ketone
Alkylation
Ó 2011 Elsevier Ltd. All rights reserved.
Asymmetric Catalysis
Alcohols
Homogeneous Catalysis
i) 1 (2-10 mol %)
OH
1. Introduction
O
hex/tol, rt
ZnR"2
Ti(Oi-Pr)4
+
+
R
R"
R
R'
ii) aq. NH4Cl
R'
Despite significant effort, the use of asymmetric catalysts to pre-
pare tetrasubstituted tertiary stereocenters with high enantiose-
lectivity remains challenging.1e3 One class of reactions that establish
such stereocenters is the asymmetric addition of organometallic re-
agents to ketones, which provides valuable enantioenriched tertiary
alcohols.4e7 Tertiary alcohols are important building blocks for the
synthesis of pharmaceuticals and natural products. In 2002 we in-
troduced the first efficient and highly enantioselective catalyst for the
addition of alkyl groups to ketones (Scheme 1).8,9 This catalyst system
also promotes the addition of aryl-,10,11 vinyl-,12,13 and dienylzinc re-
agents13 to ketones with enantioselectivities >90%. Ligand 1 has been
applied to tandem enantioselective additions to enones-
diastereoselective epoxidation sequences to make epoxy alcohols of
high ee and dr.5,14,15 Otherresearchershavesuccessfullyemployed1to
make tertiary alcohols with high enantioselectivity.16e22 Recently,
a number of highly enantioselective catalysts have been introduced
for the addition of organozinc23e25 and organoaluminum26e29
reagents to ketones.6,7,30
1.6 equiv
1.2 equiv
up to
99% ee
( )n
Me
Me
R" = alkyl
phenyl
vinyl
Me
Me
O2S NH HN
SO2
dienyl
1 (n=2)
2 (n=1)
OH
HO
Scheme 1. Asymmetric organozinc additions to ketones with catalyst derived from
ligands 1 and 2.
We are interested inidentifyingotherdiaminebackbones withthe
goal of developing catalysts that exhibit high reactivity and enantio-
selectivity with challenging substrates. In 2004 we synthesized the
trans-1,2-diaminocyclopentane-based ligand 2 (Scheme 1).31 Al-
though high enantioselectivities were obtained with ligand 2, they
didnotsurpassthoseofthecyclohexaneanalogue1. Wehypothesized
that the decreased enantioselectivity of 2 was due to the greater
conformational flexibility of the cyclopentane backbone.31 We
therefore sought to prepare ligands with more rigid diamine back-
bones and increased dihedral angles. In this article, we describe the
* Corresponding author. Fax: þ52 222 229 2419; e-mail address: cecilia.anaya@
udlap.mx (C. Anaya de Parrodi).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.022

4468
G. Huelgas et al. / Tetrahedron 67 (2011) 4467e4474
synthesis and screening of ligands based on the C2-symmetric 11,12-
diamino-9,10-dihydro-9,10-ethanoanthracene diamine32 backbone.
In some cases, catalysts derived from these ligands are more enan-
tioselective than the original catalyst derived from 1. Additionally, we
present the structural determination of ligand 1 and a dinuclear ti-
tanium complex of ligand 1. Non-linear effects with ligand 1 were
examined in the asymmetric addition of diethylzinc to acetophenone.
Me
Me
O
O2S
NH
NH2
NEt3 (2 equiv.)
+
CH2Cl2:CH3CN
(1:1), r.t
78% yield
NH
O2S
O
ClO2S
NH2
2. Results and discussion
O
(S)-4
(2.0 equiv.)
Me
Me
The efficiency and enantioselectivity of members of a catalyst
family are dependent on many factors, including the ligand bite an-
gle.33,34 It is known that the dihedral angle in diamine-based ligands
can have a significant impact on catalyst enantioselectivity and
efficiency.35e37 We therefore decided to alter the bite angle of the
diamine backbones of ligands 1 and 2 and examine the impact on the
enantioselective alkylation of ketones. The trans-1,2-diamino cyclo-
hexane backbone has an NeCeCeN dihedral angle of around 60ꢀ. In
contrast, the C2-symmetric 11,12-diamino-9,10-dihydro-9,10-etha-
noanthracene diamine32 has an NeCeCeN dihedral angle over >110ꢀ
(Fig. 1). We therefore set out to prepare ligands for the asymmetric
alkylation of ketones with anthracene-derived diamine backbones.
(R,R)-3
(1.0 equiv.)
(11R,12R)-S,S-5
Me
Me
OH
O2S
NH
1) NaBH4 (7 equiv.)
THF:EtOH (4.1), r.t.
85% y, dr = 3.2:1.0
2) chromatography
68% overall yield
dr > 15:1
NH
O2S
OH
Me
Me
(11R,12R)-S,S-7
Scheme 2. Synthesis of ligand 7.
NH2
NH2
NH2
NH2
Me
Me
O
O2S
NH
H
H
H
NH2
NH2
NEt3 (2.0 equiv.)
NH2
NH2
>110o
+
~60o
CH2Cl2:CH3CN
(1:1), r.t
80% yield
O
ClO2S
NH2
NH
NH2
H
(S)-4
(2.0 equiv.)
O2S
O
Fig. 1. Dihedral angles for trans-1,2-diaminocyclohexane and trans-11,12-diamino-
9,10-dihydro-9,10-ethanoanthracene.
(S,S)-3
(1.0 equiv)
Me
Me
(11S,12S)-S,S-6
3. Synthesis of the ligands
Me
Me
OH
The ligand syntheses began from resolved 11,12-diamino-9,10-
dihydro-9,10-ethanoanthracene diamine32 (3) and (S)-camphor
sulfonyl chloride, (S)-4, as outlined in Schemes 2 and 3, respectively.
Reaction of the diamine (R,R)-3 with 2 equiv of (S)-camphor sulfonyl
chloride, (S)-4, in the presence of 2 equiv triethylamine resulted in
formation of the dione (11R,12R)-S,S-5 in 78% isolated yield after
purification on silica gel (Scheme 2).
Reduction of the dione ligand (11R,12R)-S,S-5 was accomplished
with excess sodium borohydride in THF/ethanol31 (4:1) to provide
diols as a 3.2:1.0 mixture of exoeexo/exoeendo diastereomers (85%
yield, Scheme 2). The major diastereomer (11R,12R)-S,S-7 was isolated
in 68% yield by flash chromatography. Preparation of the di-
astereomeric diketone (11S,12S)-S,S-6 was performed using diamine
(S,S)-3 with sulfonyl chloride (S)-4 (Scheme 3). After purification on
silica gel, the desired dione (11S,12S)-S,S-6 was isolated in 80% yield.
The diketone (11S,12S)-S,S-6 was reduced asabove and gave (11S,12S)-
S,S-8 with 3.7:1.0 diastereomeric ratio in 80% yield. Similarly, the de-
sired exoeexo diastereomer was separated from the minor exoeendo
diastereomer by flash chromatography to provide 8 in 64% yield.
1) NaBH4 (7 equiv.)
THF:EtOH (4.1), r.t.
80% y, dr = 3.7:1.0
O2S
NH
2) chromatography
64% overall yield
dr > 20:1
NH
O2S
OH
Me
Me
(11S,12S)-S,S-8
Scheme 3. Synthesis of ligand 8.
crystallography (Fig. 2).38 An X-ray structural determination of
(11S,12S)-S,S-8 was also performed and the structure is shown in
Fig. 3.38 Finally, crystals of 1 were grown from CH2Cl2 and benzene
(that was not dried) and an ORTEP of 1 is shown in Fig. 4.38 An earlier
structure determination of the ligand 1 was reported as ortho-
rhombic, space group P21212.21,16 We found that the crystal is
monoclinic, space group P21, but with a
b
angle of 90.008ꢀ; it forms
(or c
a pseudo-merohedral twin by rotation of 180ꢀ about the a
*
*
)
3.1. Structural determination of ligands 5, 8, and 1
reciprocal axis that causes it to mimic orthorhombic symmetry.
Using a twin matrix of {10 0 0 ꢁ10 0 0 ꢁ1}, the twinning parameter
refined to a value of 0.1977 (7) and the least squares R-factor, R1, was
Crystals of (11R,12R)-S,S-5 were grown from hexanes and
dichloromethane and the structure determined by X-ray

G. Huelgas et al. / Tetrahedron 67 (2011) 4467e4474
4469
Fig. 2. ORTEP of diketone ligand precursor (11R,12R)-S,S-5.
Fig. 4. ORTEP of diol ligand 1.
Table 1
Dihedral angles and N/N distances for 5, 8, 1, and 9
NeCeCeN (ꢀ)
N/N (A)
ꢁ
Compound
5
8
1
9
113.9 (3)
112.7 (4)
60.8 (4)a
43.9 (4)
3.415 (4)
3.485 (5)
2.900 (10)a
2.702 (3)
a
Mean value of the four independent molecules of 1.
titanium complex of ligand 1, we reflected on our structural and
mechanistic study of (BINOLate)Ti-based catalysts for the asym-
metric alkylation ofaldehydes. Wehad shown that in the presence of
Ti(O-i-Pr)4 that di- and trinuclear adducts (BINOLate)Ti2(O-i-Pr)6
and (BINOLate)Ti3(O-i-Pr)10 were formed.43 We presented evidence
that dinuclear (BINOLate)Ti2(O-i-Pr)6 was catalytically active in the
asymmetricaddition of alkylzinc reagentstoaldehydes,44 consistent
with Nakai’s proposed mechanism.45 Given that both the BINOL-
based asymmetric additions to aldehydes45,46 and the addition of
alkyl groups to ketones with catalyst formed from 1 (Scheme 1) are
both conducted in the presence of superstoichiometric titanium
tetraisopropoxide, we decided to examine reaction of 2 equiv of
Ti(NMe2)2(O-i-Pr)2 with 1. The reactionwas performed in hexanes at
room temperature as outlined in Scheme 4. The reaction flask was
then subjected to reduced pressure to remove the liberated N,N-
dimethyl amine. Freshhexanes was added and the volatiles removed
two more times to insure the N,N-dimethylamine was removed to
prevent the coordination to titanium.4,47 The resulting oil was dis-
solved in dichloromethane and layered with diethyl ether. Upon
cooling to ꢁ30 ꢀC, crystals of 9 formed and were isolated for X-ray
analysis.38
Fig. 3. ORTEP of diol ligand (11S,12S)-S,S-8.
0.0361. The asymmetric unit consists of four molecules of the ligand
plus two benzene molecules and a water molecule.
The NeCeCeN dihedral angle and the N/N distance for ligands
ꢀ
ꢀ
ꢁ
ꢁ
5 (113.9 and 3.415 A) and 8 (112.7 and 3.485 A) are listed in Table 1.
These can be compared to the same parameters in the structure of
ligand 1, whichhasan NeCeCeNdihedralangle of60.8ꢀ andaverage
ꢁ
distance between the nitrogen atoms of 2.905 A.
3.2. Synthesis and structure of the titanium complex of 1
The structure of the ligand adduct is shown in Fig. 5 along with
a simplified representation. In the drawing, the bicyclic framework
To understand how the ligand 1 binds to titanium, we set out to
synthesize and crystallize the titaniumeligand adduct. Both our
42
group4,39e41 and the Gagne group reported that titanium amide
ꢀ
complexes, such as Ti(NMe2)4 and Ti(NMe2)2(O-i-Pr)2 readily reac-
ted with bis(sulfonamide) ligands to liberate N,N-dimethylamine
and form bis(sulfonamido)Ti(NMe2)2 and bis(sulfonamido)Ti(O-i-
Pr)2 complexes, respectively. In planning for our synthesis of the
Scheme 4. Synthesis of 9.

4470
G. Huelgas et al. / Tetrahedron 67 (2011) 4467e4474
Fig. 5. ORTEP of 9 and simplified drawing. The bicyclic camphor moieties have been replaced with red curves in the drawing.
of the camphor-derived moieties has been replaced with red
curves. The structure consists of two titanium centers, one in the
pocket of the chiral ligand and the second bridging to the ligand
through a sulfonyl oxygen and a sulfonamido nitrogen. There are
two bridging isopropoxy groups connecting the titanium centers.
The central titanium exhibits dissimilar bond lengths to the sulfo-
100
80
60
40
20
0
ꢁ
ꢁ
namido nitrogens [Ti1eN1, 2.038 (2) A and Ti1eN2, 2.259 (3) A],
with the distance to N1 in line with related structures.41 The
Ti1eN2 distance is likely elongated due to a weak interaction of Tiꢀ2
ꢁ
with N2 [2.371 (3) A]. The sum of the angles around N2 is 351 ,
indicating a small distortion from planarity due to interaction with
Ti2. The TieO bond lengths of the terminal alkoxides range from
ꢁ
1.775 (2)e1.842 (2) A. As expected, the bridging alkoxides exhibit
ꢁ
longer distances [1.913 (2)e2.186 (2) A] and the bridges are un-
0
20
40
60
80
100
symmetrical with the central titanium Ti1 closer to O6 and the
peripheral Ti2 closer to O5. The titanium interaction with the sul-
fonyl (Ti2eO7) is 2.128 (2) A, which is less then in mononuclear
ee of 1 (%)
ꢁ
Fig. 6. A plot of ee of 1 against product ee in the asymmetric addition of diethylzinc to
acetophenone (Scheme 1).
bis(sulfonamido)Ti(O-i-Pr)2
complexes.41
Interestingly,
the
NeCeCeN dihedral angle of 9 in the coordinated ligand is 43.9ꢀ,
notably less than in the structure of the free ligand 1 (60.8ꢀ) and
quite different from unligated 8 (112.7ꢀ). The N/N distance of
behavior suggests that the central titanium in the pocket of the chiral
ligand does not interact with another titanium adduct of 1.
ꢁ
ꢁ
2.70 A in 9 is similar to that found in the free ligand 1 (2.90 A, Table
1).
After we obtained the structure of the dinuclear titanium adduct
9,48 Yus reported NMR studies of 1 with varying equivalents of ti-
tanium tetraisopropoxide.16,21 Although the NMR spectra are
complex, it was proposed that they provide evidence for a dinuclear
adduct, such as 9.
3.4. Enantioselective additions of diethylzinc to ketones with
ligands 7 and 8
The diastereomeric bis(sulfonamide) diols
7 and 8 were
employed in the asymmetric addition of diethylzinc to various
ketones at 2 and 5 mol % ligand loading. As shown in Table 2, the
ketone substrates were combined with 1.2 equiv titanium tetrai-
sopropoxide and 1.6 equiv diethylzinc in toluene. Reactions were
performed at room temperature for 24 h then quenched with wa-
ter. These conditions are very close to those used with ligand 1,8
facilitating comparison.
Diastereomeric ligands 7 and 8 were employed with acetophe-
none (entry 1) and derivatives. With acetophenone, 7 exhibited
greater conversion after 24 h at both 2 and 5 mol % ligand loading,
but 8 exhibited higher enantioselectivity, reaching 99% enantiose-
3.3. Examination of catalyst enantioselectivity as a function
of the ee of 1
Evaluation of enantioenriched catalysts for non-linear behavior is
a powerful mechanistic probe.34,49 We therefore varied the ee of the
ligand 1 in the asymmetric addition of diethylzinc to acetophenone
and examined the ee of the product by chiral stationary phase HPLC.
The results of this study are illustrated in Fig. 6 and clearly indicate
that there is no non-linear behavior. The absence of non-linear
lectivity at
5 mol % catalyst. It is noteworthy that both

G. Huelgas et al. / Tetrahedron 67 (2011) 4467e4474
4471
Table 2
Enantioselectivities using ligands 7 and 8 with various ketones substrates. Enantioselectivities and yields with ligand 1 are given for the purpose of comparison and are
previously reported8
O
HO Et
R1
1) Ligand 7 or 8
+
ZnEt2
Ti(Oi-Pr)4
+
R1
R2
R2
toluene, 24 h, 25° C
2) H2O
1.2 equiv.
1.6 equiv.
Entry
1
Substrate
Product
2 mol % 7 ee
5 mol % 7 ee
2 mol % 8 ee
5 mol % 8 ee
1 ee [% yield]
(config)a [% yield]b
(config)a [% yield]b
(config)a [% yield]b
(config)a [% yield]b
O
HO Et
89 (S) [60]
92 (S) [58]
89 (S) [75]
94 (S) [32]
99 (S) [50]
96 (S) [91]
96 [71]
O
O
HO Et
HO Et
2
3
92 (S) [98]
99 (S) [78]
96 (S) [82]
99 (S) [82]
99 [78]
98 [56]
99 (S) [70]
99 (S) [88]
CF3
CF3
O
Et OH
4
5
6
7
d
d
d
d
99 (R) [65]
19 (R) [61]
d
99 (R) [98]
23 (R) [85]
24 (R) [98]
99 [35]
88 [79]
d
O
HO Et
n-Bu
61 (R) [78]
53 (R) [62]
n-Bu
O
HO Et
HO Et
O
d
65 (R) [16]
37 (S) [68]
d
d
76 (R) [20]
53 (S) [51]
89 [82]
90 [80]
Cl
Cl
O
HO Et
8
40 (S) [25]
a
The enantiomeric excess was determined by HPLC using a Chiralcel OD-H or AD-H. The absolute configuration or the sign of the predominant enantiomer is indicated in
parentheses.
b
The yields were obtained after column chromatography on deactivated silica gel (SiO2/Et3N¼2.5% v/v; hexanes/EtOAc 95%).
diastereomeric catalysts gave the (S)-enantiomer of the tertiary
alcohol product with high ee. Thus, it is clear that the stereo-
chemistry of the bicyclic alkoxide moiety bound to titanium, that is,
largely responsible for the control of asymmetric induction and the
stereocenters of the diamine play a secondary role. When 2 mol %
catalyst derived from ligand 1 (Scheme 1) was used in the asym-
metric addition of diethylzinc to acetophenone, the (S)-product
was formed with 96% enantioselectivity and 96% yield after 29 h.8
The diastereomer of 1, derived from (S,S)-trans-diaminocyclohex-
ane, also gave the (S)-tertiary alcohol, however, the ee was only 31%
and the reaction conversion after 24 h was only 15%.48 Thus, the
diamine in 1 has a larger impact on the enantioselectivity and ac-
tivity than the diamine in 7 and 8.
and 96%, respectively. With 3-trifluoromethyl acetophenone, both
ligands were highly enantioselective and provided ethyl addition
product with 99% ee. a-Tetralone underwent addition of diethylzinc
with catalyst derived from 1 with >99% ee, but the yield was only
35% due to competitive aldol condensation.8 Catalysts derived from
7 and 8 also exhibited excellent enantioselectivities (99%) with
a-tetralone and up to 98% yield with ligand 8.
Alkyl aryl ketones with alkyl groups larger than methyl are more
challenging substrates. The catalysts must differentiate the two
lone pairs of the carbonyl group to achieve high enantioselectivity.
When the size of the alkyl and aryl substituents is similar, the
differentiation becomes more difficult. With valerophenone, cata-
lysts derived from 7 and 8 gave 61 and 23% enantioselectivity, re-
spectively. These values are lower than the 88% enantioselectivity
observed with catalyst derived from ligand 1. Similar enantiose-
lectivities were observed with ligands 7 and 8 with butyrophenone.
Substituted acetophenones also proved to be good substrates
(entries 2 and 3). Thus, 3-methyl acetophenone underwent addi-
tion promoted with ligands 7 and 8 with enantioselectivities of 92

4472
G. Huelgas et al. / Tetrahedron 67 (2011) 4467e4474
The chlorinated substrate 3-chloropropiophenone also proved
challenging for catalysts derived from 7 and 8, which gave enan-
tioselectivities of 65 and 76%, respectively (entry 7). Catalyst de-
rived from 1 gave higher enantioselectivity (89%) but required
10 mol % ligand loading and longer reaction time (44 h) to achieve
82% yield. With catalyst derived form 1, trans-4-phenyl-3-buten-2-
one also gave higher enantioselectivity (90%) than with 7 or 8 (37%
and 53% enantioselectivity, respectively, entry 8). Thus, while cat-
alysts derived from 7 and 8 perform very well with acetophenone
derivatives, 1 gave better results overall.
(d, J¼2.6 Hz, 2H), 3.55 (m, 4H), 3.00 (d, J¼15.0 Hz, 2H), 2.21e2.43
(m, 4H), 1.76e2.11 (m, 8H), 1.36e1.48 (m, 2H), 1.03 (s, 6H), 0.89 (s,
6H). 13C NMR (50 MHz, CDCl3)
d
¼214.6, 140.0, 137.4, 126.9, 126.8,
126.1, 124.6, 62.0, 59.2, 51.7, 50.6, 48.9, 43.2, 27.6, 26.3, 20.6, 20.3. IR
(film): 3279, 2958, 1736, 1457, 1429, 1417, 1392, 1375, 1331, 1268,
1201, 1145, 1115, 1102, 1066, 1051, 1025, 967, 924, 907, 869, 855, 762,
734, 701 cmꢁ1
.
FABþ: m/z [Mþ1]þ calcd for C36H45O6N2S2:
665.2707; found: 665.2719. Compound 5 was recrystallized from
hexanes/CH2Cl2 (8:1), colorless prism 0.444ꢂ0.172ꢂ0.172 mm3;
ꢁ
ꢁ
C36H44N2O6S2, monoclinic, I 2 a¼16.743 (2) A, b¼, 19.508 (3) A
c¼11.430 (2) A, Z¼4, dcalcd¼1.189 mg/m3, V¼3713.6 (9)
A
3
ꢁ
ꢁ
4. Summary and outlook
m
¼0.187 mmꢁ1 F(000)¼1416. A set of 12,599 reflections was col-
lected at 298 (2) K, 6684 independent reflections [Rint¼0.0283].
€
In this study we report the synthesis and characterization of two
new diastereomeric ligands for the asymmetric addition of orga-
nozinc reagents to ketones. These ligands are based on the enan-
tioenriched 11,12-diamino-9,10-dihydro-9,10-ethanoanthracene,
which has a large NeCeCeN dihedral angle and larger bite angle
than trans-1,2-diaminocyclohexane. These ligands were examined
in the asymmetric addition of diethylzinc to a variety of ketones.
Surprisingly, it was found that the configuration of the diamine
played only a minor role in the catalyst enantioselectivity with the
best substrates and a more significant role with more challenging
substrates. In some cases, the catalysts derived from 7 and 8 out-
performed the catalyst formed from 1. In cases where the enan-
tioselectivities were comparable, the new ligands exhibited
Bruker Smart diffractometer, APEX AXS CCD area detector, omega
scans.
5.2.2. Data for (11S,12S)-S,S-6. White solid (1.0 g, 80% yield)
mp¼328 ꢀC; ½a 2D0
ꢃ
þ37.1 (c 1.0, CHCl3). 1H NMR (200 MHz, CDCl3)
d
¼7.24e7.39 (m, 4H), 7.17e7.21 (m, 4H), 5.05 (d, J¼8.8 Hz, 2H), 4.45
(d, J¼2.6 Hz, 2H), 3.72 (m, 4H), 3.52 (d, J¼14.6 Hz, 2H), 3.01 (d,
J¼15 Hz, 2H), 2.05e2.27 (m, 8H), 1.81e1.91 (m, 4H), 1.00 (s, 6H),
0.87 (s, 6H). 13C NMR (50 MHz, CDCl3)
d¼215.1, 139.8, 137.7, 126.9,
126.8, 126.1, 124.7, 61.3, 59.5, 52.7, 51.0, 49.1, 43.3, 27.6, 27.0, 20.6,
20.3. IR (film): 3278, 2958, 1739, 1549, 1525, 1456, 1416, 1392, 1375,
1331, 1270, 1216, 1146, 1115, 1101, 1066, 1052, 1026, 967, 923, 869,
855, 834, 796, 763, 733, 702, 680 cmꢁ1. FABþ: m/z [Mþ1]þ calcd for
C36H45O6N2S2: 665.2719; found: 665.2715.
improved yields (up to 60% higher than 1 with
a-tetralone). We also
report the structure of a dinuclear titanium complex employing
ligand 1. Under catalytic conditions, catalyst derived from 1
exhibited no non-linear effects.
5.3. Preparation of bis(sulfonamide) diol
We continue to search for new ligands for ketone substrates that
remain challenging.
Bis(sulfonamide) dione (450 mg 1 equiv) was charged to the
reaction vessel with a 4:1 mixture of THF and EtOH (20 mL). NaBH4
(5.6 mmol, 7 equiv) was added over 5 min. The reaction mixture
was stirred at room temperature for 1 h and quenched with satu-
rated NH4Cl (5 mL). The organic solvents were removed from the
two-phase mixture under reduced pressure. To the resulting
aqueous mixture was added CH2Cl2 (25 mL), and the organic layer
was extracted with CH2Cl2 (3ꢂ25 mL), the combined organic layer
was washed with H2O (25 mL) dried over MgSO4, and concentrated
in vacuo. The product was purified by column chromatography on
silica gel (hexanes/EtOAc 70:30 as eluent).
5. Experimental section
5.1. General methods
All manipulations involving titanium tetraisopropoxide,
diethyl-zinc, were carried out under an inert atmosphere. NMR
spectra were obtained on a Varian 200 MHz, Fourier transform
spectrometer. 1H NMR spectra were referenced to tetramethylsi-
lane and 13C{H} NMR spectra were referenced to residual solvent.
Titanium tetraisopropoxide and all liquid ketone substrates were
distilled prior to use. Diamine 3 was prepared according to litera-
ture procedure.32 Proton and carbon NMR spectra for the alcohol
products matched those in the literature for entries 1e5, 7, and 88
and entry 6.50
5.3.1. Data for (11R,12R)-S,S-7. White solid (680 mg 68% yield)
mp¼270 ꢀC; ½a 2D0
ꢃ
ꢁ60.2 (c 1.0, CHCl3). 1H NMR (200 MHz, CDCl3)
d
¼7.35e7.39 (m, 4H), 7.19e7.24 (m, 4H), 4.37 (d, J¼2.6 Hz, 2H), 4.23
(d, J¼9.0 Hz, 2H), 4.00 (m, 2H), 3.55 (m, 4H), 3.07 (b, 2H), 2.92 (d,
J¼13.6 Hz, 2H), 1.71 (m, 8H), 1.20e1.31 (m, 4H), 1.04 (s, 6H), 0.90 (m,
2H), 0.81 (s, 6H). 13C NMR (50 MHz, CDCl3)
d¼139.6, 137.0, 127.2,
5.2. Preparation of (11R,12R)-N,N0-bis[(S)-camphorsulfonyl]-
11,12-diamino-9,10-dihydro-9,10-ethanoanthracene dione
127.1, 126.1, 124.8, 61.8, 54.7, 51.1, 51.0, 49.3, 44.8 39.6, 31.1, 28.0,
21.3, 20.6. IR (film): 3533, 3255, 2955, 2933, 2880, 1549, 1456, 1390,
1371, 1324, 1262, 1142, 1115, 1101, 1074, 1059, 1027, 982, 881, 855,
To a solution of 300 mg (1.27 mmol) of trans-11R,12R-diamino-
9,10-dihydro-9,10-ethanoanthracene and 260 mg (2.5 mmol) Et3N
in 10 mL of MeCN was slowly added a solution of 640 mg
(2.54 mmol) of (S)-(þ)-10ecamphorsulfonyl chloride in 10 mL of
CH2Cl2. The resulting mixture was stirred at room temperature for
24 h. The mixture was then washed with 25 mL of 10% aqueous
Na2SO4, extracted with 3ꢂ25 mL of CH2Cl2, and the combined or-
ganic phase was dried over MgSO4. The solvent was then removed
under reduced pressure. The white solid obtained was purified by
column chromatography on silica gel (hexanes/EtOAc 80:20 as
eluent).
761, 701 cmꢁ1
.
FABþ: m/z [Mþ1]þ calcd for C36H49O6N2S2:
669.3032; found: 669.3025.
5.3.2. Data for (11S,12S)-S,S-8. White solid (277 mg 64% yield)
mp¼255 ꢀC; ½a 2D0
ꢃ
ꢁ19.1 (c 1.0, CHCl3). 1H NMR (200 MHz, CDCl3)
d
¼7.36e7.40 (m, 4H), 7.19e7.24(m, 4H), 4.38 (d, J¼2.6 Hz, 2H), 4.20
(d, J¼9.2 Hz, 2H), 3.99 (m, 2H), 3.59 (m, 4H), 3.47 (d, J¼14 Hz, 2H),
3.08 (m, 2H), 1.74 (m, 8H), 1.35 (m, 6H), 1.04 (s, 6H), 0.81 (s, 6H). 13C
NMR (50 MHz, CDCl3)
d
¼139.5, 137.1, 127.2, 127.1, 126.0, 125.0, 61.9,
54.7, 51.0, 51.1, 49.3, 44.9, 39.6, 31.1, 28.0, 21.3, 20.6. IR (film): 3531,
3251, 2956, 2880, 1721, 1621, 1596, 1549, 1525, 1456, 1389, 1371,
1324, 1263, 1236, 1212, 1141, 1114, 1101, 1073, 1058, 1027, 1012, 982,
923, 881, 855, 834, 795, 761, 736, 701 cmꢁ1. FABþ: m/z [Mþ1]þ calcd
for C36H49O6N2S2: 669.3032; found: 669.3036. Recrystallized from
hexanes/CH2Cl2 (5:1), colorless prism 0.376ꢂ0.178ꢂ0.136 mm3;
5.2.1. Data for (11R,12R)-S,S-5. White solid (450 mg 78% yield)
mp¼325 ꢀC; ½a 2D0
ꢃ
ꢁ9.2 (c 1.0, CHCl3). 1H NMR (200 MHz, CDCl3)
d
¼7.24e7.38 (m, 4H), 7.16e7.20 (m, 4H), 4.75 (d, J¼8.2 Hz, 2H), 4.44

G. Huelgas et al. / Tetrahedron 67 (2011) 4467e4474
4473
ꢁ
C37H50Cl2N2O6S2, orthorhombic, P 212121 a¼11.510 (2) A, b¼13.536
5.4.6. Preparation of 3-phenylheptan-3-ol. (1) In the presence of
ligand 7: 78% yield, 61% ee as an oil, HPLC, Chiralcel column AD-H,
v(hexane)/v(i-propanol)¼98:2, flow rate 0.5 mL/min, 254 nm UV
detector, retention time t1: 28.9 min, retention time t2: 32.0 min. (2)
In the presence of ligand 8: 85% yield, 23% ee.
3
3
ꢁ
ꢁ
ꢁ
(2) A, c¼24.506 (4) A, Z¼4, dcalcd¼1.311 mg/m , V¼3818.1 (10) A
m
¼0.326 mmꢁ1 F(000)¼1600. A set of 31,224 reflections was col-
lected at 298 (2) K, 7000 independent reflections [Rint¼0.0856];
€
Bruker Smart diffractometer, APEX CCD area detector, omega scans.
5.4. General procedure for ethylation of ketones
5.4.7. Preparation of 3-phenylhexan-3-ol. (1) In the presence of li-
gand 7: 62% yield, 53% ee as an oil, HPLC, Chiralcel column OD-H,
v(hexane)/v(i-propanol)¼95:5, flow rate 0.5 mL/min, 254 nm UV
detector, retention time t1: 21.4 min, retention time t2: 22.4 min. (2)
In the presence of ligand 8: 98% yield, 24% ee.
The bis(sulfonamide) diol 7 or 8 (5 mol %, 33 mg) was weighed
into the reaction vessel and diethylzinc (1.0 M toluene, 1.6 equiv,
1.6 mL) and titanium(IV) isopropoxide (1.2 equiv, 1.2 mL) were
added at room temperature. After 10 min, the substrate ketone
(1.0 equiv, 1 mmol) was added neat or as a solution in toluene
(1 mL). The homogeneous reaction mixture was stirred at room
temperature. After 24 h the reaction was quenched with H2O
(5 mL), diluted with EtOAc, filtered through Celite, and layers
separated. The aqueous layer was extracted with EtOAc (2ꢂ40 mL)
and the combined organic layers were washed with brine, dried
over MgSO4, and concentrated in under reduced pressure. The
resulting residue was purified by flash chromatography on deacti-
vated silica gel (Et3N/SiO2¼2.5% v/v, hexanes/EtOAC 95:5) to afford
the ethyl addition products. These alcohols were fully characterized
and compared with the data reported in the literature. The ee value
was determined by HPLC on a Daicel OD-H or AD-H column.
5.4.8. Preparation of 1-cloro-3-phenylpentan-3-ol. (1) In the pres-
ence of ligand 7: 16% yield, 65% ee as an oil, HPLC, Chiralcel column
AD-H, v(hexane)/v(i-propanol)¼99:1, flow rate 0.5 mL/min, 254 nm
UV detector, retention time t1: 27.2 min, retention time t2: 28.5 min.
(2) In the presence of ligand 8: 20% yield, 76% ee.
5.4.9. Preparation of (1E)-3-methyl-1-phenylpent-1-en-3-ol. (1) In
the presence of ligand 7: 68% yield, 37% ee as an oil, HPLC, Chiralcel
column AD-H, v(hexane)/v(i-propanol)¼99:1, flow rate 0.5 mL/min,
254 nm UV detector, retention time t1: 9.6 min, retention time t2:
11.5min. (2) In the presence of ligand 8: 51% yield, 53% ee.
Acknowledgements
5.4.1. Probing non-linear behavior. The reactions were performed
using 10 mol % of ligand 1 to facilitate accurate weighing of the
enantiomeric ligands. The enantiomeric ligands were individually
weighted and combined in the reaction vessel. The diethylzinc
solution (1.0 M in toluene, 1.6 equiv) and the titanium(IV) iso-
propoxide (1.4 M toluene solution, 1.2 equiv) were added at room
temperature. After 5e10 min, the acetophenone (1.0 equiv) was
added neat. The homogeneous reaction mixture was stirred at
room temperature for 18 h. After completion, the reaction mixture
was quenched with saturated aqueous solution NH4Cl, extracted
into CH2Cl2, concentrated under reduced pressure, and purified by
column chromatography. The ee was determined by GC using
This article is dedicated to Prof. Dean Toste, winner of the 2011
Tetrahedron Young Investigator Award, for his numerous important
contributions to synthetic chemistry. CAP thanks CONACYT Project
55802 and GHS thanks Postdoctoral Scholarship CONACYT 290523.
PJW thanks the US NSF (CHE-0848467) and NIH (National Institute
of General Medical Sciences, GM58101) for partial support of this
ꢀ
work. We thank F.J. Perez and L. Velasco for technical assistance.
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