Unexpected efficiency of non-C2-symmetric bis(hydroxyamide)- based zinc-chelate catalysts

Article abstract of DOI:10.1002/chir.20958

Asymmetric bis(hydroxyamide)-based zinc-chelate catalysts are able to promote the enantioselective addition of diethylzinc to benzaldehyde in the absence of titanium with yields and ees comparable, or inclusively superior, to their C₂-symmetric

Full text of DOI:10.1002/chir.20958

CHIRALITY 23:523–526 (2011)
Unexpected Efficiency of Non-C2-Symmetric Bis(hydroxyamide)-
Based Zinc-Chelate Catalysts
´
´
´
ESTHER M. MARQUEZ SANCHEZ-CARNERERO, TOMAS DE LAS CASAS ENGEL, BEATRIZ LORA MAROTO, AND
*
SANTIAGO DE LA MOYA CERERO
Departamento de Quı´mica Orga´nica I, de Universidad Complutense de Madrid, Facultad de Ciencias Quı´micas,
Ciudad Universitaria s/n, Madrid, Spain
This article is dedicated to Prof. Carmen Na´jera on the occasion of her 60th birthday
ABSTRACT
Asymmetric bis(hydroxyamide)-based zinc-chelate catalysts are able to pro-
mote the enantioselective addition of diethylzinc to benzaldehyde in the absence of titanium
with yields and ees comparable, or inclusively superior, to their C2-symmetric analogues. This
unexpected fact demonstrates that the previously established assumption on the necessity of
using C2-symmetric bis(hydrdoxyamides) to generate C2-symmetric zinc-chelate catalysts can
be discarded, which expand the possibilities for designing new ligands based on the interesting
C
VV
hydroxyl-amide functional grouping. Chirality 23:523–526, 2011.
2011 Wiley-Liss, Inc.
KEY WORDS: asymmetric catalysis; chiral ligands; zinc catalysts; enantioselective additions;
bis(hydroxyamides)
INTRODUCTION
constitute a new class of ligand able to efficiently promote
the enantioselective addition of organozinc reagents to alde-
hydes in the absence of titaninum.19–21 Moreover, with
regard to the aforementioned problems on the ligand’s syn-
thetic accessibility, bis(hydroxyamides) 4 are cheap, as they
are very easy to obtain enantiopure from a chiral starting ma-
terial coming from the Chiral Pool (e.g., 5 in Fig. 2).19–21
Additionally, hydroxyamides are more chemically inert than
the corresponding amino alcohols, which makes them to be
highly interesting for developing long-life reusable catalysts.
Unfortunately, the extraordinary efficiency of these new
ligands based in hydroxyamide seems to be related with the
possibility of generating a C2-symmetric zinc-chelate catalyst
6 (Fig. 3), which requires the use of C2-symmetric ligands
The enantioselective addition of organozinc reagents to
aldehydes promoted by substoichiometric amounts of a chi-
ral ligand is one of the most important reactions in asymmet-
ric catalysis (Scheme 1).1–13 The reaction leads to enantioen-
riched secondary alcohols, which can be used as synthetic
intermediates for the preparation of a great deal of high-value
molecules, such as natural and non-natural products with bio-
logical activities or new materials with interesting physico-
chemical properties. Some interesting examples are
described in Refs. 1 and 7. On the use of the reaction for the
preparation of chiral liquid crystals, see Ref. 11 and recent
examples on the preparation of chiral building blocks of in-
terest are: Refs. 12 and 13. Moreover, the required organo-
zinc reagents are easy to prepare and store, which is an addi-
tional advantage for the reaction, and so is the diversity of
the reagents that can be used.14
Despite the big number of chiral ligands described so far
for this reaction, commonly dialkylamino alcohols such as
Noyori’s DAIB15 (1 in Fig. 1), an optimal ligand has not been
developed yet: There is not any really versatile ligand able to
perform a highly enantioselective addition of a wide range of
organozinc reagents (alkyl, aryl, alkenyl, or alkynylzinc) to a
wide range of aldehyde substrates (aromatic, aliphatic, heter-
oaromatic, sterically hindered, electronically deactivated,
etc.). However, in the last years, important advances in this
line have been achieved, as it is demonstrated by the develop-
ing of the Perica`s’s ligand 216 or, more recently, by the devel-
oping of the Wang’s ligand 317,18 (Fig. 1). Unfortunately,
most of the new highly versatile ligands are expensive when
it comes to their synthesis, as they usually show complex
structures with enantiopurity coming from chirality-transfer
agents (racemic-resolution or asymmetric-synthesis steps are
usually involved in the ligand preparation). As a conse-
quence, the transfer of the reaction to the industry is difficult,
as evidenced by the almost nonexistent industrial processes
of enantioselective organozinc addition to aldehydes.
having
a
conformationally restricted two-carbon-length
spacer between the two amide groups.21 This structural
restriction, which has not been deeply checked, strongly
diminishes the possibilities for designing new optimized
ligands of this interesting new structural type (exploring
structural diversity in ligand design).16
According to all the above exposed, we became interested
in checking the activity of new ketopinic-acid-derived bis(hy-
droxyamide)-based ligand leading to asymmetric, instead of
C2-symmetric, zinc-chelate catalysts of the type of 6.
EXPERIMENTAL
Materials and Methods
Common solvents were dried and distilled by standard procedures. All
starting materials and reagents were obtained commercially and used
without further purifications. Flash chromatography purifications were
Contract grant sponsor: Spain Government; Contract grant numbers:
CTQ2007-67103-C02/ BQU; CTQ2010-180176
Contract grant sponsor: UCM-Santander; Contract grant numbers: 910107
*Correspondence to: Santiago Moya Cerero, Departamento de Qu´ımica
Orga´nica I, de Universidad Complutense de Madrid, Facultad de Ciencias
Qu´ımicas, Ciudad Universitaria s/n, 28040-Madrid, Spain.
E-mail: santmoya@quim.ucm.es
Received for publication 17 December 2010; Accepted 15 February 2011
DOI: 10.1002/chir.20958
Published online 26 April 2011 in Wiley Online Library
(wileyonlinelibrary.com).
In this researching line, we have recently demonstrated
that ketopinic-acid-derived bis(b-hydroxyamides) 4 (Fig. 2)
C
VV
2011 Wiley-Liss, Inc.

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SANCHEZ-CARNERERO ET AL.
524
Fig. 2. (1)-Ketopinic acid derived bis(hydroxyamides).
(11) (2.00 g, 4.67 mmol), methanol (30 ml) and NaBH4 (0.71 g, 18.68
mmol). The mixture was refluxed for 24 h under argon. After cooling it
down to room temperature, water (10 ml) was added and the resulting
mixture concentrated under reduced pressure to evaporate methanol.
The obtained residue was diluted with chloroform (20 ml). Water (20
ml) was added and the resulting layers separated. The aqueous layer
was extracted with chloroform (33 10 ml). The combined organic layers
were washed with brine (13 20 ml) and dried with anhydrous Na2SO4.
After filtration and solvent evaporation under reduced pressure, the resi-
due was purified by flash column chromatography (silica gel, ethyl ace-
Scheme 1. Enantioselective addition of organozinc reagents to aldehydes.
performed on silica gel (230–400 mesh ASTM). Melting points are
uncorrected. NMR spectra were recorded at 208C in CDCl3, and the re-
sidual solvent peak was used as internal standard. FTIR spectra were
obtained using the thin-layer technique. GC analyses were realized at
1208C in a chromatograph equipped with a capillary silicon-gum (SGL-1)
column and a FID, and using nitrogen as mobile phase. Chiral-HPLC
analyses were realized at r.t. in a chromatograph equipped with a capil-
lary Chiralpak-IC column and a DAD, and using hexane/isopropanol
(98:2) as mobile phase. MS were recorded using the EI (70 eV) or ESI
ionization techniques. HRMS were realized using the peak-matching
method (EI) or FTMS (ESI).
20
tate) (1.98 g, 98% yield). White solid. Mp: 217–2198C. [a]D 2105.0 (c
0.21, CHCl3). 1H NMR (CDCl3, 300 MHz), d: 4.33–4.14 (m, 4H, CHꢀꢀN
and CHꢀꢀOH), 4.11 (d, J 5 5.6 Hz, 1H, CHꢀꢀOH), 3.35–3.24 (m, 1H,
CHꢀꢀN), 3.17–3.08 (m, 2H, CHꢀꢀN), 3.02 (dd, J 5 12.97, 12.97 Hz, 1H,
CHꢀꢀN), 2.59 (br s, 2H, OH), 2.08–1.98 (m, 1H), 1.98–1.88 (m, 2H),
1.88–1.79 (m, 2H), 1.79–1.64 (m, 5H), 1.63–1.51 (m, 4H), 1.38 (s, 3H,
CH3), 1.37 (s, 3H, CH3), 1.34–1.15 (m, 1H), 1.12–0.97 (m, 1H), 1.08 (s,
3H, CH3), 1.06–1.02 (m, 1H), 1.00 (s, 3H, CH3) ppm. 13C NMR (CDCl3,
75 MHz), d: 174.2 (NꢀꢀC¼O), 172.7 (NꢀꢀC¼O), 77.4 (CHꢀꢀOH), 76.5
(CHꢀꢀOH), 61.2 (C), 60.2 (C), 50.7 (C), 50.4 (C), 49.3 (CH2ꢀꢀN), 48.4
(CH2ꢀꢀN), 45.4 (CH2ꢀꢀN), 44.9 (CH), 44.7 (CH), 43.6 (CH2ꢀꢀN), 41.9
(CH2), 40.9 (CH2), 29.6 (CH2), 29.4 (CH2), 29.2 (CH2), 26.9 (CH2), 26.8
(CH2), 22.1 (CH3), 21.9 (CH3) ppm. FTIR, m: 3420.6 (br, w), 1608.8 (s)
cm21. MS (ESI), m/z (%): 433 ([M 1 1]1, 8), 887 ([2M 1 23]1, 100).
HRMS (ESI), m/z: 433.3073 (calcd. for C25H41N2O4: 433.3061).
Ligand Syntheses
Ligand 7. N,N0-Bis{[(1S,4R)-7,7-dimethyl-2-oxonorborn-1-yl]carbonyl}ho-
mopiperazine (11) In a round-bottom flask, equipped with a magnetic
stirrer, (1S)-ketopinic acid (9) (3.04 g, 16.5 mmol), EDC hydrochloride
(3.52 g, 18.2 mmol), DMAP (2.25 g, 18.2 mmol), and homopiperazine
(10) (0.84 g, 8.3 mmol) were dissolved in CH2Cl2 (10 ml), and the mix-
ture was stirred at room temperature for 24 h. Water (5 ml) was then
added, and the resulting layers were separated. The aqueous layer was
extracted with CH2Cl2 (33 5 mL). The combined organic layers were
washed successively with 10% HCl (13 5 ml), water (13 5 ml), 10%
NaOH (23 5 ml), water (13 5 ml), and brine (1x5 ml), and dried with
anhydrous Na2SO4. After filtration and solvent evaporation under
reduced pressure, the residue was purified by flash column chromatog-
raphy (silica gel, hexane/ethyl acetate 2:1) (2.65 g, 75% yield). White
Ligand 8. (2S)-2-Methyl-1,4-bis{[(1S)-7,7-dimethyl-2-oxonorborn-1-
yl]carbonyl}piperazine (14) In a round-bottom flask, equipped with a
magnetic stirrer and a water condenser, (2S)-2-methylpiperazine (13)
(57 mg, 0.6 mmol) was dissolved in dry THF (3 ml) under argon. Then,
triethylamine (118 mg, 1.2 mmol) and (1S)-ketopinic acid chloride
(12)22 (121 mg, 0.6 mmol) in dry THF were added. The mixture was
refluxed for 24 h. After this time, the mixture was cooled down to r.t.
and filtered under reduced pressure. The residue was dissolved in chlo-
roform (10 ml), water was added (10 ml), and the layers were separated.
The organic layer was washed with 10% NaOH (13 5 ml), H2O (13 5
ml), and brine (13 5 ml). Then, the organic layer was dried with anhy-
drous MgSO4. After filtration and solvent evaporation under reduced
pressure, the residue was purified by flash column chromatography
(silica gel, hexane/ethyl acetate 1:1) (101 mg, 42% yield). 1H NMR
(CDCl3, 300 MHz), d: 5.03–4.72 (m, 1H), 4.62–4.21 (m, 1H), 3.85–3.45
(m, 3H), 3.36–3.06 (m, 1H), 2.97–2.65 (m, 1H), 2.49 (ddd, J 5 18.4 Hz, J
5 4.8 Hz, J 5 1.6 Hz, 2H), 2.21–1.97 (m, 8H), 1.89 (d, J 5 18.5 Hz, 1H),
1.87 (d, J 5 18.5 Hz, 1H), 1.49–1.35 (m, 2H), 1.22 (s, 6H, CH3), 1.204 (s,
3H, CH3), 1.200 (s, 6H, CH3) ppm. 13C NMR (CDCl3, 75 MHz), d: 212.8
solid. Mp: 136–1388C. [a]D 119.0 (c 0.15, CHCl3). 1H NMR (CDCl3,
20
300 MHz), d: 4.27–3.20 (m, 7H), 2.52–2.47 (m, 2H), 2.36–1.56 (m,12H),
1.45 (m, 2H), 1.35–0.77 (m, 13H) ppm. 13C NMR (CDCl3, 75 MHz), d:
212.6 (C¼O), 212.2 (C¼O), 169.0 (NꢀꢀC¼O), 168.1 (NꢀꢀC¼O), 67.3 (C),
67.2 (C), 50.7 (C), 50.6 (C), 49.2 (CH2), 48.3 (CH2), 46.8 (CH2), 43.9
(CH2), 43.6 (CH2), 43.4 (CH2), 42.84 (CH), 42.79 (CH), 28.2 (CH2), 28.0
(CH2), 27.9 (CH2), 27.1 (CH2), 27.0 (CH2), 21.3 (CH3), 21.1 (CH3), 20.7
(CH3) ppm. FTIR, m: 1783.4 (s), 1621.1 (s) cm21. MS (EI), m/z (%): 429
([M 1 1]1, 2), 879 ([2M 1 23]1, 100). HRMS (EI), m/z: 429.2751 (calcd.
for C25H37N2O4: 429.2748).
N,N0-Bis{[(1S,2R,4R)-7,7-dimethyl-2-hydroxynorborn-1-yl]carbonyl}homo-
pipera-zine (7). A two-necked round-bottom flask, equipped with a
magnetic stirrer and
a water condenser was charged with N,N’-
bis{[(1S,4R)-7,7-dimethyl-2-oxonorborn-1-yl]carbonyl}homopiperazine
Fig. 1. Some efficient ligands for the addition of organozinc reagents to
Fig. 3. Catalyst model postulated for bis(hydroxyamides) of the type of 4
aldehydes.
and based on two-carbon-length diamine spacers.
Chirality DOI 10.1002/chir

BIS(HYDROXYAMIDE)-BASED ZINC-CHELATE CATALYSTS
(C), 212.6 (C), 167.3 (C), 67.5 (C), 67.4 (C), 50.7 (C), 50.6 (C), 46.5
525
(CH2), 44.7 (CH), 43.7 (CH2), 43.6 (CH2), 43.0 (CH), 42.1 (CH2), 27.1
(CH2), 27.0 (CH2), 21.2 (CH3), 21.2 (CH3), 21.0 (CH3), 20.9 (CH3), 15.1
(CH3).
(2S)-2-Methyl-1,4-bis{[(1S,2R)-7,7-dimethyl-2-hydroxynorborn-1-yl]carbo-
nyl}pi-perazine (8). A total of 40 mg (0.09 mmol) of (2S)-2-methyl-1,4-
bis{[(1S)-7,7-dimethyl-2-oxonorborn-1-yl]carbonyl}piperazine (14) were
reacted following the experimental procedure for the preparation of 7.
20
32 mg (79% yield). White solid. Mp: 214–2168C. [a]D 21.24 (c 1.45,
CHCl3). 1H NMR (CDCl3, 300 MHz), d: 4.71 (br s, 2H, OH), 4.38–4.11
(m, 3H), 4.17 (dd, J 5 7.2 Hz, J 5 3.8 Hz, 2H, CHꢀꢀOH), 3.40–2.98 (m,
3H), 2.06–1.72 (m, 11H), 1.65 (t, J 5 4,1 Hz, 2H, CHꢀꢀN), 1.60–1.49 (m,
2H), 1.390 (s, 3H, CH3), 1.387 (s, 3H, CH3), 1.34–1.22 (m, 2H), 1.19–1.11
(m, 9H, CH3) ppm. 13C NMR (CDCl3, 75 MHz), d: 172.4 (NꢀꢀC¼O),
171.6 (NꢀꢀC¼O), 78.3 (CHꢀꢀOH), 77.9 (CHꢀꢀOH), 60.9 (C), 60.7 (C),
50.8 (C), 50.6 (C), 48.0 (CH2), 47.9 (CH2), 44.80 (CH), 44.79 (CH), 42.0
(CH2), 41.7 (CH2), 30.3 (CH2), 29.9 (CH2), 27.1 (CH2), 22.25 (CH3),
22.19 (CH3), 21.72 (CH3), 21.70 (CH3), 14.1 (CH3) ppm. FTIR, m: 3420
(wide, w), 1610 (str) cm21. MS (ESI), m/z (%): 455 ([M 1 23]1, 56), 433
([M 1 1]1, 18). HRMS (ESI), m/z: 433.30493 (calcd. for C25H41N2O4,
433.30608).
Scheme 2. Preparation of the studied ligand.
stage of the ligand. Moreover, in this last case, the presence
of a methyl group on the amine ring makes the ligand to be
more sterically shielded than its parent 5, which can exert a
negative effect on the catalytic activity.*
Asymmetric Reaction
Both ligands were prepared in two easy steps as shown in
Scheme 2: amidation of (1)-ketopinic acid with the corre-
sponding commercial diamine (75% yield for the preparation
of 11, and 42% for the preparation of 14),y followed by a che-
moselective and highly stereoselective reduction of the cor-
responding bis(ketoamide) with sodium borohydride (98%
yield for 7 and 76% yield for 8). The catalytic activity of
ligands 7 and 8 was tested in the addition of diethylzinc to
benzaldehyde. Table 1 shows the obtained results.
Typical procedure. Into a 10-ml round-bottom flask, equipped with
a magnetic stirrer under argon and containing the corresponding ligand
(0.02 mmol), diethylzinc solution (1.10 mmol, 1.0 M in hexanes) was
added at room temperature. The mixture was stirred at room tempera-
ture for 5 min. The corresponding aldehyde (1.0 mmol) was then added,
and the reaction mixture was stirred at room temperature for 5 h. The
reaction was quenched by the addition of 10% HCl (3 ml). The resulting
mixture was extracted with ether (33 3 ml). The combined organic
layers were submitted to celite filtration and solvent evaporation. The
obtained residue was dissolved in HPLC-grade hexanes and submitted
to analysis by GC and chiral HPLC.
Ligand 7 turned out to be more efficient than its analo-
gous 5 (93% vs. 88% ee), even though the C2-symmetry is lost
in the corresponding zinc-chelate catalyst. Moreover, the effi-
ciency affect not only to the reached enantioselectivity but
also to the reaction rate as well as both the ligand and diethil-
zinc loadings. Thus, by using ligand 7 instead of 5, the enan-
tioselective addition can be successfully completed in 1 h by
using just 1.1 equiv of Et2Zn and 2% mol equiv of catalyst.
This interesting improvement in the catalytic activity can
be easily explained on the basis of the higher flexibility of
the new diamine spacer, which leads to a less strained zinc-
dialcoxide catalyst 6, allowing the formation of more-stable
controlling transition states. Moreover, despite the duplica-
tion of the number of possible involved diastereomeric transi-
tion states, due to the lost of the C2 symmetry in the zinc-
chelate catalyst, the C2-symmetry lost must also increase the
energetic gap between the controlling pro-R and pro-S transi-
tion-state couple, as the reached enantioselectivity was
enhanced.
RESULTS AND DISCUSSION
In our previous studies on how structural variations on the
amine moiety could affect the catalytic activity of bis(hydrox-
yamides), we demonstrated that ligands having too flexible
or too long diamine spacers are less efficient in the enantio-
selective addition of diethylzinc to benzaldehyde.21 In this
context, bis(hydroxyamides) based on two-carbon-length
cyclic diamine spacers are privileged ligands (i.e., 5 in Fig.
2). Based on these findings, we have chosen two simple ana-
logues of 5 for our current study (7 and 8 in Fig. 4).
Ligand 7 is a near analogue of 5, where the piperazine
spacer of the last has been substituted by its homologue
more-flexible seven-membered homopiperazine (1,4-diaze-
pan). Therefore, the new ligand maintains the C2-symmetry
of parent 5, but differently such a symmetry is lost when the
corresponding zinc-chelate catalyst 6 is formed (note that an
alone C2 axe is possible in the structure of ligand 7, whereas
two orthogonal C2 axes are possible in the structure of ligand
5). On the other hand, the 2-methylpiperazine-based ligand
8 also leads to an asymmetric zinc-chelate catalyst of the
type of 6, but in this case, the C2 symmetry was lost at the
Strikingly, asymmetric ligand 8 keeps the good catalytic
activity as well, even though it is more sterically crowded
than its analogous 5 (see page footnote on page 3). However,
in this case, the ee was slightly lower (86%), probably due to
such a hinder, but the ligand was still very active (97% yield
in 2 h for 1.1 equiv of diethylzinc and 2% catalyst loading).
*A higher steric hindrance around the nitrogen can cause a decrease on
the catalytic activity of the hydroxyamide-based ligands (see Ref. 19).
yFor the diacylation of homopiperazine with ketopinic acid, EDC was used
as the acid activator. However, the diacylation of 2-methylpiperazine under
the same conditions did not yield the corresponding bis(ketoamide), prob-
ably due to steric reasons. Nevertheless, the desired 2-methylpiperazine-
based bis(ketoamide) could be obtained by using ketopinyl chloride as acy-
lating reagent.
Fig. 4. Studied ketopinic-derived bis(hydroxyamide)-based ligands.
Chirality DOI 10.1002/chir

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526
SANCHEZ-CARNERERO ET AL.
TABLE 1. Catalytic activity of bis(hydroxyamides) 7 and 8 in enantioselective addition of diethylzinc to benzaldehyde
1-Phenylpropan-1-ol
Equivalents
of Et2Zna
Equivalents
of ligand
Ligand
t (h)
Yield (%)b
ee (%)c
Conformationc
References
5
5
7
8
2.0d
2.0
1.1
1.1
0.05
0.02
0.02
0.02
5
5
1
2
97
95
98
97
90
88
93
86
R
R
R
R
19–21
–
–
–
Previous results for ligand 5 are included for comparison.
a1.0 M in hexanes.
bDetermined by GC.
cDetermined by chiral HPLC (Chiralpak IC).
d1 ml of additional hexane was added.
and ketones catalyzed by immobilized chiral ligands. Mini Rev Org
Chem 2010;7:10–22.
CONCLUSIONS
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The good catalytic activity reached with the ketopinic-acid-
derived bis(hydroxyamide)-based ligands 7 and 8 show that
it is possible to use diamine spacers leading to asymmetric
bis(hydroxyamide)-based zinc-chelate catalysts for a success-
ful design of new ligands of this interesting type. This fact
expands the structural diversity in the ligand design, which
will allow a better rational study on the origin of the catalytic
activity (SAR studies) with the object of developing required
new cheap ligands with optimized benefits.
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