New Supported β-Amino Alcohols as Efficient Catalysts for the Enantioselective Addition of Diethylzinc to Benzaldehyde under Flow Conditions

Article abstract of DOI:10.1021/ol026805o

(Matrix Presented) Polymeric monoliths 10 containing an amino alcohol moiety derived from an industrial waste material represent one of the best ligands for the enantioselective catalytic addition of ZnEt₂ to benzaldehyde (99% ee), being recove

Full text of DOI:10.1021/ol026805o

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3947-3950
New Supported â-Amino Alcohols as
Efficient Catalysts for the
Enantioselective Addition of Diethylzinc
to Benzaldehyde under Flow Conditions
M. Isabel Burguete,† Eduardo Garc´ıa-Verdugo,† Mar´ıa J. Vicent,†
,†
Santiago V. Luis,* Helmut Pennemann,‡ Nikolai Graf von Keyserling,‡ and
,‡
Ju1rgen Martens*
Departamento de Qu´ımica Inorga´nica y Orga´nica, E.S.T.C.E. UniVersitat Jaume I,
P.O. Box 224, E-12080 Castello´n, Spain, and Fachbereich Chemie,
UniVersita¨t Oldenburg, Carl-Von-Ossietzky-Str. 9-11, 26129 Oldenburg, Germany
luiss@mail.uji.es
Received August 28, 2002
ABSTRACT
Polymeric monoliths 10 containing an amino alcohol moiety derived from an industrial waste material represent one of the best ligands for
the enantioselective catalytic addition of ZnEt2 to benzaldehyde (99% ee), being recoverable and usable under flow conditions.
Development of environmentally friendly chemical processes
is one of the main challenges for chemical research in this
century.1 In this context, catalysis represents one of the most
attractive approaches. Enantioselective synthesis based on
transition metal-catalyzed processes is a field of increasing
interest in organic chemistry because of their high efficiency
for stereoselective synthesis. A great number of those
catalysts are needed in pharmaceutical, food, and agricultural
industries for the enantioselective synthesis of organic
compounds due to their high economical importance in those
fields.2 In the development of chiral catalysts, the use of
starting materials of easy accessibility and low cost is highly
desirable. Thus, the synthesis of chiral ligands derived from
compounds of the so-called chiral pool has been the most
useful. An alternative and attractive approach is the use of
chiral industrial waste materials. Some of us have been
involved, in recent years, in the design of different low-cost
and effective chiral ligands using (all-R)-2-azabicyclo [3.3.0]-
octane-3-carboxylic acid as the starting material, which is a
waste material generated in the industrial process of syn-
thesizing the ACE inhibitor Ramipril at Aventis.3,4 Encour-
aged by the high catalytic enantioselectivity induced by some
of those homogeneous ligands and in the search of more
efficient, recoverable, and environmentally friendly catalysts,
we decided to investigate the corresponding heterogeneous
catalysts derived from 1. Besides the above-mentioned
(2) (a) Brown, C. Chirality in Drug Design and Synthesis; Academic
Press: New York, 1990. (b) Brown, J. M. Tetrahedron: Asymmetry 1991,
2, 481-732. (c) Ojima, I., Ed. Catalytic Asymmetric Synthesis, 2nd ed.;
Wiley-VCH: New York, 2000. (d) Noyori, R. Asymmetric Catalysis in
Organic Synthesis; Wiley: New York, 1994.
† E.S.T.C.E. Universitat Jaume I.
‡ Universita¨t Oldenburg.
(1) Eissen, M.; Metzger, J. O.; Schmidt, E.; Schneidewind, U. Angew.
Chem., Int. Ed. 2002, 41, 415-436.
(3) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical
Substances, 4th ed.; Thieme: Stuttgart, 2001; pp 1785-1787.
10.1021/ol026805o CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/08/2002

advantages derived from the use of 1 as the starting material,
it is important to note that heterogeneous chiral catalysts are,
in principle, best suited for industrial applications, in
particular due to the possibility of their use in continuous
flow systems.5 In this ideal system, the solution containing
the reagents is feed into a reactor in which a chiral
heterogeneous catalyst promotes their transformation to the
desired chiral products. The need for catalyst separation is
suppressed, and the products can be easily isolated just by
removing the solvent, increasing the efficiency, and reducing
the environmental impact of the whole process.
Scheme 1a
Enantioselective addition of dialkylzinc to aldehydes in
the presence of chiral promoters such as chiral â-amino
alcohols has been shown to be a useful method of inducing
asymmetric carbon-carbon bond formation.6,7 Some chiral
amino alcohols derived from 1 act as excellent ligands for
this enantioselective reaction.4 Here we report the results
obtained for this reaction with both heterogeneous and
homogeneous ligands synthesized from 1. Some of the
polymer-supported ligands prepared have shown an optimal
behavior in terms of activity, selectivity, and enantioselec-
tivity, being able to act efficiently in flow systems. An
increase in selectivity and enantioselectivity has been
observed upon immobilization, and those features are
maintained for several catalytic cycles.
According to former results and to a preliminary screening
on different supported â-amino alcohols derived from 1 as
catalysts for the enantioselective addition of diethylzinc to
benzaldehyde, we decided to focus our work on the prepara-
tion and study of supported catalysts such as 7 and 10,
bearing phenyl groups at the R-position. This diphenyl
hydroxymethylene moiety is present in a huge number of
asymmetric catalysts and has been termed the “magic
group”.8
To obtain a better understanding of the behavior of a given
heterogeneous catalyst, it is absolutely necessary to evaluate
the activity of the homogeneous analogues. It is well-known
that results obtained in an enantioselective transformation
can dramatically change when going from homogeneous to
a Reagents and conditions: (a) Pd/C. (b) SO2Cl/MeOH. (c)
PhCH2Cl (1.2 equiv), 80%. (d) PhMgCl, THF, ref 4a. (e) 3 (3
equiv), Merrifield Resin (1 equiv, loading 1.1 mequiv/g, 1% cross-
linking), NaHCO3 (6 equiv), THF, quant. (f) PhMgCl, THF, quant.
(g) 4-Chlorovinylbenzene (1.2 equiv), NaHCO3 (2.5 equiv), 18 h,
70 °C, 40% (ref 11b). (h) PhMgX (3 equiv), 75% (ref 15). (i)
9/DVB/VB/toluene/1-dodecanol, AIBN, 80 °C, 99%.
heterogeneous phases.9-11 For that reason, the synthesis of
the homogeneous catalyst 5 was carried out (see, Scheme
1) as the first step.
(4) (a) Wallbaum, S.; Martens, J. Tetrahedron: Asymmetry 1991, 2,
1093-1096. (b) Wilken, J.; Kossenjans, M.; Saak, W.; Pohl, S.; Martens,
J. Liebigs Ann. Chem. 1997, 573-579. (c) Wassmann, S.; Wilken, J.;
Martens, J. Tetrahedron: Asymmetry 1999, 10, 4437-4445. (d) Kossenjans,
M.; Soebert, M.; Wallbaum, S.; Harms, K.; Martens, J.; Aurich, H. G.; J.
Chem. Soc., Perkin Trans. 1 1999, 2353-2365. (e) Graf von Keyserlingk,
N.; Martens, J. Eur. J. Org. Chem. 2002, 301-308.
(8) (a) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem. Soc.
1987, 109, 7111-7115. (b) Braun, M. Angew. Chem., Int. Ed. 1996, 35,
519.
(5) (a) Sherrington, D. C. Chemistry of Waste Minimization; Clark, J.
H., Ed.: Blackie: London, 1995; Chapter 6, p 141. (b) de Miguel, Y. R.;
Brule´, E.; Margue, R. G. J. Chem. Soc., Perkin Trans. 1 2001, 3085-
3094. (c) Clapham, B.; Reger, T. S.; Janda, K. D. Tetrahedron 2001, 57,
4637-4662.
(6) For general references, see: (a) Noyori, R.; Kitamura, M Angew.
Chem., Int. Ed. Engl. 1991, 30, 49-69. (b) Soai, K.; Niwa, S.; Chem. ReV.
1992, 92, 833-856. (c) Pu, L.; Yu, H. B.; Chem. ReV. 2001, 101, 757-
852.
(7) For examples of heterogeneous catalysts in Et2Zn additions, see: (a)
Itsuno, S.; Sakurai, Y.; Ito, K.; Marayuma, T.; Nakahama, S.; Fre´chet, J.
M. J. J. Org. Chem. 1990, 55, 304-310. (b) Liu., G.; Ellman, J. A. J. Org.
Chem. 1995, 60, 7712-7713. (c) Halm, C.; Kurth, K. Angew. Chem., Int.
Ed. 1998, 37, 510-512. (d) Vidal-Ferran, A.; Bampos, N.; Moyano, A.;
Perica´s, M. A.; Riera, A.; Sanders, J. K. M. J. Org. Chem. 1998, 63, 6309-
6318. (e) Holte, P.; Wijgergangs, J.-P.; Thijs, L.; Zwanenburg, B. Org.
Lett. 1999, 1, 1095-1097. (f) Brouwer, A. J.; Linden, H. J.; Liskamp, R.
M. J. J. Org. Chem. 2000, 65, 1750-1757. (g) Seller, H.; Rheiner, P. B.;
Seebach, D. HelV. Chim. Acta 2002, 85, 352-387.
(9) (a) Altava, B.; Burguete, M. I.; Escuder, B.; Luis, S. V.; Salvador,
R. V.; Fraile, J. M.; Mayoral, J. A.; Royo, A. J. J. Org. Chem. 1997, 62,
3126-3134. (b) Annis, D. A.; Jacobsen, E. N. J. Am. Chem. Soc. 1999,
121, 4147-4154. (c) Adria´n, F.; Burguete, M. I.; Luis, S. V.; Fraile, J. M.;
Mayoral, J. A.; Royo, A. J.; Garc´ıa, J. I.; Garc´ıa, J.; Garc´ıa-Espan˜a, E.;
Sa´nchez, M. C. Eur. J. Inorg. Chem. 1999, 2347-2354. (d) Altava, B.;
Burguete, M. I.; Garc´ıa-Verdugo, E.; Luis, S. V.; Pozo, O.; Salvador, R.
V. Eur. J. Org. Chem. 1999, 2263-2267. (e) Altava, B.; Burguete; M. I.;
Collado, M.; Garc´ıa-Verdugo, E.; Luis, S. V.; Salvador, R. V.; Vicent, M.
J. Tetrahedron Lett. 2001, 42, 1673-1675. (f) Hu, J.; Zhao, G.; Ding, Z.;
Angew. Chem., Int. Ed. 2001, 40, 1109-1111.
(10) (a) Altava, B.; Burguete, M. I.; Garc´ıa, J. I.; Luis, S. V.; Fraile, J.
M.; Mayoral, J. A.; Vicent, M. J. Angew. Chem., Int. Ed. 2000, 39, 1503-
1506.
(11) (a) Kamahori, K.; Ito, K.; Itsuno,S. J. Org. Chem. 1996, 61, 8321-
8324. (b) Altava, B.; Burguete, M. I.; Garc´ıa-Verdugo, E.; Luis, S. V.;
Salvador, R. V.; Vicent, M. J. Tetrahedron 1999, 55, 12897-12906. (c)
Burguete, M. I.; Fraile, J. M.; Garc´ıa, J. I.; Garc´ıa-Verdugo, E.; Herrer´ıas,
C. I.; Luis, S. V.; Mayoral, J. A. J. Org. Chem. 2001, 66, 8893-8901.
3948
Org. Lett., Vol. 4, No. 22, 2002

On the other hand, the synthesis of the supported chiral
auxiliary 7 was initially achieved by the grafting of 3 onto
a Merrifield resin (1.1 mmol Cl/g) to obtain 6 and further
reaction of this polymer with an excess of phenyl Grignard
reagent, using the general methodology developed for the
preparation of supported amino alcohols from natural amino
acids.9e-d A quantitative transformation of polymeric func-
tional groups was achieved as shown by the use of FT-IR
and FT-Raman spectroscopy as well as gel-phase 13C
NMR.9a,d,11c
entry 6 of Table 1, a slight decrease in the enantioselectivity
was observed, 80 vs 89%ee
In some cases chiral-supported catalysts prepared by
polymerization have been reported to give better asymmetric
inductions than those obtained through grafting.11 Accord-
ingly, vinylic derivative 9 was prepared in order to obtain
the related supported catalyst 10 by polymerization. From
the different polymerization techniques, we selected mono-
lithic columns using divinylbenzene and styrene as comono-
mers for the preparation of 10.12 These types of material are
the most suitable for the preparation of flow systems due to
their porosity properties. The morphology of these macro-
porous materials, when appropriately tailored, avoids diffu-
sion problems and allows them to act as stable and easily
recoverable microreactors.10,13
The catalytic behavior of the soluble ligand 5 was
evaluated for the enantioselective addition of ZnEt2 to
benzaldehyde (Scheme 2). In a typical procedure, the reaction
Different polymerization mixtures were evaluated in order
to synthesize the polymeric catalyst 10. A mixture containing
40 wt % monomers (10 mol % 9/90 mol % DVB; no styrene
was used) and 60 wt % toluene-1-dodecanol as the porogenic
mixture (10 wt % toluene) provided monoliths with the
desired morphology and properties. The monolithic column
allowed the design of a flow system (Figure 1) in which the
Scheme 2
was carried out at rt in toluene for 24 h with a catalyst
concentration of 2-20 mol % relative to the aldehyde. In
general, the chemical yields obtained for 12 after fractional
distillation ranged from 74 to 88%. Regarding the enantio-
selectivity, a typical and expected nonlinear relationship was
found (entries 1-4, Table 1), enantioselectivities being
optimal for catalyst concentrations of 10% or higher.
Table 1. ZnEt2 Addition to Benzaldehyde at 25 °C in the
Presence of Ligands 5 and 7
entry
ligand
mol %b
yield (%)c
ee (%)d
1
2
3
4
5
6
5
5
5
5
7
7a
2
5
10
20
10
10
74
74
85
88
83
74
70 (R)
75 (R)
87 (R)
90 (R)
89 (R)
80 (R)
Figure 1. Schematic representation of the flow-bed reactor used
in this work. (A) Reactor: macroporous monolithic rod of DVD/
9. (B) Reservoir 1: Zn2Et/PhCHO/12/13 in anhydrous toluene. (C)
Reservoir 2: toluene (anhydrous solvent to wash the reactor at the
end of the reaction). (E) Four-port ways valve. (D) HPLC Gilson
pump.
a Reused catalyst. b Percent molar value of the catalyst relative to
benzaldehyde. c Determined by NMR. d Determined by HPLC (Chiralcel
OD) or GC.
The heterogeneous ligand 7 was tested for the diethyl zinc
reaction using 10 mol % chiral catalyst and conditions similar
to those used with the homogeneous catalysts. Good catalytic
behavior was observed in terms of yield and enantioselec-
tivity (entry 5, Table 1). The supported catalyst provided an
enantioselectivity similar to that obtained with the homoge-
neous ligand (5, 87% ee; 7, 89% ee). It is worth noting that,
in many cases, a decrease of the asymmetric induction has
been observed when the immobilization is carried out due
to the effects induced by the polymeric matrix.9 Additionally,
the reuse of catalyst 7 was also assayed. As can be seen in
column was attached to a pump and the reaction mixture
(ZnEt2 and benzaldehyde) was pumped continuously through
the chiral column over a period of 24 h. After this time, the
pump was stopped and the reaction was quenched and
analyzed. With this experimental setup, an excess of ZnEt2
(12) (a) Svec, F.; Fre´chet, J. M. J. Science 1996, 273, 205-211. (b) Tripp,
J. A.; Stein, J. A.; Svec, F. Org. Lett. 2000, 2, 195-198.
(13) (a) Hodge, P.; Sung, D. W. L.; Stratford, P. W. J. Chem. Soc., Perkin
Trans. 1 1999, 16, 2335-2342. (b) Mayr, M.; Mayr, B.; Buchmeiser, M.
R. Angew. Chem., Int. Ed. 2001, 40, 3839-3842.
Org. Lett., Vol. 4, No. 22, 2002
3949

was used as well as a relatively diluted concentration of the
reactants. The final ratio of catalyst/benzaldehyde was
approximately 10%. The results showed an excellent catalytic
efficiency. A quantitative conversion of benzaldehyde was
obtained, along with a selectivity of 85% for the formation
of 12 and 99% ee. These figures represent the best enanti-
oselectivities obtained to date for this reaction with a
supported catalyst. As a matter of fact, columns of polymer
10 prepared as described above provided significantly better
enantioselectivities than those obtained with the homoge-
neous analogues and with the polymer prepared by grafting.
This improvement in the efficiency could be related to the
formation of more appropriated chiral cavities during the
polymerization process or to the isolation of the catalytic
10
sites provided by the high degree of cross-linking used.
On the other hand, the changes on the reaction conditions
(concentrations, ratios of catalyst/11 on the column, etc.)
needed for the flow system could also play a role in this
context. Finally, we have to consider that the high flow rates
provided by the monolithic columns avoid diffusional
problems that have been previously reported when using
highly cross-linked resins.
Figure 2. Reuse of the supported catalyst. Each cycle is a 24 h
reaction. Cycle 2 after 24 h of 1. Cycle 3 after 48 h of 1. Cycle 4
after 2 weeks of 1. Selectivity is described as the 12/13 ratio, and
enantioselectivity (ee) is described as a function of the (R)-12/(S)-
12 ratio.
as well as with the use of this catalytic system in other
asymmetric transformations. However, the present results
clearly show the great potential of the use of functional
monoliths derived from industrial chiral waste materials in
order to design new, efficient, and environmentally friendly
catalysts having exceptional long-term stability.
Even more interesting results were observed when the
catalyst was reused. This catalytic system could be reused
for four successive runs, obtaining again very high yields
without any loss of its catalytic efficiency, both in terms of
selectivity (12/13 ratio) and enantioselectivity ((R)-12/(S)-
12 ratio) (see Figure 2). Similar long-term stability of
supported catalysts has been previously reported for mono-
lithic Ti-TADDOLates.10 These results open the way for the
potential application of those catalysts for continuous-flow
systems.
Acknowledgment. We thank the Spanish C.I.C.Y.T.
(Project MAT99-1176) for financial support.
Supporting Information Available: General experimen-
tal procedures. This material is available free of charge via
the Internet at http://pubs.acs.org.
Additional work is being carried out with the use of
different aldehydes to establish the scope of this reaction,
OL026805O
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Org. Lett., Vol. 4, No. 22, 2002