Towards more chemically robust polymer-supported chiral catalysts for the reactions of aldehydes with dialkylzincs.

Article abstract of DOI:10.1016/S0960-894X(02)00276-7

N-Methyl-alpha,alpha-diphenyl-L-prolinol derivatives with para-bromo substituents in one or both of the phenyl rings are easily bound to crosslinked polystyrene beads containing phenylboronic acid residues using Suzuki reactions. When the products were used as catalysts for the reactions of aldehydes with diethylzinc in toluene at 20 degrees C, the alcohols were produced in chemical yields >90% and with ees of upto 94%. The better of the two supported catalysts gave ees only 0-9% lower than those obtained with the corresponding soluble catalyst. One of the supported catalysts was recycled successfully nine times.

Full text of DOI:10.1016/S0960-894X(02)00276-7

Bioorganic & Medicinal Chemistry Letters 12 (2002) 1803–1807
Towards More Chemically Robust Polymer-Supported Chiral
Catalysts for the Reactions of Aldehydes with Dialkylzincs
Roger J. Kell, Philip Hodge,* Mohammad Nisar and David Watson
Chemistry Department, University of Manchester, Oxford Road, Manchester, M13 9PL, UK
Received 28 November 2001; accepted 19 February 2002
Abstract—N-Methyl-a,a-diphenyl-l-prolinol derivatives with para-bromo substituents in one or both of the phenyl rings are easily
bound to crosslinked polystyrene beads containing phenylboronic acid residues using Suzuki reactions. When the products were
used as catalysts for the reactions of aldehydes with diethylzinc in toluene at 20 ꢀC, the alcohols were produced in chemical yields
>90% and with ees of upto 94%. The better of the two supported catalysts gave ees only 0–9% lower than those obtained with the
corresponding soluble catalyst. One of the supported catalysts was recycled successfully nine times. # 2002 Elsevier Science Ltd.
All rights reserved.
Asymmetric syntheses achieved using PS chiral catalysts
are a particularly attractive type of synthesis. Thus, (i)
at the end of the reaction period the soluble chiral pro-
ducts are easily freed of the PS catalyst by filtration, (ii)
at the same time the PS catalyst is recovered for possible
reuse, and (iii) because of advantages (i) and (ii) it
becomes acceptable to use relatively large amounts of
catalyst to obtain high-percentage enantiomeric excesses
(% ees) and/or increased reaction rates. Many attempts
have been made to prepare PS versions of the better
chiral catalysts,1À3 but it is not a trivial exercise and in
many cases the % ees achieved have been significantly
lower in the supported systems. Usually this is because
not enough attention has been given to the four impor-
tant factors that need to be considered if a conventional
organic reaction is to be converted successfully into a PS
one.4 These are: (i) the reactive site accessibility, (ii)
possible site–site interactions, (iii) possible micro-
environmental effects, and (iv) the effect of the method
of attachment on the ‘active site’ of the catalyst.5,6
because the reactions take place slowly without any
added catalyst to give racemic products. For example,
benzaldehyde in toluene at 20 ꢀC reacts with diethylzinc
to give racemic 1-phenylethanol in ca. 15% yield in 18 h.6
Accordingly, the PS catalysts operate in a competitive
situation and unless a sufficient proportion of the PS
catalytic sites are readily accessible, the reactions that
give racemates will make significant contributions to the
overall reactions and consequently relatively low % ees
will be obtained.
It is often claimed that PS chiral catalysts can be recy-
cled, but recycling is rarely studied in any detail. One
factor neccessary for a PS catalyst to be recycled suc-
cessfully many times is a robust link between the cata-
lyst moieties and the support. Another is that the
catalyst moieties themselves must be chemically stable.
Very little information is available on this latter point
because in practice laboratory chemists rarely re-use
catalysts. Recently we showed, however, that PS cata-
lyst 1 slowly loses its activity when used repeatedly to
catalyse examples of Reaction 1, and detailed studies
suggest that this is due to the secondary alcohol group
being oxidised, possible reversibly.18 This decline in
performance could, therefore, probably be avoided by
using catalysts that contain tertiary rather than second-
ary alcohol groups. Analogues of catalyst 1 that contain
tertiary alcohol groups have not been studied before,
An important asymmetric synthesis is the reaction of
aldehydes in toluene with dialkylzincs [Reaction 1]. The
reaction is catalysed by b-tertiary-aminoalcohols.7,8
Various PS chiral b-amino alcohols have been used as
catalysts6,9À18 and the earlier work has been reviewed.8
With the reactions of aldehydes with dialkylzincs pre-
paring successful PS catalysts is a particular challenge
*Corresponding author. Tel.: +44-161-275-4707; fax :+44-161-275-
4273; e-mail: philip.hodge@man.ac.uk
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00276-7

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R. J. Kell et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1803–1807
but derivatives of N-methyl-a,a-diphenylprolinol (2)
satisfy the structural requirement and have been shown
to be excellent catalysts in many asymmetric syntheses
including examples of Reaction 1.7,8 Accordingly the
preparation of PS N-methyl-a,a-diphenylprolinol deri-
vatives was investigated.
a,a-Diphenyl-l-prolinol (5) is conveniently prepared
without any racemisation problems by the reaction of a-
N-carbonic anhydride 6 21 with phenylmagnesium bro-
mide.22 This synthesis was repeated successfully (44%
yield based on proline) to give a,a-diphenyl-l-prolinol
(5) and the product was N-methylated (55% yield) by
the Eschweiler–Clark method23 to give compound 2.
An analogous synthesis was then carried out by reacting
the anhydride 6 with a mixture of phenylmagnesium
bromide and 4-bromophenylmagnesium bromide24 (mol
ratio, 60:40). The viscous oil obtained (Product I) was,
as expected, a mixture of compounds 5 and 7. The mass
spectrum (chemical ionisation) had a peak at 253 due to
the unbrominated product and peaks at 331 and 333
corresponding to monobromo products 7 with 79Br and
81Br. By elemental analysis it contained 2.7% of Br.
Attempts to separate the mixture by column chromato-
graphy failed, so it was directly N-methylated using the
Eschweiler–Clark method23 to give Product II contain-
ing compound 2 and the monobromo diastereoisomers
4. By GC, the mol ratio was 85:15. As only the bromo
compounds 4 are capable of taking part in a Suzuki
coupling, the coupling was carried out using Product II.
Whilst it is intended to subsequently develop separate
syntheses of each isomer of 4, in these initial studies the
mixture was considered to be satisfactory as it is not
expected that the isomers will result in either very dif-
ferent reactivities or % ees.
Three approaches for attaching N-alkyl-a,a-diphenyl-
prolinol moieties to polymer beads are via the 4-hydroxyl
group of a derivative prepared from hydroxyproline,16
via the N-substituent,6,15 or via the phenyl groups.
Attachment via the 4-hydroxyl group will often result in
sensitive linkages and attachment via the N-substituent
has been shown to interfere with the ‘active site’,6,15 but
attachment via the phenyl groups, which does not
appear to have been studied before, would not be
expected to interfere.
The PS boronic acid 3 was prepared via the direct
lithiation of 1% crosslinked polystyrene beads.25 The
final beads contained 2.39% of B, corresponding to 2.21
mmol/g of residues 3. A suspension of the beads was
then reacted with Product II and a mixture of 2 M
sodium carbonate, 1,2-dimethoxyethane and tetra-
kistriphenylphosphinepalladium[0] at 80–85 ꢀC for 4
days, using the general procedure described previously,19
to bring about the Suzuki coupling shown in Reaction 2.
This afforded PS Catalyst A that, by elemental analysis
contained 1.82% of nitrogen, corresponding to a loading
of 1.30mmol of the diastereoisomeric a,a-diaryl-l-proli-
nol residues 8 per gram, and 0.00% of boron indicating
the complete removal of residues 3.
Recently, we described the attachment of various
achiral moieties to polystyrene beads using Suzuki cou-
plings between appropriate aryl bromides and PS boro-
nic acid 3.19 We now report that this same method can
be used successfully to attach N-methyl-a,a-diphenyl-l-
prolinol diastereoisomers 4 with a para-bromo sub-
stituent in one of the phenyl rings to crosslinked poly-
styrene beads [see Reaction 2]. The method has the
attractive features that (i) it is a one-pot procedure, (ii)
since the Suzuki reaction is tolerant of many functional
groups20 the catalyst moiety can be attached without
any need for protecting groups and the reaction system
need not be dry, (iii) the catalyst moieties are bound by
a very robust bond, and (iv) by using extended reaction
times the beads are easily freed by hydrolysis of the
boronic acid residues 3 that do not take part in the
Suzuki couplings.
PS Catalyst B was prepared in order to assess the effect
on catalyst performance of binding the catalyst moieties
through both phenyl groups.4 The preparative method
was similar to that used with PS Catalyst A. First the

R. J. Kell et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1803–1807
1805
anhydride 6 was reacted with 4-bromophenylmagne-
sium bromide.24 This reaction surprisingly afforded a
mixture (Product III) (25% yield based on proline) that
not only contained the dibromo compound 9 but also
the monobromo diastereoisomers 7. The mass spectrum
(chemical ionisation) had peaks at 409, 411 and 413
79
corresponding to dibromo products with 2Â Br,
81
79Br+81Br, 2Â Br, and at 331 and 333 corresponding
to monobromo products with 79Br and 81Br. By ele-
mental analysis it had N 3.7% and Br 35.8% (expected
for C17H17Br2NO N 3.4% and Br 38.9%). Attempts to
achieve crystallisation of the oil or significant resolution
by column chromatography failed. It is not clear how
the debromination occurred but it was probably the
result of a further Grignard reaction followed by
quenching with water. Product III was N-methylated
(70% yield) using the Eschweiler–Clark reaction23 to
give Product IV containing, by GC analysis, the
dibromo compound 10 and the monobromo diastereo-
isomers 4 in the ratio 78:22. Product IV was reacted with
beads containing residues 3, under Suzuki conditions
similar to those used previously, to give PS Catalyst B.
By elemental analyses the catalyst contained 1.64%
nitrogen, 2.90% bromine and 0.00% of boron. This
corresponds to a loading of 1.17 mmol of N-methyl-a,a-
diaryl-l-prolinol residues per g and a degree of sub-
stitution of 0.18, 31% of which bore a bromo group and
were therefore residues 11. Assuming all the bromo
groups in the starting material were equally reactive and
bearing in mind the composition of the feedstock, this
suggests that ca. 35% of the N-methyl-a,a-diaryl-l-
prolinol residues were ‘single bound’ and 65% ‘double
bound’. The latter residues 12 correspond to a sig-
nificant increase in crosslinking (ca. 12%) and therefore
will lead to reduced access to the ‘active sites’.4 In sum-
mary, therefore, Catalyst B was considered to have 65%
of the N-methyl-a,a-diaryl-l-prolinol moieties as resi-
dues 12, 31% as residues 11 and 4% as residues 8.
The examples of Reaction 1 investigated were carried
out for 20h in toluene at 20 ꢀC under nitrogen with an
aldehyde to dialkylzinc ratio of 1.00:1.10: see ref 26 for
details. For the reactions using the PS catalysts the
reaction vessel was a tube and after an appropriate
amount of catalyst had been placed in the tube it was
sealed with a septum cap. All solutions were then added
or removed using a syringe. In this way once one reac-
tion was complete the catalyst left in the tube could be
re-used easily. One charge of PS catalyst was used for a
series of reactions: see below and Table 1. Yields of the
recovered materials were >95% and, when diethylzinc
was used, >95% of the recovered materials were the
chiral alcohols. The % ees were determined by GC over
a chiral stationary phase as in previous studies.6,17,18
To determine what mol% of PS catalyst A was appro-
priate to use, three tubes were set up for reactions using
5, 10and 30mol% of catalyst and they were used for a
series of reactions between various aldehydes and die-
thylzinc. It is evident from the results summarised in
Table 1, entries 1, 3 and 5–9, that whilst in general good
% ees were obtained with a range of aldehydes the %
ees generally improved as the mol% of the catalyst
increased. Since 5 mol% of the soluble catalyst 2 is
usually sufficient to obtain the optimal % ees, this result
suggests that perhaps only ca. 20% of the PS sites are
Table 1. The % ees obtained from reactions of various aldehydes with dialkylzincs catalysed by compound 2 or PS derivativesa
Entry
Aldehyde
Reagentb
% ee of alcohol product using various catalystsc
PS Catalyst A
10mol% d
PS Catalyst B
30mol% d
Catalyst 2
5 mol%
5 mol%d
30mol% e
1
2
3
4
5
6
7
8
9
Benzaldehyde
Benzaldehyde
E
M
E
M
E
M
E
E
78
—
85
—
83
—
—
—
—
79
—
88
—
85
—
8081
71
88
23f
94
83
86
46
83
—
8094
—
81
—
93
70g
4-Chlorobenzaldehyde
4-Chlorobenzaldehyde
4-Carbomethoxybenzaldehyde
4-Carbomethoxybenzaldehyde
b-Naphthaldehyde
—
95
—
—
84
Cinnamaldehyde
Cyclohexanecarboxaldehyde
78
—
65
—
—
—
E
51
aReactions carried out in toluene at 20 ꢀC with an aldehyde to dialkylzinc ratio of 1.00:1.10.
bE, diethylzinc; M, dimethylzinc.
cThe % ee was determined by analytical GC using a chiral column — see refs 6, 17 and 18 for details.
dAll reactions were carried out with the same sample of PS catalyst. The reactions were carried out in the order listed.
eAll the eight reactions listed in this column were carried out with the same sample of PS catalyst. The five reactions carried out using diethylzinc
were carried out first in the order given, then the three reactions with dimethylzinc were carried out in the order given. Re-use of the catalyst a ninth
time in a repeat of the first entry gave alcohol product with 87% ee.
fYield only 44% — remainder of the product includes benzyl alcohol (20%), acetophenone (6%), starting material (9%) and unidentified com-
pounds (21%).
gYield only 41% — remainder of the product includes benzyl alcohol (42%), acetophenone (7%), starting material (8%) and unidentified com-
pounds (2%).

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R. J. Kell et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1803–1807
readily accessible. Such a low percentage may arise
because there are interactions between the ‘active sites’
which the amount of diethylzinc present can not com-
pletely break up (see mechanistic discussion in ref 17).
That is, there is a further type of crosslinking.
9% higher. The explanation may in part be due to site–
site interactions producing crosslinks that limit swelling
and hence limit access to the ‘active sites’,4 but there are
other possible explanations. Thus, the reactions that
give racemates can take place both in the beads and in
the surrounding solvent, whereas the PS catalyst can
only influence the course of the reaction when the solu-
ble reactants (i.e., the aldehydes and dialkylzincs) are
within the beads. As a consequence the relative rates of
the catalysed and uncatalysed reactions depend crucially
on the distribution of the soluble reactants between the
bead phase and the solution phase. The present results
suggest a substantial fraction of the soluble reactants
are outside the beads.
Using 30mol% of PS catalyst, benzaldehyde, 4-chloro-
benzaldehyde and 4-carbomethoxy-benzaldehyde were
treated with dimethylzinc. As has been found in other
studies,10,13,27 these reactions were generally less satis-
factory than those with diethylzinc. It is not clear why
this should be. Thus, the % ees of the alcohol products
were significantly lower and the reactions were less
clean: see Table 1 entries 2, 4 and 6 and footnotes f and
g. Whilst, by GC–MS, the reaction with diethylzinc
gave <1% each of benzyl alcohol and propiophenone,
the reactions with dimethylzinc gave substantial
amounts of benzyl alcohol and acetophenone. How
such large amounts of benzyl alcohol are formed is not
clear, but the acetophenone presumably arises from by
hydride transfer from the initial product of addition of
dimethylzinc to benzaldehyde. We have suggested
before that reactions of this type cause PS catalysts such
as 1 to lose activity on repeated use.18 Such a side reac-
tion would not be possible with the PS N-methyl-a,a-
diaryl-l-prolinols used here.
In summary, using the approach summarised in Reac-
tion 2, PS catalysts containing N-methyl-a,a-diphenyl-
l-prolinol residues were easily prepared. The catalyst
moieties were bound through one or both phenyl resi-
dues. When PS catalyst A was used at 30mol% in tol-
uene at 20 ꢀC for examples of Reaction 1 involving
diethylzinc, the expected alcohols were obtained in 78–
94% ees. The PS catalysts recycle well and PS Catalyst
A was used successfully nine times. Where comparisons
can be made with the results obtained with the soluble
analogue 2, the PS catalysts usually afford somewhat
lower % ees. In part, this is due to the PS catalysts
having to compete with the background reactions
that give racemic alcohol products. Given the success
of the present study, in future work we propose to
prepare PS catalysts using the pure isomers of com-
pounds 4 and to use them for extended periods in flow
systems.18
Attention was next turned to PS Catalyst B. A series of
reactions was carried out between various aldehydes
and diethylzinc using one charge of 30mol% of PS
Catalyst B. It is evident from the results in Table 1 that
with this catalyst the % ees were 9% less on average
than those obtained with PS Catalyst A. This is
undoubtedly due to the fact that many of the catalyst
moieties are ‘double bound’. Apart from increasing the
extent of crosslinking, ‘double binding’ also means the
catalytic sites are on crosslinks and so are generally less
accessible than those on simple side chains.
Acknowledgements
We thank the EPSRC for Ph.D. (R.J.K.) and M.Sc.
(M.N.) Studentships.
It was hoped that the PS catalysts would recycle well.
The most extensively recycled sample was the charge of
PS Catalyst A which was used for all the eight reactions
carried out using 30mol% of the catalyst: see Table 1
and footnote e. After the eighth reaction, the reaction
summarised in entry 1 was repeated. It gave an ee of
87% compared with an ee of 88% for the first reaction.
This is encouraging and suggests that the present cata-
lyst moieties are more robust than those used in the PS
catalyst 1 studied previously.17,18
References and Notes
1. Clapham, B.; Reger, T. S.; Janda, K. D. Tetrahedron 2001,
57, 4637.
2. Hodge, P. In Innovation and Perspectives in Solid Phase
Synthesis; Epton, R., Ed; SPCC, Birmingham, 1990; p. 273.
3. De Miguel, Y. R. J. Chem. Soc., Perkin Trans. 1 2000,
4213.
4. Hodge, P. Chem. Soc. Rev. 1997, 26, 417.
5. Hodge, P.; Khoshdel, E.; Waterhouse, J.; Frechet, J. M. J.
J. Chem. Soc., Perkin Trans. 1 1985, 2327.
6. Hodge, P.; Kell, R. J.; Ma, J.; Morris, H. Aust. J. Chem.
1999, 52, 1041.
7. Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757.
8. Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833.
9. Itsuno, S.; Frechet, J. M. J. J. Org. Chem. 1987, 52, 4140.
10. Soai, K.; Niwa, S.; Watanabe, M. J. Org. Chem. 1988, 53,
927.
For comparison purposes reactions were also carried out
with soluble catalyst 2: see reference 28. When diethyl-
zinc was used the chemical yields, like those with the PS
catalysts, were >90%. The % ees obtained with this
catalyst are given in Table 1 and are in excellent agree-
ment with those reported in the literature8,23 bearing
in mind that the present reactions were carried out in
toluene at 20 ꢀC whereas most of the literature reactions
were carried out in hexane at 0 ꢀC. The % ees obtained
with catalyst 2 should be compared with those obtained
using 30mol% of PS Catalyst A. It is evident that
whilst the reactions catalysed by compound 2 in some
cases afford the same % ees, in other cases they are upto
11. Soai, K.; Niwa, S.; Watanabe, M. J. Chem. Soc., Perkin
Trans. 1 1989, 109.
12. Soai, K.; Watanabe, M. J. Chem. Soc., Chem. Comm.
1990, 43.
13. Itsuno, S.; Sakurai, Y.; Ito, K.; Maruyama, T.; Naka-
hama, S.; Frechet, J. M. J. J. Org. Chem. 1990, 55, 304.

R. J. Kell et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1803–1807
1807
14. Zhang, Z.; Hodge, P.; Stratford, P. W. Reactive Polym.
1991, 15, 71.
15. Watanabe, M.; Soai, K. J. Chem. Soc., Perkin Trans. 1
1994, 837.
16. Liu, G.; Ellman, J. A. J. Org. Chem. 1995, 60, 7712.
17. Sung, D. W. L.; Hodge, P.; Stratford, P. W. J. Chem.
Soc., Perkin Trans. 1 1999, 1463.
18. Hodge, P.; Sung, D. W. L.; Stratford, P. W. J. Chem.
Soc., Perkin Trans. 1 1999, 2335.
liquid) in toluene (5 mL) was then added dropwise over 15 min
and when the addition was complete stirring was continued at
20 ꢀC for 20h. At the end of this period the organic layer was
syringed off. The beads were washed twice with toluene (2Â10
mL). The combined organic solutions were washed succes-
sively with hydrochloric acid (50mL of 1 M) and distilled
water (100 mL), then dried over anhydrous magnesium sul-
phate. Evaporation of the solvent gave the crude product as a
yellow oil (recoveries were >95%). As in previous stud-
ies,6,17,18 an 1H NMR spectrum was recorded and a GC run to
determine both the % ee and the chemical yield (the percen-
tage of aldehyde in the recovered product converted into the
desired alcohol: this was >95% when diethylzinc was used but
see footnotes in Table 1 for reactions using dimethylzinc). The
PS catalyst in the tube was then used for the next reaction.
27. Noyori, R.; Kitamura, M. Angew. Chem., Intl. Ed. Engl.
1991, 30, 49.
28. The catalyst 2 (5% mol) was dissolved in toluene (5 mL)
and the solution cooled in an ice bath. A 1.1 M solution of
diethylzinc solution in toluene (5.0mL) [or a 2.0M solution of
dimethylzinc in toluene (2.75 mL, 5.5 mmol)] was added
dropwise over 30min. The aldehyde (2.5 mmol) in toluene (5
mL) was added and the mixture was stirred at 20 ꢀC for 20h.
At the end of the reaction period the reaction was quenched
with 1 N hydrochloric acid, and the organic products were
extracted with ethyl acetate (50mL). The extract was washed
with water and dried over anhydrous magnesium sulphate.
The residue left after evaporation of the solvent under reduced
pressure was fractionally distilled in vacuum (1 mm of Hg)
from bulb-to-bulb to give a mixture of the enantiomeric alco-
hols. The % ee was determined by GC analysis as described
above.
19. Kell, R. J.; Hodge, P.; Nisar, M.; Williams, R. T. J. Chem.
Soc., Perkin Trans. 1 2001, 3403.
20. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
21. Daly, W. H.; Poche’, D. Tetrahedron Lett. 1988, 29, 5859.
22. Mathre, D. J.; Jones, T. K.; Xavier, L. C.; Blackstock, T. J.;
Reamer, R. A.; Mohan, J. J.; Jones, E. T. T.; Hoogsteen, K.;
Baum, M. W.; Grabowski, E. J. J. J. Org. Chem. 1991, 56, 751.
23. Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem.
Soc. 1987, 109, 7111.
24. Schiemenz, G. P. Org. Synth. Collec. Vol. V 1973, 496.
25. Farrall, M. J.; Frechet, J. M. J. J. Org. Chem. 1976, 41,
3877.
26. The PS catalyst (5, 10, or 30% with respect to the alde-
hyde) and a small magnetic stirrer bar were placed in a tube
(100Â20mm) sealed with a septum cap. Nitrogen was passed
through the tube via syringe needles. Dry toluene (5 mL) was
syringed into the tube and the mixture was left for 30min for
the beads to swell. The mixture was chilled using an ice bath
and a 1.1 M solution of diethylzinc in toluene (5.0mL, 5.5
mmol) [or a 2.0M solution of dimethylzinc in toluene (2.75
mL, 5.5 mmol)] was added dropwise, again using a syringe.
When the addition was complete the mixture was stirred for 60
min at 20 ꢀC. The aldehyde (5.0mmol, freshly distilled if a