In situ enzymatic screening (ISES): A tool for catalyst discovery and reaction development

Article abstract of DOI:10.1002/1521-3773(20020503)41:9<1614::AID-ANIE1614>3.0.CO;2-5

Can enzymes help organic chemists identify new transition-metal catalysts? The first example of the in situ enzymatic monitoring of an organic transformation is described. Thus, a transition-metal-mediated allylic-amination reaction in the organic layer (

Full text of DOI:10.1002/1521-3773(20020503)41:9<1614::AID-ANIE1614>3.0.CO;2-5

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[Rh(nbd)2]SbF6 (2.3 mg, 0.0045 mmol) in methanol (3 mL) in a glovebox.
After the mixture was stirred for 10 min, the substrate (0.5 mmol) was
added. The hydrogenation was performed at room temperature under H2
(20 psi) for 12 48 h. After carefully releasing the hydrogen, the reaction
mixture was passed through a short silica-gel plug to remove the catalyst.
The resulting solution was used directly for chiral GC or HPLC to measure
the enantiomeric excess. For the hydrogenation of dehydroamino acids, the
enantiomeric excesses were measured after conversion into their corre-
sponding methyl esters by treatment with TMSCHN2 (TMS ˆ trimethyl-
silyl).
Helical Chiral Polymers without Additional
Stereogenic Units: A New Class of Ligands in
Asymmetric Catalysis**
Michael Reggelin,* Melanie Schultz, and
Michael Holbach
Soluble polymers may be promising ligands in transition
metal catalysis for a number of reasons. The reisolation of the
chiral catalyst by precipitation or ultrafiltration should be
easy, and all the analytical and kinetic advantages of a
reaction in homogenous phase should be maintained. If the
polymer is chiral and nonracemic, asymmetric induction can
be expected, and finally, a number of beneficial effects related
to the macromolecular state of the system may allow for the
synthesis of novel ligands with properties not achievable with
micromolecules. These effects include, for example, cooper-
ativity and chiral amplification as observed in polyisocy-
anates.[1]
The most obvious way to prepare a polymeric chiral soluble
ligand is to attach only one metal binding site per polymer
chain. This was rather successful in the asymmetric dihydrox-
ylations described by Bolm et al.[2] and Janda et al.[3] The
major disadvantage of this approach is the very low density of
reactive centers per unit mass. To improve this situation it is
necessary to prepare multiple-site polymeric catalysts with
uniform microenvironments. The polybinaphthols prepared
by Pu et al. appear to be successful examples of this strategy.[4]
The remaining problems with these ligands include the
necessity to prepare the enantiomerically pure monomers
and the question of contraproductive interactions of the
different sources of chirality (planar chirality of the mono-
mers and helical chirality of the polymer). Indeed, we think
that for the phosphane-modified helical chiral dodecapeptides
developed by Gilbertson et al.[5] the major reason for the
failure to achieve good enantioselectivities in asymmetric
hydrogenation reactions is such a contraproductive interac-
tion between the centrochirality of the constituting amino
acids and the helical secondary structure. Facing this situation
we felt it would be best to erase all sources of chirality except
the helicity of a stereoregular and configurationally stable
polymer containing donor atoms such as nitrogen or phos-
phorus.
Received: February 4, 2002 [Z18637]
[1] For recent reviews, see: a) T. Ohkuma, M. Kitamura, R. Noyori in
Catalytic Asymmetric Synthesis (Ed.: I. Ojima), Wiley-VCH, Wein-
heim, 2000, p. 1; b) J. M. Brown in Comprehensive Asymmetric
Catalysis (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Berlin, 1999, p. 121.
[2] W. S. Knowles, Acc. Chem. Res. 1983, 16, 106.
[3] H. B. Kagan, T.-P. Dang, J. Am. Chem. Soc. 1972, 94, 6429.
[4] M. D. Fryzuk, B. Bosnich, J. Am. Chem. Soc. 1977, 99, 6262.
[5] H. Brunner, W. Pieronczyk, B. Schˆnhammer, K. Streng, I. Bernal, J.
Korp, Chem. Ber. 1981, 103, 2280.
[6] K. Achiwa, J. Am. Chem. Soc. 1976, 98, 8265.
[7] U. Nagel, E. Kinzel, J. Andrade, G. Prescher, Chem. Ber. 1986, 119,
3326.
[8] A. Miyashita, A. Yasuda, H. Takaya, K. Toriumi, T. Ito, T. Souchi, R.
Noyori, J. Am. Chem. Soc. 1980, 102, 7932.
[9] M. J. Burk, J. R. Lee, J. P. Martinez, J. Am. Chem. Soc. 1994, 116,
10847.
[10] a) G. Zhu, P. Cao, Q. Jiang, X. Zhang, J. Am. Chem. Soc. 1997, 119,
1799; b) G. Zhu, X. Zhang, J. Org. Chem. 1998, 63, 9590.
[11] A. S. C. Chan, W. Hu, C.-C. Pai, C.-P. Lau, J. Am. Chem. Soc. 1997,
119, 9570.
[12] Q. Jiang, Y. Jiang, D. Xiao, P Cao, X. Zhang, Angew. Chem. 1998, 110,
1203; Angew. Chem. Int. Ed. 1998, 37, 1100.
[13] a) T. Imamoto, J. Watanabe, W. Yoshiyuki, H. Masuda, H. Yamada, H.
Tsuruta, S. Matsukawa, K. Yamaguchi, J. Am. Chem. Soc. 1998, 120,
1635; b) I. D. Gridnev, M. Yasutake, N. Higashi, T. Imamoto, J. Am.
Chem. Soc. 2001, 123, 5268; c) I. D. Gridnev, Y. Yamanoi, N. Higashi,
H. Tsuruta, M. Yasutake, T. Imamoto, Adv. Synth. Catal. 2001, 343,
118.
[14] Y. Yamanoi, T. Imamoto, J. Org. Chem. 1999, 64, 2988.
[15] D. Xiao, Z. Zhang, X. Zhang, Org. Lett. 1999, 1, 1679.
[16] P. J. Pye, K. Rossen, R. A. Reamer, N. N. Tsou, R. P. Volante, P.
Reider, J. Am. Chem. Soc. 1997, 119, 6207.
[17] A. R. Muci, K. R. Campos, D. A. Evans, J. Am. Chem. Soc. 1995, 117,
9075.
[18] Evans reported that the sense of asymmetric induction for metalation
of phosphane sulfide and phosphane borane is the same (see reference
[17]). The configuration of the hydrogenation product of TangPhos 1
is also consistent with the results reported for BisP*, which indicates
that TangPhos and BisP* has the same configuration at the phospho-
rus atom.
[19] Imamoto reported that the metallation of cyclic phosphane borane
occurs exclusively trans to the bulky tert-butyl group; see: A. Ohashi,
T. Imamoto, Acta Crystallogr. Sect. C 2000, 56, 723.
[20] G. Zon, K. E. DeBruin, K. Naumann, K. Mislow, J. Am. Chem. Soc.
1969, 91, 7023.
We followed the work of Okamoto et al.[6, 7] and prepared
two chiral polymers by helix-sense selective anionic polymer-
ization of sterically congested methacrylates by using a chiral
nonracemic base mixture as initiator (Scheme 1, Table 1). The
chiral initiator was prepared by mixing either (‡)- or (À)-1-
(2-pyrrolidinomethyl)pyrrolidine ((S)- or (R)-4) and the
diamine 3 with one equivalent of nBuLi at room temperature
in toluene. This mixture was added to solutions of the
monomers 1 and 2 so that the monomer/initiator ratio was
[21] M. J. Burk, Y. M. Wang, J. R. Lee, J. Am. Chem. Soc. 1996, 118, 5142.
[22] For the detailed synthesis of 3, see Supporting Information.
[*] Prof. Dr. M. Reggelin, Dipl.-Chem. M. Schultz, M. Holbach
Institut f¸r Organische Chemie
Technische Universit‰t Darmstadt
Petersenstrasse 22, 64287Darmstadt (Germany)
Fax : (‡49)6151-16-5531
E-mail: re@oc.chemie.tu-darmstadt.de
[**] We thank Degussa AG for generous gifts of transition metal salts.
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Angew. Chem. Int. Ed. 2002, 41, No. 9

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Table 2. Allylic alkylations of 1,3-diphenylprop-2-enyl acetate with dimethyl
malonate.[a]
Entry Ligand[a]
[Pd]
[mol%][b]
Solvent
T
t
Yield ee
Config.[e]
[8C] [h] [%][c] [%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17(
18
19
3
3
10
10
10
10
25
10
25
CH2Cl2 25
CH2Cl2 40
CH2Cl2 25
CH2Cl2 40
CH2Cl2 40
CH2Cl2 40
CH2Cl2 40
CH2Cl2 25
CH2Cl2 40
48
14
0
0
(‡)-4
14 65[f]
9.9
0
R
2
2
1
1
90
40
90 48
0
0
40 570
(‡)-poly-2 10
(‡)-poly-2 10
(‡)-poly-2 10
(‡)-poly-2 10
(‡)-poly-1 10
(‡)-poly-1 25
(‡)-poly-1 10
(‡)-poly-1 25
(À)-poly-1 10
À)-poly-1 25
rac-poly-1 10
rac-poly-1 25
72
72
14
14
72 12
72 66[f]
48 74
14 79[f]
70 88[f]
40 81[f]
70 92[f]
40 78[f]
0
0
0
0
THF
C6H6
60
80
CH2Cl2 25
CH2Cl2 25
CH2Cl2 40
CH2Cl2 40
CH2Cl2 40
CH2Cl2 40
CH2Cl2 40
CH2Cl2 40
29
R
R
R
R
S
33
27
32
28
33
0
Scheme 1. Helix sense selective polymerization of methacrylates 1 and 2
with the additives 3 and 4.
S
15:1. After the reaction times compiled in Table 1, the
resulting polymers were isolated following published proce-
dures.
0
[a] 24 mol% repeating unit (based on substrate 1,3-diphenylprop-2-enyl
acetate) or 60 mol% in experiments with 10 or 25 mol% Pd, respectively.
[b] Based on substrate. [c] Yields of isolated product. [d] Determined by
1H NMR in the presence of 20 mol% of the chiral shift reagent [Eu(hfc)3],
hfc ˆ 3-(heptafluoropropyl-hydroxymethylene)-d-camphorate. [e] By compar-
ison with reference [12]. [f] Quantitative conversion according to TLC.
To explore the suitability of these polymers as chiral ligands
À
in asymmetric C C bond forming processes we chose the
palladium catalyzed allylic subsitution reaction with 1,3-
diphenylprop-2-enyl acetate as substrate and dimethyl malo-
nate (DMM) as nucleophile (Scheme 2, Table 2).[8 11] First, we
mixed 27.2 mg (84mmol monomeric units) of poly-2 and and
6.4 mg (17.5mmol) of dimeric [{Pd(m3-C3H5)Cl}2] in CH2Cl2 at
room temperature. After one hour 88 mg (350 mmol) of the
substrate and 139 mg (1.05 mmol) of DMM were added. This
corresponded to 10 mol% Pd and a [N]:[Pd] ratio of 2.4:1
which reflects our initial assumption that a bidentate complex
involving two consecutive turns of the helix might be formed.
Not unexpectedly after our experience with the monomer 2,
no reaction with the substrate (Table 2, entries 8 11) could
be observed. Although a negative result at first sight, these
experiments confirm the complete absence of any residual 4
and any interference of the nitrogen-containing end group
(see above).
We suspected the nitrogen atom in poly-2 is not accessible
enough to be complexed by palladium and therefore hoped
that the situation would be improved when the nitrogen atom
is in the 3-position in the pyridine ring. This was indeed the
case. As already stated the monomer 1 is an active catalyst
(Table 2, entries 6 and 7), and to our delight this was also true
for the polymer (‡)-poly-1 (entries 12 15). Moreover, we
found a significant enantiomeric enrichment in the resulting
Scheme 2. Allylic substitution of 1,3-diphenylprop-2-enyl acetate (5)
catalyzed by palladium complexes generated in situ.
looked for potential catalytic activity of the nitrogen-contain-
ing compounds 3 and 4 used in the anionic polymerization.
Especially the former was of interest, because it is incorpo-
rated into the polymer as the end group. Entries 1 and 2 show
that 3 does not catalyze the reaction at all. On the contrary,
(‡)-4 is active and produces (R)-6 with a slight enantiomeric
excess of about 10%. For that reason we meticulously purified
the polymers to avoid any contamination with this chiral
1
diamine (checked by H NMR spectroscopy and gel perme-
ation chromatography (GPC)). Next, we looked for the
catalytic activity of the monomers and found that only 1 is
active and furnishes 6 with 57% yield (entries 4 7).
After this preparatory work we tried to prepare Pd
complexes from the polymers. In a typical experiment we
Table 1. Helix sense selective polymerization of methacrylates 1 and 2.[a]
‰gŠ
Monomer[b]
Polymer[c]
Initiator[c]
t [h]
Yield [%][d]
DP[e]
Mw/Mn
Tacticity[f]
[a]
[f]
25
Entry
365
1
2
3
4
2
1
1
1
(‡)-poly-2
(‡)-poly-1
(À)-poly-1
rac-poly-1
(‡)-4
(‡)-4
(À)-4
rac-4
4
89
34
59
50
40
271.19
34
1.15
> 99
> 99
> 99
> 99
‡ 1452
‡ 1385
À 1475
0
43
48
48
1.12
371.21
[a] All polymerizations were carried out with 1.0 g of monomer in toluene at À788C. The monomer:initiator ratio was 15:1. [b] The monomer structure
corresponds to R in Scheme 1. [c] For abbreviations see Figure 1. [d] Fraction insoluble in methanol and benzene/hexane. [e] DP ˆ degree of polymerization.
Determined by GPC (poly(methyl methacrylate) (PMMA) standard) after acidic hydrolysis and conversion to PMMA. [f] Determined by 1H NMR analysis
of the derived PMMA. [g] c ˆ 1.0, CHCl3:2,2,2-trifluoroethanol (9:1 by volume).
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substitution product 6 (27 33% ee). With 10 mol% Pd at
408C the reaction was virtually quantitative as judged by
TLC. The yields of isolated products were somewhat lower
and variable because of the very small amounts handled in
these initial experiments. The major enantiomer formed in the
experiments with the polymer derived from the (‡)-4-
containing initiator mixture was R-configured. To verify our
expectation that the product configuration would be inverted
when the configuration of the catalyst is inverted, we repeated
the experiment with the polymer having the opposite helical
sense (entries 16 and 17). As expected we now obtained (S)-6
in very high yield and with the same ee.
Finally, we used rac-poly-1 obtained by polymerization with
rac-4/3-nBuLi as initiator. This time rac-6 was isolated which
shows that the observed selectivities are indeed a direct
consequence of the helical chiral nature of the polymer. At
this point it is important to note that the investment of chiral
nonracemic material (here 4) is extremely low. In the ideal
case a polymerization reaction, in which one mole of chiral
initiator is employed, produces n moles of homochiral
coordination sites in the resulting polymer. The whole process
can be interpreted as an autoinductive multiplication of chiral
units. Furthermore, different helical ligands exhibiting differ-
ent chiral environments can be synthesized by using the same
cheap auxiliary.
To learn more about the complexed polymers we studied
their chiroptical properties and their NMR spectra. From the
CD spectra it is obvious that complexation took place without
disrupting the helical chiral structure of the polymers (Fig-
ure 1). When we calculated the molar masses of the repeating
units with a [N]:[Pd] ratio of 1:1, the chiroptical properties of
the palladium complexes became close to those of the
uncomplexed polymers. This appears to be reasonable if one
assumes that the carbonyl chromophore, which gives rise to
the absorption at 237nm, is largely unaffected by the
palladium complexation involving the nitrogen atom of the
remote pyridine ring. This interpretation is corroborated by
our NMR results (Figure 2).
Figure 2. Downfield portion of 500 MHz sensitivity-enhanced gradient-
HSQC spectra showing CH correlations of the carbon atoms flanking the
nitrogen atom. A) Monomeric 1. B) Monomeric Pd complex. C) Polymeric
1. D) Polymeric Pd complex.
HSQC spectra. From these it is obvious that the polymer-
ization of 1 entails a strong reduction of the 1H chemical shift
difference of the protons flanking the nitrogen atom (Fig-
ure 2, cf. A and C as well as B and D; Dd ˆ 0.22 ppm and
0.37ppm, respectively). On the other hand the corresponding
carbon shifts are only marginally affected. In contradiction to
this behavior, complexation by palladium ([N]:[Pd] ˆ 1:1) is
accompanied by a significant downfield shift of carbon atoms
1 and 2. This is true for both the monomeric and the polymeric
complex (Figure 2A, 2B, and 2C, 2D, respectively). We
interpret these chemical shift alterations as evidence of
successful complexation of the polymer by palladium. When
we increased the [N]:[Pd] ratio to 2:1 (not shown) the
complexation was incomplete as indicated by the persistence
of signals from the uncomplexed polymer. This finding is in
accordance with a monodentate complex which corroborates
our interpretation of the results from the CD data.
To study the influence of the polymerization process as well
as the one evoked by complexation we recorded a series of
From these results it can be concluded that poly-1 forms
monodentate complexes with palladium and that the resulting
complex is able to catalyze the allylic substitu-
tion reaction. Furthermore the enantiomeric
excesses of the products are a direct and sole
consequence of the uniform helicity of the
polymeric ligand employed. Thus, it is the first
example of an asymmetric induction in a
À
catalytic C C bond forming reaction that
involves a uniformly configured polymeric
helical chiral ligand lacking any other elements
of chirality. Although this is an encouraging
first step we are aware that the system must be
improved considerably with respect to both
reactivity and enantioselectivity. At present, we
are working on ligands with alternative coordi-
nation sites and the exploitation of the already
mentioned cooperative effects in polyisocya-
nates.
Figure 1. CD spectra of poly-1 and the corresponding palladium complexes. The CD spectra
were recorded in CH2Cl2 solutions at 258C with polymer concentrations of 37.2 to
78.8 nmolmonomerunitsmLÀ1
.
Received: February 5, 2002 [Z18660]
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Angew. Chem. Int. Ed. 2002, 41, No. 9
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