Planar- and central-chiral N,O-[2.2]paracyclophane ligands: Non-linear-like effects and activity

Article abstract of DOI:10.1002/adsc.200505274

The non-linear-like effect (NLLE), activity, temperature dependence, and kinetics of hydroxy-[2.2]paracyclophane ketimine ligands have been investigated with the 1,2-addition reaction of diethylzinc to cyclohexanecarbaldehyde. A linear correlation between the enantiomeric excess of AHPC ketimine ligands bearing a phenylethyl side group and the product was observed with 0.5 mol% of catalyst loading. On increasing the catalyst loading to 4 mol%, a precipitate of the inactive heterochiral species was formed and resulted in a positive non-linear-like effect. The enantiomeric ratio was found to have linear temperature dependence.

Full text of DOI:10.1002/adsc.200505274

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DOI: 10.1002/adsc.200505274
Planar- and Central-Chiral N,O-[2.2]Paracyclophane Ligands:
Non-Linear-Like Effects and Activity
Frank Lauterwasser, Sylvia Vanderheiden, Stefan Bräse*
Institut für Organische Chemie, Universität Karlsruhe (TH), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax: (þ49)-721-608-8581, e-mail: braese@ioc.uka.de
Dedicated to Professor Dr. Dieter Enders on the occasion of his 60th birthday.
Received: July 12, 2005; Accepted: January 12, 2006
Abstract: The non-linear-like effect (NLLE), activity,
temperature dependence, and kinetics of hydroxy-
[2.2]paracyclophane ketimine ligands have been in-
vestigated with the 1,2-addition reaction of diethyl-
zinc to cyclohexanecarbaldehyde. A linear correla-
tion between the enantiomeric excess of AHPC keti-
mine ligands bearing a phenylethyl side group and
the product was observed with 0.5 mol % of catalyst
loading. On increasing the catalyst loading to
4 mol %, a precipitate of the inactive heterochiral
species was formed and resulted in a positive non-
linear-like effect. The enantiomeric ratio was found
to have linear temperature dependence.
alkynyl[24] zinc reagents with aldehydes or imines,[19,20,23]
can be efficiently controlled by the application of hy-
droxy[2.2]paracyclophane ketimine ligands.[17]
We recently reported the synthesis of the [2.2]paracy-
clophane-based ketimine ligands (RP,S)-2, (SP,S)-2,
(RP,S)-3, and (SP,S)-3 and their application in asymmet-
ric catalysis such as the addition of zinc reagents to alde-
hydes.[19] During these studies, we observed not only that
these ligands are highly active,[21,25] but also that they dis-
play mismatched and matched cases.[19,22] In general, the
[2.2]paracyclophane backbone determines the configu-
ration of the product. However, it was possible to fine-
tune the ligand system by adjusting the side groups.
The successful applications of these [2.2]paracy-
clophane-based ligands led to further investigations of
this system. In this manuscript, we disclose our findings
which lead to a deeper understanding of this ligand class.
We present studies of the non-linear-like effect
(NLLE)[26] with the enantiomeric pairs 1 and 3, respec-
tively. In addition, we investigated the activity of the dia-
Keywords: asymmetric catalysis; catalytic activity;
non-linear-like effect; paracyclophanes
Asymmetric catalysis often displays a relationship be- stereomers (RP,S)-2 and (SP,S)-2 and the diastereomers
tween selectivity and reactivity. Intricate molecular (RP,S)-3 and (SP,S)-3. Further, we performed studies on
mechanisms with a number of rate constants often the temperature effect and kinetic studies of the system
lead to complex rate laws. The latter have not been elu- with (RP,S)-3 and (SP,S)-3.
cidated in most cases although attempts have been made
For the 1,2-addition reaction we chose cyclohexane-
to unravel them.[1] Features such as non-linear effects,[2] carbaldehyde (C6H11CHO) as the substrate. The corre-
autocatalysis,[3] reservoir effects, chiral poisoning,[4] and sponding secondary alcohol was transformed into an es-
asymmetric activation[5] have been discovered in asym- ter to achieve better separation on a GC chiral station-
metric catalytic reactions.[6] In particular, the strong ary phase.[27] The results for the different ketimine li-
non-linear effect associated with Noyoriꢀs DAIB ligand gands are shown in Table 1.
in the addition of diethylzinc to benzaldehyde has been
The [2.2]paracyclophane-based ligands 1–3 showed
complete conversion and enantiomeric excesses of
thoroughly investigated.[7a]
Since the initial reports of Reich and Cram,[8] the field 84% ee for ligands 1, 95% and 93% ee for ligands 2
of [2.2]paracyclophane chemistry has grown considera- and 95% ee for ligands 3 in this reaction (Table 1). It is
bly.[9] The chemical behavior of [2.2]paracyclophanes is important to note that both enantiomers of the product
currently well understood allowing predictable modifi- with similar enantiomeric excesses can be produced by
cation of this relatively stable class of molecules.[10–13]
using diastereomers with a different planar-chiral type
Within the last few years, various new paracyclophane stereochemistry and the same stereogenic center
ligands have been used for asymmetric catalysis.[14–17] In (matched pair). As mentioned before, the paracyclo-
particular, the asymmetric 1,2-addition reaction of zinc phane backbone determines the configuration of the de-
reagents[18] such as alkyl,[19–21] alkenyl,[22] aryl[23] and sired product: (RP,S) and (RP,R) ligands produced the
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Frank Lauterwasser et al.
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Table 1. Results for the addition of diethylzinc to cyclohex-
anecarbaldehyde. 1) C6H11CHO (0.5 mmol), 2 mol % of li-
gand, 1 mL of Et2Zn (1 M in hexanes), 1 mL of toluene,
08C, 12 h; 2) Ac2O, 24 h, room temperature.
Entry
Ligand
Conversion[a]
ee[b]
1
2
3
4
5
6
7
8
(SP,S)-1
(RP,R)-1
(RP,S)-1
(SP,S)-2
(RP,S)-2
(SP,S)-3
(RP,R)-3
(RP,S)-3
>99
>99
>99
>99
>99
>99
>99
>99
84 (R)
84 (S)
84 (S)
95 (R)
93 (S)
95 (R)
95 (S)
95 (S)
[a]
Determined by GC.
Determined by GC (CP-Chirasil-Dex).
[b]
Figure 2. Results for the studies of the non-linear effect of the
ligands (SP,S)/(RP,R)-1. 1) C6H11CHO (0.5 mmol), 0.5–
4 mol % of ligand, 1 mL of Et2Zn (1 M in hexanes), 1–
4 mL of toluene, 08C, 12 h; 2) Ac2O, 24 h, room temperature.
tiomeric excess of the ligand and the enantiomeric ex-
cess of the desired product. Due to the bulkiness of the
[2.2]paracyclophane system we expected a linear corre-
lation between the enantiomeric excess of the ligand and
the enantiomeric excess of the desired product. Howev-
er, we observed precipitation of inactive heterochiral
complexes (Scheme 1), especially with low enantiomer-
ic excess of the ligand. We were not able to get suitable
crystals for X-ray analysis from the precipitate. We also
Figure 1. Planar- and central-chiral N,O-[2.2]paracyclophane
ligands.
(S) product and the (SP,S) ligands led to the formation of tried to filter the precipitate to determinate the actual
the (R) product. enantiomeric composition of the ligands in solution. Un-
The first NLLE studies were carried out with ligands fortunately, the precipitate was too fine to remove it
(SP,S)/(RP,R)-1 under standard conditions for this sys- completely. However, we assume that the observed pre-
tem, 2 mol % of the ligands (SP,S)/(RP,R)-1 at 08C for cipitate is the heterochiral dimer with two zinc species
12 h with 1 mL of toluene as co-solvent. The results bridged between the alkoxy-oxygen atoms (see Scheme
are shown in Figure 2. Unexpectedly, the ligand system 1).[7a] Therefore, we observe a non-linear-like effect for
showed a positive non-linear effect between the enan- this system described above.
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Planar- and Central-Chiral N,O-[2.2]Paracyclophane Ligands
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Figure 3. Results for the non-linear effect studies for the li-
gands (SP,S)/(RP,R)-3. 1) C6H11CHO (0.5 mmol), 4 mol % of
ligand, 1 mL of Et2Zn (1 M in hexanes), 1 mL of toluene,
08C, 12 h; 2) Ac2O, 24 h, room temperature.
non-linear effect (Figure 3). In this case, no inactive het-
erochiral dimer complexes were formed at any concen-
tration investigated (up to 10%), and no solubility prob-
lems occurred. Presumably, the sidechain ofthe ligand is
responsible for this effect.
Scheme 1. Equilibria of ligands 1.
The general procedure for producing the ligands pro-
ceeds via the diastereomeric resolution.[11,19,21] Because
Based on this observation, it was necessary to deter- of this we studied the difference in activity between
mine whether this phenomenon was a result of increased the diastereomeric pair (RP,S)-2 and (SP,S)-2 and the di-
catalyst loading or catalyst solubility. We carried out the astereomeric pair (RP,S)-3 and (SP,S)-3 with the same
same reaction while varying catalyst concentrations and 1,2-addition reaction. Confirming the results of the for-
solvent volumes. As shown in Figure 2, increasing the mer study, it was found that the diastereomers showed
amount of the catalyst to 4 mol % led to a stronger pos- similar selectivity.[19,22,28] Both diastereomers showed
itive non-linear-like effect. This trend was further sup- complete conversion after 12 h at 08C with similar enan-
ported by increasing the ligand loading to 20 mol % tiomeric excesses of 93% ee (S) and 95% ee (R) for
which resulted in an even stronger non-linear-like effect. (RP,S)-2 and (SP,S)-2, respectively. The diastereomers
To prevent the formation of the inactive heterochiral 3 both reached enantiomeric excesses of 95% ee. To fig-
species, we increased the amount of the co-solvent tol- ure out if there are differences in the activity of the dia-
uene and decreased the catalyst loading. The results stereomeric pairs we mixed the diastereomeric pairs in
are also shown in Figure 2. We observed a nearly linear various ratios as shown in Table 2 and Table 3.
effect for 2 mol % of ligand and 4 mL of toluene [1 mL
of Et2Zn (1 M in hexanes), 08C, 12 h] and for 1 mol %
ligand and 1 mL toluene. A linear effect was observed
for 0.5 mol % and 4 mL of toluene (Figure 2). The pos-
itive non-linear-like effect described above can be com-
Table 2. Activity studies with different ratios between the
diastereomeric pair (RP,S)-2 and (SP,S)-2. 1) C6H11CHO
(0.5 mmol), 2 mol % of ligand, 1 mL of Et2Zn (1 M in hex-
anes), 1 mL of toluene, 08C, 12 h; 2) Ac2O, 24 h, room tem-
pletely attributed to the insolubility of the inactive dim-
er. On the other hand, by diluting the system, a linear ef-
fect is observed and no inactive heterochiral dimer is
formed. At this point, it has to be mentioned that the de-
scribed ligand systems display a high reactivity com-
pared to most other ligand systems described in the liter-
ature.
To see if this observed effect with the enantiomeric
pair (SP,S)/(RP,R)-1 is transferable to other ligands we
investigated the enantiomeric pair (SP,S)/(RP,R)-3
more in detail. Interestingly, a positive non-linear effect
was not observed when using the enantiomeric pair
(SP,S)/(RP,R)-3, where a catalyst loading of 4 mol %
with 1 mL of toluene showed a very slight negative
perature.
Entry
de [(SP,S)-2:(RP,S)-2]
Conversion[a]
ee [%][b]
1
2
3
4
5
6
7
8
9
100
60
40
0
20
40
60
80
100
>99
>99
>99
>99
>99
>99
>99
>99
>99
95 (R)
76 (R)
64 (R)
46 (R)
40 (R)
24 (R)
1 (S)
38 (S)
93 (S)
[a]
Determined by GC.
Determined by GC (CP-Chirasil-Dex).
[b]
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Table 3. Activity studies with different ratio between the dia-
stereomeric pair (RP,S)-3 and (SP,S)-3. 1) C6H11CHO
(0.5 mmol), 2 mol % of ligand, 1 mL of Et2Zn (1 M in hex-
anes), 1 mL of toluene, 08C, 12 h; 2) Ac2O, 24 h, room tem-
perature.
Table 4. Temperature dependence of the enantiomeric excess
achieved by ligand (SP,S)-3. 1) C6H11CHO (0.5 mmol),
2 mol % of ligand, 1 mL of Et2Zn (1 M in hexanes), 1 mL
of toluene, 12 h; 2) Ac2O, 24 h, room temperature.
Entry
Temperature [ 8C]
ee [%]
Entry
de [(SP,S)-3:(RP,S)-3]
Conversion[a]
ee [%][b]
1
2
3
4
5
À20
À5
5
35
50
96.0
95.2
94.6
93.3
90.9
1
2
3
4
5
6
7
8
9
100
81
60
41
21
20
41
57
79
100
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
95 (R)
76 (R)
62 (R)
46 (R)
30 (R)
2 (S)
22 (S)
37 (S)
63 (S)
95 (S)
10
[a]
Determined by GC.
Determined by GC (CP-Chirasil-Dex).
[b]
The results are shown in Figure 4. The ketimine ligand
(SP,S)-2 is more active than the ketimine ligand (RP,S)-2,
by the factor of 3.5.[29] A similar study showed that
(SP,S)-3 is roughly 1.6 times faster than (RP,S)-3. There-
fore, we observed nearly the same activity for both dia-
stereomers for the AHPC-based ligand 3.
In addition, we investigated the temperature depend-
ence of the enantiomeric excess of the product in the
same 1,2-addition reaction. Within the temperature
Figure 5. Eyring plot [ln(er) vs. 1/T]. Temperature depend-
ence of the enantiomeric excess achieved by ligand (SP,S)-3.
1) C6H11CHO (0.5 mmol), 2 mol % of ligand, 1 mL of
Et2Zn (1 M in hexanes), 1 mL of toluene, 12 h; 2) Ac2O,
range we investigated (À208C to 508C), we found no in- 24 h, room temperature.
termediate maximum enantiomeric excess. A maximum
would be explained by the principle of isoinversion de-
veloped by Scharf et al.[30,31]
In summary, we have presented the first selectivity
Initial kinetic studies revealed that full conversion was and activity studies of various [2.2]paracyclophane keti-
achieved after 12 h, however the enantiomeric excess re- mine ligands. To the best of our knowledge this is the
mained constant.
first non-linear-like effect study reported in diethylzinc
chemistry, which can be completely attributed to the in-
solubility of an inactive dimer being formed with certain
diastereomers. Furthermore, we found no maximum for
the enantiomeric excess over a wide range of tempera-
ture, while the enantiomeric excess remained constant
over the reaction time. Due to their decreased tendency
to dimerize and the very low loading necessary for cata-
lyst activity, in comparison with other ligands, they pres-
ent highly active catalysts for asymmetric 1,2-addition
reactions due to the lack of dimerization. In contrast
to other ligands having more than one stereogenic cen-
ter such as ferrocene ligands, neither mismatched cases
nor large differences in rate constants of two diaster-
eomers can be observed.
Figure 4. Activity studies with different ratios between the dia-
stereomeric pair (S)-2 and (S)-3, respectively. 1) C6H11CHO
(0.5 mmol), 2 mol % of ligand, 1 mL of Et2Zn (1 M in hex-
anes), 1 mL of toluene, 08C, 12 h; 2) Ac2O, 24 h, room tem-
perature.
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Planar- and Central-Chiral N,O-[2.2]Paracyclophane Ligands
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ford an orange solid; yield: 106 mg (78%); Rf ¼0.14 (pentane/
diethyl ether, 9:1); mp 153–1548C; [a]2D0: þ297 (c 0.35,
CHCl3); 1H NMR (500 MHz, CDCl3): d¼1.71 (d, J¼6.5 Hz,
3H), 2.28 (s, 3H), 2.41 (ddd, J¼12.9, 9.2, 7.1 Hz, 1H), 2.56
(ddd, J¼12.7, 10.1, 4.9 Hz, 1H), 2.86 (ddd, J¼13.8, 9.4,
7.1 Hz, 1H), 2.97 (ddd, J¼12.5, 9.4, 2.2 Hz, 1H), 3.04 (ddd,
J¼13.4, 10.1, 2.7 Hz, 1H), 3.17–3.31 (m, 2H), 3.46 (ddd, J¼
12.7, 10.0, 2.5 Hz, 1H), 4.88 (q, J¼6.5 Hz, 1H), 6.12 (dd, J¼
7.6, 1.8 Hz, 1H), 6.20 (d, J¼7.6, 1H), 6.44 (d, J¼7.3 Hz, 1H),
6.49 (dd, J¼7.8, 1.7 Hz, 1H), 6.59 (dd, J¼7.9, 1.8 Hz, 1H),
7.03 (dd, J¼7.6, 1.8 Hz, 1H), 7.33–7.37 (m, 1H), 7.44–7.50
(m, 2H), 7.53–7.57 (m, 2H), 15.97 (bs, 1H); 13C NMR
(125 MHz, CDCl3): d¼20.39, 24.98, 30.49, 33.91, 35.38, 37.23,
58.09, 122.24, 125.63, 126.49, 127.07, 127.33, 128.86, 129.47,
130.21, 131.47, 132.67, 136.27, 137.64, 139.95, 140.88, 163.27,
170.14; IR (KBr): n¼3413 (br), 3067 (w), 3033 (w), 3011 (w),
2927 (m), 1582 (m), 1499 (w), 1436 (m), 1298 (m) cmÀ1; MS
(70 eV, EI): m/z (%)¼369 (95) [Mþ], 265 (58), 160 (63), 132
(7), 105 (100), 91 (5), 77 (5); HR-MS-EI: m/z¼369.2094 (calcd.
for C26H27NO: 369.2093).
Experimental Section
General Remarks
1H NMR: Bruker AM 400 (400 MHz), Bruker DRX 500
(500 MHz); d¼7.26 ppm for CHCl3. Description of signals:
s¼singlet, bs¼broad singlet, d¼doublet, m¼multiplet, dd¼
doublet of doublet, ddd¼doublet of dd, q¼quartet, p¼quin-
tet. Thespectra were analyzed according to first order rules. All
coupling constants are absolute values. 13C NMR: Bruker AM
400 (100 MHz), Bruker DRX 500 (125 MHz); d¼77.00 ppm
for CHCl3. IR: KBr pellets on a Bruker IFS88 IR; EI-HR-
MS: Thermo Quest Finnegan MAT 90 (70 eV). GC analytical
(achiral stationary-phase): Hewlett-Packard HP 5890 Series
II, 12 mꢀ0.25 mm capillary column HP I (carrier gas N2).
Enantiomeric excesses were determined by GC on a chiral sta-
tionary phase (CP-Chirasil-Dex). Optical rotations were deter-
mined on a Perkin Elmer 241 polarimeter (Na, 589 nm). Melt-
ing points were measured with a MEL-TEMPII, Laboratory
Devices Inc. USA. TLC: silica gel-coated aluminium plates
(Merck, silica gel 60, F254). Detection under UV light at
254 nm. Chemicals, solvents, reagents, and chemicals were pur-
chased from Acros, Aldrich, Fluka, and Merck.
(RP,R)-5-(1’-Cyclohexylethyliminoethyl)-4-
hydroxy[2.2]paracyclophane (3)
General Procedure for the Catalysis Reaction
To a 10-mL vial under an argon atmosphere containing the ap-
propriate amount of the chiral ligand dissolved in the appropri-
ate amount of dry toluene as a co solvent, 1.0 mL of a 1 M sol-
ution of diethylzinc in hexane was added at room temperature.
The mixture was stirred for 30 min at room temperature and
cooled down to the desired temperature. After an additional
30 min at the desired temperature, 0.5 mmol of the aldehyde
was added slowly and the reaction mixture was stirred for
12 h at the desired temperature. The reaction mixture was
quenched with acetic anhydride and was allowed to stir for
24 h at room temperature. The reaction mixture was then
quenched with saturated ammonium chloride solution, then di-
luted with diethyl ether, the organic phase was washed twice
with water, once with brine, and then dried over MgSO4.
Enantiomerically pure (RP)-5-acetyl-4-hydroxy[2.2]paracyclo-
phane (AHPC) (0.10 g, 0.37 mmol) was dissolved in 50 mL of
toluene and (R)-cyclohexylethylamine (0.14 g, 1.13 mmol)
was added. After adding a catalytic amount of dibutyltin di-
acetate, the reaction mixture was refluxed with a Dean–Stark
apparatus for 40 h. After removal of the solvent under reduced
pressure, the residue was purified by flash chromatography to
afford an orange solid; yield: 113 mg (81%); Rf ¼0.17 (pentane/
diethyl ether, 9:1); mp 110–1118C; [a]2D0: þ611 (c 0.27,
CHCl3); 1H NMR (400 MHz, CDCl3): d¼1.23–1.20 (m, 1H),
1.23 (d, J¼6.5 Hz, 3H), 1.24–1.31 (m, 2H), 1.32–1.42 (m,
2H), 1.58–1.68 (m, 1H), 1.72–1.80 (m, 1H), 1.84–1.95 (m,
3H), 2.00–2.20 (m, 1H), 2.30 (s, 3H), 2.52 (ddd, J¼13.2, 10.6,
5.5 Hz, 1H), 2.67 (ddd, J¼13.3, 9.8, 5.5 Hz, 1H), 2.93 (ddd,
J¼13.3, 9.5, 5.5 Hz, 1H), 3.01 (ddd, J¼13.1, 10.6, 2.8 Hz,
1H), 3.10 (ddd, J¼12.3, 9.7, 2.2 Hz, 1H), 3.17 (ddd, J¼12.6,
9.9, 5.1 Hz, 1H), 3.34–3.38 (m, 1H), 3.41 (ddd, J¼12.6, 10.1,
(RP,R)-5-(1’-Phenylethyliminoethyl)-4-
hydroxy[2.2]paracyclophane (1)
¼
2.5 Hz, 1H), 3.60 (p, J 6.5 Hz, 1H), 6.16 (d, J¼7.6 Hz, 1H),
6.35 (dd, J¼7.8, 2.0 Hz, 1H), 6.41 (d, J¼7.6 Hz, 1H), 6.51
(dd, J¼7.8, 1.8 Hz, 1H), 6.65 (dd, J¼8.1, 2.0 Hz, 1H), 6.99
(dd, J¼7.8, 1.8 Hz, 1H), 16.70 (bs, 1H); 13C NMR (100 MHz,
CDCl3): d¼18.60, 19.50, 26.36, 26.42, 26.68, 29.18, 30.10,
30.52, 33.88, 35.56, 37.42, 44.36, 58.02, 121.62, 124.94, 127.08,
129.90, 130.24, 131.42, 132.70, 136.20, 137.60, 140.16, 140.74,
165.44, 168.81; IR (KBr): n¼2973 (s), 2932 (s), 2851 (s), 1869
(w), 1591 (m), 1443 (m) cmÀ1; MS (70 eV, EI): m/z (%)¼375
(38) [Mþ], 271 (100), 188 (50), 162 (44), 104 (55); HR-MS-EI:
m/z¼375.2560 (calcd. for C26H27NO: 375.2562).
Enantiomerically pure (RP)-5-acetyl-4-hydroxy[2.2]paracyclo-
phane (AHPC) (0.10 g, 0.37 mmol) was dissolved in 50 mL of
toluene and (R)-phenylethylamine (0.14 g, 1.13 mmol) was
added. After adding a catalytic amount of dibutyltin diacetate,
the reaction mixture was refluxed with a Dean–Stark appara-
tus for 40 h. After removal of the solvent under reduced pres-
sure, the residue was purified by flash chromatography to af-
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Frank Lauterwasser et al.
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Acknowledgements
[16] U. Wçrsdorfer, F. Vçgtle, F. Glorius, A. Pfaltz, Prakt.
Chem. 1999, 341, 445–448.
We thank the DFG(SFB 380) for financial support and Dr.
Klaus Ditrich, BASF AG, Germany, for donation of chiral
amines (Chipros).
[17] For an account see: S. Bräse, S. Dahmen, S. Hçfener, F.
Lauterwasser, M. Kreis, R. E. Ziegert, Synlett 2004,
2647–2669.
[18] For a recent review, see: L. Pu, Tetrahedron 2003, 59,
9873–9886.
[19] F. Lauterwasser, M. Nieger, H. Manissikamäki, K. Nätti-
nen, S. Bräse, Chem. Eur. J. 2005, 11, 4509–4525.
[20] S. Dahmen, S. Bräse, J. Am. Chem. Soc. 2002, 124, 5940–
5941.
[21] S. Dahmen, S. Bräse, Chem. Commun. 2002, 26–27.
[22] S. Dahmen, S. Bräse, Org. Lett. 2001, 3, 4119–4122.
[23] N. Hermanns, S. Dahmen, C. Bolm, S. Bräse, Angew.
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[24] S. Dahmen, Org. Lett. 2004, 6, 2113–2116.
[25] For other reactive, monomeric ligand systems suitable
for asymmetric 1,2-reactions: a) P. Wipf, J. G. Pierce, X.
Wang, Tetrahedron: Asymmetry 2003, 14, 3605–3611;
b) A. L. Braga, M. W. Paixao, D. S. Luedtke, C. C. Sil-
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[26] The non-linear-like effect (NLLE) is different to the es-
tablished non-linear effect (NLE) found in diethylzinc
additions to aldehydes, e.g., described in ref.[6] Hence,
we named this effect as non-linear-like effect (NLLE)
in this manuscript. We thank the anonymous reviewer
for this useful comment.
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