Ni-Catalyzed Asymmetric Cycloisomerization of Dienes by Using TADDOL Phosphoramidites

Article abstract of DOI:10.1002/chem.201500352

A library of α,α,α,α-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL)-based phosphoramidites has been synthesized and applied in the Ni-catalyzed cycloisomerization of different dienes. Through the systematic variation of the three structural motifs of the

Full text of DOI:10.1002/chem.201500352

DOI: 10.1002/chem.201500352
Full Paper
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Transition Metal Catalysis |Hot Paper|
Ni-Catalyzed Asymmetric Cycloisomerization of Dienes by Using
TADDOL Phosphoramidites**
Christian Schmitz, Walter Leitner,* and Giancarlo Franciò*[a]
Dedicated to Professor Günther Wilke on the occasion of his 90th birthday
Abstract: A library of a,a,a,a-tetraaryl-1,3-dioxolane-4,5-di-
methanol (TADDOL)-based phosphoramidites has been syn-
thesized and applied in the Ni-catalyzed cycloisomerization
of different dienes. Through the systematic variation of the
three structural motifs of the lead structure, that is, the
amine moiety, the protecting group, and the aryl sub-
stituents, the ligand features could be optimized for the
asymmetric cycloisomerization of the model substrate dieth-
yl diallylmalonate. The substrate scope of the new catalytic
system was extended to other diallylic substrates, including
unsymmetrical dienes. Overall remarkably high activities of
up to approximately 13500 hÀ1, very high selectivities
toward five-membered exo-methylenecyclopentanes, and
enantioselectivities of up to 92% ee have been achieved.
Introduction
and enantioselectivities for the formation of the thermodynam-
ically least favored chiral products of type B, thus providing an
exocyclic methylene group for subsequent transformations.
A first example of asymmetric diene cycloisomerization was
Transition-metal-catalyzed carbon-carbon bond formations
belong to the most intensively studied transformations in
organic synthesis.[1] In this regard, the catalytic cycloisomeriza-
tion of a,w-dienes provides a powerful and atom-efficient tool
for the construction of carbo- and heterocyclic molecules from
readily available olefinic substrates.[2] These fundamental con-
stituents of natural products, pharmaceutical compounds, and
functional materials could be in principle prepared through
a cycloisomerization step. A number of achiral transition-metal
catalyst systems based on Pd,[3] Ni,[3j,4] Rh,[3h,5] Ru,[6] Pt,[7] and
Ti[8] are known to deliver the individual five-membered ring
products B–D with high levels of regio- and chemoselectivities
(Scheme 1).
´
reported by Bogdanovic in the 1970s. A cationic Ni complex
containing a P*-stereogenic menthyl-based phosphane ligand
selectively catalyzed the cycloisomerization of 1,6-heptadiene
(X=CH2) and diallyl ether (X=O), albeit with low optical yields
of up to 37% ee.[9] Wilke described the asymmetric cycloisome-
rization of 1,6-heptadiene (X=CH2) with the P*-stereogenic
azaphospholene ligand all-(R)-1[10] to give the corresponding
exo-methylenecyclopentane of type B in 94% yield and high
enantioselectivity (93% ee at À308C).[11] In 1998, Heumann and
Moukhliss[3i] reported the asymmetric cycloisomerization of di-
ethyl diallylmalonate (X=C(CO2Et)2). By using a catalyst system
based on [Pd(CH3CN)2Cl2], 2 equivalents of AgBF4, and either
(R,R)-4,4’-dibenzylbisoxazoline or (À)-sparteine, enantiomeric
excesses up to 60% were achieved, albeit with low
conversions and poor regioselectivities.[3c,i,12]
However, only very few examples for enantioselective
catalysts have been reported so far. The main challenge is the
design of catalytic systems that combine high chemo-, regio-,
More recently, we have investigated the scope of Ni-based
catalysts involving the Wilke azaphospholene all-(R)-1 and 1,1’-
bi-2-naphthol (BINOL)-based phosphoramidites 2[13] and 3[14,15]
as ligands for inter- and intramolecular olefin dimerization re-
actions (Figure 1).[16] Systems based on these ligands and the
[Ni(allyl)(cod)]+ (cod=1,5-cyclooctadiene) precursor afforded
active catalysts for the asymmetric cycloisomerization of dieth-
yl diallylmalonate (X=C(CO2Et)2) and N,N-diallyltosylamide (X=
NTs; Ts =tosyl). By using the Wilke azaphospholene all-(R)-1,
the corresponding five-membered ring products of type B
were formed in moderate-to-high enantioselectivities (up to 80
and 54% ee for X=C(CO2Et)2 and NTs, respectively), thus pro-
viding the best currently found values for these substrates.[17]
Furthermore, we reported the highly chemo- and regio-
selective cycloisomerization of unsymmetrically substituted
Scheme 1. Cycloisomerization of 1,6-dienes (X=CH2, C(CO2R)2, O, NÀR, etc.).
[a] Dr. C. Schmitz, Prof. W. Leitner, Dr. G. Franciò
Institut für Technische und Makromolekulare Chemie
RWTH Aachen University
Worringerweg 2, 52074 Aachen (Germany)
E-mail: leitner@itmc.rwth-aachen.de
francio@itmc.rwth-aachen.de
[**] TADDOL=a,a,a,a-tetraaryl-1,3-dioxolane-4,5-dimethanol.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500352.
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Figure 1. Ligands used in previous studies.
1,6-dienes and bis-allylamines with this catalytic system.[18] The
possibility of tandem sequences that involve asymmetric cyclo-
isomerization as an initial CÀC bond-forming step was also
shown. Although the utilization of monodentate BINOL phos-
phoramidites 2 and 3 led to moderate enantioselectivities (up
to 46% ee for X=C(CO2Et)2) and low catalyst activities (turn-
over frequency (TOF)ꢀ37 hÀ1),[16a,c,17a] the structural diversity of
this ligand type, achievable through a modular and straightfor-
ward synthesis, suggested phosphoramidites as attractive lead
structures for further development.
Encouraged by the past and recent work of Alexakis,[19]
Rovis,[20] Suginome,[21] Fürstner,[22] and others,[23] who showed
that a,a,a,a-tetraaryl-1,3-dioxolane-4,5- dimethanol (TADDOL)-
based ligands may lead to more active and selective catalysts
than their BINOL-based analogues in several transformations,
we started a detailed study on the use of TADDOL-derived
phosphoramidite ligands[24] in the Ni-catalyzed asymmetric
cycloisomerization of 1,6-dienes.
Scheme 2. Synthesis of monodentate TADDOL phosphoramidites with
different amine moieties. Boc=tert-butoxycarbonyl, MS=molecular sieves.
Results and Discussion
Herein, we describe an iterative variation sequence of the
TADDOL phosphoramidite lead structure that comprises the
amine moiety, the protecting group, and the aryl substituents
(Figure 2). Fine tuning of the electronic, steric, and chiral coop-
As the first structural motif, variation of the amine moiety was
investigated. A broad variety of amines that possess different
steric properties was evaluated, including cyclic, acyclic, achiral,
and chiral amines (Scheme 2). In the latter case, additional
cooperative effects may occur that contribute to enhanced
stereocontrol in catalysis.
The first set of ligands L1–L7 was synthesized from an
achiral amine with acyclic and cyclic structures by using di-
ethylamine, diisopropylamine, dicyclohexylamine, pyrrolidine,
piperidine, morpholine, and N-methylpiperazine with (R,R)-
TADDOL as building blocks. For the synthesis of ligands L1–L7,
the respective amine was dissolved in CH2Cl2 in the presence
of triethylamine. The solution was cooled to 08C and a solution
of the (R,R)-TADDOL chlorophosphite 4[25] was added dropwise
within 15 minutes. Afterwards, the reaction mixture was al-
lowed to reach room temperature and stirred for 6–18 hours,
thus resulting in full conversion of the chlorophosphite. After
filtration through a pad of basic alumina, the ligands were
obtained in sufficient purity (91–99% based on 31P and
1H NMR spectroscopic analysis) for catalytic application and
in moderate-to-high yields (52–97%; Scheme 2).
Figure 2. TADDOL-based phosphoramidite ligands and the three structural
motifs that allow the systematic optimization of the catalytic performances.
erative effects led eventually to an optimized catalyst for the
cycloisomerization of the model substrate diethyl diallylmalo-
nate, thus setting a new benchmark for this transformation.
The substrate scope of the new catalytic system was extend-
ed to other diallylic substrates, also including the asymmetric
cycloisomerization of unsymmetrical dienes for the first time.
Overall, remarkable high activities, very high selectivities
toward exo-methylenecyclopentanes of type B, and enantiose-
lectivities of up to 92% ee have been achieved.
The ligands were tested in the asymmetric cycloisomeriz-
ation with diethyl diallylmalonate (5a) as a model substrate
with a catalyst loading of 0.5 mol%. The catalytically active
species was generated in situ from the respective ligand and
[Ni(allyl)(cod)]BArF[17a] (the results are summarized in Table 1).
A high conversion was observed after 6 hours in almost all
cases with good-to-high selectivities toward the desired exo-
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(45% ee) than the diastereomeric (S,S,S)-L9 (30% ee). Ligands
L8 and L9 promoted the preferential formation of opposite
enantiomers, thus indicating that the chirality of the diol back-
bone is the dominating control factor, whereas moderate
cooperative effects of the different chiral elements were
observed. The same behavior was also observed with L10 and
L11 bearing a bulky C2-symmetric chiral amine moiety, which
gave quite poor enantioselectivities of 22 and 19% ee for the
+ and À enantiomers, respectively.
Table 1. Cycloisomerization of diethyl diallylmalonate by using
monodentate TADDOL-based ligands.
Ligand
t [h]
Cv. [%]
Sel. [%][a]
ee [%][b]
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L12
L13
L14
L15
L16
L17
L18
L19
L20
L21
L22
6
6
6
6
6
6
6
6
6
6
6
6
6
6
1
1
1
1
1
1
6:1
6
>99
78
74
92
>99
93
66
99
99
98
85
50
92
85
95
>99
99
99
95
69
71
84
97
92
93
91
91
90
94
81
40
96
58
89
96
95
91
92
83
92:94
73
32 (À)
16 (À)
9 (À)
The outcome obtained so far with L1–L11 indicates that fur-
ther optimization of the ligand structure should concentrate
on amines with a cyclic structure that contain small substitu-
ents and a C1 symmetry. The catalytic results achieved with
ligands L12–L16 fully corroborated this assumption. Ligand
L12, based on (R)-N-benzyl-1-phenylethylamine, led to low
conversion, poor selectivity, and an almost racemic mixture,
thus confirming that an increase in steric bulk relative to L9 is
unfavorable for the reaction under investigation. Also, L13, de-
rived from the primary amine (S)-1-phenylethylamine, resulted
in a racemic mixture of 6a. The use of L14, based on cis-2,6-di-
methylpiperidine, a ligand sterically more demanding than L5,
gave poor (enantio)selectivity. In contrast, both diastereomers
of the related ligands L15 and L16, prepared from C1-symmet-
ric (S)-2-methylpiperidine and (R,R)- or (S,S)-TADDOL, resulted
in the highest enantioselectivities hitherto with 55 and 57% ee
for the À and + enantiomers, respectively. Remarkably, full
conversion was obtained with both ligands within one hour,
which corresponds to a lower limit of the TOF of 200 hÀ1.
Finally, the best ligands L15 and L16, combining a cyclic pi-
peridine and a C1-symmetric amine fragment with additional
chiral information, provided the basis for further manipulation
of the ligand structure. To this aim, C1-symmetric piperidine de-
rivatives, such as (R)-N-Boc-3-methylpiperazine, (R)-2-methyl-
10 (+)
43 (À)
36 (À)
52 (À)
45 (À)
30 (+)
22 (À)
19 (+)
2 (À)
1 (À)
9 (À)
55 (À)
57 (+)
56 (À)
35 (+)
53 (À)
66 (À)
67 (À):67 (À)
32 (+)
96
99:97
92
[a] Selectivity toward 6a. [b] Determined by means of chiral HPLC
analysis.
methylenecyclopentane (6a). Low enantioselectivities toward
the (À) enantiomer were achieved with L1–L3, in which in-
creasing steric demand of the amine part resulted in a decrease
of activity and enantioselectivity. In the case of the five-
membered pyrrolidine-based ligand L4, the opposite product
enantiomer was obtained preferentially with a low level of
enantioselectivity (i.e., 10% ee). Most promising was the result
achieved with L5, which incorporated piperidine, thus leading
to full conversion, 92% selectivity, and 43% ee (+ enantiomer).
Thus, two other ligands with a six-membered-ring amine
moiety were applied in catalysis. Morpholine-based L6 showed
a lower activity and enantioselectivity relative to L5, whereas
the new N-methylpiperazine-based ligand L7 achieved 66%
conversion and higher enantioselectivity (52% ee).
1,2,3,4-tetrahydroquinoline,
(rac)-trans-decahydroquinoline,
and pinene-piperidine derivative 10[26] were selected and the
corresponding new ligands L17–L22 were synthesized
(Scheme 2) and applied in the cycloisomerization of 5a.[27] In
this set of experiments, good results were obtained with
almost all the ligands based on a six-membered nitrogen
heterocycle. The diastereomeric ligands L17 and L18 derived
from (R)-N-Boc-3-methylpiperazine gave results similar to the
outcome achieved with L15 and L16. By using ligand L19,
synthesized from (R)-2-methyl-1,2,3,4-tetahydroquinoline and
(R,R)-TADDOL, an enantiomeric excess of 53% was achieved. A
significantly higher enantioselectivity of 66% was obtained
with L20 based on trans-decahydroquinoline,[27] albeit with
a moderate isomer selectivity toward 6a of 83%. The best
ligand of the series was the pinene-piperidine/(R,R)-TADDOL-
based ligand L21 with a conversion of 97% within one hour,
selectivity of 94% toward the desired exo-methylenecyclopen-
tane (6a), and an enantioselectivity of 67% ee. The diastereo-
meric ligand L22, based on (S,S)-TADDOL, led to considerably
lower (enantio)selectivity.
Next, a series of ligands based on chiral amines were synthe-
sized and evaluated in catalysis. By using the same procedure
as above, phosphoramidites L8 and L9 were prepared in good
yields from (S)-N-methyl-1-phenylethylamine and (R,R)- or (S,S)-
TADDOL, respectively. For the synthesis of the ligands L10 and
L11, (S,S)-bis(1-phenylethyl)amine was dissolved in THF, treated
with nBuLi, and then added to a solution of (R,R)- or (S,S)-
TADDOL chlorophosphite 4, respectively, in THF at À608C.
Again, the resulting phosphoramidites were purified by
filtration over basic alumina and obtained in preparatively
useful purity and excellent yields (i.e., 95–98%).
Thus, the pinene-piperidine-based TADDOL-phosphoramidite
L21, which led to the best results so far, was selected as the
most suitable amine for optimization of the TADDOL fragment
of the ligand. Both the variation of the acetonide protecting
Both L8 and L9 led to active and selective nickel catalysts,
whereby (R,R,S)-L8 resulted in higher enantioselectivity
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Scheme 3. Synthesis of TADDOL phosphoramidites with different diol
protecting groups.
group and the phenyl substituents were subsequently
addressed.
First, TADDOL derivatives 7, 8,[28] and 9[22a] with different
protecting groups for the peripheric diol moiety were used for
the synthesis of the novel ligands L23–L25, respectively, with
pinene-piperidine 10 as the amine part (Scheme 3). For the
methylphenyl-protected ligand L23, two diastereomers
(dP =138.3 and 138.6 ppm (60 and 40%, respectively)) were
obtained and used without further separation in catalysis.[29]
In general, the diol protecting group had almost no effect
on activity, selectivity, or enantioselectivity (Table 2, entries 1–
4). The same enantiomeric excess of 67% (À enantiomer) was
Scheme 4. Synthesis of TADDOL derivatives and ligands thereof with
different aryl substituents on the TADDOL backbone.
were synthesized. The synthesis of 12a–12h was realized by
a Grignard reaction of acetonide-protected (R,R)-diethyl tartrate
11 and commercially available arylmagnesium halides or aryl
bromides and magnesium. After purification by column chro-
matography, the TADDOL derivatives were obtained in 22–
78% yield and used for the synthesis of the corresponding
new ligands L26–L34 obtained in 41–74% yield (Scheme 4).
The catalytic results demonstrate the remarkable impact of
the substitution pattern of the aryl substituents on activity,
selectivity, and enantioselectivity (Table 2, entries 5–13). Here,
ligands L26 and L27, bearing tert-butyl or trifluoromethyl
groups in the 3,5-position led to a drop in activity, isomer se-
lectivity, and enantioselectivity. In particular, the cyclization
products of type C and D were obtained preferentially in the
presence of L26, and the desired exo-methylenecyclopentane
(6a) was only formed with 36% ee.
Moreover, the introduction of substituents at the para
position (i.e., L28–L30) did not result in an improvement with
respect to the parent ligand L21. A strong electron-donating
methoxy group slowed down the reaction considerably and
led to an ee value of only 7%. In direct comparison, an elec-
tron-withdrawing chloro substituent did not significantly affect
the catalyst activity, yet a poor ee value of 34% was achieved.
Ligand L30, with a 4-tBu-Ph substituent, gave similar results to
L21, albeit with a slightly decreased isomer selectivity.
Finally, L31, bearing 2-Me-Ph substituents in the TADDOL
backbone, led to a significant improvement. Here, 93% conver-
sion, 96% isomer selectivity, and 73% ee were achieved. Con-
sequently, an increased steric demand without significantly
changing the electronic properties of the aryl substituent
seems to be beneficial for the reaction. This assumption was
confirmed by the results with L32 and L33, featuring sterically
demanding 2-naphthyl or 9-phenanthryl substituents. Al-
though L32 gave an enantioselectivity comparable to L21 (71
vs. 67% ee, respectively), the use of L33 achieved an even
higher enantioselectivity of 76% ee, albeit at the expense of
catalyst activity and selectivity. The best result was obtained
Table 2. Cycloisomerization of diethyl diallylmalonate by using TADDOL
phosphoramidites L21–L34.[a]
Entry
Ligand
Ar
Cv. [%]
Sel. [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14[e]
L21
L23
L24
L25
L26
L27
L28
L29
L30
L31
L32
L33
L34
L34
Ph
Ph
Ph
Ph
97
91
96
97
62
75
63
89
92
93
90
41
98[d]
92
94
94
91
94
15
38
46
79
85
96
91
48
96
95
67 (À)
67 (À)
67 (À)
62 (À)
36 (À)
23 (À)
7 (À)
3,5-(tBu)2-Ph
3,5-(CF3)2-Ph
4-OMe-Ph
4-Cl-Ph
4-tBu-Ph
2-Me-Ph
2-naphthyl
9-phenanthryl
2-Et-Ph
2-Et-Ph
34 (À)
64 (À)
73 (À)
71 (À)
76 (À)
80 (À)
88 (À)
[a] Reaction conditions: 0.5 mol% [Ni(allyl)(cod)]BArF, 0.55 mol% ligand,
1 h, CH2Cl2, RT. [b] Regioselectivity toward 6a. [c] Determined by chiral
HPLC. [d] Yield of the isolated product mixture=93%. [e] 0.1 mol%
[Ni(allyl)(cod)]BArF, 0.11 mol% ligand, 16 h, toluene, À208C.
achieved with ligands L23 and L24 as with the acetonide-pro-
tected ligand L21. Only the more flexible methyl-protected
phosphoramidite L25 gave a slightly lower ee value of 62%;
the activity and selectivity remained unaffected.
Next, the influence of the aryl substituents on the TADDOL
backbone was investigated in more detail. For this purpose,
TADDOL derivatives 12a–12h bearing various aryl substituents
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when L34, bearing a 2-Et-Ph substituent, was used. The Ni cat-
alyst based on this ligand gave a conversion of 98%, a selectivi-
ty of 96% toward the desired exo-methylenecyclopentane
(6a), and an enantiomeric excess of 80% (À; Table 2, entry 13).
After optimization of the reaction conditions (see Table S1 in
the Supporting Information for full details), this result could be
further improved to 88% ee, even at 0.1 mol% catalyst loading
by lowering the reaction temperature to À208C and using tol-
uene instead of CH2Cl2 as the reaction medium (Table 2,
entry 14). These results represent the highest ee values in the
asymmetric cycloisomerization of diethyl diallylmalonate re-
ported up to now and illustrate the great potential and the
high variability of TADDOL-based phosphoramidites.
A conversion–time profile was compiled to sample the reac-
tion at defined time intervals to investigate the activity of the
catalyst system in more detail (Figure 3). A conversion of 45%
Scheme 5. Ni-catalyzed cycloisomerization of symmetrical and unsymmetri-
cal 1,6-dienes 5a–5e and diallyltosylamide (5 f). Reaction conditions: [a] cat.
0.11 mol%, toluene, 16 h, À208C; [b] cat. 0.5 mol%, CH2Cl2, RT, 3 h; [c] cat.
1.0 mol%, CH2Cl2, RT, 14 h. cv.=conversion, sel.=selectivity, Y=yield (refers
to the isolated product mixture).
pentane (6c) was obtained with 93% selectivity and 86% ee at
95% conversion by using L34.
The cycloisomerization of unsymmetrically substituted
1,6-dienes imposes additional challenges on the control of
selectivity because the addition of the catalytically active nickel
hydride can occur either at the terminal or internal double
bond. The addition to the terminal double bond leads to cyclic
products with a trisubstituted double bond, which can have
an E or Z configuration. In contrast, the addition to the higher
substituted internal double bond yields products with an exo-
cyclic methylene group.[18,31]
Figure 3. Conversion–time profile of the cycloisomerization of diethyl
diallylmalonate by using [Ni(allyl)(cod)]BArF and L34 (CH2Cl2, RT, 0.1 mol%
catalyst).
was found after just two minutes. After five minutes, 68% of
the initial substrate had been converted, thus corresponding
to a TOF2 min of approximately 13500 hÀ1 and exceeding the
previously investigated BINOL phosphoramidites and the all-
(R)-1 Wilke ligand by at least one order of magnitude. Nearly
quantitative conversion (97%) was reached within one hour.
The selectivity was 90% at the beginning and further increased
along the reaction,[30] whereas the enantioselectivity was
constant throughout the reaction. Within 60 minutes, 97%
conversion, 96% selectivity, and 83% ee were obtained.
Next the substrate scope of the best catalysts was evaluated
in the asymmetric cycloisomerization of various 1,6-diene
substrates (Scheme 5). The catalyst system was conveniently
prepared in situ from [Ni(allyl)(cod)]BArF and L34 or L20 (see
Table S2 in the Supporting Information for details of the full
screening).
The (E)-diethyl allylcrotylmalonate (5d) underwent cycloiso-
merization in a less selective manner relative to symmetrical
1,6-diene substrates. The major product exo-ethylidencyclopen-
tane (5d) with an internal E-configured trisubstituted double
bond was formed with 56% isomer selectivity and 57% ee by
using L34. When (E)-phenyl-substituted malonate substrate 5e
was used, high selectivities were observed again, thus leading
to the chiral (E)-exo-benzylidencyclopentane (6e). In this case,
L34 led to 95% isomer selectivity with 84%ee. Consequently,
the regio- and enantio-differentiating abilities of the catalyst
benefit from the increased steric demand of the phenyl group
in 5e relative to the methyl substituent in 5d.
Finally, the cycloisomerization of N,N-diallyltosylamide (X=
NTs; 5 f) was investigated, thus representing a feasible route to
five-membered chiral N-heterocycles. Up to now, only low-to-
moderate enantioselectivities have been achieved for this class
of substrate, from which the best result was obtained by using
the Wilke azaphospholene all-(R)-1 and [Ni(allyl)(cod)][Al(pftb)4]
(i.e., 99% selectivity and 54% ee; pftb=perfluoro-tert-
butoxide).[17b]
The cycloisomerization of the sterically demanding di-tert-
butyl diallylmalonate (5b) proceeded with 94% conversion,
97% selectivity toward the desired exo-methylenecyclopentane
(6b), and 92% ee by using L34. In the cycloisomerization of
4,4-hydroxymethyl-1,6-heptadiene (5c), exo-methylenecyclo-
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For determination of the ee value by 13C NMR spectroscopy, the
chlorinated solvent was replaced by diethyl ether and the cycloiso-
merization products were reduced to the corresponding diols by
LiAlH4 (6 equiv). After extraction with diethyl ether and drying over
sodium sulfate, a sample of the diol was dissolved in CDCl3 and
treated with anhydrous pyridine and (À)-menthoxyacetyl chloride.
The resulting solution was washed with water, dried over sodium
sulfate, filtered through flourisil, and analyzed by means of quanti-
tative dept45 13C NMR (150 MHz) spectroscopy with D1=10 s and
a spectral width of 30 ppm.
For the cycloisomerization of 5 f, various TADDOL phosphor-
amidites were applied, which led to good results in the case of
the malonate substrates (see Table S3 in the Supporting
Information for details of the full screening). The best result
was obtained by using L20 and [Ni(allyl)(cod)]BArF to give full
conversion, 99% selectivity toward the desired exo-methylene
N-heterocyclic product 6 f, and 59% ee.
Full details of the experimental procedures for the synthesis of the
TADDOL derivatives, TADDOL-phosphoramidites, and 1,6-dienes are
available in the Supporting Information.
Conclusion
A library of 34 monodentate TADDOL-based phosphoramidites
have been synthesized (including 25 new ligands) and evalu-
ated in the cycloisomerization of the benchmark substrate
diethyl diallylmalonate. By using a sequential optimization ap-
proach, first the amine part of the ligand was systematically
varied and the novel pinene-piperidine species was identified
as the best suited N-moiety. The subsequent introduction of
different protecting groups on the TADDOL backbone had
little effect on catalysis, whereas a major improvement could
be achieved through variation of the aryl substituents. In par-
ticular, the ligand bearing ortho-ethylphenyl groups resulted in
the best outcome of the series by giving an enantiomeric
excess of up to 88% and a selectivity of 95% toward the de-
sired chiral exo-methylenecyclopentane under the optimized
reaction conditions. This catalyst showed very high activity
with an initial TOF value of approximately 13500 hÀ1. Finally,
the substrate scope was evaluated and enantiomeric excesses
of up to 92% were achieved. Even for challenging unsymmetri-
cal 1,6-dienes, an ee value of up to 84% was obtained.
Acknowledgements
The authors thank Julia Wurlitzer and Hannelore Eschmann
(ITMC, RWTH Aachen University) for the GC and HPLC analysis.
Furthermore, we thank Moritz Pilaski, Rebekka Bohmann, and
Katharina Holthusen for experimental support. The research
that led to these results received funding from the European
Community (FP-7 integrated project SYNFLOW, grant
agreement no. 246461).
Keywords: asymmetric catalysis · cycloisomerization · nickel ·
phosphoramidites · TADDOL
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Received: January 27, 2015
Published online on May 26, 2015
Chem. Eur. J. 2015, 21, 10696 – 10702
www.chemeurj.org
10702
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim