Monomeric Cinchona Alkaloid-Based Catalysts for Highly Enantioselective Bromolactonisation of Alkynes

Article abstract of DOI:10.1002/chem.201604003

The cinchona alkaloid dimer (DHQD)₂PHAL has been shown to be a broadly applicable catalyst for asymmetric halogenations. However, this catalyst does not have to be dimeric and a class of monomeric quinidine and quinine-derived catalysts was prepared, often showing superior selectivity in bromolactonisations of terminal alkynoic acids. Mechanistic investigations show that these organocatalysts act as host molecules that can bind carboxylic acid-based substrates as guests with substantial binding constants. Based on these findings, it is proposed that this class of catalysts is bifunctional in nature activating the halogenating agent as well as the nucleophile in electrophilic halogenation reactions.

Full text of DOI:10.1002/chem.201604003

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Accepted Article
Title: Monomeric cinchona alkaloid-based catalysts for highly
enantioselective bromolactonisation of alkynes
Authors: Michael Wilking, Constantin G Daniliuc, and Ulrich Hennecke
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Monomeric cinchona alkaloid-based catalysts for highly
enantioselective bromolactonisation of alkynes
Michael Wilking, Constantin G. Daniliuc and Ulrich Hennecke*[a]
Abstract: The cinchona alkaloid dimer (DHQD)2PHAL has been
shown to be broadly applicable catalyst for asymmetric
as a Lewis base towards the halogenating agent/the electrophilic
a
halogen and is therefore involved in catalysis.[4a,b] Nicolaou
suggested a similar activation of the halogenating agent by this
nitrogen, but also pointed out the important role of the bridging
phthalazine moiety as hydrogen bond acceptor to orient allylic
alcohol substrates.[4d] During our studies on the enantioselective
bromolactonisation of dialkynoic acid we discovered the rather
tight binding of the substrate carboxylic acids to the
(DHQD)2PHAL catalyst 1.[4h] However, it is currently not clear how
these discoveries translate from one reaction to another and
many mechanistic questions remain, including the importance of
the dimeric nature of these catalyst.
halogenations. However, this catalyst does not have to be dimeric and
a class of monomeric quinidine and quinine-derived catalysts was
prepared
which
shows
often
superior
selectivities
in
bromolactonisations of terminal alkynoic acids. Mechanistic
investigations show that these organocatalysts act as host molecules
that can bind carboxylic acid-based substrates as guests with
substantial binding constants. Based on these findings it is proposed
that this class of catalysts is bifunctional in nature activating the
halogenating agent as well as the nucleophile in electrophilic
halogenation reactions.
Introduction
The electrophilic halogenation of carbon-carbon multiple bonds is
one of the fundamental reactions of organic chemistry.
Dihalogenation,
halolactonisation
and
related
halofunctionalisations are often applied in organic synthesis
including complex natural product synthesis.[1] However, only
during the last years, reagent-controlled, enantioselective
variants of this class of reactions have been developed.[2] In many
cases, specific organocatalysts have been designed for one
specific class of asymmetric halogenations, but their general
applicability seems to be limited.[3,4] Probably the most broadly
applicable catalysts in this area, are the dimeric cinchona alkaloid
derivatives (DHQD)2PHAL
1 and the pseudoenantiomeric
(diastereomeric) (DHQ)2PHAL 2 (Figure 1).[4,5] These catalysts,
originally developed as chiral ligands for the Sharpless
bishydroxylation[6], were introduced as organocatalysts for
halogenation by Borhan to asymmetric chlorolactonisations.[4a]
Subsequently, they were found to be efficient, enantioselective
organocatalysts for a range of other halogenations including
haloamidations, dichlorination, dearomatizing bromocyclizations,
bromolactonizations of alkynes and other reactions.[4,5] Despite
this numerous reports, the mechanistic understanding of these
catalysts is limited and this limited knowledge on the role of the
different components of these molecules has hindered the
systematic improvement of the catalyst’s properties. Borhan
investigated the interaction of catalyst 1 with the stoichiometric
halogenating agent and found that the quinuclidine core is acting
Figure 1. The pseudoenantiomeric (diastereomeric), dimeric cinchona alkaloid
derivatives (DHQD)2PHAL 1 and (DHQ)2PHAL 2.
These are key question to be answered, which should enable
rational development of catalysts for enantioselective
halogenation of unsaturated carbon-carbon bonds. Therefore we
set out to prepare a range of new cinchona alkaloid-based
phthalazine derivatives on the one hand to study the importance
of the different parts of the molecules and their relevance to
catalysis. On the other hand we wanted to improve the catalysts
performance and specifically address the shortcomings of the
conventional
(DHQD)2PHAL
1
in
enantioselective
bromolactonisation of alkynoic acids, e.g. lower enantioselectivity
with terminal alkynes.
[a]
Dr. Michael Wilking, Dr. Constantin G. Daniliuc and PD Dr. Ulrich
Hennecke
Results and Discussion
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Correnstraße 40, 48149 Münster (Germany)
E-mail: ulrich.hennecke@uni-muenster.de
(DHQD)2PHAL 1 can be easily prepared from dihydroquinidine
and 1,4-dichlorophthalazine in
a
nucleophilic aromatic
substitution reaction.[6] If derivatives with only one alkaloid
substituent are desired, simple adjustment of the stoichiometry
Supporting information for this article is given via a link at the end of
the document.
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allows
monochlorophthalazine
the
preparation
of
dihydroquinidine
Already
give a much more rigid catalyst (see also below). Already catalyst
3d carrying a di(naphthyl) substituted alkoxy group was not only
3b
((DHQD)PHALCl).[7]
Sharpless used this intermediate to prepare dihydroquinidine-
based phthalazine ligands containing only one alkaloid.[7]
Following this lead a small liberary of monomeric (DHQD)PHAL
derivatives with (mostly alkoxy) substituents of different sterical
demand was prepared (Figure 2, see Supporting Information for
experimental details).
a highly active catalyst (92% yield), but also induced
bromolactonisation with a good enantioselectivity of 85:15 er, very
comparable to (DHQD)2PHAL 1 (entry 8). Catalyst 3e with even
larger phenantryl substituents proved to be even more selective
and provided bromoenol lactone 6a with an excellent 94:6 er
(entry 9). This is a clear improvement over the commercial
(DHQD)2PHAL 1 and enables for the first time the highly
enantioselective bromolactonisation of terminal alkynes.
Additionally, the pseudoenantiomeric catalyst of 3e, catalyst 4,
was prepared based on dihydroquinine. Whereas the standard
dimeric dihydroquinine derivative (DHQ)2PHAL 2 provided the
product in 51% and with an enantioselectivity of 19:81 er (entry 3),
bromolactonisation of 5a using the monomeric derivative 4 as
catalyst proceeded with excellent enantioselectivity (6:94 er) and
the product ent-6a was obtained in moderate yield (55%, entry
10).
Table 1. Evaluation of new cinchona alkaloid-based organocatalysts in
alkyne bromolactonisation[a]
Figure 2. Phthalazine-substituted cinchona alkaloid derivatives prepared and
applied as organocatalysts.
Entry
Catalyst
Yield 6a (%)[b]
er[c]
These monomeric dihydroquinidine derivatives were now
investigated as catalysts in a model reaction, in this case the
bromolactonisation of dialkynoic acid 5a (Table 1). Without a
catalyst present, this reaction does not proceed to a significant
extent under the chosen reaction conditions (entry 1). As a
reference reaction the bromolactonisation of this compound using
the dimeric (DHQD)2PHAL 1 provided the bromoenol lactone 6a
in 90% yield and with an enantioselectivity of 86:14 er (entry 2).[4h]
If instead of 1 only dihydroquinidine was used as a catalyst, the
product was obtained in lower yield (74%) and as a racemate
(entry 4). This showed that without the phthalazine moiety, no
enantioselective catalysis was possible. If the phthalazine moiety
was reintroduced to give catalyst 3a without any further
substituent, a more active catalyst was obtained (88% yield) and
a moderate enantioselectivity of 67:33 er was observed (entry 5).
Adding small substituents to the 4-position of the phthalazine led
to moderate changes in activity and selectivity, depending on the
nature of the substituent (entries 6,7). An electron-withdrawing
chlorine substituent (catalyst 3b) reduced the activity of the
catalyst (63% yield) while retaining similar selectivity (63:37 er).
An electron-donating benzyloxy-group on the other hand led to an
increased activity (92% yield), however, the selectivity of this
catalyst was rather low. This low selectivity might be due to the
rather high flexibility of the benzyloxy group. Therefore catalysts
3d and 3e were prepared containing much more sterically
demanding secondary alcohols as substituents, which should
1
2
3
4
5
6
7
8
9
10
-
< 5
90
51
74
88
63
92
92
99
55
50:50
86:14
19:81
50:50
67:33
63:37
55:45
85:15
94:6
(DHQD)2PHAL 1
(DHQ)2PHAL 2
Dihydroquinidine
3a
3b
3c
3d
3e
4
6:94
[a] Experiments were conducted on a 0.3 mmol scale, see Supporting
Information for further details. [b] Isolated yields after column
chromatography. [c] Determined by HPLC on chiral stationary phases.
The investigations clearly showed that a suitable catalyst for the
bromolactonisation required three important moieties in the
catalyst: firstly, the alkaloid, which carries the required chirality.
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Secondly the phthalazine moiety, which was required for good
catalytic performances and selectivity.[8] And lastly a third group,
which should be sterically demanding to achieve excellent
enantioselectivity. In the commercial catalyst (DHQD)2PHAL 1
this is the second alkaloid, but our experiments show that this
group can be easily replaced by simple secondary alcohols. This
should allow the optimisation of this type of catalyst to achieve
higher selectivities in many kinds of halogenation reactions.
Nevertheless, for improving the catalyst it would be also very
helpful if the precise function of the different functional groups in
the catalyst and their mechanistic relevance would be known.
Previous reports suggested, that the two mechanistically
important functionalities should be the quinuclidine ring and the
phthalazine moiety. Based on Borhans findings and similar NMR
experiments under our reactions conditions, it can be postulated
that the quinuclidine ring is involved in the activation of the
halogenating agent.[4a,b] If this happens via formation of an
N-bromo ammonium salt or by Lewis base activation of NBS is
not yet fully clear.[4a,4b] In our case the nature of the brominating
agent does not have a significant influence on the selectivity
suggesting that the succinimide (or another imide/amide) is not
involved in the stereo-determining step making first possibility
more likely.[4h] The phthalazine moiety could be involved in the
interaction of the catalyst with the substrate, in our case the
diynoic acids 5.
spectra of mixtures of 3e and 5f showed significant concentration-
depended shifts of most signals. This data was applied to Job plot
analysis (Figure 3A), which supports the formation of a 1:1
complex between 3e and 5f. To determine the association
constant Ka the fluorescence properties of 3e were utilised and
fluorescence titrations of 3e with increasing amounts of 5a or 5f
were conducted. The observed fluorescence increase upon
addition of 5f to 3e was plotted against the concentration of 5f
(Figure 3B). To extract an association constant from the resulting
binding isotherm a non-linear fitting procedure assuming 1:1
complex formation was employed.[9] This provided an association
constant of approximately Ka = 48500 for the complex between
3e and 5f, equal to a ΔGbinding of 6.4 kcal/mol at room temperature.
For diynoic acid 5a similar results were obtained including an
association constant of Ka = 26900 (see Supporting Information
for details). These experiments clearly established that
pthalazine-modified cinchona alkaloids such as compounds 1-4
can act as host molecules binding carboxylic acids as guests with
rather substantial association constants. Currently we have no
structural information on this binding event, but a key interaction
should be the formation of a hydrogen bond between one of the
Lewis basic nitrogens of the catalyst and the carboxylic acid group
of the substrates. The rather high association constants suggest
that further interactions, including for example dispersive
interactions with the large aromatic groups of the catalyst,
contribute to the binding of the substrate. This finding is especially
interesting in the light of Borhan’s and Jackson’s recent proposal
that chlorolactonisation of alkenoic acids proceed by an concerted
AdE3-type mechanism including nucleophile-assisted alkene
activation (NAAA).[10] Taken together with our results, this
suggests that the binding of the unsaturated alkenoic or alkynoic
acids to the catalyst does not only place these substrates in a
chiral environment (as demonstrated by the diastereotopic
propargyl groups of the carboxylic acids 5 in the NMR spectra),
but that the Lewis basic organocatalysts 1 or 3 activate the
carboxylic acid group (via formation of a hydrogen bond) and via
NAAA also the alkene for halogenation.
Figure 3. Titration experiments of catalyst 3e with substrate 5f. A: 1H-NMR
titration in CDCl3 at 308 K with [c]3e + [c]5f = 0.3 mmol/L. The Job plot is based
on the chemical shift of the –OMe signal of 5f (other signals provided similar
plots, see Supporting Information). B: Fluorescence titration of 3e (0.1 mmol/L
in CHCl3) with increasing amounts of 5f (black data points). The fluorescence of
3e was observed at 370 nm. The gray line shows the fitted binding isotherm.
To investigate the potential binding of 5 to phthalazine-modified
cinchona alkaloids we turned to NMR titration experiments (see
SI for details). These experiments strongly indicate that carboxylic
acids 5 bind rather tightly to the catalysts 1 and 3e as the NMR
spectra show that the two propargyl groups of 5 become
diastereotopic upon addition of a catalyst. However, with the
commercially available catalyst 1 it proved difficult to establish a
binding constant or binding stoichiometry based on these NMR
titrations. Initial titration experiments with catalyst 3e and
carboxylic acid 5f at room temperature (299 K) in CDCl3 were also
not conclusive due to line-broadening of some signals in the NMR
spectra (possibly caused by host-guest exchange on the
timescale of the NMR experiment). At slightly elevated
temperature (308 K) this problem could be overcome and NMR
Figure 4. Crystal structure of catalyst 3d (thermal ellipsoids are shown with 15%
probability) and schematic conformation around the C8-C9-bond.
The investigations suggest that catalysts 1-4 might very likely be
bifunctional, catalyzing the addition of the electrophile (the
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bromine) and the nucleophile (the carboxylic acid group) at the
same time. This idea is further corroborated by the solid state
structure of catalyst 3d, which could be determined by X-ray
crystallography (Figure 4). The structure shows that the quinidine
part of the catalyst adopts the anti-open conformation.[11} This
quinidine conformation leads to an overall conformation of the
catalyst, in which the quinuclidine nitrogen and the two nitrogen
atoms of the phthalazine moiety point into the same direction
enabling bifunctional catalysis. Furthermore, the sterically
demanding secondary alcohol and the quinoline group form a type
of chiral pocket, in which the substrate could bind. Taken together
these findings supports a synergistic activation of electrophile and
nucleophile to induce a highly enantioselective addition to the
alkyne.
and further investigations are needed to establish the preferred
conformation(s) of this type of organocatalysts in solution.
Table 2. Scope of bromolactonisation using DHQD-derived catalysts.[a]
Entry
Starting
material
R1, R2
Product,
yield (%)b,d
Erc,d
1
2
3
4e
5
6
7
8
9
5a
5b
5c
5d
5e
5f
Ph, H
6a, 99 (90)
6b, 96 (81)
6c, 86 (58)
6d, 80 (91)
6e, 79 (65)
6f, 74 (79)f
6g, 99 (98)f
6h, 93 (90)f
6i, 82 (92)f
94:6 (86:14)
93:7 (81:19)
79:21 (63:37)
76:24 (92:8)
69:31 (78:22)
56:44 (86:14)f
95:5 (96:4)f
4-FC6H4, H
Et, H
CH2OTBDPS, H
H, H
COOMe, H
Ph, Me
5g
5h
5i
3-ClC6H4, Me
Ph, 4-ClC6H4
93:7 (95:5)f
Figure 5. Crystal structure of catalyst 4 (thermal ellipsoids are shown with 15%
probability) and schematic conformation around the C8-C9-bond.
85:15 (96:4)f
[a] Experiments were conducted on a 0.3 mmol scale, see Supporting
Information for further details. [b] Isolated yields after column
chromatography. [c] Determined by HPLC on chiral stationary phases. [d]
Values in parenthesis provide data for reactions with (DHQD)2PHAL as
catalyst. [e] 1 mol% catalyst. [f] Taken from reference 4h.
What remains to be explained is the difference in catalytic activity,
but not enantioselectivity between the pseudoenantiomeric
catalysts 1 and 2 or 3e and 4. The catalysts of the quinidine series
consistently led to higher yields of bromolactonisation products. A
hint on a potential explanation arose when crystals of catalyst 4
were obtained and the crystal structure was determined by X-ray
crystallography (Figure 5). Although the solid state structure of
this catalyst is in general comparable to 3d there are clear
difference in detail. Obviously, catalyst 4 contains phenantryl-
instead of naphthyl substituents, which leads to differences in the
positioning of these groups. Much more remarkable is
conformation of the quinine moiety including the C8-C9 bond of
the alkaloid, which adopts the anti-closed conformation. This
conformation places the catalytically relevant N1-atom of the
quinuclidine moiety and the phthalazine moiety far away from
each other making bifunctional catalysis impossible. This could
explain, why catalyst 4 is significantly less active than its
pseudoenantiomeric counterparts 3d/3e. Catalyst 4 would require
either a conformational reorganisation to become competent as a
bifunctional catalyst or might even not be a bifunctional catalyst at
all. A critical point is that this theory is based on the conformation
of the alkaloid moiety in two crystal structures, e.g. in the solid
state and not in solution. The different conformations of the
catalysts 3d and 4 could be also caused by crystal packing effects
After identifying 3e as an improved catalyst for the
bromolactonisation of terminal alkynes, the scope of this catalyst
for the bromolactonisation of terminal alkyne-containing
substrates was investigated (Table 2). In all but two cases, the
new catalyst 3e performed better or at least equally well than
(DHQD)2PHAL 1. Starting materials with aryl rings as R1
substituents were cyclised in excellent yields and with excellent
enantioselectivites (94:6, 93:7 er, respectively, entries 1,2). A
clear improvement was also observed for the sterically very
challenging dialkynoic acid 5c with an ethyl group as R1. Using
(DHQD)2PHAL 1 this cyclization proceeded to give the product 6c
in only 58% yield and with moderate enantioselectivity (63:37 er).
Using catalyst 3e cyclization was much more efficient (86% yield)
and the selectivity was improved to 79:21 er. For starting material
5d the situation was different and while catalyst 3e led to
acceptable results even with 1 mol% of catalyst (80% yield, 76:24
er) DHQD2PHAL 1 was this time the slightly better catalyst (91%
yield, 92:8 er). For starting material 5e results with (DHQD)2PHAL
1 and catalyst 3e were roughly comparable with similar yields
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(79% vs 65%) and enantioselectivities (69:31 vs. 78:22 er, entry
5). Malonate-derived 5f carrying a carboxy methyl group as R1
was a problematic starting material for catalyst 3e. Although yield
remained high, bromolactonisation proceeded only with very low
enantioselectivity. Catalyst 3e is not only a very good catalyst for
the bromlactonisation of substrates containing terminal alkenes,
but is equally well applicable for bromolactonisation of substrates
containing internal alkynes and for alkene bromolactonisation.
Compounds 5g and 5h carrying a methyl substituent at the
alkynes (R2 = Me) could be cyclised to give the bromenol lactones
6g and 6h in excellent yield (99% and 93%) and with an
enantioselectivity of 95:5 er and 93:7 er, values almost identical
to those obtained with (DHQD)2PHAL 1. For aryl substituted 5h
again a good yield of 82% was obtained, this time with a slightly
reduced enantioselectivity of 85:15 er.
To show catalyst’s 3e broad applicability it was also used under
slightly modified Borhan conditions[4a] (commercially available
DCDMH was used instead of DCDPH) in the chlorolactonisation
of alkenoic acid 7 (Scheme 1). Again, catalyst 3e performed well
and the product could be isolated in 71% yield and with a good
enantioselectivity of 89:11 er. This compares well to the results of
64% yield and 94:6 er, obtained with (DHQD)2PHAL under
identical conditions.
was obtained in only 42% yield and with a slightly reduced
enantioselectivity (16:84 er, Table 3, entry 3). This again shows
that catalysts from the quinine series are less efficient than their
quinidine counterparts in this type of bromolactonisations.
Table 3. Bromolactonisation using 1 mol% catalyst loading.a
Entry
Starting
material
R1
Catalyst
Product,
yield (%)b
Erc
1
2
3
4
5
6
7
5a
5a
5a
5g
5g
5h
5h
H
1
6a, 93
86:14
94:6
H
3e
4
6a, 98
H
ent-6a, 42
6g, 99
6g, 74
6h, 99
6h, 84
16:84
95:5
Me
1
Me
3e
1
94:6
4-ClC6H4
4-ClC6H4
97:3
3e
82:18
[a] Experiments were conducted on a 0.3 mmol scale, see Supporting
Information for further details. [b] Isolated yields after column
chromatography. [c] Determined by HPLC on chiral stationary phases.
Scheme 1. Enantioselective chlorolactonisation of an alkenoic acid.
These reactions could also be conducted on gram scale without
any problems (Scheme 2). Bromolactonisation of 1 g 5a with
1 mol% catalyst 1 gave the product 6a in 89% yield and with an
enantioselectivity of 86:14 er. Simple fractional crystallisation
from cyclohexane led to the separation of the racemate rac-6a in
17% overall yield and basically enantiopure 6a in 71% yield.
Crystals of both the racemate and the enantiopure fraction were
suitable for X-ray analysis and both crystal structures were solved.
The absolute configuration of the major enantiomer of 6a could
be determined to be (R), in agreement with our previous
assignment.[4h] With catalyst 3e similar results were obtained in
the bromolactonisation of 5b. Again only 1 mol% catalyst was
sufficient to obtain the product 6b on a 3 mmol scale in excellent
yield (91%) and as expected for 3e with the same very high
enantioselectivity (93:7 er) than in the small scale experiments.
Taken together these experiments show that this method for the
enantioselective bromolactonisation of alkynoic acid is very
robust, efficient and applicable to large scale synthesis without
any problems.
Further studies revealed that the dihydroquinidine-based
organocatalysts are very robust catalysts under the reaction used
for bromlactonisation of dialkynoic acids. Yields and
enantioselectivies observed in the model reaction of 5a to 6a were
not influenced by water, air or impure solvents. Even more
interesting was the fact that the catalyst loading could be reduced
from 10 mol% to 1 mol% without any effect on the reaction yield
or enantioselectivity, at least for the quinidine-based catalysts
(see Supporting Information, table S1, for a table showing the
connection between catalyst loading and enantioselectivity).
Bromolactonisation of terminal dialkynoic acid 5a with either
catalyst 1 or 3e delivered the product 6a in exactly the same
enantioselectivity, whether using 10 or 1 mol% catalyst (Table 3,
entries 1,2). Similar behaviour was also observed for internal
alkynes, which were obtained with highly similar yields and
selectivities using either 10 or 1 mol% of catalyst (entries 4-7).
The only exception was catalyst 4. With 10 mol% loading of this
catalyst the enantioselectivity was almost identical to the
selectivity obtained with the pseudoenantiomeric catalyst 3e, but
the yield of 6a was already significantly lower (55%, 6:94 er, Table
1). When only 1 mol% catalyst 4 was applied, this effect was even
more pronounced and the reaction became slow. The product 6a
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Experimental Section
General procedure for enantioselective halolactonisation of diynoic acids
In a predried and Argon-filled Schlenk-tube the corresponding diynoic acid
(0.300 mmol, 1.0 equiv.) and the catalyst (0.030 mmol, 10 mol%, or 0.003
mmol, 1 mol%) were dissolved in dry CHCl3 (3 mL) and dry n-hexane
(3 mL) and the resulting solution was stirred for 30 min at 30 °C. NBS
(64.1 mg, 0.360 mmol, 1.2 equiv.) was added at -30 °C and the reaction
was stirred for 15 h at this temperature. The reaction was stopped by the
addition of Na2S2O3-solution (sat. aq. sol., 6 mL) and CH2Cl2 (10 mL), the
phases were separated and the aqueous phase was extracted with CH2Cl2
(2×10 mL). The combined organic phases were dried over Na2SO4, filtered
and the solvent was removed in vacuo. Purification of the crude mixture by
column chromatography over a short silica column provided the respective
cyclization products.
For further experimental details including experimental procedures for the
preparation of catalysts and starting materials, copies of NMR spectra and
HPLC data and details on NMR and fluorescence titrations, see Supporting
Informations. CCDC 1400023 - 1400027 contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Scheme 2. Enantioselective bromolactonisation on mmol scale. Crystal
structures of rac-6a and (R)-6a are shown with thermal ellipsoids 15%
probability.
Acknowledgements
Financial support by the WWU Münster and the DFG (HE 6020/2-
1, HE 6020/2-2, HE 6020/3-1) is gratefully acknowledged.
Conclusions
Keywords: alkynes • cyclisation • enantioselectivity •
halogenation • organocatalysis
Although quinidine and quinine-based, phthalazine-containing
organocatalyst have been shown to be broadly applicable in
asymmetric halogenations, their mechanistic understanding is still
limited. Herein, we have shown new evidence for the bifunctional
nature of these catalysts including titration experiments that
establish phthalzine-substituted cinchona alkaloids as efficient
host molecules for carboxylic acids. By binding to unsaturated
carboxylic acids such as alkenoic or alkynoic acids these catalysts
provide a chiral environment in which halogenation can take place.
The formation of a hydrogen bond between one of the Lewis basic
nitrogens of the catalyst and the carboxylic acid could activate this
group for cyclization and/or via nucleophile-assisted alkene
activation also activate the alkene or alkyne for halogenation by
an electophilic halogenating agent.
The monomeric cinchona alkaloid derivatives reported in this
manuscript are efficient catalysts for enantioselective
bromolactonisations of alkenoic and alkynoic acids. This shows
that dimeric nature of compounds such as (DHQD)2PHAL is not
required for high enantioselectivities in organocatalytic
halogenations. For many terminal alkynes monomeric catalysts
provide even significantly improved selectivities. Another
advantage of the monomeric catalysts 3 and 4 is their modular
design. The secondary alcohol component provides only steric
bulk and could be easily replaced by other substituents. This
should allow the adaption of these catalysts to a wide range of
different enantioselective halogenation reactions just by the
selection of suitable substituents at the phthalazine moiety.
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Asymmetric halogenation: A new
class of monomeric, phthalazine-
substituted cinchona alkaloid
derivatives enables highly
Michael Wilking, Constantin G. Daniliuc
and Ulrich Hennecke*
Page No. – Page No.
enantioselective halocyclizations.
These catalysts act as host
molecules towards carboxylic acids
guests leading towards efficient
chiral induction.
Monomeric cinchona alkaloid-based
catalysts for highly enantioselective
bromolactonisation of alkynes
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