Enantioselective, desymmetrizing bromolactonization of alkynes

Article abstract of DOI:10.1021/ja402910d

Asymmetric bromolactonizations of alkynes are possible using a desymmetrization approach. The commercially available catalyst (DHQD) ₂PHAL promotes these cyclizations in combination with cheap NBS as a bromine source to give bromoenol lactones in high yield and with high enantioselectivity. The bromoenol lactone products, containing a tetrasubstituted alkene and a quaternary stereocenter, are valuable building blocks for synthetic chemistry.

Full text of DOI:10.1021/ja402910d

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Enantioselective, Desymmetrizing Bromolactonization of Alkynes
Michael Wilking, Christian Mück-Lichtenfeld, Ulrich Hennecke, and Constantin Gabriel Daniliuc
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja402910d • Publication Date (Web): 16 May 2013
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Enantioselective, Desymmetrizing Bromolactonization of Al-
kynes
Michael Wilking, Christian Mück-Lichtenfeld, Constantin G. Daniliuc and Ulrich Hennecke*
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Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany
Supporting Information Placeholder
conjugated alkynes have not been reported. Herein, we disclose
our findings on organocatalytic halocyclizations of diynoic acids
which have led to the development of highly enantioselective,
desymmetrizing halolactonizations of non-conjugated alkynes.
ABSTRACT: Asymmetric Bromolactonizations of alkynes are
possible using a desymmetrization approach. The commercially
available catalyst (DHQD)2PHAL promotes these cyclizations in
combination with cheap NBS as bromine source to give bromoe-
nol lactones in high yield and with high enantioselectivity. The
bromoenol lactone products, containing a tetra-substituted alkene
and a quaternary stereocenter, are valuable building blocks for
synthetic chemistry.
Et
Et
N
N
O
Ar
O
H
H
MeO
N
OMe
N
N
The first halolactonization reactions of alkenoic acids have
been discovered more than a century ago.1 Since then halolactoni-
zations and related halocyclizations have been widely used in
organic synthesis due to the mild reaction conditions, high chemo-
and regioselectivity and functional group tolerance.2 In many
cases, halolactonizations proceed with high diastereoselectivities
if the starting material already contains a stereogenic element
(substrate control).3 However, reagent-controlled stereoselective
variants have been missing and only recently such methods have
been developed.3,4 Early stoichiometric attempts led only to mod-
erate enantioselectivities or showed a limited substrate scope.5
Catalytic, enantioselective iodoetherifications were described by
Kang using transition metal salen complexes as catalyst, but the
application of this method to iodolactonizations requires large
amounts of catalysts.6 An asymmetric, organocatalytic method
was developed by the Borhan group in 2010 showing that dimeric
chinchona alkaloid derivatives such as (DHQD)2PHAL 1a (Figure
1) are efficient organocatalysts for highly enantioselective chloro-
lactonizations of alkenoic acids.7 At about the same time organo-
catalysts for highly enantioselective bromo- and iodolactoniza-
tions were reported by several other groups including thiocarba-
mates (Yeung)8, trisimidazolines (Fujioka)9 and ureas (Jacob-
sen)10. This rapid development has continued and several more
structurally different organocatalysts for enantioselective halolac-
tonizations have been reported since then.11 Some of these cata-
lysts are also applicable to related asymmetric halocyclization
reactions of amides.12 Similarly, new catalysts have been de-
scribed for other asymmetric alkene halogenations such as ha-
loetherifications, halogen-induced semipinacol rearrangements
and alkene dihalogenations.13 Asymmetric halolactonizations
have not only been described for alkenes, but also for conjugated
(Z)-enynes.14 Tang et al. demonstrated that the halogenation in
this case takes place at the C-C-triple bond followed by vinylo-
gous addition of the nucleophile to give chiral, brominated al-
lenes. However, enantioselective halocyclizations of simple, non-
Ph
N
N
N
O
O
N
N
Ph
(DHQD)2PHAL (DHQD)2AQN (DHQD)2PYR (DHQD)2PYDZ
1a 1b 1c 1d
Ph
Ph
NH
Et
HO
N
N
H
H
OMe
N
N
Ph
Ph
N
HN
N
Ph
Ph
trisimidazoline 2
dihydroquinidine 3
Figure 1. Organocatalysts used in enantioselective halogenations.
Bromination of a simple alkynoic acid using NBS leads most
likely to the formation of a bromirenium ion (the analog of the
bromonium ion) followed by a lactonization to give exclusively
the (E)-alkene.15 As the bromirenium ion and the resulting alkene
are non-stereogenic, the resulting 2-bromoenol lactone is formed
without a new stereocenter. To make an asymmetric cyclization
possible we chose a desymmetrization approach16 on diynoic
acids using model substrate 4a, easily available by dipropargyla-
tion/monohydrolysis of dimethyl malonate. Upon treatment with
1.2 equivalents NBS diynoic acid 4a undergoes a 5-exo bromolac-
tonization to give chiral bromoenol lactone 5a containing a qua-
ternary stereocenter in the backbone (Table 1). Without a catalyst
this reaction is rather slow at low temperature. Upon addition of
trisimidazoline catalyst 2 complete and selective conversion to
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(E)-bromoenol lactone 5a was observed in less than 15 h. The
product was formed with a small, but significant enantiomeric
excess (58:42 er, table 1, entry 1), showing that enantioselective
halolactonizations of alkynes are possible. Significantly improved
enantiomeric ratios were obtained using (DHQD)2PHAL 1a as
catalyst (83:17 er, entry 2). Other dimeric chinchona alkaloid-
derived catalysts or simple monomeric dihydroquinidine 3 led to
mixed results. The pyridazine-bridged dihydroquinidine dimer
(DHQD)2PYDZ 1d catalyzed the formation of product 5a with
good yield and a moderate er (74:26, entry 5). Monomeric dihy-
droquinidine 3 or dimeric derivatives containing non-pyridazine
bridges were ineffective and gave only low yields and selectivities
(entries 3, 4, 7). This points to the importance of the pyridazine
unit to achieve high enantioselectivities. The pseudoenantiomeric
catalyst (DHQ)2PHAL 1e performed similar to 1a providing the
product with slightly lower enantioselectivity (25:75 er, entry 6).
The use of alternative halogen sources did not give improved
results. The chlorinating agent NCS did not induce a cyclization
(entry 8). NIS on the other hand initiated iodolactonization to give
the iodoenol lactone I-5a with an enantioselectivity lower than in
the corresponding bromolactonization (74:26 er, entry 9). Substi-
tuting NBS for other brominating agents such as DBDMH had
only minor effects on the yield and enantioselectivity (entry 10,
see also SI). A further improvement in enantioselectivity could be
achieved by carefully controlling the reaction conditions including
solvent and temperature (entries 11-14). A reaction temperature of
-30°C proved to be optimal while the reaction was best conducted
in a mixture of a chlorinated solvent (CHCl3) and a hydrocarbon
(toluene or n-hexane, see also SI). The product 5a was rather
labile towards hydrolysis and could be isolated in pure form only,
when a very short silica column was used for chromatography.
Nevertheless, under the optimized reaction conditions (1.2 equiv.
NBS, 10 mol% (DHQD)2PHAL, -30 °C, CHCl3/n-hexane 1/1) the
product 5a was obtained in 81% yield and with an enantioselec-
tivity of 86:14 er. The absolute configuration of 5a was assigned
to be 3R based on its crystal structure.17
aReactions were conducted on a 0.1 mmol scale; isolated yield.
bless than 5% conversion. cReaction conducted in CHCl3/n-hexane
1/1.
Under the optimized conditions the scope of the reaction was
investigated (Table 2). Dialkynoic acids with terminal alkynes
such as 4a or 4f gave the products 5a and 5f, respectively, with
good yields and in good enantioselectivity (entries 1, 6). Howev-
er, if the alkynes were internal alkynes carrying an alkyl or aryl
substituent, the products were formed with significantly higher
enantiomeric ratios. Methyl substituted alkynes led to the for-
mation of the products with generally very good yields (above
90%) and excellent enantioselectivity above 95:5 er (entries 2, 7,
10, 11). Malonate 4c with an ethyl-substituted triple bond yielded
the product 5c again with very good yield and good enantioselec-
tivity (88:12 er, entry 3). Alkynoic acids with electron neutral or
electron deficient aromatic substituents on the alkynes cyclized
with good yields and high enantioselectivity as well (entries 4, 5,
8, 9). Interestingly, in these cases the catalyst did not only influ-
ence the stereoselectivity of the reaction, but also the regioselec-
tivity. If, for example, substrate 4h was reacted with NBS without
any catalyst, a sluggish cyclization occurred leading to a mixture
of regioisomeric products resulting from 5-exo or the 6-endo
cyclization. Upon addition of the (DHQD)2PHAL 1a catalyst,
exclusively 5-exo cyclization to the product 5h was observed
again. The fourth substituent at the quarternary carbon atom (R1)
had a smaller influence on the reaction and a range of different
groups were well tolerated. The enantioselectivities observed with
starting materials derived from malonic acid (R1 = CO2Me, entries
1-5), phenyl acetic acids (R1 = Ph, C6H4R, entries 6-11) or even
acetic acid (R1 = H, entry 12) were similar and clearly more de-
pended on the alkyne substituent. However, when substituent R1
was a CH2OH group carrying a 4-bromobenzoyl protecting group,
even a terminal alkyne reacted to the product 5m with very high
enantioselectivity (er 97:3, entry 13). As mentioned earlier, only a
pseudoenantiomer of 1a, (DHQ)2PHAL 1e, is commercially
available. To investigate, if the pseudoenantioneric catalyst 1e is
equally efficient as 1a, we cyclized starting materials 5b and 5i
using this catalyst. The enantiomeric products ent-5 were obtained
with slighty lower, but still very good yields and in almost equally
high enantioselectivities when compared to the standard condi-
tions.
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Table 1. Halolactonization of dialkynoic acid 4a
Table 2. Reaction scope
Entry
1
Reagent
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NCS
NIS
Catalyst
2
T (°C)
-78 - rt
-78 - rt
-78 - rt
-78 - rt
-78 - rt
-78 - rt
-78 - rt
-78 - rt
-78 - rt
-78 - rt
0
Yield (%)a
er
86
77
15
17
64
56
30
58:42
83:17
48:52
53:47
74:26
25:75
52:48
-
2
1a
1b
1c
1d
1e
3
3
4
5
Entry
Acid
4a
4b
4c
4d
4e
4f
R1
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Ph
R2
Yield (%)a
5a, 79
5b, 91
5c, 90
5d, 83
5e, 92
5f, 90
er
6
1
2
3
4
5
6
7
8
9
H
Me
86:14
95:5
88:12
98:2
98:2
85:15
96:4
92:8
96:4
7
b
8
1a
1a
1a
1a
1a
1a
1a
-
Et
9
99 (I-5a)
70
74:26
83:17
80:20
86:14
76:24
86:14
Ph
10
11
12
13
14c
DBDMH
NBS
NBS
NBS
NBS
4-ClC6H4
H
88
-30
79
4g
4h
4i
Ph
Me
5g, 98
5h, 94
5i, 92
-50
45
Ph
Ph
-30
81
Ph
4-ClC6H4
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tion of the carboxylic acid group should abolish catalyst activity.
To test this hypothesis we treated diynoic acid 4f with two equiva-
lents of potassium carbonate and 18-crown-6 to prepare a soluble
potassium salt in situ and cyclized this salt under standard reac-
tion conditions. The product 5f was obtained in good yield (67
%), but as a racemate (Scheme 1, middle). The interaction of the
catalyst with the carboxylic acid group was further substantiated
by NMR experiments. Upon mixing one equivalent of catalyst 1a
with one equivalent of diynoic acid 4a the alkynyl and propargyl
protons of 4a split into two sets of signals indicating that these
groups have become diastereotopic upon binding of diynoic acid
4a to the catalyst 1a. (see SI for details). Our experiments show
that the interaction of the catalyst 1a with the carboxylic acid
group is very important supporting the second mechanistic scenar-
io.18 This interaction might take place at the pyridazine nitrogen,
as only pyridazine-bridged catalysts (1a, 1d, 1e) led to good
enantioselectivities. However, that does not mean that the activa-
tion of the carboxylic acid is the only function of catalyst 1a and it
is possible that it is a bifunctional catalyst activating the brominat-
ing agent NBS as well as demonstrated by Borhan for chlorinating
agents.7,19 A schematic drawing of a possible transition state, in
line with Borhan’s7 and Nicolaou’s13g proposals, indicates the
activation of the carboxylic acid by the pyridazine unit (Scheme 1,
bottom).
10
11
4j
4k
4l
4-FC6H4
3-ClC6H4
H
CH2OR3
CO2Me
Ph
Me
Me
5j, 98
5k, 90
96:4
95:5
93:7
97:3
5:95
6:94
12
Me
5l, 95
13b
14c
15c
4m
4b
4i
H
5m, 82
Me
ent-5b, 86
ent-5i, 76
4-ClC6H4
aReactions were conducted on a 0.3 mmol scale; isolated yield.
8
9
bR3 4-BrBz. c(DHQ)2PHAL 1e was used instead of
=
(DHQD)2PHAL 1a.
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Scheme 1. Halocyclizations of diynol 6 and the potassium
salt of 4f. Schematic of a possible transition state.
Scheme 2. Gram scale synthesis of 5g and subsequent se-
lective hydrogenation.
From a mechanistic point of view, enantioselective halolac-
tonizations of alkynes are highly interesting. The halogenation of
an alkene leads to the formation of a halonium ion, which is in
most cases already chiral. However, the corresponding halirenium
ions formed by the halogenation of an alkyne are planar and
therefore achiral. This leads to two possible mechanistic scenarios
for our desymmetrizing alkyne halolactonizations: the catalyst
could direct an initial irreversible halogenation to only one of the
two alkynes, creating a stereocenter remote from the side of halo-
genation, followed by a subsequent cyclization. In the case of
such an irreversible, catalyst-mediated enantioselective halogena-
tion, only rarely precedented in the literature16, the subsequent
reaction should not be of high importance. Alternatively, the
formation of the halirenium ion might be reversible and the cata-
lyst is activating the carboxylic acid group for a cyclization onto
only one of the two possible, enantiomeric halirenium ions
formed in equilibrium. To better understand the function of the
catalyst we conducted several experiments. When diynol 6 was
treated with NBS, no reaction was observed with or without cata-
lyst 1a (Scheme 1, top). This confirms that the activation of the
carboxylic acid nucleophile plays a significant part in this reac-
tion. If we assume that catalyst’s 1a most important function is to
bind and activate the carboxylic acid group of the starting material
via a hydrogen bond or deprotonation, than the prior deprotona-
To demonstrate the practicality of our protocol we conducted
a gram scale cyclization experiment. Diynoic acid 4g (1.00 g, 4.16
mmol) was cyclized under standard conditions to give 1.31 grams
(4.10 mmol) of bromoenol lactone 5g (Scheme 2, top). Yield and
enantioselectivity remain as high as in small scale experiments.
Bromoenol lactone 5g is a valuable building block for further
modification. For example, the C-C-triple bond can be selectively
hydrogenated to give butyl-substituted bromenol lactone 8 in
excellent yield (93%) while leaving the sensitive bromoenol
moity intact (Scheme 2, bottom).
In conclusion, we present herein the first highly enantioselec-
tive halolactonization of simple, non-conjugated alkynoic acids.
The reaction allows the rapid and stereoselective synthesis of
bromoenol lactones containing a tetra-substituted alkene and an
all-carbon quaternary stereocenter. These molecules are not only
of interest as valuable building blocks for synthetic chemistry, but
also in medicinal chemistry. 2-Haloenol lactones are covalent
inhibitors of serine proteases such as chymotrypsin functioning
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through a unique mechanism-based pathway.15,20 Our method
allows the rapid, stereoselective synthesis of these compounds.
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ASSOCIATED CONTENT
Supporting Information
(12) (a) Jaganathan, A.; Garzan, A.; Whitehead, D. C.; Staples, R. J.;
Borhan, B. Angew. Chem. Int. Ed. 2011, 50, 2593. (b) Zhou, L.;
Chen, J.; Tan, C. K.; Yeung, Y.-Y. J. Am. Chem. Soc. 2011, 133,
9164. (c) Chen, J.; Zhou, L.; Yeung, Y.-Y. Org. Biolmol. Chem.
2012, 10, 3808.
Experimental procedures and characterization data for all com-
pounds. Details on the X-ray structure determination, CD spectra
and DFT calculations. This material is available free of charge via
the Internet at http://pubs.acs.org.
9
(13) (a) Cai, Y.; Liu, X.; Hui, Y.; Jiang, J.; Wang, W.; Chen, W.; Lin,
L.; Feng, X. Angew. Chem. Int. Ed. 2010, 49, 6160. (b) Rauniyar,
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Org. Lett. 2011, 13, 860. (d) Huang, D.; Wang, H.; Xue, F.;
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Cai, Y.; Liu, X.; Jiang, J.; Chen, W.; Lin, L.; Feng, X. J. Am.
Chem. Soc. 2011, 133, 5636. (f) Denmark, S. E.; Burk, M. T.
Org. Lett. 2012, 14, 256. (g) Nicolaou, K. C.; Simmons, N. L.;
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Tu, Y.-Q.; Zhang, F.-M.; Tan, J.-M. J. Am. Chem. Soc. 2011, 133,
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Z.-M.; Chen, Z.-H.; Li, J. Chem. Sci. 2011, 2, 1839. (j) Müller, C.
H.; Wilking, M.; Rühlmann, A.; Hennecke, U. Synlett 2011,
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Chem. Soc. 2012, 134, 10389. (l) Wang, Y.-M.; Wu, J.; Hoong,
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2012, 51, 3923. (n) Chen, F.; Tan, C. K.; Yeung, Y.-Y. J. Am.
Chem. Soc. 2013, 135, 1232. (o) Brindle, C. S.; Yeung, C. S.; Ja-
cobsen, E. N. Chem. Sci. 2013, 4, 2100.
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Tang, A. J. Am. Chem. Soc. 2010, 132, 3664. (b) Zhang, W.; Liu,
N.; Schienebeck, C. M.; Decloux, K.; Zheng, S.; Werness, J. B.;
Tang, W. Chem.--Eur. J. 2012, 18, 7296.
(15) Krafft, G. A.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1981,
103, 5459.
(16) For desymmetrizing halolactonizations of alkenes, see: Kitagawa,
O.; Taguchi, T. Synlett 1999, 1191.
(17) See Supporting Information for details. All other compounds
were assigned accordingly. This assignment is supported by the
CD spectrum compound 5i which was calculated using DFT
methods (see Supporting Information for details).
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AUTHOR INFORMATION
Corresponding Author
ulrich.hennecke@uni-muenster.de
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support by the WWU Münster, the “Fond der Chem-
ischen Industrie” and the DFG (HE 6020/2-1) is gratefully
acknowledged.
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(18) Note that also Fujioka’s trisimidazoline catalyst 2 is able to in-
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antioselective halogenation, but a selective activation of the car-
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(19) For an NMR spectrum of a 1:1 mixture of catalyst 1a and NBS
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