Catalytic enantioselective halolactonization of enynes and Alkenes

Article abstract of DOI:10.1002/chem.201103809

New organocatalysts have been developed for the enantioselective halolactonization of (Z)-1,3-enynes and 1,1-disubstituted alkenes. In the case of 1,3-enynes, the carboxylate nucleophile and halogen electrophile were added to the conjugated π-system from the same face. Up to 99%ee was achieved for the 1,4-syn-bromolactonization of conjugated (Z)-1,3-enynes. Based on the results from the enyne halolactonization, a second generation of catalysts was designed for simple olefins. Up to 91%ee was observed for chlorolactonization of 1,1-disubstituted alkenes. The catalysts developed for the enantioselective halolactonization of both enynes and alkenes are composed of a cinchona alkaloid skeleton tethered to a urea group.

Full text of DOI:10.1002/chem.201103809

FULL PAPER
DOI: 10.1002/chem.201103809
Catalytic Enantioselective Halolactonization of Enynes and Alkenes
Wei Zhang,[a] Na Liu,[a] Casi M. Schienebeck,[a] Kyle Decloux,[a] Suqing Zheng,[a]
Jenny B. Werness,[b] and Weiping Tang*[a]
Abstract: New organocatalysts have
been developed for the enantioselec-
tive halolactonization of (Z)-1,3-enynes
and 1,1-disubstituted alkenes. In the
case of 1,3-enynes, the carboxylate nu-
cleophile and halogen electrophile
were added to the conjugated p-system
from the same face. Up to 99% ee was
achieved for the 1,4-syn-bromolactoni-
zation of conjugated (Z)-1,3-enynes.
Based on the results from the enyne
halolactonization, a second generation
of catalysts was designed for simple
olefins. Up to 91% ee was observed for
chlorolactonization of 1,1-disubstituted
alkenes. The catalysts developed for
the enantioselective halolactonization
of both enynes and alkenes are com-
posed of a cinchona alkaloid skeleton
tethered to a urea group.
Keywords: alkenes
·
allenes
·
enynes · halogens · halolactoniza-
tion · organocatalysts
Introduction
easily elaborated.[8] In 1992, Taguchiꢀs group reported the
first reagent-controlled enantioselective halolactonization
and achieved 65% ee by using a stoichiometric amount of
a chiral titanium complex.[9] Numerous efforts have been de-
voted to this area since then.[10] Low selectivity, however,
was observed in these early studies. In 2009, Gaoꢀs group
achieved up to 83% ee for the iodolactonization of 4-aryl-
pent-4-enoic acids by using a Salen–Co complex.[11] In 2010,
several highly enantioselective halolactonizations of 1,1-di-
Halogen-promoted addition of nucleophiles to alkenes is
one of the most important and versatile reactions in organic
chemistry and has been widely used in synthesis.[1] However,
reagent-controlled enantioselective addition of halogen and
various other nucleophiles to alkenes has remained elusive
until recently.[2] In 2003, Kangꢀs group reported a highly
enantioselective iodocyclization of g-hydroxy-cis-alkenes by
using Salen–Co or Salen–Cr catalysts.[3] In 2007, Ishiharaꢀs
group achieved up to 99% ee for the iodocyclization of
polyprenoids by using a stoichiometric amount of chiral
phosphoramidites.[4] One example of enantioselective di-
AHCTUNGTREGsNNUN ubstituted olefins appeared. Borhanꢀs group first found that
up to 90% ee could be obtained for the chlorolactonization
of 4-arylpent-4-enoic acids by using hydroquinidine 1,4-
phthalazinediyl diether ((DHQD)2PHAL)[12] as the cata-
lyst.[13,14] The groups of Jacobsen,[15] Yeung,[16] and Fujioka[17]
developed three different chiral catalysts for the enantiose-
lective iodo- and bromolactonization of 1,1-disubstituted al-
kenes. The scope of the bromolactonization was expanded
to 6-endo-cyclization of 1,2-disubstituted olefins in one of
the above catalytic systems.[18] Various other enantioselec-
tive additions of halogens and nucleophiles to alkenes have
also been developed recently.[19]
In 2009, we reported a catalyst-mediated diastereoselec-
tive 1,4-bromolactonization of conjugated 1,3-enynes
[Eq. (1); NBS=N-bromosuccinimide].[20] Unlike the well-
known anti-halolactonization of simple alkenes, the carbox-
ylic acid nucleophile and bromine electrophile were added
to the conjugated enyne from the same face in the presence
chlorination of olefins by employing
a stoichiometric
amount of a chiral reagent was described in the total synthe-
sis of napyradiomycin A1 by Snyderꢀs group.[5] In 2011, Nic-
olaouꢀs group reported a catalytic method for the dichlorina-
tion of alkenes with up to 81% ee.[6] It is also worth men-
tioning that a chiral peptide-catalyst-mediated highly enan-
tioselective bromination was recently developed by Millerꢀs
group for dynamic kinetic resolution of biaryl atropisom-
ers.[7]
Among all halocyclizations, halolactonization is arguably
the most versatile because the resulting lactone can be
[a] W. Zhang, N. Liu, C. M. Schienebeck, K. Decloux, Dr. S. Zheng,
Prof. Dr. W. Tang
of 1,4-diazabicycloACTHNUTRGNE[NUG 2.2.2]octane (DABCO) as the catalyst.
High syn-diastereoselectivity (d.r.=10:1 to 20:1) was ob-
served for most basic amine catalysts (e.g., 4-dimethylami-
nopyridine (DMAP), Et3N, 1,8-diazabicycloACTHNUGRTENUNG[5.4.0]undec-7-
ene (DBU), and DABCO), whereas neutral nucleophilic
catalysts (for example, Ph3P, DMF, hexamethylphosphor-
amide (HMPA), and hexamethylphosphorous triamide
(HMPT)) generally yielded poor selectivity (d.r.=1:1 to
3:1). This novel DABCO-catalyzed syn-1,4-bromolactoniza-
The School of Pharmacy, University of Wisconsin
Madison, WI 53705-2222 (USA)
Fax : (+1)608-262-5345
E-mail: wtang@pharmacy.wisc.edu
[b] J. B. Werness
Department of Chemistry, University of Wisconsin
Madison, WI 53706-1322 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103809.
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tion worked for both (E)- and (Z)-1,3-enynes 1 and 2. It
provided bromoallene products 3 and 4, respectively, with
complementary stereochemistry.[21] Over 20:1 diastereomeric
ratios were obtained for almost all substrates (with one ex-
ception: d.r.=10:1 when R3 =tBu) by using just 2 mol% of
the DABCO catalyst. Di-, tri-, and tetrasubstituted allenes
were prepared stereoselectively and efficiently under very
mild conditions. We also found that chlorolactonization of
1,3-enynes did not occur in the presence of N-chlorosuccini-
mide (NCS) and DABCO. The iodolactonization of 1,3-
enynes worked in the absence of any catalyst. The iodoal-
lenyl lactone products, however, were not very stable. Inter-
estingly, the bromoallene moiety is present in dozens of nat-
ural products, whereas neither chloroallene nor iodoallene
has been found in naturally occurring compounds.[1j,21a,b]
We subsequently developed a bifunctional chiral catalyst
for the enantio- and diastereoselective 1,4-bromolactoniza-
tion of conjugated (Z)-1,3-enynes.[22] This represents one of
the first highly enantioselective halolactonizations.[2c] In this
full account, we describe the scope, limitations, and mecha-
nistic studies of the bifunctional-catalyst-mediated enantio-
selective 1,4-syn-bromolactonization of conjugated 1,3-
enynes. We also report for the first time our efforts towards
the enantioselective halolactonization of simple olefins by
modifying the bifunctional catalysts that we have developed
for the halolactonization of 1,3-enynes.
Scheme 1. Screening of catalysts for the enantioselective bromolactoniza-
tion of enyne 2a (Bn=benzyl, Ts=tosyl).
excess (58% ee) was obtained for lactone 4a derived from
(Z)-enyne 2a [Eq. (3)].
Results and Discussion
Because of the nature of syn-addition for the 1,4-bromolac-
tonization of 1,3-enynes, a bifunctional chiral catalyst may
easily interact with both the carboxylic acid nucleophile and
the halogen electrophile in an enantioselective cyclization
reaction. We first examined cinchona alkaloids as the cata-
lyst because they are structurally similar to DABCO and
might retain the high diastereoselectivity. We found that cat-
alytic amounts of cinchonidine 5a (Scheme 1) mediated the
highly diastereoselective cyclization of both (E)- and (Z)-
enynes 1a and 2a. Although product 3a was isolated as
a nearly racemic mixture [Eq. (2)], a moderate enantiomeric
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Enantioselective Halolactonization
FULL PAPER
We then prepared various derivatives of cinchona alka-
loids as catalysts for the enantioselective bromolactonization
of (Z)-enyne 2a under the conditions shown in Equa-
tion (3). We found that the ee values dropped significantly
with 9-alkoxy, 9-siloxy, and the 9-epimeric cinchonidines
(5b–5e and 6, Scheme 1). This suggests that the OH group
at the 9 position in catalyst 5a plays an important role in
the induction of enantioselectivity. This 9-OH group likely
served as a hydrogen-bond donor rather than an acceptor.
We then converted the 9-OH group in catalyst 5a into dif-
ferent hydrogen-bond donors,[23] such as an amide group in
catalyst 7 and a (thio)urea group in catalyst 8. We observed
a 30% ee for amide 7a. Interestingly, the diastereomeric
amide 7b provided the racemic product, which again con-
firmed the importance of the stereochemistry of the C9 po-
sition. Catalysts containing a urea group (8a, 8b, and 8d)
improved the enantioselectivity significantly. Notably, new
urea catalysts 8b and 8d performed better than the known
catalyst 8a, which was first reported in 2005 by several
groups.[24] Catalyst 8b with a 9S configuration was much
better than its 9-epimer 8c. We were surprised that thiourea
catalyst 8e, with a 9S configuration, was not capable of cata-
lyzing the reaction, whereas its 9-epimer 8 f provided
a nearly racemic product. We suspected that thiourea 8e
was oxidized more readily by NBS than its epimer 8 f. How-
ever, efforts to isolate the oxidation product of these cata-
lysts were fruitless. The tosyl group in catalysts 8b or 8d
was proven to be critical as much lower selectivity was ob-
served if it was replaced by other groups, as in catalysts 8g,
8h, 8i, and 8j. The corresponding pseudo-enantiomeric cat-
alyst 8k, derived from quinidine, yielded the other enantio-
mer selectively although only a 43% ee was obtained.
We then prepared substrates 2b–2k and explored the
scope of this catalytic enantioselective enyne bromolactoni-
zation [Eq. (4)]. Similar results were obtained for substrates
with a terminal alkyne (Table 2, entry 1). The reaction
Table 2. Scope of the enantioselective bromolactonization of (Z)-1,3-
enynes bearing an aliphatic carboxylic acid.[a,b]
Entry
Substrate
Yield
[%]
ee
[%]
1
2
3
2b, R1 =H
71
77
72
76
87
70
70
90
90
90
90
88
90
92
2c, R1 =nPr
2d, R1 =iPr
4[c]
5
2e, R1 =tBu
2 f, R1 =TES
2g, R1 =CH2OPh
2h, R1 =CH2OPMB
6
7
8
62
93
9
82
86
80
81
10
[a] Reaction conditions: NBS (120 mol%) was added to a solution of 2
and 8d (20 mol%) in ClCH2CH2Cl and the solution was stirred at RT for
0.5–10 h. [b] The d.r. values of product 4 were over 20:1 except for com-
pound 2e. [c] d.r.=10:1.
We then optimized the conditions for the enantioselective
bromolactonization of (Z)-enyne 2a by using urea catalyst
8d (Table 1). The highest enantioselectivity (89% ee) was
observed in 1,2-dichloroethane (Table 1, entry 6). The enan-
tioselectivity dropped at lower temperatures (Table 1, en-
tries 7 and 8). When the catalyst loading was decreased to
10 mol%, a lower ee was obtained (Table 1, entry 9).
worked well for (Z)-enynes with various terminal substitu-
ents (Table 2, entries 2–7; PMB=para-methoxybenzyl), in-
cluding sterically hindered tBu and triethylsilyl (TES)
groups (Table 2, entries 4 and 5). The observed d.r. values
were >20:1 for almost all substrates except 2e (Table 2,
entry 4). A nitrogen tether could also be tolerated by the re-
action (Table 2, entry 8). The ee dropped to 80% for a sub-
strate with a carbon linker (Table 2, entry 9). The reaction
time was longer (ꢀ10 h) for substrates with electron-with-
drawing groups on the terminal position of the enyne
(Table 2, entries 6, 7, and 9). Trisubstituted olefin 2k yielded
a tetrasubstituted allene in 81% ee (Table 2, entry 10).
We then examined the formation of seven-membered lac-
tones from substrates 2l–2t, containing a benzoic acid motif
[Eq. (5)]. Cyclization of enyne 2l provided lactone 4l in
high enantioselectivity, albeit in lower conversion (Table 3,
entry 1). Surprisingly, mainly 1,2-addition products were ob-
tained for substrate 2m, containing a methoxy-substituted
benzoic acid motif (Table 3, entry 2). In contrast, electron-
Table 1. Screening of conditions for the enantioselective bromolactoniza-
tion of enyne 2a.[a,b]
Entry
Catalyst
([mol%])
Solvent
T
[8C]
Yield
[%]
ee
[%]
G
1
2
3
4
5
6
7
8
9
8d (20)
8d (20)
8d (20)
8d (20)
8d (20)
8d (20)
8d (20)
8d (20)
8d (10)
CHCl3
toluene
CH2Cl2
EtOAc
RT
RT
RT
RT
RT
RT
À20
0
71
55
84
58
49
72
60
67
62
80
89
59
87
85
89
65
85
80
CH3CN
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
RT
[a] Reaction conditions: NBS (120 mol%) was added to a solution of 2a
and 8d (20 mol%) in the given solvent and the solution was stirred at
the indicated temperature for 0.5 h. [b] The d.r. values of product 4a
were over 20:1.
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W. Tang et al.
Table 3. Scope of the enantioselective bromolactonization of (Z)-1,3-
(for example, 2g, 2h, and 2j), however, the DABCO-medi-
ated bromolactonization required a much longer reaction
time than for the urea catalyst 8d. Interestingly, when we
tried to prepare racemic products derived from enynes bear-
ing a benzoic acid moiety, we found no reaction occurred by
using 20 mol% of either DABCO or simple urea
BnNHC(O)NHTs alone. In the case of substrate 2n, the ad-
dition of both DABCO (20 mol%) and urea
BnNHC(O)NHTs (20 mol%) provided a 12% yield of race-
mic lactone (Æ)-4n and acid 2n was recovered in 82% yield
after 12 h. Other substrates also gave the corresponding rac-
emic lactone products in similar yields under these condi-
tions. For example, yields of 12% of racemic (Æ)-4o, 20%
of racemic (Æ)-4r, and 9% of racemic (Æ)-4t were isolated
by using the combination of DABCO and simple urea
BnNHC(O)NHTs. These results suggest that cinchona alka-
loid derivative 8d might be a bifunctional catalyst, in which
both the quinuclidine and urea groups are essential for the
halocyclization of enynes bearing the less reactive benzoic
acid nucleophile.
enynes, bearing a substituted benzoic acid.[a,b]
Entry
1
Substrate 2
Yield
[%]
ee
[%]
44 (79)[c]
97
2
3
4
2m, R2 =OMe
2n, R2 =Cl
0
72
74
–
98
99
2o, R2 =CF3
The relative stereochemistry of all bromoallenyl lactones
was assigned based on our previous study.[20] The absolute
stereochemistry of the bromoallene motif could be assigned
based on Loweꢀs rule for allenes.[25] The X-ray structure of
lactone 4n further confirmed the assignment of both the rel-
ative and absolute stereochemistry of the bromoallenyl lac-
tone product.[26]
In addition to six- and seven-membered lactones, we also
studied the formation of five-membered lactone 4u. Un-
fortunately, only 47% ee was observed for the bromolactoni-
zation of (Z)-1,3-enyne 2u under the standard conditions
[Eq. (6)].
5
6
7
8
68
85
80
88
97
94
97
95
9
76
98
During our initial study, we obtained nearly racemic prod-
ucts from the cinchonidine-mediated bromolactonization of
(E)-1,3-enyne 1a [Eq. (2)]. With catalyst 8d in hand, we re-
examined the enantioselective bromolactonization of (E)-
enyne 1a. Only 37% ee, however, was observed for the bro-
moallenyl lactone product 3a under the standard conditions.
Surprisingly, 70% ee was obtained for (E)-enyne 1b under
the same conditions [Eq. (7)]. Although complete conver-
sion was achieved for enyne 1a, only 33% conversion could
be reached after 12 h for enyne 1b. Low or no conversion
was observed for enyne 1b when DABCO or simple urea
BnNHC(O)NHTs was used alone. About 30% conversion
[a] Reaction conditions: NBS (120 mol%) was added to a solution of 2
and 8d (20 mol%) in ClCH2CH2Cl and the solution was stirred at RT for
0.5–10 h. [b] The d.r. values of product 4 were over 20:1. [c] The yield of
79% is based on recovered starting material.
withdrawing groups improved the conversion and still re-
tained the high enantioselectivity, with ee values up to 99%
(Table 3, entries 3–9). Ketone and nitro groups could be tol-
erated under the bromolactonization conditions (Table 3,
entries 5 and 7–9). The ortho-substituent in substrates 2q
and 2s did not interfere with the efficiency and enantiose-
lectivity of the bromolactonization (Table 3, entries 6 and 8).
For most substrates with an aliphatic carboxylic acid, the
bromolactonization was completed in about 0.5 h by using
either DABCO or urea 8d as the catalyst. In some cases
was obtained when
a
mixture DABCO and urea
BnNHC(O)NHTs was employed as the catalyst for substrate
1b. We were unable to improve both the ee and conversion
for this type of substrate under various conditions.
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Enantioselective Halolactonization
FULL PAPER
the halogenation reagent should have a minimal impact on
the enantioselectivity if adduct 8d-Br was responsible for
the selectivity. Hydrogen-bond activation of NBS or TBCO
by chiral catalyst 8d, shown in Scheme 2, may explain the
dramatically different enantioselectivity we observed in
Table 4. In the case of NBS, the distance between the chiral
catalyst and the enyne substrate was relatively small. The
catalyst was placed far away from the enyne substrate when
TBCO was employed as the halogenation reagent. The
structures of DBDMH and NBP are similar to that of NBS
and similar ee values were therefore observed. The sulfona-
mide part of NBSa clearly had a detrimental effect on the
enantioselectivity.
We also premixed NBS and catalyst 8d (20 mol%) in
ClCH2CH2Cl and stirred for 20 min before the addition of
enyne 2a to encourage the formation of adduct 8d-Br. We
found that the ee value of product 4a dropped to 54%
under these conditions. A longer premixing time (4 h) fur-
ther reduced the selectivity to 26% ee. These results indicate
that the reaction between NBS and catalyst 8d might occur
in the absence of the substrate but appears to be an unde-
sired pathway. No change in ee was observed when the cata-
lyst was premixed with the substrate before the addition of
NBS. Activation of NBS by catalyst 8d through hydrogen
bonding is consistent with these results. Our data in
Scheme 1 also suggest that the free OH and urea groups at
the C9 position in the cinchona alkaloid are likely to be a hy-
drogen-bond donor.
We also examined the effect of the halogenation reagent
on the enantioselectivity. We observed significantly different
ee values when the halogenation reagent was changed from
NBS to tetrabromocyclohexadienone (TBCO), as shown in
Table 4, entries 1 and 2. Slightly different enantioselectivity
was obtained when NBS was replaced by unsymmetrical di-
bromodimethylhydantoin (DBDMH) or bulky N-bromoph-
thalimide (NBP), as shown in Table 4, entries 3 and 4. NBS
was chosen over NBP mainly because it was easier to
remove the succinimide than the phthalimide byproduct.
The nearly racemic lactone was isolated when N-bromosac-
charin (NBSa) was employed as the brominating reagent
(Table 4, entry 5).
Table 4. The enantioselective bromolactonization of (Z)-1,3-enyne 2a
with different brominating reagents.[a]
Based on previous NMR and computational investigations
on cinchona alkaloid catalyzed reactions,[28] we proposed
a working model for the enantioselective 1,4-syn-bromolac-
tonization of (Z)-1,3-enynes, as shown in Scheme 3.[24] The
Entry
Bromination reagent
Catalyst
Yield
[%]
ee
[%]
1
2
3
4
5
NBS
8d
8d
8d
8d
8d
72
60
37
–
89
35
83
91
4
TBCO
DBDMH
NBP
NBSa
34
[a] Reaction conditions: The bromination reagent (120 mol%) was added
to a solution of 2a and 8d (20 mol%) in ClCH2CH2Cl and the solution
was stirred at RT for 0.5 h. The d.r. values of product 4a were over 20:1.
Prior to our study, it was proposed that halogenation re-
agents could be activated by chiral nucleophilic promoters[4]
or Lewis acids.[27] For catalyst 8d, either the quinuclidine ni-
trogen or urea group might activate NBS through formation
of a new electrophilic brominating species 8d-Br or through
hydrogen bonding, respectively (Scheme 2). The structure of
Scheme 3. A working model for bromolactonization of (Z)-1,3-enynes
mediated by catalyst 8d.
carboxylic acid of the substrate was deprotonated by the
quinuclidine nitrogen of catalyst 8d to form an ion pair
under the reaction conditions. The high syn diastereoselec-
tivity could be the result of ionic interactions between the
negatively charged carboxylate and the positively charged
catalyst, which was associated with NBS through hydrogen
bonds. Catalyst 8d serves as a bifunctional catalyst by inter-
acting with both the carboxylate nucleophile and the NBS
electrophile. The configuration of the product derived from
this model was consistent with the isolated major enantio-
mer.
Scheme 2. Possible activation modes for the 8d-catalyzed enantioselec-
tive bromolactonization.
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W. Tang et al.
After the development of catalyst 8d for the enantioselec-
tive halolactonization of 1,3-enynes, we then tried to extend
the scope of the reaction with respect to the substrate from
enynes to simple alkenes. Prior to our investigation, it was
reported that halolactonization of 4-arylpent-4-enoic acids
affords the highest enantioselectivity (83% ee).[11] Thus, we
examined the halolactonization of alkene 9a mediated by
catalyst 8d [Eq. (8)]. Unfortunately, nearly racemic chloro-
and bromolactonization products (10a and 11a) were ob-
tained.
Scheme 5. Screening of catalysts for enantioselective chlorolactonization
of alkene 9a.
quinine with different nitrobenzoic acids, reduction of the
nitro group to the amine, and formation of urea with tosyli-
socyanate. We then studied the above catalysts for the enan-
tioselective chlorolactonization of 1,1-disubstituted alkene
9a by using 1,3-dichloro-5,5-dimethylhydantoin (DCDMH)
as the halogen source and dichloroethane (DCE) as the sol-
vent [Eq. (9)]. Although the enantioselectivity was low for
all catalysts, it appeared that the length of the linker corre-
lated with the ee. Catalyst 12c with a para-substituted ben-
zoate linker provided a higher ee than catalysts with shorter
or longer linkers. Catalysts 12e, 12 f, and 12g with flexible
linkers gave lower selectivity than catalyst 12c. The ee of
product 10a was improved from 30 to 55% by using catalyst
12h.
The above result was not a surprise to us considering the
completely different mode of addition in the halolactoniza-
tion of 1,3-enynes than in simple alkenes (Scheme 4). Based
on the model that we proposed for enantioselective 1,4-syn-
halolactonization of 1,3-enynes mediated by catalyst 8, we
Scheme 4. Bifunctional chiral catalysts for 1,4-syn addition to 1,3-enynes
and 1,2-anti addition to alkenes.
In our previous enantioselective 1,4-bromolactonization
reaction, urea catalyst 8b, containing a tosyl group, was
a slightly better catalyst than 8a, containing the more com-
envisioned that catalyst 12, with an appropriate linker be-
tween the quinuclidine and urea groups, might be able to ac-
commodate the anti-orientation of halogenation reagent X
and carboxylate nucleophile Y during their addition to
simple alkenes (Scheme 4). Despite extensive investigations
into (thio)urea catalysts derived from cinchona alkaloids,
the (thio)urea group was, in most cases, placed either at the
C9 position,[24] as shown in 8, or at the C6’ position[29] of the
aromatic quinoline ring.[30] Catalysts having a linker between
the C9 position of the quinuclidine skeleton and the (thio)-
urea group would represent a new class of bifunctional cata-
lysts.[31]
monly
used
3,5-bistrifluoromethylbenzene
group
(Scheme 1). We were surprised that dramatically different
results were observed for the 1,2-chlorolactonization of
olefin 9a (catalysts 12c vs. 12i and 12h vs. 12k). The poor
result obtained from thiourea catalyst 12j was consistent
with our previous observations (Scheme 1).
We examined the chlorolactonization of 1,1-disubstituted
alkene 13 and 1,2-disubstituted alkene 15 [Eqs. (10) and
(11), respectively] for the formation of six-membered lac-
To maintain the rigid scaffold of the catalyst, we decided
to first examine benzoate linkers. Catalysts 12a–12d
(Scheme 5) were prepared in three steps—esterification of
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Enantioselective Halolactonization
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results (Table 5, entries 18 vs. 21). Although the exact
reason for this observation is not clear, all of our data sug-
gest that tosyl ureas should be examined in addition to the
commonly used aryl ureas for asymmetric catalysis involving
hydrogen-bond activation.[23] It is also worth mentioning
that catalyst 12h worked well at room temperature whereas
previous enantioselective halolactonizations were generally
performed at À40 to À808C.[13,15–17]
tones. Completely racemic products 14 and 16, however,
were obtained.
We then focused on optimizing the enantioselective halo-
lactonization of substrate 9a under different conditions by
varying the solvent, temperature, and catalyst loading
(Table 5). The highest enantioselectivity by using a single
We examined the effect of halogenation reagents on the
halolactonization of 9a in the presence of catalyst 12h
(20 mol%) in CHCl3/PhMe (1:1) at room temperature.[32]
The ee dropped from 89 to 83% when DCDMH was re-
placed with NCS. Less than 15% ee values were observed
for both the bromolactonization and iodolactonization of
substrate 9a by using NBS and NIS as the halogenation re-
agent, respectively.
Table 5. Screening of reaction conditions for the enantioselective chloro-
lactonization of substrate 9a.[a]
With the optimized conditions in hand, we studied the
scope of the enantioselective chlorolactonization of alkene 9
[Eq. (12)]. Good yields and ee values were obtained for
a number of aryl substituted olefins (Table 6). Among the
para-halogen-substituted styrenes, higher enantioselectivity
was observed for the substrates containing the more elec-
tron-withdrawing group (Table 6, entries 2–4). This was
a general trend for several other substrates with para- or
meta-substituents (Table 6, entries 5–8). Substrate 9i with an
ortho-fluoro substituent was less successful than its para
counterpart 9b (Table 6, entries 9 vs. 2). When the R group
was a simple alkyl group or an electron-rich aromatic group,
the enantioselectivity dropped significantly (Table 6, en-
tries 10 and 11). Similar limitations were also observed in
previous enantioselective chlorolactonization reactions.[13]
The absolute stereochemistry of product 10 was determined
by comparing the optical rotations of known compounds.[13]
The enantioselective chlorolactonization of substrates 9a,
9b, 9c, and 9g was also studied by Borhanꢀs group by using
(DHQD)2PHAL as the catalyst. The ee for these substrates
ranged from 80–89%.[13] For catalyst (DHQD)2PHAL, the
two cinchona alkaloids are linked by a phthalazine ring at
the 1,4-position. The distance between the two cinchona al-
kaloid units in catalyst (DHQD)2PHAL is similar to that in
catalyst 12h. Borhanꢀs group proposed that protonated
(DHQD)2PHAL served as a hydrogen-bond donor to acti-
vate the halogenation reagent. It is possible that the urea
moiety in catalyst 12h has the same function as one proton-
ated cinchona alkaloid unit in (DHQD)2PHAL.
Entry
Solvents
T
[8C]
Catalyst
([mol%])
ee
[%]
G
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
DCE
CHCl3
CHCl3
toluene
THF
CF3CH2OH
CH3CN
CH2Cl2
CH2Cl2/PhMe (1:1)
DCE/PhMe (1:1)
CHCl3/PhMe (1:1)
CHCl3/PhMe (2:1)
CHCl3/PhMe (1:2)
CHCl3/PhMe (1:3)
CHCl3/hexane (1:2)
CHCl3/PhMe (1:1)
CHCl3/PhMe (1:1)
CHCl3/PhMe (1:1)
CHCl3/PhMe (1:1)
CHCl3/PhMe (1:1)
CHCl3/PhMe (1:1)
RT
RT
0
12h (20)
12h (20)
12h (20)
12h (20)
12h (20)
12h (20)
12h (20)
12h (20)
12h (20)
12h (20)
12h (20)
12h (20)
12h (20)
12h (20)
12h (20)
12h (20)
12h (20)
12h (5)
55
47
47
47
29
À8
27
51
85
80
86
83
85
82
70
86
80
91
89
80
0
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
À20
À40
RT
RT
RT
RT
12h (1)
12h (0.1)
12k (5)
[a] Reaction conditions: DCDMH (110 mol%) was added to a solution
of 9a and 12h or 12k (20 mol%) in a given solvent and the solution was
stirred at the indicated temperature until completion.
solvent was obtained in DCE (Table 5, entries 1–8). During
our investigations, several enantioselective halolactoniza-
tions of 1,1-disubstituted alkenes were reported by other
groups.[13,15–17] Binary solvents were found to be beneficial or
even critical in several systems.[13,16] The ee values were
indeed improved dramatically when we used a mixture of
two solvents (Table 5, entries 9–15). The highest selectivity
was obtained by using a mixture of chloroform and toluene
in a volume ratio of 1:1 (Table 5, entry 11) at room tempera-
ture. Lowering the temperature did not improve the enan-
tioselectivity (Table 5, entries 16 and 17). However, lowering
the catalyst loading slightly improved the selectivity
(Table 5, entries 18 and 19). Even at 0.1 mol% catalyst load-
ing, we still observed 80% ee for product 10a (Table 5,
entry 20).
The enantioselectivity of the 1,4-bromolactonization of
1,3-enynes dropped significantly when the halogenation re-
agent and catalyst were premixed before the addition of
enyne substrate. Similar results were observed for the cata-
lyst-12h-mediated chlorolactonization of alkenes, suggesting
that the reaction between catalyst 12h and halogenation re-
agent DCDMH was not desired. The halogenation reagent
was likely activated by urea through hydrogen bonds for
enantioselective 1,2-chlorolactonization as well.
We also compared catalysts 12h and 12k under the opti-
mized conditions and again observed dramatically different
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Table 6. Scope of the enantioselective chlorolactonization of 1,1-disubsti-
tuted alkenes.[a,b]
have presented here may provide insights for further ad-
vancing this important class of reactions. The halocyclization
methods that we have developed may be applied to the syn-
thesis of halogen-containing synthetic intermediates or halo-
gen-containing natural products directly.[1,21]
Entry
1
Substrate
Yield
[%][b]
ee
[%]
Experimental Section
Procedure for the preparation of catalyst 8d [Eq. (13)]: A solution of 4-
methylbenzenesulfonyl isocyanate (1.84 g, 6.8 mmol) in dry toluene
(10 mL) was slowly added to a solution of known amine S1[24] (2.20 g,
92
91
2
3
4
5
6
7
9b, R1 =F
99
92
95
87
76
92
87
84
80
85
82
75
9c, R1 =Cl
9d, R1 =Br
9e, R1 =CH3C(O)
9 f, R1 =BnOCH2
9g, R1 =CH3
6.8 mmol) in dry toluene (20 mL) at room temperature. The mixture was
stirred overnight, and the solvent was removed under vacuum. The resi-
due was purified by column chromatography on silica gel (hexane/ace-
tone/triethylamine=40:20:1 as eluent) to afford urea 8d (3.30 g, 81%) as
an off-white amorphous solid. [a]2D5 =À15.8 (c=1.0 in CHCl3); 1H NMR
(400 MHz, CDCl3, TMS): d=0.95–0.99 (m, 1H), 1.72–1.89 (m, 4H), 2.19–
2.33 (m, 3H), 2.48–2.58 (m, 1H), 2.98–3.04 (m, 2H), 3.56–3.68 (m, 2H),
3.96–4.04 (m, 1H), 4.37–4.41 (m, 1H), 5.00–5.12 (m, 2H), 5.45–5.72 (m,
4H), 6.96–7.04 (m, 2H), 7.22–7.40 (m, 2H), 7.48–7.62 (m, 3H), 7.94–8.00
(m, 1H), 8.53–8.64 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=21.5,
24.8, 25.5, 27.0, 37.1, 41.8, 53.3, 53.7, 55.9, 56.3, 59.1, 102.2, 117.0, 122.4,
126.4, 128.5, 129.0, 131.5, 137.8, 141.2, 141.8, 142.8, 144.7, 147.6, 158.9,
160.2 ppm; IR: n˜ =3300, 2945, 1621, 1594, 1509, 1243, 1128 cmÀ1; HRMS
(ESI) calcd for C28H32N4O4SNa: 521.2218 [M+23]; found: 521.2215.
8
9
83
80
83
73
10
11
85
90
39
16
Procedure for the preparation of catalyst 12h [Eqs. (14) and (15)]: Et3N
(1.2 mL) and para-nitrobenzoyl chloride (0.92 g, 5.8 mmol) was added to
a solution of commercially available dihydroquinine hydrochloride S2
[a] Reaction conditions: DCDMH (110 mol%) was added to a solution
of 9 and 12h (5 mol%) in CHCl3/PhMe (1:1) and the solution was stirred
at RT until completion. [b] All yields are isolated yields.
Conclusion
We have developed two novel cinchona urea catalysts, 8d
and 12h, and demonstrated their utility in the enantioselec-
tive halolactonization of (Z)-1,3-enynes and 1,1-disubstitut-
ed olefins, respectively. The modular scaffold of these cata-
lysts should provide easy access to many new bifunctional
catalysts for enantioselective halocyclizations and other
(1.79 g, 4.9 mmol) in CH2Cl2 (50 mL) at 08C. The mixture was stirred at
room temperature overnight. Solvent was removed under vacuum. A so-
lution of 1m aqueous NaOH (50 mL) was added and the mixture was ex-
tracted with EtOAc three times and dried over MgSO4. The crude prod-
uct was used directly in the next step without further purification. A solu-
tion of the crude product in EtOH (30 mL) was heated to 708C. SnCl2
(1.12 g) was added to the above solution and it was stirred for 1 h. The
mixture was poured onto ice and quenched with saturated aqueous
NaHCO3 to adjust the pH to 7.0. The mixture was extracted with EtOAc
and dried over MgSO4. The product was purified by flash column chro-
matography by using EtOAc as the eluent to yield intermediate S3
(1.68 g, 72%). A solution of TsNCO (0.663 g, 3.5 mmol) in THF (10 mL)
ACHTUNGTRENNUNG(thio)urea-promoted reactions. We also found for the first
time that tosyl urea 12h worked significantly better than
conventional aryl urea 12k. This observation may have
broad implications in chiral urea-mediated reactions. De-
spite the progress made by us and others in the area of
enantioselective halolactonization, the scope of this reaction
is still very limited for each catalyst. The studies that we
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Enantioselective Halolactonization
FULL PAPER
was added dropwise to a solution of S3 (1.68 g, 3.5 mmol) in THF
(20 mL) and the mixture was stirred at room temperature overnight.
After removing the solvent under vacuum, the product was purified by
flash column chromatography with 20% methanol in EtOAc to afford
catalyst 12h (1.72 g, 76%).
Compound S3: [a]2D5 =À127 (c=1.0 in MeOH); 1HNMR (400 MHz,
CDCl3, TMS): d=0.88 (t, J=8 Hz, 3H), 1.24 (t, J=8 Hz, 1H), 1.41–1.57
(m. 2H), 1.72 (s, 1H), 1.88–1.93 (m. 1H), 2.03 (s, 1H), 2.69–2.93 (m, 4H),
3.38 (q, J=8 Hz, 1H), 3.94 (s, 3H), 4.08–4.14 (q, J=8 Hz, 1H), 4.35 (s,
2H), 6.58 (d, J=8 Hz, 2H), 6.70 (d, J=8 Hz, 1H), 7.34 (d, J=8 Hz, 1H),
7.52 (s, 1H), 7.88 (d, J=8 Hz, 2H), 8.00 (d, J=12 Hz,1H), 8.70 ppm (d,
J=4 Hz, 1H); 13CNMR (100 MHz, CDCl3): d=166.0, 158.0, 151.9, 147.7,
144.9, 144.8, 132.0, 127.4, 122.1, 119.0, 118.8, 113.9, 101.8, 73.7, 60.6, 59.8,
55.8, 51.0, 50.2, 37.6, 27.5, 26.4, 25.6, 23.8, 14.4, 12.2 ppm; IR : n˜ =2360,
1705, 1603, 1025 cmÀ1; HRMS (ESI) calcd for C27H31N3O3 +H: 446.2438
[M+H]; found: 446.2460.
[2] For selected reviews on enantioselective halogenation, see: a) O. Ki-
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Compound 12h: [a]2D5 =À95 (c=0.25 in CHCl3); 1HNMR (500 MHz,
DMSO): d=0.95 (q, J=4 Hz, 3H), 1.26 (s, 1H), 1.60–1.74 (m, 2H), 1.91–
1.96 (m, 3H), 2.27 (s, 1H), 2.35 (s, 3H), 2.52 (s, 1H), 3.34–3.65 (m, 6H),
3.93 (m, 1H), 4.04 (s, 3H), 7.16 (s, 1H), 7.44 (s, 2H), 7.49 (d, J=8 Hz,
1H), 7.64 (d, J=8 Hz, 2H), 7.72–7.77 (m, 3H), 8.01 (d, J=8 Hz, 1H),
8.68 (d, J=4 Hz, 1H), 9.11 ppm (s, 1H); 13CNMR (125 MHz, DMSO):
d=164.4, 159.5, 158.8, 148.0, 147.8, 144.7, 144.0, 141.5, 140.6, 132.1, 130.8,
129.2, 127.0, 126.3, 123.0, 119.8, 118.8, 117.1, 102.5, 71.4, 58.2, 57.2, 51.5,
50.2, 35.1, 25.1, 24.5, 23.6, 21.6, 20.4, 12.2 ppm; IR: n˜ =1726, 1621, 1232,
1170, 769 cmÀ1
; HRMS (ESI) calcd for C35H38N4O6S+H: 643.2585
[M+Na]; found: 643.2594.
General procedure for bromolactionization of conjugated enynes: Cata-
lyst 8d (10.2 mg, 0.02 mmol) and NBS (21.4 mg, 0.12 mmol) were sequen-
tially added to a solution of acid 2 (0.1 mmol) in 1,2-dichloroethane, di-
rectly purchased from Fisher. The reaction mixture was stirred at RT
until the starting material had disappeared, as indicated by TLC. The re-
action mixture was concentrated under vacuum and purified directly by
flash column chromatography, eluting with ethyl acetate and hexanes.
General procedure for chlorolactonization of alkenes: Catalyst 12h
(3.3 mg, 0.005 mmol) and DCDMH (21.7 mg, 0.11 mmol) were sequen-
tially added to a solution of acid 9 (0.10 mmol) in CHCl3 and PhMe (1:1,
5 mL). The reaction mixture was stirred at RT until the starting material
had disappeared, as indicated by TLC. The reaction mixture was concen-
trated under vacuum and purified directly by flash column chromatogra-
phy, eluting with ethyl acetate and hexanes.
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Acknowledgements
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We thank the University of Wisconsin and the donors of the Petroleum
Research Fund (48092-G1) for funding. W.T. is grateful for a Young In-
vestigator Award from Amgen.
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Received: December 4, 2011
Revised: March 9, 2012
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Published online: && &&, 2012
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www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Enantioselective Halolactonization
FULL PAPER
Wearing a halo: New organocatalysts
have been developed for the enantio-
selective 1,4-syn-bromolactonization of
conjugated (Z)-1,3-enynes and the 1,2-
chlorolactonization of 1,1-disubstituted
alkenes (see scheme). Up to 99 and
91% ee values, respectively, were ach-
ieved for these two halolactonizations.
Organocatalysis
W. Zhang, N. Liu, C. M. Schienebeck,
K. Decloux, S. Zheng, J. B. Werness,
W. Tang* ....................... &&&& — &&&&
Catalytic Enantioselective Halolactoni-
zation of Enynes and Alkenes
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
11
&
ÞÞ
These are not the final page numbers!