Asymmetric, organocatalytic bromolactonization of allenoic acids

Article abstract of DOI:10.1055/s-0034-1378278

Asymmetric, reagent-controlled bromolactonizations of allenoic acids have been achieved by using (DHQD)₂PHAL as catalyst. A range of substrates can be cyclized in good yields and moderate to good enantioselectivities under operationally simple conditions. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0034-1378278

LETTER
▌1701
lAettserymmetric, Organocatalytic Bromolactonization of Allenoic Acids
Bromolactonization of Allenoic Acids
Michael Wilking, Constantin G. Daniliuc, Ulrich Hennecke*
Westfälische Wilhelms-Universität Münster, Organisch-Chemisches Institut, Corrensstr. 40, 48149 Münster, Germany
Fax +49(251)8336523; E-mail: ulrich.hennecke@uni-muenster.de
Received: 04.04.2014; Accepted after revision: 12.05.2014
cated that organocatalysts such as (DHQD)2PHAL (1a)
probably bind to the carboxylic acid moiety of such a sub-
strate, activating this group for nucleophilic attack on a
cyclic halonium intermediate.8,12 If this interaction with
the carboxylic acid group is indeed key to highly enanti-
oselective halolactonizations of alkenoic and alkynoic ac-
ids, we assumed that allenoic acids might also be suitable
substrates for this catalyst.
Abstract: Asymmetric, reagent-controlled bromolactonizations of
allenoic acids have been achieved by using (DHQD)2PHAL as cat-
alyst. A range of substrates can be cyclized in good yields and mod-
erate to good enantioselectivities under operationally simple
conditions.
Key words: allenes, asymmetric synthesis, cyclization, electrophil-
ic addition, halogenation
Et
Et
Halocyclization reactions such as iodolactonization are
powerful synthetic transformations with widespread ap-
plication in natural product synthesis.1 Asymmetric ver-
sions have been developed for a range of halocyclizations2
including halolactonizations,3 cyclohaloetherifications,4
cyclohaloaminations5 and other halofunctionalization re-
actions.5e,6 These reactions can be distinguished by the nu-
cleophilic group that cyclizes onto the cyclic halonium ion
(haliranium ion) initially formed by the halogenation of
the C–C double bond of an alkene. The halogenation at
the C–C double bond is a general feature of these reac-
tions and only a few examples of asymmetric halocycliza-
tions onto other types of unsaturated C–C bonds are
known. Tang and co-workers reported asymmetric bro-
molactonizations onto 1,3-enynes catalyzed by an alka-
loid-based urea catalyst,7 whereas Hennecke and co-
workers described desymmetrizing bromolactonizations
on diynoic acids using the dimeric cinchona alkaloid-
based catalyst (DHQD)2PHAL (1a; Figure 1).8 Neverthe-
less, no asymmetric, organocatalytic halocyclizations
have yet been described on allenes.9 Highly diastereose-
lective, substrate-controlled halolactonizations of allenoic
acids have been reported by Ma and co-workers, who
showed that the planar chirality of an allene is efficiently
transferred during the halocyclization.10 Formal asymmet-
ric bromocyclizations of allenes were described by the
Toste group.11 They showed that the vinyl gold species re-
sulting from an enantioselective gold-induced allene cy-
clization can be trapped by using a brominating agent,
leading to the bromocyclization product. However, be-
cause no direct asymmetric, organocatalytic halolactoni-
zations of allenes are known, we set out to investigate this
reaction on allenoic acids.
N
N
O
O
Ar
H
H
MeO
OMe
N
N
Ph
N
N
N N
O
O
N
N
Ph
(DHQD)2PHAL
(DHQD)2AQN
(DHQD)2PYR
(DHQD)2PYDZ
1a
1b
1c
1d
Ph
Ph
MeO
OMe
N
NH
HN
S
H
N
O
N
H
N
N
OMe
Ph
Ph
N
HN
Ph
Ph
trisimidazoline
thiocarbamate
2
3
Figure 1 Organocatalysts for asymmetric halocyclizations
Consequently, we conducted initial cyclization experi-
ments by employing reaction conditions previously opti-
mized for diynoic acids (Table 1, entry 1). Under these
reaction conditions, the bromolactonization of 4a pro-
ceeded smoothly and only the 5-exo cyclization product
5a was obtained. The identity of this 5-exo cyclization
product was confirmed by its structure in the solid state
obtained from X-ray crystallography (Figure 2).13 Product
5a was formed under these reaction conditions with an en-
antiomeric ratio of 72:28. Subsequent experiments
showed that (DHQD)2PHAL was clearly the most selec-
tive catalyst for this transformation. Other organocatalysts
based on the dimeric cinchona alkloid scaffold (Figure 1
For our initial investigations, we chose the achiral allenoic
acid 4a as our model substrate (Table 1).10a Our recent re-
sults on the bromolactonization of diynoic acids had indi-
SYNLETT 2014, 25, 1701–1704
Advanced online publication: 24.06.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1378278; Art ID: st-2014-b0284-l
© Georg Thieme Verlag Stuttgart · New York

1702
M. Wilking et al.
LETTER
and Table 1, entries 2–4) or on other backbones (23c and
3;3b Table 1, entries 5 and 6) did not induce significant
enantioselectivities.
Table 1 Optimization of Asymmetric Bromolactonization of 4a
reagent (1.2 equiv)
Br
catalyst (10 mol%)
•
O
additive (1.0 equiv)
O
H
solvent
–30 °C, 2–15 h
O
HO
5a
4a
Entry Reagent
Cat. Additive Solventa
er
1
2
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
1a
1b
1c
1d
2
–
–
–
–
–
–
–
–
–
–
–
–
CHCl3–n-hexane
CHCl3–n-hexane
CHCl3–n-hexane
CHCl3–n-hexane
CHCl3–n-hexane
CHCl3–n-hexane
CHCl3
72:28
45:55
50:50
66:34
52:48
45:55
64:36
56:44
53:47
67:33
78:22
77:23
83:17
3
4
5
Figure 2 Crystal structure of lactone 5a
6
3
7
1a
1a
1a
1a
1a
1a
1a
A: DBDMH (1.2 equiv)
(DHQD)2PHAL 1a (10 mol%)
PhCO2H (1.0 equiv)
8
CH2Cl2
R2
R2
R1
R1
or
9
n-hexane
R2
•
B: NBS (1.2 equiv)
(DHQD)2PHAL 1a (10 mol%)
Br
R2
O
O
10
11
12
13
CHCl3–toluene
CHCl3–n-hexane
CHCl3–n-hexane
H
R1
5a–e
O
R1
CHCl3–n-hexane (1:1)
DBDMH
NBAc
HO
4a–e
–30 °C, 15 h
Br
DBDMH
PhCO2H CHCl3–n-hexane
Ph
Ph
O
O
Br
H
O
O
a Mixed solvent in 1:1 ratio.
Br
H
O
O
H
Me
Me
5a
5b
5c
With catalyst 1a identified as the most selective catalyst,
the reaction conditions were further optimized.14 A sol-
vent screen revealed that the initial solvent mixture of
chloroform and n-hexane (1:1) turned out to be optimal
(Table 1, entries 1 and 7–10). Chloroform alone led only
to an enantiomeric ratio of 64:36 and the use of dichloro-
methane or n-hexane gave almost racemic products.
When a mixture of chloroform and toluene was used, the
selectivity did not improve (67:33 er; entry 10). Further
experiments with different ratios of chloroform and hex-
ane in the solvent mixture showed no positive effect on
the enantioselectivity.14 However, the selectivity could be
improved by changing the brominating agent to 1,3-dibro-
mo-5,5-dimethylhydantoin (DBDMH). By using this
commercially available reagent the product was formed
with an enantiomeric ratio of 78:22 (entry 11). N-Bromo
acetamide was almost equally selective (77:23 er; entry
12). Finally, benzoic acid was added to the reaction,
which led to a further improvement in the enantiomeric
ratio to 83:17. This positive effect of benzoic acid as ad-
ditive in halolactonizations using catalyst 1a was previ-
ously described by Borhan and co-workers,3a and more
systematically studied by Braddock and co-workers in
bromolactonizations.15 In our case, the effect was small,
but significant.
A: 58% (83:17 er)
B: 65% (72:28 er)
A: 47% (74:26 er)
B: 58% (60:40 er)
A: 86% (73:27 er)
B: 86% (75:25 er)
Ph
Ph
Br
Me
Me
O
O
H
Br
O
O
H
5d
5e
A: 69% (60:40 er)
B: 45% (56:44 er)
A: 55% (61:39 er)
B: 72% (75:25 er)
Scheme 1 Reaction scope of the asymmetric bromolactonization of
allenoic acids 4a–e
With the optimized reaction conditions (conditions A) in
hand, the asymmetric bromolactonization of a range of al-
lenoic acids was studied (Scheme 1).16 Allenoic acid 4a
was cyclized to product 5a in 58% yield and with an se-
lectivity of 83:17 er. An allenoic acid with dimethyl sub-
stitution at the allene (4b) underwent bromolactonization
in moderate yield (47%) and moderate selectivity (74:26
er).17 Terminal allenes could also be cyclized; allenoic
acid 4c, with a terminal allene and a diphenyl substitution
at the 2-position, could be cyclized in good yield (86%)
and again moderate enantioselectivity (73:27 er). When
Synlett 2014, 25, 1701–1704
© Georg Thieme Verlag Stuttgart · New York

LETTER
Bromolactonization of Allenoic Acids
1703
the phenyl groups were replaced by methyl groups in different unsaturated C–C bonds. We chose to compare
compound 4d, cyclization proceeded with 69% yield and starting materials related to our desymmetrizing alkyne
low enantioselectivity (60:40 er). A special case proved to lactonizations to be able to include alkynes into the com-
be allenoic acid 4e, with a cyclohexyl substituent at the al- parison (Scheme 2). In general, the bromolactonizations
lene and diphenyl-substituents next to the carboxylic acid of starting materials 6a–c proceeded smoothly under reac-
group. When 4e was reacted under the optimized condi- tion conditions A as well as conditions B. No significant
tions for allenoic acids including benzoic acid as additive effect of the additive or halogenating agent on the stere-
(conditions A),16 the cyclization was somewhat sluggish, oselectivities of the reactions was observed. Dialkenoic
the yield moderate (55%), and the selectivity low (61:39 acid 6a underwent bromolactonization with excellent
er). Interestingly, however, when the cyclization condi- yield and moderate diastereoselectivity (3.5:1) as well as
tions for diynoic acids8 (conditions B)18 with NBS and enantioselectivity (75:25 er). The related diynoic acid 6b
without additive were used, the yield of product 5e im- also cyclized in excellent yield under both conditions. The
proved to 72% and the enantioselectivity was also signif- enantioselectivity was slightly higher without the addition
icantly higher (75:25 er). This result indicated that the use of benzoic acid (86:14 vs. 84:16 er), but the effect was
of the benzoic acid additive might not be advantageous for very small. The bromolactonization of the diallenoic acid
all substrates, which is an observation previously made by 6c also proceeded with good yields (83 and 86% yield, re-
Braddock and co-workers for the bromolactonization of spectively) and good diastereoselectivity (6:1 and 5:1, re-
alkenoic acids.15 Subsequently, all substrates were also spectively), however, the enantioselectivity was
treated under conditions B without the benzoic acid addi- surprisingly low and the major diastereomer was obtained
tive (and with NBS as brominating agent, Scheme 1).18 in almost racemic form (54:46 and 53:47 er, respectively).
Cyclizations under conditions B showed that the use of
Our results, taken together with many other reports from
DBDMH and the benzoic acid (conditions A) does not
the literature, show that the catalyst (DHQD)2PHAL is
lead to generally improved enantioselectivities. Whereas
relatively broadly applicable in halolactonization reac-
tions and provides moderate to high enantioselectivities
with many substrates. This now also includes allenoic ac-
ids, which undergo bromolactonization with moderate to
good enantioselectivities. The catalyst (DHQD)2PHAL
seems to accept a range of different unsaturated carbon–
carbon bonds, but high selectivities depend on the carbox-
the enantioselectivity on our model substrate 4a and alle-
noic acid 4b is higher using conditions A, the terminal al-
lenes 4c and 4d showed similar yields and selectivities
under both reaction conditions. Indeed, with substrate 4e,
as discussed above, the situation is reversed and the addi-
tive-free conditions are superior.
Overall, these results show that asymmetric, organocata- ylic acid functionality or related functional groups with a
lytic bromolactonizations of allenoic acids are possible similar pKa such as carboxylic acid amides and sulfon-
and proceed with moderate to good enantioselectivities. amides.
The results also show that the optimal reaction conditions
for each substrate might be different.
Acknowledgment
Financial support by the WWU Münster, the ‘Fonds der Chemi-
schen Industrie’ and the DFG (HE 6020/2-1) is gratefully acknow-
ledged.
A: DBDMH (1.2 equiv)
(DHQD)2PHAL 1 (10 mol%)
PhCO2H (1.0 equiv)
or
B: NBS (1.2 equiv)
(DHQD)2PHAL 1 (10 mol%)
O
O
Supporting Information for this article is available online
HO
•
O
at
http://www.thieme-connect.com/products/ejournals/journal/
CHCl3–n-hexane (1:1)
10.1055/s-00000083.SunogIpimrfiantoSuIpg
n
fonirtat
ori
–30 °C, 15 h
•
•
Br
6a–c
7a–c
References and Notes
O
O
O
O
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O
O
•
Br
Br
Br
7a
7b
7c
A: 99% [3.5:1 dr,
75:25 er (major)]
B: 99% [3.5:1 dr,
74:26 er (major)]
A: 98% (84:16 er)
B: 93% (86:14 er)
A: 83% [6:1 dr,
54:46 er (major)]
B: 86% [5:1 dr,
53:47 er (major)]
Scheme 2 Bromolactonizations of structurally related carboxylic ac-
ids 6a–c
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1701–1704

1704
M. Wilking et al.
LETTER
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(16) Enantioselective Halolactonization using 1,3-Dibromo-
5,5-dimethylhydantoin (DBDMH); General Procedure
(Conditions A): In a flame-dried Schlenk tube, the
corresponding carboxylic acid (0.300 mmol, 1.0 equiv),
benzoic acid (36.6 mg, 0.300 mmol, 1.0 equiv) and
(DHQD)2PHAL (23.4 mg. 30.0 μmol, 10 mol%) were
dissolved in anhydrous CHCl3/n-hexane (1:1, 6 mL), cooled
to –30 °C and stirred for 15 min. DBDMH (103 mg,
0.360 mmol, 1.2 equiv) was added and stirring was
continued at that temperature for 15 h. Sat. aq Na2S2O3 (6
mL) was added to the reaction mixture and the aqueous layer
was extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were dried over Na2SO4, filtered, and the
solvents were removed in vacuo. Purification by flash
chromatography afforded the desired cyclization product.
(17) The isolated yield of 5b was surprisingly low because full
conversion of the starting material was observed and no
detectable side products were formed (6-endo cyclization
product was not formed). The reason for the low mass
balance is unclear. Similar observations were made for 5d
and 5e.
(18) Enantioselective Halolactonization using N-
Bromosuccinimide (NBS; General Procedure
(Conditions B): In a flame-dried Schlenk tube, the
corresponding carboxylic acid (0.300 mmol, 1.0 equiv) and
(DHQD)2PHAL (23.4 mg. 30.0 μmol, 10 mol%) were
dissolved in anhydrous CHCl3/n hexane (1:1, 6 mL), cooled
to –30 °C and stirred for 15 min. NBS (64.1 mg,
0.360 mmol, 1.2 equiv) was added and stirring was
continued at that temperature for 15 h. Sat. aq Na2S2O3 (6
mL) was added to the reaction mixture and the aqueous layer
was extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were dried over Na2SO4, filtered, and the
solvents were removed in vacuo. Purification by flash
chromatography afforded the desired cyclization product.
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Synlett 2014, 25, 1701–1704
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