The group 16 donor atoms sulfur (S), selenium (Se) and tellurium (Te) act as Lewis
bases. The Lewis base catalyzed halogenation of organic substrates, in which an n–σ*
interaction between a Lewis base chalcogenide and a Lewis acidic halogen source leads
to an electrophilic halogen species, has been well documented in the literature.[1 ] Denmark et al. established a variety of chiral and achiral Lewis bases, such as
selenides and sulfides, for the activation of halogens.[2 ] In recent decades, various research groups have been involved in the development
of catalytic halocyclization reactions by utilizing chalcogenide-based catalysts.[3 ]
[4 ] In 2012, Yeung and co-workers reported the synthesis of medium-ring-sized seven-membered
bromolactones using a sulfur-based organocatalyst.[5 ] However, catalytic asymmetric halogenation of medium-sized rings has not yet been
explored. In contrast to the enantioselective halogenation of five- and six-membered
rings,[6 ] enantioenriched medium-sized halolactones are rare, despite their potential applications
in the synthesis of biologically relevant molecules.[7 ]
Sulfide-catalyzed electrophilic bromination of various substrates has been achieved.
Yeung and co-worker reported the triphenylphosphine sulfide catalyzed bromocyclization
of amides to afford oxazolidines and oxazines.[8 ] Similarly, Mukherjee and Tripathi described selective oxidation of secondary alcohols
with NBS using a thiourea derivative as the catalyst.[9 ] Moreover, Denmark and Burk accomplished the iodolactonization of alkenoic acids
with N -iodosuccinimide catalyzed by the Lewis base, n -Bu3 P=S.[3c ]
Numerous methodologies have been reported for the catalytic, enantioselective bromofunctionalization
of alkenes.[1d ]
[6c ]
[10 ] In 2010, Yeung et al. developed a thiocarbamate which acts as a Lewis base for the
enantioselective bromofunctionalization of alkenes. This sulfur-based catalyst has
been employed in the cyclization of various disubstituted alkenes to obtain enantioenriched
halolactones, 3-bromopyrrolidines, and 3,4-dihydroisocoumarins.[10h,11 ]
Our group has also been actively involved in selenium-catalyzed halocyclizations of
alkenoic acids, where selenium plays a vital role in the transformation.[12 ] Inspired by our recent development of the regioselective synthesis of medium-sized
bromo/iodolactones and bromooxepanes using a catalytic amount of a monoselenide (Scheme
[1a ]),[12b ] herein we present our results on the stereoinduction of normal- and medium-size
rings (Scheme [1b ]). Studies on catalytic, enantioselective, chalcogenide-catalyzed medium-sized halogenation
reactions are still lacking. Furthermore, the cyclization of linear-chain alkenoic
acids is not a favorable process due to enthalpic and entropic factors.[12b ] Substrates with an alkyl chain possess a high degree of flexibility that brings
a negative entropy change during intramolecular cyclization reactions.[13 ] Therefore, significant research is still required for the preparation of new chiral
Lewis bases and diverse structural analogues.
Scheme 1 Chalcogenide-catalyzed halogenation with formation of medium-sized rings
In continuation of our studies on organochalcogen chemistry,[12 ]
[14 ] we rationalized that the Lewis base sulfur would be able to activate a halogen for
the synthesis of highly strained, medium-sized rings. Thus, we have designed a range
of novel C
2 -symmetric sulfur-based chiral catalysts for the synthesis of enantioenriched bromolactones.
Initially, the bromolactonization of 4-phenyl-4-pentenoic acid (1a ) was carried out using 1.2 equivalents of NBS and 5 mol% of the chiral catalyst in
dichloromethane at –78 °C. We screened thiophene dicarboxylates such as (–)-menthol-based
cat 1 and found that it catalyzed the bromolactonization reaction, however, no enantioselectivity
was observed (Scheme [2 ]).
Scheme 2 Catalyst screening
Further, we attempted to incorporate a nitrogen-based chiral scaffold to make an effective
chiral catalyst and chose various cinchona alkaloid as skeletons. However, the resulting
catalysts, quinine cat 2 and cinchonine cat 3 (Scheme [2 ]), had no effect on the enantioselectivity and only racemic mixtures were obtained.
Surprisingly, changing the skeleton to dihydroquinine (DHQN) cat 4 (Scheme [2 ]) resulted in an enantioselectivity (ee) of 31%. To further improve the enantioselectivity,
we explored the impact of the ligand on the structure of the catalyst. Two sites in
the catalyst were tuned: (i) the ester and amide units, and (ii) the O -alkoxy substituents on the hydroquinine unit, which was accomplished by demethylation
followed by alkylation. The C
2 -symmetry of the scaffold also simplified the catalyst design and modification. Moreover,
different substituents have been introduced to tune the steric hindrance. The catalyst
was modified by demethylation using sodium ethylthiolate followed by incorporation
of different alkyl chains such as n -butyl, n -hexyl, tert -butyl, iso -butyl, 2-butane and 2-methylpropane[15 ] (Scheme [3 ]). Similarly, the azide formed from the O -mesylated derivative of DHQN followed by azide reduction and hydrolysis provided
9-amino-(9-deoxy)-epi -cinchona alkaloids (DHQN-NH2 ).[16 ] Thus, the alkoxy or amine derivative of the cinchona alkaloid was treated with 2,5-thiophenedicarbonyl
dichloride under basic conditions to afford catalysts cat 5 –9 and cat 10 –12 , respectively. These bifunctional sulfur-based catalysts were then subjected to the
asymmetric bromocyclization reaction.
Scheme 3 Synthesis of modified catalysts
Table 1 Optimization of the Reaction Conditionsa
Entry
Cat.
Solvent
Time (h)
Yield (%)b
ee (%)c
1
cat 5
CH2 Cl2
16
88
36
2
cat 5
toluene
20
75
15
3
cat 5
CHCl3
28
85
34
4
cat 5
hexane
30
80
45
5
cat 5
toluene/CH2 Cl2 (1:1)
35
87
38
6
cat 5
CHCl3 /toluene (1:1)
32
85
62
7
cat 5
CHCl3 /toluene (1:2)
10
81
44
8
cat 5
CHCl3 /hexane (1:1)
24
90
60
9
cat 5
CHCl3 /hexane (1:2)
31
97
83
10
cat 6
CHCl3 /hexane (1:2)
88
92
60
11
cat 7
CHCl3 /hexane (1:2)
68
87
55
12
cat 8
CHCl3 /hexane (1:2)
80
89
66
13
cat 9
CHCl3 /hexane (1:2)
50
92
45
14
cat 11
CHCl3 /hexane (1:2)
40
85
52
a All reactions were carried out with 1a (0.1 mmol), NBS (0.12 mmol) and the chiral catalyst (5 mol%) in 2 mL of solvent at
–78 °C in a 10 mL Schlenk tube under nitrogen. The reaction progress was monitored
by TLC.
b Yield of isolated 2a .
c Enantiopurity was determined by HPLC analysis using a ChiralPak IC-3 column.
When the reaction of 1a and NBS was conducted with C
2 -symmetric sulfur-based cat 5 (5 mol%) in dichloromethane (CH2 Cl2 ), the desired bromolactone 2a was obtained in 88% yield with poor enantioselectivity (36% ee) within 16 hours (Table
[1 ], entry 1). Next, various solvent systems were explored to improve the selectivity
of the reaction. We observed that among several solvents, including dichloromethane,
chloroform and toluene, the reaction in the less polar solvent hexane proceeded with
modest enantioselectivity (45% ee) (entries 2–4). On varying the polarity with mixed
solvent systems, CHCl3 /hexane (1:2) showed the highest efficiency with an optimum 83% ee being obtained
(entries 5–9). The nonpolar solvent mixture reduced the noncatalyzed reaction and
strengthened the polar interaction among the alkenoic acid, NBS, and the catalyst,
resulting in enhancement of the enantioselectivity. The hexyl substitution on the
quinolone moiety of thiophene dicarboxylate cat 6 , under the same conditions, gave a lower enantioselectivity (entry 10). Similarly,
reactions with cat 7 , cat 8 and cat 9 occurred with low enantioselectivity (entries 11–13). Furthermore, screening the
efficient isopinocampheylamine/cinchonine framework, endeavoring to increase the acidity
of the carboxylate in cat 10 –12 by replacement with an amide functional group, however, resulted in a racemic mixture
for cat 10 , moderate 52% ee for cat 11 (entry 14), and 43% ee for cat 12 , respectively. Also, the use of additives failed to improve the stereoselectivity.
Having optimized the catalyst and reaction conditions, we next investigated the substrate
scope. A broad range of 4-phenyl-4-pentenoic acids containing aromatic substituents
on the olefin was converted into the corresponding bromolactones with high yields
and good to moderate enantioselectivities (Figure [1 ]). In particular, better results were obtained with the substrates 1b and 1c having electron-rich methyl and methoxy groups at the para positions of the aromatic rings, with the lactones 2b and 2c being obtained with 82% and 66% ee, respectively. Electron-deficient fluoro-, chloro-,
and difluoro-substituted substrates 1d –f provided bromolactones 2d –f with good enantioselectivities (43–66%). The X-ray crystal structure of 4-fluorophenyl
γ-lactone 2d is shown in Figure [1 ]. Biphenyl-substituted alkenoic acid 1g provided bromolactone 2g with moderate selectivity (27% ee).
Figure 1 Scope of catalytic enantioselective halo/seleno lactonization
When N -iodosuccinimide (NIS) was used as the halogen source, γ-iodolactone 2h was formed with 31% enantiomeric excess. By utilizing this protocol, five-membered
selenolactone 2i
[17 ] was also prepared with 13% enantioselectivity and 62% yield. Furthermore, when 5-phenyl-5-hexanoic
acid was subjected to the bromocyclization with NBS in the presence of 5 mol% of chiral
catalyst 5 in CHCl3 /hexane (1:1) at –60 °C, the desired product 2aa was obtained with 34% ee.
Next, the synthesis of various seven-membered bromo- and iodolactones was explored
starting from the corresponding alkenoic acids (Figure [2 ]). Bromolactone 3a with a phenyl ring attached was obtained as a racemic mixture using the developed
protocol. Lactones 3b –i having an additional heteroatom in the chain were obtained in good to excellent yields
(22–82%) and moderate to low enantiomeric excesses, which can be attributed to the
reduction of transannular strain in the presence of the heteroatom. Electron-withdrawing
Cl and NO2 substituents on the aromatic rings yielded products 3d ,e with low enantioselectivities (<20%). Interestingly, electron-donating Me and OMe
substituents induced slightly higher enantioselectivities (>30%) in products 3f ,g . Polyaromatic bromolactone 3h containing a naphthyl ring was obtained with 14% ee.
Figure 2 Scope of the enantioselective formation of seven-membered bromo/iodolactones
We speculate that the halocyclization reaction proceeds through a rigid transition
state model, in which the olefin–olefin halogen exchange[18 ] and the transannular strain in the ring[13 ] could be suppressed through Lewis basic sulfur[1 ] or via hydrogen bond activation. The n -butyl moiety on the quinine scaffold leads to a pocket in which the carboxylic acid
of the substrate was deprotonated by the quinine nitrogen of cat 5 to form an ion pair (Scheme [4 ]). Cat 5 serves as a bifunctional catalyst by interacting with both the carboxylate nucleophile
and the NBS electrophile, facilitating 5-exo cyclization to form desired five- to seven-membered halolactones.
Scheme 4 Proposed working model
In conclusion, we have developed a novel C
2 -symmetric sulfur-based chiral catalyst for the enantioselective bromolactonization
of alkenoic acids.[19 ] This protocol allows for the asymmetric synthesis of γ-, δ- and ω-lactones and selenolactones.
Further mechanistic studies and investigations of this class of catalysts in another
asymmetric electrophilic cyclization reactions are underway.
