A. Armstrong et al. / Tetrahedron Letters 54 (2013) 7004–7008
7005
catalyst loading to maintain good enantioselectivity.12 Notably,
Table 1
Initial screening of additive effect in (DHQD)2PHAL (1) catalyzed bromolactonization
the e.r. recorded by us (91:9) for this substrate giving c-lactone 3
is comparable to those reported by Yeung (95:5),4c Yeung
(95:5),4f Martin (86:14),4h and Kim (88:12)4l with bespoke catalyst
systems.
With the optimum conditions delineated13 for the
bromolactonization of 1,1-disubstituted alkene 2 with catalytic
(DHQD)2PHAL 1, we sought to examine their applicability to other
substrates 4–1414 (Table 2). In each case the catalytic asymmetric
bromolactonization reactions were run with and without benzoic
acid as additive.15
Asymmetric bromolactonization of homologous substrate 4
gave (S)-d-lactone 4a in 94:6 e.r. (entry 1), in a remarkable
improvement from 59:41 without added benzoic acid. This level
of enantioselectivity is directly comparable to that reported previ-
ously by Fujioka (94:6)4a and Yeung (96:4)4f for this substrate. 1,2-
c
Entrya
Additiveb
Additive pKa
Yield 3d (%)
e.r. 3e
1
2
3
4
5
6
7
8
9
—
—
92
96
92
86
94
94
93
93
96
95
89
95
63:37
67:33
50:50
50:50
70:30
79:21
80:20
83:17
83:17
80:20
84:16
91:9
CH3CO2H
CF3CO2H
4.76
0.23
2.83
3.37
4.14
3.44
3.55
3.69
4.20
3.65
4.20
HO2CCH2CO2H
4-MeOC6H4CO2H
4-FC6H4CO2H
4-NO2C6H4CO2H
4-NCC6H4CO2H
4-CF3C6H4CO2H
C6H5CO2H
Disubstituted Z-alkene 5 (entry 2) gave (S,S)-
lectively in 91:9 e.r., again with an improvement from 82:18 with-
out added benzoic acid. There is
single report4e on the
c-lactone 5a regiose-
10
11
12f
9-Anthroic acid
C6H5CO2H
a
asymmetric bromolactonization of Z-alkene 5 to bromolactone 5a
(97.5:3.5 e.r.), and the off-the-shelf combination of (DHQD)2PHAL
1 and benzoic acid compares not unfavorably. For 1,2-disubsti-
tuted E-alkene 6, a mixture of both endo 6a and exo 6b cyclization
adducts were formed, each in only moderate e.r. (entry 3), where
added benzoic acid was mildly detrimental for the former, and
mildly beneficial for the latter. In this case, the bespoke catalysts
of Yeung4d and Martin4h clearly outperform the (DHQD)2PHAL
(1)-benzoic acid system, where endo 6a was obtained regioselec-
tively in each case with reported e.r.s of 96:4 and 98:2, respec-
tively. However, we note that in the (DHQD)2PHAL (1)-benzoic
acid system, the endo:exo ratio and the e.r. for each adduct are
not constant throughout the course of the reaction.16 A control
reaction with resubmission of these products to the reaction con-
ditions showed that they did not interconvert nor undergo a
change in e.r. This implicates a change in catalyst performance as
the reaction proceeds as the concentration of acid substrate de-
creases. Trisubstituted alkene 7, underwent regioselective lacton-
a
Reaction conditions: 0.16 mmol 2, 1.0 equiv NBS, 10 mol% 1, 1:1 hexanes:CHCl3
(8 mL), [2]0 = 21 mM, 1 h, À20 °C.
b
100 mol% loading of additive.
Aqueous pKa values.
Isolated yield after column chromatography.
e.r. determined by chiral HPLC methods (see Supplementary data); the absolute
c
d
e
configuration of the major enantiomer was determined to be (S)-configured (see
main text).
f
Reaction performed in toluene as the solvent.
it was selected for our initial studies. We also selected NBS as the
electrophilic bromine source. In such an initial (DHQD)2PHAL (1)
catalyzed experiment, bromolactone
3 was rapidly produced
(<1 h) in excellent isolated yield and, in agreement with Borhan,
moderate% ee (Table 1, entry 1). The major enantiomer was found
to be (S)-configured by comparison of the sign and magnitude of its
optical rotation with the known (R)-(+)-enantiomer.4c Interest-
ingly, this stands in contrast to the (R)-configured chlorolactones
produced in Borhan’s study with the same substrate and catalyst.3
We then explored the addition of stoichiometric quantities of ali-
phatic and aromatic carboxylic acids to the bromolactonization
reactions. The addition of acetic acid (entry 2) had little effect on
the e.r., and addition of the stronger aliphatic acids, trifluoroacetic
(entry 3) and malonic acids (entry 4) returned essentially racemic
bromolactone 3. On the other hand, the use of aromatic carboxylic
acids as additives gave rise to significant and beneficial increases in
e.r. (entries 5–11). Here, electron- deficient benzoic acids perform
best (entries 6–9), but there is not a perfect correlation between
e.r. and pKa, and the use of benzoic acid itself (entry 10) as an addi-
tive provides similarly improved enantioselectivity. 9-Anthroic
acid (entry 11) was the most beneficial additive in terms of e.r.,
but in this case small quantities of inseparable 9-bromoanthra-
cene9 were generated in the reaction mixture, which complicated
subsequent e.r. HPLC analysis. For these reasons, inexpensive and
readily available benzoic acid was selected as an additive for fur-
ther study.
ization to give (S,S)-c-lactone 7a in 86:14 e.r., where in the
reaction without benzoic acid a similar level of asymmetric induc-
tion was observed (entry 4). The bromolactonization of the trisub-
stituted alkene 4,5-dimethylpent-4-enoic acid has also been
reported by Martin,4h giving a
c
-lactone also in 86:14 e.r. For tetra-
substituted alkene 8 - which has not previously been reported in
an asymmetric bromolactonization reaction—(S)- -lactone 8a
c
was formed exclusively, with a moderate level of asymmetric
induction, but no significant improvement was observed with
added benzoic acid (entry 5). To complete the substitution pattern
in this series, the bromolactonization of terminal alkene 9 was
explored. As for the tetrasubstituted substrate, an asymmetric
bromolactonization has not been reported for this substrate, and
in our system a moderate level of asymmetric induction was
observed, both with and without benzoic acid (entry 6).
For vinyl benzoic acid 11, bromolactonization without added
benzoic acid gave the exo cyclization adduct 11a exclusively, but
essentially as a racemate (entry 8). With added benzoic acid the
e.r. increased dramatically to 83:17 in favor of the (S)-configured
bromolactone, and this compares with a reported e.r. of 67:33 by
Yeung.4g The previously unreported bromolactonization of allyl
benzoic acid 12 shows a similar dramatic effect on addition of ben-
zoic acid (entry 9). The bromolactonization of stilbene carboxylic
acid 10 was also explored, where Yeung had reported an optimized
reaction to give endo 10a and exo 10b in a 2:1 ratio, with e.r.s of
86:14 and 90:10, respectively.4g With the (DHQD)2PHAL-benzoic
acid system (entry 7), the exo adduct 10b is instead preferred,
but the e.r. for each bromolactone is much reduced. Interestingly,
and as for substrate 6 (and evidently for the same reason), the
In a screen of reaction solvents, it was found that alcoholic
solvents were not suitable since they are competitively oxidized.
Solvents with lower dielectric constants gave higher enantioselec-
tivities,10 with toluene being the optimum solvent delivering
bromolactone
3
with an e.r. of 91:9 (Table 1, entry 12).11
Accordingly toluene became the solvent of choice, where a control
experiment with no catalyst demonstrated that there was no back-
ground bromolactonization. It was also established that in toluene
the e.r. was insensitive to initial substrate concentration, and that
ca. 100 mol% benzoic acid as additive should be used at 10 mol%