.
Angewandte
Communications
Table 1: Optimization of the reaction conditions.
NaCl and KCl, afforded lactone 3 with lower enantioselec-
tivity than with LiCl (entries 8 and 9), providing further
evidence that this effect was particular to lithium. However,
lithium tetrafluoroborate and lithium triflate did not produce
lactone 3 with levels of stereoinduction as high as those
achieved with lithium chloride (entries 10 and 11).[15] The data
currently support the need for both ions to obtain high levels
of enantioselectivity and that there is not an observable
increase in overall rate vs. reaction without Li+ (for example,
Table 1, entry 1 vs. entry 6). Further investigation of this
phenomenon is underway. Having established that lithium
chloride was the optimal Lewis acid additive, various chiral
NHCs were examined to enhance the diastereo- and enan-
tioselectivity of the reaction. Employing chiral azolium
catalysts B–E resulted in a wide range of diastereo- and
enantioselectivities, with the 2,6-diethylphenyl substituted
Entry Variation of the standard conditions Conv. [%][a] d.r.[a] ee [%][b]
1
2
3
4
5
6
no Lewis acid
99
99
99
99
99
99
1.1:1 34
1.5:1 35
1:1 52
1.8:1 70
2:1 77
2.5:1 90
1.2:1 35
1.2:1 53
1:1 47
Mg(OtBu)2 (50 mol%)
Ti(OiPr)4 (50 mol%)
LiCl (50 mol%)
LiCl (1 equiv)
LiCl (2 equiv)
7
LiCl (2 equiv), [12]crown-4 (4 equiv) 99
8
9
NaCl (2 equiv)
KCl (2 equiv)
LiBF4 (2 equiv)
LiOTf (2 equiv)
99
99
99
99
99
66
99
99
triazolium precatalyst
B being the catalyst of choice
10
11
12
13
14
15
16
1:1 62
(entries 12–15). We discovered that with only 5 mol%
catalyst B similar levels of conversion and selectivity were
obtained (entry 16).
With the optimized reaction conditions, we surveyed the
synthesis of lactones from isatins with varying nitrogen
protecting groups and substitution around the aromatic ring
(Scheme 1, 3–14). Both electron-withdrawing and electron-
donating substituents on the aromatic ring were well accom-
modated, providing the lactone products in 1.6–3.0:1 d.r. and
3.7:1 39
2.8:1 92
1.1:1 38
1.7:1 32
1.4:1 50
2.4:1 96
(+)-B, LiCl (2 equiv)
(ꢀ)-C, LiCl (2 equiv)
(ꢀ)-D, LiCl (2 equiv)
(ꢀ)-E, LiCl (2 equiv)
5mol% (+)-B, 10 mol% DBU, LiCl 99
(2 equiv)
[a] Determined by 1H NMR spectroscopy (500 MHz) of the unpurified
reaction. [b] Enantiomeric excess determined by HPLC analysis.
DBU=diazabicycloundecene, Mes=2,4,6-Me3C6H2.
ꢀ
86–99% ee. Notably, the isatin bearing an unsubstituted N H
group provides the desired product 7 in high ee and yield. A
slight decrease in enantioselectivity was observed in the case
of products derived from either an isatin bearing a p-
methoxyphenyl protecting group (5) or a 5-methoxy isatin
(13), which gave 87% and 86% ee, respectively. Interestingly,
the 6-bromo isatin delivered lactone 11 with exquisite
diastereoselectivity (20:1) and high enantioselectivity (90%).
Structural modification of the cinnamaldehyde compo-
nent was also explored (Scheme 1, 15–21). Both electron-
withdrawing and electron-donating groups were tolerated,
furnishing the desired lactones in good yields (81–93%) and
high enantioselectivities (91–98%). With enals bearing a b-
alkyl substituent, both the yields and the level of enantioin-
duction decreased significantly, as is typical with many NHC–
homoenolate reactions.[2] With 2-hexenal and crotonalde-
hyde, lactones 22 and 23 were obtained with good diastereo-
selectivity, but in modest yield (49% and 39%, respectively),
and low enantioselectivity (13% and 25% ee, respectively).
As a number of 3-hydroxy indole natural products contain
alkyl substituents, for example the maremycins (Figure 1), it
was necessary to re-examine conditions for the b-alkyl enals.
With the previously optimized conditions, lactone 23 was
obtained in 36% yield and 25% ee (Table 2, entry 1). The low
yield could be partially attributed to the unexpected forma-
tion of enal 24 through a g-alkylation pathway. An extensive
screen of solvents and Lewis base additives yielded no
improvement in efficiency, enantioselectivity, or suppression
of enal 24 (results not shown). Interestingly, when the
annulation reaction was carried out with catalyst A in the
absence of lithium chloride, lactone 23 was obtained in 76%
yield, with no observable amounts of 24, albeit with dimin-
ished levels of enantioselectivity. The increase in yield
diastereo- and enantioselectivity. Unfortunately, in the pres-
ence of 50 mol% of either Mg(OtBu)2 or Ti(OiPr)4, lactone 3
was obtained with only a modest increase in diastereoselec-
tivity or enantioselectivity, respectively (entries 2 and 3). No
significant improvement in stereoselectivity was observed
upon extensive variation of the reaction components, includ-
ing stoichiometry, temperature, solvent, and the nature of the
Lewis acid. We next turned our attention toward the use of
lithium chloride as a potential mild Lewis acid additive.[9]
Gratifyingly, the addition of 50 mol% lithium chloride
provided lactone 3 as an approximate 2:1 mixture of
diastereomers; more importantly, this result was associated
with an increase in enantioselectivity to 70% ee (entry 4). A
significant difference in both diastereo- and enantioselectivity
was observed by increasing the amount of lithium chloride
(entries 4–6). Two equivalents of LiCl proved optimal, and
lactone 3 was obtained in 2.5:1 d.r. and 90% ee (entry 6).
With these initial results, we next investigated this ion
effect on enantioselectivity.[14] The sequestration of the
lithium cation from the reaction mixture by addition of an
excess of [12]crown-4 delivered lactone 3 with diminished
diastereo- and enantioselectivity, which is similar to what was
observed when the reaction was run without a Lewis acid
(Table 1, entry 7). Other alkali metal chloride salts, such as
2
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
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