Journal of the American Chemical Society
Communication
Michael additions of various aryl acetic acid esters to α,β-
unsaturated aldehydes, thereby enabling selective synthesis of
all four product stereoisomers with two adjacent stereocenters.
To develop a stereodivergent Michael addition of a range of
aryl acetic acid esters including those that do not possess
highly acidic protons at the benzylic position, we wondered if a
chiral iminium electrophile could react with a chiral enolate
(an activated nucleophile) generated in situ from a reaction
with a chiral Lewis base catalyst and form a C−C bond.
Among various chiral Lewis bases, we considered benzote-
tramisole (BTM)14 that was reported to form C1-ammonium
enolates by reacting with acyl precursors such as aryl acetic
acid esters and react with high facial selectivity.15 In particular,
BTM has been shown to readily displace the aryloxide of ester
substrates bearing electron-deficient aryloxides, and this
aryloxide could rebound to the acyl group upon carbon−
carbon bond formation, thus regenerating a BTM catalyst; the
low nucleophilicity of such aryloxide would prevent the direct
reaction with electrophilic reaction partners.6g,7b,16 This
strategy has been successfully combined with transition metal
catalysis in synergistic catalytic reactions.6g,7b,16d−n However,
the chemical and kinetic compatibility of this catalytic cycle
with organocatalytic cycles such as a cycle leading to iminium
activation has remained unknown. Moreover, it has been
uncertain whether the reaction between chiral iminium and
enolate intermediates can accomplish stereodivergence,
because of the potential matched/mismatched interactions at
the transition state.
Table 1. Anti-Selective Synergistic Organocatalytic Michael
Additions: Effect of Reaction Parameters
a
entry
deviation from standard conditions
yield (%)
ee (%)
1
2
3
4
5
6
7
8
none
no (S)-N1
no (S)-BTM
83
<5
<5
83
<5
48
64
27
28
37
27
68
41
27
99
−
−
93
−
98
99
n.d.
n.d.
99
99
99
77
87
(S)-N2, instead of (S)-N1
(2S,5S)-N3, instead of (S)-N1
(S)-TM, instead of (S)-BTM
with 10% benzoic acid
4-NO2C6H4, instead of C6F5 of 1a
2,4,6-F3C6H2, instead of C6F5 of 1a
THF, instead of DCM
toluene, instead of DCM
0 °C, instead of −10 °C
rac-N1, instead of (S)-N1
9
10
11
12
13
14
rac-BTM, instead of (S)-BTM
a
1
Determined by H NMR analysis with 1,1,2,2-tetrachloroethane as
an internal standard. Only anti-diastereomer was observed in all cases.
To assess the synergistic stereoselective Michael additions,
we chose phenyl acetic acid pentafluorophenyl ester (1a) and
cinnamaldehyde (2a) as our model substrates. Upon exploring
various reaction parameters, we determined that the anti-
product 3aa can be obtained as a single diastereomer in 83%
yield with 99% ee in the presence of (S)-pyrrolidine N1 and
(S)-BTM as catalysts (Table 1, entry 1).17 No Michael
addition was observed in the absence of either of the catalysts
(entries 2 and 3). The reactions with other (S)-amine catalysts
or (S)-TM proceeded in lower yield or enantioselectivity
(entries 4−6). Whereas an acid cocatalyst is commonly used in
iminium activation,11 the acid additive was not necessary
(entry 7). The reactions produced low yields of 3aa when
varying the aryloxide leaving group of 2a (entries 8 and 9),
solvents (entries 10 and 11), or temperature (entry 12). The
coupling reaction with either of the racemic catalysts resulted in
inferior yield and enantioselectivity (entries 13 and 14);
notably, the product was obtained as a single diastereomer,
indicating that either chiral catalyst can control the relative
stereochemistry and that anti-selectivity is strongly favored.
The scope of aryl acetic acid esters that reacted with
cinnamaldehyde (2a) under our synergistic organocatalytic
conditions through the use of (R)-N1 and (R)-BTM as
catalysts is summarized in Table 2a; in most cases, the product
was obtained as a single anti-diastereomer with >99% ee. The
aryl group of the pentafluorophenyl esters can be para-
substituted (electron-rich: 3ba, 3ca/electron-poor: 3da, 3ea,
3fa), meta-substituted (3ga), or ortho-substituted (3ha) phenyl
rings, reacting with 2a to produce a single stereoisomer of 1,5-
aldehyde esters in generally high yields. The Michael additions
with esters bearing strong electron-withdrawing groups such as
2,4,5-trifluorophenyl or p-nitrophenyl moieties proceeded to
afford products 3ja and 3ka in good yields with high dr (24:1
and 18:1).18 Pentafluorophenyl esters bearing naphthyl or 2-
thienyl groups also underwent the additions in high yields with
complete selectivity (3la and 3ma).
Under our synergistic organocatalytic conditions, the
Michael additions of phenyl acetic acid pentafluorophenyl
ester (1a) to various β-aromatic α,β-unsaturated aldehydes
containing para-substituted phenyl groups or a 2-furyl ring
proceeded smoothly to furnish the corresponding 1,5-
dicarbonyl products as an anti-diastereomer in good yields
with 96−99% ee (Table 2b).
In addition, the C−C bond formation between β-methyl
substituted α,β-unsaturated aldehyde 2g and 1a occurred to
produce (R,S)-3ag with >99% ee and 7:1 dr but in 33% yield
(eq 1).19
To examine the stereodivergence of our synergistic organo-
catalytic process, we attempted the synthesis of a syn-
diastereomer of 3aa by altering the relative chirality of the
catalyst in the reaction of 1a with 2a (eq 2). Indeed, the syn-
product was afforded as a major diastereomer with 99% ee and
8:1 dr, indicating that the catalysts could govern the relative
stereochemistry of the process. However, the yield was only
74
J. Am. Chem. Soc. 2021, 143, 73−79
Kim, Byungjun
