.
Angewandte
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Table 1: Condition optimization.[a]
and material communities where enantiomerically enriched
b2-amino acids are used. Notably, the synthesis of b3-amino
acids from a-aryloxyacetaldehydes and aryl-aldehyde-
derived imines by NHC catalysis has been previously
reported by Scheidt and co-workers.[11]
Our reaction design is further illustrated in Figure 1c. The
deprotonation of the NHC pre-catalyst (NHC·HX) by base
can lead to two new catalysts, a free NHC (I) and a Brønsted
acid (base·HX; catalyst II). Under the co-activation of I and
II, the enal substrate 1 turns into an azolium enolate
intermediate (III), as previously reported by Bode and co-
workers[12a,b] and our group.[12c] Concurrently, promoted by
acid catalyst II, the N,O-acetal substrate 2[13] splits into the
formaldehyde-derived iminium ion IV and methanol. The
iminium ion IV behaves as an electrophilic substrate to
undergo a Mannich reaction with III, followed by trapping of
the resulting acyl azolium with the methanol molecule, which
was generated in the previous step, to release the NHC
catalyst and form the b2-amino ester in high optical purity.[14]
A more complete pathway is detailed in the Supporting
Information.
Notably, the combined use of NHC and either Lewis or
Brønsted acid catalysts have recently been described by the
groups of Scheidt,[15] Rovis,[16] You,[17] Xu,[18] Snyder,[19] Yao,[20]
as well as our own group.[21] In the previous studies, the acid
cocatalysts were used to improve the reaction yields or
selectivities. In particular, Rovis and co-workers reported an
enal homoenolate addition to a,b-unsaturated imines pro-
moted by an in situ generated acid cocatalyst.[16] In our
present study, the in situ generated Brønsted-acid co-catalyst
plays two critical roles: one is to switch the regioselectivity of
the enal substrate by forming III (Figure 1c) through proto-
nation of the b-carbon atom of the homoenolate intermediate
(see the Supporting Information).[12] The other is to catalyze
the formation of the formaldehyde-derived iminium ion (as
an electrophilic reactant) and methanol (as a nucleophilic
reactant) from the N,O-acetal substrate. Imines are important
nitrogen sources in organic synthesis.[22] However, imines (or
iminiums) derived from formaldehyde are challenging sub-
strates in asymmetric catalytic reactions because of the high
reactivities and thus difficult to control both the chemo- and
stereoselectivities.[23] Our approach offers mild, weakly acidic
conditions which allow controlled in situ generation of
a formaldehyde-derived iminium from its N,O-acetal precur-
sor for highly chemo- and enantioselecitve reactions.
Entry
NHC
Base
T [oC]
3a
e.r.[c]
3a’
Yield [%][b]
Yield [%][b]
1
2
3
4
5
6
7
8
A
B
C
A
A
A
A
A
A
A
A
A
NaOAc
NaOAc
NaOAc
DBU
DIPEA
Et3N
DMAP
K2CO3
Et3N
RT
RT
RT
RT
RT
RT
RT
RT
408C
408C
408C
408C
61
46
45
trace
76
77
67
50
76
95:5
91:9
86:14
n.d.
95:5
95:5
95:5
95:5
95:5
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
18
n.d.
n.d.
10
9
10
11[d]
12[e]
–
Et3N
Et3N
trace
68
63
n.d.
n.d.
n.d.
95:5
95:5
[a] Reaction conditions unless otherwise specified: 1a (0.2 mmol), 2
(0.1 mmol), NHC (0.02 mmol), base (0.02 mmol), CH2Cl2 (1 mL), RT,
24 h. [b] Yield of isolated product based on 2. [c] Enantiomeric ratio of
3a, determined by chiral-phase HPLC analysis. The absolute config-
uration of the major enantiomer was assigned by comparison with the
literature (see the Supporting Information). [d] 0.15 mmol of 1a was
used. [e] 0.1 mmol of 1a was used. DBU=1,8-diazabicycloundec-7-ene,
DIPEA=N,N-diisopropylethylamine, DMAP=4-timethylaminopyridine,
Mes=2,4,6-trimethylphenyl, n.d.=not determined.
formation, likely because DBU was not a suitable base to
promote the azolium enolate intermediate formation
(entry 4).[12a,b] Weaker organic bases such as DIPEA, Et3N,
and DMAP could effectively mediate this reaction, with Et3N
giving the best result in 77% yield and 95:5 e.r. (entries 5–7).
An inorganic base such as K2CO3 was also compatible with
this reaction, albeit furnishing the product in a lower yield
(entry 8). We next found that slightly raising the reaction
temperature to 408C could afford a cleaner reaction mixture
(with less side product 3a’ formed; entries 9 versus 6) which
was easier to handle technically, during product purification,
without sacrificing the product yield and e.r. value. The
reaction did not proceed without the addition of an external
base (entry 10). It appeared that the N,O-acetal substrate
itself is not a sufficient base. Decreasing the amount of the
enal substrate led to slightly lower yields (entries 11 and 12).
A major side reaction was self-redox conversion of 1a into the
hydrocinnamic acid methyl ester 3a’.[25]
Key results of our initial reaction optimization are
summarized in Table 1. The enal 1a and N,O-acetal 2 were
chosen as the model substrates to test the feasibility of this
proposed cooperative catalysis strategy. To our delight, when
the aminoindanol-derived triazolium salt A[12a] was used as an
NHC precatalyst and NaOAc was used as a base, the desired
b2-amino ester 3a was isolated in 61% yield and 95:5 e.r.
(Table 1, entry 1). Replacing A with the triazolium salt B[24a]
resulted in a decrease in yield and e.r. value (entry 2). The
phenylalanine-derived precatalyst C[24b] could also mediate
the reaction but with less satisfactory results (entry 3). We
then chose A, first developed by Bode and co-workers, for
further optimization of the reaction conditions. The use of
a strong organic base (DBU) led to nearly no product
With the optimal reaction conditions in hand (Table 1,
entry 9), we first established the generality of this reaction. As
shown in Table 2, a board range of enals exhibiting diverse
electronic and steric properties were explored.[26] The use of
cinnamaldehyde (1a) afforded the desired product 3a in 76%
yield and 95:5 e.r. Enals with electron-donating (4-Me and 4-
OMe) or electron-withdrawing groups (4-F, 4-Cl, and 4-Br)
2
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Angew. Chem. Int. Ed. 2015, 54, 1 – 6
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