Angewandte
Communications
Chemie
Table 1: Examination of reaction conditions.[a]
proceeds to afford the chiral biaryls 3 and 4 with excellent
enantioselectivities. A noteworthy feature of this reaction is
that the atroposelectivity of the products was completely
controlled by the choice in the hydroxyaniline derivative.
Whereas use of the o-hydroxyaniline derivatives furnished
chiral biaryls with excellent enantioselectivities in favor of the
R isomer, use of the m-hydroxyaniline derivative reversed the
atroposelectivity to furnish the S isomer of the biaryl in
a highly enantioselective manner.
We selected 1 as a substrate for three reasons (Figure 1):
1) ease of ring opening to form the biaryl imine 2; 2) high
affinity of the resulting 2 to chiral phosphoric acids (CPA);
Entry
Catalyst (X)
Yield [%]
ee [%][b]
1
2
3
4
5
6
2,4,6-(iPr)3C6H2 (6a)
9-anthryl (6b)
2,4-(CF3)2C6H3 (6c)
4-PhC6H4 (6d)
75
80
86
74
91
75
72
83
98
33
30
47
13
59
73
81
84
90
SiPh3 (6e)
Si(3-FC6H4)3 (6 f)
Si(3-FC6H4)3 (6 f)
Si(3-FC6H4)3 (6 f)
Si(3-FC6H4)3 (6 f)
7[c,d]
8[c,e]
9[c,e,f]
Figure 1. Three reasons for the substrate selection.
[a] Unless otherwise noted, all reactions were conducted with the lactol
5a (0.10 mmol), hydroxyaniline 8a (0.11 mmol), and Hantzsch ester 9a
(0.15 mmol) in the presence of 10 mol% 6 and 4ꢀ M.S. in toluene
(1.0 mL) at room temperature. [b] Enantiomeric ratio was determined by
HPLC analysis using a chiral stationary phase. [c] 5ꢀ M.S. was employed
instead of 4ꢀ M.S. [d] 0.01 M. [e] 0.005 M. [f] 2-Amino-5-(trifluorome-
thyl)phenol (8b) was employed instead of 8a. M.S.=molecular sieves.
and 3) ease of modification of the aromatic ring of the aniline
moiety, a feature which would strongly affect both reactivity
and enantioselectivity. The selection of the transformation
from 2 was also important to achieve the high selectivity. We
envisaged that the transfer hydrogenation was suited for this
purpose because of the high reliability of the chiral phospho-
ric acid catalysis.[15–17]
by X-ray crystallographic analysis (see the Supporting
Information).[18]
An initial trial was conducted under reductive amination
conditions starting with the lactol 5a, not 1a, for streamline
the screening of reaction conditions (catalysts and anilines):
a solution of 5a in toluene was treated with 1.1 equivalents of
o-hydroxyaniline (8a) and 1.5 equivalents of the Hantzsch
ester 9a in the presence of 4ꢀ M.S. and 10 mol% of
a phosphoric acid (Table 1). When TRIP (6a), which
showed excellent catalytic performance in the asymmetric
transfer hydrogenation of imines,[16,17] was employed, the
transfer hydrogenation reaction proceeded smoothly to
afford the biaryl 3aa in 75% yield with 33% ee (entry 1).
Catalysts bearing 9-anthryl groups (6b) and 2,4-(CF3)2C6H3
groups (6c) resulted in moderate selectivities (entries 2 and
3). The catalyst 6d, having biphenyl groups, was also
ineffective (entry 4). The catalyst 6e, having SiPh3 groups
gave the desired adduct in 91% yield with 59% ee (entry 5).
Motivated by the results, we examined the aryl moiety on the
silyl group in detail. Gratifyingly, the catalyst 6 f, bearing Si(3-
FC6H4)3 groups, gave 3aa with 73% ee (entry 6). Finally, we
found that the key to achieving satisfactory enantioselectivity
was the concentration of the reaction medium and the use of
modified o-hydroxyaniline. When the concentration of the
reaction medium was lowered from 0.1 to 0.01m, and further
to 0.005m, the selectivity was improved to 81 and 84% ee,
respectively (entries 7 and 8). Use of the CF3-substituted o-
hydroxyaniline derivative 8b further improved the selectivity
to give corresponding adduct 3ab in 98% yield with 90% ee
(entry 9). The absolute stereochemistry of 3a was determined
Then, we carried out the reaction with the initially
planned 1a [Eq. (1)]. When 1a was subjected to the reaction
conditions (same as entry 8 in Table 1), 3aa was obtained in
75% yield with 85% ee, which was almost identical to the
result when 5a was used as the substrate. Further examination
was therefore conducted with 5 as the starting material, from
a practical point of view.
Interestingly, excellent selectivity (93% ee) was also
achieved when the m-hydroxyaniline derivative 10 was used
in the presence of the hydrogenated binaphthyl-type phos-
phoric acid 7b (see Table 1). bearing 9-anthryl groups
(Scheme 3). The important feature here is that the adducts
3ab and 4a showed opposite signs in optical rotation values,
and implied that atroposelectivity was controlled by the
position of the hydroxy group of aniline. We confirmed the
reversal of the atroposelectivity by transforming the ana-
logues of 3 and 4 into a common compound (see the
Supporting Information for details).
2
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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