Angewandte
Chemie
estingly, in other cases, the pThr-peptides deliver a slightly
higher e.r. (substrate 6 f; see below).
substitution at the quinoline C2-position (6j-6k) led to
products with lower e.r. for reasons that are not fully
understood (Table 2, entries 19–20). Finally, exchange of the
urea for acetamide (6l) and carbamate (6m) resulted in
slower reaction rates but similar and even higher e.r.
compared to isostere 6a (Table 2, entries 21–22).The absolute
stereochemistry of the major product was determined explic-
itly for compound 7 f by X-ray crystallography.[17]
With catalyst 5e in hand, we turned our attention to
substrate scope, and the catalyst was found to function well
for substrates with variations at the 8-position (Table 2). For
example, benzylic ureas (6b–6 f) led to products with up to
92:8 e.r. at RT (Table 2, entries 3, 5, 7, 9, and 11), while
aliphatic ureas (6g–6i) are also tolerated (Table 2, entries 13,
15, 17). Lowering the temperature to 48C led to increases in
e.r. in many cases (e.g., 94:6 e.r.; Table 2, entries 4, 6, 8, and
10), although extended reaction times were generally
required. Parenthetically, in the case of 6 f, we observed that
the pThr peptide delivers a slightly higher e.r. than the (R)-
TRIP catalyst 2a (13:87 e.r. for 6 f over 24 h). Aliphatic
We have begun to study the possible mechanism of action
1
of the pThr-containing peptides by examining the H NMR
chemical shifts upon mixing peptide 5e with substrate 6b or
HEH (Figure 2a–d). On the one hand, these additives have
little effect on the shift of the i + 3 NHMet signal (Figure 2,
red). Since this resonance is characteristic of a 10-membered
ring intramolecular H-bond with
=
the pThr C O (a b-turn), the
Table 2: Substrate Scope.[a,b]
addition of the substrates may not
perturb this key catalyst secondary
structural feature. On the other
hand, the NHpThr signal (Figure 2,
yellow) appears to broaden signifi-
cantly and that of i + 2 NHAcpc
(Figure 2, orange) shifts downfield
in the presence of either 6b or
HEH, thus suggesting the forma-
tion of intermolecular interactions
(e.g, through H-bonding) between
the catalyst and substrates. Down-
field shifts are also observed for the
quinoline C7 (blue) and C4
(purple) proton signals, as well as
Entry
Substrate
R1
R2
t [h]
T
Conv.[c]
[%]
Yield[d]
[%]
e.r.[e]
1
2
24
51
RT
48C
99
92
92
86
82:18
82:18
6a
Me
3
4
24
51
RT
48C
97
86
84
82
91:9
94:6
6b
6c
6d
Me
Me
Me
5
6
24
51
RT
48C
99
86
76
79
90:10
94:6
7
8
24
51
RT
48C
96
88
74
81
92:8
94:6
À
for a quinoline urea N H signal.
These chemical shift perturbations
are consistent with salt formation
between 5e and 6b.[19] The down-
9
10
24
51
RT
48C
96
86
74
79
92:8
94:6
6e
Me
À
field shift of a quinoline C8 N H
11
12
24
51
RT
48C
99
86
79
70
90:10
93:7
6 f
Me
Me
signal (Figure 2, green) could also
be ascribed to an H-bond with 5e.
Further evidence for this H-bond
was revealed through the reduction
of 2-methylquinoline with 5e, since
the lack of directing group yields
product with only 58:42 e.r.. Taken
together, these observations sup-
port a reaction for which enantio-
selectivity derives from the forma-
tion of noncovalent interactions
between 6 and the b-turn peptide
catalyst 5e (Figure 2e).
13
14
30
51
RT
48C
92
92
79
86
86:14
90:10
6g
15
16
36
51
RT
48C
97
86
73
70
88:12
90:10
6h
6i
Me
Me
17
18
30
51
RT
48C
91
83
86
74
83:17
87:13
19
20
6j
iPr
24
24
RT
RT
94
97
71
84
77:23
6k
Cy
75:25[g]
21
22
6l
Me
Me
24
24
RT
RT
52
68
n/a[f]
n/a[f]
89:11
79:21
In conclusion, we report the
development of pThr-containing
peptides as a CPA scaffold. Strik-
ingly, this framework, which lacks
the C2-symmetry of better known
CPA scaffolds, is able to overcome
the existence of both non-equiva-
lent tautomeric states and the
many rotatable bonds extant
within the catalyst. It achieves this
6m
[a] Reported results are the average of two trials. [b] Conditions: 0.06 mmol 6, peptide 5e (10 mol%),
HEH (2.5 equiv), dichloromethane (0.05m with respect to 5e). [c] Conversion (conv.) was determined by
comparing the 1H NMR integrations of the quinoline aromatic peaks for the substrates and products.
[d] Yield of isolated product after column chromotography. [e] Enantiomeric ratios were determined by
HPLC using an OD-H column. [f] 6l and 6n co-eluted with oxidized Hantzsch ester pyridine (HEox) and
could not be isolated. [g] Enantiomeric ratios were determined by chiral HPLC using an AD-H column.
Angew. Chem. Int. Ed. 2015, 54, 11173 –11176
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