.
Angewandte
Communications
We envisioned that an enantioselective variant might be
available through a desymmetrization reaction[7,8] of 1,4-
dienes. Recently, gold-catalyzed enantioselective desymmet-
rization by nucleophilic addition to alkynes has been reported
either through differentiation of enantiotopic alkynes[9] or
nucleophiles.[10] In contrast, successful implementation of
a desymmetrization strategy to the tandem alkoxylation/3,3-
sigmatropic rearrangement reaction does not rely on enan-
tiocontrol of the nucleophilic addition because this step forms
achiral intermediate A. Rather, the proposed mechanism and
the chirality transfer experiment suggest that the catalysts
must exert influence over the sigmatropic rearrangement[11,12]
event and thus differentiate between enantiotopic transition
states B and B’ (Figure 2b) On the basis of this intriguing
possibility, herein we describe our efforts to develop a gold(I)-
catalyzed asymmetric tandem alkoxylation/Claisen rear-
rangement reaction enabled by a strategic desymmetrization
of 1,4-dienes (Figure 2b).
product, it also resulted in decreased enantioselectivity
(entries 4 and 5). Thus, DTBM-Segphos (L4) was chosen as
the ligand for further optimization. Various solvents were
screened (entries 6–9), revealing that nonpolar solvents such
as benzene gave the best results (1,3/3,3 = 17:1, > 95%
conversion, 85% ee).[14] Interestingly, when the reaction was
conducted in DCM, the opposite sense of enantioinduction
was obtained (entry 6). Other silver salts besides AgBF4 were
investigated and showed no improvement; however, we found
that an increased loading of AgBF4 (0.2 equiv) led to
improved regio- and enantioselectivity (entry 10). Addition-
ally, decreasing the reaction temperature and employing
a solvent mixture of toluene/benzene (4:1) afforded improved
enantioselectivity without loss of regioselectivity (entry 11).
Finally, when the reaction was run at À208C, the desired 3,3-
rearrangement product 5a was isolated in 89% yield and
93% ee (entry 12).
With the optimized conditions in hand, we next examined
the substrate scope of this reaction (Table 2). Phenyl groups
(R1 = Ar) with various substituents were investigated first.
Electron donating groups (Me, MeO) at para-, meta-, or
ortho-positions of the phenyl ring are well tolerated, affording
the desired products in good yield with high enantioselectivity
The 1,4-diene 4a was chosen as the model substrate
(Table 1). Sterically demanding ligands with various chiral
backbones were examined (entries 1–5).[13] Among them,
DTBM-Segphos (L4) gave the best performance, not only in
enantioselectivity but also in regioselectivity. Although the
less sterically hindered DM-Segphos ligand (L5) dramatically
diminished the formation of the undesired 1,3-rearrangement
Table 2: Scope of substrates.[a,b]
Table 1: Optimization of the reaction conditions.[a]
Entry
Product 5
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
5a (R1 =Ph)
89
90
92
87
94
88
89
81
90
90
89
86
60
93
95
90
92
95
96
86
84
93
93
80
60
93
5b (R1 =2-MeC6H4)
5c (R1 =4-MeC6H4)
5d (R1 =3-MeOC6H4)
5e (R1 =2-MeOC6H4)
5 f (R1 =4-MeOC6H4)
5g (R1 =2-FC6H4)
5h (R1 =2-ClC6H4)
5i (R1 =4-FC6H4)
5j (R1 =1-naphthyl)
5k (R1 =2-furyl)
Entry
L
Solvent
5a/5a’[b] Conv. [%][b] ee [%][c]
1
2
3
4
5
6
7
(R)-L1 toluene
(S)-L2 toluene
(R)-L3 toluene
(S)-L4 toluene
(S)-L5 toluene
(S)-L4 CH2Cl2
(S)-L4 CCl4
9:1
6:1
3:1
60
>95
>95
>95
>95
À27
48
À33
13:1
>20:1
3:1
82
70
>95
>95
À61
9
6:1
73
10
11
12
13[e]
8
(S)-L4 Et2O
8:1
>95
81
5l (R1 =Me)
9
(S)-L4 PhH
(S)-L4 PhH
17:1
19:1
20:1
14:1
>95
>95
85
88
91
93
10[d]
5m (R1 =tBu)
11[d,e] (S)-L4 PhH/toluene (5:1)
12[d,f] (S)-L4 PhH/toluene (1:2)
>95
>95(89)[g]
14
15
5n (R2 =CO2Bn)
5o (R2 =CO2Allyl)
85
90
86
91
16
5p (R3 =Allyl)
89
88
[a] Reaction conditions: 3 mol% gold catalyst, 6 mol% AgBF4,
0.05 mmol 4a, 20 mg 4 molecular sieves, 1 mL toluene, RT. [b] Ratio of
5a/5a’ and the conversion of 4a were determined by 1H NMR analysis of
the crude product. [c] Determined by chiral HPLC, the minus sign
indicates reversed absolute stereochemistry relative to optimized
results. [d] 20 mol% AgBF4 was used. [e] The reaction was conducted at
08C. [f] The reaction was conducted at À208C for 4 h. [g] Isolated yield is
given in parentheses.
[a] Reaction conditions: 3 mol% (S)-L4-(AuCl)2 catalyst, 20 mol%
AgBF4, 0.05 mmol substrate, 20 mg 4 molecular sieves, 1 mL toluene
and 0.5 mL benzene, at À208C for 4 h. [b] Unless noted, the regiose-
lectivity of [3,3]/[1,3]>12:1. [c] Yield of the isolated product. [d] Deter-
mined by chiral HPLC. [e] [1,3]-rearrangement product was also isolated
in 35% yield.
8530
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 8529 –8532