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Catalytic Kinetic Resolution of Spiro-epoxyoxindoles with 1-Naphthols: Switchable Asymmetric Tandem Dearomatization/oxa-Michael Reaction and Friedel-Crafts Alkylation of 1-Naphthols at C4-Position Gongming Zhu, Yiping Li, Guangjun Bao, Wangsheng Sun, Liwu Huang, Liang Hong, and Rui Wang ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b03268 • Publication Date (Web): 09 Jan 2018 Downloaded from http://pubs.acs.org on January 9, 2018
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ACS Catalysis
Catalytic Kinetic Resolution of SpiroSpiro-epoxyoxindoles with 11-Naphthols: Switchable Asymmetric Tandem Dearomatization/oxaDearomatization/oxa-Michael ReacReaction and FriedelFriedel-Crafts Alkylation of 11-Naphthols at C4C4-Position Gongming Zhu,†,# Yiping Li,‡,# Guangjun Bao,‡ Wangsheng Sun,*, ‡ Liwu Huang,† Liang Hong,*,† and Rui Wang*,‡ † School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. ‡ Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China. Keywords: asymmetric catalysis, dearomatization, Friedel-Crafts alkylation, kinetic resolution, 1-naphthols, spirooxindoles ABSTRACT: Switch the chemo- or regioselectivity from identical starting materials under readily tunable reaction conditions represents a great challenge in medicinal and synthetic organic chemistry. Herein, we report the asymmetric dearomatization/oxaMichael reaction and Friedel-Crafts alkylation of 1-naphthols at C4 position, wherein the chemoselectivity could be switched easily by using different reaction conditions without changing the catalyst and the substrates. The reactions feature the asymmetric Friedel-Crafts alkylation of 1-naphthols at C4 position and the asymmetric dearomatization without using specific substrates or the stepwise protocols.
The development of a simple and efficient strategy for the enantioselective synthesis of structurally and stereochemically diverse compounds with biologically relevant frameworks, is an important goal in modern medicinal and organic chemistry.1 To access structurally varied compounds, chemists have developed selective transformations of the same starting materials into two or more different products simply by tuning the choice of catalyst.2 However, the design and right choice of a suitable catalyst to vary products in an enantioselective manner is still considered to be difficult. An ideal but challenging strategy is to switch the chemo- or regioselectivity from identical starting materials and catalyst under readily tunable reaction conditions.
the Friedel-Crafts reaction at C4 position of 1-naphthol with quinone monoacetal.5 However, the asymmetric Friedel-Crafts reaction of 1-naphthols at C4 position has never been reported. On the other hand, the asymmetric dearomatization of phenols has recently evolved as an efficient method for the synthesis of chiral cyclohexadienones which could be used for further many transformations.6 Despite the progress in this area, the reported methods focused on the use of the specific 1-substituted 2-naphthol substrates7 or the stepwise protocols including the first oxidative dearomatization progress and the subsequent asymmetric reaction.8 The direct asymmetric dearomatization of 1-naphthols still remains elusive to date. To fill these deficiencies, herein we first present the asymmetric Friedel-Crafts alkylation and dearomatization of 1naphthols at C4 position, wherein the chemoselectivity could be switched easily by using different reaction conditions without changing the catalyst and the substrates.
Figure 1. Multisite Reactivity of 1-Naphthol.
Phenols are readily available starting materials and possess multiple reactive sites, which make them extremely versatile precursors for biologically active natural products and pharmaceuticals.3 In this context, the O-alkylation and the FriedelCrafts reaction at C2 position have been widely investigated,4 in contrast, the regioselective reaction at C4 position remains elusive (Figure 1). Just recently, Kita and co-workers reported
Scheme 1. Reactions of Spiro-epoxyoxindoles with 1Naphthols. Results and Discussion
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3,3’-Disubstituted oxindoles are frequently found in a wide range of bioactive natural products and pharmaceuticals.9 With the development of more practical methods to terminal spiroepoxyoxindoles,10 the ring-opening of spiro- epoxyoxindoles with nucleophiles has emerged as an attractive approach to 3,3’-disubstituted oxindoles.11 Hajra11a and Wei11b have disclosed that Lewis acid could catalyze the Friedel-Crafts reaction at C2 position of phenols with spiro-epoxyoxindoles (Scheme 1a). More recently, we have realized an efficient catalytic kinetic resolution of racemic spiro-epoxyoxindoles with the simultaneous enantioselective Friedel-Crafts alkylation of indoles.12 Intrigued by these work and our recent interests in the construction of oxindole derivatives,11d,12, 13 we first tested the reaction of 1-naphthol 2a with spiro-epoxyoxindole (rac)-1a in the presence of a chiral phosphoric acid catalyst 3a.14 Unfortunately, the reaction gave a complex product mixtures. In addition to the expected Friedel-Crafts product at C2 position and O-alkylation product, we also isolated FriedelCrafts product at C4 position and a new structure of 4a that we have not predicted. Though the result was poor, we were excited as this was the first example that 1-naphthols participated in the direct dearomatization at C4 position. Enantioselective reaction
tandem
dearomatization/oxa-Michael
After disclosing the interesting and unexpected result, we decided to investigate the feasibility of this novel dearomatization/oxa-Michael reaction. However, several challenges have to be encountered for achieving good results. First, the chemoand regioselectivity are challenging as both spiroepoxyoxindoles and 1-naphthols have multiple reactive sites, and at least eight different isomers might be obtained. Second, the control of both diastereo- and enantioselectivities is equally challenge as three continuous stereocenters including one
Page 2 of 8
quaternary stereocenter are formed. After many attempts, we found that this reaction underwent the kinetic resolution to give both the resolved spiro-epoxyoxindole and the ringopening products in the presence of a phosphoric acid catalyst. The studies were initiated by evaluating the reaction between spiro-epoxyoxindole (rac)-1a and 1-naphthol 2a using chiral phosphoric acid 3a as the catalyst in toluene at room temperature. Indeed, this acid could promote the reaction and gave the resolved spiro-epoxyoxindole 1a and the other four different isomers 4a, 5a, 6a and 7a with a ratio of 3:3:4:1. Gratifyingly, the reaction favored the ring-opening from the hinder side without the observation of the products from the less hindered side (Table 1, entry 1). Encouraged by this promising result, we then screened several chiral phosphoric acids with different substituents and backbones to improve the selectivities (Table 1, entries 2-7). Phosphoric acid 3e afforded the best results in terms of regio- and chemoselectivity (20:1:1:2), and enantioselectivities (94% ee of 4a and 98% ee of 1a) (Table 1, entry 5). Various solvents were then evaluated and significant solvent effect was observed (Table 1, entries 8-16). The reaction did not proceed in THF or Et2O, but gave major dearomatization/oxa-Michael product 4a in aromatic solvents like toluene, xylene, mesitylene (Mes) and 1,3,5-triisopropylbenzene (TIPB). Interestingly, the reaction afforded the major FriedelCrafts alkylation at C4 position when PhF or PhCF3 was used. The good regioselectivity and >99% ee of 1a was obtained in Mes, while excellent regioselectivity and 95% ee of 4a in TIPB. We then tried mixed solvents of Mes/TIPB, which gave excellent regioselectivity of >20:1:1:1, 96% ee of 4a and 97% ee of 1a (Table 1, entry 17). The yield and enantioselectivity could be further improved by improving the ratio of 1a:2a. In this case, both epoxide 1a and product 4a were isolated with high yields and enantioselectivities (47% yield, >99% ee and 41% yield, 97% ee respectively) (Table 1, entry 18).
Table 1. Optimization of the Tandem Dearomatization/Oxa-Michael Reaction.a
entry
Cat.
solvent
t (h)
4a:5a:6a:7ab
4a d.r.b
4a ee (%)c
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5a ee (%)c
6a ee (%)c
7a ee (%)c
1a ee (%)c
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3a
Tol
17
3:3:4:1
>20:1
15
6
0
28
38
2
3b
Tol
17
1:1:1:1
>20:1
19
18
25
23
13
3
3c
Tol
7
5:1:4:1
>20:1
1
-
15
-
27
4
3d
Tol
7
1:2:2:1
>20:1
17
6
45
38
49
5
3e
Tol
17
20:1:1:2
>20:1
94
-
-
-
98
6
3f
Tol
7
1:2:3:1
>20:1
32
43
14
29
21
7
3g
Tol
7
1:1:1:1
>20:1
61
2
21
14
48
8
3e
Xyl
17
10:1:1:1
>20:1
91
-
-
-
>99
9
3e
Mes
17
10:1:1:1
>20:1
93
-
-
-
>99
10
3e
PhF
4
3:1:1:10
>20:1
83
-
-
30
59
11
3e
PhCF3
4
2:1:1:12
-
-
-
-
68
97
12
3e
CHCl3
40
2:1:1:4
>20:1
93
-
-
60
48
13
3e
CH2Cl2
10
15:1:8:40
>20:1
74
-
-
3
55
14
3e
THF
40
-
-
-
-
-
-
-
15
3e
Et2O
40
-
-
-
-
-
-
-
16
3e
TIPB
20
>20:1:1:1
>20:1
95
-
-
-
93
17
3e
Mes/TIPB =1:1
14
>20:1:1:1
>20:1
96 (39)d
-
-
-
97 (43)d
18e
3e
Mes/TIPB =1:1
35
>20:1:1:1
>20:1
97 (41)d
-
-
-
99 (47)d
a
Unless otherwise noted, the reaction was carried out in 0.25 mmol scale in 1 ml solvent at 25 ℃ with the ratio of 1a/2a/3 = 1.0/1.0/0.1. Determined by 1H NMR of crude mixture. cDetermined by chiral HPLC on a Chiralcel IC column. dIsolated yield was given in the parenthesis. eThe reaction was carried out in 0.25 mmol scale in 2 ml solvent at 15 ℃ with the ratio of 1a/2a/3 = 1.25/1.0/0.125. b
We next examined the scope of this reaction under the optimal reaction conditions (Table 2). The reaction worked well for a variety of substituted spiro-epoxyoxindoles, providing the resolved epoxides (R)-1 and dearomatization/oxa-Michael products 4 in high yields and enantioselectivities. Though higher reactivity was observed with the electron-donating groups, minimal impact on selectivities was observed, regardless of the electronic nature, bulkiness or positions of the substituents (Table 2, entries 1-9). Further exploration of the substrate scope was focused on a serious of 1-naphthols. All of them gave excellent results (Table 2, entries 10-16). In addition, hindered anthracen-1-ol also proved to be a suitable substrate (Table 2, entry 17). The absolute configuration of 4l was determined by single-crystal X-ray diffraction analysis (Scheme 2a).15
To further expand the potential of this transformation, we investigated different protecting groups and removal of protecting groups of spiro-epoxyoxindoles (Table 2, entries 1826). Among the tested protecting groups, all of them had little effect on the selectivities of the reaction. Notably, when protected with TBS, the spiro-epoxyoxindole with 5-F or 5-Cl substituent could react smoothly with 1-naphthol, which was sluggish with Bn protecting group (Table 2, entries 4-5 vs entries 25-26). Furthermore, the removal of TBS protecting group was easy. In the presence of TBAF, the deprotection product 8 was obtained in quantitative yield with complete retention of the stereochemical integrity (Scheme 2b), whose absolute configuration was determined by X-ray analysis.15
Table 2. Scope of the Tandem Dearomatization/Oxa-Michael Reaction.a
Entry
R1
R2
R3
t (h)
1
H
Bn
H
35
(R)-1
4 b
c
ee
Yieldb
eec
4a, 41
97
1a, 47
>99
Yield
sd >353
2
5-Me
Bn
H
18
4b, 40
95
1b, 45
97
168
3
5-MeO
Bn
H
10
4c, 32
97
1c, 40
96
279
4
5-F
Bn
H
72
-
-
-
-
5
5-Cl
Bn
H
72
-
-
-
-
6
6-Cl
Bn
H
24
4d, 41
96
1d, 40
>99
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7
6-Br
Bn
H
35
4e, 46
98
1e, 45
96
390
8
7-Me
Bn
H
10
4f, 42
97
1f, 41
>99
>354
9
7-Cl
Bn
H
168
4g, 35
98
1g, 37
>99
>481
10
H
Bn
6-Me
25
4h, 48
97
1a, 42
98
920
11
H
Bn
6-MeO
22
4i, 46
99
1a, 43
98
1131
12
H
Bn
6-Ph
18
4j, 40
98
1a, 42
96
390
13
H
Bn
6-Cl
23
4k, 41
95
1a, 45
96
151
14
H
Bn
6-Br
40
4l, 40
95
1a, 43
>99
>211
15
H
Bn
7-Cl
24
4m, 46
96
1a, 45
99
253
16
H
Bn
7-MeO
35
4n, 41
96
1a, 42
97
200
17
H
Bn
35
4o, 48
94
1a, 47
98
154
18
H
Me
H
31
4p, 41
95
1h, 42
95
146
19
H
MOM
H
30
4q, 48
98
1i, 49
96
390
20
H
Allyl
H
21
4r, 42
96
1j, 44
97
210
21
H
Ac
H
72
4s, 44
98
1k, 49
98
461
22
H
Boc
H
24
4t, 40
96
1l, 38
>99
>253
23
H
PMB
H
27
4u, 43
96
1m, 40
97
205
24
H
TBS
H
16
4v, 46
94
1n, 47
95
119
25
5-F
TBS
H
72
4w, 41
98
1o, 45
95
389
26
5-Cl
TBS
H
89
4x, 42
>99
1p, 40
96
973
a
All reactions were carried out by using catalyst 3e (0.025 mmol), 1 (0.25 mmol), 2 (0.20 mmol), in Mes:TIPB 1:1 (2 mL) with r.r. > 20:1, d.r. > 20:1. bIsolated yield. cDetermined by chiral HPLC analysis. dCalculated conversion and selectivity factors: conv. = ee1/(ee1 +ee4), s = ln[(1 − C)(1 − ee1)]/ln[(1 − C)(1 + ee1)].16
Scheme 2. X-Ray Structures of Compound 4l and 8. Switchable asymmetric Friedel-Crafts reaction at C4 position During the optimization of the dearomatization/oxa-Michael reaction, we found an interesting solvent effect17 that the use of PhF or PhCF3 as the solvent exhibited different chemoselec-
tivity to afford the major C4 Friedel-Crafts product 7a. The use of PhCF3 afforded the major Friedel-Crafts product 7a in promising enantioselectivity of 68% (Table 3, entry 1). With the decrease of catalyst loading, the ratio of product 7a to 4a and the enantioselectivity of 7a were increased (Table 3, entries 1-3). The yield and enantioselectivity could be improved by simply increasing the concentration of reactants (Table 3, entries 3-5). When the amount of 1-naphthol was reduced to 0.6 equivalent, the ee of 7a could be improved to 87% (Table 3, entry 6). Better enantioselectivity was observed for 7a with the use of CH3CO2H as an additive18, but a slight loss of ee was obtained for the resolved (R)-1a (Table 3, entry 7). Thus, starting from the same substrates and catalyst, the dearomatiza-tion/oxa-Michael reaction can switch to Friedel-Crafts reaction easily by turning reaction conditions. Consequently, we next investigated the generality of the reaction with respect to the substituents on both substrates (Table 4). Spiro-epoxyoxindoles with electron-donating or electron-withdrawing substituents proved to be excellent substrates in this Friedel-Crafts reaction, and afforded the expected products 7 and the resolved epoxides (R)-1 in high yields and enantioselectivities (Table 4, entries 1-5). The substituent was also accommodated on the naphthol ring, and good results were obtained (Table 4, entry 6).
Table 3. Optimization of Asymmetric Friedel-Crafts Reaction Conditions.a
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ACS Catalysis
time (h)
(R)-1a
7a
additive
7a:4ab
36
-
6:1
38
48
-
8:1
33
60
-
11:1
1:1
48
-
1:1
36
-
2.5
1:0.6
42
-
12:1
33
87
32
99
2.5
1:0.6
56
CH3CO2H
12:1
31
91
36
91
entry
M (mol/L)
X
1
0.1
10
1:1
2
0.1
5
1:1
3
0.1
2.5
1:1
4
0.2
2.5
5
0.5
2.5
6
0.5
7
0.5
1a:2a
yield (%)d
ee (%)c
68
39
97
71
35
98
31
78
27
99
12:1
34
81
33
98
13:1
35
82
36
97
yield (%)
d
ee (%)
c
a Unless otherwise noted, the reaction was carried out in PhCF3 at 15 ℃. bDetermined by 1H NMR of crude mixture. cDetermined by chiral HPLC on a Chiralcelpak IC column. dIsolated yield.
Meanwhile, the unreacted spiro-epoxyoxindoles (R)-1 were recovered in yields of 37-49% and ees of 90->99% (Tables 2 and 4). Thus, in addition to serving as a switchable dearomatization/oxa-Michael reaction and Friedel-Crafts reaction, this reaction constitutes an efficient kinetic resolution of (rac)spiro-epoxyoxindoles 1. The resolved spiro-epoxyoxindoles (R)-1a could be converted into the enanti opure 9 by the regio-
and stereoselective ring-opening with sodium azide from the less hindered side without the use of a catalyst. Subsequent reduction of 9 with PPh3 afforded 10 without any loss of enantioselectivity, which could be used in the synthesis of (S)-(-)spirobrassinin, a natural product isolated from Pseudomonas cichorii inoculated Chinese cabbages and Japanese radishes (Scheme 3).19
Table 4. Scope of Asymmetric Friedel-Crafts Reaction.a HO OH
O R1
R3
O
O R3
+
N Bn 1
3e (2.5 mol%) CH3CO2H (1 eq) PhCF3, t, 15 ℃
OH O
R1
R1
+
N Bn
2
(R)-1
7
(R)-1
7
entry
R1
R3
t (h)
1
H
H
56
7a, 31
2
5-Me
H
30
7b, 32
yield (%)
b
sd
yield (%)b
ee (%)c
91
1a, 36
91
67
96
1b, 38
99
252
ee (%)
c
O N Bn
3
6-Cl
H
132
7c, 41
90
1d, 38
93
65
4
6-Br
H
83
7d, 31
92
1e, 39
91
77
5
7-Me
H
35
7e, 35
90
1f, 44
96
74
6
H
6-Br
83
7f, 30
92
1a, 43
90
73
a
All reactions were carried out by using catalyst 3e (0.02 mmol), 1 (0.20 mmol), 2 (0.12 mmol), in PhCF3 (0.4 mL). bIsolated yield. Determined by chiral HPLC analysis. dCalculated conversion and selectivity factors: conv. = ee1/(ee1 +ee4), s = ln[(1 − C)(1 − ee1)]/ln[(1 − C)(1 + ee1)].16 c
Scheme 3. Transformation of (R)-1a.
To identify the “matched/mismatched” effect of the reaction, we investigated the reaction of 1-naphthol 2a with both enantiomeric forms of spiro-epoxyoxindole 1a in catalyst 3e (Table 5). The matched reaction of (S)-1a gave product 4a in 98% yield and 99% ee, while the mismatched reaction of (R)1a did not proceed and (R)-1a was recovered in 96% yield and
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99% ee. Similar “matched/mismatched” effect was also observed for the Friedel-Crafts reaction.
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(CIF). This material is available free of charge via the Internet at http://pubs.acs.org.”
AUTHOR AUTHOR INFORMATION
Table 5. “Matched/mismatched” Effect.a
Corresponding Author *
[email protected] *
[email protected] *
[email protected] (R)-1a
4a
Author Contributions
1a
Conv.
Yield (%)b
ee (%)c
Yield (%)b
ee (%)c
# These authors contributed equally.
(rac)-1a
51
41
97
47
>99
The authors declare no competing financial interests.
(S)-1a
>95
98
99
-
-
(R)-1a
95
93
99
-
-
(R)-1a
