A new chiral C1-symmetric NHC-catalyzed addition to α-aryl substituted α,β-disubstituted enals: Enantioselective synthesis of fully functionalized dihydropyranones

Article abstract of DOI:10.1039/c5cc00118h

The first enantioselective NHC-catalyzed activation of α-aryl substituted α,β-disubstituted unsaturated aldehyde is successfully developed via a highly-active acyl azolium intermediate. The new C₁-symmetric biaryl-saturated imidazolium exhibits a superior ability to enable previously unavailable transformation, and the corresponding fully functionalized dihydropyranones are efficiently synthesized in high yields with excellent enantioselectivities. This journal is

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ARTICLE TYPE
A New Chiral C1ꢀSymmetric NHCꢀCatalyzed Addition to αꢀAryl
Substituted α,βꢀDisubstituted Enals: Enantioselective Synthesis of Fully
Functionalized Dihydropyranones
Hong Lu, JinꢀYu Liu, ChenꢀGuang Li, JunꢀBing Lin, YongꢀMin Liang and PengꢀFei Xu*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
to fully substituted dihydropyranones which are otherwise
50 difficult to obtain in high yields and excellent selectivities.
The first enantioselective NHCꢀcatalyzed activation of αꢀaryl
substituted α,βꢀdisubstituted unsaturated aldehyde is
successfully developed via
a highlyꢀactive acyl azolium
10 intermediate. The new C1ꢀsymmetric biarylꢀsaturated
imidazolium exhibits a superior ability to enable previously
unavailable transformation, and the corresponding fully
functionalized dihydropyranones are efficiently synthesized
in high yields with excellent enantioselectivities.
15 Over the past decade, a large number of new catalysts and novel
strategies have been developed to enable previously unavailable
transformations.1 Despite these significant improvements,
however, the reaction of αꢀbranched α,βꢀdisubstituted unsaturated
aldehydes, especially αꢀaryl substituted α,βꢀdisubstituted enals, is
20 still a long standing and challenging issue for asymmetric
catalysis due to their steric hindrance and low reactivity.2 Neither
organocatalysis nor metalꢀbased approaches have afforded to the
stereoselective functionalization of these sterically congested
substrates.3 As a consequence, the activation of elusive αꢀaryl
25 substituted α,βꢀdisubstituted enals is still highly desired and will
significantly extend the scope of asymmetric catalysis.
Fig.1 NHC catalysts examined in this study.
Due to the great potential for extending substrate scopes and
achieving unprecedented transformations,4 oxidative Nꢀ
heterocyclic carbenes (NHCs) catalysis has received substantial
30 attention and experienced very rapid development in the past
decade.5 Dozens of intriguing chemical entities with improved
complexity and diversity have been readily constructed in a
stereocontrolled fashion via α,βꢀunsaturated acyl azolium
intermediates.6,7 With our ongoing interest in the exploration of
35 practical asymmetric organoctalysis,8 we envisioned that the
elusive asymmetric activation of challenging αꢀaryl substituted
α,βꢀdisubstituted enals might be achieved using C1ꢀsymmetric
biarylꢀsaturated imidazolium.9 Herein we present the first
asymmetric Michael addition to αꢀaryl substituted α,βꢀ
40 disubstituted enals through oxidative NHC catalysis, giving rise
In our initial study, several achiral NHC catalysts were
screened to evaluate their ability to promote the reaction of αꢀ
55 phenyl substituted enal 1a and acetyl acetone 2a by using
diazabicyclo[5.4.0]undecene (DBU, 10 mol%) and oxidant 4 in
o
THF at 10 C (Fig. 1). To our delight, the saturated imidazolium
catalyst 5c could give the desired fully functionalized
dihydropyranone 3a in a short time (Table 1, entries 1–4). To
60 uncover the asymmetric variants of this process, NHCs 5e and 5f,
which had been used to formal [3+2] annulation of α,βꢀ
unsaturated aldehydes with acyl phosphonates, were screened
(Table 1, entries 5 and 6).10a The reactions proceeded smoothly in
high yield yet with a moderate stereocontrol. Further efforts
65 toward improving catalyst performance revealed that NHCs with
more electronꢀdonating and bulkier substituents did not offer
satisfactory results (Table 1, entries 7–9). Considering the
superior ability of CF3 group toward tuning the stereoelectronic
effect in catalyst design, we expected that the introduction of CF3
70 group into such type of catalysts would provide a beneficial effect
toward reactivity and selectivity. Then catalyst 5j and its
enantiomer 5k were synthesized and evaluated. Surprisingly,
State Key Laboratory of Applied Organic Chemistry, College of
Chemistry and Chemical Engineering, Lanzhou University, Lanzhou
730000, P. R. China.
45 E-mail: xupf@lzu.edu.cn
† Electronic Supplementary Information (ESI) available: Experimental
procedures and spectra of all new compounds. CCDC 1037041. See
DOI: 10.1039/b000000x/
catalysts 5j led to
a
very encouraging yield with good
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DOI: 10.1039/C5CC00118H
diastereoselectivity and excellent enantioselectivity while catalyst
enantioselectivities. The steric and electronic properties of the
5k gave only slightly improved results (Table 1, entries 10 and 30 aryl at αꢀposition of unsaturated aldehydes had noticeable effect
11). Next, different solvents were investigated and THF was
found to be an optimal one (Table 1, entries 12–15). Further
screening of the temperatures and bases showed 25 C and DBU
on the outcome of the action. Only small substituent at the ortho-
position of the phenyl group could give the desired result (Table
2, entry 2). But the steric influence of the substituents at meta- or
para-position of the phenyl was not obvious (entries 3–7 versus
o
5
to be promising (Table 1, entries 16–22). When 3 equivalents of
2a and 0.5 mL THF were used, a highly efficient and prominent 35 entries 8–12). Electronꢀdonating substituents gave higher levels
selectivity was obtained (Table 1, entries 23–24). However,
employing 5 mol% of 5k led to a drop inefficiency and
10 diastereoselectivity (Table 1, entry 25). Additionally, Bode’s
catalyst 5l, which has been widely used in the synthesis of
of reactivity and enantioselectivity compared to those substrates
with electronꢀwithdrawing substituents (Table 2, entries 3–5, 8–
10 versus entries 6–7, 11–17). Notably, satisfactory results could
be obtained when the bulky substituent at the para position of the
dihydropyranones, and other chiral triazolium precatalysts 5m 40 phenyl group or the αꢀposition of enal (Table 2, entries 15 and
and 5n were investigated, but only Bode’s catalyst could give the
product with good yield and moderate enantioselectivity after 12
15 hours (Table 1, entries 26–28).
18). Furthermore, the reactions could be extended to benzyl
carbonate (Table 2, entry 19). 1,3ꢀdicarbonyl compounds with
different substituents were also explored (Table 2, entries 20 and
21). The absolute configuration of the product 3v was determined
45 to be (3S, 4R) by Xꢀray crystallography (Table 2, entry 22).11 In
addition, the βꢀphenyl or αꢀmethyl disubstituted enals could also
give the product smoothly (Table 2, entries 23 and 24).
Table 1 Optimization of the reaction conditionsa
Table 2 Scope of the synthesis of fully functionalized δꢀlactonea
entry cat. temp (oC) base solvent time (h) yieldb (%) drc eed (%)
5a
5b
5c
5d
5e
5f
5g
5h
5i
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
25
40
25
25
25
25
25
25
25
25
25
25
25
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
24
24
3
24
6
6
6
6
6
64
NR
87
52
83
84
83
80
79
84
86
NR
NR
30
trace
87
83
67
64
76
78
59
87
87
85
80
73
30
2:1
ꢀ
ꢀ
ꢀ
ꢀ
time yieldb
eed
(%)
1
2
3
4
5
6
7
8
9
entry
R
R1
R2
drc
(h)
(%)
2:1
2:1
2:1
2:1
2:1
3:1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph
2ꢀFC6H4
3ꢀFC6H4
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Bn
CO2Et
CO2Et
Me
Me
Me
Me
Me
4
8
8
8
3a, 87 8:1 96
3b, 72 7:1 91
3c, 75 3:1 90
3d, 70 3:1 93
3e, 73 3:1 90
ꢀ
61
71
33
68
3ꢀClC6H4
3ꢀBrC6H4
3ꢀMeC6H4
3ꢀMeOC6H4
4ꢀFC6H4
4ꢀClC6H4
4ꢀBrC6H4
4ꢀMeC6H4
4ꢀMeOC6H4
4ꢀEtOC6H4
4ꢀamylC6H4
8
Me 3.5 3f, 90 11:1 94
Me 3.5 3g, 92 9:1 94
3:1 85/83
3:1 91/n.d.
4:1 93/83
ꢀ
ꢀ
10 5j
11 5k
12 5k
13 5k
14 5k
15 5k
16 5k
17 5k
18 5k
19 5k
20 5k
21 5k
22 5k
23e 5k
24e,f 5k
25g 5k
26 e,f 5l
27 e,f 5m
28 e,f 5n
12
12
Me
Me
Me
6
7
7
3h, 80 5:1 90
3i, 76 3:1 90
3j, 74 3:1 93
DBU toluene 48
DBU MeCN 48
DBU dioxane 48
DBU DCM
DBU
DBU
DABCO THF
Cs2CO3 THF
K2CO3 THF
NaOAc THF
NEt3
DBU
DBU
DBU
DBU
DBU
DBU
ꢀ
ꢀ
93
ꢀ
Me 3.5 3k, 90 8:1 95
Me 3.5 3l, 91 11:1 94
Me 3.5 3m, 92 9:1 98
Me 3.5 3n, 89 10:1 97
Me 3.5 3o, 90 10:1 96
Me 3.5 3p, 91 9:1 96
Me 3.5 3q, 92 10:1 96
Me 3.5 3r, 87 7:1 96
6:1
ꢀ
48
8
THF
THF
7:1
2:1
2:1
3:1
3:1
7:1
5:1
7:1
8:1
4:1
2:1
2:1
2:1
94
93
92
92
93
92
92
94
96
94
86
5
1.5
12
12
12
12
12
6
15 4ꢀcyclohexylC6H4
16 3,4ꢀMe2C6H3
17 3,4ꢀ(MeO)2C6H3
18
19
20
21
2ꢀnaphthyl
4ꢀMeOC6H4
4ꢀMeOC6H4
4ꢀMeOC6H4
Me
OMe
OEt
4
4
4
6
3s, 87 10:1 96
3t, 86 10:1 95
3u, 88 10:1 96
3v, 81 7:1 83
THF
THF
THF
THF
THF
THF
THF
22e 3,4ꢀ(MeO)2C6H3 4ꢀClPhCH2CO2 OMe
3
24
12
12
12
23
24
Ph
Me
Ph
Me 36 3w, 65 7;1 69
3x, 80 2:1 88
4ꢀClPhCH2CO2 Me
1
a
50 Unless otherwise specified, the reaction was carried out with 1 (0.1
mmol), 2 (0.3 mmol), oxidant 4 (0.1 mmol), 5k (10 mol%) and DBU (10
26
a
o
b
c
1
Conditions: Reactions performed with 1a (0.1 mmol), 2a (0.15 mmol),
oxidant 4 (0.1 mmol), NHC (10 mol%) and DBU (10 mol%) in THF (1
mol%) in THF (0.5 mL) at 25 C. Isolated yield. Determined by H
NMR analysis of the crude products. d Determined by chiralꢀphase HPLC
o
b
c
1
e
20 mL) at 10 C. Isolated yield. Determined by H NMR analysis of the
analysis. The absolute configurationof 3w was determined by Xꢀray
d
e
crude products. Determined by chiralꢀphase HPLC analysis. 0.5 mL
THF was used. f 3 equivalents of 2a were used. g 5 mol% 5k was used. n.d.
= not determined.
55 analysis (Fig. 2).
A plausible catalytic cycle is outlined in Scheme 1. We
proposed that the reaction may be initiated by the combination of
enal 1a and imidazolium NHC, the Breslow intermediate is then
oxidized to the key αꢀaryl substituted α,βꢀdisubstituted acyl
60 azolium I,12 which undergoes Michael addition and generates
intermediate II. After a tautomerization, the intermediate III
With the optimal reaction conditions established, the scope of
25 the reaction was also investigated. As shown in Table 2, in all the
cases, the reaction proceeded smoothly to afford the
corresponding fully decorated dihydropyranones in moderate to
high yields with good diastereoselectivities and excellent
2
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DOI: 10.1039/C5CC00118H
undergoes Hꢀmigration and Oꢀacylation to afford desired product 20 obtained in high yields with excellent enantioselectivities.
3a with the regeneration of the catalyst. 13
Notably, the C1ꢀsymmetric biarylꢀsaturated imidazolium, as a
robust organocatalyst, has shown powerful potential for the
activation of previously unavailable reactions and inactive
substrates. Further studies and applications of the novel NHC
25 catalyst are currently underway.
We are grateful to the NSFC (21172097, 21202070 and
21372105), the International S&T Cooperation Program of China
(2013DFR70580), the National Natural Science Foundation from
Gansu Province of China (no. 1204WCGA015), and the “111”
30 program from MOE of P. R. China.
Notes and references
1. For seclected examples, see: (a) A. T. Biju, N. Kuhl and F. Glorius,
Acc. Chem. Res., 2011, 44, 1182; (b) D. T. Cohen and K. A. Scheidt,
Chem. Sci., 2012, 3, 53; (c) Z, Du and Z, Shao, Chem. Soc. Rev.,
35
40
45
50
55
60
65
70
75
80
2013, 42, 1337; (d) G. Masson, C. Lalli, M. Benohoud and G.
Dagousset, Chem. Soc. Rev., 2013, 42, 902; (e) I. D. Jurberg, I.
Chatterjee, R. Tannerta and P. Melchiorre, Chem. Commun., 2013,
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11588; (g) M. T. Hovey, C. T. Check, A. F. Sipher and K. A. Scheidt,
Angew. Chem. Int. Ed., 2014, 53, 9603.
Fig. 2 Xꢀray crystal structure of compound 3v.
5k
O
base
Ph
EtO2
O
O
O
Ph
Ph
N
2. For αꢀalky substitueted α,βꢀdisubstituted enals, see: (a) S. Karlsson
and H.ꢀE. Högberg, Eur. J. Org. Chem., 2003, 2782;(b) H. D. King,
Z. Meng, D. Denhart, R. Mattson, R. Kimura, D. Wu, Q. Gao and J.
E. Macor, Org. Lett., 2005, 7, 3437; (c) P. Galzerano, F. Pesciaioli,
A. Mazzanti, G. Bartoli and P. Melchiorre, Angew. Chem. Int. Ed.,
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9748; (g) A. Pou and A. Moyano, Eur. J. Org. Chem., 2013, 3103;
(h) O. Lifchits, M. Mahlau, C. M. Reisinger, A. Lee, C. Farès, I.
Polyak, G. Gopakumar, W. Thiel and B. List, J. Am. Chem. Soc.,
2013, 135, 6677; for αꢀbranched enones, see: (i) K. Nishide, M.
Ozeki, H. Kunishige, Y. Shigeta, P. K. Patra, Y. Hagimoto and M.
Node, Angew. Chem. Int. Ed., 2003, 42, 4515; (j) X. Tian, C.
Cassani, Y. Liu, A. Moran, A. Urakawa, P. Galzerano, E. Arceo and
P. Melchiorre, J. Am. Chem. Soc., 2011, 133, 17934; (k) A. T.
Davies, P. M. Pickett, A. M. Z. Slawin and A. D. Smith, ACS Catal.,
2014, 4, 2696.
C
EtO2C
H
N
Mes
Ph
CF3
3a
1a
O-acylation
CF3
[O]
CO2Et
Ar
N
O
Ar
O
Ar
N
O
N
Ph
N
Ph
N
Ph
CO2Et
steric
Ph
O
Ph
N
Ph
O
H
CO2Et
Ph
Mes
Ph
Mes
IV
Ph
Mes
congested
I
I-1
2a
H-migration
Si face
attack
CO2Et
Ph
Ar
N
O
Ar
N
O
Ph
N
N
O
OH
Ph
Ph
HO
Mes
H
CO2Et
II
O
Ph
Ph
Mes
III
tautomerization
5
Scheme 1 Proposed Reaction Mechanism
3.
(a) T. Kano, Y. Tanaka, K. Osawa, T. Yurino and K. Maruoka,
Chem. Commun., 2009, 1956; (b) A. Quintard, A. Lefranc and A.
Alexakis, Org. Lett., 2011, 13, 1540; (c) M. P. Sibi, J. Coulomb and
L. M. Stanley, Angew. Chem. Int. Ed., 2008, 47, 9913.
To further demonstrate the synthetic value of this oxidative
addition reaction, product 3a with a tetrasubstituted olefin moiety
was subjected to a mild epoxidation process. Gratifyingly, the
10 desired δꢀlactone epoxide 6a, a scaffold widely existed in
numerous biologically active compounds,14 was readily achieved
with moderate yield but excellent diastereoꢀ and
enantioselectivity (Scheme 2).
4. For selected examples, see: (a) S. D. Sarkar and A. Studer, Angew.
Chem. Int. Ed., 2010, 49, 9266; (b) Z.ꢀQ. Rong, M.ꢀQ. Jia and S.ꢀL.
You, Org. Lett., 2011, 13, 4080; (c) X. Zhao, K. E. Ruhl and T.
Rovis, Angew. Chem. Int. Ed., 2012, 51, 12330; (d) J. Mo, X. Chen
and Y. R. Chi, J. Am. Chem. Soc., 2012, 134, 8810; (e) A. G.
Kravina, J. Mahatthananchai and J. W. Bode, Angew. Chem. Int. Ed.,
2012, 51, 9433; (f) E. G. Delany, C.ꢀL. Fagan, S. Gundala, A. Mari,
T. Broja, K. Zeitler and S. J. Connon, Chem. Commun., 2013, 49,
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Samanta, C. G. Daniliuc and A. Studer, Angew. Chem. Int. Ed., 2014,
53, 9622; (k) Z. Fu, K. Jiang, T. Zhu, J. Torres and Y. R. Chi, Angew.
Chem. Int. Ed., 2014, 53, 650; (l) O. Bortolini, C. Chiappe, M.
Fogagnolo, P. P. Giovannini, A. Massi, C. S. Pomellib and D. Ragno,
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H. Park, Org. Lett., 2014, 16, 1028.
O
O
H
Ph
Ph
O
O
O
O
O
m-CPBA
EtO2C
CH2Cl2, 40 o
C
EtO2C
O
O
O
24 h
H
O
6a
3a
, 96% ee
, 62% yield
d.r. >20:1, 95% ee
sterol derivative
(bioactive)
15
Scheme 2 Synthetic Application of the Chiral δꢀlactone 3a
5. For reviews on the oxidative Nꢀheterocyclic carbenes catalysis, see:
(a) C. E. I. Knappke, A. Imami and A. J. Wangelin, ChemCatChem,
2012, 4, 937; (b) S. D. Sarkar, A. Biswas, R. C. Samanta and A.
Studer, Chem. Eur. J., 2013, 19, 4664.
In summary, we have developed a practical and efficient
approach for the activation of challenging αꢀaryl substituted α,βꢀ
disubstituted unsaturated aldehydes via a newly developed NHC
catalyst, and a series of fully substituted dihydropyranones were
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and J. W. Bode, Acc. Chem. Res., 2014, 47, 696.
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5
10
15
20
25
30 9. The catalyst was often used as aligand, for selected examples, see; (a)
E. M. Vieira, M. L. Snapper and A. H. Hoveyda, J. Am. Chem. Soc.,
2011, 133, 3332; (b) F. Meng, H. Jang and A. H. Hoveyda, Chem.
Eur. J., 2013, 19, 3204; (c) V. Pace, J. P. Rae and D. J. Procter, Org.
Lett., 2014, 16, 476; (d) N. W. Mszar, F. Haeffner and A. H.
35
Hoveyda, J. Am. Chem. Soc., 2014, 136, 3362.
10. For examples on organocatalysis, see: (a) K. P. Jang, G. E. Hutson,
R. C. Johnston, E. O. McCusker, P. H.ꢀY. Cheong and K. A. Scheidt,
J. Am. Chem. Soc., 2014, 136, 76; (b) A. Lee and K. A. Scheidt,
Angew. Chem. Int. Ed., 2014, 53, 7594.
40 11. CCDC 1037041 (3v) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
the
Cambridge
Crystallographic
Data
Center
via
www.ccdc.cam.ac.uk/data_request/cif.
12. Owing to the steric congestion of intermediates Iꢀ1, we suspect that
only the transition I could participate the reaction readily.
45
50
13. With regard to the mechanism, at current stage, the pathway involving
the direct addition of enone and subsequent Claisen rearrangement
proposed by Bode et al can not be ruled out. To see ref 7c and 7d.
14. K. Uchida, T. Agatsuma, K. Hibino, S. Sasho, K. Iida, H. Onodera,
PCT WO 2011/010682A1, 2011.
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