Catalytic asymmetric synthesis of 1,3-enyne scaffolds: Design and synthesis of conjugated nitro dienynes as novel Michael acceptors and development of a new synthetic methodology

Article abstract of DOI:10.1039/c3cc48951e

A novel catalytic enantioselective synthesis of functionalized 1,3-enynes has been developed featuring the design and synthesis of conjugated nitro dienynes as a useful new class of Michael acceptors. Moreover, a simple, yet flexible catalytic cascade approach to functionalized enantioenriched acyclic α,β-enones and cyclic dienones has also been developed.

Full text of DOI:10.1039/c3cc48951e

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Catalytic asymmetric synthesis of 1,3-enyne
scaffolds: design and synthesis of conjugated
nitro dienynes as novel Michael acceptors and
development of a new synthetic methodology†
Cite this: Chem. Commun., 2014,
50, 1745
Received 23rd November 2013,
Accepted 13th December 2013
Xiang Li, Fangzhi Peng,* Mingtao Zhou, Mingjie Mo, Ruirui Zhao and Zhihui Shao*
DOI: 10.1039/c3cc48951e
www.rsc.org/chemcomm
A novel catalytic enantioselective synthesis of functionalized 1,3-enynes
has been developed featuring the design and synthesis of conjugated nitro
dienynes as a useful new class of Michael acceptors. Moreover, a simple,
yet flexible catalytic cascade approach to functionalized enantioenriched
acyclic a,b-enones and cyclic dienones has also been developed.
Fig. 1 Design of conjugated nitro dienynes 1 as a new class of Michael
acceptors.
1,3-Enynes are important structural motifs present in many naturally
occurring products and drugs1 such as terbinafine,2 a potent drug
for superficial fungal infections, and calichemicin g1,3 an effective approach to functionalized enantioenriched acyclic a,b-enones and
antitumor antibiotic. 1,3-Enynes are also versatile building blocks in cyclic dienones, two classes of synthetically useful compounds.
organic chemistry4 and materials science.5 Therefore, considerable
To target the synthesis of challenging 1,3-enynes and tackle an
efforts have been devoted to develop new methods to synthesize issue of broader significance in organic synthesis, conjugated nitro
1,3-enynes.6,7 Whereas several methods have been developed for dienynes 1 (Fig. 1) were designed. Whereas nitroolefins as Michael
their racemic synthesis,6 the asymmetric synthesis, especially cata- acceptors have been extensively investigated,9 the closely related
lytic asymmetric synthesis, of 1,3-enynes still remains a challenging conjugated nitro dienynes 1 have not been designed and synthe-
task. Recently, the Krische group reported elegant Rh-catalyzed sized, despite their potential in synthetic chemistry. Thus we began
enantioselective reductive coupling of 1,3-diynes to a-keto aldehydes our studies by developing a method for the synthesis of nitro
and a-hydroxy esters.7 However, these procedures are only applicable dienynes 1. As shown in Scheme 1, vinyl bromides 2 underwent
to the synthesis of enantioenriched 1,3-enynes with an allylic Sonogashira coupling with propargylic alcohol, leading to the
stereogenic center. To date, a general, highly enantioselective formation of corresponding alcohols 3 in high yields. Oxidation of
method for the synthesis of 1,3-enynes with a propargylic stereogenic the hydroxyl group of 3 with 2-iodoxybenzoic acid (IBX) afforded
center has not been achieved.
aldehydes 4. 4 underwent the Henry reaction with LiAlH4 as the
As part of our continuing interest in the catalytic asymmetric base10 followed by a reaction with trifluoroacetic anhydride (TFAA)
syntheses of chiral unsaturated structural motifs and building in the presence of Et3N to produce the desired nitro dienynes 1.
blocks,8 herein we report a distinct approach toward the catalytic Notably, a variety of aromatic and aliphatic nitro dienynes 1a–g
enantioselective synthesis of 1,3-enynes. This approach, featuring for could be easily prepared with complete stereocontrol.
the first time the design and synthesis of conjugated nitro dienynes
With conjugated nitro dienynes 1 in hand, we focused our
as a useful new class of Michael acceptors, provides previously attention on developing a method for the catalytic enantioselective
inaccessible enantioenriched 1,3-enynes with a propargylic stereo- synthesis of 1,3-enynes, especially with a propargylic stereogenic
genic center in good yields with high enantioselectivity. Notably, we center. We envisioned that if nitro dienynes 1 could act as novel
have further developed a simple, yet flexible novel catalytic cascade extended Michael acceptors,11 a catalytic enantioselective 1,4-addition
(not 1,6- or 1,8-addition)12 to 1 would provide a route to previously
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, inaccessible 1,3-enynes. To explore the feasibility of this method, the
School of Chemical Science and Technology, Yunnan University, Kunming 650091,
model reaction between nitro dienyne 1a and di-tert-butyl malonate
5a was investigated. Screening of chiral catalysts indicated that
China. E-mail: pengfangzhi@ynu.edu.cn, zhihui_shao@hotmail.com;
Fax: +86-871-65035538
bifunctional thioureas, which have been proved to be effective
† Electronic supplementary information (ESI) available: Representative experi-
in the Michael addition of malonates to nitroolefins,13 did not
mental procedure, compound characterization data, and copies of spectra. See
DOI: 10.1039/c3cc48951e
promote the model reaction. We then turned our attention to
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Table 2 Synthesis of various enantioenriched 1,3-enynesa
Entry
R1
R2
R3
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Ph
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Me
OEt
OEt
Me
Me
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Me
6a, 90
6b, 93
6c, 90
6d, 92
6e, 88
6f, 90
6g, 85
6h, 90
6i, 92
6j, 87
6k, 94
6l, 93
6m, 92
6n, 95
6o, 90
6p, 90
93
93
93
93
92
92
94
90
4-Me–C6H4
3-Me–C6H4
4-MeO–C6H4
4-Cl–C6H4
2-Thienyl
Me
Ph
Ph
Me
Ph
4-Me–C6H4
3-Me–C6H4
4-MeO–C6H4
4-Cl–C6H4
2-Thienyl
9
OEt
OEt
93
90
10
11d
12d
13d
14d
15d
16d
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
93 (93)e
93 (93)e
92 (92)e
93 (93)e
92 (92)e
93 (93)e
Me
Me
Me
Me
Scheme 1 Synthesis of conjugated nitro dienynes 1.
a
All reactions were performed at the 0.2 mmol scale using 1.5 equiv. of 5.
b Isolated yields. c Determined by chiral HPLC. d 1 : 1 diastereomeric mixture;
determined by 1H-NMR. e Enantiomeric excess of the diastereomer.
chiral metal catalysts. Recently, Huang and co-workers introduced a
novel chiral diamine and the corresponding Ni(II) complex. This
complex effectively catalyzed the enantioselective Michael addition
of di-tert-butyl malonate to nitroolefins.14 Therefore, we applied this a range of electron-rich and electron-deficient aryl-substituted nitro
complex to conjugated nitro dienyne substrates. Huang’s 1 : 1 NiBr2– dienynes 1b–e underwent the reaction with various 1,3-dicarbonyl
L1 complex14 promoted the reaction to afford the desired product 6a compounds smoothly to provide the desired 1,3-enynes in good
in moderate yield (56%) with moderate enantioselectivity (66% ee) yields (88–95%) with high enantioselectivity (92–93% ee). Hetero-
(Table 1, entry 1). These results highlighted the difference in aromatic substituted nitro dienyne 1f also provided good results
reactivity of our nitro dienyne substrates relative to known nitroole- (entries 6 and 16). Notably, alkyl-substituted nitro dienyne 1g was
fins. Pleasingly, Evans-type chiral Ni(II)–diamine complexes,15 which also suitable for this reaction (entries 7 and 10). It is noteworthy that
have been used extensively in asymmetric catalysis,16 efficiently no 1,6- or 1,8-addition was observed in all cases.
catalyzed the model reaction to provide the product 6a in good
To determine the absolute configuration, the 1,3-enyne 6j
yields with high enantioselectivity (entries 2–5). The use of a 1 : 2 was converted to compound 7 (eqn (1)). The (S) configuration
NiBr2–L3 complex afforded 90% yield and 93% ee (entry 3). Finally, was established by comparison of the optical rotation of 7 with
screening of solvents showed that m-xylene was still optimal.17
The present reaction serves as a general method for the enantio-
selective synthesis of functionalized 1,3-enynes. As shown in Table 2,
the previously reported value of this compound.18
(1)
Table 1 Optimization of the reaction conditionsa
To further demonstrate the utility of enantioenriched 1,3-enynes
6, these compounds were treated with TsOH for the hydrolysis–
decarboxylation reaction. Interestingly, reaction of 1,3-enyne 6a and
6k with a catalytic amount of TsOH (20 mol%) did not afford the
hydrolysis–decarboxylation products 8a0 and 10a0 but instead
directly led to acyclic a,b-enone 8a (eqn (2)) and cyclic dienone 10a
(eqn (3)) in good yields almost without loss of enantiomeric purity.
The enantioselectivity of 8a was determined via transformation into
the corresponding ester 9a.
Entry
L
NiBr2-L
Time
Yieldb (%)
eec (%)
1d
2
3
4
5
L1
L2
L3
L4
L5
1 : 1
1 : 2
1 : 2
1 : 2
1 : 2
24
15
40
40
40
56
86
90
87
87
66
ꢀ95
93
91
92
a
All reactions were performed at the 0.2 mmol scale using 1.5 equiv. of
b
c
5a with 5 mol% of catalyst. Isolated yields. Determined by chiral
HPLC. At 80 1C; 5 mol% PMP was used.
d
(2)
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(IRT13095), the NSFC (21162034, 21372193, 21362040), Doctoral
Fund of Ministry of Education of China (20135301110002), and
the Government of Yunnan Province (2012FB114, 2013FA026).
Notes and references
(3)
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Braun, A. G. Ravelo, O. Munoz-Munoz, A. Rodriguez-Afonso and J. R.
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W. Tang, Org. Lett., 2011, 13, 3664; (c) F. Liu, D. Qian, L. Li, X. Zhao
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We were excited with these unexpected results as the obtained
acyclic a,b-enones and cyclic dienones are synthetically useful but
inaccessible compounds. On the other hand, the incorporation of
1,3-enynes leading to the completely regioselective formation of synthe-
tically useful enones is also noteworthy, as there are no reports of TsOH-
catalyzed hydration reactions of 1,3-enynes.19 Only activated aryl alkynes
were previously shown to undergo TsOH-catalyzed hydration to afford
the corresponding ketones (non-activated aryl alkynes: 0–9% yields).20
In view of the importance of acyclic a,b-enones and cyclic dienones,
we investigated the scope of the cascade reactions. As shown in Table 3,
the scope of the reactions was remarkable. Various functionalized
acyclic a,b-enones 9a–f and cyclic dienones 10a–f were obtained in
good yields with high enantioselectivity. While several methods have
been developed for the syntheses of acyclic a,b-enones21 and cyclic
dienones,22 respectively, these reported protocols are not applicable to
the synthesis of our acyclic a,b-enones 9 and cyclic dienones 10.
Functionalized acyclic a,b-enones 9 represent a novel class of multi-
functional chiral synthons as they contain enone, ester and nitro
groups. Due to the vinylogous reactivity, cyclic dienones have been
demonstrated as a useful class of substrates in the enantioselective
transition-metal catalyzed23 and organocatalyzed24 reactions. However,
the reported asymmetric reactions used unfunctionalized racemic cyclic
dienone substrates.
5 K. Campbell, C. J. Kuehl, M. J. Ferguson, P. J. Stang and
R. R. Tykwinski, J. Am. Chem. Soc., 2002, 124, 7266.
6 Selected examples: (a) D. Cheng, F. Ling, Z. Li, W. Yao and C. Ma, Org.
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Campo, Org. Biomol. Chem., 2012, 10, 7603; (c) W. Zhang, M. Nishiura
and Z. Hou, Angew. Chem., Int. Ed., 2008, 47, 9700; (d) I. M. Lyapkalo
and M. A. K. Vogel, Angew. Chem., Int. Ed., 2006, 45, 4019.
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125, 11488; (b) C.-W. Cho and M. J. Krische, Org. Lett., 2006, 8, 3873.
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10 S. Belot, A. Massaro, A. Tenti, A. Mordini and A. Alexakis, Org. Lett.,
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´
11 For a review on extended Michael acceptors: A. G. Csak¨y, G. de la
´
Herran and M. C. Murcia, Chem. Soc. Rev., 2010, 39, 4080.
12 For a seminal discussion on the regioselectivity of conjugate addi-
tion to extended Michael acceptors: N. Krause and S. Tho-rand,
Inorg. Chim. Acta, 1999, 296, 1.
In conclusion, we have developed a novel catalytic enantioselective
synthesis of previously inaccessible 1,3-enynes in good yields with high
enantioselectivity. This approach features for the first time the design 13 (a) T. Okino, Y. Hoashi, T. Furukawa, X. Xu and Y. Takemoto, J. Am.
Chem. Soc., 2005, 127, 119; (b) J. Ye, D. J. Dixon and P. S. Hynes,
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14 Q. Zhu, H. Huang, D. Shi, Z. Shen and C. Xia, Org. Lett., 2009, 11, 4536.
and synthesis of conjugated nitro dienynes as a useful new class of
Michael acceptors. Moreover, we have further developed a simple, yet
flexible catalytic cascade approach to synthetically useful functionalized 15 D. A. Evans, S. Mito and D. Seidel, J. Am. Chem. Soc., 2005, 127, 9958.
16 Selected examples: (a) A. Nakamura, S. Lectard, D. Hashizume,
enantioenriched acyclic a,b-enones and cyclic dienones.
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(b) C. Fallan and H. W. Lam, Chem.–Eur. J., 2012, 18, 11214; (c) J. Chen,
We gratefully acknowledge financial support from the Program
for Changjiang Scholars and Innovative Research Team in University
J. Chen, Y. Xie and H. Zhang, Angew. Chem., Int. Ed., 2012, 51, 1024.
17 DCM: 86% yield, 86% ee; toluene: 75% yield, 78% ee.
18 D. M. Barnes, J. Ji, M. G. Fickes, M. A. Fitzgerald, S. A. King, H. E. Morton,
F. A. Plagge, M. Preskill, S. H. Wagaw, S. J. Wittenberger and J. Zhang,
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Table
3
Synthesis of various functionalized enantioenriched acyclic
a,b-enones 9 and cyclic dienones 10a
19 For a review on catalytic hydration of alkynes: L. Hintermann and
A. Labonne, Synthesis, 2007, 1121.
20 (a) N. Olivi, E. Thomas, J. Peyrat, M. Alami and J. Brion, Synlett,
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Entry R1
8, 9, Yield (%) 9, eed (%) 10, Yield (%) 10, eed (%)
1
2
3
4
5
6
Ph
78b (84)c
90
91
93
93
90
92
69
73
76
75
65
70
92
89
90
88
90
90
4-Me–C6H4 85b (85)c
3-Me–C6H4 84b (84)c
4-MeO–C6H4 83b (87)c
´
23 (a) H. Henon, M. Mauduit and A. Alexakis, Angew. Chem., Int. Ed.,
4-Cl–C6H4
2-Thienyl
73b (80)c
76b (83)c
2008, 47, 9122; (b) K.-s. Lee and A. H. Hoveyda, J. Am. Chem. Soc.,
2010, 132, 2898.
24 (a) X. Tian, Y.-K. Liu and P. Melchiorre, Angew. Chem., Int. Ed., 2012,
51, 6439; (b) X. Tian and P. Melchiorre, Angew. Chem., Int. Ed., 2013,
52, 5360.
a
All reactions were performed with 6 (0.2 mmol) and 20 mol% TsOH under
reflux. b Isolated yield of 8. c Isolated yield of 9. d Determined by chiral HPLC.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 1745--1747 | 1747