Asymmetric catalytic conjugate addition of acetaldehyde to nitrodienynes/nitroenynes: Applications to the syntheses of (+)-α-lycorane and chiral β-alkynyl acids

Article abstract of DOI:10.1021/ol501158b

The catalytic enantioselective conjugate addition of acetaldehyde to polyconjugated substrates, nitrodienynes and nitroenynes, has been accomplished using organocatalysis. Various functionalized 1,3-enynes and propargylic compounds were obtained in modera

Full text of DOI:10.1021/ol501158b

Letter
pubs.acs.org/OrgLett
Asymmetric Catalytic Conjugate Addition of Acetaldehyde to
Nitrodienynes/Nitroenynes: Applications to the Syntheses of (+)-α-
Lycorane and Chiral β‑Alkynyl Acids
Xue-Ling Meng,† Teng Liu,† Zhong-Wen Sun, Jin-Chen Wang, Fang-Zhi Peng,* and Zhi-Hui Shao*
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology,
Yunnan University, Kunming, Yunnan 650091, P. R. China
S
* Supporting Information
ABSTRACT: The catalytic enantioselective conjugate addition of
acetaldehyde to polyconjugated substrates, nitrodienynes and
nitroenynes, has been accomplished using organocatalysis. Various
functionalized 1,3-enynes and propargylic compounds were
obtained in moderate to good yields with high enantioselectivity.
The synthetic utilities of the conjugate addition reactions have
been highlighted in the concise total synthesis of (+)-α-lycorane
and the metal-free synthesis of chiral β-alkynyl acids.
he direct catalytic asymmetric conjugate addition of
nitrodienynes.7 Herein we describe the first conjugate addition
Tcarbonyl compounds to electron-deficient alkenes is one of acetaldehyde to nitrodienynes. This process, which is
catalyzed by a simple and commercially available chiral
organocatalyst, provides various highly functionalized 1,3-
enynes in moderate to good yields with high enantioselectivity.
The utility of this conjugate addition is illustrated in the context
of application to the concise total synthesis of (+)-α-lycorane.
In addition, the conjugate addition of acetaldehyde can be
extended to other polyconjugated substrates such as nitro-
enynes. Based on the development of this reaction, the metal-
free, organocatalytic synthesis of chiral β-alkynyl acids has been
achieved.
Chiral β-alkynyl acids represent an important class of
pharmaceutical compounds with diverse biological activities,
including PDE IV inhibitors, TNF inhibitors, GPR40 receptor
agonists, and GRP receptor antagonists.10 However, their
asymmetric synthesis remains a significant challenge. To date
only several asymmetric syntheses have been reported.11
Nevertheless, all these syntheses require the use of transition
metals in the key chiral center generation step. Removing
residual metals from the reaction mixtures is an important issue
in the pharmaceutical industry. Thus, the development of a
metal-free asymmetric synthesis of β-alkynyl acids is highly
desirable. To our surprise, there are no reports of a metal-free,
organocatalytic asymmetric synthesis of this important class of
compounds12 despite the obvious advantages of organo-
catalysis.13
of the most powerful tools for carbon−carbon bond
formation.1 Despite remarkable progress, the direct conjugate
addition reaction of acetaldehyde, the simplest enolizable
carbonyl compound, remains a challenge since acetaldehyde
acts as both a highly reactive nucleophile and electrophile, thus
leading to its rapid consumption by self-aldolization. Moreover,
the addition product possesses a reactive α-unsubstituted
aldehyde moiety that can potentially react further to generate
several side products.2 In 2008, the research groups of List and
Hayashi independently reported for the first time the
asymmetric conjugate addition of acetaldehyde to nitroolefins
using organocatalysis.3 Subsequently, several works on organo-
catalytic reactions involving acetaldehyde and nitroolefins have
been reported.4 In these previous reports, however, only simple,
nonfunctionalized β-nitroolefin substrates were used. There-
fore, the potential applications of these reactions are severely
limited.
In recent years, the conjugate addition of polyconjugated
substrates using metal catalysis and organocatalysis have
received increasing attention.5 However, the corresponding
conjugate addition with acetaldehyde as a nucleophile remains
elusive,6 despite the potential utility of the resulting products.
Thus, we commenced studies on this topic. In this context, we
first selected conjugate nitrodienynes recently introduced by
our group7 as polyconjugated substrates to react with
acetaldehyde since such a process would provide an
unreported, catalytic method to 1,3-enynes, which are
important structural motifs found in many natural products
and drugs,8 as well as versatile building blocks for organic
synthesis.9
The conjugate addition reaction of acetaldehyde with
nitrodienyne 1a was selected as the model reaction (Table
1). Catalyst screening indicated diarylprolinol silyl ethers14
were suitable catalysts (entries 2−6). Interestingly, trifluor-
Very recently, we have reported the enantioselective nickel-
catalyzed conjugate addition of 1,3-dicarbonyl compounds to
Received: April 21, 2014
Published: May 8, 2014
© 2014 American Chemical Society
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Letter
Heteroaryl-substituted nitro dienyne was also a suitable
substrate (entry 6). Notably, alkyl-substituted nitrodienyne
also afforded the corresponding product in good enantiose-
lectivity, albeit in moderate yields (entry 7). It is noteworthy
that no 1,6- or 1,8-addition was observed in all cases.
Table 1. Screening and Optimization of Organocatalysts and
Solvents
The catalytic asymmetric conjugate addition of acetaldehyde
to nitrodienynes could be performed on a gram scale (eq 1).
a
b
entry
catalyst
solvent
yield (%)
ee (%)
The presence of multifunctional groups such as nitro, formyl,
and enyne groups makes the conjugate addition products
obtained here important chiral building blocks in complex
molecule synthesis. The utility of the products was demon-
strated by the enantioselective total synthesis of (+)-α-lycorane.
There are only three asymmetric formal or total syntheses of
(−)-α-lycorane.15 Very recently, our group described the total
synthesis of (+)-α-lycorane, with a key nickel-catalyzed
enantioselective conjugate addition of di-tert-butyl malonate.16
We envisioned that the conjugate addition product 3 would
provide a suitable framework for the more concise, second-
generation total synthesis of (+)-α-lycorane using organo-
catalysis. As shown in Scheme 1, Pinnick oxidation17 of chiral 3
1
2
3
4
5
6
7
8
9
10
Ia
Ib
Ic
Id
Ie
II
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
trace
81
60
70
80
70
60
56
55
60
N. D.
93
90
94
94
94
Ib
Ib
Ib
Ib
95
CHCl3
81
CH3CN
88
EtOH
93
a
All reactions were performed at the 0.2 mmol scale using 10 equiv of
acetaldehyde with 10 mol % of catalyst. Determined by chiral HPLC.
b
Scheme 1. Organocatalytic Enantioselective Total Synthesis
of (+)-α-Lycorane
omethyl-substituted diarylprolinol silyl ether II, which was a
less reactive organocatalyst in the conjugate addition of
acetaldehyde to β-nitroolefins,3 was effective and provided the
conjugate addition product 2a in good enantioselectivity and
yield (entry 6). Finally, simple and commercially available chiral
diphenylprolinol trimethylsilyl ether Ib was selected as the
organocatalyst. Further optimization by variation of the solvent
was conducted, and 1,4-dioxane gave the best results. The use
of ethanol as solvent also provided good enantioselectivity and
yield (entry 10).
With the optimized reaction conditions in hand, the reaction
scope was then examined. As shown in Table 2, aryl-substituted
nitrodienynes bearing both electron-rich and -deficient aryl
groups provided highly functionalized 1,3-enyne products in
good yields with high enantioselectivity (entries 2−5).
Table 2. Catalytic Asymmetric Conjugate Addition of
Acetaldehyde with Various Nitrodienynes
a
b
entry
R
product
yield (%)
ee (%)
1
2
3
4
5
6
7
C6H5
2a
2b
2c
2d
2e
2f
81
61
65
65
70
75
51
93
84
95
85
98
86
88
4-MeO-C6H4
1,3-benzodioxole
3-Me-C6H4
4-Cl-C6H4
2-thienyl
followed by TsOH-mediated alkyne hydration provided α,β-
enone acid 5, an intermediate previously employed in our first-
generation synthesis of (+)-α-lycorane. Following the proce-
dure utilized in the first-generation synthesis of (+)-α-
lycorane,16 compound 5 was transformed into functionalized
cyclohexane 6 by a three-step sequence. With 6 in hand, we
Me
2g
a
All reactions were performed at the 0.2 mmol scale using 10 equiv of
acetaldehyde with 10 mol % of catalyst. Determined by chiral HPLC.
b
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Letter
took a significantly improved route which was different from
the first-generation campaign. Hydrogenation of 6 with Raney
nickel resulted in the direct formation of bicyclic lactam 7,
where a three-step, one-pot cascade reaction involving removal
of thioketal, reduction of the nitro group, and cyclization
occurred. Then 7 underwent a Pictet−Spengler-type cyclization
followed by LiAlH4 reduction which afforded (+)-α-lycorane.
All of the spectroscopic data for synthetic (+)-α-lycorane were
in accordance with the data reported previously.15c
Finally, the catalytic asymmetric conjugate addition reactions
of acetaldehyde to other polyconjugated substrates were
examined. Although nitrodienes were less suitable substrates,
nitroenynes18 were effective and provided the desired
products19 with a chiral carbon center at the propargylic
position20 (Scheme 2).
tural motifs found in natural products and drugs, in moderate
to good yields with high enantioselectivity. The synthetic utility
of this reaction has been highlighted in the significantly
improved second-generation total synthesis of (+)-α-lycorane.
Additionally, the catalytic enantioselective conjugate addition of
acetaldehyde to other polyconjugated substrates such as nitro
enynes has also been established. Based on the development of
this reaction, we have accomplished the metal-free, organo-
catalytic approach to chiral β-alkynyl acids. This synthesis
shows remarkable advantages to previous syntheses of this class
of compounds.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectral data, and copies of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Scheme 2. Catalytic Asymmetric Conjugate Addition of
Acetaldehyde to Nitroenynes
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zhihui_shao@hotmail.com (Z. Shao).
*E-mail: pengfangzhi@ynu.edu.cn (F. Peng).
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The conjugate products here were readily converted into
functional molecules. In view of the broad synthetic and
pharmacological utility of chiral β-alkynyl acids, we became
interested in establishing a metal-free route to the compounds
of this class. Thus, the conjugate adducts underwent the
Pinnick oxidation17 to furnish the corresponding chiral β-
alkynyl acids (Scheme 3). Recently, we also reported an
We gratefully acknowledge financial support from the NSFC
(21162034, 21372193, 21362040), the Program for Changjiang
Scholars and Innovative Research Team in University
(IRT13095), the Doctoral Fund of Ministry of Education of
China (20135301110002), the Government of Yunnan
Province (2012FB114, 2013FA026), and the Program for
Excellent Young Talents, Yunnan University.
Scheme 3. Metal-Free, Organocatalytic Synthesis of Chiral β-
Alkynyl Acids
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