A general, scalable, organocatalytic nitro-michael addition to enones: Enantioselective access to all-carbon quaternary stereocenters

Article abstract of DOI:10.1021/acs.orglett.5b00387

A tert-leucine-derived chiral diamine catalyzes the asymmetric Michael addition of nitromethane to five-, six-, and seven-membered -substituted cyclic enones with excellent enantioselectivity, offering scalable, asymmetric access to all-carbon quaternary

Full text of DOI:10.1021/acs.orglett.5b00387

Letter
pubs.acs.org/OrgLett
A General, Scalable, Organocatalytic Nitro-Michael Addition to
Enones: Enantioselective Access to All-Carbon Quaternary
Stereocenters
Xiaodong Gu, Yuanyuan Dai, Tingting Guo, Allegra Franchino, Darren J. Dixon,* and Jinxing Ye*
†
†
†
‡
,‡
,†
†Engineering Research Center of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East China
University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
‡
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, United
Kingdom
*
S Supporting Information
ABSTRACT: A tert-leucine-derived chiral diamine catalyzes the asymmetric Michael addition of nitromethane to five-, six-, and
seven-membered β-substituted cyclic enones with excellent enantioselectivity, offering scalable, asymmetric access to all-carbon
quaternary stereocenters. The reaction scope can be expanded to include linear acyclic enones, and excellent levels of
enantioselectivity are also observed. Furthermore, this organocatalytic, asymmetric nitro-Michael reaction is amenable to
multigram scale-up and applications in the construction of an eudesmane sesquiterpenoid skeleton.
3,4
he asymmetric construction of all-carbon quaternary
species.
Although transition metals and organometallic
T
stereocenters through efficient carbon−carbon bond
nucleophiles have been extensively applied in this trans-
formation, reports describing organocatalytic, metal-free ACA
to create all-carbon quaternary stereocenters are still scarce.
Nitroalkanes can be used as soft carbon pronucleophiles to
form fully substituted stereocenters by addition into β,β-
1
forming reactions is a challenging area of organic synthesis.
Their stereocontrolled formation plays a vital role in organic
chemistry because of the abundance of all-carbon quaternary
stereocenters in natural products and drugs. For instance, the
skeleton of several sesquiterpenes contains the structural
5
6
disubstituted enals or enones. To date, the organocatalytic
asymmetric nitro-Michael reaction has been mainly limited to
cyclic unactivated enones without β-branching with very few
2
feature shown in Figure 1.
Among the existing methods to build all-carbon quaternary
stereocenters, asymmetric conjugate addition (ACA) occupies a
prominent position. Asymmetric versions of the reaction can be
carried out in the presence of catalytic amounts of chiral ligands
and transition metal salts using a range of organometallic
6
exceptions. Recently, Kwiatkowski and co-workers demon-
strated the beneficial effect of high pressure (10 kbar) on the
challenging organocatalytic asymmetric conjugate addition of
6
d,f
nitroalkanes to sterically congested β,β-disubstituted enones.
Although good reaction rates and enantiocontrol can be
obtained, the high-pressure setup limits utility and prevents
easy scale-up of the reaction.
To circumvent the need for external pressure, we envisioned
a strategy in which a diamine organocatalyst of general
structure 4 (Figure 2) would be able to bring reaction partners
in close proximity, covalently binding the enone carbonyl group
(
iminium formation) and at the same time delivering the nitro
compound. We speculated that the secondary amine function
would provide the most beneficial hydrogen bonding capability
Figure 1. Selected examples of bicyclic sesquiterpene skeletons
containing all-carbon quaternary stereocenters.
Received: February 5, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00387
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of type 4 with different substituents. The catalytic performance
of diamines derived from tert-leucine (4a−d) turned out to be
strongly dependent on the nature of the ancillary (secondary or
tertiary) amine moiety. Catalyst 4a endowed with a propyl-
amine group afforded only 2% conversion over 24 h; however,
when the reaction time was extended to 7 days, the
enantiomeric excess of 7a was found to be 99% (entry 4).
9
Pleasingly, catalyst 4b, with a cyclohexylamine group, allowed
the reaction to reach 70% conversion and imparted excellent
enantioselectivity (entry 5). No reaction was observed using
catalysts 4c and 4d (entries 6−7), which possess an additional
tertiary amine functionality; this finding supports our
speculation regarding the key role of H-bond activation of
the nucleophile (Figure 2).
Two more diamines possessing the cyclohexylamino group
(
4e and f) were also tested; however, they resulted in lower
reaction rates (entries 8−9), thus demonstrating that both the
tert-leucine scaffold and the cyclohexylamine moiety are
required for optimal reactivity. When catalyst 4b was employed,
both the absence of any acidic additive and the use of 20 mol %
benzoic acid were detrimental to the reaction rate (entries 10−
Figure 2. Catalyst design for asymmetric nitro-Michael addition.
1
1).
The effect of solvent was investigated next. All solvents
for nitroalkane activation through a six-membered H-bonding
network.
except acetone provided moderate to excellent conversions and
outstanding enantioselectivity (see the Supporting Informa-
tion). With 5 mol % catalyst loading, it was still possible to
obtain conversions greater than 90% provided that the reaction
temperature was increased to 40 or 50 °C (entries 12−13).
With the optimized reaction conditions in hand, we assessed
the scope of the asymmetric Michael addition of nitromethane
to various five-, six-, and seven-membered β-substituted cyclic
enones for the generation of a quaternary stereocenter. All the
reactions proceeded with impressive stereochemical control
Aiming for activation and stereocontrol via iminium
7
8
organocatalysis, we screened the library of primary amines
depicted in Figure 2 in a test reaction between 3-
methylcyclohex-2-enone (5a) and nitromethane (6a). Reac-
tions were run for 24 h, and conversion was taken as a crude
indication of reaction rate. The primary amines 1−3 promoted
the reaction with good enantiocontrol but gave rise to
prohibitively slow reaction rates (Table 1, entries 1−3). We
then turned our attention to a series of more flexible diamines
(
96−99% ee) and moderate to good yields (Scheme 1). Most
Table 1. Diamine Organocatalyst Screening in the Michael
Addition between 5a and 6a
reactions were completed within 48 h, although longer reaction
times were required for the nitro-Michael additions to
cyclopentenones (7k and l) and for the reactions of substrates
with bulkier groups in the β positions (adducts 7e, g−i, and o).
To enhance the rate of formation of some sterically hindered
products (7g, j, and l), the catalyst loading was increased to 20
mol %, and nitromethane was used as solvent.
We next investigated nitro-Michael additions generating two
stereocenters. When 3-methylcyclohex-2-enone and 3-methyl-
cyclohept-2-enone reacted with nitroethane to afford adducts
7p and q, respectively, excellent enantioselectivity was observed
for both diastereoisomers, but the diastereomeric ratios were
close to 1:1, presumably due to facile epimerization of the
product nitroalkanes under the reaction conditions.
a
b
c
entry
catalyst
solvent
conv (%)
ee (%)
1
2
3
4
5
6
7
8
1
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH Cl
5
6
86
97
2
3
11
2
−99
d
4a
4b
4c
4d
4e
4f
4b
4b
4b
4b
99
70
0
99
0
The absolute configuration of compound 7a, determined by
10
33
15
10
15
97
94
98
87
96
96
99
99
single crystal X-ray crystallographic analysis on a derivative, is
consistent with the model presented in Figure 2.
9
e
1
1
1
1
0
1
2
3
Our catalytic methodology can be successfully applied to
simple, unsubstituted cyclic enones, thus expanding the scope
of the protocol (8a−c). These reactions proceeded with
excellent levels of enantioselectivity, although careful choice of
experimental conditions was needed to minimize the formation
of double Michael addition products and obtain good yields
(see the Supporting Information for details).
Good yields and excellent enantiocontrol were also achieved
in the nitro-Michael addition reactions to a range of β-alkyl and
β-aryl acyclic enones (8d−l). The reactions of nitromethane
with α,β-unsaturated, α′-methyl ketones were complete in 36−
f
g
h
2
2
MTBE
a
Reactions performed using 1.0 equiv of 5a (0.1 mmol, 0.5 M), 4.0
equiv of 6a, 0.1 equiv of catalyst, and 0.1 equiv of PhCO H, at 30 °C
2
b
c
for 24 h unless otherwise noted. Determined by GC. Determined by
HPLC on chiral stationary phase. Measured after 7 days. Without
PhCO H. With 0.2 equiv PhCO H. With 0.05 equiv of catalyst and
.05 equiv of PhCO H at 40 °C. With 0.05 equiv of catalyst and 0.05
d
e
f
g
2
2
h
0
2
equiv of PhCO H at 50 °C.
2
B
DOI: 10.1021/acs.orglett.5b00387
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Scope of the Asymmetric Nitro-Michael Addition
dioxane; the MVK Michael addition could be extended to ethyl
homologue 7b and cycloheptanone analogue 7m to give the
desired adducts 10 (Table 2, entries 1−3). Addition of 7a to
to Five-, Six-, and Seven-Membered β-Substituted Cyclic and
a
Acyclic Enones
Table 2. Michael Addition of 7 with Methyl Vinyl Ketone
a
and Ethyl Acrylate
R1
R2
product
yield (%)
b
entry
substrate
n
1
2
3
4
7a
1
1
2
1
Me
Et
Me
Me
Me
OEt
11a
11b
11c
11d
81
50
55
75
7b
7m
7a
Me
Me
a
Path A: 7 (1 equiv, 0.1 M), 9a (2 equiv), and K CO (1.2 equiv) in
2
3
dioxane at rt for 36 h. Path B: 7 (1 equiv, 0.1 M), 9b (2 equiv) and
b
TMG (1 equiv) in CH CN at rt for 48 h. Isolated yield over two
3
steps given.
ethyl acrylate required stoichiometric TMG in CH CN as the
3
promoter (Table 2, entry 4). Subsequently and in all cases, the
nitro group was removed smoothly with Bu SnH/AIBN,
3
affording dicarbonyl compounds 11a−d.
The desired aldol condensation of 11a (Scheme 2) was
found to proceed in refluxing dioxane using 1 equiv of solid
Scheme 2. Construction of a Sesquiterpenoid Skeleton
KOH, affording a 2:1 mixture of 12 and 13 in 61% yield.
Regioselective α-alkylations of this mixture provided com-
pounds 14 and 15 in moderate yields, the latter being a
11
precursor to eudesmane sesquiterpenes (Figure 1).
a
Reactions performed in CH Cl at 40 or 30 °C (only for 8a−i, k−l)
In summary, a powerful organocatalytic methodology to
generate all-carbon quaternary stereocenters operating via
Michael addition of nitroalkanes to β-substituted cyclic enones
under mild conditions has been developed. The feasibility of
scale-up was demonstrated using fairly low catalyst loadings (5
mol %) without affecting the excellent levels of enantiocontrol.
The nitro-Michael adducts can be readily elaborated into
interesting sesquiterpenoid skeletons. More thorough studies
on the large scale application of this organocatalytic method-
ology are ongoing in our laboratories, and the findings will be
reported in due course.
2
2
using 1.0 equiv of 5 (0.4 mmol, 0.5 M), 4.0 equiv of 6, 0.1 equiv of 4b,
and 0.1 equiv of PhCO H unless otherwise noted. Isolated yields are
given. Dr determined by GC. Ee determined by HPLC on chiral
2
b
stationary phase. With 0.05 equiv of 4b and 0.05 equiv of PhCO H.
2
c
d
With 0.2 equiv of 4b and 0.2 equiv of PhCO H in CH NO . In
2
3
2
e
CH NO (0.5 M). In AcOEt (0.5 M).
3
2
4
8 h, whereas enones with bulkier residues in the α′ position
required longer reaction times (8f, 8j−l).
A large scale preparation 7a was performed to investigate
scale-up suitability. In the presence of 5 mol % catalyst, 84 g of
product were obtained with 98% yield and 99% ee without the
need for chromatographic purification.
ASSOCIATED CONTENT
■
The applicability of this methodology was demonstrated by
the expeditious construction of a eudesmane sesquiterpenoid
skeleton. Initially, Michael additions between the nucleophilic
C-7 and simple α,β-unsaturated compounds, such as methyl
vinyl ketone (MVK, 9a) and ethyl acrylate (9b), were carried
out. Extensive screening of the conditions revealed that the
reaction of 7a with MVK could be promoted using K CO in
*
S
Supporting Information
Nitro-Michael additions, large scale Michael additions,
sesquiterpenoid skeleton syntheses, HPLC traces and NMR
spectra of Michael addition products, and determination of
absolute configuration. This material is available free of charge
via the Internet at http://pubs.acs.org.
2
3
C
DOI: 10.1021/acs.orglett.5b00387
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Majamder, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416. (c) Melchiorre,
P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47,
AUTHOR INFORMATION
Corresponding Authors
■
*
0
6
138. (d) Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.;
E-mail: yejx@ecust.edu.cn. Fax: 0086-21-64251830. Tel:
086-21-64251830.
E-mail: darren.dixon@chem.ox.ac.uk. Fax: 0044-1865-285002.
Tel: 0044-1865-275648.
Notes
Bertelsen, S.; Jørgensen, K. A. Chem. Commun. 2011, 47, 632. For
selected articles, see: (e) Xie, J.-W.; Chen, W.; Li, R.; Zeng, M.; Du,
W.; Yue, L.; Chen, Y.-C.; Wu, Y.; Zhu, J.; Deng, J.-G. Angew. Chem.,
Int. Ed. 2007, 46, 389. (f) Chen, W.; Du, W.; Duan, Y.-Z.; Wu, Y.;
Yang, S.-Y.; Chen, Y.-C. Angew. Chem., Int. Ed. 2007, 46, 7667.
*
(g) Wang, X.; Reisinger, C. M.; List, B. J. Am. Chem. Soc. 2008, 130,
The authors declare no competing financial interest.
6070.
(8) Selected examples of primary amine catalysts derived from amino
ACKNOWLEDGMENTS
acids: (a) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2005, 127, 10504.
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(
b) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F., III J. Am.
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This work was supported by the National Natural Science
Foundation of China (21272068), the Program for New
Century Excellent Talents in University (NCET-13-0800), the
Innovation Program of Shanghai Municipal Education
Commission (11ZZ56), the Fundamental Research Funds for
the Central Universities, and the People Programme (Marie
Curie Actions) of the European Union (A.F., FP7/2007-2013,
REA Grant Agreement 316955).
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DOI: 10.1021/acs.orglett.5b00387
Org. Lett. XXXX, XXX, XXX−XXX