Asymmetric organocatalytic synthesis of 2,3-allenamides from hydrogen-bond-stabilized enynamides

Article abstract of DOI:10.1021/acs.orglett.9b00839

Asymmetric catalytic synthesis of 2,3-allenamides from hydrogen-bond-stabilized enynamides in the presence of quinine-based bifunctional squaramide organocatalysts is described. This protocol forms a variety of 2,3-allenamides in high yields and excellent

Full text of DOI:10.1021/acs.orglett.9b00839

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Organocatalytic Synthesis of 2,3-Allenamides from
Hydrogen-Bond-Stabilized Enynamides
Zhi-Gang Ma,†,‡ Jie-Lu Wei,§,‡ Jun-Bing Lin,‡ Guan-Jun Wang,‡ Jia Zhou,‡ Kai Chen,‡
Chun-An Fan,*,† and Shu-Yu Zhang*,‡
†State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, China
‡Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering, Shanghai
Jiao Tong University, Shanghai 200240, China
§College of Chemistry & Pharmacy, Shaanxi Key Laboratory of Natural Products & Chemical Biology, Northwest A&F University,
Yangling, Shaanxi 712100, P. R. China
S
* Supporting Information
ABSTRACT: Asymmetric catalytic synthesis of 2,3-allena-
mides from hydrogen-bond-stabilized enynamides in the
presence of quinine-based bifunctional squaramide organo-
catalysts is described. This protocol forms a variety of 2,3-
allenamides in high yields and excellent stereoselectivities, in
which the elaborated introduction of intramolecular H-bonds
within the N,N-bidentate amide group constitutes one of the
keys to this highly enantioselective transformation. The
synthetic practicality of this reaction has been demonstrated by the axis-to-center chirality transfer of allenamides to furnish
enantiomerically enriched building blocks.
llenes featuring two perpendicular cumulated carbon−
direct preparation of 2,3-allenoates.6 In 2016, Feng and Liu
reported a highly efficient asymmetric 1,4-conjugate addition
of malonic esters to enynes with the assistance of an N,N′-
dioxide/scandium(III) complex, affording 2,3-allenyl ketones.7
Very recently, Jørgensen presented a prolinol silyl ether
promoted either aldehyde or α,β-unsaturated aldehyde
addition to alkynyl-substituted enones to yield chiral 2,3-
allenic ketones.8
However, as a nontrivial extension of these elegant works,
the catalytic 1,4-addition for asymmetric construction of 2,3-
allenamides remains elusive and unreported. Chiral allena-
mides are attractive intermediates for the construction of
multisubstituted azo-compounds and other interesting struc-
tures.4l,9,16 In this study, we present an effective methodology
for the direct asymmetric catalytic synthesis of 2,3-allenamides
from newly designed hydrogen-bond-stabilized enynamides in
combination with squaramide bifunctional catalysis.
Inspired by the pioneering asymmetric Michael addition/
isomerization reaction for the synthesis of 2,3-allenoates,6 we
originally envisioned that it might be possible to generate
chiral 2,3-allenamides by the cascade 1,4-addition/isomer-
ization reaction of nitromethane to enynamides by applying
bifunctional organocatalysis. In our initial experiments, only
1,4-addition products were detected when N,N-disubstituted
enynamides were employed (1ab and 1ac) (Scheme 2, eq 1).
A
carbon double bonds consist of one class of structurally
unique molecules in organic chemistry, and importantly the
allene units are widely distributed in natural products,
pharmaceuticals, and functional materials.1 Chiral allenes are
highly useful building blocks in organic synthesis and are even
designed as ligands/catalysts.2 Accordingly, the asymmetric
synthesis of multisubstituted allenes has received significant
research interest. Classical approaches mostly rely on the
resolution of preformed racemic allenes and chirality transfer
from enantiomerically enriched propargylic alcohols or amine
derivatives.3 Recently, some progress has been made in
catalyst-controlled stereoselective synthesis of functionalized
allenes from achiral precursors based on metal catalysis and
organocatalysis.4
As functionalized allenes, chiral 2,3-allenyl carbonyl
derivatives are important subsets that have a myriad of
applications.1−4 However, catalytic synthesis of these com-
pounds is rarely reported. Since Hayashi pioneered a metal-
catalyzed 1,4-addition to enynes for the synthesis of chiral
allenes and Tang subsequently developed an enantioselective
organic-catalyst-promoted intramolecular reaction, the 1,4-
addition for the preparation of allenes has made great
progress.5 In this context, the asymmetric 1,4-addition of
nucleophiles to conjugated enyne−carbonyl compounds has
become one of the most efficient approaches to generate
allenyl−carbonyl compounds (Scheme 1). In 2013, Zhang and
Sun first reported a quinoline thiourea-catalyzed enantiose-
lective 1,4-addition of nitroalkanes to activated enynes for the
Received: March 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00839
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Organic Letters
Letter
oxygen atom was unfavored. Based on our previous research
about the N-quinolone amide,12 this hypothesis might be
achieved with N-quinolone enynamides as the substrate due to
the interaction of its intramolecular H-bonds (Scheme 2, eq
3).13 This assumption was indeed supported by the H-bonds
(N−H···N and C−H···O) and approximately plane conforma-
tion of enyamide 1m observed in the X-ray crystal structure
(see SI), in which the oxygen and alkynyl group were on the
opposite side of the C−C single bond a. These H-bonds would
not only reduce the nucleophilicity of the oxygen atom but also
make the conformation of enynamides 1 unfavored for the
nucleophilic attack of the oxygen. Moreover, the intra-
molecular H-bonds might also intervene in the interaction
between the substrate and catalyst, according to previous
reports.14
Scheme 1. Catalytic Asymmetric 1,4-Addition for the
Synthesis of Allenes
Fortunately, the desired allene product 2a was unambigu-
ously obtained with N-quinolone enynamide 1a as the
substrate. Furthermore, the N-methyl-N-quinolone enynamide
1ah was proven to be unstable when we attempted to prepare
it (Scheme 2, eq 1). This result confirmed the stabilization
effect of H-bonds. Employing bifunctional amine-thiourea or
squaramides as the organocatalyst, we quickly identified VI as
the best catalyst, which furnished product 2a in high yield and
excellent enantioselectivity (Table 1, entries 1−6). Notably,
the thiourea catalyst IV, which had excellent performance in
addition/isomerization synthesis of allenoates, afforded only
70:30 er (entry 4).6 Further modifications of the catalyst
structure offered no improvement (entries 7 and 8).15
Assessment of the solvents identified o-xylene, which gave
the product in an enhanced 75% yield and 98:2 er (entries 9−
12). Finally, evaluation of the temperature and the ratio of
MeNO2/o-xylene did not improve the reaction results (entries
13−16).
Scheme 2. Preliminary Experiment and Our Design
With the optimized procedure in hand, we turned our
attention to examining the reaction scopes (Scheme 3).
Different aryl substitutions on the triple bond of enyne amides
were first studied. The substituents on the aromatic ring were
tolerated well, giving corresponding allenamides with moderate
to high yields. The electronic nature had little effect on the
enantioselective. Enynamides with an electron-rich methoxy or
tertiary butyl group gave the product 2 in similar or slightly
higher er than those with electron-deficient groups (F, Cl). 2-
Naphthyl (2i) and heteroarenes, 3-thienyl (2j) and 2-thienyl
(2k), did not hinder the reaction and furnished the desired
allenes 2 in moderate yields and high optical purities. The
lower yield for 2k could be ascribed to the instability of the 2-
thienyl enyne amide 1k. Encouraged by the successful
synthesis of chiral aryl-substituted allenamides, this method-
ology was applied to alkyl-substituted starting materials.
Gratifyingly, enyne amides bearing alkyl groups with different
steric and electronic properties were also applicable (2l, 2m,
and 2n).
To further confirm the stabilization of the intramolecular
hydrogen bonds, the focus was switched to other N-aryl
eneynamides containing intramolecular hydrogen bonds. As
expected, the corresponding products 2 were afforded in high
yields and excellent enantiomeric excess (2o and 2p). This
result highlighted the stabilization and facilitation effect of H-
bonds in our 1,4-addition/isomerization reaction for asym-
metric synthesis of 2,3-allenamides. In addition to nitro-
methane, nitrocyclopentane was examined as the nucleophile
under optimized reaction conditions (2q). The reaction can
also proceed with comparable yield but diminished enantio-
This result was presumably because of the inertia and rigidity
of amide derivatives so that the 1,4-addition products could
not isomerize to allenes.10 N-Alkyl and different electronic N-
aryl-substituted enynamides were more reactive but unstable.
The isolation of a pure such enynamide was complicated by its
decomposition during silica gel chromatography or concen-
tration and led to the presence of various byproducts, for
instance, the cyclization products obtained through the
nucleophilic attack of enol/enolate oxygen to the alkyne
moiety (1ad−1ag) (Scheme 2, eq 2).11 Although the desired
allene was not obtained, this result inspired us that the
allenamide might be synthesized from stabilized enynamide.
The enynamide might be stabilized by the regulation of its
molecular conformation and increased the barrier to rotation
of the C−C bond a, so that the nucleophilic attack of the
B
DOI: 10.1021/acs.orglett.9b00839
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Organic Letters
Letter
a
a
Table 1. Condition Optimization
Scheme 3. Substrate Scope
b
c
entry
conditions
I, DCE, rt
II, DCE, rt
III, DCE, rt
IV, DCE, rt
yield (%)
er (%)
1
2
3
4
5
6
7
8
63
43
50
68
53
73
43
60
80
72
65
75
58
68
71
76
87.5:12.5
25.5:74.5
77.5:22.5
70:30
8.5:91.5
97:3
V, DCE, rt
VI, DCE, rt
VII, DCE, rt
VIII, DCE, rt
VI, toluene, rt
VI, MeCN, rt
VI, THF, rt
VI, o-xylene, rt
VI, o-xylene, 0 °C
VI, o-xylene, rt
VI, o-xylene, rt
VI, MeNO2, rt
91.5:8.5
91:9
9
97:3
94:6
10
11
12
13
95.5:4.5
98:2
98:2
97:3
d
14
15
16
e
96.5:3.5
96:4
f
a
Reaction conditions: 1a (0.2 mmol), 4 Å molecular sieve (MS) and
organocatalyst (10 mol %) in MeNO2/solvent (2.0 mL, 1:1) stirred at
b
c
the indicated temperature for 24 h. Isolated yield. Determined by
d
e
HPLC analysis. o-Xylene/MeNO2 (4:1). o-Xylene/MeNO2 (1:4).
Only MeNO2 was used as the solvent.
f
selectivity (60% yield, 72:28 er). Finally, this protocol was
applied to the late-stage combination of a chiral allene unit
with bioactive steroids, affording 2r in 51% yield and 4:1 dr
under standard conditions, regardless of the steric hindrance
introduced by the steroids. These results demonstrated the
good functional group compatibility of our method and the
potent bioapplication of our allenamides as imaging units.
To demonstrate the application of our method (Scheme 4),
the 1,4-addition/isomerization reaction was performed on a
gram scale (1.04 g, 3.5 mmol of 1a), and product 2a was
obtained without compromising the yield (82%) or optical
purity (98:2 er) (eq 1). Additionally, the resulting axially chiral
allene was transformed to densely functionalized compounds
with central chirality. As illustrated in Scheme 4, the Diels−
Alder reaction of chiral 2a with freshly distilled cyclo-
pentadiene at 80 °C in toluene led to the formation of a
mixture of adducts (endo:exo = 3.7:1), in which good chirality
transfer was observed in both the favored endoproduct 3b
(95:5 er) and exoproduct 3b′ (96:4 er) (eq 2).16 Finally, the
chiral allenamide 2a was submitted to a palladium-catalyzed [3
+ 2] cycloaddition reaction with vinyl epoxides.17 The
resulting tetrahydrofuran 3c bearing two vicinal quaternary
stereocenters was obtained with maintained enantioselectivity
a
Reaction conditions: 1 (0.2 mmol), 4 Å MS (40 mg), and VI (10
mol %) in MeNO2/o-xylene (2.0 mL, 1:1) stirred at room
b
temperature for 24 h. Run with 10 equiv of nitrocyclopentane for
4 days.
(97:3 er) in high yield (80%) and good diastereoselectivity
(9:1) (eq 3). These transformations of the resulting allenes
into highly functionalized compounds with axial chirality being
entirely converted to point chirality demonstrated that our
allenamides are conceivably important chiral intermediates in
organic synthesis.
A plausible reaction pathway was proposed in Scheme 5.
The reaction is believed to begin with deprotonation of the
nitromethane by the quinuclidine tertiary amine (TS1).
Afterward, formation of the carbon−carbon bond between
the nitrate anion and the electrophile was facilitated by the
protonated catalyst through multiple hydrogen bonds. Once
C
DOI: 10.1021/acs.orglett.9b00839
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Organic Letters
Letter
Scheme 4. Synthetic Applicability
Experimental procedures and characterization data of all
new compounds (PDF)
Accession Codes
CCDC 1894368 and 1894371 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: fanchunan@lzu.edu.cn.
*E-mail: zhangsy16@sjtu.edu.cn.
ORCID
Chun-An Fan: 0000-0003-4837-3394
Shu-Yu Zhang: 0000-0002-1811-4159
Notes
The authors declare no competing financial interest.
Scheme 5. Proposed Approaching Models for the Addition
and Protonation Steps
ACKNOWLEDGMENTS
■
This work was supported by the “Thousand Youth Talents
Plan”, NSFC (21672145 and 51733007), Shanghai Science
and Technology Committee (17JC1403700), the Drug
Innovation Major Project of the Ministry of Science and
Technology of China (2018ZX09711001-005-002), and
Shanghai Sailing Program (17YF1409000). We thank Prof.
Hong-Liang Zhong (Shanghai Jiao Tong University) for
helpful discussion and Dr. Ling−Ling Li (Shanghai Jiao
Tong University) for assistance with X-ray diffraction and
intramolecular H-bonds analysis.
the adduct formed, the negative charge was located not in the
nitro moiety but in the enol/enolate site. Thus, the H-bonds
between nitryl and protonated quinuclidine weakened, and
several hydrogen bonds between the quinolone moiety and
enol/enolate formed. Finally, the enol/enolate intermediate
was highly ordered by multiple hydrogen bonds, as shown in
TS2, so that the front face proton transfer would deliver either
directly from the conjugate acid of the catalyst or mediated by
a proton-shuttle mechanism. Therefore, the configuration of
the adduct was controlled by the highly ordered transition
state.6,18 This rationale is consistent with the absolute
configuration (Ra) of product 2e determined by X-ray crystal
structural analysis (see SI).
In summary, we have developed the first enantioselective
synthesis of 2,3-allenamides using a 1,4-addition/isomerization
methodology from hydrogen-bond-stabilized enynamides with
commercially available organocatalysts. The intramolecular
hydrogen bond of enynamides plays an important role in our
reaction, and the chemical versatility of thus-obtained allenes is
also illustrated. Gram-scale synthesis of the product and its
good axis-to-center chirality transfer demonstrated the
potential practicality of our methodology. This H-bond
stabilization strategy opens a door for chiral 2,3-allenamide
synthesis.
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