Organocatalytic enantioselective synthesis of 2,3-allenoates by intermolecular addition of nitroalkanes to activated enynes

Article abstract of DOI:10.1021/ja409080v

The first efficient intermolecular addition of nitroalkanes to activated enynes for asymmetric synthesis of 2,3-allenoates is described. It is a new addition to the limited available strategies for catalytic asymmetric synthesis of allenoates. Enabled by a new bifunctional catalyst, a range of trisubstituted allenoates can be obtained in excellent chemical and optical purity. These allenoate products with a pendant 2-nitroethyl α-substituent are useful chiral building blocks.

Full text of DOI:10.1021/ja409080v

Communication
pubs.acs.org/JACS
Organocatalytic Enantioselective Synthesis of 2,3-Allenoates by
Intermolecular Addition of Nitroalkanes to Activated Enynes
Hui Qian,† Xiuzhao Yu,‡ Junliang Zhang,*,‡ and Jianwei Sun*,†
†Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR,
China
‡Department of Chemistry, East China Normal University, Shanghai 200062, China
S
* Supporting Information
synthesis of allenoates from activated enynes has been realized
by us.10a−c In continuation of our effort in asymmetric allenoate
ABSTRACT: The first efficient intermolecular addition of
synthesis,10d we envisioned that a stereocontrolled intermolec-
nitroalkanes to activated enynes for asymmetric synthesis
of 2,3-allenoates is described. It is a new addition to the
limited available strategies for catalytic asymmetric syn-
thesis of allenoates. Enabled by a new bifunctional catalyst,
a range of trisubstituted allenoates can be obtained in
excellent chemical and optical purity. These allenoate
products with a pendant 2-nitroethyl α-substituent are
useful chiral building blocks.
ular nucleophilic addition to activated enynes can afford
enantioenriched allenes, provided that a suitable chiral bifunc-
tional catalyst could activate both the nucleophile and the
electrophile. Our initial attempt was focused on the use of
nitroalkanes as the nucleophile in view of their wide success in
stereoselective nucleophilic addition reactions.11
We started to evaluate our hypothesis with enyne 1a.
Nitromethane was initially employed as nucleophile as well as
cosolvent (Table 1). Preliminary evaluation of some chiral base
catalysts, such as cinchona-based amines Q1−3 and chiral
symmetric synthesis is fundamentally important in organic
Achemistry in view of the wide applications of enantioen- guanidine G1,8a indicated that the desired allenoate 3a could
riched materials.1 Over the past few decades, there has been
indeed be obtained in moderate yield but with good
enantioselectivity when bifunctional amine-thiourea catalyst
Q3 was used (entries 1−4).12 The reaction also gave byproduct
alkynoate 4a as a result of direct conjugate addition. Such
alkynoates are common byproducts for the synthesis of
allenoates, and base-catalyzed isomerization of alkynoates to
allenoates has been reported.8a−c,10d However, it is worth
mentioning that the previously reported catalyst of choice (G1)
for such isomerization was not capable of catalyzing the present
intermolecular addition reaction (entry 3), emphasizing the
importance of the bifunctional nature of Q3. Subsequent
modifications of the catalyst structure aiming at improving the
reaction efficiency and enantioselectivity have been tedious.
Selected results are shown (entries 4−11). Removing the
methoxy group in the quinioline moiety (Q4) resulted in both
decreased yield and diminished ratio of 3a/4a. Replacing the
thiourea unit by a guanidine (Q5) proved inferior. Tuning the
electronic property of the aryl group did not improve the results
(Q6−7). Replacing the thiourea moiety with a squaramide
(Q8) resulted in decreased enantioselectivity. After considerable
effort, we were pleased to find that saturation of the terminal
olefin unit in the cinchona backbone can improve both chemical
efficiency and stereoselectivity. Particularly, the reaction with
the new catalyst Q10, where a silyl group was incorporated,
gave both good product yield and enantioselectivity (91% ee
and 84% yield, entry 11). Brief examination of other reaction
parameters, such as solvent and temperature as well as cosolvent
ratio, identified the best conditions (Q10, DCM/2a = 4:1, 0 °C,
entry 18).
significant progress in establishing central chirality and two-
point axial chirality (e.g., BINAP). In sharp contrast, efficient
generation of three-point axial chirality, such as that in allenes,
has met with very limited success and still remains challenging
today.2 On the other hand, enantioenriched allenes are tre-
mendously important not only because of their wide occurrence
in natural products and biologically active compounds as well as
functional materials but also due to their versatility in organic
synthesis as chiral building blocks and even chiral ligands/
catalysts.3−6
2,3-Allenoates represent a particularly useful subset of allenes
with demonstrated utility.2−5 In the past two decades,
substantial efforts have been paid to the asymmetric synthesis
of 2,3-allenoates. However, for a long time, successful methods
were largely limited to the use of enantioenriched substrates or
stoichiometric amounts of chiral promoters/auxiliaries.7 Truly
catalytic asymmetric synthesis of 2,3-allenoates has not been
realized until recently.8,9 Early examples include isomerization
of alkynoates catalyzed by a chiral base (Tan and Takemoto)8a−c
and kinetic resolution of racemic allenoates (Gong).8d During
the preparation of our manuscript, Maruoka, Frantz, and Ma
independently reported three efficient protocols: phase-transfer-
catalyzed deprotonation of doubly activated allenoates followed
by substitution,8e asymmetric β-hydride elimination of enol
triflates,8f and asymmetric carbonylation of propargylic carbo-
nates,8g respectively. Herein we report a new synthesis of
trisubstituted 2,3-allenoates with bifunctional catalysis.
Catalytic synthesis of chiral electron-rich and normal allenes
by metal-catalyzed enyne addition was pioneered by Hayashi.9a−e
Tang also reported an intramolecular enyne addition for the
asymmetric synthesis of bromoallenes.9f Recently, racemic
Received: September 2, 2013
Published: November 13, 2013
© 2013 American Chemical Society
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Journal of the American Chemical Society
Communication
major product. It is obvious that 4a was subsequently converted
to allenoate 3a. It is worth mentioning that the alkynoate 4a was
obtained in enantioenriched form, and the ee values of both 3a
and 4a remained constant during the reaction progress (95 1%
ee and 90 1% ee, respectively). To further probe the nature
of the isomerization between 3a and 4a, we treated pure 3a
and 4a, respectively, with Q10 (20 mol %, DCM, 0 °C). As
shown in eq 1, both racemic and enantioenriched 4a could
be quantitatively isomerized to allenoate 3a with the same
enantioselectivity. In contrast, 3a remained untouched under the
same conditions (eqs 2−3). Particularly noteworthy is the
Table 1. Condition Optimization
a
b
c
entry catalyst
solvent/2a (v/v)
yield (3a)
ee (3a)
3a/4a
1
Q1
Q2
10%
<5%
<5%
36%
24%
17%
42%
51%
60%
53%
84%
46%
74%
60%
44%
87%
67%
−24%
0%
2.5:1
−
−
1.3:1
0.8:1
0.3:1
0.8:1
6:1
d
2
3
d
G1
−
4
Q3
84%
84%
67%
47%
5%
5
Q4
6
Q5
7
Q6
8
Q7
DCM/2a (1:1)
9
Q8
78%
91%
91%
83%
87%
88%
84%
90%
91%
96%
3.0:1
2.3:1
10:1
5.3:1
5.6:1
6.7:1
3.8:1
10:1
11:1
8.4:1
10
11
12
13
14
15
16
17
Q9
Q10
Q10
Q10
Q10
Q10
Q10
Q10
Q10
THF/2a (1:1)
Et2O/2a (1:1)
toluene/2a (1:1)
2a only
DCM/2a (4:1)
DCM/2a (9:1)
DCM/2a (4:1)
unchanged optical purity of racemic 3a, indicating the
isomerization is irreversible. The failure to observe any starting
1a in these reactions (eq 1−3) suggests that the first step
(nitroalkane addition) is also irreversible. Thus, catalyst Q10 is
capable of catalyzing both the addition and the isomerization.
Inspired by the above results, we were curious about the
possibility of improving the product purity (allenoate/alkynoate
ratio). Thus, we subjected the isolated product mixture of 3a/
4a (12:1 ratio) to the isomerization conditions (eq 4). To our
delight, 3a was obtained in essentially pure form without
e
f
18
89%
a
The reaction was run with 1a (0.1 mmol), catalyst (0.02 mmol), and
solvent (1.0 mL) for 12 h. The yield was determined by GC analysis
b
with n-decane as an internal standard. The ee value was determined
c
by HPLC. The ratio was determined by 1H NMR of the crude
d
e
f
mixture. Low conversion. Run at 0 °C. Isolated combined yield of
3a and 4a.
erosion in its optical purity. We have confirmed that this iso-
merization step can be retarded by the presence of nitro-
methane, which explains the slow and/or incomplete isomer-
ization under the standard one-pot conditions.
In order to know the possible interconversion of 3a and 4a,
With the established reaction conditions and the option to
further improve the product purity by isomerization (eq 4), we
next examined the reaction scope. As shown in Table 2, a wide
range of enynes and nitroalkanes can participate smoothly
in the efficient process to form the desired trisubstituted
allenoates 3 (mostly in pure form) with excellent efficiency and
enantioselectivity. Allenoates with different ester groups, such
as alkyl and aryl groups with different steric and electronic
properties, can all be synthesized efficiently (3a−f). Enynes
with different substituents on the triple bond, including aryl and
bulky alkyl groups, are suitable substrates. The mild conditions
can tolerate a variety of functional groups, such as esters,
mesylates, amides, ethers, nitriles, etc. In addition to nitro-
methane, other nitroalkanes with α-hydrogen are also excellent
nucleophiles for this process (3q−v). It is worth mentioning
that with a reduced catalyst loading (e.g., 10 mol %), the
reaction can also proceed with comparable efficiency and
enantioselectivity, except that the initially obtained 3/4 ratio is
lower but can be enhanced by isomerization. With a reduced
we monitored the reaction progress by GC (Figure 1). Under
Figure 1. Reaction progress monitored by GC analysis with ndecane
as the internal standard.
the standard conditions (Table 1, entry 18), the reaction reached
full conversion within 5 h, producing alkynoate 4a initially as the
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Communication
a
Table 2. Reaction Scope
a
b
The reaction was run with 0.5 mmol of enyne 1. The loading of nitroalkane: 35 equiv for MeNO2 and 9 equiv for other nitroalkanes. The ratio in
c
the parentheses is after isomerization with Q10, as shown in eq 4. This entry has also been run with 1.2 equiv of nitroalkane. It was incomplete after
66 h. More nitroalkane (additional 1.8 equiv) was added. After additional 20 h: 3v/4v >25:1, 83% yield, 94% ee.
loading of the nitroalkane, the reaction could also give compar-
able results, although an extended reaction time is required
(Table 2, footnote for 3v). Finally, the catalyst Q10 used in our
reaction has all been recovered in excellent yield by silica gel
chromatography, and the recovered catalyst was proved to be
equally effective.
To further confirm the competence of Q10 as an excellent
isomerization catalyst for enantioselective synthesis of allenoates
from racemic alkynoates, we have separately synthesized racemic
alkynoate 5 and tested its isomerization. As shown in eq 5, in
the presence of Q10, the asymmetric isomerization proceeded
smoothly at 40 °C to afford allenoate 6 with both excellent
efficiency and enantioselectivity.8a−c
nitrogen. As shown in TS1, the resulting conjugate acid of the
catalyst has multiple interactions with the nucleophile and
electrophile: (1) the double hydrogen bonding between the
thiourea moiety and the nitro anion; (2) the ammonium unit can
also activate the electrophile by hydrogen bonding with the
carbonyl group. Thus, this highly ordered transition state, in which
both of the reaction partners are oriented by the catalyst, facilitates
the C−C bond formation with a low-activation barrier. The initially
formed enol/enolate intermediate is planner and achiral. Thus, the
following proton shift determines the product stereochemistry. As
shown in TS2, the planar enol intermediate is oriented by multiple
hydrogen bonds so that the proton from the thiourea N−H is
delivered to the front face of the γ-position to form the desired
allenoate product, in which the catalyst serves as a chiral proton
shuttle.13,14 Overall, the bifunctional feature of the catalyst is not
only important for lowering the activation barrier in the first C−C
bond formation step but also crucial to the second stereocontrolled
protonation step. The rationale is consistent with the observed
product absolute stereochemistry as well as the incompetence of
some monofunctional catalysts during catalyst screening.
We have carried out some derivatizations to demonstrate the
utility of the allenoate products. For example, in the presence of
CuBr2 as the promoter, the enantioenriched allenoate 3u
underwent efficient cyclization to form the highly substituted
lactone 7. Particularly notable is the excellent axial-to-central
chirality transfer (eq 6).15 Additionally, nucleophilic γ-additions
of allenoates have been well-explored.16 It is also noteworthy
We have proposed two transition states to rationalize the
reaction mechanism and the origin of the observed absolute
stereochemistry (Figure 2). We believe that the reaction begins
with deprotonation of the nitroalkane by the quinuclidine
that the allenoates synthesized in our reaction have a 2-nitroethyl
substituent at the α position, which can serve as an intramolecular
nucleophile to add to the γ-position (see SI). Such allenoates have
never been efficiently synthesized before, even in racemic form.
Figure 2. Plausible transition states.
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Pu, X.; Qi, X.; Lynch, V.; Radha, A.; Ready, J. M. J. Am. Chem. Soc.
2011, 133, 18066.
In summary, we have developed the first intermolecular
asymmetric synthesis of 2,3-allenoates by bifunctional catalysis.
It is a new addition to the small family of catalytic asymmetric
syntheses of allenoates without using stoichiometric amounts
of chiral reagents or starting materials. Enabled by the new
bifunctional catalyst, the reactions between various nitroalkanes
and activated enynes proceed efficiently under mild conditions
with good functional group compatibility, and these trisub-
stituted allenoates were mostly obtained in excellent optical as
well as chemical purity (without contamination by alkynoates).
The cinchona-based thiourea catalyst is crucial to the success
because it not only provides a highly ordered transition state to
promote the first C−C bond formation but also serves as an
excellent proton shuttle in the second enantioselectivity-
determining step. Moreover, it can also function as an excellent
isomerization catalyst for the conversion from racemic
alkynoates to highly enantioenriched allenoates. These trisub-
stituted allenoates with a pendant 2-nitroethyl α-substituent
have been synthesized for the first time, and they are versatile
synthetic intermediates toward other useful building blocks.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Examples of catalytic asymmetric synthesis of allenes other than
2,3-allenoates: (a) Matsumoto, Y.; Naito, M.; Uozumi, Y.; Hayashi, T.
J. Chem. Soc., Chem. Commun. 1993, 1468. (b) Han, J. W.; Tokunaga,
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M.; Ikeda, H.; Nagano, T.; Hayashi, T. J. Am. Chem. Soc. 2001, 123,
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(e) Nishimura, T.; Makino, H.; Nagaosa, M.; Hayashi, T. J. Am. Chem.
Soc. 2010, 132, 12865. (f) Zhang, W.; Zheng, S.; Liu, N.; Werness, J.
B.; Guzei, I. A.; Tang, W. J. Am. Chem. Soc. 2010, 132, 3664.
(g) Imada, Y.; Nishida, M.; Kutsuwa, K.; Murahashi, S.-I.; Naota, T.
AUTHOR INFORMATION
Corresponding Authors
sunjw@ust.hk
■
jlzhang@chem.ecnu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Org. Lett. 2005, 7, 5837. (h) Sapu, C. M.; Backvall, J.-E.; Deska, J.
̈
Financial support was provided by Hong Kong RGC (ECS-
605812) and Science and Technology Commission of Shanghai
Municipality (12XD1402300).
Angew. Chem., Int. Ed. 2011, 50, 9731. (i) Boutier, A.; Kammerer-
Pentier, C.; Krause, N.; Prestat, G.; Poli, G. Chem.Eur. J. 2012, 18,
3840. (j) Li, H.; Muller, D.; Guenee, L.; Alexakis, A. Org. Lett. 2012,
14, 5880. (k) Li, Z.; Boyarskikh, V.; Hansen, J. H.; Autschbach, J.;
Musaev, D.; Davies, H. M. L. J. Am. Chem. Soc. 2012, 134, 15497.
(l) Wan, B.; Ma, S. Angew. Chem., Int. Ed. 2013, 52, 441.
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