Asymmetric “Acetylenic” [3+2] Cycloaddition of Nitrones Catalyzed by Cationic Chiral PdII Lewis Acid

Article abstract of DOI:10.1002/asia.201801016

Highly enantioselective [3+2] cycloaddition of ynones and nitrones has been developed. Very bulky ligand, DTBM-SEGPHOS, was used for an effective asymmetric induction over distal reaction centers on the linear ynone dipolarophile and for prevention of Pd^II catalyst deactivation by coordination of the nitrones. The reaction has wide scope of substrates in both ynones and nitrones.

Full text of DOI:10.1002/asia.201801016

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Asymmetric "Acetylenic" [3+2] Cycloaddition of Nitrones
Catalyzed by Cationic Chiral Pd(II) Lewis Acid
Authors: Koichi Mikami and Kazuya Honda
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To be cited as: Chem. Asian J. 10.1002/asia.201801016
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Asymmetric “Acetylenic” [3+2] Cycloaddition of Nitrones
Catalyzed by Cationic Chiral Pd(II) Lewis Acid
Kazuya Honda and Koichi Mikami*
Abstract: Highly enantioselective [3+2] cycloaddition of ynones and
nitrones was developed. Very bulky ligand, DTBM-SEGPHOS, was
Table 1. Optimization of the reaction conditions
used for effective asymmetric induction over distal reaction centers on
the linear ynone dipolarophile and for prevention of Pd(II) catalyst
deactivation by coordination of the nitrones. The reaction has wide
scope of substrates in both ynones and nitrones.
The chiral Lewis acid-catalyzed asymmetric cycloadditions are
the most useful method for constructing optically active multi-
functionalized cyclic compounds.[1] An enormous amount of
reaction systems have been reported in the various type of Lewis
acid-catalyzed cyclization ([4+2] cycloaddition, Diels-Alder, [2+2]
cycloaddition).[2] The [3+2] cycloaddition of nitrone and α,β-
unsaturated carbonyl compound is also well-studied, and many
catalyst systems have been applied. However, the vinylic enone
diporalophiles were used in almost all systems reported and the
example of acetylenic ynone is extremely limited.
Lewis acid catalysts, when used in ynone system, give, however,
the lower enantioselectivity because the ynone reaction center is
far distal from carbonyl group, coordinated by the chiral Lewis acid
catalysts than the enone system due to the linear configuration of
ynone.[3a] Reports on the asymmetric reaction of ynone were thus
limited to few Diels-Alder reactions[3] and only one [3+2]
cycloaddition system.[4] The Lewis acid approach for a wide
scope of chiral dihydroisooxazole derivatives from ynones and
nitrones was not established, in spite of their potential application
as the bioisosteres of pyrazole compounds as COX-2 and KSP
inhibitors.[5]
Entry[a]
Ag salt
AgSbF6
AgPF6
AgPF6
AgPF6
AgPF6
AgPF6
AgPF6
AgPF6
AgPF6
AgPF6
AgPF6
AgPF6
Solvent
Yield[b] [%]
27
ee[c] [%]
8
1
CH2Cl2
2
CH2Cl2
94
94
3
CH2Cl2/Toluene = 1:1
CH2Cl2/MeCN = 1:1
CH2Cl2/DME = 1:1
CH2Cl2/Dioxane = 1:1
CH2Cl2/THF = 1:1
CH2Cl2/TBME = 1:1
CH2Cl2/nBu2O = 1:1
CH2Cl2/Et2O = 1:1
CH2Cl2/Et2O = 3:1
CH2Cl2/Et2O = 1:3
>99
31
93
4
22
5
93
93
6
96
93
7
53
92
8
86
94
9
90
94
10
11
12
>99
93
>99
93
We have studied the cationic Pd(II) Lewis acid-catalyzed 1,2-
and 1,4-addition of the α-ketoester compounds.[6] The catalysts
have high catalytic activity and very bulky ligand availability
without change of square planner configuration in a different
manner from the Cu(II) catalyst.[7] We here report the highly
enantioselective [3+2] dipolar cycloaddition of nitrone and ynone
catalyzed by very bulky DTBM-SEGPHOS-Pd(II) catalyst for the
asymmetric induction on the distal reaction center and prevention
of catalyst deactivation by the coordination of nitrone substrates.
97
92
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol) in solvent (2 mL) [b]
Isolated yield [c] Determined by the HPLC analysis.
However, the dihydroisooxazole product 3aa was obtained in
quite low yield and selectivity (27%, 8% ee) under the reaction
conditions. Benzaldehyde was observed via decomposition of
nitrone. The decomposition of nitrone took place by the highly
cationic Lewis acid catalyst. Thus, the Lewis acidity of the catalyst
was reduced using PF6 instead of SbF6 (entry 2); The yield and
selectivity were drastically improved (94%, 94 %ee). Various
mixed solvent systems with coordinating ones were examined to
fine-tune the Lewis acidity of the Pd catalysts (entry 3-12); The
dichloromethane and diethyl ether mixed solvent (entry 10) gave
the cycloadduct in the highest yield and enantioselectivity (>99%,
>99% ee).
n
Our study started with the reaction of Bu substituted ynone 1a
and (Z)-N-methyl phenyl nitrone 2a (1.2 eq.) with DTBM-
SEGPHOS (L)-Pd(SbF6)2 catalyst (5 mol%) in dichloromethane
(Table1, entry1).
[a]
Prof. Dr. K. Mikami, Dr. K. Honda
Department of Applied Chemistry
Tokyo Institute of Technology
Tokyo 152-8552, Japan
E-mail: mikami.k.ab@m.titech.ac.jp
Supporting information for this article is given via a link at the end of
the document.
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Table 2. Ligand effects
2
3
4
5
6
7
AgPF6
AgNTf2
AgBF4
AgOTf
AgOTs
AgReO4
>99
81
>99
22
86
88
97
87
>99
93
91
94
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol) in solvent (2 mL) [b]
Isolated yield [c] Determined by the HPLC analysis.
Entry[a]
Ligand
Yield[b] [%]
>99
>99
>99
96
ee[c] [%]
94
1
2
3
4
5
6
7
(S)-DTBM-SEGPHOS
(S)-DTBM-MeO-BIPHEP
(S)-DTB-MeO-BIPHEP
(S)-DTBM-BINAP
(S)-DM-BINAP
The scope of ynone dipolarophile was clarified to be wide (Table
4). The 1°-3° alkyl-substituted ynones (1a-d) gave the
cycloadducts (3aa-da) in quantitative yields and with very high
enantioselectivities. Protected propargyl alcohol derivatives (1e-
f) were also employable; However the benzyl-protected ynone
(1e) gave the product in moderate enantioselectivity. In contrast,
the reaction did not proceed with trimethylsilyl-substituted one
(1g) which had high reactivity in the acetylenic Diels-Alder
reactions.[3] Aryl-subsituted ynones also showed high reactivities
and gave the cycloadducts in high enantioselectivities except for
the ortho-functionalized one (1k) which had large steric effect.
95
95
91
34
68
(S)-Tol-BINAP
20
23
(S)-BINAP
32
33
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol) in solvent (2 mL) [b]
Isolated yield [c] Determined by the HPLC analysis.
Table 4. Scope of ynone dipolarophiles[a][b]
The ligand effects were then maximized (Table 2). The bulky
ligands with small bite angle such as DTBM-SEGPHOS (entry 1),
DTBM-MeO-BIPHEP (entry 2) and DTB-MeO-BIPHEP (entry 3)
gave
excellent
yields
and
enantioselectivities.
The
enantioselectivity attained by DTBM-BINAP (entry 4) was lower
because steric effect was decreased by its large bite angle. When
less sterically demanding catalysts were used, the
enantioselectivity was further lowered (entry 5-7). The
improvement of yield was attained by bulky ligand to indicate that
the bulky ligands prevented the catalyst deactivation by
coordinating of nitrone or products.
The effects of counter anions are exemplified in Table 3.
Surprizingly, the reaction proceeded with lower Lewis acidic
-
catalysts like BF4 , OTf- and OTs- counter anions. However, the
clear relationship was not observed between the Lewis acidity of
the catalyst and yield or enantioselectivity. These results imply
that the strongly Lewis acidic complex has higher catalytst acitivity
and that the deactivation of the catalyst by the nitrone
competitively takes place.
[a] Reaction conditions: 1a-p (0.1 mmol), 2a (0.12 mmol) in solvent (2 mL)
[b] All of yields are isolated yield and enantiomeric excesses are determined
by the HPLC analysis. [c] Reaction was performed at -20 °C.
Table 3. Effects of counter anions
Both electrone donating (1m-n) and withdrawing (1o) substituent
were employable as the terminal functional group.
benzo[d][1,3]dioxolyl ynone (1n) requred -20 °C because of its
poor solubility to the solvents at lower (-40 °C) temperature. The
The
Entry[a]
1
Ag salt
Yield[b] [%]
61
ee[c] [%]
AgSbF6
36
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vinyl-substituent had high reactivity and only α,β-cycloadduct
formed in high regioselectivity.
Finally, the mechanism of asymmetric induction in the
cycloaddition was clarified by DFT calculations. In acetylenic
[3+2] cycloaddition, the absolute configuration of product was
determined by both enantioface selectivity and endo/exo
selectivity in four different transition states (TSs) (Figure 1). The
absolute configuration of the product controlled by (S)-DTBM-
SEGPHOS-Pd(II) catalyst was (R)-configuration.[8] The result
indicated that this reaction proceeded through either exo/top side-
TS or endo/bottom side-TS.
The scope of nitrones was also found to be wide (Table 5). The
nitrones derived from aromatic aldehyde (2a-l) gave the
corresponding cycloadduts in high yields and selectivities,
regardless of their electronic and steric effects; Strong electron-
donating p-methoxy (2b), electron-withdrawing p-trifluoromethyl
(2d), sterically demanding p-biphenyl (2e), o-tol (2g), 3,5-xylyl
group (2i) were employable. Especially, o-substituted nitrones
(2g, j, l) gave the products in excellent selectivity. The yield of 2-
furyl nitrone (2m) was low because the catalyst was deactivated
by coordination of hetero-aromatic moiety. While vinyl nitrone
(2n) was also employable, the selectivity of product was quite low.
Alkyl nitrone (2o-q) had low reactivity and the reaction must be
performed at -20 °C. In this reaction, the seric effects of
substituent on nirone was important to achieve high selectivity
because the product from less hindered phenethyl nitrone (2o)
and stylyl nitrone (2n) were similar selectivity.
Table 5. Scope of nitrones[a][b]
Figure 1. Four transition states of [3+2] cycloaddition.
The α-ketoester compound coordinate to the Pd(II) center in five-
membered ring chelation[ref] and the equatorial aryl groups on
phosphine atoms of ligand shield the enantioface.
The
stereogenic center was generated by approach the reactant from
the opposite side to equatorial aryls (Figure 2). When (S)-ligand
was used, the reactant approach was limited from top side via
exo/top side-TS.
Figure 2. Asymmetric induction with (S)-Pd(II) Lewis acid catalyst.
The computational analysis was performed to compare the
energies of these possible TSs. All the calculations were
performed with B3LYP[9a]-D3BJ[9b]/6-31G*(Pd: LANL2DZ)/IEF-
PCM[9c]/CH2Cl2 level and Gaussian09 rev.D01[9d] was used as
calculation software. Methyl 2-oxopent-3-ynoate, (Z)-N-methyl-1-
phenylmethanimine oxide and (CH2PMe2)2Pd2+ were used as a
model system. The energy diagram of the reaction was shown in
Figure 3; The results indicate that the reaction proceeded through
the stepwise rather than concerted mechanism because of two
TSs localized; C-O bond formation TS (TS1) and C-C bond
formation TS (TS2) were found and IRC calculations gave the
zwitterionic intermediate (IM). The reason why nitrones derived
from aliphatic aldehydes (2o-q) and terminal silyl-substituted
[a] Reaction conditions: 1a (0.1 mmol), 2a-t (0.12 mmol) in solvent (2 mL)
[b] All of yields are isolated yield and enantiomeric excesses are determined
by the HPLC analysis. [c] Reaction was performed at -20 °C
More bulky isopropyl and tert-butyl nitrone (2p-q) gave the
product in good selectivity. The secondary and tertiary alkyl
groups (2r-s) were effective as the substituent on nitrogen atom,
but the N-phenyl nitrone (2t) gave the complex mixture.
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ynone (1g) have low reactivity on the cycloaddition can be
rationalized by the stepwise mechanism. The iminium cation
formed from aliphatic nitrones (2o-q) were less stable than those
from aryl or vinyl nitrones because aliphatic nitrones do not bear
cation stabilization substituents. The reactivity of silyl-substituted
ynone can be explained by the orbital interaction on the
zwitterionic intermediate (IM). In the concerted acetylenic Diels-
Alder reaction, terminal silyl-substituted ynones have high
reactivity because their LUMO becomes lower due to
hyperconjugation effect between δ*(C-Si) and π*(C≡C). In
contrast, this [3+2] reaction proceeds via stepwise mechanism
and the δ(C-Si) has repulsive interaction against β-anion of Pd
allenolate. The rate determining step is C-O bond formation (TS1),
and the exo-TS favors over endo-TS by 1.8 kcal/mol. The
distortion-interaction analysis indicated the existence of favorable
interaction in exo-TS (See SI). These results support the
proposed exo/top side-approach mechanism.
chromatography (hexane/AcOEt = 9/1). Almost all cycloadducts were
unstable in ambient conditions, thus they have to be stored in
refrigerator.
Acknowledgements
This research was supported by Japan Science and Technology
Agency (JST) (ACT-C: Creation of Advanced Catalytic Trans-
formation for the Sustainable Manufacturing at Low Energy, Low
Environmental Load)
Keywords: Asymmetric catalysis • Cycloaddition• Alkynes•
Palladium • Computational chemistry
[1]
[2]
(a) Corey, E. J. Angew. Chem. Int. Ed. 2002, 41, 1650. (b) Nicolau, K.
C.; Vassilikogiannakis, G.; Mägerlein, W.; Kranich, R. Chem. Eur. J. 2001,
7, 5359. (c) Kano, T.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc.
2006, 128, 2174. (d) Antonchick, A. P.; Gerding-Reimers, C.; Catarinella,
M.; Shürmann, M.; Preut, H.; Ziegler, S.; Rauh, D.; Waldmann, H. Nat.
Chem. 2010, 2, 735.
(a) Reymond, S.; Cossy, J. Chem. Rev. 2008, 108, 5359. (b) Corey, E.
J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124, 3808. (c)
Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 12686. (d)
Kanemasa, S; Oderaotoshi, Y.; Tanaka, J.; Wada, E. J. Am. Chem. Soc.
1998, 120,12355. (e) Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.; Kasano,
Y.; Minakata, S.; Komatsu, M. Org. Lett. 2003, 26, 5043. (f) Jensen, K.
B.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 1999, 64, 2353.
(a) Evans, D. A.; Miller, S. J.; Lectka, T.; Matt, P. J. Am. Chem. Soc. 1999,
121, 7559. (b) Corey, E. J.; Lee, T. W. Tetrahedron Lett. 1997, 38, 5755.
(c) Ishihara, K.; Kondo, S.; Kurihara, H.; Yamamoto, H. J. Org. Chem.
1997, 62, 3026. (d) Payette, J. N.; Yamamoto, H. Angew. Chem. Int. Ed.
2009, 48, 8060. (e) Ishihara, K.; Fushimi, M. J. Am. Chem. Soc. 2008,
130, 7532.
[3]
[4]
(a) Wei, W.; Kobayashi, M.; Ukaji, Y.; Inomata, K. Heterocycles. 2009,
78, 717. (b) Sakakura, A.; Hori, M.; Fushimi, M.; Ishihara, K. J. Am. Chem.
Soc. 2010, 132, 15550. (c) Habeeb, A. G.; Praveen, P. N.; Knaus, E. E.
J. Med. Chem. 2001, 44, 2921. (d) Alberola, A.; Gonzalez, A. M.; Laguna,
M. A.; Pulido, F. J. Synthesis 1982, 12, 1067. (e) Aschwanden, P.; Frantz,
D. E.; Carreira, E. M. Org. Lett. 2000, 2, 2331. (f) Wada, N.; Kaneko, K.;
Ukaji, Y.; Inomata, K. Chem. Lett. 2011, 40, 440. (g) Yamashita, Y.; Saito,
Y.; Imaizumi, T.; Kobayashi, S. Chem. Sci. 2014, 5, 3958. (h) Zheng, H.;
McDonald, R.; Hall, D. G. Chem. Eur. J. 2010, 16, 5454. (i) Valizadeh,
H.; Dinparast, L. Synth.Commun. 2011, 41, 291. (j) Domingo, L. R.;
Picher, M. T.; Arroyo, P.; Sa´ez. J. A. J. Org. Chem. 2006, 71, 9319. (k)
Sibi, M. P.; Dunkle, K. L.; Rane, D. Heterocycles. 2014, 88, 1639. (l) The
first organocatalysis: Alemán, J.; Fraile, A.; Marzo. L,; Ruano, J. L. G.;
Izquierdo, C.; Tendero, S. D. Adv. Synth. Catal. 2012, 354, 1665.
Merck Co., INC. PCT/US2005/028968.
Figure 3. Energy diagram of Pd(II) catalyzed [3+2] cycloaddition.
In conclusion, various ynones and nitrones provide a wide scope
of chiral dihydroisooxazoles of potential application in high yields
and enantioselectivities under the bulky (S)-DTBM-SEGPHOS-
Pd(II) Lewis acid catalysis. DFT-calculations indicated that the
reactions proceed via stepwise pathway and first C-O bond
formation is the rate determining step. The (R)-products are
formed via exo/top side-TS with (S)-Pd(II) catalysts.
[5]
[6]
Experimental Section
(a) Mikami, K.; Kawakami, Y.; Aikyama, K.; Aikawa, K. J. Am. Chem. Soc.
2007, 129, 12950. (b) Aikawa, K.; Hioki, Y.; Mikami, K. J. Am. Chem. Soc.
2009, 131, 13922. (c) Aikawa, K.; Hioki, Y.; Mikami, K. Org. Lett. 2010,
12, 5716. (d) Aikawa, K.; Hioki, Y.; Shimizu, N.; Mikami, K J. Am. Chem.
Soc. 2011, 133, 20092. (e) Aikawa, K.; Kondo, D.; Honda, K.; Mikami, K.
Chem. Eur. J. 2015, 21, 1.
General procedure for 1,3-dipolar cycloaddition: To a solution of
PdCl2[(S)-DTBM-SEGPHOS] (6.8 mg, 0.005 mmol) in CH2Cl2/Et2O = 0.9
mL : 1.0 mL mixed solvent was added AgPF6 (2.8 mg, 0.011 mmol) at
room temperature under argon atmosphere. After stirring for 1 hour, ethyl
2-oxooct-3-ynoate (1a) (19.8 mg, 0.1 mmol) and (Z)-N-methyl-1-
phenylmethanimine oxide (2a) (16.2 mg, 0.12 mmol) in CH2Cl2 (0.1 mL)
were added to the mixture at −40 °C. After stirred at same temperature
for 48 hours, the reaction mixture was directly loaded on the short pad of
silica-gel (hexane/AcOEt = 2/1) and evaporated under reduced pressure.
The crude product was purified by silica-gel column or almina
[7]
(a) Jørgensen, K. A.; Johannsen, M.; Yao, S.; Audrain, H.; Thorhauge, J.
Acc. Chem. Res. 1999, 32 605. (b) Johnson, J. S.; Evans, D. A. Acc.
Chem. Res. 2000, 33, 325.
[8]
[9]
Absolute configuration was determined by the optical rotation of reported
enal compound derived from product 3ha. See supporting information.
(a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Grimme, S.; Ehrlich,
S.; Goerigk, L. J. Comp. Chem. 2011, 32, 1456. (c) Scalmani, G.; Frisch,
M. J. J. Chem. Phys. 2010, 132, 114110. (d) Gaussian 09, Revision D.01,
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Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.;
Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A.;
Peralta, Jr. J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.;
Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.;
Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.;
Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin,
R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J.
B.; Ortiz, J. V.; Cioslowski, J. and Fox, D. J. Gaussian, Inc., Wallingford
CT, 2009.
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Kazuya Honda and Koichi Mikami*
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Title
Asymmetric “Acetylenic” [3+2]
Cycloaddition of Nitrones Catalyzed
by Cationic Chiral Pd(II) Lewis Acid
Highly enantioselective [3+2] cycloaddition of ynones and nitrones was developed.
Very bulky ligand, DTBM-SEGPHOS, was used for effective asymmetric induction
over distal reaction centers on the linear ynone dipolarophile and for prevention of
Pd(II) catalyst deactivation by coordination of the nitrones. The reactions exhibit
wide scope of substrates in both ynones and nitrones.
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