Organocatalyzed formal [2 + 2] cycloaddition of ketimines with allenoates: Facile access to azetidines with a chiral tetrasubstituted carbon stereogenic center

Article abstract of DOI:10.1021/ol401817q

An enantioselective organocatalyzed aza-MBH-type reaction of ketimines and allenoates has been developed. The present formal [2 + 2] cycloaddition produces highly functionalized azetidines with a chiral tetrasubstituted carbon stereogenic center in good to excellent yields and high enantioselectivities.

Full text of DOI:10.1021/ol401817q

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Organocatalyzed Formal [2 þ 2]
Cycloaddition of Ketimines with
Allenoates: Facile Access to Azetidines
with a Chiral Tetrasubstituted Carbon
Stereogenic Center
Shinobu Takizawa, Fernando Arteaga Arteaga, Yasushi Yoshida, Michitaka Suzuki,
and Hiroaki Sasai*
The Institute of Scientific and Industrial Research (ISIR), Osaka University,
Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan
sasai@sanken.osaka-u.ac.jp,
Received June 28, 2013
ABSTRACT
An enantioselective organocatalyzed aza-MBH-type reaction of ketimines and allenoates has been developed. The present formal [2 þ 2]
cycloaddition produces highly functionalized azetidines with a chiral tetrasubstituted carbon stereogenic center in good to excellent yields and
high enantioselectivities.
The simple construction of highly functionalized chiral
organic molecules is a subject of intensive research. The aza-
MoritaꢀBaylisꢀHillman (aza-MBH) reaction between an
R,β-unsaturated carbonyl compound and an imine is recog-
nized as one of the most fruitful carbonꢀcarbon bond
forming reactions and is catalyzed by nucleophilic amines
or phosphines.1 The products of the aza-MBH reaction
are highly functionalized allylic amines which are useful
building blocks for medicinal chemistry.2 A significant
number of works on the asymmetric aza-MBH reactions
have been reported;3 however a few describe the aza-MBH
reaction of ketimines4,5 which can construct tetrasubstituted
carbon units. Ketimines, in particular unconjugated ket-
imines, are considerably less reactive and unstable compared
to aldimines, and enantioface differentiation of ketimines is
more difficult because of the smaller steric and electronic
differences between the two substituents on the prochiral
carbon. Therefore, effective enantioselective construction
of chiral tetrasubstituted carbon stereogenic centers via the
aza-MBH reaction of ketimines has been a challenge in
asymmetric synthetic chemistry.6 Herein, we describe the
organocatalyzed aza-MBH-type reactions initiated by highly
selective γ-addition of allenoates to N-tosyl R-ketimine esters,
furnishing azetidines with a chiral tetrasubstituted carbon
stereogenic center in good to excellent yields and high
enantioselectivities.
(1) (a) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968,
41, 2815. (b) Baylis, A. B.; Hillman, M. E. D. German Patent 2,155,113,
1972 [Chem. Abstr. 1972, 77, 34174q].
(2) For recent reviews on applications of MBH adducts to bioactive
molecules, see: (a) Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev.
2009, 109, 1. (b) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem. Rev.
2010, 110, 5447. (c) LimaꢀJunior, C. G.; Vasconcellos, M. L. A. A.
Bioorg. Med. Chem. 2012, 20, 3954.
(3) For recent reviews on enantioselective MBH reaction, see: (a)
Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46,
4614. (b) Wei, Y.; Shi, M. Acc. Chem. Res. 2010, 43, 1005. (c) Wang,
S.-X.; Han, X.; Zhong, F.; Wang, Y.; Lu, Y. Synlett 2011, 2766.
(4) Shi and Li et al., Chen et al., and our group independently
developed the first enantioselective aza-MBH reaction of ketimines;
see: (a) Hu, F.-L.; Wei, Y.; Shi, M.; Pindi, S.; Li, G. Org. Biomol. Chem.
2013, 11, 1921. (b) Yao, Y.; Li, J.-L.; Zhou, Q.-Q.; Dong, L.; Chen, Y.-C.
(5) As the first aza-MBH studies of ketimines, Ye reported
achiral Lewis base catalyzed formal [n
þ
2] cycloadditions of
ꢀ
Chem.;Eur. J. 2013, 19, 9447. (c) Takizawa, S.; Remond, E.; Arteaga,
ketimines with allenoates; see: (a) Chen, X.-Y.; Lin, R.-C.; Ye, S. Chem.
Commun. 2012, 48, 1317. (b) Chen, X.-Y.; Ye, S. Eur. J. Org. Chem.
2012, 5723.
ꢀ
F. A.; Yoshida, Y.; Sridharan, V.; Bayardon, J.; Juge, S.; Sasai, H.
Chem. Commun. DOI: 10.1039/C3CC44549F.
r
10.1021/ol401817q
XXXX American Chemical Society

Chiral azetidines, which represent an important class
of four-membered N-heterocycles, have received much
attention because of their utilization as ligands7 and their
biological and pharmaceutical activities.8 However, the
synthetic approaches to enantiomerically enriched azeti-
dines are generally multistep processes.7ꢀ9 The [2 þ 2]
cycloaddition is certainly one of the most powerful meth-
ods for the construction of the strained four-membered
ring.10 This strategy was successfully extended to the
construction of azetidines via diazabicyclo[2.2.2]octane
(DABCO) catalyzed formal [2 þ 2] cycloaddition as the
first aza-MBH-type reaction of allenoates with aldimines
by Shi11 in 2003 with further contributions as the enantio-
selective annulation developed by Masson and Zhu.12 As
the first step in the development of the aza-MBH reaction
of ketimines, the reaction of 1aand ethyl allenoate (2a) was
attempted using 20 mol % of achiral amines (Table 1).
Among the achiral amines we tested, DABCO and N,N-
dimethyl-4-aminopyridine (DMAP) effectively promoted
the reaction of ketimine 1a with 2a to give the desired
Table 1. Formal [2 þ 2] Cycloaddition of 1a with 2aa
yield,
ee,
b
c
entry organocat.
solvent
°C
h
%
%
1
2
3
4
5
6
7
8
9
DABCO
DMAP
THF
THF
25 96
25 96
25 96
25 24
25 24
25 24
25 24
43
20
ꢀ
ꢀ
DBU or 5 THF
0
ꢀ
β-ICD
β-ICD
β-ICD
β-ICD
β-ICD
β-ICD
THF
42
80
82
66
80
84
89
(87)d
65
1,4-dioxane
CH2Cl2
58
36
toluene
28
THF
0
0
24
24
45
THF/1,4-dioxane (1:1)
49
(69)d
10
10
6
THF/1,4-dioxane (1:1)
THF/1,4-dioxane (1:1)
0
24
(trace)e (nd)e
11
12
7
0
0
24
24
23
0
59
(6) For recent reviews and reports on catalytic enantioselective
addition of carbon nucleophiles to ketimines, see: (a) Shibasaki, M.;
Kanai, M. Chem. Rev. 2008, 108, 2853. (b) Kobayashi, S.; Mori, Y.;
Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626. (c) Liu, X.; Lin,
L.; Feng, X. Acc. Chem. Res. 2011, 44, 574. (d) Nishimura, T.; Noishiki,
A.; Tsui, G. C.; Hayashi, T. J. Am. Chem. Soc. 2012, 134, 5056. (e)
Zhang, F.-G.; Ma, H.; Nie, J.; Zheng, Y.; Gao, Q.; Ma, J.-A. Adv. Synth.
Catal. 2012, 354, 1422. (f) Yan, W.; Wang, D.; Feng, J.; Li, P.; Zhao, D.;
Wang, R. Org. Lett. 2012, 14, 2512. (g) Luo, Y.; Hepburn, H. B.;
Chotsaeng, N.; Lam, H. W. Angew. Chem., Int. Ed. 2012, 51, 8309. (h)
Feng, J.; Yan, W.; Wang, D.; Li, P.; Sun, Q.; Wang, R. Chem. Commun.
2012, 48, 8003. (i) Lv, H.; Tiwari, B.; Mo, J.; Xing, C.; Chi, Y. R. Org.
Lett. 2012, 14, 5412. (j) Wang, D.; Liang, J.; Feng, J.; Wang, K.; Sun, Q.;
Zhao, L.; Li, D.; Yan, W.; Wang, R. Adv. Synth. Catal. 2013, 355, 548.
(k) Yin, L.; Otsuka, Y.; Takada, H.; Mouri, S.; Yazaki, R.; Kumagai,
N.; Shibasaki, M. Org. Lett. 2013, 15, 698. (l) Sun, L.-H.; Liang, Z.-Q.;
Jia, W.-Q.; Ye, S. Angew. Chem., Int. Ed. 2013, 52, 5803. (m) Liu, Y.-L.;
Zhou, J. Chem. Commun. 2013, 49, 4421. (n) Hayashi, M.; Sano, M.;
Funahashi, Y.; Nakamura, S. Angew. Chem., Int. Ed. 2013, 52, 5557. (o)
Yin, L.; Takada, H.; Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed.
2013, 52, 7310.
8, 9, or 10 THF/1,4-dioxane (1:1)
ꢀ
a Reaction conditions: 1a (0.06 mmol), 2a (0.18 mmol), and catalyst
(20 mol %) in solvent (0.3 mL). b Determined by 1H NMR. c Determined
by HPLC (Daicel Chiralpak AD). d With MS 4 A. e With 20 mol % of
2-naphthol. nd: not determined.
(7) For examples, see: (a) Zhang, Z.; Li, M.; Zi, G. Chirality 2007, 19,
802. (b) Menguy, L.; Couty, F. Tetrahedron: Asymmetry 2010, 21, 2385.
(8) For examples, see: (a) Provins, L.; Christophe, B.; Danhaive, P.;
Dulieu, J.; Gillard, M.; Quere, L.; Stebbins, K. Bioorg. Med. Chem. Lett.
2007, 17, 3077. (b) Evans, G. B.; Fumeaux, R. H.; Greatrex, B.; Murkin,
A. S.; Schramm, V. L.; Tyler, P. C. J. Med. Chem. 2008, 51, 948. (c)
Cesario, C.; Miller, M. J. J. Org. Chem. 2009, 74, 5730. (d) Shimokawa,
J.; Harada, T.; Yokoshima, S.; Fukuyama, T. J. Am. Chem. Soc. 2011,
133, 17634.
(9) For recent reviews and reports on the synthesis of chiral azeti-
dines, see: (a) Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008,
108, 3988. (b) Couty, F.; Evano, G. Synlett 2009, 3053. (c) Drouillat, B.;
Wright, K.; Marrot, J.; Couty, F. Tetrahedron: Asymmetry 2012, 23,
690.
azetidine 3a (Table 1, entries 1 and 2). 1,8-Diazabicyclo-
[5.4.0]undec-7-ene (DBU) and 2-phenyl-4,5-dihydro-1H-
imidazoline (5) exhibited no catalytic activity (entry 3).
Next, various chiral amine catalysts were tested. β-Isocu-
preidine (β-ICD), an acidꢀbase organocatalyst known to
mediate enantioselective MBH processes,13 afforded 3a in
moderate yield with 80% ee (entry 4). Using of 1,4-dioxane
(entry 5) orloweringthereaction temperature(entry8) had
positive effects on the chemical yields and enantioselectiv-
ities. Furthermore, the mixed solvent of THF/1,4-dioxane
(1:1 ratio) achieved good outcomes in terms of enantio-
selectivity (entry 9). On the other hand, amide-type β-ICD
6 (with or without 20 mol % of 2-naphthol),14 cinchonine
(10) For recent reviews and reports on the [2 þ 2] cycloaddition, see:
(a) Parra, A.; Reboredo, S.; Aleman, J. Angew. Chem., Int. Ed. 2012, 51,
ꢀ
9734. (b) Pellissier, H. Tetrahedron 2012, 68, 2197. (c) Suarez-Pantiga, S.;
ꢀ
ꢀ
Hernandez-Dıaz, C.; Piedrafita, M.; Rubio, E.; Gonzalez, J. M. Adv.
Synth. Catal. 2012, 354, 1651. (d) Deng, J.; Hsung, R. P.; Ko, C. Org.
Lett. 2012, 14, 5562. (e) Faustino, H.; Bernal, P.; Castedo, L.; Lopez, F.;
Mascarenas, J. L. Adv. Synth. Catal. 2012, 354, 1658. (f) Albrecht, Ł.;
Dickmeiss, G.; Acosta, F. C.; Rodrıguez-Escrich, C.; Davis, R. L.;
Jørgensen, K. A. J. Am. Chem. Soc. 2012, 134, 2543. (g) Tyson, E. L.;
Farney, E. P.; Yoon, T. P. Org. Lett. 2012, 14, 1110. (h) Rasik, C. M.;
Brown, M. K. J. Am. Chem. Soc. 2013, 135, 1673.
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J. Am. Chem. Soc. 1999, 121, 10219. (b) Shi, M.; Xu, Y.-M. Angew.
Chem., Int. Ed. 2002, 41, 4507. (c) Kawahara, S.; Nakano, A.; Esumi, T.;
Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2003, 5, 3103. (d) Balan, D.;
Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521.
(14) (a) Abermil, N.; Masson, G.; Zhu, J. J. Am. Chem. Soc. 2008,
130, 12596. (b) Abermil, N.; Masson, G.; Zhu, J. Org. Lett. 2009, 11,
4648. (c) Abermil, N.; Masson, G.; Zhu, J. Adv. Synth. Catal. 2010, 352,
656.
(11) (a) Zhao, G.-L.; Huang, J.-W.; Shi, M. Org. Lett. 2003, 5, 4737.
(b) Zhao, G.-L.; Shi, M. J. Org. Chem. 2005, 70, 9975. (c) Guan, X.-Y.;
Wie, Y.; Shi, M. J. Org. Chem. 2009, 74, 6343. (d) Ma, G.-N.; Jiang, J.-J.;
Shi, M.; Wei, Y. Chem. Commun. 2009, 5496.
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Int. Ed. 2011, 50, 5356.
B
Org. Lett., Vol. XX, No. XX, XXXX

benzyl ether 7, cinchonidine (8), quinidine (9), and
3-(N-isopropyl-N-3-pyridinylaminomethyl)BINOL (10)15
exhibited low or no catalytic activity (entries 10ꢀ12).
Notably, neither formation of aza-MBH adduct 412 nor
the Z-configuration of azetidine 3a was observed in
any reaction; however, ethyl 2-oxo-2-phenylacetate was
formed as a side product formed via hydrolysis of 1a.
To suppress the decomposition of the moisture-sensitive
Table 2. Azetidine Formation from 1 with 2 Using β-ICDa
˚
ketimine, 4 A molecular sieves (MS 4 A) were added to the
reaction media. The addition of MS 4 A improved the
chemical yield (69%) and maintained high enantioselec-
tivity (87% ee) (entry 9).
To our delight, the optimal result was obtained when the
reaction of 1a with 2a was performed in a mixed solvent of
THF/1,4-dioxane (1:2) at ꢀ5 °C in the presence of MS 3 A
(Table 2, entry 1). Under the optimal conditions, the highly
E-selective and (R)-configured azetidines 3 were obtained
in good to excellent yields with high enantioselectivities
(92ꢀ83% ee) irrespective of the electronic nature of
substituent groups on the aromatic ring of 1.16 When
1-naphthyl ketimine 1b was utilized as a substrate, the
mixture of E- and Z-3b were obtained in a ratio of 6:1
(entry 2). The reactions of 1e and 1iꢀj (entries 5, 10, and
11) using benzyl allenoate (2b) (entry 18) led to the forma-
tion of the corresponding E-3 (79ꢀ70% yields) along with
the acyclic γ-adduct 11 (18ꢀ6% yields). Finally, optically
pure azetidine 3l could be obtained after a single recrys-
tallization (entry 13).
a Reaction conditions: 1 (0.06 mmol), 2a (0.18 mmol), β-ICD
(20 mol %) in THF/1,4-dioxane (1:2, 0.3 mL) at ꢀ5 °C. b Isolated yield.
1
c Determined by H NMR. d Determined by HPLC (Daicel Chiralpak
To demonstrate the synthetic utility of highly functiona-
lized azetidine 3, various transformations were performed
(Scheme 1). Allyl alcohol 12 was produced by DIBAL-H
reduction of 3h without over-reduction. β-Lactam 13 was
obtained in 96% yield by oxidation with O3. Subsequently,
treatment of lactam 13 with Mg/MeOH cleaved the amide
bond to provide acyclic R,R-disubstituted amino acid
derivative 14 in good yield. Finally, 3k could react with
phenylboronic acid via SuzukiꢀMiyaura cross-coupling to
quantitatively give biphenyl compound 15.
AD for 3a, 3gꢀp; Daicel Chiralpak IC for 3b, 3dꢀf; Daicel Chiralpak
AD3 for 3c; Daicel Chiralcel OD3 for 3q). e At ꢀ20 °C. f 10 mol % of
β-ICD was used. g After a single recrystallization. h Acyclic γ-adducts 11
were obtained.
Our proposed mechanism of the [2 þ 2] cycloaddition of
ketimine with allenoate using β-ICD is shown in Scheme 2.
Addition of β-ICD to allenoate 2 affords the resonance-
stabilized zwitterionic intermediate I, which could react
with ketimine 1 according to two different pathways.
Addition of the γ-carbanion to 1 would yield intermediate
IIa, which upon [2 þ 2] cyclization would give intermediate
III. To avoid steric interactions between the aryl substitu-
ent of ketimine and the quinoline backbone in the catalyst,
the reaction using β-ICD would favor the (R)-configuration
product. Finally, E-azetidine 3 would be provided by the
steric repulsion of the Ts-group and CO2R2 functionality in
Scheme 1. Synthetic Transformations of Azetidine (R)-3
(15) (a) Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005,
127, 3680. (b) Matsui, K.; Tanaka, K.; Horii, A.; Takizawa, S.; Sasai, H.
Tetrahedron: Asymmetry 2006, 17, 578. (c) Takizawa, S.; Matsui, K.;
Sasai, H. J. Synth. Org. Chem. Jpn. 2007, 65, 1089. (d) Takizawa, S.;
Inoue, N.; Sasai, H. Tetrahedron Lett. 2011, 52, 377.
(16) The absolute configuration of the azetidines was assigned by
comparison with an optical rotation of the synthetic analog reported in
the literature after the transformation to 3-phenyl-1-tosylpyrrolidine-
2,5-dione (see Supporting Information). Ghorai, M. K.; Tiwari, D. P.
J. Org. Chem. 2010, 75, 6173.
the fragmentation of III with concurrent regeneration of the
catalyst. In contrast, the addition of the R-carbanion to the
ketimine to afford aza-MBH product 4 is not supported
probably because of the steric hindrance of the ketimine
(intermediate IIb).
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Our Proposed Reaction Mechanism
Scheme 3. Formal [2 þ 2] Cycloaddition of 1h with 2a Using the
Methyl Capped β-ICD
with a chiral tetrasubstituted carbon stereogenic center in
good to excellent yields and high enantioselectivities. The
obtained azetidines were readily transformed into various
derivatives. To the best of our knowledge, the present
transformation is the first example of an enantioselective
reaction of ketimines with allenoates. Further investiga-
tion into the reaction mechanism and scope as well as its
application to the enantioselective synthesis of biologically
active compounds is currently underway.
To gain insight into the influence of protic additives
on the reaction rate,14,17 additional control studies were
performed. When the reaction of 1p and 2a (3 equiv) was
performed in the presence of β-ICD (20 mol %) and a
Brønsted acid (20 mol %), the yield of product 3p de-
creased (from 76% to 45%, 43%, 53%, and 0% using
2-naphthol, (S)-BINOL, (R)-BINOL, and benzoic acid,
respectively); however high enantioselectivities (>81% ee)
were maintained, and the formation of aza-MBH adduct 4
was not observed characteristically.18 Because using methyl
capped β-ICD resulted in low activity and selectivity, the
phenolic hydroxyl group in β-ICD could play an important
role in the intramolecular activation of the substrates to
efficiently promote the aza-MBH-type reaction with high
enantiocontrol (Scheme 3).
Acknowledgment. This study was supported by the
CREST project of the Japan Science and Technology
Corporation (JST), Grant-in-Aid for Scientific Research
on Innovative Areas “Advanced Molecular Transforma-
tionsbyOrganocatalysts”from TheMinistryofEducation,
Culture, Sports, Science and Technology (MEXT), Japan
and JST, Advanced Catalytic Transformation Program for
Carbon Utilization (ACT-C). Y.Y. thanks JSPS Research
Fellowships for Young Scientists. We acknowledge the
technical staff of the Comprehensive Analysis Center of
ISIR, Osaka University (Japan).
In summary, we have developed the enantioselective
aza-MBH-type reaction of N-tosylketimines with alleno-
ates promoted by chiral organocatalysts to form azetidines
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41, 2165.
(18) When using a Brønsted acid as an external proton source,
decomposition of ketimine was observed.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX