Highly stereoselective [4+2] cycloaddition of azlactones to β,γ-unsaturated α-ketoesters catalyzed by an axially chiral guanidine base

Article abstract of DOI:10.1002/chem.201003015

Sweet catalysis! The enantio-and diastereoselective cycloaddition reaction of azlactones with β,γ-unsaturated α-ketoesters was demonstrated by taking advantage of the multiple reactive sites on the azlactone with the use of an axially chiral guanidine-bas

Full text of DOI:10.1002/chem.201003015

DOI: 10.1002/chem.201003015
Highly Stereoselective [4+2] Cycloaddition of Azlactones to b,g-
Unsaturated a-Ketoesters Catalyzed by an Axially Chiral Guanidine Base
Masahiro Terada* and Hiroyuki Nii[a]
Dedicated to Professor Takeshi Nakai on the occasion of his 70th birthday
Oxazole-5-(4H)-ones, known as azlactones, possess multi-
ple reactive sites. The acidic nature of the C4-position
allows for the formation of an enol tautomer that functions
as a nucleophilic site and reacts with a variety of electro-
philes, whereas the electrophilic nature of the carbon atoms
at the 2- and 5-positions allows for nucleophilic attack and
the formation of ring-opened products.[1] The rich reactivity
of the azlactone scaffold enables a wide variety of transfor-
mations, which makes azlactones extremely versatile reac-
tants in synthetic organic chemistry. Among these transfor-
mations, cycloaddition reactions that utilize the multiple re-
active sites of azlactones are attractive. For example, the nu-
cleophilic C4 and electrophilic C2 atoms serve as a 1,3-
dipole, which has been applied to [3+2] cycloaddition reac-
tions and gives a general synthetic route to a variety of five-
membered nitrogen heterocycles, including pyrrolines, imi-
dazolines, and imidazoles.[1] In contrast, cycloaddition reac-
tions that take advantage of the nucleophilic C4 and electro-
philic C5 atoms have rarely been exploited.[2] Recently,
Gong and co-workers demonstrated the enantioselective
catalysis of the cycloaddition reactions of azlactones at C4
and C5 with 1,3-azabutadienes, affording enantioenriched a-
amino-d-lactams.[3] However, to the best of our knowledge,
this is the sole example of such enantioselective catalysis.[4]
Further synthetic applications of azlactones 1 to catalytic
enantioselective cycloaddition reactions remains uncultivat-
ed despite the fact that the method provides efficient access
to nitrogen-substituted cyclic compounds in an optically
active form. Therefore, we envisioned the use of b,g-unsatu-
rated a-ketoesters 2 as novel reactants for the enantioselec-
tive cycloaddition reaction of the azlactone 1 with a chiral
Brønsted base catalyst (Scheme 1). The proposed transfor-
mation would enable facile access to 2-amino sugar deriva-
tives as pharmaceutically and biologically intriguing mole-
cules. It can be assumed that the reaction involves three
consecutive transformations:[5] 1) Michael addition of the
enolate form of azlactone 1’ at the C4-position[6] to the b,g-
[a] Prof. Dr. M. Terada, H. Nii
Department of Chemistry, Graduate School of Science
Tohoku University, Aramaki, Aoba-ku
Sendai 980-8578 (Japan)
Fax : (+81)22-795-6602
E-mail: mterada@m.tohoku.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003015.
Scheme 1. Cycloaddition reaction of the b,g-unsaturated a-ketoesters 2
with azlactones 1 catalyzed by axially chiral guanidine base (R)-4.
1760
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 1760 – 1763

COMMUNICATION
unsaturated a-ketoester 2 generates acyclic intermediate A;
2) Subsequent intramolecular nucleophilic addition of the
enolate oxygen of A to the C5 atom of the azlactone subunit
results in the formation of intermediate B as a formal [4+2]
cycloaddition product; and 3) The consecutive process is ter-
minated by ring-opening of the azlactone moiety, to give an
a-amino-d-lactone derivative 3 with a sugar framework.
Herein, we report on the diastereoselective and enantiose-
lective cycloaddition reaction of 1 with 2, catalyzed by the
axially chiral guanidine 4, a chiral Brønsted base catalyst de-
veloped within our group.[7,8]
An initial investigation was conducted to explore the opti-
mal aromatic substituent (Ar) at the C2 atom of azlactone
1.[9] Substituted azlactones 1a–1h were treated with a b,g-
unsaturated a-ketoester 2a with guanidine (R)-4 (2 mol%)
as the base catalyst at room temperature in THF. As shown
in Table 1, the desired cycloaddition products 3 were ob-
tained in high yields, irrespective of the steric and electronic
properties of the Ar substituent. However, the Ar substitu-
ent displayed a marked influence on both the enantio- and
diastereoselectivity (Table 1, entries 1–8). Although the re-
action provided the cis isomers predominantly in all cases,
the introduction of electron-donating groups at the 3- and 5-
positions led to a slight decrease in selectivity for the cis
isomer (Table 1, entries 5 and 6). In contrast, dramatic posi-
tional effects on the aromatic ring were observed in terms
of enantioselectivity. Introduction of the electron-donating
methoxy group at the 4-position resulted in the formation of
racemic products (Table 1, entries 2 and 8) whereas the
slightly electron-donating methyl and electron-withdrawing
trifluoromethyl substituents gave moderate selectivity
(Table 1, entries 3 and 4). The highest enantioselectivity was
observed for the 3,5-dimethoxyphenyl substituent, albeit at
the expense of diastereoselectivity (Table 1, entry 5).
Among the aryl substituents tested, the azlactone with an
unsubstituted phenyl group was optimal in terms of the
enantio- and diastereoselectivity (Table 1, entry 1).
Although cis-3aa was obtained with high diastereoselec-
tivity (Table 1, entry 1), the enantioselectivity remained
moderate despite thorough screening of the Ar substituent.
Hence, we next optimized the reaction conditions by chang-
ing the solvent and reaction temperature (Table 2). Delight-
fully, the enantioselectivity could be slightly improved with
acyclic ethers as solvents, which gave an increase in cis se-
lectivity (Table 2, entries 3–5). Among the acyclic ethers
tested, diethyl ether displayed the highest enantio- and dia-
stereoselectivity (Table 2, entry 3). Further optimization of
the reaction conditions by lowering the reaction tempera-
ture resulted in an increase in enantioselectivity (Table 2,
entries 6 and 7). However, in the reaction conducted at
À608C for 2 h, a considerable amount of the acyclic product
5 (the Michael addition product resulting from protonation
1
of intermediate A, see Scheme 1) was detected by H NMR
spectroscopic analysis of the crude product (Table 2,
entry 7).[10] Compound 5 was transformed to the desired
cyclic product 3aa by warming the reaction to room temper-
ature, after the azlactone 1a had been consumed completely
Table 1. Enantioselective and diastereoselective cycloaddition reaction of
1 with 2a catalyzed by an axially chiral guanidine (R)-4.[a]
Table 2. Optimization of the cycloaddition reaction of 1a with 2a, cata-
lyzed by (R)-4.[a]
Entry Solvent
T
Yield [%][b] cis/trans[c] ee [%][d]
1
2
3
4
5
6
7
8
THF
RT
RT
RT
RT
94
99
97
90
97
92
86
93:7
91:9
97:3
95:5
96:4
96:4
95:5
99:1
72
69
80
79
79
88
90
91
Entry
1
3
t [h]
Yield [%][b]
cis/trans[c]
ee [%][d]
DME[e]
Et2O
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
3aa
3ba
3ca
3da
3ea
3 fa
3ga
3ha
2
6
1.5
6
4.5
2
94
95
98
92
93
70
95
97
93:7
93:7
91:9
96:4
80:20
79:21
95:5
94:6
72
6
tBuOMe
CPME[f]
Et2O
Et2O
Et2O
69
48
73
59
62
<1
RT
À208C
À608C
À608C to RT[g] 99
4.5
1.5
[a] Unless otherwise noted, all reactions were carried out by using (R)-4
(0.002 mmol, 2 mol%), 1a (0.10 mmol), and 2a (0.11 mmol, 1.1 equiv) in
the indicated solvent (0.5 mL) for 2 h. [b] Yield of the isolated product.
[c] Determined by 1H NMR spectroscopy. [d] Determined by chiral sta-
tionary-phase HPLC analysis of the major cis isomer. [e] 1,2-Dimethoxy-
ethane. [f] Cyclopentyl methyl ether. [g] Carried out at À608C for 2 h,
then warmed to room temperature and stirred for 1 h.
[a] Unless otherwise noted, all reactions were carried out with (R)-1
(0.002 mmol, 2 mol%), 1 (0.10 mmol), and 2a (0.11 mmol, 1.1 equiv) in
THF (0.5 mL) at room temperature. [b] Yield of isolated product. [c] De-
termined by 1H NMR spectroscopic analysis. [d] Determined by chiral
stationary phase HPLC analysis of the major cis isomer.
Chem. Eur. J. 2011, 17, 1760 – 1763
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1761

M. Terada and H. Nii
at À608C for 2 h. Under the optimal reaction conditions, the
cycloaddition product cis-3aa was afforded exclusively in
almost quantitative yield, and the enantiomeric excess (ee)
increased to 91% (Table 2, entry 8).
As proposed in Scheme 1, it is assumed that the reaction
has three consecutive steps involving Michael addition, cyc-
lization, and finally a ring-opening process. To confirm that
Michael addition was the initial step, we attempted to iso-
late the acyclic product 5 by quenching the reaction at a low
temperature, followed by purification using HPLC column
chromatography (Scheme 2). The diastereo- and enantiose-
Next, the substrate scope of the cycloaddition reaction of
b,g-unsaturated a-ketoesters 2 with various azlactones 1 was
investigated. As shown in Table 3, the cycloaddition reaction
is well suited to b,g-unsaturated a-ketoesters 2 that have
either an electron-withdrawing or electron-donating sub-
stituent on the aromatic ring,[11] and afforded the corre-
sponding products with similarly high enantio- and diaste-
reoselectivity (Table 3, entries 1 and 2). Introduction of al-
ternative alkyl substituents onto the benzyl group at the C4
atom on azlactone 1 resulted in a considerable decrease in
enantioselectivity however the high cis selectivity was main-
tained (Table 3, entries 3–5). Because the azlactone 1e (sub-
stituted with a 3,5-dimethoxyphenyl group at the C2-posi-
tion) gave the highest enantioselectivity (Table 1, entry 5),
we next investigated derivatives of 1e (Ar=3,5-
(MeO)2C6H3-) with a series of alkyl substituents (Table 3,
entries 6–9). In fact, an enhancement of the enantioselectivi-
ty was observed albeit with a slight reduction in diastereose-
lectivity.
Scheme 2. Mechanistic investigation of the cycloaddition reaction.
Table 3. The enantio- and diastereoselective cycloaddition reaction of a
series of azlactones 1 with 2, catalyzed by (R)-4.[a]
lectivity of the isolated acyclic product 5 were determined
to be greater than 99% cis and 90% ee. These results were
obtained after transformation of 5 into 3aa by cyclization/
ring-opening reactions using an achiral base catalyst, 1,8-
diazabicycloACTHUNTGRNEUNG[5.4.0]undec-7-ene (DBU), which was employed
to avoid kinetic optical resolution of enantioenriched 5 by
(R)-4 during the transformation.[13] The resulting cis selectiv-
ity, ee value, and absolute configuration are consistent with
those observed for the cycloaddition product obtained di-
rectly from the catalytic enantioselective reaction (98% cis,
90% ee).[14] Consequently, these results strongly suggest that
3 is formed via an enolate form of acyclic intermediate 5,
thus anionic intermediate A, and the initial Michael addi-
tion reaction can be regarded as the stereo-determining
step. More importantly, it is likely that the present cycload-
dition reaction is composed of three consecutive steps.[15]
In conclusion, we have demonstrated the enantio- and
diastereoselective cycloaddition reaction of azlactones with
b,g-unsaturated a-ketoesters catalyzed by an axially chiral
guanidine base. The most plausible pathway of the cycload-
dition reaction involves three consecutive transformations as
evidenced by the isolation and characterization of the acy-
clic intermediate, formed from the initial Michael addition.
The method provides an efficient and highly stereoselective
access to optically active a-amino d-lactones with a sugar
framework. Further studies on the development of chiral
guanidine-catalyzed stereoselective transformations with
azlactones are underway in our laboratory.
Entry
1
2
3
Yield [%][b]
cis/trans[c]
ee [%][d]
1
2
3
4
5
6
7
8
9
1a
1a
1i
2b
2c
2a
2a
2a
2a
2a
2a
2a
3ab[e]
3ac
3ia
99
84
93
97
74
80
93
80
81
98:2
94:6
91:9
87:13
>99:<1
94:6
87:13
77:23
93:7
89
88
78
80
66
81
86
85
87
1j
3ja
1k
1e
1l
1m
1n
3ka
3ea
3la
3ma
3na
[a] Unless otherwise noted, all reactions were carried out with (R)-4
(2 mol%, 0.002 mmol), 1 (0.10 mmol), and 2 (0.11 mmol, 1.1 equiv) in
Et2O (0.5 mL) at À608C for 2–4 h, then warmed to room temperature
and stirred for 1 h. [b] Yield of the isolated product. [c] Determined by
1H NMR spectroscopy. [d] Determined by chiral stationary-phase HPLC
analysis of the major cis isomer. [e] The absolute stereochemistry was un-
ambiguously determined to be 4S,5R by X-ray crystallographic analy-
sis.[12]
1762
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 1760 – 1763

Highly Stereoselective [4+2] Cycloaddition of Azlactones
COMMUNICATION
Chem. Soc. 2006, 128, 16044–16045; g) M. Nakano, M. Terada, Syn-
lett 2009, 1670–1674; h) H. Ube, M. Terada, Bioorg. Med. Chem.
Lett. 2009, 19, 3895–3898.
Experimental Section
General procedure: Compound (R)-4 (2.5 mg, 0.002 mmol) was added to
[8] For reviews of chiral guanidine catalysts, see: a) T. Ishikawa, T.
Isobe, Chem. Eur. J. 2002, 8, 552–557; b) T. Ishikawa, T. Kumamoto,
Synthesis 2006, 737–752; c) D. Leow, C.-H. Tan, Chem. Asian J.
2009, 4, 488–507; for selected examples of enantioselective catalysis
by chiral guanidine derivatives, see: d) T. Kita, A. Georgieva, Y. Ha-
shimoto, T. Nakata, K. Nagasawa, Angew. Chem. 2002, 114, 2956–
2958; Angew. Chem. Int. Ed. 2002, 41, 2832–2834; e) S. Kobayashi,
R. Yazaki, K. Seki, Y. Yamashita, Angew. Chem. 2008, 120, 5695–
5697; Angew. Chem. Int. Ed. 2008, 47, 5613–5615; f) A. Ryoda, N.
Yajima, T. Haga, T. Kumamoto, W. Nakanishi, M. Kawahata, K. Ya-
maguchi, T. Ishikawa, J. Org. Chem. 2008, 73, 133–141; g) H. Liu,
D. Leow, K.-W. Huang, C.-H. Tan, J. Am. Chem. Soc. 2009, 131,
7212–7213; h) Z. Yu, X. Liu, L. Zhou, L. Lin, X. Feng, Angew.
Chem. 2009, 121, 5297–5300; Angew. Chem. Int. Ed. 2009, 48, 5195–
5198; i) T. Misaki, G. Takimoto, T. Sugimura, J. Am. Chem. Soc.
2010, 132, 6286–6287.
a
solution of 4-benzyl-2-phenyloxazol-5ACTHNGUTERNNU(G 4H)-one (1a; 25.1 mg,
0.10 mmol) and (E)-ethyl 2-oxo-4-phenylbut-3-enoate (2a; 20.0 mL,
0.11 mmol) in Et2O (0.5 mL) at À608C. The resulting mixture was stirred
at À608C for 2 h, then warmed to room temperature and stirred for 1 h.
The reaction was quenched with aqueous NH4Cl and extracted with ethyl
acetate. The organic phase was dried over Na2SO4 and filtered. After re-
moval of the solvent under vacuum, the residue was purified by flash
column chromatography (hexane/ethyl acetate 10:1 to 4:1) to afford the
cycloaddition product 3aa (99% yield, cis/trans=99:1, 91% ee (cis)). The
diastereomeric ratio and enantiomeric excess were determined by NMR
spectroscopy of the crude product and HPLC analysis, respectively.
Acknowledgements
[9] For substituent effects of aromatic groups introduced at the C2-posi-
tion of azlactones, see: a) R. A. Mosey, J. S. Fisk, T. L. Friebe, J. J.
Tepe, Org. Lett. 2008, 10, 825–828; b) D. Uraguchi, Y. Ueki, T. Ooi,
J. Am. Chem. Soc. 2008, 130, 14088–14089; c) M. Terada, H.
Tanaka, K. Sorimachi, J. Am. Chem. Soc. 2009, 131, 3430–3431.
[10] During purification by silica gel column chromatography, acyclic
product 5 was partially transformed into cyclic product 3aa. The
yield indicated in Table 2 entry 7 (86%) was calculated after purifi-
cation of 3aa. Indeed, the acyclic product 5 was detected in greater
This work was supported by Grant-in-Aid for Scientific Research on Pri-
ority Areas “Advanced Molecular Transformation of Carbon Resources”
(no. 19020006) from MEXT, Japan. We also acknowledge Prof. T. Iwamo-
to and Prof. S. Ishida for X-ray crystal structure determination of the cy-
cloaddition product 3ab.
Keywords: amino sugar
·
asymmetric catalysis
·
cycloaddition · guanidine · organocatalysis
1
than 20% yield by H NMR spectroscopy of the crude material.
[11] The reaction of b,g-unsaturated a-ketoesters with a methyl substitu-
ent (instead of the aromatic counterpart) at the g-position gave the
product in moderate yield (56%) despite the fact that the starting
reactant, methyl-substituted a-ketoester in THF, was consumed
completely in 3 h at room temperature. A significant amount of by-
products was formed in this reaction, although the desired product
could be obtained with moderate stereoselectivity (64% cis,
54% ee).
[12] CCDC-787766 (3ab) contains the supplementary crystallographic
data for this paper. This data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
[13] It was confirmed that the cyclization/ring-opening reactions of 5
took place under the catalytic conditions with chiral guanidine base
4 (see Table 2, entries 7 and 8). In addition, at the beginning of the
reaction, acyclic intermediate 5 could be detected by TLC even at
room temperature, but this intermediate had completely disap-
peared by the end of the reaction.
[14] It can be considered that kinetic optical resolution of enantioen-
riched acyclic product 5 by chiral guanidine catalyst 4 would occur
during the following cyclization/ring-opening steps. However, it
seems unlikely that these processes occur because of the nearly
equal enantio- and diastereoselectivity observed in both cycloaddi-
tion product 3aa and acyclic intermediate 5.
[1] For reviews, see: a) J. S. Fisk, R. A. Mosey, J. J. Tepe, Chem. Soc.
Rev. 2007, 36, 1432–1440; b) N. M. Hewlett, C. D. Hupp, J. J. Tepe,
Synthesis 2009, 2825–2839.
[2] B. Sain, J. S. Sandhu, J. Heterocycl. Chem. 1986, 23, 1007–1010.
[3] J. Jiang, J. Qing, L.-Z. Gong, Chem. Eur. J. 2009, 15, 7031–7034.
[4] During the preparation of this manuscript, Feng and co-workers re-
ported the enantioselective inverse-electron-demand hetero-Diels–
Alder reaction of chalcone derivatives with azlactones at the C4-
and C5-positions, see: S. Dong, Z. Liu, X. Chen, F. Mei, Y. Zhang,
B. Gao, L. Lin, X. Feng, J. Am. Chem. Soc. 2010, 132, 10650–10651.
[5] For recent reviews of organocatalytic cascade transformations, see:
a) D. Enders, C. Grondal, M. R. M. Hꢁttl, Angew. Chem. 2007, 119,
1590–1601; Angew. Chem. Int. Ed. 2007, 46, 1570–1581; b) X. Yu,
W. Wang, Org. Biomol. Chem. 2008, 6, 2037–2046; c) C. Grondal,
M. Jeanty, D. Enders, Nat. Chem. 2010, 2, 167–178.
[6] For recent examples of enantioselective addition of azlactones to
different Michael acceptors, see: a) J. Alemꢂn, A. Milelli, S. Cab-
rera, E. Reyes, K. A. Jørgensen, Chem. Eur. J. 2008, 14, 10958–
10966; b) S. Cabrera, E. Reyes, J. Alemꢂn, A. Milelli, S. Kobbel-
gaard, K. A. Jørgensen, J. Am. Chem. Soc. 2008, 130, 12031–12037;
c) H. Jiang, M. W. Paix¼o, D. Monge, K. A. Jørgensen, J. Am. Chem.
Soc. 2010, 132, 2775–2783.
[15] We cannot completely rule out the possibility that the reaction pro-
ceeds by a concerted process, that is, by an inverse-electron-demand
hetero-Diels–Alder reaction, in parallel to the stepwise process that
is proposed as the most dominant mechanism in this transformation.
Also see reference [4].
[7] a) M. Terada, H. Ube, Y. Yaguchi, J. Am. Chem. Soc. 2006, 128,
1454–1455; b) M. Terada, T. Ikehara, H. Ube, J. Am. Chem. Soc.
2007, 129, 14112–14113; c) H. Ube, D. Uraguchi, M. Terada, J. Or-
ganomet. Chem. 2007, 692, 545–549; d) M. Terada, M. Nakano, Het-
erocycles 2008, 76, 1049–1055; e) H. Ube, N. Shimada, M. Terada,
Angew. Chem. 2010, 122, 1902–1905; Angew. Chem. Int. Ed. 2010,
49, 1858–1861; also see: f) M. Terada, M. Nakano, H. Ube, J. Am.
Received: October 19, 2010
Published online: January 5, 2011
Chem. Eur. J. 2011, 17, 1760 – 1763
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1763