Highly enantioselective photocyclization of 1-alkyl-2-pyridones to β-lactams in inclusion crystals with optically active host compounds

Article abstract of DOI:10.1021/ol026497u

equation presented Upon photoirradiation of a 1:1 inclusion complex of (-)-3 and 2-alkyl-1-pyridone (1) (R = Et, n-Pr, i-Pr, n-Bu, i-Bu) in the solid state, optically active β-lactams (2) of 91-99.5% ee were obtained in good yield.

Full text of DOI:10.1021/ol026497u

ORGANIC
LETTERS
2002
Vol. 4, No. 19
3255-3257
Highly Enantioselective Photocyclization
of 1-Alkyl-2-pyridones to â-Lactams in
Inclusion Crystals with Optically Active
Host Compounds
,†
Koichi Tanaka,* Takashi Fujiwara,† and Zofia Urbanczyk-Lipkowska‡
Department of Applied Chemistry, Faculty of Engineering, Ehime UniVersity,
Matsuyama, Ehime 790-8577, Japan, and Institute of Organic Chemistry,
Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
tanaka@en3.ehime-u.ac.jp.
Received July 10, 2002
ABSTRACT
Upon photoirradiation of a 1:1 inclusion complex of (−)-3 and 2-alkyl-1-pyridone (1) (R ) Et, n-Pr, i-Pr, n-Bu, i-Bu) in the solid state, optically
active â-lactams (2) of 91−99.5% ee were obtained in good yield.
Intramolecular [2+2]photocyclization of 2-pyridones (1) is
known to give chiral bicyclic â-lactams (2).1 The disrotatory
photocyclization of 1 in the a and b directions should give
(R,R)- and (S,S)-2, respectively. However, control of the
direction in the photochemical disrotatory ring closure is not
easy in solution. For example, Bach et al. reported that
photocylization of 2-pyridones proceeds with lower enantio-
selectivity (20-23% ee) in the presence of a chiral host
compound in solution even at low temperature.2 Relatively
high enantioselectivity has been achieved in the absolute
asymmetric photoreaction of chiral crystals of some 2-py-
ridones.3 We have also reported the enantioselective photo-
cyclization of 2-pyridones in the inclusion crystals with
optically active (-)-1,6-di(o-chlorophenyl)-1,6-diphenyl-
hexa-2,4-diyne-1,6-diol, in which the photocyclization prod-
ucts with high ee were obtained in low chemical yields.4
We have now found that highly enantioselective photocy-
clization of 2-pyridones (1) proceeds efficiently in the
inclusion crystals with optically active host compounds (3
and 4)5 derived from tartaric acid.
When a solution of (-)-3 (3.0 g, 3.2 mmol) and 1-n-butyl-
2-pyridone (1e) (0.49 g, 3.2 mmol) in toluene (30 mL) was
kept at room temperature for 12 h, a 1:1 inclusion complex
of (-)-3 and 1e was obtained as colorless prisms (3.04 g,
88% yield, mp 181-183 °C). Similarly, host (-)-3 formed
1:1 inclusion complexes with 1b-f, while the host compound
(-)-4 formed 1:1 inclusion complexes with 1a, 1b, and 1g,
and 2:1 inclusion complexes with 1c, 1d, 1e, and 1f,
respectively (Table 1). On the other hand, a new host
compound (-)-56 formed 1:2 inclusion complexes with 1a,
1b, and 1c, respectively.
Photoirradiation of a suspension of powdered 1:1 inclusion
complex of (-)-3 and 1e (2.73 g) in water (200 mL)
containing hexadecyltrimethylammonium bromide (0.2 g) as
a surfactant was carried out with a 100-W high-pressure Hg
lamp (Pyrex filter) for 53 h under stirring. The reaction
product was filtered, air-dried, and chromatographed on silica
† Ehime University.
‡ Polish Academy of Sciences.
(1) (a) Corey, E. J.; Streith, J. J. Am. Chem. Soc. 1964, 86, 950-951.
(b) De Selms, R. C.; Schleigh, W. R. Tetrahedron Lett. 1972, 3563.
(2) Bach, T.; Bergmann, H.; Harms, K. Org. Lett. 2001, 3, 601-603.
(3) Wu, L.-C.; Cheer, C. J.; Olovsson, G.; Scheffer, J. R.; Trotter, J.;
Wang, S.-L.; Liao, F.-L. Tetrahedron Lett. 1997, 38, 3135-3138.
10.1021/ol026497u CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/21/2002

did not form inclusion crystals with 1g. For example, when
a suspension of a powdered 1:1 inclusion complex of (-)-4
and 1g in water was irradiated at room temperature for 47
h, (+)-2-benzyl-2-aza-bicyclo[2.2.0]hex-5-en-3-one (2g) of
>99.5% ee was obtained in 74% yield.
Interestingly, however, host compound (-)-5 formed 1:2
inclusion complexes with 2-pyridones (1b and 1c) which,
upon photoirradiation in the solid state, gave only [4+4]
dimer (6b and 6c) in 89 and 78% yield, respectively. The
selectivity of the photodimerization in the 1:2 inclusion
conlex of (-)-5 with 2-pyridone (1b and 1c) suggests that
pairs of molecules of 2-pyridones are arranged at the best
position to produce [4+4] dimer (6b and 6c) upon photo-
irradiation. On the other hand, no photoreaction occurred
for the inclusion crystals of 3 with 1a, 4 with 1a-e, and 5
with 1a.
Table 1. Host-Guest Ratios of Inclusion Complexa
guest
host 3
host 4
host 5
1a
1b
1c
1d
1e
1f
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
2:1
2:1
2:1
2:1
1:1
1:2
1:2
1:2
-
-
-
b
1g
-
-
a Host-guest ratios were determined by 1H NMR. b No complexation
occurred.
gel with hexanes-ethyl acetate (1:1) as an eluent to give
(-)-2-butyl-2-aza-bicyclo[2.2.0]hex-5-en-3-one (2e) (0.11 g,
69% yield, [R]D -169° (c 0.4, MeOH), >99.5% ee). Similar
irradiation of a 1:1 inclusion complex of (+)-3 and 1e gave
the other enantiomer (+)-2e of >99.5% ee in 62% yield.
The optical purity was determined by HPLC on chiral
stationary phase Chiralcel OD with hexane/2-propanol
(9:1) as solvent.
To elucidate the mechanism of the enantioselective photo-
cyclization of 1-alkyl-2-pyridones to â-lactams in the inclu-
sion crystals with optically active host compounds, X-ray
crystal structure analysis of the inclusion complex was
studied.7-10 As can be seen from Figure 1, the molecular
When inclusion crystals of (-)-3 with 1b, 1c, 1d, and 1f
were irradiated as described above, optically active â-lactams
2b, 2c, 2d, and 2f were also obtained in 91, >99.5, >99.5,
and >99.5% ee, respectively (Table 2). The host compound
Table 2. Enantioselective Photocyclization of 2-Pyridones (1)
in the Inclusion Crystals with Optically Active Hosts (3-5)
irradiation conv
yield [R]D (deg)
ee
guest host
time (h)
(%) product (%) (MeOH) (%)a
1b (-)-3
1b (+)-5
168
86
109
55
53
53
66 (-)-2b
69 6b
63 (-)-2c
92 6c
83 (+)-2d
65 (-)-2e
62 (+)-2e
67 (+)-2f
71 (-)-2f
42 (+)-2g
18
90
80
79
58
69
62
32
26
74
-134
-210
91
1c
1c
(-)-3
(+)-5
>99.5
1d (-)-3
+177
-169
+171
+127
-121
+22
>99.5
>99.5
>99.5
>99.5
95
1e
1e
1f
1f
(-)-3
(+)-3
(-)-3
(-)-4
53
168
168
47
Figure 1. Solid-state structure of the (1:1) complex of 3 and 1e
showing heteroatoms as 30% probability thermal ellipsoids and
carbon atoms as spheres. Hydrogen atoms in the host molecules
are omitted for clarity. Dashed lines denote two intramolecular
O-H‚‚‚OH and one intermolecular O58-H‚‚‚O77dC hydrogen
bonds. Parallel arrangement of pyridone and A-ring of the host
restricts molecular movement of the guest 2e.
1g (-)-4
>99.5
a Optical purity was determined by HPLC (Chiralcel OD, Daicel).
4 is effective for the enantioselective photocyclization of 1g
to optically active â-lactam 2g, although host compound 3
complex between host 3 and substrate 1e is formed via
formation of a strong hydrogen bond between two comple-
mentary partners [O58‚‚‚O77 ) 2.671(8) Å, H‚‚‚O77 )
1.87(7) Å, angle 161(7)°]. Host 3 is particularly well
(4) (a) Toda, F.; Tanaka, K. Tetrahedron Lett. 1988, 29, 4299-4302.
(b) Fujiwara, T.; Tanaka, N.; Tanaka, K.; Toda, F. J. Chem. Soc., Perkin
Trans. 1 1989, 663.
(5) (a) Tanaka, K.; Honke, S.; Urbanczyk-Lipkowska, Z.; Toda, F. Eur.
J. Org. Chem. 2000, 3171-3176. (b) Tanaka, K.; Nagahiro, R.; Urbanczyk-
Lipkowska, Z. Org. Lett. 2001, 3, 1567-1569.
(6) When a solution of (+)-diethyl tartarate (171 g, 0.8 mol) and
terephthaldehyde (54 g, 0.4 mol) in toluene (500 mL) containing a catalytic
amount of TsOH was heated under reflux for 120 h, tetraester was obtained
in 58% yield after recrystallization from toluene (118 g, colorless needles,
mp 69-71 °C, [R]D -34° (c 1.0, MeOH)). A solution of the tetraester (20
g, 0.039 mol) in dry THF (50 mL) was added under stirring to a solution
of PhMgBr in THF (500 mL) prepared from Mg (12 g, 0.5 mol) and
bromobenzene (78.5 g, 0.5 mol) and the mixture was stirred for 6 h. The
usual workup gave crude crystals of host 5. Recrystallization of crude
crystals from acetone gave a 1:1 inclusion complex of 5 with acetone as
colorless prisms which upon heating gave pure 5 as a white powder (28 g,
31% yield, mp 291-293 °C, [R]D +50 ° (c 1.0, CHCl3)). 5: IR (Nujol)
(cm-1) 3370 (OH). 1H NMR (300 MHz, CDCl3) δ 2.07 (s, 2 H, OH), 3.18
(s, 2 H, OH), 5.09 (d, J ) 5.0 Hz, 2 H, CH), 5.11 (s, 2 H, CH), 5.28 (d, J
) 5.0 Hz, 2 H, CH), 7.09-7.15 (m, 44 H, Ar). Anal. Calcd for C64H54O8:
C, 80.82; H, 5.72. Found: C, 80.03; H, 6.25.
3256
Org. Lett., Vol. 4, No. 19, 2002

Å. Two other rings labeled B and C do not have contacts
below 4.3 Å with the pyridone ring. Additionally, the n-butyl
chain works as an anchor, fixing the position of atoms in
the vicinity of the amide system. The starting spacial situation
is changed during the reaction pathway when two pyridone
carbon atoms change their configuration from sp2 to sp3.
Hydrogen atoms attached to them create large repulsion with
ring A. Therefore, the only possible movement of the
pyridone C-atoms during photoreaction is outward from ring
A. This steric arrangement in the crystal would favor pathway
b, shown in Scheme 1.
Scheme 1
Acknowledgment. K.T. acknowledges financial support
from The Asahi Glass Foundation.
Supporting Information Available: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL026497U
(7) X-ray Studies of the 1:1 Complex of (-)-3 and 1e. C70H98NO9: A
0.35 × 0.15 × 0.15 mm3 crystal covered by epoxy glue was used for data
collection on a four-circle MACH3 diffractometer. Unit cell parameters: a
) 14.347(1) Å, b ) 14.4732(7) Å, c ) 28.276(4) Å, orthorhombic system,
space group P212121, Z ) 4, V ) 5871(1) Å3, Dcalc ) 1.242 mg m-3. 6715
reflections have been collected in θ range 3.13-74.22°. 3537 independent
reflections (Rint ) 0.047), corrected for Lorentz, polarization, and æ-scan
based absorption (max. and min. transmission 99.98 and 87.38, respectively),
have been used for structure solution and refinement. SHELXS978 and
SHELXL979 included in the WINGX suite of programs10 have been used
for structure solution and refinement. H-atoms from OH groups have been
found from ∆F maps and refined, otherwise, they have been included at
their calculated positions. Final atomic coordinates, bond lengths, bond
angles, torsion angles, and geometry of H-bonds have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
no. CCDC188283. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. (fax
+44 1223 336033 or e-mail deposit@ccdc.cam.ac.uk).
designed for accommodation of planar ring systems. As a
result, a planar molecule of 2e is inserted between aromatic
rings of the hosts with an efficient overlap of the pyridone
ring with the host’s phenyl ring marked A [N71‚‚‚C67 )
3.604(6) Å, O77‚‚‚C65 ) 3.385(6) Å]. The C‚‚‚C distances
between the two aromatic systems are as short as 3.81-4.2
(8) Sheldrick G. M. Program for Crystal Structures Solution; University
of Go¨ttingen: Go¨ttingen, Germany, 1977.
(9) Sheldrick G. M. Program for Refinemnt of Crystal Structures;
University of Go¨ttingen: Go¨ttingen, Germany, 1977.
(10) Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837-845.
Org. Lett., Vol. 4, No. 19, 2002
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