Enantioselective photochemical synthesis of a β-lactam via the solid state ionic chiral auxiliary method

Article abstract of DOI:10.1055/s-2001-15056

Photolysis of crystals of a carboxylic acid-containing N,N-dialkylarylglyoxylamide to which an optically pure ammonium ion (the ionic chiral auxiliary) has been attached through a salt bridge leads to a 91% isolated yield of a β-lactam in greater than 99%

Full text of DOI:10.1055/s-2001-15056

PAPER
1253
Enantioselective Photochemical Synthesis of a -Lactam via the Solid State
Ionic Chiral Auxiliary Method
E
nantiosel
o
e
ctive Photo
h
c
hemica
l
Synthesis of
a
-Lacta
R
m
. Scheffer,* Keyan Wang
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, Canada V6T 1Z1
Fax +1(604)8222847; E-mail: scheffer@chem.ubc.ca
Received 29 January 2001
it can be carried out to high conversion on a relatively
large (500 mg) scale. The present paper reports our latest
efforts in both areas.
Abstract: Photolysis of crystals of a carboxylic acid-containing
N,N-dialkylarylglyoxylamide to which an optically pure ammoni-
um ion (the ionic chiral auxiliary) has been attached through a salt
bridge leads to a 91% isolated yield of a -lactam in greater than
99% enantiomeric excess. Suspension of the crystals in hexane al-
lows the photoreaction to be carried out on a 500 mg scale, thus
demonstrating the synthetic utility of the solid state ionic chiral aux-
iliary approach to asymmetric synthesis.
The target molecule for this investigation is based on the
N,N-dialkylarylglyoxylamide system studied initially by
Aoyama and co-workers2 and subsequently by Toda et al.3
In 1979 Aoyama and co-workers showed that N,N-diiso-
propylphenylglyoxylamide (1) undergoes a photochemi-
cally-induced Yang photocyclization reaction4 in the
crystalline state to form the presumably racemic -lactam
derivative 2 as the major product along with trace
amounts of the oxazolidinone derivative 3 (Scheme 1).2a
Subsequent work on this system centered around methods
of forming -lactam 2 enantioselectively. Toda and co-
workers were the first to report that compound 1 serendip-
itously crystallizes in a chiral space group, and that pho-
tolysis of enantiomorphously homogeneous samples of
this material in the solid state leads to -lactam 2 in high
(93%) enantiomeric excess.3a This is an example of a so-
called “absolute” asymmetric synthesis,5 and later work
by Toda and co-workers showed that certain meta-substi-
tuted derivatives of glyoxylamide 1 behave similarly.3f,g
Key words: -lactam, asymmetric synthesis, chiral auxiliaries,
photochemistry, solid state
The solid state ionic chiral auxiliary approach to asym-
metric photochemical synthesis consists of the following
steps:1 an achiral reactant containing a carboxylic acid (or
amine) functional group is first treated with an optically
pure amine (or carboxylic acid) to form the corresponding
salt. After purification through recrystallization, the salt is
then irradiated in the crystalline state and the resulting
chiral photoproducts are analyzed for enantiomeric ex-
cess. The method owes its success to the fact that salts in
which either the cation or the anion is optically pure are
required to crystallize in chiral packing arrangements
(space groups) that can be thought of as providing 3-di-
mensional reaction cavities capable of differentiating
enantiomeric transition states. Kinetic control of the pho-
tochemical reaction thus leads to enantiomerically en-
riched photoproducts following removal of the chiral
auxiliary. Using this approach, high enantiomeric excess-
es (> 90%) have been obtained in a variety of solid state-
compatible photochemical reactions.1 Our current re-
search goals in this area are twofold: (1) to demonstrate
the generality of the solid state ionic chiral auxiliary meth-
od by applying it as widely as possible, and (2) to demon-
strate the synthetic utility of the method by showing that
Because the great majority of achiral compounds do not
crystallize in chiral space groups,6 and because it is virtu-
ally impossible to predict when a substance will do so, ab-
solute asymmetric synthesis is at present an unreliable
general method of preparing enantiomerically enriched
substances. This brings us to the second approach that has
been reported for the asymmetric synthesis of -lactams
such as 2. This consists of irradiating crystalline host–
guest complexes in which the glyoxylamides act as guests
and the hosts are optically pure compounds such as de-
oxycholic acid,2b (S,S)-(–)-1,6-bis(o-chlorophenyl)-1,6-
diphenylhexa-2,4-diyne-1,6-diol3c and (2R,3R)- , , , -
OH
H
O
O
Ph
N
Ph
hν, crystal
+
Ph
N
N
O
O
O
1
2
3
Scheme 1
Synthesis 2001, No. 8, 18 06 2001. Article Identifier:
1437-210X,E;2001,0,08,1253,1257,ftx,en;C00701SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1254
J. R. Scheffer, K. Wang
PAPER
tetraphenyl-1,4-dioxaspiro[4,5]decan-2,3-dimethanol.3e
9a was 202–206 °C, while that of the 1-phenylethylamine
Depending on the particular combination of host and salt 9b was 178–181 °C.
guest used, optical yields varied from negligible to nearly
quantitative.
Irradiation of each salt was carried out in two different
ways. For small-scale (5 mg) analytical runs, the crystals
One of the drawbacks of the host–guest approach de- were sandwiched between microscope slides and irradiat-
scribed above is that only certain combinations of host ed in polyethylene bags that had been sealed under a pos-
and guest lead to crystalline complexes suitable for pho- itive pressure of nitrogen. For large-scale (100–500 mg)
tolysis. Another is that the optically active host molecules preparative runs, the crystals were irradiated as a suspen-
tend to be time-consuming and expensive to prepare, and sion in deoxygenated hexanes (mixture of isomers). Best
in addition, must be separated from the reaction mixture results were obtained in each case when the irradiating
following photolysis. We therefore decided to test the sol- wavelength was 330 nm (uranium glass filter). Follow-
id-state ionic chiral auxiliary method of asymmetric syn- ing photolysis, the hexane solution was extracted with
thesis in the arylglyoxylamide system. This required the methanol and the methanol extracts were concentrated
reactant to be fitted with an acidic or basic functional and treated with ethereal diazomethane to form the corre-
group to which the ionic chiral auxiliary could be attached sponding methyl esters. The photoproducts were then pu-
by a salt bridge, and the p-carboxylic acid derivative 8 rified by column chromatography, fully characterized by
was chosen for this purpose. This compound was synthe- spectroscopic techniques, and analyzed for optical purity
sized in an expeditious and straightforward fashion as by chiral HPLC.
shown in Scheme 2.
As expected, -lactam derivative 10 was the sole product
The next step was to form crystalline salts of acid 8 with formed in the solid-state irradiation of salts 9a and 9b. Its
some optically pure amines. In this paper we describe our structure was confirmed on the basis of the spectroscopic
results with L-(–)-prolinamide and (R)-(+)-1-phenylethyl- data reported in the Experimental Section. Particularly di-
amine. Reaction of acid 8 with both amines gave the cor- agnostic were a broad OH stretch in the infrared spectrum
responding 1:1 salts 9a and 9b in excellent yield as off- at 3441 cm–1 and two methyl singlets at 1.59 and 0.91 ppm
white crystals. The melting point of the prolinamide salt in the 1H NMR spectrum (a third methyl singlet due to the
methyl ester appeared at 4.03 ppm). In terms of the enan-
O
C
O
C
Pd (II) catalyst
H3C
COOCH3
H3C
Br
CO, CH3OH
93%
4
5
SeO2
Pyridine
88%
O
O
C
1. (COCl)2
N
C
COOCH3
HOOC
COOCH3
2. (i-C3H7)2NH
90%
O
7
6
LiOH
MeOH
99%
O
O
C
CONH2
N
H
N
C
COOH
N
O
COO
CONH2
92%
N
O
H
H
8
9a
Ph
1. hν, crystal
2. CH2N2 workup
99% ee
H2N
C
H
CH3
92%
OH
O
C
Ph
COOMe
1. hν, crystal
N
COO H3N
C
2. CH2N2 workup
10-20% ee
CH3
N
O
H
O
9b
10
Scheme 2
Synthesis 2001, No. 8, 1253–1257 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Enantioselective Photochemical Synthesis of a -Lactam
1255
ary ion mass spectra (LSIMS) were determined on a Kratos Concept
IIHQ hybrid mass spectrometer. UV/VIS absorption spectra were
recorded on a Perkin–Elmer Lambda 4B spectrometer using spec-
tral grade solvents. Elemental analyses were performed by the de-
partmental microanalyst, Mr. P. Borda, on a Carlo Erba CHN
Model 1106 analyzer. Gas chromatographic analyses were per-
formed on Hewlett–Packard 5890 or 5890 Series II Plus gas chro-
matographs equipped with flame ionization detectors. A HP-5 (30
tiomeric excess in which photoproduct 10 was formed,
salts 9a and 9b gave quite different results. Analysis by
chiral HPLC showed that prolinamide salt 9a afforded -
lactam 10 in nearly quantitative ee at all conversions test-
ed, both in the pure solid state as well as in the hexane sus-
pension runs. In a dramatic demonstration of the synthetic
potential of the ionic chiral auxiliary approach to asym-
metric synthesis, a hexane suspension of 500 mg of salt 9a
was irradiated to 99% conversion to afford a 91% isolated
yield of photoproduct 10 with an ee of >99%. The use of
hexane suspensions is very convenient for salts, and there
is no practical reason why even larger scale solid state
photolyses could not be carried out by this method. In
m
0.25 mm ID) fused silica capillary column was used, and the
carrier gas was He. HPLC analyses were performed on a Waters
600E system coupled to a Waters 486 tuneable UV detector. A
Chiralcel OD column (250 mm 4.6 mm ID) from Chiral Technol-
ogies, Inc. was used for ee determinations; the solvent was 99:1
hexanes/i-PrOH. Analytical TLC was performed on commercial
pre-coated plates (E. Merck, type 5554). Preparative chromatogra-
contrast to the results with salt 9a, photolysis of crystals phy was carried out using either the flash column method with
Merck 9385 silica gel (230–400 mesh) or radial elution chromatog-
raphy on a Chromatotron (Harrison Research).
of the 1-phenylethylamine salt 9b gave photoproduct 10
in very low enantiomeric excesses that varied with the ex-
tent of conversion. For example, the ee at 52% conversion
was 18% and that at 70% conversion was 10%. We have
noted similar decreases in ee with increasing conversion
in previous solid state asymmetric induction studies,7 and
this makes the results with the prolinamide salt all the
more striking.
Methyl 4-Acetylbenzoate (5)
Following a modification of the procedure of Gerlach and Woll-
mann,9 a solution of 4-bromoacetophenone (10.0 g, 50.3 mmol),
[1,1 -bis(diphenylphosphino)ferrocene]dichloropalladium(II) com-
plex with CH2Cl2 (1:1) (1.22 g, 1.5 mmol) in MeOH (50 mL), DMF
(100 mL) and diisopropylethylamine (17.5 mL) was purged for 10
min with gaseous CO. The solution was stirred under a positive
pressure of CO for 5 h at 70 °C. The resulting dark red mixture was
quenched with 0.5 M HCl (300 mL) and extracted with benzene (3
100 mL). The combined extracts were washed with sat. NaCl (2
100 mL), dried (Na2SO4) and evaporated to dryness. Purification by
column chromatography on silica gel (petroleum ether–Et2O, 5:1)
afforded 8.2 g (93%) of methyl 4-acetylbenzoate (5) as a white sol-
id, mp 94–95 °C (Lit.10 mp 95.0–95.5 °C).
Although we do not have X-ray crystallographic data for
either salt 9a or 9b, it is interesting to speculate on the rea-
sons for the low ee in the latter case. It seems quite likely
that this is due to the occurrence of conformational enan-
tiomerism in crystals of salt 9b. Conformational enanti-
omerism refers to the situation in which the non-chiral
portion of the salt, the carboxylate anion in this case, crys-
tallizes as a 1:1 mixture of mirror image-related conform-
ers. We have encountered this situation previously in the
solid state photochemistry of chiral salts,8 and the expla-
nation for the low enantiomeric excesses obtained in these
cases is that conformational enantiomers give rise to enan-
tiomeric photoproducts. The finding that the photoprod-
ucts of such reactions are not racemic can be attributed to
the fact that conformational enantiomers form diastereo-
meric salts with the common optically pure amine, and as
such, react at somewhat different rates. When the crystals
contain only one conformational enantiomer, as is likely
IR (KBr): = 3016, 2961, 1723, 1679, 1572, 1502, 1437, 1409,
1359, 1284, 1195, 1134, 1016, 957, 870, 851, 833, 771, 744, 698,
615, 593, 530 cm–1.
1H NMR (400 MHz, CDCl3): = 8.10 (d, 2H, J = 8.5 Hz), 7.98 (d,
2H, J = 8.5 Hz), 3.93 (s, 3H), 2.62 (s, 3H).
13C NMR (75 MHz, CDCl3): = 197.48, 166.19, 140.22, 133.88,
129.80, 128.17, 52.42, 26.83.
MS (EI): m/z (%) = 178 (M+, 13.9), 163 (100), 147 (21.1), 135
(26.1), 120 (6.6), 103 (13.8), 91 (10.0), 76 (18.3).
HRMS: m/z calcd for C10H10O3: 178.0630. Found: 178.0633.
Anal. Calcd for C10H10O3: C, 67.41; H, 5.66. Found: C, 67.71; H,
the case for salt 9a, only one photoproduct enantiomer is 5.74.
produced and enantiomeric excesses are high.
4-Methoxycarbonyl- -oxo-benzeneacetic Acid (6)
Work is ongoing in our laboratory to extend the ionic
chiral auxiliary approach to other arylglyoxylamide deriv-
atives and to explore the use of covalent chiral auxiliaries
in these systems as well.
A solution of methyl 4-acetylbenzoate (5) (2.0 g, 11.2 mmol) in py-
ridine (50 mL) containing SeO2 (2.0 g, 18.0 mmol) was refluxed un-
der N2 at 100 °C for 3.5 h. The precipitate was removed by filtration
and the filtrate was evaporated. The residue was neutralized with 1
M HCl (100 mL). The mixture was extracted with Et2O (3 100
mL). The combined ethereal extracts were washed with H2O and
extracted with 1 M NaHCO3 (3 50 mL). After washing with Et2O,
the aqueous layer was acidified with concd HCl, causing the precip-
itation of a white solid. The suspension was extracted with Et2O (3
100 mL) and the ethereal layers were washed with H2O, sat. NaCl,
and dried (Na2SO4). The solvent was removed in vacuo to yield
crude product. Recrystallization from benzene gave 2.05 g (88%) of
compound 6 as a white solid, mp 99–101 °C.
All air-sensitive reactions were carried out under Ar. THF was
freshly distilled from Na-benzophenone ketyl solution. CH2Cl2 was
freshly distilled from CaH2. IR spectra were obtained from KBr pel-
lets and recorded on a Perkin–Elmer model 1710 Fourier transform
spectrometer. Mps were determined on a Fisher–Johns hot stage ap-
paratus and are uncorrected. 1H NMR spectra were collected on one
of the following instruments: Bruker AV-300, Bruker AV-400. 13
C
NMR spectra were recorded on the following spectrometers: Bruker
AV-300 (75 MHz), Bruker AV-400 (100 MHz). Low- and high-res-
olution electron impact ionization mass spectra were obtained on a
Kratos MS 50 at 70 eV. Desorption chemical ionization (DCI) mass
spectra were obtained on a Kratos MS80 instrument. Liquid second-
IR (KBr): = 3506 (br), 1729, 1680 (d), 1441, 1409, 1284, 1222,
1115, 753 cm–1.
1H NMR (300 MHz, CD3CN): = 8.14 (m, 4H), 3.91 (s, 3H).
Synthesis 2001, No. 8, 1253–1257 ISSN 0039-7881 © Thieme Stuttgart · New York

1256
J. R. Scheffer, K. Wang
PAPER
13C NMR (75MHz, CD3CN): = 187.12, 163.96, 163.33, 136.66,
136.41, 131.18, 130.62, 53.21.
Anal. Calcd for C15H19NO4: C, 64.97; H, 6.91; N, 5.05. Found: C,
65.12; H, 6.93; N, 5.15.
MS (DCI+, isobutane): m/z (%) = 209 (M+ + 1, 34.8), 181 (100), 163
(56.3), 149 (58.2), 121 (5.9), 103 (3.1), 76 (1.3).
L-Prolinamide Salt 9a
A solution of acid 8 (459 mg, 1.66 mmol) in Et2O (50 mL) was add-
ed with stirring to a solution of L-prolinamide (198 mg, 1.74 mmol)
in Et2O (100 mL). Stirring was continued for 1 h, after which time
the precipitate that had formed (596 mg, 92%) was filtered and
washed with Et2O. Recrystallization from MeOH afforded salt 9a as
pale yellow crystals, mp 202–206 °C.
HRMS (DCI+, isobutane): m/z calcd for C10H9O5 (M+ + 1):
209.0450. Found: 209.0446.
Anal. Calcd for C10H8O5: C, 57.70; H, 3.87. Found: C, 57.70; H,
3.89.
UV (CH3OH): = 205.0 (2.02 104), 259.9 (1.55 104), 349.9
(302) nm.
Methyl N,N-Bis(1-methylethyl)- -oxo-benzeneacetamide-4-
carboxylate (7)
Oxalyl chloride (12.2 g, 8.4 mL, 96 mmol) was added dropwise to
a cold (–5 °C) solution of compound 6 (2.0 g, 9.6 mmol) and DMF
(0.7 g, 0.7 mL, 9.6 mmol) in anhyd THF (30 mL). The solution was
stirred for 2 h under N2 at r.t. Unreacted oxalyl chloride along with
DMF and THF were removed in vacuo and the solid residue dis-
solved in anhyd CH2Cl2 (30 mL). Diisopropylamine (5.8 g, 8.1 mL,
57.7 mmol) was added dropwise at –5 °C under N2 and the resulting
solution stirred at r.t. for 2 h. The reaction was quenched by addition
of 1 M HCl (40 mL), the layers separated, and the aqueous layer fur-
ther extracted with CH2Cl2 (3 100 mL). The organic layers were
combined, washed with sat. NaCl (2 50 mL) and H2O (2 50 mL),
and dried (Na2SO4). Removal of the solvent in vacuo followed by
silica gel column chromatography of the residue (petroleum ether–
EtOAc, 9:1) afforded 2.52 g (90%) of amide 7 as a light yellow sol-
id, mp 128–129 °C.
IR (KBr): = 3346, 2973, 1715, 1681, 1641, 1597, 1557, 1449,
1376, 1231, 1135, 993, 826, 754, 744 cm–1.
1H NMR (300 MHz, CD3OD): = 8.09 (d, 2H, J = 8.2 Hz), 7.91 (d,
2H, J = 8.2 Hz), 4.26 (m, 1H), 3.70 (m, 2H), 3.33 (m, 2H), 2.41 (m,
1H), 2.01 (m, 3H), 1.56 (d, 6H, J = 6.8 Hz), 1.18 (d, 6H, J = 6.6 Hz).
13C NMR (75 MHz, CD3OD): = 192.06, 173.21, 172.47, 168.85,
144.70, 135.46, 130.84, 130.09, 60.87, 52.23, 47.27, 31.18, 25.25,
20.44.
MS (+LSMS, matrix: thioglycerol): m/z (%) = 392 (M+ + 1, 9.8),
278 (100), 236 (31.3), 149 (48.4), 115 (42.9), 91 (10.1).
HRMS (+LSIMS, matrix: thioglycerol): m/z calcd for C20H30N3O5
(M+ + 1): 392.2185. Found: 392.2190.
Anal. Calcd for C20H29N3O5: C. 61.36: H. 7.47: N. 10.73. Found: C,
61.07; H, 7.43; N, 10.88.
UV (CH3OH): = 204.9 (1.72 104), 255.0 (1.56 104), 360.1
(226) nm.
(R)-(+)-1-Phenylethylamine Salt 9b
IR (KBr): = 2968, 1722, 1682, 1634, 1444, 1372, 1282, 1232,
1107, 730 cm–1.
1H NMR (400 MHz, CDCl3): = 8.14 (d, 2H, J = 8.2 Hz), 7.97 (d,
2H, J = 8.2 Hz), 3.93 (s, 3H), 3.67–3.55 (m, 2H), 1.56 (d, 6H, J = 6.9
Hz), 1.15 (d, 6H, J = 6.6 Hz).
13C NMR (75 MHz, CDCl3): = 190.05, 166.32, 165.97, 136.53,
134.92, 130.07, 129.39, 52.55, 50.20, 46.20, 20.57, 20.26.
A solution of acid 8 (83 mg, 0.30 mmol) in Et2O (15 mL) was added
to a solution of (R)-(+)-1-phenylethylamine (36 mg, 0.30 mmol) in
Et2O (5 mL). The cloudy solution was stirred for 1 h, after which
time the precipitate that had formed was filtered, washed with Et2O
and dried in vacuo to afford salt 9b (110 mg, 92%) as an off-white
powder. Recrystallization from MeOH afforded off-white crystals,
mp 178–181 °C.
MS (EI): m/z (%) = 291 (M+, 0.66), 260 (4.9), 163 (35.4), 135
(10.6), 128 (71.0), 104 (11.6), 86 (100), 76 (11.0).
UV (CH3OH): = 202.6 (2.74 104), 210.0 (2.55 104), 259.9
(1.81 104), 350 (280) nm.
HRMS: m/z calcd for C16H21NO4: 291.1471. Found: 291.1469.
IR (KBr): = 3503, 2972, 2935, 1752, 1675, 1640, 1581, 1537,
1396, 1237, 1137, 997, 826, 745 cm–1.
1H NMR (300 MHz, CD3OD): = 8.08 (d, 2H, J = 8.4 Hz), 7.90 (d,
2H, J = 8.4 Hz), 7.42 (m, 5H), 4.42 (q, 1H, J = 6.9 Hz), 3.69 (m, 2H),
1.61 (d, 3H, J = 6.9 Hz), 1.56 (d, 6H, J = 6.8 Hz), 1.18 (d, 6H, J = 6.6
Hz).
Anal. Calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81. Found: C,
66.07, H, 7.38; N, 4.75.
N,N-Bis(1-methylethyl)- -oxo-benzeneacetamide-4-carboxylic
Acid (8)
A solution of compound 7 (316 mg, 1.09 mmol) in CH3OH (10 mL)
was added to a solution of LiOH H2O (230 mg, 5.4 mmol) in H2O
(30 mL). The resulting solution was stirred for 30 min at r.t. The so-
lution was acidified with 4 M HCl (5 mL) and extracted with Et2O
(3 50 mL). The combined extracts were washed with sat. NaCl (2
30 mL), dried (Na2SO4), and concentrated in vacuo to afford 300
mg (99%) of acid 8 as a light yellow solid, mp 203–205 °C.
13C NMR (100 MHz, CD3OD): = 192.09, 173.38, 168.89, 145.19,
139.94, 135.33, 130.83, 130.26, 130.06, 127.63, 52.29, 52.17,
47.45, 20.87, 20.51, 20.44.
MS (+LSIMS, Matrix: thioglycerol): m/z (%) = 399 (M+ + 1, 41.0),
300 (10.6), 278 (49.3), 236 (22.1), 149 (39.8), 122 (100), 105 (67.3).
HRMS (+LSIMS, matrix: thioglycerol): m/z calcd for C23H31N2O4
(M+ + 1): 399.2286. Found: 399.2279.
IR (KBr): = 2992, 1700, 1686, 1635, 1572, 1504, 1474, 1449,
1419, 1376, 1348, 1225, 1210, 1120, 992, 745, 730 cm–1.
1H NMR (400 MHz, CD3OD): = 8.20 (d, 2H, J = 8.6 Hz), 8.00 (d,
2H, J = 8.6 Hz), 3.70 (m, 2H), 1.56 (d, 6H, J = 6.8 Hz), 1.20 (d, 6H,
J = 6.6 Hz).
Anal. Calcd for C23H30N2O4: C, 69.32; H, 7.59; N, 7.03. Found: C,
69.23; H, 7.60; N, 7.02.
Photolysis of Prolinamide Salt 9a
As a hexane suspension: Crystals of salt 9a (500 mg, 1.28 mmol)
were crushed in a mortar and pestle and suspended in 450 mL of
HPLC grade hexanes (mixture of isomers) in a standard photochem-
ical immersion well apparatus (Ace Glass). The suspension was
thoroughly degassed under N2 and irradiated with stirring for 6.5 h
(99% conversion) using the uranium glass-filtered output ( > 330
nm) of a Hanovia 450 W medium pressure mercury lamp. After
photolysis, the suspension was placed in a separatory funnel and ex-
13C NMR (100 MHz, CD3OD): = 191.46, 168.41, 168.25, 137.44,
131.44, 130.41, 52.16, 47.52, 20.49.
MS (EI+): m/z (%) = 277 (M+, 3.4), 233 (2.4), 192 (3.6), 149 (48.6),
128 (100), 103 (3.0), 86 (75), 65 (7.4).
HRMS: m/z calcd for C15H19NO4: 277.1314. Found: 277.1311.
Synthesis 2001, No. 8, 1253–1257 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Enantioselective Photochemical Synthesis of a -Lactam
1257
tracted with MeOH (3 100 mL). The methanol extracts were con-
centrated in vacuo and treated with an excess of ethereal
diazomethane to form the corresponding methyl esters. The methy-
lated reaction mixture was subjected to flash chromatography on
silica gel (petroleum ether–EtOAc, 7:3) to afford 338 mg (91%) of
-lactam 10 as a white solid. Chiral HPLC analysis indicated an op-
tical purity of >99%. The first HPLC peak eluted (peak A) was the
predominant enantiomer.
Acknowledgement
Acknowledgement is made to the donors of the Petroleum Research
Fund, administered by the American Chemical Society, for partial
support of this research. Financial support by the Natural Sciences
and Engineering Research Council of Canada is also gratefully ack-
nowledged.
In the pure solid state: A 5 mg sample of crystalline salt 9a was
sandwiched between a pair of Pyrex plates (thickness 2 mm) and
placed in a polyethylene bag. The bag was heat-sealed under a pos-
itive pressure of N2 and situated at a distance of 50 cm from the
lamp (Advanced Radiation Corp. 1000 W Xenon Mercury lamp,
type HXSA-1000, operating at 800 W). The sample was irradiated
for 5 h, dissolved in MeOH, and treated with excess ethereal diazo-
methane. Column chromatography of the residue over silica gel (pe-
troleum ether–EtOAc, 7:3) afforded photoproduct 10 whose ee was
shown to be 99% (peak A predominating) by chiral HPLC analysis.
References
(1) (a) Gamlin, J. N.; Jones, R.; Leibovitch, M.; Patrick, B.;
Scheffer, J. R.; Trotter, J. Acc. Chem. Res. 1996, 29, 203.
(b) Scheffer, J. R. Can. J. Chem., in press.
(2) (a) Aoyama, H.; Haswgawa, T.; Omote, Y. J. Am. Chem.
Soc. 1979, 101, 5343. (b) Aoyama, H.; Miyazaki, K.;
Sakamoto, M.; Omote, Y. J. Chem. Soc., Chem. Commun.
1983, 333.
(3) (a) Toda, F.; Yagi, M.; Soda, S. J. Chem. Soc., Chem.
Commun. 1987, 1413. (b) Toda, F.; Tanaka, K.; Yagi, M.
Tetrahedron 1987, 43, 1495. (c) Kaftory, M.; Yagi, M.;
Tanaka, K.; Toda, F. J. Org. Chem. 1988, 53, 4391.
(d) Sekine, A.; Hori, K.; Ohashi, Y.; Yagi, M.; Toda, F. J.
Am. Chem. Soc. 1989, 111, 697. (e) Toda, F.; Miyamoto,
H.; Matsukawa, R. J. Chem. Soc., Perkin Trans. 1 1992,
1461. (f) Toda, F.; Miyamoto, H. J. Chem. Soc., Perkin
Trans. 1 1993, 1129. (g) Hashizume, D.; Kogo, H.; Sekine,
A.; Ohashi, Y.; Miyamoto, H.; Toda, F. J. Chem. Soc.,
Perkin Trans. 2 1996, 61.
(4) (a) Cyclobutanol products in Norrish type II photochemistry
were first reported by: Yang, N. C.; Yang, D. H. J. Am.
Chem. Soc. 1958, 80, 2913. (b) For a general review of the
Norrish/Yang type II reaction, see: Wagner, P.; Park, B.-S.
In Organic Photochemistry, Vol. 11; Padwa, A., Ed.; Marcel
Dekker: New York, 1991, Chap. 4.
(5) (a) The first example of an absolute asymmetric synthesis,
the gas-solid bromination of crystalline 4,4 -dimethyl-
chalcone, was reported by: Penzien, K.; Schmidt, G. M. J.
Angew. Chem., Int. Ed. Engl. 1969, 8, 608. (b) For a
discussion of absolute asymmetric synthesis in unimolecular
solid state photorearrangement reactions, see: Caswell, L.;
Garcia-Garibay, M. A.; Scheffer, J. R.; Trotter, J. J. Chem.
Ed. 1993, 70, 785.
(6) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates
and Resolutions; Wiley: New York, 1981, 14–18.
(7) Leibovitch, M.; Olovvson, G.; Scheffer, J. R.; Trotter, J. J.
Am. Chem. Soc. 1998, 120, 12755.
In solution: A solution of 5 mg of salt 9a in deoxygenated MeCN
(20 mL) was irradiated externally for 5 h in a Pyrex tube using a 450
W Hanovia medium pressure mercury lamp. After removal of sol-
vent and diazomethane workup, the photoproducts were separated
by column chromatography on silica gel (petroleum ether–EtOAc,
7:3). Chiral HPLC analysis of the fractions corresponding to photo-
product 10 indicated an ee of 7% (peak A predominating).
Characterization of Photoproduct 10
Mp 224–225 °C.
IR (KBr): = 3441(br), 2978, 1732, 1610, 1422, 1284, 1185, 1104,
772 cm–1.
1H NMR (300 MHz, CD2Cl2): = 8.47 (d, 2H, J = 8.7 Hz), 8.20 (d,
2H, J = 8.7 Hz), 4.03 (s, 3H), 3.68 (hept, 1H, J = 6.8 Hz), 1.83 (s,
1H), 1.59 (s, 3H), 1.45 (d, 3H, J = 6.8 Hz), 1.42 (d, 3H, J = 6.8 Hz),
0.91 (s, 3H).
13C NMR (100 MHz, CDCl3): = 168.38, 166.77, 143.62, 129.69,
129.39, 126.66, 87.87, 67.30, 52.09, 44.20, 23.78, 22.27, 21.88,
21.74.
MS (EI): m/z (%) = 291 (M+, 0.80), 260 (2.2), 206 (100), 191 (18.5),
163 (28.7), 147 (27.5), 100 (23.5).
HRMS: m/z calcd for C16H21NO4: 291.1471. Found: 291.1477.
Anal. Calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81. Found: C,
65.86; H, 7.36; N, 4.76.
Solid State Photolysis of Salt 9b
(8) Cheung, E.; Kang, T.; Netherton, M. R.; Scheffer, J. R.;
Trotter, J. J. Am. Chem. Soc. 2000, 122, 11753.
(9) Gerlach, U.; Wollmann, T. Tetrahedron Lett. 1992, 33,
5499.
(10) Smissman, E. E.; Li, J. P.; Israili, Z. H. J. Org. Chem. 1968,
33, 4231.
Photolysis of crystals of salt 9b (5 mg) between two Pyrex plates as
described above followed by diazomethane workup and column
chromatography afforded photoproduct 10 in enantiomeric excess-
es ranging from 10–18% (peak A predominating) depending on the
extent of conversion (see text).
Synthesis 2001, No. 8, 1253–1257 ISSN 0039-7881 © Thieme Stuttgart · New York