Diastereo- and enantioselective intramolecular [2+2] Photocycloaddition reactions of 3-(ω'-alkenyl)- and 3-(ω'-alkenyloxy)-Substituted 5,6-Dihydro-1H-pyridin-2-Ones

Article abstract of DOI:10.1002/chem.200902616

Abstract: 3-(ω'-Alkenyl)-substituted 5,6-dihydro-1H-pyridin-2-ones 2-4 were prepared as photocycloaddition precursors either by cross-coupling from 3-iodo-5,6-dihydro-1H-pyridin-2one (8) or-more favorably-from the corresponding α-(ωalkenyl)-substituted δ-valerolactams 9-11 by a selenylation/elimination sequence (56-62% overall yield). 3-(ω'- Alkenyloxy)-substituted 5,6-dihydro-1H-pyridin-2-ones 5 and 6 were accessible in 43 and 37% overall yield from 3-diazopiperidin-2one (15) by an ααa-chloroselenylation reaction at the 3-position followed by nucleophilic displacement of a chloride ion with an ω-alkenolate and oxidative elimination of selenoxide. Upon irradiation at λ = 254 nm, the precursor compounds underwent a clean intramolecular [2+2] photocycloaddition reaction. Substrates 2 and 5, tethered by a twoatom chain, exclusively delivered the respective crossed products 19 and 20, and substrates 3, 5, and 6, tethered by longer chains, gave the straight products 21-23. The completely regio- and diastereoselective photocycloaddition reactions proceeded in 63-83% yield. Irradiation in the presence of the chiral templates (-)-1 and (+)-31 at -75°C in toluene rendered the reactions enantioselective with selectivities varying between 40 and 85% ee. Truncated template rac-31 was prepared as a noranalogue of the well-established template 1 in eight steps and 56% yield from the Kemp triacid (24). Subsequent resolution delivered the enantiomerically pure templates (-)-31 and (+)-31. The outcome of the reactions is compared to the results achieved with 4-substituted 5,6-dihydro-1H-pyridin-2ones and quinolones.

Full text of DOI:10.1002/chem.200902616

DOI: 10.1002/chem.200902616
Diastereo- and Enantioselective Intramolecular [2+2] Photocycloaddition
Reactions of 3-(w’-Alkenyl)- and 3-(w’-Alkenyloxy)-Substituted
5,6-Dihydro-1H-pyridin-2-ones
Dominik Albrecht, Florian Vogt, and Thorsten Bach*[a]
Abstract:
5,6-dihydro-1H-pyridin-2-ones
3-(w’-Alkenyl)-substituted
2–4
elimination of selenoxide. Upon irradi-
ation at l=254 nm, the precursor com-
pounds underwent a clean intramolecu-
lar [2+2] photocycloaddition reaction.
Substrates 2 and 5, tethered by a two-
atom chain, exclusively delivered the
respective crossed products 19 and 20,
and substrates 3, 5, and 6, tethered by
longer chains, gave the straight prod-
ucts 21–23. The completely regio- and
diastereoselective photocycloaddition
reactions proceeded in 63–83% yield.
Irradiation in the presence of the chiral
templates (ꢀ)-1 and (+)-31 at ꢀ758C
in toluene rendered the reactions enan-
tioselective with selectivities varying
between 40 and 85% ee. Truncated
template rac-31 was prepared as a nor-
analogue of the well-established tem-
plate 1 in eight steps and 56% yield
from the Kemp triacid (24). Subse-
quent resolution delivered the enantio-
merically pure templates (ꢀ)-31 and
(+)-31. The outcome of the reactions is
compared to the results achieved with
4-substituted 5,6-dihydro-1H-pyridin-2-
ones and quinolones.
were prepared as photocycloaddition
precursors either by cross-coupling
from 3-iodo-5,6-dihydro-1H-pyridin-2-
one (8) or—more favorably—from the
corresponding a-(w’-alkenyl)-substitut-
ed d-valerolactams 9–11 by a selenyla-
tion/elimination sequence (56–62%
overall yield). 3-(w’-Alkenyloxy)-sub-
stituted 5,6-dihydro-1H-pyridin-2-ones
5 and 6 were accessible in 43 and 37%
overall yield from 3-diazopiperidin-2-
one (15) by an a,a-chloroselenylation
reaction at the 3-position followed by
nucleophilic displacement of a chloride
ion with an w-alkenolate and oxidative
Keywords: asymmetric synthesis ·
cycloaddition · enantioselectivity ·
hydrogen bonds · photochemistry
Introduction
alkaloid (+)-meloscine.[3] The mode of action of template 1
is based on the formation of a 1:1 complex of the substrate
with the template, in which an efficient enantioface differen-
tiation is possible. The driving force for this 1:1 association
is the fact that the homochiral complexing agent 1 cannot
dimerize in solution through hydrogen bonding due to the
bulky tetrahydronaphthalene backbone.[2c,4] As a conse-
quence, the formation of complexes with lactam substrates
becomes favorable even though hydrogen-bound dimers of
the substrates can be competitively formed.
The template-based approach to chiral photocycloaddition
products employing complexing agent (+)-1 or its enantio-
mer (ꢀ)-1 (Scheme 1) has emerged in recent years as a
useful method to achieve enantioselective photochemical re-
actions in solution.[1] In this context, intra- and intermolecu-
lar [2+2] photocycloaddition reactions of 4-substituted qui-
nolones have been particularly successful, frequently deliv-
ering the respective cyclobutane products in over 90%
enantiomeric excess (ee).[2] The enantioselective intermolec-
ular [2+2] photocycloaddition of a 4-alkylquinolone has
been recently applied to the total synthesis of the melodinus
[a] Dr. D. Albrecht, F. Vogt, Prof. Dr. T. Bach
Lehrstuhl fꢀr Organische Chemie I
Technische Universitꢁt Mꢀnchen
Lichtenbergstrasse 4, 85747 Garching (Germany)
Fax : (+49)89-289-13315
E-mail: thorsten.bach@ch.tum.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902616.
Scheme 1. Structure of the chiral complexing agent (+)-1 and its enantio-
mer (ꢀ)-1.
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FULL PAPER
To extend the scope of substrates suitable for the enantio-
selective photocycloaddition concept, we recently studied
the intramolecular [2+2] photocycloaddition of a,b-unsatu-
rated lactams that bear a vinyl group linked by an appropri-
ate spacer to the b-position of the lactam.[5] [2+2] Photocy-
cloaddition reactions of this substrate class are rare and
have not been explored comprehensively.[6] Work by us was
directed towards the synthesis and [2+2] photocycloaddi-
tion reactions of the 4-substituted five-membered 1,5-dihy-
dropyrrol-2-ones and six-membered 5,6-dihydro-1H-pyridin-
2-ones (Scheme 2). Although the photocycloaddition
strates 2–6 with which the hypothesis was to be tested are
depicted in Scheme 3.
Herein, we report our work related to the photochemistry
of 3-substituted 5,6-dihydro-1H-pyridin-2-ones. New synthet-
Scheme 3. The 3-substituted 5,6-dihydro-1H-pyridin-2-ones 2–6 as sub-
strates for an intramolecular [2+2] photocycloaddition reaction.
ic routes to the precursor compounds 2–6 were devised,
their photocycloaddition chemistry was studied, and the
question of enantioselectivity was addressed. A noranalogue
of the standard template 1 was prepared and employed in
the [2+2] photocycloaddition reaction of the precursor
compounds. The outcome of the reactions is compared with
4-substituted 5,6-dihydro-1H-pyridin-2-ones and the mecha-
nistic differences are discussed.
Scheme 2. A 1:1 complex of complexing agent (+)-1 with a substituted d-
lactam in schematic side-view and top-view representations. The sterical-
ly demanding 5,6,7,8-tetrahydronaphtho
gray ellipsoid.
ACHTUNGTNER[NUNG 2,3-d]oxazole is depicted as a
Results and Discussion
chemistry of these compounds was remarkably clean, it was
disappointing to note that the enantiomeric excess of the re-
sulting cyclobutanes was relatively low if the reactions were
conducted in the presence of complexing agent (ꢀ)-1 or
(+)-1. Only the oxygen-substituted substrate (R4 =3’-bute-
nyloxy) resulted in significant enantiomeric excess, but its
reaction rate was very low at ꢀ608C (conversion of 45%
after 29 h). The fast-reacting carbon-substituted substrates
(e.g., R4 =4’-pentenyl, 3’-butenyl) produced cyclobutanes in
enantioselectivities below 40% ee.[5] In a search for possible
explanations for this lack of enantioface differentiation, we
speculated that the substituent at the b-position, that is, C4
of a 5,6-dihydro-1H-pyridin-2-one compound, might not be
fully within the reach of the bulky 5,6,7,8-
Synthesis of starting materials: The introduction of alkenyl
substituents by cross-coupling reactions to the corresponding
3-halo-substituted 5,6-dihydro-1H-pyridin-2-ones struck us
as the most straightforward entry to 3-substituted 5,6-dihy-
dro-1H-pyridin-2-ones, such as 2–4. Indeed, we recently re-
ported the synthesis of 4-substituted 5,6-dihydro-1H-pyridin-
2-ones by Negishi cross-coupling reactions of 4-bromo-sub-
stituted 5,6-dihydro-1H-pyridin-2-ones.[7] Moreover, Torisa-
wa et al. had succeeded in the introduction of a new sub-
stituent at the 3-position of 3-iodo-substituted N-protected
5,6-dihydro-1H-pyridin-2-ones by a Negishi cross-coupling
reaction.[8] There are further reports on the displacement of
halogen substituents in a-halogenated a,b-unsaturated lac-
tams by a cross-coupling reaction.[9] Thus, we identified
iodide 8 as a suitable starting material for palladium-cata-
lyzed cross-coupling reactions (Scheme 4). Given the rela-
tively poor precedence for a-halogenation reactions of a,b-
unsaturated lactams, we were delighted to observe a suffi-
cient conversion into 8 by simply treating the known N-Boc-
tetrahydronaphthoACHTUNGTRENNUNG[2,3-d]oxazole backbone attached to the
hydrogen-bonding scaffold (Scheme 2). This explanation
seems appropriate as the first step of an intramolecular pho-
tocycloaddition at such a lactam occurs likely by addition to
C4. The chain R4 attached to C4 can turn away from the
shield because its conformation is - contrary to the substitu-
ent at C4 of quinolones (see below) - not restricted by 1,3-
allylic strain.
Although the association behavior of the substrates is also
relevant to enantioselectivity, we reasoned that substrate
variation by using a-substituted a,b-unsaturated d-lactams,
that is, 3-substituted 5,6-dihydro-1H-pyridin-2-ones, as sub-
strates in intramolecular [2+2] photocycloaddition reactions
might be sensible. Initial intramolecular attack of an appro-
priately chosen alkenyl or alkenyloxy double bond to the
photoexcited lactam should occur at C3 (Scheme 2) and
should be in the range of the steric shield. Potential sub-
Scheme 4. Synthesis of irradiation precursor 3 by a Negishi cross-coupling
reaction.
dba=dibenzylideneacetone,
DMA=dimethylacetamide,
RuPhos=2-dicyclohexylphosphino-2’’,6’’-diisopropoxy-1,1’’-biphenyl,
py=pyridine.
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4285

T. Bach et al.
[10]
protected lactam 7
with iodine (2.5 equiv) in a 1:1 mix-
Scheme 6, for which the easily accessible a-diazolactam 15
proved to be a valuable starting material.[17] The addition of
phenylselenyl chloride to a solution of 15 in dichlorome-
ture of pyridine and carbon tetrachloride at ambient temper-
ature.[11] The reaction was accompanied by N-Boc deprotec-
tion; the labile N-Boc-protected derivative of 8 could only
be isolated in low amounts and in varying yields. The subse-
quent Negishi cross-coupling reaction of 8 in dimethylaceta-
mide with pentenylzinc bromide (2 equiv), prepared from 5-
bromo-1-pentene through reductive zincation,[12] proceeded
at ambient temperature within 14 h using [Pd2ACTHNUTRGNEN(UG dba)3]
(5 mol%) as the catalyst and [RuPhos] (20 mol%)[13] as the
ligand. The desired irradiation precursor 3 was obtained in
88% yield.
Although the introduction of further substituents at the 3-
position of 8 (to the analogous lactams 2 and 4) appeared
feasible, the purification of the Negishi cross-coupling prod-
ucts was tedious. In addition, the synthesis of starting mate-
rial 7 was lengthy[10] and was more time consuming than de-
sirable. We, therefore, employed an alternative synthetic
route to lactams 2–4. The use of known a-alkenyl-substitut-
ed d-valerolactams 9–11, obtained by a-alkylation of the
parent compound,[14] allowed short access to the desired
compounds 2–4 within two steps (Scheme 5).
Scheme 6. Synthesis of irradiation precursors 5 and 6 starting from diazo
compound 15 via the a,a-adduct 16 and selenides 17 and 18.
thane delivered the a,a-adduct 16 in 78% yield through the
loss of a nitrogen molecule. Attempts to prepare the analo-
gous a-bromo adduct by the use of phenylselenyl bromide
failed due to subsequent spontaneous elimination of hydro-
gen bromide in the desired product. The addition of a Lewis
acid was not required to induce the a,a-chloroselenylation
reaction. Substitution of the chloride ion by the correspond-
ing alkenyloxy group was achieved by treatment of a,a-
adduct 16 with sodium bicarbonate in a solution of allylic al-
cohol or 3-buten-1-ol. By this means, a-selenolactams 17
and 18 could be obtained in yields of 69 and 64%.
As expected, the phenylseleno group in 17 and 18 was
susceptible to elimination under mild oxidative conditions,
as reported for 12–14 (see above). Thus, elimination of se-
lenoxide occurred very efficiently at room temperature
when the compounds were exposed to aqueous hydrogen
peroxide (9 equiv, 30% v/v) and pyridine (2.5 equiv) in di-
chloromethane, whereupon 3-(allyloxy)-5,6-dihydro-1H-pyri-
din-2-one (5) and 3-(3’-butenyloxy)-5,6-dihydro-1H-pyridin-
2-one (6) were obtained after purification in 79 and 75%
yield.
Scheme 5. Alternative approach to access irradiation precursors 2–4 start-
ing from d-lactams 9–11 via the intermediate selenides 12–14.
In the first step, the dianion generated from 9–11 by the
addition of n-butyllithium (2 equiv) was trapped with phe-
nylselenyl bromide (3 equiv) as the electrophile, thus fur-
nishing a-phenylselenylated lactams 12–14 in yields of 81–
85%. Subsequent treatment of 12–14 with aqueous hydro-
gen peroxide (9 equiv, 30% v/v) and pyridine (2.5 equiv) in
dichloromethane afforded the desired irradiation precursors
2–4 in yields of 69–75%. This synthetic path was a more
viable alternative to the Negishi cross-coupling approach
shown in Scheme 4 and delivered pure compounds in three
steps starting from commercially available d-valerolactam.
The a-alkenyloxy-substituted 5,6-dihydro-1H-pyridin-2-
ones 5 and 6 were prepared to compare their behavior in
the [2+2] photocycloaddition reactions to the alkenyl-sub-
stituted 5,6-dihydro-1H-pyridin-2-ones 2 and 3 with identical
side-chain lengths at the 3-position. Intensive studies by
Buckley and McKervey on reactions of a-diazoketones with
selenium-based reagents[15] served as a guideline for a short
access to compounds 5 and 6. Additionally, the work of Bari
and co-workers on the behavior of seleno b-lactams[16] en-
couraged us to attempt the synthetic route outlined in
AHCTUNGTREG[NNUN 2+2] Photocycloaddition reactions: Upon direct irradiation
(l=254 nm, light source: Rayonet RPR-2537 ꢃ; quartz
vessel) of lactams 2–6 (Schemes 7 and 8), an efficient [2+2]
Scheme 7. Intramolecular [2+2] photocycloaddition reactions of sub-
strates 2 and 5 to form the diastereomerically pure crossed products rac-
19 and rac-20.
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Chem. Eur. J. 2010, 16, 4284 – 4296

Template-Directed Enantioselective Photocycloaddition Reactions
FULL PAPER
photocycloadditition reaction was observed to provide the
desired tricyclic products rac-19–rac-23 in good yields. The
optimized reaction conditions were identical to conditions
previously reported.[5] The best results were achieved at
room temperature by employing dichloromethane as the sol-
vent at a substrate concentration of 5 mm. As expected from
previous reports of related reactions,[18] the photocycloaddi-
tion reactions proceeded either to the crossed or straight
photocycloaddition product, depending on the length of the
spacer. Starting from amides 2 and 5, the formation of the
straight photocycloaddition products was unlikely. The short
chain that connected the reactive centers would, in this reac-
cases, the use of anhydrous and degassed dichloromethane
was of decisive importance for the success of the [2+2] pho-
tocycloaddition reactions. In oxygen-containing solvents,
lower yields were observed due to decomposition reactions,
which were visible by coloration of the reaction mixture. All
the [2+2] photocycloaddition reactions mentioned so far
proceeded with perfect regio- and simple diastereoselectiv-
ity. The products rac-19–rac-23 were not contaminated with
other regioisomers nor with other diastereoisomers. The re-
gioselective formation of the straight versus crossed photo-
cycloaddition products was unequivocally established by the
NMR coupling pattern (1H–1H COSY) exhibited by the in-
dividual products. The [2+2] photocycloaddition reactions
gave access to new ring systems, which are difficult to pre-
pare by other methods. In addition, further reactions
through ring opening of the lactam, for example, could lead
tion mode, only result in
[2.2.0]hexane skeleton. In contrast, the formation of the
crossed cycloaddition product with the concomitant forma-
tion of a bicyclo[2.1.1]hexane core was more likely and
a highly strained bicyclo-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
indeed occurred readily. Irradiation of amides 2 and 5 deliv-
ered the anticipated diastereomerically pure products rac-19
and rac-20 in good yields with reaction times of one hour or
less (Scheme 7).
The [2 +2] photocycloaddition reactions of amides 3, 4,
and 6 (Scheme 8) were also rapid and high yielding. The
to bicyclo
ACHUTGTNRNEUG[N 2.1.1]hexanes, bicycloAHCTUNGTRENN[UGN 3.2.0]heptanes, or a bicyclo-
AHCTUNGTREG[NNNU 4.2.0]octane with an oxygen atom as a heteroatom in the 2-
position for rac-20 and rac-22. Additionally, one can consid-
er ring-opening reactions that occurred at the cyclobutane[19]
ring, thus providing access to spiro compounds in a highly
diastereoselective fashion.
Enantioselectivity–temperature and concentration variation:
Due to its easy accessibility, 5,6-dihydro-1H-pyridin-2-one 3
was selected for optimization of the reaction conditions in
the enantioselective [2+2] photocycloaddition experiments
(Table 1). According to the mode of action of the template
(see above), the stereocontrol increases by increasing the
amount of complexing agent (ꢀ)-1 (Table 1, entries 2 and 3
as well as 4 and 5) and by lowering the reaction tempera-
ture, presumably due to the more extensive formation of the
template–substrate complex. Toluene was the solvent of
choice for the reaction because it had previously been opti-
mal for the highly enantioselective [2+2] photocycloaddi-
Scheme 8. Intramolecular [2+2] photocycloaddition reactions of sub-
strates 3, 6, and 4 to form the diastereomerically pure straight products
rac-21, rac-22, and rac-23.
Table 1. Variation in the amount of complexing agent (ꢀ)-1, tempera-
ture, and substrate concentration in the [2+2] photocycloaddition reac-
tion of 3!21 and the influence on enantioselectivity.
length of the spacer between the reacting vinyl group and
the b-position of the lactam allowed for exclusive formation
of the straight products rac-21, rac-22, and rac-23 in yields
of 81, 65, and 64%, respectively. The reaction times for full
conversion varied depending on the length of the side chain.
The formation of the five-membered rings in the photocy-
cloaddition products rac-21 and rac-22 was complete after
one hour, whereas the transformation into the annelated
six-membered ring in rac-23 required two hours. Further-
more, the irradiation reactions of 5,6-dihydro-1H-pyridin-2-
ones bearing a methylene group (X=CH2) but no oxygen
atom (X=O) at the 3-position led to higher yields if all the
other parameters were unchanged (rac-19 versus rac-20 and
rac-21 versus rac-22).
Entry[a]
(ꢀ)-1
[equiv]
V
c
t
ee
G
[8C]
[mm]
[h][b]
[%][c]
1
2
3
4
5
6
4.0
2.6
2.0
2.0
2.6
2.6
ꢀ75
ꢀ75
ꢀ75
ꢀ60
ꢀ60
ꢀ75
5.0
5.0
5.0
5.0
5.0
4.0
4.0
4.0
3.5
3.5
4.0
84
84
81
79
82
83
10.0
[a] All the reactions were conducted with Rayonet RPR-2537-ꢃ lamps as
the irradiation source and in toluene as the solvent. [b] Elapsed reaction
times to achieve 100% conversion of the starting material. [c] The ee val-
ues were calculated from the enantiomeric ratios, which were determined
by chiral GC analysis.
The optimized reaction conditions delivered products of
high analytical purity after flash chromatography. In all the
Chem. Eur. J. 2010, 16, 4284 – 4296
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4287

T. Bach et al.
tion reactions of quinolones with complexing agents (+)-1
or (ꢀ)-1.[2,20]
reaction rate and after four hours of irradiation of 4, no con-
version into the desired product was observed. Although the
chiral template (ꢀ)-1 potentially suffers from decomposition
under the applied reaction conditions, substantial amounts
of the template could be easily recovered by column chro-
matography in all cases (76–91% recovery yield) except for
4 (Table 2, entry 3).
The absolute product configuration can be deduced from
the configuration of the respective 1:1 complex of the pho-
tocycloaddition precursor and template (ꢀ)-1. An approach
from the less shielded si face (relative to C4) is favored,
thus leading to the depicted products. For products 19 and
21, the configuration was conclusively proven by comparison
of measured and calculated CD spectral/optical rotation
(OR) data (see the Supporting Information).[21] The major
enantiomer exhibited a negative OR value at l=589.3 nm
and showed a negative Cotton effect below l=210 nm in
both cases. In addition, 21 showed a positive Cotton effect
at l=225 nm. These data fit perfectly the calculated values.
In addition, all the other major enantiomers 20, 22, and 23
obtained by reaction in the presence of (ꢀ)-1 were levorota-
tory, thus supporting the observation that the chirality of the
twisted lactam chromophore determines the optical proper-
ties of these compounds.
It can be inferred that an application of chiral template
(ꢀ)-1 in 2.6 equivalents is sufficient for a maximal induction
of chirality at ꢀ758C (Table 1, entries 1–3). A comparison
of entries 2 and 5 reveals that lower temperatures expected-
ly led to higher enantioselectivities with a slight decrease in
the reaction rate (Table 1, entries 3 and 4). An increase in
the substrate concentration, however, did not have a posi-
tive effect on the ee values (Table 1, entry 6). Therefore, the
reaction conditions as described in entry 2 were employed
for all subsequent enantioselective reactions in this study. It
is noteworthy that for the reaction outlined in entry 2
87% ee was observed after 53% conversion, which then de-
creased to 84% ee following complete conversion. This ob-
servation is consistent with the fact that the template slowly
decomposes at an irradiation wavelength of l=254 nm.[5]
In a subsequent series of irradiation experiments, we in-
vestigated the substrate scope for the enantioselective [2+
2] photocycloaddition reaction (Table 2). The [2+2] photo-
Table 2. Enantioselective [2+2] photocycloaddition reactions of sub-
strates 2–6 in the presence of chiral template (ꢀ)-1.
Enantioselectivity–template variation: The variable enantio-
selectivities achieved with carbon-tethered, relative to the
oxygen-tethered, 3-substituted 5,6-dihydro-1H-pyridin-2-
ones was considered to indicate a weaker template associa-
tion of the oxygen-tethered substrates relative to the
carbon-tethered substrates. Although the association con-
stants for these bimolecular complexes can be obtained by
various methods,[22] their determination is a very time-con-
suming exercise, the reliability of which is limited in cases
with poorly soluble substrates. We, therefore, wanted to
devise a slightly modified template as an alternative probe
for template association. To this end, the noranalogue of
template 1, namely, template 31, was prepared, which con-
tains a g-lactam unit as a recognition site as compared to
the d-lactam in the conventional template 1 (Scheme 9).
The synthesis commenced with the Kemp triacid (24),
which was upon successive treatment with thionyl chloride
and the known 3-amino-5,6,7,8-tetrahydronaphthalen-2-ol
(25) converted into an ortho-imidophenol.[23,24] Because the
free phenol turned out to be inseparable from impurities, it
was protected to yield the acetate 26 in 90% over three
steps. The formation of the corresponding acid chloride was
achieved with oxalyl chloride under DMF catalysis. Subse-
quent treatment with sodium azide yielded the correspond-
ing acyl azide 27 in 90% yield, which underwent a thermal
Curtius degradation in refluxing toluene containing benzyl
alcohol to trap the primary isocyanate as carbamate 28
(90% yield).[25,26] Hydrogenolytic cleavage of the resulting
benzyloxycarbonyl (Cbz) group quantitatively delivered
amine 29 as the starting material for the planned imide/
lactam rearrangement.[26] Potassium carbonate in methanol
induced the ring contraction and the acetate deprotection to
Entry[a]
Product
t
Yield
[%][b]
ee
Recovery of
[h]
[%][c]
(ꢀ)-1 [%][d]
1
2
3
4
5
19
21
23
20
22
7.0
4.0
4.0
5.5
4.0
83
80
69
84
76
90
[e]
–
n.d.[f]
40
n.d.[f]
88
61
53
60
91
[a] All the reactions were conducted at a substrate concentration of 5 mm
with Rayonet RPR-2537-ꢃ lamps as the irradiation source in toluene at
ꢀ758C. [b] Yield of the isolated products. [c] The ee values were calculat-
ed from the enantiomeric ratios, which were determined by chiral GC
analysis. [d] Yield of the recovered template (ꢀ)-1. [e] No conversion
into the desired product was observed. [f] Value could not be deter-
mined.
cycloaddition precursors were subjected to the optimized ir-
radiation conditions (see above), and the substrates contain-
ing an all-carbon tether generally provided products in
higher yields and enantioselectivities relative to those with
an oxygen atom in the tether. Additionally, the optimized
conditions for the enantioselective [2+2] photocycloaddi-
tion reactions allowed for slightly higher yields in the forma-
tion of the crossed products relative to the straight counter-
parts (Table 2). This trend was not observed for irradiation
experiments at room temperature in the absence of chiral
agent (ꢀ)-1. Interestingly, the side-chain elongation of 4
(n=3) versus 3 (n=2) resulted in a dramatic decrease in the
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Template-Directed Enantioselective Photocycloaddition Reactions
FULL PAPER
Scheme 10. Structure of the chiral complexing agent (+)-31 and its enan-
tiomer (ꢀ)-31.
Table 3. Enantioselective [2+2] photocycloaddition reactions of sub-
strates 2, 3, 5, and 6 in the presence of chiral template (+)-31.
Entry[a]
Product
t
Yield
[%][b]
ee
Recovery of
[h]
[%][c]
(+)-31 [%][d]
1
2
3
4
19
21
20
22
5.5
4.0
5.5
6.0
74
76
70
76
50
85
56
79
95
93
100
92
[a] All the reactions were conducted at a substrate concentration of 5 mm
with Rayonet RPR-2537-ꢃ lamps as the irradiation source in toluene at
ꢀ758C. [b] Yield of the isolated products. [c] The ee values were calculat-
ed from the enantiomeric ratios, which were determined by chiral GC
analysis. [d] Yield of the recovered template (+)-31.
Scheme 9. Transformation of the Kemp triacid (24) into template 31
through a Curtius rearrangement of azide 27 and subsequent lactam ring
formation of amine 29. DMAP=4-dimethylaminopyridine.
containing an all-carbon tether, however, gave lower
(Table 3, entry 1) or only slightly higher (Table 3, entry 2)
selectivities. The yields of the products were in the same
range. Template (+)-31 seems to be somewhat more stable
under the irradiation conditions because recovery of the
template was almost complete after column chromatogra-
phy.
form the desired racemic five-memered g-lactam rac-30,
which underwent cyclization to form the benzoxazole rac-31
under known conditions.[27]
Separation of the enantiomers of 31 was possible either
by semipreparative HPLC or by conventional resolution of
the diastereoisomeric carbamates that resulted from the re-
action of rac-31 with (ꢀ)-menthyl chloroformate and subse-
quent hydrolysis (see the Supporting Information).[27] The
absolute configuration was determined by NMR titration
studies by employing a previously reported method.[4b] Nota-
bly, the (+)-enantiomer of 31 corresponds to (ꢀ)-1 with
regard to its stereodirecting groups, whereas (+)-31 and
(+)-1 behave as if they were enantiomers (Scheme 10).
In a series of irradiation experiments with the four 3-sub-
stituted 5,6-dihydro-1H-pyridin-2-ones 2, 3, and the oxygen-
containing analogues 5 and 6, we investigated the influence
of the truncated complexing agent (+)-31 on their enantio-
selective [2+2] photocycloaddition reactions (Table 3)
under the optimized irradiation conditions (see above).
Upon irradiation in the presence of (+)-31, oxygen-contain-
ing substrates 5 and 6 delivered a remarkably higher enan-
tiomeric excess in the products (Table 3, entries 3 and 4)
than with (ꢀ)-1 (Table 2, entries 4 and 5). The substrates
Discussion
Although the improvements achieved with template 31 rela-
tive to 1 are not ground-breaking, it is apparent from these
results that the association behavior of the substrate with
the template plays a role in the enantioface-differentiating
process. It is also apparent, however, that the association of
5,6-dihydro-1H-pyridin-2-ones with another lactam based on
two hydrogen bonds is limited and cannot be increased with-
out significant electronic and structural changes. It can be
concluded that an enantiomeric excess of 50–85% ee can be
achieved with 3-substituted 5,6-dihydro-1H-pyridin-2-ones
in the presence of templates derived from the Kemp triacid.
Higher selectivities are not feasible presumably because the
substrate/template association is not perfect.
To understand the differences between 3- and 4-substitut-
ed 5,6-dihydro-1H-pyridin-2-ones, a closer look at the con-
formational aspects of the [2+2] photocycloaddition reac-
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4289

T. Bach et al.
tion may be helpful. Indeed, a comparison of the enantiose-
lective template-mediated [2+2] photocycloaddition reac-
tion of 3-(4’-pentenyl)-5,6-dihydro-pyridin-1H-one (3;
84% ee, 80% yield) with its 4-substituted analogue[5]
(34% ee, 80% yield) under low-temperature reaction condi-
tions reveals that the initial hypothesis (Scheme 2), which
concerned better substrate shielding of substrates with a
substituent at the 3-position, seems to hold. Productive
chair-type conformations “A1-chair” and “A2-chair” can be
responsible for rapid and very effective photocycloaddition
reactions (Scheme 11).
Scheme 12. The preferred conformation C-boat in the intramolecular [2+
2] photocycloaddition reactions of 4-substituted quinolones as opposed to
the disfavored conformation C-chair.
associated at least partially with their lower association ten-
dency. Indeed, the noranalogue of 1, namely, template 31,
provided a significantly improved enantioselectivity (see
above). The unusual behavior of 4-(4’-butenyloxy)-5,6-dihy-
dro-1H-pyridin-2-one, the regioisomer of substrate 6, which
gave high enantioselectivities (75% ee) previously, albeit at
an extremely slow conversion,[5] is not in line with the pre-
ferred conformation of the “D1-chair”, which would be ex-
pected to be highly productive but only moderately enantio-
selective. It is speculated that due to a dipole–dipole repul-
sion[28] the D2-chair conformation is preferred to lead to a
1,4-biradical, which is, however, not competent to form a
four-membered ring (the resulting product would be a trans-
Scheme 11. Conformations A1-chair, A2-chair, B1, and B2 that result in a
productive intramolecular [2+2] photocycloaddition reaction to the
straight and crossed products (via A and B, respectively).
From comparing Scheme 11 with Scheme 2, it is evident
that the alkyl chain in the A1-chair conformation folds away
from the tetrahydronaphthalene shield of the template,
whereas the steric interaction is more intense in the confor-
mation of the A2-chair substrate 3. In an analogous fashion,
the 3’-butenyl-substituted substrates react presumably
through related envelope-type conformations B1 and B2 with
fused oxabicycloACTHNUTRGNEUNG
[3.2.0]heptane). The productive D2-boat
conformation is less populated but delivers—if product for-
mation occurs—a relatively high enantiomeric excess be-
cause the butenyloxy chain is directed into the proximity of
the tetrahydronaphthalene backbone (Scheme 13).
ꢀ
the first C C formed between C3 or C4 and the respective
terminal carbon atom of the butenyl side chain. Indeed, the
4-substituted analogue of substrate 2 shows also a signifi-
cantly poorer performance in its enantioselective intramo-
lecular photocycloaddition reaction (37% ee)[5] than sub-
strate 2 itself (69% ee). Six-membered ring formation that
starts from substrate 4 is apparently not feasible at low tem-
perature due to a disfavored trajectory of the reacting cen-
ters.
Scheme 13. Conformations D accessible to 4-(4’-butenyloxy)-5,6-dihydro-
1H-pyridin-2-one. The unproductive conformation D2-chair is believed to
be preferred over the conformation D1-chair due to dipole minimization,
whereas the productive conformation D2-boat accounts for a high enan-
tioselectivity in a template-induced enantioselective intramolecular [2+
2] photocycloaddition reaction.
The relatively high enantioselectivities (ꢁ90% ee) ob-
served in the template-induced enantioselective [2+2] pho-
tocycloaddition reaction of many 4-substituted quinolones
appears at first sight to contradict the analysis provided for
4-substituted 5,6-dihydro-1H-pyridin-2-ones. As earlier men-
tioned, however, the situation in intramolecular quinolone
photocycloaddition reactions (e.g., for 4-(4’-pentenyl)quino-
lone) is different as 1,3-allylic strain disfavors the chair con-
formation “C-chair” but favors the conformation “C-boat”,
in which the steric interaction of the chain with the template
becomes significant (Scheme 12). In addition, higher associ-
ation constants of quinolones to template 1 are expected rel-
ative to 5,6-dihydro-1H-pyridin-2-ones due to the entirely
flat structure of the quinolone heterocycle.
Conclusion
In summary, the hypothesis that 3-substituted 5,6-dihydro-
1H-pyridin-2-ones react in a template-directed [2+2] photo-
cycloaddition reaction with higher enantioselectivity than
their respective 4-substituted analogues could be verified.
The intramolecular [2+2] photocycloaddition reactions of
3-(w’-alkenyl)- and 3-(w’-alkenyloxy)-substituted 5,6-dihy-
dro-1H-pyridin-2-ones proceeded with excellent regio- and
diastereoselectivites to the respective crossed or straight ad-
dition products. Enantioselectivities achieved in the pres-
ence of the chiral complexing agents (ꢀ)-1 and (+)-31
reached, in the best cases, 69% ee for 19 with 1; 85% ee for
Conformations similar to the A2-chair and B2 should also
be adopted preferentially by the oxygen analogues 5 and 6
of substrates 2 and 3. The lower enantioselectivity achieved
with these substrates in the presence of template 1 could be
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Chem. Eur. J. 2010, 16, 4284 – 4296

Template-Directed Enantioselective Photocycloaddition Reactions
FULL PAPER
added to the reaction mixture, which was stirred at 808C for 3 h. The
mixture was cooled to room temperature and stirring was stopped. The
remaining zinc dust was allowed to settle (ca. 1 h). The supernatant
liquid containing pentenylzinc bromide could be easily transferred in a
syringe and was submitted to a Negishi cross-coupling reaction (see
below).
21 with 31; 56% ee for 20 with 31; and 79% ee for 22 with
31. It is likely that a further improvement in the selectivities
requires stronger template–substrate binding, which in turn
requires tuning of the electronic properties of the template.
Current studies along these lines are in progress.
Compound 8 (63.0 mg, 282 mmol) was added to a solution of [Pd2ACHTUNGTRENNUNG(dba)3]
(13.0 mg, 14.2 mmol) and [RuPhos] (26.4 mg, 56.8 mmol) in dry dimethyl-
acetamide (2 mL) at room temperature. After the mixture had been
stirred for 10 min, the pre-prepared solution of pentenylzinc bromide was
added immediately. After the reaction mixture had been stirred at room
temperature for 14 h, the solvent was removed under reduced pressure.
Purification by flash chromatography (EtOAc) yielded 3 as a colorless
solid (41.0 mg, 248 mmol, 88%). Rf =0.50 (EtOAc, 100%; CAM, UV);
m.p. 36–388C; 1H NMR (360 MHz, CDCl3, 300 K): d=6.46 (brs, 1H),
6.31 (t, 3J=4.3 Hz, 1H), 5.79 (ddt, 3J=16.6, 3J=10.2, 3J=6.6 Hz, 1H),
5.01–4.90 (m, 2H), 3.37–3.32 (AA’XX’, m, 2H), 2.42–2.22 (m, 4H), 2.09–
2.02 (AA’XX’, m, 2H), 1.57–1.49 ppm (m, 2H); 13C NMR (90.6 MHz,
CDCl3, 300 K): d=167.5 (s), 138.7 (d), 135.3 (s), 135.0 (d), 114.6 (t), 39.8
(t), 33.4 (t), 29.8 (t), 27.8 (t), 24.3 ppm (t); IR (powder): n˜ =3188 (m),
3066 (m), 2931 (s), 1670 (vs), 1621 (vs), 1481 (m), 1427 (m), 1353 (m),
1289 (m), 1155 (m), 994 (m), 931 (m), 916 (m), 867 (m), 835 (m), 811
(m), 763 cmꢀ1 (m); MS (EI, 70 eV): m/z (%): 165 (47) [M+], 150 (19),
136 (49), 124 (37) [MꢀC3H5+], 111 (100) [MꢀC4H6+], 95 (26), 82 (83),
67 (22), 53 (27), 41 (28) [C3H5+]; HRMS (70 eV): m/z calcd for
C10H15NO: 165.1154 [M+]; found: 165.1156.
Experimental Section
General: All commercially available chemicals were used as received
without further purification. Reactions involving the water-sensitive
chemical n-butyllithium were performed in dried glassware under argon
using anhydrous solvents. Common solvents for chromatography (i.e.,
pentane, EtOAc, CH2Cl2, and MeOH) were distilled prior to use. Ceric
ammonium molybdate (CAM) or potassium permanganate were used to
visualize TLC spots, which could not be clearly detected by UV radia-
tion. IR spectra were recorded from powders (for solids) or films (for liq-
uids) in the attenuated total reflection (ATR) mode. 1H and 13C NMR
spectra were recorded in the indicated solvent. Chemical shifts are re-
ported relative to solvent residue signals as an internal standard. Appar-
ent multiplets, which occur as a result of the accidental equality of cou-
pling constants of magnetically nonequivalent protons are marked as vir-
tual (virt.). The multiplicities of the 13C NMR signals were determined by
jmod experiments. The 13C NMR spectra of all the new compounds are
presented in the Supporting Information.
3-(3’-Butenyl)-5,6-dihydro-1H-pyridin-2-one (2): Aqueous hydrogen per-
oxide (1.48 mL, 14.6 mmol, 30% v/v) was added to a solution of 3-(3’-bu-
tenyl)-3-(phenylselanyl)piperidin-2-one (12; 500 mg, 1.62 mmol) and pyri-
dine (325 mL, 320 mg, 4.05 mmol) in CH2Cl2 (15 mL) at room tempera-
ture, and the mixture was stirred for 2 h. Saturated aqueous NH4Cl
(30 mL) was added to the reaction mixture, which was extracted with
CH2Cl2 (3ꢄ30 mL). The organic extract was dried over MgSO4, filtered,
and concentrated. The crude product was purified by flash chromatogra-
phy (EtOAc) to give 2 as a colorless oil (174 mg, 1.15 mmol, 71%). Rf =
0.48 (EtOAc, 100%; CAM, UV); 1H NMR (360 MHz, CDCl3, 300 K):
d=6.31 (t, 3J=4.3 Hz, 1H), 6.39 (brs, 1H), 5.80 (ddt, 3J=16.8, 3J=10.2,
3J=6.6 Hz, 1H), 5.03–4.94 (m, 2H), 3.38–3.31 (AA’XX’, m, 2H), 2.38–
2.30 (m, 4H), 2.25–2.19 ppm (m, 2H); 13C NMR (90.6 MHz, CDCl3,
300 K): d=167.2 (s), 138.2 (d), 135.4 (d), 134.7 (s), 115.0 (t), 40.0 (t), 32.8
(t), 29.8 (t), 24.4 ppm (t); IR (film): n˜ =3195 (m), 2926 (m), 2874 (s),
1664 (vs), 1614 (vs), 1578 (w), 1477 (m), 1453 (m), 1436 (m), 1416 (m),
1291 (m), 1279 (m), 1070 (m), 1021 (m), 737 (s), 691 cmꢀ1 (m); MS (EI,
70 eV): m/z (%): 151 (100) [M+], 136 (92), 122 (22), 107 (21), 93 (19), 81
(31), 53 (39), 41 (26) [C3H5+]; HRMS (70 eV): m/z calcd for C9H13NO:
151.0997 [M+]; found: 151.0998.
Preparation of starting materials: tert-Butyl-5,6-dihydro-2-oxopyridine-
1(2H)-carboxylate (7),[10] 3-(3’-butenyl)piperidin-2-one (9),[14] 3-(4’-pente-
nyl)piperidin-2-one (10),[14] 3-(5’-hexenyl)piperidin-2-one (11),[14] 3-diazo-
piperidin-2-one (15),[17] and 3-amino-5,6,7,8-tetrahydronaphthalene-2-ol
(25)[24] were synthesized according to reported procedures. 5-Bromo-1-
pentene, 3-buten-1-ol, and the Kemp triacid (24) are commercially avail-
able.
3-Iodo-5,6-dihydro-1H-pyridin-2-one (8): Iodine (3.22 g, 12.7 mmol) was
added to a solution of tert-butyl-2-oxo-5,6-dihydro-2H-pyridine-1-carbox-
ylate (7;[10] 1.00 g, 5.07 mmol) in CCl4/pyridine (50 mL, 1:1) at room tem-
perature, and the mixture was stirred for 4 h. Saturated aqueous NH4Cl
(250 mL) was added to the reaction mixture, which was extracted with
EtOAc (3ꢄ100 mL). The organic extract was dried over MgSO4, filtered,
and concentrated. The crude product was purified by flash chromatogra-
phy (EtOAc) to give iodide 8 as a pale-yellow solid (758 mg, 3.40 mmol,
67%). Rf =0.48 (EtOAc, 100%; CAM, UV); m.p. 858C; 1H NMR
(360 MHz, CDCl3, 300 K): d=7.38 (t, 3J=4.7 Hz, 1H), 6.98 (brs, 1H),
3.51–3.47 (AA’XX’, m, 2H), 2.41–2.35 ppm (AA’XX’, m, 2H); 13C NMR
(90.6 MHz, CDCl3, 300 K): d=162.3 (s), 150.5 (d), 95.6 (s), 40.1 (t),
28.0 ppm (t); IR (powder): n˜ =3205 (s), 2872 (s), 1677 (vs), 1594 (s), 1472
(s), 1416 (m), 1398 (m), 1347 (s), 1329 (m), 1275 (s), 1229 (m), 1192 (w),
1009 (s), 989 (m), 902 (w), 880 (m), 848 (m), 772 (s), 700 cmꢀ1 (m); MS
(EI, 70 eV): m/z (%): 223 (100) [M+], 194 (55), 166 (14), 152 (3), 127 (3),
[I+], 96 (21) [MꢀI+], 53 (8), 39 (26); HRMS (70 eV): m/z calcd for
C5H6INO: 222.9494 [M+]; found: 222.9496.
3-(5’-Hexenyl)-5,6-dihydro-1H-pyridin-2-one (4): Aqueous hydrogen per-
oxide (1.09 mL, 10.7 mmol, 30% v/v) was added to a solution of 3-(5’-
hexenyl)-3-(phenylselanyl)piperidin-2-one (14; 400 mg, 1.19 mmol) and
pyridine (239 mL, 235 mg, 2.97 mmol) in CH2Cl2 (10 mL) at room temper-
ature, and the mixture was stirred for 2 h. Saturated aqueous NH4Cl
(20 mL) was added to the reaction mixture, which was extracted with
CH2Cl2 (3ꢄ20 mL). The organic extract was dried over MgSO4, filtered,
and concentrated. The crude product was purified by flash chromatogra-
phy (EtOAc) to give 4 as a colorless oil (147 mg, 821 mmol, 69%). Rf =
0.51 (EtOAc, 100%; CAM, UV); 1H NMR (360 MHz, CDCl3, 300 K):
d=6.33–6.32 (m, 1H), 5.96 (brs, 1H), 5.85 (ddt, 3J=16.9, 3J=10.1, 3J=
6.7 Hz, 1H), 5.01–4.90 (m, 2H), 3.40–3.36 (AA’XX’, m, 2H), 2.34–2.24
(m, 4H), 2.08–2.03 (m, 2H), 1.50–1.40 ppm (m, 4H); 13C NMR
(90.6 MHz, CDCl3, 300 K): d=167.4 (s), 139.1 (d), 135.5 (s), 134.8 (d),
114.4 (t), 40.0 (t), 33.7 (t), 30.2 (t), 28.7 (t), 28.1 (t), 24.3 ppm (t); IR
(film): n˜ = 3189 (m), 2928 (m), 2856 (s), 1672 (vs), 1624 (vs), 1479 (m),
1455 (m), 1428 (m), 1339 (m), 1291 (m), 1105 (m), 993 (m), 908 (m), 848
(m), 752 (m), 738 (m), 670 (m), 658 cmꢀ1 (m); MS (EI, 70 eV): m/z (%):
179 (48) [M+], 164 (9), 150 (32), 138 (100) [MꢀC3H5+], 111 (100)
[MꢀC5H8+], 95 (18), 82 (32), 67 (18), 53 (16), 41 (27) [C3H5+]; HRMS
(70 eV): m/z calcd for C11H17NO: 179.1310 [M+]; found: 179.1309.
3-(4’-Pentenyl)-5,6-dihydro-1H-pyridin-2-one (3): Synthesis with 3-(4’-
pentenyl)-3-(phenylselanyl)piperidin-2-one (13) as the starting material:
Aqueous hydrogen peroxide (848 mL, 8.38 mmol; 30% v/v) was added to
a
solution of 3-(4’-pentenyl)-3-(phenylselanyl)piperidin-2-one (13;
300 mg, 931 mmol) and pyridine (187 mL, 184 mg, 2.33 mmol) in CH2Cl2
(10 mL) at room temperature, and the mixture was stirred for 2 h. Satu-
rated aqueous NH4Cl (20 mL) was added to the reaction mixture, which
was extracted with CH2Cl2 (3ꢄ20 mL). The organic extract was dried
over MgSO4, filtered, and concentrated. The crude product was purified
by flash chromatography (EtOAc) to give 3 as a colorless solid (115 mg,
698 mmol, 75%).
Synthesis with 3-iodo-5,6-dihydro-1H-pyridin-2-one (8) as the starting ma-
terial: A mixture of dry dimethylacetamide (2 mL), iodine (7.00 mg,
27.5 mmol), and zinc dust (55.2 mg, 844 mmol) was stirred at room temper-
ature in a dry 10-mL Schlenk tube under argon until the yellow color of
iodine had disappeared. 5-Bromo-1-pentene (67.3 mL, 568 mmol) was
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T. Bach et al.
3-(3’-Butenyl)-3-(phenylselanyl)piperidin-2-one (12): A solution of n-bu-
tyllithium (2.5m, 2.61 mL, 6.52 mmol) in hexane was added dropwise to a
solution of 3-(3’-butenyl)piperidin-2-one (9;[14] 500 mg, 3.26 mmol) in dry
THF (30 mL) in an inert atmosphere at ꢀ788C. The resulting mixture
was stirred for 1 h and allowed to warm to 08C. After the reaction mix-
ture was cooled again to ꢀ788C, phenylselenyl bromide (2.31 g,
9.78 mmol) was added immediately, and the resulting mixture was al-
lowed to warm to 08C within 15 min. After the addition of saturated
aqueous NH4Cl (50 mL), the mixture was extracted with EtOAc (3ꢄ
50 mL). The organic extract was dried over MgSO4, filtered, and concen-
trated. The crude product was purified by flash chromatography (pen-
tane/EtOAc 1:1) to give 12 as a colorless oil (854 mg, 2.77 mmol, 85%).
Rf =0.27 (pentane/EtOAc 1:1; CAM, UV); 1H NMR (360 MHz, CDCl3,
300 K): d=7.67–7.64 (m, 2H), 7.40–7.35 (m, 1H), 7.32–7.28 (m, 2H), 5.94
(brs, 1H), 5.78–5.70 (m, 1H), 5.01–4.89 (m, 2H), 3.32–3.28 (m, 2H),
2.21–2.04 (m, 4H), 2.00–1.97 (m, 2H), 1.84–1.70 ppm (m, 2H); 13C NMR
(90.6 MHz, CDCl3, 300 K): d=173.0 (s), 138.3 (d), 138.0 (d), 129.3 (d),
128.9 (d), 127.6 (s), 115.0 (t), 52.3 (s), 42.6 (t), 38.0 (t), 32.2 (t), 29.8 (t),
20.3 ppm (t); IR (film): n˜ =3185 (m), 3073 (m), 2933 (m), 1649 (vs), 1483
(m), 1436 (m), 1415 (m), 1354 (m), 1327 (m), 1304 (m), 1276 (m), 1208
(m), 1116 (m), 1021 (m), 921 (m), 835 (m), 827 (m), 740 (m), 698 cmꢀ1
(m); MS (EI, 70 eV): m/z (%): 309 (18) [M+], 255 (38) [MꢀC4H6+], 152
(100) [MꢀC6H5Se+], 112 (18), 99 (35), 81 (17), 41 (14) [C3H5+]; HRMS
(70 eV): m/z calcd for C15H19NOSe: 309.0632 [M+]; found: 309.0645.
(m), 912 (m), 741 (m), 693 cmꢀ1 (m); MS (EI, 70 eV): m/z (%): 337 (8)
[M+], 256 (10) [MꢀC6H10+], 180 (100) [MꢀC6H5Se+], 152 (11) [C6H5Se+],
112 (23), 100 (11), 81 (22), 67 (10), 55 (13), 41 (14) [C3H5+]; HRMS
(70 eV): m/z calcd for C17H23NOSe: 337.0945 [M+]; found: 337.0944.
3-Chloro-3-(phenylselanyl)piperidin-2-one (16): Phenylselenyl chloride
(153 mg, 800 mmol) was added to a solution of 3-diazo-piperidin-2-one
(15;[17] 100 mg, 799 mmol) in dry CH2Cl2 (5 mL) at room temperature.
The reaction mixture was stirred for 15 min at room temperature and the
evolution of nitrogen was observed. The solvent was removed under re-
duced pressure, and the crude product was purified by flash chromatogra-
phy (pentane/EtOAc 1:1) to give 16 as a colorless oil (180 mg, 623 mmol,
78%). Rf =0.58 (EtOAc, 100%); UV); 1H NMR (360 MHz, CDCl3,
300 K): d=7.68–7.66 (m, 2H), 7.48–7.30 (m, 3H), 7.25 (brs, 1H), 3.48–
3.22 (m, 2H), 2.45–2.22 (m, 1H), 2.18–2.04 (m, 1H), 2.00–1.71 ppm (m,
2H); 13C NMR (90.6 MHz, CDCl3, 300 K): d=168.6 (s), 137.8 (d), 130.0
(d), 129.2 (d), 126.8 (s), 76.3 (s), 42.4 (t), 40.1 (t), 19.8 ppm (t); MS (EI,
70 eV): m/z (%): 288 (1) [M+], 255 (19) [MꢀCl+], 253 (100), 172 (32),
115 (66), 105 (53), 77 (20), 51 (13); HRMS (70 eV): m/z calcd for
C11H12ClNOSe: 288.9773 [M+]; found: 288.9759.
3-(Allyloxy)-3-(phenylselanyl)piperidin-2-one (17): Sodium hydrogencar-
bonate (293 mg, 3.49 mmol) was added to a solution of 16 (200 mg,
693 mmol) in dry allylic alcohol (2 mL) in an argon atmosphere, and the
reaction mixture was stirred for 15 h at room temperature. After the al-
lylic alcohol was removed under reduced pressure and brine (20 mL)
added, the mixture was extracted with EtOAc (3ꢄ20 mL). The organic
extract was dried over MgSO4, filtered, and concentrated. The crude
product was purified by flash chromatography (pentane/EtOAc 1:1) to
give 17 as a colorless solid (148 mg, 478 mmol, 69%). Rf =0.75 (EtOAc,
100%; CAM, UV); m.p. 88–908C; 1H NMR (360 MHz, CDCl3, 300 K):
d=7.57–7.55 (m, 2H), 7.34–7.28 (m, 3H), 6.20 (brs, 1H), 5.99 (ddt, 3J=
17.1, 3J=10.5, 3J=5.4 Hz, 1H), 5.33 (ddt, 2J=3.2, 3J=17.1, 4J=1.4 Hz,
3-(4’-Pentenyl)-3-(phenylselanyl)piperidin-2-one (13): A solution of n-bu-
tyllithium (2.5m, 2.39 mL, 5.98 mmol) in hexane was added dropwise to a
solution of 3-(4’-pentenyl)piperidin-2-one (10;[14] 500 mg, 2.99 mmol) in
dry THF (30 mL) in an inert atmosphere at ꢀ788C. The resulting mixture
was stirred for 1 h and allowed to warm to 08C. After the reaction mix-
ture was again cooled to ꢀ788C, phenylselenyl bromide (2.12 g,
8.97 mmol) was added immediately and the resulting mixture was then
allowed to warm to 08C within 15 min. After addition of saturated aque-
ous NH4Cl (50 mL), the mixture was extracted with EtOAc (3ꢄ50 mL).
The organic extract was dried over MgSO4, filtered, and concentrated.
The crude product was purified by flash chromatography (pentane/
EtOAc 1:1) to give 13 as a colorless solid (800 mg, 2.48 mmol, 83%).
Rf =0.29 (pentane/EtOAc 1:1; CAM, UV); m.p. 858C; 1H NMR
(360 MHz, CDCl3, 300 K): d=7.67–7.64 (m, 2H), 7.38–7.35 (m, 1H),
7.31–7.28 (m, 2H), 6.12 (brs, 1H), 5.78–5.69 (m, 1H), 4.98–4.90 (m, 2H),
3.28–3.27 (m, 2H), 2.15–1.88 (m, 6H), 1.78–1.65 (m, 2H), 1.60–1.30 ppm
(m, 2H); 13C NMR (90.6 MHz, CDCl3, 300 K): d=173.2 (s), 138.5 (d),
138.2 (d), 129.2 (d), 128.9 (d), 127.7 (s), 114.8 (t), 52.5 (s), 42.6 (t), 38.4
(t), 34.0 (t), 32.3 (t), 24.8 (t), 20.3 ppm (t); IR (powder): n˜ =3176 (m),
3054 (m), 2928 (m), 1650 (vs), 1485 (m), 1435 (m), 1414 (m), 1355 (m),
1328 (m), 1304 (m), 1275 (m), 1204 (m), 1120 (m), 1021 (m), 998 (m), 907
(m), 741 (m), 697 cmꢀ1 (m); MS (EI, 70 eV): m/z (%): 323 (4) [M+], 255
(10) [MꢀC5H8+], 166 (100) [MꢀC6H5Se+], 112 (21), 81 (10), 77 (6)
[C6H5+]; HRMS (70 eV): m/z calcd for C16H21NOSe: 323.0788 [M+];
found: 323.0782.
2
3
4
2
3
1H), 5.19 (ddt, J=3.2, J=10.5, J=1.4 Hz, 1H), 4.78 (ddt, J=13.0, J=
5.4, 4J=1.4 Hz, 1H), 4.25 (ddt, 2J=13.0, 3J=5.4, 4J=1.4 Hz, 1H), 3.39–
3.25 (m, 2H), 2.10 (ddd, 2J=14.9, 3J=11.4, 3J=3.5 Hz, 1H), 1.98–1.85
(m, 2H), 1.77–1.65 ppm (m, 1H); 13C NMR (90.6 MHz, CDCl3, 300 K):
d=168.7 (s), 137.2 (d), 134.5 (d), 128.9 (d), 128.5 (d), 128.0 (s), 116.7 (t),
89.4 (s), 68.1 (t), 42.6 (t), 36.6 (t), 19.7 ppm (t); IR (powder): n˜ =3185
(m), 3054 (m), 2934 (m), 1670 (vs), 1644 (vs), 1489 (m), 1476 (m), 1437
(m), 1421 (m), 1352 (m), 1327 (m), 1275 (m), 1208 (m), 1201 (m), 1157
(m), 1118 (m), 1041 (m), 984 (m), 943 (m), 918 (m), 827 (m), 741 (m),
730 (m), 689 cmꢀ1 (m); MS (EI, 70 eV): m/z (%): 311 (1) [M+], 154 (100)
[MꢀC6H5Se+],
157
(16)
[C6H5Se+],
126
(13),
114
(40)
[MꢀC6H5SeꢀC3H5+], 86 (15), 77 (11) [C6H5+], 41 (40) [C3H5+]; HRMS
(70 eV): m/z calcd for C14H17NO2Se: 311.0424 [M+]; found: 311.0412.
3-(3’-Butenyloxy)-3-(phenylselanyl)piperidin-2-one (18): Sodium hydro-
gencarbonate (293 mg, 3.49 mmol) was added to a solution of 16 (200 mg,
693 mmol) in dry but-3-en-1-ol (2 mL) in an argon atmosphere, and the
reaction mixture was stirred for 15 h at room temperature. After the al-
lylic alcohol had been removed under reduced pressure and brine
(20 mL) added, the mixture was extracted with EtOAc (3ꢄ20 mL). The
organic extract was dried over MgSO4, filtered, and concentrated. The
crude product was purified by flash chromatography (pentane/EtOAc
1:1) to give 18 as a colorless solid (144 mg, 444 mmol, 64%). Rf =0.77
(EtOAc, 100%; CAM, UV); m.p. 1058C; 1H NMR (360 MHz, CDCl3,
300 K): d=7.64–7.58 (m, 2H), 7.39–7.28 (m, 3H), 6.20 (br s, 1H), 5.85
3-(5’-Hexenyl)-3-(phenylselanyl)piperidin-2-one (14): A solution of n-bu-
tyllithium (2.5m, 2.21 mL, 5.52 mmol) in hexane was added dropwise to a
solution of 3-(5’-hexenyl)piperidin-2-one (11;[14] 500 mg, 2.76 mmol) in
dry THF (30 mL) in an inert atmosphere at ꢀ788C. The resulting mixture
was stirred for 1 h and allowed to warm to 08C. After the reaction mix-
ture was again cooled to ꢀ788C, phenylselenyl bromide (1.95 g,
8.27 mmol) was added immediately, and the resulting mixture was then
allowed to warm to 08C within 15 min. After the addition of saturated
aqueous NH4Cl (50 mL), the mixture was extracted with EtOAc (3ꢄ
50 mL). The organic extract was dried over MgSO4, filtered, and concen-
trated. The crude product was purified by flash chromatography (pen-
tane/EtOAc 1:1) to give 14 as a colorless oil (752 mg, 2.24 mmol, 81%).
Rf =0.31 (pentane/EtOAc 1:1; CAM, UV); 1H NMR (360 MHz, CDCl3,
300 K): d=7.67–7.63 (m, 2H), 7.37–7.26 (m, 3H), 6.20 (brs, 1H), 5.81–
5.70 (m, 1H), 4.99–4.90 (m, 2H), 3.29–3.25 (m, 2H), 2.15–1.90 (m, 6H),
1.78–1.64 (m, 2H), 1.45–1.25 ppm (m, 4H); 13C NMR (90.6 MHz, CDCl3,
300 K): d=173.6 (s), 139.1 (d), 138.5 (d), 129.5 (d), 129.1 (d), 128.0 (s),
114.8 (t), 52.9 (s), 42.9 (t), 39.0 (t), 34.0 (t), 32.5 (t), 29.5 (t), 25.1 (t),
20.6 ppm (t); IR (film): n˜ =3168 (m), 3058 (m), 2932 (m), 2859 (m), 1656
(vs), 1484 (m), 1475 (m), 1436 (m), 1351 (m), 1319 (m), 1018 (m), 989
3
3
3
2
(ddt, J=17.0, J=10.2, J=6.7 Hz, 1H), 5.15–5.03 (m, 2H), 4.18 (dt, J=
9.5, 3J=6.7 Hz, 1H), 3.72 (dt, 2J=9.5, 3J=6.7 Hz, 1H), 3.39–3.21 (m,
2H), 2.41–2.38 (m, 2H), 2.08 (ddd, 2J=3.6, 3J=14.3, 3J=11.6 Hz, 1H),
1.98–1.88 (m, 2H), 1.75–1.63 ppm (m, 1H); 13C NMR (90.6 MHz, CDCl3,
300 K): d=168.8 (s), 137.1 (d), 135.5 (d), 128.8 (d), 128.4 (d), 128.2 (s),
116.6 (t), 89.6 (s), 66.2 (t), 42.6 (t), 36.6 (t), 34.2 (t), 19.6 ppm (t); IR
(powder): n˜ = 3187 (m), 3049 (m), 2938 (m), 1671 (vs), 1644 (vs), 1487
(m), 1477 (m), 1436 (m), 1325 (m), 1271 (m), 1202 (m), 1150 (m), 1123
(m), 1071 (m), 1001 (m), 954 (m), 911 (m), 827 (m), 741 (m), 692 cmꢀ1
(m); MS (EI, 70 eV): m/z (%): 325 (1) [M+], 168 (49) [MꢀC6H5Se)+],
157 (13) [C6H5Se+], 114 (100) [MꢀC6H5SeꢀC4H7+], 86 (10), 77 (9)
[C6H5+], 55 (22) [C4H7+]; HRMS (70 eV): m/z calcd for C15H19NO2Se:
325.0581 [M+]; found: 325.0581.
4292
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 4284 – 4296

Template-Directed Enantioselective Photocycloaddition Reactions
FULL PAPER
3-(Allyloxy)-5,6-dihydro-1H-pyridin-2-one (5): Aqueous hydrogen perox-
ide (519 mL, 5.08 mmol, 30% v/v) was added to a solution of 3-(allyloxy)-
3-(phenylselanyl)piperidin-2-one (17) (150 mg, 483 mmol) and pyridine
(97.1 mL, 95.5 mg, 1.21 mmol) in CH2Cl2 (5 mL) at room temperature and
the mixture was stirred for 2 h. Saturated aqueous NH4Cl (10 mL) was
added to the reaction mixture, which was extracted with CH2Cl2 (3ꢄ
10 mL). The organic extract was dried over MgSO4, filtered, and concen-
trated. The crude product was purified by flash chromatography
(EtOAc) to give 5 (58.4 mg, 382 mmol, 79%) as a colorless oil. Rf =0.25
Column chromatography (EtOAc) yielded the desired product as a color-
less solid (8.54 mg, 55.8 mmol, 61%, 40% ee), and the complexing agent
was recovered after the reaction (88%). Rf =0.41 (EtOAc, 100%,
CAM); [a]2D0 = ꢀ15.5 (c=0.19 in CHCl3); 1H NMR (360 MHz, CDCl3,
300 K): d=5.96 (brs, 1H), 4.00 (d, 2J=6.0 Hz, 1H), 3.87 (d, 2J=6.0 Hz,
1H), 3.39–3.35 (m, 2H), 2.90 (brd, 3J=3.0 Hz, 1H), 2.58 (dd, 2J=8.2,
3J=3.0 Hz, 1H), 2.31–2.19 (m, 1H), 2.15–2.06 (m, 2H), 2.00 ppm (dd,
2J=8.2, 4J=7.4 Hz, 1H); 13C NMR (90.6 MHz, CDCl3, 300 K): d=169.0
(s), 82.1 (s), 71.3 (t), 48.8 (d), 43.0 (t), 42.9 (t), 41.1 (d), 24.1 ppm (t); IR
(powder): n˜ =2904 (m), 1667 (vs), 1494 (m), 1464 (m), 1426 (m), 1342
(m), 1246 (m), 1227 (m), 1187 (m), 1123 (m), 1064 (m), 1034 (m), 993
(m), 930 (m), 891 (m), 882 (m), 853 (m), 831 cmꢀ1 (m); MS (EI, 70 eV):
m/z (%): 153 (6) [M+], 136 (8), 125 (30), 108 (51), 99 (38), 82 (33), 69
(20), 55 (28), 41 (74); HRMS (70 eV): m/z calcd for C8H11NO2: 153.0790
[M+]; found: 153.0790.
1
(EtOAc, 100%; CAM, UV); H NMR (360 MHz, CDCl3, 300 K): d=6.51
(brs, 1H), 6.06–5.95 (m, 1H), 5.45 (t, 3J=4.6 Hz, 1H), 5.33 (dtd, 2J=1.4,
3J=17.3, 4J=2.9 Hz, 1H), 5.24 (dtd, 2J=1.4, 3J=10.5, 4J=2.9 Hz, 1H),
4.35–4.33 (m, 2H), 3.38–3.33 (AA’XX’, m, 2H), 2.41–2.36 ppm (AA’XX’,
m, 2H); 13C NMR (90.6 MHz, CDCl3, 300 K): d=163.8 (s), 146.6 (s),
132.9 (d), 118.2 (t), 107.2 (d), 69.0 (t), 39.9 (t), 22.9 ppm (t); IR (film):
n˜ =3235 (m), 2885 (m), 2857 (m), 1677 (vs), 1622 (vs), 1480 (m), 1455
(m), 1428 (m), 1338 (m), 1229 (vs), 1188 (m), 1111 (m), 1031 (m), 996
(m), 926 (m), 814 (m), 782 (m), 762 (m), 757 (m), 750 cmꢀ1 (m); MS (EI,
70 eV): m/z (%): 153 (9) [M+], 124 (31), 108 (37), 97 (27), 68 (41), 55
(37), 41 (100) [C3H5+]; HRMS (70 eV): m/z calcd for C8H11NO2:
153.0790 [M+]; found: 153.0789.
Decahydro-8-oxacyclopentaACTHNUTRGENN[GU 1,4]cyclobutaACHTUNTGREN[NUGN 1,2-c]pyridin-1-one (22): Race-
mic [2+2] photocycloaddition: 3-(3’-Butenyloxy)-5,6-dihydro-1H-pyri-
din-2-one (6; 28.0 mg, 167 mmol) in CH2Cl2 (33 mL) was irradiated for
30 min. Column chromatography (EtOAc) yielded the desired product as
a colorless oil (15.4 mg, 91.9 mmol, 55%).
Enantioselective [2+2] photocycloaddition: Chiral complexing agent (ꢀ)-
1 (82.2 mg, 233 mmol, 2.5 equiv) was added to 6 (15.0 mg, 89.7 mmol) in
toluene (17.9 mL), and the reaction mixture was irradiated for 4.0 h.
Column chromatography (EtOAc) yielded the desired product as a color-
less oil (7.95 mg, 47.5 mmol, 53%, 60% ee), and the complexing agent
was recovered after the reaction (91%). Rf =0.43 (EtOAc, 100%;
CAM); [a]2D0 = ꢀ19.5 (c=0.19, in CHCl3); 1H NMR (360 MHz, CDCl3,
300 K): d=6.38 (brs, 1H), 4.47–4.40 (m, 1H), 4.23–4.11 (m, 1H), 3.59–
3.51 (m, 1H), 3.44–3.32 (m, 1H), 3.05–2.95 (m, 1H), 2.73–2.60 (m, 1H),
2.07–2.00 (m, 1H), 1.98–1.86 (m, 2H), 1.83–1.66 (m, 2H), 1.65–1.58 ppm
(m, 1H); 13C NMR (90.6 MHz, CDCl3, 300 K): d=172.6 (s), 82.4 (s), 69.2
(t), 42.6 (d), 38.6 (t), 37.2 (d), 32.4 (t), 26.9 (t), 24.6 ppm (t); MS (EI,
70 eV): m/z (%): 167 (8) [M+], 151 (59), 136 (54), 126 (67), 97 (100), 55
(43), 41 (32); HRMS (70 eV): m/z calcd for C9H13NO2: 167.0946 [M+];
found: 167.0946.
3-(3’-Butenyloxy)-5,6-dihydro-1H-pyridin-2-one (6): Aqueous hydrogen
peroxide (397 mL, 3.89 mmol, 30% v/v) was added to a solution of 18
(120 mg, 370 mmol) and pyridine (74.7 mL, 73.2 mg, 925 mmol) in CH2Cl2
(5 mL) at room temperature, and the mixture was stirred for 2 h. Saturat-
ed aqueous NH4Cl (10 mL) was added to the reaction mixture, which
was extracted with CH2Cl2 (3ꢄ10 mL). The organic extract was dried
over MgSO4, filtered, and concentrated. The crude product was purified
by flash chromatography (EtOAc) to give 6 as a colorless solid (46.4 mg,
278 mmol, 75%). Rf =0.27 (EtOAc, 100%; CAM, UV); m.p. 328C;
1H NMR (360 MHz, CDCl3, 300 K): d=6.18 (brs, 1H), 5.96–5.78 (m,
1H), 5.45 (t, 3J=4.7 Hz, 1H), 5.17–5.05 (m, 2H), 3.79–3.75 (AA’XX’, m,
2H), 3.39–3.34 (AA’XX’, m, 2H), 2.58–2.52 (AA’XX’, m, 2H), 2.42–
2.36 ppm (AA’XX’, m, 2H); 13C NMR (90.6 MHz, CDCl3, 300 K): d=
163.6 (s), 147.0 (s), 134.2 (d), 117.2 (t), 106.6 (d), 67.3 (t), 40.0 (t), 33.2
(t), 23.0 ppm (t); IR (powder): n˜ =3343 (m), 2909 (m), 2866 (m), 1687
(vs), 1624 (vs), 1481 (m), 1450 (m), 1428 (m), 1341 (m), 1226 (vs), 1189
(m), 1110 (m), 1065 (m), 1031 (m), 987 (m), 918 (m), 821 (m), 781 (m),
752 (m), 673 cmꢀ1 (m); MS (EI, 70 eV): m/z (%): 167 (3) [M+], 126 (85),
113 (100) [MꢀC4H7+], 98 (12), 84 (50), 69 (18), 55 (82) [C4H7+], 39 (24);
HRMS (70 eV): m/z calcd for C9H13NO2: 167.0946 [M+]; found:
167.0948.
3-Azatricyclo-[5.2.1.01,6]-decan-2-one (19): Racemic [2+2] photocy-
cloaddition: 3-(3’-Butenyl)-5,6-dihydro-1H-pyridin-2-one (2; 32.0 mg,
212 mmol) in CH2Cl2 (42 mL) was irradiated for 1 h. Column chromatog-
raphy (EtOAc) yielded the desired product as a colorless solid (26.6 mg,
176 mmol, 83%). M.p. 1038C.
Enantioselective [2+2] photocycloaddition: Chiral complexing agent (ꢀ)-
1 (84.9 mg, 241 mmol, 2.5 equiv) was added to 2 (14.0 mg, 92.5 mmol) in
toluene (18.5 mL), and the reaction mixture was irradiated for 7.0 h.
Column chromatography (EtOAc) yielded the desired product as a color-
less solid (11.6 mg, 76.8 mmol, 83%, 69% ee), and the complexing agent
was recovered after the reaction (76%). Rf =0.49 (EtOAc, 100%;
CAM); [a]2D0 = ꢀ23.6 (c=0.12 in CHCl3); 1H NMR (360 MHz, CDCl3,
Irradiation experiments
General procedure for the racemic [2+2] photocycloaddition reactions:
In a quartz vessel, a solution of the respective 5,6-dihydro-1H-pyridin-2-
one derivative in anhydrous, degassed (argon purge under ultrasound for
20 min) CH2Cl2 was irradiated at room temperature and l=254 nm until
GC and TLC analysis indicated complete conversion (light source: Rayo-
net RPR-2537 ꢃ). The solvent was evaporated under reduced pressure,
and the remaining residue was purified by column chromatography to
give the desired compound.
3
300 K): d=6.00 (brs, 1H), 3.45–3.30 (m, 1H), 3.24 (virt. td, 2Jffi J=12.2,
3J=3.6 Hz, 1H), 2.45–2.40 (m, 1H), 2.35–2.25 (m, 1H), 2.15–2.01 (m,
2H), 1.97–1.80 (m, 2H), 1.78–1.65 (m, 3H), 1.51 ppm (dd, 2J=7.3, 4J=
6.6 Hz, 1H); 13C NMR (90.6 MHz, CDCl3, 300 K): d=174.5 (s), 49.0 (s),
48.3 (d), 43.1 (t), 42.8 (t), 39.9 (d), 28.4 (t), 27.4 (t), 22.6 ppm (t); IR
(powder): n˜ =2930 (m), 1644 (vs), 1485 (m), 1452 (m), 1438 (m), 1413
(m), 1362 (m), 1340 (m), 1310 (m), 1300 (m), 1267 (m), 1250 (m), 1226
(m), 1188 (m), 1151 (m), 1121 (m), 1065 (m), 1045 (m), 1020 (m), 848
(m), 831 (m), 820 (w), 806 (m), 668 cmꢀ1 (w); MS (EI, 70 eV): m/z (%):
151 (100), [M+], 136 (68), 122 (29), 107 (19), 93 (25), 85 (31), 79 (32), 67
(13), 53 (14), 39 (14); HRMS (70 eV): m/z calcd for C9H13NO: 151.0997
[M+]; found: 151.0997.
General procedure for the enantioselective [2+2] photocycloaddition re-
actions: In a quartz vessel, a solution of the respective 5,6-dihydro-1H-
pyridin-2-one derivative (c=5 mm) in anhydrous, degassed (argon purge
under ultrasound for 20 min) toluene with the addition of the chiral com-
plexing agent was irradiated at ꢀ758C and l=254 nm until GC analysis
indicated complete conversion (light source: Rayonet RPR-2537 ꢃ). The
solvent was evaporated under reduced pressure, and the remaining resi-
due was purified by column chromatography to give the desired com-
pound.
Decahydro-cyclopentaACTHUNTGRENNUG[1,4]cyclobutaACHTUNGTRENN[UGN 1,2-c]pyridine-1-one (21): Racemic
9-Oxa-3-azatricyclo[5.2.1.01,6]decan-2-one (20): Racemic [2+2] photocy-
cloaddition: 3-(Allyloxy)-5,6-dihydro-1H-pyridin-2-one (5; 27.0 mg,
176 mmol) in CH2Cl2 (35 mL) was irradiated for 30 min. Column chroma-
[2+2] photocycloaddition: 3-(4’-Pentenyl)-5,6-dihydro-1H-pyridin-2-one
(3; 32.0 mg, 194 mmol) in CH2Cl2 (39 mL) was irradiated for 30 min.
Column chromatography (EtOAc) yielded the desired product as a color-
less solid (26.0 mg, 157 mmol, 81%). M.p. 1158C.
tography (EtOAc) yielded the desired product as
a colorless solid
(17.0 mg, 111 mmol, 63%). M.p. 1338C.
Enantioselective [2+2] photocycloaddition: Chiral complexing agent (ꢀ)-
1 (83.2 mg, 236 mmol, 2.5 equiv) was added to 3 (15.0 mg, 90.7 mmol) in
toluene (18.1 mL), and the reaction mixture was irradiated for 4.0 h.
Column chromatography (EtOAc) yielded the desired product as a color-
Enantioselective [2+2] photocycloaddition: Chiral complexing agent (ꢀ)-
1 (83.8 mg, 238 mmol, 2.5 equiv) was added to 5 (14.0 mg, 91.4 mmol) in
toluene (18.3 mL), and the reaction mixture was irradiated for 5.5 h.
Chem. Eur. J. 2010, 16, 4284 – 4296
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4293

T. Bach et al.
less solid (12.0 mg, 72.6 mmol, 80%, 84% ee), and the complexing agent
were recovered after the reaction (90%). Rf =0.51 (EtOAc, 100%;
CAM); [a]2D0 = ꢀ23.6 (c=0.14 in MeOH); 1H NMR (250 MHz, CDCl3,
300 K): d=6.42 (brs, 1H), 3.60–3.48 (m, 1H), 3.33–3.22 (m, 1H), 2.79–
2.70 (m, 1H), 2.29–2.15 (m, 2H), 2.04–1.98 (m, 2H), 1.97–1.82 (m, 2H),
1.73–1.52 ppm (m, 5H); 13C NMR (90.6 MHz, CDCl3, 300 K): d=177.4
(s), 50.8 (s), 43.0 (d), 39.3 (t), 35.6 (t), 34.8 (d), 33.4 (t), 28.7 (t), 27.2 (t),
25.5 ppm (t); IR (powder): n˜ =2930 (m), 1644 (vs), 1485 (m), 1452 (m),
1438 (m), 1413 (m), 1362 (m), 1340 (m), 1310 (m), 1300 (m), 1267 (m),
1250 (m), 1226 (m), 1188 (m), 1151 (m), 1121 (m), 1065 (m), 1045 (m),
1020 (m), 848 (m), 831 (m), 820 (w), 806 (m), 668 cmꢀ1 (w); MS (EI,
70 eV): m/z (%): 165 (54) [M+], 150 (18), 137 (100), 124 (81), 111 (49),
95 (60), 82 (28), 67 (25), 53 (10), 41 (17); HRMS (70 eV): m/z calcd for
C10H15NO: 165.1154 [M+]; found: 165.1152.
(38), 44 (74), 43 (48) [C2H3O+]; HRMS (70 eV): m/z calcd for
C24H29NO6: 427.1995 [M+]; found: 427.1989.
6-(7-(Azidoformyl)-1,5,7-trimethyl-2,4-dioxo-3-azabicycloACTHNUTRGENUGN[3.3.1]nonan-3-
yl)-1,2,3,4-tetrahydronaphthene-7-yl-acetate (27): DMF (20 drops) was
added to acid 26 (3.04 g, 7.11 mmol, 1.00 equiv) in CH2Cl2 (120 mL), and
the resulting solution was cooled to 08C. Oxalyl chloride (1.81 mL,
2.71 g, 21.3 mmol, 3.00 equiv) was added to the reaction mixture, which
was stirred for additional 2 h at 08C. All the volatile compounds were re-
moved under reduced pressure at 08C, and the residue was dried under
reduced pressure. The crude acid chloride was dissolved in dry acetone
(80 mL) and cooled to 08C. Sodium azide (2.31 g, 35.5 mmol, 5.00 equiv)
was carefully added to the reaction mixture, which was slowly warmed to
ambient temperature and stirred for 16 h. The solids were removed by fil-
tration and washed with acetone (3ꢄ100 mL). The combined organic
layers were concentrated at 08C. Column chromatography (pentant/Et2O
6:4!Et2O 100%) yielded the desired product as a colorless solid (2.89 g,
6.40 mmol, 90%). Rf =0.40 (Et2O; UV, KMnO4); m.p. 2328C; 1H NMR
(360 MHz, CDCl3): d=6.91 (s, 1H), 6.88 (s, 1H), 2.79–2.76 (m, 6H), 2.15
(s, 3H), 1.97 (td, 2J=13.2 Hz, 4J=1.9 Hz, 1H), 1.80–1.75 (m, 4H), 1.47
DecahydrobenzoACHTUNGTRENNUNG[1,4]cyclobutaACHUTNGTREN[NUNG 1,2-c]pyridine-1-one (23): Racemic [2+2]
photocycloaddition: 3-(5’-Hexenyl)-5,6-dihydro-1H-pyridin-2-one (4;
36.0 mg, 201 mmol) in CH2Cl2 (40 mL) was irradiated for 2 h. Column
chromatography (EtOAc) yielded the desired product as a colorless oil
(23.0 mg, 128 mmol, 64%). Rf =0.53 (EtOAc, 100%; CAM); 1H NMR
(500 MHz, CDCl3, 300 K): d=5.76 (brs, 1H), 3.45–3.32 (m, 1H), 3.27–
3.21 (m, 1H), 2.62–2.55 (m, 1H), 2.35–2.30 (m, 1H), 2.05–1.92 (m, 2H),
1.90–1.82 (m, 1H), 1.78–1.65 (m, 4H), 1.55–1.45 (m, 4H), 1.43–1.35 ppm
(m, 1H); 13C NMR (90.6 MHz, CDCl3, 300 K): d=178.8 (s), 42.6 (s), 40.3
(t), 36.5 (d), 35.4 (d), 31.4 (t), 27.2 (t), 26.6 (t), 26.4 (t), 21.9 (t), 21.3 ppm
(t); IR (film): n˜ ~=2930 (m), 1644 (vs), 1485 (m), 1452 (m), 1438 (m),
1413 (m), 1362 (m), 1340 (m), 1310 (m), 1300 (m), 1267 (m), 1250 (m),
1226 (m), 1188 (m), 1151 (m), 1121 (m), 1065 (m), 1045 (m), 1020 (m),
848 (m), 831 (m), 820 (w), 806 (m), 668 cmꢀ1 (w); MS (EI, 70 eV): m/z
(%): 179 (100) [M+], 164 (27), 150 (34), 138 (44), 124 (51), 111 (43), 67
(21), 41 (31); HRMS (70 eV): m/z calcd for C11H17NO: 179.1310 [M+];
found: 179.1313.
2
2
(d, J=13.2 Hz, 1H), 1.32 (s, 6H), 1.27 (s, 3H), 1.27 ppm (d, J=12.7 Hz,
2H); 13C NMR (90.6 MHz, CDCl3): d=183.9 (s), 175.0 (s), 167.7 (s),
143.1 (s), 138.6 (s), 135.2 (s), 129.0 (d), 124.5 (s), 122.9 (d), 44.1 (t), 44.1
(s), 43.7 (t), 40.7 (s), 30.7 (q), 29.3 (t), 28.8 (t), 26.0 (q), 22.8 (t), 22.7 (t),
20.8 ppm (q); IR (powder): n˜ =2932 (m), 2134 (m), 1770 (m), 1701 (vs),
1506 (w), 1461 (m), 1429 (w), 1360 (m), 1325 (m), 1173 (vs), 1138 (m),
1080 (m), 1029 (m), 956 (w), 914 (w), 852 (w), 733 cmꢀ1 (m); MS (EI,
70 eV): m/z (%): 424 (14) [MꢀN2+], 382 (100), 339 (13), 296 (9), 269 (5),
253 (8), 214 (5), 191 (20), 163 (12), 121 (96), 91 (8), 55 (8) [C3H3O+];
HRMS (70 eV): m/z calcd for C24H28N2O5: 424.1998 [MꢀN2+]; found:
424.1995.
6-(7-Benzyloxycarbonylamino-1,5,7-trimethyl-2,4-dioxo-3-azabicyclo-
AHCTUNGTERG[NNUN 3.3.1]nonan-3-yl)-1,2,3,4-tetrahydronaphthene-7-yl-acetate (28): Azide
3-(6-Acetoxy-1,2,3,4-tetrahydronaphthene-7-yl)-1,5,7-trimethyl-2,4-dioxo-
27 (2.84 g, 6.27 mmol, 1.00 equiv) and benzylic alcohol (13.0 mL, 13.6 g,
125 mmol, 20.0 equiv) were heated to reflux in toluene (150 mL) for
7 days. All the volatile compounds were removed under reduced pressure
and column chromatography (pentane/Et2O 1:1!Et2O 100%) yielded
the desired product as a colorless solid (3.00 g, 5.64 mmol, 90%). Rf =
0.45 (Et2O; UV, KMnO4); m.p. 2068C; 1H NMR (360 MHz, CDCl3): d=
7.26 (brs, 5H), 6.92 (s, 1H), 6.85 (s, 1H), 5.06 (s, 2H), 4.47 (brs, 1H),
2.71–2.66 (m, 6H), 2.20 (s, 3H), 2.01 (td, J=13.2, J=2.3 Hz, 1H), 1.70–
1.67 (m, 2H), 1.58–1.56 (m, 2H), 1.51 (d, 2J=13.2 Hz, 1H), 1.41 (s, 3H),
1.39 (d, 2J=15.9 Hz, 2H), 1.31 ppm (s, 6H); 13C NMR (90.6 MHz,
CDCl3): d=176.5 (s), 168.0 (s), 154.5 (s), 143.2 (s), 138.5 (s), 136.2 (s),
135.2 (s), 130.5 (d), 128.4 (d), 127.9 (d), 127.8 (d), 124.4 (s), 122.4 (d),
66.4 (t), 53.0 (s), 46.2 (t), 44.1 (t), 40.2 (s), 29.2 (t), 28.3 (t), 26.2 (q), 26.2
(q), 22.7 (t), 22.6 (t), 20.8 ppm (q); IR (powder): n˜ =3340 (s), 2938 (m),
2926 (m), 1764 (m), 1736 (m), 1711 (s), 1682 (vs), 1517 (s), 1455 (m),
1380 (w), 1364 (m), 1267 (m), 1189 (vs), 1070 (m), 1050 (m), 965 (w), 921
(w), 897 (w), 848 (w), 747 (w), 698 cmꢀ1 (w); MS (EI, 70 eV): m/z (%):
532 (4) [M+], 490 (10) [MꢀC2H2O+], 424 (10), 382 (100) [MꢀC8H8NO2+],
339 (10), 253 (12), 191 (16), 162 (28), 121 (48) [C8H9O+], 91 (38), 43 (12)
[C2H3O+]; HRMS (70 eV): m/z calcd for C31H36N2O6: 532.2573 [M+];
found: 532.2559.
3-azabicycloACHTUNGTRENNUNG[3.3.1]nonan-7-carboxylic acid (26): The Kemp triacid (24;
2.10 g, 8.12 mmol, 1.00 equiv) was heated to reflux in thionyl chloride
(20 mL) for 24 h. The solvent was removed by distillation. The residue
was washed with toluene (2ꢄ10 mL) and dried under reduced pressure.
The crude acid chloride was dissolved in pyridine (20 mL) and 3-amino-
5,6,7,8-tetrahydronaphthalene-2-ol (25;[24] 1.86 g, 11.4 mmol, 1.40 equiv)
in pyridine (40 mL) was added dropwise. The resulting solution was
heated to reflux for 18 h and cooled to ambient temperature. The volatile
compounds were removed under reduced pressure, and the residue was
dissolved in EtOAc (200 mL). The organic layer was washed with HCl
(1m, 40 mL), and the aqueous layer was extracted with EtOAc (2ꢄ
20 mL). The combined organic layers were washed with brine (50 mL),
dried over MgSO4, filtered, and evaporated. N,N-Dimethylaminopyridine
(137 mg, 1.12 mmol, 0.14 equiv) was added to the resulting residue dis-
solved in CH2Cl2 (120 mL), and the solution was cooled to 08C. NEt3
(4.70 mL, 3.43 g, 33.9 mmol, 4.17 equiv) and acetic anhydride (3.20 mL,
3.46 g, 33.9 mmol, 4.17 equiv) were added dropwise to the reaction mix-
ture, which was warmed to ambient temperature and stirred for an addi-
tional 16 h. The solution was diluted with CH2Cl2 (100 mL), washed with
HCl (1m, 40 mL), and the aqueous layer extracted with CH2Cl2 (3ꢄ
50 mL). The combined organic layers were dried over MgSO4, filtered,
and evaporated. Column chromatography (CH2Cl2/MeOH/AcOH,
100:1:1!100:4:1) yielded the desired product as a colorless solid (3.14 g,
7.31 mmol, 90%). Rf =0.32 (CH2Cl2/MeOH/AcOH 95:5:1; UV, KMnO4);
m.p. 3088C; 1H NMR (360 MHz, [D6]DMSO): d=12.52 (brs, 1H), 7.01
(s, 1H), 6.88 (s, 1H), 2.71 (brs, 4H), 2.50 (d, 2J=13.8 Hz, 2H), 2.11 (s,
3H), 1.83 (d, 2J=13.1 Hz, 1H), 1.77–1.73 (m, 4H), 1.62 (d, 2J=13.1 Hz,
1H), 1.32 (d, 2J=13.8 Hz, 2H), 1.17 (s, 3H), 1.16 ppm (s, 6H); 13C NMR
(90.6 MHz, [D6]DMSO): d=177.1 (s), 175.1 (s), 167.3 (s), 143.1 (s), 137.0
(s), 133.8 (s), 129.6 (d), 125.3 (s), 122.2 (d), 42.8 (t), 42.8 (t), 41.0 (s), 40.0
(s), 30.3 (q), 28.5 (t), 28.2 (t), 25.6 (q), 22.4 (t), 22.2 (t), 20.3 ppm (q); IR
(powder): n˜ =3176 (m), 2959 (m), 2933 (m), 1772 (s), 1731(s), 1707 (s),
1672 (s), 1503 (w), 1450 (m), 1429 (w), 1362 (m), 1190 (vs), 1153 (vs),
1086 (w), 1080 (m), 956 (w), 903 (w), 858 (w), 757 (w), 738 cmꢀ1 (w); MS
(EI, 70 eV): m/z (%): 427 (15) [M+], 385 (48) [MꢀC2H3O+], 367 (96),
323 (100), 296 (10), 267 (54), 214 (40), 187 (22), 163 (48), 121 (80), 107
2
4
7-Amino-1,5,7-trimethyl-2,4-dioxo-3-azabicycloACTHNUTRGENUG[N 3.3.1]nonan-3-yl-1,2,3,4-
tetrahydronaphthene-7-yl-acetate (29): Carbamate 28 (2.94 g, 5.51 mmol,
1 equiv) and 10% Pd/C (530 mg, 0.50 mmol, 0.09 equiv) were suspended
in a mixture of EtOAc (150 mL) and iPrOH (15 mL) and stirred for 16 h
under an atmosphere of H2 at ambient temperature. The reaction mixture
was filtered through a pad of Celite, and the residue was washed with a
mixture of EtOAc (500 mL) and MeOH (10 mL). Evaporation of all sol-
vents yielded the desired compound as
a colorless solid (2.19 g,
5.51 mmol, quant.). Rf =0.43 (Et2O; UV, KMnO4); m.p. 1638C; 1H NMR
(360 MHz, CDCl3): d=7.04 (s, 1H), 6.86 (s, 1H), 2.75–2.71 (m, 4H), 2.20
(s, 3H), 1.99 (td, 2J=13.0, 4J=2.0 Hz, 1H), 1.87 (d, 2J=14.2 Hz, 2H),
1.78–1.74 (m, 4H), 1.45 (d, 2J=13.0 Hz, 1H), 1.39 (d, 2J=14.2 Hz, 2H),
1.28 (s, 6H), 1.17 (s, 3H), 0.92 ppm (brs, 2H); 13C NMR (90.6 MHz,
CDCl3): d=177.6 (s), 168.1 (s), 143.7 (s), 138.1 (s), 134.9 (s), 129.8 (d),
125.5 (s), 122.3 (d), 49.9 (s), 49.1 (t), 44.3 (t), 40.2 (s), 36.5 (q), 29.3 (t),
4294
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 4284 – 4296

Template-Directed Enantioselective Photocycloaddition Reactions
FULL PAPER
28.9 (t), 26.4 (q), 22.8 (t), 22.7 (t), 20.7 ppm (q); IR (powder): n˜ =3345
(s), 2921 (s), 1764 (s), 1735 (w), 1682 (vs), 1506 (m), 1459 (w), 1364 (m),
1314 (w), 1186 (vs), 1086 (w), 1050 (m), 921 (w), 902 cmꢀ1; MS (EI,
70 eV): m/z (%): 398 (6) [M+], 356 (38) [MꢀC2H2O+], 163 (100), 149
(10), 121 (8) [C8H9O+], 110 (14), 57 (22), 43 (12) [C2H3O+]; HRMS
(70 eV): m/z calcd for C23H30N2O4: 398.2206 [M+]; found: 398.2202.
Acknowledgements
Our research was supported by the Deutsche Forschungsgemeinschaft
(Schwerpunktprogramm 1179 Organokatalyse) and the Fonds der Chemi-
schen Industrie (PhD scholarships to D.A. and F.V.).
N-(3-Hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,5-trimethyl-7-oxo-6-
azabicycloACHTUNGTRENNUNG[3.2.1]octane-3-carboxamide (30): K2CO3 (2.61 g, 18.9 mmol,
[1] Reviews: a) T. Bach in Asymmetric Synthesis—The Essentials (Eds.:
S. Brꢁse, M. Christmann), Wiley-VCH, Weinheim, 2006, pp. 166–
170; b) S. Breitenlechner, P. Selig, T. Bach in Ernst Schering Founda-
tion Symposium Proceedings “Organocatalysis” (Eds.: M. T. Reetz,
B. List, S. Jaroch, H. Weinmann), Springer, Berlin, 2008, pp. 255–
280; c) C. Mꢀller, T. Bach, Aust. J. Chem. 2008, 61, 557–564.
[2] a) T. Bach, H. Bergmann, K. Harms, Angew. Chem. 2000, 112,
2391–2393; Angew. Chem. Int. Ed. 2000, 39, 2302–2304; b) T. Bach,
H. Bergmann, J. Am. Chem. Soc. 2000, 122, 11525–11526; c) T.
Bach, H. Bergmann, B. Grosch, K. Harms, J. Am. Chem. Soc. 2002,
124, 7982–7990; d) S. Brandes, P. Selig, T. Bach, Synlett 2004, 2588–
2590; e) P. Selig, T. Bach, J. Org. Chem. 2006, 71, 5662–5673.
[3] a) P. Selig, T. Bach, Angew. Chem. 2008, 120, 5160–5162; Angew.
Chem. Int. Ed. 2008, 47, 5082–5084; b) P. Selig, E. Herdtweck, T.
Bach, Chem. Eur. J. 2009, 15, 3509–3525.
[4] a) H. Bergmann, B. Grosch, S. Sitterberg, T. Bach, J. Org. Chem.
2004, 69, 970–973; b) A. Bauer, T. Bach, Tetrahedron: Asymmetry
2004, 15, 3799–3803.
[5] D. Albrecht, B. Basler, T. Bach, J. Org. Chem. 2008, 73, 2345–2356.
[6] J. P. Hehn, C. Mꢀller, T. Bach in Handbook of Synthetic Photochem-
istry (Eds.: A. Albini, M. Fagnoni), Wiley-VCH, Weinheim, 2009,
pp. 171–215.
3.5 equiv) was added to amine 29 (2.15 g, 5.40 mmol, 1 equiv) dissolved
in MeOH (250 mL), and the reaction mixture was stirred for 6 h at ambi-
ent temperature. All the volatile compounds were removed under re-
duced pressure, the residue was dissolved in water (100 mL), and the
aqueous layer was extracted with EtOAc (3ꢄ300 mL). The combined or-
ganic layers were washed with brine (100 mL), dried over MgSO4, and fil-
tered. Evaporation of the solvent yielded the desired compound as a col-
orless solid (1.92 g, 5.40 mmol, 100%). Rf =0.25 (Et2O; UV, KMnO4);
m.p. 156–1588C; 1H NMR (360 MHz, CDCl3): d=7.82 (brs, 1H), 7.48
(brs, 1H), 6.88 (s, 1H), 6.66 (s, 1H), 5.60 (brs, 1H), 2.89 (d, 2J=13.9 Hz,
1H), 2.68–2.60 (m, 4H), 2.19 (d, 2J=15.1 Hz, 1H), 1.80 (d, 2J=10.5 Hz,
1H), 1.73–1.70 (m, 4H), 1.58 (d, 2J=10.5 Hz, 1H), 1.53 (d, 2J=15.1 Hz,
1H), 1.33 (s, 3H), 1.27 (d, 2J=13.9 Hz, 1H), 1.25 (s, 3H), 1.16 ppm (s,
3H); 13C NMR (90.6 MHz, CDCl3): d=180.2 (s), 175.8 (s), 147.9 (s),
136.4 (s), 129.0 (s), 125.3 (d), 122.4 (s), 118.7 (d), 55.9 (s), 55.2 (t), 44.1
(s), 43.7 (s), 43.6 (t), 43.1 (t), 30.4 (q), 29.1 (t), 28.5 (t), 24.8 (q), 23.3 (t),
23.1 (t), 20.1 ppm (q); IR (powder): n˜ =3357 (m), 3269 (m), 3236 (m),
2926 (s), 2856 (m), 1683 (vs), 1511 (s), 1455 (w), 1426 (w), 1294 (w), 1246
(w), 727 cmꢀ1 (w); MS (EI, 70 eV): m/z (%): 356 (30) [M+], 339 (1)
[MꢀHO+], 214 (2), 194 (4), 163 (100), 146 (5), 135 (8), 110 (14), 87 (8),
57 (38), 43 (20); HRMS (70 eV): m/z calcd for C21H28N2O3: 356.2100 [M+];
found: 356.2100.
[7] D. Albrecht, T. Bach, Synlett 2007, 1557–1560.
1,3,5-Trimethyl-3-(5,6,7,8-tetrahydronaphtho
ACHTUNGERTN[NUNG 2,3-d]oxazol-2-yl)-6-
[8] Y. Torisawa, T. Soe, C. Katoh, Y. Motohashi, A. Nishida, T. Hino,
M. Nakagawa, Heterocycles 1998, 47, 655–660.
azabicyclo[3.2.1]octan-7-one (31): Bisamide 30 (1.92 g, 5.40 mmol,
ACHTUNGTRENNUNG
1 equiv) and pyridine (3.05 mL, 2.98 g, 37.7 mmol, 7.00 equiv) were dis-
solved in benzene (40 mL) and cooled to 08C. Thionyl choride (1.95 mL,
3.20 g, 26.9 mmol, 5.00 equiv) was added dropwise to the reaction mix-
ture, which was warmed to ambient temperature, stirred for 15 min, and
heated to reflux for 4 h. The solution was cooled to ambient temperature,
and all the volatile compounds were removed under reduced pressure.
The residue was dissolved in EtOAc (500 mL) and washed with HCl (1m,
100 mL) and brine (100 mL). The organic layer was dried over MgSO4,
filtered, and concentrated. Column chromatography (Et2O!CH2Cl2/
MeOH 20;1) yielded the desired product as a colorless solid (1.42 g,
4.20 mmol, 78%). The enantiomers were separated using chiral HPLC
(Daicel Chiralpak AD-H; iPrOH/hexane 95:5). Rf =0.21 (Et2O; UV,
KMnO4); m.p. 2378C; 1H NMR (360 MHz, CDCl3): d=7.28 (s, 1H), 7.13
(s, 1H), 5.33 (brs, 1H), 2.98 (td, 2J=14.2, 4J=2.0 Hz, 1H), 2.86–2.83 (m,
5H), 1.81–1.77 (m, 4H), 1.70 (td, J=10.5, J=2.2 Hz, 1H), 1.59 (dd, J=
10.5, 4J=1.7 Hz, 1H), 1.54 (d, 2J=14.2 Hz, 1H), 1.45 (d, 2J=13.8 Hz,
1H), 1.35 (s, 3H), 1.28 (s, 3H), 1.13 ppm (s, 3H); 13C NMR (90.6 MHz,
CDCl3): d=178.7 (s), 171.5 (s), 149.1 (s), 139.4 (s), 133.9 (s), 133.0 (s),
119.0 (d), 110.0 (d), 55.2 (s), 51.8 (t), 44.0 (s), 43.6 (t), 43.3 (t), 37.8 (s),
31.8 (q), 30.1 (t), 29.8 (t), 25.2 (q), 23.2 (t), 23.2 (t), 20.3 ppm (q); IR
(powder): n˜ ~=3079 (m, NH), 2922 (m), 2856 (m), 1707 (vs), 1561 (m),
1465 (w), 1477 (w), 1319 (w), 1247 (w), 1140 (w), 1077 cmꢀ1 (w); MS (EI,
70 eV): m/z (%): 338 (60) [M+], 321 (8) [MꢀHO+], 282 (10), 228 (14),
214 (100), 187 (8); HRMS (70 eV): m/z calcd for C21H26N2O2: 338.1994
[M+]; found: 338.1991.
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(ꢀ)-31: [a]2D0 =ꢀ56 (c=0.95 in CHCl3); HPLC (Daicel Chiralpak AD-H;
iPrOH/hexane 95:5): tR =18.8 min. (+)-31: [a]2D0 =+56 (c=0.98 in
CHCl3); HPLC (Daicel Chiralpak AD-H; iPrOH/hexane 95:5): tR =
19.9 min.
Chem. Eur. J. 2010, 16, 4284 – 4296
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4295

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Received: September 23, 2009
Published online: January 14, 2010
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