β-Cyclodextrin-Mediated Enantioselective Photochemical Electrocyclization of 1,3-Dihydro-2H-azepin-2-one

Article abstract of DOI:10.1021/acs.joc.7b01300

The photochemical electrocyclization reaction of the title compound in the presence of β-cyclodextrin was examined in different conditions. No enantioselectivity was observed in solution, but solid-state reactions of a 1:1 complex as a suspension or a thin film, followed by reduction, provided (1R,5R)-2-azabicyclo[3.2.0]heptan-3-one in isolated yields up to 79% and with ee values up to 45%.

Full text of DOI:10.1021/acs.joc.7b01300

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Note
#-Cyclodextrin-mediated enantioselective photochemical
electrocyclization of 1,3-dihydro-2H-azepin-2-one
Ali taher Mansour, Julien Buendia, Juan Xie, François Brisset,
Sylvie Robin, Daoud Naoufal, Ogaritte Yazbeck, and David J. Aitken
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01300 • Publication Date (Web): 22 Aug 2017
Downloaded from http://pubs.acs.org on August 23, 2017
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β-Cyclodextrin-mediated enantioselective photochemical
electrocyclization of 1,3-dihydro-2H-azepin-2-one
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§,†
§
ǁ
§
§,‡
Ali T. Mansour, Julien Buendia, Juan Xie, François Brisset, Sylvie Robin,
†
†
,§
Daoud Naoufal, Ogaritte Yazbeck, and David J. Aitken*
§
CP3A Organic Synthesis Group and Services Communs, ICMMO, UMR 8182, CNRS,
Université Paris Sud, Université Paris-Saclay, Bât 420, 15 rue Georges Clemenceau, 91405
Orsay cedex, France
†
Inorganic and Organometallic Coordination Chemistry Laboratory (LCIO), Faculty of
Sciences (I) & PRASE-EDST, Lebanese University, Hadath, Lebanon
ǁ
PPSM, UMR 8531, CNRS, ENS Paris-Saclay, Université Paris-Saclay, 61 Avenue du Président
Wilson, 94235 Cachan cedex, France
‡
UFR Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, 4 avenue de
l’Observatoire, 75270 Paris cedex 06, France
TOC graphic & Abstract
The photochemical electrocyclization reaction of the title compound in the presence of β-
cyclodextrin was examined in different conditions. No enantioselectivity was observed in
solution, but solid-state reactions of a 1:1 complex as a suspension or a thin film, followed by
reduction, provided (1R,5R)-2-azabicyclo[3.2.0]heptan-3-one in isolated yields up to 79% and
with ee values up to 45%.
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The importance of light-induced chemistry has long been appreciated and among currently
available and sustainable methodologies, organic photochemistry represents a powerful tool
1
2
for synthetic chemists. Photochirogenesis is an area of major interest, with a significant focus
3
on the use of chiral supramolecular hosts. The cyclodextrins (CDs), water-soluble cyclic
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oligosaccharides with a truncated cone shape, have been amongst the most widely employed
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and can facilitate highly selective reactions. While γ-CD is a privileged host for
photodimerizations or other bimolecular reactions, the β-CD cavity is better suited for
unimolecular transformations of small substrates. To date, two photochemical
electrocyclization reactions in the presence of β-CD have been described, implicating N-
6
7
alkylpyridones and tropolone alkyl ethers (Figure 1). In each case, solution-state reactions
gave the main photoproduct with negligible enantiomeric excess (ee), whereas solid-state
reactions proceeded with around 60% ee in the former case and 25% ee in the latter.
Curiously, the absolute configuration of the major enantiomer was not established in either
case.
In our own work on the photochemical preparation of functionalized four-membered ring
8
compounds, we recently considered the photochemical electrocyclization reaction of 1,3-
dihydro-2H-azepin-2-one (1).9,10 The transformation proceeded in ether solution in high yield
to give the racemate which was subsequently resolved. We felt that the investigation of an
alternative approach to enantiomerically enriched material was warranted, and here we
examine β-CD as a chiral host for the photochemical process (Figure 1). The photochemical 4π
electrocyclization proceeds in a disroratory fashion leading to a cis ring junction; in the
asymmetric environment of the β-CD cavity this might lead to a non-racemic product.
Figure 1. Photochemical electrocyclization reactions performed in the presence of β-CD.
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We began by evaluating the photochemical electrocyclization of azepinone 1 in water. An
aqueous solution of 1 (15 mM) was placed in a quartz tube and irradiated (λ = 254 nm) for 2
hours. This gave clean and efficient conversion into racemic 2, which was isolated in 50% yield
after lyophilisation (Scheme 1). The conversion was probably higher, but some loss of material
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1
1
1
was noted during the removal of water; even so, the otherwise clean H NMR spectrum of 2
showed some residual water content, testifying to the hydrophilicity of this product.
Scheme 1
With preparative work in mind, we had chosen the concentration in the above control reaction
1
2
to be close to the aqueous solubility limit of β-CD at room temperature (16.3 mM). However,
when 1 equivalent of azepinone 1 was added to a 15 mM aqueous solution of β-CD, a milky
white suspension formed. This suspension became a clear solution upon heating to 45 °C, and
reappeared upon cooling. We carried out some spectroscopic studies to investigate the
1
solution-state behavior. A H NMR titration experiment was performed at 40 °C, whereby
incremental amounts of 1 were added to a solution of β-CD (15 mM in D O) and the evolution
2
1
of the H chemical shifts was monitored (see ESI). While the signals for protons H
1
, H
2
, H
4
and
and
H
6
5
- located on the outside of the β-CD cavity - showed no significant change, protons H
3
H
- located on the inside of the cavity - showed an up-field shift, reaching Δδ values of
(
respectively) 0.03 and 0.07 ppm at a 1:β-CD ratio of 1:1. This suggested the presence of a
1
3
deep-penetration inclusion complex. The titration data for H of β-CD were used to evaluate
3
the binding constant using a recent adaptation of the Benesi–Hildebrand equation;14a the
–1
value of K
b
was estimated to be 35.4 M . Complex formation was also supported by a ROESY
NMR experiment, again conducted on an equimolar 1/β-CD mixture in solution at 40 °C (15
mM, D O), which displayed intermolecular cross-peaks in the uncongested part of the spectral
plot, implicating the unsaturated moiety of the azepinone and the internal β-CD protons H
and H (Figure 2).
2
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Figure 2. Expansion of part of the 600 MHz solution-state ROESY NMR spectrum of a 1:1 1/β-CD mixture (15 mM
in D O, 40 °C) showing pertinent intermolecular cross-peaks (above). Cartoon of β-CD and structure of 1 showing
2
proton locations (below).
The stoichiometry of the complex was assessed by UV spectroscopy using the continuous
variation method.5e,5i,14 A Job plot of the change in absorption at 254 nm for aqueous solutions
of varied relative molar composition suggested complex formation in a 1:1 molar ratio (Figure
3).15
0.5
0.4
0.3
0
0
0
.2
.1
.0
0
0.5
1
R
Figure 3. Job plot of UV absorption (λ = 254 nm) at different 1:β-CD molar ratios.
We then began studies of the chiral host–guest photochemical electrocyclization reaction of
azepinone 1 in the presence of β-CD in water. However, preliminary efforts were thwarted by
1
extraction problems. While H NMR analysis of irradiated reaction mixtures suggested that
complete conversion of 1 had been achieved, extensive efforts to isolate the highly water-
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soluble bicyclic cyclobutene lactam 2 (liquid–liquid extraction; lyophilisation followed by
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solid–liquid extraction) provided only small amounts of material. Previously, we had noted
1
0
that the cyclobutane lactam 3 was more soluble than 2 in organic solvents. We therefore
decided to adapt our strategy and transform photoproduct 2 into 3 prior to extraction. In
order to verify that this two-step procedure could indeed be carried out, an aqueous solution
of 1 (15 mM) was placed in a quartz tube and the solution was irradiated (λ = 254 nm) for 2
hours, as before. The transparent solution was then stirred overnight under an atmosphere of
dihydrogen in the presence of 10% Pd-C. After removal of the catalyst the aqueous solution
was extracted with ethyl acetate. Pleasingly, the organic extracts provided spectroscopically
clean racemic lactam 3 in 82% yield for 2 steps (Scheme 1).
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All photochemical studies involving β-CD were therefore carried out using the sequential
electrocyclization–reduction protocol as the standard procedure (Table 1). The first
experiment was carried out on the clear equimolar 1/β-CD solution (15 mM) at 45 °C. After 2
hours irradiation the yellow-colored solution was cooled – at which point no precipitation was
observed – and reduced to give 3 in 40% yield and with an ee of zero (entry 1). It was suspected
that the modest yield was due to thermal degradation during the irradiation, so the second
solution-state experiment was conducted at 20 °C. At this temperature, a lower concentration
(4 mM) of each component was necessary in order to obtain a clear solution (entry 2). While
the isolated yield of 3 (65%) was improved, the ee of the sample remained nil.
We therefore turned our attention to the milky white suspension formed at higher
concentration. A suspension was prepared from an equimolar 1/β-CD solution (each 15 mM),
allowing 2 hours stirring to complete the process. Following the standard procedure, the
suspension was irradiated at 5 °C then reduced to provide lactam 3 in 79% yield and with a
gratifying ee of 38% (Table 1, entry 3). When this experiment was repeated with a two-fold
excess of β-CD, the yield remained similar (75%) while the ee rose marginally to 45% (entry
).17
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Table 1. Sequential photochemical electrocyclization–reduction of azepinone 1 in the presence of β-CD.
Entry Irradiation
conditionsa
Sample
stateb
Yield 3
(%)
40
65
79
75
70
71
77
ee 3
(%)
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A, 45 °C, 2 h solution
A, 20 °C, 2 h solution
A, 5 °C, 2 h
A, 5 °C, 2 h
B, 25 °C, 7 h
c
0
suspension
38
45
0-40
36
41
42
41
d
suspension
powdere
f
B, 25 °C, 20 h powder
C, 25 °C, 5 h
C, 25 °C, 5 h
C, 25 °C, 5 h
film
film
film
g
c
77
78
a: for details of conditions A, B and C, see experimental section; b: all samples were prepared from 15 mM aqueous mixtures
of 1 and β-CD (1:1 ratio), except when otherwise indicated; c: concentrations of both 1 and β-CD were 4 mM (1:1 ratio); d:
additional solid β-CD (2 equivalents) was added to the mixture; e: solid reagents were mixed directly, no solvent used; f: for
three identical experiments, the ee values were 0%, 29% and 40%; g: concentration of 1 was 7.5 mM (1:2 ratio).
This prompted us to further examine solid-state conditions. Equimolar quantities of 1 and β-
CD were ground manually in a mortar and the fine powder placed in a quartz tube and
irradiated while the tube was rotated slowly. After 7 hours the irradiation was stopped, since
1
inspection of a small reaction sample by H NMR showed no sign of remaining 1. The powder
was dissolved in water and reduced as before, to provide 3 in around 70% yield. This
experiment was performed thrice, and for each run the ee value was different: 0%, 29% and
40% (Table 1, entry 5). These results suggested that the grinding process did not give a
reproducibly homogeneous sample mixture. Furthermore, variable amounts of caprolactam,
the reduction product of non-electrocyclized 1, were detected: 14%, 0% and 8% in the three
experiments, respectively, again was the apparent result of sample heterogeneity. In an effort
to ameliorate this, a sample of the white solid obtained from a 15 mM 1/β-CD aqueous
suspension (1:1 ratio) was air-dried and ground finely in a mortar. The powder was irradiated
for a longer period (20 h) then reduced as described above to furnish 3 in 71% yield and 36%
ee (entry 6) in addition to caprolactam by-product (7%). In these powder-state experiments,
the tube rotation resulted in the aggregation of the powder into small “snowballs” that had
to be crushed regularly for the electrocyclization to progress.
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As an alternative to the powder form of the 1/β-CD adduct, we investigated thin films. The
milky aqueous suspension made from 15 mM 1/β-CD (1:1 ratio) was spread on a glass plate
and left to air-dry to give a smooth film (thickness in the range 20–50 µm). This supported film
was irradiated until no starting material 1 remained (5 h) then it was dissolved in water and
reduced, as before, to furnish 3 in 77% yield and 41% ee (entry 7). The yield of caprolactam
by-product was now <2%. A similar experiment using a film prepared from a 15 mM β-CD
solution and 0.5 equivalents of 1 gave almost identical results (entry 8). Finally, a film obtained
by slow evaporation of a 4 mM 1/β-CD aqueous solution (1:1 ratio) was irradiated and reduced
in the same way to provide almost identical results (entry 9).
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We established the stoichiometry of the solid material implicated in the above reactions. A
suspension prepared from a 15 mM equimolar aqueous mixture of 1 and β-CD (as described
1
for entry 3) was filtered and the solid was collected and dried. H NMR signal integration of a
dilute solution in D O indicated a 1:1 ratio. A sample of the same solid was partitioned
2
between ethyl acetate and water; evaporation of these phases gave 1 from the former and β-
CD from the latter. Comparison of relative material mass indicated a 1:1 ratio of 1 and β-CD.
Interestingly, the same analyses conducted on the suspension obtained from a 1:3 aqueous
solution 1/β-CD mixture (entry 4) also indicated a 1:1 stoichiometry in the solid material.
Although single crystals of the 1:1 complex were not forthcoming, we examined solid samples
by scanning electron microscopy (SEM) and powder X-ray diffraction (PXRD) (Figure 4). In the
SEM images the 1/β-CD complex showed a fibrillar morphology in striking contrast with
azepinone 1 and β-CD alone, which showed only amorphous block structures. Similarly, the
PXRD data obtained for the 1/β-CD complex were clearly different from those for samples of
1
and β-CD alone. This provided further indication that a genuine complex is implicated, rather
than a physical mixture of two discreet substances.
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2ϴ
Figure 4. SEM images (above) and PXRD data (below) for: (a) solid 1; (b) solid β-CD; (c) solid 1/β-CD complex
(from entry 7).
In all the above experiments, HPLC analysis indicated that the same major enantiomer of 3
predominated. To determine its configuration, we transformed a typical sample of 3 (42% ee)
into the N-Boc-derivative of cis-(2-aminocyclobutyl)acetic acid 4 using a known procedure.10
The sample of 4 thus obtained had [α] 25
+33 (c 0.5, CHCl
). The literature value for (R,R)-4
10
D
3
2
7
(
97% ee) is [α]
D
+68 (c 0.96, CHCl ), indicating that our samples of 3 have a 1R,5R absolute
3
configuration (Scheme 2).
Scheme 2.
In summary, the formation of a 1:1 complex between β-CD and 1,3-dihydro-2H-azepin-2-one
allows the solid-state photochemical electrocyclization of the latter to proceed in good yield
1
in an enantioselective fashion, with ee values up to 45%. This is only the third example of a
photochemical electrocyclization reaction conducted in the presence of β-CD, and it confirms
and extends the interest and synthetic value of this supramolecular host for photochirogenetic
reactions.
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Experimental Section
General methods. 1,3-dihydro-2H-azepin-2-one 1 was prepared according to the literature.18
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β-CD was obtained commercially (Acros Organics) and was dried (50 °C, 10–2 mm Hg)
overnight. Ultrapure water (RephiLe PURIST®) was used for all reactions. Analytical grade ethyl
acetate was used for all extractions.
1
Routine NMR spectra were recorded on a Bruker AV360 (360 MHz, for H) or a Bruker DPX250
1
3
(
62.5 MHz, for C). Chemical shifts (δ) are reported in ppm with respect to the residual proton
1
signal in deuterated chloroform (δ 7.27 ppm) for H and with respect to CDCl
3
(δ 77.0 ppm)
1
3
1
for C. H NMR titration experiments were recorded on a Bruker AVII-600 (600 MHz). 2D
ROESY spectra (600 MHz) were recorded on the same instrument with a mixing time of 400
1
ms. The binding constant (K
b
) was calculated from the H NMR titration experimental data for
H3 of β-CD using the Benesi–Hildebrand equation 1/Δδ = 1/(K
Δδ is the chemical shift change induced by the presence of 1 at the specified concentration
and Δδsat is the Δδ value at saturation. The linear plot of 1/Δδ vs. 1/[1] had a slope of 1/(K
Δδsat) and an intercept at 1/Δδsat, from which K was determined.
UV spectra were recorded on an Analytik-Jena Specord 205 instrument using 1 cm quartz
b
× Δδsat × [1]) + 1/Δδsat, where
b
×
b
−4
cuvettes. Job plot experiments were performed using 4.0 × 10 M solutions of 1 and β-CD in
water, mixed to give samples of different molar fraction R = [1]/[1]+[β-CD] while maintaining
a fixed total concentration. The plot of (ΔA × R) against R, where ΔA = the difference in
absorbance at λ = 254 nm between 1 alone and 1 in the presence of β-CD, gave the R value of
the complex stoichiometry.
Enantiomeric excesses (ee) were determined using an Agilent 1260 Infinity HPLC apparatus
equipped with a Phenomenex® Lux Cellulose-2 column (250 mm × 4.6 mm; particle size 5 μm)
and a UV absorbance (210 nm) detector. Sample solutions were prepared in ethanol (1 mg
−1
mL ), and the injection volume was 5 μL. Analyses were performed using hexane/EtOH
90/10) as the mobile phase flowing at a rate of 2 mL/min; the column and the mobile phase
were thermostated at 20 ± 1 °C. Using these conditions, baseline separation was observed; t
8.1 ± 0.1 min for (1S,5S)-3 and t = 8.8 ± 0.1 min for (1R,5R)-3. In these same conditions,
caprolactam (the reduction product of azepinone 1) had t = 9.8 ± 0.2 min.
(
R
=
R
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Scanning electron microscopy was performed on a Zeiss Supra 55VP instrument equipped with
a field emission gun. The sample was deposited on a conductive aluminum sample holder and
introduced directly inside the microscope chamber which was then put under a normal
−5
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secondary high vacuum (10 /10 mbar range). The electron beam high voltage was set to 1
kV and the current to a few pA in order to observe the non-conductive products without any
conductive deposit on top.
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Powder X-ray diffraction data were collected using a Bruker diffractometer equipped with a
Micro-focus IµS source and CuKα radiation. The powders were introduced in 0.3 mm diameter
capillaries and measurements were performed in transmission mode at 25 °C. The two-
dimensional detector data were integrated into conventional 1D diffraction data using the
DIFFRAC.EVA software package V.3.0 (Bruker).
Photochemical reactions. All reactions were carried our using a Rayonet RPR-200
photochemical reactor equipped with a carousel of 254 nm lamps (16 × 6 W). Conditions A:
the aqueous solution or suspension was magnetically stirred in a vertically-held quartz tube
fitted with an internal heating/cooling finger. Conditions B: the solid sample was placed in a
horizontally-held quartz tube which was rotated mechanically (10 rpm); following the
irradiation time, the solid was dissolved in water. Conditions C: the thin film was placed on a
horizontally held tray located inside the reactor cavity; following irradiation for the specified
time using 10 lamps, the solid was dissolved in water.
General procedure for reduction. To an aqueous solution of 2 (also containing β-CD in many
cases) obtained from the photochemical reaction was added 10% Pd-C (5 mg). The mixture
was stirred under an atmosphere of H
2
(1 atm) for 16 h at room temperature then filtered
through a 0.45 μm PVDF syringe filter. The filtrate was extracted with ethyl acetate (10 × 25
mL). Combined organic phases were dried over Na
2
SO and concentrated under reduced
4
1
pressure to give 3. Sample purity was checked by H NMR and HPLC analysis.
Photochemical electrocyclization of 1 in water: cis-2-azabicyclo[3.2.0]hept-6-en-3-one 2. A
solution of azepinone 1 (50 mg, 0.46 mmol) in water (30 mL) was irradiated for 2 h at 5 °C
using Conditions A. The reaction medium was lyophilized to give 2 (25 mg, 50%) as a yellow
1
solid, mp 75-78 °C. H NMR (360 MHz, CDCl
3
) δ 2.29 (dd, J = 17.9 Hz, J = 2.9 Hz, 1H), 2.48 (dd,
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J = 17.9 Hz, J = 10.2 Hz, 1H), 3.54-3.59 (m, 1H), 4.43-4.44 (m, 1H), 6.30-6.38 (m, 2H), 6.46 (br
13
s, 1H); C NMR (62.5 MHz, CDCl
3
) δ 33.6, 41.5, 57.6, 142.2, 142.7, 178.3. These data are in full
accordance with those described previously for a sample of 2 obtained by irradiation of 1 in
ether.10
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Sequential photochemical electrocyclization–reduction of
1
in water: cis-2-
azabicyclo[3.2.0]heptan-3-one 3. A solution of azepinone 1 (50 mg, 0.46 mmol) in water (30
mL) was irradiated for 2 h at 5 °C using Conditions A. The reaction mixture was then subjected
1
directly to the General procedure for reduction to give 3 (42 mg, 82%) as a yellow oil. H NMR
(360 MHz, CDCl
3
) δ 1.86-1.96 (m, 2H), 2.21 (d, J = 17.5 Hz, 1H), 2.26-2.36 (m, 2H), 2.50 (dd, J =
13
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.8 Hz, J = 17.5 Hz, 1H), 3.06-3.20 (m, 1H), 4.04-4.13 (m, 1H), 6.53 (br s, 1H). C NMR (62.5
MHz, CDCl ) δ 25.5, 28.6, 33.3, 37.7, 54.1, 179.0. These data are in full accordance with those
3
described previously for a sample of 3 obtained by hydrogenation of 2 in ethyl acetate.10
Sample preparation. Entry numbers refer to Table 1.
Entry 1. A solution of 1 (50 mg, 0.46 mmol) in water (1 mL) was added to a solution of β-CD
(520 mg, 0.46 mmol) in water (30 mL). The mixture was heated at 45 °C to ensure it remained
a clear solution.
Entry 2. A solution of 1 (50 mg, 0.46 mmol) in water (1 mL) was added to solution of β-CD (520
mg, 0.46 mmol) in water (109 mL).
Entry 3. A solution of 1 (30 mg, 0.28 mmol) in water (1 mL) was added to a solution of β-CD
(320 mg, 0.28 mmol) in water (18 mL). Formation of a white precipitate began almost
immediately and progressed as the mixture was stirred for 2 h at rt.
Entry 4. As for entry 3, except that further solid β-CD (640 mg, 0.56 mmol) was added when
the suspension began to form.
Entry 5. Solid 1 (30 mg, 0.28 mmol) and solid β-CD (320 mg, 0.28 mmol) were ground in a
mortar until a fine powder was obtained.
Entry 6. A solution of 1 (50 mg, 0.46 mmol) in water (1 mL) was added to a solution of β-CD
(520 mg, 0.46 mmol) in water (30 mL). The white precipitate obtained after stirring for 2 h at
rt was filtered through a sintered glass funnel (porosity 3) and washed with water (10 mL).
The solid was collected, air-dried, then crushed to a fine powder in a mortar.
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Entry 7. A solution of 1 (30 mg, 0.28 mmol) in water (1 mL) was added to a solution of β-CD
(320 mg, 0.28 mmol) in water (18 mL). Formation of a white precipitate progressed as the
mixture was stirred for 2 h at rt. The milky suspension was spread on a glass plate and left to
evaporate and dry in air over 3 days.
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Entry 8. As for entry 7, using a solution of 1 (34 mg, 0.31 mmol) in water (1 mL) and a solution
of β-CD (702 mg, 0.62 mmol) in water (40 mL).
Entry 9. A solution of 1 (30 mg, 0.28 mmol) in water (1 mL) was added to a solution of β-CD
(320 mg, 0.28 mmol) in water (54 mL). The clear solution was spread on a glass plate and left
to evaporate and dry in air over 3 days.
Associated content
Supporting Information
Copies of NMR spectra and HPLC chromatograms are presented in the Electronic Supporting
Information. The ESI is available free of charge on the ACS Publications website at
http://pubs.acs.org/.
Author information
Corresponding Authors
* E-mail: david.aitken@u-psud.fr
Notes
The authors declare no competing financial interest.
Acknowledgments
The awards of a CIOES doctoral research scholarship (to A.T.M.) and a CHARMMMAT LabEx
post-doctoral fellowship (to J.B.) are acknowledged. The authors thank Ms F. Charnay-Pouget
for help with the chiral HPLC analysis, Mr J.-P. Baltaze for assistance with NMR studies, Dr R.
Guyot and Mr J. Forté for the powder XRD measurements, and Dr T. Boddaert for practical
advice regarding the photochemical reactor set-up. We are grateful to the Universitꢀ Paris Sud
(AAP-Attractivitꢀ) for financial support for the photochemical equipment.
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1. In a subsequent control reaction, we observed that up to half the amount of lactam 2 was lost
when an equimolar solution of this compound and β-CD in water was lyophilized for prolonged periods
(up to 3 days).
12. Connors, K. A. Chem. Rev. 1997, 97, 1325-1357.
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6. In further testimony of the hydrophilicity of cyclobutene lactam 2, during its photochemical
preparation in water (Scheme 1) the reaction medium remains transparent, whereas during the same
reaction conducted in ether the insoluble product 2 is deposited progressively on the walls of the
reactor.
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7. We checked that there was no enantioselection operating in the reduction stage: when a racemic
sample of 2 was hydrogenated in the presence of 1 equivalent of β-CD, 3 was obtained in racemic form.
1
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