Photoinduced cycloadditions in the diversity-oriented synthesis toolbox: Increasing complexity with straightforward post-photochemical modifications

Article abstract of DOI:10.1071/CH15266

Rapid growth of complexity and unprecedented molecular architectures is realised via the excited state intramolecular proton transfer (ESIPT) in o-acylamidobenzaldehydes and ketones followed by [4+2] or [4+4] cycloadditions with subsequent post-photochemi

Full text of DOI:10.1071/CH15266

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
http://dx.doi.org/10.1071/CH15266
Photoinduced Cycloadditions in the Diversity-Oriented
Synthesis Toolbox: Increasing Complexity with
Straightforward Post-Photochemical Modifications
A
A
A
Weston J. Umstead, Olga A. Mukhina, N. N. Bhuvan Kumar,
,
A B
and Andrei G. Kutateladze
A
Department of Chemistry and Biochemistry, University of Denver, Denver,
CO 80208, USA.
B
Corresponding author. Email: akutatel@du.edu
Rapid growth of complexity and unprecedented molecular architectures is realised via the excited state intramolecular
proton transfer (ESIPT) in o-acylamidobenzaldehydes and ketones followed by [4þ2] or [4þ4] cycloadditions with
subsequent post-photochemical modifications. The approach is congruent with diversity-oriented synthesis, whereby
photoprecursors are synthesised in a modular fashion allowing for up to four diversity inputs. The complexity of the
primary photoproducts is further enhanced using straightforward and high-yielding post-photochemical modification
steps such as reactions with nitrile oxides and nitrones, and Povarov and oxa-Diels–Alder reactions.
Manuscript received: 12 May 2015.
Manuscript accepted: 28 May 2015.
Published online: 24 July 2015.
Introduction
of rotatable bonds. All these diverse compounds are accessible
through a general and efficient strategy based on intramolecular
[4þ2] and [4þ4] cycloadditions of azaxylylenes. These inter-
mediates can be conveniently generated by the excited state
intramolecular proton transfer (ESIPT) from photoprecursors
that are, in turn, readily accessible through standard amide
bond-forming reactions (Scheme 1).
[
1]
Despite large investments in pharmaceutical R&D and a
massive synthetic effort at the bench, as reflected by the number
[
2]
of new compounds synthesised annually, new drugs – and
especially new drugs with the novel mechanisms of action – are
still rare, and the number of untreatable health conditions per-
sists. It can be safely assumed that ‘well in excess of 10000
medicinal chemistry compounds are synthesised for each
approved drug.’ Such a moderate degree of success is often
associated with the lack of structural diversity of compounds in
the existing libraries which, in turn, results from the inadequate
variety in the synthetic methods employed. Relatively few
classes of reactions are used to access the majority of the com-
Upon irradiation, o-formyl or o-acyl anilides undergo fast
and efficient ESIPT to their tautomeric form, azaxylylene, with
[
3]
[
9]
likely intersystem crossing into the triplet manifold. The
involvement of a triplet state is supported by (1) heavy atom
acceleration of the reaction upon introduction of bromine atom
in the azaxylylene precursor and (2) quenching of the cyclo-
addition reaction by such typical triplet state quenchers as oxygen
or trans-piperylene. As Scheme 1 illustrates, the reaction is
completed via another intersystem crossing and the intra-
molecular collapse of the singlet radical pair to form the
products of formal [4þ2] or [4þ4] cycloadditions. Intramolec-
ular fluorescence quenching with tethered unsaturated pendants
revealed that the cycloaddition reaction is unlikely to occur in
the singlet excited state. It was also ruled out for the ground state
[
4]
pounds prepared for biological testing, and the range of the
used reactions is noticeably biased towards the ‘easy’ chemistry
2
of sp –sp carbon coupling.
2
Photochemical reactions are conspicuously absent from
the toolbox of modern combinatorial and medicinal chemists,
although one hopes that the visible light photoredox synthetic
‘revolution’ will bring the much needed change of this status
quo.
[
5,6]
Research efforts in our group are aimed at demonstrat-
[
9]
ing the potential of photochemical methods in the context of
diversity-oriented synthesis, leading to complex and topologi-
cally novel structures, potentially attractive from the medicinal
chemistry standpoint. A sample selection of the scaffolds
synthesised through photochemical methods in our group are
presented in Fig. 1.
The compounds depicted in Fig. 1 represent eight distinct
3
molecular scaffolds, with a high content of sp -hybridised
singlet.
This photochemical reaction is fully congruent with the
philosophy of diversity-oriented synthesis. The synthesis of
the photoprecursor is straightforward and amenable to modular
assembly, allowing for up to four diversity inputs. The photo-
chemical step results in a dramatic growth of complexity,
yielding two or more distinct molecular scaffolds, which can
be further introduced into a post-photochemical reaction step.
We have previously shown that the primary photoproducts lend
themselves to various post-photochemical modifications, for
[7]
[
8]
carbons (as indicated by fsp3 value), relatively low molecular
weight (MW), optimal lipophilicity (logP) and a small number
Journal compilation Ó CSIRO 2015
www.publish.csiro.au/journals/ajc

B
W. J. Umstead et al.
HO
OH
OH
OH
O
OH
O
O
N
N
N
N
O
N
O
O
O
N
O
N
N
O
Bn
A
B
C
D
O
fsp3 ꢀ 0.53
fsp3 ꢀ 0.46
fsp3 ꢀ 0.50
fsp3 ꢀ 0.27
MW ꢀ 362.33
clogP ꢀ ꢁ1.57
MW ꢀ 230.26
clogP ꢀ 0.89
MW ꢀ 229.27
clogP ꢀ 1.54
MW ꢀ 479.53
clogP ꢀ 2.64
rotatable bonds ꢀ 0
rotatable bonds ꢀ 0
rotatable bonds ꢀ 0
rotatable bonds ꢀ 3
NO2
HO
H
OH
O
O N
2
HO
HO
N
O
N
N
N
H
O
NH
N
H
O
O
E
N
H
F
G
H
fsp3 ꢀ 0.40
fsp3 ꢀ 0.36
fsp3 ꢀ 0.52
fsp3 ꢀ 0.48
MW ꢀ 270.28
clogP ꢀ 1.04
MW ꢀ 376.41
clogP ꢀ 1.79
MW ꢀ 368.43
clogP ꢀ 1.87
MW ꢀ 349.43
clogP ꢀ 2.18
rotatable bonds ꢀ 2
rotatable bonds ꢀ 1
rotatable bonds ꢀ 2
rotatable bonds ꢀ 0
Fig. 1. A subset of diverse molecular scaffolds previously synthesised via intramolecular cycloadditions of photogenerated azaxylylenes.
R
R
N
1
O
OH
hν
ISC
NH
~
H
O
O
O
O
OH
N
R
N
3
O
a
b
OH
OH
b
a
O
O
N
HO
O
O
O
O
N
O
Scheme 1. Photochemical generation of azaxylylenes via ESIPT and their intramolecular cycloadditions.
ISC ¼ Intersystem crossing.
[
7d]
example, the Suzuki reaction.
Further modifications offered
compounds and N-phenyl-aryl-2-ylmethanimines (Povarov
reaction).
by the double bonds in the [4þ2] and [4þ4] frameworks could
allow for an increase in scaffold diversity and complexity via the
addition of dipoles or heterodienes. Thus, the aim of the current
study was to evaluate the scope of post-photochemical modifi-
cations and the opportunities for rapid access to extended
polyheterocyclic sheets of unprecedented topology. We also
utilised computer-aided property prediction for the synthesised
compounds, and assessed their skeletal diversity and other
properties. Specifically, we now report the post-photochemical
reactions of the primary [4þ4] and [4þ2] photoproducts
with phenylnitrile oxide, N-(phenylmethylene)methanamine
N-oxide, 1-oxabutadienes, generated from the 1,3-dicarbonyl
Results and Discussion
The model system for these studies was prepared via photo-
induced cyclisation of 2-(3-(fur-2-yl)propanamido)benzalde-
hyde as shown in Scheme 2. The acylation of TMS-protected
o-aminobenzyl alcohol 1, followed by pyridinium chloro-
chromate (PCC) oxidation yielded photoprecursor 2, which
upon irradiation in a Rayonet photoreactor equipped with
RPR-3500 UV lamps (a broad band 300–400nm UV source,
with lmax ,350 nm) underwent [4þ2] and [4þ4] cycloadditions
to yield two distinct polyheterocyclic scaffolds in good yields.

Photoassisted DOS: Post-Photochemical Modifications
C
O
O
i
HO
O
OH
Cl
TEA, DCM
OTMS
NH2
hν
ꢂ
O
O
~H
ii PCC
NH
N
O
N
O
O
O
2
3
4
1
[4ꢂ4]
[4ꢂ2]
Scheme 2. Synthesis of model compounds. TEA ¼ triethylamine, DCM ¼ dichloromethane, PCC ¼ pyridinium
cholorochromate.
OH
N
OH
N
N
O
PhC(Br)ꢀNOH
O
DCM,
KHCO3
O
O
O
4
5, 59 %
HO
OH
Ph
PhC(Br)ꢀNOH
O
DCM,
KHCO3
N
O
ꢂ
O
N
O
N
N
HO
Ph
O
O
6
, 61 %
OH
O
6؅
N
O
ꢂ
N
OH
ꢁ
O
Ph
Ph
N
H
H
H
H
3
O
N
N
ꢂ
O
O
O
N
O
O
7
, 63 %
7؅, 21 %
0
Scheme 3. Reactions with dipoles (6 was observed by NMR but not isolated).
The reaction occurs diastereospecifically, yielding only syn-
NMR spectra and comparison with the previously isolated
[7g]
[4þ4] and anti-[4þ2], where syn- and anti- refers to the
adducts of bromonitrile oxide.
The [4þ2] photoproduct does not tolerate the conditions
respective arrangement of the benzylic hydroxy group in the
quinolinol or benzoazacane ring, and the oxygen in furan.
[11]
for the addition of the nitrones,
degrading in the process,
whereas the [4þ4] photoproduct reacts cleanly to give two
Reactions with Dipoles
0
stereoisomers 7 and 7 in the 3 : 1 ratio (Scheme 3). Both isomers
[
10]
Both [4þ4] and [4þ2] cycloadducts react with nitrile oxides,
result from the attack of the nitrone from the least hindered exo-
face and differ in the relative position of the phenyl ring with the
phenyl group pointing away from the pyrrolidinone moiety. We
were able to obtain an X-ray structure for the major isomer 7,
and based stereochemical assignment of the minor isomer on
the results of NOE experiments. The aliphatic regions of the
generated from the corresponding oximes (Scheme 3). In both
cases, the 1,3-dipolar cycloaddition of benzonitrile oxide occurs
from the exo-face. Similarly to the previously described reaction
with bromonitrile oxide, [4þ4] cycloadduct produces two
0
regioisomers 6 and 6 in the ratio of 3 : 1, whereas [4þ2] reacts
1
0
regioselectively to give the charge-controlled 5 as the only
product. The observed differences can be explained by the ste-
reoelectronic properties of the alkenes: the [4þ2] photoproduct
possesses a dihydrofuran moiety, and the 1,3-dipolar cyclo-
addition is expected to proceed through a charge-controlled
transition state, whereas the double bond in the [4þ4] substrate
is not as polarised, hence, both regioisomers are observed. The
structure of the adducts was confirmed by analysis of their
H NMR spectra of both stereoisomers 7 and 7 possess two
separate spin systems: H –H and H –H –H . The spin–spin
coupling constant H –H is not observed experimentally. In both
a
b
c
d
e
b
e
0
cases, H signal is a triplet at 2.73 (7) or 2.82 (7 ) ppm. To
e
unambiguously prove the structure of the products, we con-
ducted NOE differences experiments for both isomers (Fig. 2).
In 7, upon irradiating the triplet H at 2.73 ppm, we see NOE of
e
3 % with H , which is indicative of the regiochemistry shown,
a

D
W. J. Umstead et al.
[
12]
as well as NOE of 13 % on H and H ,
but no signal from
H , which implies that protons H and H reside on the opposite
up in the thermodynamically favoured equatorial position.
The structure of the product was supported by the NMR data.
Among the aliphatic protons, H has the highest chemical shift,
b
c
d
d
e
0
faces of the isoxazoline ring. Similarly, in 7 , upon irradiating
the triplet H at 2.82 ppm, we see NOE of 8 % with protons H
c
observed at 5.25 ppm as a doublet, J 7.7 Hz. H is characterised
b
e
a
[
13]
and Hb,
and again indicated that the phenyl group is located
by ddd at 2.54 ppm with the spin–spin coupling constants of
10.4 Hz (with H ), 7.8 Hz (with H ), and 2.9 Hz (with H ). The
on the ‘northern’ side of the molecule, syn to the benzylic OH
group and anti to the pyrrolidone moiety. Additionally, we see
NOE on both H and H (13 % and 11 %, respectively), suggest-
a
c
d
value of the biggest constant corresponds to axial–axial interac-
tion, which puts the pyridine ring in equatorial position (Fig. 3).
Next, we attempted oxa-Diels–Alder reactions using oxabu-
c
d
ing that all three protons are syn to each other.
[
17]
tadienes,
(
generated in situ from 1,3-dicarbonyl compounds
Meldrum’s acid and dimethylbarbituric acid). The reaction
Reaction with Dichlorocarbene
One observation that we made during this study was that the
general reactivity of the remaining double bond in primary [4þ4]
photoproduct 3was very low. Product 3was then modified through
the sequence of acid-induced bicyclo[4.2.1] -bicyclo[3.3.1]
with dimethylbarbituric acid proceeds smoothly, giving one
stable product of exo-addition of the diene. The Meldrum’s acid
adduct was unstable, undergoing ketal hydrolysis followed by
decarboxylation. The structure of the product was unambigu-
ously proven by X-ray analysis. The structures of both products
[7g]
rearrangement and oxidation as shown in Scheme 4. Dichlor-
ocarbene was generated in situ from chloroform and sodium
hydroxide, but the reaction yielded a-chloroester 8, which is pre-
sumably formed as a result of Jocic–Reeve reaction of the carbene
1
are supported by H NMR analysis.
These post-photochemical modifications are not limited to
furan-based photoproducts and can be carried out with thio-
phene- and pyrrole-based systems as well. Thiophene-based
[4þ2] photoproduct 13, obtained in a manner similar to furanyl
adduct 11, was introduced into the reaction with dimethylbarbi-
turic acid (Scheme 6). The reaction yielded a single product of a
charge-controlled cycloaddition of the in situ-generated oxabu-
tadiene to the dihydrothiophene moiety of 13.
[14]
with the ketone functionality
We hypothesised that the carbene attacked from exo-side of
.
the bicyclic benzoazacane ring, and the initially formed epoxide
ꢀ
is ring-opened by the nucleophile (Cl ) from the sterically
accessible exo-side.
Hetero-Diels–Alder Reactions
00
Similarly to furan-based compounds 11 and 12 , the struc-
Expectedly, the [4þ4] adduct was not reactive in either the
Povarov or the oxa-Diels–Alder reaction. However, the [4þ2]
product possessing a much more reactive vinyl ether moiety
proved to react smoothly, yielding a single regio- and stereo-
isomer as a result of the Povarov reaction, and the reactions with
both Meldrum’s acid and barbituric acid-based s-cis oxabuta-
dienes as shown in Scheme 5.
ture of 13 was determined by NMR analysis, which was further
supported by the prediction of proton spin–spin coupling con-
stants (SSCCs). For this, we used a density functional theory
(DFT) relativistic force field method that we have recently
developed and which is based on fast and accurate scaling
[18]
of Fermi contacts.
As Fig. 4 shows, for all three post-
photochemical cycloadducts experimental SSCCs matched
the computed constants very well, leaving no doubt that our
stereochemical assignment is accurate.
[15,16]
Povarov reaction
was conducted in 2,2,2-trifluoroethanol,
as a solvent, at 408C. Again, the 2-azadiene expectedly attacks
from the less hindered exo-face, with the pyridine ring winding
Pyrrolines, such as 16, accessed via intramolecular cyclo-
additions of azaxylylenes, photogenerated from amino
acid-based pyrroles, such as 15, are also well suited for
post-photochemical modifications, although in this case an
unexpected double addition occurred. For example, when
phenylalanine-based enantiopure photoprecursor 15 was irradi-
ated in DMSO and, without further purification, subjected to
hetero-Diels–Alder reaction with methylenebarbituric acid gen-
erated in situ, the reaction yielded a product incorporating two
pyrimidinetrione moieties (Scheme 7). We believe that the first
equivalent of the diene adds to the enamine moiety, forming
Ha Hb
Ha Hb
HO
O
Ph
HO
O
Ph
Hd
He
He
Hd
N
N
O
N
O
N
O
O
Hc
Hc
7
7؅
Fig. 2. Nuclear Overhauser Enhancement experiments.
HO
OH
O
ꢁ
CCl3
TFA
[O]
O
DCM
N
O
O
N
N
O
O
O
8
3
3
؅
O
Cl
O
O
Cl
Cl
ꢁ
OEt
Cl
Cl
HOEt
Cl
O
O
O
N
O
N
N
O
O
9, 66 %
Scheme 4. Addition of dichlorocarbene to a,b-unsaturated ketone 8. TFA ¼ trifluoroacetic acid.

Photoassisted DOS: Post-Photochemical Modifications
E
transient intermediate 17 similar to 11 and 14. However, due to
additional stability of the iminium ion, intermediate 17 exists in
equilibrium with its zwitterionic form 17þ/ꢀ, which captures
the second equivalent of methylenebarbituric acid, effectively
resultingin a [2þ2þ2]product(18). We have found oneexample
To quantify the diversity of the combined mini library of the
compounds 5–18 synthesised in this work and supplemented
with previously synthesised compounds A–H, we employed
computed Tanimoto similarity coefficients. As Table 1 illus-
trates, the off-diagonal elements are in the 0.2–0.5 range for the
majority of compounds that amounts to significant scaffold
diversity.
[
22]
[19]
only of a somewhat related cycloaddition in the literature.
The structure of the product 18 was supported by additional
1
3
[20]
NMR experiments ( C APT, HMBC and HMQC), as well as
by comparison of the experimental and calculated NMR spectra,
Fig. 5. The HMBC spectrum of the initial photoproduct skeleton
revealed an expected pattern of C–H cross-peaks, indicating that
the pyrrolo-quinolinone skeleton remains unchanged. Character-
N
Ha
H
Hb
NH
HO
Hd
0
istic features observed are the protons C –H and C –H , which
d
d
are represented by two doublets at 2.14 and 2.48 ppm with
2
O
N
H
c
J 15.3 Hz. In the HMBC spectrum, these doublets exhibit
cross-peaks with quaternary carbons C and C at 51.5 and
10
c
e
O
5
by the cross-peaks with C –H and C –H in the HMBC spectrum.
6.1 ppm. The peak at 56.1 ppmisattributed tocarbonC judging
e
H ꢁH ꢀ 10.4 Hz
H ꢁH ꢀ 7.8 Hz
H ꢁH ꢀ 2.6 Hz
a
b
f
a
b
c
The peak at 51.5 ppm, which has a cross-peak with C –H, is
b
b d
attributed to carbon C . The calculated spin–spin coupling
c
constantsfor the proposed structure are inan excellent agreement
with the experiment (rmsd ¼ 0.36 Hz and mue ¼ 0.81 Hz).
It is clear that a combination of the [4þ4] and [4þ2] scaffolds
generated via the photochemical step and further modified in
simple post-photochemical steps, involving mostly 1,3-dipolar,
or [4þ2], or [2þ2þ2] cycloadditions, produced complex poly-
heterocyclic sheets with ‘visibly’ diverse frameworks. Out of the
ten compounds synthesised, nine distinct molecular scaffolds
were prepared in a total of 19 steps. Although compared with
typical combinatorial chemistry libraries, the number of com-
pounds in this library is very small; we believe that the ‘steps per
Fig. 3. Spin–spin coupling constants in structures 10.
O
O
O
N
OH
N
OH
N
O
N
N
N
O
O
S
H CꢀO, proline
S
2
CH CN/H O
3
2
O
O
14, 31 %
13
[21]
scaffold efficiency’ (2.11 steps per scaffold) is very appealing,
as is the rapid growth of complexity from the readily available
photoprecursors to the post-photochemical final products.
Scheme 6. Thiophene-based [4þ2] adduct in the reaction with dimethyl-
barbituric acid.
N
Ph
N
N
HO
H
NH
H
O
H
CF CH OH
N
3
2
O
10
, 31 %
OH
O
O
O
N
O
OH
N
N
N
O
O
O
N
O
H CꢀO, proline
CH CN/H O
N
O
2
3
2
O
4
11, 45 %
O
O
O
OH
O
O
OH
OH
N
OH
N
O
OH
O
O
O
ꢂ
H
O
O
O
O
O
O
N
O
H CꢀO, proline
CH CN/H O
2
3
2
O
O
12
12ꢃ
12ꢄ, 35 %
Scheme 5. Postphotochemical [4þ2] cycloadditions of heterodienes to primary photoproducts.

F
W. J. Umstead et al.
1
5.8
1
1
1.7
2.0
1
1
1.0
1.5
15.9
17.1
17.9
O
H
3
.0
2.8
1.6
1.5
6.5
6.7
1
1
.6
.6
4.6
4.5
2.5
2.7
2
.5
H
7
7
.3
.3
H
2.6
7.5
7.3
H
H
H
H
HO H
H
H
H
H
HO
N
N
H
7
7
.5
.4
H
7
7
.7
.4
H
H
H
3
2
.0
.9
O
1
.2
1.4
1.2
2
2
.7
.5
H
N
1
1
.2
.2
H
O
1.2
8.0
8
O
.2
N
8
.1
O
4
4
O
4.0
3.9
8
.2
H
O
.8
.6
H
H
O
O
11
1
2؆
rmsd ꢀ 0.29 Hz
mue ꢀ 0.77 Hz
rmsd ꢀ 0.19 Hz
mue ꢀ 0.46 Hz
Jexp
Jcalc
1
2.05
2.2
17.0
17.7
1
1
1
.6
.5
6.5
6.8
2
.3
O
7
7
.5
.3
2.3
H
H
H
H
HO H
H
N
7
.5
H
H
7
.4
O
- - -
1.1
1
1
.2
.2
H
N
7
.9
O
8
.1
N
S
3
.1
H
3
.1
O
14
rmsd ꢀ 0.27 Hz
mue ꢀ 0.72 Hz
0
0
Fig. 4. Comparison of experimental and predicted SSCC for compounds 11, 12 , and 14. rmsd ¼ root-mean-square deviation, mue ¼ maximum
unsigned error.
O
O
HO
H
H
N
N
O
h
ν
O
NH
N
N
O
DMSO
H CꢀO, proline
DMSO
N
2
O
Ph
Ph
15
1
6
O
O
N
N
O
N
HO
H
O
H
H
HO
H
H
H
ꢁ
N
O
ꢂ
N
O
N
O
N
N
O
H
Ph
Ph
1
7ꢂ/ꢁ
1
7
O
N
N
O
O
O
HO
H
H
H
O
N
N
O
O
N
N
N
O
H
O
N
O
Ph
1
8
, 23 %
Scheme 7. Reaction with pyrroles.
Table 2 shows comparison of the additional properties
exhibited by our compounds with the general properties of
Instructively, our mini library has compounds with higher
fsp3, lower logP values, and a very small number of rotatable
bonds, thereby making the synthesised molecules attractive
candidates for fragment-based drug discovery approach that is
compounds appearing in Journal of Medicinal Chemistry pub-
lications in 2005–2009.
[3]

Photoassisted DOS: Post-Photochemical Modifications
G
O
7
6
.1
.8
13.6
4.0
1
N
1
1
0.6
1.4
O
O
N
H
H
N
H
H
Me
O
H
1
.6
8
.0
.8
HO
H
O
N
1.6
H
7
14.7
14.4
1
1
1.3
2.1
H
H
Me
4.5
4.8
11.2
11.2
O
H
c
O
HO
H
b
a
N
d
e
H 8.4
8.5
N
H
N
f
1.2
1.3
H
O
O
N
3.4
.5
H
3
N
O
N
H
O
N
Ph
H
H
O
11.2
11.4
N
H
1
3.5
13.5
O
O
Ph
rmsd ꢀ 0.36 Hz
mue ꢀ 0.81 Hz
H
C
HMBC
Fig. 5. Selected HMBC relationships between carbon and hydrogen atoms and comparison of calculated and
experimental SSCCs for compound 18.
Table 1. Tanimoto coefficients for the library of synthesised compounds
A
B
C
D
E
F
G
H
5
6
7
9
10
11
12؆
14
18
A
B
C
D
E
F
G
H
5
1
0.37
1
0.44
0.41
1
0.47
0.32
0.31
1
0.33
0.43
0.3
0.46
0.4
0.36
0.4
0.35
0.5
0.4
0.45
0.36
0.4
0.27
0.24
0.22
0.33
1
0.37
0.22
0.34
0.29
0.25
0.25
0.21
0.33
0.31
0.3
0.33
0.34
0.27
0.43
0.37
1
0.43
0.46
0.33
0.3
0.22
0.4
0.38
0.27
0.32
0.46
0.34
0.34
0.25
1
0.39
0.33
0.34
0.3
0.52
0.37
0.44
0.36
0.67
0.44
0.34
0.44
0.4
0.29
0.35
0.32
0.39
1
0.56
0.36
0.42
0.36
0.25
0.34
0.42
0.33
0.7
0.6
0.42
0.63
0.52
0.35
0.21
0.29
0.45
0.3
0.42
0.42
0.44
1
0.48
0.37
0.49
0.28
0.31
0.48
0.4
0.55
0.5
0.43
0.31
0.39
0.4
0.52
0.37
0.52
0.45
0.3
0.38
0.39
0.44
0.65
0.5
0.53
0.49
0.65
0.57
1
0.33
0.26
0.28
0.36
0.28
0.32
0.25
0.36
0.37
0.32
0.35
0.28
0.38
0.62
0.38
1
0.42
0.26
0.37
0.4
0.37
0.11
0.47
0.27
0.33
0.43
0.38
0.44
0.56
0.6
0.42
0.48
0.43
0.52
0.33
0.42
0.38
0.46
0.4
0.25
0.36
0.46
0.34
0.5
0.41
0.32
0.24
0.34
0.46
0.27
0.34
0.36
0.38
0.63
0.4
0.31
0.22
0.27
0.33
0.32
0.44
0.42
0.46
0.52
0.55
0.39
0.52
0.28
0.37
0.33
0.37
0.34
0.52
0.58
0.47
0.54
0.48
1
0.53
0.65
0.38
0.46
0.31
0.34
0.32
0.37
0.52
0.42
0.45
0.37
0.53
1
0.33
0.35
0.26
0.67
0.42
0.33
0.35
0.31
0.46
0.38
0.49
0.38
1
0.4
1
0.34
0.35
0.34
0.36
0.29
0.37
0.34
0.38
0.32
0.35
0.25
0.32
0.42
0.46
0.45
0.34
0.32
0.39
0.25
0.26
6
7
9
0.7
0.5
1
0.7
0.7
1
0.42
0.58
0.52
0.65
0.37
0.42
0.42
0.47
0.42
0.5
0.32
0.33
0.44
0.54
0.45
0.53
0.35
0.35
1
1
1
1
1
0
1
2؆
4
8
0.31
0.37
0.26
0.26
0.57
0.62
0.38
0.28
0.33
0.38
0.49
0.38
Table 2. Comparison of the computed properties of the synthesised library and compounds appearing in the Journal of Medicinal Chemistry
3]
[
publications in 2005–2009
MW, molecular weight; fsp3, see reference [8]; clogP, calculated logP; HB, hydrogen bonds; TPSA, total polar surface area
MW
fsp3
clogP
HB donors
HB acceptors
Rotatable bonds
TPSA
Average values for present synthesised mini library
374.51
403.29
0.43
0.34
1.71
3.1
1.22
1.77
5.83
4.24
0.94
6.33
78.66
87.05
Average values for compounds reported in J. Med. Chem.
[23]
gaining momentum. Synthesised polyheterocyclic sheets 11,
photogenerated azaxylylenes and experimentally simple and
straightforward post-photochemical modifications of the pri-
mary photoproducts.
0
1
feature somewhat similar to oxatriquinane motif found in
2 , and 14 have a ‘belt’ of polyacetal moieties – a structural
[
24]
[25]
biologically active gracilins J, K, H,
and novel non-peptide HIV-1 protease inhibitors from the
Ghosh laboratory.
paracaseolide A,
Experimental
[
26]
Common solvents were purchased from Pharmco and used as
received, except for THF, which was refluxed and distilled from
sodium benzophenone ketyl before use. Common reagents were
purchased from Aldrich and used without additional purifica-
tion, unless indicated otherwise. NMR spectra were recorded at
Conclusion
In conclusion, we have demonstrated that significant structural
diversity can be generated with a high steps per scaffold effi-
ciency via a combination of intramolecular cycloadditions of
258C on a Bruker Avance III 500 MHz in CDCl (unless noted
3

H
W. J. Umstead et al.
otherwise). X-Ray structures were obtained with a Bruker
APEX II instrument (for details see Supplementary Material).
High-resolution mass spectroscopy (HRMS) was conducted on
a MDS SCIEX/Applied Biosystems API QSTARTM Pulsar i
Hybrid LC/MS/MS System mass spectrometer from the
University of Colorado at Boulder. Flash column chromato-
graphy was performed using Teledyne Ultra Pure Silica Gel
anti-12-Hydroxy-16-methyl-15-phenyl-17,19-dioxa-5,16-
1
diazapentacyclo[11.5.1.0 .0 .0
,5 6,11 14,18
]nonadeca-6,8,10-trien-
4-one (7). Using 100 mg 1 (0.41 mmol) and 0.22 g N-oxide-N-
(phenylmethylene)-methanamine (1.6 mmol), the title compound
was isolated (98 mg, 63 %). d (CDCl , 500 MHz) 7.50 (1H, d,
H
3
J 8.0), 7.39 (4H, m), 7.32 (2H, m), 7.24 (2H, m), 4.59 (1H, d,
J 4.4), 4.38 (2H, m), 3.32 (1H, d, J 8.6), 2.87 (1H, m), 2.74 (1H, t,
J 7.5), 2.58 (2H, m), 2.43 (1H, m), 2.20 (3H, s). d (CDCl ,
(230–400 mesh) on a Teledyne Isco Combiflash R using
hexanes/ethyl acetate (EtOAc) as an eluent.
f
C
3
126 MHz) 173.9, 134.0, 133.6, 132.5, 129.5, 129.1, 128.7,
1
2
28.2, 127.8, 127.8, 127.1, 102.6, 84.2, 81.4, 79.5, 77.4, 61.2,
9.6, 27.1. m/z (HRMS ESI) 385.1724; [M þ Li]þ requires
Synthesis of Photoprecursor and Photoproducts
The compounds 3, 4, and 13 were synthesised as previously
described by our group. N-hydroxy-benzenecarboximidoyl
385.1740.
syn-12-Hydroxy-16-methyl-15-phenyl-17,19-dioxa-5,16-
1,5 6,11 14,18
[
10]
[15]
bromide, (1E)-N-phenyl-1-pyridin-2-ylmethanimine, and
diazapentacyclo[11.5.1.0 .0 .0
]nonadeca-6,8,10-trien-
[
11]
N-oxide-N-(phenylmethylene)-methanamine
according to the existing procedures.
were prepared
4-one (79). Using 100 mg 1 (0.41 mmol) and 0.22 g N-oxide-N-
(phenylmethylene)-methanamine (1.6 mmol) to generate title
compound (33.0 mg, 21 %). d (CDCl , 500 MHz) 7.55 (1H, dd,
H
3
Post-Photochemical Modifications
Addition of Nitile Oxide
J 8.0, 0.9), 7.39 (6H, m), 7.25 (2H, m), 4.33 (1H, d, J 7.0), 4.19
2H, m), 3.61 (1H, d, J 7.7), 2.92 (1H, m), 2.81 (1H, t, J 7.4),
2.68 (1H, m), 2.58 (3H, s), 2.54 (1H, m). d (CDCl ,
3
(
General Procedure I. Typically, 1 equiv. photoproduct
was dissolved in EtOAc, followed by addition of 3 equiv.
N-hydroxy-benzenecarboximidoyl bromide and 6 equiv.
C
126 MHz) 173.9, 135.8, 133.9, 133.8, 132.5, 129.4, 128.9,
128.3, 128.2, 128.0, 126.8, 103.6, 83.9, 78.7, 77.7, 75.4, 55.9,
þ
KHCO . Additional 3 equiv. N-hydroxy-benzenecarboximidoyl
3
43.6, 29.9, 26.7. m/z (HRMS ESI) 385.1724; [M þ Li]
bromide and 6 equiv. KHCO were added after stirring for 12 h.
3
requires 385.1740.
Ethyl13-Chloro-4-oxo-16-oxa-5-azatetracyclo[10.3.1.0 .
1
,5
The reaction was monitored by NMR until the starting photo-
product was consumed. The resulting mixture was diluted with
water, extracted with EtOAc (3 ꢁ 20 mL), washed with brine,
dried over Na SO , and concentrated under vacuum. The
6
0
,11
]hexadeca-6,8,10,14-tetraene-13-carboxylate (9). The
following procedure was used: 0.14 g 5 (0.58 mmol) was dis-
solved in 50 mL chloroform. To this solution, 30 mg tetrabutyl-
ammonium hydrogen sulfate (0.084 mmol) and 10 mL NaOH
solution (50 % w/w) were added. The mixture was vigorously
stirred at ambient temperature for 20 h, then poured into 200 mL
water and extracted with CHCl
ed, dried over anhydrous Na
vacuum. The mixture was purified by flash chromatography to
yield the title compound (0.12 g, 66 %). d (CDCl , 500MHz)
2
4
mixture was then purified by flash chromatography.
2-Hydroxy-15-phenyl-17,19-dioxa-5,16-diazapentacyclo
1
1
,5 6,11 14,18
[
11.5.1.0 .0 .0
General procedure I was followed using 0.25 g 1 (1.0 mmol),
.2 g N-hydroxy-benzenecarboximidoyl bromide (6.2 mmol),
and 1.2 g KHCO (12.3 mmol) to generate the title compound
]nonadeca-6,8,10,15-tetraen-4-one (6).
. The organic layer was separat-
3
1
2
SO , and concentrated under
4
3
(
0.15 g, 61 %). d (CDCl , 500 MHz) 7.65 (2H, m), 7.57 (1H,
H
H
3
3
dd, J 8.4, 1.3), 7.48 (5H, m), 7.35 (1H, m), 4.86 (1H, d, J 8.8),
.78 (2H, m), 3.87 (1H, dd, J 8.8, 1.0), 2.88 (2H, m), 2.77 (1H, dt,
8.42 (1H, dd, J 8.3, 1.0), 7.38 (1H, ddd, J 8.7, 7.5, 1.6), 7.19 (1H,
dd, J 8.0, 1.4), 7.09 (1H, td, J 7.7, 1.3), 6.38 (1H, dd, J 9.9, 1.2),
5.83 (1H, d, J 9.9), 5.47 (1H, s), 4.27 (2H, m), 2.74 (2H, m), 2.42
4
J 14.1, 9.9), 2.66 (1H, ddd, J 16.7, 9.5, 0.9), 2.46 (1H, ddd,
J 14.1, 8.8, 1.0). d (CDCl , 126 MHz) 173.8, 156.3, 133.4, 133.1,
(2H, m), 1.30 (3H, t, J 7.2). d (CDCl , 126 MHz) 170.8, 167.3,
C 3
C
3
1
8
32.6, 130.7, 129.9, 129.2, 128.5, 127.6, 127.5, 126.7, 104.9,
8.1, 82.2, 77.6, 56.3, 29.4, 27.2. m/z (HRMS ESI (electrospray
133.1, 129.7, 126.9, 126.8, 126.4, 123.8, 120.4, 119.9, 85.9, 77.3,
64.2, 62.9, 30.3, 29.9, 13.8. m/z (HRMS ESI) 340.0920; [M þ
þ
þ
ionisation)) 369.1405; [M þ Li] requires 369.1427.
Li] requires 340.0928.
14-Hydroxy-11-(pyridin-2-yl)-2-oxa-10,21-diazahexacyclo
1
2-Hydroxy-15-phenyl-17,19-dioxa-5,16-diazapentacyclo
1
,5 6,11 14,18
1,21 3,12 4,9 15,20
[11.11.0.0 .0 .0 .0
[
11.6.0.0 .0 .0
General procedure I was followed using 0.25 g 2 (1.0 mmol),
.2 g N-hydroxy-benzenecarboximidoyl bromide (6.1 mmol),
and 1.2 g KHCO (12.4 mmol) to generate the title compound
]nonadeca-6(11),7,9,15-tetraen-4-one (5).
]tetracosa-4(9),5,7,15,17,19-
hexaen-22-one (10). The following procedure was used:
0.22 g (1E)-N-phenyl-1-pyridin-2-ylmethanimine (1.2 mmol)
and 0.15 g 4 (0.61 mmol) were dissolved in 1.5 mL 2,2,2-
trifluoroethanol and warmed to 408C until the reaction was
1
3
(0.14 g, 59 %). d (CDCl , 500 MHz) 7.98 (1H, d, J 8.0), 7.73
H 3
1
(
7
2H, m), 7.54 (3H, m), 7.49 (1H, td, J 7.9, 1.5), 7.46 (1H, dd, J
.5, 1.3), 7.27 (1H, td, J 7.5, 1.2), 5.81 (1H, d, J 6.2), 4.97 (1H, d,
J 3.0), 3.84 (1H, dd, J 6.2, 3.3), 3.29 (1H, t, J 3.1), 2.84 (1H, m),
complete as observed by H NMR analysis. The resulting
mixture was concentrated under vacuum and purified by flash
chromatography, yielding the title compound (80 mg, 31 %).
d (CDCl , 500 MHz) 8.74 (1H, ddd, J 4.9, 1.8, 0.9), 7.88 (1H,
H 3
td, J 7.7, 1.8), 7.85 (1H, d, J 8.1), 7.57 (1H, d, J 7.9), 7.39 (3H,
m), 7.17 (3H, td, J 7.6, 1.0), 7.11 (2H, td, J 7.5, 1.1), 6.85 (1H, td,
J 7.5, 1.2), 6.77 (2H, dd, J 7.4, 1.1), 5.25 (1H, d, J 7.7), 4.82 (1H,
d, J 1.4), 4.65 (1H, s), 3.38 (1H, dd, J 10.4, 2.5), 3.10 (1H, d, J
2
1
1
.40 (3H, m). d (CDCl , 126 MHz) 173.3, 158.7, 134.5, 130.8,
C
3
30.0, 129.8, 129.2, 128.7, 127.7, 127.1, 125.5, 122.9, 107.0,
01.4, 70.7, 57.1, 55.1, 34.1, 30.1. m/z (HRMS ESI) 369.1407;
þ
[M þ Li] requires 369.1427.
Nitrone Cycloadditions
2
.5), 2.69 (1H, ddd, J 16.3, 10.9, 8.2), 2.54 (1H, ddd, J 10.4, 7.9,
In a typical procedure, 1 equiv. photoproduct was dissolved
2.5), 2.18 (1H, dd, J 16.6, 8.6), 2.06 (1H, ddd, J 12.4, 10.9, 8.8),
1.68 (1H, dd, J 12.6, 8.0). d (CDCl , 126 MHz) 173.7, 159.2,
in 1 mL anhydrous toluene and 4 equiv. N-oxide-N-
phenylmethylene)-methanamine. The reaction was sealed in a
high-pressure reaction vessel and heated to completion as
C
3
(
149.5, 143.4, 137.1, 134.0, 130.6, 130.0, 129.9, 128.9, 128.6,
125.5, 123.8, 123.1, 121.6, 120.8, 119.3, 115.6, 100.2, 77.2,
74.7, 70.2, 56.6, 50.5, 45.9, 36.0, 29.9. m/z (HRMS ESI)
1
confirmed by H NMR analysis. The toluene was removed
under vacuum and the residue purified by flash chromatography.
þ
432.1889; [M þ Li] requires 432.1900.

Photoassisted DOS: Post-Photochemical Modifications
I
Oxa-Diels–Alder Reactions
used: 0.10 g (S)-N-(2-acetylphenyl)-3-phenyl-2-(1H-pyrrol-1-
yl)propanamide (15) (0.3 mmol) was dissolved in 1.5 mL
DMSO. This was degassed and irradiated in a Pyrex reaction
vessel under LED-365 until the reaction was complete, as
General Procedure II. Typically, 1 equiv. photoproduct and
1
equiv. 1,3-dicarbonyl compound were dissolved in 0.7 mL
dry acetonitrile. To this solution, 0.08 equiv. L-proline and
.3 equiv. 37 % aqueous formaldehyde solution were added.
1
determined by H NMR analysis. The solution was then added
1
directly to 0.05 g 1,3-dimethylbarbituric acid (0.3 mmol). To
this solution, 3.0 mg L-proline (0.024 mmol), and 0.03 mL
formaldehyde solution (37 % w/w) in water (0.39 mmol) were
added. The reaction was heated to 708C until complete con-
The reaction was stirred at ambient temperature until complete
1
consumption of the photoproduct, as determined by H NMR
analysis. The reaction was diluted with water and extracted with
EtOAc. The organic layer was separated, dried over Na SO ,
2
4
1
sumption of the photoproduct, as determined by H NMR
and concentrated under vacuum. The mixture was then purified
by flash chromatography.
analysis. The reaction was diluted with water and extracted with
EtOAc. The organic layer was separated, dried over Na SO ,
and concentrated under vacuum. The mixture was then purified
1
2-Hydroxy-16-methylidene-18,20-dioxa-5-azapentacyclo
2
4
1
,5 6,11 14,19
[
11.7.0.0 .0 .0
General procedure II was followed using 0.10 g 2 (0.41 mmol),
.06 g of Meldrum’s acid (0.41 mmol), 3.8 mg L-proline
0.033 mmol), and 0.04 mL formaldehyde solution (37 % w/w)
in water (0.53 mmol) to generate the title compound (52 mg,
5 %). d (CDCl , 500 MHz) 7.82 (1H, d, J 8.0), 7.42 (1H, td,
]icosa-6,8,10-triene-4,17-dione (129).
by flash chromatography, yielding the title compound (46 mg,
23 %). d (CDCl , 500 MHz) 8.63 (1H, dd, J 8.3, 1.2), 7.58 (1H,
H 3
dd, J 7.8, 1.5), 7.37 (1H, ddd, J 8.5, 7.3, 1.6), 7.19 (6H, m), 5.04
0
(
(1H, d, J 4.5), 4.34 (1H, d, J 11.1), 3.76 (1H, dd, J 11.2, 3.4), 3.40
(3H, s), 3.27 (3H, s), 3.22 (3H, s), 3.17 (1H, dd, J 10.6, 4.5), 2.99
(3H, s), 2.96 (1H, dd, J 13.6, 3.4), 2.78 (1H, dd, J 13.5, 11.3),
3
H
3
J 7.7, 1.5), 7.33 (1H, d, J 7.3), 7.21 (1H, td, J 7.7, 1.2), 6.59 (1H,
s), 5.77 (1H, s), 5.66 (1H, d, J 4.8), 4.64 (1H, d, J 2.4), 2.89 (1H,
dd, J 11.0, 2.5), 2.75 (3H, m), 2.47 (1H, dd, J 12.6, 8.4), 2.35
2.75 (1H, dd, J 13.5, 11.3), 2.53 (1H, qd, J 11.2, 7.2), 2.52, (1H,
d, J 14.8), 2.45 (1H, dd, J 13.6, 7.1), 2.32 (1H, d, J 14.8), 2.04
(1H, s), 1.65 (3H, s). d (CDCl , 126 MHz) 173.6, 172.1, 171.3,
C 3
(1H, tdd, J 12.7, 9.8, 1.7), 2.23 (1H, dt, J 16.4, 8.1), 2.16 (1H,
dtd, J 11.3, 4.7, 2.6). d ( CDCl , 126 MHz) 173.7, 173.7, 163.5,
1
1
5
70.7, 170.6, 150.7, 150.3, 138.2, 132.4, 130.4, 129.7, 128.8,
27.8, 126.6, 126.1, 124.7, 117.9, 78.3, 71.9, 71.5, 66.7, 56.0,
3.3, 51.4, 39.1, 37.1, 36.5, 36.0, 34.6, 29.4, 29.4, 29.3, 29.1. m/z
C
3
1
1
3
33.4, 130.9, 130.0, 130.0, 129.8, 129.3, 125.9, 123.8, 102.9,
02.0, 68.8, 51.7, 40.4, 35.8, 29.6, 27.3. m/z (HRMS ESI)
þ
þ
(HRMS ESI) 675.2742; [M þ Li] requires 675.2755.
34.1253; [M þ Li] requires 334.1267.
1
4-Hydroxy-6,8-dimethyl-2,4-dioxa-6,8,21-triazahexacyclo
1
,21 3,12 5,10 15,20
Supplementary Material
[11.11.0.0 .0 .0 .0
]tetracosa-5(10),15,17,19-tetraene-
,9,22-trione (11). General procedure II was followed using
00 mg 2 (0.41 mmol), 0.064 g 1,3-dimethylbarbituric acid
7
1
NMR spectra and X-ray structures (33 pages) are available on
the Journal’s website.
(
0.41 mmol), 3.8 mg L-proline (0.033 mmol), and 0.04 mL form-
aldehyde solution (37 % w/w) in water (0.53 mmol) to generate
the title compound (76 mg, 45 %). d (CDCl , 500 MHz) 7.89
Acknowledgement
H
3
Support of this research by the National Science Foundation (NSF CHE-
(1H, d, J 8.0), 7.48 (1H, td, J 7.8, 1.6), 7.36 (1H, dd, J 7.5, 1.5),
1
362959) and National Institutes of Health (NIH GM093930) is gratefully
7
3
2
.26 (1H, td, J 7.4, 1.2), 5.57 (1H, d, J 4.0), 4.79 (1H, d, J 2.6),
.42 (3H, s), 3.39 (3H, s), 2.90 (1H, m), 2.85 (1H, dd, J 11.6,
.6), 2.77 (1H, d, J 17.1), 2.56 (1H, dd, J 17.1, 6.5), 2.42
acknowledged.
References
(4H, m), 2.16 (1H, dddd, J 11.6, 6.5, 4.0, 1.4). dC (CDCl3,
[
1] In 2013 the R&D spending in the US pharmaceutical industry totalled
51.1 billion, the financial support for the medical research by NIH
1
1
2
26 MHz) 173.4, 163.0, 154.0, 151.0, 133.2, 130.3, 129.8,
29.1, 126.1, 124.0, 102.1, 100.0, 82.5, 69.2, 51.6, 39.6, 36.5,
9.6, 28.7, 28.1, 18.1. m/z (HRMS ESI) 418.1571; [M þ Li]þ
$
made another $30.3 billion. http://www.nih.gov/about/budget.htm,
http://www.statista.com/study/10708/us-pharmaceutical-industry-
statista-dossier/.
requires 418.1591.
1
cyclo[11.11.0.0 .0 .0 .0
tetraene-7,9,22-trione (14). General procedure II was followed
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