Conformationally constrained penta(hetero)cyclic molecular architectures by photoassisted diversity-oriented synthesis

Article abstract of DOI:10.1002/ejoc.201403620

Intramolecular cycloadditions of photogenerated azaxylylenes provide access to unprecedented polyheterocyclic scaffolds, which are suitable for subsequent postphotochemical modifications to further grow molecular complexity. Here, we explore approaches to the rapid "assembly" of new photoprecursors with nitrogen- or oxygen-rich tethers capable of producing potential pharmacophores and also compatible with subsequent 1,3-dipolar cycloadditions to furnish pentacyclic heterocycles with new structural cores, a minimal number of rotatable bonds, and a high content of sp³-hybridized carbon atoms. The modular assembly of the photoprecursors and the potential variety of postphotochemical modifications of the primary photoproducts provide a framework for the combinatorial implementation of this synthetic strategy.

Full text of DOI:10.1002/ejoc.201403620

FULL PAPER
DOI: 10.1002/ejoc.201403620
Conformationally Constrained Penta(hetero)cyclic Molecular Architectures by
Photoassisted Diversity-Oriented Synthesis
[a]
[a]
[a]
Weston J. Umstead, Olga A. Mukhina, and Andrei G. Kutateladze*
Keywords: Photochemistry / Cycloaddition / Nitrogen heterocycles / Molecular diversity
Intramolecular cycloadditions of photogenerated azaxylyl- cyclic heterocycles with new structural cores, a minimal
3
enes provide access to unprecedented polyheterocyclic scaf-
folds, which are suitable for subsequent postphotochemical
modifications to further grow molecular complexity. Here, we
explore approaches to the rapid “assembly” of new photo-
precursors with nitrogen- or oxygen-rich tethers capable of
producing potential pharmacophores and also compatible
with subsequent 1,3-dipolar cycloadditions to furnish penta-
number of rotatable bonds, and a high content of sp -hy-
bridized carbon atoms. The modular assembly of the photo-
precursors and the potential variety of postphotochemical
modifications of the primary photoproducts provide a frame-
work for the combinatorial implementation of this synthetic
strategy.
Introduction
it has been pointed out that it is the limited diversity of
scaffolds that may be one of the underlying reasons. Only
To date, the Chemical Abstracts Service (CAS) registry
contains more than 85 million substances.[ In 1965, a little
over 200 thousand new substances were added to the CAS.
In stark contrast, 2007 saw this number exceed 4 million,
of which over 3 million were small molecules.[ This awe-
inspiring growth is in sharp contrast with the number of
new molecular entities approved by the U.S. Food and Drug
Administration (FDA): a total of 1513 as of 2011. The
annual approval rate has not changed significantly with the
explosive developments in organic synthesis and has only
fluctuated between 20–40 entities annually during the last
decade.
As the search for new drug candidates is the most com-
mon motive to rationalize the expansion of modern combi-
natorial methods of synthesis, it is not surprising that the
apparent gap between the huge number of new synthetic
compounds and the tiny trickle of new molecular entities
that actually get approved by the FDA has worried many
in the field. Some lamented that combinatorial chemists
have been perhaps synthesizing mostly the wrong stuff, “this
apparent lack of productivity ... may in part reflect signifi-
cant deficiencies in the types of chemical structures gener-
ated using combinatorial approaches.”[ Hence, a vast
number of studies have focused on inspecting the differ-
ences between the structures of approved drugs and combi-
natorial libraries or libraries of natural products. Notably,
1
43 framework shapes account for approximately half of
1]
[5]
the compounds in the CAS registry, and half of the
36708 known frameworks are only present in one com-
8
pound. This limited diversity is also reflected in the struc-
tures of drugs, and the top 50 frameworks cover 48–52% of
2]
[6–8]
approved and experimental drugs.
There are additional problems associated with the struc-
[
3]
[4]
tures generated by combinatorial synthesis. First, accord-
[9,10]
ing to several studies,
the distributions of heteroatoms
in drugs, natural products, and compounds in combinato-
rial libraries differ significantly. On average, drugs and natu-
ral products have more oxygen atoms and fewer nitrogen
atoms per molecule than compounds in combinatorial li-
braries. Second, there are generally fewer rotatable bonds
in natural products and drugs than there are in compounds
in combinatorial libraries. Conformationally constrained
molecules are less vulnerable to entropic losses and often
possess tighter KD values compared with those of flexible
ligands that can form similar arrays of hydrogen bonds and
hydrophobic interactions with proteins.
The extended 3D architectures of the molecules (as op-
posed to the “flat land” of polyaromatic beads) were also
scrutinized in the context of drug design and discovery.
4]
[
11]
Lovering and coauthors, who proposed a simple satura-
3
tion parameter, fsp , demonstrated with convincing statis-
tics that increasing the saturation improves the clinical suc-
cess of drug candidates. They point out, “Advances over the
[
a] Department of Chemistry and Biochemistry,
2
2
last 10–15 years in the coupling of sp –sp carbons, as well
University of Denver,
2
Denver, CO 80208, USA
as other sp couplings, have made the preparation of mol-
E-mail: akutatel@du.edu
ecules with greater unsaturation particularly amenable to
parallel synthesis. While these advances have contributed to
drug discovery, they have also biased efforts at the bench.”
http://kgroup.du.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403620.
Eur. J. Org. Chem. 2015, 2205–2213
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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W. J. Umstead, O. A. Mukhina, A. G. Kutateladze
FULL PAPER
How do we unbias the effort at the bench without throw-
The essential aspect of this general methodology is the
ing out the baby with the water? Our approach has been to high availability of simple linear photoprecursors, which are
employ the modular “assembly” of photoprecursors from “pre-assembled” in facile and high-yielding chemical cou-
simple starting blocks through straightforward and high- pling reactions that are generally compatible with robotic-
yielding coupling reactions, including the abovementioned assisted combinatorial chemistry methods, for example,
2
2
efficient sp –sp carbon coupling reactions or other high- amide bond formation. These photoprecursors then un-
yielding reactions such as amide bond formation. Subse- dergo efficient photoinduced intramolecular cycloadditions
quent irradiation then triggers intramolecular photocycliza- with quantum yields of up to Φ = 0.75 to provide access to
[
15]
tions in these unsaturated photoprecursors. Typically, the new molecular architectures. The primary photoproducts
photochemical step imparts a spectacular increase in molec- necessarily possess higher saturation and semirigid three-
ular complexity and yields new polyheterocyclic molecular dimensional architectures but also contain reactive unsatu-
architectures with extended three-dimensional topologies, a rated moieties, which make them amenable to postphoto-
reduced number of rotatable bonds, and elevated saturation. chemical modifications for further growth of the complex-
As the selection rules for photoinduced cyclizations are very ity, increased saturation, and access to even more elaborate
[
15,16]
different from those for ground-state cycloadditions, one 3D frameworks.
For example, for pyrrole-tethered un-
gains access to polycyclic cores that are not available by saturated pendant moieties, the primary photoproduct pos-
conventional methodologies. In this context, photochemis- sesses a pyrroline ring, that is, a reactive enamine moiety,
try is a unique tool to overcome the limited diversity of which is captured in high-yielding reactions with sulfonyl
structural frameworks. Coupled with postphotochemical azides or activated in the presence of protic acids or carbon
modifications of the reactive unsaturated moieties in the electrophiles to form iminium intermediates and further
primary photoproducts, it becomes an even more powerful trapped with appropriate external or internal nucleo-
[
13]
tool in chemical and biological space exploration. The aim philes.
of this article is to show how photochemical methods with Although pyrrolines offered a ready postphotochemical
postphotochemical modifications can be applied to the syn- modification opportunity owing to the high reactivity of
thesis of a library of diverse heteroatom-rich polyhetero- the enamine moiety, another series of primary photoprod-
cycles with a limited number of rotatable bonds and rela- ucts based on furan pendant arms proved more difficult to
3
tively high saturation, that is, the Lovering fsp parameter. modify. The [4+4] adducts, that is, azacanes, which contain
The main focus of the research efforts in our laboratory an alkenyl moiety as a part of an oxabicyclo[4.2.1] core,
in recent years has been the utilization of azaxylylenes, gener- proved unreactive under classical electrophilic addition re-
ated by excited-state intramolecular proton transfer (ESIPT) actions. The [4+2] primary photoproducts, which contain a
in aromatic o-amino ketones, in intramolecular [4+4] or very reactive dihydrofuran moiety, were extremely labile
[
4+2] cycloaddition reactions to tethered unsaturated moie- and did not survive even mildly acidic conditions. In this
[12,13]
ties, namely, alkenes, furans, thiophenes, and pyrroles,
paper, we engage the primary photoproducts in postphoto-
chemical cycloaddition reactions to gain access to new
to yield new N,O,S polyheterocycles (Scheme 1).[
14]
Scheme 1. Intramolecular cycloadditions of photogenerated azaxylylenes.
206
2
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Conformationally Constrained Penta(hetero)cycles
polyheterocyclic molecular architectures and assess the ap- photogenerated azaxylylenes. Therefore, the tether is set to
plicability and appeal of these transformations in the con- introduce an additional heterocyclic ring in the photoprod-
text of photoassisted diversity-oriented synthesis.[
17]
uct. We focused on reactive carbonyl derivatives such as iso-
The other issue is the nature of the tether linking the cyanates or chloroformates, which are capable of straight-
photoactive amino ketone moiety with the unsaturated pen- forward coupling with aromatic amino ketones (Scheme 2).
dant arm. As a result of the photoinduced intramolecular The o-amino ketones 1a–1c were treated with furfuryl iso-
cyclization of the photogenerated azaxylylene, a polyhetero- cyanate (2), furoyl isocyanate [3Ј, formed in situ from furoyl
[
18]
cyclic scaffold is generated, in which the tether forms ad- chloride (3)],
ditional ring(s) that could be decorated with diverse func- situ from furfuryl alcohol (4)].
tional groups or heterocyclic pendants. As we searched for The yields ranged from moderate to good. Benzaldehyde
or furfuryl chloroformate [4Ј, formed in
[
19]
simple and efficient coupling reactions to assemble the derivatives, such as 7d, were obtained in two steps from
photoprecursors, we explored the reactions of o-ketoanil- amino alcohol 1d, which was first coupled to the furanyl
ines with isocyanates, including acyl isocyanates, to form moiety and subsequently oxidized by pyridinium chloro-
urea-based linkers, which upon irradiation introduce ad- chromate (PCC) into the photoactive amidobenzaldehyde.
ditional heterocyclic moieties such as hydantoins fused to With the exception of this case, the photoprecursor synthe-
the quinolinole or benzazocane cores. Again, this supple- sis proceeds in just one simple step from readily available
mentary diversity input allows increased complexity of the starting materials; therefore, this modular assembly of pho-
polyheterocyclic targets and enhances the systematic explo- toprecursors is amenable to robotic automation.
ration of the chemical space in the context of photoassisted
diversity-oriented synthesis.
The photoprecursors obtained in these reactions were
subsequently irradiated in a Rayonet photoreactor equipped
with RPR-3500 UV lamps to furnish quinolinols or benz-
azacanes with fused cyclic ureas, hydantoins, and cyclic
carbamates (Scheme 3, isolated yields are shown). Solvent
optimization revealed that methanol is the best solvent for
Results and Discussion
The first objective of this study was to diversify the tether irradiation. After irradiation, the reaction mixtures were
linking the photoactive aromatic amino ketone core with chromatographed to obtain pure products.
the unsaturated furan-based pendant arm by introducing
The ratio of the [4+4] to [4+2] products is noticeably af-
heteroatoms into it and then to evaluate the scope of intra- fected by the nature of the linker. In the hydantoin and
molecular [4+4] and [4+2] cycloaddition reactions of such imidazolidinone cases, the [4+4] product is formed prefer-
Scheme 2. Modular assembly of photoprecursors containing urea, acylurea, and urethane linkers.
Eur. J. Org. Chem. 2015, 2205–2213
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W. J. Umstead, O. A. Mukhina, A. G. Kutateladze
FULL PAPER
Scheme 4. Silica-gel-induced transformations in photoproducts 8c
and 9b.
initially explored and optimized with model compounds 14
and 15, which were synthesized according to the previously
[
12]
published procedures (Scheme 5). In both cases, the 1,3-
dipolar cycloaddition of bromonitrile oxide occurs from the
exo face. The [4+2] primary photoproduct reacted with
bromonitrile oxide in a regiospecific fashion to afford 16
(
structure determined by X-ray crystallography), whereas
the [4+4] photoproduct produced both regioisomers, 17 and
8, in a 1:4 ratio. The observed differences can be explained
1
by the stereoelectronic properties of the alkenes: the [4+2]
photoproduct is a vinyl ether, and the 1,3-dipolar cyclo-
Scheme 3. Products of photoinduced cycloadditions.
entially, whereas the [4+2] cycloaddition product is pre-
dominant for oxazolidinone. This trend is most pronounced
for tetralone-based photoprecursors 5b and 7b, each of
which gives only one product upon irradiation: the [4+4]
cycloadduct for 5b or the [4+2] cycloadduct for 7b. Notably,
both the [4+2] and the [4+4] photoproduct are formed as
single diastereomers, syn-[4+4] and anti-[4+2]; syn and anti
refer to the respective arrangement of the benzylic hydroxy
group in the quinolinol or benzoazacane ring and the furan
oxygen atom. The structures and stereochemistries of the
products were determined by NMR spectroscopy and were
consistent with our previous findings.[ Additionally, for
12]
11a, 11b, and 13d, (and also 16 and 21, see below) X-ray
structures were obtained.
Two of the photoproducts underwent further transfor-
mations upon chromatography. The indanone-based [4+2]
photoproduct 8c was subjected to an eliminative opening of
the N,O-ketal to afford product 8cЈ upon chromatography
(Scheme 4), and the [4+4] adduct 9b underwent the
[
4.2.1]Ǟ[3.3.1] rearrangement of its 2,5-epoxyazacane core
[20]
to yield the oxabicyclo[3.3.1]nonene scaffold.
The second objective of this study was to explore the
feasibility of facile postphotochemical modifications of the
newly generated cyclic alkenes in ground-state cycload-
dition reactions. In this context, further elaboration of the
molecular architectures was achieved by reacting the [4+4]
and [4+2] photoproducts with bromonitrile oxide generated
Scheme 5. Postphotochemical 1,3-dipolar cycloadditions to the pri-
mary photoproducts. [a] Minor regioisomer 17 was observed by
in situ from dibromoformaldoxime.[21] This reaction was NMR spectroscopy.
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Conformationally Constrained Penta(hetero)cycles
Scheme 6. 1,3-Dipolar cycloadditions to hydantoins 10a and 11a. [a] Minor regioisomer 23 was observed by NMR spectroscopy.
addition is expected to proceed through a charge-controlled the one with the greater chemical shift would belong to Hb,
transition state, whereas the double bond in the [4+4] geminal to the oxygen atom of the oxazoline ring. Upon
substrate is not as polarized, so both regioisomers are ob- irradiation of the methyl group, which is a singlet at δ =
served.
1.71 ppm, only the proton at δ = 4.92 ppm is affected with
The regiochemistry of the major product was determined a NOE enhancement of 2.4%. Thus, in this case, the elec-
by the analysis of spin–spin coupling constants and a NOE trostatic effect of lone-pair repulsion from the carbonyl
experiment. Proton H is characterized by a doublet at δ = oxygen atom overrides the stereochemical preferences. The
a
3
4
.71 ppm with J = 8.7 Hz, whereas H is represented by a observed relative stability trend is again consistent with our
b
3
doublet of doublets at δ = 3.75 ppm with J = 8.7 and DFT calculations. According to B3LYP/6-31G(d) calcula-
.0 Hz; the second constant reflects the interaction with Hc. tions, regioisomer 22 is 0.75 kcal/mol lower in energy than
Upon irradiation of the proton at δ = 3.75 ppm, a NOE of regioisomer 23. Provided that the transition state in these
1
4.6% is observed for the doublet of doublets at δ = 1,3-dipolar cycloadditions is late, the relative product sta-
4
.64 ppm belonging to H . Instructively, according to DFT bility tracks the relative height of the activation barrier.
d
calculations, the major isomer, 17, is 2 kcal/mol higher in
energy than 18, possibly owing to the unfavorable steric in-
teraction of the Br atom with the methylene group in the
dimethylene linker.
When α,β-unsaturated ketone 19, derived from the [4+4]
photoproduct 15 through the [4.2.1]Ǟ[3.3.1] rearrange-
ment and Swern oxidation, was used as a substrate in the
postphotochemical 1,3-dipolar cycloaddition, we obtained
dibromoisoxazoline 20Ј (Scheme 5). Clearly, the initially
formed isoxazoline 20 underwent additional bromination
under the reaction conditions. We hypothesize that the 1,3-
dipole precursor, dibromoformaldoxime, used in excess can
brominate the relatively stable conjugated enolate moiety of
Conclusions
We have developed a method for the photochemically as-
sisted assembly of fused hydantoins, imidazolines, and ox-
azolidinones by diversifying the tether that links the photo-
active aromatic amino ketone core to the unsaturated
furan-based pendant group. The primary photoproducts
were amenable to postphotochemical transformations to
yield complex penta(hetero)cyclic molecular architectures
characterized by a minimal number of rotatable bonds and
a high content of sp -hybridized carbon atoms (fsp ≈ 0.4).
The resulting molecular polycyclic cores could be further
decorated with functional groups or additional heterocyclic
pendants, as the bromine atom in the 3-bromoisoxazoline
moiety is readily replaced with carbon nucleophiles.[
3
3
20.
We then moved from the model compounds 14 and 15
to photoproducts 10a and 11a, which contain hydantoin
moieties (derived from photoprecursor 6a; Scheme 6). Simi-
larly to the model system, we observed exo stereochemistry
for the nitrile oxide addition. The [4+2] photoproduct again
22]
gave only one regioisomer, 21 (structure determined by X- Experimental Section
ray crystallography), whereas the [4+4] photoproduct gave
two regioisomers. However, their 5:1 ratio is now reversed,
and 22 is the major product. Compound 22 is characterized
Common solvents were purchased from Pharmco and used as is,
except for tetrahydrofuran (THF), which was heated under reflux
over potassium benzophenone ketyl and distilled before use. Com-
by two doublets with the common spin–spin coupling con- mon reagents were purchased from Aldrich and used without ad-
stant of 8.8 Hz at δ = 4.92 and 3.85 ppm. It is assumed that ditional purification, unless indicated otherwise. NMR spectra
Eur. J. Org. Chem. 2015, 2205–2213
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2209

W. J. Umstead, O. A. Mukhina, A. G. Kutateladze
FULL PAPER
were recorded at 25 °C with a Bruker Avance III 500 MHz spec-
trometer with samples in dimethyl sulfoxide (DMSO), unless noted
otherwise. The X-ray structures were obtained with a Bruker
APEX II instrument (for details see Supporting Information and
included cif files). High resolution mass spectra were obtained with
a MDS SCIEX/Applied Biosystems API QSTARTM Pulsar i
Hybrid LC/MS/MS system by Dr. Jeremy Balsbaugh from the Uni-
versity of Colorado at Boulder. Flash column chromatography was
vacuo to yield the product, which was used in the next step without
further purification.
1
-(2-Furylmethyl)-3-(4-oxotetralin-5-yl)urea (5b): General pro-
cedure B was followed. From 8-aminotetralone (0.65 g, 4.1 mmol,
equiv.) and furfuryl isocyanate (0.5 g, 4.1 mmol, 1 equiv.), the title
1
1
compound was obtained (0.79 g, 68%). H NMR (500 MHz,
CDCl ): δ = 11.68 (s, 1 H), 8.46 (dd, J = 8.6, 1.1 Hz, 1 H), 7.41
dd, J = 8.6, 7.5 Hz, 1 H), 7.37 (dd, J = 1.9, 0.8 Hz, 1 H), 6.82 (dd,
3
(
f
performed with a Teledyne Isco Combiflash R system with Tele-
J = 7.5, 1.1 Hz, 1 H), 6.33 (dd, J = 3.3, 1.9 Hz, 1 H), 6.29 (m, 1
H), 5.30 (t, J = 5.8 Hz, 1 H), 4.49 (d, J = 5.7 Hz, 2 H), 2.95 (t, J
dyne Ultra Pure Silica Gel (230–400 mesh) and hexanes/EtOAc as
the eluent.
1
3
=
6.1 Hz, 2 H), 2.66 (m, 2 H), 2.07 (m, 2 H) ppm. C NMR
): δ = 203.5, 154.7, 151.8, 145.8, 143.8, 142.2,
1039244 (for 16), and -1039245 (for 21) contain the supplementary 135.1, 121.1, 117.5, 117.2, 110.4, 107.3, 40.7, 37.3, 31.0, 22.8 ppm.
CCDC-1039241 (for 11a), -1039242 (for 11b), -1039243 (for 13d), (126 MHz, CDCl
-
3
16 2 3
H N O
[M + H]+ 285.1239; found
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
HRMS (ESI): calcd. for C16
285.1248.
1-(2-Furylmethyl)-3-(3-oxoindan-4-yl)urea (5c): General procedure
General Procedure A for the Synthesis of Compounds 6:[18] Sodium
cyanate (1.3 equiv.) was suspended in 1,2-dichlorobenzene (2 mL).
Under nitrogen, 2-furoyl chloride (1 equiv.) and tin(IV) chloride
B
was followed. From 7-amino-2,3-dihydro-1H-inden-1-one
(
3
0.50 g, 3.4 mmol, 1 equiv.) and furfuryl isocyanate (0.42 g,
.4 mmol, 1 equiv.), the title compound (0.71 g, 77%) was ob-
1
tained. H NMR (500 MHz, DMSO): δ = 9.51 (s, 1 H), 8.19 (t, 1
H), 8.16 (d, J = 8.3 Hz, 1 H), 7.60 (dd, J = 1.9, 0.9 Hz, 1 H), 7.52
(0.05–0.15 equiv.) were added. Upon complete addition, the reac-
tion mixture was heated under reflux for 3 h and then cooled to
ambient temperature. The corresponding amine (0.3–1.0 equiv.)
was then added. The reaction mixture was stirred overnight and
then filtered through a pad of Celite®. The filter cake was washed
with chloroform. The solvent was evaporated in vacuo, and the
crude material was purified by flash chromatography.
(
t, J = 7.8 Hz, 1 H), 7.04 (dd, J = 7.5, 0.9 Hz, 1 H), 6.41 (dd, J =
3
5
.2, 1.8 Hz, 1 H), 6.28 (dd, J = 3.2, 0.9 Hz, 1 H), 4.28 (d, J =
.5 Hz, 2 H), 3.04 (m, 2 H), 2.66 (m, 2 H) ppm. C NMR
1
3
(
1
126 MHz, DMSO): δ = 208.5, 156.5, 154.8, 153.2, 142.6, 140.4,
36.7, 122.1, 118.7, 115.3, 110.9, 107.2, 36.6, 36.4, 25.4 ppm.
14 2 3
H N NaO
[M + Na]+ 293.0902;
HRMS (ESI): calcd. for C15
found 293.0909.
N-[(2-Acetylphenyl)carbamoyl]furan-2-carboxamide (6a): General
procedure A was followed. From NaOCN (1.68 g, 26.0 mmol,
General Procedure C for the Synthesis of Compounds 7:[19]
A
1.3 equiv.) 2-furoyl chloride (2.0 mL, 20.0 mmol, 1 equiv.), SnCl
4
1
–
5 wt.-% phosgene (2 equiv.) solution in toluene was cooled to
78 °C under nitrogen. To this solution was added dropwise fur-
(
(
(
0.23 mL, 2.0 mmol, 0.1 equiv.), and 2Ј-aminoacetophenone
2.0 mL, 16.5 mmol, 0.8 equiv.), the title compound was obtained
1
furyl alcohol (1 equiv.) dissolved in anhydrous diethyl ether (3 mL).
Upon complete addition, the mixture was warmed to –15 °C and
stirred for 3 h, followed by an additional 30 min at 0 °C. The chlo-
rocarbamate solution was added to a stirring solution of the corre-
sponding amine (0.5–1.0 equiv.) and dry pyridine (1.1–2.0 equiv.)
dissolved in anhydrous DCM (10 mL). The mixture was stirred at
ambient temperature overnight. The mixture was quenched with
water and extracted with DCM. The organic layer was washed with
2.62 g, 59%). H NMR (500 MHz, DMSO): δ = 12.35 (s, 1 H),
1
0
0
7
0.86 (s, 1 H), 8.40 (dd, J = 8.5, 1.2 Hz, 1 H), 8.06 (dd, J = 1.8,
.8 Hz, 1 H), 8.03 (dd, J = 8.0, 1.6 Hz, 1 H), 7.73 (dd, J = 3.6,
.8 Hz, 1 H), 7.62 (ddd, J = 8.5, 7.5, 1.6 Hz, 1 H), 7.25 (ddd, J =
.9, 7.5, 1.2 Hz, 1 H), 6.75 (dd, J = 3.6, 1.7 Hz, 1 H), 2.64 (s, 3 H)
13
ppm. C NMR (126 MHz, DMSO): δ = 201.3, 158.0, 151.7, 148.3,
45.8, 138.2, 134.0, 131.8, 125.9, 123.5, 122.5, 118.0, 112.9, 29.2
1
+
ppm. HRMS (ESI): calcd. for C14
found 295.0705.
12 2 4
H N NaO [M + Na] 295.0695;
brine, dried with Na
product was further purified by flash chromatography.
2 4
SO , and concentrated in vacuo. The crude
N-[(4-Oxotetralin-5-yl)carbamoyl]furan-2-carboxamide (6b): Gene-
ral procedure A was followed. From NaOCN (1.68 g, 26.0 mmol,
2
-Furylmethyl-N-(2-formylphenyl)carbamate (7d): General pro-
cedure C was followed. From 15 wt.-% phosgene solution in tolu-
ene (6.42 mL, 9.0 mmol, 2 equiv.), furfuryl alcohol (0.44 g,
1
.3 equiv.), 2-furoyl chloride (2.0 mL, 20.0 mmol, 1 equiv.), SnCl
4
(0.35 mL, 3.0 mmol, 0.15 equiv.), and 8-aminotetralone (0.60 g,
4
1
.5 mmol, 1 equiv.), 2-aminobenzyl alcohol (0.55 g, 4.5 mmol,
equiv.), and dry pyridine (0.41 mL, 5.1 mmol, 1.1 equiv.), 2-furyl-
4
8
=
.1 mmol, 0.3 equiv.), the title compound was obtained (0.98 g,
1
8%). H NMR (500 MHz, CDCl
8.4 Hz, 1 H), 8.30 (s, 1 H), 7.59 (dd, J = 1.8, 0.8 Hz, 1 H), 7.49
t, J = 7.9 Hz, 1 H), 7.46 (dd, J = 3.6, 0.8 Hz, 1 H), 7.01 (dd, J =
3
): δ = 13.28 (s, 1 H), 8.56 (d, J
methyl N-[2-(hydroxymethyl)phenyl]carbamate (7dЈ, 0.33 g, 29%)
1
was obtained. H NMR (500 MHz, CDCl
dd, J = 1.9, 0.9 Hz, 1 H), 7.35 (td, J = 7.8, 1.6 Hz, 1 H), 7.18 (dd,
J = 7.5, 1.6 Hz, 1 H), 7.06 (td, J = 7.5, 1.2 Hz, 1 H), 6.49 (dd, J =
.2, 0.8 Hz, 1 H), 6.41 (dd, J = 3.3, 1.8 Hz, 1 H), 5.18 (s, 2 H), 4.70
3
): δ = 7.96 (s, 2 H), 7.47
(
(
7
6
.5, 1.1 Hz, 1 H), 6.63 (dd, J = 3.6, 1.7 Hz, 1 H), 3.02 (t, J =
.1 Hz, 2 H), 2.77 (m, 2 H), 2.12 (m, 2 H) ppm. 13C NMR
3
(126 MHz, CDCl
3
): δ = 201.4, 156.4, 150.6, 145.9, 145.9, 145.6,
1
3
(
1
1
s, 2 H), 2.14 (s, 1 H) ppm. C NMR (126 MHz, CDCl
3
): δ =
53.7, 149.7, 143.3, 137.4, 129.2, 129.1, 128.8, 123.6, 121.1, 110.8,
10.6, 64.0, 58.7 ppm. To 7dЈ (0.33 g, 1.3 mmol, 1 equiv.) dissolved
1
40.1, 134.2, 123.7, 120.3, 119.6, 118.2, 113.2, 40.4, 31.1, 22.7 ppm.
+
HRMS (ESI): calcd. for C16
found 321.0859.
14 2 4
H N NaO [M + Na] 321.0851;
in anhydrous DCM (20 mL) was added PCC (0.43 g, 2.0 mmol,
1.5 equiv.). The mixture was stirred at ambient temperature over-
night. The solution was filtered through a pad of silica gel and
washed thoroughly with DCM. The resulting organic layer was
General Procedure B for the Synthesis of Compounds 5: The corre-
sponding amine (1 equiv.) was dissolved in anhydrous DCM
(
(
20 mL). To this solution was added dropwise furfuryl isocyanate
1 equiv.) dissolved in anhydrous DCM (5 mL). The mixture was
concentrated in vacuo to yield pale yellow solid 7d (0.27 g, 83%).
1
stirred at ambient temperature for 8 h. The resulting mixture was
diluted with DCM and washed with water and then brine. The
3
H NMR (500 MHz, CDCl ): δ = 10.66 (s, 1 H), 9.92 (d, J =
0.7 Hz, 1 H), 8.50 (d, J = 8.5 Hz, 1 H), 7.67 (dd, J = 7.7, 1.7 Hz,
1 H), 7.63 (ddd, J = 8.8, 7.3, 1.7 Hz, 1 H), 7.48 (dd, J = 1.9, 0.8 Hz,
organic layer was dried with Na
2 4
SO and then concentrated in
2210
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 2205–2213

Conformationally Constrained Penta(hetero)cycles
H), 7.21 (td, J = 7.5, 1.0 Hz, 1 H), 6.50 (dd, J = 3.3, 0.7 Hz, 1 (m, 1 H), 1.87 (m, 1 H), 1.69 (m, 2 H) ppm. 13C NMR (126 MHz,
1
1
3
H), 6.41 (dd, J = 3.3, 1.9 Hz, 1 H), 5.21 (s, 2 H) ppm. C NMR
DMSO): δ = 169.4, 153.0, 138.9, 137.9, 133.4, 132.3, 127.6, 127.3,
(
1
126 MHz, CDCl ): δ = 195.0, 153.2, 149.4, 143.4, 141.1, 136.0, 124.7, 124.3, 97.3, 89.0, 75.5, 35.7, 31.5, 17.4 ppm. HRMS (ESI):
3
22.1, 121.4, 118.4, 110.9, 110.6, 77.2, 58.8 ppm. HRMS (ESI):
calcd. for C16
H
14
1
N
2
NaO
4
[M + Na]+ 321.0851; found 321.0856.
+
4
calcd. for C13H11NNaO [M + Na] 268.0586; found 268.0594.
Compound 10b: H NMR (500 MHz, DMSO): δ = 11.59 (s, 1 H),
7.25 (t, J = 7.7 Hz, 1 H), 7.17 (dd, J = 7.6, 1.1 Hz, 1 H), 7.05 (d,
J = 8.0 Hz, 1 H), 6.54 (t, J = 2.8 Hz, 1 H), 5.45 (s, 1 H), 4.95 (dd,
2
-Furylmethyl-N-(4-oxotetralin-5-yl)carbamate (7b): General pro-
cedure C was followed. From 15 wt.-% phosgene solution in tolu-
ene (6.42 mL, 9.0 mmol, 2 equiv.), furfuryl alcohol (0.44 g, J = 3.0, 2.2 Hz, 1 H), 3.90 (t, J = 2.4 Hz, 1 H), 2.72 (m, 1 H), 2.60
1
3
4
.5 mmol, 1 equiv.), tetralone (0.38 g, 2.3 mmol, 0.5 equiv.), and (m, 1 H), 1.90 (m, 3 H), 1.72 (m, 1 H) ppm. C NMR (126 MHz,
dry pyridine (0.9 mL, 5.1 mmol, 2.0 equiv.), the title compound
DMSO): δ = 172.1, 155.0, 147.2, 138.4, 133.9, 131.4, 127.8, 127.2,
1
(
1
(
3
0.35 g, 30%) was obtained. H NMR (500 MHz, CDCl
1.70 (s, 1 H), 8.34 (dd, J = 8.6, 1.1 Hz, 1 H), 7.45 (m, 1 H), 7.43
d, J = 8.0 Hz, 1 H), 6.89 (dt, J = 7.4, 1.0 Hz, 1 H), 6.48 (dd, J =
.3, 0.8 Hz, 1 H), 6.39 (dd, J = 3.2, 1.9 Hz, 1 H), 5.17 (s, 2 H), 2.96
t, J = 6.1 Hz, 2 H), 2.68 (dd, J = 7.3, 5.8 Hz, 2 H), 2.07 (p, J =
3
): δ =
123.4, 101.1, 94.5, 67.9, 57.9, 35.4, 29.5, 18.4 ppm. HRMS (ESI):
–
calcd. for C16
H
14
N
2
O
4
[M – H] 297.0875, found 297.0886.
Compound 5b (0.50 g, 1.8 mmol) was irradiated by general pro-
cedure D. Flash chromatography yielded 1-hydroxy-19-oxa-7,9-
(
2,5 5,9 14,18
diazapentacyclo[8.7.1.1 .0 .0
]nonadeca-3,10,12,14(18)-
6
1
5
.4 Hz, 2 H) ppm. 13C NMR (126 MHz, CDCl
49.8, 146.0, 143.2, 142.1, 134.9, 122.2, 118.2, 116.7, 110.6, 110.5,
8.6, 40.6, 31.0, 22.7 ppm. HRMS (ESI): calcd. for C16 [M
3
): δ = 202.7, 153.5,
tetraen-8-one (9b, 0.270 g, 54%) and 2-hydroxy-19-oxa-7,9-diaza-
1,5 5,9 14,18
pentacyclo[8.7.1.1 .0 .0
]nonadeca-3,10,12,14(18)tetraen-8-
H
15NO
4
one (9bЈ, 0.077 g, 15%).
+
+
H] 286.1074; found 286.1079.
1
Compound 9b: H NMR (500 MHz, DMSO): δ = 7.21 (s, 1 H), 7.09
General Procedure D for Irradiation: Solutions of the photoprecur-
sors (ca. 3.0 mm) in methanol (except where noted) were degassed
and irradiated in Pyrex or borosilicate glass reaction vessels in a
Rayonet reactor equipped with RPR-3500 UV lamps (broadband
(
m, 2 H), 6.87 (m, 1 H), 6.53 (dd, J = 5.7, 1.8 Hz, 1 H), 5.77 (dd,
J = 5.7, 1.1 Hz, 1 H), 4.46 (m, 1 H), 3.80 (dd, J = 10.8, 1.1 Hz, 1
H), 3.48 (dd, J = 10.7, 1.4 Hz, 1 H), 2.79 (m, 1 H), 2.68 (ddd, J =
1
7.4, 12.9 Hz, 5.5 1 H), 2.00 (m, 1 H), 1.84 (m, 1 H), 1.68 (m, 3
3
00–400 nm UV source with peak emission at 350 nm) until the
13
H) ppm. C NMR (126 MHz, DMSO): δ = 157.0, 138.3, 136.2,
1
reaction was complete, as determined by H NMR spectroscopy.
The solution was concentrated, and the mixture was purified by
flash chromatography.
1
3
2
35.1, 133.1, 128.1, 126.9, 126.6, 126.0, 99.6, 87.6, 75.5, 46.4, 36.0,
–
1.5, 17.7 ppm. HRMS (ESI): calcd. for C16
H
16
N
2
O
3
[M – H]
83.1083; found 283.1087.
Compound 6a (0.20 g, 0.74 mmol) was irradiated by general
procedure D with acetonitrile as the solvent. Flash chromatog-
1
Compound 9bЈ: H NMR (500 MHz, CDCl
3
): δ = 7.64 (d, J =
8
6
1
(
1
.1 Hz, 1 H), 7.25 (t, J = 7.8 Hz, 1 H), 6.92 (d, J = 7.6 Hz, 1 H),
.22 (dd, J = 9.7, 5.4 Hz, 1 H), 5.93 (d, J = 9.7 Hz, 1 H), 5.69 (s,
H), 3.84 (d, J = 5.4 Hz, 1 H), 3.68 (d, J = 1.1 Hz, 2 H), 2.93
ddd, J = 17.5, 10.0, 5.5 Hz, 1 H), 2.87 (ddd, J = 17.5, 9.6, 5.8 Hz,
H), 2.49 (ddd, J = 12.2, 6.8, 2.4 Hz, 1 H), 2.11 (m, 2 H), 1.96
raphy yielded 12-hydroxy-12-methyl-16-oxa-3,5-diazatetracyclo-
6,11
[
11.2.1.01,5.0 ]hexadeca-6(11),7,9,14-tetraene-2,4-dione
(11a,
0
[
.13 g, 63%) and 11-hydroxy-11-methyl-7-oxa-2,4-diazatetracyclo-
10.4.0.02 .0 ]hexadeca-1(12),8,13,15-tetraene-3,5-dione
,6
6,10
(10a,
0
.039 g, 19%).
13
(
m, 1 H), 1.56 (td, J = 12.3, 7.7 Hz, 1 H) ppm. C NMR
(126 MHz, CDCl ): δ = 157.55, 136.1, 131.2, 130.0, 128.8, 127.9,
125.5, 123.8, 118.0, 84.3, 77.1, 64.3, 49.4, 29.1, 26.1, 15.9 ppm.
ddd, J = 8.3, 7.1, 1.5 Hz, 1 H), 7.17 (ddd, J = 8.4, 7.2, 1.5 Hz, 1 HRMS (ESI): calcd. for C16 LiO
[M + Li]+ 291.1321; found
H), 6.65 (dd, J = 5.9, 1.7 Hz, 1 H), 5.93 (dd, J = 5.9, 1.3 Hz, 1 H), 291.1328.
1
Compound 11a: H NMR (500 MHz, DMSO): δ = 11.58 (s, 1 H),
.58 (dd, J = 8.2, 1.5 Hz, 1 H), 7.57 (dd, J = 8.1, 1.6 Hz, 1 H), 7.28
3
7
(
H
16
N
2
3
1
3
5
.53 (s, 1 H), 4.78 (t, J = 1.5 Hz, 1 H), 1.59 (s, 3 H) ppm.
NMR (126 MHz, DMSO): δ = 169.4, 153.0, 137.7, 135.8, 132.2,
29.0, 127.81, 126.01, 125.61, 124.51, 97.31, 90.31, 78.51, 26.3 ppm.
C
Compound 5c (0.30 g, 1.1 mmol) was irradiated by general pro-
cedure D. Flash chromatography yielded 1-hydroxy-18-oxa-7,9-
diazapentacyclo[8.6.1.1 .0 .0
tetraen-8-one (9c, 0.15 g, 52%) and 2-[8-hydroxy-3-oxo-2,4-diaza-
tertacyclo[6.6.1.0 .0
yl]acetaldehyde (8cЈ, 0.077 g, 26%).
1
2,5 5,9 14,17
]octadeca-3,10,12,14(17)-
+
HRMS (ESI): calcd. for C14
found 295.0709.
12 2 4
H N NaO [M + Na] 295.0695;
2,6 11,15
]pentadeca-1(14),5,11(15),12-tetraen-7-
1
Compound 10a: H NMR (500 MHz, DMSO): δ = 11.59 (s, 1 H),
7
1
2
=
1
.37 (m, 3 H), 7.28 (td, J = 7.2, 2.0 Hz, 1 H), 6.52 (t, J = 2.8 Hz,
H), 5.47 (s, 1 H), 4.87 (dd, J = 2.9, 2.2 Hz, 1 H), 3.88 (t, J =
.5 Hz, 1 H), 1.66 (s, 3 H) ppm. 13C NMR (126 MHz, DMSO): δ
Compound 9c: 1H NMR (500 MHz, DMSO): δ = 7.33 (d, J =
8.1 Hz, 1 H), 7.23 (s, 1 H), 7.15 (dd, J = 8.1, 7.3 Hz, 1 H), 6.96 (d,
J = 7.3 Hz, 1 H), 6.53 (dd, J = 5.8, 1.9 Hz, 1 H), 5.80 (dd, J = 5.8,
171.6, 154. 5, 146.9, 136.4, 133.5, 128.0, 126.2, 125.5, 125.1,
1
1
.2 Hz, 1 H), 5.09 (s, 1 H), 4.77 (t, J = 1.5 Hz, 1 H), 3.80 (d, J =
00.3, 94.0, 69.0, 58.7, 24.2 ppm. HRMS (ESI): calcd. for
0.6 Hz, 1 H), 3.48 (dd, J = 10.7, 1.4 Hz, 1 H), 3.11 (m, 1 H), 2.75
+
C
14
H
12
N
2
NaO
4
[M+ Na] 295.0695; found 295.0703.
13
(
m, 1 H), 1.93 (m, 2 H) ppm. C NMR (126 MHz, DMSO): δ =
Compound 6b (0.36 g, 1.2 mmol) was irradiated by general pro-
156.7, 145.4, 136.8, 136.4, 132.6, 128.5, 128.24, 122.6, 120.7, 100.3,
89.0, 85.9, 47.2, 41.0, 30.4 ppm. HRMS (ESI): calcd. for
cedure D. Flash chromatography yielded 1-hydroxyl-19-oxa-7,9-di-
azapentacyclo[8.7.1.12,5.0 .0
5,9
14,18
]nonadeca-3,10(18),11,13-tetra-
ene-6,8-dione (11b, 0.150 g, 43%) and 11-hydroxy-7-oxa-2,4-diaza-
15 14 2 3
C H N O
[M + H]+ 271.1083; found 271.1091.
Compound 8Јc: 1H NMR (500 MHz, DMSO): δ = 10.03 (d, J =
pentacyclo[9.7.1.02 .0 .0
6,10 15,19
,6
]nonadeca-1(19),8,15,17-tetraene-
2
7
.4 Hz, 1 H), 9.56 (d, J = 2.7 Hz, 1 H), 7.90 (d, J = 8.0 Hz, 1 H),
.30 (t, J = 7.8 Hz, 1 H), 7.03 (d, J = 7.5 Hz, 1 H), 6.36 (d, J =
3,5-dione (10b, 0.072 g, 19%).
1
Compound 11b: H NMR (500 MHz, DMSO): δ = 11.52 (s, 1 H),
2.3 Hz, 1 H), 5.24 (s, 1 H), 3.67 (dd, J = 8.9, 5.7 Hz, 1 H), 3.19
7
.33 (dd, J = 7.9, 1.2 Hz, 1 H), 7.14 (t, J = 7.8 Hz, 1 H), 6.95 (dd, (m, 1 H), 2.82 (dd, J = 15.8, 8.4 Hz, 1 H), 2.59 (dd, J = 16.8,
1
3
J = 7.5, 1.4 Hz, 1 H), 6.68 (dd, J = 5.9, 1.7 Hz, 1 H), 5.90 (dd, J
=
1
5.7 Hz, 1 H), 2.11 (m, 1 H), 1.97 (m, 2 H) ppm. C NMR
5.9, 1.2 Hz, 1 H), 5.39 (d, J = 1.3 Hz, 1 H), 4.62 (t, J = 1.5 Hz, (126 MHz, DMSO): δ = 202.2, 151.9, 144.3, 132.1, 132.0, 130.3,
H), 2.81 (m, 1 H), 2.70 (ddd, J = 17.2, 12.9, 5.6 Hz, 1 H), 2.01 121.4, 120.3, 113.6, 107.2, 78.7, 46.2, 40.9, 39.5, 30.8 ppm. HRMS
Eur. J. Org. Chem. 2015, 2205–2213
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2211

W. J. Umstead, O. A. Mukhina, A. G. Kutateladze
FULL PAPER
–
(
ESI): calcd. for C15
H
14
N
2
O
3
[M – H] 269.0926; found 269.0928.
1.7 mmol, 2.2 equiv.) was slowly added. Upon complete addition,
the mixture was stirred for 2 min until the evolution of gas stopped.
Then, the alcohol (0.19 g, 0.77 mmol, 1 equiv.) dissolved in anhy-
drous DCM (1.5 mL) was added dropwise. Upon complete ad-
Compound 7d (0.26 g, 1.1 mmol) was irradiated by general pro-
cedure D. Flash chromatography yielded 12-hydroxy-3,16-dioxa-5-
azatetracyclo[11.2.1.01,5.06,11]hexadeca-6,8,10,14-tertaen-4-one
3
dition, the mixture was stirred for 15 min, and NEt (0.54 mL,
(
[
5
13d, 0.076 g, 29 %) and 11-hydroxy-4,7-dioxa-2-azatetracyclo-
10.4.0.02 . 0 ]hexadeca-1(16),8,12,14-tertaen-3-one (12d, 0.15 g,
8%).
Compound 13d: 1H NMR (500 MHz, DMSO): δ = 7.71 (dt, J =
.0, 1.4 Hz, 1 H), 7.34 (m, 1 H), 7.30 (tdd, J = 7.8, 1.8, 0.7 Hz, 1
H), 7.25 (td, J = 7.5, 1.7 Hz, 1 H), 6.55 (dd, J = 5.8, 1.8 Hz, 1 H),
.18 (d, J = 6.4 Hz, 1 H), 5.95 (dd, J = 5.8, 1.0 Hz, 1 H), 4.91 (dd,
,6
6,10
3.9 mmol, 5 equiv.) was slowly added. Upon complete addition, the
mixture was slowly warmed to room temp. and then stirred over-
night. The reaction mixture was quenched with water and extracted
with DCM. The resulting organic layer was washed with brine,
SO , and concentrated in vacuo to yield 19 (0.11 g,
2 4
0%). The resulting solid was used in the next step without further
8
dried with Na
6
6
1
purification. H NMR (500 MHz, CDCl
3
): δ = 8.46 (dd, J = 8.4,
J = 6.4, 3.3 Hz, 1 H), 4.85 (ddd, J = 3.2, 1.8, 1.0 Hz, 1 H), 4.75 (d,
1
7
1
(
1
.2 Hz, 1 H), 7.41 (ddd, J = 8.6, 7.3, 1.6 Hz, 1 H), 7.27 (dd, J =
.8, 1.7 Hz, 1 H), 7.19 (td, J = 7.5, 1.2 Hz, 1 H), 6.79 (d, J =
0.0 Hz, 1 H), 6.19 (dd, J = 10.1, 0.7 Hz, 1 H), 5.22 (s, 1 H), 2.79
J = 10.2 Hz, 1 H), 4.49 (d, J = 10.2 Hz, 1 H) ppm. 1 C NMR
3
(126 MHz, CDCl
3
): δ = 158.6, 142.0, 140.4, 136.2, 132.7, 132.3,
1
31.9, 131.3, 130.8, 104.2, 88.5, 79.4, 73.9 ppm. HRMS (ESI):
m, 2 H), 2.55 (ddd, J = 13.5, 7.1, 4.5 Hz, 1 H), 2.41 (dt, J = 13.5,
+
calcd. for C13
H
11NNaO
4
[M + Na] 268.0586; found 268.0596.
13
0.4 Hz, 1 H) ppm. C NMR (126 MHz, CDCl
3
): δ = 192.5, 170.9,
1
143.2, 132.3, 129.5, 126.3, 125.8, 125.0, 119.9, 119.3, 86.3, 78.7,
Compound 12d: H NMR (500 MHz, DMSO): δ = 7.50 (dd, J =
+
3
2
1.0, 29.7 ppm. HRMS (ESI): calcd. for C14
42.0812; found 242.0816.
3
H11NO [M + H]
7
1
1
.8, 1.3 Hz, 1 H), 7.44 (dt, J = 7.4, 1.4 Hz, 1 H), 7.31 (tdd, J = 7.7,
.7, 0.9 Hz, 1 H), 7.25 (td, J = 7.5, 1.3 Hz, 1 H), 6.43 (t, J = 2.7 Hz,
H), 5.97 (d, J = 5.5 Hz, 1 H), 4.95 (t, J = 5.9 Hz, 1 H), 4.84 (dd,
J = 3.1, 2.2 Hz, 1 H), 4.76 (d, J = 10.1 Hz, 1 H), 4.62 (d, J =
0.1 Hz, 1 H), 3.96 (dt, J = 6.2, 2.3 Hz, 1 H) ppm. 13C NMR
126 MHz, DMSO): δ = 153.5, 146.6, 134.4, 131.9, 127.4, 125.9,
25.3, 120.9, 99.6, 98.0, 73.4, 65.8, 54.1 ppm. HRMS (ESI): calcd.
Synthesis of Dibromoformaldoxime:[21] To a solution of glyoxylic
acid monohydrate (20.3 g, 0.22 mol, 1 equiv.) in water (160 mL,
1
(
1
1
2
.4 m) was added hydroxylamine hydrochloride (19.4 g, 0.28 mol,
.3 equiv.). The mixture was stirred at ambient temperature for
4 h. NaHCO (47.7 g, 0.57 mol, 2.58 equiv.) was slowly added, fol-
3
1
+
4
for C13H11NNaO [M + Na] 268.0586; found 268.0594.
lowed by DCM (70 mL). The resulting mixture was cooled in an
ice bath, and Br (19.5 mL, 0.38 mol, 1.7 equiv.) in DCM (100 mL)
Compound 7b (0.10 g, 0.35 mmol) was irradiated by general pro-
2
was slowly added with the temperature maintained at or below
10 °C. Upon complete addition, the mixture was stirred at room
temperature for 3 h. The resulting mixture was diluted with water
cedure D. Flash chromatography yielded 11-hydroxy-4,7-dioxa-2-
2
,5 6,10 15,19
azapentacyclo[9.7.1.0 .0 .0
]nonadeca-1(18),8,15(19),16-
tetraen-3-one (12b, 0.063 g, 63%).
(
2 4
100 mL), extracted with DCM (3ϫ 30 mL), dried with Na SO ,
1
Compound 12b: H NMR (500 MHz, CDCl
3
): δ = 7.56 (dt, J = 7.9,
and concentrated in vacuo. The resulting solid was recrystallized
1.1 Hz, 1 H), 7.31 (t, J = 7.8 Hz, 1 H), 7.02 (dq, J = 7.7, 1.0 Hz, 1
from hexanes to yield a white crystalline solid (12.5 g, 28%); m.p.
H), 6.31 (t, J = 2.9 Hz, 1 H), 4.73 (dd, J = 3.2, 2.3 Hz, 1 H), 4.71
21]
6
5–66 °C (ref.[ 65–66 °C).
(d, J = 9.4 Hz, 1 H), 4.60 (d, J = 9.5 Hz, 1 H), 3.75 (t, J = 2.4 Hz,
H), 2.82 (m, 1 H), 2.72 (m, 1 H), 2.07 (m, 1 H), 1.92 (m, 3 H) General Procedure E for Nitrile Oxide Addition:[21] The photoprod-
1
13
ppm. C NMR (126 MHz, CDCl
3
): δ = 146.9, 138.0, 133.2, 128.8,
uct (1 equiv.) was dissolved in EtOAc or EtOAc/DCM. To this
solution was added dibromoformaldoxime (3 equiv.) and KHCO
[M + L]i 292.1161; (6 equiv.). Additional dibromoformaldoxime (3 equiv.) and
KHCO (6 equiv.) were usually added after 12 h. The reaction was
1
28.5, 126.7, 121.2, 99.1, 97.4, 77.2, 75.4, 69.3, 58.3, 35.4, 29.5, 18.5
3
+
ppm. HRMS (ESI): calcd. for C16
found 292.1169.
H15NLiO
4
3
monitored by NMR spectroscopy until the starting materials were
consumed. The resulting mixture was diluted with water, extracted
with EtOAc or DCM (3ϫ 20 mL), washed with brine, dried with
Postphotochemical Cycloadditions: For the model system, an equi-
molar mixture of 4-hydroxy-2,3-benzo-8-oxa-1-azatricyclo-
[
1
7.3.0.05 ]dodeca-2,6-dien-12-one (14) and 2-hydroxy-3,4-benzo-
,9
Na
2 4
SO , and concentrated in vacuo. The mixture was then purified
2-oxa-5-azatricyclo[7.2.1.05 ]dodec-3,10-dien-6-one (15) was syn-
thesized as described previously.
,9
by flash chromatography.
12
1
0
5-Bromo-12-hydroxy-17,19-dioxa-5,16-diazapentacyclo[11.5.1.01,5.
1
6-Oxa-5-azatetracyclo[10.3.1.01,5.06,11]hexadeca-6(11),7,9,14-
tetraen-4,13-dione (19): To 15 (0.40 g, 1.6 mmol, 1 equiv.) was
added CHCl (40 mL), followed by trifluoroacetic acid (TFA,
mL). The mixture was stirred at room temperature overnight. The
reaction was quenched with satd. NaHCO solution, and the or-
ganic layer was washed with brine, dried over Na SO , and concen-
6
,11 14,18
.0
]nonadeca-6(11),7,9,15-tetraen-4-one (18): General pro-
cedure E was followed with EtOAc. From 15 (0.19 g, 0.76 mmol,
equiv.), dibromoformaldoxime (0.46 g, 2.3 mmol, 3 equiv.), and
KHCO (0.46 g, 4.6 mmol, 6 equiv.), the formation of a 4:1 mixture
3
1
5
3
3
of two regioisomers of the title compound was observed. Upon
2
4
purification, the title compound (major isomer) was isolated
trated in vacuo. The resulting residue was purified by flash
chromatography to yield 13-hydroxy-16-oxa-5-azatetracyclo-
1
(
0.17 g, 63%). H NMR (500 MHz, DMSO): δ = 7.39 (m, 3 H),
7
4
.27 (m, 1 H), 5.53 (d, J = 5.8 Hz, 1 H), 4.71 (d, J = 8.6 Hz, 1 H),
.64 (dd, J = 5.8, 4.3 Hz, 1 H), 4.53 (d, J = 4.2 Hz, 1 H), 3.75 (dd,
[
10.3.1.01 .0 ]hexadeca-6(11),7,9,14-tetraen-4-one (0.30 g, 78%).
,5
6,11
1
H NMR (500 MHz, CDCl
.41 (dddd, J = 8.1, 7.4, 1.7, 0.5 Hz, 1 H), 7.30 (m, 2 H), 7.22 (td,
J = 7.5, 1.2 Hz, 1 H), 6.13 (d, J = 9.9 Hz, 1 H), 6.07 (ddd, J = 9.8,
.0, 1.2 Hz, 1 H), 5.31 (s, 1 H), 5.17 (dd, J = 5.0, 1.2 Hz, 1 H), 2.77
3
): δ = 8.38 (dd, J = 8.3, 1.2 Hz, 1 H),
J = 8.6, 1.1 Hz, 1 H), 2.68 (ddd, J = 16.1, 9.9, 8.8 Hz, 1 H), 2.55
7
1
3
(
m, 1 H), 2.46 (m, 1 H), 2.07 (m, 1 H) ppm. C NMR (126 MHz,
DMSO): δ = 173.3, 140.0, 134.3, 134.2, 133.4, 128.9, 128.4, 126.9,
04.1, 88.1, 81.7, 76.4, 61.0, 29.5, 27.3 ppm. HRMS (ESI): calcd.
for C15 LiO
Br [M + Li]+ 371.0219; found 371.0219.
5
(
1
13
m, 2 H), 2.45 (m, 2 H) ppm. C NMR (126 MHz, CDCl
3
): δ =
H
13
N
2
4
1
7
1
71.4, 133.6, 132.6, 129.3, 125.5, 124.6, 121.3, 120.9, 120.3, 85.8,
3.8, 71.0, 30.2, 29.7 ppm. Oxalyl chloride (0.07 mL, 0.84 mmol,
.1 equiv.) was dissolved in anhydrous DCM (0.9 mL), and the
15-Bromo-12-hydroxy-17,19-dioxa-5,16-diazapentacyclo[11.6.0.01,5.
6
,11 14,18
0
.0
]nonadeca-6(11),7,9,15-tetraen-4-one (16): General pro-
solution was cooled to –78 °C before dry DMSO (0.12 mL,
cedure E was followed. From 14 (0.20 g, 0.82 mmol, 1 equiv.), di-
2212
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 2205–2213

Conformationally Constrained Penta(hetero)cycles
bromoformaldoxime (1.0 g, 4.9 mmol, 6 equiv.), and KHCO
3
Acknowledgments
(
1.0 g, 9.8 mmol, 12 equiv.), the title compound was obtained
(
0.19 g, 65 %). 1H NMR (500 MHz, CDCl
3
): δ = 7.92 (d, J =
Support of this research by the National Science Foundation (NSF)
7
1
.9 Hz, 1 H), 7.49 (td, J = 7.8, 1.5 Hz, 1 H), 7.37 (dd, J = 7.5, (grant number CHE-1362959) and National Iinstitutes of Health
.5 Hz, 1 H), 7.25 (td, J = 7.5, 1.2 Hz, 1 H), 5.65 (d, J = 6.0 Hz, 1 (NIH) (grant number GM093930) is gratefully acknowledged
H), 4.79 (t, J = 2.9 Hz, 1 H), 3.51 (s, 1 H), 3.45 (dd, J = 6.0, 3.6 Hz,
1
8
=
7
C
H), 3.37 (dd, J = 3.5, 2.9 Hz, 1 H), 2.85 (ddd, J = 16.6, 9.9,
.7 Hz, 1 H), 2.48 (m, 3 H) ppm. 13C NMR (126 MHz, CDCl
173.2, 140.8, 134.2, 130.8, 129.0, 128.7, 126.1, 123.7, 106.8, 101.2,
1.0, 61.6, 41.0, 34.2, 29.9 ppm. HRMS (ESI): calcd. for
[
1] http://www.cas.org/content/counter.
3
): δ [2] CAS statistical summary 1907–2007.
[3] http://www.fda.gov/AboutFDA/WhatWeDo/History/Product
Regulation/SummaryofNDAApprovalsReceipts1938tothepresent/
default.htm.
+
15
H
13
N
2
O
4
Br [M + H] 366.0168; found 366.0181.
[4] M. Fehler, J. M. Schmidt, J. Chem. Inf. Comput. Sci. 2003, 43,
4,15-Dibromo-17,19-dioxa-5,16-diazapentacyclo[10.6.1.01,5.06,11
.
218–227.
1
0
[5] A. H. Lipkus, Q. Yuan, K. A. Lucas, S. A. Funk, W. F. Bart-
elt III, R. J. Schenk, A. J. Trippe, J. Org. Chem. 2008, 73, 4443–
14,18
]nonadeca-6(11),7,9,15-tetraene-4,13-dione (20Ј): General pro-
cedure E was followed with an EtOAc/DCM mixture. From 19
0.11 g), the title compound was obtained after flash chromatog-
4451.
(
[6] G. W. Bemis, M. A. Murcko, J. Med. Chem. 1996, 39, 2887–
1
raphy (0.13 g, 62%). H NMR (500 MHz, CD
2
Cl
2
): δ = 8.44 (m, 1
2893.
H), 7.49 (ddd, J = 8.4, 7.4, 1.8 Hz, 1 H), 7.28 (m, 2 H), 5.41 (s, 1
H), 5.15 (s, 1 H), 3.04 (ddd, J = 13.8, 8.1, 3.7 Hz, 1 H), 2.74 (m, 2
[7] G. W. Bemis, M. A. Murcko, J. Med. Chem. 1999, 42, 5095–
5099.
H), 2.30 (dt, J = 13.8, 10.1 Hz, 1 H) ppm. 1 C NMR (126 MHz,
3
[8] J. Wang, T. Hou, J. Chem. Inf. Model. 2010, 50, 55–67.
[
9] J. Szychowski, J.-F. Truchon, Y. L. Bennani, J. Med. Chem.
2 2
CD Cl ): δ = 191.8, 172.6, 141.4, 134.1, 131.0, 126.4, 126.0, 120.8,
2014, 57, 9292–9308.
1
18.1, 92.7, 90.1, 78.2, 57.7, 30.1, 28.8 ppm. HRMS (ESI): calcd.
[
[
10] P. Ertl, A. Schuffenhauer, Prog. Drug Res. 2008, 66, 217–235.
11] F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009, 52,
+
for C15
2 2 4
H10Br N O Li [M + Li] 448.9148; found 449.1726.
6752–6756.
1
7-Bromo-12-hydroxy-12-methyl-15,19-dioxa-3,5,16-triazapenta-
[
12] O. A. Mukhina, N. N. B. Kumar, T. M. Arisco, R. A. Valiulin,
G. A. Metzel, A. G. Kutateladze, Angew. Chem. Int. Ed. 2011,
50, 9423–9428; Angew. Chem. 2011, 123, 9595.
1
,5 6,11 14,18
cyclo[11.5.1.0 .0 .0
]nondeca-6(11),7,9,16-tetraene-2,4-dione
(
22): General procedure E was followed. From 11a (0.16 g,
0
6
.58 mmol, 1 equiv.), dibromoformaldoxime (0.70 g, 3.4 mmol, [13] N. N. B. Kumar, O. A. Mukhina, A. G. Kutateladze, J. Am.
equiv.), and KHCO
3
(0.70 g, 6.8 mmol, 12 equiv.), the formation
Chem. Soc. 2013, 135, 9608–9611.
[
14] For other examples of photochemical approaches to polyhetero-
cyclic scaffolds, see: a) D. A. Fort, T. J. Woltering, M. Nette-
koven, H. Knust, T. Bach, Angew. Chem. Int. Ed. 2012, 51,
of a 5:1 mixture of two regioisomers was observed. After purifica-
1
tion, the major isomer was isolated (0.12 g, 53 %). H NMR
(500 MHz, DMSO): δ = 11.89 (s, 1 H), 7.66 (dd, J = 8.1, 1.4 Hz,
10169–10172; Angew. Chem. 2012, 124, 10316; b) V. I. Martin,
1
=
H), 7.54 (dd, J = 8.1, 1.5 Hz, 1 H), 7.37 (m, 1 H), 7.25 (ddd, J
8.7, 7.3, 1.4 Hz, 1 H), 5.44 (s, 1 H), 4.92 (d, J = 8.7 Hz, 1 H),
J. R. Goodell, O. J. Ingham, J. A. Porco Jr., A. B. Beeler, J. Org.
Chem. 2014, 79, 3838–3846; c) D. A. Fort, T. J. Woltering,
A. M. Alker, T. Bach, J. Org. Chem. 2014, 79, 7152–7161.
4
3
1
2
4
.54 (d, J = 0.7 Hz, 1 H), 3.85 (dd, J = 8.7, 0.7 Hz, 1 H), 1.71 (s,
H) ppm. 13C NMR (126 MHz, DMSO): δ = 166.5, 152.8, 136.2,
35.2, 133.4, 128.8, 128.3, 127.1, 126.5, 94.9, 91.3, 88.5, 73.6, 63.5,
6.0 ppm. HRMS (ESI): calcd. for C15
01.0132; found 401.0136.
[15] W. C. Cronk, O. A. Mukhina, A. G. Kutateladze, J. Org. Chem.
2014, 79, 1235–1246.
[16] N. S. Nandurkar, N. N. B. Kumar, O. A. Mukhina, A. G. Kuta-
teladze, ACS Comb. Sci. 2013, 15, 73–76.
[M+ Li]+
3 5
H12BrN LiO
[
17] S. L. Schreiber, Science 2000, 287, 1964–1969; for a review of
diversity-oriented Synthesis see: M. Dow, F. Marchetti, A. Nel-
son, in: Diversity-Oriented Synthesis: Basics and Applications in
Organic Synthesis Drug Discovery, and Chemical Biology (Ed.:
A. Trabocchi), 2013, John Wiley & Sons, Hoboken, chapter 9.
18] M.-Z. Deng, P. Caubere, J. P. Senet, S. Lecolier, Tetrahedron
1988, 44, 6079–6086.
1
5-Bromo-12-hydroxy-12-methyl-17,19-dioxa-3,5,16-triazapenta-
1,5 6,11 14,18
cyclo[11.6.0.0 .0 .0
]nonadeca-6(11),7,9,15-tetraene-2,4-dione
21): General procedure E was followed. From 10a (0.15 g,
(
0
6
.55 mmol, 1 equiv.), dibromoformaldoxime (0.66 g, 3.2 mmol,
equiv.), and KHCO (0.66 g, 6.6 mmol, 12 equiv.), the title com-
[
3
1
pound was obtained (0.14 g, 65%). H NMR (500 MHz, DMSO):
[19] H. Steinhagen, E. J. Corey, Angew. Chem. Int. Ed. 1999, 38,
1928–1931; Angew. Chem. 1999, 111, 2054.
δ = 11.68 (s, 1 H), 7.49 (m, 2 H), 7.38 (m, 2 H), 5.73 (s, 1 H), 5.71
[
[
[
20] O. A. Mukhina, N. N. B. Kumar, T. M. Cowger, A. G. Kutatel-
adze, J. Org. Chem. 2014, 79, 10956–10971.
(
4
d, J = 6.0 Hz, 1 H), 4.02 (dd, J = 6.0, 4.2 Hz, 1 H), 3.20 (d, J =
.2 Hz, 1 H), 1.77 (s, 3 H) ppm. 1 C NMR (126 MHz, DMSO): δ
3
21] D. M. Vyas, Y. Chiang, T. W. Doyle, Tetrahedron Lett. 1984,
=
170.5, 154.7, 142.9, 135.0, 133.4, 129.0, 126.6, 126.0, 107.7, 93.9,
25, 487–90.
6
C
9.0, 59.6, 57.5, 30.6, 24.2 ppm. HRMS (ESI): calcd. for
22] A. Leonardi, G. Motta, C. Riva, L. Guarneri, D. Graziani, C.
+
15
H
12
N
3
LiO
5
[M + Li] 402.0102; found 402.0110.
De Toma, K. D. Karamfilova, 2012, US 20120059015 A1, WO
2012 004400 A1.
Supporting Information (see footnote on the first page of this arti-
Received: December 12, 2014
Published Online: Feburary 16, 2015
1
13
cle): H and C NMR spectra.
Eur. J. Org. Chem. 2015, 2205–2213
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2213