Diversity-oriented Functionalization of Cyclodienes Through Selective Cycloaddition/Ring-opening/Cross-metathesis Protocols; Transformation of a “Flatland” into Three-dimensional Scaffolds With Stereo- and Regiocontrol

Article abstract of DOI:10.1002/tcr.202000070

This article presents selective transformations of some readily available cyclodienes through simple chemical procedures into novel functionalized small-molecular entities. The syntheses hereby described involved selective cycloadditions, followed by ring

Full text of DOI:10.1002/tcr.202000070

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DOI: 10.1002/tcr.202000070
Diversity-oriented Functionalization of
Cyclodienes Through Selective
Cycloaddition/Ring-opening/Cross-
metathesis Protocols; Transformation of a
Flatland into Three-dimensional
T H E
C H E M I C A L
R E C O R D
Scaffolds With Stereo- and Regiocontrol
Loránd Kiss,*[a, b] Zsanett Benke,[a, b] Attila M. Remete,[a, b] and Ferenc Fülöp*[a, b, c]
Chem. Rec. 2020, 20, 1–14
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Abstract: This article presents selective transformations of some readily available cyclodienes
through simple chemical procedures into novel functionalized small-molecular entities. The
syntheses hereby described involved selective cycloadditions, followed by ring-opening metathesis
of the resulting β-lactam or isoxazoline derivatives and selective cross-metathesis by differ-
entiation of the olefin bonds on the alkenylated heterocycles. The cross-metathesis trans-
formations have been detailed, which were performed under various experimental conditions
with the aim of exploring chemodiscrimination of the olefin bonds and delivering the
corresponding functionalized β-lactam or isoxazoline derivatives.
Keywords: cross-metathesis, selective coupling, β-lactam, isoxazoline, functionalization
Since the ring CÀ C double bond affords a large number of
1. Introduction
possible chemical transformations, cyclic dienes with nearly
Highly functionalized small-molecular entities are considered planar shape of different ring sizes are regarded to be readily
to be promising scaffolds in drug design. Some terms such as attainable starting substances to the access of structurally
“conformational restriction”[1] “escape from flatland”[2] or diverse molecular structures. Among a large number of
“scaffold hopping”[3] have received high relevance in medicinal chemical transformations, the ring C=C bond of cyclic dienes
chemistry over the past decade. Due to their special stereo- may provide valuable β-lactams[1a,b,6] or γ-lactams,[7] which are
chemical structure, highly-functionalized three-dimensional known to be interesting precursors for the synthesis of versatile
small molecules with multiple stereogenic centers and versatile compounds. These are amino esters, oxo esters, amino acids,
chemical diversity represent interesting scaffolds in drug amino alcohols, amino ketones, azido esters, hydroxylated
development. Biological properties of a certain molecule are in amino esters, and fluorinated amino esters, possessing various
strong connection with its three-dimensional arrangement. functional elements displaying stereostructural and chemical
The introduction of a three-dimensional shape into a diversity.[1a,b,6] Furthermore, cyclic amino acids, as conforma-
compound library leads to architectural complexity and tionally rigid structures, are interesting monomers as building
increased structural diversity. Accordingly, selective and con- elements in the synthesis of various types of oligopeptides[1,8]
trolled synthetic approaches with regard to cost, generalization, and cyclic amino acid structures with pharmaceutical
and applicability towards such moieties containing sp3 hybri- importance.[1a,b,9]
dized carbon atoms are of relevant significance in synthetic
Thanks to the commercial availability of a large number of
relatively robust Ru-based metathesis catalysts, olefin meta-
organic and medicinal chemistry.[4]
Diversity-oriented synthesis (DOS) with the aim to create thesis transformations have exerted a high impact on synthetic
structurally diverse, three-dimensional small-molecular ele- chemistry and become a common and useful methodology for
ments has been applied as a well-known approach to generate the creation of molecular entities containing olefin bond over
molecular libraries. Several strategies used in DOS regarding the last twenty years. Various types of metathesis reactions
selectivity and stereocontrol of various methods were reported have become powerful tools for the formation of one or more
in the literature. The main characteristics of these strategies are CÀ C double bonds in organic molecules. By using metathesis
the application of readily available and easily accessible starting synthetic approaches, a number of sophisticated organic
materials towards the formation of complex elements with molecules, natural products, biologically active substances, and
high chemical and sterical diversity.[5]
various pharmaceuticals have been synthesized.[10,12a–f]
2. Functionalization of Cyclodienes Through
β-lactam Formation/ROM/CM Protocols
[a] L. Kiss, Z. Benke, A. M. Remete, F. Fülöp
Institute of Pharmaceutical Chemistry, University of Szeged, H-6720
Szeged, Eötvös u. 6, Hungary
[2+2] Cycloaddition of chlorosulfonyl isocyanate (CSI) to the
C=C bond is considered to be a highly useful synthetic
procedure for the construction of a β-lactam skeleton. This
cycloaddition strategy to cycloalkadienes of different ring sizes
(cyclopentadiene, cyclohexadienes, cyclooctadienes, norborna-
diene) was earlier applied efficiently in our group to create
versatile molecular entities, varied small-molecular libraries
with high chemical and structural diversity, such as amino
[b] L. Kiss, Z. Benke, A. M. Remete, F. Fülöp
University of Szeged, Interdisciplinary Excellence Centre, Institute of
Pharmaceutical Chemistry, H-6720 Szeged, Eötvös u. 6, Hungary
[c] F. Fülöp
MTA-SZTE Stereochemistry Research Group, Hungarian Academy
of Sciences, H-6720 Szeged, Eötvös u. 6, Hungary
E-mail: kiss.lorand@pharm.u-szeged.hu
Supporting information for this article is available on the WWW
under https://doi.org/10.1002/tcr.202000070
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esters, azido esters, hydroxylated amino acids, fluorinated cross-metathesis (CM) in the presence of Hoveyda-Grubbs 2
amino esters, orthogonally protected amino esters, alkenylated catalyst (HG-2) in refluxing CH2Cl2 (Scheme 1).[12b]
amino esters, various heterocycles or aryl-substituted amino
A similar behavior was observed in the case of larger ring
esters.[1a,b,11] The strategy involved further selective trans- systems of lactam derivatives. Cyclooctene-fused β-lactam
formations of the cycloalkene-fused β-lactams through their regioisomers (�)-7 and (�)-11, derived from cyclooctadienes
ring C=C bond.
6 and 10 through CSI cycloaddition, could also be converted
Due to ring strain, unsaturated β-lactam (�)-2, synthetized across ROM followed by CM to the corresponding function-
by CSI cycloaddition to norbornadiene across its ring CÀ C alized azetidinone isomers (�)-8, (�)-9, (�)-12, and (�)-13
double bond, easily suffered ring cleavage under the condition (Scheme 2).[12b]
of ring-opening metathesis (ROM) in the presence of Grubbs-
It should be noted that dialkenylated β-lactam derivatives
1 catalyst (G-1), and provided divinyl-substituted lactam (�)- described above were easily transformed into the corresponding
3. Next, azetidinone derivative (�)-3 afforded the correspond- functionalized β-amino acid derivatives.[12b]
ing dicoupled derivatives (�)-4 and (�)-5 in the reaction with
The ROM/CM protocol was effectively applied to the
methyl vinyl ketone or methyl acrylate, respectively, through access of some dialkenylated cyclopentane β-amino ester
isomers as well. An illustrative example is depicted in
Loránd Kiss completed his Ph.D. in 2002
in the Department of Organic Chemistry
at the Faculty of Sciences, Debrecen
University (Debrecen, Hungary) under the
supervision of Prof. Sándor Antus. In
2003, he joined the research team of
Professor Ferenc Fülöp at the Institute of
Pharmaceutical Chemistry, University of
Szeged (Szeged, Hungary), where he
started to work in the area of cyclic β-
amino acid chemistry. He followed post-
doctoral research in the laboratories of
Prof. Norbert De Kimpe at Ghent Uni-
versity (Ghent, Belgium), and Prof. Santos
Fustero, at the Department of Organic
Chemistry, University of Valencia (Valen-
cia, Spain). He has published more than
100 scientific papers in reputed journals.
He is currently professor and department
head at the Institute of Pharmaceutical
Chemistry, University of Szeged. His
scientific interest is directed towards the
selective functionalization β-amino acid
derivatives and on the synthesis of highly
functionalized fluorinated building blocks.
University of Szeged, and between 1998
and 2017 was the head of the Institute.
He is a member of the Hungarian Acad-
emy of Sciences and has a wide range of
research interests in synthetic organic
chemistry. His recent activities have fo-
cused on the use of amino alcohols and β-
amino acids in enzymatic transformations,
various asymmetric syntheses, foldamer
construction, and flow chemistry, in view
of the development of pharmacologically
active derivatives.
Attila M. Remete graduated as chemist in
2014 from University of Szeged (Hun-
gary). He has been working at the Institute
of Pharmaceutical Chemistry, University
of Szeged since 2010. In 2014 he started
his Ph.D. under the supervision of Loránd
Kiss and received his degree in 2019. He is
currently assistant lecturer and his recent
topic focuses on the preparation of highly
substituted fluorinated building elements
from β-amino acid derivatives.
Zsanett Benke graduated as chemist in
2017 from University of Szeged, Faculty
of Science and Informatics (Hungary). In
2017 she started her Ph.D. at the Institute
of Pharmaceutical Chemistry, University
of Szeged (Hungary) under the supervision
of Loránd Kiss. Her Ph.D. topic focuses
on the selective transformations of cyclo-
alkadienes into highly functionalized
three-dimensional molecules.
Ferenc Fülöp was born in Szank, Hungary
in 1952. He received his MSc degree in
Chemistry in 1975 and his Ph.D. in 1979
from József Attila University, Szeged,
Hungary. At the beginning of his carrier
he worked in Chinoin Pharmaceuticals,
Budapest for six years. In 1991, he was
appointed as a full professor at the
Institute of Pharmaceutical Chemistry,
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Scheme 1. Cycloaddition of CSI to norbornadiene (1) and ROM/CM of the resulting bicyclic lactam (�)-2.
Scheme 2. Cycloaddition of CSI to 1,5- (6) and 1,3-cyclooctadiene (10) and ROM/CM of formed bicyclic lactams (�)-7 and (�)-11 (yields: 48–74%).
2.1. Functionalization of Cyclodienes Through β-lactam
Scheme 3. Norbornene β-amino ester diastereoisomers (�)-14
Formation/ROM and Selective CM Protocols
(prepared by ammonolysis of cis-5-Norbornene-endo-2,3-
dicarboxylic anhydride, followed by Hofmann degradation)[12g] All CM transformations presented above, performed in the
and (�)-17 (prepared by base mediated isomerization of (�)- presence of various commercial Ru-based catalysts in refluxing
14)[12a] were subjected to ROM in the presence of four Ru- CH2Cl2, proceeded smoothly yielding the corresponding
based catalysts furnishing divinyl-substituted amino esters (�)- expected dimetathesized products. However, it was observed
15 and (�)-18 (see Scheme 3). Then the products reacted that, after a careful selection of CM reaction conditions
further under CM conditions in the presence of HG-2 catalyst regarding the catalyst, temperature, time, and catalyst loading,
in refluxing CH2Cl2 to deliver the corresponding highly a distinct behavior of the apparently similar C=C was
functionalized
cyclopentanes
(�)-16
and
(�)-19 observed. For example, divinyl-substituted lactam (�)-3, after
some experimental investigations in the reaction with acrylates
or methyl vinyl ketone, gave monocoupled products (�)-20,
(�)-21, and (�)-22 (Scheme 4).[12c]
(Scheme 3).[12a]
The observed chemodiscrimination in the chemical com-
portment of the olefin bonds in (�)-3 was explained on the
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Scheme 3. Transformation of unsaturated bicyclic amino esters (�)-14 and (�)-17 through ROM/CM protocol. Note: catalysts G-1, G-2, HG-1, HG-2 were
used in ROM; the highest yields were attained with HG-2 for (�)-14 and with HG-1 for (�)-17.
Scheme 4. Selective transformation of lactam (�)-3 under CM conditions.
basis of a hydrogen-bonding directing effect in the transition cannot function as a H-donor scaffold. In this case the reaction
state of the CM reaction, which arises between the NÀ H (as was found not to be selective and, under similar experimental
hydrogen bond donor) and RuÀ Cl (as hydrogen bond accept- conditions, afforded two monometathesized products (�)-25
or) moieties. Thus, the H-bonding structure accelerates the and (�)-26 in a ratio of 2:1 (Scheme 5).[12c]
CM of the vinyl group closest to the lactam nitrogen atom
(Figure 1).
Further investigations in view of the chemodiscrimination
of the olefin bonds were executed by using some divinyl-
The above hypothesis was corroborated by analyzing the substituted β-amino ester diastereoisomers with a cyclopentane
CM transformation of N-Boc-protected lactam (�)-24, which skeleton.
In the case of divinyl-substituted amino esters (�)-28 and
(�)-30 after some experimental investigations, CM reactions
proceeded non-selectively (Scheme 6) giving mixtures of
monometathesized products in 4:1 and 2:1 ratio. In contrast,
isomer (�)-18 under similar conditions afforded monometa-
thesized compounds (�)-31, 32, and (�)-33 (Scheme 7) in a
completely chemoselective manner.[12c]
The phenomena described above can presumably be
explained by a preferred coordinating transition state in the
CM reaction. Compound (�)-18 gives a more stable six-
membered, cis-fused chelate ring across a metallacyclobutane
intermediate, while the transformation of (�)-28 and (�)-30
Figure 1. Hydrogen-bonding directing effect in the CM reaction.
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Scheme 5. Non-selective transformation of lactam (�)-24 under CM conditions.
Scheme 6. Non-selective transformation of amino esters (�)-28 and (�)-30 under CM conditions.
Scheme 7. Selective transformation of amino ester (�)-18 under CM conditions.
involved intermediates with less stable structure (Figure 2).[12c]
Thus, formation of a stable chelate ring system disfavors CM
of the vinyl group closer to the ester function, whereas the
3. Functionalization of Cyclodienes Through
Isoxazoline Formation/ROM/CM Protocols
C=C bond next to the NHCOH moiety will react smoothly. The nitrile oxide cycloaddition protocol to access a series of
Returning to strained fused azetidinones with higher ring interesting β-amino acid derivatives containing an isoxazoline
systems, non-selective CM was described for the transforma- framework bearing functionalized cycloalkenes was efficiently
tion of lactam (�)-34 derived from 1,5-cyclooctadiene, which applied.[1a,b,13]
furnished two monometathesized compounds (�)-35 and
(�)-36 in 4:1 and 2:1 ratio, respectively (Scheme 8).[12e]
In a recent work some readily available commercial
cyclodienes were selectively transformed through nitrile oxide
In contrast to lactam (�)-34, CM of its isomer (�)-37 1,3-dipolar cycloaddition into the corresponding cycloalkene-
with ethyl and methyl acrylates and methyl vinyl ketone took fused isoxazolines (Scheme 10).[14a]
place with chemodifferentiation of the C=C bonds and,
presumably due to steric factors, provided a single mono-
metathesized product each [(�)-38, (�)-39, and (�)-40]
(Scheme 9).[12e]
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Figure 2. Structures of chelate ring intermediates.
Scheme 8. Non-selective transformation of lactam (�)-34 under CM conditions. Note: catalyst=G-1, G-2, HG-1, or HG-2.
Scheme 9. Selective transformation of lactam (�)-37 under CM conditions.
3.1. Functionalizations by ROM/CM of Cycloalkene-fused
Isoxazolines With Non-fluorinated Olefins
Similar to cycloalkane-anellated azetidinones, cycloalkene- (Scheme 11).[14]
fused isoxazolines as ring-strained systems are regarded as
ketone or methyl acrylate in the presence of HG-2, led to
dicoupled derivatives (�)-43 and (�)-44 in a CM reaction
potential model compounds for ROM. An illustrative example
3.2. Functionalizations by ROM/CM of Cycloalkene-fused
Isoxazolines With Fluorine-containing Olefins
is shown in Scheme 11. Cyclooctene-fused isoxazoline (�)-41
easily underwent ring opening in the presence of HG-1
catalyst furnishing the corresponding dialkenylated isoxazoline In earlier studies we acquired useful findings with respect to
(�)-42. Compound (�)-42, when reacted with methyl vinyl selective functionalization strategies based on the formation of
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Scheme 10. Selective synthesis of several cycloalkene-fused isoxazolines.
functionalization studies were further applied in view of the
creation of novel small molecular entities. For this reason, 1,5-
cyclooctadiene the selected starting model compound was
converted through selective nitrile oxide cycloaddition into
cyclooctene-fused isoxazoline (�)-41 which, in turn, afforded
dialkenylated izoxazoline (�)-42 by ring-opening metathesis
(ROM).[14] Our aim was to convert compound (�)-42 into
novel functionalized scaffolds and to study the chemical
behavior of practically equivalent olefin bonds in (�)-42
under CM transformations. Hereby, in this section some
preliminary results will be briefly presented.
First, methyl acrylate was applied as CM partner in the
reaction with dialkenylated isoxazoline (�)-42. The CM
reaction was systematically studied in the presence of readily
available commercial catalysts, namely Grubbs 1 (G-1),
Grubbs-2 (G-2), Hoveyda-Grubbs-1 (HG-1), and Hoveyda-
Grubbs-2 (HG-2). After several test reactions by varying
Scheme 11. Transformation of isoxazoline (�)-41 derived form 1,5-cyclo-
octadiene through ROM/CM.
°
experimental conditions [temperature (0 C, room temper-
ature, reflux), solvent (CH2Cl2/THF), reaction time], con-
cycloalkene-fused β-lactams and isoxazolines through cyclo- version of (�)-42 was detected only in the case of HG-2
additions, followed by various metathesis strategies. Similar catalyst (Scheme 12). Note, that in the case of G-1, G-2, and
Scheme 12. Transformation of (�)-42 with methyl acrylate through CM reaction.
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Scheme 13. Transformation of (�)-42 with methyl vinyl ketone through CM reaction.
HG-1 under reflux conditions at prolonged reaction time, the attempts to significantly affect the ratio of the substances
formation of unidentified polymeric materials was observed.
failed.
Since prolonged heating resulted in certain polymerization,
Compound (�)-42 was subjected to CM with methyl
acrylate by varying the amount of the ester and the catalyst. an obvious conclusion was to decompose the activity of the
The best conversion in CM was attained by using the ester in catalyst thereby avoiding polymerization taking place in the
high excess (10 equiv). However, the amount of catalyst (HG- concentrated reaction mixture. Consequently, we modified the
2, 3 mol%, 5 mol% or 10 mol%) did not significantly affect reaction workup by the addition of 2 drops of water. Thus,
the outcome regarding the conversion of the metathesis when the reaction was carried out under reflux for 2 h, a
reaction. The reaction of (�)-42 with methyl acrylate at reflux decrease of the dimetathesized product yield was observed
for 2 h afforded three products: monometathesized compounds [(�)-44, 42%]. In contrast, the isolated yield of monocoupled
(�)-45 and (�)-46 and dicoupled derivative (�)-44. The product (�)-46 increased to 10%, while the yield of the other
products, after concentration of the reaction mixture, could be monocoupled product (�)-45 was practically unchanged.
separated by means of column chromatography and charac- When the same reaction was performed at room temperature
terized on the basis of 2D NMR spectroscopic data providing for 2 h, only trace amounts of the CM products could be
CM products in 4%, 2%, and 62% isolated yields detected. However, when this CM was repeated at room
(Scheme 12, Table 1). Note, that a prolonged heating resulted temperature for a prolonged time (6 h), the yield of
in a decrease of the yield of CM products, accompanied by the monometathesized products (�)-45 and (�)-46 increased
formation of polymeric substances. Efforts have been per- significantly (Table 1, entry 4). Note, that the two mono-
formed in view of the modification of the ratio of the three coupled products [(�)-45, (�)-46] and dicoupled product
products to access monocoupled products. Unfortunately, all (�)-44 could be separated and isolated by chromatography,
and their structures were certified by means of 2D NMR
spectroscopy (COSY, HSQC, HMBC).
We continued our experimental investigations in view of
the formation of novel Michael acceptor scaffolds, by using
Table 1.
methyl vinyl ketone, another CM partner, containing a CÀ C
Entry Temperature Reaction Catalyst Yield of Yield of Yield of
double bond. In a few preliminary studies performed at reflux
time
(�)-45 (�)-46 (�)-44
temperature, we found only unidentifiable polymeric materials.
At room temperature after 6 h, in contrast, both expected
monocoupled derivatives (�)-47 and (�)-48 as well as
dicoupled CM product (�)-43 were formed. After successful
separation, the desired product materials were isolated in
moderate yields (Scheme 13, Table 2).
1*
reflux
2 h
2 h
2 h
6 h
HG-2 4%
HG-2 4%
2%
62%
42%
2** reflux
3** RT
4** RT
10%
traces of CM products
HG-2 22%
15%
32%
*workup without addition of H2O – **workup with the addition of 2
drops of H2O
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Organofluorine chemistry is considered to be a rapidly
expanding hot topic area during the last two decades. Because
of the high impact of fluorine-containing molecules in drug
design (approximately 25% of the drugs introduced to the
market contain one or more fluorine atoms) and agriculture,
the synthesis of fluorinated organic derivatives has been
recognized to be an increasing research area in synthetic
organic chemistry.[15] Moreover, the availability of a range of
fluorine-containing substrates as well as the discovery of
metathesis catalysts, tolerant to various functional groups, have
broadened the utility of metathesis strategies for the con-
struction of versatile fluorinated scaffolds.[15f]
Taking into consideration the above-mentioned relevance
of fluorine-containing organic molecules, we planned to
continue our experimental investigations with the application
of some readily available commercial fluorinated olefins as CM
partner derivatives. These included 2-bromo-3,3,3-trifluoro-
prop-1-ene, methyl 2-fluoroacrylate, 4-bromo-3,3,4,4-tetra-
fluorobut-1-ene, allyl 2,2,2-trifluoroacetate, and 2,2,2-trifluor-
oethyl acrylate. Note, that although we performed some
preliminary CM metathesis experiments using lactams derived
from cyclooctadiene or norbornadiene with fluorine-contain-
ing metathesis partners, these gave only very limited results.[12f]
CM experiments with the above-mentioned fluorine-
containing olefins have been systematically accomplished in
CH2Cl2 by variation of reaction temperature, time or type of
catalyst, and catalyst loading. It was observed that CM product
(s) were not formed with 2-bromo-3,3,3-trifluoroprop-1-ene
and methyl 2-fluoroacrylate. At reflux temperature at a longer
reaction time, again, only unidentifiable polymeric substances
could be detected (Table 3).
Table 2.
Entry Temperature Reaction Catalyst Yield of Yield of Yield of
time
(�)-47 (�)-48 (�)-43
HG-2 25% 41% 26%
1
2
RT
reflux
6 h
2 h
HG-2 unidentifiable polymeric
materials
Table 3. Reactions of isoxazoline (�)-42
Entry Olefin
Temp. Time
Catalyst Yield of
metathesis
product
RT or
Δ
2 to
1
2
(*)
(*)
0%
0%
24 h
RT or
Δ
2 to
24 h
3
4
5
RT
RT
Δ
6 h
HG-2
HG-2
HG-2
5% (**)
4% (**)
9% (**)
24 h
4 h
Unfortunately, the reaction with 4-bromo-3,3,4,4-tetra-
fluorobut-1-ene also proved to be unsuccessful. Although a
conversion to CM products occurred in the presence of HG-2
catalyst, only an inseparable mixture of mono- and dimetathe-
sized products (�)-49, (�)-50, and (�)-51 was formed in
very low yields (Table 3, Scheme 14).
(*) catalyst: G-1, G-2, HG-1, HG-2 – (**) mixtures of monocoupled
products (�)-49 and (�)-50 was detected (approximately in an 1:1
ratio)
In continuation, two fluorine-containing esters were
submitted to CM with (�)-42. In several attempts allyl 2,2,2-
trifluoroacetate provided no CM products at room temper-
ature. At reflux temperature, somewhat surprisingly, only
monometathesized compounds (�)-52 and (�)-53 were
detected, and the formation of the expected dicoupled product
was not observed. Although the monocoupled substances were
formed in modest yields, they could be separated and isolated
by means of column chromatography (Scheme 15, Table 4).
Interestingly, a somewhat similar outcome of the CM
reaction of (�)-42 with 2,2,2-trifluoroethyl acrylate could be
found. Again, the dimetathesized product was not formed at
reflux temperature. Instead, the reaction resulted in both
monocoupled derivatives (�)-55 and (�)-56, which were
separated, isolated, and characterized (Scheme 16, Table 5).
Table 4.
Entry Temperature Reaction Catalyst Yield of Yield of Yield of
time
(�)-52 (�)-53 (�)-54
HG-2 14% 12% 0%
1
2
reflux
RT
6 h
6 h
HG-2 traces of metathesis
products
Table 5.
Entry Temperature Reaction Catalyst Yield of Yield of Yield of
time
(�)-55 (�)-55 (�)-57
1
2
reflux
RT
7 h
7 h
G-2
G-2
22%
16%
0%
traces of metathesis
products
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Scheme 14. Transformation of (�)-42 with 4-bromo-3,3,4,4-tetrafluorobut-1-ene through CM reaction.
Scheme 15. Transformation of (�)-42 with allyl 2,2,2-trifluoroacetate through CM reaction.
Scheme 16. Transformation of (�)-42 with 2,2,2-trifluoroethyl acrylate through CM reaction.
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4. Conclusions
T H E C H E M I C A L R E C O R D
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In the current paper diversity-oriented synthetic procedures
have been described for the access of versatile functionalized,
three-dimensional small molecules. Chemical transformations
were based on the functionalization of cyclodienes across
cycloadditions performed with chlorosulfonyl isocyanate or
nitrile oxides. The obtained cycloalkene-fused β-lactams or
isoxazolines were converted via their ring olefin bond involving
ring-opening metathesis to the corresponding dialkenylated β-
lactams or isoxazolines. Then the products were subjected to
cross-metathesis, affording novel functionalized molecular
entities under stereocontrol. The chemical behavior of the olefin
bonds was also studied under varied experimental conditions
with chemodifferentiation taking place in their cross-meta-
thesis transformations. Further experiments in view of the
extension of the synthetic procedures thereby described,
regarding selectivity, substrate and reagent scope as well as the
conversion and robustness are currently under investigation in
our group.
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Acknowledgments
We are grateful to the Hungarian Research Foundation
(NKFIH No K 119282) for financial support. The financial
support of the GINOP-2.3.2-15-2016-00060 project is also
acknowledged. This research was supported by the EU-funded
Hungarian grant EFOP-3.6.1-16-2016-00008. Ministry of
Human Capacities, Hungary grant 20391-3/2018/FEKUS-
TRAT is also acknowledged.
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Manuscript received: June 11, 2020
Revised manuscript received: July 5, 2020
Version of record online: ■■ ■■, ■■■■
Chem. Rec. 2020, 20, 1–14
© 2020 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Wiley Online Library
13

PERSONAL ACCOUNT
L. Kiss*, Z. Benke, A. M. Remete, F.
Fülöp*
1 – 14
Diversity-oriented Functionalization
of Cyclodienes Through Selective
Cycloaddition/Ring-opening/Cross-
metathesis Protocols; Transforma-
tion of a “Flatland” into Three-di-
mensional Scaffolds With Stereo-
and Regiocontrol
The article describes selective transforma-
tions of some readily available cyclodienes
through simple chemical procedures into
novel functionalized small-molecular
entities. The syntheses were based
opening metathesis of the resulting β-
lactam or isoxazoline scaffolds and
selective cross-metathesis by discrimina-
tion of the olefin bonds on the alkeny-
lated heterocycles.
selective cycloadditions, followed by ring-