Chemodivergent and Stereoselective Access to Fused Isoxazoline Azetidines and Thietanes through [3 + 2]-Cycloadditions

Article abstract of DOI:10.1021/acs.orglett.8b02848

By combining efficient methodologies for the preparation of substituted azetines and thietes with a highly regio- and diastereoselective [3 + 2]-cycloaddition, a straightforward pathway for the synthesis of fused isoxazoline azetidines and thietanes has been designed. With minimal steps and starting from commercial sources, a new library of elaborated architectures was synthesized opening up a new class of molecules with large potential in pharmacology. Finally, a retro [2 + 2]-cycloaddition leading to substituted isoxazoles is described.

Full text of DOI:10.1021/acs.orglett.8b02848

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Chemodivergent and Stereoselective Access to Fused Isoxazoline
Azetidines and Thietanes through [3 + 2]-Cycloadditions
Andreas N. Baumann, Felix Reiners, Thomas Juli, and Dorian Didier*
̈
̈
Department of Chemistry and Pharmacy, Ludwig-Maximilians-Universitat Munchen, Butenandtstraße 5-13, 81377 Munich,
Germany
S
* Supporting Information
ABSTRACT: By combining efficient methodologies for the
preparation of substituted azetines and thietes with a highly
regio- and diastereoselective [3 + 2]-cycloaddition, a
straightforward pathway for the synthesis of fused isoxazoline
azetidines and thietanes has been designed. With minimal
steps and starting from commercial sources, a new library of
elaborated architectures was synthesized opening up a new
class of molecules with large potential in pharmacology.
Finally, a retro [2 + 2]-cycloaddition leading to substituted isoxazoles is described.
riven by the ever-increasing pace of drug discovery, small
rings, particularly strained cyclobutenes and their hetero-
D
cyclic analogs azetines and thietes, have gained increased
attention due to their great range of reactivity. The unique
possibilities afforded by strained bonds in organic synthesis have
beendignifiedfordecades.RecentadvancesbythegroupofBaran
and Carreira demonstrated the tremendous significance of
strained bioisosteres such as propellanes,1 azetidines,2 and
oxetanes3 in synthesis. Above all, there is an urgent need to
bring such groups directly and economically onto core scaffolds.
Driven by the need to push the boundaries of unexplored
structural libraries, we recently reported the synthesis of new
buildingblocks containingcyclobutenes,4 azetines,5 andthietes.6
These allowed us to develop new methodologies toward the
stereocontrolled formation of alkylidenecyclobutanes,7 alkylide-
neazetidines,8 and cyclopropylketones9 formed by oxidative ring
contraction of cyclobutenes.
Outlined herein is the stereoselective formation of fused
isoxazoline derivatives containing azetidine- and thietane-cores
by [3 + 2] dipolar cycloadditions with nitrile oxides.10 Notably,
besides the well-known β-lactams penicillin and cephalosporin,
isoxazoles, isoxazolines, and the fully saturated isoxazolidine
variantscanbefoundinnumerousbioactivesubstances11 (Figure
1). Among these very important classes of compounds, several
fused azetidine-containing substances have shown interesting
tumor activities.12 In addition, thietane cores present attractive
pharmacological properties and have been used as pesticides,13
sweetener,14 and anticancer15 drugs. Moreover, the oxidized
thietanes were described as powerful enzyme inhibitors,16
antidepressants,17 antitumor agents,18 and herbicides.19
Only a few reports describe the formation of the isoxazoline
core fused with an azetidine/thietane20 moiety, and with
restrained variety and efficiency. To fill this gap, our general
sequence for generating complexity in a modular fashion starts
withtheformationofsubstitutedunsaturatedazetinesandthietes.
In our previous work we used organometallic species such as
Figure 1. Few examples of biologically active fused four-and five-
membered heterocycles.
Grignard or lithium reagents for 1,2-nucleophilic additions on
commerciallyavailable3-thietanone6 1and1-Boc-3-azetidinone5
4 (Scheme 1) to obtain the corresponding tertiary alcohols.
Following a sequence that we recently reported,6 thiete
derivatives 3 were accessed in good yields (51 to 78%) through
intermediateformationoftertiaryalcohols2.Similarly, azetines6
were synthesized in good to excellent yields (66 to 98%), in a
sequencebasedonakeyα-lithiationofmethylatedalcohols5.21 3-
Azetinyllithium intermediates can then be used in electrophilic
trapping reactions with H2O or with boron isopropoxide. Room
temperature stable organoboronates were also used in Suzuki−
Received: September 6, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02848
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reactions performed at 80 to 100 °C proved to give the expected
products at higher rates. Running the transformationsin pressure
tubesgreatlyimprovedtheoverallconversions,butoptimalyields
were obtained under microwave irradiations (entries 1−4/6 and
7−9).Finally,theintroductionofanexcessof9a(3equiv)proved
tobeinevitable,mostlyduetoitsdimerization.Itbecameapparent
that the amount of triethylamine plays an important role, being
essential to the formation of the 1,3-dipole during the reaction.
Reactiontimestocompletionwerefurtherimprovedbyswitching
thesolventtodichloromethane(entry8), whilesimilarrateswere
observed when employing ethyl acetate instead of diethyl ether.
With an optimized cycloaddition sequence in hand, 3-
phenylthiete 3a was first used to establish the scope of 1,3 dipoles
9a−g (for details, see Supporting Information, SI) and to
investigate the regioselectivity and diastereoselectivity of the
fused thietanes (Scheme 2). Electron-donating groups on the
hydroxyl-imidoylchloride increased the yield (7b, 97%), whereas
the presence of electron-withdrawing substituents tended to
decrease the conversion into the desired compounds (7c, 90%).
Halo-substituted hydroxyl-imidoylchloride furnished 7d−e in
good yields (up to 90%). Due to the monosubstitution of the
dipolarophiles 3, only one regioisomer (see below) together with
diastereoselectivity higher than 97% was obtained. With 3-
naphtylthiete 3b, goodtoexcellentyieldswereisolated(7h−j, up
to 92%).
Scheme 1. Previous Work on Functionalization of Azetines
and Thietes and Their Transformation in [3 + 2]-
Cycloadditions
a
Thescopeofthetransformationwasestablishedbyemployinga
range of different substituted 3-thietes such as 4-methoxy-phenyl
3c, 4-fluoro-phenyl 3d, 3-bromo-phenyl 3e, and 4- or 2-biphenyl
3f/g,leadingtoasmalllibraryofunprecedentedfusedthietanesin
good to excellent yields (7k−v). It is worth noting that, using 3i
led to 7w in moderate yields (57%), X-ray crystallography
supported the proposed stereochemical outcome of this trans-
formation. Taking advantage of a simple access to substituted
thietes that we developed previously, we pushed the method
further by engaging 3-heteroarylated thiete 3j with N-
hydroxybenzimidoyl chloride 9a and N-hydroxy-4-methoxyben-
zimidoyl chloride 9b to isolate 7y−z in good to excellent yields
(84 to 94%). Switching the group on position 3 for a butyl chain
(3l) furnished the corresponding thietanes 7ab−ac in 84% and
94% yields, respectively. Unfortunately, [3 + 2] strategies on 2,3-
disubstituted-thietesdidnotaffordthedesiredfusedringsystems.
According to this simple transformation, we started to explore
[3 + 2]-cycloadditions with 3-substituted azetines.
Therefore, we used azetidines 5a−e to form mono-substituted
azetines, employing a deprotonation/elimination/deprotona-
tion/electrophilic-trappingsequence(Scheme3).Thoseazetines
were directly engaged without prior purification in [3 + 2]-
cycloadditionswithhydroxyl-imidoylchlorides9a−b. Duetothe
rearrangement and ring opening under slightly acidic conditions,
no further purification of the 3-substituted azetines were
implemented. However, for compound 8g an isolation of the 3-
azetine was possible, thus showing the efficiency of the [3 + 2]-
cycloaddition by a very good yield of 91%. Without any
purification at intermediate steps, arylated building blocks 5a−
d afforded sophisticated architectures 8a−f/h in moderate to
good yields as a single regioisomer and with high stereochemical
ratios.Itisalsoworthnotingthattheregiochemistryappearstobe
inverse compared to the thietes. Looking at the different
regiochemical outcomes of thietes and azetines after successful
[3 + 2]-cycloaddition with nitrile oxides 9a−g, a side-inversed
attack of the 1,3-dipole was observed (Figure 2). First, due to
different electronic effects on the carbon atoms 2 and 3, we
propose afavored approach with the congruent charge ( )of the
a
For 3/6: (a) Organolithium (M = Li) or organomagnesium (M =
MgBr) (1.2 equiv); reactions were performed in THF at −30 °C. For
3: (b) mCPBA (2 equiv), CH2Cl2, 0 °C to rt. (c) MsCl (3 equiv),
NEt3 (3 equiv), CH2Cl2, rt. For 6: (d) NaH, MeI, THF, 0 °C to rt.
(e) s-BuLi (2 equiv), TMEDA (1 equiv), THF, −78 °C.
Miyaura cross-coupling, affording 2,3-bis-arylated azetines.5
With efficient access to diversely substituted azetines 6 and
thietes 3, dipolar [3 + 2]-cycloadditions were undertaken.
To tackle the ambitious formation of complex fused ring
systems, we first performed optimizations to find adequate
conditions for the [3 + 2]-cycloaddition. Therefore, different
solvents, temperatures, techniques, and equivalents of the
unexpansiveoreasilyprepared22 N-hydroxybenzimidoylchloride
9a were tested (Table 1). While lower temperature did not afford
full conversions over prolonged periods of time (entries 4 and 5),
Table 1. Optimization in [3 + 2]-Cycloadditions
a
NEt3
(equiv)
temp
(°C)
9
time
(h)
conv (%)
7a/8a
entry solvent
(equiv)
b
1
2
3
4
5
6
7
8
9
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
CH2Cl2
EtOAc
1
2
4
4
4
6
6
6
6
80
80
80
40
rt
80
1
2
2
2
2
2
2
3
3
16
16
16
16
16
16
2
30/25
89/85
94/90
78/77
68/55
92/93
90/89
97/95
80/81
b
b
b
b
c
100
100
100
c
1.5
1.5
c
a
b
c
Determined by GC. Pressure tube. Microwave irradiations (6 bar).
B
DOI: 10.1021/acs.orglett.8b02848
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. [3 + 2]-Cycloaddition Towards Fused Isoxazoline
Thietanes
Scheme 3. Lithiation/Electrophilic-Trapping/[3 + 2]-
Cycloaddition Sequence Towards Fused Isoxazoline
Azetidines
a
b
0.5 mmol scale. s-BuLi (2.0 equiv), TMEDA (2.0 equiv) THF, −78
c
d
°C, 1 h. Excess, −78 °C to rt. 1,3-Dipole (2.5 equiv), CH2Cl2, 100
e
°C, 6 bar, 1 h, microwave irradiations. Isolated yield over all steps.
f
Isolated yield for step 4.
Figure 2. Proposed transition states for the [3 + 2]-cycloaddition with
nitrile oxide 9a.
Next, 2,3-disubstituted azetines were examined. In a similar
sequence, azetidines 5 were employed in the formation of the
lithiated intermediate C, andthe corresponding boronatespecies
were generatedby additionof boronisopropoxide (Scheme 4). A
subsequent Suzuki cross-coupling was performed in the presence
of Pd(dppf)Cl2·CH2Cl2 (4 mol %) and the appropriate coupling
partner (aryl iodides). Without additional purification, the
corresponding 2,3-disubstituted azetines were subjected to [3 +
2]-cycloadditions under optimized conditions. With aryl groups
on both sides, poor control of the regioselectivity was witnessed,
as a mixture of two regioisomers 10a/b (1:4.5) and 11a/b (1:3)
was isolated, showing, however, excellent diastereoisomeric
ratios. This observationsuggests thatelectron densities ofcarbon
atoms 2 and 3 are not as distinct as in monosubstituted azetines,
hence decreasing regioisomeric ratios of the transformation
a
b
0.1 mmol scale. 1,3-dipole (3 equiv), CH2Cl2, 100 °C, 6 bar, 1 h,
c
microwave irradiations. X-ray structures are reported in the SI.
1,3-dipoletothedipolarophile,thusformingasix-electronHuckel
̈
aromatic transition state.23 Second, the Boc-group in azetine
structures presumably reinforces the regiocontrol through
favorable steric repulsion, the transition state of which being
potentially stabilized by electrostatic interactions between the
two aromatic moieties and leading to one regioisomer.
C
DOI: 10.1021/acs.orglett.8b02848
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. [3 + 2]-Cycloaddition of 2-Substituted Azetines
Scheme 5. Retro-[2 + 2]-Cycloadditions Towards
Functionalized Isoxazoles
a
b
muchmorestablethantheazetidinederivatives.Fullysubstituted
isoxazoles 15d−f were also obtained in excellent yields (93 to
95%). It is important to note that isoxazole motifs are present in a
number of biologically active compounds such as the analog of
ciprofloxacin (Scheme 5).24
0.5 mmol scale. s-BuLi (2.0 equiv), TMEDA (2.0 equiv) THF, −78
c
°C, 1 h. B(OiPr)3 (1.5 equiv), −78 °C, 1 h then 0 °C, 1 h.
d
Pd(dppf)Cl2.CH2Cl2 (4 mol %), Ar−I (1 equiv), NaOH (3 equiv),
e
rt, 48 h. 1,3-Dipole (3 equiv), CH2Cl2, 100 °C, 6 bar, 1 h, μ-wave.
f
1,3-Dipole (2.5 equiv), CH2Cl2, rt, 1 h.
In summary, we have unlocked a new library of unique
isoxazolines fused with azetidine or thietane moieties with great
diastereoselectivity and regioselectivity. Moreover, using fused
isoxazoline azetidines, a new pathway to unprecedented
disubstituted isoxazoles is provided. This surely represents a
valuable tool for drug discovery and opens up an entire platform
for high throughput screenings.
(Figure2). Bearinganalkylchainatposition3andanarylchainat
position 2, the regioselectivity of the reaction raises to 16:1 (12a
and 12b), pointing out the significant role of electronic
interactions in the transition state. Consequently, the disub-
stitutedazetine6cfurnished12ingoodyield(83%)andexcellent
regioisomericratio(16:1). Incontrast, monosubstitutedazetines
atposition2(6dand6e)gaveexclusivelyoneregioisomer,and13
and 14 were isolated in 60 to 66% yields over 5 steps.
It is worth noting that the reaction already proceeded in
satisfying rate at room temperature without microwave
irradiation, pointingout the higherreactivity of theselast systems
compared to previously mentioned examples.
Considering the broad versatility of this synthetic method, we
finallysetouttoaccessdisubstitutedisoxazolesthroughretro-[2+
2]-cycloadditions (Scheme 5). Brønsted acid-catalyzed con-
ditions were applied, and the transformation proceeded in
quantitative yields within a few minutes at room temperature,
driven by the favorable formation of an aromatic ring (15a−c).
Additional support of the regiochemical outcome of the [3 + 2]
cycloaddition was provided by unambiguous assignments of
NMR signals on isoxazoles. Noteworthy, engaging previously
synthesized thietanes under same conditions, no transformation
to isoxazoles took place, concluding that these compounds are
ASSOCIATED CONTENT
■
S
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.8b02848.
Experimental procedures and characterization (IR,
HRMS,and1Hand13CNMRdata)forallnewcompounds
(PDF)
Accession Codes
CCDC 1863063−1863064 and 1872242 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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DOI: 10.1021/acs.orglett.8b02848
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
B.; Vozzolo, L.; Mok, B. J.; Lee, C. C.; Fitzmaurice, R. J.; Caddick, S.;
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dorian.didier@cup.uni-muenchen.de.
ORCID
̈
̈
Oravilahti,T.;Perakyla,M.;Palvimo,J.J.;Ihalainen,J.A.;Laatikainen,R.;
Pulkkinen, J. T. J. Med. Chem. 2012, 55, 6316−6327. (e) Song, M.-Y.;
Cao, C.-Y.; He, Q.-R.; Dong, Q.-M.; Li, D.; Tang, J.-J.; Gao, J.-M. Bioorg.
Med.Chem.2017,25,5290.(f)Castellano,S.;Kuck,D.;Viviano,M.;Yoo,
Andreas N. Baumann: 0000-0002-2811-1787
Dorian Didier: 0000-0002-6358-1485
Notes
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J.;Lopez-Vallejo,F.;Conti,P.;Tamborini,L.;Pinto, A.;Medina-Franco,
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The authors declare no competing financial interest.
(13) Renold, P.; Zambach, W.; Maienfisch, P.; Muehlebach, M. PCT
Int. Appl. WO2009080250.
ACKNOWLEDGMENTS
■
(14) Brennan, T. M.; Hendrick, M. E. U.S. 4411925.
D.D., A.N.B., and F.R. are grateful to the Fonds der Chemischen
Industrie,theDeutscheForschungsgemeinschaft(DFGgrant:DI
2227/2-1), the SFB749, and Ludwig-Maximilians University for
Ph.D. funding and financial support. Dr. Peter Mayer (LMU−
Munich) is kindly acknowledged for X-ray measurements.
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