Synthesis and Reactivity of Donor-Acceptor Substituted Aminocyclopropanes and Aminocyclobutanes

329 Pages·2016·37.695 MB·English

by  Florian Nanteuil (auth.)

Springer Theses
Recognizing Outstanding Ph.D. Research
Florian de Nanteuil

Synthesis and
Reactivity of Donor-
Acceptor Substituted
Aminocyclopropanes
and Aminocyclobutanes
Springer Theses
Recognizing Outstanding Ph.D. Research
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Florian de Nanteuil
Synthesis and Reactivity
of Donor-Acceptor
Substituted
Aminocyclopropanes
and Aminocyclobutanes
Doctoral Thesis accepted by
EPFL, the Swiss Federal Institute of Technology
in Lausanne, Switzerland
123
Author Supervisor
Dr. Florian deNanteuil Prof. Jérôme Waser
InstitutdesSciencesetIngénierieChimiques InstitutdesSciencesetIngénierieChimiques
SwissFederal Institute of Technology SwissFederal Institute of Technology
inLausanne inLausanne
Lausanne Lausanne
Switzerland Switzerland
ISSN 2190-5053 ISSN 2190-5061 (electronic)
SpringerTheses
ISBN978-3-319-23005-4 ISBN978-3-319-23006-1 (eBook)
DOI 10.1007/978-3-319-23006-1
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Parts of this thesis have been published in:
1. [4 + 2] Annulations of Aminocyclobutanes
Perrotta, D.; Racine, S.; Vuilleumier, J.; de Nanteuil, F.; Waser J. Org. Lett.
2015, ASAP, DOI: 10.1021/acs.orglett.5b00149.
2. Diester-Substituted Aminocyclopropanes: Synthesis and Use in [3 + 2]
Annulation Reactions.
Serrano E.; de Nanteuil F.; Waser J. Synlett, 2014, 25, 2285.
3. Synthesis of (Carbo)nucleoside Analogues via [3 + 2] Annulation of
Aminocyclopropanes.
Racine S.; de Nanteuil, F.; Serrano E.; Waser J. Angew. Chem., Int. Ed. 2014,
53, 8484-8487.
4. Dynamic Kinetic Asymmetric [3 + 2] Annulation Reactions of Aminocy-
clopropanes.
deNanteuil,F.;SerranoE.;PerrottaD.;WaserJ.J.Am.Chem.Soc.2014,136,
6239.
5. Synthesis of Aminocyclobutanes via Iron-Catalyzed [2 + 2] Cycloaddition.
de Nanteuil, F.; Waser J. Angew. Chem. Int. Ed. 2013, 52, 9009.
6. Catalytic Friedel-Crafts Reaction of Aminocyclopropanes.
de Nanteuil, F.; Loup, J; Waser J. Org. Lett. 2013, doi10.1021/ol401616a.
7. Catalytic Enantiospecific [3 + 2] Annulation of Aminocyclopropanes with
Ketones
Benfatti F.; de Nanteuil, F.; Waser J. Chem. Eur. J. 2012, 18, 4844.
8. Iron-Catalyzed [3 + 2] Annulation of Aminocyclopropanes with Aldehydes:
Stereoselective Synthesis of Aminotetrahydrofurans
Benfatti F.; de Nanteuil, F.; Waser J. Org. Lett. 2012, 14, 386.
9. Catalytic [3 + 2] Annulation of Aminocyclopropanes for the Enantiospecific
Synthesis of Cyclopentylamines
de Nanteuil, F.; Waser J. Angew. Chem. Int. Ed. 2011, 50, 12075.
’
Supervisor s Foreword
Many natural products display a saturated polycyclic core allowing a well-defined
arrangement of functional groups in space. They can therefore interact with bio-
logical targets with high affinity and selectivity, surpassing many synthetic drugs.
Nitrogen-containing functional groups are especially important, as the higher
electron-density of nitrogen allows stronger hydrogen bonding in biological sys-
tems.Nevertheless, theefficientsynthesis ofsuchcomplexring systems represents
a challenge for organic chemistry.
In this thesis, a general approach for accessing nitrogen-substituted hetero- and
carbocycles is presented. Through careful tuning of the electronic properties of a
nitrogen donor group and a diester acceptor group, the first [3 + 2] annulation
reaction between aminocyclopropanes and enol ethers or carbonyl compounds
became possible. The reaction proceeded under mild catalytic conditions. The
obtainedbuildingblockscanbefoundatthecoreofbioactivealkaloids,drugssuch
as Ramipril and biomolecules such as DNA and RNA. Access to enantioenriched
compoundsbecamepossiblethroughthedynamickineticasymmetricannulationof
aminocyclopropanes with enol ethers and aldehydes. This impressive transforma-
tion process was mediated by a copper catalyst bearing a commercially available
ligand and gave both cyclopentylamines and tetrahydrofurylamines in high yield
and enantioselectivity. Finally, a synthesis of donor–acceptor aminocyclobutanes
via[2+2]cycloadditionusingacheapironcatalystwasdeveloped,andtheycould
be used in [4 + 2] annulations to access cyclohexylamines.
In short, the annulation reactions developed in this thesis give access to
nitrogen-substituted four-, five- and six-membered rings, all essential building
blocks for the synthesis of bioactive compounds. These important fundamental
results can now be used to synthesize libraries of molecules for the discovery of
new bioactive chemical entities. In fact, the methodology could already be applied
in our group to the synthesis of new nucleoside analogues bearing thimine, uracil
andfluorouracilnucleobases.Whenconsideringthatabout45nucleosideanalogues
are FDA approved drugs and that the synthesized compounds have unprecedented
structures, the obtained molecules could well lead to exciting results in currently
vii
viii Supervisor’sForeword
ongoing biological tests. From the fundamental point of view, the synthetic
potential of nitrogen-substituted small rings has just begun to be investigated, and
I am certain that the work described in this thesis will serve as basis for the
discovery of new modes of C-C bond activation, catalytic methods or unprece-
dented chemical structures, and will ultimately result in the efficient synthesis of
bioactive natural products and synthetic drugs.
Lausanne Prof. Jérôme Waser
February 2015
Abstract
The development of new methodologies in organic synthesis can greatly impact
related fields such as medicinal chemistry, material science, molecular biology or
environmental science. The complexity of the molecular scaffolds required is
increasing, as is the demand for selective and efficient synthetic processes.
Additionally,thequestforenvironmentallybenignprotocolsoperatingatthelowest
possible cost are parameters which should be taken into consideration when
developing new reactions.
Molecules containing cyclic scaffolds substituted by nitrogen are ubiquitous in
natural products such as indole alkaloids or DNA nucleotides as well as in highly
potent synthetic pharmaceuticals. There is a high demand for efficient access to
these structures in order to discover molecules with new fields of applications.
The annulation of a formal dipole with a dipolarophile provides a very con-
vergent way to access carbo or heterocyclic structures via the construction of
multiple carbon-carbon bonds in one step. Donor–acceptor substituted cyclopro-
panes are known, when activated by a catalyst, to generate reactive 1,3 formal
dipoles.Therefore,theuseofnitrogen-substituteddonor–acceptorcyclopropanesin
annulationreactionswouldprovideanefficientaccesstonitrogen-substitutedcyclic
structures. The goal of this thesis was to investigate, for the first time, the inter-
molecular reactivity of aminocyclopropanes as 1,3 formal dipoles.
In this context, we developed the first catalytic [3 + 2] annulation of aminocy-
clopropaneswithenolethers.Thereactionrequiredphthalimide-substituteddonor–
acceptor cyclopropanes that were easily accessed in one step. The use of a tin
catalyst afforded a wide range of polysubstituted cyclopentylamines with high
diastereoselectivityandyieldsupto99%.Themethodoccurredwithfulltransferof
stereogenic information affording the products in enantioenriched form.
The first annulation of aminocyclopropanes with aldehydes was then reported.
Aneasy-to-handle,innocuousandinexpensiveiron-basedcatalystwasusedforthis
purpose. The use of the same phthalimide-substituted cyclopropane as before
allowed the isolation of substituted heterocycles in excellent diastereoselectivities
and yields up to99 %. The 2-aminotetrahydrofuran scaffolds arefound in thecore
ofDNAandRNAmolecules.Inordertoincreasethepotentialofourmethods,we
ix
x Abstract
adapted the reaction to less reactive ketones. In this case, the use of the same
catalyticsystemthanforenolethersgaveaminotetrahydrofuranswithaquaternary
C5 atom in high yields. The reaction turned out to be diastereoselective as well as
enantiospecific, allowing the isolation of the valuable analogues with an enantio-
meric ratio of 98:2.
Again,phthalimide-substituteddonor–acceptorcyclopropaneswereshowntobe
efficient electrophilic acceptors in the scandium triflate catalyzed Friedel-Crafts
alkylationofaromaticnucleophiles.Indolessubstitutedwithelectron-richaswellas
electron-poor groups were efficiently alkylated in the C3 position. When
C3-substituted indoles were employed, a cationic rearrangement afforded the
C2-alkylated products. The reaction tolerated a broad range of aromatic nucleo-
philes and afforded gamma amino acid derivatives present in important pharma-
cophores with high yields.
In order to access enantioenriched five-membered carbo- and heterocycles
without requiring an enantiopure starting material, we developed the first dynamic
kinetic asymmetric [3 + 2] annulation reaction of aminocyclopropanes with enol
ethers and aldehydes. The donating functionality had to be optimized and it was
found that succinimide substituted donor–acceptor cyclopropanes gave optimal
results. The reaction was catalyzed by a copper complex in combination with a
commercially available bisoxazoline ligand and tolerated both enol ethers and
aldehydes as partners. The cyclopentylamines and aminotetrahydrofurans were
obtained in up to 99 % yield and a 98:2 enantiomeric ratio. In order to expand the
range of accessible nitrogen-substituted cyclic structures, the reactivity of amino-
cyclobutanes as 1,4 dipoles was also investigated. First, an efficient access to
donor–acceptorsubstitutedaminocyclobutaneswasdeveloped.Usingthesameiron
catalyst as for the annulation of aldehydes with cyclopropanes, [2 + 2] cycload-
dition between enimides and alkylidene malonates afforded aminocyclobutanes
with a broad range of substituents. The products were obtained with yields up to
96%yieldsanddiastereoselectivitiessuperiorto20:1.Thereactionwasoptimized
inordertobeconductedeasilyonamultigramscale.Theproductswereconverted
to peptide surrogates in a three-step protocol.
Finally, these donor-acceptor substituted aminocyclobutanes were successfully
used as formal 1,4 dipoles in annulations with silyl enol ethers. Using tin tetra-
chloride at -40 °C afforded the six-membered ring analogues in yields up to 98 %
and with diastereoselectivities up to 20:1.
(cid:1) (cid:1)
Keywords Donor-acceptor substituted cyclopropanes Aminocyclopropanes
(cid:1) (cid:1)
[3+2]annulations Dynamickineticasymmetrictransformation Donor-acceptor
(cid:1) (cid:1)
substituted cyclobutanes Aminocyclobutanes [4 + 2] annulations