Organokatalizirana asimetrična sinteza derivatov dihidropiranopirola

Gregorc, Jure (avtor), Grošelj, Uroš (mentor)

V sklopu magistrskega dela sem se ukvarjal z organokatalizirano asimetrično [4+2] anuluacijo (hetero)arilidenskih derivatov Δ2-pirolin-4-ona z malononitrilom. Na modelni asimetrični pretvorbi N-metil substituiranega benzilidenskega Δ2-pirolin-4-ona sem optimiziral reakcijske pogoje (topilo, razmerje reaktantov, temperatura) ter izvedel pregled vpliva prisotnih katalitskih količin različnih kiralnih nekovalentnih bifunkcionalnih organokatalizatorjev na enantioselektivnost reakcije. Z reakcijo pri optimiziranih pogojih in ob uporabi najbolj učinkovitega bifunkcionalnega organokatalizatorja (kinuklidinska osnova z vsebovanim skvaramidnim motivom), mi je uspelo izolirati enantiomerno obogaten biciklični produkt modelne anulacije z dobrim izkoristkom (97 % ee, 92 % izkoristek, večinski (S)-enantiomer). Ista reakcija, izvedena v metanolu, je dala produkt z obrnjeno stereoselektivnostjo (93% ee; večinski (R)-enantiomer), kar je izredno redko opaženo v literaturi. Po vzpostavitvi optimiziranih pogojev sem izvedel pregled obsega reakcije (angl. ''scope'') z obravnavo enantioselektivnosti organokataliziranih [4+2] anulacij reprezentativnih, na (hetero)arilnem mestu variiranih, N-metil substituiranih derivatov Δ2-pirolin-4-ona. Sintetiziral sem racemne, na (hetero)aromatskem delu variirane dihidropiranopirole z reakcijo ustreznih Δ2-pirolin-4-onov in malononitrila v prisotnosti katalitskih količin akiralnega 1,2-diaminskega organokatalizatorja. Izolirane produkte sem ustrezno okarakteriziral in za vsakega določil pogoje ločbe enantiomerov na kiralni koloni z metodo HPLC. Pri vzpostavljenih optimiziranih asimetričnih reakcijskih pogojih sem izvedel anulacije reprezentativnih izhodnih Δ2-pirolin-4-onov in okarakteriziral izolirane neracemne produkte. Organokatalizirana pretvorba je v večini primerov potekala z visoko enantioselektivnostjo in relativno visokimi izkoristki (15 produktov, ee do 99 %, tipični izkoristki med 68 % in 97 %). Absolutna konfiguracija večinskega (S)-enantiomera je bila določena z rentgensko difrakcijo pridobljenega monokristala končnega produkta asimetrične pretvorbe. Sorodna reakcija N-nesubstituiranega benziliden Δ2-pirolin-4-onskega derivata je dala psevdo-enantiomerni produkt (99 % ee, večinski (R)-izomer), kar je v skladu s konfiguracijo izhodnega alkena ((Z)-alken→večinski (R)-produkt; (E)-alken→večinski (S)-produkt). Visoka enantioselektivnost obravnavane organokatalizirane [4+2] anulacije kaže na uporabnost razvitega pristopa za dostop do optično čistih bicikličnih gradnikov, tako kot tudi še dodatno ponazarja potencial tovrstnih nenasičenih heterocikličnih sistemov (Δ2-pirolin-4-oni) kot uporabnih substratov za razvoj novih organokataliziranih kaskadnih reakcij.

• Jezik: Slovenski jezik
• Ključne besede: bifunkcionalna nekovalentna organokataliza, asimetrična organokataliza, anulacija, Δ2-pirolin-4-oni, pirano[3, 2-b]pirol, malononitril.
• Vrsta gradiva: Magistrsko delo/naloga
• Tipologija: 2.09 - Magistrsko delo
• Organizacija: FKKT - Fakulteta za kemijo in kemijsko tehnologijo
• Leto izida: 2020
• PID: 20.500.12556/RUL-118757
• COBISS.SI-ID: 27819779
• Datum objave v RUL: 31.08.2020

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: Organocatalyzed asymmetric synthesis of dihydropyranopyrrole derivatives

Izvleček

Within the framework of this master thesis, I performed research on the organocatalyzed asymmetric [4+2] annulation of (hetero)arylidene Δ2-pyrrolin-4-one derivatives with malononitrile. Optimization of the reaction conditions (solvent, reaction stoichiometry, temperature) and evaluation of the effect of different chiral noncovalent bifunctional organocatalysts on the stereochemical outcome of the model asymmetric transformation of N-methyl substituted benzylidene Δ2-pyrrolin-4-one derivative was performed. The reaction under optimized conditions and with the use of the optimal bifunctional organocatalyst (quinine derivative with a squaramide moiety) resulted in the isolation of the enantiomerically enriched annulated bicyclic compound in high yield (97% ee, 92% yield, major (S)-enantiomer). The same reaction performed in methanol resulted in unprecedented reversal of stereoselectivity (93% ee; major (R)-enantiomer). Having established the optimal reaction conditions, the next step was to determine the scope of the investigated transformation by evaluating the stereoselectivity of the organocatalyzed [4+2] annulation of the representative N-methyl substituted (hetero)arylidene Δ2-pyrrolin-4-one derivatives. Racemic (hetero)aryl dihydropyranopyrrole derivatives were prepared with the reaction of a series of Δ2-pyrrolin-4-ones with malononitrile in the presence of an achiral 1,2-diamine organocatalyst. Isolated products were characterized and the enantiomer separation conditions were determined by HPLC analysis (use of chiral columns). Under the established optimal asymmetric conditions, transformations of the representative substrates provided the corresponding non-racemic pyranopyrroles. In most cases, the products were isolated with high enantioselectivity and moderate to high yields (15 products, up to 99% ee, typical yield between 68% and 97%). The absolute configuration of the major (S)-enantiomer of the non-racemic pyranopyrrole product was determined by a single crystal X-ray analysis. Analogous reaction of N-unsubstituted benzylidene Δ2-pyrrolin-4-one derivative gave the pseudo-enantiomeric product (99 % ee, major (R)-isomer), which is in line with the configuration of the starting alkene ((Z)-alkene→major (R)-product; (E)-alkene→major (S)-product). The high enantioselectivity of the investigated organocatalyzed [4+2] annulation proved to be a viable strategy for accessing such enantiomerically pure bicyclic compounds, as well as points to the potential use of similar unsaturated heterocyclic scaffolds (Δ2-pyrrolin-4-ones) as substrates for the further development of novel organocatalyzed cascade reactions.

• Ključne besede: bifunctional noncovalent organocatalysis, asymmetric organocatalysis, annulation, Δ2-pyrrolin-4-one, pyrano[3, 2-b]pyrroles, malononitrile.