Synthesis of Rocaglamide Natural Products Via Photochemical Generation of Oxidopyrylium Species

A method for preparing a compound with an aglain core structure, the method comprising steps of:

• producing an oxidopyrylium species (IT) by photoinduced excited state intramolecular proton transfer of a 3-hydroxychromone derivative (I);
• and
• reacting the oxidopyrylium species with a dipolarophile (IV) to obtain the aglain core-containing compound (V), wherein compounds (I), (IT), (IV) and (V) have the following chemical structures:
• wherein R1, R2, R3, R4, Rx, Ra and Rb are identical or different and selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkyl, thioaryl, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —NO2, —CN, —CF3, —CH2CF3, —CHCl2, —CH2OH, —CH2CH2OH, —CH2SO2CH3, —C(—O)Rx, —CO2(Rx), —C(═O)N(Rx)2, —OC(═O)N(Rx)2, —OC(═O)Rx, —OCO2Rx, —S(O)Rx, —S(O)2Rx, —NRx(CO)Rx, —N(Rx)CO2Rx, —N(Rx)C(═O)N(Rx)2, —N(Rx)S(O)2Rx, and —S(O)2N(R)2,
• wherein each occurrence of Rx is independently selected from the group consisting of hydrogen, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, and heteroaryl.

A method for preparing a compound with an aglain core structure, the method comprising steps of:

• producing an oxidopyrylium species (IIT) by photoinduced excited state intramolecular proton transfer of a 3-hydroxyflavone derivative (II);
• and
• reacting the oxidopyrylium species with a dipolarophile (IV) to obtain the aglain core-containing compound (V′), wherein compounds (II), (IIT), (IV) and (V′) have the following chemical structures:
• wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, Ra and Rb are identical or different and selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkyl, thioaryl, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —NO2, —CN, —CF3, —CH2CF3, —CHCl2, —CH2OH, —CH2CH2OH, —CH2SO2CH3, —C(═O)Rx, —CO2(Rx), —C(═O)N(Rx)2, —OC(═O)N(Rx)2, —OC(═O)Rx, —OCO2Rx, —S(O)Rx, —S(O)2Rx, —NRx(CO)Rx, —N(Rx)CO2Rx, —N(Rx)C(═O)N(Rx)2, —N(Rx)S(O)2Rx, and —S(O)2N(Rx)2,
• wherein each occurrence of Rx is independently selected from the group consisting of hydrogen, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, and heteroaryl.

A method for preparing an aglain derivative, the method comprising steps of:

• producing an oxidopyrylium species (IT) by photoinduced excited state intramolecular proton transfer of a 3-hydroxychromone derivative (I);
• reacting the oxidopyrylium species with a dipolarophile (IV) to obtain a compound with an aglain core structure (V);
• and
• converting the compound with an aglain core structure into an aglain derivative (VI), wherein compounds (I), (IT), (IV), (V) and (VI) have the following chemical structures:
• wherein R1, R2, R3, R4, R, Ra and Rb are identical or different and selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkyl, thioaryl, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —NO2, —CN, —CF3, —CH2CF3, —CHCl2, —CH2OH, —CH2CH2OH, —CH2SO2CH3, —C(═O)Rx, —CO2(Rx), —C(═O)N(Rx)2, —OC(═O)N(Rx)2, —OC(═O)Rx, —OCO2Rx, —S(O)Rx, —S(O)2Rx, —NRx(CO)Rx, —N(R—)CO2Rx, —N(Rx)C(═O)N(Rx)2, —N(Rx)S(O)2Rx, and —S(O)2N(Rx)2,
• wherein each occurrence of Rx is independently selected from the group consisting of hydrogen, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, and heteroaryl;
• and
• wherein R′ is selected from the group consisting of hydrogen, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —CH2OH, —CH2CH2OH, —CH2SO2CH3, —C(═O)Rx, —CO2(Rx), —C(═O)N(Rx)2, —S(O)Rx, —NRx(CO)Rx, —N(Rx)CO2Rx, —N(Rx)C(═O)N(Rx)2, and —N(Rx)S(O)2Rx,
• wherein each occurrence of Rx is independently selected from the group consisting of hydrogen, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, and heteroaryl.

A method for preparing an aglain derivative, the method comprising steps of:

• producing an oxidopyrylium species (IIT) by photoinduced excited state intramolecular proton transfer of a 3-hydroxyflavone derivative (II);
• reacting the oxidopyrylium species with a dipolarophile (IV) to obtain a compound with an aglain core structure (V′);
• and
• converting the compound with an aglain core structure into an aglain derivative (VI′), wherein compounds (II), (IIT), (IV), (V′) and (VI′) have the following chemical structures:
• wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, Ra and Rb are identical or different and selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkyl, thioaryl, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —NO2, —CN, —CF3, —CH2CF3, —CHCl2, —CH2OH, —CH2CH2OH, —CH2SO2CH3, —C(═O)Rx, —CO2(Rx), —C(═O)N(Rx)2, —OC(═O)N(Rx)2, —OC(═O)Rx, —OCO2Rx, —S(O)Rx, —S(O)2Rx, —NRx(CO)Rx, —N(Rx)CO2Rx, —N(Rx)C(═O)N(Rx)2, —N(Rx)S(O)2Rx, and —S(O)2N(Rx)2,
• wherein each occurrence of Rx is independently selected from the group consisting of hydrogen, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, and heteroaryl;
• and
• wherein R′ is selected from the group consisting of hydrogen, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —CH2OH, —CH2CH2OH, —CH2SO2CH3, —C(═O)Rx, —CO2(Rx), —C(—O)N(Rx)2, —S(O)Rx, —NRx(CO)Rx, —N(Rx)CO2Rx, —N(Rx)C(═O)N(Rx)2, and —N(Rx)S(O)2Rx,
• wherein each occurrence of Rx is independently selected from the group consisting of hydrogen, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, and heteroaryl.

A method for preparing a rocaglamide derivative, the method comprising steps of:

• producing an oxidopyrylium species (IT) by photoinduced excited state intramolecular proton transfer of a 3-hydroxychromone derivative (I);
• reacting the oxidopyrylium species obtained with a dipolarophile (IV) to obtain a compound with an aglain core structure (V);
• and
• converting the compound with an aglain core structure into a rocaglamide derivative (VII), wherein compounds (I), (IT), (IV), (V), and (VII) have the following chemical structures:
• wherein R1, R2, R3, R4, Rx, Ra and Rb are identical or different and selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkyl, thioaryl, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —NO2, —CN, —CF3, —CH2CF3, —CHCl2, —CH2OH, —CH2CH2OH, —CH2SO2CH3, C(═O)Rx, —CO2(Rx), —C(═O)N(Rx)2, —OC(═O)N(Rx)2, —OC(═O)Rx, —OCO2Rx, —S(O)Rx, —S(O)2Rx, —NRx(CO)Rx, —N(Rx)CO2Rx, —N(Rx)C(═O)N(Rx)2, —N(Rx)S(O)2Rx, and —S(O)2N(Rx)2,
• wherein each occurrence of Rx is independently selected from the group consisting of hydrogen, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, and heteroaryl.

A method for preparing a rocaglamide derivative, the method comprising steps of:

• producing an oxidopyrylium species (IIT) by photoinduced excited state intramolecular proton transfer of a 3-hydroxyflavone derivative (II);
• reacting the oxidopyrylium species obtained with a dipolarophile (IV) to obtain a compound with an aglain core structure (V′);
• and
• converting the compound with an aglain core structure into a rocaglamide derivative (VII′), wherein compounds (II), (IIT), (IV), (V′), and (VII′) have the following chemical structures:
• wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, Ra and Rb are identical or different and selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkyl, thioaryl, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —NO2, —CN, —CF3, —CH2CF3, —CHCl2, —CH2OH, —CH2CH2OH, —CH2SO2CH3, —C(═O)Rx, —CO2(Rx), —C(═O)N(Rx)2, —OC(═O)N(Rx)2, —OC(—O)Rx, —OCO2Rx, —S(O)Rx, —S(O)2Rx, —NRx(CO)Rx, —N(Rx)CO2Rx, —N(Rx)C(═O)N(Rx)2, —N(Rx)S(O)2Rx, and —S(O)2N(Rx)2,
• wherein each occurrence of Rx is independently selected from the group consisting of hydrogen, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, and heteroaryl.

A method for preparing a rocaglamide derivative, the method comprising steps of:

• producing an oxidopyrylium species (IT) by photoinduced excited state intramolecular proton transfer of a 3-hydroxychromone derivative (I);
• reacting the oxidopyrylium species obtained with a dipolarophile (IV) to obtain a compound with an aglain core structure (V);
• and
• converting the compound with an aglain core structure into a rocaglamide derivative (VIII), wherein compounds (I), (IT), (IV), (V), and (VIII) have the following chemical structures:
• wherein R1, R2, R3, R4, Rx, Ra and Rb are identical or different and selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkyl, thioaryl, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —NO2, —CN, —CF3, —CH2CF3, —CHCl2, —CH2OH, —CH2CH2OH, —CH2SO2CH3, —C(═O)Rx, —CO2(Rx), —C(═O)N(Rx)2, —OC(═O)N(Rx)2, —OC(═O)Rx, —OCO2Rx, —S(O)Rx, —S(O)2Rx, —NRx(CO)Rx, —N(Rx)CO2Rx, —N(Rx)C(═O)N(Rx)2, —N(Rx)S(O)2Rx, and —S(O)2N(Rx)2,
• wherein each occurrence of Rx is independently selected from the group consisting of hydrogen, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, and heteroaryl;
• and
• wherein R′ is selected from the group consisting of hydrogen, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —CH2OH, —CH2CH2OH, —CH2SO2CH3, —C(═O)Rx, —CO2(Rx), —C(—O)N(Rx)2, —S(O)Rx, —NRx(CO)Rx, —N(Rx)CO2Rx, —N(Rx)C(═O)N(Rx)2, and —N(Rx)S(O)2Rx,
• wherein each occurrence of Rx is independently selected from the group consisting of hydrogen, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, and heteroaryl.

A method for preparing a rocaglamide derivative, the method comprising steps of:

• producing an oxidopyrylium species (IIT) by photoinduced excited state intramolecular proton transfer of a 3-hydroxyflavone derivative (II);
• reacting the oxidopyrylium species obtained with a dipolarophile (IV) to obtain a compound with an aglain core structure (V′);
• and
• converting the compound with an aglain core structure into a rocaglamide derivative (VIII′), wherein compounds (II), (IIT), (IV), (V′), and (VIII′) have the following chemical structures:
• wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, Ra and Rb are identical or different and selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkyl, thioaryl, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —NO2, —CN, —CF3, —CH2CF3, —CHCl2, —CH2OH, —CH2CH2OH, —CH2SO2CH3, —C(═O)Rx, —CO2(Rx), —C(═O)N(Rx)2, —OC(═O)N(Rx)2, —OC(—O)Rx, —OCO2Rx, —S(O)Rx, —S(O)2Rx, —NRx(CO)Rx, —N(Rx)CO2R—, —N(Rx)C(═O)N(Rx)2, —N(Rx)S(O)2Rx, and —S(O)2N(Rx)2,
• wherein each occurrence of Rx is independently selected from the group consisting of hydrogen, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, and heteroaryl;
• and
• wherein R′ is selected from the group consisting of hydrogen, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —CH2OH, —CH2CH2OH, —CH2SO2CH3, —C(═O)Rx, —CO2(Rx), —C(═O)N(Rx)2, —S(O)Rx, —NRx(CO)Rx, —N(Rx)CO2Rx, —N(Rx)C(═O)N(Rx)2, and —N(Rx)S(O)2Rx,
• wherein each occurrence of Rx is independently selected from the group consisting of hydrogen, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, and heteroaryl.

A method for preparing a forbaglin derivative, the method comprising steps of:

• producing an oxidopyrylium species (IT) by photoinduced excited state intramolecular proton transfer of a 3-hydroxychromone derivative (I);
• reacting the oxidopyrylium species obtained with a dipolarophile (IV) to obtain a compound with an aglain core structure (V);
• and
• converting the compound with an aglain care into a forbaglin derivative (IX), wherein compounds (I), (IT), (IV), (V) and (IX) have the following chemical structures:
• wherein R1, R2, R3, R4, R, R″, Ra and Rb are identical or different and selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkyl, thioaryl, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —NO2, —CN, —CF3, —CH2CF3, —CHCl2, —CH2OH, —CH2CH2OH, —CH2SO2CH3, —C(═O)Rx, —CO2(Rx), —C(═O)N(Rx)2, —OC(═O)N(Rx)2, —OC(—O)Rx, —OCO2Rx, —S(O)Rx, —S(O)2Rx, —NRx(CO)Rx, —N(Rx)CO2Rx, —N(Rx)C(═O)N(Rx)2, —N(Rx)S(O)2Rx, and —S(O)2N(Rx)2,
• wherein each occurrence of Rx is independently selected from the group consisting of hydrogen, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, and heteroaryl.

A method for preparing a forbaglin derivative, the method comprising steps of:

• producing an oxidopyrylium species (IIT) by photoinduced excited state intramolecular proton transfer of a 3-hydroxyflavone derivative (II);
• reacting the oxidopyrylium species obtained with a dipolarophile (IV) to obtain a compound with an aglain core structure (V′);
• and
• converting the compound with an aglain core into a forbaglin derivative (IX′), wherein compounds (II), (IIT), (IV), (V′) and (IX′) have the following chemical structures:
• wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R″, Ra and Rb are identical or different and selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkyl, thioaryl, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —NO2, —CN, —CF3, —CH2CF3, —CHCl2, —CH2OH, —CH2CH2OH, —CH2SO2CH3, —C(═O)Rx, —CO2(Rx), —C(═O)N(Rx)2, —OC(═O)N(Rx)2, —OC(═O)Rx, —OCO2Rx, —S(O)Rx, —S(O)2Rx, —NRx(CO)Rx, —N(Rx)CO2Rx, —N(Rx)C(═O)N(Rx)2, —N(Rx)S(O)2Rx, and —S(O)2N(Rx)2,
• wherein each occurrence of Rx is independently selected from the group consisting of hydrogen, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, and heteroaryl.