Synthesis of tetracyclines and intermediates thereto

A method of preparing an enone of formula (VII):

• wherein:
• R3 and R4 are each independently hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORB;
• —CH2ORB;
• —CH2RB;
• —CH2N(RB)2;
• —C(═O)RB;
• —CO2RB;
• —CN;
• —SCN;
• —SRB;
• —SORB;
• —SO2RB;
• —N3;
• —NO2;
• —N(RB)2;
• —NHC(O)RB;
• —NHSO2RB;
• or —C(RB)3;
• wherein each occurrence of RB is independently hydrogen, halogen, azido, a protecting group, aliphatic, heteroaliphatic, haloaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio;
• or R3 and R4 are taken together to form ═O or ═C(RB)2;
• R5, R9, and R11 are each independently hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORC;
• —CH2ORC;
• —CH2RC;
• —CH2N(RC)2;
• —C(═O)RC;
• —CO2RC;
• —CN;
• —SCN;
• —SRC;
• —SORC;
• —SO2RC;
• —N3;
• —NO2;
• —N(RC)2;
• —NHC(O)RC;
• —NHSO2RC;
• or —C(RC)3;
• R10 is hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORC;
• —CH2ORC;
• —CH2RC;
• —CH2N(RC)2;
• —C(═O)RC;
• —CO2RC;
• —CN;
• —SCN;
• —SRC;
• —SORC;
• —SO2RC;
• —N3;
• —NO2;
• —N(RC)2;
• —NHC(O)RC;
• —NHSO2RC;
• or —C(RC)3;
• each occurrence of RC is independently hydrogen, halogen, azido, a protecting group, aliphatic, heteroaliphatic, haloaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio;
• each RP is independently hydrogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, haloaliphatic, a protecting group, substituted or unsubstituted acyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• the method comprising steps of:
• (a) deprotonating an isoxazole of formula (I):
• with a suitable base under suitable conditions and reacting it with an enone of formula (II):
• wherein:
• each occurrence of RQ is independently hydrogen, a C1-6 alkyl, —Si(ORZ)3, or —Si(RZ)3, and
• each occurrence of RZ is independently hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• or a substituted or unsubstituted heteroaryl;
• to yield a compound of formula (III):
• wherein M is a counterion generated by the suitable base;
• (b) treating the compound of formula (III) with a suitable base under suitable conditions to yield a compound of formula (IV):
• (c) heating the compound (IV) in a suitable solvent to yield a compound of formula (V):
• (d) deprotonating the compound of formula (V) with a suitable base under suitable conditions and reacting with an electrophile to give a enone of formula (VI):
• wherein R10 is hydrogen;
• (e) optionally treating the enone of formula (VI) with a suitable reagent to give a 1,4-addition product of formula (VI) wherein:
• R10 is halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORC;
• —CH2ORC;
• —CH2RC;
• —CH2N(RC)2;
• —C(═O)RC;
• —CO2RC;
• —CN;
• —SCN;
• —SRC;
• —SORC;
• —SO2RC;
• —N3;
• —NO2;
• —N(RC)2;
• —NHC(O)RC;
• —NHSO2RC;
• or —C(RC)3, and each occurrence of RC is independently hydrogen, halogen, azido, a protecting group, aliphatic, heteroaliphatic, haloaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio;
• and
• (f) treating the enone (VI) with a suitable acid under suitable conditions to epimerize R5 and yield the enone of formula (VII).

A method of preparing an enone of formula (VIIa):

• wherein:
• R5 and R11 are each independently hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORC;
• —CH2ORC;
• —CH2RC;
• —CH2N(RC)2;
• —C(═O)RC;
• —CO2RC;
• —CN;
• —SCN;
• —SRC;
• —SORC;
• —SO2RC;
• —N3;
• —NO2;
• —N(RC)2;
• —NHC(O)RC;
• —NHSO2RC;
• or —C(RC)3;
• R9 is alkyl;
• R10 is hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORC;
• —CH2ORC;
• —CH2RC;
• —CH2N(RC)2;
• —C(═O)RC;
• —CO2RC;
• —CN;
• —SCN;
• —SRC;
• —SORC;
• —SO2RC;
• —N3;
• —NO2;
• —N(RC)2;
• —NHC(O)RC;
• —NHSO2RC;
• or —C(RC)3;
• each occurrence of RC is independently hydrogen, halogen, azido, a protecting group, aliphatic, heteroaliphatic, haloaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio;
• RP is hydrogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, haloaliphatic, a protecting group, substituted or unsubstituted acyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• the method comprising steps of:
• (a) providing a compound of formula:
• wherein:
• each occurrence of RQ is independently hydrogen, a C1-6 alkyl, —Si(ORZ)3, or —Si(RZ)3, and RZ is independently hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• or a substituted or unsubstituted heteroaryl;
• (b) performing an allylic displacement with an organocuprate reagent to give a compound of formula:
• (c) oxidizing the alcohol moiety with an oxidant to give a compound of formula:
• (d) treating the resulting compound with a base to form an enone of formula (IIa):
• wherein R9 is alkyl;
• (e) deprotonating an isoxazole of formula (I):
• with a suitable base under suitable conditions and reacting it with the enone of formula (II) from step (d) to yield a compound of formula (IVa):
• (f) heating the compound (IVa) in a suitable solvent to yield a compound of formula (VI):
• wherein R10 is hydrogen;
• (g) optionally treating the enone of formula (VIa) with a suitable reagent to give a 1,4-addition product of formula (VIa) wherein R10 is halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORC;
• —CH2ORC;
• —CH2RC;
• —CH2N(RC)2;
• —C(═O)RC;
• —CO2RC;
• —CN;
• —SCN;
• —SRC;
• —SORC;
• —SO2RC;
• —N3;
• —NO2;
• —N(RC)2;
• —NHC(O)RC;
• —NHSO2RC;
• or —C(RC)3;
• and each occurrence of RC is independently hydrogen, halogen, azido, a protecting group, aliphatic, heteroaliphatic, haloaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio;
• (h) treating the enone (VIa) with a suitable acid under suitable conditions to epimerize R5 and yield the enone of formula (VIIa).

A method of preparing an enone of formula (VII):

• wherein:
• R3 and R4 are each independently hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORB;
• —CH2ORB;
• —CH2RB;
• —CH2N(RB)2;
• —C(═O)RB;
• —CO2RB;
• —CN;
• —SCN;
• —SRB;
• —SORB;
• —SO2RB;
• —N3;
• —NO2;
• —N(RB)2;
• —NHC(O)RB;
• —NHSO2RB;
• or —C(RB)3;
• wherein each occurrence of RB is independently hydrogen, halogen, azido, a protecting group, aliphatic, heteroaliphatic, haloaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio;
• or R3 and R4 are taken together to form ═O or ═C(RB)2;
• R5, R9, and R11 are each independently hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORC;
• —CH2ORC;
• —CH2RC;
• —CH2N(RC)2;
• —C(═O)RC;
• —CO2RC;
• —CN;
• —SCN;
• —SRC;
• —SORC;
• —SO2RC;
• —N3;
• —NO2;
• —N(RC)2;
• —NHC(O)RC;
• —NHSO2RC;
• or —C(RC)3;
• R10 is halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORC;
• —CH2ORC;
• —CH2RC;
• —CH2N(RC)2;
• —C(═O)RC;
• —CO2RC;
• —CN;
• —SCN;
• —SRC;
• —SORC;
• —SO2RC;
• —N3;
• —NO2;
• —N(RC)2;
• —NHC(O)RC;
• —NHSO2RC;
• or —C(RC)3;
• each occurrence of RC is independently hydrogen, halogen, azido, a protecting group, aliphatic, heteroaliphatic, haloaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio;
• each RP is independently hydrogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, haloaliphatic, a protecting group, substituted or unsubstituted acyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• the method comprising treating the enone (VI):
• with a suitable acid under suitable conditions to yield the enone of formula (VII).

A method of preparing an enone of formula (VI):

• wherein:
• R3 and R4 are each independently hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORB;
• —CH2ORB;
• —CH2RB;
• —CH2N(RB)2;
• —C(═O)RB;
• —CO2RB;
• —CN;
• —SCN;
• —SRB;
• —SORB;
• —SO2RB;
• —N3;
• —NO2;
• —N(RB)2;
• —NHC(O)RB;
• —NHSO2RB;
• or —C(RB)3;
• wherein each occurrence of RB is independently hydrogen, halogen, azido, a protecting group, aliphatic, heteroaliphatic, haloaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio;
• or R3 and R4 are taken together to form ═O or ═C(RB)2;
• R5, R9, and R11 are each independently hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORC;
• —CH2ORC;
• —CH2RC;
• —CH2N(RC)2;
• —C(═O)RC;
• —CO2RC;
• —CN;
• —SCN;
• —SRC;
• —SORC;
• —SO2RC;
• —N3;
• —NO2;
• —N(RC)2;
• —NHC(O)RC;
• —NHSO2RC;
• or —C(RC)3;
• R10 is hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORC;
• —CH2ORC;
• —CH2RC;
• —CH2N(RC)2;
• —C(═O)RC;
• —CO2RC;
• —CN;
• —SCN;
• —SRC;
• —SORC;
• —SO2RC;
• —N3;
• —NO2;
• —N(RC)2;
• —NHC(O)RC;
• —NHSO2RC;
• or —C(RC)3;
• each occurrence of RC is independently hydrogen, halogen, azido, a protecting group, aliphatic, heteroaliphatic, haloaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio;
• RP is hydrogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, haloaliphatic, a protecting group, substituted or unsubstituted acyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• the method comprising deprotonating the compound of formula (V):
• with a suitable base under suitable conditions and reacting with an electrophile to give a enone of formula (VI).

A method of preparing a compound of formula (V):

• wherein:
• R3 and R4 are each independently hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORB;
• —CH2ORB;
• —CH2RB;
• —CH2N(RB)2;
• —C(═O)RB;
• —CO2RB;
• —CN;
• —SCN;
• —SRB;
• —SORB;
• —SO2RB;
• —N3;
• —NO2;
• —N(RB)2;
• —NHC(O)RB;
• —NHSO2RB;
• or —C(RB)3;
• wherein each occurrence of RB is independently hydrogen, halogen, azido, a protecting group, aliphatic, heteroaliphatic, haloaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio;
• or R3 and R4 are taken together to form ═O or ═C(RB)2;
• R5 and R11 are each independently hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORC;
• —CH2ORC;
• —CH2RC;
• —CH2N(RC)2;
• —C(═O)RC;
• —CO2RC;
• —CN;
• —SCN;
• —SRC;
• —SORC;
• —SO2RC;
• —N3;
• —NO2;
• —N(RC)2;
• —NHC(O)RC;
• —NHSO2RC;
• or —C(RC)3;
• and
• each RP is independently hydrogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, haloaliphatic, a protecting group, substituted or unsubstituted acyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• the method comprising heating the compound (IV):
• wherein:
• each occurrence of RQ is independently hydrogen, a C1-6 alkyl, —Si(ORZ)3, or —Si(RZ)3, and each occurrence of RZ is independently hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• or a substituted or unsubstituted heteroaryl;
• at a suitable temperature in a suitable solvent to yield a compound of formula (V).

A method of preparing an enone of formula (II):

• wherein:
• R3 and R4 are each independently hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORB;
• —CH2ORB;
• —CH2RB;
• —CH2N(RB)2;
• —C(═O)RB;
• —CO2RB;
• —CN;
• —SCN;
• —SRB;
• —SORB;
• —SO2RB;
• —N3;
• —NO2;
• —N(RB)2;
• —NHC(O)RB;
• —NHSO2RB;
• or —C(RB)3;
• wherein each occurrence of RB is independently hydrogen, halogen, azido, a protecting group, aliphatic, heteroaliphatic, haloaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio;
• or R3 and R4 are taken together to form ═O or ═C(RB)2;
• and
• R11 is halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORC;
• —CH2ORC;
• —CH2RC;
• —CH2N(RC)2;
• —C(═O)RC;
• —CO2RC;
• —CN;
• —SCN;
• —SRC;
• —SORC;
• —SO2RC;
• —N3;
• —NO2;
• —N(RC)2;
• —NHC(O)RC;
• —NHSO2RC;
• or —C(RC)3;
• and each occurrence of RC is independently hydrogen, halogen, azido, a protecting group, aliphatic, heteroaliphatic, haloaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio
• each occurrence of RQ is independently hydrogen, a C1-6 alkyl, —Si(ORZ)3, or —Si(RZ)3, and RZ is independently hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted, branched or unbranched acyl;
• substituted or unsubstituted aryl;
• or a substituted or unsubstituted heteroaryl;
• the method comprising:
• (a) treating a compound of formula (II′):
• with a suitable nucleophilic reagent in the presence of a suitable silyl reagent to effect a 1,4-conjugate addition to yield a silyl enol ether of formula (IX):
• wherein R15 is a C1-6 alkyl group;
• and
• (b) treating the silyl enol ether of formula (X) with a suitable reagent to yield the enone of formula (II).

A method of preparing a compound of formula (IIa):

• wherein R9 is alkyl;
• the method comprising steps of:
• (a) providing a compound of formula:
• (b) performing an allylic displacement with an organocuprate reagent to give a compound of formula:
• (c) oxidizing the alcohol moiety with an oxidant to give a compound of formula:
• (d) treating the resulting compound with a base to form an enone of formula (IIa).