Methods and intermediates useful in the synthesis of hexahydrofuro [2,3-b]furan-3-ol

A process for preparing a compound of Formula 7a:

• comprising:
• (a) combining methanol, ethanol, n-propanol, or i-propanol, and a compound of Formula 1a:
• to give a compound of Formula 3a:
• (b) combining said compound of Formula 3a, morpholine, and EDCL to give a compound of Formula 5a:
• (c) combining said compound of Formula 5a with LiAlH4 to give a compound of Formula 6a:
• or a salt thereof, and
• (d) combining said compound of Formula 6a or a conjugate acid thereof, and NaHSO4 to give said compound of Formula 7a.

A compound of Formula 5:

• or a salt thereof, wherein:
• X is S or O;
• Y is O, —N(R3)—, or a bond;
• R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or —[C(R10)2]m—R11;
• each of R1 R2, and R3 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or —[C(R10)2]m—R11;
• or R1 and R2 taken together with the nitrogen to which they are bonded represent a 3-10 membered optionally substituted heterocyclic ring;
• or R1 and R3 taken together with the nitrogen to which they are bonded represent a 3-10 membered optionally substituted heterocyclic ring;
• R10 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
• R11 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, —OR12, —N(R12)COR13, —N(R12)C(O)OR13, —N(R12)SO2(R13), —CON(R12)(R13), —OC(O)N(R12)(R13), —OC(O)OR12, —CO2R12, —OC(O)R12, —C(O)N(OR12)(R13), or —SO2N(R2)(R3), —N(R2)S(O)2OR13;
• each of R12 and R13 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl;
• or R12 and R13 taken together represent a 5-8 membered optionally substituted heterocyclic ring;
• and
• m is 0-8.

A compound of Formula 3a:

• or a salt thereof, wherein:
• X is S or O;
• R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or —[C(R10)2]m—R11;
• R10 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
• R11 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, —OR12, —N(R12)COR13, —N(R12)C(O)OR13, —N(R12)SO2(R13), —CON(R12)(R13), —OC(O)N(R12)(R13), —OC(O)OR12, —CO2R12, —OC(O)R12, —C(O)N(OR12)(R13), or —SO2N(R12)(R13), —N(R12)S(O)2OR13;
• each of R12 and R13 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl;
• or R12 and R13 taken together represent a 5-8 membered optionally substituted heterocyclic ring;
• and
• m is 0-8;
• provided that when R is 1-butyl, then X is not O;
• further provided that when R is menthyl, then X is not O
• further provided that when R is benzyl, then X is not O.

A compound of Formula 6a:

• or a salt thereof, wherein:
• Y is O, —N(R3)—, or a bond;
• each of R1, R2, and R3 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or —[C(R10)2]m—R11;
• or R1 and R2 taken together with the nitrogen to which they are bonded represent a 3-10 membered optionally substituted heterocyclic ring;
• or R1 and R3 taken together with the nitrogen to which they are bonded represent a 3-10 membered optionally substituted heterocyclic ring;
• R10 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
• R11 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, —OR12, —N(R12)COR13, —N(R12)C(O)OR13, —N(R12)SO2(R13), —CON(R12)(R13), —OC(O)N(R12)(R13), —OC(O)OR12, —CO2R12, —OC(O)R12, —C(O)N(OR12)(R13), or —SO2N(R12)(R13), —N(R12)S(O)2OR13;
• each of R12 and R13 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl;
• or R12 and R13 taken together represent a 5-8 membered optionally substituted heterocyclic ring;
• and
• m is 0-8.

A process for preparing a compound of Formula 7:

• comprising:
• (a) combining an acid and a compound of Formula 3:
• or a salt thereof, wherein:
• Y is O, —N(R3)—, or a bond;
• each of R1 R2, and R3 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or —[C(R10)2]m—R11;
• or R1 and R2 taken together with the nitrogen to which they are bonded represent a 3-10 membered optionally substituted heterocyclic ring;
• or R1 and R3 taken together with the nitrogen to which they are bonded represent a 3-10 membered optionally substituted heterocyclic ring;
• R10 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
• R11 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, —OR12, —N(R12)COR13, —N(R12)C(O)OR13, —N(R12)SO2(R13), —CON(R12)(R13), —OC(O)N(R12)(R13), —OC(O)OR12, —CO2R12, —OC(O)R12, —C(O)N(OR12)(R13), or —SO2N(R12)(R13), —N(R12)S(O)2OR13;
• each of R12 and R13 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl;
• or R12 and R13 taken together represent a 5-8 membered optionally substituted heterocyclic ring;
• and
• m is 0-8;
• to give said compound of Formula 7.

A process for preparing a protease inhibitor comprising:

• (a) combining a reducing agent and a compound of Formula 5a:
• or a salt thereof, wherein:
• X is S or O;
• Y is O, —N(R3)—, or a bond;
• R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or —[C(R10)2]m—R11;
• each of R1 R2, and R3 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or —[C(R10)2]m—R11;
• or R1 and R2 taken together with the nitrogen to which they are bonded represent a 3-10 membered optionally substituted heterocyclic ring;
• or R1 and R3 taken together with the nitrogen to which they are bonded represent a 3-10 membered optionally substituted heterocyclic ring;
• R10 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
• R11 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, —OR12, —N(R12)COR13, —N(R12)C(O)OR13, —N(R12)SO2(R13), —CON(R12)(R13), —OC(O)N(R12)(R13), —OC(O)OR12, —CO2R12, —OC(O)R12, —C(O)N(OR12)(R13), or —SO2N(R12)(R13), —N(R12)S(O)2OR13;
• each of R12 and R13 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl;
• or R12 and R13 taken together represent a 5-8 membered optionally substituted heterocyclic ring;
• and
• m is 0-8;
• to give a compound of Formula 6a:
• or a salt thereof, wherein:
• each of Y, R1 and R2 is as defined above;
• (b) combining said compound of Formula 6a with an acid to give a compound of Formula 7a:
• (c) combining-said compound of Formula 7a with a carbamate coupling agent to give an activated carbonate;
• and
• (d) combining said activated carbonate with an amine containing protease inhibitor precursor.