Methods of Making High Enantioselective Secondary Alcohols

A method for preparing a compound of Formula 1, comprising:

• step (1a):
• reacting a compound of Formula 2 with a compound of Formula 3a in the presence of BH3, DIP-Chloride, (S)-(−)-1,1′-Bi-2-naphthol, or NaBH4;
• step (1b):
• reacting a product of step (1a) with acetic anhydride (Ac2O);
• and
• step (2):
• reacting a product of step (1b) with:
• (A) lipase acrylic resin, and Na2CO3;
• and reacting a product of step (A) with sodium methoxide in the presence of methanol;
• or
• (B) protease, and Na2CO3,
• wherein R is
• an aliphatic chain, or Rx;
• wherein Rx is hydrogen, an unsubstituted or substituted cyclic ring group, an electron withdrawing group, or an electron donating group.

A method for preparing a compound of Formula 4, comprising:

• step (1):
• reacting a compound of Formula 2 with a compound of Formula 3b in the presence of BH3, DIP-Chloride, (S)-(−)-1,1′-Bi-2-naphthol, or NaBH4;
• and
• step (2):
• reacting a product of step (1) with:
• (A) lipase acrylic resin, Na2CO3, and one of isopropenyl acetate and 2,2,2-trifluoroethyl butyrate;
• and reacting a product of step (A) with sodium methoxide in the presence of methanol;
• or
• (B) protease, Na2CO3, and one of isopropenyl acetate and 2,2,2-trifluoroethyl butyrate,
• wherein R is
• an aliphatic chain, or Rx;
• wherein Rx is hydrogen, an unsubstituted or substituted cyclic ring group, an electron withdrawing group, or an electron donating group.

A method for preparing a compound of Formula 4, comprising:

• step (1a):
• reacting a compound of Formula 2 with a compound of Formula 3b in the presence of BH3, DIP-Chloride, (S)-(−)-1,1′-Bi-2-naphthol, or NaBH4;
• step (1b):
• reacting a product of step (1a) with acetic anhydride (Ac2O);
• and
• step (2):
• reacting a product of step (1b) with:
• (A) lipase acrylic resin, and Na2CO3;
• or
• (B) protease, and Na2CO3;
• and reacting a product of step (A) with sodium methoxide in the presence of methanol
• wherein R is
• an aliphatic chain, or Rx;
• wherein Rx is hydrogen, an unsubstituted or substituted cyclic ring group, an electron withdrawing group, or an electron donating group.

A process for improving a yield or optical purity of compound (R)-1-(3-(3-N,N-dimethylaminocarbonyl)phenoxyl-4-nitrophenyl)-1-ethyl-N,N′-bis(ethylene)phosphoramidate

• and compound (S)-1-(3-(3-N,N-dimethylaminocarbonyl)phenoxyl-4-nitrophenyl)-1-ethyl-N,N′-bis(ethylene)phosphoramidate,
• comprising:
• step (a):
• asymmetric reduction,
• step (b):
• lipase/protease selective protection,
• step (c):
• phosphate installation;
• and
• step (d):
• aziridine formation.