Method for synthesizing aryl-substituted chiral tetrahydropyran ring via desymmetrization

A method for synthesizing an aryl-substituted chiral tetrahydropyran ring via desymmetrization, comprising the following steps:

• a) alcoholyzing a compound of formula I through organic small-molecule catalysis or enzyme catalysis to obtain a compound of formula III with high chiral purity, wherein a catalyst is selected from 1-((1R,2R)-2-(dimethylamino)cyclohexyl)-3-(4-(trifluoromethyl)phenyl)thiourea, 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(dimethylamino)cyclohexyl)thiourea, 1-(3,5-bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinolin-2-yl)methyl)thiourea, N—((S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinolin-2-yl)methyl)-3,5-bis(trifluoromethyl)benzenesulfonamide, 1-((1R,2R)-2-(dimethylamino)cyclohexyl)-3-phenylthiourea, or Novozym 435 lipase;
• b) reacting the compound of formula III with a methyl metal reagent to obtain a compound of formula IV;
• c) reducing a lactone in the compound of formula IV to obtain a compound of formula V;
• d) subjecting a compound of formula V-A to a copper-catalyzed hydrazination reaction to obtain a compound of formula VI;
• e) subjecting the compound of formula VI to acid-catalyzed Fisher cyclization with a pyruvic acid derivative to obtain a compound of formula VII;
• or step d) being replaced with step f):
• f) allowing a compound of formula V-B to be treated with a metal reagent and react with N,N-dimethylformamide to obtain a compound of formula VIII;
• and
• g) subjecting the compound of formula VIII to cyclization with an acrylic acid derivative to obtain a compound of formula IX;
• wherein the compound of formula I is:
• the compound of formula III is:
• the compound of formula IV is:
• the compound of formula V is:
• the compound of formula V-A is:
• the compound of formula VI is:
• the compound of formula VII is:
• the compound of formula V-B is:
• the compound of formula VIII is:
• and
• the compound of formula IX is:
• wherein in the formulas, X is Cl, Br, I,-OTf,-OMs, or —OTs;
• Y is C or N;
• R1 is C1-C6 alkyl or benzyl;
• R2 is H, Me, Et, iPr, or Bn;
• R3 is H or Boc;
• Z is —OR4;
• R4 is C1-C6 alkyl or —NR5R6;
• R5 is C1-C3 alkyl;
• and R6 is phenyl or substituted phenyl.