Antifungal compound process
The present invention relates to a process for preparing compound 1 that is useful as an antifungal agent. In particular, the invention seeks to provide new methodology for preparing compound 1 and substituted derivatives thereof.
1. A compound of formula VI* or VIa*, or a mixture thereof:
wherein each R 1 is independently halo or
each Y 1 is independently —OH, —OSO 2 -alkyl, —OSO 2 -substituted alkyl, —OSO 2 -aryl, —OSO 2 -substituted aryl, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)— substituted aryl, or halogen; and
each R 12 is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted hetrocyclyl.
2. The compound of claim 1 , wherein the compound has the formula:
wherein
Y is independently —OH, mesylate, or tosylate; and
each R 1 is independently, halo or
3. A process to prepare compound of formula VI* or VIa*, or a mixture thereof:
comprising
(i) reacting ester 6,
with morpholine to provide morpholine amide 7:
(ii) reacting morpholine amide 7:
with
to provide ketone 3,
(iii) performing olefination of ketone 3,
to provide olefin 2-5,
(iv) reacting olefin 2-5,
under asymmetric dihydroxylation conditions to provide a compound of formula 2-6b or 2-6d,
or a mixture thereof;
(v) activating the primary alcohol of 2-6b or 2-6d to provide VI* or VIa*
or a mixture thereof;
wherein M is Mg or MgX; and X is halogen;
the asymmetric dihydroxylation conditions comprise:
(i) AD-mix alpha or AD-mix beta; or
(ii) a first oxidant in catalytic amount selected from OsO 4 or K 2 OsO 2 (OH) 4 ;
(iii) a second oxidant in stoichiometric amount selected from K 3 Fe(CN) 6 or N-methylmorpholine-N-oxide;
(iv) a base selected from NaHCO 3 , Na 2 CO 3 , Cs 2 CO 3 , or K 2 CO 3 ; and
(v) a chiral ligand that is selected from (DHQ) 2 PHAL, (DHQD) 2 PHAL, (DHQD) 2 AQN, (DHQ) 2 AQN, (DHQD) 2 PYR, and (DHQ) 2 PYR; and
each R 1 is independently, halo or
each Y 1 is independently —OH, —OSO 2 -alkyl, —OSO 2 -substituted alkyl, —OSO 2 -aryl, —OSO 2 -substituted aryl, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)— substituted aryl, or halogen; and
each R 12 is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted hetrocyclyl.