Microbial conversion of indene to indandiol: a key intermediate in the synthesis of CRIXIVAN.
Indene is oxidized to mixtures of cis- and trans-indandiols and related metabolites by Pseudomonas putida and Rhodococcus sp. isolates. Indene metabolism is consistent with monooxygenase and dioxygenase activity. P. putida resolves enantiomeric mixtures of cis-1,2-indandiol by further selective oxidation of the 1R, 2S-enantiomer yielding high enantiomeric purity of cis-(1S, 2R)-indandiol, a potential intermediate in the synthesis of indinavir sulfate (CRIXIVAN), a protease inhibitor used in the treatment of AIDS. Molecular cloning of P. putida toluene dioxygenase in Escherichia coli confirmed the requirement for the dihydrodiol dehydrogenase in resolving racemic mixtures of cis-indandiol. Rhodococcus sp. isolates convert indene to cis-(1S, 2R)-indandiol at high initial enantiomeric excess and one isolate also produces trans-(1R, 2R)-indandiol, suggesting the presence of monooxygenase activity. Scale up and optimization of the bioconversions to these key synthons for chiral synthesis of potential intermediates for commercial manufacture of indinavir sulfate are described.
Buckland
B C
BC
Department of Bioprocess Research and Development, Merck & Co., Rahway, New Jersey, USA.
Drew
S W
SW
Connors
N C
NC
Chartrain
M M
MM
Lee
C
C
Salmon
P M
PM
Gbewonyo
K
K
Zhou
W
W
Gailliot
P
P
Singhvi
R
R
Olewinski
R C
RC
Sun
W J
WJ
Reddy
J
J
Zhang
J
J
Jackey
B A
BA
Taylor
C
C
Goklen
K E
KE
Junker
B
B
Greasham
R L
RL
D015195:Drug Design; D005818:Genetic Engineering; D017320:HIV Protease Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D007189:Indans / Q000378:metabolism*; D007192:Indenes / Q000378:metabolism*; D019469:Indinavir / Q000378:metabolism* / Q000494:pharmacology; D010105:Oxygenases / Q000235:genetics / Q000378:metabolism; D016958:Pseudomonas putida / Q000235:genetics / Q000378:metabolism*
D017320:HIV Protease Inhibitors; D007189:Indans; D007192:Indenes; D019469:Indinavir; C093581:indene; D010105:Oxygenases; C023172:toluene dioxygenase