Upjohn conditions

Optimization studies undertaken to influence the ratio of products, including temperature, reagent stoichiometry, and solvents were unsuccessful. It was decided that for early evaluation of maraviroc the use of DAST was acceptable. Within the discovery setting, the inseparable mixture of the difluoro and vinyl fluoro cyclohexyl esters 20 and 21 was subjected to Upjohn conditions for dihydroxylation of vinyl fluoro side product 21. After an overnight reaction, the required difluorocyclohexyl ester 20 could be isolated in high purity by flash column chromatography. Saponification gave the acid 11, which could be recrystallized from cyclohexane to furnish analytically pure material. 

Under the frequently used Upjohn-conditions, which employ a solvent mixture of H20 and tert-butanol, loss of 0s04 from the ionic liquid phase can be considerable. Addition of simple amines such as 4-dimethylamino pyridine (DMAP) significantly reduces catalyst leaching due to the formation of a zwitterionic amine-osmium adduct (see Figure 5.3), which is preferably retained in the ionic liquid phase.[62]... 

Of our two approaches, the iterative asymmetric dihydroxylation of dienoates (Scheme 1) is the most efficient in terms of steps (1 to 3 steps). For instance, dienoates, like ethyl sorbate (1.1 R = CH3), react under the Upjohn conditions (OSO4/NMO) 14) o give racemic y-ga/ac/o o-lactones in only one... 

The route used in the conversion 100 ent-98 is shown in Scheme 10 and begins with the conversion of the former compound into the acetal 101 under standard conditions. Dihydroxylation of the non-chlorinated double-bond within the latter compound using the Upjohn conditions [50] provided the diol 102 (66%) in a completely diastereoselective fashion and this was protected as the corresponding di-MOM ether 103 (88%) using MOM chloride in the presence of sodium hydride. Reductive cleavage of the acetal unit within compound 103 was readily effected in a regioselective manner with DIBAl-H and the ensuing alcohol... 

Many different co-oxidants can be used in conjunction with osmium tetroxide for the catalytic dihydroxylation reaction. The most popular is A -methylmorpholine N-oxide (NMO) the use of NMO with less than one equivalent of osmium tetroxide is often referred to as the Upjohn conditions. Other oxidants, such as [K3Fe(CN)6], tert-hutyl hydroperoxide, hydrogen peroxide or bleach are effective. In these reactions, the intermediate osmate ester is oxidized to an osmium(VIII) species that is then hydrolysed with regeneration of osmium tetroxide to continue the cycle. For example, less than 1 mol% of osmium tetroxide is needed for the dihydroxylation of the alkene 74 (5.80). 

Dihydroxylation of alkenes can be accomplished conveniently using catalytic OSO4 and the co-oxidant A-methylmorpholine A-oxide (NMO) in t-Bu0H/H20 (Upjohn conditions, see Scheme 5.80). This occurs by syn addition of the two hydroxy groups... 

Using Upjohn condition (OsOi-NMO). The utility of the Upjohn protocol for the dihydroxylation was recently demonstrated in the synthesis of bicyclic analogues of pentopyranoses, (-)-anisomycin, trisubstituted y-butyrolactone, 6-bromo-4-(l,2-dihydroxyethyl)-7-hydroxycoumarine (Bhc-diol) as a photoremovable protecting group, 3,4-dihydroxy-2-(3-methylbut-2-enyl)-3,4-dihydronaphthalen-l(2//)-one, benzo-[c]pyrano[3,2-/z]acridin-7-ones, both enantiomers of conduri-tol C tetraacetate and of mei o-conduritol-D-tetraacetate. ... 

EXTENSIONS AND COMMENTARY This base, a-ET or etryptamine, was a promising antidepressant, explored clinically as the acetate salt by Upjohn under the name of Monase. Its central stimulant activity is probably not due to its monoamineoxidase inhibition activity, but appears to stem from its structural relationship to the indolic psychedelics. It was withdrawn from potential commercial use with the appearance of an unacceptable incidence of a medical condition known as agranulocytosis, but the extra mural research into its action, among the lay population, goes on. 

Intracavernosal alprostadil was effective and well tolerated in the treatment of erectile dysfunction, according to the results of a 6-month study (funded by Pharmacia Upjohn) in 848 men (mean age 52 years) with at least a 4-month history of erectile dysfunction (12). This is provided that the individual dose is established by titration and patients receive training in injection techniques and periodic supervision during treatment. An initial dose was established for each patient and the patients then administered the alprostadil themselves at home. Of 727 evaluable patients, 682 (94%) had at least one erectile response after the injection of alprostadil, and 88% of injections lead to a satisfactory sexual response. The most commonly reported adverse event was penile pain, reported by 44% of patients, but only after 8% of injections. In just over half of the patients who had penile pain, the condition was reported as mild. Prolonged erection, penile fibrosis, and priapism occurred in 8,4, and 0.9% of patients respectively. Treatment was withdrawn because of medical events in 4% of patients, and drug-related events accounted for treatment withdrawal in 2% of patients. 

And there are opportunities for Biotech. The consolidation within the industry has reduced the number of companies investigating particular diseases or conditions. For example, in cardiovascular disease there are now only three to four truly major players Merck, Astra-Zeneca, Pfizer, and Novartis. In 1991 there were seven companies making antibiotics now there are three, dominated by Pfizer and Abbott. The R D programs of the acquired can be dropped. Pharmacia merged with UpJohn-Searle mostly for its COX-2 inhibitor (Celebrex) it dropped much of the rest of the research programs. Pharmacia is now part of Pfizer, and much of Pharmacia s research portfolio has been similarly dropped. 

Osmium tetroxide is very expensive and very toxic which made using it quite unattractive. For a long time, many people who used osmium tetroxide to convert olefins to diols—and this was long before enantioselective dihydroxylations came on the scene—used the Upjohn procedure.20 This process used catalytic amounts of osmium tetroxide, NMO (/V-methylmorpholine /V-oxidc) 87 as the stoichiometric oxidant, and one solvent phase. The solvent was water, acetone and tert-butyl alcohol. The osmate ester 86 was hydrolysed under these conditions and the osmium (VI) species was reoxidised to 0s04 by NMO. 

One of the problems encountered in the development of the AD reaction was a second cycle.23 The first cycle is the same as the cycle we saw in the Upjohn procedure with one modification. It is possible for the osmium in the osmate (VI) ester to become oxidised before hydrolysis to form an osmate (VIII) ester. If this species simply hydrolyses to diol and 0s04 then there is no problem but otherwise this is where the trouble starts. In the second cycle the osmate (VIII) ester reacts with another olefin instead of being hydrolysed. It does so with low enantioselectivity (and sometimes in the opposite sense to the first cycle) which results in the poorer enantiopurity of the product (step D rather than step C below). One way round this is to keep the olefin concentration as low as possible which can be done by adding the olefin slowly.22,23 Although slow olefin addition resulted in a profound improvement in enantiomeric excess, it was inconvenient and no way near as effective as the alternative which was to alter the conditions. The use of two phases makes it impossible for the second cycle to occur.19,24... 

More common is the general acid- or base-catalyzed addition of HCN to ketones and aldehydes to give cyanohydrins [Eq. (2)] [1]. Because of the propensity of HCN to spontaneously and exothermically polymerize under basic conditions, general acid catalysis is sometimes favored over basic media, as was the case in the recent Sumitomo [3] and Upjohn work [4, 5]. Applications of aqueous media have been reported to lead to asymmetric hydrocyanation catalysis [Eq. (3)] [6, 7]. 

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