Upjohn dihydroxylation

The Upjohn Dihydroxylation allows the sy/i-selective preparation of 1,2-diols from alkenes by the use of 0s04 as a catalyst and a stoichiometric amount of an oxidant such as NMO (N-methyl morpholine- JV-Oxide). 

From the mechanism shown in Scheme 7.23, we would expect the dihydroxylation with syn-selectivity. The cyclic intermediate may be isolated in the osmium reaction, which is formed by the cycloaddition of OSO4 to the alkene. Since osmium tetroxide is highly toxic and very expensive, the reaction is performed using a catalytic amount of osmium tetroxide and an oxidizing agent such as TBHP, sodium chlorate, potassium ferricyanide or NMO, which regenerates osmium tetroxide. For example, Upjohn dihydroxylation allows the syn-selective preparation of 1,2-diols from alkenes by the use of catalytic amount of OSO4 and a stoichiometric amount of an oxidant such as NMO. 

In contrast, using the Achmatowicz approach, only pyranoses were formed. This approach began with the Sharpless dihydroxylation of achiral vinylfuran 5.6 to install the C-5 D-absolute stereochemistry as in 5.7. The fiirfuryl alcohol 5.7 can be stereoselectively converted into the a-spiroketal 5.8 by Achmatowicz oxidation, spiroketalization, Luche reduction and TBS-protection. Upjohn dihydroxylation of 5.8 was used to prepare both the manno-S.9 and allo-SAl isomers, with the manno-isomer being formed as the major isomer (4 1) (14). 

Scheme 5. Upjohn s catalytic dihydroxylation process with 0s04 and 4-methylmorpholine /V-oxide (NMO).

Scheme 6. Corey s synthesis of gibberellic acid GA3 (22) employing the Upjohn catalytic dihydroxylation procedure.

The next key step, the second dihydroxylation, was deferred until the lactone 82 had been formed from compound 80 (Scheme 20). This tactic would alleviate some of the steric hindrance around the C3-C4 double bond, and would create a cyclic molecule which was predicted to have a greater diastereofacial bias. The lactone can be made by first protecting the diol 80 as the acetonide 81 (88 % yield), followed by oxidative cleavage of the two PMB groups with DDQ (86% yield).43 Dihydroxylation of 82 with the standard Upjohn conditions17 furnishes, not unexpectedly, a quantitative yield of the triol 84 as a single diastereoisomer. The triol 84 is presumably fashioned from the initially formed triol 83 by a spontaneous translactonization (see Scheme 20), an event which proved to be a substantial piece of luck, as it simultaneously freed the C-8 hydroxyl from the lactone and protected the C-3 hydroxyl in the alcohol oxidation state. 

Sharpless stoichiometric asymmetric dihydroxylation of alkenes (AD) was converted into a catalytic reaction several years later when it was combined with the procedure of Upjohn involving reoxidation of the metal catalyst with the use of N-oxides [24] (N-methylmorpholine N-oxide). Reported turnover numbers were in the order of 200 (but can be raised to 50,000) and the e.e. for /rara-stilbene exceeded 95% (after isolation 88%). When dihydriquinidine (vide infra) was used the opposite enantiomer was obtained, again showing that quinine and quinidine react like a pair of enantiomers, rather than diastereomers. 

Inclusion in the reaction of a cooxidant serves to return the osmium to the osmium tetroxide level of oxidation and allows for the use of osmium in catalytic amounts. Various cooxidants have been used for this purpose historically, the application of sodium or potassium chlorate in this regard was first reported by Hofmann [7]. Milas and co-workers [8,9] introduced the use of hydrogen peroxide in f-butyl alcohol as an alternative to the metal chlorates. Although catalytic cis dihydroxylation by using perchlorates or hydrogen peroxide usually gives good yields of diols, it is difficult to avoid overoxidation, which with some types of olefins becomes a serious limitation to the method. Superior cooxidants that minimize overoxidation are alkaline t-butylhydroperoxide, introduced by Sharpless and Akashi [10], and tertiary amine oxides such as A - rn e t h y I rn o r p h o I i n e - A - o x i d e (NMO), introduced by VanRheenen, Kelly, and Cha (the Upjohn process) [11], A new, important addition to this list of cooxidants is potassium ferricyanide, introduced by Minato, Yamamoto, and Tsuji in 1990 [12]. 

Diels-AUer reactions. This diene can serve as a precursor to the highly oxygenated cyclohexane derivative shikimic acid (3), as shown in Scheme 1. Oxidative desilylation of the Diels-Alder adduct 2 could not be effected with peracids, but was effected by cis-dihydroxylation (Upjohn procedure, 7, 256-257) followed by p-elimination of (CH3)3SiOH with TsOH. Introduction of the 4a,5P diol system was effected indirectly from the 4a,5a-epoxide in several steps, since direct hydrolysis of the epoxide resulted in a mixture of three triols.1... 

The Sharpless dihydroxylation method has been run at scale by Pharmacia-Upjohn with o-isopropoxy-m-methoxysytrene as substrate and /V-mcthylmorpholine /V-oxide as oxidant.160... 

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. 

The chiral ligand used is based on a phthalazine (PHAL) modified by two dihydroquinidine (DHQD) substituents. Other asymmetric dihydroxylation reactions for the synthesis of pharmaceuticals have been developed at Chirex and Pharmacia/Upjohn. 

Other reoxidants which minimize overoxidation are f-butyl hydroperoxide in the presence of Et4NOH [4], tertiary amine oxides, and most importantly N-methylmorpholine A -oxide (NMO) (Upjohn process) [14], although for tri- and particularly tetrasubstituted alkenes as substrates, trimethylaminoxide is superior to NMO [14 c], The introduction of potassium hexacyanoferrate(III) in the presence of potassium carbonate [15] substantially improved the selectivities in chiral dihydroxylations [16], although it was first reported as a co-oxidant in 1975 [17]. Industrial efforts led to an electrochemical oxidation of potassium ferrocyanide to ferricyanide in order to use electricity as the actual co-oxidant [18]. 

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... 

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. 

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. ... 

Since the publication of the Upjohn procedure in 1976, the use of N-methylmorpho-line N-oxide (NMO) based oxidants has become one of the standard methods for osmium-catalyzed dihydroxylations. However, NMO has not been fully appreciated in the asymmetric dihydroxylation for a long time since it was difficult to obtain high enantiomeric excess (ee). This drawback was significantly improved by slow addition of the alkene to the aqueous tert-BuOH reaction mixture, in which 97% ee was achieved with styrene [15]. 

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