Asymmetric dihydroxylation AD mix

The Sharpless asymmetric dihydroxylation (AD-mix-a) of the epimeric mixture of 8-allyl-perhydropyrido[l,2-c][l,3-oxazin-l-one 59 in a mixture of fBuOH and H20 at 0 °C for 17 h gave a diasteromeric mixture of dihydroxy derivative 77 in 90% yield (06OBC1587). 

Preparative Methods the acetate is prepared from dihydroquinidine and the p-chlorobenzoate is commercially available. The phthalazine-derived bis(dihydroquinidine) ligand is commercially available. A formulation of the standard reactants for the asymmetric dihydroxylation (AD-mix-p) on the small scale has been developed and is commercially available. AD-mix-p (1 kg) consists of potassium osmate (0.52 g), the phthalazine-derived ligand (5.52 g), K3Fe(CN)6 (700 g), and powdered K2CO3 (294 g). 

Keinan prepared separately the two fragments (the THF moiety and the Y-methyl-y-lactone) and used, as a key step of his sequence, the asymmetric dihydroxylation (AD-mix.-p), the very efficient Sharpless procedure for the formation of a,(3-diols. Then, the cross-coupling was performed by addition of an alkyne and a vinyl halide in the presence of palladium and copper catalysts (Fig. 6). Treatment of the unsaturated ester 48 (prepared in 4 steps from commercially available starting material, and 65 % overall yield) with AD-mix.-p in rerr-butanol/water (1 1) with methanesulfonamide for 16 h at 0 °C afforded the lactone 49 which possessed 3 carbon atoms out of the 4 with the desired absolute configuration. Inversion of the fourth stereocentre after acetonide... 

Sharpless strategy is based on the very effective asymmetric dihydroxylation (AD-mix.-a or (3) of the y,5-unsaturated ester 140 to afford directly the desired (+) or (-)-muricatacin 19 with 95 and 96 % ee, respectively, and in 74 % overall yield from tridecanal 138 (Fig. 18). The ester 140 is obtained through a Claisen rearrangement of the allylic alcohol 139. 

R,8S)-(+)-Disparlure (12) is the female sex pheromone of the gypsy moth (Lymantria dispar). Advent of Sharpless asymmetric dihydroxylation (AD) allowed several new syntheses of 12 possible. Sharpless synthesized 12 as shown in Scheme 17 [27]. Scheme 18 summarizes Ko s synthesis of 12 employing AD-mix-a [28]. He extended the carbon chain of A by Payne rearrangement followed by alkylation of an alkynide anion with the resulting epoxide to give B. Keinan developed another AD-based synthesis of 12 as shown in Scheme 19 [29]. Mit-sunobu inversion of A to give B was the key step, and the diol C could be purified by recrystallization. 

In 1988, Sharpless invented his asymmetric dihydroxylation (AD), a catalytic process to convert alkenes to optically active 1,2-diols with known absolute configuration.38 As shown in Figure 3.10, a commercially available reagent AD-mix-a (Aldrich) gives a-l,2-diol from an alkene, while AD-mix-f) affords f>-l,2-diol. This reaction was used by Crispino and Sharpless to synthesize (R)-(+)-JH III (92% ee).39 We also employed this AD reaction to synthesize (+)-JH I (61) and (+)-JH II (62).40 Figure 3.11 summarizes the synthesis of (+)-JH I by means of an AD reaction. 

The Sharpless asymmetric hydroxylation can take one of two forms, the initially developed asymmetric dihydroxylation (AD)1 or the more recent variation, asymmetric aminohydroxylation (AA).2 In the case of AD, the product is a 1,2-diol, whereas in the AA reaction, a 1,2-amino alcohol is the desired product. These reactions involve the asymmetric transformation of an alkene to a vicinally functionalized alcohol mediated by osmium tetraoxide in the presence of chiral ligands (e.g., (DHQD)2-PHAL or (DHQ)2-PHAL). A mixture of these reagents (ligand, osmium, base, and oxidant) is commercially available and is sold under the name of AD-mix p or AD-mix a (vide infra). 

Sharpless asymmetric dihydroxylation has been successfully applied to (1-cyclopentenyl)acetonitrile. Using (DHQ)PHN as a ligand in place of (DHQ)2PHAL, one of the components of AD-mix-a, (A, A)-(l, 2-dihydroxycy-clopentyl)acetonitrile was obtained after two recrystallizations, in 50% yield... 

It was of obvious interest to prepare the inhibitors 60 as their pure dia-stereoisomers, 66 and 67. Following on from our successful treatment of alkenyl /3-D-glucosides under Sharpless asymmetric dihydroxylation conditions [21], we treated the alkenes 64 with the a-AD - and /TAD -mixes - the results are summarized in Table 2. In no case did we ever obtain a satisfactory diastereo-isomeric excess of the diol 68 over the diol 69, or vice versa. A similar lack of stereoselectivity was also obtained with the triol 70 and the amine 71 [48]. 

The proper stereochemistry was achieved by enzyme catalyzed desymmetrization of the prochiral 1,3-diol 30. Candida antarctica lipase (CAL)-catalyzed transesterification yielded the monoacetate 31, which gave rise to the methyl with the proper stereochemistry 32. The generation of the desired chiral epoxide 35 was achieved by asymmetric dihydroxylation employing AD-mix-a,42 followed by epoxide formation. Base-catalyzed etherification yielded the mixture of the enantiopure (+)-heliannuol A and (-)-heliannuol D. Unfortunately these compounds correspond to the opposite d/l series and correspond to the enantiomers of the natural products (-)-heliannuol A and (+)-heliannuol D (Fig. 5.6.A). 

AD-mix-P 9-BBN Bn Boc Bz BOM CDI m-CPBA CSA Cy DBU DDQ DEAD DIAD DIBAL-H DIPT DME DMF DMAP DMSO EDC HMPA HOBT KHMDS LDA MEM MOM MoOPH NaHMDS NBS NMM NMO Piv PMB Reagent for Sharpless asymmetric dihydroxylation 9-Borabicyclo[3.3.1 ]nonyl Benzyl t-Butoxy carbonyl Benzoyl B enzyloxy methyl Carbonyldiimidazole m-Chloroperoxybenzoic acid Camphorsulfonic acid Cyclohexyl 1,8 -Diazabicy clo[5.4.0] undec-7-ene 2,3 -Dichloro-5,6-dicyano-p-benzoquinone Diethyl azodicarboxylate Diisopropyl azodicarboxylate Diisobutylaluminum hydride Diisopropyl tartrate Dimethoxyethane A,N-Dimethylformamide 4-Dimethylaminopyridine Dimethyl sulfoxide N-(3-Dimethylaminopropyl)-A -ethylcarbodiimide Hexamethylphosphoramide 1 -Hydroxybenzotriazole Potassium hexamethyldisilazane Lithium diisopropylamide Methoxyethoxymethyl Methoxymethyl Oxidodiperoxymolybdenum(pyridine)(hexamethylphophoramide) Sodium hexamethyldisilazane N - Bromosuccinimide A-Methylmorpholine A-Methylmorpholine A-oxide Pivaloyl /j-Methoxybenzyl... 

AD) and the application of a catch-and-release procedure using a supported boronic acid to effect in-line purification of the diol 20 (Scheme 5). The enantiomer of 20 could readily be obtained through the use of AD-mix-p in the Sharpless asymmetric dihydroxylation reaction. The two alcohol groups of the diol could subsequently be differentiated using an enzymatic selective protection. 

Asymmetric dihydroxylation Sharpless developed a catalytic system (AD-mix- 3 or AD-mix-a) that incorporates a chiral ligand into the oxidizing mixture which can be used for the asymmetric dihydroxylation of alkenes. The chiral ligands used in Sharpless asymmetric dihydroxylation are quinoline alkaloids, usually dihydroquinidine (DHQD) or dihydroquinine (DHQ) linked by a variety of heterocyclic rings such as 1,4-phthalhydrazine (PHAL) or pyridazine (PYR) (see section 1.6, reference 32 of Chapter 1). 

Takano, S., Yoshimitsu, T., and Ogasawara, K. (1994). Asymmetric dihydroxylation of a meso-symmetric cyclic diene Using AD-mix reagents A new enantiocontrolled route to conduritol E. J. Org. C3tem. 59 54-57. 

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