Dihydroxylation reaction Synthesis using

The oxidation of enol ethers and their derivatives is a useful method for the synthesis of a-hydroxy-ketones or their derivatives, which are versatile building blocks for organic synthesis. Since enol ethers and esters are types of olefin, some asymmetric epoxidation and dihydroxylation reactions have been applied to their oxidation. 

Andreana et al. [25] have recently invoked RCM to prepare /J,y-unsaturated <5-lactones (Scheme 3). Exposure of dienes of general type 13 to either 2 or 4 (which could be used at lower loadings) readily furnished lactones 14. For other examples of a,/ -unsaturated <5- and y-lactone synthesis by RCM see Ref. [26]. Variation of the configuration at the chiral carbons and the ligand for the asymmetric dihydroxylation reaction allows access to an array of biologically important dideoxy-sugar derivatives. 

This collection begins with a series of three procedures illustrating important new methods for preparation of enantiomerically pure substances via asymmetric catalysis. The preparation of 3-[(1S)-1,2-DIHYDROXYETHYL]-1,5-DIHYDRO-3H-2.4-BENZODIOXEPINE describes, in detail, the use of dihydroquinidine 9-0-(9 -phenanthryl) ether as a chiral ligand in the asymmetric dihydroxylation reaction which is broadly applicable for the preparation of chiral dlols from monosubstituted olefins. The product, an acetal of (S)-glyceralcfehyde, is itself a potentially valuable synthetic intermediate. The assembly of a chiral rhodium catalyst from methyl 2-pyrrolidone 5(R)-carboxylate and its use in the intramolecular asymmetric cyclopropanation of an allyl diazoacetate is illustrated in the preparation of (1R.5S)-()-6,6-DIMETHYL-3-OXABICYCLO[3.1. OJHEXAN-2-ONE. Another important general method for asymmetric synthesis involves the desymmetrization of bifunctional meso compounds as is described for the enantioselective enzymatic hydrolysis of cis-3,5-diacetoxycyclopentene to (1R,4S)-(+)-4-HYDROXY-2-CYCLOPENTENYL ACETATE. This intermediate is especially valuable as a precursor of both antipodes (4R) (+)- and (4S)-(-)-tert-BUTYLDIMETHYLSILOXY-2-CYCLOPENTEN-1-ONE, important intermediates in the synthesis of enantiomerically pure prostanoid derivatives and other classes of natural substances, whose preparation is detailed in accompanying procedures. 

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. 

The cinchona alkaloids have opened up the field of asymmetric oxidations of alkenes without the need for a functional group within the substrate to form a complex with the metal. Current methodology is limited to osmium-based oxidations. The power of the asymmetric dihydroxylation reaction is exemplified by the thousands (literally) of examples for the use of this reaction to establish stereogenic centers in target molecule synthesis. The usefulness of the AD reaction is augmented by the bountiful chemistry of cyclic sulfates and sulfites derived from the resultant 1,2-diols. 

The key step of a recent synthesis of fosfomycin is the Sharpless asymmetric di hydroxylation (AD) reaction.Dibenzyl ( )-l-propenylphosphonate is prepared in 94% yield from ( )-propenyl bromide and dibenzyl phosphite in THF at 60°C in the presence of I il.,N and catalytic amount of PdfPPh,). A modified AD-mix-a is used to speed up the dihydroxylation reaction. The resulting 5y/r-a,3-dihydroxyphosphonate is isolated in 65% yield after recrystallization and then submitted to regioselective oc-sulfonylation followed by cyclization by treatment with K CO, in acetone at room temperature to produce di benzyl (17 ,25)-l,2-epoxypropylphosphonate in 67% yield (Scheme 4.31). = Fosfomycin can be obtained by hydrogenolysis of this epoxyphosphonate. i... 

This synthesis uses both enantiomeric asymmetric dihydroxylation reactions. They are used successively to exploit the regioselectivity dictated by the inherent relative double reactivities. For certain substrates this makes the asymmetric dihydroxylation a tremendously powerful reaction. 

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. 

Scheme 8.24. Dihydroxylation reactions used for the synthesis of a-hydroxy carbonyl compounds, (a) A chiral auxiliary approach [102], (b) Application of the Sharpless AD procedure to an intermediate for the synthesis of camptothecin [104].

The c/s-dihydroxylation reaction catalyzed by these dioxygenases is typically highly enantioselective (often >98% ee) and, as a result, has proven particularly useful as a source of chiral synthetic intermediates (2,4). Chiral cis-dihydrodiols have been made available commercially and a practical laboratory procedure for the oxidation of chlorobenzene to IS, 2S)-3-chlorocyclohexa-3,5-diene-l,2-c diol by a mutant strain of Pseudomonas putida has been published (6). Transformation with whole cells can be achieved either by mutant strains that lack the second enzyme in the aromatic catabolic pathway, cw-dihydrodiol dehydrogenase (E.C. 1.3.1.19), or by recombinant strains expressing the cloned dioxygenase. This biocatalytic process is scalable, and has been used to synthesize polymer precursors such as 3-hydroxyphenylacetylene, an intermediate in the production of acetylene-terminated resins (7). A synthesis of polyphenylene was developed by ICI whereby ftie product of enzymatic benzene dioxygenation, c/s-cyclohexa-3,5-diene-1,2-diol, was acetylated and polymerized as shown in Scheme 2 (8). 

The asymmetric dihydroxylation reaction is finding increasing use as a stereoselective method in organic synthesis. For example, in a synthesis of the bioactive ace-togenin parviflorin, asymmetric dihydroxylation of the diene 83 gave, selectively, the triol 84 (5.86). The dihydroxylation reaction was nm to approximately two... 

Researchers at Merck reported SAD reaction of a styrene derivative 164 for the synthesis of the substance-P inhibitor 166 [80], SAD on 164 using AD-mix a gave crude diol 165 with 87% ee optical purity, which was further upgraded to > 99% ee upon recrystallization (Scheme 9.44). Noteworthy, of the process is that the stereochemistry created in dihydroxylation reaction is responsible for the origin in installation of all the three chiral centers in the final drug substance. 

The types of reactions that can be catalyzed by transition metal complexes are now very numerous and are very widely used in synthesis. We have already met a number of them—osmium in catalysis of dihydroxylation reactions, titanium in Sharpless epoxidation, various metals in hydrogenation reactions of alkenes, and the Ziegler-Natta process for polymerization. In this section, we will just highlight a few types that have been popular—an oxidation, some hydrogenations, and some coupling reactions. Although outline reaction mechanisms will be given, this is for interest only—they are beyond the scope of this text, and many are more complicated than is shown here. 

As is apparent from the preceding discussion, a full understanding of the observed diastereoselectivity in dihydroxylation reactions of acyclic allylic alcohols remains elusive. Thus, the use of any one model is insufficient, and a careful analysis of the steric and electronic particulars of a given substrate must be conducted. Nevertheless, an impressive number of diastereoselec-tive dihydroxylations of acyclic olefins in complex molecule synthesis attest to the central role of this transformation [42, 43], Selected examples of stereodivergent dihydroxylations reported by Danishefsky are showcased in Schemes 9.36 and 9.37 [201]. Dihydroxylation of ( )- and (Z)-unsaturated esters 287 and 290, respectively, thus proceeded with excellent diastereoselectivity. Danishefsky has proposed a transition state model based on the ground state conformations of the starting materials as determined by X-ray analysis. The dihydroxylations were thus postulated to occur from the sterically less hindered faces of the olefins, as depicted in 288 and 291. Diol 292 was subsequently converted into N-acetylneuraminic acid (293). 

The Sharpless catalytic asymmetric dihydroxylation reaction has found countless applications in synthesis, of which only a few illustrative examples are discussed. The enantioselective synthesis of the side chain 318 of the anticancer agent paclitaxel (Taxol, 320) has attracted much interest. Its preparation was accomplished on a mole-scale by Sharpless through the use of... 

Entry 10 was used in conjunction with dihydroxylation in the enantiospecific synthesis of polyols. Entry 11 illustrates the use of SnCl2 with a protected polypropionate. Entries 12 and 13 result in the formation of lactones, after MgBr2-catalyzed additions to heterocyclic aldehyde having ester substituents. The stereochemistry of both of these reactions is consistent with approach to a chelate involving the aldehyde oxygen and oxazoline oxygen. 

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