Dihydroxylation procedure

A catalytic enantio- and diastereoselective dihydroxylation procedure without the assistance of a directing functional group (like the allylic alcohol group in the Sharpless epox-idation) has also been developed by K.B. Sharpless (E.N. Jacobsen, 1988 H.-L. Kwong, 1990 B.M. Kim, 1990 H. Waldmann, 1992). It uses osmium tetroxide as a catalytic oxidant (as little as 20 ppm to date) and two readily available cinchona alkaloid diastereomeis, namely the 4-chlorobenzoate esters or bulky aryl ethers of dihydroquinine and dihydroquinidine (cf. p. 290% as stereosteering reagents (structures of the Os complexes see R.M. Pearlstein, 1990). The transformation lacks the high asymmetric inductions of the Sharpless epoxidation, but it is broadly applicable and insensitive to air and water. Further improvements are to be expected. 

Over the years, the original dihydroxylation procedure has been modified to operate catalytically, more rapidly, and in better yield. However, the last remaining task, making the dihydroxylation of a prochiral olefin enantioselective without losing all the other desirable features of the reaction, has only recently become a reality. 

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

Sharpless asymmetric dihydroxylation procedure was applied to the synthesis of the side chain of azinomycin A (equation 26)43. Horner-Emmons condensation of phospho-nate 36 with a /J-aziridine substituted acrolein afforded dehydroamino acid diene 37. Treatment of the diene with catalytic amounts of an osmium reagent and dihydroquini-dine (DHQD) p-chlorobenzoate resulted in asymmetric dihydroxylation, producing diol 38. Diol 38 was further converted to the naphthyl ester. 

Older dihydroxylation procedures once used a full equivalent of OSO4 followed by a reducing agent such as NaHS03 to reduce the osmate ester. These old procedures have been supplanted by methods using only catalytic amounts of 0s04, an exceptionally toxic and expensive reagent. 

When the Sharpless osmium-catalyzed dihydroxylation procedure is used in tandem with an aldolase-catalyzed addition, a rapid stereoselective entry to a variety of carbohydrates is achieved (Scheme 5.11).32 By judicious choice of hydroxylation and aldolase conditions, a number of the possible hexose... 

Figure 3.2 Steric requirements for the asymmetric dihydroxylation procedure as indicated by the...

The use of a dihydroxylation procedure can provide high stereoselectivity compared to a direct epoxidation method. The conditions for the dihydroxylation of 5 had to be modified due to the low solubility of the substrate and the base sensitivity of the product (Scheme 3.6). The result was a more efficient process for scale-up compared to an epoxidation [163]. 

With vinyl sulfones as the substrates for the dihydroxylation procedure, a mixture of products results of which the a-hydroxy aldehyde is the major component (Scheme 3.8) [199]. 

Use of the dihydroxylation procedure with the P-lactam-substituted alkenes 16 showed a matched-mismatched phenomenon (Scheme 3.15). Use of an achiral reagent showed little facial bias. With an alkyl or ester group rather than aryl as the other alkene substituent (R1), the selectivity diminished [311]. 

In contrast to the Jacobsen conditions, application of the Sharpless asymmetric dihydroxylation procedure [13, 15] on our substrate 5 gave much better overall performance. Chiral diol 22 could be prepared with 98-99% ee in isolated yields of 90% (Fig. 8). Moreover, since this diol was crystalline, it provided a convenient point for intermediate clean-up. 

While the Sharpless asymmetric dihydroxylation procedure proved effective in making the desired chiral cyclopropane acid intermediate from 5, several unit operations were required to make the key intermediate 2 b. Overall efficiency, however, is the key criterion for developing a long-term, cost-effective manufacturing process. Asymmetric cyclopropanation [18] certainly offered the most direct approach starting from 5, and so a number of catalyst systems known to effect this type of reaction were screened. Three catalytic systems were examined in detail for potential, as outlined in Tab. 1. 

Apart from oxygen and hydrogen peroxide, bleach is the simplest and most economical oxidant, and is videly used in industry without problems. This oxidant has only been applied in the presence of osmium complexes in two patents in the early 1970s for the oxidation of fatty acids [17]. In 2003 the first general dihydroxylation procedure of various alkenes in the presence of sodium hypochlorite as the reoxidant was described by our group [18]. Using a-methylstyrene as a model compound, 100% conversion and 98% yield of the desired 1,2-diol were demonstrated (Scheme 1.5). 

In 1999 the first AD reaction using molecular oxygen without any secondary electron transfer mediator was published [28]. Osmium(VI) was readily reoxidized to osmium(VIII) in this system. We demonstrated that the osmium-catalyzed dihydroxylation of aliphatic and aromatic alkenes proceeds efficiently in the presence of dioxygen under ambient conditions. This dihydroxylation procedure constitutes a significant advancement compared to other re-oxidation procedures (Table 1.2, entry 7). 

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