Dihydroxylations Sharpless

Selective chemical transformations can also be performed on the natural product sanglifehrin A (1) itself [19]. It is surprising that C26-C27 of 1 can be chemoselectively cis-dihydroxylated (Sharpless conditions) in a yield of 70%. The natural product can afterwards be reassembled by Julia-Kocienski olefination. The success of this operation indicates that total syntheses of sanglifehrin A (1) alternative to those by Nicolaou et al. and Paquette should be worth pursuing. 

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). 

Asymmetric epoxidation (Jacobsen) and dihydroxylation (Sharpless) are other potentially viable approach to epoxides, diols, and aminodiols. 

In Situ Protection of Diols from Dihydroxylation. Sharpless recently examined the applicability of Narasaka s dihydroxylation reaction conditions (catalytic osmium tetroxide and NMO in the presence of phenylboronic acid). The boronic acid reagent replaces the water which is normally present in dihydroxylation reactions to hydrolyze the osmate ester and liberate the diol. In this case, however, the phenyl boronic acid promotes this reaction... 

Sharpless asymmetric dihydroxylation Sharpless asymmetric epoxidation Shi epoxidation Suzuki coupling... 

Sharpless Asymmetric Dihydroxylation (AD) - Ligand pair are really diastereomers ... 

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. 

Asymmetric Sharpless dihydroxylation of olefins using catalysts supported by polymers with heterocyclic fragments 98EJ021. 

Another important reaction associated with the name of Sharpless is the so-called Sharpless dihydroxylation i.e. the asymmetric dihydroxylation of alkenes upon treatment with osmium tetroxide in the presence of a cinchona alkaloid, such as dihydroquinine, dihydroquinidine or derivatives thereof, as the chiral ligand. This reaction is of wide applicability for the enantioselective dihydroxylation of alkenes, since it does not require additional functional groups in the substrate molecule ... 

With this reaction, two new asymmetric centers can be generated in one step from an achiral precursor in moderate to good enantiomeric purity by using a chiral catalyst for oxidation. The Sharpless dihydroxylation has been developed from the earlier y -dihydroxylation of alkenes with osmium tetroxide, which usually led to a racemic mixture. 

In the following sections and before we describe the synthesis of zaragozic acid A, we give a brief historical introduction to the dihydroxylation reaction, then describe the development of the Sharpless AD and some of its recent applications. 

The interest in asymmetric synthesis that began at the end of the 1970s did not ignore the dihydroxylation reaction. The stoichiometric osmylation had always been more reliable than the catalytic version, and it was clear that this should be the appropriate starting point. Criegee had shown that amines, pyridine in particular, accelerated the rate of the stoichiometric dihydroxylation, so it was understandable that the first attempt at nonenzymatic asymmetric dihydroxylation was to utilize a chiral, enantiomerically pure pyridine and determine if this induced asymmetry in the diol. This principle was verified by Sharpless (Scheme 7).20 The pyridine 25, derived from menthol, induced ee s of 3-18% in the dihydroxylation of /rcms-stilbene (23). Nonetheless, the ee s were too low and clearly had to be improved. 

Scheme 7. The first enantioselective dihydroxylation reactions (developed by Sharpless).

Previous syntheses of terminal alkynes from aldehydes employed Wittig methodology with phosphonium ylides and phosphonates. 6 7 The DuPont procedure circumvents the use of phosphorus compounds by using lithiated dichloromethane as the source of the terminal carbon. The intermediate lithioalkyne 4 can be quenched with water to provide the terminal alkyne or with various electrophiles, as in the present case, to yield propargylic alcohols, alkynylsilanes, or internal alkynes. Enantioenriched terminal alkynylcarbinols can also be prepared from allylic alcohols by Sharpless epoxidation and subsequent basic elimination of the derived chloro- or bromomethyl epoxide (eq 5). A related method entails Sharpless asymmetric dihydroxylation of an allylic chloride and base treatment of the acetonide derivative.8 In these approaches the product and starting material contain the same number of carbons. 

The molecular modelling approach, taking into account the pyruvate—cinchona alkaloid interaction and the steric constraints imposed by the adsorption on the platinum surface, leads to a reasonable explanation for the enantio-differentiation of this system. Although the prediction of the complex formed between the methyl pyruvate and the cinchona modifiers have been made for an ideal case (solvent effects and a quantum description of the interaction with the platinum surface atoms were not considered), this approach proved to be very helpful in the search of new modifiers. The search strategy, which included a systematic reduction of the cinchona alkaloid structure to the essential functional parts and validation of the steric constraints imposed to the interaction complex between modifier and methyl pyruvate by means of molecular modelling, indicated that simple chiral aminoalcohols should be promising substitutes for cinchona alkaloid modifiers. Using the Sharpless symmetric dihydroxylation as a key step, a series of enantiomerically pure 2-hydroxy-2-aryl-ethylamines... 

Chandrasekhar, S., Narsihmulu, C., Sultana, S.S., Reddy, N.R. (2003) Osmium Tetrox-ide in Poly(ethylene glycol) (PEG) A Recyclable Reaction Medium for Rapid Asymmetric Dihydroxylation Under Sharpless Conditions. Chemical Communications, 1716-1717. 

Catalytic dihydroxylations using the osmium tetroxide-tm-butyl hydroperoxide system are largely due to Sharpless and co-workers. The aqueous 70%-i-butyl hydroperoxide is commercially available and ideal for direct use in this dihydroxylation process.60... 

Figure 3.3 Rationale for predicting the enantiofacial selectivity in Sharpless s dihydroxylation.

By using the Sharpless dihydroxylation, a variety of compounds have been transformed to diols with high enantiomeric excesses. The asymmetric dihydroxylation has a wide range of synthetic applications. As an illustration, the dihydroxylation was used as the key step in the synthesis of squalestatin 1 (3.8) (Scheme 3.2).74... 

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. 

Z,9S,10 )-9,10-Epoxyhenicos-6-ene (13) is the female sex pheromone of moths such as ruby tiger moth (Phragmatobiafuliginosa), fruit-piercing moth (Oraesia excavata), and painted apple moth (Teia anartoides). Scheme 23 summarizes Shi s synthesis of 13 based on Sharpless asymmetric dihydroxylation (AD) [36]. Mori synthesized 13 employing lipase to prepare A (Scheme 24) [37]. Alkylation of the acetylide anion C was possible neither with tosylate nor with iodide, but triflate B could alkylate C to give D. 

Posticlure [(6Z,9Z,llS,12S)-ll,12-epoxy-6,9-henicosadiene, 14] is the female sex pheromone of the tussock moth, Orgyia postica. Wakamura s first synthesis of 14 was achieved by employing Sharpless asymmetric epoxidation, and the final product was of 59% ee [38]. Mori prepared 14 of high purity as shown in Scheme 25 basing on asymmetric dihydroxylation (AD) [39]. Kumar also published an AD-based synthesis of 14 [40], which was more lengthy and less efficient than Mori s [39]. 

Scheme 69 summarizes Mori s synthesis of 45, in which was employed Sharpless asymmetric dihydroxylation (A B) as the key-step [101]. 

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