Dihydroxylation asymmetric

The Sharpless dihydroxylation method has been run at scale by Pharmacia-Upjohn with o-isopropoxy-m-methoxysytrene as substrate and NMMO as oxidant [103], 

The methodology has been extended to provide a-arylglycinols from styrenes [107], 

The resultant sulphate ester can be converted to the alcohol by acid hydrolysis. If an acid-sensitive group is present, this hydrolysis is still successful through use of a catalytic amount of sulphuric acid in the presence of 0.5-1.0 equivalents of water with tetrahydrofuran as solvent. The use of base in the formation of the cyclic sulphates themselves can also alleviate problems associated with acid-sensitive groups [117,118]. 

The familiar cw-dihydroxylation of alkenes with OSO4 or KMn04 creates two new stereogenic centres. Normally, this is of no consequence since in most applications the diol is cleaved or the alkene has a plane of symmetry. 

An asymmetric version of this reaction would be of great interest, since it would complement the asymmetric epoxidation. This has in fact been achieved by Sharpless. The source of asymmetry this time is a chiral tertiary amine, which forms a complex with osmium tetroxide. Taking their cue from the work of Wynberg (see section 6.1.1) Sharpless and co-workers discovered once again that chiral amines (66) and (67) derived from the cinchona alkaloids quinine and quinidine respectively performed well, affording enantiomeric excesses of 50-90%. 

The reaction was originally performed using a stoichiometric amount of the oxidant OSO4, with attendant problems of toxicity and cost.P2] The appeal of the method was greatly enhanced by the discovery that the asymmetric oxidation worked just as well under the more modem catalytic conditions, with only a trace of osmium tetroxide and(V-methylmorpholine(V-oxide (68) as the reoxidant. P3] The method is tolerant of a wide variety of functional groups (esters, allylic halides) and, unlike the Sharpless oxidation, has no need of an allylic hydroxyl group as an internal ligand. [ 4] 

A limitation of the catalytic procedure, unlike the stoichiometric, is that hindered and 1,1-disubstitutedalkenesgivepoore.e.s. However, simply adding the alkene slowly to the reaction mixture results in greatly improved optical yields, even with these substrates.P l Furthermore, the reaction is then actually faster. 

Stoichiometric (R = CH3CO, 1.1 eq OSO4, toluene) Catalytic (R = P-CI-C6H4CO, cat. OSO4, (68), aq acetone) Catalytic (as above but with slow addition of alkene) 

The Sharpless Os-catalyzed asymmetric dihydroxylation (AD) of olefins is a well-established and robust methodology for the synthesis of a wide range of 

Most recenhy, a new chiral ionic hquid has been prepared by combining the tetra-n-hexyl-dimethylguanidinium cation with readily available chiral anions, and 

---

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

Catalytic asymmetric dihydroxylation of alkenes with participation of insoluble polymer-bound cinchonine alkaloids 99SLI181. 

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 ... 

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. 

Figure 1. Selected bidentate ligands used in the stoichiometric asymmetric dihydroxylation (AD).

Scheme 8. The first catalytic asymmetric dihydroxylation (developed by Sharpless).

When asymmetric epoxidation of a diene is not feasible, an indirect route based on asymmetric dihydroxylation can be employed. The alkene is converted into the corresponding syn-diol with high enantioselectivity, and the diol is subsequently transformed into the corresponding trans-epoxide in a high-yielding one-pot procedure (Scheme 9.5) [20]. No cpirricrizalion occurs, and the procedure has successfully been applied to natural product syntheses when direct epoxidation strategies have failed [21]. Alternative methods for conversion of vicinal diols into epoxides have also been reported [22, 23]. 

This strategy can be applied to the synthesis of vinylepoxides, since high enantioselectivity and good regioselectivity can often be obtained in asymmetric dihydroxylation of dienes, resulting in vinylic diols [24, 25], Transformation of the diols into epoxides thus represents an alternative route to vinylepoxides. This strategy was recently employed in the synthesis of (+)-posticlure (Scheme 9.6) [26]. 

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. 

Kinetic resolution of racemic allylic acetates has been accomplished via asymmetric dihydroxylation (p. 1051), and 2-oxoimidazolidine-4-carboxy-lates have been developed as new chiral auxiliaries for the kinetic resolution of amines. Reactions catalyzed by enzymes can be utilized for this kind of resolution. ... 

For other examples of asymmetric dihydroxylation, see Yamada, T. Narasaka, K. Chem. Lett., 1986,131 Tokles, M. Snyder, J.K. Tetrahedron Lett., 1986, 27, 3951 Annunziata,... 

Mehrmann SJ, Abdel-MagidAF, Maryanoff CA, Medaer BP (2004) Non-Salen Metal-Catalyzed Asymmetric Dihydroxylation and Asymmetric Aminohydroxylation of Alkenes. Practical Applications and Recent Advances. 6 153-180 De Meijere, see Wu YT (2004) 13 21-58 Manage S, see Fontecave M (2005) 15 271-288... 

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. 

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... 

Amino-Hydroxylation. A related reaction to asymmetric dihydroxylation is the asymmetric amino-hydroxylation of olefins, forming v/c-ami noalcohols. The vic-hydroxyamino group is found in many biologically important molecules, such as the (3-amino acid 3.10 (the side-chain of taxol). In the mid-1970s, Sharpless76 reported that the trihydrate of N-chloro-p-toluenesulfonamide sodium salt (chloramine-T) reacts with olefins in the presence of a catalytic amount of osmium tetroxide to produce vicinal hydroxyl p-toluenesulfonamides (Eq. 3.16). Aminohydroxylation was also promoted by palladium.77... 

Subsequently, stoichiometric asymmetric aminohydroxylation was reported.78 Recently, it was found by Sharpless79 that through the combination of chloramine-T/Os04 catalyst with phthalazine ligands used in the asymmetric dihydroxylation reaction, catalytic asymmetric aminohydroxylation of olefins was realized in aqueous acetonitrile or tert-butanol (Scheme 3.3). The use of aqueous rerr-butanol is advantageous when the reaction product is not soluble. In this case, essentially pure products can be isolated by a simple filtration and the toluenesulfonamide byproduct remains in the mother liquor. A variety of olefins can be aminohydroxylated in this way (Table 3.1). The reaction is not only performed in aqueous medium but it is also not sensitive to oxygen. Electron-deficient olefins such as fumarate reacted similarly with high ee values. 

Dihydroxylation and asymmetric dihydroxylation of electronically deficient conjugate alkenes have been developed in aqueous media. These reactions were discussed in Chapter 3. 

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 41 summarizes Couladouros s synthesis of the oviposition attractant pheromone of the Southern house mosquito (Culexpipiensfatigans)y (5R,6S)-6-acetoxy-5-hexadecanolide (28) [66]. The key-steps are (i) -selective Schlosser olefination (A B), asymmetric dihydroxylation (B C), and lactonization of carbonate C to the desired 6-lactone with inversion at C-5. 

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

---