The Asymmetric Dihydroxylation

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. 

The reason for the decrease in the enantiomeric excess observed in changing from stoichiometric to catalytic conditions was demonstrated to be due to a second catalytic cycle in which the chiral 

The low rate of reaction for trisubstituted olefins was shown to be a result of slow hydrolysis of the osmium glycolate 29. However, this hydrolysis can be accelerated by a factor of up to 50 simply by the addition of methanesulfonamide.26 This modification permits the AD to be performed at lower temperature, which nearly always results in an increase in the stereoselectivity of the reaction.27 

As discussed in Chapter 19, the concept of reagent control has revolutionized chemistry in the latter part of the 20th century. By 

A noteworthy feature of the Sharpless Asymmetric Epoxidation (SAE) is that kinetic resolution of racemic mixtures of chiral secondary allylic alcohols can be achieved, because the chiral catalyst reacts much faster with one enantiomer than with the other. A mixture of resolved product and resolved starting material results which can usually be separated chromatographically. Unfortunately, for reasons that are not yet fully understood, the AD is much less effective at kinetic resolution than the SAE. 

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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 ... 

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... 

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. 

Chiral compounds 91a and 91b, as shown in Table 4-15, were first reported by Jacobsen et al.55 for the asymmetric dihydroxylation of olefins. These catalysts can be used for asymmetric dihydroxlation of a variety of substrates. 

The asymmetric dihydroxylation protocol was the second massive contribution by Professor Barry Sharpless to synthetic organic chemistry. The first procedure, introduced with Katsuki, involves the catalytic asymmetric epoxida-tion of allylic alcohols. A typical example is shown in Scheme 17, wherein ( )-allylic alcohol (23) is epoxidized with tert-b utyl hyd roperox ide, in the presence of titanium tetra-isopropoxide and optically active diethyl tartrate to give the... 

Table 4. Calculated and experimental enantioselectivities in the asymmetric dihydroxylation with different alkenes and bases (adapted from Ref. 28).

Polymer-supported [e.g. 8, 9] and silica-supported [10] cinchona alkaloids have been used in the asymmetric dihydroxylation of alkenes using osmium tetroxide. Enantiomeric excesses >90% have been achieved for diols derived from styrene derivatives. 

About a decade after the discovery of the asymmetric epoxidation described in Chapter 14.2, another exciting discovery was reported from the laboratories of Sharpless, namely the asymmetric dihydroxylation of alkenes using osmium tetroxide. Osmium tetroxide in water by itself will slowly convert alkenes into 1,2-diols, but as discovered by Criegee [15] and pointed out by Sharpless, an amine ligand accelerates the reaction (Ligand-Accelerated Catalysis [16]), and if the amine is chiral an enantioselectivity may be brought about. 

Excitingly, the electrochemical Os-catalyzed asymmetric dihydroxylation of olefins with Sharpless s ligands yielding the chiral diol (138) via the chiral adduct (137) has been reported [184]. The asymmetric dihydroxylation of olefins (136) is performed by recycling a catalytic amount of potassium ferricyanide [K3Fe(CN)6] in the presence... 

After the "asymmetric epoxidation" of allylic alcohols at the very beginning of the 80 s, at the end of the same decade (1988) Sharpless again surprised the chemical community with a new procedure for the "asymmetric dihydroxylation" of alkenes [30]. The procedure involves the dihydroxylation of simple alkenes with N-methylmorpholine A -oxide and catalytic amounts of osmium tetroxide in acetone-water as solvent at 0 to 4 °C, in the presence of either dihydroquinine or dihydroquinidine p-chlorobenzoate (DHQ-pClBz or DHQD-pClBz) as the chiral ligands (Scheme 10.3). 

Scheme 4.13 Solid-phase attached catalysts for the asymmetric dihydroxylation of alkenes.

Janda, Bolm and Zhang generated soluble polymer-bound catalysts for the asymmetric dihydroxylation by attaching cinchona alkaloid derivatives to polyethylene glycol monomethyl ether (MeO-PEG) [84—87]. Since these polymeric catalysts like (24) are soluble in many common solvents they are often as effective as their small homogenous counterparts. Janda et al. prepared catalyst (24) in which two dihydroquinidine (DHQD) units were linked together by phthalazine and finally were attached to MeO-PEG via one of the bicyclic ring system moieties (Scheme... 

Other functionalized supports that are able to serve in the asymmetric dihydroxylation of alkenes were reported by the groups of Sharpless (catalyst 25) [88], Sal-vadori (catalyst 26) [89-91] and Cmdden (catalyst 27) (Scheme 4.13) [92]. Commonly, the oxidations were carried out using K3Fe(CN)g as secondary oxidant in acetone/water or tert-butyl alcohol/water as solvents. For reasons of comparison, the dihydroxylation of trons-stilbene is depicted in Scheme 4.13. The polymeric catalysts could be reused but had to be regenerated after each experiment by treatment with small amounts of osmium tetroxide. A systematic study on the role of the polymeric support and the influence of the alkoxy or aryloxy group in the C-9 position of the immobilized cinchona alkaloids was conducted by Salvadori and coworkers [89-91]. Co-polymerization of a dihydroquinidine phthalazine derivative with hydroxyethylmethacrylate and ethylene glycol dimethacrylate afforded a functionalized polymer (26) with better swelling properties in polar solvents and hence improved performance in the dihydroxylation process [90]. 

R. Riedl, R. Tappe and A. Berkessel, Probing the scope of the asymmetric dihydroxylation of polymer-bound olefins. Monitoring by HRMAS NMR allows for reaction control and on-bead measurement of enantiomeric excess, J. Am. Chem. Soc., 1998,120, 8994-9000. 

The Sharpless asymmetric dihydroxylation has played a prominent role in enantioselecitve organic synthesis. Two groups have recently reported improvements in the procedure. Osmo E.O. Horni of the University of Oulu, Finland has found (J. Org. Chem. 2004,69,4816) that sodium chlorite is a more efficient reoxidant than is the usual K,[Fe(CN)J. Carlos A.M. Alfonso of the Instituto Superior , Lisbon has reported (J. Org. Chem. 2004,69,4381) that the asymmetric dihydroxylation can... 

A polymeric cinchona alkaloid-derived ligand 44 was prepared and used to catalyze the asymmetric dihydroxylation of olefins (see the diagram below).66 Both aliphatic and aromatic olefins afforded diols with good enantioselectivities. 

Important extensions of proline catalysis in direct aldol reactions were also reported. Pioneering work by List and co-workers demonstrated that hydroxy-acetone (24) effectively serves as a donor substrate to afford anfi-l,2-diol 25 with excellent enantioselectivity (Scheme 11) [24]. The method represents the first catalytic asymmetric synthesis of anf/-l,2-diols and complements the asymmetric dihydroxylation developed by Sharpless and other researchers (described in Chap. 20). Barbas utilized proline to catalyze asymmetric self-aldoli-zation of acetaldehyde [25]. Jorgensen reported the cross aldol reaction of aldehydes and activated ketones like diethyl ketomalonate, in which the aldehyde... 

The asymmetric dihydroxylation of dienes has been examined, originally with the use of NMO as the cooxidant for osmium [56a] and, more recently, with potassium ferricyanide as the cooxidant [56b], Tetraols are the main product of the reaction when NMO is used, but with K3Fe(CN)6, ene-diols are produced with excellent regioselectivity. The example of dihydroxylation of trans.trans-1,4-diphenyl-1,3-butadiene is included in Table 6D.3 (entry 21). One double bond of this diene is hydroxylated in 84% yield with 99% ee when the amounts of K3Fe(CN)6 and K2C03 are limited to 1.5 equiv. each. Unsymmetrical dienes are also dihydroxy-lated with excellent regioselectivity. In these dienes, preference is shown for (a) a bans over a cis olefin, (b) the terminal olefin in a,p,y,8-unsaturated esters, and (c) the more highly substituted olefin [56b],... 

We thank David J. Benisford for the use of his excellent bibliography of the asymmetric dihydroxylation literature. 

Permanganese is a common oxidative reagent, the application of which to the asymmetric oxidative cyclization of 1,5-dienes has been reported by Brown (Scheme 3.14). The addition of acetic acid is quite important for the reaction to proceed, and highly functionalized tetrahydrofurans are obtained in a range of 58 to 75% ee, in diastereoselective manner [35]. Another oxidative transformation using KMn04 with a chiral ammonium salt has been investigated. Scheme 3.15 illustrates the asymmetric dihydroxylation of electron-deficient olefins to chiral diols in the... 

The development of polymeric cinchona-derived PTCs was triggered by the group of Jew and Park in 2001 [8]. The group paid particular attention to the fact that the cinchona alkaloids have demonstrated great utility in the Sharpless asymmetric dihydroxylation. Especially, it was noted that the significant improvements in both stereoselectivity and scope of the asymmetric dihydroxylation were achieved when the dimeric ligands of two independent cinchona alkaloid units attached to heterocyclic spacers were used, such as (DHQ)2-PHAL or (DHQD)2-PYR (Figure 4.4) [9]. 

The chiral ligand consists of a diphenylpyrimidine (PYR) 39, which is connected to two dihydroquinidine (DHQD) molecules 40. Dihydroquinidine (DHQD) 40 and dihydroquinine (DHQ) 41 are diastereomers. However, in the asymmetric dihydroxylation, they behave like pseudo-enantiomers, giving diols of opposite configuration. 

With this aim, the group of Norrby developed a transition state force field for the study of the asymmetric dihydroxylation reaction [91]. This force field is purely developed from quantum mechanical reference data [92]. In their studies they use different ligands from the first generation (where the amine ligands are the alkaloids dihydroquine or dihydroquinidine) and second generation (where a symmetric linker couples two alkaloid units), and several alkenes. The calculated ee s are in very good agreement with experiment. 

There are many other examples of highly efficient catalytic asymmetric syntheses. These include the asymmetric dihydroxylation of alkenes and certain homogeneous catalyzed hydrogenations. The latter will be discussed in the context of redox reactions in Sections 17.3.2 and 17.4.7. Further examples for catalytic asymmetric syntheses also mentioned in this book are the proline-catalyzed cyclohexenone annulations in Figure 12.19. 

B. B. Lohray, Recent Advances in the Asymmetric Dihydroxylation of Alkenes, Tetrahedron Asymmetry 1992, 3, 1317-1349. 

The Nobel Prize in Chemistry 2001 was awarded to three researchers for their pioneering work in the field of asymmetric catalysis. One of them, K. Barry Sharpless, was honored for the epoxidations named after him (Section 3.4.6). The second reason for the award was his development of the asymmetric dihydroxylation (AD Figure 17.21). The Sharpless reactions that were honored with the Nobel Prize have three things in common first, they are oxidations, second, they are catalytic asymmetric syntheses, and third, they owe their high enan-tiocontrol to the additive control of stereoselectivity. In the introductory passages to... 

Figure 17.21 (part II) shows the 1 1 complex from (DHQD)2-PHAL and 0s04 together with the stereostructure, which is derived from the previous discussion, in the transition state of the asymmetric dihydroxylation. Here, the alkene nestles between the amine-complexed 0s04 on the one side and the methoxyquinoline residue on the other. The enantioselectivity of the dihydroxylation is the result of the alkene s preference to nestle in this niche with the orientation shown here. This orientation is characterized by the fact that no repulsion may occur between the alkene and the bottom of this niche, i.e., the central heterocycle of (DHQD)2-PHAL. This is the case if and only if the. s/r-bound hydrogen atom (as the smallest double bond substituent in the substrate) points in the direction of the central heterocycle. 

Examples for determining enantiomeric excess on a resin has been reported. 13C MAS-NMR was used to monitor the asymmetric dihydroxylation of 10-undecenoic acid supported on Wang-resin and to determine the ee of the dihydroxylation product derivatized with R-(+)-Mosher s acid [74]. The MAS-NMR results agreed to better than 1% with those obtained from HPLC performed on the freed material following cleavage from the resin. 

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. 

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