Dihydroxylation, asymmetric conditions

The strategy eluded to in Scheme 7.3.6 is elaborated upon in Scheme 8.10.3 and involves the allyl sugar derivative shown. Conversion of the allyl group to the phosphonium salt is accomplished in eight steps. Wittig olefination with the illustrated protected aldehyde provides the cis olefin which is dihydroxylated under asymmetric conditions and selectively protected as the PMB ether. 

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. 

In studies directed toward the total synthesis of tedanolide [38], the addition of y-substituted ketene acetal 60 to aldehyde 84 generated unsaturated ester 85 in 62% yield (Scheme 30). The resulting double bond could be further functionalized by applying Sharpless asymmetric dihydroxylation conditions. Hence diol 86, which represents the mismatched case due to unfavorable... 

Reactions have been carried out adjacent to the epoxide moiety in order to examine the effects, if any, that the epoxide has on subsequent reactions with respect to the regio- and stereochemical outcome. Dihydroxylation using osmium tetraoxide and Sharpless asymmetric dihydroxylation reactions have been extensively studied using substrates 29 and 31. Initial studies centred on the standard dihydroxylation conditions using AT-methylmorpholine-AT-oxide and catalytic osmium tetraoxide. The diastereomeric ratios were at best 3 2 for 29 and 2 1 for 31, indicating that the epoxide unit had very little influence on the stereochemical outcome of the reaction. This observation was not unexpected, since the epoxide moiety poses minimal steric demands (Scheme 21). 

The protected diol side-chain of 456 is introduced by asymmetric dihydroxylation and directs diastereoselectivity in the formation of 457 and 458 by lithiation. The most acidic position of 456, between the two methoxy groups, is first protected by silylation. Suzuki coupling of 459 with the boronic acid 460 gives the kinetic product 461—the more severe hindrance to bond rotation in this compound does not allow equilibration to the more stable atropisomer of the biaryl under the conditions of the reaction. 

More recently, in light of the development of the Sharpless asymmetric dihydroxylation protocol [20], we have approached the synthesis of diols such as 14 (Scheme 2) from the alkene. Thus, treatment of the alkenyl D-glucosides 15 vmder the conditions of the Sharpless dihydroxylation gave a range of diols 16 with varying diastereoisomeric excesses (Table 1). One of these mixtures of diols, upon recrystallization, yielded the pure diastereoisomer, namely the diol 14. This procedure now gives a very rapid and efficient entry into one of the precursor diols for the synthesis of the optically-pure epoxides [21]. 

It was of obvious interest to prepare the inhibitors 60 as their pure dia-stereoisomers, 66 and 67. Following on from our successful treatment of alkenyl D-glucosides under Sharpless asymmetric dihydroxylation conditions [21], we treated the alkenes 64 with the a-AD - and AD -mLxes - the results are summarized in Table 2. In no case did we ever obtain a satisfactory diastereo-isomeric excess of the diol 68 over the diol 69, or vice versa. A similar lack of stereoselectivity was also obtained with the triol 70 and the amine 71 [48]. 

The focus of this chapter is to acquaint the reader with details of catalytic asymmetric dihydroxylation with osmium tetroxide and the scope of results that one can expect to achieve with current optimum conditions. The literature through mid-1992 has been reviewed in compiling this chapter. Osmium tetroxide catalyzed hydroxy]ations of olefins and acetylenes are the subject of an extensive review by Schroder published in 1980 [2a]. A comprehensive review of research and industrial applications of asymmetric dihydroxylations is in preparation [2b]. 

Sharpless asymmetric dihydroxylation of simple allylsilanes yields the corresponding diols 182 with moderate enantioselectivity (equation 154)273. However, when 183 is treated under similar conditions, substituted /-lactones 184a and 184b are obtained in high diastereo- and enantioselectivities (equation 155)274-277. 

A variation within the osmium-catalysed asymmetric dihydroxylation (AD) of alkenes has been described that yields cyclic boronic esters from alkenes in a straightforward manner. A protocol based on the Sharpless AD conditions (for enantiose-lective oxidation of prochiral olefins) has been developed that gives cyclic boronic esters, rather than free diols, with excellent enantiomeric excesses. Some of the... 

Different polyethylene glycol polymers were used in various papers and proved to be very reliable and useful for different classes of molecules their use for the synthesis of peptides [180, 181], of peptidomimetics [182] and of oligosaccharide libraries [183] was reported as the development and the use of a new PEG-linked traceless linker [184, 185], the selection of ligands for asymmetric Sharpless dihydroxylation [186-188], the use of PEG-linked triarylphosphines for LPCS requiring Mitsunobu or Staudinger conditions [189], the use of PEG-based supports to prepare a library of [l,4]oxazepine-7-ones [190] and the use of PEG-supported Schiff bases for the synthesis of a-substituted amino acids [191], Other examples of soluble polymers used for LPCS may include cellulose[192], polyacrylamide [193] polyvinyl alcohol [194, 195], various copolymers [196, 197] and NCPS [198-200]. Three excellent reviews [201-203] summarized the properties of PEG and other soluble polymers and their applications to the synthesis of peptides, oligonucleotides,... 

Using potassium osmate (0.5-2 mol%) in the presence of an organic base, e.g. quinuclidine, in aqueous tert-butanol at pH 10.4, a variety of olefins was converted to the corresponding vie-diols in high yield. Apparently reoxidation of os-mium(VI) to osmium(VIII) with dioxygen is possible under alkaline conditions. When chiral bases were used asymmetric dihydroxylation was observed (see Section 4.7) albeit with moderate enantioselectivities. 

Scheme 5.11. Tandem asymmetric dihydroxylation coupled with aldolase conditions. A = aldolase, P = PC>32. ...

Asymmetric dihydroxylation of the three thiophene acrylates 153-155 at 0°C under the standard conditions was very slow. Increasing the temperature only led to decomposition of the thiophene ring. However, satisfactory results could be attained by increasing the ligand twofold (up to 2mol%). The yields of the (27 ,3iJ)-dihydroxy derivatives (Equations 76-78) were in the 50-60% range, with an ee of 99% <2002TL3813>. 

The diols (97) from asymmetric dihydroxylation are easily converted to cyclic sulfite esters (98) and thence to cyclic sulfate esters (99). ° This two-step process, reaction of the diol (97) with thionyl chloride followed by ruthenium tetroxide catalyzed oxidation, can be done in one pot if desired and transforms the relatively unreactive diol into an epoxide mimic, i.e. the 1,2-cyclic sulfate (99), which is an excellent electrophile. A survey of reactions shows that cyclic sulfates can be opened by hydride, azide, fluoride, thiocyanide, carboxylate and nitrate ions. ° Benzylmagnesium chloride and the anion of dimethyl malonate can also be used to open the cyclic sulfates.Opening by a nucleophile leads to formation of an intermediate P-sulfate anion (100) which is easily hydrolyzed to a p-hydroxy compound (101). ° Conditions for catalytic acid hydrolysis have been developed that allow for selective removal of the sulfate ester in the presence of other acid sensitive groups such as acetals, ketals and silyl ethers. ... 

In addition to being an efficient chiral controller in a number of stereoselective transformations of chiral acrylates, (i.e. the Diels-Alder reaction, the conjugate reduction, the asymmetric dihydroxylation, and the nitrile oxide cycloaddition ) the bomanesultam (11) has been shown to be an exceptionally efficient chiral auxiliary for stereoselective aldol condensations (eqs eq 3 and eq 4). Depending upon the reaction conditions, A -propionylsultam can produce either the syn or anti aldol product with an excellent diastereoselectivity, Furthermore, good diastereoselectiv-ities are also observed for the corresponding acetate aldol reaction (eq 5), ... 

A soluble polymer-bound version of the asymmetric dihydroxylation ligand is provided by DHQD-PHAL-OPEG-OMe, a polyethylene glycol derivative [152, 153]. The use of a PEG system with a ligand at each end allowed the dihydroxylation reaction to be run in a continuous flow system with a membrane to retain the ligand. Under these conditions, metal leaching was observed [154]. 

Not surprisingly, fhe classical Os-catalyzed asymmetric dihydroxylation of olefins (cf. Section 2.2) continues to be of interest. The basic principles, such as type of catalyst, stay relatively fhe same and instead efforts are concentrated on making the reaction more suitable for operation under process-like conditions. A modification fhat could improve fhe operabihty is to replace the conventional t-BuOH/ H2O solvent mixture by ionic liquid containing mixtures, either as a monophasic... 

The discovery of iron complexes that can catalyze olefin czs-dihydroxylation led Que and coworkers to explore the possibility of developing asymmetric dihydroxylation catalysts. Toward this end, the optically active variants of complexes 11 [(1R,2R)-BPMCN] and 14 [(1S,2S)- and (lP-2P)-6-Me2BPMCN] were synthesized [35]. In the oxidation of frans-2-heptene under conditions of limiting oxidant, 1R,2R-11 was foimd to catalyze the formation of only a minimal amount of diol with a slight enantiomeric excess (ee) of 29%. However, 1P-2P-14 and 1S,2S-14 favored the formation of diol (epoxide/diol = 1 3.5) with ees of 80%. These first examples of iron-catalyzed asymmetric ds-dihydroxylation demonstrate the possibility of developing iron-based asymmetric catalysts that may be used as alternatives to currently used osmium-based chemistry [45]. 

Of our two approaches, the iterative asymmetric dihydroxylation of dienoates (Scheme 1) is the most efficient in terms of steps (1 to 3 steps). For instance, dienoates, like ethyl sorbate (1.1 R = CH3), react under the Upjohn conditions (OSO4/NMO) 14) o give racemic y-ga/ac/o o-lactones in only one... 

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