Sharpless asymmetric system

Omura devised an efficient asymmetric synthesis of the 3a-hydroxyfuroindoline ring system required for the total synthesis of madindoline A (172) and B <00JA2122>. Thus, Sharpless asymmetric oxidation of tryptophol (170) led to the desired product 171 in 99% ee in a fashion consistent with the Sharpless epoxidation mnemonic <80JA5976>. 

Shi and coworkers developed a method using silyl enol ethers and in situ generated chiral dioxirane derivatives. Lopp and coworkers could develop an asymmetric dihydroxy lation method for racemic 2-hydroxymethyl ketones 202a-c, using TBHP as oxygen source in combination with the Sharpless catalytic system Ti(OPr-i)4/DET, yielding... 

Asymmetric epoxidation, dihydroxylation, aminohydroxylation, and aziridination reactions have been reviewed.62 The use of the Sharpless asymmetric epoxidation method for the desymmetrization of mesa compounds has been reviewed.63 The conformational flexibility of nine-membered ring allylic alcohols results in transepoxide stereochemistry from syn epoxidation using VO(acac)2-hydroperoxide systems in which the hydroxyl group still controls the facial stereoselectivity.64 The stereoselectivity of side-chain epoxidation of a series of 22-hydroxy-A23-sterols with C(19) side-chains incorporating allylic alcohols has been investigated, using m-CPBA or /-BuOOH in the presence of VO(acac)2 or Mo(CO)6-65 The erythro-threo distributions of the products were determined and the effect of substituents on the three positions of the double bond (gem to the OH or cis or trans at the remote carbon) partially rationalized by molecular modelling. 

Three synthetic approaches were used to provide armodafinil during the process development by Cephalon/Novasep.34 Since the racemic modafinil is commercially available, the resolution via preferential crystallization of modafinic acid 6 was employed for phase I clinical trials and was subsequently replaced by large-scale chiral chromatography. Meanwhile, an economical enantioselective synthetic route was developed by using asymmetric oxidation catalyzed by a titanium (IV) isopropoxide and diethyl tartrate with cumene hydroperoxide (the Sharpless/Kagan system).363... 

Figure 2.19 Oxygen transfer to the alkene using the Kalsuki-Sharpless asymmetric epoxidation system.

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). 

Aminohydroxylation of unsymmetrically substituted alkenes, in contrast to dihydroxylation, may give two possible regioisomers of aminoalcohol derivatives but asymmetric aminohydroxylation, by using the same catalytic system as that used for Sharpless asymmetric dihydroxylation, can be highly regioselective as well as enantioselective. 

The Sharpless asymmetric epoxidation of allyl alcohol gives the glycidol derivative 61 in 90% ee after in situ tosylation of 60 [63]. This process is working on a multiton-a-year scale (Arco Co., USA), facilitating the synthesis of a variety of /0-blockers. Asymmetric dihydroxylation of the allyl ether 63 catalyzed by a combined system of OSO4 and the cinchona alkaloid-based ligand 65 allows the commercial synthesis of the propranolol intermediate 64 in 91 % (Sepracor Co., USA) [64]. 

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. 

Miscellaneous Reagents. Chloramine-T/Osmium Tetroxide. The Sharpless asymmetric aminohydroxylation system for olefins (4-MeC6H4S02N(Na)Cl/ OsCVcinchona alkaloid derived catalysts)340,341 converts silyl enol ethers into a-(p-tosylamino) ketones in 34-40% yield and 76-92% ee (see Eq. 99).342... 

The bis(tetrahydrofuranyl) Annonaceous acetogenin ( + )-(15,16,19,20,23,24)-hexepiuva-ricin (74), has been synthesized utilizing a polyepoxide cascade reaction. The diiodide 70 is transformed into the bis-allylic alcohol 72, which is subsequently converted to a C2-sym-metric diepoxide utilizing the Sharpless asymmetric epoxidation reaction. Selective mono-tosylation of the primary hydroxyl groups served to desymmetrize the system. An acid-catalyzed deketalization followed by simultaneous epoxide opening affords the erythro trans threo trans erythro-conf gmdXion present in the tosylate 73. Transformation of 73 to the desired 74 completes the synthesis [32] (Scheme 17). 

There can be no doubt that the reliability of the Sharpless reaction amongst many different classes of allyl alcohol contributes to its success as a synthetic tool in asymmetric synthesis. Another remarkable attribute of the Sharpless asymmetric epoxidation is the very high level of discrimination between enantiomers of secondary allylic alcohols leading to the wide use of this system for the kinetic resolution of these substrates. The kinetic resolution (Figure 4.5) was first reported using stoichiometric amounts of titanium/tartrate, but catalytic amounts of titanium may also be employed. ... 

Spiro- and 1,2-fused Bicyclic Systems. Spiroketals involving C-glycosidic structures can more correctly be considered to be chain-extended sugars (Chapter 2, Section 2.3). Sharpless asymmetric dihydroxylation of 5-aryl-2-vinylfuran... 

No discussion on catalytic asymmetric synthesis would be complete without mention of the Sharpless asymmetric epoxidation of allylic alcohols [34]. This utilises a Ti(IV)-tartrate catalyst and /-butyl hydroperoxide as the oxidant. High enantioselectivity can be achieved using this system for a wide variety of allylic alcohols. Commercial applications, however, are at present limited to relatively small scale production. 

This catalytic system allows three independent transformations to occur in sequence the Heck reaction, N-oxidation and asymmetric dihydroxylation (AD). The mechanism of the Heck reaction is discussed in the previous section. Here we take a closer look at the last two steps. They are coupled processes, based on the Sharpless asymmetric dihydroxylation reaction [22, 23]. Several recent reviews on Sharpless asymmetric dihydroxylation cover the general synthetic aspects [24-27], together with methods for immobilization of the osmium catalysts [28]. 

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