Sharpless dihydroxylation, enantioselective

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 ... 

Scheme 55 Electrochemical enantioselective Sharpless dihydroxylation of alkenes.

Stilbene diols such as 3 are gaining prominence both as synthetic intermediates and as effective chiral auxiliaries. While the diols can be prepared in high by Sharpless dihydroxylation, it would be even more practical to prepare them by direct asymmetric pinacol coupling. N. N. Joshi of the National Chemical Laboratory in Pune reports (J. Org. Chem. 68 5668,2003) that 10 mol % of the inexpensive Ti salen complex 2 is sufficient to effect highly enantioselective and diastereoselective pinacol coupling of a variety of aromatic aldehydes. Most of the product diols are brought to >99% by a single recrystallization. 

The use of chiral amines enables enantioselective conversions, such as (DHQ)2-PHAL and (DHQD)2-PHAL in the Sharpless Dihydroxylation. 

Several enantioselective approaches to vitamin E (1), based on resolution of the products, the use of enantiopure natural building blocks, auxiliary controlled reactions and asymmetric oxidations have been described. In addition, a palladium-catalyzed asymmetric allylic alkylation reaction to build up the chiral chroman framework has been employed by Trost. Tietze and coworkers have developed asymmetric syntheses of the chiral chroman moiety using either the selective ally-lation of an alkyl methyl ketone or a Sharpless dihydroxylation as the key step. However, none of these methods is efficient enough for an industrial approach. ... 

Enantioselective sharpless dihydroxylation Euran addition Hetero-Diels-Alder addition Long-chain sugars... 

We dedicate a large part of this chapter to two very important, and extraordinarily useful, enantioselective methods - catalytic asymmetric epoxidation (AE) and catalytic asymmetric dihydroxylation (AD). Impressively, both these methods were developed by Professor Barry Sharpless s research group and are therefore often referred to as the Sharpless epoxidation and the Sharpless dihydroxylation. Both are examples of ligand-accelerated catalysis. 

It is certainly appropriate for us to describe here some of the important aspects of Sharpless dihydroxylation methodology. This background is essential to chemists who do, or are thinking about doing, the reactions. However, a detailed discussion of, for instance, the mechanism of the reaction, or the explanations behind the origin of the enantioselectivity, are beyond the scope of this book and so, where this sort of thing is described at all, it is done mostly from an empirical standpoint. 

From the standpoint of general applicability, and scope the osmium-catalyzed asymmetric dihydroxylation of alkenes (Sharpless dihydroxylation) has reached a level of effectiveness which is unique among asymmetric catalytic methods . In the presence of an optimized catalyst ligand system nearly every class of olefin can be dihydroxylated with high enantioselectivities. 

In addition to enantioselective dihydroxylation, Professor Sharpless devised a widely used method for enantioselective epoxidation (Section 16.9). The 2001 Nobel Prize in Chemistry was shared among Sharpless for enantioselective oxidations and Knowles and Noyori (Section 14.14) for enantioselective hydrogenations. 

The first asymmetric synthesis of (20 S)-camptothecin using catalytic asymmetric induction was achieved by Fang et al. in 1994 [74], They carried out a catalytic enantioselective synthesis of Comins s intermediate (23) in order to avoid the use of the expensive chiral auxiliary, 8-phenylmenthol, or similar compound. Intramolecular Heck reaction of pyridine derivative (26) gave the cyclic olefins (27) and (28) in a ratio 1 8. The allylic ether (27) can be isomerized to (28) upon treatment with Wilkinson s catalyst [75], Asymmetric Sharpless dihydroxylation of (28) proceeded successfully when 2,5-diphenyl-4,6-bis(9-0-dihydroquinidyl)pyrimidine [(DHQD)2-PYR] was used as the chiral catalyst [76], and subsequent oxidation gave (29) in 94% ee. Treatment of (29) with acid gave the target molecule (23, Scheme 2.5), which was converted to (20S)-camptothecin in 2 steps using the Comins s procedure [73]. 

Zhao, Y Xing, X. Zhang, S. Wang, D. Z. N,N-Dimethylaminobenzoates Enable Highly Enantioselective Sharpless Dihydroxylations of 1,1-Disubstituted Alkenes. Org. Biomol. Chem. 2014,12,4314-4317. 

Various catalytic enantioselective procedures for cx-hydroxylation of ketones rely on silicon enolates. In view of the relative nonpolar character of silyl enol ethers and silyl ketene acetals and taking into account similarities in the chemical behavior with electron-rich alkenes like enol, ethers, or enamines, it was an obvious idea trying to apply the classical protocols for olefin oxidation - like Sharpless dihydroxylation [248] and epoxidation procedures of Jacobsen [249] and Shi [250] - to silicon enolates. 

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

In 1980, Hengtges and Sharpless published a seminal report that dihydroxylation occurred in a good enantioselective manner when the reaction was carried out in the presence of a chiral amine, dihydroqunidine acetate (DHQD-Ac) or dihydroquinine acetate (DHQ-Ac). DHQD and DHQ are diastereomers to each other, but they behaved like enantiomers in this reaction (Scheme 42).167... 

In 1988, Sharpless and co-workers reported that dihydroxylation was catalytically effected, with good enantioselectivity and remarkable ligand acceleration, when DHQD or DHQ p-chlorobenzoate... 

DHQD-CL or DHQ-CL) was used as the chiral auxiliary.175,176 However, the enantioselectivity observed under catalytic conditions was inferior to that observed under stoichiometric conditions. The addition of triethylammonium acetate, which increases the rate of hydrolysis of the Osvm-glycolate intermediate, improved enantioselectivity. A further improvement in enantioselectivity was brought about by the slow addition of substrates (Scheme 44).177 These results indicated that the hydrolysis of the Osvm-glycolate intermediate (57) was slow under those conditions and (57) underwent low enantioselective dihydroxylation (second cycle). Thus, Sharpless et al. proposed a mechanism of the dihydroxylation including a second cycle (Scheme 45).177 Slow addition reduces the amount of unreacted olefin in the reaction medium and suppresses the... 

In 1975, Sharpless et al. reported that imino-osmium trioxides underwent aminohydroxylation (Scheme 54).208,209 t0 perform aminohydroxylation with high efficiency, regio-, chemo-, and enantioselectivity must be addressed. This had made the practical realization of aminohydroxylation difficult. However, the development of asymmetric dihydroxylation, as described in the preceding section, propelled the study of asymmetric aminohydroxylatyion forward and, in 1996, Sharpless et al. reported a highly enantioselective version of catalytic aminohydroxylation... 

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. 

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