Hydroxy carbonyl compounds chiral

An alkene activated by an electron-withdrawing group—often an acrylic ester 2 is used—can react with an aldehyde or ketone 1 in the presence of catalytic amounts of a tertiary amine, to yield an a-hydroxyalkylated product. This reaction, known as the Baylis-Hillman reaction, leads to the formation of useful multifunctional products, e.g. o -methylene-/3-hydroxy carbonyl compounds 3 with a chiral carbon center and various options for consecutive reactions. 

Oxidation of silyl enol ethers. Oxidation of silyl enol ethers to a-hydroxy aldehydes or ketones is usually effected with w-chloroperbenzoic acid (6, 112). This oxidation can also be effected by epoxidation with 2-(phenylsulfonyl)-3-( p-nitrophenyl) oxaziridine in CHC1, at 25-60° followed by rearrangement to a-silyloxy carbonyl compounds, which are hydrolyzed to the a-hydroxy carbonyl compound (BujNF or H,0 + ). Yields are moderate to high. Oxidation with a chiral 2-arene-sulfonyloxaziridine shows only modest enantioselectivity. 

Lithium borohydride, 92 (lR,2S)-N-Methylephedrine-0-pro-pionate, 308 Norephedrine, 200 2-Oxazolidones, chiral, 225 (2R,4R)-Pentanediol, 237 Potassium triethylborohydride, 260 Other hydroxy carbonyl compounds (R)-( + )- and (S)-( - )-2,2 -Bis-(diphenylphosphine)-1,1 -binaphthyl, 36 Ketones... 

The asymmetric aldol reaction is one of the most important topics in modern catalytic synthesis [54]. The products, namely />-hydroxy carbonyl compounds, have a broad range of applications and play a key role in the production of pharmaceuticals [55], Since the discovery of the catalytic asymmetric aldol reaction with enolsi-lanes by Mukaiyama et al. [56], steady improvements of the metal-catalyzed asymmetric aldol reaction have been made by many groups [57]. For this type of aldol reaction a series of chiral metal catalysts which act as Lewis acids activating the aldol acceptor have been shown to be quite efficient. It was recently shown by the Shibasaki group that the asymmetric metal-catalyzed aldol reaction can be also performed with unmodified ketones [57a], During the last few years, several new concepts have been developed which are based on use of organocatalysts [58], Enolates and unmodified ketones can be used as aldol donors. 

A study on the chiral complexation preferences of three series of cyclic a-hydroxy carbonyl compounds (Scheme 3.26) has been carried out using DFT and MP2 calculations. The dimer formation study has been preceded by a conformational exploration of the isolated monomers of the parent compounds. In addition, three possible dimers have been considered initially in the dimers of the parent compound, discarding those with the highest energies for the rest of the derivatives. 

I. Alkorta et al., Chiral recognition in cyclic a-hydroxy carbonyl compounds A theoretical study. J. Phys. Chem. A 109, 3262-3266 (2005)... 

The reaction of carbonyl substrates with oxygen in basic media has been utilized by Shioiri and co-workers to generate optically active a-hydroxy carbonyl compounds when a quaternary ammonium salt such as /V-(4-trifluoromethylphenylmethyl)cinchoninium bromide (2) is employed as a chiral catalyst102. Enantiomeric excesses up to 74% have been realized by using this simple methodology (Table 10). 

Dibenzyl peroxydicarbonate has been used for the oxidation of both chiral and achiral lithium or potassium enolates to form carbonates of a-hydroxy carbonyl compounds. Dibenzyl peroxydicarbonate, prepared from aqueous hydrogen peroxide and benzyl chlo-roformate under basic conditions, was preferred for mechanistic studies to the commonly used MoOPH in view of the easier preparation of 0-labelled compounds . 

Several oxaziridines related to (14) (eq 8) have been used, most notably in the enantioselective oxidation of sulfides to sulfoxides, of selenides to selenoxides, and of alkenes to oxiranes, It is also the reagent of choice for the hydroxylation of lithium and Grignard reagents and for the asymmetric oxidation of enolates to give a-hydroxy carbonyl compounds, - A similar chiral fluorinating reagent has also been developed, ... 

Highly acid sensitive a-siloxy epoxides (108 R1 = R2 = Me) are available in good to excellent yields through the epoxidation of silyl enols ethers (107) with jV-sulfonyloxaziridine (63b) <87JOC954>. Hydrolysis of (108) gave the a-hydroxy carbonyl compound (109) in good-to-excellent yield (55-95%) and represents an alternative to peracids usually used to effect this transformation known as the Rubottom reaction. With chiral nonracemic TV-sulfonyloxaziridines the ees of (109) were low (7-11% ee) because of the poor facial discrimination between the re and si faces of the silyl enol ether (Scheme 20). 

The most widely used application of (V-sulfonyloxaziridines is for the synthesis of a-hydroxy carbonyl compounds (125), a key structural unit found in many biologically important molecules (Scheme 24). Compounds containing this array are also useful as chiral auxiliaries and as synthetic building blocks for asymmetric synthesis. Although a number of indirect methods have been devised to prepare a-hydroxy carbonyl compounds, the enolate oxidation protocol, using (V-sulfonyloxaziridines, is undoubtedly the most versatile because of the great diversity of metal enolate... 

Of particular concern with a-hydroxy carbonyl compounds is the stereochemistry of the hydroxy group attached to the stereogenic carbon because biological activity is often critically dependent on its orientation. A-Sulfonyloxaziridines have played a prominent role in the stereoselective synthesis of this key structural element (Scheme 25). Enantiomerically and diastereomerically enriched materials have been prepared by (1) the hydroxylation of chiral nonracemic enolates with racemic A-sulfonyloxaziridines, for example (63a) (2) the asymmetric hydroxylation of prochiral enolates with enantiopure A-sulfonyloxaziridines and (3) a combination of the first two, double stereodifferentiation. 

The product stereochemistry for reagent-induced hydroxylations are under the control of a noncovalently bound chiral reagent which avoids the introduction and eventual removal of the chiral auxiliary as discussed in the preceding section. This method requires an enantiopure N-sulfonyloxaziridine of which (camphorylsulfonyl)oxaziridines (74), (114), and (158) have proven the most useful <92CRV919>. Both epimeric a-hydroxy carbonyl compounds are readily available because the antipodal oxidant controls the absolute stereochemistry of the product (Scheme 25). Oxaziridines (74) and (114) are commercially available. 

Asymmetric allyation of carbonyl compounds to prepare optically active secondary homoallyhc alcohols is a useful synthetic method since the products are easily transformed into optically active 3-hydroxy carbonyl compounds and various other chiral compounds (Scheme 1). Numerous successful means of the reaction using a stoichiometric amount of chiral Lewis acids or chiral allylmetal reagents have been developed and applied to organic synthesis however, there are few methods available for a catalytic process. Several reviews of asymmetric allylation have been pubHshed [ 1,2,3,4,5] and the most recent [5] describes the work up to 1995. This chapter is focussed on enantioselective allylation of carbonyl compounds with allylmetals under the influence of a catalytic amount of chiral Lewis acids or chiral Lewis bases. Compounds 1 to 19 [6,7,8,9,10,11,12,... 

Catalytic asymmetric aldol reactions have emerged as one of the most powerful carbon-carbon bond-forming processes affording synthetically useful, optically active /3-hydroxy carbonyl compounds [36]. Among them, chiral Lewis acid-catalyzed reactions of aldehydes with silyl enol ethers are one of the most promising methods. Although several successful examples have been developed since 1990 [37], most of the reactions have to be conducted at low reaction temperatures (e.g., — 78°C) in aprotic anhydrous solvents such as dry dichloromethane, toluene, and propionitrile. 

An indirect route to a-hydroxy carbonyl compounds uses enol ethers as substrates for dihydroxylations (Scheme 8.24). The primary product is a vicinal hydroxy-hemiacetal which fragments to afford an a-hydroxyketone, rendering the overall route a two-step conversion of ketone to a-hydroxy ketone. The stereochemically important step can use a chiral auxiliary or enantioselective catalysis [64]. The sense of asymmetric induction found in Oppolzer s sulfonamide, shown in Scheme 8.24a... 

Scheme 8.24. Dihydroxylation reactions used for the synthesis of a-hydroxy carbonyl compounds, (a) A chiral auxiliary approach [102], (b) Application of the Sharpless AD procedure to an intermediate for the synthesis of camptothecin [104].

Davis oxaziridine reagents such as 1 have exhibited ample synthetic utility as oxidizing agents for the hydroxylation of enolates to provide a-hydroxy carbonyl compounds, such as 2 with superb yield. When the oxaziridine is chiral and nonracemic, the hydroxylation has been shown to proceed with high stereoselectivity.1... 

Despite high yield, the Rubottom oxidation is limited by the necessity for synthesis of the requisite silane ethers. The direct oxidation of enolates has thus emerged as the preferred method for the stereoselective formation of a-hydroxy carbonyl compounds because of the method s effectiveness for both acyclic and cyclic substrates. Davis s oxaziridine reagents have proved to be ideally suited for the one-step enolate hydroxylation process. The following chiral oxaziridine reagents have been utilized effectively in this protocol and will be showcased throughout the chapter. 

Chiral glycolate equivalents for the asymmetric s)mthesis of a-hydroxy-carbonyl compounds (heterocycles as chiral auxiliaries) 07BCJ1451. 

Likewise, this procedure provides a route for the reduction of a,/3-epoxy ketones and a, -epoxy esters to generate the corresponding /3-hydroxy carbonyl compounds (eqs 7 and 8). The epoxy ketone substrates may be derived from Sharpless asymmetric epoxidation. Consequently, this procedure provides a means to prepare a variety of chiral, nonracemic 8-hydroxy carbonyl compounds that are difficult to acquire by more traditional procedures. 

Aldol reactions are ubiquitous in synthetic organic chemistry to generate intermediates of antihypertensive dmgs and calcium antagonists. Chiral p-hydroxy carbonyl compounds can readily be converted to 1, i-syn and anfr-diols and amino alcohols, which are the building blocks in many natural products such as antibiotics and pheromones and in many biologically active compounds. Aldol products have successfully been converted to key synthetic intermediates of epithilone A and bryostatin 7. ... 

A chiral lanthanide complex catalyzes asymmetric Mukaiyama aldol reactions in aqueous media (Scheme 24). The changes in the water-coordination number is key to the mechanism of die catalytic reaction. The precatalysts yielded -hydroxy carbonyl compounds from aliphatic and aryl substrates widi high diastereomeric ratios and enantiomeric excesses of up to 49 1 and 97%, respectively. 

In another context, a nickel catalyst generated in situ from chiral N,N -dioxide 11 was applied by Feng et al to induee the asymmetric carbonyl-ene reaction of glyoxal derivatives with alkenes to provide the eorresponding y,5-unsaturated a-hydroxy carbonyl compounds." As shown in Scheme 10.19, these products were obtained in high yields and with excellent enantioselectivities of up to >99% ee. It was noteworthy that this catalyst system exhibited a remarkably broad substrate scope. For example, neither the electronic properties nor the... 

The aldol reaction is an important carbon-carbon bond-forming method for constructing p-hydroxy carbonyl compounds in which new stereogenic centers are created. Especially, regio- and stereoselective aldol reactions are the most useful for organic synthesis of complex molecular skeletons [11-15]. From a viewpoint of atom economy, an aldol reaction via direct formation of an enolate with a catalytic amoimt of base is highly desired, and high Brpnsted basicity of the alkaline-earth metal compounds is suitable for this purpose. In recent researches on chiral alkaline-earth metal catalysis, direct-type asymmetric aldol and related reactions have been developed. 

A variety of a-heterosubstituted ketones and similar substrates are reduced by Sml2 under mild conditions, to form unsubstituted ketones. The heteroatom functionalities that can be re-ductively cleaved include halides (-1, -Br, -Cl), -SR, -S(0)R, -SO2R, and -OR (Molander and Hahn, 1986b Smith et al., 1988). Reductive cleavage of some of these heteroatom substituents requires the presence of HMPA as cosolvent for greater efficiency (Kusuda et al., 1989). a,f-Qpoxy ketones are also reduced to 0-hydroxy carbonyl compounds as shown in eq. (13) (Otsubo et al., 1987a). This is an important pathway for the synthesis of chiral f-hydroxy carbonyl compounds as the chiral substrates are easily synthesized by the sharpless epoxidation reactions. -epoxy esters require more vigorous conditions and the presence of HMPA for efficient reduction. 

The enantioenriched diols produced by SAD have also found prominent utility as building blocks for chiral alpha-hydroxy carbonyl compounds. An excellent early example from industry appears in the catalytic enantio-selective synthesis of 20-(S)-camptothecin disclosed by researchers at Glaxo in 1994. This biologically active isomer and other related analogues were the subject of investigation as cancer treatments. The convergent synthesis relies on efficient and selective dihydrorylation of enol ether 165 which after in situ oxidation with iodine affords a-hydro y lactone 166 in 94% ee. Three additional steps were required for elaboration of 166 to 20-(5)-camptothecin which had previously been established in a synthesis by Comins and co-workers (Scheme 14.62). ... 

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