Chiral acetal cleavage

The new heterocyclic derivative 130 has been shown to be an efficient chiral auxilliary for asymmetric desymmetrization of cyclic meso-l,2-diols via diastereoselective acetal cleavage . 

Chiral acetals/ketals derived from either (R,R)- or (5,5 )-pentanediol have been shown to offer considerable advantages in the synthesis of secondary alcohols with high enantiomeric purity. The reaction of these acetals with a wide variety of carbon nucleophiles in the presence of a Lewis acid results in a highly diastereoselective cleavage of the acetal C-0 bond to give a /1-hydroxy ether, and the desired alcohols can then be obtained by subsequent degradation through simple oxidation elimination. Scheme 2-39 is an example in which H is used as a nucleophile.97... 

TiCL-induced cleavage of chiral acetal can be used to prepare /i-adrencrgic blocking agents 95 bearing the glycerol structure (Scheme 2-40).98... 

It has since been proved that malate synthase proceeds with inversion independently of any assumption about isotope effect. This has been done via a lyase system that splits malate to acetate21—a methylene-to-methyl conversion. By using methylene-labeled malate and generating chiral acetate, it could be shown unambiguously that this cleavage is an inversion. When the lyase reaction was applied to malate formed from chiral acetate by malate synthase, it was found that the acetate thus generated was of the same chirality as the starting material. This proved that there is also inversion in the reaction of malate synthase. 

Having established the chiral synthesis of levoglucosenone 1 and its functionalized analogues in both enantiomeric forms, we next investigated the exploitation of 26, the functionalized isolevoglucosenone, for the enantiocontrolled construction of natural products on the basis of its inherent convex-face selectivity and functionality, in particular, the alkoxymethyl handle for the acetal cleavage. 

Chiral homoallylic alcohols. The chiral acetals 2 formed from an aldehyde and 1. undergo titanium-catalyzed coupling with allyltrimcthylsilane with marked stereoselectivity. Highest sterco.selectivity is usually obtained with the mixed catalyst TiClj-Ti(0-/-Pr)j (6 5). Cleavage of the chiral auxiliary, effected by oxidation to the ketone followed by -elimination, provides optically active alcohols (4) with —95% ee (equation I). ... 

Synthesis of Unnatural (S)-Proline Derivatives. The condensation of pivaladehyde with (S)-proline yields stereoselec-tively, after lithiation and reaction with an electrophile, the hi-cyclic compound (28), which is a versatile educt for the synthesis of many a-suhstituted proline analogs (29) (eq 12). The reactions proceed via the formation of a chiral lithium enolate without the use of a chiral auxiliary (self-reproduction of chirality). The reaction with a variety of electrophiles cis to the t-Bu group yields a plethora of a-substituted (5)-proline derivatives (29). A limitation of this strategy is the acetal cleavage of some substituted products (28). ... 

Cleavage of chiral acetals. ( 4/ ,6/ )-4,6-Dimethyl-l,3-dioxanes undergo reductive ring opening to give mainly the product with (5)- configuration at the newly formed stereogenic center. 

AcetalkatUm. As a Lewis acid, not only does Sc(OTf) promote acetalization, but chiral acetals undergo stereoselective cleavage in its presence. 

While the diastereoselective cleavage of cyclic chiral acetals is quite well established [108-110], enantioselective variants, e.g., desymmetrizations of me o-acetals [Eq. (7)], are much less reported. The group of Harada used chiral aryl-boron Lewis acids for the enantioselective ring cleavage of 1,3-dioxolanes by si-lyl enol ethers as carbon nucleophiles [111, 112]. 

Due to its Lewis acidity, DIBAL can be used in the reductive cleavage of acetals (see also Aluminum Hydride). Chiral acetates are reduced with enantioselectivity (eq 12) P Oxidation of the intermediate alcohol followed by /3-elimination gives an optically active alcohol, resulting in a net enantioselective reduction of the corresponding ketone. 

Introduction. (l/ ,5i -2//-l,5-Benzodithiepin-3(4/ -one 1,5-dioxide (C2-symmetric his-sulfoxide 1) has been used as a chiral auxiliary for asymmetric desymmetrization of cyclic meso-1,2-diols via diastereoselective acetal cleavage reaction. The procedure consists of three steps (eq 1), that is, acetalization (step 1), acetal cleavage reaction followed by benzylation (step 2), and hydrolysis of the vinyl ether (step 3). Due to the Ca-symmetry of 1, the chiral auxiliary gives only one product in step 1. In addition, no regio- or geometric isomers of the enol ether are formed in step 2. This reagent can be recovered by acid-promoted hydrolysis and reused. 

The nucleophilic cleavage of a C-0 bond in a chiral acetal to give a wide range of products has been investigated under a broad range of conditions. Examples are plentiful with numerous nucleophiles that are effective in the... 

Numerous other nucleophiles participate in highly diastereoselective reactions with chiral acetals (Scheme 6.9). A few selected examples include the introduction of acetylene [30] and of cyanide [31] to give the chiral pro-pargylic alcohol 45 and the optically active cyanohydrins 46 and 47, respectively. Furthermore, Alexakis and Mangenay observed that diastereoselective acetal cleavages can be carried out with organocuprates to give 48 with 95 5 diastereoselectivity [32]. 

A number of processes involving chiral acetals have been examined in the synthesis of pharmaceutically important compounds. In one example, a synthesis of the antiinflammatory drug naproxen (80) includes a diastereoselective bromination reaction to furnish bromide 78 (dr 93 7, Scheme 6.15) [45]. Intramolecular rearrangement gives ester 79 with >99 1 diastereo-selectivity after recrystallization. Subsequent acidic cleavage of the auxiliary followed by reduction (H2 Pd-C) of the bromide that is adventitiously introduced on the naphthyl core afforded naproxen (80). 

Bohman and Allenmark resolved a series of sulphoxide derivatives of unsaturated malonic acids of the general structure 228. The classical method of resolution via formation of diastereoisomeric salts with cinchonine and quinine has also been used by Kapovits and coworkers " to resolve sulphoxides 229, 230, 231 and 232 which are precursors of chiral sulphuranes. Miko/ajczyk and his coworkers achieved optical resolution of sulphoxide 233 by utilizing the phosphonic acid moiety for salt formation with quinine. The racemic sulphinylacetic acid 234, which has a second centre of chirality on the a-carbon atom, was resolved into pure diastereoisomers by Holmberg. Racemic 2-hydroxy- and 4-hydroxyphenyl alkyl sulphoxides were separated via the diastereoisomeric 2- or 4-(tetra-0-acetyl-D-glucopyranosyloxy)phenyl alkyl sulphoxides 235. The optically active sulphoxides were recovered from the isolated diastereoisomers 235 by deacetylation with base and cleavage of the acetal. Racemic 1,3-dithian-l-oxide 236... 

The extremely high selectivity for tandem cycloaddition, the ease of manipulation of the nitroso acetals, and the release of the vinyl ether appendage in the hydrogenolytic cleavage constitute ideal features for asymmetric modifications of the cycloadditions with chiral vinyl ethers. As discussed in Section 8.3.2.1 (Inter [4+2]/inter [3+2] cycloadditions of nitroalkenes), the stereochemical course depends on the Lewis acids. The results are summarized in Scheme 8.38.179 The high levels and complementary selectivity with three chiral vinyl ethers and two kinds of Lewis acids (Ti- and Al-based Lewis acids) are presented in this scheme. 

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