Asymmetric chiral auxiliary-directed

Chiral Auxiliary-Directed Asymmetric Radical Domino Processes... 

The landmark report by Winstein et al. (Scheme 3.6) on the powerful accelerating and directing effect of a proximal hydroxyl group would become one of the most critical in the development of the Simmons-Smith cyclopropanation reactions [11]. A clear syw directing effect is observed, implying coordination of the reagent to the alcohol before methylene transfer. This characteristic served as the basis of subsequent developments for stereocontrolled reactions with many classes of chiral allylic cycloalkenols and indirectly for chiral auxiliaries and catalysts. A full understanding of this phenomenon would not only be informative, but it would have practical applications in the rationalization of asymmetric catalytic reactions. 

The discovery of viable substrate-direction represents a major turning point in the development of the Simmons-Smith cyclopropanation. This important phenomenon underlies all of the asymmetric variants developed for the cyclopropanation. However, more information regarding the consequences of this coordinative interaction would be required before the appearance of a catalytic, asymmetric method. The first steps in this direction are found in studies of chiral auxiliary-based methods. 

To date, direct asymmetric synthesis of optically active chiral-at-metal complexes, which by definition leads to a mixture of enantiomers in unequal amounts thanks to an external chiral auxiUary, has never been achieved. The most studied strategy is currently indirect asymmetric synthesis, which involves (i) the stereoselective formation of the chiral-at-metal complex thanks to a chiral inductor located either on the ligand or on the counterion and then (ii) removal of this internal chiral auxiliary (Fig. 4). Indeed, when the isomerization of the stereogenic metal center is possible in solution, in-... 

Besides their application in asymmetric alkylation, sultams can also be used as good chiral auxiliaries for asymmetric aldol reactions, and a / -product can be obtained with good selectivity. As can be seen in Scheme 3-14, reaction of the propionates derived from chiral auxiliary R -OH with LICA in THF affords the lithium enolates. Subsequent reaction with TBSC1 furnishes the 0-silyl ketene acetals 31, 33, and 35 with good yields.31 Upon reaction with TiCU complexes of an aldehyde, product /i-hydroxy carboxylates 32, 34, and 36 are obtained with high diastereoselectivity and good yield. Products from direct aldol reaction of the lithium enolate without conversion to the corresponding silyl ethers show no stereoselectivity.32... 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted much interest for their various applications in different synthetic transformations.2 Such simple structures, directly related to far better known chiral oxazolidinones,11,12,57 have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations, but mainly in condensation of their /V-acyl derivatives with aldehydes. Chiral OZTs have shown interesting characteristics in anti-selective aldol reactions58 or combined asymmetric addition. 

It is worthwhile emphasising that the abovementioned syntheses using chiral auxiliaries covalently bound to the substrate bearing the prochiral center prior to the creation of the new asymmetric centre mean converting the problem of enantiofacial recognition into a problem of diastereofacial selectivity i.e. the pair of enantiomers 41 and 42 are actually obtained from hydrolysis of two different diastereomers 39 and 40. In fact, "direct enantioselectivity" can only be attained by using an external chiral catalyst,23 as shown in Figure 9.1 [26]. 

The pyrrolobenzodiazepine-5,11 -diones II have been utilized in asymmetric syntheses of both the cis- and tra i-decahydro-quinoline alkaloids (Schemes 21 and 22). For example, reduction of 100 with 4.4 equiv. of potassium in the presence of 2 equiv. of t-BuOH, followed by protonation of the resulting enolate with NH4CI at —78 °C gave the cA-fused tetra-hydrobenzene derivative 101.Amide-directed hydrogenation of 101 gave the hexahydrobenzene derivative with diastereo-selectivity greater than 99 1. Removal of the chiral auxiliary and adjustment of the oxidation state provided aldehyde 103 which was efficiently converted to the poison frog alkaloid (+)-pumiliotoxin C. 

Numerous studies have been directed toward expanding the chemistry of the donor/ac-ceptor-substituted carbenoids to reactions that form new carbon-heteroatom bonds. It is well established that traditional carbenoids will react with heteroatoms to form ylide intermediates [5]. Similar reactions are possible in the rhodium-catalyzed reactions of methyl phenyldiazoacetate (Scheme 14.20). Several examples of O-H insertions to form ethers 158 [109, 110] and S-H insertions to form thioethers 159 [111] have been reported, while reactions with aldehydes and imines lead to the stereoselective formation of epoxides 160 [112, 113] and aziridines 161 [113]. The use of chiral catalysts and pantolactone as a chiral auxiliary has been explored in many of these reactions but overall the results have been rather moderate. Presumably after ylide formation, the rhodium complex disengages before product formation, causing degradation of any initial asymmetric induction. 

The utilization of a-amino acids and their derived 6-araino alcohols in asymmetric synthesis has been extensive. A number of procedures have been reported for the reduction of a variety of amino acid derivatives however, the direct reduction of a-am1no acids with borane has proven to be exceptionally convenient for laboratory-scale reactions. These reductions characteristically proceed in high yield with no perceptible racemization. The resulting p-amino alcohols can, in turn, be transformed into oxazolidinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions, enolates of N-acyl oxazolidinones have been used in conjunction with asymmetric alkylations, halogenations, hydroxylations, acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

Chiacchio et al. (43,44) investigated the synthesis of isoxazolidinylthymines by the use of various C-functionalized chiral nitrones in order to enforce enantioselec-tion in their cycloaddition reactions with vinyl acetate (Scheme 1.3). They found, as in the work of Merino et al. (40), that asymmetric induction is at best partial with dipoles whose chiral auxiliary does not maintain a fixed geometry and so cannot completely direct the addition to the nitrone. After poor results with menthol ester-and methyl lactate-based nitrones, they were able to prepare and separate isoxazo-lidine 8a and its diastereomer 8b in near quantitative yield using the A-glycosyl... 

In late 1975, Enders et al.156) started a research project directed towards the development of a new synthetic method for asymmetric carbon-carbon bond formation. A new chiral auxiliary, namely the (S)-proline derivative SAMP (137), was allowed to react with aldehydes and ketones to give the hydrazones (138), which can be alkylated in the a-position in an diastereoselective manner 157,158). Lithiation 159) of the SAMP hydrazones (138), which are formed in excellent yields, leads to chelate complexes of known configuration 160). Upon treatment of the chelate complexes with alkyl halogenides the new hydrazones (139) are formed. Cleavage of the product hydrazones (139) leads to 2-alkylated carbonyl compounds (140). 

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. 

This procedure describes the use of pseudoephedrine as a chiral auxiliary for the asymmetric alkylation of carboxylic acid amides. In addition to the low cost and availability in bulk of both enantiomeric forms of the chiral auxiliary, pseudoephedrine, a particular advantage of the method is the facility with which the pseudoephedrine amides are formed. In the case of carboxylic acid anhydrides, the acylation reaction occurs rapidly upon mixing with pseudoephedrine. Because pseudoephedrine amides are frequently crystalline materials, the acylation products are often isolated directly by crystallization, as illustrated in the procedure above. 

Despite growing importance of axially chiral biaryls as chiral auxiliaries in asymmetric synthesis, direct synthetic methods accessing to the enantiomerically enriched biaryls from achiral precursors are still very rare, Application of asymmetric cross-coupling to construction of the chiral biaryls is one of the most exciting strategies to this goal. The reported application... 

Camphor and camphor-derived analogues are used frequently as chiral auxiliaries in asymmetric synthesis (cf Chapter 23). There have been numerous reports in the use of camphor imine as templates to direct enantioselective alkylation for the synthesis of a-amino acids, a-amino phos-phonic acids, a-substituted benzylamines, and a-amino alcohols (e.g., Scheme 5.9).43 47 Enantiomeric excesses of the products range from poor to excellent depending on the type of alkyl halides used. 

---