Chiral auxiliaries, diastereoselectivity, asymmetric

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... 

The reaction was first carried out with the substrate bearing the chiral auxiliary. Scheme 5-64 shows the asymmetric cyclopropanation reaction using 2,4-pentandiol as a chiral auxiliary.115 Scheme 5-65 illustrates the use of optically pure 1,2-frafts-cyclohexanediol as a chiral auxiliary in asymmetric Simmons-Smith cyclopropanation.116 Excellent yield and diastereoselectivity are obtained in most cases. 

The nonracemic 2/7-1,3-benzoxazin-4(3//)-one 202 was successfully applied as a chiral auxiliary in asymmetric transformations the titanium enolate-mediated aldol reactions of its A-acyl derivatives provided the products in high yields and with excellent diastereoselectivity <1996SL455, 1996TL5565>. 

The A -acyl derivatives of 4-substituted-3,4,5,6-tetrahydro-27/-l,3-oxazin-2-ones proved to behave as effective chiral auxiliaries in asymmetric enolate alkylations and aldol reactions, the stereoselectivities of which were found to be higher for 4-isopropyl than for 4-phenyl derivatives <2006OBC2753>. The transformations of 4-isopropyl-6,6-dimethyl-3-propa-noyl-3,4,5,6-tetrahydro-2/7-l,3-oxazin-2-one 251 to 252 or 253 proceeded with excellent diastereoselectivities (Scheme 47). 6,6-Dimethyl substitution within the oxazine ring facilitated exclusive exocyclic cleavage upon hydrolysis of the C-alkylated and the aldol products 252 and 253, to furnish a-substituted carboxylic acids 254 or a-methyl-/ -hydroxycarboxylic acids 256. 

Stereosectivity is a broad term. The stereoselectivity in cyclopropanation which has been discussed in the above subsection, in fact, can also be referred to as diastereoselectivity. In this section, for convenience, the description of diastereoselectivity will be reserved for selectivity in cyclopropanation of diazo compounds or alkenes that are bound to a chiral auxiliary. Chiral diazoesters or chiral Ar-(diazoacetyl)oxazolidinone have been applied in metal catalysed cyclopropanation. However, these chiral diazo precursors and styrene yield cyclopropane products whose diastereomeric excess are less than 15% (equation 129)183,184. The use of several a-hydroxy esters as chiral auxiliaries for asymmetric inter-molecular cyclopropanation with rhodium(II)-stabilized vinylcarbenoids have been reported by Davies and coworkers. With (R)-pantolactone as the chiral auxiliary, cyclopropanation of diazoester 144 with a range of alkenes provided c yield with diastereomeric excess at levels of 90% (equation 130)1... 

R)-(-)-2,2-Diphenylcyclopentanol (1) is a highly effective chiral auxiliary in asymmetric synthesis. Hydrogenation of chiral 0-acetamidocrotonates derived from this alcohol has afforded the corresponding 0-amido esters with high diastereoselectivity (96% de).6 In addition, (R)-1 has been used as a chiral auxiliary in Mn(lll)-based oxidative free-radical cyclizations to provide diastereomerically enriched cycloalkanones (60% de).7 Our interest in (R)-(-)-2,2-diphenylcyclopentanol is its utility as a chiral auxiliary in Lewis acid-promoted, asymmetric nitroalkene [4+2] cycloadditions. The 2-(acetoxy)vinyl ether derived from alcohol (R)-1 is useful for the asymmetric synthesis of 3-hydroxy-4-substituted pyrrolidines from nitroalkenes (96% ee).8 In a similar fashion, a number of enantiomerically enriched (71-97% ee) N-protected, 3-substituted pyrrolidines have been prepared in two steps from 2-substituted 1-nitroalkenes and (R)-2,2-diphenyl-1-ethenoxycyclopentane (2) (see Table).9... 

Asymmetric Radical Reactions. Several reports have documented the utility of nonracemic fra/w-2,5-dimethylpyrrolidine as a chiral auxiliary in asymmetric radical reactions. For example, the addition of -hexyl, cyclohexyl, and f-butyl radicals to the chiral acrylamide of 4-oxopentenoic acid provided four diastere-omeric products resulting from a- and p-addition (eq 7). The isomers resulting from p-addition were formed with no diastereoselectivity however, the isomers resulting from a-addidon were formed in ratios of 16 1,24 1, and 49 1. Unfortunately, the application of this chemistry is limited due to the poor regioselectivity in the addition and difficulty in removal of the chiral auxiliary. 

Asymmetric Pericyclic Reactions. Several reports illustrate the utility of fra/is-2,5-dimethylpyirolidine as a chiral auxiliary in asymmetric Claisen-type rearrangements, [4 + 2], and [2 + 2] cycloaddition reactions. The enantioselective Claisen-type rearrangement of N,0-ketene acetals derived from tram-2,5-dimethylpyrrolidine has been studied. For example, the rearrangement of the iV.O-ketene acetal, formed in situ by the reaction of A-propionyl-fra/w-(25,55)-dimethylpyrrolidine with ( )-crotyl alcohol, affords the [3,3]-rearrangement product in 50% yield and 10 1 diastereoselectivity (eq 9). 

In 2001, Tungler and coworkers described the diastereoselective hydrogenation of N (1 methylpyrrole 2 acetyl) (S) proline methyl ester (32) using the Rh/C as cata lyst [40]. By introducing (S) proline moiety as chiral auxiliary, high asymmetric induction was obtained. When 32 was subjected to 5% Rh/C catalyst in methanol with 20 bar H2, the reduced product 33 was obtained with full conversion and 95% de. This substrate induced asymmetric reduction and was effective only to (2 pyrrolyl) acetic acid derivatives (Scheme 10.30). 

The utility of thiazolidinethione chiral auxiliaries in asymmetric aldol reactions is amply demonstrated in a recent enantioselective synthesis of apoptolidinone. This synthesis features three thiazolidinethione propionate aldol reactions for controlling the configuration of 6 of 12 stereogenio centers <05JA13810>. For example, addition of aldehyde 146 to the enolate solution of A -propionyl thiazolidinethione 145 produces aldol product 147 with excellent selectivity (>98 2) for the Evans syn isomer. Compound 145 also undergoes diastereoselective aldol addition with bisaryl aldehyde 148 to give the Evans syn product 149, which is converted to eupomatilone-6 in 6 steps <05JOC9658>. 

To date the most general chiral auxiliary mediated asymmetric Ireland-Claisen rearrangement is that of Corey et al. (Scheme 4.44) [47]. They found that treatment of crotyl propionates and related esters afforded good yields, diastereoselectivities and enantioselectivities of the pentenoic acid products. The rearrangements also occurred at significantly lower temperature than the silyl ketene acetals. A key advantage of the chemistry is that the chiral auxiliary attachment, Ireland-Claisen rearrangement, and auxiliary removal all occur in one pot. 

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. 

Some achiral precursors in enantioselective asymmetric synthesis are indicated in Figure 2. In order to be used in diastereoselective asymmetric syntheses they need to bear a functional group able to give a temporary linkage to the chiral auxiliary. The asymmetric synthesis is a process of dessymmetrization of an achiral precursor (removal of all the elements of symmetry reflection, eg Sn elements). 

In Diels-Alder (D-A) reactions, racemic products are obtained from enantiomeric diene or dienophile. D-A reactions are widely applied in the synthesis of bioactive asymmetric natural products and hence enantio- and diastereoselectivities of the D-A reactions are very much needed to get the desired products as major products. Several approaches have been developed in the last three decades in this respect by the use of different Lewis acid catalysts as chiral auxiliary or asymmetric catalysts. Catalytic D-A reactions have twofold benefits. On one side, it provides high enantiomeric/ diastereomeric excess of product and on the other side, it affords high yield of products by reducing the activation energy of the transition states (TSs). In NED D-A reactions, it lowers the LUMO energy of the dienophile and in lED D-A reactions, it lowers the energy of LUMO of the diene so that the reaction occurs at low temperature with ease (Fig. 3.10). At higher temperature the stereoselectivity of the D-A reactions is lost. 

CHMO.. has been used in the diastereoselective oxidation of different p-hydroxy sulfides to the corresponding chiral p-hydroxy sulfoxides. Chiral p-hydroxy sulfoxides represent interesting compounds used as chiral auxiliaries in asymmetric synthesis, asymmetric ligands, or as building blocks for the synthesis of cyclic sulfides, benzoxathiepines, allylic alcohols, or leukotrienes [27]. The sulfoxidation of these substrates is a kinetic resolution, in which both the sulfide and the sulfoxide can be obtained in chiral form. Oxidation of the cyclohexyl derivative (Table 6.1, entry 2) by a semipurified preparation of in the presence of the enzymatic... 

The first three sections of this chapter describe diastereoselective alkylations of chiral enolates including heteroatom-substituted enolates [15, 20]. Section 3.4 deals with the class of enolate alkylations that have typically been included under the rubric of chiral-auxiliary-controlled processes. As suggested by the term, the auxiliary is only transiently utilized and, following alkylation, is subsequently excised. The facile use of chiral auxiliaries in asymmetric enolate alkylations has played and continues to play a pivotal role in the stereoselective formation of new C-C bonds. After a brief survey of the relatively few developments in catalytic enantioselective enolate alkylations (Section 3.5) [21, 22], selected examples of enolate a-hydroxylations (Section 3.6) [23-25] and a-halogenations (Section 3.7) [26, 27] are covered. The corresponding a-aminations of enolates are discussed in Chapter 10, describing stereoselective formation of a-amino acids. 

Oppolzer s acylated camphorsultams (147, Equation 12) remain a classic among chiral auxiliaries for asymmetric synthesis and have been successfully applied in a variety of mechanistically distinct chemical transformations [88, 91]. The corresponding enolates can readily be prepared with a variety of strong bases and have been shown to undergo diastereoselective alkylation with a range of activated and non-activated electrophilic reagents. An illustrative example is the formation of 149 in dr >99 1 [91]. The sense... 

One of the most successful classes of chiral auxiliaries for asymmetric synthesis is that of Enders proline-based hydrazines, namely (S)-l-amino-2-methoxymethylpyrrolidine (SAMP, 74) and its (R)-enantiomer RAMP (Scheme 11.11) [68]. Enders has reported that chiral hydrazones such as 75 undergo diastereoselective additions with organolithium reagents. The facile removal of the auxiliary by reductive cleavage of the N-N bond enables it as a versatile tool for the synthesis of a wide range of chiral secondary amines [69, 70]. As shown in Scheme 11.11, the secondary amine 77 was thus prepared in 73 % overall yield and 93 % ee [69]. 

Lewis acid-mediated asymmetric Diels-Alder reactions between 2H-azirines 59, bearing chiral auxiliaries, with enophiles such as 60 afforded mixtures of bicyclic aziridine-2-carboxylates 61 (Scheme 3.20) [68]. 8-Phenylmenthol appeared to be the auxiliary of choice in this reaction in terms of yield and diastereoselectivity. 

The reaction of methyl 4-formyl-2-mcthylpentanoate and the chiral (Z)-2-butenylboronate clearly shows 52b-103, however, that the chiral auxiliary is not sufficiently enantioselective to increase the diastereoselectivity to >90% in either the matched [( + )-auxiliary] or mismatched [(—)-auxiliary] case. This underscores the requirement that highly enantioselective chiral reagents be utilized in double asymmetric reactions. 

Simple 1,2,4-triazole derivatives played a key role in both the synthesis of functionalized triazoles and in asymmetric synthesis. l-(a-Aminomethyl)-1,2,4-triazoles 4 could be converted into 5 by treatment with enol ethers <96SC357>. The novel C2-symmetric triazole-containing chiral auxiliary (S,S)-4-amino-3,5-bis(l-hydroxyethyl)-l,2,4-triazole, SAT, (6) was prepared firmn (S)-lactic acid and hydrazine hydrate <96TA1621>. This chiral auxiliary was employed to mediate the diastereoselective 1,2-addition of Grignard reagents to the C=N bond of hydrazones. The diastereoselective-alkylation of enolates derived from ethyl ester 7 was mediated by a related auxiliary <96TA1631>. 

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