Lewis acids chiral auxiliary

As for the characteristic controlling of stereochemistry during aldol reaction, the Evans aldol reaction has been extensively modified through the application of Lewis acids, chiral auxiliaries (e.g., oxazolidone, oxadiazinones, thiazolidinethione " ), chelating metals, etc. 

Sihi MP, JiJG, SauskerJB, Jasperse CP. Free radical-mediated intermolecular coryug te additions. Effect of the Lewis acid, chiral auxiliary, and additives on diastereoselectivity. JAm Chem Soc. 1999 121 7517-7526. 

Radical reactions have been recognised only recently for the construction of enantiomerically pure compounds (Renaud and Sibi 2001 Zimmerman and Sibi 2006). In addition to substrate- or auxiliary-induced diastereoselective radical reactions, and in addition to the use of chiral Lewis acids, chiral hydrogen atom donors or chiral transition metal complexes, template molecules can be used to generate a chiral environment and induce chirality to the substrate. With the chiral complexing agent 12, enantioselective radical reactions were achieved with enantiomeric excesses up to 99% ee. 

Evans synthesis of bryostatin 2 (113) also relied upon asymmetric aldol reactions for the introduction of most of the 11 stereocenters [58], At different points, the synthesis used control from an auxiliary, a chiral Lewis acid, chiral ligands on the enolate metal and substrate control from a chiral aldehyde. Indeed, this represents the current state of the art in the aldol construction of complex polyketide natural products. 

To accelerate aUylation with aUylstaimanes, addition of a Lewis acid is often required, because coordination of the Lewis acid to the carbonyl can enhance the electrophilicity of the substrate and facilitate the couphng reaction. Since Yamamoto showed that a nonracemic Lewis acid, chiral (acyloxy)borane (CAB), catalyzed enantioselective allylation [73], chiral Lewis acid catalysts have been extensively developed. Above all, easily available chiral compounds such as BINOL and BINAP have been most frequently used as chiral auxiliaries [74], and enantioselective allylations of C-N double bonds and of carbonyl groups have been achieved [48a, 75]. 

Asymmetric Diels-Alder reactions using a dienophile containing a chiral auxiliary were developed more than 20 years ago. Although the auxiliary-based Diels-Alder reaction is still important, it has two drawbacks - additional steps are necessary, first to introduce the chiral auxiliary into the starting material, and then to remove it after the reaction. At least an equimolar amount of the chiral auxiliary is, moreover, necessary. After the discovery that Lewis acids catalyze the Diels-Alder reaction, the introduction of chirality into such catalysts has been investigated. The Diels-Alder reaction utilizing a chiral Lewis acid is truly a practical synthetic transformation, not only because the products obtained are synthetically useful, but also because a catalytic amount of the chiral component can, in theory, produce a huge amount of the chiral product. 

Aziridination remains less well developed than epoxidation. Nevertheless, high selectivity in inline aziridination has been achieved through the use of chiral sulfi-nimines as auxiliaries. Highly successful catalytic asymmetric aziridination reactions employing either sulfur ylides or diazo esters and chiral Lewis acids have been developed, although their scope and potential applications in synthesis have yet to be established. 

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 stereogenic centers may be integral parts of the reactants, but chiral auxiliaries can also be used to impart facial diastereoselectivity and permit eventual isolation of enantiomerically enriched product. Alternatively, use of chiral Lewis acids as catalysts can also achieve facial selectivity. Although the general principles of control of the stereochemistry of aldol addition reactions have been well developed for simple molecules, the application of the principles to more complex molecules and the... 

Camphor-derived sulfonamide can also permit control of enantioselectivity by use of additional Lewis acid. These chiral auxiliaries can be used under conditions in which either cyclic or noncyclic TSs are involved. This frequently allows control of the syn or anti stereoselectivity.143 The boron enolates give syn products, but inclusion of SnCl4 or TiCl4 gave excellent selectivity for anti products and high enantioselectivity for a range of aldehydes.145... 

These examples and those in Scheme 2.6 illustrate the key variables that determine the stereochemical outcome of aldol addition reactions using chiral auxiliaries. The first element that has to be taken into account is the configuration of the ring system that is used to establish steric differentiation. Then the nature of the TS, whether it is acyclic, cyclic, or chelated must be considered. Generally for boron enolates, reaction proceeds through a cyclic but nonchelated TS. With boron enolates, excess Lewis acid can favor an acyclic TS by coordination with the carbonyl electrophile. Titanium enolates appear to be somewhat variable but can be shifted to chelated TSs by use of excess reagent and by auxiliaries such as oxazolidine-2-thiones that enhance the tendency to chelation. Ultimately, all of the factors play a role in determining which TS is favored. 

Scheme 2.25 shows some examples of additions of enolate equivalents. A range of Lewis acid catalysts has been used in addition to TiCl4 and SnCl4. Entry 1 shows uses of a lanthanide catalyst. Entry 2 employs LiC104 as the catalyst. The reaction in Entry 3 includes a chiral auxiliary that controls the stereoselectivity the chiral auxiliary is released by a cyclization using (V-methylhydroxylamine. Entries 4 and 5 use the triphenylmethyl cation as a catalyst and Entries 6 and 7 use trimethylsilyl triflate and an enantioselective catalyst, respectively. 

As is the case for aldol addition, chiral auxiliaries and catalysts can be used to control stereoselectivity in conjugate addition reactions. Oxazolidinone chiral auxiliaries have been used in both the nucleophilic and electrophilic components under Lewis acid-catalyzed conditions. (V-Acyloxazolidinones can be converted to nucleophilic titanium enolates with TiCl3(0-/-Pr).320... 

The highly ordered cyclic TS of the D-A reaction permits design of diastereo-or enantioselective reactions. (See Section 2.4 of Part A to review the principles of diastereoselectivity and enantioselectivity.) One way to achieve this is to install a chiral auxiliary.80 The cycloaddition proceeds to give two diastereomeric products that can be separated and purified. Because of the lower temperature required and the greater stereoselectivity observed in Lewis acid-catalyzed reactions, the best diastereoselectivity is observed in catalyzed reactions. Several chiral auxiliaries that are capable of high levels of diastereoselectivity have been developed. Chiral esters and amides of acrylic acid are particularly useful because the auxiliary can be recovered by hydrolysis of the purified adduct to give the enantiomerically pure carboxylic acid. Early examples involved acryloyl esters of chiral alcohols, including lactates and mandelates. Esters of the lactone of 2,4-dihydroxy-3,3-dimethylbutanoic acid (pantolactone) have also proven useful. 

An 8-phenylmenthol ester was employed as the chiral auxiliary to achieve enantioselectivity in the synthesis of prostaglandin precursors.83 The crucial features of the TS are the anti disposition of the Lewis acid relative to the alcohol moiety and a tt stacking with the phenyl ring that provides both stabilization and steric shielding of the a-face. 

These reactions exhibit excellent diastereoselectivity derived from the chiral oxazo-lidinone auxiliary. The Lewis acid forms a chelate with the oxazoline and presumably also serves to enhance reactivity. In addition to ethyl, other primary, secondary, and tertiary alkyl radicals, as well as acetyl and benzoyl radicals were used successfully in analogous reactions. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

Two mechanisms are possible for the Cu-mediated aziridination using PhI=NTs as a nitrogen source (i) aziridination via Cu-nitrenoid species (L Cu=NTs) and (ii) aziridination via a L (Cu—PhI=NTs) adduct, in which the Cu complex functions as a Lewis acid catalyst. Jacobsen et al. demonstrated that the enantioselectivity of the aziridination using (48) as the chiral auxiliary did not depend on the nitrogen precursors.1 5 This supports the intermediacy of the Cu-nitrenoid... 

However, most asymmetric 1,3-dipolar cycloaddition reactions of nitrile oxides with alkenes are carried out without Lewis acids as catalysts using either chiral alkenes or chiral auxiliary compounds (with achiral alkenes). Diverse chiral alkenes are in use, such as camphor-derived chiral N-acryloylhydrazide (195), C2-symmetric l,3-diacryloyl-2,2-dimethyl-4,5-diphenylimidazolidine, chiral 3-acryloyl-2,2-dimethyl-4-phenyloxazolidine (196, 197), sugar-based ethenyl ethers (198), acrylic esters (199, 200), C-bonded vinyl-substituted sugar (201), chirally modified vinylboronic ester derived from D-( + )-mannitol (202), (l/ )-menthyl vinyl ether (203), chiral derivatives of vinylacetic acid (204), ( )-l-ethoxy-3-fluoroalkyl-3-hydroxy-4-(4-methylphenylsulfinyl)but-1 -enes (205), enantiopure Y-oxygenated-a,P-unsaturated phenyl sulfones (206), chiral (a-oxyallyl)silanes (207), and (S )-but-3-ene-1,2-diol derivatives (208). As a chiral auxiliary, diisopropyl (i ,i )-tartrate (209, 210) has been very popular. 

Chromium carbene complexes have also been known to react with imine equivalents to afford /3-lactam derivatives234. Furthermore, [3 + 2]-cycloaddition of an alkenylchromium carbene 133 with imines proceeded to afford 3-pyrroline derivatives 134 in the presence of a Lewis acid catalyst (Equation (21)),235 where GaClj or Sn(OTf)2 were efficient promoters. Alkenylcarbenes bearing chiral auxiliaries afforded the desired cycloadduct in optically pure form. 

The sulfonyl group is achiral in itself but has prochiral oxygens, and sultanas have served as important auxiliaries in chiral reactions. Scheme 4 shows a simple example of selective coordination of a chiral Lewis acid to the sulfonyl oxygen. 

The Lewis acid-promoted [4+ 2]-cycloaddition reaction of the allenic ester 103 having a camphor-derived chiral auxiliary with cydopentadiene provided the adduct with excellent Jt-facial selection, leading to an enantioselective synthesis of (-)-/l-san-talene [92]. 

In this section, the literature about Diels-Alder reactions will be presented in a conceptual and illustrative way. After a profound introduction dealing with the development of mechanistic understanding of the Diels-Alder reaction, some interesting recent synthetic developments and applications will be presented. The reaction types and fields of interest are structured in such a way that they can be easily linked to ongoing research from the past ten years. Special attention will be paid to the application of chiral auxiliaries and chiral Lewis acids in asymmetric Diels-Alder reactions. 

The synthesis of enantiomerically enriched compounds can be accomplished by application of chiral Lewis acids or chiral auxiliaries attached to either one of the reactants. The latter application41,42 will be discussed in this section. 

In most reported cases, the covalently bound chiral auxiliary has been attached to the dienophile via an acyl linkage, but there are also many examples known in which the auxiliary has been attached to the diene via an acyl, alkyl or heteroatom linkage, the first example of the latter being Trost s diene147. Lewis acids are often added to the reaction mixtures when the chiral auxiliary attached to the dienophile contains an additional Lewis basic site. This is not only to enhance the reaction rate, but especially to enhance the diastereofacial selectivity by complexing to the dienophile in a bidentate fashion. This makes the dienophile more conformationally rigid. 

Sudo and Saigo153 reported the application of ds-2-amino-3,3-dimethyl-l-indanol derived l,3-oxazolidin-2-one 231 as a chiral auxiliary in asymmetric Diels-Alder reactions. The TV-crotonyl and TV-acryloyl derivatives were reacted with cyclopentadiene, 1,3-cyclohexadiene, isoprene and 2,3-dimethyl-l,3-butadiene, using diethylaluminum chloride as the Lewis acid catalyst. The reactions afforded the expected cycloadducts in moderate to high yields (33-97%) with high endo selectivities and high de values (92% to >98%). 

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