Chiral phosphonate reagents

The concept of desymmetrization through intermoiecuiar HWE reactions using chiral phosphonate reagents was independently demonstrated by two research... 

Sulfoxides without amino or carboxyl groups have also been resolved. Compound 3 was separated into enantiomers via salt formation between the phosphonic acid group and quinine . Separation of these diastereomeric salts was achieved by fractional crystallization from acetone. Upon passage through an acidic ion exchange column, each salt was converted to the free acid 3. Finally, the tetra-ammonium salt of each enantiomer of 3 was methylated with methyl iodide to give sulfoxide 4. The levorotatory enantiomer was shown to be completely optically pure by the use of chiral shift reagents and by comparison with a sample prepared by stereospecific synthesis (see Section II.B.l). The dextrorotatory enantiomer was found to be 70% optically pure. 

A novel chiral phosphonic amide-SiCl4 complex has also been found to serve as a catalyst for additions of allenyltributyltin to aldehydes (Table 9.45) [78], The reaction is limited to aromatic aldehydes because of competing formation of silylated chloro-hydrins from aliphatic aldehydes and the SiCI4 reagent. 

More recently, the chiral phosphonate 85 has been used as a CDA with chiral amines to form diastereomeric phosphonic amides (86)79 which are analyzed by 31P-NMR spectroscopy for the determination of enantiomeric ratios. The reagent is readily prepared from (5)-2-butanol and phosphorous trichloride, and all a-amino acids and amines thus far examined react quantitatively in a few hours at room temperature in aqueous ethanol79. 

We now analyze the Still-Gennari reaction of Figure 11.17. The reagents there are the enantiomerically pure chiral phosphonate A, with which you are familiar from Figure 11.16,... 

We now analyze the Still-Gennari olefination of Figure 9.18. The reagents there are the enantiomerically pure chiral phosphonate A, with which you are familiar from Figure 9.17, and an enantiomerically pure a-chiral aldehyde B. The diastereoselectivity of the formation of the crucial alkoxide intermediate(s) is in this case determined by the interplay of three factors ... 

The first highly diastereoselective hydrophosphonylation of heterocyclic imines, 3-thiazolines (330) by a chiral phosphorus reagent BINOL, has been performed. The relative configuration of BINOL and the newly formed stereogenic centre in the a-amino phosphonic acid derivatives (331) have been elucidated by X-ray analysis. 

Relatively strong bases are used for the deprotonation of phosphonate reagents, and the phosphonate-stabilized carbanions formed are more basic than the corresponding phosphorane reagents. Such conditions may be incompatible with base-sensitive aldehydes and ketones, causing epimerization of chiral compounds or... 

The utility of Davis chiral oxaziridine reagents has been more recently applied to the synthesis of optically active a-hydroxy phosphonates. Two groups have been largely responsible for developments in this area. Principally, Wiemer and co-workers have demonstrated the highly enantioselective hydroxylation of a series of benzyl phosphonates. As shown below for 69, hydroxylation makes use of oxaziridine 6, proceeding in moderate... 

Finally, Inanaga reported a rare example of scandium catalysis with a preformed complex bearing a fluorinated axial chiral phosphonate. This fluorination of 3-keto esters employed N-fluoro pyridinum triflate as reagent, a rare case in which NFSl did not represent the superior reagent [46]. 

The chiral phosphonates 31a,e, possessing optically active BINOL as an auxiliary, also demonstrated their ability as asymmetric inducers in the dissymmetrization of carbonyl compounds. In order to achieve both high enantioselectivity and good chemical yield, addition of zinc chloride was quite effective in these transformations [8]. It is known that bicydo[3.3.0]octane derivatives usually adopt either W-, S-, or V-shaped conformations, and the observed stereochemistry of the alkene 92a was best explained by considering an initial approach of the nucleophile to the W-shaped bicyclo[3.3.0]octanone in the direction in which steric interaction between the reagent and the substrate is minimized. 

The reagents most widely applied to the dissymmetrization of ketones are chiral HWE phosphonate reagents possessing an 8-phenyhnenthyl auxiliary on their carboalkoxy portion. Using reagents of this type, high diastereoselectivity has been achieved [58-60] (Scheme 7.14), and this may be due to the presence of the phenyl... 

The anions of the HWE reagents 27a,b were reacted with the chiral monoketone 99 to afford the corresponding Z- and -olefins 100 and 101 with high diastereo-meric excesses, depending upon which enantiomer of the chiral phosphonate was employed. The olefinic products thus obtained served as key intermediates in the synthesis of prostacyclin derivatives [59, 60]. A closely related chiral reagent, 24, bearing 8-phenylnormenthol [67], both enantiomeric forms of which are readily accessible, provided an improved diastereoselectivity in favor of the -isomer 101 (Scheme 7.16). 

Some years later, the first investigations [19, 49, 66] of the preparative value of this method were carried out by using chiral reagents 17. In the reaction of two equivalents of racemic cis-2,4-dimethylcydohexanone 113 with the anion of chiral phosphonate 17b, kinetic resolution took place to give the -alkene 114 with excellent enantioselectivity in 60% yield based on the reagent employed, after treatment of the adduct with AcOH (Scheme 7.19). 

Under PKR conditions, two enantiomeric substrates are simultaneously converted into two structurally and configurationally different chiral products by reaction with chiral reagents or catalysts. It has been shown that to achieve the same selectivity, the selectivity factor s can be significantly lower for PKR than for a traditional kinetic resolution. As yet, there has been only one report of an asymmetric HWE reaction under PKR conditions [88], in which one equivalent of racemic aldehyde 143 was converted into alkene products 144 and 145 by reaction with half an equivalent each of two chiral phosphonates 28 and 20 bearing different chiral auxiliaries (Scheme 7.24). These alkene products, 144 and 145, were readily separable as a result of the difference in polarity between the two auxiliaries. It was clearly shown that the diastereoselectivities of the alkene products were dramatically improved compared to those obtained in the respective individual kinetic resolutions, especially in the case of alkene 145. 

The first example is the stereoselective introduction of the a side chain into 3-oxacarbacyclin and 3-oxaisocarbacydin molecules by reaction with chiral HWE reagents. Reaction of the THP-protected ketone 153 with three equivalents of chiral phosphonate 24 in the presence of LiCl gave an E/Z mixture of the aJS-unsaturated ester (E Z = 95 5) [67] (Scheme 7.26). The desired E-isomer 154 was isolated after deprotection of the THP groups and converted into the 3-oxacarbacyclin 155 as well as 3-oxaisocarbacydin [94]. 

In the total synthesis of bryostatins, chiral HWE reagents have been used for the stereocontrolled transformation of the C13 ketone to the C13-C30-unsaturated enoate [68]. The reaction of macrocyde 102a with chiral phosphonate 31a provided the a,j8-unsaturated ester of Z-stereochemistry, 103a, with a diastereoselectivity of Z/E = 85 15 (75% isolated yield of the Z-isomer, 103a). The obtained Z-isomer 103a was successfully converted into bryostatin by several subsequent chemical... 

Upon initial examination, how one could control chirality in a reaction where the product is an alkene (no new sp centers are formed) which is inherently achiral could be asked. Despite this impression, asymmetric variations of the Wittig reaction have been reported. One approach is to use a chiral auxiliary in the ester moiety of a phosphonate. The first example of a chiral Witting made use of menthol as a chiral auxiliary Reaction of the ketone 86 with the chiral HWE reagent 87 gave rise to 88. However, the levels of chiral induction were not reported. 

The ranges of substrates whose configuration can be assigned by these methods have increased significantly recently and include primary, secondary, and tertiary alcohols, diols, carboxylic acids, primary and secondary amines, and sulfoxides. Appropriate chiral auxiliary reagents have been developed for each case that produces derivatives such as esters, amides, hemiacetals, phosphonates, etc. This review covers all those chiral substrates, the reagents and methods most commonly used and attempts to offer a critical assessment of each method. 

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. 

A variety of optically active 4,4-disubstituted allenecarboxylates 245 were provided by HWE reaction of intermediate disubstituted ketene acetates 244 with homochiral HWE reagents 246 developed by Tanaka and co-workers (Scheme 4.63) [99]. a,a-Di-substituted phenyl or 2,6-di-tert-butyl-4-methylphenyl (BHT) acetates 243 were used for the formation of 245 [100]. Addition of ZnCl2 to a solution of the lithiated phos-phonate may cause binding of the rigidly chelated phosphonate anion by Zn2+, where the axially chiral binaphthyl group dictates the orientation of the approach to the electrophile from the less hindered si phase of the reagent. Similarly, the aryl phosphorus methylphosphonium salt 248 was converted to a titanium ylide, which was condensed with aromatic aldehydes to provide allenes 249 with poor ee (Scheme 4.64) [101]. 

Chiral Davis oxaziridines allow the oxidation of phosphonates to a-hydroxy-phosphonates in good ee with apparently wide generality and with a sense of induction that is well controlled by the chirality of the reagent used.109 mCPBA oxidation of a bi-cyclic e do-camphorylsulfonylimine surprisingly resulted in an exo-camphorylsulfonyl-oxaziridine, whereas all other camphorylsulfonylimines resulted only in endo-oxaziiidines.110 Asymmetric oxidation of sulfides to sulfoxides and the a-hydroxylation of enolates were predicted by models in which steric interactions are minimized. 

Recent developments in this area include the use of poly[hydroxy(tosyloxy)-iodo]styrenes [80], chiral 2-(a-alkoxyalkyl) analogs of [hydroxy(tosyloxy)-iodo]benzene [81 - 83], and iodine(III)-phosphonate and -phosphinate reagents [84] for C-oxygen bond formation at a-carbon. Oxysulfonylations at the a-carbon atoms of carboxylic anhydrides with [hydroxy(sulfonyloxy)iodo]arenes have also been documented [85]. 

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