Reactions of Substrates with Chiral Auxiliaries

DIASTEREOSELECTIVE REACTIONS OF SUBSTRATES WITH CHIRAL AUXILIARIES 

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Diastereoselective Reactions of Substrates with Chiral Auxiliaries 851... 

Hie use of chiral catalysts as an approach to enantiomer icaliy enriched products by means of coppet-mediated substitution reactions is covered in this chapter. Reactions in which a chiral auxiliary resides in the leaving group of the substrate w ill also he dealt with, since these reactions provide direct and efBcient routes to single enantiomers of the desired products. Most studies so far have been concerned with allylic substrates, with a new chiral center being produced in the course of a selec-... 

Two methods have been developed to provide enantiomerically enriched cycloadducts using the chromium-mediated [6 + 2]- and [6 + 4]-cycloadditions one involving a chiral resolution and the other involving the attachment of a chiral auxiliary to the triene. The lipase resolution method provides access to either enantiomer of the chromium complex, albeit with moderate enantiomeric excesses (Scheme 34).119 The [6 + 4]- and [6 + 2]-reactions of chiral substrates such as 116 which are available by the attachment of a removable chiral auxiliary (R ) to the triene moiety are highly diastereoselective (Equation (17)).120... 

Camphor sultam derivatives have proved to be effective chiral auxiliaries in many different types of asymmetric reactions. As shown in Scheme 5-44, chiral camphor sulfam can be applied in the synthesis of (—)-pulo upone precursor 151 using an intramolecular Diels-Alder reaction. A Wittig reaction of 148 with 147 connects the chiral auxiliary to the substrate, and subsequent intramolecular Diels-Alder reaction via transition state 150 affords product 151. Compound 151 already has the stereochemistry of (—)-pulo upone 153.72... 

Dipolar addition is closely related to the Diels-Alder reaction, but allows the formation of five-membered adducts, including cyclopentane derivatives. Like Diels-Alder reactions, 1,3-dipolar cycloaddition involves [4+2] concerted reaction of a 1,3-dipolar species (the An component and a dipolar In component). Very often, condensation of chiral acrylates with nitrile oxides or nitrones gives only modest diastereoselectivity.82 1,3-Dipolar cycloaddition between nitrones and alkenes is most useful and convenient for the preparation of iso-xazolidine derivatives, which can then be readily converted to 1,3-amino alcohol equivalents under mild conditions.83 The low selectivity of the 1,3-dipolar reaction can be overcome to some extent by introducing a chiral auxiliary to the substrate. As shown in Scheme 5-51, the reaction of 169 with acryloyl chloride connects the chiral sultam to the acrylic acid substrate, and subsequent cycloaddition yields product 170 with a diastereoselectivity of 90 10.84... 

Asymmetric cyclopropanations of Michael acceptors with ylides have been explored for a number of substrates modified with chiral auxiliaries. The reactions of 47 with Ph3P=CMe2,48 (equation 119)259 and of 49 with 50 (equation 120)260-261 proceed with excel-... 

A Lewis-acid-mediated intramolecular cyclization of allenyl stannane 344 furnishes 2,6- //-tetrahydropyran as the major product, the stereochemistry of which can be switched to syn with moderate effect if a propargylstannane 345 is used as a substrate (Equation 147, Table 16) <1996TL3059>. The stereoselectivity observed in an analogous system, the intramolecular cyclization of y-alkoxyallyl stannanes 346 with a tethered aldehyde, can be controlled by changing the geometry of the alkene (Scheme 83) <1997JOC7439>. y-Alkoxyallyl stannanes are also known to cyclize both diastereoselectively and enantioselectivity, by incorporation of both a chiral auxiliary and a chiral catalyst respectively into the reaction <1999JOC4901>. 

Asymmetric amplification is the direct consequence of species of racemic composition being stable and of low reactivity. It should be found in all reactions dealing with chiral auxiliaries. One can expect such a phenomenon in diastereo-selective reactions performed on chiral substrates (e.g., reduction of a keto steroid by a chiral catalyst) or kinetic resolution, a hypothesis that has just recently been confirmed.82-83... 

An ingenious extension of the Tsuji-Trost reaction was the cornerstone of Oppolzer s enantioselective synthesis of a heteroyohimbine alkaloid, (-t-j-B-isorauniticine (267) [117]. Substrate 263 was prepared from a commercially available glycinate equivalent by Malkylation, installation of the sultam chiral auxiliary followed by a sultam-directed C-alkylation. As illustrated in Scheme 48, the crucial double cyclization was accomplished by the treatment of 263 with Pd(dba), Bu,P, in the presence of carbon monoxide (1 atm) in acetic acid to give enone 264 and two other stereoisomers in a 67 22 11 ratio. In this case, an allyl carbonate, rather than an allyl acetate, was used as the allyl precursor. Since carbonate is an irreversible leaving group, formation of the n-allylpalladium complex occurs readily. In the presence of Pd(0), the allylic carbonate is converted into a n-allylpalladium complex with concurrent release of CO, and... 

Ultimately, it was determined that protected allyl alcohols, tetralkoxy silanes, and silyl ethers were the best substrates for these transformations. Alkyl or allyl silyl ethers (120) provided products such as 121 in >85% de and good 74-92% ee with Rh2(S-DOSP)4 as the catalyst (Scheme 27) [98], Extension of the reaction to alkoxysilanes, generated 122 in 88 to >94% de and 81-96% ee. Interestingly, this catalyst did not seem to be compatible with benzyl silyl ethers, and the products were formed with low selectivity (<40% ee). It was found that the use of either a chiral auxiliary or phthalimide Rh2(PTTL)4 resulted in improved results [31]. 

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