Asymmetric synthesis with chiral reagents

Farina, V., Roth, G. P. Asymmetric synthesis with chiral reagents derived from a-pinene. Chimica Oggi 1999, 17, 39-47. 

Asymmetric synthesis with chiral reagents and chiral catalysts... 

ASYMMETRIC SYNTHESIS WITH CHIRAL REAGENTS AND CHIRAL CATALYSTS... 

Lewis acids of chiral metal aryloxides prepared from metal reagents and optically active binaphthol derivatives have played a significant role in asymmetric synthesis and have been extensively studied.23 However, in Diels-Alder reactions, the asymmetric induction with chiral metal aryloxides is, in most cases, controlled by steric interaction between a dienophile and a chiral ligand. This kind of interaction is sometimes insufficient to provide a high level of enantioselectivity. 

Due to their configurational instability, asymmetric synthesis involving these reagents must usually be done with the aid of chiral auxiliaries that block one side of the nucleophilic carbon atom against electrophilic attack (passive volume) or fix the metal on one side by chelation (active volume)l9. 

Reviews on stoichiometric asymmetric syntheses M. M. Midland, Reductions with Chiral Boron Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 2, Academic Press, New York, 1983 E. R. Grandbois, S. I. Howard, and J. D. Morrison, Reductions with Chiral Modifications of Lithium Aluminum Hydride, in J. D. Morrison, ed.. Asymmetric Synthesis, Vol. 2, Chap. 3, Academic Press, New York, 1983 Y. Inouye, J. Oda, and N. Baba, Reductions with Chiral Dihydropyridine Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 4, Academic Press, New York, 1983 T. Oishi and T. Nakata, Acc. Chem. Res., 17, 338 (1984) G. Solladie, Addition of Chiral Nucleophiles to Aldehydes and Ketones, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 6, Academic Press, New York, 1983 D. A. Evans, Stereoselective Alkylation Reactions of Chiral Metal Enolates, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 1, Academic Press, New York, 1984. C. H. Heathcock, The Aldol Addition Reaction, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 2, Academic Press, New York, 1984 K. A. Lutomski and A. I. Meyers, Asymmetric Synthesis via Chiral Oxazolines, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 

E. Block, Olefin synthesis via deoxygenation of vicinal diols, Org. React. (N.Y.) 1984, 30, 457. M. M. Midland, Asymmetric reduction with organoborane reagents, Chem. Rev. 1989,89, 1553. H. C. Brown and P. V. Ramachandran, Asymmetric reduction with chiral organoboranes based... 

Related Allylboronate Reagents. A stereoselective synthesis of anti 1,2-diols has been achieved by using a DIPT-modified ( )-y-[(cyclohexyloxy)dimethylsilyl]allylboronate reagent. This reagent is best applied in double asymmetric reactions with chiral aldehydes such as o-glyceraldehyde acetonide (eq 9). 

The tartrate-derived crotylboronate reagents are most useful in the context of double asymmetric reactions with chiral aldehydes [118, 203]. Equations (11.16)-(11.19) demonstrate the utility of ( )-219 and (Z)-213 in the synthesis of dipropionate adducts 105-108. 

Marshall s chiral allenylmetal reagents have been utilized in double asymmetric reactions with chiral aldehydes for the synthesis of polypropionate natural products. All four dipropionate diastereomers are accessible from the reactions of chiral allenylmetal reagents with a-chiraI-y5-alkoxy aldehydes 97 (153, 158, 276, 277]. The BF3-OEt2-catalyzed addition of allylstannane (l )-218a to aldehyde 97a occurs in high yield and diastereoselectivity to give the xyn.syn-dipropionate 395, presumably through either the synclinal or antiperiplanar Felkin transition states 396 and 397 (Eq. (11.31)). 

Nonracemic sulfoxides are very important reagents in asymmetric synthesis, but the classical preparations of these reagents often call for tedious separations ( 1.7). Recendy, more direct routes involving asymmetric oxidation of sulfides have been introduced. These oxidations can be conducted other with chiral reagents or with sulfides bearing chiral residues. 

A number of highly enantioselective chiral allyl organometallic reagents have been described in the literature. These are of considerable interest both for the asymmetric synthesis of homoallyl alcohols as well as in double asymmetric reactions with chiral C=X electrophiles. - Two distinct groups of chiral allyl metal reagents can be identified those with conventional, easily introduced chiral auxiliaries and ones in which the center of chirality is a structural component of the reagent (e.g. allyl metal compounds with substituents at C-1). These are discussed separately in the sections that follow. 

Some thermally forbidden [2 + 2]-cycloaddition reactions can be promoted by Lewis acids1-6. With chirally modified Lewis acids, the opportunity for application in asymmetric synthesis of chiral cyclobutanes arises (for a detailed description of these methods see Sections D.l. 6.1.3.. D.l. 61.4. and references 7, 28-30). Thus, a chiral titanium reagent, generated in situ from dichloro(diisopropoxy)titanium and a chiral diol 3, derived from tartaric acid, catalyzes the [2 + 2]-cycloaddition reaction of 2-oxazolidinone derivatives of a,/ -unsalurated acids 1 and the ketene thioacetal 2 in the presence of molecular sieves 4 A with up to 96 % yield and 98% ee. Fumaric acid substrates give higher yields and enantiomeric excesses than acrylic acid derivatives8. Michael additions are almost completely suppressed under these reaction... 

An asymmetric synthesis of chiral binaphthyls has been accomplished utilizing naphthyloxazolines. The method is based on the facile displacement of an o-methoxyl group in aryloxazolines by various nucleophiles (13). The aromatic substitution process has now also been found to proceed with o-methoxynaphthyloxazolines (Fig. 10). A number of nucleophilic reagents smoothly displaced the methoxyl group to and after hydrolysis led to 1-substituted-2-naphthoic acids Utilization of this efficient coupling... 

Figure 12. Asymmetric synthesis of chiral birmphthyls, 29, by reaction with naphthyl Grignard reagents. Ratios of diastereomers are given.

Insofar as the closely related asymmetric synthesis with an asymmetric P-N chelate is concerned, the crucial step is the one in which the chiral Grignard reagent reacts with the palladium (or nickel)-haloalkyl complex with displace-... 

For the performance of an enantioselective synthesis, it is of advantage when an asymmetric catalyst can be employed instead of a chiral reagent or auxiliary in stoichiometric amounts. The valuable enantiomerically pure substance is then required in small amounts only. For the Fleck reaction, catalytically active asymmetric substances have been developed. An illustrative example is the synthesis of the tricyclic compound 17, which represents a versatile synthetic intermediate for the synthesis of diterpenes. Instead of an aryl halide, a trifluoromethanesul-fonic acid arylester (ArOTf) 16 is used as the starting material. With the use of the / -enantiomer of 2,2 -Z7w-(diphenylphosphino)-l,F-binaphthyl ((R)-BINAP) as catalyst, the Heck reaction becomes regio- and face-selective. The reaction occurs preferentially at the trisubstituted double bond b, leading to the tricyclic product 17 with 95% ee. °... 

Of course, the key limitation of the ylide-mediated methods discussed so far is the use of stoichiometric amounts of the chiral reagent. Building on their success with catalytic asymmetric ylide-mediated epoxidation (see Section 1.2.1.2), Aggarwal and co-workers have reported an aza version that provides a highly efficient catalytic asymmetric synthesis of trans-aziridines from imines and diazo compounds or the corresponding tosylhydrazone salts (Scheme 1.43) [68-70]. 

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