Chiral amides, synthesis

An asymmetric synthesis of 1-aryltetrahydroisoquinolines 79 from chiral amide 78 was reported <96TL(37)4369>. Optically active cis- or rranj-1,3-disubstituted tetrahydro-isoquinolines can he prepared hy a modification of this procedure. 

Tandem azidination- and hydroazidination-Hiiisgen [3 +2] cycloadditions of ynamides are regioselective and chemoselective, leading to the synthesis of chiral amide-substituted 1,2,3-triazoles <06OBC2679>. A series of diversely l-substituted-4-amino-l,2,3-triazoles 132 were synthesized by the copper-catalyzed [3+2] cycloaddition between azides 130 and ynamides 131 <06T3837>. 

The use of a chiral auxiliary group on the ketene iminium salt permits the enantioselective synthesis of cyclobutanones. These salts offer a wider scope for asymmetric induction than ketenes since there are two substituents on the nitrogen of these salts which are not present on the oxygen of ketenes. Use of a chiral amide 8 or a geminal ehloroenaminc 10 permits the enantioselective synthesis of cyclobutanones 9 and 11. respectively, with enantiomeric excesses ranging from 55-97%. ... 

Enantioselectire alkylation of amides. Two laboratories12 have used (S)-prolinol as the chiral auxiliary for a synthesis of chiral amides. Alkylation of the enolate of the amide 1 (prepared with LDA or f-butyllithium) proceeds with pronounced... 

Diastereoselective Michael additions of enolates, prepared from the chiral amides (127) and (128), to prochiral a.p-unsaturated esters were utilized in the synthesis of (+)-dehydroiridodiol (129) and its isomer (130 Scheme 49).143... 

A chiral synthesis of epibatidine is achieved by using a chiral amide derived from camphorsultam instead of the ester 450... 

The physical properties of 2 were modified by introduction of polar substituents to improve both antiviral potency and hydrophilicity. These studies led to the discovery of L-689,502 (3) and L-693,549 (4), each bearing a polar, hydrophilic substituent at the para position of the P/ phenyl ring.7-9 Both compounds indeed displayed improved solubilities and antiviral potencies (Table 24.1). An inhibitor with pseudo-C2-symmetry, L-700,417 (5) was designed by rotation of the C-terminal half of 1 around the central hydroxyl-bearing carbon (Figure 24.2).10 Askin and co-workers reported a concise and practical synthesis of compounds 2-5 by diastereoselective alkylation of a chiral amide enolate derived from (I.S, 2/f)-aminoindanol.n This strategy, which efficiently used the cis-aminoindanol platform as chiral auxiliary, is fully detailed later in this chapter. 

FIG. 20. Synthesis of rhodium catalysts containing chiral amide ligands. 

Chiral amides, pyrrolidine derivatives, in asymmetric synthesis 92 PAC1849. 

The interest in chiral lithium amides and their structures was sparked in the beginning of the 1990s when they proved useful in asymmetric synthesis. Over the years several chiral lithium amides have been structurally characterized. In this section the chiral lithium amides are discussed separately, depending on their structural basis. The chiral lithium amides with chelating groups constitute a central class of chiral amides widely used in various enantioselective reactions. 

Direct synthesis of atropisomeric benzamides and anilides from prochiral precursors has been reported using chiral-amide-mediated deprotonation of 2,6-dimethyl-substituted ben-zamide and anilide chromium complexes. A screening of amides revealed that (R,R) 3 was the most selective in the deprotonation of the benzylic methyl groups (Scheme 51)92 94. 

The same approach was used with LiSIBP and LiBnPAT, upon incremental addition of LiHMDS in THF solution, as a potential model for the study of the alkylation of chiral amide-enolate aggregates. From the average values for ATagg (respectively, 560 and 760 M 1) and the values of the ratio LmXed/ (respectively, 100 and 20), the initial alkylation was estimated to involve 40% of monomeric enolate (although it represents less than 1% of the species in solution), a situation unsuitable for asymmetric synthesis (Scheme 83)256. 

Deactivation of the amide carbonyl by N-lithiation directs the second lithiation to the ortho position to the amide group. The dilithio compound is stabilized by intramolecular chelation. Larcheveque and coworkers used a chiral amide that was obtained from the reaction between an optically active epihydrin and an anhydride for the asymmetric synthesis of ketones or of substituted acids76 (equation 13). 

The obvious approach for chiral synthesis would be to find a chiral starting material, such as a natural amino acid, carbohydrates, carboxylic acids or terpene. The major source of these chiral starting materials sometimes called chirons is nature itself. The synthesis of a complex enantiopure chemical compound from a readily available enantiopure substance such as natural amino acids is known as chiral pool synthesis. For example, chiral lithium amides 1.39 that are used for several types of enantioselective asymmetric syntheses can be prepared in both enantiomeric forms starting from the corresponding optically active amino acids, and these are often available commercially. 

Silyl enol ethers react with aldehydes in the presence of chiral boranes or other additives " to give aldols with good asymmetric induction (see the Mukaiyama aldol reaction in 16-35). Chiral boron enolates have been used. Since both new stereogenic centers are formed enantioselectively, this kind of process is called double asymmetric synthesis Where both the enolate derivative and substrate were achiral, carrying out the reaction in the presence of an optically active boron compound ° or a diamine coordinated with a tin compound ° gives the aldol product with excellent enantioselectivity for one stereoisomer. Formation of the magnesium enolate anion of a chiral amide, adds to aldehydes to give the alcohol enantioselectively. 

We chose to explore the intramolecular alkylation of amide enolates as a potential stereoselective route to cis pyrethroid cyclopropane carboxylates. If the relationship between the stereoselection in enolate formation and ring closure is operable, amide enolates would be an excellent means of developing a stereoselective synthesis of cis products (8). Furthermore, recent progress in achieving enantioselection in the intermolecular alkylation of chiral amide enolates would provide a means of obtaining optically active pyrethroid acids (Figure 6) (9-13). 

The first chemoenzymatic synthesis of organoselenium containing amines was recently reported by Andrade and Silva (Figure 14.7) [10]. Compounds containing a selenium atom have important antioxidant and anti inflammatory activities. Lipase mediated acylation of amine 13 gave the corresponding chiral amides 14 and amines 13 with excellent enantioselectivity (up to 99% ee). 

The Mitsunobu reaction has been used by It6 and co-workers as a key step in the synthesis of unnatural (+)-a-skytanthine (184) (196). The chiral amide 210 (197) was subjected to an aza-Claisen rearrangement, and the resulting amide 211 was reduced with LiAlU to afford the amine 212 in 80% yield. A hydroboration-oxidation sequence led to a mixture of amino alcohols 213, which was heated at 100°C for 24 h in the presence of cyanomethylene-trimethylphosphorane (CMMP) to yield a 92 8 mixture of cis- and rrans-fused isomers 214 and 215 in 81% yield from 212. 

Among the ethers of prolinol, (5)-2-methoxymethylpyrrolidinc [SMP, (S)-10] has found most applications. It is readily prepared from prolinol by the normal sodium hydride/iodo-methane technique9,13 (sec also Section 2.3. for O-alkylations of other amino alcohols) and is also commercially available. An improved synthesis from proline avoids the isolation of intermediates and gives the product (which is highly soluble in water) by continuous extraction14. SMP has been used as the lithium salt in deprotonation and elimination reactions (Section C.) and as an auxiliary for the formation of chiral amides with carboxylic acids, which in turn can undergo carbanionic reactions (Sections D.l.3.1.4., D.l. 1.1.2.. D.l. 1.1.3.1., in the latter experimental procedures for the formation of amides can be found). Other important derivatives are the enamines of SMP which are frequently used for further alkylation reactions via enolates (Sections D.l.1.2.2.. where experimental procedures for the formation of enamines are... 

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