Lactams chiral bicyclic—

Chiral bicyclic lactams as useful precursors and templates for asymmetric syntheses 97CC1. 

Similarly a marked increase of regioselectivity has been shown in the catalyzed Diels-Alder reactions of the chiral bicyclic lactame 24 (Scheme 3.9) with a variety of dienes [27] (isoprene, mircene, (E,E)-L4-dimethylbutadiene, 2,3-di-methylbutadiene, 2-siloxybutadiene). The catalyzed reactions were more regio-selective and totally enJo-antz-diastereoselective anti with respect to the bridgehead methyl group). The results of the cycloadditions with isoprene and mircene are reported in Scheme 3.9. The cycloadducts have then been used to provide interesting fused carbocycles [28] with high enantiomeric purity as shown in Scheme 3.10. 

The studies of the reactivity of saturated pyrrolo[2,l- )oxazoles are in general associated with the reactivity of Meyers chiral bicyclic lactams and their applications in asymmetric synthesis. 

S(-)-5-n-Heptylpyrrolidinone. Chiral Bicyclic Lactams as Templates to Pyrrolidines and Pyrrolidinones. 

The asymmetric syntheses of carnosadine (lS,2S)-74 [101] and of its protected derivatives as conformationally constrained surrogates for arginine have also been reported [102]. Different 2-substituted 1-aminocyclopropanecarboxylic acids have also been prepared by azidation of optically active 2-chloro-2-cyclo-propylideneacetates [103] and from the cyclopropanation of chiral bicyclic lactams [104]. 

The electrophilic fluorination of chiral bicyclic lactams (prepared from the epimers of pyroglutamic acid) by means of A-fluoro sulfonimide (NFSI) yields l- and d-4, 4-difluoroglutamic acids and 4,4-difluoroglutamines (Figure 5.21). They have also been prepared with a good ee starting from ethyl (/ )-bromodifluoroalaninate. ... 

Chiral bicyclic lactams have been successfully utilized by Meyers as chiral dipolarophiles in highly diastereoselective azomethine ylide cycloadditions (73). Treatment of the ylide precursor 218 with the unsaturated, non-racemic dipolar-ophile 219 in the presence of a catalytic amount of TFA led to the formation of tricyclic adducts 220 and 221 in excellent yields (85-100%). The diastereofacial preference for the reaction was dependent on the nature of R with a methyl group... 

Table 9. a.x-Disubstituted Alkanoates and 4,4-Disubstituted 2-Cycloalken-l-ones by Alkylation of Eno-lates from Substituted Chiral Bicyclic Lactams, Followed by Cleavage1 3,5 7,13... 

Chiral 4,4-disubstituted cyclohexenones.1 The chiral bicyclic lactam 2, obtained by reaction of 4-acetylbutanoic acid with 1, on dialkylation gives mainly the diastereomer from endo-attack, with the highest diastereoselectivity obtained by using the larger electrophile in the second alkylation. Hydride reduction followed by hydrolysis furnished 4,4-dialkylated cyclohexenones (4) in >95% ee. 

Chiral 4,4-dialkyl-l-cyclopentenones.1 The chiral bicyclic lactam 2, derived from levulinic acid and 1, on monoalkylation exhibits slight if any selectivity regardless of the electrophile. However, a second alkylation exhibits high endo-selectivity. This product (3), after reductive cleavage, furnishes a keto aldehyde that is cyclized by base to a chiral 4,4-disubstituted-2-cyclopentenone (4). Either antipode of 4 can be prepared by the sequence of alkylation. 

ASYMMETRIC SYNTHESIS OF 4,4-DIALKYLCYCLOHEXENONES FROM CHIRAL BICYCLIC LACTAMS (RM-ETHYL-4-ALLYL-2-CYCLOHEXEN-1-ONE... 

Chiral bicyclic lactams such as those described here are useful in reaching a variety of chiral quaternary carbon derivatives. Thus, 1 can be doubly alkylated to the... 

METHOXYCARBONYL-1,1,6-TRIMETHYL-1,4,4a,5,6,7,8,8a-OCTAHYDRO-2,3-BENZOPYRONE, an intramolecular Diels-Alder reaction is responsible for the diastereoselectivity. The stereoselective 1,4-functionalization of 1,3-dienes is exemplified by a two-step process leading to cis- and trans-1-ACETOXY-4-(DICARBOMETHOXYMETHYL)-2-CYCLOHEXENE. The effectiveness of a silyl hydride in providing a means for erythro-directed reduction of a p-keto amide is applied in a route to ERYTHRO-1 -(3-HYDROXY-2-METHYL-3-PHENYL-PROPANOYLJPIPERIDINE. This is followed by an asymmetric synthesis based on a chiral bicyclic lactam leading to (R)-4-ETHYL-4-ALLYL-2-CYCLOHEXEN-1-ONE. The stereoselectivity with which acetoxy migration can operate to an adjacent radical center is reflected in the one-step reaction that gives rise to 1,3,4,6-TETRA-O-ACETYL-2-DEOXY-a-D-GLUCOPYRANOSE. 

High diastereofacial selectivity (84% de) was obtained in the photoaddition of ethylene to the chiral bicyclic lactam 188 with preferential approach from the expected convex side96. The photoproduct was used as the key step in the synthesis of enantiomerically... 

Unfortunately, the chiral bicyclic triazolium salt that had been found to be an excellent catalyst for the enantioselective intermolecular benzoin condensation proved to be ineffective in the intramolecular reaction. In searching for alternative catalysts, we synthesized the novel triazolium salts 19 and 20, starting from easily accessible enantiopure polycyclic y-lactams (Schemes 9.4 and 9.5) that finally delivered good results in the enantioselective intramolecular cross-benzoin condensation [35]. 

Cyclopropanation of lactams,1 This reagent adds to the chiral bicyclic lactams 2 (13,18-19) to form endo-cyclopropanated adducts (3) in >93% de. These adducts are hydrolyzed to optically active cyclopropanes (4). 

In 1995, Boeckman et al. disclosed a highly diastereoselective aldol reaction using the ligand 79 derived from chiral bicyclic lactam28 (Scheme 2.1z). The imide 80, readily prepared from bicyclic lactam 79 and propionyl chloride, was converted to the boron Z-enolate, which was then treated with a representative series of aldehydes at -40° C for 48 hours. The levels of diastereoselectivity observed in reactions of boron enolate derived from 80 are comparable to those... 

Solid-state photolysis of host-guest complexes of 2-alkylpyridones 34 with the optically active host compounds 4, 6a, 7a,b caused disrotatory [2 4- 2] photocyclization to give chiral bicyclic p-lactams (+) or (— )-35 with high enantiosel ectivities (Scheme 8) [54]. For instance, the 1 1 complex of 2-methylpyridone 34a with (/ ,/ )-(— )-6a produced the optically pure P-lactam (+ )-35a in 93% chemical yield at 15% conversion. 

Chiral Bicyclic Lactams Useful Precursors and Templates for Asymmetric Synthesis. Meyers, A. L Brenget, G. P. Chem. Commun, 1997, 1. 

S-(-)-5-HEPTYL-2-PYRROLIDINONE. CHIRAL BICYCLIC LACTAMS AS TEMPLATES FOR PYRROLIDINES AND PYRROLIDINONES (2-Pyrrolldlnone, 5-heptyl-, (S)-)... 

Chiral bicyclic lactams are excellent precursors to a wide variety of chiral, non-racemic carbocycles including cyclopentenones, cyclohexenones, cyclopropanes, indanones, naphthalenones, and asymmetric keto acids.3 Recently they have been applied to the synthesis of chiral, non-racemic pyrrolidines and pyrroiidinones,4 that are medicinally and synthetically important molecules.5 The three-step procedure described here provides an efficient route (overall yield 46%) to (S)-5-heptyl-2-pyrrolidinone of high enantiomeric purity. The scheme below illustrates this reaction. 

The chiral auxiliary method may be used for the synthesis of all-carbon quaternary stereocentresThus, chiral bicyclic thioglycolate lactam 1.50 is alkylated three times and... 

Preparative Methods the chiral bicyclic lactams are easily procured via condensation of commercially available (15, 25)-(+)-2-amino-l-phenyl-1,3-propanediol and the appropriate 5-keto acid (eq 1). - Similar bicyclic lactams have been prepared from other amino alcohols and have been extensively utilized in the stereocontrolled formation of quaternary carbon-carbon bonds. ... 

Degnan, A. P., Meyers, A. I. Total Syntheses of (-)-Herbertenediol, (-)-Mastigophorene A, and (+)-Mastigophorene B. Combined Utility of Chiral Bicyclic Lactams and Chiral Aryl Oxazolines. J. Am. Chem. Soc. 1999,121,2762-2769. 

The reactions of 1,2-aminoalcohols 1.60 (R = i-Pr, tert-Bu, Ph, R = H) or 1.79 (R = H) with y- or 6-ketoacids generate chiral bicyclic lactams 1.90 and 1.91. The chemistry of this class of reagents has also been developed by Meyers and coworkers [261, 327, 348], and another access to these compounds has also been proposed [327],... 

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