Bicyclic lactam, synthesis

An alternative method in the synthesis of alkaloids, photochemical rearrangement of endocyclic nitrones into bicyclic lactams has drawn special attention. Analyses of photochemical rearrangement and application of modified conditions of the Barton reaction testify to the comparability of results obtained in these approaches (Scheme 2.89) (460). 

In the synthesis of the azabicyclic core of the Stemona alkaloids, methyl (2/W,3.9/ ,3a/W)-2-(2-cthoxycarbonylethyl)-hexahydropyrrolo[l,2- ]isoxazole-3-carboxylate was hydrogenolyzed over 10% Pd-C in EtOAc and acetic acid at room temperature to give after cyclization the bicyclic lactam 153 <2005JOC3157> (Equation 22). This route was also used to produce pyrrozilidinone-based dipeptide isosteres <2005T8836>. 

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. 

Meyers lactams are widely used in synthesis of substituted synthons of interest and their functionalization is carried out under strong base conditions giving C-alkyl derivatives. Alkylation of bicyclic lactam 182 with electrophiles (alkyl, allyl, benzyl halides, chlorophosphonate), and a strong base (j-BuLi, LiHMDS, or KHMDS HMDS = hexamethyldisilazide) in THF at — 78 °C gave an endo-exo mixture of products where the major one is the rro/o-compound 183 in good yields. The ratios were determined by H NMR spectroscopy and are usually up to... 

Bicyclic lactams 189 are uniquely suited as precursors for the synthesis of chiral substituted 4,5-dihydro-277-pyridazinones 190 by hydrolysis with NH2NH2 and HC1 in dioxane at 85 °C. The reaction gave, as a side product, the ketoacid 191 in some cases (Equation 32) <2003TL7997>. 

Abstract The coupling of 2-azabicyclo[2.2.1]hept-5-en-3-one and trimethylsily-lacetylene or phei rlacetylene under Domino Heck conditions gives compounds 2a-c and 4a-c in moderate yields and cyclopentene derivatives, 3a-c in low yields. The procedure can be of use for the synthesis of alkynyl bicyclic lactams. 

Since the migrating group retains its configuration, the use of enantiomerically enriched oximes provides a direct entry to enantiomerically pure lactams. These lactams may be used as a key building block for the synthesis of diverse compounds. Westermann and Gedrath applied this strategy to the stereoselective synthesis of enantiomerically pure o-.a-disubstituted a-amino acids (equation 135), bicyclic lactams and the spirocyclic framework of Histrionicotoxins (equation 136). 

Another similar application was in the production of bicyclic lactams 357 that might serve as building blocks for the synthesis of conformationally restricted peptides (equation 137). 

The reaction of several a-amino acid esters with 0-lactones in chloroform solution gave hydroxyamide esters (equation 50), said to be useful fungicides (74JAP(K)74127918>. Enamines derived from cyclohexanone react smoothly with 0-propiolactone to give 3-(2-cyclo-hexanonyl)propionamides in reasonable yields (equation 51). No acylation of the enamine is observed. This reaction has been used as a key step in a new synthesis of 8-aza steroids (75JOC50). Cyclohexanone imines react in the same manner, except that the expected initial product cyclizes to give bicyclic lactams and enaminones (equation 52) (80T3047). 

Si-Lactams. The synthesis of /5-lactams employing organoiron complexes as intermediates (8, 454-455) has been extended to the preparation of bicyclic lactams, in particular to the new carbopenams. A synthesis of 2-methylcarbopenam (1) is shown in equation (I). 

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

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... 

Both complexes 12 and 13 are active toward atom-transfer cyclization of N-allyltrichloracetamides [40]. Of particular interest is the synthesis of a pyrrozi-lidine alkaloid skeleton. Much milder conditions are needed when using ruthenium-based catalysts instead of copper derivatives, although a high catalyst loading (30 mol %) is still required. Thus, an N-functionalized vinyl pyrrolidine is smoothly converted at room temperature into a bicyclic lactam, in 90% and 85% yield with complexes 12 and 13, respectively. The product is a precursor of the pyrrozilidine alkaloids trachelantamidine and pseudohehotridane (Eq. 10). 

Synthesis of l-aza-5-silabicyclo[5.2.0]nonan-9-one, a silylated bicyclic lactam 329 (Figure 20) which shows antimicrobial activity against Gram positive bacteria was also achieved <1995JOC8403>. 

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

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. 

An efficient use of bicyclic lactams as chiral precursors to 4-substituted cyclopentenones and cyclohexenones has been illustrated by the synthesis... 

In a recent application, cw-aminoindanol has been employed as a rigid diastereocontrol element in the alkylation of bicyclic lactams and thiolactams of which they are a component. The resulting products form the basis of an enantioselective synthesis of alkaloids. 

The Weinreb group has used an intramolecular imino Diels-Alder cycloaddition as the key step in a total synthesis of the fungal neurotoxin slaframine (74) (equation 25). Thus, thermolysis of acetate (71) produced an intermediate A -acyl imine (72) which underwent [4 + 2] cycloaddition to afford bicyclic lactam (73) as a 1.8 1 mixture of epimers. Both compounds were converted to the natural product in a few steps. 

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