Lactams intramolecular cycloadditions

Intramolecular [n2 + 2] photocycloadditions are equally numerous and many have considerable synthetic potential. 4-(But-3-enyloxy)quinol-(l//)2-one (254), for example, is converted into a mixture of isomeric adducts 255 and 256 on irradiation in methanol.208 Intramolecular cycloaddition has also been observed in the pyrimidinedione 257209 and in the dehydrovaline acrylamide 258 which on irradiation in dioxane affords the novel /1-lactam system 259.210... 

Sha et al. (45) reported an intramolecular cycloaddition of an alkyl azide with an enone in an approach to a cephalotaxine analogue (Scheme 9.45). Treatment of the bromide 205 with NaN3 in refluxing methanol enabled the isolation of compounds 213 and 214 in 24 and 63% yields, respectively. The azide intermediate 206 underwent 1,3-dipolar cycloaddition to produce the unstable triazoline 207. On thermolysis of 207 coupled with rearrangement and extrusion of nitrogen, compounds 213 and 214 were formed. The lactam 214 was subsequently converted to the tert-butoxycarbonyl (t-Boc)-protected sprrocyclic amine 215. The exocyclic double bond in compound 215 was cleaved by ozonolysis to give the spirocyclic ketone 216, which was used for the synthesis of the cephalotaxine analogue 217. 

The photoisomerization of A.A -dibenzylstyrylacetamidc (1) to the tricyclic lactam 2 in methanol in 95% yield represents the first example of an intramolecular cycloaddition of a styrene chromophore to an arene.0... 

In the presence of NaH in DMF, /3-lactams 104 underwent intramolecular cycloaddition to afford bicyclic oxathiazepines 105 <1981TL3695>. 

Recently, lupinine 4 and epi-lupinine 139 were also synthesized by Takayama s group (85H2913) based on an intramolecular imino Diels-Alder reaction (Scheme 20). Thermolysis of acetate 141 in toluene containing sodium hydrogen carbonate in a sealed tube at 200 C for 2 hr gave lactam 143 in 80% yield via desulfonylation and subsequent intramolecular cycloaddition of 142. 

The distance and angle of the frontier orbitals, which depend on the ring size of the central ring and the nature of X, are the decisive factors for an intramolecular cycloaddition. Clearly, the distance a in systems with central three-membered rings (X = CHj, O) is too large for an intercyclic [(2a + 2a) + 2n] reaction, hence intracyclic retro[2ff-t-2(7] and [2 t-f 2tc] additions dominate. The corresponding )8-lactam derivative 7 gives the intercyclic [(2(t 4- 2[Pg.2204]

Cyclization and cycloaddition. Aminocarbene complexes behave like amino-ketenes under photochemical conditions. With the participation of a benzene ring, cyclization leads to aminonaphthols, whereas the amino ketenes can also be trapped with imines to form )3-lactams. Intramolecular capture of analogous ketenes by an aldehyde leads to /S-lactones." The intermolecular process gives much inferior results. 

C2-Symmetric pyrrolidines have been employed as chiral auxiliaries effectively. Intramolecular cycloadditions of keteniminium salts as well as reactions with imines furnishing 3-lactams have been reported in the literature. ... 

They react with alkenes to give cyclobutanone derivatives, and their intramolecular cycloadditions are well known. Ketenes have been used in the synthesis of y-lactams, drug intermediates and other area as chemical intermediates. 

Intramolecular cycloadditions do not feature as prominently in this section as in the next, but one recent example is the formation in low yield of the strained /3-lactam (18) by irradiation of the precursor (17) in dioxan or pyridine (Scheme 4). "... 

Dipolar cycloaddition of azides with olefins provides a convenient access to triazolines, cyclic imines, and aziridines and hence is a valuable technique in heterocyclic synthesis. For instance, tricyclic -lactams 273 - 276 have been synthesized using the intramolecular azide-olefin cycloaddition (lAOC) methodology (Scheme 30) [71]. 

Diastereoselective intramolecular 1,3-dipolar cycloadditions of alkylidene-cyclopropyl nitrones provide spirocyclopropylisoxazolidines. These compounds have been shown to undergo either thermally induced ring expansion to octahydro[l]pyrindin-4-ones or to acid induced ring contraction into fS-lactams with concomitant loss of ethylene (Scheme 2.218) (710-716). Use of chiral auxiliaries, that is (L)-2-acetoxylactate can lead to enantiomerically enriched heterocycles (715). 

Density functional theory calculations (B3LYP/6-31G level) have provided an explanation for the stereodivergent outcome of the Staudinger reaction between acyl chlorides and imines to form 2-azetidinones (/3-lactams). When ketene is formed prior to cycloaddition, preferential or exclusive formation of ct5-j6-lactam (50) is predicted. If, however, the imine reacts directly with the acid chloride, the step that determines the stereochemical outcome is an intramolecular 5n2 displacement, and preferential or exclusive formation of trans isomer (51) is predicted. These predictions agree well with the experimental evidence regarding the stereochemical outcome for various reactants and reaction conditions. 

Alcaide et al. (68,69) recently published their smdies of the intramolecular 1,3-dipolar cycloaddition reactions of alkynyl-p-lactams in which they found that the desired cycloaddition was in competition with a reverse-Cope elimination. The reaction of alkynyl aldehydes 37a-c with Al-methylhydroxylamine afforded a mixture of products depending on the reaction conditions and the chain length separating the alkyne and the lactam (Scheme 1.8). Thus, up to three separate... 

Cycloaddition to endocyclic unsaturation has been used by many researchers for the preparation of isoxazoUdinyl adducts with y-lactams derived from pyrogluta-minol and is discussed later in this chapter as a synthesis of unusual amino acids (Scheme 1.20, Section 1.6) (79,80). A related a,p-unsaturated lactam has been prepared by a nitrone cycloaddition route in the total synthesis of the fungal metabolite leptosphaerin (81). A report of lactam synthesis from acyclic starting materials is given in the work of Chiacchio et al. (82) who prepared isoxazolidine (47) via an intramolecular nitrone cycloaddition reaction (Scheme 1.11). 

The acyclic precursor is an oc, 3-unsaturated amido aldehyde that was condensed with iV-methylhydroxylamine to generate the nitrone ( )-48, which then underwent a spontaneous cycloaddition with the alkene to afford the 5,5-ring system of the isoxazolidinyl lactam 47. The observed product arises via the ( )-nitrone transition state A [or the (Z)-nitrone equivalent] in which the position of the benzyl group ot to the nitrone effectively controls the two adjacent stereocenters while a third stereocenter is predicted from the alkene geometry. Both transition states maintain the benzyl auxiliary in an equatorial position and thus avoid the unfavorable 1,3-diaxial interaction with the nitrone methyl or oxygen found in transition state B. Semiempirical PM3 calculations confirm the extra stability, predicting exclusive formation of the observed product 47. Related cycloadducts from the intramolecular reaction of nitrones containing ester- rather than amide-tethered alkene functionality are also known (83-85). 

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