Sequential carbophilic addition of organolithium reagents and N-acyliminium ion cyclization of N-phenethylimides 1 affords the substituted isoquinolones 3 in high yields, with the possibility of varying the substituent at the C-1 position of the isoquinoline ring by changing the organolithium reagent. Ready access to the isoquinoline nucleus via Parham-type cyclization of imides 2 is also described. We have shown that iodinated imides 2 tolerate the metal-halogen exchange in the presence of the imide group, and the intramolecular cyclization of the so-obtained aromatic organometallic derivatives leads to the corresponding enamides 4. Both approaches have allowed the efficient preparation of various types of the isoquinoline class of alkaloids, just by changing the substitution pattern on the readily available starting imides. Thus, we have developed convenient alternative routes for the synthesis of benzo[a]quinolizidones and their 2-oxa analogs, isoindoloisoquinolones, dibenzo[a,h]quinolizidones, and thiazolo- and oxazolo[4,3-a]isoquinolones.

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Diastereoselective conjugate addition of a-lithiodithioacetals to a,b-unsaturated bicyclic lactams is described. Typical yields of the resulting tetrahydropyrrolo[2,1-a]isoquinolinones ranged 60-90% with facial diastereoselectivities of >95:5, when there is a bulky butyl group at the α−position to the nitrogen atom. Cis or trans isomers could be obtained exclusively by using 1,3-dithianyllithium or bis(phenylthio)methyllithium as nucleophiles, respectively. The presence of a methyl group at the 10b position of the heterocyclic system diminished the steroeselectivity. In selected diastereomeric byciclic lactams the acyl group was unmasked.A few years ago we became interested in pursuing an approach to the synthesis of Erythrina alkaloids. 1 We conceived a synthetic strategy that could involve 1,4-additions on the a,b-unsaturated lactam unit of certain dihydropyrrolo[2,1-a]isoquinolinones, and thus considered potential methods for the construction of this type of heterocycles. We were particularly attracted to the extensive and pioneering work of Corey and Seebach, 2 who have demonstrated that carbon-carbon bonds can be effectively generated using sulfur-stabilized anions. In this context, a-lithiodiothioacetals are particularly useful acyl anion equivalents and provide an umpolung to the normal pattern of reactivity of the carbonyl group. 3 While there has been much discussion of the factors governing regiochemistry of additions of the metalated dithioacetals to a,b-unsaturated carbonyl compounds, 4 it has been reported that these anions can give 1,4-addition on a,b-unsaturated carbonyl systems. In general, the addition is reversible and the 1,4-adduct is favoured in polar solvents at higher temperatures for long reaction times. 3,5 Compared with some other classes of conjugate acceptors, 6 a,b-unsaturated amides and lactams are less well known. Several authors have demonstrated that lithiated 1,3-dithianes undergo conjugated addition to tertiary crotonamides, thioamides, and d-lactams. 7 The resulting amide enolates may be quenched with electrophiles to give a,b-dialkylated products. The scope and synthetic use of this conjugate addition reaction with unsaturated amides was illustrated by Snieckus and Rubiralta who used it to construct a lignan natural product and the skeleton of Aspidosperma alkaloids, respectively. 7Herein, we report a stereoselective conjugate addition of a-lithiodithioacetals to the a,b-unsaturated lactam unit of the 5,6-dihydropyrroloisoquinolones. This strategy has allowed us to introduce both nucleophilic and electrophilic centres attached to the pyrrolidine nucleus, which could be useful for furher transformations.The starting 5,6-dihydropyrrolo[2,1-a]isoquinolinones 1 were prepared using N-acyliminium ion chemistry. 8 Thus, we have recently described that these unsaturated g-lactams can be efficiently prepared from N-(3,4-dimethoxyphenethyl)-cis-norbor-5-en-2,3-dicarboximide via tandem carbophilic addition-N-acyliminium ion cyclization sequence, followed by retro-Diels-Alder reaction. 9 ...

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Tandem Carbophilic Addition-N-Acyliminium Ion Cyclization for the Synthesis of Functionalized Pyrrolo(2,1-a)isoquinolones: Key Intermediates for the Preparation of Erythrina-Type Alkaloids.-Carbophilic addition of organolithium reagents (II) to the succinimide (I) gives a mixture of the adducts (III) and (IV) which on treatment with TFA yield the pyrroloisoquinolines (V) via cyclization of an intermediate N-acyliminium ion. Application of this methodology to educt (VI) provides the compound (IX) which is subjected to retro-Diels-Alder reaction, affording the α,β-unsaturated pyrroloisoquinolone (X), immediate precursor of Erythrina-type alkaloids. -(MANTECA, I.; SOTOMAYOR, N.; VILLA, M.-J.; LETE, E.; Tetrahedron Lett. 37 (1996) 43, 7841-7844; Dep. Quim. Org., Fac. Cienc., Univ. Pais Vasco,