Enantiodivergent synthesis of C-10b-substituted pyrrolo[2,1-a]isoquinolines starting from an enantiomerically pure N-phenethylnorborn-5-en-endo-2,3-dicarboxyimide 3a, with a 2-exo-hydroxy-10-bornylsulfinyl group as a chiral auxiliary, has been developed. The key transformations are derived from diastereoselective intramolecular cyclization of aryllithiums and alpha-amidoalkylation reactions, with the ethylidene bridge of the norbornene moiety dictating the stereochemical outcome in both types of reactions. Thus, the organolithium addition-intramolecular alpha-amidoalkylation sequence on imide 3a afforded stereoselectively the R configuration at C-12b, whereas the tandem Parham cyclization-intermolecular alpha-amidoalkylation reactions on the corresponding iodinated imide 3b occurred with complete control of stereoselectivity, leading to the epimer at C-12b. Subsequent reductive removal of the chiral auxiliary and retro-Diels-Alder reaction afforded (10bS)- and (10bR)-pyrroloisoquinolines 1 in high yields and optical purities (>99% ee).
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 ...
a-Hydroxylactams, derived from organolithium addition to an enantiomerically pure N-phenethylnorborn-5-en-endo-2,3-dicarboxyimide with a 2-exo-hydroxy-10-bornylsulfinyl group as chiral auxiliary, undergo efficient and highly diastereoselective Nacyliminium ion cyclization. Subsequent removal of the auxiliary and retro-Diels-Alder reaction lead to the enantioselective synthesis of C-10b substituted 5,6-dihydropyrrolo[2,1-a]isoquinolines.The pyrrolo[2,1-a]isoquinolines represent a structural fragment of erythrinan alkaloids with significant pharmacological activity. These compounds possess antidepressant, 1 muscarinic agonist, 2 and antileukemic 3 properties. Moreover, they can be used as PET radiotracers for imaging serotonin uptake sites. 4 The importance of the pyrrolo[2,1-a]isoquinolines 1 is further enhanced by their utility as advanced intermediates for the synthesis of erythrinan alkaloids. 5 Thus, introduction of a C-4 unit into a dihydropyrroloisqouinoline by the Diels-Alder reaction or a [2+2] photocycloaddition is among the most important procedures for building up the erythrinan ring system. 6 These methods have also been applied to the total synthesis of enantiomerically pure aromatic erythrinan alkaloids, using L-DOPA as precursor of a chiral pyrroloisoquinolone. 7 However, both strategies require several steps for the removal of the carboxyl group of the starting amino acid in the final stages of the synthesis.On the other hand, we have reported that N-phenethylnorborn-5-en-endo-2,3-dicarboxyimide could be considered as a synthetic equivalent of N-phenethylmaleimide in the organolithium addition-N-acyliminium ion cyclization sequence, as it carries a masked a,b-unsaturated imide moiety, that could be released by a retro-Diels-Alder reaction. 8 This methodology has been extended to the use of functionalized organolithium reagents capable of 1,2-addition to the carbonyl group, such as 3-(2-trimethylsilyl-1,3-dithian-2-yl)propyllithium. Thus, the synthesis of C-10b functionalized dihydropyrrolo[2,1-a]isoquinolines, immediate precursors for erythrinan alkaloids via intramolecular conjugate additions, has been accomplished.In this context, our next challenge was to achieve the asymmetric synthesis of these nitrogen heterocycles. Thus, we reasoned that if a chiral auxiliary is appended to the norbornene moiety, enantiomerically pure isoindoloisoquinolines 2 could be obtained. Removal of the chiral auxiliary, followed by retro Diels-Alder reaction would afford enantiopure C-10b substituted dihydropyrrolisoquinolines 1. This methodology would open up an asymmetric route to erythrinan alkaloids avoiding the release of the carboxyl group required in the above-described protocols. 7 For this purpose, we chose the 2-exo-hydroxy-10-bornylsulfinyl group as chiral auxiliary. 9 Thus, our imide precursor would be (2-exo-hydroxy-10-bornyl)sulfinylnorbornenimide 3 (Scheme 1).Scheme 1 Retrosynthetic analysis. Preparation of imide 3 was carried out using the procedure developed by Arai 9a,b for related substrates, which...
Fused pyridine derivativesFused pyridine derivatives R 0450 Enantiodivergent Synthesis of Pyrrolo[2,1-a]isoquinolines Based on Diastereoselective Parham Cyclization and α-Amidoalkylation Reactions. -The key steps in the synthesis of the (R)-configurated pyrroloisoquinolines (X) are regioselective alkylation of the imide (III) and stereoselective cyclization of the resulting α-hydroxylactams. The preparation of the (S)-isomers is achieved via Parham cyclization of the iodide (XI) and subsequent alkylation of the hydroxylactam (XII) which proceeds with complete inversion of configuration. -(GONZALEZ-TEMPRANO, I.; OSANTE, I.; LETE*, E.; SOTOMAYOR, N.; J.
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