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Transformation of β-carboline derivatives into optically active entities were studied and the de and ee values of the resulted compounds were detected.

1‐Methyl‐3,4‐dihydro‐β‐carboline (1) was C‐acylated with optically active sulfinyl derivatives (2) into the 1‐methyl group. Reduction of the C˭N double bond resulted in diastereomers (4, 5) of different ratios. After separation of diastereomers and removal of the chiral sulfinyl moiety, enantiomers of 1‐methyl‐1,2,3,4‐tetrahydro‐β‐carboline (6) were obtained from different enantiomeric excess. The diastereomers were separated by normal phase chromatography. It was proven that the resolution efficiency was much better with this type of separation method compared with very popular reversed phase chromatography. Embedded reversed phase column (Supelcosil ABZ + Plus) gave higher resolution than conventional C‐18 stationary phases and monoliths (Chromolith Performance RP‐18e), but retention time is high and low solubilities of derivatives caused detection problems and base line noise.

Reversed (RP-HPLC) and normal phase chromatographic (NP-HPLC) separations have been developed for diastereomers ofN-acyl-1-methyl-1,2,3,4-tetrahydo-β-carbolines which are acylated derivatives of simple natural β-carboline alkaloids. Separations of derivatives having different acyl moieties in theO,O-diacyl-tartaric acid ester subtituent differed remarkably. Little or no resolution in either NP-HPLC or RP-HPLC could be achieved with the diacetyl-tartrate derivative. Base-line separation by RP-HPLC but no separation by NP-HPLC was possible with the bulkier and more apolar dipivaloyl derivative. Retention order of the bis-benzoylated diastereomers was reversed and separation time increased dramatically by RP-HPLC. Good separation of the medium polarity, but rigid,N-camphanyl derivative by NP-HPLC has been achieved, whereas RP-HPLC could not be used for separation of these diastereomers. Separability of different diastereomers was highly dependent on polarity and rigidity of the derivatizingN-acyl moieties. Conformational analysis by molecular mechanics and comparison of the lowest energy conformational states of the diastereomers was applied to rationalise separation-retention behaviour of stereoisomers by RP-HPLC.

Treatment of 1-methyl-3,4-dihydro-β-carboline with sulfonyl chlorides provided C-acylated products, which preferred vs. indole-N-acylated derivatives.

4-Oxoazetidine-2-carbaldehydes reacted with 1,1,1-trichloro-2,2,2-trifluoroethane in the presence of zinc powder to afford 2,2-dichloro-3,3,3-trifluoropropanols. By addition of acetic anhydride 2-chloro-1,1,1-trifluoro-2-alkenes and acetylated 2-chloro-1,1-difluoro-1-alken-3-ols were isolated.

Publisher Summary This chapter focuses on the 3(2H)-Isoquinolinones and their saturated derivatives. The name 3(2H)-isoquinolinones is used for the lactam structure to emphasize the connection with derivatives saturated in the hetero ring or in the aromatic ring of the isoquinolinone skeleton or both. One of the most widespread methods of synthesizing 3(2H)-isoquinolinones is the cyclization of esters of o-acyl-phenylacetic acids with appropriate amines. 1, 4-Dihydro-3(2H)-isoquinolinones are structural isomers of the well-known dihydrocarbostyril and dihydroisocarbostyril nitrogen heterocycles. The chapter discusses 5, 6, 7,8-Tetrahydro-3(2H)-isoquinolinones. Several derivatives of the unsaturated and saturated lactams mentioned in the chapter have been submitted to pharmacological investigations, and various biological activities were found. An attempt is made to enumerate some derivatives together with their biological properties. Such compounds are shown in the lactam structure.

Treatment of 1-methyl-3,4-dihydro-β-carboline with sulfonyl chlorides provided C-acylated products, which preferred vs. indole-N-acylated derivatives.

Cyclization reactions with polyphosphoric acid of 3-aryl-3-hydroxypropionanilides carrying a p-nitro- 7a or p-amino substituent 10 on the C-3 phenyl group were investigated. In the case of p-nitro substitution the preferred reaction is, instead of cyclization, the elimination of water to give the corresponding cinnamic acid derivative. On the other hand, reaction of the p-amino-substituted analogue gave the new compound 4-(4-aminophenyl)-3,4-dihydroquinolin-2(1H)-one (2b) in a good yield. The intermediate product of the cyclization was isolated and its structure established.

7,8‐Dimethoxytetralin‐2‐one (1), an important intermediate for the synthesis of compounds possessing biological activity, was synthesized by simple reaction steps from commercially available starting materials.

Publisher Summary This chapter focuses on the 3(2H)-Isoquinolinones and their saturated derivatives. The name 3(2H)-isoquinolinones is used for the lactam structure to emphasize the connection with derivatives saturated in the hetero ring or in the aromatic ring of the isoquinolinone skeleton or both. One of the most widespread methods of synthesizing 3(2H)-isoquinolinones is the cyclization of esters of o-acyl-phenylacetic acids with appropriate amines. 1, 4-Dihydro-3(2H)-isoquinolinones are structural isomers of the well-known dihydrocarbostyril and dihydroisocarbostyril nitrogen heterocycles. The chapter discusses 5, 6, 7,8-Tetrahydro-3(2H)-isoquinolinones. Several derivatives of the unsaturated and saturated lactams mentioned in the chapter have been submitted to pharmacological investigations, and various biological activities were found. An attempt is made to enumerate some derivatives together with their biological properties. Such compounds are shown in the lactam structure.

The pentacyclic alkaloid 1 could be synthesized by an intramolecular [4+2] cycloaddition reaction of intermediate 11, which had been obtained from tryptamine derivative 4 and aldehyde 5. After full epimerization of 13 the cyclization reaction furnished a mixture of 14a and 14b. Separation of the stereoisomers 14a and 14b and subsequent reduction with LiA1H 4 resulted in (±)-iboxyphylline (14a -> 1) and its epimer, (±)-20-epiiboxyphylline (14b -> 15).

Starting from 5-ethyldihydrofuran-2(3H)-one (9) we prepared aldehydes (6 and 7) which, in a [4+2] cycloaddition reactions with the tryptamine derivative (8) gave, as a final step, compounds (13 and 22) having D-seco-pseudoaspidospermane skeleton. We synthesized (±)-20-epiibophyllidine (4) via the benzoate ester (15) or the mesylate (17) of alcohol (14) which had been obtained from 13, while the catalytic hydrogenation of 22 led to (±)-ibophyllidine (3) via full epimerization, cyclization and reduction steps in one operation.

Reaction of tryptamine derivative (2b) and acetate ester (11) built up from 2-(chloromethylene)butanal (4) resulted in enamino ketone (14). Dehydration of 14 and subsequent intramolecular [4+2] cycloaddition led to 15-oxovincadifformine (15). Regio- and stereoselective reduction of the latter molecule supplied 15β-hydroxyvincadifformine (1).

4-Benzylidene-1-phenyl-1,4-dihydro-3(2H)isoquinolinone (2), 4-benzyl-1-phenyl-3(2H)isoquino-linone (3) and 4-benzyl-3-ethoxy-1-phenylisoquinoline (6) have been hydrogenated on palladium-charcoal catalyst. The structure of the products and the ratio of the stereoisomers have been determined by nmr spectroscopy and by LIS measurements with Eu(dpm)3.

In reactions of 1-phenyl-1,4-dihydro-3-(2H)benzoisoquinolinones with benzaldehyde in the presence of a strong base, the final result can be ring substitution with aromatization or only aromatization of the starting isoquinolinone, depending on the position of the ring junction ([f] or [h]), in the 5-methyl derivative the latter process becomes predominating. In the system sodium hydride-dimethylformamide, containing no aromatic aldehyde, methylation at site 4 occurs. Using compounds labelled with deuterium, it has been established that the 4-benzyl or 4-methyl derivatives with aromatic structures are formed through hydride ion migrations.

Die Strukturen von 4-Benzyliden-1-phenyl-1,2,3,4-tetrahydro-3-isochinolinon 1E, seinem Photoisomeren 1Z sowie der durch katalytische Hydrierung gewonnenen Verbindungen 3a und 3b wurden mittels 1H-, LIS-1H-, 13C-NMR- und NOE-Messungen bestimmt. Es zeigte sich, daβ die katalytische Hydrierung der Benzylidenderivate 1E und 1Z stereoselektiv verlauft. Stereochemical Studies on 4-Benzylidene-1,2,3,4-tetrahydro-3-isoquinolinones and their Hydrogenated Derivatives The structures of 4-benzylidene-1-phenyl-1,2,3,4-tetrahydro-3-isoquinolinone 1E, its photoisomer 1Z, and of the products 3a, b obtained by catalytic hydrogenation were determined using 1H-, LIS-1H-, 13C-NMR, and NOE measurements. The catalytic hydrogenation of the benzylidene derivatives 1E and 1Z was proven to be stereoselective.

1, 4-Dihydro-1-[4′-(ethylaminoacetyl)-aminophenyl]-3 (2H)-isoquinolinone was labelled with 14C in two different positions: in one case in position 3 of the isoquinoline ring, in the other case in the carbonyl group of the ethylaminoacetyl moiety.

A new route of preparing 1,4-dihydro-3(2 H )-isoquinolinones and 5,6,7,8-tetrahydrolsoquinolinones was developed by the hydrogenation of 3(2 H )-isoquinolinones. The 1,4-dihydro compounds 1 - 8 , were also prepared by synthesis, when the cis - trans ratio significantly differed from that of the products obtained by hydrogenation. Relative configurations and site of conformational equilibria were established by n.O.e. difference n.m.r. spectroscopy. Compounds 2 , 4 , 5 and 6 had practically one main conformation, whereas 1 , 3 , and 7 occurred as two boat conformers in equilibrium. Complete 1H and 13C signal assignments were achieved by different 2D homo- and heteronuclear correlation measurements.

4-Benzylidene-1-phenyl-1,4-dihydro-3(2H)-isoquinolinone, the intermediary product of the carbonyl condensation reaction between 1-phenyl-1,4-dihydro-3(2H)-isoquinolinone and benzaldehyde, rearranges in the presence of an equivalent quantity of sodium hydride into 4-benzyl-1-phenyl-3(2H)-isoquinolinone. As the possibility of the migration of the hydrogen at C-1 in the form of a proton or a hydrogen atom (radical reaction) was excluded, the mechanism of the rearrangement could be depicted as an intermolecular hydride anion migration. In case of the 1-(4-pyridyl)- and 1-(3-pyridyl)-1,4-dihydro-3(2H)-isoquinolinones, however, the rearrangement can be carried out also in polyphosphoric acid and in this case a proton loss-proton gain mechanism was proved.