Benzazepine alkaloids

Secophthalideisoquinoline enol lactones of type 128 were used by Klotzer et al. (95,103-105) for the synthesis of benzazepine system 129 which was further transformed to alkaloids of rhoeadine type. 

The l-benzyl-tetrahydro-3H-3-benzazepin-2-one (130) with phosphorus oxychloride in boiling toluene cyclizes directly to the indenoazepine (131), a valuable intermediate for the synthesis of protopine alkaloids (80T317) (see Section 5.16.5). 

Synthesis of Benzazepine Alkaloids and Related Compounds T. Kametani and K. Fukumoto, Heterocycles, 1975, 3, 931-1004. 

Treatment of the isoquinolinium methiodide 1 with sodium methoxide in methanol for two hours at reflux temperature gave the tetrahydroisoquinoline 2 in quantitative yield, and not the anticipated benzazepine 3. This unexpected result was then exploited as follows for a "biomimetic" synthesis of the alkaloid litebamine. Thus, quaternisation of (S)-0,0-diacetylboldine 4 with iodoacetonitrile in methylene chloride (41%) followed by treatment of the salt with NaOMe/MeOH gave litebamine 5 (69%). 

A new synthetic route to the phthalide-isoquinoline and spiro-benzyl-isoquinoline alkaloids has been developed. The indeno[2,l-a]benzazepine (105),... 

A photochemical preparation of a Cephalotaxus alkaloid synthon (20) has been reported (Scheme 2).10 The readily accessible maleimide (17) was iodinated with iodine and silver trifluoroacetate, in 71% yield, and the resulting compound was transformed in two steps (70% overall yield) into the methylene-pyrrolone (18) by the action of methylmagnesium iodide followed by dehydration. Irradiation of (18) afforded (19) (46% yield), which, by successive hydrogenation and reduction with lithium aluminium hydride, gave the dihydro-pyrrolo[2,l-b][3]benzazepine (20). This derivative has served as a key intermediate in the total synthesis of cephalo-taxine described previously (see Vol. 7 of these Reports). 

Benzyl- and 2-phenethylenaminoketones (XXII Y = NR, n = 1,2) can be cyclized in good yields to quinolines and benzazepines (Table 7, numbers 14 and 15). The cyclization has also been used to prepare a precursor of the alkaloid lycorane [Eq. 

A range of alkaloids including isoquinoline, indolizidine, benzazepine, oxazine, quinoline and indole alkaloids were examined as potential inhibitors of eukaryote protein kinases such as PKC, MLCK and PKA. Only three oxazine alkaloids and four isoquinoline-based alkaloids and inhibitors of the protein kinases tested. A narrow structural and protein kinase target specificity, was observed. (+)-Boldine (39) and bulbocapnine (40) are specific for MLCK, while apomorphine (41) and sanguinarine (42) are for PKA. 

Synthetic work on rhoeadan and other benzazepine alkaloids has been reviewed. The synthesis of benzindenoazepines from l-benzoyl-3,4-dihydroisoquinolines cf. Vol. 6, p. 158) has been applied to the preparation of methylenedioxy analogues, e.g. (162). An alternative to the published procedure... 

A comprehensive review concerning the synthesis of the Cephalotaxus alkaloids has appeared/ Another review incorporates this subject in the context of the synthesis of alkaloids which embody in part a benzazepine framework/... 

The alkaloids of the rhoeadine group are benzazepines and essentially bear the same relationship to the indanobenzazepines as do the secoberberines (section 10) to the spirobenzylisoquinolines (section 13). 

A vast array of structurally unrelated compounds interacts with a I-adrenoreceptor subtypes, which makes it inherently difficult to determine the structural requirements leading to receptor subtypes selectivity (Ruffolo et al., 1995 Leonard et al., 1996 Kenny et al., 1997). The majority of a,-adrenoreceptor antagonists displays a competitive mechanism of action and belongs to a variety of different structural classes such as yohimbanes, ergot alkaloids, quinazolines, A-arylpiperazines, imidazolines, phenylalkylamines, benzodioxanes, indoles, 1,4-dihydro-pyridines, hetero-fused 3-benzazepines, dibenzoquino-lizines. 

R5 = H), respectively. Derivatives of these parent bases have been known since the early 1900s. The benzazepine skeleton has been found to be a component of natural products, e.g., Amaryllidaceae and Papaveraceae alkaloids. Derivatives of the benzazepines have been of interest to medicinal chemists for their wide range of biological activity. 

Condensation of 57 with homoveratraldehyde (60) in the presence of molecular sieves, followed by sodium borohydride reduction, affords the chromium tricarbonyl complex 61 in moderate overall yield. The acid-promoted cyclization of 61 proceeds with retention of configuration to afford, after air decomplexation, optically pure (/ )-( + )- -phenyl- 3-methyl-l,2,4,5-tetrahydrobenz[d]azepine (62) (Scheme 12) [14]. The l,2,4,5-tetrahydro-3//-benz-[[Pg.145]

The synthesis of benzazepines by the acid-catalyzed cyclization of 7 (-(2-arylethyl)-7 (-methyl-2-sulfinylacetamides is a convenient alternative to this acid-catalyzed cyclization. Thus treatment of the amide (172) (Equation (17)) with trifluoracetic anhydride affords the benz(. This method has been used in a first synthesis of the benzopyranobenzazepine alkaloid ( +)-clavizepine <94SL49>. 

In addition to the pathway leading to the protoberberines, a second one leading to the protopine alkaloids has now been elucidated at the enzyme level utilizing plant cell cultures as the enzyme source. Since the protopines are regarded as the biosynthetic precursors of the benzazepine and benzophenanthri-dine alkaloids (refs. 36-39) these now can be the target of further enzymatic investigations. 

Application of the Bradsher reaction to the synthesis of natural products has also been reported. The first total synthesis of benzopyrano-benzazepine alkaloid ( )-clavizepine, 54, was accomplished using a Bradsher reaction as the key step. Thus the tricyclic core of 54 was assembled by stannic chloride indueed cyclization of 55 to afford a mixture of 56 and 57. If methanol-free dichloromethane was used in this cyelization, then 56 could be obtained as the sole produet in 66% yield. Alternatively, 56 could be converted in 57 in excellent yield with PPTS. 

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