Dihydroisoquinoline alkaloids

The piperideine derivatives have not been studied as extensively as the analogous pyrrolines (151,152). The imino structure has been established, for example, for the alkaloid y-coniceine (146) (46). The great influence of conjugation on the structure is seen with l-(a-picolyl)-6,7-methylenedioxy-3,4-dihydroisoquinoline (47), possessing an enamine structure, whereas the analogous 1-methyl derivative (48) possesses an imine structure according to infrared spectra (152,153). 

The Bischler-Napieralski reaction involves the cyclization of phenethyl amides 1 in the presence of dehydrating agents such as P2O5 or POCI3 to afford 3,4-dihydroisoquinoline products 2. This reaction is one of the most commonly employed and versatile methods for the synthesis of the isoquinoline ring system, which is found in a large number of alkaloid natural products. The Bischler-Napieralski reaction is also frequently used for the conversion of N-acyl tryptamine derivatives 3 into p-carbolines 4 (eq 2). 

Wender and Aube have independently described the use of the Bischler-Napieralski reaction in the synthesis of Yohimban alkaloids. Aube s approach involved the cyclization of indole 50 followed by reduction of the resulting dihydroisoquinoline... 

Leptopinine 82 possesses the 3,4-dihydro-isoquinolin-7-ol moiety without further conjugation and was isolated as yellow powder from Hypecoum leptocarpum after several extractions with hydrochloric acid so that this alkaloid was finally isolated as a chloride (Scheme 29). The formation of a mesomeric betaine from this dihydroisoquinoline derivative is unlikely because on addition of base no significant changes of the UV spectra were observed (99P339). A similar structure is Pycnarrhine Pycnarrhena longifolia), which was isolated as a hydroxide (81P323). 

Following the communcation in 2004, a full report appeared that described type Ilac cyclocondensation reactions between dihydroisoquinolines and a-nitrocinnamates leading to complex fused pyrroles <06JOC9440>. The latter were converted into the lamellarin alkaloids and related analogues. 

Isoquinoline alkaloids. The regioselective allylation of N-acyl heterocycles (13, 10) can be used for synthesis of isoquinoline alkaloids. Thus simultaneous reaction of the dihydroisoquinoline (1) with a diunsaturated acyl chloride (2) and allyltributyltin affords the 1,2-adduct (3), which undergoes a Diels-Alder cyclization... 

Several 1-benzylisoquinoline alkaloids have been synthesized utilizing the above reaction sequence. For example, takatonine (34) has been obtained from Reissert compound 27 via alkylation with p-methoxybenzyl chloride and subsequent hydrolysis and quatemarization with methyl iodide 17). Similarly, es-cholamine (37) has been prepared from A-benzoyl-l-cyano-6,7-meth-ylenedioxy-1,2-dihydroisoquinoline (28) and 3,4-methylenedioxybenzyl chloride (77) as shown in Scheme 6. 

Two similar pathways have been reported (79) for the total synthesis of a pseudobenzylisoquinoline-type alkaloid, rugosinone (43), isolated as a minor component of Thalictrum rugosum. As shown in Scheme 8 the anion of N-benzoyl-l-cyano-6,7-methylenedioxy-l,2-dihydroisoquinoline (28) was reacted... 

The total synthesis of pavinane alkaloid platycerine (89) (Scheme 14) has been accomplished successfully (26) via 1-benzylisoquinoline derivative 91 obtained from Reissert intermediate 90. Quatemarization of 91 with methyl iodide followed by lithium aluminum hydride reduction supplied 1,2-dihydroisoquinoline 92, which on treatment with a 7 5 mixture of formic acid and phosphorous acid gave ( )-platycerine (89) in 60-70% yield. 

The 1-substituted 3,4-dihydroisoquinoline (87) was reduced with chiral reducing agent (62) to the corresponding alkaloids (88) in excellent optical yields (e.e. = 60 to 87 %) 94). 

The photochemical electrocyclization of conjugated iminium salts 160, formed by protonation of 2-azadienes 159, led to isoquinolin-4-ones 162, presumably through hydrolysis and oxidation of the dihydroisoquinoline intermediates 161 (85TL5213) (Scheme 39). A closely related reaction served as the key step for a short synthesis of the pentacyclic marine alkaloid ascididemin as reported by Moody, Rees, and Thomas [90TL(31)4375 92T3589] the central reaction involves a 67r-electron pho-tocyclization of a syn- aza stilbene in sulfuric acid. 

Isoquinoline synthesis Bischler-Napieralski synthesis is used to synthesize isoquinolines. (3-phenylethylamine is acylated, and then cyclodehy-drated using phosphoryl chloride, phosphorus pentoxide or other Lewis acids to yield dihydroisoquinoline, which can be aromatized by dehydrogenation with palladium, for example in the synthesis of papaverine, a pharmacologically active isoquinoline alkaloid. 

Members of the tetracyclic dibenzopyrrocoline alkaloid family can be prepared by the intramolecular ring closure of l-(o-halobcnzyl)-tetrahydroisoquinoline derivatives. (3.38.)47 The analogous transformation of dihydroisoquinolines (3.39.) proceeds probably through the isomeric enamine form obtained by the tautomeric shift of the double bond 48 The palladium-carbene catalyst system applied in these reactions was also effective in the preparation of indoline, indolizidine and pyrrolizidine derivatives 49... 

This reagent has been used to reduce several 3,4-dihydroisoquinoline derivatives to optically active alkaloids in 60-85% ee. 

These structures were confirmed by syntheses. The amide 3 prepared from known compounds was reacted with phosphorus oxychloride in acetonitrile to generate a dihydroisoquinoline which on reduction, diazotization, and treatment with activated copper gave dihydro-imeluteine. Dehydrogenation to the natural alkaloid was effected by... 

The 3,4-dihydroisoquinoline system is also encountered in this family of alkaloids. The assignment of chemical shifts to the aromatic carbon atoms of the substituted 3,4-dihydroisoquinolines (21-25 in Fig. 3 and Table III) followed directly from the application of the appropriate substituent parameters to the shifts reported for 20 (22) and from a consideration of the resonance effect of the carbon-nitrogen double bond. This latter point is especially evident in the methiodide salts, 24 and 25, where charge delocalization causes C-4a, C-6, and C-8 to appear at lower field than their counterparts C-8a, C-l, and C-5, respectively. Carbon-1 was readily recognized as the lowest field resonance because of its imine character. 

The best catalyst for this transformation was AgSbFg (10 mol%), and (3-ketoesters, malonates, and silyl enol ethers have been used for the nucleophilic addition on the pyridinium intermediate DD. The dihydroisoquinolines 48 have been further used in several reactions in order to assemble the framework of various alkaloids. One example is given in the formation of dihydroisoquinoline 49, bearing a pendent a, 3-unsaturated ketone. Compound 49 can rearrange to the tetracycle 50 (related to the core structure of karachine, Scheme 5.23), using TMSOTf, via a tandem Michael addition-Mannich reaction process (intermediates EE and FF). 

Similar methodology was used in the synthesis of 3-methyl derivatives of the alkaloids thalactamine, doryanine, and 6,7-dimethoxy-A-methyl-l(2//)-isoquinolone652. The S l reaction between 0rr/20-halogenobenzylamines and enolates derived from a series of ketones and aldehydes affords 1,2-dihydroisoquinolines, from which the isoquinoline derivatives can be obtained by dehydrogenation and the 1,2,3,4-tetrahydroisoquinolines by reduction653. The products of the S l reactions of (2-halo-4,5-dimethoxyphenyl)acetic... 

The l3C-NMR spectral data of benzo[a]quinolizidine compounds have been reported (154,282,283), and many examples from the isoquinoline alkaloids have been reviewed by Hughes and MacLean (284) (Volume XVIII, Chapter 3, in this treatise). As described in Section III, B, l3C-NMR spectroscopy, together with H-NMR and UV spectroscopy, has also played the leading role in the confirmation of the endocyclic double-bond structure in the dihydroisoquinoline moiety of 0-methylpsychotrine (7)... 

Total synthesis of protoberberine alkaloids via the route involving enamide photocyclization consists of nonoxidative photocyclization of the 2-aroyl-l-methylene-3,4-dihydroisoquinolines and the subsequent metal-hydride reduction of the photocyclized lactams. This simple combination of reactions for alkaloid synthesis provides one of the most convenient synthetic routes to this group of popular alkaloids. 

Benzazocines were also prepared on a solid support from otherwise unstable dihydroisoquinolines. Syntheses of a variety of alkaloid-like benzoazocines were reported to occur in very good yields <2004AGE1681>. 

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