Modified Pomeranz-Fritsch

Reticuline (38), one of the most important intermediates in the biosynthesis of opium alkaloids, has been synthesized in racemic form (Scheme 7) (78). 6-Methoxy-7-benzyloxyisoquinoline (39), prepared from O-benzylisovanillin via a modified Pomeranz-Fritsch isoquinoline synthesis, was treated with benzoyl chloride and potassium cyanide to obtain Reissert compound 40. Alkylation of the anion generated from 40 with 3-benzyloxy-4-methoxybenzyl chloride gave the corresponding 1-substituted Reissert compound 41 which was hydrolyzed in alkaline medium to 1-benzylisoquinoline derivative 42. Quatemarization of 42 with methyl iodide followed by sodium borohydride reduction and debenzylation led to ( )-reticuline (38) in about 25% overall yield from 39. 

An advantage of the modified Pomeranz-Fritsch synthesis is that the 1,2-dihydroisoquinolines can be reacted in situ with electrophiles, yielding 1,4-dihydroisoquinolinium salts that react with nucleophiles at C-3 (see Section 3.3.3). Such a single pot procedure can be used to form complex 1,2,3,4-tetrahydroisoquinolines. 

Moreover, this procedure should provide a useful route to construct the 1,2,3,4-tetrahydroisoquinoline nucleus in a modified Pomeranz-Fritsch-type procedure shown in Scheme 5. 

The Bobbitt modified Pomeranz-Fritsch reaction allows the preparation of enantiopure tetrahydroisoquinolines. During the studies directed toward the total synthesis of ET 743 and its analogues, S.J. Danishefsky and co-workers utiiized this transformation for the preparation of a key tetrahydroisoquinoline intermediate. The cyclization precursor was efficiently synthesized from the enantiopure benzylamine derivative by A/-alkylation with excess diethylbromoacetal. The resulting compound was subjected to QN hydrochloric acid at 0 °C and slowly warmed to ambient temperature overnight. The desired tetrahydroisoquinoline was formed as a 4 1 mixture of diastereomers. 

The shortest synthesis of papaverine was achieved in the laboratory of R. Hirsenkom starting from racemic stilbene oxide and using a modified Pomeranz-Fritsch reaction The aminolysis of the stilbene oxide led to the formation of the cyclization precursor, which upon treatment with excess benzoyl chloride, underwent cyclization to give the N-benzoyl 1,2-dihydroisoquinoline derivative. Reduction under Wolff-Kishner conditions afforded papaverine. 

As noted previously, 7,8-dioxygenated tetrahydroisoquinoline alkaloids may be synthesized by a modified Pomeranz-Fritsch reaction. Application of the Bischler-Napieralski or Pictet-Spengler reactions usually leads to cyclization in an undesired sense, e.g., in (29 X = H) to the 2- rather than to the 6-position. This can be avoided by blocking the 2-position with a bromine function. Thus homopetaline (30 R = CH2CH2C6H4-p-OMe) has been synthesized from (29 R = CH2CH2C6H4-p-OMe) in four steps, the bromo-substituent being removed by catalytic hydrogenation over Raney nickel in the final step.41... 

The Pschorr reaction was described in connection with the synthesis of the papaverine (3) derivatives (350, 351). The synthesis of petaline (5b) was accomplished (352, 353). Escholamine (4a) and takatonine (4c) were synthesized by a modified Pomeranz-Fritsch reaction (354). The phenolic oxidation of (f )-(-)-N-methylcoclaurine (7c) and (S)-(+)-reticuline (7f) with peroxidase proved to be a failure (355). The oxidation of reticuline with ferricyanide yielded isoboldine (24c) and pallidine (43b) and the byproducts vanillin and thalifoline (2c) (355). A new synthesis of 3-oxo-papaverine was developed (356), and the Eschweiler-Clark method for the synthesis of codamine (7r) was modified (357). Oxidation of reticuline (7f) by enzymatic systems from homogenized P. rhoeas in the presence of hydrogen peroxide gave ( )-/3-hydroxyreticuline (10) (358). 

The diphenyl ether 1 was converted to the morpholinamide 2, which after cyclization to the enamine 3 and hydrolysis furnished the tricyclic ketone 4. Interestingly, in the modified Pomeranz-Fritsch cyclization step, one of a pair of ethoxyl rather than hydroxyl racemates was isolated. Catalytic hydrogenolysis and reductive iV-methylation completed the synthesis shown below ... 

Construction of the required spiro system was performed through a modified Pomeranz-Fritsch sequence (see Scheme 25.1). The nitrogen function had to be acetylated before cyclization with formation of ring B could be carried out. The sodium borohydride reduction to furnish ochrobirine proceeded with a high degree of specificity. 

Modified Pomeranz-Fritsch isoquinoline ring closure... 

Benzylideneaminoacetoaldehyde acetals prepared from benzaldehydes have been key intermediates of a well-established method for isoquinoline synthesis known as the Pomeranz-Fritsch reaction (Scheme 16, route a) [49,50], Intramolecular cycliza-tion of this type of imines under acidic conditions provided isoquinolines, where the two-carbon substituent on the nitrogen atom was transformed into a part of the isoquinoline ring. For the synthesis of 8-fluoroisoquinohne, the application of the standard procedure gave a low yield of the desired product (3 % in two steps from 2-fluorobenzaldehyde) [51]. However, in the modified procedure using ethyl chloro-formate, trimethyl phosphite, and titanium tetrachloride for the cyclization step [52] provided 6-fluoroisoquinoline from 4-fluorobenzaldehyde in 34 % overall yield (Scheme 17) [25],... 

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