Enamide cyclizations in alkaloid synthesis

Chapter 4. Application of Enamide Cyclizations in Alkaloid Synthesis Ichiya Ninomiya and Takeaki Naito... 

Enamide cyclizations, application in alkaloid synthesis, 22, 189 (1983) Enzymatic transformation of alkaloids, microbial and in vitro, 18, 323 (1981) Ephedra bases, 3, 339 (1933)... 

One of the major areas of research in enamide chemistry has been the application of enamide cyclization to the synthesis of natural alkaloids and related heterocyclic compounds. Ever since Ninomiya and co-workers discovered nonoxidative photocyclization of the A-benzoylenamine-type ena-mides in 1969 (9), several types of alkaloids have been synthesized, starting from enamides of rather simple structures, by applying enamide cyclization under both photochemical and thermal conditions. 

Regiochemistry of enamide photocyclization in this synthesis can also be controlled by the use of an ortho substituent that acts as an eliminating group on cyclization to the root of the substituent. Thus, the omethoxyl and bromo groups are used for this regioselective cyclization as exemplified by a number of total syntheses of alkaloids (19,20) (Scheme 37). 

Reversed regioselectivity in aryl radical additions to enamides and enamines can also be observed with aryl substituents on the alkene [86]. This cyclization type has been successfully applied in the synthesis of protoberberines and the pavine alkaloids. Argemonine (39) was obtained from a 6-exo cyclization of 40 passing through a well-stabilized benzylic radical (Scheme 15). 

By taking advantage of these features, enamide cyclization has shown its great versatility in the synthesis of a wide variety of isoquinoline and indole alkaloids. 

In this chapter, we first summarize more or less basic works on the synthesis of the common and basic skeletons of various types of natural alkaloids, aiming at their application to total synthesis, and also those works that seem applicable to the above syntheses, and then collected works on total syntheses of alkaloids via the route involving enamide cyclization. 

The cyclization of l-methylene-2-nicotinoylisoquinolines 27 under three different conditions, photochemical, thermal, and acylating conditions, are compared (73). Starting from the above enamide (27), Ninomiya et al. (73) synthesized 10-azaberbine as the major product by simple heating at 195-200°C, whereas 12-azaberbine was the major product under acylating condition as shown in Table II. Further, total synthesis of alamarine (33), the only alkaloid having an azaberbine structure, was synthesized via the route involving enamide cyclization under both thermal and photochemical conditions (73) as shown in Scheme 71. 

Novel synthetic applications of the photocyclization of enamides have been reported. Preparation of the fused quinolone (23) from the enaraide (24) was achieved by photocyclization and subsequent elimination of a suitably positioned methoxyl group Reductive photocyclization of enamides, usually carried out in the presence of sodium borohydride, is of particular value in the synthesis of alkaloids. Cyclization of the enamide (25) to the... 

The enamine cyclization reaction has not been utilized in organic synthesis to the same extent as the corresponding enamide reaction. Schultz and Chiu have utilized this reaction in an approach to the synthesis of the aspidosperma alkaloids. Irradiation of compound 37 produces tetracyclic compound 38 in 71% yield (equation 11). 

The Pummerer rearrangement has been employed in tandem with other reactions to enable complex transformations to be carried out efficiently and in a one-pot manner. Studies of these have been reported mainly by Padwa who has utilized such transformations in the syntheses of natural products. A particularly intriguing cascade sequence involving the Pummerer rearrangement was employed in the synthesis of the alkaloid jamtine, 57. " Padwa et al. synthesized the bromo-enamide 55 in a 4 1 (Z/ ) mixture of isomers. Treatment of the isomeric mixture with camphorsulfonic acid caused the the sulfoxide to undergo a Pummerer/Mannich ion cyclization, which was then followed by a spontaneous Pictet-Spengler reaction to furnish the isoquinoline core. Although a 5 2 1 1 mixture of diastereoisomers was obtained, the desired diastereoisomer 56 was formed preferentially. This was attributed to a 4 r-Nazarov-type conrotatory electrocyclisation which controls the direction of closure from the a-acylthionium ion intermediate. 

In the synthesis of the alkaloid Gelsemine, the intramolecular cyclization catalyzed by AgOTf and Ag2C03 of a carbamoyl chloride to an enamide function provided the polycylic skeleton of the natural product in an elegant and efficient way (eq 67). ... 

Synthesis of alkaloids enamide cyclizations for, 22,189 (1983) lead tetraacetate oxidation in, 36, 70 (1989)... 

A multicomponent reaction/cyclization strategy was employed to synthesize simplified cyclopeptide alkaloid analogues 82. The enamide double bond found in many natural derivatives is missing, but biologically active cyclopeptide alkaloids with a hydrated enamide double bond (like sanjoi-nine G1 [55, 56]) are known. The synthesis is considerably simplified by omitting this unsaturation, obviously not required for biological activity. 

There are two types of enamides readily available for the simple synthesis of protoberberine alkaloids via the route involving photocyclization. One is the 2-acyl-1-benzylideneisoqui noline-type enamide that has a stilbene structure in the molecule and is known to undergo a six -electron conrota-tory electrocyclic cyclization to a dihydrophenanthrene and subsequent dehydrogenation (103), and thus provides a useful synthetic route to apor-phine alkaloids. The second is the 2-aroyl-l-methyleneisoqui noline-type enamide that gives the 8-oxoberbine in good yields on irradiation. 

Dicentrine and Dicentrinone. Dicentrine (283) was synthesized by photo-cyclization of the o-bromo- and chloroenamides 282a and b by Cava et al. (138) the former enamide (282a) was best suited for the synthesis of the alkaloids in view of yield and reaction time (Scheme 103). 

The hydrogen abstraction, in this instance, presumably occurs at the P-carbon of the enone (139). The resultant biradical ring closes to afford the observed products. The ic-ic excited triplet state is involved in the conversion of the enone (141) into the spiroketone (142). The reaction again involves hydrogen abstraction by the ft-carbon followed by cyclization within the biradical. Photocyclization of enamides such as (143) has led to a new synthetic approach to the yohimbine anreserpine type alkaloids. " The photocyclization of the enone (144) provides a route for the synthesis of 3.10-dimethoxyprotoberberines. ... 

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