Yohimbine alkaloids rings

After an interval of more than 20 years, a second synthesis of ( )-deserpidine and the achievement of some stereoisomers of ( )-raunescine (114) have been reported by Szdntay and co-workers (250,255). The basic idea of this linear total synthesis was similar to that utilized by them for the synthesis of yohimbine alkaloids. First, tetracyclic key intermediate 467 was prepared (253), in which the methoxy substituent of the side chain, on the one hand, represents the future C-18—O bond of the end product and will, on the other hand, control the regioselectivity of the Dieckmann ring closure. 

The arbitrary classification of Rauwolfia alkaloids (91) is simplified here, and it is slightly different from a recent arrangement (92). The Rauwolfia alkaloids can all be regarded as yohimbinoid derivatives as shown in Chart I, viz. the yohimbines (all yohimbine isomers) 18-hydroxyyohimbines (reserpine-type alkaloids) ring E heterocycles and their anhydronium analogs (ajmalicine, serpentine) ajmaline-type (which includes sarpagine) and compounds of unknown constitution. 

As shown in Chart 5.1, a wide variety of alkaloid skeleta are derivable from Type I precursor and tryptamine by further ring closures. It is worth pointing out that in so far as they have been investigated, they all have had the same stereochemistry for the carbon equivalent to C-15 of yohimbine. In this chapter, certain tetrahydro-j8-carboline alkaloids, viz., the yohimbines, their ring E seco equivalents and ring E oxygen heterocycles will be discussed since they show much chemistry in common. Over the years most of their degradation products have been synthesized, they have been interrelated, their absolute stereochemistries derived, and some have been synthesized. For these reasons they have become valuable reference compounds. 

In the initial applications of Diels-Alder chemistry to yohimbine alkaloid synthesis, the Kametani (24-27) and Takano (28) groups have both examined reactions between furan derivatives and maleic anhydride. In the initial investigations of Kametani and his coworkers (24) (Scheme 3.10), the Diels-Alder adduct (57) of furan and maleic anhydride underwent bromolactonization to give the tricyclic carboxylic acid 58 (94). This compound has four [C(15), C(16), C(17), and C(18)] of the five contiguous stereocenters of the reserpine E-ring in place. Acid 58 was converted to diazoketone 59 which underwent Wolff rearrangement followed by tryptamine trapping to afford amide 60. Bischler-Napieralski cyclization of this substance afforded the tetracyclic... 

Isobe and his coworkers (29, 30) utilized Diels-Alder reactions in a quite different fashion in their synthetic approaches to the yohimbine alkaloids. An optically active dienophile was treated with a diene to form the DE ring skeleton which was then elaborated to produce the target yohimbines. 

The primary alcohol was converted to methyl ester 171 which was hydrolyzed to hemiacetal 172, the ring closed form of aldehydo-alcohol 173 and a precursor of 3-epialloyohimbine (9). While the syntheses of the target molecules were not completed, the work of Polniaszek and Stevens illustrates how Cope rearrangements can be used effectively to generate cis-fused DE-ring precursors of the yohimbine alkaloids. 

In the first part of this survey, approaches to yohimbine alkaloid synthesis which involved initial elaboration of the DE-ring system followed by introduction of the tryptophyl unit and subsequent C-ring closure were addressed. 

Enamide and enamine photocyclizations (9, 13, 14, 113) are central to yet another strategy which has been successfully employed by Ninomiya (9, 13, 14, 61-71), Kametani (74), and Atta-ur-Rahman (72, 73) in the synthesis of yohimbine alkaloids. These approaches typically begin with harmalane (336) which contains the ABC unit of the pentacyclic yohimbine targets (Scheme 3.56). Condensation of harmalane with an appropriately substituted cyclohexene carboxylic acid or benzoyl chloride 337 affords seco D-ring intermediate 338. To effect D-ring closure, the enamide chromophore in 338 is photocyclized to form pentacyclic enamide 339. Alternatively, photoreaction... 

One strategy which has been successfully utilized in yohimbine alkaloid synthesis involves the use of cyclization reactions of either pyridinium or isoquinolinium cations to install the respective D or DE-ring units. Wenkert and his coworkers have popularized this methodology, as exemplified by their synthesis of hexahydroyohimbine (473) (Scheme 3.82) (131). In this sequence, AT-tryptophylpyridinium salt 468, prepared by reaction of 3-formylpyridine and tryptophyl bromide, was treated with the enolate anion of methyl aceto-acetate to afford isoquinolone 469. Methylation of this material provided isoquinolinium salt 472 which upon reduction followed by acid mediated cyclization provided yohimbane 473. This methodology represents a rather... 

Chatteijee has synthesized a variety of yohimbine alkaloids utilizing 3-isochromanone derivatives as DE-ring precursors (Scheme 3.89) (140). For... 

Cleavage of the hetero ring in a number of extended tetrahydro-j8-carboline systems was observed in the course of structural elucidation of tetrahydro-jS-carboline alkaloids. A few examples only will be given. The indole derivative 287 was isolated as one of the products of the selenium dehydrogenation of yohimbine (358 R = and... 

Carbocyclic variants related to ajmalicine such as yohimbine are likely to arise from dehy-drogeissoschizine by the mechanism indicated in Figure 6.77. Yohimbine is found in Yohimbe bark (Pausinystalia yohimbe, Rubiaceae) and Aspidosperma bark (Aspidosperma species Apocy-naceae) and has been used in folk medicine as an aphrodisiac. It does have some pharmacological activity and is known to dilate blood vessels. More important examples containing the same carbocyclic ring system are the alkaloids found in species of Rauwolfla, especially R. serpentina (Apocynaceae). Reserpine and deserpi-dine (Figure 6.78) are trimethoxybenzoyl esters of yohimbine-like alkaloids, whilst rescinnamine is... 

The indole ring system 14 is particularly important and occurs widely in nature. Tryptophan 23 is one of the essential amino acids and is found in most proteins. Its metabolites include tryptamine 24. 3-Indoleacetic acid 25 is an important plant growth hormone. The indole alkaloids, exemplified by yohimbine 26, are an important family of natural products. 

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