Yohimbine alkaloids syntheses

A novel approach to yohimbine alkaloid synthesis by Meyers 86... 

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... 

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. 

A final illustration of how Dieckmann cyclizations have been utilized in yohimbine alkaloid synthesis is found in the work of Winterfeldt and coworkers (59, 60). In these studies, this methodology was employed to construct the pentacyclic alkaloid skeleton found in thioketal 335 (Scheme 3.55). Reaction of j5-enaminoester 327, prepared by condensation of tryptamine and... 

An early application of enamide photocyclizations to yohimbine alkaloid synthesis is illustrated by Ninomiya and coworkers synthesis of yohimbane (120), epiyohimbane (347) and alloyohimbane (82) (Scheme 3.57) (61, 63, 69). These compounds were prepared by a short sequence starting with har-malane (336) which was condensed with acid chloride 341 to provide enamide 342. Irradiation of 342 in benzene followed by reduction afforded a mixture of the stereoisomeric pentacyclic lactams 344, 345, and 346 which were reduced to provide yohimbane (120), epiyohimbane (347), and alloyohimbane (82), respectively. While the yield of the photocyclization process was modest, this route demonstrated how enamide photocyclizations can be used to rapidly construct pentacyclic yohimbane targets. 

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... 

The general method for the synthesis of different indoloquinolizine alkaloids via IV-tryptophyl 3-substituted pyridinium salts, developed by Wenkert and his collaborators, has been extended for the synthesis of yohimbine alkaloids (227-229). 

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 phenanthridine skeleton is synthesized by photocyclization of the enamides prepared from cyclohexanonimines and benzoyl chlorides (17,18). The benzo[c]phenanthridine skeletons are formed from the enamides prepared from 2-tetralonimines and benzoyl chlorides (19,20). More conveniently, the skeletons of protoberberine alkaloids are readily synthesized from the enamides prepared by simple acylation of 1 -methyl-3,4-dihy-droisoquinolines with benzoyl chlorides (21-24). This berbine synthesis is one of the most typical examples of the application of enamide photocyclization to alkaloid synthesis and can be further extended to the facile synthesis of the skeletons of the yohimbine group of indole alkaloids (25,26). 

Indole alkaloids, synthesis and biosynthesis of 87H(25)617. Yohimbine, total synthesis of 90YGK206. 

Yohimbine alkaloids possess a characteristic pentacyclic indole skeleton. Representative members of the family include the rauwolfia (reserpine and deserpidine) and the yohimbines. A wide range of medicinal properties has been associated with these compounds and extensive studies have been carried out on the synthesis of the yohimbine alkaloids, including enantioselective syntheses [13,14]. In our approach, we view the acetylenic sulfoxide as a two-carbon synthon for the C3-C14 segment of the pentacyclic system (see 27). The chirali-... 

Lee AWM, Chan WH, Mo T (1996) Chiral acetylenic sulfoxides in enantioselective synthesis Asymmetric synthesis of pentacyclic yohimbine alkaloids. Presented at the 212th American Chemical Society National Meeting, Orlando... 

As with the PictetASpengler reaction, the Bischler-Napieralski cyclization has been used in alkaloid synthesis. For example, a synthesis of yohimbine and related alkaloids began with enantiomerically pure amide [364],... 

Up to the 1960s, the treatment of atherosclerosis was only symptomatic. [363] Thus, for example for lowering blood pressure, there was used an extract from the snake-shaped roots of Rauwolfia serpentina, which was already known to the ancient Hindus (Fig. 5.149). [364] In 1952, EmU Schlittler (1906-1979) of the Ciba company isolated reserpine as its hypotensive principle, and determined its constitution. In particular, he also recognised the relationship to the large class of yohimbine alkaloids. The first constitutional total synthesis was achieved in 1956 by R. B. Woodward. [365-367] It counts as one of his most notable contributions to modern synthetic chemistry and formed the basis of industrial processes for the synthesis of this drug. In 1989, Gilbert Stork published a stereospecific total synthesis. [368]... 

Brown RT, Pratt SB (1980) Stereoselective synthesis of yohimbine alkaloids from secologanin. J Chem Soc Chem Commun 165-167... 

This chapter will address developments in yohimbine synthesis of the past 10-12 years. A number of reviews have already been published in this area (3-15). Additionally, the spectroscopic properties of these alkaloids have also been investigated (16-18) although a discussion is beyond the scope of this chapter. Unlike other reviews in this field, this report will focus exclusively on the approaches designed to tackle the synthetic challenges presented by the yohimbine alkaloids and will be organized by the methodologies actually used rather than by the specific natural product targets. 

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