Aspidosperma

Synthesis The final stages are very similar to Review Problem 20 (frames 212-3). TM 249 is an intermediate in Stork s synthesis of Aspidosperma alkaloids. Stork s method was actually a variation on the one we have proposed ( J. Amer. Chem. Soc., 1963, 85, 2872) ... 

In the case of the aspidosperma structure, the 5-mcmbcrcd C-ring is constructed from the A -acyl substituent. For the kopsine skeleton, an allyl group is installed and used to form the C6-C20 bridge. 

Floriani has recently examined bark from Aspidosperma quebracho bianco Schlecht f. pendulas Speg, in which he found the known alkaloids, quebrachine (yohimbine) and aspidospermine, as well as Hesse s aspidosamine, C2gH2g02N2, and a new base, aspidospermicine, Ci Hj ON, l-SHjO (1938). Hartmann and Schlittler have shown that the alkaloid vallesine from Vallesia glabra (Apocynaceae) is aspidospermine, and this has been confirmed by Deulofeu et aJ. who have also found it in V. dichotoma. Later Schlittler and Rottenberg by chromatographic analysis of the mother liquors of aspidospermine isolated a second alkaloid for which they used the old name Vallesine (1948). ... 

Snyder has conducted similar chemistry but with the goal of generating carbon skeletons for the total synthesis of alkaloids. Using indole 84 as a dienophile, the canthine alkaloid skeleton 85 was produced. Access to aspidosperma alkaloids was obtained when 86 was transformed into 87. 

The intramolecular cycloaddition reaction of enamides has been exploited in alkaloid synthesis (81JOC3763). One successful application is provided by the total synthesis of the fused indolizidine 5 from 4 as a 1 1 mixture of epimers in 43% total yield 5 is a key intermediate in aspidosperma alkaloid synthesis (79JA3294). 

The ability of 1,2 (or l,6)-dihydropyridines to undergo a Diels-Alder reaction with dienophiles such as methyl vinyl ketone, methyl acrylate, and acrylonitrile has been utilized in the synthesis of polyfunctional isoquinuclidine as a key intermediate in the synthesis of aspidosperma- and iboga-type alkaloids (66JA3099). 

The yellow colored, sparcely soluble 5-ethyl-2-methyl-l l/f-pyrido[3,4-u] carbazolium 347 isolated from Aspidosperma gilbertii exists as a hydroxide after filtration of the corresponding iodide over basic aluminum oxide. A short synthesis was described (80CB3245). The Pyrido[3,4-a]carbazole ring system is present in the alkaloid AG-1, whereas Cryptolepine (348) possesses the indolo[3,2-b]quinoline moiety (65MI1). 

This methodology has been used in the synthesis of aspidosperma alkaloids220,221, the construction of an ABC ring precursor for steroids 222 and the preparation of an optically active phenanthronc in 93% ee 223. / -Substituted Michael acceptors such as methyl ( )-2-butenoate are generally unreactive with A-cycloalkylidene-l-phenylethanamines, however ( )-2-butenoyl cyanide is a useful alternative. This is shown in the synthesis of enantiomerically pure cis-dimethyl substituted bicyclic lactams224. 

Likewise, treatment of sulfoxide 1254 with Me3CSi(Me)20Tf 987/NEt3 induces rearrangement via 1255 to give 30% of the aspidosperma alkaloid 1256 and 25% starting material 1254 [51] (Scheme 8.20). 

Scheme 3.62. Domino radical hydrogen abstraction-cyclization procedure in the synthesis towards Aspidosperma alkaloids.

The sequence could even be prolonged by including a Pummerer reaction. Thus, treatment of 4-103 with trifluoroacetic acid (TFA) gave the furan 4-104, which underwent a cycloaddition to furnish 4-105 the erythryna skeleton 4-109 was obtained after subsequent addition of a Lewis acid such as BF3- Et20 (Scheme 4.23) [33]. It can be assumed that 4-106, 4-107 and 4-108 act as intermediates. In a more recent example, these authors also used the procedure for the synthesis of indole alkaloids of the Aspidosperma type [34]. 

We became particularly interested in strychnine when we noticed that the tetracycle 21 (Scheme 4.6), which might be readily available by an intramolecular Diels-Alder cycloaddition of a tryptamine-derived aminodiene, contains much of the complexity of this popular alkaloid target. In fact, this tetracycle is common to many indole monoterpene alkaloids including members of the Strychnos, Aspidosperma, and... 

For a Lewis-acid-mediated cyclization reaction of a tryptamine-derived vinylogous amide that affords the Aspidosperma skeleton, see Huizenga RH, Pandit UK (1991) Tetrahedron 47 4155 1164... 

In an alternative approach to annulation across the indole 2,3-tt system, Padwa and coworkers have reported approaches to the pentacyclic and hexacyclic frameworks of the aspidosperma and kopsifoline alkaloids respectively that involve as the key step a Rh(II)-promoted cyclization-cycloaddition cascade <06OL3275, 06OL5141>. As illustrated in their approach to ( )-aspidophytine 150, Rh2(OAc)4-catalyzed cyclization of a diazo ketoester 148 affords a carbonyl ylide dipole that undergoes [3+2]-cycloaddition across the indole 2,3-tt bond to generate 149 <06OL3275>. 

David Wilkins obtained his Ph.D. in 1986 working with Professor A. H. Jackson and Dr. P. V. R. Shannon at University College Cardiff, Wales, working on the synthesis of the Aspidosperma indole alkaloids. He then did two years of postdoctoral studies with Professor P. M. Cullis at the University of Leicester, UK, working on the mechanism of thiophosphoryl-transfer reactions. In 1989, he joined the medicinal chemistry department at what was then Boots Pharmaceuticals in Nottingham (UK) and which became part of BASF Pharma in 1995. In 2001, he joined Key Organics Ltd., where he is currently employed as a principal chemist in the Contract Synthesis Department. 

The study of Fuji et al. shows that the addition of lithium enolate 75 to ni-troamine 74 is readily reversible quenching conditions are thus essential for getting a good yield of product 76. An equilibrium mixture of the adducts exists in the reaction mixture, and the elimination of either the prolinol or lactone moiety can take place depending on the workup condition (Scheme 2-34). A feature of this asymmetric synthesis is the direct one pot formation of the enantiomer with a high ee value. One application of this reaction is the asymmetric synthesis of a key intermediate for indole type Aspidosperma and Hun-teria alkaloids.68 Fuji69 has reviewed the asymmetric creation of quaternary carbon atoms. 

An investigation of Aspidosperma marcgravianum (23) led to the isolation of 18,19-dihydroantirhine (14). The quaternary Ab-(3-methochloride derivative of 14 (compound 15) was previously found in Hunteria eburnea Pichon (22). 

Tetradehydro-18,19-dihydrocorynantheol (16) has been isolated from Aspidosperma marcgravianum (23). The structure of 16 has been determined on the basis of spectral data and by comparing the alkaloid with a semisynthetic... 

Alkaloids 3,4,5,6-tetradehydrositsirikine (44) and 10-methoxysitsirikine (45) have recently been isolated from Aspidosperma oblongum by Robert et al. (24) and characterized in full spectral detail. 

Though the isolation of isositsirikine and 16-epiisositsirikine from Aspidosperma oblongum (24) and also their IV-oxide derivatives from A. marcgravianum (23) has been reported, the stereochemical assignment of C-16 was, however, uncertain. 

The structural formula of aspexcine, isolated first from Aspidosperma excel-sum Benth. and identified as a 10-methoxyisositsirikine (4), had to be corrected. Recently, Verpoorte et al. (53) established that, instead of a corynane skeleton, aspexcine has a 10-methoxy, normal yohimbane structure. 

At the same time, 10-methoxyisositsirikine has been isolated from Aspidosperma oblungum by Robert et al. and proved to be different from aspexcine in reported spectral data (24). The isositsirikine structure was verified by H-NMR and MS spectra. However, on the basis of the assigned 16S configuration, it should be correctly named as 10-methoxy-16-epiisositsirikine. 

New normal yohimbine-type alkaloids, isolated or characterized, together with their primary sources, are listed in Table I. Note that aspexcine, isolated from Aspidosperma excelsum Benth., has earlier been characterized as a 10-methoxyisositsirikine. This alkaloid, however, proved to be identical with excel-sinine (81) (53) (see Section II.B. 14.). 

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