Structure alkaloids

In spite of the diverse nature of alkaloid structures, two structural units, i.e. fused pyrrolidine and piperidine rings in different oxidation states, appear as rather common denominators. We therefore chose to give several examples for four types of synthetic reactions which have frequently been used in alkaloid total synthesis and which provide generally useful routes to polycyclic compounds with five- or six-membered rings containing one nitrogen atom. These are ... 

Dibenz[h,e]azepine-6,11-diones ent-Morphinan nomenclature, 1, 29 Morphinan, 1,2,3,4-tetrahydro-nomenclature, 1, 29 14-a-Morphinan, N-methyl-synthesis, 1, 480 Morphinans nomenclature, 1, 29 as pharmaceuticals, 1, 148 synthesis, 2, 377 Morphine, 2, 512 as analgesic, 1, 167 as metabolite of normorphine, 1, 235 as pharmaceutical, 1, 146, 147, 148 synthesis, 1, 480 Morphine alkaloids structure, 4, 534 Morphin-7-en nomenclature, 1, 29 Morphinone, dihydro-as pharmaceutical, 1, 147 Morpholine — see also 1,4-Oxazine, tetrahydrocarcinogenicity, 1, 229 corrosion inhibitor, 1, 409 metabolism, 1, 226 nomenclature, 3, 996 structure, 2, 5 synthesis, 2, 89 Morpholine, 4-aciyloyl-polymers, 1, 291 Morpholine, alkenyl-polymers, 1, 291... 

Sencor — see l,2,4-Triazin-5-one, 4-amino-6-t-butyl-3-methylthio-Senecio alkaloids structure, 7, 658 Senepoxide, 7, 192 Senkirkine conformation, 7, 703 structure, 7, 658 Sensitizing dyes... 

There are a number of other synthetic substances analogous with or approximating to the cinchona alkaloid structure which it is more convenient to deal with in discussing the correlation of chemical structure with pharmacological action in this group (p. 469). 

Chondrodendron polyanthum, 371 Chondrodendron tomentosum, 363, 371, 373, 377, 391 alkaloids, 376 Chondrodine, 363, 364 Chondrofoline, 364, 365 Chrycentrine, 172, 313 Chiysanthemine, 773 Chrysanthemum cineraricefoHum, 773 Chuchuara, 781 Chuehuhuasha, 781 Cicuta virosa, 13 Cinchamidine, 419, 429 Cinchene, 439 Cinchenine, 438, 439, 440 apoCinchenine, 440, 441 Cincholoipon, 438 Cincholoiponic acid, 438, 443 Cinchomeronic acid, 183 Cinchona alkaloid structure, synthesis, 457 Cinchona alkaloids, bactericidal action of some derivatives, 478 centres of asymmetry, 445 constitution, 435 formulae and characters of transformation products, 449, 451 general formula, 443 hydroxydihydro-bases, 448, 452-4 melting-points and specific rotations, 446... 

The oxidation of amines by mercuric acetate is an old reaction (54) which up until recent years was employed primarily to modify alkaloid structures (55). A systemic study of the oxidizing action of mercuric acetate by Leonard and co-workers led to the development of a general method for the synthesis of enamines from cyclic tertiary amines. An observation made after a large number of compounds were oxidized, but which is worth noting at the onset, is that a tertiary hydrogen alpha to the nitrogen atom is removed preferentially to a secondary a-hydrogen. 

The molecular modelling approach, taking into account the pyruvate—cinchona alkaloid interaction and the steric constraints imposed by the adsorption on the platinum surface, leads to a reasonable explanation for the enantio-differentiation of this system. Although the prediction of the complex formed between the methyl pyruvate and the cinchona modifiers have been made for an ideal case (solvent effects and a quantum description of the interaction with the platinum surface atoms were not considered), this approach proved to be very helpful in the search of new modifiers. The search strategy, which included a systematic reduction of the cinchona alkaloid structure to the essential functional parts and validation of the steric constraints imposed to the interaction complex between modifier and methyl pyruvate by means of molecular modelling, indicated that simple chiral aminoalcohols should be promising substitutes for cinchona alkaloid modifiers. Using the Sharpless symmetric dihydroxylation as a key step, a series of enantiomerically pure 2-hydroxy-2-aryl-ethylamines... 

Under somewhat modified conditions (H2S04 on silica), this reaction has been successfully applied to a complex alkaloid structure.119... 

The H-NMR technique has proved to be a valuable tool for structural determinations of tropane alkaloids and their synthetic analogs, and H-NMR data are now available for most of the basic tropane alkaloid structures (42,59,142-146). Recent high-frequency H-NMR data of some basic tropane alkaloids are summarized in Table IV. 

G. E. Martin, M. Solntseva and A. J. Williams, Applications of 15N NMR spectroscopy in alkaloid chemistry, in Modern Alkaloids Structure, Isolation, Synthesis and Biology, E. Fattorusso and O. Taglialatela-Scafati (eds.), Wiley, New York, 2008, pp. 409-476. 

Since the last major review of the biosynthesis of the monoterpenoid indole alkaloids (97), there have been several full and partial 98-104) reviews of various aspects of the work that has been conducted since 1974. Two major developments have dominated the field in this period, namely, the demonstrations that (i) strictosidine (33) is the universal precursor of the monoterpenoid indole alkaloids and (ii) selected cell-free systems of C. roseus have the ability to produce the full range of alkaloid structure types, including the bisindoles. This section traces some aspects of these developments, paying particular attention to work been carried out with C. roseus, and omitting work, important though it may be, on other monoterpenoid indole alkaloid-producing plants, e.g., Rauwolfia, Campto-theca, and Cinchona. 

Intrigued by the hypothesis of a dehydrosecodine (120) as a key bioge-netic intermediate in the natural generation of alkaloid structures of both the Aspidosperma (tabersonine, 121) and the Iboga (catharanthine, 21) types (Scheme 33) 108, 109) we developed efficient biomimetic synthe-... 

In the course of our synthetic efforts, we discovered a new, unnatural conformational isomer of the VBL piperidine ring (see Chapter 2, this volume, for details). This compound is inactive with the microtubule system in vitro and is poorly cytotoxic to cultured tumor cells (Fig. 5b). Therefore, the functional determinism of the C-20 position of VBL-like molecules mediates reactions, as yet unknown, that are dependent on the binary alkaloid structure and on the natural stereochemical configuration at C-16 and C-14 as well as on the conformation of the cleavamine moiety. 

Laterally lithiated tertiary amides are more prone to self-condensation than the anions of secondary amides, so they are best lithiated at low temperature (—78 °C). N,N-Dimethyl, diethyl (495) and diisopropyl amides have all been laterally lithiated with aUcyllithiums or LDA, but, as discussed in Section I.B.l.a, these functional groups are resistant to manipulation other than by intramolecular attack" . Clark has used the addition of a laterally lithiated tertiary amide 496 to an imine to generate an amino-amide 497 product whose cyclization to lactams such as 498 is a useful (if rather low-yielding) way of building up isoquinoline portions of alkaloid structures (Scheme 194) ". The addition of laterally lithiated amines to imines needs careful control as it may be reversible at higher temperatures. ... 

This is the latest volume in the series "The Alkaloids Chemistry and Biology and covers a group of alkaloids comprising the carbazole nucleus. Single-topic volumes in this series have been rare, and the last one discussed antitumor alkaloids and was published as Volume 25 in 1985. This is the first volume dedicated to a single alkaloid structure type since Volume 8, which dealt with the monoterpene indole alkaloids over 40 years ago. 

N. Asano, Naturally occurring iminosugars and related alkaloids Structure, activity and applications, in P. Compain and O. R. Martin, (Eds.), Iminosugars From Synthesis to Therapeutic Applications, Wiley, Chichester, 2007, pp. 7-24. 

Medical applications of alkaloids have led to the production of drugs and drug components. They can be based on pure natural alkaloids, as in the case of extracts. Purified alkaloids, partially and even totally synthesized compounds based on the natural alkaloid structure, are also used. Chemically modified alkaloids are yet another example. Chemically modifying the structure affects biological activity. The general trend in modern medicine is to develop compounds that are biologically more active than those found in nature. This is achieved in many cases by alkaloid modifications and synthesis. However, natural compounds themselves are very important because they are the basis for artificial drugs. Moreover, alkaloids used as natural products are important... 

Molinski, T. F. 1993. Marine pyridoacridines alkaloids Structure, synthesis, an biological chemistry. Chemical Reviews, 93 1825-1838. 

Dioxo-3-isoparteine was isolated from Lupinus sericeus (143). The mass spectrum, with M+ at miz 262 and signals at miz 234 (M" — 28) and 206 (M+ - 56), is characteristic for 10- and 17-oxosparteines and successive splitting of two carbonyl groups. Oxidation of p-isosparteine (14) by potassium ferricyanide resulted in 10-oxosparteine (108) as well as 10,17-dioxo-p-isospar-teine (109) (Scheme 13). This confirmed the alkaloid structure. Although 109 was found as a natural compound it had already been synthesized by Bohlmann et al. (144). The problems of configuration and conformation of sparteine (6), a-isosparteine (7), and (3-isosparteine (14) were discussed (145). 

Figure 3.9. Some of the many better known alkaloid structures. From Kutchan TM. (1995). Alkaloid biosynthesis—the basis for metabolic engineering of medicinal plants. Plant Cell, 7, 1059-70.

Mercuric acetate has been used for the oxidation of amine groups to give modified alkaloid structures [105-120]. 

Thus far, in the alkaloid series discussed, the nitrogen atom has always been part of the core of the alkaloid structure, rather than acting in a dipolarophilic manner in the cycloaddition of the carbonyl ylide. Recently, Padwa et al. (117) addressed this deficiency by conducting model studies to synthesize the core of ribasine, an alkaloid containing the indanobenzazepine skeleton with a bridging ether moiety (Scheme 4.57). Padwa found that indeed it was possible to use a C = N it-bond as the dipolarophile. In the first generation, a substituted benzylidene imine (219) was added after formation of the putative carbonyl ylide from diazoketone 218. The result was formation of both the endo and exo adduct with the endo adduct favored in an 8 1 ratio. This indicates that the endo transition state was slightly favored as dictated by symmetry controlled HOMO—LUMO interactions. 

Determination of Alkaloid Structures I, Isolation, Characterization and Physical Methods A. W. Sangster, J. Chem. Educ., 1960, 37, 454-459. 

---