Polycyclic Alkaloids

Primary and secondary amines also react with epoxides (or in situ produced episulfides )r aziridines)to /J-hydroxyamines (or /J-mercaptoamines or 1,2-diamines). The Michael type iddition of amines to activated C—C double bonds is also a useful synthetic reaction. Rnally unines react readily with. carbonyl compounds to form imines and enamines and with carbo-tylic acid chlorides or esters to give amides which can be reduced to amines with LiAlH (p. Ilf.). All these reactions are often applied in synthesis to produce polycyclic alkaloids with itrogen bridgeheads (J.W. Huffman, 1967) G. Stork, 1963 S.S. Klioze, 1975). 

Enamines in which the double-bond shift is sterically prevented afford only the ammonium salts. Their spectra in the C=C stretching vibration region does not differ greatly from that of the free amine spectrum (171). For example, neostrychnine (159) has vc c 1666 cm and its perchlorate at 1665 cm . Salts of quinuclideine (92) and the polycyclic alkaloid trimethylconkurchine have similar properties. 

The methodology based on the addition of nucleophiles at the a- and y -positions of A -alkylpyridinium salts to give substituted 1,2- and 1,4-dihydropyridines (often not isolated) as intermediates, respectively, which can be further elaborated into complex polycyclic alkaloids, was reviewed by Joan Bosch and M.-Lluiesa Bennasar in 1995 (95SL587). 

Entries 5 to 8 are synthetic applications in more complex molecules. Entries 5 and 6 illustrate the diphenylphosphoroyl azide method. Entry 7 was used in the late stages of the synthesis of an antitumor macrolide, zampanolide, to introduce the amino group. The ultimate target molecule in Entry 8 is himandrine, one of several polycyclic alkaloids isolated from an ancient plant species. 

Intramolecular bicyclization of tosylamide with alkynyliodonium salt (see Scheme 31), developed by Feldman and co-workers (95JA7544), is also applicable to the synthesis of A-tosylpiperidine derivatives related to polycyclic alkaloids (Eq. 40). Examples leading to seven-membered rings have also been reported. 

The central five-membered ring of Manzamine A (315), a member of a family of antileukimic and antibacterial marine polycyclic alkaloids, has been constructed using intramolecular azomethine ylide technology (88). Model studies on the construction of the central ABC rings, by condensation of the aldehyde 316 prepared by standard chemistry with sarcosine ethyl ester, furnished the desired ABC ring system as a single diastereoisomer in 45% yield (Scheme 3.105). 

Since the discovery of amphimedine by Schmitz and co-workers in 1983 [36], the polycyclic alkaloids based on the pyrido[, /]acridine skeleton have emerged as a well-defined class of marine metabolites, with significant biological activities, isolated from sponges and tunicates [37]. The less common group of sulfide pyridoacridines were only obtained from tunicates and they include the shermilamines, the varamines-lissoclins-diplamine group, and tintamine, another polycyclic alkaloid closely related to them. 

The tandem double intramolecular 4 + 3/3 + 2-cycloaddition of the nitroalkene (10) produced the nitroso acetal (11) in 77% yield. Further functional group manipulations allowed for the conversion to the partial core (12) of the complex polycyclic alkaloid daphnilactone B in high yield (Scheme 3).6 The tandem intramolecular 4 + 2/3 + 2-cycloaddition cascade of 1,3,4-oxadiazoles (13) to polycyclic adducts (14) was investigated by considering the tethered initiating dienophile, the tethered dipolarophile, the 1,3,4-oxadiazole C(2) and C(5) substituents, the tether lengths and sites, and the central heterocycle (Scheme 4).7... 

These intramolecular bicyclizations can provide an efficient entry into polycyclic alkaloid skeleta several specific examples of bicyclizations are shown in Scheme 68 [136]. Alkynyliodonium salts 181,183,185, and 187,key precursors in these reactions, are conveniently prepared from the appropriate alkynylstan-nanes and can be used without additional purification. 

Fused tetra- and pentacyclic aromatic alkaloids are a new, emerging group of compounds from marine organisms. Amphimedine (187) was isolated from a Pacific sponge (Amphimedon sp.) as a cytotoxic compound in 1983 and was the first example of a polycyclic alkaloid (158). A pigment from the sea anemone Calliactis parasitica, named calliactine, has been known for many years, but the structure elucidation of calliactine was a difficult problem (159). In 1987 the structure of calliactine was proposed to be 188 on the basis of modern spectroscopic methods as well as chemical... 

Addition takes place at the nitrogen atom, because of steric factors, in derivatives of dehydroquinuclidine and some polycyclic alkaloids such as trimethylconkurchine, neostrychnine, etc.37 A curious formation of a nortricyclene derivative from 2-A-hexamethyIeneimino-bicyclo[l,2,2]-2-heptene (39) on treatment with perchloric acid199 has been claimed. 

Synthesis of polycyclic alkaloids using an intramolecular double Michael reaction 93AG(E)1010. 

If nitroalkenes are employed as heterodienes in hetero Diels-Alder reactions instead of nitrosoalkenes, cyclic nitrones are formed. These cycloadducts undergo numerous subsequent reactions, and especially the combination of this hetero Diels-Alder reaction with a 1,3-dipolar cycloaddition is an extremely powerful tool for the synthesis of polycyclic alkaloids. This domino [4+ 2]/[3+ 2] cycloaddition chemistry has been comprehensively reviewed by Denmark and Thorarensen very recently, and this review also covers many hetero Diels-Alder reactions of nitroalkenes being not part of this sequential transformation [5]. Therefore the present article will focus on some selected examples which might highlight the advanced state of the art concerning stereocontrol of these reactions. On the other hand, an insight shall be given into the multitude of polycyclic structures accessible by means of nitroalkene cycloaddition chemistry. 

A key step in the synthesis of 12-epi-lycopodine reported by Wiesner and coworkers is the intramolecular [2 + 2] photocycloaddition of a vinylogous imide and an allene. Irradiation of photosubstrate 46 produced a single cyclobutane 47, in which the allene added to the vinylogous imide anti to the methyl group (Scheme 13)31. Photoadduct 47 was converted to ketal-alcohol 48 via a three-step sequence of ketalization, epoxida-tion and reduction. Hydrolysis of the ketal unmasked the /Miydroxy ketone functionality. Retro-aldol fragmentation followed by aldol closure gave hydroxyketone 49, which was readily converted to the polycyclic alkaloid 12-epi-lycopodine. 

This reasoning, actually nothing more than a mere ramification of the classic mechanistic description of AdN reactions, turned out to be truly productive in the elaboration of an efficient and general approach to the solution of many synthetic problems. One of the first examples of the successful utilization of a sequence of independent additions of Nu and E to Michael acceptors was described by Stork,who took advantage of this stepwise plan to achieve a short-route preparation of 97 (Scheme 2.31), the advanced intermediate in the synthesis of the polycyclic alkaloid lycopodine. 

The total synthesis of polycyclic alkaloid (-)-stemoamide was achieved in the laboratory of M. Mori via a ruthenium carbene catalyzed enyne metathesis. The cyclization was effected by 5 mol% of catalyst in benzene at 50 °C. After 11h of stirring under these conditions, 87% of the 5,7-fused bicyclic system was formed. 

Three polycyclic alkaloids that contain this ring system as part of their structures, plakinidines A 78, B 79, and C 80, were isolated from the marine sponge Plakortis sp. (see Section II,C,1 on pyrido[3,2-c]acridines). 

Saframycin belongs to a family of complex polycyclic alkaloids endowed with spectacular antiproliferative activity. The successful demonstration that analogues of the natural product are clinically effective for the treatment of solid tumors has stimulated intense efforts towards the total synthesis and medicinal chemistry of these alkaloids. Myers and Lanman adapted their solution phase synthesis of saframycin to a ten-step solid phase synthesis, leading to the preparation of 16 analogues [40]. The key steps are two Pictet-Spengler reactions, which are used... 

The bispidine backbone (bispidine= 3,7-diazabicyclo[3.3.1]nonane) I is a simplified derivative of the natural product sparteine, 2 (see Chart 1 shown is the structure of a-isosparteine). Sparteine, a polycyclic alkaloid, occurs in a wide range of plants and has a variety of medical and chemical applications. It has been investigated extensively, for example, as a cardiac antiarrhyfhmia (1, 2), an ion channel blocker (3,4), and an uterotonic dmg (5). It was also used as a chiral base... 

Since then, more polycyclic alkaloids whose rings lack methyl groups have been described. Retro-biogenetic analyses of the new related metabolites have been proposed in recent publications. These studies have outlined how the seemingly varied frameworks of such compounds are actually analogous. 

The structural unit of this subtype of polycyclic alkaloid is a 3-alkyl substituted pyridine, where remote terminal oxime, amine, methoxy amine, nitro, imine oxide or methoxy-oxime fuctionalities are characteristic in the monomeric forms. Polymeric pyridinium salts attached to a long linear carbonated chain through positions 1 and 3 are a substructural feature in a second subgroup of alkaloids. Related reduced dihydropyridinium salts have also been known since the discovery of haliclamine A and B. (See Tables 5 and 6 for C-NMR data). 

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