Naturally occuring alkaloids

Carbonylation of halides in the presence of primary and secondary amines at I atm affords amides[351j. The intramolecular carbonylation of an aryl bromide which has amino group affords a lactam and has been used for the synthesis of the isoquinoline alkaloid 498(352], The naturally occurring seven-membered lactam 499 (tomaymycin, neothramycin) is prepared by this method(353]. The a-methylene-d-lactam 500 is formed by the intramolecular carbonylation of 2-bromo-3-alkylamino-l-propene(354]. 

Several of the naturally occurring indoles also have clinical importance. The dimeric vinca alkaloid vincristine and closely related compounds were among the first of the anti-mitotic class of chemotherapeutic agents for cancer[14]. The mitomycins[15] and derivatives of ellipticine[16] are other examples of compounds having anti-tumour activity. Reserpine, while not now a major drug, was one of the first compounds to show beneficial effects in treatment of mental disorders[17]... 

The actions of the naturally occurring materials now known as alkaloids were probably utilized by the early Egyptians and/or Sumarians (1). However, the beginnings of recorded, reproducible isolation from plants of substances with certain composition first took place in the early nineteenth century. Then in close succession, narcotine [128-62-1] (1, now called noscopine, C22H23NOy) (2) and morphine (2, R = H) (3) (both from the opium poppy, Papaver somnijerum E.) were obtained. 

The Opiates. The International Narcotics Control Board—Vienna, tracks the tick production of narcotic dmgs and annually estimates world requkements for the United Nations. Thek most recent pubHcation (100) points out that more than 95% of the opium for Hcit medical and scientific purposes is produced by India and, in a declining trend, only about 600 t was utilized in 1988. This trend appears to be due to the fact that the United States, the largest user of opium for alkaloid extraction, reduced the amount of opium being imported from about 440 t in 1986 to 249 t in 1987 and 224 t in 1988. The United States used about 48 t of morphine (2, R = H) in 1988, most (about 90%) being converted to codeine (2, R = CH3) and the remainder being used for oral adrninistration to the terminally ill (about 2 t) and for conversion to other materials of minor commercial import which, while clearly alkaloid-derived, are not naturally occurring. 

Miscellaneous Pharmaceutical Processes. Solvent extraction is used for the preparation of many products that ate either isolated from naturally occurring materials or purified during synthesis. Among these are sulfa dmgs, methaqualone [72-44-6] phenobarbital [50-06-6] antihistamines, cortisone [53-06-5] estrogens and other hormones (qv), and reserpine [50-55-5] and alkaloids (qv). Common solvents for these appHcations are chloroform, isoamyl alcohol, diethyl ether, and methylene chloride. Distribution coefficient data for dmg species are important for the design of solvent extraction procedures. These can be determined with a laboratory continuous extraction system (AKUEVE) (244). 

Opioids. Morphine [57-27-2] C yH NO, (8) the most prevalent and analgesicaHy potent of the naturally occurring opium alkaloids (qv), has been used as an anesthetic premedication for over one hundred years (93). It has also been used as an iv analgesic for the last four decades, and, since 1969, in high doses as an anesthetic agent (117). 

For many years oral xanthines, shown in Table 2, were the preferred first-line treatment for asthma in the United States, and if the aerosol and oral formulations of P2" go sts are considered separately, as they are in Table 1, this was still the case in 1989. Within this class of compounds theophylline (8), or one of its various salt forms, such as aminophylline [317-34-0] (theophylline ethylenediamine 2 l), have been the predominant agents. Theophylline, 1,3-dimethylxanthine [58-55-9], is but one member of a class of naturally occurring alkaloids. Two more common alkaloids are theobromine (9), isomeric with theophylline and the principal alkaloid in cacao beans, and caffeine, (10), 1,3,7-Trimethylxanthine [58-08-2], found in coffee and tea. 

Aledicine. A wide variety of alkaloids (qv) contain the quinoline ring system this fact accounts, in large measure, for the extensive synthetic research reported (107). In addition to the naturally occurring compounds, a large number of synthetic quinolines, eg, (22) and (23), have been prepared and studied for use in medicine. Table 3 presents selected examples. 

As exemplified in the present procedure, the reaction has been optimized and extended in scope it affords functionalized benzocyclobutenes as well as substituted isoquinolines in high yields. Benzocyclobutenes have been used as intermediates in the synthesis of many naturally occurring alkaloids, - steroids,polycyclic terpenoids,and anthracycline antibiotics. The traditional routes leading to the preparation of benzocyclobutenes have been... 

For the purposes of this book, an alkaloid is regarded as a relatively complex, organic base, occurring naturally in a plant and usually possessing marked pharmacological activity. This excludes simple, naturally Occurring bases and the biological amines, which are adequately dealt with... 

Hantzsch 2 gave the name pseudo bases to those carbinols that gave salts with acids by the elimination of water and a simultaneous change of constitution. Such carbinols are common among the nitrogen heterocyclic compounds and the naturally occurring alkaloids e.g., berberine, sanguinarine, chelerythrine. 

The high enantioselectivity of the exo product opens up a new and readily accessible route to an enantioselective synthesis of interesting isoquinoline alkaloids (Scheme 6.15) [35]. The tricyclic isoxazolidine exo-15b was obtained from the 1,3-dipolar cydoaddition reaction as the pure exo isomer and with 58% ee [34]. As shown in Scheme 6.15 the exo product from the 1,3-dipolar cydoaddition was converted into 17 in two steps without racemization at the chiral center. In addition to the illustrated synthesis, the 6,7-dimethoxy-derived isoxazolidine exo-15b is a very useful precursor for the synthesis of naturally occurring isoquinoline alkaloids [36-40]. 

Many alkaloids have pronounced biological properties, and a substantial number of the pharmaceutical agents used today are derived from naturally occurring amines. As a few examples, morphine, an analgesic agent, is obtained from the opium poppy Papaver somnifemm. Cocaine, both an anesthetic and a central nervous system stimulant, is obtained front the coca bush Erythroxylon coca, endemic to upland rain forest areas of Colombia, Ecuador, Peru, Bolivia, and western Brazil. Reserpine, a tranquilizer and antihypertensive, comes from powdered roots of the semitropical plant Rauwolfia serpentina. Ephedrine, a bronchodilator and decongestant, is obtained front the Chinese plant Ephedra sinica. 

Alkaloid (Chapter 2 Focus On) A naturally occurring organic base, such as morphine. 

Intramolecular Mannich reactions of iminium 1 and acyliminium ions (see Section D.1.4.5.) with electron-rich double bonds are important reactions in the synthesis of naturally occurring alkaloids. In general, the iminium ions are not isolated but produced as intermediates. 

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