Stemofoline alkaloids

H-NMR Chemical Shifts (5, ppm) and Coupling Constants (/, Hz) for the Stemofoline Alkaloid Group. 

Stemofoline is an insecticidal alkaloid produced in the leaves and stems of the plant Stemona japonica. It has a good spectrum of activity, with rapid action, and is a potent agonist of the nicotinic acetylcholine receptor in insects. These features make it a promising lead, except that its highly complex polycyclic structure is a real challenge for synthesis (Figure 3). 

Stemona alkaloids. Root extracts of the medicinal plants Stemona japonica and S. tuberosa (Stemona-ceae) have been used in Chinese and Japanese folk medicine as insecticides, anthelmintics, and as drugs for the treatment of tuberculosis, bronchitis and pertussis. Responsible for the activities is a group of more than 20 polycyclic alkaloids with diverse structures, e.g. protostemonine CjsHsiNOj, Mr 417.50, mp. 172-173 °C, [alD +148° (CH3OH) and stemofoline. 

Alkaloids of the roots of plants of the Stemonaceae have insecticidal activity. Several alkaloids have been isolated from the root extracts that have been used to eradicate zooparasites from man and agricultural animals. Among these are stemospironine (13), stemofoline (14), and stemonine (15) (Fig. 29.4) (Sakata et al., 1978). 

There are also several examples of imidate-derived azomethine yhdes reported in the Hterature. For example, the Gin group described a clever use of these 1,3-dipoles in an approach to the azatricychc core of some stemofoline members of the stemona alkaloid family. The formation of the azomethine ylide 164 occurred upon exposure of pyrroUdine 163 to triflic anhydride and tetrabutylammonium triphenyldifluorosihcate (TBAT Scheme 35) (2008T3629). Cycloaddition of the resulting dipole across the pendant vinyl sulfide fiomished 165 in 71% yield. Enol triflate 165 was then reduced to give the saturated side chain in 166 in 89% yield by the action of Pd/C under an H.2 atmosphere. The enolate derived from 166 was treated with ethyl iodoa-cetate in the presence of hexamethylphosphoramide (HMPA) followed by... 

The stemofoline group comprises some of the structurally more complex representatives of the Stemona alkaloids, and currently ten alkaloids have been described stemofoline (48) 17,22,53,54), oxystemofoline (49) (77), methoxystemofline (50) (77), 2 -hydroxystemofoline (51) 22,36), 16,17-didehydro-16( )-stemofoline (52) 22,54), also named as didehydrostemofoline, l, 2 -didehydrostemofoline or asparagamine A (5,55),... 

The absolute configuration of stemofoline (48) was established by X-ray analysis of its hydrobromide monohydrate (heavy-atom method) (5i), while the alkaloids oxystemofoline (49) and methoxystemofoline (50) had their relative configurations assigned after 2D-NMR studies (77). 

Stemofoline type Stemona alkaloids Occurrence and Properties. 

Comparison of the H-NMR data of stemofoline (48), oxystemofoline (49), and 2 -hydroxystemofoline (51) reveals only small differences in the chemical shifts, except for the hydrogens of the side chain attached to C3. The same observations hold for the C-NMR data of these alkaloids. The H-NMR spectra of 16,17-didehydro-16( )-stemofo-hne (52) and 16,17-didehydro-4(i ),16( )-stemofoline (53) basically differ only by the chemical shift of the methyl at CIO which appears slightly shielded (1.38 ppm) in 16,17-didehydro-16( )-stemofohne (52) as compared to the corresponding signal (1.46 ppm) in 16,17-didehydro-4( ),16( )-stemofoline (53). As photoisomerization of 16,17-didehydro-4( ),16( )-stemofohne (53) to 16,17-didehydro-16( )-stemofoline (52) was achieved under fluorescent light, the possibility that 16,17-didehydro-16( )-stemofoline (52) is an artifact derived from 16,17- dehydro-4(i ),16( )-stemofoline (53) cannot be ruled out at this point. Comparison of the H-NMR data of 16,17-didehydro-16( )-stemofohne (52) with those of stemofoline (48) reveals, besides the expected differences for the signals... 

The first alkaloid to be reported was stemocurtisine (58), isolated from the roots of 5. curtisii, the structure of which was established by X-ray crystallography. The piperidine ring adopts a chair-hke conformation, and it displays an ether bridge involving Cl and C9. The acetal-like nature of C9 is confirmed by the presence of a signal at 120.5 ppm in its C-NMR spectrum. The absolute configuration is not known, but it is assumed to be the same as the one in those alkaloids with the same C/D ring substructure [stemofoline (48)] (57). The same alkaloid was also isolated from the roots of Stemona sp. (56). 

Stemokerrin (59) was isolated from the roots of 5. kerri (HG 889) and its relative configuration was firmly established by X-ray crystallography, which revealed the pyrido[l,2-n]azepine substructure and the Z configuration of the double bond at C12-C13, which is also present in other Stemona alkaloids, such as protostemonine (19) and stemofoline (48) (56). The presence of a 1 -hydroxypropyl substituent (or its O-methyl derivative) attached to C4 is another distinct feature of this group of Stemona alkaloids [except for stemocurtisine (58)]. Comparison of the C-NMR data of stemocurtisine (58)... 

Overall, the first total synthesis of ( + /—)-didehydrostemofoline (52) was carried out in 27 steps from A -terc-butoxycarbonyl-l-hydroxymethyl-3-methoxy pyrrrole with less than 1 % yield featuring a Diels-Alder and an aza-Cope-Mannich reaction as the key transformations in the first preparation of a member of the stemofoline family of Stemona alkaloids possessing the Z configuration of the tetrahydrofuranylidene butenolide substituent. 

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