Solenopsin A and

As shown in Table I, this reaction sequence has wide generality and is readily applicable to the straightforward synthesis of various naturally occurring alkaloids such as coniine,9 pumiliotoxin C,11 1 and solenopsin A and B.11 Oxime sulfonates of either linear or cyclic structures may be used. Obviously, the regioselectivity of the reaction follows the general rule of... 

Treatment of a wide variety of oxime sulfonates with several equivalents of alkyl-aluminum reagents in CH2CI2 resulted in formation of the imines, which were directly reduced with excess DIBAH to give the corresponding amines, as shown in Sch. 19. This organoaluminum-promoted Beckmann Rearrangement of oxime sulfonates has been successfully applied to the stereoselective synthesis of naturally occurring alkaloids, pumiliotoxin C, and solenopsin A and B, as illustrated in Sch. 20 [43]. 

Cyclic imines will not be dealt with in this review as the conversion is often simply achieved. Mention will be made to the stereoselective reduction involved in the preparation of Solenopsin A and B (131), two naturally occurring piperidine alkaloids isolated from the venom of the fire ant. The desired trans isomer 131 was obtained with > 95% selectivity, using LAH (7 equiv) and trimethylaluminum (7 equiv) in THF. This selectivity could be reversed by using LAH (7 equiv) and NaOMe (14 equiv). °... 

A range of oxymethyl aryl silanes and germanes have been made and tested as muscarinic antagonists and antifungicides, while 3-silylated pyridines are precursors to 4-pyridones and the substituted piperidine (-)-solenopsin A, and bis(foimylphenyl)silanes are used in P-manocycle thesis. Benzylsilanes cross-couple with allylsilanes using vanadium(V) u>... 

Improved synthesis by this method has been achieved in order to obtain solenopsin A (Id) more stereoselectively 388). A cis and trans mixture of pyridine derivative 158, obtained from 156 by the Wittig reaction, was reduced by Raney nickel catalyst in the presence of PtOj to yield the m-piperidine (Ic). The Af-nitroso derivative 159, obtained from Ic by treatment with isoamyl nitrite, was treated with potassium rert-butoxide and then subjected to hydrogenolysis over Raney nickel to give a mixture of ( )-solenopsin A (Id, 1 part) and its isomer (Ic, 1 part) (Scheme 3). 

Some intramolecular aminations of olefins have been reported for solenopsin A (Id) and its isomer (Ic) (389-392). The dimer (200) of methyl vinyl ketone was converted to the ketone (202) by a standard procedure. Borohydride reduction of 202, followed by acid-catalyzed cyclization, yielded an exo/endo (60/40)... 

A synthesis of arecoline (17) from acetaldehyde has been described.17 Sederine (18) is a minor base occurring in Sedum acre-, its structure has been settled by spectral and chemical study, but its stereochemistry has yet to be established.18 A new total synthesis of racemic solenopsin A (19) (fire-ant venom) has been published the pathway is outlined in Scheme 2.19... 

Diketones and their aldol-derived cyclohexenones are obtained from alkylation of l-benzyl-2,6-di-cyanopiperidine followed by hydrolysis. - This dicyano analog of (47) provides a new method for the synthesis of rra/u-2-mediyl-6-ui ecylpiperidine (solenopsin), a-propylpiperidine (coniine) and other 2,6- alkylpiperidine alkaloid. 

C=NOH CHNHi, Oximes are reduced selectively to amines in the presence of carbon-carbon double bonds by NaBH4 and M0O3. NaBH4 and NiCl2 6H20 effect reduction of both groups in 90-95% yield. This reduction was used in the final steps in a synthesis of solenopsin A (1), a constituent of fire ant venom (equation I). 

Wasserman et al. utilized an intramolecular imine-epoxide ring opening/cyclization process <88TL4973> to synthesize heterotropanes and substituted piperidines (Scheme 20). This methodology has been applied to the total syntheses of piperidine-based alkaloids (+)-teneraic acid <89TL6077> and ( )-solenopsin-A <88TL4977>. 

A number of groups have reported syntheses of various ant toxins see, for example, Y. Moriyama et al., Tetrahedron Letters, 1977, 825 R.K. Hill and T. Yuri, Tetrahedron, 1977, 33, 1559). A total synthesis of solenopsin-A is illustrative (K. Fuji, K. Ichikawa and E. Fujita, Chem.pharm. Bull., 1979, 27, 3183) (Scheme 5). 

SL2528>. Aliphatic aldehydes react with the chiral vinylsilane 256 in an InCls-induced aza-silyl-Prins reaction to provide 1,6-trans tetrahydropyridines 257. Hydrogenolysis gave the natural products (-)-solenopsin A (R = -CnH23) and (+)-e/>i-dihydropinidine (R = -Pr), 258 (Scheme 77) <05SL2101>. 

Ant venoms from the genus Solenopsis have provided an array of 2,6-disubstituted piperidines, including 197-206. A review of the fungicidal, insecticidal and repellent activity of these alkaloids has appeared [476]. Both solenopsin A (198a) and isosolenopsin A (200) were potent inhibitors (Ki = 0.16 pM and 0.24 pM, respectively) of [ HJ-perhydrohistrionicotoxin binding to sites associated with the nicotinic receptor-gated ion channel in the Torpedo califomica electric organ [477]. 

Reaction of A -alkoxycarbonylpyridinium salts with Qrignard reagents has been used in synthesis of natural products Lupinine (92) (93JOC(58)7732), Solenopsin A (93) (94TL(35)829), and 2,3-dihydro-4-pyridones (94TL(35)3927>. 

Reding MT, Buchwald SL (2008) Short enantioselective total syntheses of the piperidine alkaloids (S)-coniine and (2/f,6/f)-tram -solenopsin A via catalytic asymmetric imine hydrosilylation. Chem Res Toxicol 21 2061-2064... 

Secondary Amines.—Two recent syntheses of solenopsin A (5) have exemplified a variety of approaches, new and improved, to the synthesis of secondary... 

Ruthenium catalyst 8 has been also coupled with CALB in the DYKAT of 1,5-diols 46 and 47 (Figure 14.14a), affording the enantiomerically pure diacetates in high yields, precursors of chiral 2,6-disubstituted piperidine and 3,5-disubstituted morpholine, respectively [51]. A similar procedure has been reported for the preparation of enantiopure antiangiogenic (+)-solenopsin A (Figure 14.14b) [48]. 

Application of the DYKAT of 1,5-diols. (a) Synthesis of 2,6-dis-ubstituted and 3,5-disubstituted six-membered chiral heterocycles. (b) Preparation of enantiopure (+)-solenopsin A. 

Leijondahl, K., Boren, L., Braun, R., and Backvall, J.-E. (2009). Enzyme- and ruthenium-catalyzed dynamic kinetic asymmetric transformation of 1,5-diols. Application to the synthesis of (+)-Solenopsin A. /. Org. Chem., 74,1988-1993. 

Some enantio- and diastereomerically enriched diacetates were used to prepare valuable enantiopure heterocycles (Scheme 57.20). Thus, diacetates 81b and 81g, obtained from 80b and 80g, respectively, were submitted to mild basic hydrolysis and subsequent mesylation. The reaction of the resulting dimesylate 82b,g with sodium tosylamide in N, A-dimethylformamide (DMF) gave access to the corresponding piperidine (5,5)-83b or morpholine (5,5)-83g with >99% ee and good overall yield (>42%). Similarly, enantiopure diacetate 81d, obtained from diol 80d, was used as the chiral pool to prepare (+)-solenopsin A. After seven... 

Buchwald reported an important advance in enantioselective C=N reductions with the chiral titanocene catalyst 186 (X,X = l,l -binaphth-2,2 -diolate) [137]. The reduction of cyclic imines with 186 and silanes afforded products with high selectivity however, reductions of acyclic imines were considerably less selective. It was suggested that this arose from the fact that, unlike cyclic imines, acyclic imines are found as mixtures of equilibrating cis and trans isomers. An important breakthrough was achieved with the observation that in situ activation of the difluoride catalyst 187 (X = F) gave a catalytically active titanium hydride species that promotes the hydrosilylation of both cyclic and acyclic amines with excellent enantiomeric excess [138]. Subsequent investigations revealed that the addition of a primary amine had a beneficial effect on the scope of the reaction [138, 139]. A demonstration of the utility of this method was reported by Buchwald in the enantioselective synthesis of the alkaloid frans-solenopsin A (190), a constituent of fire-ant venom (Scheme 11.29) [140]. 

A variety of alkaloids bind to or intercalate with DNA or DNA/RNA processing enzymes and affect either transcription or replication (quinine, harmane alkaloids, melinone, berberine), act at the level of DNA and RNA polymerases (vinblastine, coralyne, avicine), inhibit protein synthesis (sparteine, tubulosine, vincrastine, lupanine), attack electron chains (pseudane, capsaicin, solenopsine), disrupt biomembranes and transport processes (berbamine, ellipticine, tetrandrine), and inhibit ion channels and pumps (nitidine, caffeine, saxitoxin). In addition, these natural products attack a variety of other systems that can result in serious biochemical destabilization... 

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