Monomorine alkaloids

Kibayashi and coworkers have used enantiometrically pure allylic silyl ethers obtained from amino acids in cycloaddition with nitrones (Eq. 8.49).71 Cyclic nitrone reacts with a chiral allyl ether to give selectively the exo and erythro isomer (de 90%). Optically active alkaloids containing a piperidine ring such as (+)-monomorine,71c (+)-coniine,71a and (-)-oncinotine71b have been prepared from the addition product. 

The first asymmetric synthesis of (-)-monomorine I, an enantiomer of the natural alkaloid, by Husson and co-workers starts with the chiral 2-cyano-6-oxazolopiperidine synthon (385) prepared from (-)-phenylglycinol (384), glu-taraldehyde (383), and KCN (443). Alkylation of 385 with an iodo ketal led to the formation of a single product (386). The cyano acetal (386) was treated with silver tetrafluoroborate and then zinc borohydride to afford a 3 2 mixture of C-6 epimeric oxazolidine (387) having the (2S) configuration. Reaction of 387 with... 

Trifluorinated analogues of monomorin, an indolizidin-type alkaloid that is an ant pheromone,and of vincamine derivatives have been described (Figure 4.54). ... 

Perhydropyridol[2,l-h][l,3]oxazines are used in the synthesis of in-dolizidines (gephyrotoxins and monomorine-I) [88H(27)1575 91SL44, 91SL878] and histrionicotoxin (91SL44) alkaloids. 

Perhydropyrido[l,2-fr][l,2]oxazine 10 was applied in the total synthesis of (-)-monomorine I, an indolizidine alkaloid, to control the stereoselectivity (09S655). 

The reductive Raney nickel desulfurisation of thioamides is used routinely in the alkaloid series. It proved efficient for the synthesis of Vinca alkaloid related compounds [21], a vinblastine precursor [127], 19-hydroxytubo-taiwine [170], and (-)-monomorine [171]. 

Disubstituted indolizidines, unlike many classes of amphibian alkaloids, are not unique to amphibians. 3,5-Disubstituted indolizidines such as monomorine I [(5Z,9Z)-195B] occur in ants of the genera Monomorium and Solenopsis (125,129,134). Some of the ant indolizidines are as follows (5Z,9Z)-3-n-butyl-5-methylindolizidine (monomorine I), (5Z,9Z)-3- -ethyl-5-methylindolizidine, (5Z,9Z)-3-hexyl-5-methylindolizidine, and (5 ,9Z)-3-butyl-5-(4-pentenyl)indolizidine. A series of 5-substituted indolizidines, the piclavines, were reported recently from a marine tunicate (Clavelina picta) (135). 

On the other hand, when a methyl substituent is present at C-4, i.e., 5b, low asymmetric induction is observed and only a 64 36 diastereomeric mixture of the bicyclic cis- and trans-dihydro-1,2-oxazine lactams 6 is recovered. The relative stereochemistry of the c/s-product is assigned by NOE measurements in the spectra of the compound obtained by hydrogenation. The major adduct constitutes the key intermediate in the synthesis of the alkaloid (+)-monomorine. 

These have been much less popular, but some examples have been reported. These involve only alkenyltins containing one additional moiety on the G-carbon this substituent can be trimethylsilylmethyl (leading to functionalized allylsilanes [37] or divinyl ketones (Scheme 4-10) [38]) or trifluoromethyl [39]. The substituent can also be in the /3-position (E-geometry) examples have been reported by Parrain et al. [40] and Castano et al., the latter having used the coupling reaction of a jS-stannyl enone as the key step in the preparation of the indolizidine alkaloid ( )-monomorine here the coupling step is followed by an immediate in-situ reduction of the intermediate enone, the mechanism of which is unclear (Scheme 4-11) [41J. 

The concise enantioselective total synthesis of (+)-monomorine I, a 3,5-dialkyl-substituted indolizidine alkaloid, was completed by S. Blechert et al. using a sequential cross-metathesis double reductive cyclization strategy. The enedione substrate was prepared in two steps. The Stetter reaction between the masked equivalent of acrolein and butyl vinyl ketone was followed by a retro Diels-Alder reaction under flash vacuum pyrolysis (FVP) conditions. 

All the currently known indolizidine and quinolizidine alkaloids isolated from ants are illustrated in Fig. 6. (+ )-Monomorine I (427), the well-studied trail pheromone constituent of the Pharaoh ant Monomorium pharaonis), and the analogs 428-431 were described in the earlier volumes in this series. These five compounds are 3,5-disubstituted indolizidines bearing short saturated or mono-unsaturated hydrocarbon chains. The relative stereochemistry in monomorine VI (430) still remains unknown, while that of 431 was atypical for the class at the time of its isolation 380). The structural resemblance of fiiis group of alkaloids to the... 

The synthesis of indolizidine 195B (450) has in general been the fortuitous result of indifferent diastereoselectivity in routes to its diastereomer monomorine I (427). The racemic alkaloid accompanied ( )-monomorine I, and sometimes other diastereomers, in several post-1985 syntheses (393,397,399,400,402,403). Enantioselective syntheses of 450 published during the period 1985-1993, most of them also producing 427, were discussed in Volume 44 of this treatise (2), while post-1993 enantioselective syntheses leading to mixtures of 427 and 450 were detailed in Section V.A of this chapter (404,410,413,415,419). A conference paper describing the synthesis of (+ )-450 and the C-5 epimer (+ )-595 was also highlighted in Volume 44 this work has subsequently been published with full experimental details (468). 

The Wacker-Tsuji oxidation has been applied in the synthesis of alkaloids as well. In an enantioselective total synthesis of (+)-monomorine 1, alkene 95 was oxidized to ketone 96, which was converted to (+)-monomorine I 97).6S> In addition, the synthesis of ABE tricyclic analogs of methyllycaconitine used a Wacker oxidation-aldol strategy to append the B ring to the AE fragment.7"... 

The indolizidine alkaloid (+ )-monomorine I (373), isolated from Pharaoh s ant Mono-morium pharaonis, is the first example of an indolizidine alkaloid found in the animal kingdom. One enantioselective total synthesis of 373 exploits an asymmetric cycloaddition of nitrone 370 to the chiral allylic ether 369, which is prepared from 349. The conversion of 349 to a tosylate followed by treatment with -propylmagnesium bromide in the presence of... 

Components of the venom of fire ants of the genus Solenopsis, e. g., 5. invicta which consists of a complex mixture of 2-methyl-6-alkylpiperidines. In contrast to the monomorines both the cis- and the /rons-isomers occur in nature. The latter have the (2/f,6/f)-configu-ration while the cis-alkaloids exist in the (2/J,6S)-con-figuration. 

Indolizine is the core structure of many of the naturally occurring alkaloids such as swainso-nine (a potent inhibitor of Golgi alpha-mannosidase II, an immunomodulator and a potential chemotherapy drug), monomorine (might be used to lure ants to their doom), gephyrotoxin (muscarinic antagonist), and lamellarins (HIV-1 integrase inhibition and antibiotic activity) [6]. 

Previous treatment of the indolizidine and quinohzidine alkaloid constituents of ant secretions may be found in Volume 55 of this series. An important review describing the defensive chemistry of ants, by Leclerq et al., deals with the occurrence, stmcture, function, and total synthesis of all the major groups of ant alkaloids, especially monomorine I vide infra. Section 6.1.2)... 

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