Rhazinilam synthesis

An enantiospecific, gold-catalyzed pyrrole annelation reaction was utilized in a total synthesis of rhazinilam 95 <06JACS10352>. Specifically, treatment of allene 81 with gold triflate - triphenylphosphine led to the formation of annelated pyrrole 82, which was subsequently converted into 95. A gold-catalyzed direct coupling of pyrroles with 1,3-dicarbonyls led to the formation (3-(pyrrol-2-yl)enones <06ASC331>. 

Intramolecular C-H functionalizations were employed for the synthesis of a precursor to (—)-rhazinilam, an antitumor agent. Using a chiral auxiliary good ee s were achieved (Equation (202)).164... 

A stoichiometric dehydrogenation reaction has been utilized for the synthesis of the natural product Rhazinilam in which the key step was a platinum-mediated C-H activation, followed by P-elimination (213,214). This step is shown in Scheme 50. 

C-H activation remains an important topic for catalysis even after thirty years of intensive research. The potential shortcuts it offers for many present routes to a wide variety of chemicals that are produced will continue to inspire industrial and academic research [32], An interesting example involves the enantiospecific, coordination-directed C-H bond functionalisation in the synthesis of a natural product, rhazinilam, an anti-tumor agent. The resulting vinyl moiety obtained in the dehydrogenation was subsequently carbonylated to form a cyclic amide [33],... 

Based on this precedent, Nelson et al. used an intramolecular reaction in the total synthesis of (-)-rhazinilam. In this context, trisubstituted allenes are excellent precursors for a diastereoselective heterocyclic annulation that highlights the usefulness of this reaction in target-oriented synthesis [49]. In this case, the aforementioned catalyst that yielded the best results was [AuPPh3OTf], affording a higher yield and diastereoselectivity than Pd(II). 

Such an example has been demonstrated by Johnson and Sames, who chose a platinum-mediated dehydrogenation as a key step in the synthesis of the antimitotic rhazinilam 33 (Scheme 6) [20], The key intermediate 27 was converted into the imine 28, which was allowed to react with Me Pt(//-SMe2)]2 to afford the platinum complex 29. Subsequent treatment with triflic acid resulted in elimination of methane and furnished the cationic complex 30. Upon thermolysis in trifluoroethanol, the complex lost a second methane molecule, which resulted in the activation of the ethyl group. A subsequent /1-hydride elimination gave the hydrido-Pt(n) complex 31. Treatment with aqueous KCN followed by hydrox-ylamine removed the platinum and yielded the liberated amine 32. Johnson and Sames added a homologization and a macrolactamization and completed the total synthesis of rhazinilam (33) by removal of the carboxyl group. 

Scheme 6. Pt-mediated dehydrogenation in the total synthesis of rhazinilam.

The Aspidosperma family of indole alkaloids has inspired many synthetic strategies for the construction of their pentacyclic framework of the parent compound aspidospermidine (366), since the initial clinical success of two derivatives, vinblastine (10) and vincristine, as anticancer agents. The alkaloids such as (-)-rhazinal (369) and (-)-rhazinilam (6) have been identified as novel leads for the development of new generation anticancer agents [10,11]. Bis-lactams (-)-leucunolam (370) and (-t-)-epi-leucunolam (371) have bio-genetic and structural relationships with these compounds [236]. Recently, enantioselective or racemic total syntheses of some of the these natural product were achieved. One successful synthesis was the preparation of the tricyclic ketone 365, an advanced intermediate in the synthesis of aspidospermidine (366), from pyrrole (1) (Scheme 76) [14]. The key step is the construction of the indolizidine 360, which represents the first example of the equivalent intramolecular Michael addition process [14,237,238]. The DIBAL-H mediated reduction product was subject to mesylation under the Crossland-... 

The synthesis of the enantiomerically enriched (74% ee) tetrahydroin-dolizine 368 is the most crucial step for synthesis of (-)-rhazinal (369), (-)-rhazinilam (6), (-)-leucunolam (370) and (+)-epz-leucunolam (371) alkaloids [239]. The selective intramolecular conjugate additions of pyrrole to N-tethered Michael acceptors were achieved by using chiral organocatalyst 320c (Scheme 77). 

In the context of the total synthesis of ( )-rhazinilam, an intramolecular hydroarylation of an allene (Scheme 12.23) was investigated.41 The authors report that the Ag(I) complexes were completely ineffective, while AUCI3 delivered 27% of the product and a mixture of 5 mol% AuC13/20 mol% AgOTf gave 82%. The optimum was then reached with 5 mol% Ph3PAuOTf (92% yield). In all cases, the diastereoselectivity was better than 92 8. 

This review, after covering general aspects concerning the structure, occurrence and biological activity in the allocolchicinoid, stegane and rhazinilam series, will focus on recent work related to the semi-synthesis and total synthesis of these molecules together with structure-activity relationships. 

The tubulin-binding properties of (-)-rhazinilam were discovered through screening of a number of Malaysian plant extracts [60]. Natural (-)-rhazinilam induces tubulin spiralization, inhibiting tubulin assembly in the same way as vinblastine-like alkaloids, and protects microtubules from cold disassembly such as with paclitaxel [67]. This effect has never been observed with other microtubule poisons. For this reason, and despite the in vivo inactivity of (-)-rhazinilam [67], a number of analogues have been prepared by semi-synthesis and total synthesis (see Sections 3.1.3. and 3.2.3.) in order to improve the pharmacological properties of this molecule. 

Fig. (8). Biomimetic semi-synthesis of rhazinilam [88,89] (mCPBA = m-chloroperbenzoic acid)...

Finally, one has to mention the work of Levy and co-workers who described the semi-synthesis of D-ring seco-rhazinilam analogues from (-)-tabersonine using an Emde degradation and /nCPBA oxidation [90]. The. veco-analogue 50 is only twice less active than rhazinilam on the inhibition of microtubules disassembly, illustrating that the absence of the D-ring is not strictly deleterious to the antitubulin activity [91,92]. 

In the three different approaches envisaged for the total syntheses of rhazinilam, the construction of the pyrrole ring was operated in two different manners a Knorr-type reaction in the Smith synthesis and a 1,5-electrocyclization of an allyl-iminium compound in the Sames and Magnus syntheses. 

Soon after the structure elucidation of rhazinilam, Smith and coworkers published its semi-synthesis and racemic total synthesis in the same report [62]. The total synthesis, Fig. (30), started with a Knorr-type... 

After separation of the desired major diastereoisomer 154, the removal of the chiral auxiliary furnished vinyl compound 151 in enantiomerically pure form. The latter was directly converted to the 9-membered lactam 144 in 58% yield via a palladium-catalyzed carbonylation (10 atm CO, HCOOH, DME, 150°C). Removal of the methyl ester as previously described furnished (-)-rhazinilam. This elegant work constitutes the first asymmetric total synthesis of the natural product. 

Fig. (32). Total synthesis of (-)-rhazinilam by Sames [152] (TfOH = triflic acid = trifluoromethanesulfonic acid)...

In 2001, Magnus and co-workers reported a straightforward synthesis of racemic rhazinilam by initial construction of the pyrrole ring from a piperidone, Fig. (33) [154]. The sequential alkylation of piperidone 155 with iodoethane and allyl bromide furnished piperidone 156, having the requisite C-20 substitution of rhazinilam. After formation of the thiophenyl iminoether 157, A-alkylation with allyl bromide 158 furnished the corresponding iminium intermediate which underwent 1,5-... 

Fig. (34). Synthesis of phenyl-pyrrole analogues of rhazinilam by Thai [92]...

Biphenyl-carbamate 164d, the most active analogue of rhazinilam to date, was taken as a lead and its synthesis was re-examined for the purpose of adaptation to the construction of a library of analogues, Fig. (36) [161]. 

Fig. (36). Synthesis of racemic biaryl-carbamate analogues of rhazinilam by Baudoin-Gueritte [161]...

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