Total synthesis rhazinilam

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>. 

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.

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. 

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)...

A base-induced cyclization involving the substituted nitrobenzene 423 and the imine 424 gave the fused pyrrole 425, a crucial intermediate in a total synthesis of ( )-rhazinilam (Equation 119) <2001T8647>. 

The total synthesis of the trip3rrole alkaloid, butylcycloheptylprodiogiosin 84, confirmed a structural assignment that had come under question <05AG(E)2777>. An enantioselective synthesis of the tricyclic m3Tmicarin alkaloids was reported <05OL4423>. As mentioned previously, a total synthesis of ( )-rhazinilam 76 was communicated <050L5207>. 

Gaunt and co-workers have also completed the first total synthesis of rhazinicine, a related natural product to rhazinilam, achieved in 11 steps from commercial materials using a short synthetic strategy that demonstrates how iterative... 

In addition, the same group postulated the formation of the mixture of bases in acid to involve transannular nucleophilic attack of N-4 on the protonated amide with subsequent dehydration and cleavage of the C-20-C-21 bond. The resulting cation 174 has several possible fates, depending on four alternative proton losses and stabilization of the carbonium ion by addition of water (see Scheme 4). The structure of rhazinilam was also confirmed by total synthesis, and this will be described in Section IV, A,27 of this chapter. 

The structure elucidation of rhazinilam (172) by spectral and chemical means (81) and by X-ray crystallography (82) was discussed in Section II,F,3. In addition, a partial synthesis from (+)-l,2-dehydroasidosper-midine (171) was described (84). Smith and co-workers have also described an elegant total synthesis of rhazinilam (172) (84). 

Rhazinilam (110) has been the subject of a total synthesis which is as different in conception in the indole alkaloid synthetic area as the alkaloid s structure is amongst its peers. (—)-Rhazinilam has been obtained, by a route... 

The total synthesis (Scheme 25) of ( )-rhazinilam was achieved by viewing the alkaloid as a derivative of a 3-phenylpyrrole. Thus 2-methoxycarbonyl-4-(2-nitrophenyl)pyrrole was first synthesized and then the aliphatic portion of the molecule introduced by alkylation at the pyrrole nitrogen [ —>(111)] and the carbon skeleton completed by intramolecular Friedel-Crafts alkylation [— (112)] at the only available pyrrole a-position. 

Regjoselective C—H alkenylation of N-methyl-4-aryl-lH-pyrrole carboxylates (88) with alkenes—primarily acrylamides, acrylates and acrylonitrile—was observed by Lin, Yao, and coworkers to be dependent on the solvent used in the coupling (2014OL4884). As such, C-2 selectivity (89) was achieved when toluene was used as the solvent while inclusion of DMSO favored the C-5 product (87). The authors postulated that the carboxylate-assisted chelation of the palladium catalyst, which occurs readily in toluene, is overridden in the strongly coordinating solvent DMSO and results in an electrophibc C—H activation at the more electron-rich C-5 position. An apphcation of this work to the total synthesis of (it)-rhazinilam was also described in this account. 

One representative application of indole/pyrrole C-H arylation is the total synthesis of rhazinilam developed by Trauner (Scheme 17.15) [68a]. Treatment of 60 with conditions similar to those reported by Fagnou resulted in the formation of coupling product 61 in 47% yield. After several steps, the synthesis of rhazinilam was achieved. Trauner [68b] also synthesized rhazinal, a congener of rhazinilam, by this intramolecular C-H arylation method. 

Scheme 17.15 Total synthesis of rhazinilam via intramolecular C-H/C-X coupling.

Pyrroles are electron-rich heteroaromatic systems which easily undergo electrophilic substitution at the 2-position. Nelson, Liu, and coworkers utilized allenes of type 72 bearing pyrrole skeleton as intramolecular electrophiles, PPhjAuOTf as catalyst, and successfully constructed a six-membered hetero-cychc ring in the product 73 with a highly diastereoselectivity (dr = 97 3), which was a key intermediate in an enantioselective total synthesis of (—)-rhazinilam 74 (Scheme 12.33) [38]. 

Gu Z, Zakarian A. Total synthesis of rhazinilam axial to point chirality transfer in an enantiospecific Pd-catalyzed transannular cyclization. Org. Lett. 2010 12 4224-4227. 

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