Rhazinilam synthesis rhazinal

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). 

Our own interest in the synthesis of the Amaryllidaceae alkaloids arose when we recognised that, in common with colchicine (1), (—)-rhazinilam (31) and (—)-rhazinal (32) are both spindle toxins although their mode of action is different in that, like TaxoF, they exert their biological effects by inhibiting the depolymerisation of microtubules. This prompted us to develop syntheses of these compounds and certain biogenetically related ones such as (+)-ep -leuconolam (33) and (—)-leuconolam (34) ([35, 36] for an excellent and very recent review on all of the reported S3mtheses of rhazinilam see [37]). 

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. 

Synthesis by Direct Cross-Coupling Reaction Trauner and co-workers and Bowie and Trauner reported on a concise total synthesis of racemic rhazinilam 122 and rhazinal 123, axially chiral phenylpyrroles having potent antimitotic properties, through an aromatic C—H activation (Scheme 23.24). " To construct the lactam ring of the title compounds, the authors proposed the use of a palladium-catalyzed direct intramolecular cross-coupling reaction. 

Recently, the group of Hanessian reported an extension of MacMillan s organocatalytic aromatic alkylation to 3-aminocrotonaldehyde in the concise synthesis of an advanced precursor of a drug prototype for the treatment of migraine headaches [83]. An example that does not involve indoles as aromatic nucleophiles but pyrroles in the synthesis of natural products was reported in 2006 by Banwell and coworkers [84]. They accompHshed, via the common intermediate 94 obtained by means of an intramolecular F-C type alkylation, the syntheses of the alkaloids (—)-rhazinal, (—[-rhazinilam, (—[-leuconolam, and (-l-)-ept-leuconolam via the highly enantioselective creation of a quaternary stereocenter (Scheme 35.25). 

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