Rhazine

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). 

A new rhazinilam derivative, rhazinal (349) has been obtained from a Malayan Kopsia species [232]. The spectral data indicated that rhazinal is the S-formyl derivative of rhazinilam. Rhazinal (349) represents the first instance of a naturally occurring rhazinilam derivative which... 

Rhazine (akuammidine) A. scholaris fruits and trunk bark 41... 

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]). 

Scheme 4 Total syntheses of (—)-rhazinal (32), (—)-rhazmilam (31), (+)-epi-leuconolam (33) and (—)-leuconolam (34)...

We have employed a related reaction sequence to prepare a lower homologue of rhazinal and then shown that this retains many of the potent anti-mitotic properties of the natural product [39]. 

The Banwell group employed an organocatalytic intramolecular Friedel-Crafts cyclization to synthesize the alkaloids (—)-rhazinal (288), (—)-rhazinilam (289), ( )-leuconolam (290), and (-i-)-ep/-leuconolam (291) (261). The spindle toxin (-)-... 

Banwell MG, Beck DAS, Willis AC (2006) Enantioselective Total Syntheses of the Alkaloids (-)-Rhazinal, (-)-Rhazinilam, (-)-Leuconolam and (-l-)-epi-Leuconolam. Arkivoc 3 163... 

Kam TS, Tee YM, Subramaniam G (1998) Rhazinal, a Formylrhazinilam Derivative from a Malayan Kopsia. Nat Prod Lett 12 307... 

Bowie AL, Trauner D (2009) Total Synthesis of (-t-/—)-Rhazinal Using Novel Palladium-Catalyzed Cyclizations. J Org Chem 74 1581... 

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. 

Two C-H catalytic activation reactions were employed in a synthesis of rhazinal 3.23 (Scheme 3.20). The starting material was prepared from a readily available aldehyde 3.24, An aldol reaction installed a methylene group a to the carbonyl. This was followed by addition of methyl lithium and a Johnson-Claisen rearrangment... 

Scheme 16.12 Synthesis of rhazinal a comparison of intramoiecuiar and intermoiecuiar C-H functionaiization strategies.

In contrast, Gu and coworkers achieved the synthesis of rhazinal by using an intermoiecuiar C-H arylation of pyrroles at the C3 position and subsequent Heck alkylation (Scheme 16.12b) [26]. When iodopyrrole 60 was reacted with aryl iodide 61 in the presence of catalytic PdCl2, PPh3, and excess amounts of norbornene (6 equiv.), a Catellani-type reaction occurred to give intermediate 62. This intermediate then underwent reductive elimination and norbornene release... 

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