Synthesis of (±)-desethylrhazinal using a tandem radical addition-cyclization process

Article abstract of DOI:10.1039/c0ob00572j

The indolizidine ring system present in (±)-rhazinal, was assembled using a xanthate-based sequential intermolecular radical addition-cyclization process. The novel (±)-desethylrhazinal was prepared in seven steps in approximately 12% overall yield from 2

Full text of DOI:10.1039/c0ob00572j

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Synthesis of ( )-desethylrhazinal using a tandem radical addition-cyclization
process†
Ehecatl Paleo, Yazmin M. Osornio and Luis D. Miranda*
Received 13th August 2010, Accepted 1st October 2010
DOI: 10.1039/c0ob00572j
The indolizidine ring system present in ( )-rhazinal, was
assembled using a xanthate-based sequential intermolec-
ular radical addition-cyclization process. The novel ( )-
desethylrhazinal was prepared in seven steps in approximately
12% overall yield from 2-formylpyrrole, using this strategy.
In connection with our interest of developing new syntheses of
polycyclic compounds with an embedded heterocyclic system via
tandem radical addition-cyclization processes,6 we were interested
in using a sequential intermolecular radical addition-oxidative
cyclization process (Scheme 1), to construct the A-B indolizidine
ring system of rhazinal 1. The proposed tandem carbon–carbon
bond forming process would provide all the necessary functional
groups for the construction of the nine-member lactam by the
corresponding coupling process. At this stage, we recognized
that the desethyl congener 5b, could be readily prepared from
commercially available 5-bromopentene (8b) and 2-formylpyrrole
(7), giving access to the novel ( )-desethylrhazinal 3 congener.
Thus, to examine the feasibility of the cascade radical process we
focused on the synthesis of 3 and 4a. The complete approach to
the synthesis of 3 entails the tandem radical process to secure
the indolizidine ring system 3, a Suzuki-Miyaura cross coupling
reaction to create the C–C bond of the biaryl system and a
macrolactamization reaction (Scheme 1). It has been previously
demonstrated that the xanthate-based radical chemistry developed
by Zard, et al., afforded satisfactory results in related tandem
processes, therefore we elected to use the readily available xanthate
9 as the source of the radical 6.6a,7
The alkaloid (-)-rhazinal (1) is a tetracyclic pyrrole fused system
which was isolated from the stem extracts of a Malayan Kopsia
species in 1998 by Kam and coworkers (Fig. 1).1 (-)-Rhazinal
has also been prepared by Vilsmeier–Haack formylation of the
closely related (-)-rhazinilam alkaloid (2), isolated from Melodinus
australia, Rhazya stricta (Apocynaceae) and the Malasian plant
Kopsia singapurensis (Ridlay).2
Fig. 1 Antitumor alkaloids rhazinilam and rhazinal.
Similar to taxol and vincristine, rhazinilam have been reported
to disrupt the tubulin and microtubule polymerization dynamics
required for the normal mitotic division of cells.3 Unfortunately,
it was inactive in human clinical trials.3a Nevertheless, these
compounds have been considered as important leads in the
quest to find a new generation of anticancer agents, and have
recently attracted considerable attention both in the biological
and synthetic communities. The first total synthesis of rhazinal
described by Banwell and coworkers in 2003, was based on the use
of the pyrrole system as the donor in an intramolecular Michael-
type addition process to construct the indolizidine ring system
of the alkaloid.4 In 2009 Trauner and Bowie reported a concise
synthesis of ( )-rhazinal using an oxidative Heck cyclization to
construct the nine-membered lactam and a palladium-catalyzed
direct coupling to assemble the indolizidine ring system.5
Instituto de Qu´ımica, Universidad Nacional Auto´noma de Me´xico, Circuito
Exterior, Ciudad Universitaria, Coyoacan, Me´xico, D.F. 04510, Mexico.
E-mail: lmiranda@servidor.unam.mx; Tel: +52 (55) 5622 4440
† Electronic supplementary information (ESI) available: General exper-
imental procedures, characterization data and NMR spectra. See DOI:
10.1039/c0ob00572j
Scheme 1 Retrosynthetic analysis of rhazinal.
Org. Biomol. Chem., 2011, 9, 361–362 | 361
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The required mesylate 8a was prepared as reported previously.4a
N-Alkylation of the 2-formylpyrrole (7) with the mesylate 8a and
5-bromopentene (8b) afforded 5a and 5b respectively, in good
yields (Scheme 2). With these substrates in hand, we were in a
position to realize the radical process. To our delight, exposure of
a refluxing solution of the corresponding pyrrole 5 and xanthate
97 in 1,2-dichlorethane (DCE) under typical radical-forming
conditions, i.e., portionwise (7 h) addition of 1.3 eq of dilauroyl
peroxide (DLP) to a refluxing solution, led to the formation of
pyrrole 4a and 4b as the major products in 71% and 69% yield,
respectively. Interestingly, addition of a tertiary (reaction of 5a) or
a secondary (reaction of 5b) radical onto the pyrrole nucleus did
not significantly affect the outcome of the reaction. Noteworthy,
xanthate derivatives 10a–b that would come from the normal
addition/xanthate-transfer mechanism, frequently observed in
related processes, was not detected in the reaction media.7 Thus,
this two-step synthetic sequence gave access to 4a (Scheme 2).
It is worth mentioning that the methyl-ester congener has been
transformed into the ( )-rhazinal 1 previously.4a
Scheme 3 Synthesis of ( )-desethylrhazinal.
Acknowledgements
Financial support from the CONACYT (No. 82643) is gratefully
acknowledged. We also thank R. Patin˜o, A. Pen˜a, E. Huerta E.
Garc´ıa-Rios, L. Velasco, and J. Pe´rez for technical support.
References
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Scheme 2 Preparation of indolizidines 4a and 4b via a tandem addi-
tion/cyclization process.
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To complete the synthesis of 3, pyrrole 4b was regioselectively
iodinated to afford 11. Then, the Suzuki-Miyaura cross coupling
of 11 with the N-Boc-aniline boronic ester 12 occurred using
Buchwald SPhos ligand and yielded the 3-aryl pyrrole 13. Finally,
ester saponification followed by the removal of the N-Boc
protecting group afforded the corresponding amino acid which,
without further purification, was submitted to the construction of
the nine-member lactam to deliver the ( )-desethylrhazinal 3 in
29% yield over three steps (Scheme 3).
In conclusion, we have achieved the synthesis of ( ) desethyl-
rhazinal using a tandem radical addition-cyclization process, in
seven steps and approximately 12% overall yield, and a practical
short protocol to construct an advanced intermediate in the
synthesis of ( )-rhazinal 1, both from 2-formylpyrrole. We are
currently studying the feasibility of this synthetic strategy for the
synthesis of ( )-rhazinal, ( )-rhazinilam and other members of the
Kopsia alkaloid family.
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43, 4683–4686; See also 6a.
362 | Org. Biomol. Chem., 2011, 9, 361–362
This journal is
The Royal Society of Chemistry 2011
©