As part of our ongoing research program in the area of
nucleophilic catalysis using phosphines,4,5 we disclosed a [4
+ 2] annulation between 2-alkyl-2,3-butadienoates and
imines.6 We envisioned, as an entry into the various
macroline indole alkaloids, to employ our [4 + 2] annulation
between allenes and imines. Specifically, use of allenoate
8, combined with imine 7, derived from indole-2-carboxal-
dehyde, can afford tricycle 6 (Scheme 1). Acid-mediated
Scheme 2. Synthesis of Tetracycle 13a/b via
Phosphine-Catalyzed [4 + 2] Annulation/Intramolecular
Friedel-Crafts Acylation
Scheme 1. Retrosynthetic Plan for the Construction of 3
available [(alkoxycarbonyl)methylene]triphenylphosphorane
9a/b was reacted with ethyl bromoacetate to provide phos-
phonium bromide 10a/b. Treatment of 10a/b with acetyl
chloride (1 equiv) in the presence of triethylamine (Et3N, 2
equiv) furnished the desired diester allenes 8 and 8b in 73
and 53% yield, respectively, over two steps. o-Nitrobenze-
nesulfonamide was condensed with indole-2-carboxaldehydes
11a and 11b under the influence of titanium(IV) chloride
(TiCl4) and Et3N to provide imines 7a and 7b in 79 and
88% yield, respectively. Thus formed, solid imine 7a/b was
reacted with allenoate 8/8b in the presence of 30 mol % of
tributylphosphine in methylene chloride at room temperature.
The [4 + 2] annulation products 12a and 12b were obtained
in 73 and 84% yield as a 3:1 and 1:1 mixture of diastere-
oisomers, respectively. The poorer diastereoselectivity for
imine 7b, derived from Na-Boc-protected indole-2-carbox-
aldehyde, is in accord with our observation that imines
derived from benzaldehydes with bulky (bigger than fluoride)
ortho-substituents displayed poorer cis-diastereoselectivity.5
The acid-catalyzed epimerization of the C5 carboxylic ester
had previously been observed,7 so we proceeded to treat the
mixture of inseparable diastereoisomers 12a with hydro-
chloric acid (HCl) in ethyl acetate at room temperature. This
resulted in the facile intramolecular Friedel-Crafts acylation
to give bridged bicycle 13a in 90% yield.8 For 12b,
deprotection of the tert-butoxycarbonyl group on the indole
nitrogen (Na-Boc) and the concomitant intramolecular Friedel-
intramolecular Friedel-Crafts acylation of 6 can provide
quick access to tetracycle 5, which can be a common
intermediate for further elaboration to macroline indole
alkaloids. Especially, deprotection of the Nb-sulfonyl group,
followed by methylation, reductive deoxygenation of the C6
ketone, and reduction of the R,â-unsaturated ester to the
allylic alcohol were envisaged to furnish intermediate 3,
which was a precursor to alstonerine and macroline.2 Herein,
we report a nine-step synthesis of this key intermediate 3 in
31% overall yield.
Our synthesis commenced with the preparation of previ-
ously unreported allenoate 8 (Scheme 2). Commercially
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