Concise total synthesis of (±)-aspidospermidine via an oxidative Hosomi-Sakurai process

Article abstract of DOI:10.1039/b903530c

A concise total synthesis of (±)-aspidospermidine has been achieved in twelve steps from inexpensive 4-ethylphenol, based on an oxidative Hosomi-Sakurai reaction via the concept of "aromatic ring umpolung".

Full text of DOI:10.1039/b903530c

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Concise total synthesis of (Æ)-aspidospermidine via an oxidative
Hosomi–Sakurai processw
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Cyrille Sabot, Kimiaka C. Guerard and Sylvain Canesi*
Received (in College Park, MD, USA) 19th February 2009, Accepted 14th April 2009
First published as an Advance Article on the web 27th April 2009
DOI: 10.1039/b903530c
A concise total synthesis of (Æ)-aspidospermidine has been
achieved in twelve steps from inexpensive 4-ethylphenol, based
on an oxidative Hosomi–Sakurai reaction via the concept of
‘‘aromatic ring umpolung’’.
elicited substantial interest in the synthetic arena. Aspido-
spermidine and aspidospermine contain a pentacyclic ring
system and five asymmetric centers. The usual strategy used
to produce these compounds is generally based on the
formation of a key intermediate 6, first described by Stork
and Dolfini.10 Since then, many other syntheses or formal
syntheses have been reported.11
Electron-rich aromatic compounds such as phenols, anilines,
and their derivatives normally express nucleophilic reactivity.
However, oxidative activation1–3 can convert these aromatics
into reactive electrophilic intermediates, which may be
intercepted with appropriate nucleophiles in synthetically
useful yields. Thus, oxidative attack of a phenol4 with
iodobenzene diacetate (DIB), an environmentally benign and
inexpensive reagent, in the presence of allyltrimethylsilane
promotes an oxidative Hosomi–Sakurai process5 that
produces products 3 in 37–84% yield.5d The erstwhile electron-
rich aromatic substrate expresses electrophilic character in this
reaction. The overall transformation may thus be thought of
as involving ‘‘aromatic ring umpolung’’,6 Fig. 1.
Our approach, based on aromatic ring umpolung, starts
with a polysubstituted phenol 7.12 This compound can be
rapidly converted into the corresponding dienone 8 via a
bimolecular oxidative Hosomi–Sakurai process in 56% yield
by DIB oxidation in the presence of allyltrimethysilane and a
perfluorinated solvent such as trifluoroethanol (TFE) or
hexafluoroisopropanol (HFIP). The use of a polysubstituted
phenol such as 7, containing removable directing groups, is
very important in order to force the subsequent allyltrimethyl-
silane to locate exclusively at position 4. The corresponding
dienone 8 is treated under hydroboration conditions to pro-
duce alcohol 9 in 72% yield. The latter is activated with mesyl
chloride to generate compound 10 in 97% yield, Scheme 1.
Compound 10 is thus produced rapidly from 7 via the
oxidative allylation strategy. At this point the nitrogen moiety
is efficiently introduced by an SN2 reaction between 10 and the
corresponding anion of 1113 to afford the sulfonamide 12 in
89% yield. This product contains protected secondary amine
and alcohol groups which represents a good precursor of the
main tricyclic core of aspidospermidine. The nosylamide or
Fukuyama’s sulfonamide14 was chosen because it is known to
be easily cleaved under mild reaction conditions, Scheme 2.
Indeed, the elaboration of aspidospermidine required
a method for the stereoselective construction of the main
This concept provides new strategic opportunities in
synthetic chemistry. Indeed, this method has already allowed
us to develop an innovative method directly applicable to the
expeditious total syntheses of natural products.7 In this
communication, we illustrate a new use of the concept by a
direct application of a bimolecular oxidative Hosomi–Sakurai
condition in connection with a fully stereocontrolled total
synthesis of (Æ)-aspidospermidine, 4. Compound 4 belongs
to the family of aspidosperma alkaloids (Fig. 2).8 The complex
architecture and biological activities of these products9 have
Fig. 1 Aromatic ring umpolung.
Scheme 1 Oxidative Hosomi–Sakurai reaction.
Fig. 2 Aspidosperma alkaloid family.
Laboratoire de Me´thodologie et Synthe`se de Produits Naturels,
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Universite du Quebec a Montreal, C.P. 8888, Succ. Centre-Ville,
Montreal, Quebec, Canada H3C 3P8.
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E-mail: canesi.sylvain@uqam.ca
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for all new compounds along
1
with copies of H and 13C NMR spectra. See DOI: 10.1039/b903530c
Scheme 2 Alkylation of sulfonamide 11.
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Chem. Commun., 2009, 2941–2943 | 2941

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tricyclic core. We envisaged, by means of Fukuyama’s
deprotection, generating the free secondary amine, which
could cyclize (6-exo-trig), to produce the first heterocycle.
Intriguingly, addition of thiophenolate, under these condi-
tions, leads to compound 16 via a substitution of the bromide
by a thioether. This transformation, occurring in 85% yield,
takes place via four successive distinct steps: (1) nucleophilic
aromatic substitution (SNAr) deprotection leads to the corres-
ponding free amine 13; (2) addition of thiophenol leads to
compound 14; (3) substitution of the bromide by an SN2
process generates 15; and (4) a final retro-Michael reaction
produces 16. At this point, the addition of the free amine on
the dienone is not observed, Scheme 3.
Scheme 5 Formal total syntheses of (Æ)-aspidospermine, (Æ)-aspido-
spermidine and (Æ)-quebrachamine.
Treatment of compound 16 with TBAF produces the free
alcohol and bicyclic ring 19 in 87% yield. Once again, different
transformations occurred in the same pot: (1) desilylation of
the TBDMS moiety produces 17; (2) the free amine reacts via a
Michael process to afford the bicyclic compound 18; (3)
desilylation of the TMS group occurs to produce 19, Scheme 4.
The action of mesyl chloride on compound 19 results in the
formation of the corresponding chloride 21 in 79% yield.
Compound 21 is obtained probably due to the formation of
the corresponding aziridinium 20 in the medium, which is
opened by nucleophilic attack by the released chloride. Treat-
ment of 21 with a base such as potassium tert-butoxide leads
to the desired tricyclic compound 22 in 84% yield. At this
point, treatment of compound 22 with RANEYs nickel in
ethanol produces 6 in 85% yield. This sequence of reactions,
including a Fukuyama and Michael–retro-Michael tandem
process, offers an efficient access to key intermediate 6, known
as formal synthesis of aspidospermine, aspidospermidine and
quebrachamine,11m Scheme 5.
Scheme 6 Synthesis of (Æ)-aspidospermidine.
To complete the total synthesis, the known tricycle 6
is converted to (Æ)-aspidospermidine via a Fischer indole
synthesis,15 as demonstrated first by Stork and Dolfini.10
Indeed, treatment of compound 6 with phenylhydrazine at
reflux leads to the hydrazone 23, which is converted to imine
24 in acetic acid. The latter is reduced in the same pot by
LiAlH4 to produce (Æ)-aspidospermidine, 4, in 43% yield
overall, Scheme 6.
In summary, a concise and fully diastereoselective synthesis
of (Æ)-aspidospermidine is accomplished in ten steps from
phenol 7 in 5.4% yield overall. This novel synthesis is based on
a first application of a bimolecular oxidative Hosomi–Sakurai
reaction. In addition, an efficient method to produce the
bicyclic ring of this compound via a Fukuyama–Michael
tandem process has been developed. Formal total syntheses
of (Æ)-aspidospermine and (Æ)-quebrachamine have also been
presented. This work demonstrates the potential of ‘‘aromatic
ring umpolung’’, further applications of which are under study
in our laboratories.
The authors thank the Donors of the Petroleum Research
Fund (ACS PRF), administered by the American Chemical
Society, for support of this research. We are also very grateful
to the Natural Sciences and Engineering Research Council of
Canada (NSERC) and to the provincial government of
Quebec (FQRNT).
Scheme 3 Fukuyama and Michael–retro-Michael tandem process.
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Chem. Commun., 2009, 2941–2943 | 2943