Asymmetric synthesis of fortucine and reassignment of its absolute configuration

Article abstract of DOI:10.1002/chem.201402323

A convergent and enantioselective synthesis of fortucine was achieved from the starting materials tyrosine methyl ester and 3-hydroxy-4- methoxybenzaldehyde. The synthesis is based on two key steps mediated by a hypervalent iodine reagent. This work has enabled us to reassign the absolute configuration of the natural product reported in the literature. A multi-tool for total synthesis: A convergent and enantioselective synthesis of fortucine was achieved from the starting materials tyrosine methyl ester and 3-hydroxy-4-methoxybenzaldehyde. The synthesis is based on two key steps mediated by a 'multi-tool' hypervalent iodine reagent (see scheme).

Full text of DOI:10.1002/chem.201402323

DOI: 10.1002/chem.201402323
Communication
&
Organic Synthesis
Asymmetric Synthesis of Fortucine and Reassignment of Its
Absolute Configuration
Marc-Andrꢀ Beaulieu,[a] Xavier Ottenwaelder,[b] and Sylvain Canesi*[a]
Abstract: A convergent and enantioselective synthesis of
fortucine was achieved from the starting materials tyro-
sine methyl ester and 3-hydroxy-4-methoxybenzaldehyde.
The synthesis is based on two key steps mediated by a hy-
pervalent iodine reagent. This work has enabled us to re-
assign the absolute configuration of the natural product
reported in the literature.
Lycorine alkaloids are natural products isolated from Amarylli-
daceae species of flowering plants[1] that possess antiviral and
antitumor activities.[2] Compounds within this family have at-
Figure 1. Lycorine alkaloid members reported in the literature.
tracted substantial interest in the synthetic community since
the isolation and characterization of (À)-lycorine 1, which is
the most prevalent phenanthridine Amaryllidaceae alkaloid.[3]
advantage of our asymmetric synthesis is that we were able to
Their main core contains a tetracyclic pyrrolo[d,e]phenan-
thridine skeleton, as illustrated in the structure of lycorine 1.
While most lycorine alkaloids have a trans-B/C-ring junction,
a few have a cis junction, including (+)-fortucine 2, which is
a molecule isolated from the fortune variety of narcissus,[4] as
well as (+)-kirkine 3,[5] and (À)-siculinine 4.[6] Without experi-
mental evidence, (+)-fortucine 2 was originally proposed[4] to
have the absolute configuration shown in Figure 1, probably
by analogy with the closely related (À)-lycorine 1.
determine the correct absolute configuration of natural fortu-
cine. Our synthesis of fortucine starts from l-tyrosine-methyl
ester 8 and 3-hydroxy-4-methoxybenzaldehyde 5 along a retro-
synthetic pathway presented in Scheme 1. These segments are
joined through an amide functionality 9, which is used as an
amine-protecting group and is later reduced to install the re-
quired cycloamine. This approach presents an interesting alter-
native to common protecting-group-free strategies,[8] since
a functional protecting group not only masks the reactivity of
a sensitive ensemble but also carries a moiety of the final
target. We also decided to involve hypervalent iodine reagents
in several steps of the synthesis due to their lower environ-
mental impact compared to heavy metal reagents. Thus,
a Wipf-type strategy[9] based on the Kita oxidative dearomati-
zation process[10] is used to provide stereoselectivity and is fol-
lowed by an oxidative decarboxylation process[11] to yield the
final product.
In this paper, we present a convergent, asymmetric synthesis
of one enantiomer of fortucine 2 and firmly establish its abso-
lute configuration. The only synthesis of fortucine in the litera-
ture was reported by Zard and co-workers,[7] in which the
preparation of the main tetracyclic core of fortucine employed
an elegant radical cascade transformation as a key step. How-
ever, since it is not an asymmetric synthesis, the authors could
not confirm the absolute configuration of natural fortucine.
Meanwhile, the same group also revised the initial proposed
structure of kirkine 3, a natural related isomer which probably
has the same absolute configuration as fortucine. A significant
The hydroxyl group of the inexpensive starting material 3-
hydroxy-4-methoxybenzaldehyde 5 was protected using triiso-
propylchlorosilane (TIPSCl). Subsequent treatment with iodine
and silver nitrate produced compound 6 in 73% yield over
two steps. The aldehyde functionality was oxidized to the de-
sired acyl chloride in the presence of CuCl2 and tBuOOH,[12] fol-
lowed by a Vilsmeier activation[13] to yield compound 7 in 75%
overall yield (Scheme 2).
[a] M.-A. Beaulieu, Prof. S. Canesi
Dꢀpartement de chimie, Universitꢀ du Quꢀbec ꢁ Montrꢀal
Laboratoire de Mꢀthodologie et Synthꢂse de Produits Naturels
C.P.8888, Succ. Centre-Ville, Montrꢀal, QC, H3C 3P8 (Canada)
Fax: (+1)514-987-4054
E-mail: canesi.sylvain@uqam.ca
At this stage, compound 7 was attached through the amino
group to l-tyrosine methyl ester 8 by using the Schotten–Bau-
mann reaction and the ester functionality was selectively trans-
formed into a carboxylic acid under mild Krapcho-like condi-
tions[14] to avoid deprotecting the phenol group, leading to in-
termediate 9 in 71% overall yield. Compound 9 represents the
[b] Prof. X. Ottenwaelder
Department of Chemistry and Biochemistry
Concordia University, 7141 Sherbrooke W
Montreal, QC, H4B 1R6 (Canada)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402323.
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The required tetracyclic system was produced from
the functionalized synthon 11 by a Heck-type carbo-
palladation process. First, the ketone functionality
was quantitatively transformed into the pre-activated
enol-ether 12 in the presence of TBS-triflate, which
also converted the tertiary alcohol moiety into the
corresponding silyl ether required at the end of the
synthesis. The intramolecular C–C coupling was per-
formed by treatment of 12 with tetrakis(triphenyl-
phosphine)palladium, to yield the desired cis tetracy-
clic pyrrolo[d,e]phenanthridine skeleton 13 in 85%
yield. The observed cis stereoselectivity is rationalized
by the planar geometry of the lactam segment. It
should be noted that compound 13 represents the
main core of several natural products of the same
family (Figure 1). The alkene migration necessary to
reach final product 2 entails the Julia-type transfor-
mation[16] brilliantly used by Zard and co-workers
during their synthesis of fortucine.[7] Following their
approach, treatment of compound 13 with ortho-methoxythio-
phenol and NEt3 enabled the kinetic formation of 14 through
a 1,4-addition in 93% yield (Scheme 4).
Scheme 1. Retrosynthetic analysis of a monochiral form of fortucine.
The secondary alcohol functionality in the structure of enan-
tiopure fortucine was obtained in 96% yield by treatment of
14 with LiBH4, which was chosen based on its superior stereo-
selectivity. Subsequently, an acetate group was quantitatively
introduced onto the alcohol moiety as a protecting group to
yield compound 15. The enantiopurity of 15 was verified by
Scheme 2. Formation of the aromatic subunit.
first key intermediate in the synthesis. Using a remark-
able methodology developed by Wipf and co-work-
ers, this phenol was readily dearomatized and stereo-
selectively transformed into the functionalized bicy-
clic system 11. The stereochemistry is guided by the
chiral center of the tyrosine.[15] This elegant process[9]
occurs through an oxidative lactonization mediated
by the hypervalent iodine reagent leading to com-
pound 10 in 50% yield. Subsequent treatment in the
presence of potassium methoxide produces the de-
sired bicyclic core 11 in 95% yield with high stereo-
selectivity (Scheme 3).
Scheme 4. Formation of the main tetracyclic system.
NMR spectroscopy by coupling the acid derivative of
15 with (S)-(À)-a-methylbenzylamine. At this stage,
the ester functionality was quantitatively transformed
into a carboxylic acid by using a Krapcho-like trans-
formation that is mild enough to avoid deprotecting
the hydroxyl groups. Further treatment with mCPBA
produced sulfone 16 in 98% yield. The sulfonyl
group was required for the final step to enable the
introduction of the alkene functionality by a Julia-like
transformation. The carboxylic acid moiety that ena-
bled us to control the diastereoselectivity of the tet-
Scheme 3. Formation of the bicyclic core.
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racyclic core was removed using a second strategic step medi-
ated by a hypervalent iodine reagent,[17] following a noteworthy
protocol developed by Boto, Hernandez, and Suarez.[11] Howev-
er, this strategy was only successful when the alcohol moiety
was previously protected as an acetate to prevent its oxidation
to a ketone promoted by the hypervalent species. An oxidative
decarboxylation process on the carboxylic acid 16, mediated
by diacetoxyiodobenzene and iodine, was used to first gener-
ate an iminium ion which was further reduced to 17 by the ad-
dition of triethylsilylane in 51% yield (Scheme 5).
with the literature.[5,7] However, the optical rotation of our syn-
thetic 2, [a]2D0 =À63 (c=0.04 in ethanol), had the opposite sign
from that reported in the literature for natural fortucine,
[a]2D0 = +66 (c=0.23 in ethanol).[4a] In addition, our synthesized
fortucine has the opposite Cotton effect at 285 nm compared
with the natural product, as assessed by circular dichroism
spectroscopy.[4] To determine the actual absolute configuration
of our enantiopure compound, we performed a crystallographic
analysis of four crystals of the final precursor 18 (Figure 2a).[18]
The presence of S and Si heavy elements in this molecule guar-
antees unequivocal assignment of the absolute con-
figuration as drawn in Scheme 6 (Flack parameter of
0.00(2)). Circular dichroism experiments also con-
firmed that the crystals had the same positive Cotton
effect at 285 nm as the whole sample, further con-
firming that the X-ray structure is representative of
the whole sample.[19] Hence, we undoubtedly synthe-
sized the reported enantiomer of fortucine, but the
isolated natural product ent-2 is actually its mirror
image, with the correct absolute structure reassigned
as drawn in Figure 2b. This means that the total syn-
thesis of natural fortucine could be obtained from d-
tyrosine methyl ester by the same synthetic pathway.
By analogy, we reason that the accepted absolute
configuration of (+)-kirkine,[5,7] which appears as
a natural related isomer of fortucine, is probably also
incorrect.
Scheme 5. Elaboration of the main core of fortucine.
To conclude the synthesis, the lactam subunit used as a pyr-
rolidine protecting group and the acetate functionality were
reduced in the presence of DIBAL-H in 80% yield. Subsequent
treatment with K2CO3 in methanol resulted in TIPS deprotec-
tion, producing phenol 18 in 95% yield. Compound 18 is the
final precursor to fortucine, and was transformed into the
target by treatment with lithium naphthalene (Julia-type con-
ditions[16]) in 65% yield (Scheme 6). A similar transformation
with sodium amalgam in methanol was first demonstrated by
Zard and co-workers.[7] Formally, the transformation of the
enone moiety present in 13 into the cyclohexenol moiety in
fortucine represents a reductive isomerization process.
Figure 2. a) ORTEP representation at 50% ellipsoid probability of 18 in the
The confirmation of the structure and absolute configuration
of 2 was carried out by using several techniques. At this stage,
the NMR and mass spectrometry data for 2 were in agreement
solid-state structure of 18·1= H2O. Hydrogen atoms were removed for clarity,
3
except those on the asymmetric carbon atoms. b) Corrected absolute con-
figuration of (+)-fortucine.
In summary, an asymmetric synthesis of fortucine
has been achieved by using l-tyrosine methyl ester
as the sole precursor of chirality on three asymmetric
carbon atoms. The synthesis was based on two key
steps mediated by a hypervalent iodine reagent. In
addition, this work has enabled the reassignment of
the absolute configuration of this natural product.
Scheme 6. Final steps of the synthesis.
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Acknowledgements
We thank D. McLaughlin and M. S. Askari (Concordia University)
for help with the circular dichroism and crystallography experi-
ments. We are very grateful to the Natural Sciences and Engi-
neering Research Council of Canada (NSERC), the Canada
Foundation for Innovation (CFI), and the provincial govern-
ment of Quebec (FQRNT and CCVC) for their precious financial
support in this research.
Keywords: aromatic ring umpolung · hypervalent iodine ·
natural products · oxidation · total synthesis
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[19] By comparison, natural (+)-fortucine has a negative Cotton effect at
282 nm.[4a]
Received: February 23, 2014
Published online on && &&, 0000
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Communication
COMMUNICATION
&
Organic Synthesis
M.-A. Beaulieu, X. Ottenwaelder,
S. Canesi*
&& – &&
A multi-tool for total synthesis: A con-
vergent and enantioselective synthesis
of fortucine was achieved from the
starting materials tyrosine methyl ester
and 3-hydroxy-4-methoxybenzaldehyde.
The synthesis is based on two key steps
mediated by a ‘multi-tool’ hypervalent
iodine reagent (see scheme).
Asymmetric Synthesis of Fortucine
and Reassignment of Its Absolute
Configuration
According to Greek mythology…
…the species of plant Fortune
Narcissus of Amarillydaceaes (shown
on the right side of the cover
illustration) grew exactly where
Narcissus drowned while he was
admiring his own reflection (or his
mirror image) in the water. The
illustration of this story serves as an
appropriate analogy for the
synthesis of the mirror image of
fortucine, a bioactive product
isolated from the leaves of this
plant, described by S. Canesi and
co-workers in their Communication
on page && ff. in that the
presented asymmetric synthesis has
allowed the reassignment of the
absolute configuration of the
natural product as presented on the
top face of the cover.
Chem. Eur. J. 2014, 20, 1 – 5
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