Enantioselective synthesis of xanthatin

Article abstract of DOI:10.1002/chem.201402735

The enantioselective synthesis of cytostatic and antibiotic xanthatin (1 a) is reported. As a key intermediate, a bicyclic compound 2 was identified, which can be readily synthesized from methyl-2-furoic acid in diastereo- and enantiomerically pure form.

Full text of DOI:10.1002/chem.201402735

DOI: 10.1002/chem.201402735
Communication
&
Total Synthesis
Enantioselective Synthesis of Xanthatin
Andreas Bergmann[a] and Oliver Reiser*[a, b]
Abstract: The enantioselective synthesis of cytostatic and
antibiotic xanthatin (1a) is reported. As a key intermedi-
ate, a bicyclic compound 2 was identified, which can be
readily synthesized from methyl-2-furoic acid in diastereo-
and enantiomerically pure form. Compound 2 can be
functionalized regio- and stereoselectively at C-6 and C-7,
allowing the facile introduction of the functionalities
found in xanthatin, as well as the synthesis of derivatives
thereof. Moreover, a robust strategy for the introduction
of the exo-methylene group at C-3, commonly found in
many sesquiterpenes, was developed that makes use of
masking the alkene in the a,b-unsaturated carbonyl
system by O-pivaoyl, which is stable under acidic and mild
Scheme 1. Retrosynthetic analysis of xanthatin.
basic conditions but eliminated upon treatment with
strong bases.
mediate 2, which allows a flexible late-stage introduction of
the functional groups at C-6 and C-7, for example, those re-
quired for xanthatin. Moreover, we disclose a robust strategy
for the introduction of the chemically sensitive exo-methylene
group at C-3 position, being a key element in many sesquiter-
pene lactones (Scheme 1).
The sesquiterpene lactone xanthatin (1a) is found along with
other xanthanolides in several members of the Xanthium
family.[1] These substances have impressive biological activities,
such as anticarcinogenic, antimycotic, antibacterial (among
others, against methicillin-resistant staphylococcus areus (mini-
g-Butyrolacton 6 is readily available in a four-step sequence
in high enantio- (>99% ee) and diastereoselectivity (trans/cis
98:2) on multigram scale from methyl-2-furoate, featuring an
asymmetric cyclopropanation, ozonolysis, and an allylation/ret-
roaldol/lactonization cascade process.[7] The latter was previ-
ously reported by us after allylation of 5 by a work-up with
mal inhibitory concentration (MIC) 7.8 mgmLÀ1 [2f]
and various
)
other properties[2] along with low toxicity.[2b] For this reason,
xanthanolides have become an important target for natural-
product synthesis, starting with the first synthesis of 11,13-di-
hydroxanthatin reported by Evans and Morken in 2005.[3] Xan-
thatin itself was first synthesized by Shishido and co-workers in
2008[4] followed by a first and second generation synthesis by
Shindo and co-workers in 2010[5a] and 2013,[5b] as well as by
a formal synthesis converging with a key intermediate of
Shindo[5a] and co-workers in 2012.[6] All these routes have in
common that the chiral center at C-7 was set early on in the
synthesis utilizing the stereoselective functionalization of chiral
oxazolidinones (Evans auxiliary approach). In contrast, our syn-
thetic approach utilizes an asymmetric catalytic cyclopropana-
tion of methyl-2-furoate (4) leading to the bicyclic key inter-
[a] A. Bergmann, Prof. Dr. O. Reiser
Institut fꢀr Organische Chemie, Universitꢁt Regensburg
Universitꢁtsstrasse 31, 93053 Regensburg (Germany)
Fax: (+49)941-943-4121
E-mail: oliver.reiser@chemie.uni-regensburg.de
[b] Prof. Dr. O. Reiser
Current address: Department of Chemistry
Tokyo Institute of Technology, 2-12-1 O-okayama
Meguro-ku, Tokyo 152-8551 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402735.
Scheme 2. Synthesis of the bicyclic core structure 2 of xanthatin.
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Communication
point for binding to a cell membrane. The structure of 11 a
was unambiguously confirmed by X-ray structure analysis.
To finish the synthesis of xanthatin, the introduction of the
a-exo-methylene group at C-3 and the side chain had to be ac-
complished. In deciding the order of events, we were faced
with the dilemma that once the desired functionality at C-6 is
installed, various positions along the conjugated a,b,g,d-unsa-
turated carbonyl chain become highly acidic and thus enoliza-
ble. Although various methods for the introduction of exo-
methylene groups at the a-position of a lactone are known,[13]
they all require enolization of the lactone. On the other hand,
the a-exo-methylene-g-butyrolactone moiety is a strong Mi-
chael acceptor, making it unstable in the presence of even
weak nucleophiles under acidic and basic conditions; more-
over, isomerization of the exo-methylene double bond into the
g-butyrolactone ring occurs under basic conditions. Thus, once
this group is installed, considerable constrains on the transfor-
mations possible are present to convert the ester group to the
side chain at C-6. Orienting experiments indeed revealed that
introduction of any type of electrophile at C-3 is not feasible
once the unsaturated side chain at C-6 is present. Likewise, we
were unable to cleanly reduce the ester group at C-6 to an al-
dehyde once the exo-methylene group at C-3 was installed.
However, the following strategy proved to be successful:
Base-induced hydroxymethylation with gaseous formaldehyde
followed by pivalylation gave rise to 13 as a mixture of C-3
epimers, which was without consequences, because this ste-
reocenter is destroyed in the later course of the synthesis.[14]
The pivaloyl group proved to be a very suitable choice to
mask the a-exo-methylene-g-butyrolactone unit, being stable
under reductive, oxidative, acidic and weak basic conditions.
Conversion of the tert-butyl ester to aldehyde 14 proceeded
best in a stepwise fashion involving ester hydrolysis, activation
of the carboxylic acid as a mixed anhydride,[15] reduction to its
corresponding alcohol, and reoxidation with manganese diox-
Scheme 3. Stereoselective functionalization of 2 at C-5 and C-7 positions.
Ba(OH)2·8H2O,[7d] the protocol developed here (MeOH/NEt3)
allows this transformation in considerable improved yields, es-
pecially on larger scale. From compound 6, iodide 7 was ob-
tained as a single stereoisomer by an Appel-type reaction from
its corresponding alcohol, which in turn was generated by che-
moselective reduction of the aldehyde in 6. Following Kno-
chel’s protocol[8] in the modification[9] introduced by Kiyota,
the sp3–sp3 coupling of 7 with tert-butyl-2-(bromomethyl)acry-
late[10] proceeded with remarkable efficiency, giving rise to 8 in
quantitative yield. Ring-closing metathesis completed the syn-
thesis of 2, representing the bicyclic core structure of xanthatin
(Scheme 2).
The X-ray structure of 2 revealed the chair-like conformation
of its seven-membered ring, with allylic hydrogens on C-5 and
C-8 positions being differentiated by their axial and equatorial
positions (Scheme 3). The axial hydrogens are ideally aligned
with the adjacent p system of the C=C double bond to under-
go an ene reaction. In combination with the steric preference
of an eneophile to attack the sterically less hindered side of
the double bond, we were pleased to see that indeed the allyl-
ic oxidation[11] of 2 with selenium dioxide took place with per-
fect regio- and 1,3-diastereoinduction, giving rise to 9 as single
stereoisomer. Given that 5,7-bicyclic trans-anellated lactones
are a widely occurring structural motif in sesquiterpene natural
products, showing a broad substitution pattern in the seven-
membered ring, we believe that the transformations shown
herein will be of value for stereoselective modification of such
systems in general. Thus, transforming 9 to the allyl acetate 10
set the stage for the introduction of nucleophiles at C-7: Alkyl
cuprates,[12] generated in situ from their corresponding alkyl
lithium compound and CuCN, cleanly reacted in an SN2’ pro-
cess anti-selective to 11, as was exemplified for the methyl de-
rivative 11 a being required for the synthesis of xanthatin, as
well as for the octyl derivative 11 b, having a potential anchor
Scheme 4. Final steps in the synthesis of xanthatin 1a and side-chain ana-
logues 1b–c.
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ide. Elimination of pivalic acid under strong basic conditions
rapidly occurred to give rise to the desired a-exo-methylene-g-
butyrolactone 15. Although any type of Wittig elongation of
the aldehyde was not successful either on 14 or 15, borontri-
fluoride-mediated Mukaiyama aldol reaction of 15 and with tri-
methyl(prop-1-en-2-yloxy)silane[16] to 16 followed by acid-in-
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(Scheme 4).
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Acknowledgement
This work was supported by the Deutsche Forschungsgemein-
schaft (RE 948-9/1).
Keywords: allylic oxidation · exo-methylene group · synthetic
methods · total synthesis · xanthanolides
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Received: March 23, 2014
Published online on && &&, 0000
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Total Synthesis
A. Bergmann, O. Reiser*
&& – &&
Enantioselective Synthesis of
Xanthatin
Organic hardcore: The enantioselective
synthesis of cytostatic and antibiotic
xanthatin is reported. As a key inter-
mediate, the bicyclic compound A was
identified (see scheme), which can be
readily synthesized from 2-furoic acid in
diastereo- and enantiomerically pure
form. Moreover, a new strategy for the
introduction of the exo-methylene
group at C-3, commonly found in many
sesquiterpenes, was developed.
&
&
Chem. Eur. J. 2014, 20, 1 – 4
www.chemeurj.org
4
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!