Non-natural elemane as the stepping stone for the synthesis of germacrane and guaiane sesquiterpenes

Article abstract of DOI:10.1021/ol3031999

The synthesis of hydroxyelemane 5 from (R)-carvone and its utilization as a common synthetic scaffold to produce structurally diverse germacrane and guaiane sesquiterpenes are described. A highly enantio- and stereoselective biomimetic tandem oxy-Cope/ene rearrangement was used as the key reaction to access the 10-membered macrocyclic core of germacranes and the condensed 5-7 carbocycles of guaiane sesquiterpenes. Additionally, reactions of furanoguaianes under acidic or oxidizing reagents have been investigated, and preliminary results of these conversions are presented.

Full text of DOI:10.1021/ol3031999

ORGANIC
LETTERS
2013
Vol. 15, No. 1
152–155
Non-natural Elemane as the “Stepping
Stone” for the Synthesis of Germacrane
and Guaiane Sesquiterpenes
Elissavet E. Anagnostaki and Alexandros L. Zografos*
Department of Chemistry, Laboratory of Organic Chemistry, Aristotle University of
Thessaloniki,University Campus, 54124 Thessaloniki, Greece
alzograf@chem.auth.gr
Received November 20, 2012
ABSTRACT
The synthesis of hydroxyelemane 5 from (R)-carvone and its utilization as a common synthetic scaffold to produce structurally diverse
germacrane and guaiane sesquiterpenes are described. A highly enantio- and stereoselective biomimetic tandem oxy-Cope/ene rearrangement
was used as the key reaction to access the 10-membered macrocyclic core of germacranes and the condensed 5À7 carbocycles of guaiane
sesquiterpenes. Additionally, reactions of furanoguaianes under acidic or oxidizing reagents have been investigated, and preliminary results of
these conversions are presented.
Sesquiterpenes are plant-derived compounds often used
in traditional medicine1 against inflammation and cancer.2
Comprising more than 5000 members,3 sesquiterpene
subfamilies provide an infinite synthetic challenge for
organic chemists because of their complex molecular
diversity4 and rich biological profile.5 Sesquiterpenoid-
derived drugs from thapsigargin (1),6 parthenolide (2),7
and artemisinin (3)8 (Figure 1) are now in clinical trials for
anarray of tumor celllines. More specifically, parthenolide
(2), a 6,12-germacranolide, was found to selectively reduce
the growth of tumor cells7 by its potent ability to inhibit an
NF-κB signaling pathway.2 Yet, despite the promising
array of biochemical behavior, the true clinical potential for
these compounds and especially their isomeric 8,12-sesqui-
terpene analogues has barely been tapped. Taxonomically,
(1) Merfort, I. Curr. Drug Targets 2011, 12, 1560–1573.
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N.; Kitagawa, I. Chem. Lett. 1986, 85–86. (b) Takahashi, T.; Nemoto, H.;
Kanda, Y.; Tsuji, J.; Fukazawa, Y.; Okajima, T.; Fujise, Y. Tetrahedron
1987, 43, 5499–5520.
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Hogenauer, K.; Simic, O.; Antonello, A.; Hunger, U.; Smith, M. D; Ley,
S. V. Chem.;Eur. J. 2007, 13, 5688–5712. (c) Sun, L.; Shah, F.; Helal,
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r
10.1021/ol3031999
Published on Web 12/20/2012
2012 American Chemical Society

8,12-members represent half of the components isolated
from Nature. Although numerous synthetic strategies
exist in order to access the carbocyclic cores of 6,12-
germacranolides9 and 6,12-guaianolides,10 rather few
references appear in the literature for the synthesis of
isomeric 8,12-germacranolides and 8,12-guaianolides,11
and even fewer study their biological profile.
Figure 2. Initial retrosynthetic plan for the synthesis of furano-
germenone (4).
Despite the direct accessibility to the syn-carveol 8,15 its
oxidation to the ketone 7 was perceived to be rather prob-
lematic. Thus, when it was allowed to be oxidized under a
number of reported conditions (chromium pyrazole,16
TEMPO,17 PCC,18 PDC,18b t-BuOOH in the presence of
metals,19 etc.), an inconsistent, inseparable mixture of oxi-
dized products was observed in very low yields (5À12%).
After extended experimentation, it was found that when
anti-carveol 1020 was used instead of 8 in reaction under
singlet oxygen conditions,21 a 2:1 diastereoisomeric mix-
ture of R- and β-hydroxylated products was obtained,
which after selective protection of secondary alcohols with
pivaloyl group and chromatographic purification led to
the desired compound 11 in 39% overall yield (Scheme 1).
Hydroxyl migration of the unprotected tertiary alcohol
followed by direct oxidation with PCC22 afforded the R,β-
unsaturated ketone 12. 1,4-Conjugated addition of vinyl
group, promoted by copper iodide,23 produced the alky-
lated product 13 in high diastereoselectivity (ratio 12:1)
favoring the syn-orientation between the methyl and the
Figure 1. (A) Biosynthetic correlation of sesquiterpenoids and
(B) selected examples of biological active sesquiterpenoids.
Intrigued by the structural infinity and the possible bio-
logical activity of these sesquiterpenes, our group initiated
a research effort to discover a novel and efficient synthetic
route to 8,12-sesquiterpene motifs. The rich diversity of
this class is well delineated by the existence of germacrane,
guaiane, pseudoguaiane, elemane, eudesmane, and linde-
nane subfamilies (Figure 1).4 In a hypothetical carbocyclic
sesquiterpene biosynthetic pyramid, germacranes lay on
top accounting for all the presented diversity. However,
the exact nature and sequence of these biosynthetic steps
are currently unknown, and their investigation remains a
challenging task.12 On the basis of this biosynthetic hy-
pothesis, furanogermenone(4)13 was envisionedasanideal
common synthetic scaffold to access the rich diversity of
the 8,12-subfamily. Retrosynthesis of 4was designed through
an nonreversible oxy-Cope rearrangement of the non-natural
elemane compound 5, avoiding the known equilibration
between germacrane and elemane pair which predomi-
nantly produces the elemane component.14 Elemane 5could
then be disconnected to carveol 8 utilizing an array of
sequential oxidation and alkyl addition steps (Figure 2).
(15) Garver, L.; Van Eikeren, P. J. Org. Chem. 1976, 41, 2273–2274.
(16) Sakagami, M.; Muratake, H.; Natsume, M. Chem. Pharm. Bull.
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10, 4715–4718. (b) Vatele, J.-M. Tetrahedron 2010, 66, 904–912.
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Takahashi, T. Bull. Chem. Soc. Jpn. 1985, 58, 146–151. (b) Fousteris,
M. A.; Koutsourea, A. I.; Nikolaropoulos, S. S.; Riahi, A.; Muzart, J.
J. Mol. Catal. A-Chem. 2006, 250, 70–74. (c) Dauben, W. G; Lorber, M.;
Fullerton, D. S. J. Org. Chem. 1969, 34, 3587–3592. (d) Nakayama, M.;
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J. R. Tetrahedron Lett. 2005, 46, 1067–1070. (b) The enantiomeric excess
of compound 10 was calculated to be 72%. This material was chirally
resolved to 93% ee.
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Org. Lett., Vol. 15, No. 1, 2013
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pivaloate group. Epoxidation with the strict use of one
equivalent of m-CPBA,24 followed by subsequent epoxide
cleavage in methanolic KOH, provided furan compound
14.25 Deprotection of pivaloyl group under basic condi-
tions led to the free alcohol which was readily oxidized by
DMP to the respective ketone 15.26 Finally, nucleophilic
addition of 2-propene to the ketone was accomplished by
using 2-bromopropene with t-BuLi27 providing diastereo-
selectively (dr = 20:1) isomer 5 in 70% yield.
isomer in 58% yield along with 8% of compound 22
(Figure 3 and Scheme 2).
Inspired by the elegant work of Barriault and his group
on tandem oxy-Cope/ene reactions,30 we aimed to explore
the ability of elemane 5 to serve as a common synthetic
scaffold to the synthesis of diverse guaiane structures. Thus,
when 5 was heated to the higher temperature of 140 °C for
prolonged reaction times the same products 20 and 22 were
observed in 40% and 8% yields, respectively.
Scheme 1. Total Syntheses of Furanogermenone (4) and Its
Oxidized Congener 17
Figure 3. Transition states in tandem oxy-Cope/ene reaction.
Comparison ofthe absoluteand relative stereochemistry
of the two newly formed stereocenters in 20 and 22 with
those present in natural guaiane components shows their
perfect matching, pointing out a potential discovery of a
biomimetic transformation. The high enantio- and diaste-
reoselectivity observed in oxy-Cope and ene reaction can be
rationalized through the transition states shown in Figure 3.
Specifically, heating compound 5 rearranges the six-
membered ring to the 10-membered enol carbocycle 18.
The macrocycle exists exclusively in conformation 18 due
to the energetically demanding rotation of tetrasubstituted
enol moiety inside the macrocycle (Figure 3).27 Selective
protonation from the least hindered face of 18 delivers 4A
in high enantioselectivity compared to the starting carveol
10. The initially formed conformer 4A directs the methyl
group axially, leading to disfavored 1,3- and 1,5-diaxial
interactions. In order for the ene reaction to proceed, the
When compound 5 was heated to 120 °C, a thermal oxy-
Cope reaction initiated accomplishing, to our delight, the
first total synthesis of furanogermenone4 in 42% yield and
high enantioselectivity (87% ee)28 along with unreacted
starting material 5. Furanogermenone 4 was readily oxi-
dized under singlet oxygen conditions to provide the methy-
lated congener of curdionolide A29 (17) albeit in low yield.
Interestingly, when 4 was insistently heated to 140 °C for
12 h in toluene, a highly stereoselective ene-type reaction
was observed affording furanÀguaiane 20 as a single
ꢀ
(24) Fuchs, S.; Zinn, S.; Beck, T.; Mosandl, A. J. Agric. Food Chem.
1999, 47, 4100–4105.
(25) Furan moieties incorporated in these systems were found to be
prone to uncontrollable oxidations thus, special care was given that all
molecules bearing furan functionality to be handled in the absence of
light and oxygen.
(26) Yick, C.-Y.; Wong, H. N. C. Tetrahedron 2001, 57, 6935–6940.
(27) Sauer, E. L. O.; Hooper, J.; Woo, T.; Barriault, L. J. Am. Chem.
Soc. 2007, 129, 2112–2119.
(28) The enantiomeric excess was calculated based on the optical
rotation of the natural component. The enantiomeric excess was further
supported by the observed 1H NMR diasteromeric ratio of the SAMP
hydrazone of compound 25.
(30) For excellent studies on the topic: (a) Sauer, E. L. O.; Barriault,
L. J. Am. Chem. Soc. 2004, 126, 8569–8575. (b) Barriault, L.; Deon,
D. H. Org. Lett. 2001, 3, 1925–1927. (c) Arns, S.; Lebrum, M.-E.; Grise,
C. M.; Denissova, I.; Barriault, L. J. Org. Chem. 2007, 72, 9314–9322. (d)
Arns, S.; Barriault, L. Chem. Commun. 2007, 2211–2221. (e) Hooper, J.;
Sauer, E. L. O.; Arns, S.; Woo, T. K.; Barriault, L. Chem.;Eur. J. 2010,
16, 14124–14130.
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(29) Lou, Y.; Zhao, F.; Wu, Z.; Peng, K.-F.; Wei, X.-C.; Chen, L.-X.;
Qiu, F. Helv. Chim. Acta 2009, 92, 1665–1672.
154
Org. Lett., Vol. 15, No. 1, 2013

methyl group should be positioned favorly axial against
the keto group either by rotating the double bond or through
conformer 4B. Both of them can undergo an ene-type
reaction. Reaction through rotation of the double bond still
directs the methyl group to an axial orientation, whereas in
4B the methyl group is positioned in a pseudoequatorial
position, thus favoring 20 over 19.
spontaneous oxidation (Scheme 2). Attempts to ratio-
nalize this transformation revealed a direct correlation
of the free tertiary alcohol and the ability of guaiane
to be oxidized. This oxidation was found to be acceler-
ated on silica gel while it is prohibited in the complete
absence of molecular oxygen. Based on these facts, we
assumed that a hydroxyl promoted delivery of molec-
ular oxygen initiates the reaction on the furan ring
producing intermediate 23. Decomposition of the en-
doperoxide to hydroperoxide with subsequent intra-
molecular trap of the R-position of the furan by the
secondary alcohol leads to intermediate 24 and finally
to compound 25.
Scheme 2. Elemane 5 as a Common Scaffold To Access Diverse
Sesquiterpenoids
In conclusion, there is a high demand for reaction
sequences that lead to diverse structures of biologically
interesting scaffolds. The present study illustrates a highly
efficient route to the synthesis of divergent germacrane,
guaiane and furomelampolide natural core structures
emerging from the different cyclization modes of the
common non-natural elemane scaffold 5. The syntheses
of the three distinct classes of sesquiterpenes described
above have been evolved relying either on the development
of a highly enantioselective oxy-Cope reaction for the
construction of germacranes or its advancement to the
completediastereoselectiveoxy-Cope/enereactioncascade
to access guaiane structural motifs. Reactions that direct
guaiane 20 either to furomelampolide 21 through an acidic
retro-ene reaction or to the congested 25 by its sponta-
neous oxidation have also been explored shedding light
upon potential existing biosynthetic transformations. The
common non-natural elemane scaffold 5 is expected to be
proven applicable in the synthesis of other diverge members
of the sesquiterpene family such as lindenanes, eudesmanes,
pseudoguaianes, etc., providing a reliable entry to prevali-
dated libraries of sesquiterpenoids. Further studies on these
directions are currently in progress and will be communi-
cated in due course.
Compound 20 can serve in its own right as an excellent
precursor for the synthesis of natural-like sesquiterpene
scaffolds. Thus, when it was directly treated with TFA,
a retro-ene reaction led selectively to the formation of
melambolide core producing compound 21 in quantative
yield (Scheme 2). Following our mechanistic hypothesis
for the ene-reaction, the structurally locked melambolide
21 is not expected to permit the favorable orientation
between the ketone and the methyl group for the initiation
of the reaction. Indeed, when compound 21 was heated
between 140 and 200 °C, no formation of guaiane 19 or 20
was observed even after prolonged reaction times.
Acknowledgment. We are grateful toProf. J. Gallos and
Pharmathen SA for their support.
Supporting Information Available. Experimental pro-
cedures and characterization data for all compounds.
This material is available free of charge via the Internet
at http://pubs.acs.org
Furanoguaiane 20 was also found to be extremely
sensitive upon standing. Thus, leaving a sample of 20 in
deuteriurated chloroform for 2 days at 5 °C led to the
selective formation of lactole product 25 through its
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 1, 2013
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