Total synthesis and structural confirmation of ent-galbanic acid and marneral

Article abstract of DOI:10.1021/ol8010216

(Chemical Equation Presented) By capitalizing on a highly selective Claisen rearrangement, ent-galbanic acid 1 and (+)-marneral 2 have been synthesized. The relative configurations of (+)-1 and (+)-2 were unambiguously established by X-ray crystallographi

Full text of DOI:10.1021/ol8010216

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2853-2856
Total Synthesis and Structural Confirmation
of ent-Galbanic Acid and Marneral
Andrei Corbu, Manuel Perez, Maurizio Aquino, Pascal Retailleau, and
Simeon Arseniyadis*
Institut de Chimie des Substances Naturelles, CNRS, F-91198 Gif-sur-YVette, France
simeon.arseniyadis@icsn.cnrs-gif.fr
Received May 3, 2008
ABSTRACT
By capitalizing on a highly selective Claisen rearrangement, ent-galbanic acid 1 and (+)-marneral 2 have been synthesized. The relative
configurations of (+)-1 and (+)-2 were unambiguously established by X-ray crystallographic analysis of the precursors 11a and 20, with the
absolute configuration ensuing from their derivation from R-pulegone. In this way, the controversial issue of the configuration of galbanic acid
was unequivocally settled.
Galbanic acid, a known constituent of the gum-resins
galbanum1 and asafetida,2 is a sesquiterpene coumarin ether,
Scheme 1
showing antibiotic3 and hepatoprotective properties.4 It
occurs in plants from the genus Ferula, accompanied by
coumarins with acyclic as well as monocyclic sesquiterpene
skeleta, and was assigned structure (-)-1 (Scheme 1).
Although originally described as an antibiotic principle,
galbanic acid was recently demonstrated to synergize the
activity of antibiotics rather than simply mimick their
antibacterial activity5 opening up interesting applications for
deaths each year than AIDS in the U.S.6 Surprisingly, the
structure of galbanic acid is still debated. The original
the treatment of MRSA (methicillin-resistant Staphylococcus
aureus) infections, a scourge currently accounting for more
assignment made by Bagirov et al. was later revised by Lee
et al.7 who proposed structure 3, reverting the relative
(1) Structure and stereochemistry of galbanic acid from galbanum:
Bagirov, V. Y.; Scheichenko, V. I.; Veselovskaya, N. V.; Sklyar, Y. E.;
Savina, A. A.; Kir’yanova, I. A. Khim. Prir. Soedin. 1980, 16, 620–623.
(2) (a) Isolation from asafetida: Appendino, G.; Tagliapetra, S.; Nano,
G. M.; Jakupovic, J. Phytochemistry 1994, 35, 183–186. (b) Appendino,
G.; Maxia, L.; Bascope, M.; Houghton, P. J.; Sanchez-Duffhues, G.; Mun˜oz,
E.; Sterner, O. J. Nat. Prod. 2006, 69, 1101–1104.
configurations at C8 and C9, after extensive NMR investiga-
tions.
This structure revision has been mentioned in several
articles, but to the best of our knowledge, neither a total
(3) (a) Racnicer, S. K.; Veeravally, J. Chem. Ind. (London); 1975; Vol.
431, No 12. (b) Artamonov, A. F.; Nusipbekova, K. A.; Nigmatullina, F. S.;
Dzhienbaev, B. Zh. Chemistry of Natural Compounds; 1997; Vol. 33, No
2, pp 162-164.
(5) Shahverdi, A. R.; Fakhimi, A.; Zarrini, G.; Dehghan, G.; Iranshahi,
M. Biol. Pharm. Bull. 2007, 30, 1805–1807.
(6) Bancroft, E. A. J. Am. Med. Assoc. 2007, 298, 1803–1804.
(7) Lee, S.-G.; Ryu, S. Y.; Ahn, J. W. Bull. Korean Chem. Soc. 1998,
19, 384–386.
(4) Syrov, V. N.; Khushbactova, Z. A.; Nabiev, A. N. Farmakol.
Toksikol. 1990, 53, 41.
10.1021/ol8010216 CCC: $40.75
Published on Web 06/06/2008
2008 American Chemical Society

Scheme 2
(E)-vinyl iodide 9 (Scheme 8), respectively. The key step in
our route involved the mercury-catalyzed Claisen rearrange-
ment of allyl-alcohol 15, itself accessible in five straight-
forward steps from 7. This should allow the stereoselective
introduction of the side chain at C10, which would be
ultimately one-carbon homologated to 19. Linking to the
coumarin could be subsequently performed at C11 by
converting the free hydroxyl functionality into a tosylate
leaving group followed by an ether formation.
Figure 1. Simplified schematic representation of Appendino’s and
Marner’s biogenetic proposals.
synthesis nor the ambiguity inherent in the structural revision8
has yet been addressed. Galbanic acid 1 bears structural
similarities with marneral 2,9 an alleged precursor of
triterpenoid iridals, themselves precursors of irones, which
suggests a common biogenetic origin. Marneral has been
suggested to derive from an acyclic precursor through a series
of cyclizations, 1,2-hydride, shifts and methyl migrations
(Figure 1),10 and one could assume a similar biosynthetic
sequence for the derivation of galbanic acid from umbelli-
prenin (5). The squalene to C10-epi marnerol sequence has
been successfully reproduced in a laboratory setting by
Marner and co-workers by using van Tamelen’s biomimetic
cyclization of 2,3-epoxysqualene,11 while Matsuda et al.12
have validated the Marner proposal that oxidosqualene
cyclizes en route to iridals via a B-ring boat intermediate to
marneral 2, providing the first experimental proof of a Grob
fragmentation in triterpene synthesis. On the other hand,
Appendino et al., while revising the structure of asacoumarin
B to galbanic acid, proposed a different biogenetic origin
for this compound,2a via a fragmentative, rather than a
cyclizative route, suggesting mogoltadone 6 as the biogenetic
precursor of galbanic acid (Figure 1).
Scheme 3
Elaboration of 7 began with the installation of the methyl
and ester groups at C9 using standard literature conditions
to afford 10 and its C-/O-biscarboxymethylated counterpart,
which was recycled by basic treatment (see Supporting
Information). After chromatographic separation, standard
reduction with LiAlH4 produced the primary-secondary diol
intermediates 11a and 11b in quantitative yield and 87:11
ratio, respectively. The major diol (11a) was protected as
its tert-butyldimethylsilyl ether 12 to be used in the allyl-
Claisen reaction (Scheme 3).
The stereochemistry of 11a was unequivocally established
by an X-ray crystallographic analysis (Figure 2). The one-
pot allyl-Claisen rearrangement conditions, reported by Dams
et al.13 on cis-pulegol derivatives, did not work with 12.
Instead, the stereoselective introduction of the side chain at
C10 has been cleanly achieved by first inducing the rear-
rangement of 11a in AcOH14 leading to 14 along with diene
13 (75% yield, 12:1 ratio, Scheme 3).
In this communication, we have developed a divergent
strategy to both galbanic acid and marneral, based on the
coupling of commercially available (R)-pulegone-derived
right halves 19 and 31 with umbelliferone 8 (Scheme 2) and
(8) The three stereogenic centres of galbanic acid are contiguous,
with the central one being tetrasubstituted. Within this structural context,
it is difficult to translate dipolar interactions into a configurational
assignment.
(9) Matsuda et al. (see ref 11) named this compound Marneral (and its
corresponding alcohol 33 Marnerol) in recognition of the pioneering work
of Marner on iridals. 2 has never been isolated but was hypothesized to be
the first carbocyclic precursor in the biosynthesis of iridals. (a) Marner,
F.-J.; Krick, W.; Gellrich, B.; Jaenicke, L.; Winter, W. J. Org. Chem. 1982,
47, 2531–2538. (b) Marner, F.-J. Curr. Org. Chem. 1997, 1, 153–186. (c)
Lamshoft, M.; Schmickler, H.; Marner, F.-J. Eur. J. Org. Chem. 2003, 727–
733.
(10) Marner, F.-J.; Longerich, I. Liebigs Ann. Chem. 1992, 269–272.
(11) (a) Marner, F.-J.; Kasel, T. J. Nat. Prod. 1995, 58, 319–323. (b)
Sharpless, K. B.; van Tamelen, E. E. J. Am. Chem. Soc. 1969, 91, 1848–
1849.
(13) CH3C(OEt)3, C2H5CO2H, H2O, 3 h at 138 °C: Dams, I.; Bialonska,
A.; Ciunik, Z.; Wawrzenczyk, C. Tetrahedron: Asymmetry 2005, 16, 2087–
2097.
(12) Xiong, Q.; Wilson, W. K.; Matsuda, S. P. T. Angew. Chem., Int.
Ed. 2006, 45, 1285–1288.
(14) Eschinasi, E. H. J. Org. Chem. 1970, 35, 2010–2012.
2854
Org. Lett., Vol. 10, No. 13, 2008

Scheme 5
Figure 2. ORTEP view of the molecular structure of 11a.
The stereochemistry of 16 was established by an X-ray
crystallographic analysis on 20, obtained by reduction of the
aldehyde at C2 (Figure 3).
The rearranged diol 14, subsequent to a TBS-protection
at C11, underwent the desired Claisen rearrangement upon
heating at 190 °C in the presence of vinyl ether and mercuric
acetate as a catalyst,15 affording 16 in 80% yield along with
its C10-R epimer (92:8 ratio, Scheme 4).16
Initial efforts to couple 19 with 8 under conventional
heating for the etherification met with total failure. Degrada-
tion of starting material was detected, and no reasonably
clean product could be isolated from the reaction mixture.
Coupling of the precursor alcohol with umbelliferone under
Mitsunobu conditions (DIAD, PPh3, ROH)18 did not proceed
either, yielding only starting materials. On the basis of these
negative outcomes, we turned our attention to a microwave-
assisted coupling. Hence, applying Williamson etherification
conditions in the presence of 18-Crown-619 produced a clean
transformation affording the desired coupling of 8 and 19,
though in very low yield (6%, along with 70% of recovered
starting material).
Scheme 4
Having secured the requisite C8, C9, C10 pattern for the
core cyclohexane subunit 16, a common intermediate for
galbanic acid 1 and marneral 2, the stage was set for chain
elongation prior to etherification for the former and double
chain elongation prior to coupling for the latter. Thus,
alkoxymethylenation of 16 afforded the corresponding enol
ether 17 as a mixture of E/Z isomers, which was subsequently
converted to the required ester 18.17 The latter was desilylated
to its corresponding C11 alcohol, which was taken to the
required tosylate 19 (Scheme 4).
Figure 3. ORTEP view of the molecular structure of 20.
To account for the stereochemical outcome of the Claisen
rearrangement, we could consider that the reaction proceeds
through one of the two half-chair conformers i and ii, with
the latter reacting faster, as it contains a pseudoequatorial
methyl at C9 and an equatorial methyl at C8, compared to
the energetically unfavorable conformer i. It is therefore
proposed that C10-C1 bonding occurs through the more
accessible ꢀ-face of conformer ii (PM3 minimized most
reactive transition structure involved in this process) leading
preferentially to 16 (Scheme 5).
The methyl galbanate 21 thus obtained (Scheme 6), which
is also a natural product and which showed identical spectral
data with the one we prepared starting from natural galbanic
acid ([R]D +24 (c 1.00, CHCl3), lit.:20 [R]D -25.8 (c 1.16,
CHCl3)), was then saponified to the target 1. A comparison
of the physical properties of the natural and synthetic
galbanic acid finally assessed its relative configuration,
(18) Jackson, R. F. W.; Raphael, R. A. J. Chem. Soc., Perkin Trans. 1
1984, 535–539.
(15) Burgstahler, A. W.; Nordin, I. C. J. Am. Chem. Soc. 1961, 83, 198–
206.
(19) Gonzales-Garcia, E. M.; Grognux, J.; Wahler, D.; Reymond, J.-L.
HelV. Chim. Acta 2003, 86, 2458–2470.
(16) For closely related Claisen rearrangements, see: Ireland, R. E.;
Varney, M. D. J. Org. Chem. 1983, 48, 1829–1833.
(17) Piancatelli, G.; Scettri, A.; D’Auria, M. Tetrahedron Lett. 1977,
3483–3484.
(20) The observed specific rotation of synthetic galbanic acid 1 ([a]D
+26 (c 1.00, CHCl3)) was found to be opposite in sign with that of the
natural product ([a]D -23 (c 1.00, CHCl3)), thus establishing the absolute
configuration of galbanic acid as (8S), (9S), (10S).
Org. Lett., Vol. 10, No. 13, 2008
2855

Scheme 6
Scheme 8
confirming the original one proposed by Bagirov.21 In further
trials to establish the viability of coumarine-ether formation
on a model available to us from our previous studies, we
have again encountered a high level of difficulty implement-
ing the segment coupling (Scheme 7). In particular C-O
bond formation at the sterically congested center has been
Scheme 7
protecting group interchange at C3. Treatment of the latter
with 9-BBN in THF, followed by addition of PdCl2(dppf)
and the geometrically pure vinyl iodide 9,24 afforded the
desired coupling product 32 in 67% isolated yield. TBS
deprotection of the latter afforded marnerol 33, which was
converted by a Swern oxidation to marneral 2, both
spectroscopically indistinguishable from the oxidosqualene
cyclase generated biosynthetic substances.12
The work described in this paper has secured both the
relative and the absolute configuration of galbanic acid (1)
and marneral (2). Starting from an (R)-pulegone-derived
cyclohexane core, subunit coupling for ent-galbanic acid
(+)-1 was accomplished in very low yield by using
microwave-assisted etherification, while the B-alkyl Suzuki-
Miyaura coupling afforded marneral 2 in good yield. Though
no optimization was done, the route followed is operationally
simple and validated the structure of both targets. The
confirmation of the original stereostructure of galbanic acid
warns against over-relying on NMR data even in apparently
simple molecular contexts.25
difficult on 2222 containing a similar R-neopentylic substitu-
tion pattern. Coumarin-ether 24 was obtained in still lower
yield (4%). Further model studies employed cyclohexyl
tosylate 25. Moving only one carbon farther from the
neopentylic center, segment coupling proceeded smoothly
under conventional heating to give the galbanic acid analogue
(26) in high yield (80%).
With a route to common intermediate 16 established, we
turned to the one-carbon homologation at C12 (from this
point on, squalene numbering proposed by Marner et al. is
used) prior to the key B-alkyl Suzuki coupling23 en route
for marnerol 33 and marneral 2. The alkyl-borane precursor
31 was prepared by the efficient eight-step sequence, as
depicted in Scheme 8. Wittig methylenation of 16 into
C3-C4 olefin 27 and subsequent hydroboration-oxidation
furnished the requisite alcohol 28, which was acetyl-protected
at C3 to afford 29 in 67% yield over three steps. The presence
of orthogonal protecting groups on the side chains at C3 and
C12 positions provides the opportunity to extend the chain
at C12 via a selective TBS-deprotection of the latter. Swern
oxidation and finally a second Wittig olefination afforded
30, which was taken to the required boronate precursor for
the B-alkyl Suzuki-Miyaura coupling, providing 31 after
Acknowledgment. We thank Professor Giovanni Appen-
dino Universita del Piemonte Orientale, Novara, for supply-
ing natural galbanic acid and helpful discussions and Dr J.
Arteaga, Universidad de Huelva (Spain), for helping in
preliminary experiments to prepare starting materials 10-12.
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Bagirov, V. Y.; Bankovskii, V. I.; Scheichenko, V. I.; Kabanov,
V. S.; Zakharov, P. I. Khim. Prir. Soedin. 1974, 516–517.
(22) Arseniyadis, S.; Yashunsky, D. V.; Mun˜oz Dorado, M.; Brondi
Alves, R.; Wang, Q.; Potier, P. L.; Toupet, L. Tetrahedron 1996, 52, 6215–
6232.
OL8010216
(24) (a) Corbu, A.; Gauron, G.; Castro, J. M.; Dakir, M.; Arseniyadis,
S. Org. Lett. 2007, 9, 4745–4748. (b) Corbu, A.; Aquino, M.; Pratap, T. V.;
Retailleau, P.; Arseniyadis, S. Org. Lett. 2008, 10, 1787–1790.
(25) Six-membered rings can adopt various conformations, while a
shortage of functional groups causes extensive signal overlapping.
(23) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483. (b)
Chemler, S. R.; Trauner, D.; Danishevsky, S. Angew. Chem., Int. Ed. 2001,
40, 4544–4568.
2856
Org. Lett., Vol. 10, No. 13, 2008