Total synthesis of aspercyclide C

Article abstract of DOI:10.1039/b512877c

The first total synthesis of (+)-aspercyclide C (1) is reported using a kinetically controlled RCM reaction to form the 11-membered, unsaturated lactone ring of this bioactive diaryl ether macrolide. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b512877c

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Total synthesis of aspercyclide C{
Alois Fu¨rstner* and Christoph Mu¨ller
Received (in Cambridge, UK) 14th September 2005, Accepted 28th September 2005
First published as an Advance Article on the web 17th October 2005
DOI: 10.1039/b512877c
can be applied. Outlined below is the first total synthesis of
The first total synthesis of (+)-aspercyclide C (1) is reported
using a kinetically controlled RCM reaction to form the
11-membered, unsaturated lactone ring of this bioactive diaryl
ether macrolide.
aspercyclide C 1 aiming to explore some of these possibilities.
Encouraged by previous successful implementations of ring
closing metathesis (RCM) into the total synthesis of natural
products containing medium sized rings,5 we chose this methodo-
logy for the formation of the lactone moiety in 1. Despite the now
well established fact that RCM can provide access to virtually all
ring sizes ¢5,6 applications to 11-membered carbo- and hetero-
cycles remain scarce and are sometimes rather low yielding.7
Moreover, one has to keep in mind that RCM usually affords
(E,Z)-mixtures whenever the incipient ring is large enough to
accommodate both isomers, as is the case in aspercyclide C. The
only method to impose selectivity on the formation of a medium
sized ring by RCM known to date relies upon ‘thermodynamic vs.
kinetic control’ during ring closure. This strategy was developed
as part of a recent total synthesis of the herbicidal decalactone
herbarumin and allowed for the first deliberate preparation of
either stereoisomer of a given olefinic target.8 Specifically,
advantage was taken of the fact that ‘second generation’ catalysts
will scramble the newly formed olefin and hence deliver the
thermodynamic cycloalkene,9 whereas the use of less active ‘first
generation’ catalysts allows trapping of the kinetic isomer.
Provided that the (E)- and (Z)-isomer of a medium sized
cycloalkene are sufficiently different in energy, good levels of
stereoselectivity can be attained.8
Binding of immunoglobulin E (IgE) to the human high-affinity
IgE receptor FceRI located in the membrane of mast cells and
basofils is a pivotal step in triggering allergic disorders.1 Upon
cross linking of the resulting IgE?FceRI complex by multivalent
allergens, a signal transduction cascade is activated which can
ultimately manifest itself in diseases such as allergic rhinitis or
asthma. Although IgE and its high affinity receptor therefore
constitute highly relevant biochemical targets, any ‘‘anti-IgE
therapy’’ copes with the problem of how to selectively disrupt
the interaction between two large proteins.2 Hence, it may not
come as a surprise that small molecule IgE-antagonists are
essentially unknown.3
Only recently, a group at Merck has reported the isolation of a
family of natural products claimed to exert such a function.
Though only moderately active (IC50 of 200 mM for aspercyclide
A (2)), the aspercyclides 1–3 constitute a very first hit meriting
further investigation.4 These fungal metabolites were extracted
from the culture broth of an Aspergillus sp. derived from a soil
sample collected in Tanzania. They consist of an 11-membered
unsaturated lactone moiety flanked by a differently substituted
diaryl ether backbone. While these structural features invite a host
of modifications that should allow for a detailed mapping and
optimisation of structure/activity relationships, the rather strained
nature of the targets sets serious limitations as to the methods that
Unfortunately, however, this useful concept seems to find its
limitations in the projected case. According to our semi-
empirical calculations, the O-protected stereoisomer (E)-4 is only
¡ 1.8 kcal mol21 more stable than its isomer (Z)-4,{ thus making
appreciable levels of thermodynamic control during RCM rather
unlikely. Because possible kinetic preferences during ring closure
remain difficult to predict,10 the aspercyclide C case highlights
once more the as yet incomplete understanding of and missing
reagent-control over metathetic transformations.11
Max-Planck-Institut fu¨r Kohlenforschung, D-45470, Mu¨lheim/Ruhr,
Germany. E-mail: fuerstner@mpi-muelheim.mpg.de;
Fax: +49 208 306 2342; Tel: +49 208 306 2994
{ Electronic supplementary information (ESI) available: Experimental
procedure for the oxyallylation and the RCM reaction, spectroscopic data
of compounds 13 and 17, and copies of pertinent NMR spectra. See DOI:
10.1039/b512877c
Despite these concerns, a total synthesis of 1 was pursued
starting from commercial 2-methyl-6-nitrobenzoic acid (Scheme 1).
Esterification followed by reduction of the nitro group in 5 with
H2 over Pd/C and conversion of the resulting aniline 6 to the
corresponding aryl bromide by a Sandmeyer reaction gave
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 5583–5585 | 5583

View Article Online
out to be more difficult than anticipated, good yields of diene 15
could be secured by the Mukaiyama method,17 thus setting the
stage for the envisaged closure of the medium sized ring by RCM.
As outlined above, our semi-empirical calculations had shown
that both stereoisomers of the resulting cycloalkene are similar in
energy, thus suggesting that thermodynamic control should be
counterproductive in this particular case. As a result, an attempt
was made to cyclize diene 15 with the aid of the ‘first generation’
Grubbs carbene complex (PCy3)2Cl2RuLCHPh which is known to
equilibrate cycloalkenes only slowly due to its reduced activity
towards disubstituted olefins.18 Although ring closure remained
incomplete (¡ 50% conversion after 5 d at 80 uC using up to
50 mol% of catalyst added in portions over the course of the
reaction), NMR inspection of the crude product showed that
(E)-17 had formed exclusively, indicating that the desired isomer
must be kinetically favoured. Gratifyingly, the ‘second generation’
complex 16 (20 mol%, added in 2 portions) bearing an
N-heterocyclic carbene ligand19 also gave appreciable selectivity,
even though scrambling of the product initially formed should be
more facile due to the higher reactivity of this catalyst. The
reaction was best performed in dilute (2 mM), refluxing toluene
solution,20 giving product 17 in 69% yield with an E : Z ratio of
5 : 1 after 4 h reaction time (Scheme 3). The fact that the isomer
distribution did not change significantly with time even though
fresh catalyst was introduced in portions over the course of the
reaction can only be rationalized by assuming a high kinetic barrier
towards isomerization.21 In line with this notion, pure (E)-17
remained unchanged when exposed to high loading of catalyst 16
(up to 50 mol%) under an ethylene atmosphere.
Scheme 1 Reagents and conditions: [a] MeI, K2CO3, acetone, reflux,
98%; [b] H2 (1 atm), Pd/C (10% w/w), EtOH, quant.; [c] NaNO2/HBr; then
CuBr, HBr, 0 uC A r.t., 97%; [d] Ph3PCH3Br, NaHMDS (2.1 equiv.),
THF, 70%; [e] CuO, K2CO3, pyridine, 130 uC, 55%; [f] aq. NaOH, MeOH,
then aq. HCl quant.
multigram amounts of 7. Ullmann coupling12 of this compound
with phenol 9 (accessible in 70% yield in one step from commercial
aldehyde 8, PPh3CH3Br and 2.1 equiv. of NaHMDS) was
promoted by CuO and K2CO3 in pyridine at 130 uC (sealed
tube),13 affording product 10 in 55% isolated yield. This outcome is
respectable in view of the crowded neighbourhood of the diaryl
ether bridge. Saponification of the methyl ester under standard
conditions gave acid 11 without incident.
Flash chromatography allowed for the isolation of the desired
product (E)-17 in pure form from the crude reaction mixture,
whereas analytical samples of the (Z)-isomer could only be
An anti-selective Duthaler–Hafner oxy-allylation reaction14–16
provided rapid access to the aliphatic segment in optically active
form (Scheme 2). Specifically, deprotonation of allyl p-methoxy-
phenyl (PMP) ether 12 with sec-BuLi at 278 uC followed by
transmetallation of the resulting allyllithium species with (S,S)-14
furnished an organotitanium reagent which transferred its
functionalized allyl substituent to hexanal to give homoallyl
alcohol 13 in 69% isolated yield (anti : syn . 95 : 5, ee 5 92%).
Although the esterification of this compound with acid 11 turned
Scheme 2 Reagents and conditions: [a] sec-BuLi, then complex 14,
hexanal, THF/Et2O, 278 uC, 69%; [b] acid 11, N-methyl-2-chloropyri-
dinium iodide, Et3N, MeCN, reflux, 82%.
Scheme 3 Reagents and conditions: [a] see text; [b] CAN, MeCN/H2O,
0 uC, 67%; [c] BBr3, CH2Cl2, 278 uC A 0 uC, 40%.
5584 | Chem. Commun., 2005, 5583–5585
This journal is ß The Royal Society of Chemistry 2005

View Article Online
6 (a) R. H. Grubbs and S. Chang, Tetrahedron, 1998, 54, 4413; (b)
A. Fu¨rstner, Angew. Chem., Int. Ed., 2000, 39, 3012; (c) M. Schuster and
S. Blechert, Angew. Chem., Int. Ed. Engl., 1997, 36, 2036.
7 (a) K. C. Nicolaou, T. Montagnon, G. Vassilikogiannakis and
C. J. N. Mathison, J. Am. Chem. Soc., 2005, 127, 8872; (b)
J. D. Winkler, J. M. Holland, J. Kasparec and P. H. Axelsen,
Tetrahedron, 1999, 55, 8199; (c) T. R. Hoye and M. A. Promo,
Tetrahedron Lett., 1999, 40, 1429; (d) Y. J. Kim and D. Lee, Org. Lett.,
2004, 6, 4351; (e) G. Vassilikogiannakis, I. Margaros and M. Tofi, Org.
Lett., 2004, 6, 205; (f) M. Arisawa, C. Kato, H. Kaneko, A. Nishida and
M. Nakagawa, J. Chem. Soc., Perkin Trans. 1, 2000, 1873; (g)
K. Go¨rlitzer and A. Lorenz, Pharmazie, 2004, 59, 763; (h) S. C. Cho,
P. H. Dussault, A. D. Lisec, E. C. Jensen and K. W. Nickerson, J. Chem.
Soc., Perkin Trans. 1, 1999, 193; (i) M. Delgado and J. D. Martin,
J. Org. Chem., 1999, 64, 4798; (j) S. E. Denmark and S.-M. Yang, J. Am.
Chem. Soc., 2002, 124, 2102; (k) J. M. Daugherty, M. Jime´nez and
P. R. Hanson, Tetrahedron, 2005, 61, 6218.
obtained by preparative HPLC.§ With the desired cycloalkene
in hand, the completion of the synthesis was straightforward,
comprising an oxidative cleavage of the PMP-ether with CAN22
followed by demethylation using BBr3 in CH2Cl2 at 278 uC. While
the spectroscopic data of synthetic aspercyclide C (1) are in
excellent agreement with those reported in the literature,§ the
optical rotation of our sample ([a]2D3 +229.7 (c 0.39, MeOH)) is
significantly higher than that given in ref. 4 ([a]2D3 +122.5 (c 0.4,
MeOH)). Despite this discrepancy in magnitude, the match of all
other data leaves no doubt that the constitution and stereo-
chemistry of 1 have previously been correctly assigned by
spectroscopic means.
Generous financial support by the Max-Planck-Gesellschaft, the
Fonds der Chemischen Industrie (Kekule´ stipend to C. M.), and
the Merck Research Council is gratefully acknowledged. We thank
Dr C. Nevado for her help with the semi-empirical calculations.
8 A. Fu¨rstner, K. Radkowski, C. Wirtz, R. Goddard, C. W. Lehmann
and R. Mynott, J. Am. Chem. Soc., 2002, 124, 7061.
9 (a) C. W. Lee and R. H. Grubbs, Org. Lett., 2000, 2, 2145; (b)
A. Fu¨rstner, O. R. Thiel, N. Kindler and B. Bartkowska, J. Org. Chem.,
2000, 65, 7990; (c) A. Fu¨rstner, O. R. Thiel and L. Ackermann, Org.
Lett., 2001, 3, 449; (d) A. B. Smith, C. M. Adams and S. A. Kozmin,
J. Am. Chem. Soc., 2001, 123, 990; (e) Z. Xu, C. W. Johannes,
A. F. Houri, D. S. La, D. A. Cogan, G. E. Hofilena and A. H. Hoveyda,
J. Am. Chem. Soc., 1997, 119, 10302.
Notes and references
{ Calculations were carried out using PC Spartan ’02, Wavefunction Inc.
Conformational analyses were performed with an MMFF force field, single
point energies were calculated (HF-3-21G*) for the minimum energy
conformer of each stereoisomer.
10 For an in-depth computational study see: S. F. Vyboishchikov and
W. Thiel, Chem.–Eur. J., 2005, 11, 3921.
§ Physical and spectroscopic data: A compilation of the data of the
metathesis products (E)-17 and (Z)-17 as well as copies of their NMR
spectra can be found in the Supporting Information. Physical and
spectroscopic data of aspercyclide C (1): mp 188–189 uC; [a]23D 5 +229.7u
(c 0.39, MeOH); 1H NMR (400 MHz, CDCl3): d 7.13 (t, J 5 8.0 Hz, 1 H),
7.07 (t, J 5 7.9 Hz, 1 H), 6.98 (dd, J 5 8.1 Hz, J 5 1.6 Hz, 1 H), 6.90 (d,
J 5 7.6 Hz, 1 H), 6.68 (bd, J 5 7.6 Hz, 1 H), 6.65 (d, J 5 8.4 Hz, 1 H), 6.27
(d, J 5 15.9 Hz, 1 H), 5.99 (dd, J 5 15.9 Hz, J 5 9.5 Hz, 1 H), 5.22 (dt,
J 5 9.3 Hz, J 5 2.0 Hz, 1 H), 4.04 (t, J 5 9.3 Hz, 1 H), 2.37 (s, 3 H), 2.07
(m, 1 H), 1.72–1.65 (m, 3 H), 1.55 (m, 2 H), 1.37 (m, 4 H), 0.93 (t, J 5 7.0 Hz,
3 H); 13C NMR (100 MHz, CDCl3): d 167.8, 153.7, 150.0, 141.9, 137.5,
135.4, 132.5, 130.3, 128.1, 126.7, 126.0, 125.0, 121.4, 115.5, 114.7, 77.5, 77.0,
31.6, 31.6, 25.3, 22.5, 19.5, 14.0; IR (film): 3248, 2957, 2924, 2859, 1709,
1588, 1458, 1267, 963, 763; MS (EI) m/z (rel. intensity): 382 ([M+], 1), 282
(50), 264 (29), 254 (22), 253 (100), 236 (30), 211 (10), 135 (19); HR-MS (EI)
calcd.: 405.1675 [(M + Na)+]; found: 405.1672; elemental analysis calcd. for
C23H26O5: C 72.23, H 6.85; found: C 72.18, H 6.73%. For copies of the
NMR spectra of 1, see Supporting Information.{
11 For rings with ¢ 12 atoms, ring closing alkyne metathesis (RCAM)
followed by semi-reduction is a reliable method to exert stereocontrol,
cf.: (a) A. Fu¨rstner and P. W. Davies, Chem. Commun., 2005, 2307; (b)
A. Fu¨rstner and G. Seidel, Angew. Chem., Int. Ed., 1998, 37, 1734; (c)
A. Fu¨rstner and L. Turet, Angew. Chem., Int. Ed., 2005, 44, 3462 and
literature cited therein.
12 Reviews: (a) J. S. Sawyer, Tetrahedron, 2000, 56, 5045; (b) S. V. Ley and
A. W. Thomas, Angew. Chem., Int. Ed., 2003, 42, 5400.
13 N. N. Kulkarni, V. S. Kulkarni, S. R. Lele and B. D. Hosangadi,
Tetrahedron, 1988, 44, 5145.
14 A. Hafner, R. O. Duthaler, R. Marti, G. Rihs, P. Rothe-Streit and
F. Schwarzenbach, J. Am. Chem. Soc., 1992, 114, 2321.
15 For recent applications of the oxy-allylation in natural product synthesis
see: (a) D. Castoldi, L. Caggiano, L. Panigada, O. Sharon, A. M. Costa
and C. Gennari, Angew. Chem., Int. Ed., 2005, 44, 588; (b) J. Cossy,
C. Willis, V. Bellosta and L. Saint-Jalmes, Synthesis, 2002, 951.
16 For an early application of a Duthaler–Hafner reaction in combination
with RCM from our group, see: A. Fu¨rstner and K. Langemann, J. Am.
Chem. Soc., 1997, 119, 9130.
17 T. Mukaiyama, M. Usui, E. Shimada and K. Saigo, Chem. Lett., 1975,
1045.
18 P. Schwab, R. H. Grubbs and J. W. Ziller, J. Am. Chem. Soc., 1996,
118, 100.
19 (a) A. Fu¨rstner, O. R. Thiel, L. Ackermann, H.-J. Schanz and
S. P. Nolan, J. Org. Chem., 2000, 65, 2204; (b) A. Fu¨rstner,
L. Ackermann, B. Gabor, R. Goddard, C. W. Lehmann, R. Mynott,
F. Stelzer and O. R. Thiel, Chem.–Eur. J., 2001, 7, 3236.
20 (a) K. Yamamoto, K. Biswas, C. Gaul and S. J. Danishefsky,
Tetrahedron Lett., 2003, 44, 3297; (b) C. A¨ıssa, R. Riveiros, J. Ragot
and A. Fu¨rstner, J. Am. Chem. Soc., 2003, 125, 15512.
21 For a related example of kinetic control during the formation of a
10-membered ring with the aid of a ‘second generation’ catalyst see
ref. 15a.
22 (a) T. Fukuyama, A. A. Laird and L. M. Hotchkiss, Tetrahedron Lett.,
1985, 26, 6291; (b) M. Petitou, P. Duchaussoy and J. Choay,
Tetrahedron Lett., 1988, 29, 1389.
1 J.-P. Kinet, Annu. Rev. Immunol., 1999, 17, 931.
2 (a) P. Jardieu, Curr. Opin. Immunol., 1995, 7, 779; (b) For the structure
of the human high-affinity IgE receptor see: S. C. Garman, J.-P. Kinet
and T. S. Jardetzky, Annu. Rev. Immunol., 1999, 17, 973.
3 For peptidic antagonists of the high-affinity IgE receptor see:
G. R. Nakamura, M. E. Reynolds, Y. M. Chen, M. A. Starovasnik
and H. B. Lowman, Proc. Natl. Acad. Sci. U. S. A., 2002, 99, 1303 and
literature cited therein.
4 S. B. Singh, H. Jayasuriya, D. L. Zink, J. D. Polishook,
A. W. Dombrowski and H. Zweerink, Tetrahedron Lett., 2004, 45,
7605.
5 (a) A. Fu¨rstner and T. Mu¨ller, Synlett, 1997, 1010; (b) A. Fu¨rstner
and K. Langemann, J. Org. Chem., 1996, 61, 8746; (c) A. Fu¨rstner
and O. R. Thiel, J. Org. Chem., 2000, 65, 1738; (d) A. Fu¨rstner and
K. Radkowski, Chem. Commun., 2001, 671; (e) A. Fu¨rstner, O. Guth,
A. Du¨ffels, G. Seidel, M. Liebl, B. Gabor and R. Mynott, Chem.–Eur.
J., 2001, 7, 4811; (f) A. Fu¨rstner and M. Schlede, Adv. Synth. Catal.,
2002, 344, 657.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 5583–5585 | 5585