Concise strategy to the core structure of the macrolide queenslandon

Article abstract of DOI:10.1021/ol062479r

(Diagram presented) The fully functionalized core structure of the macrolactone queenslandon was prepared using a novel strategy consisting of a glycolate aldol reaction and hydroboration of the derived enol ether 17 followed by Suzuki cross-coupling with an iodostyrene. After conversion of the cross-coupling product to the seco acid 22, Mitsunobu macrolactonization and protecting group manipulations led to the queenslandon model 5.

Full text of DOI:10.1021/ol062479r

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5833-5836
Concise Strategy to the Core Structure
of the Macrolide Queenslandon
Anton S. Khartulyari, Manmohan Kapur, and Martin E. Maier*
Institut fu¨r Organische Chemie, UniVersita¨t Tu¨bingen, Auf der Morgenstelle 18,
72076 Tu¨bingen, Germany
martin.e.maier@uni-tuebingen.de
Received October 8, 2006
ABSTRACT
The fully functionalized core structure of the macrolactone queenslandon was prepared using a novel strategy consisting of a glycolate aldol
reaction and hydroboration of the derived enol ether 17 followed by Suzuki cross-coupling with an iodostyrene. After conversion of the
cross-coupling product to the seco acid 22, Mitsunobu macrolactonization and protecting group manipulations led to the queenslandon
model 5.
Benzolactones represent an important subclass among the
polyketides.1-3 The ones that feature an acetate as a starter
unit normally contain a 14-membered macrolactone. The
benzoic acid part in these compounds is the result of an
intramolecular aldol condensation. Often a double bond or
a ketomethylene function is located next to the aryl ring.
The aliphatic sector is generally functionalized with hydroxyl
or keto groups. Several benzolactones are depicted in Figure
1. Even though their structures are quite similar, each of them
displays a characteristic and unique type of biological
activity. Thus, the benzolactone core clearly is an important
privileged structure. Queenslandon (1) was isolated from the
strain Chrysosporium queenslandicum IFM51121.4 This
macrolactone showed distinct activity against fungi but was
devoid of antibacterial activity. The classical benzolactone,
the fungal metabolite zearalenone (2), shows oestrogenic
activity.5 The antitumor activity seems to be connected to
(1) Zotchev, S. B.; Stepanchikova, A. V.; Sergeyko, A. P.; Sobolev, B.
N.; Filimonov, D. A.; Poroikov, V. V. J. Med. Chem. 2006, 49, 2077-
2087.
(2) Lergier, J. G.; Broadbelt, L. J.; Hatzimanikatis, V. J. Am. Chem. Soc.
2005, 127, 9930-9938.
(3) Staunton, J.; Weissman, K. Nat. Prod. ReV. 2001, 18, 380-416.
(4) Hoshino, Y.; Ivanova, V. B.; Yazawa, K.; Ando, A.; Mikami, Y.;
Zaki, S. M.; Karam, A.-Z. A.; Youssef, Y. A.; Gra¨fe, U. J. Antibiot. 2002,
55, 516-519.
Figure 1. Some typical 14-membered benzolactones with a methyl
substituent.
10.1021/ol062479r CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/08/2006

the inhibition of cyclin-dependent kinases. The resorcylic
acid lactone L-783,277 (3), a fungal metabolite as well, was
reported to be a selective inhibitor of MEK, a threonine/
tyrosine specific kinase resulting in antitumor activity.6 With
regard to the biological activity, the unsaturated ketone is
important. Another prominent member of the benzolactone
family of natural products, radicicol (4), confers its antitumor
activity through inhibition of the chaperone HSP90.7 The
related pochonins seem to target HSP90 as well, inducing
antiviral and antiparasitic activity.8 It follows that the
benzolactones are important lead structures for the search
of novel antitumor compounds.9 In particular, structure-
activity studies might illuminate key factors that make out
the difference in the binding of a certain kinase.10
could make this strategy less ideal.13,14 Instead, we opted
for a Mitsunobu macrolactonization strategy. As a further
key disconnection, a Suzuki coupling at the vinylic position
(C9-C10) was envisioned.15 The necessary alkyl-borane, in
turn, should result from a diastereoselective hydroboration
of an exocyclic enol ether. The stereocenter at C13 would
be the result of a glycolate aldol reaction.
The aldehyde 10 was synthesized starting from racemic
propylene oxide [(()-6] in four steps (Scheme 1). Jacobsen
Scheme 1. Synthesis of Aldehyde 10
In this paper, we describe the synthesis of the queens-
landon analogue 5 based on the key bond-forming reactions
indicated in Figure 2. Major challenges that we recognized
resolution furnished the (R)-epoxide (+)-6 in 99% ee.16
Opening of this epoxide with either the Grignard reagent 7a
or 7b in the presence of catalytic amounts of CuI led to the
corresponding secondary alcohols 8a and 8b, respectively.
The hydroxy acetal 8a turned out to be rather sensitive
toward internal transacetalization. It was therefore im-
mediately protected with tert-butyldiphenylsilyl chloride
(TBDPSCl). Hydrolysis of the acetal in compound 9a
provided aldehyde 10.17 The six-membered acetal 8b could
be isolated in higher yield (75% vs 58%) and found to be
more stable. However, cleavage of the acetal function on
the silyl-protected 9b was less efficient.
Figure 2. Key retrosynthetic disconnections for the queenslandon
model compound 5.
from a synthetic point of view were the connection of the
aliphatic chain to the aryl ring and the creation of the
carbohydrate-like sector. For the macrolactonization, a ring-
closing metathesis (RCM) strategy might be considered.11,12
However, steric hindrance around the styrene double bond
The Andrus glycolate 14 was prepared essentially accord-
ing to the literature from p-methoxybenzylalcohol, but one
step was slightly modified (Scheme 2).18,19 Thus, we found
that the Wittig-Horner condensation of phosphonate 11 with
anisaldehyde using NaOMe as a base gave only low yields
of the stilbene 12 irrespective of the solvent (DMF or THF).
(5) (a) Hidy, P. H.; Baldwin, R. S.; Greasham, R. L.; Keith, C. L.;
McMullen, J. R. AdV. Appl. Microbiol. 1977, 22, 59-82. (b) Bennett, J.
W.; Klich, M. Clin. Microbiol. ReV. 2003, 16, 497-516.
(6) Dombrowski, A.; Jenkins, R.; Raghoobar, S.; Bills, G.; Polishook,
J.; Pelaez, F.; Burgess, B.; Zhao, A.; Huang, L.; Zhang, Y.; Goetz, M. J.
Antibiot. 1999, 52, 1077-1088.
(7) (a) Janin, Y. L. J. Med. Chem. 2005, 48, 7503-7512. (b) Turbyville,
T. J.; Wijeratne, E. M. K.; Liu, M. X.; Burns, A. M.; Seliga, C. J.; Luevano,
L. A.; David, C. L.; Faeth, S. H.; Whitesell, L.; Gunatilaka, A. A. L. J.
Nat. Prod. 2006, 69, 178-184.
(8) Hellwig, V.; Mayer-Bartschmid, A.; Mu¨ller, H.; Greif, G.; Kleymann,
G.; Zitzmann, W.; Tichy, H.-V.; Stadler, M. J. Nat. Prod. 2003, 66, 829-
837.
(13) For the synthesis of zearalenone via RCM, see: Fu¨rstner, A.; Thiel,
O. R.; Kindler, N.; Bartkowska, B. J. Org. Chem. 2000, 65, 7990-7995.
(14) For the synthesis of zearalenone via intramolecular Stille coupling,
see: Kalivretenos, A.; Stille, J. K.; Hegedus, L. S. J. Org. Chem. 1991, 56,
2883-2894.
(15) For recent reviews, see: (a) Suzuki, A. Chem. Commun. 2005,
4759-4763. (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.
2005, 117, 4516-4563; Angew. Chem. Int. Ed. 2005, 44, 4442-4489.
(16) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 1307-1315.
(9) For a summary of synthetic strategies to the related benzolactone
enamides, see: Yet, L. Chem. ReV. 2003, 103, 4283-4306.
(10) Cohen, P. Nat. ReV. 2002, 1, 309-315.
(17) For the synthesis of a related aldehyde from lactate, see: Haynes,
R. K.; Lam, W. W. L.; Yeung, L.-L.; Williams, I. D.; Ridley, A. C.; Starling,
S. M.; Vonwiller, S. C.; Hambley, T. W.; Lelandais, P. J. Org. Chem. 1997,
62, 4552-4553.
(11) Parenty, A.; Moreau, X.; Campagne, J. M. Chem. ReV. 2006, 106,
911-939.
(12) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199-2238.
5834
Org. Lett., Vol. 8, No. 25, 2006

Scheme 2. Synthesis of the Andrus Glycolate 14
Scheme 3. Aldol Reaction, Protection, Tebbe Olefination,
Hydroboration, and Suzuki Cross-Coupling
A much better yield could be realized with potassium tert-
butoxide as base. Dihydroxylation20 of alkene 12 using AD-
mix-R led to diol 13. Reaction of diol 13 with di-n-butyltin
oxide followed by treatment with tert-butyl bromoacetate
gave the glycolate 14.
Aldehyde 10 and glycolate 14 were combined via an aldol
reaction employing the dicyclohexylboron enolate of 14 in
the presence of Et3N forming the anti adduct 15 with high
selectivity (9:1 dr) (Scheme 3).18 The aldol product 15 is
somewhat prone to retro aldol reaction. Therefore, its
secondary alcohol function was immediately protected as a
MOM ether. Other attempts at protecting the alcohol of 15
(TBSOTf or TIPSOTf and base, BnBr and Ag2O) were not
successful. Nevertheless, this route allowed for the con-
venient preparation of 16 in gram amounts. The substrate
for the key Suzuki cross-coupling reaction was prepared in
high yield by Tebbe olefination of dioxanone 16 using Petasis
conditions.21 Following addition of 9-BBN to the enol ether
17, the intermediate borane 18 was subjected to a palladium-
catalyzed coupling reaction with iodostyrene 19.22 The latter
was obtained by a Takai reaction23,24 with an E/Z-ratio of
5:1.22 Applying an excess (2 or more equiv) of 19 in the
Suzuki coupling with 18 delivered the alkene 20 enriched
in the desired E-isomer (E/Z > 20:1).
ester with LiOH at reflux proceeded essentially in quantita-
tive yield. Macrolactone formation of hydroxy acid 22 under
Mitsunobu conditions (DEAD, Ph3P, toluene, 0 °C) gave rise
to lactone 23 in high yield (78%). Most likely, conforma-
tional constraints on the backbone, imposed by the dioxane
ring, facilitate formation of the macrocycle. Cleavage of the
Scheme 4. Synthesis of Macrolactone 24 via Mitsunobu
Macrolactonization
To reach the hydroxy acid 22, the silyl ether of 20 was
cleaved with an excess of the HF/pyridine complex at -20
°C in THF (Scheme 4). TBAF in THF, even at reflux, left
the starting material unchanged. Saponification of the methyl
(18) (a) Andrus, M. B.; Meredith, E. L.; Sekhar, B. B. V. S. Org. Lett.
2001, 3, 259-262. (b) Andrus, M. B.; Mendenhall, K. G.; Meredith, E. L.;
Soma Sekhar, B. B. V. Tetrahedron Lett. 2002, 43, 1789-1792. (c) Andrus,
M. B.; Meredith, E. L.; Simmons, B. L.; Sekhar, B. B. V. S.; Hicken, E. J.
Org. Lett. 2002, 4, 3549-3552.
(19) See Supporting Information.
(20) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M.; Xu,
D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768-2771. (b) Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483-
2547.
(21) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392-
6394.
(22) Kapur, M.; Khartulyari, A.; Maier, M. E. Org. Lett. 2006, 8, 1629-
1632.
(23) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408-7410.
(24) Auge, J.; Boucard, V.; Gil, R.; Lubin-Germain, N.; Picard, J.; Uziel,
J. Synth. Commun. 2003, 33, 3733-3739.
Org. Lett., Vol. 8, No. 25, 2006
5835

dioxane in macrolactone 23 could be accomplished with
excess ceric ammonium nitrate in a CH3CN/H2O mixture at
0 °C resulting in diol 24.22
Scheme 5. Selective Monoprotection, Oxidation, and Global
Deprotection
Crystallization of lactone 24 from methanol provided
crystals suitable for X-ray analysis. An ORTEP plot of 24
is shown in Figure 3 indicating the configurations at the chiral
Figure 3. X-ray structure of macrolactone 24.
centers and the conformation of the macrocycle. The X-ray
structure additionally proved the facial selectivity of the
hydroboration step (17 f 18), originally inferred from NMR
data.
sector of queenslandon (1). The synthesis involved 16 steps
and proceeded with good overall yield from racemic pro-
pylene oxide (6). All chiral centers were essentially obtained
via catalytic methods (Jacobsen resolution, ADH). We also
note that the chiral dioxane moiety served multiple purposes
as a chiral auxiliary in the aldol reaction, then as the
controller in the diastereoselective hydroboration step, and
as a conformational constraint during the Mitsunobu macro-
lactonization. The same strategy should allow for the
preparation of further queenslandon analogues and the natural
product itself.
As a final challenge, differentiation of the two secondary
hydroxy functions remained. A related transformation was
described by Kirschning et al. in their total synthesis of
tonantzitlolone where two outside hydroxyl groups of a triol
were protected with triethylsilyl chloride (TESCl) and
imidazole as base.25 In the case at hand, the monosilylation
of 24 with TESCl was indeed possible but the reaction was
rather slow, taking up to three weeks. Using the more reactive
TESOTf (1.5 equiv), 2,6-lutidine as base, and low temper-
ature (-50 °C), we obtained the desired silyl ether 25 in
50% yield within 12 h (Scheme 5). Besides ether 25, some
starting material plus a double protected derivative were
present in the reaction mixture. Subsequent oxidation of
alcohol 25 with Dess-Martin periodinane gave ketone 26.
Global deprotection of 26 under acidic conditions provided
the queenslandon analogue 5. Additionally, deprotection of
24 led to triol 27.
Acknowledgment. Financial support by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen
Industrie is gratefully acknowledged. Manmohan Kapur
thanks the Alexander von Humboldt foundation for a
postdoctoral fellowship. We also thank Dr. Ca¨cilia Maichle-
Mo¨ssmer for the X-ray structures and Graeme Nicholson for
measuring the HRMS spectra.
The regiochemistry in the selective ether formation was
inferred from the COSY NMR spectrum of the final
compound, dihydroxyketone 5. Most supportive in the
assignment was the absence of a cross-peak between 11-H
and 13-H (see Supporting Information). Rather prominent
correlations were seen for the methine H’s, 11-H and 13-H,
with their neighboring methylene groups. The keto group
resonates at δ ) 212.5 ppm in the 13C NMR spectrum.
Preliminary cytotoxicity assays (L929 mouse fibroblast cells)
on macrolactone 5 showed an IC50 of 40 µg mL-1. At the
same concentration, 27 was less active, reaching an inhibition
of 40%.26
Note Added after ASAP Publication: Mitsunobu mac-
rolactonization was incorrectly identified as Yamaguchi
macrolactonization in the version published ASAP November
8, 2006; the corrected version was published ASAP No-
vember 10, 2006.
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds reported
and copies of NMR spectra for important intermediates. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we developed an efficient asymmetric
synthesis of macrolactone 5, featuring the complete aliphatic
OL062479R
(26) These assays were performed in the group of Dr. Florenz Sasse,
Helmholtz-Zentrum fu¨r Infektionsforschung GmbH, Chemische Biologie,
Inhoffenstrasse 7, 38124 Braunschweig, Germany.
(25) Jasper, C.; Wittenberg, R.; Quitschalle, M.; Jakupovic, J.;
Kirschning, A. Org. Lett. 2005, 7, 479-482.
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