An avenue to the sordarin core adaptable to analog synthesis

Article abstract of DOI:10.1021/ol701547r

We describe a synthesis of ketones 3 (X = O-R or CN; Y = H or alkyl), which are useful building blocks for the preparation of analogs of the potent antifungal agent sordarin, 1. Congeners of 1 constructed from 3 should permit detailed SAR investigations of the terpenoid core of the natural product.

Full text of DOI:10.1021/ol701547r

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4119-4122
An Avenue to the Sordarin Core
Adaptable to Analog Synthesis
Huan Liang,‡ Arnaud Schule´,§ Jean-Pierre Vors,¶ and Marco A. Ciufolini*,‡,§
Department of Chemistry, UniVersity of British Columbia, 2036 Main Mall,
VancouVer, British Columbia V6T 1Z1, Canada, Laboratoire de Synthe`se et
Me´thodologies Organiques, UMR 5181, UniVersite´ Claude Bernard Lyon 1 and Ecole
Supe´rieure de Chimie, Physique, Electronique de Lyon, 43 Bd. du 11 NoVembre 1918,
69622 Villeurbanne, France, and Bayer CropScience SA, 14-20 Rue Pierre Baizet,
69009 Lyon, France
ciufi@chem.ubc.ca
Received June 30, 2007
ABSTRACT
We describe a synthesis of ketones 3 (X
) O−R or CN; Y ) H or alkyl), which are useful building blocks for the preparation of analogs of
the potent antifungal agent sordarin, 1. Congeners of 1 constructed from 3 should permit detailed SAR investigations of the terpenoid core
of the natural product.
Fungal organisms are the etiologic agents of a number of
human pathologies, which become especially problematic in
immunocompromised individuals such as AIDS and cancer
patients.1 Fungal infections are also of major concern in
agriculture, where they can significantly reduce yields and
diminish profitability.2 The search for new antifungal agents
thus remains a key objective both in medicine and in
agricultural science.
fungal elongation factor 2.4 Sordarin, 1, has been the focus
of considerable structure-activity research, but efforts have
concentrated on modification of the glycosyl unit.5 It is
known that the aglycone of sordarins, which is termed
sordaricin, 2, may be O-alkylated to yield congeners that
are endowed with activity comparable to that of the natural
product;6 however, except for the fact that bioactivity is
retained upon replacement of the CHO group in 1 with a
Substances that exert antifungal action by novel mecha-
nisms are of special interest, and noteworthy in such a context
is a family of natural products known as the sordarins3
(Figure 1), which block protein synthesis by inhibiting the
‡ University of British Columbia.
§ Universite´ Claude Bernard Lyon 1 and Ecole Supe´rieure de Chimie,
Physique, Electronique de Lyon.
¶ Bayer CropScience SA.
(1) (a) Rupp, S. Fut. Microbiol. 2007, 2, 141. (b) Klepser, M. E.
Pharmacotherapy 2006, 26, 68. (c) Onyewu, C.; Heitman, J. Anti-Infect.
Agents Med. Chem. 2007, 6, 3. (d) Richardson, M. D.; Warnock, D. W.
Fungal Infection: Diagnosis and Management, 3rd ed.; Blackwell Publish-
ing: Malden, MA, 2003.
(2) Modern Crop Protection Compounds; Kraemer, W., Schirmer, U.,
Eds.; Wiley-VCH: Weinheim, Germany, 2007.
(3) Hauser, D.; Sigg, H. P. HelV. Chim Acta 1971, 54, 1178 and
references cited therein.
Figure 1. Sordarin (1), sordaricin (2), and ketones 3 targeted in
the present study.
10.1021/ol701547r CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/20/2007

CN substituent,6 no information is in the public domain with
respect to the role of the subunits that adorn the terpenoid
core (the COOH group, the isopropyl substituent, the
cyclopentane ring).
Scheme 1. Preparation of the Requisite Cyclopentenones
A resurgence of interest in sordarins has occurred in the
past few years, as attested by recent synthetic activity7 that
nicely complements early work dating from 1993.8 The
chemistry developed during these important efforts could
surely be harnessed to furnish analogs that may clarify the
function of the various segments of the sordarin core. A more
practical alternative might be to focus on ketones 3, which,
arguably, could be expeditiously elaborated to sordarin
analogs displaying variously modified terpenoid units. A
concise avenue to 3 is presented herein, together with a
discussion of unusual chemical properties observed for
various synthetic intermediates.
10, reacted under identical conditions to give 12, via a
thermodynamic enolate. Michael reaction of ketoesters 11
and 12 with acrolein in the presence of 2 mol % of DBU
proceeded in quantitative yield (Scheme 2). Larger quantities
Our approach to 3 emphasizes low cost and ease of
execution, while regarding issues of absolute stereocontrol
as secondary, at least at this stage. The retrosynthetic
considerations adumbrated in Figure 2 identified enones 5
Scheme 2. Michael-Baylis-Hillman Avenue to Enones
14-16
Figure 2. Retrosynthetic analysis of ketones 3.
of DBU promoted incomplete conversion, seemingly due to
the acceleration of a competing retro-Michael expulsion of
acrolein from the products. Aldehydes 13 and 15 are sensitive
materials that degrade easily on silica gel. Fortunately, they
emerged in a state of high purity and were utilized in the
subsequent Baylis-Hillman14 step without purification. The
kinetics of the latter reaction are notoriously slow. In neat
acrylonitrile, 13 reacted at a reasonable rate, but 15 required
more than 4 days to advance to 16 (68% chromatographed).
The reasons behind the poor reactivity of 15 remain unclear.
A 9-fold rate acceleration was achieved under Aggarwal
conditions (La(OTf)3 and triethanolamine as cocatalysts),15
but to the slight detriment of yield (50% chromatographed).
In either case, the reaction furnished 14 and 16 as a mixture
of alcohol diastereomers. However, this was inconsequential,
because the alcohol in question is destined to undergo
and 6 as suitable starting points for our effort. The preparation
of these educts proceeded from 1,3-diones 7 and 8 (Scheme
1). Thus, 7 was converted into 9 with MeOH/TiCl4,9 while
10 was best prepared by O-methylation of 810 with Me2SO4/
K2CO3. Deprotonation of 2-unsubstituted enone 9 with
LHMDS produced a kinetic enolate, which reacted with the
Mander reagent11 to yield the known12 11 (Scheme 1). In
accord with Koreeda,13 however, the 2-substituted analog,
(4) (a) Capa, L.; Mendoza, A.; Lavandera, J. L.; Gomez de las Heras,
F.; Garcia-Bustos, J. F. Antimicrob. Agents Chemother. 1998, 42, 2694.
(b) Shastry, M.; Nielsen, J.; Ku, T.; Hsu, M.-J.; Liberator, P.; Anderson,
J.; Schmatz, D.; Justice, M. C. Microbiology 2001, 147, 383.
(5) (a) Bueno, J. M.; Chicharro, J.; Fiandor, J. M.; Gomez de las Heras,
F.; Huss, S. Bioorg. Med. Chem. Lett. 2002, 12, 1697. (b) Serrano-Wu, M.
H.; St. Laurent, D. R.; Carroll, T. M.; Dodier, M.; Gao, Q.; Gill; P.;
Quesnelle, C. A.; Marinier, A.; Mazzucco, C. E.; Regueiro-Ren, A.; Stickle,
T. M.; Wu, D.; Yang, H.; Yang, Z.; Zheng, M.; Zoeckler, M. E.; Vyas, D.
M.; Balasubramanian, B. N. Bioorg. Med. Chem. Lett. 2003, 13, 1419 and
references cited therein.
(11) Crabtree, S. R.; Mander, L. N.; Sethi, S. P. Org. Synth. 1990, 70,
256.
(12) Compound 11 is known: (a) Irie, H.; Katakawa, J.; Tomita, M.;
Mizuno, Y. Chem. Lett. 1981, 637. (b) Boschelli, D.; Smith, A. B., III;
Stringer, O. D.; Jenkins, R. H., Jr.; Davis, F. A. Tetrahedron Lett. 1981,
22, 4385.
(13) (a) Koreeda, M.; Liang, Y.; Akagi, H. J. Chem. Soc., Chem.
Commun. 1979, 449. (b) Koreeda, M.; Liang, Y. Tetrahedron Lett. 1981,
22, 15.
(14) Reviews: (a) Ciganek, E. Org. React. 1997, 51, 201. (b) Basavaiah,
D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003, 103, 811. (c) Awad,
L.; Demange, R.; Zhu, Y.-H.; Vogel, P. Carbohydr. Res. 2006, 341, 1235.
(15) Aggarwal, V. K.; Mereu, A.; Tarver, G. J.; McCague, R. J. Org.
Chem. 1998, 63, 7183.
(6) Tse, B.; Balkovec, J. M.; Blazey, C. M.; Hsu, M.-J.; Nielsen, J.;
Schmatz, D. Bioorg. Med. Chem. Lett. 1998, 8, 2269.
(7) (a) Mander, L. N.; Thomson, R. J. Org. Lett. 2003, 5, 1321. (b)
Mander, L. N.; Thomson R. J. J. Org. Chem. 2005, 70, 1654. (c) Kitamura,
M.; Chiba, S.; Narasaka, K. Chem. Lett. 2004, 33, 942. (d) Chiba, S.;
Kitamura, M.; Narasaka, K. J. Am. Chem. Soc. 2006, 128, 6931.
(8) Kato, N.; Kusakabe, S.; Wu, X.; Kamitamari, M.; Takeshita, H. J.
Chem. Soc., Chem. Commun. 1993, 1002.
(9) Clerici, A.; Pastori, N.; Porta, O. Tetrahedron 2001, 57, 217.
(10) Majetich, G.; Song, J.-S.; Ringold, C.; Nemeth, G. A.; Newton, M.
G. J. Org. Chem. 1991, 56, 3973 and references cited therein.
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Org. Lett., Vol. 9, No. 21, 2007

ultimate oxidation to a ketone, thereby removing stereo-
genicity at the level of the associated C atom. The diaster-
eomeric mixtures of 14 and 16 were thus advanced through
the synthesis without separation.
Scheme 4. Chemistry of Cyanoenones
Sordaricin-like scaffolds displaying a bridgehead oxygen
functionality were reached upon exposure of 14 and 16 to
excess trialkylsilyl triflate/Et3N at room temperature. This
induced formation of a presumed bis-trialkylsilyl derivative
such as 17 (not isolated), which underwent a spontaneous
intramolecular Diels-Alder reaction to furnish the expected
adducts as mixtures of diastereomers. The transformation
proceeded best when TIPS-OTf was used as the silylating
agent, resulting in formation of 18 and 21 in 72% and 61%
chromatographed yield, respectively. As exemplified in
Scheme 3 with 19, the use of TES-OTf in the same reaction
cyanodienes.21 In spite of our hope that the intramolecular
nature of the reaction would overcome kinetic barriers, 27
proved to be stable up to 160 °C, above which temperature
it decomposed.
Scheme 3. Assembly of a Sordarin Core with Bridgehead
Oxygen Functionalities
The reluctance of 27 to cyclize to 28 contrasts with the
facile reaction of the corresponding ester-substituted cyclo-
pentadiene,19 suggesting that the HOMO energy of 27 must
be significantly lower than that of its ester-substituted
relative. Semiempirical methods detected no appreciable
differences in energies between the frontier molecular orbitals
(FMOs) of the COOMe- and CN-substituted cyclopenta-
dienes shown in Table 1,22 even though the Hammett σ
Table 1. Calculated Orbital Energies (eV)
afforded a lower 52% yield. Complete regioselectivity (500
1
MHz H NMR) was observed in all such reactions, as
expected on the basis of bond polarization in both diene and
dienophile units. In particular, diagnostic 1H coupling
constants were observed for the bridgehead, exo, and endo
protons (cf. Hb, Hx, and He in 18-21) situated on the
emerging bicyclo[2.2.1]heptane system.16 The conversion of
19 to diketone 23 (mixture of i-Pr epimers) served to
demonstrate a critical desilylation-oxidation step.
values for a CN group are more positive than those of a
COOMe group.23 However, DFT calculations (6-31G*)
(19) The reaction in question is (refs 7a,b, 8):
Educts suitable for the synthesis of congeners of 3 that
exhibit a bridgehead CN group were obtained from 16 upon
protection of the secondary alcohol as a TBS ether17 and
reaction with diethylaluminum cyanide18 (Scheme 4). The
resultant 25 was then advanced to 27, which we wished to
convert to 28 by an intramolecular Diels-Alder reaction.
The presence of an electron-withdrawing CN group on both
diene and dienophile units of 27 was not a concern per se:
an electronically similar cycloaddition proceeds easily19 and
with the correct regioselectivity.20 A potentially more serious
obstacle was the notoriously poor Diels-Alder reactivity of
(20) The cyclopentadiene unit in 27 lacks an oxygen substituent that
might direct formation of the correct regioisomer of the adduct. However,
A produces B only (ref 18), consistent with the fact that 2,4-pentadienoic
acid reacts with acrylic acid to give a cycloadduct that displays vicinal
COOH groups (Davalian, D.; Garratt, P.; Koller, W.; Mansuri, M. J. Org.
Chem. 1980, 45, 4183). On this basis, we anticipated good regioselectivity
in the Diels-Alder cyclization of 27.
(21) Snyder, H. R.; Poos, G. I. J. Am. Chem. Soc. 1950, 72, 4104.
However, 1-cyanocyclopentadiene may be more reactive than other cyano-
dienes, in that it combines with tetracyanoethylene (admittedly a highly
reactive dienophile) even at -25 °C: Banert, K.; Koehler, F.; Meier, B.
Tetrahedron Lett. 2003, 44, 3781.
(22) These molecules are computationally more tractable mimics of the
actual systems. Calculations were carried out with the Hyperchem package,
available from Hypercube, Inc. (www.hyper.com).
(23) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry, 5th
ed.; John Wiley & Sons, New York, 2001; pp 368 ff.
(16) For example, for 18, Jbx ) 4.1 Hz; Jbe ) 0 Hz; Jex ) 13.6 Hz. For
20, Jbx ) 4.4 Hz; Jbe ) 0 Hz; Jex ) 13.1 Hz. See Supporting Information
for full details.
(17) Protection as a TES ether resulted in intermediates that reacted
poorly in the steps delineated in Scheme 5.
(18) Nagata, W.; Yoshioka, M. Org. React. 1984, 25, 255.
Org. Lett., Vol. 9, No. 21, 2007
4121

carried out on MM+-optimized structures revealed a much
lower HOMO energy for the cyano compound relative to
its ester analog (∆E ≈ 1 eV), thereby accounting for the
problematic reaction of 27.
Scheme 5. Assembly of a Sordarin Core with a Bridgehead
Cyano Functionality
A plausible cure for the above problem was to induce
Diels-Alder cyclization of a more reactive enol silyl ether
derivative of 25, as seen earlier in Scheme 3. But in sharp
contrast to 14-16, cyanoenone 25 proved to be fiercely
resistant to enol silylation,24 even under Corey-Gross25
conditions. Such a reluctance to form a silyl enol ether was
mystifying in light of the reportedly uneventful O-silylation
of 4-oxo-2-pentene-carbonitrile.26 In order to determine
whether inherent barriers exist to the enolization of 25, the
compound was treated with NaH in THF. This led to a
product 29 of intramolecular Michael reaction (29%; Scheme
4), signaling that the enolate in question is, after all,
accessible, and that the failure of the foregoing silylation
reactions was attributable to an insufficient kinetic reactivity
of the base employed for the deprotonation of the substrate.27
Accordingly, 25 was exposed to the action of LHMDS
(excess)28 and LiCl29 in THF-HMPA, in the presence of
TBSCl. Compound 30 thus emerged in 82% yield30 (Scheme
5). In yet another manifestation of the HOMO-lowering
influence of the CN substituent, siloxy diene 30 exhibited
no proclivity whatsoever to undergo intramolecular Diels-
Alder reaction at room temperature. This behavior contrasts
with that of its congeners of the type 17. Indeed, cyclization
required heating at 140 °C for 12 h (toluene, pressure tube,
77% chromatographed). Fortunately, product 31 emerged as
a single regioisomer (1H NMR).31 The target ketone, 33, was
easily reached from 31 upon treatment with pyridine-HF
complex, which induced selective release of the TBS group
from the secondary alcohol and uneventful Dess-Martin
oxidation of the emerging 32. This achieved the construction
of a sordarin precursor in which a CN group substitutes for
the bridgehead carboxy functionality of 1.
We believe that ketones of the type 23 and 33 are quite
valuable for a study of the structure-activity relationship
of the terpenoid segment of sordarin. The straightforward
approach to these intermediates presented herein should
facilitate the search for new antifungal agents of interest in
human medicine as well as in agrochemical technology.
(24) Trialkylsilyl halides/tertiary amines in the presence of Lewis acids
(Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807),
trialkylsilyl triflates (Review: Bach, T.; Brummerhop, H. J. Prak. Chem.
1999, 341, 410), bis(trimethylsilyl) acetamide (Cameron, D. W.; Feutrill,
G. I.; Perlmutter, P. Tetrahedron Lett. 1981, 22, 3273) or bis(trimethylsilyl)
trifluoroacetamide (Fattori, D.; de Guchteneere, E.; Vogel, P. Tetrahedron
Lett. 1989, 30, 7415), or TMSI/HMDS (Miller, R. D.; McKean, D. R.
Synthesis 1979, 73), over a range of temperatures, had no effect on 25: the
enone was recovered unchanged from all such reactions.
(25) Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1984, 25, 495.
(26) Hosokawa, T.; Aoki, S.; Murahashi, S. Synthesis 1992, 558.
(27) The “enormous mechanistic complexity” of ketone deprotonation
(Hall, P. L.; Gilchrist, J. H.; Collum, D. B. J. Am. Chem. Soc. 1991, 113,
9571) invites prudence in formulating simplistic explanations for the
observed phenomena.
(28) A significant excess of Li-base was essential in the present case,
even though excess base may actually inhibit enolization - at least in the
case of esters: Sun, X.; Collum, D. B. J. Am. Chem. Soc. 2000, 122, 2452.
(29) It is well established that lithium halides enhance the reactivity of
organolithium species (the “LiX effect”): (a) Seebach, D. Angew. Chem.,
Int. Ed. Engl. 1988, 27, 1624. (b) Jackman, L. M.; Rakiewicz, E. F. J. Am.
Chem. Soc. 1991, 113, 1202. (c) Bunn, B. J.; Simpkins, N. S. J. Org. Chem.
1993, 58, 533. (d) Lipshutz, B. H.; Wood, M. R.; Lindsley, C. W.
Tetrahedron Lett. 1995, 36, 4385. (e) Pratt, L. M.; Newman, A.; St. Cyr,
J.; Johnson, H.; Miles, B.; Lattier, A.; Austin, E.; Henderson, S.; Hershey,
B.; Lin, M.; Balamraju, Y.; Sammonds, L.; Cheramie, J.; Karnes, J.; Hymel,
E.; Woodford, B.; Carter, C. J. Org. Chem. 2003, 68, 6387.
Acknowledgment. We thank Bayer CropScience and the
CNRS (BDI fellowship to A. S.), the University of British
Columbia, the Canada Research Chair Program, NSERC,
CIHR, and MerckFrosst Canada for financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data for the compounds de-
scribed herein. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL701547R
(30) The corresponding TMS enol ether was too labile, while the TES
enol ether afforded poor yields in the subsequent intramolecular Diels-
Alder reaction.
(31) For 31, Jbx ) 3.9 Hz; Jbe ) 0 Hz; Jex ) 13.5 Hz.
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