Stereoselective synthesis of the cytotoxic 14-membered macrolide aspergillide a

Article abstract of DOI:10.1021/jo9027038

Chemical Equation Presentation A stereoselective synthesis of the cytotoxic 14-membered macrolide aspergillide A has been performed. The preparation of a c/s-2,6-disubstituted tetrahydropyran ring via stereoselective reduction of an intermediate cyclic hemiacetal was one key feature of the synthesis. The macrocyclic lactone ring was created by means of a ring-closing metathesis (RCM), whereby the new C=C bond displayed exclusively the undesired Z configuration. Conversion to the required E configuration was achieved via photochemical isomerization.

Full text of DOI:10.1021/jo9027038

pubs.acs.org/joc
14-membered macrolides that possess a tetrahydropyran
Stereoselective Synthesis of the Cytotoxic
14-Membered Macrolide Aspergillide A
ring not forming part of a hemiacetal or acetal moiety.3,4
This and the aforementioned bioactivities prompted us and
other groups to initiate total syntheses of these compounds.
†
Santiago Dıaz-Oltra, Cesar A. Angulo-Pachon,
†
ꢀ
ꢀ
Juan Murga,*,† Miguel Carda,† and J. Alberto Marco*,‡
†
´
Departamento de Quımica Inorganica y Organica,
Universitat Jaume I, E-12071 Castellon, Spain, and
ꢀ
ꢀ
ꢀ
‡
´
ꢀ
Departamento de Quımica Organica, Universitat de
Valencia, E-46100 Burjassot, Valencia, Spain
jmurga@qio.uji.es; alberto.marco@uv.es
Received December 23, 2009
FIGURE 1. Correct stereostructures of aspergillides A (1), B (2),
and C (3).
In the beginning of 2009, Uenishi et al. published their
synthesis of a compound with structure 2, then assumed it
corresponded to aspergillide A.5 However, these authors
found that their synthetic compound had spectral properties
identical with those reported for aspergillide B. The latter
compound was thus assigned structure 2, which led to the
need of a revised structure for aspergillide A. Still more
recently, Kuwahara et al. published a total synthesis of
aspergillide C and confirmed it to have structure 3
(Figure 1).6 Shortly afterward, we published our own synth-
esis of aspergillide B (2),7 thus confirming the findings of
Uenishi and his group. Finally, the group that isolated the
natural compounds was able to perform X-ray diffraction
analyses8 of suitable derivatives of aspergillides A and B.
Their and the previous synthetic studies led to the definitive
assignment of 1 and 2, respectively, as the correct structures
of these two natural compounds.9
A stereoselective synthesis of the cytotoxic 14-membered
macrolide aspergillide A has been performed. The pre-
paration of a cis-2,6-disubstituted tetrahydropyran ring
via stereoselective reduction of an intermediate cyclic
hemiacetal was one key feature of the synthesis. The
macrocyclic lactone ring was created by means of a
ring-closing metathesis (RCM), whereby the new CdC
bond displayed exclusively the undesired Z configura-
tion. Conversion to the required E configuration was
achieved via photochemical isomerization.
In the present paper, we wish to publish the first total
synthesis of aspergillide A, now known to be 1. The retro-
synthesis, depicted in Scheme 1, relies in part on that used for
aspergillide B (2).7 Indeed, the only difference between 1 and
2 is the configuration at C-3. However, this apparently minor
issue crucially affects the retrosynthetic concept as it involves
(3) Neopeltolide (14-membered macrolide containing a cis-2,6-disubsti-
tuted tetrahydropyran ring): Wright, A. E.; Botelho, J. C.; Guzman, E.;
Harmody, D.; Linley, P.; McCarthy, P. J.; Pitts, T. P.; Pomponi, S. A.; Reed,
J. K. J. Nat. Prod. 2007, 70, 412–416. The structure reported in this paper has
been later corrected as a consequence of synthetic efforts of several groups.
For a review on this compound, see: Gallon, J.; Reymond, S.; Cossy, J. C. R.
Chim. 2008, 11, 1463–1476.
(4) Pochonin J (benzofused 14-membered macrolide containing a trans-
2,6-disubstituted tetrahydropyran ring): Shinonaga, H.; Kawamura, Y.;
Ikeda, A.; Aoki, M.; Sakai, N.; Fujimoto, N.; Kawashima, A. Tetrahedron
Lett. 2009, 50, 108–110.
(5) Hande, S. M.; Uenishi, J. Tetrahedron Lett. 2009, 50, 189–192.
(6) Nagasawa, T.; Kuwahara, S. Org. Lett. 2009, 11, 761–764. For a more
recent synthesis, see: Panarese, J. D.; Waters, S. P. Org. Lett. 2009, 11, 5086–
5088.
The aspergillides A, B, and C (1-3, see comments below)
are three 14-membered macrolides isolated from a strain of
the marine-derived fungus Aspergillus ostianus cultivated in a
bromine-modified medium.1,2 The compounds showed
cytotoxic activity in the micromolar range against mouse
lymphocytic leukemia cells (L1210). Their stereostruc-
tures show some unusual features. For instance, only two
recent examples have been reported of naturally occurring,
ꢀ
(7) Dıaz-Oltra, S.; Angulo-Pachon, C. A.; Kneeteman, M. N.; Murga, J.;
Carda, M.; Marco, J. A. Tetrahedron Lett. 2009, 50, 3783–3785. When we
started our work, the synthesis of Hande and Uenishi had not yet been
reported. Our initial synthetic target therefore was aspergillide A, still
believed to be 2.
(1) Kito, K.; Ookura, R.; Yoshida, S.; Namikoshi, M.; Ooi, T.; Kusumi,
T. Org. Lett. 2008, 10, 225–228.
(8) Ookura, R.; Kito, K.; Saito, Y.; Kusumi, T.; Ooi, T. Chem. Lett. 2009,
38, 384.
(2) These compounds should not be confused with a group of other
structurally unrelated metabolites of the same name isolated from Aspergillus
terreus. See: Golding, B. T.; Rickards, R. W.; Vanek, Z. J. Chem. Soc.,
Perkin Trans. I 1975, 1961–1963.
(9) Two more recent syntheses of aspergillide B have been reported: (a)
Liu, J.; Xu, K.; He, J.-M.; Zhang, L.; Pan, X.-F.; She, X.-G. J. Org. Chem.
2009, 74, 5063–5066. (b) Nagasawa, T.; Kuwahara, S. Biosci. Biotechnol.
Biochem. 2009, 73, 1893–1894.
DOI: 10.1021/jo9027038
r
Published on Web 02/09/2010
J. Org. Chem. 2010, 75, 1775–1778 1775
2010 American Chemical Society

Dıaz-Oltra et al.
JOCNote
SCHEME 1. Retrosynthetic Analysis of Aspergillide A (1)
obtaining 5 or a similar derivative with use of a Mukaiya-
ma-type C-glycosidation under various conditions were not
satisfactory. We always obtained mixtures of cis-2,6- and
trans-2,6-disubstituted tetrahydropyran where the desired
cis isomer was never the major compound.16 We were finally
successful with a modified methodology (Scheme 2). Addi-
tion of the lithium enolate of ethyl acetate to lactone 6 at low
temperature gave lactol 7 as a mixture of stereoisomers at the
olefinic bond and at the hemiketal carbon. Treatment of this
mixture with Et3SiH/BF3 Et2O11a,b provided 8, which dis-
3
played an exclusively cis relationship at the stereocenter pair
C-3/C-7 (aspergillide numbering), as demonstrated by the
observation of a NOE between H-3 and H-7 (see the Sup-
porting Information). As the precursor lactone 6, 8 was also
a ca. 9:1 E/Z mixture. Alkaline hydrolysis of 8 gave the
desired acid 5 in almost quantitative yield.
the methodology needed to create the relative configuration
of the stereocenters C-3/C-7.10-12
Retrosynthetic opening of the lactone ring by means of
ring-closing metathesis (RCM)13 and hydrolytic cleavage of
the ester moiety gives rise to the known alcohol 414 as well as
to acid 5. As in our recently published synthesis of aspergil-
lide B, we planned to create the tetrahydropyran ring10 of 5
through a stereocontrolled Mukaiyama-type C-glycosida-
tion15 of a suitable lactol derivative prepared through reduc-
tion of the δ-lactone 6.7 In contrast to the previous synthesis,
however, the glycosidation has now to be performed under
conditions conducive to the formation of a cis-2,6-disubsti-
tuted tetrahydropyran system.
Mindful of our synthesis of 2,7 we first submitted 5 to cross
metathesis17 with alcohol 4 in the presence of Grubbs
second-generation catalyst Ru-II to yield 9 in 41% yield as
a ca. 7:3 E/Z mixture. The subsequent macrolactonization,
performed according to the Yamaguchi procedure,18 had an
unexpected outcome, however. Only the minor Z isomer of 9
underwent cyclization to lactone (Z)-10 in 28% yield (based
on the whole starting material). Apparently, the major E
isomer decomposed under these conditions and could not be
isolated. Variations in the reaction conditions did not lead
to success, either. Attempts at macrolactonization under
Shiina,19 Trost,20 or Keck21 conditions were also fruitless.
The starting hydroxy acid 9 was the only defined compound
isolated from the reaction mixture, with partial decomposi-
tion also taking place.
Our initial experiments based on the experience gained in
the synthesis of 27 were disappointing. All attempts at
(10) For reviews on various synthetic methods for the preparation of
tetrahydropyran derivatives, see: (a) Boivin, T. L. B. Tetrahedron 1987, 43,
3309–3362. (b) Kotsuki, H. Synlett 1992, 97–106. (c) Clarke, P. A.; Santos, S.
Eur. J. Org. Chem. 2006, 2045–2053. (d) Piccialli, V. Synthesis 2007, 2585–
2607. (e) Smith, A. B. III; Fox, R. J.; Razler, T. M. Acc. Chem. Res. 2008, 41,
675–687.
(11) For examples of synthesis of cis-2.6-disubstituted tetrahydropyran
rings, see: (a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976–4978. (b) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.;
Prunet, J. A.; Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540–7552. (c)
Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem. Soc. 2001, 123, 8420–8421.
(d) Berberich, S. M.; Cherney, R. J.; Colucci, J.; Courillon, C.; Geraci, L. S.;
Kirkland, T. A.; Marx, M. A.; Schneider, M. F.; Martin, S. F. Tetrahedron
In view of this, we decided to change the order of the steps
needed for the creation of the macrocyclic ring. Esterification
of 4 and 5 under Yamaguchi conditions17 provided compound
11, still as an E/Z mixture. However, when subjected to ring-
closing metathesis, ester 11 gave exclusively lactone (Z)-10 in a
(16) With respect to the reaction conditions used in our previous synthesis
of aspergillide B,7 where the trans (major) to cis (minor) ratio was ca. 2.6:1,
changes in temperature, solvent, and Lewis acid were investigated without
improvements in the cis-trans ratio. Furthermore, the enolsilanes of acetic
acid and ethyl acetate were tried in addition to tert-butyl thioacetate but the
cis-trans ratio was not ameliorated in this way. Finally, we tried to convert
the undesired C-3 epimer of 8 into 8 via a base-catalyzed retro-Michael/
Michael sequence (equilibration). Again, variable mixtures were obtained
with no synthetically satisfactory percentages of the desired 8.
ꢀ
2003, 59, 6819–6832. (e) Pattenden, G.; Gonzalez, M. A.; Little, P. B.; Millan,
D. S.; Plowright, A. T.; Tornos, J. A.; Ye, T. Org. Biomol. Chem. 2003, 1,
4173–4208. (f) Das, S.; Li, L.-S.; Sinha, S. C. Org. Lett. 2004, 6, 123–126. (g)
Kang, E. J.; Cho, E. J.; Ji, M. K.; Lee, Y. E.; Shin, D. M.; Choi, S. Y.; Chung,
Y. K.; Kim, J. S.; Kim, H.-J.; Lee, S.-G.; Lah, M. S.; Lee, E. J. Org. Chem.
2005, 70, 6321–6329. (h) Li, D.-R.; Zhang, D.-H.; Sun, C.-Y.; Zhang, J.-W.;
Yang, L.; Chen, J.; Liu, B.; Su, C.; Zhou, W.-S.; Lin, G.-Q. Chem.;Eur. J.
2006, 12, 1185–1204. (i) Troast, D. M.; Yuan, J.; Porco, J. A., Jr. Adv. Synth.
Catal. 2008, 350, 1701–1711.
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rings, see ref 11a and: (a) Horita, K.; Oikawa, Y.; Yonemitsu, O. Chem.
Pharm. Bull. 1989, 37, 1698–1704. (b) Micalizio, G. C.; Pinchuk, A. N.;
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E. M. J. Org. Chem. 2003, 68, 9274–9283. (d) Williams, D. R.; Patnaik, S.;
Plummer, S. V. Org. Lett. 2003, 5, 5035–5038. (e) De Vicente, J.; Huckins,
J. R.; Rychnovsky, S. D. Angew. Chem., Int. Ed. 2006, 45, 7258–7262.
(17) (a) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900–
1923. (b) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360–11370. (c) Vernall, A. J.; Abell, A. D. Aldrichim.
Acta 2003, 36, 93–105. (d) Schrodi, Y.; Pederson, R. L. Aldrichim. Acta 2007,
40, 45–52.
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Chem. Soc. Jpn. 1979, 52, 1989–1993.
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Jafarpour, L.; Nolan, S. P. Adv. Organomet. Chem. 2000, 46, 181–222. (c)
Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29. (d) Love, J. A.
In Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim,
Germany, 2003; Vol. 2, pp 296-322. (e) Grubbs, R. H. Tetrahedron 2004, 60,
7117–7140. (f) Astruc, D. New J. Chem. 2005, 29, 42–56. (g) Hoveyda, A. H.;
Zhugralin, A. R. Nature 2007, 450, 243–251.
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2000, 2385–2394.
(15) (a) Mukaiyama, T. Aldrichim. Acta 1996, 29, 59–76. (b) Mukaiyama,
T.; Matsuo, J.-I. In Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH:
Weinheim, Germany, 2004; Vol. 1, Chapter 3. (c) Mitchell, T. A.; Zhao, C.; Romo,
D. J. Org. Chem. 2008, 73, 9544–9551. For a review on synthesis of C-
glycosides, see: Du, Y.; Linhardt, R. J.; Vlahov, I. R. Tetrahedron 1998, 54,
9913–9959.
(20) Trost, B. M.; Chisholm, J. D. Org. Lett. 2002, 4, 3743–3745. For an
application, see: Kim, C. H.; An, H. J.; Shin, W. K.; Yu, W.; Woo, S. K.;
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2001, 123, 10200–10206.
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SCHEME 2. Stereoselective Synthesis of Aspergillide A (1)a
RCM process is thermodynamically controlled.22 However,
even though the macrolide ring of 1 is formally 14-membered
from the point of view of the atom periphery and thus
relatively flexible, the presence of the tetrahydropyran ring
may impose certain conformational restraints which make
the formation of (E)-10 kinetically disfavored. Thus, the
formation of (Z)-10 in the RCM may also be kinetically
controlled. Indeed, compound (Z)-10 is obtained in very
high yield when using catalyst Ru-I, which is assumed to
work under kinetic conditions.13 The more active, second-
generation catalyst Ru-II, however, is known to cause E/Z
isomerizations, thus approaching thermodynamic (equili-
brium) conditions. Thus, if compound (E)-10 shows some
instability under the RCM conditions, this could explain the
eroded yield observed when using catalyst Ru-II.
Since only the isomer with the Z-configured olefinic bond
was available with good yield, we investigated ways to invert
its configuration. After some experimentation,24 we found
that irradiation of a solution of lactone (Z)-10 in dry,
deoxygenated toluene gave rise to a photostationary equi-
librium in which 30% of the Z isomer was converted into
(E)-10 (24% isolated yield, based on recovered starting
material).25,26 Unfortunately, attempts at cleavage of the
benzyl group in (E)-10 under several conditions27 were
unsuccessful. Again, an inversion in the order of steps pro-
vided the solution. Cleavage of the benzyl group in (Z)-10
was performed through treatment with DDQ in wet
CH2Cl2.28 This yielded the Z lactone 12, which was subjected
as above to photochemical isomerization of the CdC bond.
This afforded a mixture of 12 and its E isomer (56% isolated
yield, based on recovered starting material), the spectral data
of which matched those of natural aspergillide A (1).1
In summary, the synthesis of the cytotoxic, 14-membered
macrolide aspergillide A in a stereoselective way has been
reported for the first time. This confirms its stereostructure
and establishes as well its absolute configuration.
Experimental Section
General Features. See the Supporting Information.
aAcronyms and abbreviations: DMAP, 4-(N,N-dimethylaminopyridine);
DDQ, 2,3-dichloro-5,6-dicyano-p-benzoquinone; Cy, cyclohexyl; Mes,
mesityl (2,4,6-trimethylphenyl); tol, toluene.
(2S)-Hept-6-en-2-yl 2-[(2R,3S,6R)-3-(Benzyloxy)-6-(prop-
1E,Z-enyl)tetrahydro-2H-pyran-2-yl]acetate (11). A solution of
acid 5 (174 mg, 0.6 mmol) in dry THF (15 mL) was cooled to 0 °C
under N2. Then, triethylamine (210 μL, 1.5 mmol) and 2,4,6-
trichlorobenzoyl chloride (188 μL, 1.2 mmol) were added drop-
wise, followed by stirring at room temperature for 2 h. Alcohol 4
(82 mg, 0.72 mmol) and DMAP (183 mg, 1.5 mmol) were
very high yield. Furthermore, both the first- and the second-
generation ruthenium catalysts Ru-I and Ru-II yielded (Z)-10
as the sole reaction product, with Ru-I giving higher yields
(99% vs 67%, see the Experimental Section).
These facts deserve some comment. The markedly high
stereoselectivity is worth mentioning since the stereochemi-
cal outcome of RCM reactions which give rise to medium-
sized or large rings (g10 atoms)22 is not always predictable
with full certainty. In the present case, molecular mechanics
calculations showed that (Z)-10 is much more stable than
(E)-10.23 This suggests that the formation of (Z)-10 in the
ꢀ
(24) (a) I2/hν (no reaction): Nazare, M.; Waldmann, H. Chem.;Eur. J.
2001, 7, 3363–3376. (b) PhSH/AIBN, C6H6, 4 (dec): Paquette, L. A.; Chang,
S.-K. Org. Lett. 2005, 7, 3111–3114.
(25) The mutual coupling constant of the olefinic protons in (Z)-10 (11
Hz) and (E)-10 (15.2 Hz) is clearly indicative of the configuration of the CdC
bond.
(26) The aromatic solvent toluene acts here as a sensitizer: Inoue, Y.;
Yamasaki, N.; Tai, A.; Daino, Y.; Yamada, T.; Hakushi, T. J. Chem. Soc.,
Perkin Trans. II 1990, 1389–1394. See also: Mori, T.; Inoue, Y. In CRC
Handbook of Organic Photochemistry and Photobiology; Horspool, W.,
Lenci, F., Eds.; CRC Press: Boca Raton, FL, 2004; Chapter 16.
(27) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synth-
esis, 4th ed.; John Wiley and Sons: Hoboken, NJ, 2007; pp 106-120.
(28) For cleavage of p-methoxybenzyl ethers under these conditions, see:
Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O. Tetra-
hedron 1986, 42, 3021–3028. For uses in the cleavage of benzyl ethers, see: (a)
Ikemoto, N.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 9657–9659. (b)
Paterson, I.; Smith, J. D.; Ward, R. A. Tetrahedron 1995, 51, 9413–9436. (c)
Blakemore, P. R.; Browder, C. C.; Hong, J.; Lincoln, C. M.; Nagornyy, P. A.;
Robarge, L. A.; Wardrop, D. J.; White, J. D. J. Org. Chem. 2005, 70, 5449–
5460.
(22) For reviews on the uses of this reaction for the synthesis of macro-
cycles, see: (a) Prunet, J. Angew. Chem., Int. Ed. 2003, 42, 2826–2830. (b)
ꢀ
Gradillas, A.; Perez-Castells, J. Angew. Chem., Int. Ed. 2006, 45, 6086–6101.
(c) Majumdar, K. C.; Rahaman, H.; Roy, B. Curr. Org. Chem. 2007, 11,
1339–1365.
(23) The structures of (E)- and (Z)-10 were first optimized with the aid of
semiempirical methods (PM3). Energies were then refined by means of HF/6-
31G* calculations. These were found to predict a higher thermodynamic
stability for lactone (Z)-10 as compared with (E)-10 by an energy difference
of about 15 kcal/mol.
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dissolved in dry THF (9 mL) and added via syringe to the reaction
mixture, with further stirring for 16 h at the same temperature.
Workup (extraction with Et2O) and column chromatography on
silica gel (hexanes-EtOAc, 19:1) furnished 11 (215 mg, 93%) as a
ca. 9:1 E/Z mixture: colorless oil; 1H NMR (signals from the major
E isomer) δ 7.35-7.25 (5H, br m), 5.80-5.70 (1H, m), 5.70-5.60
(1H, m), 5.44 (1H, ddq, J= 15.5, 5.8, 1.8 Hz), 5.00 (1H, dq, J= 17,
2 Hz), 4.94 (2H, m), 4.62 (1H, d, J = 11.6 Hz), 4.44 (1H, d, J =
11.6 Hz), 3.80 (1H, m), 3.76 (1H, td, J = 9, 4 Hz), 3.19 (1H, m),
2.86 (1H, dd, J = 14.7, 3.7 Hz), 2.40 (1H, dd, J = 14.7, 8.3 Hz),
2.28 (1H, m), 2.15-2.00 (2H, m), 1.80-1.75 (1H, m), 1.66 (3H, br
2.85 (1H, dd, J = 11.8, 2.5 Hz), 2.36 (1H, t, J = 11.8 Hz), 2.28 (1H,
br q, J = ∼10 Hz), 2.16 (1H, m), 1.80 (1H, m), 1.70-1.40 (7H, br
m), 1.27 (3H, d, J = 6.5 Hz) (OH proton not visible); 13C NMR δ
173.5 (C), 135.7, 128.1, 81.6, 74.9, 70.2, 69.9 (CH), 39.1, 34.5, 33.7,
32.0, 28.1, 25.9 (CH2), 20.9 (CH3); IR νmax 3440 (br, OH), 1720
(CdO) cm-1; HR ESMS m/z 277.1414 (M þ Naþ), calcd for
C14H22O4Na 277.1416.
(1R,5S,11R,14S)-14-Benzyloxy-5-methyl-4,15-dioxabicyclo-
[9.3.1]pentadec-9(E)-en-3-one (E-10). A solution of compound
(Z)-10 (34.5 mg, ∼0.1 mmol) in deoxygenated toluene-d8
(1.5 mL) was placed in a quartz NMR tube. The solution was
then irradiated under N2 bubbling using a medium-pressure 125 W
Hg lamp (refrigerated to -20 °C). Periodic checking by means of
1H NMR revealed that the maximum conversion (about 30%) was
achieved after ca. 6 h (further irradiation caused progressive
decomposition). Removal of the solvent under reduced pressure
was followed by column chromatography of the residue on silica
gel. Elution with hexanes-EtOAc (19:1) gave recovered (Z)-10
(11.5 mg) whereas elution with hexanes-EtOAc (9:1) gave (E)-10
(5.5 mg, 24% based on recovered starting material): colorless oil;
[R]D -28.2 (c 0.13; CHCl3); 1H NMR δ 7.40-7.30 (5H, m), 5.82
(1H, ddd, J = 15.2, 8.3, 1.5 Hz), 5.75 (1H, ddd, J = 15.2, 8.8, 3.5
Hz), 5.00 (1H, m), 4.62, 4.58 (2H, AB system, J = 11.2 Hz), 4.48
(1H, dd, J = 12.5, 4 Hz), 4.30 (1H, br t, J ≈ 6 Hz), 3.28 (1H, m),
2.63 (1H, dd, J = 15.5, 12.5 Hz), 2.35-2.25 (3H, m), 2.15 (1H, m),
2.00-1.90 (2H, m), 1.85-1.80 (2H, m), 1.60-1.50 (2H, m), 1.40
(1H, m), 1.22 (3H, d, J = 6.5 Hz); 13C NMR δ 170.3, 136.6 (C),
136.6, 132.6, 128.4 (ꢀ2), 127.5 (ꢀ3), 73.6, 71.4, 70.9, 70.1 (CH),
71.3, 41.1, 32.3, 31.1, 23.9, 23.0, 20.1 (CH2), 18.7 (CH3); IR νmax
1727 (CdO) cm-1; HR ESMS m/z 367.1888 (M þ Naþ), calcd for
C21H28O4Na 367.1885.
d, J ≈ 6 Hz), 1.60-1.35 (6H, br m), 1.18 (3H, d, J = 6.5 Hz); 13
C
NMR (signals from the major E isomer) δ 171.1, 138.2 (C), 138.4,
131.3, 128.4 (ꢀ2), 127.7 (ꢀ2), 127.5, 126.6, 77.6 (ꢀ2), 76.6, 70.6
(CH), 114.5, 70.5, 38.7, 35.3, 33.4, 30.9, 29.0, 24.5 (CH2), 19.9, 17.7
(CH3); IR νmax 1732 (CdO) cm-1; HR ESMS m/z 409.2351 (M þ
Naþ), calcd for C24H34O4Na 409.2355.
(1R,5S,11R,14S)-14-(Benzyloxy)-5-methyl-4,15-dioxabicy-
clo[9.3.1]pentadec-9(Z)-en-3-one (Z-10). Grubbs ruthenium cat-
alyst Ru-I (82 mg, ca. 0.1 mmol) was dissolved under N2 in dry,
deoxygenated CH2Cl2 (500 mL). After the solution was heated to
reflux, diene 11 (193 mg, 0.5 mmol) dissolved in dry, deoxygenated
CH2Cl2 (30 mL) was added slowly via syringe (within 1 h) to the
reagent solution. The reaction mixture was then stirred at reflux for
an additional 6 h. After cooling to room temperature, the reaction
was quenched through addition of DMSO29 (0.4 mL) followed by
stirring overnight. Removal of all volatiles under reduced pressure
and column chromatography of the residue on silica gel (hex-
anes-EtOAc, 19:1) yielded (Z)-10 (172 mg, 99%) as a single
stereoisomer (when the reaction was performed with catalyst Ru-
II, the yield was 67%): colorless oil; [R]D þ67.5 (c 1.13; CHCl3); 1H
NMR δ 7.35-7.25 (5H, br m), 5.63 (1H, tdd, J = 11, 5.2, 2 Hz),
5.18 (1H, dd, J = 11, 2.5 Hz), 5.04 (1H, m), 4.65 (1H, d, J = 11.7
Hz), 4.44 (1H, d, J = 11.7 Hz), 4.06 (1H, br d, J = 11 Hz), 3.74
(1H, td, J = 10.2, 2.5 Hz), 3.16 (1H, m), 2.90 (1H, dd, J = 11.7, 2.5
Hz), 2.28 (3H, m), 1.85-1.80 (1H, m), 1.70-1.40 (7H, br m), 1.24
(3H, d, J = 6.5 Hz); 13C NMR δ 173.3, 138.3 (C), 135.4, 128.3
(ꢀ2), 128.1, 127.6, 127.5 (ꢀ2), 80.0, 76.5, 75.0, 69.6 (CH), 70.5,
39.2, 34.4, 31.7, 29.4, 28.0, 25.9 (CH2), 20.9 (CH3); IR νmax 1720
(CdO) cm-1; HR ESMS m/z 367.1884 (M þ Naþ), calcd for
C21H28O4Na 367.1885. Its key stereochemical features were sup-
ported by NOE masurements:
(1R,5S,11R,14S)-14-Hydroxy-5-methyl-4,15-dioxabicyclo-
[9.3.1]pentadec-9(E)-en-3-one (aspergillide A, 1). A solution of
compound 12 (25.5 mg, 0.1 mmol) in deoxygenated toluene-d8
(1.5 mL) was placed in a quartz NMR tube. The solution was then
irradiated under N2 bubbling using a medium-pressure 125 W Hg
lamp (refrigerated to -20 °C). Periodic checking by means of 1H
NMR revealed that the maximum conversion (about 40%) was
achieved after ca. 6 h (further irradiation caused progressive
decomposition). Removal of the solvent under reduced pressure
was followed by column chromatography of the residue on silica
gel. Elution with hexanes-EtOAc (4:1) gave recovered 12 (12 mg)
whereas elution with hexanes-EtOAc (1:1) gave 1 (7.6 mg, 56%
based on recovered starting material): colorless oil; [R]D -51.7 (c
0.33; CHCl3), lit.1 [R]D -59.5 (c 0.45; CHCl3); 1H NMR δ 5.82
(1H, ddd, J = 15.2, 8.3, 1.5 Hz), 5.75 (1H, ddd, J = 15.2, 9.3, 3
Hz), 4.98 (1H, m), 4.30-4.25 (2H, m), 3.60 (1H, m), 2.66 (1H, dd,
J = 15.3, 13 Hz), 2.42 (1H, dd, J = 15.3, 4.4 Hz), 2.35-2.10 (3H,
br m), 2.00-1.90 (2H, m), 1.85 (1H, m), 1.75 (1H, m), 1.60-1.50
(2H, m), 1.45 (1H, m), 1.23 (3H, d, J = 6.5 Hz) (OH proton not
detected); 13C NMR δ 170.0 (C), 137.2, 132.2, 74.1, 71.6, 71.3,
66.9 (CH), 40.6, 32.3, 31.2, 23.8, 22.1, 21.9 (CH2), 18.7 (CH3); IR
ν
max 3450 (br, OH), 1724 (CdO) cm-1; HR ESMS m/z 277.1417
(M þ Naþ), calcd for C14H22O4Na 277.1416. The physical
(1R,5S,11R,14S)-14-Hydroxy-5-methyl-4,15-dioxabicyclo-
[9.3.1]pentadec-9(Z)-en-3-one (12). A solution of lactone (Z)-10
(69 mg, 0.2 mmol) was dissolved under N2 in CH2Cl2 (15 mL)
and treated at room temperature with DDQ (454 mg, 2 mmol) and
pH 7 phosphate buffer solution (1.5 mL). The reaction mixture was
then stirred at room temperature for 16 h. Workup (extraction with
CH2Cl2) was followed by column chromatography on silica gel.
Elution with hexanes-EtOAc (19:1) gave recovered (Z)-10 (23mg)
whereas elution with hexanes-EtOAc (4:1) afforded lactone 12
(29.5 mg, 87% based on recovered starting material): colorless oil;
[R]D þ42.9 (c 0.77; CHCl3); 1H NMR δ 5.65 (1H, dddd, J = 10.5,
8.5, 6, 2.5 Hz), 5.20 (1H, dd, J = 10.5, 2 Hz), 5.04 (1H, m), 4.08
(1H, br d, J ≈ 9.3 Hz), 3.58 (1H, td, J = 11.8, 2.5 Hz), 3.38 (1H, m),
properties of synthetic 1 match those reported for aspergillide A.1
Acknowledgment. Financial support has been granted by
the Spanish Ministry of Science and Technology (projects
CTQ2005-06688-C02-01 and CTQ2005-06688-C02-02), the
ꢀ
Conselleria de Educacion, Ciencia y Empresa de la General-
itat Valenciana (project ACOMP07/023), and the BANCA-
JA-UJI Foundation (project P1-1B-2008-14).
Supporting Information Available: Description of general
features and graphical 1H and 13C NMR spectra of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(29) Anh, Y.-M.; Yang, K.; Georg, G. I. Org. Lett. 2001, 3, 1411–1413.
1778 J. Org. Chem. Vol. 75, No. 5, 2010