Enantioselective formal total synthesis of (+)-aspergillide C

Article abstract of DOI:10.1021/ol902154p

An enantioselective formal total synthesis of the cytotoxic macrolide (+)-aspergillide C has been accomplished from (S)-(-)-glyceraldehyde acetonide and the Danishefsky-Kitahara diene. Strategic transformations include a hetero Diels-Alder reaction, Ferri

Full text of DOI:10.1021/ol902154p

ORGANIC
LETTERS
2009
Vol. 11, No. 21
5086-5088
Enantioselective Formal Total Synthesis
of (+)-Aspergillide C
Joseph D. Panarese and Stephen P. Waters*
Department of Chemistry, The UniVersity of Vermont, 82 UniVersity Place,
Burlington, Vermont 05405
stephen.waters@uVm.edu
Received September 17, 2009
ABSTRACT
An enantioselective formal total synthesis of the cytotoxic macrolide (+)-aspergillide C has been accomplished from (S)-(-)-glyceraldehyde
acetonide and the Danishefsky-Kitahara diene. Strategic transformations include a hetero Diels-Alder reaction, Ferrier-type addition, and
palladium-catalyzed oxidative lactonization to set key stereocenters within the dihydropyran core, followed by fragment coupling via (E)-
selective Julia-Kocienski olefination.
In 2008, three secondary metabolites, aspergillides A-C
(Figure 1), were isolated by Kusumi and co-workers from a
marine-derived fungus, Aspergillus ostianus strain 01F313,
collected off the coast of Pohnpei.1 Importantly, aspergillides
A-C displayed cytotoxicity against mouse lymphocytic
leukemia cells (L1210) with LD50 values of 2.1, 71.0, and
2.0 µg/mL, respectively.
The structures of aspergillides A-C were originally
assigned through a combination of spectroscopic methods,
and their absolute stereochemistry was determined through
Mosher’s ester analysis. However, a 2009 synthesis of
aspergillides A and B by Uenishi suggested discrepancies
in the relative stereochemistry originally assigned for these
compounds.2 Shortly after, Kusumi reported corrected
structural assignments for aspergillides A and B via X-ray
crystallographic analysis of their C(4) m-bromobenzoate
ester derivatives.3 Aspergillides A and B were found to
be diastereomeric at C(3) rather than at C(13) as originally
proposed. This year, additional synthetic efforts have
confirmed the revised structures shown in Figure 1.4,5
Figure 1. Confirmed structures of aspergillides A-C.
Because of their promising bioactivities and interesting
architectures, we also viewed the aspergillides as attractive
synthetic targets. Moreover, the aspergillide scaffold could
lend itself to diverse structural modifications in projected
syntheses of biologically active congeners. In this Letter, we
describe our enantioselective approach to the synthesis of
(4) Total syntheses of aspergillide B subsequent to ref 2: (a) Liu, J.;
Xu, K.; He, J.; Zhang, L.; Pan, X.; She, X. J. Org. Chem. 2009, 74, 5063–
5066. (b) Diaz-Oltra, S.; Angulo-Pachon, C. A.; Kneeteman, M. N.; Murga,
J.; Carda, M.; Marco, J. A. Tetrahedron Lett. 2009, 50, 3783–3785. (c)
Nagasawa, T.; Kuwahara, S. Biosci. Biotechnol. Biochem. 2009, 73, 1893–
1894.
(1) Kito, K.; Ookura, R.; Yoshida, S.; Namikoshi, M.; Ooi, T.; Kusumi,
T. Org. Lett. 2008, 10, 225–228.
(2) Hande, S. M.; Uenishi, J. Tetrahedron Lett. 2009, 50, 189–192.
(3) Ookura, R.; Kito, K.; Saito, Y.; Kusumi, T.; Ooi, T. Chem. Lett.
2009, 38, 384.
(5) Total synthesis of aspergillide C: Kuwahara, S.; Nagasawa, T. Org.
Lett. 2009, 11, 761–764.
10.1021/ol902154p CCC: $40.75
Published on Web 10/09/2009
 2009 American Chemical Society

(+)-aspergillide C (3) that intersects at a late stage with
Kuwahara’s recently reported synthesis.5
We envisaged that aspergillide C could be reached from
lactone (+)-4 after saponification, protecting group adjust-
ment, and macrolactonization (Scheme 1). In turn, intermedi-
Scheme 2. Preparation of Lactone (+)-13
Scheme 1. Retrosynthetic Analysis of (+)-Aspergillide C
nucleophile was considered. The diastereoselectivity of
Ferrier-type additions of carbon-centered nucleophiles onto
similar glycal systems can be dependent upon the nature of
the nucleophile.11 While use of a highly reactive silyl ketene
acetal would provide a product with the correct oxidation
level at C(1), use of a moderately reactive silyl enol ether
could provide a greater degree of 2,6-trans selectivity.11
Ultimately, tert-butyldimethylsilyl vinyl ether (11, Scheme
2)12 was selected with the expectation that the resultant
aldehyde product could be easily oxidized to the requisite
carboxylic acid. Initial attempts at effecting the addition with
Lewis acids such as BF3·OEt2, TiCl2(OiPr)2, and Ti(OiPr)4
led to complex product mixtures. Gratifyingly, conducting
the reaction in a 3.0 M solution of lithium perchlorate in
ethyl acetate13 at rt afforded the desired aldehyde (+)-12 in
87% yield.14 As expected, a subsequent Pinnick oxidation15
smoothly provided carboxylic acid (+)-6 in nearly quantita-
tive yield.
ate (+)-4 could be accessed from aldehyde 5 and a sulfone
fragment through E-selective Julia-Kocienski olefination.
The lactone moiety in 5 could be obtained through palladium-
catalyzed oxidative cyclization of carboxylic acid (+)-6. The
2,6-trans relationship of the dihydropyran ring in (+)-6 could
be realized through Ferrier-type addition of a suitable two-
carbon nucleophile onto allylic acetate (+)-7, which could
be reached from the cycloadduct of diene 8 and optically
pure (S)-(-)-glyceraldehyde acetonide (9).
The synthesis commenced with a zinc-mediated hetero
Diels-Alder (HDA) reaction of (S)-(-)-glyceraldehyde
acetonide (9), prepared from L-(+)-arabinose,6 and the
Danishefsky-Kitahara diene7 (8) to afford dihydropyrone
(-)-10 (Scheme 2). In accord with prior accounts, dihydro-
pyrone (-)-10 was isolated as a single diastereomer as
predicted by Felkin’s model, thereby securing the requisite
configuration at C(7).8 Reduction of the carbonyl function
in (-)-10 under Luche’s conditions9 followed by acetylation
afforded (+)-7.
With the olefin in glycal (+)-7 now having migrated after
Ferrier reaction from C(3-4) to C(4-5) as shown in acid
(+)-6 and C(1) now at the appropriate oxidation level, an
opportunity was at hand to form a key bond via Pd-catalyzed
With the intention of fastening the side chain at C(3) via
Ferrier-type addition,10 the identity of a suitable two-carbon
(10) (a) Ferrier, R. J. Top. Curr. Chem. 2001, 215, 153–175, and
references therein. (b) Ferrier, R. J. J. Chem. Soc. A 1964, 5543–5449.
(11) cf. Paterson, I.; Smith, J. D.; Ward, R. C. Tetrahedron 1995, 51,
9413–9436.
(6) (a) Baker, S. B. J. Am. Chem. Soc. 1952, 74, 827–828. (b)
MaloneyHuss, K. E. Synth. Commun. 1985, 15, 273–277.
(7) (a) Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807–
7808. (b) Danishefsky, S.; Kitahara, T.; Schuda, P. F. Org. Syn. 1990, 7,
312–315.
(12) (a) Srisiri, W.; Padais, A. B.; Hall, H. K., Jr. J. Org. Chem. 1994,
59, 5424–5432. (b) Jung, M. E.; Blum, R. E. Tetrahedron Lett. 1977, 43,
3791–3794.
(13) (a) Grieco, P. A.; Speake, J. D. Tetrahedron Lett. 1998, 39, 1275–
1278. (b) Grieco, P. A. Aldrichimica Acta 1991, 24, 59–66.
(14) Only trace amounts of what was presumably the 2,6-cis isomer
(8) (a) Danishefsky, S.; Kobayashi, S.; Kerwin, J. F., Jr. J. Org. Chem.
1982, 47, 1981–1982. (b) Ohmori, K. Bull. Chem. Soc. Jpn. 2004, 77, 875–
885.
1
could be detected in the H HMR spectra of crude reaction mixtures.
(9) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454–
5459.
(15) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981,
37, 2091–2096.
Org. Lett., Vol. 11, No. 21, 2009
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19
Wacker-type oxidative lactonization. Such a transformation
would achieve three important goals: (i) to introduce the
requisite oxygen at C(4) with strict stereocontrol, (ii) to once
again make use of an olefin migration to the desired C(5-6)
site, and (iii) to utilize the newly formed lactone as an
“internal” protecting group during later transformations.
Exposure of acid (+)-6 to the cyclization conditions de-
scribed by Larock16 afforded lactone (+)-13 in 78% yield.
A suitable optically active starting material for the
C(9-14) segment of aspergillide C was found in com-
mercially available S-(+)-5-hexen-2-ol (14, Scheme 3),
gel-supported NaIO4 in CH2Cl2 attention was given to
fragment coupling of 5 and (+)-18 via a Kocienski-modified
Julia olefination (Scheme 4).19 After a survey of bases,
Scheme 4. Fragment Coupling via Modified Julia Olefination
Scheme 3. Preparation of Sulfone Fragment (+)-18
solvents, and additives, the use of LHMDS in THF favored
the desired E-olefin almost exclusively in modest yield, while
the use of KHMDS led to considerable erosion of selectivity
(2:1 E/Z) but with similar yield. These results correlate well
with those of She and co-workers, who used a Julia tactic in
a very recent synthesis of ent-aspergillide B.4a
The final stage of the synthesis would require hydrolysis
of the lactone in (+)-4, protecting group adjustment, and
macrolactonization. Indeed, during the course of our work,
an alternate path to (+)-4 and its successful elaboration to
(+)-aspergillide C by such a sequence was reported by
Kuwahara.5 Our synthetic route to (+)-4, obtained in a nine-
step longest linear sequence from (S)-(-)-glyceraldehyde
acetonide in 17% overall yield, now constitutes a formal
synthesis. Continued efforts toward the preparation of the
remaining members of the aspergillide series are in progress.
which after protection of the alcohol function provided PMB
ether (+)-15.17 Hydroboration-oxidation of the terminal
olefin in (+)-15 furnished primary alcohol (+)-16. Following
the method of Kocienski,18 a Mitsunobu-type reaction
between (+)-16 and 1-phenyl-1H-tetrazole-5-thiol gave
sulfide (+)-17, which after oxidation with ammonium
heptamolybdate and H2O2 afforded sulfone fragment (+)-
18.
Acknowledgment. We gratefully acknowledge the Uni-
versity of Vermont for financial support. This work was also
generously supported by the Vermont Genetics Network
through Grant Number P20 RR16462 from the INBRE
Program of the National Center for Research Resources
(NCRR), a component of the National Institutes of Health
(NIH).
After removal of the acetonide moiety in (+)-13 and
oxidative scission of the resultant vicinal diol with silica-
(16) Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298–
5300.
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Liu, J.; Zhang, L.; He, J.; He, L.; Ma, B.; Pan, X.; She, X.
Tetrahedron: Asymmetry 2008, 19, 906–911.
(18) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, P. Synlett
1998, 26–28.
(19) Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622–
2624. Attempts at carrying out the 1,2-diol scission under aqueous conditions
consistently afforded the hydrate derivative of aldehyde 5.
OL902154P
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Org. Lett., Vol. 11, No. 21, 2009