A unified total synthesis of aspergillides A and B

Article abstract of DOI:10.1021/ol100463a

An enantioselective total synthesis of aspergillides A and B has been accomplished based on a unified strategy, wherein a hydroxy-directed, highly chemoselective olefin cross-metathesis and a diastereoselective intramolecular oxa-conjugate cyclization were employed to forge the 2,6-substituted tetrahydropyran substructure.

Full text of DOI:10.1021/ol100463a

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1848-1851
A Unified Total Synthesis of
Aspergillides A and B
Haruhiko Fuwa,* Hiroshi Yamaguchi, and Makoto Sasaki
Graduate School of Life Sciences, Tohoku UniVersity, 2-1-1 Katahira,
Aoba-ku, Sendai 980-8577, Japan
hfuwa@bios.tohoku.ac.jp
Received February 24, 2010
ABSTRACT
An enantioselective total synthesis of aspergillides A and B has been accomplished based on a unified strategy, wherein a hydroxy-directed,
highly chemoselective olefin cross-metathesis and a diastereoselective intramolecular oxa-conjugate cyclization were employed to forge the
2,6-substituted tetrahydropyran substructure.
Aspergillides A-C were isolated from the marine fungus
Aspergillus ostianus strain 01F313, cultured in a bromine-
modified medium by Kusumi and co-workers.1 These natural
products are characterized by a 14-membered macrolactone
core structure embedded with a 2,3,6-trisubstituted tetrahy-
dropyran ring. Kusumi et al. initially proposed the structures
of aspergillides A-C as 1-3, respectively, on the basis of
extensive NMR analysis and the modified Mosher’s method
(Figure 1). However, chemical synthesis of the proposed
Figure 1. Proposed and corrected structures of aspergillides.
structure of 1 by the Uenishi group revealed nonidentity of
synthetic 1 with natural aspergillide A.2 Instead, the spec-
troscopic properties of synthetic 1 matched those of natural
total synthesis of aspergillides A and B (i.e., (-)-4 and (-)-
aspergillide B. Soon thereafter, the Kusumi group unequivo-
1, respectively) based on a unified strategy.
cally determined the correct structure of natural aspergillides
Our synthesis plan toward (-)-aspergillide A (4) is
summarized in Scheme 1. The 14-membered macrolactone
A and B to be represented by structures 4 and 1, respectively,
through X-ray crystallographic analysis.3 The intriguing
molecular structure and the cytotoxic properties of as-
pergillides against mouse lymphocytic leukemia cells (L1210)
with LD50 values of 2.0-71 µg/mL have led to significant
interest from synthetic chemists.2,4–6 Herein we report our
(4) Total synthesis of aspergillide A: (a) Nagasawa, T.; Kuwahara, S.
Tetrahedron Lett. 2010, 51, 875–877. (b) D´ıaz-Oltra, S.; Angulo-Pacho´n,
C. A.; Murga, J.; Carda, M.; Marco, J. A. J. Org. Chem. 2010, 75, 1775–
1778.
(5) Total synthesis of aspergillide B: (a) D´ıaz-Oltra, S.; Angulo-Pacho´n,
C. A.; Kneeteman, M. N.; Murga, J.; Carda, M.; Marco, J. A. Tetrahedron
Lett. 2009, 50, 3783–3785. (b) Nagasawa, T.; Kuwahara, S. Biosci.
Biotechnol. Biochem. 2009, 73, 1893–1894. (c) Liu, J.; Xu, K.; He, J.;
Zhang, L.; Pan, X.; She, X. J. Org. Chem. 2009, 74, 5063–5066.
(6) Total synthesis of aspergillide C: Nagasawa, T.; Kuwahara, S. Org.
Lett. 2009, 11, 761–764. Formal synthesis of aspergillide C: Panarese, J. D.;
Waters, S. P. Org. Lett. 2009, 11, 5086–5088.
(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.
10.1021/ol100463a  2010 American Chemical Society
Published on Web 03/18/2010

Scheme 1. Unified Synthesis Plan toward 1 and 4
Scheme 2. Synthesis of Common Intermediate 8
core of 4 was planned to be accessed by macrolactonization
of hydroxy acid 5. The C9-C10 bond of 5 would be formed
via Suzuki-Miyaura coupling7 of vinyl iodide 6 and an
alkylborane derived from olefin 7. We expected that the 2,6-
cis-tetrahydropyran 6 would be efficiently constructed via
an intramolecular oxa-conjugate cyclization of enoate 8 under
thermodynamic conditions.8 In turn, 8 was traced back to
allylic alcohol 9 by planning a chemoselective olefin cross-
metathesis (CM),9 where the phenyl and silyloxy groups
would reduce the reactivity of the C8-C9 double bond
toward initiation of olefin cross-metathesis. We envisioned
that (-)-aspergillide B (1) could also be synthesized ac-
cording to the above synthesis plan, except that the 2,6-trans-
tetrahydropyran subunit 12 would be derived from 8 by an
intramolecular oxa-conjugate cyclization under kinetic condi-
tions. Thus, both 1 and 4 were planned to be synthesized
from the common intermediate 8.10
olefin of 13 with disiamylborane followed by oxidative
workup afforded alcohol 14 in 88% yield. TEMPO/
PhI(OAc)2 oxidation12 of 14 and one-pot Wittig reaction
afforded enoate 15 in 95% yield (E/Z > 20:1). DIBALH
reduction of 15 gave allylic alcohol 16 in 100% yield, which
was subjected to Sharpless asymmetric epoxidation using
(+)-DET as a chiral auxiliary to yield epoxy alcohol 17 (89%
yield). Iodination under standard conditions followed by zinc
reduction of the derived iodo-epoxide afforded allylic alcohol
9 in 100% yield for the two steps. Chemoselective olefin
CM of 9 with methyl acrylate under the influence of 5 mol
% of the Grubbs second-generation catalyst (G-II)13 pro-
ceeded smoothly to deliver enoate 18 in 90% yield without
affecting the styrene moiety (E/Z > 20:1). No trace amount
of the possible ring-closing metathesis (RCM) product was
detected. The observed remarkable chemoselectivity can be
ascribed to H-bonding of the allylic alcohol with the chlorine
atom of the Grubbs catalyst, which results in the formation
of an unfavorable conformational constraint for the RCM
(Figure 2).14 Thus, the CM of 9 would occur via the Ru-
alkylidene complex A in an open-chain conformation, while
the RCM of 9 would have to proceed via ruthenacyclobutane
B by breaking the H-bonding within A and/or highly strained
ruthenacyclobutane C. Protection of the hydroxy group
within 18 (MOMCl, i-Pr2NEt, 90% yield) and removal of
The synthesis of the key intermediate 8 is illustrated in
Scheme 2. The known homoallylic alcohol 1011 was
protected with TBSCl/imidazole to give silyl ether 13 in
100% yield. Chemoselective hydroboration of the terminal
(7) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457–2483. (b) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2001, 40, 4544–4568. (c) Kotha, S.; Lahiri, K.; Kashinath,
D. Tetrahedron 2002, 58, 9633–9695. (d) Suzuki, A. Chem. Commun. 2005,
4759–4763.
(8) For discussions on the stereochemical outcome of intramolecular
oxa-conjugate addition, see: (a) Betancort, J. M.; Mart´ın, V. S.; Padro´n,
J. M.; Palazo´n, J. M.; Ram´ırez, M. A.; Soler, M. A. J. Org. Chem. 1997,
62, 4570–4583. (b) Schneider, C.; Schuffenhauer, A. Eur. J. Org. Chem.
2000, 73–82.
(9) For a review, see: Connon, S. J.; Blechert, S. Angew. Chem., Int.
Ed. 2003, 42, 1900–1923.
(12) Mico, A. D.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J. Org. Chem. 1997, 62, 6974–6977.
(10) Although aspergillide A (4) is the C3-epimer of aspergillide B (1),
Kusumi et al. reported that interconversion between 1 and 4 was not possible
(ref 3). Accordingly, 1 and 4 have to be synthesized independently.
(11) Hanawa, H.; Uraguchi, D.; Konishi, S.; Hashimoto, T.; Maruoka,
K. Chem.sEur. J. 2003, 9, 4405–4413.
(13) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956.
(14) (a) Hoveyda, A. H.; Lombardi, P. J.; O’Brien, R. V.; Zhugralin,
A. R. J. Am. Chem. Soc. 2009, 131, 8378–8379. (b) Hoye, T. R.; Zhao, H.
Org. Lett. 1999, 1, 1123–1125.
Org. Lett., Vol. 12, No. 8, 2010
1849

Scheme 4. Total Synthesis of Aspergillide B (1)
Figure 2. Plausible rationale for chemoselective CM of 9.
the TBS group with TBAF buffered with AcOH led to enoate
Scheme 5. Total Synthesis of Aspergillide A (4)
8 (89% yield).
Intramolecular oxa-conjugate cyclization of 8 by exposure
to KOt-Bu (0.05 equiv) in THF at -78 °C for 30 min gave
rise to 2,6-trans-tetrahydropyran trans-19 in 96% yield with
excellent diastereoselectivity (dr ) 17:1) (Scheme 3). In
contrast, treatment of 8 with DBU in toluene at 135 °C
afforded thermodynamically favored 2,6-cis-tetrahydropyran
(cis-19) in 81% yield with high diastereoselectivity (dr )
11:1). The stereochemistries of cis-19 and trans-19 were
established by NOE experiments. Thus, either syn-19 or anti-
19 could be synthesized from 8 in a stereoselective manner
simply by switching the reaction conditions.
Scheme 3. Intramolecular Oxa-Conjugate Cyclization of 8
) ca. 5:1) in good overall yield. The minor Z-isomer was
removedbyflashchromatographyonsilicagel.Suzuki-Miyaura
coupling of 12 with an alkylborane, derived from olefin 7,
under the influence of the PdCl2(dppf)·CH2Cl2/Ph3As catalyst
system and aqueous Cs2CO3 (DMF, room temperature)16
afforded E-olefin 20 in 73% yield. Hydrolysis gave hydroxy
acid 11 in 88% yield, whose macrolactonization under
Yamaguchi conditions17 (2,4,6-Cl3C6H2COCl, Et3N, THF;
(15) (a) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408–7410. (b) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115,
4497–4513.
Completion of the total synthesis of (-)-aspergillide B
(1) is illustrated in Scheme 4. Ozonolysis of the double bond
of trans-19 followed by Takai olefination15 of the derived
aldehyde gave (E)-vinyl iodide 12 as the major isomer (E/Z
(16) Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014–
11015.
(17) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989–1993.
1850
Org. Lett., Vol. 12, No. 8, 2010

then DMAP, toluene, 100 °C) successfully delivered the 14-
membered macrolactone 21 in 73% yield. Finally, cleavage
of the MOM group with LiBF4 (aq CH3CN, 72 °C)5c
furnished synthetic (-)-aspergillide B (1) in 94% yield,
whose spectroscopic properties (1H, 13C NMR, IR, HRMS)
as well as specific rotation ([R]D) were in full accordance
with those reported for natural (-)-1.1
Total synthesis of (-)-aspergillide A (4) was accomplished
from cis-19 in a similar manner to that described for (-)-1
(Scheme 5).18 The spectroscopic properties and specific
rotation of synthetic (-)-4 matched with those of the
authentic sample.
In conclusion, we have accomplished the total synthesis
of aspergillides A and B based on a unified strategy that
involves (i) a hydroxy-directed, highly chemoselective olefin
cross-metathesis reaction of allylic alcohol 9 and (ii) a
diastereoselective intramolecular oxa-conjugate cyclization
of 8 to construct either 2,6-cis- or 2,6-trans-substituted
tetrahydropyran substructure.
Acknowledgment. We thank Professors Shigefumi Ku-
wahara (Tohoku University) and Takenori Kusumi (Tokyo
Institute of Technology) for providing us with copies of 1H
and 13C NMR spectra of aspergillides A and B. This work
was supported in part by a Grant-in-Aid for Scientific
Research from MEXT, Japan.
(18) It should be noted, however, that macrolactonization of 5 proved
to be a difficult task, giving 23 in only 20% yield. At higher concentrations
(1 mM or above), only a trace amount of 23 was formed and the major
product was the corresponding dimer. The difficulty associated with the
macrolactonization of 5 can be ascribed to the conformation of the 2,3,6-
trisubstituted tetrahydropyran of 23, which adopts a chair conformation with
all three substituents being axially disposed (ref 3). In contrast, the
tetrahydropyran of 5 is in a chair conformation with all three substituents
occupying equatorial positions. Thus, it is likely that the energetically
favored “all-equatorial” chair conformer of the tetrahydropyran ring of 5
would have to flip to the energetically disfavored “all-axial” chair conformer
before the macrolactonization took place. To suppress the undesired
dimerization, the reaction had to be performed under high-dilution conditions
(0.2 mM). However, at the same time, a significant amount of 5 was
decomposed under these conditions, resulting in the low yield of 23.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and copies of 1H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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