Enantioselective total synthesis of aspergillide C

Article abstract of DOI:10.1021/ol802803x

(Chemical Equation Presented) The first enantioselective total synthesis of aspergillide C, a cytotoxic 14-membered macrotide isolated from the marine-derived fungus Aspergillus ostianus, has been accomplished from a commercially available chiral glycidol

Full text of DOI:10.1021/ol802803x

ORGANIC
LETTERS
2009
Vol. 11, No. 3
761-764
Enantioselective Total Synthesis of
Aspergillide C
Tomohiro Nagasawa and Shigefumi Kuwahara*
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science,
Tohoku UniVersity, Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
skuwahar@biochem.tohoku.ac.jp
Received December 4, 2008
ABSTRACT
The first enantioselective total synthesis of aspergillide C, a cytotoxic 14-membered macrolide isolated from the marine-derived fungus Aspergillus
ostianus, has been accomplished from a commercially available chiral glycidol derivative by a 12-step sequence involving an expeditious
preparation of a cyclic acetal intermediate and a trans-selective Ferrier-type two-carbon homologation reaction.
Aspergillides A-C were recently isolated by Kusumi and
co-workers from a bromine-modified 1/2PD (potato-dextrose)
culture medium of the marine-derived fungus Aspergillus
ostianus strain 01F313 and found to exhibit significant
cytotoxicity against mouse lymphocytic leukemica cells
(L1210) with LD50 values of 2.1, 71.0, and 2.0 µg/mL,
respectively.1 Based on spectroscopic analyses including
NOESY experiments and the modified Mosher methodology,
they proposed structures 1, 2, and 3 for aspergillides A, B,
and C, respectively (Figure 1). The molecular architectures
unprecedented in natural products.2,3 Quite recently, Uenishi
and co-workers achieved the first total synthesis of the
proposed structures of aspergillides A and B (1 and 2,
respectively) and revealed that the spectroscopic and physical
data of their synthetic compound 1 matched those reported
by Kusumi et al. for aspergillide B, while the data of
synthetic 2 were different form those reported either for
aspergillide A or for aspergillide B.4 On the basis of these
findings, Uenishi et al. concluded that the genuine structure
of aspergillide B must be represented by structure 1 (13S
form) and the real structure of aspergillide A should be
(1) Kito, K.; Ookura, R.; Yoshida, S.; Namikoshi, M.; Ooi, T.; Kusumi,
T. Org. Lett. 2008, 10, 225–228.
(2) For the only synthesis of a non-natural 14-membered macrolide
containing a 2,6-trans-substituted tetrahydropyran ring, see: Zacuto, M. J.;
Leighton, J. L. Org. Lett. 2005, 7, 5525–5527.
(3) For examples of natural 14-membered macrolides containing a 2,6-
cis-substituted tetrahydropyran ring either as a hemiacetal or as a nonhemi-
acetal form, see: (a) Sone, H.; Kigoshi, H.; Yamada, K. J. Org. Chem.
1996, 61, 8956–8960. (b) Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus,
C.; Roussakis, C. J. Am. Chem. Soc. 1996, 118, 11085–11088. (c) Zampella,
A.; D’Auria, M. V.; Minale, L. Tetrahedron 1997, 53, 3243–3248. (d) Trost,
B. M.; Gunzner, J. L.; Dirat, O.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124,
10396–10415. (e) Tan, L. T.; Ma´rquez, B. L.; Gerwick, W. H. J. Nat. Prod.
2002, 65, 925–928. (f) Luesch, H.; Yoshida, W. Y.; Harrigan, G. G.; Doom,
J. P.; Moore, R. E.; Paul, V. J. J. Nat. Prod. 2002, 65, 1945–1948. (g)
Wright, A. E.; Botelho, J. C.; Guzma´n, E.; Harmody, D.; Linley, P.;
McCarthy, P. J.; Pitts, T. P.; Pomponi, S. A.; Reed, J. K. J. Nat. Prod.
2007, 70, 412–416. (h) Youngsaye, W.; Lowe, J. T.; Pohlki, F.; Ralifo, P.;
Panek, J. S. Angew. Chem., Int. Ed. 2007, 46, 9211–9214.
Figure 1. Structures of aspergillides A-C proposed by Kusumi et al.
of aspergillides A-C immediately captured our interest, since
the 14-membered macrolide structures incorporating a 2,6-
trans-substituted tetrahydro- or dihydropyran ring were totally
10.1021/ol802803x CCC: $40.75
Published on Web 01/07/2009
2009 American Chemical Society

reinvestigated. Prompted by the unique structural features
and significant cytotoxicity of aspergillides, we also em-
barked on their total synthesis. As part of our synthetic
studies on aspergillides, we describe herein the first total
synthesis of aspergillide C (3) from a commercially available
glycidol derivative via 12 steps, which confirmed the
structure of aspergillide C proposed by Kusumi et al.
Scheme 2. Three-Step Preparation of 7
Our retrosynthetic analysis of aspergillide C (3) is shown
in Scheme 1. We considered that the target molecule 3 should
Scheme 1. Retrosynthetic Analysis of Aspergillide C (3)
of camphorsulfonic acid was added to the reaction mixture,
which induced the formation of the 6-membered cyclic acetal
ring as well as the removal of the TBS protecting group,
giving a 79% yield of the desired product 12 in one pot as
a 15:1 epimeric mixture with the anomerically favored
R-epimer predominating.8 Thus, the preparation of 12 was
achieved in only two steps (72% yield) from the com-
mercially available siloxy epoxide 9.9,10 The alcohol 12 was
then oxidized smoothly to aldehyde 7, which set the stage
for chain-elongation by the Julia olefination reaction.
The preparation of sulfone segment 16 corresponding to
the C9-C14 portion of aspergillide C was conducted in a
straightforward manner from known ester 1311 via six steps
(Scheme 3). Reduction of 13 with DIBAL gave an aldehyde
be obtained via macrolactonization of seco acid 4, the
protected allylic alcohol moiety of which in turn would be
installable through halolactonization of 5 followed by de-
hydrohalogenation of the resulting halolactone intermediate
and hydrolytic cleavage of the lactone ring. To construct the
2,6-trans-substituted dihydropyran structure in 5, we planned
to utilize a Ferrier-type reaction between cyclic acetal 6 and
a silyl ketene acetal. The E double bond in the side chain of
6 would be formed by the Julia olefination of aldehyde 7
with sulfone 8. The cyclic acetal 7 seemed to be readily
prepared via epoxide ring-opening of commercially available
epoxide 9 with known acetylenic compound 10.
Scheme 3. Preparation of Sulfone Segment 16
According to the synthetic plan, we began our synthesis
of 3 with the preparation of the cyclic acetal 7 (Scheme 2).
Exposure of the epoxide 95 to the lithium acetylide generated
from 106 with n-BuLi in the presence of BF3·OEt2 afforded
11.7 The acetylenic alcohol 11 was then subjected to catalytic
hydrogenation conditions using Lindlar’s catalyst in EtOH
to semihydrogenate the triple bond. After checking the
disappearance of 11 by TLC monitoring, a catalytic amount
intermediate, which was then converted to unsaturated ester
14 by the Wittig reaction. Chemoselective reduction of the
double bond of 13 was effected smoothly by use of NaBH4/
NiCl2 in MeOH,12 and the resulting ester was further reduced
with LiAlH4 to give alcohol 15 in excellent yield. Conversion
of 15 to the Kocienski-type sulfone 16 was carried out
uneventfully according to the literature procedure.13
(4) Hande, S. M.; Uenishi, J. Tetrahedron Lett. 2009, 50, 189–192.
(5) (a) Posp´ısil, J.; Marko´, I. E. Tetrahedron Lett. 2006, 47, 5933–5937.
(b) Jamieson, A. G.; Sutherland, A. Org. Lett. 2007, 9, 1609–1611. (c)
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.
(8) The stereochemical assignment to each epimer was supported by
comparison of the 1H NMR data of the epimeric mixture with those reported
for analogous compounds: Jurczak, J.; Bauer, T. Tetrahedron 1986, 42,
5045–5052.
(6) Le Coq, A.; Gorgues, A. Org. Synth. 1980, 59, 10–15.
(7) (a) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391–394.
(b) Ferna´ndez-Gonza´lez, M.; Alonso, R. J. Org. Chem. 2006, 71, 6767–
6775.
(9) For the preparation of the (2S,6S)-stereoisomer of 12 from tri-O-
acetyl-D-glucal in five steps, see: Valverde, S.; Hernandez, A.; Herradon,
B.; Rabanal, R. M.; Martin-Lomas, M. Tetrahedron 1987, 43, 3499–3504
.
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Org. Lett., Vol. 11, No. 3, 2009

With the two segments 7 and 16 in hand, we moved on to
their coupling by the Julia-Kocienski reaction and elabora-
tion of the resulting product to lactone intermediate 21
bearing the carbon skeleton and functionalities corresponding
appropriately to those of aspergillide C (3) (Scheme 4). The
treated with KI3/NaHCO3 to give iodolactone 20, the
stereochemistry of which was assigned from its NOE
correlations (see the conformational diagram in Scheme 4).
Dehydroiodination of 20 was found to be problematic due
to side reactions triggered probably by deprotonation at the
R-position of the lactone carbonyl (for example, retro-oxy-
Michael cleavage of the dihydropyran ring).18 In the event,
this transformation was carried out using DBU in THF at
room temperature to give 21 in a moderate overall yield of
45% from 19; heating the reaction mixture led to a complex
mixture of products.
Scheme 4. Preparation of Lactone Intermediate 21
Having secured the properly functionalized lactone inter-
mediate 21, we proceeded to the final stage of the synthesis
(Scheme 5). Hydrolysis of the lactone 21 with aq LiOH (1.2
Scheme 5. Completion of the Synthesis of Aspergillide C (3)
coupling of 7 and 16 was conducted by exposing 7 to the
potassium anion generated from 16 according to Kocienski’s
procedure to afford 17 as a 10:1 E/Z mixture favoring the
desired E isomer.13 Installation of an acetate unit at the
anomeric position of 17 was effected by the Ferrier-type
reaction using silyl ketene acetal 1814 in the presence of
BF3·OEt2 in CH3CN,15 delivering the desired trans-substituted
ester 19 and its cis isomer in isolated yields of 65% and
25%, respectively,16 after chromatographic separation.17 The
olefinc ester 19 was hydrolyzed with an aqueous NaOH
solution, and the resulting reaction mixture was directly
equiv) in THF gave a lithium carboxylate salt, which after
evaporation of the water-containing solvent under reduced
pressure, was treated with 4.5 equiv of TBSOTf in DMF in
presence of DMAP and imidazole.19 TLC monitoring of the
reaction indicated that both the carboxylate anion and the
hydroxyl group of the carboxylate intermediate were pro-
tected smoothly to give a bis-TBS intermediate. Fortunately,
addition of a small amount of water to the reaction mixture
brought about selective deprotection of the TBS ester group,
giving 22 in quantitative yield over the two steps. The PMB
protecting group of 22 was then removed by DDQ oxidation,
and the resulting seco acid 23 was subjected to the Yamagu-
chi lactonization conditions to furnish 3 as a white crystalline
solid (mp 115.5-116 °C) after deprotection of the TBS ether
group. The 1H and 13C NMR of 3 were identical with those
reported for natural aspergillide C, and the specific rotation
of 3 {[R]25D +83 (c 0.14, MeOH)} was equal in sign to that
(10) For the preparation of analogous compounds of 12 by asymmetric
hetero-Diels-Alder approaches, see: (a) Mikami, K.; Motoyama, Y.; Terada,
M. J. Am. Chem. Soc. 1994, 116, 2812–2820. (b) Bauer, T.; Chapuis, C.;
Jezewski, A.; Kozak, J.; Jurczak, J. Tetrahedron: Asymmetry 1996, 7, 1391–
1404. (c) Bhatt, U.; Christmann, M.; Quitschalle, M.; Claus, E.; Kalesse,
M. J. Org. Chem. 2001, 66, 1885–1893. (d) Kwiatkowski, P.; Asztemborska,
M.; Jurczak, J. Tetrahedron:Asymmetry 2004, 15, 3189–3194.
(11) (a) Li, S.; Xu, R.; Bai, D. Tetrahedron Lett. 2000, 41, 3463–3466.
(b) Nakano, M.; Kikuchi, W.; Matsuo, J.; Mukaiyama, T. Chem. Lett. 2001,
424–425. (c) Andrus, M. B.; Shih, T.-L. J. Org. Chem. 1996, 61, 8780–
8785. Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964–
12965.
(12) Satoh, T.; Nanba, K.; Suzuki, S. Chem. Pharm. Bull. 1971, 19,
817–820.
of natural aspergillide C {[R]25 +66.2 (c 0.19, MeOH)},1
D
(13) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26–28.
(14) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
12964–12965.
(17) At this stage, a small amount of the Z-isomer of 19 originating
from the 10:1 E/Z selectivity in the conversion of 7 to 17 could be removed
by column chromatography.
(15) (a) Paterson, I.; Smith, J. D.; Ward, R. A. Tetrahedron 1995, 51,
9413–9436. (b) Gaertzen, O.; Misske, A. M.; Wolbers, P.; Hoffmann,
H. M. R. Synlett 1999, 1041–1044. (c) Backes, J. R.; Koert, U. Eur. J.
Org. Chem. 2006, 2777–2785.
(18) The difficulty in this dehydroiodination step would be ascribable
to the fact that the ꢀ-elimination of 20 demands the transition state to adopt
an energetically unfavorable conformation in which the iodine atom and
the olefinic side chain are in a 1,3-diaxial relationship.
(16) For theoretical studies on stereoselectivity in this type of substitution
reaction, see: (a) Yang, M. T.; Woerpel, K. A J. Org. Chem. 2009, 74,
545–553. (b) Krumper, J. R.; Salamant, W. A.; Woerpel, K. A. Org. Lett.
2008, 10, 4907–4910.
(19) (a) Keck, G. E.; Romer, D. R. J. Org. Chem. 1993, 58, 6083–
6089. (b) Jayasundera, K. P.; Brodie, S. J.; Taylor, C. M. Tetrahedron 2007,
63, 10077–10082.
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although the magnitude of the former was considerably larger
than the latter.
Acknowledgment. This work was financially supported,
in part, by a Grant-in-Aid for Scientific Research (B) from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan (No. 16380075). We also thank Ms.
Yamada (Tohoku University) for measuring the NMR and
mass spectra.
In conclusion, the first total synthesis of aspergillide C
(3) was accomplished in 7.3% overall yield from the
commercially available chiral glycidol derivative 9 via 12
steps (or 7.5% from the known ester 13 through 15 steps)
using the one-pot preparation of cyclic acetal 12 from
acetylenic alcohol 11 and the Ferrier-type two-carbon ho-
mologation of 17 to 19 as the key transformations. The
synthesis of the revised structure of aspergillide B (1) from
the iodolactone 20 is now underway.
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL802803X
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Org. Lett., Vol. 11, No. 3, 2009