Total synthesis of auripyrone b using a non-Aldol Aldol-Cuprate opening process

Article abstract of DOI:10.1021/ol100985n

(Figure presented) A non-aldol aldol-cuprate opening generates the polypropionate 11 from the epoxy ether 14 in eight steps as a single diastereomer. A highly stereoselective aldol reaction of 8 with 9 gives the aldol product 7 in high yield and excellent diastereoselectivity, due to double stereodifferentiation. This compound was used for an efficient synthesis of the natural product auripyrone B 2 in only 20 steps and 8% overall yield from 14 using a late-stage spiroketalization onto a stable hemiketal as the final key step.

Full text of DOI:10.1021/ol100985n

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2872-2875
Total Synthesis of Auripyrone B Using a
Non-Aldol Aldol-Cuprate Opening
Process
Michael E. Jung,* Manon Chaumontet, and Ramin Salehi-Rad
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles,
405 Hilgard AVenue, Los Angeles, California 90095
jung@chem.ucla.edu
Received April 29, 2010
ABSTRACT
A non-aldol aldol-cuprate opening generates the polypropionate 11 from the epoxy ether 14 in eight steps as a single diastereomer. A highly
stereoselective aldol reaction of 8 with 9 gives the aldol product 7 in high yield and excellent diastereoselectivity, due to double
stereodifferentiation. This compound was used for an efficient synthesis of the natural product auripyrone B 2 in only 20 steps and 8% overall
yield from 14 using a late-stage spiroketalization onto a stable hemiketal as the final key step.
Auripyrones A (1) and B (2), two polypropionate natural
products from the Japanese species of sea hare Dolabella
auricularia (Aplysiidae) (Figure 1), were isolated and
characterized by Yamada and co-workers in 1996.1
Extensive NMR investigation of these compounds revealed
a complex, fully substituted spiroketal core in a double
anomerically favored configuration in which all of the the
substituents are positioned equatorially except for the C10
methyl and the C11 acyloxy groups. Differing only in the
nature of their C11 acyloxy side chains, auripyrones A
(1) and B (2) also possess a common tetrasubstituted
γ-pyrone moiety and exhibited potent cytotoxicity against
HeLa S3 cells with IC50 values of 260 and 480 ng/mL,
respectively.
In the past few years, two total syntheses of auripyrone A
(1) have been reported: one by Perkins2 which uses the Evans
dipropionate methodology3 for the synthesis of the polypro-
pionate backbone and a biomimetic cyclization of an acyclic
triketone intermediate to generate the spiroketal moiety and
(1) Suenaga, K.; Kigoshi, H.; Yamada, K. Tetrahedron Lett. 1996, 37,
5151–5154.
(2) Lister, T.; Perkins, M. V. Angew. Chem., Int. Ed. 2006, 45, 2560–
2564.
(3) (a) Evans, D. A.; Gage, J. R. Org. Synth. 1989, 68, 77–91. (b) Evans,
D. A.; Ennis, M. D.; Le, J. J. Am. Chem. Soc. 1984, 106, 1154–1156. (c)
Evans, D. A.; Ng, H. P.; Clark, J. S.; Rieger, D. L. Tetrahedron 1992, 48,
2127–2142.
Figure 1
10.1021/ol100985n  2010 American Chemical Society
Published on Web 05/25/2010

the other by our group4 employing a tandem non-aldol aldol5/
Paterson lactate-derived aldol6 process to generate the
stereopentad core and a regioselective hemiketalization of a
keto diol followed by cyclization onto the stable hemiketal
to afford the spiroketal moiety. Recently, Kigoshi and co-
workers published7 a synthesis of auripyrone A 1 and the
first total synthesis of auripyrone B 2, establishing the
absolute configuration of the C2′ carbon of the natural
product. The key steps of their synthesis are a diastereose-
lective aldol reaction between a γ-pyrone and an optically
active aldehyde for the preparation of the stereopentad
backbone, and a late stage spiroketalization of a triketone
intermediate analogous to the Perkins’ approach. This very
recent report prompts us to present our total synthesis of
auripyrone B 2.
the C-14 epimers of the elimination product of auripyrone
A (1). In the natural product, the C-14 methyl moiety resides
exclusively in the equatorial position to presumably prevent
an undesired syn-pentane interaction with the C-11 methyl
substituent.8 However, elimination of the C-12 acyloxy group
along with the C-11 hydrogen moiety generates the alkene
and thereby creates a conformational change, displacing the
C-11 methyl substituent away from its original equatorial
position. This conformational change would in turn diminish
the syn-pentane effect and could lead to epimerization at the
C-14 position under basic conditions to give the epimer 5
as a minor product.
We next set about synthesizing the key alcohol intermedi-
ate 3 via a two-step approach (Scheme 2). Reduction of
It might be assumed that the most direct approach toward
the synthesis of auripyrone B 2 would involve the depro-
tection of the acyl moiety of auripyrone A 1 followed by
coupling of the appropriate acyl side chain. However,
attempts to remove the acyl substituent of auripyrone A 14
under acidic or basic conditions were generally unsuccessful
in providing the desired alcohol 3 (Scheme 1). Deprotection
Scheme 2
Scheme 1
auripyrone A (1) with DIBAL-H afforded the diol 6 in 83%
yield and 9:1 diastereomeric ratio, the major diastereomer
being the axial alcohol due to the approach of the hydride
from the less hindered ꢀ-face of the enoate.9,10 Despite
numerous efforts to selectively oxidize the allylic alcohol
of 6, we were unable to generate the desired intermediate 3.
Consequently, we decided to introduce the appropriate acyl
moiety earlier in our synthesis of auripyrone B (2).
According to our retrosynthetic analysis (Scheme 3),
auripyrone B (2) was envisioned to arise from the key
intermediate 7 through regioselective hemiketalization of the
keto diol followed by spiroketalization onto the stable
hemiketal.4 The key aldolate 7 could be obtained from a fully
matched11 double stereodifferentiating12 anti aldol reaction
of the boron enolate of the ketone 8 with the aldehyde 9.
The aldehyde 9 would in turn originate through a sequence
of acylation, desilylation, and oxidation from the γ-pyrone
10 which could result from the key aldehyde 11 as described
previously.4 The stereopentad 11 would arise from the anti-
cuprate13 opening of the epoxide 12 followed by selective
protection of the secondary alcohol via the p-methoxyben-
with a variety of acidic conditions led to the decomposition
of the natural product, while basic conditions afforded a
separable mixture of two eliminated products 4 and 5 rather
than the desired alcohol 3. The high propensity of auripyrone
A (1) to undergo E2-elimination under basic conditions
presumably originates from the antiperiplanar relationship
of the C-11 hydrogen and the C-12 acyloxy moieties.
Although no crystal structures were obtained, based on NMR
studies, we tentatively propose the structures of 4 and 5 as
(7) Hayakawa, I.; Takemura, T.; Fukasawa, E.; Ebihara, Y.; Sato, N.;
Nakamura, T.; Suenaga, K.; Kigoshi, H. Angew. Chem., Int. Ed. 2010, 2401–
2404.
(8) Hoffmann, R. W. Angew. Chem., Int. Ed. 2000, 39, 2054–2070.
(9) Lopez, R.; Poupon, J.-C.; Prunet, J.; Ferezou, J.-P.; Ricard, L.
Synthesis 2005, 64, 4–661.
(4) Jung, M. E.; Salehi-Rad, R. Angew. Chem., Int. Ed. 2009, 48, 8766–
8769.
(5) (a) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1993, 115,
12208–12209. (b) Jung, M. E.; Hoffmann, B.; Rausch, B.; Contreras, J. M.
Org. Lett. 2003, 5, 3159–3161.
(10) The stereochemistry at the new allylic alcohol center C-15 was
assigned on the basis of the coupling constant between H-15 and H-14
(2.4 Hz) indicating that they were cis and not trans-diaxial.
(11) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Rieger, D. L. J. Am. Chem.
Soc. 1995, 117, 9073–9074.
(6) (a) Paterson, I.; Wallace, D. J.; Velazquez, S. M. Tetrahedron Lett.
1994, 35, 9083–9086. (b) Paterson, I.; Wallace, D. J. Tetrahedron Lett.
1994, 35, 9087–9090. (c) Paterson, I.; Wallace, D. J.; Cowden, C. J.
Synthesis 1998, 639–652.
(12) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem.,
Int. Ed. 1985, 24, 1–30.
Org. Lett., Vol. 12, No. 12, 2010
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Scheme 3
Scheme 4
desired stereopentad 11 in 98% yield. Although this syn non-
aldol aldol5/anti cuprate opening13 strategy is less convergent
than our previously reported4 tandem non-aldol aldol/
Paterson lactate-derived aldol approach, it nonetheless
provides an alternate, highly reliable route for multigram
synthesis of the stereopentad 11 as a single diastereomer.
We next turned our attention to the synthesis of the key
intermediate 7 (Scheme 5). There was no way of knowing
zylidene acetal and oxidation of the primary alcohol to the
aldehyde. The epoxide 12 could be obtained from the aldolate
13 through a sequence of Wittig olefination, reduction, and
Sharpless epoxidation.14 The syn-aldolate 13 was proposed
to arise from the non-aldol aldol rearrangement5 of the
optically active epoxy silyl ether 14.4
The synthesis commenced with the assembly of the
stereopentad 11 (Scheme 4). Treatment of the known epoxy
silyl ether 144 with TESOTf and Hunig’s base at -45 °C
provided the desired syn non-aldol aldol product in 86% yield
and 20:1 diastereomeric ratio which was subjected to Wittig
olefination conditions with ethyl 2-triphenylphosphora-
nylidene acetate to afford in 88% yield the E-enoate 15.
Reduction of the E-enoate 15 with DIBAL-H (92% yield)
followed by stereoselective epoxidation of the E-allylic
alcohol under Sharpless conditions13 furnished the epoxide
12 in 87% yield as a single diastereomer. Treatment of the
epoxy alcohol 12 with lithium dimethylcuprate provided the
desired diol 16 in 83% yield, setting the desired anti
stereochemistry. To conclude the synthesis of the stereo-
pentad 11, the diol 16 was subsequently reacted with
p-methoxybenzaldehyde dimethyl acetal and catalytic PPTS15
to afford the p-methoxybenzylidene acetal 17 in 89% yield
and 16:1 diastereomeric ratio. Selective reduction of the
acetal 17 with DIBAL-H in dichloromethane provided
exclusively, in 86% yield, the primary alcohol which was
oxidized with Dess-Martin periodinane16 to provide the
Scheme 5
the absolute configuration of the C2′ ester stereocenter in
auripyrone B (2), but since the C17-20 and C28 portions
of the auripyrones had the (S) configuration, we concluded
that the ester stereocenter would likely have the (S) config-
uration as well, a decision that was shown to be correct. Thus,
the alcohol 10, obtained from the key stereopentad 11 in
(13) (a) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873–3888. (b)
Jung, M. E.; Lee, W. S.; Sun, D. Org. Lett. 1999, 1, 307–310.
(14) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–
5976.
(15) PPTS was the catalyst of choice for this reaction since more acidic
catalysts such as CSA led to the deprotection of the triethylsilyl (TES) ether
group and the formation of multiple products.
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Org. Lett., Vol. 12, No. 12, 2010

four steps as previously reported,4 was subjected to Yamagu-
chi esterification conditions17 with (S)-2-methylbutanoic
acid18 to give the polypropionate 18 in 97% yield. Treatment
of the silyl ether 18 with HF·pyridine furnished the primary
alcohol, which was oxidized with Dess-Martin periodinane
to afford the aldol precursor 9 in 92% yield over two steps.
A fully matched11 double stereodifferentiating12 anti-aldol
reaction of the boron enolate of the ketone 8 with the
aldehyde 9 provided the aldolate 7 in 81% yield and 20:1
diastereomeric ratio.19
a stable hemiketal provides a highly efficient method for the
synthesis of auripyrone B (2) from the key aldolate inter-
mediate 7 in four steps and 48% overall yield. In contrast,
our attempts to generate the spiroketal moiety of auripyrone
through acidic cyclization of an acyclic triketone intermedi-
ate, obtained from the key intermediate 7 through a three-
step sequence of desilylation, double oxidation, and PMB
deprotection afforded the natural product in less than 10%
yield. The poor yield in the spiroketalization of this particular
acyclic triketone intermediate, which was also observed by
Kigoshi and co-workers in their total synthesis of auripyrone
B (2) (17%),7 arises from a rapid acid-catalyzed 1,5-acyl
migration21 between the C-9 and C-11 hydroxy moieties
leading to the formation of multiple byproduct. This problem
is circumvented in our spiroketalization approach where the
stable hemiketal platform serves as a pseudoprotecting group
for the C-9 hydroxy substituent to prevent 1,5-acyl migration,
providing a highly efficient route for the synthesis of the
spiroketal moiety of the natural product.
To conclude the synthesis of auripyrone B (2) (Scheme
6), the alcohol 7 was oxidized to the corresponding diketone
Scheme 6
In summary, we have reported the total synthesis of
auripyrone B (2) in 20 steps and 8% yield from the known
epoxide 14, utilizing a syn non-aldol aldol/anti cuprate
opening strategy to generate the polyketide backbone and a
highly efficient late-stage cyclization onto a stable hemiketal
platform for the synthesis of the spiroketal moiety.
Acknowledgment. This work was supported by the
National Science Foundation (CHE 0614591). R.S.-R. was
an NIH Chemistry-Biology Interface trainee, 2005-8, and
thanks the NIH Medical Scientist Training Program (MSTP)
at UCLA for generous financial support. M.C. was funded
by a grant from the Fondation pour la Recherche Me´dicale.
Supporting Information Available: Experimental pro-
cedures and proton and carbon NMR data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL100985N
with Dess-Martin periodinane, followed by concurrent
removal of the PMB and TES ethers with ceric ammonium
nitrate, resulting exclusively in the stable hemiketal 19 as a
single diastereomer in 66% yield over two steps. Oxidation
of the hemiketal 19 with Dess-Martin periodinane16 afforded
the diketone which was treated with Amberlyst-15 to furnish
auripyrone B (2) as a single diastereomer in 72% yield over
two steps. The NMR data for the synthetic material matched
that of the natural product.20 This cyclization approach onto
(16) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
(17) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989–1993.
(18) (S)-2-Methylbutanoic acid was obtained via Jones oxidation of
commercially available (S)-2-methyl-1-butanol.
(19) Careful aqueous workup of the reaction is crucial. Quenching with
pH 7 buffered solution at 0 °C is necessary to prevent acyl migration.
(20) We thank Professors Kiyoyuki Yamada (Nagoya) and Kiyotake
Suenaga (Keio) for providing the spectroscopic data.
(21) Unpublished results. Salehi-Rad, R. Ph.D. Thesis, UCLA, 2009.
Org. Lett., Vol. 12, No. 12, 2010
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