Total synthesis of paracaseolide A

Article abstract of DOI:10.1021/ol303447r

The total synthesis of paracaseolide A, a valuable cell-cycle progression inhibitor, was accomplished in 8 steps from known compounds, with 6.6% overall yield. The synthetic strategy creates strong potential for diversification.

Full text of DOI:10.1021/ol303447r

ORGANIC
LETTERS
2013
Vol. 15, No. 3
613–615
Total Synthesis of Paracaseolide A
Tezcan Guney and George A. Kraus*
Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
gakraus@iastate.edu
Received December 17, 2012
ABSTRACT
The total synthesis of paracaseolide A, a valuable cell-cycle progression inhibitor, was accomplished in 8 steps from known compounds, with
6.6% overall yield. The synthetic strategy creates strong potential for diversification.
Paracaseolide A (1) was isolated in 2011 from the stem
bark of the Chinese mangrove Sonneratia paracaseolaris by
the Guo group.1 Their analysis identified 1 as an effective
Scheme 1. Retrosynthetic Analysis
inhibitor against dual specificity phosphatase CDC25B
with an IC50 value of 6.44 μM.2 Cell division cycle 25
(CDC25) phosphatases play a crucial role in regulating
cell-cycle progression.2 Small molecule inhibitors such as
quinones and thiazolones have already proven effective
toward slowing the growth of cancerous cells.2 With its
unique tetracyclic molecular architecture compared to pre-
viously reported inhibitors, coupled with our earlier work in
the area,3 1 attracted our attention as a synthetic challenge.
Although a synthesis of 1 was recently described4 based
on the likely biosynthesis, our route is concise, strategically
distinct, and flexible toward the generation of analogs.
Obtaining suitable quantities of paracaseolide A and other
analogs would greatly advance the creation of a structureÀ
activity profile.
We recognized that the tetraquinane oxa-cage bis-lactone
structure was characterized by a concave and convex
surface, which we could use to our advantage to introduce
functionality in a stereocontrolled manner. We envisioned
that 1 would arise from a tandem vicinal difunctionaliza-
tion of an R,β-unsaturated lactone3 to form 2, followed by
elimination to install the requisite unsaturation (Scheme 1).
We utilized the symmetric bis-lactone 4, prepared according
to Wu and co-workers,5 which was advantageous in the
concise realization of 1.
Our synthesis begins with enedione 5, prepared by oxida-
tion of 2,5-dimethylfuran (Scheme 2).5 A DielsÀAlder
reaction of 5 with 1,3-cyclohexadiene followed by ozono-
lysis and oxidation of the hemiacetal with PCC provided
the symmetrical bis-lactone 4 in 20% yield over three
steps.5 Functionalization of 4 via an enolate intermediate
(1) Chen, X.-L.; Liu, H.-L.; Li, J.; Xin, G.-R.; Guo, Y.-W. Org. Lett.
2011, 13, 5032.
(2) (a) Huang, W.; Li, J.; Zhang, W.; Zhou, Y.; Xie, C.; Luo, Y.; Li,
Y.; Wang, J.; Li, J.; Lu, W. Bioorg. Med. Chem. 2006, 16, 1905.
(b) Lavecchia, A.; Giovanni, C. D.; Novellino, E. Mini-Rev. Med. Chem.
2012, 12, 62.
(3) Kraus, G. A.; Gupta, V.; Mokhtarian, M.; Mehanovic, S.; Nilsen-
Hamilton, M. Bioorg. Med. Chem. 2010, 18, 6316.
(4) Noutsias, D.; Vassilikogiannakis, G. Org. Lett. 2012, 14, 3565.
(5) (a) Lin, C.-C.; Wu, H.-J. J. Chin. Chem. Soc. 1995, 42, 815. All 1H
and 13C NMR characterization data matched their reported values.
(b) Alternatively, MMPP can be used for the oxidation of 2,5-dimethyl-
furan: Dominguez, C.; Csaky, A. G.; Plumet, J. Tetrahedron Lett. 1990,
31, 7669.
r
10.1021/ol303447r
2013 American Chemical Society
Published on Web 01/16/2013

conditions,6 which only returned starting material, even
after prolonged reaction times. In contrast, switching to
m-CPBA cleanly resulted in the oxidation to yield the
sulfoxide,7 without any evidence of overoxidation to the
sulfone. We planned to eliminate the sulfoxide immedi-
ately following the oxidation, but interestingly, we noticed
that the sulfoxide was partially eliminated even at room
temperature after 2 h, as observed by TLC and 1H NMR.
Heating the sulfoxide at 75 °C for 5 min was enough
to induce the complete elimination to afford 3 in 85%
yield.
Scheme 2. Synthesis of Paracaseolide A
The ensuing vicinal difunctionalization8 allowed the
introduction of both alkyl chains in a tandem 1,4-addition/
aldol reaction. The normal addition involves adding 3 to a
solution of the copper and organomagnesium compounds;
however, in our system, a complex mixture resulted. The key
to the success of the reaction was utilizing inverse addition, as
described by other researchers.9 In alignment with inverse
addition, dodecyl magnesium bromide was added to a
solution of 3 and CuBr Me2S at À78 °C, after which the
3
solution was warmed to 0 °C before adding the aldehyde to
produce a 72% yield of alcohol 2 as a single diastereomer.
The dehydration of 2 was unexpectedly problematic
when we attempted a mesylation/elimination reaction
utilizing excess triethylamine (10 equiv) and mesyl chloride
(5 equiv) sequentially added at 0 °C, followed by warming
thereactionmixtureto40°C in dichloromethane over 12 h.
Only 42% of the desired elimination product resulted,
along with a diasteromeric mixture of mesylates and
decomposition byproducts. After a number of trials, we
found that regulating the temperature was critically im-
portant to reduce byproduct formation. Specifically,
triethylamine and mesyl chloride were initially added at
À78 °C, which was followed by bringing the temperature
to 80 °C after DBU10 addition to favor elimination and
increase the yield of trans olefin 7 to 65%. The culmination
of the synthesis involved a second simultaneous oxidation/
elimination step, which converted 7 into parcaseolide A (1)
in 90% isolated yield. The identity of 1 was confirmed by
1H NMR, 13C NMR, and mass spectral characterization
data which exactly matched those found in the literature.1,4
In summary, paracaseolide A (1) was expeditiously
accomplished in 8 steps from known compounds, with
6.6% overall yield. Overcoming the initial solubility
challenges and successfully pairing two transformations
in single pot procedures greatly contributed to the
overall efficiency of the total synthesis. Furthermore, the
presented multiple challenges, since the compound was
only soluble in halogenated solvents and highly polar
solvents such as DMF, but not in THF, diethyl ether, or
acetonitrile. In addition to solubility difficulties, deproto-
nation was not straightforward since treating 4 with lithium
diisopropylamide, lithium tetramethylpiperidine, potassium
tert-butoxide, or potassium hydride led to either decomposi-
tion or recovery of starting material. Alternatively, forming
the enol silyl ether with TMSOTf also led to a number of
products, presumably due to fragmentation of the silylated
intermediate. Fortunately, sodium hydride in DMF at 0 °C,
after only 3 h, in the presence of excess diphenyl disulfide,
afforded bis-sulfide 6 in 92% yield.
(8) For additional reading on tandem vicinal difunctionalization, see:
(a) Chapdelaine, M.; Hulce, M.Organic Reactions; Paquette, L. A., Ed.;
John Wiley & Sons, Inc.: New York, NY, 1990; Vol. 38, Chapter 2, p 225.
(b) Taylor, R. J. K. Synthesis 1985, 4, 364. (c) Han, Y.-K.; Paquette,
L. A. J. Org. Chem. 1979, 44, 3731. (d) Zoretic, P. A.; Yu, B. C.; Biggers,
M. S.; Caspar, M. L. J. Org. Chem. 1990, 55, 3954.
The subsequent oxidation/elimination stepwas designed
based on the symmetric nature of 6. We first tried using
the mild oxidizing agent sodium periodate under standard
(9) (a) Posner, G. H. Organic Reactions; Dauren, W. G., Ed.; John
Wiley & Sons, Inc.: New York, NY, 1972; Vol. 19, Chapter 1, p 1.
(b) Nielsen, E. B.; Munch-Petersen, J.; Jorgensen, P. M.; Refn, S. Acta
Chem. Scand. 1959, 13, 1943. (c) Munch-Petersen, J. Bull. Soc. Chim. Fr.
1966, 471.
(10) For the utilization of DBU for the elimination of mesylates, see:
(a) Mendelsohn, B. A.; Lee, S.; Kim, S.; Teyssier, F.; Aulakh, V. S.;
Ciufolini, M. A. Org. Lett. 2009, 11, 1539. (b) Schmidt, V. A.; Alexanian,
E. J. J. Am. Chem. Soc. 2011, 133, 11402.
(6) (a) Leonard, N. J.; Johnson, C. R. J. Org. Chem. 1962, 27, 282.
(b) Hiskey, R. G.; Harpold, M. A. J. Org. Chem. 1967, 32, 3191.
(7) For additional information on sulfoxide oxidationÀelimination,
see: (a) Trost, B. M. Chem. Rev. 1978, 78, 363. (b) Rousch, W. R.; Walts,
A. E. J. Am. Chem. Soc. 1984, 106, 721. (c) Nemoto, H.; Nagai, M.;
Fukumoto, K.; Kametani, T. J. Org. Chem. 1985, 50, 2764. (d) Krafft,
M. E.; Kennedy, R. M.; Holton, R. A. Tetrahedron Lett. 1986, 27, 2087.
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Org. Lett., Vol. 15, No. 3, 2013

distinctive framework of the tetraquinane oxa-cage bis-
lactone structure allowed the stereocontrolled introduc-
tion of functionality. However, successfully optimizing
conditions for the pivotal tandem 1,4-addition/aldol trans-
formation amplifies the potential of our synthetic pathway
for comprehensive functionalization.
Supporting Information Available. Experimental pro-
1
cedures, full spectroscopic data, and copies of H and 13C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
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