Communication
RSC Advances
form intermediate(s)
3
and thereby switch the reaction re-protonation of the dienolate intermediate in a-position is
sequence to the right pathway in Scheme 1. For this preliminary favored.
study we used a set of different Lewis acids (Al, Sc, In, B, Zn, Fe)
In summary, we have presented a short and highly efficient
in different oxidation states. In reactions employing Lewis acids synthesis of paracaseolide A. Key steps of this approach involve
such as Me3Al, Me2AlCl, AlBr3, FeCl3 or FeCl2 no conversion was an a-iodination of a butenolide, a Suzuki cross-coupling and a
observed. Other reagents tested (in particular ZnBr2 and FeBr3) thermal Diels–Alder reaction. Thus, the tetracyclic natural
seem to catalyze the dimerization, these experiments however product is assembled in only ve steps starting from commer-
met with only moderate success and low yields were obtained. cially available and inexpensive a-angelica lactone. With an
Selected examples are shown in Table 2. For instance, treatment overall yield of 25% our synthesis represents the most efficient
of butenolide 4 with 0.5 equivalents of ZnBr2 in reuxing approach to this natural product reported to date. In addition,
CH2Cl2 resulted in formation of C7-epi 1 in 20% yield and preliminary results on a Lewis acid catalyzed [4 + 2]-cycloaddi-
elimination product 20 in 13% yield (Table 2, Entry 2). Addition tion/dehydration sequence (or vice versa) are presented. In none
of molecular sieves and over-stoichiometric use of ZnBr2 of the cases studied natural paracaseolide A was formed. Quite
generated the g-alkylidene butenolide12a 20 and compound 18 interestingly however, a whole set of novel products could be
(a constitutional isomer of 1) in low yields of 4% and 8%, identied, all of which in principle represent different modes of
respectively, along with 11% of the formal [4 + 4]-cycloaddition dimerization of the putative paracaseolide A precursor. It is
product 21 (Table 2, Entry 3). Employment of FeBr3 gave rise to therefore tempting to speculate that some of these compounds
13% of C7-epi 1 and another two new products 22 and 23 in low may be natural products as well.
yields (Table 2, Entry 4). The formation of 22 is rationalized by a
sequence of Claisen condensation/ketalization/oxa-1,6-addition
connecting two butenolide monomers. Compound 23 seems to
be generated through an aldol reaction of two ring-opened
Acknowledgements
monomers followed by a subsequent lactonization and water We thank Julia Steike (University of Hamburg) for conducting
elimination. Only poor conversion was observed in InBr3 Suzuki reactions with alkenylboronate 17. We are also grateful
mediated reactions, whereas employment of ZnCl2, Zn(OTf)2, for nancial support by the Fonds der Chemischen Industrie.
Sc(OTf)3 or BCl3 as Lewis acids resulted in the formation of
elimination product 20.
Our concluding experiments were dedicated to shed light on
the conversion of C7-epi 1 to 1. Vassilikogiannakis and co-
Notes and references
workers did not observe diastereomer C7-epi 1 in their thermal
Diels–Alder dimerization of 4. Hence, they proposed a C7-
epimerization under the reaction conditions.4 However, a
thermal interconversion was recently ruled out by Khan and
Mehta in experiments subjecting either 1 or C7-epi 1 to pro-
longed heating.8
1 X.-L. Chen, H.-L. Liu, J. Li, G.-R. Xin and Y.-W. Guo, Org. Lett.,
2011, 13, 5032.
2 (a) W. Huang, J. Li, W. Zhang, Y. Zhou, C. Xie, Y. Luo, Y. Li,
J. Wang, J. Li and W. Lu, Bioorg. Med. Chem., 2006, 16, 1905;
(b) A. Lavecchia, C. D. Giovanni and E. Novellino, Mini-Rev.
Med. Chem., 2012, 12, 62.
Hence, the establishment of the natural C7-stereoisomer
remains obscure.10 In none of our experiments on Lewis acid
catalyzed dimerizations of 4 we observed any formation of 1 (i.e.
epimerization of C7-epi 1). Though rather unlikely with regard
to the fused polycyclic ring system one may also consider a base
mediated epimerization aer formation of the tetracycle. We
therefore subjected epi-7-paracaseolide A (C7-epi 1) to basic
reaction conditions (Scheme 4). At prolonged reaction time in
the presence of DBU as a base (THF reux) the somewhat
expected isomer 24 with a shied double bond (yet another
constitutional isomer of 1) was produced. Formation of the
natural paracaseolide A epimer 1 was not detected. Apparently,
3 C. Lammer, S. Wagerer, R. Saffrich, D. Mertens, W. Ansorge
and I. Hoffmann, J. Cell Sci., 1998, 111, 2445.
4 D. Noutsias and G. Vassilikogiannakis, Org. Lett., 2012, 14,
3565.
5 For a review on Diels–Alder cycloadditions in natural
product synthesis, see: K. C. Nicolaou, S. A. Snyder,
T. Montagnon and G. Vassilikogiannakis, Angew. Chem.,
Int. Ed., 2002, 41, 1668.
6 T. Guney and G. A. Kraus, Org. Lett., 2013, 15, 613.
7 C.-C. Lin and H.-J. Wu, J. Chin. Chem. Soc., 1995, 42, 815.
8 L. Vasamsetty, F. A. Khan and G. Mehta, Tetrahedron Lett.,
2013, 54, 3522.
9 For reviews and selected examples of the discovery and
investigation of Diels-Alderases, see: (a) G. Pohnert,
ChemBioChem, 2001, 2, 873; (b) E. M. Stocking and
R. M. Williams, Angew. Chem., Int. Ed., 2003, 42, 3078; (c)
H. Oikawa and T. Tokiwano, Nat. Prod. Rep., 2004, 21, 321;
(d) H. Oikawa, Bull. Chem. Soc. Jpn., 2005, 78, 537; (e)
W. L. Kelly, Org. Biomol. Chem., 2008, 6, 4483; (f)
K. A. Miller, S. Tsukamoto and R. M. Williams, Nat. Chem.,
2009, 1, 63; (g) H. J. Kim, M. W. Ruszczycky, S.-H. Choi,
Y.-N. Liu and H.-W. Liu, Nature, 2011, 473, 109.
Scheme 4 Base mediated isomerization.
This journal is ª The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 21280–21284 | 21283