STUDIES TOWARDS THE ENANTIOSELECTIVE SYNTHESIS OF α-CYCLOPIAZONIC ACID AND RELATED TETRAMIC ACIDS Wolfgang Rudolf Christian Beyer; Daniel Gallenkamp; Jürgen Scherkenbeck* Fachgruppe Chemie, Bergische Universität Wuppertal, Gaußstrasse 20, 42119 Wuppertal, Germany. [email protected] Introduction Retrosyntheses Route A TBDPSO α-Cyclopiazonic acid (CPA) is a metabolite produced by Penicillium and
(R)-Carvone (7) Aspergillus fungi. Its first isolation was reported by Holzapfel in 1968.
Due to its complex ring structure and its potential as antimalarial drug
CPA inhibits the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA).
CPA represents a highly interesting lead structure. Up to date only
As shown by x-ray crystal structure analyses Thapsigargin as well as the
syntheses of racemic CPA have been published. Following the Knight
structurally related Artemisinin, a novel drug against malaria, bind to
synthesis (route A) the optically active key intermediate 1 should be
SERCA, too. Recently CPA has been found to inhibit both chloroquine
available by an enantioselective aziridination or by a diastereoselective
sensitive (3D7) and resistant (K1) strains of Plasmodium falciparum in
Michael addition and subsequent azidation.[3c] The complementary route
the low micromolar range (1.5 - 3.0 µM).
B is based on a chiral pool synthesis starting from (R)-Carvone 7. Structurally Simplified CPA Analogues Synthesis of Intermediate 1 via Route A
Based on preceding structure activity investigations the tetramic acid
The diastereoselective Michael addition of Grignard reagent 22 to 2
moiety was found to be an essential part of the pharmacophoric unit.
afforded 19 in good to excellent diastereomeric ratios. The protected
Additionally molecular modeling studies suggest that the complete ring
optically active key intermediate 1 can be obtained following the Knight
architecture of CPA might not be necessary for SERCA inhibition. To
procedure with a modified reduction step. The direct enantioselective
prove this hypothesis the structurally simplified tricyclic CPA analogues
catalytic aziridination of 4 and subsequent reaction with acetic acid 15 and 16 were designed and synthesized.
yielded the ring-opened product 31 in an one-pot-reaction. 19a: R=phenyl (d.r. 94:6) 19b: R=isopropyl (d.r. 85:15) Reagents and Conditions: (a) TFAA, pyr, DCM, rt, over night, 87%; (b) IPy2BF4, HBF4, DCM/TFA 10:1, rt, over night, 92%; (c) 17, Pd(PPh3)4 10 mol%, Na2CO3 (aq), THF/toluene 1:1, 80 °C, 24-53 h, Reagents and Conditions:
THF/H2O, 38%; 2. pivaloylchloride, NEt3, (S)-4-
55%; (d) TfOH, CHCl3, rt, 6 h, 63%; (e) NaOH (aq), EtOH, reflux, over night, 89%; (f) SOCl2, MeOH,
phenyloxazolidinone or (S)-4-isopropyloxazolidinone, BuLi, THF, -78 °C; b) CuSPh, 22, THF, low
rt, over night, 69%; (g) 1. 18, toluene, 110 °C, 30 min, 2. KOtBu, 110 °C, 30 min, 67%
temp., 61%; c) KHMDS, trisyl azide, THF, -78 °C; d) 1. Cu(OTf)2, 21, PhINNs, DCM, 2. AcOH Synthesis of Intermediate 6 via Route B Summary
Intermediate 25 was prepared in six steps from (R)-Carvone following
• A route to simplified tricyclic CPA analogues including the tetramic acid
literature procedures. Attempts to convert 23b directly to 24 by an
has been developed. This synthesis offers an easy access to CPA
organocatalytic alkylation of imine 28 failed, probably due to sterically
analogues by combinatorial variations of the aromatic and tetramic acid
hindrance of the isopropenyl group. As an alternative we prepared
bromides 25a and 25b in high diastereoselectivities. Bromide 25b was then used as an electrophile for the alkylation of 29. Depending on the
• The optically active key intermediate 20 (route A) was prepared by
reaction conditions phenol 26 or the Michael addition product 29 were
diastereoselective Michael addition using Evans chiral auxiliaries. 31
isolated. The 1,4-addition can be avoided by protecting the carbonyl
was obtained by a direct catalytic aziridination.
• Carvone derivative 25a (route B) was synthesized by a highly regio-
and diastereoselective bromination of 23a with ammonium tribromide.
TMSOTf, TEA, 30
TMSOTf, TEA, 30
TMSOTf, TEA, 30
TMSOTf, TEA, 30 Preferences:
TMSCl, TEA, 30  Holzapfel, C.W. Tetrahedron, 1968, 24, 2101. 23b: R=Me  a) Søhoel, H.; Jensen, A.-M. L.; Møller, J. V.; Nissen, P.; Denmeade, S. R.;
Isaacs, J. T.; Olsen, C. E.; Christensen, S. B. Bioorg. Med. Chem., 2006, 14, 2810. b)
Moncoq, K.; Trieber, C. A.; Young, H. S. J. Biol. Chem., 2007, 282, 9748.  a) Kozikowski, A. P.; Greco, M. N.; Springer, J. P. J. Am. Chem. Soc., 1984, 106,
6873. b) Muratake, H.; Natsume, M. Heterocycles, 1985, 23, 1111. c) Haskins, C. M.; Reagents and Conditions: a) 28, proline,
DMSO or DCM or THF, no product isolated; b)
Knight, D. W. Chem. Commun., 2005, 3162.
see table; c) KOH, 29, cat. O-Allyl-N-(9-  Gonzalez, M. A.; Ghosh, S.; Rivas, F.; Fischer, D; Theodorakis, E. A. Tetrahedron Letters, 2004, 45, 5039. 25b: R=Me
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