Cpa_turin_2008

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.
beyer@uni-wuppertal.de
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.[1]
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.[3] 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.[2] 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.[4] 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
[1] Holzapfel, C.W. Tetrahedron, 1968, 24, 2101.
23b: R=Me
[2] 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.
[3] 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-
[4] Gonzalez, M. A.; Ghosh, S.; Rivas, F.; Fischer, D; Theodorakis, E. A. Tetrahedron
Letters, 2004, 45, 5039.
25b: R=Me

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