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Approaches to the Synthesis of Arisugacin A

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Approaches to the Synthesis of Arisugacin A Tetrahedron 63 (2007) 3682–3701 Approaches to the synthesis of arisugacin A Michael E. Jung* and Sun-Joon Min Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095-1569, United States Received 19 January 2007; revised 20 February 2007; accepted 21 February 2007 Available online 24 February 2007 Abstract—Approaches to the synthesis of the important acetylcholinesterase inhibitor, arisugacin A, are described. Two different routes to the key AB ring system are described: the first utilizes an intramolecular Diels–Alder reaction on a furan substrate and the second a6p-electrocyclization of a substituted triene followed by cycloaddition with singlet oxygen. The successful synthesis of a fully functional- ized AB ring system of arisugacin A, the tetraol 52 from hydroxy-b-ionone 22 in 16 steps and 9.3% overall yield is described. Several useful synthetic transformations to this molecule and its analogues are reported, e.g., the formation of the furan Diels–Alder cycloadduct 14 and its conversion into the oxa-bridged structures 17 and 21, the preparation of the dienes 25 and 26 and the conversion of the later into the endo- peroxide 30 and its diol 36, the preparation of the endoperoxide 40 and the oxa-bridged system 42, and finally the use of the enelactone 43 and its ultimately successful conversion into 52. In addition, several novel rearrangements are described, producing the unusual compounds 62, 65, and 67. Finally, the successful coupling of the pyrone unit to the AB ring system is described to give compounds 70 and 71. The novel reduction of these compounds to the cyclic ether 74 is described. Ó 2007 Elsevier Ltd. All rights reserved. 1. Introduction the angular methyl and hydroxyl groups at the AB and BC ring junctures having the trans–anti–trans relationship. Arisugacin A (1a), a compound isolated in 1997 from a strain With respect to its three-dimensional structure, a docking of Penicillium sp. FO-4259, is a potent and specific inhibitor simulation of arisugacin A with AChE showed that this rel- of acetylcholinesterase (AChE), which may be clinically atively flat compound when stretched out as a long sheet useful for the treatment of Alzheimer’s disease (AD), the appeared to reside in the extended narrow active site of most common form of dementia.1 The inhibitory activity AChE.1b Because of its structural complexity, its therapeutic of arisugacin A reduces the rate of hydrolysis of acetyl- significance, and limited supply from natural sources, choline (ACh), a neurotransmitter in the cholinergic neuron synthetic chemists have been attracted to this compound. system, thereby increasing the amount of ACh in the brain.2 Recently, both the O˜ mura and Hsung groups have Moreover, this compound shows a higher selectivity for independently reported total syntheses of arisugacin A using AChE in the nervous system than for butyrylcholinesterase a formal [3+3] cycloaddition strategy to construct the (BuChE), which should reduce the unfavorable side effects dihydro-pyranopyrone ring system.4 associated with non-specific inhibitors such as tacrine.3 In our retrosynthetic analysis of arisugacin A (Scheme 1), As shown in Figure 1, arisugacin A consists structurally of we envisioned a coupling of the pyrone unit with the ad- a tetracyclic ring core possessing four contiguous stereocen- vanced AB ring system at a late synthetic stage. The highly ters and an aryl group connected to an a-pyrone moiety with oxygenated decalin system 3 would derive from R3 R2 R1 R2 R3 Arisugacin A (1a) H OMe OMe O O 1 R Arisugacin B (1b) H OMe H 1c O Me Territrem A ( ) -OCH2O- OMe 12b 6a O Territrem B (1d) OMe OMe OMe 12a OH Me 4a Territrem B (1e) OMe OH OMe OH Me Me Figure 1. Arisugacin A and its family. * Corresponding author. Tel.: +1 310 825 7954; fax: +1 310 206 3722; e-mail: [email protected] 0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2007.02.085 M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701 3683 O O Ar OH O O O CO2R Me Me OR Me Me Me 1 OH OH Me OH OH OH OH OH Me Me Me Me Me Me 2 3 4 Route A O O Z Me Z Me Me O Me Me 4 O O Intramolecular DA reaction 7 Me Me Me Me 5 Z = CN, COOBn 6 Z = CN, COOBn Route B R'O CO2R R'O CO R Me Me 2 R'O CO R Me Me Me 2 Me 4 OH OH O Me Me Me Me O 89Me Me Singlet oxygen 10 R'O HO Me Me Electrocyclization O CO2R Me Me Me Me Me Me 11 12 Scheme 1. Retrosynthetic analysis. dihydroxylation of the advanced intermediate 4, which afforded the desired cycloadduct 14 as a single would be formed via two different approaches. First, we diastereomer in 91% yield in the presence of dimethylalumi- could construct the oxa-bridged compound 5 using an intra- num chloride (Scheme 2). Diimide reduction9 of the endo- molecular Diels–Alder reaction of furan (IMDAF), which cyclic double bond of 14 gave the ketone, which was has already been studied in our group (Route A).5,6 In this selectively converted to the b-alcohol in 64% yield using case, one would expect the stereochemistry of the fused lithium in ammonia. We conducted the sequence of hydro- ring juncture in the AB ring system to be trans since (1) boration and oxidation as described below to afford the the exo cycloadduct (keto group in the exo position) would free or PMB protected hydroxy aldehydes 17 and 21ab al- be favored over the endo cycloadduct and (2) the trans though their yields were not optimized. Unfortunately, all at- ring juncture is much more stable in these systems. The tempts to open the oxygen-bridged ring of compounds 17 key feature of the second approach (Route B) is the construc- and 21ab to the corresponding trans fused decalin system us- tion of the bicyclic core by a 6p-electrocyclization7 of the ing bases such as DBU, NaOH or LDAwere unsuccessful. In triene 11 followed by cycloaddition with singlet oxygen.8 We fact, we could observe only epimerization of the proton a to assumed that the stereochemical outcome in the reaction of the aldehyde. Presumably, the oxa-tricyclic starting mate- the diene 10 with singlet oxygen would be controlled by the rials 17 and 21ab are more stable than the hydroxy enal steric interaction between the angular methyl group and the products 18 and 19 under these basic conditions because the incoming oxygen, which would also lead to the trans fused 1,3-diaxial interaction between the angular and C2 methyl decalin system. Herein, we describe the synthesis of the groups is somewhat reduced when C1 and C8 are linked highly oxygenated AB ring system of arisugacin A and our by the oxygen bridge. However, although we were unable approach toward the total synthesis of the natural product. to synthesize the desired compounds 18 or 19 via this route, we used the oxa-bridged compounds 17 and 21a as 2. Results and discussion the coupling material in subsequent reactions. This will be discussed in a later section. 2.1. Synthesis of AB ring system using an IMDAF reaction 2.2. Synthesis of AB ring system via electrocyclization/ singlet oxygen cycloaddition In recent work in our laboratory,5 we demonstrated the construction of oxygen-bridged bicyclic ring systems using The second approach toward the AB ring system began by the IMDAF reaction. IMDAF reactions of the precursors to investigating the key electrocyclization. Thus, we first syn- the AB ring system having alkene dienophiles, e.g., the thesized the two triene precursors having different electron- ester 6a and the nitrile 6b, gave the expected cycloadducts withdrawing groups, i.e., the ester and nitrile (Scheme 3). 5ab in low yields, presumably due to a facile retro Diels– Hydroxy b-ionone 22, easily prepared in two steps from Alder reaction.5 However, the analogous allenic ketone 13 a-ionone,10 was protected as the tert-butyldimethylsilyl 3684 M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701 O R O Me Me R MeAlCl O Me Me 2 O Me O ref 5 Me Me Me Me 6a 5a R = CO2Bn 6% R = CO2Bn 6b R = CN 11% 5b R = CN O CH O HO C 2 Me Me Me Me O Me b,c Me O Me a O O ref 5 Me Me Me Me Me Me 13 14 15 OH HO HO CHO RO CHO Me H Me Me Me 8 Me d e Me O O 2 1 OH Me Me Me Me Me Me 16a 17 ( -H) 18 R = H 16b ( -H) 19 R = PMB PMBO PMBO CHO Me Me Me Me f g,h 15 O O Me Me Me Me 20 21a ( -H) 21b ( -H) Scheme 2. Reagents and conditions: (a) Me2AlCl, CH2Cl2, À20 C, 91%; (b) KO2CN]NCO2K, AcOH, CH2Cl2, À78 Cto23 C; (c) Li/NH3,Et2O, MeOH, À33 C, 64% (+12% starting material); (d) BH3$DMS, H2O2, NaOH, 77% (16a/16b¼2.2:1); (e) Dess–Martin periodinane, CH2Cl2, 72% (from 16a); (f) PMBOC(NH)CCl3, TfOH, Et2O, 89%; (g) BH3$DMS, H2O2, NaOH, 25%; (h) Dess–Martin periodinane, CH2Cl2, 85% (21a/21b¼2.1:1). OH TBSO TBSO R Me Me Me a,b or c d Me O R Me Me Me Me Me Me Me Me 22 23 R = CO Et 25 2 R = CO2Et 24 R = CN 26 R = CN HO CO Et TBSO CN Me 2 Me Me Me 25 e R = CO2Et Me Me Me Me 25a 27 Scheme 3.
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