Arisugacins

Otoguro K, Kuno F, Omura S, Arisugacins, selective acetylcholinesterase inhibitors of microbial origin, Pharmacol Ther 76 45-54, 1997. 

Kuno F, Otoguro K, Shiomi K, et ai, Arisugacins A and B, novel and selective acetylcholinesterase inhibitors from Penicillium sp FO-4259.1. Screening, taxonomy, fermentation, isolation and biological activity, f Antibiot, 49 742-746, 1996. 

Other procedures using TPAP/NMO/PMS/CH Cl include steps in the synthesis of (+)-altholactone (lactol to lactone) [78] antheliolide A [168] the AChE inhibitor (+)-arisugacin A and B (primary alcohol to aldehyde step also) [83] the marine macrolide amphidinolide T1 [169] the alkaloid (+)-batzelladine D cf. mech. 

Arisugacin not only demonstrates impressive potency in inhibiting AChE with an IC50 value of 1 nM, but more importantly, it is highly selective for AChE since >18 flM is required to inhibit butyrylcholinesterase [BuChE], In contrast, tacrine and other inhibitors are less selective for AChE. In the case of tacrine, it is actually more selective for BuChE with an IC50 value of 12 nM, thereby raising concerns about its potential in liver damage.13... 

As a final note in this retrosynthetic analysis, arisugacin A [1] represents a stmcture that is unique but modest in complexity. 

However, because the 67t -electron electrocyclic ring-closure of the respective 1-oxatriene 43 has been found to be reversible,20 37 41 a favorable diastereoselectivity could still be achieved leading to the thermodynamically more stable isomer 10, in which the C6a methyl is (3, in the event that 44 is the initial major product. The pentacycle 10 is more favored than its C6a-epimer 44 [the C6a methyl is a] by about 2.40 kcal mol 1 using PM3 calculations [Spartan ]. In addition, calculations showed that arisugacin A 1 itself is more stable with a 3-C6a-methyl than the isomer 45 [C6a methyl is a] by 4.79 Kcal mol 1 [Figure 5]. 

It is noteworthy that stereochemical control of the two new stereogenic centers at C4a and Cl2b ultimately stems from the stereochemistry at Cl through the intramolecular Diels-Alder reaction. Hence, an optically pure 46 should lead to an enantioselective preparation of a-epoxy lactone 48, thereby ultimately leading to an enantioselective synthesis of arisugacin A [1], LAH reduction of ( )-a-epoxy lactone 48 led to epoxy diol 49 in 78%... 

The synthetic sample matched spectroscopically [co-spectra of H NMR in pyridine- s] and analytically [TLC in 2 1 EtOAc hexane 2 1 ether hexane 1 9 acetone CHCI3] with the natural (+)-arisugacin A. 

To achieve synthesis of (-)-arisugacin A [1], (7 J-89 was obtained readily from 2-methyl-l,3-cyclohexanedione 88 in 4 steps with an overall yield of 46%, featuring vinylogous ester formation, Stork-Danheiser double alpha methylation,52,68,69 vinyl Grignard addition followed by acidic work-up,68 and an asymmetric CBS reduction [Scheme 21].70,71... 

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