Syntheses of 8-carba-physostigmine enantiomers 2a and 2b via optically active intermediates 9a and 9b are described. The key synthetic intermediate 9 was prepared via a [2 + 2] cycloaddition of indene 4 and dichloroketene, followed by Beckmann rearrangement, reduction and resolution. (-)-Physostigmine (1) is a naturally occuring acetylcholinesterase inhibitor which has been evaluated extensively in patients with Alzheimer's disease. The short half-life and high toxicity of physostigmine may account for the inconsistent efficacy shown in clinical studies. In an attempt to decrease the potential for both side effects and metabolic and chemical lability, we sought to replace the central NMe group of the physostigmine nucleus with a methylene to provide the closely related 8-carba-physostigmine analog 2. We report herein the total synthesis of the optically pure 1,2,3,3a,8,8a-hexahydro-1-ethyl-3a-methyl-5-hexylcarbamoyloxy-indeno[2,1-b]pyrrole enantiomers, 2a and 2b. Our synthesis proceeds as illustrated in Scheme I by way of the key synthetic intermediate 9, which can be resolved into its pure enantiomers. A solution of 6-methoxy-1-indanone (3) was added dropwise to a solution of MeMgBr in dry THF at 0°C to give indene 4 in 83% yield after silica column chromatography. [2 + 2] Cycloaddition of indene 4 and dichloroketene, generated from trichloroacetylchloride, POCl3, and activated Zn in refluxing anhydrous ether afforded dichlorocyclobutanone derivative 5, which was subsequently dechlorinated without purification. Dehalogenation of 5 with activated Zn and NH4Cl in MeOH at 40-45°C gave cyclobutanone 6 in 73% overall yield as white crystals, mp 71-72°C, after silica gel column chromatography. Compounds 5 and 6 are thermolabile; e.g., when the reduction of 5 is conducted with Zn in refluxing acetic acid, indene 4 and several unidentified products are observed. Treatment of 6 with NH2OH·HCl and sodium acetate in MeOH afforded a 1:1 mixture of E and Z isomers of oxime 7 as evidenced by 1H NMR. Beckmann rearrangement of the oxime mixture 7 by the use of several different reagents (e.g., SOCl2, H2SO4, TsCl/THF-H2O-NaOH, TsCl/NEt3, MsCl/NEt3, etc.) in each case led to a mixture of lactam regioisomers as well as other unidentified products. The best conditions found for conversion to the desired regioisomer 8 were the use of 1.0 eq each of NaH and tosyl chloride in CH2Cl2 at 0°C, followed by stirring at r.t. for 15 hr. The desired lactam 8 was produced as a white solid, mp 197-198°C, in 60% yield after triturating the crude residue with ether. Reduction of 8 with LiAlH4 gave amine 9 as an oil in quantitative yield. Compound 9 was also generated directly by reaction of oxime 7 with 5 eq. of DIBAL at 0°C; however, column purification was required and compound 9 was isolated in only 30% yield. Resolution of 9 was achieved by several recrystallizations of the corresponding di-p-toluoyl-L-tartaric acid salts. Base treatment of each salt provided enantiomers 9a and 9b as oils with >97% ee. Both enantiomers were converted to the corresponding N-carbamate diastereomers, 10a and 10b, by reaction with (S)-1-(phenyl)ethyl isocyanate, and the optical purity was determined by 1H NMR. The absolute configuration of 9b at C3a and C8a was determined by X-ray crystal structure analysis of the corresponding salt and found to be the same as that of unnatural (+)-physostigmine. Both 9a and 9b were independently converted to the final products 2a and 2b. N-Ethyl derivative 11 was obtained in quantitative overall yield by acetylation (Ac2O/NEt3/CH2Cl2), followed by reduction with 3 eq. BH3·DMS. Demethylation followed by reaction with hexyl isocyanate afforded (-)- and (+)-8-carba-physostigmine analogs 2a and 2b as oils in 90% overall yield. The corresponding di-p-toluoyl-L-tartrate salts were prepared as a form suitable for biological studies. The (-)-isomer 2a (IC50 of 20 ± 7 nM), having the same absolute configuration as that of physostigmine (IC50 of 128 ± 14 nM), is about 12 fold more potent than the (+)-isomer 2b (IC50 of 233 ± 22 nM) in the acetylcholinesterase inhibition assay. In summary, replacement of the central NMe of the physostigmine nucleus by a methylene group affords a more potent, longer half-life and less toxic acetylcholinesterase inhibitor. It is reported that (-)-physostigmine is more potent than (+)-physostigmine, which is similar to our result in which compound 2a, which possesses the same absolute configuration as that of physostigmine, is more potent than 2b.