Synthesis of the physostigmine ring system from cycloprop[b]indoles

Abstract

I C0,Et ( l a -d 1 a; R1 = Me,R2 = H b; R1 = Me,R2 = OMe c ; R 1 = R2 = M e d; R ' = -C5Hll,R2 = H ( 2 a -d 1 ( 3 a -d ) J SCHEME 1 We now describe the transformation of the cyclo-iodide in refluxing acetone gave the N-methyl derivative prop[b]indole (2) into derivatives of the physostigmine (4a) in 13% yield, from which a Rosenmund synthesis ring system. gave deoxyeserine in two steps., In a similar, manner, Heating compound (2a) with 10% potassium hydroxide the cycloprop[b]indoles (2b-d) were converted into the B. Gilbert, '

Ring-opening, cycloaddition and rearrangement reactions of nitrogen-substituted cyclopropane derivatives

“…184 Another example, involving a N,N-bis(trimethylsilyl)aminocyclopropane substrate, is (Table 9), which can be achieved either under acidic 190,191 or under basic conditions. 174,175,192,193 In the latter case (entries 1,5−7), hydrolysis of the carbamate group of the substrates restores the +M donating power of the nitrogen atom and triggers ring-opening. The last two examples also involve hydrolysis of cyanide groups.…”

“…It is worth pointing out that starting from certain substrates, unusual selectivity can be observed with respect to the cyclopropane ring-opening, i.e. with cleavage of the distal cyclopropane bond relative to the nitrogen atom(Schemes 60 and 61) 161,167,174,175,176. Direct heterolytic rupture of this bond is a distinct possibility in these examples, the resulting cationic centre being tertiary and stabilised by mesomeric effect.…”

“…Formation of carbon-nitrogen bondsAn early example of ring-opening followed by internal attack of the resulting iminium ion by a nitrogen atom is illustrated by the synthesis of the aminal 113, the structure of which is related to physostigmine, a reversible cholinesterase inhibitor alkaloid drug (Scheme 76). An access to the skeleton of physostigmine from a bicyclic donor-acceptor cyclopropane 175. An impressive application of this type of reaction is illustrated by the cyclisations of substrates of the general formula 114 (Scheme 77) 197,198.…”

Catalytic [3+2] Annulation of Aminocyclopropanes for the Enantiospecific Synthesis of Cyclopentylamines

“…Donor-acceptor aminocyclopropanes have been mostly used as 1,4-imino carbonyl precursors, [10] as well as in a few rare ring-opening reactions. [11] In 2010, we applied them in an efficient formal homo-Nazarov cyclization for the synthesis of natural alkaloids. [12] However, a formal cycloaddition approach would be inherently more convergent and efficient to access molecular complexity.…”

“…[13] Importantly, phthalimide-substituted cyclopropanes can be obtained in a single step on a multigram scale from commercially available Nvinylphthalimide and diazomalonates by Rh-catalyzed cyclopropanation. [14] On the other hand, removal of one of the ester groups led again to an unreactive cyclopropane (4 e; [7][8][9][10][11][12]. Immediately, the exceptional reactivity of cyclopropane 4 d became apparent, as full conversion could be obtained with a broad range of Lewis acids.…”