Untitled

Abstract

Our recently reported titanium‐mediated transformation of N,N‐dialkylcarboxamides to cyclopropylamines has been applied to N,N‐dibenzyl‐2‐benzyloxyacetamide using a variety of alkylmagnesium bromides to yield 1‐(benzyloxymethyl)‐1‐(dibenzylamino)cyclopropane (15a, 48%) and 2‐substituted analogs 15b−f (33−48%). These have been transformed in just a few steps into N‐Boc‐protected methyl esters of 1‐aminocyclopropanecarboxylic acid (1, 29% overall), coronamic acid (2, 35%) and norcoronamic acid (21%), 2,3‐methanoglutamic acid (21g, 19%) and 2,3‐methanoornithine (21l, 12%). Similarly, the corresponding derivatives of 3,4‐methano‐γ‐aminobutyric acid (26, 23%) and 4‐spirocyclopropane‐γ‐butyrolactam (32, 44%) have been synthesized.

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

“…The table also indicates, as expected, that nitrocyclopropane derivatives substituted with a second withdrawing group at the same carbon atom are particularly activated compounds (entries 11−12). 25 1-(tert-Butoxycarbonylamino) cyclopropanecarboxylic acid (MeOD) 1.29 8 22 1-(tert-Butoxycarbonylamino) cyclopropanecarboxylic acid (CDCl 3 ) 1.41 9 26 Dimethyl cyclopropane-1,1-dicarboxylate (CD 2 Cl 2 ) 1.45 10 27 Cyclopropane-1,1-dicarboxylic acid (not specified) 1.88 11 28 [2,6-Bis(l,l-dimethylethyl)-4-methoxyphenyl]-l-nitro-lcyclopropancarboxylate (CDCl 3 )…”

Titanium-mediated syntheses of cyclopropylamines

“…As reported by the same group, this efficient transformation can also be carried out with substoichiometric amounts of Ti(OiPr) 4 (5-10 mol%) [57,58]. Four years later, development of a very useful and highly versatile preparation of cyclopropylamines was initiated by de Meijere et al [59][60][61][62][63][64][65][66][67][68]. N ,N -Dialkylaminocyclopropanes (11) with up to three additional substituents are readily obtained from carboxylic acid N ,N -dialkylamides (8) and ethyl-as well as substituted ethylmagnesium halides in the presence of titanium tetraisopropoxide or, even better, methyltitanium triisopropoxide.…”

“…Applying only a few simple operations, the dibenzylaminocyclopropanes 90-R, prepared as described above from N ,N -dibenzyl-a-benzyloxyacetamide in 33-48% yield (see Scheme 5 and Table 2), have been transformed into N -Boc-protected methyl esters of some interesting amino acids 95-R containing a cyclopropane moiety (Scheme 20) [66,67]. Several such analogues of natural amino acids, also referred to as methanoamino acids, exhibit important biological activities [102c,102d].…”

“…Two potentially biologically active analogues of the important c-aminobutyric acid, the N -Boc-protected methyl 3,4-methano-c-aminobutyrate 110 and the 4-spirocyclopropane-c-butyrolactam 114, have been obtained in 55% and 44% overall yield, respectively (Scheme 23) [66,67]. The access to 114, however, has recently been further improved by a one-step preparation with 68% yield (see Table 6, entry 16) [95].…”

A Concise Stereoselective Synthesis of 2‐Substituted 1‐Aminocyclopropanecarboxylic Acids

“…The typical synthetic approaches include (i) dialkylation of glycine or malonate derivatives, (ii) 1,3‐dipolar cycloaddition involving diazomethane and β‐substituted acrylic acid derivatives, and (iii) intramolecular cyclization of γ‐substituted α‐amino butyric acid derivatives. More recently, thede Meijere variant of the Kulinkovich cyclopropanation reaction made it possible to prepare some α‐ACCs of biological interest 5,4d. A number of rather specific approaches to optically active ACCs involved asymmetric additions of ylides,6 rhodium‐catalyzed cyclopropanations,7 and the use of amino acid equivalents8 or cyclopropyl lactone chirons as building blocks 9.…”