Convenient Preparation of α-Amino Acids with Bicyclopropylidene and Other Methylenecyclopropane Moieties

Abstract

Racemic bicyclopropylidenyl‐ (rac‐11) and methylenespiropentyl‐ (rac‐17) substituted alanines have been synthesized by iodination of bicyclopropylidenyl‐ and methylenespiropentylmethanols 7, 13, nucleophilic substitution of the iodine in 8, 14 with the enolate of ethyl α‐(diphenylmethyleneamino)acetate (O'Donnell's glycine equivalent) and deprotection of 9, 15 in 24 and 18% overall yield, respectively. N‐Methylbicyclopropylidenylalanine rac‐22, was obtained from the Michael adduct of (bicyclopropylidenyl)magnesium bromide 18 to enamine 19 and deprotection of the carbamate 20 (23% overall yield). Racemic (1‐amino‐2‐methylenespiropentane)‐ (37), (1‐amino‐2‐methylenecyclopropane)‐ (3), and (1‐aminobicyclopropylidene)carboxylic acid (39) were prepared as hydrochlorides by tert‐butoxycarbonylation of the lithiated methylenespiropentane (6), methylenecyclopropane (4), or bicyclopropylidene (5) intermediates with di‐tert‐butyl pyrocarbonate (Boc2O), repeated lithiation of the tert‐butyl esters 29, 30, and 33 with LDA and subsequent carboxylation, Curtius degradation of the half esters 31, 32, and 34 followed by deprotection in 11, 45, and 4% overall yields, respectively. Compound 37 was also prepared from bicyclopropylidene (5) following the same procedure, but with rearrangement in the last but one step, in 19% overall yield. An attempted Hofmann degradation of the bicyclopropylidenecarboxamido ester 40 with NBS failed and gave only bromohydrin 44 (27%), but with bis(acetoxy)iodobenzene provided carbamate 46a, b in 76 amd 79% yield, respectively. Along this route with subsequent deprotection of 46b, the amino acid 39 could be prepared in up to 10% overall yield from bicyclopropylidene.

Scalable synthesis of (1-cyclopropyl)cyclopropylamine hydrochloride

“…Curtius degradation of the acid 2 via the corresponding azide, according to the Weinstock protocol [19–20] as previously employed in different examples [2,25], furnished the N -Boc-protected (1-cyclopropyl)cyclopropylamine 3 in 76% yield. It was essential to carefully dry the solution of the intermediate azide, otherwise the yield of 3 dropped dramatically, and the desired product was accompanied by 1,3-di(bicyclopropyl)urea ( 5 ) in up to 50% yield (Scheme 1).…”

Productive Syntheses of 1-Ethynylcyclopropylamine and 1-Ethynylcyclobutylamine¹

“…Curtius degradation of the acid 8 according to the Weinstock protocol 19 as previously employed in a different example, 20 furnished the N-Boc-protected 1-(trimethylsilylethynyl)cyclopropylamine 9 (95% yield), which was fully deprotected by treatment with potassium fluoride in dimethylformamide-water and subsequently with hydrogen chloride in diethyl ether. The amine hydrochloride 3•HCl was thus obtained from cyclopropylacetylene (6) in 39% overall yield (Scheme 2).…”

“…Deprotonation of 16 at the propargylic position had to be carried out with n-butyllithium at ambient temperature without cooling, in fact the temperature rose to 31°C for six hours, and subsequent treatment with powdered dry ice gave the crude carboxylic acid 17 in 63% yield. Curtius degradation of 17 again employing the Weinstock protocol 19,20 furnished the N-Boc-protected 1-(trimethylsilylethynyl)cyclobutylamine 18 in 38% overall yield from the silylated acetylene 16.…”

“…The carbamates 9 and 18 were prepared and deprotected in two consecutive steps applying a modified protocol of our previously published procedure. 20 To a stirred solution of the crude acid 8 or 17 in anhyd acetone was added Et 3 N dropwise at -5°C. After additional stirring at this temperature for 15 min, a solution of ethyl chloroformate in acetone was added at the same temperature over a period of 1 h, and the resulting mixture was stirred at this temperature for an additional 1.5 h. Then a solution of NaN 3 in H 2 O was added over a period of 1 h, and the reaction mixture was stirred at 0°C for 1.5 h, then poured into ice-cold water and extracted with Et 2 O and pentane.…”

Spiro[2.2]pentane as a Dissymmetric Scaffold for Conformationally Constrained Analogues of Glutamic Acid: Focus on Racemic 1-Aminospiro[2.2]pentyl-1,4-dicarboxylic Acids

“…Our initial approach to the synthesis of 1-amino-spiro[2,2]pentyl-1,4-dicarboxylic acids ( 22a − d ) began with the preparation of the key intermediate tert -butyl (methylenecyclopropyl)carboxylate (±)- 14 from commercially available 2-bromopropene ( 15 ) and tert -butyl diazoacetate 23 by a dirhodium(II) tetraacetate catalyzed cyclopropanation as depicted in Scheme .

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