Selective Cleavage of N-Benzyl-Protected Secondary Amines by Triphosgene

Abstract

A series of competition experiments has revealed that selective cleavage of N-benzyl-protected secondary amines can be achieved with triphosgene, thereby providing a useful range of carbamoyl chlorides.

3,4′-Linked bis(piperidines) related to the haliclonacyclamine class of marine alkaloids: synthesis using crossed-aldol chemistry and preliminary biological evaluations

“…The benzyl group was chosen to protect the secondary amine residue of 4-piperidinone because of its ease of removal with triphosgene. 10 Our first experiments (Scheme 1) rapidly established that the previously unreported but readily prepared N,Ndimethylhydrazone (DMH) derivative, 7 (100%), of ketone 6 was smoothly C-ethylated upon sequential treatment with BuLi then ethyl iodide. 11 After workup the required ketone 2 was obtained in 81% yield and thereby representing a useful improvement upon a previously reported 12 route to this compound.…”

“…Concentration of fraction A (R f 0.25 in 3 : 2 v/v ethyl acetate/hexane) afforded compound 4 (5.30 g, 64%) as a clear, yellow oil. 1 H NMR (500 MHz) d 7.35-7.24 (10H, complex m), 5.56 (1H, broad s), 3.60 (2H, AB q ), 3.58 (2H, AB q ), 3.12 (1H, broad dd, J = 9.3 and 5.2 Hz), 3.01 (2H, dd, J = 5.2 and 2.2 Hz), 2.98 (1H, m), 2.94 (1H, m), 2.78 (1H, m), 2.62 (1H, dd, J = 11.3 and 9.2 Hz), 2.58-2.42 (4H, complex m), 2.08 (2H, m); 13 C NMR (125 MHz) d 208.6 (C), 138.1 (C), 138.0 (C), 132.6 (CH), 129.2 (CH), 128.9, (CH), 128.3 (CH), 128.2 (CH), 127.3 (CH), 127.0 (CH), 123.1 (C), 62.8 (CH 2 ), 62.2 (CH 2 ), 57.1 (CH 2 ), 56.7 (CH), 53.6 (CH 2 ), 52.9 (CH 2 ), 49.6 (CH 2 ), 40.9 (CH 2 ), 28.5 (CH 2 ); IR (NaCl, film) n max 3026, 2908, 2800, 2759, 1715, 1493, 1453, 1364, 1349, 1186, 1123, 1027 cm -1 ; MS (EI) m/z 360 (M + ∑ , 19%), 325 (5), 269 (13), 241 (40), 199 (36), 185 (10), 172 (15), 134 (11), 91 (100); HRMS calcd for C 24 H 28 N 2 O (M + ∑ ) 360.2202. Found 360.2201.…”

A Chemoenzymatic Total Synthesis of the Structure Assigned to the Alkaloid (+)-Montabuphine

“…As a prelude to carrying out the Pictet−Spengler reaction, the lactam carbonyl within compound 18 was removed using aluminum hydride generated in situ from AlCl 3 and LiAlH 4 . The PMB residue associated with the resulting pyrrolidine 19 (89%) was cleaved using triphosgene and the carbamoyl chloride 20 so-formed was subjected to acid-catalyzed hydrolysis and thus providing the amino-alcohol 21 in 88% yield from precursor 19 . Treatment of compound 21 with a mixture of paraformaldehyde and formic acid at 80 °C for 16 h effected the desired Pictet−Spengler reaction but this was accompanied by formylation of the free hydroxyl group within the substrate and such that the formate ester 22 was obtained in 97% yield.…”

Chemoenzymatic Approaches to the Montanine Alkaloids: A Total Synthesis of (+)-Brunsvigine

“…Because the looming Pictet-Spengler reaction requires the presence of acid-stable hydroxyl protecting groups, the MOM-ether residues within compound 21 were removed using aqueous HCl in methanol and the ensuing diol 22 (73%) subjected to reaction with triphosgene. 20 Use of this reagent not only resulted in the conversion of the cis-diol residue within substrate 22 into the acid-stable cyclic carbonate but also effected cleavage of the PMB-protected amine to form the corresponding carbamoyl chloride 23 which was immediately treated with aqueous dioxane in the presence of traces of HCl to give the cyclic secondary amine 24 (42% from 22). Treatment of the last compound with paraformaldehyde in aqueous formic acid at 80°C effected the pivotal Pictet-Spengler reaction to generate compound 25 (65%) embodying the full pentacyclic framework of target (+)-brunsvigine.…”