DMAP-assisted sulfonylation as an efficient step for the methylation of primary amine motifs on solid support

Abstract

Several multistep strategies were developed to ensure single methylation of amines on solid support. These strategies rely on the introduction of the o-NBS protecting/activating group as a key step. We found that the state-of-the-art strategies fail for the methylation of several primary amine motifs, largely due to inefficient sulfonylation. Here we show that using the superior nucleophilic base DMAP instead of the commonly used base collidine as a sulfonylation additive is essential for the introduction of the o-NBS group to these amine motifs. DFT calculations provide an explanation by showing that the energy barrier of the DMAP intermediate is significantly lower than the one of the collidine. We demonstrate that using DMAP as a sole additive in the sulfonylation step results in an overall effective and regioselective N-methylation. The method presented herein proved highly efficient in solid-phase synthesis of a somatostatin analogue bearing three N α-methylation sites that could not be synthesized using the previously described state-of-the-art methods.

Diffusion-Enhanced Amide Bond Formation on a Solid Support

“…To confirm the observation that the low-MER reaction in HSS can be a viable alternative to using high MER in a shaker, we synthesized the hexapeptide, Trp-Trp-Lys-Thr-Phe-Gly-NH2 (SOM), derived from somatostatin using both mixing methods. 45,46 Coupling reactions were performed with 1.5 MER in HSS (SOM-3), with 1.5 MER in a shaker (SOM-1), or with 3 MER in a shaker (SOM-2) for 1 h each. The crude from each reaction after cleavage was analyzed using HPLC-MS (Figure 4).…”

Diffusion Enhanced Amide Bond Formation on Solid Support

“…The accumulative effect of mixing in HSS compared to a shaker was evaluated by synthesizing the hexapeptide Trp-Trp-Lys-Thr-Phe-Gly-NH2 (SOM), which is a sequence derived from the somatostatin hormone and also contains few difficult coupling steps. 25,26 The multiple coupling steps synthesis of SOM was performed via three different routes. In the first two routes, all coupling steps were performed in a shaker using either 1.5 or 3 MER (SOM-1 and SOM-2 respectively).…”

Bifunctional Brønsted Base Catalyzed Mannich Reaction of β‐Alkoxy α‐Keto Amides: Stereocontrolled Entry to Functionalized Amino Diols

“…Diisopropyl a-keto amide 1c reacted with both aromatic and aliphatic p-nosyl N-protected imines to produce the corresponding Mannich adducts 12 and 13 with high diastereoselectivity, albeit with moderate enantioselectivity for the aliphatic adduct 13.I nterestingly,t he methodology resulted also compatible [b] d.r. [c] ee with morpholine derived a-keto amide 1d to produce the enantioenriched adducts 14-16.L ikewise, modificationi nt he nature of the alkoxym oiety did not substantially affect either reactivity or selectivity (adducts [17][18][19], confirming the high versatility of the method. As noted above, the stereochemical outcome of the stereoselectiver eduction of the Mannicha dducts,promoted by K-Selectride,c ould be inverted (Scheme 2) to efficiently produce, under treatment with Et 3 B/NaBH 4 ,a12:88 mixture of anti,syn:syn,syn diastereoisomers from which the major syn,syn adduct 20 was isolated in 58 %y ield.…”

“…[18] An interesting feature of nosyl protected amines is that they can be easily transformedi ns econdary aminest hrough alkylation followed by deprotection. [19] Methylation of adduct 11 a, and subsequent p-nosyl cleavage, produced the corresponding secondary amine 22 in 50 %o verall yield. This approach highlights the structuralv ersatility of the catalytic Mannich reaction displayed, because the nosylg roup allows access to either primary or secondary amines.…”