1.1,3,5-Tri- and 1,3,4,5-tetra-substituted 1,4-diazepin-2-one solid-phase synthesis.
Iden HS1, Lubell WD. J Comb Chem. 2008 Sep-Oct;10(5):691-9. doi: 10.1021/cc8001052. Epub 2008 Aug 8.
Solid-phase syntheses of 1,3,5-tri-substituted and 1,3,4,5-tetra-substituted 1,4-diazepin-2-ones 15-18 have been accomplished by employing inexpensive commercially available alpha- and beta-amino acids on Wang resin. Reductive amination of the imine formed by condensation of Wang aldehyde resin respectively with beta-alaninate 2 and beta-homophenylalaninate 3, followed by aminoacylation with a set of alpha-N-Boc amino acids (Phe epsilon-( Z)-Lys, and Leu) gave tertiary amide resins 7 and 8. Exposure of resins 7 and 8 to an excess of vinyl magnesium bromide in the presence of copper cyanide gave the corresponding gamma,delta-unsaturated ketone resins 9 and 10 by way of a cascade addition. Diazepinones were made by Boc deprotection and intramolecular reductive amination. To diversify the heterocycle, N-alkylation was performed using a series of alkyl halides. Alternatively, diazepinones 15e-g were obtained from treatment of methyl beta-alaninate resins 4 and 20 under similar copper-catalyzed cascade conditions to afford the gamma,delta-unsaturated ketone 21, which was acylated using alpha-N-Fmoc-amino acids (Phe, Trp, gamma-(t-Bu)-Glu).
2.New building block for polyhydroxylated piperidine: total synthesis of 1,6-dideoxynojirimycin.
Rengasamy R1, Curtis-Long MJ, Seo WD, Jeong SH, Jeong IY, Park KH. J Org Chem. 2008 Apr 4;73(7):2898-901. doi: 10.1021/jo702480y. Epub 2008 Mar 12.
(3R,4S)-3-Hydroxy-4-N-allyl-N-Boc-amino-1-pentene 10, an important precursor for the synthesis of polyhydroxylated piperidines, has been achieved as a single diastereomer without racemization via vinyl Grignard addition to N-Boc-N-allyl aminoaldehyde 9, which was derived from an enantiopure natural amino acid. Having forged a tetrahydropyridine ring scaffold 13 from 10 in 85% yield via RCM using Grubbs II catalyst, we were able to effect its stereodivergent dihydroxylation, via a common epoxide intermediate to yield a range of interesting hydroxylated piperidines, including ent-1,6-dideoxynojirimycin (ent-1,6-dDNJ) 1 (28% overall yield) and 5-amino-1,5,6-trideoxyaltrose 2 (29% over all yield) in excellent dr. To the best of our knowledge, our synthesis of ent-1,6-dDNJ 1 is the most expeditious to date.
3.Diastereo- and enantioseparation of a N(α)-Boc amino acid with a zwitterionic quinine-based stationary phase: focus on the stereorecognition mechanism.
Ianni F1, Carotti A1, Marinozzi M1, Marcelli G1, Di Michele A2, Sardella R3, Lindner W4, Natalini B1. Anal Chim Acta. 2015 Jul 23;885:174-82. doi: 10.1016/j.aca.2015.06.001. Epub 2015 Jun 9.
A chiral chromatography method enabling the simultaneous diastereo- and enantioseparation of N(α)-Boc-N(4)-(hydroorotyl)-4-aminophenylalanine [Boc-Aph(Hor)-OH, 1] was optimized with a quinine-based zwitterionic stationary phase. The polar-ionic eluent system consisting of ACN:MeOH:water-49.7:49.7:0.6 (v/v/v) with formic acid (4.0mM) and diethylamine (2.5mM), allowed the successful separation of the four acid stereoisomers: αd,d-/d,l-1=1.08; αd,l-/l,d-1=1.08; αl,d-/l,l-1=1.40. According to the in-house developed synthetic procedure and the recorded electronic circular dichroism spectra, the following stereoisomeric elution order was readily established in the optimal chromatographic conditions: d,d-1<d,l-1<l,d-1<l,l-1. With the aim of better understanding the molecular basis of the retention behaviour of the four stereoisomers in the employed chromatographic system and conditions, a computational protocol consisting in molecular dynamics simulations was applied.
4.Synthesis of new unnatural N(α)-Fmoc pyrimidin-4-one amino acids: use of the p-benzyloxybenzyloxy group as a pyrimidinone masking group.
ElMarrouni A1, Heras M. Org Biomol Chem. 2015 Jan 21;13(3):851-8. doi: 10.1039/c4ob02235a.
The p-benzyloxybenzyloxy group is used to mask the oxo function of the 4(3H)-pyrimidinone ring in the synthesis of new unnatural amino acids. The synthetic approach is based on an aromatic nucleophilic substitution reaction between 4-[4-(benzyloxy)benzyloxy]-2-(benzylsulfonyl)pyrimidine and the nucleophilic side chain of several N(α)-Boc amino esters, as the key step, followed by a series of standard protecting group transformations. p-Benzyloxybenzyloxy is efficiently removed under mild acid conditions to recover the 4(3H)-pyrimidinone system.
