Geometry, transition states, and vibrational spectra of boron isostere of N‐methylacetamide by ab initio calculations

Abstract

ABSTRACT:The basic unit of the peptide, the COONH bond, is responsible for imparting specific secondary structural features to peptides. Many modifications, such as isosteric/bioisosteric replacement of this basic unit, have been made to alter the properties of peptides. Isosteric replacement of the nitrogen atom by boron (boron peptides) is another plausible way of changing peptide characteristics. Like Nmethylacetamide (NMA), acetylmethylborane, or BMA, is a good model for studying boron peptides. The potential energy surface (PES) of BMA has been studied by Hartree-Fock (HF), density functional theory (DFT), and post-HF methods. The PES of BMA is an inverted form of the NMA hypersurface. Two minima and two saddle points of index 1 have been identified on this PES and fully optimized at the HF, Becke's three-parameter exchange functional and the gradient-corrected functional of Lee, Yang, and Paar, second-order Møller-Plesset (full), and quadratic configuration interaction method with single and double substitutions followed by a perturbative treatment of triple substitutions (QCISD) levels of theory. The minima correspond to structures with "omega" values close to 90°and 270°, and the transition states have omega values around 0°and 180°. The energy barrier for rotation around the "omega bond" is found to be 4.3 kcal/mol at the QCISD/6-31G* level, which is much lower than the 16 -23 kcal/mol barrier in NMA. The unique shape of the PES of BMA and the low barrier to rotation can be well explained by second-order orbital interaction studies. Normal-mode analysis reveals a significant shift in the BOH stretching frequency of BMA from that in alkyl boranes and borane-phosphine complexes. The replacement of nitrogen by boron bestows on such peptides greater proteolytic stability, more flexibility around the omega angle, and a unique preference for positive angles, all of which are absent in peptides of natural origin.

Stationary Points on the PES of N-Methoxy Peptides and Their Boron Isosteres: An Ab Initio Study

“…We had earlier reported the geometry of BMA (Figure 3) which is the boron isostere of N-methylacetamide, at the QCISD/6-31G* level of theory. 14 The B-O bond length in BMAOH (Figure 3) is 1.356 Å in the GM and 1.369 Å in the LM at the MP2(full)/6-31+G* level of theory. 15 The B-O bond length in BMA-BOM (5B) is found to be 1.362 Å in the GM and 1.358 Å in the LM structures (Table 5) at the MP2(full)/6-31+G* level of theory.…”

“…The changes in the bond lengths from the ground to the TS are relatively small. Some geometric parameters for alkylboranes, arylboranes, and borane complexes have been reported, but there are no experimental data for acylboranes such as BMA 14 (Figure 3) and BMAOH 15 (Figure 3). We had earlier reported the geometry of BMA (Figure 3) which is the boron isostere of N-methylacetamide, at the QCISD/6-31G* level of theory.…”

Quantum Mechanical Methods for Drug Design

“…Malde and coworkers have investigated boron analogs of natural peptides by QM to find the secondary structural preferences and the impact on stability of different substitutions on boron [127][128][129].…”

The −BF–NH– Link as a Peptide-Bond Surrogate

“…Aminoboranes, for instance, present both good hydrocarbon isosterism and interesting pharmacological properties . According to theoretical studies of boron substitution at either Cα, C′, or N peptidic sites, − and in contrast to fluoroalkenes, boron isosteres present more realistic flexibility around the pseudo amide bond, even if they do not attain the right peptide rigidity.…”