Synthesis and Stereochemical Assignment of Crypto‐Optically Active ²H₆‐Neopentane

Abstract

The determination of the absolute configuration of chiral molecules is at the heart of asymmetric synthesis. Here we probe the spectroscopic limits for chiral discrimination with NMR spectroscopy in chiral aligned media and with vibrational circular dichroism spectroscopy of the sixfold-deuterated chiral neopentane. The study of this compound presents formidable challenges since its stereogenicity is only due to small mass differences. For this purpose, we selectively prepared both enantiomers of (2) H6 -1 through a concise synthesis utilizing multifunctional intermediates. While NMR spectroscopy in chiral aligned media could be used to characterize the precursors to (2) H6 -1, the final assignment could only be accomplished with VCD spectroscopy, despite the fleetingly small dichroic properties of 1. Both enantiomers were assigned by matching the VCD spectra with those computed with density functional theory.

Synthesis of Enantiopure C3‐Symmetric Triangular Molecules

“…The VCD spectrum calculated for the (1 R ,2 S )‐isomer matched the VCD spectrum of the D 6 ‐trimer 14 prepared using Rh 2 [( S )‐NTTL] 4 (Figure B), and thus its absolute configuration was assigned as 1 R ,2 S , which is in agreement with the stereochemical assignment deduced from the structure of the trialdehyde 3 (see Scheme b). In other words, the VCD analysis assigns exact stereochemistry to the D‐labeled hydrocarbon 14 , which exhibited no obvious electronic circular dichroism …”

Assigning the absolute configuration of single aliphatic molecules by visual inspection

“…Previously, assignment of enantiomers without chromophores, e.g., chiral alkanes 11 , 12 and many natural products, which display very small optical rotations, was particularly difficult and led to high uncertainties and well-documented misassignments 13 . Although isolation and structure elucidation of natural products has progressed dramatically 14 , their identification by direct observation of single molecules would eliminate some persistent problems connected with natural product isolation and/or total synthesis, e.g., limited compound availability and a necessity for further functionalization requiring additional synthetic steps.…”

Determination of the Absolute Configurations of Chiral Alkanes – An Analysis of the Available Tools

“…In 2015, we presented the AC assignment of hexadeuterated neopentane 2 H 6 ‐ 6 employing VCD spectroscopy. [ 80 ] An alternative enantioselective synthesis of ( S )‐ 2 H 6 ‐ 6 was carried out in the Marek group using alkylidenecyclopropane ( S )‐ 33 [ 81 ] as the starting point (Figure 9A). When reacted with the Negishi zirconocene reagent, [ 82 ] ( S )‐ 33 underwent allylic C–H bond activation followed by selective C–C bond cleavage.…”