Determination of the absolute configuration of (+)-neopentyl-1-d alcohol by neutron and x-ray diffraction analysis.

Abstract

The absolute configuration of (+)-neopentyl-1-d alcohol, prepared by the reduction of 2,2-dimethylpropanal-l-d by actively fermenting yeast, has been determined to be S by neutron diffraction. The neutron study was carried out on the phthalate half ester of neopentyl-l-d alcohol, crystallized as its strychnine salt. The absolute configuration ofthe (-)-strychninium cation was first determined by an x-ray anomalous dispersion study of its iodide salt. The chiral skeleton of strychnine then served as a reference from which the absolute configuration of the -O-CHD-C(CH3)3 group of neopentyl phthalate was determined. Difference Fourier maps calculated from the neutron data showed unambiguously that the -0-CHD-C(CH3)3 groups of both independent molecules in the unit cell had the S configuration. This work proves conclusively that the yeast system reduces aldehydes by delivering hydrogen to the re face of the carbonyl group. The enzymatic reduction of an aldehyde to an alcohol is an important example of a stereospecific biological process that has been studied extensively (1). It is a prototype reaction for many biochemically significant transformations involving the coenzyme NADH. In addition, optically active deuterated alcohols of the type R-CHD-OH have been of great importance in the elucidation of the stereochemistry of displacement reactions at primary carbons (1).The stereospecificity of enzymatic acetaldehyde reduction and ethanol oxidation was established (2-4) when it was discovered that reduction of acetaldehyde-1-d with NADH and yeast alcohol dehydrogenase (ADH) gave ethanol-1-d, which, upon enzymatic reoxidation, returned only acetaldehyde-1-d without loss of deuterium (Scheme I): chemistries were identical. Although neopentyl-1-d and benzyl-1-d alcohols have not been produced by reductions using purified NADH and yeast ADH, it is firmly believed that the NADH/yeast ADH system is responsible for those reductions in the actively fermenting yeast system. The structure ofhorse liver ADH, which is closely related to yeast ADH, has been determined to 2.4-A resolution by x-ray diffraction techniques (9)(10)(11)(12)(13)(14). A model of the active site has been proposed in which the oxygen atom of the substrate binds directly to the zinc atom, which fixes the orientation of the substrate with respect to the coenzyme and controls the stereospecificity of the reaction (14). In this mechanism, direct hydrogen transfer from NADH to substrate is believed to take place.For the most part, the absolute configurations of deuterated alcohols (R-CHD-OH) have been determined by comparison ofNMR and polarimetry data with related molecules ofknown stereochemistry (15, 16). For example, the absolute configuration of ethanol-1-d has been deduced by correlation with a pyranose sugar whose configuration at the CHD center was established by NMR (17) and by correlation with 2-butanol-2-d (18) and pentane-2-d (19) of known configuration. In addition, the absolute configuration of glycolic-d acid, determined by neutron diffrac...

Hydrophilic and hydrophobic pockets at surfaces of strychninium self-assemblies in pseudopolymorphous crystals of strychninium salts

“…A similar set of hydrogen bonds is observed in the majority of known crystals of strychninium salts. 5,13,16,17,[19][20][21][22][23][24][25][26][27][28] It is noteworthy that near the strong ionic N-H + … O 2 hydrogen bonds, only weak C19-H19 … p (q) hydrogen bonds are observed in the majority of crystals of strychninium salts (see Fig. 6).…”

“…6). Among thirty one known crystal structures of strychninium salts (including the four reported here) for which atomic coordinates are available, 5,13,16,17,[19][20][21][22][23][24][25][26][27][28][29][30] there are twenty six crystal structures for which strychninium cations form pillars stabilized by C19-H19 … p (q) hydrogen bonds. The C19-H19 … p (q) hydrogen bond seems to be one of the most favored connections of strychninium cations.…”

Chirality determination in crystals

“…The specificity of neutron diffraction is that it allows the study of magnetic chirality, which is a very important area in material science, but will not be developed here 8,9 . Single crystal neutron diffraction can also be used to determine the absolute configuration of chemical compounds, using a co‐crystallized chiral reference, 10,11 or through resonant scattering of targeted isotopes embedded in the molecule of interest 12,13 . However, these methods have not been widely used, as they require large crystals, not easily accessible neutron sources and suffer from a limitation of the number of usable isotopes and very high absorption of most of them.…”

Naphthyl Groups in Chiral Recognition: Structures of Salts and Esters of 2‐Methoxy‐2‐naphthylpropanoic Acids

“…Yeast alcohol dehydrogenase converts (S)-(1-2 H 1 )ethanol into (1-2 H)acetoaldehyde in the presence of nicotinamide adenine dinucleotide (NAD + ), a coenzyme. [35] However, to the best of our knowledge, the stereoselectivity of AaSDR-1 and its orthologues have not yet been identified.…”