The prediction of the absolute stereochemistry of primary and secondary 1,2-diols by 1H NMR spectroscopy: principles and applications

The absolute configuration of 1,2-diols formed by a primary and a secondary (chiral) hydroxyl group can be deduced by comparison of the 1H NMR spectra of the corresponding (R)- and bis-(S)-MPA esters (MPA = methoxyphenylacetic acid). This method involves the use of the chemical shifts of substituents L1/L2 attached to the secondary (chiral) carbon, and of the hydrogen atom linked to the chiral center (C alpha-H) as diagnostic signals. Theoretical (AM1, HF, and B3 LYP calculations) and experimental data (dynamic and low-temperature NMR spectroscopy, studies on deuterated derivatives, constant coupling analysis, circular dichroism (CD) spectra, and NMR studies with a number of diols of known absolute configuration) prove that the signs of the delta delta(RS) obtained for those signals correlate with the absolute configuration of the diol. A graphical model for the reliable assignment of the absolute configuration of a 1,2-diol by comparison of the NMR spectra of its bis-(R)- and bis-(S)-MPA esters is presented.     

Relative and absolute stereochemistry of secondary/secondary diols: low-temperature 1H NMR of their bis-MPA esters

Comparison of the room- and low-temperature 1H NMR spectra of the bis-(R)- or bis-(S)-MPA ester derivative of an open chain sec,sec-1,2-diol allows the easy determination of its relative stereochemistry and in some cases absolute configuration. If the diol is anti, its absolute configuration can be directly deduced from the signs of DeltadeltaT1T2 for substituents R1/R2, but if the relative stereochemistry of the diol is syn, the assignment of its absolute configuration requires the preparation of two derivatives (both the bis-(R)- and bis-(S)-MPA esters), comparison of their room-temperature 1H NMR spectra, and calculation of the DeltadeltaRS signs for the methines Halpha(R1) and Halpha(R2) and R1/R2 protons. The reliability of these correlations is validated with 17 diols of known absolute configuration used as model compounds.     

Assignment of the absolute configuration of alpha-chiral carboxylic acids by 1H NMR spectroscopy

The prediction of the absolute configuration of alpha-chiral carboxylic acids from the 1H NMR spectra of their esters with (R)- and (S)-ethyl 2-hydroxy-2-(9-anthryl) acetate [(R)- and (S)-9-AHA, 5] is discussed. Low-temperature NMR experiments, MM, semiempirical, and aromatic shielding effect calculations allowed the identification of the main conformers and showed that, in all esters studied, conformer ap is the most stable. A simple model for the assignment of the absolute configuration from NMR data is presented, and its reliability is corroborated with acids 6-31 of known absolute configuration. In addition to 5, other auxiliary reagents with open (32-38) and cyclic (39-42) structures have also been studied. trans-(+)- and (-)-2-phenyl-1-cyclohexanol (41) was found to be particularly efficient and produced delta delta RS values similar to those of 5.     

Absolute configuration of secondary alcohols by 1H NMR: in situ complexation of alpha-methoxyphenylacetic acid esters with barium(II)

A novel methodology that allows the assignment of the absolute configuration of chiral secondary alcohols by NMR using only one derivative is presented. All that is needed is (a) the derivatization of the alcohol of unknown configuration with one enantiomer--either the (R)- or the (S)--of alpha-methoxyphenylacetic acid (MPA), (b) the recording of the 1H NMR spectrum of the resulting ester in MeCN-d3, and (c) addition of a barium(II) salt [i.e. Ba(ClO4)2] to the NMR tube till saturation and recording of a second spectrum. The assignment of the R/S configuration to the alcohol takes a few minutes and consists on the comparison of the signs of the shifts (Deltadelta(Ba)) produced by addition of the barium(II) with those predicted for the (R) and the (S) enantiomers in accordance to a simplified model that reflects the conformational changes produced by the complexation with barium and their consequences in the chemical shifts. These conformational changes are based on experimental NMR and CD results showing that the formation of a barium(II) complex with the MPA ester moves the conformational equilibrium between syn- (sp) and anti-periplanar (ap) forms toward the most stable ones (sp), and that this leads to the increase of the shielding caused by the MPA phenyl group on a certain substituent of the alcohol. In addition, ab initio Hartree-Fock (HF) and density functional theory (DFT) calculations provide further evidence on the formation, structure, and stability of the complexes with Ba2+, Mg2+, and the influence of the solvent. The general applicability of this methodology and the reliability of the configurational assignment were assured by the study of about twenty alcohols of known configuration and diverse structural features. Its scope and limitations have also being established and other representative cations (i.e. Li+, Rb+, Cs+, Mg2+, Ca2+, Sc3+, V3+, Zn2+) were also evaluated. The procedure proposed is simple, fast, and cheap because it requires a very small amount of sample, only one derivatization, and the recording of only two 1H NMR spectra at rt. A graphical guide to facilitate the application of this new method is included at the end of the paper.     

Determination of molecular stereochemistry using vibrational circular dichroism spectroscopy: absolute configuration and solution conformation of 5-formyl-cis,cis-1,3,5-trimethyl-3-hydroxymethylcyclohexane-1-carboxylic acid lactone

The determination of the absolute configuration of chiral molecules is an important aspect of molecular stereochemistry. Vibrational circular dichroism (VCD) is the extension of electronic CD into the infrared region where fundamental vibrational transitions occur. VCD has a number of advantages over all previous methods of absolute configuration assignment. The absolute configuration and predominant solution-state conformation in CDCl(3) of the chiral lactone, 5-formyl-cis,cis-1,3,5-trimethyl-3-hydroxymethylcyclohexane-1-carboxylic acid lactone, 1, obtained by the comparison of measured and calculated VCD spectra, are reported. It is found that (-)-1 corresponds to the absolute configuration (1S,3S,5R)-1.     

Determination of Absolute Configuration of Acyclic 1,2‐Diols with [Mo2(OAc)4], Part 2: New Structural Evidence toward a Rationale of the Method: What Remains of [Mo2(OAc)4] in DMSO Solution?

The nature of the CD-active species obtained by mixing dimolybdenum tetraacetate and a chiral 1,2-diol in DMSO has been studied by different techniques (1D and 2D (1)H NMR, CD, UV/Vis) with two substrates, (R)-phenyl-1,2-ethanediol (1) and (R,R)-butane-2,3-diol (2). The diol/dimolybdenum adducts have diagnostic CD spectra whose sign correlates with the absolute configuration of the organic substrate. It is demonstrated that, in DMSO solution, the acetate ligands of [Mo(2)(OAc)(4)] dissociate to a large extent under the action of the dissolved water, yielding acetic acid and a polyhydrated dimolybdenum species. Addition of a 1,2-diol leads to chelation with formation of one main active species for 2 and two for 1, all with 1:1 stoichiometries at diol/dimolybdenum molar ratios less than 1.5. Only a small fraction (less than 20 %) of the 1,2-diol is bound. The structures of the active complexes are estimated on the basis of NMR spectra, by correlating the observed chemical shifts with the quadruple bond diamagnetic anisotropy. In the predominating complexes for 1 and 2, the 1,2-diol moiety bridges the Mo(2) core forming a six-membered ring.     

A New Stereoselective Synthesis of Phosphiranes

The synthesis of phosphiranes from primary phosphines and diol ditosylates was found to be stereoselective, and chiral phosphiranes were prepared from optically pure diols. The four optical isomers of 1-mesityl-2,3-dimethylphosphirane, (2S,3S)-(+)-3, (2R,3R)-(-)-4, anti-cis-(meso)-5, and syn-cis-(meso)-6, were all synthesized from mesitylphosphine and the corresponding diol ditosylates. Compound 6 was unstable, but compounds 3, 4, and 5 were all isolated in pure form. Their structure assignments were based on the NMR coupling constants J(P-H) and J(P-C). The phosphiranes were transformed into tungsten pentacarbonyl complexes. Tungsten tetracarbonyl-triphenylphosphine complexes (22, 23, 24) of compounds 3, 4, and 5 were synthesized in high yields by the reaction of the phosphiranes and W(CO)(4)(PPh(3))(THF). The absolute stereochemistry of the phosphiranes 3, 4, and 5 was determined by X-ray crystal structure analysis of compounds 22, 23, and 24. Stereochemical effects on NMR coupling constants and mass spectra of the phosphiranes are discussed.     

The 1H NMR method for the determination of the absolute configuration of 1,2,3-prim,sec,sec-triols

The absolute configuration of 1,2,3-prim,sec,sec-triols can be assigned by comparison of the 1H NMR spectra of the tris-(R)- and the tris-(S)-MPA ester derivatives. An experimental demonstration of this correlation with 24 triols of known absolute configuration and a protocol using two parameters-Deltadelta(RS)(H3) and the difference between Deltadelta RS (H2) and Deltadelta RS (H3) = absolute value (Delta(Deltadelta RS))-for its application to the determination of the absolute configuration of other triols are presented.     

Selective photochemistry at stereogenic metal and ligand centers of cis-[Ru(diphosphine)2(H)2]: preparative, NMR, solid state, and laser flash studies

Three ruthenium complexes Λ-[cis-Ru((R,R)-Me-BPE)(2)(H)(2)] Λ-R,R-Ru1H(2), Δ-[cis-Ru((S,S)-Me-DuPHOS)(2)(H)(2)] Δ-S,S-Ru2H(2), and Λ-[cis-Ru((R,R)-Me-DuPHOS)(2)(H)(2)] Λ-R,R-Ru2H(2) (1 = (Me-BPE)(2), 2 = (Me-DuPHOS)(2)) were characterized by multinuclear NMR and CD spectroscopy in solution and by X-ray crystallography. The chiral ligands allow the full control of stereochemistry and enable mechanistic studies not otherwise available. Oxidative addition of E-H bonds (E = H, B, Si, C) was studied by steady state and laser flash photolysis in the presence of substrates. Steady state photolysis shows formation of single products with one stereoisomer. Solid state structures and circular dichroism spectra reveal a change in configuration at ruthenium for some Δ-S,S-Ru2H(2)/Λ-R,R-Ru2H(2) photoproducts from Λ to Δ (or vice versa) while the configuration for Λ-R,R-Ru1H(2) products remains unchanged as Λ. The X-ray structure of silyl hydride photoproducts suggests a residual H(1)···Si(1) interaction for Δ-[cis-Ru((R,R)-Me-DuPHOS)(2)(Et(2)SiH)(H)] and Δ-[cis-Ru((R,R)-Me-DuPHOS)(2)(PhSiH(2))(H)] but not for their Ru(R,R-BPE)(2) analogues. Molecular structures were also determined for Λ-[cis-Ru((R,R)-Me-BPE)(2)(Bpin)(H)], Λ-[Ru((S,S)-Me-DuPHOS)(2)(η(2)-C(2)H(4))], Δ-[Ru((R,R)-Me-DuPHOS)(2)(η(2)-C(2)H(4))], and trans-[Ru((R,R)-Me-DuPHOS)(2)(C(6)F(5))(H)]. In situ laser photolysis in the presence of p-H(2) generates hyperpolarized NMR spectra because of magnetically inequivalent hydrides; these experiments and low temperature photolysis with D(2) reveal that the loss of hydride ligands is concerted. The reaction intermediates [Ru(DuPHOS)(2)] and [Ru(BPE)(2)] were detected by laser flash photolysis and have spectra consistent with approximate square-planar Ru(0) structures. The rates of their reactions with H(2), D(2), HBpin, and PhSiH(3) were measured by transient kinetics. Rate constants are significantly faster for [Ru(BPE)(2)] than for [Ru(DuPHOS)(2)] and follow the substrate order H(2) > D(2) > PhSiH(3) > HBpin.     

Absolute configuration of 1,n-diols by NMR: the importance of the combined anisotropic effects in bis-arylmethoxyacetates

The absolute configuration of a 1,n-diol can be assigned from the (1)H NMR spectra of its (R)- and (S)-AMAA diesters if the chemical shifts are interpreted as the result of the joint action of the two chiral auxiliaries.     

Cross interaction between auxiliaries: the chirality of amino alcohols by NMR

The absolute configuration of sec/prim- and prim/sec-1,2-amino alcohols is determined by comparison of the (1)H NMR chemical shifts of the auxiliary OMe or CalphaH groups at the corresponding bis-( R) and bis-( S)-MPA derivatives. This is the first NMR method that allows the assignment of absolute configuration without resorting to the shifts of hydrogens at the substrate and is based on the cross anisotropic interactions between auxiliaries.     

The assignment of the absolute configuration of diethyl hydroxy- and aminophosphonates by 1H and 31P NMR using naproxen as a reliable chiral derivatizing agent

The assignment of the absolute configuration of hydroxy- and aminophosphonates by their double derivatization with commercially available naproxen is presented. The correlation between the spatial arrangement around the stereogenic carbon center and the signs of the DeltadeltaRS allows determination of the absolute configuration of hydroxy- and aminophosphonates by simple comparison of the 1H and 31P NMR spectra of the (R)- and (S)-naproxen ester or amide derivatives. Extensive conformational analysis (theoretical calculations, low-temperature experiments) supported by the NMR studies of structurally diverse naproxen esters and amides of hydroxy- and aminophosphonates proved that a simplified model can be successfully used.     

Role of barium(II) in the determination of the absolute configuration of chiral amines by 1H NMR spectroscopy

The assignment of the absolute configuration of alpha-chiral primary amines by complexation of their MPA derivatives with Ba2+ and NMR analysis of the changes generated is presented. All that is required is (a) the derivatization of the amine of unknown configuration with one enantiomer of the auxiliary reagent (MPA), either (R) or (S)-alpha-methoxyphenylacetic acid, (b) the recording of the 1H NMR spectrum of the resulting amide in MeCN-d3, (c) the addition of Ba(ClO4)2 to the NMR tube, and (d) the recording of a second spectrum after a few minutes of shaking. The above steps take a few minutes and are followed by an analysis of the shifts (measured as Deltadelta(Ba)) produced on the L1 and L2 substituents of the amine by the addition of Ba2+ and their comparison with those expected from the conformational changes produced by the complexation. The conformational changes initiated by complexation have been subjected to NMR and CD studies, which showed that the formation of the complex shifts the equilibrium from an antiperiplanar (AP) to a synperiplanar (SP) form, leading to an increase of the shielding by the phenyl group of MPA of the substituent of the amine located on the same side. In addition, theoretical calculations [density functional theory (DFT)] provide further support for the formation, structure, and stability of the complexes. The general applicability of this method and the trustworthiness of the resulting configurational assignment were guaranteed with a series of amines of known absolute configuration and varied structures, used as test compounds. The method proposed is simple, fast, and inexpensive, and it requires a very small amount of sample, only one derivatization, and the recording of just two 1H NMR spectra at room temperature. A graphical guide to simplify the application of this method is included.     

Determination of absolute stereochemistry of natural alicyclic glycosides by 1H NMR spectroscopy without application of chiral reagents--an indication

A study has been made of the 1H NMR spectra of peracetylated beta-glucopyranosides and alpha-arabinopyranosides obtained by reaction of D- and L-glucoses, and L- and D-arabinoses with either (R)- or (S)-2-octanols. The obtained and literature data show that 1H NMR spectra may be used to determine the absolute configuration of the aglycone moieties of some alicyclic glycosides without the need to synthesize derivatives with chiral reagents, as long as the absolute configuration of their monosaccharide moiety is known or vice versa. Spectra of marine steroid glycosides and their acetates containing glycosylated side chains as alicyclic fragments were also examined. It was shown that analysis of 1H NMR spectra for the determination of the absolute configuration is more applicable in the cases when glycosides have the same substitution in the D-ring of the aglycone moiety.     

The assignment of absolute configuration of cyanohydrins by NMR

Derivatization of aldehyde cyanohydrins as (R)- and (S)-MPA esters and comparison of the corresponding 1H- and 13C-NMR spectra allows the assignment of their absolute configuration.     

Selective excitation 1D-NMR experiments for the assignment of the absolute configuration of secondary alcohols

Routine selective excitation experiments, easy to set up on modern NMR spectrometers, allow for the determination of the absolute configuration of chiral secondary alcohols by double derivatization directly in the NMR tube. As a general method, TOCSY1D with selective excitation of the α proton in the MPA esters and with a short mixing time reveals only the nearby protons in the coupling network. Typically, the analysis takes less than 30 min. A longer mixing time, selective excitation of other signals, or NOESY1D experiments can be used for measuring ΔδRS of other protons.     

Anomalous stereochemistry of pyrazolato-3,5-dicarboxylato-bridged dinuclear chromate(III) complexes containing ethylenediamine-N,N'-dicarboxylates with entrapped unstable conformations: X-ray structure of Na[Cr2(eddp)(mu-pzdc)].6H2O

Several new pyrazolato-3,5-dicarboxylato (pzdc) bridged dinuclear chromate(III) complexes containing linear tetradentate O-N-N-O type ligands were synthesized and structurally characterized. Among them, the X-ray structure of the eddp complex Na[Cr2(eddp)(mu-pzdc)].6H2O (eddp = ethylenediamine-N,N'-dipropionate) was determined to have a (sym-cis)-(unsym-cis) geometrical configuration with intramolecular three-center hydrogen bonds, entrapping the unfavored sym-cis configuration for the Cr(eddp) moiety as well as the favored unsym-cis one. As a pair of positional disorders, there were also found to be two conformational isomers with respect to the absolute configurations of the coordinated asymmetric nitrogen atom at the G (in-plane) ring for the unsym-cis moiety. Moreover, chiral pzdc-bridged dinuclear complexes with another type of O-N-N-O ligand, 1,2-cyclohexanediamine-N,N'-diacetate (cdda), were successfully synthesized, isolated, and characterized by column chromatographic behavior, elemental analysis, and chiroptical spectra. There were two diastereomers for Na[(R,R-cdda)Cr(mu-pzdc)Cr(S,S-cdda)] and only one isomer for Na[(R,R-cdda)Cr(mu-pzdc)Cr(R,S-cdda)] and Na[(R,R-cdda)Cr(mu-pzdc)Cr(edda)] (R,R- or S,S- and R,S-cdda = R,R-trans- or S,S-trans- and R,S-cis-1,2-cyclohexanediamine-N,N'-diacetate, and edda = ethylenediamine-N,N'-diacetate). From their circular dichroism (CD) spectra, these complexes could exhibit the delta-delta absolute configuration with ((sym-cis-R,R-cdda)-(unsym-cis-edda or S,S- or R,S-cdda)) geometrical configuration, indicating the abnormal eq-eq (N-Ceq) configuration for the R,R-cdda. The comparison among the CD spectra of the ((cdda)-(cdda)) complexes revealed that two diastereomers of the ((R,R-cdda)-(S,S-cdda)) complex correspond to the conformational isomers resulting from the difference in geometrical orientations of the secondary amine protons on two coordinated asymmetric nitrogen atoms with the opposite absolute configuration in the unsym-cis-S,S-cdda moiety. In a series of the pzdc-bridged Cr(III) complexes the anomalous conformations in two different geometrical configurations could be entrapped probably owing to stereognostic coordination through the intramolecular N-H...O hydrogen bond interaction.     

The use of MPA amide for the assignment of absolute configuration of a sterically hindered cyclic secondary amine by 'mix and shake' NMR method

We present here a new method using methoxyphenylacetic acid (MPA) as the chiral derivatizing agent (CDA) for the assignment of absolute configuration of cyclic secondary amines. The MPA amides were prepared using the purification-free 'mix and shake' method. A detailed conformational analysis for the two diastereomeric amides was conducted by 2D NMR experiments and molecular mechanics calculations. We have established that, in the most stable conformation of each syn rotamer of MPA amides, the H-alpha in the MPA moiety is oriented toward the bulky substituent group at the asymmetric carbon in the chiral amine, presumably to avoid steric and/or electrostatic interactions. The observed NMR data were correlated with the conformational model to allow unambiguous assignment of absolute configuration of secondary amines. The results demonstrate that the MPA can be used as a useful CDA in the case of sterically crowded cyclic secondary amines from which the MTPA amides are usually difficult to make.     

Chiral trialkanolamine-based hemicryptophanes: synthesis and oxovanadium complex

[reaction: see text] A novel class of chiral hemicryptophane hosts has been synthesized in diastereoisomerically pure form, namely, M-(R,R,R)-1a/P-(S,S,S)-1a and M-(S,S,S)-1b/P-(R,R,R)-1b. The C3-symmetrical precursor 9 was prepared, using either (R)- or (S)-glycidyl nosylate, repectively, as the chiral pool reactant and subsequently cyclized (trimerized) in the presence of Sc(OTf)3. The four stereoisomers were fully characterized and displayed two pairs of mirror-image CD spectra, which were used to determine their absolute configuration. The formation of the oxovanadium(V) complex of hemicryptophane 1a is also reported.     

"Mix and shake" method for configurational assignment by NMR: application to chiral amines and alcohols

[reaction: see text] A new methodology for determining absolute configurations by NMR in just a few minutes is presented. The required derivatives are obtained by mixing a solid matrix-bound auxiliary reagent (MPA, MTPA, or BPG) with the chiral substrate (primary amines or secondary alcohols) directly in the NMR tube. The NMR spectra of the derivatives are obtained without any type of separation, workup, or manipulation. The use of a 1:2 (R)/(S)-MPA resin permits the configurational assignment to be carried out with just one spectrum.