2-Methoxy-2-(1-naphthyl)propionic acid,a powerful chiral auxiliary for enantioresolution of alcohols and determination of their absolute configurations by the 1H NMR anisotropy method

Racemic 2-methoxy-2-(1-naphthyl)propionic acid (1, MαNP acid) was enantioresolved as its esters derived from various chiral alcohols. For example, a diastereomeric mixture of esters prepared from (±)-1 and (1R,3R,4S)-(−)-menthol was easily separated by HPLC on silica gel yielding esters (−)-2a and (−)-2b, the separation factor α=1.83 being unusually large. The ¹H NMR chemical shift differences, Δδ=δ(R)–δ(S), between diastereomers 2a and 2b, are much larger than those of conventional chiral auxiliaries, e.g. Mosher’s MTPA and Trost’s MPA acids. This acid 1 is therefore very powerful for determining the absolute configuration of chiral alcohols by the ¹H NMR anisotropy method. Solvolysis of the separated esters yielded enantiopure acids (S)-(+)-1 and (R)-(−)-1, which are useful for enantioresolution of racemic alcohols.     

2-Cyano-2-indolylpropanoic acid as a chiral derivatizing agent for the absolute configuration assignment of secondary alcohols and primary amines by 1H NMR and VCD

A convenient approach for the absolute configuration assignment of secondary alcohols in the (8R,1′R,2′S,5′R)-15,25, (8S,1′R,2′S,5′R)-15,25, (8R,1′R)-21–24, and (8S,1′R)-21–24 ester series, and of primary amines in the (8R,1′R)-32–37 and (8S,1′R)-32–37 amide series, by means of ¹H NMR and VCD spectroscopy, using 2-cyano-2-indolylpropanoic acid as a chiral derivatizing agent is presented. DFT calculations were carried out to demonstrate the anisotropic effect of the indole skeleton on the chiral alcohol or the amine fragment. Vibrational circular dichroism (VCD) measurements of the above series indicated a VCD bisignated couplet resulting from the interaction of the ester carbonyl group and the CN group. The absolute configuration assignments were further tested by X-ray diffraction analysis.     

A general method for the synthesis of enantiopure aliphatic chain alcohols with established absolute configurations. Part 1. Application of the MαNP acid method to acetylene alcohols

A method using (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid 1 (MαNP acid) has been applied to acetylene alcohols 4–14 to determine their absolute configurations by ¹H NMR anisotropy and/or X-ray crystallography. Diastereomeric MαNP esters prepared from racemic acetylene alcohols and (S)-(+)-MαNP acid 1 were easily separable by HPLC on silica gel. From the ¹H NMR anisotropy Δδ data of separated diastereomeric MαNP esters {Δδ = δ (R,X) − δ(S,X) = δ(2nd fr.) − δ(1st fr.)}, the absolute configurations of the first eluted esters were determined. This MαNP acid method has been successfully applied to various acetylene alcohols 4–12 and 14. In the case of MαNP esters 21b, 24a, and 26a, their absolute configurations were unambiguously determined by X-ray crystallography, which confirmed the absolute configuration assignments performed by ¹H NMR anisotropy. These acetylene alcohol MαNP esters can serve as key intermediates for the synthesis of enantiopure aliphatic chain alcohols with established absolute configurations as described in Part 2 of this series.     

Heterocycles 35. CaL-B mediated synthesis of enantiomerically pure (R)- and (S)-ethyl 3-(2-arylthiazol-4-yl)-3-hydroxypropanoates

Herein we present the lipase catalyzed synthesis of four new enantiomerically pure (R)- and (S)-ethyl 3-(2-arylthiazol-4-yl)-3-hydroxypropanoates and their butanoates by enzymatic enantioselective acylation of the racemic alcohols rac-1a–d and by ethanolysis of the corresponding racemic esters rac-2a–d mediated by lipase B from Candida antarctica (CaL-B) in organic solvents. In terms of stereoselectivity and activity, both procedures, the acylation and alcoholysis, are successful (50% conversion, E ≫ 200). The absolute configuration of the resolution products was determined by a detailed ¹H NMR study of the Mosher’s derivatives of (S)-1a.     

Are the absolute configurations of 2-(1-hydroxyethyl)-chromen-4-one and its 6-bromo derivative determined by X-ray crystallography correct? A vibrational circular dichroism study of their acetate derivatives

The vibrational circular dichroism (VCD) spectra of the acetate derivative, 3, of 2-(1-hydroxyethyl)-chromen-4-one, 1, and the acetate derivative, 4, of 6-bromo-2-(1-hydroxyethyl)-chromen-4-one, 2, in the CO stretching region are reported. Density functional theory (DFT) predictions of the VCD spectra of the CO stretching modes of (R)-3 and (R)-4 are in excellent agreement with the experimental spectra for (+)-3 and (+)-4, demonstrating that the absolute configurations of both molecules are (R)-(+)/(S)-(−). Since acetylation of (+)-1 and (+)-2 yields (+)-3 and (+)-4, this in turn leads to (R)-(+)/(S)-(−) for both 1 and 2. The absolute configurations of (−)-1 and (−)-2 were previously determined using X-ray crystallography to be R and S, respectively. Our results lead to the conclusion that the previously reported absolute configuration of 1 is incorrect.This work is the first to apply the ‘conformational rigidification via chemical derivatisation’ methodology to the determination of absolute configuration using VCD spectroscopy and illustrates its utility in determining the absolute configurations of chiral alcohols and, by extension, other classes of chiral molecules containing flexible functional groups.     

Absolute configuration reassignment of two chromanes from Peperomia obtusifolia (Piperaceae) using VCD and DFT calculations

Previous analysis of the ECD spectra of two prenylated benzopyrans isolated from Peperomia obtusifolia, by means of the helicity rule for the chromane chromophore, resulted in the incorrect assignment of their absolute configuration, (S) instead of (R) for a deduced P-helicity of the chromane ring for the (+)-enantiomers. This was discovered by the application of DFT calculations and VCD spectroscopy. Experimental and calculated (B3LYP/6-31G(d)) VCD and IR spectra were compared, and a definitive absolute configuration of (+)-1 and (+)-2 is reassigned directly in solution as (R). The assumption of equatorial positioning of bulky groups, shown here to be invalid for the title molecules, is the underlying cause of the previous incorrect assignment of absolute configuration. Moreover, TDDFT (B3LYP/6-311++G(2d,2p)//B3LYP/6-31G(d)) calculations of ECD spectra have shown that both P- and M-helicity of the heterocyclic ring, for a given absolute configuration, lead to the same sign for the ¹L_b ECD band, thus bringing into question the validity of the empirical ECD helicity rule for chromane molecules.     

Sharpless asymmetric dihydroxylation as the key step in the enantioselective synthesis of spirocyclic σ1 receptor ligands

The enantioselective synthesis of fluorinated spirocyclic σ₁ ligands involved three key steps: (1) the Sharpless asymmetric dihydroxylation of 2-bromostyrene 5 provided enantiomerically pure diols (R)-6 and (S)-6 establishing the stereogenic center; (2) the intramolecular opening of the oxirane ring of (R)-11 and (S)-11, which occurred with excellent regioselectivity and complete inversion of configuration giving access to enantiomerically pure alcohols (S)-7a and (R)-7a; (3) the treatment of alcohols (S)-7b and (R)-7b with DAST, which led to the fluoromethyl derivatives (S)-1 and (R)-1 without racemization. X-ray crystal structure analysis of the tosylate (R)-13 confirmed the absolute configuration of the spirocyclic compounds as well as the enantioselectivity during the Sharpless asymmetric dihydroxylation of 5. The (S)-configured fluoromethyl derivative (S)-1 revealed a high σ₁ affinity (K_i = 1.8 nM), high eudismic ratio (factor 8) and high selectivity over the σ₂ subtype (667-fold).     

Crystal and molecular structure of the levorotatory (1R,2S)-ephedrinium (S)-t-butylsulfinylacetate: a definitive proof of the absolute configuration of enantiomeric t-butyl methyl sulfoxides

The levorotatory enantiomer of t-butylsulfinylacetic acid 3 was obtained in the reaction of the α-carbanion of (+)-t-butyl methyl sulfoxide 1 with carbon dioxide. The same enantiopure form of the acid 3 was isolated from its diastereomerically pure levorotatory salt 5 with (−)-(1R,2S)-ephedrine. The structure of this salt was determined by X-ray analysis and the absolute configuration (S) at sulfur was ascribed to the t-butylsulfinylacetate anion. Consequently, the absolute configuration (S) was assigned to the acid (−)-3 and its precursor (+)-t-butyl methyl sulfoxide 1.     

Diastereospecific addition of Grignard reagents to 3,3′,4,4′-tetramethyl-1,1′-diphosphaferrocene-2-carboxaldehyde

The reaction of both enantiomers of 3,3′,4,4′-tetramethyl-1,1′-diphosphaferrocene-2-carboxaldehyde 1 with EtMgBr and PhMgBr has been studied. It has been found that addition of a Grignard reagent to the carbonyl group of 1 proceeds diastereospecifically. The configuration of the sp³ stereogenic centre formed in this reaction has been determined by single crystal X-ray diffraction and can be explained assuming exo-attack of the nucleophile on the s-cis-conformation of 1. The circular dichroism spectra of the product 1,1′-diphosphaferrocenyl alcohols are also reported and discussed.     

Absolute configuration of 2-hydroxy-2-(1-naphthyl)propionic acid as determined by the 1H NMR anisotropy method

Enantiopure 2-hydroxy-2-(1-naphthyl)propionic acid (+)-2 was prepared by the stereoselective Grignard reaction of 1-naphthylmagnesium bromide with (1R,3R,4S)-menthyl pyruvate 3 or (1R,3R,4S)-8-phenylmenthyl pyruvate 4, and the absolute configuration of acid (+)-2 was unambiguously determined to be S by the ¹H NMR anisotropy method.     

The absolute configuration of an inherently chiral phosphonatocavitand and its use toward the enantioselective recognition of l-adrenaline

An inherently chiral ABii diphosphonato cavitand (±)-4 bearing a single quinoxaline bridging moiety was synthesized and resolved by chiral HPLC. Its chiroptical properties were investigated and VCD experiments allowed the determination of its absolute configuration. Distinguishable diastereomeric complexes in solution with l-adrenaline were observed by ¹H and ³¹P NMR together with a noticeable enantio-discrimination at 253 K (dr ～2:1) in favor of the dextrorotatory cavitand (+)-4.     

Absolute configuration of hypothemycin and 5′-O-methylhypothemycin from Phoma sp.—a test case for solid state CD/TDDFT approach

Two metabolites, the known antitumor macrolide hypothemycin 1 and its new 5′-O-methyl ether, 5′-O-methylhypothemycin 2, and the known steroid ergosterol 3, were isolated from a Phoma sp. The structures were elucidated by means of spectroscopic data analysis, and the absolute configuration of hypothemycin 1 was confirmed by single crystal X-ray analysis in combination with the new solid-state CD/TDDFT methodology. Since the solid-state CD spectrum shows contributions from intermolecular interactions in the crystal, 1 represents a critical test case for our solid-state CD/TDDFT approach.     

Sedum alkaloids—VII : Structure and synthesis of (+)-4-hydroxysedamine and (+)-4-hydroxyallosedamine

The structures of (+)-4-hydroxysedamine ¹ and (+)-⁴-H-hydroxyallosedamine ², two new minor alkaloids from Sedum itacre, are reported 1 and 2 were synthesized, and their absolute configuration established, via the optically pure tetrahydro 1,3-oxazines 17 and 18.     

Crucigasterins A-E, antimicrobial amino alcohols from the Mediterranean colonial ascidian Pseudodistoma crucigaster

Five new unsaturated 2-amino-3-alcohols, crucigasterins A-E (2-6), were isolated together with known related compound 7 from the Mediterranean ascidian Pseudodistoma crucigaster and characterised as diacetyl derivatives (2a-6a) by spectroscopic methods. The threo-relative configuration of the amino alcohol portion was inferred by NOE analysis of the oxazolidinone derivative of crucigasterin A (2) as well as by ¹³C NMR comparison with synthetic threo and erythro model compounds. The co-occurring metabolites were assumed to have the same relative configuration as 2 by comparison of the diagnostic carbon value of C-1. The absolute stereochemistry of compound 7 that had not been previously reported was determined by applying the modified Mosher’s method on the corresponding N-acetyl derivative. The same absolute configuration was suggested for the other co-occurring crucigasterins by biogenetic considerations. Antibacterial and antifungal activities of selected crucigasterins were also evaluated.     

Determination of absolute configuration using vibrational circular dichroism spectroscopy: the chiral sulfoxide 1-thiochroman S-oxide

We have determined the absolute configuration of the chiral sulfoxide 1-thiochroman S-oxide 1 using vibrational circular dichroism (VCD) spectroscopy. The VCD spectrum of a CCl₄ solution of 1 was analyzed using density functional theory (DFT), which predicts three stable conformations of 1, separated by <1 kcal/mol. The VCD spectrum predicted using the DFT/GIAO methodology for the equilibrium mixture of the three conformations of (S)-1 is in excellent agreement with the experimental spectrum of (+)-1. The absolute configuration of 1 is therefore (R)-(−)/(S)-(+). (+)-1 and (−)-1 of high enantiomeric excess (e.e.) were synthesized in high yields via asymmetric oxidation of 1-thiochroman 2 using Ti(iso-PrO)₄/(R,R)-1,2-diphenylethane-1,2-diol/H₂O/tert-butyl hydroperoxide and Ti(iso-PrO)₄/l-diethyl tartrate/H₂O/cumene hydroperoxide, respectively.     

Determination of the absolute configuration of nodulisporacid A by the concise synthesis of four stereoisomers via three-component reaction and one-pot construction of the framework

Four stereoisomers of nodulisporacid A (1) were synthesized by the concise approach which includes three-component reaction and subsequent one-pot construction of the whole framework. The ¹H NMR comparison of the derivatives (10-12) revealed the absolute configuration of natural 1 to be 4R,4′R,6′R.     

(±)-Pyriindolin with a 2,2′-bipyridine-spiro[furan-3,3′-indoline] chimeric skeleton from the endophytic Streptomyces albolongus EA12432

(±)-Pyriindolin (1) with a rare molecular backbone formed by fusing a 2,2′-bipyridine nucleus into a spiro[furan-3,3′-indoline] skeleton, was isolated from the Streptomyces albolongus EA12432. The constitution and the relative configuration of (±)-1 were determined by extensive spectroscopic analyses, ¹³C calculation and DP4+ probability analysis. The absolute configurations of optically pure (+)-1 and (?)-1 which were obtained after a chiral high performance liquid chromatography (HPLC) separation were further identified by electronic circular dichroism (ECD) calculations. (+)- and (?)-Pyriindolins displayed moderate cytotoxicity against HCT-116 cell line with the half-maximal inhibitory concentration (IC₅₀) values of 2.89 ± 0.17 µmol/L and 4.47 ± 0.26 µmol/L, respectively.     

Application of chiral bidentate NMR solvents for assignment of the absolute configuration of alcohols: scope and limitation

The ¹³C NMR behaviors of several cyclic and biaryl secondary alcohols as well as acyclic tertiary alcohols have been studied in the chiral bidentate NMR solvent BMBA-p-Me (1). An empirical rule has been advanced to correlate the absolute configuration of each type of alcohols with the ¹³C chemical shift behaviors in (R,R)- and (S,S)-BMBA-p-Me.     

Syntheses of Enantiopure Aliphatic Secondary Alcohols and Acetates by Bioresolution with Lipase B from <em>Candida antarctica</em>

The lipase B from Candida antarctica (Novozym 435^?, CALB) efficiently catalyzed the kinetic resolution of some aliphatic secondary alcohols: (±)-4-methylpentan-2-ol (1), (±)-5-methylhexan-2-ol (3), (±)-octan-2-ol (4), (±)-heptan-3-ol (5) and (±)-oct-1-en-3-ol (6). The lipase showed excellent enantioselectivities in the transesterifications of racemic aliphatic secondary alcohols producing the enantiopure alcohols (>99% ee) and acetates (>99% ee) with good yields. Kinetic resolution of rac-alcohols was successfully achieved with CALB lipase using simple conditions, vinyl acetate as acylating agent, and hexane as non-polar solvent.     

Application of deuterated THENA for assigning the absolute configuration of chiral secondary alcohols

The structure of a constrained bicyclic chiral derivatizing agent (CDA), 1,2,3,4-tetrahydro-1,4-epoxynaphthalene-1-carboxylic acid, THENA 1, was modified by replacing both exo-methylene protons with deuterium atoms. The modified CDA, THENA-d₂2, could be used to assign the absolute configuration of chiral secondary alcohols with good reliability. Compared with THENA, the multiplicity of the methylene proton signals in the ¹H NMR spectra of THENA-d₂ derivatives is less complicated and the new CDA thus offers simpler NMR spectra for data interpretation.