(−)‐(3S)‐3‐(Tosylamino)butano‐4‐lactone,a Versatile Chiral Synthon for the Enantioselective Synthesis of Different Types of Polyamine Macrocycles: Determination of the Absolute Configuration of (−)‐(R)‐Budmunchiamine A

(−)‐(3S)‐3‐(Tosylamino)butano‐4‐lactone ( 1 ) and its derivative ethyl (−)‐(3S)‐4‐iodo‐3‐(tosylamino)butanoate ( 2 ) are presented as easily accessible chiral building blocks for the construction of a range of different macrolactam frameworks important for the synthesis of naturally occurring polyamine alkaloids as well as for establishing a substance library of such compounds, including S‐containing derivatives for biological tests. In addition to that, the absolute configuration of the spermine alkaloid (−)‐(R)‐budmunchiamine A ( 3 ) from Albizia amara was determined by total synthesis according to the new methodology.     

Synthesis and Olfactory Evaluation of (+)‐ and (−)‐γ‐Ionone

The synthesis of enantiomerically pure (+)‐ and (−)‐γ‐ionone 3 is reported. The first step in the synthesis is the diastereoisomeric enrichment of 4‐nitrobenzoate derivatives of racemic γ‐ionol 12 . The enantioselective lipase‐mediated kinetic acetylation of γ‐ionol 13b afforded the acetate 14 and the alcohol 15 , which are suitable precursors of the desired products (−)‐ and (+)‐ 3 , respectively. The olfactory evaluation of the γ‐ionone isomers shows a great difference between the two enantiomers both in fragrance response and in detection threshold. The selective reduction of (−)‐ 3 and (+)‐ 3 to the γ‐dihydroionones (−)‐(R)‐ 16 and (+)‐(S)‐ 17 , respectively, allowed us to assign unambiguously the absolute configuration of the γ‐ionones.     

A Stereospecific `2‐Aza‐divinylcyclopropane' Rearrangement

The stereochemical course of the thermal 2‐aza‐Cope rearrangement of the optically pure acyl azide (−)‐(1S)‐ 5 was investigated by determination of the absolute configuration of the rearrangement product (1R,8S)‐ 9 . The reaction proceeds by a sequence of stereospecific steps from 5 to an equilibrating mixture of exo‐ and endo‐isocyanates 6 and 7 . The endo‐isomer 7 undergoes Cope rearrangement to the putative intermediate 8 , which is trapped and characterized as the adduct 9b of butan‐1‐ol. The absolute configuration of 9b was determined by its reduction to the amide 20 , and determination of the X‐ray structure of the N‐camphanoylamide 21 derived from camphanic acid of known absolute configuration.     

A Case Study on the Resolution of the 1‐i‐Butyl‐3‐methyl‐3‐phospholene 1‐Oxide via Diastereomeric Complex Formation Using TADDOL Derivatives and via Diastereomeric Coordination Complexes Formed from the Calcium Salts of O,O′‐Diaroyl‐(2R,3R)‐tartaric Acids

The resolution of 1‐i‐butyl‐3‐methyl‐3‐phospholene 1‐oxide was studied applying TADDOL [(−)‐(4R,5R)‐4,5‐bis(diphenylhydroxymethyl)‐2,2‐dimethyldioxolane], spiro‐TADDOL [(−)‐(2R,3R)‐α,α,α′,α′‐tetraphenyl‐1,4‐dioxaspiro[4.5]decan‐2,3‐dimethanol], or the acidic and neutral Ca²⁺ salts of (−)‐O,O′‐dibenzoyl‐ and (−)‐O,O′‐di‐p‐toluoyl‐(2R,3R)‐tartaric acid as the resolving agent. The absolute configuration of the P‐asymmetric center was determined by circular dichroism spectroscopy and related quantum chemical calculations. In one instance, the single crystal of the diastereomeric complex incorporating i‐butyl‐3‐phospholene oxide and spiro‐TADDOL was subjected to X‐ray analysis, which suggested a feasible hypothesis for the efficiency of the resolution process under discussion that may be an example for the “solvent‐inhibited” resolution.     

Enzyme‐Catalyzed Stereoselective Synthesis of Two Novel Carbasugar Derivatives

Enzymatic resolution of racemic 1,4,5,6‐tetrachloro‐2‐(hydroxymethyl)‐7,7‐dimethoxybicyclo[2.2.1]hept‐5‐ene (rac‐ 1 ) using various lipases in vinyl acetate as acetyl source was studied. The obtained enantiomerically enriched (+)‐(1,4,5,6‐tetrachloro‐7,7‐dimethoxybicyclo[2.2.1]hept‐5‐en‐2‐yl)methyl acetate ((+)‐ 2 ; 94% ee), upon treatment with Na in liquid NH₃, followed by Amberlyst‐15 resin in acetone, provided (−)‐5‐(hydroxymethyl)bicyclo[2.2.1]hept‐2‐en‐7‐one ((−)‐ 7 ), which is a valuable precursor for the synthesis of carbasugar derivatives. Subsequent Baeyer–Villiger oxidation afforded a nonseparable mixture of bicyclic lactones, which was subjected to LiAlH₄ reduction and then acetylation. The resultant compounds (−)‐ 11 and (+)‐ 12 were submitted to a cis‐hydroxylation reaction, followed by acetylation, to afford the novel carbasugar derivatives (1S,2R,3S,4S,5S)‐4,5‐bis(acetoxymethyl)cyclohexane‐1,2,3‐triyl triacetate ((−)‐( 13 )) and (1R,3R,4R,6R)‐4,6‐bis(acetoxymethyl)cyclohexane‐1,2,3‐triyl triacetate ((−)‐( 14 )), respectively, with pseudo‐C₂‐symmetric configuration. The absolute configuration of enantiomerically enriched unreacted alcohol (−)‐ 1 (68% ee) was determined by X‐ray single‐crystal analysis by anchoring optically pure (R)‐1‐phenylethanamine. Based on the configurational correlation between (−)‐ 1 and (+)‐ 2 , the absolute configuration of (+)‐ 2 was determined as (1R,2R,4S).     

Substrate‐Dependent Stereospecificity of Tyl‐KR1: An Isolated Polyketide Synthase Ketoreductase Domain from Streptomyces fradiae

The stereospecificity of an enzymatic reaction depends on the way in which a substrate and its enantiomer bind to the active site. These binding modes cannot be easily predicted. We have studied the stereospecificity and stereoselectivity of the ketoreductase domain Tyl‐KR1 of the tylactone polyketide synthase from Streptomyces fradiae by analysing the stereochemical outcome of the reduction of five different keto ester substrates. The absolute configuration of the Tyl‐KR1 reduction products was determined by using vibrational circular dichroism (VCD) spectroscopy combined with quantum chemical calculations. The conversion of only one of the tested substrates, 2‐methyl‐3‐oxovaleric acid N‐acetylcysteamine thioester, afforded the expected anti‐(2R,3R) configuration of the α‐methyl‐β‐hydroxyl ester product, representing the stereochemistry observed for the physiological polyketide product tylactone. For all other substrates, which were modified with respect to the type of ester and/or the chain length (C₄ instead of C₅), the opposite configuration (anti‐(2S,3S)) was obtained with significant enantio‐ and diastereoselectivity. Inversion of both stereocentres suggests completely different binding modes invoked by only minor modifications of the substrate structure.     

Enantiomeric high‐performance liquid chromatography resolution and absolute configuration of 6β‐benzoyloxy‐3α‐tropanol

The absolute configuration of the naturally occurring isomers of 6β‐benzoyloxy‐3α‐tropanol ( 1 ) has been established by the combined use of chiral high‐performance liquid chromatography with electronic circular dichroism detection and optical rotation detection. For this purpose (±)‐ 1 , prepared in two steps from racemic 6‐hydroxytropinone ( 4 ), was subjected to chiral high‐performance liquid chromatography with electronic circular dichroism and optical rotation detection allowing the online measurement of both chiroptical properties for each enantiomer, which in turn were compared with the corresponding values obtained from density functional theory calculations. In an independent approach, preparative high‐performance liquid chromatography separation using an automatic fraction collector, yielded an enantiopure sample of _OR(+)‐ 1 whose vibrational circular dichroism spectrum allowed its absolute configuration assignment when the bands in the 1100–950 cm^‐1 region were compared with those of the enantiomers of esters derived from 3α,6β‐tropanediol. In addition, an enantiomerically enriched sample of 4 , instead of _OR(±)‐ 4 , was used for the same transformation sequence, whose high‐performance liquid chromatography follow‐up allowed their spectroscopic correlation. All evidences lead to the _OR(+)‐(1S,3R,5S,6R) and _OR(?)‐(1R,3S,5R,6S) absolute configurations, from where it follows that samples of 1 isolated from Knightia strobilina and Erythroxylum zambesiacum have the _OR(+)‐(1S,3R,5S,6R) absolute configuration, while the sample obtained from E. rotundifolium has the _OR(?)‐(1R,3S,5R,6S) absolute configuration.     

Facile Synthesis of Diastereoisomerically and Optically Pure 2‐Substituted Hexahydro‐1H‐pyrrolizin‐3‐ones

We report a short synthetic route that provides optically active 2‐substituted hexahydro‐1H‐pyrrolizin‐3‐ones in four steps from commercially available Boc (tert‐but(oxy)carbonyl))‐protected proline. Diastereoisomers (−)‐ 11 and (−)‐ 12 were assembled from the proline‐derived aldehyde (−)‐ 8 and ylide 9 via a Wittig reaction and subsequent catalytic hydrogenation (Scheme 3). Cleavage of the Boc protecting group under acidic conditions, followed by intramolecular cyclization, afforded the desired hexahydro‐1H‐pyrrolizinones (−)‐ 1 and (+)‐ 13 . Applying the same protocol to ylide 19 afforded hexahydro‐1H‐pyrrolizinones (−)‐ 25 and (−)‐ 26 (Scheme 5). The absolute configuration of the target compounds was determined by a combination of NMR studies (Figs. 1 and 2) and X‐ray crystallographic analysis (Fig. 3).     

A chiral 1,4-oxazin-2-one: asymmetric synthesis versus resolution,structure, conformation and VCD absolute configuration

1,4-Oxazin-2-one 3 is obtained from 2-pinanone in 4 steps and 78% overall yield. Enantiopure (e.e. >99%) (R)-(+)-3 and (S)-(−)-3 were obtained through chiral supercritical fluid chromatography (using a semi preparative Chiralpak AS column) with almost quantitative recovery of material. The structure and the boat-conformation of the lactone ring have been determined by NMR and the absolute configuration determined by VCD.     

Synthesis of the Natural Product Building Block 5‐(3‐Bromophenyl)‐4‐hydroxy‐5‐methylhexan‐2‐one and its Chiral Characterization by Using Chiroptical Spectroscopy

The absolute configuration of 5‐(3‐bromophenyl)‐4‐hydroxy‐5‐methylhexan‐2‐one, an intermediate in the synthesis of various natural products, is assigned by using vibrational circular dichroism (VCD), electronic circular dichroism (ECD), and optical rotatory dispersion (ORD). Experimental spectra were compared to density functional theory (DFT) calculations of the molecule with known configuration. These three techniques independently confirm that the absolute configuration is (S)‐5‐(3‐bromophenyl)‐4‐hydroxy‐5‐methylhexan‐2‐one, thus enabling us to assign the absolute configuration with high reliability. The reliability of the VCD analysis was assessed quantitatively by using the CompareVOA program. We found that, in cases in which the agreement between theory and experiment was very good, a value of 10 cm^?1 for the triangular weighting function gave a more‐realistic discriminative power between enantiomers than the default value of 20 cm^?1.     

Resolution of (S,S)‐4‐(2,2,4‐tri­methyl­chroman‐4‐yl)­phenyl camphanate and its 4‐chromanyl epimer by crystallization

Dianin's compound (4‐p‐hydroxy­phenyl‐2,2,4‐tri­methyl­chroman) has been resolved by crystallization of the (S)‐(−)‐camphanic esters (S,S)‐ and (R,S)‐4‐(2,2,4‐tri­methyl­chroman‐4‐yl)­phenyl 4,7,7‐tri­methyl‐3‐oxo‐2‐oxabi­cyclo[2.2.1]heptane‐1‐carboxyl­ate, both C₂₈H₃₂O₅, from 2‐methoxy­ethanol, yielding the pure S,S diastereomer. The relative stereochemistry of both diastereomers has been determined by X‐ray crystallography, from which the absolute stereochemistry could be deduced from the known configuration of the camphanate moiety. The crystallographic conformations have been analysed, including the 1:1 disorder of the R,S diastereomer.     

Coulomb Explosion Imaged Cryptochiral (R,R)‐2,3‐Dideuterooxirane: Unambiguous Access to the Absolute Configuration of (+)‐Glyceraldehyde

The absolute configuration of (R,R)‐2,3‐dideuterooxirane, which has been independently determined using Coulomb explosion imaging, has been unambiguously chemically correlated with the stereochemical key reference (+)‐glyceraldehyde. This puts the absolute configuration of D (+)‐glyceraldehyde on firm experimental grounds.     

Chemo‐Enzymatic Synthesis and Determination of the Absolute Configuration of Both Enantiomers of Methyl trans‐5‐Oxo‐2‐pentylpyrrolidine‐3‐carboxylate Precursors of the Aza Analogues of (+)‐ and (−)‐Methylenolactocin

Enantiomerically pure methyl esters of (+)‐(2R,3S)‐ and (−)‐(2S,3R)‐5‐oxo‐2‐pentylpyrrolidine‐3‐carboxylic acid with 99% and 98% ee were obtained by enzymatic resolution of the corresponding racemic mixture using α‐chymotrypsin and pig‐liver acetone powder, respectively. Their absolute configurations were established by chemical methods, i.e., conversion of the trans‐γ‐lactam moiety to the corresponding γ‐lactone of known configuration. The favorable interactions between the trans‐γ‐lactam and α‐chymotrypsin were rationalized by molecular‐mechanics calculations, which suggest a different situation for the cis‐diastereoisomer.     

Crystal and molecular structure and determination of absolute configuration of two enantimers of methoxycarbonylmethyl carboxymethyl sulfoxide

Crystal and molecular structures of two enantiomers of methoxycarbonylmethyl carboxymethyl sulfoxide 2 ( 2(−) and 2(+) ) have been determined by X-ray methods. Crystals of 2 are orthorhombic, space group P2₁2₁2₁, Z = 4, with a = 5.1900(4) Å, b = 8.7960(7) Å, and c = 18.489(2) Å in 2(−) and a = 5.1897(7) Å, b = 8.787(1) Å, and c = 18.520(2) Å in 2(+). Structures 2(−) and 2(+) were refined to R factors equal to 0.041 and 0.052, respectively. The absolute configuration at the sulfur atom in enantiomer 2(−) with [α]equation/tex2gif-stack-1.gif = −20° (MeOH) is R_s. (In 2(+) , where [α]equation/tex2gif-stack-2.gif equals + 20° (MeOH), the absolute configuration at S atom is S_s.) In compounds 2(−) and 2(+) , a strong intermolecular hydrogen bond O3 H3 … O1 occurs.     

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.     

Stereospecific Synthesis of (+)-β-Sesquiphellandrene

The structure and absolute configuration of (−)-β-Sesquiphellandrene ((−)- 1a ) is shown to be (6S)-2-methyl-6-[(1′R)-4-methylidenecyclohex-2-enyl]hept-2-ene by stereospecific synthesis of its enantiomer ((+)- 1a ) and of a further (6S,1′S)-diastereoisomer ((+)- 1b ). Characteristic spectroscopic differences in both diastereoisomeric series are discussed.     

Elucidation of the absolute configuration of rhizopine by chiral supercritical fluid chromatography and vibrational circular dichroism

The absolute configuration of rhizopine, an opine‐like natural product present in nitrogen‐fixing nodules of alfalfa infected by rhizobia, is elucidated using a combination of state‐of‐the‐art analytical and semi‐preparative supercritical fluid chromatography and vibrational circular dichroism spectroscopy. A synthetic peracetylated racemate was fractionated into its enantiomers and subjected to absolute configuration analysis revealing that natural rhizopine exists as a single enantiomer. The stereochemistry of non‐derivatized natural rhizopine corresponds to (1R,2S,3R,4R,5S,6R)‐4‐amino‐6‐methoxycyclohexane‐1,2,3,5‐tetraol.     

Total Syntheses of the Spermine Alkaloids (−)‐(R,R)‐Hopromine and (±)‐Homaline

The diastereoselective synthesis of the spermine alkaloid (R,R)‐hopromine ( 2 ) is described. The as yet unknown absolute configuration of naturally occurring (−)‐hopromine ( 2 ) is (R,R) and was established by comparison of the reported specific rotation of the natural product with that of the synthetic one. Preparation of the characteristic bis‐8‐membered lactam scaffold was carried out by convergent build‐up of basic chiral azalactam units 21a and 21b and subsequent iterative linking (Schemes 5 and 6). Key steps in the analogous syntheses of 4‐alkyl‐hexahydro‐1,5‐diazocin‐2(1H)‐ones 21a and 21b were the introduction of the unbranched alkyl side chains into their common precursor 14 via cuprate reaction and the Sb(OEt)₃‐assisted cyclization of the open‐chain intermediates 20a and 20b , respectively (Schemes 3 and 4). The chiral iodoester 14 was prepared from commercially available (+)‐L ‐aspartic acid ( 12 ). Based on the synthetic strategy developed for (R,R)‐hopromine ( 2 ), a rapid access to the parent alkaloid homaline ( 1 ) in its (±)‐form is given.     

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.     

A Facile Method to Determine the Absolute Structure of Achiral Molecules: Supramolecular‐Tilt Structures

Achiral compounds 4‐methoxy‐4‐(p‐methoxyphenyl)cyclohexanoneethylene ketal ( 2 ), 4‐hydroxy‐4‐(p‐methoxy phenyl)cyclohexanoneethylene ketal ( 3 ), and 3,5‐dimethyl‐4‐nitropyrazole ( 4 ) crystallized in chiral structures and the samples showed an enantiomeric excess. We have determined the absolute structures of these compounds by using X‐ray diffraction with copper radiation at low temperatures. Moreover, we have also established the prevalent absolute structures in these samples, by comparing their calculated and solid‐state vibrational circular dichroism (VCD) spectra. The consistency of this method was confirmed by using (R,R)‐2,8‐diiodo‐4,10‐dimethyl‐6 H,12H‐5,11‐methano‐dibenzo[b,f][1,5]diazocine, Tröger′s base, (R,R)‐ 1 , as a chiral compound of known absolute configuration.