One‐Handed Helical Screw Direction of Homopeptide Foldamer Exclusively Induced by Cyclic α‐Amino Acid Side‐Chain Chiral Centers

Chiral cyclic α,α‐disubstituted amino acids, (3S,4S)‐ and (3R,4R)‐1‐amino‐3,4‐(dialkoxy)cyclopentanecarboxylic acids ((S,S)‐ and (R,R)‐Ac₅c^dOR; R: methyl, methoxymethyl), were synthesized from dimethyl L ‐(+)‐ or D ‐(?)‐tartrate, and their homochiral homoligomers were prepared by solution‐phase methods. The preferred secondary structure of the (S,S)‐Ac₅c^dOMe hexapeptide was a left‐handed (M) 3₁₀ helix, whereas those of the (S,S)‐Ac₅c^dOMe octa‐ and decapeptides were left‐handed (M) α helices, both in solution and in the crystal state. The octa‐ and decapeptides can be well dissolved in pure water and are more α helical in water than in 2,2,2‐trifluoroethanol solution. The left‐handed (M) helices of the (S,S)‐Ac₅c^dOMe homochiral homopeptides were exclusively controlled by the side‐chain chiral centers, because the cyclic amino acid (S,S)‐Ac₅c^dOMe does not have an α‐carbon chiral center but has side‐chain γ‐carbon chiral centers.     

Preferred 3D-structure of peptides rich in a severely conformationally restricted cyclopropane analogue of phenylalanine

Terminally blocked, homo-peptide amides of (R,R)-1-amino-2,3-diphenylcyclopropane-1-carboxylic acid (c3diPhe), a chiral member of the family of Calpha-tetrasubstituted alpha-amino acids, from the dimer to the tetramer, and diastereomeric co-oligopeptides of (R,R)- or (S,S)-c3diPhe with (S)-alanine residues to the trimer level were prepared in solution and fully characterized. The synthetic effort was extended to terminally protected co-oligopeptide esters to the hexamer, where c3diPhe residues are combined with achiral alpha-aminoisobutyric acid residues. The preferred conformations of the peptides were assessed in solution by FT-IR absorption, NMR, and CD techniques, and for seven oligomers in the crystal state (by X-ray diffraction) as well. This study clearly indicates that c3diPhe, a sterically demanding cyclopropane analogue of phenylalanine, tends to fold peptides into beta-turn and 3(10)-helix conformations. However, when c3diPhe is in combination with other chiral residues, the conformation preferred by the resulting peptides is also dictated by the chiral sequence of the amino acid building blocks. The (S,S)-enantiomer of this alpha-amino acid, unusually lacking asymmetry in the main chain, strongly favors the left-handedness of the turn/helical peptides formed.     

Chiral differentiation of some cyclic β‐amino acids by kinetic and fixed ligand methods

Differentiation of β ‐amino acid enantiomers with two chiral centres was investigated by kinetic method with trimeric metal‐bound complexes. Four enantiomeric pairs of β ‐amino acids were studied: cis‐(1R,2S)‐, cis‐(1S,2R)‐, trans‐(1R,2R)‐ and trans‐(1S,2S)‐2‐aminocyclopentanecarboxylic acids (cyclopentane β ‐amino acids), and cis‐(1R,2S)‐, cis‐(1S,2R)‐, trans‐(1R,2R)‐, and trans‐(1S,2S)‐2‐aminocyclohexanecarboxylic acids (cyclohexane β ‐amino acids). The results showed that the choice of metal ion (Cu²⁺, Ni²⁺) and chiral reference compound (α‐ and β ‐amino acids) had an effect on the enantioselectivity. Especially, aromaticity of the reference compound was noted to enhance the enantioselectivity. The fixed‐ligand kinetic method, a modification of the kinetic method, was then applied to the same β ‐amino acids, with dipeptides used as fixed ligands. With this method, dipeptide containing an aromatic side chain enhanced the enantioselectivity. Copyright © 2009 John Wiley & Sons, Ltd.     

Solid‐state conformations of linear depsipeptide amides with an alternating sequence of α,α‐disubstituted α‐amino acid and α‐hydroxy acid

Depsipeptides and cyclodepsipeptides are analogues of the corresponding peptides in which one or more amide groups are replaced by ester functions. Reports of crystal structures of linear depsipeptides are rare. The crystal structures and conformational analyses of four depsipeptides with an alternating sequence of an α,α‐disubstituted α‐amino acid and an α‐hydroxy acid are reported. The molecules in the linear hexadepsipeptide amide in (S)‐Pms‐Acp‐(S)‐Pms‐Acp‐(S)‐Pms‐Acp‐NMe₂ acetonitrile solvate, C₄₇H₅₈N₄O₉·C₂H₃N, ( 3b ), as well as in the related linear tetradepsipeptide amide (S)‐Pms‐Aib‐(S)‐Pms‐Aib‐NMe₂, C₂₈H₃₇N₃O₆, ( 5a ), the diastereoisomeric mixture (S,R)‐Pms‐Acp‐(R,S)‐Pms‐Acp‐NMe₂/(R,S)‐Pms‐Acp‐(R,S)‐Pms‐Acp‐NMe₂ (1:1), C₃₂H₄₁N₃O₆, ( 5b ), and (R,S)‐Mns‐Acp‐(S,R)‐Mns‐Acp‐NMe₂, C₃₀H₃₇N₃O₆, ( 5c ) (Pms is phenyllactic acid, Acp is 1‐aminocyclopentanecarboxylic acid and Mns is mandelic acid), generally adopt a β‐turn conformation in the solid state, which is stabilized by intramolecular N—H…O hydrogen bonds. Whereas β‐turns of type I (or I′) are formed in the cases of ( 3b ), ( 5a ) and ( 5b ), which contain phenyllactic acid, the torsion angles for ( 5c ), which incorporates mandelic acid, indicate a β‐turn in between type I and type III. Intermolecular N—H…O and O—H…O hydrogen bonds link the molecules of ( 3a ) and ( 5b ) into extended chains, and those of ( 5a ) and ( 5c ) into two‐dimensional networks.     

Conformation of Peptides Containing a Chiral α‐Ethylated α,α‐Disubstituted α‐Amino Acid: (S)‐α‐Ethylleucine (=(2S)‐2‐Amino‐2‐ethyl‐4‐methylpentanoic Acid) within Sequences of Dimethylglycine and Diethylglycine Residues

An optically active (S)‐α‐ethylleucine ((S)‐αEtLeu) as a chiral α‐ethylated α,α‐disubstituted α‐amino acid was synthesized by means of a chiral acetal auxiliary of (R,R)‐cyclohexane‐1,2‐diol. The chiral α‐ethylated α,α‐disubstituted amino acid (S)‐αEtLeu was introduced into the peptides constructed from 2‐aminoisobutyric acid (=dimethylglycine, Aib), and also into the peptide prepared from diethylglycine (Deg). The X‐ray crystallographic analysis revealed that both right‐handed (P) and left‐handed (M) 3₁₀‐helical structures exist in the solid state of CF₃CO‐(Aib)₂‐[(S)‐αEtLeu]‐(Aib)₂‐OEt ( 14 ) and CF₃CO‐[(S)‐αEtLeu]‐(Deg)₄‐OEt ( 18 ), respectively. The IR, CD, and ¹H‐NMR spectra indicated that the dominant conformation of pentapeptides 14 and CF₃CO‐[(S)‐αEtLeu]‐(Aib)₄‐OEt ( 16 ) in solution is a 3₁₀‐helical structure, and that of 18 in solution is a planar C₅ conformation. The conformation of peptides was also studied by molecular‐mechanics calculations.     

Conformational studies on peptides having chiral five-membered ring amino acid with two azido or triazole functional groups within the sequence of Aib residues

The chiral cyclic α,α-disubstituted α-amino acid, (3R,4R)-1-amino-3,4-diazido-1-cyclopentanecarboxylic acid [(R,R)-Ac₅c^dN3], was introduced into achiral α-aminoisobutyric acid (Aib) peptides. The azido groups of (R,R)-Ac₅c^dN3 in the peptides were efficiently converted into 1,2,3-triazole functional groups. FTIR, ¹H NMR, and CD spectra revealed that the dominant conformations of all peptides in solution were 3₁₀-helical structures without controlling the helical-screw sense. X-ray crystallographic analyses of peptides containing (R,R)-Ac₅c^dN3 showed that both the right-handed (P) and left-handed (M) 3₁₀-helical structures were present in the crystal state.     

In Situ Deprotection and Incorporation of Unnatural Amino Acids during Cell‐Free Protein Synthesis

The S30 extract from E. coli BL21 Star (DE3) used for cell‐free protein synthesis removes a wide range of α‐amino acid protecting groups by cleaving α‐carboxyl hydrazides; methyl, benzyl, tert‐butyl, and adamantyl esters; tert‐butyl and adamantyl carboxamides; α‐amino form‐, acet‐, trifluoroacet‐, and benzamides; and side‐chain hydrazides and esters. The free amino acids are produced and incorporated into a protein under standard conditions. This approach allows the deprotection of amino acids to be carried out in situ to avoid separate processing steps. The advantages of this approach are demonstrated by the efficient incorporation of the chemically intractable (S)‐4‐fluoroleucine, (S)‐4,5‐dehydroleucine, and (2S,3R)‐4‐chlorovaline into a protein through the direct use of their respective precursors, namely, (S)‐4‐fluoroleucine hydrazide, (S)‐4,5‐dehydroleucine hydrazide, and (2S,3R)‐4‐chlorovaline methyl ester. These results also show that the fluoro‐ and dehydroleucine and the chlorovaline are incorporated into a protein by the normal biosynthetic machinery as substitutes for leucine and isoleucine, respectively.     

Synthesis and Conformational Characterisation of Hexameric β‐Peptide Foldamers by Using Double POAC Spin Labelling and cw‐EPR

A selected set of terminally protected β‐hexapeptides, each containing two nitroxide‐based (3R,4R)‐4‐amino‐1‐oxyl‐2,2,5,5‐tetramethylpyrrolidine‐3‐carboxylic acid (POAC) residues combined with four (1S,2S)‐2‐aminocyclopentane‐1‐carboxylic acid (ACPC) residues, was synthesised by using solution methods and was fully characterised. The two POAC residues are separated in the sequences by different numbers of intervening ACPC residues. The conformational features of the doubly spin‐labelled β‐hexapeptides were examined in chloroform by FTIR absorption and continuous‐wave electron paramagnetic resonance spectroscopic techniques. In particular, the biradical exchange coupling (J) between two POAC residues within each peptide indicates unambiguously that the secondary structure overwhelmingly adopted is the 12‐helix. Taken together, these results support the view that POAC is an excellent β‐amino acid for exploring this type of helical conformation in doubly labelled β‐peptides.     

(1R,3R,4S)‐1‐Benzyl‐3‐(tert‐butyldimethylsilyloxy)‐4‐(hydroxymethyl)pyrrolidine–borane: novel B—H...H—O hydrogen bonding

The absolute configuration of the title cis‐(1R,3R,4S)‐pyrrolidine–borane complex, C₁₈H₃₄BNO₂Si, was confirmed. Together with the related trans isomers (3S,4S) and (3R,4R), it was obtained unexpectedly from the BH₃·SMe₂ reduction of the corresponding chiral (3R,4R)‐lactam precursor. The phenyl ring is disordered over two conformations in the ratio 0.65:0.35. The crystallographic packing is dominated by the rarely found donor–acceptor hydroxy–borane O—H...H—B hydrogen bonds.     

Telaprevir: helical chains based on three‐point hydrogen‐bond connections

The crystal structure of the title compound [systematic name: (1S,3aR,6aS)‐2‐((2S)‐2‐{[(2S)‐2‐cyclohexyl‐2‐(pyrazine‐2‐carbonylamino)acetyl]amino}‐3,3‐dimethylbutanoyl)‐N‐[(3S)‐1‐(cyclopropylamino)‐1,2‐dioxohexan‐3‐yl]‐3,3a,4,5,6,6a‐hexahydro‐1H‐cyclopenta[c]pyrrole‐1‐carboxamide], C₃₆H₅₃N₇O₆, contains two independent molecules, which possess distinct conformations and a disordered cyclopenta[c]pyrrolidine unit. In the crystal, molecules are linked into helical chains via three‐point N—H...O hydrogen‐bond connections in which three NH and three carbonyl groups per molecule are utilized. The chiralities of the six stereocentres per molecule inferred from this study are in agreement with the synthetic procedure.     

Synthesis and chiroptical properties of L‐valine‐containing poly(phenylacetylene)s with (a)chiral pendant terminal groups

Poly(phenylacetylene)s containing L ‐valine residues (P 1 ) with (a)chiral pendant terminal groups R^(*) [?(HC?C{C₆H₄CONHCH[CH(CH₃)₂]COO? R^(*)})_n?]; R^(*) = 1‐octyl (P 1 o), (1S,2R,5S)‐(+)‐menthyl [P 1 (+)], (1R,2S,5R)‐(?)‐menthyl [P 1 (?)] are designed and synthesized. The polymers are prepared by organorhodium catalysts in high yields (yield up to 88%) with high molecular weights (M_w up to ?6.4 × 10⁵). Their structures and properties are characterized by NMR, IR, TGA, UV, and circular dichroism analyses. All the polymers are thermally fairly stable (T_d ≥ 320 °C). The chiral moieties induce the poly(phenylacetylene) chains to helically rotate in a preferred direction. The chirality of the pendant terminal groups affects little the helicity of the polymers but their bulkiness stabilizes the helical conformation against solvent perturbation. The backbone conjugation and chain helicity of the polymers can be modulated continuously and reversibly by acid. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 2117–2129, 2006     

Diastereomeric differentiation of norbornene amino acid peptides by electrospray ionization tandem mass spectrometry

A new class of diastereomeric pairs of non‐natural amino acid peptides derived from butyloxycarbonyl (Boc‐)protected cis‐(2S,3R)‐ and trans‐(2S,3S)‐β‐norbornene amino acids including a monomeric pair have been investigated by electrospray ionization (ESI) tandem mass spectrometry using quadrupole time‐of‐flight (Q‐TOF) and ion‐trap mass spectrometers. The protonated cis‐BocN‐β‐nbaa (2S,3R) (1) (βnbaa = β‐norbornene amino acid) eliminates the Boc group to form [M+H–Boc+H]⁺, whereas an additional ion [M+H–C₄H₈]⁺ is formed from trans‐BocN‐β‐nbaa (2S,3S) (2). Similarly, it is observed that the peptide diastereomers (di‐, tri‐ and tetra‐), with cis‐BocN‐β‐nbaa (2S,3R)‐ at the N‐terminus, initially eliminate the Boc group to form [M+H–Boc+H]⁺ which undergo further fragmentation to give a set of product ions that are different for the peptides with trans‐BocN‐β‐nbaa (2S,3S)‐ at the N‐terminus. Thus the Boc group fragments differently depending on the configuration of the amino acid present at the N‐terminus. It is also observed that the peptide bond cleavage in these peptides is less favoured and most of the product ions are formed due to retro‐Diels‐Alder fragmentation. Interestingly, sodium‐cationized peptide diastereomers mainly yield a series of retro‐Diels‐Alder fragment ions which are different for each diastereomer as they are formed starting from [M+Na–Boc+H]⁺ in peptides with cis‐BocN‐β‐nbaa (2S,3R)‐ at the N‐terminus, and [M+Na–C₄H₈]⁺ in peptides with trans‐BocN‐β‐nbaa (2S,3S)‐ at the N‐terminus. All these results clearly indicate that these diastereomeric pairs of peptides yield characteristic product ions which help distinguish the isomers. Copyright © 2009 John Wiley & Sons, Ltd.     

Enantioselective Synthesis of α‐Hydroxy Amides and β‐Amino Alcohols from α‐Keto Amides

Synthesis of enantiomerically enriched α‐hydroxy amides and β‐amino alcohols has been accomplished by enantioselective reduction of α‐keto amides with hydrosilanes. A series of α‐keto amides were reduced in the presence of chiral Cu^II/(S)‐DTBM‐SEGPHOS catalyst to give the corresponding optically active α‐hydroxy amides with excellent enantioselectivities by using (EtO)₃SiH as a reducing agent. Furthermore, a one‐pot complete reduction of both ketone and amide groups of α‐keto amides has been achieved using the same chiral copper catalyst followed by tetra‐n‐butylammonium fluoride (TBAF) catalyst in presence of (EtO)₃SiH to afford the corresponding chiral β‐amino alcohol derivatives.     

The First Fully Planar C5‐Conformation of Homooligopeptides Prepared from a Chiral α‐Ethylated α,α‐Disubstituted Amino Acid: (S)‐Butylethylglycine (=(2S)‐2‐Amino‐2‐ethylhexanoic Acid)

An optically active α‐ethylated α,α‐disubstituted amino acid, (S)‐butylethylglycine (=(2S)‐2‐amino‐2‐ethylhexanoic acid; (S)‐Beg; (S)‐ 2 ), was prepared starting from butyl ethyl ketone ( 1 ) by the Strecker method and enzymatic kinetic resolution of the racemic amino acid. Homooligopeptides containing (S)‐Beg (up to hexapeptide) were synthesized by conventional solution methods. An ethyl ester was used for the protection at the C‐terminus, and a trifluoroacetyl group was used for the N‐terminus of the peptides. The structures of tri‐ and tetrapeptides 5 and 6 in the solid state were solved by X‐ray crystallographic analysis, and were shown to have a bent planar C₅‐conformation (tripeptide) and a fully planar C₅‐conformation (tetrapeptide) (see Figs. 1 and 2, resp.). The IR and ¹H‐NMR spectra of hexapeptide 8 revealed that the dominant conformation in CDCl₃ solution was also a fully planar C₅‐conformation. These results show for the first time that the preferred conformation of homopeptides containing a chiral α‐ethylated α,α‐disubstituted amino acid is a planar C₅‐conformation.     

Conformational Study of Heteropentapeptides Containing an α‐Ethylated α,α‐Disubstituted Amino Acid: (S)‐Butylethylglycine (=2‐Amino‐2‐ethylhexanoic Acid) within a Sequence of Dimethylglycine (=2‐Aminoisobutyric Acid) Residues

Heteropentapeptides containing the α‐ethylated α,α‐disubstituted amino acid (S)‐butylethylglycine and four dimethylglycine residues, i.e., CF₃CO‐[(S)‐Beg]‐(Aib)₄‐OEt ( 4 ) and CF₃CO‐(Aib)₂‐[(S)‐Beg]‐(Aib)₂‐OEt ( 7 ), were synthesized by conventional solution methods. In the solid state, the preferred conformation of 4 was shown to be both a right‐handed (P) and a left‐handed (M) 3₁₀‐helical structure, and that of 7 was a right‐handed (P) 3₁₀‐helical structure. IR, CD, and ¹H‐NMR spectra revealed that the dominant conformation of both 4 and 7 in solution was the 3₁₀‐helical structure. These conformations were also supported by molecular‐mechanics calculations.     

Characterization,crystal structure and cytotoxic activity of a rare iridoid glycoside from Lonicera saccata

A new iridoid glycoside, methyl (3R,4R,4aS,7S,7aR)‐3‐hydroxy‐7‐methyl‐5‐oxooctahydrocyclopenta[c]pyran‐4‐carboxylate‐3‐O‐β‐d ‐(1′S,2′R,3′S,4′S,5′R)‐glucopyranoside, named loniceroside A, C₁₇H₂₆O₁₀, ( 1 ), was obtained from the aerial parts of Lonicera saccata. Its structure was established based on an analysis of spectroscopic data, including 1D NMR, 2D NMR and HRESIMS, and the configurations of the chiral C atoms were determined by X‐ray crystallographic analysis. The single‐crystal structure reveals that the cyclopenta[c]pyran scaffold is formed from a five‐membered ring and a chair‐like six‐membered ring connected through two bridgehead chiral C atoms. In the solid state, the glucose group of ( 1 ) plays an important role in constructing an unusual supramolecular motif. The structure analysis revealed adjacent molecules linked together through intermolecular O—H…O hydrogen bonds to generate a banded structure. Furthermore, the banded structures are linked into a three‐dimensional network by interesting hydrogen bonds. Biogenetically, compound ( 1 ) carries a glucopyranosyloxy moiety at the C‐3 position, representing a rare structural feature for naturally occurring iridoid glycosides. The growth inhibitory effects against human cervical carcinoma cells (Hela), human lung adenocarcinoma cells (A549), human acute mononuclear granulocyte leukaemia (THP‐1) and the human liver hepatocellular carcinoma cell line (HepG2) were evaluated by the MTT method.     

A Novel 2H‐Azirin‐3‐amine as a Dipeptide (Aib‐Hyp) Synthon

The synthesis of methyl (2S,4R)‐4‐(benzyloxy)‐N‐(2,2‐dimethyl‐2H‐azirin‐3‐yl)prolinate ( 10 ), a novel 2H‐azirin‐3‐amine (`3‐amino‐2H‐azirine'), is described (Scheme 1). The reaction of methyl (2S,4R)‐N‐(2‐methylpropanoyl)‐4‐(benzyloxy)prolinate ( 7 ) with Lawesson reagent gave methyl (2S,4R)‐4‐(benzyloxy)‐N‐[2‐(methylthio)propanoyl]prolinate ( 8 ) and consecutive treatment with COCl₂, 1,4‐diazabicyclo[2.2.2]octane (DABCO), and NaN₃ led to 10 . The use of 10 as a building block of the dipeptide Aib‐Hyp (Aib=2‐aminoisobutyric acid, Hyp=(2S,4R)‐4‐hydroxyproline) is demonstrated by the syntheses of several model peptides (Scheme 2 and Table). The benzyl protecting group of the 4‐OH function in Hyp in the model peptides has been removed in good yields.     

Synthesis,Structural Characterisation and Stereochemical Investigation of Chiral Sulfur‐Functionalised N‐Heterocyclic Carbene Complexes of Palladium and Platinum

Palladium and platinum complexes containing a sulfur‐functionalised N‐heterocyclic carbene (S‐NHC) chelate ligand have been synthesised. The absolute conformations of these novel organometallic S‐NHC chelates were determined by X‐ray structural analyses and solution‐phase 2D ¹H–¹H ROESY NMR spectroscopy. The structural studies revealed that the phenyl substituents on the stereogenic carbon atoms invariably take up the axial positions on the Pd‐C‐S coordination plane to afford a skewed five‐membered ring structure. All of the chiral complexes are structurally rigid and stereochemically locked in a chiral ring conformation that is either (R_s,S,R)‐λ or (S_s,R,R)‐δ in both the solid state and solution.     

New Optically Active 2H‐Azirin‐3‐amines as Synthons for Enantiomerically Pure 2,2‐Disubstituted Glycines: Synthesis of Synthons for Tyr(2Me) and Dopa(2Me), and Their Incorporation into Dipeptides

The synthesis of novel unsymmetrically 2,2‐disubstituted 2H‐azirin‐3‐amines with chiral auxiliary amino groups is described. Chromatographic separation of the mixture of diastereoisomers yielded (1′R,2S)‐ 2a , b and (1′R,2R)‐ 2a , b (c.f. Scheme 1 and Table 1), which are synthons for (S)‐ and (R)‐2‐methyltyrosine and 2‐methyl‐3′,4′‐dihydroxyphenylalanine. Another new synthon 2c , i.e., a synthon for 2‐(azidomethyl)alanine, was prepared but could not be separated into its pure diastereoisomers. The reaction of 2 with thiobenzoic acid, benzoic acid, and the amino acid Fmoc‐Val‐OH yielded the monothiodiamides 11 , the diamides 12 (cf. Scheme 3 and Table 3), and the dipeptides 13 (cf. Scheme 4 and Table 4), respectively. From 13 , each protecting group was removed selectively under standard conditions (cf. Schemes 5–7 and Tables 5–6). The configuration at C(2) of the amino acid derivatives (1R,1′R)‐ 11a , (1R,1′R)‐ 11b , (1S,1′R)‐ 12b , and (1R,1′R)‐ 12b was determined by X‐ray crystallography relative to the known configuration of the chiral auxiliary group.     

Metabolism of Deuterated erythro‐Dihydroxy Fatty Acids in Saccharomyces cerevisiae: Enantioselective Formation and Characterization of Hydroxylactones

Epoxides of fatty acids are hydrolyzed by epoxide hydrolases (EHs) into dihydroxy fatty acids which are of particular interest in the mammalian leukotriene pathway. In the present report, the analysis of the configuration of dihydroxy fatty acids via their respective hydroxylactones is described. In addition, the biotransformation of (±)‐erythro‐7,8‐ and ‐3,4‐dihydroxy fatty acids in the yeast Saccharomyces cerevisiae was characterized by GC/EI‐MS analysis. Biotransformation of chemically synthesized (±)‐erythro‐7,8‐dihydroxy(7,8‐²H₂)tetradecanoic acid ((±)‐erythro‐ 1 ) in the yeast S. cerevisiae resulted in the formation of 5,6‐dihydroxy(5,6‐²H₂)dodecanoic acid ( 6 ), which was lactonized into (5S,6R)‐6‐hydroxy(5,6‐²H₂)dodecano‐5‐lactone ((5S,6R)‐ 4 ) with 86% ee and into erythro‐5‐hydroxy(5,6‐²H₂)dodecano‐6‐lactone (erythro‐ 8 ). Additionally, the α‐ketols 7‐hydroxy‐8‐oxo(7‐²H₁)tetradecanoic acid ( 9a ) and 8‐hydroxy‐7‐oxo(8‐²H₁)tetradecanoic acid ( 9b ) were detected as intermediates. Further metabolism of 6 led to 3,4‐dihydroxy(3,4‐²H₂)decanoic acid ( 2 ) which was lactonized into 3‐hydroxy(3,4‐²H₂)decano‐4‐lactone ( 5 ) with (3R,4S)‐ 5 =88% ee. Chemical synthesis and incubation of (±)‐erythro‐3,4‐dihydroxy(3,4‐²H₂)decanoic acid ((±)‐erythro‐ 2 ) in yeast led to (3S,4R)‐ 5 with 10% ee. No decano‐4‐lactone was formed from the precursors 1 or 2 by yeast. The enantiomers (3S,4R)‐ and (3R,4S)‐3,4‐dihydroxy(3‐²H₁)nonanoic acid ((3S,4R)‐ and (3R,4S)‐ 3 ) were chemically synthesized and comparably degraded by yeast without formation of nonano‐4‐lactone. The major products of the transformation of (3S,4R)‐ and (3R,4S)‐ 3 were (3S,4R)‐ and (3R,4S)‐3‐hydroxy(3‐²H₁)nonano‐4‐lactones ((3S,4R)‐ and (3R,4S)‐ 7 ), respectively. The enantiomers of the hydroxylactones 4, 5 , and 7 were chemically synthesized and their GC‐elution sequence on Lipodex^® E chiral phase was determined.