Lipase mediated enantiomer and diastereomer separation of 2,2′-[1,2- and 1,3-phenylenebis(oxy)]dicyclohexanols

Separation of diastereomeric and enantiomeric mixtures of 2,2′-[1,2- and 1,3-phenylenebis(oxy)]dicyclohexanols rac-3a and meso-3a, and rac-3b and meso-3b—resulting from the reactions of pyrocatechol 1a and resorcinol 1b with cyclohexene oxide 2—were performed using acetylation catalyzed by the highly stereoselective Candida antarctica lipase B (Novozym 435). The absolute configurations of the resulting diols (S,S,S,S)-3a,b, monoacetates (R,R,S,S)-4a,b and diacetates (R,R,R,R)-5a,b were assigned on the basis of the steric analogy to the acetylation of racemic trans-2-phenoxycyclohexanol rac-6 with the same enzyme resulting in the known acetate (−)-(R,R)-7.     

Masked constrained cysteines: diastereoselective and enantioselective synthesis of 1-amino-2-mercaptocyclopropanecarboxylic acid derivatives

A diastereoselective and enantioselective synthesis of (Z)-1-benzoylamino-2-tritylsulfanylcyclopropanecarboxylic acid derivatives 8a,b and 9a,b was achieved starting from (−)- or (+)-menthyl 2-benzoylamino-3-tritylsulfanylacrylates 3a,b. Compounds 3 were reacted with diazomethane giving the corresponding pyrazolines 4a,b and 5a,b. These compounds, on melting, were transformed, under steric control, into the cyclopropaneamino acid derivatives (R,R)-8a,b and (S,S)-9a,b. The synthesis of a large class of chiral 2-S-alkyl-1-aminocyclopropanecarboxylic acid derivatives is possible after removing the trityl protecting group and subsequent alkylation reactions.     

Traceless chirality transfer from a norbornene β-amino acid to pyrimido[2,1-a]isoindole enantiomers

The synthesis of two enantiomeric pairs of pyrimidoisoindoles 9a, 9b and 10a, 10b is reported. During a domino ring-closure reaction, followed by cycloreversion, the chirality of diendo-(?)-(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide [(?)-1] was successfully transfered to heterocycles (+)-9a, (+)-10a, (?)-9b, (?)-10b and (?)-10c.     

Perhydro-1,3-benzoxazines derived from (−)-8-aminomenthol as ligands for the catalytic enantioselective addition of diethylzinc to aldehydes

The catalytic potency of a series of perhydro-1,3-benzoxazines prepared from (?)-8-aminomenthol was examined in the enantioselective addition of diethylzinc to aldehydes. When (2R,3S,3aS,4aR,6R,8aS)-2-isopropyl-6,9,9-trimethyl-3-phenyldecahydro-4aH-pyrrolo[2,1-b][1,3]benzoxazin-3-ol 7b was used as a chiral ligand, 1-substituted propanols with an (R)-configuration were obtained in high yields and enantiomeric excesses up to >99%. The catalyst can be recovered and used without any loss in its activity.     

Reactions of β-substituted amines-IV: Kinetics and stereochemistry of the thermal to (r) 3-chloro-1-ethylpiperidine,and the stereo-chemical course of their reactions with nucleophiles

The rate of the thermal rearrangement of (S) 2 chloromethyl-1-ethylpyrrolidine [(S)-1a] to (R)-3-chloro-1-ethylpiperidine [(R) 2a] has been examined at three temperatures in benzene by PMR and polarimetry. The rearrangement was shown to be completely stereospecific and to obey a simple first order rate law. The calculated E_a ΔH3 and ΔS3 were 22 ± 2 $\text{kcal}\text{mole}$ (25°), 21 ± 2.5 $\text{kcal}\text{mole}$ (25°) and - 10 ± 2 e.u. (0°K) respectively. The effect of solvents having differing dielectric constants was also studied. A transition state 9'a and an ion pair intermediate 3a are suggested for the rearrangement. The stereochemical course of the reactions of (S)-1a, (R)-2a and (S)-2a with hydroxide and methoxide ions have been shown to be 100% stereospecific with an uncertainty of about 1%. The absolute configurations of all optically active reactants and products [(S)- and (R)-4a, (S)-4b (R)- and (S)-5a, (R)-5b, (S,S')-6a, (S,R')-7a and (R,R')-8a] were established by chemical correlations with known compounds or by ORD and chemical inference. The ring opening of both the primary and secondary aziridinium ion positions of 1-azonia-1-ethylbicyclo [3.1.0]hexane [(S)-3a] by nucleophiles proceeds entirely by S_N2 processes. The conversion of (R)-1-ethyl-3-hydroxypiperidine [(R)-5a] to (S)-2a. HCl with thionyl chloride in chloroform proceeds by inversion with 4.8% racemization, whereas the thermal rearrangement of (S)-1a to (R)-2a occurs with complete retention of absolute configuration.     

Enzymatic desymmetrization of meso cis-2,6- and cis,cis-2,4,6-substituted piperidines. Chemoenzymatic synthesis of (5S,9S)-(+)-indolizidine 209D

The stereoselective acylation of meso piperidines 3a,b by vinyl acetate (solvent and acyl donor) in the presence of Candida antarctica lipase gave the corresponding (2S,6R) and (2S,4R,6R) monoesters 2a,b in high enantiomeric purity. (5S,9S)-(+)-Indolizidine 209D was prepared in eight steps from (2S,6R)-2a.     

Synthesis of novel β-amino alcohols and their application in the catalytic asymmetric sulfoxidation of sulfides

Novel chiral norephedrine-based β-amino alcohol ligands containing a thiophene ring were prepared from norephedrine and substituted furan carbaldehydes (methyl- or ethyl-substituted) and used in combination with VO(acac)₂ for the asymmetric oxidation of aryl methyl sulfides using H₂O₂ as an oxidant. Amino alcohol derived Schiff bases 4,5a–b gave higher enantiomeric excesses than amino alcohol-derived reduced Schiff based ligands 6,7a–b. Of these chiral ligands, (1S,2R)-5b and (1S,2R)-7b gave high yields (90%) with moderate to high enantioselectivities (78%, 96% ee, respectively). The oxidation of other aryl methyl sulfides with (1S,2R)-5b and (1S,2R)-7b as ligands afforded the corresponding sulfoxides in 60–89% yields and with 92–99% ee.     

Reduced collagen cross links: the first synthesis of all the possible (2S,2′S)-stereoisomers of 5-hydroxylysinonorleucine and of 5,5′-dihydroxylysinonorleucine in enantiomerically pure form

The paper reports the first enantioselective synthesis of all the possible collagen reduced cross links as described: (2S,2′S,5R)- and (2S,2′S,5S)-5-hydroxylysinonorleucine 3a and 3b, (2S,2′S,5R,5′R)-5,5′-dihydroxylysinonorleucine 4a, (2S,2′S,5R,5′S)-5,5′-dihydroxylysinonorleucine 4b and (2S,2′S,5S,5′S)-5,5′-dihydroxylysinonorleucine 4c. The Williams’ glycine template methodology was used both for the introduction of a stereogenic at the α-position and for an easy protection of the amino acidic functionalities during the synthesis of the dimeric amino acids.     

Synthesis and evaluation of new chiral diols based on the dicyclopentadiene skeleton

The resolution by Lipase PS of rac-5 (from reduction of ketone 6, obtained from dicyclopentadiene with a new environment-friendly synthesis) gives (2S)-5, which was further reduced to the endo(2R)-1a alcohol. The endo(2S)-1b alcohol was obtained from camphor with a multistep synthesis. Pinacol couplings of 3a,b, carried out with Mg/Hg or Corey's general procedure respectively, afforded with high diastereoselectivity the C₂ symmetry diols (2R,2′R)-2a and (2S,2′S)-2b, with endo oriented OH functions. The enantiogenic power of the endo alcohol (2R)-1a and (2S)-1b and of the diols (2R,2′R)-2a and (2S,2′S)-2b was tested towards the LiAlH₄ reduction of acetophenone. The C₂ symmetry appears to play a fundamental role.     

Synthesis of trihydroxy quinolizidine alkaloids: 1,3-addition reaction of allylmagnesium bromide to a sugar nitrone

The synthesis of (1R,2R,3S,9aR) and (1R,2R,3S,9aS) trihydroxy quinolizidine alkaloids 3a and 3b from d-glucose derived nitrone 4 is described. The key transformation involves the 1,3-addition of allylmagnesium bromide to nitrone 4 that afforded high diastereoselectivity in the presence of TMSOTf. The N-O bond reductive cleavage, N-Cbz protection, ozonolysis, Wittig olefination, lactum formation and reductive amination cascade afforded the target compounds 3a and 3b in good overall yield.     

Complementary kinetic and thermodynamic resolution of a chiral biaryl axis

The condensation of 2′-formylbiphenyl-2-carboxylic acid 4 with (S)-valinol proceeds under kinetic control to give a major product, (4bR,7S,aS)-6,7-dihydro-7-isopropyldibenz[c,e]oxazolo[3,2-a]azepin-9(4bH)-one 6a (84%), in which the biaryl axis has the (S)-configuration. Heating 6a at 140°C with a catalytic amount of acid gives rise to an equilibrium dominated by the diastereoisomeric (4bS,7S)-lactam 6b (6a:6b ratio 27:73), in which the biaryl unit has the (R)-configuration. The structures of both lactams were established by X-ray crystallography; no other diastereoisomers were obtained.     

Lipase-catalyzed synthesis of a tri-substituted cyclopropyl chiral synthon: a practical method for preparation of chiral 1-alkoxycarbonyl-2-oxo-3-oxabicyclo[3.1.0]hexane

An efficient method for the preparation of optically active enantiomers of 1-ethoxycarbonyl-2-oxo-3-oxabicyclo[3.1.0]hexane 1 has been developed. Treatment of 1 with lipase Amano PS gave (1S,5R)-1-carboxy-2-oxo-3-oxabicyclo[3.1.0]hexane 4a which was converted to (1S,5R)-1-ethoxycarbonyl-2-oxo-3-oxabicyclo[3.1.0]hexane 1a with high enantiomeric purity (98.0% ee, 75% yield), while the (1R,5S)-lactone ester 1b remained intact. A simple procedure for the recovery of 4a from the reaction mixture was also established.     

Preparation of enantiomerically pure (1S,2S)-1-aminocyclopropanephosphonic acid from methylcyclopropanone acetal via spirophosphonate intermediates

An easy and efficient one-pot reaction from readily available methylcyclopropanone acetal (2S)-4b gave the spirophosphonates 8a–b with excellent diastereoselectivity. These phosphonates, after catalytic hydrogenolysis and hydrolysis, furnished the enantiomerically pure (1S,2S)-1-amino-2-methylcyclopropanephosphonic acid 3b (analogue of (1R,2S)-allo-norcoronamic acid).     

Advanced procedure for the enzymatic ring opening of unsaturated alicyclic β-lactams

Enantiopure β-amino acids 1a–4a and β-lactams 1b–4b were prepared simultaneously through the lipolase-catalysed enantioselective ring opening of unsaturated racemic β-lactams (±)-1-(±)-4. High enantioselectivities (E>200) were observed when the reactions were performed with 1 equiv of water in iPr₂O at 70 °C. The resolved (1R,2S)-amino acids (yield⩾45%) and (1S,5R)-, (1S,6R)- and (1S,8R)-lactams (yield⩾47%) could be easily separated. The ring opening of lactam enantiomers 1b–4b with 18% HCl afforded the corresponding β-amino acid hydrochlorides 1c·HCl–4c·HCl (ee >95%).     

Preparation of (1R,8S)- and (1S,8R)-9-azabicyclo[6.2.0]dec-4-en-10-one: potential starting compounds for the synthesis of anatoxin-a

9-Azabicyclo[6.2.0]dec-4-en-10-one (±)-2, obtained from cyclooctadiene by addition of chlorosulfonyl isocyanate, was N-hydroxymethylated to (±)-3 and then resolved by lipase-catalysed asymmetric acylation of the primary OH group at the (S)-stereogenic centre. High enantioselectivity (E=94) was observed when lipase PS and vinyl butyrate were used in di-iso-propyl ether at −15°C, resulting in the enantiomerically enriched ester 3a and alcohol 3b (e.e. ≥92%). Treatment of 3a and 3b with NH₄OH/MeOH afforded the corresponding β-lactams (1R,8S)-2a and (1S,8R)-2b (e.e. ≥93%), potential starting compounds in anatoxin-a synthesis. The ring opening of lactams (±)-2, (±)-7, 3a and 3b, followed by reduction, resulted in racemic 4–6 and 8 and enantiomeric 4a, 4b, 5a and 5b eight-membered cyclic β-amino acid derivatives.     

Stereocontrolled synthesis of enantiomerically pure unsaturated analogues of 2,6-DAP. Part 5

An efficient new stereocontrolled synthesis of (2R,6R)-(+)- and (2S,6S)-(−)-2,6-diamino-4-methylene-1,7-heptanedioic acid 8a and 9a, respectively, has been accomplished starting from the glycine-derived chiral synthon 1. The enantiomerically pure α-alkyl derivatives 8b–d and 9b–d have also been synthesized. The absolute configuration of the new stereocenters was assigned on the basis of ¹H NMR spectra.     

Synthese von (5,10)-(7,8)-Bisepoxiden aus α- und β-4-Phenyl-1,2,4-triazolin-3,5-dion-Addukten von Vitamin D3 und Röntgenstrukturanalyse eines der Benzoylderivate

Oxidation of the α- and β-4-phenyl-1,2,4-triazolin-3,5-dione adducts of vitamin D₃ (2 and1) withMCPBA yields two diastereomeric mixtures of the (5,10)-(7,8)-dioxiranes3 a,3 b,3 c and4 a,4 b respectively. The corresponding benzoates5 a,5 b,6 a and6 b were prepared and the X-ray crystal structure of5 b was determined. This analysis proved5 b to be the (5R, 1 OS)-(7R, 8R)-dioxirane of the β-resp. (6S)-4-phenyl-1,2,4-triazolin-3,5-dione adduct1 of vitamin D₃.     

Concise and practical synthesis of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6-iminosugars

The syntheses of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6 iminosugars 1a and 1b, respectively, from d-glucose are described. The key transformations in this reaction sequence include regio-selective epoxide ring opening with N-benzylamine followed by intramolecular reductive amination of amino-aldehyde.     

The absolute configuration of the palmarumycins C9, C10, and C12 by quantum-mechanical calculations of CD spectra

The absolute configurations of the palmarumycins C₉ 1a, C₁₀ 2, and C₁₂ 3 were assigned by comparison of the quantum-mechanically calculated with the experimental CD spectra as (2R,3S,4aS,8aR), (2R,3R,4S,4aS,8aR), and (2R,3R,4R), respectively.     

Polyhydroxylated pyrrolizidines. Part 8. Enantiospecific synthesis of looking-glass analogues of hyacinthacine A5 from DADP

(1R,2S,3S,5R,7aR)-1,2-Dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine[(−)-3-epihyacinthacine A₅, 1a] and (1S,2R,3R,5S 7aS)-1,2-dihydroxy-3-hydroxymethylpyrrolizidine[(+)-3-epihyacinthacine A₅, 1b] have been synthesized either by Wittig's or Horner-Wadsworth-Emmond's (HWE's) methodology using aldehydes 4 and 9, both prepared from (2S,3S,4R,5R)-3,4-dibenzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (2, partially protected DADP), and the appropriate ylides, followed by cyclization through an internal reductive amination process of the resulting α,β-unsaturated ketones 5 and 10, respectively, and total deprotection.