Synthesis of poly(lactide‐ran‐MOHEL) and its biodegradation with proteinase K

Homopoly(L ‐lactide) and homopoly(D,L ‐lactide) were almost inert for biodegradation with tricine buffer or normal enzymes such as bromelain, pronase, and cholesterol esterase but biodegradable with proteinase K. Significantly enhanced biodegradation was observed when an optically active (R)‐ or (S)‐3‐methyl‐4‐oxa‐6‐hexanolide (MOHEL) unit was introduced into poly(L ‐lactide) [poly(L ‐LA)] or poly(D,L ‐lactide) [poly(D,L ‐LA)] sequences. Poly[L ‐LA‐ran‐(R)‐MOHEL] in molar ratios of 86/14 to 43/57 showed good biodegradability that was independent of crystallinity. The biodegradation of polymers with proteinase K increased in the following order: poly[D,L ‐LA‐ran‐(R)‐MOHEL] > poly[L ‐LA‐ran‐(R)‐MOHEL] > poly[D,L ‐LA‐ran‐(S)‐MOHEL] > poly[L ‐LA‐ran‐(S)‐MOHEL] > poly(R)‐MOHEL > poly(D,L ‐LA). The number‐average molecular weight, molecular weight distribution, glass‐transition temperature, and melting temperature did not change before and after the biodegradation of poly[L ‐LA‐ran‐(R)‐MOHEL], indicating that the degradation occurred from the polymer surface. © 2001 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 1374–1381, 2001     

Mixed Oligoureas Based on Constrained Bicyclic and Acyclic β‐Amino Acids Derivatives: On the Significance of the Subunit Configuration for Folding

The combination of a non‐functionalized constrained bicyclo[2.2.2]octane motif along with urea linkages allowed the formation of a highly rigid 2.5_12/14 helical system both in solution and the solid state. In this work, we aimed at developing stable and functionalized systems as promising materials for biological applications in investigating the impact of this constrained motif and its configuration on homo and heterochiral mixed‐oligourea helix formation. Di‐, tetra‐, hexa‐, and octa‐oligoureas alternating the highly constrained bicyclic motif of (R) or (S) configuration with acyclic (S)‐β³‐amino acid derivatives were constructed. Circular dichroism (CD), NMR experiments, and the X‐ray crystal structure of the octamer unequivocally proved that the alternating heterochiral R/S sequences form a stable left‐handed 2.5‐helix in contrast to the mixed (S/S)‐oligoureas, which did not adopt any defined secondary structure. We observed that the (?)‐synclinal conformation around the C_α? C_β bond of the acyclic residues, although sterically less favorable than the (+)‐synclinal conformation, was imposed by the (R)‐bicyclic amino carbamoyl (BAC) residue. This highlighted the strong ability of the BAC residue to drive helical folding in heterochiral compounds. The role of the stereochemistry of the BAC unit was assessed and a model was proposed to explain the misfolding of the S/S sequences.     

Determination of Absolute Configuration of Decipinone,a Diterpenoid Ester with a Myrsinane‐Type Carbon Skeleton,by NMR Spectroscopy

The absolute configuration of decipinone ( 2 ), a myrsinane‐type diterpene ester previously isolated from Euphorbia decipiens, has been determined by NMR study of its axially chiral derivatives (aR)‐ and (aS)‐N‐hydroxy‐2′‐methoxy‐1,1′‐binaphthalene‐2‐carboximidoyl chloride ((aR)‐MBCC ( 3a ) and (aS)‐MBCC ( 3b )). The absolute configurations at C(7) and C(13) of 2 determined were (R) and (S), respectively. Therefore, considering the relative configuration of 2 , the absolute configuration determined was (2S,3S,4R,5R,6R,7R,11S,12R,13S,15R).     

Stereocontrol of the Schiff Base of Substituted Benzaldehyde to Staudinger Cycloaddition Reaction

Syntheses of 4 novel chiral azetidin-2-one derivatives,which were characterized by ^1H NMR,IR,specific rotation and elemental analysis,through Staudinger cycloaddition reaction of Schiff base of benzaldehyde with chlorine substitution at different position in benzene ring,were described.For the first time,this type of 3S,4R configuration azetidin-2-one monocrystals with many chiral centers [(3S,4R)-3-hydroxy-N-[(S)-(1-phenyl)ethyl]-4-(2‘‘-chlorophenyl)-azetidin-2-one monocrystal]were obtained,the structures of which were determined by X-ray diffraction analysis.The effects of Schiff base of benzaldehyde with chlorine substitution at different position in benzene ring on stereoselectivity of Staudinger cycloaddition reaction products were discussed and the results are showed as below:2-chlorophenyl Schiff base favored to yield 3S,4R configuration product,but 4-chlorophenyl Schiff base favored to yield 3R,4S configuration product.The reaction orientation of 2,4-dichlorophenyl Schiff base was determined by corporate effect of 2- and 4-chlorine,and that of the 4-chlorine was more obvious.In contrast to 4-chlorophenyl,although the main product was 3R,4S configuration,3-chlorophenyl owned lower selectivity.     

Identification of (6R)‐5,6,7,8‐Tetrahydro‐D‐monapterin (=(6R)‐2‐Amino‐5,6,7,8‐tetrahydro‐6‐[(1R,2R)‐1,2,3 ‐trihydroxypropyl]pteridin‐4(3H)‐one) as the Native Pteridine in Tetrahymena pyriformis

The structure of the native pteridine in Tetrahymena pyriformis was determined as (6R)‐5,6,7,8‐tetrahydro‐D ‐monapterin (=(6R)‐2‐amino‐5,6,7,8‐tetrahydro‐6‐[(1R,2R)‐1,2,3‐trihydroxypropyl]pteridin‐4(3H)‐one; 4 ). First, the configuration of the 1,2,3‐trihydroxypropyl side chain was confirmed as D ‐threo by the fluorescence‐detected circular dichroism (FDCD) spectrum of its aromatic pterin derivative 2 obtained by I₂ oxidation (Fig. 1). The configuration at the 6‐position of 4 was determined as (R) by comparison of its hexaacetyl derivative 6 with authentic (6R)‐ and (6S)‐hexaacetyl‐5,6,7,8‐tetrahydro‐D ‐monapterins 6 and 7 , respectively, in the HPLC, LC/MS, and LC‐MS/MS (Figs. 3 – 6). (6R)‐5,6,7,8‐Tetrahydro‐D ‐monapterin ( 4 ) is a newly discovered natural tetrahydropterin.     

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).     

Reaction of Optically Active Oxiranes with Thiofenchone and 1‐Methylpyrrolidine‐2‐thione: Formation of 1,3‐Oxathiolanes and Thiiranes

The SnCl₄‐catalyzed reaction of (?)‐thiofenchone (=1,3,3‐trimethylbicyclo[2.2.1]heptane‐2‐thione; 10 ) with (R)‐2‐phenyloxirane ((R)‐ 11 ) in anhydrous CH₂Cl₂ at ?60° led to two spirocyclic, stereoisomeric 4‐phenyl‐1,3‐oxathiolanes 12 and 13 via a regioselective ring enlargement, in accordance with previously reported reactions of oxiranes with thioketones (Scheme 3). The structure and configuration of the major isomer 12 were determined by X‐ray crystallography. On the other hand, the reaction of 1‐methylpyrrolidine‐2‐thione ( 14a ) with (R)‐ 11 yielded stereoselectively (S)‐2‐phenylthiirane ((S)‐ 15 ) in 56% yield and 87–93% ee, together with 1‐methylpyrrolidin‐2‐one ( 14b ). This transformation occurs via an S_N2‐type attack of the S‐atom at C(2) of the aryl‐substituted oxirane and, therefore, with inversion of the configuration (Scheme 4). The analogous reaction of 14a with (R)‐2‐{[(triphenylmethyl)oxy]methyl}oxirane ((R)‐ 16b ) led to the corresponding (R)‐configured thiirane (R)‐ 17b (Scheme 5); its structure and configuration were also determined by X‐ray crystallography. A mechanism via initial ring opening by attack at C(3) of the alkyl‐substituted oxirane, with retention of the configuration, and subsequent decomposition of the formed 1,3‐oxathiolane with inversion of the configuration is proposed (Scheme 5).     

New Optically Active 2H‐Azirin‐3‐amines as Synthons for Enantiomerically Pure 2,2‐Disubstituted Glycines

The synthesis of novel 2,2‐disubstituted 2H‐azirin‐3‐amines with a chiral amino group is described. Chromatographic separation of the diastereoisomer mixture yielded the pure diastereoisomers (1′R,2R)‐ 4a – e and (1′R,2S)‐ 4a – e (Scheme 1, Table 1), which are synthons for the (R)‐ and (S)‐isomers of isovaline, 2‐methylvaline, 2‐cyclopentylalanine, 2‐methylleucine, and 2‐(methyl)phenylalanine, respectively. The configuration at C(2) of the synthons was determined by X‐ray crystallography relative to the known configuration of the chiral auxiliary group. The reaction of 4 with thiobenzoic acid, benzoic acid, and the dipeptide Z‐Leu‐Aib‐OH ( 12 ) yielded the monothiodiamides 10 , the diamides 11 (Scheme 2, Table 3), and the tripeptides 13 (Scheme 3, Table 4), respectively.     

Chiral Salan Aluminium Ethyl Complexes and Their Application in Lactide Polymerization

Synthetic routes to aluminium ethyl complexes supported by chiral tetradentate phenoxyamine (salan‐type) ligands [Al(OC₆H₂(R‐6‐R‐4)CH₂)₂{CH₃N(C₆H₁₀)NCH₃}‐C₂H₅] ( 4 , 7 : R=H; 5 , 8 : R=Cl; 6 , 9 : R=CH₃) are reported. Enantiomerically pure salan ligands 1–3 with (R,R) configurations at their cyclohexane rings afforded the complexes 4 , 5 , and 6 as mixtures of two diastereoisomers ( a and b ). Each diastereoisomer a was, as determined by X‐ray analysis, monomeric with a five‐coordinated aluminium central core in the solid state, adopting a cis‐(O,O) and cis‐(Me,Me) ligand geometry. From the results of variable‐temperature (VT) ¹H NMR in the temperature range of 220–335 K, ¹H–¹H NOESY at 220 K, and diffusion‐ordered spectroscopy (DOSY), it is concluded that each diastereoisomer b is also monomeric with a five‐coordinated aluminium central core. The geometry is intermediate between square pyramidal with a cis‐(O,O), trans‐(Me,Me) ligand disposition and trigonal bipyramidal with a trans‐(O,O) and trans‐(Me,Me) disposition. A slow exchange between these two geometries at 220 K was indicated by ¹H–¹H NOESY NMR. In the presence of propan‐2‐ol as an initiator, enantiomerically pure (R,R) complexes 4 – 6 and their racemic mixtures 7 – 9 were efficient catalysts in the ring‐opening polymerization of lactide (LA). Polylactide materials ranging from isotactically biased (P_m up to 0.66) to medium heterotactic (P_r up to 0.73) were obtained from rac‐lactide, and syndiotactically biased polylactide (P_r up to 0.70) from meso‐lactide. Kinetic studies revealed that the polymerization of (S,S)‐LA in the presence of 4 /propan‐2‐ol had a much higher polymerization rate than (R,R)‐LA polymerization (k_SS/k_RR=10.1).     

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 Synthesis of (+)‐Gracilamine Based on an Oxidative Phenolic Coupling Reaction and Determination of Its Absolute Configuration

The enantioselective total synthesis of (+)‐gracilamine ( 1 ) is described. The strategy features a diastereoselective phenolic coupling reaction followed by a regioselective intramolecular aza‐Michael reaction to construct the ABCE ring system. The configuration at C3a in 1 was controlled by the stereocenter at C9a, which was selectively generated (91 % ee) by an organocatalytic enantioselective aza‐Friedel–Crafts reaction developed by our research group. This synthesis revealed that the absolute configuration of (+)‐gracilamine is 3aR, 4S, 5S, 6R, 7aS, 8R, 9aS.     

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.     

Catalytic Asymmetric Total Synthesis of Leucinostatin A

This review describes our efforts toward achieving catalytic asymmetric total synthesis of leucinostatin A, a compound that interferes with the tumor‐stroma interaction. The synthesis utilizes four catalytic asymmetric reactions, including direct‐type reactions exemplified by high atom‐economy, and three C?C bond forming reactions. Thorough analysis of the NMR data, HPLC profiles, and biologic activity led us to unambiguously revise the absolute configuration regarding the 6‐position of the AHMOD residue side chain from S (reported) to R. Other examples of previously reported important studies on the stereoselective synthesis of HyLeu and AHMOD are also described.     

Confirmation of the Absolute (3R,3′S,6′R)‐Configuration of (all‐E)‐3′‐Epilutein

Circular dichroism (CD) spectroscopy was used to distinguish between the isomeric (all‐E)‐configured 3′‐epilutein ( 2 ) and 6′‐epilutein ( 8 ) to establish the absolute configuration of epilutein samples of different (natural and semisynthetic) origin, including samples of 2 obtained from thermally processed sorrel. Thus, the CD data of lutein ( 1 ) and epilutein samples ( 2 ) were compared. Our results unambiguously confirmed the (3R,3′S,6′R)‐configuration of all epilutein samples. Compound 2 was thoroughly characterized, and its ¹³C‐NMR data are published herewith for the first time.     

A Highly Efficient Synthesis of Optically Active Ferrocenylethylamines via Hydride Reduction of Chiral Ferrocenylketimines

Due to using (R)‐ or (S)‐α‐methylbenzylamine as a chiral auxiliary, and low‐temperature regime for reduction of the intermediate ferrocenyl‐mono‐ or 1,1′‐bis‐ketimines, the corresponding secondary mono‐ or 1,1′‐bis‐amines were prepared with high diastereoselectivity. Removal of the α‐methylbenzyl group afforded the optically active primary mono‐ and bis‐ferrocenylethylamines in high yields. The absolute configuration of (R,R)‐ 3a and (S,S)‐ 3b was determined by X‐ray single crystal diffraction.     

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.     

Determination of the Absolute Configuration of (−)‐Mirtazapine by Vibrational Circular Dichroism

The absolute configuration of the (−)‐enantiomer of mirtazapine was determined by means of vibrational circular dichroism (VCD). The observed VCD of (−)‐mirtazapine showed excellent correlation with the calculated VCD of the (R)‐enantiomer. This is in agreement with the absolute configuration as determined by independent synthesis starting from (R)‐phenylglycine.     

Reaction of Elemol with Acetic Acid/Perchloric Acid: Characterization of a Novel Oxide and (+)‐β‐Cyperone

The minor unidentified compounds of the acetic acid/perchloric acid dehydration of elemol ( 1 ) were fully characterized. The structure and relative configuration of the less polar fragrant compound 2 , named elemoxide, was deduced by 1D‐ and 2D‐NMR data including C,C‐connectivity, NOE, and NOESY experiments. The absolute configuration was established as (3S,3aR,7aR)‐1,3,3a,4,7,7a‐hexahydro‐6‐isopropyl‐1,1,3,3a‐tetramethylisobenzofuran ( 2 ) on the basis of its preparation from elemol ( 1 ). (+)‐β‐cyperone ( 3 ), a known sesquiterpene, was also identified as a minor product of the reaction. A plausible mechanistic explanation for the formation of elemoxide ( 2 ) and (+)‐β‐cyperone ( 3 ) is presented.     

双功能手性联萘酚配体在炔基锌对醛的不对称加成反应选择性能研究

单体2-溴吡啶, 2-溴-5-甲基吡啶, 2-氯-4-氟吡啶, 2-氯-3-三氟甲基吡啶分别与( R )-3,3′-二硼酸-2,2′-二甲氧基-1,1′-联萘 [( R )-2]在钯催化下, 通过Suzuki交叉耦合反应合成得到四个类似手性化合物( R )-3a-d。将它们应用到炔基锌对醛的不对称催化加成反应中,结果表明( R )-3a和( R )-3b的催化效果不好, 而( R )-3d只对脂肪醛有很好的催化效果,( R )-3c则对这类不对称催化反应均有很好的催化效果, 能给出高达95%的收率和99%的选择性结果。结果还表明所产生相应炔丙醇异构体构型为S,这与手性催化剂构型相反。     

Secondary Interactions or Ligand Scrambling? Subtle Steric Effects Govern the Iridium(I) Coordination Chemistry of Phosphoramidite Ligands

The like and unlike isomers of phosphoramidite (P*) ligands are found to react differently with iridium(I), which is a key to explaining the apparently inconsistent results obtained by us and other research groups in a variety of catalytic reactions. Thus, the unlike diastereoisomer (aR,S,S)‐[IrCl(cod)( 1 a )] ( 2 a ; cod=1,5‐cyclooctadiene, 1 a =(aR,S,S)‐(1,1′‐binaphthalene)‐2,2′‐diyl bis(1‐phenylethyl)phosphoramidite) forms, upon chloride abstraction, the monosubstituted complex (aR,S,S)‐[Ir(cod)(1,2‐η‐ 1 a ,κP)]⁺ ( 3 a ), which contains a chelating P* ligand that features an η² interaction between a dangling phenyl group and iridium. Under analogous conditions, the like analogue (aR,R,R)‐ 1 a′ gives the disubstituted species (aR,R,R)‐[Ir(cod)( 1 a′ ,κP)₂]⁺ ( 4 a′ ) with monodentate P* ligands. The structure of 3 a was assessed by a combination of X‐ray and NMR spectroscopic studies, which indicate that it is the configuration of the binaphthol moiety (and not that of the dangling benzyl N groups) that determines the configuration of the complex. The effect of the relative configuration of the P* ligand on its iridium(I) coordination chemistry is discussed in the context of our preliminary catalytic results and of apparently random results obtained by other groups in the iridium(I)‐catalyzed asymmetric allylic alkylation of allylic acetates and in rhodium(I)‐catalyzed asymmetric cycloaddition reactions. Further studies with the unlike ligand (aS,R,R)‐(1,1′‐binaphthalene)‐2,2′‐diyl bis{[1‐(1‐naphthalene‐1‐yl)ethyl]phosphoramidite} ( 1 b ) showed a yet different coordination mode, that is, the η⁴‐arene–metal interaction in (aS,R,R)‐[Ir(cod)(1,2,3,4‐η‐ 1 b ,κP)]⁺ ( 3 b ).