Enantiomerically pure chiral pyridino-crown ethers: synthesis and enantioselectivity toward the enantiomers of α-(1-naphthyl)ethylammonium perchlorate

Seven new enantiomerically pure chiral pyridino-crown ethers (S,S)-4–(R,R)-10 were prepared. Three of them [(S,S)-4, (S,S)-7 and (R,R)-10] contain one, and two of them [(S,S)-5 and (S,S)-8] contain two linker chains with a terminal double bond. These linker chains were connected to the carbon atom at position 9 (opposite the pyridine moiety) of the macrocycle. The terminal double bond of the linker makes it possible to attach these ligands to silica gel to obtain chiral stationary phases (CSPs). The enantioselectivity of the new ligands toward the enantiomers of α-(1-naphthyl)ethylammonium perchlorate (NEA) was also determined by a titration ¹H NMR method.     

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.     

Effects of reaction temperature and acyl group for lipase-catalyzed chiral binaphthol synthesis

Candida antarctica lipase-catalyzed hydrolysis of O-butyryl-BINOL [(±)-3] or O-butyryl-6,6′-dibromo-BINOL [(±)-5] yielded optically active BINOL [(R)-1] or 6,6′-dibromo-BINOL [(R)-4] with high enantiomeric excess at 80 °C. Reaction temperature and acyl group of substrate had a great influence on the reactivity and enantioselectivity, respectively, of lipase-catalyzed hydrolysis for chiral binaphthol synthesis.     

Enantiomerically pure chiral phenazino-crown ethers: synthesis,preliminary circular dichroism spectroscopic studies and complexes with the enantiomers of 1-arethyl ammonium salts

Enantiomerically pure chiral crown ethers containing the phenazine unit [(R,R)-2–(S,S)-8] were prepared by two types of cyclization reactions. Ligands (R,R)-2, (R,R)-3, (S,S)-4, (R,R)-5, (R,R)-6 and (R,R)-7 were prepared from phenazine-1,9-diol 9 and the appropriate ditosylates (S,S)-10–(S,S)-15 in weak basic conditions with complete inversion of configuration. Ligands (S,S)-2, (S,S)-7 and (S,S)-8, however, were prepared from 1,9-dichlorophenazine 19 and the appropriate diols (S,S)-16–(S,S)-18 in strong basic conditions with retention of configuration. Enantiomeric recognition of most of the chiral ligands with α-(1-naphthyl)ethylammonium perchlorate (NEA) and α-phenylethylammonium perchlorate (PEA) has been studied by CD spectroscopy.     

A novel dynamic kinetic resolution accompanied by intramolecular transesterification: asymmetric synthesis of a 4-hydroxymethyl-2-oxazolidinone from serinol derivatives

Reaction paths of the one-pot reaction of (R)-2-(α-methylbenzyl)amino-1,3-propanediol (1) and 2-chloroethyl chloroformate with DBU giving (4S,αR)-4-hydroxymethyl-3-(α-methylbenzyl)-2-oxazolidinone [(4S)-2] (94% de) were investigated. Intermediates of this reaction, 2-chloroethyl (2S)- and 2-chloroethyl (2R)-3-hydroxy-2-[(αR)-α-methylbenzyl]aminopropyl carbonates [(2S)-4 and (2R)-4], were synthesized individually. After the addition of DBU to the respective solution of the carbonate (2S)-4 and that of (2R)-4 in dichloromethane, the intramolecular transesterification between (2S)-4 and (2R)-4 and the diastereoselective intramolecular cyclization proceeded to afford (4S)-2 in high diastereomeric excess. Therefore, two monocarbonates (2S)-4 and (2R)-4 were kinetically resolved by this cyclization during the intramolecular transesterification between (2S)-4 and (2R)-4. We found that this process involved dynamic kinetic resolution accompanied by intramolecular transesterification.     

Non-classical control of solid-state aggregation-induced enhanced circularly polarized luminescence in chiral perylene diimides

Organic fluorescent molecules are gaining importance because of their potential applications in many devices. Optically active N,N′-bis((1R)-1-naphthylethyl)perylene-3,4,9,10-tetracarboxylic diimide [(R,R)-1-BNP] and N,N′-bis((1R)-2-naphthylethyl)perylene-3,4,9,10-tetracarboxylic diimide [(R,R)-2-BNP] and their antipode, [(S,S)-1-BNP and (S,S)-2-BNP], emit aggregation-induced enhanced (AIEnh) circularly polarized luminescence (CPL) on both a solid organic polymer film (poly(methyl methacrylate)) and solid inorganic KBr pellet. An opposite chirality is essential for generating CPL of inverted sign. However, a pair of enantiomeric organic molecules may not always be easy to prepare. Interestingly, the chiral perylene fluorophores synthesized in this study can emit both positive and negative AIEnh-CPL in the solid state, depending on their position on the naphthylene groups. In addition, no CPL was observed in these compounds from their dilute solutions.     

Substrate engineering: Effects of different N-protecting groups in the CAL-B-catalysed asymmetric O-acylation of 1-hydroxymethyl-tetrahydro-β-carbolines

In the frame of substrate engineering, the steric effect of different N-protecting groups on the enantioselectivity and reaction rate of CAL-B-catalysed (S)-selective O-acylation of N-protected 1-hydroxymethyl-tetrahydro-β-carbolines was investigated. Excellent enantioselectivities (E?>?200) were observed when the acylation of N-Boc [(±)-1], N-Cbz [(±)-3], and N-Fmoc-protected [(±)-4] substrates was performed with the use of CAL-B and acetic anhydride in toluene at 60?°C. The resolution of N-acetyl-protected substrate (±)-2 showed excellent E (>200) after 30?min, but as the reaction progressed, E started decreasing after 2 days, because of N→O and O→N acyl migrations. Preparative resolutions of (±)-3 and (±)-4 resulted in unreacted amino alcohols (R)-3 and (R)-4 and esters (S)-7a and (S)-8a with good enantiomeric excesses (≥88%) and high yields (≥44%).     

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.     

Different recognitions of (E)- and (Z)-1,1′-binaphthyl ketoximes using lipase-catalyzed reactions

Lipase-catalyzed hydrolysis of (E)-2-[α-(acetoxyimino)benzyl]-1,1′-binaphthyl [(±)-1a] and (Z)-2-[α-(acetoxyimino)benzyl]-1,1′-binaphthyl [(±)-1b] yielded optically active (E)-2-[α-(hydroxyimino)benzyl]-1,1′-binaphthyl [(S)-2a] and (Z)-2-[α-(hydroxyimino)benzyl]-1,1′-binaphthyl [(R)-2b], respectively, with high enantiomeric excess. Selectivity for the opposite enantiomer of the axial binaphthyl skeleton was shown by (Z)-isomer 1b against (E)-isomer 1a.     

Syntheses of pyridin-4-ylium chirons: applications in a synthesis of (+)-coniine

The compounds (3R,5S)-(+)-5-methyl-3-phenyl-2,3,5,6,7,8-hexahydro-oxazolo[3,2-a]pyridin-4-ylium iodide 4 and (3R,5S)-(+)-5-n-propyl-3-phenyl-2,3,5,6,7,8-hexahydro-oxazolo[3,2-a]pyridin-4-ylium iodide 5 were synthesized in two steps starting from the bicyclic thiolactam trans (3R,2aS)-(−)-5-thio-3-phenyl-2,3,6,7,8,2a-hexahydro-oxazolo[3,2-a]pyridine 1. In addition, starting from 5 an enantiospecific synthesis of (+)-coniine 7 was achieved.     

Insight into the mechanism of diazocompounds transformation catalyzed by hetero cuboidal clusters [Mo3CuQ4(MeBPE)3X4]+, (Q = S,Se; X = Cl,Br): The catalytically active species

Two enantiomerically pure trinuclear compounds of formula (P)-[Mo₃S₄{(R,R)-Me–BPE}₃Br₃]Br and (P)-[Mo₃Se₄{(R,R)-Me–BPE}₃Cl₃]Cl, (P)-1b.Br and (P)-1c.Cl, respectively, have been synthesized in a good yield and a stereospecific manner by excision of polymeric [Mo₃Q₇X₄]_n (Q = S or Se, X = Cl or Br) phases with (R,R)-Me–BPE{1,2-bis[(2R,5R)-2,5-(dimethylphospholan-1-yl)]ethane}. They have been transformed into chiral hetereo cuboidal compounds [Mo₃S₄{(R,R)-Me–BPE}₃Br₃]PF₆, (P)-2b.PF₆, and [Mo₃Se₄{(R,R)-Me–BPE}₃Cl₃]PF₆, (P)-2c.PF₆, by reaction with copper salts. All these compounds have been characterized by ³¹P NMR, IR, UV–Vis, mass spectrometry, elemental analysis, and chiral dichroism. The catalytic potential of tetranuclear cuboidal compounds has been assessed in the paradigm intermolecular cyclopropanation reaction of styrene with ethyl diazoacetate. Results are compared with those obtained for the analogue [Mo₃S₄{(R,R)-Me–BPE}₃Cl₃]PF₆, (P)-2a.PF₆. The catalytic data demonstrate that the Se derivative (P)-2c.PF₆ is less reactive than the S analogues, but it leads to a similar product distribution as the sulfide analogue (P)-2a.PF₆. By contrast, exchange of chlorine by the bulky bromine gives rise to a catalyst which makes the carbene dimerization more competitive. These data agree with temporal breaking of one of the Cu–Q bonds to generate an active catalytic species.     

Synthesis of modified H4-BINOL ligands and their applications in the asymmetric addition of diethylzinc to aromatic aldehydes

Two new ligands (S,S)-3-(1,1′-bi-2-naphthol-3-yl)-5,6,7,8-tetrahydro-1,1′-bi-2-naphthol [(S,S)-1] and (S)-3-(morpholin-4-ylmethyl)-H₄-BINOL [(S)-2] have been synthesized via Suzuki cross-coupling reaction and a Mannich-type reaction, respectively. In the presence of titanium tetraisopropoxide, 0.8 mol % of ligand (S,S)-1 catalyzed the asymmetric addition of diethylzinc to aromatic aldehydes in good yield and with high enantioselectivity.     

Effect of the alkyl chain length of 1,1′-binaphthyl esters in lipase-catalyzed amidation

Lipase-catalyzed amidation of 2-[2-(ethoxycarbonyl)ethyl]-1,1′-binaphthyl [(±)-3] yielded optically active (S)-3 and 2-[2-(2-cyanoethylaminocarbonyl)ethyl]-1,1′-binaphthyl [(R)-6a] with high enantiomeric excess. For these lipase-catalyzed amidations, the optimal alkyl chain length between the binaphthyl ring and the ester group was determined to be an ethylene spacer.     

Photoinduced electron transfer-initiated asymmetric cyclization of N-benzoyl-α-dehydronaphthylalanine alkyl esters carrying chiral and bulky auxiliaries

The irradiation of the title compounds [(Z)-1] having (S)-(+)-sec-butyl, (−)-mentyl and related chiral auxiliaries in methanol and 1,2-dichloroethane containing 2-(diethylamino)ethanol afforded chiral auxiliary-substituted (4S,5S)-, (4R,5R)-, (4R,5S)- and (4S,5R)-4,5-dihydrooxazole derivatives (2) along with (E)-1. It was found that the photoinduced electron transfer-initiated cyclization of 1 gives either of the two diastereomers for cis-2 and trans-2 in diastereomeric excess whose value varies from 6% to 81% depending on solvent and chiral auxiliary.     

Total synthesis of (4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles F

Total synthesis of (4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles F 3 was achieved from the chiral bithiazole-type primary alcohols [(S)- and (R)-4-ethoxycarbonyl-2′-(1-hydroxymethylethyl)-2,4′-bithiazoles 8], which were obtained based on the enzymatic resolution of racemic alcohol 8 and its acetate 9. From a direct comparison by means of chiral HPLC between natural cystothiazole F 3 and synthetic compounds [(4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles 3], natural cystothiazole F 3 was found to be a 33:67 diastereomeric mixture [(4R,5S,6E,14S)-3:(4R,5S,6E,14R)-3 = 33:67].     

Synthesis of (3′R,5′S)-3′-hydroxycotinine using 1,3-dipolar cycloaddition of a nitrone

To synthesize (3′R,5′S)-3′-hydroxycotinine [(+)-1], the main metabolite of nicotine (2), cycloaddition of C-(3-pyridyl)nitrones 3a, 3c, and 15 with (2R)- and (2S)-N-(acryloyl)bornane-10,2-sultam [(2R)- and (2S)-8] was examined. Among them, l-gulose-derived nitrone 15 underwent stereoselective cycloaddition with (2S)-8 to afford cycloadduct 16, which was elaborated to (+)-1.     

Total synthesis of the 5-epimers of naturally occurring (−)-hyacinthacine A5 and unnatural (+)-hyacinthacine A4

(1R,2S,3R,5S,7aR)-1,2-Dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine 10 [(+)-5-epihyacinthacine A₅] and (1R,2S,3R,5S,7aS)-1,2-dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine 17 [ent-5-epihyacinthacine A₄] have been synthesized by either Horner–Wadsworth–Emmons (HWE) or Wittig methodology using aldehydes 6 and 13, prepared from (2R,3S,4R,5R)-3,4-dibenzyloxy-N-benzyloxycarbonyl-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine 5 (partially protected DALDP) and (2R,3S,4R,5S)-3,4-dibenzyloxy-N-benzyloxycarbonyl-2,5-bis(hydroxymethyl)-2′-O-pivaloylpyrrolidine 12 (partially protected DGADP), respectively, and the appropriated ylide, followed by cyclization through an internal reductive amination process of the corresponding intermediate pyrrolidinic ketones 7 and 14 and subsequent deprotection.     

Stereoisomeric bis(phenylglycinol)malonamide gelators: rare examples of gelling meso-compounds

Gelation of malonamides was investigated for the first time. Bis(phenylglycinol)malonamide 1, and methyl-, dimethyl-, ethyl-, diethyl- and isopropylmalonamides 2, 3, 4, 5 and 6, respectively, exhibited profoundly different gelling properties. Monoalkyl malonamides are efficient organogelators, and their gelling properties strongly depend on their stereochemistry. In contrast, symmetrically substituted dialkymalonamides, that is, (R,R)-dimethylmalonamide 3 and (R,R)-diethylmalonamide 5 as well as the unsubstituted 1 lack any gelation ability. Methyl derivative (R,R)-2 is an excellent, and its ethyl analogue (R,R)-4 a moderate gelator of toluene, p-xylene and tetralin while the isopropyl derivative (R,R)-6 shows only very weak gelation of tetralin and some more polar solvents. Meso diastereoisomers (R,r,S)-2 and (R,s,S)-2, as well as (R,r,S)-4 and (R,s,S)-4), each possessing a pseudoasymmetric centre represent very rare examples of gelling meso-compounds. The racemate 4 (rac-4) showed more efficient gelation of some solvents than the pure enantiomer (R,R)-4, while rac-2 failed to gel any of the solvents which were efficiently gelled by (R,R)-2.     

Reactions of a hydrido(hydrosilylene)tungsten complex with oxiranes

Reactivity of a hydrido(hydrosilylene)tungsten complex, Cp¹(CO)₂(H)WSi(H)[C(SiMe₃)₃] (1), toward oxiranes was investigated. Treatment of 1 with racemic mono-substituted oxiranes with a substituent R (R = Ph, vinyl, ^tBu, or ⁿBu) at room temperature produced dihydrido(vinyloxysilyl)tungsten complexes, (E)- and/or (Z)-Cp¹(CO)₂(H)₂W{Si(H)(OCHCHR)[C(SiMe₃)₃]} [(E/Z)-2: R = Ph, (E)-3: R = vinyl, (E)-4: R = ^tBu, (E/Z)-5: R = ⁿBu] in high yields via regioselective ring-opening of oxiranes. When the substituent R on oxirane was relatively large, (E)-isomers (2, 3, and 4) were obtained predominantly (87–97%), while the substituent was a relatively small ⁿBu group, an approximately 1:1 mixture of (E)- and (Z)-isomers [(E/Z)-5] was obtained. Reaction of 1 with 2,2-dimethyloxirane afforded the corresponding complex, Cp¹(CO)₂(H)₂W{Si(H)(OCHCMe₂)[C(SiMe₃)₃]} (6), quantitatively. A reaction mechanism is also discussed.     

Polyhydroxylated pyrrolizidines. Part 4: Total asymmetric synthesis of unnatural hyacinthacines from a protected derivative of DGDP

(1R,2R,3S,5R,7aR)-1,2-Dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine [(+)-3-epi-hyacinthacine A₃] 1 and (1R,2R,3S,7aR)-1,2-dihydroxy-3-hydroxymethylpyrrolizidine [(+)-3-epi-hyacinthacine A₂] 2 have been synthesized by Wittig's methodology using aldehyde 6, prepared from (2R,3R,4R,5S)-3,4-dibenzyloxy-N-benzyloxycarbonyl-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl) pyrrolidine 3 (a partially protected DGDP), and the appropriated ylides, followed by cyclization through an internal reductive amination process of the resulting α,β-unsaturated ketone 7 and aldehyde 8, respectively, and total deprotection.