Facile Preparation of Chiral 1, 3‐Diols via Stereoselective Transfer Hydrogenation of 1, 3‐Diones

Asymmetric reduction of 1, 3‐diones catalyzed by (S, S)‐TsD‐PEN‐Ru(II) complex in a mixture of formic add‐triethylamine proceeded with a substrate/catalyst molar ratio of 100 to give (S, S)‐l,3‐diols with excellent diastereomeric (98.6% de) and enantiomeric purities ( > 99% ee). Other C₂‐symmetric diols were also obtained in almost quantitative yields with high diastereomeric (80.0%‐84.2% de) and enantiomeric purities ( > 99% ee).     

Synthesis of trans‐4‐hydroxy‐L‐proline‐based telechelic prepolymers and poly(ester‐urethane)

The synthesis of hydroxyproline‐based telechelic prepolymers by the condensation polymerization of trans‐4‐hydroxy‐N‐benzyloxycarbonyl‐L ‐proline methyl ester was investigated. All the polymerizations were carried out in the melt with stannous octoate as the catalyst and with different diols. The products were characterized by differential scanning calorimetry, proton nuclear magnetic resonance, infrared spectrophotometry, and inherent viscosity (η_inh). According to the analytic results, the η_inh value of the prepolymers depended on the kind and amount of diols that were added. With an increase in the 1,6‐hexanediol feed from 2 to 10 mol %, there was a decrease in η_inh from 0.78 to 0.41 along with a decrease in the glass‐transition temperature (T_g ) from 63 to 42 °C. When 2 mol % of different kinds of diols were used, η_inh ranged from 0.78 to 0.21, and T_g varied from 70 to 43 °C. These new prepolymers could be linked to poly(ester‐urethane) by the chain extender 1,6‐hexamethylene diisocyanate. The poly(ester‐urethane) was amorphous, and the T_g was 76 °C. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 2449–2455, 2000     

Double Catalytic Kinetic Resolution (DoCKR) of Acyclic anti‐1,3‐Diols: The Additive Horeau Amplification

The concept of a synergistic double catalytic kinetic resolution (DoCKR) as described in this article was successfully applied to racemic acyclic anti ‐1,3‐diols, a common motif in natural products. This process takes advantage of an additive Horeau amplification involving two successive enantioselective organocatalytic acylation reactions, and leads to diesters and recovered diols with high enantiopurities. It was first developed with C ₂‐symmetrical diols and then further extended to non‐C ₂‐symmetrical anti diols to prepare useful chiral building blocks. The protocol is highly practical as it only requires 1 mol % of a commercially available organocatalyst and leads to easily separable products. This procedure was applied to the shortest reported total synthesis of (+)‐cryptocaryalactone, a natural product with anti‐germinative activity.     

Synthesis and examination of antimicrobial properties of aminomethylated derivatives C<Subscript>6</Subscript>–C<Subscript>7</Subscript> of alicyclic diols

Synthesis of C₆–C₇ alicyclic diols was studied by a catalytic oxidation of cyclohexene, norbornene and their methyl derivatives in the presence of heterogenized molybdenum-containing catalysts. By a triple condensation of the diols with formaldehyde and secondary amines a synthesis of their aminomethylated derivatives with various substituents at nitrogen atom was examined. Antimicrobial properties of the synthesized amino alcohols in M-10 oil as additives with fungicidal and bactericidal activities were studied.     

Synthesis and Thermal Properties of Biodegradable Poly(ester‐urethane)s Based on Chemo‐Synthetic Poly[(R,S)‐3‐hydroxybutyrate]

A series of telechelic oligo[(R,S)‐3‐hydroxybutyrate]‐diols (PHB‐diols) was synthesized from ethyl (R,S)‐3‐hydroxybutyrate (ethyl (HB)) and four different aliphatic diols, namely, 1,4‐butanediol, 1,6‐hexanediol, 1,8‐octanediol and 1,10‐decanediol by transesterification and condensation in bulk. The structures of the synthesized oligomers were confirmed by ¹H NMR spectroscopy and MALDI‐TOF mass spectroscopy. The use of 1,4‐butanediol results in an oligoester with hydroxyl functionality of approximately 2. In the case of the higher aliphatic diols, the number average functionalities were found to be lower than 2. These differences were ascribed to side reactions which occur during polymerization, yielding unreactive end groups. Other novel families of biodegradable poly(ester‐urethane)s were synthesized either from PHB‐diol alone, or PHB‐diol mixed with poly(ε‐caprolactone)‐diol (PCL‐diol), poly(butylene adipate)‐diol (PBA‐diol) or poly(diethylene glycol adipate)‐diol (PDEGA‐diol). In each case, 1,6‐hexamethylene diisocyanate was used as a nontoxic connecting agent. The homopolymers prepared from PCL‐diol, PBA‐diol and PDEGA‐diol were also synthesized for the sake of comparison. All the prepared copolymers possess high molecular weight with glass transition temperature (T_g) values varying from –54 to –23°C. Some of the prepared copoly(ester‐urethane)s are partially crystalline with melting temperatures (T_m's) varying from 37 to 56°C.     

Variations of solvent and substitution pattern in Pb(OAc)4 mediated domino reactions

The effect of solvent on oxidative cleavage of the Hajos–Parrish ketone derived hydrindene–diols 1, and Wieland–Miescher ketone derived octaline–diols 2 with Pb(OAc)₄ is presented. Various solvents were screened and compared for these domino reactions. Changing the solvent influenced the reaction rate, product distribution, and chemical yield in the octalin–diol series, while no-effect was detected in the lower homologue hydrindene–diol series. The use of a cheap, readily available chiral carboxylic acid, such as (S)-2-acetoxypropionic acid gave diastereomeric mixtures when performed in the racemic series, offering the potential of a chemical resolution. The influence of the substitution pattern on the substrate was also investigated on variously substituted derivatives of 1. Diols 38 failed to give any detectable amount of IMDA type ring closure, leading only to dialdehyde 39. For the compounds studied, alkyl or carboxyalkyl substituents on the olefin 41 and 44 led to incomplete cascade transformation due to steric interference caused by the alkyl or acyl groups. The oxidative cleavage of unsaturated diols 46 and 48 derived from monocyclic precursors, used as templates to determine whether any unsaturated 1,2-diol could be regarded as a substrate, is also described.     

Water as an efficient medium for the synthesis of tetrahydro-β-carbolines via Pictet-Spengler reactions

A mild and efficient protocol for the Pictet-Spengler reaction in water using an acid catalyst has been described. The condensation of tryptophan, tryptamine, and N_b-benzyl tryptophan with different aldehydes having both electron-withdrawing and -donating substituents in the presence of a catalytic amount of TFA in water furnished tetrahydro-β-carbolines in good isolated yields. A salient feature of the water mediated Pictet-Spengler reaction was the general trend observed during the condensation of Trp-OMe and aryl/aliphatic aldehydes furnishing diastereomeric mixtures with a preference for the cis-isomer.     

Synthesis of meta‐Functionalized Pyridines by Selective Dehydrogenative Heterocondensation of β‐ and γ‐Amino Alcohols

New reactions that convert alcohols into important classes of compounds are becoming increasingly important as their development contributes to the conservation of our fossil carbon feedstock and the reduction of CO₂ emissions. Two key catalytic alcohol conversion concepts are borrowing hydrogen or hydrogen autotransfer and acceptorless dehydrogenative condensation. Herein, we combined both concepts to synthesize meta ‐functionalized pyridines. First, diols and amines were linked to β‐amino alcohols, which can then undergo a selective dehydrogenative heterocondensation with γ‐amino alcohols. Iridium catalysts stabilized by PN₅P pincer ligands that were developed in our laboratory mediate the reactions most efficiently. All of the 3‐aminopyridines that we describe in this paper have been synthesized for the first time, emphasizing the degree of innovation of this method and the problems associated with the synthesis of such meta ‐functionalized pyridines.     

Asymmetric Strecker synthesis of enantiopure 2,4-ethanothreonines

The second generation asymmetric synthesis reported herein proceeds via a Strecker reaction of chiral ketimines, obtained from the condensation of racemic 2-methoxycyclopentanone and (S)- and (R)-1-phenylethylamine. In the key stereodifferentiating step, the cyanide addition leads to mixtures of diastereomeric nitriles, the composition of which dramatically changes under the influence of protic and aprotic solvents. Hydrolysis of the nitriles to carboxamides with concd H₂SO₄ yielded diastereomeric mixtures of carboxamides each of which was hydrogenolysed and hydrolysed after separation to the four stereoisomers of the 1-amino-2-methoxy- and 1-amino-2-hydroxy-cyclopentanecarboxylic acid. Their stereochemistry was established by NMR methods and by X-ray analyses of the trans as well as the cis configured compounds.     

Sensitive RP-HPLC Enantioseparation of (<Emphasis Type="Italic">RS</Emphasis>)-Ketamine via Chiral Derivatization Based on (<Emphasis Type="Italic">S</Emphasis>)-Levofloxacin

Enantioseparation of (RS)-ketamine has been achieved in the form of its diastereomeric hydrazones. A new chiral reagent was synthesized from enantiomerically pure (S)-levofloxacin by converting its carboxyl group into a hydrazide derivative: the reagent provided a reaction site for the ketonic group present in (RS)-ketamine. Because of the structural feature of the chiral reagent formation of diastereomeric hydrazones of (RS)-ketamine was successful without protection of its amino group. The diastereomeric hydrazones were separated on a reversed-phase C₁₈ column with a mobile phase consisting of MeCN and 0.1% TFA under gradient elution from 35 to 65% of MeCN. The limit of detection was found to be 3.2 and 3.4 nmol for first and second eluting diastereomeric hydrazones, respectively. The separation mechanism and elution order of the diastereomeric hydrazones were proposed and supported by developing the geometry optimized ‘lowest energy’ structures of the two diastereomeric hydrazones using DFT-based Gaussian software.     

Synthesis and Biological Activity of 7,8,9‐Trideoxy‐ and 7R DesTHP‐Peloruside A

The stereoselective syntheses of 7,8,9‐trideoxypeloruside A ( 4 ) and a monocyclic peloruside A analogue lacking the entire tetrahydropyran moiety ( 3 ) are described. The syntheses proceeded through the PMB‐ether of an ω‐hydroxy β‐keto aldehyde as a common intermediate which was elaborated into a pair of diastereomeric 1,3‐syn and ‐anti diols by stereoselective Duthaler–Hafner allylations and subsequent 1,3‐syn or anti reduction. One of these isomers was further converted into a tetrahydropyran derivative in a high‐yielding Prins reaction, to provide the precursor for bicyclic analogue 4 . Downstream steps for both syntheses included the substrate‐controlled addition of a vinyl lithium intermediate to an aldehyde, thus connecting the peloruside side chain to C15 (C13) of the macrocyclic core structure in a fully stereoselective fashion. In the case of monocyclic 3 macrocyclization was based on ring‐closing olefin metathesis (RCM), while bicyclic 4 was cyclized through Yamaguchi‐type macrolactonization. The macrolactonization step was surprisingly difficult and was accompanied by extensive cyclic dimer formation. Peloruside A analogues 3 and 4 inhibited the proliferation of human cancer cell lines in vitro with micromolar and sub‐micromolar IC₅₀ values, respectively. The higher potency of 4 highlights the importance of the bicyclic core structure of peloruside A for nM biological activity.     

Reactions stereoselectives des alkylmagnesiens secondaires avec les anhydrides et lactones rigides

High stereoselectivity was observed in the reactions of secondary alkylmagnesium compounds with bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride $\text{1}$ and lactone 2 leading respectively to the formation of $\text{trans}$ diastereomeric lactones and $\text{erythro}$ primary-secondary diols.     

Asymmetric Hydrogenation of α-Hydroxy Ketones: A Reaction Sensitive toward Electronic Effect of Substrates

以[RuCl2(benzene)]2 和 SunPhos为原料现场制备的催化剂,催化不对称氢化α-羟基酮类化合物可获得手性1, 2-二醇类化合物,ee值最高达99%。     

A supramolecular ladder motif in 2‐(2,2,6,6‐tetra­methyl­piperidin‐1‐yl­oxy)­propane‐1,3‐diol

An O—H⋯O hydrogen‐bonded step‐ladder motif was observed in the crystal structure of the title compound, C₁₂H₂₅NO₃. The ladder arrangement is typical of 1,2‐ and 1,3‐diols with a synclinal orientation of the diol functionality.     

Asymmetric syntheses with r-α -hydroxypropionaldehyde : Temperature dependence of the diastereomeric product ratio

In an effort to test the applicability of the semi-empirical model for asymmetric induction⁵ to reactions of α-hydroxycarbonyl compounds, we monitored the diastereomeric ratio of diols obtained from the reactions of R-α-hydroxypropionaldehyde with LAH, MeLi and PhLi as a function of temperature and reagent concentration. In all these reactions the predominant diastereomer had the RR-configuration. However, whereas the diastereomeric product ratio of the first two reactions was enthalpy controlled, i.e. enthalpy favored the “correct” or predominant diastereomer, that of the reaction involving PhLi favored the “incorrect”, or minor diastereomer. In this reaction the diastereomeric ratio was entropy controlled. The usefulness and limitations of this model are discussed.     

Asymmetric Synthesis of Bicyclic Diol Derivatives through Metal and Enzyme Catalysis: Application to the Formal Synthesis of Sertraline

Enzyme‐ and ruthenium‐catalyzed dynamic kinetic asymmetric transformation (DYKAT) of bicyclic diols to their diacetates was highly enantio‐ and diastereoselective to give the corresponding diacetates in high yield with high enantioselectivity (99.9 % ee). The enantiomerically pure diols are accessible by simple hydrolysis (NaOH, MeOH), but an alternative enzyme‐catalyzed ester cleavage was also used to give the trans‐diol (R,R)‐ 1 b in extremely high diastereomeric purity (trans/cis=99.9:0.1, >99.9 % ee). It was demonstrated that the diols can be selectively oxidized to the ketoalcohols in a ruthenium‐catalyzed Oppenauer‐type reaction. A formal enantioselective synthesis of sertraline from a simple racemic cis/trans diol 1 b was demonstrated.     

Synthesis of Chiral Cyclohexenones from α-Campholenic,Fencholenic, and β-Campholenic Derivatives

Summary. Optically active dimethylcyclohexenones, potential building blocks for enantioselective syntheses of various naturally active substances, were prepared. These compounds were obtained by oxidation with KMnO₄/Pb(OAc)₄ or ozonolysis of the corresponding cyclopentenic precursors, followed by aldol condensation. During the course of the preparation intermediate diols and chiral polyfunctional carbonyl derivatives were separated and identified analytically.     

Gold(I)‐Catalyzed Enantioselective Desymmetrization of 1,3‐Diols through Intramolecular Hydroalkoxylation of Allenes

A gold(I)‐catalyzed enantioselective desymmetrization of 1,3‐diols was achieved by intramolecular hydroalkoxylation of allenes. The catalyst system 3‐F‐dppe(AuCl)₂ /(R)‐C₈‐TRIPAg proved to be specifically efficient to promote the desymmetrizing cyclization of 2‐aryl‐1,3‐diols, which have proven challenging substrates in previous reports. Multisubstituted tetrahydrofurans were prepared in good yield with good enantioselectivity and diastereoselectivity by this method.     

A Mild and Highly Efficient Synthesis of Chiral N‐Dichloroacetyl‐4‐ethyl‐1,3‐oxazolidines

Chiral 2‐amino‐butanols ( 4 and 5 ) were obtained via the isolation of diastereomeric salt. Then, chiral compounds ( 6 – 9) were synthesized by a sequential procedure involving condensation of chiral 2‐amino‐butanol with ketone and dichloroacetyl chloride. All the compounds were characterized by IR, ¹H NMR, ¹³C NMR, and element analysis. The absolute configurations of ( S )‐ 8 was determined by X‐ray crystallography.     

Bestimmung des Chiralitätssinns der enantiomeren 2,6-Adamantandiole

Determination of the Chirality Sense of the Enantiomeric 2,6-Adamantanediols The enantiomers of 2,6-adamantanediol ( 1 ) are resolved via the diastereoisomeric camphanoates. The (2R,6R)-chirality sense for (?)- 1 and (2S,6S) for (+)- 1 was determined by chemical correlation with (?)-(1R,5R)-bicyclo[3.3.1]nonan-2,6-dion ((1R,5R)- 3 ) of known absolute configuration in the following way: alkylation of the bis(pyrrolidine enamine) of (?)-(1R,5R)- 3 with CD₂I₂ and hydrolysis of the product gives the enantiomer 4 of (4,4-D₂)-2,6-adamantanedione. Reduction of 4 with LiAlH₄ leads to one enantiomer (Scheme 2) of each of the three diols 5 – 7 of known absolute configuration. The three diols are themselves configurational isomers due to the presence of the CD₂ group, but correspond otherwise entirely to the enantiomeric diols 1 . Accordingly, they can also be separated by means of their diastereoisomeric camphanoates to give the diols 5 / 6 and 7 . These samples are easily distinguished and identified by their characteristic ¹H-NMR spectra (cf. Fig. 2). This allows to identify the (2R,6R)- and (2S,6S)-enantiomer of 1 on the basis of their behavior in the resolution experiment analogous to that of the diols 5 / 6 and 7 , respectively. The diol (?)- 1 must have the (2R,6R)-configuration because it forms, like the diols 5 / 6 , with (?)-camphanic acid the diastereoisomeric ester less soluble in benzene. The diol (+)- 1 has (2S,6S)-configuration, because it forms, like 7 , with (+)-camphanic acid the diastereoisomeric ester less soluble in benzene. The bis(4-methoxybenzoate) of (?)-(2R,6R)- 1 shows chiroptical properties which are in accordance with Nakanishi's rule for two chromophores having coupled electric dipol transition moments arranged with a left-handed torsion angle.