Mixture Of Diastereoisomers Research Articles

Pirouetting in chiral [2]catenanes

AbstractOne of the best known classes of mechanically interlocked molecules is the category of [2]catenanes, which exhibit donor‐acceptor interactions between the 1,5‐dioxynaphthalene (DNP) units in a crown ether and the bipyridinium units in the tetracationic cyclophane, cyclobis(paraquat‐p‐phenylene) (CBPQT4+). In order to gain an in‐depth understanding and appreciation of the stereochemistry and dynamic behavior of these [2]catenanes, chiral analogues—having both the DNP ring, which is capable of displaying planar chirality, and the axially chiral binaphthol (BINAP) moiety (as both enantiomers and as the racemic modification), in a crown ether, in addition to the CBPQT4+ cyclophane—have been synthesized using a template‐directed protocol. Dynamic 1H NMR spectroscopy shows that (i) the presence of immutable axial chirality, arising from the BINAP moiety in the crown ether component, leads to no induction of diastereoselectivity—the chiral catenanes exist as a mixture of diastereoisomers in solution at low temperatures in the approximate ratio of 1:1, (ii) the barrier (ΔGcD̊) to the interconversion between these two diastereoisomers is 7.9 ± 0.1 kcal mol−1 at 171 K, and (iii) no induction of diastereoselectivity is observed upon the addition of a chiral solvating agent to the chrial catenanes. The pattern of behavior in the variable temperature 1H NMR spectra and the low ΔTGcD̊ value indicates that the dynamic process involving the interconversion between these two diastereoisomers is one of a pirouetting nature. Of the four possible diastereoisomers, only two, (R)‐(pR/pS) or (S)‐(pR/pS), are shown to exist in solution.

Oxidation von Methylpiperidin-Derivaten unter Berücksichtigung der Chiralität / Oxidation of Methylpiperidine Derivatives with Regard to Chirality

When 2-(2-methyl-1-piperidinyl)ethanol derivatives 3a and 3b were dehydrogenated with Hg(II)- EDTA, an iminium function involving the tertiary α-carbon atom of the piperidine ring is formed regioselectively. Cyclization of these intermediates yielded diastereomeric mixtures of oxazolidines 7a and 7b, in solutions of which hydroxy-enamine species 8a/9a and 8b/9b, respectively, could be detected by NMR spectroscopy. A hydroxy-enamine derived from 7a could be trapped by cycloaddition to tetrazine 10. Protonation of the oxazolidines generated the iminium salts 6a/6b・X with loss of a chirality center. For prevention of different directions of ring dehydrogenation in the 2-(3-methyl- 1-piperidinyl)ethanol compounds, the 6-position was blocked with two methyl groups. With amino alcohol 17, the isolation of one of the racemates in pure form was achieved, which by dehydrogenation produced a diastereoisomeric lactam mixture 18, as shown by NMR spectroscopy. Reaction of 2-(4-methyl-1-piperidinyl)ethanol 19 with Hg(II)-EDTA gave rise to a diastereomeric lactam mixture 21 in the ratio 60 : 40. From enantiomerically pure phenyloxiranes, the amino alcohols R(-)-19 and S(+)-19 became available. Their dehydrogenation under standardized conditions always showed a spreading range of isomeric lactams, which could not be separated.

Condensation of Quinolin‐6‐amine with 5‐(p‐Methoxyphenyl)cyclohexane‐1,3‐dione and Substituted Benzaldehydes.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Coniferin dimerisation in lignan biosynthesis in flax cells

[ 13C 2]-Coniferin was provided to a flax ( Linum usitatissimum L.) cell suspension to monitor subsequent dimerisation by MS and NMR. The label was mainly incorporated into a 8–8′-linked lignan, lariciresinol diglucoside, a 8–5′-linked neolignan, dehydrodiconiferyl alcohol glucoside and a diastereoisomeric mixture of a 8- O-4′-linked neolignan, guaiacylglycerol-β-coniferyl alcohol ether glucoside. This latter compound is reported for the first time in flax. The strong and transient increase in these compounds in fed cells was concomitant with the observed peak in coniferin content. These results suggest (i) a rapid metabolisation of coniferin into lignans and neolignans and indicate the capacity of flax cells to operate different types of couplings, and (ii) a continuous synthesis and subsequent metabolisation of coniferin-derived dimers all over the culture period.

Solvent-Controlled Stereoselective Formation of a Cyclic Ether in the Lewis Acid-Mediated Allylation of an α-Chloroacetoxy Acyclic Ether. Very High Stereoselectivity in CH3CN vs Low Stereoselectivity in CH2Cl2

The MgBr2.OEt2-mediated intramolecular allylation of a 4:1 diastereoisomeric mixture of the alpha-chloroacetoxyl ether 1a bearing the A-G/JK ring system of brevetoxin B in CH2Cl2 gave a 1:1 diastereoisomeric mixture of the trans- and cis-cyclization products 4a and 5a having the A-G/I-K ring system, while that in CH3CN afforded the trans-isomer 4a nearly as the single product. To help clarify a reason for this marked solvent effect in the cyclization of the brevetoxin B precursor, DFT computations for the starting materials, intermediates, transition states, and products were carried out. The cyclization would proceed through a carbocation intermediate 3a having sp2 flat structure (SN1 type mechanism) in CH2Cl2, in which the activation energies leading to both diastereoisomers are approximately identical, while in CH3CN alkylnitrilium salts 6a would be formed through the coordination of CH3CN to the carbocation leading to an sp3-type intermediate in which sever steric hindrance takes place in the transition state leading to the undesired diastereoisomer. The scope of this novel solvent-controlled stereoselectivity was tested for simple compounds. In small model compounds the marked solvent dependence was absent, but the model bearing two consecutive cyclic ether rings 1b exhibited a remarkable solvent effect similar to that observed in the brevetoxin B system.

Linear versus Angular Fischer Indole Annulation: Relative Configuration Determines Regioselectivity

AbstractFischer indole synthesis with bicyclic ketones yields regioselectively linear annulated tetracyclic products when starting from ketones with a relative trans configuration. On the other hand, starting materials with a relative cis configuration give exclusively angular annulated indole derivatives. The starting materials were prepared in optically active form in three steps by a sequence of asymmetric Michael reaction, aldol condensation, and catalytic hydrogenation. The last step yields a mixture of cis and trans diastereoisomers which can be separated by column chromatography. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Hantzsch-Type Three-Component Approach to a New Family of Carbon-Linked Glycosyl Amino Acids. Synthesis of C-Glycosylmethyl Pyridylalanines,

C-Glycosylmethyl pyridylalanines reported in this paper constitute a novel family of glycosyl amino acids that contain a pyridine ring linking the carbohydrate and amino acid residues. These amino acids may serve to prepare nonnatural glycopeptides displaying firmly bound carbohydrate fragments through a rigid and highly stable tether. A viable route to these new hybrid molecules has been opened via thermally induced Hantzsch-type cyclocondensation using an aldehyde-ketoester-enamino ester system. To one of these reagents was attached a C-glycosyl residue, while to another was bound an amino acid fragment. In a one-pot optimized methodology, the dihydropyridine was not isolated while its purification was carried out by removal of unreacted material and side products using polymer-supported scavengers. Then the dihydropyridine (mixture of diastereoisomers) was oxidized by a polymer-bound oxidant to give the target pyridine bearing the two bioactive residues. In this way a range of eight compounds (58-68% yield) was prepared in which the elements of diversity were (i) the gluco and galacto configurations of the pyranose ring, (ii) the alpha- and beta-configurations at the anomeric center, and (iii) the positions of the carbohydrate and amino acid sectors in the pyridine ring. The orthogonal functional group protection in these amino acids allowed their easy incorporation into oligopeptides via sequential amino and carboxylic group coupling.

Glycosidic juvenogens: Derivatives bearing α,β-unsaturated ester functionalities

A series of the protected alkyl glycosides 5a/ 5b– 12a/ 12b was synthesized from the parent isomeric alcohols (insect juvenile hormone bioanalogs; juvenoids), 4-[4′-(2″-hydroxycyclohexyl)methylphenoxy]-3-methyl-but-2-enoic acid ethyl ester ( 1a/ 1b– 4a/ 4b; racemic structures) and ( 1a– 4a; enantiopure structures). Cadmium carbonate was used as a promoter of this Koenigs–Knorr reaction, and the products were obtained in 82–92% yields. Deprotection of the carbohydrate functionality of 5a/ 5b– 12a/ 12b was carefully performed using ethanolysis in the presence of zinc acetate, due to the presence of another ester functionality in the aglycone part of the molecule of protected alkyl glycosides. Resulting alkyl glycosides 13a/ 13b– 20a/ 20b (diastereoisomeric mixtures) and 13a– 20a (enantiopure compounds), biochemically activated hormonogenic compounds (juvenogens), were obtained in 82–93% yields. Finally, chiral HPLC separation of the diastereoisomeric mixtures of alkyl glycosides was applied to get sufficient quantities of the respective enantiomers 13b– 20b of the alkyl glycosides for their structure elucidation and 13C chemical shift assignment by 1H and 13C NMR spectroscopy. Partial introductory entomological screening tests of the target alkyl glycosides 13a/ 13b– 20a/ 20b were performed on the red firebug ( Pyrrhocoris apterus). The results of this biological testing clearly demonstrated the time-extended effect of several juvenogens on P. apterus due to their biochemical activation, i.e., hydrolysis of the juvenogen molecule, which results in liberation of the biologically active juvenoid in the insect organism.

A synthetic strategy using Witkop's pyrroloindole for (−)-debromoflustramine B, (+)- ent-debromoflustramine B and (+)- ent-debromoflustramide B

While prenylation of (−)-Witkop's pyrroloindole ( 2), secured from l-tryptophan under standard N-alkylation conditions, led to a ca. 1:1 diastereoisomeric mixture of two C 3a-alkylated indolenines 3 and 4, use of phase-transfer conditions altered this to ca. 1:2. Reduction followed by N-prenylation of the resulting secondary amines gave C, N-dialkylated products. The derived separable diastereoisomeric (−)- and (+)-Barton esters 19a and 19b were then converted into (−)-debromoflustramine B and (+)- ent-debromoflustramine B, respectively. A novel reaction involving oxygen and the carbanion derived from Barton ester 19b led to (+)- ent-debromoflustramide B. Treatment of N 8-prenylated Witkop's pyrroloindole 5 with Lewis acid (BF 3·Et 2O) uncovered a new clean intramolecular cyclisation involving the prenyl unit.

Stereoselective Quaternization of α-Amino Phenylacetonitriles Mediated by a Remote Sulfinyl Group

Enantiomerically pure alpha-substituted alpha-amino phenylacetonitriles have been readily prepared from 2-p-tolylsulfinylbenzaldimines following a two-step sequence: a moderately stereoselective hydrocyanation of the imines and a completely stereoselective quaternization of the resulting diastereoisomeric mixture of alpha-amino phenylacetonitriles with different alkylating or acylating reagents in the presence of KHMDS. Theoretical calculations support a stereoselectivity control exerted by the remote sulfinyl group, as long as it is responsible for the conformational preferences of the benzyllithium intermediates, which suffer the attack of the electrophiles to the less hindered diastereotopic face.

Formal Synthesis of (−)‐Aphanorphine Using Sequential Photomediated Radical Reactions of Dithiocarbamates

Aphanorphine (1), an alkaloid isolated from the freshwater blue-green alga Aphanizomenon flos-aquae, has attracted considerable attention from the synthetic community owing to its structural similarity to natural and non-natural analgesics such as morphine, eptazocine, and pentazocine (Scheme 1). Approaches to aphanorphine developed to date have all relied on the formation of the B or C ring to complete theC-norbenzomorphan skeleton, typically exploiting the rigidity of the bridged tricyclic 3-benzazepine structure to set the second stereocenter from a preexisting quaternary benzylic stereocenter at C1, or from an abranched amine at C4. In this communication we present a complementary strategy for the synthesis of aphanorphine which is characterized by the late-stage incorporation of the aromatic A ring, and formation of the pyrrolidine C ring through a novel carbon–carbon bondforming reaction. We have recently reported a new method for the generation of carbamoyl (aminoacyl) radicals from dithiocarbamate precursors, and their subsequent intramolecular addition—dithiocarbamate group-transfer reactions with alkenes. Application of this methodology to the synthesis of the core 6-azabicyclo[3.2.1]octane ring system of aphanorphine was envisaged based upon a regioselective 5-exo-trig cyclization of carbamoyl radical 2 followed by dithiocarbamate group transfer to give the functionalized bicyclic lactam 3 (Scheme 1). It was further envisaged that the dithiocarbamate group in 3 would provide a handle for phenol annulation. Critical to the success of such an approach is the ability of carbamoyl radicals generated from dithiocarbamate precursors to undergo potentially difficult cyclizations onto unactivated alkenes. 4] Previous work by Quirante, Bonjoch, et al. had shown that a-amino radicals undergo analogous cyclizations onto alkenes carrying electron-withdrawing groups at C9a (aphanorphine numbering); however, unactivated alkenes did not undergo cyclization. The effect of a further alkene substituent at C1, which may also disfavor 5-exo-trig cyclization, was not evaluated. An asymmetric synthesis of the requisite secondary cyclohexenylamine is outlined in Scheme 2 and relies on Ellman6s sulfinamide auxiliary to set the amino-substituted stereocenter destined to be C4 of aphanorphine. 8] Condensation of enantiomerically pure (R)-tert-butanesulfinamide (5) with commercially available cis-4-heptenal gave the expected (E)-sulfinimine 6 (Scheme 2). Addition of 2methylallylmagnesium chloride gave rise to sulfinamide 7 in excellent yield as a 83:17 mixture of diastereoisomers. The configuration of the major stereoisomer 7 was predicted to be R on the basis of the Ellman model and was ultimately proven through a formal synthesis of ( )-aphanorphine. Separation of the two diastereomers could not be achieved at this stage, and so the mixture was carried through the following steps. Following N-methylation of 7, 1,7-diene 8 was subjected to ring-closing metathesis using the Grubbs second-generation catalyst, which furnished the trisubstituted alkene 9 in excellent yield. Finally removal of the sulfinyl auxiliary under acidic conditions gave the hydrochloride salt 10. At this stage, a single recrystallization of 10 gave enantiomerically pure material. Scheme 1. Analgesics structurally related to aphanorphine and a retrosynthesis of ( )-aphanorphine (1).

Stereoselective synthesis of β-hydroxy-α-amino acids β-substituted with non-aromatic heterocycles

We have stereoselectively synthesised β-hydroxy-α-amino acids β-substituted with non-aromatic heterocycles by means of a condensation reaction between enantiomerically pure heterocyclic aldehydes and the ( R)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (Schöllkopf’s reagent) as a chiral auxiliary. The stereocontrolled addition gave mixtures of diastereoisomers whose steric configurations were assigned on the basis of spectroscopic data and X-ray analysis. Upon controlled hydrolysis, the adducts were transformed into the corresponding methyl esters of β-hydroxy-β-heterocyclic substituted α-amino acids.

Reaction of 5-Allyl-2,3,5-trichloro-4,4-dimethoxycyclopent-2-en-1-one with amino acids

5-Allyl-2,3,5-trichloro-4,4-dimethoxycyclopent-2-en-1-one reacts with L-proline and L-methionine methyl esters to give diastereoisomeric mixtures of the corresponding chlorine replacement products at C3.

Condensation of quinolin-6-amine with 5-(p-methoxyphenyl)-cyclohexane-1,3-dione and substituted benzaldehydes

New 12-aryl-9-(p-methoxyphenyl)-8,9,10,12-tetrahydro-7H-benzo[b][4,7]phenanthrolin-11-ones having two asymmetric carbon atoms (C9 and C12) were synthesized by three-component condensation of quinolin-6-amine with 5-(p-methoxyphenyl)cyclohexane-1,3-dione and substituted benzaldehydes. According to the 1H NMR data, the products are mixtures of diastereoisomers.

Pteridines. Part CXVII

AbstractA series of side chain reactions starting from the 6‐ and 7‐styryl‐substituted 1,3‐dimethyllumazines 1 and 21 as well as from the 6‐ and 7‐[2‐(methoxycarbonyl)ethenyl]‐substituted 1,3‐dimethyllumazine 2 and 22 were performed first by addition of Br2 to the CC bond forming the 1′,2′‐dibromo derivatives 3, 4, 24, and 26 in high yields (Schemes 1 and 3) (lumazine=pteridine‐2,4(1H,3H)‐dione). Treatment of 3 with various nucleophiles gave rise to an unexpected tele‐substitution in 7‐position and elimination of the Br‐atoms generating 7‐alkoxy‐ (see 5 and 6), 7‐hydroxy‐ (see 7) and 7‐amino‐6‐styryl‐1,3‐dimethyllumazines (see 8–11) (Scheme 1). On the other hand, 4 underwent, with dilute DBU (1,8‐diazabicyclo[5.4.0]undec‐2‐ene), a normal HBr elimination in the side chain leading to 18, whereas treatment with MeONa afforded a more severe structural change to 19. Similarly, 24 and 26 reacted to 27, 32, and 33 under mild conditions, whereas in boiling NaOMe/MeOH, 24 gave 7‐(2‐dimethoxy‐2‐phenylethyl)‐1,3‐dimethyllumazine (30) which was hydrolyzed to give 31 (Scheme 3). From the reactions of 4 and 24 with DBU resulted the dark violet substance 20 and 25, respectively, in which DBU was added to the side chain (Scheme 2). The styryl derivatives 1 and 21 could be converted, by a Sharpless dihydroxylation reaction, into the corresponding stereoisomeric 6‐ and 7‐(1,2‐dihydroxy‐2‐phenylethyl)‐1,3‐dimethyllumazines 34–37 (Scheme 4). The dihydroxy compounds 34 and 35 were also acetylated to 38 and 39 which, on catalytic reduction followed by formylation, yielded the diastereoisomer mixtures 40 and 41. Deacetylation to 42 and 45 allowed the chromatographic separation of the diastereoisomers resulting in the isolation of 43 and 44 as well as 46 and 47, respectively. Introduction of a 6‐ or 7‐ethynyl side chains proceeded well by a Sonogashira reaction with 6‐ (48) or 7‐chloro‐1,3‐dimethyllumazine (55) yielding 49–51 and 56–58 (Scheme 5). The direction of H2O addition to the triple bond is depending on the substituents since the 6‐ (49) and 7‐(phenylethynyl)‐1,3‐dimethyllumazine (56) showed attack at the 2′‐position yielding 53 and 60, in contrast to the 6‐ (51) and 7‐ethynyl‐1,3‐dimethyllumazine (58) favoring attack at C(1′) and formation of 6‐ (52) and 7‐acetyl‐1,3‐dimethyllumazine (59).

5-Arylidene Derivatives of Meldrum’s Acid as Synthons in Pyrano[4,3-b]pyran Synthesis

The reactions of 5-arylidene derivatives of Meldrum’s acid with ethyl vinyl ether or N-vinyl-2-oxazolidinone yielded trans-trans-(2,4:4,7)-pyrano[4,3-b]pyrans, cis-trans-(2,4:4,7)-pyrano[4,3-b]pyrans, or diastereoisomeric mixtures of pyrano[4,3-b]pyrans and reactions with 3,4-dihydro-2H-pyran afforded Michael adducts. The reactions of 5-arylidene derivatives of Meldrum’s acid with cyanoacetic acid derivatives do not provide appropriate pyrans.

Palladium‐Catalyzed Three‐Component Tethering: Synthesis of 1‐Alkoxy‐1H‐furo[3,4‐c]pyridine‐3‐ones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Chemosystematic Value of Flavonoids from Crataegus x macrocarpa (Rosaceae) with special Emphasis on (R)‐ and (S)‐Eriodictyol‐7‐O‐glucuronide and Luteolin‐7‐O‐glucuronide

The chemotaxonomic investigation of Crataegus x macrocarpa, a hybrid of C. laevigata and C. rhipidophylla, presents the qualitative and quantitative composition of its flavonoid pattern in relationship to its parent species for the first time. Six flavonoids were identified as vitexin-2''-O-rhamnoside (1), vitexin (2), isovitexin (3), rutin (4), hyperoside (5), and isoquercitrin (6). Furthermore, two flavonoids were isolated from C. x macrocarpa and identified as a diastereoisomeric mixture of (R)- and (S)-eriodictyol-7-O-beta-D-glucuronide (7) and luteolin-7-O-beta-D-glucuronide (8) by means of 1D- and 2D-NMR, MS, and UV experiments. Compounds 7 and 8 were isolated for the first time from Crataegus species. While missing in C. laevigata, their occurrence in C. rhipidophylla additionally emphasizes its chemotaxonomic relationship to C. x macrocarpa.

A Novel Heterospirocyclic 2H-Azirin-3-amine as Synthon for 3-Aminothiolane-3-carboxlic Acid

The heterospirocyclic 2H-azirin-3-amine (9), i.e., N-methyl-N-phenyl-5-thia-1-azaspiro[2.4]hept-1-en-2-amine, was prepared from the commercially available thiolane-3-one (10) via the corresponding 3-carbonitrile (11) and 3-thiocarboxamide (14). This azirine reacted with thiobenzoic acid to give 3-benzoylamino-N-methyl-N-phenylthiolane-3-thiocarboxamide (15). With N-protected valine, the protected dipeptides (16) and (17), which contain a heterocyclic amino acid, were obtained as mixtures of diastereoisomers.

Stereoselective Methylation of 1-(Diphenylphosphanyl)-2-[(methoxycarbonyl)methyl]ferrocene. The Crystal Structures of the Methylated Ester and Its Palladium(II) Complex with an Auxiliary 2-[(Dimethylamino)methyl]phenyl Ligand.

Treatment of racemic 1-(diphenylphosphanyl)-2-[(methoxycarbonyl)methyl]ferrocene successively with NaN(SiMe3)2 and methyl iodide affords the C-alkylated product, 1-(diphenylphosphanyl)-2-[1-(methoxycarbonyl)ethyl]ferrocene (6), as a mixture of diastereoisomers in ca. 10:1 ratio, from which the major (S,Rp/R,Sp)-diastereoisomer is easily isolated by crystallisation. (S,Rp/R,Sp)-6 reacts with [Pd(LNC)(MeCN)2]ClO4 (LNC = 2-[(dimethylamino-κN)- methyl]phenyl-κC1) to give the cationic bis-chelate complex (S,Rp/R,Sp)-[Pd(LNC)(6-κ2O,P)]- ClO4 (9). The structures of (S,Rp/R,Sp)-6 and 9 have been determined by single-crystal X-ray diffraction. Hydrolysis of ester 6 to the corresponding carboxylic acid proved to be difficult, being complicated by racemisation at the chiral carbon atom and oxidation of the phosphanyl group.