Unusual Totally Selective Cyclodimerization of Epoxides: Synthesis of a Pair of Diastereoisomers of Enantiopure 2,5‐Disubstituted‐1,4‐Dioxanes with C2 Symmetry

The synthesis of the C₂‐symmetrical (2R,5R)‐ and (2S,5S)‐2,5‐bis‐[(S)‐1‐(dibenzylaminoalkyl)]‐1,4‐dioxanes 1 or 2 in enantiopure form is reported. Compounds 1 and 2 were obtained by a completely selective and unusual cyclodimerization of chiral (2R,1′S)‐ or (2S,1′S)‐2‐(1‐aminoalkyl)epoxides 3 or 4 promoted by a mixture of diisopropylamine and boron trifluoride⋅diethyl etherate complex. The structure of the obtained dioxane was established by single‐crystal X‐ray diffraction analysis. A mechanism has been proposed to explain this transformation.     

Synthesis of Ruthenium Hydride Complexes Containing beta‐Aminophosphine Ligands Derived from Amino Acids and their use in the H2‐Hydrogenation of Ketones and Imines

The new complexes RuHCl(PPh₂CH₂CHRNH₂)₂ and RuHCl(PPh₂CH₂CHRNH₂)(R‐ binap), R=H (Pgly), R=Me [(R)‐Pala] were prepared by the substitution of the PPh₃ ligands in RuHCl(PPh₃)₃ or RuHCl(PPh₃)[(R)‐binap] with beta‐aminophosphines derived from amino acids. The complex trans‐RuHCl(Pgly)[(R)‐binap] has been characterized by X‐ray crystallography. The complex trans‐RuHCl[(S)‐Ppro]₂ where (S)‐Ppro is derived from proline was also prepared and characterized by X‐ray crystallography. These were used as catalyst precursors in the presence of a base (KOPr‐i or KOBu‐t) for the hydrogenation of various ketones and imines to the respective alcohols and amines with H₂ gas (1–11 atm) at room temperature. Acetophenone was hydrogenated to (S)‐1‐phenylethanol in low ee (up to 40%) when catalyzed by the enantiomerically pure complexes. These complexes are especially active in the hydrogenation of sterically congested and electronically deactivated ketones and imines and are selective for the hydrogenation of CO bonds over CC bonds.     

Stereoselective Modulation of P‐Glycoprotein by Chiral Small Molecules

Inhibition of drug efflux pumps such as P‐glycoprotein (P‐gp) is an approach toward combating multidrug resistance, which is a significant hurdle in current cancer treatments. To address this, N‐substituted aryloxymethyl pyrrolidines were designed and synthesized in their homochiral forms in order to investigate the stereochemical requirements for the binding site of P‐gp. Our study provides evidence that the chiral property of molecules could be a strategy for improving the capacity for interacting with P‐gp, as the most active compounds of the series stereoselectively modulated this efflux pump. The naphthalene‐1‐yl analogue (R)‐2‐[(2,3‐dichlorophenoxy)methyl]‐1‐(naphthalen‐1‐ylmethyl)pyrrolidine) [(R)‐ 7 a ] emerged foremost for its potency and stereoselectivity toward P‐gp, with the S enantiomer being nearly inactive. The modulation of P‐gp by (R)‐ 7 a involved consumption of ATP, thus demonstrating that the compound behaves as a P‐gp substrate.     

Synthesis of enantiopure oxoindolo‐quinolizines

Methyl (1S,3S and 1R,3S)‐1‐(2, 2‐dimethoxyethyl)‐1,2,3,4‐tetrahydrocarboline‐3‐carboxylate ( 3 ) was hydrolyzed in the presence of sodium hydroxide to give (1S,3S and 1R,3S)‐1‐(2,2‐dimethoxyethyl)‐1,2,3,4‐tetrahydrocarboline‐3‐carboxylic acid ( 4 ), which was reduced with LiAlH₄ to provide (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐3‐hydroxymethyl‐1,2,3,4‐tetrahydrocarbolines ( 10 ), and then amidated in ammonia containing methanol to obtain (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐1,2,3,4‐tetrahydrocarboline‐3‐carboxamide ( 14 ). Acylation of (1S,3S and 1R,3S)‐ 3 , (1S,3S and 1R,3S)‐ 4 , (1S,3S)‐ 10 , (1R, 3S)‐ 10 , (1S, 3S)‐ 14 and (1R,3S)‐ 14 afforded the corresponding methyl (1S,3S and 1R,3S)‐1‐(2,2‐dimethoxyethyl)‐ 2‐(1,3‐dioxobutyl)‐1,2,3,4‐tetrahydrocarbolines‐3‐carboxylate ( 6 ), (1S,3S and 1R,3S)‐1‐(2,2‐dimethoxyethyl)‐2‐(1,3‐dioxobutyl)‐1,2,3,4‐tetrahydrocarboline‐3‐carboxylic acid ( 5 ), (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐2‐(1,3‐dioxobutyl)‐3‐(1,3‐dioxobutyl)oxymethyl‐1,2,3,4‐tetrahydrocarboline ( 11 ), (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐2‐(1,3‐dioxobutyl)‐1,2,3,4‐tetrahydrocarboline‐3‐carboxamide ( 15 ), respectively. After Aldol reaction, dehydration and dehydrogenation the desired (6S)‐6‐substituted 4,6,7,12‐tetrahydro‐4‐oxoindolo[2,3‐a]quinolizines 8 , 9 , 12 , 13 , and 16 were obtained. Their anticancer activities in vitro were investigated.     

Chemical Synthesis of the Epimeric (23R)‐ and (23S)‐Fluoro Derivatives of Bile Acids via Horner–Wadsworth–Emmons Reaction

A method for the synthesis of two (23R)‐ and (23S)‐epimeric pairs of 23‐fluoro‐3α,7α,12α‐trihydroxy‐5β‐cholan‐24‐oic acid and 23‐fluoro‐3α,7α‐dihydroxy‐5β‐cholan‐24‐oic acid is described. The key intermediates, 23,24‐dinor‐22‐aldehyde peracetates were prepared from cholic and chenodeoxycholic acids via the 24‐nor‐22‐ene, 24‐nor‐22ξ,23‐epoxy, and 23,24‐dinor‐22‐aldehyde derivatives. The Horner–Wadsworth–Emmons reaction of the 23,24‐dinor‐22‐aldehydes using triethyl 2‐fluoro‐2‐phosphonoacetate in the presence of LiCl and 1,8‐diazabicyclo[5,4,0]undec‐7‐ene (DBU), and subsequent hydrogenation of the resulting 23ξ‐fluoro‐22‐ene ethyl esters, followed by hydrolysis, gave a mixture of the epimeric (23R)‐ and (23S)‐fluorinated bile acids which were resolved efficiently by preparative RP‐HPLC. The stereochemical configuration of the fluorine atom at C‐23 in the newly synthesized compounds was confirmed directly by the X‐ray crystallographic data. The ¹H and ¹³C NMR spectral differences between the (23R)‐ and (23S)‐epimers were also discussed.     

Efficient Asymmetric Synthesis of 2,6‐Disubstituted 2H‐Dihydropyrans via a Catalytic Hetero‐Diels–Alder/Allylboration Sequence

[4+2] Cycloaddition of (E)‐3‐borylacrolein 1 with ethyl vinyl ether, catalysed by chromium complex (1R,2S) or (1S,2R) 2 , led to the corresponding cycloadducts with high diastereo‐ and enantioselectivities. Further reaction with aldehydes offers an attractive asymmetric route to synthetically useful substituted 3,4‐dihydro‐2H‐pyrans.     

On the Metabolically Active Form of Metaglidasen: Improved Synthesis and Investigation of Its Peculiar Activity on Peroxisome Proliferator‐Activated Receptors and Skeletal Muscles

Metaglidasen is a fibrate‐like drug reported as a selective modulator of peroxisome proliferator‐activated receptor γ (PPARγ), able to lower plasma glucose levels in the absence of the side effects typically observed with thiazolidinedione antidiabetic agents in current use. Herein we report an improved synthesis of metaglidasen′s metabolically active form halofenic acid (R)‐ 2 and that of its enantiomer (S)‐ 2 . The activity of the two stereoisomers was carefully examined on PPARα and PPARγ subtypes. As expected, both showed partial agonist activity toward PPARγ; the investigation of PPARα activity, however, led to unexpected results. In particular, (S)‐ 2 was found to act as a partial agonist, whereas (R)‐ 2 behaved as an antagonist. X‐ray crystallographic studies with PPARγ were carried out to gain more insight on the molecular‐level interactions and to propose a binding mode. Given the adverse effects provoked by fibrate drugs on skeletal muscle function, we also investigated the capacity of (R)‐ 2 and (S)‐ 2 to block conductance of the skeletal muscle membrane chloride channel. The results showed a more beneficial profile for (R)‐ 2 , the activity of which on skeletal muscle function, however, should not be overlooked in the ongoing clinical trials studying its long‐term effects.     

Enantioselective Synthesis of Chiral β‐Aryloxy Alcohols by Ruthenium‐Catalyzed Ketone Hydrogenation via Dynamic Kinetic Resolution (DKR)

A highly efficient enantioselective synthesis of chiral β‐aryloxy alcohols by the {RuCl₂[(S)‐SDP][(R,R)‐DPEN]} [(S_a,R,R)‐ 1a ; SDP=7,7′‐bis(diarylphosphino)‐1,1′‐spirobiindane; DPEN=trans‐1,2‐diphenylethylenediamine] complex‐catalyzed asymmetric hydrogenation of racemic α‐aryloxydialkyl ketones via dynamic kinetic resolution (DKR) has been developed. Enantioselectivities of up to 99% ee with good to high cis/anti‐selectivities (up to>99:1) were achieved.     

Optically Active 4‐Substituted (S)‐2‐Phenyl‐2‐oxazolines

(R)‐4‐Hydroxymethyl‐2‐phenyl‐2‐oxazoline (R)‐ 1 ) was prepared from (L)‐serine. The respective tosylate ((S)‐ 2 ) was converted into sulfides (S)‐ 4 and (S)‐ 5 , and sulfone (S)‐ 6 , useful starting materials for the elaboration of additional chiral centers. A previously reported [ α]_D ²⁵ value for (R)‐ 4 is corrected.     

Palladium(II) Complexes of C2‐Bridged Chiral Diphosphines: Application to Enantioselective Carbonyl‐Ene Reactions

(11bR,11′bR)‐4,4′‐(1,2‐Phenylene)bis[4,5‐dihydro‐3H‐dinaphtho[2,1‐c:1′,2′‐e]phosphepin] [abbreviated as (R)‐BINAPHANE], (3R,3′R,4S,4′S,11bS,11′bS)‐4,4′‐bis(1,1‐dimethylethyl)‐4,4′,5,5′‐tetrahydro‐3,3′‐bi‐3H‐dinaphtho[2,1‐c:1′,2′‐e]phosphepin [(S)‐BINAPINE], (1S,1′S,2R,2′R)‐1,1′‐bis(1,1‐dimethylethyl)‐2,2′‐biphospholane [(S,S,R,R)‐TANGPHOS] and (2R,2′R,5R,5′R)‐1,1′‐(1,2‐phenylene)bis[2,5‐bis(1‐methylethyl)phospholane] [(R,R)‐i‐Pr‐DUPHOS] are C₂‐bridged chiral diphosphines that form stable complexes with palladium(II) and platinum(II) containing a five‐membered chelate ring. The Pd(II)‐BINAPHANE catalyst displayed good to excellent enantioselectivities with ee values as high as 99.0% albeit in low yields for the carbonyl‐ene reaction between phenylglyoxal and alkenes. Its Pt(II) counterpart afforded improved yields while retaining satisfactory enantioselectivity. For the carbonyl‐ene reaction between ethyl trifluoropyruvate and alkenes, the Pd(II)‐BINAPHANE catalyst afforded both good yields and extremely high enantioselectivities with ees as high as 99.6%. A comparative study on the Pd(II) catalysts of the four C₂‐bridged chiral diphosphines revealed that Pd(II)‐BINAPHANE afforded the best enantioselectivity. The ee values derived from Pd(II)‐BINAPHANE are much higher than those derived from the other three Pd(II) catalysts. A comparison of the catalyst structures shows that the Pd(II)‐BINAPHANE catalyst is the only one that has two bulky (R)‐binaphthyl groups close to the reaction site. Hence it creates a deep chiral space that can efficiently control the reaction behavior in the carbonyl‐ene reactions resulting in excellent enantioselectivity.     

Synthesis of 6‐amino acid substituted 4,6,7,12‐tetrahydro‐4‐oxoindolo[2,3‐a]quinolizines

In the presence of Na₂CO₃ (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐2‐(1,3‐dioxobutyl)‐3‐(1,3‐dioxo‐butyl)oxymethyl‐1,2,3,4‐tetrahydrocarboline ( 1 ) were transformed into (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐2‐(1,3‐dioxobutyl)‐3‐hydroxymethyl‐1,2,3,4‐tetrahydrocarboline ( 2 ), which were cyclized to (6S)‐3‐acetyl‐6‐hydroxymethyl‐4,6,7,12‐tetrahydro‐4‐oxoindolo[2,3‐a]quinolizine ( 4 ), via(6S,12bS)‐ and (6S,12bR)‐3‐acetyl‐2‐hydroxyl‐6‐hydroxymethyl‐1,2,3,4,6,7,12,12b‐octahydro‐4‐oxoindolo[2,3‐a]quinoline ( 3 ). (6S)‐ 4 was coupled with Boc‐Gly, Boc‐L‐Asp(β‐benzyl ester), or Boc‐L‐Gln to give 6‐amino acid substituted (6S)‐3‐acetyl‐4,6,7,12‐tetrahydro‐4‐oxoindolo[2,3‐a]quinolizines 5a , 5b , or 5c , respectively. After the removal of Boc from (6S)‐ 5a (6S)‐3‐acetyl‐6‐glycyl‐4,6,7,12‐tetrahydro‐4‐oxoindolo[2,3‐a]quinolizine ( 6 ) was obtained. The anticancer activities of (6S)‐ 5 and (6S)‐ 6 in vitro were tested.     

Asymmetric 1,3‐Dipolar Cycloaddition Reaction between α,β‐Unsaturated Aldehydes and Nitrones Catalyzed by Well‐Defined Iridium or Rhodium Catalysts

Reaction of the complexes (S_M,R_C)‐[(η⁵‐C₅Me₅)M{(R)‐Prophos}(H₂O)](SbF₆)₂ (M=Rh, Ir) with α,β‐unsaturated aldehydes diastereoselectively gave complexes (S_M,R_C)‐[(η⁵‐C₅Me₅)M{(R)‐Prophos}(enal)](SbF₆)₂ which have been fully characterized, including an X‐ray molecular structure determination of the complex (S_Rh,R_C)‐[(η⁵‐C₅Me₅)Rh{(R)‐Prophos}(trans‐2‐methyl‐2‐pentenal)](SbF₆)₂. These enal complexes efficiently catalyze the enantioselective 1,3‐dipolar cycloaddition of the nitrones N‐benzylideneaniline N‐oxide and 3,4‐dihydroisoquinoline N‐oxide to the corresponding enals. Reactions occur with excellent regioselectivity, perfect endo selectivity and with enantiomeric excesses up to 94 %. The absolute configuration of the adduct 5‐methyl‐2,3‐diphenylisoxazolidine‐4‐carboxaldehyde was determined through its (R)‐(−)‐α‐methylbenzylamine derivative.     

Synthesis and Pharmacological Evaluation of Enantiomerically Pure GluN2B Selective NMDA Receptor Antagonists

To determine the eutomers of potent GluN2B‐selective N‐methyl‐d ‐aspartate (NMDA) receptor antagonists with a 3‐benzazepine scaffold, 7‐benzyloxy‐3‐(4‐phenylbutyl)‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepin‐1‐ols (S)‐ 2 and (R)‐ 2 were separated by chiral HPLC. Hydrogenolysis and subsequent methylation of the enantiomerically pure benzyl ethers of (S)‐ 2 and (R)‐ 2 provided the enantiomeric phenols (S)‐ 3 and (R)‐ 3 [3‐(4‐phenylbutyl)‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepine‐1,7‐diol] and methyl ethers (S)‐ 4 and (R)‐ 4 . All enantiomers were obtained with high enantiomeric purity (≥99.7 % ee). The absolute configurations were determined by CD spectroscopy. R‐configured enantiomers turned out to be the eutomers in receptor binding studies and two‐electrode voltage clamp experiments. The most promising ligand of this compound series is the R‐configured phenol (R)‐ 3 , displaying high GluN2B affinity (K_i=30 nm ), high inhibition of ion flux (IC₅₀=61 nm ), and high cytoprotective activity (IC₅₀=93 nm ). Whereas the eudismic ratio in the receptor binding assay is 25, the eudismic ratio in the electrophysiological experiment is 3.     

Semi‐synthesis and Structure–Activity Relationship of Neuritogenic Oleanene Derivatives

(3S,4R)‐23,28‐Dihydroxyolean‐12‐en‐3‐yl (2E)‐3‐(3,4‐dihydroxyphenyl)acrylate ( 1 a ), which possesses significant neuritogenic activity, was isolated from the traditional Chinese medicine (TCM) plant, Desmodium sambuense. To confirm the structure and to assess biological activity, we semi‐synthesized 1 a from commercially available oleanolic acid. A series of novel 1 a derivatives was then designed and synthesized for a structure–activity relationship (SAR) study. All synthetic derivatives were characterized by analysis of spectral data, and their neuritogenic activities were evaluated in assays with PC12 cells. The SAR results indicate that the number and position of the hydroxy groups on the phenyl ring and the triterpene moiety, as well as the length of the (saturated or unsaturated) alkyl chain that links the phenyl ring with the triterpene critically influence neuritogenic activity. Among all the tested compounds, 1 e [(3S,4R)‐23,28‐dihydroxyolean‐12‐en‐3‐yl (2E)‐3‐(3,4,5‐trihydroxyphenyl)acrylate] was found to be the most potent, inducing significant neurite outgrowth at 1 μm .     

A New Class of 3′‐Sulfonyl BINAPHOS Ligands: Modulation of Activity and Selectivity in Asymmetric Palladium‐Catalysed Hydrophosphorylation of Styrene

Palladium‐catalysed monophosphorylation of (R)‐2,2′‐bisperfluoroalkanesulfonates of BINOL (R^F=CF₃ or C₄F₉) by a diaryl phosphinate [Ar₂P(O)H] followed by phosphine oxide reduction (Cl₃SiH) then lithium diisopropylamide‐mediated anionic thia‐Fries rearrangement furnishes enantiomerically‐pure (R)‐2′‐diarylphosphino‐2′‐hydroxy‐3′‐perfluoralkanesulfonyl‐1,1′‐binaphthalenes [(R)‐ 8ab and (R)‐ 8g–j ], which can be further diversified by Grignard reagent (RMgX)‐mediated CF₃‐displacement [→(R)‐ 8c–f ]. Coupling of (R)‐ 8a–j with (S)‐1,1′‐binaphthalene‐2,2′‐dioxychlorophosphine (S)‐ 9 generates 3′‐sulfonyl BINAPHOS ligands (R,S)‐ 10a–j in good yields (43–82%). These new ligands are of utlility in the asymmetric hydrophosphonylation of styrene ( 1 ) by 4,4,5,5‐tetramethyl‐1,3,2‐dioxaphospholane 2‐oxide ( 2 ), for which a combination of the chiral ligands with either [Pd(Cp)(allyl)] or [Pd(allyl)(MeCN)₂]⁺/NaCH(CO₂Me)₂ proves to be a convenient and active pre‐catalyst system. A combination of an electron‐rich phosphine moiety and an electron‐deficient 3′‐sulfone moiety provides the best enantioselectivity to date for this process, affording the branched 2‐phenethenephosphonate, (−)‐iso‐ 3 , in up to 74% ee with ligand (R,S)‐ 10i , where Ar=p‐anisyl and the 3′‐SO₂R group is triflone.     

Enantioselective Cobalt‐Catalyzed [6+2] Cycloadditions of Cycloheptatriene with Alkynes

The enantioselective cobalt‐catalyzed [6+2] cycloadditions of cycloheptatriene 1 with alkynes 2 is reported. Chiral phosphoramidites based on 3,3′‐disubstituted (R)‐BINOL appeared to be efficient ligands, affording the corresponding cycloadducts with good yields and up to 92 % ee. A vibrational circular dichroism study afforded the absolute configuration of new chiral (+)‐(1S,6R)‐7‐phenyl[4.2.1]bicyclo‐ nonatriene 3a and (−)‐(1S,6R)‐7‐trimethylsilyl[4.2.1]bicyclononatriene 3c .     

Synthesis of Diastereomeric 1,4‐Diphosphine Ligands Bearing Imidazolidin‐2‐one Backbone and Their Application in Rh(I)‐Catalyzed Asymmetric Hydrogenation of Functionalized Olefins

The diastereomeric 1,4‐diphosphine ligands, (S,S,S,S)‐ 1a , (R,S,S,R)‐ 1b and (R,S,S,S)‐ 1c , with the imidazolidin‐2‐one backbone were synthesized, and utilized for an investigation of the effects of backbone chirality on the enantioselectivity in the Rh(I)‐catalyzed hydrogenation of various functionalized olefinic substrates. It was found that the catalytic efficiencies are largely dependent on the configurations of the α‐carbons to phosphine. Thus, the Rh complex of the pseudo‐C₂‐symmetrical diphosphine, (R,S,S,S)‐ 1c , showed excellent enantioselectivities (93.0–98.6% ees) in the hydrogenations of a broad spectrum of substrates, and especially in the hydrogenations of methyl α‐(N‐acetyamino)‐β‐arylacrylates (95.3–97.0% ees). However, the enantioselectivities obtained with the C₂‐symmetrical (R,S,S,R)‐ 1b were largely dependent on the substrate (19.8–97.3% ees). The Rh complex of ligand 1a having the (S,S,S,S)‐configuration showed the lowest catalytic efficiency for all of the substrates examined (0–84.8% ees).     

Design of gem‐Difluoro‐bis‐Tetrahydrofuran as P2 Ligand for HIV‐1 Protease Inhibitors to Improve Brain Penetration: Synthesis,X‐ray Studies,and Biological Evaluation

The structure‐based design, synthesis, biological evaluation, and X‐ray structural studies of fluorine‐containing HIV‐1 protease inhibitors are described. The synthesis of both enantiomers of the gem‐difluoro‐bis‐THF ligands was carried out in a stereoselective manner using a Reformatskii–Claisen reaction as the key step. Optically active ligands were converted into protease inhibitors. Two of these inhibitors, (3R,3aS,6aS)‐4,4‐difluorohexahydrofuro[2,3‐b]furan‐3‐yl(2S,3R)‐3‐hydroxy‐4‐((N‐isobutyl‐4‐methoxyphenyl)sulfonamido)‐1‐phenylbutan‐2‐yl) carbamate ( 3 ) and (3R,3aS,6aS)‐4,4‐difluorohexahydrofuro[2,3‐b]furan‐3‐yl(2S,3R)‐3‐hydroxy‐4‐((N‐isobutyl‐4‐aminophenyl)sulfonamido)phenylbutan‐2‐yl) carbamate ( 4 ), exhibited HIV‐1 protease inhibitory K_i values in the picomolar range. Both 3 and 4 showed very potent antiviral activity, with respective EC₅₀ values of 0.8 and 3.1 nM against the laboratory strain HIV‐1_LAI. The two inhibitors exhibited better lipophilicity profiles than darunavir, and also showed much improved blood–brain barrier permeability in an in vitro model. A high‐resolution X‐ray structure of inhibitor 4 in complex with HIV‐1 protease was determined, revealing that the fluorinated ligand makes extensive interactions with the S2 subsite of HIV‐1 protease, including hydrogen bonding interactions with the protease backbone atoms. Moreover, both fluorine atoms on the bis‐THF ligand formed strong interactions with the flap Gly 48 carbonyl oxygen atom.     

Automated Synthesis of (rac)‐, (R)‐, and (S)‐[18F]Epifluorohydrin and Their Application for Developing PET Radiotracers Containing a 3‐[18F]Fluoro‐2‐hydroxypropyl Moiety

To introduce the 3‐[¹⁸F]fluoro‐2‐hydroxypropyl moiety into positron emission tomography (PET) radiotracers, we performed automated synthesis of (rac)‐, (R)‐, and (S)‐[¹⁸F]epifluorohydrin ([¹⁸F] 1 ) by nucleophilic displacement of (rac)‐, (R)‐, or (S)‐glycidyl tosylate with ¹⁸F^? and purification by distillation. The ring‐opening reaction of (R)‐ or (S)‐[¹⁸F] 1 with phenol precursors gave enantioenriched [¹⁸F]fluoroalkylated products without racemisation. We then synthesised (rac)‐, (R)‐, and (S)‐ 2‐{5‐[4‐(3‐[¹⁸F]fluoro‐2‐hydroxypropoxy)phenyl]‐2‐oxobenzo[d]oxazol‐3(2H)‐yl}‐N‐methyl‐N‐phenylacetamide ([¹⁸F] 6 ) as novel radiotracers for the PET imaging of translocator protein (18 kDa) and showed that (R)‐ and (S)‐[¹⁸F] 6 had different radioactivity uptake in mouse bone and liver. Thus, (rac)‐, (R)‐, and (S)‐[¹⁸F] 1 are effective radiolabelling reagents and can be used to develop PET radiotracers by examining the effects of chirality on their in vitro binding affinities and in vivo behaviour.     

Bornane with integrated push–pull butadienes

The {3-[bis(alkylthio)methylene]-1,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylidene}malononitriles ((1R,4S)- 2 , (1S,4R)- 2 and (1R,4S)- 3 ) were prepared starting from 1,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylidenemalononitriles (1R, 4R)- 1 and (1S,4S)- 1 ) arisen from (+)-, (–)-camphor. The reaction of (1R,4S)- 2 with bromine yielded the (1S,8R)-8,11,11-trimethyl-3-methylthio-5-oxo-4-thiatricyclo-[6.2.1.0^2,7]undeca-2,6-diene-6-carbonitrile ( 8 ) after hydrolysis of the initially formed (1S,8R)-6-cyano-8,11,11-trimethyl-3-methylthio-4-thia-tricyclo[6.2.1.0^2,7]undeca-2,6-diene-5-iminium bromide ( 7 ).