Synthesis of Derivatives of the Optically Active β‐Amino Acids from (+)‐Car‐2‐ene

The reaction of (+)‐car‐2‐ene ( 4 ) with chlorosulfonyl isocyanate (=sulfuryl chloride isocyanate; ClSO₂NCO) led to the tricyclic lactams 6 and 8 corresponding to the initial formation both of the tertiary carbenium and α‐cyclopropylcarbenium ions (Scheme 2). A number of optically active derivatives of β‐amino acids which are promising compounds for further use in asymmetric synthesis were synthesized from the lactams (see 16, 17 , and 19 – 21 in Scheme 3).     

Chiral Enol Oxazolines and Thiazolines as Auxiliary Ligands for the Asymmetric Synthesis of Ruthenium‐Polypyridyl Complexes

Various ligands, such as (Z)‐1‐phenyl‐2‐[(4S)‐4‐phenyl‐4,5‐dihydro‐1,3‐oxazol‐2‐yl]ethen‐1‐ol ((S)‐ 1a ) and (Z)‐1‐phenyl‐2‐[(4S)‐4‐phenyl‐4,5‐dihydro‐1,3‐thiazol‐2‐yl]ethen‐1‐ol ((S)‐ 1c ), were investigated as auxiliaries for the asymmetric synthesis of chiral ruthenium(II) complexes. The reaction of these chiral auxiliary ligands with [RuCl₂(dmso)₄], 2,2′‐bipyridine (bpy, 2.2 equiv), and triethylamine (10 equiv) in DMF/PhCl (1:8) at 140 °C for several hours diastereoselectively provided the complexes Λ‐[Ru(bpy)₂{(S)‐ 1a ? H}] (Λ‐(S)‐ 2a , 52 % yield, 56:1 d.r.) and Λ‐[Ru(bpy)₂{(S)‐ 1c ? H}] (Λ‐(S)‐ 2c , 48 % yield, >100:1 d.r.) in a single step after purification. Both Λ‐(S)‐ 2a and Λ‐(S)‐ 2c could be converted into Λ‐[Ru(bpy)₃](PF₆)₂ by replacing the bidentate enolato ligands with bpy, under retention of configuration, induced by either NH₄PF₆ as a weak acid (from Λ‐(S)‐ 2a : 73 % yield, 22:1 e.r.; from Λ‐(S)‐ 2c : 77 % yield, 22:1 e.r.), TFA as a strong acid (from Λ‐(S)‐ 2a : 72 % yield, 52:1 e.r.; from Λ‐(S)‐ 2c : 85 % yield, 25:1 e.r.), methylation with Meerwein′s salt (from Λ‐(S)‐ 2a : 59 % yield, 46:1 e.r.; from Λ‐(S)‐ 2c : 86 % yield, 37:1 e.r.), ozonolysis (from Λ‐(S)‐ 2a : 56 % yield, 22:1 e.r.; from Λ‐(S)‐ 2c : 43 % yield, 6.3:1 e.r.), or oxidation with a peroxy acid (from Λ‐(S)‐ 2a : 72 % yield, 45:1 e.r.; from Λ‐(S)‐ 2c : 79 % yield, 8.5:1 e.r.). This study shows that, except for the reaction with NH₄PF₆, oxazoline‐enolato complex Λ‐(S)‐ 2a provides Λ‐[Ru(bpy)₃](PF₆)₂ with higher enantioselectivities than analogous thiazoline‐enolato complex Λ‐(S)‐ 2c , which might be due to the higher coordinative stability of the thiazoline‐enolato complex, thus requiring more prolonged reaction times. Thus, this study provides attractive new avenues for the asymmetric synthesis of non‐racemic ruthenium(II)‐polypyridyl complexes without the need for using a strong acid or a strong methylating reagent, as has been the case in all previously reported auxiliary methods from our group.     

The Asymmetric Synthesis of the [D8]‐Labeled (−)‐(S)‐Dihydroxyverbacine,the Terminal Precursor in the Biogenesis of the Macrobicyclic Spermine Alkaloids Aphelandrine and Orantine

The asymmetric synthesis of the unlabeled and [D₈]‐labeled terminal precursors, 4 ((−)‐(S)‐dihydroxyverbacine) and 19 , respectively, in the biogenesis of the spermine alkaloids aphelandrine ( 5 ) and orantine ( 6 ), respectively, is described. A partial synthesis of the alkaloid (−)‐(S)‐[(E)‐4‐methoxycinnamoyl]buchnerine ( 10 ) is also presented.     

Structural diversity in imidazolidinone organocatalysts: a synchrotron and computational study

(S)‐1‐(Methylaminocarbonyl)‐3‐phenylpropanaminium chloride (S2·HCl), C₁₀H₁₅N₂O⁺·Cl⁻, crystallizes in the orthorhombic space group P2₁2₁2₁ with a single formula unit per asymmetric unit. (5R/S)‐5‐Benzyl‐2,2,3‐trimethyl‐4‐oxoimidazolidin‐1‐ium chloride (R3 and S3), C₁₃H₁₉N₂O⁺·Cl⁻, crystallize in the same space group as S2·HCl but contain three symmetry‐independent formula units. (R/S)‐5‐Benzyl‐2,2,3‐trimethyl‐4‐oxoimidazolidin‐1‐ium chloride monohydrate (R4 and S4), C₁₃H₁₉N₂O⁺·Cl⁻·H₂O, crystallize in the space group P2₁ with a single formula unit per asymmetric unit. Calculations at the B3LYP/6–31G(d,p) and B3LYP/6–311G(d,p) levels of the conformational energies of the cation in R3, S3, R4 and S4 indicate that the ideal gas‐phase global energy minimum conformation is not observed in the solid state. Rather, the effects of hydrogen‐bonding and van der Waals interactions in the crystal structure cause the molecules to adopt higher‐energy conformations, which correspond to local minima in the molecular potential energy surface.     

Asymmetric Reaction of Simple Nitro Compounds with Chiral 1,3‐Oxazolidin‐2‐ones

The chiral oxazolidinone 1 (=[(3aS,6R,7aR)‐tetrahydro‐8,8‐dimethyl‐2‐oxo‐4H‐3a,6‐methano‐1,3‐benzoxazol‐3‐yl](oxo)acetaldehyde) was found to react stereoselectively with simple nitro compounds in the presence of Al₂O₃ or Bu₄NF?3 H₂O (TBAF) as catalysts, affording the diastereoisomeric nitro alcohols 3 – 6 with good asymmetric induction. When Al₂O₃ was used, the (S)‐configuration at the center bearing the OH group was generated, with the relative syn‐configuration for the major diastereoisomers. In the case of the nitro‐aldol reaction catalyzed by TBAF, an opposite asymmetric induction was found for two nitro compounds. In contrast to 1 , compound 12 (=((4R,5S)‐4‐methyl‐2‐oxo‐5‐phenyl‐1,3‐oxazolidin‐3‐yl)(oxo)acetaldehyde), a derivative of Evans auxiliary, gave rise to poor asymmetric induction in Henry reactions.     

Non‐iterative Asymmetric Synthesis of C15 Polyketide Spiroketals

The 2,2′‐methylenebis[furan] ( 1 ) was converted to 1‐{(4R,6S))‐6‐[(2R)‐2,4‐dihydroxybutyl]‐2,2‐dimethyl‐1,3‐dioxan‐4‐yl}‐3‐[(2R,4R)‐tetrahydro‐4,6‐dihydroxy‐2H‐pyran‐2‐yl)propan‐2‐one ((+)‐ 18 ) and its (4S)‐epimer (?)‐ 19 with high stereo‐ and enantioselectivity (Schemes 1–3). Under acidic methanolysis, (+)‐ 18 yielded a single spiroketal, (3R)‐4‐{(1R,3S,4′R,5R,6′S,7R)‐3′,4′,5′,6′‐tetrahydro‐4′‐hydroxy‐7‐methoxyspiro[2,6‐dioxabicyclo[3.3.1]nonane‐3,2′‐[2H]pyran]‐6′‐yl}butane‐1,3‐diol ((?)‐ 20 ), in which both O‐atoms at the spiro center reside in equatorial positions, this being due to the tricyclic nature of (?)‐ 20 (methyl pyranoside formation). Compound (?)‐ 19 was converted similarly into the (4′S)‐epimeric tricyclic spiroketal (?)‐ 21 that also adopts a similar (3S)‐configuration and conformation. Spiroketals (?)‐ 20 , (?)‐ 21 and analog (?)‐ 23 , i.e., (1R,3S,4′R,5R,6′R)‐3′,4′,5′,6′‐tetrahydro‐6′‐[(2S)‐2‐hydroxybut‐3‐enyl]‐7‐methoxyspiro[2,6‐dioxabicyclo[3.3.1]nonane‐3,2′‐[2H]pyran]‐4′‐ol, derived from (?)‐ 20 , were assayed for their cytotoxicity toward murine P388 lymphocytic leukemia and six human cancer cell lines. Only racemic (±)‐ 21 showed evidence of cancer‐cell‐growth inhibition (P388, ED₅₀: 6.9 μg/ml).     

An improved synthesis of enantiomerically pure RWJ 69442, a development candidate for the treatment of benign prostatic hyperplasia

This report describes an improved synthesis of enantiomerically pure (S)‐2‐[4‐(Dimethylamino)phenyl]‐2,3‐dihydro‐N‐[2‐hydroxy‐3‐[4‐[2‐(1‐methylethoxy)‐phenyl]‐1‐piperazinyl]propyl]‐1,3‐dioxo‐1H‐isoindole‐5‐carboxamide (RWJ 69442), a potent and selective α_la‐adrenergic receptor antagonist for the treatment of benign prostatic hyperplasia. The synthesis highlights less hazardous reagents, easier purification and higher enantiomeric purity. The N‐benzyl‐N—t‐butoxycarbonyl amine 6 could serve as an enantiomerically pure chiral building block for asymmetric synthesis.     

Preparation and structural analysis of (±)‐cis‐ethyl 2‐sulfanylidenedecahydro‐1,6‐naphthyridine‐6‐carboxylate and (±)‐trans‐ethyl 2‐oxooctahydro‐1H‐pyrrolo[3,2‐c]pyridine‐5‐carboxylate

Bicycle ring closure on a mixture of (4aS,8aR)‐ and (4aR,8aS)‐ethyl 2‐oxodecahydro‐1,6‐naphthyridine‐6‐carboxylate, followed by conversion of the separated cis and trans isomers to the corresponding thioamide derivatives, gave (4aSR,8aRS)‐ethyl 2‐sulfanylidenedecahydro‐1,6‐naphthyridine‐6‐carboxylate, C₁₁H₁₈N₂O₂S. Structural analysis of this thioamide revealed a structure with two crystallographically independent conformers per asymmetric unit (Z′ = 2). The reciprocal bicycle ring closure on (3aRS,7aRS)‐ethyl 2‐oxooctahydro‐1H‐pyrrolo[3,2‐c]pyridine‐5‐carboxylate, C₁₀H₁₆N₂O₃, was also accomplished in good overall yield. Here the five‐membered ring is disordered over two positions, so that both enantiomers are represented in the asymmetric unit. The compounds act as key intermediates towards the synthesis of potential new polycyclic medicinal chemical structures.     

A Tricyclic Template Derived from (2S,4R)-4-Hydroxyproline for the Synthesis of Protein Loop Mimetics

A tricyclic diketopiperazine, formally derived by coupling (2S,4S)-4-aminoproline (Pro(NH₂)) and (2S,4R)-4-(carboxymethyl)proline (Pro(CH₂COOH)), is synthesized starting from readily available (2S,4R)-4-hydroxyproline. The resulting tricyclic template has carboxy and amino groups to which a peptide chain may be attached. The Fmoc-protected template 5 is incorporated into the cyclic molecule cyclo(-Ala¹-Asn²-Pro³-Asn⁴-Ala⁵-) ( 6 ) where Pro(NH₂)⁷ = Pro(CH₂COOH)⁸ represents the template, using solid-phase peptide synthesis with cyclization in solution. The molecule is shown by NMR and dynamic simulated annealing methods to adopt a preferred conformation in aqueous solution, which includes an extended backbone at the residues Asn²-Pro³-Asn⁴, and a type-Iβ-turn at . These studies show that this novel template may be used in the synthesis of cyclic peptide and protein mimetics having defined secondary structure in aqueous environments.     

Eight‐Step Enantioselective Total Synthesis of (−)‐Cycloclavine

The first enantioselective total synthesis of (−)‐cycloclavine was accomplished in 8 steps and 7.1 % overall yield. Key features include the first catalytic asymmetric cyclopropanation of allene, mediated by the dirhodium catalyst Rh₂(S‐TBPTTL)₄, and the enone 1,2‐addition of a new TEMPO carbamate methyl carbanion. An intramolecular strain‐promoted Diels–Alder methylenecyclopropane (IMDAMC) reaction provided a pivotal tricyclic enone intermediate with more than 99 % ee after crystallization. The synthesis of (−)‐ 1 was completed by a late‐stage intramolecular Diels–Alder furan (IMDAF) cycloaddition to install the indole.     

An efficient asymmetric synthesis of (4R,8R)‐4,8‐dimethyldecanal,the most active component of natural Tribolure

An asymmetric synthesis of (4R,8R)‐4,8‐dimethyldecanal, the most active component of natural tribolure, was achieved through an asymmetric methylation as a key step and chiral‐pool strategy. Natural tribolure is a mixture of four stereoisomers, (4R,8R)/(4R,8S)/(4S,8R)/(4S,8S), and their ratio is 4/4/1/1. However, the (4R,8R)‐isomer is the most active one. Based on a chiral‐pool strategy, we used a recycled chiral molecular (R)‐4‐(Benzyloxy)‐3‐methylbutanal that we exploited in our previous article. After executing a C5 + C5 + C2 synthetic plan, the target molecule was obtained in nine linear steps and in 36.8% overall yield.     

A Phosphine‐Catalyzed Novel Asymmetric [3+2] Cycloaddition of C,N‐Cyclic Azomethine Imines with δ‐Substituted Allenoates

Catalytic asymmetric [3+2] cycloadditions of C,N‐cyclic azomethine imines with δ‐substituted allenoates have been developed in the presence of (S)‐Me‐f‐KetalPhos, affording functionalized tetrahydroquinoline frameworks in good yields with high diastereo‐ and good enantioselectivities under mild condition. The substrate scope has been also examined. This is the first time that δ‐substituted allenoates have been applied as a δ,γ‐C?C bond participated C₂ synthon in asymmetric synthesis.     

Asymmetric Total Synthesis of (−)‐Englerin A through Catalytic Diastereo‐ and Enantioselective Carbonyl Ylide Cycloaddition

An asymmetric total synthesis of the guaiane sesquiterpene (?)‐englerin A, a potent and selective inhibitor of the growth of renal cancer cell lines, was accomplished. The basis of the approach is a highly diastereo‐ and enantioselective carbonyl ylide cycloaddition with an ethyl vinyl ether dipolarophile under catalysis by dirhodium(II) tetrakis[N‐tetrachlorophthaloyl‐(S)‐tert‐leucinate], [Rh₂(S‐TCPTTL)₄], to construct the oxabicyclo[3.2.1]octane framework with concomitant introduction of the oxygen substituent at C9 on the exo‐face. Another notable feature of the synthesis is ruthenium tetraoxide‐catalyzed chemoselective oxidative conversion of C9 ethyl ether to C9 acetate.     

An Improved Asymmetric Synthesis of Unusual Amino Acid (2S,3S)‐3‐Hydroxyproline

Abstract

An improved three‐steps method for the conversion of N‐benzyl (S)‐3‐hydroxypyrrolidin‐2‐one 6 to (2S,3S)‐3‐hydroxyproline 1 is reported. The key step is the reductive cyanation of 6. The synthesis of 1 constitutes a formal asymmetric synthesis of (2S,3S)‐3‐hydroxyproline betaines 2.     

Synthesis of the Potassium Channel Opener (3S,4R)‐3,4‐Dihydro‐4‐(2,3‐dihydro‐2‐methyl‐3‐oxo‐pyridazin‐6‐Yl)oxy‐3‐hydroxy‐6‐(3‐hydroxyphenyl)sulphonyl‐2,2,3‐trimethyl‐2H‐benzo[b]pyran

The preparation of the potassium channel opener (3S,4R)‐3,4‐dihydro‐4‐(2,3‐dihydro‐2‐methyl‐3‐oxo‐pyridazin‐6‐yl)oxy‐3‐hydroxy‐6‐(3‐hydroxyphenyl)sulphonyl‐2,2,3‐trimethyl‐2H‐benzo[b]pyran (1) as a single enantiomer is reported. Considerable improvements have been implemented with respect to the original synthesis that allow for the preparation of multigram quantities of the final target compound. The optimized synthesis consists of a six‐step linear sequence whose key step is an asymmetric epoxidation protocol through the use of Jacobsen's (S,S)‐(+)‐N,N′‐bis(3,5‐di‐tert‐butylsalicylidene)‐1,2‐cyclohexanediaminomanganese(III) chloride catalyst.     

Synthesis of Enantiopure C3‐Symmetric Triangular Molecules

An asymmetric synthesis of C ₃‐symmetric triangular macrocycles is reported. 1‐Methylsulfonyl‐4‐(4‐vinylphenyl)‐1,2,3‐triazole undergoes a rhodium(II)‐catalyzed cyclotrimerization to establish an enantiopure C ₃‐symmetric triangular macrocycle motif. This method can be applied to the synthesis of an enantiopure hydrocarbon, which owes its chirality to asymmetric distribution of H/D atoms on the benzene rings.     

Asymmetric Synthesis of All Possible Stereomers of 4‐Aminoglutamic Acid via Michael Condensation of Chiral Ni(II) Complexes of Glycine and Dehydroalanine

A new method for asymmetric synthesis of all possible stereomers of 4‐aminoglutamic acid has been developed. The method is based on asymmetric Michael condensation of the nucleophilic moiety of glycine and electrophilic moiety of dehydroalanine in their chiral Ni(II) complexes of the Schiff's bases with (S)‐ and (R)‐2‐N‐(N′‐benzylprolyl)aminobenzophenones, resulting in the formation of dimeric complexes of 4‐aminoglutamic acid. Stereoselectivity of the asymmetric condensation of the complexes exceeded 94%. The condensation of nucleophilic and electrophilic complexes in four possible combinations has resulted in the formation of dimeric complexes of all the stereomers of 4‐aminoglutamic acid: (2S,4S), (2S,4R)‐meso and (2R,4R). Optically active stereomers of 4‐aminoglutamic acid with high optical purity were isolated after decomposition of the dimeric complexes.     

Structure,Stereochemistry and Dynamics of Tetranuclear Polyhydride Clusters Containing Chiral Heterobidentate Phosphanes

A novel chiral phosphane (S)‐2‐(4‐isopropyl‐2‐oxazoline‐2‐yl)phenyl‐di‐N‐pyrrolylphosphane (S‐PyrPOx) based on asymmetric oxazoline ring has been prepared and characterised. Reaction of this ligand and its phenyl‐substituted analogue (S‐PhPOx) with H₄Ru₄(CO)₁₂ and H₃RhOs₃(CO)₁₂ gave substituted derivatives H₄Ru₄(CO)₁₀(1,1‐PhPOx) ( 2 ), H₄Ru₄(CO)₁₀(1,1‐PyrPOx) ( 3 ), and H₃RhOs₃(CO)₁₀(1,1‐PyrPOx) ( 4 ), which were structurally characterised by X‐ray crystallography in solid state and by a variety of multinuclear NMR spectroscopic measurements in solution. In all studied clusters the coordinated ligands form five‐membered chelate rings through phosphorus and nitrogen atoms of oxazoline moiety to afford a novel chiral center associated with the substituted metal atom. The substitution reactions demonstrate extremely high stereoselectivity, which results in formation of only one diastereomer in all three cases to give S,S isomer in 2 and S,R isomer in 3 and 4 .     

A pair of epimeric 13‐hydroxy‐2,3,6,7‐tetra­methoxy‐8b,11,12,12a,13,13a‐hexa­hydro‐9H‐9a‐aza­cyclo­penta­[b]tri­phenyl­ene‐10‐ones

The structures of two compounds which are intermediates in the synthesis of phenanthroindolizidine alkaloids have been determined. (8bS,13aS,14R,14aR)‐8b,9,11,12,13,13a,14,14a‐Octa­hydro‐14‐hydroxy‐2,3,6,7‐tetra­methoxy­dibenzo­[f,h]pyrrolo[1,2‐b]­isoquinolin‐11‐one acetone solvate, C₂₄H₂₇NO₆·C₃H₆O, (II), crystallizes in a chiral space group with one solvent mol­ecule (acetone) present in the asymmetric unit. On the other hand, (8bS,13aS,14S,14aR)‐8b,9,11,12,13,13a,14,14a‐octa­hydro‐14‐hydroxy‐2,3,6,7‐tetra­methoxy­dibenzo­[f,h]pyrrolo[1,2‐b]­isoquinolin‐11‐one, C₂₄H₂₇NO₆, (III), crystallizes in a centrosymmetric space group with two mol­ecules in the asymmetric unit and with no solvent present. The two mol­ecules in the asymmetric unit of (III) are structurally the same. Compounds (II) and (III) are epimers at the C atom carrying the OH group; otherwise they are very similar in structure.     

Novel and Stereospecific Synthesis of (2S)‐3‐(2,4,5‐Trifluorophenyl)propane‐1,2‐diol from D‐Mannitol

A stereospecific synthesis of (2S)‐3‐(2,4,5‐trifluorophenyl)propane‐1,2‐diol from D ‐mannitol has been developed. The reaction of 2,3‐O‐isopropylidene‐D ‐glyceraldehyde with 2,4,5‐trifluorophenylmagnesium bromide gave [(4R)‐2,2‐dimethyl‐1,3‐dioxolan‐4‐yl](2,4,5‐trifluorophenyl)methanol in 65% yield as a mixture of diastereoisomers (1 : 1). The Ph₃P catalyzed reaction of the latter with C₂Cl₆ followed by reduction with Pd/C‐catalyzed hydrogenation gave (2S)‐3‐(2,4,5‐trifluorophenyl)propane‐1,2‐diol with >99% ee and 65% yield.