Enantioselective Divergent Synthesis of (−)‐cis‐α‐ and (−)‐cis‐γ‐Irone by Using Wilkinson’s Catalyst

A simple, efficient synthesis is reported for (?)‐cis‐α‐ and (?)‐cis‐γ‐irone, two precious constituents of iris oils, in ≥99 % diastereomeric and enantioselective ratios. The two routes diverge from a common intermediate prepared from (?)‐epoxygeraniol. Of general interest in this approach is the installation of the enone moiety of irones through a NHC?Au^I‐catalyzed Meyer–Schuster‐like rearrangement of a propargylic benzoate and the use of Wilkinson’s catalyst for the stereoselective hydrogenation of a prostereogenic exocyclic double bond to secure the critical cis stereochemistry of the alkyl groups at C2 and C6 of the irones. The stereochemical aspects of this reaction are rationally supported by DFT calculation of the conformers of the substrates undergoing the hydrogenation and by a modeling study of the geometry of the rhodium η² complexes involved in the diastereodifferentiation of the double bond faces. Thus, computational investigation of the η² intermediates formed in the catalytic cycle of prostereogenic alkene hydrogenation by using Wilkinson’s catalyst could be highly predictive of the stereochemistry of the products.     

Chemoselectivity Control in the Asymmetric Hydrogenation of γ‐ and δ‐Keto Esters into Hydroxy Esters or Diols

The asymmetric hydrogenation of aromatic γ‐ and δ‐keto esters into optically active hydroxy esters or diols under the catalysis of a novel DIPSkewphos/3‐AMIQ–Ru^II complex was studied. Under the optimized conditions (8 atm H₂ , Ru complex/t‐C₄H₉OK=1:3.5, 25 °C) the γ‐ and δ‐hydroxy esters (including γ‐lactones) were obtained quantitatively with 97–99 % ee. When the reaction was conducted under somewhat harsh conditions (20 atm H₂ , [t‐C₄H₉OK]=50 mm , 40 °C), the 1,4‐ and 1,5‐diols were obtained predominantly with 95–99 % ee. The reactivity of the ester group was notably dependent on the length of the carbon spacer between the two carbonyl moieties of the substrate. The reaction of β‐ and ?‐keto esters selectively afforded the hydroxy esters regardless of the reaction conditions. This catalyst system was applied to the enantioselective and regioselective (for one of the two ester groups) hydrogenation of a γ‐?‐diketo diester into a trihydroxy ester.     

Pd(II)‐Catalyzed Tandem Enantioselective Methylene C(sp3)−H Alkenylation–Aza‐Wacker Cyclization to Access β‐Stereogenic γ‐Lactams

Herein, we describe an unprecedented cascade reaction to β‐stereogenic γ‐lactams involving Pd(II)‐catalyzed enantioselective aliphatic methylene C(sp³)?H alkenylation–aza‐Wacker cyclization through syn‐aminopalladation. Readily available 3,3′‐substituted BINOLs are used as chiral ligands, providing the corresponding γ‐lactams with broad scope and high enantioselectivities (up to 98 % ee).     

Methyl 2‐O‐β‐d‐glucopyranosyl‐α‐l‐rhamnopyranoside

The overall conformation of the title compound, C₁₃H₂₄O₁₀, is described by the glycosidic torsion angles ?_H (H1_g—C1_g—O2_r—C2_r) and ψ_H (C1_g—O2_r—C2_r—H2_r), which have values of 13.6 and 16.1°, respectively. The former is significantly different from the value predicted by consideration of the exo‐anomeric effect (?_H～ 60°) and from that in solution (?_H～ 50°), as determined previously by NMR spectroscopy. An intramolecular O3_r—H?O2_g hydrogen bond may help to stabilize the conformation in the solid state. The orientation of the hydroxy­methyl group of the glucose residue is gauche–gauche, with a torsion angle ω (O5_g—C5_g—C6_g—O6_g) of ?70.4 (4)°. Both pyranose rings are in their expected chair conformations, i.e.⁴C₁ for d ‐glucose and ¹C₄ for l ‐rhamnose.     

Nickel(0)-Catalyzed Enantioselective [3+2] Annulation of Cyclopropenones and α,β-Unsaturated Ketones/Imines

Ni⁰-catalyzed chemo- and enantioselective [3+2] cycloaddition of cyclopropenones and α,β-unsaturated ketones/imines is described. This reaction integrates C−C bond cleavage of cyclopropenones and enantioselective functionalization by carbonyl/imine group, offering a mild approach to γ-alkenyl butenolides and lactams in excellent enantioselectivity (88–98 % ee) through intermolecular C−C activation.     

Preparation of Protected β2‐ and β3‐Homocysteine, β2‐ and β3‐Homohistidine,and β2‐Homoserine for Solid‐Phase Syntheses

The Ser, Cys, and His side chains play decisive roles in the syntheses, structures, and functions of proteins and enzymes. For our structural and biomedical investigations of β‐peptides consisting of amino acids with proteinogenic side chains, we needed to have reliable preparative access to the title compounds. The two β³‐homoamino acid derivatives were obtained by Arndt–Eistert methodology from Boc‐His(Ts)‐OH and Fmoc‐Cys(PMB)‐OH (Schemes 2–4), with the side‐chain functional groups' reactivities requiring special precautions. The β²‐homoamino acids were prepared with the help of the chiral oxazolidinone auxiliary DIOZ by diastereoselective aldol additions of suitable Ti‐enolates to formaldehyde (generated in situ from trioxane) and subsequent functional‐group manipulations. These include OH→O^tBu etherification (for β²hSer; Schemes 5 and 6), OH→STrt replacement (for β²hCys; Scheme 7), and CH₂OH→CH₂N₃→CH₂NH₂ transformations (for β²hHis; Schemes 9–11). Including protection/deprotection/re‐protection reactions, it takes up to ten steps to obtain the enantiomerically pure target compounds from commercial precursors. Unsuccessful approaches, pitfalls, and optimization procedures are also discussed. The final products and the intermediate compounds are fully characterized by retention times (t_R), melting points, optical rotations, HPLC on chiral columns, IR, ¹H‐ and ¹³C‐NMR spectroscopy, mass spectrometry, elemental analyses, and (in some cases) by X‐ray crystal‐structure analysis.     

Oxidative β‐Csp3−H Functionalization of tBuOH: A Selective Radical/Radical Cross‐Coupling Access to β‐Hydroxy Thioethers

An oxidative β‐Csp³?H functionalization of tert‐butanol (tBuOH) for the construction of C?S bonds through an iodine‐catalyzed Csp³?H/S?H coupling was successfully achieved. Different kinds of mercaptans were shown to be good coupling partners, affording the desired products in good yields. This protocol not only offers a novel method for the synthesis of β‐hydroxy thioethers, but also provides an effective strategy for selective radical/radical cross‐coupling.     

Investigation of the stereodynamics of tris‐(α‐diimine)–transition metal complexes by enantioselective dynamic MEKC

Enantiomerization of octahedral tris(α‐diimine)–transition metal complexes was investigated by enantioselective dynamic MEKC. Varying both the transition metal ion (Fe²⁺, Fe³⁺, and Ni²⁺) and the bidentate diimine ligand (1,10‐phenanthroline and 2,2′‐bipyridyl), the enantiomer separations were performed either in a 100 mM sodium tetraborate buffer (pH 9.3) or in a 100 mM sodium tetraborate/sodium dihydrogenphosphate buffer (pH 8.0) both containing sodium cholate as chiral surfactant. The unified equation of dynamic chromatography was employed to determine apparent reaction rate constants from the electropherograms showing distinct plateau formation. Apparent activation parameters ΔH^? and ΔS^? were calculated from temperature‐dependent measurements between 10.0 and 35.0°C in 2.5 K steps. It was found that the nature of the central metal ion and the ligand strongly influence the enantiomerization barrier. Surprisingly, complexes containing the 2,2′‐bipyridyl ligand show highly negative activation entropies between ?103 and ?116 J (K mol)^?1 while the activation entropy of tris(1,10‐phenanthroline) complexes is positive indicating a different mechanism of interconversion. Furthermore, it was found that the Ni²⁺ complexes are stereostable under the conditions investigated here making them a lucent target as enantioselective catalysts.     

Asymmetric Catalytic Formal 1,4‐Allylation of β,γ‐Unsaturated α‐Ketoesters: Allylboration/Oxy‐Cope Rearrangement

A highly enantioselective formal conjugate allyl addition of allylboronic acids to β,γ‐unsaturated α‐ketoesters has been realized by employing a chiral Ni^II/N,N′‐dioxide complex as the catalyst. This transformation proceeds by an allylboration/oxy‐Cope rearrangement sequence, providing a facile and rapid route to γ‐allyl‐α‐ketoesters with moderate to good yields (65–92 %) and excellent ee values (90–99 % ee). The isolation of 1,2‐allylboration products provided insight into the mechanism of the subsequent oxy‐Cope rearrangement reaction: substrate‐induced chiral transfer and a chiral Lewis acid accelerated process. Based on the experimental investigations and DFT calculations, a rare boatlike transition‐state model is proposed as the origin of high chirality transfer during the oxy‐Cope rearrangement.     

Electrophilic Alkylations of Vinylsilanes: A Comparison of α‐ and β‐Silyl Effects

Kinetics of the reactions of benzhydrylium ions (Aryl₂CH⁺) with the vinylsilanes H₂C?C(CH₃)(SiR₃), H₂C?C(Ph)(SiR₃), and (E)‐PhCH?CHSiMe₃ have been measured photometrically in dichloromethane solution at 20 °C. All reactions follow second‐order kinetics, and the second‐order rate constants correlate linearly with the electrophilicity parameters E of the benzhydrylium ions, thus allowing us to include vinylsilanes in the benzhydrylium‐based nucleophilicity scale. The vinylsilane H₂C?C(CH₃)(SiMe₃), which is attacked by electrophiles at the CH₂ group, reacts one order of magnitude faster than propene, indicating that α‐silyl‐stabilization of the intermediate carbenium ion is significantly weaker than α‐methyl stabilization because H₂C?C(CH₃)₂ is 10³ times more reactive than propene. trans‐β‐(Trimethylsilyl)styrene, which is attacked by electrophiles at the silylated position, is even somewhat less reactive than styrene, showing that the hyperconjugative stabilization of the developing carbocation by the β‐silyl effect is not yet effective in the transition state. As a result, replacement of vinylic hydrogen atoms by SiMe₃ groups affect the nucleophilic reactivities of the corresponding C?C bonds only slightly, and vinylsilanes are significantly less nucleophilic than structurally related allylsilanes.     

Asymmetric Hydrogenation of α,β‐Unsaturated Nitriles with Base‐Activated Iridium N,P Ligand Complexes

Although many chiral catalysts are known that allow highly enantioselective hydrogenation of a wide range of olefins, no suitable catalysts for the asymmetric hydrogenation of α,β‐unsaturated nitriles have been reported so far. We have found that Ir N,P ligand complexes, which under normal conditions do not show any reactivity towards α,β‐unsaturated nitriles, become highly active catalysts upon addition of N,N‐diisopropylethylamine. The base‐activated catalysts enable conjugate reduction of α,β‐unsaturated nitriles with H₂ at low catalyst loadings, affording the corresponding saturated nitriles with high conversion and excellent enantioselectivity. In contrast, alkenes lacking a conjugated cyano group do not react under these conditions, making it possible to selectively reduce the conjugated C?C bond of an α,β‐unsaturated nitrile, while leaving other types of C?C bonds in the molecule intact.     

Radical‐initiated polymerization of β‐methyl‐α‐methylene‐γ‐butyrolactone

β‐Methyl‐α‐methylene‐γ‐butyrolactone (MMBL) was synthesized and then was polymerized in an N,N‐dimethylformamide (DMF) solution with 2,2‐azobisisobutyronitrile (AIBN) initiation. The homopolymer of MMBL was soluble in DMF and acetonitrile. MMBL was homopolymerized without competing depolymerization from 50 to 70 °C. The rate of polymerization (R_p) for MMBL followed the kinetic expression R_p = [AIBN]^0.54[MMBL]^1.04. The overall activation energy was calculated to be 86.9 kJ/mol, k_p/k_t^1/2 was equal to 0.050 (where k_p is the rate constant for propagation and k_t is the rate constant for termination), and the rate of initiation was 2.17 × 10^?8 mol L^?1 s^?1. The free energy of activation, the activation enthalpy, and the activation entropy were 106.0, 84.1, and 0.0658 kJ mol^?1, respectively, for homopolymerization. The initiation efficiency was approximately 1. Styrene and MMBL were copolymerized in DMF solutions at 60 °C with AIBN as the initiator. The reactivity ratios (r₁ = 0.22 and r₂ = 0.73) for this copolymerization were calculated with the Kelen–Tudos method. The general reactivity parameter Q and the polarity parameter e for MMBL were calculated to be 1.54 and 0.55, respectively. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 1759–1777, 2003     

Dye‐Labeled Cα‐Tetrasubstituted α‐Amino Acids

We report the synthesis of pyrene‐ and carboxyfluorescein labeled C^α‐tetrasubstituted amino acids (TAAs). The fluorescent dye can be coupled to the TAA before or after its incorporation into a peptide sequence using a Suzuki‐type C? C bond formation.     

Gold‐catalyzed Reactions of 3‐Alkynyloxireno[2, 3‐b]chromenones to Form 3(2H)‐Furanones via a Domino Pathway

3(2H)‐Furanones are efficiently generated from 3‐alkynyl oxireno[2,3‐b]chromenones by an Au/DDQ‐catalyzed domino reaction through a pathway composed of cyclization, C? C cleavage, nucleophilic addition, oxidation, and nucleophilic addition. It was found that stoichiometric AuCl₃ or catalytic Au with stoichiometric DDQ can oxidize the benzylic sp³ C? H bond to facilitate nucleophilic addition.     

Application of a CC Bond‐Forming Conjugate Addition Reaction in Asymmetric Dearomatization of β‐Naphthols

A C? C bond‐forming conjugate reaction was successfully applied to the enantioselective dearomatization of β‐naphthols. A C(sp2)? C(sp3) bond is formed by using propargylic ketones as reactive partners. Good to excellent Z/E ratios and ee values were obtained by employing an in situ generated magnesium catalyst. Further transformations of the Z‐configured C? C double bond in the products were achieved under mild reaction conditions. Moreover, the stereocontrolling element of this magnesium‐catalyzed dearomatization reaction was explored by computational chemistry.     

Enantioselective Synthesis of α‐Hydroxy Amides and β‐Amino Alcohols from α‐Keto Amides

Synthesis of enantiomerically enriched α‐hydroxy amides and β‐amino alcohols has been accomplished by enantioselective reduction of α‐keto amides with hydrosilanes. A series of α‐keto amides were reduced in the presence of chiral Cu^II/(S)‐DTBM‐SEGPHOS catalyst to give the corresponding optically active α‐hydroxy amides with excellent enantioselectivities by using (EtO)₃SiH as a reducing agent. Furthermore, a one‐pot complete reduction of both ketone and amide groups of α‐keto amides has been achieved using the same chiral copper catalyst followed by tetra‐n‐butylammonium fluoride (TBAF) catalyst in presence of (EtO)₃SiH to afford the corresponding chiral β‐amino alcohol derivatives.     

Enantioselective Synthesis and Physicochemical Properties of Libraries of 3‐Amino‐ and 3‐Amidofluoropiperidines

The enantioselective syntheses of 3‐amino‐5‐fluoropiperidines and 3‐amino‐5,5‐difluoropiperidines were developed using the ring enlargement of prolinols to access libraries of 3‐amino‐ and 3‐amidofluoropiperidines. The study of the physicochemical properties revealed that fluorine atom(s) decrease(s) the pK_a and modulate(s) the lipophilicity of 3‐aminopiperidines. The relative stereochemistry of the fluorine atoms with the amino groups at C3 on the piperidine core has a small effect on the pK_a due to conformationnal modifications induced by fluorine atom(s). In the protonated forms, the C?F bond is in an axial position due to a dipole–dipole interaction between the N?H⁺ and C?F bonds. Predictions of the physicochemical properties using common software appeared to be limited to determine correct values of pK_a and/or differences of pK_a between cis‐ and trans‐3‐amino‐5‐fluoropiperidines.     

Chiral γ‐Lactams by Enantioselective Palladium(0)‐Catalyzed Cyclopropane Functionalizations

Cyclopropanes fused to pyrrolidines are important structural features found in a number of marketed drugs and development candidates. Typically, their synthesis involves the cyclopropanation of a dihydropyrrole precursor. Reported herein is a complementary approach which employs a palladium(0)‐catalyzed C? H functionalization of an achiral cyclopropane to close the pyrrolidine ring in an enantioselective manner. In contrast to aryl–aryl couplings, palladium(0)‐catalyzed C? H functionalizations involving the formation of C(sp³)? C(sp³) bonds of saturated heterocycles are very scarce. The presented strategy yields cyclopropane‐fused γ‐lactams from chloroacetamide substrates. A bulky Taddol phosphonite ligand in combination with adamantane‐1‐carboxylic acid as a cocatalyst provides the γ‐lactams in excellent yields and enantioselectivities.     

Preparation of (S,S)‐Fmoc‐β2hIle‐OH, (S)‐Fmoc‐β2hMet‐OH,and (S)‐Fmoc‐β2hTyr(tBu)‐OH for Solid‐Phase Syntheses of β2‐ and β2/β3‐Peptides

The preparation of three new N‐Fmoc‐protected (Fmoc=[(9H‐fluoren‐9‐yl)methoxy]carbonyl) β²‐homoamino acids with proteinogenic side chains (from Ile, Tyr, and Met) is described, the key step being a diastereoselective amidomethylation of the corresponding Ti‐enolates of 3‐acyl‐4‐isopropyl‐5,5‐diphenyloxazolidin‐2‐ones with CbzNHCH₂OMe/TiCl₄ (Cbz=(benzyloxy)carbonyl) in yields of 60–70% and with diastereoselectivities of >90%. Removal of the chiral auxiliary with LiOH or NaOH gives the N‐Cbz‐protected β‐amino acids, which were subjected to an N‐Cbz/N‐Fmoc (Fmoc=[(9H‐fluoren‐9‐yl)methoxy]carbonyl) protective‐group exchange. The method is suitable for large‐scale preparation of Fmoc‐β²hXaa‐OH for solid‐phase syntheses of β‐peptides. The Fmoc‐amino acids and all compounds leading to them have been fully characterized by melting points, optical rotations, IR, ¹H‐ and ¹³C‐NMR, and mass spectra, as well as by elemental analyses.     

Elementary reaction analysis of the radical polymerization of α‐ethyl β‐N‐(α′‐methylbenzyl)itaconamates carrying (RS)‐ and (S)‐α‐methylbenzylaminocarbonyl groups

The polymerizations of α‐ethyl β‐N‐(α′‐methylbenzyl)itaconamates carrying (RS)‐ and (S)‐α‐methylbenzylaminocarbonyl groups (RS‐EMBI and S‐EMBI) with dimethyl 2,2′‐azobisisobutyrate (MAIB) were studied in methanol (MeOH) and in benzene kinetically and with electron spin resonance (ESR) spectroscopy. The initial polymerization rate (R_p) at 60 °C was given by R_p = k[MAIB]^{0.58 ± 0.05}[RS‐EMBI]^{2.4 ± 0.l} and R_p = k[MAIB]^{0.61 ± 0.05}[S‐EMBI]^{2.3 ± 0.l} in MeOH and R_p = k[MAIB]^{0.54 ± 0.05}[RS‐EMBI]^{1.7 ± 0.l} in benzene. The rate constants of initiation (k_df), propagation (k_p), and termination (k_t) as elementary reactions were estimated by ESR, where k_d is the rate constant of MAIB decomposition and f is the initiator efficiency. The k_p values of RS‐EMBI (0.50–1.27 L/mol s) and S‐EMBI (0.42–1.32 L/mol s) in MeOH increased with increasing monomer concentrations, whereas the k_t values (0.20?7.78 × 10⁵ L/mol s for RS‐EMBI and 0.18?6.27 × 10⁵ L/mol s for S‐EMBI) decreased with increasing monomer concentrations. Such relations of R_p with k_p and k_t were responsible for the unusually high dependence of R_p on the monomer concentration. The activation energies of the elementary reactions were also determined from the values of k_df, k_p, and k_t at different temperatures. R_p and k_p of RS‐EMBI and S‐EMBI in benzene were considerably higher than those in MeOH. R_p of RS‐EMBI was somewhat higher than that of S‐EMBI in both MeOH and benzene. Such effects of the kinds of solvents and monomers on R_p were explicable in terms of the different monomer associations, as analyzed by ¹H NMR. The copolymerization of RS‐EMBI with styrene was examined at 60 °C in benzene. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 1819–1830, 2003