Direct Catalytic Asymmetric Vinylogous Additions of α,β‐ and β,γ‐Butenolides to Polyfluorinated Alkynyl Ketimines

We report a Zn‐ProPhenol catalyzed asymmetric Mannich reaction between butenolides and polyfluorinated alkynyl ketimines to obtain vinylogous products featuring two contiguous tetrasubstituted stereogenic centers. Notably, this is the first successful use of ketimines in the ProPhenol Mannich process, and the reaction offers a new approach for the preparation of pharmaceutically relevant products possessing trifluoromethylated tetrasubstituted alkylamines. The reaction can be performed on large scale with reduced catalyst loading without impacting its efficiency. Moreover, the acetylene moiety can be further elaborated using various methods.     

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.     

(E)‐,(Z)‐Parallel Preparative Methods for Stereodefined β,β‐Diaryl‐ and α,β‐Diaryl‐α,β‐unsaturated Esters: Application to the Stereocomplementary Concise Synthesis of Zimelidine

Parallel and practical methods for the preparation of both (E)‐ and (Z)‐β‐aryl¹‐β‐aryl²‐α,β‐unsaturated esters 1 and (E)‐ and (Z)‐α‐aryl¹‐β‐aryl²‐α,β‐unsaturated esters 2 are described. These methods involve accessible, robust, stereocomplementary N‐methylimidazole (NMI)‐mediated enol tosylations (14 examples, 70–99 % yield), as well as stereoretentive Suzuki–Miyaura cross‐couplings (36 examples, 64–99 % yield). The highlighted feature of the present protocol is the use of parallel and stereocomplementary approaches to obtain highly (E)‐ and (Z)‐pure products 1 and 2 by utilizing sequential enol tosylations and cross‐coupling reactions. An expeditious and parallel synthesis of (E)‐ and (Z)‐zimelidine ( 3 ), which is a highly representative selective serotonin reuptake inhibitor (SSRI), was performed by utilizing the present methods.     

Synthesis and characterization of new α,β‐unsaturated γ‐lactones: Alkyl 3‐acetyl‐4‐hydroxy‐2‐methyl‐5‐oxo‐2,5‐dihydrofuran‐2‐ylcarbamates

A convenient procedure for the preparation of carbamate derivatives of 5‐oxo‐2,5‐dihydrofuran ( 3 ) was described. The method is based on the Michael type addition of three alkyl carbamates ( 2 ) with 4‐acetyl‐5‐methyl‐2,3‐dihydro‐2,3‐furandione ( 1 ). According to ¹H nmr spectra of compounds show tautomeric forms ( 3,4,5 ) in CDC1₃. In the solid state the synthesized compounds are enol forms ( 3 ). The products were characterized with molecular spectroscopic methods.     

MALDI imaging mass spectrometry of β‐ and γ‐crystallins in the ocular lens

Lens crystallin proteins make up 90% of expressed proteins in the ocular lens and are primarily responsible for maintaining lens transparency and establishing the gradient of refractive index necessary for proper focusing of images onto the retina. Age‐related modifications to lens crystallins have been linked to insolubilization and cataractogenesis in human lenses. Matrix‐assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) has been shown to provide spatial maps of such age‐related modifications. Previous work demonstrated that, under standard protein IMS conditions, α‐crystallin signals dominated the mass spectrum and age‐related modifications to α‐crystallins could be mapped. In the current study, a new sample preparation method was optimized to allow imaging of β‐ and γ‐crystallins in ocular lens tissue. Acquired images showed that γ‐crystallins were localized predominately in the lens nucleus whereas β‐crystallins were primarily localized to the lens cortex. Age‐related modifications such as truncation, acetylation, and carbamylation were identified and spatially mapped. Protein identifications were determined by top‐down proteomics analysis of lens proteins extracted from tissue sections and analyzed by LC‐MS/MS with electron transfer dissociation. This new sample preparation method combined with the standard method allows the major lens crystallins to be mapped by MALDI IMS.     

Efficient Synthesis of α‐Benzylidene‐γ‐methyl‐γ‐butyrolactones

A concise synthesis of α‐benzylidene‐γ‐methyl‐γ‐butyrolactones 5a – g from substituted benzaldehydes is described. Compounds 1a – g on reaction with phosphorane 2 , provide the pentenoates 3a – g , which can be hydrolyzed to the acids 4a – g . The latter are cyclized to the corresponding butyrolactones 5a – g in excellent yields. The pentenoates 3a – g , on acid catalyzed cyclization, also provide 5a – g in very high yields.     

Copper(I)‐Mediated Denitrogenative Macrocyclization for the Synthesis of Cyclic α3β‐Tetrapeptide Analogues

A copper(I)‐mediated denitrogenative reaction has been successfully developed for the preparation of cyclic tetrapeptides. The key reactive intermediate, ketenimine, triggers intramolecular cyclization through attack of the terminal amine group to generate an internal β‐amino acid with an amidine linkage. The chemistry developed herein provides a new synthetic route for the preparation of cyclic α₃β‐tetrapeptide analogues that contain important biological properties and results in rich structural information being obtained for conformational studies. With the success of this copper(I)‐catalyzed macrocyclization, two histone deacetylase inhibitor analogues consisting of the cyclic α₃β‐tetrapeptide framework have been successfully synthesized.     

Diastereocontrolled Monoprotodeboronation of β‐Sulfinimido gem‐Bis(boronates): A General and Stereoselective Route to α,β‐Disubstituted β‐Aminoalkylboronates

β‐Aminoalkylboronic acids are bioisosteres of the pharmaceutically important class of β‐amino acids but few stereoselective methods exist for their preparation. The 1,2‐addition of lithiated 1,1‐diborylalkanes onto chiral N‐tert‐butanesulfinyl aldimines produces β‐sulfinimido gem‐bis(boronates) in good to excellent yields with high diastereoselectivity. The optimized conditions involve the use of rubidium fluoride and water, and are compatible with functionalized alkyl, aryl, alkenyl, and alkynyl substituents. Under these conditions, the geminal quaternary alkyl bis(pinacolatoboryl) intermediates undergo a highly diastereoselective monoprotodeboronation to afford a wide range of syn‐α,β‐disubstituted β‐aminoalkylboronates. This novel application of protodeboronation chemistry was shown to result from a kinetically controlled, diastereotopic‐group‐selective B?C bond protolysis dictated by the configuration of the adjacent stereogenic C?N center. Facile acidic cleavage of the sulfinimide auxiliary produces the free aminoboronates with high enantiomeric purity.     

Acyclic Branched α‐Fluoro Ketones for the Direct Asymmetric Mannich Reaction Leading to the Synthesis of β‐Tetrasubstituted β‐Fluoro Amines

The preparation of acyclic β‐fluoro amines bearing tetrasubstituted fluorine stereocenters is described via a direct Zn/ProPhenol‐catalyzed Mannich reaction. The reaction utilizes branched vinyl or alkynyl α‐fluoro ketones that can be coupled with a range of aryl, heteroaryl, vinyl, or cyclopropyl aldimines in high yield and with excellent diastereo‐ (up to >20:1) and enantioselectivity (up to 99 %). The use of readily cleaved tert‐butoxycarbonyl (Boc) or carboxybenzyl (Cbz) imine protecting groups adds utility to the reaction by allowing for easy access to the free amine products under mild and chemoselective reaction conditions.     

A facile and efficient synthesis of diethyl α,α‐chlorofluoroalkanephosphonates

A facile and efficient synthetic methodo‐ logy for the preparation of diethyl α,α‐chlorofluoro‐ alkanephosphonates is described. A wide variety of diethyl α‐hydroxyphosphonates were investigated by a two‐step halogenation procedure, which includes nucleophilic chlorination with PPh₃ and CCl₄ and electrophilic fluorination with N‐fluorobisbenzene‐ sulfonimide. Aromatic and aliphatic α,α‐chlorofluoro‐ phosphonates could be prepared by this method with acceptable yields. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:250–255, 2010; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20604     

Phosphine‐Catalyzed Enantioselective γ‐Addition of 3‐Substituted Oxindoles to 2,3‐Butadienoates and 2‐Butynoates: Use of Prochiral Nucleophiles

The first phosphine‐catalyzed enantioselective γ‐addition with prochiral nucleophiles and 2,3‐butadienoates as the reaction partners has been developed. Both 3‐alkyl‐ and 3‐aryl‐substituted oxindoles could be employed in this process, which is catalyzed by a chiral phosphine that is derived from an amino acid, thus affording oxindoles that bear an all‐carbon quaternary center at the 3‐position in high yields and excellent enantioselectivity. The synthetic value of these γ‐addition products was demonstrated by the formal total synthesis of two natural products and by the preparation of biologically relevant molecules and structural scaffolds.     

Synthesis of Highly Substituted Pyridines through Copper‐Catalyzed Condensation of Oximes and α,β‐Unsaturated Imines

A copper‐catalyzed condensation reaction of oxime acetates and α,β‐unsaturated ketimines to give pyridine derivatives is reported. The reaction features mild conditions, high functional‐group compatibility, and high regioselectivity with respect to unsymmetrical oxime acetates, thus allowing the preparation of a wide range of polysubstituted pyridines, many of which are not readily accessible by conventional condensation methods.     

Chemical Kinetic Resolution of Unprotected β‐Substituted β‐Amino Acids Using Recyclable Chiral Ligands

The first chemical method for resolution of N,C‐unprotected β‐amino acids was developed through enantioselective formation and disassembly of nickel(II) complexes under operationally convenient conditions. The specially designed chiral ligands are inexpensive and can be quantitatively recycled along with isolation of the target β‐substituted‐β‐amino acids in good yields and excellent enantioselectivity. The method features a broad synthetic generality including β‐aryl, β‐heteroaryl, and β‐alkyl‐derived β‐amino acids. The procedure is easily scaled up, and was used for the synthetically and economically advanced preparation of the anti‐diabetic drug sitagliptin.     

5β,6β‐Epoxy‐17‐oxoandrostan‐3β‐yl acetate and 5β,6β‐epoxy‐20‐oxopregnan‐3β‐yl acetate

In the title compounds, C₂₁H₃₀O₄, (I), and C₂₃H₃₄O₄, (II), respectively, which are valuable intermediates in the synthesis of important steroid derivatives, rings A and B are cis‐(5β,10β)‐fused. The two molecules have similar conformations of rings A, B and C. The presence of the 5β,6β‐epoxide group induces a significant twist of the steroid nucleus and a strong flattening of the B ring. The different C17 substituents result in different conformations for ring D. Cohesion of the molecular packing is achieved in both compounds only by weak intermolecular interactions. The geometries of the molecules in the crystalline environment are compared with those of the free molecules as given by ab initio Roothan Hartree–Fock calculations. We show in this work that quantum mechanical ab initio methods reproduce well the details of the conformation of these molecules, including a large twist of the steroid nucleus. The calculated twist values are comparable, but are larger than the observed values, indicating a possible small effect of the crystal packing on the twist angles.     

13‐cis‐β,β‐Carotene and 15‐cis‐β,β‐carotene

13‐cis‐β,β‐Carotene, C₄₀H₅₆, crystallizes with a complete molecule in the asymmetric unit, whereas 15‐cis‐β,β‐carotene, also C₄₀H₅₆, has twofold symmetry about an axis through the central bond of the polyene chain. The polyene methyl groups are arranged on one side of the polyene chains for each molecule and the 6‐s‐cisβ end groups, with the cyclohexene rings in half‐chair conformations, are twisted out of the planes of the polyene chains by angles ranging from 41.37 (17) to 52.2 (4)°. The molecules in each structure pack so that the arms of one occupy the cleft of the next, and there is significant π–π stacking of the almost‐parallel polyene chains of the 15‐cis isomer, which approach at distances of 3.319 (1)–3.591 (1) Å.     

Ligand‐Enabled β‐C–H Arylation of α‐Amino Acids Without Installing Exogenous Directing Groups

Herein we report acid‐directed β‐C(sp³)‐H arylation of α‐amino acids enabled by pyridine‐type ligands. This reaction does not require the installation of an exogenous directing group, is scalable, and enables the preparation of Fmoc‐protected unnatural amino acids in three steps. The pyridine‐type ligands are crucial for the development of this new C(sp³)‐H arylation.     

Total Synthesis of (+)‐Chinensiolide B from α‐Santonin

A short and efficient total synthesis of (+)‐chinensiolide B is reported, starting from commercially available α ‐santonin. This strategy could be used for rapid preparation of chinensiolides and their derivative for further structure activity relationship studies.     

Functional polyesters prepared by polymerization of α‐allyl(valerolactone) and its copolymerization with ε‐caprolactone and δ‐valerolactone

We report the ring‐opening homopolymerization of α‐allyl(valerolactone), compound 2 , and its copolymerization with ε‐caprolactone and δ‐valerolactone using stannous(II) catalysis. Although the polymerization of substituted δ‐valerolactones has received little attention for the preparation of functional polyesters, we found that compound 2 may be incorporated in controllable amounts into copolymers with other lactones, or simply homopolymerized to give a highly functionalized, novel poly(valerolactone). The presence of the pendant allyl substituent had a substantial impact on the thermal properties of these materials relative to conventional polyesters prepared from lactones, and most of the polymers presented here are liquids at room temperature. Dihydroxylation of the pendant allyl groups gave polyesters with increased hydrophilicity that degraded more or less rapidly depending on their extent of functionality. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 1983–1990, 2002     

Controlled Heterocyclization/Cross‐Coupling Domino Reaction of β,γ‐Allendiols and α‐Allenic Esters: Method and Mechanistic Insight for the Preparation of Functionalized Buta‐1,3‐dienyl Dihydropyrans

Starting from β,γ‐allendiols and α‐allenic acetates, a chemo‐ and regiocontrolled palladium‐catalyzed methodology has provided access to enantiopure 3,6‐dihydropyrans that bear a buta‐1,3‐dienyl moiety. Thus, it has been demonstrated for the first time that the preparation of six‐membered heterocycles through cross‐coupling reactions of two different allenes can be accomplished. These heterocyclization/cross‐coupling reactions have been developed experimentally and their mechanisms have additionally been investigated by a computational study.     

5-雄烯-3β, 7α, 17β-三醇和5-雄烯-3β, 7β, 17β-三醇的合成

以5-雄烯二醇为原料,用微生物转化的方法合成了两个重要的神经甾体5-雄烯-3β, 7α, 17β-三醇和5-雄烯-3β, 7β, 17β-三醇。所用菌种总枝毛霉为我们自己筛选,并首次应用于5-雄烯-3β, 7α, 17β-三醇和5-雄烯-3β, 7β, 17β-三醇的合成中。