Enantioselective Hydrogenation of β‐Acylamino Acrylates Catalyzed by Rhodium(I)‐Monophosphite Complexes

Chiral rhodium(I) complexes bearing monophosphite ligands, prepared from chiral Binol and (L )‐menthol, were found to be efficient catalysts for the asymmetric hydrogenation of β‐acylamino acrylates with ee values up to 94%.     

Titanium‐Catalyzed Enantioselective Synthesis of α‐Ambrinol

We describe the first enantioselective synthesis of the odorant compound (−)‐α‐ambrinol (96% ee) from commercial geranylacetone. The key steps are a Jacobsen’s asymmetric epoxidation and a titanium‐catalyzed stereoselective cyclization initiated by radical epoxide opening. The oxirane ring opening proceeds with retention of configuration at the epoxide chiral center, giving a secondary alcohol which can be advantageously exploited to raise the ee provided by the synthetic sequence. We also synthesized (+)‐α‐ambrinol by a closely related procedure, showing the synthetic versatility of combining titanium‐catalyzed cyclization with Jacobsen’s epoxidation reactions.     

A Practical Synthesis of α‐Fluoroketones in Aqueous Media by Decarboxylative Fluorination of β‐Ketoacids

A practical and novel process for the decarboxylative fluorination of β‐ketoacids in water in the presence of phase transfer catalyst has been developed, affording a series of α‐fluoroketones in good to excellent yields. Furthermore, a preliminary investigation for the catalytic asymmetric transformation was performed and a proposed mechanistic pathway for this catalytic process was proposed.

     

Enantioselective Hydrogenation of α‐Dehydroamino Acid Esters Catalyzed by Rhodium Complexes with Chiral Bisaminophosphine Ligands

A highly efficient strategy for the synthesis of a series of chiral bisaminophosphine ligands was well established with several remarkable features. The synthetic utility of these ligands was explored for rhodium‐catalyzed asymmetric hydrogenations of α‐dehydroamino acid esters. Up to 98% ee values were achieved for the enantioselective synthesis of aminocarboxylic acids and their derivatives, which are very important chiral building blocks for the synthesis of a variety of natural products and biologically active molecules.     

Organocatalytic Enantioselective Aziridination of α‐Substituted α,β‐Unsaturated Aldehydes: Asymmetric Synthesis of Terminal Aziridines

The first example of a highly enantioselective organocatalytic aziridination of α‐substituted α,β‐unsaturated aldehydes is presented. The reaction is catalyzed by simple chiral amines and gives access to highly functional terminal azirdines containing an α‐tertiary amine stereocenter in high yields and enantiomeric ratios (95.5:4.5–98:2).     

Ruthenium(II)‐Catalyzed Protocol for Preparation of Diverse α,β‐ and β,β‐Dihaloenones from Diazodicarbonyls

Efficient one‐step syntheses of α,β‐ and β,β‐dihaloenones were achieved by ruthenium(II)‐catalyzed reactions between cyclic or acyclic diazodicarbonyl compounds and oxalyl chloride or oxalyl bromide in moderate to good yields. This methodology offers several significant advantages, which include ease of handling, mild reaction conditions, one‐step reaction, and the use of an effective and non‐toxic catalyst. The synthesized compounds were further transformed into highly functionalized novel molecules bearing aromatic rings on the enone moiety using the Suzuki reaction.

     

Regio‐ and Enantioselective Copper‐Catalyzed 1,4‐Conjugate Addition of Trimethylaluminium to Linear α,β,γ,δ‐Unsaturated Alkyl Ketones

A regio‐ and enantioselective copper‐catalyzed 1,4‐conjugate addition of trimethylaluminium to linear δ‐aryl‐substituted α,β,γ,δ‐unsaturated alkyl ketones was developed. A series of γ,δ‐unsaturated alkyl ketones were obtained in good yields with high regio‐ and enantioselectivity (up to 88% ee and 96:4 dr). Expansion of the reaction scope to substrates containing aromatic heterocycles also afforded good yields and enantioselectivities (up to 91% ee) with very high regioselectivities, exclusively providing the single 1,4‐products.

     

Enantioselective N‐Heterocyclic Carbene‐Catalyzed [3+3] Annulation of α,β‐Unsaturated Esters with Methyl Ketoimine

Herein, we disclose the N‐heterocyclic carbene (NHC)‐catalyzed [3+3] annulation of challenging esters with methyl ketoimines for the highly enantioselective synthesis of intriguing δ‐lactams featuring various substituent patterns. The annulation occurs under mild conditions and offers good tolerance, good yields and excellent enantioselectivities. The six‐membered heterocyclic products are valuable for the synthesis of bioactive molecules.

     

Molecular Basis for the Enantioselective Ring Opening of β‐Lactams Catalyzed by Candida antarctica Lipase B

Lipase B from Candida antarctica (CAL‐B) catalyzes the slow, but highly enantioselective (E>200), ring‐opening alcoholysis of two bicyclic and two 4‐aryl‐substituted β‐lactams. Surprisingly, the rate of the reaction varies with the nature of the alcohols and was fastest with either enantiomer of 2‐octanol. A 0.5‐g scale reaction with 2‐octanol as the nucleophile in diisopropyl ether at 60 °C yielded the unreacted β‐lactam in 39–46% yield (maximum yield is 50%) with ≥96% ee. The product β‐amino acid esters reacted further by polymerization (not isolated or characterized) or by hydrolysis due to small amounts of water in the reaction mixture yielding β‐amino acids (7–11% yield, ≥96% ee). The favored enantiomer of all four β‐lactams had similar 3‐D orientation of substituents, as did most previously reported β‐lactams and β‐lactones in similar ring‐opening reactions. Computer modeling of the ring opening of 4‐phenylazetidin‐2‐one suggests that the reaction proceeds via an unusual substrate‐assisted transition state, where the substrate alcohol bridges between the catalytic histidine and the nitrogen of the β‐lactam. Computer modeling also suggested that the molecular basis for the high enantioselectivity is a severe steric clash between Ile189 in CAL‐B and the phenyl substituent on the slow‐reacting enantiomer of the β‐lactam.     

Access to Both Enantiomers of α‐Chloro‐β‐keto Esters with a Single Chiral Ligand: Highly Efficient Enantioselective Chlorination of Cyclic β‐Keto Esters Catalyzed by Chiral Copper(II) and Zinc(II) Complexes of a Spiro‐2,2′‐bischroman‐Based Bisoxazoline Ligand

The spiro‐2,2′‐bichroman‐based chiral bisoxazoline ligands (SPANbox) were found to be highly efficient in copper(II)‐ and zinc(II)‐catalyzed asymmetric chlorinations of cyclic β‐keto esters with N‐chlorosuccinimide (NCS) as the chlorination reagent, to give the corresponding α‐chloro‐β‐keto esters in excellent yields in 5–30 min with ee values up to 97%. The copper(II) triflate and zinc(II) triflate complexes of a single SPANbox ligand demonstrated complementary results to each other with respect to the enantioselection, affording both antipodes of the chlorinated product enantiomers with good to excellent optical purities.     

Ruthenium‐Catalyzed Oxidation of the Porphyrin β,β′‐Pyrrolic Ring: A General and Efficient Approach to Porpholactones

We describe an efficient ruthenium‐catalyzed oxidation of the β,β′‐pyrrolic ring on the porphyrin periphery. Through the conversion of a β,β′‐double bond to a lactone moiety, the direct preparation of porpholactones from porphyrins is achieved, which previously suffered from needing toxic reagents, multiple synthetic steps and low yields. The generality of this method has been investigated with various porphyrins with different electronic and steric effects, even some metalloporphyrins, and so represents a general and efficient approach for the synthesis of the intriguing porpholactone derivatives.     

Enantioselective Synthesis of cis‐4‐Formyl‐β‐lactams via Chiral N‐Heterocyclic Carbene‐Catalyzed Kinetic Resolution

An efficient synthesis of optically pure cis‐4‐formyl‐β‐lactams (up to 99% ee) by a chiral NHC‐catalyzed ring expansion reaction has been realized, featuring the ready availability of both the substrate and the catalyst, and the mild reaction conditions. The current method is also suitable for the synthesis of enantioenriched 4‐formyl‐β‐lactams and succinimides containing quaternary carbon centers.     

A Simple Organocatalytic Enantioselective Cyclopropanation of α,β‐Unsaturated Aldehydes

A highly chemo‐ and enantioselective organocatalytic cyclopropanation of α,β‐unsaturated aldehydes with bromomalonate and 2‐bromoacetoacetate esters is presented. The reaction is catalyzed by chiral amines and gives access to 2‐formylcyclopropanes in high yields and up to 99 % ee.     

Experimental and Computation Studies on Candida antarctica Lipase B‐Catalyzed Enantioselective Alcoholysis of 4‐Bromomethyl‐β‐lactone Leading to Enantiopure 4‐Bromo‐3‐hydroxybutanoate

Both enantiomers of optically pure 4‐bromo‐3‐hydroxybutanoate, which is an important chiral building block in the syntheses of various biologically active compounds including statins, were synthesized from rac‐4‐bromomethyl‐β‐lactone through kinetic resolution. Candida antarctica lipase B (CAL‐B) enantioselectively catalyzes the ring opening of the β‐lactone with ethanol to yield ethyl (R)‐4‐bromo‐3‐hydroxybutanoate with high enantioselectivity (E>200). The unreacted (S)‐4‐bromomethyl‐β‐lactone was converted to ethyl (S)‐4‐bromo‐3‐hydroxybutanoate (>99% ee), which can be further transformed to ethyl (R)‐4‐cyano‐3‐hydroxybutanoate, through an acid‐catalyzed ring opening in ethanol. Molecular modeling revealed that the stereocenter of the fast‐reacting enantiomer, (R)‐bromomethyl‐β‐lactone, is ∼2 Å from the reacting carbonyl carbon. In addition, the slow‐reacting enantiomer, (S)‐4‐bromomethyl‐β‐lactone, encounters steric hindrance between the bromo substituent and the side chain of the Leu278 residue, while the fast‐reacting enantiomer does not have any steric clash.     

Highly Enantioselective Michael Addition of Cyclic 1,3‐Dicarbonyl Compounds to β,γ‐Unsaturated α‐Keto Esters

A highly enantioselective Michael addition of cyclic 1,3‐dicarbonyl compounds to β,γ‐unsaturated α‐keto esters catalyzed by amino acid‐derived thiourea‐tertiary‐amine catalysts is presented. Using 5 mol% of a novel tyrosine‐derived thiourea catalyst, a series of chiral coumarin derivatives were obtained in excellent yields (up to 99%) and with up to 96% ee under very mild conditions within a short reaction time.     

Highly Enantioselective Phase‐Transfer Catalytic α‐Alkylation of α‐tert‐Butoxycarbonyllactams: Construction of β‐Quaternary Chiral Pyrrolidine and Piperidine Systems

A new enantioselective α‐alkylation of α‐tert‐butoxycarbonyllactams for the construction of β‐quaternary chiral pyrrolidine and piperidine core systems is reported. α‐Alkylations of N‐methyl‐α‐tert‐butoxycarbonylbutyrolactam and N‐diphenylmethyl‐α‐tert‐butoxycarbonylvalerolactam under phase‐transfer catalytic conditions (solid potassium hydroxide, toluene, −40 °C) in the presence of (S,S)‐3,4,5‐trifluorophenyl‐3,3′,5,5′‐tetrahydro‐2,6‐bis(3,4,5‐trifluorophenyl)‐4,4′‐spirobi[4H‐dinaphth[2,1‐c:1′,2′‐e]azepinium] bromide [(S,S)‐NAS Br] (5 mol%) afforded the corresponding α‐alkyl‐α‐tert‐butoxycarbonyllactams in very high chemical (up to 99%) and optical yields (up to 98% ee). Our new catalytic systems provide attractive synthetic methods for pyrrolidine‐ and piperidine‐based alkaloids and chiral intermediates with β‐quaternary carbon centers.     

Chiral Bioinspired Non‐Heme Iron Complexes for Enantioselective Epoxidation of α,β‐Unsaturated Ketones

Chiral bioinspired iron complexes of N₄ ligands based on the ethylenediamine backbone display remarkable levels of enantioselectivity for the first time in the asymmetric epoxidation of α,β‐unsaturated ketones using hydrogen peroxide (up to 87% ee) or peracetic acid as oxidant, respectively. Notablely, isotopic labeling with H₂¹⁸O strongly demonstrated that there is a reversible water binding step prior to generation of the significant intermediate. Besides, the complex [L₂Fe(III)₂(μ‐O)(μ‐CH₃CO₂)]³⁺ usually derived from the decay of the LFe(IV)O species or thermodynamic sinks for a number of iron complexes was identified by HR‐MS. In addition, the possible mechanisms were proposed and LFe(V)O species may be the main active intermediate in the catalytic system.     

Rhodium‐Catalyzed Asymmetric Hydroformylation of 1,1‐Disubstituted Allylphthalimides: A Catalytic Route to β3‐Amino Acids

The high enantioselective rhodium‐catalyzed hydroformylation of 1,1‐disubstituted allylphthalimides has been developed. By employing chiral ligand 1,2‐bis[(2S,5S)‐2,5‐diphenylphospholano]ethane [(S,S)‐Ph‐BPE], a series of β³‐aminoaldehydes can be prepared with up to 95% enantioselectivity. This asymmetric procedure provides an efficient alternative route to prepare chiral β³‐amino acids and alcohols.