Dynamic kinetic resolution of hemiaminals using a novel DMAP catalyst

We describe the first catalytic dynamic kinetic resolution of hemiaminals mediated by an organocatalyst. A 0.1-1 mol % catalyst loading is effective for the dynamic kinetic resolution of hemiaminals to produce esters up to 88% ee in high yields. A 10 mol % catalyst loading resulted in a decreased selectivity, whereas the selectivity increased at 50 °C. The absolute configuration is assigned on the basis of the empirical Cotton effect rule.     

Fluorescence-based screening of asymmetric acylation catalysts through parallel enantiomer analysis. Identification of a catalyst for tertiary alcohol resolution

A technique for high-throughput screening of kinetic resolution catalysts is reported. The method relies on carrying simultaneous kinetic resolutions in a multiwell plate format wherein each well contains a unique catalyst and a small amount of a pH-activated fluorescent sensor (3). By conducting experiments such that each catalyst is evaluated in parallel in the presence of each isolated enantiomer, an indication of catalyst activity is obtained on a per enantiomer basis. Catalysts that are highly active for one enantiomer but modestly active for another are then reevaluated in conventional kinetic resolutions. From these screens, a highly selective (k(rel) = 46) pentapeptide (4) was obtained for a model secondary alcohol (1). In addition, peptide 10 was found to afford excellent selectivities (k(rel) > 20) for a number of alcohol substrates (9a-9f) in the traditionally challenging tertiary class.     

Dynamic kinetic resolution of secondary alcohols with a readily available ruthenium-based racemization catalyst

An easy to handle and stable racemization catalyst for secondary alcohols is obtained by an in situ mixture of readily available [Ru(cymene)Cl₂]₂ with chelating aliphatic diamines. Optimization of the reaction revealed that N,N,N′,N′-tetramethyl-1,3-propanediamine as ligand racemizes aromatic alcohols completely within 5 h. This easy to handle and stable catalytic system is combined with a lipase-catalyzed resolution to provide an efficient dynamic kinetic resolution of secondary alcohols.     

Homobenzotetramisole: an effective catalyst for kinetic resolution of aryl-cycloalkanols

Homobenzotetramisole (HBTM), a ring-expanded analogue of the previously reported catalyst BTM, displays higher catalytic activity and a different structure-selectivity profile. It displays good enantioselectivities in kinetic resolution of secondary benzylic alcohols but is particularly effective for 2-aryl-substituted cycloalkanols.     

Rhodium-catalyzed kinetic resolution of tertiary homoallyl alcohols via stereoselective carbon-carbon bond cleavage

A nonenzymatic kinetic resolution of tertiary homoallyl alcohols has been developed through a rhodium-catalyzed retro-allylation reaction under simple conditions. Selectivity factors of up to 12 have been achieved by employing (R)-H8-binap as the ligand, and the reaction can be conducted on a preparative scale.     

Structure-selectivity relationships and structure for a peptide-based enantioselective acylation catalyst

Studies of analogues of a recently discovered enantioselective peptide-based catalyst for enantioselective acylation reactions have led to mechanistic insight and improved catalysts. Systematic replacement of each residue within the parent peptide with alanine of the appropriate stereochemistry allows for an unambiguous evaluation of the kinetic role of each amino acid side chain in the catalyst. The results of the alanine scan support a bifunctional catalysis mechanism at the heart of the origin of enantioselectivity. In addition, an experimentally derived solution structure of the peptide-based catalyst is presented that supports a key role for each residue within the peptide chain.     

Identification of a metagenome-derived esterase with high enantioselectivity in the kinetic resolution of arylaliphatic tertiary alcohols

35 metagenome-derived esterases bearing a GGG(A)X motif were screened for activity and enantioselectivity in the hydrolysis of a range of tertiary alcohol acetates. Most of the active esterases showed little or no enantioselectivity in the hydrolysis of the terpinyl acetate, linalyl acetate and 3-methylpent-1-yn-3-yl acetate. However, one esterase showed excellent enantioselectivity (E > 100) in the kinetic resolution of 1,1,1-trifluoro-2-phenylbut-3-yn-2-yl acetate as confirmed by a preparative scale reaction.     

A highly enantioselective phosphabicyclooctane catalyst for the kinetic resolution of benzylic alcohols

A new class of chiral phosphines belonging to the P-aryl-2-phosphabicyclo[3.3.0]octane family (PBO) has been prepared by enantioselective synthesis starting from lactate esters and 2,2-dimethylcyclopentanone enolate 5. A selective enolate alkylation method has been developed for preparation of 9 and 10 using a chelating ester substituent in the triflate alkylating agent 11. Subsequent conversion to the PBO catalysts 2 and 39 relies on a diastereoselective cyclization from the cyclic sulfate 17 and LiPHAr to afford the more hindered endo-aryl phosphines. These phosphines function as efficient catalysts for the kinetic resolutions of aryl alkyl carbinols by benzoylation (16, 21, 22) or iso-butyroylation in the case of the less hindered aryl alkyl carbinol substrates. With o-substituted aryl alkyl carbinols, the enantioselectivities exceed 100, and s = 380 +/- 10 has been demonstrated in the case of methyl mesityl carbinol. The PBO-catalyzed acylations probably involve a P-acylphosphonium carboxylate intermediate and a tightly ion paired transition state.     

A new optical resolution method of tertiary acetylenic alcohol utilizing complexation with brucine

Some tertiary acetylenic alcohols were resolved efficiently utilizing complexation with brucine. The crystal structure of 1:1 brucine complex of 1-(o-bromophenyl)-1-phenyl-2-propynol ($\text{1}$$\text{d}$) was reported.     

A practical concept for the kinetic resolution of a chiral secondary alcohol based on a polymeric silane

The paper describes our preliminary studies on the use of PMHS as a functionalizable polymer and hydride source for the kinetic resolution of secondary alcohols via chiral Cu(I)-catalyzed dehydrogenative silylating process. The chiral phosphine that chelates the Cu metal center has little influence on the selectivity factor of the kinetic resolution. The use of a stereogenic silane appears to be a key requirement to reach enantiodifferentiation in such a process.     

Air-stable racemization catalyst for dynamic kinetic resolution of secondary alcohols at room temperature

[reaction: see text] A novel racemization catalyst was synthesized for the dynamic kinetic resolution (DKR) of alcohols with a lipase at room temperature in the air. Furthermore, a polymer-supported derivative was also synthesized and tested as a recyclable catalyst for the aerobic DKR of alcohols.     

Expanded substrate scope and catalyst optimization for the catalytic kinetic resolution of N-heterocycles

The scope, reactivity, and selectivity of the chiral hydroxamic acid-catalyzed kinetic resolution of chiral amines are improved by a new catalyst structure and a more environmentally friendly reaction protocol. In addition to increasing selectivity across all substrates, these conditions make possible the resolution of N-heterocycles containing lactams or other basic functional groups that can inhibit the catalyst.     

A polymer-supported proline-based diamine catalyst for the kinetic resolution of racemic secondary alcohols.

The preparation of polymer-supported proline-based diamine catalyst 12 for the kinetic resolution of racemic mixtures of secondary alcohols is described. Not only is the catalyst effective for the resolution of a host of different alcohols, it can also be recovered and reused several times without loss of either activity or selectivity. The catalyst has been used in conjunction with a polymer-supported sequestration strategy, giving rise to an essentially pure mixture of resolved products that can be separated using flash chromatography.     

New oligomeric catalyst for the hydrolytic kinetic resolution of terminal epoxides under solvent-free conditions

The solvent-free hydrolytic kinetic resolution of terminal epoxides catalyzed by a new oligomeric (salen)Co complex 2 is described. Extremely low loadings of catalyst were used to provide all epoxides examined in good yields and >99% ee under ambient conditions within 24 h.     

Organocatalytic kinetic resolution of a planar-chiral ferrocenecarbaldehyde

The proline-catalyzed aldol reaction of racemic 2-(2′-pyrimidyl)ferrocenecarbaldehyde with acetone in DMSO at room temperature constitutes as the first example of an organocatalytic kinetic resolution of a planar-chiral compound. The selectivity factor of the kinetic resolution is 9.2, and the stereochemical outcome of the process can be easily rationalized by the standard mechanistic model of the proline-catalyzed aldol reaction.     

New air-stable iron catalyst for efficient dynamic kinetic resolution of secondary benzylic and aliphatic alcohols

We herein report a catalyst system for the dynamic kinetic resolution of secondary alcohols by combining the enzymatic resolution with an iron-catalyzed racemization. A new air-stable tricarbonyl (cyclopentadienone)iron complex is identified as the active racemization catalyst for this transformation without any additive. Various substrates including benzylic, heteroaromatic, aliphatic alcohols can be used and afford the corresponding esters in good yields and with excellent enantioselectivities.     

Acid zeolites as alcohol racemization catalysts: screening and application in biphasic dynamic kinetic resolution

Acid zeolites were screened as heterogeneous catalysts for racemization of benzylic alcohols. The most promising zeolites appeared to be H-Beta zeolites, for which the optimal reaction conditions were studied in further detail. The zeolite performance was compared to that of homogeneous acids and acid resins under similar reaction conditions. In a second part of the research, H-Beta zeolites were applied in dynamic kinetic resolution (DKR) of 1-phenylethanol, which was conducted by means of a two-phase approach and which resulted in yields smoothly crossing the 50% border up to 90%, with an enantiomeric excess of >99%. To explore the applicability of this biphasic methodology, several other substrates were examined in the standard racemization reaction and in the biphasic dynamic kinetic resolution.     

Highly efficient dynamic kinetic resolution of secondary aromatic alcohols at low temperature using a low-cost sulfonated sepiolite as racemization catalyst

A highly efficient dynamic kinetic resolution system for secondary aromatic alcohol using low-cost sulfonated sepiolite as a racemization catalyst has been developed. The system operates at 25 °C, achieves good ee_p (>99%) and substrate conversion ratio (>99%), is applicable to a variety of substrates and can be reused more than 10 times.     

Electrification of a Milstein-type catalyst for alcohol reformation

Novel energy and atom efficiency processes will be keys to develop the sustainable chemical industry of the future. Electrification could play an important role, by allowing to fine-tune energy input and using the ideal redox agent: the electron. Here we demonstrate that a commercially available Milstein ruthenium catalyst (1) can be used to promote the electrochemical oxidation of ethanol to ethyl acetate and acetate, thus demonstrating the four electron oxidation under preparative conditions. Cyclic voltammetry and DFT-calculations are used to devise a possible catalytic cycle based on a thermal chemical step generating the key hydride intermediate. Successful electrification of Milstein-type catalysts opens a pathway to use alcohols as a renewable feedstock for the generation of esters and other key building blocks in organic chemistry, thus contributing to increase energy efficiency in organic redox chemistry.

Electrification of the Milstein catalyst enabled successful molecular electrocatalytic oxidation of ethanol to the four-electron products acetate and ethyl acetate.

In order to achieve the goals of the Sustainable Development Scenario (SDS) of the International Energy Agency, the chemical industry''s emission should decline by around 10% before 2030.^1,2 This could be achieved by increasing energy efficiency and the usage of renewable feedstocks. In this respect, molecular electrocatalytic alcohol oxidation could be powerful tool by potentially providing energy and atom efficiency for organic synthesis and energy applications.^2–7 Besides the use of aminoxyl-derivatives,^8–13 especially the seminal work of Vizza, Bianchini and Grützmacher demonstrated that (transfer)-hydrogenation (TH) catalysts could be activated electrochemically and used in a so-called “organometallic fuel cell”.¹⁴ Other TH systems are however mostly limited to two electron oxidations of secondary or benzylic alcohols (Scheme 1A).^15–21Open in a separate windowScheme 1(A) Advantages/limitation of electrochemical homogeneous alcohol oxidation using well-defined catalysts. (B) Current efforts to electrify acceptor-less alcohol dehydrogenation (AAD) systems due to their large range of application in thermal catalysis.As an exception, Waymouth et al. recently reported an example of the intramolecular coupling of vicinal benzylic alcohols to the corresponding esters.^19,22 In order to extend the range of possible catalysts candidates, the Waymouth group recently also explored the possibility to use an iron-based acceptor-less alcohol dehydrogenation (AAD) catalysts²³ for electrocatalytic alcohol oxidation (Scheme 1B).²⁴ The stability under electrochemical conditions in this case is limited to <2 turnovers, but it opens the door to explore a wide range of AAD reactions under electrochemical conditions. Here, we demonstrate that a commercially available Milstein-type AAD catalyst (1)²⁵ is competent for the electrocatalytic alcohol oxidation of ethanol to ethyl acetate and acetate (Scheme 1B).The cyclic voltammogram (CV) of complex 1 (Fig. 1) shows a quasi-reversible diffusive one electron oxidation wave at 0.2 V (all potentials are referenced vs. Fc⁺/Fc⁰) in 0.2 M NaPF₆ THF/DFB (2 : 1) (DFB = 1,2 difluoro benzene) assigned to the Ru(ii)–Ru(iii) couple (see ESI, section 2.2^†). The addition of 1 to a 10 mM sodium ethoxide (NaOEt) solution in 200 mM ethanol (EtOH) in 0.1 M NaPF₆ (2 : 1 THF/DFB) gives rise to several waves at ca. −0.5, 0.0 and 0.2 V with currents significantly higher than in the absence of catalysts or substrate, indicative of possible catalytic turnover (Fig. 2). Gradual increase of the EtOH concentration from 200 mM to 1 M is accompanied by the disappearance of the first wave at −0.5 V, while a new oxidation wave appears at ca. −0.25 V (Fig. 2, light to dark green traces).Open in a separate windowFig. 1Scan rate dependence of a 1 mM solution of 1 in in 2 : 1 THF/DFB + 0.2 M NaPF6 (from light to dark green: 0.05, 0.1, 0.2, 0.3, 0.4 and 0.5 V s⁻¹, 3 mm GC electrode). Inset: evolution of the peak current as a function of the square root of the scan rate.Open in a separate windowFig. 2CVs of 10 mM NaOEt (grey) and of 5 mM 1 + 5 mM NaOEt with increasing concentrations of EtOH (from light to dark green: 200, 400, 600, 800 and 1000 mM) in 2 : 1 THF/DFB + 0.2 M NaPF₆. Scan rate 0.1 V s⁻¹, electrode: 3 mm diameter GC electrode.Increasing the base loading gradually from 5 to 20 mM yields a stark increase of current at this new wave at ca. −0.25 V (Fig. 3). Using (TBA)PF₆ instead of NaPF₆ (used to avoid Hofmann-elimination²⁶) gave similar results (see ESI, section 2.2–2.5 and section 4^†). In order to assess catalytic turnover under preparative conditions, controlled potential electrolysis (CPE) was performed. CPE experiments were run in pure ethanol (to reduce cell resistance) in the presence of 0.1 M electrolyte of well soluble bases (e.g. NaOEt, LiOH, see ESI section 4^†). CPE in 0.1 M LiOH with 1 mM 1 at E = 0 V vs. Fc^0/+ delivered ca. 15 mM of acetate and 6 mM of ethyl acetate, corresponding to 21 turnovers (per 4 electrons, or 42 turnovers per two electrons) and a faradaic efficiency (FE) of ca. 62% (see ESI section 4.3^†). In the absence of applied potential (OCP, open circuit potential), no ethyl acetate was formed (see ESI, section 4.4^†). Likewise, in the absence of catalyst, the passed charge was significantly lower (7C vs. 40C) with no detected formation of ethyl acetate. The low FE could be due to catalyst degradation, as Ru-nanoparticle formation is observed on the electrode post CPE (confirmed by SEM/Elemental mapping, see ESI section 5^†). Noteworthy, rinse-test CPE and a CPE using a simple Ru-precursor, RuCl₃, did not show any ethyl acetate formation and gave similar results to blank experiments, indicating that Ru-nanoparticles are probably not the active catalyst species and that catalyst instability could be responsible for low FE. Further studies are underway to fully understand catalyst speciation under preparative conditions (see ESI section 4.7^†) the observed catalytic activity of 1 compares well in terms of TON and product selectivity with other molecular homogeneous TH systems, with most systems being limited to the two-electron oxidation of secondary or benzylic alcohols. The Waymouth group reported a NNC ruthenium pincer for the oxidation of isopropanol to acetone with a TON of 4.¹⁸ The same group reported on the usage of phenoxy mediators with an iridium pincer complex, reaching a TON of 8 for the same reaction.²² Bonitatibus and co-workers demonstrated the activity of an iridium-based systems with a TON of 32 for the formation of p-benzaldehyde.¹⁷ Appel and co-workers reported on a nickel (TON = 3.1)¹⁵ and a cobalt triphos systems (TON = 19.9)¹⁶ for benzaldehyde formation from benzyl alcohol. To the best of our knowledge, there is only one acceptor-less alcohol dehydrogenation (AAD) catalyst that has been activated electrochemically so-far,²⁴ generating acetone with a TON <2. Only a handful of molecular systems are known to catalyze the electrochemical four electron alcohol reformation to esters, however at significantly higher potentials (1.15 V vs. Fc⁺/Fc⁰).^2,27,28 Thus, although not designed for electrochemical applications, 1 shows high activity for the challenging 4 electron oxidation of aliphatic substrates.Open in a separate windowFig. 3CV of 5 mM NaOEt (grey), 5 mM of 1 + 1 M EtOH with varying concentrations of base (5, 10, 15, and 20 mM NaOEt, light to dark green) in 2 : 1 THF/DFB + 0.2 M NaPF₆. Scan rate 0.1 V s⁻¹, electrode: 3 mm diameter GC electrode.To achieve the transposition from thermal to electrochemical TH, both Grützmacher et al. and Waymouth took advantage of a fast equilibrium between the alcohol substrate and a metal hydride intermediate that could be readily oxidized. The chemistry of ruthenium pincer AAD systems is well studied (Scheme 2)^25,29–33 and allows for a putative assignment of the observed CV-behavior. In the presence of excess base and alcohol (Fig. 2 and ​and3),3), 1 is expected to yield dearomatized complex 2,²⁵ as well as the alkoxide species 3.^25,32 We might therefore assign the first wave at −0.5 V to the oxidation of dearomatized complex 2 and the wave around 0 V to the oxidation of the alkoxide complex 3. Indeed, independently synthesized samples of 2 and 3 (in the presence of excess ethanol) give rise to oxidation half-waves at −0.45 V and −0.1 V respectively (see ESI, section 3 and 5.2^†). This is also in agreement with the observed behavior upon increasing the alcohol concentration with the expected consumption of dearomatized species 2 and concomitant disappearance of the first oxidation wave at −0.5 V. The equilibrium between 2, 3 and 4 has been reported³² and addition of excess ethanol to 2 is thus not only generating 3, but also is expected to deliver 4 (Scheme 2). The appearance of a new anodic wave at ca. −0.25 V (Fig. 2) is thus attributed to the increasing formation of 4 upon addition of larger amounts of EtOH. Complex 4 is relatively unstable in solution,^25,32,33 and decomposes in the presence of electrolyte (see ESI section 3.1^†). DFT calculations were thus used to predict its oxidation potential (see ESI, section 6^†), which was in reasonable agreement with the observed wave (−0.19 V). The DFT calculations also confirmed the assignment of the other waves related to the dearomatized complex 2 (−0.33 V) and the ethoxide species 3 (−0.1 V). A more detailed mechanistic analysis remains currently hampered by the chemical instability of 4 under the employed reaction conditions, as well as difficulties to isolate 3 in the solid state (limiting kinetic measurements). DFT calculations were thus used to get a better view on possible reaction pathways (Schemes 2, ​,33 and ESI section 6.3^†). The oxidation of 4 at −0.19 V (DFT) yields the radical cation 5, with a calculated pK_a in THF of 8.2. In the presence of NaOEt, 5 should thus deprotonate readily to give radical 6, which has an extremely negative oxidation potential of −2.1 V. At the potential it is generated, 6 should thus directly be oxidized to cationic complex 7. This cationic species 7 has a calculated pK_a of 22.7 in THF, which is in good agreement with experimental data from the Saouma group on a similar system.²⁶ The high pK_a of 7 in THF also validates the need for a strong base (e.g. NaOEt) to reform dearomatized 2. Both Grützmacher and co-workers,¹⁴ as well as Waymouth²⁴ have noted that the accelerating effect during electrocatalysis stems from the oxidation of a metal hydride intermediate that is generated by fast chemical steps. In order to verify this hypothesis and to exclude an electrochemical activation of this hydride formation step, transition state barriers were computed (Scheme 3). Taking the dearomatized complex 2 as a reference point, a first step will form the alkoxide species 3 (TS₀ = 21.2 kcal mol⁻¹). Oxidizing 2 to 8 slows down the formation of the alkoxide species (T_S0^ox = 27.5 kcal mol⁻¹), most-likely due to decreased basicity of the ligand. From the alkoxide species 3 dihydride 4 is formed via a linear, charge-separated transition state TS₁ (15.7 kcal mol⁻¹). The role of such linear transition states was highlighted recently in the case of ruthenium pincer catalysis for alcohol oxidation.^34–37 In principle, it might be envisioned that the oxidation of the metal center could be an additional driving force for this hydride abstraction step. However, after oxidation, the energy span^38,39 rises by about 11 kcal mol⁻¹ (TS₁^ox = 24.7 kcal mol⁻¹). Likewise, a beta-hydride elimination via side-arm opening is not accelerated either by oxidation (TS₂^ox = 37.5 kcal mol⁻¹, see ESI section 6.4^†). It thus seems that the generation of 4 is not accelerated by electron transfer steps and relies on a thermally activated chemical step. Importantly, alkoxide solutions were shown to be excellent hydride donors electrochemically, further corroborating that under the employed basic conditions, generation of 4 from 3 should be fast.⁴⁰ Oxidation of 4 to 5 also doesn''t accelerate thermal intramolecular release of H₂ (TS_3B^ox = 37.5 kcal mol⁻¹), which is significantly higher than neutral thermal H₂-releasing states (TS_3A and TS_3B). The experimentally observed acceleration via electron-transfer is thus proposed to follow a classical ECEC mechanism initiated by the oxidation of 4 to 5 (at roughly −0.19 V (DFT)), followed by deprotonation and re-oxidation as described above, finally delivering 2 at the electrode surface. Importantly, at the electrode surface 2 and 3 should be oxidized at the employed potentials, but based on DFT-calculations, these pathways are thought to be non-productive (Scheme 3) and could explain the low catalyst life-time and degradation under electrochemical conditions.Open in a separate windowScheme 2Reactivity of pyridine-based ruthenium complexes via dearomatization/aromatization, as well as DFT-based.Open in a separate windowScheme 3DFT-calculated energy landscape for the neutral (black dotted lines and bars) and cationic surface (blue dotted lines and bars) of ethanol dehydrogenation starting from 2 or its cationic analogue 8.