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A modular synthesis for chiral and non-symmetrical salalen ligands (i.e., mono-reduced salens), carrying an imine and an amine functionality has been developed. The ligands can be assembled in situ by Schiff base formation of an N-(2-hydroxybenzyl)diamine with a salicylic aldehyde, thus allowing rapid and easy variation/optimization of the ligand structure. Aiming at optimal activity and enantioselectivity in the titanium-catalyzed asymmetric epoxidation of non-functionalized olefins, a positional scanning of the two ligand halves was carried out. High epoxide yields were achieved, and up to 98 % ee. The composition of the titanium complex catalysts was determined by high resolution mass spectrometry and X-ray crystallography for one selected example.

A practical biocatalytic method for the synthesis of aliphatic β-halogenated (S)-alcohols as epoxide precursors by means of an enantioselective reduction of the corresponding ketones with recombinant whole cells, bearing an alcohol dehydrogenase and a glucose dehydrogenase, was developed. The biotransformations operate at high substrate concentrations of up to 208 g/L, and afford the (S)-β-halohydrins with both high conversions of >95 % and enantioselectivities of >99 % ee. Base-induced cyclization of the β-halohydrin intermediates gave the desired (S)-epoxides in high yield and enantiomeric purity (>99 % ee).

In the area of catalytic asymmetric epoxidation, the highly enantioselective transformation of cyclic enones and quinones is an extremely challenging target. With the aim to develop new and highly effective phase-transfer catalysts for this purpose, we conducted a systematic structural variation of PTCs based on quinine and quinidine. In the total of 15 new quaternary ammonium PTCs, modifications included, for example, the exchange of the quinine methoxy group for a free hydroxyl or other alkoxy substituents, and the introduction of additional elements of chirality through alkylation of the alkaloid quinuclidine nitrogen atom by chiral electrophiles. For example, the well-established 9- anthracenylmethyl group was exchanged for a “chiral” anthracene in the form of 9-chloromethyl-[(1,8-S;4,5-R)-1,2,3,4,5,6,7,8-octahydro-1,4:5,8-dimethanoanthracene. The asymmetric epoxidation of vitamin K₃ was used as the test reaction for our novel PTCs. The readily available PTC 10 (derived from quinine in three convenient and high-yielding steps) proved to be the most enantioselective catalyst for this purpose known to date: At a catalyst loading of only 2.50 mol %, the quinone epoxide was obtained in 76 % yield and with 85 % ee (previously: ≤34 % ee), using commercial bleach (aqueous sodium hypochlorite) as the oxidant. To rationalize the sense of induction effected by our novel phase-transfer catalysts, a computational analysis of steric interactions in the intermediate chlorooxy enolate–PTC ion pair was conducted. Based on this analysis, the sense of induction for all 15 novel PTCs could be consistently explained.

Starting from enantiomerically pure 5,10,15,20-tetrakis[(1S,4R,5R,8S)-1,2,3,4,5,6,7,8-octahydro-1,4 : 5,8-dimethanoanthracene-9-yl]porphyrin, treatment with CrCl₂ and subsequent air oxidation afforded the corresponding Cr(III) complex, with chloride as counterion, in 96% yield. Anion exchange with AgBF₄ gave the corresponding tetrafluoroborate. These hitherto unknown chiral chromium porphyrins are efficient and highly enantioselective catalysts for the hetero-Diels–Alder reaction of aliphatic, aromatic, and heteroaromatic aldehydes with dienes of varying electron density. In the case of 1-methoxy-3-(trimethylsilyloxy)butadiene (“Danishefsky's diene”), enantiomeric excesses >90% were achieved in a number of cases, with furfural affording the highest ee (97%). Metal-coordinating aldehydes such as pyridine-2-carbaldehyde do not inactivate the Cr(III) porphyrin catalyst. The cycloaddition of less electron-rich dienes (such as 1-methoxybutadiene) is effected as well, affording diastereoselectivities up to >99 : 1, and enantiomeric excesses >80%.

The hydrolytic kinetic resolution (HKR) of terminal epoxides, using chiral chromium(III)-salen catalysts based on DIANANE (endo,endo-2,5-diaminonorbornane), was studied. A broad substrate scope was found for the chromium(III)-DIANANE catalysts, and very low loadings (down to 0.05 mol %) were needed to achieve high enantiomeric purities of both the remaining epoxides and the product diols (up to >99 % ee). Besides monosubstituted epoxides, 2-methyl-2-n-pentyloxirane, which is an example for 2,2-disubstituted epoxides, could be ring-opened in an asymmetric fashion with water in the presence of an electronically tuned chromium(III)-DIANANE complex.

A new type of chromium-salen complex bearing DIANANE (endo,endo-2,5-diaminonorbornane) as chiral backbone has been synthesized and applied to the hetero-Diels–Alder reaction of Danishefsky’s diene with various aldehydes. The reactions afford the corresponding 2-substituted 2,3-dihydro-4H-pyran-4-ones in high yields and enantioselectivities (up to 96 % ee). The effect of different counteranions of the complex on reactivity as well as enantioselectivity has been investigated. Besides Danishefsky’s diene, reaction of the less reactive 1-methoxybutadiene with benzaldehyde and ethyl glyoxylate can be effected by the chromium catalysts as well.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Racemization wanted: The dynamic kinetic resolution of secondary alcohols can be achieved by a simple and readily available catalyst system. Substrate racemization is effected at room temperature by a combination of (racemic) 1,1′-bi-2-naphthol (binol) or 2,2′-biphenol with AlMe₃, and a lipase performs enantiospecific acylation (see scheme).

The ability of microemulsions to dissolve polar and non-polar components with a huge internal interface can overcome the reagent incompatibilities frequently encountered in organic reactions. We investigated model epoxidation reactions of α,β-unsaturated enones and alkaline hydrogen peroxide in different nonionic microemulsions, both in the presence and absence of a phase-transfer agent (PTA). The obtained reaction profiles were compared with those for the corresponding surfactant-free two-phase systems. In addition, we defined a time constant τ as a measure for the rate of turnover. The epoxidation of trans-chalcone using an n-alkyl-polyoxyethylene surfactant based microemulsion was fastest in the system with the PTA (τ=66 min) and slightly slower without the PTA (τ=77 min). It was still slower in the two-phase system with a PTA (τ=114 min) and extremely sluggish without a phase-transfer agent. With n-alkyl β-D-glucopyranoside as the surfactant the conversion was twice as fast than in the former microemulsion systems, but the PTA did not accelerate the reaction further (τ=35 and 33 min). The epoxidation of vitamin K₃, the second model system, was extremely accelerated. It proceeded a factor of approximately 35 faster in the microemulsion (τ=1.44 min) than in the corresponding two-phase system (τ=57 min).

Racemisierung erwünscht: Die dynamische kinetische Racematspaltung sekundärer Alkohole gelang mit einem einfachen und sehr leicht zugänglichen Katalysatorsystem: In situ wird aus (racemischem) 1,1′-Bi-2-naphthol (Binol) oder 2,2′-Biphenol und AlMe₃ ein Aluminiumkatalysator erzeugt, der das Substrat bei Raumtemperatur racemisiert, und eine Lipase gewährleistet die enantiospezifische Acylierung (siehe Schema).

Novel tasks for a venerable molecule: Bifunctional organocatalysts of the type shown, with a quasi Lewis acidic urea or thiourea unit and a Brønsted basic amine functionality, effect the dynamic kinetic resolution of azlactones with high enantioselectivity. N-Benzoyl amino acid esters were obtained with up to 91 % ee in high yields from racemic azlactones.

Neue Aufgaben für ehrwürdige Moleküle: Bifunktionale Organokatalysatoren mit einer quasi-Lewis-sauren Harnstoff- oder Thioharnstoff-Einheit und einer Brønsted-basischen Aminofunktion bewirken die dynamische kinetische Racemattrennung von Azlactonen mit hoher Enantioselektivität: N-Benzoylaminosäureester mit bis zu 91 % ee konnten in hohen Ausbeuten aus racemischen Azlactonen gewonnen werden.

Eine profitable Scheidung: Ein organokatalytisches Verfahren überführt die leicht zugänglichen racemischen Oxazinone 1 durch kinetische Racematspaltung unter katalytischer Ringöffnung in die wertvollen enantiomerenreinen β-Aminosäurederivate 2 (bei 53 % Umsatz >99 % ee des zurückbleibenden Oxazinons 1, 88 % ee des Esters). Der Organokatalysator 3, ein Thioharnstoff, ist modular aufgebaut, leicht zugänglich und kann in Mengen von nur 1 Mol-% eingesetzt werden.

The epoxidation of cyclooctene and 1-octene with hydrogen peroxide was studied kinetically in HFIP (1,1,1,3,3,3-hexafluoro-2-propanol)/1,4-dioxane mixtures. In the case of cyclooctene, no additional catalyst was applied, whereas the epoxidation of 1-octene was run in the presence of phenylarsonic acid as catalyst. For both reaction types, two kinetic regimes can be distinguished: at low HFIP concentration (n_HFIP/n_total≤0.15), both the catalyzed and the uncatalyzed reaction show first order dependence on the HFIP concentration. This result is interpreted by the HFIP “charge template” for the uncatalyzed epoxidation (as postulated by Shaik and Neumann) and by the formation of an arsonic acid mono-HFIP ester for the catalyzed reaction. At high HFIP concentration (n_HFIP/n_total≥0.5), both reaction types are up to ca. 5 orders of magnitude faster and show ca. 12^th order dependence on the HFIP concentration. We propose that the dramatic accelerations observed at high HFIP concentrations are brought about by HFIP clusters. Based on literature data (Fioroni, Roccatano, Hong, Suhm), it is concluded that the epoxidation reactions studied here take place in a HFIP coordination sphere comprising ca. 12 HFIP molecules, and that this coordination sphere effects the enormous increases in epoxidation rates. This mechanistic model bears resemblance to enzymatic reactions taking place in and being catalyzed by a protein matrix.

Proline catalysis of the asymmetric direct aldol reaction involves both the secondary amine function and the carboxyl group of the amino acid. N-Sulfonylcarboxamides are known to be of similar acidity as carboxylic acids, and three N-arylsulfonyl derivatives of L-proline amide were synthesized as functionalized and versatile derivatives of L-Pro. Their catalytic performance was evaluated in the direct aldol addition of acetone to 4-nitrobenzaldehyde. Significantly improved reactivities and enantioselectivities were achieved in various solvents at low catalyst loadings (5–10 mol %) and at room temperature, with ees ranging up to 98%, whereas L-proline itself afforded a maximum ee of 80% (in DMSO). Thus, N-arylsulfonyl derivatives of proline amide represent a novel class of highly enantioselective catalysts for direct aldol reactions. Furthermore, the N-arylsulfonyl substituent suggests possibilities for incorporation into larger catalyst assemblies (including immobilization) without affecting the catalytically active functional groups.

We report the use of three enantiomerically pure and electronically tuned ruthenium carbonyl porphyrin catalysts for the asymmetric cyclopropanation and epoxidation of a variety of olefinic substrates. The D₄-symmetric ligands carry a methoxy, a methyl or a trifluoromethyl group at the 10-position of each of the 9-[anti-(1,2,3,4,5,6,7,8-octahydro-1,4:5,8-dimethanoanthracene)]-substituents at the meso-positions of the porphyrin. Introduction of a CF₃-substituent in this remote position resulted in greatly improved catalyst stability, and turnover numbers of up to 7 500 were achieved for cyclopropanation, and up to 14 200 for epoxidation, with ee values typically >90 % and ≈80 %, respectively. In one example, the axial CO ligand at the ruthenium was exchanged for PF₃, resulting in the first chiral ruthenium porphyrin with a PF₃ ligand reported to date. In cyclopropanations with ethyl diazoacetate, the latter catalyst performed exceedingly well, and gave a 95 % ee in the case of 1,1-diphenylethylene as substrate.

Catalytic asymmetric addition of vinylic halides and triflates to aldehydes, with useful levels of stereoinduction, has been achieved for the first time using the salen-type ligand (S,S)-5 (see scheme; PMB=para-methoxybenzyl), which contains the novel endo,endo-2,5-diamino norbornane building block. This asymmetric Nozaki–Hiyama–Kishi reaction leads to the coupling of various halides and aldehydes with high yields and enantioselectivities (up to 92 % ee).

We report the synthesis of three novel and chiral salicylic aldehyde building blocks 6−8, each in both enantiomerically pure forms. Two of these salicylic aldehydes were prepared from (+)-camphene and each bear a [2.2.1]bicycloheptyl substituent ortho to the salicylic hydroxy group. In the third case, the chiral element at the 6-position is a (1-phenylethyl) group. The synthetic sequences consisted of ortho-alkylation of para-cresol with either camphene or styrene and subsequent ortho-formylation of the product phenols. The chromatographic separation of enantiomers was accomplished through the diastereomeric imines obtained from condensation of the racemic salicylic aldehydes with (R)-phenylglycinol. Finally, the absolute configurations of two of the salicylic aldehydes were established by X-ray crystallography. For this purpose, the (1-phenylethyl)-substituted salicylic aldehyde was condensed with L-valinamide, and the relative configuration of the resulting Schiff base diastereomer 12 was determined. In the second case, the racemic intermediate phenol rac-15 was separated by HPLC on a chiral stationary phase, ortho-brominated, and analyzed by anomalous X-ray scattering. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Enantiomerically pure trans-2-aminocyclohexanecarboxylic acid is an important building block for helical β-peptides. We report here that this amino acid can be obtained from trans-cyclohexane-1,2-dicarboxylic acid in good yield by a simple one-pot procedure comprising cyclization to the anhydride, amide formation with ammonia, and a subsequent Hofmann-type degradation with phenyliodine(III) bis(trifluoroacetate) (PIFA) as the oxidant. The N-Fmoc- and N-BOC-protected derivatives were obtained by treatment of the amino acid with Fmoc-OSu and BOC₂O, respectively. The N-BOC derivative could be prepared in even better overall yield by a one-pot procedure leading directly from trans-cyclohexane-1,2-dicarboxylic acid to the N-BOC-protected amino acid. Both enantiomers of the starting trans-1,2-cyclohexanedicarboxylic acid can be obtained easily and in large quantities by separating commercially available racemic trans-1,2-cyclohexanedicarboxylic acid using either (R)- or (S)-1-phenethylamine. X-ray crystallography of the diastereomerically pure salt obtained from (R)-1-phenethylamine revealed that the configuration of the diacid component is (1R,2R), and not (1S,2S) as reported in the literature. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

What a difference the solvent makes! Unlike in conventional solvents, nonstrained ketones such as cyclohexanone react smoothly with hydrogen peroxide in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) to give lactones. The reaction proceeds via an isolatable spiro-bisperoxide, which undergoes a highly exothermic acid-catalyzed rearrangement to two equivalents of lactone (see Equation and IR thermogram).

Das Solvens macht den Unterschied: Anders als in konventionellen Lösungsmitteln reagieren ungespannte Ketone wie Cyclohexanon mit Wasserstoffperoxid in 1,1,1,3,3,3-Hexafluor-2-propanol (HFIP) glatt zu Lactonen. Die Reaktion verläuft über ein isolierbares Spiro-Bisperoxid, das in einer stark exothermen Reaktion säurekatalysiert zu zwei Äquivalenten des Lactons umlagert (siehe Gleichung und IR-Thermogramm).

Das kombinatorische Auffinden katalytischer Aktivität erfordert das Zusammenspiel von Bibliothekssynthese und geeigneten Assays. Mit dem Testsubstrat 1 wurden in einer Bibliothek Undecapeptide gefunden (z. B. A), die in Gegenwart von Zr⁴⁺ die Phosphathydrolyse beschleunigen.

The combinatorial discovery of novel catalytic activity requires both library synthesis and suitable assays. By means of the test substrate 1, undecapeptides such as A were identified within a library that accelerate phosphate hydrolysis in the presence of Zr⁴⁺.