Bo Richter

Organocatalytic Asymmetric Synthesis of Functionalized 3,4-Dihydropyran Derivatives

In the last few years, the field of organocatalysis has attracted much attention in the chemical community. It has been proven to be a useful tool in the development of new methodologies in order to obtain easy stereoselective access to optically active molecules of, for example, biological importance. Chiral secondary amines are very powerful organocatalysts giving rise to highly stereoselective transformations of carbonyl compounds, such as the enantioselective a-, b-, and g-functionalization of aldehydes. Furthermore, a new concept dealing with singly occupied molecular orbital (SOMO) organocatalysis has emerged recently. In these reactions the chiral secondary amines catalyze the formation of a single bond and stereocenter; however, a further advantage of these compounds in organocatalysis is the possibility to obtain multiple bonds and new stereocenters in terms of diastereoand enantioselective domino, one-pot, and multicomponent reactions. A large group of important natural products, such as carbohydrates, alkaloids, polyether antibiotics, pheromones and iridoids, contain polyfunctionalized pyran derivatives as subunits. The common way to access 3,4-dihydropyrans is, for example, by an inverse-electron-demanding hetero-Diels– Alder reaction between a,b-unsaturated carbonyl compounds with electron-rich alkenes. We envisioned that it might be possible to develop an organocatalytic reaction for the formation of enantiomerically enriched 3,4-dihydropyrans as outlined in Scheme 1. This strategy is based on the initial Michael addition of a 1,3-cycloalkanedione to an a,bunsaturated aldehyde in the presence of an organocatalyst followed by a subsequent cyclization reaction. Initial studies showed that the addition of 1,3-cyclopentadione to a,b-unsaturated aldehydes, which after cyclization results in the formation of 3,4-dihydropyrans, proceeds in toluene under slightly acidic conditions in the presence of a secondary amine as the catalyst. With these promising findings in hand, we performed a screening in order to optimize the conditions in the reaction of cinnamaldehyde 1a with 1,3-cyclopentadione 2a. Various organocatalysts 4a–e, solvents and reaction temperatures were tested and a selection of results is presented in Table 1. The screening of different secondary amines as catalysts in toluene revealed that (S)-2-[bis(3,5-bistrifluoromethylphenyl)trimethyl-silanyloxymethyl]pyrrolidine (4a) gave full conversion affording the 3,4-dihydropyran 3a with 72% ee (Table 1, entry 1). Surprisingly, when (S)-2-(diphenyl(trimethylsilyloxy)methyl)pyrrolidine (4b) was used as the catalyst, no formation of 3a was detected (Table 1, entry 2). Proline 4d, as well as proline amide 4e, were unable to catalyze the reaction (Table 1, entries 4, 5). The use of (S)-diphenyl(pyrrolidin-2-yl)methanol (4c) resulted in 38% yield and 40% ee (Table 1, entry 4). To our surprise, even though both catalyst 4a and 4c are derived from the (S)-conformation, the opposite enantiomers of 3a are formed in these reactions. After finding the appropriate catalyst for the reaction, different solvents and temperatures were screened. Choosing CH2Cl2 at ambient temperature as the solvent increased the yield of 3a to 59% and the enantioselectivity to 75% ee (Table 1, entry 6). Less promising results were obtained in EtOH and Et2O, compared with toluene (Table 1, entries 7, 8). Using CH2Cl2 and lowering the temperature to 4 8C allowed 65% of the product to be isolated with an enantioselectivity of 84% ee (Table 1, entry 9). Further improvement was obtained by performing the reaction at 35 8C which afforded the final key parameters: temperature at 35 8C, [a] P. T. Franke, B. Richter, Prof. Dr. K. A. Jorgensen Danish National Research Foundation: Center for Catalysis Department of Chemistry Aarhus University, 8000 Aarhus C (Denmark) Fax: (+45)8919-6199 E-mail : kaj@chem.au.dk Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200800850. Scheme 1. Retrosynthetic analysis.

Organocatalytic Domino Michael–Knoevenagel Condensation Reaction for the Synthesis of Optically Active 3‐Diethoxyphosphoryl‐2‐oxocyclohex‐3‐enecarboxylates

Versatile dominoes: A novel, organocatalytic, Michael-Knoevenagel condensation domino reaction of ethyl 4-diethoxyphosphoryl-3-oxobutanoate with various aryl- and aliphatic-substituted alpha,beta-unsaturated aldehydes catalyzed by a chiral diarylprolinol ether has been successfully performed. The reaction proceeds in a highly enantio- and diastereoselective manner giving access to optically active 6-substituted-3-diethoxyphosphoryl-2-oxocyclohex-3-enecarboxylates (see scheme).A novel, organocatalytic, highly enantio- and diastereoselective synthetic approach towards optically active 6-substituted-3-diethoxyphosphoryl-2-oxocyclohex-3-enecarboxylates is presented. Our methodology utilizes a Michael-Knoevenagel domino reaction sequence of ethyl 4-diethoxyphosphoryl-3-oxobutanoate and alpha,beta-unsaturated aldehydes catalyzed by a chiral diarylprolinol ether. The cyclohexenecarboxylates obtained are particularly well suited for the preparation of highly functionalized cyclohexene and cyclohexane derivatives, with up to four chiral centers and high levels of stereocontrol.

Enantioselective Organocatalytic Approach to α-Methylene-δ-lactones and δ-Lactams

We present the first enantioselective organocatalytic approach for the synthesis of alpha-methylene-delta-lactones and delta-lactams. Our methodology utilizes the Michael addition of unmodified aldehydes to ethyl 2-(diethoxyphosphoryl)acrylate as the key step affording highly enantiomerically enriched adducts, which can be transformed into the target compounds maintaining the high stereoselectivity achieved in the first step. This methodology has been shown to be general and various optically active gamma-substituted alpha-methylene-delta-lactones and delta-lactams can be easily accessed.

Organocatalytic asymmetric “anti-Michael” reaction of β-ketoesters

The first organocatalytic “anti-Michael” reaction of cyclic-β-ketoesters to unsaturated double bonds is described in a highly asymmetric version leading to the synthesis of α,α′-disubstituted branched double bonds as optically active Baylis–Hillman-like adducts.

Variable-temperature structural studies on valence tautomerism in cobalt bis(dioxolene) molecular complexes

A variable-temperature single-crystal structural study of five valence tautomeric cobalt molecular complexes, CoII(3,5-DBSQ)2(DBPy)2 (1), CoII(3,5-DBSQ)2(DBPy)2·1.33C7H8 (1S), CoII(3,5-DBSQ)2(DCPy)2·C7H8 (2S), CoII(3,5-DBSQ)2(TBPy)2 (3) and CoII(3,5-DBSQ)2(TCPy)2 (4) (S = toluene, 3,5-DBSQ = 3,5-di-tert-butylsemiquinonate, DBPy = 3,5-dibromopyridine, DCPy = 3,5-dichloropyridine, TBPy = 3,4,5-tribromopyridine and TCPy = 3,4,5-trichloropyridine) is reported. The re-crystallization of (1S) in toluene at 277 K resulted in a concomitant formation of a solvent-free polymorph, CoII(3,5-DBSQ)2(DBPy)2 (1). Thermally induced valence tautomerism (VT) is observed only in (1S), (1) and (2S) [hs-CoII(3,5-DBSQ)2L2 ↔ ls-CoIII(3,5-DBSQ)(3,5-DBCat)L2 (hs = high spin, ls = low spin, 3,5-DBCat = 3,5-di-tert-butylcatecholate)], whereas (3) and (4) remain locked in the hs-CoII(3,5-DBSQ)2 state during cooling of the sample. Multi-temperature single-crystal studies demonstrate the change in cobalt coordination environment during the VT conversion. The non-solvated compound (1) shows a sharp VT transition (T1/2 ∼ 245 K with ΔT ∼ 10 K) from hs-CoII(3,5-DBSQ)2(DBPy)2 to ls-CoIII(3,5-DBSQ)(3,5-DBCat)(DBPy)2 oxidation state, whereas the other polymorph with lattice solvent (1S) results in a broad transition (T1/2 ∼ 150 K with ΔT ∼ 100 K). This increase in the VT transition temperature for (1) relative to (1S) illustrates the effect of lattice solvent on the VT transition mechanism. Additionally, the influence of halogen substitutions on the pyridine ring is discussed with respect to observed VT behaviour in the studied compounds.