An Asymmetric Route to β-Aminoalanine Derivatives through Michael Addition of Amides, Imides, and Isatins to a Chiral Dehydroalanine Ni(II) Complex.

This study has demonstrated that the readily available and inexpensive 3-(trans-3'-alkyl/arylpropenoyl)oxazolidin-2-ones, featuring high electrophilicity and conformational homogeneity, are synthetically superior Michael acceptors over the conventionally used alkyl enoylates, allowing for a remarkable improvement in reactivity and, in most cases, diastereoselectivity of the addition reactions with a Ni(II) complex of the chiral Schiff base of glycine with (S)-o-[N-(N-benzylprolyl)amino]benzophenone. Kinetically controlled diastereoselectivity in the corresponding Michael addition reactions between the Ni(II) complex of glycine and the oxazolidin-2-ones was systematically studied as a function of steric, electronic, and position effects of the substituents on the starting Michael acceptor. In both aliphatic and aromatic series the simple diastereoselectivity was found to be virtually complete, affording the products via the corresponding TSs with the approach geometry like. The face diastereoselectivity of the reactions between the Ni(II) complex of glycine and the 3-(trans-3'-alkylpropenoyl)oxazolidin-2-ones was found to depend exclusively on the steric bulk of the alkyl group on the starting Michael acceptor. In contrast, the face diastereoselectivity in the reactions of aromatic oxazolidin-2-ones with the Ni(II) complex of glycine was shown to be controlled predominantly by the electronic properties of the aryl ring. In particular, the additions of the Ni(II) complex of glycine with 3-(trans-3'-arylpropenoyl)oxazolidin-2-ones, bearing electron-withdrawing substituents on the phenyl ring, afforded the (2S,3R)-configured products with synthetically useful diastereoselectivity and in quantitative chemical yields, thus allowing for an efficient access to the sterically constrained beta-aryl-substituted pyroglutamic and glutamic acids.

This paper describes a systematic study of addition reactions between the chiral Ni(II) complex of the Schiff base of glycine with (S)-o-[N-(N-benzylprolyl)amino]benzophenone and (S)- or (R)-3-[(E)-enoyl]-4-phenyl-1,3-oxazolidin-2-ones as a general and synthetically efficient approach to beta-substituted pyroglutamic acids and relevant compounds. These reactions were shown to occur at room temperature in the presence of nonchelating organic bases and, most notably, with very high (>98% diastereomeric excess (de)) stereoselectivity at both newly formed stereogenic centers. The stereochemical outcome of the reactions was found to be overwhelmingly controlled by the stereochemical preferences of the Michael acceptors, and the chirality of the glycine complex influenced only the reaction rate. Thus, in the reactions of both the (S)-configured Ni(II) complex and the Michael acceptors, the reaction rates were exceptionally high, allowing preparation of the corresponding products with virtually quantitative (>98%) chemical and stereochemical yields. In contrast, reactions of the (S)-configured Ni(II) complex and (R)-configured Michael acceptors proceeded at noticeably lower rates, but the addition products were obtained in high diastereo- and enantiomeric purity. To rationalize the remarkably high and robust stereoselectivity observed in these reactions, we consider an enzyme-substrate-like mode of interaction involving a topographical match or mismatch of two geometric figures. Excellent chemical and stereochemical yields, combined with the simplicity and operational convenience of the experimental procedures, render the present method of immediate use for preparing various beta-substituted pyroglutamic acids and related compounds.

Within this thesis, the development of peptides as highly efficient catalysts for asymmetric conjugate addition reactions of aldehydes to nitroolefins is described. The tripeptide TFA*H-Pro-Pro-Asp-NH2 1 was originally developed and established as an efficient catalyst for asymmetric aldol reactions. Based on insight gained from conformational analysis it was predicted that 1 and closely related peptides may also serve as catalysts for asymmetric 1,4-addition reactions. Indeed, TFA*H-D-Pro-Pro-Asp-NH2 21 proved to be a highly effective catalyst for asymmetric conjugate addition reactions of aldehydes to nitroolefins. A broad scope of different substrate combinations including aliphatic and aromatic nitroolefins as well as linear, ?-branched and aromatic aldehydes reacted readily in the presence of as little as 1 mol% of 21 to the desired ?-nitroaldehydes in high yields (82-99 %), high diastereoselectivities (syn:anti = 4:1->99:1) and very high enantioselectivities (88-98 % ee). Thus, 21 proved to be significantly more active and applicable to a broader substrate scope compared to other amine based catalysts that had previously been developed for 1,4- addition reactions of aldehydes to nitroolefins. In addition, the peptidic catalyst 21 also offered solutions to other challenges encountered with the other amine based catalysts and allowed for using only a small excess of the aldehyde providing the products within a reasonable reaction time. Analysis of the structural and functional prerequisites for high catalytic efficiency within catalysts 21 led then to the establishment of the closely related peptide TFA*H-D-Pro-Pro- Glu-NH2 56 as an even more effective catalyst for conjugate addition reactions of aldehydes and nitroolefins including the functionalised ?-nitroacrolein dimethylacetal (up to quant. yields, syn:anti ratio up to >99:1, up to 99 % ee). Even nitroethylene, the simplest of all nitroolefins, reacts readily with functionalised and non-functionalised aldehydes. The derivatisation of the corresponding products offered a new entry into the synthesis of monosubstituted ?2-amino acids, previously only accessible by using chiral auxiliaries. Extensive kinetic studies allowed for further insight into the reaction mechanism and led to the establishment of improved reaction conditions. Only as little as 0.1 mol% of 56 was required for the corresponding reactions, which is the lowest catalyst loading that has been achieved for enamine catalysis to date. A further benefit of the peptidic catalyst is that, in contrast to many other organocatalysts, no additives are necessary to obtain the desired products in very high yields and selectivities. Further conformational studies indicated that peptide 56 is more rigid than usual tripeptides but still bear a significant degree of conformational freedom. Therefore, the right degree of flexibility might be the key to the effectiveness of peptides as asymmetric catalysts. These studies demonstrate the high potential of short peptides as efficient catalysts and establish a basis for further investigations. These may include the application of peptides as catalysts for other 1,4-addition reactions using different Michael donors (e.g. ketones, malonates, nitroalkanes) and Michael acceptors (e.g. ?,?-unsaturated aldehydes and ketones, ?-disubstitued nitroolefins). Also new challenging transformations such as e.g. ?-alkylation of aldehydes or complex cascade reactions might become accessible by using peptides as catalysts.

Within this manuscript the synthesis of a new generation of Ni(II) complexes that contain a secondary rather than a tertiary amino group, as well as the unusual chemoselectivity, was demonstrated in alkyl halide alkylations and Michael addition reactions. The complete C-H chemoselectivity observed in these reactions suggests that coordination of nitrogen to a metal has a significant synthetic potential as protecting a group without the need of introducing a transient N-C substituent. These new complexes have also proven highly synthetically useful nucleophilic glycine equivalents for the simple and highly diastereoselective synthesis of β-sub­stituted pyroglutamic acids via their reactions with chiral Michael acceptors.

The work being reported here deals with the design of a new type of "N-H" Ni(II) complexes of glycine Schiff bases and study general aspects of their reactivity. It was confirmed that the presence of NH function in these Ni(II) complexes does not interfere with the homologation of the glycine residue, rendering these derivatives of high synthetic value for the general synthesis of α-amino acids. In particular, the practical application of these NH-type complexes was demonstrated by asymmetric synthesis of various β-substituted pyroglutamic acids via Michael addition reactions with chiral Michael acceptors.

A class of ionic liquid supported (ILS) (S)-pyrrolidine sulfonamide organocatalyst (1c), which was developed earlier in our lab, has been applied to a wider range of Michael addition reaction, involving various aryl-substituted nitroolefins and a series of aldehydes. Catalyst 1c catalyzes Michael additions in which only 2 equivalents of aldehydes to each equivalent of nitroolefin are required. With 10 mol% of ILS catalyst 1c loading, moderate to excellent yields (51- 98%) with moderate enantioselectivities (28-83% ee) and high diastereoselectivities (syn/anti ratio up to 97/3) were obtained. Moreover, the catalyst 1c could be easily recycled and reused for at least 5 times with slightly reduced activities. Keywords: Aldehydes, asymmetric catalysis, ionic liquid, michael addition, nitroolefins, cornerstone, enantioselective, organocatalytic, methyl

A new organocatalyst for the asymmetric Michael addition reaction of aldehydes with β‐nitrostyrenes is developed by coupling D‐proline with (S)‐1‐triflicamido‐3‐phenylpropan‐2‐amine, which in turn is prepared from L‐phenylalaninol. The Michael addition products were obtained in very high yields (up to 93 %) and with excellent enantioselectivity (up to 97 % ee) and high diastereoselectivity (up to >99:1 dr). The catalyst is effective for reactions between α‐branched aldehydes and β‐nitrostyrenes.

Synthesis of fluorine-containing α-amino acids in enantiomerically pure form via homologation of Ni(II) complexes of glycine and alanine Schiff bases

Review: 144 refs.

An efficient approach to the asymmetric synthesis of (L)-allo-isomers of β-substituted α-aminobutanoic acid is described. The chiral NiII complex of a Schiff's base derived from (S)-o-[N-(N-benzylprolyl)amino]benzophenone (BBP) and glycine was treated with acetaldehyde in MeOH. The addition proceeds with high diastereoselectivity to give, if catalysed by MeONa, the corresponding complex of (R)-threonine, and, if catalysed by Et3N, the corresponding complex of (S)-allo-threonine. The (R)-threonine complex was converted into the chiral NiII complex of dehydroaminobutanoic acid, and a X-ray diffraction structural study of its major isomer showed that the dehydroaminobutanoic acid moiety was in the E-configuration. The complex, in turn, entered into Michael addition reactions with nucleophiles, including MeOH, EtOH, PhSH, and PhCH2SH. The reaction proceeded with high diastereoselectivity, producing predominantly complexes of the allo-threonine derivatives (d.e. > 90%). Diastereoisomerically and enantiomerically pure α-amino acids were obtained after chromatographic purification, decomposition of the complexes, and recovery of the initial chiral auxiliary, BBP. The thiol addition reaction is accompanied by a side reaction leading to the formation of sizeable amounts of the vinylglycine complex. An approach to the synthesis of optically active vinylglycine starting with racemic methionine is described.

Asymmetric Michael addition reactions of aldehydes with nitrostyrenes catalyzed by functionalized chiral ionic liquids

π-Allyltricarbonyliron lactone complexes, η4-dienetricarbonyliron complexes and their relatives offer an interesting approach to the problem of acyclic stereocontrol. Functional groups appended to the organic ligand frequently adopt a preferred conformation. This, combined with the steric bulk of the Fe(CO)3 moiety provides a means for controlling the addition of reagents to such pendant functionality in a defined manner. Thus addition of nucleophiles to aldehydes and ketones affords a route to diastereoisomerically pure secondary and tertiary alcohols while olefinic functionality in the side-chain can be utilised in stereoselective dihydroxylations, Diels–Alder and Michael addition reactions. Just as the formation of arene Cr(CO)3 complexes modifies reactivity at the α-position of arene substituents, the Fe(CO)3 group of η4-diene and trimethylenemethane tricarbonyliron complexes can be used to stabilise an adjacent positive charge. Trapping of the carbocation resulting from ionisation of an α-carbinol occurs with high diastereoselectivity, providing an unusual and useful stereoselective SN1-type reaction. Such highly stereoselective reactions have been put to good use in the preparation of a number of biologically interesting natural products.

π-Allyltricarbonyliron lactone complexes, η4-dienetricarbonyliron complexes and their relatives offer an interesting approach to the problem of acyclic stereocontrol. Functional groups appended to the organic ligand frequently adopt a preferred conformation. This, combined with the steric bulk of the Fe(CO)3 moiety provides a means for controlling the addition of reagents to such pendant functionality in a defined manner. Thus addition of nucleophiles to aldehydes and ketones affords a route to diastereoisomerically pure secondary and tertiary alcohols while olefinic functionality in the side-chain can be utilised in stereoselective dihydroxylations, Diels–Alder and Michael addition reactions. Just as the formation of arene Cr(CO)3 complexes modifies reactivity at the α-position of arene substituents, the Fe(CO)3 group of η4-diene and trimethylenemethane tricarbonyliron complexes can be used to stabilise an adjacent positive charge. Trapping of the carbocation resulting from ionisation of an α-carbinol occurs with high diastereoselectivity, providing an unusual and useful stereoselective SN1-type reaction. Such highly stereoselective reactions have been put to good use in the preparation of a number of biologically interesting natural products.

Synthesis of β-hydroxyenones and its application toward development of tetrahydro-4H-pyran-4-one in an atom-economic fashion is limited. This manuscript describes a ruthenium-catalyzed atom-economic coupling of pent-2-yne-1,5-diols and Michael acceptors as an efficient route for the synthesis of β-hydroxyenones with excellent yields and high regioselectivity. The β-hydroxyenones further undergo a 6-endo trig cyclization under acid-catalyzed conditions to deliver the tetrahydro-4H-pyran-4-ones with high diastereoselectivity. An intramolecular aldol condensation under mild basic conditions and palladium-catalyzed oxidative aromatization was developed for the synthesis of hexahydro-6H-isochromen-6-ones and isochromanols, respectively, from highly substituted tetrahydro-4H-pyran-4-ones with excellent yield and diastereoselectivity. Overall, this work demonstrates the synthetic potential toward the synthesis of oxacycles like tetrahydro-4H-pyran-4-ones, hexahydro-6H-isochromen-6-ones, and isochromanols via an atom-economic catalysis.

The asymmetric synthesis of β-lactams : Stereocontrolled Asymmetric Tandem Michael Additions and Subsequent Alkylations of E-[(η 5-C 5H 5)Fe(CO)(PPH 3)COCH = CHME]. X-ray Crystal Structure of (RS)-E-[(η 5-C 5H 5) Fe (CO) (PPH 3) COCH = CHME