Self‐Regeneration of Stereocenters (SRS)—Applications, Limitations, and Abandonment of a Synthetic Principle

Abstract

In the same manner that the Nasobem, Stiimpke's mythical creature, teaches his child the peculiar way of life of the species Nasobema lyricum, the work of Seebach et al. on the self-regeneration of stereocenters has been governed by a fanciful idea. On the way, many tricks have been learned and much knowledge gained. Finally, they have come back down to earth and find themselves once again in the unimaginative world of enantiomer separation for the synthesis of enantiomerically pure compounds. In order to replace a substituent at a single stereogenic center of a chiral molecule without racemization, a temporary center of chirality is first generated diastereoselectively, the original tetragonal center is then trigonalized by removal of a substituent, a new ligand is introduced, again diastereoselectively, and finally, the temporary center is removed. By means of these four steps (the "Self-Regeneration of Stereocenters", SRS), 2-and 3-amino-, hydroxy-, and sulfanylcarboxylic acids have been successfully alkylated with formation of tertiary carbon centers and without the use of a chiral auxiliary. Use of this methodology has allowed the potential of these inexpensive chiral building blocks to be expanded considerably. This article aims to demonstrate (using, in part, examples from natural product syntheses) that chiral heterocyclic acetals with enamine, enol ether, enolate, dienolate, enoate, radical, and acyliminium functionalities and also those that are potential reactants for Michael additions and pericyclic processes (for example, electron-rich and electronpoor dienophiles and dienes) are now easily accessible, more often than not, in both enantiomeric forms. Stereogenic nitrogen atoms of aziridines, boron atoms of cyclic or linear systems, and stereogenic planes of x-complexes can also be used as the temporary chirality element in other approaches to the realization of the SRS principle. Enantiomerically pure derivatives of, for example, glycine, hydroxy-and sulfanylacetic acid, 3-aminopropanoic acid, and 3-oxocarboxylic acids can be prepared by resolution of racemic mixtures via diastereoisomeric salts or by chromatography on a chiral column. Hence, the extensive reactivity of compounds developed to test the SRS principle and, above all, the outstanding stereoselectivities of the reactions can be put to good use even when no suitable chiral precursor is availabl-ven though this amounts to an abandonment of the principle! The readily available 2-tertbutyl-l,3-imidazolidin-3-one, -0xazolid-in-5-one, -dioxin-3-one, and -hydropyrimidinone (all of which contain a single stereogenic center at the acetal C atom) can thus be used in the preparation of a vast range of 2-amino-and 3-hydroxycarboxylic acids, and no chiral auxiliary has to be removed or regenerated during these procedures. (One example is the synthesis of 4-fluoro-MeBmt, a derivative of the C, amino acid found in cyclosporin.) In the final chapter we will discuss the most useful findings gained from investigations into both the self-regeneration of ste...

Experimental and Theoretical Conformational Analysis of 5‐Benzylimidazolidin‐4‐one Derivatives – a ‘Playground’ for Studying Dispersion Interactions and a ‘Windshield‐Wiper’ Effect in Organocatalysis

“…7) of calculated (gas phase) and measured (solid phase) structures, and the matching results of (solution phase) NMR investigations 8 ) 9 ) indicate that we do not have to deal with counter-ion or crystal-packing effects in a discussion of the conformations A -D: the observed structures mainly reflect the intramolecular interactions. 7 ) For the S22 benchmark set of non-covalent interactions, the mean absolute devations (MAD) of B3LYP/6-31G(d) and B3LYP/def2-QZVP are 2.8 and 3.7 kcal/mol, respectively.…”

“…-There is a rising interest in understanding the detailed mechanisms of organocatalysis [1 -8]. The imidazolidinones [9], which MacMillan introduced as organocatalysts [5d], are mainly used for activation of a,b-unsaturated aldehydes, through iminium ions as reactive intermediates. In the (S)-phenylalanine-derived imidazolidinones 1, the benzyl (Bn) group at C(5) is considered to provide the main contribution to steric shielding of the (E)-iminium-ion top face, so that nucleophiles approach preferentially from the bottom face.…”

Biomimetic Synthesis of (.+-.)-Galanthamine and Asymmetric Synthesis of (-)-Galanthamine Using Remote Asymmetric Induction

“…Originally, synthesis of chiral 1,3-imidazolidin-5-one and its application to chiral induction was reported by Seebach, who proposed the concept as Self Regeneration of Stereocenters (SRS). [62][63][64] Among naturally abundant amino acids, phenylalanine and valine were chosen as the chiral auxiliary to form the fused imidazolidinone because the bulky isopropyl and benzyl groups on amino acid residues would provide promising stereoselectivities. In the beginning, we simply expected that the spontaneous Michael addition after deprotection of R 1 in B would progress diastereoselectively to afford cyclic ether (C) with the desired configuration.…”

“…The configuration of the major isomers was also supported by the experimental data in the synthesis of imidazolidinone derivatives, which was reported by Seebach. [62][63][64] The amino group of 29a was next protected with a trifluoroacetyl group to prepare 30a, a substrate of the phenol coupling. The imidazolidinone derivatives 30b and 30c were also prepared from 29b and 29c in order to compare the coupling reactions.…”

Synform Issue 2009/05

“…"Our group, engaged in the chemistry and biology of β-and α-peptides, was actually lured into the field of organocatalysis by statements in the literature 2 about the role of oxazolidinones in proline catalysis, which read like this: the Seebach oxazolidinones [3][4][5] are parasitic, non-productive, deadend species," explained Professor Seebach. A closer look in the ETH laboratories led to the proposal of an alternative mechanism for proline catalysis, with oxazolidinones as key players. 6 "This was supported by the recent demonstration that such an oxazolidinone (dubbed SolPro) is superior to proline as a catalyst," 7 confirmed Professor Seebach.…”