Alkylation of amino acids without loss of the optical activity: preparation of .alpha.-substituted proline derivatives. A case of self-reproduction of chirality

245

175

Fragment-based drug discovery (FBDD) has proven to be an effective means of producing high-quality chemical ligands as starting points for drug-discovery pursuits. The increasing number of clinical candidate drugs developed using FBDD approaches is a testament of the efficacy of this approach. The success of fragmentbased methods is highly dependent on the identity of the fragment library used for screening. The vast majority of FBDD has centered on the use of sp 2 -rich aromatic compounds. An expanded set of fragments that possess more 3D character would provide access to a larger chemical space of fragments than those currently used. Diversity-oriented synthesis (DOS) aims to efficiently generate a set of molecules diverse in skeletal and stereochemical properties. Molecules derived from DOS have also displayed significant success in the modulation of function of various "difficult" targets. Herein, we describe the application of DOS toward the construction of a unique set of fragments containing highly sp 3 -rich skeletons for fragment-based screening. Using cheminformatic analysis, we quantified the shapes and physical properties of the new 3D fragments and compared them with a database containing known fragment-like molecules.library development | probe discovery

Section: Resultsmentioning

confidence: 99%

“…This compound was chosen as a starting building block because of its enantiomerically pure quaternary carbon center that would enable access to spirobicyclic compounds. Furthermore, both antipodes of 3 can also be obtained using the methodology of Seebach (25).…”

Section: Resultsmentioning

confidence: 99%

Route to three-dimensional fragments using diversity-oriented synthesis

Hung

Ramek²,

Wang³

et al. 2011

245

175

“…In a 1 H NMR study, we found that in the proline-catalyzed reaction of acetone with isobutyraldehyde or pivaldehyde in d 6 -DMSO, proline is initially quantitatively engaged in oxazolidinone formation. Seebach had previously used these oxazolidinones in an elegant overall asymmetric ␣-alkylation reaction of proline (32). The formation of oxazolidinones in the proline-catalyzed intermolecular aldol reaction, however, can best be characterized in terms of a parasitic equilibrium that, whereas unwanted and rate-diminishing, would still allow for turnover.…”

Section: Resultsmentioning

confidence: 99%

New mechanistic studies on the proline-catalyzed aldol reaction

List

Hoang

Martin

2004

323

144

The mechanism of the proline-catalyzed aldol reaction has stimulated considerable debate, and despite limited experimental data, at least five different mechanisms have been proposed. Complementary to recent theoretical studies we have initiated an experimental program with the goal of clarifying some of the basic mechanistic questions concerning the proline-catalyzed aldol reaction. Here we summarize our discoveries in this area and provide further evidence for the involvement of enamine intermediates. D iscovered in the early 1970s, the Hajos-Parrish-EderSauer-Wiechert reaction (1, 2), a proline-catalyzed intramolecular aldol reaction, represents not only the first asymmetric aldol reaction invented by chemists but also the first highly enantioselective organocatalytic transformation [1(4) 3 2(5) 3 3(6)] (Eq. 1 of Scheme 1) (3-6). Inspired by Nature's phenomenal enzymes, which catalyze direct asymmetric aldolizations of unmodified carbonyl compounds (7, 8), we have recently extended the Hajos-Parrish-Eder-Sauer-Wiechert reaction to the first intermolecular variant (7 ϩ 8 3 9) (Eq. 2 of Scheme 1) (9), and to several other reactions including prolinecatalyzed asymmetric Mannich (10), Michael (11), ␣-amination (12), and intramolecular enolexo aldolization reactions (10 3 11) (13) (Eq. 3 of Scheme 1) (14-18).Similar to the aldolase enzymes, proline catalyzes direct asymmetric aldol reactions between two different carbonyl compounds to provide aldol products in excellent yields and enantioselectivities. Early on it has been speculated that in addition to operating on related substrates, both class I aldolases and proline may also share a similar enamine mechanism (19,20). However, there has been some debate over several mechanistic aspects of the reaction, and a number of alternative models have been proposed. For example, Hajos (1) suggested a mechanism that involves the ''activation'' of one of the enantiotopic acceptor carbonyl groups as a carbinol amine (A of Scheme 1). At least the stereochemistry of this model was questioned by Jung (19) soon after its initial proposal. An enamine mechanism was suggested by various groups already in the 1970s and 1980s (19-21). Nonlinearity studies by Agami and colleagues (21) have led to the proposal of a side-chain enamine mechanism that involves two proline molecules in the C-C-bondforming transition state, one engaged in enamine formation and the other as a proton transfer mediator (B of Scheme 1). Swaminathan et al. (22) favor a heterogeneous aldolization mechanism on the surface of crystalline proline (C of Scheme 1), despite the fact that many proline-catalyzed aldolizations are completely homogenous. Agami's widely accepted twoproline mechanism was recently challenged when we proposed a homogenous one-proline enamine mechanism for the intermolecular variant in which the various proton transfers are mediated by proline's carboxylic acid functionality (9). On the basis of density functional theory calculations, subsequently proposed a very similar mechanism for the in...

“…Rather than the enamine, thermodynamics favor the oxazolidinone constitutional isomer, in which one C─O-and one C─H-σ-bond are gained at the expense of one C─C-π-bond and one O─H-σ-bond: [1] In view of the catalytic action of proline, oxazolidinone formations with aldehyde or ketone substrates are best described as parasitic equilibria because they are not leading to product but inhibit its formation (14). Although aldehyde-derived "Seebach oxazolidinones" (15)(16)(17) have long been known, their ketone analogues have only recently been detected and characterized by us (14) and later isolated also by Seebach et al (18). Interestingly, the condensation product of acetone and proline has also been detected by Marquez and Metzger using mass spectrometry (19).…”

mentioning

confidence: 99%

Crystal structures of proline-derived enamines

Bock

Lehmann

List

2010

The isolation and structural characterization of both aldehyde-and ketone-derived proline enaminones are reported and discussed. Crystal structures of 10 proline enamines provide information on stereochemical aspects, i.e., double bond configuration and synvs. anti-positioning of the carboxylate relative to the enamine double bond. Furthermore, the obtained crystal structures are compared with the density functional theory-calculated structures of the ground and transition state and the postulated SeebachEschenmoser transition state.enamine catalysis | mechanism | organocatalysis