The Enantioselective Dakin–West Reaction

Abstract

Here we report the development of the first enantioselective Dakin-West reaction, yielding a-acetamido methylketones with up to 58 %eewith good yields.T wo of the obtained products were recrystallized once to achieve up to 84 %ee. The employed methylimidazole-containing oligopeptides catalyze both the acetylation of the azlactone intermediate and the terminal enantioselective decarboxylative protonation. We propose ad ispersion-controlled reaction path that determines the asymmetric reprotonation of the intermediate enolate after the decarboxylation.Even though the Dakin-West (DW) reaction dates back to 1928, [1] it is still one of the most effective synthetic procedures to prepare a-acylamido ketones from primary a-amino acids.[2] Generally,t he treatment of an amino acid with an acid anhydride and base,t ypically pyridine,a te levated temperature provides the desired product upon liberation of CO 2 (Scheme 1). Numerous modifications of the original reaction conditions were developed, [2] including catalytic variants, [3] broadening its scope and applicability.U nsurprisingly,the DW reaction found application in the preparation of a-acylamido ketones as valuable precursors for various biologically active compounds, [4] and even in Woodwards fundamental total synthesis of strychnine.[5] Remarkably,n o asymmetric variant has been developed to date,thus restricting the use of this important reaction in modern synthetic chemistry.According to the currently accepted mechanism, [6] the reaction of an amino acid with the anhydride leads to the Nacetyl derivative 1 and subsequently to the mixed anhydride 2 (Scheme 2). Cyclization of 2 provides the oxazol-5(4H)-one (azlactone) 3.S uch azlactones are acidic owing to the formation of resonance stabilized enolate 4 upon deprotonation. Subsequent acetylation may occur at the enolate oxygen atom (affording 5)ordirectly at the carbon atom to give 6. [7] However, 6 is exclusively produced under the typical DW reaction conditions because of concomitant O!Cacyltransfer (Steglich rearrangement).[8] Opening of 6 with acetic acid, formed in previous steps,t ot he mixed anhydride 7 and transacylation gives the b-keto acid 8, [6f] which is prone to decarboxylation upon deprotonation. This final reaction step affords the desired a-acetamido methylketone 10,l ikely via enolate 9.Other pathways,for example,the acylationof2 to directly give 7, [9] were discussed as well but have been shown to be rather improbable.I ti se vident from this mechanistic picture that the intermediacyo f4 and 9 (Scheme 2) leads to the observed complete racemization, making an asymmetric reaction ad ifficult endeavor. We surmized, however, that an enantioselective decarboxylative protonation [10] of 8 (via 9) would afford enantioenriched products.Herein we show that this is indeed possible with at ailor-made catalytic system.We chose synthetic oligopeptides as catalysts [11] as these should be well-suited for binding the amino acid derived intermediates,a sd emonstrated for such platforms in acyl tra...

Asymmetric Catalysis Mediated by Synthetic Peptides, Version 2.0: Expansion of Scope and Mechanisms

“…Though several advances have been made to this reaction since 1928, 188 it was not rendered asymmetric until 2016, when Schreiner and coworkers reported the first enantioselective DW reaction using Pmh-containing peptide catalysts. 189 The authors envisioned that a Pmh-containing peptide catalyst could serve multiple roles along the putative DW reaction pathway (Figure 69). 189 Amino acid 4.39 is first converted to the mixed anhydride, followed by cyclodehydration to oxazolone intermediate I.…”

“…189 The authors envisioned that a Pmh-containing peptide catalyst could serve multiple roles along the putative DW reaction pathway (Figure 69). 189 Amino acid 4.39 is first converted to the mixed anhydride, followed by cyclodehydration to oxazolone intermediate I. Subsequent acetylation of I affords oxazole II, which can undergo a Steglich rearrangement to form α-acyl oxazolone intermediate III.…”

“…Schreiner and coworkers also investigated the mechanism of this reaction using DFT calculations. 189 The exact nature of the decarboxylative step is not clear; however, asymmetric induction is believed to stem from the deprotonation of IV, release of carbon dioxide, and subsequent enantioselective protonation of enolate V. Possible complexes between enolate V and protonated peptide 4.41 were therefore computed. The lowest-energy complex, shown in Figure 70, reveals the close proximity (1.94 Å) of the α-carbon of V to the protonated Pmh residue.…”

“… , In the presence of a base at elevated temperatures, carbon dioxide is evolved from 4.39 en route to the α-acylamido ketone product, providing a thermodynamic driving force for this multistep process. Though several advances have been made to this reaction since 1928, it was not rendered asymmetric until 2016, when Schreiner and coworkers reported the first enantioselective DW reaction using Pmh-containing peptide catalysts …”

Anion-π Enzymes

“… 1 Of particular interest is the creation of conceptually innovative catalysts that operate with anion-π interactions, 2 − 5 ion pair-π interactions, 6 halogen bonds, 7 − 9 chalcogen bonds, 10 , 11 and so on, i.e., the unorthodox counterparts of cation-π interactions, ion pairs, and hydrogen bonds. At the same time, explicit attention to more conventional interactions such as dispersion forces 12 , 13 or to long-distance effects along α-helical macrodipoles 14 contributes much to current progress with a conceptually innovative catalyst design. Among unorthodox interactions, anion-π interactions arguably are the youngest, most elusive, most debated, least used and, perhaps, the most promising.…”