We present a novel concept for the in situ control of site-selectivity of catalytic acetylations of partially protected sugars using light as external stimulus and oligopeptide catalysts equipped with an azobenzene moiety. The isomerizable azobenzene-peptide backbone defines the size and shape of the catalytic pocket, while the π-methyl-l-histidine (Pmh) moiety transfers the electrophile. Photoisomerization of the E- to the Z-azobenzene catalyst (monitored via NMR) with an LED (λ = 365 nm) drastically changes the chemical environment around the catalytically active Pmh moiety, so that the light-induced change in the catalyst shape alters site-selectivity. As a proof of principle, we employed (4,6-O-benzylidene)­methyl-α-d-pyranosides, which provide a change in regioselectivity from 2:1 (E) to 1:5 (Z) for the monoacetylated products at room temperature. The validity of this new catalyst-design concept is further demonstrated with the regioselective acetylation of the natural product quercetin. In situ irradiation NMR spectroscopy was used to quantify photostationary states under continuous irradiation with UV light.

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.

Herein, we report the oligopeptide-catalyzed site-selective acylation of partially protected monosaccharides. We identified catalysts that invert site-selectivity compared to N-methylimidazole, which was used to determine the intrinsic reactivity, for 4,6-O-protected glucopyranosides (trans-diols) as well as 4,6-O-protected mannopyranosides (cis-diols). The reaction yields up to 81% of the inherently unfavored 2-O-acetylated products with selectivities up to 15:1 using mild reaction conditions. We also determined the influence of protecting groups on the reaction and demonstrate that our protocol is suitable for one-pot reactions with multiple consecutive protection steps.

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...

Wegen der grolen Empfindlichkeit der Antipyrin-nnd PyrazoloncarbonsLuren, von denen es bisher nicht gelang, die Stlurechloride, die zn den meisten Bldehydsynthesen gebraucht wurden, darzustellen, wnrden zunachst die weit weniger empfindlichen Pyrazole nnd Chlorpyrazole nntersucht.Von dem 1-Phenyl-3-methyl-5-chlorpyrazol b m . der zngehihigen 4-CarbonsLnre ausgehend, wnrde nach folgenden Methoden vergeblich versncht, den l-Phenyl-3-methyl-5-chlorpyrazol-4-aldehyd zu erhalten: 1. Gat.termann-Koch. M. 31, 65, '173 (1010); C. 1788, I (1910). I)3 J. pr.[2] 61, 88.