Conformational Control of Tetrahydropyran‐Based Hybrid Dipeptide Catalysts Improves Activity and Stereoselectivity

Abstract

Herein, we introduce and demonstrate how carbohydrates can be used as conformational control units of organocatalysts to tune their catalytic properties. New hybrid dipeptide-like organocatalysts based on ζ-sugar aminoacids and proline were prepared and tested for the asymmetric Michael addition of aldehydes to βnitrostyrenes. Taking full advantage of the modular nature of the carbohydrate motif, both reactivity and stereoselectivity were significantly improved. By simple structural changes, such as the elimination of the methoxy group in the C4 position of the tetrahydropyran ring, we obtained two complementary catalysts that allow access to both enantiomers of the g-nitroaldehydes with excellent yields, diastereoselectivity, and enantiomeric excesses between 97 and 99%, using a catalytic load even below 1 mol%.

Enantioselective Michael Addition of Aldehydes to β‐Nitrostyrenes Catalyzed by (S)‐N‐(D‐Prolyl)‐1‐triflicamido‐3‐phenylpropan‐2‐amine

“…The compound 1 was prepared from L‐phenylalaninol as reported by Miura . 1 was coupled with N ‐Boc derivatives of L‐ and D‐proline using standard peptide coupling conditions (EDC · HCl, HOBt, DIPEA, DCM, 0 °C – r.t.).…”

“…The success of Wennemers's catalysts has prompted other groups to come up with similar proline containing peptide derivatives as catalysts for asymmetric Michael addition reactions. Among these, Lecouvey's peptides containing a phosphonic acid side chain and the proline‐sugar amino acid conjugates by Martín have resulted in excellent yields and very high stereoselectivity (Figure ). Inspired by the triflicamide catalysts developed by Wang and the peptides of Wennemers, we have recently developed D‐prolyl‐2‐(triflicamidopropyl)pyrrolidine as a very efficient catalyst for the Michael addition reaction between β‐nitrostyrenes and aldehydes (Figure ).…”

Synthesis and Applications of Carbohydrate-Based Organocatalysts

“…Aiming to modify the folded-unfolded conformations of the sugar prolinamides, Martín and co-workers described, two years later [ 157 ], the synthesis of analogues of the organocatalysts 337 , 339 and 340 (see Figure 25 ) lacking the methoxy group at the C-3 position. The compounds 344 and 345 ( Scheme 91 ) were prepared from the diol 341 , easily obtained [ 158 ] by isomerization of the d -glucal 312 , hydrogenation and deacetylation by transesterification.…”

“…After regioselective benzoylation of the primary alcohol of 341 and activation of the secondary alcohol as mesylate, the diester was treated with sodium azide to afford the known azido-ester 342 [ 159 ]. Methanolysis of the benzoate ester and 1,4-conjugate addition of the resulting alcohol to t -butyl acrylate under phase transfer conditions gave 343 [ 157 ]. Reduction of the azide to amine function and coupling with N -Boc- d - or l -proline led, after O - and N -deprotection with trifluoroacetic acid, to the stereoisomers 344 and 345 .…”

“…Application of the above-mentioned reaction sequence to the diol 325 (see Scheme 88 ) allowed preparation of the couple of stereoisomers 348 and 349 ( Scheme 92 ) [ 157 ]. On the other hand, the 1,4-conjugate addition of 325 to t -butyl acrylate gave the alcohol 346 that was reacted with N -Boc- l -proline in the presence of DCC to afford, after deprotection, the sugar-proline ester organocatalyst 347 ( Scheme 92 ).…”