Highly Enantioselective Organocatalytic Addition of Aldehydes to N‐(Phenylmethylene)benzamides: Asymmetric Synthesis of the Paclitaxel Side Chain and Its Analogues

Abstract

Easily side-tracked: A simple route to the paclitaxel side chain and its analogues is based on the (R)-proline-catalyzed addition of aldehydes to N-(phenylmethylene)benzamides, followed by oxidation of the resulting protected alpha-hydroxy-beta-benzoylaminoaldehydes (92-99 % ee). Esterification of the subsequent phenylisoserine derivatives with baccatin III gives paclitaxel analogues (see scheme).A simple highly enantioselective organocatalytic addition of aldehydes to N-(phenylmethylene)benzamides is presented. The application of (R)-proline as the catalyst and subsequent oxidation of the protected alpha-hydroxy-beta-benzoylaminoaldehydes (92-99 % ee) gives access to esterification-ready phenylisoserine derivatives such as the protected paclitaxel (taxol) side chain. Esterification of these derivatives with baccatin III gives access to the cancer chemotherapeutic substance paclitaxel and its analogues that do not exist in nature.

Enantioselective Organocatalytic Michael Additions of Oxyacetaldehydes to Nitroolefins

“…Ethyl 3-nitroacrylate (17) afforded product 23 in good yield (88 %) and with high enantioselectivity (syn 95 % ee, anti 93 % ee; Scheme 3). In the same reaction under Hayashi's conditions, [20] the product was isolated in 85 % yield with 92 % ee (both diastereomers). The addition proceeded also with aliphatic nitroalkene 18 and ferrocenyl derivative 19, but in these cases, products 24 and 25 were isolated only in low yields.…”

“…[19] Cordova used benzyloxyacetaldehyde in the Mannich reaction for the synthesis of the side chain of Paclitaxel. [20] Recently, Hayashi successfully utilized conjugate addition of 3-pentyloxyacetaldehyde to nitroacrylate en route to Oseltamivir. [21] These examples show the usefulness of oxyacetaldehydes in synthesis.…”

Organocatalytic alkylation of carbohydrate‐containing aldehydes with dihydroquinoline N,O‐acetals: Absolute configuration of 1,2‐dihydroquinolines

“…In view of the use of particularly valuable glycidic aldehydes 1a,b , the experimental conditions reported in Table make use of half equivalent of this reaction component, whereas in our prior reports, an excess of aldehyde (3.0 equivalents) was generally used . Benzyloxyacetaldehyde ( 1c ) has already been used as the nucleophilic component in highly enantioselective proline‐catalyzed Mannich‐type reactions, but proved to be a challenging substrates for prolinol‐based catalyzed reactions . In our experiments, the addition of 1c to in situ generated N‐acyl‐quinolinium ion both using organocatalysts L1 or L2 , afforded the corresponding diastereoisomeric products 7 ac and 8 ac with very low diastereoselectivity and enantioselectivity (entries 1 and 2, Table ).…”

Metal–Organocatalytic Tandem Azide Addition/Oxyamination of Aldehydes for the Enantioselective Synthesis of β‐Amino α‐Hydroxy Esters

“…Among the organocatalyzed syntheses of amino aldehydes, the synthesis of β‐amino aldehydes through the Michael addition of a nitrogen nucleophile to an iminium intermediate has attracted our interest, because we have been involved in the study of asymmetric cascade organocatalytic reactions involving the iminium‐catalyzed Michael addition of various nucleophiles to α,β‐unsaturated aldehydes 6–8. The cascade reaction conditions involving 2,2,6,6‐tetramethylpiperidinyloxy (TEMPO) and azide may afford synthetically and pharmaceutically useful β‐amino α‐hydroxy carbonyl compounds (Scheme ),9 which have been synthesized by various methods,10,11 for example, the oxyamination of alkenes,10 hydroxylation of β‐amino enolates,11h amination of keto esters,11i Henry reaction of carbonyl compounds,11j,11k,11l Mannich reaction of α‐oxyaldehydes,11m,11n reduction of α‐acetoxy‐β‐enamino esters,11o and reduction of β‐amino α‐keto esters 11p. In comparison to the previously reported methods, the proposed organocatalyzed tandem addition approach may afford enantiomerically enriched β‐amino α‐hydroxy carbonyl precursors from commercially available starting materials with step economy without the use of expensive and highly air‐ and moisture‐sensitive metal complexes.…”