Double Asymmetric Induction in Organocatalyzed Aldol Reactions: Total Synthesis of (+)‐2‐epi‐Hyacinthacine A₂and (–)‐3‐epi‐Hyacinthacine A₁

Abstract

The stereodivergent synthesis of two hyacinthacine analogues, which relies on an organocatalyzed aldol addition, is described. The aldol addition of dioxanone to an α‐N‐carbobenzyloxy‐substituted chiral aldehyde, promoted by both (R)‐ and (S)‐proline, proceeds in reasonable yields with acceptable diastereomeric ratios. The success of the reaction may be due to the use of an acyclic aldehyde acceptor, which allows reagent control of the stereochemical outcome of the key aldolization step in both the matched and mismatched cases.

On the Asymmetric Induction in Proline‐Catalyzed Aldol Reactions: Reagent‐Controlled Addition Reactions of 2,2‐Dimethyl‐1,3‐dioxane‐5‐one to Acyclic Chiral α‐Branched Aldehydes

“…In one of these asymmetric syntheses, we used a chiral α‐substituted acceptor . Aldol addition of dioxanone 1 to chiral acyclic α‐amino aldehyde 2a , promoted with ( R )‐proline, proceeded in good yield and with synthetically useful diastereoselectivity . In addition, with ( S )‐proline as organocatalyst, the reaction proceeded smoothly and with excellent diastereoselectivity, which is in agreement with the results of Cordova[5c] and several other groups .…”

“…Compound 5: The above general procedure was followed by using dioxanone 1 (436 mg, 3.35 mmol), aldehyde 2a (676 mg, 2.30 mmol), and ( S )‐proline (50 mg, 0.44 mmol) in DMF (5.2 mL). Purification of the crude residue by column chromatography (SiO 2 ; petroleum ether/ethyl acetate = 6:4) afforded aminal 5 (575 mg, 59 %) as white crystals, followed by diastereoisomeric aldol 4a (97 mg, 10 %).…”

“…A tactical combination of organocatalyzed aldol reaction of dioxanone 1 and reductive amination recently allowed us to synthesize optically pure iminosugars that possess common natural iminosugar's frameworks, such as members of the piperidine, pyrrolizidine, and indolizidine series. In one of these asymmetric syntheses, we used a chiral α‐substituted acceptor . Aldol addition of dioxanone 1 to chiral acyclic α‐amino aldehyde 2a , promoted with ( R )‐proline, proceeded in good yield and with synthetically useful diastereoselectivity .…”

Pyrrolizidine alkaloids: occurrence, biology, and chemical synthesis

“…95 Davies provided full details 96 Concise syntheses of (+)-2-epi-hyacinthacine A 2 146 and (-)-3epi-hyacinthacine A 1 159 (Scheme 29) were achieved from (S)glutamic acid via aldehyde 156. 100 Reagent controlled organocatalytic aldol addition of 2,2-dimethyl-1,3-dioxan-5one to this aldehyde with the (S)-and (R)-enantiomers of the proline catalyst resulted in diastereomers 157 and 158, respectively, the former existing predominantly in the hemiaminal form shown. These two intermediates were then taken separately through short sequences of deprotection and reductive amination to provide the target molecules.…”

Organocatalytic and enantioselective Michael reaction between α-nitroesters and nitroalkenes. Syn/anti-selectivity control using catalysts with the same absolute backbone chirality

“…While obtaining one or other mirror image of the target molecule can also be easily achieved by selecting the correct enantiomer of the catalyst, the relative configuration is typically governed by intrinsic factors associated to the mechanistic profile of the reaction and very often the formation of the major diastereoisomer is determined from the very beginning of the reaction and therefore access to any stereoisomer at will from the same set of starting materials with full absolute and relative stereocontrol is not trivial. Previous reports show that the diastereoselection can be directed by different approaches that include the modification of reaction conditions [ 7 – 9 ], the incorporation of additives or co-catalysts [ 10 – 13 ], the modification of some structural features of the substrate [ 14 – 15 ], the use of two catalysts that are structurally different to each other and that can also operate independently through a single transition state with minimal matched/mismatched interactions [ 16 – 22 ] or finally the concurrent use of two cycle-specific catalysts, in which each of them is exclusively involved in the formation of one stereocentre and therefore has to overcome the stereochemical bias exerted by the stereocentres generated in the previous steps [ 23 – 26 ].…”