Jose L. Vicario

Cooperative dienamine/hydrogen-bonding catalysis: enantioselective formal [2+2] cycloaddition of enals with nitroalkenes.

The cyclobutane scaffold is a structural motif incorporated into a wide range of naturally occurring products, as well as into transiently generated intermediates in primary and secondary metabolism. Moreover, the reactivity pattern shown by cyclobutanes when exploiting ring strain as a driving force to facilitate novel reactivity has also opened the way for their use as intermediates in the synthesis of complex molecules. However, despite their interest, the development of methodologies for the stereocontrolled synthesis of cyclobutanes has received little attention over the years. In this context, the [2+2] cycloaddition represents one of the most straightforward approaches for the stereoselective construction of this structure with several reported and efficient examples, which rely on the use of chiral ligands, auxiliaries, or Lewis acid catalysts. Within this context, we wondered if aminocatalysis could contribute to this field by facing the challenge of setting up an enantioselective version of a [2+2] cycloaddition reaction between a,b-unsaturated aldehydes and nitroalkenes. We were inspired by recent work by Seebach, Hayashi, and coworkers, and Blackmond and co-workers (Scheme 1) in which kinetic and structural studies of O-trimethylsilyldiphenylprolinol-catalyzed Michael addition of aldehydes to nitroolefins led to the detection of an aminonitrocyclobutane intermediate, which was identified as a resting state for the catalyst. Taking this discovery into account, we hypothesized that enolizable enals could undergo a similar reaction based on the dienamine activation mode where the catalyst would be able to undergo turnover, thus furnishing a final nitrocyclobutane product. In fact, literature precedent exists for the related [2+2] cycloaddition of enamines with electronpoor alkenes, thus showing that this process can occur spontaneously without the need of photochemical activation. In contrast, there is also literature precedent which shows that the reaction of nitroalkenes with enolizable a,bunsaturated aldehydes under dienamine catalysis leads to the exclusive formation of Michael-type adducts through the selective a-functionalization of the dienamine intermediate and therefore no opportunity arises for cyclobutane formation. Herein, we wish to present our initial results on a novel chiral secondary amine catalyzed enantioselective formal [2+2] cycloaddition of enolizable a,b-unsaturated aldehydes with a-hydroxymethyl-substituted nitroalkenes which leads to the formation of cyclobutanes in a single step (Scheme 2). This reaction is in sharp contrast with previously published work which, as already mentioned, shows the preference for dienamine intermediates generated from enals to undergo Scheme 1. a) Previous work: addition to nitroolefins throuh enamine catalysis. b) Working hypothesis: formal [2 + 2] cycloaddition through dienamine catalysis. TMS = trimethylsilyl.

Enantioselective Organocatalytic Domino Oxa-Michael/Aldol/Hemiacetalization: Synthesis of Polysubstituted Furofuranes Containing Four Stereocenters†

The discovery of new methodologies for the synthesis of complex molecules in the shortest and most efficient way is a key field of research. In this context, domino or cascade reactions represent an advantage for the straightforward construction of biologically relevant compounds because they allow construction of complex molecules in an efficient way, thereby minimizing the number of laboratory operations and the generation of waste chemicals. Additionally, when stereochemistry is a fundamental parameter to be controlled, domino processes arise as an effective approach for constructing the target molecule with good stereoselectivity. Among the different methodologies described in the chemical literature, organocatalytic enantioselective domino reactions represent a useful and competitive tool for the generation of molecular complexity from readily available and cheap starting materials, as well as displays exceptional performance with regard to stereochemical control. More advantages of this methodology are related to the fact that organocatalysts are very often commercially available, environmentally friendly, water compatible, air stable, and robust reagents. Additional benefits are associated with the tolerance of the catalysts and the reactive intermediates to the presence of moisture or air in the reaction medium, which leads to an advantage in operational simplicity when carrying out the reaction. A particularly interesting situation is the use of chiral amines as catalysts in domino processes which are initiated by Michael-type reactions. Chiral amines can activate a,bunsaturated aldehydes or ketones by the reversible formation of an iminium ion which, after the conjugate addition step, delivers in intermediate enamine ready to participate in a subsequent reaction, therefore providing an opportunity for a domino process to occur. Related to this topic, several stereoselective amine-catalyzed cascade reactions initiated by conjugate additions have been reported, most of them involving a C C bond formation in the cascade-initiating Michael reaction step and also some examples can be found in which a hetero-Michael reaction has been employed to start the process. Importantly, it has to be pointed out that oxaMichael-initiated domino reactions have received little attention, just as the organocatalytic oxa-Michael reaction, which still remains a rather unexplored transformation. This lack of attention is mainly a result of the reversibility of the conjugate addition process, which very often makes the oxa-Michael addition products configurationally unstable. An additional difficulty associated with this reaction is related to the low nucleophilicity of the alcohol functionality, which therefore requires a prior deprotonation step to activate it as an alkoxide ion. As a consequence of this the scope of the alcohols suitable candidates to be used as oxygen nucleophiles in oxa-Michael reactions is restricted to compounds of enhanced acidity. In fact, literature examples are exclusively limited to the use of functionalized phenols as nucleophiles (in oxa-Michael-initiated cascade reactions or intramolecular versions) and also a couple of elegant procedures have been reported by Jørgensen and co-workers for the b-hydroxylation of a,b-unsaturated aldehydes and by List and coworkers for the b-hydroxylation of enones using oximes and hydroperoxides, respectively, as O nucleophiles. In this context, and in connection with our ongoing efforts to develop new organocatalytic reactions, we report herein a novel amine-promoted asymmetric domino reaction between dihydroxyacetone dimer and a,b-unsaturated aldehydes, which leads to the enantioselective formation of hexahydrofuro[3,4-c]furanes in a single step (Scheme 1). This transformation consists of an initial oxa-Michael reaction, a subsequent intramolecular aldol reaction, and lastly a hemiacetalization step, and it proceeds with the generation of four new stereocenters. Remarkably, the intramolecular aldol reaction step involves the participation of a ketone as internal electrophile, therefore generating a quaternary stereocenter. This reaction is in contrast with the other reported organo-

Organocatalytic enantioselective aza-Michael reaction of nitrogen heterocycles and α,β-unsaturated aldehydes

The asymmetric organocatalytic aza-Michael reaction of several nitrogen heterocycles and α,β-unsaturated aldehydes has been studied in detail; under the optimised conditions, the conjugate addition products have been obtained in high to excellent enantioselectivities.

An Amine-Catalyzed Enantioselective [3+2] Cycloaddition of Azomethine Ylides and α,β-Unsaturated Aldehydes: Applications and Mechanistic Implications

The catalytic enantioselective [3+2] cycloaddition between azomethine ylides and α,β-unsaturated aldehydes catalyzed by α,α-diphenylprolinol has been studied in detail. In particular, the reaction has been extended to the use of 2-alkenylidene aminomalonates generated in situ as azomethine ylide precursors. These reactions lead to the formation of pyrrolidines containing a 5-alkenyl side chain with potential for chemical manipulation. Moreover, a detailed and concise computational study has been carried out to understand the exact nature of the mechanism of this reaction and especially the consequences derived from the incorporation of the chiral secondary amine catalyst on the reaction pathway.

Organocatalytic Enantioselective Synthesis of Highly Functionalized Polysubstituted Pyrrolidines

The organocatalytic conjugate addition of different aldehydes to beta-nitroacrolein dimethyl acetal, generating the corresponding highly functionalized nitroaldehydes in high yields and with high stereoselectivities, has been studied in detail. These transformations have been achieved by using both readily available starting materials in a 1:1 ratio as well as commercially available catalysts at a 10 mol % catalyst loading. Furthermore, a very short and efficient protocol has been devised for the preparation of highly enantioenriched pyrrolidines containing two or three contiguous stereocenters starting from the obtained Michael adducts. 3,4-Disubstituted pyrrolidines have been obtained in a single step by Zn-mediated chemoselective reduction of the nitro group followed by intramolecular reductive amination, and trisubstituted homoproline derivatives have been prepared by means of an olefination reaction and a cascade process involving chemoselective reduction of the nitro group followed by a fully diastereoselective intramolecular aza- Michael reaction.

Enantio- and Diastereoselective Synthesis of Substituted Tetrahydro-1H-isochromanes through a Dynamic Kinetic Resolution Proceeding under Dienamine Catalysis

Racemic 5-acyloxydihydropyranones react with enolizable α,β-unsaturated aldehydes in the presence of a chiral secondary amine catalyst furnishing a wide range of differently substituted tetrahydro-1H-isochromanes with excellent results. The reaction relies on the activation of the enal by the catalyst through the formation of a dienamine intermediate, which undergoes a Diels-Alder/elimination cascade reaction. Moreover, the overall transformation also results in a highly efficient dynamic kinetic resolution process, furnishing the final adducts in high yields and excellent diastereo- and enantioselectivities.

Enantioselective Conjugate Addition of Donor–Acceptor Hydrazones to α,β-Unsaturated Aldehydes through Formal Diaza–Ene Reaction: Access to 1,4-Dicarbonyl Compounds

Donor-acceptor monosubstituted hydrazones participate as suitable reagents able to undergo an enantioselective formal diaza-ene reaction with α,β-unsaturated aldehydes under chiral secondary amine catalysis. This constitutes a new approach for the enantioselective conjugate addition of hydrazones to enals under metal-free conditions and leads to the formation of γ-hydrazono carboxylic acids after oxidation/[1,3]-H shift. The methodology is also useful for the synthesis of enantioenriched β-substituted α-keto-1,5-diesters by using the hydrazone moiety as a masked carbonyl group.

Catalytic Enantioselective [5+2] Cycloaddition between Oxidopyrylium Ylides and Enals under Dienamine Activation

Benzopyrylium ylides generated in situ from 1-acetoxyisochroman-4-ones reacted with α,β-unsaturated aldehydes in the presence of a bifunctional secondary-amine/squaramide catalyst to furnish [5+2] cycloaddition products in good yield with high diastereo- and enantioselectivity. The reaction proceeds by dienamine activation and involves β,γ-functionalization of the enal. The dienamine intermediates showed exclusive β,γ-reactivity and provided direct access to compounds with the 8-oxabicyclo[3.2.1]octane framework. The ability of the bifunctional secondary-amine/squaramide catalyst to engage in hydrogen-bonding interactions with the ylide made it particularly effective in terms of both the yield and the stereoselectivity of the transformation.

Favoring Trienamine Activation through Unconjugated Dienals: Organocatalytic Enantioselective Remote Functionalization of Alkenes

Unconjugated 2,5-dienals are more reactive substrates than the corresponding fully conjugated α,β,γ,δ-unsaturated aldehydes towards organocatalytic activation through trienamine intermediates. This difference in reactivity has been demonstrated in the Diels-Alder reaction with nitroalkenes, a reaction that proceeds with clean β,ε-selectivity to afford the final products in high yields and stereoselectivities, the related polyconjugated 2,4-dienals being completely unreactive.

5-Mercaptotetrazoles as Synthetic Equivalents of Nitrogen-Contaning Functional Groups. The Case of the Organocatalytic Enantioselective aza-Michael Reaction

5-Mercaptotetrazoles have been identified as useful and versatile Michael donors in enantioselective amine-catalyzed aza-Michael reactions with α,β-unsaturated aldehydes, showing excellent behavior as N-nucleophiles instead of their usual trend to react as S-nucleophiles. In addition several unprecedented chemical modifications on the tetrazolothione moiety have been carried out leading to the enantioselective preparation of different compounds incorporating nitrogen-containing functionalities such as oxazinimines, formamidines, ureas and isoureas.