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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.

A simple enzymatic synthesis of (3S,4R)-(+)-4-hydroxy-3-phenyltetrahydroisoquinolines

Abstract An efficient versatile method is presented for the stereospecific synthesis of (+)-4-hydroxy-3-phenyltetrahydroisoquinolines 11 and 12 using (R)-arylcyanohydrins as the chiral starting material. From this asymmetric core, the synthetic process proceeds with development of the S absolute stereochemistry for the phenyl group at C-3 and the R configuration at C-1 of the target heterocycle. As the protective group protocol allows the stereospecific deprotection at C-4, (3S,4R)-(+)-4-hydroxy-3-phenyltetrahydroisoquinolines have been prepared using this process.

Silicon-mediated isoquinoline synthesis: preparation and stereochemical characterization of 4-hydroxy-3-phenylisoquinolines

Abstract The silicon-mediated synthesis of 4-hydroxy-6,7-dimethoxy-3-phenylisoquinoline derivatives is reported. The described procedure implies synthetically useful yields and a high degree of stereoselectivity.

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.

Highly regio- and stereoselective addition of organolithium reagents to extended conjugate amides using (S,S)-(+)-pseudoephedrine as chiral auxiliary.

The conjugate addition of organolithium reagents to polyunsaturated conjugate amides containing (S,S)-(+)-pseudoephedrine as chiral auxiliary has been studied in detail. The reaction proceeded with good 1,4-selectivity and excellent stereoselectivity, affording the corresponding addition products with good yields and as highly diastereoenriched isomers. Removal of the chiral auxiliary by reduction or hydrolysis has allowed the preparation of polyfunctionalized chiral building blocks incorporating an alkene moiety suitable for further transformations.

Asymmetric Synthesis of Arylglycines and Their Use as Chiral Templates for the Stereocontrolled Synthesis of 7,8-Disubstituted 3-Aryl-1,2,3,4-tetrahydroisoquinolin-4-ols

A synthetic technique for the asymmetric synthesis of arylglycines has been optimized, reaching the target amino acids in only four steps with good yields and with enantiomeric excesses higher than 99%. The key step consisted of a stereocontrolled electrophilic amination reaction of (S,S)-(+)-pseudoephedrine-based arylacetamide enolates with di-tert-butylazodicarboxylate. The arylglycines thus obtained turned out to be excellent chiral templates for the production of chiral, nonracemic 7,8-disubstituted 3-aryl-1,2,3,4-tetrahydroisoquinolines, through use of a synthetic sequence involving: (1) reduction of the arylglycines to the parent arylglycinols, (2) N-benzylation with appropriately substituted aromatic aldehydes and (3) Swern oxidation followed by acid-catalysed cyclization of the obtained α-amino aldehydes.

Stereocontrolled synthesis of 2-aryl tetralones. Application in the synthesis of B/C hexahydrobenzo[c]phenanthridine alkaloids

Abstract Hexahydrobenzo[ c ]phenanthridines possessing a B/C cis ring junction have been synthesized in a stereoselective way starting from chiral non-racemic 2-aryl-tetralones prepared by asymmetric alkylation of ( + )-( S , S )-pseudoephedrine based arylacetamide enolates with appropriately functionalized 2-aryl-1-iodoethane electrophiles. Subsequent transformations (intramolecular Friedel–Crafts acylation, stereocontrolled reductive amination and Pictet–Spengler cyclization) yielded the target heterocycles in good overall yields and in excellent stereoselectivities.