Chiral enamines cycloaddition

The stereoselective intermolecular cycloaddition of azides to chiral cyclopenta-none enamines was reported, but both product yields and enantiomeric excesses (ee) were low (24) (Scheme 9.24). Ethyl azidoformate (115) and A-mesyl azido-formamimidate (116) underwent 1,3-dipolar cycloaddition with the monosubsti-tuted chiral enamine 114 to give products 117 and 118 in low yields with ee of 24 and 18%, respectively. Intermolecular cycloaddition of the A-mesyl azidoforma-mhnidate 116 with the disubstituted C2-symmetric chiral enamine 119 proceeded with good diastereoselectivity to give compound 120 in 18% yield. On cleavage of the enamine unit, compound 120 afforded 118 with low ee. 

The domino process probably involves the chiral enamine intermediate 2-817 formed by reaction of ketone 2-813 with 2-815. With regard to the subsequent cycloaddition step of 2-817 with the Knoevenagel condensation product 2-816, it is interesting to note that only a normal Diels-Alder process operates with the 1,3-bu-tadiene moiety in 2-817 and not a hetero-Diels-Alder reaction with the l-oxa-1,3-butadiene moiety in 2-816. The formed spirocyclic ketones 2-818/2-819 can be used in natural products synthesis and in medicinal chemistry [410]. They have also been used in the preparation of exotic amino acids these were used to modify the physical properties and biological activities of peptides, peptidomimetics, and proteins... 

Asymmetric induction has been observed in some of these cycloaddition reactions with the use of chiral enamines ". For example, reaction of L-proline derived enamines (e.g. 95) with methyl vinyl ketone (equation 17) afforded, after hydrolysis, chiral cyclohexenones (e.g. 96) with optical yields up to 50%. ... 

High asymmetric induction was reported in the cycloaddition of 2-sulfonyldienes with chiral enamines. For example, reaction of 2-phenylsulfonyl-l,3-pentadiene (146) with enamine I47 leads to adduct 148 as only one diastereoisomer (equation 29) for which the absolute stereochemistry was determined by X-ray diffraction. 

Most asymmetric Diels-Alder reactions have the chiral auxiliary attached to the dienophile as an ester or an amide. There is no such obvious place to attach an auxiliary to a diene but the chiral analogue 161 of Danishefsky s diene has a C2 symmetric amine 164 attached as an enamine. Cycloaddition without a Lewis acid gives good selectivity in the formation of adduct21 162. Reduction and hydrolysis releases the enone 163 in reasonable ee. 

Adduct 106 is obtained as a single diastereomer in the cycloaddition of chiral enamine 104 to 2-phenylsulfonyl-l,3-butadiene (105). The chiral pyrrolidine can be removed from the adduct in 55% yield via Cope elimination57. 

Inverse-electron demand cycloaddition reactions of chiral enamines with 2-phenylsulfonyl-1,3-diene in toluene at high temperature have been studied, furnishing the cycloadducts in moderate yield and selectivity... 

Reactions of//-acylimines with electron-rich alkenes furnish 5,6-dihydro-l,3-oxazines. Low to moderate diastereoselectivities were observed for the combination of chiral N-acylimines and achiral enamines, Highly selective reactions are observed in cycloadditions of chiral enamines with achiral dienes as well as with chiral dienes in the case of a matched pair. 

J0rgensen and Juhl reported the first organocatalytic enantioselective inverse-electron-demand hetero-Diels-Alder reaction of aldehydes (e.g., 71) and enones (e.g., 72) with excellent diastereo- and enantioselectivity. Scheme 3.26 [41], The reaction utilizes a chiral enamine intermediate as an alkene in catalytic asymmetric cycloaddition reactions. 

Chiral enamine, dienamine, and trienamine intermediates have been shown to catalyse asymmetric Diels-Alder reactions via HOMO activation. These Diels-Alder reactions generally occur with high chemo-, regio-, and stereo-selectivities. ° The effect of the viscosity of pyridinium-based ionic liquids, with tetrafluoroborate and bis(trifluorosulfonimide) anions, on the kinetics of intra- and inter-molecular Diels-Alder reactions has been investigated. Results show that the intramolecular cycloaddition reaction is less susceptible to viscosity variations than the intermolecular reaction. 

In the synthesis of six-membered cyclic nitronates (35) by the (42 + 43) cycloaddition, facial discrimination can be achieved by introducing enantiomerically pure chiral fragments into nitro olefin (42) (147, 157) enamine (117), or enol (134). In addition, Prof. Seebach (96) and postgraduate students supervised by Prof. Denmark (158) successfully used chiral LA for facial discrimination. 

The reaction of 5(4H)-oxazolones (32) and miinchnones with triphenylvinylphos-phonium bromide (33) provides a mild synthesis of substituted pyrroles (34) (Scheme 11). The cycloaddition-elimination reactions of 5-imino-l,2,4-thiadiazolidin-3-ones with enamines and ester enolates produce 2-iminothiazolidines. " Chiral isomtinchnone dipoles show jr-facial diastereoselectivity with IV-phenyl- or A -methyl-maleimide in refluxing benzene. ... 

If the mesomeric stabilization is provided by a double bond, the lithiated species is a homoenolate synthon, as shown in Scheme 44a. Reaction with an electrophile typically occurs at the y-position, yielding an enamine, which can then be hydrolyzed to a carbonyl compound. An important application of this approach is to incorporate a chiral auxiliary into the nitrogen substituents so as to effect an asymmetric synthesis. 2-AzaaUyl anions (Scheme 44b), which are generated by tin-lithium exchange, can be useful reagents for inter- and intramolecular cycloaddition reactions. ... 

The reaction of vinyl ethers and enamines with nitroalkenes is highly regiose-lective, with only the head-to-head adduct observed. The endo approach of the dienophile is preferred in the thermal cycloaddition, however, the mode of approach can be controlled by the choice of the Lewis acid promoter (214). Facial discrimination has been obtained by the use of chiral groups on the both the nitroalkene (215,216) and the enamine (217) or vinyl ether (218), as well as with chiral Lewis acids (46,66,94,219,220). 

Asymmetric induction in the [2 + 2] cycloaddition of enamines, e.g. 42, with methyl ( )-4-oxo-4-(2-oxo-l,3-oxazolidin-3-yl)-2-butenoate (41) has been reported (equation 7)35. The reaction is promoted by a chiral titanium reagent generated in situ from dichlorodiisopropoxytitanium and a tartrate-derived chiral 1,4-diol (43). In the presence of excess amounts of the titanium reagent, 77% ee of cycloadduct 44 was achieved together with 45. The reaction also works with only a catalytic amount of the chiral reagent. 

An enantioselective aryloxylation of aldehydes is based on their prior conversion to an enamine through reaction with a chiral secondary amine catalyst. A subsequent inverse HDA reaction with o-quinones leads to 3-alkyl-2-hydroxy-l,4-benzodioxins with ee ca. 80% (Scheme 47). Manipulation allows the synthesis of (S)-2-alkyl-2,3-dihydro-l,4-benzodioxins <07TL1605>. In like manner, racemic nitidanin, which possesses antimalarial properties, has been synthesised through a regioselective cycloaddition of an o-quinone with a protected 3-arylpropen-l-ol <07TL771>. 

The use of optically active enamines in [2 + 2] cycloadditions with thiocarbonyl 5.5-dioxides gives asymmetric induction in the product thiirane 1,1-dioxides. Thus, when thioformaldehyde S,S-dioxide, generated from methanesulfonyl chloride and triethylamine, is treated with optically active AM-phenylethyl-Af-methylpropanal enamine, a mixture of diastereomeric thietane 1.1-dioxides 6 is formed quantitatively. Removal of the chiral 1-phenylethyl auxiliary followed by Hoffmann elimination gives (-+ )-(5)-2-methyl-2//-thiete 1,1-dioxide (7) with 6% ee1,8. 

Better yields, but lower enantiomeric excesses, were obtained by an alternative method, the cycloaddition of ethoxycarbonyl azide, followed by irradiation to give the aziridine64. Interestingly, the opposite configuration at the stereogenic center was formed by the two methods. The enantiomeric excess of the product was determined by ketalization with (2/, 3/ )-2,3-butanediol and GC or l3C-NMR analyses of the reaction mixture. The choice of the chiral auxiliary is crucial unfortunately, the enamine derived from //ww-2,5-dimethyl pyrrolidine does not react with either the nitrene or the azide. 

Stereoselective Diels-Alder reactions have been performed variously, using chirally modified sulfines as dienophiles, chiral ynamines, SMP enamines, SMP acrylamides, and the in situ preparation of SMP A-acylnitroso dienophiles. The [2 + 2] cycloaddition reactions of chiral keteniminium salts obtained from SMP amides with alkenes have been studied. ... 

A chiral zw a-metallocene triflate complex catalyzes the Diels-Alder cycloaddition reaction between an oxazolidinone-based dienophile and cyclopentadiene [206]. Triflate in titanocene and zirconocene complexes is labile [207,208] and thus the polarity of solvent influences the reactivity and enantioselectivity. Asymmetric hydrogenation of imines and enamines catalyzed by chiral aw a-titanocene catalyst provides amines with high enantioselectivity [209,210]. 

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