Enamines stereocontrol

The intramolecular Heck reaction presented in Scheme 8 is also interesting and worthy of comment. Rawal s potentially general strategy for the stereocontrolled synthesis of the Strychnos alkaloids is predicated on the palladium-mediated intramolecular Heck reaction. In a concise synthesis of ( )-dehydrotubifoline [( )-40],22 Rawal et al. accomplished the conversion of compound 36 to the natural product under the conditions of Jeffery.23 In this ring-forming reaction, the a-alkenylpalladium(n) complex formed in the initial oxidative addition step engages the proximate cyclohexene double bond in a Heck cyclization, affording enamine 39 after syn /2-hydride elimination. The latter substance is a participant in a tautomeric equilibrium with imine ( )-40, which happens to be shifted substantially in favor of ( )-40. 

Oare, D. A., Stereochemistry of the Base-Promoted Michael Addition Reaction, 19, 227 Acyclic Stereocontrol in Michael Addition Reactions of Enamines and Enol Ethers, 20, 87 Okamoto, Yoshio, Optically Active Polymers with Chiral Recognition Ability, 24, 157. 

The first stereocontrolled syntheses of juvabione are described in Schemes 13.11 and 13.12. Scheme 13.10 is a retrosynthetic analysis corresponding to these syntheses. These syntheses have certain similarities. Both start with cyclohexenone. There is a general similarity in the fragments that were utilized, but the order of construction differs. In the synthesis shown in Scheme 13.11, the crucial step for stereochemical control is step B. The first intermediate is constructed by a [2 + 2] cycloaddition between reagents of complementary polarity, the electron-rich enamine and the electron-poor enone. The cyclobutane ring is then opened in a process which corresponds to retrosynthetic step Ha => Ilia in... 

Whatever the explanation for the stereocontrol, these processes are quite useful synthetically, enabling one to prepare nearly pure erythro or threo diastereomers in high yield. A number of groups have shown that by using a chiral auxiliary in the enamine, ester or amide unit, products of very high enantiomeric excess can be obtained.69... 

Michael Addition Reactions of Enamines and Enol Ethers, Acyclic Stereocontrol... 

The existence of the enamine intermediate of proline-catalyzed reaction with acetone as a donor was detected by mass analysis [54], but not by aH NMR. The formation of the presumed enamine intermediate generated from pyrrolidine-acetic acid and isobutyraldehyde was confirmed by 1H NMR [29a]. In this study, the enamine formation in the presence of pyrrolidine-acetic acid was observed within 5 min, but the enamine was shown to form only very slowly in the absence of acid. In these pyrrolidine derivative-acid combination catalysts, the acid component was shown to be important both for faster enamine formation and for the stereocontrol in the C-C bond-forming step. These catalyst systems are essentially split-proline systems that allow for the contributions of the pyrrolidine and carboxylate functionalities of proline to be probed independently. 

A new diastereoselective and enantioselective synthesis of a-amino-y-oxo acid esters has been reported involving the alkylation of enamines with acyliminoacetates (78). The stereocontrol is attributed to formation of a Diels-Alder like transition state (79). Ring opening of the adduct leads to a zwitterion or alkylated enamine, hydrolysis of which gives the single diastereoisomer (80 de > 96%)174 (Scheme 71). The use of a chiral ester [R = ( + )- or ( —)-menthyl or (—)-8-phenylmenthyl] converted this process into an enantioselective reaction (de and ee 24-67%). Since the reaction proceeds with complete anti-diastereoselectivity the two stereoisomers, enantiomeric at the two new stereogenic centres, could readily be separated by fractional crystallization. The main isomer of 80 (X = CH2), obtained in 80% yield, was shown to have the (l S, 2R)-configuration174. 

C. H. Heathcock, in Asymmetric Synthesis (Ed. J. P. Morrison), Vol. 3, Academic Press, New York, 1984, p. Ill for a review of stereocontrol in Michael addition reactions of enamines and enol ethers, see Reference 27. 

Acyclic Stereocontrol in Michael Addition Reaction of Enamines and Enol... 

The enamine geometry 32 is cmcial for the stereocontrol in organocatalytic aldehyde-aldehyde couplings amines of type 31 are convenient catalysts for enantioselective enamine-aldol reactions. Examples are shown in Scheme 24 [126,131,132,133,134,135]. 

ACYCLIC STEREOCONTROL IN MICHAEL ADDITION REACTIONS OF ENAMINES AND ENOL ETHERS 87... 

Stereocontrol in allylamine to enamine isomerisation in hydrogenation and 1,5-hydrogen shift in conjugated dienes, catalyzed by metal derivatives. 

Similarly, aza-annulation with an acyclic substrate resulted in a high degree of stereocontrol. These results suggested that intramolecular hydrogen bonding of the intermediate enamine controlled the enamine geometry and served to restrict rotation of the chiral auxiliary (eq. 103).116 In this case, 507 was sensitive to hydrolysis, and isolation was performed after hydrolysis to 508. 

In one of the first reported stereoselective alkylation reactions [18], Yamada described the use of a methyl prolinate as chiral auxiliary in the methylation of a cyclohexanone-derived enamine (Fig. 3 reaction D).The low stereoselectivity of the reaction clearly depends on the possibility for the alkylation to occur on a different conformation of the enamine, namely the one in which the C-C double bond is transoid to the stereocenter, that thus cannot exert any useful stereocontrol. 

To overcome this problem, Whitesell and Felman [19] introduced the use of a C2-symmet-ric chiral auxiliary, (S,S)-trans 2,5-dimethylpyrrolidine, to generate the enamine (reaction E). Rotation around the N-C bond simply results in a topomerization [5] and, therefore, in the reduction of the number of the non-stereocontrolled attacks by the electrophile. Since the appearance of this seminal paper, C2-symmetric reagents have become a standard tool in the hands of the organic chemists interested in stereoselective synthesis [20]. 

Intramolecular enamine formation between an aldehyde or ketone and the nitrogen atom of a piperidine ring can serve as the key step in the preparation of quinolizidine derivatives. For example, the ketal (184), prepared by double addition of the lithio derivative (183) to 6-methoxy-2,3,4,5-tetrahydropyridine, can be easily cyclized to the quinolizidine derivative (185) by double acid-catalyzed deprotection, cyclization, and dehydration (Scheme 31). These reactions constitute the first steps of a stereocontrolled total synthesis of the alkaloid ( )-porantherine <87JA4940>. 

Further work has been carried out to study the facial diastereoselectivity of the addition of benzaldehyde to alkenes. ° In this study the three enamines (49)-(51) were used as the substrates to which benzaldehyde was added photochemically. The results show that addition does occur to all three enamines but with varying degrees of success as far as diastereoselectivity is concerned. Thus addition to (49) gives the two oxetanes (52) and (53) but with only 32% de. Poorer selectivity is observed with (50) when (54) and (55) are obtained. The best de of 62% is achieved from (51) where the products are (56) and (57). The photochemical addition of the aldehydoester (58) to the enamine (59) results in the formation of the oxetane (60). This product is obtained in around 30% yield and it can be transformed into racemic oxetin (61). Bach has reviewed the stereocontrol that can be exercised on the formation of oxetanes. The regioselectivity of the addition of triplet carbonyl compounds to alkenes has been interpreted for the first time in terms of hard and soft acid-base systems. The authors of this report suggest that there is overall good agreement between HSAB prediction and experimental fact. 

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