Intramolecular Michael reaction enantioselective

Apart form the aforementioned highly enantioselective hetero-Diels-Alder reactions, that proceed with very low catalyst loadings, the catalytically accessible enolates have also been used for related intramolecular Michael reactions (Philips et al. 2007) and for the desym-metrization of 1,3-diketones yielding cyclopentenes via an intramolecular aldol reaction (Wadamoto et al. 2007). The formation of cyclopentenes, however, presents a special case, so—depending on the stereochemical nature of the enone substrates (s-cis or s-trans) and the stereochemistry of the final products—two different mechanisms are discussed in the literature. Whereas /ran.v-cycl open (cries are proposed to be available upon conjugate addition of a homoenolate to chalcones,... 

Phillips EM, Wadamoto M, Chan A, Scheldt KA (2007) A highly enantioselective intramolecular Michael reaction catalyzed by V-heterocyclic carbenes. Angew Chem Int Ed 46 3107-3110... 

A variety of nucleophiles can be added in a conjugate manner to a,p-unsaturated ketones. The reaction is reversible, so the main difficulty is finding conditions that drive the equilibrium to the right. For catalytic enantioselective Michael reactions, see Krause, N. Hoffinann-Roder, A. Synthesis 2001,171-196. For intramolecular Michael reactions see Little, R.D. Masjedizadeh, M. R. Wallquist, O. Mcloughlin, J. 1. Org. React. 1995, 47, 315-552. 

An asymmetric intramolecular Michael-aldol reaction which leads to nonracemic tricyclic cyclobutanes is performed by using TMSOTf andbis[(/ )-l-phenylethyl]amine as chiral amine, but only moderate enantioselectivities are reached (eq 68). A similar reaction sequence can also be carried out with TMSOTf and HMDS as base, with (—)-8-phenylmenthol as the chiral auxiliary however, the iodotrimethylsilane-HMDS system is more efficient in terms of yield and diastereoselectivity. The combination EtsN/TMSOTf (or some other trialkylsilyl triflates) has been used to accomplish an intramolecular Michael reaction, which was the key step for the synthesis of sesquiterpene (=E)-ricciocarpin A. ... 

Scheme 2.23 Enantioselective intramolecular Michael reaction for the synthesis of cyclopentanes.

With the development of the enantioselective allylic-allylic alkylation of a,a-dicyanoalkenes and MBH carbonates by dual organocatalysis of commercially available modified cinchona alkaloids and (5)-BINOL, Chen and co-workers have delivered an elegant construction of cyclohexene derivatives. The intramolecular Michael reaction of allylic allylic alkylation product 75a could be cyclized to give the desired cyclohexene 76 in the presence of DBU (Scheme 4.25). In the presence of nucleophile BnNH2, allylic compound 75b furnished an imexpected cyclic product 77 rather than the formal double Michael adduct. Interestingly, the reaction of a,a-dicyanoalkene 79 and MBH carbonate 80 under optimized catalytic conditions directly afforded cyclohexene derivatives 81a-c in... 

The first intramolecular Michael reaction catalysed by a primary amine-thiourea was reported by Lu and coworkers. The synthesis of trans-dihydrobenzofurans proceeded in high yields and enantioselectivities, albeit in unsatisfactory diastereoselectivity transicis 88/12) utilising catalyst 42 (Scheme 19.45). To address the poor selectivity, after the end of the reaction the mixture was heated under reflux, which resulted in the transformation of the ds-isomer to the thermodynamically favourable trarzs-isomer, via an enamine-mediated enolisation. 

The enantioselective intramolecular Michael reaction is attractive since it provides an efliecient way for the construction of chiral, cyclic carbon skeletons, which are common motifs in natural products. The first organocataly tic asymmetric intramolecular Michael reaction was disclosed by Fonseca and List in 2004 [108]. In the presence of MacMillan... 

In 2009, Christmann and co-workers [111] disclosed a Ranhut-Currier-type intramolecular Michael reaction via dienamine activation for the construction of iridoid framework. Catalyzed by J0rgensen-Hayashi catalyst 7, the reaction proceeded well to afford the cyclopentene derivatives including (+)-rotundial in moderate to good yields with good enantioselectivities (Scheme 5.53). 

Chen and co-workers [72] reported an asymmetric quadruple amino catalytic domino reaction catalyzed by secondary amines. The reaction consists of a quadruple iminium-enamine-iminium-enamine cascade reaction initiated by a Michael addition of oxindole 114 to the enal and a subsequent intramolecular Michael reaction between the enamine formed in the previous step and the unsaturated oxindole to yield intermediate 116. Next, this intermediate reacts with another molecule of enal via a Michael addition of the oxindole to the enal. The sequence ends with an intramolecular aldol reaction between the preformed enamine and the aldehyde. This organocascade reaction affords highly complex spirooxindoles 118 bearing six contiguous chiral centers in excellent yields and with excellent diastereo- and enantioselectivities (Scheme 10.31). 

Hayashi Y, Gotoh H, Tamura T, Yamaguchi H, Masui R, Shoji M (2005) Cysteine-Derived Organocatalyst in a Highly Enantioselective Intramolecular Michael Reaction. J Am Chem Soe 127 16028... 

Intramolecular Michael Reaction of Aldehydes. Imidazolidinone catalyst 1 mediates the asymmetric intramolecular Michael addition of simple aldehydes to enones at rt (eq 15). The reaction is thought to proceed via an enamine mechanism but a dual-activation mechanism involving both enamine and iminium catalysis can also be considered. When a catalytic amount of 1 was used, products were obtained in excellent yield although in low enantioselectivity (eq 15). Better selectivity was observed, however, when catalyst 2 was used (eq 15). 

Subsequently, List reported the first organocatalytic intramolecular Michael reaction of multifunctional aldehydes 10. Although this reaction could also be catalyzed by L-proline, both diastereo- and enantioselectivity were low. MacMillan s chiral imidazolidinone 9 gave much better results and the cyclic ketoaldehydes 11 could be obtained efficiently (Scheme 36.3) [8a]. 

It is interesting to note that the oxa-analogous Michael addition was reported for the first time in 1878 by Loydl et al. [19] in their work on the synthesis of artificial malic acid, which was five years ahead of the discovery of the actual Michael reaction described first by Komnenos [20], Claisen [21], and later Michael in 1887 [22] as one of the most important methods for C—C bond formation. In continuation of the early work on the oxa-Michael addition [23], the inter- and intramolecular additions of alkoxides to enantiopure Michael acceptors has been investigated, leading to the diastereo- and enantioselective synthesis of the corresponding Michael adducts [24]. The intramolecular reaction has often been used as a key step in natural product synthesis, for example as by Nicolaou et al. in the synthesis of Brevetoxin B in 1989 [25]. The addition of oxygen nucleophiles to nitro-alkenes was described by Barrett et al. [26], Kamimura et al. [27], and Brade and Vasella [28]. 

In addition to the stabilized carbanions, electron-rich aromatic compounds, for example indole derivatives have emerged as new Michael donors [25], In these reactions, aromatic sp2-C-H transformation is involved. These reactions are described in detail in Section 111.1.3.1.3. A highly enantioselective intramolecular Stetter reaction, in which umpolung reactivity of a formyl group was accomplished using a chiral triazolium salt, has also been reported by Rovis [26]. 

The first enantioselective total synthesis of tetracyclic sesquiterpenoid (+)-cyclomyltaylan-5a-ol, isolated from a Taiwanese liverwort, was accomplished by H. Hagiwara and co-workers. They started out from Hajos-Parrish ketone analogue, (S)-(+)-4,7a-dimethyl-2,3,7,7a-tetrahydro-6/-/-indene-1,5-dione, that could be synthesized from 2-methylcyclopentane-1,3-dione and ethyl vinyl ketone in an acetic acid-catalyzed Michael addition followed by an intramolecular aldol reaction. The intramolecular aldol reaction was carried out in the presence of one equivalent (S)-(-)-phenylalanine and 0.5 equivalent D-camphorsulfonic acid. The resulting enone was recrystallized from hexane-diethyl ether to yield the product in 43% yield and 98% ee. Since the absolute stereochemistry of the natural product was unknown, the total synthesis also served to establish the absolute stereochemistry. 

From 1988 to 1990, Ihara and co-workers modified the above synthesis approach to develop an asymmetric total synthesis of (-)-tylophorine [(-)- ] via an intramolecular double Michael reaction of a,p-imsaturated esters. Their work proved that the absolute configuration of naturally occurring (-)-tylophorine is (R). Two different chiral auxiliaries, (-)-phenylmenthol [52, 53] or (2R,4S,5R)-(-)-4-(tert-butyldimethylsiloxymethyl)-5-hydroxy-2-phenyl-1,3-dioxane(BDH), were employed [53, 54]. The reactions are summarized in Scheme (2). The resulting (E, E)-esters (26) and (27) underwent a double Michael reaction through proposed transition states (A) (B), respectively, to give a highly enantioselective product (28 and 29, respectively). (-)-... 

For the asymmetric synthesis of the 2-substituted chromane 7 via the intramolecular Michael addition reaction of 6, Merschaert et al. also employed natural cinchona alkaloids such as HCD as catalysts (Scheme 9.3) [3]. Here again, the 9-0 functionalization and dehydroxylation of the natural alkaloid showed a large negative effect, indicating that the presence of the 9-OH group is needed to achieve both good kinetics and enantioselectivity. Moreover, C3 modifications of this parent alkaloid did not lead to any significant improvement in the results in terms of the enantioselectivity and catalytic activity. 

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