Diels-Alder reaction chiral auxiliary-controlled

It has been shown that the sulfinyl group present as chiral auxiliary either in dienophiles or in dienes is very useful for controlling the enantio- and diastereofacial selectivity in the asymmetric Diels-Alder reaction [43]. A wide variety of enantiomerically pure cyclohexadienedicarboxylates has been produced by cycloaddition of the sulfinylmaleate 39 with several dienes under catalyzed... 

It was clear that 1 would be derived from a Diels-Alder adduct. There has been a great deal of work in recent years around the development of enantioselective catalysts for the Diels-Alder reaction, but the catalysts that have been developed to date only work with activated dienophile-diene combinations. For less reactive dienes, it is still necessary to use chiral auxiliary control. One of the more effective of those was the known camphor-derived tertiary alcohol, so that was used in this project. Diels-Alder cycloaddition of the diene 4 with the enantiomerically-pure enone 5 led to the adduct 6 with high diastereocontrol. Oxidative cleavage led to the acid 7, which was carried on to the bis-enone I. 

The aldol reaction illustrated in eq 2 has been applied to the targeted synthesis of a number of complex molecules including Tylosin, Hapalosin, the antibiotic Sinefungin, and the HIV protease Saquinavir inhibitor. Oxazolidinone-type chiral auxiliaries derived from 1 have also been employed for the control of Diels-Alder reactions of attached acryloyl or crotonyl groups. ... 

In addition to being an efficient chiral controller in a number of stereoselective transformations of chiral acrylates, (i.e. the Diels-Alder reaction, the conjugate reduction, the asymmetric dihydroxylation, and the nitrile oxide cycloaddition ) the bomanesultam (11) has been shown to be an exceptionally efficient chiral auxiliary for stereoselective aldol condensations (eqs eq 3 and eq 4). Depending upon the reaction conditions, A -propionylsultam can produce either the syn or anti aldol product with an excellent diastereoselectivity, Furthermore, good diastereoselectiv-ities are also observed for the corresponding acetate aldol reaction (eq 5), ... 

They also reported the intramolecular version of this asymmetric Diels-Alder reaction [53]. ( , )-Trienecarboximides of type 45 derived from chiral oxazolidones undergo Me2AlCl-catalyzed intramolecular Diels-Alder reactions affording bicyclic compounds 46 with high endo and diastereoselectivity (endolexo = -100 1). The stereochemistry is controlled by the stereogenic center at C4 of the chiral auxiliary (Xc) (Sch. 29). 

Control of the stereochemistry of the Diels-Alder reaction by means of a chiral center in the substrate is a versatile means of synthesizing cychc systems stereoselec-tively [347]. For preparation of ring systems with multi-stereogenic centers, in particular, the diastereoselective Diels-Alder reaction is, apparently, one of the most dependable methods. The cyclization of optically active substrates has enabled asymmetric synthesis. Equation (147) shows a simple and very efficient asymmetric Diels-Alder reaction, starting from commercially available pantolactone [364,365], in which one chlorine atom sticking out in front efficiently blocks one side of the enone plane. A fumarate with two chiral auxiliaries afforded virtually complete stereocontrol in a titanium-promoted Diels-Alder reaction to give an optically active cyclohexane derivative (Eq. 148) [366,367]. A variety of diastereoselective Diels-Alder reactions mediated by a titanium salt are summarized in Table 13. 

There are other considerations than mere analogy. If R represents some chiral auxiliary, a Diels-Alder reaction on 124 gives a product 125 with two new chiral centres, one, at C-2 in exactly the same place as in the aldol products such as 107. Michael (conjugate) addition to 124 on the other hand gives a compound 122 with only one new chiral centre (C-3) one atom further away from the chiral auxiliary. Another substitution pattern 128 still creates a new chiral centre at C-2 in the Diels-Alder adduct 129 but this time Michael addition does the same. However, the new centre is not created in the conjugate addition step, as that gives the enolate 127, but in the protonation of 127, an inherently less well controlled and probably reversible step. We shall therefore consider Diels-Alder reactions first and tackle the more troublesome Michael additions in the next section. 

Anti stereochemistry in six-membered rings Conformational control from a chiral centre in the cyclohexenone Remote stereochemical control in five-membered rings prostaglandins Regio- and stereochemical control in open chain compounds Asymmetric induction by a chiral auxiliary on the enolate Tandem Michael-Michael Reactions One Conjugate Addition Follows Another Double Michael or Diels-Alder reaction ... 

The studies reported last year on the stereoisomeric control of the photo-induced Diels Alder reaction of maleic anhydride with homo-chiral anthracene derivatives such as (46) have been extended using 320-400 nm radiation, and this gives the head-to-tail anthracene dimer as well as the previously reported adduct (47) with excellent diastereoselectivity. The thermal and photochemical retroaddition process has been examined and the results suggest that this facile process may promote the anthracene as a new chiral auxiliary. 

The first approach to this problem was to attach the chiral auxiliary to the diene by a vinylogous trans-esterification reaction of chiral alcohols with the 3-alkoxy enones (Scheme 21). This reaction was used to construct a variety of chiral dienes including the menthol and phenmenthol dienes (55a) and (55b) by transesterification followed by enol silylation using the Simchen procedure (RsSiOTf taN). However, these dienes exhibit poor diastereofacial selectivity despite the precedent for high stereochemical control in homo Diels-Alder reactions by the use of similar auxiliaries on a,P-unsaturated enones. ... 

The auxiliary-controlled, noncatalyzed [4 + 2] cycloaddition of homodienophiles has been thoroughly studied and the results are often compared with Lewis acid catalyzed reactions (see Section 1.6.1,1.1.2.2.2.). A very interesting version of dienophiles bearing a chiral auxiliary are chiral vinylic sulfoxides in which the chirality results from the dissymmetric sulfur atom. The first example studied is the Diels-Alder reaction of ( + )-(/ )-4-methylphenyl vinyl sulfoxide (1) with cyclopentadiene (2), in which four possible diastereomers 3-6 are obtained in an endojexo ratio of (5 + 6)/(3 + 4) 64 36. The diastereomers are further separated the (2 /J)-isomers (3 and 5) being favored. Desulfuration produces pure ( + )- or (-)-dehydronorcamphor. 

In general, cycloadditions catalyzed by Lewis acids proceed at significantly lower temperatures and with higher selectivities than their uncatalyzed counterparts. Factors that contribute to the increased selectivity of the catalyzed reactions include lower temperatures and more organized transition states. For enthalpy-controlled reactions, lowering temperatures increases selectivity (recall Section 1.4, equation 1.5). Coordination of a Lewis acid to the enone carbonyl not only activates the enone by electron withdrawal, it also restricts conformational motion and thereby reduces the number of competing transition states. Figure 6.12 illustrates several chiral auxiliaries for dienophile modification that have been used in the Diels-Alder reaction. 

In addition to serving as a key stereochemical controlling element for synthesis of indinavir,5 the title compound has proven to be a remarkably versatile chiral ligand and auxiliary for a range of asymmetric transformations including Diels-Alder reactions,13 carbonyl reductions,14 diethylzinc additions to aldehydes,15 and enolate additions.16... 

Interactive chiral auxiliary-controlled Diels-Alder reaction... 

It appeared more attractive to carry out a Diels-Alder reaction with control of both, its regio- and stereo-chemistry. In 1975, Corey published a diastereose-lective Diels-Alder reaction with the use of 8-phenylmenthol as a chiral auxiliary. The Lewis acid fulfils two tasks on the one hand, it increases the reactivity by lowering the LUMO of the dienophile [219] on the other hand, it stabilises the s-trans conformation for steric reasons. The attack of the diene on the s-cis-dienophUe would lead to the opposite absolute stereochemistry in the product. The Diels-Alder reaction occurs diastereoselectively, because the Si-facial half of the prochiral double bond is effectively shielded by 7t-stacking with the phenyl ring of the auxiliary. In this reaction, four new stereogenic centres are generated all at once. The yield of the desired diastereomer amounts to 89 %. 

A pioneering application of C-H activation to natural-product synthesis is in a synthesis of ibogamine 3.24 (Scheme 3.11). ° An asymmetric Diels-Alder reaction set up the chirality. The chirality was controlled by the use of a chiral auxiliary on the diene 3.18. Reductive amination then connected the Diels-Alder product 3.19 to an indole moiety. Palladium-catalysed cyclization then generated the bicyclic alkene 3.23. In this reaction. 

The Chiral auxiliary [(C5H5)Fe(CO)(PPh3)] affords excellent stereochemical control in a variety of reactions of attached acyl ligands. Such reactions include enolate and dienolate chemistry, aldol and Diels-Alder reactions, and tandem Michael... 

Esters have also been investigated as chiral controlling groups on the diene partner. Trost documented the use of dienes such as 110, incorporating a mandelic acid ester as the chiral auxiliary (Equation 9) [66]. Excellent face selectivity was observed in the Diels-Alder reaction between 110 and ju-glone (109), giving the product 111 with high diastereoinduction (>97 3) and in 98 % yield. 

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