6-endo aldol reaction

S)-proline-catalyzed reaction is not sufficient therefore, a large number of (S)-proline-derived secondary amine catalysts have been developed. Primary amine catalysts derived from natural amino acids and cinchona alkaloids have also emerged as highly versatile and powerful catalysts [25]. For example, in the intramolecular 6-endo aldol reaction of diketone 43, quinine-derived primary amine 44 in acetic acid affords the cyclic ketone (S)-46 in 94% yield with 90% ee (Scheme 28.3) (S)-prohne gives the cycUzation product in low yield with moderate ee. In addition, the pseudo-enantiomeric quinidine-derived primary amine 45 deUvers the opposite product, the (R)-enantiomer 46, with similar yield and enantioselectivity [26]. 

The first example of an organocatalytic enantio-group-differentiating intramolecular G-endo aldol reaction catalyzed by (S)-proline was the Hajos-Parrish-Eder-Sauer-Wiechert cyclization [24]. Although impressive, the synthetic scope of the... 

Bis(oxazoline)-type complexes, which have been found useful for asymmetric aldol reactions, Diels-Alder, and hetero Diels-Alder reactions can also be used for inducing 1,3-dipolar reactions. Chiral nickel complex 180, which can be prepared by reacting equimolar amounts of Ni(C10)4 6H20 and the corresponding (J ,J )-4,6-dibenzofurandiyl-2,2 -bis(4-phenyloxazoline) (DBFOX/Ph) in dichloromethane, can be used for highly endo-selective and enantioselective asymmetric nitrone cycloaddition. The presence of 4 A molecular sieves is essential to attain high selectivities.88 In the absence of molecular sieves, both the diastereoselectivity and enantioselectivity will be lower. Representative results are shown in Scheme 5-55. 

The amino acid derived chiral oxazolidinone 188 is a very commonly used auxiliary in Diels-Alder and aldol reactions. However, its use in diastereoselective 1,3-dipolar cycloadditions is less widespread. It has, however, been used with nitrile oxides, nitrones, and azomethine ylides. In reactions of 188 (R = Bn, R =Me, R = Me) with nitrile oxides, up to 92% de have been obtained when the reaction was performed in the presence of 1 equiv of MgBr2 (303). In the absence of a metal salt, much lower selectivities were obtained. The same observation was made for reactions of 188 (R = Bn, R = H, R = Me) with cyclic nitrones in an early study by Murahashi et al. (277). In the presence of Znl2, endo/exo selectivity of 89 11 and up to 92% de was observed, whereas in the absence of additives, low selectivities resulted. In more recent studies, it has been shown for 188 (R =/-Pr, R = H, R =Me) that, in the presence of catalytic amounts of Mgl2-phenanthroline (10%) (16) or Yb(OTf)3(20%) (304), the reaction with acyclic nitrones proceeded with high yields and stereoselectivity. Once again, the presence of the metal salt was crucial for the reaction no reaction was observed in their absence. Various derivatives of 188 were used in reactions with an unsubstituted azomethine ylide (305). This reaction proceeded in the absence of metal salts with up to 60% de. The presence of metal salts led to decomposition of the azomethine ylide. 

A recent general study on the reactivity of 3-mono-O-activated dienes 2-6 having an alkyl group at C-l and 2-7 in the presence of a Lewis acid was performed by Palenzuela et al. [72]. The best yields of the cycloadducts 2-8 were obtained with BF3-OEt2 in diethyl ether with an endo/exo-selectivity of 6 1 (Fig. 2-2). Good results were also found with LiBF4 in acetonitrile/benzene. Aldol reactions [73], silatropic ene reactions [74] and loss of the silyl group [75] were not observed under these conditions. 

The authors used (5)-carvotanacetone (dihydrocarvone) as starting material (Scheme 34). To prepare the linearly conjugated sUylenol ether, they used the Kharash protocol and attained y-alkylation by Mukaiyama aldol reaction with trimethylorthoformate (195). The ketoacetal 295 was a-hydroxylated according to Rubottom by silylenol ether formation followed by epoxidation and silyl migration. Acid treatment transformed 296 to the epimeric cyclic acetals 297 and 298. endo-Aceta 297 was equilibrated thereby increasing the amount of exo-acetal 298. The necessary unsaturated side chain for the prospected radical cyclization was introduced by 1,4-addition of a (trimethylsilyl)butynylcopper compound. 

In the next example, the chiral ketone happens to be optically pure but it is still an example of relative stereocontrol. We shall see more of relative stereocontrol with optically pure materials in Chapter 30. We saw in the Diels-Alder reaction that different features of reactivity are responsible for different aspects of resulting stereochemistry — geometry of starting materials, stereospecificity of reaction and endo selectivity all have their part to play. Ketone 177 is reacted with a boron chloride to give boron enolate 178. Significantly, this is a trans enolate which means we can expect an anti relationship from the aldol reaction which we do indeed see 179. 

Galatsis group [14] reported a study on an NARC sequence involving (i) aldol reactions of enolates derived from the kinetic deprotonation of unsaturated esters, such as 25 and 28, to ketones (Fig. 9) and aldehydes (Fig. 10) followed by (ii) endo-cyclisation via intramolecular iodoetherification. As the enolates used in the study were racemic and the aldol reactions stereorandom, it would be interesting to repeat this work using a chiral auxiliary (e.g. a chiral amide). This should ensure high levels of enantio- and diastereo-selectivity. 

After development of the proline-catalyzed intermolecular aldol reaction by List, Lemer and Barbas in 2000 [16], which led to intense world-wide investigation, List himself developed a further intramolecular proline catalyzed cyclization which was enol-exo in nature as opposed to the enol-endo type cyclization of the Hajos-Parrish-Eder-Sauer-Wiechert process (Scheme 1.15). A range of substrates were applied using the methodology and excellent enantioselectivities were obtained [17]. 

The first intramolecular version of the proline-catalyzed aldol reaction led to the formation of a srx-membered ring (A, Scheme 3.3) [4]. This intramolecular ring-closing process is the 6-enol-endo aldolization. There is a limited number of reports describing processes leading to cyclic molecules via organocatalytic aldolizations, most of which are catalyzed by L-proline [8]. 

The intramolecular aldol reaction is an often used approach to the synthesis of cycUc compounds, especially five- and six-membered rings [23]. The two carbonyl components of the substrate react intramolecularly as both electrophiles and as nucleophiles in addition, they form two different nucleophilic intermediates, namely, endo 40 and exo 41 aldol (Figure 28.4). Another type of intramolecular reaction is the transannular aldol reaction, which may be considered as simultaneously endo and exo. 

Di-f-menthyl acetoxymethylenemalonate (67) is another chiral dienophile that has been utilized in asymmetric Diels-Alder reactions [51]. High-pressure-mediated addition of 67 to furan produced a mixture of labile endo and exo cycloadducts (i.e., 68) that were immediately converted into the corresponding acetonides 69. The reductive retrograde aldol reaction of the entio-product 69 resulted in the formation of (3-D-ribofuranosylmalonate 70. Analogous manipulation of the exo product gave the corresponding synthetic L-analog (Scheme 13.21) [51]. 

Annual Volume 71 contains 30 checked and edited experimental procedures that illustrate important new synthetic methods or describe the preparation of particularly useful chemicals. This compilation begins with procedures exemplifying three important methods for preparing enantiomerically pure substances by asymmetric catalysis. The preparation of (R)-(-)-METHYL 3-HYDROXYBUTANOATE details the convenient preparation of a BINAP-ruthenium catalyst that is broadly useful for the asymmetric reduction of p-ketoesters. Catalysis of the carbonyl ene reaction by a chiral Lewis acid, in this case a binapthol-derived titanium catalyst, is illustrated in the preparation of METHYL (2R)-2-HYDROXY-4-PHENYL-4-PENTENOATE. The enantiomerically pure diamines, (1 R,2R)-(+)- AND (1S,2S)-(-)-1,2-DIPHENYL-1,2-ETHYLENEDIAMINE, are useful for a variety of asymmetric transformations hydrogenations, Michael additions, osmylations, epoxidations, allylations, aldol condensations and Diels-Alder reactions. Promotion of the Diels-Alder reaction with a diaminoalane derived from the (S,S)-diamine is demonstrated in the synthesis of (1S,endo)-3-(BICYCLO[2.2.1]HEPT-5-EN-2-YLCARBONYL)-2-OXAZOLIDINONE. 

In the Mukaiyama aldol additions of trimethyl-(l-phenyl-propenyloxy)-silane to give benzaldehyde and cinnamaldehyde catalyzed by 7 mol% supported scandium catalyst, a 1 1 mixture of diastereomers was obtained. Again, the dendritic catalyst could be recycled easily without any loss in performance. The scandium cross-linked dendritic material appeared to be an efficient catalyst for the Diels-Alder reaction between methyl vinyl ketone and cyclopentadiene. The Diels-Alder adduct was formed in dichloromethane at 0°C in 79% yield with an endo/exo ratio of 85 15. The material was also used as a Friedel-Crafts acylation catalyst (contain-ing7mol% scandium) for the formation of / -methoxyacetophenone (in a 73% yield) from anisole, acetic acid anhydride, and lithium perchlorate at 50°C in nitromethane. 

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