Stereoselectivity cross-aldol reactions

Butyraldehyde undergoes stereoselective crossed aldol addition with diethyl ketone [96-22-0] ia the presence of a staimous triflate catalyst (14) to give a predominantiy erythro product (3). Other stereoselective crossed aldol reactions of //-butyraldehyde have been reported (15). 

Scheme 7.2 Stereoselective crossed-aldol reaction of aldehydes.

The Denmark phosphoramide organocatalyst has recently been applied in the first catalytic, diastereoselective, and enantioselective crossed-aldol reaction of aldehydes [86]. It is worthy of note that such controlled stereoselective selfcondensation of aldehydes has previously found no general application, because of many side-reactions, e.g. polyaldolization, and dehydration of the products. Several previously developed solutions have limitations. In a first step the Denmark group developed a procedure for generation of stereodefined trichlorosilyl enolates of aldehydes with high geometrical purity. Use of these geometrically pure (Z) and... 

Cross aldol reaction between two different aldehydes and/or ketones without prior activation or protection should provide a straightforward methodology for the synthesis of aldols, Mahrwald recently reported that treatment of aldehydes with TiCU and NEta (or TMEDA) gives rise to syn- do reaction in good yields (Eqs 38 and 39) [141], This method was extended to the aldehyde-ketone cross aldol reaction catalyzed by TiCU [142], an advantage of which is that reaction occurs at the more encumbered a-position of unsymmetrical ketones, as illustrated in Eqs (40) and (41) [143], The use of aliphatic aldehydes instead of PhCHO usually reduced stereoselectivity. When TiCU was replaced by a catalytic amount of BuTi(0-/-Pr)4Li, the aldol reaction was followed by the Tischenko reaction [144], Methyl vinyl ketone trimerized to give a chlorinated cyclic product with TiCU [145],... 

Tin(n) triflate mediated cross aldol reactions between a-bromo ketone (124 Scheme 56) and aldehydes afford iyn-a-bromo-P-hydroxy ketones (125) with high stereoselectivity. The resulting halohydrins are converted to the corresponding (Z)-2,3-epoxy ketones (126). Chiral aldehyde (127) reacts with lithium alkynide (128) followed by mesylation and base treatment to give chirally pure ( )-epoxide (129). The initially formed alkoxide anion should be trapped in situ by mesylation, otherwise partial racemization takes place owing to benzoate scrambling (Scheme 56). ... 

The use of lanthanide metal enolates in the aldol reaction has, to date, only been developed to a synthetically useful level in the case of cerium (Scheme S and Table 7). Stereoselectivities are no better than those of lithium enolates, but the cerium enolates of ketones woik well in crossed aldol additions to ketones (Table 7, entries 1-7) and sterically hindered aldehydes (Table 7, entries 9 and 10). Such crossed aldol reactions do not often work well with lithium enolates as enolate equilibration, retroaldolization and steric retardation of addition occur. Imamoto et al. have shown that cerium enolates (44), formed from anhydrous CeCb (1.2 equiv.) and the preformed lithium enolates of ketones in THF at -78 C, undergo such aldol reactions to give the corresponding p-hydroxy ketones (46), usually in high yield. The cerium suppresses the retroaldol reaction by efficient chelation of the aldolate (45). A similar effect is known for zinc halide mediated aldol reactions (Volume 2, (Chapter 1.8). The stereoselectivity of the... 

Lewis-acid-promoted alkylations of silylenol ethers and silyl ketene acetals [195] with Co-complexed acetylenic acetals [196] and acetylenic aldehydes [197,198] (Scheme 4-56) also proceed with fair to excellent syn diastereoselectivity, in contrast to the low selectivity reactions of the free acetylenic derivatives [199, 200]. Reactions of the complexed aldehydes with lithium enolates are stereospecific, with (Z)-enolates giving syn selectivity and ( )-enolates anti selectivity [201]. The complementary stereoselectivity of the crossed aldol reactions of free and cobalt-complexed propynals with silyl ketene 0,S-acetals has been elaborated by Hanoaka exclusive syn selectivity is exhibited by the complexes and high anti selectivity is found with pro-... 

The fact that many published homochiral intermediates lack any functionality at the future 7-position makes these less than ideal for the efficient synthesis of aglycones. Kishi has developed a synthesis of 11-deoxyanthracyclinones in which both 7- and 9-hydroxyl functions are introduced stereoselectively during the construction of ring-A. Thus asymmetric crossed aldol reaction of the acetal 193 with 194 gave a 17 1 mixture of 195 and its C-7 epimer. Base catalysed cyclisation followed by removal of the C-10 ester function yielded the trans-dioxygenated product 197. This was epimerised to give an 8 1 mixture of 198... 

Scheme 7.19 Stereoselective diarylprolinols catalysed self-aldol and cross-aldol reactions of acetaldehyde.

Scheme 7.21 Stereoselective one-pot processes starting with a prolinol Ik catalysed cross-aldol reaction.

Scheme 7.22 Stereoselective prolinol Ik catalysed cross-aldol reactions employing alkynyl aldehydes and formaldehyde.

In organocatalytic cross-aldol reactions of two different aldehydes through the enamine intermediate first reported by MacMillan and Northrop, the a d-cross-aldol adduct could be obtained in a highly stereoselective fashion. However, most such reactions required the use of sterically hindered aliphatic aldehydes, from which the enamine intermediates are rather difficult to form, or aromatic aldehydes as electrophile. In the direct aldol reaction between simple aliphatic aldehydes (enolisable aldehydes), both aldehydes can perform the double role of nucleophile and electrophile, and consequently, two cross-aldol adducts and two homo-aldol adducts would be possible products with each having four stereoisomers. To differentiate two... 

The reaction, if not controlled, can give a very complicated mixture of products due to reactivity, chemoselectivity, regioselectivity, and stereoselectivity issues. The synthesis of aldols with defined stereocenters in an efficient diastereo- and enantio-controlled fashion can be achieved with nature s aldolaze enzymes [2]. Their ability to control the enantioselectivity of the direct aldol reaction led chemists to the development of one of the most important C-C bond formation reactions. In the modem aldol reaction, a preformed enolate is added to a carbonyl compound even though the direct cross-aldol reaction is a more attractive approach [3]. 

The introduction of a halogen at the a-position in an acceptor aldehyde influences the course of the cross-aldol reaction by imposing steric constraints and by activating the carbonyl group towards electrophilic attack [144]. As a result, a-haloaldehyde preferentially reacts as an acceptor in L-proline-catalyzed reactions, affording aldols with rzwft-stereoselectivity. 

The cross-aldol reaction is actively studied with the aim of improved control of the stereoselectivity.58 The use of silyl enol ethers for a condensation with aldehydes constitutes important progress, but catalysis by Lewis acids can be unsatisfactory for acid labile substrates, and the predominant anti stereoselectivity is not always optimal. An attempt was made to solve this problem by running the reaction sonochemically in the presence of alumina, without any solvent.59 products are absent, and the anti-isomer forms predominantly (Eq. 16). 

The aldol reaction has long been recognized as one of the most useful synthetic tools. Under classical aldol reaction conditions, in vhich basic media are usually employed, dimers, polymers, self-condensation products, or a,j5-unsaturated carbonyl compounds are invariably formed as byproducts. The lithium enolate-mediated aldol reaction is regarded as one useful synthetic means of solving these problems. Besides the vell-studied aldol reaction based on lithium enolates, very versatile regio- and stereoselective carbon-carbon bond forming aldol-type reactions have been established in our laboratory by use of boron enolates (1971), silicon enolates-Le vis acids (1973), and tin(II) enolates (1982). Here we describe the first t vo topics, boron and silicon enolate-mediated crossed aldol reactions, in sequence. 

Furthermore, the combined use of a catalytic amount of 9 with SiCU allowed for the broadly useful, stereoselective double aldol reaction of ketones with aldehydes as depicted in Scheme 7.21 [36]. This asymmetric transformation involved the initial cross aldol reaction between ketone and aldehyde controlled by 9 and subsequent enolization of the resulting trichlorosilyl ether activated by 9 to generate the chiral cyclic enol ether that, in turn, underwent a second aldol process with another aldehyde in a diastereoselective fashion. 

Polyoxometalates (POMs) are transition metal oxygen clusters with well-defined atomic coordination structures. POMs are used as functional nano-colloidal materials and also as supports for catalysts via ion-pair interactions due to their acidic properties. Combinations of chiral diamines and POM 225 effectively catalyze enamine-based aldol reactions. Less than 1 mol% of chiral amine loading is suf-ficientto catalyze the reaction (Table 28.10, entries 1 and 2) [114]. Highly diastereo-and enantioselective cross-aldol reactions of aldehydes are accomplished using chiral diamine-POM 226 under emulsion conditions (entries 3 and 4) [115]. Sul-fonated polystyrene or fluoropolymer Nafion NR50 are also good supports for the immobilization of primary-tertiary diamines. The catalyst 227 can be recovered by filtration and reused for at least four cycles with no loss of stereoselectivity (entries 5 and 6) [116]. 

Mahrwald reported that simple L-histidine could promote cross aldol reactions of aldehydes in water with good activity and moderate to good stereoselectivity (Scheme 5.5) [16],... 

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