Diastereoselective cross-aldol

The reaction of an a-halo carbonyl compound with zinc, tin, or indium together with an aldehyde in water gave a direct cross-aldol reaction product (Eq. 8.90).226,227 A direct Reformatsky-type reaction occurred when an aromatic aldehyde reacted with an a-bromo ester in water mediated by zinc in low yields. Recently, it was found that such a reaction mediated by indium was successful and was promoted by son-ication (Eq. 8.91).228 The combination of BiCl3-Al,229 CdCl2-Sm,230 and Zn-Et3B-Eb0231 is also an effective mediator. Bismuth metal, upon activation by zinc fluoride, effected the crossed aldol reaction between a-bromo carbonyl compounds and aldehydes in aqueous media. The reaction was found to be regiospecific and syn-diastereoselective (Eq. 8.92).232... 

The aldehyde-aldehyde aldol reactions were first nsed in a natural product synthesis setting by Pihko and Erkkila, who prepared prelactone B in only three operations starting from isobutyraldehyde and propionaldehyde (Scheme 40). Crossed aldol reaction under proline catalysis, followed by TBS protection, afforded protected aldehyde 244 in >99% ee. A highly diastereoselective Mukaiyama aldol reaction and ring closure with aqueous HE completed the synthesis [112]. 

Denmark utilized chiral base promoted hypervalent silicon Lewis acids for several highly enantioselective carbon-carbon bond forming reactions [92-98]. In these reactions, a stoichiometric quantity of silicon tetrachloride as achiral weak Lewis acid component and only catalytic amount of chiral Lewis base were used. The chiral Lewis acid species desired for the transformations was generated in situ. The phosphoramide 35 catalyzed the cross aldolization of aromatic aldehydes as well as aliphatic aldehydes with a silyl ketene acetal (Scheme 26) [93] with good yield and high enantioselectivity and diastereoselectivity. 

Cross aldol reactions of silyl enol ethers with acetals (25 - 26, and 27 - 28) are also mediated by EGA. The reaction runs smoothly at —78 °C in a CH2CI2— —LiClO —Et NClO —(Pt) system. At an elevated temperature protonation of both enol ether and acetal occurs competitively to give 28 in a poor yield. Table 5 summarizes yields and diastereoselectivities of 28 obtained by EGA, TiCl TMSOTf and TrtClO 5 . The EGA method is superior to TiCl with regard to the stereocontrol, and comparable with TMSOTf and TrtClO in both stereocontrol and yield. 

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... 

The lower yield may be explained by the fact that linear aldehydes also undergo self-aldol condensation, which is in direct competition with the crossed-aldol reaction. Aromatic aldehydes as the carbonyl component led to reduced diastereoselectivity. For example, the (.S )-prolinc-catalyzed aldol reaction of 4 with ort/tochlorobenzaldehyde proceeded with a good yield of 73%, but with an anti/syn ratio of only 4 1 and enantiomeric excesses of 86% ee (anti) and 70% ee (syn). 

The stereochemical course of several Co2(CO)6-mediated reactions has been studied. For example, although alkynyl aldehydes undergo crossed aldol condensation with trimethylsilyl enol ethers with little stereoselectivity, their hexacarbonyldicobalt derivatives react with moderate to excellent syn diastereoselectivity.96 101 The mechanism behind this selectivity has not been fully elucidated and is complicated by the lluxional nature of the intermediate cations. This stereoselective reaction has been successfully applied to the synthesis of /3-lactam antibiotics.100... 

In the studies on the synthesis of the antitumor agents esperamicin and calicheamicin by Magnus et al. [93], an aldol reaction was found suitable for macrocyclization after a number of unsuccessful attempts. Thus, as shown in Scheme 54, the diynene core structure (165) of the two antitumor agents was synthesized from the dicobalt hexacarbonyl derivative 163. When 163 was treated with n-BujBOTf/DABCO/EtjN in CHzClj-THF the aldol product 164 was isolated as a single stereoisomer in 45% yield. Although alkynyl aldehydes undergo similar crossed aldol condensation, their dicobalt hexacarbonyl derivatives react with moderate to excellent syn diastereoselectivity [94]. 

The first catalytic, diastereoselective and enantioselective cross-aldol reactions of aldehydes have also been documented. Geometrically defined trichlorosilyl enolate derivatives of aldehydes undergo diastereoselective addition to a wide range of aldehyde acceptors with good enantioselectivity. The use of chiral Lewis base (138) was critical for achieving useful enantioselectivity. ... 

A very elegant asymmetric synthesis of D-ribose from achiral starting materials has been presented by Mukaiyama and coworkers [36]. It is based on the cross-aldolization of crotonaldehyde and enoxysilane 74 in the presence of an enantiomerically pure diamine 75, the chiral inducer (Scheme 13.33). High diastereoselectivity anti syn > 98 2) and high... 

The total syntheses of 3-deoxy-D-nZ 6>- and 3-deoxy-D-araZ m6>-hexose were realized via the cross-aldolization of 2,3-O-isopropylene-D-glyceraldehyde (R)-24 and 1,1-dimethoxyacetone (Scheme 13.62). The key step of the synthesis is the diastereoselective reduction of one of the aldols 179 via boron chelates. Treatment of 179 with triisobutylborane, and then with NaBH4 gives syn-1,3 181 and anti-1,3-diol 182 in a ratio 95 5. Acidic hydrolysis provides... 

The use of Ln(OTf)3 in the activation of aldehydes other than formaldehyde was also investigated [18], Several examples of the present aldol reaction of silyl enol ethers with aldehydes are listed in Table 14-1. In every case, the aldol adducts were obtained in high yields in the presence of a catalytic amount of Yb(OTf)3, Gd(OTf)3, or Lu(OTf)3 in aqueous media. Diastereoselectivities were generally good to moderate. One feature in the present reaction is that water-soluble aldehydes, for instance, acetaldehyde, acrolein, and chloroacetaldehyde, can be reacted with silyl enol ethers to afford the corresponding cross aldol adducts in high yields (entries 5-7). Some of these aldehydes are commercially supplied as water solutions and are appropriate for direct use. Phenylglyoxal monohydrate also worked well (entry 8). It is known that water often interferes with the aldol reactions of aldehydes with metal enolates and that, in the cases where such water... 

The catalyhc efficiency of L-proline in ionic liquid was enhanced by the addition of DMF as cosolvent, which may be largely due to tlie increased mass transfer in the presence of DMF [79c]. Thus, the use of only 5 mol% L-proline was sufficient to accomplish the cross-aldol reactions of aliphatic aldehydes, affording a-alkyl-P-hydroxyaldehydes with extremely high enanhoselectivihes (>99% ee) in moderate to high diastereoselectivities (diastereomeric raho 3 1 >19 1). However, under the same reaction conditions, much lower ee-values and yields were observed in a one-pot synthesis of pyranose derivahves by sequential cross-aldol reachons. The L-proline immobilized in the ionic liquid layer could be recovered and reused without any deterioration in catalytic efficiency, with the diastereoselectivity,... 

Of course, a systematic comprehensive analysis of all literature published on the asymmetric cross aldol reaction goes beyond the purpose of this chapter, thus attention is focused on the best achievements reported for catalysts working under neat conditions in the presence of an aqueous phase (Scheme 1.2). Generally, zzzZz-diastereoselectivity is observed, while the opposite. sv/z-diaslcr-eoselectivity is often exhibited by oc-hydroxyketones. 

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 cross-aldol reaction between propionaldehyde (5a, R =Me in Scheme 4.12) and p-nitrobenzaldehyde gave the corresponding compound anti-29 (> 88% yield, 88% de and 99% ee), which has been used as the asymmetric key step in the synthesis of trichostatin A [76], In a similar way, using propionaldehyde (Sa, R =Me in Scheme 4.12) and an excess isobutyraldehyde (4 equiv, R =j-Pr) catalyzed by proline (10 mol%), product anti-29 (98% de and 99% ee) was obtained. Subsequent diastereoselective Mukaiyama aldol reaction followed by lactonization gave prelactone B [77]. The synthesis of (-)-enterolactone has been achieved by a cross-aldol reaction between methyl 4-oxobutyrate and 3-methoxybenzaldehyde catalyzed by proline (20 mol%) as a key step [78],... 

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