Mukaiyama-aldol reactions diastereoselectivity

A Lewis acid-catalyzed vinylogous Mukaiyama aldol reaction between 2-trialkylsilyloxyfurans and a-substituted ketones proceeded diastereoselectively... 

Pro-chiral pyridine A-oxides have also been used as substrates in asymmetric processes. Jprgensen and co-workers explored the catalytic asymmetric Mukaiyama aldol reaction between ketene silyl acetals 61 and pyridine A-oxide carboxaldehydes 62 <06CEJ3472>. The process is catalyzed by a copper(II)-bis(oxazoline) complex 63 which gave good yields and diastereoselectivities with up to 99% enantiomeric excess. 

Based on these results, Kalesse et al. applied the vinylogous Mukaiyama aldol reaction in their total synthesis of ratjadone [33, 34]. In the synthesis of the C14-C24 segment (A-fragment), the vinylogous aldol reaction was used together with different Lewis acids to achieve the addition of this diacetate syn-thon in a diastereoselective manner under Felkin control (Scheme 23). 

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]. 

The vinylogous Mukaiyama aldol reaction of 2-(TMS-oxy)furans with methacro-leins, catalysed by boron trifluoride etherate, has been studied experimentally and computationally, to identify the factors behind observed diastereoselectivities.143... 

In the Mukaiyama aldol reaction, Zr cationic catalysts can be used. They act very quickly and require only low catalyst loadings (0.5% [Cp2Zr(OTf)2 thf ). But, the reactions show only modest diastereoselectivity. ... 

The aldol reaction of ketene silyl acetals with several aldehydes (Mukaiyama aldol reaction) assisted by Li has been described briefly by Reetz et al. Wirth 5.0 m LPDE a clean reaction began within 1 h with the sole formation of the silylated aldol 112, whereas the use of a catalytic amount (3 mol %) of LiC104 in Et20 (3 mol % LPDE) required a reaction time of 5 days for 86 % conversion. As observed in the hetero-Diels-Alder reaction of a-alkoxyaldehyde, the higher rate of reaction of 79 compared with that of benzaldehyde can be attributable to chelation. Indeed, the use of 3 mol % LPDE required only 20 h at room temperature for complete uptake of 79 with a diastereoselectivity (syn-113lanti-113) of >96 % (Sch. 55). 

LiC104 was shown to be a more compatible Lewis acid for chelation in an ethereal solvent—when TiCU, a typical chelation agent for a-alkoxyaldehydes, was used in EtaO for alkylation of 79, moderate diastereoselectivity (68 32) was obtained. Rapid injection NMR studies of the TiCU-promoted chelation-controlled Mukaiyama aldol reaction and the Sakurai reaction show that an acyclic transition state must be involved in which the silyl groups never reach the carbonyl oxygen atom. In LPDE-mediated enolsilane additions silylated products predominate. Obviously, the mechanism is different—it is a group-transfer aldol reaction [107]. 

The Mukaiyama aldol reaction of carbonyl substrates with silyl enol ethers is the most widely accepted of Lewis acid-promoted reactions. Many Lewis acids for the reaction have been developed and used enantioselectively and diastereoselectively. In 1980, catalytic amounts of la were found by Noyori et al. to effect aldol-type condensation between acetals and a variety of silyl enol ethers with high stereoselectivity [2c,20]. Unfortunately, la has poor Lewis acidity for activation of aldehydes in Mukaiyama s original aldol reaction [21]. Hanaoka et al. showed the scope and limitation of 11-cat-alyzed Mukaiyama aldol reaction, by varying the alkyl groups on the silicon atom of silyl enol ethers [22]. Several efforts have been since been made to increase the reactivity and/or the Lewis acidity of silicon. One way to enhance the catalyst activity is to use an additional Lewis acid. 

The directed aldol reaction in the presence of TiC found many applications in natural product synthesis. Equation (7) shows an example of the aldol reaction utilized in the synthesis of tautomycin [46], in which many sensitive functional groups survived the reaction conditions. The production of the depicted single isomer after the titanium-mediated aldol reaction could be rationalized in terms of the chelation-controlled (anft-Felkin) reaction path [37]. A stereochemical model has been presented for merged 1,2- and 1,3-asymmetric induction in diastereoselective Mukaiyama aldol reaction and related processes [47]. 

The asymmetric total syntheses of mtamycin B and oligomycin C was accomplished by J.S. Panek et al. In the synthesis of the C3-C17 subunit, they utilized a Mukaiyama aldol reaction to establish the C12-C13 stereocenters. During their studies, they surveyed a variety of Lewis acids and examined different trialkyl silyl groups in the silyl enol ether component. They found that the use of BFs OEta and the sterically bulky TBS group was ideal with respect to the level of diastereoselectivity. The stereochemical outcome was rationalized by the open transition state model, where the orientation of the reacting species was anti to each other, and the absolute stereochemistry was determined by the chiral aldehyde leading to the anti diastereomeric Felkin aldol product. 

Mukaiyama aldol reaction Good yields of adducts are obtained in the Zr-catalyzed process. However, due to operation of two possible competing reaction pathways, low diastereoselectivities are generally observed. 

The TiCLrmediated Mukaiyama aldol reactions between 7r-allyltricarbonyliron lactone complexes and chiral aldehydes were well documented by Ley and coworkers [37]. (/ )-Trimethylsilyl enol ether 23 (>96% ee) was prepared from the methyl ketone complex 22 by treatment with MesSiOTf/EtsN in CH2CI2 and this was then reacted with (R)- and (5)-2-benzyloxypropanal 24 under the influence of TiCl4 in CH2CI2 at -78 °C. Although the reactions proceeded very slowly and apparent hydrolysis of the silyl enol ether occurred, the aldol products 25 and 26 were isolated in excellent diastereoselectivity in both cases (Scheme 1-8). Interest-... 

As mentioned previously, it can be more difficult to predict syn anti diastereoselectivity in Mukaiyama aldol reactions of substituted ketones. However, the reward of high stereocontrol in these reactions is attainable as shown in Scheme 9-12. While the second example shows disappointing aldehyde face selectivity, there is strong enolate facial bias 5-anti in both 32 and 33). Therefore,... 

The synthesis of the C1-C9 fragment 120 began with an auxiliary controlled aldol reaction of the chloroacetimide 121, where chlorine is present as a removable group to ensure high diastereoselectivity in what would otherwise have been a non-selective addition (Scheme 9-39). The Lewis acid-catalyzed, Mukaiyama aldol reaction of dienyl silyl ether 122 with / -chiral aldehyde 123 proceeded with 94%ds, giving the 3-anti product 124, as predicted by the opposed dipoles model [3]. Anti reduction of the aldol product and further manipulation then provided the C1-C9 fragment 120 of the bryostatins. 

A similar aluminum cation was also available in the Mukaiyama-aldol reaction. It is worth noting that the t-butyldimethylsilyloxy (TBSO) group, which otherwise is unable to make chelation complex with neutral bidentate Lewis acids, is under chelation control with excess Me2AlCl or MeAlfJh. [12]. Aldehyde and ketone carbonyls are capable of participating in the chelation-controlled aldol reaction to give anti-6 with high diastereoselectivity (Scheme 6.4). 

The Mukaiyama aldol reaction has been successfully catalyzed by a tin complex prepared from Sn(OTf)2 and a chiral diamine [82]. The diastereoselectivity and the enantioselectivity may be remarkably high, both close to 99%. 

In order to reverse the diastereoselectivity in the aldol reaction, the Lewis acid-catalyzed silyl enol ether addition (73) (Mukaiyama aldol reaction) was examined. Since the Mukaiyama aldol reaction is assumed to be proceeded via an acyclic transition state, a chelation controled aldol reaction of the a-alkoxy aldehyde should be possible (74). In the presence of TiCU, the silyl enol ether derived from 14 was reacted with aldehyde 13, followed by desilylation to afford the desired anti-Felkin product 122a as a single adduct (Scheme 21). Based on precedents for chelation-controlled Mukaiyama aldol reaction (74), the exceptional high selectivity in this reaction would be accounted for by chelation of TiCl4 with the C23-methoxy group of the aldehyde 13 (eq. 13). On the other hand, when the lithium enolate derived from 14 was treated with the aldehyde 13, followed by desilylation, it gave a 1 4 ratio of the two epimers in favour of the undesired (22S)-aldol product... 

Keck et al. have used the lactone annulation procedure developed in their laboratory to install the lactone moiety by reaction of the lithium enolate of methylacetate with a (3-acetoxy aldehyde [108]. The other key steps include a diastereoselective Lewis acid mediated (Z)-crotylstannane aldehyde addition, a highly selective Lewis acid promoted Mukaiyama aldol reaction and an arari-selective Sml2 reduction of a p-hydroxyketone. The preparation of the C8-C15 fragment of (-)-pironetin started with the chelation-controlled addition of (Z)-crotyl tri-n-butylstannane to the (3-benzyloxy-aldehyde 153 in the presence of TiCU [109] to give the... 

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],... 

A silver salt dramatically reverses the diastereoselectivity of a titanium-chloride-mediated vinylogous Mukaiyama aldol reaction of a chiral vinylketene silyl N, 0-acetal with ethyl glyoxolate. ° ... 

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