Silyl ketene acetals reactions with aldehydes

Zhu and Panek s total synthesis [148] is described in Scheme 89. After conversion of aldehyde 609 to di-benzyl acetal, treatment with chiral crotylsilane 610 afforded l,2-5y -611 with high stereo- and enantioselectivity. The oxidative cleavage of the double bond and subsequent aldol reaction with silyl ketene acetal 612 provided 613, which was converted into a,P-unsaturated ester 614 via Wittig olelination. The C8 methyl group was stereoselectively introduced by treatment with dimethylcuprate in the presence of TMSCl. DIB AH treatment differentially reduced the C3 and CIO esters to alcohol and aldehyde, respectively. Protection of the alcohol as silyl ether followed by the Wittig reaction afforded 615. In a manner similar to Danishefsky s synthesis [142d], an inteimolecular Suzuki... 

Acylhydrazones, R CH=N-NHCOR , undergo stereoselective Mannich reactions with silyl ketene acetals to give j8-hydrazido esters, using activation by a chiral silicon Lewis acid. Alternatively, the use of silyl ketene imine gives a /3-hydrazido nitrile. Enantioselective (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) hydrazone alkylation of aldehydes and ketones is the subject of a computational study, providing a useful screening method for possible new candidates. " ... 

Six-membered chiral acetals, derived from aliphatic aldehydes, undergo aldol-type coupling reactions with silyl ketene acetals in the presence of TiCU with high diastereoselectivity (eq 15). This procedure, in combination with oxidative destructive elimination of the chiral auxiliary, has been applied to the preparation of (i )-(+)-Q -lipoic acid and mevinolin analogs. ... 

Paterson et al. [98] in their attempt used a similar disconnection for rhizopodin as described by Menche (fragments 144 and 149) (Scheme 2.151). However, unlike, Menche, they used silyl ketene acetal 16 in an asynunetric VMAR for the addition to ( )-iodoacrolein (142) to obtain dioxinone 143 in 94% ee. Methanolysis removed the aceto-nide, and the subsequent Narasaka reduction [99] provided the syn-diol 144 in 80% yield and a 10 1 selectivity for the desired isomer. The synthesis of segment 149 started with aldehyde 145, which was ultimately derived from Roche ester. Carbon chain extension was achieved through a chelation-controlled Mukaiyama aldol reaction with silyl ketene acetal 146, which installed the new chiral center with excellent stereocontrol (20 1 dr). For the installation of the third secondary alcohol, six-membered lactone 148 was obtained by treatment with K COj in methanol. Subsequent borane reduction provided stereospecifically the desired alcohol, which was then further transformed to the desired acid (149). 

TABLE 3-4. Reaction of Silyl Ketene Acetals with Aldehydes... 

Three years after the discovery of the asymmetric BINOL phosphate-catalyzed Mannich reactions of silyl ketene acetals or acetyl acetone, the Gong group extended these transformations to the use of simple ketones as nucleophiles (Scheme 25) [44], Aldehydes 40 reacted with aniline (66) and ketones 67 or 68 in the presence of chiral phosphoric acids (R)-3c, (/ )-14b, or (/ )-14c (0.5-5 mol%, R = Ph, 4-Cl-CgH ) to give P-amino carbonyl compounds 69 or 70 in good yields (42 to >99%), flnfi-diastereoselectivities (3 1-49 1), and enantioselectivities (72-98% ee). 

Scheme 8.8 Mukaiyama aldol reactions of silyl ketene acetals with aldehydes.

Aldol Reactions of Ester Derivatives. The Titanium(IV) C/tlor/dc-catalyzed addition of aldehydes to 0-silyl ketene acetals derived from acetate and propionate esters proceeds with high stereoselectivity. Formation of the silyl ketene acetal was found to be essential for high diastereoselectivity. Treatment of the silyl ketene acetal, derived from deprotonation of the acetate ester with LICA in THF and silyl trapping, with a corresponding aldehyde in the presence of TiCU (1.1 equiv) afforded the addition products in 93 7 diastereoselectivity and moderate yield (51-67%). Similarly, the propionate ester provides the anti-aldol product in high antilsyn selectivity (14 1) and facial selectivity (eq 4). 

The use of CABs prepared from the sulfonamides of amino acids to introduce asymmetry into the Diels-Alder reaction was reported simultaneously by Takasu and Yamamoto [14] and by Helmchen and co-workers [13]. Because of the capacity of boron to complex the carbonyl moiety in this type of eatalyst, it is clear they might be effective in promoting the reaction of silyl ketene acetals with various aldehydes. 

This reaction of silyl ketene acetals with aldehydes, using 29 as a stoichiometric chiral reagent (Eq. 46), was reported by Reetz et al. [42]. The aldol addition of l-(trimethyl-siloxy)-l-methoxy-2-methyl-l-propene and 3-methylbutanal provides the aldol in only 57 % yield, but with 90 % ee. 

The use of CAB as a chiral reagent seems to be more effective for this reaction, which proceeds faster and with higher yields and enantiomeric excess. Kiyooka et al. first described the use of various chiral oxaborolidines, derived from sulfonamides of a-amino acids and borane, in the course of the selective aldol reaction between silyl ketene acetals and aldehydes (Eq. 47) [43a]. Stereoselectivity and yields were relatively high. 

Condensations. The reaction of silyl ketene acetals with aldehydes favors enals over saturated aldehydes, when promoted by BUjSnClO. The catalyst is obtained from reaction of trityl perchlorate and tributyltin hydride. 

In a novel departure from the traditional approach to the asymmetric Mukaiyama aldol, Denmark has reported a Lewis base-catalyzed aldol addition reaction of enol trichlorosilanes and aldehydes. These unusual silyl ketene acetals are readily prepared by treatment of the tributylstannyl enolates 246 with SiC (Eq. 51). In the initial ground-breaking studies, the methyl acetate-derived trichlorosilyl ketene acetal 247 was shown to add rapidly to a broad range of aldehydes at -80 C to give adducts (89-99% yield, Eq. 52). 

A catalytic enantioselective aldol-type reaction of ketene silyl acetals with achiral aldehydes also proceeds smoothly with 3a, which can furnish erythro p-hydroxy esters with high optical purities (Equation 42) [42b, c]. A remarkable finding is the sensitivity of this reaction to the substituents of the starting silyl ketene acetals. The reactions of silyl ketene acetals derived from more common ethyl esters are totally stereorandom, and give a mixture of syn and anti isomers in even ratios with improved chemical yields. In sharp contrast, the use of silyl ketene acetals generated from phenyl esters leads to good diastereo- and enantioselectivities with excellent... 

In the Mukaiyama addition of the aldol reaction [16], silyl ketene acetals or silyl enol ethers are added to aldehydes in a reaction mediated by Lewis acids or fluoride. Here again the Z-syn correlation is sometimes not observed [69, 70]. Thus, the Z-syn, E-anti correlation seems to be a rule with several exceptions [71]. 

Akiyama and coworkers, who had pioneered BINOL-derived phosphoric acids, noticed that aldimines 365 available from 2-aminophenol and aromatic, heteroaromatic, and cinnamyl aldehydes can be activated by the chiral acid catalyst 367, so that they are electrophilic enough to react with silyl ketene acetals 366 in diastereoselective and enantioselective Mannich reactions. Thus, P-amino esters 368 are formed with a high preference for the syn-diastereomers that are obtained in high enantiomeric excess (Scheme 5.96) [182]. 

In 2009, List introduced a binaphthyl-derived, chiral disuUbnimide (28) as a new structural motif of a powerful chiral Bronsted add that could activate simple aldehydes [80, 81]. Evaluation of the catalytic activity and stereocontrolling ability of 28 in the Mukaiyama aldol reaction of silyl ketene acetal with naphthaldehyde revealed that 28 was not only far more reactive than phosphoric acid 29 and phos-phoramide 30 but also capable of affording the aldol product with high enantiose-lectivity (Scheme 7.53). 

While catalyst 28 may directly protonate the aldehyde to form an ion pair, an alternative yet more hkely mechanism was proposed (Figure 7.6). The initial silyla-tion of 28 by ketene silyl acetal may occur to form an N-sUyl disulfonamide that could then activate the aldehyde as an actual catalyst through sUyl transfer to generate an O-silylated oxonium cation paired with disulfonitriide anion. Therefore, the stereochemical outcome would be determined in the reaction of this ion pair with silyl ketene acetal to give the product through the intermediate shown in Figure 7.6. 

AldolCondensations. Cation-exchanged montmorillonites accelerate the aldol condensation of silyl enol ethers with acetals and aldehydes. Similarly, the aldol reaction of silyl ketene acetals with electrophiles is catalyzed by solid-acid catalysts. Neither report discussed the use of iron montmorillonite for these reactions however, some reactivity is anticipated. 

The stereoselectivity in TiCU-promoted reaction of silyl ketene acetals with aldehydes may be improved by addition of Triph-enylphosphine (eq 12). Enol ethers, as well as enol acetates, can be the nucleophile (eqs 13 and 14). 2-Acetoxyfuran, in analogy to vinyl acetates, reacts with aldehydes to furnish 4-substituted butenolides under the influence of TiCU (eq IS). ... 

The Mukaiyama aldol reaction refers to Lewis acid-catalyzed aldol addition reactions of silyl enol ethers, silyl ketene acetals, and similar enolate equivalents,48 Silyl enol ethers are not sufficiently nucleophilic to react directly with aldehydes or ketones. However, Lewis acids cause reaction to occur by coordination at the carbonyl oxygen, activating the carbonyl group to nucleophilic attack. 

Entries 4 and 9 are closely related structures that illustrate the ability to control stereochemistry by choice of the Lewis acid. In Entry 4, the Lewis acid is BF3 and the (3-oxygen is protected as a f-butyldiphenylsilyl derivative. This leads to reaction through an open TS, and the reaction is under steric control, resulting in the 3,4-syn product. In Entry 9, the enolate is formed using di-n-butylboron triflate (1.2 equiv.), which permits the aldehyde to form a chelate. The chelated aldehyde then reacts via an open TS with respect to the silyl ketene acetal, and the 3,4-anti isomer dominates by more than 20 1. 

The (3-methoxy group in Entry 12 has a similar effect. The aldehydes in Entries 13 and 14 also have a-methyl-(3-oxy substitution and the reactions in these cases are with a silyl ketene acetal and silyl thioketene acetal, respectively, resulting in a 3,4-syn relationship between the newly formed hydroxyl and a-methyl substituents. 

Silyloxy)alkenes were first reported by Mukaiyama as the requisite latent enolate equivalent to react with aldehydes in the presence of Lewis acid activators. This process is now referred to as the Mukaiyama aldol reaction (Scheme 3-12). In the presence of Lewis acid, anti-aldol condensation products can be obtained in most cases via the reaction of aldehydes and silyl ketene acetals generated from propionates under kinetic control. 

Besides their application in asymmetric alkylation, sultams can also be used as good chiral auxiliaries for asymmetric aldol reactions, and a / -product can be obtained with good selectivity. As can be seen in Scheme 3-14, reaction of the propionates derived from chiral auxiliary R -OH with LICA in THF affords the lithium enolates. Subsequent reaction with TBSC1 furnishes the 0-silyl ketene acetals 31, 33, and 35 with good yields.31 Upon reaction with TiCU complexes of an aldehyde, product /i-hydroxy carboxylates 32, 34, and 36 are obtained with high diastereoselectivity and good yield. Products from direct aldol reaction of the lithium enolate without conversion to the corresponding silyl ethers show no stereoselectivity.32... 

---