Ketene faciality

In a related publication, Kobayashi and his team reported on Zr-catalyzed asymmetric Mannich reactions that utilize the more electron-rich oxygenated ketene acetals shown in Scheme 6.28 [93], A noteworthy aspect of this study was that the levels of syn/anti diaste-reocontrol proved to be dependent on the nature of the alkoxide substituent whereas the (3-TBS acetals predominantly afforded the syn isomer, the OBn derivatives afforded a larger amount of the anti isomer. As before, the presence of an additive, this time 1,2-dimeth-ylimidazole (DMI), proved to be important with regard to the level of Ti-facial selectivity. The phenol activating group can be removed by the same procedure as reported previously, with essentially identical degrees of efficiency (see Scheme 6.27). 

Ketene acetal sulfoxide 30 has been used as a chiral ketoester ketene acetal equivalent, because it undergoes a ready enantiocontrolled reaction with cyclopentadiene at -78°C in the presence of BF3 yielding a 96 4 mixture of endo and exo adducts with complete n-facial selectivity (Scheme 15) [44]. The endo selectivity decreased with other catalysts, but the 7r-facial selectivity remained complete, whereas under thermal conditions (139 °C, 15 h) a mixture of the four possible adducts was obtained. The adduct 31 was transformed into (+)-(lRy4R)-norbornenone in a four-step sequence. 

The use of substituted pyridines in organic synthesis has broad application. The activation of the pyridine ring toward nucleophilic attack is well known in the literature. The products of such reactions are often dihydropyridines which can serve as intermediates in more complex synthetic strategies. Rudler and co-workers have reported on the nucleophilic addition of bis(trimethylsilyl)ketene acetals to pyridine (26). The 1,4-addition product 27 was then cyclized with iodine to afford bicycle 28 in 90% overall yield <02CC940>. Yamada has elegantly shown that facial selectivity can be achieved and chiral 1,4-dihydropyridines accessed in high yield and de (29—>30) <02JA8184>. 

The si facial preference displayed by the reagent is enhanced in reactions proceeding through Lewis acid-catalyzed open transition states.Thus, when reacted with the ketene silyl acetal shown (eq 2) under zinc iodide catalysis, a 96 4 ratio of products was obtained. The corresponding uncatalyzed reaction led to an 85 15 mixture of the same products in similar yield. ... 

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 first example of an asymmetric [2 + 2] cycloaddition of a ketene to an aldehyde was reported in 1994 by Miyano and coworkers [28]. They found that chiral aluminum catalysts prepared from different 3,3 -disubstituted BINOL derivatives resulted in low to modest asymmetric induction for a range of aliphatic and aromatic aldehydes. There does not seen to be a correlation between asymmetric induction and the size of the aldehyde. The data in Table 5 show that the optimum ligand for this reaction is triphenylsilyl substituted BINOL. It is curious that the catalyst prepared from this ligand and the catalyst prepared from BINOL result in opposite facial selectivity with... 

N, P ] and [P, P ] Aldehydes with an a-stereocenter exhibit unusually high diastereofacial preferences for the addition of silyl enol ethers and ketene acetals with Lewis acid assistance (81). Heathcock and Uehling found good levels of facial discrimination in the addition of silyl enol ethers to chiral enones (Scheme 38, Table 11) (82). With the more substituted silyl enol ether, only one diastereomeric addition product is obtained (Eq. [1], Scheme 38). Use of a prostereogenic silyl enol ether allows control over the relative... 

TiCU-mediated addition of silyl enol ether (95) to chiral a-amino aldehyde (94) was reported to proceed with good chelation control, albeit in poor yield (equation 28). Effective chelation control was also reported in the TiCU-mediated reactions of chiral a-alkoxy and p-alkoxy acyl cyanides (96) and (97) with silyl enol ether (95 equations 29 and SO). Reaction of acyl cyanide (97) with the ( )-silyl enol ether (93) gave a single stereoisomer as a result of complete chelation control and syn simple stereoselection (equation 31). Additions of silyl enol ethers and silyl ketene acetals to (-)-menthyl phenyl-glyoxylate and pyruvate were reported to proceed with moderate facial selectivity the best result (84 16) is shown in equation (32). ... 

Aldol reaction of esters. The combination of reagents promotes enolboration, and subsequent reaction under kinetically controlled conditions (-78°) leads predominantly to the anti isomers. At higher temperatures (-40° 0°) the syn isomers are produced with high facial selectivity. The ( /Z)-isomerization of the boryl ketene ethers is promoted by EtjNHOTf that is present in the reaction mixture. 

Ishizaki et al. found that use of a triisopropylsilyl (TIPS) protecting group gave optimal facial selectivity in the Ireland-Claisen rearrangement of C5 hydroxyalkyl substituted allylic alkene, with the silyl ketene acetal attacking anti to the O-sUyl group (Scheme 4.33) [35]. The rearrangement presumably proceeded via a chair-... 

Also in 1993, Hauske and JuUn reported a similar Ireland-Claisen rearrangement of an acyclic C6 carbamate (Scheme 4.35) [39]. The authors examined three different silyl ketene acetals in the rearrangement, although no experimental details were provided. AU three examples apparently proceeded with complete facial selectivity with respect to the allyUc alkene to afford the syn stereochemistry between the aUyl group and the NHBoc group in the conformation shown. The same rationale for facial selectivity can be applied as for Mulzer s results in the previous scheme. The reason for the low C2,C3 synjanti diastereoselectivity in the propionate example was not addressed. A lack of control of enolate geometry or post-rearrangement epimerization are both possible. 

The earliest examples of Ireland-Claisen rearrangements of allyl silyl ketene acetals bearing a stereocenter at C6 were reported by Cha and Lewis in 1984 (Scheme 4.36) [40]. In contrast to the nitrogen C6 substituents, oxygen substituents exhibited considerably less facial bias. Rearrangements of the acetate esters of either the Eor Z alkenes gave only 1.3 1 and 1.4 1 C3,C6 anti.syn ratios, respectively. 

Similarly, but in the cyclic series, the thio-Claisen rearrangement of substrates derived from chiral thiolactams was reported to be facile but poorly stereoselective [129]. The low stereocontrol observed in both cases may be explained by the lack of facial selectivity resulting from the free rotation around the C-N bond of the N,S-ketene acetals. This critical issue has been solved either by constructing a rigid bicyclic framework or by using C2-symmetric amines as chiral inductors. The former strategy, developed by Meyers et al. [45], involved bicycUc thiolactams, which were transformed into N,S-ketene acetals by deprotonation with LDA, followed by S-allylation with various allyl halides (Scheme 9.27). 

Danishefsky has described a substrate-controlled Johnson-Claisen rearrangement outcome when a single diastereomer, identified as ester 360, was independently produced fi-om (E)- and (Z)-isomers of alcohol 359." Subsequently this process was studied by Aviyente, Ozturk, and Hotik. The Computational studies of the ( )- and (Z)-ketene acetals originating fi om 359 revealed that facial selectivity was controlled due to steric interactions of... 

Diaz-Ortiz A, Diez-Barra E, de la Hoz A, Prieto R Moreno A, Langa F, Prange T, Neuman A (1995) Facial selectivity in cycloadditions of a chiral ketene acetal under microwave irradiation in solvent-free conditions. Configurational assignment of the cycloadducts by NOESY experiments and molecular mechanics calculations. J Oig Chem 60 4160-4166... 

Given that the highly reactive acetate-derived silyl ketene acetal 24 displayed a broad substrate scope with respect to the aldehyde, we decided to explore other ester-derived silyl ketene acetals. Again, our hope was that these more reactive nucleophiles would maintain broad reactivity with respect to the aldehyde. The diastereoselectivity of this catalyst system could also be investigated, in this case by employing propanoate-derived silyl ketene acetals. The catalyst had already shown a high level of control over the facial approach of the nucleophile to the activated... 

---