Ketene acetals, vinylogous

As an extension of this work, these authors have applied this catalyst system to vinylogous asymmetric Mukaiyama-type aldol reactions, involving silyl vinyl ketene acetals and pyruvate esters. These reactions afforded the corresponding y,5-unsaturated a-hydroxy diesters with quaternary centres in high yields and enantioselectivities of up to 99% ee (Scheme 10.25). It was shown that the presence of CF3CH2OH as an additive facilitated the turnover of the catalyst. 

For applications in total synthesis this method was also thought to be applicable to chiral aldehydes, leading to matched and mismatched situations. Therefore, vinylogous ketene acetal 40 was put to reaction with chiral aldehyde 44 and both enantiomers of Carreira s catalyst. Reaction of aldehyde 44 with the (S)-Tol-BINAL-CuF catalyst (matched case) produced only one diastereomeric... 

Scheme 17 Vinylogous aldol reaction with y-substituted ketene acetal 40 using Carreira s catalyst...

Denmark et al. used all possible combinations of methyl-substituted vinylogous ketene acetals with three different aldehydes under their catalytic condi-... 

Scheme 25 Vinylogous Mukaiyama aldol reaction of aldehyde 53 and ketene acetal 54 catalyzed by different Lewis acids...

Scheme 26 Vinylogous Mukaiyama aldol reaction using y-substituted ketene acetals...

With conditions that allow for the diastereoselective addition of y-substi-tuted vinylogous ketene acetals various aldehydes were tested. Compounds 66 and 68 exhibited very good syn (4/5) and Felkin (5/6) selectivity even though the chiral center at C3 would disfavor the Felkin product (Scheme 28). 

Catalytic, enantioselective addition of silyl ketene acetals to aldehydes has been carried out using a variant of bifunctional catalysis Lewis base activation of Lewis acids.145 The weakly acidic SiCU has been activated with a strongly basic phor-phoramide (the latter chiral), to form a chiral Lewis acid in situ. It has also been extended to vinylogous aldol reactions of silyl dienol ethers derived from esters. 

Hydrogen bond-promoted asymmetric aldol reactions and related processes represent an emerging facet of asymmetric proton-catalyzed reactions, with the first examples appearing in 2005. Nonetheless, given their importance, these reactions have been the subject of investigation in several laboratories, and numerous advances have already been recorded. The substrate scope of such reactions already encompasses the use of enamines, silyl ketene acetals and vinylogous silyl ketene acetals as nucleophiles, and nitrosobenzene and aldehydes as electrophiles. 

Anthraquinones. A regioselective synthesis of polyhydroxyanthraquinones is based on Diels-Alder reactions of 1 with chloro-substituted naphthoquinones. An example is the synthesis of 1,6-dihydroxyanthraquinone (3) from 3-chlorojuglone (2). Analogous syntheses are possible by use of vinylogous ketene acetals related to... 

In another example, a-bromo ketone (34) was used to alkylate the thioamide (33) in hopes of obtaining directly the vinylogous amide (35 Scheme 8). However, abstraction of an undesired proton in the a-thioiminium salt formed the S,N-ketene acetal as in a previously described example. This proposed intermediate then rearranged and dehydrated to produce the thiophene (36) as the major product. 

Warming the above a-thioiminium salt in the presence of the thiophile and base was critical in order to accomplish the sulfide-contraction process. At ambient temperature, work-up of the same reaction mixture produced the oxolactam analog of (102) as the major product (74%) along with a small amount (12%) of vinylogous carbamate (103). In order to better understand the underlying mechanism that prevailed under ambient versus elevated temperatures, NMR studies were conducted on the a-thioiminium salt (107). This intermediate, when dissolved in deuterated chloroform at ambient temperature in the presence of DBU, was converted immediately to a proposed S,N-ketene acetal (108 Scheme 23). Triphenylphosphine had no effect on the iminium salt. Aqueous work-up yielded the lactam (109), which is consistent with formation of the S,N-ketene acetal. However, wanning the intermediate (107) in the presence of the base and thiophile allowed the reaction to eventually proceed via the sulfur-extrusion pathway, due to the reversibility of the S,N-ketene acetal formation. 

Denmark SE, Heemstra JR (2006) Lewis base activatimi of Lewis acids. Vinylogous aldol addition reactions of conjugated N,0-silyl ketene acetals to aldehydes. J Am Chem Soc 128 1038-1039... 

The a,P-unsaturated esters 12 and 14, spirobislactone 16, and vinylogous lactone 18 are smoothly methylenated by Petasis reagent. Silyl esters 22 and 24 are converted to silyl enol ethers 23 and 25. Carbonate 20 can be methylenated to give ketene acetal 21. Amide 26 and lactams can be methylenated, however the reaction is generally sluggish and the complete separation of Ti species is usually difficult. In a similar manner, thioester 28 and selenoester 30 are converted to alkenyl sulphide 29 and alkenyl selenide 31, respectively. Additionally it has been demonstrated that acyl silanes can be converted to the corresponding alkenyl silanes. 

Brisson, C., and P. Brassard Regio-specific Reactions of some Vinylogous Ketene Acetals with Haloquinones and Their Regio-selective Formation by Dienolization. J. Org. Chem. 46, 1810 (1981). 

Different orbital coefficients and/or electrophilic susceptibility have been used to rationalize the fact that vinylogous ketene acetals unfold their nucleophilicity at the y-position... 

With respect to variation of the nucleophile component in the vinylogous aldol methodology, a,P-unsaturated amide-derived, conjugated N,0-sUyl ketene acetals could be employed under similar conditions as included in Scheme 7.8 [13]. 

This system based on the catalysis of 28 was extended to the development of vinylogous and bis-vinylogous Mukaiyama aldol reactions, which displayed good to excellent enantioselectivity and broad applicability with respect to sUyl ketene acetals of higher vinylogy (Scheme 7.54) [82]. 

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