Boron Trifluoride Etherate aldol reactions

For a 0.20 mmol scale reaction Boron trifluoride etherate (1.2 equiv.) is added to a solution of the aldehyde (purified according to literature, " 2.0 equiv.) in diethyl ether (0.82 mL) at room temperature. After 30 s, the solution is added dropwise over 1-2 min to a cooled (-78 °C) solution of the silyl enol ether (1.0 equiv.) in CH2CI2 (1.23 mL, 2 1). The reaction mixture is maintained at this temperature until the reaction is complete (TLC). Upon completion of the reaction, EtsN (3.0 equiv.) is added, the reaction mixture stirred for 1-2 min, and then filtered through a pad of Celite washing the residues with CH2CI2 (100 mL). Concentration of the filtrate in vacuo affords a crude mixture of silylated and nonsilylated aldol products. The crude product is dissolved in THF (0.5 mL) and then treated with HF-pyridine (0.5 mL of a 2.25 mol L" solution in THF) at room temperature. After 30 min, the reaction mixture is poured into sodium hydrogen carbonate solution-Et20 (5 mL, 1 1). The layers are separated and the aqueous phase extracted with... 

A Mukaiyama-type aldol reaction of silyl ketene thioacetal (48) with an aldehyde with large and small a-substituents (e.g. Ph and Me), catalysed by boron trifluoride etherate, gives mainly the iyn-isomer (49), i.e. Cram selectivity. For the example given, changing R from SiBu Me2 to Si(Pr )3 raises the syn preference considerably, which the authors refer to as the triisopropylsilyl effect. Even when the and R groups are as similar as ethyl and methyl, a syn. anti ratio of 5.4 was achieved using the triisopropylsilyl ketene thioacetal. 

Allyltributyltin, 10 Boron trifluoride etherate, 43 Di-jjL-carbonylhexacarbonyldicobalt, 99 Grignard reagents, 138 Ketenylidenetriphenvlphosphorane, 154 Methoxyamine, 177 Reformatsky reagent, 346 Tin(IV) chloride, 300 Tributylcrotyltin, 10 Aldol reactions General considerations, 202 Directed aldols using imines Norephedrine, 200... 

Asymmetric induction in the aldol reaction of enolsilane and metal enolate nucleophiles with yS-substituted aldehydes gives rise to both excellent yields and good diastereoselectivities (equation 128)507. The best diastereoselectivity was obtained using a trimethylsilyl enolate in the presence of boron trifluoride-etherate (92 8 anti. syn). The key step in the synthesis of the N-terminal amino acid analogue of nikkomycin B and Bx (nucleoside peptide antibiotics) has been performed using this type of methodology508. 

This procedure illustrates a general method for the preparation of crossed aldols. The aldol reaction between various silyl enol ethers and carbonyl compounds proceeds smoothly according to the same procedure (see Table I). Sllyl enol ethers react with aldehydes at -78°C, and with ketones near 0°C. Note that the aldol reaction of sllyl enol ethers with ketones affords good yields of crossed aldols which are generally difficult to prepare using lithium or boron enolates. Lewis acids such as tin tetrachloride and boron trifluoride etherate also promote the reaction however, titanium tetrachloride is generally the most effective catalyst. 

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... 

Barton oxidation was the key to form the 1,2-diketone 341 in surprisingly high yield, in order to close the five-membered ring (Scheme 38). The conditions chosen for the deprotection of the aldehyde, mercuric oxide and boron trifluoride etherate, at room temperature, immediately led to aldol 342. After protection of the newly formed secondary alcohol as a benzoate, the diketone was fragmented quantitatively with excess sodium hypochlorite. Cyclization of the generated diacid 343 to the desired dilactone 344 proved very difficult. After a variety of methods failed, the use of lead tetraacetate (203), precedented by work performed within the stmcmre determination of picrotoxinin (1), was spectacularly successful (204). In 99% yield, the simultaneous formation of both lactones was achieved. EIcb reaction with an excess of tertiary amine removed the benzoate of 344 and the double bond formed was epoxidized with peracid affording p-oxirane 104 stereoselectively. Treatment of... 

Anions formed from group 6 and manganese Fischer carbene complexes undergo aldol condensations with aldehydes and ketones. Allylic carbenes exclusively react in the y position with aldehydes affording dienyl-substituted carbenes. For alkoxy-substituted carbenes, the presence of an excess Lewis acid see Lewis Acids Bases), such as boron trifluoride etherate, titanium tetrachloride, or tin tetrachloride is required for the reaction to proceed in reasonable yield. The initial aldol product can be isolated without elimination (Scheme 12). ... 

The isolation of the initial aldol products from the condensation of the enolates of carbene complexes and carbonyl compounds is possible if the carbonyl compound is pretreated with a Lewis acid. As indicated in equation (9), the scope of the aldol reaction can also be extended to ketones and enolizable aldehydes by this procedure. The condensations with ketones were most successful when boron trifluoride etherate was employed, and for aldehydes, the Lewis acid of choice is titanium tetrachloride. The carbonyl compound is pretreated with a stoichiometric amount of the Lewis acid and to this is added a solution of the anion generated from the caibene complex. An excess of the carbonyl-Lewis acid complex (2-10 equiv.) is employed however, above 2 equiv. only small improvements in the overall yield are realized. 

The reduction of 569e with lithium aluminum hydride followed by monoprotection with er -butyldimethylsilyl chloride and Dess-Martin oxidation of the free hydroxyl group to an aldehyde affords 610. An aldol reaction of 610 with ( S)-(y-alkoxyallyl)stannane (611) in the presence of boron trifluoride etherate provides exculsively, in 80% yield, the alcohol 612. Ozonolysis of the olefin followed by sodium borohydride reduction affords diol 613, which is converted to acetonide 614 (Scheme 135). Interestingly, alcohol 612, the double bond of which is susceptible to stereocontrolled introduction of hydroxyl groups, could lead to o)-deoxy sugars [197]. 

Boron trifluoride is a highly moisture-sensitive gas (31). It is utilized in esterification, ether formation, Friedel-Crafts alkylation and acylation, and Lewis acid-catalyzed Diels-Alder reactions. A more widely used, easy-to-handle and convenient liquid source of BF3 is boron trifluoride etherate [BF3-0(C2H5)2] (32). Its main usage as catalyst is in the direct esterification of all types of acids, rearrangements, aldol condensation, and Lewis acid-catalyzed Diels-Alder reactions. It is the most frequently used acid in epoxide ring opening and rearrangement (33). 

Kopecky and Rychnovsky also targeted leucascandrolide A to demonstrate their Mukaiyama Aldol-Prins (MAP) method (Scheme 38) [78]. The MAP reaction generates an oxocarbenium intermediate from an enol ether and an aldehyde, which is capable of imdergoing a Prins cyclization with the pendant allylsilane. Aldehyde 278 (from Scheme 73, Eq. 1) in the presence of enol ether 142 and boron trifluoride etherate underwent the MAP cascade without incident. The reaction mixture was treated with sodium borohydride to reduce any of the unreacted aldehyde and simplify purification. Desired alcohol 143 was then isolated in 78 % yield as a 5.5 1 mixture of diastereomers. 

TiCU is a powerful activator of carbonyl groups and promotes nucleophilic attack by a silyl enol ether. The product is a titanium salt of an aldol which, on hydrolysis, yields a p-hydroxy ketone. TiCU is generally the best catalyst for this reaction. The temperature range for reactions with ketones is normally 0-20 °C aldehydes react even at —78 °C, which allows for chemoselec-tivity (eq 9). In a- or p-alkoxy aldehydes, the aldol reaction can proceed with high 1,2- or 1,3-asymmetric induction. With the nonchelating Lewis acid Boron Trifluoride Etherate, the diastere-oselectivity may be opposite to that obtained for the chelating TiCU or Tin(IV) Chloride (eq 10). ... 

The influence of Lewis acids on the diastereoselectivity of the cycloaddition of /f-alkoxyalde-hydes has also been studied35. Magnesium bromide, highly effective for a-alkoxyaldehydes, fails in the case of the cycloaddition of aldehyde 10 to diene 2 and the reaction does not exhibit any selectivity, probably due to a change of mechanism to Mukaiyama s aldol type. One reason may be the change of solvent from tetrahydrofuran to a mixture of benzene and diethyl ether. The additions of aldehyde 10 to other dienes are more selective but diastereoselectivity is still much lower than for the a-alkoxy aldehydes. Boron trifluoride-diethyl etherate complex also leads to a mixture of four possible products. Excellent selectivity is achieved for the titanium(IV) chloride catalyzed addition of aldehyde 10a to diene 2b, 11c is obtained as the only product. 

Attention now turned to the aldol reaction of methyl ketone 27 with chiral aldehyde 9d. Motivated by our previous success with a Mukaiyama aldol reaction (see Section 2.3), we aimed to employ an analogous procedure with methyl ketone 27. Formation of silyl enol ether 37 was achieved by treatment with tri-methylsilyl triflate and triethylamine. The Lewis acid-mediated aldol reaction proceeded smoothly once more, although full conversion to aldol 26 could not be attained. Reaction of 37 with aldehyde 9d at -78 °C in the presence of boron trifluoride diethyl etherate provided aldol 26 in 58% yield over two steps together with 38% recovered methyl ketone 27 (Scheme 12). In an effort to improve the yield, the reaction time was extended to 3 h. Interestingly, this did not result in any significant increase in the yield of aldol 26 (56% yield). 

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