Aldol boron Lewis acids promoted

In sharp contrast to the utility of chiral boron Lewis acids, chiral aluminum Lewis acids have been little used for asymmetric aldol reactions of silyl enolates since the first example reported by Reetz et al. [115]. Fujisawa et al. have reported that an equimolar amount of a chiral Lewis acid prepared from Et2AlCl and a bor-nane-2,3-diol promotes the aldol reaction of 48 in moderate yields with good enantioselectivity [127]. 

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. 

Conjugate addition reactions, including the Robinson annulation, which make use of reactive Michael acceptors such as methyl vinyl ketone, can suffer from low yields of the desired adduct. The basic conditions required for enolate formation can cause polymerization of the vinyl ketone. Further difficulties arise from the fact that the Michael adduct 42 and the original cyclohexanone have similar acidities and reactivities, such that competitive reaction of the product with the vinyl ketone can ensue. These problems can be minimized by the use of acidic conditions. Sulfuric acid is known to promote the conjugate addition and intramolecular aldol reaction of 2-methylcyclohexanone and methyl vinyl ketone in 55% yield. Alternatively, a silyl enol ether can be prepared from the ketone and treated with methyl vinyl ketone in the presence of a Lewis acid such as a lanthanide triflate" or boron tri fluoride etherate (BF3 OEt2) and a proton source to effect the conjugate addition (followed by base-promoted aldol closure). 

In this context, lipshutz et al. reported in 2000 a catalytic reductive aldol reaction of enones and aldehydes with [PhsPCuHjs (5 mol%) and PhMe2SiH (150mol%) [46]. The two-step reaction was carried out in one pot, without isolation of the intermediate sUyl enol ethers, efficiently providing the b-hydroxyketones in high yield. Lewis acids such as BF3 or TiCLj are used to promote the second step involving aldol reaction of the enol silane. In place of hydrosilanes, dialkylboranes could be employed as hydride sources, circumventing the need to introduce additional Lewis acids. Here, the aldol products are formed via intermediacy of the boron-enolates, with 5y -selectively for acychc enones and antz-selectively for cycHc enones [47-50]. 

The use of Lewis acids in MBH reactions at lower temperature in the presence of an additive furnishes either halo aldol " or halo methyl enone " as the major product while, at room temperature, the formation of the usual MBH adduct has also been reported. " However, recently, Iwamura et al " have reported the formation of a hemiacetal through aqueous workup during a boron tribromide promoted MBH reaction of p-nitrobenzaldehyde with cyclohexenone. In an earlier observation, Li et al. " reported the formation of an unidentified side product (10%) in the TiC -mediated MBH reaction of p-nitrobenzaldehyde with a,p-cycloalkenone. 

In 1993, a tris(pentafluorophenyl)boron was first recognized by Yamamoto and co-workers as a water-tolerant Lewis acid catalyst in the aldol reaction of silyl enol ethers (237). Subsequently, Kobayashi and co-workers developed the first strategy for catalytic generation of boron enolates, employing catalytic amount of diphenylborinic acid (Ph2BOH) to promote the Mukaiyama aldol reaction in the presence of sodium dodecyl sulfate (SDS) (Scheme 59). The authors presumed that the active species of the reactions are boron enolates. Perhaps it is the first example of catalytic use of a boron source in boron enolatemediated diastereoselective aldol reactions (238). 

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). ... 

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