Asymmetric hydroxymethylation

Chiral Bi(OTf)3-Catalyzed Asymmetric Hydroxymethylation in Aqueous Media. 3... 

Formaldehyde is one of the most important Cl electrophiles in organic synthesis. Whereas hydroxymethylation of enolate components with formaldehyde provides an efficient method to introduce a Cl functional group at the a-position of carbonyl groups, few successful examples of catalytic asymmetric hydroxymethylation have been reported (for other examples of asymmetric hydroxymethylation, see [30-33] for examples of catalytic asymmetric hydroxymethylation without using silicon enolates, see [32, 34, 35]). 

The same 43/water biphasic system efficiently works for the Michael addition of indoles to a,P-unsaturated enones, the Mannich reaction in its one-pot three-component version, the allyl stannylation of carbonyl compounds and the asymmetric hydroxymethylation of silylenolethers. The last reaction (Figure 45) is carried out in the presence of the chiral bipyridine 45. ... 

Catalytic asymmetric hydroxymethylation of silicon enolates nsing a ScCOTOj-S complex as the catalyst was achieved (Scheme 15.16). In this reaction, a commercial aqueous solution of formaldehyde can be used, and as a result, this process can be conducted very easily and safely. This new catalytic system provides not only a useful method to synthesize optically active [3-hydroxymethylated carbonyl compounds but also a guide to various kinds of catalytic asymmetric C-C bond-forming reactions in aqueous media. 

Scheme 25 Catalytic asymmetric hydroxymethylation of silicon enolates using a chiral scandium catalyst...

Chiral Lewis acid catalysis in aqueous media is known to be very difficult to attain, because most chiral Lewis acids are not stable in the presence of water, even using water-compatible Lewis acids. A breakthrough in this field has been reported in catalytic asymmetric hydroxymethylation in aqueous media [170]. It was found that a combination of Sc(OTf)3 and ligand (3) worked effectively in the reaction of a commercially available formaldehyde water solution with several types of silyl enol ethers (Scheme 12.74) [171]. 

Catalytic asymmetric hydroxymethylation of silicon enolates with an aqueous formaldehyde solution has been developed by Kobayashi et ah using a bismuth triflate associated with a chiral bipyridine in a DME/H2O mixture the reaction proceeded smoothly in the presence of 1 mol% catalyst to afford the hydroxymethylated adducts in high yields and 77-93% ee. Chiral anionic surfactants associated with Ga(OTf)3, Cu(OTf)2, or Sc(OTf)3 catalyzed Mukaiyama aldol reactions in water with moderate to good diastereo-and enantioselectivities. ... 

Fig. 4 shows c.d.-difference spectra that are due to the presence of a hydroxymethyl group in one member of the pair. The pairs of pyranoses have the same conflguration about each asymmetric carbon atom that is part of the ring. Three related pairs have the same conflguration at the carbon atoms near the hydroxymethyl group and give very similar difference spectra. The similarity indicates that the rotameric distribution for the hydroxymethyl group is similar for each of these pairs. This is to be expected, as all three sugars have 4-hydroxyl groups oriented equatorially, but the relationship is certainly not obvious from the c.d. spectra themselves (see Fig. 3). In contrast, when the conflguration near the hydroxymethyl group...

T. Shioiri, A. Bohsako, A. Ando, Importance of the Hydroxymethyl-quinudidine Fragment in the Catalytic Asymmetric Adol Readions Utilizing Quaternary Ammonium Fluorides derived from Cinchona Akaloids , Heterocycles 1996, 42, 93-97. 

Hydroxymethylation. The reagent undergoes asymmetric conjugate addition to tolylsulfinylcycloalkenones such as 2. The product after reductive desulfinylation (3) and hydrogenolysis furnishes (S)-( - )-3-hydroxymethylcycloalkanones (4) in high enantiomeric purity. 

Table 2) [43], The hydroxymethylation proceeded smoothly using an aqueous formaldehyde solution to afford the desired adducts in high yields with high enantioselectivities. It is noteworthy that asymmetric quaternary carbons were constructed with high selectivities. 

ASYMMETRIC SYNTHESIS OF (M)-2-HYDROXYMETHYL-1-(2-HYDROXY-4,6-DIMETHYLPHENYL)NAPHTHALENE VIA A CONFIGURATIONALLY UNSTABLE... 

Shi and coworkers developed a method using silyl enol ethers and in situ generated chiral dioxirane derivatives. Lopp and coworkers could develop an asymmetric dihydroxy lation method for racemic 2-hydroxymethyl ketones 202a-c, using TBHP as oxygen source in combination with the Sharpless catalytic system Ti(OPr-i)4/DET, yielding... 

SCHEME 132. Direct asymmetric a-hydroxylation of 2-hydroxymethyl ketones... 

Polymer-linked tartrate esters have been prepared and used for asymmetric epoxidation in efforts to simplify reaction workup procedures and to allow recycling of the chiral tartrate [21]. The tartrates were linked through an ester bond to either a hydroxymethyl or a hydroxyethyl group on the polymer backbone to form 4 and 5, respectively. 

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