A-Hydroxy ketones, protected

An interesting application of intermediates 214 is their reaction with protected a-hydroxy ketones 216 as electrophilic reagents. After final hydrolysis under acidic conditions (2 M HCl), the corresponding substituted 6,8-dioxabicyclo[3.2.1]-octanes 217 were obtained. Among them, frontalin (R = R = Me, R = R = H) and brevicomins (R = Me, R = H, R or R = Et) are particularly important because they are beetle... 

Enol ethers, and in particular silylated ends (see Volume 2, Chapter 2.3), react with peroxy acid reagents to give initially a silyloxy qpoxide, which rearranges with silyl migration to yield an a-silyloxy ketone, " as in Scheme 3. The net result is that a ketone is converted to a protected a-hydroxy ketone, and the stereochemistry b determined by the least hindered approach of the peroxy acid to the enol. 

Comparative examples of the Wittig reaction and the Peterson alkenation with ketones (353 equation 82) and (355 equation 83), epoxy ketones (351 equation 81), or protected a-hydroxy ketones (348 equation 80) have tqtpeared. The reactions can proceed with high kinetic control for the (Z)-isomer and, as a result, the Peterson technology may form complementary isomers to the Wittig reaction. ... 

The correlation of rate of addition with diastereoselectivity was demonstrated in a series of experiments that involved reacting Me2Mg with protected a-hydroxy-ketones. As the protecting group was changed from a methyl etherto a trimethylsilyl ether and then through a series of... 

It is also possible to oxygenate an enolate to give the corresponding acyloin (an a-hydroxy ketone) or alkoxy derivative. Reaction of an enolate anion with oxygen and trimethylphosphite [(MeO)3P], for example, gives an a-hydroxy derivative. 3 Reaction of an enol ether such as 105 with 3,3-dimethyldioxirane leads to the protected a-hydroxy ketone (106), in an example taken from Danishefsky s synthesis of myrocin An effective oxygenation reagent for enolate anions is MoOPh, and a typical use is taken from work by Vedejs to... 

Asymmetric reductions of a-fiinctionalized ketones, such as a-hydroxy ketones, a-halo ketones, a-sulfonoxy ketones, 1,2-diketones, a-keto acetals or thio ketals, acyl cyanides and a-amino or imino ketones with boron-based chiral reducing agents in a stoichiometric or catalytic manner have been reviewed. The oxazaborolidine-catalyzed borane reduction of protected a-hydroxy ketones, a-keto acetals and a-sulfonoxy ketones has been discussed in more detail. 

Protected a-hydroxy ketones. Enantiomerically pure terminal 1,2-diols are important synthetic intermediates for numerous applications (45, 46). We first... 

Figure 5. CBS reduction of THP-protected a-hydroxy ketones using...

Z-Trisubstituted allylic alcohols are obtained from protected a-hydroxy-ketones in a lithium-free Wittig reaction and 1-bromo-olefins (and hence acetylenes) are produced from the reaction of Ph3P=CHBr with aldehydes. References to two syntheses of substituted-allenes have appeared Ph3P=C(R )C02R and R R C=C=0 (generated in situ from the acid chloride... 

In a reaction sequence202 protected a-hydroxy sulphones were alkylated, after which acid hydrolysis followed by mild basic hydrolysis gave ketones. The protecting group used was the 1-ethoxyethyl ether, and overall yields for the sequence were generally modest (equation 89). 

Continuing with the diastereomerically pure tricycle 56, an 11-step sequence consisting of redox and protective group chemistry was necessary to generate a / -hydroxy keton (58) suitable for a retro-aldol addition via an intermediate alkoxide to the highly substituted cyclopentanone 52 (Scheme 6). 

Addition to a-aikoxy carbonyl compounds. n-Butylmagncsium bromide reacts stercosclcctivcly with protected, chiral a-hydroxy ketones. For example, reaction of the Grignard reagent with the MEM ether of 3-hydroxy-2-decanone in THF leads to the f/ireo-product [>95% isolated yield (equation I)]. The stereoselectivity is much lower when n-butyllilhium is used in addition the solvent plays an important role. Stereoselectivity is lower in C5H, 2, CH2CI2, and ether. A number of protective... 

The employment of trityl trifluoroborate is particularly interesting. This reagent is able to introduce trityl groups on both primary and secondary alcohols54 and to selectively oxidize secondary trityl ethers to ketones in the presence of primary trityl ethers.55 Thus, treatment of diols with trityl trifluoroborate leads to tritylation of both alcohols followed by oxidation of the secondary trityl ether, resulting in the formation of a ketone possessing a trityl-protected primary alcohol. A work-up by mild acidic hydrolysis provides the deprotection of the primary trityl ether and formation of a hydroxy ketone.54... 

These differences in the control of the product stereochemistry have recently been investigated by molecular modeling techniques [60,154], From these studies, the relevance of the side-chain of isoleucine 476 (PDCS.c.) (Table 2) for the stereo-control during the formation of aromatic a-hydroxy ketones became obvious, since this side-chain may protect one site of the ot-carbanion/enamine 6 (Scheme 3) against the bulky aromatic cosubstrate. Nevertheless, the smaller methyl group of acetaldehyde can bind to both sites of the a-carbanion/en-amine. The preference for one of the two acetoin enantiomers has been interpre-tated in terms of different Boltzmann distributions between the two binding modes of the bound acetaldehyde [155],... 

Spiroketalization. The synthesis of talaron ycin B (3) with four chiral centers by cyclization of an acyclic precursor presents stcrcot hcmical problems. A solution involves cyclization of a protected (3-hydroxy ketone witii only one chiral center. Because of thermodynamic considerations (i.e.. all substituents being equatorial and the anomcric effect), cyclization of 1 with HgCl, in CH,CN lollowcd by acetonation results in the desired product (2, 65% yield) with a stereoselectivity of —10 1. Final steps involve conversion of the hydroxymethyl group to ethyl by tosylation and displacement with lithium dimethylcupratc (80% yield) and hydrolysis of the acetonidc group. 

Few methods for the a-hydroxylation of aldehydes are available. This is a reflection of their notorious instability towards polymerization and rearrangement to a-hydroxy ketones. All the useful procedures generate protected a-hydroxy aldehydes. 

Enders and coworicers have shown that deprotonation of chiral SAMP/RAMP hydrazones (or their substituted analogs) derived from ketones or aldehydes, followed by reaction with Davis oxaziridine reagent provides the a-hydroxy hydrazones in moderate yield but with high diastereoselectivity. Direct unmasking or protection followed by unmasking provides the corresponding a-hydroxy ketones or aldehydes respectively (Scheme 24). Both antipodes of the hydroxylated compounds are available by appropriate choice of (5)- or (R)-proline-deiived auxiliaries. The direction of induction is predictable, if not wholly uniform (R substitution alters the a-stereochemistry for aldehyde hydrazones). The process clearly provides a valuable approach to both systems. 

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