Hydroxyacetone, synthesis

Using (31) as the nucleophile, FSA has been shown to accept several aldehydes as acceptor components for preparative synthesis [91]. In addition to (31), it also utilizes hydroxyacetone as an alternative donor to generate 1-deoxysugars such as (66) regioselectively (Figure 10.25). 

Figure 10.25 Inverted approach for aldose synthesis using FruA catalysis, and application ofthe strategy for deoxysugar synthesis based on a phosphorothioate analog synthesis of 1-deoxysugars by FSA catalyzed addition of hydroxyacetone.

Using a similar strategy, Wong et al. have also reported the synthesis of several iminocyclitols [52]. These authors use 2-azido aldehydes as acceptor to prepare five-membered iminocyclitols and N-Cbz-3-amino aldehydes to prepare six-membered iminocyclitols. Taking advantage of the donor tolerance of FSA, they also employ hydroxyacetone and l-hydroxy-2-butanone to obtain several known and novel iminocyclitols. 

A small amount of the previously unknown p-hydroxyphenyl-co-hydroxyacetone (XX), obviously derived from p-hydroxyphenylglycerol 0-aryl ether elements, was also isolated from fraction A, and its structure was established by synthesis 26). 

Another Ru(BINAP)-catalyzed asymmetric hydrogenation that has been performed at manufacturing scale involves the reduction of a functionalized ketone. The reduction of hydroxyacetone catalyzed by [NH2Et2]+[ RuCl(p-tol-BINAP) 2 (li-CI)3 (39) proceeds in 94% ee (Scheme 12.11).46 The chiral diol (40) is incorporated into the synthesis of levofloxacin (41), a quinolinecarboxylic acid that exhibits marked antibacterial activity. Current production of 40 is 40 tons per year by Takasago International Corp.46... 

It turns out that one of the best ketones for these asymmetric crossed aldol reactions is hydroxy-acetone 96. Combination with isobutyraldehyde 89 gives an aldol that is also an anti-diol 97 with almost perfect selectivity.21 The proline enamine of hydroxyacetone is evidently formed preferentially on the hydroxy side. You will recall from chapter 25 that asymmetric synthesis of anti-diols is not as easy as that of syn diols. 

An a-hydroxyacetone oxime anchor (Figure 19.11) has been developed by Haner and coworkers [273] for the phosphoramidite RNA synthesis. The 2 -protected oligoribonucleotides are detached from the respective macroporous polystyrene support (initial loading 30junolg 1) as the 3 -phosphates during 30min of concentrated aqueous ammonia-ethanolic methylamine (1 1 v/v) treatment at 65 °C. The authors have postulated [3-elimination with the formation of 2-nitrosopropene as a plausible mechanism for 3 -phosphate liberation. 

Replacement of side chain carbon C21 by thioester sulfur retains corticoid activity and at the same time provides a function that is destroyed by serum enzymes. The synthesis starts with the potent antiallergic agent flumethasone (32-1). Reaction of that steroid with periodic acid cleaves the terminal bond in the hydroxyacetone side chain to give the hydroxyl acid 32-2 (Scheme 7.32). Steric hindrance around the acid invoke the need for extra activation of that function. Reaction of 32-2 with diphenyl chlorophosphate thus provides the mixed anhydride 32-3. This intermediate is not isolated but reacted in situ with AA -thioformamido chloride. The transient new mixed anhydride, 32.4, then undergoes an internal O to S rearrangement to give the acyl thioacid 32-5. Saponification with sodium hydroxide affords the corresponding thioacid. Alkylation of that intermediate with fluoromethyl bromide then yields the fluoromethyl thioester fluticasone (32-6). 

A three-component Mannich reaction between p-methoxybenzaldehyde (116), hydroxyacetone (117), and 102 was used successfully to buUd up the two consecutive stereogenic centers of 118, an intermediate in the synthesis of (+)-epi-cytoxazone (119), as shown by Sudalai et al. (99) (Scheme 27). Cytotoxazone was isolated from Streptomyces sp. and is a potent inhibitor of the signaling... 

A soln. of methylcyanamide in tetrahydrofuran dil. with an equal amount of water, stirred, treated with hydroxyacetone followed by dropwise addition of aq. 2 N NaOH whereupon the temp, rises to 40-45°, and stirring continued 2 hrs. 4-methyl-2-methylaminooxazole. Y 65%. F. e. s. A. F. Cockerill et al.. Synthesis 797(5, 591. 

The exceptionally high stereoselectivity found in proline-catalyzed aldol reactions involving hydroxyacetone has recently been used in a total synthesis of brassinolide (156), a steroidal plant-growth regulator [128]. Readily available aldehyde 151 underwent proline-catalyzed aldolization with hy-... 

The fructose 6-phosphate aldolase (ESA) from E. coli is a novel class I aldolase that catalyzes the reversible formation of fructose 6-phosphate from dihydroxyacetone and o-glyceraldehyde 3-phosphate it is, therefore, functionally related to transaldolases [245]. Recent determination of the crystal structure of the enzyme sho ved that it also shares the mechanistic machinery [246]. The enzyme has been sho vn to accept several aldehydes as acceptor components for preparative synthesis. In addition to dihydroxyacetone it also utilizes hydroxyacetone as an alternative donor to generate 1-deoxysugars, for example 118, regioselectively (Eigure 5.52) [247]. 

Other syntheses of natural products have capitalized on the 38C2-catalyzed aldol addition of hydroxyacetone to install 1,2-syn-diol functionality. Aldolase antibody 38C2 was also used for synthesis of brevicomins 59-61 (Scheme 6.7) [23] and 1-deoxy-L-xylulose (62) (Scheme 6.8) [24]. Antibody 38C2-catalyzed kinetic resolution of a tertiary aldol was used for the synthesis of (+)-frontalin (63) (Scheme 6.9) [10]. 

The Mannich reaction is an excellent method for the synthesis of P-amino carbonyl compounds and their derivatives, and unmodified primary amino acids were found to be enormously useful for this important reaction. Cdrdova et al. [42] reported the first primary amino acid-promoted three-component Mannich reaction of ketone, p-anisidine, and aldehydes primary amino acids, such as L-alanine and L-vahne, were excellent catalysts and led to the formation of Mannich products with up to >99% ee. Barbas and coworkers [31] also showed L-tryptophan catalyzed the direct threeMannich reaction of hydroxyacetone, p-anisidine, and aromatic aldehydes good yields, high diastereoselectivity, and excellent ee were attainable. 

The simple primary-tertiary diamine salts can be successfully applied in the aldol reactions of a-hydroxyketones with good activity and excellent stereoselectivity. Notably, the catalyst enabled the reaction of dihydroxyacetone (DHA), a versatile C3-building block in the chemical and enzymatic synthesis of carbonhydrates. By employing either free or protected DHA, syn- or anh-diols could be selectively formed with excellent enantioselectivity (Scheme 5.7). Since enantiomers of diamine 26 and 29 are readily available, this class of chiral primary amine catalysts thus functionally mimics four types of DHA aldolases in nature [17b]. Later, simple chiral primary-tertiary diamine 27 derived from amino acid was also found to be a viable catalyst for the iyn-selective aldol reactions of hydroxyacetone and free DHA (Scheme 5.7) [18]. 

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