Benzyloxyacetaldehyde

In a total synthesis of the macrolidc antibiotic cytovaricin, the highly stereoselective addition of (47 ,5iS )-4-methyl-3-(1 -oxopropyl)-5-phenyl-1,3-oxazolidin-2-one to benzyloxyacetaldehyde is one of the key steps giving the adduct which serves as the C, —Cfi unit in the target molecule95 ... 

Finally, the necessity arose for the synthesis of pentulose 21, labeled with, 3C on the central carbons, C-2 and C-3, for an independent biosynthetic study, which is reported in Section III.5.27 The doubly labeled ester 34 (Scheme 14) is readily available by a Wittig- Homer condensation of benzyloxyacetaldehyde with commercially available triethylphosphono-(l,2-l3C2)acetate. Chirality was introduced by the reduction of ester 34 to the allylic alcohol, which produced the chiral epoxide 35 by the Sharpless epoxidation procedure. This was converted into the tetrose 36, and thence, into the protected pentulose 37 by the usual sequence of Grignard reaction and oxidation. 

The adduct derived from (a-benzyloxyacetaldehyde (97 % ee) is an important intermediate en route to compactin and mevinolin [76]. In contrast, modest enantioselectivity was attained when the cycloadditions were catalyzed by a chiral BINOL-ytterbium-derived catalyst [77]. Pyridines were used as additives, and the best enantioselection (93% ee) was attained only in the case of p-methoxybenzaldehyde using 2,6-lutidine. 

This and similar catalysts are effective with silyl ketene acetals and silyl thioketene acetals.155 One of the examples is the tridentate pyridine-BOX-type catalyst 18. The reactivity of this catalyst has been explored using a- and (3-oxy substituted aldehydes.154 a-Benzyloxyacetaldehyde was highly enantioselective and the a-trimethylsilyoxy derivative was weakly so (56% e.e.). Nonchelating aldehydes such as benzaldehyde and 3-phenylpropanal gave racemic product. 3-Benzyloxypropanal also gave racemic product, indicating that the (i-oxy aldehydes do not chelate with this catalyst. 

The efficiency of catalysts 86-89 for the asymmetric aldol reaction of a series of nucleophiles toward benzyloxyacetaldehyde was studied. For example, compound 89c was found to be an excellent catalyst for the asymmetric aldol reaction of silylketene acetal derivatives of t-butyl thioacetate, ethyl thioacetate, and ethyl acetate with benzyloxyacetaldehyde. In the presence of 0.5 mol% of the catalyst, the asymmetric aldol reaction took place at —78°C in CH2C12, affording the respective /i-hydroxy esters with excellent enantioselectivity (Scheme 3-32). 

Figure 27. X-ray crystal structure of 274d benzyloxyacetaldehyde complex. [Adapted from (233).]...

Benzyloxyacetaldehyde Acetaldehyde, (phenylmethoxy)- (9) (60656-87-3) Allyltributylstannane Stannane, allyltributyl- (8) Stannane, tributyl-2-propenyl- (9) (24850-33-7)... 

Benzyloxyacetaldehyde is purchased from the Aldrich Chemical Company Inc., and distilled under vacuum before use. 

Ethoxy-3-methoxybenzyl alcohol 6, 2-(2-methoxyphenoxy)ethanol 8 and 1,3-dihydroxy-2-(2-methoxyphenoxy)propane 13 were formed from the B-0-4 dimer 1 in intact cultures, but not identified in the in vitro system. They axe probably formed secondeirily by reduction of initial cleavage products formed by the enzyme. In fact, this fungus reduces 4-ethoxy-3-methoxybenzaldehyde 7 and 2-benzyloxyacetaldehyde to the corresponding alcohols, il-ethoxy-3-methoxybenzyl alcohol 6 and a compound similar to 8, 2-benzyloxyethanol, respectively (23). 

Reactions of the same carbonyl ylide intermediate with aldehydes are even more fruitful. The Rh2(OAc)2 catalyzed reaction proceeds at room temperature in the presence of 2 mol% of the catalyst, but the diastereoselectivity is disappointingly low (endo/exo = 49 51, Scheme 11.56). However, when 10 mol% of the cocatalyst Yb(OTf)3 is added, the reaction becomes highly exo-selective (endo/ exo = 3 97) (198). Suga has extended this Lewis acid catalyzed carbonyl ylide cycloaddition reaction to catalyzed asymmetric versions. The chiral cocatalyst employed is ytterbium(III) tris(5)-1,1 -binaphthyl-2,2 -diyl phosphonate, Yb[(S) BNP]3 (10 mol%). In the reaction of methyl o-(diazoacetyl)benzoate with benzyloxyacetaldehyde in the presence of Rh2(OAc)2 (2 mol%) at room temperature with the chiral Yb catalyst, the diastereoselectivity is low (endo/exo = 57 43) and the enantiopurity of the endo-cycloadduct is 52% ee. 

Mukiayama aldol reactions between silyl enol ethers and various carbonyl containing compounds is yet another reaction whose stereochemical outcome can be influenced by the presence of bis(oxazoline)-metal complexes. Evans has carried out a great deal of the work in this area. In 1996, Evans and coworkers reported the copper(II)- and zinc(II)-py-box (la-c) catalyzed aldol condensation between benzyloxyacetaldehyde 146 and the trimethylsilyl enol ether [(l-ferf-butylthio)vinyl]oxy trimethylsilane I47. b82,85 Complete conversion to aldol adduct 148 was achieved with enantiomeric excesses up to 96% [using copper(II) triflate]. The use of zinc as the coordination metal led to consistently lower selectivities and longer reaction times, as shown in Table 9.25 (Eig. 9.46). 

TABLE 9.25. MUKAIYAMA ALDOL REACTION OF BENZYLOXYACETALDEHYDE AND A TRIMETHYLSILYL ENOL ETHER"... 

The ether extract is washed thoroughly with sodium bicarbonate solution, the solvent evaporated, and the residue distilled in vacuum. The benzyloxyacetaldehyde thus obtained boils at 115°/15 mm. 

Patulin 36 has been synthesized in six steps (41.3% overall yield) starting with 35 and benzyloxyacetaldehyd <95TL7175>. 

The synthetic utility of this methodology was demonstrated in the asymmetric construction of the C3-C14 segment of antitumor macrolide laulimalide (50).18 Using Cu(OTf)2-ent-2 as catalyst, Danishefsky s diene reacted with benzyloxyacetaldehyde 51 to provide cycloadduct 52 in 76% yield and 85% ee. Standard synthetic manipulations on dihydropyran 52 led to the C3-C14 segment 49 of laulimalide (Scheme 17.16). 

Mandal completed the total synthesis of (—)-ebelactone A (9), which is an inhibitor of esterases, lipases, and N-formylmelhionine aminopeptidases located on the cellular membrane of various cell strains3 (Scheme 4.2d). The synthesis began with Evans s yyn-aldol reaction between A-propionyloxazolidinone (10) and benzyloxyacetaldehyde to afford the vyn-aldol adduct 11 in 95%... 

Gel emulsions were applied successfully for the first time in aldol additions of DHAP to phenylacetaldehyde and benzyloxyacetaldehyde as model aldehydes catalyzed by RAMA [24]. The first interesting observation was that the stability of RAMA in water-in-oil gel emulsions improved by 25-fold compared to that in dimethylformamide/water l/4v/v co-solvent mixture. The reported experimental data concluded that both the highest enzymatic activities and equilibrium yields were observed in water-in-oil gel emulsion systems with the lowest water-oil interfacial tension attained with the most hydrophobic oil component (i.e. tetradecane, hexadecane, and squalane). 

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