A-benzyloxyacetaldehyde

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. 

An enantioselective process which provides a powerful illustration of this phenomena has been documented by Evans (Scheme 11) [24]. In this work, the addition of enol silanes 79 to a-benzyloxyacetaldehyde is catalyzed by the optically active Cu(ll) bis(oxazoline) complex 80, furnishing adducts 82 in excellent... 

Accordingly, the Evans protocol, when applied to A-propionyl oxazolidinone 51 derived from ephedrine, leads to the predominant formation of the diastere-omeric syw-aldols, again with outstanding stereoselectivity. In this case, the enolate attacks the Re-hce of aldehydes with high preference. The procedure is illustrated in Scheme 4.48 for an aldol addition to a-benzyloxyacetaldehyde yielding the crude product 213 in a diastereomeric ratio of higher than 99 1. After recrystallization, the stereochemically homogeneous aldol adduct 213 was transformed into the Weinreb amide 214 in the course of a total synthesis of the macrolide antibiotic cytovaricin. In the transamination step, the chiral auxiliary 46 was recovered [111]. 

The reaction was intensively studied for a-benzyloxyacetaldehyde 219a. When catalyzed by the PYBOX complex 217, various silyl ketene (O and S) acetals 220 give acetate aldol adducts 221 in high chemical yields and enantioselectiv-ity, as shown in Scheme 5.67. Compared with many protocols for asymmetric Mukaiyama reactions, the low catalyst loading (as little as 0.5 mol%) is remarkable. PYBOX catalysis is also an efficient tool for vinylogous Mukaiyama aldol additions, as illustrated also in Scheme 5.67 for acetoacetate-derived silicon enolate... 

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 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). 

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). 

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"... 

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%... 

Cordova and co-workers have studied the double aldol reaction of benzyloxyacetaldehyde using various a-aminoacids as catalysts. With L-proline and hydroxy-L-proline a tetrose and the L-allose derivative 33 were obtained in 41 and 28% yield, respectively, and with an enantiomeric excess higher than 98% (O Scheme 26). As expected, with D-proline as catalyst, the corresponding D-allose derivative was obtained with the same ease in a one-pot operation [151]. 

In addition to processes involving thioacetate aldols, Mikami has studied the aldol addition reaction of thiopropionate-derived enolsilanes 58, 59 (Eq. (8.14)). The Z-enol silane derived from terr-butyl thiopropionate undergoes addition to benzyloxyacetaldehyde to give products as a 92 8 anti syn mixture of diastereo-mers with the major anti stereoisomer 61 isolated in 90% ee. The additions of E... 

Ketene and aldehydes undergo [2+2] cycloaddition in the presence of aluminum catalysts (Scheme 6.56). The reaction involves either isolable or in situ-generated unstable ketenes and is regarded as a variant of the aldol reaction. During the development of the Al(l I l)-calalyzed ketene-aldehyde reaction, the optically active Al(in)-triamine complex 88 was found to catalyze the cyclocondensation of acetyl bromide (AcBr) and benzyloxyacetaldehyde, with di(isopropyl)ethylamine (DIEA)... 

Our first approach, which looked very attractive, was based on a catalytic asymmetric hetero Diels-Alder reaction between butadiene and trityloxyacetaldehyde (Fig. 3). This reaction would have been highly atom economic, and if it could be done with a chiral catalyst, would lead directly to 2-(S)-trityloxymethyl-3,6-dihydro-2H-pyran 6 (Fig. 4) that could be used to make 1. There is a precedent in the literature for such a hetero Diels-Alder reaction, where benzyloxyacetaldehyde reacts... 

An enantioselective version of the above reactions has been reported. Lewis acids such as Yb(OTf)3 can profoundly affect the stereochemical outcome of the carbonyl ylide 1,3-dipolar cycloadditions [137]. This provided an indication to effect asymmetric carbonyl ylide cycloaddition using a chiral Lewis acid. The first example of such asymmetric induction using the chiral lanthanide catalysts has been reported [138,139]. For example, the reaction of diazoacetophenone 89 with benzyloxyacetaldehyde, benzyl pyruvate and 3-acryloyl-2-oxazoHdinone in the presence of chiral 2,6-bis(oxazolinyl)pyridine ligands and scandium or ytterbium complexes furnished the corresponding cycloadducts 165-167 with high enantioselectivity (Scheme 53). 

More efficient in terms of the number of steps (six) and overall yield (41%) was a later synthesis from Boukouvalas and co-workers (Scheme 7.2) (302). Bis-silyl-protected 3-hydroxymethyl 2,4-dihydrofuran-2-one (359) was selectively deprotected/condensed with benzyloxyacetaldehyde to give the alcohol, which was protected as a pivalate ester and subjected to selective desilylation then TEMPO-mediated oxidation. The resulting aldehyde 361 was then cyclized with a Lewis acid. Elimination of pivalic acid from ester 362 gave mainly the desired ylidenebutenolide regioisomer and the natural product (348). 

A second example is presented in Scheme 9.50, where the dihexafluoroanti-monate [2 (SbFg) ] complex with (5,5)-diphenyl[bis(oxazolinyl)pyridine]Cu(II) is seen to coordinate with benzyloxyacetaldehyde (2-benzyloxyethanal,... 

Thus, the vinylogons aldol is no exception, and, as shown in Scheme 9.51, use of the same oxazoline-derived catalyst and the same benzyloxyacetaldehyde (2-benzyloxyethanal, C6H5CH2OCH2CHO) on l-methoxy-l,3-bis(trimethylsilyloxy)-1,3-butadiene results in a 97% yield (of a 15 1 mixture of anti.syn) of vinylogous aldol products (after hydrolysis). 

Scheme 9.50. A representation of the reaction (in the direction shown by the arrow) between dihexafluoroantimonate [2 (SbFe) ] (5, 5 )-diphenyl[bis(oxazolinyl)pyridine]Cu(II) with benzyloxyacetaldehyde (2-benzyloxyethanal [CeHsCH20CH2CH0]) (after Evans, D. A. Kozlowski, M. C. Murry, J. A. Burgey, C. S. Campos, K. R. Connell, B. T. Staples, R. J. 7. Am. Chem. Soc., 1999,121, 669).

Scheme 9.51. The result of the copper-oxazohne-derived catalyst to promote the reaction between 2-benzyloxyacetaldehyde (2-benzyloxyethanal, C6HSCH2OCH2CHO) and l-methoxy-l,3-bis(trimethylsilyloxy)-13-butadiene. The reaction results in a 97% yield of methyl (35, 55 )-6-benzyloxy-3,5-dihydroxyhexanoate, the vinylogous aldol product (after hydrolysis). See Evans,D. Woerpel,K.A. Scott,M. I.ylngeH. Chem. Int. (i., 1992,57,430.

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