Aldehydes, p-alkoxy

The stereoselectivity of aldol addition is also affected by chelation.81 a- and P-Alkoxy aldehydes can react through chelated structures with Li+ and other Lewis acids that can accommodate two donor groups. 

The sterochemistry of additions of allyltri-n-butyltin (1) and crotyltri-n-butyltin (5) with 3-alkoxy aldehydes is more complex. In the allyltin reactions, useful diastereofacial selectivity is observed only with TiCU (4.6 1) or SnCU (9 1). Optimum stereoselectivity in the reaction of the p-alkoxy aldehyde 11 with 5 is observed in the reaction catalyzed by BF, etherate, which results mainly in the product of Cram-Felkin control (equation I). The highest chelation-controlled selectivity in reactions of 5 with the p-benzyloxy aldehyde 12 is obtained with MgBr, (equation II). 

Chiral 1,3-diols. Chiral p-alkoxy aldehydes react with compounds of the type RTiCI, at - 78° to form derivatives of 1,3-diols with high 1,3-asymmetric induction (equation I). High 1.3-asymmctric induction is also observed in aldol condensations of these aldehydes catalyzed by TiCL (equations II and III). 

High 1,3- and 1,4-asymmetric induction is possible in addition reactions to chiral P-alkoxy aldehydes. The reaction with allylsilanes catalyzed by TiC shows high diastcr-eofacial selectivity (equation II). Essentially only one. vv -adduct of two possible dias-tereomers is obtained in reactions with silyl enol ethers (equation III). 

The P-hydroxy thioester products may be transformed to 1,3-diols by LiAlH4 reduction. Protection of the hydroxyl group followed by reaction with DIBAL-H leads to the corresponding P-alkoxy aldehydes.Alternatively, treatment with a cuprate reagent produces the corresponding ketone. ... 

A high level of 1,3-asymmetric induction was achieved by the assistance of a Lewis acid. Complexa-tion of a P-alkoxy aldehyde with TiCU followed by addition of Bu2Zn, allylsilane or silyl enol ethers at -78 C results in chelation-controlled products in >85% selectivities (Scheme 12). > Even a considerable level of 1,4-asymmetric induction is observed with the MeiZn-TiCU system (equation 33). ... 

Reetz, M. T., Kesseler, K., Jung, A. Aldol-additions to a- and p-alkoxy aldehydes the effect of chelation on simple diastereoselectivity. 

Masamune and coworkers have examined the facial selectivity of the (Z)-lithium enolates of 3-penta-none and ethyl cyclohexyl ketone with a series of P-alkoxy aldehydes having stereocenters at both the a-and p-position (equation 110 Table 18). In the six-mernbered chelate, the methyl and R groups are on the same side of the ring, and it may be seen from the data in Table 18 that the nature of R influences the facial preference of the chiral aldehyde. Another example of this effect is seen in equation (54). 

Additions of enol silanes to p-alkoxy aldehyde (85 equation 25) are reported in Table 17. High selectivity (chelation control) was obtained with TiCU via complex (78 entries 1, 2). The same preference for isomers (86) and (87) was obtained with BF3 via complex (80), which simulates chelation. The influence of chelation on simple stereoselection is also evident in the reactions of achiral aldehydes (90) and (92) with silyl enol ethers (Z)-(91) and ( )-(93), which are usually moderately anti selective in their reactions with aldehydes incapable of chelation high syn selectivity was obtained irrespective of the enol ether geometry (equations 26 and 27). - ... 

In the Held of chiral electrophiles, diastereoselective additions of enolsilanes to chiral a-fluoro-a-methyl-P-alkoxy aldehydes, a-methyl aldehydes, a-alkoxy aldehydes, a,p-dialkoxy aldehydes and a-methyl-P-alkoxy aldehydes were reported to proceed with good stereocontrol following Felkin-Anh or chelation models (c/. Section 2.4.4.1). Very good selectivities were reported in the addition of enolsilanes to chiral imines, particularly those derived from carbohydrates (Scheme 17 and 18).i. 6... 

The cyclic model applies mainly for a-alkoxy carbonyls 5-membered chelate), whereas P-alkoxy carbonyls 6-membered chelate) are less selective in most cases. An exception is the addition of cuprates to P-alkoxy aldehydes having an a-stereo-center (entry 5). 

Ethyl tetrahydrofuran-2-carboxylates. p-Alkoxy carbonyl compounds in which the alkoxy group is readily detached in the presence of a Lewis acid undergo condensation with ethyl diazoacetate. Tin(IV) chloride is a suitable catalyst for P-alkoxy aldehydes, but it requires zirconium(IV) chloride to effect a reaction with P-alkoxy ketones. 

The hi degrees of selectivity (>98 2) found in these reactions are possible not only in acyclic substrates, but also in cyclic a-alkoxy ketones and in more ccmiplex systems. The scope of diis selective reaction, however, is limited to a-hydroxy ketones, as reaction with p-alkoxy aldehydes proceeds with no selectivity. 

The reactions of allylboronates with a-methyl-P-alkoxy aldehydes provides propionate adducts which are useful for the synthesis of polypropionate... 

Fig. 1 Solution structures of p-alkoxy aldehyde complexes in CH2CI2.

Fig. 3 Allylstannane addition to a p-alkoxy-aldehyde reported following two protocols, normal" and "inverse. ...

Additionally, we have observed in our previous work with and NMR spectroscopy that the SnCl4 complexation of p alkoxy aldehydes is in general fairly complex, much more so than with MgBr2 or TiCl4. Therefore, we decided to study from a mechanistic point of view the Lewis acid mediated additions of allylstannanes to various alkoxy aldehydes with SnCl4 as the Lewis acid. As a tool, we elected to use Sn NMR spectroscopy. We will say more about the advantages of this technique later but for now we point out that with SnCl4 as Lewis acid and on allylstannane as reactant, this technique allows one to observe not only the Lewis acid, but the complexes derived from the Lewis acid and substrate, in addition to whatever allylstannanes are involved in the reaction. 

In contrast, the Mukaiyama aldol reaction used in the Heathcock synthesis of the C29-C44 fragment of spongistatin proceeded with comparatively reduced diastereoselectivity. The stereochemically complex enol silane 30 was eoupled to 29, a 2,3-57 -p-alkoxy aldehyde, resulting in... 

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