Alkoxyaldehydes

The reaction between a-alkoxyaldehydes and allylsilanes is highly stereoselective in favor of chelation-controlled products if tin(IV) chloride is used as the Lewis acid, whereas boron trifluoride gives modest stereoselectivity in favor of the nonchelation-controlled product58. 

For Lewis acid induced reactions between a-alkoxyaldehydes and allylstannanes, either Cram or chelation control is observed depending on the choice of Lewis acid and the O-substituent88. 

Effective chelation control was observed for a- and /i-alkoxyaldehydes using magnesium bromide as the Lewis acid115. 

The stereoselectivity of reactions between optically active a-methyl-y-alkoxyallylstannancs and a-alkoxyaldehydes has been investigated with matched or mismatched pairings depending on whether addition to a chelated or nonchelated aldehyde is involved 121. 

The addition of lithium enolates to 2-alkoxyaldehydes occurs either in a completely non-stereoselective manner, or with moderate selectivity in favor of the product predicted by the Cram-Felkin-Anh model28 ( nonchelation control 3, see reference 28 for a survey of this type of addition to racemic aldehydes). Thus, a 1 1 mixture of the diastereomeric adducts results from the reaction of lithiated tert-butyl acetate and 2-benzyloxypropanal4,28. 

Titanium enolates, which are weak Lewis acids, add to 2-alkoxyaldehydes with remarkable stereoselectivity under nonchelation control 1. Thus, 2-benzyloxypropanal is attacked by the tris(isopropyloxy)titanium enolate 7 preferably from the 57-face, to give a 87 13 mixture of adducts with complete simple diastereoselectivity3,1. 

Several a-methyl-(3-alkoxyaldehydes show a preference for 23-syn-3A-anti products on reaction with Z-enolates. A chelated TS can account for the observed stereochemistry.85 The chelated aldehyde is most easily approached from the face opposite the methyl and R substituents. 

Normally, the addition of C-nucleophiles to chiral a-alkoxyaldehydes in organic solvents is opposite to Cram s rule (Scheme 8.15). The anti-Cram selectivity has been rationalized on the basis of chelation control.142 The same anti preference was observed in the reactions of a-alkoxyaldehydes with allyl bromide/indium in water.143 However, for the allylation of a-hydroxyaldehydes with allyl bromide/indium, the syn isomer is the major product. The syn selectivity can be as high as 10 1 syn anti) in the reaction of arabinose. It is argued that in this case, the allylindium intermediate coordinates with both the hydroxy and the carbonyl function leading to the syn adduct. 

The heterobimetallic asymmetric catalyst, Sm-Li-(/ )-BINOL, catalyzes the nitro-aldol reaction of ot,ot-difluoroaldehydes with nitromethane in a good enantioselective manner, as shown in Eq. 3.78. In general, catalytic asymmetric syntheses of fluorine containing compounds have been rather difficult. The S configuration of the nitro-aldol adduct of Eq. 3.78 shows that the nitronate reacts preferentially on the Si face of aldehydes in the presence of (R)-LLB. In general, (R)-LLB causes attack on the Re face. Thus, enantiotopic face selection for a,a-difluoroaldehydes is opposite to that for nonfluorinated aldehydes. The stereoselectivity for a,a-difluoroaldehydes is identical to that of (3-alkoxyaldehydes, as shown in Scheme 3.19, suggesting that the fluorine atoms at the a-position have a great influence on enantioface selection. 

Allylstannanes undergo diasterospecific additions to chiral a-alkoxyaldehydes, as shown in reaction 45295. Stereospecific additions to aldehydes are attained in the presence of... 

Keck et al have obtained similar results in the reaction of (Z)- y-silyloxyallyl-tributyltin with a- and (3-alkoxyaldehydes (equation II). A single adduct is usually formed, that with a syn, vic-diol unit. 

The lithium enolate of di-i-butyl malonate undergoes a stereoselective aldol reaction with Qf-alkoxyaldehydes to give anft-l,2-diol derivatives in the case of the highly hindered 2-trityloxypropanal, the stereochemistry is reversed. 

We thus turned to alternative strategies for synthesizing aldehyde 3. Particularly attractive was the proposal that sugar-like materials could be constructed via the reaction of an allyl ether anion and an a-alkoxyaldehyde (Figure 5).10,11 For this approach to be successful, it would be necessary to control (i) the regioseiectivity of the reaction of the allyl ether anion, 0 (jj) the syn (threo) or anti (erythro) relationship generated in concert with the new C-C bond, and (iii) this new C(2)-C(3) relationship with respect to the chiral center (C(4)) already present in the aldehyde reaction partner. 

A similar stereoselectivity has been noted for the TiCl4-mediated condensation of [i-alkoxyaldehydes with silyl enol ethers. 

This enantioselective preparation of allylic alcohols has been applied to the synthesis of the side chain of prostaglandins . The addition to functionalized aldehydes, such as 483, allows the synthesis of C2-symmetrical 1,4-diols, such as 484, with excellent diastereoselectivity and enantioselectivity . An extension of this method allows the synthesis of C3-symmetrical dioF . Aldol-type products result from the catalytic enantioselective addition of functionalized dialkylzincs to 3-TIPSO-substituted aldehydes, such as 485, followed by a protection-deprotection and oxidation sequence affording 486 in 70% yield and 91% ee (Scheme 118) . The addition to a-alkoxyaldehydes provides a... 

There are some examples on diastereoslective reactions between ketenes and imines [54-61]. However, the number of computational studies dealing with these reactants is scarce [59, 62-64]. As an example of Staudinger reaction in which the chirality source is at the C4 position of the ring being formed, our group studied the reaction between methoxyketene (38) and imine (S)-(39) derived from (S)-a-alkoxyaldehydes to yield the corresponding cis-(3-lactam (3S,4R)-(40) (Scheme 9). 

The Evans reaction, involving f, y-unsaturated oxazolidinones and f),y-unsaturated aldehydes was unprecedented (but, according to the literature, Evans aldolizations of a-alkoxyaldehydes worked well).16... 

In view of the well-documented successful Evans aldolization of a-alkoxyaldehydes, we were very surprised and disappointed by the negative results observed when attempting to couple 10 with an oxazolidinone as shown in Equation 2. 

In most cases chiral carbonyl compounds also afford low stereoselectivity. As for the related Passerini reaction, even the use of aldehydes that are known to give excellent asymmetric induction in the reaction with other kinds of C-nucleophiles, results in low or moderate diastereoisomeric ratios. For example, both norbornyl aldehyde 39 [47] and a-alkoxyaldehyde 40 [3, 48] gave drs lower than 2 1 (Scheme 1.16). The same happens with ortho-substituted chromium complex 41 [49], which usually leads to very high asymmetric induction in other nucleophilic additions. Finally, //-substituted aldehyde 42 [50] gave poor results as well. 

More interestingly, it was found that in the condensation of allylstannane 191 with a-alkoxyaldehyde 193, the stereochemistry of the final adduct could be controlled by the amount of Lewis acid employed. Remarkably, if one equivalent of SnCl4 is used, the anti-homoallylic alcohol 194 is produced exclusively (Scheme 13.68) [87]. In stark contrast, if two equivalents of SnCl4 are employed, the reaction produces only the syn-homoallylic alcohol 195. 

But this - and other examples16 - indicate, that chelation control is apparently limited in a-alkoxyaldehydes where the chelating ether oxygen resides in a medium ring, probably because of reduced Lewis basicity of the ether oxygen. 

The addition of diorganozinc reagents to a-alkoxyaldehydes furnishes selectively protected 1,2-diols.19 Applications toward the synthesis of pheromones like (-)-exo- and (-)-endo-brevicomin 2 and 3 exploits the catalytic nature of the stereochemical induction, e.g. the newly formed chiral centre depends only on the configuration of the chiral catalyst 1. 

Pentadienylindium, a vinylog of allylindium, reacts with carbonyl compounds regioselectively at the 7-position to give 1,4-pentadiene derivatives (Scheme 7).107-109 n the presence of InCl3, pentadienylstannane similarly reacts with a-alkoxyaldehydes to produce the corresponding 7-adducts (Scheme 8).110... 

When a-alkoxyaldehyde substrates were subjected to organocatalytic conditions, a highly enantioselective aldol dimerization reaction occurred6 (Scheme 2.3f). Substrates bearing relatively electron-rich alkoxy groups provide dimers... 

Reaction of a chiral a-alkoxyaldehyde with a prochiral enol silyl ether catalyzed by SnCl4 results in a single diastereomer with additional -selectivity (equation II). 

Chelation can also result in significant diastereoselectivity. Thus the reaction of an achiral (3-hydroxy aldehyde catalyzed by TiCl4 results in syn- and anti-adducts in the ratio 94 6 (equation III). Finally, a chiral (3-alkoxyaldehyde when complexed with TiCl4 can... 

By changing the configuration of the chiral catalyst precursor (DBNE), stereoselective synthesis of optically active syn (78% de) and anti (91% de) 1,3-diols has been reported in the addition of diethylzinc to optically active p-alkoxyaldehyde (eq 22). The method has an advantage over the R2Zn-TiCl4 method,which is only anti selective. 

The aldol reaction of ketene silyl acetals with several aldehydes (Mukaiyama aldol reaction) assisted by Li has been described briefly by Reetz et al. Wirth 5.0 m LPDE a clean reaction began within 1 h with the sole formation of the silylated aldol 112, whereas the use of a catalytic amount (3 mol %) of LiC104 in Et20 (3 mol % LPDE) required a reaction time of 5 days for 86 % conversion. As observed in the hetero-Diels-Alder reaction of a-alkoxyaldehyde, the higher rate of reaction of 79 compared with that of benzaldehyde can be attributable to chelation. Indeed, the use of 3 mol % LPDE required only 20 h at room temperature for complete uptake of 79 with a diastereoselectivity (syn-113lanti-113) of >96 % (Sch. 55). 

LiC104 was shown to be a more compatible Lewis acid for chelation in an ethereal solvent—when TiCU, a typical chelation agent for a-alkoxyaldehydes, was used in EtaO for alkylation of 79, moderate diastereoselectivity (68 32) was obtained. Rapid injection NMR studies of the TiCU-promoted chelation-controlled Mukaiyama aldol reaction and the Sakurai reaction show that an acyclic transition state must be involved in which the silyl groups never reach the carbonyl oxygen atom. In LPDE-mediated enolsilane additions silylated products predominate. Obviously, the mechanism is different—it is a group-transfer aldol reaction [107]. 

In the reaction of a-alkoxyaldehydes the stereochemical outcome is different— reactions in the pericyclic mode now lead preferentially to the 5,6-anti product. The reaction of chiral a-benzyloxyaldehyde 6 under the influence of MgBr2 afforded a single pyrone 7, which was consistent with a chelation-control product [9b,12]. A chelated complex was formed, and the exo transition state III was preferred because of steric repulsion between the diene and the chelated ring (Sch. 4). 

In addition to the aforementioned X-ray analysis to disclose the structure of a few crystalline titanium chelates, and NMR studies have been performed to provide evidence for the chelation structure of a- and /1-oxycarbonyl compounds in solution [33-35]. Approximate solution structures for -alkoxyaldehydes are as shown in Fig. 7 [34]. The mechanism of chelation-controlled reactions of organotitanium reagents has been investigated experimentally [5] and theoretically [36], and the subject has been reviewed [10]. The formation of a chelate structure with titanium metal at the center plays a pivotal role in determining the reactivity and selectivity [37] in many synthetic reactions as shown in the following discussion. 

Figure 7. Solution structures of /J-alkoxyaldehyde-TiCh complexes determined by NMR spectroscopy (aldehyde H omitted for clarity).

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