Aldehydes achiral

New auxiliaries and reaction methods are now available for the stereoselective synthesis of all members of the stereochemical family of propionate aldol additions. These also include improvements on previously reported methods that by insightful modification of the original reaction conditions have led to considerable expansion of the versatility of the process. In addition to novel auxiliary-based systems, there continue to be unexpected observations in diastereoselective aldol addition reactions involving chiral aldehyde/achiral enolate, achiral aldehyde/chir-al enolate, and chiral aldehyde/chiral enolate reaction partners. These stereochemical surpri.ses underscore the underlying complexity of the reaction process and how much we have yet to understand. 

If the a carbon atom of an aldehyde or a ketone is a chnality center its stereo chemical integrity is lost on enolization Enolization of optically active sec butyl phenyl ketone leads to its racemization by way of the achiral enol form... 

The foregoing examples do not represent useful chiral formyl anion equivalents in a direct sense since the stereoselectivity of the initial addition to aldehydes is poor, although as has been explained, the situation is salvaged by oxidation and re-reduction. On the other hand, by lithiation at the 2 position of the achiral oxazo-lidine 53 in the presence of (-)-sparteine followed by addition of benzaldehyde, useful levels of d.e. and e.e. are achieved directly (98TA3125). For example, by adding MgBr2 before the benzaldehyde, the major product obtained is 54 in 80% d.e. and 86% e.e. 

By treatment of a racemic mixture of an aldehyde or ketone that contains a chiral center—e.g. 2-phenylpropanal 9—with an achiral Grignard reagent, four stereoisomeric products can be obtained the diastereomers 10 and 11 and the respective enantiomer of each. 

A valuable feature of the Nin/Crn-mediated Nozaki-Takai-Hiyama-Kishi coupling of vinyl iodides and aldehydes is that the stereochemistry of the vinyl iodide partner is reflected in the allylic alcohol coupling product, at least when disubstituted or trans tri-substituted vinyl iodides are employed.68 It is, therefore, imperative that the trans vinyl iodide stereochemistry in 159 be rigorously defined. Of the various ways in which this objective could be achieved, a regioselective syn addition of the Zr-H bond of Schwartz s reagent (Cp2ZrHCl) to the alkyne function in 165, followed by exposure of the resulting vinylzirconium species to iodine, seemed to constitute a distinctly direct solution to this important problem. Alkyne 165 could conceivably be derived in short order from compound 166, the projected product of an asymmetric crotylboration of achiral aldehyde 168. 

Boland applied this methodology to Garner s aldehyde, and found the addition to be substrate-controlled rather than reagent-controlled (Scheme 9.13b) [68]. Viny-lepoxide 15 could thus also be obtained with high diastereoselectivity with achiral 9-MeO-9-BBN. 

The aldehyde structures and the tosylhydrazone salts were varied in an extensive study of scope and limitations, with use of both achiral and chiral sulfur ylides [73]. Aromatic aldehydes were excellent substrates in the reaction with benzaldehyde-derived ylides, whereas aliphatic aldehydes gave moderate yields and transxis ratios. 

The addition of an achiral organometallic reagent (R M) to a chiral carbonyl compound 1 (see Section 1.3.1.1.) leads to a mixture of diastercomers 2 (syn/anti) which can be either racemic, or enantiomerically enriched or pure, depending on whether the substrates are race-mates or pure enantiomers. This section incorporates only those reactions starting from optically pure a-amino aldehydes, however, optical purity of the starting material has not been demonstrated in all cases. 

As well as the addition of achiral organometallic reagents to chiral aldehydes (see also Sections 1.3.2. and 1.3.3.), the addition of chiral organometallic reagents to carbonyl compounds is a well-known and intensively studied process which may lead to enantiomerically and/or diastereomerically enriched products. Chiral organometallic reagents can be classified into three groups ... 

I.3.3.3.3.I.2. Simple Diastereosclectivity Reactions with Achiral Aldehydes and Ketones... 

In contrast to the 2-butenylboranes, 2-butcnylboronates have found widespread application in acyclic diastereoselective synthesis owing to their ease of preparation (Section 1.3.3.3.3.1.1.), configurational stability and highly stereoselective reactions with aldehydes3 4. The results of reactions of substituted allylboronates and representative achiral aldehydes are summarized in Table 1. 

I.3.3.3.3.I.3. Relative Asymmetric Induction Reactions of Chiral Aldehydes with Achiral Allylboron Reagents... 

Several detailed studies of reactions of achiral aiiylboronates and chiral aldehydes have been reported4,52 - 57. Diastereofacial selectivity in the reactions of 2-(2-propenyl)- or 2-(2-butenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolanes with x-methyl branched chiral aldehydes are summarized in Table 252, 53, while results of reactions with a-heteroatom-substituted aldehydes are summarized in Table 34,52d 54- 57. 

Finally, 2-allyl-4,5-tra ,s-diphenyl-l,3-bis(4-methylphenylsulfonyl)-l,3,2-diazaborolidincs have been used74. The 2-propenyl derivative undergoes highly stereoselective reactions with achiral aldehydes (95 - 97% ee) the ( )-2-butenyl derivatives (91-95% ee) and the analogous 2-chloro- and 2-bromo-2-propenyl derivatives (84-99% ee) also give excellent results in reactions with achiral aldehydes. 

The enantioselectivities of the reactions of representative achiral aldehydes and chiral allylboron reagents arc compared in Table 4. A comparison of the enantioselectivities of the (Z )-2-butenyl reagents appears in Table 5, while Table 6 provides a similar summary of the reactions of the (Z)-2-butenyl and 3-methoxy-2-propcnyl reagents. A 3-diphenylamino-2-propenyl reagent was recently reported102. 

Table 4. 1-Substituted 3-Butenols from Chiral 2-Propenylboron Reagents and Achiral Aldehydes...

Results of the asymmetric 2-propenylborations of several chiral a- and /i-alkoxy aldehydes are presented in Table 11 74a-82 84. These data show that diisopinocampheyl(2-propenyl)borane A and l,3-bis(4-methylphenylsulfonyl)-4,5-diphenyl-2-propenyl-l,3,2-diazaborolidine C exhibit excellent diastereoselectivity in reactions with chiral aldehydes. These results are in complete agreement with the enantioselectivity of these reagents in reactions with achiral aldehydes (Section 1.3.3.3.3.1.4.). In contrast, however, the enantioselectivity of reactions of the tartrate 2-propenylboronate B (and to a lesser extent the tartrate (/i)-2-butenylhoronate)53b is highly... 

Dimethylphenylsilyl-2-propenylboronate 7 is more enantioselective (81-87% ee with achiral aldehydes) than the 2-[cyclohexyloxy(dimethyl)silyl] compound 8 (64-72% ee), and consequently the former generally gives better results especially in mismatched double asymmetric reactions. Nevertheless, the examples show that appreciable double diastereoselection may be achieved with both reagents in many cases. 

Chiral, nonracemic allylboron reagents 1-7 with stereocenters at Cl of the allyl or 2-butenyl unit have been described. Although these optically active a-substituted allylboron reagents are generally less convenient to synthesize than those with conventional auxiliaries (Section 1.3.3.3.3.1.4.), this disadvantage is compensated for by the fact that their reactions with aldehydes often occur with almost 100% asymmetric induction. Thus, the enantiomeric purity as well as the ease of preparation of these chiral a-substituted allylboron reagents are important variables that determine their utility in enantioselective allylboration reactions with achiral aldehydes, and in double asymmetric reactions with chiral aldehydes (Section 1.3.3.3.3.2.4.). 

The greater diastercosclectivity of (Z)-l-methoxy-2-butenylboronate 412-25 compared with the 1-chloro derivative 31 33 demonstrated in reactions with achiral aldehydes (Section 1.3.3.3.3.1.) suggests that double asymmetric reactions of chiral aldehydes with 4 will also be more selective than reactions with 3. The data summarized below provide an indication of the magnitude of this effect. 

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