A-Substituted aldehydes

Table 1.3 Asymmetric Diels-Alder reactions of a-substituted aldehydes catalyzed by 7 [10a,d ...

Enamines 1 are useful intermediates in organic synthesis. Their use for the synthesis of a-substituted aldehydes or ketones 3 by reaction with an electrophilic reactant—e.g. an alkyl halide 2, an acyl halide or an acceptor-substituted alkene—is named after Gilbert Stork. 

The Stork enamine reaction is an important and versatile method for the synthesis of a-substituted aldehydes and ketones. Such products should in principle also be... 

Deprotonation of allylic aryl sulfoxides leads to allylic carbanions which react with aldehyde electrophiles at the carbon atom a and also y to sulfur . With benzaldehyde at — 10 °C y-alkylation predominates , whereas with aliphatic aldehydes at — 78 °C in the presence of HMPA a-alkylation predominates . When the a-alkylated products, which themselves are allylic sulfoxides, undergo 2,3-sigmatropic rearrangement, the rearranged compounds (i.e., allylic sulfenate esters) can be trapped with thiophiles to produce overall ( )-l,4-dihydroxyalkenes (equation 24). When a-substituted aldehydes are used as electrophiles, formation of syn-diols 27 occurs in 40-67% yields with diastereoselectivities ranging from 2-28 1 (equation 24) . ... 

If the substituents are nonpolar, such as an alkyl or aryl group, the control is exerted mainly by steric effects. In particular, for a-substituted aldehydes, the Felkin TS model can be taken as the starting point for analysis, in combination with the cyclic TS. (See Section 2.4.1.3, Part A to review the Felkin model.) The analysis and prediction of the direction of the preferred reaction depends on the same principles as for simple diastereoselectivity and are done by consideration of the attractive and repulsive interactions in the presumed TS. In the Felkin model for nucleophilic addition to carbonyl centers the larger a-substituent is aligned anti to the approaching enolate and yields the 3,4-syn product. If reaction occurs by an alternative approach, the stereochemistry is reversed, and this is called an anti-Felkin approach. 

Entry 2 involves the use of a sterically biased enol boronate with an a-substituted aldehyde. The reaction, which gives 40 1 facial selectivity, was used in the synthesis of 6-deoxyerythronolide B and was one of the early demonstrations of the power of double diastereoselection in synthesis. In Entry 3, the syn selectivity is the result of a chelated TS, in which the (3-p-methoxybenzyl substituent interacts with the tin ion.120... 

The diastereoselectivity observed in simple systems led to investigation of enantiomerically pure aldehydes. It was found that the E- and Z-2-butenylboronates both exhibit high syn-anti diastereoselectivity with chiral a-substituted aldehydes. However, only the Z-isomer also exhibited high selectivity toward the diastereotopic faces of the aldehyde.38... 

P-Allyl-to-(isopinocampheyl)borane exhibits high stereoselectivity in reactions with chiral a-substituted aldehydes.40 The stereoselectivity is reagent controlled, in that there is no change in stereoselectivity between the two enantiomeric boranes in reaction with a chiral aldehyde. Rather, the configuration of the product is determined by the borane. Both enantiomers of (Ipc)2BH are available, so either enantiomer can be prepared from a given aldehyde. 

These reagents were also examined with chiral a-substituted aldehydes. The allylbo-ration reagent dominates the enantioselectivity in both matched and mismatched pairs. 

Use of oxygenated stannanes with a-substituted aldehydes leads to matched and mismatched combinations.181 For example, with the y-MOM derivative and a-benzyloxypropanal, the matched pair gives a single stereoisomer of the major product, whereas the mismatched pair gives a 67 33 syntanti mixture. The configuration at the alkoxy-substituted center is completely controlled by the chirality of the stannane. 

The combination of reagents and methods can provide for stereochemical control of addition to a-substituted aldehydes.195 An application of the methodology can be found in the synthesis of (+)-discodermolide that was carried out by J. A. Marshall and co-workers and is described in Scheme 13.69. 

Allyboration of chiral aldehydes (12,17). The borane 1, prepared from (+ )-a-pinene, reacts with a chiral, a-substituted aldehyde such as 2 with 96 4 diaster-eofacial selectivity. Reaction of 2 with ent-1, prepared from (-)-a-pinene, shows reversed facial selectivity (5 95). ... 

In general, a good level of predictability is now associated with the sense of asymmetric induction in aldol condensations of achiral enolates and chiral a-substituted aldehydes. At present, the perturba-... 

The presence of a stereogenic center on the aldehyde can strongly inlinence the diastereoselectivity in allylboration reactions, especially if this center is in the a-position. Predictive rules for nucleophilic addition on snch a-snbstitnted carbonyl substrates such as the Felkin model are not always snitable for closed transition structures.For a-substituted aldehydes devoid of a polar substituent, Roush has established that the minimization of ganche-ganche ( syn-pentane ) interactions can overrule the influence of stereoelectronic effects. This model is valid for any 3-monosubstituted allylic boron reagent. For example, althongh crotylboronate (E)-7 adds to aldehyde 39 to afford as the major prodnct the diastereomer predicted by the Felkin model (Scheme 2), " it is proposed that the dominant factor is rather the minimization of syn-pentane interactions between the Y-snbstitnents of the allyl unit and the a-carbon of the aldehyde. With this... 

As demonstrated in the course of a total synthesis of the macrolide bafilo-mycin, double diastereoselective additions can be useful even in the mismatched manifold. For example, the crotylation of chiral a-substituted aldehyde 167 with (E)- affords an 85 15 ratio of diastereomers favoring the desired anti-anti product (Scheme 17). Without a chiral tartrate reagent, the undesired anti-syn diastereomer would be intrinsically favored from aldehyde 167. The use of the appropriate tartrate reagent, the (R,R) unit in this instance, overturns this preference to afford an acceptable ratio of the two separable dias-teomers. 

Analysis of results for a-substituted aldehydes with E- and Z-enolates indicates that the cyclic transition states shown below are favored with lithium and boron enolates.64a... 

Allyl-bis(isopinocampheyl)borane exhibits high stereoselectivity in reactions with chiral a-substituted aldehydes.39... 

MAD-mediated alkylation. a-Substituted aldehydes complexed with 1 or 2 undergo anti-selective alkylation with Grignard reagents. In general 2 is more effective than l.3 Example ... 

This reagent also adds to chiral a-substituted aldehydes with Cram diastereo-selectivity.7 Example ... 

Further transformations of the intermediate alkenyloxydialkylboranes (46), as shown in Scheme 10, include aqueous hydrolysis to the homologated aldehydes or ketones 30 electrophilic additions to afford the corresponding a-dialkylaminomethyl aldehydes and ketones (47),31 and a-halogenated (48)32 or a-arylselenylated aldehydes or ketones (49) 33 transmetallation-alkylation to afford a-substituted aldehydes or ketones (50) 34 and aldol condensations with aldehydes (51).35 These reagents offer the equivalent of the tandem 1,4-conjugate addition-electrophile-trapping protocol. A prototypical prosta-... 

A titanium complex derived from chiral /V-arencsulfonyl-2-amino-1 -indanol [20], a cationic chiral iron complex [21], and a chiral oxo(salen)manganese(V) complex [22] have been developed for the asymmetric Diels-Alder reaction of oc,P-unsaturated aldehydes with high asymmetric induction (Eq. 8A.11). In addition, a stable, chiral diaquo titanocene complex is utilized for the enantioselective Diels-Alder reaction of cyclopentadiene and a series of a.P Unsaturated aldehydes at low temperature, where catalysis occurs at the metal center rather than through activation of the dienophile by protonation. The high endo/exo selectivity is observed for a-substituted aldehydes, but the asymmetric induction is only moderate [23] (Eq. 8A. 12). 

To address limitations in the use of glyceraldehyde acetonide (43) as a three-carbon chiral building block, butane-2,3-diacetal-protected glyceraldehyde (44, R1 = R2 = H) has been prepared. It undergoes diastereoselective aldol reactions with a range of carbonyl compounds esters, thioesters, and ketones. The work has been extended (g) to other derivatives such as the a-substituted aldehyde (44, R1 = Me, allyl) and the methyl ketone (44, R2 = Me).122a,b... 

Table 5.2 The diastereoselectivity of the MBH reaction in the addition of a-substituted aldehydes to acrylates under ultrasound irradiation.

Besides, furfural polymerizes in the presence of an acid catalyst with phenol, urea, and acetone. In this regard, the phenol-furfural and urea-furfural resins are important [221-223], Furfural reacts usually as does all a-substituted aldehydes in this regard, with phenol it condenses in the presence of either alkali or acid to form synthetic resins in a reaction that is very similar to that of phenol with formaldehyde or acetaldehyde [223],... 

Stereogenic Wittig reactions of nonstabilized ylides of the structure Ph3P+—CH —R2 have been studied in-depth in many instances. They give the cis-configured oxaphosphetane rapidly, with the rate constant kcis, and reversibly (Figure 9.7). On the other hand, the same nonstabilized ylide produces the /ran.v-oxaphosphetane slowly, with the rate constant ktrans, and irreversibly. The primary product of the [2+2]-cycloaddition of a nonstabilized P ylide to a substituted aldehyde is therefore a cis-oxaphosphetane. Why this is so has not been ascertained despite the numerous suggestions about details of the mechanism which have been made. 

Not only does acetone undergo a highly enantioselective aldol reaction, but hydroxy acetone exhibits excellent stereoselectivity to produce the anti-aldol products 75 (Scheme 2.3d). For example, L-proline catalyzed the aldol reaction between hydroxy acetone and cyclohexanecarbaldehyde to furnish the anti -diol in 60% yield with a greater than 20 1 diastereomeric ratio. The enantiofacial selectivity of the anti-isomer was higher than >99%. Diastereoselectivities are very high with a-substituted aldehydes, whereas low selectivities are recorded in reactions with aromatic aldehydes and with a-unsubstituted aliphatic aldehydes. It is noteworthy that the levels of enantiofacial selectivity for the anti -aldol products... 

Aldehydes react very fast with 2-lithio-l,3-dithiane (161) even at very low temperatures, whereas ketones need higher temperatures175-181. Stereochemical control of the new stereocenter can be achieved with a-substituted aldehydes or conveniently with 2-substituted... 

Both chiral amines42 and chiral protonating agents43 have been used for the enantioselective deracemisation of a-substituted aldehydes and ketones via the derived enamine. However, the enantiomeric excesses achieved were usually not very high and there have been no new developments reported in this area41. 

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