A-Unbranched aldehydes

An important feature of this reaction is that in contrast to most other catalytic asymmetric Mannich reactions, a-unbranched aldehydes are efficient electrophiles in the proline-catalyzed reaction. In addition, with hydroxy acetone as a donor, the corresponding syn-l, 2-aminoalcohols are furnished with high chemo-, regio-, diastereo-, and enantioselectivities. The produced ketones 14 can be further converted to 4-substituted 2-oxazolidinones 17 and /i-aminoalcohol derivatives 18 in a straightforward manner via Baeyer-Villiger oxidation (Scheme 9.4) [5]. 

McDonald performed an asymmetric synthesis of D-desosamine, with high selectivity, by diastereoselective addition of TMS-acetylene to an a-unbranched aldehyde obtaining the propargylic alcohol [23]. The reaction proceeded in nearly 100 % diastereoselectivity albeit in moderate (60 %) yield (Eq. 19). 

The diphenylprolinol silyl ether 45a catalyst was developed by the Hayashfs group for the addition of a-unbranched aldehydes to aryl and alkyl substituted nitroolefins [35]. This catalyst, as well as the perfluoroalkyl derivative 45b [36],... 

Other aromatic aldehydes provided products with similar enantiomeric excess. Although a-unbranched aldehydes such as pentanal did not yield any significant amount of the desired aldol products, the reaction of isobutyraldehyde gave the corresponding aldol product in 97% yield and 96% ee. The reaction is considered to proceed via an enamine mechanism. The enantioselectivity of the reaction can be explained in terms of a metal-free version of a six-membered transition state... 

The reaction was shown to proceed in a stereoconvergent manner, as both the Z- and the E-ketene acetal stereoisomers furnished the trans-fS-lactone exclusively. On the other hand, when the same reaction was conducted with SnCl4 as Lewis acid, the ds-fi-lactone 3 was obtained in moderate yield and high stereoselectivity [2]. Here, only a-unbranched aldehydes gave acceptable yields (Scheme 8.1). 

SCHEME 11.1. Enamine mediated a-amination of a-unbranched aldehydes with azodicarboxylate esters by using, L-proline 1 and sulfonamide 2 as catalysts. 

SCHEME 11.8. A -Nitrosoaldol reaction of a-unbranched aldehydes promoted by catalysts 11 and 12. 

Reactions between ketone donors and aldehyde acceptors strrMigly depend on the nature of the aldehyde. While a-disubstimted aldehydes normally react easily, unbranched ones often undergo self-addition reactions. List et al. reported one of the first examples of a direct aldol addition of ketones to a-unbranched aldehydes en route to a natural product in 2001 (44). The operationally simple reaction between 13 and 19 in the presence of catalytic amounts of (5)-12 furnished the enantiomerically enriched p-hydroxy-ketone 20 in moderate yield. The reduced yield can be rationalized by the concomitant formation of the crmdensation product 21, which is one of the limiting factors in such reactions (besides the self reaction of a-unbranched aldehydes). Intermediate 20 can then be further converted to the bark beetle pheromone (5)-ipsenol (22) in two more steps (Scheme 6). 

Proline-catalyzed aldolizations of acetone with a-unbranched aldehydes. 

At the time these relatively modest results represented the state-of-the-art in direct catalytic asymmetric aldolizations with a-unbranched aldehyde acceptors. Neither Shibasaki s nor Trost s bimetallic catalysts, the only alternative catalysts available, gave superior results. Moreover, even non-asymmetric amine-catalyzed cross aldolizations with a-unbranched acceptors are still unknown. That the practicality of the process can compensate for the modest yield and enantioselectivity was illustrated by a straightforward synthesis of the natural pheromone (S)-ipsenol (139) from aldol 136d, featuring a high-yielding Stille coupling (Scheme 4.27). 

In addition to ketones, aldehydes can also be used as aldol donors in pro-line-catalyzed reactions [144]. Barbas et al. found that treating acetaldehyde solutions tvith proline provided aldehyde 185, an aldol trimer of acetaldehyde, in 84% ee and 4% yield (Scheme 4.42, Eq. (1)) [145, 146]. As shotvn by Jorgensen et al., other simple a-unbranched aldehydes can also be used as donors in proline-catalyzed cross aldolization tvith activated non-enolizable ketone acceptors to give aldols 188 in high enantioselectivity and yield (Scheme 4.42, Eq. (2)) [147]. 

A wide range of aromatic esters has been prepared in up to 99% yield by NHC-catalysed aerobic reaction of aromatic aldehydes with aryl boronic acids (ArB(OH)2) under mild conditions. By appropriate selection of the NHC catalyst, a-unbranched aldehydes can be converted to amide, ester, or carboxylic acid through oxidation by NCS in CH2Cl2. ... 

The formation of isomeric aldehydes is caused by cobalt organic intermediates, which are formed by the reaction of the olefin with the cobalt carbonyl catalyst. These cobalt organic compounds isomerize rapidly into a mixture of isomer position cobalt organic compounds. The primary cobalt organic compound, carrying a terminal fixed metal atom, is thermodynamically more stable than the isomeric internal secondary cobalt organic compounds. Due to the less steric hindrance of the terminal isomers their further reaction in the catalytic cycle is favored. Therefore in the hydroformylation of an olefin the unbranched aldehyde is the main reaction product, independent of the position of the double bond in the olefinic educt ( contrathermodynamic olefin isomerization) [49]. 

The allenic stannanes react with aldehydes under the influence of Lewis acids such as BF3 and MgBr2. Unbranched aldehydes are not very stereoselective, but branched aldehydes show a strong preference for the syn adduct. 

At present, most enamine-catalyzed aldol reactions are reliable only with electron-poor aromatic aldehyde acceptors, hi addition, a handful of aliphatic aldehydes (e.g. isobutyraldehyde or pivalaldehyde) are often used as acceptors. The use of unbranched aldehyde acceptors is difficult, and generally only modest yields have been obtained. In addition, unsaturated aldehydes are curiously absent from the list of commonly used acceptors. On a positive side, it should be noted that even potentially racemizing a-chiral aldehydes have been employed as acceptors. As an example, in the recent synthesis of caUipeltoside C, MacMillan and coworkers were able to employ protected Roche aldehyde 113 as a starting material (Scheme 22) [204]. 

The present method is practical and efficient as it employs readily available enantioenriched propargylic alcohols as precursors to the allenylindium reagents. With achiral aldehydes the diastereoselectivity is high for branched aldehydes, moderate for unbranched aldehydes, and low for benzaldehyde (Table I). With cHral a-methyl aldehydes the additions proceed under effective reagent control to afford anti adducts of high ee and with excellent diastereoselectivity (eq. 1 and 2). Comparable results were obtained with 3 1 dimethyl sulfoxide-tetrahydrofuran (DMSO-THF) as the solvent. 

While cyclohexanecarbaldehyde and pivaldehyde, being a-branched aldehydes, are excellent substrates for most ligands leading to nearly perfect enantioselec-tion, unbranched aldehydes still remain cumbersome substrates. 

When the reaction is carried out with a ketone the product is known as a ketal. With low molecular weight unbranched aldehydes and ketones the equilibrium lies to the right. If it is desired to make acetals or ketals of higher molecular weight molecules, the removal of water is necessary to drive the equilibrium to the right (23). 

Trost has exploited the asymmetric alkynylation of an a-unbranched acetaldehyde in an elegant synthesis of the core of the mitomycin analog FR900482 [22]. This is a remarkable example wherein an enolizable aldehyde participates in the addition reaction. It has been suggested that this is critical for the success of these substrates, because the aldehyde undergoes reversible enolization. (Eq. 18). 

For satisfactory diemo- and stereoselectivity, most catalytic, direct cross-aldol methods are limited to the use of non enolizable (aromatic, a-tert-alkyl) or kineti-cally non enolizable (highly branched, ,/funsaturated) aldehydes as acceptor carbonyls. With aromatic aldehydes, however, enantioselectivity is sometimes moderate, and the dehydration side-product may be important. With regard to the donor counterpart, the best suited pronucleophile substrates for these reactions are symmetric ketones (acetone) and ketones with only one site amenable for enolization (acetophenones). With symmetric cyclic or acyclic ketones superior to acetone, syn/anti mixtures of variable composition are obtained [8b, 11, 19a]. Of particularly broad scope is the reaction of N-propionylthiazolidinethiones with aldehydes, which regularly gives high enantioselectivity of the syn aldol adduct of aromatic, a,fi-unsaturated, branched, and unbranched aldehydes [13]. 

As shown in Table 16, (i )-propargyl mesylate (ee > 95%) reacts with cyclohexanecarboxaldehyde in the presence of Ini and 5 mol% of a palladium catalyst to give, via an allenylindium intermediate, the adduct with high enantiomeric excess.55,56 The addition is most efficient in 3 1 THF-HMPA and 1 1 THF-DMPU solvents. The Anti syn ratios are excellent with a-branched aldehydes but only modest with unbranched and conjugated aldehydes. 

As shown in Table 27, from aromatic and branched ahphatic aldehydes the respective olefins were obtained in excellent yields and with high preference for -isomers. Unbranched aldehydes tend to give products with a low yield and the preference for Z-isomers. It is noteworthy that neither phenyltetra-zolyl (FT) nor tert-butyltetrazolyl (TBT) sulfones could be applied in this reaction. 

Attempts to access enantioenriched /3 ,y-dioxygenated allylic stannanes through Lewis acid-catalyzed 1,3-isomerization of the a,d-dioxygenated isomers were unsuccessful owing to the facile elimination of BusSnOR from these intermediates (Eq. 60) [76]. Transmetalation with InCls in the presence of an aldehyde proceeds without elimination, however, to afford the anti adduct as the major diastereomer (Table 44). In additions to unbranched aldehydes, higher yields were obtained with... 

An analogous process has been developed for unbranched aldehydes which can be transformed into a-amino ketones when oxidized in the presence of an secondary amine and iodine, as the mediator, in aqueous terf-butanol. The actual reactive species is probably the enamine which is attacked by iodine cations and subsequently by water. Carbonyl transposition reaction releases iodine anions which can be anodically reoxidized [197]. 

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