Aldehydes from enols

This enolate can then react with a plethora of electrophiles, setting a new stereocenter by a diastereoface-selective reaction. The simplest electrophile to trap enolate 71 is H" ", which can, for example, originate from methanol [89] or diphenyl acetaldehyde (as a readily enolizable aldehyde) [90] leading to the acy-lated catalyst species (Fig. 38). The free catalyst is regenerated by acyl-group transfer to methanol(ate) or the aldehyde-derived enolate, producing methyl or enolesters 72/73 in good yields and enantioselectivities. 

Provided that the reaction occurs through a chairlike TS, the E anti/Z syn relationship will hold. There are three cases that can lead to departure from this relationship. These include a nonchair TS, that can involve either an open TS or a nonchair cyclic TS. Internal chelation of the aldehyde or enolate can also cause a change in TS structure. 

Trialkylstannyl enolates can be prepared from enol acetates by reaction with trialkyltin alkoxides and are sufficiently reactive to add to aldehydes. Uncatalyzed addition of trialkylstannyl enolates to benzaldehyde shows anti stereoselectivity.31... 

Stereochemical Control by the Aldehyde. A chiral center in an aldehyde can influence the direction of approach by an enolate or other nucleophile. This facial selectivity is in addition to the simple syn, anti diastereoselectivity so that if either the aldehyde or enolate contains a stereocenter, four stereoisomers are possible. There are four possible chairlike TSs, of which two lead to syn product from the Z-enolate and two to anti product from the A-enolate. The two members of each pair differ in the facial approach to the aldehyde and give products of opposite configuration at both of the newly formed stereocenters. If the substituted aldehyde is racemic, the enantiomeric products will be formed, making a total of eight stereoisomers possible. 

Intermolecular cross aldolization of metallo-aldehyde enolates typically suffers from polyaldolization, product dehydration and competitive Tishchenko-type processes [32]. While such cross-aldolizations have been achieved through amine catalysis and the use of aldehyde-derived enol silanes [33], the use of aldehyde enolates in this capacity is otherwise undeveloped. Under hydrogenation conditions, acrolein and crotonaldehyde serve as metallo-aldehyde enolate precursors, participating in selective cross-aldolization with a-ketoaldehydes [24c]. The resulting/ -hydroxy-y-ketoaldehydes are highly unstable, but may be trapped in situ through the addition of methanolic hydrazine to afford 3,5-disubstituted pyridazines (Table 22.4). 

The correlation between allylboronic ester stereochemistry and aldehyde diastereoface selection stands in contrast to the behavior of stereochemicaUy defined lithium enolates, which generally exhibit a preference for the Cram mode of addition to chiral aldehydes from either enolate geometry (cf, eqs. [72]-[77]). The stereochemical... 

The stereoselectivity resulting from interactions of chiral aldehydes and enolates has been useful in the construction of systems with several contiguous chiral centers. 

I. From Aldehydes and Ketones with 1-Alkoxy-l-lithiocyclopropanes and from Enol Ethers by Cyclopropanation... 

From enol acetates 2-3 Treatment of aldehydes or ketones with base... 

Exercise 17-11 The direct halogenation of aldehydes under either acidic or basic conditions is complicated by side reactions involving either oxidation of the aldehyde —CHO group or additions to the—CH—0 double bond. Therefore the synthesis of a-halo aldehydes by the procedure described for ketones is not of much practical value. a-Haio aldehydes can be prepared indirectly from the enol ethanoate of the aldehyde. The enol ethanoate is made by treating the aldehyde with ethanoic anhydride and potassium ethanoate. The overall sequence follows ... 

Tetrasubstituted pyrroles could be obtained by skeletal rearrangement of 1,3-oxazolidines, a reaction that is substantially accelerated by microwave irradiation. Dielectric heating of a 1,3-oxazolidine 7, absorbed on silica gel (1 g silica gel/mmol) for 5 min in a household MW oven (900 W power) cleanly afforded the 1,2,3,4-tetrasubstituted pyrrole 8 in 78% yield, thus reducing the reaction time from hours to minutes (Scheme 5) [24], 1,3-Oxazolidines are accessible in one-pot, two-step, solvent-free domino processes (see also Sect. 2.6). The first domino process, a multi-component reaction (MCR) between 2 equivalents of alkyl propiolate and 1 equivalent of aldehyde furnished enol ethers 9 (Scheme 5). Subsequent microwave-accelerated solvent-free reactions of enol ethers 9 with primary amines on silica support afforded intermediate 1,3-oxazolidines, which in situ rearranged to the tetrasubstituted pyrroles (2nd domino process). Performed in a one-pot format, these... 

Modem variants of the Mukaiyama aldol addition start from silyl enol ethers, not from enol ethers, and use an aldehyde instead of the acetal as the electrophile. Mukaiyama aldol additions of this kind have been included in the C,C coupling reactions that build the basic repertoire of modem synthetic chemistry and can even be performed in a catalytic enantioselective fashion. 

As can be expected, use of ethyl diazoacetate procides y-oxoesters15) ory-oxocarboxylic acids 16) from enol ethers. Emploging the Julia method with 25 leads to the p,y-unsaturated aldehyde 26. Thus, this sequence establishes an overall a-vinylation of a given aldehyde n 17 18). 

The alkylation of doubly deprotonated 6-hydroxy esters, an example of which 1s described 1n the procedure above, 1s not just a useful alternative to the diastereoselective aldol-type addition, but can supply enantiomerically pure products from appropriate precursors, and it can be used for the preparation of a/x-disubstituted derivatives (see 4 in Scheme 1). These were hitherto not available stereoselectively from enolates of a-branched esters and aldehydes. 

Two key intermediates in the production of vitamin A are citral and the so-called C5 aldehyde. In the modem routes to these intermediates, developed by BASF and Hoffmann-La Roche, catalytic technologies are used (see Fig. 2.29 and 2.30). Thus, in the synthesis of citral, the key intermediate is 2-methyl-l-butene-4-ol, formed by acid-catalyzed condensation of isobutene with formaldehyde. Air oxidation of this alcohol over a silver catalyst at 500°C (the same catalyst as is used for the oxidation of methanol to formaldehyde) affords the corresponding aldehyde. Isomerization of 2-methyl-l-butene-4-ol over a palladium-on-charcoal catalyst affords 2-methyl-2-butene-4-ol. The latter is then reacted with the aldehyde from the oxidation step to form an enol ether. Thermal Claisen rearrangement of the enol ether gives citral (see Fig. 2.29). 

Other functional polyfluorinated compounds are available by addition of perhaloalkyl halides to enol derivatives, e.g. formation of 1 and 2 (see also Table 4). The adducts formed from enol acetates or enol ethers are not very stable and their hydrolysis to give a-perhaloalkyl aldehydes or ketones is often rapid. However, the enol derivatives can be transformed either to give ketals using alcohols or to give various products by oxidation and reduction reactions. The peculiar perfluoroalkyl iodide addition to enamines is spontaneous at room temperature, e.g. formation of 3. ... 

A stoichiometric amount of 3f catalyzed the asymmetric aldol reaction of aldehydes with enol silyl ethers and subsequent asymmetric reduction, in one pot, to afford syn 1,3-diols with high enantioselectivity (Eq. 49) [43b]. With a variety of aldehydes, 1,3-diols were obtained in moderate yields (53-70 %) with high syn diastereoselectivity. The syn 1,3-diols prepared from aliphatic aldehydes in the reaction (in EtCN as sol-... 

Acetals are a versatile alternative to aldehydes and ketones which have wide applicability in the titanium-mediated aldol reaction [51], Equation (10) shows the difference between an acetal and the parent aldehyde in the diastereoselective aldol reaction [52]. In this example the latter results in better diastereoselectivity than the former. The reactivity of an aldehyde and its acetal have been compared (Eq. 11) [53]. More examples of the directed aldol reaction starting from enol derivatives of aldehydes and ketones are summarized in Table 1. 

A similar electron transfer mechanism has been proposed for photosensitized electron transfer catalysis of the Mukaiyama-aldol reaction of aldehydes and ketones with enol silanes [301], Photoinduced electron transfer from enol silanes to a monocationic -bridged porphyrin [302, 303] leads to the production of a... 

Two possible routes are suggested for osazone formation under the usual conditions. The first involves formation of the phenylhydrazone, isomerization to an enolic form XLI followed by the loss of aniline to form an imino ketone XLII (or an imino aldehyde from a ketose) which is then converted to the osazone. Isbell depicts this reaction in terms... 

In conclusion, C-C bond formation on carbohydrates has absorbed lots of widely used methods from general synthetic organic chemistry. Typical among these methods are intramolecular alkylation and intramolecular condensation of aldehyde with enolates, phosphonates, and nitro-stabilized anions. Metal-mediated radical reactions, cycloadditions, and rearrangements have also been applied frequently. 

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