Retro aldol processes

Cinnamaldehyde has been efficiently isolated in high purity by fractional distillation from cassia and cinnamon bark essential oils. This material has been utili2ed in several manufacturing protocols (39—41) for the preparation of natural ben2aldehyde through a retro-aldol process. Since the late 1970s the demand for natural flavors has increased dramatically. This demand has led to a corresponding requirement for a more extensive line of readily available natural aroma chemicals for flavor creation. 

Ogasawara and coworkers have also published a complete series of threefold anionic domino reactions, all of which are based on an initial retro-aldol process. For instance, starting from chiral bicyclo[3.2.1]octenone 2-437, a formal total synthesis of (-)-morphine (2-445) [233] has been successfully performed (Scheme 2.103) [234]. Transformation of 2-437 into the substrate 2-488, necessary for the domino reaction, was achieved in seven linear steps. The domino process was then initiated by simply refluxing a solution of 2-438 in benzene in the presence of ethy-... 

This same concept applies to spiroannulations of six membered rings and is illustrated in a synthesis of acorenone B 155 as outlined in Scheme 547). The notion of alkylative carbonyl transposition permits the spiro enone 156 to become a logical intermediate. The standard analysis by a retro-aldol process translates the spiro ring system of acorenone B into a geminal alkylation problem as revealed by... 

Ketals 147, 148 and 149 cleanly photolysed to give the expected products 150-153 by an analogous photo-retro-aldol process in aqueous solution (pH > 7) (equation 74). 

C((x)-C(p) bond cleavage in a-amino acids is precedented by the PLP-containing enzyme serine hydroxymethyltransferase, interconverting serine with glycine and a formaldehyde equivalent, but in that case C-C bond cleavage is a retro aldol process This route is not obviously open to ACPC (9). 

Mg enolates generated from Mg bisamides can be used in aldol addition reactions with alkyl, aryl, and cyclic ketones. As shown in Scheme 3.40, these reactions are significant in that the self-coupling of ketones in aldol reactions to give tertiary yS-hydroxyketones are also possible. More specifically, these transformations are achieved principally by the use of relatively high reaction temperatures between 25 °C and 60 °C. Such conditions are a notable departure from the widely used lithium-mediated aldol additions, where increasing the reaction temperature results in retro-aldol processes and also elimination of LiOH to give enone products [30]. 

CHsONa, La(OTf)3, MeOH, 97-100% yield. This method was developed specifically for the isomerization free cleavage of 6-cAo-acetoxybicyclo-[2.2.2]octan-2-ones. " Isomerization can occur through a retro aldol process in the presence of base. 

The 5-nitrotetrahydro-l,3-oxazine (217) is obtained from 2-hydroxymethyl-2-nitro-1,3-propanediol (216) by treatment with l,3,5-trimethylhexahydro-l,3,5-triazine. When reacted with metal alkoxides, it yields the corresponding nitronate (218) through a retro-aldol process which proceeds with loss of formaldehyde (Scheme 61) <85TL323>. 

An unexpected bridged bicyclic furan was formed by rearrangement of a tetrahydroxydecalinone, as illustrated below. Presumably the reaction proceeds via a base-promoted retro-aldol process <04TL6753>. 

Snider published the synthesis of desmethylamino FR901483 in 1998 [9] and one year later, the first total synthesis of natural (-)-FR901483 [2]. The disconnective analysis is outlined in Scheme 5. The key step in the retrosynthetic analysis is the disassembly of the azatricyclic structure of 1 by a retro-aldol process, which leads to aldehyde 6. In the forward sense, while this approach should provide efficient access to the ring system,... 

Only moderate variations in kinetic ElZ) ratios are observed except for LHDS, which favored the thermodynamically more stable (Z) enolate. The sterically demanding LTMP favored formation of the kinetic E enolate.22 An equilibration process is clearly occurring, possibly by an aldol addition — retro-aldol process that was suggested by Rathke and co-workers (via 26). The aldol condensation will be discussed in Section 9.4.A. Addition of HMPT (hexamethylphosphorus triamide) destabilizes and deaggregates aldolate 26, promoting equilibration. 

Basavaiah et al. have developed a similar domino Michael-Mukaiyama-retro-aldol process of cyclic enones with acetals, which conveniently were promoted by mixing a sulfide, TBDMSOTf, in the presence of the Hiinig s base. 

Careful experiments using deuterated substrate 55 by Kakinuma and Eguchi revealed that (1) the Perrier carbocyclization of 55 involved no retro-aldol process and was thus an irreversible reaction and (2) the overall cyclization reaction was nonstereoselective with respect to the C-6 methylene site fScheme 12.15). Based on the results of complete stereochemical scrambling at C-6 in cyclized product 57, Kakinuma and Eguchi proposed the presence of radical intermediate 56. They also suggested that the cyclization might be a radical process, although this model could not explain the stereoselectivity at C-5. 

Most of the hydroxylated pulvinic acids from Basidiomycetes were first synthesised (7i, 200, 607, 608, 609) using the classical methods of VoLHARD 687) and Asano (52). For unsymmetrically substituted pulvinic acids such as xerocomic acid (72) the procedure is shown in Scheme 12 202). The use of sodium hydride as base in the second condensation step is recommended ( ) in order to reduce contamination of the dinitrile (99) with symmetrical by-products which arise via retro-aldol processes when sodium ethoxide is used. This route has also been followed for the synthesis of " C-labelled compounds 514). 

If one starts with the separately prepared enolsilylether 81, mercury-catalyzed cyclization gives a high yield of 79, while the easy-to-make aldol 82 leads to 80 after a thermal retro-aldol process (34). 

The reverse, retro-aldol process follows the same pathway, each step run in reverse ... 

When enol esters derived from P-diketones are used in the photocycloaddition reaction with an alkene (de Mayo s reaction), a hydrolysis of the ester group of the cyclobutyl intermediate allows opening of the cyclobutane ring by a retro-Aldolization process and the formation of medium-ring cychc compounds. Similarly, hydrolysis of the cycloadduct obtained by irradiation of 3-carbomethoxycyclopentenone in the presence of a P-ketoester allowed facile access to ( )-norasteriscanoHde (Scheme 18). 

Dibenzoylmethane undergoes a de Mayo-type photoaddition reaction at the carbonyl group of BQ, NQ, and 9,10-anthraquinone to give hydroxyoxetanes that, on further irradiation, afford 1,5-diketones in reasonable yield by a retro-Aldol process. " The reaction is outlined in Figure 87.5 for NQ and the addition is reported to be reversed by 254-nm radiation, as is the conversion of the hydroxyoxetane to the 1,5-diketone with 300-nm radiation. 

Aldol reaction is well known to be an intrinsically reversible process. Microscopically, asymmetric retro aldol reaction would address those challenging substrates which are normally sluggish under the typical asymmetric aldol conditions. Unfortunately, though principally conceivable, such asymmetric retro aldol processes remain basically underdeveloped in asymmetric synthesis. In their further explorations on chiral primary amine catalysis, Luo group found that simple chiral primary-tertiary diamine such as 24,26,27,29, 33 catalyze unprecedentedly stereoselective retro aldol reactions (Scheme 5.13). 

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