Aldol rearrangement, retro

In systems which preclude retro-aldol condensations, benzilic acid rearrangement of 11,12-diketones affords normal C-norsteroids in fair yields. For example, 11,12-diketotigogenin (82) is converted to the C-nor-(5oc,9(, 22a)-spirostane (83) in 65 % yield by barium oxide in boiling aqueous methyl-cellosolve. ... 

The first step in the nonreversible degradation reactions is the formation of a reactive a-dicarbonyl species through the p-elimination of a hydroxide ion. The subsequent reaction pathways to all degradation products can be described by just five reaction types, namely, p-elimination, benzilic acid rearrangement, a-dicarbonyl cleavage, aldol condensation, and retro-aldol condensation (see Fig. 7).31 Retro-aldol condensation and a-dicarbonyl cleavage involve C-C bond... 

Leaving the (retro-)aldol addition-initiated threefold anionic domino processes, we are now describing sequences which are initiated by a SN-type transformation. In particular, domino reactions based on SN/1,4-Brook rearrangement/SN reactions are well known. For example, the group of Schaumann obtained functionalized cyclopentanols of type 2-461 by addition of lithiated silyldithioacetals 2-458 to epoxy-homoallyl tosylates 2-459 in 41-75% yield (Scheme 2.106) [248]. 

A solution of the ester (56) and the tetrahydropyranyl ether (57) was irradiated to form the intermediate compound (58), which would rearrange through a retro-aldol reaction and a hemiacetal formation route to the less strained six-membered heterocycle (59). The hemiacetal (59) could be converted to loganin (55) in several steps Z3>. 

Aldoses generally undergo benzilic acid-type rearrangements to produce saccharinic acids, as well as reverse aldol (retro-aldol) reactions with j3-elimination, to afford a-dicarbonyl compounds. The products of these reactions are in considerable evidence at elevated temperatures. The conversions of ketoses and alduronic acids, however, are also of definite interest and will be emphasized as well. Furthermore, aldoses undergo anomerization and aldose-ketose isomerization (the Lobry de Bruyn-Alberda van Ekenstein transformation ) in aqueous base. However, both of these isomerizations are more appropriately studied at room temperature, and will be considered only in the context of other mechanisms. 

Due to the 18-CH3 —> 17-CH3 shift, a carbocation centered at C13 is formed, and further 14a-H elimination originates the A13-double bond. 16p-Epimers can be formed due to an acid-catalyzed retro-aldol equilibrium involving the 16-hydroxy-20-keto function of the rearranged steroid, under the reaction conditions employed, which is responsible for the epimerization at C16, as previously discussed by Herzog et al. [125, 126] and reviewed by Wendler (Scheme 34) [111]. 

The formation of monohydroxy acids having chains of four, three, or two carbons can be rationalized with the same mechanism of oxidation of the corresponding enediol. The 1,2-enediol can rearrange to the 2,3- or 3,4-enolates, which undergo the oxidative cleavage. Alternatively, the enediol may undergo a retro-aldol condensation followed by oxidation. 

The procedure of isotope effect studies will be illustrated on several examples. First one concerns studies of phosphonate-phosphate rearrangement (Scheme 1). Phosphite 3 reacts in the presence of triethylamine with o-nitrobenzaldehyde (Pudovik reaction) to form 1-hydroxyphosphonate 4 as mixture of two diastereo-isomers, 1 1. Amine also catalyses the reverse refro-phospho-aldol (retro-Abramov) reaction of 1-hydroxyphosphonate to phosphite and aldehyde and rearrangement to phosphate 5. In acetonitrile at 65°C Pudovik reaction is much faster than of retro-Abramov reaction and phosphonate-phosphate rearrangement, which rates are comparable. Important fact for the mechanism elucidation was experimental evidence that rearrangement occurs with retention of configuration at phosphorus atom.49... 

The central bond in (photochemically) easily accesible bicyclo[n.2.0]-alkan-2-ones (n = 3,4) can be cleaved by retro-aldol reaction (cf. Sch. 2), but also by treatment with Broenstedt- and Lewis-acids. This is shown in Sch. 16 for the synthesis of (i)descarboxyquadrone (55) starting from indenone 56 via the cycloadduct 57 which reacts with HC1 to 58 [69], or by the preparation of the AB-ring core of Taxol 59 from cyclopentenone 60 via cycloadduct 61 which rearranges to 62 in the presence of TiCl4 [70]. 

The surprising rearrangement of an aminocycloheptenone to the aminoacylcyclo-pentenone skeleton321 is achieved by a nucleophilic attack of the hydroxide ion at the -position of an enaminone, a special reaction known only for a-ketoenamines. This step is followed by a retro-aldol cleavage of the cycloheptanone ring and a subsequent aldol cyclization yields the cyclopentane derivative (equation 240). 

In an alternative approach to molecules of this type, Dauben and Hart examined the base-catalyzed rearrangement of vinylogous 0-hydroxy ketones such as 305 and 308 (Scheme 48).321 Their conversion to 306 and 309 can be accounted for in terms of a vinylogous retro-aldol condensation followed by intramolecular 1,4 addition of an intermediate dienolate to the resulting enone moiety. Subsequent to this reaction, conjugation of the double bond away from the ring juncture followed by a transannular vinylogous aldol condensation produces the observed products. 

Figure 4 Deoxyxylulose phosphate isomero-reductase (DXR) catalyzed conversion of DXP 11 into MEP 12 (a) a-ketol rearrangement, (b) retro-aldol/aldol reaction. Fosmidomycin 19, a DXR inhibitor.

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