Aldol reaction ring size

Several cyditol derivatives of varying ring size, for example, (69)/(70), have been prepared based on an enzymatic aldolization as the initial step. Substrates carrying suitably installed C,H-acidic functional groups such as nitro, ester, phosphonate (or halogen) functionalities made use of facile intramolecular nucleophilic (or radical) cyclization reactions ensuing, or subsequent to, the enzyme-catalyzed aldol addition (Figure 10.27) [134—137]. 

The transformation of VIII/3 to VIII/4 is called a fragmentation1 [3] [4]. As in the aldol reaction the reverse version of the fragmentation also is known (VIII/4 — VIII/3). An example of this reaction type is the so-called Prins reaction the acid catalyzed (base catalysis is also possible) addition of an olefin to formaldehyde in order to get a 1,3-diol. Further examples are known in the field of transannular reactions in medium-sized rings [5],... 

Aldol reaction between a ketone and an aldehyde can be controlled by prior conversion of the ketone into the ethyloxalyl derivative before reaction with the aldehyde. The keto-lactone so formed is decomposed to an alkene moiety with base. This method is particularly well suited to the formation of a-alkylidene-cyclo-alkanones (ring size >6) and a-alkylidene-y-lactones (Scheme 73). ... 

When we extended the activated olefins to cyclohept-2-en-l-one and cyclooct-2-en-l-one we found that the reaction is very complicated, because the Lewis bases, solvents and the ring-size of the cyclic enone can all significantly affect the MBH reaction rate and even the reaction product. The reaction of cyclohept-2-en-l-one with A-arylidene-4-methylbenzenesulfonamides afforded the usual MBH adducts 203 along with abnormal adducts 204, whereas the corresponding reaction of cyclooct-2-en-l-one provided different aldol products (205-207) depending upon the Lewis base employed (no MBH adduct was formed in any of the cases) (Scheme 2.104). Moreover, the formation of aldol products 209 along with the usual MBH adducts 208 has been observed in the reaction between cyclopent-2-en-l-one and aromatic aldehydes in the presence of BU3P (Scheme 2.105). 

Shiina, I., Hashizume, M., Yamai, Y., Oshiutni, H., Shimazaki, T, Takasuna, Y, and Ibuka, R. (2005) Enantioselective total synthesis of octalactin A using asymmetric aldol reactions and a rapid lactonization to form a medium-sized ring. Chem, Ear, J 11, 6601-6608. 

The obtained syn diastereoselectivity with acyclic ketone donors could be explained by Z-enamine transition state (Scheme 5.8), whereas the reactions of cyclic ketones such as protected DHA, which are capable only of forming fi-enamine due to ring size constraints, give preferentially fl h-aldol adducts (Scheme 5.8). These models can be applied to other primary-tertiary diamine catalyzed aldol reactions. 

Three-cmbon ring expansionThe cyclic p-keto esters 1 with a 4-oxopentyl group at the a-position do not undergo the expected aldol condensation on treatment with KOC(CH3)3 in DMSO, but undergo ring expansion to medium-size ketones (2). The reaction may involve aldol and retro-aldol condensation. A similar... 

In fact, diketones in a medium sized ring give several transannular reactions such as pinacol coupling [equation (i)] or aldolization [equation The later reaction also occurs during hydrogenation of aliphatic monoketones under favorable conditions (Pd-on-carbon, zeolite, 200°C, 4 X 10 kPa) to produce methyl isobutyl ketone from acetone (in 96%) -... 

In some cases, there is a competition within a molecule for closure to rings of different sizes. If the closure is an irreversible reaction such as alkylation of an enolate, kinetic control may allow three-membered ring closure to predominate over five-membered as in Equation 8.17 [27]. The electrophilic carbon closer to the nucleophilic site is found first, in spite of the incorporation of ring strain. With reversible reactions, the thermodynamic product predominates. That is, the low strain five- or six-membered rings whl form to the exclusion of three- or four-membered alternatives (Scheme 8.13). In Claisen and aldol cychzations, five- and six-membered rings are not in competition with each other. Seven-membered rings may sometimes be closed readily without high dilution (Eq. 8.18) [28]. 

Next, let s consider a problem similar to we encountered for mixed aldol condensations. Which a-catbon atom will react with which carbonyl carbon atom if rings of similar size could result Under the reaction conditions, all possible enolates can form in low concentration. Thus, we can consider the various carbonyl groups and determine which is more likely to react with the nucleophilic carbon atom of an enolate. If one carbonyl group is an aldehyde and the other a ketone, the answer to the question is easy because the aldehyde carbonyl group is more susceptible to attack by a nucleophile. 

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