Intramolecular aldol addition

Microbial degradation of validamycin A (8) with a cell suspension of Pseudomonas dentrificans afforded validamine (202) and valienamine (203). Hydrogenolysis of validamycin B, followed by acid hydrolysis, yielded hydroxy validamine (204). Valiolamine (205) was isolated and shown to be a component of validamycin G. ° Biosynthesis of these carba-glycosylamines was extensively studied, and the intramolecular aldol addition of the... 

Intermediate 29-1 contains the tricyclic skeleton of longifolene, shorn of its substituents, but containing carbonyl groups suitably placed so that the methyl groups at C(2) and C(6) and the C(11) methylene can be introduced. The retrosynthetic Step 29-1 =+ 29-11 corresponds to an intramolecular aldol addition. However, 29-11 is clearly strained relative to 29-1, and so (with OR = OH) should open to 29-1. 

Butenschon and co-workers nicely demonstrated that treatment of (benzocydobu-tendione)tricarbonylchromium(O) (178) with an excess of lithiated methoxyallene 42 gives the tricyclic complex 179. It is the result of a dianionic oxy-Cope rearrangement and a subsequent intramolecular aldol addition (Eq. 8.32) [112]. 

Upon fonnation of intermediate LI, conjugate addition to a chalcone and subsequent proton transfer is proposed to lead to enolate LIII (Scheme 37). An intramolecular aldol addition provides activated carboxylate LIV in which alkoxide acylation regenerates the catalyst and delivers p-lactone LVI which, upon decarboxylation, gives rise to a trisubstituted cyclopentene. 

A particularly important example is the Robinson annulation, a procedure which constructs a new six-membered ring from a ketone.83 84 The reaction sequence starts with conjugate addition of the enolate to methyl vinyl ketone or a similar enone. This is followed by cyclization involving an intramolecular aldol addition. Dehydration frequently occurs to give a cyclohexenone derivative. Scheme 2.10 shows some examples of Robinson annulation reactions. 

The C-l oxygen was introduced at step F-l by enolate oxidation. The C ring was constructed by building up a substituent at C-l6 (steps G and H) and then performing an intramolecular aldol addition (step I). 

The best chemical and optical yields in the above reactions are obtained by using (S)- or (R)-proline. Some 19-norsteroids are prepared on an industrial scale from products of intramolecular aldol additions catalyzed by (S)-proline 68). 

Zinc bisenolate 136 (Figure 11) is prepared by the transmetallation of propiophenone lithium enolate with 0.5 equivalents of ZnBr2 136 reacts with aldehydes, both aliphatic and aromatic, in a domino aldol reaction which mimics the action of aldolases167. The first aldol reaction between 136 and the aldehyde produces zinc aldolate 137, which then undergoes a second intramolecular aldol addition to adduct 138. Spontaneous hemiacetalization affords 139, where all large substituents occupy equatorial positions168. 

The /l-hydroxy ketone is the intermediate formed in the intramolecular aldol addition step, and the diketone that leads to it is the intermediate that is formed in the conjugate addition step. The relationship of the starting materials to the intermediates and product is now more evident. 

The first step is a Ferrier mercuration9 reaction on the enol ether double bond, which initiates ring-opening of the pyranoside to form 13 (Scheme 11.5). An intramolecular aldol addition reaction then ensues to give 14. After 0-mesylation, 15 undergoes an Elcb elimination reaction via enolate 16. 

Because a 1,4-diketone has two different sets of a-hydrogens, two different intramolecular addition products can potentially form—one with a five-membered ring, the other with a three-membered ring. The greater stability of five- and six-membered rings causes them to be formed preferentially (Section 2.11). In fact, the five-membered ring product is the only product formed from the intramolecular aldol addition of a 1,4-diketone. 

The intramolecular aldol addition of a 1,6-diketone potentially can lead to either a seven- or a five-membered ring product. Again, the more stable product—the one with the five-membered ring—is the only product of the reaction. 

Diketones and 1,7-diketones undergo intramolecular aldol additions to form six-membered ring products. 

If the preference for formation of a six-membered ring were not so great, what other cyclic product would be formed from the intramolecular aldol addition of... 

The first stage of a Robinson annulation is a Michael reaction that forms a 1,5-dike-tone. You just saw that a 1,5-diketone undergoes an intramolecular aldol addition when treated with base—this is the second stage of the Robinson annulation. Notice that a Robinson annulation results in a product that has a 2-cyclohexenone ring. 

In an aldol addition, the enolate of an aldehyde or a ketone reacts with the carbonyl carbon of a second molecule of aldehyde or ketone, forming a j8-hydroxyaldehyde or a jS-hydroxyketone. The new C—C bond forms between the a-carbon of one molecule and the carbon that formerly was the carbonyl carbon of the other molecule. The product of an aldol addition can be dehydrated to give an aldol condensation product. In a Claisen condensation, the enolate of an ester reacts with a second molecule of ester, eliminating an OR group to form a j8-keto ester. A Dieckmann condensation is an intramolecular Claisen condensation. A Robinson annulation is a ring-forming reaction in which a Michael reaction and an intramolecular aldol addition occur sequentially. 

Substituted pyrrole-2-carboxylic esters 19 are synthesized from A-tolylsulfonyl glycine ester 17 and vinyl ketones Kenner synthesis) [42]. By Michael addition and intramolecular aldol addition, they first yield pyrrolidine-2-carboxylic esters 18. These are converted into pyrroles by succesive H2O and sulfmic acid eliminations. 

Cyclization products of a completely different type are formed if C(8) of an extended dieneketene plays the role of an electrophilic center capable of taking part in an intramolecular aldol addition. Scheme 21 illustrates what happens in such cases. 

Scheme 21. Intramolecular Aldol Addition of an Extended Dieneketene Where C(8) Plays the Role of an Electrophilic Center [72f]...

Yields of the cyclized product are in the range 49—69%. Cyclization of a-bromo-carboxylates of o>-hydroxy-aldehydes to macrolides by an intramolecular aldol addition has been carried out by formation of the aluminium enolate (Zn, Et2Al-Cl) yields vary between 35 and 68%. 

This and other information show that nine Cg units from malonyl-coenzyme A and one C3 unit from propionyl-coenzyme A condense to form the linear polyketide intermediate shown below. These units are joined by acylation reactions that are the biosynthetic equivalent of the malonic ester synthesis we studied in Section 18.7. These reactions are also similar to the acylation steps we saw in fatty acid biosynthesis (Special Topic E in WileyPLUS). Once formed, the linear polyketide cyclizes by enzymatic reactions akin to intramolecular aldol additions and dehydrations (Section 19.6). These steps form the tetracyclic core of akiavinone. Phenolic hydroxyl groups in akiavinone arise by enolization of ketone carbonyl groups present after the aldol condensation steps. Several other transformations ultimately lead to daunomycin ... 

Intramolecular Aldol Additions via Secondary Amine Catalysis... 

The reductive coupling of bis(enones) is another reaction class that may involve alkene-derived metallacyclopentanes. Treatment of a symmetrical bis(enone) 89 tvith bis(r] -cy-cloocta-l,5-diene)nickel(0) (2) and butyllithium/zinc(II) chloride leads to coupling of the two enone -carbons followed by an intramolecular aldol addition to afford bicyclo[3.3.0]-octanols 90 (Scheme Sterically hindered enones have also been shovm to partic-... 

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