Aldol isomerization

Scheme 4.15 Enzymatic synthesis of L-glucose and L-fucose by aldolization/isomerization.

The 3.8-nonadienoate 91, obtained by dimerization-carbonylation, has been converted into several natural products. The synthesis of brevicomin is described in Chapter 3, Section 2.3. Another royal jelly acid [2-decenedioic acid (149)] was prepared by cobalt carbonyl-catalyzed carbonylation of the terminal double bond, followed by isomerization of the double bond to the conjugated position to afford 149[122], Hexadecane-2,15-dione (150) can be prepared by Pd-catalyzed oxidation of the terminal double bond, hydrogenation of the internal double bond, and coupling by Kolbe electrolysis. Aldol condensation mediated by an organoaluminum reagent gave the unsaturated cyclic ketone 151 in 65% yield. Finally, the reduction of 151 afforded muscone (152)[123]. n-Octanol is produced commercially as described beforc[32]. 

Class (2) reactions are performed in the presence of dilute to concentrated aqueous sodium hydroxide, powdered potassium hydroxide, or, at elevated temperatures, soHd potassium carbonate, depending on the acidity of the substrate. Alkylations are possible in the presence of concentrated NaOH and a PT catalyst for substrates with conventional pX values up to - 23. This includes many C—H acidic compounds such as fiuorene, phenylacetylene, simple ketones, phenylacetonittile. Furthermore, alkylations of N—H, O—H, S—H, and P—H bonds, and ambident anions are weU known. Other basic phase-transfer reactions are hydrolyses, saponifications, isomerizations, H/D exchange, Michael-type additions, aldol, Darzens, and similar... 

Certain starting materials may give rise to the non-selective formation of regioisomeric enolates, leading to a mixture of isomeric products. Furthermore a ,/3-unsaturated carbonyl compounds tend to polymerize. The classical Michael procedure (i.e. polar solvent, catalytic amount of base) thus has some disadvantages, some of which can be avoided by use of preformed enolates. The CH-acidic carbonyl compound is converted to the corresponding enolate by treatment with an equimolar amount of a strong base, and in a second step the a ,/3-unsaturated carbonyl compound is added—often at low temperature. A similar procedure is applied for variants of the aldol reaction. 

Treatment of the minor product formed in the intramolecular aldol cyclization of 2,5-heptanedione (Problems 23.30 and 23.31) with aqueous NaOH converts it into the major product. Propose a mechanism to account for this base-catalyzed isomerization. 

Remote olefins are maintained in BINAP-Rh(l)-catalyzed allylic amine isomerizations 1. (CH3)2CO, aq. NaOH (aldol condensatlon/dehydratlon) 2. H2, Pt/C... 

It is noteworthy that reaction diastereoselectivity closely parallels the isomeric purity of the allyiboronates, thus underscoring the requirement that the method of reagent synthesis be highly stereoselective. The data presented in Table 1 also provide strong evidence for the involvement of chair-like, cyclic transition states, analogous to the transition states previously invoked for aldol reactions46. 

Overall yield using yields of chromatographed, isomericaliy pure aldol products. b Elimination requires forcing conditions ( )-isomer probably formed by isomerization of the kineticaily formed (Z)-isomer. The anti.anti- and anti.svn-aldol products were not separable. 

Figure 10.26 Short enzymatic synthesis of L-fucose and hydrophobic analogs, and of L-rhamnose, by aldolization-ketol isomerization, including kinetic resolution of racemic hydroxyaldehyde precursors.

Under other reaction conditions, the product can result from thermodynamic control. Aldol reactions can be effected for many compounds using less than a stoichiometric amount of base. In these circumstances, the aldol reaction is reversible and the product ratio is determined by the relative stability of the various possible products. Thermodynamic conditions also permit equilibration among the enolates of the nucleophile. The conditions that lead to equilibration include higher reaction temperatures, protic or polar dissociating solvents, and the use of weakly coordinating cations. Thermodynamic conditions can be used to enrich the composition in the most stable of the isomeric products. 

As already discussed for aldol and Robinson annulation reactions, proline is also a catalyst for enantioselective Mannich reactions. Proline effectively catalyzes the reactions of aldehydes such as 3-methylbutanal and hexanal with /V-arylimines of ethyl glyoxalate.196 These reactions show 2,3-syn selectivity, although the products with small alkyl groups tend to isomerize to the anti isomer. 

In Section 3.5 on alkene isomerization, it was mentioned that Li and co-workers reported a RuCl2(PPh3)3-catalyzed shuffling of functional groups of allylic alcohols in water (Eq. 3.35).140 Since the reaction proceeds through an enol intermediate, allyl alcohols can thus be considered as enol equivalents.203 This has been developed into an aldol-type reaction by reacting allyl alcohols with aldehyde (Scheme 3.11).204 The presence of In(OAc)3 promoted the aldol reaction with a-vinylbenzyl alcohol and aldehyde.205... 

Heck reactions can also be combined with anion capture processes, animations, metatheses, aldol and Michael reactions, and isomerizations. The anion capture process has also been widely used with other Pd-catalyzed transformations. Outstanding examples of many different combinations have been developed by Grigg and coworkers, though not all of them match the requirements of a domino process. All of these reactions will be detailed here, despite the fact the nature of these intermediate transformations would also have permitted their discussion in Chapter 2. 

Epoxides are reactive substrates, which can easily be isomerized to give aldehydes or ketones. Kulawiec and coworkers have combined a Pd-catalyzed isomerization of mono and diepoxide 6/1-348 or 6/1-349 and 6/1-352 or 6/1-353, followed by an aldol condensation to give either cyclopentenones or cyclohexenones 6/1-350, 6/1-351, 6/1-354 and 6/1-355, respectively (Scheme 6/1.89) [165]. 

Scheme 6/4.38. Domino isomerization/aldol reaction of allylic alcohols and aldehydes using (COT)Fe(CO)3 as catalyst.

In contrast to the Johnson s D —> A-ring construction approach, Brown devised an A —> D-ring construction approach [22]. Starting from Wieland-Miescher ketone (30), a common source of the A, B-rings in the de novo synthesis of steroids, the C-ring was introduced via hydrazone allylation, ozonolysis, aldol condensation, and olefin isomerization (31 > 32). The D-ring was assembled by a reductive alkylation... 

As predicted, l,2,3,4-13C-labeled acetone dicarboxylate (15) provided an intact three-carbon chain into lycopodine. It also helped to explain why two molecules of pelletierine (12) were not incorporated (Scheme 6.3) [12]. As before, lysine (6) is converted to piperideine (8) via a decarboxylation. Then a Mannich reaction of labeled 15 with 8 provides pelletierine 12. The other half of the molecule to be incorporated must be pelletierine-like (12-CC>2Na), still containing one of the carboxylates. An aldol reaction of the two pelletierine fragments and a series of transformations leads to phlegmarine 9. Oxidation of 9 involving imine formation between N-C5, isomerization to the enamine and then cyclization onto an imine (at N-C13), provides lycopodine 10. Phlegmarine 9 and lycopodine 10 are proposed as... 

In order to gain more insight into this proposed mechanism, Montgomery and co-workers tried to isolate the intermediate metallacycle. This effort has also led to the development of a new [2 + 2 + 2]-reaction.226 It has been found that the presence of bipyridine (bpy) or tetramethylethylenediamine (TMEDA) makes the isolation of the desired metallacycles possible, and these metallacycles are characterized by X-ray analysis (Scheme 56).227 Besides important mechanistic implications for enyne isomerizations or intramolecular [4 + 2]-cycloadditions,228 the TMEDA-stabilized seven-membered nickel enolates 224 have been further trapped in aldol reactions, opening an access to complex polycyclic compounds and notably triquinanes. Thus, up to three rings can be generated in the intramolecular version of the reaction, for example, spirocycle 223 was obtained in 49% yield as a single diastereomer from dialdehyde 222 (Scheme 56).229... 

Though several intermolecular catalytic reductive aldol additions are reported, corresponding reductive cyclizations have received less attention. The first reported reductive aldol cyclization involves use of a (diketonato)cobalt(ll) precatalyst in conjunction with PhSiHj as terminal reductant.48,486 The reductive cyclization is applicable to aromatic and heteroaromatic enone partners to form five- and six-membered rings. As demonstrated by the reductive cyclization of mono-enone mono-aldehyde 65a to afford aldol 65b, exceptionally high levels of ty -diastereoselectivity are observed. Interestingly, exposure of the substrate 65a to low-valent nickel in the presence of excess Et2Zn provides the isomeric homoaldol cyclization product 65c via reductive coupling to the enone /3-position (Scheme 43).47a... 

The high levels of, sy -diastereoselectivity suggest aldolization through a closed Zimmerman-Traxler-type transition structure via intermediacy of the Z-enolate. When the transformation is performed using PhSiDj, a single deuterium is incorporated at the /3-position of the product as an equimolar mixture of epimers, inferring rapid isomerization of the kinetically formed cobalt enolate prior to cyclization or reversible aldol addition. The stereochemistry of the deuterated product was established by single crystal neutron diffraction analysis (Scheme 44). 

The isomerization of an O-silyl ketene acetal to a C-silyl ester is catalyzed by a cationic zirconocene—alkoxide complex [92], This catalysis was observed as a side reaction in the zirconocene-catalyzed Mukaiyama aldol reactions and has not yet found synthetic use. The solvent-free bis(triflate) [Cp2Zr(OTf)2] also catalyzes the reaction in nitromethane (no reaction in dichloromethane), but in this case there may be competitive catalysis by TMSOTf (cf. the above discussion of the catalysis of the Mukaiyama aldol reaction) [91] (Scheme 8.51). 

A novd example of a catalytic enantioselective domino process1201 is the inter-intramolecular nitro-aldol reaction described by Shibasaki et al which generates substituted indanones. As catalyst a praseodym-heterobimetallic complex with binaph-thol as chiral ligand is employed. Treatment of keto-aldehyde 41 with nitromethane in the presence of the catalyst 46 at -40 °C and successive warming to room temperature affords diredly the produd 42 in an overall yield of 41 % and 96 % ee after several recrystallizations (scheme 9). As intermediates the nitromethane adduct 43 and the hemiacetal 44 can be proposed. In a second aldol reaction 44 leads to 45 which isomerizes to the thermodynamically more stable epimer 42. 

These retro-Aldol and -Michael reactions can, obviously, follow an isomerization of the aldose to the corresponding ketose, leading thereby to different Aldol fragments or retro-Michael products. Keto-enol exchange as well as the retro-... 

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