Dianion aldol condensation

Dianion aldol condensation reactions with Evans oxazolidinones or Oppolzer sultams as chiral auxiliaries have been demonstrated to be a useful method to generate the core skeleton of furofurans with diastereoselectivities of 5 1-20 1. Stereoselective total syntheses of the furofuran lignans (-l-)-eudesmin, (+)-yangambin, (—)-eudesmin, and (-)-yangambin according to this procedure have been reported (Equation 102) <2006TL6433>. 

The catalysed alkylation of l//,4//-pyrazol-5-ones is solvent dependent. In benzene, bis-alkylation occurs at the 4-position whereas, in a carbon disulphide benzene mixture, O-alkylation is observed, although the major product (4, Scheme 5.22) results from nucleophilic attack by the pyrazolone on the carbon disulphide, followed by alkylation of the dithiolate dianion [92]. The catalysed reaction of 2-thiono-3-aryl-thiazolidin-4-ones with alkylating agents under soliddiquid two-phase conditions results in alkylation at the 5-position (60-80%) [93]. The aldol condensation of the thiazolidinones with aryl aldehydes is also catalysed by quaternary ammonium salts. 

Three tactical approaches were surveyed in the evolution of our program. As outlined in Scheme 2.7, initially the aldol reaction (Path A) was performed direcdy between aldehyde 63 and the dianion derived from tricarbonyl 58. In this way, it was indeed possible to generate the Z-lithium enolate of 58 as shown in Scheme 2.7 which underwent successful aldol condensation. However, the resultant C7 P-hydroxyl functionality tended to cyclize to the C3 carbonyl group, thereby affording a rather unmanageable mixture of hydroxy ketone 59a and lactol 59b products. Lac-tol formation could be reversed following treatment of the crude aldol product under the conditions shown (Scheme 2.7) however, under these conditions an inseparable 4 1 mixture of diastereomeric products, 60 (a or b) 61 (a or b) [30], was obtained. This avenue was further impeded when it became apparent that neither the acetate nor TES groups were compatible with the remainder of the synthesis. 

In 1988, an improved synthesis of orlistat (1) was reported by the Hoffmann-La Roche discovery chemistry. The scheme involved a pivotal P-lactone 14. In the approach, an aldol condensation of aldehyde 7 with the dianion generated from octanoic acid and two equivalents of LDA. After tosylic acid-facilitated lactonization and Jones oxidation, the resultant lactone 14/14 was hydrogenated to establish two additional chiral centers. A battery of somewhat tedious protections and deprotections transformed 15 to P-lactone 19 via the intermediacy of 16,17, and 18. Six additional steps then converted P-lactone 19 to orlistat (1). This route may provide better overall yield in comparison to the previous scheme. However, too many protections and deprotections render this approach less elegant and not very practical for large-scale process. 

These reactions can also be made enantioselective (in which case only one of the four isomers predominates) ° ° by using chiral enol derivatives, chiral aldehydes or ketones, or both. ° " Chiral bases can be used, such as prohne, ° prohne derivatives, or chiral additives, used in conjunction with the base. ° A chiral binaphthol dianion has been used to catalyze the reaction. Chiral auxiharies ° ° have been developed that can be used in conjunction with the aldol condensation, as well as chiral catalysts and chiral ligands " ... 

Michael addition of the dianions derived from -dicarbonyl compounds facilitated yet another annulation - Michael addition of a dianion then intramolecular aldol condensation (Scheme 6.89) [112]. Complexation of ATPH with trans-chal-cone (112) in CH2CI2 at -78 °C, followed by treatment with the dianion of methyl acetoacetate gave, after quenching with aqueous HCl, bicyclic product 113 in a nearly quantitative yield. This system can be used for elaboration of the bicyclo [3,5,l]undecane ring system in 114, as can be found in the backbones of terpenoids and the taxol family. 

A.V. The Noyori Open-Chain Model. In the Mukaiyama reaction, the Zimmerman-Traxler and Evans models are not satisfactory for predicting diastereoselectivity. Several open (nonchelated) transition states have been considered as useful models. The condensation reaction of carboxylic acid dianions with aldehydes indicated that anti selectivity increased with increasing dissociation of the gegenion (the cation, M+),224 When analyzing an aldol condensation that does not possess the bridging cation required for the Zimmerman-Traxler model, an aldehyde and enolate adapt an eclipsed orientation as they approach. Noyori reported syn selectivity for the reaction of a mixture of (Z)-silyl enol ether 389 and ( )-silyl enol ether 390 with benzaldehyde in the presence of the cationic tris-(diethylamino) sulfonium (TAS).225 xhis reaction is clearly a variation of the Mukaiyama reaction, which does not usually proceed with good diastereoselectivity... 

Aldol condensation with aldoximes 0,C-Dianions as intermediates... 

The addition of the enolate of a 1,3-diketone to carbon disulfide generates a dianion, e.g. 55, which, following two successive S-alkylations, can produce 2-methylthio-3-acyl thiophenes 56. The first alkylation requires a 2-halo-carbonyl compound (a 2-halo-ketone in the example in Scheme 78) to allow the ring closure via an intramolecular aldol condensation and then a second with iodomethane to complete the sequence [126]. 

The dianiotf derived from a j3-ketoester by sequential treatment with sodium hydride and n-butyl-lithium alkylates exclusively at the y-position initial sodium enolate formation precludes the formation of carbonyl addition products and subsequent artifacts observed in the use of n-butyl-lithium alone. In addition to providing a convenient route to y-alkylated aceto-acetic esters, such dianions undergo ready aldol condensation, leading, after dehydration, to y3-unsaturated /3-ketoesters (Scheme 25). 

Very high diastereoselectivities are observed in the aldol condensations of secondary thioamide dianions (Z-configuration) with aldehydes. In this reaction the magnesium dianions afford threo aldol products, whereas the monoanion generated from the A -silyl derivatives of the same secondary thioamides affords the cry/Aro-alcohol. This therefore presents a versatile and selective synthesis of both isomers of P-hydroxy-thioamides. 

The photostimulated arylation of ketone enolate ions has been shown to be of fairly wide scope, although the reaction fails with the enolate ions of acetophenone and several -dicarbonyl compounds and is impeded by steric crowding. Coupled with new, mild methods for the regeneration of the carbonyl group (see Section 4), the chemistry of azomethine ketone derivatives has taken on new dimensions. The alkylation of such derivatives has been of particular interest recently. For example, two groups of workers have shown that only yn-dianions are formed on metalation of oximes. Furthermore, the dianions are configurationally stable, allowing alkylation and aldol condensation to be effected stereo-specifically (Scheme 22). - . 

Cydopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcydopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsucdnate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic acid or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

Aldol-iype Condensation. Dimetalation of (R)-(+)-3-(p-tolylsulfinyl)propionic acid with Lithium Diisopropylamide produces a chiral homoenolate dianion equivalent which reacts with carbonyl compounds to afford p-sulfinyl-y-hydroxy acids these spontaneously cyclize to give the corresponding p-sulfinyl 7-lactones (eq 2) ... 

To achieve type c aldolization, the monoprotected heptaketone (148) was prepared as shown in Scheme 6. ° Condensation of the dianion of 2,4-pentanedione with the ethylene ketal of diethyl 3-oxo-glutarate presumably affords (148). However, the substance eludes isolation or even spectral identification. Instead, naphthalene derivative (149) is obtained in 39% yield. Further aldolization, dehydration, and removal of the ethylene glycol moiety provides the naturally occurring anthrone (150). 

One of the most complex molecules yet prepared by these biomimetic approaches is the x-etetramid (158 Scheme 7). The 3-pyrrolidinoglutaric acid diamide (153) is condensed with two equivalents of the dianion of r-butyl acetoacetate. The putative intermediate (154) undergoes spontaneous cyclization to provide the naphth ene derivative (155). This substance is transformed by a sequence of steps into naph-thalenopyrone (156), which is extended by reaction with an isoxazole dianion. Spontaneous aldolization again occurs, yielding the anthracene derivative (157). Closure of the final ring ensues when (157) is treated with HI. 

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