Stereoselective Claisen condensation

T. Nakata et al. developed a simple and efficient synthetic approach to prepare (+)-methyl-7-benzoylpederate, a key intermediate toward the synthesis of mycalamides. The key steps were the Evans asymmetric aldol reaction, stereoselective Claisen condensation and the Takai-Nozaki olefination. The diastereoselective Claisen condensation took place between a 5-lactone and the lithium enolate of a glycolate ester. 

The statine 12 was prepared by Claisen condensation of valine with methyl acetate followed by stereoselective reduction of the /J-keto ester, following precedents as in Jouillie s total synthesis [38] of tamandarin. The Boc group... 

The synthetic route to 619 is a rather lengthy 27-step sequence outlined in Scheme 87 [192]. The first key reaction is a Wittig olefination of 606 with phosphorane 620 to give 621 with > 98% Z-selectivity. Subsequent Claisen rearrangement of the free alcohol 622 provides 623 with >98% stereoselectivity. Dieckmann condensation followed by decarboxylation gives the thermodynamically more stable ran -cyclopentanone 624 trans cis ratio = 7 1). 

A partial synthesis of villalstonine (322) has been achieved by Cook, following the biomimetic method of LeQuesne (223), by condensation of synthetic (-i-)-macroline (338), or the more stable macroline equivalent (341), with natural pleiocarpamine (342) in ().2N HCl, to furnish villalstonine (Scheme 22). The (+)-macroline was prepared starting from the optically active tetracyclic ketone 343, prepared from D-(-i-)-tryptophan by an en-antiospecific Pictet Spengler reaction and stereocontrolled Dieckmann cyclization. The synthesis (Scheme 23) features the use of a stereoselective Claisen rearrangement, followed by stereospecific hydroboration-oxidation of the exocyclic methylene function at C(16), to install the required C(15) and C(16) stereochemistry (225-227). 

The first total synthesis of the intricate Stemona alkaloid (+ /—)-isostemofoline (224) was reported by Kende and coworkers 81) starting from 1,2-hexanediol (225) which was straightforwardly converted to 227 (Scheme 22) 82). Reductive cycUzation with sodium hydrosulfite in refluxing aqueous ethanol, and protection of the unstable pyrrole as tert-butyl carbamate, afforded 228 in five steps with 12% overall )deld. The key bicyclic ketone 231 was assembled by [4 + 3] cycloaddition of pyrrole 228 and diazoester 229 promoted by rhodium octanoate dimer, followed by enol silane deprotection, exo-specific hydrogenation, and nucleophilic decarboxylation (47% overall yield). Sodium methoxide-catalyzed aldol condensation of ketone 231 and furfural provided the Q-j/i-unsaturated ketone 232 whose olefin configuration was established by nOe studies. Allylation of 232 provided a 2.4 1 mixture of ketone 234 and the corresponding allylic enol ether 233, which could be converted to the former via a stereoselective Claisen rearrangement. 

Among alkali metal enolates, those derived from ketones are the most robust one they are stable in etheric solutions at 0 C. The formation of aldehyde enolates by deprotonation is difficult because of the very fast occurring aldol addition. Whereas LDA has been reported to be definitely unsuitable for the generation preformed aldehyde enolates [15], potassium amide in Hquid ammonia, potassium hydride in THE, and super active lithium hydride seem to be appropriate bases forthe metallation of aldehydes [16]. In general, preformed alkali metal enolates of aldehydes did not find wide application in stereoselective synthesis. Ester enolates are very frequently used, although they are more capricious than ketone enolates. They have to be formed fast and quantitatively, because otherwise a Claisen condensation readily occurs between enolate and ester. A complication with ester enolates originates from their inherent tendency to form ketene under elimination... 

Polypropionates possessing chiral chains compose a big group of natural products called polyketides. Polyketides are produced in nature by Claisen condensation and the subsequent reduction. However, people think that aldol reactions should be adequate to construct polypropionate skeletons because an aldol reaction constructs two stereo-genic centers at the a and 3 positions. For example, as shown in Scheme 8.1, erythromycin A would be synthesized by repetition of aldol reactions and manipulation of (3-hydroxy groups. Therefore, the stereoselective aldol reaction should be a key to the synthesis of polypropionates, and chemists have developed many types of aldol reactions. ... 

Triflates of titanium and tin are effective catalysts for various condensations of carbonyl compounds [I2I, 122, 123, 124, 125] Claisen and Dieckmann type condensations between ester functions proceed under mild conditions in the presence of dichlorobis(trifluoromethanesulfonyloxy)titaiiiuin(rV) and a tertiary amine (equations 59 and 60) These highly regio- and stereoselective condensations were used successfully m the synthesis of carbohydrates [122]... 

Detailed investigations indicate that the enolization process (LDA, THF) affords enolates 37 and 38 with at/east 97% (Z)-stereoselection. Related observations have recently been reported on the stereoselective enolization of dialkylthioamides (38). In this latter study, the Ireland-Claisen strategy (34) was employed to assign enolate geometry. Table 10 summarizes the enolization stereo selection that has been observed for both esters and amides with LDA. Complementary kinetic enolization ratios for ketonic substrates are included in Table 7. Recent studies on the role of base structure and solvent are now beginning to appear in the literature (39,40), and the Ireland enolization model for lithium amide bases has been widely accepted, A tabular survey of the influence of the ester moiety (ORj) on a range of aldol condensations via the lithium enolates is provided in Table 11 (eq. [24]). Enolate ratios for some of the condensations illustrated may be found in Table 10. It is apparent from these data that ( )-enolates derived from alkyl propionates (Rj = CH3, t-C4H9) exhibit low aldol stereoselectivity. In contrast, the enolates derived from alkoxyalkyl esters (Rj = CHjOR ) exhibit 10 1 threo diastereo-... 

Only limited precedent exists for the stereoselective enolization and subsequent condensation of a-heteroatom-substituted esters 48a and 48b (eq. [29]). Ireland has examined the enolization process for a-amino ester derivatives where the Claisen rearrangement (chair-preferred transition states) was employed to ascertain enolate geometry (Scheme 10) (43). These results imply that 48a [X = N(CH2Ph)2 ] exhibits only modest selectivity for ( )-enoIate formation under the... 

There is a pronounced preference for the formation of a trans double bond in the Claisen-Schmidt condensation of methyl ketones. This stereoselectivity arises in the dehydration step. In the transition state for elimination to a cis double bond, an unfavorable steric interaction between the ketone substituent (R) and the phenyl group occurs. This interaction is absent in the transition state for elimination to the trans double bond. 

Among the most important reactions in organic synthesis are those that form carbon-carbon bonds. Classically this was accomplished using base-catalyzed reactions such as the aldol, Claisen, and Knoevenagel condensation reactions. Modem versions of these reactoins often display remarkable stereoselectivity.1 Unfortunately, many types of carbon atoms cannot be joined together by these reactions, for example, an aryl carbon to another aryl carbon. It took the development of transition metal-catalyzed reactions before new types of carbon-carbon and carbon-heteroatom bonds could be created. Of particular note in this regard are the reactions catalyzed by palladium, usually in its 0 or +2 oxidation state.2,3,4,5... 

This disconnection led to the C3 synthon 48 (and hence to its already familiar synthetic equivalent 44) and C9 amino dialdehyde 47. The Michael addition of malonic ester to acrolein was employed for the synthesis of the key starting material 49. The Claisen ester condensation of the latter followed by decarboxylation and reductive aminolysis led to the preparation of amino-bis-acetal 47a. The respective amino dialdehyde 47, generated in situ by a controlled hydrolysis of the acetal groups of 47a, reacted smoothly with acetonedicarboxylic diester and gave the required adduct 46 in a good yield and nearly complete stereoselectivity. 

Thermal degradation led to the oxo compounds including [(N02)N0)][Ti0(F3CS03)4], Tilv triflate complexes efFiciently catalyze a variety of reactions including the conversion of acetophenones to 1,3,5-triarylbenzenes,658 the nucleophilic ring opening of epoxides,659 Diels—Alder reactions,660 selective Claisen and Dieckmann ester condensations,661 esterification reactions,662 Fries rearrangements,663 homoaldol reactions,664 sequential cationic and anionic polymerizations,641 and the stereoselective synthesis of m-arabinofuranosides.606... 

These two milestone syntheses were soon followed by others, and activity in this field continued to be driven by interest in the biologically active esters of cephalotaxine. In 1986, Hanaoka et al. (27) reported the stereoselective synthesis of ( )-cephalotaxine and its analog, as shown in Scheme 4. The amide acid 52, prepared by condensation of ethyl prolinate with 3,4-dimethoxyphenylacetyl chloride, followed by hydrolysis of the ethyl ester, was cyclized to the pyrrolobenzazepine 53 by treatment with polyphos-phoric acid, followed by selective O-alkylation with 2,3-dichloropropene (54) in the presence of sodium hydride. The resulting enol ether 55 underwent Claisen rearrangement on heating to provide C-allylated compound 56, whose reduction with sodium borohydride yielded the alcohol, which on treatment with 90% sulfuric acid underwent cationic cyclization to give the tetracyclic ketone 57. Presumably, this sequence represents the intramolecular version of the Wichterle reaction. On treatment with boron tribromide, ketone 57 afforded the free catechol, which was reacted with dibromometh-ane and potassium fluoride to give methylenedioxy derivative 58, suited for the final transformations to cephalotaxine. Oxidation of ketone 58... 

In 1991, the Danishefsky group disclosed the synthesis of the C-28-C-49 subunit of rapamycin utilizing the combination of the Perrier carbocyclization reaction and an Ireland-Claisen rearrangement (see Section 12.3.3. Scheme 12.21T The Perrier carbocyclization of 5-enopyranoside 86, prepared from 2-deoxy-d-glucose derivative (Section 12., Scheme 12.2ST followed by elimination of the p-hydro group gave cyclohexenone 152 tScheme 12.40T Luche reduction of 152 afforded cyclohexenol 83 stereoselectively. Condensation of 83 with carboxylic acid 84, prepared from (i )-3-(benzylojg )-2-methylpropanal, provided ester 82 in 75% yield. 

Historical perspective C. H. Heathcock, Comp. Org. Syn. 2, 133-179 (1991). General review T. Mukaiyama, Org. React. 28,203-331 (1982). Application of lithium and magnesium enolates C. H. Heathcock, Comp. Org. Syn. 2, 181-238 (1991) of boron enolates B. M. Kim etal, ibid. 239-275 of transition metal enolates I. Paterson, ibid. 301-319. Stereoselective reactions of ester and thioester enolates M. Braun, H. Sacha, J. Prakt. Chem. 335,653-668 (1993). Review of asymmetric methodology A. S. Franklin, I. Paterson, Contemp. Org. Syn. 1,317-338 (1994). Cf. Claisen-Schmidt Condensation Henry Reaction Ivanov Reaction Knoevenagel Condensation Reformatskv Reaction Robinson Annulation. 

In 1972, Ireland and Mueller reported the transformation that has come to be known as the Ireland-Claisen rearrangement (Scheme 4.2) [1]. Use of a lithium dialkylamide base allowed for efficient low temperature enolization of the allyUc ester. They found that sUylation of the ester enolate suppressed side reactions such as decomposition via the ketene pathway and Claisen-type condensations. Although this first reported Ireland-Claisen rearrangement was presumably dia-stereoselective vide infra, Section 4.6.1), the stereochemistry of the alkyl groups was not an issue in its application to the synthesis of dihydrojasmone. 

One of the key steps in the stereoselective synthesis of the HMG-CoA reductase inhibitor mevilonin 208 described by Wovkuhch and Uskokovic [45] involved a Claisen-Johnson rearrangement Accordingly, aUyUc alcohol 210 prepared in few steps from (S)-pulegone 209 gave rise, after condensation with triethyl orthopropionate, to ester 211 as a 89/11 mixture of diastereomers (Scheme 6.32). 

These bulky aluminium aryloxides will also promote a variety of carbon-carbon bond forming reactions with a high degree of regio and stereoselectivity. Examples include Michael addition to a,/S-unsaturated ketones, Diels-Alder additions, and Claisen rearrangements. In the case of Diels-Alder reaction, ATPH promoted the exo-selective condensation of a,/6-unsaturated ketones with dienophiles. The Claisen rearrangement can be catalysed by ATPH and its more Lewis acidic 4-bromo derivative. A series of chiral aluminium aryloxides were also synthesized and have been applied to asymmetric Claisen rearrangements, aldol reactions, and aldehyde alkylations. ... 

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