Base-catalyzed equilibration

When necessary, the trans cis ratio can be improved by base-catalyzed equilibration. 

Polydimethylsiloxane Oligomers Synthesized by a Base Catalyzed Equilibration Process,... 

Base catalyzed equilibrations of hydroxyl terminated siloxane oligomers can also be achieved, however these systems can sometimes be complicated by the attack of base to the (OH) end groups to form [(CH2)x 0- X+] type species, which may also cleave the siloxane bonds. This generally results in the loss of terminal functionality in the oligomers produced, which is of course not desirable. 

In the equilibration studies previously cited, two mechanisms for the interconversion of aldol diastereoisomers are possible, the most obvious being via the retroaldol process (28). In some instances, however, base-catalyzed equilibration via the aldolate enolate 18 is certainly possible (eq. [11a]), and such enolates are well documented as useful intermediates in synthesis (19). For example, Frdter has demonstrated that aldolate enolate 18a may be generated from... 

The diastereoselectivity is reversed in the alkylation of the enolate derived from the structurally very similar bicyclic lactam, tetrahydro-3-phenyl-l//.577-pyrrolof 1,2-c]oxazol-5-one (3). Thus, the major diastereomer 4 produced has the tram relationship between the newly introduced substituent in the pyrrolidine ring and the fused oxazolidine ring residue11,12. Only active electrophiles such as iodomethane, 3-halopropenes or (halomethyl)benzenes react11,12. Base-catalyzed equilibration of the product obtained by reaction with 3-bromocyclohexene gives a 50 50 mixture of the cis- and rra s-diastereomers11. 

Exercise 18-45 Write a mechanism for the base-catalyzed equilibration of a,/3- and /3,-y-unsaturated esters. Which isomer would you expect to predominate Why does this type of isomerization proceed less readily for the carboxylate anions than for the esters Would -y.S-unsaturated esters rearrange readily to the a,/3-unsaturated esters Why, or why not ... 

Racemic colchiceine was obtained by Corrodi and Hardegger by a base-catalyzed equilibration of the Schiff base obtained by reacting deacetyl-colchiceine with benzaldehyde (34). Aldimine-ketimine isomerization was found to be the mechanism by which the racemization had occurred (35). The optical resolution of deacetylcolchiceine was accomplished with cam-phorsulfonic acids, affording, after O-methylation with diazomethane, separation of the enolate isomers and after N-acetylation, unnatural (+)-and natural (-)- colchicine (Fig. 1). Racemization of colchicine in refluxing acetic anhydride followed by mild hydrolysis of the intermediate triacetate represents a much improved method of preparing ( )-colchicine (36). The Blade-Font procedure was later extended to the preparation of ( )-3-demethylcolchicine and other racemic analogs (5). 

After the identification of aprepitant as a clinical candidate, Merck invested considerable process research toward an improved synthesis of aprepitant, which culminated in the elegant manufacturing process shown in Scheme 6.21,22 The key step relies on displacement of a trifluoroacetate from intermediate 48 by the optically active alcohol intermediate 49. The synthesis of 49 was accomplished via an oxazaborolidine-catalyzed borane reduction of the corresponding acetophenone. Although the displacement resulted in an almost equal mixture of the two diastereomers 50 and 51, the desired diastereomer 50 could be recovered in high yield by base-catalyzed equilibration of the mixture and crystallization. Addition of p-fluorophenyl magnesium bromide followed by hydrogenolysis afforded the key intermediate 40, which can be readily converted to 1 as detailed in the previous synthesis. 

The methyl-substituted BCR is useful for the construction of some iridoid cyclopentanoids. Keto alcohol (137), a crucial intermediate for a synthesis of ( )-chrysomelidial (138), can be prepared from the cycloadduct (108) of cyclopentenone and the methyl-TMM synthon (equation 145)7 This expedient approach to the keto cohol, four steps and 83% overall yield from the bifunctional reagent (107), is a considerable improvement over a previous 14-step sequence using conventional methodologies. Although the initial bicyclic ketone (108) is a 1 1 epimeric mixture, base-catalyzed equilibration of the products from ozonolysis results in only one epimer, having the required stereochemistry. This... 

Magnus was the first to develop extensive synthetic applications of the Pauson-Khand preparation of the bicyclo[3.3.0]oct-l-en-3-one system. His efforts amply demonstrate the degree to which the high level of functionality in the Pauson-Khand products can be directly utilized in building more complex structures. A formal synthesis of the antitumor sesquiterpene coriolin illustrates a very efficient sequence for construction of the third ring in the linearly fused triquinane series in the presence of considerable functionality (Schemes 10 and 18). A synthesis of the related triquinane hirsutic acid utilizes the observation that the proper stereochemical relationship between the substituents at C-7 and the ring-fusion carbon (C-5) of the bicyclo[3.3.0]oct-l-en-3-one system, while not controllable in the cycloaddition reaction itself, may be readily established by acid- or base-catalyzed equilibration (equation 54 and Scheme 19). ... 

The usual way of preparing such aminopropyl-terminated siloxanes is the synthesis via a base-catalyzed equilibration reaction [1, 2]. A more convenient way is the termination reaction of silanol-terminated siloxanes with special organofimctional silanes [3,4]. 

C-14 epimer 100 via base-catalyzed equilibration and subsequent reduction of the a,/ -unsaturated ketone 9 was also carried out. Thus the formal total synthesis of ( )-morphine has been accomplished by employing the oxidation of the aziridinium salt as a key step. 

In sharp contrast, the ylide (325) rearranges spontaneously above -5 C to give a mixture of cis- and frartj-sulfides (326) and (327) in a 25 1 ratio. The fact that the stereochemistry of the reaction products is under kinetic control was demonstrated by the base-catalyzed epimerization of (326) and (327) to a thermodynamic 1 19 ratio. Ammonium ylides also undergo ring contraction but with complete cis dia-stereoselectivity (Scheme 84). Base-catalyzed equilibration affords some trans isomer. The high dia-stereoselectivities displayed in these reactions contrasts with the poor and rather unpredictable ones observed for acyclic ylide rearrangements (c/. Section 3.10.5.4). In all of the cases examined, the endo transition state endo-(32S) is highly favored over the exo transition state exo-(32S) (Scheme 85). A... 

The synthesis was begun, as shown in Scheme 4.19, by the Cu -catalyzed conjugate addition of allyl Grignard reagent to (4- )-pulegone (86) (88%). Base-catalyzed equilibration afforded a mixture of diasteromers (85 15 trans cis) from which the major isomer 87 could be separated chromatographically. Stereospecific bishydroxylation from the si face of the allyl group then led to a 76% yield of hemiketal 88. 

By employing (S)-Chiraphos as the chiral ligand, synthesis of the tricyclic nitroergoline derivative depicted in the next diagram is achieved with 69% enantiomeric excess45. Diop, Norphos, DIPAMP, and BINAP give only low asymmetric inductions. The more stable nwi.v-product is probably formed via base-catalyzed equilibration of the product. 

The stereochemical course of the subsequent Michael addition of malonic ester to the unsaturated ketone (23) proved to be unexpected. The kinetically controlled product 27 of addition was obtained in the presence of sodium methoxide and an excess of dimethyl malonate however, the thermodynamically preferred ester 28, also obtainable by base-catalyzed equilibration of 27, was the major product of the reaction. According to the IR (absence of Bohlmann bands) and NMR spectra, both 27 and 28 contained cis-quinolizidine ring systems formed possibly by reversible retro-Michael cleavage of the C-3 to Aj, bond in 23. This possibility explains the observed rapid destruction of 23 in the presence of very strong base with simultaneous appearance of a UV maximum at 410 nm presufiaably due to the conjugated enone system present in 29. 

Kantor SW, Grubb WT, Osthoff RC (1954) The mechanism of the add-catalyzed and base-catalyzed equilibration of siloxanes. J Am Chem Soc 76 5190... 

Base-Catalyzed Equilibration of Keto and Enol Tautomers (Section i6.9A)... 

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