Stereoselectivity protonation

Alkali metal counterion has been found to control the enolate protonation stereoselectivity.12 This remarkable phenomenon has been reported for lithium and potassium enolates of a norborneol derivative. 

From a synthetic point of view it is important that the desired anions can be produced by widely different routes. However, the stereoselectivity of the protonation may well depend on the method of production of the carbanion since the isolated anion itself cannot be protonated but rather a complex mixture containing ions, solvent molecules, etc. (vide infra). Table 1 lists the various methods for anion formation which are described in this section. In some cases neutral substrates can be protonated stereoselectively (enamines Sections 2.1.4.4. and 2.1.7. ketenes Section 2.1.5. and 2.1.9. as well as enones Section 2.1.8.). 

The large sulfur atom is a preferred reaction site in synthetic intermediates to introduce chirality into a carbon compound. Thermal equilibrations of chiral sulfoxides are slow, and parbanions with lithium or sodium as counterions on a chiral carbon atom adjacent to a sulfoxide group maintain their chirality. The benzylic proton of chiral sulfoxides is removed stereoselectively by strong bases. The largest groups prefer the anti conformation, e.g. phenyl and oxygen in the first example, phenyl and rert-butyl in the second. Deprotonation occurs at the methylene group on the least hindered site adjacent to the unshared electron pair of the sulfur atom (R.R. Fraser, 1972 F. Montanari, 1975). 

The Birch reductions of C C double bonds with alkali metals in liquid ammonia or amines obey other rules than do the catalytic hydrogenations (D. Caine, 1976). In these reactions regio- and stereoselectivities are mainly determined by the stabilities of the intermediate carbanions. If one reduces, for example, the a, -unsaturated decalone below with lithium, a dianion is formed, whereof three different conformations (A), (B), and (C) are conceivable. Conformation (A) is the most stable, because repulsion disfavors the cis-decalin system (B) and in (C) the conjugation of the dianion is interrupted. Thus, protonation yields the trans-decalone system (G. Stork, 1964B). 

The C—C double bond in the cyclopentene ring can be cleaved by the osmium tetroxide-periodate procedure or by photooxygenation. The methoxalyl group on C-17 can, as a typical a-dicarbonyl system, be split off with strong base and is replaced by a proton. Since this elimination occurs with retention of the most stable configuration of the cyclization equi-hbrium, the substituents at C-17 and C-18 are located trans to one another. The critical introduction of both hydrogens was thus achieved regio- and stereoselectively. 

Proton-catalyzed olefin cyclizations of open-chain educts may give tri- or tetracyclic products but low yields are typical (E.E. van Tamelen, 1968, 1977 see p. 91). More useful are cyclizations of monocyclic educts with appropriate side-chains. The chiral centre to which the chain is attached may direct the steric course of the cyclization, and several asymmetric centres may be formed stereoselectively since the cyclizations usually lead to traas-fused rings. 

The thioboration of terminal alkynes with 9-(alkylthio)-9-borabicyclo[3.3.1]-nonanes (9-RS-9-BBN) proceeds regio- and stereoselectively by catalysis of Pd(Ph,P)4 to produce the 9-[(Z)-2-(alkylthio)-l-alkeny)]-9-BBN derivative 667 in high yields. The protonation of the product 667 with MeOH affords the Markownikov adduct 668 of thiol to 1-alkyne. One-pot synthesis of alkenyl sulfide derivatives 669 via the Pd-catalyzed thioboration-cross-coupling sequence is also possible. Another preparative method for alkenyl sulfides is the Pd-catalyzed cross-coupling of 9-alkyl-9-BBN with l-bromo-l-phe-nylthioethene or 2-bromo-l-phenylthio-l-alkene[534]. 

The stereoselectivity of elimination of 5 bromononane on treatment with potassium ethox ide was described in Section 5 14 Draw Newman projections or make molecular models of 5 bromononane showing the conformations that lead to cis 4 nonene and trans 4 nonene respec tively Identify the proton that is lost in each case and suggest a mechanistic explanation for the observed stereoselectivity... 

Potassium Alkoxides. The most widely used potassium bases are potassium tert-hu. oAde [865-47-4] (KTB) and potassium / i -amylate [41233-93-6] (KTA). These strong alkoxide bases offer such advantages as base strength (pX = 18), solubiUty (Table 5), regio/stereoselectivity because of bulky alkyl groups, and stabiUty because of the lack of a-protons. On storage, KTB and KTA have long shelf Hves under inert atmosphere (see... 

Although not of industrial importance, several asymmetric syntheses of (R)-pantolactone (9) have been developed. Stereoselective abstraction of the j Z-proton of the achiral 1,3-propanediol derivative (23) by j -butyUthium-(-)-sparteine, followed by carboxylation and hydrolysis, results in (R)-pantolactone in 80% yield and 95% ee (53). 

We have previously seen (Scheme 2.9, enby 6), that the dehydrohalogenation of alkyl halides is a stereospecific reaction involving an anti orientation of the proton and the halide leaving group in the transition state. The elimination reaction is also moderately stereoselective (Scheme 2.10, enby 1) in the sense that the more stable of the two alkene isomers is formed preferentially. Both isomers are formed by anti elimination processes, but these processes involve stereochemically distinct hydrogens. Base-catalyzed elimination of 2-iodobutane affords three times as much -2-butene as Z-2-butene. 

Gluconolactone shows no exchange. The reason is that the tetrahedral intermediate is formed and breaks down stereoselectively. Even though proton exchange can occur in the tetrahedral intermediate, the anomeric effect leads to preferential loss of the axial oxygen. 

Tliese observed stereoselectivites can be forcned by ryn addition at low temperatut [60a] to afford tlie E adduct Selective for temperatures, requires ritlier forenation allenyl etiolate or isomerization of tlie Z a stereoselective protonation. Recetit mecliat... 

When n-BuLi is used instead of t-BuLi, the byproduct after desulfinylation (n-BuS(O)Ph) possesses an acidic proton, which is abstracted by the metalated epoxide. Hence, overall, a stereoselective protodesulfmylation is achieved. This can be used for the asymmetric synthesis of epoxides, such as that of (-)-disparlure from enantiopure sulfoxide 222 (Scheme 5.53) [78]. 

The classical aldol addition, which is usually run in protic solvents, is reversible. Most modern aldol methodologies, however, rely on highly reactive preformed metal enolates, whereby proton donors are rigorously excluded. As a consequence, the majority of recent stereoselective aldol additions are performed under kinetic control. Despite this, reversibility and, as a consequence, an equilibration of yrn-aldolates to a t/-aldolates by retro-aldol addition, should not be excluded a priori. 

The relative ease of H/D exchange of the methylene protons of benzyl methyl sulfoxide is markedly influenced by the nature of the base and the solvent used, as shown in Table 12. The data reveal that rather high stereoselectivities can be observed when alkyllithium-THF is used. 

If the carbanion has even a short lifetime, 6 and 7 will assume the most favorable conformation before the attack of W. This is of course the same for both, and when W attacks, the same product will result from each. This will be one of two possible diastereomers, so the reaction will be stereoselective but since the cis and trans isomers do not give rise to different isomers, it will not be stereospecific. Unfortunately, this prediction has not been tested on open-chain alkenes. Except for Michael-type substrates, the stereochemistry of nucleophilic addition to double bonds has been studied only in cyclic systems, where only the cis isomer exists. In these cases, the reaction has been shown to be stereoselective with syn addition reported in some cases and anti addition in others." When the reaction is performed on a Michael-type substrate, C=C—Z, the hydrogen does not arrive at the carbon directly but only through a tautomeric equilibrium. The product naturally assumes the most thermodynamically stable configuration, without relation to the direction of original attack of Y. In one such case (the addition of EtOD and of Me3CSD to tra -MeCH=CHCOOEt) predominant anti addition was found there is evidence that the stereoselectivity here results from the final protonation of the enolate, and not from the initial attack. For obvious reasons, additions to triple bonds cannot be stereospecific. As with electrophilic additions, nucleophilic additions to triple bonds are usually stereoselective and anti, though syn addition and nonstereoselective addition have also been reported. 

The anomeric configuration is set in the reductive lithiation step, which proceeds via a radical intermediate. Hyperconjugative stabilization favors axial disposition of the intermediate radical, which after another single electron reduction leads to a configurationally stable a-alkoxylithium intermediate. Protonation thus provides the j9-anomer. The authors were unable to determine the stereoselectivity of the alkylation step, due to difficulty with isolation. However, deuterium labeling studies pointed to the intervention of an equatorially disposed a-alkoxylithium 7 (thermodynamically favored due to the reverse anomeric effect) which undergoes alkylation with retention of configuration (Eq. 2). 

The reaction must occur by axial addition (39) to give (40) which may be protonated on either side of the double bond, but gives the all equatorial product (37) stereoselectively,... 

The E2 process is not only stereoselective, but it is also stereospecific. However, in this case, the p position has more than one proton, so the stereospecificity of this reaction is not relevant. 

Carbonyls. The stereochemistry of the Wittig olefin synthesis has been reviewed. /i-a/u-Stereoselective olefin synthesis via /3-oxido-ylides is possible only in the presence of soluble lithium salts. Protonation of jS-oxido-ylides prepared from salt-free ylides leads to mixtures of erythro-and r/jr o-betaines and hence to mixtures of cis- and rm/i5-olefins. 

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