Stereoselectivity in alkylation

The chelated lithium anions 1 and 2, derived from enantiomerically pure tetrahydroisoquino-line-amidines or -oxazolines, exhibit high induced stereoselectivity in alkylation reactions (Section D.l.1.1.1.3.1.). 

Meyers has demonstrated that chiral oxazolines derived from valine or rert-leucine are also effective auxiliaries for asymmetric additions to naphthalene. These chiral oxazolines (39 and 40) are more readily available than the methoxymethyl substituted compounds (3) described above but provide comparable yields and stereoselectivities in the tandem alkylation reactions. For example, addition of -butyllithium to naphthyl oxazoline 39 followed by treatment of the resulting anion with iodomethane afforded 41 in 99% yield as a 99 1 mixture of diastereomers. The identical transformation of valine derived substrate 40 led to a 97% yield of 42 with 94% de. As described above, sequential treatment of the oxazoline products 41 and 42 with MeOTf, NaBKi and aqueous oxalic acid afforded aldehydes 43 in > 98% ee and 90% ee, respectively. These experiments demonstrate that a chelating (methoxymethyl) group is not necessary for reactions to proceed with high asymmetric induction. 

Stereoselectivity in the condensation reaction of 2-arylethylamines with carbonyl compounds to give 1,2,3,4-tetrahydroisoquinoline derivatives was somewhat dependent on whether acid catalysis or superacid catalysis was invoked. Particularly in the cases of 2-alkyl-N-benzylidene-2-phenethylamines, an enhanced stereoselectivity was observed with trifluorosulfonic acid (TFSA) as compared with the weaker acid, trifluoroacetic acid (TFA). Compound 43 was cyclized in the presence of TFA to give modest to good transicis product ratios. The analogous compound 44 was cyclized in the presence of TFSA to give slightly improved transicis product ratios. 

Another stereoselective /1-alkylation was found by Posner and coworkers in the treatment of (S)-( +)-( )- 1-octenyl sulfoxide 190 and (S)-(+)-( )- 1-propenyl sulfoxide... 

Radical cascades that feature a 7-exo acyl radical cyclization followed by a 6-exo or 5-exo alkyl radical cyclization proceed with very good yields and diastereoselectivities. Two examples are shown in Reaction (80), where treatment of 100 with E3B, air, and (TMS)3SiH provided the tricycle 101 in excellent yields as a single diastereomer. Interestingly, the bulky silyl ether moiety is not required to achieve stereoselectivity in this process. 

Some examples of alkylation reactions involving relatively acidic carbon acids are shown in Scheme 1.3. Entries 1 to 4 are typical examples using sodium ethoxide as the base. Entry 5 is similar, but employs sodium hydride as the base. The synthesis of diethyl cyclobutanedicarboxylate in Entry 6 illustrates ring formation by intramolecular alkylation reactions. Additional examples of intramolecular alkylation are considered in Section 1.2.5. Note also the stereoselectivity in Entry 7, where the existing branched substituent leads to a trans orientation of the methyl group. 

The preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

The requirement that an enolate have at least one bulky substituent restricts the types of compounds that give highly stereoselective aldol additions via the lithium enolate method. Furthermore, only the enolate formed by kinetic deprotonation is directly available. Whereas ketones with one tertiary alkyl substituent give mainly the Z-enolate, less highly substituted ketones usually give mixtures of E- and Z-enolates.7 (Review the data in Scheme 1.1.) Therefore efforts aimed at increasing the stereoselectivity of aldol additions have been directed at two facets of the problem (1) better control of enolate stereochemistry, and (2) enhancement of the degree of stereoselectivity in the addition step, which is discussed in Section 2.1.2.2. 

The syntheses in Schemes 13.45 and 13.46 illustrate the use of oxazolidinone chiral auxiliaries in enantioselective synthesis. Step A in Scheme 13.45 established the configuration at the carbon that becomes C(4) in the product. This is an enolate alkylation in which the steric effect of the oxazolidinone chiral auxiliary directs the approach of the alkylating group. Step C also used the oxazolidinone structure. In this case, the enol borinate is formed and condensed with an aldehyde intermediate. This stereoselective aldol addition established the configuration at C(2) and C(3). The configuration at the final stereocenter at C(6) was established by the hydroboration in Step D. The selectivity for the desired stereoisomer was 85 15. Stereoselectivity in the same sense has been observed for a number of other 2-methylalkenes in which the remainder of the alkene constitutes a relatively bulky group.28 A TS such as 45-A can rationalize this result. 

Chapter 1 deals with alkylation of carbon nucleophiles by alkyl halides and tosylates. We discuss the major factors affecting stereoselectivity in both cyclic and acyclic compounds and consider intramolecular alkylation and the use of chiral auxiliaries. 

Alkylation of norbornene with acrylic acid derivatives occurs with ruthenium catalysts like [RuCl2(C6H6)]2/Zn in protic solvent.31 (,E)-o -2-norbonylacrylates are obtained with high regio- and stereoselectivity in good yields. 

The availability of non-racemic oxepins through tandem catalytic RCM and Zr-catalyzed kinetic resolution has additional important implications. Optically pure heterocycles that carry a heteroatom within their side chain (cf. (S)-14 in Scheme 3) can be used in stereoselective uncatalyzed alkylations. The alcohol, benzyl ether or MEM-ethers derived from (S)-14 readily undergo directed [10] and diastereoselective alkylations when treated with a variety of Grignard reagents [11]. 

Boranes have opened the door to asymmetric reduction of carbonyl compounds. The first attempt at modifying borane with a chiral ligand was reported by Fiaud and Kagan,75 who used amphetamine borane and desoxyephedrine borane to reduce acetophenone. The ee of the 1-phenyl ethanol obtained was quite low (<5%). A more successful borane-derived reagent, oxazaborolidine, was introduced by Hirao et al.76 in 1981 and was further improved by Itsuno and Corey.77 Today, this system can provide high stereoselectivity in the asymmetric reduction of carbonyl compounds, including alkyl ketones. 

Stereoselective alkylations, 12 165-166 Stereoselective hydrolysis, 16 400 Stereoselective propene polymerization, catalyst symmetries for, 16 104 Stereoselectivity, in a-olefin insertion, 16 99-102... 

This means that if a reaction is carried out on a compound that has no stereoisomers, it cannot be stereospecific but at most stereoselective. The concerted reactions, including SN2 displacements, E2 elimination of alkyl halides, anti and Syn addition to alkenes are all stereoselective. In the case of chiral or geometric substrates the nature of the product depends on the unique stereoelectronic requirement of the reaction. These are examples of stereospecific reactions. 

In summary, a number of effective chiral reducing agents have been developed based on the modification of LAH. Excellent results have been obtained with aryl alkyl ketones and a,p-acetylenic ketones. However, dialkyl ketones are reduced in much lower enantiomeric excess. This clearly indicates that steric effects alone do not control stereoselectivity in these reductions. Systematic studies have been carried out with the objective of designing improved reagents. A better understanding of the mechanisms and knowledge of the active species is required in order to provide more accurate models of the transition states of the key reduction steps. 

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-... 

In Yamada s retrosynthetic analysis (Scheme 11), elisabethin C (26) is traced back to lactone 64 which would be converted into 26 by deoxygenation and chain elongations. Key intermediate 64 could be obtained by a stereoselective Dieckmann cyclization. The required ester lactone precursor 65 would be accessible from 66 by a series of oxidation reactions. Further disconnection would lead to commercially available (+)-carvone (67). Stereoselective successive alkylation of 67 and reduction of the enone should deliver 66 [30]. 

An application to the asymmetric synthesis of enantiomer-ically pure tram-hexahydroanthracen-9-ones is shown in Scheme 6. It should be possible to carry out a second stereoselective reductive alkylation of the benzoyl group in 22 as was demonstrated in the related hydrofluoren-9-one and... 

---