Lithium enolate stereoselective alkylation

A number of methods have been developed for accomplishing aldol addition reactions in a stereoselective manner. The preformed lithium enolates of alkyl esters normally react with aldehydes to give mixtures of the two diastereomeric g-hydroxy esters (eq 1). However, the enolates derived from... 

The second reaction creates a lithium enolate and alkylates it. It is again stereospecific at the unchanged chiral centre but stereoselective at the newly created quaternary centre. Finally, acetal hydrolysis preserves the new quaternary centre unchanged (stereospecific) by a mechanism that is the reverse of the first step... 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

For enolates with additional functional groups, chelation may influence stereoselectivity. Chelation-controlled alkylation has been examined in the context of the synthesis of a polyol lactone (-)-discodermolide. The lithium enolate 4 reacts with the allylic iodide 5 in a hexane THF solvent mixture to give a 6 1 ratio favoring the desired stereoisomer. Use of the sodium enolate gives the opposite stereoselectivity, presumably because of the loss of chelation.61 The solvent seems to be quite important in promoting chelation control. 

Alkylations of this type also proved to be sensitive to the cation. Good stereoselectivity (15 1) was observed for the lithium enolate, but the sodium and potassium enolates were much less selective.75 This probably reflects the weaker coordination of the latter metals. 

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. 

Table 2-5 summarizes the results of the asymmetric alkylation (Scheme 2-17) of the lithium enolates derived from 22 or 23.28 When chiral auxiliary 22 or 23 is involved in the alkylation reactions, the substituent at C-4 of the oxazolidine ring determines the stereoselectivity and therefore controls the stereogenic outcome of the alkylation reaction. 

Compound 17 is the so-called (+)-Prelog-Djerassi lactonic acid derived via the degradation of either methymycin or narbomycin. This compound embodies important architectural features common to a series of macrolide antibiotics and has served as a focal point for the development of a variety of new stereoselective syntheses. Another preparation of compound 17 is shown in Scheme 3-7.11 Starting from 8, by treating the boron enolate with an aldehyde, 20 can be synthesized via an asymmetric aldol reaction with the expected stereochemistry at C-2 and C-2. Treating the lithium enolate of 8 with an electrophile affords 19 with the expected stereochemistry at C-5. Note that the stereochemistries in the aldol reaction and in a-alkylation are opposite each other. The combination of 19 and 20 gives the final product 17. 

Besides their application in asymmetric alkylation, sultams can also be used as good chiral auxiliaries for asymmetric aldol reactions, and a / -product can be obtained with good selectivity. As can be seen in Scheme 3-14, reaction of the propionates derived from chiral auxiliary R -OH with LICA in THF affords the lithium enolates. Subsequent reaction with TBSC1 furnishes the 0-silyl ketene acetals 31, 33, and 35 with good yields.31 Upon reaction with TiCU complexes of an aldehyde, product /i-hydroxy carboxylates 32, 34, and 36 are obtained with high diastereoselectivity and good yield. Products from direct aldol reaction of the lithium enolate without conversion to the corresponding silyl ethers show no stereoselectivity.32... 

Covalently bonded chiral auxiliaries readily induce high stereoselectivity for propionate enolates, while the case of acetate enolates has proved to be difficult. Alkylation of carbonyl compound with a novel cyclopentadienyl titanium carbohydrate complex has been found to give high stereoselectivity,44 and a variety of ft-hydroxyl carboxylic acids are accessible with 90-95% optical yields. This compound was also tested in enantioselective aldol reactions. Transmetalation of the relatively stable lithium enolate of t-butyl acetate with chloro(cyclopentadienyl)-bis(l,2 5,6-di-<9-isopropylidene-a-D-glucofuranose-3-0-yl)titanate provided the titanium enolate 66. Reaction of 66 with aldehydes gave -hydroxy esters in high ee (Scheme 3-23). 

During the last decade, a substantial number of novel (sometimes even stereoselective) strategies for the preparation of allenic prostaglandins have been devised. The approach used by Patterson involves a three-component coupling via a 1,4-addi-tion of the organocopper compound 121 to the enone 120, followed by alkylation of the enolate formed with the bromide 122 (Scheme 18.40) [121]. However, due to the notoriously low reactivity in the alkylation of the mixed copper-lithium enolate formed during the Michael addition [122], the desired product 123 was obtained with only 28% chemical yield (the alkylation was not even stereoselective, giving 123 as a 1 1 mixture of diastereomers). 

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-... 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

Treatment of the potentially electrophilic Z-xfi-unsaturated iron-acyl complexes, such as 1, with alkyllithium species or lithium amides generates extended enolate species such as 2 products arising from 1,2- or 1,4-addition to the enone functionality are rarely observed. Subsequent reaction of 2 with electrophiles results in regiocontrolled stereoselective alkylation at the a-position to provide j8,y-unsaturated products 3. The origin of this selective y-deproto-nation is suggested to be precoordination of the base to the acyl carbonyl oxygen (see structures A), followed by proton abstraction while the enone moiety exists in the s-cis conformation23536. 

Iron-acyl enolates, such as 2, prepared by x-deprotonation of the corresponding acyl complexes with lithium amides or alkyllithiums, are nearly always generated as fs-enolates which suffer stereoselective alkylation while existing as the crmt-conformer which places the carbon monoxide oxygen anti to the enolate oxygen (see Section 1.1.1.3.4.1.). These enolates react readily with strong electrophiles, such as primary iodoalkanes, primary alkyl sulfonates, 3-bromopropenes, (bromomethyl)benzenes and 3-bromopropynes, a-halo ethers and a-halo carbonyl compounds (Houben-Weyl, Volume 13/9 a, p 413) (see Table 6 for examples). 

Reviews on stoichiometric asymmetric syntheses M. M. Midland, Reductions with Chiral Boron Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 2, Academic Press, New York, 1983 E. R. Grandbois, S. I. Howard, and J. D. Morrison, Reductions with Chiral Modifications of Lithium Aluminum Hydride, in J. D. Morrison, ed.. Asymmetric Synthesis, Vol. 2, Chap. 3, Academic Press, New York, 1983 Y. Inouye, J. Oda, and N. Baba, Reductions with Chiral Dihydropyridine Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 4, Academic Press, New York, 1983 T. Oishi and T. Nakata, Acc. Chem. Res., 17, 338 (1984) G. Solladie, Addition of Chiral Nucleophiles to Aldehydes and Ketones, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 6, Academic Press, New York, 1983 D. A. Evans, Stereoselective Alkylation Reactions of Chiral Metal Enolates, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 1, Academic Press, New York, 1984. C. H. Heathcock, The Aldol Addition Reaction, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 2, Academic Press, New York, 1984 K. A. Lutomski and A. I. Meyers, Asymmetric Synthesis via Chiral Oxazolines, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 

The second synthesis of lasubine II (6) by Narasaka et al. utilizes stereoselective reduction of a /3-hydroxy ketone O-benzyl oxime with lithium aluminum hydride, yielding the corresponding syn-/3-amino alcohol (Scheme 5) 17, 18). The 1,3-dithiane derivative 45 of 3,4-dimethoxybenzaldehyde was converted to 46 in 64% yield via alkylation with 2-bromo-l,l-dimethoxyethane followed by acid hydrolysis. Treatment of the aldol, obtained from condensation of 46 with the kinetic lithium enolate of 5-hexen-2-one, with O-benzylhydroxylamine hy-... 

The lithium enolate remains and can be alkylated with an alkyl halide in the usual way. When there are hydrogen atoms at both ring junction positions, axial alkylation occurs just as you should now expect, and a new ketone with three stereogenic centres is formed with >95% stereoselectivity. 

On the other hand, lithium enolates derived from substituted endocyclic ketones have largely been exploited in the synthesis of steroids since the regioselectivity of their deprotonation can be controlled and high levels of 1,2- and 1,3-stereoselection occur9,418. The control is steric rather than electronic, with the attack directed to the less substituted ji-face of the enolate for conformationally rigid cyclopentanones, whereas stereoelectronic control becomes significant for the more flexible cyclohexanones. Finally, an asymmetric variant of the formation of a-branched ketones by hydration of camphor-derived alkynes followed by sequential alkylation with reactive alkyl halides of the resulting ketones was recently reported (Scheme 87)419. 

The backbone modification of dedicated peptides through the regio- and stereoselective alkylation of their polylithiated enolates was essentially addressed by Seebach s group200,481 483. Critical to the success of this procedure was the ability to solubilize the peptides and their polylithio derivatives in THF by the addition of lithium salts. 

Recent studies have suggested that coordination with a lithium cation may be responsible for the stereochemical outcome in Meyers-type enolate alkylations . In fact, the hypothesis that the diastereofacial selectivity observed in these reactions might result from specific interactions with a solvated lithium cation was already proposed in 1990 . Nevertheless, the potential influence exerted by solvation and lithium cation coordination was not supported by a series of experimental results reported by Romo and Meyers , who stated that it would appear that neither the aggregation state of the enolate nor the coordination sphere about lithium plays a major role in the observed selectivity. This contention is further supported by recent theoretical studies of Ando , who carried out a detailed analysis of the potential influence of solvated lithium cation on the stereoselective alkylation of enolates of y-butyrolactones. The results showed conclusively that complexation with lithium cation had a negligible effect on the relative stability of the transition states leading to exo and endo addition. The stereochemical outcome in the alkylation of y -butyrolactones is determined by the different torsional strain in the endo and exo TSs. 

Evans and Leahy reported on a method for the rhodium-catalyzed allylic alkylation using copper enolates, generated by transmetalation of the corresponding lithium enolates (equation 19). These enolates are softer and less basic nucleophiles than lithium enolates and therefore problems typically associated with enolate nncleophiles in metal-allyl chemistry can be avoided. A copper(I) enolate, derived from acetophenone derivative 63, was used as nucleophile in a regio- and stereoselective rhodinm-catalyzed alkylation of the in situ activated allylic alcohol 62. Thereby, the synthesized ketone 64, a key intermediate in the total synthesis of (—)-sugiresinol dimethyl ether (65), was produced as the only detectable regioisomer with complete conservation of enantiomeric excess. 

In the laboratory of T.F. Jamison, the synthesis of amphidinolide T1 was accomplished utilizing a catalytic and stereoselective macrocyclization as the key step. ° The Myers asymmetric alkylation was chosen to establish the correct stereochemistry at the C2 position. In the procedure, the alkyl halide was used as the limiting reagent and almost two equivalents of the lithium enolate of the A/-propionyl pseudoephedrine chiral auxiliary was used. The alkylated product was purified by column chromatography and then subjected to basic hydrolysis to remove the chiral auxiliary. 

Lithium enolates having a-methyl substituents, such as (33b) and the related species (37b), derived from S-t-butylcyclohexanone, show a somewhat greater stereoselectivity of axial alkylation than the corresponding a-unsubstituted compounds. For example, the enolate (37a) gave the products (38a) and (39a) in a 68 32 ratio upon treatment with methyl iodide in THF, while the 2-methyl-substituted derivative (37b) gave an 83 17 mixture of (38b) and (39b) upon reaction with trideuteriomethyl iodide in DME (Scheme 18). Similarly, a greater stereoselectivity for axial alkylation has been observed for other a-substituted enolates compared with their counterparts lacking a-substituents. - ... 

Angular alkylations of lithium enolates of hydrindanones with carbonyl groups in the five- or six-membered rin yield cw-fused products with almost complete stereoselectivity. The lithium enolate of bicyclo [2.2.1]heptan-2-one undergoes exo alkylation with very high stereoselectivity. The presence of a syn methyl group at C-7 reduces the preference for exo alkylation, but it is still preferred over endo alkylation by about 3 1 unless a 5,6-double bond is also present then, endo attack is preferred. The expected steric effects control the stereochemistry of alkylation of other bridged bicyclic systems. - ... 

---