Condensation lithium enolates

Difunctional target molecules are generally easily disconnected in a re/ro-Michael type transform. As an example we have chosen a simple symmetrical molecule, namely 4-(4-methoxyphenyl)-2,6-heptanedione. Only p-anisaldehyde and two acetone equivalents are needed as starting materials. The antithesis scheme given helow is self-explanatory. The aldol condensation product must be synthesized first and then be reacted under controlled conditions with a second enolate (e.g. a silyl enolate plus TiCl4 or a lithium enolate), enamine (M. Pfau, 1979), or best with acetoacetic ester anion as acetone equivalents. 

In contrast, fluorinated ketones have been used as both nucleophilic and electrophilic reaction constituents The (Z)-lithium enolate of 1 fluoro 3,3-di-methylbutanone can be selectively prepared and undergoes highly diastereoselec-tive aldol condensations with aldehydes [7] (equation 8) (Table 4)... 

Table 10 shows examples of. vvn-sclcctive enolate condensations with imines using different types of enolates. All enolates used in these experiments were prepared based on the corresponding lithium enolate by treatment with different Lewis acids, where the lithium enolates themselves were generated with lithium diisopropylamide (LDA) at — 78 °C. 

The same elimination strategy was used for the synthesis of the natural product (i )-(-)-dysidazirine 15 as is shown in Scheme 10 [23]. The requisite aziri-dine ester was prepared by treatment of sulfimine 19 with the lithium enolate of methyl bromoacetate. This reaction is a Darzens-type condensation leading to czs-M-sulfinylaziridine ester 20. The elimination of sulfenate was accomplished in the same manner as mentioned above (see Scheme 9). The natural product 15 (see Fig. 1) was obtained in 42% yield. Attempts to prepare azirinomycin 14 in a similar fashion all failed [23]. 

Ester enolates are somewhat less stable than ketone enolates because of the potential for elimination of alkoxide. The sodium and potassium enolates are rather unstable, but Rathke and co-workers found that the lithium enolates can be generated at -78° C.69 Alkylations of simple esters require a strong base because relatively weak bases such as alkoxides promote condensation reactions (see Section 2.3.1). The successful formation of ester enolates typically involves an amide base, usually LDA or LiHDMS, at low temperature.70 The resulting enolates can be successfully alkylated with alkyl bromides or iodides. HMPA is sometimes added to accelerate the alkylation reaction. 

As with the above pyrrolidine, proline-type chiral auxiliaries also show different behaviors toward zirconium or lithium enolate mediated aldol reactions. Evans found that lithium enolates derived from prolinol amides exhibit excellent diastereofacial selectivities in alkylation reactions (see Section 2.2.32), while the lithium enolates of proline amides are unsuccessful in aldol condensations. Effective chiral reagents were zirconium enolates, which can be obtained from the corresponding lithium enolates via metal exchange with Cp2ZrCl2. For example, excellent levels of asymmetric induction in the aldol process with synj anti selectivity of 96-98% and diastereofacial selectivity of 50-200 116a can be achieved in the Zr-enolate-mediated aldol reaction (see Scheme 3-10). 

Directed Aldol Condensations with Preformed Lithium Enolates in the Presence of Zinc Chloride... 

Our second approach involved condensation of the lithium enolate of acetate 32 with aldehyde 28. In the event, the aldol reaction afforded an 85 % yield of a ca. 5 1 mixture of C3 epimers with the desired diastereomer (35) comprising the major product. 

Three tactical approaches were surveyed in the evolution of our program. As outlined in Scheme 2.7, initially the aldol reaction (Path A) was performed direcdy between aldehyde 63 and the dianion derived from tricarbonyl 58. In this way, it was indeed possible to generate the Z-lithium enolate of 58 as shown in Scheme 2.7 which underwent successful aldol condensation. However, the resultant C7 P-hydroxyl functionality tended to cyclize to the C3 carbonyl group, thereby affording a rather unmanageable mixture of hydroxy ketone 59a and lactol 59b products. Lac-tol formation could be reversed following treatment of the crude aldol product under the conditions shown (Scheme 2.7) however, under these conditions an inseparable 4 1 mixture of diastereomeric products, 60 (a or b) 61 (a or b) [30], was obtained. This avenue was further impeded when it became apparent that neither the acetate nor TES groups were compatible with the remainder of the synthesis. 

Traditional models for diastereoface selectivity were first advanced by Cram and later by Felkin for predicting the stereochemical outcome of aldol reactions occurring between an enolate and a chiral aldehyde. [37] During our investigations directed toward a practical synthesis of dEpoB, we were pleased to discover an unanticipated bias in the relative diastereoface selectivity observed in the aldol condensation between the Z-lithium enolate B and aldehyde C, Scheme 2.6. The aldol reaction proceeds with the expected simple diastereoselectivity with the major product displaying the C6-C7 syn relationship shown in Scheme 2.7 (by ul addition) however, the C7-C8 relationship of the principal product was anti (by Ik addition). [38] Thus, the observed symanti relationship between C6-C7 C7-C8 in the aldol reaction between the Z-lithium enolate of 62 and aldehyde 63 was wholly unanticipated. These fortuitous results prompted us to investigate the cause for this unanticipated but fortunate occurrence. 

We next contemplated whether the unsaturation site could be encompassed in the context of a properly positioned benzo linkage. We were intrigued to discover that excellent diastereoface selectivity was obtained in the aldol condensation of the Z-lithium enolate with the benzyl-substituted formyl moiety, entry g. 

Tab. 2.1 This depicts our rationalization of the observed relative face selectivity and the effects of substitution on the pendant alkyl chain of the aldehyde in the observed ratio of diastereomers obtained in the aldol condensation of the Z-lithium enolate 74 and subsituted a-methy aldehydes.

The medicinally important )3-lactam antibiotic thienamycin (34) has stimulated several investigations into the application of the aldol reaction for the introduction of the hydroxyethyl moiety with the indicated Cg and Cg stereochemistry (29,30). Low-temperature enolization (LDA, THF) of either 35 (29a,b) or 36 (30) and subsequent condensation with excess acetaldehyde afforded the illustrated kinetic aldol adducts (eqs. [22] and [23]). In both examples the modest levels of threo diastereoselection are comparable to related data for unhindered cyclic ketone lithium enolates. Related condensations on the penam nucleus have also been reported (31). 

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-... 

Stereoselective Aldol Condensations of Dialkylamide Lithium Enolates... 

Condensation of the Lithium Enolate Derived from 53 with Representative Aldehydes (eq. [32])... 

Earlier studies had demonstrated that such enolates would participate in aldol condensations with aldehydes however, the stereochemical aspects of the reaction were not investigated (68). For the cases summarized in Table 25, the zirconium enolates were prepared from the corresponding lithium enolates (eq. [54]). Control experiments indicated that no alteration in enolate geometry accompanies this ligand exchange process, and that the product ratio is kinetically controlled (35). From the cases illustrated, both ( )-enolates (entries A-E) and (Z)-enolates (entries F-H) exhibit predominant kinetic erythro diastereoselection. Although a detailed explanation of these observations is clearly speculative, certain aspects of a probable... 

Extensive investigations have been directed toward the development of chiral ester enolates that might exhibit practical levels of aldol asymmetric induction. Much of the early work in this area has been reviewed (111). In general, metal enolates derived from chiral acetate and propionate esters exhibit low levels of aldol asymmetric induction that rarely exceed 50% enantiomeric excess. The added problems associated with the low levels of aldol diastereoselection found with most substituted ester enolates (cf. Table 11) further detract from their utility as effective chiral enolates for the aldol process. Recent studies have examined the potential applications of the chiral propionates 121 to 125 in the aldol condensation (eq. [94]), and the observed erythro-threo diastereoselection and diastere-oface selection for these enolates are summarized in Table 31. For the six lithium enolates the threo diastereoselection was found to be... 

Condensation of the Lithium Enolates Derived from Esters 121 to 125 with Benzaldehyde (eq. [94]) (112)... 

The aldol condensations of the chiral lithium enolate 132 have been demonstrated to exhibit excellent erythro diastereoselection as... 

Recently, the improved chiral ethyl ketone (5)-141, derived in three steps from (5)-mandelic acid, has been evaluated in the aldol process (115). Representative condensations of the derived (Z)-boron enolates (5)-142 with aldehydes are summarized in Table 34b, It is evident from the data that the nature of the boron ligand L plays a significant role in enolate diastereoface selection in this system. It is also noteworthy that the sense of asymmetric induction noted for the boron enolate (5)-142 is opposite to that observed for the lithium enolate (5)-139a and (5>139b derived from (S)-atrolactic acid (3) and the related lithium enolate 139. A detailed interpretation of these observations in terms of transition state steric effects (cf. Scheme 20) and chelation phenomena appears to be premature at this time. Further applications of (S )- 41 and (/ )-141 as chiral propionate enolate synthons for the aldol process have appeared in a 6-deoxyerythronolide B synthesis recently disclosed by Masamune (115b). 

The chiral A/ -propionyl-2-oxazolidones (32 and 38) are also useful chiral auxiliaries in the enantioselective a-alkylation of carbonyl compounds, and it is interesting to observe that the sense of chirality transfer in the lithium enolate alkylation is opposite to that observed in the aldol condensation with boron enolates. Thus, whereas the lithium enolate of 37 (see Scheme 9.13) reacts with benzyl bromide to give predominantly the (2/ )-isomer 43a (ratio 43a 43b = 99.2 0.8), the dibutylboron enolate reacts with benzaldehyde to give the (3R, 25) aldol 44a (ratio 44a 44b = 99.7 0.3). The resultant (2R) and (25)-3-phenylpropionic acid derivatives obtained from the hydrolysis of the corresponding oxazolidinones indicated the compounds to be optically pure substances. 

A. Condensations of lithium enolates under kinetic control O... 

The synthesis in Scheme 13.30 uses stereoselective aldol condensation methodology. Both the lithium enolate and the boron enolate method were employed. The enol derivatives were used in enantiomerically pure form, so the condensations are examples of double stereodifferentiation (Section 2.1.3). The stereoselectivity observed in the reactions is that predicted for a cyclic transition state for the aldol condensations. 

Lithium ester enolate-imine condensation has been used for the preparation of / -lactam rings via addition at the imine moiety <1996H(43)1057>. But treatment of imino derivatives of the pyridazine 293 with the lithium enolate of ethyl a,a-dimethylacetate 294 in THE led to the formation of the pyrido[3,4-r/ pyridazine 295 and its oxidized form 296. Compound 295 was obtained by nucleophilic attack of the carbanion species at C-5 of the pyridazine ring followed by cyclization (Equation 24) <1996JHC1731>. 

Zinc enolates obviously give a better induction than the corresponding lithium enolates. This condensation also occurs with good yields with various enolates generated from ketones, esters and lactones, however, the enantiomeric excesses are poor27. 

Aldol reactions of magnesium enolates are frequently more diastereoselective than the corresponding reactions of lithium enolates. The aldol condensation proceeds via a cyclic transition state in agreement with the Zimmerman-Traxler chelated model . 

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