Anti-aldol reactions

Recently, Evans has reported diastereoselective magnesium hahde-catalyzed anti-aldol reactions of chiral Af-acyloxazolidinones 88 (equation 115) and A-acylthiazolidine-thiones 90 (equation 116) . ... 

Whereas the thermodynamic route described above relied on reagent control to establish the spongistatin C19 and C21 stereocentres, the discovery of highly stereoselective 1,5-anti aldol reactions of methyl ketones enabled us to examine an alternative,16 substrate-based stereocontrol route to 5. Regioselective enolisation of enantiomerically pure ketone 37, derived from a readily available biopolymer, gave end... 

The CD-spiroacetal subunit of the spongistatins proved to be of an appropriate level of complexity that several different synthetic strategies were evaluated. Access to the desired spiroacetal 5 was readily achieved by acid catalysed equilibration of the mixture of spiroacetals in aprotic solvents, followed by separation and recycling of the undesired isomer. Furthermore, the 1,5-anti aldol reaction of methyl ketones proved invaluable for construction of certain portions of the target molecule. 

A new thiol auxiliary (45, R = COEt) participates in boron-mediated anti-aldol reactions with aldehydes with high yield and de.124 Reaction of the product with (g> nucleophiles displaces it (in the form of the thiol, 45 R = H), converting the aldol product under mild conditions into esters, thiolates, phosphonates, alcohols, or acids. 

The myxalamides and the phenalamides have attracted some synthetic attention. A partial synthesis of myxalamide D (4) was reported by Cox and Whiting in which an anti aldol reaction was used to set the C-12/C-13 stereochemistry.4 In addition, a total synthesis of 2 was described by Andrus In this approach, an asymmetric alkylation set the distal stereocenter (C-16), while an asymmetric crotylboration created the anti stereorelationship at C-12/C-13. In contrast to the other synthetic efforts, the approach to 1 described in this chapter would enable a single asymmetric reaction early in the synthesis to produce the anti C-12/C-13 relationship as well as set the distal C-16 stereocenter.5... 

As outlined in Scheme 22, the synthesis of the C1-C6 subunit 95 commenced with the anti aldol reaction of the ethyl ketone 100, prepared in three steps from Roche ester 18, and acetaldehyde, with in situ reduction to give diol 103 (>30 ldr) [130, 132-136, 145, 146], Completion of 103 then required a series of protecting group manipulations... 

As shown in Scheme 23, the lithium-mediated anti aldol reaction of the aryl ester 97 and aldehyde 98 gave the expected Felkin-Anh adduct 112 (30 ldr) [147, 148],... 

Masamune et al. applied the newly developed enantioselective anti-aldol reaction to the syntheses of two key fragments of miyakolide 5, a bryostatin-like marine metabolite5 (Scheme 2.2e). The readily synthesized aldehyde 8 was treated with chiral enol borinate generated from the ester 3 to give the aldol 9 in 85%... 

The 1,3-anti-selective reduction was utilized in the total synthesis of the structurally unique compound (+)-clavosolide A (23)6 (Scheme 4.2g). The 1,5-anti -aldol reaction of a dibutylboron enolate of 24 with the aldehyde 25 proceeded smoothly to afford the (3-hydroxy ketone 26 in 93% yield and >96 4 diastereoselectivity. Compound 26 was subsequently treated with... 

Gennari, C., Hewkin, C. T., Molinari, F., Bemardi, A., Comotti, A., Goodman, J. M., Paterson, I. The rational design of highly stereoselective boron enolates using transition-state computer modeling a novel, asymmetric anti aldol reaction for ketones. J. Org. Chem. 1992, 57, 5173-5177. 

The use of a,y -chiral ketones has been studied (Scheme 9-11). In general, the a-stereocenter of the ketone controls the sense of addition and this can be seen in the boron-mediated anti aldol reaction of ketone 30 where the configuration of the C5 stereocenter makes little difference to the selectivity of the reaction [15]. 

The use of these auxiliaries in anti aldol reactions has been described, though not by generation of the anticipated ( )-enolate. Instead, the typical (Z)-enolate is formed, and then precomplexation of a Lewis acid with the reacting aldehyde diverts the reaction away from a cyclic transition state [23]. The contrasting stereochemical trends of the catalyzed and non-catalyzed reactions are evident in an early approach to muamvatin (Scheme 9-13) [24]. Alternatively, Oppolzer has reported the Lewis acid catalyzed anti aldol reaction of a silyl enol ether derived from sultam 38 [25]. In general, however, this methodology has seen limited use in the synthesis of complex natural products. 

Several alternative auxiliaries for obtaining anti aldol products are available [26]. For example, the lactate-derived ketone (R)-39, as developed in our laboratories, displays high levels of stereocontrol in boron-mediated anti aldol reactions (Scheme 9-14) [27]. Simple manipulations of the aldol product 40 allows the gen-... 

The synthesis of the C19-C32 subunit 73 employed the boron-mediated anti aldol reaction of enolate 19 (see Scheme 9-8) with aldehyde 75 followed by an anti reduction to install the four contiguous stereocenters (Scheme 9-25). Both reactions proceeded with characteristic high selectivities (>97%ds) and further manipulations then afforded aldehyde 73. 

An anti aldol reaction with Felkin control was now needed to couple the two spiroacetal fragments and generate the correct stereochemistry at C15 and C f, of the spongistatins. A study of the individual fragments indicated that while the enolate showed little facial selectivity, the aldehyde component had a considerable bias for the desired Felkin product. Best results were obtained with the lithium-mediated aldol coupling, which gave adduct 104 in good yield and acceptable selectivity [56 c]. 

In the Evans synthesis of the polypropionate region (Scheme 9-45), the boron-mediated anti aldol reaction of -ketoimide ent-25 with a-chiral aldehyde 145 afforded 146 with 97% ds in what is expected to be a matched addition. Adduct 146 was then converted into aldehyde 147 in readiness for union with the C -Cs ketone. This coupling was achieved using the titanium-mediated syn aldol reaction of enolate 148 leading to the formation of 149 with 97% ds. 

The completion of the synthesis of ebelactone A required an anti aldol reaction of a suitable three-carbon unit to proceed with and-Felkin selectivity, i.e. a mismatched reaction. Conversion of thioester 280 into its ( )-enol borinate and reaction with aldehyde 279 gave two anti aldol adducts, unfortunately with little stereochemical preference. The minor isomer 281 from this reaction was used in the successful synthesis of ebelactone A (274), and the same chemistry, now using thioester 282, was employed to complete the first synthesis of ebelactone B (275). 

At the time, many unsuccessful attempts were made to improve the selectivity of the mismatched anti aldol reaction mentioned above, outlining the limitations of some chiral ligands or auxiliaries at overcoming inherent substrate bias in anti aldol reactions. Since the completion of this work, we have introduced the lactate-derived ketones (/ )- and (S)-39, which should now allow the stereoselective synthesis of the ebelactones. As shown in Scheme 9-75, each enantiomer of the parent ketone acts as a propionate equivalent with a covalently attached auxiliary which will overturn the facial bias of most aldehydes [27, 28]. 

Use of diisopinocampheyl boron chloride in place of the triflate affords E(0)-enolates, but the isopinocampheyl ligands were ineffective for anti aldol reactions [48]. Encouraged by the molecular mechanics analysis of the ZfOj-enolate additions, Gennari and Paterson used computational methods to design a new boron ligand for use with E(G)-enolates [97]. The design was cued by Still s comment [98] that cis-2-... 

Stereoselective anti-aldol reactions. As part of a synthesis of polypropionate natural products, Evans et al. have studied the stereoselectivity of the reaction of isobutyraldehyde with the chiral /3-kctoimide la, which has been shown to undergo syn-sclectivc aldol reactions.4 Surprisingly, the (E)-boron cnolatc, generated in ether from dicyclohexylchloroborane and ethyldimcthylaminc, reacts with isobutyraldehyde to give the anti, am/-aldol 2 and the syn, anri-aldol 2 in the ratio 84 16. Similar diastereoselectivity obtains with the reaction of the isomeric /3-kctoimide lb. 

The 1,5-anti-aldol reaction was performed with chiral boron enolate of 325 and aldehyde 327, prepared by Evans asymmetric alkylation, cross metathesis, and Wittig homologation (Scheme 72), to afford 324 with a 96 4 diastereoselectivity. Stereoselective reduction of C9-ketone provided the 5y -l,3-diol, which was exposed to catalytic f-BuOK to give 2,6-cis-tetrahyderopyran 333 via an intramolecular Michael reaction. Finally, methyl etherification, deprotection, hydrolysis of ester, and Yamaguchi macrolac-tonization yielded the leucascandrolide macrolide 201 (Scheme 73). 

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