Evans asymmetric aldol reactions reactions

In the total synthesis of (+)-trienomycins A and F, Smith et al. used an Evans aldol reaction technology to construct a 1,3-diol functional group8 (Scheme 2.1i). Asymmetric aldol reaction of the boron enolate of 14 with methacrolein afforded exclusively the desired xyn-diastereomer (17) in high yield. Silylation, hydrolysis using the lithium hydroperoxide protocol, preparation of Weinreb amide mediated by carbonyldiimidazole (CDI), and DIBAL-H reduction cleanly gave the aldehyde 18. Allylboration via the Brown protocol9 (see Chapter 3) then yielded a 12.5 1 mixture of diastereomers, which was purified to provide the alcohol desired (19) in 88% yield. Desilylation and acetonide formation furnished the diene 20, which contained a C9-C14 subunit of the TBS ether of (+)-trienomycinol. 

Phenylalanine-derived oxazolidinone has heen used in O Scheme 52 as a chiral auxiliary for as)rmmetric cross-aldolization (Evans-aldol reactions [277,278,279,280,281,282,283,284, 285]). The 6-deoxy-L-glucose derivative 155 has heen prepared by Crimmins and Long [286] starting with the condensation of acetaldehyde with the chlorotitanium enolate of O-methyl glycolyloxazohdinethione 150. A 5 1 mixture is obtained from which pure 151 is isolated by a single crystallization. After alcohol silylation and subsequent reductive removal of the amide, alcohol 152 is obtained. Swem oxidation of 152 and subsequent Homer-Wadsworth-Emmons olefination provides ene-ester 153. Sharpless asymmetric dihydroxylation provides diol 154 which was then converted into 155 (O Scheme 60) (see also [287]). 

Stevastelins are depsipeptides exhibiting immunosuppressant activity. The first total synthesis of stevastelin B was described by Y. Yamamoto and co-workers. To construct four consecutive stereocenters, the Evans aldol reaction and the Roush asymmetric allylation were utilized. In the allylation step, the authors used (S,S)-diisopropyltartrate-derived ( )-crotyl boronate. The anti homoallylic alcohol product formed as the only diastereomer. 

Asymmetric Evans aldol reaction (11,379—381).2 The boron cnolatc of the Iivans imide 1 is widely used for preparation of chiral syn-aldols 2. However, if the boron enolate is generated at —78° and then treated with the aldehydes prccomplexcd... 

The synthesis of three fragments 278, 282, and 285 for the C21-C42 bottom segment is summarized in Scheme 41. The Eschenmoser-Claisen rearrangement of amido acetal of 276, which was prepared via 2-bromocyclohexenone by Corey s asymmetric reduction, afforded amide 277. Functional group manipulation including chain elongation provided Evans-type amide 278. The Evans aldol reaction of boron enolate of 279 with aldehyde 280 stereoselectively afforded 281, which was converted into aldehyde 282 through a sequence of seven steps... 

The Evans aldol reaction of chiral, crotonyl-substituted oxazolidinones had proven effective for the asymmetric synthesis of hydroxypropionates... 

Paterson s synthesis is based on a short and eflScient asymmetric route to the simplified erythronolide derivative 120 (R=TBS) by using an Evans aldol reaction for the preparation of the C2-C4 and Cg-Cjo fragments. 

The concept developed for the asymmetric Sn-catalyzed aldol reaction with chiral Ar,AT-ligand by Mukaiyama and co-workers was further extended by Evans and co-workers with bidentate bis(oxazoline) and tridentate pyridylbis(oxazoline) ligands (186). After a survey of ligand architecture, the best level of asymmetric induction was exhibited by [Sn(S,S)-pybox](OTf)2 138 for the Mukaiyamai aldol reaction of substituted silylketene acetal and methyl pyruvate. Noteworthy, the... 

Two Evans aldol reactions were used to create the C5 and Cl stereocenters in the asymmetric synthesis of a Taxol C-ring with chloroacetyl oxazolidinone 33, giving the Evans syn-aldol 45 as a single diastereomer in 77% yield. ... 

The first asymmetric total synthesis of xestodecalactone B and C was recently accomplished in 10 steps with an overall yield of 22%. The key step involves the use of Evans aldol reaction to establish the C-9 configuration. Initial attempts to use an N-acetyloxazolidinone boryl enolate afforded the corresponding aldol product as a nearly 1 1 ratio of diastereomers. A switch to the boryl enolate of thiomethylacetyloxazo-lidinone 68, which is an acetate aldol equivalent, generated the product 69 with high diastereoselectivity (92% de). Subsequent desulfiuization with n-BuaSnH and AIBN was required to remove the thiol functionality. 

Bravo and co-workers report asymmetric syntheses of fluoroalkylamino compoimds via chiral sulfoxides and the stereoselective synthesis of p-fluoroalkyl-p-amino alcohol units using chiral sulfoxides and the Evans aldol reaction. Begde and colleagues discuss the stereoselective and enantioselective synthesis of trifluoromethyl amino alcohols and fluoroalkyl isoserinates. Hoffman reports the aysmmetric fluorination of a-aminoketones, while... 

A key step in the synthesis of the spiroketal subunit is the convergent union of intermediates 8 and 9 through an Evans asymmetric aldol reaction (see Scheme 2). Coupling of aldehyde 9 with the boron enolate derived from imide 8 through an asymmetric aldol condensation is followed by transamination with an excess of aluminum amide reagent to afford intermediate 38 in an overall yield of 85 % (see Scheme 7). During the course of the asymmetric aldol condensation... 

We now tum our attention to the C21-C28 fragment 158. Our retrosynthetic analysis of 158 (see Scheme 42) identifies an expedient synthetic pathway that features the union of two chiral pool derived building blocks (161+162) through an Evans asymmetric aldol reaction. Aldehyde 162, the projected electrophile for the aldol reaction, can be crafted in enantiomerically pure form from commercially available 1,3,4,6-di-O-benzylidene-D-mannitol (183) (see Scheme 45). As anticipated, the two free hydroxyls in the latter substance are methylated smoothly upon exposure to several equivalents each of sodium hydride and methyl iodide. Tetraol 184 can then be revealed after hydrogenolysis of both benzylidene acetals. With four free hydroxyl groups, compound 184 could conceivably present differentiation problems nevertheless, it is possible to selectively protect the two primary hydroxyl groups in 184 in... 

Double asymmetric induction (See section 1.5.3) can also be employed in aldol reactions. When chiral aldehyde 15 is treated with achiral boron-mediated enolate 14, a mixture of diastereomers is obtained in a ratio of 1.75 1. However, when the same aldehyde 15 is allowed to react with enolates derived from Evans auxiliary 8, a syn-aldol product 16 is obtained with very high stereo-... 

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). 

Commerqon et al.40 developed a method based on an Evans-type auxiliary-controlled aldol reaction. Subsequent treatment of the aldol product with base produced the standard epoxide compound for the asymmetric synthesis of the taxol side chain (Scheme 7-84). 

Another classic transformation, a catalytic asymmetric version of which has been the focus of serve-ral studies is the aldol reaction. Evans, Camera and Shibasaki are three of the active researchers in this area. 

In addition to Evans CuflD-catalyzed and Carreira s Ti-catalyzed asymmetric aldol reactions, there is omit Shibasaki s La-catalyzed protocol1141 A recent total synthesis of one of the more celebrated targets of the nineties, epothilone A, utilizes both an enan-tioseledive Al-catalyzed cyanide addition to an aldehyde (75 —> 77) and a La-catalyzed enantioseled-... 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted important interest thanks to there various applications in different synthetic transformations. These simple structures, directly related to the well-documented Evans oxazolidinones, have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations (7V-enoyl derivatives), but mainly in condensation of their 7V-acyl derivatives on aldehydes. Those have shown interesting characteristics in anti-selective aldol reactions or combined asymmetric addition. Normally, the use of chiral auxiliaries which can accomplish chirality transfer with a predictable stereochemistry on new generated stereogenic centers, are indispensable in asymmetric synthesis. The use of OZTs as chiral copula has proven efficient and especially useful for a large number of stereoselective reactions. In addition, OZT heterocycles are helpful synthons that can be specifically functionalized. 

Alkylation of Enolates Asymmetric syntheses involving enolate reactions such as alkylations, aldol additions and acylations in which the chiral auxiliary A -H is both readily obtained and easily recoverable after the desired bond construction had been achieved by Evans et al.175). 

Recently, a conceptually different synthesis of MeBmt using an asymmetric glycine aldol reaction was reported by Evans and Weber [29]. The key step consists in the stereochemically controlled condensation of the chiral glycine enolate synthon (23) with the (R)-aldehyde (24) mediated by stannous triflate (tin salt of trifluoromethanesulphonic acid). The desired syn-aldol adduct (25) was isolated in form of the heterocyclic compound (26). The sense of asymmetric induction in the aldol reaction was established by conversion of (26) over three steps into uniform MeBmt (3). 

The approach for the enantioselective aldol reaction based on oxazolidinones like 22 and 23 is called Evans asymmetric aldol reaction.14 Conversion of an oxazolidinone amide into the corresponding lithium or boron enolates yields the Z-stereoisomers exclusively. Reaction of the Z-enolate 24 and the carbonyl compound 6 proceeds via the cyclic transition state 25, in which the oxazolidinone carbonyl oxygen and both ring oxygens have an anti conformation because of dipole interactions. The back of the enolate is shielded by the benzyl group thus the aldehyde forms the six-membered transition state 25 by approaching from the front with the larger carbonyl substituent in pseudoequatorial position. The... 

Stereoselective syntheses of several unnatural amino acids were required to initiate this work. Evans group used asymmetric reactions of chiral enolates to generate these starting materials, as illustrated in the diagram shown below. In this particular example, an isothiocyanate functionality traps the alcohol of an aldol product giving a thiooxazolidinone that provides O- and N-protection in subsequent steps. 

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