Aldol reactions Evans

Asymmetric aldol condensation using an acyl oxazolidinone, the Evans chiral auxiliary. 

Transformation of enolizable a-haloketones to esters, carboxylic acids, or amides via alkoxide-, hydroxide-, or amine-catalyzed rearrangements, respectively. 

Favorskii, A. E. J. Prakt. Chem. 1895, 51, 533. Aleksei E. Favorskii (1860-1945), bom in Selo Pavlova, Russia, studied at St. Petersburg State University, where he became a professor in 1900. 

Harmata, M. Wacharasindhu, S. Org. Lett. 2005, 7, 2563. (quasi-Favorskii rearrangement). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 92, Springer-Verlag Berlin Heidelberg 2009 

Evans aldol reaction. In Name Reactions for Homologations-Part IT, Li, J. J., Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2009, pp 532—553. (Review). 

The observed stereoselectivity in the Evans aldol reaction can be explained by the ZImmerman-Traxler transition state model. There are eight possible transition states, four of which would lead to the anti aldol product. These, however, are disfavored due to the presence of unfavorable 1,3-diaxial interactions (not depicted below). The possible transition states leading to the syn aldol product are shown below. The preferred transition state leading to the product is transition state A, where the dipoles of the enolate oxygen and the carbonyl group are opposed, and there is the least number of unfavored steric interactions. 

Glucolipsin A, a glycolipid possessing glycokinase-activating properties, was discovered at Bristol-Myers Squibb, but the absolute stereochemistry of the natural product remained elusive. A. Furstner and co-workers elucidated the absolute stereochemistry via synthesis and spectroscopic analysis of the natural macrolide and its Cj-symmetric stereoisomers. In their approach, they utilized the Evans aldol reaction that provided the syn aldol product with good yield and excellent diastereoselectivity. 

L Boger et al. reported the total synthesis of bleomycin A2. They devised an efficient synthesis for the construction of the tripeptide S, tetrapeptide S, and pentapeptide S subunits of the natural product. In their strategy, they utilized an Evans aidoi reaction between the (Z)-enolate derived from (S)-4-isopropyl-3-propionyl-oxazolidin-2-one and A/-Boc-D-alaninal. In order to synthesize one of the diastereomers of the pentapeptide S subunit, they carried out an Evans aidoi reaction between the same aldehyde and the (Z)-enolate of (R)-4-isopropyl-3-propionyl-oxazolidin-2-one. The formation of the diastereomeric syn aldol product in this reaction clearly shows that the stereochemical outcome of the transformation is determined by the chiral auxiliary. 

The asymmetric total synthesis of cytotoxic natural product (-)-FRI 82877 was accomplished by D.A. Evans and co-workers. To establish the absolute stereochemistry, a boron mediated aldol reaction was utilized applying (R)-4-benzyl-A/-propionyl-2-oxazolidinone as a chiral auxiliary to yield the syn aldol product. 

The aldol reaction is an important carbon-carbon bond formation reaction. The general concept of the reaction involves the nucleophilic addition of a ketone enolate to an aldehyde to form a P-hydroxy ketone, or aldol , a structural unit found in many naturally occurring molecules and pharmaceuticals. Since the aldol addition reaction creates two new stereocenters, up to four stereoisomers may result. The Evans aldol reaction performs a diasteroselective aldol transformation using an Evans s acyl oxazolidinone (also known as Evans chiral auxiliary), a chiral carbonyl compound that creates a temporary chiral enolate for the aldol addition. Upon subsequent removal of the auxiliary, the desired aldol stereoisomer is revealed.  

The iV-acyloxazolidinone derivatives 6, are easily prepared by acylation of commonly available chiral oxazolidinones 4 (both enantiomeric forms) with acyl chlorides 5.  

The boron-mediated aldol reaction of an Evans s acyl oxazolidinone with an aldehyde affords the Evans-syn aldol adduct 9. The process proceeds via formation of the Z enolate that reacts with the aldehyde, presumably through a well ordered six-membered, chair-shaped Zimmerman-Traxler model 

to afford essentially a single diastereomeric aldol product out of four possible isomers. 

A proposed highly ordered chelated transition states for aldol additions using titanium enolates of thiazolidinethiones has been proposed by Crimmins. Crimmins s thiazoldinethione aldol proceeds with high diasteroselectivity for the Evans or non-Evans syn-product depending on the stoichiometry of the Lewis acid as well as the nature and amount of the 

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This radical cyclization strategy was utilized for the synthesis of the smaller fragment silyl ether 54 as well (Scheme 8). Evans aldol reaction of the boron eno-late derived from ent-32 with aldehyde 33, samarium(III)-mediated imide methyl ester conversion, and protecting group exchange led to tosylate 51. Elaboration of 51 to ketone 53 was achieved under the conditions used for construction of the second tetrahydrofuran moiety of 49 from 46. A highly diastereoselective reduc-... 

Access to the corresponding enantiopure hydroxy esters 133 and 134 of smaller fragments 2 with R =Me employed a highly stereoselective (ds>95%) Evans aldol reaction of allenic aldehydes 113 and rac-114 with boron enolate 124 followed by silylation to arrive at the y-trimethylsilyloxy allene substrates 125 and 126, respectively, for the crucial oxymercuration/methoxycarbonylation process (Scheme 19). Again, this operation provided the desired tetrahydrofurans 127 and 128 with excellent diastereoselectivity (dr=95 5). Chemoselective hydrolytic cleavage of the chiral auxiliary, chemoselective carboxylic acid reduction, and subsequent diastereoselective chelation-controlled enoate reduction (133 dr of crude product=80 20, 134 dr of crude product=84 16) eventually provided the pure stereoisomers 133 and 134 after preparative HPLC. 

In a similar manner, a new strategy to access the fumagilol skeleton was reported. RCM of diene 29, which was synthesized by the Evans aldol reaction, was carried out using Ic in the presence of Ti(0 Pr)4 to give a key cyclohexanone intermediate 30 [Eq. (6.22)]. This compound was readily converted to fumagilol " ... 

As outlined in Schemel3, the synthesis of the C15-C24 subunit 56 started with an Evans aldol reaction between the aldehyde 57 and 58 [108-111], Transformation into aldehyde 59 and a Brown crotylation then gave 60 [117], which was converted into 56 in five steps. 

As shown in Scheme 36, the Novartis group s large-scale (20-25kg) preparation of Smith s common precursor 31 began with the established Evans aldol reaction between the Roche ester-derived aldehyde 32 and the propionimide 33 [65],... 

Makino and others carried out a computational study on the Evans aldol reaction of dimethylborinate 12BMe2 with acetaldehyde7 (Scheme 2.1h). The AMI semiempirical calculations indicate that six-membered chairlike transition state A, which would lead to formation of the major syn-isomer, is more stable than B by 3.0kcal/mol, providing a theoretical confirmation of the experimental observations. 

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. 

Non-Evans Aldol Reactions. Either the syn- or onri-aldol adducts may be obtained from this family of imide-derived eno-lates, depending upon the specific conditions employed for the reaction. Although the illustrated boron enolate affords the illustrated jyn-aldol adduct in high diastereoselectivity, the addition reactions between this enolate and Lewis acid-coordinated aldehydes afford different stereochemical outcomes depending on the Lewis acid employed (eq 35). Open transition states have been proposed for the Diethylaluminum Chloride mediated, anti-selective reaction. These anfi-aldol reactions have been used in kinetic resolutions of 2-phenylthio aldehydes. ... 

To date, two total syntheses of myriaporone 4 are known. This chapter is based on the total synthesis of myriaporone 4 published by Taylor et al. in 2004. The synthesis of a chiral precursor, which has also been employed for the total synthesis of related compounds, was published by the same group in 1998. The linear total synthesis starts with an enantiomerically pure molecule from the chiral pool that delivers the stereogenic center at C-12 of the final product, employs Evans aldol reactions as key steps for stereoselective chain elongations and additionally includes reduction/oxidation steps as well as protecting group chemistry. 

The following Evans aldol reaction employs the enolate 54 of an a,(3-unsaturated system 50.Such enolates may attack in the a- or y-position to an electrophile. However, because of the energetically accessible cyclic six-membered Zimmerman-Traxler transition state in comparison to a possible cyclic eight-membered transition state, only product 24 is formed. 

The third step is an Evans aldol reaction and employs the enolate of 26 that is the enantiomer of 50 that was used in the previous aldol reaction. The stereochemistry of the reaction is entirely reagent-controlled. Can you draw the favored transition state and predict the stereochemical outcome of the reaction ... 

The last reaction of this sequence is another Evans aldol reaction employing the enantiomer of the a,p-unsaturated ketone that was used before. From the stereochemical outcome of the reaction it can be seen that the existing stereogenic centers do not influence the induced selectivity. 27 is formed exclusively as one enantiopure diastereomer via transition state 67. 

The linear synthesis of the title compound started from an enantiopure building block with one stereogenic center. The other six stereogenic centers were introduced by two reagent-controlled Evans aldol reactions, an unselective 1,3-dipolar cycloaddition with subsequent separation of the diastereomers, and a substrate-controlled epoxidation step. 

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. 

Evans aldol reaction Reaction of boron enolates with aldehydes to afford syn aldol products. 162... 

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