Evans aldol reaction, boron enolates

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 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. ... 

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

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. 

Though either enantiomer of a yyn-aldol can be made by using the right auxiliary in an Evans aldol reaction the anti aldols cannot be made this way. The addition of a Lewis acid catalyst transforms the situation.13 Using the valine-derived chiral auxiliary 89, the same Z-boron enolate 111 is used but the aldehyde is added in the presence of a threefold excess of the Lewis acid Et2AlCl. The product is predominantly one enantiomer of an anh-aldol 112. 

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 vinyl iodide equivalent to 162 was synthesized in the form of 167 from propargyl alcohol 163 as shown in Scheme 18. Olefin geometry was selectively achieved by alkyl zirconation followed by iodination (164) and Evans aldol reaction with a chiral enolate from 165 in the presence of the boron triflate as catalyst. The aldol 166 was reduced into 167 to accomplish the short segment. 

A research group at Novartis also utilized Evans aldol reaction in a straightforward synthesis of (/ ,/ )-methylphenidate hydrochloride (ritalin hydrochloride), the drug well known for the treatment of attention deficit hyperactivity disorder (AD HD). In the key step, displayed in Scheme 4.58, N-acylated oxazolidinone 249, the standard boron enolate addition to 5-chloropentanal, yielded 250 as a single diastereomer that was transformed in several steps into Ritalin hydrochloride. In the aldol step, temperatures lower than -20 °C could be avoided, what makes the procedure applicable in a manufacturing scale [130]. 

A good example of the qi/z-Evans aldol reaction is demonstrated by the Novartis synthesis of (+ymethylphenidate 204, a treatment for ADHD in children. Treatment of compound 199 with n-Bu2BOTf and DIPEA followed by aldehyde 200 afforded the 1,2-syn Aldol product 202. Initial Lewis acid complexation followed by deprotonation led to preferential (Z)-enolate formation. In this case, the use of a boron Lewis acid which can only coordinate to two heteroatoms led to syn stereochemistiy governed by a chair-like Zimmerman-Traxler transition state 201 (Scheme 14.72). Following mesylation of the secondary alcohol, the auxiliary was removed under reductive conditions and the resultant alcohol transformed into (-l-)-methylphenidate 204. 

Ketones, in which one alkyl group R is sterically demanding, only give the trans-enolate on deprotonation with LDA at —12°C (W.A. Kleschick, 1977, see p. 60f.). Ketones also enolize regioseiectively towards the less substituted carbon, and stereoselectively to the trans-enolate, if the enolates are formed by a bulky base and trapped with dialkyl boron triflates, R2BOSO2CF3, at low temperatures (D A. Evans, 1979). Both types of trans-enolates can be applied in stereoselective aldol reactions (see p. 60f.). 

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

Scheme 5 details the asymmetric synthesis of dimethylhydrazone 14. The synthesis of this fragment commences with an Evans asymmetric aldol condensation between the boron enolate derived from 21 and trans-2-pentenal (20). Syn aldol adduct 29 is obtained in diastereomerically pure form through a process which defines both the relative and absolute stereochemistry of the newly generated stereogenic centers at carbons 29 and 30 (92 % yield). After reductive removal of the chiral auxiliary, selective silylation of the primary alcohol furnishes 30 in 71 % overall yield. The method employed to achieve the reduction of the C-28 carbonyl is interesting and worthy of comment. The reaction between tri-n-butylbor-... 

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... 

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-... 

Although the results are easily rationalised in the case of the a-alkylation (attack of the electrophile at the Re face, i.e., attack from the less hindered a face), in the aldol condensation it is somewhat more difficult to rationalise and several factors should be considered. According to Evans [14] one possible explanation for the diastereofacial selection observed for these chiral enolates is illustrated in Scheme 9.14. In the aldol reactions, the more basic carbonyl group of the aldehyde partner interacts with the chelated boron enolate 45 to give the "complex" A which may... 

As shown in Scheme 9.31, the (S)-enolate (100a), from Evans reagent 100. reacts on its Re face if the metal is not coordinated to the oxazolidone carbonyl group at the time of electrophilic attack, which is the normal situation in an uncatalysed boron enolate aldol reaction (see Scheme 9.14) and on the Si face if the metal is coordinated to the oxazolidone carbonyl group (lOOb), which is the normal situation in enolate alkylation (see 9.3.2). 

This dual behaviour must allow control of the configuration at the a carbon atom in an aldol reaction, provided that one can control whether or not the metal is chelated at the time the aldol condensation occurs. Thornton and Nerz-Stormes [35] reported an approach to this problem by using titanium enolates to obtain "non-Evans" 5jn-aldols. On the other hand, Heathcock and his associated found that aldehydes react with chelated boron enolates 100b to afford the anh-aldols 102 or the "non-Evans" i yn-aldols 103 depending upon the reaction conditions (Scheme 9.32). 

Evans [369] and Masamune [370,371] have pioneered the use of thioesters for stereocontrol of the aldol reaction. The accompanying scheme summarizes the reactions of boron and silicon enolates of t-butyl thiopropanoate with aldehydes [372]. Both reactions are stereoconvergent. (Z) and (E)-enolates afford the same diastereoisomer syn with the boron... 

Evans type aldolizations using boron or lithium enolates are mechanistically different. Although both reactions lead predominantly to 2,3-syrc-aldols, the enantioselectivities are inverted i.e. whereas in our original strategy (5)-oxazolidinones lead to the desired 2(5), 3(5) aldols, the same result via lithium enolates requires switching to (R)-oxazolidinones. This change of selectivity has been explained by differing... 

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... 

---