Evans aldolization

A nice and convergent approach to both compounds makes use of RCM to form the 5-membered building block 71, which mimics the carbohydrate part of the nucleosides. The necessary diene precursor 69 is readily assembled via Evans aldol chemistry. RCM then affords the ring in almost quantitative yield (69->70), leaving the chiral centers and the free hydroxyl group intact. Removal of the chiral auxiliary by reductive cleavage, attachment of the base by means of jt-allylpalladium chemistry, and a final deprotection step complete these highly efficient syntheses [46]. 

O OPMB Ph3P=C(C02Et)Me O OPMB Evans aldol O OPMB... 

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 " ... 

The Evans reaction, involving f, y-unsaturated oxazolidinones and f),y-unsaturated aldehydes was unprecedented (but, according to the literature, Evans aldolizations of a-alkoxyaldehydes worked well).16... 

We attributed the failure of the reaction to the presence of an unstable deconjugated system and thought that, perhaps, protection of the double bond during the Evans aldolization might help solving the problem. It appeared to us that aldehyde 10 perfectly fulfilled our requirements it should withstand the Evans aldolization conditions yet the phenylselenenyl group should be easy to remove afterwards. This aldehyde was synthesized as shown in Scheme 3. 

In view of the well-documented successful Evans aldolization of a-alkoxyaldehydes, we were very surprised and disappointed by the negative results observed when attempting to couple 10 with an oxazolidinone as shown in Equation 2. 

In the first step, leading directly to the deselenylated aldol product 31, Evans aldolization was followed by treatment of the reaction mixture with NBU4IO4 to effect the oxidative removal of the phenylselenenyl group. Significant differences between this sequence and our previous model studies were observed. 

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],... 

The Evans-aldol method using a boron enolate derived from chiral iV-acyloxazolidinone reacted with aldehydes to give syn-aldols via attack exclusively on the re face of the double bond of the enolate (Equation (177)). Unexpected and unusual si face attack was resulted in the reaction with fluorine-containing carbonyl compounds such as trifluoro acetaldehyde (Equation (178)).680 681... 

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. 

Glucolipsin A (21) is a macrocyclic dilactone natural product that exhibits glucokinase-activating properties. Fiirstner et al. employed an Evans aldol strategy to synthesize the syn -aldol intermediate 2310 (Scheme 2.1j). The aldol reaction of the boron enolate of 14 with 14-methylpentadecanal (22) delivered the yyn-aldol product 23 in essentially diastereomerically pure form (99% de) after purification. Subsequent glycosidation of the alcohol 23 with trichloroacetimidate (24) was facilitated by catalytic amounts of TMSOTf (20 mol %) to afford the key intermediate (25) in moderate yield. 

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. ... 

---