Esters diastereoselective additions

One of the first examples of this type of reaction, using a chiral alcohol as an auxiliary, was the asymmetric synthesis of 2-hydroxy-2-phenylpropanoic acid (atrolactic acid, 3, R1 =C6H5 R3 = CH3) by diastereoselective addition of methyl magnesium iodide to the men-thyl ester of phcnylglyoxylie acid4,5 (Table 22). 

Tin(Il) shows considerable affinity towards nitrogen, therefore is expected to activate the imino group. The diastereoselective addition of tin(II) enolates derived from thioesters 1 to x-imino-esters 2 is reported12. This reaction proceeds smoothly to afford. vi w-/j-amino acid derivatives 3 (d.r. 95 5) in good yields. Lithium, magnesium, and zinc enolates do not react while titanium enolates give the adducts in low yield with preferential formation of the anti-isomer. 

Lithium ester enolate addition to imines has been used for the construction of optically active p-lactams, e.g. 64 and the lithium enolates have been found to be superior to other metal derivatives for both yields and diastereoselectivity in some cases <00H(53)1479>. Immobilized lithium ester enolates have been utilized for the first time <00OL907> and soluble polymer supported imines were used to obtain N-unsubstituted azetidin-2-ones under mild conditions <00CEJ193>. Both lithium and titanium enolates have been employed to obtain cholesterol absorption inhibitors <99TA4841>. Lithium ynolates 65 add to imines to provide P-lactams in good to excellent yield <00TL5943>. 

Metzner reports that lithium dithioenolates, which are softer nucleophiles than the corresponding carbonyl enolates, add kinetically in a 1,4-mode exclusively to ot, 3-enones and the diastereoselectivity preferences are similar to that for ester enolate additions.l43a d Typically, kinetic deprotonation of dithioesters affords predominantly the (Z)-enethiolate (170) which is opposite to that for esters 139 thus, with ( )-enones, anti adducts (172) are obtained. In contrast, the addition of methyl dithioacetate to ot,P-disubstituted enones affords predominantly syn adducts (174 and 175) which is a consequence of intramolecular protonation of the resultant enolate (Scheme 68).143e... 

In contrast, few examples of conjugate additions of nonallylic a-sulfinyl (or a-sulfonyl) carbanions have been reported (for allylic oc-sulfinyl carbanion additions, see Section 1.2.2.5.1). Notable is the dia-stereoselective addition of alkyl f-butyl sulfoxides (245) to a,(3-unsaturated esters (equation 20)187 which is complementary to the diastereoselective addition of enolates to 3-substituted-a,f3-unsaturated sulfoxides (equation 20). 

In the pioneering work by Wilcox and Gaudino, a straightforward route to the carbocyclic analogue of D-fructofuranose, 64, and its 6-phosphate derivative was delineated [14a,b]. As shown in Scheme 9, the first move consisted of Wittig olefination of benzyl-protected arabinose 60 with carboxy-tert-butylmethylene triphenyl phosphorane to deliver unsaturated ester 61, which was then cleverly elaborated into dibromide 62 via a reaction cascade encompassing Swem oxidation of the secondary OH, ester hydrolysis, diastereoselective addition of dibromomethyl lithium, and carboxylic acid methylation. 

Not much is currently known concerning diastereoselective addition of metal enolates to ketones 48,108), but selectivities are expected to be lower. In case of titanium enolates, several examples have been studied 77). The reaction shown in Equation 67 involves an ester-enolate21 and proceeds strictly in a 1,2 manner with 90% diastereoselectivity. The observation is significant because similar reactions with aldehydes are essentially stereo-random77). Also, the lithium analog of 203 affords a 1 1 mixture of diastereomers. Diastereoface-selectivity in Equation 67 is not an exception, because 203 adds to acetophenone and pinacolone to afford 85 15 and >76 24 diastereomer mixtures, respectively 77). Although stereochemical assignments have not been made in all cases, the acetophenone adduct was converted stereospecifically into the p-lactone which was decarboxylated to yield an 85 15 mixture of Z- and E-2-phenyi-2-butene 77). 

B. Diastereoselective Additions of Ester Enolates to Carbonyl Groups. 386... 

Diastereoselective addition to 4-substituted 2,3-didehydropyroglutamate esters reveals the entry cis to the ester group. Unexpectedly, 5-(/-butyldimethylsiloxy)-2-cyclohexenone reacts with MeCu(CN)Li in a cis-selective manner (cisUrans >99 I)." ... 

Interestingly, enamines attack the terminal olefinic carbon of l,l-bis(ethoxycarbonyl)-2-vinylcyclopropane (42), with ring opening of the cyclopropane ring, in contrast to sodiomalonic ester which attacks the more substituted cyclopropane carbon. With diethyl cyclopropylmethylideneraalonate (43) reaction occurs at the jff-carbon and the cyclopropyl ring remains intact (Scheme 27). Titanium tetrachloride catalyses the highly diastereoselective addition of enamines to 2,2-dimethoxyethyl crotonate. ... 

In a separate, elegant use of 165, Rychnovsky and coworkers have carried out a diastereoselective addition of methyl acetate-derived silyl ketene acetal to aldehyde 174 to afford adduct 175 in high diastereomeric purity (Scheme 15) [102]. Hydroxy ester 175 was subsequently employed as an intermediate in the total synthesis of the polyene macrolide antibiotic Roflamycoin. This work highlights a novel application of the chiral catalyst system in reagent-controlled coupling of chiral functionahzed substrates which by themselves display only mod-... 

Diastereoselective addition of a propionate unit to an achiral aldehyde is an important process in organic synthesis (see Section 1.7.2.3 for the reaction with chiral aldehydes). This process can be achieved with full control by the judicious choice of a thiol ester and a dialkylboryl triflate. As shown in Scheme 16, the (0)-enolate (19) generated from S-r-butyl propanethioate, dicyclopentylboryl triflate and diisopropylethylamine furnishes, upon reaction with an aldehyde, the anti aldol product (20). The syn product (21) is obtained from the Z(0)-enolate (22) derived from the reaction of 5-phenyl propanethioate with 9-borabicyclo[3.3.1]non-9-yl triflate (9-BBNOTf). 

Reaction with a-ketoesters. In a regio- and diastereoselective addition reaction, chelation control provides optically active a-hydroxy esters. 

As previously discussed, 2 -i- 2 photocycloaddition can be stereoselective when carried out with rigid starting materials. When unsaturated lactam 178, prepared in a few steps from levulinic acid and (S)-( -f )-valinol, was subjected to photocycloaddition with ethylene, a very diastereoselective addition (de = 85%) takes place [152] (Scheme 29). Acidic methanolysis produces the corresponding esters and recovered valinol. Preferential formation of 179 involves an attack of ethylene from the convex side of the molecule. 

The required ketosulfoxide 69 (Scheme 15) was obtained in two steps in a one-pot procedure from 1,4-dimethoxybenzene (66). Ortho Hthiation of 66, lithium-copper exchange, and addition to methyl acrylate gave ester 67. Reaction of the anion obtained from (R)-methyl(p-tolyl)sulfoxide (68) [89] by treatment with LDA, with ester 67 afforded ketone 69. Diastereoselective addition of diethylaluminum cyanide to the carbonyl group of 69 [90] furnished sulfinylcyanohydrin 70 as the sole product. The (S) configuration of the new stereogenic center was inferred from the previous studies of acycUc P-ketosulfoxides [91,92]. 

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