Propionate enolate

Covalently bonded chiral auxiliaries readily induce high stereoselectivity for propionate enolates, while the case of acetate enolates has proved to be difficult. Alkylation of carbonyl compound with a novel cyclopentadienyl titanium carbohydrate complex has been found to give high stereoselectivity,44 and a variety of ft-hydroxyl carboxylic acids are accessible with 90-95% optical yields. This compound was also tested in enantioselective aldol reactions. Transmetalation of the relatively stable lithium enolate of t-butyl acetate with chloro(cyclopentadienyl)-bis(l,2 5,6-di-<9-isopropylidene-a-D-glucofuranose-3-0-yl)titanate provided the titanium enolate 66. Reaction of 66 with aldehydes gave -hydroxy esters in high ee (Scheme 3-23). 

Recently, the improved chiral ethyl ketone (5)-141, derived in three steps from (5)-mandelic acid, has been evaluated in the aldol process (115). Representative condensations of the derived (Z)-boron enolates (5)-142 with aldehydes are summarized in Table 34b, It is evident from the data that the nature of the boron ligand L plays a significant role in enolate diastereoface selection in this system. It is also noteworthy that the sense of asymmetric induction noted for the boron enolate (5)-142 is opposite to that observed for the lithium enolate (5)-139a and (5>139b derived from (S)-atrolactic acid (3) and the related lithium enolate 139. A detailed interpretation of these observations in terms of transition state steric effects (cf. Scheme 20) and chelation phenomena appears to be premature at this time. Further applications of (S )- 41 and (/ )-141 as chiral propionate enolate synthons for the aldol process have appeared in a 6-deoxyerythronolide B synthesis recently disclosed by Masamune (115b). 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

The reaction of enolates with aldehydes or ketones to produce /3-hydroxy carbonyl derivatives is a very common and a very useful way to make carbon-carbon bonds. A fundamental stereochemical feature of the reaction is diat two new chiral centers are produced from achiral starting materials. Hence syn and anti diastereomers will be produced, each as a pair of enantiomers. This is shown schematically for the reaction of a propionate enolate with isobutyraldehyde. Because they have different energies, the syn and anti diastereomers will be... 

S. G. Davies, H. M. Kellie, and R. Polywka, Opening of carbohydrate 5,6-epoxides with chiral acetate and propionate enolate equivalents attached to the iron chiral auxiliary [(C5H5)Fe(CO)P(Ph)3], Tetrahedron Asymmetry, 5 (1994) 2563-2570. 

As above (eq 1), a major drawback of this reagent is the lack of a readily available enantiomer. There are many alternative methods for the enantioselective propionate aldol reaction. The most versatile chirally modified propionate enolates or equivalents are N-propionyl-2-oxazolidinones, a-siloxy ketones, boron enolates with chiral ligands, as well as tin enolates. Especially rewarding are new chiral Lewis acids for the asymmetric Mukaiyama reaction of 0-silyl ketene acetals. Most of these reactions afford s yw-aldols good methods for the anri-isomers have only become available recently. ... 

The ( )- and (Z)-crotylboronates provide selectivity in the best cases comparable to that obtained with other crotylboration procedures. Combining ease of preparation, stability, and selectivity the tartrate-modified (E)- and (Z)-crotylboronates are highly useful propionate enolate equivalents. 

Duthaler s chiral propionic enolate titanium compound (Duthaler s reagent Scheme 766) has been used to introduce stereochemistry in the asymmetric synthesis of a protein phosphotase inhibitor tautomycin.2026... 

The 10% decrease in enantiomeric excess compared with that observed for the propionate enolate (91) is reflected in the double asymmetric synthesis outlined in Scheme 42 and Table 9 (see Table 7 for com parison). ... 

Duthaler and colleagues have used diacetone glucose as a ligand on titanium to induce enantioselectivity in the addition of acetate and propionate enolates (Scheme 5.20 [105,106]. The most interesting feature of the addition of the titanium enolate of tert-butyl acetate (Scheme 5.20a) is that the best selectivities were achieved at room temperature, making this procedure one of the most promising for scaleup... 

Although the asymmetric addition of propionate enolates (outlined above) is a valuable synthetic tool, its use is restricted to targets that are amenable to a linear synthetic plan. Aldol additions may also be used to couple two large fragments in a convergent synthesis, but such reactions are not amenable to auxiliary based... 

The C-12 to C-17 segment (645) of ( + )-aplasmomycin has been synthesized from 590 as shown in Scheme 94 [148]. In the first step, an aldol condensation of isopropyl propionate enolate with 590 produces 638 as a mixture of isomers. After conversion to enone 640, reduction of the carbonyl with NaBH4-CeCl3 gives alcohol 641 as a single isomer. A second reduction of642 with zinc borohydride gives a separable mixture of isomers, the major isomer... 

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