Silyl ketene acetals chiral aldehydes

A titanium catalyst 20 that incorporates binaphthyl chirality along with imine and phenolic (salen) donors is highly active in addition of silyl ketene acetals to aldehydes.160... 

Catalytic, enantioselective addition of silyl ketene acetals to aldehydes has been carried out using a variant of bifunctional catalysis Lewis base activation of Lewis acids.145 The weakly acidic SiCU has been activated with a strongly basic phor-phoramide (the latter chiral), to form a chiral Lewis acid in situ. It has also been extended to vinylogous aldol reactions of silyl dienol ethers derived from esters. 

Jorgensen and co-workers reported the asymmetric additions of a silyl ketene acetal to aldehydes (40) using the chiral bis-sulfonamide catalyst 27 [109]. Among the limited number of aldehydes examined, adducts were obtained in moderate to high yields (41-90%) and modest levels of ee (30-56% Table 6.44). The corresponding mono-sulfonamide catalyst was inactive under the reported conditions. 

This reaction of silyl ketene acetals with aldehydes, using 29 as a stoichiometric chiral reagent (Eq. 46), was reported by Reetz et al. [42]. The aldol addition of l-(trimethyl-siloxy)-l-methoxy-2-methyl-l-propene and 3-methylbutanal provides the aldol in only 57 % yield, but with 90 % ee. 

The use of CAB as a chiral reagent seems to be more effective for this reaction, which proceeds faster and with higher yields and enantiomeric excess. Kiyooka et al. first described the use of various chiral oxaborolidines, derived from sulfonamides of a-amino acids and borane, in the course of the selective aldol reaction between silyl ketene acetals and aldehydes (Eq. 47) [43a]. Stereoselectivity and yields were relatively high. 

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-... 

Table IV. Ratio of Diastereoisomers in the Lewis Acid Mediated Reaction of Chiral Silyl Ketene Acetals with Aldehydes.

This concept has been further applied to the development of various stereoselective bond-forming reactions using chiral bis-phosphoramides as catalysts. The most well-explored system is the aldol addition of silyl ketene acetals to aldehydes [6). In general, combination of a catalytic amount of 2 and a stoichiometric quantity of SiCl, was very effective for the reactions of methyl acetate-derived silyl ketene acetal with various aldehydes (Scheme 7.5). 

Another chiral auxiliary for controlling the absolute stereochemistry in Mukaiyama aldol reactions of chiral silyl ketene acetals has been derived from TV-methyl ephedrine.18 This has been successfully applied to the enantioselec-tive synthesis of various natural products19 such as a-methyl-/ -hydroxy esters (ee 91-94%),18,20 a-methyl-/Miydroxy aldehydes (91% ee),21 a-hydrazino and a-amino acids (78-91% ee),22 a-methyl-d-oxoesters (72-75% ee),20b cis- and trans-l1-lactams (70-96% ee),23 and carbapenem antibiotics.24... 

Besides their application in asymmetric alkylation, sultams can also be used as good chiral auxiliaries for asymmetric aldol reactions, and a / -product can be obtained with good selectivity. As can be seen in Scheme 3-14, reaction of the propionates derived from chiral auxiliary R -OH with LICA in THF affords the lithium enolates. Subsequent reaction with TBSC1 furnishes the 0-silyl ketene acetals 31, 33, and 35 with good yields.31 Upon reaction with TiCU complexes of an aldehyde, product /i-hydroxy carboxylates 32, 34, and 36 are obtained with high diastereoselectivity and good yield. Products from direct aldol reaction of the lithium enolate without conversion to the corresponding silyl ethers show no stereoselectivity.32... 

Denmark utilized chiral base promoted hypervalent silicon Lewis acids for several highly enantioselective carbon-carbon bond forming reactions [92-98]. In these reactions, a stoichiometric quantity of silicon tetrachloride as achiral weak Lewis acid component and only catalytic amount of chiral Lewis base were used. The chiral Lewis acid species desired for the transformations was generated in situ. The phosphoramide 35 catalyzed the cross aldolization of aromatic aldehydes as well as aliphatic aldehydes with a silyl ketene acetal (Scheme 26) [93] with good yield and high enantioselectivity and diastereoselectivity. 

Three years after the discovery of the asymmetric BINOL phosphate-catalyzed Mannich reactions of silyl ketene acetals or acetyl acetone, the Gong group extended these transformations to the use of simple ketones as nucleophiles (Scheme 25) [44], Aldehydes 40 reacted with aniline (66) and ketones 67 or 68 in the presence of chiral phosphoric acids (R)-3c, (/ )-14b, or (/ )-14c (0.5-5 mol%, R = Ph, 4-Cl-CgH ) to give P-amino carbonyl compounds 69 or 70 in good yields (42 to >99%), flnfi-diastereoselectivities (3 1-49 1), and enantioselectivities (72-98% ee). 

Aldol condensation of a-amino silyl ketene acetals (l).10 2-Dibenzylami-noketene trimethylsilyl acetals (1) react with aldehydes premixed with TiCl4 to give a-amino-p-hydroxy carboxylic esters (2) with moderate to high syn-selectivity. Surprisingly, TiCl4-catalyzed reaction of 1 with a chiral a-alkoxy aldehyde proceeds with low asymmetric induction. 

This technology has been apphed as part of the total synthesis of myx-alamide A (Scheme 56) [139]. The stereoselective aldol reaction between aldehyde 218 and the propionate 219 dehvered, after reduction, protection, and acylation, ester 220 as a single isomer. After -silyl ketene acetal formation a [3,3]-sigmatropic rearrangement accompanied by 1,3-chirality transfer took place. This, together with the uniform prochirality at the double bonds of the... 

Ester Enolate Aldol Additions to Aldehydes. Among the first examples of aldol additions employing chiral Lewis bases as catalysts were the additions of trichlorosilyl ketene acetals to aldehydes. Silyl ketene acetal 7 could be generated by metathesis of methyl tributylstannylacetate with SiCL. Treatment of 7 with benzaldehyde and 10 mol % of a phosphoramide in CH2CI2 at —78°C afforded aldol products in good to high yields with moderate enantioselectivities for all phosphoramides employed. Reaction of 7 with pivalaldehyde provided aldol products in similar yields and with slightly improved enantioselectivities. The increase in stereoselection is presumably attributed to a less com-... 

Diastereoselective Additions of Chiral Silyl Ketene Acetals to Chiral Aldehydes... 

TiCU-mediated addition of silyl enol ether (95) to chiral a-amino aldehyde (94) was reported to proceed with good chelation control, albeit in poor yield (equation 28). Effective chelation control was also reported in the TiCU-mediated reactions of chiral a-alkoxy and p-alkoxy acyl cyanides (96) and (97) with silyl enol ether (95 equations 29 and SO). Reaction of acyl cyanide (97) with the ( )-silyl enol ether (93) gave a single stereoisomer as a result of complete chelation control and syn simple stereoselection (equation 31). Additions of silyl enol ethers and silyl ketene acetals to (-)-menthyl phenyl-glyoxylate and pyruvate were reported to proceed with moderate facial selectivity the best result (84 16) is shown in equation (32). ... 

Six-membered chiral acetals, derived from aliphatic aldehydes, undergo aldol-type coupling reactions with a-silyl ketones, silyl enol ethers," and with silyl ketene acetals " in the presence of titanium tetrachloride with high diastereoselectivities (equation 41) significant results are reported in Table 20. This procedure, in combination with oxidative destructive elimination of the chiral auxiliary, has been applied... 

Zhu and Panek s total synthesis [148] is described in Scheme 89. After conversion of aldehyde 609 to di-benzyl acetal, treatment with chiral crotylsilane 610 afforded l,2-5y -611 with high stereo- and enantioselectivity. The oxidative cleavage of the double bond and subsequent aldol reaction with silyl ketene acetal 612 provided 613, which was converted into a,P-unsaturated ester 614 via Wittig olelination. The C8 methyl group was stereoselectively introduced by treatment with dimethylcuprate in the presence of TMSCl. DIB AH treatment differentially reduced the C3 and CIO esters to alcohol and aldehyde, respectively. Protection of the alcohol as silyl ether followed by the Wittig reaction afforded 615. In a manner similar to Danishefsky s synthesis [142d], an inteimolecular Suzuki... 

Enoxysilacyclobutanes. These compounds can be prepared by Wurtz coupling of 3-chloropropyltrichlorosiIane with Mg in ether. Introduction of one alkyl group is accomplished by reaction with an organolithium reagent, and the silyl chloride can then be used for the formation of silyl enol ethers. Such 0-silyl ketene acetals are extremely reactive in aldol condensations with aldehydes without catalysts. The reaction is syn-selective. An asymmetric version uses silyl ketene acetals bearing a chiral Si-alkoxy (e.g., 8-phenylmenthoxy) group instead of an alkyl substituent. 

When applied to the Mukaiyama reaction, the principles of stereodifferentiation can lead to excellent dias-tereoselection and enantioselection. When silyl ketene acetal 465 was reacted with chiral aldehyde 466 in the presence of TiCl4, a 75% yield of 467 and 468 was obtained as a 98 2 mixture, favoring 467. ... 

Few other asymmetrie reactions have been performed using insoluble or soluble polymer-supported ligands. The first example is a Mukaiyama-aldol condensation between silyl ketene acetal and different aldehydes using polymeric Box analog of 99 as chiral ligands and Cu(OTf)2 as metal soiu ce in water (Scheme 147) [216]. When using benzaldehyde as substrate, yields were very low (12-34%) and ee were moderate (40-62%) whatever the polymer-supported Box. The same level of enantioseleetivity was observed with other aldehydes while the yield was better with all the ligand/Cu complexes used. 

Acylhydrazones, R CH=N-NHCOR , undergo stereoselective Mannich reactions with silyl ketene acetals to give j8-hydrazido esters, using activation by a chiral silicon Lewis acid. Alternatively, the use of silyl ketene imine gives a /3-hydrazido nitrile. Enantioselective (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) hydrazone alkylation of aldehydes and ketones is the subject of a computational study, providing a useful screening method for possible new candidates. " ... 

---