Silyl ketene acetals synthesis

Schemes 28 and 29 illustrate Curran s synthesis of ( )-hirsutene [( )-1]. Luche reduction58 of 2-methylcyclopentenone (137), followed by acetylation of the resulting allylic alcohol, furnishes allylic acetate 138. Although only one allylic acetate stereoisomer is illustrated in Scheme 28, compound 138 is, of course, produced in racemic form. By way of the powerful Ireland ester enolate Clai-sen rearrangement,59 compound 138 can be transformed to y,S-unsaturated tm-butyldimethylsilyl ester 140 via the silyl ketene acetal intermediate 139. In 140, the silyl ester function and the methyl-substituted ring double bond occupy neighboring regions of space, a circumstance that favors a phenylselenolactonization reac-...

The Ireland-Claisen reaction of ( )-vinylsilanes has been applied to the stereoselective synthesis of syn- and c/nti-2-substituted 3-silyl alkcnoic acids. a R-2-Alkyl-3-silyl acids are prepared by rearrangement of ( )-silyl ketene acetals which are generated in situ from the kinetically formed (Z)-enolate of the corresponding propionate ester40. Chelation directs the stereochemistry of enolization of heteroelement-substituted acetates in such a way that the syn-diastereomers are invariably formed on rearrangement403. 

Hepatite Virus NS3/4A having the pyrrolidine-5,5-trans-lactam skeleton [83], starting from (R)- and (S)-methionine, respectively. The key step is the addition of the proper silyl ketene acetal to an iminium ion, e.g., that generated by treatment of the intermediate 177 with boron trifluoride, which provided the adduct 178 with better diastereoselectivity than other Lewis acids. Inhibitors of hepatitis C virus NS3/4A were efficiently prepared by a similar route from (S)-methionine [83]. The addition of indole to a chiral (z-amino iminium ion was a completely diastereoselective step in a reported synthesis of tilivalline, a natural molecule which displays strong cytotoxicity towards mouse leukemia L 1210 [84]. 

Mermerian AH, Fu GC (2005) Catalytic enantioselective construction of all-carbon quaternary stereocenters synthesis and mechanistic studies of the C-acylation of silyl ketene acetals. J Am Chem Soc 127 5604—5607... 

A recent synthesis of P-D lactone (Scheme 13.51) used an enantioselective catalytic approach. A conjugate addition of a silyl ketene acetal derived from an unsaturated ester gave an unsaturated lactone intermediate. The catalyst is CuF-(S )-tol-BINAP.30 The catalytic cycle for the reaction is shown below. 

The synthesis of Baccatin HI shown in Scheme 13.57, which was completed by a group led by the Japanese chemist Teruaki Mukaiyama, takes a different approach for the previous syntheses. Much of the stereochemistry was built into the B-ring by a series of acyclic aldol additions in Steps A through D. A silyl ketene acetal derivative... 

The reaction of silyl ketene acetal addition to nitrones has been used for the synthesis of optically active (2S,3S)-benzoyl- and /V- oc-phenyl isoserine (636a) of isoxazolidine nucleoside-analog of thymine polyoxine C(636b) and of... 

Two procedures were developed for C,C-coupling reactions of silyl esters of primary AN. One approach involves two steps and the synthesis of intermediate SENAs according to standard procedures. Another procedure is based on the one-pot reaction of AN with the DBU/TBSOTf system in a ratio of 1 1.1 followed by the addition of silyl ketene acetal and a catalytic amount of TBSOTf. 

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... 

Related catalytic enantioseiective processes Representative examples of other catalytic asymmetric Mannich additions are depicted in Scheme 6.31. In 1997, Tomioka demonstrated a Li-catalyzed synthesis of functionalized p-lactams that proceeds through a catalytic enantioseiective Mannich reaction (promoted by 103) [95], and a year later Lectka and his team published a series of reports concerning additions of silyl ketene acetals... 

The reaction of Cjq with silylated nucleophiles [47] requires compounds such as silyl ketene acetals, silylketene thioacetals or silyl enol ethers. It proceeds smoothly and in good yields in the presence of fluoride ions (KF/18-crown-6) (Scheme 3.10). The advantage of the latter synthesis is the realization of the cyclopropanation under nearly neutral conditions, which complements the basic conditions that are mandatory for Bingel reactions. Reaction with similar silyl ketene acetals under photochemical conditions and without the use of F does not lead to methanofullerenes but to dihydrofullerene acetate [48]. 

For the anionic polymerization of methacrylonitrile (MAN), many initiators have been developed, which include alkali-metal alkyls such as butyllithium [42], triphenylmethylsodium [43], phenylisopropylpotassium [43], the disodium salt of living a-methylstyrene tetramer [44], alkali-metal amides [45], alkoxides [46], and hydroxide [47], alkali metal in liquid NH3 [48], quaternary ammonium hydroxide [49], and a silyl ketene acetal coupled with nucleophilic or Lewis acidic catalysts [50]. However, only a single example of the synthesis of PMAN with narrow molecular-weight distribution can be cited, and the reported number-average molecular weights were much higher than those calculated from the stoichiometry of the butyllithium initiator [42]. 

Allylic esters of fluoroacetic acid were used in the Ireland silyl ketene acetal rearrangement procedures by the Welch group at Albany [164]. For example, Eq. (53) shows a highly diastereoselective rearrangement which formed an early stage in syntheses of 2,3-dideoxy-2-fluoro-3-C-methyl pentose nucleosides [165, 166]. If a stereoselective synthesis of a functionalised monofluorocompound is... 

The synthesis of natural products by chirality transfer from carbohydrates has been used for a total synthesis of (-)-(7S)-nonactic acid (199). The furanoid glycal (197) was prepared from D-mannose, which is the appropriate chiral precursor (Scheme 46) (80JOC4259). A [3,3]-sigmatropic rearrangement of the silylated ketene-acetal (198) led to the control of the C-2 configuration. The intermediate furanoid glycal was prepared in ten steps from the carbohydrate precursor. 

The use of aryl-A3-iodanes for C-heteroatom bond formation at the a-carbon atoms of ketones and / -dicarbonyl compounds, and related transformations of silyl enol ethers and silyl ketene acetals, has been exhaustively summarized in recent reviews (Scheme 27) [5,8]. Reactions of this type are especially useful for the introduction of oxygen ligands (e. g., L2 = OH, OR, OCOR, 0S02R, OPO(OR)2), and have been extensively utilized for the synthesis of a-sulfonyl-oxy ketones and a-hydroxy dimethyl ketals. 

Fu has demonstrated that acetate anion attack on the silicon center of the silyl ketene acetal, as well as formation of an acyl pyridinium salt, contribute towards the promotion of these reactions [62]. Additionally, silyl ketene imines have also been shown to participate in analogous asymmetric C-acylation reactions to yield chiral quaternary nitriles, and this method was employed as a key step in the synthesis of verapamil [65]. 

Claisen rearrangements of silyl ketene acetals have been used in numerous syntheses, including the synthesis of the ionophore antibiotic Calcimycin outlined in Figure Si3.12. 

The photo-SNl reaction with particular classes of alkenes - namely enamines, silyl enol ethers and silyl ketene acetals - affords a smooth synthesis of a-aryl ketones,... 

Fig. 11.43. Claisen-Ireland rearrangement of two O-allyl-O-silyl ketene acetals. 7ran.v-sclective synthesis of disubstituted and E-selective synthesis of trisubstituted alkenes.

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... 

Owing to the urgent need of new drugs for the treatment of AIDS, many methods for converting the title lactones into antiviral dideoxynucleosides have been devised within the past few years. A viable synthesis of the potent anti-HIV agent 3 -deoxy-2, 3 -dehydrothymidine (d4T, 21) relies on trans selective sulfenylation of the lactone-derived silyl ketene acetal (20) with iV-(phenylthio)- -caprolactam (eq 11). In comparable fashion, (21) and related nucleosides have been prepared through seleneny-lation of (20). ... 

In Kiyooka s approach to acetate aldols by use of a stoichiometric amount of 3f, the enantiomeric excess obtained in the reaction with silyl ketene acetals derived from a-unsubstituted acetates was much lower (ca 10-20 %) than that obtained in the reaction with l-ethoxy-2-methyl-l-(trimethylsiloxy)-l-propene (> 98 % ee). Introduction of an removable substituent, e.g., a methylthio or bromo substituent, after aldol reaction at the a-position of chiral esters, resolved this problem [43e], Asymmetric synthesis of dithiolane aldols was achieved in good yield by using the silyl ketene acetal derived from l,3-dithiolane-2-carboxylate in the 3f-promoted aldol reaction, and desulfurization of the dithiolane aldols resulted in production of the acetate aldols in high enantiomeric purity (Eq. 56). 

Kiyooka et al. reported that the 3i-catalyzed aldol reaction of a silyl ketene acetal involving a dithiolane moiety with y3-siloxy aldehyde resulted in the production of syn and anti 1,3-diols with complete stereoselectivity depending on the stereochemistry of the catalyst used [45b]. This methodology was applied to the enantioselective synthesis of the optically pure lactone involving a syn-l,3-diol unit, known to be a mevinic acid lactone derivative of the HMG-CoA reductase inhibitors mevinolin and compac-tin (Sch. 2). 

This methodology also enables stereospecific synthesis of the side-chain of taxol [56]. The A-benzoyl-3-phenylisoserine side chain at C-13 of the taxol molecule is essential for its antitumor activity. The stereoselectivity in this reaction depends on the geometry of the silyl ketene acetal (Eq. 77). The reaction of the (E)-ketene acetal with (i )-27 produces the anti adduct with high stereoselectivity anttsyn = 98 2, 92 % de anti). In contrast, the reaction of the (Z)-silyl ketene acetal with S)-27 produces the enantiomerically pure syn adduct (symanti = > 99 1, > 99 % de syn). Aus, our methodology provides the first practical and efficient route for the preparation of both diastereomers of an a-hydroxy /3-amino ester. The syn adduct 52 is transformed to the desired A-benzoyl-(27 ,35)-phenylisoserine methyl ester by hydrogenolysis over a palladium catalyst then the Schotten-Baumann reaction. 

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