Chiral dienol ethers

Regio-, enantio-, and diastereo-selective vinylogous aldol additions of silyl dienol ethers to aldehydes use a Lewis base (a chiral bis-BINAP-phosphoramide) to activate a Lewis acid (silicon tetrachloride).139... 

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. 

The use of chiral diamine 60 with Sn(OTf)2/Bu2Sn(OAc)2 promotes Mukaiya-ma aldol reactions, and such an example was used in a recent synthesis of Tax-ol , in which adduct 61 was obtained with 99% ds and 96% ee (Scheme 9-20) [42J. Other notable contributions to this field have been made using dienolate chemistry. For example, the titanium complex 62 promotes aldol reactions of silyl dienol ethers (Scheme 9-21). Products 63 and ent-63 were then used in the synthesis of macrolactin A (64) [43],... 

In the previous synthesis, two asymmetric aldol reactions using dienyl silyl ethers were described, one using a chiral Lewis acid for stereoinduction while the other used substrate control from a chiral aldehyde. This can be compared with the use of chiral dienolate 131 in the synthesis of a Ci-Cie fragment of the bryo-statins (Scheme 9-41) [59J. Here, the menthyl-derived auxiliary is covalently attached to the enolate, and again an excellent level of asymmetric induction was achieved on addition to aldehyde 132 to give adduct 133. 

Ester-based chiral auxiliaries have also beat used in other settings. P-Alk-oxyesters 1.27 of (R)-1 -phenylethanol 1.1 (R = Me, Ar = Ph) or (5)-1-naphthyl-ethanol 1.1 (R = Me, Ar = 1-Np) are transformed into dural synthons by reactions with a lithiated carbanion a to phosphorous followed by hydrogenolysis [194], Ethers 1.28 of chiral alcohols 1.1 undergo selective alkylations or hydroxyalkyla-tions [169]. The auxiliaries can be removed by hydrogenolysis. Enol or dienol ethers 1.29 and 1 JO suffer [2+2] [195, 196] or [4+2] cycloadditions [49, 197,198, 199], The best stereoselectivities are obtained when the chiral auxiliary is 1.1 (R = r-Pr, Ar=Ph), 1.4 (R=Ph), 1.5 (R = Ph), 1.10 or 1.13. These auxiliaries are cleaved either by acid treatment [199] or by other means in subsequent steps. Acetylene ethers G OC=CR derived from 1.5 (R=Ph) [199a] can undergo stereoselective Pauson-Khand reactions [200, 201], The auxiliaries are removed by treatment of the products with Sml2 in THF-MeOH. 

Bretmaier and coworkers [49] recommended dienol ethers of chiral alcohols 1.30 The cycloadditions with maleic anhydride are selective provided the chiral alcohol is traas-2-phenylcyclohexanol 1.5 (R = Ph) (Figure 9.48). The introduction of methyl groups on the phenyl ring increases the selectivity. Tins result is... 

Seebach and co-workers have explored the uses of enantiomerically pure dienolates (18) and silyl dienol ethers derived from dioxinones as chiral synthetic equivalents of the acetoacetic ester dianion. Reactions were carried out principally with aldehydes, and are regio- and diastereoselective (Scheme 7) <89AG(E)472,91CB1845>. 

The chiral alcohols are mainly employed as esters or enol ethers. Esters with carboxylic acids can be obtained by any convenient esterification technique. Dienol ethers were obtained by transetherification with the ethyl enol ether of a 1,3-diketone, followed by Wittig reaction8 silyldienol ethers were obtained by the method of Danishefsky11-12 and simple enol ethers by mercury-catalyzed transetherification13. Esters and enol ethers have been used as chiral dienophiles or dienes in diastereoselective Diels-Alder reactions (Section D. 1.6.1.1.1.1.). (R)-l-Phenylethanol [(R)-4] has been used for enantioselective protonation (Section C.) and the (S)-enantiomer as chiral leaving group in phenol ethers for the synthesis of binaphthols (Section B.2.) the phenol ethers are prepared as described for menthol in the preceding section. (S)-2-Octanol [(S)-2] has found applications in the synthesis of chiral allenes (Section B.I.). 

The authors assumed that the catalytically active species might be a copper(I) complex originating from reduction by the silyl dienolate 214. As a consequence, the aldol reaction was performed with the chiral copper(I) complex [Cu(OfBu)-(S)-270], and identical results in terms of the stereochemical outcome were obtained. In addition, the reaction was followed by react IR. The study led to evidence of a copper(I) enolate as the active nucleophile, and the catalytic cycle also shown in Scheme 5.77 was proposed. The reaction of the copper(I) complex Cu(OiBu)-(S)-270 with silyl dienolate 214 represents the entry into the catalytic cycle. Under release of trimethylsilyl triflate, the copper enolate 272 forms, whose existence is indicated by in situ IR spectroscopy. Its exact structure remains unclear, but the description as O-bound tautomer is plausible. Upon reaction with the aldehyde, the copper aldolate 273 is generated, which is then silylated by means of the silyl dienol ether 214 to give the (isolable) silylated alcohol 274 from which the aldol product 271 is liberated during the acidic workup [132b]. 

Silyl dienol ethers also participate in the asymmetric aldol-type transformation. For example, silyl 1,3-dienol ethers react with aldehydes exclusively at the diene terminus in an enantioselective manner in the presence of a chiral titanium (Scheme 3-81) or copper catalyst, whereas the asymmetric reaction of... 

Campagne and Bluet recently reported the catalytic asymmetric vinylogous Mukaiyama aldol (CAVM) reaction of aldehydes with dienol silyl ether 15 using chiral ammonium fluorides as an activator. For example, the CAVM reaction of isobutyr-aldehyde with 15 in the presence of 10 mol% of 4b in THF at room temperature led to the formation of the vinylogous aldol product 16 in 70% yield with 20% ee. The ee-value was improved to 30% by conducting the reaction at 0 °C (Scheme 9.6) [16]. 

Asymmetric Diels-Alder reactions of dienes substituted widi a removable chiral moiety with prochiral dienophiles have been much less extensively studied. Hie few successful examples involve ester or ether derivatives of 1,3-dienols. 

LDA, LiCl) afforded the dienolate intermediate, which was alkylated with iodoethane. Four additional steps including a reductive cleavage of the chiral auxiliary, the protection of the resulting primary alcohol, the oxidative cleavage of the double bond under Johnson-Lemieux conditions, and the formation of the silyl enol ether led to the desired fragment 187. 

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