Silyl dienolates, additions

TITANIUM-MEDIATED ADDITION OF SILYL DIENOL ETHERS TO ELECTROPHILIC GLYCINE A SHORT SYNTHESIS OF 4-KETOPIPECOLIC ACID HYDROCHLORIDE (Pipecolic acid, 4-oxo-, hydrochloride)... 

Several other chiral Lewis acids have also been reported to effect asymmetric aldol reactions. Kruger and Carreira59 reported a catalytic aldol addition of silyl dienolate to a range of aldehydes in the presence of a bisphosphanyl-Cu(II) fluoride complex generated in situ from (iS )-Tol-BINAP, Cu(OTf)2, and (Bu4N)Ph3SiF2. Aromatic, heteroaromatic, and a,/ -unsaturated aldehydes provided the aldol adducts with up to 95% ee and 98% yield (Scheme 3-33). 

The Schneider group independently reported an asymmetric vinylogous Mannich reaction (Scheme 27) [47]. Addition of silyl dienolates 73 to A-PMP-protected imines 74 was promoted by phosphoric acid (R)-3g (5 mol%, R = Mes) with mesityl substituents to afford tra i -a,p-nnsatnrated 8-amino esters 75 in high yields (66-94%) together with good enantioselectivities (80-92% ee). 

Significant efforts have extended the scope of catalytic enantioselective Mukaiyama aldol addition reactions beyond the acetate and propionate enoxysilanes and have been used traditionally. Recent reports describe novel addition reactions of silyl dienolates along with isobutyrate-derived enol silanes. 

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. 

A catalytic, enantioselective approach towards the synthesis of polyol chains has recently been reported by Carreira et al. and has been applied in a synthesis of the polyol subunit of amphotericin B (Scheme 5) [13]. Aldol addition of the silyl dienolate 26 to furfural (27) catalyzed by the Tol-BlNAP-CuF -complex (2 mol-%) gives rise to the addition product 28 in 95 % yield and >99 % ee after one recrystallization. Spectroscopic evidence indicates that a copper dienolate is formed in situ from the silyl dienolate 26 and is actually the active nucleophile [14], Standard transformations including a j-yw-selective reduction of the ft-hydroxy ketone by the method of Prasad and the oxidative conversion of the furan ring to the car-... 

Aldol Addition. A catalyst generated upon treatment of Cu(OTf)2 with the (5,5)-r-Bu-box ligand has been shown to be an effective Lewis acid for the enantioselective Mukaiyama aldol reaction. The addition of substituted and unsubstituted enolsilanes at -78 °C in the presence of 5 mol % catalyst was reported to be very general for various nucleophiles, including silyl dienolates and enol silanes prepared from butyrolactone as well as acetate and propionate esters. 

The catalytic system using 62 is applicable to highly enantioselective preparation of acetoacetate aldol adducts (Scheme 10.55) [152]. The use of 1-3 mol% 62 and 0.4 equiv. 2,6-lutidine promotes the aldol reaction of a variety of aldehydes with silyl dienolate 64 in good to high optical yields. The dienolate addition provides a convergent and enantioselective route to 1,3-polyols by appending a protected acetoacetate in a single step. The 62-catalyzed aldol reactions of methyl acetate TMS enolate and dienolate 64 have been used in the total syntheses of Rofla-mycoin [153] and Macrolactin A [154], respectively. In the latter both enantiomers... 

In addition to the efficiency exhibited by catalyst 165 with a broad spectrum of aldehydes in acetate aldol addition reactions, this catalyst has been shown to function competently in enantioselective additions of dienol silane 87. The requisite dienolate is readily synthesized from 2,2,6-trimethyl-4H-l,3-dioxin-4-one 84 (diketene-i-acetone adduct) by deprotonation with LDA and quenching with MejSiCl (Eq. 24). Dioxinone 84 is commercially available at a nominal price in addition, the silyl dienolate 87 is easily purified by distillation and stable to prolonged storage. The addition reactions of 87 with aldehydes were conducted with 1-3 mol % of 165 at 0 °C (Eq. 25). A variety of aldehydes serve as substrates and give aldol adducts in 79-97% yields and up to 99% ee after a single recrystallization. 

Carreira and co-workers have described a Cu-mediated process that effects the catalytic, enantioselective addition of silyl dienolates 87 to aldehydes [24]. The active complex that is believed to initiate the reaction is readily prepared in situ upon mixing optically active bisphosphine, Cu(OTf)2 and (Bu4)NPh3SiF2 in THE (Eq. 58). The addition reactions catalyzed by this system proceed with a broad range of aldehydes to afford adducts 88 in up to 95% ee and 98% yield. Moreover, the reaction may be conducted on a preparative multigram scale utilizing as little as 0.5 mol % of 273 without deleterious effects on the product enantiomeric excess or yields. 

Finally, silyl dienol ethers (20) have been shown to react with bromonaphthoquinones (21) in a mode described as a formal oxidative addition process (Scheme 9) <9iJOC9l>. 

Vinylogous aldol-type reaction of aromatic and heteroaromatic aldehydes with silyl dienol ethers 21.115, derived from a,p-unsaturated esters, also proceeded smoothly, furnishing exclusively the y-addition products 21.116 (>99 1) with high enantioselectivity in the range of 82-98%... 

The Mannich reaction and its variants have been reviewed, mainly focussing on asymmetric catalysis thereof. Catalytic, enantioselective, vinylogous Mannich reactions have also been reviewed, covering both direct and silyl dienolate methods. Another review surveys Mannich-type reactions of nitrones, oximes, and hydrazones. A pyrrolidine-thiourea-tertiary amine catalyses asymmetric Mannich reaction of N-Boc-imines (e.g. Ph-Ch=N-Boc) with ethyl-4-chloro-3-oxobutanoate to give highly functionalized product (16). Addition of triethylamine leads to one-pot intramolecular cyclization to give an 0-ethyl tetronic acid derivative (17). ... 

The catalytic version of this type of reaction was realized by using acetoacetate derived O-silyl dienolate as nucleophiles in the presence of Carreira s catalyst, giving acetoacetate y-adducts in high yields and enantiomeric excesses [119] (Scheme 14.42). The products are ubiquitous structural subunits in biologically active natural products such as the polyene macrolide antibiotic and medicinally important HMG-CoA reductase inhibitors. This aldol addition can also be catalyzed by BINOL-Ti complex in the presence of 4A MS with moderate to good enantioselectivity [120]. The same catalyst system was also efficient in the asymmetric aldol reaction between the aldehydes and Chan s diene [ 1,3-bis-(trimethylsilyloxy)-l-methoxy-buta-1,3-diene] and other related silyl enol ethers [121, 122] (Scheme 14.43) or the functionalized silyl enol ether such as 2-(trimethylsilyloxy)furan with good to excellent enantioselectivities [123]. 

Lewis acids catalyse regio- and diastereo-selective additions of silyl dienolates to fluorinated sulfinylimines, RF-CH=N-S(=0)-Bu allowing access to new chiral a-fluoroalkyl amines. 

A tunable and highly regio- and diastereo-selective addition of acyclic silyl dienolates (6) to several a-fluoroalkyl sulfinylimines (7) has been developed. By appropriate 0 choice of the Lewis acid catalyst, two new chiral a-fluoroalkyl amines (8) and (9) have been obtained in good yields and excellent diastereoselectivities (up to >99 1 dr), respectively (Scheme 3). The high regio- and diastereo-selectivities of different Lewis acid-catalysed reactions have been explained by different transition states. In the case of the TMSOTf-catalysed reaction, the -configuration of the newly formed chiral carbon centre in products (9) could be explained by a non-chelated transition state in which... 

Mukaiyama Aldol and Related Processes. The Carreira group has developed an asymmetric catalytic aldol reaction that involves addition of a silyl dienolate to an aldehyde partner in the presence of a chiral catalyst generated in situ from (S)-Tol-BINAP, Cu(OTf)2, and TBAT, e.g., eq... 

In the presence of titanium(IV) chloride, silyl dienol ether 55 derived from an a,/i-unsaturated aldehyde reacts tvith acetal 54 selectively at the y-position to give d-alkoxy-a,j5-unsaturated aldehydes 56, albeit in lotv yields. Because titanium(IV) chloride is strongly acidic, polymerization of silyl dienol ether 55 proceeds. In these reactions addition of tetraisopropoxyti-tanium(IV) to titanium(IV) chloride increases the yield dramatically [28a] -vitamin A is successfully synthesized by utilizing this aldol reaction of silyl dienol ether 55 (Scheme 3.2) [28b]. 

Scheme 5.63 Vinylogous aldol addition of silyl dienolate 203a mediated by titanium-BINOL complex enantioselective synthesis of phorbaside A building block 205.

Moreover, the protocol could be used for a vinylogous Mukaiyama aldol addition and offered a solution to the problem of the asymmetric acetoacetate aldol reaction. Thus, 2 mol% of the catalyst 198 is enough to promote the addition of silyl dienolate 214 to various aldehydes to give, after desilylation, O-protected P-keto-5-hydroxy esters [113]. The protocol is illustrated for an addition to P-stannylpropenal 213. Depending on the enantiomer of the catalyst 198 or ent-198 chosen to mediate the aldol addition, enantiomeric products 215 and ent-215 were obtained in 92% ee. In an elegant convergent total synthesis, both enantiomers were incorporated into macrolactin A, as shown in Scheme 5.65 [114,115]. 

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]. 

Scheme 5.77 Carreira s copper-catalyzed vinylogous aldol addition of silyl dienolate 214 postulated catalytic cycle.

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