Double ketoester reduction

The power of Noyori s Ru -BINAP system in ketone reductions has been amply demonstrated in numerous complex molecule syntheses. Schreiber, for example, has disclosed a route to the macrolide antibiotic mycoticin A (221, Scheme 2.27) [139] that relies on a strategy involving two-directional chain synthesis [140]. Catalytic asymmetric reduction of diketone 216 affords the C2-symmetric diol 217. Conversion of 217 into bis(ketoester) 218 then allows double ketone reduction to furnish 219, which was subsequently elaborated into the skipped polyol chain 220 of mycoticin A (221). 

Novel C2-symmetric thiophene-containing ligands have recently been prepared and utilized in asymmetric synthesis. Dithiophene 158 was utilized as a ligand in the asymmetric reduction of p-ketoesters (prostereogenic carbonyl) and acrylic acids (carbon-carbon double bond) <00JOC2043>. Dibenzo[b]thiophene 159 was utilized as a ligand in enantioselective Heck reactions of 2-pyrrolines <00SL1470>. 

Molander has also studied the Sml2-mediated double Barbier additions of alkyl dihalides to ketoesters.22,23 These impressive anionic-anionic, inter-molecular-intramolecular sequences require the use of Nil2 as an additive and irradiation with visible light and allow access to a range of bicyclic and tricyclic systems. The reactions proceed by reduction of the more reactive alkyl halide, intermolecular Barbier addition to the ketone, lactonisation and a second Barbier addition to the lactone carbonyl (Scheme 6.18).22... 

These catalytic reductions are relatively slow, requiring high pressures or high temperatures, and chiral P-ketoesters racemize faster than they can be reduced. As it happens, reduction of one enantiomer is considerably faster than reduction of the other. This is a case of double asymmetric induction (see Section 1.5) applied to a... 

While only 1.0 equiv. of PMHS is needed to complete the reduction of some ketones e. g. a,a,a-trifluoroacetophenone (Ic) and methyl phenylglyoxylate (Id), excess PMHS is necessary in most cases. As shown in Table 1, inconplete conversions are mostly observed for the reduction of relatively acidic substrates i. e. y ketoesters If and Ig and /0-ketoamides Ih and li (pKa = 10-13). Therefore, a likely hypothesis is that the [Zn-diamine]/PMHS system is active not only for the reductive reaction of the carbonyl function, but also for the oxidative silylation of any enolisable group. Thus, the enol-silyl ether produced would hydrolyze back in methanol to the free enol, accounting for the consumption of extra equiv. of PMHS. Nevertheless, this hypothesis does not accotmt for the reduction of imine 3a, since no inqirovement in the conversion is noted on doubling the amount of PMHS (Scheme 3, Table 1). Other imines e. g. 3b, are readily reducible with the present Zn-diamine-methanol system. 

Iqbal and his co-workers reported a synthesis of 2,5-disubstituted tetrahydrofurans from y,8-unsaturated alcohols (Scheme 33) (62). The stereochemistry of the C-2 and C-3 centres was set up with some selectivity by reduction of the p-ketoester 242. Epoxidation of the terminal double bond... 

Synthesis of racemic (178) is shown in Scheme 37. Ketoester (177), synthesized from naphthalene-1,6-diol via 5-methoxy-2-tetralone, was converted into compound (180) by successive methylation at C-4, acetali-zation at C-3, reduction of the ester group to hydroxymethyl group, epoxidation of the C-5, C-6 double bond, and ring opening of the epoxide. Birch reduction of diol (180) with 18 equivalents of lithium in liquid ammonia followed by acid hydrolysis and subsequent methyl acetalization... 

Since steric hindrance disfavours cyclization for substrates with internal P-substitution, double-bond isomerization is often a competing pathway. Indeed, West found that reductive Nazarov cyclizations (see Section 3.4.S.2) of either trans- or cw-disubstituted enones 49a or 49b, both produced a single diastereomeric product 50a. The stereochemistry of 50a corresponds to a conrotatory cyclization of trans-isomer 49a, thereby indicating that while the trans-isomer 49a cyclizes, the cw-isomer 49b first isomerizes before cyclization. Recent studies by Frontier and co-workers on polarized Nazarov cyclizations also found that in the case of alkylidene p ketoester substrates (for example, see 46), reaction rates depended on the competing rate of isomerization, which depended on the nature of the P-... 

The double reduction of jff-ketoester methoxymethyl enol ethers (88) is reported by an American school o high-yield method for the hydro-genolysis of the /S-carbonyl function treatment with lithium in ammonia causes reduction of the conjugated double bond, elimination of methoxy-methanol, and further reduction to give the saturated ester (89). This procedure is equally effective on the corresponding /3-ketoacids. ... 

By using this same Dieckmann cyclization strategy. Wenkert and his coworkers have accomplished a synthesis of raunescine (288) (Scheme 3.54) (58). Accordingly, ketoester 319 was benzylated to provide enol ether 325. Sequential reduction of the double bond and ketone of 325 by the protocol employed in the deserpidine synthetic route provided the C(18) alcohol 326. Acylation of the hydroxyl group and hydrogenolysis gave raunescine. Similar to the efforts of Szantay, Wenkert s investigations clearly demonstrate how Dieckmann cyclization chemistry can be applied to the synthesis of a variety of yohimbine alkaloids. 

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