A-alkyl P-ketoesters

Remarkably, the reaction also tolerated the use of differently substituted a-alkyl-p-ketoesters as Michael donors, leading to the formation of compounds containing two contiguous stereogenic centers, one of them a quaternary one, in good diastereo- and enantioselectivities (Scheme 4.6). Masked cyclic 1,3-diketones such as 2-hydroxy-1,4-naphthoquinols have also been successfully applied in this context also showing the extraordinary performance of catalyst 68a in terms of both yields and enantioselectivities. There is also one example of a vinylogous Michael reaction between a,a-disubstituted dicyanoacrylates and nitroalkenes for which Takemoto s catalyst has also been identified as the most efficient promoter of the reaction. Moreover a solid-supported version of this catalyst has also been developed by Takemoto himself and tested in the reaction of diethylmalonate with nitrostyrene with success. ... 

Scheme 4.37 Enantioselective Michael addition of a-alkyl P-ketoesters to a,P-unsaturated aldehydes and application to the total synthesis of (+ ytanikolide.

In the context of finding out efficient syntheses of enantiomerically pure multifunctional molecules containing a chiral quaternary carbon atom. Brown reported the KR of representative a-alkyl-P-ketoesters and a-tertiary ketones with B-chlorodiisopinocampheylborane (DlPCl), with the simultaneous preparation of the alcohols with de and ee >90% [67]. As an example, reduction of the Dieckmann ester 89 with O.SOMequiv of (—)-DlPCl at room temperature for 2h afforded, after the usual diethanolamine work-up, the recovered ketone (R)-89 in 43% yield (90% ee). A 37% yield of the methyl l-methyl-2-hydroxycyclopentanecarboxylates 90 with a cis trans ratio 3 97 was reported. The (IS, 2S)-trans-isomer showed 96% ee. Increasing the ratio reagent substrate improved the efficiency of the KR of the ketone, at the expense of the diastereomeric excess and enantiomeric excess of the... 

The exposure of electron-rich species such as amines, hydrazines, or enolate anions to an oxidant results in ET, which generates a free (or metal-bonded) radical or radical cation [91]. Eor example, the oxidation of a-alkyl p-ketoester (112) with Mn results in enolization to yield 113 in the ratedetermining step, and this is followed by ET to form the electrophilic radical 114 [92] (Scheme 9.14). In the HAS reaction, cyclohexadienyl radicals 115 are oxidized by Mn(OAc)j to cation 116, which by deprotonation regenerates the aromatic system 117. 

Asymmetric induction in intramolecular C-H insertion reactions was first reported by McKervey and co-workers [53], who used chiral Rh(II) prolinate 17a (Eq. 5.24). Although enantiocontrol was low, this report established the feasibility of the methodology and left open advances that were subsequently made by Ikegami and Hashimoto, who were able to convert a-diazo-p-ketoester 47 into cyclopentanone 48 with 18a (Eq. 5.25) with 32-76% ee, dependent on the substituent Z and the size of the ester alkyl group [54,116],... 

A considerable number of pyrroles 30 with alkyl, alkenyl, or aryl substituents were synthesized by spontaneous cyclization of the enyne precursors 31 (when R = H, Ph, CH2OTHP), or upon treatment of 31 with the catalytic system PdCV KCl (when = H), or alternatively, by treatment of 31 with CuCb (when R H) <03JOC7853>. Treatment of y-ketoalkynes with amines in the presence of catalytic amounts of platinum dichloride constitutes a new route to 1,2,3,5-substituted pyrroles <03AG(E)2681>. An intramolecular rhodium(lI)-catalyzed N-H insertion reaction of 5-amino-7,Y-difluoro-a-diazo-P-ketoesters has been used for the synthesis of a series of 3-fluoropyrroles <03OL745>. 

As noted earlier in the alkylation study of a-fluoro phosphorus ylides, hydrolysis of the resultant a-fluoro phosphonium salts and a-fluorophosphonates do not necessarily parallel each other. This difference is again exhibited in the hydrolysis of the acylated products of the a-fluoro ylides. For example, the acylation product (10) is readily hydrolyzed at room temperature to give the desired a-fluoro-p-ketoester. The results of the acylation-hydrolysis of (4) with a variety of alkyl, cycloalkyl and aryl acyl halides are summarized in Table HI. 

A recent synthesis of (+)-nitramine (275) and (-)-isonitramine (276) has been reported [611]. Resolution of an a-substituted p-ketoester with pig liver esterase was the key improvement to provide the required chiral quaternary carbon. Subsequent cyclization of the piperidine ring gave 275 and 276. In a recent synthesis of sibirine (277), a-deprotonation/alkylation of an imine gave an intermediate having the required quaternary carbon,... 

Dieckmann and Claisen condensations. Dieckmann cyclization and Claisen condensation of M-acylpyrazoles are catalyzed by MgBr -RjN. Note that a practical >ynthesis of a-acylamino-P-ketoesters employs MgClj-EtjN to induce the reaction between alkyl hydrogen (acylamino)malonates and acyl chlorides. ... 

Keto esters represent interesting substrates that permit ready and various opportunities for further stmctural manipulation, but until 2002 only limited asymmetric a-alkylation procedures were developed [85]. In 2002, Dehmlow et al. [86] demonstrated the use of cinchonidinium bromide Ic in asymmetric a-alkylation of p-ketoester 24 when the corresponding benzylated product 29 (Scheme 8.11, entry 1) was obtained in excellent yield (97%), satisfying 46% ee. Better results in terms of enantioselectivity (up to 97% ee) were reported by Kim and co-workers [87], who showed the effectiveness of bulky cinchonine-derived catalysts IL in asymmetric a-alkylation of P-ketoesters(Scheme 8.11, entry 2). An asymmetric a-alkylation procedure with broad generahty in terms of the stmcture of P-ketoesters 25 and alkyl hahdes under PTC with C2-symmetric PTC L was developed by Maruoka and co-workers [88] (Scheme 8.11, entry 3). Further optimization led to the development of a reliable route for the asymmetric synthesis of not only a,a-dialkyl-P-hydroxy and p-amino esters, but also functionalized aza-cyclic a-amino esters [89], a-alkylated ketolactones [90], and functionalized a-benzoyloxy-P-ketoesters [91]. Shghtly changed catalyst XXV (Scheme 8.12) was also successfully used for the constmction of enantiomerically enriched various a-alkyl-a-fluoro-P-keto esters... 

SCHEME 8.12. Asymmetric alkylation of a-fluoro p-ketoester 30 using PTC. 

All lation of Garbanions. Concentrated N a OH—hen syl triethyl amm onium chloride is the base/catalyst system normally used for this type of process (20). Classes of compounds alkylated in this way include phenylacetonitriles, ben2ylketones, simple aUphatic ketones, certain aldehydes, aryl sulfones, P-ketosulfones, P-ketoesters, malonic esters and nitriles, phenylacetic esters, indene, and fluorene (see Alkylation). 

Hydride and 1,2-alkyl shifts represent the most common rearrangement reactions of carbenes and carbenoids. They may be of minor importance compared to inter-molecular or other intramolecular processes, but may also become the preferred reaction modes. Some recent examples for the latter situation are collected in Table 23 (Entries 1-10, 15 1,2-hydride shifts Entries 11-15 1,2-alkyl shifts). Particularly noteworthy is the synthesis of thiepins and oxepins (Entry 11) utilizing such rearrangements, as well as the transformations a-diazo-p-hydroxyester - P-ketoester (Entries 6, 7) and a-diazo-p-hydroxyketone -> P-diketone (Entry 8) which all occur under very mild conditions and generally in high yield. 

Similar to the case of Suzuki couplings (6.1.2), ally lie alkylations can also be run in neat water as solvent in the presence of surfactants. In addition to the general solubihzation effect, the amphiphiles may also have a specific influence on the reaction rate. For example, the reaction of the P-ketoester substrate on Scheme 6.22 with allyl acetate, catalyzed by [Pd(PPh3)4] was only slightly accelerated by the anionic SDS (1.5 h, 18 % yield), however, the reaction rate dramatically increased in the presence of the cationic CTAB and the neutral Triton X-100 detergents, leading to 74 % and 92% yields in 1.5 h and 5 min ( ), respectively [51]. Several other carbonucleophiles were alkylated in such emulsions with excellent yields. 

One of the most powerful strategies for asymmetric ring construction is to desymmelrize a preformed ring. Yasamusa Hamada of Chiba University in Japan has reported (J. Am. Chem. Soc. 2004, /26, 3690) that the inexpensive diaminophosphine oxide 2 nicely catalyzes the asymmetric alkylation of the cyclohexanone carboxylate 1 to give 3. Although no examples were given, this asymmetric alkylation would probably work as well with heterocyclic P-ketoesters. 

As described previously [63], P-ketoester 111 [Fig. (31)] was subjected to Baker s yeast reduction to afford the optically active P-hydroxyester 112 (60-80% yield). Dianion alkylation of 112 with (E)-3-methyl-4-(0-tert-butyldimehtylsilyl)-2-butene afforded the desired a-alkyl product 113 in 58-70% isolated yield. 

With BINAPO as ligand, the alkylation of dibenzoate 92 with p-ketoester 101 provides the mono-alkylated product 102 in modest ee (Scheme 8E.13) [65], Subsequently, a simultaneous allylation-Heck annulation reaction provided the pentacycle 103, which was further function-... 

Muzart and coworkers have reported a new catalytic enantioselective protonation of prochiral enolic species generated by palladium-induced cleavage of p-ketoesters or enol carbonates of a-alkylated 1-indanones and 1-tetralones [21 ]. Among the various (S)-p-aminocycloalkanols examined, 17 and 18 were effective chiral catalysts for the asymmetric reaction and (J )-enriched a-alkylated 1-indanones and 1-tetralones were obtained with up to 72% ee. In some cases, the reaction temperature affected the ee. 

The base-catalyzed reaction of P-ketoesters such as ethyl acetoacetate (acetoacetic ester) (3.2) with the alkyl halide gives monosubstituted P-ketoesters. In a similar manner, on treatment with a base and alkyl halide, a disubstituted ethyl acetoacetate is formed. 

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