Vicinal ketoesters – key intermediates in the total synthesis of natural products

This review summarizes examples for the application of vicinal ketoesters such as α-ketoesters, mesoxalic esters, and α,β-diketoesters as key intermediates in the total synthesis of natural products utilizing their electrophilic keto group as reactive site. Suitable key reactions are, e.g., aldol additions, carbonyl ene reactions, Mannich reactions, and additions of organometallic reagents. The vicinal arrangement of carbonyl groups allows the stabilization of reactive conformations by chelation or dipole control.


Introduction
Vicinal ketoesters contain a carbonyl group adjacent to an ester group. One keto group results in α-ketoesters 1 and two vicinal keto groups lead to α,β-diketo esters 2 (Scheme 1). On the other hand, two carboxylic acid functionalities adjacent to a keto group result in mesoxalic diesters 3, or mesoxalic ester amides 4. The increased electrophilicity of the keto group and the high density of these complex functional groups make such structures attractive as key intermediates for the total synthesis of natural products [1]. Thus, the high electrophilicity of the central carbonyl group in α,β-diketoesters 2 allows the formation of stable hydrates 5. In case of an enolizable position enolization (2→6) is facilitated.
The chemistry of vicinal polycarbonyl compounds such as vicdiketoesters has been investigated in depth by Wasserman, Parr [2] and Gleiter, Rubin [3]. Important contributions for the use of α,β-diketoesters in stereoselective transformations came from Doyle's group [4,5]. One remarkable example is the diastereoselective intramolecular aldol addition of ketones such as 7 (Scheme 2) [5]. Brønsted-acid catalysis leads via a transition state 8 to the aldol 9, while the use of chelating Lewis acids results via 10 in the epimeric aldol 11.

(−)-Preussochromone D
A similar approach was chosen in the synthesis of the structurally related natural product preussochromone D (30) reported by Koert et al. [13]. The synthesis commenced with the efficient production of alcohol 26 from 5-hydroxy-4H-chromen-4-one (25, Scheme 5) [14]. The ketoester moiety was build up via oxidation and nucleophilic addition of methyl diazoacetate, yielding alcohol 27. Subsequent oxidation gave α-ketoester 28 which was used in an intramolecular, Lewis acid-mediated aldol reaction, presumably via tridentate complex transition state III, to give diol 29 as a single diastereomer. Inversion of the secondary alcohol and deprotection gave preussochromone D (30).
The α-ketoester 41 was accessible from amide 38, which in turn was obtained from allylic alcohol 37. Oxidation and Horner-Wadsworth-Emmons reaction with phosphonate 39 delivered the silyl enol ether 40, which was deprotected and Scheme 6: Synthesis of an α-ketoester through Riley oxidation and its use in an α-ketol rearrangement in the synthesis of (−)-jiadifenoxolane A (36) [15].

(+)-Camptothecin
In the formal synthesis of the pentacyclic, antiproliferative quinoline alkaloid camptothecin (65), Peters et al. used an α-ketoester moiety in an auxiliary controlled approach towards the only stereogenic center present in the natural product (Scheme 10) [25]. First, the ketoacid 60 was esterified with 8-phenylmenthol (61) to yield the α-ketoester 62, followed by nucleophilic addition of isopropenylmagnesium bromide to give α-hydroxyester 63 in excellent yield and diastereoselectivity. Eight additional steps gave the bicyclic compound 64 which was already known from previous camptothecin syntheses.

Isoretronecanol
The α-ketoester moiety can also be used in photochemical reactions, as shown by Gramain et al. in the synthesis of the pyrrolizidine alkaloid (rac)-isoretronecanol (69, Scheme 11) [26]. A Claisen condensation of the lithium enolate of N-acetylpyrrolidine (66) with diethyl oxalate gave the ketoester 67. Irradiation of compound 67 with a medium pressure mercury lamp in Pyrex ® glassware triggered a 1,6-HAT leading to biradical X which combined to the racemic pyrrolizidine 68 as a 1:1 mixture of diastereomers. Three more steps gave the target compound 69 in 31% overall yield.

Corynoxine
Hiemstra et al. used the α-ketoester moiety for different purposes in the syntheses of a range of oxindole alkaloids. The start of the synthesis of (rac)-corynoxine (76) was the conversion of tryptamine (70) to oxindole 71, which was used in a chemoselective Mannich reaction with aldehyde 72, introducing the α-ketoester moiety (Scheme 12) [27].
The major trans-isomer 73 was further converted to the natural products corynoxine and rychnophylline. The minor cis-isomer 74 was used in an intramolecular Tsuji-Trost reaction, where the ketoester served as a nucleophile, which build up the piperidine ring and selectively set the desired cis-substitution. Subsequent transesterification gave the α-ketoester 75, which was used in a Wittig reaction. The undesired Z-configured double bond was isomerized to the E-alkene and final hydrogenation delivered corynoxine (76).
cyclic alkaloid isolated from the plant Galanthus gracilis, (Scheme 13) [28]. The synthesis started from readily available sesamol (79) and imine 78 which gave the advanced intermediate 80 in ten steps. An intramolecular Mannich reaction of compound 80 with α-ketoester 81 furnished compound 82 with the last ring of the target (+)-gracilamine (83), which was accessible after two further steps.

Mesoxalic diesters and ester amides as key intermediates (+)-Awajanomycin
Diethyl mesoxalate (90a) is a valuable building block due to the high density of carbon atoms in high oxidation states. As a victricarbonyl compound, its central keto group is an especially potent electrophile. The Koert group used this reactivity in their synthesis of (+)-awajanomycin (92), a marine natural product with a γ-lactone-δ-lactam core structure (Scheme 15) [30,31]. Key step was an asymmetric allylboration of diethyl mesoxalate (90a) with boronate 89, which was easily accessible through a Matteson homologation of dichloromethyl boronate 88. The reaction of (Z)-alkenyl boronate 89 with mesoxalate 90a delivered product 91 through the six-membered transition state XI. Eight further steps accomplished the total synthesis of (+)-awajanomycin (92).

(−)-Aplaminal
Dimethyl mesoxalate (90b) was used by Smith and Liu in the synthesis of the cytotoxic metabolite (−)-aplaminal (96), which was isolated from the sea hare Aplysia kurodai [32]. The natural product is characterized by a triazabicyclo
started with benzaldehyde 97 and indole 99 which were converted to the indole building blocks 98 and 100, respectively. These were connected to bisindole 101, which reacted with mesoxalic ester amide 102 in a Friedel-Crafts reaction followed by a spontaneous lactamization to give (rac)-cladoniamide G (103). The mesoxalic ester amide 102 was synthesized from malonyl chloride 104 through amidation and Regitz diazotransfer, yielding diazo compound 105. Subsequent oxidation and dehydration of the resulting hydrate through shortpatch distillation gave the desired vic-tricarbonyl compound 102.

Conclusion
The variety of examples prove that vicinal ketoesters are valuable synthetic intermediates for the synthesis of complex target structures such as natural products. α-Ketoesters, mesoxalic esters, and α,β-diketoesters can be used bearing an electrophilic keto group as reactive site. The vicinal arrangement of carbonyl groups allows the stabilization of reactive conformations by chelation or dipole control. Suitable key reactions are e.g., aldol additions, carbonyl ene reactions, Mannich reactions, and addi-