A-Diazo- 3-keto esters

The strained bicyclic carbapenem framework of thienamycin is the host of three contiguous stereocenters and several heteroatoms (Scheme 1). Removal of the cysteamine side chain affixed to C-2 furnishes /J-keto ester 2 as a possible precursor. The intermolecular attack upon the keto function in 2 by a suitable thiol nucleophile could result in the formation of the natural product after dehydration of the initial tetrahedral adduct. In a most interesting and productive retrosynthetic maneuver, intermediate 2 could be traced in one step to a-diazo keto ester 4. It is important to recognize that diazo compounds, such as 4, are viable precursors to electron-deficient carbenes. In the synthetic direction, transition metal catalyzed decomposition of diazo keto ester 4 could conceivably furnish electron-deficient carbene 3 the intermediacy of 3 is expected to be brief, for it should readily insert into the proximal N-H bond to... 

The diazo function in compound 4 can be regarded as a latent carbene. Transition metal catalyzed decomposition of a diazo keto ester, such as 4, could conceivably lead to the formation of an electron-deficient carbene (see intermediate 3) which could then insert into the proximal N-H bond. If successful, this attractive transition metal induced ring closure would accomplish the formation of the targeted carbapenem bicyclic nucleus. Support for this idea came from a model study12 in which the Merck group found that rhodi-um(n) acetate is particularly well suited as a catalyst for the carbe-noid-mediated cyclization of a diazo azetidinone closely related to 4. Indeed, when a solution of intermediate 4 in either benzene or toluene is heated to 80 °C in the presence of a catalytic amount of rhodium(n) acetate (substrate catalyst, ca. 1000 1), the processes... 

We initially observed [4, 5] that an a-diazo / -keto ester 5 would, on exposure to a catalytic amount of Rh2(OAc)4, undergo smooth cyclization to the cyclopentane derivative 6 (Scheme 16.2). The a-diazo / -keto ester 5 is readily prepared by diazo transfer [6] from... 

A new synthesis of cr-substituted and a,a-disubstituted a-amino acid derivatives based on the ammonium ylide formation/[2,3]-sigmatropic rearrangement has been recently reported by Clark s group.Decomposition of a-diazo -keto ester 153 was studied in detail with Rh2(OAc)4, Cu(acac)2, and Cu(hfacac)2 as the catalyst. Cu(acac)2 and Cu(hfacac)2 gave similar results, but Rh2(OAc)4 turned out less effective (Equation (23)). 

Enandoselective tandem carbonyl ylide formation-cycloaddition of a-diazo- -keto esters is achieved in hexane with [Rh2(5-DOSP)4] (1 mol %) at room temperature to give the corresponding cycloadducts with moderate enantioselectivity [73] (Eq. 8A.49). 

Ytterbium triflate-catalyzed Michael addition of iV-methylindole to mesityl oxide 452 was carried out using a modification of the Kerr procedure (4% of Yb(OTf>3, 4equiv of compound 452) <1996SL1047, 1998CJC1256> to give the desired 4-(indol-3-yl)-4-methyl-2-pentanone 453 in 81% yield (Scheme 96) <2001TL6835>. Product 453 was converted into the a-diazo- )-keto ester 454 having an iV-methylindole unit. 

If desired, the a-diazo -keto ester can be purified by a low-tcmpcrature crystallization. The diazo ester (10 g.) is cooled to —70° to —75° in a dry ice-acetone bath, and crystallization is initiated by rubbing. Caution The rubbing should not be continued after crystallization has been initiated) This material is treated with 5 ml. of anhydrous ether which has been previously cooled, and the mixture is filtered with suction. The residue... 

Another synthesis starts with an a-diazo- -keto ester (3) readily prepared from an acid chloride and diazoacetic ester. The ester (3) reacts with triphenylphosphine... 

Tetrakis(l,T-binaphthyl-2,2 -diyl phosphate) complexes (119) are reported to be much more effective catalysts than the more commonly used carboxylate complexes for enantioselective intramolecular, tandem, carbonyl ylide forma-tion/cycloaddition of a-diazo- -keto esters. The ring-opening reactions of epoxides with diphenyl phosphorazidate (120) have been investigated. A wide range of epoxide substrates have been studied and the products, (121) or (122), depend on the substrate structure. The microbial hydroxylation of novel phos-... 

Transition metal-catalysed methods for carbenoid insertion into C-H bonds remain well documented. The asymmetric intramolecular Cu(II)-catalysed C-H insertion reactions of (i) a-diazo-/ -keto esters and phosphonates and (ii) a-diazo sulfones have been described. One can note that the optimal reaction conditions have been found to be quite similar regardless of the nature of the carbenoid precursor the best conditions featured CUCI2 as Cu(II)-source, bis(oxazoline) (68) as chiral ligand and sodium tetrakis[3,5-bis(trifluoromethyl)phenyl] borate (i.e., NaBARF) as additive. Under the so-optimized reaction conditions, each of these carbenoid sources have been eonverted into five-membered cyclopentanone-based derivatives (69), whereas a-sulfonyl diazo esters (70) have led to six-membered cyclic compounds (71), thus featuring a distinct but well-known selectivity. In a related work, the asymmetric C-H insertion cyclization of (70) to (71) has also been achieved under Rh(II)-catalysis, using a combination of Rh2(5-pttl)4 (72) as chiral catalyst and menthyl ester as chiral auxiliary. As already mentioned in the previous section, allene-containing substrates (49) have been shown to undergo an intramolecular C-H insertion process under Rh(II)-catalysis. ... 

Intermediate 37 can be transformed into ( )-thienamycin [( )-1)] through a sequence of reactions nearly identical to that presented in Scheme 3 (see 22— 1). Thus, exposure of /(-keto ester 37 to tosyl azide and triethylamine results in the facile formation of pure, crystalline diazo keto ester 4 in 65 % yield from 36 (see Scheme 5). Rhodium(n) acetate catalyzed decomposition of 4, followed by intramolecular insertion of the resultant carbene 3 into the proximal N-H bond, affords [3.2.0] bicyclic keto ester 2. Without purification, 2 is converted into enol phosphate 42 and thence into vinyl sulfide 23 (76% yield from 4).18 Finally, catalytic hydrogenation of 23 proceeds smoothly (90%) to afford ( )-thienamycin... 

A recent example of this intramolecular tandem transformation is the Rh(ii)-catalyzed reaction of diazo keto ester 71. Depending on the structure of the diazo compound, a push-pull dipole intermediate derived from 71 can be trapped either by a tethered vinyl group (when n = 0) or by an indole 7r-bond (when n=l) (Equation (11)). This result clearly demonstrates a critical role of the conformation of the cycloaddition transition state. 

Carbacephalosporins The ketene-imine cyclization described above has been extended to a synthesis of a chiral carbacepham (4). This synthesis uses a dihy-droanisole group as the equivalent of a p-keto ester. Thus the azetidinone 1, obtained in 80% yield by the above route, was reduced and acylated in situ to provide 2. Ozonization followed by a rhodium-catalyzed cyclization of an a-diazo-P-keto ester provides 3, which is a useful intermediate to various substituted car-bacephams such as 4. 

Various 7-azi do-h-hydroxy diazo keto esters, e.g. (125), have been found to undergo smooth Rh(II)-catalysed cyclization to afford 2-carboethoxy substituted 3(2//)-furanones as a single diastereoisomer. The authors165 proposed that the formation of e.g. (128) involves insertion of the rhodium carbenoid into the adjacent O—H bond to... 

The diazo keto ester 154 is prepared from the p-keto ester 153 using tosyl azide or p-NBSA.69,70 The diazo ester (156) could not be prepared by diazo transfer with TsN3/NEt3, since elimination usually occurs to yield acrylate.71 A diazo transfer agent, l-ethyl-2-azidopyridinium tetrafluoroborate, successfully converted isoindole keto ester (155) to diazo keto ester (156).71... 

Recently, it was found that chiral bis(oxazoline)-CuOTf complexes are also efficient catalysts in the case of a-diazo -keto sulfones whose bulk has a significant influence on the enantio-selectivity (eq 78). The modest results observed with the parent a-diazo 8-keto esters could be attributed to the lack of this steric element. 

Galiullina SV, Zakharova VM, Kantin GP, Nikolaev VA (2007) Chemistry of diazocarbonyl compounds XXX. Development of a synthetic approach to pyridazine structure via Wittig reaction of fluoroalkyl-containing diazo keto esters. Russ 1 Org Chem 43 607-614... 

McKervey and Ye have developed chiral sulfur-containing dirhodium car-boxylates that have been subsequently employed as catalysts for asymmetric intramolecular C-H insertion reactions of y-alkoxy-ot-diazo-p-keto esters. These reactions produced the corresponding ci -2,5-disubstituted-3(2H)-furanones with diastereoselectivities of up to 47% de. Moreover, when a chiral y-alkoxy-a-diazo-p-keto ester containing the menthyl group as a chiral auxiliary was combined with rhodium(II) benzenesulfoneprolinate catalyst, a considerable diastereoselectivity enhancement was achieved with the de value being more than 60% (Scheme 10.74). 

Scheme 10.74 Rh-catalysed intramolecular C-H insertions of y-alkoxy-a-diazo-P-keto esters with sulfonamide ligands.

A second route was devised using chiral /3-keto ester 14, which was identified as our precursor for 2 [7]. This idea was in analogy with the carbapenem chemistry [8], as depicted in Scheme 2.4, where Masamune reaction [9] for carbon elongation, diazo-transfer, and transition metal-mediated carbene insertion reaction [10] were employed as key steps sequentially. 

There are two important rhodium-catalyzed transformations that are broadly used in domino processes as the primary step. The first route is the formation of keto carbenoids by treatment of diazo keto compounds with Rh11 salts. This is then followed by the generation of a 1,3-dipole by an intramolecular cyclization of the keto carbenoid onto an oxygen atom of a neighboring keto group and an inter- or intramolecular 1,3-dipolar cycloaddition. A noteworthy point here is that the insertion can also take place onto carbonyl groups of aldehydes, esters, and amides. Moreover, cycloadditions of Rh-carbenes and ring chain isomerizations will also be discussed in this section. 

The above transformation takes place via the catalytic effect of copper (I), which generated the corresponding carbenoid from a-diazo-p-keto esters. These Cu-carbenoides react with the thiocarbonyl group of thioamides, after cyclocondensation to afford 2-aryl-l,3-thiazole-5-carboxylates (Scheme 18).40... 

Using this approach, we have successfully predicted the major product from the cyclization of more than 30 a-diazo esters and a-diazo yS-keto esters [15]. Not all rhodium-mediated intramolecular C-H insertion reactions will proceed to give a single dominant diastereomer. Our interest in this initial investigation was to develop a model for the transition state that will allow us to discern those cyclizations that will proceed with high diastereoselectivity. 

Pirrang, Liu, and Morehead [22] have elegandy demonstrated the application of saturation kinetics (Michaehs-Menten) to the rhodium(II)-mediated insertion reactions of a-diazo /9-keto esters and a-diazo /9-diketones. Their method used the Eadie-Hofstee plot of reaction velocity (v) versus v/[S] to give and K, the equilibrium constants for the catalytic process. However, they were unable to measure the Michaelis constant (fC ) for the insertion reactions of a-diazo esters because they proved to be too rapid. 

Functionalised 2,3-dihydro-l,4-dioxins can be synthesised in a three step-sequence from P-keto esters. The key step is the insertion of a Rh-carbenoid derived from an a-diazo-p-keto ester into an 0-H bond of a 13-diol <99H(51)1073>. The reaction of 2-(l,4-dioxenyl)alkanols with silyl enol ethers yields 23-disubstituted 1,4-dioxanes. When 13-bis(trimethylsilyloxy)-cyclobut-l-ene is used, the expected cyclobutanone products are accompanied by a spirocyclopropane derivative <99TL863>. 1,4-Dioxane-monochloroborane 57 is a highly reactive hydroborating reagent <990L315>. 

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