Keto-carbene insertion

The synthesis of agarospirol (epihinesol) portrays an efficient stereoselective approach to spiro[4-5] decanes based on the intramolecular keto-carbene insertion reaction (A— B) and cleavage of the derived cyclopropyl alcohol (C) to give a spiroketone. 

For a route to spiro[4-5] decanes based on intramolecular keto-carbene insertion in substituted cyclohexenes, see M. Mongrain, J. LaFontaine, A. Belanger and P. Deslongchamps, Canad. j. Chem., 48, 3273 (1970) and P. M. McCurry, Tetrahedron Lett., 1845 (1971). An interesting synthesis of spiro systems by o, a annelation of enamines has been developed by D. J. Dunham and R. G. Lawton, J. Amer. Chem. Soc., 93, 2074 (1971). 

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. 

The insertion of keto carbene to the N—H bond in 361 to form the carbapenem ring system 362 is a commercially established synthesis [119]. 

When the carbene and amine centers are separated by a three-carbon chain, carbene insertion into the N—H bond results in the formation of pyrrolidine derivatives. Both a-diazocarbonyl compounds 58 and a-diazo jS-keto ester 59 give, under the action of Rh2(OAc)4, products of carbenoid insertion into the amide N — H bonds in near quantitative yields. 

In a synthesis of an analogue of the antibacterial carbapenems, the keto-y-lactam (36.2) is converted in four steps (including carbene insertion, diphenyl-... 

The Ru-porphyrin catalyst immobilized on PEG was also useful in catalytic cyclopropanations, carbene insertion chemistry, and aziridination reactions. While the TONs in the aziridination reaction were only modest, catalyst 43 was substantially more efficient in the formation of (Z)-2-phenyl-4-(methoxy-carbonylmethylene)-l,3-dioxolanes from y-benzyloxy-a-diazo-jS-keto methyl esters than the corresponding low molecular weight Ru-porphyrin (Eq. 16). Adding ether to the reaction mixture quantitatively precipitated the catalyst 43, eliminating the need for column chromatography to separate the catalyst and reaction products. 

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... 

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... 

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 methoxyketene 297, coordinated to Cr carbonyl, is formed from methoxy-carbene easily by insertion of CO under irradiation [90]. An ester is formed by the reaction of ketene with alcohol. The aminocarbene complex 298 was prepared from benzamide and converted to phenylalanine ester 300 under irradiation of sunlight in alcohol via ketene 299 [91]. The eight-membered lactone 304 was prepared in high yield by the reaction of the alkyne 301 having the OH group in a tether with Cr carbene without irradiation. The vinylcarbene 302 is formed at first and converted to the vinylketene intermediate 303 as expected. The keto lactone 304 is formed from 303 by intramolecular reaction with the OH group and hydrolysis [92],... 

Dirhodium(II)-catalysed reaction of a 3-indolyl a-diazo-/5-keto ester in the presence of hexanamide results in competing metal carbene N-H insertion and Wolff rearrangement (Scheme 85).128... 

Rh-catalysed intramolecular insertion into thiophene. 59, 204 cycloaddition to uracils, 55, 1% Carbene, 5,6-cycloadduct with 2H-thiopyran, 59, 225 Carbenes, a-keto-perfluoroalkyl-, generation, trapping. 60, 40 Carbenes, Fischer, reaction with N-(hexafluoroisopropylidene) amides,... 

Alkylidenecarbenes are valuable intermediates for intermolecular C-H insertion reactions. They allow for a stereo-controlled synthesis of 2,5-diyhdrofurans, since C-H insertion proceeds with retention of configuration at an existing stereocenter. Upon using the Seyferth method for alkylidene carbene formation with the ketoaldehyde 32, the alkylidene intermediate of the aldehyde underwent 1,2-hydride shift, whereas the alkylidene formed from the keto function underwent 1,5-C-H insertion to give the dihydrofuran product (Equation 52) <2005TL7483>. 

Then the carboxylic acid was converted (via the acid chloride) to the diazoketone (Chapter 9), and decomposition of the latter via the carbene and insertion produced the substituted cyclopropane. Next, the keto group was converted to a methylene unit via the Wittig, and thermolysis generated the third cyclopentyl ring. Dissolving metal reduction and epimerization in sodium ethoxide set the stage for conversion of the ester to an alkyl group. 

Generation of Carbenes from Diazo Compounds. Both PdCl2 and Pd(OAc)2 are used for carbene generation from azo compounds. The cyclopentenone carboxylates have been prepared by intramolecular insertions of the carbenes generated from a-diazo-/8-keto esters (eq 61)7 ... 

Readily accessible and bench-stable a-keto carbonyl compounds have been evaluated for their potential as carbene sources. The concept has been validated using tris(dimethylamino)phosphorus as stoichiometric promoter and has been successfully applied to the insertion into various N-H bonds and 0-H bonds of phenols. 

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