Bicyclic keto ester

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... 

Bicyclic keto ester (22) was needed for conformational studies. The common atoms are marked ( ) and the obvious disconnections of this symmetrical molecule require double alkylation of cyclohexanone with a reagent such as (23), Double 1,5-diCO disconnection of (22) is impossible as you will discover if you attempt it. 

Kinetic resolution results of ketone and imine derivatives are indicated in Table 21.19. In the kinetic resolution of cyclic ketones or keto esters, ruthenium atrop-isomeric diphosphine catalysts 25 induced high enantiomer-discriminating ability, and high enantiopurity is realized at near 50% conversion [116, 117]. In the case of a bicyclic keto ester, the presence of hydrogen chloride in methanol served to raise the enantiomer-discriminating ability of the Ru-binap catalyst (entry 1) [116]. 

This bicyclic keto ester (3) was used for synthesis of the ginkolide bilobalide 4. 

Bicyclic keto esters can easily be prepared by a process called a,a -annulation.29 Thus, treatment of the enamine of cyclopentanone (64) with ethyl a-(bromomethyl)acrylate (98) affords, after work-up, the bicyclic keto ester (99) in 80% yield (equation IS).2911 The mechanism probably involves an initial Michael addition and elimination (or a simple Sn2 or Sn2 alkylation) followed by an intramolecular Michael addition of the less-substituted enamine on the acrylate unit. The use of the enamine of 4,4-bis(ethoxycarbonyl)cyclohexanone (100 equation 26) with (98) gives a 45% yield of the adaman-tanedione diester (101) (yield based on 100 70% when based on 98) via a,a -annulation followed by Dieckmann condensation.29 Enamines of heterocyclic ketones can also serve as the initial nucleophiles, e.g. (102) and (103) give (105) via (104), formed in situ, in 70% yield (Scheme 11 ).29>... 

Other investigators have used a new synthetic route103 in which the spiro[4,5]decane system is formed by condensation of a -dicarbonyl compound [e.g. (221)] with a cyclopropyl phosphonium salt (222).104 The bicyclic keto-ester (223) produced in this way was subsequently converted into ( )-anhydro-/3-rotunol (224), ( )-/3-vetivone (220), ( )-/3-vetispirene (225), ( )-linesol (226), and ( )-a-vetispirene (227) (Scheme 27). 03 An alternative approach to the vetispirane system involves Et[Pg.82]

Cyclization. Treatment of the unsaturated enol phosphate ester 1 with 1 equiv. of mercury(II) trifluoroacetate in nitromethane at 0° followed by aqueous sodium chloride produced the mercurated bicyclic keto ester 2 in 60% yield along with 20% of the monocarbocyclic product 3. Keto ester 2 is an intermediate in a total synthesis of aphidicolin (4). This reaction is the first example of the use of a mercury(II) salt tor simultaneous construction of two carbocyclic rings. ... 

A spectacular example is the synthesis of the bicyclic keto-ester 93. Two consecutive Michael disconnections reveal the a extended enolate of cyclohexanone 95 and methyl acrylate. The synthesis is even easier kinetic enolisation of cyclohexenone with LDA and reaction with methyl... 

Marshall and Ruden have reported a stereoselective synthesis of nootkatone (298) in which the keto-ester (299) was annelated with tmns-pent-3-en-2-one to give the bicyclic keto-ester (300). The ethylidene moiety was converted to the 7 -acetyl group by epoxidation, acid-catalysed rearrangement, and basic equilibration. After bis-ketalisation of the diketo-ester (301) the carbomethyoxy-group was converted to the 5a-methyl group in three steps and a subsequent Wittig reaction yielded racemic nootkatone (298). An earlier synthesis of noot-... 

Shinkai, L, R. A. Reamer, F. W. Hartner, T. Liu, and M. Sletzinger A Direct Transformation of Bicyclic Keto Esters to V-Formimidoyl Thienamycin. Tetrahedron Letters 23, 4903 (1982). 

Some weak electrophilic reagents, which are usually inert toward azoles, also react with quaternized azoles. Diazonium salts yield phenylhydrazones (Scheme 48) in a reaction analogous to the Japp-Klingemann transformation of /S-keto esters into phenylhydrazones in the dithiolylium series illustrated the product has bicyclic character. Cyanine dye preparations fall under this heading (see also Section 4.02.1.6.5). Monomethine cyanines are formed by reaction with an iodo quaternary salt, e.g. Scheme 49. Tri- and penta-methinecar-bocyanines (384 n = 1 and 2, respectively) are obtained by the reaction of two molecules of a quaternary salt with one molecule of ethyl orthoformate (384 n = 1) or/S-ethoxyacrolein acetal (384 n =2), respectively. 

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... 

Another Lewis acid-catalyzed atom-transfer domino radical cyclization, to produce various bicyclic and tricyclic ring skeletons, has been developed by Yang and coworkers [54]. Reactions of the a-bromo-(3-keto ester 3-125 with Yb(OTf)3 and Et3B/02 led to the bicycle 3-126 in 85 % yield (Scheme 3.33). The reaction proceeds via a (>-endo-Irig and 5-exo-trig cyclization after initial abstraction of the bromine... 

Combinatorial solution-phase cycloadditions of (1Z,4R, 5R )-4-benzoylamino-5-phenylpyrazolidin-3-on-l-azomethine imines 320 to 3-keto esters afforded a library of 26 highly pure bicyclic pyrazolidinones 713 in 6-89% yields and in 14-100% de. Most of the products were isolated as mixtures of the major (13, 23, 3/ , 5/ , 6/ )-epimers 713 and the minor (1R, 2A, 3R, 5R, 6R )-epimers 714 (Scheme 113). Epimerization of these cycloadducts at the anomeric position in solution was confirmed by H NMR spectroscopy <2007MI717>. 

Bicyclic y-lactones,7 These lactones can be obtained by intramolecular reductive cyclization of unsaturated keto esters with Sml2 in THF-HMPT. Example ... 

The initial medicinal chemistry route to the azabicyclo[3.3.0]octane-3-carboxylic acid produced the azabicyclo system in a diastereoselective but racemic manner, and required a classical resolution to achieve enantioenriched material (Teetz et al., 1984a, b 1988). Reaction of (R)-methyl 2-acetamido-3-chloropropanoate (43) and 1-cyclopentenylpyrrolidine (44) in DMF followed by an aqueous acidic work-up provided racemic keto ester 45 in 84% yield (Scheme 10.11). Cyclization of 45 in refluxing aqueous hydrochloric acid provided the bicyclic imine, which was immediately reduced under acidic hydrogenation conditions. The desired cis-endo product 46 was obtained upon recrystaUization. The acid was protected as the benzyl ester using thionyl chloride and benzyl alcohol, providing subunit 47 as the racemate. Resolution of 47 was accomplished by crystallization with benzyloxy-carbonyl-L-phenylalanine or L-dibenzoyl-tartaric acid. 

CC 400 (1975) (a-hydroxy, halo and formyloxy ketones x-keto acid a- and jS-keto esters) 315 (1977) (x-PhSO, O, OAc ketones) 456 (1978) (trifluoromethyl ketones) 908 (1979) (bicyclic ketone) 599 (1983) (/ -keto carboxylates) 138 (1986) (2,2-dithioalkan-l-ones) 1368 (1987) 03-keto ester)... 

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