Cyclopropane-1,1-diesters

Cyclopropane fission. Cyclopropane-1,1-diesters suffer reductive opening, and this process can be used to generate ester bishomoenolates. " ... 

The application of d5-2,3-disubstituted cyclopropane 1,1-diesters to [3 + 2]-annulations with aldehydes under the promotion of AICI3 can result in the formation of the desired polysubstituted tetrahydrofuran products... 

The Lewis-acid-promoted formal intramolecular 3 + 2-cycloaddition of cyclopropane 1,1-diesters with allenes (25) produced [4.3.0]nonanes (26) and [3.2.1]octanes (27) by parallel-cycloaddition and cross-cycloaddition, respectively (Scheme 8). Similarly, the Lewis-acid-catalysed formal intramolecular 3 + 2-cycloaddition reactions of cyclopropane 1,1-diesters with alkenes produced bridged[n.2.1]carbocyclic compounds with excellent stereo- and regio-selectivity under mild conditions. This reaction has been successfully applied to the total synthesis of tetracyclic diterpenoids phallocladanol and phallocladene. ... 

The title compound also exhibits affinity for /3-dicarbonyl compounds, enabling their use as leaving groups in retro-Claisen reactions (eq 29) or cyclopropane-1,1-diester ring openings. ... 

One significant limitations of both methods described above is that some types of donor-acceptor cyclopropanes such as the extensively studied 2-substituted cyclopropane-1,1-diesters are unable to produce the desired azides under then-conditions. In this regard, in 2015, Trushkov et al. developed a general and efficient method for ring-opening of various donor-acceptor cyclopropanes with NaN3 to synthesize a variety of polyfunctional azides (Scheme 6.27) [82]. The process proceeds with excellent regioselectivity and provides the products in moderate to... 

The cyclopropane cyclizations by elimination of triflinic acid (CF3S02H) are readily effected by basic treatment of triflones (trifluoromethyl alkyl sulfones) with activated /-protons (equations 46 and 47)39. The cyclopropane diesters 45 are formed on treatment of 44 with potassium hydride in DMSO or sodium methoxide in methanol (equation 48). In contrast, the monoester 46 failed to give the desired cyclopropane40. Addition of carbanions derived from /f, y-unsaturated phenyl sulfones to a, /i-unsaturated carboxylic esters and subsequent elimination of benzenesulfinate ion give cyclopropanes possessing the unsaturated side chain and the ester function in trans positions (equation 49)41. 

The cyclopropane diester (800) bearing a vicinal acetylenic moiety, when treated with Co2(CO)s, affords the formation of the dicobalt hexacarbonyl complex (801). It undergoes a smooth cycloaddition with a,N -diphenylnitrone, in the presence of Sc(OTf)3, to form the corresponding dicobalt hexacarbonyl complex of tetraydro-l,2-oxazine (802). De-complexation of adduct (802) gives 6-ethynyl-tetrahydro-l,2-oxazine (803) (Scheme 2.332) (856). 

Scandium triflate catalyses a highly diastereoselective addition of imines to 1,1-cyclopropane diesters to give multi-substituted pyrrolidines.77... 

In a preliminary study toward the total synthesis of the kopsane alkaloid 140, which may exhibit cholinergic activity, the formal [3 + 2] annulation reaction of 3-alkylindoles with 1,1-cyclopropane diesters was studied in the presence of Yb(OTf)3 either at elevated temperature or at high pressure. For example, N-methyltetrahydrocarbazole (141) with styryl-substituted cyclopropane 142 produced a mixture of diastereomeric adducts 143a and 143b (3 1) in 49% yield at 1.3 GPa for 7 days (Scheme 39) [89]. 

Previously cyclopropane-1,1-dicarboxylic acid had been prepared2-4 by hydrolysis of the corresponding diester. The preparation of 1,1-dicarboalkoxycyclopropanes by a conventional double alkylation of diethyl malonate with 1,2-dibromoethane was severely complicated by the recovery of unreacted diethylmalonate. This required a rather difficult distillation to separate starting material and product. In fact, many commercially offered lots of cyclopropane diester contain extensive amounts of diethyl malonate. Furthermore, preparation of the diacid required a separate and relatively slow saponification of the diester.5... 

Initially applied to thermal cydoaddition of fumarates of chiral alcohols with anthracene [118] (Figure I.34.a), cooperativity was extended to other reactions of symmetrical diesters. While reactions of mixed diesters bearing a single chiral alcohol residue are poorly stereoselective, those of symmetrical diesters can be quite useful. Indeed, the formation of cyclopropane diesters 43 from succinic add diesters and BrCB Cl is poorly diastereoselective when using a mixed methyl and menthyl ester. But it becomes highly diastereoselective when performed with symmetrical dimenthyl esters (Figure I.34.b). 

Diesters.—Michael addition of malonic ester enolates to chiral a/3-unsaturated aldimines (obtained from optically pure a-amino-acids) gives, after hydrolysis, aldehyde-diesters (125) in variable chemical (26—54%) and optical (36—86%) yields. The amino-acid components are recovered optically pure. Attack of simple nucleophiles on the bromoalkylidene malonate (126) gives cyclopropane diesters (127) in good yields. A ready, five-step route to the bicyclo[l,l,0]butane triester (128) has been described. ... 

Danishefsky and co-workers have continued their investigations on the nucleophilic cleavage of activated cyclopropanes. Alkyl-substituted cyclopropane diesters (210) show a preferance for cleavage of the C-1—C-2 bond, with the alkyl... 

A tandem ring opening-cyclization reaction of 2-substituted 1,1-cyclopropane-diesters with N-benzyl imines in the presence of 5 mol% of Sc(OTf)3 was developed [149]. The 2,3,5-substituted pyrrolidines were obtained in moderate to high yields (42-98%) with high diaster eoselectivities (cis/trans = 8/1-30/1). 

The enantioselective 3 + 3-cycloaddition reaction of aromatic azomethine imines with donor-acceptor cyclopropane diesters produced 6,6,6-tricyclic dihydroquinolines in high yields (99%) and up to 98% ee. The side-arm-modified In-TOX/Ni(II) complex was shown to be an effective stereoselective catalyst for this reaction. The formal 3 + 3-cycloaddition reaction of allylic phosphonium ylides (127) to a, -unsaturated carbonyls (128) formed multi-substituted benzenes (129) in high yields (36-93%) (Scheme 38). °... 

Catalytie [34-2] annulation of enantiomerically pure aminocyclopropanes leads to the enantiospecific synthesis of cyclopentylamines (Scheme 6.3). The presence of a phthalimide group on the cyclopropane diester is essential to impart high yield and selectivity for the reaction [5]. 

A radical approach toward the cycloaddition of activated cyclopropane diesters... 

The cobalt complexed cyclopropane diester 4 was then reacted with a variety of aldehydes in the presence of boron trifluoride etherate in dichloromethane to afford the desired tetrahydrofurans 5 in high yields with poor diastereoselective control (Scheme 10.6). The cycloaddition reaction was limited to electron deflcient aromatic, aliphatic, and functionalized aldehydes, where no reaction was observed with electron rich aromatic aldehydes. The tetrahydrofurans were obtained as a 1 1 mixture of cis- and fran -isomers, where the best diastereomeric ratio obtained was 2 1 (5d) in favor of the fran -isomer. Modifying the temperature of the reaction had little effect on the diastereoselectivity. Confirmation of the stereochemistry was achieved by X-ray and NMR analysis of the separated diastereoisomers, including... 

In 2007, Kang et al. improved the method conducted by Sibi and coworkers by maintaining the diastereoselectivity of the reaction of which Kerr and coworkers had originally reported, as well as maintaining excellent enantioselectivity with monosubstituted cyclopropane diesters [26]. This was achieved with the trisoxazoline Ugand as shown in Scheme 10.29. 

Through the progression of the cycloaddition reaction of cyclopropane diesters with nitrones, Sapeta and Kerr thought it wise to investigate the mechanism of this [3+3] dipolar cycloaddition. 

The methodology used by Carson and Kerr and Young et al. in the synthesis of oxazines has been applied toward the synthesis of two complex natural products (+)-phyllantidine and Nakadomarin A [32,33]. In the total synthesis of (+) phyllantidine, the oxazine core was afforded through a three-component coupling of the cyclopropane diester, hydroxyl-amine, and aldehyde in the presence of ytterbium triflate [32] (Scheme 10.34). The oxazine was afforded as a 12 1 mixture of diastereoisomers, where the major isomer showed the required cw-relationship between C and C of the oxazine. The natural product was afforded in 11 steps starting from the oxazine core in an overall yield of 6%. 

The synthesis of isatisine A113 started with the formation of the tetrahydroftiran ring through a Lewis acid-catalyzed cycloaddition reaction of the chiral (5)-vinyl cyclopropane diester 23 and iV-tosyl-indole-2-carboxaldehyde 24 (Scheme 10.42) [40]. 

The discovery that imines undergo a cycloaddition reaction with activated cyclopropane diesters to afford 2,5-disubstimted pyrrolidines was a significant development on previous methods. However, the substrate scopes of the imines used were limited to aryl substituents, where no reaction was observed with aliphatic imines. Kerr and coworkers originally thought that the substrate scope could be improved by the use of oxime ethers, as they envisioned this would increase the nucleophilicity of the nitrogen toward... 

However, the diastereoselectivity of the reaction for the formation of the 2,5-cis cycloadducts were poor compared to the diastereoselectivity observed with the oxime ether cyclopropane diesters [43]. It was thought that this happened due to a decrease in selectivity for the formation of the Z-aza-iminium intermediate. To overcome this issue, the Boc-... 

A RADICAL APPROACH TOWARD THE CYCLOADDITION OF ACTIVATED CYCLOPROPANE DIESTERS... 

Cyclopropane Derivatives. 2,2-Dimethylcyclopropanenitrile [5722-11-2] (4) has been made by preparing the di-/)-toluenesulfonate of neopentyl glycol and treating the diester with potassium cyanide (35). 

In contrast to ethyl diazoacetate, diethyl diazomalonate reacts with allyl bromide in the presence of Rh2(OAc)4 to give the ylide-derived diester favored by far over the cyclopropane (at 60 °C 93 7 ratio). This finding bespeaks the greater electrophilic selectivity of the carbenoid derived from ethyl diazomalonate. For reasons unknown, this property is not expressed, however, in the reaction with allyl chloride, as the carbenoids from both ethyl diazoacetate and diethyl diazomalonate exhibit a similarly high preference for cyclopropanation. 

Substitution of the VCP is tolerated both on and adjacent to the cyclopropane ring. Diester-substituted and heteroatom (O, NTs) tethers are well tolerated. Reactions were conducted with 2-10 mol% catalyst at up to 0.20 M, as illustrated. Most importantly, reactions with the naphthalene catalyst were found to be more rapid than those with other catalysts. For example substrate 54 is readily converted in >99% yield to cycloadduct 55 in only 15 min at room temperature (entry 1). Complex 93 efficiently catalyzes the reactions of both alkynes and alkenes with VCPs, offering greater generahty than thus far observed with non-rhodium catalysts. This catalyst is particularly advantageous in the cases of substrates 100 and 102, for which the desired product is not formed cleanly with Wilkinson s catalyst due to product isomerization. 

In 1992, Trost and his co-workers investigated desymmetrization of cyclic w j-o-diesters with lithium sulfonyl-methylenenitronate as a nucleophile in the presence of Trost s ligand 118, where the corresponding cyclic compounds are obtained with an excellent enantioselectivity via intramolecular cyclization (Scheme 15),103,103a Asymmetric cyclopropanation and lactone annulation are achieved according to this protocol (Scheme Nitroalkanes can also be employed as carbon-centered nucleophiles in lieu of malonates (Scheme 17). ... 

Dehydrohalogenation sometimes leads to cyclization which gives cycloalkanes or heterocycles. The fluorinated diester 1 has proved to be a convenient source of polyfluoroalkylated cyclopropanes. Reaction of 1 with aqueous potassium hydroxide gives 2- HA //-hepta-fluorobutyl)cyclopropane-l, 1 -dicarboxylic acid (2) in quantitative yield.120 The diethyl ester 3 ot this acid is obtained in a yield of 87% by the reaction of 1 with sodium ethoxide in anhydrous ethanol.120... 

The intermediacy of >/2-cyclopropene complexes of nickel has been proposed in catalyzed 2+1 reactions of free cyclopropene with electron-poor olefins, to give vinylcyclo-propanes. For example, the reaction of fumarate esters with 3,3-disubstituted cyclopropenes in the presence of Ni(COD)2 catalyst gave vinyl-substituted trans-2,3-cyclopropane dicarboxylate esters (equation 235)72 302. However, when maleic esters were used instead, a mixture of both cis and trans vinylcyclopropane diesters is obtained. 

The stabilized arsonium ylides reacted either with a,/3-unsaturated diketones or diesters to form corresponding cyclopropanes (72). 

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