Cyclopropane diester

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... 

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