Kulinkovich reaction

The key component of the antitumor antibiotic cleomycin, (S)-cleonin, was prepared from (R)-serine using the Kulinkovich reaction as the key step in the laboratory of M. Taddei. The methyl ester of A/-Cbz serine acetonide was exposed to freshly prepared ethylmagnesium bromide in the presence of substoichiometric amounts of titanium tetraisopropoxide to afford the desired cyclopropylamine in good yield. Subsequent functional group manipulations gave (S)-cleonin. 

Cyclopropylamines and their substituted derivatives are important building blocks in a large number of biologically active compounds. The synthesis of potentially biologically active A/,A/-dimethyl bicyclic cyclopropylamines from N-allylamino acid dimethylamides by the intramolecular variant of the Kulinkovich reaction was accomplished by M.M. Joullie and co-workers. 

Cha et al. developed a stereocontrolled synthesis of bicyclo[5.3.0]decan-3-ones from readily available acyclic substrates. Acyclic olefin-tethered amides were first subjected to the intramolecular Kulinkovich reaction to prepare bicyclic aminocyclopropanes. This was followed by a tandem ring-expansion-cyclization sequence triggered by aerobic oxidation. The reactive intermediates in this tandem process were aminium radicals (radical cations). The p-anisidine group was chosen to lower the amine oxidation potential. This substituent was crucial for the generation of the aminium radical (if Ar = phenyl, the ring aerobic oxidation is not feasible). 

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The extension of the Kulinkovich reaction to succinimide 75 gave a new entry into substituted indolizidines. Initially, it was demonstrated that reacting 75 under the Kulinkovich conditions, with terminal alkenes and... 

Schemes. The productive three-step synthesis of bicyclopropylidene (1) utilizing the Kulinkovich reaction of methyl cyclopropanecarboxylate [14]...

Other interesting spirocyclopropanated bicyclopropylidenes, the ring-anne-lated compounds 80a, b have also been prepared applying the Kulinkovich reaction [69, 70] (Scheme 14). The starting materials 79 were obtained by alkoxy-carbonylcarbene addition onto cyclooctene and bicyclo[6.1.0]non-l-ene, respectively. 

Scheme 13. Convergent synthesis of spirocyclopropanated bicyclopropylidenes 55-57 and 61 via repetitive application of the Kulinkovich reaction [14]...

An attempted approach to bis(bicyclopropylidenyls) of type 87 utilizing the Kulinkovich reaction turned out to be unfruitful although the twofold cyclo-propanation of the diester 84 prepared from butadiene, worked perfectly well, and the conversion of the biscyclopropanol 85 to the dibromide 86 also gave a good yield (60%), the twofold dehydrobromination of 86 afforded only 1.7% of a mixture of meso- and d,l-S7 (Scheme 15) [56 a]. However, the direct oxidative coupling of two molecules of lithiobicyclopropylidene was accomplished under... 

The Kulinkovich reaction has been widely developed, offering important synthetic potential. Thus, the intramolecular and enantioselective variants have been reported. More recently, similar Ti-mediated reactions were reported which allow the synthesis of tertiary and primary cyclopropylamines from N,N-dialkylamides [5,6] and nitriles [7], respectively. 

In this context, zirconium chemistry could open up new prospects for developing deoxygenative approaches to cyclopropanes. The Zr-assisted variant of the Kulinkovich reaction has been reported (Scheme 4, Eq. 1) [10]. Cyclopropanols were also formed, as by-products in addition to homoallylic alcohols, from aliphatic acid chlorides (Eq. 2) [ 10]. The conversion of acid chlorides (and also esters in several cases) into the corresponding homoallylic alcohols... 

Cyclopropane derivatives. The intramolecular Kulinkovich reaction of 2-substituted 5-hexenoyl bomanesultams is a useful method for the synthesis of chiral endo-2-substituted bicyclo[3.1.0]hexan-l-ols. Extension of the reaction scope to amides results in the formation of cyclopropylamines and cyclopropylstannanes. ... 

The recently reported rearrangement of /rani-silyl enol ethers 33 is of special interest because the preparation also involves construction of a hydroxy-substituted three-membered ring via the Kulinkovich reaction. ... 

A-Benzyl-3-azabicyclo[3.1.0]hexan-l-ols, which are readily available from a Kulinkovich reaction, are converted by CAN into benzaimulated l-azabicyclo[3.3.1]-nonan-3-ones. ° This oxidation pathway differs from that mediated by FeCls. 

Kulinkovich reaction. Optimal conditions for the preparation of 1,2-disubstimted cyclopropanols from methyl esters in ether or THF involve 1 equivalent of ( -PrO)4Ti,... 

Functionalized cyclopropanes. The reductive coupling of esters with 1-alkenes by a Grignard reagent and titanium alkoxide gives rise to cyclopropanols (the Kulinkovich reaction). With the use of ethylene carbonate, the condensation gives rise to 2-substituted cyclopropanone hemiacetals. An intramolecular version delivers bicyclic products. ... 

The Kulinkovich reaction is the titanium-catalysed synthesis of cyclo-propanols from carbo ylic esters and Grignard reagents. The reaction is very diastereoselective, and an asymmetric variant was described by Corey et al. in 1994, by using the spirotitanate 79 (Scheme 7.48). Since this work, only a few titanium-catalysed asymmetric syntheses of cyclopropanols were reported, with enantiomeric excesses never higher than 80%. ... 

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