Cyclopropanation, stereochemistry reactions

The stereoselection in the cyclization of each diastereomer was examined independently. The stereochemical outcome of the cyclization should be predictable based on our assumption regarding the relationship between enolate stereochemistry and cyclopropane stereochemistry, the principles of asymmetric, intermolecular alkylation of optically active amides (9-13) and the assumption that the mechanism of cyclopropane formation involves a straightforward back-side, %2 reaction. In the case of the major diastereomer, the natural tendency of the enolate to produce the cis-cyclopropane will oppose the facial preference for the alkylation of the chiral enolate. Consequently, poorer stereochemical control would be ejected in the ring closure. In the minor diastereomer these two farces are working in tandem, and high degrees of stereocontrol should result. 

Recently, the stereochemical definitions of the addition of carbenes to C-C double bonds have been summarized. The term stereoselectivity refers to the degree of selectivity for the formation of cyclopropane products having endo vs. exo or, alternatively, syn vs. anti orientation of the substituents in the carbene species relative to substituents in the alkene substrate. The term stereospecificity refers to the stereochemistry of vicinal cyclopropane substituents originating as double-bond substituents in the starting alkene, i.e. a cyclopropane-forming reaction is stereospecific if the cisjtrans relationship of the double-bond substituents is retained in the cyclopropane product. Diastereofacial selectivity refers to the face of the alkene to which addition occurs relative to other substituents in the alkene substrate. Finally, enantioselectivity refers to the formation of a specific enantiomer of the cyclopropane product. 

The copper-catalyzed methylene transfer from sulfonium ylidcs to electron-rich olefins proceeds stereospecifically and probably involves a methylene copper complex15. Sulfonium, sulfoxonium, and (dialkylamino)sulfoxonium ylides are nucleophilic species and, in uncatalyzed reactions, only good Michael acceptors are attacked16 (see also Vol. IV/3, p 139 and Vol. E 11 2, p 1422). The cyclopropanation proceeds stepwise via a zwitterion, and therefore the olefin configuration is not necessarily reflected in the cyclopropane stereochemistry. Thus, both dimethyl ( )- or (Z)-2-butenedioate react with dimethylamino(phenyl)sulfoxonium methylide to give the //ww-substituted cyclopropane 4 only1. ... 

All cyclopropane-forming reactions. Watch stereochemistry In all these reaction.s the original stereochemical relationships around the double bond are preserved. 

A singlet carbene adds stereospecifically, meaning that reaction with a cis-alkene gives only ds-cyclopropane, and reaction with a frans-alkene gives trans-cyclopropane. The reaction of the triplet carbene is not stereospecific, however, and the product is a mixture of isomers. The difference in stereochemistry arises because the singlet carbene can add in one step (equation 5.39),... 

Dopieralski P, Ribas-Arino J, Marx D (2011) Force-transformed free energy surfaces and trajectory shooting simulations reveal the mechano-stereochemistry of cyclopropane ringopening reactions. Angew Chem Int Ed 50 7105-7108... 

Linear correlations in the stoicheoimetric cyclopropanation by W(CHPh)(C0)5 with alkenes in a comparison with the catalytic reactions of Rh2(0Ac) suggest a unifying mechanism. Cyclopropanation stereochemistry is determined by interactions in the TT-complex and at the ring forming stage. 

Ethyl-5-methyl (3R, 5R) and (3R, 55) derivatives Elucidation of the stereochemistry of the pyrazoline-> cyclopropane reaction 77JA2740... 

Chemo- and stereoselective reduction of (56) to (55) is achieved In highest yield by sodium borohydride in ethanol. The isolated ketone is reduced more rapidly than the enone and (55) is the equatorial alcohol. Protection moves the double bond out of conjugation and even the distant OH group in (54) successfully controls the stereochemistry of the Simmons-Smith reaction. No cyclopropanation occurred unless the OH group was there. Synthesis ... 

The enyne cross metathesis was first developed in 1997 [170,171]. Compared to CM it benefits from its inherent cross-selectivity and in theory it is atom economical, though in reality the aUcene cross-partner is usually added in excess. The inabihty to control product stereochemistry of ECM reactions is the main weakness of the method. ECM reactions are often directly combined with other transformations like cyclopropanation [172], Diels-Alder reactions [173], cychsations [174] or ring closing metathesis [175]. 

From the point of view of both synthetic and mechanistic interest, much attention has been focused on the addition reaction between carbenes and alkenes to give cyclopropanes. Characterization of the reactivity of substituted carbenes in addition reactions has emphasized stereochemistry and selectivity. The reactivities of singlet and triplet states are expected to be different. The triplet state is a diradical, and would be expected to exhibit a selectivity similar to free radicals and other species with unpaired electrons. The singlet state, with its unfilled p orbital, should be electrophilic and exhibit reactivity patterns similar to other electrophiles. Moreover, a triplet addition... 

Addition reactions with alkenes to form cyclopropanes are the most studied reactions of carbenes, both from the point of view of understanding mechanisms and for synthetic applications. A concerted mechanism is possible for singlet carbenes. As a result, the stereochemistry present in the alkene is retained in the cyclopropane. With triplet carbenes, an intermediate 1,3-diradical is involved. Closure to cyclopropane requires spin inversion. The rate of spin inversion is slow relative to rotation about single bonds, so mixtures of the two possible stereoisomers are obtained from either alkene stereoisomer. 

Based on these mechanisms and ligand structures, various transition-state models to explain the stereochemistry of asymmetric cyclopropanation reactions have been proposed. For details, see the reviews17- 1 and the references cited for Figure 12. 

The fact that Schrock s proposed metallocyclobutanes decomposed to propylene derivatives rather than cyclopropanes was fortunate in that further information resulted regarding the stereochemistry of the olefin reaction with the carbene carbon, as now the /3-carbon from the metal-locycle precursor retained its identity. The reaction course was consistent with nucleophilic attack of the carbene carbon on the complexed olefin, despite potential steric hindrance from the bulky carbene. Decomposition via pathways f-h in Eq. (26) was clearly confirmed in studies utilizing deuterated olefins (67). 

The species identified as XA reacts with styrene to give the expected cyclopropane. The rate constant for this reaction is ca 200 times less than the corresponding rate constant for 3BA (Table 6). Also, use of the deuterium-labeled a-methylstyrene reveals that the cyclopropanation occurs with essentially total retention of stereochemistry. Moreover, precisely the same result is obtained when this carbene is formed by triplet sensitization rather than by direct irradiation. These findings also point to a reaction originating from a singlet carbene. 

The analogous process involving allylic epoxides is more complex, as issues such as the stereochemistry of substituents on the ring and on the alkene play major roles in determining the course of the reaction [38]. Addition of the Schwartz reagent to the alkene only occurs when an unsubstituted vinyl moiety is present and, in the absence of a Lewis acid, intramolecular attack in an anti fashion leads to cyclopropane formation as the major pathway (Scheme 4.10). cis-Epoxides 13 afford cis-cyclopropyl carbinols, while trans-oxiranes 14 give mixtures of anti-trans and anti-cis isomers. The product of (S-elimi-... 

Although the reaction of a titanium carbene complex with an olefin generally affords the olefin metathesis product, in certain cases the intermediate titanacyclobutane may decompose through reductive elimination to give a cyclopropane. A small amount of the cyclopropane derivative is produced by the reaction of titanocene-methylidene with isobutene or ethene in the presence of triethylamine or THF [8], In order to accelerate the reductive elimination from titanacyclobutane to form the cyclopropane, oxidation with iodine is required (Scheme 14.21) [36], The stereochemistry obtained indicates that this reaction proceeds through the formation of y-iodoalkyltitanium species 46 and 47. A subsequent intramolecular SN2 reaction produces the cyclopropane. 

Evans suggests that the catalyst resting state in this reaction is a 55c Cu alkene complex 58, Scheme 4 (35). Variable temperature NMR studies indicate that the catalyst complexes one equivalent of styrene which, in the presence of excess alkene, undergoes ready alkene exchange at ambient temperature but forms only a mono alkene-copper complex at -53°C. Addition of diazoester fails to provide an observable complex. These workers invoke the metallacyclobutane intermediate 60 via a formal [2 + 2] cycloaddition from copper carbenoid alkene complex 59. Formation of 60 is the stereochemistry-determining event in this reaction. The square-planar S Cu(III) intermediate 60 then undergoes a reductive elimination forming the cyclopropane product and Complex 55c-Cu, which binds another alkene molecule. 

The specific feature of the bonds also affects its chemical behaviour and the stereochemistry of substitution reactions. For example in the conversion of (-) trans -2, 3 diphenyl cyclopropane carboxylic acid into (+) 1, 3 diphenylallene the optical activity is retained. 

The ammonium catalyst can also influence the reaction path and higher yields of the desired product may result, as the side reactions are eliminated. In some cases, the structure of the quaternary ammonium cation may control the product ratio with potentially tautomeric systems as, for example, with the alkylation of 2-naph-thol under basic conditions. The use of tetramethylammonium bromide leads to predominant C-alkylation at the 1-position, as a result of the strong ion-pair binding of the hard quaternary ammonium cation with the hard oxy anion, whereas with the more bulky tetra-n-butylammonium bromide O-alkylation occurs, as the binding between the cation and the oxygen centre is weaker [11], Similar effects have been observed in the alkylation of methylene ketones [e.g. 12, 13]. The stereochemistry of the Darzen s reaction and of the base-initiated formation of cyclopropanes under two-phase conditions is influenced by the presence or absence of quaternary ammonium salts [e.g. 14], whereas chiral quaternary ammonium salts are capable of influencing the enantioselectivity of several nucleophilic reactions (Chapter 12). 

The formation of cyclopropanes from 7C-deficient alkenes via an initial Michael-type reaction followed by nucleophilic ring closure of the intermediate anion (Scheme 6.26, see also Section 7.3), is catalysed by the addition of quaternary ammonium phase-transfer catalysts [46,47] which affect the stereochemistry of the ring closure (see Chapter 12). For example, equal amounts of (4) and (5) (X1, X2 = CN) are produced in the presence of benzyltriethylammonium chloride, whereas compound (4) predominates in the absence of the catalyst. In contrast, a,p-unsatu-rated ketones or esters and a-chloroacetic esters [e.g. 48] produce the cyclopropanes (6) (Scheme 6.27) stereoselectively under phase-transfer catalysed conditions and in the absence of the catalyst. Phenyl vinyl sulphone reacts with a-chloroacetonitriles to give the non-cyclized Michael adducts (80%) to the almost complete exclusion of the cyclopropanes. 

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