Stereochemistry of cyclopropanes

Can Hyperconjugation in a 1,3-Diradical Control the Stereochemistry of Cyclopropane Ring Opening and Make a Singlet the Electronic Ground State of the Diradical ... 

Intramolecular reactions of the type of sequence 8-68 are interesting because the stereochemistry of cyclopropanation is controlled by the diene geometry (see examples in the review of Davies, 1993). They are also useful because of the enan-tioselectivities that can be obtained in these reactions (see Sect. 8.8, Schemes 8-75 to 8-78). 

The formation of isomeric mixtures of cyclopropanes is not an issue in intramolecular reactions between vinylcarbenoids and dienes because the Stereochemistry of cyclopropanation is controlled by diene geometry. In the case of 102 where the double bond nearest the ester tether is trans, cyclopropanation would generate cis-divinylcyclo-propanes which would readily rearrange to cycloheptadienes (Table 15). The intramolecular cyclopropanation of trom -dienes by vinylcarbenoids is feasible even though the intermolecular cyclopropanation of a tran -alkene does not occur. Several examples of this type of intramolecular reaction are shown in Table 15. ° In contrast, when the double bond nearest the tether is cis, as with 103, the tra j-divinylcy-clopropane 104 is formed in 94% yield (Scheme 37). ... 

Mechano-Stereochemistry of Cyclopropane Ring-Opening Reactions... 

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... 

Chiral oxazolidinone also controlled the stereochemistry of cyclopropanation of enamides 102 (Scheme 1.53) [88]. Cyclopropane 103 was obtained in good yields with high diastereomeric excesses. 

The geometry of the alkene unit served as good control for the stereochemical course of the reaction. For example, Six and coworkers reported that the stereochemistry of cyclopropanes 432 and 433 was controlled by the geometry of the alkene unit, and a stereospecific reaction progressed (Scheme 1.203) [285],... 

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

The stereochemistry of the resulting cyclopropane product (.s vn vs anti) was rationalized from a kinetic study which implicated an early transition state with no detectable intermediates. Approach of the alkene substrate perpendicular to the proposed carbene intermediate occurs with the largest alkene substituent opposite the carbene ester group. This is followed by rotation of the alkene as the new C—C bonds begin to form. The steric effect of the alkene substituent determines... 

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]. 

Examples of the use of dimethylsulfonium methylide and dimethylsulfoxonium methylide are listed in Scheme 2.21. Entries 1 to 5 are conversions of carbonyl compounds to epoxides. Entry 6 is an example of cyclopropanation with dimethyl sulfoxonium methylide. Entry 7 compares the stereochemistry of addition of dimethylsulfonium methylide to dimethylsulfoxonium methylide for nornborn-5-en-2-one. The product in Entry 8 was used in a synthesis of a-tocopherol (vitamin E). 

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 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-... 

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. 

Although the effect of quaternary ammonium salts on the stereochemistry of the two-phase condensation reaction of a-chloroacetonitrile with acrylonitriles to form cyclopropanes [4, 7] is not as pronounced as with the Darzens reaction, it can be rationalized in an analogous manner (Scheme 12.2). In the absence of the catalyst, the more highly stabilized anion (4a) is favoured leading to the preferential production of the cis isomer (5). As with the Darzens reaction, addition of the catalyst causes diffusion of the anions (4a) and (4b), as ion-pairs, into the bulk of the organic phase where their relative stabilities are similar and a more equal ratio of the two isomeric cyclopropanes (5) and (6) results (Table 12.2). 

Carbenes can add to cts- or irans-ole ns to form cyclopropanes in two different ways the original stereochemistry of the olefin may be retained, when the reaction is stereospecific, or the original stereochemistry of the olefin may be lost, in which case the reaction is regarded as nonstereospecific. This fact was recognized at a very early date by Shell who postulated the following rules for [1 + 23-cycloaddition of a carbene to an olefin ... 

The experimental ratio of ds- to trans-cyclopropane 43 46, i.e. the stereo-specifity of the reaction cannot be considered as a simple indication of singlet or triplet percentage of RaC , since the stereochemistry of the cyclo-addition depends on many factors. Photolysis produces the exdted 5i-state of the diazoalkane 41. This compound can lose nitrogen and form the singlet carbene 42 (So-state). 42 can add directly in a stereospecific manner if ki is large. If, however, intersystem crossing 42 45 (Aisc is large) competes favorably with... 

Bis-oxazoline ligands can also be produced by oxidative coupling of the copper derivative of diastereoisomerically pure 306 (Scheme 145) . Further lithiations of the product 317, which was produced as single diastereoisomer, occur (as in Scheme 143) at the second site adjacent to the oxazoline, giving, for example, 318, despite the (presumably) less favourable stereochemistry of the lithiation step. Bisoxazolines 318 direct the asymmetric copper-catalysed cyclopropanation of styrene using diazoacetate. 

Electron transfer-induced nucleophilic addition to several otho cyclopropane compounds was also studied. The nucleophilic addition of methanol to quadricy-clane radical cation 8 produces the two methanol adducts 53 and 54. The stereochemistry of the methoxy groups in these structures identifies the preferred direction of nucleophilic attack upon the intermediate radical cations 8. Detailed NOE experiments delineate the structure of 53 and establish conclusively that the norbomene derivative 54 contains a 7-fl ri-methoxy group. The stereochemistry of both is compatible with stereospecific nucleophilic attack exclusively firom the exo-position. 7-Methylenequadricyclane also is attacked exclusively from the exo-face.These results can be explained via backside attack with inversion of configuration. 

The various reactions of cyclopropane radical cations discussed in the preceding section have elucidated several facets of their reactivity. The results raise questions concerning the factors that determine the products observed. More significantly, we will consider whether the structures, the stereochemistry, and the chirality of the products can be related unambiguously to the structures of the radical cationic intermediates, particularly to their spin- and charge-density distributions. 

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