Trans-Disubstituted cyclopropanes

If dichlorocarbene is generated in the presence of an alkene, addition to the double bond occurs and a dichlorocyclopropane is formed. As the reaction of dichlorocarbene with ds-2-pentene demonstrates, the addition is stereospecific, meaning that only a single stereoisomer is formed as product. Starting from a cis alkene, for instance, only cis-disubstituted cyclopropane is produced starting from a trans alkene, only trans-disubstituted cyclopropane is produced. 

Several VCD studies have been reported to date on three- and four-membered chiral ring molecules. The first of these by Heintz and Keiderling (62) focused on trans disubstituted cyclopropanes. These molecules have a rigid ring and a twofold axis of symmetry the substituents included carbomethoxy, carboxy, chlorocarbonyl, and cyano groups. The purpose of this study was to elucidate the basic VCD features of a series of structurally related molecules and to... 

At first compounds with only two substituents shall be considered. For the trans-disubstituted cyclopropanes II equations 2, 3 and 5 take the form of equation 9. 

Normally the chiral auxiliaries are introduced and removed in the asymmetric synthesis of Simmons-Smith reactions of allylic alcohols to provide mostly /rani-disubstituted cyclopropanes. Stereoselective syntheses of c -disubstituted cyclopropanes are difficult to achieve. Starting from (Z)-3-phenylprop-2-en-l-ol (80a) and (Z)-6-phenylhex-2-en-l-ol (80b), the corresponding c -disubstituted cyclopropanes 81a and 81b were prepared by first treating them with diethylzinc followed by diethyl (- -)-(/ ,7 )-tartrate (DET). A zinc-bridged intermediate is assumed to be formed first. This is subsequently treated with diethylzine and diiodomethane to give the products 81. The reaction conducted at — 12 "C gave the cyclopropanated products 81a and 81b with 70 and 81% ee, respectively.This method has the advantages that the introduction of the chiral auxiliary to the substrate and its removal are not neccessary and that both cis- and trans-disubstituted cyclopropanes could be prepared from (Z)- and ( )-allylic alcohols, repectively. 

With this acetal, instead of hydrolyzing the intermediate benzyllithium, one can let it warm to room temperature, and an internal nucleophilic substitution takes place, whereby the acetal moiety behaves as a leaving group, and a trans-disubstituted cyclopropane is formed in 60-70% yield [39,41]. The first-formed stereogenic center remains unaffected in this second step, whereas the benzylic lithiated carbon is able to epimerize [38,39], leading to the more stable trans-cyclopropane [42-44] (Scheme 20). 

These results showed that the yield of the cycloaddition diminished significantly when performed with the trans-disubstituted cyclopropane. It also proved their original theory that the reaction took place through a stepwise mechanism with inversion of configuration, which takes place in Sn2 nucleophilic additions [28]. 

Taking 1,2-disubstituted cyclopropane as an example, retro synthesis analysis shows that there are three possible ways to disconnect the three-membered ring—a, b, and c as shown in Figure 5-11. Route a involves the addition of methylene across a double bond, and this is often a stereospecific conversion or Simmons-Smith reaction.92 One can clearly see that route b or c will encounter the issue of cis/trans-product formation. 

Asymmetric allylic C-H activation of more complex substrates reveals some intrinsic features of the Rh2(S-DOSP)4 donor/acceptor carbenoids [135, 136]. Cyclopropanation of trans-disubstituted or highly substituted alkenes is rarely observed, due to the steric demands of these carbenoids [16]. Therefore, the C-H activation pathway is inherently enhanced at substituted allylic sites and the bulky rhodium carbenoid discriminates between accessible secondary sites for diastereoselective C-H insertion. As a result, the asymmetric allylic C-H activation provides alternative methods for the preparation of chiral molecules traditionally derived from classic C-C bond-forming reactions such as the Michael reaction and the Claisen rearrangement [135, 136]. 

Singlet and triplet carbenes exhibit different properties and, to great extent, show markedly different chemistry . For example, a singlet carbene will add to a c/ -disubstituted alkene to produce only cis-disubstituted cyclopropane products (and to a rara-disubstituted alkene to produce only /rara-disubstituted cyclopropane products), while a triplet carbene will add non-stereospecifically to produce a mixture of cis and trans products. 

In addition to H and 13C chemical shifts, vicinal 1H,1H coupling constants provide another tool for the stereochemical assignment of disubstituted cyclopropanes, as the cis or trans relationship of the substituents can be determined from the absolute values, often without the need to compare diastereomers. The relationship is ... 

Kinetic studies by Doering and his collaborators at Harvard150-154 based on five sets of chiral 1,2-disubstituted cyclopropanes, with 1-cyano, 2-(phenyl or propen-2 -yl or -(E)-propenyl or phenylethynyl) (3) and 1 -phenyl-2-(propen-2 -yl) (4) substitution, established the ralative rotational propensities of these substituents and tested the proposition that they might be related to substituent moments of inertia. In all of these cases, the balance between one-center and two-center epimerizations from a trans isomer, reflected in (kt + k2) kl2, was fairly constant, ranging from 1.4 1 to 2.1 1. The kinetic advantages for one-center epimerizations at cyano-substituted carbons for the four cases studied were modest and not especially system-dependent the k, k2 ratios were 2.5,2.2,2.4 and 1.8, thus establishing that rotational propensities are not dictated by some simple function of the moments of inertia of substituents. 

All of the experimental and theoretical work on the stereomutations of cyclopropanes and vinylcyclopropanes covered above seems consistent with and understandable in terms of kinetically significant involvements of Cj(ts), Cs(ts) and EF(ts) structures and partitionings of EE trimethylene intermediates resulting in the formation of klt k2 and kl2 products at comparable rates. For trans-1,2-disubstituted cyclopropanes, neither the Smith mechanism (one-center stereomutations only) nor any two-center-only formulation can be correct, as demonstrated by Crawford and Lynch in 1968143 and reinforced by numerous subsequent studies (Figures 2 and 3). 

However, the use of Rh2(MPPIM)4 provides enhanced enantiocontrol for cyclopropanation of trans-disubstituted double bonds, up to 96% ee in the cases examined [89]. Trisubstitutec allylic double bonds, even that in famesyl diazoacetate (33, Eq. 5.17) [90], undergo effective, efficient, and highly enantioselective cyclopropanation (Eq. 5.17). Product yields are high except foi those cases in which steric factors appear to limit olefin approach to the metal carbene center. 

Once again, cis-disubstituted olefins lead to higher enantioselectivities than do trans-disubstituted olefins, but here the differences are not as great as they were with allyl diazoacetates. Both allylic and homoallylic diazoacetamides also undergo highly enantioselective intramolecular cyclopropanation (40-43) [93,94], However, with allylic a-diazopropionates enantiocontrol i s lower by 10-30% ee [95], The composite data suggest that chi ral dirhodium(II) carboxamide catalysts are superior to chiral Cu or Ru catalysts for intramolecular cyclopropanation reactions of allylic and homoallylic diazoacetates. 

Dirhodium(II) tetrakis(carboxamides), constructed with chiral 2-pyrroli-done-5-carboxylate esters so that the two nitrogen donor atoms on each rhodium are in a cis arrangement, represent a new class of chiral catalysts with broad applicability to enantioselective metal carbene transformations. Enantiomeric excesses greater than 90% have been achieved in intramolecular cyclopropanation reactions of allyl diazoacetates. In intermolecular cyclopropanation reactions with monosubsti-tuted olefins, the cis-disubstituted cyclopropane is formed with a higher enantiomeric excess than the trans isomer, and for cyclopropenation of 1-alkynes extraordinary selectivity has been achieved. Carbon-hydro-gen insertion reactions of diazoacetate esters that result in substituted y-butyrolactones occur in high yield and with enantiomeric excess as high as 90% with the use of these catalysts. Their design affords stabilization of the intermediate metal carbene and orientation of the carbene substituents for selectivity enhancement. 

Having documented that we are perplexed by the differences we found for the enthalpies of formation of simple cyclopropyl and phenyl derivatives, it is premature and perhaps foolish to go from singly to doubly substituted species and expect any better understanding. Steric repulsion between vicinal groups on a cyclopropane may be expected, and hence the trans-isomQv of 1,2-dimethylcyclopropane is expected to be more stable than the cis. This is correct the enthalpies of formation of trans-1,2- and cis-1,2-dimethylcyclopropane (20c and 20b, X = Me) respectively, are (-30.7 0.8) and (-26.3 0.6) kJ moF for the liquids, and-3.8 and 1.7 kJmoF for the gases. The 1,1-dimethyl isomer (20a, X = Me) is more stable yet (-33.3 0.7) and (-8.2 1.2) kJ moF for the liquid and gas, respectively. What comparisons with benzene derivatives can we make With the 1,1-disubstituted cyclopropane isomer, seemingly none. With the cw-l,2-isomer, let s try the o-disubstituted benzene, o-xylene (47a, X = Me). With the trans-l,l-isomcr, let s try the -xylene isomer (47b,... 

In Figure 5 the optical rotatory dispersions and CD spectra of some frans-disubstituted cyclopropane hydrocarbons are displayed Compound 1 has C2 symmetry and with respect to the cyclopropane subunit also 114 and 115 have a local C2 symmetry. Trans-1,2-dimethylcyclopropane (1) exhibits a continuous CD rising to a positive Cotton effect... 

B. Vibrational Circular Dichroism of Trans-1,2-Disubstituted Cyclopropanes... 

The ultimate test of the theoretical predictions for the mechanism of cyclopropane stereomutation would be to use an optically active disubstituted cyclopropane in which the substituents were just isotopes of hydrogen. This is a challenging problem both from a synthetic standpoint and from an analytical one. The analytical difficulty is particularly acute because one has to analyze a small, volatile molecule for both optical purity and cis-trans isomer ratio, and both measurements have to rely solely on the difference between isotopes. There are no functional groups to be used as handles for an optically active NMR shift reagent and so determination of optical purity must come from direct measurement of rotations—with a probable maximum specific rotation of < 1 ° ... 

Ionic additions which transform cyclopropenes into cyclopropanes are well known. The electrophilic addition of sulphenyl halides proceeds by a two-step mechanism to give trans-disubstituted products but with little regioselectivity. Cyclic sulphonium ion intermediates are probably involved as illustrated for 1-methylcyclopropene. Electrophilic... 

In disubstituted cyclopropanes, cyclobutanes and cyclopentanes, assignment of configuration, cis or trans, is made with respect to a plane through the molecule. Cyclopentanes and most cyclobutanes are not planar, but this does not pose a significant problem. Cyclohexanes are also non-planar. Using the above method it can take a while to decide whether the relative configurations of some disubstituted cyclohexanes are cis or trans. For these compounds we employ an alternative method based on dihedral angles. 

In the H NMR spectrum it is possible to discern a four-spin system of the AMX2 type for the three different kinds of proton of the c)s-l,2-disubstituted cyclopropane ring. The X2 protons form a doublet of doublets with cis coupling Hz) and trans coupling... 

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