Cope rearrangement transition state conformation

The Cope rearrangement is the conversion of a 1,5-hexadiene derivative to an isomeric 1,5-hexadiene by the [3,3] sigmatropic mechanism. The reaction is both stereospecific and stereoselective. It is stereospecific in that a Z or E configurational relationship at either double bond is maintained in the transition state and governs the stereochemical relationship at the newly formed single bond in the product.137 However, the relationship depends upon the conformation of the transition state. When a chair transition state is favored, the EyE- and Z,Z-dienes lead to anli-3,4-diastereomcrs whereas the E,Z and Z,/i-isomcrs give the 3,4-syn product. Transition-state conformation also... 

The Cope rearrangement of acyclic substrates predominantly proceeds through a chairlike transition state, and substituents R prefer to occupy equatorial, rather than axial, positions when a free choice of transition state conformations is possible. As a consequence, substituents R in equatorial positions lead to E double bonds, and axial substituents to Z double... 

A significant difference between the Claisen and the Cope rearrangement is that both C-3 and C-4 in the pericyclic carbon framework may be stereogenic centers. The stereochemical outcome of such rearrangements has been demonstrated by the classical investigations on the rearrangement of 3,4-dimethyl-l, 5-hexadienes (32)274. For example, the rearrangement of meso-32 results in the nearly exclusive formation of ( ,Z)-2,6-octadiene (33) via a chair transition state conformation, whereas rac-32 affords a 90 f 0 mixture of the ( , )- and (Z.Z)-iso-mers via chair A and chair B. 

Cope substrates derived from bicyclo[2.2.2]oct-5-en-2-ones with an fWo vinyl group undergo Cope rearrangements via boatlike transition state conformations to yield cw-fused decalins, as exemplified by the rearrangement of 1107S. Product 4 is used in the synthesis of lucidu-line 1075,1076, and 6 in the synthesis of reserpine 1077 1078. 

There are perhaps only two research areas in which the quantitative estimation of steric factors is routinely done, namely for hindered biphenyls (Cooke and Harris, 1967) and rotational or pseudorotation barriers in ethanes and cyclic compounds (Allinger et al., 1967). There are indications, however, that this interest is widening. Simonetta and Favini (1966) performed conformational calculations on the Cope rearrangement via chair or boat transition states and indicated that the orbital preference emphasized in a previous section should be supplemented with a steric factor. 

The X-ray crystal structure for AZ-28 has a variety of structural features that are consistent with the proposed mechanism operative for the oxy-Cope rearrangement. The antibody binds the transition stage analog in a chair-like conformation, consistent with the preferred chair transition state for this pericyclic reaction (Doering and Roth, 1962). The positions of the C-2 and C-5 atoms are fixed in the antibody-bound hapten molecule in a similar fashion, the C-2 and C-5 positions in the hexadiene substrate should be held in a fixed position by conserved van der Waals interactions locking in the two phenyl substituents in the antibody combining site. This bound conformation of the acyclic (47T + 2er) system of the hexadiene substrate should enforce a molecular conformation close to the transition state for the rearrangement reaction, consistent with the catalysis observed for AZ-28. 

In acyclic systems, Claisen rearrangements show a well-established prefoence for chair-like transition states. With crotyl propenyl ether, the chair selectivity amounts to 97-98% at 142 C, which corresponds to an approx. 3 kcal mol difference between the fiee energy of activation (AAG ) of chair and boat TS (equation 26). The preference for a chair-like geometry in the TS is even more pronounced in the Cope reaiT ement 99.7% of the 3,4-dimethylhexa-1,5-diene rearranges at 225 C via a chair-like TS, corresponding to a AAG chair-boat of -5.7 kcal mol" . - The latter result closely parallels the difference in energy of the chair and boat conformations of cyclohexane (5-6 kcal mol" ). ... 

In cyclic systems, however, conformational constraints can override the inherent preference for chairlike transition states in Cope as well as Claisen rearrangements and lead to a partial involvement if not a dominance of boat-like TS structures. In the Ireland rearrangement of lactones of type (247), for example, chair-like transition state (249) is accessible only when the diaxial bridging methylene chain becomes sufficient in length (n = 7, Scheme 44). The preference of boat-like transition state (250) over (251) is due to a serious A - -type interaction between the endocyclic oxygen atom and pseudoaxial substituent R in (251). 

Two common six-membered rearrangements of 1,5-dienes have Y as either oxygen (Claisen rearrangement) or carbon (Cope rearrangement). Both are reversible and favor the more stable product. The preceding example problem demonstrated that they were thermally allowed An+2 suprafacial retention processes. As in the Cope example problem above, the transition state for the reaction commonly resembles the chair conformation of cyclohexane. Figure 12.29 shows a biochemical example of the Claisen rearrangement. 

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