Enediynes cyclic

Strain and antiaromaticity in cyclic enediynes 11 Control of strain through ligand-metal coordination 16 Steric assistance of ortho substituents 17... 

Table 1 Calculated c-d distances and stabilities of cyclic enediynes...

An extensive computational analysis expanded the range of the c-d distances for reactive cyclic enediynes to 2.9-3.4 A.38 By comparing unsubstituted enediynes with dialkyl-substituted enediynes, it was found that the activation enthalpy is dependent on factors other than the c-d distance and that reactivity hinges on a subtle interplay of steric and electronic effects that accompany distortion caused by incorporation into a macrocycle. For example, since alkyl substituents stabilize acetylenic bonds to a greater extend than olefinic bonds,39 such substituents stabilize the starting material, thus increasing both the activation barrier and the reaction endothermicity. 

The antiaromatic region is not important for the reactivity of the parent enediyne because the activation energy is determined only by the energy difference between the reactant and the TS. However, for the cyclic enediynes in Fig. 7 in which the C1-C6 distances are 3.39 and 2.92 A, respectively, antiaromaticity of the reactant should be relevant to the reaction kinetics. In addition, the role of repulsion between the in-plane filled orbitals is accentuated by a parallel decrease in the attractive two-electron interaction between the re and re orbitals which vanishes at the 3.2 A distance between the terminal carbon atoms. 

This analysis confirms that the effect of cyclic constraints is not purely steric but also has an electronic component. Another aspect of this dichotomy is shown in Fig. 11 which illustrates the decrease in the energy gap between the frontier in-plane rc-MOs. The decrease in the C1-C6 distance destabilizes the occupied MO where the interaction between the end orbitals is antibonding and, at the same time, stabilizes the empty MO where the 7i -orbitals overlap constructively. As a result, the efficiency of the photochemical Bergman cyclization should increase and, indeed, the most efficient photo-Bergman cyclizations reported in the literature involve cyclic enediynes.43 Again, the analogy with interrupted [2 + 2] photocycloaddition is instructive. 

Strain-based systems work the same way as the cyclic enediynes they reduce the c-d distance in the molecule. The first example was provided by Buchwald and coworkers,45 who used metal complexation of a PPh2 substituted enediyne to produce a species with considerably lower activation barrier (compared to the non-coordinated enediyne) (Scheme 10). 

Cyclic enediynes, see under Enediynes Cycloalkyl cations, NMR spectroscopy, 142-144... 

Since allylsilane can be considered as a very soft nucleophile because of the involvement of o-7i conjugation between the -electrons of the double bond and the o-electrons in the carbon-silicon bond, the addition of allylsilanes to ,/3-unsaturated enone moiety occurs exclusively via 1,4-addition19,20. A typical Sakurai-Hosomi reaction is illustrated in the reaction of allylsilane 66 with enone 67 in the presence of TiCU to give 68 which is used for the synthesis of a cyclic enediyne (equation 45)108. A similar reaction has been used for the synthesis of ewf-herbasolide 70 from enone 69 (equation 46)109. Prenylsilane undergoes 1,4-addition with squaric acid chloride 71 followed by dechlorosilylation to give 72 as the predominant product (equation 47). Interestingly, other simple allylsilanes react in a 1,2-addition fashion to yield 73110. 

Intramolecular Lewis acid-promoted reaction of coordinated propargylic ether with the silyl enol ether in 158 has been applied successfully to the construction of the highly strained 10-membered cyclic enediyne system 159, present in esperamycin and calicheamycin [39,40]. The enediyne system 157 was prepared by the Pd-catalysed Sonogashira coupling of (Z)-l,2-dichloroethylene (154) with two different terminal alkynes 155 and 156. 

For example, as shown by calicheamicin, cyclic enediynes have a lower activation barrier than acyclic enediynes. As suggested by Nicolaou in 1988, the distance between the acetylenic carbons that form the covalent bond influences the rate of cyclization. Another theory developed by Magnus and Snyder is based on the molecular strain between ground state and transition slate this seems to be more general, especially for strained cyclic systems. Often, as both the distance and the strain are not known, the development of suitable precursors remains difficult, as exemplified by the following enediyne, in which a slight change leads to a cycloaromatization ... 

Cyclic enediynes.4 A Ramburg-Backlund reaction of the cyclic diynes 1 furnishes cyclic enediynes. 

A carbene insertion route to the P-lactam fused cyclic enediyne (31) has been developed <02TL4241>. 

Nicolau developed the cd reaction criteria based on two observations. First, based on MM2 structures, the cd distance in calichaemicin is 3.35 A and the molecule is stable. However, after activation to give 33 (Figure 4.11), the distance contracts to 3.16 A and cyclization occurs spontaneously. Second, Nicolaou and coworkers prepared a series of cyclic enediynes 45a-h. Their cd distances, as estimated by MM2, and their stabilities are shown in Table 4.10, along with a few related compounds. (It is important to mention that MM2 grossly underestimates the cd distance in the parent enediyne 38 MP2 estimates that this distance is... 

TABLE 4.11 DFT-Computed cd Distances and Activation Enthalpies for Acyclic and Cyclic Enediynes"... 

Schreiner was unable to find either transition states or products for the cyclization of the smallest cyclic enediynes, 50 and 51. These are simply too... 

Z-Distannylethenes are prepared by palladium-catalyzed addition of ditins to acetylene [2], and the bis(trimethylstannyl) compound has been used in a novel and highly efficient ring closure to give cyclic enediynes via a double coupling with alkynyl iodide functionalities (Scheme 4-20) [58-61]... 

In the total synthesis of the strained cyclic enediynes 145, the highly substituted macrocyclic enediyne was constructed by intermolecular two-fold Pd-catalzed coupling of the a,ftj-di(iodoalkyne) moietes in 144 with cw-l,2-bis(trimethylstannyl)ethene in 80% yield [Eq. (49)] [70]. 

Carotene has been prepared by treating the a,a -dianion generated from starting sul-phone with bromine or iodine followed by rearrangement (equation 25). Utilizing the Ramberg-Backlund reaction, an interesting cyclic enediyne has been made (equation 26). ... 

Schreiner, P. R. Cyclic enediynes relationship between ring size, alkyne carbon distance, and cyclization barrier. Chem. Commun. 1998, 483 84. 

Synthetic studies on structurally novel bioactive nine-membered cyclic enediynes with an annulated oxirane fragment 04YGK226. 

It is impossible to describe in detail in this chapter all the formidable synthetic efforts that have been dedicated to the total synthesis of natural and artificial enediynes. However, we will try to summarize here the main strategies that have been employed in the preparation of cyclic enediyne rings. In most cases complex bicyclic or polycyclic compounds have been prepared by one of these methodologies. 

Cyclic enediynes have been obtained also by elimination of a suitable propargylic alcohol on a preformed cyclic diyne.5 An example is shown in Scheme 19.7, where the cyclization was accomplished through a Nozaki-Hiyama intramolecular allyl bromide addition to an aldehyde.5 This method proved successful for the synthesis of a particular enediyne that, because of conformational biases, could not be obtained by the strategies described above. 

Alcohols of general formula 27 may also be obtained by base-promoted [2,3] Wittig sigmatropic rearrangement. This method has been applied for the synthesis of 9-membered cyclic enediynes. ... 

Cyclic Enediynes Fused with Arenes Through the Double Bond... 

Cyclic Enediynes Fused with Other Rings Through Carbons 7-10... 

The fusion of a 10-membered cyclic enediyne with another ring is expected to stabilize it against cycloaromatization provided that ... 

This family of compounds, constituted mainly by a series of [7.3.1] derivatives, but including also [7.4.1], [8.3.1] and [9.3.1] polycyclic compounds, is characterized by the fact that the same synthetic strategy was followed for their preparation. That is, the formation of the cyclic enediyne system was achieved by the attack of the acyclic enediyne onto an aldehyde by one of the methods described above and illustrated in Scheme 19.17 for the formation of [7.3.1] systems. 

Danishefsky, S. Shair, M.D. Observations in the chemistry and biology of cyclic enediyne antibiotics Total syntheses of calicheamicin y/ and dynemicin A. J. Org. Chem. 1996, 61, 16-44. 

Banfi, L. Basso, A. Guanti, G. Rational design, synthesis, and reactivity of lactendiynes, a new class of cyclic enediynes ortho-fused with the P-lactam ring. Tetrahedron 1997, 53, 3249-3268. 

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