Cascade cyclization of 1-(2-yl-3-phenylprop-2-enyl)-6-oxo-1,6-dihydropyridine-2-carbonitrile radical: Mechanistic insights from DFT study

Computational and Theoretical Chemistry 1044 (2014) 1–9

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Cascade cyclization of 1-(2-yl-3-phenylprop-2-enyl)-6-oxo-1, 6-dihydropyridine-2-carbonitrile radical: Mechanistic insights from DFT study Lang Yuan, Hai-Tao Yu ⇑ Key Laboratory of Functional Inorganic Material Chemistry, Ministry of Education, School of Chemistry and Materials Science, Heilongjiang University, Harbin 150080, China

a r t i c l e

i n f o

Article history: Received 26 March 2014 Received in revised form 5 June 2014 Accepted 8 June 2014 Available online 18 June 2014 Keywords: Cascade radical cyclization Regioselectivity Intrinsic reaction barrier Reaction mechanism Marcus theory

a b s t r a c t Hybrid DFT calculations of mechanism of the titled reaction have been carried out by employing the BHandHLYP method combined with the 6-311++G(d,p), 6-311G(d,p), 3-21G, and LANL2DZ basis sets. The calculated results indicated that the radical precursor (Z)-1-(2-iodo-3-phenylprop-2-enyl)-6-oxo1,6-dihydropyridine-2-carbonitrile prefers to undergo a deiodination to provide the titled free radical, followed by a tandem radical cyclization to construct several tetracyclic radical intermediates. The mechanism of the cascade radical cyclization was evaluated by the computed activation Gibbs free energies, intrinsic reaction barriers, attack angles, and orbital interaction energies. Further, we also explored the H-abstraction oxidations of the formed tetracyclic radicals by different abstractors. An excellent agreement with the available experiment was observed. The present investigation of reaction mechanism would be helpful not only for understanding the nature of radical chemistry but also for further experimental explorations. Ó 2014 Elsevier B.V. All rights reserved.

1. Introduction The cytotoxic quinoline alkaloid camptothecin, as well as its analogs mappicine and mappicine ketone (nothapodytine A and nothapodytine B), is of interest as antiviral and antitumor agents [1–18]. A wide variety of approaches to these alkaloids and their derivatives have been developed [19–38], which focused on constructing ring-fused molecular skeletons, as shown in Scheme 1. In previous experimental works, radical addition/cyclization methods were frequently used by Curran [39–41], Bennasar [32,38], and Bowman [42,43] because of the unique advantages of radical reactions. In particular, Bowman performed his pioneering study of constructing B and C rings by an intramolecular cascade radical cyclization method [43], and the proposed reaction pathways are depicted in Scheme 2. Some intramolecular cycloadditions and domino radical cyclizations have been well documented [44–64]. In the investigation by Bowman and coworkers [43], they postulated several seemingly rational channels to the experimentally observed product (Scheme 2), which are described as follows: The radical precursor (Z)-1-(2-iodo-3-phenylprop2-enyl)-6-oxo-1,6-dihydropyridine-2-carbonitrile (1) undergoes a ⇑ Corresponding author. Tel.: +86 451 86608576. E-mail address: [email protected] (H.-T. Yu). http://dx.doi.org/10.1016/j.comptc.2014.06.004 2210-271X/Ó 2014 Elsevier B.V. All rights reserved.

Diels–Alder cycloaddition–elimination to give the product 2, or alternatively deiodinates in the present of SnMe3 to generate the titled vinyl radical 3. If the deiodination occurs, the resulting 3 will cyclize in 5-exo mode into the iminyl radical 4 with a successful construction of C ring. Then, the iminyl radical 4 undergoes either a 5-exo ring closure to the spirocyclic intermediate 5, followed by a neophyl-like rearrangement (radical cyclization and ringexpansion) to the aromatic p-radical 6 (Path II), or a direct 6-endo cyclization into 6 (Path I). The two possible pathways can lead to the formation of the B ring skeleton. Finally, the aromatic p-radical 6 is oxidatively trapped by H-abstractors to afford the tetracyclic product 2. For the suggested reaction mechanism by Bowman and coworkers [43], there exist several questions which need to be further considered. First, for the mentioned Diels–Alder cycloaddition–elimination and tandem radical cyclization, they suggested that the latter is dominant [43]. A blank experiment with 1 in absence of SnMe3 gave the corresponding tetracyclic product 2 in a relatively low yield [43], which implied that the Diels–Alder cycloaddition–elimination pathway is experimentally possible. However, why cannot the cycloaddition–elimination channel keep competitive with the radical cyclization pathway? Second, for the suggested cascade radical cyclization, the regioselectivity of cyclization of the iminyl radical 4 onto aryl ring is puzzling because the 5-exo process is

2

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Scheme 1. Ring skeleton of alkaloid camptothecin.

obviously favorable in reaction kinetics and the 6-endo radical cycloaddition (Path I) possesses a considerably thermodynamical preference. Therefore, which effect controls the formation of the product 2 remains an open question. Third, the formation of the spiro radical intermediate 5 and further neophyl-like rearrangements are thermodynamically less favorable because of the largely steric hindrance in forming ring-fused intermediates. So then the question becomes: Can the thermodynamical contribution to reaction barrier make the kinetic advantage of the 5-exo reaction disappear and lead to a higher-lying 5-exo transition state than the thermodynamically advantageous 6-endo process? Last, if the radical cyclization of the iminyl radical 4 proceeds in 5-exo fashion, the resulting carbon-centered radical 5 can cyclize onto isopyrrole ring to access to two different intermediates with CCC and CCN three-membered rings, respectively. Then, which ring-fused intermediate is dominant? The favored channel is of interest because for the ortho-substituted phenyl ring analogue the radicals generated by way of ring expansions of ring-fused intermediates are disparate and can further undergo H-loss oxidations to afford different heterocyclic products [43], whereas the ring-expansion reactions of the two ring-fused intermediates in the present system would result in the same nonradical product. Therefore, it is very necessary to conduct an investigation of the favored pathway for rationalizing the related reaction mechanism and forecasting correctly reaction products. Concerning the aforementioned questions, we herein report a detailed theoretical result of the titled reaction. We hope this investigation will be helpful not only in understanding the nature of intramolecular radical cyclizations but also in constructing N-containing heterocyclic compounds by radical cyclization methods in future experiments. 2. Computational details In this study, the BHandHLYP [65,66] method combined with 6311++G(d,p) (for C, H, N, O atoms), LANL2DZ (for Sn on radical oxidation pathways by Sn(CH3)3), and 3-21G (for Sn and I atoms

in deiodination and Diels–Alder cycloaddition–elimination reactions) basis sets [67–71] was employed to perform all calculations of stationary points and frequencies. Vibrational analysis verified the identity of each stationary point as either a minimum or a transition state. In all calculations, we used the polarizable continuum model (PCM) [72–74] with t-BuPh as solvent to take into account bulk solvent effects. By calculating the solvent-corrected free energies of stationary points through the reactions, a Gibbs free-energy profile was constructed. The related energies and structural data are given in Supplementary material. Further, we also calculated the orbital interaction energies of several key transition states by the Natural Bond Orbital (NBO) method [75–79]. In order to evaluate thermodynamical and kinetic effects of activation processes, we used the Marcus theory [80–85] to separate their contributions to reaction barrier. The method was originally developed for describing charge transfer problems, and now it has been widely applied to various organic reactions [86–93]. In a reaction, the activation barrier (DE–) is composed of intrinsic barrier ðDE– 0 Þ and thermodynamic contribution ðDE– Þ and can be described as therm

1 ðDER Þ2 – – DE– ¼ DE– 0 þ DEtherm ¼ DE0 þ DER þ 2 16DE– 0

ð1Þ

in which DER represents the thermodynamic reaction energy. Therefore, the intrinsic barrier can be regarded as the barrier of a thermoneutral process without thermodynamic bias, i.e., a stereoelectronic requirement. By rearranging Eq. (1), an intrinsic reaction barrier can be calculated by the equation

DE– 0 ¼

DE–  12 DER þ

qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 2 ðDE– Þ  DE– DER 2

ð2Þ

3. Results and discussion 3.1. Reaction pathways As shown in Scheme 3, the radical precursor 1 can undergo a vinyl-iodine bond cleavage by Sn(CH3)3 to give key reactant radical 3 via the transition state TS3 to initiate cascade radical cyclization, or alternatively proceed via the transition state TS1 to afford the cycloadduct 8, followed by a 1,4-conjugate HI-elimination via the transition state TS2 to generate the experimentally observed product 2 (Diels–Alder cycloaddition–elimination pathway). Fig. 1 depicts the Gibbs free energy profile of the intramolecular cascade radical cyclization of 3. The first ring-closing reaction in the tandem radical cyclization can proceed via two different pathways, involving the intramolecular attacks of the carbon-centered

Scheme 2. Proposed reaction pathways.

L. Yuan, H.-T. Yu / Computational and Theoretical Chemistry 1044 (2014) 1–9

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Scheme 3. Calculated relative enthalpies (kcal/mol, in square brackets) and Gibbs free energies (kcal/mol, in parenthesis) of species on the iodine-abstraction and intramolecular cycloaddition–elimination pathways using the BHandHLYP method combined with 6-311++G(d,p) (for C, H, N, O atoms) and 3-21G (for Sn and I atoms) basis sets. t-BuPh was employed as solvent. The temperature is 298.15 K and the pressure is 1 atm.

Fig. 1. Calculated free energy profile of the tandem radical cyclization at the BHandHLYP/6-311++G(d,p) level of theory with t-BuPh as solvent. Relative free energies are in kcal/mol. The temperature is 298.15 K and the pressure is 1 atm.

vinyl radical at carbon and nitrogen atoms of nitrile to undergo cyclization following 5-exo and 6-endo pathways into the iminyl radical 4 and cycloadduct radical 9, respectively. The nitrogencontaining heterocycle 9 is a nonsignificant radical intermediate, as discussed in next section. However, the iminyl radical 4 is a considerable species because the subsequent radical cyclizations start from it. As can be noted in Fig. 1 that the radical cyclizations of the iminyl radical 4 in 5-exo and 6-endo modes onto aryl ring can generate the spiroheterocyclic radical 5 and tetracyclic radical 6

through the transition states TS6 and TS7, respectively. The radical centers (two resonant carbon atoms) of the spiroheterocyclic radical 5 can attack the C@C and C@N bonds of isopyrrole ring to access to ring-fused radical intermediates 10 and 11, respectively. Further, 10 can undergo ring-expansion reactions to generate either the six-membered ring 12 via TS10 or the seven-membered ring 13 via TS11. In the same way, 11 can be converted into 6 via TS12. Therefore, the cyclization of 5 onto the C@N bond generates the aromatic p-radical 6, whereas the cyclization onto the C@C

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bond gives another aromatic p-radical 12. The most important difference between 6 and 12 concerns the sites of radical centers and bridgehead hydrogen atoms. Because of the existence of bridgehead hydrogen atoms, 1,2-H shift reactions of 13, 6, and 12 were expected. In optimizations, 13 was found to be able to undergo a 1,2-H shift to 14 via TS13; however, the transition state separating 6 and 12 could not be located, although a comparable computational cost was paid. After the tandem radical cyclization, the following processes are to convert the formed tetracyclic radicals to nonradical products. Because hexamethylditin (Me3Sn–SnMe3), used in the experiment [43], can only provide trimethyltin radical (SnMe3), no hydrogen source was expected. Thus, the reductions of the formed tetracyclic radicals can be avoided under the given experimental conditions, i.e., the most possible termination reactions of these tetracyclic radicals are to be oxidatively trapped. Furthermore, because no unambiguous H-abstractors were proposed in the experiment [43], we herein considered two radical traps, SnMe3 and CH3, which are the most possible in this system. Given is the calculated Gibbs free energy profile of H-abstraction reactions along with the related stationary point energies and free energy barriers in Fig. 2. 3.2. Reaction mechanism and regioselectivities 3.2.1. Deiodination and Diels–Alder cycloaddition–elimination channels First, let’s investigate the deiodination and Diels–Alder cycloaddition–elimination pathways shown in Scheme 3. The iodineabstraction reaction is slightly exothermic with a reaction enthalpy (DrH) of 8.96 kcal/mol. Its free energy barrier height of 10.10 kcal/mol indicates that the iodine-loss reaction by SnMe3 is kinetically favorable. Although the Diels–Alder cycloaddition– elimination pathway is more exothermic (DrH = 37.26 kcal/mol) than the iodine-abstraction channel by 28.30 kcal/mol, it is kinetically less favorable because of a very high cycloaddition free energy barrier (45.04 kcal/mol). By comparing the free energy

barriers and transition state heights of the two pathways with the undermentioned energies and barriers of the cascade radical cyclization and subsequent radical oxidations, one can readily draw a conclusion that the iodine-abstraction of 1 is more possible than the intramolecular cycloaddition–elimination. It has been widely known that a Diels–Alder addition reaction generally possesses a very high activation barrier [94–100] and the reductive removals of I and Br atoms from the compounds bearing vinyl- or alkyl-halogen bonds by SnMe3 or SnBu3 are very easy [101–106]. 3.2.2. Cyclizations of vinyl radical onto nitrile group After iodine atoms are abstracted by SnMe3, the newly formed radical 3 will undergo intramolecular cyclizations onto nitrile in 5-exo and 6-endo fashions to afford radicals 4 and 9, respectively, as depicted in the Gibbs free energy profile (Fig. 1). The activation free energies of the 5-exo and 6-endo cyclizations via TS4 and TS5 are 6.68 kcal/mol and 19.97 kcal/mol, respectively, and the corresponding reaction enthalpies (see Table S2 in Supplementary material) to 4 and 9 are 27.14 kcal/mol and 11.23 kcal/mol, respectively, which indicate that the 5-exo process is thermodynamically and kinetically more favorable than the 6-endo pathway. Thereby, the regiochemistry of the first step in the cascade radical cyclization becomes apparent, i.e., it should be a carbon-philic cyclization, not a nitrogen-philic cyclization. The favored carbonphilic 5-exo cyclization of carbon-centered radicals onto nitrile group has been frequently observed in previous investigations [42,43,107–109]. The thermodynamical preponderance of the 5-exo cycloadduct 4 relative to the 6-endo cycloadduct 9 mainly comes from the low-strained in-plane structure of the singly occupied molecular orbital (SOMO) of the exocyclic iminyl radical in 4 and the high-lying endocyclic carbon-centered radical in 9. Relative to the thermodynamical effect, the kinetic aspect seems to be somewhat more complex. Fig. 3(a) gives the attack angles in the ring-closing transition states TS4 and TS5 along with the corresponding values in the reactant radical 3 and intermediates 4 and 9. By the optimized

Fig. 2. Calculated free energy profile of H-abstraction reactions using the BHandHLYP method combined with 6-311++G(d,p) (for C, H, N, O atoms) and LANL2DZ (for Sn atom) basis sets. t-BuPh was employed as solvent. Relative free energies are in kcal/mol. The temperature is 298.15 K and the pressure is 1 atm.

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Fig. 3. Key angles and dihedral angles in cyclization steps and the calculated intrinsic reaction barriers at the BHandHLYP/6-311++G(d,p) level of theory with t-BuPh as solvent. The angles are in degree. All shown energies (in kcal/mol) are electronic total energies with ZPVE correction.

geometries we can know that the 5-exo and 6-endo cyclizations proceed in in-plane mode. The attack angles (\C1C2N3) in 3 and TS4 are 108.9° and 114.9°, respectively, only a difference of 6.0°. However, a larger difference of 46.1° in the attack angle (\C1N3C2, 55.0° in 3 and 100.1° in TS5) can be noticed for the 6-endo cyclization, which implies that the activation process from 3 to TS5 bears a larger steric resistance than 3 ? TS4. Therefore, the kinetic barrier for 3 ? TS5 should be higher than that for 3 ? TS4. The presumption can be further identified by the computed intrinsic reaction barriers shown in Fig. 3(a), i.e., if the thermodynamical effect is ignored, the 5-exo transition state TS4 (17.35 kcal/mol) is 7.50 kcal/mol lower than the 6-endo transition state TS5 (24.85 kcal/mol). When the thermodynamical effect is included, the reaction exothermicity lowers the heights of TS4 and TS5 by 10.67 kcal/mol and 4.88 kcal/mol and further leads to the activation barriers of 6.68 kcal/mol and 19.97 kcal/mol for the 5-exo and 6-endo processes, respectively. Thereby, the thermodynamical contribution to reaction barrier does not change the predominance of 5-exo relative to 6-endo. Based on the discussion above one can find that the steric effect in 3 ? TS5 seems to be stronger than that in 3 ? TS4 despite the fact that both of the 5-exo and 6-endo cyclizations are exothermic. Further, this can also be elucidated by the early transition state character of TS4 relative to TS5, i.e., the steric resistance is less important in TS4. Furthermore, the steric

hindrance change can be illuminated by the bending angles (\ C4C2N3) of 153.1° (in TS4) and 144.4° (in TS5), as shown in Fig. 3(a), indicating very apparently sideways attacks of radical centers (in plane with p system) at carbon and nitrogen atoms. Thereby, the preferred 5-exo regioselectivity is dominated by the steric resistance required for forming cyclization transition state. The most interesting aspects of regiochemistry involve the kinetic nature of cyclizations of vinyl radical onto nitrile group and therefore worth discussing again. The aforementioned kinetic dominance can be further understood from orbital interactions. Table 1 Orbital interaction energies (Eint, in kcal/mol) between SOMO and the attacked p orbital by NBO method at the BHandHLYP/6-311G(d,p) level of computation. Species

Orbitalsa

Eint

TS4

SOMO pC2-N3(b spin) SOMO ? pC2N3 (a spin) pC2–N3(b spin) SOMO SOMO ? pC2N3 (a spin) pC2–C3(b spin) SOMO SOMO ? pC2C3 (a spin) pC2–C3(b spin) SOMO SOMO ? pC2C3 (a spin)

35.65 35.15 34.78 23.72 164.50 74.22 86.02 55.40

TS5 TS6 TS7

a

Atom numbers were given in Fig. 3.

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Table 1 listed the orbital interaction energies, computed by the NBO method at the BHandHLYP/6-311G(d,p) level of theory, between SOMO and the attacked p orbitals in cyclization transition states. The computed SOMO-p and SOMO-p interaction energies in TS4 are 35.65 kcal/mol and 35.15 kcal/mol, respectively, while the SOMO-p and SOMO-p overlaps in TS5 are worth 34.78 kcal/ mol and 23.72 kcal/mol, respectively. The higher interaction energy for SOMO-p than that for SOMO-p in TS4 and TS5 suggests that an electrophilic character dominates the two intramolecular cyclizations of the vinyl radical 3. This somewhat deviates from the general consensus that most of radicals are nucleophilic and undergo addition reactions via the ‘‘classical’’ SOMO ? p interaction. It should also be noted that the nucleophilic interactions (SOMO ? p) in TS4 and TS5 cannot be completely neglected, especially in TS4 that the interaction energy of SOMO-p is only 0.5 kcal/mol lower than that of SOMO-p. Moreover, TS4 takes precedence over TS5 in total interaction energy (Table 1), and the 5-exo cyclization of 3 thus possesses a significantly kinetic advantage over the 6-endo cyclization. 3.2.3. Cyclizations of iminyl radical onto phenyl ring After the five-membered ring C is successfully constructed by cyclization of vinyl radical onto nitrile group in the preferred 5-exo fashion, the resulting iminyl radical 4 becomes a notable intermediate because the final products come from ring closure reactions of 4. As can be seen in Fig. 1 that the nitrogen-centered iminyl radical 4 can cyclize onto phenyl ring in 6-endo and 5-exo modes into the tetracyclic radical 6 and spiroheterocyclic radical 5, respectively. The 6-endo cyclization proceeds via TS7 with a free energy barrier of 17.08 kcal/mol, while the 5-exo reaction via TS6 possesses a free energy barrier of 23.70 kcal/mol. The former is higher than the latter by 6.62 kcal/mol. Also, the endo adduct 6 is thermodynamically more stable than the exo adduct 5 by an enthalpy difference of 19.63 kcal/mol. Therefore, the intramolecular cyclization in 6-endo mode is more favorable than the competing 5-exo ring closure reaction. The higher thermodynamical stability of 6 than 5 involves two possible reasons. One is the delocalization effect of unpaired electron and the other results from a higher ring strain in the spiroheterocyclic 5 than that in the aromatic p-radical 6. Although the unpaired electrons in the radical intermediates 6 and 5 can be well delocalized by a p resonance, the delocalization on two cycles in 6 seems to be more effective in resonance energy than 5 with only one resonance ring. Relative to thermodynamical effects, the kinetic factors affecting activation barriers are scarcely intelligible. In the first cyclization step as discussed above, the steric repulsion in activation processes is governed by attack angles. However, the situation is somewhat different in the second cyclization step. As displayed in Fig. 3(b), the attack angles increase by 8.2° (\ N1C2C3) and 42.7° (\ N1C3C2) in the 6-endo (4 (97.6°) ? TS7 (105.8°)) and 5exo (4 (58.9°) ? TS6 (101.6°)) activation processes, respectively. The relatively larger change in attack angle for the 5-exo activation than that for the 6-endo activation announces a kinetic advantage of 6-endo over 5-exo. However, the calculated intrinsic reaction barriers (Fig. 3(b)), 17.57 kcal/mol for TS6 and 18.85 kcal/mol for TS7, indicate that the 5-exo process should be slightly more favorable in stereoelectronic effect than the 6-endo process. This unwonted result should be contributed to different attack orientations in the two cyclizations. Several key dihedral angles in TS6 and TS7 are given in Fig. 3(c). Based on the computed dihedral angles (h(N1C2C3C4)) of 123.7° and 109.3° in TS7 and TS6, respectively, we can know that the phenyl ring (A ring) deviates from the molecular surface decided by C and D rings. However, in 4, the molecular skeleton comprising A, C, and D rings is almost planar. Thus, in the activation process 4 ? TS6, the deviation of aryl ring from the

molecular surface requires a rotation around the C3AC6 single bond. Because no apparent steric resistance exists, the torsional motion requires only a low rotational barrier [110–112]. Thereby, the observed ordering of kinetic barriers should not be attributed to the attack angles in TS6 and TS7. As discussed in the first step of the tandem radical cyclization, the ring-closing reactions proceed in an in-plane mode and the reaction barriers are controlled by attack angles. In the second cyclization step with an out-ofplane attack pattern, which factor dominates the kinetic barrier ordering? A noticeable change is that the C2AH5 bond in TS6 is almost coplanar arrangement with phenyl ring (dihedral angle h(H5C2C3C4) = 172.3°), whereas there is a less coplanar arrangement between the C2AH5 bond and phenyl ring based on the computed dihedral angle (h(H5C2C3C4)) of 147.0° in TS7. Therefore, it is very reasonable to think that the stronger CAH bond torsion in TS7 than that in TS6 should be responsible for the lower kinetic barrier for 5-exo than that for 6-endo. Although the kinetic barrier for the 6-endo cyclization is higher than that for the 5-exo cycloaddition, the thermodynamical contribution to barrier makes a dramatic change in the ordering of activation barriers for the 6-endo and 5-exo processes. As shown in Fig. 3(b), the 6-endo reaction is exothermic by 7.47 kcal/mol and the 5-exo reaction is endothermic by 11.98 kcal/mol. The contribution of exothermicity to activation lowers the 5-exo barrier by 3.55 kcal/mol, while the endothermcity increases the 6-endo barrier by 6.50 kcal/mol. The change in barrier height resulting from thermodynamical contribution makes the 6-endo transition state (TS7, 15.30 kcal/mol) lower in energy than the 5-exo transition state (TS6, 24.07 kcal/mol), which is entirely different from the fact that the intrinsic reaction barrier (TS7, 18.85 kcal/mol) for the 6endo reaction is slightly higher than that (TS6, 17.57 kcal/mol) for the 5-exo cyclization (Fig. 3(b)). Therefore, the iminyl radical 4 prefers to cyclize in 6-endo mode and the resulting 6 is thermodynamically controlled, although the stereoelectronic effect seems to be definite preference for the 5-exo cyclization. Table 1 lists the orbital interaction energies, computed by the NBO method at the BHandHLYP/6-311G(d,p) level of theory, between SOMO and the attacked p orbital in the cyclization transition states TS6 and TS7. The SOMO-p and SOMO-p interaction energies in TS6 are 164.50 kcal/mol and 74.22 kcal/mol, respectively, while the SOMO-p and SOMO-p overlaps in TS7 are worth 86.02 kcal/mol and 55.40 kcal/mol, respectively. It seems that the electrophilic character is more apparent than the nucleophilic character on both 5-exo and 6-endo cyclizations because the SOMO-p overlap possesses a higher interaction energy than the SOMO-p overlap. Furthermore, the larger total interaction energy in TS6 than that in TS7 indicates that the 5-exo process is more favorable in kinetic barrier than the 6-endo cycloaddition. This is in good agreement with the calculated intrinsic barriers shown in Fig. 3(b). 3.2.4. Neophyl-like rearrangement pathways Generally, 5-exo and 6-endo pathways are competitive in intramolecular radical cyclization reactions [44–64,113–116]. The resulting five- and six-membered radicals have been suggested to be capable of transforming into each other via neophyl-like rearrangements [45,113–115]. However, most of the presumptions for the neophyl-like rearrangement mechanism have proved to be improbable because the ring-fused intermediates on rearrangement pathways are usually high-lying and the neophyl-like rearrangements cannot effectively compete with the direct oxidation and reduction of the 5-exo and 6-endo radicals [44,116]. In this investigation, the spiroheterocyclic radical 5 seems to be possible to isomerize into the intermediates 12 and 13 via the neophyl-like rearrangement pathways shown in Fig. 1. In 5, the resonance effect of unpaired electron makes the radical center

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localize mainly at the two sp2 carbon atoms adjacent to the spirocentered sp3 carbon. The two sp2 carbon atoms can attack the C@C and C@N bonds of isopyrrole ring to generate ring-fused radicals 10 and 11, and the corresponding C- and N-philic transition states TS8 and TS9 lie 5.66 kcal/mol and 11.13 kcal/mol higher than the reference point 3 (Fig. 1), respectively, which suggests that the Cphilic cyclization is more favorable than the N-philic cycloaddition. Moreover, the N- and C-philic annulations are endothermic by 15.99 kcal/mol and 11.00 kcal/mol, respectively (see Table S2). The higher thermodynamical stability of 10 than 11 should be attributed to the more stable CCC three-membered ring than the CCN three-membered ring and a stronger electron delocalization of N atom in 10 than that in 11. Because 5 cannot be expected to oxidize at the given experimental conditions and the neophyl-like rearrangements have very high reaction barriers, the reverse process (5 ? TS6 ? 4) seems to be more possible for the spiroheterocyclic intermediate 5. Thereby, spiro nonradical species should not be considered as reaction products, which is in good accordance with the experimental results [43]. 3.2.5. Oxidations of tetracyclic radicals After the tandem radical cyclization, the following oxidative trapping can generate tetracyclic nonradical products. As described in the section above, no unambiguous H-abstractors were proposed in the experiment [43]. Therefore, we herein employed two radical traps, SnMe3 and CH3. The calculated H-loss reaction profiles (Fig. 2) indicate that these H-abstraction reactions are extremely exothermic and their free energy barriers vary from 19.93 kcal/mol to 28.64 kcal/mol. Therefore, the H-abstraction reactions can proceed under the given thermodynamical conditions. Furthermore, the free energy barriers of these H-abstraction reaction by SnMe3 or CH3 suggest that for the same abstraction reaction the CH3 seems to be more effective H-abstractor than  SnMe3. Although the reverse reaction 6 ? TS7 ? 4 is more favorable than the H-loss reactions, the products coming from the Hloss reactions of 12, 13, and 14 are impossible because of the high-lying neophyl-like rearrangement transition states. In other words, the final nonradical products are dominated by the preferred radical cyclization pathway, i.e., for the reactant radical 3, the consecutive 5-exo and 6-endo tandem radical cyclization channel is more favorable than other pathways and the constructed polycyclic radical thus prefers 6, not 12, 13, or 14. Therefore, the final nonradical product 2, identified by the available experiment [43], comes from the H-loss oxidation of 6. 4. Conclusions For the initial reactant 1, the deiodination by vinyl-iodine bond cleavage by Sn(CH3)3 is more favorable than the Diels–Alder cycloaddition–elimination pathway, and the resulting radical 3 is kinetically controlled. In the first step of the tandem radical cyclization, the computed results of intrinsic reaction barriers and orbital interaction energies indicate that the intramolecular 5-exo cyclization of 3 onto nitrile into the radical intermediate 4 has significantly kinetic and thermodynamical advantages over the 6-endo cyclization. In the second step of the sequential radical cyclization, the iminyl radical 4 can cyclize onto phenyl ring in 5-exo and 6endo modes to give the spiroheterocyclic 5 and tetracyclic 6, respectively. The calculated intrinsic barriers, attack angles, and orbital interaction energies give a 6-endo precedence over 5-exo, although the 5-exo reaction is kinetically favorable. The preferred tetracyclic radical 6, thus, is thermodynamically controlled, while the formation of 5 seems to be impossible. The indirect route with very high reaction barriers, involving the 5-exo ring closure of 4 and the following neophyl rearrangements of 5 to the

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ring-expanded radicals 12, 13, 14, can be reasonably considered to be of minor importance. Therefore, the final nonradical product 2 is formed via the H-abstraction oxidation of 6. Acknowledgements The authors are grateful for the financial support from the National Natural Science Foundation of China (Grant No. 21173072) and Program for Innovative Research Team in University (The Ministry of Education of China, Grant No. IRT-1237). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.comptc.2014.06. 004. These data include MOL files and InChiKeys of the most important compounds described in this article. References [1] D. Bom, D.P. Curran, A.J. Chavan, S. Kruszewski, S.G. Zimmer, K.A. Fraley, T.G. Burke, Novel A,B,E-ring-modified camptothecins displaying high lipophilicity and markedly improved human blood stabilities, J. Med. Chem. 42 (1999) 3018–3022. [2] V.J. Venditto, E.E. Simanek, Cancer therapies utilizing the camptothecins: a review of the in vivo literature, Mol. Pharmaceutics 7 (2010) 307–349. [3] M.E. Wall, M.C. Wani, C.E. Cook, K.H. Palmer, A.T. McPhail, G.A. Sim, Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from camptotheca acuminate, J. Am. Chem. Soc. 88 (1966) 3888–3890. [4] T.-S. Wu, Y.-Y. Chan, Y.-L. Leu, C.-Y. Chern, C.-F. Chen, Nothapodytines A and B from nothapodytes foetida, Phytochemistry 42 (1996) 907–908. [5] Y.H. Hsiang, R. Hertzberg, S. Hecht, L.F. Liu, Camptothecin induces proteinlinked DNA breaks via mammalian DNA topoisomerase I, J. Biological Chem. 260 (1985) 14873–14878. [6] Y. Kawato1, M. Aonuma, Y. Hirota, H. Kuga, K. Sato, Intracellular roles of SN38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11, Cancer Res. 51 (1991) 4187–4191. [7] W.J. Slichenmyer, E.K. Rowinsky, R.C. Donehower, S.H. Kaufmann, The current status of camptothecin analogues as antitumor agents, J. Natl. Cancer Inst. 85 (1993) 271–291. [8] P.J. Burke, P.D. Senter, D.W. Meyer, J.B. Miyamoto, M. Anderson, B.E. Toki, G. Manikumar, M.C. Wani, D.J. Kroll, S.C. Jeffrey, Design, synthesis, and biological evaluation of antibody-drug conjugates comprised of potent camptothecin analogues, Bioconjugate Chem. 20 (2009) 1242–1250. [9] H. Zhang, X.-q. Wang, W.-b. Dai, R.A. Gemeinhart, Q. Zhang, T.-l. Li, Pharmacokinetics and treatment efficacy of camptothecin nanocrystals on lung metastasis, Mol. Pharmaceutics 11 (2014) 226–233. [10] A. Galbiati, C. Tabolacci, B.M.D. Rocca, P. Mattioli, S. Beninati, G. Paradossi, A. Desideri, Targeting tumor cells through chitosan-folate modified microcapsules loaded with camptothecin, Bioconjugate Chem. 22 (2011) 1066–1072. [11] K. Bandyopadhyay, R.A. Gjerset, Protein kinase CK2 is a central regulator of topoisomerase I hyperphosphorylation and camptothecin sensitivity in cancer cell lines, Biochemistry 50 (2011) 704–714. [12] A.V. Yurkovetskiy, A. Hiller, S. Syed, M. Yin, X.M. Lu, A.J. Fischman, M.I. Papisov, Synthesis of a macromolecular camptothecin conjugate with dual phase drug release, Mol. Pharmaceutics 1 (2004) 375–382. [13] P.A. McCarron, W.M. Marouf, D.J. Quinn, F. Fay, R.E. Burden, S.A. Olwill, C.J. Scott, Antibody targeting of camptothecin-loaded PLGA nanoparticles to tumor cells, Bioconjugate Chem. 19 (2008) 1561–1569. [14] D. Bom, D.P. Curran, S. Kruszewski, S.G. Zimmer, J.T. Strode, G. Kohlhagen, W. Du, A.J. Chavan, K.A. Fraley, A.L. Bingcang, L.J. Latus, Y. Pommier, T.G. Burke, The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity, J. Med. Chem. 43 (2000) 3970–3980. [15] N. Wu, X.-W. Wu, K. Agama, Y. Pommier, J. Du, D. Li, L.-Q. Gu, Z.-S. Huang, L.K. An, A novel DNA topoisomerase I inhibitor with different mechanism from camptothecin induces G2/M phase cell cycle arrest to K562 cells, Biochemistry 49 (2010) 10131–10136. [16] Y.-q. Shen, E. Jin, B. Zhang, C.J. Murphy, M.-h. Sui, J. Zhao, J.-q. Wang, J.-b. Tang, M.-h. Fan, E.V. Kirk, W.J. Murdoch, Prodrugs forming high drug loading multifunctional nanocapsules for intracellular cancer drug delivery, J. Am. Chem. Soc. 132 (2010) 4259–4265. [17] C.J. Thomas, N.J. Rahier, S.M. Hecht, Camptothecin: current perspectives, Bioorg. Med. Chem. 12 (2004) 1585–1604. [18] D.J. Adams, M.L. Wahl, J.L. Flowers, B. Sen, M. Colvin, M.W. Dewhirst, G. Manikumar, M.C. Wani, Camptothecin analogs with enhanced activity against human breast cancer cells. II. Impact of the tumor pH gradient, Cancer Chemoth. Pharm. 57 (2006) 145–154.

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