Relative Reactivity of Benzothiophene-Fused Enediynes in the

Article Cite This: J. Org. Chem. 2018, 83, 2788−2801

pubs.acs.org/joc

Relative Reactivity of Benzothiophene-Fused Enediynes in the Bergman Cyclization Anna G. Lyapunova,†,∥ Natalia A. Danilkina,†,∥ Andrey M. Rumyantsev,‡ A. F. Khlebnikov,† Mikhail V. Chislov,§ Galina L. Starova,† Elena V. Sambuk,‡ Anastasia I. Govdi,† Stefan Bras̈ e,*,⊥,# and Irina A. Balova*,† †

Institute of Chemistry, Saint Petersburg State University (SPbSU), Universitetskaya nab. 7/9, 199034 Saint Petersburg, Russia Department of Genetics and Biotechnology, Saint Petersburg State University (SPbSU), Universitetskaya nab. 7/9, 199034 Saint Petersburg, Russia § Research Centre for Thermogravimetric and Calorimetric Research, St. Petersburg State University, Universitetskaya nab. 7/9, 199034 Saint Petersburg, Russia ⊥ Institute of Organic Chemistry (IOC), Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany # Institute of Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, D-76344 Eggenstein-Leopoldshafen, Germany ‡

S Supporting Information *

ABSTRACT: To find promising analogues of naturally occurring enediyne antibiotics with a sufficient reactivity in the Bergman cyclization and moderately stable under isolation and storage, a scale of relative enediynes reactivity was created on the basis of calculated free activation energies for the Bergman cyclization within 12 known and new benozothiophene, benzene, and cinnoline annulated 9- and 10-membered enediynes. To verify the predicted reactivity/stability balance, three new carbocyclic enediynes fused to a benzothiophene core bearing 3,4,5-trimethoxybenzene, fluoroisopropyl, and isopropenyl substituents were synthesized using the Nicholastype macrocyclization. It was confirmed that annulation of a 3,4,5-trimethoxybenzene moiety to a 10-membered enediyne macrocycle imparts high reactivity to an enediyne while also conferring instability under ambient temperature. Fluoroisopropylsubstituted 10-membered enediyne from the opposite end of the scale was found to be stable while moderately reactive in the Bergman cyclization. Along with the experimentally confirmed moderate reactivity (DSC kinetic studies), (fluoroisopropyl)enediyne showed a significant DNA damaging activity in plasmid cleavage assays comparable with the known anticancer drug Zeocin.

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INTRODUCTION

Cyclic enediynes only of these sizes, usually after special triggering, are able to undergo thermally induced Bergman cycloaromatization6,7 at ambient temperatures (T ≤ 37 °C), affording highly reactive biradicals. The latter damage DNA through single- or double-strand breaks leading to a cell death involving different cellular mechanisms.1,8 Nowadays enediynes are still of great interest for the discovery of novel anticancer agents9−13 and in other fields, i.e., for the synthesis of polymers14−17 and polyaromatic compounds using transition metal catalysts and other reaction mechanisms.18−29 By today, numerous derivatives with a (Z)hexa-3-en-1,5-diyne scaffold have been synthesized and explored. There are several detailed recent reviews devoted to the synthesis of naturally occurring enediynes and their ana-

(Z)-Hexa-3-en-1,5-diyne moiety is a unique structural unit responsible for the antineoplastic and antimicrobial activity of naturally occurring enediyne antibiotics.1 It has been shown that the key feature of their biological mechanism of action is the Bergman cyclization (BC) of a (Z)-hexa-3-en-1,5-diyne moiety as a part of 9- or 10-membered macrocycles (Scheme 1).2−5 Scheme 1. Bergman Cyclization as a Key Feature of DNACleaving Properties of Cyclic Enediynes

Received: December 24, 2017 Published: February 5, 2018 © 2018 American Chemical Society

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DOI: 10.1021/acs.joc.7b03258 J. Org. Chem. 2018, 83, 2788−2801

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The Journal of Organic Chemistry Scheme 2. Synthetic Route Towards Heterocycle-Fused Enediynes

Scheme 3. Nicholas Reaction and Known Analogues of Natural Enediynes Synthesized through the Nicholas-Type Macrocyclization

logues,1,30−33 9-membered and other highly strained enediynes,34 complexes of enediynes with metals.35 Investigation of structure−activity relationships either experimentally or by computational methods is one of the important trends in the chemistry of enediynes.32,36,37 Analysis of the data published revealed that many of the structural features affect the activity of enediynes in the Bergman cyclization.37 However, a number of distinctions in structural parameters of enediynes and different quantitative parameters for the evaluation of enediynes reactivity in the Bergman cyclization complicate comparison of patterns essential for an “optimal structure” with a good reactivity along with a reasonable stability. Recently we have reported the synthetic approach to acyclic enediynes fused to heterocycles based on iodocyclization of ofunctionalized (buta-1,3-diynyl)arenes and the Sonogashira coupling as key steps (Scheme 2).38−40 Depending on functional groups in starting acetylenes, acyclic enediynes can contain a required functional group at a precise triple bond. This regioselectivity came from the synthetic route and is of crucial importance for the macrocyclization stage.39,41,42 Among macrocyclization methods used for enediynes the Nicholas reaction seems to be one of the most promising for the construction of 10-membered macrocycles that has been reviewed in details by Magnus.43 The Nicholas reaction44,45 is a general synthetic method based on the interaction of Co2(CO)6-stabilized propargylic carbocations46 with nucleophiles. This reaction has a broad application in the organic synthesis.47,48 The significant bending of bond angles in Cocomplexes43 and stability of Co-protected propargylic carbocations46 allowed this reaction to be employed as a unique macrocyclization tool in the synthesis of cycloalkynes49−52 including natural enediynes.43 There are recent examples of interaction of Co2(CO)6-stabilized propargylic carbocations derived from different functional groups in a propargylic position, i.e., OH,51−53 OR,54,55 COH,56 cyclopropane 1,1diester57), with different nucleophiles (heteroatom functions,49−52,58−61 arenes with electron donating groups,53,62,63

enoles,53,64,65 allylsilanes53,55,56 and double bonds54,55,60) (Scheme 3). Since the Magnus’ review only few macrocyclic analogues of natural enediynes 1−4 have been synthesized by the Nicholas macrocyclization.64,66−68 Although the nature of both nucleophilic and electrophilic groups can be varied in starting acyclic enediynes to give a variety of carbo- and heteroenediynes, all examples reported earlier involved the Nicholas macrocyclization using only enol ethers as a nucleophilic functional group (Scheme 3). We also successfully used the Nicholas reaction for the synthesis of 11-membered 5 and 10-membered oxaenediynes 6, 7 fused to a benzothiophene within OH-group as a nucleophilic moiety (Scheme 3).41 Both 10-membered compounds 6, 7 were moderately stable during isolation and storage, while they displayed a good activity in DNA plasmid cleavage assays. In continuation of the research devoted to benzothiophenefused enediynes we decided to investigate how the structure of an enediyne cycle influences the reactivity of benzothiophene annulated enediynes in the Bergman cyclization. Herein we report the results of the theoretical and experimental investigations of the series of enediynes annulated with benzothiophene aiming to create a scale of relative reactivity of benzothiophene-fused enediynes and to elucidate the border structures in the terms of stability/reactivity. The Nicholas reaction as a macrocyclization tool for the construction of different carbocyclic enediynes was chosen to vary the structure of an enediyne core fused to a benzothiophene.

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RESULTS AND DISCUSSION DFT Calculations for the Evaluation of Enediynes Reactivity. To estimate relative stability/reactivity balance and to verify it by the synthesis and investigation of key enediyne structures within benzothiophene-fused 10-membered enediynes, 12 enediynes were analyzed using calculated free activation energies values and experimentally estimated kinetic parameters for known structures. 2789


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Table 1. Reactivity Evaluation of Benzothiophene-, Benzene- and Cinnoline-Fused Enediynes in the Bergman Cyclization by DFT Calculationsa

a

Geometry optimization of reactants and transition states were performed using B3LYP with the 6-31G++(d,p) basis set. Because of the open shell nature of the transition-states, calculations on these structures were performed using BS-UB3LYP (broken-spin-symmetry, unrestricted) calculations.72 For the computational details see the Supporting Information. bThe distance between the termini of the enediyne moiety. cEnediyne 8 was synthesized only as Co2(CO)6-complex.41 dZPVE-corrected relative electronic energy, B3LYP/6-31++G(d,p).73

ene) 10, fluoroisopropyl 12, isopropenyl 13, and formyl 15 groups, which can be synthesized through the Nicholas

Among these series there are four new 10-membered benzothiophene-fused enediynes bearing trimethoxy(o-phenyl2790


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The Journal of Organic Chemistry macrocyclization. Additionally reported previously 9-membered benzothiophene 8 and benzene 9 annulated compounds and 10-membered enediynes fused to benzothiophene (6, 7) benzene (16, 17), two benzenes (11) and cinnoline (14) were chosen (Table 1). Of special note that reported Bergman cyclization rate constants,70,73 half-life values71 and onset temperatures from DSC measurements41 were obtained under different conditions. Therefore, these parameters can serve just for qualitative assessment of reactivity of known enediynes. As a consequence, only appropriate calculated parameters might be used for the development of a relative reactivity scale of enediynes and for choosing enediynes with desirable reactivity/stability balance for the synthesis. DFT calculations were performed by B3LYP and BS-UB3LYP level with the 631G++(d,p) basis set. It has been shown previously that B3LYP activation energies values are good ones in predicting relative trends in the reactivity within a family of enediynes.74 On the basis of the published data, two parameters may be considered for evaluating of enediynes reactivity: the cddistance and the activation energy. In earlier works the cddistance parameter (the distance between acetylenic atoms taking part in the Bergman cyclization) was pointed out as the crucial measure of enediynes reactivity.2 However, this parameter should be analyzed with caution, because it does not correlate with the activation energy for all enediynes, especially in the case of strained enediynes.37,72,75,76 It is not surprising that there is not a satisfactory correlation between the cd-distance values and the free activation energies within a series of chosen enediynes 8−17 (Table 1, Figure 1, black line). However, we found that the correlation can be improved under separate analysis of benzene- and benzothiophene-fused enediynes (Figure 1, red and blue lines). Taken together, our results show that the annulation of an enediyne system with a benzothiophene ring (Figure 1, blue dots) leads to a decrease in the activation barriers for reaching the cyclization transition state (TS) compared to their benzenefused analogues (Figure 1, red dots). Thus, for pairs of similar

benzene- and benzothiophene-fused enediynes with the close cd-distance values (8 and 9; 10 and 11; 6, 7 and 16, 17) the differences in activation energies vary from 2 to 5 kcal/mol. To explain the increase in reactivity of enediynes as a result of annulation with a benzothiophene ring the deviation of CCC bond angles (β, β′ and γ, γ′) from normal alkyne values (180°) was analyzed for pairs of enediynes 7 and 16; 10 and 11 (Figure 2). The angles values were taken from calculated optimized enediynes geometries.77 The deviation from 180° reflects the strain energy of cyclic enediynes and the strain release upon the formation of TSs with an assumption that the TSs of the Bergman cylization are more product-like according to the Hammond’s postulate (i.e., either benzene- or benzothiophene-fused 1,4-phenylene diradical) and therefore possess almost the same level of ring strain within the enediynes studied. The deviation of β and β′ angles from 180° is considerably higher than for γ and γ′ angles.77 Therefore, the value of (360 − (β + β′)) was analyzed. As will readily be observed the deviation of β and β′ angles values are markedly higher for benzothiophene-fused enediyne than for benzene-fused ones while comparing compound bearing similar enediyne scaffolds (enediynes 7 and 16; 10 and 11, Figure 2). This difference comes from increased values of α and α′ angles for 10membered enediyne cycles joined with 5-membered benzothiophene in comparison with 6- membered benzene. Using this line of reasoning it leads to the increase of strain for benzothiophene-fused enediynes and higher strain release during the TS formation. Therefore, the benzothiophenefused enediynes are expected to be highly reactive in the Bergman cyclization than their benzene-fused analogues. We checked whether it is possible to use the deviation value (360 − (β + β′)) as a parameter for the evaluation of enediynes reactivity.77 This structural parameter being applied for the whole series of enediynes from Table 1 or for only benzenefused enediynes provides similar correlation with free activation energy values in comparison with the correlation for cddistances and ΔG‡(298). At the same time the deviation of (β + β′) from 360° gives correlation with worse R2 factor in the case of separate analysis for benzothiophene-fused enediynes (Figure 3). The reason could be that the TS geometry is neglected. Therefore, we decided to analyze the free activation energy dependence on the change of sum of CCC bond angles (β, β′, δ, δ′) in enediynes and TSs (Figure 4). As expected ΔG‡(298) is linear in the difference of sum of bond angles values with a higher R2 factor for the whole series of enediynes in comparison with parameters used before (cd-distance and deviation of (β + β′) from 360° in starting enediynes) that confirms that the comparison of reactivity of enediynes of different types should be made only on the basis of the geometries of both starting enediynes and TSs. Turning back to the series of enediynes studied (Table 1) expected higher reactivity of oxaenediynes 6, 7 than their carbocyclic analogues 12 and 13 (the difference in ΔG‡(298) ∼ 1 kcal/mol) should be highlighted and discussed. All three parameters analyzed before correlate with higher reactivity of oxacycles. Thus, the cd-distance for oxaenediynes 6, 7 is shorter than for carbocycles 12 and 13; the deviation of (β + β′) from 360° is higher and the difference of sum of CCC bond angles between enedynes and TSs is lower. All these features might be the result of geometry distortions arose from difference in length of C−C and C−O bonds (∼0.1 Å) or

Figure 1. A plot of free activation energy vs cd-distance values for benzothiophene-fused enediynes (BT), blue dots, benzene-fused enediynes (B), red dots and a cinnoline-fused enediyne (C), a green dot with data linear fitting for benzothiophene-fused enediynes, blue line, benzene-fused enediynes, red line, and for all structures without separation, black line. 2791


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Figure 2. Exploration of different reactivity for benzene- and benzothiophene-fused enediynes in the Bergman cyclization.

Figure 3. A plot of free activation energy vs (360 − (β + β′)) values for benzothiophene-fused enediynes (BT), blue dots, benzene-fused enediynes (B), red dots and a cinnoline-fused enediyne (C), a green dot with data linear fitting for benzothiophene-fused enediynes, blue line, benzene-fused enediynes, red line, and for all structures without separation, black line. Figure 4. A plot of free activation energy vs difference of sum of bond angles (β, β′, δ, δ′) in enediyne and TS for benzothiophene-fused enediynes (BT), blue dots, benzene-fused enediynes (B), red dots and a cinnoline-fused enediyne (C), a green dot with data linear fitting for benzothiophene-fused enediynes, blue line, benzene-fused enediynes, red line, and for all structures without separation, black line.

probably because of endocyclic hyperconjugation. It has been found earlier that endocyclic propargylic C−O bond affects oxacyclooctynes stability and reactivity with azides leading to decrease in activation energies due to facilitating of alkyne bending by effect of endocyclic hyperconjugation.78,79 However, in the case of analysis based on geometries and strain of enediynes and TSs, electronic factors are discounted while electronic parameters influence the reactivity of enediynes significantly,32,37 It has been estimated that electron-withdrawn groups (EWG) attached directly to triple bonds facilitate the cyclization of enediynes.80 Acceleration effect of EWG has been found for para-substituted diethynylbenzenes,81 ortho-substituted ones (electronic ortho-effect),74 for cyclic enediynes bearing EWG in a propargylic position82 and for enediynes fused to acceptor heterocycles.70,83 In contrast enediynes with EWG at a vinyl position possessed less reactivity in the Bergman cyclization.84 Therefore, it should be particularly emphasized that only the activation energy values, which reflect all structural and electronic parameters, should be taken into account for the

prediction and comparison of enediynes reactivity in the Bergman cyclization. Therefore, a scale of relative reactivity of benzothiophene-fused enediynes was built on the basis of the calculated values of free activation energies (Table 1, Figure 5). Calculations revealed that additional annulation of benzothiophene-fused 10-membered enediyne cycle with a benzene ring provides compound 10 with free activation energy value of 21.7 kcal/mol, which is close to the ΔG‡(298) for dibenzoenediyne 11 (23.7 kcal/mol) (Table 1, entries 3, 4). With reference to Table 1, it can be seen that compound 10 and 11 lay between highly reactive and unstable 9-membered enediynes 8, 9 (Entries 1, 2) and quite reactive while stable under workup oxacycles 6, 7 fused to a benzothiophene (Entries 5, 6). Enediyne 11 is the only known example of dibenzene-fused 2792


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Figure 5. Scale of relative reactivity for benzothiophene-fused enediynes in the Bergman cyclization.

Scheme 4. Synthesis of Starting Co2(CO)6-Enediyne Complexes

bond is orthogonal to the plane of the macrocycle, whereas in the case of formylenediyne CO moiety lays in plane of the macrocycle, that may influence some transannular interaction of CH2 hydrogen atoms and result in the difference of ΔG‡(298) values. Taking also into account lower for ∼1 kcal/mol activation barriers for oxaenediynes 6, 7 in the Bergman cyclization than for carbocyclic analogues 12 and 13 (Table 1, Entries 5, 6 and 7, 8) both cycles 12, 13 are expected to be slightly more stable and less reactive in the Bergman cyclization than oxacycles 6, 7 which were found to be stable enough during isolation and storage while still active producing 20% of single strand cleavage of PM2 DNA being incubated at 37 °C only for 30 min at a 4 mM concentration range.41 Therefore, compounds 12, 13 were chosen as the second and the third synthetic target structures from the opposite end of the relative stability/reactive scale for enediynes fused to a benzothiophene (Figure 5). Synthesis of Enediynes. Following the approach discussed in the Introduction (5-methoxypenta-1,3-diyn-1-yl)trimethylsilane 18 was used to obtain the key 3-iodo-2(methoxymethylethynyl)benzothiophene 20 by the Sonogashira coupling86−88 and the electrophile-assisted cyclization89−91 as it has been described previously for the synthesis of oxacycle 7.41 The second in the synthetic sequence Sonogashira coupling of iodothiophene 20 with enyne 21b and with TMS-alkyne 21a under one-pot TMS-deprotection

enediynes, which underwent the spontaneous Bergman cyclization during the last synthetic step, i.e., alkylation of corresponding diacetylid anion, derived from bis(ethynyl)benzene and butyllithium, with 1,2-phenylenedimethanol di-ptoluenesulfonate.69 Taking into account that the Nicholas reaction allows to avoid highly reactive reagents during the last synthetic step, benzothiophene-fused analogue 10, was chosen as the most reactive enediyne for the experimental verification of the reactivity scale (Figure 5). The introduction of MeOgroups into benzene ring was necessary to increase its nucleophilicity in order to assist the Nicholas macrocyclization. According to the DFT calculations it was concluded that the formyl derivative 15 is even less reactive than known OHsubstituted benzene- 17 and cinnoline-fused 14 enediynes (Entries 9−11). The latter one underwent the Bergman cyclization in i-PrOH at 75 °C with T1/2 ∼ 4 h 30 min and produced 50% of single strand cleavage of ϕX174 plasmid DNA at 4 mM concentration range after 24 h at 40 °C.70 At the same time fluoroisopropyl- 12 and isopropenyl-substituted 13 enediynes should be more reactive than cinnolinoenediyne 14 (entries 7−9). The difference in free activation energies for isopropenyl- 13 and formylenediyne 15 of 0.9 kcal/mol is of special interest. The reason may be found in the geometry of the most stable conformers of isopropenyl- and formylenediynes used for the calculation of free activation energies, which differ significantly.85 Thus, for isopropenylenediyne the exocyclic double 2793


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The Journal of Organic Chemistry Scheme 5. Synthesis and the Spontaneous Bergman Cyclization of 10-Membered Enediyne 10

Scheme 6. Nicholas Macrocyclization of Co-Complex 23ba

conditions92 afforded two acyclic enediynes 22a,b in excellent yields (Scheme 4). The complexation of both acyclic enediynes 22a,b with Co2(CO) 8 proceeded in high regioselectivity within a MeOCH2-substituted triple bond affording Co2(CO)6-complexes 23a,b (Scheme 4). The regioselectivity observed is in a good accordance with known facts that more stable complexes are formed with less electron-enriched triple bond because of the complexes extra stabilization by enhanced back-donation from the Co d-orbitals to the π* MO of the triple bond.93,94 The regioselectivity of complexation also fully corresponds with the regioselectivity observed for other MeOCH2-substituted enediynes.41 It is important to keep in mind that the Co-complex 23b is the common starting compound for both target structures 12 and 13, because the formation of both isopropenyl and Fisopropyl moieties has been observed during the Nicholas cyclization depending on the nature of starting materials and acids.95−98 Therefore, with two starting Co-complexes for the Nicholas cyclization in hand we were ready to synthesize target 10-memered enediynes. The cyclization of aryl-substituted complex 23a was carried out using BF3·OEt2 under high dilution conditions. The desired 10-membered complex 24 was isolated as a main product in 23% yield (Scheme 5).99 An attempt to improve the yield of 24 using Brönsted acid (HBF4·OEt2) for the generation of a Coprotected propargylic cation failed: a complex mixture of the desired macrocycle and byproducts was obtained. The mildest known decomplexation conditions, which have been developed especially for the deprotection of cobalt complexes of enediynes, involve the use of tetrabutylammonium fluoride (TBAF).100 The treatment of the Co-complex 24 with TBAF at room temperature did not give the target enediyne 10. The spontaneous Bergman cyclization of compound 10 took place immediately followed by the decomplexation; therefore, it was possible to isolate only polyaromatic compound 25 in 14% yield instead of desired 10membered cycle 10 (Scheme 5). To improve the yield of the compound 25 the decomplexation was carried out in i-PrOH as an “H”-donor source. Surprisingly the reaction did not proceed at all in this case. The replacement of i-PrOH with 1,4cyclohexadiene in THF allowed the Bergman cyclization product 25 to be isolated in 28% yield (Scheme 5). For the synthesis of enediynes 12 and 13 the Nicholas-type macrocyclization of Co-complex 23b through the isobutenyl group was carried out initially using BF3·OEt2. Previously these conditions for the cyclization resulted in the formation of both isopropenyl and fluoroisopropyl groups depending on the structure of starting compounds.95,97,98 In the case of Cocomplex 23b the reaction gave both expected Co-complexes 26, 27 along with the OH-substituted macrocycle 28 (Scheme 6).

Reagents and conditions: (A) BF3·OEt2 (1.05 equiv), 0 °C to rt, 4 h; (B) HBF4·OEt2 (4.0 equiv), −10 to 0 °C, 8 h.

a

The replacement of the Lewis acid with HBF4·OEt2 led to the yield increase of Co-complex of F-isopropyl enediyne 26 up to 30%, while the yield of the compound 27 decreased to 3%. This result correlate with the reported earlier for the Nicholas cyclization through dialkyl-substituted double bond.96 However, this conditions also afforded macrocyclic byproducts with hydrated Co-free triple bond 29, 30 (Scheme 6).101 Notably, that the similar hydration of a triple bond has been observed previously under HBF4-promoted substitution of a triazene function in alkynylaryltriazenes with a fluorine.102 We also noticed that the formation of OH-substituted macrocycle 28 was not observed when HBF4·OEt2 was employed. The final deprotection of both 10-membered Co-complexes with fluoroisopropyl 26 and isopropenyl 27 groups using anhydrous TBAF solution in THF proceeded smoothly giving two stable 10-membered enediynes 12, 13 (Scheme 7). Scheme 7. Co-Decomplexation in the Synthesis of 10Membered Enediynes 12, 13

The X-ray data obtained for enediyne 12 gave the cd-distance value of 3.38 Å (Figure 6), which differs from the calculated one for 0.05 Å (3.43 Å, Table 1).99 Thus, the Nicholas macrocylization using isobutenyl nucleophilic function was found to be more suitable for the synthesis of fluoroisopropyl-substituted enediyne 12 than for another synthetic target 13. Despite the yield of F-isopropyl 2794


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subtracting the RT value affording ΔH‡(298) = 26.4 ± 1.0 and 25.8 ± 0.6 kcal/mol.110 The obtained values of activation enthalpy are in a good agreement with calculated one for enediyne 12 (ΔH‡(298) = 26.7 kcal/mol).111 In order to obtain the second experimental point to verify the developed scale of enediynes relative stability/reactivity we chose oxaenediyne 7, which was synthesized in four steps starting from 3-iodo-2-ethynylbenzothiophene by the procedure described recently.41 The obtained data revealed the Ea value of 25.1 ± 0.6 kcal/mol and ΔH‡(298) of 24.5 ± 0.6 kcal/ mol, which is also in good agreement with the calculated enthalpy of activation (25.0 kcal/mol). Notice that Tonset obtained previously for the oxaenediyne 7 and its isomer 6 at a heating rate of 20 K/min differ from each other for ∼20 °C, despite the close values of calculated free activation energies (Entries 5 and 6, Table 1).41 However, current measurements for enediyne 7 gave higher values of Tonset. Thus, Tonset at heating rate of 15 K/min was found to be 83 °C.110 We also found, that despite two sets of measurements for the compound 12 gave close values of Ea, the values of Tonset and Tpeak obtained after two runs at four different heating rates differed for ∼23−27 °C and for ∼7−8 °C, respectively.110 Therefore, one can conclude that express method for the evaluation of enediynes reactivity by DSC based on measurements of Tonset at a single heating rate106 should be applied with caution in order to avoid some misunderstandings. Therefore, the Ea values obtained from the DSC measurements should be used rather than Tonset for the comparing of reactivity within the series of enediynes. The data obtained illustrate quite a good verification of developed scale of enediynes relative reactivity which reflects even minimal differences in activation parameters (∼1 kcal/ mol). Therefore, we assume that DFT calculation of activation parameters for the Bergman cyclization of enediynes using B3LYP and BS-UB3LYP/6-31++g(d,p) level can be successfully used for newly designed enediynes without special triggering futures with a desired level of stability/reactivity balance. Biological Studies. Finally, the ability of enediyne 12 to induce DNA damage was analyzed using plasmid cleavage assay. Despite the fact that an enediyne moiety is supposed to be responsible for the DNA damage, a benzothiophene ring may impart intercalation ability to the whole enediyne molecule that is also possible mechanism for the DNA disruption. This suggestion is made on the base of known fact that small flat heteroindene scaffolds supply to biomolecules intercalation ability.112 This fact has an important bearing on choosing control standard. Therefore, a glycopeptide antibiotic Zeocin known as an intercalating DNA-damaging agent113 was taken as a positive control. Solutions of enediyne at concentration of 0.125, 0.25, 0.5, 1, and 2 mM were prepared in 70% aqueous DMSO because of poor solubility of enediyne 12 at higher concentration of water. The solutions of Zeocin at the same concentration range were prepared in PBS buffer, because being dissolved in 70% aqueous DMSO Zeocin was found to be inactive as a DNA cleavage agent. A period of 33 hours was chosen as an incubation time at 37 °C. The obtained data revealed that enediyne is able to cleave supercoiled plasmid producing open circular and linear forms by induction of DNA strand breaks. The DNA cleavage ability of enediyne observed is comparable to the one demonstrated by Zeocin (Figure 7). It is important that unlike Zeocin which induced only single

Figure 6. Molecular structure of 10-membered enediyne 12.

substituted Co-complex 26 on the macrocyclization step did not exceed 30%, the applied synthetic sequence allowed fluoroisopropyl 10-membered enediyne 12 to be accessible within six synthetic steps in 13% overall yield. Taking into account the synthetic accessibility of F-enediyne 12 and the widespread interest in fluorinated organic compounds103−105 and unique pharmacological properties of fluorinated molecules,103 we decided to concentrate on properties studying of Fisopropylenediyne 12. The macrocylization of Co-complex 23b in larger scale under conditions B (Scheme 7) allowed fluorosubstituted 10membered cycle 26 to be obtained in quantities enough for further kinetic and biological experiments. Of special note is that the enediyne 12 is stable while handling and in storage under Ar at −18 °C for months, while under heating in isopropanol at 100 °C for 1 h, enediyne 12 affords a polyaromatic product 31 in 85% yield (Scheme 8). Scheme 8. Bergman Cyclization of 10-Membered Enediyne 12

Kinetic Studies. Then we turned to kinetic experiments for the measurement of the Bergman cyclization activation energy for the enediyne 12. The DSC technique has been employed previously for this purpose for the series of ortho-substituted diethynylbenzenes,74 and in this case could be a good express alternative for kinetic measurements of enediynes reactivity in solution. We suppose that the reaction product of the Bergman cyclization in solid state is a polyaromatic polymer, because it is known that the radical polymerization follows the Bergman cyclization of enediynes under heating in a heating bath set at their peak DSC temperature.106 However, one should keep in mind other possible processes that may occur under heating of enediynes in neat, i.e., dimerization of enediynes with expected lower activation barriers compared to the Bergman cyclization activation energies.107 The formation of biradicals of a benzofulvene-type was also discussed.108 These processes, especially dimerization, could be a reason for overestimated data for some enediyne derivatives obtained by DSC.74 Kinetic DSC experiments for enediyne 12 in solid state were performed at four different heating rates as two sets of measurements. The activation energy for the Bergman cyclization was determined by the ASTM E698 standard procedure109 using the Arrhenius plot that gave Ea value of 27.0 ± 1.0 kcal/mol and 26.4 ± 0.6 kcal/mol. The Ea values can be converted to the enthalpy of activation (ΔH‡(298)) by 2795


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reactions were purchased from commercial suppliers. Catalysts Pd(PPh3)4 and Pd(PPh3)2Cl2 and Co2(CO)8 were purchased from Sigma-Aldrich. Solvents were dried under standard conditions; chemicals were used without further purification. 3-Iodo-2-(3methoxyprop-1-yn-1-yl)benzo[b]thiophene (20),41 trimethyl[3(3,4,5-trimethoxyphenyl)-1-propynyl]silane (21a)114 and 6-methylhept-5-en-1-yne (21b)115 were synthesized by known procedures without any modification. All reactions were carried out under argon in oven-dried glassware. Evaporation of solvents and concentration of reaction mixtures were performed in vacuo at 25−35 °C on a rotary evaporator. Thin-layer chromatography (TLC) was carried out on silica gel plates (Silica gel 60, UV 254) with detection by UV or staining with a basic aqueous solution of KMnO4. Normal-phase silica gel (Silica gel 60, 230−400 mesh) was used for preparative column chromatography. Preparative thin-layer chromatography (PTLC) was performed on precoated glass TLC plates with Silica 60 UV254 (thickness of layer 1 mm). Melting points (mp) determined are uncorrected. Differential scanning calorimetry (DSC) experiments were carried out with a DSC calorimeter. DSC samples (0.3−0.8 mg) were investigated in 40 μL aluminum crucibles with pierced lids at different heating/cooling rates from 5 to 20 °C/min under a flow of nitrogen (50 mL/min). Compounds 7 and 12 were heated from 10 to 200 °C, followed by cooling to 10 °C and heating to 200 °C for the second time. 1H, 19F and 13C NMR spectra were recorded at 400, 376.5, and 100 MHz, respectively, at 25 °C in CDCl3 without the internal standard. The 1H NMR data are reported as chemical shifts (δ), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad), coupling constants (J, given in Hz), and number of protons. The 19F NMR data are reported as chemical shifts (δ). The 13 C NMR data are reported as the chemical shifts (δ) with coupling constant J(C−F) for F-containing compounds. Chemical shifts for 1H and 13C are reported as δ values (ppm) and referenced to residual solvent (δ = 7.26 ppm for 1H; δ = 77.16 ppm for 13C). The 19F spectra are referenced through the solvent lock (2H) signal according to IUPAC recommended secondary referencing method. Chemical shifts for 19F are reported as δ values (ppm) relative to CCl3F. Highresolution mass spectra (HRMS) were determined using electron impact ionization (EI), 70 eV, or fast atom bombardment (FAB) ionization with 3-nitrobenzyl alcohol (3-NBA) matrix. These mass spectra were measured using a double-focusing sector field instrument with reversed Nier−Johnson geometry. HRMS were also measured using electrospray ionization (ESI) in the mode of positive ion registration with a TOF mass analyzer. The single-crystal X-ray diffraction studies were carried out on a diffractometer at 100(2) K using Cu Kα radiation (λ = 1.54180 Å). Using Olex2,116 the structure was solved with the Superflip structure solution program117 using Charge Flipping and refined with the ShelXL refinement package118 using Least Squares minimization. 2-(3-Methoxyprop-1-yn-1-yl)-3-{3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl}benzo[b]thiophene (22a). To a stirred solution of the 3-iodo-2-(3-methoxyprop-1-yn-1-yl)benzothiophene 20 (566 mg, 1.73 mmol) in DMF (10.0 mL) were added Pd(PPh3)4 (99.7 mg, 86 μmol, 5 mol %), CuI (33 mg, 0.17 mmol, 10 mol %) and KF (500 mg, 8.63 mmol, 5 equiv). The reaction vial was sealed, evacuated, and flushed with Ar several times. Then MeOH (552 mg, 17.3 mmol, 0.700 mL, 10 equiv) followed by the solution of TMStrimetoxyphenylacetylene 21a (624 mg, 2.24 mmol, 1.3 equiv) in DMF (2.5 mL) were added. The reaction mixture was allowed to stir at 40 °C for 20 h. The reaction mixture was cooled, poured into a saturated solution of NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with a saturated solution of NH4Cl and two times with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Purification by column chromatography on silica gel using cyclohexane/ethyl acetate (5:1) as the eluent gave 22a (631 mg, 90%) as a beige solid, mp 78−79 °C. 1H NMR (400 MHz, CDCl3, δ) 3.44 (s, 3H), 3.85 (s, 3H), 3.88 (s, 6H), 3.94 (s, 2H), 4.40 (s, 2H), 6.73 (s, 2H), 7.39−7.43 (m, 2H), 7.71−7.76 (m, 1H), 7.86−7.90 (m, 1H). 13C NMR (100 MHz, CDCl3, δ) 26.5, 56.3, 57.9, 60.7, 61.0, 76.2, 79.6, 94.7, 94.9, 105.2, 122.3, 123.49, 123.51, 125.0, 125.2, 126.4, 132.2,

Figure 7. Electrophoregrams of pPIC9-AOX1-PHO5 plasmid after exposure to 0.125, 0.25, 0.5, 1, and 2 mM concentrations of enediyne 12 (A) and Zeocin (B). CCC, covalently closed circular plasmid; OC, open circular form; L, linear form; M, 1 kb DNA ladder (Evrogen). Relative band intensity on electrophoregrams was analyzed for 5 replica probes for each concentration of enediyne 12 (C) and Zeocin (D). Error bars represent the standard error of the mean.

strand DNA breaks enediyne 12 in a concentration range of more than 0.5 mM demonstrated ability to cleave DNA through both single and double strands.

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CONCLUSIONS The scale of relative reactivity for the series of cyclic enediynes was developed using DFT calculations (B3LYP and BSUB3LYP/6-31++g(d,p) level) of the Bergman cyclization free activation energy and verified by data obtained experimentally in kinetic DSC experiments. The scale allowed predicting the border structures in the term of stability/reactivity ratio for benzothiophene annulated 10-membered enediynes which were synthesized using the Nicholas-type macrocyclization through aryl and butenyl nucleophilic groups. The high reactivity of benzothiophen-arene-fused enediyne undergoing the spontaneous Bergman cyclization at room temperature justifies the upper limit of the scale of 21.5 kcal/mol. Enediyne bearing Fisopropyl substituent with free activation energy of 27.2 kcal/ mol from the other end of the reactivity scale were found to be synthesizable while moderately reactive in the Bergman cyclization, which is also in a very good agreement with the predicted reactivity. 10-Membered F-isopropyl enediyne induced DNA damage giving both open circular and linear forms of DNA. The activity of F-isopropyl enediyne is of the same range as for an intercalating DNA-damaging agent Zeocin. On the basis of all experimental and calculated data obtained, one can conclude that for choosing of stable enediyne structures while reactive in the Bergman cyclization and DNA cleavage assays without special triggering, free activation energy for the Bergman cyclization should lay in the range of ∼26−27 kcal/mol. The refinement of borders of free activation energy gap for an “optimal structure” with invoking of other heteroenediynes and enediynes fused to other heterocycles is under investigation.

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EXPERIMENTAL SECTION

General Information and Methods. Solvents, reagents, and chemicals (o-iodothioanisole, propargyl alcohol, ethynyltrimethylsilane, 3,4,5-trimethoxybenzyl alcohol and but-3-yn-1-ol) used for 2796


Article


δ) 3.53 (d, J = 18.4 Hz, 1H), 3.85 (s, 3H), 3.86 (s, 3H), 3.97 (s, 3H), 4.08 (d, J = 18.4 Hz, 1H), 4.45 (d, J = 13.6 Hz, 1H), 4.66 (d, J = 13.6 Hz, 1H), 6.49 (s, 1H), 7.32−7.40 (m, 2H), 7.70−7.76 (m, 2H). 13C NMR (100 MHz, CDCl3, δ) 26.8, 33.6, 56.2, 60.0, 60.8, 78.7, 80.0, 98.9, 102.5, 108.5, 116.0, 122.6, 123.1, 125.3 (2C, two signals overlap), 126.5, 130.8, 138.1, 139.5, 141.4, 151.5, 152.5, 153.5, 198.9, 199.8. HRMS (FAB) (m/z) calcd for C29H19Co2O9S [M + H]+, 660.9408, found 660.9406. Single crystals of 24 were grown from n-hexane/ethyl acetate (25:1) solution by slow evaporation of the solvent until visual beginning of crystallization. A suitable crystal was selected. Dark-red crystal. C29H18Co2O9S (660.35), monoclinic, a = 14.7863(3) Å, b = 7.78776(18) Å, c = 23.6336(4) Å, β = 90.3536(18)°, V = 2721.41(10) Å3, T = 100(2), space group P21/n (no. 14), Z = 4, μ(Cu Kα) = 10.748, 27561 reflections measured, 4915 unique (Rint = 0.0591) which were used in all calculations. The final wR2 was 0.1014 (all data) and R1 was 0.0544 (>2sigma(I)). Crystallographic data (excluding structure factors) for the structures reported in this work have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 1529628. Copies of the data can be obtained free of charge on application to The Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. (fax: int. code +(1223)336−033; e-mail: [email protected]). Synthesis of 8,9,10-Trimethoxy-7,12-dihydroanthra[2,3-b]benzo[d]thiophene 25 (One-Pot Deprotection of Complex 24/ Bergman Cyclization). Method A. To a solution of complex 24 (38 mg, 57 μmol) in THF (2.5 mL) 1.00 M solution of TBAF in THF (0.115 mmol, 0.115 mL, 2 equiv) was added. The reaction mixture was stirred at room temperature until completion of the reaction (TLC, 1.5 h). Then the solvent was evaporated under reduced pressure and the crude product was purified by column chromatography to give 3 mg of 25 (14%) as a bright yellow oil. 1H NMR (400 MHz, CDCl3, δ) 3.88 (s, 3H), 3.89 (s, 3H), 3.95 (s, 3H), 4.06 (br s, 4H), 6.70 (s, 1H), 7.40−7.47 (m, 2H), 7.80 (s, 1H), 7.81−7.85 (m, 1H), 8.05 (s, 1H), 8.11−8.15 (m, 1H). 13C NMR (100 MHz, CDCl3, δ) 29.6, 36.7, 56.3, 61.1, 61.2, 107.0, 120.0, 121.4, 121.6, 122.3, 123.0, 124.4, 126.5, 132.6, 133.7, 134.1, 135.6, 136.2, 137.6, 139.7, 140.7, 150.9, 152.0. HRMS (EI) (m/z) calcd for C23H20O3S [M]+, 376.1128, found 376.1128. Method B. To a solution of complex 24 (23 mg, 35 μmol) in THF (1.1 mL) 1,4-cyclohexadiene (80.0 mg, 1.0 mmol, 29 equiv) followed by 1.00 M solution of TBAF in THF (70.0 μmol, 70.0 μL, 2 equiv) was added. The reaction mixture was stirred at room temperature for 1.5 h. Then the solvent was evaporated under reduced pressure and the crude product was purified by column chromatography to give 3.7 mg of 25 (28%) as a bright yellow oil. BF3·OEt2 Promoted Cyclization of 23b. To an argon-flushed, cooled (−78 °C) stirred solution of acyclic enediyne Co-complex 23b (104 mg, 0.175 mmol) in DCM 123 mL (c = 0.0014 M) was added BF3·OEt2 (26.0 mg, 23.0 μL, 0.181 mmol). The resulting mixture was stirred at this temperature for 1 h, then it was allowed to warm to room temperature and was stirred at room temperature until the reaction was complete (TLC, 3 h). Then the reaction mixture was cooled to 0 °C and quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated, washed with water, dried with anhydrous Na2SO4, and concentrated under reduced pressure to yield a crude mixture of products, which was separated by column chromatography using petroleum ether/ethyl acetate (25:1 → 10:1) as the eluent to give 21 mg of complex 26 (21%), 9.5 mg of 27 (10%), 19.5 mg of 28 (19%). η2-Co2(CO)6-Complexed Fluoroisopropyl Enediyne 26. Dark red solid. The complex decomposed without melting upon heating to 300 °C. 1H NMR (400 MHz, CDCl3, δ) 1.40 (d, J = 22.0 Hz) and 1.46 (d, J = 22.0 Hz) (6H), 1.67−1.88 (m, 2H), 2.37 (br s, 1H), 2.70 (br s, 2H), 3.36−3.60 (m, 2H), 7.31−7.47 (m, 2H), 7.62−7.87 (m, 2H). 13C NMR (100 MHz, CDCl3, δ) 19.4, 22.7 (d, 2J = 25.0 Hz), 26.6 (d, J = 25.0 Hz), 30.7 (d, J = 8.7 Hz), 37.8 (d, J = 4.3 Hz), 52.6 (d, J = 20.6 Hz), 79.6, 80.0, 98.0 (d, J = 169.8 Hz), 99.1, 102.9, 116.2, 122.5, 123.2, 125.35, 125.43, 138.8, 139.5, 150.6, 199.3. 19F NMR (376.5 MHz, CDCl3, δ) −133.2. HRMS (FAB) (m/z) calcd for C23H17Co2O4FS [M − 2CO]+, 525.9490, found 525.9491.

137.0, 138.6, 139.0, 153.5. HRMS (EI) (m/z) calcd for C24H22O4S [M]+, 406.1233, found 406.1232. 2-(3-Methoxyprop-1-yn-1-yl)-3-(6-methylhept-5-en-1-yn-1yl)benzo[b]thiophene (22b). To a stirred solution of the 3iodobenzothiophene 20 (440 mg, 1.34 mmol) in DMF (10.0 mL) were added Pd(PPh3)4 (77.5 mg, 67 μmol, 5 mol %), PPh3 (35.2 mg, 0.13 mmol, 10 mol %), and diisopropylamine (1.09 g, 1.50 mL, 10.73 mmol, 8.00 equiv). The reaction vial was evacuated and flushed with Ar several times. After that, CuI (38.3 mg, 0.2 mmol, 15 mol %) was added, and the reaction vial was sealed and flushed with Ar. Solution of 6-methylhept-5-en-1-yne (21b) (290 mg, 2.68 mmol, 2 equiv) in DMF (4.0 mL) was added with a syringe. The reaction mixture was allowed to stir at 50 °C for 46 h. Then the reaction mixture was cooled, poured into a saturated solution of NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with a saturated solution of NH4Cl and two times with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Purification by column chromatography on silica gel using cyclohexane/ethyl acetate (50:1) as the eluent gave 22b (359 mg, 87%) as an orange oil. 1H NMR (400 MHz, CDCl3, δ) 1.68 (s, 3H), 1.76 (s, 3H), 2.36−2.41 (m, 2H), 2.57 (t, J = 7.2 Hz, 2H), 3.50 (s, 3H), 4.44 (s, 2H), 5.29−5.34(m,, 1H), 7.37−7.44 (m, 2H), 7.69−7.73 (m, 1H), 7.83−7.87 (m, 1H). 13C NMR (100 MHz, CDCl3, δ) 18.0, 20.5, 25.9, 27.7, 57.8, 60.7, 73.8, 79.7, 94.5, 97.7, 122.1, 122.9, 123.7, 124.1, 124.2, 125.1, 126.3, 133.4, 138.5, 139.1. HRMS (EI) (m/z) calcd for C20H20OS [M]+, 308.1229, found 308.1229. Synthesis of Co-Complexes 23. To a solution of enediyne 22a,b in dry toluene (c = 0.0056 M) was added dicobalt octacarbonyl (1.05 equiv), and the mixture was stirred under argon at room temperature for 45 min −1.5 h. After completion of the reaction, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography. Complex 23a. Complex 23a was synthesized according to the general procedure from enediyne 22a (72.0 mg, 0.177 mmol) and dicobalt octacarbonyl (68.0 mg, 0.200 mmol). Reaction time was 45 min. Purification of the crude product by column chromatography using cyclohexane/ethyl acetate (5:1) as the eluent gave 23a (120 mg, 98%) as a black oil. 1H NMR (400 MHz, CDCl3, δ) 3.50 (s, 3H), 3.86 (s, 3H), 3.88 (s, 6H), 3.90 (s, 2H), 4.78 (s, 2H), 6.69 (s, 2H), 7.37− 7.40 (m, 2H), 7.71−7.73 (m, 1H), 7.85−7.88 (m, 1H). 13C NMR (100 MHz, CDCl3, δ) 26.9, 56.2, 59.1, 61.0, 73.5, 95.9, 97.7, 105.1, 118.2, 122.3, 123.0, 125.2, 125.8, 131.9, 136.9, 138.8, 141.3, 145.4, 153.5, 199.0 (two signals overlap with others). HRMS (FAB) (m/z) calcd for C30H22Co2O10S [M]+, 691.9592, found 691.9591. Complex 23b. Complex 23b was synthesized according to the general procedure from enediyne 22b (345 mg, 1.12 mmol) and dicobalt octacarbonyl (402 mg, 1.17 mmol). Reaction time was 1.5 h. Purification of the crude product by column chromatography using cyclohexane/ethyl acetate (50:1) as the eluent gave 23b (619 mg, 93%) as a black oil. 1H NMR (400 MHz, CDCl3, δ) 1.67 (s, 3H), 1.75 (s, 3H), 2.35−2.41 (m, 2H), 2.55 (t, J = 7.5 Hz, 2H), 3.59 (s, 3H), 4.88 (s, 2H), 5.28 (t, J = 5.9 Hz, 1H), 7.35−7.42 (m, 2H), 7.70 (d, J = 7.2 Hz, 1H), 7.82 (d, J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ) 18.0, 20.8, 25.9, 27.5, 59.2, 73.6, 75.2, 77.8, 95.9, 100.8, 118.8, 122.2, 122.9, 123.2, 125.2, 125.7, 133.5, 138.8, 141.3, 144.6, 199.1. HRMS (EI) (m/z) calcd for C26H20Co2O7S [M]+, 593.9588, found 593.9587. Co-Complex 24. To an argon-flushed, cooled (−10 °C) stirred solution of acyclic enediyne Co-complex 23a (210 mg, 0.303 mmol) in DCM (233 mL, c = 0.0013 M) was added BF3·OEt2 (45.0 mg, 40.0 μL, 0.316 mmol, 1.05 equiv). After 10 min the cooling bath was removed and the reaction mixture was stirred until the reaction was complete (TLC, 2 h). Then the reaction mixture was cooled to 0 °C and quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated, washed with water, dried with anhydrous Na2SO4, and concentrated under reduced pressure to yield a crude mixture of products, which was purified by column chromatography two times: first time using petroleum ether/ethyl acetate (10:1) and second time with petroleum ether/ethyl acetate (25:1) to give 46 mg of complex 24 (23%) as a dark red solid. The complex decomposed without melting upon heating to 300 °C. 1H NMR (400 MHz, CDCl3, 2797


Article

The Journal of Organic Chemistry η2-Co2(CO)6-Complexed Isopropenyl Enediyne 27. Dark red solid. The complex decomposed without melting upon heating to 300 °C. 1H NMR (400 MHz, CDCl3, δ) 1.73−1.89 (m, 5H), 2.73−277 (m, 3H), 3.36 (dd, J = 15.0, 8.2 Hz, 1H), 3.57 (d, J = 15.0 Hz, 1H), 4.90 (br s, 1H), 4.94 (br s, 1H), 7.34−7.41 (m, 2H), 7.72 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 2H). 13C NMR (100 MHz, CDCl3, δ) 18.0, 20.3, 30.6, 37.8, 50.4, 79.1, 80.0, 98.3, 100.5, 112.0, 116.6, 122.5, 123.4, 125.4, 125.6, 138.7, 139.8, 147.3, 149.9, 199.5. HRMS (FAB) (m/z) calcd for C23H16Co2O4S [M − 2CO]+, 505.9428, found 505.9428. η2-Co2(CO)6-Complexed Hydroxyenediyne 28. Dark red solid. The complex decomposed without melting upon heating to 300 °C. 1 H NMR (400 MHz, CDCl3, δ) 1.29 (s, 3H), 1.32 (s, 1H), 1.34 (s, 3H), 1.70−1.79 (m, 1H), 1.96−2.02 (m, 1H), 2.08−2.12 (m, 1H), 2.57−2.65 (m, 1H), 2.68−2.75 (m, 1H), 3.46 (dd, J = 15.1, 5.5 Hz, 1H), 3.54 (dd, J = 15.1, 2.5 Hz, 1H), 7.33−7.40 (m, 2H), 7.72 (d, J = 7.4 Hz, 1H), 7.77 (d, J = 7.3 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ) 20.2, 26.2, 28.9, 32.1, 38.8, 54.3, 74.0, 79.2, 81.3, 100.5, 104.3, 116.5, 122.5, 123.2, 125.35, 125.40, 138.9, 139.4, 150.3, 199.5. HRMS (FAB) (m/z) calcd for C23H18Co2O5S [M − 2CO]+, 523.9533, found 523.9535. HBF4·OEt2 Promoted Cyclization of 23b. To an argon-flushed, cooled (−10 °C) stirred solution of acyclic enediyne Co-complex 23b (509 mg, 0.857 mmol) in DCM 650 mL (c = 0.0013 M) was added tetrafluoroboric acid diethyl ether complex (207 mg, 174 μL, 1.28 mmol, 1.5 equiv). The resulting mixture was stirred at this temperature for 1 h and then 3 h at 0 °C. Then additional amount of HBF4·OEt2 (124 mg, 104 μL, 0.77 mmol, 0.6 equiv) was added to the reaction mixture four times with an interval of 1 h. After the addition of the last portion the reaction mixture was stirred for 1 h at 0 °C and quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated, washed with water, dried with anhydrous Na2SO4, and concentrated under reduced pressure to yield a crude mixture of products, which was separated by column chromatography using petroleum ether/ethyl acetate (25:1 → 10:1) as the eluent to give 150 mg of complex 26 (30%), 16 mg of 27 (3%), 91 mg of 29 (18%), 20 mg of 30 (4%). η 2 -Co 2(CO)6 -Complex 29. Dark red solid. The complex decomposed without melting upon heating to 300 °C. 1H NMR (400 MHz, CDCl3, δ) 1.43 (d, J = 21.8 Hz) and 1.40 (d, J = 21.8 Hz) (6H), 1.64−1.74 (m, 2H), 1.81−2.02 (m, 2H), 2.15−2.25 (m, 1H), 2.92−3.01 (m, 2H), 3.14 (dd, J = 15.7, 9.1 Hz, 1H), 3.44 (dd, J = 15.7, 1.5 Hz, 1H), 7.34−7.44 (m, 2H), 7.71−7.75 (m, 1H), 7.95−8.00 (m, 1H). 13C NMR (100 MHz, CDCl3, δ) 23.2, 24.2 (d, J = 25.0 Hz), 26.5 (d, J = 25.0 Hz), 27.3 (d, J = 5.8 Hz), 37.3 (d, J = 5.6 Hz,), 43.0, 50.7 (d, J = 20.7 Hz), 78.9, 97.6 (d, J = 169.8 Hz), 100.5, 121.8, 124.0, 125.7, 126.0, 133.6, 138.7, 139.5, 148.7, 199.0, 203.1. 19F NMR (376.5 MHz, CDCl3, δ) −137.0 (s, 1F). HRMS (FAB) (m/z) calcd for C25H20Co2FO7S [M + H]+, 600.9572, found 600.9574. η 2 -Co 2(CO)6 -Complex 30. Dark red solid. The complex decomposed without melting upon heating to 300 °C. 1H NMR (400 MHz, CDCl3, δ) 1.19 (s, 3H), 1.20 (s, 3H), 1.61−1.68 (m, 1H), 1.70−1.83 (m, 2H), 1.85−1.95 (m, 1H), 2.17−2.29 (m, 1H), 2.94− 3.00 (m, 2H), 3.05 (dd, J = 15.9, 8.8 Hz, 1H), 3.21 (s, 3H), 3.49 (dd, J = 15.8, 1 Hz, 1H), 7.35−7.43 (m, 2H), 7.68−7.74 (m, 1H), 8.03−8.09 (m, 1H). 13C NMR (100 MHz, CDCl3, δ) 21.8, 23.3, 24.1, 27.8, 38.4, 49.0, 50.1, 79.5, 102.0, 121.6, 124.4, 125.7, 126.0, 132.7, 139.1, 139.3, 149.7, 199.1, 202.5. (FAB) (m/z) calcd for C26H23Co2O8S [M + H]+, 612.9772, found 612.9774. General Procedure for the Synthesis of Macrocycles 12, 13. To a solution of Co2(CO)6-complex of macrocycle 26 or 27 in THF 1.00 M solution of tetrabutylammonium fluoride in THF was added (1.8−2.6 equiv). The reaction mixture was stirred at 20 °C. After completion of the reaction (TLC control) a small amount of silica gel was added to the reaction mixture and the solvent was evaporated under reduced pressure. Crude product loaded on silica gel was purified by column chromatography. 9-(2-Fluoropropan-2-yl)-6,7,12,13-tetradehydrobenzo8,9,10,11-tetrahydrobenzo[b]cyclodeca[d]thiophene 12. Compound 12 was synthesized from 26 (76.0 mg, 0.130 mmol) and 1.00 M

solution of TBAF in THF (260 μL, 0.260 mmol) in THF (5.0 mL). Reaction time was 2.5 h. Purification of the crude product by column chromatography using petroleum ether/ethyl acetate (25:1) as the eluent gave 25.5 mg of 12 (66%) as a light red solid. The mp cannot be measured, because the Bergman cyclization occurs prior to melting. 1 H NMR (400 MHz, CDCl3, δ) 1.39 (d, J = 21.7 Hz, 6H), 1.87−2.00 (m, 1H), 2.07−2.17 (m, 1H), 2.27−2.37 (m, 2H), 2.42−2.50 (m, 1H), 2.67−2.80 (m, 2H), 7.34−7.42 (m, 2H), 7.72−7.77 (m, 2H). 13C NMR (100 MHz, CDCl3, δ) 22.2, 23.7 (d, J = 7.5 Hz), 24.0 (d, J = 25.0 Hz), 24.6 (d, J = 24.5 Hz), 32.2 (d, J = 6.2 Hz), 50.7 (d, J = 21.3 Hz), 78.4, 78.7, 97.5 (d, J = 169.6 Hz), 104.6, 106.2, 122.8 (2C, two signals overlap), 125.1, 125.8, 128.4, 129.7, 136.2, 138.2. 19F NMR (376.5 MHz, CDCl3, δ) −139.4 (s, 1F). HRMS (FAB) (m/z) calcd for C19H17FS [M]+, 296.1030, found 296.1028. Single crystals of 12 were grown from n-hexane/ethyl acetate (25:1) solution by slow evaporation of the solvent until the beginning of crystals’ formation. A suitable crystal was selected. Light red crystals, C19H17FS (296.38), crystal size 0.2 × 0.15 × 0.15 mm, monoclinic, space group P21/n (no. 14), a = 9.3050(3) Å, b = 13.9740(3) Å, c = 12.0297(4) Å, α = 90°, β = 108.745(4)°, γ = 90°, V = 1481.23(8) Å3, Z = 4, ρ = 1.329 Mg/m−3, μ(Cu Kα) = 1.941 mm−1, F(000) = 624.0. 9049 Reflections measured (10.018° ≤ 2Θ ≤ 144.988°), 2918 unique (Rint = 0.0269, Rsigma = 0.0270) which were used in all calculations, 192 parameters. The final R1 was 0.0372 (I > 2σ(I)) and wR2 was 0.1014 (all data). S = 1.055, largest diff. peak/hole = 0.37/−0.25 e Å−3. Crystallographic data (excluding structure factors) for the structures reported in this work have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 1487148. Copies of the data can be obtained free of charge on application to The Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. (fax: int. code +(1223)336−033; e-mail: [email protected]. ac.uk). 9-(Prop-1-en-2-yl)-6,7,12,13-tetradehydrobenzo-8,9,10,11tetrahydrobenzo[b]cyclodeca[d]thiophene 13. Compound 13 was synthesized from 27 (23.9 mg, 0.0430 mmol) and 1.00 M solution of TBAF in THF (110 μL, 0.110 mmol) in THF (2.50 mL). Reaction time was 1.5 h. Purification of the crude product by column chromatography using petroleum ether/ethyl acetate (50:1) as the eluent gave 13 (6.2 mg, 53%) as a beige solid. The mp cannot be measured, because the Bergman cyclization occurs prior to melting. 1H NMR (400 MHz, CDCl3, δ) 1.76 (s, 3H), 2.00−2.12 (m, 2H), 2.43− 2.51 (m, 1H), 2.54−2.58 (m, 2H), 2.63−2.75 (m, 2H), 4.72 (s, 1H), 4.78 (s, 1H), 7.32−7.41 (m, 2H), 7.73−7.78 (m, 2H). 13C NMR (100 MHz, CDCl3, δ) 19.6, 21.6, 27.2, 35.5, 49.4, 78.5, 78.6, 105.1, 106.5, 110.3, 122.76, 122.78, 125.1, 125.7, 128.5, 129.8, 136.3, 138.1, 149.2. HRMS (ESI) (m/z) calcd for C19H16AgS [M + Ag]+, 383.0018, found 383.0002. 8-(2-Fluoropropan-2-yl)-7,8,9,10-tetrahydrobenzo[b]naphtho[2,3-d]thiophene 31. The mixture of 12 (12 mg, 40.5 μmol) and isopropanol (12 mL) in a vial was sealed and degassed. Then the reaction mixture was stirred at 100 °C for 1 h and cooled to room temperature. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography using petroleum ether/ethyl acetate (50:1) as the eluent to give 31 (10.3 mg, 85%) as a white solid. mp 119−120 °C. 1H NMR (400 MHz, CDCl3, δ) 1.43 (d, J = 22.0 Hz, 6H), 1.49−1.60 (m, 1H) overlaps with signal of water, 2.00−2.18 (m, 2H), 2.72−2.80 (m, 1H), 2.94−3.142(m, 3H), 7.39−7.44 (m, 2H), 7.57 (s, 1H), 7.79−7.89 (m, 1H), 7.87 (s, 1H), 8.05−8.11 (m, 1H). 13C NMR (100 MHz, CDCl3, δ) 24.3 (d, J = 25.2 Hz), 24.6 (d, J = 5.5 Hz), 24.7 (d, J = 25.0 Hz), 30.1, 31.3 (d, J = 6.9 Hz), 44.5 (d, J = 22.4 Hz), 97.6 (d, J = 166.6 Hz), 121.3, 121.4, 122.80, 123.0, 124.3, 126.4, 133.5, 134.0, 135.6, 136.0, 137.1, 139.6. 19F NMR (376.5 MHz, CDCl3, δ) −140.4. HRMS (ESI) (m/z) calcd for C19H19AgFS [M + Ag]+, 405.0237, found 405.0222. 9-(2-Fluoropropan-2-yl)-6,7-didehydro-9,10,11,12tetrahydrobenzo[b]cyclodeca[d]thiophen-13(6H)-one (32). Compound 32 was synthesized from 29 (72.4 mg, 0.12 mmol) and 1.00 M solution of TBAF in THF (217 μL, 0.217 mmol) in THF (5.0 mL). Reaction time was 3 h. Purification of the crude product by column chromatography using petroleum ether/ethyl acetate (10:1) as 2798


Article

The Journal of Organic Chemistry the eluent gave 32 (34.8 mg, 92%) as a white solid. mp 184−185 °C. 1 H NMR (400 MHz, CDCl3, δ) 1.31 (d, J = 22.1 Hz), 1.40 (d, J = 21.8 Hz), 1.50−1.58 (m, 1H) overlaps with the signal of water, 1.81−1.93 (m, 2H), 2.27−2.38 (m, 1H), 2.40−3.57 (m, 3H), 2.82 (d, J = 17.0, Hz, 1H), 3.64−3.7 (m, 1H), 7.38−7.48 (m, 2H), 7.71−7.77 (m, 1H), 8.45−8.52 (m, 1H). 13C NMR (100 MHz, CDCl3, δ) 21.1 (d, J = 7.4 Hz), 22.9 (d, J = 25.1 Hz), 24.0, 25.9 (d, J = 24.9 Hz), 29.5 (d, J = 6.4 Hz), 40.8, 46.1 (d, J = 21.1 Hz), 78.7, 97.3 (d, J = 169.1 Hz), 107.5, 121.9, 125.4, 126.0, 126.4, 130.8, 137.5, 138.1, 140.6, 199.0. 19F NMR (376.5 MHz, CDCl3, δ) −136.4 (s, 1F). HRMS (ESI) (m/z) calcd for C19H19KFOS [M + K]+, 353.0772, found 353.0761. Kinetic Measurement for the BC of Enediynes 7 and 12 by DSC. Samples of 0.54−0.62 mg were heated under argon atmosphere (90 mL/min) in aluminum crucibles with pierced lid. Heating rates 5, 10, 15, 20 K/min were used. Energy of activation was determined by the ASTM E698 standard procedure.109 Plasmid Cleavage Assays for Enediyne 12. pPIC9-AOX1PHO5 (9130 bp) Plasmid119 (83.3 μg) was dissolved in PBS buffer (500 μL, 137 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4, 2 mM KH2PO4, pH 7.4) to a concentration of 166.6 ng/μL. The resulting solution (6 μL, 1 μg of plasmid) was added to concentrated solutions (0.178, 0.357, 0.714, 1.428, and 2.857 mM) of enediyne 24 in DMSO (14 μL) and Zeocin solutions of the same concentration range in PBS (14 μL) to obtain solutions of enediyne and Zeocin in concentration range of 0.125, 0.25, 0.5, 1, and 2 mM. All samples were incubated at 37 °C for 33 h and analyzed using electrophoresis in 1% (w/v) agarose gel. Images were taken with ChemiDoc MP system (BioRad). The results were analyzed with ImageJ and GraphPad Prism software.

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cial support. The research was carried out by using the equipment of the SPbSU Resource Centres: Centre for Magnetic Resonance, Thermogravimetric and Calorimetric Research Centre, Centre for Chemical Analysis and Materials Research, Centre for X-ray Diffraction Studies, Educational Resourse Center of Chemistry, Center for Molecular and Cell Technologies and Computer Centre. The authors are thankful to Dr. I. Chislova for the help with DSC measurements, Dr. A. Ivanov for the measurement of NMR spectra of Co-complexes, and Dr. I. Rodionov for the discussion of kinetic measurements.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b03258. Crystallographic data for compounds 12 and 24 (CIF) Copies of 1H, 13C, 19F NMR spectra for all compounds synthesized, details of kinetic studies of enediyne 7 and 12 by DSC with copies DSC thermograms, computational details, calculated bond angles (β−δ, β′−δ′) and deviations and difference of bond angles discussed, calculated enthalpies of activation, X-ray details for compounds 12 and 24 (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Natalia A. Danilkina: 0000-0002-1693-0056 Andrey M. Rumyantsev: 0000-0002-1744-3890 A. F. Khlebnikov: 0000-0002-6100-0309 Anastasia I. Govdi: 0000-0001-6403-8241 Stefan Bräse: 0000-0003-4845-3191 Irina A. Balova: 0000-0002-8593-4755 Author Contributions ∥

Anna G. Lyapunova and Natalia A. Danilkina contributed equally to this work. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study was supported by Saint Petersburg State University (SPbSU) (grant numbers 12.40.537.2017 and 12.40.515.2017) and by RFBR grant 17-03-00910. A.G.L. acknowledges the Deutscher Akademischer Austauschdienst (DAAD) for finan2799


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