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A Synthetic and Mechanistic Investigation of the Chromium Tricarbonyl-Mediated Masamune−Bergman Cyclization. Direct Observation of a Ground-State Triplet p-Benzyne Biradical Kai E. O. Ylijoki, Séverine Lavy, Angelika Fretzen,† and E. Peter Kündig* Department of Organic Chemistry, University of Geneva, 30 Quai E. Ansermet, CH-1211 Geneva 4, Switzerland

Théo Berclaz Department of Physical Chemistry, University of Geneva, 30 Quai E. Ansermet, CH-1211 Geneva 4, Switzerland

Gérald Bernardinelli and Céline Besnard Laboratory of X-ray Crystallography, University of Geneva, 24 Quai E. Ansermet, CH-1211 Geneva 4, Switzerland S Supporting Information *

ABSTRACT: A new room-temperature chromium tricarbonylmediated cycloaromatization of enediynes is reported. The reaction occurs with both cyclic and acyclic enediynes in the presence of [Cr(CO)3(η6-naphthalene)] and both a coordinating solvent and a hydrogen atom source, providing chromium−arene complexes in reasonable yield and good diastereocontrol. The mechanism of the reaction has been probed through DFT computational and spectroscopic methods. These studies suggest that direct C1−C6 bond formation from an η6-enediyne complex is the lowestenergy path, forming a metal-bound p-benzyne biradical. NMR spectroscopy suggests that enediyne alkene coordination occurs in preference to alkyne coordination, forming a THF-stabilized olefin intermediate; subsequent alkyne coordination leads to cyclization. While biradical quenching occurs rapidly and primarily via the singlet biradical, the triplet state biradical is detectable by EPR spectroscopy, suggesting intersystem crossing to a triplet ground state.

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INTRODUCTION Initially regarded as a mechanistic curiosity, the Masamune− Bergman cyclization has generated significant interest since the initial reports of the 1970s (eqs 1 and 2).1 This surge of interest

DNA backbone, ultimately leading to double-strand DNA cleavage and cell death.

We were first drawn to enediyne chemistry when we conceived that an analogue of the calicheamicin enediyne core (2) might be constructed via the sequence shown in Scheme 1, whereby a planar chiral π−arene complex formed via a nucleophile addition/hydride abstraction reaction3 would react by a trans-nucleophile/electrophile double addition,4 followed by ring closing via a “double stitching cyclization”.5 Unfortunately, we were stymied by the finding that deprotonation and diastereoselective alkylation of the benzylic position occur in preference to the desired nucleophilic/ electrophilic addition sequence (Scheme 1). The excellent diastereocontrol (>98:2) likely results from conformational

was driven by the discovery of the enediyne family of natural antitumor agents, such as calicheamicin and esperamicin (Figure 1).2These remarkably cytotoxic compounds display a mode of action wherein a cycloaromatization of the enediyne moiety occurs within the minor groove of the DNA double helix, generating a singlet p-benzyne biradical intermediate (i.e., 1). This biradical selectively abstracts hydrogen atoms from the © XXXX American Chemical Society

Received: May 17, 2012

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dx.doi.org/10.1021/om300427j | Organometallics XXXX, XXX, XXX−XXX

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Figure 1. Examples of naturally occurring enediyne compounds.

reaction temperature (200 °C vs r.t.). Nicolaou noted that the reaction temperature varies with the distance between the enediyne alkyne termini (i.e., the c−d distance), with a separation of ca. 3.25 Å required to achieve reasonable reaction rates at room temperature.7 A transition-metal-mediated means of controlling the c−d distance, thereby lowering the reaction temperature, was reported by O’Connor, producing ruthenium arene complexes at r.t. (eq 3).8 Given our long-standing interest

locking of the alkyne arm, leading to successive diastereoselective deprotonation and alkylation exo to the metal (Scheme 2). Scheme 1

in the preparation and functionalization of chromium−arene complexes,9 and the intriguing possibility of revisiting enediyne chemistry from a vastly different perspective, we believed that this process would make an interesting extension of our current synthetic methodologies. Here, we report our initial synthetic results along with a mechanistic investigation, wherein we present evidence for the formation of chromium−olefin complexes and triplet state p-benzyne biradicals as reaction intermediates.

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RESULTS AND DISCUSSION We initiated our investigation by examining the reaction of (Z)dodeca-6-en-4,8-diyne (7a) with Cr(CO)3(η6-naphthalene) (9). Cr complex 9 is known to readily liberate naphthalene in the presence of coordinating solvents to generate Cr(CO)3(sol)3,10 which we reasoned would behave similarly to the Cp*Ru+ fragment. We were pleased to find that a 22% yield of Cr−arene complex 8a was produced at room temperature in THF (eq 4). The yield is improved to 72% in a 1:3 THF/1,4-

Scheme 2

While this unexpected reaction was reasonably general and presented an interesting opportunity for asymmetric synthesis via planar chirality transfer, broad utility was not investigated.6 Comparing the early cyclization reports of Masamune and Bergman, the most striking difference is the large variation in B


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cyclohexadiene solvent mixture. In the absence of a coordinating solvent or when the steric bulk of the terminal substituents is increased, no products are obtained. We were interested in extending the reaction scope beyond simple enediynes to substrates relevant to complex molecule synthesis. To this end, we prepared the bicyclic enediyne substrate 15, with Cr-mediated dearomatization11 and Nicholas reactions12,13 as key steps (Scheme 3). Under standard thermal Scheme 3

Figure 2. X-ray crystal structure of chromium−arene complex 16 with non-hydrogen atoms represented by thermal ellipsoids at the 50% probability level. Final residuals: R1 = 0.039, wR2 = 0.048.

Scheme 4

conditions, enediyne 15 cyclizes after 7 days in 1,4-cyclohexadiene at 142 °C, providing product 17 in 92% yield. Under our Cr-mediated conditions, we were again pleased to find that Cr−arene complex 16 was obtained in a reasonable 59% yield at r.t. Complex 16 is formed as a single diastereomer, with the Cr(CO)3 approach occurring from the least-hindered face of the enediyne, as confirmed by single-crystal X-ray diffraction (Figure 2).14 Oxidative demetalation will readily liberate the organic product.9a,15 Interestingly, when the analogous transformation was attempted under O’Connor’s [RuCp*(NCMe)3]+-mediated conditions, a mixture of diastereomers was obtained; spectroscopically homogeneous material could only be obtained in 28% yield by complexation of arene 17 to [RuCp*(MeCN)3][PF6]. We were unable to grow a crystal of Ru complex 18 suitable for X-ray crystallographic analysis; however, we believe that the diastereomer is analogous in the chromium complex 16. Two mechanisms for product formation can readily be envisaged (Scheme 4): direct C1−C6 cyclization of a coordinated enediyne (Path A), or C2−C5 bond formation via oxidative coupling, followed by reductive elimination, and bond homolysis (Path B).16 To better understand the potential energy surface of the reaction, we undertook a UB3LYP DFT computational investigation of the cycloaromatization process (Figure 3).17 As one would predict, Path B is significantly disfavored, having an overall activation energy of 80.4 kcal/mol; in comparison, Path A has a barrier of only 16.7 kcal/mol. The c−d distance of INT1 is calculated to be 3.142 Å, well within the favorable distance predicted by Nicolaou, and much shorter

Figure 3. UB3LYP/6-31G* potential energy surface (free energies, kcal/mol).

C


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signal at 5.35 ppm, assigned to the deuterated product complex 20. The apparent abstraction of deuterium from THF-d8 is immediately suggestive of radical intermediacy. When 1,4-CHD is used as cosolvent, identical intermediate and deuterated product signals are observed, as well as two new peaks at 5.82 and 5.74 ppm, corresponding to the protio complex 21. This difference in proton chemical shift resulting from isotopic labeling is surprisingly large. The intermediate signal at 6.15 ppm may be attributed to the vinylic protons of an alkene complex, although the downfield shift is contrary to what is expected of low-valent metal/olefin species; unfortunately, due to low concentration and the transient nature of this intermediate, we were unable to obtain an adequate 13C NMR spectrum. To address this shortcoming, we employed the unreactive model substrate 7b to obtain a steady intermediate complex concentration (eq 6). In THF-d8, rapid, yet incomplete, conversion to the intermediate complex is observed by 1H NMR spectroscopy, with new signals emerging at 6.31 and 0.31 ppm (Figure 5). 13C NMR spectroscopy of this mixture clearly indicates the formation of a new complex with signals at 236.3 (CO), 104.9 (CC), 95.6 (CC), 83.8 (CC), and 0.57 (TMS) ppm. The large chemical shift difference of the alkene carbons (ca. 38 ppm) again suggests an alkene complex. Very small chemical shift changes (ca. 7 ppm) demonstrate that the alkyne units are not coordinated to the metal, suggesting that the intermediate is most likely the THF-stabilized chromium− alkene complex 23. To verify the proposed THF coordination, we performed an NMR tube experiment wherein a CD2Cl2 solution of enediyne 7b and Cr complex 9 was titrated with THF. Ligand exchange was not observed in the absence of coordinating solvent and only occurred at a reasonble rate upon addition of 5 equiv of THF. Interestingly, the 13C NMR spectrum of the resulting complex displayed only one clear signal for THF at 26.0 ppm, with a second very broad and weak signal at ca. 70 ppm (Figure 6). Upon cooling to −80 °C, the second carbon signal was stronger, yet still broad, suggesting rapid coordination/dissociation at room temperature; minor decomposition products were also observed. To permit cyclization, the weakly coordinated THF ligands must dissociate to allow alkyne coordination. We probed the reaction of enediyne 19 with 9 in THF-d8 by low-temperature 1 H NMR spectroscopy (Figure 7). At −80 °C, we were already able to observe a new, low-intensity peak at 5.36 ppm. Upon warming to −60 °C, a second smaller peak at 5.17 ppm splits away from the larger signal. As the temperature is increased, the separation between the peaks grows. Interestingly, at 20 °C, these peaks are still visible, but slowly disappear. We have not observed such peaks during r.t. NMR tube investigations, suggesting that, at low temperature, a concentration sufficient to allow detection can be established. We are hesitant to assign identities to such weak signals. However, the existence of two intermediates between the olefin complex and the final cyclized product is suggested, which we believe are related to alkyne complexation. The intermediacy of a biradical species in the Bergman cyclization has long been assumed; however, direct observation of such an intermediate via EPR spectroscopy has only recently been achieved.19 On the basis of a combination of computational17,20 and experimental1f,21 investigations, the p-benzyne biradical ground state is believed to be of singlet multiplicity and is favored by ca. 3.8 kcal/mol. Kinetic investigations have shown that these singlet biradicals react ca. 100 times slower

than the experimentally determined value for the free enediyne (4.32 Å).18 While Path B is not considered active at ambient temperature, it is interesting to note that the transition state for C1−C5 bond formation (TS1-3) occurs with concomitant CO migratory insertion (Figure 4); deinsertion occurs upon

Figure 4. Transition-state structures from Figure 3. Key distances are in angstroms.

reductive elimination (TS3-4). Only η6-bound enediyne complexes lead to products; attempts to locate an η2,η2dialkyne complex led to species wherein the chromium is bound to the inner π bonds of the alkynes. Saddle points connecting these alkyne complexes to experimentally observed products could not be located. With direct C1−C6 cyclization (Path A) of an η6-enediyne established as the most likely mechanism for cycloaromatization, we spectroscopically examined the reaction of (Z)tetradeca-7-en-5,9-diyne (19) with 9, hoping to detect intermediates (eq 5). In situ infrared spectroscopy was

inconclusive due to overlap between the signals of starting material and intermediate species; clear product formation only became apparent upon addition of 1,4-cyclohexadiene, suggesting that the early mechanistic steps are reversible. 1H NMR spectroscopy in THF-d8 in the absence of 1,4cyclohexadiene clearly indicates rapid formation of an intermediate with a characteristic proton signal at 6.15 ppm. This peak is subsequently consumed, to be replaced by a new D


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Figure 5. 1H and 13C NMR spectra of complex 23 (green stars). Red squares indicate Cr complex 9, blue squares indicate enediyne 7b, and black squares indicate free naphthalene.

Figure 6. 13C NMR (100 MHz, CD2Cl2) spectra of complex 23 at 25 and −80 °C. THF signals are indicated by red arrows.

Cr−arene biradical complex is of triplet multiplicity (Figure 3, INT2). Davidson has computationally predicted that the triplet ground state is favored by p-benzyne substituents that interact strongly with the aryne π space, weakly with the σ space, and are weakly electron-withdrawing, all features that describe Cr(CO)3.20f To test our computational prediction, we performed an EPR study of the reaction and were pleased to observe a clear multiplet, consistent with a metal-bound (g = 2.0105) triplet state biradical (Figure 8). Simulation with D = 18 MHz and E = 4 MHz led to a good fit with the experimental spectrum when a further hyperfine interaction of 21 MHz with two protons (I = 1/2) is taken into account. Low signal intensity precluded observation of the Δms = 2 transition. Conservation of angular momentum predicts that a singlet biradical is first to form, suggesting that intersystem crossing to a lower-energy triplet state is occurring (eq 7).

Figure 7. 1H NMR (400 MHz, THF-d8) spectrum showing reaction intermediates (red and blue arrows) and emerging product complex 20 (green arrow).

than their monoradical analogues, potentially due to the “coupled” nature of the biradical electrons; a triplet state biradical is expected to behave as a monoradical.22 We were, therefore, surprised when our calculations suggested that the weakly preferred (ΔGS−T = 1.8 kcal/mol) ground state of the

Biradicals can be quenched through solvent-cage or escape reaction pathways. Because of spin restrictions, a triplet E


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tion of enediynes, which proceeds in reasonable yields at ambient temperature to provide chromium−arene complexes. This reaction proceeds with high diastereocontrol, in contrast to the Ru-mediated system. Mechanistically, a triplet groundstate p-benzyne biradical was observed to lie on the reaction path, consistent with computational predictions. Radical intermediacy presents the possibility of further functionalization via intra- or intermolecular trapping with reagents other than hydrogen atom donors. Further investigations and catalytic studies are being pursued.

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EXPERIMENTAL SECTION

General. All manipulations on air-sensitive compounds were performed under a nitrogen atmosphere using standard Schlenk techniques or in a drybox. All solvents were dried by passing them through activated Al2O3 (SolvtekH purification system). Solvents were degassed via three freeze−pump−thaw cycles. All other reagents were used without further purification. Flash column chromatography was performed with Silicycle silca gel (40−63 μm). IR spectra were recorded on a PerkinElmer Spectrum One spectrophotometer. In situ IR spectra were recorded on a Mettler Toledo ReactIR. EPR spectra were recorded on a Bruker 300 (X-band, 100 kHz field modulation) spectrometer. 1H NMR and 13C NMR spectra were recorded on either a Bruker Avance 300 (1H, 300 MHz), Bruker AMX-400 (1H, 400 MHz; 13C, 100 MHz), or Bruker AMX-500 (1H, 500 MHz) spectrometer. 1H NMR chemical shifts are reported relative to residual protiated solvent. 13C NMR chemical shifts are reported relative to the deuterated solvent. Electrospray (ES) mass spectra were obtained using an Applied Biosystems API 150EX LC/MS system. Elemental analyses were performed by H. Eder of the Service de Mycroanalyse, Section de Pharmacie, Université de Genève. All computations were conducted with the Spartan’10 computational software package.24 Initial stationary point searches were carried out with the semiempirical PM3 method.25 These structures were then used as starting points for geometry optimization at the UB3LYP26/631G* level. Vibrational analyses were carried out to confirm the nature of all stationary points and to calculate the thermal corrections (enthalpy and entropy) for 298 K, 1 bar, gas phase. The following compounds were prepared by published procedures: 2,6-bis(trimethylsilyl)anisole (10),27 [Cr(CO)3(η6-2,6-bis(trimethylsilyl)anisole)] (11),28 (Z)-5-chloropent-4-en-2-yn-1-ol,29 (Z)-1,6-bis(trimethylsilyl)hexa-3-en-1,5-diyne 7b,11 (Z)-tetradeca-7-en-5,9-diyne (19),30 [RuCp*(MeCN)3]PF6,31 and [Cr(CO)3(η6-C10H8)] (9).32 Experimental Details. [Cr(CO)3(η6-1,2-Dipropylbenzene)] (8a). Under N2, (Z)-dodeca-6-en-4,8-diyne 7a (40 mg, 0.25 mmol) and 9 (67 mg, 0.50 mmol) were dissolved in degassed 1,4-cyclohexadiene (1.90 mL). THF (0.60 mL) was added, and the reaction mixture was stirred for 8 h in the dark. All volatiles were evaporated, and the crude mixture was purified by flash column chromatography (100% pentane, then 95:5 pentane/ether) to afford 8a (54 mg, 72%) as a yellow solid. IR: 2962 (w), 2931 (w), 2873 (w), 1952 (s), 1858 (s), 1456 (w), 1417 (w), 1380 (w), 1261 (w), 1089 (w), 1020 (w), 820 (w), 747 (w), 664 (s), 629 (s). 1H NMR (400 MHz, C6D6): δ 4.48 (m, 4H), 2.11 (m, 2H), 1.86 (m, 2H), 1.19 (m, 4H), 0.70 (t, J = 7.3 Hz, 6H). 13C NMR (100 MHz, C6D6): δ 234.6, 112.1, 94.1, 92.1, 34.2, 24.6, 14.4. Electrospray MS m/z calculated for C15H18O3Cr, 298.0661; found, 298.0656. Analysis calculated for C15H18O3Cr: C, 60.40%; H, 6.08%. Found: C, 60.39%; 5.86%. 4-(Prop-2-yn-1-yl)-2-(trimethylsilyl)-5-vinylcyclohex-2-enone (12). n-Butyllithium (1.6 M in hexane, 15.50 mL, 24.50 mmol) was added to tetravinyltin (1.20 mL, 6.40 mmol) at r.t., and the resulting white suspension was stirred for 1 h. This suspension was then cooled to −78 °C, and degassed THF (16 mL) was added. The solution was added to a degassed THF solution (40 mL) of Cr(CO)3(η6-di-orthotrimethylsilylanisole) (3.11 g, 8.00 mmol) at −78 °C. The temperature was increased to −10 °C over 3.5 h. The mixture was cooled to −78 °C, and DMPU (10.30 mL, 84.80 mmol) and propargyl bromide (80% weight solution in toluene, 8.80 mL, 80.00 mmol) were added

Figure 8. Experimental and simulated EPR spectra of triplet p-benzyne biradical 25.

biradical reacting via a cage-type pathway is unlikely, necessitating escape-type pathways and a higher probability for mixed product formation. With a triplet ground state established, it is interesting to note that, spectroscopically, only the dideutero and protio complexes 20 and 21 are observed; no mixed complexes 22 are detected by 1H or 2H NMR. The lifetime of a solvent-caged radical is ca. 10−10 s and when compared to the 108 s−1 rate of intersystem crossing,23 it is very likely that singlet biradical quenching is rapid, with only a very small portion undergoing intersystem crossing to the lowerenergy triplet state. We believe that the above observations are consistent with the following mechanistic proposal (Scheme 5): Cr− Scheme 5

naphthalene complex 9 is solvated by THF to produce the unsaturated (thf)2Cr(CO)3 complex 26. This unsaturated species will reversibly complex enediyne through the alkene moiety in preference to the alkyne (27). The labile THF ligands dissociate to allow complexation of the alkyne termini (28), subsequently decreasing the c−d distance. Direct C1−C6 bond formation occurs to yield the singlet biradical species 29, which is then rapidly quenched by hydrogen atom abstraction through a cage-type mechanism to yield the final product 32. Despite this rapid quenching, a small quantity of the biradical undergoes intersystem crossing to the lower-energy triplet state 31. This biradical is quenched via escape-type pathways, to yield the identical final product. In conclusion, we have demonstrated the viability of a chromium-mediated variant of the O’Connor cycloaromatizaF


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methylpyridine (13.34 g, 64.96 mmol) in CH2Cl2 (50 mL) was added via syringe. The resulting brown solution was stirred at −10 °C for 15 min and then quenched with sat. aq. NaHCO3 solution (150 mL). The aq. phase was extracted with CH2Cl2 (3 × 150 mL). The combined organic layers were washed with an aq. sat. NaHCO3 solution (3 × 150 mL) and dried over MgSO4. All volatiles were removed, and the crude product was purified by flash chromatography (100% pentane, then 80:20 pentane/CH2Cl2) to afford 956 mg (38%) of product as a brown oil. IR: 2280 (s), 1618 (s), 1454 (m), 1330 (s), 1162 (w), 812 (s). 1H NMR (400 MHz, C6D6): δ 6.55 (d, J = 5.3 Hz, 1H), 6.29 (d, J = 9.9 Hz, 1H), 5.66 (ddd, J = 17.1, 10.6, 6.6 Hz, 1H), 5.28 (dt, J = 9.6, 2.8 Hz, 1H), 4.90 (m, 2H), 3.52 (m, 2H), 2.74 (m, 1H), 2.30 (m, 1H), 2.15 (m, 1H), 2.02 (m, 1H), 0.24 (s, 9H). 13C NMR (100 MHz, C6D6): δ 141.6, 140.1, 115.0, 109.5, 52.0, 39.7, 39.5, 38.6, 26.3, −1.3. Electrospray MS m/z calculated for C25H23O7SiCo2, 580.9877; found, 580.9859. 12-Trimethylsilyl-14-vinylbicyclo[8.3.1]tetradeca-5,12-dien-3,7diyn-11-one (15). To a solution of 14 (143 mg, 0.25 mmol) in THF (20 mL) at 0 °C was added a solution of iodine (938 mg, 3.70 mmol) in THF (15 mL). The resulting solution was warmed to r.t. and stirred for 2 h in the dark. The mixture was poured into a solution of sat. aq. NaHCO3 (60 mL), aq. sodium thiosulphate (1 M, 60 mL), and ether (120 mL). The aq. phase was extracted with ether (3 × 120 mL). The combined organic layers were washed with brine (3 × 120 mL) and dried over MgSO4. The volatiles were removed, and the crude product was purified by flash column chromatography (95:2 pentane/ether) to provide 69 mg (94%) of product as a yellow oil. IR: 2280 (s), 1656 (m), 1611 (m), 1450 (m), 1328 (s), 822 (s). 1H NMR (400 MHz, C6D6): δ 6.49 (d, J = 2.8 Hz, 1H), 5.29 (m, 3H), 4.84 (m, 2H), 4.12 (q, J = 8.8 Hz, 1H), 3.21 (ddd, J = 16.9, 3.3, 2.0 Hz, 1H), 2.53 (dd, J = 17.2, 4.5 Hz, 1H), 2.35 (dd, J = 16.9, 4.3 Hz, 1H), 1.96 (m, 3H), 0.33 (s, 9H). 13C NMR (100 MHz, C6D6): δ 200.1, 158.3, 143.7, 140.7, 122.3, 120.8, 116.5, 97.7, 95.8, 84.2, 83.4, 46.7, 52.8, 38.2, 25.9, 23.5, −1.1. Electrospray MS m/z calculated for C19H22OSiNa, 317.1337; found, 317.1335. [Cr(CO)3(η6-8-(Trimethylsilyl)-12-vinyl-10,11-dihydro-5H-6,10methanobenzo[9]annulen-7(6H)-one)] (16). Under N2, 15 (29 mg, 0.10 mmol) and 9 (54 mg, 0.20 mmol) were dissolved in degassed 1,4cyclohexadiene (0.76 mL). THF (0.24 mL) was added, and the reaction mixture was stirred for 6 h in the dark. All volatiles were removed, and the crude product was purified by flash column chromatography (95:5 cyclohexane/EtOAc) to afford 15 (31 mg, 59%) as a yellow solid. IR: 3087 (w), 2953 (w), 2922 (w), 1957 (s), 1869 (s), 1655 (m), 1589 (w), 1443 (w), 1351 (w), 1333 (w), 1246 (m), 1145 (w), 1033 (w), 836 (m), 665 (m), 626 (m). 1H NMR (400 MHz, C6D6): δ 6.16 (dd, J = 5.7, 1.5 Hz, 1H), 5.53 (ddd, J = 17.3, 10.5, 6.4 Hz, 1H), 4.82 (m, 2H), 4.31 (m, 3H), 4.12 (dd, J = 5.3, 1.5 Hz, 1H), 2.65 (d, J = 14.5 Hz, 1H), 2.30 (m, 2H), 2.29 (m, 1H), 2.16 (t, J = 6.4 Hz, 1H), 2.04 (m, 1H), 1.95 (dd, J = 15.1, 7.5 Hz, 1H), −0.05 (s, 9H). 13C NMR (100 MHz, C6D6): δ 234.0, 233.7, 201.1, 155.7, 145.3, 140.9, 115.7, 145.3, 140.9, 115.7, 110.7, 108.4, 96.7, 94.4, 91.6, 91.5, 52.8, 47.8, 39.5, 39.5, 38.2, −1.2. Electrospray MS m/z calculated for C22H25O4SiCr, 433.0927; found, 433.1002. Thermal Cyclization of Enediyne 15. A solution of enediyne 15 (26 mg, 0.09 mmol) in 1,4-cyclohexadiene (2.60 mL) under nitrogen was heated at 142 °C in a sealed tube for 7 days. All volatiles were removed, and the crude product was purified by flash column chromatography (95:5 pentane/ether) to afford 17 (24 mg, 92%) as a pale yellow solid. IR: 2921 (m), 1651 (s), 1589 (m), 1491 (w), 1456 (w), 1348 (m), 1338 (m), 1241 (m), 1218 (m), 1124 (w), 985 (w), 918 (m), 856 (s), 744 (s). 1H NMR (400 MHz, C6D6): δ 6.90 (m, 3H), 6.68 (m, 1H), 6.33 (dd, J = 5.7, 1.5 Hz, 1H), 5.85 (ddd, J = 17.3, 10.5, 6.4 Hz, 1H), 4.91 (m, 2H), 2.99 (dd, J = 14.3, 7.5 Hz, 1H), 2.69 (m, 4H), 2.39 (m, 2H), −0.01 (s, 9H). 13C NMR (100 MHz, C6D6): δ 156.0, 141.7, 131.2, 129.6, 128.6, 126.9, 114.8, 53.2, 47.7, 41.2, 41.0, 38.0, −1.5 (quaternary carbons not observed). Electrospray MS m/z calculated for C19H24OSiNa, 319.1488; found, 319.1491. [RuCp*(η 6 -8-(Trimethylsilyl)-12-vinyl-10,11-dihydro-5H-6,10methanobenzo[9]annulen-7(6H)-one)][PF6] (18). Enediyne 15 (50 mg, 0.17 mmol) and [RuCp*(NCMe)3]PF6 (53 mg, 0.11 mmol) were

sequentially. The solution was slowly warmed to r.t. and stirred overnight. All volatiles were evaporated. The residue was stirred for 1.5 h. The crude mixture was concentrated and diluted with ether (30 mL). The crude product was extracted with ether (3 × 30 mL), and the organic layers were washed with brine (3 × 30 mL). All volatiles were evaporated. The crude product was adsorbed on silica gel from an ether solution and purified by flash column chromatography (98:2 pentane/ether) to afford 1.03 g (55%) of product as a yellow oil. IR: 3333 (m), 2955 (m), 1667 (s), 1600 (w), 1367 (w), 1246 (s), 848 (s). 1 H NMR (400 MHz, CDCl3): δ 7.12 (s, 1H), 5.67 (m, 1H), 5.14 (d, J = 10.2 Hz, 1H), 5.12 (br s, 1H), 2.42 (m, 6H), 2.03 (br s, 1H), 0.16 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 201.7, 159.4, 142.3, 139.2, 117.2, 81.5, 70.9, 44.7, 43.8, 41.4, 21.9, −1.2. Electrospray MS m/z calculated for C14H21OSi, 233.1356; found, 233.1367. (Z)-8-(4-((tert-Butyldimethylsilyl)oxy)-3-(trimethylsilyl)-6-vinylcyclohexa-2,4-dien-1-yl)octa-4-en-2,6-diyn-1-ol (13). A degassed CH2Cl2 solution (81 mL) of 12 (1.14 g, 4.93 mmol) and Et3N (1.40 mL, 9.85 mmol) was stirred for 30 min before addition of tertbutyldimethylsilyltrifluoromethanesulfonate (1.70 mL, 7.39 mmol). After 2 h, all volatiles were evaporated to give the crude product. Purification by flash column chromatography (98:2 pentane/Et3N) afforded 1.67 g (98%) of product as a yellow oil. IR: 3403 (w), 2930 (w), 2280 (m), 1730 (m), 1720 (m), 1618 (m), 1593 (m), 1521 (m), 1456 (m), 1424 (w), 1392 (w), 1367 (w), 1330 (m), 1230 (s), 1158 (s), 1056 (m), 1025 (m), 768 (m), 741 (m). 1H NMR (400 MHz, C6D6): δ 6.27 (d, J = 3.3 Hz, 1H), 5.66 (ddd, J = 16.9, 9.8, 8.1 Hz, 1H), 5.06 (d, J = 16.4 Hz, 1H), 4.94 (dd, J = 10.1, 1.8 Hz, 1H), 4.75 (d, J = 4.3 Hz, 1H), 3.02 (dt, J = 8.8, 4.0 Hz, 1H), 2.25 (m, 2H), 2.10 (m, 1H), 1.80 (t, J = 2.8 Hz, 1H), 0.98 (s, 9H), 0.29 (s, 9H), 0.18 (d, J = 4.8 Hz, 6H). 13C NMR (100 MHz, C6D6): δ 152.4, 141.1, 138.4, 128.1, 115.1, 101.7, 82.7, 70.7, 43.6, 39.4, 26.6, 21.8, 18.9, −0.3, −3.8. Electrospray MS m/z calculated for C20H35OSi2, 347.2226; found, 347.2230. A solution of this oil (371 mg, 1.07 mmol) in degassed toluene (3 mL) was added to a suspension of Pd(PPh3)4 (81 mg, 0.08 mmol) and CuI (41 mg, 0.21 mmol) in degassed toluene (6 mL), followed by (Z)-5-chloropent-4-en-2-yn-1-ol (0.19 mL, 1.60 mmol), and freshly distilled n-BuNH2 (0.16 mL, 1.60 mmol). The reaction mixture was stirred at r.t. overnight. A sat. aq. NH4Cl solution (10 mL) was added, and the product was extracted with ether (3 × 15 mL). The organic layers were washed with water and brine and dried over MgSO4. All volatiles were removed, and the crude product was purified by flash column chromatography (98:2 pentane/Et3N, then 90:10 pentane/ether) to provide 364 mg (80%) of product as a yellow oil. IR: 3420 (w), 2954 (m), 2928 (m), 2214 (w), 1623 (s), 1572 (m), 1473 (m), 1407 (m), 1361 (m), 1330 (m), 1245 (s), 1203 (s), 835 (s). 1 H NMR (400 MHz, C6D6): δ 6.26 (br s, 1H), 5.70 (m, 1H), 5.54 (m, 2H), 5.13 (d, J = 17.2 Hz, 1H), 4.95 (d, J = 10.1 Hz, 1H), 4.79 (m, 1H), 4.08 (s, 2H), 3.16 (m, 1H), 2.40 (m, 3H), 0.98 (s, 9H), 0.29 (s, 9H), 0.19 (dd, J = 5.0, 1.8 Hz, 6H). 13C NMR (100 MHz, C6D6): δ 152.5, 141.3, 141.2, 138.5, 120.6, 118.5, 115.2, 101.7, 97.2, 95.5, 83.3, 80.8, 51.6, 43.4, 39.7, 26.6, 23.1, 18.9, −0.3, −3.8 (quaternary carbons not observed). Electrospray MS m/z calculated for C25H39O2Si2, 427.2483; found, 427.2501. ((Z)-12-Trimethylsilyl-14-vinylbicyclo[8.3.1]tetradeca-5,12-diene3,7-(6,7-η2)-diyne-11-one)hexacarbonyldicobalt (14). To a degassed hexane solution (1 mL) of 13 (164 mg, 0.38 mmol) was added a hexane solution (1 mL) of dicobalt octacarbonyl (143 mg, 0.42 mmol). The reaction mixture was stirred for 2 h at r.t., then all volatiles were removed. The crude product was purified by flash column chromatography (98:2 pentane/Et3N) to provide 203 mg (75%) of product as a brown oil. IR: 2280 (s), 2055 (m), 2026 (m), 1618 (m), 1454 (m), 1330 (s), 1162 (w). 1H NMR (400 MHz, C6D6): δ 6.24 (s, 1H), 6.21 (br s, 1H), 5.73 (m, 1H), 5.49 (d, J = 10.1 Hz, 1H), 5.12 (d, J = 16.4 Hz, 1H), 4.99 (d, J = 9.9 Hz, 1H), 4.78 (m, 3H), 3.03 (m, 1H), 2.40 (m, 3H), 0.99 (s, 9H), 0.31 (s, 9H), 0.20 (s, 6H). 13C NMR (100 MHz, C6D6): δ 140.8, 140.7, 136.0, 115.2, 113.0, 101.5, 64.5, 43.5, 39.5, 26.6, 18.9, −0.4, −3.6 (quaternary carbons not observed). Electrospray MS m/z calculated for C31H39O8Si2Co2, 713.0841; found, 713.0878. This oil (3.09 g, 4.33 mmol) was dissolved in dry CH2Cl2 (420 mL) under N2 and cooled to −15 °C. 2,6-Di-tert-butyl-4G


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dissolved in degassed THF (3.60 mL). The solution was stirred at r.t. for 18 h. The volatiles were removed, and the crude product (65 mg) was crystallized from 1:1 CH2Cl2/ether to provide 32 mg (28%) of product as a brown solid. IR: 2916 (m), 1657 (s), 1588 (m), 1451 (m), 1388 (m), 1334 (w), 1246 (s), 1207 (w), 1142 (m), 1074 (w), 1031 (m), 995 (w), 927 (m), 833 (s), 742 (s), 699 (s). 1H NMR (400 MHz, CD2Cl2): δ 6.79 (dd, J = 5.8, 1.8 Hz, 1H), 5.81 (ddd, J = 17.1, 10.6, 6.6 Hz, 1H), 5.57 (m, 2H), 5.43 (d, J = 5.6 Hz, 1H), 5.37 (d, J = 5.6 Hz, 1H), 5.06 (m, 2H), 3.00 (m, 3H), 2.80 (m, 4H), 1.89 (s, 15H), −0.16 (s, 9H). 13C NMR (100 MHz, CD2Cl2): δ 201.2, 156.6, 146.0, 140.3, 116.4, 103.1, 100.2, 96.5, 90.2, 89.4, 87.1, 87.1, 53.3, 46.8, 37.4, 37.2, 37.0, 10.6, −1.5. Electrospray MS m/z calculated for C29H39OSiRu, 533.1808; found, 533.1794. 1 H NMR Investigation of the Reaction of Enediyne 7b with Cr Complex 9. (Z)-1,6-Bis(trimethylsilyl)hexa-3-en-1,5-diyne 7b (55 mg, 0.25 mmol) and 9 (35 mg, 0.12 mmol) were dissolved in THF-d8 (0.75 mL) under N2 and placed in a Young NMR tube. The NMR spectra were monitored. Rapid formation of a new intermediate was observed. The labile nature of the product allowed only NMR spectroscopic characterization. 1H NMR (400 MHz, THF-d8): δ 6.31 (s, 2H), 0.31 (s, 18H). 13C NMR (100 MHz, THF-d8): δ 236.3 (CO), 104.9 (CC), 95.6 (CC), 83.8 (CC), 0.57 (TMS). Low-Temperature 1H NMR Study of the Reaction of Enediyne 19 with Cr Complex 9. (Z)-Tetradeca-7-en-5,9-diyne 19 (65 mg, 0.35 mmol) and 9 (96 mg, 0.35 mmol) were dissolved in THF-d8 (0.75 mL) under N2 and placed in a Young NMR tube. The tube was immediately cooled to −78 °C in a dry ice/acetone bath. The NMR spectrometer was cooled to −80 °C prior to introduction of the cold sample. The sample was slowly warmed to room temperature, and a 1 H NMR spectrum was taken every 10 °C. Rapid formation of new intermediates was observed. The labile nature and low concentration of the intermediates allowed only NMR spectroscopic characterization. Only characteristic signals are listed. Each signal corresponds to a different species. 1H NMR (400 MHz, THF-d8, −30 °C): δ 6.31 (s), 5.30 (br s), 5.17 (br s). 1H NMR (400 MHz, THF-d8, 20 °C): δ 6.15 (s), 5.36 (s, product), 5.05 (br s), 4.69 (s). EPR Spectroscopic Study of the Reaction of Enediyne 19 with Cr Complex 9. (Z)-Tetradeca-7-en-5,9-diyne 19 (17 mg, 0.09 mmol) and 9 (25 mg, 0.09 mmol) were dissolved in THF-d8 (0.75 mL) under N2 and placed in a quartz EPR tube. The reaction was monitored by EPR spectroscopy as it warmed to room temperature. Up to 20 scans were accumulated to increase signal intensity. Attempts to detect the Δms = 2 forbidden transition remained unsuccessful due to the low intensity of the signal. 1 H NMR Study of the Reaction of Enediyne 19 with Cr Complex 9. (Z)-Tetradeca-7-en-5,9-diyne 19 (69 mg, 0.37 mmol) and 9 (103 mg, 0.37 mmol) were dissolved in THF-d8 (0.75 mL) under N2 and placed in a Young NMR tube. 1,4-Cyclohexadiene (35 μL, 0.37 mmol) was added. 1H NMR spectra were gathered at frequent intervals. The rapid formation of two products was observed. Each product is listed separately. Only the characteristic signals are listed. 1H NMR (product 1, 500 MHz, THF-d8): δ 5.82 (br s), 5.74 (br s). 1H NMR (product 2, 500 MHz, THF-d8): δ 5.35 (br s). 2H NMR (product 2, 300 MHz, THF): δ 6.83.

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†

Ironwood Pharmaceuticals, Inc., 301 Binney Street, Cambridge, MA 02142. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the Swiss National Science Foundation and the University of Geneva is gratefully acknowledged. (1) (a) Darby, N.; Kim, C. U.; Salaün, J. A.; Shelton, K. W.; Takada, S.; Masamune, S. Chem. Commun. 1971, 1516. (b) Jones, R. B.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660. (c) Johnson, G. C.; Stofko, J. J., Jr.; Lockhart, T. P.; Brown, D. W.; Bergman, R. G. J. Org. Chem. 1979, 44, 4215. (d) Lockhart, T. P.; Mallon, C. B.; Bergman, R. G. J. Am. Chem. Soc. 1980, 102, 5976. (e) Lockhart, T. P.; Comita, P. B.; Bergman, R. G. J. Am. Chem. Soc. 1981, 103, 4082. (f) Lockhart, T. P.; Bergman, R. G. J. Am. Chem. Soc. 1981, 103, 4091. (2) (a) Wenk, H. H.; Winkler, M.; Sander, W. Angew. Chem., Int. Ed. 2003, 42, 502. (b) Galm, U.; Hager, M. H.; Van Lanen, S. G.; Ju, J.; Thorson, J. S.; Shen, B. Chem. Rev. 2005, 105, 739. (c) Joshi, M. C.; Rawat, D. S. Chem. Biodiversity 2012, 9, 459. (3) (a) Fretzen, A.; Ripa, A.; Liu, R. G.; Bernardinelli, G.; Kündig, E. P. Chem.Eur. J. 1998, 4, 251. (b) Fretzen, A.; Kündig, E. P. Helv. Chim. Acta 1997, 80, 2023. (4) (a) Pape, A. R.; Kaliappan, K. P.; Kündig, E. P. Chem. Rev. 2000, 100, 2917. (5) (a) Nicolaou, K. C.; Chakraborty, T. K.; Piscopio, A. D.; Minowa, N.; Bertinato, P. J. Am. Chem. Soc. 1993, 115, 4419. (b) Shair, M. D.; Yoon, T.-Y.; Mosny, K. K.; Chou, T. C.; Danishefsky, S. J. J. Am. Chem. Soc. 1996, 118, 9509. (6) For further discussion and experimental details, see the Supporting Information. (7) Nicolaou, K. C.; Zuccarello, G.; Riemer, C.; Estevez, V. A.; Dai, W.-M. J. Am. Chem. Soc. 1992, 114, 7360. (8) (a) O’Connor, J. M.; Lee, L. I.; Gantzel, P.; Rheingold, A. L.; Lam, K.-C. J. Am. Chem. Soc. 2000, 122, 12057. (b) O’Connor, J. M.; Friese, S. J.; Tichenor, M. J. Am. Chem. Soc. 2002, 124, 3506. (c) O’Connor, J. M.; Friese, S. J.; Rodgers, B. L. J. Am. Chem. Soc. 2005, 127, 16342. (d) O’Connor, J. M.; Friese, S. J. Organometallics 2008, 27, 4280. (9) Lead references: (a) Enriquez-Garcia, A.; Ouizem, S.; Cheng, X.; Romanens, P.; Kündig, E. P. Adv. Synth. Catal. 2010, 352, 2306. (b) Mercier, A.; Urbaneja, X.; Yeo, W. C.; Chaudhuri, P. D.; Cumming, G. R.; House, D.; Bernardinelli, G.; Kündig, E. P. Chem. Eur. J. 2010, 16, 6285. (c) Lavy, S.; Pérez-Luna, A.; Kündig, E. P. Synlett 2008, 2621. (d) Cumming, G. R.; Bernardinelli, G.; Kündig, E. P. Chem.Asian J. 2006, 1, 459. (10) (a) Kündig, E. P.; Perret, C.; Spichiger, S.; Bernardinelli, G. J. Organomet. Chem. 1985, 286, 183. (b) Zhang, S.; Shen, J. K.; Basolo, F.; Ju, T. D.; Lang, R. F.; Kiss, G.; Hoff, C. D. Organometallics 1994, 13, 3692. (11) Kündig, E. P.; Pape, A. Top. Organomet. Chem. 2004, 7, 71. (12) (a) Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207. (b) Teobald, B. J. Tetrahedron 2002, 58, 4133. (13) For lead references on a related macrocyclization, see: (a) Magnus, P.; Carter, P. A. J. Am. Chem. Soc. 1988, 110, 1626. (b) Magnus, P.; Lewis, R. T.; Huffman, J. C. J. Am. Chem. Soc. 1988, 110, 6921. (14) Crystal data for complex 16: C22H41CrO4Si; Mr = 432.51; monoclinic; P21/n; a = 10.3241(7) Å, b = 15.1982(9) Å, c = 13.3413(10) Å; β = 94.973(6)°; V = 2085.5(2) Å3; Z = 4; μ = 0.63 mm−1; dx = 1.377 Mg m−3; Mo Kα radiation (λ = 0.71073 Å); 8000 reflections measured at 220 K on a STOE IPDS 2 diffractometer, 6075 independent reflections, 3793 reflections with I > 2.0σ(I). Data were corrected for Lorentz and polarization effects, and for absorption (Tmin, Tmax = 0.759, 0.868). Full-matrix, least-squares refinement gave

ASSOCIATED CONTENT

S Supporting Information *

Discussion and experimental details for the diastereocontrolled benzylic functionalization of propargylic substituted Cr(η6arene)(CO)3 complexes, CIF files for complexes 5a and 16, and all computationally determined stationary points in Figure 3. This material is available free of charge via the Internet at http://pubs.acs.org.

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Organometallics

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final values of R1 = 0.039, wR2 = 0.048, and S = 1.76. Computing details: Data collection, cell refinement, and data reduction, STOE XAREA; structure solution, Superflip; structure refinement, CRYSTALS. CCDC-882300 contains the supplementary crystallographic data for 16. These data can be obtained free of charge via www.ccdc. cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; Fax: (+44) 1223-336-033; or E-mail: [email protected]). (15) Kündig, E. P. Top. Organomet. Chem. 2004, 7, 3. (16) O’Connor, J. M. Personal communication. Geneva, 2011. (17) UB3LYP gives reliable energetics for thermal Bergman cyclizations: Gräfenstein, J.; Hjerpe, A. M.; Kraka, E.; Cremer, D. J. Phys. Chem. A 2000, 104, 1748. (18) McMahon, R. J.; Halter, R. J.; Fimmen, R. L.; Wilson, R. J.; Peebles, S. A.; Kuczkowski, R. L.; Stanton, J. F. J. Am. Chem. Soc. 2000, 122, 939. (19) (a) Usuki, T.; Inoue, M.; Akiyama, K.; Hirama, M. Chem. Lett. 2002, 31, 1148. (b) Usuki, T.; Mita, T.; Lear, M. J.; Das, P.; Yoshimura, F.; Inoue, M.; Hirama, M.; Akiyama, K.; Tero-Kubota, S. Angew. Chem., Int. Ed. 2004, 43, 5249. (c) Usuki, T.; Inoue, M.; Akiyama, K.; Hirama, M. Biorg. Med. Chem. 2005, 13, 5218. (d) Usuki, T.; Nakanishi, K.; Ellestad, G. A. Org. Lett. 2006, 8, 5461. (e) Usuki, T.; Kawai, M.; Nakanishi, K.; Ellestad, G. A. Chem. Commun. 2010, 46, 737. (20) Lead references: (a) Kraka, E.; Cremer, D. J. Am. Chem. Soc. 1994, 116, 4929. (b) Cramer, C. J.; Nash, J. J.; Squires, R. R. Chem. Phys. Lett. 1997, 277, 311. (c) Cramer, C. J.; Debbert, S. Chem. Phys. Lett. 1998, 287, 320. (d) Chen, W.-C.; Chang, N.-Y.; Yu, C.-H. J. Phys. Chem. A 1998, 102, 2484. (e) Jones, G. B.; Warner, P. M. J. Am. Chem. Soc. 2001, 123, 2134. (f) Clark, A. E.; Davidson, E. R. J. Org. Chem. 2003, 68, 3387. (g) Wang, E. B.; Parish, C. A.; Lishka, H. J. Chem. Phys. 2008, 129, 44306. (h) Li, X.; Paidus, J. J. Chem. Phys. 2008, 129, 174101. (i) Karton, A.; Kaminker, I.; Martin, J. M. L. J. Phys. Chem. A 2009, 113, 7610. (21) Wenthold, P. G.; Squires, R. R.; Lineberger, W. C. J. Am. Chem. Soc. 1998, 120, 5279. (22) (a) Logan, C. F.; Chen, P. J. Am. Chem. Soc. 1996, 118, 2113. (b) Schottelius, M. J.; Chen, P. J. Am. Chem. Soc. 1996, 118, 4896. (23) Kaptein, R. Adv. Free-Radical Chem. 1975, 5, 338. (24) Spartan ’10; Wavefunction, Inc.; Irvine, CA, 2011; http://www. wavefun.com. (25) (a) Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209. (b) Stewart, J. J. P. J. Comput. Chem. 1989, 10, 221. (c) Stewart, J. J. P. J. Comput. Chem. 1991, 12, 320. (d) Stewart, J. J. P. J. Mol. Model. 2004, 10, 155. (26) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785. (b) Becke, A. D. J. Chem. Phys. 1993, 98, 1372. (c) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (27) Crowther, G. P.; Sundberg, R. J.; Sarpeshkar, A. M. J. Org. Chem. 1984, 49, 4657. (28) Kündig, E. P.; Sau, M.; Perez-Luna, A. Synlett 2006, 2114. (29) Basak, A.; Shain, J. C.; Khamrai, U. K.; Rudra, K. R. J. Chem. Soc., Perkin Trans. 1 2000, 1955. (30) Faller, J. W.; Crabtree, R. H.; Habib, A. Organometallics 1985, 4, 929. (31) Steinmetz, S.; Schenk, W. A. Organometallics 1999, 18, 943. (32) Desobry, V.; Kündig, E. P. Helv. Chim. Acta 1981, 64, 1288.

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