Ready Access to the Echinopines Skeleton via Gold(I)-Catalyzed Alkoxycyclizations of Enynes

The [3,5,5,7] tetracyclic skeleton of echinopines has been stereoselectively accessed through a gold(I)-catalyzed alkoxycyclization of cyclopropyl-tethered 1,6-enynes. The key bicyclo[4.2.1]nonane core of the enyne precursors was readily assembled by means of a Co-catalyzed [6 + 2] cycloaddition. Furthermore, the attempted alkoxycyclization of 1,5-enyne substrates revealed an uncovered cyclopropyl rearrangement that gives rise to [3,6,5,7] tetracyclic structures.


■ INTRODUCTION
Echinopines A and B (1 and 2) were isolated in 2008 from the roots of Echinops spinosus and feature an unprecedented [3,5,5,7]-membered-ring tetracyclic skeleton (Scheme 1), which probably originates biosynthetically from a guaiane precursor. 1 This complex carbon framework holds five contiguous stereogenic centers, two of them being adjacent quaternary stereocenters. Despite the fact that no biological activity has been reported to date for 1 and 2, the unique architecture of these sesquiterpenes has constituted an appealing challenge for the synthetic community and several syntheses of echinopines have been accomplished to date. 2−7 The key feature in all these syntheses is the establishment of the unique [3,5,5,7] skeleton, and to this aim conceptually very different ring-forming sequences have been successfully established. 8 However, the assembly of the complex polycyclic framework of the echinopines skeleton is not easily addressed by conventional methods, as evidenced by the lengthy existing syntheses, and it is in most of the cases delayed to one of the last steps of the sequence.
Gold(I) catalysis constitutes a powerful tool for the construction of complex polycyclic architectures from relatively simple enyne substrates under mild reaction conditions. 9−12 A concise synthesis of the complex polycyclic framework of the echinopines skeleton could easily provide access to structural analogues for further evaluation of their biological properties. In this context, we envisioned a gold(I)-catalyzed alkoxycyclization of cyclopropyl-tethered tricyclic 1,5-(3) or 1,6-enynes (4) as the key step for the ready access to the tetracyclic skeleton of echinopines via 5-endo or 5-exo cyclization, respectively (Scheme 1). 13−16 This transformation would stereoselectively lead to echinopine-based tetracyclic products bearing different groups suited for further functionalization.

■ RESULTS AND DISCUSSION
Our approach for the synthesis of tricyclic enynes 3 and 4 relied on a cobalt-catalyzed [6 + 2] cycloaddition between cycloheptatriene and an internal alkyne as the key step to build the bicyclo[4.2.1]nonane core. 17,18 Thus, orthogonally protected diol 5a afforded cycloadduct 6a, which upon monodeprotection and cyclopropanation of the tetrasubstituted olefin from the less sterically hindered face gave rise to tricyclic compound 8a (Scheme 2). Oxidation of the primary alcohol and subsequent homologation employing the Ohira−Bestmann reagent provided 1,5-enyne 3a.
Initial attempts to perform the alkoxycyclization of 3a with methanol as the external nucleophile in the presence of different cationic gold(I) complexes A−D only provided methyl ketone 10 as a result of the formal hydration of the terminal alkyne (Scheme 3). 19 −22 Moreover, when the reaction was performed under strictly anhydrous conditions, the corresponding dimethyl acetal 11 could be isolated, which rapidly decomposed to 10 under ambient conditions, thus demonstrating that the addition of methanol to the terminal alkyne of 3a is favored over the attack of the alkene moiety. Similar results were obtained when other alcohols were employed as the external nucleophiles.
The use of carbonucleophiles such as indole, 1,3-diketones, and electron-rich benzenes only resulted in the recovery of unreacted 3a. Nevertheless, when the reaction of 3a was performed with commercially available gold(I) complex A in the presence of acetic acid, complete conversion of 3a was achieved in 1 h, leading to the formation of rearranged product 12 in up to 61% yield (Scheme 4). A closer mechanistic inspection of this transformation suggested that the gold(I)catalyzed reaction initially forms intermediate 14 that rearranges to form allyl cation 15, which is trapped by acetic acid. DFT calculations indicated that the formation of intermediate 16 that leads to 12 is thermodynamically favored over the formation of 17, which is predicted to be the driving force for the rearrangement to take place. This result further illustrates the influence of the cyclopropane functionality on the reaction pathways followed in the gold(I)-catalyzed cyclizations of cyclopropane-tethered 1,5-enynes 23 and underscores the propensity of the strained tetracyclic system of echinopines to undergo rearrangements. 6 In order to unequivocally ensure the structure of 12, the acetate moiety was cleaved to form alcohol 18, which was converted into the corresponding crystalline p-nitrobenzoate derivative 19, whose structure was confirmed by X-ray diffraction (Scheme 5). 24 In addition, a related system having one of the double bonds reduced was also examined with the aim of promoting a rearrangement toward the echinopine skeleton on the basis of the higher stability of carbocation 24 over 22 predicted by DFT calculations. Thus, 18 could be selectively hydrogenated in the presence of Crabtree's catalyst to give 20, which was converted into tertiary carbocation 22 via triflate 21. Nonetheless, the rearranged product was not observed and only nonrearranged elimination product 23 was isolated under different reaction conditions. The synthesis of the homologous 1,6-enyne 4a commenced with the cobalt-catalyzed [6 + 2] cycloaddition between cycloheptatriene and alkyne 25 followed by treatment with N-iodosuccinimide, which afforded vinyl iodide 27 (Scheme 6). Kumada cross-coupling of 27 with (3-(trimethylsilyl)prop-2-yn-1-yl)magnesium bromide furnished 28, which was treated with HF·py to give allylic alcohol 29. Cyclopropanation of the tetrasubstituted olefin followed by deprotection of the terminal alkyne and protection of the primary alcohol gave rise to tricyclic 1,6-enyne 4a. However, all attempts to perform the alkoxycyclization of 4a in the presence of different gold(I) complexes provided only traces of the cyclized tetracyclic product and resulted in the formation of methyl ketone 31 as the major product.
Aldehydes 9a,b 25 were next employed as the platform to access a series of tricyclic 1,6-enynes featuring different functionalities at the propargylic position. Thus, the addition of ethynylmagnesium bromide provided 4b,c as single diastereoisomers and their alkoxycyclization was investigated Scheme 3. Formal Hydration of 3a Scheme 4. Gold-Catalyzed Rearrangement of 3a a using methanol as the external nucleophile in the presence of a series of gold(I) complexes spanning a range of electrophilicities. The desired alkoxycyclization products could only be detected from the reactions carried out in the presence of phosphine−gold(I) complexes, whereas gold(I) complexes bearing NHC and phosphite ligands gave complex mixtures. 26 Cationic gold(I) complex B provided the best results, and the use of the alcohol as the solvent proved to be optimal for the alkoxycyclization of enynes 4b,c to afford regio-and stereoselectively tetracyclic products 32a−c, which feature the [3,5,5,7] tetracyclic skeleton of echinopines (Scheme 7). While the reaction of 4b with methanol provided 32a as a single regioisomer, the analogous reaction of 4c gave rise to a 5:1 mixture of regioisomers. Nonetheless, changing the external nucleophile from methanol to allyl alcohol in the reaction of 4c resulted in the exclusive formation of 32c as the sole isomer. The structure of tetracycles 32a−c could be confirmed from the X-ray crystal structure of 32a. 24 Interestingly, the propargylic alcohol of enynes 4b,c was substituted by a second molecule of alcohol in the gold(I)catalyzed cyclization process. In order to elucidate the order of events in this transformation, the closely related system 34 in which the 1,3-diene had been reduced to the corresponding alkane was submitted to the optimized reaction conditions for the gold(I)-catalyzed alkoxycyclization (Scheme 8). However, after 2 h only hydroxyketone 35 and unreacted 34 were detected from the crude mixture and no substitution of the propargylic alcohol was observed. 26 This result supports a catalytic cycle in which the propargylic alcohol in 4b,c is eliminated after the cyclization of the enyne by the attack of a molecule of methanol to intermediate 36, which generates α,βunsaturated gold(I) carbene intermediate 37. 27 The attack of a second molecule of alcohol to 37 forms 38, which releases tetracycles 32 by protodeauration (Scheme 9).
Ketoenynes 4d,e were also prepared by direct oxidation of 4b,c, and their alkoxycyclization under the optimized reaction conditions provided mixtures of the two possible regioisomeric products 39a′,b′ and 39a″,b″, 28 which could be separated by preparative chromatography (Scheme 10). Water could also be used as the external nucleophile to afford inseparable mixtures of regioisomeric allylic alcohols 39c′,d′/39c″,d″ in moderate yields.
■ EXPERIMENTAL SECTION General Remarks. Chemicals and solvents for chromatography were used as received. Solvents used in reactions under an inert atmosphere were dried by passing through an activated alumina column on a solvent purification system. Analytical thin-layer chromatography was carried out using TLC-aluminum sheets with 0.2 mm of silica gel (Merck FG254) with UV light as the visualizing agent or an acidic solution of vanillin in ethanol as the developing agent. Purifications by chromatography were carried out using flash grade silica gel (SDS Chromatogel 60 ACC, 40−60 mm). Preparative TLC was performed on 20 cm × 20 cm silica gel plates. Organic solutions were concentrated under reduced pressure on a rotary evaporator. NMR spectra were recorded at 298 K on 300, 400, and 500 MHz devices. 1 H and 13 C chemical shifts (δ) are given in ppm relative to TMS, and coupling constants (J) in Hz. Mass spectra were recorded employing TOF mass analyzers (ESI, APCI). Melting points were determined by observation of the fusion of the solids placed in a capillary, through a magnifying glass. Crystal structure determinations were carried out using a diffractometer equipped with an APPEX 2 4K CCD area detector, an FR591 rotating anode with Mo Kα radiation, Montel mirrors as the monochromator, and a Kryoflex low temperature device (T = −173°C). Full-sphere data collection was used with ω and φ scans. Programs used: data collection APEX-2, data reduction Bruker Saint V/.60A, and absorption correction SADABS. Structure solution and refinement: crustal structure solution was achieved using direct methods as implemented in SHELXTL and visualized using the program XP. Missing atoms were subsequently located from difference Fourier synthesis and added to the atom list. Least-squares refinement on F 2 using all measured intensities was carried out using the program SHELXTL. All non-hydrogen atoms were refined including anisotropic displacement parameters.