Metal-free alkene carbooxygenation following tandem intramolecular alkoxylation/Claisen rearrangement: stereocontrolled access to bridged [4.2.1] lactones

A metal-free intramolecular tandem sequence involving alkoxylation, Claisen rearrangement and lactone expansion has been achieved.


Introduction
Bridged [4.2.1] lactones are widely distributed heterocycles found in various natural products such as hushinone and citrinovirin, and bioactive compounds (Fig. 1). 1 However, such bicyclic frameworks bearing both a medium ring and bridged unit are regarded as difficult skeletons to construct due to entropic effects and the ring strain factor, 2 and very few methods have been reported to date. 1, 3 Hence, novel and stereocontrolled synthesis of bridged [4.2.1] lactone motifs allowing structurally diverse modication is in great demand in both organic and medicinal chemistry.
Difunctionalization of unactivated olens in a single operation is one of the most valuable transformations in organic chemistry. 4 Among them, alkene carbooxygenation is particularly attractive as this approach provides an efficient access to various oxygen-containing molecules, especially the valuable Oheterocycles, and various synthetic methods have been developed. 4 However, examples of catalytic alkene carbooxygenation via a direct C-O cleavage are quite scarce, and the C-O cleavage in these cases is invariably initiated by transition metal-catalyzed oxidative addition (Scheme 1a). 5,6 For example, Douglas et al. reported an elegant protocol for the rhodium-catalyzed intramolecular alkene oxyacylation reaction via an acyl C-O bond activation. 6a,b In 2012, Nakao et al. disclosed an intramolecular oxycyanation of alkenes by palladium/BPh 3 catalysis. 6c Thus, the development of an alternative approach for the catalytic cleavage of the C-O bond and the addition reaction to the alkenes is highly desirable.
Because of their high bond-forming efficiency and atom economy, catalytic tandem intramolecular alkoxylation/Claisen rearrangements have received signicant attention. 7 In particular, such a cascade cyclization of alkynyl allyl ethers could lead to the formation of various valuable O-heterocycles, which is also established by Hashmi, Liu, Gagosz, Miyata, and others (Scheme 1a). 8-10 While these achievements are impressive, almost all of these approaches rely on the use of noble metals such as gold and platinum as catalysts. In our recent study on the catalytic tandem reactions of ynamides for heterocycle synthesis, 11,12 we realized the rst metal-free intramolecular alkoxylation/Claisen rearrangement of indole-linked ynamideallyl ethers (Scheme 1b). Interestingly, the resulting sixmembered lactone intermediate further underwent an unprecedented Brønsted acid-catalyzed intramolecular carbooxygenation of olens by C-O bond cleavage involving ring opening, carbocation rearrangement, and then ring closing. This Brønsted acid catalysis led to the highly efficient and stereocontrolled formation of valuable indole-fused bridged [4.2.1] lactones. Furthermore, such an asymmetric cascade cyclization was also realized by employing a traceless chiral directing group. The mechanistic rationale for this cascade reaction is strongly supported by a variety of control experiments. In this paper, we wish to report the results of our detailed investigations of this novel cascade cyclization, including the substrate scope, synthetic applications, biological tests and mechanistic studies.

Results and discussion
Inspired by our previous work on the indolyl ynamide chemistry, 12d-f we chose an indole-tethered ynamide 1a as the model substrate for the initial study. As shown in Table 1, indole-fused lactone 2aa was obtained in the presence of most non-noble metals (Table 1, entries 1-4), with Cu(OTf) 2 giving the best yield of the desired 2aa (Table 1, entry 4). Different from Hashmi's protocol, 8b N-methyl methanesulfonamide here not only serves as the directing group to achieve regioselective attack at the Nterminus of alkyne, but also can be removed spontaneously and regarded as a traceless directing group. Surprisingly, indolefused bridged [4.2.1] lactone 2a was detected as the main product by employing In(OTf) 3 or Fe(OTf) 3 as catalysts (Table 1, entries 5-6). Of note, typical gold catalysts, such as Ph 3 PAuNTf 2 and IPrAuNTf 2 , were not effective in promoting this reaction and the decomposition of 1a was observed in these cases (Table  1, entries 7-8). Various Brønsted acids were also evaluated, but typical organic acids (e.g., TFA, MsOH, and TsOH) were not capable of catalyzing the reaction. 13 Gratifyingly, HOTf and HNTf 2 (Table 1, entries 9-10) could effectively catalyze this cascade cyclization, 14 and the bridged lactone 2a was obtained in 81% yield in the latter case (Table 1, entry 10). The reaction proved to be less efficient when it was performed at 60 C (Table 1, entry 11) or in other solvents. 13 The observed excellent efficiency with HNTf 2 as the catalyst can be explained by its high Brønsted acidity combined with the low nucleophilicity of its counterion. 15,16 Scheme 1 Catalytic alkene carbooxygenation via a C-O cleavage. With the optimal reaction conditions in hand (Table 1, entry 10), the scope of this novel tandem reaction was explored (Table 2). This metal-free cascade cyclization proceeded efficiently to furnish a series of indole-fused bridged [4.2.1] lactones in mostly good to excellent yields. For instance, various indolyl-substituted ynamides bearing both electron-donating and -withdrawing groups could be readily converted into the desired indole-fused bicyclic skeletons 2a-2p with yields ranging from 60% to 86%. In particular, the functional groups, such as CF 3 , CN and CO 2 Me, were well tolerated under this Brønsted acid catalysis. Further investigation of N-protecting groups demonstrated that the Bs-and Ms-protected substrates 1q-1r gave slightly improved yields. In addition, an ynamide with a methyl group (R 1 ¼ Me) was also a suitable substrate for this tandem reaction to afford the corresponding 2s in 63% yield (dr: 4 : 1). This result clearly indicated that [3,3] rearrangement, but not [1,3] rearrangement, 17 was presumably involved in this multiple cascade sequence. 13 Furthermore, the reaction also occurred smoothly with various aryl-or methylsubstituted ynamides (R 2 ¼ aryl, Me), and the desired 2t-2z containing a quaternary carbon center could be formed in 60-75% yields by employing 30 mol% of HNTf 2 as the catalyst. Importantly, excellent diastereoselectivity (>20 : 1) was achieved in all cases except for the substrate 1s. The molecular structures of 2a, 2s and 2u were conrmed by X-ray diffraction. 18 Thus, this metal-free protocol provides a highly convenient and practical route for the preparation of valuable bridged [4.2.1] lactones.
In addition, this multiple cascade reaction was also applicable to other electron-rich aromatic ring-substituted ynamides such as benzofuran-, pyrrole-, and alkoxy arene-tethered ynamides 3a-3c, delivering the desired bridged [4.2.1] lactones 4a-4c in serviceable yields with excellent dr values (>20 : 1), as depicted in eqn (1)- (3). Of note, the use of HFIP as an additive led to a signicantly improved yield in the case of 3c (eqn (3)). 19 Attempts to extend the reaction to non-terminal alkenesubstituted ynamide 3d, indole-linked ynamide-allyl amine 3e and sulde 3f led to the formation of complicated mixtures. Although our attempts to employ various chiral Brønsted acids such as chiral phosphoric acids and chiral phosphoric amides to catalyze this cascade cyclization failed probably due to the fact that their acidity is not strong enough, the chiral bridged [4.2.1] lactones could be synthesized by employing a chiral oxazolidinone instead of N-methyl methanesulfonamide as the directing group. 20 As shown in eqn (4), it was found that the tert-butyl substituted oxazolidinone-derived chiral ynamide 5d gave the best enantioselectivity, and the desired chiral bridged [4.2.1] lactone 2a-ent was formed in 55% yield with 95% ee in the presence of 30 mol% of HNTf 2 as the catalyst and 1.5 equiv. of water as the additive. Thus, the chiral auxiliary can be regarded as a traceless directing group to introduce the chirality in a very facile manner. It should be mentioned that signicant racemization was observed when prolonging the reaction time. 13 The scope of this asymmetric intramolecular alkoxylationinitiated tandem reaction was further examined by using tertbutyl substituted oxazolidinone-derived chiral ynamides. As depicted in Table 3, the reaction proceeded smoothly with various chiral ynamides 5, allowing the facile synthesis of the corresponding enantioenriched bridged [4.2.1] lactones 2-ent in serviceable yields with excellent ee values (91-99% ee) and excellent dr values (>20 : 1). Of note, (R)-tert-butyl substituted oxazolidinone-derived chiral ynamide 5d 0 could also undergo smooth cascade cyclization to deliver the desired 2a-ent 0 with the opposite enantioselectivity.
The potential synthetic utility of this protocol was then demonstrated by the facile diversication of bridged lactone 2a, and importantly, excellent diastereoselectivity was achieved in all cases (Scheme 2). For example, the Ts group in lactone 2a, prepared on a gram scale in 72% yield, was easily removed by treatment with TBAF to afford the corresponding 2ab in 75% yield. In addition, the lactone part of 2a could be selectively reduced to furnish the hemiacetal 2ac (91%, dr > 10 : 1) with DIBAL-H. By contrast, the use of Et 3 SiH led to the total reduction of the lactone to produce the desired 2ad in almost quantitative yield. Interestingly, 2a could also be oxidized with DDQ to deliver 2ae in 95% yield. Moreover, the ring of lactone 2a was readily opened by employing PhLi, leading to the stereocontrolled construction of cyclohepta [b]indole scaffold 2af, frequently occurring in natural products and bioactive molecules. 21 Finally, the chiral 2a-ent could be further transformed into the indole-fused cycloheptanone 2ah with the ee maintained, and its structure was conrmed by X-ray diffraction, 18 which also determined the absolute conguration of 2aent. 22 Considering the bioactivity reported in the literature for bridged [4.2.1] lactone systems, 1 we also tested the above Table 3 Reaction scope for the construction of chiral bridged [4.2.1] lactones 2-ent a a Reaction conditions: 5 (0.2 mmol), HNTf 2 (0.06 mmol), water (0.3 mmol), dry DCE (2 mL), 30 C, in vials; yields are those for the isolated products; determined by HPLC analysis. b 40 C, 20 min. c 30 min. d Using (R)-congured ynamide 5d 0 as the substrate.
To understand the reaction mechanism, several control experiments were conducted. First, we performed deuterium labeling studies and found that no deuterium loss was observed, thus ruling out any possible reaction pathways involving a hydride shi (eqn (5)). Importantly, 2aa was readily converted into 2a in 95% yield in the presence of HNTf 2 while no 2a was formed without an acid catalyst, 13 strongly supporting the notion that 2aa is the key intermediate for this tandem reaction (eqn (6)). In addition, the formation of cyclohepta [b] indole 2ai (dr > 20 : 1) was detected when 2aa was treated with 10 equiv. of MeOH in the presence of HNTf 2 , which indicates that the cationic intermediate is presumably involved in such a tandem sequence (eqn (7)). Of note, 2a could not be converted into 2ai in the presence of HNTf 2 and MeOH. 13 Moreover, the cascade cyclization of ynamide 3g or 3h under the standard conditions only led to the formation of the corresponding 4ga (42%) or 4ha (85%), and no desired bridged lactone product was observed (eqn (8) and (9)). These results further suggest that the intramolecular alkene insertion into the C-O bond proceeds via a carbocation pathway, and the generation of a stable electronrich benzylic carbocation is the key for this lactone expansion process. Finally, it was found that signicant incorporation of 18 O (>85%) into the product 2a was observed in the presence of 18 O-labelled water (10 equiv.), indicating that the oxygen atom on the carbonyl group of 2a originates from water. 13 Based on the above experimental observations, a plausible mechanism to rationalize the formation of indole-fused bridged [4.2.1] skeleton 2 is proposed (Scheme 3). Initially, the alkoxy group attacks the acid-activated ynamide 1 to form the Claisen rearrangement precursor A via a keteniminium intermediate, which undergoes typical [3,3] rearrangement and subsequent trapping by trace water, delivering the indole-fused lactone D 23 (that is, 2aa in the case of substrate 1a) along with the generation of sulfonamide. Brønsted acid further promotes the ring opening of lactone D to produce the carbocation intermediate F via C-O bond cleavage. Finally, the carbocation of F is trapped by an intramolecular electron-rich alkenyl group to generate another carbocation intermediate G, which is further captured by the intramolecular carboxylic acid group to afford the nal product 2. 24 Notably, the low nucleophilicity of Tf 2 N À might be important to maintain the cationic nature and/or reactivity of certain intermediates involved. 15

Conclusions
In summary, we have developed a novel Brønsted acid-catalyzed intramolecular alkoxylation-initiated tandem sequence, which represents the rst metal-free intramolecular alkoxylation/ Claisen rearrangement to the best of our knowledge. Signicantly, an unprecedented Brønsted acid-catalyzed intramolecular alkene insertion into the C-O bond via a carbocation pathway was discovered, which may serve as an alternative approach for alkene carbooxygenation via a direct C-O cleavage. This method enables efficient and stereocontrolled access to This journal is © The Royal Society of Chemistry 2019 valuable indole-fused [4.2.1] lactones under mild reaction conditions, providing ready access to biologically relevant scaffolds in a single synthetic step from an acyclic precursor. Moreover, such an asymmetric cascade cyclization was also realized by employing a traceless chiral directing group. A mechanistic rationale for this novel tandem reaction is well supported by a variety of control experiments. In addition, our preliminary biological tests showed that some of these newly synthesized indole-fused lactones exhibited their bioactivity as antitumor agents against different breast cancer cells, melanoma cells, and esophageal cancer cells. Thus, we believe that this novel multiple cascade reaction will not only inspire chemists to design new rearrangement processes, but also encourage them to nd their potential usefulness in organic and medicinal chemistry.

Conflicts of interest
There are no conicts to declare.