Gold(I)-Catalyzed Stereoselective Cyclization of 1,3-Enyne Aldehydes by 1,3-Acyloxy Migration/Nazarov/Aldol Cascade
Stereoselective synthesis of bicyclo[3.3.0]octenones from chiral 1,3-enyne aldehydes bearing propargylic acetates is described. The method is based on a Au(I)-catalyzed domino sequence with concomitant transfer of chirality involving 1,3-acyloxy migration followed by Nazarov cyclization and an unprecedented aldol addition. The method furnishes densely functionalized bicyclic structures in high yields, up to 97% ee, and good diastereoselectivity.
Introduction<!>Results and Discussion<!>Table 1 Optimization of reaction conditions.a<!>Conflicts of interest
<p>In recent years, Au(I) complexes have been demonstrated to be powerful catalysts for the activation of alkynes, giving rise to a diversity of new and efficient catalytic transformations leading to high molecular complexity. 1 Among these, Au(I)-catalyzed reactions of enynes bearing propargylic carboxylates have been found to be especially versatile. 2 A particularly valuable feature of Au-catalysis is that it enables sequential formation of numerous C-C bonds via cascading cycloisomerization processes. Herein, we document a stereoselective process in which acyclic propargylic enynes with pendant aldehydes are converted into optically active, highly functionalized diquinanes. The cascade reaction proceeds through 1,3-acyloxy migration, Nazarov cyclization, and aldol addition. Thus, in one pot the method leads to the generation of functionalized, fused five-memberred rings bearing three contiguous stereocenters. In pioneering studies, Zhang and Wang reported the Au(I)-catalyzed synthesis of cyclopentenones from readily available enyne esters. 3 The proposed mechanism involves 1,3-acyloxy migration followed by Nazarov cyclization, [1,2]-hydride shift, deauration, and hydrolysis of the intermediate cyclopentadienyl acetate formed (C, Figure 2a). 4 In light of the mechanistic model, we wondered whether aldehydes incorporated into the starting enynes could be trapped in situ by C and form diquinanes (2). 5 The consequence of such a process is to add an aldol addition reaction to a cascade that includes 1,3migration and Nazarov cyclization, which to our surprise was unprecedented. This would require that aldehydes in the starting enynes are compatible with and survive the intervening steps and thereby subsequently be engaged as electrophile. In the ideal scenario, Au(I) would function as a catalyst in all three fundamental steps of the cascading sequence: 1,3-acyloxy migration, Nazarov cyclization, and aldol reaction. In 2009, Malacria and Fensterbank demonstrated that the Au(I)-vinylcarbene 6 formed from Nazarov cyclization (5) could participate in intramolecular cyclopropanations with substrates incorporating olefin side chains (Figure 2b). 4,7 Importantly, this is the sole example of concomitant transfer of chirality from an enantioenriched propargylic acetate. The fact that optically active propargyl acetates furnish optically active cycloalkanes led to the suggestion of an intermediate "bent-allene" complex (A) 4,8 that serves as the conduit for the transmission of the stereochemical information in the starting materials to enantioenriched products. 9 Accordingly, starting from a readily accessible chiral linear precursor, the domino reaction would be envisioned to give rise to highly functionalized optically active bicyclo[3.3.0]octenones with the configuration of the starting propargyl acetate potentially determining the configuration of all three stereocenters in the final product. We recently reported the first asymmetric total synthesis of (-)-merochlorin A (7), relying on the key Au(I)-catalyzed reaction cascade described herein to access the diquinane core (Fig. 3). 10 Intrigued by the significant potential of this transformation, we were interested in investigating this novel reaction cascade for its general applicability as a synthetic method for the synthesis of optically active bicyclo[3.3.0]octanes, which are abundant structural motifs in natural products. 11</p><p>LAu CHO ? ?</p><p>[1,2]-H shift/ deauration 2 a) Mechanistic Working Model:</p><!><p>Our synthetic studies commenced with the investigation of readily available chiral enyne (R)-1a (98% ee, Table 1). Thus, 1a was treated with various gold complexes. While AuCl 3 , AuCl(PPh 3 )/AgSbF 6 , and Ipr AuCl/AgSbF 6 (11) furnished enone 2a in either poor yield or with poor chirality transfer, treatment of 1a with 5 mol% Au(MeCN)(JohnPhos)SbF 6 (Echavarren's catalyst, 3) 12 in THF gave 2a in 71% yield, 91% ee, and a d.r. of 85:15 (entry 4). It is noteworthy that 6% of aldol acetate 10a was isolated, a product arising from acetate transfer during the terminating aldol reaction. Furthermore, initial screening revealed that the reaction benefits from the presence of 0.2 vol% H 2 O in the reaction mixture (see Supporting Information, SI), which is consistent with prior reports of H 2 O favoring the formation of A. 4a Screening of reaction media (entries 4-7) revealed that solvents other than THF led to decreased d.r. and increased formation of acetate 10a. Interestingly, when the reaction was conducted in CH 2 Cl 2 in the absence of water, aldol acetate 10a was found to be the dominant product (entry 5). When the influence of the reaction temperature was investigated, optimal performance was found at -10 °C, leading to 76% of the desired bicyclo[3.3.0]octenone with 93% ee and 89:11 d.r. (entry 8).</p><!><p>Entry Catalyst Solvent Yield 2 [b] Yield 3 [b] ee [c] d.r. With the optimized reaction conditions in hand, the scope of this method was examined next (Table 2). In the event, arenes incorporating various substituents were examined. Electron withdrawing groups (CF 3 , CO 2 Me, Cl, F) were well tolerated, leading to the isolation of the corresponding pentalenes in high yields and ee (2a-2f). Ortho-fluorinated arene 2g showed some deleterious effects on chirality transfer. Strikingly, however, >20:1 d.r. was observed. A 3-naphthyl group was also compatible, affording 2h in 86% yield and 91% ee. Electron donating groups were found to be problematic. 13 However, the cyclization of protected aniline and phenol proceeded smoothly, furnishing the corresponding enones 2i and 2j in high yield and ee. The observed diastereoselectivity may be explained by consideration of a pair of possible transition states TS1 and TS2 (Table 2), in which the former suffers from destabilizing nonbonding interactions absent in the latter.</p><p>Table 2 Substrate scope of the stereoselective 1,3-acyloxy migration/Nazarov/aldol sequence a a Reaction conditions: 5 mol% 3, 0.2 vol% H 2 O, THF (0.05 M), -10 °C. b Reaction warmed to RT after 16 h. c Isolated yield over two steps from the primary alcohol.</p><p>We next examined enyne aldehydes substituted with aliphatic groups. Enyne 1k bearing a methyl substituent was found to be a suitable substrate, affording 2k in 63% yield with 90% ee, albeit poor diastereoselectivity. Nevertheless, introduction of a sterically more demanding isopropyl led to increased 90:10 d.r. (2l). Benzyloxy-substituted alkyl chain was tolerated to give 2m in 72% yield and 95% ee. Pentalene 2n including a benzoyl-protected alcohol is an intermediate of the total synthesis of (-)merochlorin A (7) 10 and was obtained with excellent transfer of chirality (97% ee) from the acyclic starting material (98% ee). These findings considerably expand the utility of the procedure developed, as it allows for the synthesis of highly functionalized aliphatic bicyclo[3.3.0]octenones. The absolute configuration was determined by X-ray crystallographic analysis of 2e and 2j, which confirmed the mechanistic model established by Fensterbank and Malacria for 6 (Fig. 4, see SI). A salient feature of this transformation is the formation of a quaternary center at a ring junction. Such substitution would otherwise be cumbersome to access via conventional synthetic approaches such as arylation or alkylation of this sterically hindered position. Fig. 4 Absolute configuration assigned by X-ray crystallographic analysis of (R,R,R)-2e and (R,R,R)-2j. For ORTEP representations the thermal ellipsoids are shown at 50% probability.</p><p>To further demonstrate the utility of this method, we were curious to explore if the aldehyde is able to undergo the aldol reaction when placed at a different position within the starting material. For this purpose, we synthesized enyne 11 (d.r. >20:1) using Enders' SAMP protocol (see SI). 14 Remarkably, triquinane 12 was isolated as a single diastereomer in 60% yield when 11 was subjected to the standard reaction conditions (5 mol% 3, 0.2 vol% H 2 O, THF) at room temperature (Fig. 5). Furthermore, propargylic enyne 13 (E/Z = 6:1) underwent smooth cyclization to give enone 14 (74%, 78% ee) as a single diastereomer. The absolute configuration of 14 was determined by X-ray crystallographic analysis. Much to our delight, the Au(I)-catalyzed reaction cascade developed herein is thus useful for the synthesis of enantioenriched bicyclo[3.3.0]octane, spiro [4.4]nonane and tricyclo[6.3.0.01,5]undecane systems.</p><p>In 1974, Mukaiyama and co-workers reported the reaction of vinyl acetates with acetal-and carbonyl compounds in the presence of strong Lewis acids (TiCl 4 , SnCl 4 , BF 3 •Et 2 O) to afford the corresponding aldol products in modest yield. 7 In light of this report, the aldol reaction described of a cyclopentadienyl acetate in the presence of the Lewis acidic Au(I)-catalyst is remarkable, because Au(I) is believed to be a weaker Lewis acid towards carbonyls than Ti(IV), Sn(IV), and BF 3 . 15,16 In principle, two different mechanistic pathways can be proposed (Fig. 6). Acetate 15, formed after initial 1,3-acyloxy migration/Nazarov cyclization, may first be hydrolyzed under the employed standard reaction conditions (Table 1, entry 8) to give cyclopentadienyl enolate 16, which then undergoes intramolecular aldol reaction to afford pentalene 1. Importantly, while the initial hydrolysis may be mediated by the Au(I)-catalyst, this pathway fails to account for the formation of acetate 10. Alternatively, the aldol reaction could proceed directly form the enol acetate to give 17, which then could either undergo hydrolysis to produce enone 1 or suffer intramolecular acetate transfer to afford acetate 10.  Optimization studies (Table 1) revealed that the Au(I)-catalyzed tandem 1,3-acyloxy migration/Nazarov cyclization/aldol reaction sequence occurs in the absence of water. In particular, if the reaction is conducted in dry solvents such as THF or CH 2 Cl 2 , acetate 10a is isolated as the major product (Fig. 7, A). Furthermore, isolated enol acetate 18 does not participate in intramolecular aldol reaction or hydrolysis under the standard reaction conditions in absence of the Au(I)-catalyst (Fig 7, B). However, treatment of 18 with 5 mol% of Echavarren's catalyst (3) furnished the desired products 2a and 10a in high yield. In summary, these results suggest that the Au(I)-catalyst is involved in all three reaction steps and the terminal aldol reaction indeed proceeds directly from the enol acetate. Nevertheless, the possibility of a second operative pathway via initial hydrolysis of 18 in wet solvent in the presence of Au(I)- catalyst cannot be entirely excluded. We surmise that the water present under the standard reaction conditions primarily suppresses the acetate transfer via hydrolysis of oxocarbenium ion intermediate 17 (Fig. 6). In conclusion, a Au(I)-catalyzed stereoselective tandem 1,3-acyloxy migration/Nazarov/aldol cascade has been developed. In a single step, this method allows for the generation of two rings bearing three contiguous stereocenters, one of them being quaternary. The bicyclo[3.3.0]octenones obtained are isolated in high yields and with high stereoselectivity. The ability of intermediate cyclopentadienyl acetates to undergo intramolecular gold(I)-catalyzed aldol reaction constitutes a reactivity pattern with great potential to provide the foundation for new cascading sequences leading to highly functionalized building blocks. Studies to apply this method to complex systems and to include it in further total syntheses of natural products are currently ongoing in our laboratories and will be reported in due course.</p><!><p>The authors declare no conflict of interest.</p>