Gold-catalyzed stereoselective cycloisomerization of allenoic acids for two types of common natural γ-butyrolactones

γ-(E)-Vinylic and γ-alkylic γ-butyrolactones are two different types of lactones existing extensively in animals and plants and many of them show interesting biological activities. Nature makes alkylic γ-butyrolactones by many different enzymatic lactonization processes. Scientists have been mimicking the natural strategy by developing new catalysts. However, direct and efficient access to γ-(E)-vinylic γ-butyrolactones is still extremely limited. Here, we wish to present our modular allene approach, which provides an efficient asymmetric approach to (E)-vinylic γ-butyrolactones from allenoic acids by identifying a new gold complex as the catalyst. Based on this cycloisomerization strategy, the first syntheses of racemic xestospongiene and xestospongienes E, F, G, and H have been realized and the absolute configurations of the chiral centers in xestospongienes E and F have been revised. In addition, by applying a C–O bond cleavage-free hydrogenation, the syntheses of naturally occurring γ-alkylic γ-lactones, (R)-4-tetradecalactone, (S)-4-tetradecalactone, (R)-γ-palmitolactone, and (R)-4-decalactone, have also been achieved.

N atural products are a big treasure for human beings, which exhibit rich academic and industrial potentials due to their structural diversity and biological activities. As we know, γ-butyrolactones with common structures of γ-(E)vinylic and alkylic γ-butyrolactones, E-I 1-4 and II 5-10 , exist extensively in nature and many of them have been identified with interesting biological potentials, such as anti-HIV 1 , antifungal 2,9 , cytotoxic 3 , anti-bacterial 7 , anti-proliferative 8 activities, etc., featuring applications in pharmacy (Fig. 1). Some of these lactones, especially for aliphatic γ-butyrolactones, are also common flavor source in plants and food, which involved in several metabolic pathways 11 .

Results
Synthesis of AuCl(LB-Phos). At the beginning, we treated (R a )-4,5-tridecadienoic acid (R a )-5a (for its synthesis from aldehyde and terminal alkyne, see: Supplementary Tables 1 and 2) as the model substrate. After screening of some commonly used gold catalysts such as AuCl, AuCl(IPr), Au 2 Cl 2 (dppm), Au 2 Cl 2 (dppm) combined with AgOTs was identified as the first generation catalyst to afford the desired γ-1(E)-alkenyl (S)-γ-butyrolactone (S, E)-6a in a quantitative yield with a E/Z selectivity of 93:7 and 96% ee in CHCl 3 at room temperature for 3 h ( Table 1, entry 1). For the purpose of improving the E/Z selectivity, we tried to identify a more stereoselective catalyst. Based on our recent development of monophosphine ligands 44 , some of the gold complexes of these ligands have been prepared. AuCl(LB-Phos), the structure of which was determined by X-ray single crystal diffraction study ( Fig. 3) 45 , is one of them.
Optimization of reaction conditions. With this rather sterically bulky AuCl(LB-Phos), gladly, an E/Z selectivity of 97:3 with 100% yield and 97% ee was observed, indicating that the new catalyst was able to control both the C=C stereoselectivity and ensure the efficiency of chirality transfer (    5,[7][8]. In the absence of AgOTs, the expected product 6a was obtained in only 8% yield with 92% recovery of (R a )-5a after 24 h (Table 1, entry 9), and the lactonization couldn't take place by just using AgOTs (Table 1, entry 10), indicating the significance of the gold-catalysis. Examining the effect of different salts showed the importance of the counter anion: AgPF 6 resulted in the same E/Z-selectivity but with a lower ee of 92% ( Substrate scope. With the optimized reaction conditions in hand, differently substituted 4,5-allenoic acids (R a )-5 were treated with AuCl(LB-Phos) to afford γ-1(E)-alkenyl (S)-γ-butyrolactones in high yields (93-98%) with an excellent axial-to-center chirality transfer and E/Z-selectivity (up to >99:1 E/Z) ( Table 2): R could be primary alkyl: n-heptyl (6a), n-butyl (6b), n-undecyl (6c), and phenylethyl (6g), or branched alkyl: i-Pr (6d), and Cy (6e). The reaction of benzyl-substituted (R a )-5f should be conducted at −40°C for 6 h to keep the enantioselectivity due to the observed racemization at 25°C (6f) (compare entry 6 with entry 7 in Natural γ-vinylic γ-butyrolactones E-I  Fig. 2 Known approaches and the designed general protocol to γ-butyrolactones E-I and II. a Nature's enzymatic approaches; b Baeyer-Villiger oxidation; c Alkenoate dihydroxylation; d Allene enantioselective approach described in refs. [14][15][16] . e Au-catalyzed chirality transfer-based asymmetric cyclization of allenoic acids (this work) Table 2). Functional groups including benzyl group, C=C, and C≡C bonds were also tolerated (6f, 6g, 6h, and 6i).
The effect of different gold catalysts. The results of different gold catalysts combined with AgOTs in CHCl 3 are listed in Table 3, which showed that AuCl(LB-Phos) was indeed the best catalyst (Table 3, entry 6).
Synthesis of racemic xestospongiene. Such a strategy should deliver a direct entry to the optically active natural γbutyrolactone with common structure E-I as shown in Fig. 1a. Xestospongienes are a series of brominated polyunsaturated lipids isolated from the Chinese marine sponge Xestospongia testudinaria (shown in Fig. 1a) 4 . No total synthesis has been reported yet. Thus, 7-((tert-butyldimethylsilyl)oxy)heptanal 7 underwent 1,2-addition reaction with ethyl magnesium bromide to yield propargylic alcohol 8. Methylation of 8 via deprotonation with NaH, followed by quenching with MeI, and subsequent removal  Table 1 Optimization of the reaction conditions for AuCl(LB-Phos)-catalyzed stereoselective cyclization of 4,5-allenoic acid (R a )-5a  (2 mL) were stirred at room temperature for 15 min under nitrogen atmosphere; then 0.2 mmol (R a )-5a and solvent (1 mL) were added a Determined by 1 H NMR of the crude product using 1,3,5-trimethylbenzene as internal standard b Determined by chiral high-performance liquid chromatography (HPLC) analysis c 2.5 mol% Au 2 Cl 2 (dppm) was used instead of AuCl(LB-Phos) d The reaction was conducted at 25°C e 1,2-DCE: 1,2-dichloroethane f 92% recovery of (R a )-5a g The reaction was conducted in the absence of AuCl(LB-Phos); 100% recovery of (R a )-5a of the TBS group via acidic hydrolysis yielded the primary alcohol 9 with a terminal C-C triple bond in 88% yield. Fe(III)-catalyzed aerobic oxidation of 9 afforded aldehyde 10 in 62% yield 46 . Wittig olefination of the aldehyde functionality in 10 afforded the terminal alkyne 1c 47 , which underwent the ATA (allenylation of terminal alkynes) reaction with methyl 4-oxobutanoate 2k (readily available from γ-butyrolactone in 2 steps 48 ) in the presence of diphenylprolinol rac-3a in a sealed tube at 130°C 49 to yield 4,5-allenoate rac-4ck in 64% yield. Through hydrolysis, allenoic acid rac-5k was prepared in 96% yield with a d.r. of 1.07:1, which underwent the gold-catalyzed cycloisomerization with 10 mol% catalyst at −30°C for 24 h (for details, see Supplementary Table 4) to afford rac-xestospongiene in an excellent yield and E/Z ratio of 99:1 (Fig. 5).

Discussion
A facile strategy for general asymmetric synthesis of two types of common γ-butyrolactones from readily available common chemicals-terminal alkynes and aldehydes-has been developed by applying the newly identified catalyst, AuCl(LB-Phos), with the stereoselectivity of up to >99:1 E/Z and >99% ee. The first total syntheses of xestospongienes E, F, G, and H have been realized with high stereoselectivity. In addition, the C-O bond cleavagefree hydrogenation led to a general access to naturally occurring γ-alkyl γ-butyrolactones, such as (R)-4-tetradecalactone, (S)-4-tetradecalactone, (R)-γ-palmitolactone, and (R)-4-decalactone, efficiently with ee of 93-96%. Such a modular solution to two different types of optically active γ-butyrolactones will surely stimulate further interest in the synthetic and bio-potential of these compounds and identifying even better aromas for human life. Further studies on this area are being carried out in our laboratory.

Methods
General method for cycloisomerization of alkadienoic acids. To a dry Schlenk tube were added AgOTs (0.0142 g, 0.05 mmol, weighed in glove box, 98%), AuCl (LB-Phos) (0.0299 g, 0.05 mmol), and CHCl 3 (5 mL) under nitrogen atmosphere sequentially. After stirring for 15 min, (R)-trideca-4,5-allenoic acid (R a )-5a (0.2108 g, 1 mmol) and CHCl 3 (5 mL) were added. After being continuously stirred at 25°C for 3 h, the reaction was complete as monitored by thin layer chromatography (TLC). Data availability. All data that support the findings of this study are available in the online version of this paper in the accompanying Supplementary Methods (including experimental procedures, compound characterization data).
The X-ray crystallographic coordinates for structure of AuCl(LB-Phos) reported in this study has been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number CCDC 1558142. This data can be obtained free