Subtitle: Catalytic asymmetric polyene cyclization of homofarnesol to norbergris ether
The polyene cyclization reaction is one of the most complex and challenging reactions in nature. Catalyzed by enzymes, multiple carbon-carbon bonds, ring systems and chiral centers are constructed from acyclic precursors in one step, and then complex molecular backbones are assembled from simple precursors. For example, squalene cyclase (SHC) is able to efficiently convert acyclic triterpene squalene to pentacyclic (+)-hopene (Figs. 1a, 1b). According to the Stork-Eschenmoser hypothesis, cyclases are able to facilitate substrate pre-organization and conformational selection, stabilize transient charges, and specifically select the initial protonation site (Figs. 1c, 1d). In addition, squalene is also considered to be a biosynthetic precursor of triterpene (+)-ambergris alcohol (the main component of ambergris), and the most important odor component in ambergris is the rare natural terpenoid compound (−)-ambergris ether (2a), which is generally formed by photooxidation of (+)-ambergris alcohol. To date, the most effective synthesis method of (−)-ambergris ether is polyene cyclization using genetically engineered SHCs. Inspired by SHC and other terpene cyclases, chemists have worked to develop small molecule catalysts to achieve polyene cyclization, but precise control of product distribution and stereochemistry is not an easy task (Figure 1c) because: 1) regioselective protonation of distal double bonds of polyene substrates is critical to avoid the formation of by-products6 and 7; 2) undesirable diastereomers produced by cyclopedanasol 3 protonation were formed in a stepwise process; 3) Enantiometric control of the entire cyclization process to obtain a single enantiomer ambergris is extremely challenging.
Recently, a research team led by Nobel laureate and professor of the Max Planck Institute for Coal Research in Germany (click to view the introduction) successfully achieved an asymmetric polyene cyclization reaction of high farnesol using a chiral super Brønsted acid catalyst with confined spatial structure - iminobisphosphospholimididate (IDPi) developed in the group (Fig. 1e), and constructed (−)- with good yield and excellent enantioselectivity and diastereoselectivity. Ambergris ether and sesquiterpene lactone natural product (+)-perilla lactone. Experimental studies have shown that the reaction is mainly carried out through a synergistic pathway consistent with the Stork-Eschenmoser hypothesis, while mechanistic studies have shown that the enzyme-like microenvironment of the IDPi catalyst is essential for achieving ultra-high selectivity. The results were published in Nature.
Figure 1. (−)-The origin of ambergris ether and its polyene cyclization synthesis. Image source: Nature
First, the authors selected (3E,7E)-homofarnesol as the template substrate to screen solvents and chiral Brønsted acid catalysts, and the results showed that fluorinated alcohols such as hexafluoroisopropanol (HFIP) could significantly improve the reactivity, and the IDPi catalyst could convert homofarnesol to norabnesin 2a and its minor diastereomers 5β,8α,9β-norabrisole 2c. Based on this, the authors optimized the IDPi catalyst with diverse structures (Fig. 2a), and the results showed that the catalyst 8d (HFIP as solvent) could obtain product 2a with a yield of 40% and a value of 7:93 e.r., and further screening showed that the spirocyclohexyl-2-fluorenyl-substituted IDPi catalyst 8g (perfluorobutanol PFTB as solvent) could achieve a yield of 54%, a > of 20:1 d.r. and a value of 95:5 The e.r. value is obtained to obtain product 2a, which means that the IDPi catalyst is able to form two C-C bonds and one C-O bond in a one-step process, while simultaneously performing stereo control of four stereocenters, including a quaternary carbon stereocenter. In addition, a complex mixture of products was obtained when the reaction was performed with a strongly acidic but less structurally constrained PADI catalyst 9 (Fig. 2b), further demonstrating the importance of the catalyst-confined active site. As shown in Figure 2c, the authors also performed a ten-gram scale synthesis, and after quantitative recovery and purification, the catalyst was quantitatively recovered and purified with a yield of 52%, a value of 92:8 d.r., and a value of 95:5 e.r. to (−)-norbergris ether (5.2 g), and some cyclized products 5 and 10 (both yields of 47%), which corresponds to a theoretical volume productivity of 296 g l-1 in a 20 h reaction time, while the currently optimized (−)-norbergris ether biocatalytic production process is 72 The complete conversion of 300-450 g l-1 (3E,7E)-homofarnesol can be achieved within h. Finally, the authors also applied the method to the asymmetric synthesis of the natural product (+)-perilla lactone, a key intermediate in the industrial synthesis of ambergris ether (Fig. 2D). Specifically, the reaction of (3E,7E)-faranic acid (prepared from (E)-nerolidol) in an IDPi catalyst at 8g and PFTB yielded the desired natural product with a yield of 46%, a >value of 7:1 d.r., and a value of 94:6 e.r.12.
Figure 2. Optimization and scale-up of reaction conditions. Image source: Nature
In order to further explore the mechanism of polyene cyclization, the authors conducted a series of experiments. Specifically: 1) there are two possible mechanisms for the formation of tricyclic compound 2a from linear polyene 1a (Fig. 3a), namely the synergistic cyclization cascade mechanism and the stepwise formation mechanism; 2) In two independent experiments, small but statistically significant 13C KIEs were observed for each double bond of the recovered (3E,7E)-homofarnesol (Figure 2b), indicating that protonation and C-C bond formation proceeded simultaneously; 3) Deuterium labeling experiments at -40°C showed that only a single deuteration site (i.e., 3eq) was observed for IDPi 8g-catalyzed polyene cyclization product 2a, suggesting that most of the (−)-ambergris ole was produced by synergistic polyene cyclization in the presence of IDPi 8g (Fig. 3c), while multiple deuterium labeling sites were observed for PADI-catalyzed polyene cyclization product 2a, which is characteristic of the stepwise process; 4) All possible diastereomers of homofarnesol were placed under IDPi 8g catalyzed conditions for polyene cyclization (Figure 3d), and according to the Stork-Eschenmoser hypothesis, each diastereomer could be cyclized by synergistic polyene to form the corresponding tricyclic ether product, although (3E,7Z)- and (3Z,7Z)-homofarnesol (1c and 1d) would need to be raised to -30 °C for conversion.
Figure 3. Mechanistic studies. Image source: Nature
To gain insight into the origin of the high chemoselectivity, diastereoselectivity, and enantioselectivity, the authors reacted substrate 1a in HFIP or PFTB solvents and monitored the enantiomeric and diastereomeric ratios by gas chromatography and high-performance liquid chromatography (HPLC) (Figs. 4a, 4b), which showed that the enantioselectivity and diastereoselectivity of product 2a remained essentially unchanged in PFTB (95:5 e.r. and >). 20:1 d.r.), but in HFIP, the enantioselectivity of product 2a increases (91:9→95:5 e.r.) and decreases (2a:2c:>) with enantioselectivity as the reaction progresses20:1→89:11 d.r.), and the cyclic perfarnesol intermediates 3a and 3c were also detected, and the ratio of 3a:3c changed from 1:2 to 2:1 during the reaction, indicating that the kinetic extra-ring double bond product 3c isomerized to the thermodynamic intra-ring double bond isomer 3a, and the enantiomer ratio of α-isomer 3a (16:84 e.r.) was significantly lower than that of γ-isomer 3c (1:99), indicating the existence of kinetic resolution. In addition, 5β,8α,9β-ambergris ether2C was obtained at a similar enantiomer ratio (1.5:98.5) throughout the reaction (Fig. 4D), indicating that it was formed by protonation of the 3C axial conformational isomer; The increase in the enantiomer ratio of ambergris ether can be explained by the protonation of the 3C equatorial conformational isomer and the formation of the enantiopure ambergris ether, so the protonation of the enantiopure γ-cycloperfarnesol 3C equatorial and axial conformational isomers may be the reason for the observed increased enantioselectivity and decreased enantioselectivity. In contrast, the high diastereoselectivity observed in PFTB for 2a appears to be the result of highly synergistic polyene cyclization and stepwise pathway inhibition. To explore this hypothesis, the authors investigated the reactivity of the monocyclic intermediates by placing individual isomers (3a, 3b, and 3c) under reaction conditions (Fig. 4c), which showed that only γ-cycloperfarnesol 3c was converted to the ambergris ether isomers 2a and 2c in HFIP, and the α- and β-isomers 3a and 3b produced only trace tricyclic ethers (<5%); In PFTB, the conversion rates of 3a, 3b, and 3c were all <5%, which is consistent with the deuterium labeling experiment, indicating that protonation of single-ring intermediates does not occur in the stepwise pathway at -40°C. On the other hand, partial cyclization product 5 and isomerization product 10 (due to protonation of monocyclic intermediates) were obtained when the reaction was performed at -30 °C, suggesting that the restricted active site of IDPi prefers the more accessible double bond near the alcohol over the crowded cyclohexene. In summary, the authors suggest that the key to the high diastereoselectivity and enantiomeric selectivity obtained using catalyst 8g is that the synergistic reaction pathway is superior to the stepwise process (Fig. 4D).
Figure 4. Origin of diastereoselectivity and enantioselectivity, reactivity of single-ring intermediates, and possible mechanisms. Image source: Nature
summary
Prof. Benjamin List's group used the IDPi catalyst to achieve a challenging asymmetric polyene cyclization reaction, and constructed (−)-norbergris ether and sesquiterpene lactone natural products (+)-perilla lactones with good yields and excellent enantioselectivity and diastereoselectivity. Experimental studies have shown that the reaction is mainly carried out through a synergistic pathway consistent with the Stork-Eschenmoser hypothesis, while mechanistic studies have shown that the enzyme-like microenvironment of the IDPi catalyst is essential for achieving ultra-high selectivity. It is foreseeable that this method will be widely used in the related polyene cyclization reactions, and may accelerate the asymmetric synthesis process of natural products, drug molecules, and fragrances.
The catalytic asymmetric polyene cyclization of homofarnesol to ambrox
Na Luo, Mathias Turberg, Markus Leutzsch, Benjamin Mitschke, Sebastian Brunen, Vijay N. Wakchaure, Nils Nöthling, Mathias Schelwies, Ralf Pelzer, Benjamin List
Nature, 2024, DOI: 10.1038/s41586-024-07757-7
Instructor introduction
Benjamin List
https://www.x-mol.com/university/faculty/50088