The catalytic asymmetric polyene cyclization of homofarnesol to ambrox

Abstract

Polyene cyclizations are among the most complex and challenging transformations in biology. In a single reaction step, multiple carbon-carbon bonds, ring systems and stereogenic centres are constituted from simple, acyclic precursors^1-3. Simultaneously achieving this kind of precise control over product distribution and stereochemistry poses a formidable task for chemists. In particular, the polyene cyclization of (3E,7E)-homofarnesol to the valuable naturally occurring ambergris odorant (-)-ambrox is recognized as a longstanding challenge in chemical synthesis^1,4-7. Here we report a diastereoselective and enantioselective synthesis of (-)-ambrox and the sesquiterpene lactone natural product (+)-sclareolide by a catalytic asymmetric polyene cyclization by using a highly Brønsted-acidic and confined imidodiphosphorimidate catalyst in the presence of fluorinated alcohols. Several experiments, including deuterium-labelling studies, suggest that the reaction predominantly proceeds through a concerted pathway in line with the Stork-Eschenmoser hypothesis^8-10. Mechanistic studies show the importance of the enzyme-like microenvironment of the imidodiphosphorimidate catalyst for attaining exceptionally high selectivities, previously thought to be achievable only in enzyme-catalysed polyene cyclizations.

Fig. 1. Origin of the ambergris odorant (−)-ambrox and its synthesis by polyene cyclizations.

a, Polyene cyclization of squalene to (+)-hopene and (+)-ambrein catalysed by class II terpene cyclases and formation of the odorant (−)-ambrox from (+)-ambrein, the main constituent of ambergris. b, Active site of SHC in complex with its inhibitor 2-azasqualene (PDB code: 1UMP) (ref. ). The conserved DXDD motif required for substrate protonation is highlighted. c, Mechanistic considerations for the polyene cyclization of (3E,7E)-homofarnesol to (−)-ambrox. d, Stork–Eschenmoser hypothesis for the stereospecific antiparallel addition of carbenium ion to an alkene in 1,5-polyolefin cyclizations. e, Catalytic asymmetric concerted polyene cyclization of (3E,7E)-homofarnesol to (−)-ambrox realized in this work. Depictions of SHC and the substrate/catalyst model have been rendered using UCSF Chimera X (refs. ^,).

Fig. 2. Reaction optimization and scale-up.

a, Catalyst screening and optimization of the polyene cyclization of (3E,7E)-homofarnesol to (−)-ambrox. See Supplementary Information for details. b, Stacked gas chromatography traces of the crude reaction mixture obtained with PADI 9 (top) and IDPi 8g (middle) as catalysts. Enantiopure (−)-ambrox is shown as a reference (bottom). c, Scale-up of the catalytic asymmetric polyene cyclization in the presence of IDPi catalyst 8g in PFTB affording (−)-ambrox. d, Technical synthesis of (3E,7E)-homofarnesic acid 11 from (E)-nerolidol and catalytic asymmetric polyene cyclization of 11 to (+)-sclareolide. r.t., room temperature; d.r., diastereomeric ratio; e.r., enantiomeric ratio; e.e., enantiomeric excess.

Fig. 3. Mechanistic studies.

a, Mechanistic scenarios for a concerted and a stepwise pathway. b, ¹³C KIEs observed at natural abundance in recovered 1a. The experiment was performed in duplicate and the standard deviation is shown. c, Deuterium-labelling study in PFTB-d₁ at −40 °C using (S,S)-IDPi catalyst 8g or (S)-PADI catalyst 9 with the respective ²H{¹H} NMR spectrum of the tricyclic ether fraction. d, Polyene cyclization of all possible homofarnesol diastereomers to the corresponding tricyclic ethers and rationalization of the obtained products by the respective transition states according to the Stork–Eschenmoser hypothesis.

Fig. 4. Origin of diastereo- and enantioselectivity, reactivity of monocyclic intermediates and mechanistic proposal.

a, Identified intermediates and products in the reaction of 1a to 2a in HFIP or PFTB. b, Yield, enantiomeric excess (e.e.) and diastereomeric excess (d.e.; 2a:2c) over time in HFIP/1H,1H-perfluorooctan-1-ol at −23 °C according to gas chromatography and HPLC analysis. c, Reactivity of cyclohomofarnesols 3 in HFIP and PFTB. d, Mechanistic proposal for the formation of 2a and its diastereomer 2c in HFIP/1H,1H-perfluorooctan-1-ol and PFTB.