One-step catalytic asymmetric synthesis of all-syn deoxypropionate motif from propylene: Total synthesis of (2R,4R,6R,8R)-2,4,6,8-tetramethyldecanoic acid

In nature, many complex structures are assembled from simple molecules by a series of tailored enzyme-catalyzed reactions. One representative example is the deoxypropionate motif, an alternately methylated alkyl chain containing multiple stereogenic centers, which is biosynthesized by a series of enzymatic reactions from simple building blocks. In organic synthesis, however, the majority of the reported routes require the syntheses of complex building blocks. Furthermore, multistep reactions with individual purifications are required at each elongation. Here we show the construction of the deoxypropionate structure from propylene in a single step to achieve a three-step synthesis of (2R,4R,6R,8R)-2,4,6,8-tetramethyldecanoic acid, a major acid component of a preen-gland wax of the graylag goose. To realize this strategy, we focused on the coordinative chain transfer polymerization and optimized the reaction condition to afford a stereo-controlled oligomer, which is contrastive to the other synthetic strategies developed to date that require 3–6 steps per unit, with unavoidable byproduct generation. Furthermore, multiple oligomers with different number of deoxypropionate units were isolated from one batch, showing application to the construction of library. Our strategy opens the door for facile synthetic routes toward other natural products that share the deoxypropionate motif.The deoxypropionate motif, an alternately methylated alkyl chain containing multiple stereogenic centers, is a common substructure found in natural products synthesized by bacteria, fungi, and plants (Fig. 1) (1). Because of the range of biological activities and abundance of this motif in natural products, its synthesis has received a great amount of attention (2, 3).Open in a separate windowFig. 1.Selected examples of natural products containing the deoxypropionate motif.In nature, the deoxypropionate motif is synthesized by using propionyl-CoA (or methylmalonyl-CoA) as a C3 building block (Fig. 2A). The deoxypropionate chain propagates by Claisen condensation of propionyl-CoA and acyl-CoA moiety at the chain end. After consecutive reduction of the β-ketone, dehydration, and asymmetric reduction of the carbon–carbon double bond, the deoxypropionate motif is elongated. We predicted that if the preparation of the deoxypropionate motif were possible by the asymmetric oligomerization of propylene, which is one of the simplest C3 building blocks, we could construct the analog of biosynthetic pathway in an even simplified manner (Fig. 2B).Open in a separate windowFig. 2.Synthesis of the deoxypropionate motif. (A) Biosynthetic scheme. (B) Synthesis by asymmetric oligomerization of propylene (current study). (C) Synthesis by iterative asymmetric carboalumination (7). (D) Synthesis by iterative asymmetric conjugate addition (11).To demonstrate our strategy, we chose (2R,4R,6R,8R)-2,4,6,8-tetramethyldecanoic acid 1 as a synthetic target. This carboxylic acid is a natural product containing the deoxypropionate motif, and is a major acid component of preen-gland wax of the graylag goose (4). Its total synthesis has been reported by two groups, both involving the oxidation of (2R,4R,6R,8R)-2,4,6,8-tetramethyldecan-1-ol 2. By using our strategy, this intermediate 2 can be constructed in a single step, significantly shortening the overall synthetic route.Conventionally, the deoxypropionate motif has been synthesized mainly using iterative reactions of complex building blocks or stoichiometric amount of organometallic reagents with unavoidable byproduct generation (e.g., inorganic salts) at each step. Previously reported synthetic routes include enolate alkylation (5, 6), carboalumination (7), organocuprate displacement (8), homologation of boronic esters (9), and conjugate addition (10). In addition, due to their iterative nature, long reaction sequences of 3–6 steps per unit were required to yield the desired products. As for the synthesis of 2, Liang et al. used an asymmetric carboalumination (Fig. 2C) (7), whereas ter Horst et al. used an asymmetric conjugate addition of methylcopper species (Fig. 2D) (11). Due to the iterative nature of methyl-branched chiral center formation, these syntheses required a total of 8–17 steps. Recently, convergent strategies for the synthesis of the deoxypropionate motif have been reported to shorten the synthetic route but generation of byproducts remains unavoidable (12, 13).Notably, propylene polymerization catalysts have rarely been used in the stereoselective oligomerization for synthesis of short oligomers, despite the great effort that has been devoted to the development of both homogeneous and heterogeneous catalysts for the highly isoselective propylene polymerization (14, 15). In 1987, Pino et al. reported an asymmetric propylene oligomerization catalyzed by enantiomerically pure chiral zirconocene in the presence of dihydrogen to afford saturated isotactic oligopropylenes (16). Kaminsky et al. later reported the preparation of moderately stereoregular oligomers with unsaturated chain end, which can be converted to other functional groups (17). To achieve natural product synthesis by the asymmetric oligomerization of propylene, a combination of stereoselectivity, functionalizability, and control over initiating groups is required. We herein report the one-step diastereoselective and enantioselective construction of the deoxypropionate motif by coordination chain transfer polymerization using an alkylmetal species as a chain-transfer agent (CTA) (18, 19). Our objective is to achieve highly stereoselective propylene oligomerization using this method. In addition, it is expected that the resulting oligomers will be end-capped with metals, thus enabling further functionalization.