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

Significance

Synthetic strategies for deoxypropionate motif reported to date mainly use iterative elongations, thus requiring many reaction steps to obtain the desired natural product. Additionally, such methods also require the preparation of complex building blocks. Here, we have developed a one-step construction of deoxypropionate motif by stereo-controlled propylene oligomerization. Our method using propylene as a very simple building block provides the shortest, three-step access to a natural product whose preparation conventionally required at least 10 steps. Furthermore, multiple oligomers with different number of deoxypropionate units can be isolated from the same oligomerization product, enabling the construction of library. Because deoxypropionate motif is found in a variety of biologically active compounds, our method would impact the field of synthetic organic chemistry.

Abstract

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).

Fig. 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).

Fig. 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.

Results and Discussion

Optimization of Reaction Conditions for Diastereoselective Propylene Oligomerization.

Zirconocene rac-ethylenebis(4,5,6,7-tetrahydroindenyl)zirconium(IV) dichloride (rac-3-Cl₂), a highly isoselective olefin polymerization catalyst, was used for the propylene oligomerization. The reaction conditions were first optimized to afford oligomeric alkanes. Namely, the generated alkylmetal species were quenched by proton and the yields of the alkanes were determined by GC analysis. The conditions examined for propylene oligomerization are summarized in Table 1. Using ∼2,000 equiv. (against rac-3-Cl₂) of AlMe₃ as a CTA, propylene was charged under constant pressure (1 bar) at 0 °C (entry 1). The product mixture was then quenched by aqueous HCl and analyzed by GC and GC-MS. The polypropylene product mixture obtained in entry 1 contained both solid and liquid components, although no oligopropylenes shorter than 12-mer were observed, even in the liquid phase. When the reaction temperature was raised to 40 °C, oligomerization proceeded, but many stereo- and regioisomers were observed by GC following protonation of alkylaluminum species 4 (entry 2; see SI Appendix, Fig. S11 for GC trace). Using ZnEt₂ as the CTA, a single peak was detected for each oligomer of the oligopropylenes 5 at 0 °C (entry 3, Fig. 3, Bottom), whereas the use of bis(cyclopentadienyl)zirconium(IV) dichloride (Cp₂ZrCl₂) resulted in formation of multiple peaks for each oligomer (Fig. 3, Top). Considering that the rac-3-Cl₂ and Cp₂ZrCl₂ complexes form highly isotactic and atactic polypropylenes (20), respectively, the existence of a single peak for each oligomer (Fig. 3, Bottom) implies that oligomerization took place in a highly diastereoselective manner with rac-3-Cl₂. The difference of diastereoselectivity between entries 2 and 3 may be explained by the observation by Longo et al.: Stereospecificity of propylene insertion into a metal--carbon bond is very high for metal–CH₂CH₃, but it is much lower for metal–CH₃ (21). Thus, we used a combination of rac-3-Cl₂ and ZnEt₂ for the following experiments. Oligopropylenes 5 were end-capped with Zn before protonation, as confirmed by GC-MS analysis of the products quenched by D₂O compared with those quenched by MeOH (SI Appendix, Fig. S22).

Table 1.

Oligomerization of propylene

^*(A) Propylene was added using a balloon. (B) Reaction vessel was charged with propylene before oligomerization. (C) Propylene was added under constant pressure. See SI Appendix for detailed procedures.

^†Against 3-Cl₂.

^‡Based on the amount of M in MR_n.

^§Diastereomeric ratio (d.r.) of 4-mer 5 calculated from GC trace based on peak area.

^¶Amount of vinylidene-terminated 4-mer 5′ against main diastereomer of 4-mer 5. Calculated from GC trace, based on peak area. n.d., not determined.

Fig. 3.

GC traces of the crude product 5 from oligomerizations using Cp₂ZrCl₂ (Top) and rac-3-Cl₂ (entry 3, Bottom). Peaks indicated with asterisks correspond to the impurities derived from solvent or catalyst.

The effect of reaction temperature on oligomerization was then investigated. When the reaction temperature was increased from –20 °C to 0 °C, the ratio of short oligomers (trimer and tetramer) increased, possibly due to faster transmetallation between Zr and Zn (entries 3, 4, and 5). However, larger amounts of vinylidene-terminated oligopropylenes 5′ were also obtained at elevated temperatures, possibly originating from the undesired β-hydride elimination. We therefore concluded that the optimal temperature for construction of the deoxypropionate structure was –20 °C.

The ratio of propylene and the CTA used was also influential. As the amount of ZnEt₂ was increased from ∼2,000 equiv. to ∼5,000 equiv. (against rac-3-Cl₂), the ratio of shorter oligomers increased, possibly due to the increased possibility of transmetallation from Zr to Zn (entry 6). When the reaction was carried out in the stainless steel autoclave with a higher initial propylene pressure, activity was improved compared with when a balloon filled with propylene was used as the gas source (entries 7 and 8). Diastereoselectivity also improved, although the reason for this remains unclear. In the case of the tetramer, for example, the sum of the minor peak areas shown was <1% versus the main product peak. The activity was further improved with a constant propylene pressure of 2.0 bar (entry 9). A longer reaction time resulted in a higher yield (entry 10), whereas a higher reaction temperature afforded higher ratios of the shorter oligomers and a lower diastereoselectivity (entries 9, 11, and 12). Under the same reaction conditions, the amount of ZnEt₂ was again decreased from ∼5,000 equiv. to ∼2,000 equiv., and the activity was improved (entry 13). We therefore selected the conditions outlined in entry 13 as our optimal conditions, as these conditions gave high diastereoselectivity, alkane/alkene ratio, and yield. For entry 13, the yield of each oligomer, based on the amount of zinc used, was estimated by integration of the GC peak areas using decane as an internal standard, giving the following oligomeric yields: trimer = 9.6%, tetramer = 7.9%, and pentamer = 6.5%.

Asymmetric Oligomerization, Consecutive Oxidation, and Separation of Oligomer/Alcohols.

Following optimization of the oligomerization conditions, the process was expanded to asymmetric oligomerization (Fig. 4A). By using (S,S)-3-Cl₂ instead of racemic mixture, oligomerization was carried out under the same conditions as outlined in entry 13 in Table 1 to afford oligomers in the similar yields: trimer = 12%, tetramer = 10%, and pentamer = 8.2%. Then the in situ oxidation of alkylzinc species 4 was performed using dioxygen at 0 °C for 2 h (22, 23), giving the corresponding alcohols 6 as major products, as observed by GC (Fig. 4B, Top) and GC-MS analyses. The resulting tetramer/alcohol 2 was successfully isolated from a mixture of alcohols by a series of chromatographic processes. The crude mixture was first purified by silica-gel column chromatography (hexane/ethyl acetate = 10:1 vol/vol) to remove alkanes. The resulting alcohol mixture was then separated by reverse-phase HPLC. The purity of the separated 2 (3.8% yield based on ZnEt₂) was confirmed by GC (Fig. 4B, Bottom), ¹H NMR (SI Appendix, Fig. S3), and ¹³C NMR (SI Appendix, Fig. S4) analyses (for analytical methods, please see the SI Appendix) (7, 11, 24), and the enantiomeric excess was confirmed by chiral GC analysis to be ≥99% compared with rac-2 that was prepared using rac-3-Cl₂ (Fig. 4C). The product 2 exhibited an optical rotation of ${\text{[α]}}_{\mathrm{D}}^{24}$ = +7.11 (c = 0.51, CHCl₃), which is similar to the reported values of 2 (11, 24).

Fig. 4.

Asymmetric oligomerization of propylene and subsequent oxidation, and isolation of 2. (A) Optimized procedure for the asymmetric oligomerization of propylene, and successive oxidation to the alcohol. (B) GC traces of the crude alcohol products from asymmetric oligomerization using (S,S)-3-Cl₂, and subsequent O₂ oxidation (Top) and isolated 2 (Bottom). (C) Chiral GC traces of rac-2 synthesized using rac-3-Cl₂ (Top) and 2 synthesized using (S,S)-3-Cl₂ (Bottom).

Three-Step Synthesis of 1.

Isolated tetramer/alcohol 2 was then oxidized to corresponding carboxylic acid 1 in two steps according to the literature procedure (7). The three-step total yield of 1 based on the amount of zinc was 1.2%. Thus, the synthesis of 1 in three steps as described above is the shortest known sequence to date. In addition, the propylene oligomerization and oxidation sequence can be incorporated into the synthetic route to the insect pheromone, 9-norlardolure, as its synthesis from compound 2 is already reported in literature (Fig. 5) (25).

Fig. 5.

Literature conversion of 2 to 9-norlardolure (25).

Simultaneous Synthesis of Multiple Oligomers.

The unique feature of our strategy is that all oligomer/alcohols given as side products also have the deoxypropionate motif because C3 building unit is used for elongation. To demonstrate application to the construction of library, we isolated trimer, tetramer, and pentamer/alcohols simultaneously from the crude mixture of oligomers by reverse-phase HPLC. After one more round of purification of each fraction by reverse-phase HPLC, pure oligomers were isolated. Each oligomer was characterized by ¹H and ¹³C NMR and GC-MS analyses (detailed characterization including optical rotation values are provided in the SI Appendix).

Concluding Remarks

In summary, we established a one-step route to the construction of the all-syn deoxypropionate motif, found in a number of natural products, by the asymmetric oligomerization of propylene, with both stereoselectivity and chain-end functionalizability. This methodology enabled the shortest reported preparation of 1 in only three steps. We also demonstrated that multiple oligomers with different number of deoxypropionate units can be simultaneously isolated from one batch, showing application of this strategy to the construction of library. To allow the application of this method to a broad range of natural products, installation of a functional moiety into the initiating group and the use of alternative chain-end functionalization are required, along with chain length control to improve the yields of the desired oligomers. Studies in these fields are currently underway in our laboratory.

Methods

Representative Procedure for Asymmetric Propylene Oligomerization and Subsequent Oxidation.

A mixture of (S,S)-3-Cl₂ (0.43 mg, 1.0 µmol, Aldrich), 8.9 wt% (Al) methylaluminoxane solution in toluene (0.30 g, 1.0 mmol, Tosoh Finechem), 1.0 M ZnEt₂ solution in toluene (2.0 mL, 2.0 mmol, Tokyo Chemical Industry), and toluene (dehydrated, 1.0 mL, Kanto Chemical) was stirred under constant propylene pressure (0.20 MPa) in a 50-mL stainless steel autoclave for 16 h at –20 °C. Following propylene venting, the reaction vessel was warmed to 0 °C, and oxygen was bubbled through the reaction mixture for 2 h. Aqueous HCl (20 mL, 1 M) was then added, and the crude mixture was sonicated for 10 min before filtration. The separated organic phase was concentrated for purification by silica-gel column chromatography (Hex/EtOAc = 10:1 vol/vol). Each fraction was analyzed by GC (InertCap 5MS/Sil, GL Sciences), and those containing 2 were collected and evaporated. Following further purification by RP-HPLC (Mightysil RP-18 GP, Kanto Chemical, eluted with MeOH), 16.3 mg (3.8% yield from ZnEt₂) of 2 was obtained as a colorless oil. Further details can be found in the SI Appendix.