One-step catalytic asymmetric synthesis of all-syndeoxypropionate motif from propylene: Total synthesisof (2R,4R,6R,8R)-2,4,6,8-tetramethyldecanoic acidYusuke Ota (太田祐介)a,1, Toshiki Murayama (村山駿輝)a,1, and Kyoko Nozaki (野崎京子)a,2

aDepartment of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan

Edited by Jerrold Meinwald, Cornell University, Ithaca, NY, and approved January 26, 2016 (received for review September 23, 2015)

In nature, many complex structures are assembled from simplemolecules by a series of tailored enzyme-catalyzed reactions. Onerepresentative example is the deoxypropionate motif, an alternatelymethylated alkyl chain containing multiple stereogenic centers, whichis biosynthesized by a series of enzymatic reactions from simplebuilding blocks. In organic synthesis, however, the majority of thereported routes require the syntheses of complex building blocks.Furthermore, multistep reactions with individual purifications arerequired at each elongation. Here we show the construction of thedeoxypropionate structure from propylene in a single step toachieve a three-step synthesis of (2R,4R,6R,8R)-2,4,6,8-tetrame-thyldecanoic acid, a major acid component of a preen-gland waxof the graylag goose. To realize this strategy, we focused on thecoordinative chain transfer polymerization and optimized the re-action condition to afford a stereo-controlled oligomer, which iscontrastive to the other synthetic strategies developed to datethat require 3–6 steps per unit, with unavoidable byproduct gen-eration. Furthermore, multiple oligomers with different number ofdeoxypropionate units were isolated from one batch, showingapplication to the construction of library. Our strategy opens thedoor for facile synthetic routes toward other natural products thatshare the deoxypropionate motif.

deoxypropionate | propylene | coordinative chain transfer polymerization

The deoxypropionate motif, an alternately methylated alkylchain 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 biologicalactivities and abundance of this motif in natural products, itssynthesis has received a great amount of attention (2, 3).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 Claisencondensation of propionyl-CoA and acyl-CoA moiety at the chainend. After consecutive reduction of the β-ketone, dehydration, andasymmetric reduction of the carbon–carbon double bond, thedeoxypropionate motif is elongated. We predicted that if thepreparation of the deoxypropionate motif were possible bythe asymmetric oligomerization of propylene, which is one of thesimplest C3 building blocks, we could construct the analog ofbiosynthetic pathway in an even simplified manner (Fig. 2B).To demonstrate our strategy, we chose (2R,4R,6R,8R)-2,4,6,8-

tetramethyldecanoic acid 1 as a synthetic target. This carboxylicacid is a natural product containing the deoxypropionate motif,and is a major acid component of preen-gland wax of the graylaggoose (4). Its total synthesis has been reported by two groups,both involving the oxidation of (2R,4R,6R,8R)-2,4,6,8-tetrame-thyldecan-1-ol 2. By using our strategy, this intermediate 2 can beconstructed in a single step, significantly shortening the overallsynthetic route.Conventionally, the deoxypropionate motif has been synthesized

mainly using iterative reactions of complex building blocks or stoi-chiometric amount of organometallic reagents with unavoidable

byproduct generation (e.g., inorganic salts) at each step. Previouslyreported synthetic routes include enolate alkylation (5, 6), car-boalumination (7), organocuprate displacement (8), homologationof boronic esters (9), and conjugate addition (10). In addition, due totheir iterative nature, long reaction sequences of 3–6 steps per unitwere required to yield the desired products. As for the synthesis of2, Liang et al. used an asymmetric carboalumination (Fig. 2C) (7),whereas ter Horst et al. used an asymmetric conjugate addition ofmethylcopper species (Fig. 2D) (11). Due to the iterative natureof methyl-branched chiral center formation, these syntheses re-quired a total of 8–17 steps. Recently, convergent strategies forthe synthesis of the deoxypropionate motif have been reported toshorten the synthetic route but generation of byproducts remainsunavoidable (12, 13).Notably, propylene polymerization catalysts have rarely been

used in the stereoselective oligomerization for synthesis of shortoligomers, despite the great effort that has been devoted to thedevelopment of both homogeneous and heterogeneous catalystsfor the highly isoselective propylene polymerization (14, 15). In1987, Pino et al. reported an asymmetric propylene oligomeri-zation catalyzed by enantiomerically pure chiral zirconocene inthe presence of dihydrogen to afford saturated isotactic oligo-propylenes (16). Kaminsky et al. later reported the preparationof moderately stereoregular oligomers with unsaturated chainend, which can be converted to other functional groups (17). Toachieve natural product synthesis by the asymmetric oligomer-ization of propylene, a combination of stereoselectivity,

Significance

Synthetic strategies for deoxypropionate motif reported todate mainly use iterative elongations, thus requiring manyreaction steps to obtain the desired natural product. Addi-tionally, such methods also require the preparation of complexbuilding blocks. Here, we have developed a one-step con-struction of deoxypropionate motif by stereo-controlled pro-pylene oligomerization. Our method using propylene as a verysimple building block provides the shortest, three-step accessto a natural product whose preparation conventionally re-quired at least 10 steps. Furthermore, multiple oligomers withdifferent number of deoxypropionate units can be isolatedfrom the same oligomerization product, enabling the con-struction of library. Because deoxypropionate motif is found ina variety of biologically active compounds, our method wouldimpact the field of synthetic organic chemistry.

Author contributions: Y.O. and K.N. designed research; Y.O., T.M., and K.N. performedresearch; Y.O., T.M., and K.N. analyzed data; and Y.O., T.M., and K.N. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.1Y.O. and T.M. contributed equally to this work.2To whom correspondence should be addressed. Email: nozaki@chembio.t.u-tokyo.ac.jp.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1518898113/-/DCSupplemental.

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functionalizability, and control over initiating groups is required.We herein report the one-step diastereoselective and enan-tioselective construction of the deoxypropionate motif bycoordination chain transfer polymerization using an alkyl-metal species as a chain-transfer agent (CTA) (18, 19). Ourobjective is to achieve highly stereoselective propylene oligo-merization using this method. In addition, it is expected that theresulting oligomers will be end-capped with metals, thus en-abling further functionalization.

Results and DiscussionOptimization of Reaction Conditions for Diastereoselective PropyleneOligomerization. Zirconocene rac-ethylenebis(4,5,6,7-tetrahy-droindenyl)zirconium(IV) dichloride (rac-3-Cl2), a highly isoselectiveolefin polymerization catalyst, was used for the propylene oligomer-ization. The reaction conditions were first optimized to affordoligomeric alkanes. Namely, the generated alkylmetal specieswere quenched by proton and the yields of the alkanes weredetermined by GC analysis. The conditions examined forpropylene oligomerization are summarized in Table 1. Using∼2,000 equiv. (against rac-3-Cl2) of AlMe3 as a CTA, pro-pylene was charged under constant pressure (1 bar) at 0 °C(entry 1). The product mixture was then quenched by aqueousHCl and analyzed by GC and GC-MS. The polypropyleneproduct mixture obtained in entry 1 contained both solid andliquid components, although no oligopropylenes shorter than12-mer were observed, even in the liquid phase. When thereaction temperature was raised to 40 °C, oligomerizationproceeded, but many stereo- and regioisomers were observedby GC following protonation of alkylaluminum species 4(entry 2; see SI Appendix, Fig. S11 for GC trace). Using ZnEt2as the CTA, a single peak was detected for each oligomerof 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 eacholigomer (Fig. 3, Top). Considering that the rac-3-Cl2 andCp2ZrCl2 complexes form highly isotactic and atactic poly-propylenes (20), respectively, the existence of a single peakfor each oligomer (Fig. 3, Bottom) implies that oligomeriza-tion took place in a highly diastereoselective manner with rac-3-Cl2. The difference of diastereoselectivity between entries 2and 3 may be explained by the observation by Longo et al.:Stereospecificity of propylene insertion into a metal–carbonbond is very high for metal–CH2CH3, but it is much lower for

OH OHO2C

OH

OH

OH

O

HO

O

NH

N

OH

O

O

OI

HO

nPr O H

O

OH

CO2H

NC

HO

OH

O

EtOH

O

Ionomycin

acid (1)

H

Fig. 1. Selected examples of natural products containing the deoxy-propionate motif.

A

C D

B

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).

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metal–CH3 (21). Thus, we used a combination of rac-3-Cl2and ZnEt2 for the following experiments. Oligopropylenes 5 wereend-capped with Zn before protonation, as confirmed by GC-MSanalysis of the products quenched by D2O compared with thosequenched by MeOH (SI Appendix, Fig. S22).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 andZn (entries 3, 4, and 5). However, larger amounts of vinylidene-terminated oligopropylenes 5′ were also obtained at elevatedtemperatures, possibly originating from the undesired β-hydrideelimination. We therefore concluded that the optimal tempera-ture 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 oligomersincreased, possibly due to the increased possibility of trans-metallation from Zr to Zn (entry 6). When the reaction wascarried out in the stainless steel autoclave with a higher initialpropylene pressure, activity was improved compared with when aballoon filled with propylene was used as the gas source (entries7 and 8). Diastereoselectivity also improved, although the reasonfor this remains unclear. In the case of the tetramer, for example,the sum of the minor peak areas shown was <1% versus the mainproduct peak. The activity was further improved with a constantpropylene pressure of 2.0 bar (entry 9). A longer reaction timeresulted in a higher yield (entry 10), whereas a higher reactiontemperature afforded higher ratios of the shorter oligomers anda lower diastereoselectivity (entries 9, 11, and 12). Under the

same reaction conditions, the amount of ZnEt2 was again de-creased from ∼5,000 equiv. to ∼2,000 equiv., and the activity wasimproved (entry 13). We therefore selected the conditions out-lined in entry 13 as our optimal conditions, as these conditionsgave high diastereoselectivity, alkane/alkene ratio, and yield. Forentry 13, the yield of each oligomer, based on the amount of zincused, was estimated by integration of the GC peak areas using

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 constantpressure. See SI Appendix for detailed procedures.†Against 3-Cl2.‡Based on the amount of M in MRn.§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.

5 10 15 20Retention time (min.)

rac-3-Cl2

Cp2ZrCl2

*

4-m

er

deca

ne

(inte

rnal

st

anda

rd)

3-m

er

5-m

er

6-m

er

7-m

er

*

*

*

Fig. 3. GC traces of the crude product 5 from oligomerizations usingCp2ZrCl2 (Top) and rac-3-Cl2 (entry 3, Bottom). Peaks indicated with asteriskscorrespond to the impurities derived from solvent or catalyst.

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decane as an internal standard, giving the following oligomericyields: trimer = 9.6%, tetramer = 7.9%, and pentamer = 6.5%.

Asymmetric Oligomerization, Consecutive Oxidation, and Separationof Oligomer/Alcohols. Following optimization of the oligomeriza-tion conditions, the process was expanded to asymmetric oligo-merization (Fig. 4A). By using (S,S)-3-Cl2 instead of racemicmixture, oligomerization was carried out under the same conditionsas outlined in entry 13 in Table 1 to afford oligomers in the similaryields: trimer = 12%, tetramer = 10%, and pentamer = 8.2%. Thenthe in situ oxidation of alkylzinc species 4 was performed usingdioxygen at 0 °C for 2 h (22, 23), giving the correspondingalcohols 6 as major products, as observed by GC (Fig. 4B, Top)and GC-MS analyses. The resulting tetramer/alcohol 2 wassuccessfully isolated from a mixture of alcohols by a series ofchromatographic processes. The crude mixture was first puri-fied by silica-gel column chromatography (hexane/ethyl ace-tate = 10:1 vol/vol) to remove alkanes. The resulting alcoholmixture was then separated by reverse-phase HPLC. The purityof the separated 2 (3.8% yield based on ZnEt2) was confirmed byGC (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 enantiomericexcess was confirmed by chiral GC analysis to be ≥99% com-pared with rac-2 that was prepared using rac-3-Cl2 (Fig. 4C). Theproduct 2 exhibited an optical rotation of ½α�24D = +7.11 (c = 0.51,CHCl3), which is similar to the reported values of 2 (11, 24).

Three-Step Synthesis of 1. Isolated tetramer/alcohol 2 was thenoxidized to corresponding carboxylic acid 1 in two stepsaccording to the literature procedure (7). The three-step totalyield of 1 based on the amount of zinc was 1.2%. Thus, the syn-thesis of 1 in three steps as described above is the shortest knownsequence to date. In addition, the propylene oligomerization andoxidation sequence can be incorporated into the synthetic route tothe insect pheromone, 9-norlardolure, as its synthesis from com-pound 2 is already reported in literature (Fig. 5) (25).

Simultaneous Synthesis of Multiple Oligomers. The unique featureof our strategy is that all oligomer/alcohols given as side productsalso have the deoxypropionate motif because C3 building unit isused for elongation. To demonstrate application to the con-struction of library, we isolated trimer, tetramer, and pentamer/alcohols simultaneously from the crude mixture of oligomers byreverse-phase HPLC. After one more round of purification ofeach fraction by reverse-phase HPLC, pure oligomers were iso-lated. Each oligomer was characterized by 1H and 13C NMR andGC-MS analyses (detailed characterization including opticalrotation values are provided in the SI Appendix).

Concluding RemarksIn summary, we established a one-step route to the constructionof the all-syn deoxypropionate motif, found in a number of naturalproducts, by the asymmetric oligomerization of propylene, with bothstereoselectivity and chain-end functionalizability. This methodol-ogy enabled the shortest reported preparation of 1 in only threesteps. We also demonstrated that multiple oligomers with differentnumber of deoxypropionate units can be simultaneously isolatedfrom one batch, showing application of this strategy to the con-struction of library. To allow the application of this method to abroad range of natural products, installation of a functional moietyinto the initiating group and the use of alternative chain-endfunctionalization are required, along with chain length control toimprove the yields of the desired oligomers. Studies in thesefields are currently underway in our laboratory.

MethodsRepresentative Procedure for Asymmetric Propylene Oligomerization andSubsequent 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, TokyoChemical Industry), and toluene (dehydrated, 1.0 mL, Kanto Chemical) wasstirred under constant propylene pressure (0.20 MPa) in a 50-mL stainlesssteel autoclave for 16 h at –20 °C. Following propylene venting, the reactionvessel was warmed to 0 °C, and oxygen was bubbled through the reactionmixture for 2 h. Aqueous HCl (20 mL, 1 M) was then added, and the crudemixture was sonicated for 10 min before filtration. The separated organic

A

B

C

Fig. 4. Asymmetric oligomerization of propylene and subsequent oxida-tion, and isolation of 2. (A) Optimized procedure for the asymmetric oligo-merization of propylene, and successive oxidation to the alcohol. (B) GCtraces 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 synthesizedusing (S,S)-3-Cl2 (Bottom).

23

PCCH

O3

DABCO, O2Cu(OAc)2 (bipy)

O

3

BH3 THF(S)-Me-CBS

OH 3

HCOOH

OCHO9-Norlardolure

(Insect pheromone)

Fig. 5. Literature conversion of 2 to 9-norlardolure (25).

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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, KantoChemical, eluted with MeOH), 16.3 mg (3.8% yield from ZnEt2) of 2 wasobtained as a colorless oil. Further details can be found in the SIAppendix.

ACKNOWLEDGMENTS. We are grateful to Prof. S. Hanessian (Université deMontréal), Prof. L. R. Sita (University of Maryland), and Prof. E. Negishi(Purdue University) for helpful discussions. We thank H. Waragai (University ofTokyo) for optical rotationmeasurements. Thework was supported by the JapanSociety for the Promotion of Science (JSPS) KAKENHI Grant 15H03807. T.M. andY.O. are grateful to JSPS for Program for Leading Graduate Schools [MaterialsEducation Program for the Future Leaders in Research, Industry, and Technology(MERIT)]. Y.O. is grateful to JSPS for Research Fellowship for Young Scientists.

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