A General Asymmetric Synthesis of (R)-Matsutakeol and Flavored Analogs

An efficient and practical synthetic route toward chiral matsutakeol and analogs was developed by asymmetric addition of terminal alkyne to aldehydes. (R)-matsutakeol and other flavored substances were feasibly synthesized from various alkylaldehydes in high yield (up to 49.5%, in three steps) and excellent enantiomeric excess (up to >99%). The protocols may serve as an alternative asymmetric synthetic method for active small-molecule library of natural fatty acid metabolites and analogs. These chiral allyl alcohols are prepared for food analysis and screening insect attractants.


Introduction
Many natural unsaturated alcohols 1-6 (Figure 1) are very important fatty acid metabolites derived from fungi [1] and plants [2].These substances have been found in nutrient, pharmaceutical, and agricultural use, as their structural diversity and variety of biological activities.For examples, the chiral allyl alcohols 6a-c (Figure 1) are a class of important flavor substances and dietary supplements which are widely used in the food industry [3][4][5].(R)-matsutakeol 6a isolated from matsutake [6], has been found to possess antitumor properties [3].Effects of inhibition on fungal spore germination and mushroom and plant development have also been discovered [7].Recently, (R)-matsutakeol 6a and its analogs are widely used in insecticidal compositions as effective attractants for some harmful hematophagous insects [8,9].In particular, the enantioselectivity and chiral configuration of the compounds directly determined biological activities such as smell and taste [10].
Scheme 1. Retro-synthetic analysis of matsutakeol and its natural analogs reported in the latest literature.Scheme 1. Retro-synthetic analysis of matsutakeol and its natural analogs reported in the latest literature.Scheme 2. Zn-catalyzed asymmetric direct addition of terminal alkynes to aldehydes.

Results and Discussion
Herein we report the asymmetric synthesis of (R)-matsutakeol and its natural analogs.In our previous work (Scheme 2) [50], the reaction conditions were optimized for the stereoselective addition of methyl propiolate to aliphatic aldehydes, and the highest enantiomeric excess values (97%-99% ee) of (S)-alkynol product 13 were afforded by (R,R)-ProPhenol/Zn complex.It is developed in a general strategy toward the total synthesis of C17 polyacetylenes such as virol A and virol C [50].
Table 1.Synthesis of chiral alkynol units 13a-e of C17 polyacetylenes via the asymmetric addition of methyl propiolate to aliphatic aldehydes a .
a Unless otherwise noted, the reaction was carried out on a 1.0 mmol scale in toluene (1.0 mL).b Isolated yields.c The ee values were determined by chiral HPLC.
As shown in Scheme 3, treatment of compounds 13a-c with LiOH in THF gave the corresponding carboxylic acid intermediates [38], which were then subjected to the CuCl-catalyzed decarboxylation directly, producing the chiral propargyl alcohols 12a-c in good yields (83%-86%) and without loss of enantio-selectivity (99% ee).Reduction of compounds 12a-c with NaBH4 in the presence of Ni(OAc)2 gave (R)-matsutakeol 6a and its natural analogs 6b and 6c in good yields (82%-85%) [51].However, the ee values of (R)-matsutakeol and analogs could not be directly resolved by HPLC on a chiral column Scheme 2. Zn-catalyzed asymmetric direct addition of terminal alkynes to aldehydes.

Results and Discussion
Herein we report the asymmetric synthesis of (R)-matsutakeol and its natural analogs.In our previous work (Scheme 2) [50], the reaction conditions were optimized for the stereoselective addition of methyl propiolate to aliphatic aldehydes, and the highest enantiomeric excess values (97%-99% ee) of (S)-alkynol product 13 were afforded by (R,R)-ProPhenol/Zn complex.It is developed in a general strategy toward the total synthesis of C17 polyacetylenes such as virol A and virol C [50].
Table 1.Synthesis of chiral alkynol units 13a-e of C17 polyacetylenes via the asymmetric addition of methyl propiolate to aliphatic aldehydes a .Scheme 2. Zn-catalyzed asymmetric direct addition of terminal alkynes to aldehydes.

Results and Discussion
Herein we report the asymmetric synthesis of (R)-matsutakeol and its natural analogs.In our previous work (Scheme 2) [50], the reaction conditions were optimized for the stereoselective addition of methyl propiolate to aliphatic aldehydes, and the highest enantiomeric excess values (97%-99% ee) of (S)-alkynol product 13 were afforded by (R,R)-ProPhenol/Zn complex.It is developed in a general strategy toward the total synthesis of C17 polyacetylenes such as virol A and virol C [50].
Table 1.Synthesis of chiral alkynol units 13a-e of C17 polyacetylenes via the asymmetric addition of methyl propiolate to aliphatic aldehydes a .
a Unless otherwise noted, the reaction was carried out on a 1.0 mmol scale in toluene (1.0 mL).b Isolated yields.c The ee values were determined by chiral HPLC.
As shown in Scheme 3, treatment of compounds 13a-c with LiOH in THF gave the corresponding carboxylic acid intermediates [38], which were then subjected to the CuCl-catalyzed decarboxylation directly, producing the chiral propargyl alcohols 12a-c in good yields (83%-86%) and without loss of enantio-selectivity (99% ee).Reduction of compounds 12a-c with NaBH4 in the presence of Ni(OAc)2 gave (R)-matsutakeol 6a and its natural analogs 6b and 6c in good yields (82%-85%) [51].However, the ee values of (R)-matsutakeol and analogs could not be directly resolved by HPLC on a chiral column a Unless otherwise noted, the reaction was carried out on a 1.0 mmol scale in toluene (1.0 mL); b Isolated yields; c The ee values were determined by chiral HPLC.
As shown in Scheme 3, treatment of compounds 13a-c with LiOH in THF gave the corresponding carboxylic acid intermediates [38], which were then subjected to the CuCl-catalyzed decarboxylation directly, producing the chiral propargyl alcohols 12a-c in good yields (83%-86%) and without loss of enantio-selectivity (99% ee).Reduction of compounds 12a-c with NaBH 4 in the presence of Ni(OAc) 2 gave (R)-matsutakeol 6a and its natural analogs 6b and 6c in good yields (82%-85%) [51].However, the ee values of (R)-matsutakeol and analogs could not be directly resolved by HPLC on a chiral column conveniently.Therefore, derivatization of compounds 6a-c through introducing 3,5-dinitrobenzoyl moiety to the natural molecules, directly afforded compounds 21a-c in nearly quantitative yields (93%-95%) and 99% ee.The BINOL-ZnEt2-Ti (IV) complex catalyzed asymmetric addition of trimethylsilylacetylene to the aliphatic aldehydes was well developed by Pu's group [20,22,34].It is also a practical approach for providing chiral acetylene alcohols.In the optimization procedure, to increase the catalyst loading of (R,R)-ProPhenol 16b (entry 1 and 2) and to reduce the temperature (entry 2 and 3) could slightly improve the ee value, of product 13a' (Table 2, entry 2, 72% yield, 78% ee).Compared to addition catalyzed by (R,R)-ProPhenol 16b, almost no product was detected at −10 °C (Table 2, entry 4).The reaction yields and optical yields were increased on increasing the amount of BINOL (Table 2, entry 5-7).When the amount of BINOL was increased to 60%, there was no obvious improvement in yield and ee value (entry 7, 67% yield, 81 % ee).Compared to the reaction catalyzed by (R,R)-ProPhenol 16b (entry 2, 72% yield, 78% ee and entry 3, 74% yield, 76% ee), the asymmetric addition of trimethylsilylacetylene by using BINOL as chiral ligand could be smoothly carried out at room temperature, affording higher ee value and almost the same yield (entry 6, 71% yield, 80% ee).Herein, we attempted to synthesize the above natural products 6a-c on gram scale, by employing the (S)-BINOL 17b as the catalyst.As shown in Scheme 4, (S)-BINOL efficiently catalyzed the asymmetric addition of trimethylsilylacetylene with the corresponding aliphatic aldehydes 14a-c, affording compounds 13a'-c' in moderate yields (71%-72%) and enantioselectivities (80%-82% ee), slightly lower than those of compounds 13a-c.K2CO3-promoted deprotection of trimethyl group of compounds 13a'-c' under mild conditions gave compounds 12a-c in good yields (87%-89%) [52].The BINOL-ZnEt 2 -Ti (IV) complex catalyzed asymmetric addition of trimethylsilylacetylene to the aliphatic aldehydes was well developed by Pu's group [20,22,34].It is also a practical approach for providing chiral acetylene alcohols.In the optimization procedure, to increase the catalyst loading of (R,R)-ProPhenol 16b (entry 1 and 2) and to reduce the temperature (entry 2 and 3) could slightly improve the ee value, of product 13a (Table 2, entry 2, 72% yield, 78% ee).Compared to addition catalyzed by (R,R)-ProPhenol 16b, almost no product was detected at −10 • C (Table 2, entry 4).The reaction yields and optical yields were increased on increasing the amount of BINOL (Table 2, entry 5-7).When the amount of BINOL was increased to 60%, there was no obvious improvement in yield and ee value (entry 7, 67% yield, 81 % ee).Compared to the reaction catalyzed by (R,R)-ProPhenol 16b (entry 2, 72% yield, 78% ee and entry 3, 74% yield, 76% ee), the asymmetric addition of trimethylsilylacetylene by using BINOL as chiral ligand could be smoothly carried out at room temperature, affording higher ee value and almost the same yield (entry 6, 71% yield, 80% ee).conveniently.Therefore, derivatization of compounds 6a-c through introducing 3,5-dinitrobenzoyl moiety to the natural molecules, directly afforded compounds 21a-c in nearly quantitative yields (93%-95%) and 99% ee.The BINOL-ZnEt2-Ti (IV) complex catalyzed asymmetric addition of trimethylsilylacetylene to the aliphatic aldehydes was well developed by Pu's group [20,22,34].It is also a practical approach for providing chiral acetylene alcohols.In the optimization procedure, to increase the catalyst loading of (R,R)-ProPhenol 16b (entry 1 and 2) and to reduce the temperature (entry 2 and 3) could slightly improve the ee value, of product 13a' (Table 2, entry 2, 72% yield, 78% ee).Compared to addition catalyzed by (R,R)-ProPhenol 16b, almost no product was detected at −10 °C (Table 2, entry 4).The reaction yields and optical yields were increased on increasing the amount of BINOL (Table 2, entry 5-7).When the amount of BINOL was increased to 60%, there was no obvious improvement in yield and ee value (entry 7, 67% yield, 81 % ee).Compared to the reaction catalyzed by (R,R)-ProPhenol 16b (entry 2, 72% yield, 78% ee and entry 3, 74% yield, 76% ee), the asymmetric addition of trimethylsilylacetylene by using BINOL as chiral ligand could be smoothly carried out at room temperature, affording higher ee value and almost the same yield (entry 6, 71% yield, 80% ee).Herein, we attempted to synthesize the above natural products 6a-c on gram scale, by employing the (S)-BINOL 17b as the catalyst.As shown in Scheme 4, (S)-BINOL efficiently catalyzed the asymmetric addition of trimethylsilylacetylene with the corresponding aliphatic aldehydes 14a-c, affording compounds 13a'-c' in moderate yields (71%-72%) and enantioselectivities (80%-82% ee), slightly lower than those of compounds 13a-c.K2CO3-promoted deprotection of trimethyl group of compounds 13a'-c' under mild conditions gave compounds 12a-c in good yields (87%-89%) [52].Herein, we attempted to synthesize the above natural products 6a-c on gram scale, by employing the (S)-BINOL 17b as the catalyst.As shown in Scheme 4, (S)-BINOL efficiently catalyzed the asymmetric addition of trimethylsilylacetylene with the corresponding aliphatic aldehydes 14a-c, affording compounds 13a -c in moderate yields (71%-72%) and enantioselectivities (80%-82% ee), slightly lower than those of compounds 13a-c.K 2 CO 3 -promoted deprotection of trimethyl group of compounds 13a -c under mild conditions gave compounds 12a-c in good yields (87%-89%) [52].Following the same procedures as shown in Scheme 3, compounds 6a-c were obtained in moderate yields (81%-83%) and nearly without loss of enantioselectivities (79%-82% ee, the ee values were measured by HPLC after derived by 3,5-dinitrobenzoyl chloride).The enantiomeric purity of 21a-c could be improved to over 99% ee by slow recrystallization from diethylether/n-hexane (1:5) at a low temperature.Subsequently, the esters 21a-c could be quantitatively hydrolyzed to the corresponding chiral alcohols 6a-c followed in our previous group research [22].
Following the same procedures as shown in Scheme 3, compounds 6a-c were obtained in moderate yields (81%-83%) and nearly without loss of enantioselectivities (79%-82% ee, the ee values were measured by HPLC after derived by 3,5-dinitrobenzoyl chloride).The enantiomeric purity of 21a-c could be improved to over 99% ee by slow recrystallization from diethylether/n-hexane (1:5) at a low temperature.Subsequently, the esters 21a-c could be quantitatively hydrolyzed to the corresponding chiral alcohols 6a-c followed in our previous group research [22].

Materials and Methods
All reactions were performed under an argon atmosphere.Solvents were dried according to standard procedures and distilled before use.All reagents were purchased commercially and used without further purification, unless stated otherwise. 1H-and 13 C-NMR spectra were recorded at 300 and 75 MHz, respectively.High-resolution mass spectra were recorded on an agilent instrument by the TOF MS technique.Enantiomeric excesses (ee) were determined by chiral HPLC analyses using a chiral column (Chiralpak OD-H, AD-H, OJ-H), and elution with isopropanol-hexane.The optical rotations were measured on PERKIN ELMER 341 Polarimeter. 1 H-, 13 C-NMR spectra and HPLC chromatography of the chiral products are in the Supplementary Materials.

General Procedure of Asymmetric Addition of Methyl Propiolate to Aliphatic Aldehydes (Table 1)
To a stirred solution of methyl propiolate (84 mg, 1 mmol), (S,S)-ProPhenol (128 mg, 0.2 mmol), triphenylphosphine oxide (111 mg, 0.4 mmol) in toluene (1 mL), dimethylzinc (2.5 mL, 1.2 M in toluene, 3 mmol) was added slowly at −10 °C.After stirring for 1.5 h at −10 °C, aldehyde (1.5 mmol) in toluene (3 mL) was added via syringe at a slow rate in 24 h at −10 °C, and quenched with water (10 mL).The mixture was filtered through a celite pad.The aqueous phase was extracted with ether.The combined organic phases were washed with saturated brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure.The residue was purified by silica gel chromatography to get the product [25,36].

Materials and Methods
All reactions were performed under an argon atmosphere.Solvents were dried according to standard procedures and distilled before use.All reagents were purchased commercially and used without further purification, unless stated otherwise. 1H-and 13 C-NMR spectra were recorded at 300 and 75 MHz, respectively.High-resolution mass spectra were recorded on an agilent instrument by the TOF MS technique.Enantiomeric excesses (ee) were determined by chiral HPLC analyses using a chiral column (Chiralpak OD-H, AD-H, OJ-H), and elution with isopropanol-hexane.The optical rotations were measured on PERKIN ELMER 341 Polarimeter. 1 H-, 13 C-NMR spectra and HPLC chromatography of the chiral products are in the Supplementary Materials.

General Procedure of Asymmetric Addition of Methyl Propiolate to Aliphatic Aldehydes (Table 1)
To a stirred solution of methyl propiolate (84 mg, 1 mmol), (S,S)-ProPhenol (128 mg, 0.2 mmol), triphenylphosphine oxide (111 mg, 0.4 mmol) in toluene (1 mL), dimethylzinc (2.5 mL, 1.2 M in toluene, 3 mmol) was added slowly at −10 • C.After stirring for 1.5 h at −10 • C, aldehyde (1.5 mmol) in toluene (3 mL) was added via syringe at a slow rate in 24 h at −10 • C, and quenched with water (10 mL).The mixture was filtered through a celite pad.The aqueous phase was extracted with ether.The combined organic phases were washed with saturated brine solution, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure.The residue was purified by silica gel chromatography to get the product [25,36].

General Procedure for the Synthesis of Chiral Alkynols 12 from Propargyl Alcohols 13
A solution of the chiral alkynol (5 mmol) and THF (60 mL) were cooled to 0 • C, 1 M aq LiOH (25 mmol, 5 eq) was added at a slow rate.The solution was warmed to rt and stirred for an additional 1 h before it was quenched with 1M aq NaHSO 4 (50 mL).The aqueous phase was extracted by ethyl acetate.The combined organic phases were dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure.The residue was dissolved in acetonitrile (12 mL), CuCl (0.5940 g, 6 mmol, 1.2 eq) was added in one portion to the mixture.The mixture was allowed to warm to r.t. and stirred for another 13 h.The aqueous phase was extracted by ether.The combined organic phases were dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure.The residue was purified by silica gel chromatography to get the product.

General Procedure for the Selective Reduction of the Chiral Alkynols 12
To a stirred solution of nickel acetate tetrahydrate (352 mg, 2 mmol) in ethanol (5 mL) under hydrogen, sodium borohydride (76 mg, 2 mmol) in ethanol (2 mL) was added at 0 • C.After stirring for 1 h at 25 • C, ethylenediamine (481 mg, 8 mmol) was added.The reaction mixture was stirred for another 10 min before chiral alkynol (2 mmol) in ethanol (2 mL) was added slowly to the reaction mixture at 0 • C. The reaction was allowed to proceed at 25 • C under hydrogen for 6 h at 25 • C. The mixture was filtered through a celite pad, diluted with ether, and concentrated under reduced pressure.The residue was purified by silica gel chromatography to get the product.

General Procedure of Asymmetric Addition of Ethynyltrimethylsilane to Aliphatic Aldehydes
To a stirred solution of ethynyltrimethylsilane (3922 mg, 40 mmol), (S)-BINOL (1144 mg, 4 mmol), HMPA (3584 mg, 20 mmol) in methylene chloride (120 mL), diethylzinc (40 mL, 40 mmol) was added slowly at 0 • C.After stirring for 16 h at 25 • C, Titanium(IV) isopropoxide (2842 mg, 10 mmol) was added and the stirring was continued for another 1 h at 25 • C. Then an aldehyde (10 mmol) was added and the reaction was allowed to proceed at 25 • C for another 6 h before being quenched with water (20 mL).The mixture was filtered through a celite pad.The aqueous phase was extracted with ether.The combined organic phases were washed with saturated brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure.The residue was purified by silica gel chromatography to get the product [34,40].

General Procedure for the Synthesis of chIral Alkynols 12 from Propargyl Alcohols 13
To a stirred solution of chiral alkynol (10 mmol) in methanol (20 mL), potassium carbonate (2764 mg, 20 mmol) was added slowly at 0 • C.After stirring for 20 h at 25 • C, water (20 mL) was added slowly at 0 • C. The reaction mixture was concentrated under reduced pressure.The aqueous phase was extracted with ether.The combined organic phases were washed with saturated brine solution, dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure.The residue was purified by silica gel chromatography to get the product.

General Procedure for the Selective Reduction of the Chiral Alkynols 12
To a stirred solution of nickel acetate tetrahydrate (1408 mg, 8 mmol) in ethanol (20 mL) under hydrogen, sodium borohydride (303 mg, 8 mmol) in ethanol (8 mL) was added at 0 • C.After stirring for 1 h at 25 • C, ethylenediamine (481 mg, 8 mmol) was added.The reaction mixture was stirred for another 10 min before chiral alkynol (8 mmol) in ethanol (8 mL) was added slowly to the reaction mixture at 0 • C. The reaction was allowed to proceed at 25 • C under hydrogen for 6 h at 25 • C. The mixture was filtered through a celite pad, diluted with ether, and concentrated under reduced pressure.The residue was purified by silica gel chromatography to get the product.
3.9.General Procedure for the Recrystallization to Improve Optical Purity Dinitrobenzoates (5 mmol) were dissolved in diethyl ether at room temperature, then n-hexane was added slowly to the mixture until a white precipitate occurred.A small portion of diethyl ether was added and the white precipitate was dissolved.The mixture was cooled to −30 • C and stayed for 48 h to get a white crystal of the dinitrobenzoate.

Figure 1 .
Figure 1.Natural unsaturated alcohols derived from fungi and plant.

Figure 1 .
Figure 1.Natural unsaturated alcohols derived from fungi and plant.

Figure 1 .
Figure 1.Natural unsaturated alcohols derived from fungi and plant.

a
The reaction was carried out on a 0.5 mmol scale in toluene (0.5 mL), the organozinc reagent was Me2Zn; b The reaction was carried out on a 0.5 mmol scale in DCM (6.0 mL), the organozinc reagent was Et2Zn, Et2Zn:Ti(O i Pr)4:aldehyde = 4:1:1; c Isolated yields; d The ee values were determined by chiral HPLC.

a
The reaction was carried out on a 0.5 mmol scale in toluene (0.5 mL), the organozinc reagent was Me2Zn; b The reaction was carried out on a 0.5 mmol scale in DCM (6.0 mL), the organozinc reagent was Et2Zn, Et2Zn:Ti(O i Pr)4:aldehyde = 4:1:1; c Isolated yields; d The ee values were determined by chiral HPLC.

a
The reaction was carried out on a 0.5 mmol scale in toluene (0.5 mL), the organozinc reagent was Me 2 Zn; b The reaction was carried out on a 0.5 mmol scale in DCM (6.0 mL), the organozinc reagent was Et 2 Zn, Et 2 Zn:Ti(O i Pr) 4 :aldehyde = 4:1:1; c Isolated yields; d The ee values were determined by chiral HPLC.

3. 8 .
General Procedure for the Esterification Reaction and Determination of Enantiomeric Excess by HPLC Triethylamine (909 mg, 9 mmol) and 3,5-dinitrobenzoyl chloride (1660 mg, 7.2 mmol) were added to a stirred solution of the chiral alcohol (6 mmol) in CH 2 Cl 2 (40 mL) at −5 • C. The mixture was stirred for 5 h at 25 • C before water (10 mL) was poured into the mixture at 0 • C. The aqueous phase was extracted with ether and combined organic phases were washed with saturated brine solution, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure.The residue was purified by silica gel chromatography to get the product.3.8.1.Synthesis of (R)-Oct-1-en-3-yl-3,5-dinitrobenzoate: (R)-21a

Table 2 .
Screening of reaction conditions and ligands of asymmetric addition of

Table 2 .
Screening of reaction conditions and ligands of asymmetric addition of 15 with 14a.

Table 2 .
Screening of reaction conditions and ligands of asymmetric addition of