Organocatalytic Approach for Short Asymmetric Synthesis of (R

Feb 28, 2018 - Organocatalytic Approach for Short Asymmetric Synthesis of (R)-Paraconyl Alcohol: Application to the Total Syntheses of IM-2, SCB2, and...
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Cite This: J. Org. Chem. 2018, 83, 4167−4172

Organocatalytic Approach for Short Asymmetric Synthesis of (R)‑Paraconyl Alcohol: Application to the Total Syntheses of IM-2, SCB2, and A‑Factor γ‑Butyrolactone Autoregulators Abhijeet M. Sarkale, Amit Kumar, and Chandrakumar Appayee* Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar, Gujarat 382355, India S Supporting Information *

ABSTRACT: (R)-Paraconyl alcohol is found to be a key intermediate for the syntheses of many γ-butyrolactone autoregulators. The chiral auxiliary approach and enzymatic resolution are the two common strategies employed so far in the literature for the asymmetric synthesis of (R)-paraconyl alcohol. Herein, we report the first organocatalytic approach for the short asymmetric synthesis of (R)-paraconyl alcohol in four steps and by a single column purification. Asymmetric syntheses of IM-2, SCB2, and Afactor γ-butyrolactone autoregulators were achieved from (R)-paraconyl alcohol in three steps. hiral γ-butyrolactones are the most common structural motifs in a wide variety of bioactive natural products and pharmaceuticals.1 2,3-Disubstituted γ-butyrolactone autoregulators have been isolated from Streptomyces species, which trigger the production of commercially significant antibiotics2 and pigments.3 A total of 14 such autoregulators have been isolated and chemically identified so far. Based on the functional groups and stereochemistry of the side-chain, γ-butyrolactone autoregulators have been classified as A-factor type (possessing 1′-keto group), virginiae butanolide type (possessing a 1′-(S)-hydroxyl group), and IM-2 type (possessing a 1′-(R)-hydroxyl group) autoregulators (Figure 1).4 Many synthetic methodologies have been developed for the syntheses of A-factor,5 virginiae butanolides,6 and IM-27,6c type natural products. (R)-Paraconyl alcohol 1 has been considered as an important chiral intermediate for the syntheses of most of these autoregulators5a,c,6b,8 and other bioactive molecules.9 Racemic synthesis of paraconyl alcohol and its application toward butyrolactone autoregulators10 and other natural products11 were also reported in the literature. The chiral auxiliary approach5a and enzymatic resolution5c,12a,b are the two common strategies have been reported in the literature so far for the asymmetric synthesis12 of (R)-paraconyl alcohol 1 in seven steps. Through the chiral auxiliary approach, alcohol 1 was obtained from oxazolidinone 2 in seven steps with an 8% overall yield (Figure 2).5a By lipase-mediated enzymatic

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© 2018 American Chemical Society

Figure 1. γ-Butyrolactone autoregulators and (R)-paraconyl alcohol 1.

resolution, alcohol 1 was obtained from diester 3 in seven steps with a 9% overall yield and 83% ee.12a In this paper, we report the first organocatalytic approach for the asymmetric synthesis of (R)-paraconyl alcohol 1 starting from methyl 4-oxobutanoate 4 in four steps in a 35% yield and 95% ee after single column chromatography purification. We have also applied this methodology for the asymmetric syntheses of IM-2, SCB2, and A-factor γ-butyrolactone autoregulators in three steps. Received: January 15, 2018 Published: February 28, 2018 4167

DOI: 10.1021/acs.joc.8b00122 J. Org. Chem. 2018, 83, 4167−4172

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The Journal of Organic Chemistry

Scheme 1. Asymmetric Synthesis of (R)-Paraconyl Alcohol 1

After achieving the short synthesis of (R)-paraconyl alcohol 1, its application to the total syntheses of IM-2, SCB2, and Afactor γ-butyrolactone autoregulators was explored. For the total synthesis of IM-2, initially, acylation followed by a reduction strategy was envisaged. Accordingly, (R)-paraconyl alcohol 1 was subjected to silyl protection to synthesize TBS ether 8 (95%) followed by acylation using NaHMDS (sodium bis(trimethylsilyl)amide) and butyryl chloride at −78 °C to form ketone 9 in an 87% yield. Diastereoselective reduction of ketone 9 was studied with reducing agents such as NaBH4, Zn(BH4)2, and CeCl3·7H2O/NaBH4. Among them, CeCl3· 7H2O/NaBH4 (Luche reduction) in MeOH at −20 °C was found to be more effective to produce diastereomeric alcohols in a 90% isolated yield and 70:30 dr. The major diastereomeric alcohol 10 (63%) was purified by silica gel column chromatography (Scheme 2).

Figure 2. Asymmetric synthesis of (R)-paraconyl alcohol 1.

For the synthesis of (R)-paraconyl alcohol 1, the asymmetric α-hydroxymethylation of aldehyde 4 using aqueous formaldehyde was conceived as a key step. Though chiral amine catalyzed aldol reactions are one of the most studied carbon− carbon bond forming reactions in the past few decades,13 the use of formaldehyde as an aldehyde partner is less explored in the literature.14 α-Hydroxymethylated aldehydes were found to be unstable for purification and hence further oxidized to carboxylic acids using Pinnick oxidation.14b,c Although L-proline successfully catalyzed the aldol reaction of methyl 4-oxobutanoate 4 with benzaldehydes,15 we observed that the similar reaction with formaldehyde failed to give an aldol product. On the other hand, the aldol reaction of methyl 6-oxohexanoate with formaldehyde catalyzed by (S)-diphenylprolinol trimethylsilyl ether has been reported to give an αhydroxymethylated product with >99% ee.14b Using the similar reaction conditions, we have obtained only a moderate (78% ee) enantioselectivity for the α-hydroxymethylation of methyl 4-oxobutanoate 4. To achieve a higher product ee for the α-hydroxymethylation of methyl 4-oxobutanoate 4, we have used the general procedure reported14d for the α-hydroxymethylation of aldehydes by Hayashi et al. with slight modifications. (The reaction concentration was doubled, and NaCl was used as an additive.) Accordingly, methyl 4-oxobutanoate 4 was reacted with aqueous formaldehyde in the presence of (S)-diarylprolinol and NaCl in toluene and methanol at 0 °C for 6 days. The crude α-hydroxymethylated product was oxidized to carboxylic acid 5 using Pinnick oxidation. As acid 5 was partially cyclized to (S)-paraconic acid 6 during work up conditions, the crude reaction mixture was treated with 6 M HCl to undergo complete cyclization. The crude (S)-paraconic acid 6 was further reduced using BH3·Me2S to give (R)paraconyl alcohol 1 in a 35% isolated yield and 95% ee after silica gel column chromatography (Scheme 1). Enantiomeric excess of alcohol 1 was determined by converting it into chromophoric 4-tert-butylbenzoate derivative 7 (details in the Experimental Section).

Scheme 2. Synthesis of TBS ether of IM-2 through Acylation Followed by Reduction

An alternative method for the synthesis of alcohol 10 was developed involving a direct aldol reaction of lactone 8 with NaHMDS16 and butyraldehyde at −78 °C to rt to obtain alcohol 10 in a 70% yield with 67:33 dr. The major diastereomeric alcohol 10 (47%) was purified by silica gel column chromatography. TBS group in alcohol 10 was conveniently deprotected using HCl in diethyl ether to achieve 4168

DOI: 10.1021/acs.joc.8b00122 J. Org. Chem. 2018, 83, 4167−4172

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IM-2 12 in a 94% isolated yield (Scheme 3). Similarly, lactone 8 was reacted with octan-1-al to form major aldol product 11 (42%), which was subjected to HCl in diethyl ether to generate SCB2 13 in a 95% isolated yield.

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EXPERIMENTAL SECTION

General Information. All reactions were carried out in oven-dried glassware unless otherwise noted. Except as otherwise indicated, all reactions were magnetically stirred and monitored by thin-layer chromatography using Merck precoated silica gel plates. Column chromatography was done with 60−120 mesh silica gel supplied by Merck. Commercially available reagents and solvents were used without further purification except as indicated below. Methanol, dichloromethane, and toluene (PhMe) were freshly distilled over calcium hydride under an atmosphere of dry argon prior to use. THF was freshly distilled over sodium under an atmosphere of dry nitrogen prior to use. Organic solutions were concentrated using a Heidolph rotary evaporator. NMR spectra were recorded on a Bruker 500 MHz spectrometer in chloroform-d. Chemical shifts (δ) are reported in parts per million (ppm) relative to the internal standard (TMS, 0.00 ppm). Multiplicities are given as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). Optical rotations were measured using a Rudolph Research Analytical polarimeter. HPLC analysis was performed by an Agilent Technologies 1260 infinity instrument with an IA chiral column (25 cm) using the given conditions. Infrared spectra were taken on a PerkinElmer FTIR spectrometer. The HRMS data for all of the compounds were recorded (in positive ion mode) with a Waters Synapt-G2S ESI-QTOF Mass instrument. (R)-4-(Hydroxymethyl)dihydrofuran-2(3H)-one (1). A round-bottom flask equipped with magnetic stir bar was charged with a (S)bis(3,5-bis(trifluoromethyl)phenyl)(pyrrolidin-2-yl)methanol (4.7 g, 9.0 mmol) and NaCl (8.7 g) under an argon condition. The flask was capped with a rubber septum, and toluene (13.5 mL) and methanol (1.5 mL) were added by syringe at 0 °C. Formaldehyde (6.7 mL of 37% aq solution, 90.0 mmol) was added to the vigorously stirring heterogeneous mixture. This was allowed to stir for 15 min before distilled methyl 4-oxobutanoate 417 (3.14 mL, 30.0 mmol) was added. The reaction was stirred at 0 °C for 6 days, and then the solvent was removed in vacuo to afford a colorless liquid. The crude product was then dissolved in tert-butanol (150 mL), and 2-methyl-2-butene (31.9 mL, 300.0 mmol) was added; the mixture was allowed to stir. To the stirring solution was added a solution of NaClO2 (10.84 g, 120.0 mmol) and NaH2PO4·H2O (16.54 g, 120.0 mmol) in H2O (75 mL), and the reaction was capped with a rubber septum with a needle as an outlet. The resulting biphasic solution was stirred for 7 h at which point the tert-butanol was removed in vacuo to afford an aqueous residue. The residue was acidified with 10% HCl and saturated with sodium chloride. The aqueous layer was then extracted with EtOAc (3 × 100 mL); the organic extracts were dried with Na2SO4, and the solvent was removed in vacuo to afford crude acid 5. The crude product 5 was dissolved in THF (80 mL), and H2O (20 mL) was added to it. The resulting solution was stirred for 10 min at 0 °C, and then 6 M HCl (60 mL) was added. The round-bottom flask was capped with a rubber septum, and the mixture was stirred at room temperature. After 24 h, THF was removed in vacuo, and the aqueous layer was then extracted with EtOAc (3 × 80 mL). The organic extracts were dried with Na2SO4, and the solvent was removed in vacuo to afford crude (S)-paraconic acid 6. Crude paraconic acid 6 was dissolved in dry THF (14.4 mL), and BH3·SMe2 (2 M solution in THF; 48 mL, 96 mmol) was added dropwise over 30 min at 0 °C. The mixture was stirred for 7.5 h before quenching with MeOH (50 mL) at 0 °C. The volatiles were removed in vacuo (at 30 °C). More MeOH (50 mL) was added, and the mixture was again concentrated in vacuo (repeated 2 times). The crude product was purified by column chromatography on silica gel [CH2Cl2/MeOH (97:3)] to yield the title compound 1 as a clear liquid (1.22 g, 35% after 4 step): Rf = 0.4 [CH2Cl2/MeOH (9:1)]; 1H NMR (500 MHz, CDCl3) δ 4.41 (t, J = 8.5 Hz, 1H), 4.22 (t, J = 8.5 Hz, 1H), 3.66−3.68 (m, 2H), 2.75−2.76 (m, 1H), 2.61 (dd, J = 9.0, 18.0 Hz, 1H), 2.39 (dd, J = 5.5, 18.0 Hz, 1H), 2.31 (br, 1H); 13C NMR (125 MHz, CDCl3) δ 177.9, 70.9, 62.9, 37.1, 30.9; IR (neat) ν 3394, 2919, 2880, 1750, 1418, 1389, 1179 cm−1; HRMS (ESI) m/z

Scheme 3. Synthesis of IM-2 and SCB2 through a Direct Aldol Reaction

Acylation of lactone 8 using NaHMDS and acid chloride 1410f at −78 °C gave ketone 15 in a 52% yield. Deprotection of the silyl group in 15 using tetrabutylammonium fluoride in THF resulted in a 70% isolated yield of A-factor 16 along with its hemiketal form5d in a 3:1 ratio (Scheme 4). The obtained spectral data of IM-2 12, SCB2 13, and A-factor 16 are in good agreement with those reported in the literature.7 Scheme 4. Synthesis of A-Factor

In conclusion, we have developed the first organocatalytic approach for a short asymmetric synthesis of (R)-paraconyl alcohol 1 starting from methyl 4-oxobutanoate 4 in four steps with a 35% isolated yield and 95% ee after single column purification. (S)-Diaryl prolinol was used as a catalyst for the asymmetric α-hydroxymethylation of methyl 4-oxobutanoate 4 using aqueous formaldehyde. We have also accomplished the total synthesis of IM-2 12, a γ-butyrolactone autoregulator, through the direct aldol reaction in just three steps from (R)paraconyl alcohol 1 with a 42% overall yield. The alternate method was developed through acylation followed by reduction to obtain a higher overall yield (49%) but in four steps. We have also shown the application of (R)-paraconyl alcohol 1 for the asymmetric syntheses of SCB2 13 through the direct aldol reaction and A-factor 16 through acylation. Our synthetic methodology for the short synthesis of (R)-paraconyl alcohol 1 shall also be applied for the synthesis of other 2,3-disubstituted γ-butyrolactone natural products. 4169

DOI: 10.1021/acs.joc.8b00122 J. Org. Chem. 2018, 83, 4167−4172

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The Journal of Organic Chemistry calcd for C5H9O3 [M + H]+ 117.0546, found 117.0566; [α]24 D −41.4 (c 1.12, CHCl3 for 95% ee) [lit.5a −42.4 (c 6.8, CHCl3)]. (R)-(5-Oxotetrahydrofuran-3-yl)methyl-4-(tert-butyl)-benzoate (7). A solution of 4-tert-butylbenzoyl chloride (53 μL, 0.27 mmol) in CH2Cl2 (900 μL) was added dropwise to a stirred solution of 1 (21 mg, 0.18 mmol), triethylamine (37 μL, 0.36 mmol), and DMAP (2.2 mg, 0.018 mmol) in CH2Cl2 (900 μL) at 0 °C. The reaction was allowed to stir at the same temperature for 30 min, and then the temperature was slowly raised to room temperature. After stirring overnight, the reaction mixture was quenched with water (1 mL), acidified with 1 M HCl, and extracted with CH2Cl2 (3 × 5 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give the crude ester, which was further purified by column chromatography [hexane/EtOAc (85:15)] resulting in the pure ester 7 (41 mg, 82% yield): Rf = 0.4 [hexane/EtOAc (3:2)]; HPLC analysis DAICEL CHIRALPAK IA, 4.6 mm × 250 mm (hex/IPA = 80:20, 0.5 mL/min, 254 nm), tR (minor) = 17.5 min, tR (major) = 18.9 min, 95% ee; 1H NMR (500 MHz, CDCl3) δ 7.94 (d, J = 7.5 Hz, 2H), 7.47 (d, J = 7.5 Hz, 2H), 4.50 (t, J = 8.0 Hz, 1H), 4.40 (dd, J = 4.5, 11.5 Hz, 1H), 4.33 (dd, J = 6.5, 11.5 Hz, 1H), 4.26 (dd, J = 5.5, 8.5 Hz, 1H), 3.04 (m, 1H), 2.74 (dd, J = 9.0, 18.0 Hz, 1H), 2.47 (dd, J = 6.0, 18.0 Hz, 1H), 1.34 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 176.0, 166.3, 157.3, 129.5, 126.5, 125.6, 70.4, 64.8, 35.1, 34.7, 31.1; IR (neat) ν 2964, 1779, 1720, 1275, 1189, 775 cm−1; HRMS (ESI) m/z calcd for C16H21O4 [M + H]+ 277.1434, found 277.1441; [α]24 D −27.0 (c 1.0, CHCl3 for 95% ee). (S)-4-(((tert-Butyldimethylsilyl)oxy)methyl)dihydrofuran-2(3H)one (8). To a solution of alcohol 1 (1.0 g, 8.6 mmol) in dichloromethane (69 mL) was added imidazole (1.17 g, 17.2 mmol) and tert-butyldimethylsilyl chloride (TBSCl) (2.59 g, 17.2 mmol). The reaction mixture was stirred at room temperature for 24 h and quenched by the slow addition of water (35 mL). The organic phase was separated, dried (sodium sulfate), and concentrated in vacuo. The crude product was purified by column chromatography on silica gel [hexane/EtOAc (93:7)] to yield the title compound 8 as a colorless oil (1.88 g, 95% yield): Rf = 0.4 [hexane/EtOAc (4:1)]; 1H NMR (500 MHz, CDCl3) δ 4.37 (t, J = 8.5 Hz, 1H), 4.19 (dd, J = 5.5, 9.0 Hz, 1H), 3.59−3.66 (m, 2H), 2.69−2.74 (m, 1H), 2.56 (dd, J = 9.0, 17.5 Hz, 1H), 2.38 (dd, J = 9.0, 17.5 Hz, 1H), 0.89 (s, 9H), 0.05 (s, 6H); 13 C NMR (125 MHz, CDCl3) δ 177.0, 70.5, 63.3, 37.3, 30.7, 25.8, 18.2, −5.5; IR (neat) ν 2930, 2856, 1780, 1423, 1254, 1171, 1107, 837 cm−1; HRMS (ESI) m/z calcd for C11H23O3Si [M + H]+ 231.1411, found 231.1399; [α]25 D −19.8 (c 2.4, CHCl3 for 95% ee). General Procedure for the Acylation Reaction of Lactone 8. To a solution of 8 (3.04 mmol) in dry THF (32 mL) under argon at −78 °C was added sodium bis(trimethylsilyl)amide (1.0 M in THF; 7.60 mL, 7.60 mmol) followed after a 1.5 h delay by alkanoyl chloride (3.95 mmol), and the mixture was stirred at −78 °C for 4 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with diethyl ether (3 × 50 mL). The combined organic fractions were dried (sodium sulfate) and concentrated in vacuo. (3R)-4-(((tert-Butyldimethylsilyl)oxy)methyl)-3-butyryldihydrofuran-2(3H)-one (9). By following the above general procedure using butanoyl chloride, compound 9 was obtained. The crude product was purified by column chromatography on silica gel [hexane/EtOAc (97:3)] to yield the title compound 9 as a colorless oil (793 mg, 87%): Rf = 0.4 [hexane/EtOAc (9:1)]; 1H NMR (500 MHz, CDCl3) δ 4.39 (t, J = 8.5 Hz 1H), 4.12 (t, J = 8.0 Hz, 1H), 3.62−3.63 (m, 3H), 3.17− 3.18 (m, 1H), 2.93 (dt, J = 7.0, 15.0 Hz, 1H), 2.60 (dt, J = 6.5, 15.0 Hz, 1H), 1.62−1.66 (m, 2H), 0.94 (t, J = 7.5 Hz, 3H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 202.7, 172.5, 69.2, 62.0, 54.7, 44.4, 39.4, 25.7, 18.2, 16.8, 13.5, −5.6; IR (neat) ν 2956, 2858, 1772, 1717, 1471, 1102, 834 cm−1; HRMS (ESI) m/z calcd for C15H29O4Si [M + H]+ 301.1830, found 301.1826; [α]27 D −19.5 (c 3.3, CHCl3 for 95% ee). (3R)-4-(((tert-Butyldimethylsilyl)oxy)methyl)-3-(6methylheptanoyl)dihydrofuran-2(3H)-one (15). By following the above general procedure using alkanoyl chloride 14,10f compound 15 was obtained. The crude product was purified by column

chromatography on silica gel [hexane/EtOAc (98:2)] to yield the title compound 15 as a colorless oil (562 mg, 52%): Rf = 0.4 [hexane/ EtOAc (9:1)]; 1H NMR (500 MHz, CDCl3) δ 4.39 (t, J = 8.5 Hz 1H), 4.12 (dd, J = 6.5, 9.0 Hz, 1H), 3.62−3.65 (m, 3H), 3.16−3.20 (m, 1H), 2.95 (dt, J = 7.0, 18.0 Hz, 1H), 2.62 (dt, J = 7.5, 18.0 Hz, 1H), 1.49−1.62 (m, 3H), 1.25−1.33 (m, 2H), 1.15−1.20 (m, 2H), 0.87 (t, J = 6.5 Hz, 15H), 0.05 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 202.7, 172.4, 69.2, 62.0, 54.7, 42.5, 39.4, 38.6, 27.8, 26.8, 25.7, 23.6, 22.5, 18.1, −5.6; IR (neat) ν 2954, 2858, 1774, 1718, 1471, 1105, 836 cm−1; HRMS (ESI) m/z calcd for C19H37O4Si [M + H]+ 357.2456, found 357.2451; [α]24 D −16.4 (c 1.0, CHCl3 for 95% ee). (3R,4S)-4-(((tert-Butyldimethylsilyl)oxy)methyl)-3-butyryldihydrofuran-2(3H)-one (10). To a solution of 9 (166 mg, 0.55 mmol) in methanol (5.5 mL) at −20 °C was added CeCl3·7H2O (309 mg, 0.83 mmol) in one portion followed by the addition of NaBH4 (63 mg, 1.66 mmol). The reaction mixture was stirred at −20 °C for 7 h, after which it was quenched with a saturated aqueous NH4Cl solution (5 mL), and 1 M HCl was added until the reaction mixture became clear. The mixture was extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with water, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel [hexane/EtOAc (93:7)] to yield the title compound 10 as a colorless oil (105 mg, 63%). General Procedure for the Aldol Reaction. To a solution of 8 (1.0 mmol) in dry THF (10 mL) under argon at −78 °C was added sodium bis(trimethylsilyl)amide (1.0 M in THF; 2.5 mL, 2.5 mmol) followed after a 2 h delay by aldehyde (2.0 mmol). The reaction mixture was allowed to reach rt and stirred for 12 h at the same temperature. The reaction mixture was quenched with a saturated aqueous NH4Cl solution (10 mL) and extracted with diethyl ether (3 × 10 mL). The combined organic fractions were dried (sodium sulfate) and concentrated in vacuo. (3R,4S)-4-(((tert-Butyldimethylsilyl)oxy)methyl)-3-((R)-1hydroxybutyl)dihydrofuran-2(3H)-one (10). By following the above general procedure using butanal, compound 10 was synthesized. The crude product was purified by column chromatography on silica gel [hexane/EtOAc (93:7)] to yield the title compound 10 as a colorless oil (142 mg, 47%): Rf = 0.4 [hexane/EtOAc (4:1)]; 1H NMR (500 MHz, CDCl3) δ 4.37 (t, J = 9.0 Hz, 1H), 4.03 (t, J = 8.5 Hz, 1H), 3.86 (m, 1H), 3.67 (m, 2H), 3.00 (br, 1H), 2.58−2.68 (m, 2H), 1.41−1.64 (m, 4H), 0.94 (t, J = 7.5 Hz, 3H), 0.89 (s, 9H), 0.07 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 178.2, 70.9, 68.8, 62.7, 47.4, 40.5, 36.7, 25.8, 18.8, 18.2, 13.9, −5.5; IR (neat) ν 3463, 2956, 2858, 1757, 1471, 1253, 1174, 833 cm−1; HRMS (ESI) m/z calcd for C15H31O4Si [M + H]+ 303.1986, found 303.1979; [α]25 D −16.2 (c 3.1, CHCl3 for 95% ee). (3R,4S)-4-(((tert-Butyldimethylsilyl)oxy)methyl)-3-((R)-1hydroxyoctyl)dihydrofuran-2(3H)-one (11). By following the above general procedure using octanal, compound 11 was synthesized. The crude product was purified by column chromatography on silica gel [hexane/EtOAc (95:5)] to yield the title compound 11 as a colorless oil (150 mg, 42%): Rf = 0.4 [hexane/EtOAc (4:1)]; 1H NMR (500 MHz, CDCl3) δ 4.37 (t, J = 8.5 Hz, 1H), 4.03 (t, J = 8.0 Hz, 1H), 3.85 (m, 1H), 3.67 (m, 2H), 2.98 (br, 1H), 2.58−2.69 (m, 2H), 1.56−1.61 (m, 2H), 1.29 (br, 10H), 0.89 (s, 12H), 0.07 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 178.0, 71.2, 68.8, 62.7, 47.3, 40.6, 34.6, 31.8, 29.4, 29.2, 25.8, 25.6, 22.6, 18.2, 14.0, −5.6; IR (neat) ν 3451, 2954, 2856, 1754, 1464, 1253, 1105, 835 cm−1; HRMS (ESI) m/z calcd for C19H39O4Si [M + H]+ 359.2613, found 359.2633; [α]25 D −14.6 (c 1.0, CHCl3 for 95% ee). General Procedure for Silyl Group Deprotection. To a solution of silyl ether (0.38 mmol) in THF (3.6 mL) at 0 °C was added 1 M HCl in Et2O (3.12 mL, 3.12 mmol). The reaction mixture was allowed to warm up to room temperature and stirred overnight. The solvent was removed under reduced pressure. (3R,4R)-3-((R)-1-Hydroxybutyl)-4-(hydroxymethyl)dihydrofuran2(3H)-one (12). By following the above general procedure, compound 12 was synthesized from 10. The crude product was purified by column chromatography on silica gel [CH2Cl2/MeOH (100:0 to 97:3)] to yield the title compound 12 as a colorless liquid (68 mg, 4170

DOI: 10.1021/acs.joc.8b00122 J. Org. Chem. 2018, 83, 4167−4172

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The Journal of Organic Chemistry

of Technology Gandhinagar for the facilities and financial support.

94%): Rf = 0.4 [CH2Cl2/MeOH (9:1)]; 1H NMR (500 MHz, CDCl3) δ 4.42 (t, J = 8.5 Hz, 1H), 3.96−4.03 (m, 2H), 3.73 (dd, J = 5.0, 11.0 Hz, 1H), 3.64−3.68 (dd, J = 6.5, 11.0 Hz, 1H), 2.80−3.30 (br, 2H), 2.72−2.84 (m, 1H), 2.64 (dd, J = 4.5, 9.0 Hz, 1H), 1.36−1.64 (m, 4H), 0.94 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 177.5, 70.6, 68.5, 62.9, 49.2, 40.1, 36.0, 19.1,13.9; IR (neat) ν 3383, 2959, 2874, 1748, 1382, 1181 cm−1; HRMS (ESI) m/z calcd for C9H17O4 [M + H]+ 189.1121, found 189.1131; [α]24 D −3.1 (c 2.0, CHCl3 for 95% ee) [lit.7 −6.7 (c 0.89, CHCl3 for 99% ee)]. (3R,4R)-4-(Hydroxymethyl)-3-((R)-1-hydroxyoctyl)dihydrofuran2(3H)-one (13). By following the above general procedure, compound 13 was synthesized from 11. The crude product was purified by column chromatography on silica gel [CH2Cl2/MeOH (100:0 to 98:2)] to yield the title compound 13 as a colorless liquid (88 mg, 95%): Rf = 0.4 [CH2Cl2/MeOH (9:1)]; 1H NMR (500 MHz, CDCl3) δ 4.41 (t, J = 8.5 Hz, 1H), 4.01 (m, 1H), 3.98 (t, J = 8.5 Hz, 1H), 3.75 (dd, J = 5.0, 10.0 Hz, 1H), 3.68 (dd, J = 6.5, 10.5 Hz, 1H), 2.95 (br, 1H), 2.73−2.81 (m, 1H), 2.65 (dd, J = 5.0, 9.5 Hz, 1H), 1.57−1.63 (m, 1H), 1.48−1.55 (m, 2H), 1.25−1.35 (m, 10H), 0.88 (t, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 177.2, 70.9, 68.4, 63.0, 49.0, 40.2, 34.0, 31.8, 29.4, 29.2, 25.8, 22.6, 14.1; IR (neat) ν 3418, 2922, 2852, 1742, 1464, 1181, 837 cm−1; HRMS (ESI) m/z calcd for C13H25O4 [M + H]+ 245.1747, found 245.1765; [α]24 D −3.8 (c 1.0, CHCl3 for 95% ee). (3R)-4-(Hydroxymethyl)-3-(6-methylheptanoyl)dihydro-furan2(3H)-one (16). A round-bottom flask was charged with compound 15, and tetra-n-butylammonium fluoride (1.0 M in tetrahydrofuran; 492 μL, 7.0 mmol) was added dropwise. The reaction mixture was kept at room temperature for 24 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution (1 mL) and extracted with diethyl ether (2 × 10 mL). The combined organic fractions were dried (sodium sulfate) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel [CH2Cl2/EtOAc (100:0 to 95:5)] to yield compound 16 (major) along with its hemiketal form5d in a 3:1 ratio as a colorless liquid (12 mg, 70%): Rf = 0.4 [CH2Cl2/EtOAc (8:2)]; 1H NMR (500 MHz, CDCl3) δ 4.44 (dd, J = 8.5, 9.0 Hz 1H), 4.15 (dd, J = 6.5, 9.0 Hz, 1H), 3.67 (m, 3H), 3.21−3.27 (m, 1H), 2.97 (dt, J = 7.5, 18.0 Hz, 1H), 2.65 (dt, J = 7.5, 18.0 Hz, 1H), 1.63−1.57 (m, 2H), 1.56−1.50 (m, 1H), 1.29−1.34 (m, 2H), 1.17−1.20 (m, 2H), 0.86−0.87 (dd, J = 7.5 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 202.9, 172.3, 69.0, 61.9, 55.0, 42.5, 39.2, 38.7, 27.8, 26.8, 23.5, 22.5; IR (neat) ν 3456, 2953, 2869, 1764, 1716, 1384, 1171 cm−1; HRMS (ESI) m/z calcd for C13H23O4 [M + H]+ 243.1591, found 243.1584; [α]24 D −8.1 (c 1.0, CHCl3 for 95% ee) [lit.5c −13.1 (c 1.18, CHCl3)].

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00122. Copies of 1H NMR and 13C NMR spectra of all products and HPLC chromatograms of 7 (PDF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Chandrakumar Appayee: 0000-0003-1165-4918 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This paper is dedicated to Professor Srinivasan Chandrasekaran (Indian institute of Science, Bangalore) on the occasion of his 72nd birthday. The authors are grateful to the Indian Institute 4171

DOI: 10.1021/acs.joc.8b00122 J. Org. Chem. 2018, 83, 4167−4172

Note

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