Paraconyl Alcohol - ACS Publications

Subscriber access provided by Kaohsiung Medical University

Note

An Organocatalytic Approach for Short Asymmetric Synthesis of (R)-Paraconyl Alcohol: Application to the Total Syntheses of IM-2, SCB2 and A-Factor #-Butyrolactone Autoregulators Abhijeet M Sarkale, Amit Kumar, and Chandrakumar Appayee J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00122 • Publication Date (Web): 28 Feb 2018 Downloaded from http://pubs.acs.org on February 28, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

The Journal of Organic Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

An 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 Supporting Information Placeholder

ABSTRACT: (R)-Paraconyl alcohol is found to be a key intermediate for the syntheses of many γ-butyrolactone autoregulators. 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 a first organocatalytic approach for the short asymmetric synthesis of (R)-paraconyl alcohol in four steps and single column purification. Asymmetric syntheses of IM-2, SCB2 and A-factor γ-butyrolactone autoregulators were achieved from (R)-paraconyl alcohol in three steps.

Chiral γ-butyrolactones are the most common structural motifs in wide variety of bioactive natural products and pharmaceuticals.1 2,3-Disubstituted γ-butyrolactone autoregulators have been isolated from Streptomyces species that trigger production of commercially significant antibiotics2 and pigments3. Fourteen such autoregulators have been isolated and chemically identified so far.

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

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

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 1′-(S)-hydroxyl group) and IM-2 type (possessing 1′-(R)-hydroxyl group) autoregulators (Figure 1).4

Many synthetic methodologies have been developed for the syntheses of A-factor5, virginiae butanolides6 and IM27,6c type natural products. (R)-Paraconyl alcohol 1 have been considered as an important chiral intermediate for the syntheses of most of these autoregulators5a,5c,6b,8 and other bioactive molecules.9 Racemic synthesis of para-

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

conyl alcohol and its application towards butyrolactone autoregulators10 and other natural products11 were also reported in the literature. Chiral auxiliary approach5a and enzymatic resolution5c,12a,b are the two common strategies have been so far reported in the literature for the asymmetric synthesis12 of (R)-paraconyl alcohol 1 in seven steps. Through chiral auxiliary approach, alcohol 1 was obtained from oxazolidinone 2 in seven steps with 8% overall yield (Figure 2).5a By lipase-mediated enzymatic resolution, alcohol 1 was obtained from diester 3 in seven steps with 9% overall yield and 83% ee.12a In this paper, we report a first organocatalytic approach for the asymmetric synthesis of (R)-paraconyl alcohol 1 starting from methyl 4-oxobutanoate 4 in four steps with 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 Afactor γ-butyrolactone autoregulators in three steps. Scheme 1. Asymmetric synthesis (R)-paraconyl alcohol 1

To achieve higher product ee for the αhydroxymethylation of methyl 4-oxobutanoate 4, we have used the general procedure reported14d for the αhydroxymethylation of aldehydes by Hayashi et al. with slight modification (reaction concentration was doubled and NaCl was used as an additive). Accordingly, methyl 4oxobutanoate 4 was reacted with aqueous formaldehyde in presence of (S)-diarylprolinol and NaCl in toluene and methanol at 0 °C for 6 days. The crude αhydroxymethylated 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 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 (see experimental section). After achieving short synthesis of (R)-paraconyl alcohol 1, its application to the total syntheses of IM-2, SCB2 and A-factor γ-butyrolactone autoregulators was explored. Scheme 2. Synthesis TBS ether of IM-2 through acylation followed by reduction

For the synthesis of (R)-paraconyl alcohol 1, 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 use of formaldehyde as an aldehyde partner is less explored in the literature14. 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 aldol reaction of methyl 4-oxobutanoate 4 with benzaldehydes,15 we observed that the similar reaction with formaldehyde failed to give aldol product. On the other hand, aldol reaction of methyl 6-oxohexanoate with formaldehyde catalyzed by (S)-diphenylprolinol trimethyl silyl ether has been reported to give α-hydroxymethylated product with >99% ee.14b Using the similar reaction conditions, we have obtained only moderate (78% ee) enantioselectivity for the α-hydroxymethylation of methyl 4-oxobutanoate 4.

For the total synthesis of IM-2, initially, acylation followed by 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 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 90% isolated yield and 70:30 dr. The major diastereomeric alcohol 10 (63%) was purified by silica gel column chromatography (Scheme 2). Scheme 3. Synthesis of IM-2 and SCB2 through direct aldol reaction


Page 2 of 7

Page 3 of 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry for the short synthesis of (R)-paraconyl alcohol 1 shall also be applied for the synthesis of other 2,3-disubstituted γbutyrolactone natural products. Experimental section General information

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 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 IM-2 12 in 94% isolated yield (Scheme 3). Similarly, lactone 8 was reacted with octan-1-al to form major aldol product 11 (42%) that was subjected to HCl in diethyl ether to generate SCB2 13 in 95% isolated yield. Scheme 4. Synthesis of A-factor

Acylation of lactone 8 using NaHMDS and acid chloride 1410f at –78 °C gave ketone 15 in 52% yield. Deprotection of silyl group in 15 using tetrabutylammonium fluoride in THF resulted in 70% isolated yield of A-factor 16 along with its hemiketal form5d in 3:1 ratio (Scheme 4). Spectral data of IM-2 12, SCB2 13 and A-factor 16 obtained are in good agreement with that of reported in the literature.7 In conclusion, we have developed first organocatalytic approach for a short asymmetric synthesis of (R)paraconyl alcohol 1 staring form methyl 4-oxobutanoate 4 in four steps with 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 total synthesis of IM-2 12, a γbutyrolactone autoregulator through direct aldol reaction in just three steps from (R)-paraconyl alcohol 1 with 42% overall yield. Alternate method was developed through acylation followed by reduction to obtain higher overall yield (49%) but in four steps. We have also shown application of (R)-paraconyl alcohol 1 for the asymmetric syntheses of SCB2 13 through direct aldol reaction and Afactor 16 through acylation. Our synthetic methodology

All reactions were carried out in the oven dried glassware unless otherwise noted. Except as otherwise indicated, all reactions were magnetically stirred and monitored by thin-layer chromatography using Merck pre-coated 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 were 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 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 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 the compounds were recorded (in positive ion mode) with Waters Synapt-G2S ESI-Q-TOF 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(3,5bis(trifluoromethyl)phenyl)(pyrrolidin-2-yl)methanol (4.7 g, 9.0 mmol) and NaCl (8.7 g) under argon condition. The flask was capped with a rubber septum, toluene (13.5 mL) and methanol (1.5 mL) was 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 the mixture 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), 2-methyl-2-butene (31.9 mL, 300.0 mmol) was added and 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 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 a 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 rubber septum and 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 drop wise over 30 min at 0 °C and 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 calcd for C5H9O3 [M+H]+: 117.0546, found: 117.0566; [α]D24 = −41.4 (c = 1.12, CHCl3 for 95% ee) [lit.5a, −42.4 (c = 6.8, CHCl3)]. (R)-(5-oxotetrahydrofuran-3-yl)methyl-4-(tertbutyl)-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 minutes and then slowly raised to room temperature. After stirring for 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 were dried (Na2SO4) and concentrated under reduced pressure to give 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 × 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]D24= −27.0 (c = 1.0, CHCl3 for 95% ee).

(S)-4-(((tertbutyldimethylsilyl)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 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); 13C 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]D25 = −19.8 (c = 2.4, CHCl3 for 95% ee). General procedure for acylation reaction of lactone 8 To a solution of 8 (3.04 mmol) in dry THF (32 mL) un° der argon at –78 C was added sodium bis(trimethylsilyl)amide (1.0 M in THF; 7.60 mL, 7.60 mmol) followed after 1.5 h delay by alkanoyl chloride (3.95 mmol), and the mixture 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). The combined organic fractions were dried (sodium sulfate) and concentrated in vacuo. (3R)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3butyryldihydrofuran-2(3H)-one 9 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)]; 1 H 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]D27 = −19.5 ( c = 3.3, CHCl3 for 95% ee). (3R)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(6methylheptanoyl)dihydrofuran-2(3H)-one 15 Following the above general procedure using alkanoyl chloride 1410f, 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


Page 4 of 7

Page 5 of 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry 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]D24 = −16.4 ( c = 1.0, CHCl3 for 95% ee). (3R,4S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3butyryldihydrofuran-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 a one portion followed by the addition of the 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 and 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 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 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)-1-hydroxybutyl)dihydrofuran-2(3H)-one 10 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]D25 = −16.2 (c = 3.1, CHCl3 for 95% ee). (3R,4S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3((R)-1-hydroxyoctyl)dihydrofuran-2(3H)-one 11 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]D25 = −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)di-hydrofuran-2(3H)-one 12 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, 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]D24= −3.1 (c = 2.0, CHCl3 for 95% ee) [lit.7a, −6.7 (c = 0.89, CHCl3 for 99% ee)]. (3R,4R)-4-(hydroxymethyl)-3-((R)-1hydroxyoctyl)di-hydrofuran-2(3H)-one 13 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]D24 = −3.8 (c = 1.0, CHCl3 for 95% ee). (3R)-4-(hydroxymethyl)-3-(6methylheptanoyl)dihydro-furan-2(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 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 (so-



dium 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 3:1 ratio as a colorless liquid (12 mg, 70%). Rf = 0.4 [CH2Cl2:EtOAc (8:2)]; 1H NMR (500 MHz, CDCl3) 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]D24= −8.1 (c = 1.0, CHCl3 for 95% ee) [lit.5c, −13.1 (c = 1.18, CHCl3)].

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. 1 13 Copies of H NMR and C NMR spectra of all products, and HPLC chromatograms of 7 (PDF)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] ORCID Chandrakumar Appayee: 0000-0003-1165-4918

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT 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 of Technology Gandhinagar for the facilities and financial support.

REFERENCES (1) (a) Corre, C.; Song, L.; O’Rourke, S.; Chater, K. F.; Challis, G. L. Proc. Natl. Acad. Sci. 2008, 105, 17510–17515. (b) Lin, L.; Zhao, Q.; Li, A. N.; Ren, F.; Yang, F.; Wang, R. Org. Biomol. Chem. 2009, 7, 3663–3665. (c) Waché, Y.; Aguedo, M.; Nicaud, J.M.; Belin, J.-M. Appl. Microbiol. Biotechnol. 2003, 61, 393–404. (d) Kitson, R. R. A.; Millemaggi, A.; Taylor, R. J. K. Angew. Chem., Int. Ed. 2009, 48, 9426–9451. (e) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. 1985, 24, 94–110. (f) Seitz, M.; Reiser, O. Curr. Opin. Chem. Biol. 2005, 9, 285–292. (2) (a) Nihira, T.; Shimizu, Y.; Kim, H. S.; Yamada, Y. J. Antibiot. 1988, 41, 1828–1837. (b) Weber, T.; Welzel, K.; Pelzer, S.; Vente, A.; Wohlleben, W. J. Biotechnol. 2003, 106, 221–232. (c) Ueki, T.; Kinoshita, T. Org. Biomol. Chem. 2004, 2, 2777–2785. (d) Morin, J. B.; Adams, K. L.; Sello, J. K. Org. Biomol. Chem. 2012, 10, 1517–1520. (e) Zou, Z.; Du, D.; Zhang, Y.; Zhang, J.; Niu, G.; Tan, H. Mol. Microbiol. 2014, 94, 490–505. (f) Takano, E.; Nihira, T.; Hara, Y.; Jones, J. J.; Gershater, C. J.; Yamada, Y.; Bibb, M. J. Biol. Chem. 2000, 275, 11010–11016. (g) Willey, J. M.; Gaskell, A. A. Chem. Rev. 2011, 111, 174–187. (h) Kitani, S.; Doi, M.; Shimizu, T.; Maeda, A.; Nihira, T. Arch. Microbiol. 2010, 192, 211–220.

(i) Shikura, N.; Yamamura, J.; Nihira, T. J. Bacteriol. 2002, 184, 5151–5157. (3) Sato, K.; Nihira, T.; Sakuda, S.; Yanagimoto, M.; Yamada, Y. J. Ferment. Bioeng. 1989, 68, 170–173. (4) (a) Sakuda, S.; Yamada, Y. Tetrahedron Lett. 1991, 32, 1817– 1820. (b) Hsiao, N.-H.; Nakayama, S.; Merlo, M. E.; de Vries, M.; Bunet, R.; Kitani, S.; Nihira, T.; Takano, E. Chem. Biol. 2009, 16, 951–960. (c) Kawachi, R.; Akashi, T.; Kamitani, Y.; Sy, A.; Wangchaisoonthorn, U.; Nihira, T.; Yamada, Y. Mol. Microbiol. 2000, 36, 302–313. (d) Yamada, Y.; Sugamura, K.; Kondo, K.; Yanagimoto, M.; Okada, H. J. Antibiot. 1987, 40, 496–504. (e) Sidda, J. D.; Poon, V.; Song, L.; Wang, W.; Yang, K.; Corre, C. Org. Biomol. Chem. 2016, 14, 6390–6393. (f) Horinouchi, S.; Beppu, T. Proc. Jpn. Acad., Ser. B. 2007, 83, 277–295. (g) Waki, M.; Nihira, T.; Yamada, Y. J. Bacteriol. 1997, 179, 5131–5137. (5) (a) Crawforth, J. M.; Fawcett, J.; Rawlings, B. J. J. Chem. Soc., Perkin Trans. 1 1998, 1721–1726. (b) Morin, J. B.; Adams, K. L.; Sello, J. K. Org. Biomol. Chem. 2012, 10, 1517–1520. (c) Mori, K.; Yamane, K. Tetrahedron 1982, 38, 2919–2921. (d) Parsons, P. J.; Lacrouts, P.; Buss, A. D. J. Chem. Soc., Chem. Commun. 1995, 437–438. (6) (a) Takabe, K.; Mase, N.; Matsumura, H.; Hasegawa, T.; Iida, Y.; Kuribayashi, H.; Adachi, K.; Yoda, H.; Ao, M. Bioorg. Med. Chem. Lett, 2002, 12, 2295–2297. (b) Mori, K.; Chiba, N. Eur. J. Org. Chem. 1990, 1990, 31–37. (c) Mizuno, K.; Sakuda, S.; Nihira, T.; Yamada, Y. Tetrahedron 1994, 50, 10849–10858. (7) Elsner, P.; Jiang, H.; Nielsen, J. B.; Pasi, F.; Jørgensen, K. A. Chem. Commun. 2008, 5827–5829. (8) Mori, K. Tetrahedron 1983, 39, 3107–3109. (9) Mattei, P.; Boehringer, M.; Di Giorgio, P.; Fischer, H.; Hennig, M.; Huwyler, J.; Koçer, B.; Kuhn, B.; Loeffler, B. M.; MacDonald, A.; Narquizian, R.; Rauber, E.; Sebokova, E.; Sprecher, U. Bioorg. Med. Chem. Lett. 2010, 20, 1109–1113. (10) (a) Weinstabl, H.; Suhartono, M.; Qureshi, Z.; Lautens, M. Angew. Chem., Int. Ed. 2013, 52, 5305–5308. (b) Qureshi, Z.; Weinstabl, H.; Suhartono, M.; Liu, H.; Thesmar, P.; Lautens, M. Eur. J. Org. Chem. 2014, 2014, 4053–4069. (c) Crotti, A. E. M.; Bronze-Uhle, E. S.; Nascimento, P. G. B. D.; Donate, P. M.; Galembeck, S. E.; Vessecchi, R.; Lopes, N. P. J. Mass Spectrom. 2009, 44, 1733–1741. (d) Biswas, A.; Swarnkar, R. K.; Hussain, B.; Sahoo, S. K.; Pradeepkumar, P. I.; Patwari, G. N.; Anand, R. J. Phys. Chem. B 2014, 118, 10035−10042. (e) Kakiuchi, S.; Yamada, N.; Fujiie, S.; Tsukada, H.; Taniguchi, E. Kuwano, E. J. Fac. Agr., Kyushu Univ. 2000, 45, 125−133. (f) Chavan, S. P.; Pasupathy, K.; Shivasankar, K. Synth. Commun. 2004, 34, 397–404. (11) (a) Campbell, M. M.; Fox, J. L.; Sainsbury, M.; Liu, Y. Tetrahedron 1989, 45, 4551–4556. (b) Malla, R. K.; Bandyopadhyay, S.; Spilling, C. D.; Dutta, S.; Dupureur, C. M. Org. Lett. 2011, 13, 3094–3097. (12) (a) Mori, K.; Chiba, N. Eur. J. Org. Chem. 1989, 1989, 957– 962. (b) Comini, A.; Forzato, C.; Nitti, P.; Pitacco, G.; Valentin, E. Tetrahedron: Asymmetry 2004, 15, 617−625. (c) Kanger, T.; Kriis, K.; Paju, A.; Pehk, T.; Lopp, M. Tetrahedron: Asymmetry 1998, 9, 4475–4482. (d) Posner, G. H.; Weitzberg, M.; Jew, S.-S. Synth. Commun. 1987, 17, 611–620. (e) Bronze-Uhle, E. S.; de Sairre, M. I.; Donate, P. M.; Frederico, D. J. Mol. Catal. A: Chem. 2006, 259, 103–107. (13) (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395–2396. (b) Kotrusz, P.; Kmentová, I.; Gotov, B.; Toma, Š.; Solčániová, E. Chem. Commun. 2002, 222, 2510–2511. (c) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573–575. (d) Tang, Z.; Yang, Z.-H.; Chen, X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. J. Am. Chem. Soc. 2005, 127, 9285–9289. (e) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc. 2005, 128, 734–735. (f) Mlynarski, J.; Bas, S. Chem. Soc. Rev. 2014, 43, 577– 587.


Page 6 of 7

Page 7 of 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry (14) (a) Casas, J.; Sundén, H.; Córdova, A. Tetrahedron Lett. 2004, 45, 6117–6119. (b) Boeckman, R. K.; Miller, J. R. Org. Lett. 2009, 11, 4544–4547. (c) Boeckman, R. K.; Biegasiewicz, K. F.; Tusch, D. J.; Miller, J. R. J. Org. Chem. 2015, 80, 4030–4045. (d) Yasui, Y.; Benohoud, M.; Sato, I.; Hayashi, Y. Chem. Lett. 2014, 43, 556–558. (e) Liu, X.-L.; Liao, Y.-H.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. J. Org. Chem. 2010, 75, 4872–4875. (f) Ji, C.-B.; Liu, Y.-L.; Cao, Z.-Y.; Zhang, Y.-Y.; Zhou, J. Tetrahedron Lett. 2011, 52, 6118–6121. (g) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983– 1986.

(15) (a) Hajra, S.; Giri, A. K. J. Org. Chem. 2008, 73, 3935–3937. (b) Hajra, S.; Garai, S.; Hazra, S. Org. Lett. 2017, 19, 6530–6533. (16) Other bases like LiHMDS (lithium bis(trimethylsilyl)amide) in similar reaction conditions gave 60:40 dr and LDA (lithium diisopropylamide) resulted in traces of product 10 along with complete decomposition of starting compounds. (17) Commercially available methyl 4-oxobutanoate 4 (CAS Number: 13865−19−5) have been easily accessed following the literature procedure, Ref: Gannett, P. M.; Nagel, D. L.; Reilly, P. J.; Lawson, T.; Sharpe, J.; Toth, B. J. Org. Chem. 1988, 53, 1064– 1071.


Paraconyl Alcohol - ACS Publications

Recommend Documents