A concise synthesis of paraconic acids: (−)-methylenolactocin and (−)-phaseolinic acid

Tetrahedron: Asymmetry 22 (2011) 1114–1119

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A concise synthesis of paraconic acids: ()-methylenolactocin and ()-phaseolinic acid Rodney A. Fernandes ⇑, Asim K. Chowdhury Department of Chemistry, Indian Institute of Technology Bombay, Powai, Maharashtra, Mumbai 400076, India

a r t i c l e

i n f o

Article history: Received 5 May 2011 Accepted 17 May 2011 Available online 14 June 2011

a b s t r a c t A concise synthesis of ()-methylenolactocin and ()-phaseolinic acid, the common members of the paraconic acids, is described. The synthesis is based on regioselective asymmetric dihydroxylation and the orthoester Johnson–Claisen rearrangement of allyl alcohol with a vicinal diol functionality as the key steps. The synthesis was completed in 10 steps with overall yields of 4.1% for ()-methylenolactocin and 4.3% for ()-phaseolinic acid. Ó 2011 Elsevier Ltd. All rights reserved.

1. Introduction Paraconic acids are a class of highly substituted c-butyrolactones with a b-COOH group and a-methyl or methylene group and display a range of stereochemical relationship of substituents on adjacent carbon centers (Fig. 1). They are isolated from various species of lichen, moss and fungus and possess important biological activities including antitumor, antifungal, antibacterial and antibiotic.1 These interesting biological activities have prompted many researchers to devise synthetic routes toward these natural products. A number of total2–6 and formal7 syntheses have been reported for this class of compounds in racemic2 and enantiopure3–6 forms. ()-Methylenolactocin 3 was isolated by Nakayama et al. from the culture filtrate of the fungus Penicillium sp.1c Its structure was determined to be 3carboxy-2-methylene-4-nonanolide by spectroscopic data. It is active against some gram-positive bacteria and it prolongs the life span of mice inoculated with Ehrlich carcinoma.1c It has been synthesized by several research groups in both racemic2c,d,h,m and as enantiomerically pure forms.3b,4a,b,h,5a,b,i,m,n,6i,k,l ()-Phaseolinic acid 6 was isolated from the culture filtrate of the phytotoxic fungus Macrophomina phaseolina.1d It differs from methylenolactocin in having an a-methyl substituent and more importantly the cis-placement of b,c-substituents. It has been synthesized in racemic2a,e and enantiomerically pure forms.3d,e,4a,e,5a,k,6e,i Over the course of studies directed toward the enantioselective synthesis of bioactive natural products employing the orthoester Johnson–Claisen rearrangement of allyl alcohols with a chiral vicinal diol functionality,8 we became interested in the synthesis of ()-methylenolactocin 3 and ()-phaseolinic acid 6 employing asymmetric dihydroxylation of a c,d-olefinic bond of an a,b,c,d-unsaturated ester and the orthoester Johnson–Claisen rearrangement as the key steps. ⇑ Corresponding author. Fax: +91 22 25767152. E-mail address: [email protected] (R.A. Fernandes). 0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2011.05.007

O O HO

R = n-C11H23: (+)-nephrosteranic acid 1 R = n-C13H27: (+)-roccellaric acid 2

R

O

O

R = n-C5H11: (-)-methylenolactocin 3 R = n-C11H23: (-)-nephrosterinic acid 4 R = n-C13H27: (-)-protolichesterinic acid 5

O HO R

O O O HO

R = n-C11H23: (+)-nephrosterinic acid ent-4 R = n-C13H27: (+)-protolichesterinic acid ent-5

R

O

O

R = n-C5H11: (-)-phaseolinic acid 6 R = n-C13H27: (-)-nephromopsinic acid 7 R = n-C13H26COCH3: (-)-dihydropertusaric acid 8

O HO O

R

O O HO O

R = n-C13H27: (+)-lichesterinic acid 9 R = n-C12H24COOH: (+)-praesorediosic acid 10 R = n-C12H24CH2OAc: (-)-13-acetoxylichesterinic acid 11

R Figure 1. Paraconic acids.

2. Results and discussion The retrosynthetic route to 3 and 6 is shown in Scheme 1. Removal of the free hydroxyl group in 12a, the conversion of the b-vinyl bond to a carboxylic acid group and the stereoselective a-methylene group introduction would give title compound 3. Similarly, the introduction of an a-methyl group in the b-COOH

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O

O

cleave/oxidise to acid

HO H

O

LiHMDS, THF -78 oC, 1.5 h

EtO

OH

OHC

+

remove

86%

H introduce =CH2

O (-)-methylenolactocin 3

16 O

O

17

12a

O

EtO

O

Ph3P, PhH, rt, 6h

cleave/oxidise to acid

HO H

remove

Me O

70% OH

OH

15

K3Fe(CN)6, K2CO3 MeSO2NH2 K2OsO4.2H2O

H introduce CH3

O

O

12b

O

(-)-phaseolinic acid 6

O EtO

Johnson-Claisen rearangement

14

asymmetric dihydroxylation

O

(DHQD)2-PHAL t-BuOH/H2O (1:1) 0 oC, 12 h, 61%

O HO

EtO

(i) Me2C(OMe)2, Me2CO p-TSOH (cat), rt 12 h, 98%

OH

O EtO

14

O

OH

(ii) DIBAL-H, CH2Cl2 0 oC, 2.5 h, 95%

13 18

O

EtO 15

OH

(MeO)3CMe, toluene EtCO2H (cat), reflux 24 h, then rt, 4M HCl MeOH, 12 h, 12a (59%) 12b (22%)

O

O

EtO

+

HO

OHC

16

O

17

13

(MeO)3CMe, xylene EtCO2H (cat), reflux 4 h, then rt, 4M HCl MeOH, 12 h, 12a (46%) 12b (42%)

or

Scheme 1. Retrosynthetic analysis of 3 and 6.

containing intermediate from 12b would give ()-phaseolinic acid 6. The b,c-disubstituted-c-lactones 12a and 12b were the products of orthoester Johnson–Claisen rearrangement of allyl alcohol 13 which had a vicinal chiral diol functionality. Compound 13 could be obtained via the regioselective asymmetric dihydroxylation of the distant olefinic bond of a,b,c,d-unsaturated ester 14 followed by usual acetonide formation and ester group reduction. Dienenoate 14 can be obtained from the ethyl propiolate 16 addition to aldehyde 17, followed by PPh3 mediated ‘allene’ type rearrangement9 of 15. Thus, from the common intermediate allyl alcohol 13, both 3 and 6 can be synthesized. The synthesis was initiated by assembling the precursor b,cdisubstituted-c-lactones 12a and 12b as shown in Scheme 2. The addition of lithiated ethyl propiolate 16 to aldehyde 17 produced the hydroxy alkynoate 15 (86%). The Ph3P mediated ‘allene’ type rearrangement9 of 15 gave the all trans-dienoate 14 in good yields (70%). The enantio- and regioselective asymmetric dihydroxylation10 of 14 afforded diol 18 (61%, 97% ee11). The acetonide protection of diol 18 (98%) and subsequent DIBAL-H reduction of the ester group gave 13 in 95% yield.12 The orthoester Johnson–Claisen rearrangement13 of the allyl alcohol 13 with a chiral vicinal diol functionality with trimethylorthoacetate in the presence of a catalytic amount of propionic acid in toluene solvent over 24 h and the same-pot hydrolysis provided a mixture of 12a/12b in a 2.5:1 ratio. The same reaction in xylene solvent over 4 h gave a mixture of 12a/ 12b in a 1.1:1 ratio.8b From the toluene reaction, the mixture was easily separated by silica gel flash column chromatography to give 12a in 59% and 12b in 22% yields. From the xylene reaction 12b was obtained in 42% and 12a in 46% yields.8b Lactone 12a has the required functionality to set the b,c-stereocenters of the target molecule 3 while the free hydroxyl group in the side chain needs to be removed. Similarly 12b with cis-b,c-substituents is a precursor for 6. The final stage leading to the completion of the synthesis of ()methylenolactocin and ()-phaseolinic acid is shown in Scheme 3.

OH

OH

+

O O

12a

O O

12b

Scheme 2. Synthesis of separable diastereomeric c-lactones 12a and 12b.

The hydroxyl group in 12a was converted into a xanthate to give 19a in 71% yield. Similarly, 12b afforded 19b (70%). Next, the AIBN/nBu3SnH mediated removal of the xanthate group from 19a gave b-vinyl-c-lactone 20a in quantitative yield. Compound 19b upon similar removal of the xanthate group gave 20b. The ozonolytic cleavage of the vinyl bond in 20a and further oxidation efficiently placed the desired b-carboxylic acid group to provide 21a in good yields of 95%. Similarly, 20b provided 21b in 92% yield. The a-methylene group was introduced following the literature procedure.4h The treatment of 21a with methoxy magnesiummethylcarbonate followed by formaldehyde and N-methylaniline gave ()-methylenolactocin 3 in 64% yield, ½a25 D ¼ 7 (c 0.12, 4h MeOH), lit.5a ½a20 ½a20 D ¼ 10 (c 0.5, MeOH), lit. D ¼ 6:8 (c 0.5, MeOH). The stereoselective introduction of a-methyl group in 21b using NaHMDS/MeI gave ()-phaseolinic acid 6 in quantitative 6g yield, ½a25 ½a25 D ¼ 117 (c 0.10, CHCl3), lit. D ¼ 112 (c 0.26, CHCl3). The spectroscopic data for 3 and 6 were in full agreement with the literature data.5a 3. Conclusions In conclusion, we have efficiently synthesized ()-methylenolactocin and ()-phaseolinic acid in 10 steps and overall yields of 4.1% and 4.3%, respectively. The synthesis features the regioselective

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R'

OH

R

CS2, NaH, THF, 0 oC, 1 h then MeI, 0 oC to rt, 2 h

H O O R = H, R' = -CH=CH2, 12a R = -CH=CH2, R' = H, 12b S R'

O

R

O

S

Bu3SnH, AIBN (cat), toluene reflux, 6 h quantitative

H

O R = H, R' = -CH=CH2, 19a, 71% R = -CH=CH2, R' = H, 19b, 70% R'

(i) O3, CH2Cl2, -78 oC, 0.5 h then Me2S, -78 oC, 1 h, rt, 2 h

R

O

H

(ii) CrO3, H2SO4, acetone, 0 oC 20 min

O

R = H, R' = -CH=CH2, 20a R = -CH=CH2, R' = H, 20b O

O

HO

HO

H

H

O O

21a

H

O

H

O 21b

95%

(i) MeOMgOCO2Me DMF, 135 oC, 60h (ii) CH2O, N-methylaniline AcOH, NaOAc rt, 2.5 h, 64% (two steps)

92%

NaHMDS THF, -78 °C 1.5 h, MeI, -78 °C 2 h, quant.

O

O

HO

HO

H

H Me O

H

O (-)-methylenolactocin 3

O

H

O (-)-phaseolinic acid 6

Scheme 3. Synthesis of ()-methylenolactocin and ()-phaseolinic acid.

asymmetric dihydroxylation and the orthoester Johnson–Claisen rearrangement of the allyl alcohol with a chiral vicinal diol functionality as the key steps. Both diastereomers obtained in the latter reaction were separately converted into the desired target molecules exhibiting a versatile strategy that has significant potential for further extension to the synthesis of other paraconic acids. 4. Experimental 4.1. General Flasks were oven or flame dried and cooled in a desiccator. Dry reactions were carried out under an atmosphere of Ar or N2. Solvents and reagents were purified by standard methods. Thin-layer chromatography was performed on EM 250 Kieselgel 60 F254 silica gel plates. The spots were visualized by staining with KMnO4 or by UV lamp. The 1H NMR and 13C NMR were recorded on Varian

Mercury Plus, AS400 spectrometer and Bruker, AVANCE III 400 spectrometer. The chemical shifts are based on TMS peak at d = 0.00 pm for 1H NMR and the CDCl3 peak at d = 77.00 ppm (t) in 13C NMR. The IR spectra were obtained on Perkin Elmer Spectrum One FT-IR spectrometer. Optical rotations were measured with Jasco DIP-370 digital polarimeter. HRMS was recorded using a Micromass: Q-Tof micro (YA-105) spectrometer. HPLC was performed with JASCO-(PU-2080PLUS Pump with UV-2075PLUS Detector. 4.1.1. Ethyl 4-hydroxynon-2-ynoate 15 To a solution of ethylpropiolate 16 (2.15 g, 21.96 mmol, 1.1 equiv) in dry THF (60 mL) at 78 °C was added LiHMDS (23.3 mL, 27.96 mmol, 1.2 M solution in THF, 1.4 equiv), and the mixture was stirred at 78 °C for 1.5 h. Aldehyde 17 (2.0 g, 19.97 mmol) in THF (15 mL) was added at 78 °C and stirring was continued for 30 min. The reaction mixture was quenched with a satd aq NH4Cl solution and warmed to room temperature. It was diluted with water and extracted with EtOAc (4  50 mL). The combined organic layers were washed with water, brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc, 9:1) to give 15 (3.4 g, 86%) as a colorless oil. IR (CHCl3): mmax 3419, 2958, 2934, 2863, 2238, 1715, 1467, 1368, 1248, 1020, 861, 752, 636 cm1. 1 H NMR (400 MHz, CDCl3): d 0.89 (t, J = 6.7 Hz, 3H, CH3), 1.10– 1.40 (m, 7H, CH3, H-8, H-7), 1.40–1.60 (m, 2H, H-6), 1.70–1.90 (m, 2H, H-5), 1.91 (brs, 1H, –OH), 4.24 (q, J = 7.2 Hz, 2H, OCH2), 4.48 (t, J = 6.7 Hz, 1H, H-4). 13C NMR (100 MHz, CDCl3): d 13.9 (2C), 22.4, 24.6, 31.3, 36.8, 62.1, 62.2, 76.5, 87.9, 153.5. HRMS (ESI+): Calcd for [C11H18O3 + H] 199.1334. Found: 199.1340. 4.1.2. (2E,4E)-Ethyl nona-2,4-dienoate 14 To a solution of 15 (4.1 g, 20.68 mmol) in benzene (30 mL) was added PPh3 (6.51 g, 24.82 mmol, 1.2 equiv) at room temperature and the resulting mixture was stirred for 6 h. It was then diluted with petroleum ether/EtOAc (95:5, 80 mL) and filtered through a pad of silica gel. The filtrate was concentrated and the residue purified by silica gel column chromatography (petroleum ether/EtOAc, 95:5) to give 14 (2.64 g, 70%) as a colorless oil. IR (CHCl3): mmax 2959, 2934, 2873, 1724, 1467, 1370, 1304, 1270, 1179, 1121, 1030, 981, 861, 725, 696, 544 cm1. 1H NMR (400 MHz, CDCl3): d 0.89 (t, J = 7.1 Hz, 3H, CH3), 1.10–1.50 (m, 7H, CH3, H-8, H-7), 2.10–2.30 (m, 2H, H-6), 4.18 (q, J = 7.1 Hz, 2H, OCH2), 5.77 (d, J = 15.3 Hz, 1H, H-olefin), 6.07–6.20 (m, 2H, H-olefin), 7.25 (dd, J = 15.3, 9.8 Hz, 1H, H-olefin). 13C NMR (100 MHz, CDCl3): d 13.8, 14.2, 22.2, 30.8, 32.6, 60.1, 119.1, 128.3, 144.7, 145.1, 167.3. HRMS (ESI+): Calcd for [C11H18O2 + H] 183.1385. Found: 183.1391. 4.1.3. (4R,5R,E)-Ethyl 4,5-dihydroxynon-2-enoate 18 To a mixture of K3Fe(CN)6 (13.39 g, 40.66 mmol, 3.0 equiv), K2CO3 (5.62 g, 40.66 mmol, 3.0 equiv), MeSO2NH2 (1.29 g, 13.55 mmol, 1.0 equiv), (DHQD)2PHAL (106 mg, 0.136 mmol, 1.0 mol %) and K2OsO42H2O (20 mg, 0.0542 mmol, 0.4 mol %) in t-BuOH–H2O (1:1, 136 mL) at 0 °C was added olefin 14 (2.47 g, 13.55 mmol) in one portion. The reaction mixture was stirred at 0 °C for 12 h and then quenched with solid Na2SO3 (5.0 g). The stirring was continued for an additional 45 min and the solution extracted with EtOAc (5  50 mL). The combined organic layers were washed with 10% aqueous KOH, water, brine, dried (Na2SO4) and concentrated. Silica gel column chromatography of the crude product (petroleum ether/EtOAc, 6:4) as eluent gave 18 (1.79 g, 61%) as a colorless oil. ½a25 D ¼ þ38:2 (c 0.22, CHCl3). IR (CHCl3): mmax 3434, 2958, 2935, 2873, 1710, 1659, 1467, 1395, 1370, 1307, 1281, 1217, 1180, 1131, 1093, 1040, 981, 871, 757, 668 cm1. 1H NMR (400 MHz, CDCl3): d 0.91 (t, J = 7.0 Hz, 3H, CH3), 1.05–1.60 (m, 9H, CH3, H-8, H-7, H-6), 2.09 (bs, 2H, -OH), 3.45–3.60 (m, 1H,

R. A. Fernandes, A. K. Chowdhury / Tetrahedron: Asymmetry 22 (2011) 1114–1119

H-5), 4.08–4.16 (m, 1H, H-4), 4.21 (q, J = 7.0 Hz, 2H, OCH2), 6.12 (dd, J = 15.7, 1.7 Hz, 1H, H-2), 6.94 (dd, J = 15.7, 5.0 Hz, 1H, H-3). 13 C NMR (100 MHz, CDCl3): d 14.0, 14.1, 22.6, 27.7, 32.7, 60.6, 74.0, 74.1, 122.3, 147.1, 166.5. HRMS (ESI+): Calcd for [C11H20O4 + Na] 239.1259. Found: 239.1264. 4.1.4. (4R,5R,E)-4,5-(Isopropylidenedioxy)nona-2-ene-1-ol 13 To a solution of diol 18 (1.06 g, 4.90 mmol) in acetone (30 mL) were added p-TsOH (catalytic) and 2,2-dimethoxypropane (1.51 mL, 1.28 g, 12.25 mmol, 2.5 equiv) and the reaction mixture stirred at room temperature for 12 h. Next, NaHCO3 (0.2 g) was added and the mixture stirred for an additional 30 min and then filtered through a pad of silica gel. The filtrate was concentrated to give virtually pure acetonide ester (1.23 g, 98%) as a colorless oil. This was used directly for the next reaction without further purification. ½a25 D ¼ þ6:2 (c 0.22, CHCl3). IR (CHCl3): mmax 2986, 2960, 2935, 2873, 1725, 1662, 1459, 1380, 1371, 1302, 1258, 1167, 1113, 1098, 1051, 979, 875, 857, 812, 758, 625 cm1. 1H NMR (400 MHz, CDCl3): d 0.90 (t, J = 7.1 Hz, 3H, CH3), 1.0–1.80 (m, 9H, CH3, H-8, H-7, H-6), 1.41 (s, 3H, CH3), 1.44 (s, 3H, CH3), 3.71–3.77 (m, 1H, H-5), 4.12–4.17 (m, 1H, H-4), 4.21 (q, J = 7.1 Hz, 2H, OCH2), 6.11 (dd, J = 15.6, 1.5 Hz, 1H, H-2), 6.86 (dd, J = 15.6, 5.8 Hz, 1H, H-3). 13C NMR (100 MHz, CDCl3): d 13.8, 14.1, 22.6, 26.6, 27.2, 28.0, 31.7, 60.5, 80.2, 80.6, 109.2, 122.6, 144.1, 166.0. HRMS (ESI+): Calcd for [C14H24O4 + H] 257.1753. Found: 257.1762. To a solution of the above acetonide ester (1.23 g, 4.8 mmol) in CH2Cl2 (40 mL) was added DIBAL-H (10.6 mL, 10.6 mmol, 1 M solution in hexane, 2.2 equiv) dropwise at 0 °C and the reaction mixture stirred for 2.5 h. It was then quenched by adding a saturated aq solution of potassium-sodium tartrate and stirred vigorously at room temperature for 1 h. The solution was extracted with CH2Cl2 (4  40 mL) and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether/EtOAc, 4:1) to provide the allyl alcohol 13 (0.977 g, 95%) as a colorless oil. ½a25 D ¼ þ22:8 (c 0.22, CHCl3). Other spectroscopic data and analysis were the same as reported earlier.8b 4.1.5. (4S,5R)-5-[(R)-1-Hydroxypentyl]-4-vinyl-4,5dihydrofuran-2(3H)-one 12a and (4R,5R)-5-[(R)-1hydroxypentyl]-4-vinyl-4,5-dihydrofuran-2(3H)-one 12b To a solution of allyl alcohol 13 (0.60 g, 2.80 mmol) in toluene (15 mL) were added trimethylorthoacetate (3.36 g, 28.0 mmol, 10.0 equiv) and EtCO2H (catalytic) and the solution refluxed for 24 h. After cooling to room temperature, the volatile material was removed under reduced pressure and the residue (0.77 g) was used directly for the next reaction without any further purification. Analysis of the crude methyl ester by 1H NMR indicated a diastereomer mixture (2.5:1). To a solution of crude methyl ester in MeOH (30 mL) was added 4 M HCl (5 mL), and stirred for 12 h at room temperature. It was then quenched with powdered NaHCO3 (1.0 g) and filtered. The filtrate was concentrated and the residue purified by silica gel flash column chromatography (petroleum ether/EtOAc, 9:1) to provide 12b (0.122 g, 22%) as a colorless oil. Further elution gave 12a (0.327 g, 59%) as a colorless oil. Data for 12a: ½a25 D ¼ 48:9 (c 0.12, CHCl3). Data for 12b: ½a25 ¼ 50:5 (c 0.8, CHCl 3). Other spectroscopic data and analysis D for 12a and 12b were the same as reported earlier.8b 4.1.6. (4S,5R)-5-[(R)-1-Hydroxypentyl]-4-vinyl-4,5dihydrofuran-2(3H)-one 12a and (4R,5R)-5-[(R)-1hydroxypentyl]-4-vinyl-4,5-dihydrofuran-2(3H)-one 12b The orthoester Johnson–Claisen rearrangement reaction of 13 in xylene solvent over 4 h was performed in a manner similar to that reported earlier8b to give 12a (46%) and 12b (42%).

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4.1.7. S-Methyl O-(R)-1-[(2R,3S)-5-oxo-3-vinyltetrahydrofuran2-yl]pentyl carbonodithioate 19a To a mixture of lactone 12a (0.21 g, 1.06 mmol) and CS2 (0.9 ml, 14.83 mmol, 14.0 equiv) in THF (8 mL) was added in portions NaH (31 mg, 1.27 mmol, 1.2 equiv) at 0 °C and the reaction mixture was stirred at 0 °C for 1 h. Next, MeI (0.93 ml, 2.1 g, 14.83 mmol, 14 equiv) was added and stirred at room temperature for 2 h. The reaction was quenched with a saturated aq NH4Cl solution and diluted with EtOAc (15 mL). The solution was extracted with EtOAc (4  30 mL) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether/ EtOAc, 95:5) to give xanthate 19a (0.217 g, 71%) as a colorless oil. ½a25 D ¼ þ58:2 (c 0.14, CHCl3). IR (CHCl3): mmax 3081, 2956, 2928, 2860, 1787, 1645, 1459, 1420, 1379, 1217, 1163, 1059, 976, 926, 861, 759, 677 cm1. 1H NMR (400 MHz, CDCl3): d 0.89 (t, J = 7.0 Hz, 3H, CH3), 1.1–1.51 (m, 4H, H-40 , H-30 ), 1.71–1.85 (m, 1H, H-20 ), 1.86–2.0 (m, 1H, H-20 ), 2.44 (dd, J = 17.7, 8.6 Hz, 1H, HA-4), 2.58 (s, 3H, S–CH3), 2.76 (dd, J = 17.7, 8.9 Hz, 1H, HB-4), 2.94–3.10 (m, 1H, H-3), 4.36 (dd, J = 7.0, 2.1 Hz, 1H, H-2), 5.15– 5.25 (m, 2H, H-vinyl), 5.72–5.85 (m, 1H, H-vinyl), 5.94–5.99 (m, 1H, H-10 ). 13C NMR (100 MHz, CDCl3): d 13.8, 19.2, 22.5, 27.2, 30.6, 34.6, 41.0, 80.8, 84.0, 118.4, 135.6, 175.2, 216.3. HRMS (ESI+): Calcd for [C13H20O3S2 + H] 289.0933. Found: 289.0938. 4.1.8. S-Methyl O-(R)-1-[(2R,3R)-5-oxo-3-vinyltetrahydrofuran2-yl]pentyl carbonodithioate 19b The title compound was prepared from 12b (0.13 g, 0.656 mmol) by a procedure similar to that described for the conversion of 12a to 19a to afford 19b (0.132 g, 70%) as a colorless oil. ½a25 D ¼ 34:7 (c 0.12, CHCl3). IR (CHCl3): mmax 3021, 2960, 2928, 2873, 1783, 1643, 1467, 1418, 1217, 1164, 1063, 969, 931, 758, 668 cm1. 1H NMR (400 MHz, CDCl3): d 0.90 (t, J = 7.1 Hz, 3H, CH3), 1.31–1.35 (m, 4H, H-40 , H-30 ), 1.81–1.88 (m, 2H, H-20 ), 2.57 (s, 3H, S-CH3), 2.6 (d, J = 10.0 Hz, 2H, H-4), 3.35–3.46 (m, 1H, H3), 4.73 (dd, J = 8.3, 2.2 Hz, 1H, H-2), 5.18–5.26 (m, 2H, H-vinyl), 5.60–5.67 (m, 1H, H-vinyl), 5.67–5.72 (m, 1H, H-10 ). 13C NMR (100 MHz, CDCl3): d 13.9, 19.3, 22.5, 27.1, 29.5, 33.8, 42.4, 81.3, 81.8, 119.8, 133.0, 175.8, 214.5. HRMS (ESI+): Calcd for [C13H20O3S2 + H] 289.0933. Found: 289.0941. 4.1.9. (4S,5S)-5-Pentyl-4-vinyl-4,5-dihydrofuran-2(3H)-one 20a A mixture of 19a (0.230 g, 0.797 mmol), Bu3SnH (3.22 mL, 3.48 g, 11.96 mmol, 15.0 equiv) and AIBN (catalytic amount) in toluene (15 mL) was stirred at reflux for 6 h. It was then concentrated and the residue purified by silica gel flash column chromatography (petroleum ether/EtOAc, 95:5) to provide 20a (0.145 g, quant.) as a colorless oil. ½a25 D ¼ 79:6 (c 0.4, CHCl3). IR (CHCl3): mmax 3083, 2932, 2861, 1782, 1645, 1466, 1380, 1264, 1208, 1168, 996, 946, 922, 758, 682, 527 cm1. 1H NMR (400 MHz, CDCl3): d 0.89 (t, J = 6.8 Hz, 3H, CH3), 1.15–1.78 (m, 8H, H-40 , H-30 , H-20 , H-10 ), 2.45 (dd, J = 17.2, 10.3 Hz, 1H, HA-3), 2.69 (dd, J = 17.2, 8.1 Hz, 1H, HB3), 2.73–2.89 (m, 1H, H-4), 4.15 (dt, J = 8.4, 3.7 Hz, 1H, H-5), 5.15–5.21 (m, 2H, H-vinyl), 5.67–5.77 (m, 1H, H-vinyl). 13C NMR (100 MHz, CDCl3): d 13.9, 22.4, 25.4, 31.5, 33.6, 35.5, 46.3, 84.8, 118.0, 135.7, 175.9. HRMS (ESI+): Calcd for [C11H18O2 + H] 183.1385. Found: 183.1391. 4.1.10. (4R,5S)-5-Pentyl-4-vinyl-4,5-dihydrofuran-2(3H)-one 20b The title compound was prepared from 19b (0.230 g, 0.797 mmol) by a procedure similar to that described for the conversion of 19a to 20a to provide 20b (0.145 g, quant.) as a colorless oil. ½a25 D ¼ 35:6 (c 0.24, CHCl3). IR (CHCl3): mmax 3020, 2957, 2931, 2861, 1778, 1466, 1420, 1351, 1217, 1171, 1140, 1025, 946, 926, 758, 670 cm1. 1H NMR (400 MHz, CDCl3): d 0.89 (t, J = 6.7 Hz,

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3H, CH3), 1.23–1.43 (m, 6H, H-40 , H-30 , H-20 ), 1.44–1.66 (m, 2H, H10 ), 2.44 (dd, J = 17.3, 5.6 Hz, 1H, HA-3), 2.71 (dd, J = 17.3, 8.1 Hz, 1H, HB-3), 3.11–3.21 (m, 1H, H-4), 4.50 (ddd, J = 9.2, 6.4, 4.3 Hz, 1H, H5), 5.12–5.23 (m, 2H, H-vinyl), 5.76 (ddd, J = 17.0, 10.3, 8.7 Hz, 1H, H-vinyl). 13C NMR (100 MHz, CDCl3): d 13.9, 22.4, 25.3, 30.8, 31.5, 34.7, 43.1, 83.3, 118.0, 134.0, 176.3. HRMS (ESI+): Calcd for [C11H18O2 + H] 183.1385. Found: 183.1389. 4.1.11. (2S,3R)-5-Oxo-2-pentyltetrahydrofuran-3-carboxylic acid 21a A solution of vinyl lactone 20a (0.145 g, 0.8 mmol) in CH2Cl2 (25 mL) was cooled to –78 °C and a stream of O3/O2 was bubbled through the reaction mixture for 30 min. The reaction was quenched with Me2S (0.5 mL) and stirred for 1 h at –78 °C and for a further 2 h at room temperature. The mixture was concentrated to give the crude aldehyde (0.147 g), which was used directly for the next reaction. To a solution of the crude aldehyde in acetone (10 mL) at 0 °C was dropwise added Jones’ reagent [0.5 mL; (Jones reagent: CrO3 (1.33 g) dissolved in H2O (3 mL). To this solution was added conc. H2SO4 (1.2 mL) at 0 °C, and finally H2O (1 mL) to give a transparent orange solution]. The reaction mixture was stirred at 0 °C for 20 min and then excess Jones’ reagent was destroyed by adding isopropanol (1 mL). The volatiles were removed under reduced pressure, and a brine solution (5 mL) was added after which the reaction mixture was extracted with EtOAc (5  30 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether/EtOAc, 1:1) to provide 21a (0.151 g, 95%) as a white solid. Mp 103–105 °C. ½a25 D ¼ 39:6 (c 0.16, CHCl3). IR (CHCl3): mmax 3467, 3020, 2930, 2856, 1779, 1746, 1461, 1217, 1021, 910, 770, 669 cm1. 1H NMR (400 MHz, CDCl3): d 0.90 (t, J = 6.6 Hz, 3H, CH3), 1.11–1.56 (m, 6H, H-40 , H-30 , H-20 ), 1.65–1.85 (m, 2H, H-10 ), 2.81 (dd, J = 18.0, 9.6 Hz, 1H, HA-4), 2.94 (dd, J = 18.0, 8.6 Hz, 1H, HB-4), 3.05–3.15 (m, 1H, H-3), 4.57–4.65 (m, 1H, H-2). 13C NMR (100 MHz, CDCl3): d 13.9, 22.4, 24.8, 31.3, 31.9, 35.3, 45.4, 81.8, 174.4, 176.0. HRMS (ESI+): Calcd for [C10H16O4 + H] 201.1127. Found: 201.1132. 4.1.12. (2S,3S)-5-Oxo-2-pentyltetrahydrofuran-3-carboxylic acid 21b The title compound was prepared from 20b (0.145 g, 0.8 mmol) by a procedure similar to that described for the conversion of 20a to 21a to provide 21b (0.147 g, 92%) as a white solid. Mp 102– 104 °C. ½a25 D ¼ 44:1 (c 0.16, CHCl3). IR (CHCl3): mmax 3465, 3020, 2931, 1781, 1718, 1441, 1217, 1025, 911, 769, 669 cm1. 1H NMR (400 MHz, CDCl3): d 0.89 (t, J = 7.1 Hz, 3H, CH3), 1.25–1.75 (m, 8H, H-40 , H-30 , H-20 , H-10 ), 2.71 (dd, J = 17.7, 8.5 Hz, 1H, HA-4), 2.90 (dd, J = 17.7, 5.1 Hz, 1H, HB-4), 3.42–3.52 (m, 1H, H-3), 4.67 (dd, J = 13.7, 7.1 Hz, 1H, H-2). 13C NMR (100 MHz, CDCl3): d 13.9, 22.4, 25.5, 31.2, 31.3, 31.9, 44.2, 80.3, 175.0, 175.6. HRMS (ESI+): Calcd for [C10H16O4 + H] 201.1127. Found: 201.1131. 4.1.13. (2S,3R)-4-Methylene-5-oxo-2-pentyltetrahydrofuran-3carboxylic acid/()-methylenolactocin 3 Methoxy magnesium methylcarbonate (Stiles’ reagent, 8.5 mL, 17.08 mmol, 38.0 equiv, 2 M solution in DMF) was added under an inert atmosphere to 21 (90 mg, 0.45 mmol) and the solution stirred at 135 °C for 60 h. After cooling, the reaction mixture was acidified by the dropwise addition of cold 10% HCl (30 mL) at 0 °C. Then CH2Cl2 (50 mL) was added to the mixture and stirred for 0.5 h. The aqueous layer was extracted with CH2Cl2 (4  50 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was treated with 5 mL of a freshly prepared stock solution [HOAc (20 mL), 37% formaldehyde in water (15 mL), N-methylaniline (5.2 mL) and NaOAc (0.6 g)] and stirred for 3 h at room temperature. A brine solution

(40 mL, containing 4 mL concd HCl) was added and the aqueous layer extracted with Et2O (5  30 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel flash column chromatography (CH2Cl2/EtOAc, 95:5) to provide 3 (61 mg, 64%) as a white so5a lid. Mp 81–83 °C, lit.3a 82–84 °C. ½a25 D ¼ 7:0 (c 0.12, CH3OH). lit. 20 20 4h ½aD ¼ 10 (c 0.5, MeOH), lit. ½aD ¼ 6:8 (c 0.5, MeOH). IR (CHCl3): mmax 3352, 3020, 2930, 1763, 1720, 1216, 1115, 1025, 929, 760, 669 cm1. 1H NMR (400 MHz, CDCl3): d 0.89 (t, J = 6.7 Hz, 3H, CH3), 1.11–1.58 (m, 6H, H-40 , H-30 , H-20 ), 1.65–1.81 (m, 2H, H-10 ), 3.62–3.64 (m, 1H, H-3), 4.78–4.83 (m, 1H, H-2), 6.02 (d, J = 2.8 Hz, 1H, H-methylene), 6.47 (d, J = 2.8 Hz, 1H, H-methylene). 13C NMR (CDCl3, 100 MHz): d 13.9, 22.4, 24.4, 31.3, 35.7, 49.4, 78.8, 125.8, 132.4, 168.2, 173.8. HRMS (ESI+): Calcd for [C11H16O4 + H] 213.1127. Found: 213.1135. 4.1.14. (2S,3S,4S)-4-Methyl-5-oxo-2-pentyltetrahydrofuran-3carboxylic acid/(–)-phaseolinic acid 6 To a solution of 21b (20 mg, 0.10 mmol) in THF (4 mL) at –78 °C was added NaHMDS (0.22 mL, 0.22 mmol, 1.0 M solution in THF, 2.2 equiv) and stirred for 1.5 h. Next, MeI (0.063 mL, 0.142 g, 1.0 mmol, 10.0 equiv) was added and the mixture stirred at – 78 °C for 2 h and then allowed to warm to –20 °C. Next, 2 M HCl (1.0 mL) was added and the mixture extracted with EtOAc (5  15 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether/EtOAc, 1:1) as eluent to provide 6 (21.4 mg, quantitative) as a white solid. Mp 138– 6g 140 °C, lit.1d 139–140 °C. ½a25 D ¼ 117 (c 0.10, CHCl3), lit. 25 ½aD ¼ 112 (c 0.26, CHCl3). IR (CHCl3): mmax 3021, 2959, 2930, 2861, 1775, 1717, 1524, 1459, 1420, 1382, 1216, 1017, 984, 759, 669, 625 cm1. 1H NMR (400 MHz, CDCl3): d 0.89 (t, J = 7.0 3H, CH3), 1.21–1.57 (m, 6H, H-40 , H-30 , H-20 ), 1.33 (d, J = 7.1 Hz, 3H, CH3), 1.57–1.67 (m, 2H, H-10 ), 3.0–3.09 (m, 1H, H-4), 3.22 (dd, J = 9.6, 8.2, 1H, H-3), 4.69–4.73 (m, 1 H, H-2). 13C NMR (100 MHz, CDCl3): d = 13.9, 14.4, 22.4, 25.3, 31.0, 31.3, 36.4, 51.6, 77.4, 174.8, 177.5. HRMS (ESI+): Calcd for [C11H18O4 + H] 215.1283. Found: 215.1289. Acknowledgements The authors are indebted to IRCC, IIT-Bombay and the Department of Science and Technology, New Delhi (Grant No. SR/S1/OC25/2008) for financial support. A.K.C. is grateful to Council of Scientific and Industrial Research (CSIR) New Delhi for a research fellowship. References 1. (a) Turk, A. O.; Yilmaz, M.; Kivanc, M.; Turk, H. Z. Naturforsch. (C) 2003, 58, 850; (b) Kumar, K. C. S.; Muller, K. J. Nat. Prod. 1999, 62, 817; (c) Park, B. K.; Nakagawa, M.; Hirota, A.; Nakayama, M. J. Antibiot. 1988, 41, 751; (d) Mahato, S. B.; Siddiqui, K. A. I.; Bhattacharya, G.; Ghosal, T.; Miyahara, K.; Sholichin, M.; Kawasaki, T. J. Nat. Prod. 1987, 50, 245; (e) Cavallito, C. J.; Fruehauf, D. M.; Bailey, J. H. J. Am. Chem. Soc. 1948, 70, 3724. 2. (a) Selvakumar, N.; Kumar, P. K.; Reddy, K. C. S.; Chary, B. C. Tetrahedron Lett. 2007, 48, 2021; (b) Bazin, S.; Feray, L.; Vanthuyne, N.; Siri, D.; Bertrand, M. P. Tetrahedron 2007, 63, 77; (c) Maiti, G.; Roy, S. C. J. Chem. Soc., Perkin Trans. 1 2006, 403; (d) Biel, M.; Kretsovali, A.; Karatzali, E.; Papamatheakis, J.; Giannis, A. Angew. Chem., Int. Ed. 2004, 43, 3974; (e) Pohmakotr, M.; Harnying, W.; Tuchinda, P.; Reutrakul, V. Helv. Chim. Acta 2002, 85, 3792; (f) Loh, T. P.; Lye, P. L. Tetrahedron Lett. 2001, 42, 3511; (g) Mandal, P. K.; Roy, S. C. Tetrahedron 1999, 55, 11395; (h) Mandal, P. K.; Maiti, G.; Roy, S. C. J. Org. Chem. 1998, 63, 2829; (i) Lertvorachon, J.; Meepowpan, P.; Thebtaranonth, Y. Tetrahedron 1998, 54, 14341; (j) Chen, M. J.; Liu, R. S. Tetrahedron Lett. 1998, 39, 9465; (k) Forster, A.; Fitremann, J.; Renaud, P. Tetrahedron Lett. 1998, 39, 7097; (l) Ghatak, A.; Sarkar, S.; Ghosh, S. Tetrahedron 1997, 53, 17335; (m) Saicic, R. N.; Zard, S. Z. Chem. Commun. 1996, 1631; (n) Sarkar, S.; Ghosh, S. Tetrahedron Lett. 1996, 37, 4809; (o) Carlson, R. M.; Oyler, A. R. J. Org. Chem. 1976, 41, 4065; (p) Damon, R. E.; Schlessinger, R. H. Tetrahedron Lett. 1976, 17, 1561; (q) Martin, J.; Watts, P.

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3.

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5.

6.

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