Olefin cross-metathesis based approach for the first total synthesis of phomopsolidone B and total synthesis of phomopsolidone A

Tetrahedron: Asymmetry xxx (2016) xxx–xxx

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Olefin cross-metathesis based approach for the first total synthesis of phomopsolidone B and total synthesis of phomopsolidone A Kasa Shiva Raju, Gowravaram Sabitha ⇑ Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 28 April 2016 Accepted 1 June 2016 Available online xxxx

The first total synthesis of phomopsolidone B and the total synthesis of phomopsolidone A have been achieved based on an olefin cross-metathesis approach starting from L-(+)-diethyl tartrate. Ó 2016 Published by Elsevier Ltd.

1. Introduction In 2014, Abou-Mansour et al.1 isolated the new furanones, phomopsolidone A and B (Fig. 1) along with other metabolites from three different strains of the fungus Phomopsis sp. of Grapevine plants showing esca symptoms in Ticino, Switzerland. Esca, is a grapevines trunk disease, which does not spread rapidly, but builds up progressively in a vineyard over a number of years, leading to a general decline in vigor and yield of the vines.2 Phomopsolidones A 1 and B 2 display weak phytotoxic and antibacterial activities. The structures of furanones were elucidated by spectroscopic analyses including two-dimensional NMR and mass spectrometry and by comparison to the literature data. The structural features of 1 and 2 include a c-lactone core, a side chain of syn 1,2-diol system, and an E-double bond.

O OH

OH

O

O

OH

O

OH

O

O

O phomopsolidone A 1

O phomopsolidone B 2

Figure 1. Structures of phomopsolidone A 1 and phomopsolidone B 2.

Recently, the first total synthesis of phomopsolidone A 1 was reported by our group3 by employing a chelation controlled aldehyde–alkyne coupling reaction. No synthesis of phomopsolidone B 2 has been reported so far. In order to achieve the first total synthesis of 2 and also to synthetically provide sufficient amounts of 2 ⇑ Corresponding author. Tel.: +91 40 27191629; fax: +91 27160512.

for the exact evaluation of its additional activities, we carried out a synthetic study of 2. Herein we report the first total synthesis of 2 and the total synthesis of 1 from the known chiral building block L(+)-diethyl tartrate (DET). 2. Results and discussion The retrosynthetic analysis of 1 and 2 is shown in Scheme 1. Phomopsolidone B 2 could be obtained from olefin cross-metathesis reaction between the tiglic acid derivative of (S)-5-((S)-1hydroxyallyl)dihydrofuran-2(3H)-one 3 and the known olefinic diol 5.4 The dihydrofuranone derivative 3 could be synthesized from L-(+)-DET via esterification with tiglic acid 9. Similarly, phomopsolidone A 1 can be accessed from olefin cross-metathesis reaction between a tiglic acid derivative of (S)-5-((S)-1-hydroxyallyl)furan-2(5H)-one 4 and a known olefinic diol 5.4 The furanone derivative 4 could be synthesized from L-(+)-DET via esterification with tiglic acid 9. Thus, the synthesis of 2 began with the known ester 65 prepared from L-(+)-DET (Scheme 2). Treatment of ester 6 with PTSA/MeOH resulted in the deprotection of the acetonide group with simultaneous lactone ring formation to afford (S)-5-((S)-1-hydroxyallyl)dihydrofuran-2(3H)-one 86 in 90% yield. Esterification of the free hydroxy group in 8 with tiglic acid 9 afforded 3 in 85% yield. On the other hand, fragment 5 was synthesized from L-(+)-DET following the literature procedure.4 Olefin cross-metathesis reaction between lactone 3 and olefinic diol 5 in the presence of Grubbs’ cat-II7 in CH2Cl2 at reflux resulted in the target lactone, phomopsolidone B 2 in 70% yield. The spectroscopic and physical data (1H and 13C NMR, and [a]D) of phomopsolidone B 2 were identical with the natural product1 and thus established the absolute configuration of 2. The synthesis of phomopsolidone A 1 began with the known olefinic alcohol 114 obtained from L-(+)-DET (Scheme 3). Alcohol

E-mail addresses: [email protected], [email protected] (G. Sabitha). http://dx.doi.org/10.1016/j.tetasy.2016.06.002 0957-4166/Ó 2016 Published by Elsevier Ltd.

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K. Shiva Raju, G. Sabitha / Tetrahedron: Asymmetry xxx (2016) xxx–xxx O OH

phosphonate8 to yield the Z-unsaturated ester 7, exclusively. The coupling constant values confirmed the geometry of the product. Treatment of ester 7 with PTSA/MeOH furnished (S)-5-((S)-1hydroxyallyl)furan-2(5H)-one 12 in a one-pot reaction via a two step sequence (acetonide deprotection and lactonization). Esterification of the free hydroxy group in 12 with tiglic acid 9 afforded 4 in 80% yield. Olefin cross-metathesis reaction between the lactone 4 and olefinic diol4 5 in the presence of Grubbs’ cat-II7 in CH2Cl2 at reflux furnished the target lactone, phomopsolidone A 1 in 70% yield. The spectroscopic and physical data (1H and 13C NMR, and [a]D) of phomopsolidone A 1 were identical with the natural product1 as well as with the authentic sample prepared by us.3

O

O

OH

OH

O

O

OH

phomosolidone B 2

O

O

O OH

O

phomosolidone A 1 O OH

O

O

+

+

OH

5

O

3

5

OH

O

4

O

O

O L -(+)-DET

L-(+)-DET

OEt O

3. Conclusion

O

O

O

6

O

OMe

7

Scheme 1. Retrosynthetic analysis.

L-(+)-DET

O

ref 5

a

4.1. General

OEt

O

8

6

O

4. Experimental

OH

O

O O

O

OH OH

HOOC

O

O 5

9

OH OH

b

3

O

O

c phomosolidone B 2

O

O

Scheme 2. Synthesis of phomopsolidone B. Reagents and conditions. (a) PTSA, CH2Cl2, rt, 3 h, 90%; (b) Tiglic acid, DCC, DMAP, CH2Cl2, 0 °C, 30 min, 85%; (c) G-II catalyst, CH2Cl2, reflux, 12 h, 70%.

O

O L-(+)-DET

ref 4

a

OH

O

O 11

7

O

OMe

O HOOC

OH

O

9

b 12

O

c

4

O O

O O

OH OH

O

HO 5 d

We have performed a stereoselective total synthesis of phomopsolidone B in overall yield of 53.5% from reported intermediate 6 and the total synthesis of phomopsolidone A in an overall yield of 40.3% from intermediate 11 by means of a versatile strategy using olefin cross-metathesis as the key step.

OH phomosolidone A 1

O O

Scheme 3. Synthesis of phomopsolidone A. Reagents and conditions. (a) (i) Dess– Martin periodinane, NaHCO3, CH2Cl2, 0 °C, 2 h (ii) cis-Wittig, THF, 78 °C, 1 h, 80% (over 2 steps); (b) PTSA, CH2Cl2, rt, 3 h, 90%; (c) Tiglic acid, DCC, DMAP, CH2Cl2, 0 °C, 30 min, 80%; (d) G-II catalyst, CH2Cl2, reflux, 12 h, 70%.

11 upon oxidation with Dess Martin periodinane in DCM, afforded the aldehyde, which without isolation was subjected to a Wittig reaction with bis-2,2,2-(trifluoromethyl)(ethoxy carbonyl methyl)

Reactions were conducted under N2 in anhydrous solvents such as CH2Cl2, THF and EtOAc. All reactions were monitored by TLC (silica-coated plates and visualized under UV light). n-Hexane (bp 60–80 °C) was used. Yields refer to chromatographically and spectroscopically (1H and 13C NMR) homogeneous material. Air sensitive reagents were transferred by syringe or double-ended needle. Evaporation of solvents was performed at reduced pressure on a Buchi rotary evaporator. 1H and 13C NMR spectra of samples in CDCl3 were recorded on Varian FT-400 MHz, Varian FT-500 MHz and Bruker UXNMR FT-300 MHz (Avance) spectrometers. Chemical shifts (d) are reported relative to TMS (d = 0.0) as an internal standard. Mass spectra were recorded E1 conditions at 70 eV on ES-MSD (Agilent technologies) spectrometers. Column chromatography was performed on silica gel (60–120 mesh) supplied by Acme Chemical Co., India. TLC was performed on Merck 60 F-254 silica gel plates. Optical rotations were measured with JASCO DIP-370 Polarimeter. 4.1.1. (S)-5-((S)-1-Hydroxyallyl)dihydrofuran-2(3H)-one 8 A stirred solution of 6 (250 mg, 1.096 mmol) in CH2Cl2 (5 mL) was treated with catalytic amount PTSA for 3 h at rt. When the reaction was complete (TLC), the mixture was diluted with CH2Cl2 (5 mL) and solid NaHCO3 was added after which it was stirred for a further 15 min. The mixture was then filtered through a short pad of Celite and the Celite pad was washed with CH2Cl2 (3
10 mL). The solvent was evaporated and the residue was purified by column chromatography (silica gel, 40% EtOAc/Hexane) to yield 8 (140 mg, 90%) as a light yellow oil. [a]25 D = +20.0 (c .25, CHCl3). IR (neat) mmax: 3422, 2924, 2857, 1766, 1189, 1039 cm1. 1H NMR (400 MHz, CDCl3): d 5.90 (m, 1H), 5.38 (m 2H), 4.48 (m, 1H), 4.17 (m, 1H), 2.57 (m, 2H), 2.25 (m, 1H), 2.15 (m, 1H); 13C NMR (CDCl3, 100 MHz): d 176.3, 135.0, 118.2, 82.4, 74.6, 28.3, 23.4; HRMS (ESI) for C7H10O3Na [M+Na]+ found 165.0539, calcd 165.0545. 4.1.2. (S)-1-((S)-5-Oxotetrahydrofuran-2-yl)allyl (E)-2-methylbut2-enoate 3 The homoallylic alcohol 8 (80 mg, 0.330 mmol) was dissolved in 5 mL of CH2Cl2 and cooled to 0 °C. Tiglic acid 9 (39 mg, 0.3966 mmol), DCC (174 mg, 0.845 mmol) and a catalytic amount of DMAP (1 mg) were added to the reaction mixture, and stirred

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for 30 min. The resulting mixture was filtered through a short pad of silica to remove the solid N,N0 -dicyclohexylurea and washed thoroughly with ether. The solvent was removed under an aspirator vacuum, and the crude product was purified by column chromatography (hexane/EtOAc: 7:3) to obtain 3 (108 mg, 85%) as a colorless oil. [a]25 D = 5.4 (c 0.28, CHCl3). IR (neat) mmax: 2924, 2853, 1780, 1646, 1129, 1034 cm1; 1H NMR (400 MHz, CDCl3): d 6.92 (m, 1H), 5.88 (m, 1H), 5.40 (m 2H), 5.35 (m, 1H), 4.68 (ddd, J = 7.9, 5.9, 4.5 Hz, 1H), 2.53 (m, 2H), 2.31 (m, 1H), 2.07 (m, 1H), 1.85–1.80 (m, 6H); 13C NMR (CDCl3, 100 MHz): d 176.6, 166.5, 138.6, 131.6, 128.1, 120.0, 80.0, 75.0, 28.0, 24.0, 14.5, 12.0; HRMS (ESI) for C12H16O4 Na [M+Na]+ found 247.0973, calcd 247.0986. 4.1.3. ((1S,4S,5S,E)-4,5-Dihydroxy-1-((S)-5-oxotetrahydrofuran-2yl)hex-2-en-1-yl-(E)-2-methylbut-2-enoate 2 (phomopsolidone B) A solution of Grubbs’ II catalyst (5 mg, 0.0066 mmol) in CH2Cl2 (1 mL) was added dropwise to a solution of diol 5 (21 mg, 0.2008 mmol) and lactone 3 (30 mg, 0.1339 mmol) in CH2Cl2 (2 mL) at rt, and the mixture was refluxed for 12 h. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (50% Hexane/EtOAc) to give 2 as a as a colorless oil (30 mg, 70%). [a]25 D = 10.5 (c 0.32, MeOH). IR (neat) mmax: 3422, 2926, 2854, 1773, 1654, 1187, 1051 cm1; 1H NMR (400 MHz, CDCl3): d 6.90 (qq, J = 7.0, 1.3 Hz, 1H), 5.85 (m, 2H), 5.45 (dd, J = 5.3, 4.4 Hz, 1H), 4.69 (ddd, J = 7.9, 5.6, 4.2 Hz, 1H), 3.91 (m, 1H), 3.64 (1H), 2.53 (m, 2H), 2.32 (m, 1H), 2.07 (m, 1H), 1.85– 1.80 (m, 6H), 1.17 (d, J = 6.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): d 176.7, 166.7, 138.9, 135.2, 128.0, 126.1, 80.0, 76.3, 74.5, 70.5, 28.0, 23.7, 18.9, 14.6, 12.1; HRMS (ESI) for C15H22O6Na [M+Na]+ found 321.1306, calcd 321.1309. 4.1.4. (4R,7R)-7-Acetoxy-7-((4R,5S)-5-((S)-1-acetoxyethyl)-2,2dimethyl-1,3-dioxolan-4-yl)hept-1-en-5-yn-4-ylacrylate 7 To a solution of alcohol 11 (100 mg, 0.632 mmol) in dry CH2Cl2 (5 mL), Dess Martin Periodinane (536 mg, 1.26 mmol) and NaHCO3 (106 mg, 1.26 mmol) were added at 0 °C under a nitrogen atmosphere. The turbid solution was allowed to warm to room temperature and stirred for 2 h. The reaction was diluted with CH2Cl2 (5 mL) and quenched with saturated aqueous NaHCO3 (10 mL), and saturated aqueous Na2S2O3 (10 mL). The mixture was vigorously stirred until a clear solution was formed. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2
10 mL). The combined organic extracts were washed with brine (1
15 mL), dried over anhydrous Na2SO4, filtered and concentrated and purified by silica gel column chromatography (20% EtOAc/hexane) to afford aldehyde. A solution of bis-2,2,2-(trifluoromethyl)(ethoxy carbonyl methyl)phosphonate (217 mg, 0.570 mmol) in THF (5 mL) was added slowly to a stirred solution of NaH (28 mg, 0.684 mmol) in THF (5 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 30 min. Then the mixture was cooled to 78 °C and the above crude aldehyde in THF was added dropwise over 10 min. The resulting mixture was stirred at 78 °C for 30 min. The mixture was then quenched with satd NH4Cl (2 mL) and the product was extracted with EtOAc (2
10 mL), and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by using silica gel column chromatography (10% EtOAc/Hexane) to afford (Z)-olefin ester 7 (106 mg, 80% over 2 steps) as a colourless liquid. [a]25 D = +15.4 (c 0.24, CHCl3). IR (neat) mmax: 2926, 2852, 1726, 1239, 1059 cm1; 1H NMR (300 MHz, CDCl3): d 6.17 (dd, J = 11.7, 8.5 Hz, 1H), 5.96 (dd, J = 11.7, 1.2 Hz, 1H), 5.88 (m, 1H), 5.43 (m, 2H), 4.48 (m, 1H), 4. 36 (m, 1H), 3.70 (s, 3H), 1.41 (d, J = 3.7 6H); 13C NMR (CDCl3, 75 MHz): d 165.7, 142.7, 133.3, 123.0, 122.5, 110.1, 81.2, 81.1. 51.7, 27.0, 26.7; HRMS (ESI) for C11H16O4Na [M+Na]+ found 235.0953, calcd 235.0968.

3

4.1.5. (S)-5-((S)-1-Hydroxyallyl)furan-2(5H)-one 2 A stirred solution of 7 (50 mg, 0.2358 mmol) in CH2Cl2 (5 mL) was treated with catalytic amount PTSA for 3 h at rt. When the reaction was complete (TLC), the mixture was diluted with CH2Cl2 (5 mL) and solid NaHCO3 was added and it was stirred for a further 15 min. The mixture was then filtered through a short pad of Celite and the Celite pad was washed with CH2Cl2 (3
10 mL). The solvent was evaporated and the residue was purified by column chromatography (silica gel, 40% EtOAc/Hexane) to yield 12 (30 mg, 90%) as a light yellow oil. [a]25 D = 20.3 (c 0.24, CHCl3). IR (neat) mmax: 3420, 2925, 2853, 1740, 1150 cm1; 1H NMR (400 MHz, CDCl3): d 7.45 (dd, J = 5.7, 1.5 Hz, 1H), 6.21 (dd, J = 5.7, 1.9 Hz, 1H), 5.87 (m, 1H) 5.40 (m, 2H), 5.02 (m, 1H), 4.28 (m, 1H); 13C NMR (CDCl3, 100 MHz): d 172.4, 153.0, 134.2, 123.0, 119.9 85.3, 73.4; HRMS (ESI) for C7H8O3Na [M+Na]+ found 163.0386, calcd 163.0398. 4.1.6. (S)-1-((S)-5-Oxo-2,5-dihydrofuran-2-yl)allyl(E)-2-methylbut -2-enoate 4 Homoallylic alcohol 12 (15 mg, 0.1071 mmol) was dissolved in 5 mL of CH2Cl2 and cooled to 0 °C. Tiglic acid 9 (13 mg, 0.1285 mmol), DCC (33 mg, 0.160 mmol) and a catalytic amount (1 mg) of DMAP were added to the reaction mixture and stirred for 30 min. The resulting mixture was filtered through a short pad of silica to remove the solid N,N0 -dicyclohexylurea and washed thoroughly with ether. The solvent was removed using an aspirator vacuum, and the crude product was purified by column chromatography (hexane/EtOAc: 8:2) to obtain 4 (19 mg, 80%) as a colorless oil. [a]25 D = 11.9 (c 0.20, CHCl3). IR (neat) mmax: 2920, 2853, 1750, 1650, 1153 cm1; 1H NMR (400 MHz, CDCl3): d 7.41 (dd, J = 5.7, 7.3 Hz, 1H), 6.90 (m, 1H), 6.19 (dd, J = 7.7, 5.7, Hz, 1H), 5.89 (m, 1H) 5.6 (m 1H), 5.4 (m, 2H), 5.20 (m, 1H), 1.83–1.80 (m, 6H); 13C NMR (CDCl3, 75 MHz): d 172.2, 166.5, 152.3, 139.0, 131.2, 127.9 123.3, 120.3, 83.3, 72.4, 14.5, 12.0; HRMS (ESI) for C12H14O4Na [M+Na]+ found 245.0793, calcd 245.0813. 4.1.7. (1S,4S,5S,E)-4,5-Dihydroxy-1-((S)-5-oxo-2,5-dihydrofuran-2yl)hex-2-en-1-yl(E)-2-methylbut-2-enoate) 1 (phomopsolidone A) A solution of Grubbs’ II catalyst (2 mg, 0.0022 mmol) in CH2Cl2 (1 mL) was added dropwise to a solution of diol 5 (7 mg, 0.0675 mmol) and lactone 4 (10 mg, 0.045 mmol) in CH2Cl2 (1 mL) at rt, and the mixture was refluxed for 24 h. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (50% Hexane/EtOAc) to give 1 (10 mg, 70%) as a colorless oil. [a]25 D = 16.2 (c 0.16, MeOH). IR (neat) mmax: 3450, 2924, 2854, 1711, 1649, 1022, 769 cm1; 1H NMR (400 MHz, CDCl3): d 7.43 (dd, J = 5.7, 1.5 Hz, 1H), 6.91 (m, 1H), 6.19 (dd, J = 5.7, 1.9 Hz, 1H), 5.90–5.82 (m, 2H) 5.62 (dd, J = 6.2, 4.2 Hz, 1H), 5.20 (m, 1H), 3.90–3.89 (m, 1H), 3.68–3.64 (m, 1H), 1.87–1.79 (m, 6H), 1.19 (d, J = 6.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 172.3, 166.5, 152.3, 139.1, 135.5, 127.5 125.8, 123.4, 83.2, 76.2, 71.7, 70.3, 18.9, 14.5, 11.9; HRMS (ESI) for C15H20O6Na [M+Na]+ found 319.1132, calcd 319.1152. Acknowledgements K.S.R. thanks UGC, India for the award of fellowship. All the authors thank CSIR, India for financial support as part of XII Five Year plan program under title ORIGIN (CSC-0108). Supplementary data Supplementary data (1H NMR and 13C NMR spectra of all compounds) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.06.002.

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