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The first stereoselective non-biological synthesis of chiral 6-pentyl-2H-pyran-2-ones: total synthesis of metabolites isolated from Trichoderma spp and Penicillium isolates
Tetrahedron Letters 57 (2016) 4560–4562
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The first stereoselective non-biological synthesis of chiral 6-pentyl-2H-pyran-2-ones: total synthesis of metabolites isolated from Trichoderma spp and Penicillium isolates José Alvano Pérez-Bautista, Rosa Luisa Meza-León, Silvano Cruz-Gregorio, Leticia Quintero ⇑, Fernando Sartillo-Piscil ⇑ Facultad de Ciencias Químicas de la Benemérita Universidad Autónoma de Puebla (BUAP), 14 Sur Esq. San Claudio, San Manuel, 72570 Puebla, Mexico
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Article history: Received 2 August 2016 Revised 23 August 2016 Accepted 29 August 2016 Available online 31 August 2016 Keywords: Total synthesis Chiron approach 2H-Pyran-2-ones Stereoselective allylation Trichoderma metabolites Penicillium isolates
a b s t r a c t The total synthesis of three chiral 6-pentyl-2H-pyran-2-ones (metabolites of Trichoderma spp and Penicillium isolates) is reported. With the preservation of the configurational integrity of one stereogenic center (2S of the chiron 7,3-LXF), these total syntheses permitted the confirmation of the absolute configuration of two of them (1 and 2). Since the optical rotation data of one natural metabolite was not disclosed in the original publication, its enantiopure synthesis (R-3) did not permitted either the confirmation or revision of the absolute configuration. The present approach involves a selective furanose acetolysis, a stereoselective allylation of an intermediate acetal and a Pd-catalyzed b-elimination reaction. Ó 2016 Elsevier Ltd. All rights reserved.
Secondary metabolites isolated from Trichoderma species have gained popularity in the past two decades due to their potential role as biological control agents.1 One of the most biologically active metabolites is the 6-pentyl-2H-pyran-2-one (6PP), which is known as a volatile antifungal metabolite with inhibitory activity for the growth of various phytopathogen fungi.2 Other metabolites such as 1 and 2 have been biosynthesized via metabolization of 6PP by Trichoderma strains to study its mode of action as potential biocontrol agent.3 Similarly, metabolites 3 has been biologically synthesized from 6PP by a range of Penicillium isolates4 (Fig. 1). Despite the biological importance of these metabolites, a stereoselective synthesis has not been reported yet; only a racemic synthesis of 1 and 2 from 6PP was accomplished,3 wherein their absolute configuration was determined based on NMR analysis of the corresponding Mosher’s esters. On the other hand, metabolite 3, obtained from Penicillium isolates, has not had its absolute configuration defined, in fact, its optical rotation was not reported, and its absolute configuration remains unknown.4 Therefore, it is crucial a full characterization of these metabolites not only by NMR
⇑ Corresponding authors. Tel.: +52 222 229 5500; fax: +52 222 245 4972. E-mail addresses: [email protected] (L. Quintero), fernando. [email protected] (F. Sartillo-Piscil). http://dx.doi.org/10.1016/j.tetlet.2016.08.089 0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
but also by total synthesis; especially for the confirmation of the absolute configuration, as the Mosher’s method is sometimes limited to secondary alcohols that are not too sterically hindered.5 Thus, a stereoselective approach that could provide an enantiopure avenue to these metabolites is highly desirable. The present letter reports, starting from the versatile chiron 7,3lactone-xylofuranose derivative (7,3-LXF),6 the total synthesis and the confirmation of the absolute configuration of two metabolites isolated from Trichoderma spp (1 and 2), and the synthesis of 6((20 R)-hydroxypentyl)-2H-pyran-2-one (R-3), which may be the metabolite isolated from the biotransformation of 6PP by the Penicillium isolates.4 The use of this versatile chiron 7,3-LXF (which is prepared in only two-steps from diacetone-D-glucose),6e would permit, not only the confirmation or revision of the absolute configuration of the targeted metabolites, but also a rapid access to the 2H-pyran-2-one moiety and to the stereocontrolled construction of the pentyl skeleton. To this end, it was necessary to selectively cleave the furanose ring at the anomeric position to form an intermediate that would enable the incorporation of the chiral propyl carbon chain and eventually the construction of the heterocyclic moiety (Scheme 1). By following a protocol, in which the furanose ring of various 1,2-O-isopropylidene pentofuranoside derivatives were selectively opened to their respective peracetylated derivatives,7 the chiron 7,3-LXF was transformed into diacetylated 5 in good yield.8
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Me3Si
OH O
O
O
O
OAc OAc
OH
1
6PP
H
O
OAc O
OH
O
O
5
3
O
O 7
O
O
7,3-LXF
O
O
O
O
O
OAc
1'S
2'R
O
O
1'S
OAc ent-2 [α ]D= -78.3 (c 0.65, CHCl3) lit3 [α]D= Not reported OH
2'R
O
Bu3SnH, AICN
1'S
90%
OR ent-1; R = H
85%
O
OR
O
SiMe3 BF3 OEt2
95%
OH ent-1
O
5
O
OAc Ac2O, Py
1'S
OAc OAc O
O
OH ent-1 [α]D= -190.1 (c 0.11, MeOH) lit3 [α]D= +122.5 (c 0.11, MeOH)
2'R
Scheme 1. Synthesis plan for metabolites 1, 2, and 3.
O
1'S
OH
7,3-lactone-xylofuranose derivatve (7,3-LXF)
O
6
2'R
1. H2/Pd(OH)2 2. AcOH, H2SO4 72% in two steps
2'R
1, 2, and 3
O O
Ac2O, AcOH O H2SO 4 74%
O
O
Scheme 3. Stereochemical outcome in allylation of 5 and representative NOE interactions observed for 6.
O
O
AcO
AcO
OH
source of 2H-pyran-2-one source of chirality moiety within the pentyl carbon chain
O
O
O
Figure 1. Representative metabolites biologically synthesized from 6PP by Trichoderma strains and Penicillium isolates.
O
HH OO
O
H
BF 3 OEt2
O
O
2'R
H
O
OAc
2
O
H
8; R = S
S N
N
N
N
2'R
O
O
R-3 [α ]D= -74.7 (c 0.85, CHCl3) lit4 [α]D= Not reported
90%
Scheme 4. Completion of the syntheses of (10 S,20 R)-()-1, (10 S,20 R)-()-2 and (20 R)()-3.
Pd(OAc) 2 O
O 7
O
O
60%
O
O 6
O
O
Scheme 2. Synthesis of chiral 2-pyrone (7).
Stereoselective chain elongation was achieved by treating compound 5 with allyltrimethylsilane in the presence of BF3OEt2 to obtain allylated compound 69 in good yield and as the sole diastereoisomer.10 Allylated compound 6 was subjected to palladium-catalyzed b-elimination11 to thus obtain chiral 2-pyrone 712 in good yield (Scheme 2). The absolute configuration of the new stereogenic center in 6 was determined by 2D-NOESY experiments (20 R). The stereochemical outcome is understood in terms of the Felkin–Anh model (Scheme 3).13 Chiral 2-pyrone 7 was transformed into (10 S,20 R)-1 in a two steps one-pot protocol: first double-bond hydrogenation with H2/Pd(OH)2 and then an acid hydrolysis of 1,3-dioxolane moiety with a mixture of acetic and H2SO4.14 While NMR data matched perfectly to those reported by Collado and co-workers,3 the negative sign of optical rotation ([a]D = 190.1 (c 0.11, MeOH)) indicates that the enantiomer of the naturally occurring metabolite (lit.3 [a]D = +122.5 (c 0.11, MeOH)) was obtained (ent-1), confirming thus the absolute configuration of natural metabolite 1 as 10 R,20 S. Although optical rotation of metabolite 2 was not reported,1a,3 putative antipode of the natural product (2) was obtained (ent-2) by acetylation reaction of ent-1 (Scheme 4).15 Like metabolite 2, optical rotation of metabolite 3 was not disclosed in the original report;4 however, reporting the total synthesis of R-3
along with its optical rotation will be valuable for assigning the absolute configuration of the naturally occurring metabolite as soon as its optical rotation is reported. Thus, synthesis of R-3 was achieved in two steps:16 transformation of ent-1 into its respective thiocarbonate derivative (8) with 1,10 -thiocarbonyldiimidazole followed by Barton–McCombie desoxygenation17 reaction with Bu3SnH in refluxing toluene. NMR data of R-3 matched perfectly to those reported by Conney and Lauren (Scheme 4).4 In summary, we have developed a stereoselective total synthesis of three chiral 6-pentyl-2H-pyran-2-one derivatives. Two of them [(10 R,20 S)-()-1, (10 R,20 S)-()-2] are enantiomers of the metabolites isolated from Trichoderma spp. Due to the lack of optical rotation value of the metabolite isolated from Penicillium isolates 6-(2-hydroxypentyl)-2H-pyran-2-one (3), the total synthesis of R-3 did not permit either confirm or revise its absolute configuration; however, we provide full characterization that would be sufficient once the optical rotation of the natural metabolite is reported. Acknowledgments We gratefully acknowledge financial support from CONACYT (Scholarship number of JAPB 353911) and Benemérita Universidad Autónoma de Puebla (BUAP-VIEP). References and notes 1. (a) Monte, E. Int. Microbiol. 2001, 4, 1–4; (b) Rubio, B. M.; Hermosa, R.; Reino, J. L.; Collado, I. G.; Monte, E. Fungal Genet. Biol. 2009, 46, 17–27. 2. Poole, P. R.; Whitaker, G.; Ward, B. G. J. Sci. Food Agric. 1998, 77, 81–86.
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3. Daoubi, M.; Pinedo-Rivilla, C.; Rubio, M. B.; Hermosa, R.; Monte, E.; Aleu, J.; Collado, I. G. Tetrahedron 2009, 65, 4834–4840. 4. Cooney, J. M.; Lauren, D. R. J. Nat. Prod. 1999, 62, 681–683. 5. (a) Wagner, A. J.; David, J. G.; Rychnovsky, S. D. Org. Lett. 2011, 13, 4470–4473; (b) Amagata, T. 2.18-Misassigned Structures: Case Examples from the Past Decade (Eds. In Chief). In Comprehensive Natural Products II; Lew, M., HungWen, L., Eds.; Elsevier: Oxford, 2010; pp 581–621; (c) Nicolaou, K. C.; Snyder, S. A. Angew. Chem., Int. Ed. 2005, 44, 1012–1044. 6. Representative examples: (a) Gesson, J. P.; Jacquesy, J. C.; Mondon, M. Tetrahedron Lett. 1987, 28, 3945–3948; (b) Gesson, J. P.; Jacquesy, J. C.; Mondon, M. Tetrahedron 1989, 45, 2627–2640; (c) Bessodes, M.; Benamghar, R.; Antonakis, K. Carbohydr. Res. 1990, 200, 493–496; (d) Baskaran, S.; Vasu, J.; Kodukulla, R. P. K.; Trivedi, G. K. Tetrahedron 1996, 52, 4515–4526; (e) Ramírez, E.; Sánchez, M.; Meza-León, R. L.; Quintero, L.; Sartillo-Piscil, F. Tetrahedron Lett. 2010, 51, 2178–2180; (f) Ramírez, E.; Quintero, L.; Meza-León, R. L.; SosaRivadeneyra, M.; Cruz-Gregorio, S.; Sartillo-Piscil, F. Tetrahedron Lett. 2013, 54, 5751–5754. 7. Valdivia, V.; Hernández, A.; Rivera, A.; Sartillo-Piscil, F.; Loukaci, A.; Fourrey, J.-L. Tetrahedron Lett. 2005, 46, 6511–6514. 8. (5R,6S)-6-((4S,5R/S)-2,2-Dimethyl-5-acetoxy-1,3-dioxolan-4-yl)-3-acetoxy2,3-dihydro-2H-pyran-2-one (5). To a solution of unsaturated 7,3-lactonexylofuranose derivative 7,3-LXF (500 mg, 2.36 mmol) in acetic anhydride (0.23 mL), was added acetic acid (0.13 mL). The resulting mixture was cooled in an ice bath before to add 23 lL of sulfuric acid. The reactant mixture was stirred for 4 h at 0 °C (monitored by tlc) then was neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (3 20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered, concentrated at reduced pressure and the residue was purified by column chromatography (SiO2, ethyl acetate/hexane, 1/3) to afford 349 mg of 5 as a colorless oil in 74% of yield. [a]20 D = 134.2 (c 1.0, CHCl3). NMR data reported as a mixture of diastereoisomers with a 3/1 ratio. 1H NMR (500 MHz, CDCl3, ppm) d 1.45 (s, 1H), 1.46 (s, 3H), 1.51 (s, 3H), 1.55 (s, 1H), 2.107 (s, 3H), 2.11 (s, 2H), 2.12 (s, 3H), 4.51 (dd, J = 7.7, 3.5 Hz, 0.3H), 4.54 (dd, J = 5.5, 3.0 Hz, 1H), 4.75 (dd, J = 5.5, 3.0 Hz, 1H), 4.82 (dd, J = 7.7, 3.0 Hz, 0.3H), 5.19 (dd, J = 6.0, 3.0 Hz, 0.3H), 5.51 (dd, J = 5.7, 2.7 Hz, 1H), 6.19 (d, J = 3.5 Hz, 0.3H), 6.24 (d, J = 10.0 Hz, 1H), 6.26 (d, J = 10.0 Hz, 0.3H), 6.46 (d, J = 3.0 Hz, 1H), 6.95 (dd, J = 10.0, 5.5 Hz, 1H), 6.99 (dd, J = 10.0, 5.7 Hz, 0.3H). 13C NMR (75 MHz, CDCl3) d 20.5, 20.6, 21.1, 21.2, 25.8, 26.2, 26.6, 28.1, 61.0, 61.3, 76.2, 77.3, 77.4, 80.1, 92.7, 95.9, 112.8, 113.5, 124.9, 125.1, 139.3, 139.9, 161.0, 161.6, 169.6, 169.7, 169.8, 170.1. HRMS (AIMS AccuTOFMS) m/z [M+H]+ calcd for C14H19O8: 315.1080; found: 315.1089. 9. This stereoselective allylation reaction is similar to that applied to furanose derivatives. See representative examples: (a) Cortezano-Arellano, O.; Quintero, L.; Sartillo-Piscil, F. J. Org. Chem. 2015, 80, 2601–2608; (b) Hernández-García, L.; Quintero, L.; Höpfl, H.; Sosa, M.; Sartillo-Piscil, F. Tetrahedron 2009, 65, 139– 144; (c) Tellado-García, F.; De Armas, P.; Marrero-Tellado, J. J. Angew. Chem., Int. Ed. 2000, 39, 2727–2729. 10. (5R,6S)-6-[(4S,5R)-5-Allyl-2,2-dimethyl-1,3-dioxolan-4-yl]-5-acetoxy-5,6dihydro-2H-pyran-2-one (6). To a solution of a,b-unsaturated lactone 5 (500 mg, 1.59 mmol) in CH2Cl2 (9 mL) was added allyltrimethylsilane (731 mg, 6.39 mmol). The resulting mixture was cooled to 40 °C to drip BF3OEt2 (451 mg, 3.18 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h (monitored by tlc) before to add H2O (15 mL). The reaction was extracted with CH2Cl2 (3 20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered through a pad of cotton, the filtrate was concentrated at reduced pressure and the residue was purified by column chromatography (SiO2, ethyl acetate/hexane 1/3) to afford 402 mg of 6 20 as colorless oil in 85% of yield. [a]D = 99.0, (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3, ppm) d 1.39 (s, 3H), 1.40 (s, 3H), 2.11 (s, 3H), 2.38 (m, 2H), 3.96 (dd, J = 8.2, 3.2 Hz, 1H), 4.54 (dt, J = 8.0, 6.0 Hz, 1H), 4.53 (t, J = 3.5 Hz, 1H), 5.12 (m, 1H), 5.15 (apparent dm, J = 11.0 Hz, 1H), 5.53 (ddd, J = 5.5, 4.0, 1.0 Hz, 1H), 5.84 (m, 1H), 6.20 (dd, J = 10.0, 0.75 Hz, 1H), 6.85 (dd, J = 10.0, 5.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) d 20.7, 26.6, 27.2, 37.0, 62.4, 75.4, 75.9, 78.1, 109.7, 118.2, 124.6, 133.1, 140.1, 162.0, 170.1. HRMS (AIMS AccuTOFMS) m/z [M+H]+ calcd for C15H21O6: 297.1338; found: 297.1312. 11. (a) Tsuji, J.; Yamakawa, T.; Kaito, M.; Mandai, T. Tetrahedron Lett. 1978, 19, 2075–2078; (b) Trost, B. M.; Verhoeven, T. R.; Fortunak, J. M. Tetrahedron Lett. 1979, 20, 2301–2304. 12. 6-[(4S,5R)-5-Allyl-2,2-dimethyl-1,3-dioxolan-4-yl]-2H-pyran-2-one (7). To a round flask of 25 mL was charged with Pd(OAc)2 (37.8 mg, 0.17 mmol), DMSO (5 mL), allylated substrate 6 (500 mg, 1.7 mmol) and AcOH (5 mL). The reaction mixture was allowed to react at 60 °C for 72 h or until de consumption of substrate (monitored by tlc). The reaction was quenched with saturated NH4Cl (10 mL) and extracted with ethyl acetate (3 100 mL). The combined organic
13.
14.
15.
16.
17.
layers were dried over anhydrous sodium sulfate and filtered through a pad of cotton. The filtrate was concentrated at reduced pressure and the residue was purified by column chromatography (SiO2, ethyl acetate/hexane 1/5) to afford 1 238.4 mg of 7 as a brown oil in 60% of yield, [a]20 D = 69.4 (c 1.0, CHCl3). H NMR (500 MHz, CDCl3, ppm) d 1.48 (s, 3H), 1.49 (s, 3H), 2.46 (dtt, J = 14.5, 7.0, 1.0 Hz, 1H), 2.62 (m, 1H), 4.19 (ddd, J = 8.0, 7.0, 4.0 Hz, 1H), 4.35 (d, J = 8.0 Hz, 1H), 5.15 (apparent dm, J = 10.0 Hz, 1H), 5.19 (dq, J = 17.0, 1.5 Hz, 1H), 5.85 (m, 1H), 6.25 (dd, J = 9.5, 1.0 Hz, 1H), 6.33 (dt, J = 6.5, 1.0 Hz, 1H), 7.32 (dd, J = 9.5, 6.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 26.2, 27.2, 36.5, 78.3, 79.3, 102.5, 110.4, 115.1, 118.4, 132.8, 143.1, 161.4, 162.4. HRMS (AIMS AccuTOFMS) m/z [M ]+ calcd for C13H16O4: 236.1049; found: 236.1055. Representative examples on the use of the Felkin-Anh model in cyclic oxocarbenium ions: (a) Schmitt, A.; Reissig, H.-U. Eur. J. Org. Chem. 2000, 3893–3901; (b) Schmitt, A.; Reissig, H.-U. Synlett 1990, 40–42. 6-[(10 S,20 R)-1,2-Dihydroxypentyl]-2H-pyran-2-one (ent-1). To a solution of 7 (500 mg, 1.69 mmol) in ethyl acetate (9 mL) was added Pd(OH)2 (37.9 mg, 0.1 mmol) under a hydrogen atmosphere. The reaction was stirred for 20 min, the solids were filtered off, the filtrate was concentrated under reduced pressure and the residue was dissolved in 3 mL of a mixture of CH3COOH/ H2SO4/H2O (46/16/38). The resulting solution was stirred for 12 h or until de consumption of substrate (monitored by tlc). The reaction was neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (3 20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered through a pad of cotton. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, ethyl acetate/hexane, 1/5) to afford 302 mg of ent-1 as a white powder (72%). Mp = 124–125 °C. [a]20 D = 190.1 (c = 1.0, CH3OH); 1 13 lit.3 = [a]25 C NMR spectra matched D = +122.5 (c 0.11, MeOH)]. The H and those values reported by Collado.3 1H NMR (500 MHz, CDCl3) d 0.96 (t, J = 7.2 Hz, 3H), 1.53 (m, 2H), 1.64 (m, 2H), 2.34 (br s, 1H), 3.0 (d, J = 7.5 Hz, 1H), 4.03 (apparent. dd, J = 7.5, 3.4 Hz, 1H), 4.27 (dd, J = 7.0, 3.0 Hz, 1H), 6.21 (d, J = 9.5 Hz, 1H), 6.39 (d, J = 6.5 Hz, 1H), 7.36 (dd, J = 9.5, 6.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 13.9, 18.9, 35.5, 71.7, 73.2, 102.8, 114.3, 143.6, 162.0, 165.0. 6-[(10 S,20 R)-Diacetoxypentyl]-2H-pyran-2-one (ent-2). To a solution of diol ent1 (6.0 mg, 0.03 mmol) in acetic anhydride (2.0 mL) was added dry pyridine (0.66 mL). The mixture was stirred for 24 h at room temperature. The excess of acetic anhydride was then eliminated with cyclohexane and acetone and evaporated under reduced pressure. The residue was purified by column chromatography (SiO2, ethyl acetate/hexane, 1/7) to afford 8.1 mg of ent-2 as a 1 13 colorless oil in (95%) of yield. [a]20 C NMR D = 78.3 (c 0.65, CHCl3). The H and spectra matched those values reported by Collado.3 1H NMR (500 MHz, CDCl3, ppm) d 0.92 (t, J = 7.23 Hz, 3H), 1.35 (m, 2H), 1.57 (m, 2H), 2.04 (s, 3H), 2.16 (s, 3H), 5.35 (dt, J = 8.7, 4.5 Hz, 1H), 5.51 (d, J = 5.1 Hz, 1H), 6.18 (d, J = 6.6 Hz, 1H), 6.25 (d, J = 9.6 Hz, 1H), 7.8 (dd, J = 9.6, 6.6 Hz, 1H). 13C NMR (125 MHz, CDCl3) d 13.7, 18.4, 20.6, 20.7, 32.4, 71.8, 72.3, 103.7, 115.8, 142.5, 159.5, 160.8, 169.5, 170.0. 6-[(4S,5R)-5-Propyl-2-thioxo-1,3-dioxolan-4-yl]-2H-pyran-2-one (8). To a solution of diol ent-1 (20 mg, 0.1 mmol) in CH2Cl2 (30 mL) was added 1,10 thiocarbonyldiimidazole (21.5 mg, 0.12 mmol). The resulting mixture was stirred for 24 h at room temperature. After the consumption of substrate, the solvent was evaporated and the residue was purified by column chromatography (SiO2, ethyl acetate/hexane, 1/5) to afford 21.7 mg of thiocarbonate 8 as a brown oil (90%) of yield. [a]20 D = 201.2 (c 1.0, CHCl3). 1 H NMR (300 MHz, CDCl3, ppm) d 1.02 (t, J = 7.2 Hz, 3H), 1.57 (m, 2H), 1.91 (m, 2H), 4.97 (dt, J = 7.2, 5.7 Hz, 1H), 5.12 (d, J = 6.0 Hz, 1H), 6.37 (d, J = 9.6 Hz, 1H), 6.40 (d, J = 6.6 Hz, 1H), 7.37 (dd, J = 9.6, 6.6 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 13.5, 17.8, 35.5, 81.6, 85.3, 103.4, 117.0, 142.4, 156.4, 159.8, 189.6. HRMS (AIMS AccuTOFMS) m/z [M+H]+ calcd for C11H13O4S: 241.0535; found: 241.0545. 6-((20 R)-Hydroxypentyl)-2H-pyran-2-one (R-3). To a solution of thiocarbonate 8 (20 mg, 0.083 mmol) in dry and degassed toluene (5.0 mL) at 80 °C was slowly added a solution of Bu3SnH (36.34 mg, 1.248 mmol) and 1,10 -azobiscyclohexanecarbonitrile (8.0 mg, 0.032 mmol) dissolved in 3 mL of toluene. The reaction mixture was stirred for 40 min at 80 °C. The resulting mixture was evaporated under reduced pressure and the residue was purified by column chromatography (SiO2, ethyl acetate/hexane, 1/5) to afford 13.6 mg of R-3 as 1 13 colorless oil (90%). [a]20 C NMR spectra D = 74.7 (c 0.85, CHCl3). The H and matched those values reported by Cooney and Lauren.4 1H NMR (300 MHz, CDCl3, ppm) d 0.95 (t, J = 6.7 Hz, 3H), 1.37–1.54 (m, 4H), 2.55 (dd, J = 14.4, 8.5 Hz, 1H), 2.68 (dd, J = 14.7, 3.6 Hz, 1H), 4.07 (m, 1H), 6.09 (d, J = 6.6 Hz, 1H), 6. 19 (d, J = 9.3 Hz, 1H), 7.28 (dd, J = 9.3, 6.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 13.9, 18.7, 39.4, 41.9, 69.0, 104.5, 113.6, 143.6, 162.7, 163.7. (a) McCombie, S. W.; Motherwell, W. B.; Tozer, M. J. Org. React. 2011, 161–432; (b) Crich, D.; Quintero, L. Chem. Rev. 1989, 89, 1413.
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The first stereoselective non-biological synthesis of chiral 6-pentyl-2H-pyran-2-ones: total synthesis of metabolites isolated from Trichoderma spp and Penicillium isolates José Alvano Pérez-Bautista, Rosa Luisa Meza-León, Silvano Cruz-Gregorio, Leticia Quintero ⇑, Fernando Sartillo-Piscil ⇑ Facultad de Ciencias Químicas de la Benemérita Universidad Autónoma de Puebla (BUAP), 14 Sur Esq. San Claudio, San Manuel, 72570 Puebla, Mexico
a r t i c l e
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Article history: Received 2 August 2016 Revised 23 August 2016 Accepted 29 August 2016 Available online 31 August 2016 Keywords: Total synthesis Chiron approach 2H-Pyran-2-ones Stereoselective allylation Trichoderma metabolites Penicillium isolates
a b s t r a c t The total synthesis of three chiral 6-pentyl-2H-pyran-2-ones (metabolites of Trichoderma spp and Penicillium isolates) is reported. With the preservation of the configurational integrity of one stereogenic center (2S of the chiron 7,3-LXF), these total syntheses permitted the confirmation of the absolute configuration of two of them (1 and 2). Since the optical rotation data of one natural metabolite was not disclosed in the original publication, its enantiopure synthesis (R-3) did not permitted either the confirmation or revision of the absolute configuration. The present approach involves a selective furanose acetolysis, a stereoselective allylation of an intermediate acetal and a Pd-catalyzed b-elimination reaction. Ó 2016 Elsevier Ltd. All rights reserved.
Secondary metabolites isolated from Trichoderma species have gained popularity in the past two decades due to their potential role as biological control agents.1 One of the most biologically active metabolites is the 6-pentyl-2H-pyran-2-one (6PP), which is known as a volatile antifungal metabolite with inhibitory activity for the growth of various phytopathogen fungi.2 Other metabolites such as 1 and 2 have been biosynthesized via metabolization of 6PP by Trichoderma strains to study its mode of action as potential biocontrol agent.3 Similarly, metabolites 3 has been biologically synthesized from 6PP by a range of Penicillium isolates4 (Fig. 1). Despite the biological importance of these metabolites, a stereoselective synthesis has not been reported yet; only a racemic synthesis of 1 and 2 from 6PP was accomplished,3 wherein their absolute configuration was determined based on NMR analysis of the corresponding Mosher’s esters. On the other hand, metabolite 3, obtained from Penicillium isolates, has not had its absolute configuration defined, in fact, its optical rotation was not reported, and its absolute configuration remains unknown.4 Therefore, it is crucial a full characterization of these metabolites not only by NMR
⇑ Corresponding authors. Tel.: +52 222 229 5500; fax: +52 222 245 4972. E-mail addresses: [email protected] (L. Quintero), fernando. [email protected] (F. Sartillo-Piscil). http://dx.doi.org/10.1016/j.tetlet.2016.08.089 0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
but also by total synthesis; especially for the confirmation of the absolute configuration, as the Mosher’s method is sometimes limited to secondary alcohols that are not too sterically hindered.5 Thus, a stereoselective approach that could provide an enantiopure avenue to these metabolites is highly desirable. The present letter reports, starting from the versatile chiron 7,3lactone-xylofuranose derivative (7,3-LXF),6 the total synthesis and the confirmation of the absolute configuration of two metabolites isolated from Trichoderma spp (1 and 2), and the synthesis of 6((20 R)-hydroxypentyl)-2H-pyran-2-one (R-3), which may be the metabolite isolated from the biotransformation of 6PP by the Penicillium isolates.4 The use of this versatile chiron 7,3-LXF (which is prepared in only two-steps from diacetone-D-glucose),6e would permit, not only the confirmation or revision of the absolute configuration of the targeted metabolites, but also a rapid access to the 2H-pyran-2-one moiety and to the stereocontrolled construction of the pentyl skeleton. To this end, it was necessary to selectively cleave the furanose ring at the anomeric position to form an intermediate that would enable the incorporation of the chiral propyl carbon chain and eventually the construction of the heterocyclic moiety (Scheme 1). By following a protocol, in which the furanose ring of various 1,2-O-isopropylidene pentofuranoside derivatives were selectively opened to their respective peracetylated derivatives,7 the chiron 7,3-LXF was transformed into diacetylated 5 in good yield.8
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Me3Si
OH O
O
O
O
OAc OAc
OH
1
6PP
H
O
OAc O
OH
O
O
5
3
O
O 7
O
O
7,3-LXF
O
O
O
O
O
OAc
1'S
2'R
O
O
1'S
OAc ent-2 [α ]D= -78.3 (c 0.65, CHCl3) lit3 [α]D= Not reported OH
2'R
O
Bu3SnH, AICN
1'S
90%
OR ent-1; R = H
85%
O
OR
O
SiMe3 BF3 OEt2
95%
OH ent-1
O
5
O
OAc Ac2O, Py
1'S
OAc OAc O
O
OH ent-1 [α]D= -190.1 (c 0.11, MeOH) lit3 [α]D= +122.5 (c 0.11, MeOH)
2'R
Scheme 1. Synthesis plan for metabolites 1, 2, and 3.
O
1'S
OH
7,3-lactone-xylofuranose derivatve (7,3-LXF)
O
6
2'R
1. H2/Pd(OH)2 2. AcOH, H2SO4 72% in two steps
2'R
1, 2, and 3
O O
Ac2O, AcOH O H2SO 4 74%
O
O
Scheme 3. Stereochemical outcome in allylation of 5 and representative NOE interactions observed for 6.
O
O
AcO
AcO
OH
source of 2H-pyran-2-one source of chirality moiety within the pentyl carbon chain
O
O
O
Figure 1. Representative metabolites biologically synthesized from 6PP by Trichoderma strains and Penicillium isolates.
O
HH OO
O
H
BF 3 OEt2
O
O
2'R
H
O
OAc
2
O
H
8; R = S
S N
N
N
N
2'R
O
O
R-3 [α ]D= -74.7 (c 0.85, CHCl3) lit4 [α]D= Not reported
90%
Scheme 4. Completion of the syntheses of (10 S,20 R)-()-1, (10 S,20 R)-()-2 and (20 R)()-3.
Pd(OAc) 2 O
O 7
O
O
60%
O
O 6
O
O
Scheme 2. Synthesis of chiral 2-pyrone (7).
Stereoselective chain elongation was achieved by treating compound 5 with allyltrimethylsilane in the presence of BF3OEt2 to obtain allylated compound 69 in good yield and as the sole diastereoisomer.10 Allylated compound 6 was subjected to palladium-catalyzed b-elimination11 to thus obtain chiral 2-pyrone 712 in good yield (Scheme 2). The absolute configuration of the new stereogenic center in 6 was determined by 2D-NOESY experiments (20 R). The stereochemical outcome is understood in terms of the Felkin–Anh model (Scheme 3).13 Chiral 2-pyrone 7 was transformed into (10 S,20 R)-1 in a two steps one-pot protocol: first double-bond hydrogenation with H2/Pd(OH)2 and then an acid hydrolysis of 1,3-dioxolane moiety with a mixture of acetic and H2SO4.14 While NMR data matched perfectly to those reported by Collado and co-workers,3 the negative sign of optical rotation ([a]D = 190.1 (c 0.11, MeOH)) indicates that the enantiomer of the naturally occurring metabolite (lit.3 [a]D = +122.5 (c 0.11, MeOH)) was obtained (ent-1), confirming thus the absolute configuration of natural metabolite 1 as 10 R,20 S. Although optical rotation of metabolite 2 was not reported,1a,3 putative antipode of the natural product (2) was obtained (ent-2) by acetylation reaction of ent-1 (Scheme 4).15 Like metabolite 2, optical rotation of metabolite 3 was not disclosed in the original report;4 however, reporting the total synthesis of R-3
along with its optical rotation will be valuable for assigning the absolute configuration of the naturally occurring metabolite as soon as its optical rotation is reported. Thus, synthesis of R-3 was achieved in two steps:16 transformation of ent-1 into its respective thiocarbonate derivative (8) with 1,10 -thiocarbonyldiimidazole followed by Barton–McCombie desoxygenation17 reaction with Bu3SnH in refluxing toluene. NMR data of R-3 matched perfectly to those reported by Conney and Lauren (Scheme 4).4 In summary, we have developed a stereoselective total synthesis of three chiral 6-pentyl-2H-pyran-2-one derivatives. Two of them [(10 R,20 S)-()-1, (10 R,20 S)-()-2] are enantiomers of the metabolites isolated from Trichoderma spp. Due to the lack of optical rotation value of the metabolite isolated from Penicillium isolates 6-(2-hydroxypentyl)-2H-pyran-2-one (3), the total synthesis of R-3 did not permit either confirm or revise its absolute configuration; however, we provide full characterization that would be sufficient once the optical rotation of the natural metabolite is reported. Acknowledgments We gratefully acknowledge financial support from CONACYT (Scholarship number of JAPB 353911) and Benemérita Universidad Autónoma de Puebla (BUAP-VIEP). References and notes 1. (a) Monte, E. Int. Microbiol. 2001, 4, 1–4; (b) Rubio, B. M.; Hermosa, R.; Reino, J. L.; Collado, I. G.; Monte, E. Fungal Genet. Biol. 2009, 46, 17–27. 2. Poole, P. R.; Whitaker, G.; Ward, B. G. J. Sci. Food Agric. 1998, 77, 81–86.
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3. Daoubi, M.; Pinedo-Rivilla, C.; Rubio, M. B.; Hermosa, R.; Monte, E.; Aleu, J.; Collado, I. G. Tetrahedron 2009, 65, 4834–4840. 4. Cooney, J. M.; Lauren, D. R. J. Nat. Prod. 1999, 62, 681–683. 5. (a) Wagner, A. J.; David, J. G.; Rychnovsky, S. D. Org. Lett. 2011, 13, 4470–4473; (b) Amagata, T. 2.18-Misassigned Structures: Case Examples from the Past Decade (Eds. In Chief). In Comprehensive Natural Products II; Lew, M., HungWen, L., Eds.; Elsevier: Oxford, 2010; pp 581–621; (c) Nicolaou, K. C.; Snyder, S. A. Angew. Chem., Int. Ed. 2005, 44, 1012–1044. 6. Representative examples: (a) Gesson, J. P.; Jacquesy, J. C.; Mondon, M. Tetrahedron Lett. 1987, 28, 3945–3948; (b) Gesson, J. P.; Jacquesy, J. C.; Mondon, M. Tetrahedron 1989, 45, 2627–2640; (c) Bessodes, M.; Benamghar, R.; Antonakis, K. Carbohydr. Res. 1990, 200, 493–496; (d) Baskaran, S.; Vasu, J.; Kodukulla, R. P. K.; Trivedi, G. K. Tetrahedron 1996, 52, 4515–4526; (e) Ramírez, E.; Sánchez, M.; Meza-León, R. L.; Quintero, L.; Sartillo-Piscil, F. Tetrahedron Lett. 2010, 51, 2178–2180; (f) Ramírez, E.; Quintero, L.; Meza-León, R. L.; SosaRivadeneyra, M.; Cruz-Gregorio, S.; Sartillo-Piscil, F. Tetrahedron Lett. 2013, 54, 5751–5754. 7. Valdivia, V.; Hernández, A.; Rivera, A.; Sartillo-Piscil, F.; Loukaci, A.; Fourrey, J.-L. Tetrahedron Lett. 2005, 46, 6511–6514. 8. (5R,6S)-6-((4S,5R/S)-2,2-Dimethyl-5-acetoxy-1,3-dioxolan-4-yl)-3-acetoxy2,3-dihydro-2H-pyran-2-one (5). To a solution of unsaturated 7,3-lactonexylofuranose derivative 7,3-LXF (500 mg, 2.36 mmol) in acetic anhydride (0.23 mL), was added acetic acid (0.13 mL). The resulting mixture was cooled in an ice bath before to add 23 lL of sulfuric acid. The reactant mixture was stirred for 4 h at 0 °C (monitored by tlc) then was neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (3 20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered, concentrated at reduced pressure and the residue was purified by column chromatography (SiO2, ethyl acetate/hexane, 1/3) to afford 349 mg of 5 as a colorless oil in 74% of yield. [a]20 D = 134.2 (c 1.0, CHCl3). NMR data reported as a mixture of diastereoisomers with a 3/1 ratio. 1H NMR (500 MHz, CDCl3, ppm) d 1.45 (s, 1H), 1.46 (s, 3H), 1.51 (s, 3H), 1.55 (s, 1H), 2.107 (s, 3H), 2.11 (s, 2H), 2.12 (s, 3H), 4.51 (dd, J = 7.7, 3.5 Hz, 0.3H), 4.54 (dd, J = 5.5, 3.0 Hz, 1H), 4.75 (dd, J = 5.5, 3.0 Hz, 1H), 4.82 (dd, J = 7.7, 3.0 Hz, 0.3H), 5.19 (dd, J = 6.0, 3.0 Hz, 0.3H), 5.51 (dd, J = 5.7, 2.7 Hz, 1H), 6.19 (d, J = 3.5 Hz, 0.3H), 6.24 (d, J = 10.0 Hz, 1H), 6.26 (d, J = 10.0 Hz, 0.3H), 6.46 (d, J = 3.0 Hz, 1H), 6.95 (dd, J = 10.0, 5.5 Hz, 1H), 6.99 (dd, J = 10.0, 5.7 Hz, 0.3H). 13C NMR (75 MHz, CDCl3) d 20.5, 20.6, 21.1, 21.2, 25.8, 26.2, 26.6, 28.1, 61.0, 61.3, 76.2, 77.3, 77.4, 80.1, 92.7, 95.9, 112.8, 113.5, 124.9, 125.1, 139.3, 139.9, 161.0, 161.6, 169.6, 169.7, 169.8, 170.1. HRMS (AIMS AccuTOFMS) m/z [M+H]+ calcd for C14H19O8: 315.1080; found: 315.1089. 9. This stereoselective allylation reaction is similar to that applied to furanose derivatives. See representative examples: (a) Cortezano-Arellano, O.; Quintero, L.; Sartillo-Piscil, F. J. Org. Chem. 2015, 80, 2601–2608; (b) Hernández-García, L.; Quintero, L.; Höpfl, H.; Sosa, M.; Sartillo-Piscil, F. Tetrahedron 2009, 65, 139– 144; (c) Tellado-García, F.; De Armas, P.; Marrero-Tellado, J. J. Angew. Chem., Int. Ed. 2000, 39, 2727–2729. 10. (5R,6S)-6-[(4S,5R)-5-Allyl-2,2-dimethyl-1,3-dioxolan-4-yl]-5-acetoxy-5,6dihydro-2H-pyran-2-one (6). To a solution of a,b-unsaturated lactone 5 (500 mg, 1.59 mmol) in CH2Cl2 (9 mL) was added allyltrimethylsilane (731 mg, 6.39 mmol). The resulting mixture was cooled to 40 °C to drip BF3OEt2 (451 mg, 3.18 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h (monitored by tlc) before to add H2O (15 mL). The reaction was extracted with CH2Cl2 (3 20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered through a pad of cotton, the filtrate was concentrated at reduced pressure and the residue was purified by column chromatography (SiO2, ethyl acetate/hexane 1/3) to afford 402 mg of 6 20 as colorless oil in 85% of yield. [a]D = 99.0, (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3, ppm) d 1.39 (s, 3H), 1.40 (s, 3H), 2.11 (s, 3H), 2.38 (m, 2H), 3.96 (dd, J = 8.2, 3.2 Hz, 1H), 4.54 (dt, J = 8.0, 6.0 Hz, 1H), 4.53 (t, J = 3.5 Hz, 1H), 5.12 (m, 1H), 5.15 (apparent dm, J = 11.0 Hz, 1H), 5.53 (ddd, J = 5.5, 4.0, 1.0 Hz, 1H), 5.84 (m, 1H), 6.20 (dd, J = 10.0, 0.75 Hz, 1H), 6.85 (dd, J = 10.0, 5.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) d 20.7, 26.6, 27.2, 37.0, 62.4, 75.4, 75.9, 78.1, 109.7, 118.2, 124.6, 133.1, 140.1, 162.0, 170.1. HRMS (AIMS AccuTOFMS) m/z [M+H]+ calcd for C15H21O6: 297.1338; found: 297.1312. 11. (a) Tsuji, J.; Yamakawa, T.; Kaito, M.; Mandai, T. Tetrahedron Lett. 1978, 19, 2075–2078; (b) Trost, B. M.; Verhoeven, T. R.; Fortunak, J. M. Tetrahedron Lett. 1979, 20, 2301–2304. 12. 6-[(4S,5R)-5-Allyl-2,2-dimethyl-1,3-dioxolan-4-yl]-2H-pyran-2-one (7). To a round flask of 25 mL was charged with Pd(OAc)2 (37.8 mg, 0.17 mmol), DMSO (5 mL), allylated substrate 6 (500 mg, 1.7 mmol) and AcOH (5 mL). The reaction mixture was allowed to react at 60 °C for 72 h or until de consumption of substrate (monitored by tlc). The reaction was quenched with saturated NH4Cl (10 mL) and extracted with ethyl acetate (3 100 mL). The combined organic
13.
14.
15.
16.
17.
layers were dried over anhydrous sodium sulfate and filtered through a pad of cotton. The filtrate was concentrated at reduced pressure and the residue was purified by column chromatography (SiO2, ethyl acetate/hexane 1/5) to afford 1 238.4 mg of 7 as a brown oil in 60% of yield, [a]20 D = 69.4 (c 1.0, CHCl3). H NMR (500 MHz, CDCl3, ppm) d 1.48 (s, 3H), 1.49 (s, 3H), 2.46 (dtt, J = 14.5, 7.0, 1.0 Hz, 1H), 2.62 (m, 1H), 4.19 (ddd, J = 8.0, 7.0, 4.0 Hz, 1H), 4.35 (d, J = 8.0 Hz, 1H), 5.15 (apparent dm, J = 10.0 Hz, 1H), 5.19 (dq, J = 17.0, 1.5 Hz, 1H), 5.85 (m, 1H), 6.25 (dd, J = 9.5, 1.0 Hz, 1H), 6.33 (dt, J = 6.5, 1.0 Hz, 1H), 7.32 (dd, J = 9.5, 6.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 26.2, 27.2, 36.5, 78.3, 79.3, 102.5, 110.4, 115.1, 118.4, 132.8, 143.1, 161.4, 162.4. HRMS (AIMS AccuTOFMS) m/z [M ]+ calcd for C13H16O4: 236.1049; found: 236.1055. Representative examples on the use of the Felkin-Anh model in cyclic oxocarbenium ions: (a) Schmitt, A.; Reissig, H.-U. Eur. J. Org. Chem. 2000, 3893–3901; (b) Schmitt, A.; Reissig, H.-U. Synlett 1990, 40–42. 6-[(10 S,20 R)-1,2-Dihydroxypentyl]-2H-pyran-2-one (ent-1). To a solution of 7 (500 mg, 1.69 mmol) in ethyl acetate (9 mL) was added Pd(OH)2 (37.9 mg, 0.1 mmol) under a hydrogen atmosphere. The reaction was stirred for 20 min, the solids were filtered off, the filtrate was concentrated under reduced pressure and the residue was dissolved in 3 mL of a mixture of CH3COOH/ H2SO4/H2O (46/16/38). The resulting solution was stirred for 12 h or until de consumption of substrate (monitored by tlc). The reaction was neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (3 20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered through a pad of cotton. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, ethyl acetate/hexane, 1/5) to afford 302 mg of ent-1 as a white powder (72%). Mp = 124–125 °C. [a]20 D = 190.1 (c = 1.0, CH3OH); 1 13 lit.3 = [a]25 C NMR spectra matched D = +122.5 (c 0.11, MeOH)]. The H and those values reported by Collado.3 1H NMR (500 MHz, CDCl3) d 0.96 (t, J = 7.2 Hz, 3H), 1.53 (m, 2H), 1.64 (m, 2H), 2.34 (br s, 1H), 3.0 (d, J = 7.5 Hz, 1H), 4.03 (apparent. dd, J = 7.5, 3.4 Hz, 1H), 4.27 (dd, J = 7.0, 3.0 Hz, 1H), 6.21 (d, J = 9.5 Hz, 1H), 6.39 (d, J = 6.5 Hz, 1H), 7.36 (dd, J = 9.5, 6.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 13.9, 18.9, 35.5, 71.7, 73.2, 102.8, 114.3, 143.6, 162.0, 165.0. 6-[(10 S,20 R)-Diacetoxypentyl]-2H-pyran-2-one (ent-2). To a solution of diol ent1 (6.0 mg, 0.03 mmol) in acetic anhydride (2.0 mL) was added dry pyridine (0.66 mL). The mixture was stirred for 24 h at room temperature. The excess of acetic anhydride was then eliminated with cyclohexane and acetone and evaporated under reduced pressure. The residue was purified by column chromatography (SiO2, ethyl acetate/hexane, 1/7) to afford 8.1 mg of ent-2 as a 1 13 colorless oil in (95%) of yield. [a]20 C NMR D = 78.3 (c 0.65, CHCl3). The H and spectra matched those values reported by Collado.3 1H NMR (500 MHz, CDCl3, ppm) d 0.92 (t, J = 7.23 Hz, 3H), 1.35 (m, 2H), 1.57 (m, 2H), 2.04 (s, 3H), 2.16 (s, 3H), 5.35 (dt, J = 8.7, 4.5 Hz, 1H), 5.51 (d, J = 5.1 Hz, 1H), 6.18 (d, J = 6.6 Hz, 1H), 6.25 (d, J = 9.6 Hz, 1H), 7.8 (dd, J = 9.6, 6.6 Hz, 1H). 13C NMR (125 MHz, CDCl3) d 13.7, 18.4, 20.6, 20.7, 32.4, 71.8, 72.3, 103.7, 115.8, 142.5, 159.5, 160.8, 169.5, 170.0. 6-[(4S,5R)-5-Propyl-2-thioxo-1,3-dioxolan-4-yl]-2H-pyran-2-one (8). To a solution of diol ent-1 (20 mg, 0.1 mmol) in CH2Cl2 (30 mL) was added 1,10 thiocarbonyldiimidazole (21.5 mg, 0.12 mmol). The resulting mixture was stirred for 24 h at room temperature. After the consumption of substrate, the solvent was evaporated and the residue was purified by column chromatography (SiO2, ethyl acetate/hexane, 1/5) to afford 21.7 mg of thiocarbonate 8 as a brown oil (90%) of yield. [a]20 D = 201.2 (c 1.0, CHCl3). 1 H NMR (300 MHz, CDCl3, ppm) d 1.02 (t, J = 7.2 Hz, 3H), 1.57 (m, 2H), 1.91 (m, 2H), 4.97 (dt, J = 7.2, 5.7 Hz, 1H), 5.12 (d, J = 6.0 Hz, 1H), 6.37 (d, J = 9.6 Hz, 1H), 6.40 (d, J = 6.6 Hz, 1H), 7.37 (dd, J = 9.6, 6.6 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 13.5, 17.8, 35.5, 81.6, 85.3, 103.4, 117.0, 142.4, 156.4, 159.8, 189.6. HRMS (AIMS AccuTOFMS) m/z [M+H]+ calcd for C11H13O4S: 241.0535; found: 241.0545. 6-((20 R)-Hydroxypentyl)-2H-pyran-2-one (R-3). To a solution of thiocarbonate 8 (20 mg, 0.083 mmol) in dry and degassed toluene (5.0 mL) at 80 °C was slowly added a solution of Bu3SnH (36.34 mg, 1.248 mmol) and 1,10 -azobiscyclohexanecarbonitrile (8.0 mg, 0.032 mmol) dissolved in 3 mL of toluene. The reaction mixture was stirred for 40 min at 80 °C. The resulting mixture was evaporated under reduced pressure and the residue was purified by column chromatography (SiO2, ethyl acetate/hexane, 1/5) to afford 13.6 mg of R-3 as 1 13 colorless oil (90%). [a]20 C NMR spectra D = 74.7 (c 0.85, CHCl3). The H and matched those values reported by Cooney and Lauren.4 1H NMR (300 MHz, CDCl3, ppm) d 0.95 (t, J = 6.7 Hz, 3H), 1.37–1.54 (m, 4H), 2.55 (dd, J = 14.4, 8.5 Hz, 1H), 2.68 (dd, J = 14.7, 3.6 Hz, 1H), 4.07 (m, 1H), 6.09 (d, J = 6.6 Hz, 1H), 6. 19 (d, J = 9.3 Hz, 1H), 7.28 (dd, J = 9.3, 6.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 13.9, 18.7, 39.4, 41.9, 69.0, 104.5, 113.6, 143.6, 162.7, 163.7. (a) McCombie, S. W.; Motherwell, W. B.; Tozer, M. J. Org. React. 2011, 161–432; (b) Crich, D.; Quintero, L. Chem. Rev. 1989, 89, 1413.