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DOI: 10.1039/C5RA09186A (Paper) RSC Adv., 2015, 5, 53471-53476

Total synthesis and stereochemical assignment of cryptolatifolione†

Luiz F. T. Novaesa, Ariel M. Sarottib and Ronaldo A. Pilli*a
aDepartamento de Química Orgânica, Instituto de Química, Universidade Estadual de Campinas (Unicamp), CP 6154, CEP 13084-971, Campinas, São Paulo, Brazil. E-mail: pilli@iqm.unicamp.br
bInstituto de Química Rosario, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario-CONICET, Suipacha 531, S2002LRK Rosario, Argentina

Received 16th May 2015 , Accepted 10th June 2015

First published on 10th June 2015

Abstract

An enantioselective total synthesis of cryptolatifolione and its C-8 epimer is presented in a protecting-group-free fashion. The synthesis relied on the use of a catalytic double Krische allylation, catalytic olefin metathesis and a C–H oxidation. Comparison of spectroscopic data of the synthetic isomers and natural product made possible the unambiguous elucidation of the absolute configuration of cryptolatifolione.

Introduction

The dihydropyranone motif is found in several natural products from different sources. Fostriecin (CI-920),1 bitungolide A2 and cryptomoscatone D2 3 contain this motif and were isolated from bacteria Streptomyces pulveraceus, from the sponge Theonella swinhoei, and from the bark of the tree Cryptocaria mandiocanna, respectively.

Compounds containing dihydropyranone ring display a broad range of pharmacological properties, including antitumoral,4 antimicrobial5 and antiparasite6 activity, inhibition of HIV protease7 and hepatitis C virus polymerase,8 induction of apoptosis9 and molluscicidal properties.10

This class has attracted considerable interest from synthetic research groups, and from 2006 to 2012 over 60 targets being accomplished by total synthesis.11 We have reported the total synthesis and structural elucidation of some dihydropyranones in recent years, such as coibacins A–B,12 and cryptomoscatones D1 and D2.13

In this context, we drove our attention to a natural lactone isolated by Wijewardene and coworkers from the bark of Cryptocaria latifolia in 1996, christened by us as cryptolatifolione.14 The configuration of the stereogenic center at C-6 was assigned by the authors as R, but the configuration at C-8 remains unknown (see Scheme 1). In this communication, we report a total synthesis of cryptolatifolione and its C-8 epimer, envisioning structural elucidation.


image file: c5ra09186a-s1.tif
Scheme 1 Retrosynthetic plan for cryptolatifolione.

Assuming the absolute stereochemistry at C-6 as R, we planned the synthesis of two epimers at C-8 in order to establish unequivocally the absolute configuration of cryptolatifolione with C–C bonds being constructed by catalytic methods: a double Krische allylation of commercially available 1,3-propanediol (1) employing iridium catalysis, followed by ring closing metathesis (RCM) and an E-selective cross metathesis, to secure the six-membered ring and the E-double bond, respectively (Scheme 1).

Results and discussion

Synthesis of acrylate 4 began with the enantioselective iridium catalyzed allylation of commercial 1,3-propanediol (1)15 to provide diol 2 in 60% yield, diastereoisomeric ratio higher than 20[thin space (1/6-em)]:[thin space (1/6-em)]1 and enantiomeric excess higher than 99% (Scheme 2).16 The C2-symmetric diol 2 was monoprotected as the PMB ether in 71% yield, followed by esterification with acryloyl chloride to afford acrylate 4 in 93% yield. In the next step, we aimed to construct the dihydropyran-2-one moiety via the ring closing metathesis reaction of acrylate 4, but we were surprised to observe the exclusive formation of the seven-membered ring 5 using Grubbs' catalyst I (92% yield) or II (93% yield). In order to circumvent this undesired reactivity, we exposed cycloheptene 5 to Grubbs' catalyst I or II, in refluxing CH2Cl2 for few days, aiming to promote a sequence of ring opening/ring closing metathesis which might lead to the desired dihydropyran-2-one 6.17 Unfortunately, only cycloheptene 5 was recovered after these attempts (Scheme 2).
image file: c5ra09186a-s2.tif
Scheme 2 First approach to cryptolatifolione.

Triene 4 is composed by two olefins of type I (allylic) and one olefin of type II (acrylate), using the classification by Grubbs and coworkers.18 Considering that reaction between two olefins of type I is faster than a reaction of one olefin of type I and another of type II,18 and the inertness of cycloheptene 5 to ring opening/ring closing metathesis (Scheme 2), we decided to replace the acrylate (type II) by an allyl group (type I), and install the carbonyl in a later stage via a C–H oxidation. Furthermore, in this approach, the PMB group would be replaced by an acetate, which is part of the structure of cryptolatifolione, thus envisioning a protecting group-free synthesis.

In order to explore such approach, C2-symmetric diol 2 was treated with allyl bromide to produce alcohol 7 in 75% yield, followed by esterification with acetic anhydride in 71% yield (Scheme 3). In the ring-closing metathesis reaction step, we tested five commercial ruthenium catalysts (11–15, Table 1). Catalyst 11 and 14 furnished low selectivity in favor of dihydropyran 9 (entries 1 and 4). Although we observed a discrete increment in the selectivity upon reduction of reaction temperature with catalyst 11, it was accompanied with a decrease in the yield (entry 2). Eventually, catalysts containing N-heterocyclic carbene (NHC) ligand showed high yields and high selectivity in favor of dihydropyran 9 (entries 3, 5 and 6), and we were pleased to observe that using only 1 mol% of Grubbs' catalyst II (12), dihydropyran 9 could be obtained in high selectivity (>95[thin space (1/6-em)]:[thin space (1/6-em)]5) in 85% yield (entry 7).


image file: c5ra09186a-s3.tif
Scheme 3 Synthesis of dihydropyran 9.
Table 1 Screening of condition for RCM

image file: c5ra09186a-u1.tif
Entry Catalyst Loading Temperature Ratio 9/10 Yield
1 11 5 mol% 40 °C 59[thin space (1/6-em)]:[thin space (1/6-em)]41 88%
2 11 5 mol% 0 °C 63[thin space (1/6-em)]:[thin space (1/6-em)]37 74%
3 13 5 mol% 40 °C 94[thin space (1/6-em)]:[thin space (1/6-em)]6 80%
4 14 10 mol% 40 °C 72[thin space (1/6-em)]:[thin space (1/6-em)]28 86%
5 15 10 mol% 40 °C 92[thin space (1/6-em)]:[thin space (1/6-em)]8 82%
6 12 5 mol% 40 °C >95[thin space (1/6-em)]:[thin space (1/6-em)]5 86%
7 12 1 mol% 40 °C >95[thin space (1/6-em)]:[thin space (1/6-em)]5 85%

The next step was a selective allylic radical-based C–H oxidation at C-2 position of dihydropyran 9 to install the desired lactone. To answer the question whether C-2 would be more easily oxidized than the other two competing allylic positions (C-5 and C-9), we performed DFT calculations using Gaussian 09.19 The relative C–H bond strength for the three competing radical oxidation reactions were estimated by computing the relative stability of the radical species resulting from homolytic C–H bond cleavage at the UB3LYP/6-31+G** level of theory.20 Our calculations suggested that the radical centered on C-2 would be more stable than those centered on C-5 or C-9 (ΔΔG = 6.2 and 6.5 kcal mol−1, respectively). This result encouraged us to pursue our goals, and after several experimentation we found that the use of PCC and pyridine selectively oxidized the C-2 position to furnish the dihydropyranone 16 in 61% yield. The last C–C bond was constructed via a cross-metathesis reaction using symmetric 3-hexene as partner of 16, the product presented the new double bond with exclusively E-selectivity (Scheme 4).


image file: c5ra09186a-s4.tif
Scheme 4 Synthesis of epimer 17 (ΔΔG values are relative energies of the correspondent allylic radical species).

Synthesis of dihydropyran-2-one 23, the C-8 epimer of lactone 17, was conducted in a similar fashion (Scheme 5). Stereogenic center at C-8 was inverted in a sequence of oxidation with Dess–Martin periodinane (DMP) and diastereoselective reduction, to furnish 1,3-syn compound as the major isomer (d.r. 79[thin space (1/6-em)]:[thin space (1/6-em)]21) in 64% yield (2 steps). Alcohol 19 was acetylated with acetic anhydride, and the resulting triene 20 was used in the optimized conditions for RCM reaction, obtaining the dihydropyran 21 as a single isomer in 71% yield (2 steps). C–H oxidation21 and cross-metathesis reaction were performed under similar conditions as previously described, to produce epimer 23 in 49% yield for the last 2 steps.


image file: c5ra09186a-s5.tif
Scheme 5 Synthesis of epimer 23.

Comparison of the 13C NMR spectrum of natural cryptolatifolione and synthetic epimers 17 and 23 made possible the unequivocal assignment of the 1,3-syn relationship in the natural product (Fig. 1). The [α]D value of synthetic 23 (+93, c 1.4, CHCl3) is in good agreement with the reported for the natural compound [α]D (c 1.4, CHCl3) = +97.8.


image file: c5ra09186a-f1.tif
Fig. 1 Comparison of 13C NMR data (Δδ) of natural cryptolatifolione and synthetic epimers 17 and 23.

Conclusions

In summary, we developed the first total synthesis of cryptolatifolione (23) in 8 steps and 10% overall yield, and its epimer at C-8 in 6 steps and 17% overall yield. The syntheses feature construction of four C–C bonds by catalytic methods, and use of a C–H oxidation to install the carbonyl group in a protecting-group-free fashion.

Experimental section

General

Starting materials and reagents were obtained from commercial sources and used as received unless otherwise specified. Dichloromethane, triethylamine and N,N-diisopropylethylamine were treated with calcium hydride and distilled before use. Tetrahydrofuran and 1,4-dioxane were treated with metallic sodium and benzophenone and distilled before use. Anhydrous dimethylformamide and pyridine were obtained from Aldrich. Anhydrous reactions were carried out with continuous stirring under atmosphere of dry nitrogen. Progress of the reactions was monitored by thin-layer chromatography (TLC) analysis (Merck, silica gel 60 F254 on aluminum plates). 1H NMR and 13C NMR were recorded on Bruker 250, 500 or 600, the chemical shifts (δ) were reported in parts per million (ppm) relative to deuterated solvent as the internal standard (CDCl3 7.26 ppm, 77.0 ppm), coupling constants (J) are in hertz (Hz). Mass spectra were recorded on a Waters Xevo Q-Tof apparatus operating in electrospray mode (ES). Infrared spectra with Fourier transform (FTIR) were recorded on a Thermo Scientific Nicolet iS5, the principle absorptions are listed in cm−1. The values of optical rotation were measured at 25 °C in a polarimeter Perkin-Elmer 341, with sodium lamp, the measure is described as follow [α]DT (c (g/100 mL), solvent). IUPAC names of the compounds were generated using ChemBioDraw Ultra 13.0. HPLC analyses were carried out using Waters 2695 Alliance® equipment, all experiments were realized at room temperature with a photodiode array detector. GC analyses were performed on Agilent 6890 Series instrument equipped with FID detector. NMR spectra were processed using ACD/NMR Processor Academic Edition version 12.01.
(4R,6R)-Nona-1,8-diene-4,6-diol (2). A pressure tube was charged with [Ir(cod)Cl2] (104 mg, 0.15 mmol, 5 mol%), Cs2CO3 (393 mg, 1.20 mmol, 40 mol%), 4-chloro-3-nitrobenzoic acid (121 mg, 0.60 mmol, 20 mol%) and (R)-BINAP (189 mg, 0.30 mmol, 10 mol%). The tube was purged with nitrogen, and dry 1,4-dioxane (15 mL) was added followed by allyl acetate (3.3 mL, 30 mmol, 10 eq.), the pressure tube was sealed and heated at 90 °C for 30 min. The mixture was cooled to rt, then a solution of 1,3-propanediol (231 mg, 3.00 mmol, 1 eq.) in 1,4-dioxane (15 mL) was added to the reaction, which was heated at 90 °C for 3.5 days. The solvent was evaporated in vacuo, and the brown residue was subjected to flash chromatography (SiO2, hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc, 75[thin space (1/6-em)]:[thin space (1/6-em)]25 to 60[thin space (1/6-em)]:[thin space (1/6-em)]40) to give the diol 2 (281 mg, 1.80 mmol) as an yellowish oil in 60% yield. TLC (SiO2): Rf = 0.30 (hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc 60[thin space (1/6-em)]:[thin space (1/6-em)]40). [α]D25 = −30 (c 1.0, CHCl3), for ent-diol: [α]D,lit = +35 (c 1.0, CHCl3).22 1H NMR (250 MHz, CDCl3): δ 5.79 (ddt, J = 17.7, 9.8, 7.1 Hz, 2H), 5.16–5.02 (m, 4H), 3.97 (quint., J = 5.8 Hz, 2H), 3.06 (br. s, 2H), 2.25 (t, J = 6.6 Hz, 4H), 1.61 (t, J = 5.8 Hz, 2H). 13C NMR (62.9 MHz, CDCl3): δ 134.8 (2CH), 118.1 (2CH2), 68.2 (2CH), 42.1 (2CH2), 41.6 (CH2). d.r. > 20[thin space (1/6-em)]:[thin space (1/6-em)]1, e.e. > 99%.
(4R,6R)-6-((4-Methoxybenzyl)oxy)nona-1,8-dien-4-ol (3). NaH (42 mg, 1.1 mmol, 1.1 eq., 60% in mineral oil) and TBAI (36 mg, 0.096 mmol, 0.1 eq.) were added to a solution of diol 2 (150 mg, 0.96 mmol, 1 eq.) in dry DMF (5 mL) at rt. After 10 min, PMBCl (146 μL, 1.1 mmol, 1.1 eq.) was added, and the reaction was stirred for 18 h. Water (50 mL) was added to the reaction, and the mixture was extracted with ether (3 × 50 mL), then the organic phases were combined, dried (MgSO4), and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2, hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc, 75[thin space (1/6-em)]:[thin space (1/6-em)]25) to give the alcohol 3 (188 mg, 0.68 mmol) as a colorless oil in 71% yield. TLC (SiO2): Rf = 0.43 (hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc 75[thin space (1/6-em)]:[thin space (1/6-em)]25). [α]D25 = −52 (c 1.0, CHCl3). 1H NMR (250 MHz, CDCl3): δ 7.31–7.22 (m, 2H), 6.91–6.83 (m, 2H), 5.82 (ddt, J = 17.7, 9.7, 7.1 Hz, 1H), 5.80 (ddt, J = 17.2, 9.9, 7.1 Hz, 1H), 5.16–5.02 (m, 4H), 4.57 (d, J = 11.1 Hz, 1H), 4.44 (d, J = 11.1 Hz, 1H), 3.93 (quint., J = 5.9 Hz, 1H), 3.83–3.71 (m, 1H), 3.79 (s, 3H), 2.58 (br. s, 1H), 2.52–2.28 (m, 2H), 2.25–2.15 (m, 2H), 1.69–1.60 (m, 2H). 13C NMR (62.9 MHz, CDCl3): δ 159.4 (C), 135.1 (CH), 134.6 (CH), 130.5 (C), 129.6 (2CH), 117.7 (CH2), 117.5 (CH2), 114.0 (2CH), 75.9 (CH), 71.1 (CH2), 67.7 (CH), 55.4 (CH3), 42.3 (CH2), 39.8 (CH2), 38.2 (CH2). IR (NaCl, film): 3441 (broad), 2916, 1514, 1248, 1071, 1036, 914, 820 cm−1. HRMS: (ESI) calculated for C17H24O3Na [M + Na]+: 299.1618, found: 299.1628.
(4R,6R)-6-((4-Methoxybenzyl)oxy)nona-1,8-dien-4-yl acrylate (4). DIPEA (50 μL, 0.28 mmol, 3 eq.) was added to a solution of alcohol 3 (26 mg, 0.094 mmol, 1 eq.) in dry CH2Cl2 (7 mL) at 0 °C. After 5 min, acryloyl chloride (16 μL, 0.19 mmol, 2 eq.) was added, and the reaction was stirred for 2 h. Brine (10 mL) was added to the reaction, and the mixture was extracted with CH2Cl2 (2 × 20 mL), then the organic phases were combined, dried (MgSO4), and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2, hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc, 90[thin space (1/6-em)]:[thin space (1/6-em)]10) to give the acrylate 4 (29 mg, 0.088 mmol) as a colorless oil in 93% yield. TLC (SiO2): Rf = 0.30 (hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc 90[thin space (1/6-em)]:[thin space (1/6-em)]10). [α]D25 = −88 (c 1.0, CHCl3). 1H NMR (250 MHz, CDCl3): δ 7.32–7.22 (m, 2H), 6.90–6.82 (m, 2H), 6.39 (dd, J = 17.2, 1.4 Hz, 1H), 6.10 (dd, J = 17.2, 10.3 Hz, 1H), 5.92–5.66 (m, 3H), 5.29 (quint., J = 6.3 Hz, 1H), 5.17–5.01 (m, 4H), 4.50 (d, J = 10.6 Hz, 1H), 4.32 (d, J = 10.6 Hz, 1H), 3.79 (s, 3H), 3.54–3.42 (m, 1H), 2.44–2.26 (m, 4H), 1.78–1.69 (m, 2H). 13C NMR (62.9 MHz, CDCl3): δ 165.8 (C), 159.3 (C), 134.4 (CH), 133.6 (CH), 130.6 (C), 130.5 (CH2), 129.8 (2CH), 128.9 (CH), 118.0 (CH2), 117.6 (CH2), 113.9 (2CH), 74.6 (CH), 71.3 (CH2), 70.7 (CH), 55.4 (CH3), 39.5 (CH2), 38.9 (CH2), 38.5 (CH2). IR (NaCl, film): 2917, 1720, 1636, 1514, 1405, 1193, 1037, 990 cm−1. HRMS: (ESI) calculated for C20H26O4Na [M + Na]+: 353.1723, found: 325.1724.
(1R,6R)-6-((4-Methoxybenzyl)oxy)cyclohept-3-en-1-yl acrylate (5). Grubbs' catalyst 1st generation (7.0 mg, 8.2 μmol, 10 mol%) was added to a solution of acrylate 4 (27.1 mg, 82 μmol, 1 eq.) in CH2Cl2 (16 mL) at 40 °C. After 90 min, the solvent was removed in vacuo, and the residue was subjected to flash chromatography (SiO2, hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc, 90[thin space (1/6-em)]:[thin space (1/6-em)]10) to give the acrylate 5 (22.7 mg, 75 μmol) as a brownish oil in 92% yield. TLC (SiO2): Rf = 0.20 (hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc 90[thin space (1/6-em)]:[thin space (1/6-em)]10). [α]D25 = −30 (c 1.0, CHCl3). 1H NMR (250 MHz, CDCl3): δ 7.30–7.22 (m, 2H), 6.90–6.82 (m, 2H), 6.37 (dd, J = 17.4, 1.7 Hz, 1H), 6.08 (dd, J = 17.2, 10.3 Hz, 1H), 5.85–5.65 (m, 3H), 5.18 (tt, J = 7.7, 3.8 Hz, 1H), 4.47 (s, 2H), 3.79 (s, 3H), 3.74–3.65 (m, 1H), 2.50–2.37 (m, 4H), 2.25–2.12 (m, 2H). 13C NMR (62.9 MHz, CDCl3): δ 165.5 (C), 159.2 (C), 130.8 (C), 130.5 (CH2), 129.3 (2CH), 129.0 (CH), 128.6 (CH), 127.1 (CH), 113.9 (2CH), 72.1 (CH), 69.9 (CH2), 69.3 (CH), 55.4 (CH3), 41.4 (CH2), 33.7 (CH2), 33.3 (CH2). IR (NaCl, film): 2935, 1719, 1513, 1195, 1076, 1048, 754 cm−1. HRMS: (ESI) calculated for C18H22O4Na [M + Na]+: 325.1410, found: 325.1410.
(4R,6R)-6-(Allyloxy)nona-1,8-dien-4-ol (7). NaH (360 mg, 9 mmol, 2 eq., 60% in mineral oil) was added to a solution of diol 2 (703 mg, 4.5 mmol, 1 eq.) in dry DMF (20 mL) at rt. After 10 min, allyl bromide (482 μL, 5.4 mmol, 1.2 eq.) was added, and the reaction was stirred for 30 min. Water (100 mL) was added to the reaction, and the mixture was extracted with ether (3 × 50 mL), then the organic phases were combined, dried (MgSO4), and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2, hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc, 90[thin space (1/6-em)]:[thin space (1/6-em)]10 to 75[thin space (1/6-em)]:[thin space (1/6-em)]25) to give the alcohol 7 (662 mg, 3.4 mmol) as a colorless oil in 75% yield. TLC (SiO2): Rf = 0.50 (hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc 75[thin space (1/6-em)]:[thin space (1/6-em)]25). [α]D25 = −46 (c 1.0, CHCl3). 1H NMR (250 MHz, CDCl3): δ 5.96–5.66 (m, 3H), 5.28–5.00 (m, 6H), 4.07 (ddt, J = 12.6, 5.5, 1.4 Hz, 1H), 3.96 (ddt, J = 12.6, 5.7, 1.3 Hz, 1H), 3.96–3.94 (m, 1H), 3.72–3.63 (m, 1H), 2.75 (br. s, 1H), 2.45–2.15 (m, 4H), 1.63–1.56 (m, 2H). 13C NMR (62.9 MHz, CDCl3): δ 135.0 (CH), 134.9 (CH), 134.4 (CH), 117.6 (CH2), 117.4 (CH2), 116.9 (CH2), 76.3 (CH), 70.3 (CH2), 67.6 (CH), 42.3 (CH2), 39.7 (CH2), 38.2 (CH2). IR (NaCl, film): 3388 (broad), 2978, 2918, 1073, 995, 914 cm−1. HRMS: (ESI) calculated for C12H20O2Na [M + Na]+: 219.1356, found: 219.1368.
(4R,6R)-6-(Allyloxy)nona-1,8-dien-4-yl acetate (8). Triethylamine (619 μL, 4.4 mmol, 5 eq.) and DMAP (22 mg, 0.18 mmol, 0.2 eq.) were added to a solution of alcohol 7 (173 mg, 0.88 mmol, 1 eq.) in dry CH2Cl2 (15 mL) at 0 °C. After 5 min, acetic anhydride (214 μL, 2.2 mmol, 2.5 eq.) was added, and the reaction was stirred for 2 h. Brine (20 mL) was added to the reaction, and the mixture was extracted with CH2Cl2 (2 × 20 mL), then the organic phases were combined, dried (Na2SO4), and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2, hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc, 90[thin space (1/6-em)]:[thin space (1/6-em)]10) to give acetate 8 (172 mg, 0.72 mmol) as a colorless oil in 82% yield. TLC (SiO2): Rf = 0.41 (hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc 90[thin space (1/6-em)]:[thin space (1/6-em)]10). [α]D25 = −75 (c 1.0, CHCl3). 1H NMR (250 MHz, CDCl3): δ 5.96–5.64 (m, 3H), 5.28–4.98 (m, 7H), 4.03 (dd, J = 12.3, 5.5 Hz, 1H), 3.87 (dd, J = 12.3, 6.0 Hz, 1H), 3.38 (quint., J = 5.7 Hz, 1H), 2.38–2.20 (m, 4H), 2.01 (s, 3H), 1.70–1.60 (m, 2H). 13C NMR (62.9 MHz, CDCl3): δ 170.5 (C), 135.1 (CH), 134.2 (CH), 133.5 (CH), 117.8 (CH2), 117.4 (CH2), 116.9 (CH2), 74.7 (CH), 70.5 (CH2), 70.3 (CH), 39.3 (CH2), 38.6 (CH2), 38.5 (CH2), 21.2 (CH3). IR (NaCl, film): 2917, 2849, 1739, 1374, 1238, 1081, 917 cm−1. HRMS: (ESI) calculated for C14H22O3Na [M + Na]+: 261.1461, found: 261.1464.
(R)-1-((R)-3,6-Dihydro-2H-pyran-2-yl)pent-4-en-2-yl acetate (9). Grubbs' catalyst 2nd generation (5 mg, 6 μmol, 1 mol%) was added to a solution of allyl ether 8 (143 mg, 0.60 mmol, 1 eq.) in CH2Cl2 (120 mL) at 40 °C. After 60 min, the solvent was removed in vacuo, and the residue was subjected to flash chromatography (SiO2, hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc, 90[thin space (1/6-em)]:[thin space (1/6-em)]10) to give the dihydropyran 9 (108 mg, 0.51 mmol) as a brownish oil in 85% yield. TLC (SiO2): Rf = 0.37 (hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc 90[thin space (1/6-em)]:[thin space (1/6-em)]10). [α]D25 = −5 (c 1.0, CHCl3). 1H NMR (250 MHz, CDCl3): δ 5.85–5.67 (m, 3H), 5.26–5.03 (m, 3H), 4.23–4.03 (m, 2H), 3.48 (tt, J = 8.8, 4.1 Hz, 1H), 2.40–2.25 (m, 2H), 2.10–1.90 (m, 2H), 2.03 (s, 3H), 1.75–1.65 (m, 2H). 13C NMR (62.9 MHz, CDCl3): δ 170.6 (C), 133.5 (CH), 126.5 (CH), 124.0 (CH), 117.8 (CH2), 70.2 (CH), 70.1 (CH), 65.9 (CH2),40.1 (CH2), 39.3 (CH2), 31.3 (CH2), 21.2 (CH3). IR (NaCl, film): 2917, 1738, 1383, 1241, 1091, 918 cm−1. HRMS: (ESI) calculated for C12H18O3Na [M + Na]+: 233.1148, found: 233.1168.
(R)-1-((R)-6-Oxo-3,6-dihydro-2H-pyran-2-yl)pent-4-en-2-yl acetate (16). PCC (291 mg, 1.35 mmol, 3 eq.) and pyridine (219 μL, 2.7 mmol, 6 eq.) were added to a solution of dihydropyran 9 (94.6 mg, 0.45 mmol, 1 eq.) in CH2Cl2 (20 mL) at 40 °C. After 12 h, a second portion of PCC (291 mg, 1.35 mmol, 3 eq.) was added to the mixture. After a second period of 12 h, the mixture was filtered through a double layered plug containing celite and silica, the plug was flushed with EtOAc. The solvent was removed in vacuo, and the residue was subjected to flash chromatography (SiO2, hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc, 75[thin space (1/6-em)]:[thin space (1/6-em)]25) to give the dihydropyranone 16 (62 mg, 0.28 mmol) as a colorless oil in 61% yield. TLC (SiO2): Rf = 0.15 (hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc 75[thin space (1/6-em)]:[thin space (1/6-em)]25). [α]D25 = +22 (c 1.0, CHCl3). 1H NMR (250 MHz, CDCl3): δ 6.86 (dt, J = 9.6, 4.1 Hz, 1H), 6.02 (dt, J = 9.9, 1.7 Hz, 1H), 5.74 (ddt, J = 17.4, 9.8, 7.1 Hz, 1H), 5.23–5.05 (m, 3H), 4.56–4.44 (m, 1H), 2.42–2.28 (m, 4H), 2.10–1.98 (m, 1H), 2.04 (s, 3H), 1.85 (ddd, J = 14.8, 9.2, 3.6 Hz, 1H). 13C NMR (62.9 MHz, CDCl3): δ 170.2 (C), 163.7 (C), 144.7 (CH), 132.8 (CH), 121.3 (CH), 118.3 (CH2), 74.5 (CH), 69.4 (CH), 38.8 (2CH2), 29.5 (CH2), 21.0 (CH3). IR (NaCl, film): 2919, 1727, 1384, 1237, 1040, 819 cm−1. HRMS: (ESI) calculated for C12H16O4Na [M + Na]+: 247.0941, found: 247.0935.
8-epi-Cryptolatifolione (17). Grubbs' catalyst 2nd generation (7.6 mg, 9 μmol, 10 mol%) was added to a solution of alkene 16 (20.2 mg, 90 μmol, 1 eq.) and trans-3-hexene (192 μL, 1.53 mmol, 17 eq.) in CH2Cl2 (0.9 mL) at rt. After 1 h, the solvent was removed in vacuo, and the residue was subjected to flash chromatography (SiO2, hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc, 75[thin space (1/6-em)]:[thin space (1/6-em)]25) to give 7-epi-cryptolatifolione (17, 19.8 mg, 78 μmol) as a colorless oil in 87% yield. TLC (SiO2): Rf = 0.20 (hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc 75[thin space (1/6-em)]:[thin space (1/6-em)]25). [α]D25 = +21 (c 1.4, CHCl3). 1H NMR (600 MHz, CDCl3): δ 6.85 (ddd, J = 9.8, 5.3, 3.2 Hz, 1H), 6.00 (ddd, J = 9.8, 2.1, 1.3 Hz, 1H), 5.55–5.49 (m, 1H), 5.34–5.28 (m, 1H), 5.12–5.07 (m, 1H), 4.50–4.44 (m, 1H), 2.36–2.27 (m, 4H), 2.06–1.96 (m, 2H), 2.02 (s, 3H), 1.82 (ddd, J = 14.9, 9.4, 3.8 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (62.9 MHz, CDCl3): δ 170.3 (C), 163.9 (C), 144.7 (CH), 136.2 (CH), 123.0 (CH), 121.5 (CH), 74.7 (CH), 70.1 (CH), 38.9 (CH2), 37.7 (CH2), 29.6 (CH2), 25.6 (CH2), 21.1 (CH3), 13.7 (CH3). IR (NaCl, film): 2963, 2923, 1737, 1383, 1240, 1041, 820 cm−1. HRMS: (ESI) calculated for C14H20O4Na [M + Na]+: 275.1254, found: 275.1261.
(R)-6-(Allyloxy)nona-1,8-dien-4-one (18). Dess–Martin periodinane (267 mg, 0.61 mmol, 1 eq.) was added to a solution of alcohol 7 (120 mg, 0.61 mmol, 1 eq.) in CH2Cl2 (6 mL) at 0 °C. The reaction was stirred at 0 °C for 2 h, then solvent was removed in vacuo, and the residue was subjected to flash chromatography (SiO2, hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc, 95[thin space (1/6-em)]:[thin space (1/6-em)]5) to give ketone 18 (107 mg, 0.55 mmol) as a colorless oil in 90% yield. TLC (SiO2): Rf = 0.35 (hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc 90[thin space (1/6-em)]:[thin space (1/6-em)]10). [α]D25 = −52 (c 1.0, CHCl3). 1H NMR (250 MHz, CDCl3): δ 5.99–5.68 (m, 3H), 5.27–5.03 (m, 6H), 4.08–3.86 (m, 3H), 3.19 (d, J = 7.0 Hz, 2H), 2.69 (dd, J = 16.3, 7.7 Hz, 1H), 2.49 (d, J = 16.1, 4.7 Hz, 1H), 2.39–2.19 (m, 2H). 13C NMR (62.9 MHz, CDCl3): δ 207.2 (C), 134.8 (CH), 133.9 (CH), 130.3 (CH), 118.9 (CH2), 117.8 (CH2), 116.8 (CH2), 74.6 (CH), 70.4 (CH2), 48.7 (CH2), 46.7 (CH2), 38.4 (CH2). IR (NaCl, film): 3079, 2980, 2916, 1716, 1641, 1076, 919 cm−1. HRMS: (ESI) calculated for C12H18O2Na [M + Na]+: 217.1199, found: 217.1207.
(4S,6R)-6-(Allyloxy)nona-1,8-dien-4-ol (19). A solution of L-selectride in THF (1 M, 1.6 mL, 1.6 mmol, 3 eq.) was added to a solution of ketone 18 (103 mg, 0.53 mmol, 1 eq.) in THF (11 mL) at −78 °C and the mixture was stirred for 3 h at the same temperature. An aqueous solution of HCl (1 M, 20 mL) was added and the mixture was extracted with EtOAc (2 × 20 mL). The organic phases were combined, dried (Na2SO4), and concentrated. The residue was subjected to flash chromatography (SiO2, hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc, 90[thin space (1/6-em)]:[thin space (1/6-em)]10) to give alcohol 19 (74 mg, 0.38 mmol) as a colorless oil in 71% yield. The purified product contains the minor diastereoisomer 7. TLC (SiO2): Rf = 0.50 (hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc 75[thin space (1/6-em)]:[thin space (1/6-em)]25). [α]D25 = −56 (c 1.0, CHCl3). Major isomer: 1H NMR (250 MHz, CDCl3): δ 5.97–5.65 (m, 3H), 5.29–5.00 (m, 6H), 4.18–4.05 (m, 1H), 4.02–3.76 (m, 2H), 3.71–3.59 (m, 1H), 3.16 (br. s, 1H), 2.41–2.13 (m, 4H), 1.68–1.53 (m, 2H). Major isomer: 13C NMR (62.9 MHz, CDCl3): δ 134.8 (CH), 134.3 (CH), 133.7 (CH), 117.6 (CH2), 117.25 (CH2), 117.20 (CH2), 79.1 (CH), 70.8 (CH), 69.6 (CH2), 42.0 (CH2), 40.0 (CH2), 38.0 (CH2). IR (NaCl, film): 3426 (broad), 3077, 2921, 2859, 1641, 1074, 996, 915 cm−1. HRMS: (ESI) calculated for C12H20O2Na [M + Na]+: 219.1356, found: 219.1355. d.r. = 79[thin space (1/6-em)]:[thin space (1/6-em)]21.
(4S,6R)-6-(Allyloxy)nona-1,8-dien-4-yl acetate (20). Triethylamine (239 μL, 1.7 mmol, 5 eq.) and DMAP (8.4 mg, 69 μmol, 0.2 eq.) were added to a solution of alcohol 19 (66.7 mg, 0.34 mmol, 1 eq.) in dry CH2Cl2 (16 mL) at 0 °C. After 5 min, acetic anhydride (83 μL, 0.85 mmol, 2.5 eq.) was added, and the reaction was stirred for 2 h. Brine (20 mL) was added to the reaction, and the mixture was extracted with CH2Cl2 (2 × 20 mL), then the organic phases were combined, dried (Na2SO4), and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2, hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc, 90[thin space (1/6-em)]:[thin space (1/6-em)]10) to give acetate 20 (68.7 mg, 0.29 mmol) as a colorless oil in 85% yield. The purified product contains the minor diastereoisomer 8. TLC (SiO2): Rf = 0.41 (hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc 90[thin space (1/6-em)]:[thin space (1/6-em)]10). [α]D25 = −14 (c 1.0, CHCl3). Major isomer: 1H NMR (250 MHz, CDCl3): δ 5.96–5.62 (m, 3H), 5.28–5.00 (m, 7H), 4.07–3.82 (m, 2H), 3.42 (quint., J = 6.0 Hz, 1H), 2.36–2.20 (m, 4H), 1.99 (s, 3H), 1.88–1.61 (m, 2H).

Major isomer: 13C NMR (62.9 MHz, CDCl3): δ 170.4 (C), 135.0 (CH), 134.1 (CH), 133.4 (CH), 117.8 (CH2), 117.3 (CH2), 116.6 (CH2), 75.4 (CH), 70.7 (CH), 69.5 (CH2), 38.8 (CH2), 37.8 (CH2), 37.5 (CH2), 21.1 (CH3). IR (NaCl, film): 3079, 2979, 2921, 1738, 1384, 1239, 1079, 917 cm−1. HRMS: (ESI) calculated for C14H22O3Na [M + Na]+: 261.1461, found: 261.1466.

(S)-1-((R)-3,6-Dihydro-2H-pyran-2-yl)pent-4-en-2-yl acetate (21). Grubbs' catalyst 2nd generation (2.4 mg, 2.8 μmol, 1 mol%) was added to a solution of allyl ether 20 (66.7 mg, 0.28 mmol, 1 eq.) in CH2Cl2 (30 mL) at 40 °C. After 30 min, the solvent was removed in vacuo, and the residue was subjected to flash chromatography (SiO2, hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc, 90[thin space (1/6-em)]:[thin space (1/6-em)]10) to give the dihydropyran 21 (49 mg, 0.23 mmol) as a brownish oil in 83% yield. The purified product contains the minor diastereoisomer 9. TLC (SiO2): Rf = 0.37 (hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc 90[thin space (1/6-em)]:[thin space (1/6-em)]10). [α]D25 = +65 (c 1.0, CHCl3). Major isomer: 1H NMR (250 MHz, CDCl3): δ 5.83–5.64 (m, 3H), 5.20–5.01 (m, 3H), 4.15–4.08 (m, 2H), 3.64–3.42 (m, 1H), 2.40–2.25 (m, 2H), 2.05–1.80 (m, 3H), 2.00 (s, 3H), 1.72–1.58 (m, 1H). Major isomer: 13C NMR (62.9 MHz, CDCl3): δ 170.6 (C), 133.5 (CH), 126.2 (CH), 123.8 (CH), 117.8 (CH2), 70.7 (CH), 70.5 (CH), 65.6 (CH2), 39.6 (CH2), 38.7 (CH2), 30.9 (CH2), 21.2 (CH3). IR (NaCl, film): 2921, 1735, 1384, 1242, 1090, 1023, 918 cm−1. HRMS: (ESI) calculated for C12H18O3Na [M + Na]+: 233.1148, found: 233.1147.
(S)-1-((R)-6-Oxo-3,6-dihydro-2H-pyran-2-yl)pent-4-en-2-yl acetate (22). PCC (149 mg, 0.69 mmol, 3 eq.) and pyridine (112 μL, 1.38 mmol, 6 eq.) were added to a solution of dihydropyran 21 (48.4 mg, 0.23 mmol, 1 eq.) in CH2Cl2 (10 mL) at 40 °C. After 12 h, a second portion of PCC (149 mg, 0.69 mmol, 3 eq.) was added to the mixture. After a second period of 12 h, the mixture was filtered through a double layered plug containing celite and silica, the plug was flushed with EtOAc. Solvent was removed in vacuo, and the residue was subjected to flash chromatography (SiO2, hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc, 75[thin space (1/6-em)]:[thin space (1/6-em)]25) to give the dihydropyranone 22 (31 mg, 0.14 mmol) as a colorless oil in 60% yield. The purified product contains a single diastereoisomer. TLC (SiO2): Rf = 0.18 (hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc 75[thin space (1/6-em)]:[thin space (1/6-em)]25). [α]D25 = +89 (c 0.56, CHCl3). 1H NMR (500 MHz, CDCl3): δ 6.86 (ddd, J = 9.8, 6.1, 2.4 Hz, 1H), 6.02 (dd, J = 9.6, 1.8 Hz, 1H), 5.73 (ddt, J = 17.1, 10.2, 7.0 Hz, 1H), 5.14–5.06 (m, 3H), 4.53–4.45 (m, 1H), 2.51–2.43 (m, 1H), 2.40–2.35 (m, 2H), 2.34–2.25 (m, 1H), 2.16 (ddd, J = 14.8, 9.0, 6.1 Hz, 1H), 2.06 (s, 3H), 1.89 (ddd, J = 14.5, 7.2, 3.8 Hz, 1H). 13C NMR (62.9 MHz, CDCl3): δ 170.7 (C), 163.9 (C), 144.7 (CH), 132.8 (CH), 121.4 (CH), 118.5 (CH2), 75.0 (CH), 69.5 (CH), 38.8 (CH2), 38.7 (CH2), 29.1 (CH2), 21.1 (CH3). IR (NaCl, film): 2957, 2917, 1733, 1384, 1239, 1041 cm−1. HRMS: (ESI) calculated for C12H16O4Na [M + Na]+: 247.0941, found: 247.0946.
Cryptolatifolione (23). Grubbs' catalyst 2nd generation (8.1 mg, 9.5 μmol, 10 mol%) was added to a solution of alkene 22 (21.3 mg, 95 μmol, 1 eq.) and trans-3-hexene (203 μL, 1.62 mmol, 17 eq.) in CH2Cl2 (1.4 mL) at rt. After 1 h, the solvent was removed in vacuo, and the residue was subjected to flash chromatography (SiO2, hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc, 75[thin space (1/6-em)]:[thin space (1/6-em)]25) to give cryptolatifolione (23, 19.4 mg, 77 μmol) as a colorless oil in 81% yield. TLC (SiO2): Rf = 0.61 (hexanes[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc 50[thin space (1/6-em)]:[thin space (1/6-em)]50). [α]D25 = +93 (c 1.4, CHCl3). 1H NMR (500 MHz, CDCl3): δ 6.85 (ddd, J = 9.8, 6.1, 2.1 Hz, 1H), 6.00 (dd, J = 9.6, 2.1 Hz, 1H), 5.58–5.50 (m, 1H), 5.35–5.27 (m, 1H), 5.06–4.99 (m, 1H), 4.51–4.44 (m, 1H), 2.51–2.43 (m, 1H), 2.33–2.23 (m, 3H), 2.13 (ddd, J = 14.8, 9.3, 6.0 Hz, 1H), 2.04 (s, 3H), 2.00 (quint., J = 7.2 Hz, 2H), 1.88 (ddd, J = 14.5, 7.3, 3.7 Hz, 1H), 0.95 (t, J = 7.5 Hz, 3H). 13C NMR (62.9 MHz, CDCl3): δ 170.7 (C), 164.0 (C), 144.7 (CH), 136.4 (CH), 122.9 (CH), 121.4 (CH), 75.2 (CH), 70.0 (CH), 38.7 (CH2), 37.7 (CH2), 29.1 (CH2), 25.6 (CH2), 21.1 (CH3), 13.7 (CH3). IR (NaCl, film): 2963, 2932, 1734, 1384, 1241, 1039, 970, 821 cm−1. HRMS: (ESI) calculated for C14H21O4 [M + H]+: 253.1434, found: 253.1434.

Acknowledgements

The authors thank Dr Rodrigo V. Pirovani and Dr Carolina M. Avila for helpful discussions, and Prof. Dr Marcos N. Eberlin, Prof. Dr Fábio C. Gozzo and Hugo C. R. de Jesus for HRMS analyses. This work was made possible by grants from FAPESP (proc. #09/51602-5) and CNPq (L.F.T.N., proc. #131015/2014-1).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of 1H and 13C NMR spectra of products, HPLC, GC chromatograms and computational methods. See DOI: 10.1039/c5ra09186a
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