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Total Synthesis of (+)-Iresin Bian-Lin Wang, Hai-Tao Gao, and Wei-Dong Z. Li J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00365 • Publication Date (Web): 23 Apr 2015 Downloaded from http://pubs.acs.org on April 25, 2015

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Total Synthesis of (+)-Iresin † Bian-Lin Wang, a Hai-Tao Gao, a and Wei-Dong Z. Lia, b, * a

State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou

730000, P. R. China b

Innovative Drug Research Centre, Chongqing University, Chongqing 401331, P. R.

China E-mail: [emailprotected] * Fax / Phone: 0086-(0)23-65678459

ABSTRACT: The first asymmetric total synthesis of (+)-iresin (4), a historically important ent-Drimane sesquiterpene lactone, was realized from aldehyde 3 via cyclic orthoester 6 in 5 steps. Notable transformations in this synthesis include a tandem trifluoroperacetic

acid

(TFPAA)-mediated

Baeyer−Villiger

oxidation−olefin

epoxidation−epoxy ester cyclization, regioselective Burgess dehydration, and regioselective Fétizon oxidative lactonization. Keywords: Homoiodo allylsilane, (+)-Iresin, Burgess reagent, Fétizon reagent, Total synthesis † In memory of Carl Djerassi

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Drimane (known also as Iresane) sesquiterpenoids constitute a group of widely occurring terpene natural products possessing a characteristic bicyclofarnesol skeleton (Figure 1).1 Thus, the Drimane was once regarded as the missing biogenetic link between the lower and higher terpenoids.2 Oxygenated Drimane sesquiterpenoids exhibit a wide range of significant biological activities,1,

3

such as antifeedant,

insecticidal, and cytotoxic, have stimulated a great deal of attention on synthetic development.4 (+)-Iresin (4), a unique ent-Drimane sesquiterpene lactone, was first isolated by Djerassi and co-workers5 in 1954 from the Mexican herb plant Iresine celosioides (known as “herb of the mayas”) and characterized6 in 1958 by extensive chemical, spectroscopic methods, and X-ray crystallographic study as the tricyclic dihydroxy lactone 4. Full NMR spectroscopic assignments of 4 appeared in 2005.7 The sole documented classical synthetic study on 4 by Pelletier and Prabhakar8 in 1968 led to the total synthesis of isoiresin in a racemic form. O HO

I

O

CHO PMBO

ref. 9 SiR3 HO

O O O

2

HO

3

( )-Andrographolide (1) this work

OH

O O HO HO Drimane

(+)-Iresin (4)

( )-Drimenol

Figure 1. Structure of (+)-iresin and previous total synthesis of (−)-andrographolide (1) from homoiodo allylsilane epoxide 2 via aldehyde intermediate 3

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In a previous publication of this serial study,9 we have reported the total synthesis of (−)-andrographolide (1) from an homoiodo allylsilane epoxide 2 by a conformationally directed biomimetic cationic cyclization to form aldehyde 3 as a pivotal intermediate (Figure 1). We describe in this Note the first asymmetric total synthesis of (+)-iresin (4) from the same intermediate 3. The conversion of aldehyde 3 to lactone 4 requires the elaboration of an unsaturated γ-lactone function which would be achieved via oxidative cleavage of the formyl carbon and regioselective olefin formation and subsequent lactonization. The synthetic route to 4 commenced with aldehyde 3 is outlined in Schemes 1 and 2. To facilitate the Baeyer−Villiger oxidation,10 3 was converted to the corresponding methyl ketone derivative 5 via a standard methylation−oxidation procedure. After screening of peroxy acids, freshly prepared trifluoroperacetic acid (TFPAA, ca. 0.2 M) was found to be the optimal oxidant in the presence of excess Na2HPO4 in CH2Cl2 at 0 °C. Keto olefin 5 was thus transformed to the cyclic orthoester 611 as the major product (53%), along with the corresponding hydrolytic product monoacetates 7a and 7b (17%).11a,

e

The stereostructure of 6 was confirmed by a single crystal X-ray

diffraction analysis.12 It is worthwhile to note that not only the Baeyer−Villiger oxygenation of the keto function occurred smoothly, but also the olefin epoxidation and subsequent epoxide-opening−cyclization took place leading to the cyclic orthoester 6. The acetonide function of 5 was also unexpectedly cleaved under these reaction conditions. The unusual one-pot formation of cyclic orthoester 6 could be understood via the intramolecular rearrangement of an epoxy ester intermediate 5a as depicted in Scheme 1, based on serial mechanistic studies by Giner et al. 11c−e Acidic hydrolysis of orthoester 6 afforded a product mixture of monoacetates 7a and 7b, 11a, e which was subjected to acetylation to give the tetrakis-acetate 8 in 68% yield from 6 (Scheme 2). Standard dehydration of 8 employing various dehydrating agents (i.e. MsCl, SOCl2, or POCl3) in the presence of pyridine or Et3N led to, after deacetylation, regioisomer 10 predominatedly (2.6∼4.1 : 1) in good yield. In contrast, with Burgess’ reagent (3 eq.),13 dehydration of 8 in warm benzene (50 °C) gave, after deacetylation, the desired regioisomer 9 as the major product (4.8 : 1) in 70% overall yield.14

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With 9 and 10 in hand, we selected the Fétizon’s reagent15 for the final oxidative lactonization (Scheme 2). To our delight, oxidation of 9 with freshly prepared Fétizon reagent in refluxing benzene produced the desired target lactone (+)-iresin (4) chemoselectively in 78% yield, along with aldehyde 11 in 14% yield. Reduction of 11 with NaBH4 at 0 °C in methanol gave (+)-iresin (4) in 86% yield. Synthetic 4 exhibits identical spectroscopic data with those of reported (+)-iresin.5, 6 Further structural confirmation of synthetic 4 was provided by the X-ray crystallographic analysis of the bis-para-bromobenzoate derivative 14.6e, 16 Interestingly, oxidation of 10 with excess Fétizon reagent in refluxing benzene furnished lactone aldehyde 12 chemoselectively in 91% yield, which was reduced with NaBH4 at 0 °C to give lactone 13 in 92% yield. The structure of synthetic 13, known as isoiresin,8, 17 was further confirmed by a single crystal X-ray crystallographic analysis.18

Scheme 1. Synthesis of orthoester 6 from aldehyde 3

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Scheme 2. Total syntheses of (+)-iresin (4) and (−)-isoiresin (13)

CONCLUSION

In summary, the first asymmetric total syntheses of (+)-iresin (4) and (−)-isoiresin (13) were achieved from readily accessible aldehyde 3 in 5 and 6 steps, respectively. Notable transformations include the peroxidation of keto olefin 5 with TFPAA leading to

cyclic

orthoester

6

via

a

tandem

Baeyer−Villiger

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epoxidation−epoxy ester cyclization, regioselective dehydration of 8 with Burgess reagent, as well as the regioselective Fétizon oxidative γ-lactonization of 9 and 10. The biomimetic synthetic approach19 demonstrated here for the ent-Drimanes would be equally effective for other Drimane sesquiterpenoids, i.e. starting from synthetically readily accessible pseudo-antipodal intermediate 15.9

EXPERIMENTAL SECTION

General For product purification by flash column chromatography, silica gel (200~300 mesh) and petroleum ether (bp. 60~90 °C) were used unless otherwise noted. All solvents were purified and dried by standard techniques, and distilled prior to use. Other commercially available reagents were used as received without further purification unless otherwise indicated. All organic extracts were dried over anhydrous sodium sulfate or magnesium sulfate. All moisture-sensitive reactions were carried out under an atmosphere of nitrogen in glassware that had been flame-dried under vacuum. 1H and 13C NMR spectra were recorded on a 400 MHz spectrometer with TMS as an internal reference and CDCl3 as solvent, unless otherwise indicated. IR spectra were recorded on a FT-IR spectrometer as liquid film or KBr pellet. HRMS were acquired on a FT-ICR spectrometer. Melting points were measured on a hot stage and were uncorrected. 1-((4aR,6aS,7R,10aS,10bR)-3,3,6a,10b-tetramethyl-8-methylenedecahydro-1H -naphtho[2,1-d][1,3]dioxin-7-yl)propan-2-one (5). To a stirred solution of aldedyde (1.20 g, 3.92 mmol) in dry Et2O (20 mL) was added 2.5 ml of CH3Li (1.6 M in

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diethylether, 4.0 mmol) dropwise at 0 °C under N2. After being stirred for 10 min, the reaction mixture was quenched with water (2.0 mL). The ethereal layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was used in the next step without further purification. DMSO (610 mg, 7.81 mmol) in CH2Cl2 (4.0 mL) was added dropwise to a solution of oxalic dichloride (0.33 mL, 3.87 mmol) in CH2Cl2 (4.0 mL) at −78 °C under N2. After stirring for 15 min, the solution of crude alcohol in CH2Cl2 (6.0 mL) was added via syringe, and the reaction was stirred an additional 1 h at −78 °C. Et3N (2.2 mL, 15.7 mmol) was added, and the reaction was stirred for 10 min at −78 °C. The bath was removed, the resulting mixture was stirred for 20 min at room temperature. The mixture was partitioned between H2O (15 mL) and CH2Cl2 (30 mL), and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2 × 15 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (petroleum ether/EtOAc = 8:1) to give compound 5 (1.15 g, 92% from 3) as a colorless oil: Rf = 0.51 (petroleum ether/EtOAc = 8:1); [α]20 +20 (c 1.0, CHCl3); IR (film): νmax 3078, D 2936, 2891, 1717, 1644, 1374, 1227, 1095, 885 cm–1; 1H NMR (400 MHz, CDCl3): δ 4.77 (s, 1H), 4.37 (s, 1H), 3.97 (d, J = 11.6 Hz, 1H), 3.50 (dd, J = 8.4, 4.0 Hz, 1H), 3.18 (d, J = 11.6 Hz, 1H), 2.68 (dd, J = 17.2, 10.4 Hz, 1H), 2.45−2.38 (m, 3H), 2.17 (s, 3H), 2.08 (td, J = 12.0, 4.8 Hz, 1H), 2.02−1.96 (m, 1H), 1.81−1.71 (m, 2H), 1.58 (ddd, J = 23.6, 7.6, 5.6 Hz, 1H), 1.41 (s, 3H), 1.37 (s, 3H), 1.35−1.26 (m, 3H), 1.21 (s, 3H), 0.91 (s, 3H) ppm;

13

C NMR (100 MHz, CDCl3): δ 208.3, 148.3, 107.2, 99.0,

76.4, 63.9, 52.0, 51.1, 40.1, 37.8, 37.7, 37.3, 34.4, 30.1, 27.2, 26.1, 25.3, 25.0, 23.0, 16.5 ppm; HRMS (ESI): calcd For C20H33O3 [M+H]+ 321.2424; found 321.2428. (3S,5aR,7aS,8R,9R,11aR,11bR)-8-(hydroxymethyl)-3,8,11a-trimethyldecahydr o-1H-3,5a-epoxynaphtho[1,2-e][1,3]dioxepin-9-ol (6). To a stirred solution of 50 % aq H2O2 (112 mg, 1.65 mmol) in CH2Cl2 (8.0 mL) was added TFAA (0.28 mL, 1.99 mmol) at 0 ºC. After being stirred for 25 min, powdered Na2HPO4 (1.13 g, 7.96 mmol) was added to the mixture, then the solution of 5 (106 mg, 0.33 mmol) in CH2Cl2 (2.0

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ml) was added dropwise over 5 min. After stirring for 25 min at 0 °C, the reaction mixture was quenched with 5 mL of saturated aqueous Na2S2O3. The resulting mixture was extracted with ethyl acetate (3 × 30 mL), and the combined organic extracts were washed with water and brine, dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 1:2 petroleum ether/EtOAc to give 6 as white solids (55 mg, 53%) and the mixture of monoacetate products (7a and 7b, 19 mg, 17%). Compound 6: Rf = 0.39 (petroleum ether/EtOAc = 1 : 2); mp 118−121 °C; [α]20 D +6 (c 1, CHCl3); IR (KBr): νmax 3365, 2938, 2886, 1463, 1402, 1301, 1134, 863 cm–1; 1

H NMR (400 MHz, CDCl3): δ 4.26 (d, J = 11.2 Hz, 1H), 4.03 (dd, J = 12.4, 5.6 Hz,

1H), 3.87 (d, J = 7.2 Hz, 1H), 3.82 (d, J = 12.4 Hz, 1H), 3.43−3.35 (m, 3H), 2.82 (d, J = 7.6 Hz, 1H), 2.73 (s, 1H), 1.92−1.84 (m, 3H), 1.78−1.67 (m, 2H), 1.62 (dd, J = 12.8, 3.2 Hz, 1H), 1.58−1.49 (m, 1H), 1.55 (s, 3H), 1.26 (s, 3H), 1.14 (s, 3H), 0.94−0.89 (m, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 119.7, 80.3, 79.8, 74.8, 63.9, 58.7, 53.7, 50.2, 42.4, 37.4, 36.9, 33.6, 27.2, 22.7, 22.3, 18.5, 16.7 ppm; HRMS (ESI): calcd For C17H28O5 [M+H]+ 313.2010; found 313.2003. X-ray crystallographic data of 6: C17H28O5, triclinic, space group: P1, a = 6.108 (2) Å, b = 7.159 (3) Å, c = 20.206 (7) Å, α = 97.983(18)°, β = 91.80 (2)°, γ = 111.632(18)°, Z = 1, dcalcd = 1.281 g/cm3, R1(I > 2σ(I)) = 0.0451, wR2 = 0.1065. Compound 7a: 1H NMR (400 MHz, CD3OD): δ 4.15 (d, J = 11.2 Hz, 1H), 4.06 (d, J = 11.2 Hz, 1H), 3.95 (d, J = 10.8 Hz, 1H), 3.91 (dd, J = 12.0, 4.0 Hz, 1H), 3.76 (dd, J = 11.6, 2.8 Hz, 1H), 3.40−3.34 (m, 2H), 2.05 (s, 3H, CH3CO), 1.95 (d, J = 12.8 Hz, 1H), 1.85−1.70 (m, 3H), 1.65−1.63 (m, 2H), 1.54−1.49 (m, 1H), 1.21 (s, 3H), 1.45−1.37 (m, 2H), 1.06 (s, 3H), 0.97 (t, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CD3OD): δ 173.0, 81.2, 74.6, 71.8, 65.2, 59.5, 56.5, 56.4, 43.8, 39.0, 38.7, 38.3, 28.4, 23.6, 21.0, 19.0, 17.8 ppm. Compound 7b: 1H NMR (400 MHz, CD3OD): δ 4.25−4.24 (m, 2H), 4.14 (d, J = 11.2 Hz, 1H), 3.43 (d, J = 10.8 Hz, 1H), 3.40−3.34 (m, 2H), 3.20 (d, J = 10.8 Hz, 1H), 2.01 (s, 3H, CH3CO), 1.89 (dt, J = 13.2, 3.2 Hz, 1H), 1.82−1.79 (m, 1H), 1.73−1.63 (m, 6H), 1.40 (t, J = 3.6 Hz, 1H), 1.22 (s, 4H), 0.98 (s, 3H); 13C NMR (100 MHz, CD3OD): δ 173.1, 81.1, 74.7, 69.8, 65.2, 63.0, 56.5, 53.6, 43.8, 39.0, 38.6, 38.1, 28.3, 23.5, 21.3, 19.0, 17.4 ppm.

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((1R,2R,4aS,5R,6R,8aR)-6-acetoxy-2-hydroxy-5,8a-dimethyldecahydronaphth alene-1,2,5-triyl)tris(methylene) triacetate (8). To a stirred solution of 6 (260 mg, 0.83 mmol) in THF (4.0 mL) were added 6 N aq HCl (2.0 ml). After 30 min, the reaction mixture was diluted with water (5.0 ml) and extracted with ethyl acetate (4 × 20 mL). The combined organic extracts were washed with water and brine, dried over Na2SO4, and concentrated in vacuo to give solid mixture of monoacetate products 7a and 7b. To a solution of products 7a and 7b in pyridine (2.0 ml) was added Ac2O (0.50 mL, 5.3 mmol) and DMAP (9 mg, 0.074 mmol). After stirring overnight at room temperature, the reaction mixture was extracted with ethyl acetate, then washed with saturated NaHCO3 solution, water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (petroleum ether/EtOAc = 3:1) to give compound 8 (257 mg, 68% from 6, 80% from mixture of 7a and 7b) as a colorless oil. Compound 8: Rf = 0.50 (petroleum ether/EtOAc = 1 : 1); [α]20D –27 (c 1.0, CHCl3); IR (film): νmax 3498, 2949, 1738, 1441, 1372, 1246, 1037, 985 cm–1; 1H NMR (400 MHz, CDCl3): δ 4.59 (dd, J = 9.6, 7.2 Hz, 1H), 4.36 (d, J = 12.0 Hz, 1H), 4.28 (d, J = 4.0 Hz, 2H), 4.17 (d, J = 12.0 Hz, 1H), 3.98 (d, J = 11.2 Hz, 1H), 3.95 (d, J = 11.6 Hz, 1H), 2.09 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 1.97 (d, J = 13.2 Hz, 1H), 1.85−1.80 (m, 2H), 1.76−1.69 (m, 4H), 1.49−1.41(m, 1H), 1.34−1.25 (m, 2H), 1.07 (d, J = 12.0 Hz, 1H), 1.04 (s, 3H), 1.03 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 170.9, 170.9, 170.6, 170.5, 79.7, 72.6, 70.9, 65.0, 61.3, 55.1, 53.3, 41.1, 37.6, 37.5, 23.3, 22.7, 21.2, 21.1, 20.9, 18.1, 16.2 ppm; HRMS (ESI): calcd For C23H40NO9 [M+NH4]+ 474.2698; found 474.2704. ((1S,4aS,5R,6R,8aR)-6-hydroxy-5,8a-dimethyl-1,4,4a,5,6,7,8,8a-octahydronap hthalene-1,2,5-triyl)trimethanol

(9)

and

((4aS,5R,6R,8aR)-6-hydroxy-5,8a-dimethyl-3,4,4a,5,6,7,8,8a-octahydronaphthale ne-1,2,5-triyl)trimethanol (10). Compound 8 (250 mg, 0.55 mmol) in 2 ml of benzene was added dropwise to a solution of Burgess reagent (390 mg, 1.64 mmol, Burgess reagent was prepared according to the literature methods13d) in 3 mL of benzene at 50 °C under N2. After being stirred for 1 h at 50 °C, the reaction mixture was diluted with water (5.0 ml) and extracted with diethyl ether (3 × 10 mL). The combined organic layers was washed with water and brine , dried over Na2SO4, and

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concentrated in vacuo to give a liquid residue. The residue was dissolved in dry CH3OH (5.0 mL) and NaOCH3 (148 mg, 2.74 mmol) was added. The reaction mixture was stirred for 3 h, then filtered through a pad of Celite, eluting with CHCl3/CH3OH (10 : 1). The resulting filtrate was concentrated under reduced pressure and purified by flash silica gel column chromatography CHCl3/CH3OH (25 : 1) to give 86 mg (58%) of 9 as white solids and 18 mg (12%) of 10 as white amorphous solids. Compound 9: Rf = 0.46 (CHCl3/CH3OH = 10 : 1); mp 160−162 °C; [α]20 –3 (c 1.0, CH3OH); IR (KBr): νmax 3327, 2930, 2858, 1707, 1448, 1363, 1024, D 994 cm–1 ; 1H NMR (400 MHz, CD3OD): δ 5.77 (t, J = 2.4 Hz, 1H), 4.23 (d, J = 12.8 Hz, 1H), 4.19 (d, J = 11.2 Hz, 1H), 3.95 (d, J = 12.8 Hz, 1H), 3.83 (dd, J = 11.2 , 2.4 Hz, 1H), 3.62 (dd, J = 10.8, 7.2 Hz, 1H), 3.48 (d, J = 11.2 Hz, 1H), 3.39 (dd, J = 11.2, 4.4 Hz, 1H), 2.19−2.05 (m, 3H), 1.96 (t, J = 14.8 Hz, 1H), 1.82−1.74 (m, 2H), 1.38−1.29 (m, 2H), 1.20 (s, 3H), 0.79 (s, 3H) ppm; 13C NMR (100 MHz, CD3OD): δ 138.7, 126.3, 81.4, 66.8, 65.0, 61.3, 55.9, 51.7, 43.1, 38.8, 36.5, 28.8, 24.4, 23.3, 16.1 ppm; HRMS (ESI): calcd For C15H26O4Na [M+Na]+ 293.1723; found 293.1727. Compound 10: Rf = 0.55 (CHCl3/CH3OH = 10 : 1); [α]20 D –81 (c 1.2, CH3OH); IR (film): νmax 3340, 2937, 2858, 1700, 1448, 1359, 1017 cm–1 ; 1H NMR (400 MHz, CD3OD): δ 4.20 (d, J = 12.0 Hz, 2.0H), 4.13 (d, J = 11.2 Hz, 1H), 4.02 (d, J = 11.6 Hz, 1H), 3.94 (d, J = 12.4 Hz, 1H), 3.41 (d, J = 11.2 Hz, 1H), 3.36 (dd, J = 10.8, 5.6 Hz, 1H), 2.35 (dd, J = 18.0, 5.6 Hz, 1H), 2.12 (ddd, J = 18.4, 11.6, 7.2 Hz, 1H), 1.95−1.77 (m, 4H), 1.51−1.42 (m, 2H), 1.22 (s, 3H), 1.23−1.21 (m, 1H), 1.00 (s, 3 H) ppm; 13C NMR (100 MHz, CD3OD): δ 144.3, 136.8, 81.1, 65.2, 63.2, 57.6, 52.9, 43.7, 39.0, 35.5, 31.2, 28.9, 23.4, 21.6, 20.1 ppm; HRMS (ESI): calcd For C15H30NO4 [M+NH4]+ 288.2169; found 288.2173. Synthesis of (+)-Iresin (4). A mixture of 9 (57 mg, 0.21 mmol), silver carbonate−Celite (0.57 g/mmol, 600 mg, 1.05 mmol, Fétizon reagent was prepared according to the literature methods15d) in 3 mL of benzene was heated to refluxed for 5 h, cooled and filtered through a pad of Celite (ethyl acetate). The solvent was removed in vacuo and the residue was then purified by silica gel column

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chromatography (petroleum ether/EtOAc = 1 : 1) to give (+)-Iresin 1 (44 mg, 78%) as colorless crystals and aldehyde 11 (8 mg, 14%) as a white solid. NaBH4 (2 mg, 0.052 mmol) at 0 °C was added to a solution of aldehyde in CH3OH (1 mL). After stirring for 10 min at 0 °C, the reaction mixture was diluted with water (3.0 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with 1 N aq HCl, water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (petroleum ether/EtOAc = 1:1) to give iresin (7 mg, 86% from 11) as white solids. Iresin (4): Rf = 0.47 (AcOEt); mp 139−142 °C, (Lit.5 mp 140−142 °C); [α]20 +20 (c 1.0, CHCl3), D (Lit.5 [α]28D +21); IR (film): νmax 3383, 2931, 2870, 1755, 1687, 1423, 1221, 1028, 964 cm–1; 1H NMR (400 MHz, CDCl3): δ 6.86 (ddd,J = 3.6, 3.6, 3.6 Hz, 1H), 4.40 (dd, J = 9.2, 9.2 Hz, 1H), 4.26 (d, J = 10.4 Hz, 1H), 4.02 (dd, J = 9.2, 9.2 Hz, 1H), 3.54−3.49 (m, 2H), 3.12 (dd, J = 8.8, 2.0 Hz, 1H), 3.00 (d, J = 4.4 Hz, 1H), 2.83−2.77 (m, 1H), 2.51(dddd, J = 20.0, 4.8, 4.0, 4.0 Hz, 1H), 2.18−2.10 (m, 1H), 1. 89−1.79 (m, 2H), 1.68 (ddd, J = 13.6, 3.6, 3.6 Hz, 1H), 1.50 (dd, J = 12.0, 5.2 Hz, 1H), 1.35 (ddd, J = 13.6, 13.6, 4.0 Hz, 1H), 1.28 (s, 3H), 0.77 (s, 3H) ppm;

13

C NMR (100 MHz,

CDCl3): δ 169.8, 135.8, 127.0, 80.4, 67.2, 63.3, 50.6, 50.0, 42.1, 37.1, 33.7, 27.3, 24.6, 22.1, 14.3 ppm; HRMS (ESI): calcd For C15H23O4 [M+H]+ 267.1591; found 267.1585. Aldehyde 11: Rf = 0.64 (AcOEt); mp 145−147 °C; [α]20D +35 (c 0.6, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 10.00 (d, J = 1.2 Hz, 1H), 6.86 (d, J = 3.2 Hz, 1H),

4.44 (dd, J = 8.8, 8.8 Hz, 1H), 4.03 (dd, J = 8.8, 8.8 Hz, 1H), 3.37 (br d, J = 7.6 Hz, 1H), 2.85−2.80 (m, 2H), 2.67 (dddd, J = 20.4, 5.2, 4.0, 4.0 Hz, 1H), 2.49−2.45 (m, 1H), 1.97−1.94 (m, 2H), 1.75 (ddd, J = 13.6, 4.4, 4.4 Hz, 1H), 1.66 (dd, J = 11.6, 6.0 Hz, 1H), 1.42−1.35 (m, 1H), 1.34 (s, 3H), 0.74 (s, 3H) ppm;

13

C NMR (100 MHz,

CDCl3): δ 206.4, 169.5, 134.6, 127.1, 76.9, 67.2, 51.9, 50.6, 49.4, 37.3, 34.2, 27.7, 24.5, 19.6, 13.6 ppm. Synthesis of (− −)-isoiresin (13). Lactonization of 10 to aldehyde 12 (91% yield) was carried out by a procedure analogous to that of 9. Compound 12: white solids; Rf = 0.57 (AcOEt); mp 151−154 °C; [α]20 –67 (c 1.0, CHCl3); 1H NMR (400 MHz, D

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CDCl3): δ 9.83 (d, J = 2.4 Hz, 1H), 4.77−4.65 (m, 2H), 3.29 (br s, 1H), 3.16 (d, J = 10.0 Hz, 1H), 2.52−2.47 (m, 1H), 2.29−2.15 (m, 2H), 2.07−1.95 (m, 2H), 1.86−1.80 (m, 1H), 1.76 (ddd, J = 13.2, 3.6, 3.6 Hz, 1H), 1.55 (dd, J = 12.8, 4.4 Hz, 1H),1.47 (d, J = 12.0 Hz, 1H), 1.37 (s, 3H), 1.09 (s, 3H) ppm;

13

C NMR (100 MHz, CDCl3): δ

206.9, 173.7, 167.9, 124.1, 77.0, 68.3, 52.5, 51.5, 36.4, 34.0, 27.8, 21.5, 20.1, 19.2, 18.2 ppm. Reduction of aldehyde 12 to isoiresin (13) (92% yield) was carried out by a procedure analogous to that of aldehyde 11. Isoiresin (13): colorless crystals; Rf = 0.46 (AcOEt); mp 217−220 °C; [α]20 –62 (c 1.0, CHCl3); IR (KBr): νmax 3303, 2924, D 2853, 1736, 1670, 1643, 1430, 1384, 1196, 1011, 989 cm–1; 1H NMR (400 MHz, CDCl3): δ 4.76−4.62 (m, 2H), 4.23 (dd, J = 11.2, 2.0 Hz, 1H), 3.54−3.49 (m, 1H), 3.41 (t, J = 9.6 Hz, 1H), 2.72 (dd, J = 8.8, 2.4 Hz, 1H), 2.61 (d, J = 4.0 Hz, 1H), 2.43 (dt, J = 18.0, 2.8 Hz, 1H), 2.17−2.10 (m, 1H), 2.03−1.86 (m, 3H), 1.73 (ddd, J = 12.8, 3.2, 3.2 Hz, 1H), 1.53−1.45 (m, 2H), 1.31 (s, 3H), 1.14 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 174.0, 169.2, 123.8, 80.1, 68.1, 63.8, 51.0, 42.9, 36.0, 33.8, 27.5, 22.6, 21.7, 21.5, 18.1 ppm; HRMS (ESI): calcd For C15H23O4 [M+H]+ 267.1591; found 267.1586. X-ray crystallographic data of 13: C15H22O4, orthorhombic, space group: C2221, a = 6.580 (6) Å, b = 12.892 (15) Å, c = 32.76 (3) Å, Z = 8, dcalcd = 1.359 g/cm3, R1(I > 2σ(I)) = 0.0357, wR2 = 0.0836. Preparation of bis-(4-Br)benzoate derivative 14 of (+)-iresin (4). To a stirred solution of (+)-iresin (4) (43 mg, 0.16 mmol) in dry pyridine (2 mL) was added p-bromobenzoyl chloride (177 mg, 0.81 mmol) and DMAP (2 mg, 0.016 mmol) at room temperature. When the consumption of iresin was complete (monitored by TLC), the reaction mixture was extracted with ethyl acetate, then washed with saturated NaHCO3 solution, water and brine, dried over Na2SO4, and concentrated to give light yellow solid residue, which after purification by flash column chromatography on silica gel (benzene/EtOAc = 30:1) afforded 14 (97 mg, 95%) as colorless crystals. Rf = 0.30 (petroleum ether/EtOAc = 1 : 2); mp 208−211 °C, (Lit.6e mp 211.5−212 °C); [α]20 –50 (c 1.6, CHCl3); IR (KBr): νmax 3014, 2890, 1760, 1741, 1689, 1590, 1480, D

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The Journal of Organic Chemistry

1291, 1012, 846 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.81−7.78 (m, 4H), 7.53 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 3.2 Hz, 1H), 4.96 (dd, J = 9.6, 6.4 Hz, 1H), 4.87 (d, J = 12.0 Hz, 1H), 4.59 (d, J = 11.6 Hz, 1H), 4.45 (dd, J = 9.2, 9.2 Hz, 1H), 4.08 (dd, J = 9.2, 9.2 Hz, 1H), 2.92−2.87 (m, 1H), 2.63 (dd, J = 20.0, 4.4 Hz, 1H), 2.53−2.45 (m, 1H), 1.96−1.91 (m, 2H), 1.81−1.75 (m, 2H), 1.60−1.52 (m, 1H), 1.23 (s, 3H), 0.92 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 169.4, 165.8, 165.3, 135.1, 131.9, 131.6, 131.1, 130.9, 128.8, 128.7, 128.4, 128.3, 127.0, 80.2, 66.9, 64.1, 50.3, 50.2, 41.7, 36.9, 33.9, 25.1, 23.7, 22.1, 13.8 ppm; HRMS (ESI): calcd For C29H29Br2O6 [M+H]+ 633.0305; found 633.0309. X-ray crystallographic data of 16:6e C29H28Br2O6, monoclinic, space group: P21, a = 6.2860 (12) Å, b = 7.3672 (15) Å, c = 28.272 (6) Å, β = 92.047 (13)°, Z = 2, dcalcd = 1.605 g/cm3, R1(I > 2σ(I)) = 0.0530, wR2 = 0.1339.

ACKNOWLEDGEMENTS We thank the National Natural Science Foundation (21132006) for financial support. The Cheung Kong Scholars program and the scholars program of Chongqing University are gratefully acknowledged.

ASSOCIATED CONTENT Supporting Information:

1

H and 13C NMR spectra for all compounds 4−6, 7a, 7b,

8−14, and X-ray crystallographic data for compounds 6, 13, 14, CIF files for compounds 6, 13, 14. This material is available free of charge via the Internet at http://pubs.acs.org.

REFERENCES 1. For excellent reviews on the occurrence, biological activity and synthesis of Drimane sesquiterpenoids, see: (a) Jansen, B. J. M.; de Groot, Ae. Nat. Prod. Rep.

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2004, 21, 449−477. (b) Jansen, B. J. M.; de Groot, A. Nat. Prod. Rep. 1991, 8, 309−318. 2. (a) Ruzicka, L. Experientia 1953, 9, 357−367. (b) Parker, W.; Roberts, J. S.; Ramage, R. Quarterly Rev., Chem. Soc. 1967, 331−363. (c) Rücker, G. Angew. Chem., Int. Ed. 1973, 12, 793−806. 3. For selected recent reports: (a) Xu, D.; Sheng, Y.; Zhou, Z.-Y.; Liu, R.; Leng, Y.; Liu, J.-K. Chem. Pharm. Bull. 2009, 57, 433−435. (b) Stierle, D. B.; Stierle, A. A.; Girtsman, T.; McIntyre, K.; Nichols, J. J. Nat. Prod. 2012, 75, 262−266. (c) Felix, S.; Sandjo, L. P.; Opatz, T.; Erkel, G. Beilstein J. Org. Chem. 2013, 9, 2866−2876. (d) Felix, S.; Sandjo, L. P.; Opatz, T.; Erkel, G. Bioorg. Med. Chem. 2014, 22, 2912−2918. 4. For an eariler review, see: (a) Jansen, B. J. M.; de Groot, A. Nat. Prod. Rep. 1991, 8, 319−337. For selected recent reports: (b) Suzuki, Y.; Nishimaki, R.; Ishikawa, M.; Murata, T.; Takao, K.-i.; Tadano, K.-i. J. Org. Chem. 2000, 65, 8595−8607. (c) Justicia, J.; Oltra, J. E.; Barrero, A. F.; Guadano, A.; Gonzalez-Coloma, A.; Cuerva, J. M. Eur. J. Org. Chem. 2005, 712−718. (d) D’Acunto, M.; Monica, C. D.; Izzo, I.; De Petrocellis, L.; Di Marzo, V.; Spinella, A. Tetrahedron 2010, 66, 9785−9789. (e) Shi, H.; Fang, L.; Tan, C.; Shi, L.; Zhang, W.; Li, C.-C.; Luo, L.; Yang, Z. J. Am. Chem. Soc. 2011, 133, 14944−14947. 5. Djerassi, C.; Sengupta, P; Herran, J.; Walls, F. J. Am. Chem. Soc. 1954, 76, 2966−2968. 6. (a) Djerassi, C; Rittel, W.; Nussbaum, A. L.; Donovan, F. W.; Herran, J. J. Am. Chem. Soc. 1954, 76, 6410−6411. (b) Djerassi, C.; Rittel, W. J. Am. Chem. Soc. 1957, 79, 3528−3534. (c) Djerassi, C.; Donovan, F. W.; Burstein, S.; Mauli, R. J. Am. Chem. Soc. 1958, 80, 1972−1977. (d) Djerassi, C.; Burstein, S. J. Am. Chem. Soc. 1958, 80, 2593. (e) Rossmann, M. G.; Lipscomb, W. N. Tetrahedron 1958, 4, 275−293. (f) Rossmann, M. G.; Lipscomb, W. N. J. Am. Chem. Soc. 1958, 80, 2592−2593. (g) Djerassi, C.; Burstein, S. Tetrahedron 1959, 7, 37−46.

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7. Rios, M. Y.; Berber, L. A. Magn. Reson. Chem. 2005, 43, 339−342. 8. Pelletier, S. W.; Prabhakar, S. J. Am. Chem. Soc. 1968, 90, 5318−5320. 9. Gao, H.-T.; Wang, B.-L.; Li, W.-D. Z. Tetrahedron 2014, 70, 9436−9448. 10. (a) Krow, G. T. Org. React. 1993, 43, 251−798. (b) Villamizar, J.; Plata, F.; Canudas, N.; Tropper, E.; Fuentes, J.; Orcajo, A. Synth. Commun. 2006, 36, 311−320. (c) Chauvet, F.; Coste-Manière, I; Martres, P.; Perfetti, P.; Waegell, B.; Zahra, J.-P. Tetrahedron Lett. 1996, 37, 3695−3696. (d) Ochiai, M.; Yoshimura, A.; Miyamoto, K.; Hayashi, S.; Nakanishi, W. J. Am. Chem. Soc. 2010, 132, 9236−9239. 11. For examples on cyclic orhtoester formation, see: (a) Giner, J.-L.; Ferris, W. V., Jr.; Mullins, J. J. J. Org. Chem. 2002, 67, 4856−4859. (b) Giner, J.-L.; Faraldos, J. A. J. Org. Chem. 2002, 67, 2717−2720. For mechanistic studies on the epoxy ester−orthoester rearrangement, see: (c) Giner, J.-L.; Li, X.-Y.; Mullins, J. J. J. Org. Chem. 2003, 68, 10079−10086. (d) Giner, J.-L. J. Org. Chem. 2005, 70, 721−724. (e) Giner, J.-L.; Faraldos, J. A. Helv. Chim. Acta 2003, 86, 3613−3622. (f) Nicolaou, K. C.; Nantermet, P. G.; Ueno, H.; Guy, R. K.; Couladouros, E. A.; Sorensen, E. J. J. Am. Chem. Soc. 1995, 117, 624−633. 12. For detailed X-ray crystallographic data, see Supporting Information. CCDC 1013827 contains the supplementary crystallographic data for compound 6. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. 13. (a) Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744−4745. (b) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org. Chem. 1973, 38, 26−31. (c) Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1972, 94, 6135−6141. (d) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. Williams, W. M. Org. Synth. 1987, 6, 788−791. (e) Lamberth, C. J. Prakt. Chem. 2000, 342, 518−522. 14. The ratio of regioisomers was determined by 1H NMR spectroscopic analysis of a crude product mixture of 9a and 10a:

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15. (a) Fétizon, M.; Golfier, M.; Louis, J.-M. J. Chem. Soc., Chem. Commun. 1969, 1118−1119. (b) Fétizon, M.; Golfier, M.; Mourgues, P. Tetrahedron Lett. 1972, 43, 4445−4448. (c) Kakis, F. J.; Fétizon, M.; Douchkine, N.; Golfier, M.; Mourgues, P.; Prange, T. J. Org. Chem. 1974, 39, 523−533. (d) Balogh, V.; Fétizon, M.; Golfier, M. J. Org. Chem. 1971, 36, 1339−1341. (e) Heathcock, C. H.; Stafford, J. A.; Clark, D. L. J. Org. Chem. 1992, 57, 2575−2585. 16. For detailed X-ray crystallographic data, see Supporting Information. CCDC 1013829 contains the supplementary crystallographic data for compound 13. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. 17. Crabbe, P.; Burstein, S.; Djerassi, C. Bull. Soc. Chim. Belg. 1958, 67, 632−641. 18. For detailed X-ray crystallographic data, see Supporting Information. CCDC 1013828 contains the supplementary crystallographic data for compound 14. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. 19. For earlier biomimetic approaches to the bicyclofarnesol skeleton, see: (a) van Tamelen, E. E.; Hessler, E. J. J. Chem. Soc., Chem. Commun. 1966, 411−413. (b) van Tamelen, E. E.; Coates, R. M. J. Chem. Soc., Chem. Commun. 1966, 413−415.

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Total synthesis of (+)-iresin. - PDF Download Free (2024)

FAQs

What is the most famous total synthesis? ›

Friedrich Wöhler discovered that an organic substance, urea, could be produced from inorganic starting materials in 1828. That was an important conceptual milestone in chemistry by being the first example of a synthesis of a substance that had been known only as a byproduct of living processes.

What is the total synthesis method? ›

Total synthesis is the science of constructing molecules from simple starting materials. It often deals with complex molecular architectures that require a thorough retrosynthetic problem-solving analysis [7]. Total synthesis and the discovery of new synthetic methodologies have always been intimately related.

What was the first total synthesis? ›

At the dawn of the twenty-first cen- tury, the state of the art and science of total synthesis is as healthy and vigor- ous as ever. The birth of this exhilarat- ing, multifaceted, and boundless sci- ence is marked by Wöhler s synthesis of urea in 1828.

Who is the father of total synthesis? ›

Robert Burns Woodward, who received the 1965 Nobel Prize for Chemistry for several total syntheses (e.g., his 1954 synthesis of strychnine), is regarded as the father of modern organic synthesis.

What is the difference between synthesis and total synthesis? ›

Answer: Partial synthesis ; when a desired compound is obtained from an intermediate product of reaction, called partial synthesis. ... Total synthesis; when a desired product is prepared by converting the starting material through many steps, called total synthesis.

What are the different types of total synthesis? ›

Total synthesis is accomplished either via a linear or convergent approach. In a linear synthesis—often adequate for simple structures—several steps are performed sequentially until the molecule is complete; the chemical compounds made in each step are called synthetic intermediates.

What are the three types of synthesis? ›

There are 3 different types of synthesis reactions:
  • Synthesis of multiple elements.
  • Synthesis of multiple compounds.
  • Synthesis of an element and a compound.

What is the difference between biosynthesis and total synthesis? ›

Like traditional total synthesis, where the goal is to construct a desired target molecule from easily available precursors, total biosynthesis endeavors to take simple, biologically relevant starting materials and convert them into a natural product.

What is the difference between semisynthesis and total synthesis? ›

The compounds created through semisynthesis have a higher molecular weight and/or more complex molecular structures than those produced from total synthesis. As the process involves fewer steps, the medicinal products derived from semisynthesis tend to be cheaper.

What is total synthesis of drugs? ›

Total synthesis offers a key approach to the production of natural medicines if sufficient quantities cannot be obtained due to low natural abundance or lack of efficient fermentation or semi-synthesis methods.

What is the total synthesis of natural products? ›

Total synthesis of natural products is an important discipline of organic chemistry that has enabled the development of new synthetic methods and strategies for the preparation and study of the structure and reactivity of complex naturally occurring products.

What is the most popular synthesis? ›

The top 5 synthesis types are Subtractive, Additive, Wavetable, FM, and Granular.
  • Subtractive Synthesis is perhaps the most common form. ...
  • Wavetable Synthesis employs the use of a table with various switchable frequencies played in certain orders (wavetables).

What is the most common form of synthesis? ›

Subtractive synthesis is perhaps the most common form.

What is the best example of synthesis? ›

For example, when you report to a friend the things that several other friends have said about a song or movie, you are engaging in synthesis. However, synthesizing is much more than simply reporting. Synthesis is related to, but not the same as, classification, division, or comparison and contrast.

What is the most common type of synthesis? ›

Subtractive Synthesis

This type of synthesis is the most commonly used. It's associated with the classic synths that started it all. The waveforms most commonly used in subtractive synthesis is are square, saw, sine and triangle.. A square wave has a naturally rich, buzzy sound with lots of overtones.

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