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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Tetrahedron. Author manuscript; available in PMC 2010 June 27.
Published in final edited form as:
Tetrahedron. 2009 June 27; 65(26): 5051–5055.
doi:  10.1016/j.tet.2009.03.097
PMCID: PMC2699279
NIHMSID: NIHMS108175

De Novo Asymmetric Syntheses of (+)-Goniothalamin, (+)-Goniothalamin oxide and 7,8-Bis-epi-Goniothalamin using Asymmetric Allylations

Abstract

A highly enantio- and diastereoselective approach to either enantiomer of (+)-goniothalamin, (+)-goniothalamin oxide and 7,8-bis-epi-goniothalamin oxide has been developed from achiral cinnamyl alcohol or cinnamaldehyde. The asymmetry of the synthesis was installed by means of a Krische or Leighton allylation. The remaining stereochemistry was installed by a diastereoselective epoxidation.

1. Introduction

Over the past decade, there have been several syntheses of Goniothalamin (3a)i and Goniothalamin oxide (3b)ii derivatives. Goniothalamin was first isolated in 1967 from the bark of Cryptocarya caloneura and was assigned to have (S)-stereochemistry.iii However, the stereochemistry was later revised to the (R) configuration.iv Interestingly, it was recently discovered that both enantiomers possess potent cytotoxicity toward a range of cancer cell lines.i In addition, several derivatives of Goniothalamin have been discovered from a variety of tropical/subtropical plants including; Cryptocarya moschata,iv Bryonopsis laciniosa,v and various Goniothalamusvi species. These natural products have shown cytotoxicity on a variety of cells lines including: MCF-7, T47D, and MDA-MB-231 (breast carcinoma); HeLa (human cervical carcinoma); HL-60 (leukemia carcinoma); Caov-3 (ovarian carcinoma).vii More recently, several bis-lactone antitumor natural products, goniolactones, were isolated from Goniothalamus cheliensis.viii Of the goniolactones we were most interested in Goniolactone A (1).

Goniolactone A (1) can be envisioned as the epoxide opening dimer between two natural products altholactone (2a) and goniothalamine oxide (3b). Recently we have prepared both enantiomers of altholactone (2a) as well as all of its 2,3-diastereomers (2b–d) using asymmetric catalysis.ix As part of our interest in the synthesis and biological investigation of goniolactone A (1) and analogues, we became interested in the synthesis of both enantiomers of goniothalamin oxide (3b) as well as its 7,8-bis-epimer (3c). While all of the previous syntheses of the goniothalamin oxide derived their asymmetry from the chiral pool or chiral reagents,ii we were interested in a de novo asymmetric approach that would use asymmetric catalysis to install the three stereocenters in goniothalamin oxide and its diastereomer from achiral starting materials. In particular, we were interested in a de novo synthesis that used the recently reported Krische allylation of primary alcohols.x Herein we describe our successful efforts to implement this strategy for the de novo synthesis of goniothalamin oxide (3b) as well as its 7,8-bis-epimer (3c).xi

Our strategy for the total synthesis of (R)-(+)-goniothalamin oxide is outlined in Scheme 1. We, like many others,ii initially envisioned gaining access to either enantiomer of (R)-(+)-goniothalamin oxide, as well as its epoxide diastereomer, by means of an asymmetric allylation of commercially available trans-cinnamaldehyde (7 to 6). Divergent diastereoselective epoxidation of 6 should provide epoxides 5a and 5b. Finally, acylation and ring-closing metathesis of the resulting dienes 4a and 4b should provide both the desired natural product 3b and target molecule 3c. Because of our previous experience with the Leighton allylation, we decided to initially pursue its use.xii However, due to our interest in devising a “de novo” asymmetric synthesis, we were also interested in investigating the use of the Krische allylation of trans-cinnamyl alcohol 8.

Scheme 1
Goniothalamin oxide Retrosynthesis

2. Results and Discussion

2.1. Approach to (R)-(+)-goniothalamin oxide

Our synthesis began with the Krische allylation of the trans-cinnamyl alcohol 8 (Scheme 2). To our delight using the iridium with the (R)-Cl, MeOBIPHEP system described by Krische provided good yields of the enantiomeric homoallylic alcohol 6, with high enantiomeric purities (90% ee). Similarly, the Krische allylation of the trans-cinnamyl alcohol 8 with the (S)-Cl, MeOBIPHEP gave the enantiomeric homoallylic alcohol (ent)-6. For comparison purposes, the enantioselective allylation of trans-cinnamaldehyde 7 was preformed using the (S,S)-Leighton reagentxiii to furnish secondary alcohol 6 in 95% yield with excellent stereoselectivity (>95% ee).

Scheme 2
Leighton versus Krische allylation

We next investigated the chemo- and stereoselective epoxidation of the internal double bond (Scheme 3). This was most easily accomplished for diastereomer 5b using t-BuOOH and catalytic VO(acac)2 in refluxing benzene. Under these conditions the (1R,2′R,3′R)-diastereomer 5b was produced in an 80% yield with a 10>1 diastereoselectivity. Unfortunately we were unable to find a similarly selective epoxidation of 6 to selectively form the (1S,2′S,3′R)-diastereomer 5a. Our optimal conditions (mCPBA in CH2Cl2 at 0 °C) furnish a 70% yield of a 1.5:1 mixture of 5a to 5b. The mixture of diastereomers was inseparable by flash chromatography, but could be cleanly separated following the acylation reaction (Scheme 4).

Scheme 3
Stereoselective Epoxidation of 6
Scheme 4
Acylation of epoxides

Both the pure diastereomer 5b and the mixture of epoxides 5a/5b could be acylated using acrylic acid, DMAP/DCC in CH2Cl2 (70% yield). The mixture of acylated products 4a/4b was then easily separated by flash chromatography to give two pure diastereomers. The (1S,2′S,3′R)-diastereomer 4a was used to complete the total synthesis of (R)-(+)-goniothalamin oxide, whereas the (1R,2′R,3′R)-diasteromer 4b was used to prepare the diasteromeric epoxide 3c.

An improved synthesis of the minor diastereomer 4a was found by switching the acylation and epoxidation steps (Scheme 5). Exposing 6 to the same acylating conditions (DMAP/DCC in CH2Cl2, 70% yield) provided good yields of triene 9. To our delight exposure of triene 9 to mCPBA in CH2Cl2 at 0 °C selectively furnish the desired diastereomer in 70% yield and in >10:1 diastereoselectivity.xiv

Scheme 5
Acylation then epoxidation

With selective routes to the three desired acrylates 9, 4a and 4b, we turned to the metathesis ring closure to form the target molecules 3a–c. Thus exposing methylene chloride solutions of triene 9, diene 4a and diene 4b gave 75%, 75% and 70% yields of (R)-(+)-goniothalamin 3a, (R)-(+)-goniothalamin oxide 3b and 7,8-bis-epi-(R)-(+)-goniothalamin 3c, respectively. Both syntheses provide material with physical and spectral date that matched the data reported in the literature.i,ii

3. Conclusions

In conclusion, a de novo asymmetric approach to (+)-goniothalamin 3a, (+)-goniothalamin oxide 3b and 7,8-bis-epi-goniothalamin oxide 3c has been developed. Goniothalamin oxide was achieved in only 4 steps and 23% overall yield from achiral cinnamyl alcohol. Key to the successful approach is the use of a Krishe allylation. Further application of this approach to the synthesis of various Goniolactone A is ongoing.

4. Experimental Section

4.1. General

1H and 13C spectra were recorded on 270 and 600 MHz spectrometers. Chemical shifts were reported relative to internal tetramethylsilane (δ 0.00 ppm) or CDCl3 (δ 7.26 ppm) or CD3OD (δ 4.89 ppm) for 1H and CDCl3 (δ 77.1 ppm) or CD3OD (δ 49.15 ppm) for 13C. Optical rotations were measured with a digital polarimeter in the solvent specified. Infrared (IR) spectra were obtained on a FT-IR spectrometer. Flash column chromatography was performed on ICN reagent 60 (60–200 mesh) silica gel. Analytical thin-layer chromatography was performed with precoated glass-backed plates (K6F 60Å, F254) and visualized by quenching of fluorescence and by charring after treatment with p-anisaldehyde or phosphomolybdic acid or potassium permanganate stain. Rf values were obtained by elution in the stated solvent ratios (v/v). Ether, THF, methylene chloride and triethylamine were dried by passing through activated alumina (8 × 14 mesh) column with nitrogen gas pressure. Ir(cod)Cl]2 and (R)-Cl, MeO-BIPHEP were purchased from Sigma/Aldrich, other commercial reagents were used without purification unless otherwise noted. Air and/or moisture-sensitive reactions were carried out under an atmosphere of argon/nitrogen using oven/flamed-dried glassware and standard syringe/septa techniques.

4.1.1. (3R,E)-1-Phenylhexa-1,5-dien-3-ol (6)

To a solution of E-cinnamaldehyde 7 (478 mg, 3.62 mmol) in 5 mL of CH2Cl2 at −20 °C was added (S,S)-Leighton Reagent (1.0 g, 1.81 mmol) in 4 mL of CH2Cl2 at −20 °C. After stirring for 5 min the solution was stored in a freezer for 20 hrs. The reaction was quenched with 1N HCl (10%), sat. NH4Cl aqueous solution, and then diluted with EtOAc then passed through celite. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to afford the crude product. Flash chromatography on silica gel (8:2 (v/v) hexane/EtOAc) provided compound 6 (600 mg, 95% yield) as a yellow oil. Rf = 0.4 (8:2 (v/v) hexane/EtOAc). Spectral data gave a satisfactory match to previous reports.xv [α]25D = 30 (c 1.6, CHCl3); IR (neat, cm−1) 3348, 1640, 1493, 964, 913, 746, 691; 1H NMR (CDCl3, 600 MHz) 7.39 (m, 2H), 7.32 (m, 2H), 7.24 (m, 1H), 6.62 (d, J = 15.6 Hz, 1H), 6.18 (dd, J = 15.6, 6.6 Hz, 1H), 5.87 (dddd, J = 17.4, 10.2, 7.2, 7.2 Hz, 1H), 5.19 (m, 2H), 4.37 (dd, 6.6, 6.6 Hz, 1H), 2.42 (m, 2H), 1.85 (s, 1H); 13C NMR (CDCl3, 600 MHz) δ 136.6, 134.0, 131.5, 130.4, 128.5, 127.6, 126.4,118.5, 71.7, 42.0; HRMS (CI) calcd for [C12H14O + Na]+: 197.0945, Found: 197.0942

4.1.2. (3S,E)-1-Phenylhexa-1,5-dien-3-ol (ent-6)

To a pressure tube under argon was added cinnamyl alcohol 8 (107.3 mg, 0.8 mmol), [Ir(cod)Cl]2 (13.6 mg, 0.02 mmol), (S)-Cl, MeO-BIPHEP (26.1 mg, 0.04 mmol), Cs2CO3 (52.1 mg, 0.16 mmol) and m-nitrobenzoic acid (13.3 mg, 0.08 mmol). The solution was heated to 50 °C for 10 min then allyl acetate (800 mg, 8.0 mmol) was added to the solution. The pressure tube was sealed and the solution was heated to 100 °C for 24 hrs. The solution was cooled to rt and the solvent was removed. The residue was purified using silica gel flash chromatography eluting with 5~15% EtOAc/hexane (plus 1% triethylamine) to give 95.1 mg (0.545 mmol, 68%) of 6 (Rf = 0.4 in 8:2 (v/v) hexane/EtOAc).xv [α]25D = −25 (c 1.6, CHCl3); IR (neat, cm−1) 3348, 1640, 1493, 964, 913, 746, 691; 1H NMR (CDCl3, 600 MHz) 7.39 (m, 2H), 7.32 (m, 2H), 7.24 (m, 1H), 6.62 (d, J = 15.6 Hz, 1H), 6.18 (dd, J = 15.6, 6.6 Hz, 1H), 5.87 (dddd, J = 17.4, 10.2, 7.2, 7.2 Hz, 1H), 5.19 (m, 2H), 4.37 (dd, 6.6, 6.6 Hz, 1H), 2.42 (m, 2H), 1.85 (s, 1H); 13C NMR (CDCl3, 600 MHz) δ 136.6, 134.0, 131.5, 130.4, 128.5, 127.6, 126.4,118.5, 71.7, 42.0; HRMS (CI) calcd for [C12H14O + Na]+: 197.0945, Found: 197.0942

4.1.3. (1R,2′S,3′S)-3′-phenyloxiran-2′-yl)but-3-en-1-ol (5b)

To a solution of product (1R,E)-1-phenylhexa-1,5-dien-3-ol 6 (150 mg, 0.861 mmol) in 7 mL of benzene was added VO(acac)2 (3 mg, 12 μmol) to produce a green colored solution. After 10 min of stirring t-BuOOH (85 mg, 0.947 mmol) was added to the solution which was accompanied by a color change to a pale yellow/orange color. The reaction was quenched with a sat. NaHCO3 aqueous solution. The layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to afford crude product. Flash chromatography on silica gel (9:1 (v/v) hexane/EtOAc) provided compound 5b (119 mg, 71% yield) as a colorless oil. Spectral data gave a satisfactory match to previous reports.xvi Rf = 0.3 (8:2 (v/v) hexanes:EtOAc); [α]25D = 26 (c 0.4, CHCl3); IR (neat, cm−1) 3439, 1642, 917; 1H NMR (CDCl3, 270 MHz) 7.32 (m, 5H), 5.90 (ddt, J = 16.8, 10.2, 7.2, 7.2 Hz, 1H), 5.17 (m, 2H), 3.99 (dddd, J = 4.8, 4.8, 4.0, 4.0 Hz, 1H), 3.97 (d, J = 1.8 Hz, 1H), 3.10 (dd, J = 3.0, 1.8 Hz, 1H), 2.35(m, 2H), 2.03(m, 1H); 13C NMR (CDCl3, 600 MHz) δ 136.8, 133.4, 128.5, 128.3, 125.7, 118.4, 68.3, 64.2, 55.0, 37.9; HRMS (CI) calcd for [C12H14O2 + Na]+: 213.0894, Found: 213.0892

4.1.4. (1R,2′S,3′S)-3′-phenyloxiran-2′-yl)but-3-enyl acrylate and (1R,2′R,3′R)-3′-phenyloxiran-2′-yl)but-3-enyl acrylate (4a/4b)

To a solution of product (1R,E)-1-phenylhexa-1,5-dien-3-ol 6 (150 mg, 0.861 mmol) in 5 mL of CH2Cl2 was cooled and stirred in an ice bath at 0°C as a solution of mCPBA (163 mg, 0.947 mmol) in 3 ml of CH2Cl2 was added dropwise. The mixture was washed with 10% Na2CO3 (2 × 5 ml) and brine (7 ml). The combined organic layers were dried over anhydrous Na2SO4, and concentrated to afford crude product. Flash chromatography on silica gel (9:1 (v/v) hexane/EtOAc) provided compound 5a/5b (131 mg, 80% yield) as a colorless oil. Rf = 0.3 (8:2 (v/v) hexanes:EtOAc). This mixture was inseparable and used as is.

To a solution of 3′-phenyloxiran-2′-yl)but-3-en-1-ol 5a/5b (100 mg, 0.526 mmol) in 7 mL of CH2Cl2 was added acyrilic acid (75 mg, 1.05 mmol), DCC (217 mg, 1.05 mmol), and DMAP (4 mg) at room temperature. After stirring for 6 hrs the reaction was diluted with ether, passed through celite, and extracted with 1M aqueous NaHSO4 and then sat. aqueous NaHCO3. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. Flash chromatography on silica gel (9.5:0.5 (v/v) hexanes/EtOAc) provided compound 4a/4b (90 mg, 70% yield, 1.5:1, 4a/4b) as a colorless oil.

4a Rf = 0.59 (8:2 (v/v) hexanes:EtOAc); [α]25D = 61 (c 0.4, CHCl3); IR (neat, cm−1) 1731, 1240, 1186, 1046; 1H NMR (CDCl3, 600 MHz) 7.30 (m, 5H), 6.43 (dd, J = 17.3, 1.5 Hz, 1H), 6.12 (dd, J = 17.1, 10.4 Hz, 1H), 5.84 (m, 2H), 5.16 (m, 2H), 4.99 (ddd, J = 7.2, 5.2, 3.2 Hz, 1H), 3.94 (d, J = 2.0 Hz, 1H), 3.07 (dd, J = 5.7, 2.0 Hz, 1H), 2.57 (m, 2H); 13C NMR (CDCl3, 600 MHz) δ 165.3, 136.6, 132.4, 131.3, 128.5, 128.3, 128.1, 125.6, 118.5, 72.1, 61.8, 57.3, 35.8; HRMS (CI) calcd for [C15H16O + Na]+: 267.0997, Found: 267.0999

4b Rf = 0.58 (8:2 (v/v) hexanes:EtOAc); IR (neat, cm−1) 1731, 1406, 1373, 1240, 1186, 1046, 984; 1H NMR (CDCl3, 270 MHz) 7.29 (m, 5H), 6.48 (dd, J = 17.3, 1.5 Hz, 1H), 6.17 (dd, J = 17.0, 7.0 Hz, 1H), 5.83 (m, 2H), 5.14 (m, 2H), 4.98 (dd, J = 12.6, 6.7, 1H), 3.79 (d, J = 2.0 Hz, 1H), 3.17 (dd, J = 5.9, 2.0 Hz, 1H), 2.54 (m, 2H); 13C NMR (CDCl3, 600 MHz) δ 165.6, 136.5, 132.4, 131.6, 128.7, 128.6, 128.4, 125.8, 119.1, 73.1, 62.7, 56.7, 36.2; HRMS (CI) calcd for [C15H16O + H]+: 245.1178, Found: 245.1182.

4.1.5. (9)

To a solution of product 6 (100 mg, 0.573 mmol) in 7 mL of CH2Cl2 was added acrylic acid (82 mg, 1.14 mmol), DCC (236 mg, 1.14 mmol), and DMAP (4 mg) at room temperature. After stirring for 6 hrs the reaction was diluted with ether, passed through celite, and extracted with 1M aqueous NaHSO4 and then sat. aqueous NaHCO3. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. Flash chromatography on silica gel (9.5:0.5 (v/v) hexanes/EtOAc) provided compound 9 (92 mg, 70% yield) as a colorless oil. With spectral data that matched the reported data:i 1H NMR (600 MHz, CDCl3): d 7.41–7.25 (m, 5H), 6.92 (dt, 1H, J = 9.5 and 4.0 Hz), 6.72 (d, 1H, J = 15.9 Hz), 6.27 (dd, 1H, J = 15.9 and 6.2 Hz), 6.08 (d, 1H, J = 9.5 Hz), 5.10 (q, 1H, J = 6.9 Hz), 2.56–2.52 (m, 2H). 13C NMR (125 MHz, CDCl3): d 163.5, 144.5, 135.5, 132.8, 128.5 (2C), 128.1 (2C), 126.4, 125.5, 121.4, 77.8, 29.8

4.1.6. (1R,2′R,3′R)-3′-phenyloxiran-2′-yl)but-3-enyl acrylate (4b)

To a solution of 3b (120 mg, 0.629 mmol) in 10 mL of CH2Cl2 was added acrylic acid (188 mg, 2.61 mmol), DCC (538 mg, 2.61 mmol), and DMAP (4 mg) at room temperature. After stirring for 6 hrs the reaction was diluted with ether, passed through celite, and extracted with 1M aqueous NaHSO4 and then sat. aqueous NaHCO3. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. Flash chromatography on silica gel (9.5:0.5 (v/v) hexanes/EtOAc) provided compound 4b (92.2 mg, 60% yield) as a colorless oil.

4.1.7. (R)-(+)-goniothalamin (3a)

To a solution 9 (25 mg, 0.11 mmol) in 5 mL of CH2Cl2 was added Grubbs (I) catalyst (9 mg, 0.011 mmol) at room temperature. Stirring commenced for 4 hrs at reflux conditions and then the reaction was concentrated. Flash chromatography on silica gel (7:3 (v/v) hexane:EtOAc) provided compound 3a (17 mg, 77% yield) as a dark oil. (Note: Color caused by Grubbs catalyst) Spectral data gave a satisfactory match to previous reports. [α]25D + 165 (c 1.0, CHCl3);, IR (neat, cm−1) 1724, 1610, 1241, 815; 1H NMR: δ 7.34 (m, 5H), 6.94 (ddd, J = 9.7, 4.9, 3.7 Hz, 1H), 6.74 (d, J = 16, 1H), 6.30 (dd, J = 16, 6.5, 1H), 6.10 (ddd, J = 9.6, 1.7, 1.7, 1H), 5.10 (m, 1H), 2.59 (m, 2H); 13C NMR: δ 164.1, 144.8, 135.9, 133.3, 128.9, 128.5, 126.9, 125.8, 121.9, 78.1, 30.1; HRMS (CI) calcd for [C13H12O2 + H]+: 201.0916 Found: 201.0920.

4.1.8. (R)-(+)-goniothalamin oxide (3b)

To a solution of 4a (25 mg, 0.10 mmol) in 7 mL of CH2Cl2 was added Grubbs (I) catalyst (8 mg, 0.010 mmol) at room temperature. After stirring for 4 hrs at reflux the reaction was concentrated. Flash chromatography on silica gel (7:3 (v/v) hexane:EtOAc) provided compound 5 (17 mg, 77% yield) as a dark oil. (Note: Color caused by Grubbs catalyst) Rf = 0.9 (8:2 (v/v) hexanes:EtOAc). Spectral data gave a satisfactory match to previous reports.xvii [α]25D + 100 (c 0.4, CHCl3); IR (neat, cm −1) 1724, 1247, 1041, 815; 1H NMR (CDCl3, 600 MHz) 7.34 (m, 5H), 6.94 (ddd, J = 9.7, 4.9, 3.7 Hz, 1H), 6.08 (ddd, J = 9.6, 3.7, 1.7, 1H), 4.45 (ddd, J = 9.1, 5.8, 5.8 Hz, 1H), 3.89 (d, J = 1.9 Hz, 1H), 3.27 (dd, J = 5.6, 1.9 Hz, 1H), 2.59 (m, 2H); 13C NMR (CDCl3, 600 MHz) δ 163.7, 144.2, 135.7, 128.7, 128.6, 125.7, 121.6, 77.1, 61.5, 57.3, 25.9; HRMS (CI) calcd for [C13H13O3 + Na]+: 239.0684 Found: 239.0686.

4.1.9. 7,8-bis-epi-(R)-(+)-goniothalamin oxide (3c)

To a solution of 4b (25 mg, 0.10 mmol) in 7 mL of CH2Cl2 was added Grubbs (I) catalyst (8 mg, 0.010 mmol) at room temperature. After stirring for 4 hrs at reflux the reaction was concentrated. Flash chromatography on silica gel (7:3 (v/v) hexane:EtOAc) provided compound 6 (17 mg, 77% yield) as a dark oil. Rf = 0.86 (8:2 (v/v) hexanes:EtOAc); [α]25D – 5.4 (c 1.0, CHCl3); IR (neat, cm−1) 1724, 1386, 1247, 1041, 815, 698; 1H NMR (CDCl3, 270 MHz) 7.33(m, 5H), 6.92 (ddd, J = 8.7, 5.4, 3.0 Hz, 1H), 6.08 (ddd, 9.9, 2.6, 1.7 1H), 4.68 (ddd, J = 8.7, 4.7, 3.7 Hz, 1H), 4.08 (d, J = 1.9 Hz, 1H), 3.24 (dd, J = 3.7, 1.9 Hz, 1H), 2.62 (m, 2H); 13C NMR (CDCl3, 600 MHz) δ 162.8, 143.9, 135.9, 128.6, 128.6, 125.7, 121.6, 75.1, 62.1, 55.0, 26.2; HRMS (CI) calcd for [C13H13O3 + H]+: 217.0785 Found: 217.0866.

Figure 1
Goniothalamin -based derivatives
Scheme 6
Ring-Closing Metathesis of 4a, 4b and 9

Acknowledgments

We are grateful to NIH (GM63150) and NSF (CHE-0415469) for the support of our research program and NSF-EPSCoR (0314742) for a 600 MHz NMR at WVU.

Footnotes

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References and Notes

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xii. (a) Guo H, Mortensen MS, O’Doherty GA. Org Lett. 2008;10:3149–3152. [PubMed] (b) Li M, O’Doherty GA. Org Lett. 2006;8:6087–6090. [PubMed] (c) Li M, O’Doherty GA. Org Lett. 2006;8:3987–3990. [PubMed] (d) Gao D, O’Doherty GA. J Org Chem. 2005;70:9932–9939. [PubMed]
xiii. Previous approaches to goniothalamin and goniothalamin oxide used the Brown AllylBIpc2 reagent, see: refs i and ii. We have found that the Leighton reagent works equally well in terms of stereochemical outcome and allows for a significantly simpler product isolation procedure, see: Kubota K, Leighton J. Angew Chem Int Ed. 2003;42:946–948. [PubMed]
xiv. Precedent for this epoxidation stereoselectivity can be found in Marko’s synthesis of (+)-(R)-goniothalamin oxide, see; ref iib.
xv. Nakajima M, Saito M, Shiro M, Hashimoto S. J Am Chem Soc. 1998;120:6419.
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