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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Synthesis (Stuttg). Author manuscript; available in PMC 2010 September 1.
Published in final edited form as:
Synthesis (Stuttg). 2009 September 1; 2009(17): 2840–2846.
doi:  10.1055/s-0029-1216912
PMCID: PMC2921946
NIHMSID: NIHMS183691

Towards the Total Synthesis of 3-Hydroxyvibsanin E

In 1999 Fukuyama reported the isolation of 3-hydroxyvibsanin E (1) (Figure 1) from Viburnum awabuki1 with an additional finding in Viburnum suspensum three years later.2 Across the entire spectrum of vibsane natural products α-hydroxylation is very rare,3,4 occuring only at position 3 of the bridged 7-membered ring class [e.g. 3-hydroxy-15-O-methylcyclovibsanin A (2),5 furanovibsanin A (3),6 and 3-O-methylfuranovibsanin A (4)6] (Figure 1). Although, the assumed later stage p450 enzymatic oxidation7 to introduce the single hydroxyl group at position 3 is biosynthetically elegant it posses a considerable increase in the degree of synthetic challenge over the non-hydroxylated family members. Recently, we disclosed a combined effort which resulted in the total syntheses of both (−)-epi-5-vibsanin E (5)8 and (±)-vibsanin E (6).9 On this basis we felt that the methodology devised to prepare 5 and 6, and the experience gained from individual efforts10,11 on other vibsane natural products, could be applied to the more challenging hydroxylated family members, specifically 3-hydroxyvibsanin E (1) (Figure 1).

Figure 1
α-Hydroxylated and related vibsane family members

Key to this endeavour would be the use of Davies’ tricyclic advanced intermediate 7,10 generated by means of two cycloadditions: 1) a rhodium-catalysed [4+3] cycloaddition to give 8 from 9, and 2) a subsequent heteronuclear [4+2] cycloadditon (Scheme 1). The tricyclic intermediate 7 has been effectively used in the synthesis of both (−)-epi-5-vibsanin E (5)8 and (±)-vibsanin E (6)9 as summarized in scheme 1. In order to apply 7 to the synthesis of 3-hydroxyvibsanin E (1), a regioselective C—H hydroxylation of one of the intermediates in Scheme 1 would be required.12 In this paper, we summarize the model studies to develop a selective C—H hydroxylation, followed by its application to studies toward the total synthesis of (±)-3-hydroxyvibsanin E (1).

Several reasonable approaches are available for the selective C—H hydroxylation of vibsane-related intermediates. Williams reported11f that Koser’s reagent13 [PhI(OH)(OTs)] was superior to that of Davis’ reagent (PhCHONSO2Ph)14 in producing 16, when investigating α-hydroxylation of tricycle 15. In the case of 7, however, Davies10b found that the Davis’ reagent was superior affording 17 in 53% yield.10b Williams11g found that a vastly improved protocol over both of the above procedures was the Rubottom oxidation15 of 18 giving 19 in 80% yield (Scheme 2).

With this knowledge in-hand the approach shown in scheme 3 toward 3-hydroxyvibsanin E (1) was taken. The stereospecfic cuprate addition product 108 was doubly deprotected to unmask the ketone and primary alcohol. Treatment of 20 with t-butyldimethylsilyl trifluoromethansulfonate (TBSOTf) reprotected the primary alcohol and trapped out regiospecifically the thermodynamic silyl enol ether 21. Subjecting 21 to dimethyl dioxirane (DMDO) provided the epoxide 22, which could be isolated, but was directly treated with boron trifluoride etherate to facilitate epoxide ring opening. However, instead of the ring opening affording 24, the hydroxyketone 23 was obtained. Subsequent exposure of 23 to sodium hydride was required to complete the transformation of 21 into 24 (as determined by X-ray crystal structure analysis, Figure 2), which occurred in high yield (71% over three steps) (Scheme 3).

Figure 2Figure 2
X-Ray crystal structure analysis of compounds 24, 26 and 27 at the 30% elipsoid probability level

O-Allylation of the lithium enolate derived from 24 proceeded smoothly in 81% yield. The Claisen rearrangement occurred in only moderate yield to give 26 and 27 (d.r. 3:1; respectively) [as determined by X-ray crystal structure analysis (Figure 2)], albeit steroselectively in favour of the desired anti-isomer 26, which is almost certainly due to the bulky OTBS group perturbing the upper face. Regioselective deprotection of the primary alcohol (i.e. 26) was initially troublesome, but boron trifluoride etherate was found to be the reagent of choice providing the free alcohol 28 in 78% yield. Swern oxidation gave aldehyde 29 in modest yield (67%), which was directly converted to the tricarbonyl analogue 30 in 50% yield using the previously described Wacker protocol (Scheme 4).9

Application of the modified Anders-Gaβner reaction,16 via ylid 14,17 to aldehyde 30 afforded 3-O-t-butyldimethylsilyloxyvibsanin E (31) in 40% yield as a single E-isomer. All attempts, however, to remove the TBS protecting group from this system proved impossible. Very aggresive protocols lead to hydrolysis of the enol acetate side chain, whereas all others returned starting material. Even the use of tetrafluorosilane, reported to remove problematical TBS groups from tertiary substituted OTBS groups,18 failed to deliver the target molecule 1 (Scheme 5).

Other silyl protecting groups were then investigated, such as trimethylsilyl (TMS), but these protecting groups were found not to survive boron trifluoride treatment at either stage of the route present i.e. in scheme 4 and and5.5. Attempts to circumvent these issues, for example, deprotection of aldehyde 30 with a range of reagents either returned starting material or resulted in decomposition. Considering previous work has shown that the enol acetate sidechain does not survive Wacker conditions11g we came to the disappointing conclusion that this approach would not yield 3-hydroxyvibsanin E (1).

In conclusion, application of a modified route to that used for the total synthesis of both (−)-epi-5-vibsanin E (5) and (±)-vibsanin E (6) afforded the TBS protected form of 3-hydroxyvibsanin E (31). Attempts at the deprotection of the TBS group to generate 3-hydroxyvibsanin E (1) were unsuccessful. We hope that this report inspires others to contemplate alternative approaches to this molecule, and related family members.

Experimental

1H and 13C n.m.r spectra were recorded on Bruker AV400 (400.13MHz; 100.62 MHz), AV300 (300.13 MHz; 75.47 MHz) and DRX500 (500.13 MHz; 125.76 MHz) instruments in the solvents specified. Coupling constants are given in Hz and chemical shifts are expressed as δ values in ppm. High resolution electrospray ionisation (HRESIMS) accurate mass measurements were recorded in positive mode on a Bruker MicrOTOF–Q (quadrupole – Time of Flight) instrument with a Bruker ESI source. Accurate mass measurements were carried out with external calibration using sodium formate as reference calibrant. Lo w a n d high resolution electron impact ionisation mass measurements were recorded on a Finnigan MAT 900XL–T R A P ( E I 7 0 e V ) u s i n g perfluorokerosene–H as reference calibrant. Column chromatography was undertaken on silica gel (Flash Silica gel 230–400 mesh), with distilled solvents. Anhydrous solvents were prepared according to Perin and Armarego, ‘Purification of laboratory solvents’, 3rd Ed. Tetrahydrofuran was freshly distilled from a sodium/benzophenone still. Melting points were determined on a Fischer Johns Melting Point apparatus and are uncorrected. Fine chemicals were purchased from the Aldrich Chem. Co. Microwave irradiation was conducted with a CEM Discover microwave in 10 mL pressurized vials. Crystallographic data for structures 24, 26, and 27 have been deposited with the Cambridge Crystallographic Data Centre (CCDC 737635 - 737637) and may be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336 033, or e-mail: ku.ca.mac.cdcc@tisoped.

Alcohol 20

A mixture of 10 (500 mg, 1.31 mmol) in MeOH (25 mL), water (3 mL) and aqueous hydrochloric acid (2 mL, 10M) was stirred at 55 °C for 2 hours. The mixture was quenched with saturated sodium bicarbonate solution (10 mL) and then the methanol was removed in vacuo and the mixture extracted with dichloromethane (3 × 15 mL). The combined organic layer was washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo which afforded an oil. The crude oil was purified by flash chromatography (1:1 ether:pet. spirit) to give 20 (0.29 g, 78%) as a white solid, m.p. 123–125 °C. 1H NMR (300 MHz, CDCl3) δ 1.02 (s, 3H), 1.08 (s, 3H), 1.10–1.17 (m, 3H), 1.23 (s, 3H), 1.40–1.48 (m, 2H), 1.52–1.63 (m, 2H), 2.08 (brs, OH), 2.18–2.27 (m, 2H), 2.55 (dd, J = 11.8, 2.9 Hz, 1H), 2.58–2.63 (m, 1H), 2.60–2.71 (t, J = 11.6 Hz, 1H), 3.49–3.57 (m, 2H), 3.73 (dd, J = 10.7, 4.9 Hz, 1H), 4.22 (dd, J = 12.0, 0.6 Hz, 1H). 13CNMR (75 MHz, CDCl3) δ 19.5, 23.4, 27.8, 28.6, 29.8, 32.9, 41.8, 42.5, 43.0, 44.3, 44.8, 49.9, 59.2, 64.8, 71.1, 213.4. HRMS Calculated for [C16H26NaO3]+: 289.1774, Found: 289.1763

TBS–protection of alcohol 20

To a solution of alcohol 20 (600 mg, 2.24 mmol) in anhydrous DCM (20 mL) at −78 °C was added anhydrous triethylamine (1.25 mL, 8.96 mmol) followed by tert–butyldimethylsilyltrifluoromethane sulfonate (1.29 mL, 5.60 mmol) dropwise. The reaction was stirred at −78 °C for 30 mins then stirred for a further 30 mins at 0 °C. The reaction was then poured onto ice–cold saturated sodium bicarbonate solution (10 mL) and then extracted with diethyl ether (3 × 15 mL). The combined organic layer was washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo which gave an oil that was purified by flash chromatography (1:20 ether:pet. spirit) to give 21 (1.12 g, 88%) as a white solid, m.p. 58–61 °C. 1H NMR (400 MHz, C6D6) δ 0.07 (s, 3H), 0.08 (s, 3H), 0.09 (s, 3H), 0.16 (s, 3H), 0.81 (s, 3H), 0.82–0.91(m, 2H), 0.98 (s, 9H), 1.00 (s, 9H), 1.07–1.08 (m, 1H), 1.14 (s, 3H), 1.24 (s, 3H), 1.38 (ddd, J = 14.8, 7.4, 3.8 Hz, 1H), 1.61 (app. dq, J = 13.2, 3.3 Hz, 1H), 1.89 (qd, J = 13.4, 3.7 Hz, 1H), 2.15–2.23 (m, 2H), 2.26–2.32 (m, 1H), 2.47–2.56 (m, 1H), 2.67–2.72 (m, 1H), 3.35 (dd, J = 9.8, 8.2 Hz, 1H), 3.57 (dd, J = 9.8, 5.4 Hz, 1H), 3.86 (d, J = 11.9 Hz, 1H), 4.77 (d, J = 11.9 Hz, 1H). 13C NMR (100 MHz, C6D6) δ −5.3, −5.2, −4.2, −3.8, 18.3, 18.5, 19.9, 24.1, 25.8, 26.0 (3C), 26.2 (3C), 27.8, 32.5, 33.3, 34.8, 39.7, 42.0, 46.4, 47.7, 61.4, 64.9, 73.5, 115.9, 147.1. HRMS Calculated for C28H54O3Si2: 494.3611, Found: 494.3611.

Hydroxylation of 21

To a solution of 21 (1.12 g, 2.19 mmol) in distilled acetone (10 mL) at −78 °C was added a solution of dimethyl dioxirane (27 mL, 2.19 mmol, 0.06 M solution in acetone) over 5 mins. After stirring for a further 5 mins the cold–bath was removed and the solvent removed in vacuo [the acetone was removed into an in–line trap cooled with liquid nitrogen and excess dimethyl dioxirane in the trap was quenched with cyclohexene (5 mL)] which afforded 22 as a white solid (1.13 g), m.p. 54–56°C which was used immediately in the next step without further purification. 1H NMR (400 MHz, C6D6) δ 0.10 (s, 3H), 0.11 (s, 3H), 0.23 (s, 3H), 0.34 (s, 3H), 0.60 (dd, J = 14.4, 4.6 Hz, 1H), 0.73 (s, 3H), 0.87 (td, J = 13.5, 13.4, 4.1 Hz, 1H), 0.98 (s, 9H), 0.99 (s, 9H), 1.04–1.09 (m, 1H), 1.10 (s, 3H), 1.16 (s, 3H), 1.36–1.44 (m, 1H), 1.69 (ddd, J = 13.4, 6.4, 3.3 Hz, 1H), 1.78–1.89 (m, 2H), 2.13 (dd, J = 13.8, 10.7 Hz, 1H), 2.22–2.28 (m, 1H), 2.29 (d, J = 14.0 Hz, 1H), 2.44 (dd, J = 7.6, 3.8 Hz, 1H), 3.43 (dd, J = 9.8, 7.3 Hz, 1H), 3.59 (dd, J = 9.8, 5.6 Hz, 1H), 3.70 (d, J = 12.1 Hz, 1H), 4.12 (d, J = 12.1 Hz, 1H). 13C NMR (100 MHz, C6D6) δ −5.2 (2C), −3.3, −2.8, 18.0, 18.6, 20.6, 23.3, 26.0 (3C), 26.0, 26.3 (3C), 27.3, 33.2, 34.4, 35.5, 37.9, 38.1, 42.0, 44.3, 41.1, 63.0, 65.0, 73.2, 91.5

The crude epoxide was dissolved in anhydrous dichloromethane (25 mL), under an atmosphere of argon, cooled to −78 °C and then freshly distilled boron trifluoride diethyl etherate (27 µL, 0.22 mmol) was added dropwise. The reaction was stirred for 10 mins then poured onto ice–cold saturated sodium bicarbonate solution (10 mL) and then extracted with dichloromethane (3 × 15 mL). The combined organic layer was washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo which afforded an oil. Purification by flash chromatography (1:1 ethyl acetate:pet. spirit) gave 23 (0.69 g, 80%, 2 steps) as a white solid, m.p. 108–109 °C. 1H NMR (400 MHz, CDCl3) δ 0.01 (s, 3H), 0.03 (s, 3H), 0.87 (s, 9H), 0.87–0.89 (m, 1H), 0.96 (s, 3H), 1.14 (s, 3H), 1.33 (s, 3H), 1.17–1.26 (m, 1H), 1.38–1.46 (m, 1H), 1.48–1.58 (m, 2H), 1.62–1.72 (m, 2H), 2.11 (dt, J = 15.0, 2.3 Hz, 1H), 2.34 (td, J = 6.0, 1.9 Hz, 1H), 2.81 (dd, J = 12.0, 4.0 Hz, 1H), 3.04 (dd, J = 12.0, 8.2 Hz, 1H), 3.17 (s, OH), 3.45 (d, J = 12.2 Hz, 1H), 3.48 (dd, J = 10.0, 7.3 Hz, 1H), 3.63 (dd, J = 10.0, 4.7 Hz, 1H), 3.84 (d, J = 12.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ −5.5 (2C), 18.2, 21.9, 24.3, 25.9 (3C), 26.8, 29.8, 32.8, 36.3, 36.6, 40.4, 41.7, 42.4, 45.7, 63.9, 66.6, 73.8, 75.7, 211.8. HRMS Calculated for [C22H40NaO4Si]+: 419.2588, Found: 419.2586.

TBS–protection of 23

To a solution of hydroxyketone 23 (0.69 g, 1.75 mmol) in anhydrous THF (25 mL) under an atmosphere of argon at 0 °C was added NaH (175 mg, 4.4 mmol, 60% dispersion in mineral oil) in one portion. After 5 mins tert–butyldimethylsilyl chloride (0.34 g, 2.28 mmol) was added and the reaction was then stirred at 55 °C for 2 hours. The mixture was poured onto ice–cold saturated sodium bicarbonate solution (10 mL) and then extracted with ether (3 × 15 mL). The combined organic layer was washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo which gave an oil that was purified by flash chromatography (1:10 ether: pet. spirit) affording 24 (0.80 g, 89%) as a white solid, m.p. 115.5–116.5 °C. 1H NMR (400 MHz, CDCl3) δ −0.04 (s, 3H), −0.01 (s, 6H), 0.06 (s, 3H), 0.86 (s, 9H), 0.86 (s, 9H), 0.98–1.09 (m, 1H), 0.99–1.10 (m, 2H), 1.05 (s, 3H), 1.10 (s, 3H), 1.21–1.27 (m, 1H), 1.29 (s, 3H), 1.37–1.43 (m, 1H), 1.44–1.51 (m, 2H), 2.11 (dd, J = 11.0, 2.2 Hz, 1H), 2.26 (app. t, J = 5.3 Hz, 1H), 2.46 (dt, J = 14.9, 2.1, 2.1 Hz, 1H), 3.20 (dd, J = 13.0, 11.0 Hz, 1H), 3.37 (d, J = 11.1 Hz, 1H), 3.61 (m, 2H), 4.07 (d, J = 11.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ −5.6, −5.6, −3.2, −1.8, 18.1, 18.3, 19.4, 23.6, 25.8 (3C), 25.9 (3C), 27.4, 28.3, 33.1, 37.4, 39.1, 41.4, 42.8, 43.9, 44.2, 64.5, 65.8, 73.1, 75.9, 211.5. HRMS Calculated for [C28H54NaO4Si2]+: 533.3453, Found: 533.3433.

Allylation of 24

To a solution of ketone 24 in (0.35 g, 0.69 mmol), in THF (6 mL) at −78°C under an atmosphere of argon was added a freshly prepared solution of lithium diisopropylamide dropwise [generated from n–butyllithium (0.52 mL, 0.76 mmol, 1.48 M in hexanes) and diisopropylamine (116 µL, 0.83 mmol) at 0°C in THF (2 mL)]. After 5 mins the reaction was warmed to 0°C and stirred for 30 mins, after which time anhydrous HMPA (1.5 mL) and allyl iodide (140 mg, 0.83 mmol) were added consecutively, dropwise. After 5 mins TLC analysis showed complete consumption of starting material and the mixture was poured onto ice–cold saturated sodium bicarbonate solution (10 mL) and then extracted with diethyl ether (3 × 15 mL). The combined organic layer was washed with aqueous lithium chloride (2 × 15 mL, 10%), brine (10 mL), dried (Na2SO4) and concentrated in vacuo which gave a residue that was purified by flash chromatography (1:20 ether: pet. spirit) affording 25 (0.31 g, 81%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ −0.08 (s, 3H), 0.00 (s, 3H), 0.01 (s, 3H), 0.04 (s, 3H), 0.81–0.85 (m, 1H), 0.83 (s, 9H), 0.86 (s, 9H), 1.03–1.10 (m, 1H), 1.07 (s, 3H), 1.31 (s, 3H), 1.19–1.37 (m, 3H), 1.63–1.72 (m, 1H), 1.98–2.14 (m, 2H), 2.16–2.22 (m, 1H), 2.47 (dt, J = 14.3, 2.3 Hz, 1H), 3.11 (d, J = 10.8 Hz, 1H), 3.40 (dd, J = 9.6, 7.3 Hz, 1H), 3.77 (dd, J = 9.6, 5.8 Hz, 1H), 4.25–4.07 (m, 2H), 4.08–4.25 (m, 2H), 40 (d, J = 10.8 Hz, 1H), 4.89 (d, J = 8.2 Hz, 1H), 5.15 (app. dq, J = 10.5, 1.5 Hz, 1H), 5.30 (app. dq, J = 17.3, 1.7 Hz, 1H), 5.99 (dddd, J = 17.3, 10.4, 5.4, 4.9 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ −5.4, −5.3, −3.8, −1.9, 18.1, 18.3, 22.3, 24.2, 25.9 (6C), 27.2, 32.1, 32.5, 33.7, 40.7, 43.5, 44.7, 50.3, 66.2, 67.8, 68.1, 73.5, 75.7, 105.8, 116.4, 134.0, 154.6. HRMS Calculated for [C31H58NaO4Si2]+: 573.3766, Found: 573.3765.

Claisen rearrangement of 25

A solution of O–allylated material 25 (260 mg, 0.47 mmol) in solution of anhydrous toluene (4 mL) and DMSO (0.5 mL) under an atmosphere of argon was heated under microwave irradiation for 95 min. (maximum temperature 180 °C, 300 W). The solvent was removed in vacuo which afforded crystals that were purified by flash chromatography (1:10 ether:pet. spirit) giving C–allylated isomers anti (26) (150 mg, 58%), m.p. 116–119°C and syn (27) (45 mg, 17%) m.p. 122–123°C as colourless crystals. Anti-isomer 26 1H NMR (400 MHz, CDCl3) δ 0.02 (s, 3H), 0.03 (s, 3H), 0.05 (s, 3H), 0.17 (s, 3H), 0.81–0.86 (m, 2H), 0.86 (s, 9H), 0.88 (s, 9H), 1.03 (ddd, J = 17.1, 14.7, 3.1 Hz, 1H) 1.11 (s, 3H), 1.15 (s, 3H), 1.25–1.33 (m, 1H), 1.13–1.24 (m, 2H), 1.30 (s, 3H), 1.45 (dq, J = 12.7, 2.9 Hz, 1H), 2.20 (app. t, J = 4.9, Hz, 1H), 2.25–2.32 (m, 1H), 2.41–2.50 (m, 1H), 2.55 (dt, J = 14.9, 2.2 Hz, 1H), 3.43–3.52 (m, 1H), 3.49 (d, J = 11.4 Hz, 1H), 3.68 (dd, J = 10.8, 4.1 Hz, 1H), 3.74 (dd, J = 10.8, 1.7 Hz, 1H), 3.97 (d, J = 11.2 Hz, 1H), 4.88–4.81 (m, 1H), 4.96 (ddd, J = 17.0, 3.5, 1.3 Hz, 1H), 5.66 (ddt, J = 17.0, 10.1, 7.0 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ −5.8, −5.7, –1.7 (2C), 17.9, 18.5, 18.9, 23.8, 25.8 (3C), 26.1 (3C), 27.4, 30.4, 34.0, 34.3, 37.2, 37.8, 43.0, 44.2, 45.2, 47.0, 61.0, 64.5, 73.1, 76.6, 116.1, 137.5, 213.1. HRMS Calculated for [C31H58NaO4Si2]+: 573.3766, Found: 573.3756. Syn-isomer 27 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 3H), 0.02, (s, 3H), 0.07 (s, 3H), 0.08 (s, 3H), 0.83 (s, 9H), 0.85 (s, 9H), 0.85–0.86 (m, 1H), 0.94 (s, 3H), 1.14–1.21 (m, 1H), 1.16 (s, 3H), 1.36 (s, 3H), 1.43 (dd, J = 14.3, 6.8 Hz, 1H), 1.56–1.65 (m, 2H), 1.65–1.75 (m, 1H), 1.77–1.89 (m, 1H), 1.91–2.07 (m, 1H), 2.08–2.19 (m, 1H), 2.40 (td, J = 6.8, 1.8 Hz, 1H), 2.58–2.69 (m, 1H), 3.21 (dd, J = 11.3, 6.7 Hz, 1H), 3.50 (d, J = 12.5 Hz, 1H), 3.55 (dd, J = 11.4, 1.9 Hz, 1H), 3.58–3.61 (m, 1H), 3.65 (d, J = 12.5 Hz, 1H), 4.97–5.01 (m, 1H), 5.00–5.08 (m, 1H), 5.70 (ddt, J = 17.1, 10.1, 7.0 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ −5.5, −5.4, −2.8, −2.4, 18.0, 18.7, 24.3, 24.5, 25.9 (3C), 26.1 (3C), 26.4, 32.5, 32.9, 34.6, 34.7, 37.9, 39.9, 40.3, 49.1, 53.3, 60.5, 69.3, 74.2, 80.8, 116.9, 136.2, 211.8. HRMS Calculated for [C31H58NaO4Si2]+: 573.3766, Found: 573.3774.

Deprotection of 26

To a solution of 26 (260 mg, 0.47 mmol) in anhydrous acetonitrile (20 mL) under an atmosphere of argon at 0 °C was added dropwise, freshly distilled, boron trifluoride diethyl etherate (70 µL, 0.57 mmol). After 5 minutes the ice bath was removed and the reaction stirred for 40 minutes at room temperature after which time TLC analysis revealed complete consumption of starting material. A saturated solution of sodium bicarbonate (10 mL) was then added and the acetonitrile was removed in vacuo. The mixture was then extracted with ethyl acetate (3 × 20 mL) and the combined organic layers were washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo which afforded a residue that was purified by flash chromatography (1:20, ether:dichloromethane) affording alcohol 28 as a colourless solid (160 mg, 78%), mp.182–184 °C. 1H NMR (300 MHz, CDCl3) δ 0.05 (s, 3H), 0.16 (s, 3H), 0.87 (s, 9H), 0.97–1.08 (m, 1H), 1.11 (s, 3H), 1.13–1.26 (m, 4H), 1.27–1.38 (m, 2H), 1.18 (s, 3H), 1.30 (s, 3H), 1.47–1.54 (m, 1H), 2.22 (app. t, J = 5.3 Hz, 1H), 2.29–2.39 (m, 1H), 2.46–2.59 (m, 2H), 3.39 (ddd, J = 11.5, 8.7, 5.0 Hz, 1H), 3.48 (d, J = 11.3 Hz, 1H), 3.74–3.88 (m, 2H), 3.99 (d, J = 11.2 Hz, 1H), 4.90 (ddt, J = 10.3, 2.2, 1.1, Hz, 1H), 5.04 (ddd, J = 17.1, 3.4, 1.6 Hz, 1H), 5.69 (dddd, J = 16.5, 10.1, 7.7, 6.3 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ −1.9, −1.7, 18.5, 19.1, 23.8, 26.0 (3C), 27.2, 29.9, 34.1, 34.3, 37.2, 38.1, 42.3, 44.0, 45.1, 47.1, 61.4, 64.4, 73.1, 76.6, 116.2, 137.6, 212.5. HRMS Calculated for [C25H44NaO4Si]+: 459.2901, Found: 459.2923.

Aldehyde 29

To a stirred solution of oxalyl chloride (64 µL, 0.73 mmol) in anhydrous dichloromethane (10 mL) under an argon atmosphere at –78°C was added dimethylsulfoxide (65 µL, 0.92 mmol) dropwise. After 10 mins a solution of alcohol 28 (160 mg, 0.37 mmol) in dichloromethane (2 mL) was added dropwise. After 1 hour at –78°C excess anhydrous triethylamine (308 µL, 2.2 mmol) was added and stirring continued at that temperature for a further 15 mins. The solution was warmed to 0°C and stirred for 20 mins, then diluted with dichloromethane (30 mL), washed with brine (10 mL) and dried (MgSO4). Evaporation in vacuo gave a residue which was subjected to column chromatography (1:20, ether:dichloromethane) affording ketoaldehyde 29 (108 mg, 67 %) as a colourless solid, mp. 87–89 °C. 1H NMR (300 MHz, CDCl3) δ 0.06 (s, 3H), 0.17 (s, 3H), 0.86–0.91 (m, 1H), 0.89 (s, 9H), 1.00 (s, 3H), 1.07–1.15 (m, 1H), 1.12 (s, 3H), 1.17–1.28 (m, 2H), 1.31 (s, 3H), 1.35–1.45 (m, 1H), 1.59–1.67 (m, 1H), 1.86–1.96 (m, 2H), 2.29 (app. t, J = 5.2 Hz, 1H), 2.46 (dddt, J = 14.0, 9.4, 6.8, 1.3 Hz, 1H), 2.64 (dt, J = 15.0, 2.2 Hz, 1H), 3.52 (d, J = 11.2 Hz, 1H), 3.67 (ddd, J = 12.1, 9.6, 3.5 Hz, 1H), 4.00 (d, J = 11.2 Hz, 1H), 4.87–5.00 (m, 2H), 5.59 (ddt, J = 17.2, 10.1, 7.0, 7.0 Hz, 1H), 9.51 (d, J = 5.7 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ −1.9, −1.68, 18.5, 18.8, 23.6, 26.0 (3C), 27.3, 30.2, 33.6, 34.5, 36.5, 38.2, 43.7, 44.0, 59.3, 64.7, 73.1, 77.2, 117.6, 129.0, 135.5, 201.8, 209.0. HRMS Calculated for [C25H42NaO4Si]+: 457.2745, Found: 457.2759.

Tricarbonyl 30

Ketoaldehyde 29 (134 mg, 0.31 mmol) was dissolved in a mixture of N,N–dimethylformamide and water (7:1, 4 mL), and to this was added palladium dichloride (5 mg, 28 µmol) and copper (II) chloride dihydrate (53 mg, 0.31 mmol). The reaction mixture was then stirred under a balloon of oxygen for 1 hour. Filtration through celite followed by evaporation under high vacuum gave a residue which was subjected to column chromatography (1:20, ether : dichloromethane) affording tricarbonyl 30 (70 mg, 50%) as a colorless low melting wax. 1H NMR (400 MHz, C6D6) δ 0.10 (s, 3H), 0.12 (s, 3H), 0.69 (td, J = 13.3, 4.9 Hz, 1H), 0.81 (s, 3H), 0.82–0.99 (m, 4H), 1.04 (s, 9H), 1.06 (s, 3H), 1.07–1.14 (m, 1H), 1.16 (s, 3H), 1.30–1.37 (m, 1H), 1.62 (s, 3H), 2.15 (app. t, J = 4.9 Hz, 1H), 2.21 (dd, J = 18.2, 5.6 Hz, 1H), 2.66–2.71 (m, 1H), 2.74 (dd, J = 18.2, 6.8 Hz, 1H), 3.54 (d, J = 11.0 Hz, 1H), 4.18 (ddd, J = 12.1, 6.7, 5.6 Hz, 1H), 4.36 (d, J = 11.0 Hz, 1H), 9.34 (d, J = 5.5 Hz, 1H). 13C NMR (100 MHz, C6D6) δ −2.3, −1.6, 18.8, 19.2, 23.6, 26.3 (3C), 27.5, 29.8, 30.2, 34.2, 36.3, 39.1, 39.8, 43.6, 43.9, 44.0, 60.4, 65.3, 72.8, 77.5, 201.0, 204.8, 209.0. HRMS Calculated for [C25H42NaO5Si]+: 473.2694, Found: 473.2684.

3–OTBS–Vibsanin E 31

A suspension of [(3–methylbut–2–enoyloxy)methyl]triphenylphosphonium chloride11h (127 mg, 0.31 mmol) in anhydrous tetrahydrofuran (5 mL) under an argon atmosphere was sonicated for 10 minutes until a uniform milky dispersion had formed. The mixture was then cooled to –78°C and a solution of sodium bis(trimethylsilyl)amide solution (340 µL, 0.34 mmol, 1M solution in THF) was added strictly dropwise. The brightly orange coloured reaction mixture was stirred for 10 minutes then a solution of tricarbonyl 30 (70 mg, 0.16 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise and after complete addition the solution turned colourless. The reaction was stirred for 2 minutes then the mixture was poured onto saturated ice–cold sodium bicarbonate (5 mL) and extracted with diethyl ether (3 × 15 mL). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (1:10, ethyl acetate : pet. spirit ) affording 31 (34 mg, 40%) as a colourless paste. 1H NMR (400 MHz, C6D6) δ 0.03 (s, 3H), 0.09 (s, 3H), 0.74 (ddd, J = 13.5, 13.3, 4.8 Hz, 1H), 0.81–0.87 (m, 1H), 0.85 (s, 3H), 0.90–0.99 (m, 2H), 1.01 (s, 9H), 1.12–1.29 (m, 2H), 1.13 (s, 3H), 1.20 (s, 3H), 1.36 (d, J = 1.3 Hz, 3H), 1.67 (app. t, J = 11.7 Hz, 1H), 1.75 (s, 3H), 2.04 (d, J = 1.2 Hz, 3H), 2.22 (app. t, J = 4.0 Hz, 1H), 2.52 (dd, J = 18.4, 3.7 Hz, 1H), 2.69 (dd, J = 18.3, 8.6 Hz, 1H), 2.77 (dt, J = 14.9, 2.1 Hz, 1H), 3.55 (d, J = 11.0 Hz, 1H), 4.13 (ddd, J = 12.1, 8.6, 3.8 Hz, 1H), 4.43 (d, J = 11.0 Hz, 1H), 5.34 (dd, J = 12.0, 11.7 Hz, 1H), 5.60–5.58 (m, 1H), 7.19 (d, J = 12.3 Hz, 1H). 13C NMR (100 MHz, C6D6) δ −2.5, −1.6, 18.7, 19.5, 20.3, 23.7, 26.2 (3C), 27.0, 27.6, 30.0, 31.5, 34.9, 36.3, 39.4, 41.6, 43.3, 44.1, 45.3, 48.3, 65.2, 72.9, 77.2, 115.2, 116.7, 135.4, 159.6, 163.3, 205.5, 210.6. HRMS Calculated for [C31H50NaO6Si]+:569.3269, Found: 569.3251.

Acknowledgement

We thank The University of Queensland, Australian Research Council (DP0666855) and the National Institutes of Health (GM080337) for financial support. Prof. Fukuyama from the Tokushima Bunri University (Japan) is gratefully acknowledged for providing NMR spectra of 3-hydroxyvibsanin E. HMLD has financial interests in Dirhodium Technologies, Inc., a company that manufactures chiral dirhodium catalysts.

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