Ti(III)-Catalyzed, concise synthesis of marine furanospongian diterpenes

Abstract

A bioinspired procedure for the straightforward synthesis of marine furanospongian diterpenes is described. The key step is the titanocene(III)-catalyzed radical cascade cyclization of the suitable epoxy-polyprene.

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Introduction

In recent years radical cyclizations of epoxypolyenes catalyzed by Cp₂TiCl (Nugent's reagent)^1–4 have become powerful tools in organic synthesis.^5–8 In fact this reaction has facilitated considerably the straightforward synthesis of several cyclic terpenes, including monoterpenoids, such as karahanaenone;⁹ sesquiterpenoids, such as trans-4(11),8-daucadiene,⁹ isodrimenediol,¹⁰ 3β-hydroxydihydroconfertifolin,¹⁰ tuberiferin,¹¹ and dehydrobrachylaenolide;¹¹ diterpenoids, such as 3β-hydroxymanool,¹² rostratone,^13,14 aphidicolin,¹⁴ pyripyropene A,¹⁴ barekoxide,⁹ and laukarlaool;⁹ triterpenoids, such as 3β-hydroxymalabaricatriene¹² and achilleol A;¹⁵ meroterpenoids, such as stypoldione,¹² zonarone¹⁶ and zonarol;¹⁶ and the ambergris-type odorant α-ambrinol.¹⁷ We have extended the Ti(III)-catalyzed radical cascade cyclization to the synthesis of furanospongian diterpenes, thus reinforcing the hypothesis that with a judicious choice of epoxy-polyprene starting material this method allows the straightforward synthesis of terpenoids with many different skeletons.

Results and discussion

Spongian diterpenes constitute a subfamily of marine terpenoids with a spongian skeleton (1)¹⁸ among which furanospongian diterpenes such as 2 and 3 incorporate a heteroaromatic furan D ring.¹⁸

Chart 1 Spongian skeleton (1) and chemical structure of furanospongian diterpenes 2 and 3.

Furanoditerpenoids 2 and 3 were first isolated from the nudibranch Glossodoris atromarginata¹⁹ and the sponge Spongia officinalis,²⁰ respectively, and have proved to exert a cytotoxic effect on tumor cells,²¹ antiviral activity,²¹ and an inhibitory effect on the development of sea-urchin embryos.²² These terpenoids are scarce in nature, however, and harvesting their biological sources from the sea is no easy task. Within this context, chemical synthesis may provide additional supplies to facilitate their pharmacological study. In fact, the total synthesis of 2 and 3 was reported as long ago as 1995,²³ and four years later both compounds were prepared from S−(+)-carvone.²⁴ Nevertheless, the total synthesis of these products requires more than twenty steps^23,25 and twelve or thirteen for preparation from (+)-carvone,²⁴ and even then affords low overall yields.

It is well known that the biosynthesis of steroids derives from the enzyme-catalyzed cyclization of 2,3-epoxy-squalene.²⁶ Inspired by this biosynthesis, we deemed that the synthesis of furanospongian diterpenoid 2 could be efficiently achieved by means of the key titanocene(III)-catalyzed cascade cyclization of epoxy-geranylgeraniol (5) (Scheme 1). Eventually, ketone 2 would be reduced to 1.

Scheme 1 Bioinspired retrosynthetic analysis of 2.

As expected, the titanocene(III)-catalyzed cascade cyclization of racemic epoxy-geranylgeraniol derivative 6, the starting material for our synthesis of stypoldione,¹² gave a 36% yield of tricyclic olefin 7 bearing the crucial exocyclic double bond (Scheme 2). This yield should be regarded as entirely satisfactory if we bear in mind that this Ti(III)-catalyzed cyclization selectively afforded a product containing three fused (trans/anti/trans) six-membered rings, an exocyclic alkene, and six stereogenic centers out of 192 possible regio- and stereoisomers.

Scheme 2 Synthesis of 2 and 3 from epoxy-polyprene 6. (a) Cp₂TiCl₂ (0.2 equiv.), Mn (8 equiv.), Me₃SiCl (4 equiv.), 2,4,6-collidine (7 equiv.), THF, rt, 12 h, 36%; (b) K₂CO₃, MeOH, 5 °C, 3 h, 85%; (c) MCPBA, DCM, 5 °C, 2 h, 95%; (d) Dess–Martin periodinane, rt, 5 h, 99%; (e) p-TsOH; DCM–DMSO, 50 °C, 6 h, 73%; (f) ref. 10, 1 step, 75%.

Simple saponification of acetate 7 unmasked the primary alcohol group of 8, which directed the following epoxidation reaction to give stereoselectively a 95% yield of β-epoxide 9 (stereochemistry of the oxirane ring was tentatively assigned due to the β-disposition of the hydroxyl-methyl directing group). Dess–Martin oxidation of diol 9 afforded an almost 100% yield of ketoaldehyde 10, which already had in place the epoxide and carbonyl functions required for the next heterocyclization step. Subsequently, the acidic treatment of 10 provided a 73% yield of synthetic furanospongian diterpene 2, the NMR data of which matched those reported for the natural product isolated from G. atromarginata.¹⁹ Thus, the synthesis of 2 from epoxy-polyene 6 was completed in only five steps to afford a 21% overall yield, substantially improving on the synthetic procedures mentioned above.^23,24 Moreover, the reduction of ketone 2 to diterpene 3 has already been reported,²⁴ and so Scheme 2 also represents the formal synthesis of the metabolite from the sponge S. officinalis (3) in six steps. Bearing in mind that titanium is one of the most abundant safe transition metals on Earth,²⁷ our results suggest that this titanocene(III)-catalyzed procedure might become a general method for the synthesis of furanospongian diterpenes.

Experimental

General methods

The general details have been described elsewhere.²⁸ Silica gel was used as solid support for flash chromatography. Compounds 2,¹⁹6,¹² and 7¹² are known and their NMR spectra matched those previously reported.

Cp₂TiCl-catalyzed cyclization of epoxy-polyprene 6

Strictly deoxygenated THF (4 mL) was added to a mixture of Cp₂TiCl₂ (21 mg, 0.086 mmol) and Mn dust (188 mg, 3.44 mmol) under an Ar atmosphere and the suspension was stirred at room temperature until it turned lime green (after about 15 min). Then, a solution of epoxy-polyprene 6 (150 mg, 0.43 mmol) and 2,4,6-collidine (0.36 mL, 3.0 mmol) in THF (0.5 mL), and Me₃SiCl (0.21 mL, 1.72 mmol) were added and the solution was stirred for 12 h. The reaction was then quenched with 2N HCl and extracted with Et₂O. The organic layer was washed with brine, dried (anhyd. Na₂SO₄), and the solvent removed. The residue was dissolved in THF (4 mL) and stirred with Bu₄NF (350 mg, 1.72 mmol) for 3 h. The mixture was then diluted with Et₂O, washed with brine, dried (anhyd. Na₂SO₄), and the solvent removed. The residue was submitted to flash chromatography (hexane–AcOEt 8 : 2) affording 7 (54 mg, 36% yield). The NMR data of 7 matched those previously reported.¹²

Preparation of diol 8

A solution of compound 7 (38 mg, 0.110 mmol) in MeOH (1 mL) was cooled to 5 °C and K₂CO₃ (95 mg, 0.69 mmol) was added. The reaction mixture was stirred for 3 h, the solvent was then removed and the residue was diluted in Et₂O and washed with brine. The organic layer was dried (anhyd. Na₂SO₄) and the solvent removed. The residue was submitted to flash chromatography (hexane–EtOAc, 7 : 3) to give diol 8 (29 mg, 85%) as an amorphous solid. IR (film) ν_max cm⁻¹ = 3337, 2850, 1644, 1442; ¹H NMR (500 MHz, CDCl₃): δ = 4.93 (d, J = 1.0 Hz, 1 H-16a), 4.64 (br d, J = 1.0 Hz, 1 H-16b), 3.82 (dd, J = 11.0, 3.8 Hz, 1 H-15a), 3.78 (dd, J = 10.9, 9.4 Hz, 1 H-3), 3.22 (dd, J = 11.6, 4.8 Hz, 1 H-15b), 3.15–3.09 (m, 1H), 2.41 (ddd, J = 12.8, 4.2, 2.4 Hz, 1 H), 1.95 (dd, J = 9.7, 3.4 Hz, 1 H), 1.78 (dt, J = 12.5, 3.1 Hz, 1 H), 1.73–1.20 (m, 11 H), 0.99 (s, 3H), 0.81 (s, 3H), 0.77 (s, 3 H), 0.72 (s, 3 H); ¹³C NMR (126 MHz, CDCl₃, DEPT): δ = 147.5 (C), 106.2 (CH₂), 78.8 (CH), 59.7 (CH), 59.4 (CH), 58.7 (CH₂), 55.3 (CH), 40.6 (CH₂), 39.1 (C), 38.8 (C), 38.5 (CH₂), 37.6 (CH₂), 37.5 (C), 29.7 (CH₂), 28.3 (CH₃), 27.3 (CH₂), 18.6 (CH₂), 16.3 (CH₃), 16.2 (CH₃), 15.3 ppm (CH₃); HRMS (FAB): calcd. for C₂₀H₃₄NaO₂ [M + Na]⁺ 329.2457, found 329.2478.

Synthesis of epoxide 9

A solution of diol 8 (25 mg, 0.081 mmol) in CH₂Cl₂ (5 mL) was cooled to 5 °C and MCPBA (70%) (25 mg, 0.1 mmol) was added. The reaction mixture was stirred for 2 h and then diluted with Et₂O. The ethereal solution was washed with 0.5 M Na₂S₂O₄, saturated aqueous Na₂CO₃ and brine, dried (anhyd. Na₂SO₄) and the solvent was removed. The residue was submitted to flash chromatography (hexane–EtOAC, 95 : 5) to give epoxide 9 (24 mg, 95%) as an amorphous solid. IR (film) ν_max cm⁻¹ = 3510, 2850 1213; ¹H NMR (500 MHz, CDCl₃): δ = 3.63 (dd, J = 11.6, 3.3 Hz, 1 H-15a), 3.43 (dd, J = 11.3, 10.4 Hz, 1 H-3), 3.24 (dd, J = 11.6, 4.7 Hz, 1 H-15b), 3.21 (dd, J = 3.7, 2.1 Hz, 1 H-16a), 2.72 (d, J = 3.7 Hz, 1 H-16b), 2.00–1.93 (m, 1 H), 1.88 (dd, J = 10.2, 3.2, 1 H), 1.83–1.78 (m, 2 H), 1.76–1.20 (m, 11 H), 1.00 (s, 3 H), 0.86 (s, 3 H), 0.85 (s, 3 H), 0.79 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ = 78.7 (CH), 59.1 (CH), 58.8 (CH₂), 57.9 (C), 55.2 (CH), 54.6 (CH), 51.7 (CH₂), 40.5 (CH₂), 39.3 (C), 38.8 (C), 38.5 (CH₂), 37.4 (C), 36.1 (CH₂), 29.7 (CH₃), 28.0 (CH₂), 27.2 (CH₂), 18.2 (CH₂), 16.6 (CH₃), 16.3 (CH₃), 15.3 (CH₃) ppm. HRMS (FAB): calcd. for C₂₀H₃₄NaO₃ [M + Na]⁺ 345.2406, found 345.2425.

Synthesis of aldehyde 10

Dess–Martin periodinane (58 mg, 0.136 mmol) was added to a solution of epoxide 9 (20 mg, 0.062 mmol) in CH₂Cl₂ (3 mL) at room temperature. The reaction mixture was stirred for 5 h and then diluted with CH₂Cl₂. The CH₂Cl₂ solution was washed with a saturated solution of a 1 : 1 mixture of NaHCO₃ and Na₂SO₃ and with brine. After drying and removal of the solvent the residue was submitted to flash chromatography (hexane–EtOAc, 95 : 5) to give aldehyde 10 (19 mg, quant.) as an amorphous solid. IR (film) ν_max cm⁻¹ = 2851, 1737, 1706; ¹H NMR (500 MHz, CDCl₃) δ = 9.58 (d, J = 3.4 Hz, 1H-15), 3.15–3.10 (m, 1H-16a), 2.72 (d, J = 3.3 Hz, 1H-16b), 2.54–2.44 (m, 3H), 2.0–1.90 (m, 2H), 1.85 (dt, J = 12.8, 2.9 Hz, 1H), 1.75–1.5 (m, 9H), 1.24 (s, 3H), 1.11 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H) ; ¹³C NMR (151 MHz, CDCl₃, DEPT) δ 219.7 (C), 205.0 (CH), 66.9 (CH), 60.4 (CH), 57.3 (CH), 54.7 (CH₂), 49.9 (C), 43.2 (C), 42.3 (CH₂), 41.7 (CH₂), 39.7 (C), 38.2 (CH₂), 36.5 (CH₂), 27.1 (C), 23.5 (CH₂), 21.7 (CH₂), 18.8 (CH₃), 16.8 (CH₃), 11.3 ppm (2CH₃); HRMS (FAB): m/z calcd. for C₂₀H₃₀O₃Na [M + Na]⁺: 341.2093; found: 341.2110.

Synthesis of furanospongian diterpene 2

To a solution of aldehyde 10 (15 mg, 0.05 mmol) in CH₂Cl₂ (0.18 mL) and DMSO (0.27 mL) a solution of anhydrous PTSA in DMSO (0.27 mL, 330 mg p-TsOH mL⁻¹) was added. The reaction mixture was warmed to 50 °C and stirred for 6 h. The reaction mixture was then diluted with diethyl ether and washed with brine. The organic layer was dried over Na₂SO₄ and the solvent removed. The residue was submitted to flash chromatography to give furanospongian diterpene 2 (11 mg, 73%). The NMR data of synthetic 2 matched those previously reported for the natural product.¹⁹

Conclusion

Here we describe a novel procedure for the straightforward synthesis of bioactive spongian diterpenes 2 and 3. The key step is the titanocene(III)-catalyzed radical cascade cyclization of epoxy-polyprene 6.

Acknowledgements

This work was financed by the Spanish MICINN (Project CTQ2011-24443) and the Regional Government of Andalucía (Projects P07-FQM-3213 and P10-FQM-6050). The authors thank their English colleague Dr Jon Trout for revising their English text.

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Footnote

† Electronic Supplementary Information (ESI) available. See DOI: 10.1039/c2ra22281g

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