Total Synthesis and Absolute Configuration of the Marine Norditerpenoid Xestenone

Xestenone is a marine norditerpenoid found in the northeastern Pacific sponge Xestospongia vanilla. The relative configuration of C-3 and C-7 in xestenone was determined by NOESY spectral analysis. However the relative configuration of C-12 and the absolute configuration of this compound were not determined. The authors have now achieved the total synthesis of xestenone using their developed one-pot synthesis of cyclopentane derivatives employing allyl phenyl sulfone and an epoxy iodide as a key step. The relative and absolute configurations of xestenone were thus successfully determined by this synthesis.


Introduction
The norditerpenoid xestenone (Figure 1) was first isolated from the marine sponge Xestospongia vanilla in 1988 [1]. Its planar structure was determined by 1 H-and 13 C-NMR and mass spectral analysis. The stereochemistry comprises two cis fused cyclopentane rings, as determined by the NOE correlation between the methyl protons at C-17 and the methine proton at C-3, although the relative configuration of C-12 and the absolute configuration were not determined. Moreover, no biological activity has been reported for xestenone, although various bioactive compounds that have been isolated from several Xestospongia sponges [2]. The authors recently reported a stereocontrolled one-pot synthesis of cyclopentane derivatives possessing a quaternary carbon, which involved: 1) reaction of an anion derived from allyl phenyl sulfone with epoxy iodide I to give epoxysulfone II; 2) in situ deprotonation of II to generate an epoxysulfone anion III and 3) intramolecular cyclization to give cyclopentane derivative IV (Scheme 1) [3]. This one-pot synthesis of cyclopentane derivatives has now been applied to the total synthesis of xestenone, and in this paper the authors wish to report on the successful total synthesis of xestenone and its complete structural determination. Scheme 1. One-pot synthesis of cyclopentane derivatives.

Retrosynthetic analysis
The authors planned to synthesize both xestenone and 12-epi-xestenone, since the relative configuration at C-12 of xestenone was unknown at the onset (Scheme 2). Xestenone was obtained from secoxestenone by intramolecular aldol condensation [4]. Secoxestenone would be obtained from α,β-unsaturated ketone A by 1,2-reduction of α,β-unsaturated ketone at C-12 and oxidation of the hydroxy group at C-2 and C-8. The α,β-unsaturated ketone A would be obtained from aldehyde B by the Horner-Wadsworth-Emmons reaction using known phosphonate C [5]. For the right hand fragment of xestenone, aldehyde B would be synthesized from cyclopentane D through various chemical functionalizations. Cyclopentane D would be constructed by our developed stereocontrolled one-pot synthesis of cyclopentane derivatives using trisubstituted epoxy iodide E and allyl phenyl sulfone [3]. Epoxy iodide E would be obtained from alcohol F.

TBSO I O
The sulfonyl carbanion prepared from allyl phenyl sulfone (2.3 eq.) and n BuLi (2.2 eq.) was reacted with epoxy iodide 4 at −20 °C. Following confirmation of the disappearance of 4 by TLC, n BuLi (1.2 eq.) and Me 3 Al (1.5 eq.) were added at −78 °C to give cyclopentane 5 as the sole product (98%; Scheme 4). The trans-configuration of the vinyl and 1-hydroxy-2-silyloxyethyl groups in cyclopentane 5 was determined by NOE correlation between the vinyl proton at C-2 and methyl protons at C-17. The stereoselectivity of this reaction is presumably the result of steric hindrance between the phenyl sulfonyl group and the 1-hydroxy-2-silyloxyethyl group in the intermediate sulfonyl carbanion.

Scheme 4. Synthesis of intermediate 5.
Protection of the secondary hydroxy group of 5 with TBSOTf and 2,6-lutidine (Scheme 5) furnished bis-silyl ether 6 (quant.). The phenylsulfonyl group in 6 was removed by treatment with Na(Hg) and Na 2 HPO 4 to give trisubstituted (E)-olefin 7 as a sole product (quant.). The E-configuration of the trisubstituted olefin in 7 was determined by NOE correlation between the vinyl proton at C-2 and methyl protons at C-17, and the vinyl proton at C-2 and methylene protons at C-9. Diastereoselective hydroboration-oxidation of E-olefin 7 with catecholborane furnished a mixture of diol 8 and triol 8a. The stereochemistry of diol 8 was elucidated by NOESY spectral analysis. The NOE correlation between the methyl protons at C-17 and methine proton at C-3, and the methine proton at C-2 and methine proton at C-8 in diol 8 suggested that the methyl group and methine proton of cyclopentane were oriented in the same β-configuration. The mixture of diol 8 and triol 8a was treated with p-TsOH･H 2 O in acetone to give acetonide 9 (95%, 2 steps). Subsequent deprotection of the acetonide group in 9 and oxidative cleavage of the 1,2-diol with HIO 4 ･2H 2 O afforded hemiacetal 10, which was converted to homoallylic alcohols 11a (50%, 2 steps) and 11b (36%, 2 steps). These alcohols were easily separated by silica gel chromatography. The relative configurations of these homoallylic alcohols 11a and 11b were determined by chemical conversion and NOESY spectral analysis. Compounds 11a and 11b were converted to tetrahydrofurans 12a and 12b by treatment with p-TsCl, DMAP and Et 3 N (Scheme 6). The NOE correlations of 12a between the methylene protons at C-9 and methyl protons at C-17, and one of the methylene protons at C-4 and methyl protons at C-1 suggested that the C-1 methyl group and allyl group were oriented on different faces of the tetrahydrofuran ring, therefore, the stereochemistry of the hydroxy group at C-8 in homoallylic alcohol 11a was found to adopt a β-configuration. The NOE correlations of 12b between the methine proton at C-2 and methine proton at C-3, the methine proton at C-2 and methine proton at C-8, the methine proton at C-8 and methyl protons at C-17, the methine proton at C-3 and methyl protons at C-17, and the methyl protons at C-1 and one of the methylene protons at C-4 were observed. The results suggested that the C-1 methyl group and allyl group were oriented on the same face of the tetrahydrofuran ring. Therefore, the stereochemistry of the hydroxy group at C-8 in homoallylic alcohol 11b was found to adopt an α-configuration. Both homoallylic alcohols 11a and 11b could be converted to xestenone. However, the chemical yield of the later steps in this synthesis from α-alcohol 11b was low. Therefore, α-alcohol 11b was converted into β-alcohol 11a by inversion of the C-8 stereocenter. The hydroxy group at C-2 in α-alcohol 11b was protected with TBDPSCl and imidazole to give TBDPS ether, which was oxidized with IBX [8] to afford the ketone. Diastereoselective reduction of the ketone with NaBH 4 to the alcohol, followed by deprotection of the TBDPS group with TBAF furnished a mixture of the desired β-alcohol 11a (69%, 4 steps) and α-alcohol 11b (14%, 4 steps).   β-Alcohol 11a was converted to bis-silyl ether 13 by treatment with TBSOTf and 2,6-lutidine (99%), and was followed by ozonolysis to give aldehyde 14 (quant.), thereby completing the synthesis of the right hand fragment of xestenone in 14 steps from known alcohol 1 [6] (Scheme 7). Treatment of aldehyde 14 with the anion of phosphonate 15 [5] in THF at r.t. provided α,β-unsaturated ketone 16 (49%). 1,2-Reduction of the α,β-unsaturated ketone 16 with NaBH 4 in the presence of CeCl 3 ･7H 2 O in MeOH [9] furnished allylic alcohol 17 as an inseparable mixture (99%, 1:1). Protection of the hydroxy group in allylic alcohol 17 with TrCl and DMAP in pyridine provided the trityl ether, and was followed by desilylation with TBAF to give diol 18 (quant., 2 steps). Oxidation of two hydroxy groups in diol 18 with TFAA, DMSO and Et 3 N generated diketone 19 (95%). Lewis acid-mediated deprotection of the trityl group in diketone 19 with Yb(OTf) 3 furnished diketone 20 as an inseparable diastereomeric mixture of the hydroxy group at C-12 (79%). Diketone 20 corresponds to secoxestenone. Moreover, the CD spectrum of the synthetic 21 matched that of the natural product [1]. The CD spectrum of the synthetic 21 showed a positive Cotton effect at 323 nm and a negative Cotton effect at 258 nm. The absolute configuration of the hydroxy group at C-12 in 21 was determined by comparing the 1 H-NMR data of the two diastereomeric esters (MPA esters) [10]. The absolute configuration of the hydroxy group at C-12 in 12-epi-21 was determined by the same method. As a result, the absolute stereochemistry of the three chiral centers in xestenone was determined to be 3S, 7S and 12R. 12-epi-xestenone (12-epi-21) was converted to xestenone (21) by a Mitsunobu reaction.

General
Optical rotations were measured using a Jasco P-1030 polarimeter. Melting points (mp) were measured using a Yazawa melting point apparatus BY-2 and are uncorrected. IR spectra were recorded using a Jasco FT-IR/620 spectrometer. UV spectra were recorded using a Jasco V-550 spectrophotometer. Circular dichroism (CD) spectra were measured with a Jasco J-720 spectropolarimeter. 1 H-and 13 C-NMR spectra were recorded on a Bruker DRX-400 or a Bruker Biospin AV-600 spectrometer. Chemical shifts are given on the δ (ppm) scale using tetramethylsilane (TMS) as the internal standard (s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; m, multiplet; br, broad). High resolution ESIMS (HRESIMS) spectra were obtained using a Micromass LCT spectrometer. Elemental analysis data were obtained using an Elemental Vavio EL. Flash column chromatography was performed using Kanto Chemical Silica Gel 60N (spherical, neutral) 40-50 μm.

Conversion from diol 11b to diol 11a
To a solution of diol 11b (50.0 mg, 0.252 mmol) in DMF (252 μL) were added imidazole (21.0 mg, 0.308 mmol) and TBDPSCl (83.5 mg, 0.304 mmol) and the mixture was stirred at r.t. for 1 hr. The mixture was diluted with Et 2 O, washed with saturated aqueous NaHCO 3 solution, H 2 O and brine and then dried. The crude mixture was diluted with Et 2 O and filtered through a silica gel pad. The filtrate was concentrated to afford the crude alcohol. To a solution of the crude alcohol in CH 3 CN (2.5 mL) was added IBX (212 mg, 0.757 mmol) at r.t. After stirring for 30 min at 80 °C, the mixture was diluted with Et 2 O and then filtered through a Celite pad. Removal of the solvent gave a residue which was filtered through a silica gel pad to afford the crude ketone. To a solution of the crude ketone in MeOH (2.5 mL) was added NaBH 4 (28.6 mg, 0.756 mmol) at r.t. After stirring for 2 hr under reflux, the mixture was diluted with Et 2 O, washed with H 2 O and brine and then dried. Removal of the solvent gave a residue which was then filtered through a silica gel pad to afford the crude alcohols. To a solution of the crude alcohols in THF (2.5 mL) was added TBAF (760 μL, 0.760 mmol, 1.0 M in THF solution) at r.t. After stirring for 12 hr at 40 °C, the mixture was diluted with Et 2 O, washed with H 2 O and brine and then dried. Removal of the solvent gave a residue which was then purified by silica gel column chromatography (hexane/AcOEt = 4:1) to generate diol 11a (34.6 mg, 69%) and diol 11b (6.9 mg, 14 %).

Conversion of 12-epi-21 to 21
To a solution of 12-epi-21 (1.7 mg, 0.006 mmol) in THF (59 μL) were added Ph 3 P (2.3 mg, 0.009 mmol) and p-NO 2 BzOH (1.5 mg, 0.009 mmol) at r.t. After stirring for 10 min, DIAD (1.8 mg, 0.009 mmol) was added and the mixture was stirred for an additional 2 hr. The crude mixture was diluted with Et 2 O and filtered through a silica gel pad. The filtrate was then concentrated to afford the crude ester. To a solution of the crude ester in MeOH (200 μL) was added K 2 CO 3 (12.2 mg, 0.088 mmol) at r.t. After stirring for 30 min at the same temperature, the mixture was diluted with Et 2 O and then filtered through a silica gel pad. Removal of the solvent gave a residue which was then purified by silica gel column chromatography (hexane/AcOEt = 2:1) to generate xestenone (21, 1.6 mg, 95% yield).

Conclusions
The first total synthesis of xestenone has been accomplished via the stereocontrolled one-pot synthesis of cyclopentane derivatives using allyl phenyl sulfone as the key step. Moreover, the authors have determined that the absolute configuration of xestenone is 3S, 7S and 12R.