A concise enantioselective synthesis of the guaiane sesquiterpene (−)-oxyphyllol

(−)-Oxyphyllol was prepared in only 4 steps from an epoxy enone that already served as an intermediate for the total synthesis of the anticancer guaiane (−)-englerin A. A regio- and diastereoselective Co(II)-catalyzed hydration of the olefin and a transannular epoxide opening were used as the key reactions.


Introduction
The hydroazulene framework is present in many natural products that are often associated with interesting biological properties [1,2]. The guaiane sesquiterpene (−)-oxyphyllol (1) has been isolated from the roots of the Thai medicinal plant Phyllanthus oxyphyllus [3]. A recent enantioselective synthesis of the unnatural enantiomer of 1 enabled a structural revision of this compound and established its relative and absolute configuration as depicted in Figure 1 [4]. During the total synthesis of (−)-9-deoxyenglerin A, compound 1 had already been prepared enantiomerically pure in 14 steps starting from (−)-isopulegol [5]. Remarkably, its cinnamate [(−)-9-deoxyenglerin A] displayed a cytotoxic activity in the μM range against several cancer cell lines [5]. Herein we report a concise enantioselective access to (−)-oxyphyllol (1) in a few preparatively simple operations.

Results and Discussion
Recently, we developed an efficient access to the anticancer guaiane (−)-englerin A (5) starting from (−)-photocitral A (6), which in turn can be prepared in only 2 steps from commercially available (−)-isopulegol through dual catalysis [6]. Due to the structural similarity of the hydroazulene core in (−)-oxyphyllol (1) and 5, we decided to use a modification of our route to 5 for the synthesis of 1 that would also constitute a formal synthesis of the related guaiane (+)-orientalol E (2) [4,7]. As illustrated in Scheme 1, we selected tertiary alcohol 3 as a retrosynthetic precursor for 1. The acetyl group of 3 can be utilized to generate the isopropyl group, and a regioselective transannular epoxide opening would construct the oxygenbridged bicyclic hydroazulene framework. Alcohol 3 was traced back to the known epoxy enone 4 that already served as an intermediate for the total synthesis of 5 [6].
As shown in Scheme 2, we first planned to use the known diol 7, which is available by diastereoselective dihydroxylation of 4 [6]. Since a chemoselective deoxygenation of the secondary alcohol of 7 would give rise to the desired intermediate 3, we investigated a radical defunctionalization strategy [8]. To this end, we tried to prepare the thionocarbonate 8 from 7 with phenyl chlorothionoformate [9,10]. However, all attempts at selective activation of the secondary hydroxy group led to the cyclic product 9 instead. A similar problem was already encountered earlier [11]. Scheme 3 depicts the efficacious completion of the synthesis of (−)-oxyphyllol (1) from 4. To our delight, a direct regio-and diastereoselective Co(II)-catalyzed hydration [12] of the olefin in 4 succeeded to give the required α-stereoisomer 3 in 58% isolated yield after chromatographic separation of the minor β-alcohol. Compared to the envisaged deoxygenation route (Scheme 2), this key transformation saved 2 steps and paved the Scheme 2: Attempted selective deoxygenation of diol 7. a) 1 mol % K 2 OsO 4 , NMO, acetone, water, THF, rt, 97%, diastereomeric ratio = 2:1 (ref. [6]); b) PhOC(S)Cl, pyridine, CH 2 Cl 2 , 0 °C to rt, 42% 9.
way for a final reaction sequence that was based on our synthesis of (−)-englerin A (5) [6]. Thus, Wittig olefination of the acetyl group in 3 afforded the sensitive vinyl epoxide 10 along with some cyclized product 11. In contrast to the smooth transannular epoxide opening [13,14] encountered during the synthesis of 5, an attempted complete cyclization of 10 to give 11 during acidic work-up of the methylenation reaction led to considerable decomposition. Fortunately, catalytic amounts of ytterbium triflate accomplished a high yielding formation of the oxygen-bridged bicyclic hydroazulene 11. Finally, hydrogenation of 11 proceeded uneventfully to deliver the target molecule 1 nearly quantitatively.

Conclusion
In summary, we have accomplished a short enantioselective total synthesis of (−)-oxyphyllol (1) and thus, a formal synthesis of (+)-orientalol E (2) as well by a modification of our previously developed route for setting up the oxygen-bridged framework present in (−)-englerin A (5). The reaction sequence presented herein allows the preparation of the guaiane 1 in only 10 steps with an overall yield of 22% starting from (−)-photocitral A (6).

Experimental
General information: Tetrahydrofuran and dichloromethane were dried and purified by passage through a MB-SPS-800 device using molecular sieves. All commercially available reagents were used as received. Reactions were performed under argon atmosphere. Thin layer chromatography (TLC) was performed on Merck silica gel 60 F 254 0.2 mm precoated plates. Product spots were visualized by UV light at 254 nm and subsequently developed using anisaldehyde solution as appropriate. Flash column chromatography was carried out using silica gel The solution was cooled to 0 °C, and phenyl chlorothionoformate (10.3 mg, 60 μmol) was added. The solution was warmed to room temperature and stirred for 72 h. Then silica gel was added, and the solvents were removed in vacuo. Purification by flash chromatography (isohexane/ethyl acetate 2:1) afforded thionocarbonate 9 (4.9 mg, 17 μmol, 42%) as a colorless solid.  After stirring for 5 min at room temperature, ethyl acetate was added, and the mixture was filtered through a plug of silica gel. Purification of the residue by flash chromatography (isohexane/ ethyl acetate 2:1) afforded a mixture of olefin 10 and the cyclized product 11 as a colorless oil.

Supporting Information
The Supporting Information contains 1 H and 13 C NMR spectra for compounds 1, 3, 9 and 11.
Supporting Information File 1