Synthesis of spongidine A, D and petrosaspongiolide L methyl ester using pyridine C-H functionalization
An efficient strategy for the synthesis of the potent phospholipase A2 inhibitors spongidine A and D is presented. The tetracyclic core of the natural products was assembled via an intramolecular hydrogen atom transfer-initiated Minisci reaction.A divergent late-stage functionalization of the tetracyclic ring system was also used to achieve a concise synthesis of petrosaspongiolide L methyl ester. Scheme 1. Retrosynthetic analysis.
<!>ARTICLE Journal Name<!>Conflicts of interest<!>Please do not adjust margins<!>Synthesis of Compounds<!>Spongidine A<!>Rf<!>Petrosaspongiolide L methyl ester 11
<p>Spongidine A and D are tetracyclic pyridinium alkaloids with either acetic or ethanesulfonic acid side chains attached to the pyridine nitrogen. They were isolated in 1996 near the coast of Tongoa from an unidentified sponge and exhibit potent inhibitory activity against soluble phospholipase A 2 (sPLA 2 ). Remarkably, spongidines possess a higher selectivity toward sPLA 2 inhibition than the known PLA 2 inhibitor manoalide. 1,2 Petrosaspongiolide L, a structurally related natural product, was isolated in 1987/88 from Petrosaspongia Nigra found near New Caledonia. In contrast to the spongidines, petrosaspongiolide L possesses a neutral pyridine with a propionic acid substituent at C16. Petrosaspongiolide L shows moderate cytotoxicity (5.6 M) against non-small-cell lung carcinoma (NSCLC-N6). 3 The pronounced biological activities within the spongidine class coupled with the challenging isolation from natural sources have spurred endeavors to establish more reliable access by chemical synthesis. 4,5 Only recently, Basabe and co-workers reported the first synthesis of spongidine A and D. [6][7][8][9] We initiated our program toward the synthesis of spongidine alkaloids with the aim to establish a short and flexible synthetic route to efficiently access the different substitution patterns found in these natural products. Despite advances in the development of new methods for late-stage C-H functionalization, application to the synthesis of complex target molecules remain rare. 10 Here, we show the selective C-H functionalization of pyridines enables the efficient synthesis of spongidine natural products. Owing to the identical core structures of spongidines A and D as well as petrosaspongiolide L, we identified chloropyridine 1 as a key intermediate in our retrosynthetic analysis (Scheme 1). In the synthetic direction, the spongidine natural products should be accessible from this intermediate via hydrodehalogenation/N-alkylation, while petrosaspongiolide L should be attainable by a C-H functionalization of C16. An intramolecular Minisci reaction of a suitable tertiary radical derived from intermediate 2 was envisioned as the key step for forging the C8-C14 bond, setting the quaternary stereocenter at C8 and providing access to chloropyridine 1. In order to direct the attack to C14, we decided to place a chlorine substituent at the C21 position of pyridine 2. The C16 position appeared inaccessible to an intramolecular attack due to the formation of an energetically unfavorable eight-membered ring. Pyridine 2 could be obtained by B-alkyl Suzuki coupling between a suitable borane obtained from alkene 3 and pyridine 4. These coupling partners are readily accessible from (+)-sclareolide and 3amino-2-chloropyridine 5, respectively. The synthesis commenced with the preparation of alkene 3 from (+)-sclareolide using our previously established two-step procedure (Scheme 2).</p><p>Reduction of (+)-sclareolide with LiAlH 4 and in-situ benzylation was followed by a Wittig-type fragmentation of the intermediate 2-methyl benzyl ether (not shown) to give alkene 3 in multigram quantities. 11 Iodide 4 was prepared from pyridine 5 on gram scale in 91% yield using a Sandmeyer reaction. 12,13 The coupling of 3 and 4 required intensive optimization. Using standard coupling conditions, e.g. Pd(dppf)Cl 2 as catalyst, only 46% yield of the desired product could be isolated. In addition, significant -hydride elimination, as well as homocoupling of the iodide 4 was observed. Gratifyingly, using Buchwald's precatalyst XPhos Pd G2, 14 no hydride elimination products and only trace amounts of homocoupling products were detected. Under these conditions, the coupling product 2 was isolated in 73% yield on gram scale. While contemplating the use of N-phthalimidoyl oxalates for radical generation, we quickly recognized the incompatibility of the acidic reaction conditions of the Minisci reaction and the acid-labile nature of the radical precursor. 15 Instead, we opted for a hydrogen atom transfer (HAT) initiated radical generation from an exocyclic alkene (Scheme 3). Hence, alkene 6 was synthesized in excellent yield and selectivity by low-temperature elimination of tertiary alcohol 2 using SOCl 2 (exo:endo > 15:1 by 1 H NMR of the crude reaction mixture). Next, we evaluated several reported conditions for hydrogen atom transfer-initiated Minisci reaction with alkene 6. [16][17][18] Although recent interest in the Minisci reaction has led to the development of diverse conditions for its initiation, applications in the context of complex molecule synthesis remain limited. 19,20 To our dismay, using Fe(acac) 3 , PhSiH 3 with either TFA or BF 3 •OET 2 we only observed the decomposition of the starting material at either 23 °C or 60 °C. Remarkably, performing the reaction in a pressure tube at elevated temperatures (120 °C) led to product formation along with substantial amounts of unreacted starting material. While increasing the initial amounts of Fe(acac) 3 or PhSiH 3 also resulted in the decomposition of starting material, we observed that the renewed addition of Fe(acac) 3 , PhSiH 3 and TFA after brief heating to 120 °C gave full conversion. Under the optimized conditions, we were able to isolate chloropyridine 1 in 49% yield (see Table 1 in the Supporting Information for details). The radical addition is highly diastereoselective as only a single diastereomer was detected. The (R)-configuration of the newly formed quaternary center can be rationalized by the orientation of the chloropyridine moiety away from the sterically shielding methyl group at C10 and was proven via X-ray crystallography. 21 Interestingly, we did not detect any dehalogenated or hydrogenated side products under the optimized reaction conditions. Mechanistically, we hypothesize that the hydrogen atom transfer of a [Fe]-H species onto the alkene generates the tertiary radical A, which attacks the electron-poor chloropyridine moiety in the C16 position. The necessity for the forcing reaction conditions is presumably a reflection of the high kinetic barrier for addition to the chloropyridine. Further oxidation and proton loss of the resulting radical cation yields chloropyridine 1 (see Scheme SI1 in the Supporting Information for details). 17,18,22,23 With chloropyridine 1 in hand, we began to study the hydrogenolysis of the carbon-chlorine bond (Scheme 4). Under a variety of conditions, we either observed no conversion (Pd/C, H 2 using either NaHCO 3 /NaOAc or TFA as an additive) or decomposition of starting material (Zn/AcOH). Interestingly, sparging the reaction solvent and Pd/C with H 2 before the addition of substrate leads to the formation of pyridine 7 in 78% yield. This finding might be rationalized by the poisoning effect of pyridine on catalytically active palladium species. 24 Initially, we tried to reproduce Basabe's procedure to alkylate pyridine 7 with either bromoacetic acid or sodium 2bromoethanesulfonate. 7 During our investigation, we encountered problems handling the small solvent volume employed (2.0 M, using 0.01 mL bromobenzene or DMF, respectively), which resulted in a low conversion of starting material in our hands. Therefore, we opted for a procedure consisting of alkylation with bromoacetic acid ethyl ester and subsequent ester hydrolysis. The reaction of pyridine 7 with bromoacetic acid ethyl ester occurred smoothly after 24 h at 23 °C (Scheme 4). Subsequently, we cleaved the corresponding ethyl ester with hydrogen bromide at elevated temperature (50-90 °C, 20 h) to yield spongidine A in quantitative yield. 25 Spongidine D was synthesized in 48% yield through alkylation of 7 with sodium 2bromoethanesulfonate and sodium iodide in DMF (0.055 M) at 100 °C for 4 d. The obtained analytical data matched the published data. 1,6,7 In order to synthesize petrosaspongiolide L, we were faced with the challenge of selectively functionalizing the C16-H bond in either chloropyridine 1 or pyridine 7. From the outset, we were concerned that a second Minisci reaction might be inhibited by the reduced electrophilicity of the dialkylated pyridine. Indeed, attempts to utilize a Minisci reaction led only to the decomposition of the starting material (AIBN, (SiMe 3 ) 3 SiH, Br(CH 2 ) 2 COOBn). 22,26 Despite the failure of our Minisci approach multiple methods for selective C-H functionalization of pyridines at the C-2 position have been developed in recent years. We started our investigation with a rhodium-catalyzed alkylation using various esters of acrylic acid. However, we were unable to detect the alkylated products using either 1 or 7 directly or the corresponding pyridine N-oxides (formed in situ using DMDO). 27,28 Afterward, we investigated the phosphonium salt formation of pyridines (Tf 2 O, PPh 3 , CH 2 Cl 2 , −78 °C), in hopes of subsequently displacing the resulting phosphonium leaving group with a carbon nucleophile. Unfortunately, neither a change of base (DBU or NEt 3 ) nor the addition of PPh 3 or base at 23 °C led to the formation of the desired phosphonium salt and only complex mixtures were obtained. 29 Gratifyingly, the selective lithiation of chloropyridine 1 with n-BuLi and 2dimethylaminoethanol at -78 °C generated an aryllithium species that could be trapped with I 2 to give chloroiodopyridine 8 in 31% yield along with 52% unreacted starting material (Scheme 5). [30][31][32] We were able to increase the yield of this transformation to 75% yield by extending the lithiation time from 2 h to 4 h. Subsequently, we used a Sonogashira reaction to couple chloroiodopyridine 8 and propargyl alcohol to provide alkyne 9 in 98% yield. 33 Next, the simultaneous hydrogenation of the alkyne and the hydrogenolysis of the carbon-chlorine bond was investigated. The previously established conditions for the hydrogenolysis of chloropyridine 1 using MgO and Pd/C proved unsuccessful and led to no conversion of starting alkyne 9, even when applying 30 bar of hydrogen pressure. However, changing the base from MgO to KOH 34 and using over-stoichiometric amounts of Pd/C led to the formation of alcohol 10 in quantitative yield. We then investigated a variety of oxidizing agents to synthesize the carboxylic acid from alcohol 10. To our dismay, the oxidation of alcohol 10 to either the corresponding aldehyde (using Dess-Martin periodinane, SO 3 •pyridine, NCS/SMe 2 ) or carboxylic acid (using RuCl 3 /H 5 IO 6 , PDC, PCC, TEMPO/PIDA, Pt/O 2 , TPAP/NMO) was unsuccessful under a variety of conditions, yielding only complex mixtures. Fortunately, after the global hydrogenolysis of 9, a Heyns oxidation with atmospheric oxygen generated petrosaspongiolide L methyl ester 11 in 60% yield. 35 Lastly, we attempted the hydrolysis of the methyl ester to furnish petrosaspongiolide L. While we were able to convert the methyl ester to the acid (using LiOH) and confirm its generation via high-resolution mass spectrometry, we were unable to isolate petrosaspongiolide L due to decomposition upon attempted isolation.</p><p>In conclusion, we have accomplished an efficient entry into the spongidine alkaloids. Our approach utilizes a radical disconnection and late-stage C-H functionalization to increase step efficiency. 36,37 The tetracyclic ring system of the spongian terpene alkaloids was formed in a single step using a rare example of an intramolecular hydrogen atom transfer-initiated Minisci reaction. This synthetic strategy enabled the short synthesis of spongidine A and D in only 7 steps from (+)sclareolide in 11% and 5% yield, respectively (previously 2% and</p><!><p>Please do not adjust margins Please do not adjust margins 1% yield over 23 steps) 7 . Furthermore, we identified and synthesized chloropyridine 1 as a platform intermediate that might be valuable in the synthesis of other spongian terpene alkaloids and showcased this approach in the synthesis of petrosaspongiolide L methyl ester.</p><!><p>There are no conflicts to declare.</p><!><p>Please do not adjust margins  (1.0 eq.)</p><p>x PhSiH3 (2.5 eq.)</p><p>TFA (1.0 eq.), 2-Propanol, 120 °C, 15 min, then TFA (1.0 Eq.), 120 °C, 15 min 37% 2 x Fe(acac)3</p><p>(1.0 eq.)</p><p>PhSiH2(Oi-Pr) (2.5 eq. + 20 eq.) TFA (1.0 eq.), 2-Propanol, 120 °C, 20 min, then TFA (1.0 eq.), 120 °C, 4.5 h 19% 2 x Fe(acac)3</p><p>(1.0 eq.)</p><p>x PhSiH3 (2.5 eq.)</p><p>TFA (1.3 eq.), 2-Propanol, 120 °C, 10 min, then TFA (1.3 eq.), 120 °C, 20 min 49%</p><!><p>Ether S1</p><p>To LiAlH4 (535 mg, 14.1 mmol, 0.70 eq.) in THF (5 mL) at 0 °C was added a solution of (+)-sclareolide (5.04 g, 20.1 mmol, 1.0 eq.) in THF (25 mL) over 5 min. After 30 min at the same temperature Rochelle salt (6.84 g, 24.2 mmol, 1.2 eq.), DMF (80 mL), tetrabutylammonium iodide (751 mg, 2.03 mmol, 10 mol%), freshly ground KOH (4.51 g, 80.5 mmol, 4.0 eq.) and 2-Me-C6H4CH2Cl (10.5 mL, 60.4 mmol, 3.0 eq.) were added successively, and the reaction mixture was heated to 45 °C for 17 h. Water was added, and the mixture was diluted with EtOAc. The organic phase was separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed repeatedly with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, n-pentane/EtOAc 10:1) to afford ether S1 (6.78 g, 18.9 mmol, 94%) as a colorless oil. The spectral data matched the previously obtained data. 1 Alkene 3</p><p>To a solution of ether S1 (7.67 g, 21.4 mmol, 1.0 eq.) in THF (170 mL) at −78 °C was added a solution of n-BuLi (34.2 mL, 2.5 M in hexane, 85.6 mmol, 4.0 eq.). After 10 min at that temperature, the reaction mixture was warmed to −13 °C (change of cooling baths) and stirred for 90 min. Water was added, and the reaction mixture was diluted with EtOAc. The organic phase was separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, n-pentane/EtOAc 1:0 to 15:1 to 10:1) to afford alkene 3 (2.19 g, 9.24 mmol, 43%) as a white solid. The spectral data matched the previously obtained data. 1 Iodide 4</p><p>3-Amino-2-chloropyridine 5 (5.00 g, 38.9 mmol, 1.0 eq.) was added to HCl (6 M, aq., 40.2 mL) at 0 °C. NaNO2 (4.29 g, 62.2 mmol, 1.6 eq.) in H2O (20.0 mL) was added dropwise to the reaction mixture over 5 min followed by the dropwise addition of KI (15.5 g, 93.3 mmol, 2.4 eq.) in H2O (20.0 mL). The reaction mixture was stirred for 5 min at 0 °C and 50 min at 23 °C. NaOH (5 M, aq., 77.8 mL) and EtOAc were added. The phases were separated, and the aqueous phase was extracted with EtOAc (2x). The combined organic extracts were washed consecutively with a saturated aqueous solution of Na2S2O3 and brine. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, n-pentane/EtOAc 15:1 to 10:1) to afford the title compound (8.33 g, 35.2 mmol, 91%) as a white solid.</p><p>Rf = 0.64 (n-pentane/EtOAc, 5:1). The spectral data matched the previously obtained data. 2,3 Alcohol 2</p><p>Alkene 3 (1.30 g, 5.50 mmol, 1.6 eq.) and 9-BBN dimer (1.68 g, 13.8 mmol, 3.9 eq.) were mixed and heated to 60 °C for 20 min. The reaction mixture was heated to 85 °C for 70 min. Subsequently, toluene (degassed by sparging with Ar for 20 min, 3.0 mL) was added, and heating was continued at 85 °C for 70 min. After cooling to 60 °C NaOH (degassed by sparging with Ar for 20 min, 7.10 mL, 3 M, 21.3 mmol, 6.0 eq.) was added, and the mixture was stirred for 10 min. Afterward, 1,4-dioxane (degassed by sparging with Ar for 20 min, 15.0 ml), iodide 4 (850 mg, 3.55 mmol, 1.0 eq.) and XPhos Pd G2 (140 mg, 177 mol, 5 mol%) were added sequentially. The flask was rinsed with 1,4-dioxane (degassed by sparging with Ar for 20 min, 3.0 ml) and stirred at that temperature for 24 h. The reaction mixture was cooled to 23 °C and water and EtOAc were added. The organic phase was separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, n-pentane/EtOAc 4:1 to 1:1) to afford the title compound (902 mg, 2.58 mmol, 73%) as a white solid.</p><p>Rf = 0.28 (n-pentane/EtOAc, 3:1).</p><p>[] D 27 = +31.9 (c = 0.48, CHCl3). A solution of alcohol 2 (168 mg, 480 mol, 1.0 eq.) and NEt3 (dried by distillation over CaH2, 0.67 mL, 0.49 g, 4.80 mmol, 10.0 eq.) in CH2Cl2 (16.0 mL) was cooled to −118 °C (ethanol, N2(l)) and SOCl2 (0.10 mL, 0.17 g, 1.44 mmol, 3.0 eq.) in CH2Cl2 (4.0 mL) was added dropwise over the wall of the flask over 10 min. The reaction mixture was allowed to warm to −78 °C (ethanol, dry ice) over 90 min. Methanol (0.5 mL) was added, and the reaction mixture was warmed to 23 °C. A saturated aqueous solution of NaHCO3 and CH2Cl2 was added successively. The phases were separated, and the aqueous phase was extracted with CH2Cl2 (2x). The combined organic extracts were washed with brine. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, n-pentane/EtOAc 1:0 to 40:1 to 25:1 to 10:1) to afford the title compound (157 mg, 472 mol, 98%) as a colorless liquid, which slowly crystallized. Rf = 0.61 (n-pentane/CHCl3, 2:1).</p><p>[] D 27 = +45.0 (c = 0.42, CHCl3). ) and PhSiH3 (13.6 L, 11.9 mg, 107 mol, 2.5 eq.) were added sequentially and the reaction was heated to 120 °C for 20 min. After cooling to 23 °C the mixture was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (SiO2, n-pentane/EtOAc 70:1 and 11:1) to afford the title compound (7.0 mg, 21.1 mol, 49%) as a colorless solid. Crystals suitable for X-ray crystallography were obtained after the evaporation of a MeCN/CH2Cl2 mixture. Rf = 0.18 (toluene/CHCl3, 1:1).</p><p>[] D 27 = −26.7 (c = 0.48, CHCl3). A suspension of Pd/C (10 wt%, 12.1 mg, 11.3 mol, 0.4 eq.) and MgO (10.3 mg, 255 mol, 9.0 eq.) in EtOH (1 mL) was purged with H2 (balloon) for 2 min. Then a solution of chloropyridine 1 (9.4 mg, 28.3 mol, 1.0 eq.) in THF/EtOH (1:1, 4 mL) was added, and purging was continued for 2 min. The reaction mixture was stirred at 23 °C for 15 h under an H2 (balloon) atmosphere. The suspension was filtered through a short silica pad with EtOAc/CHCl3 (1:1) as the eluent. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (SiO2, n-pentane/EtOAc/NEt3 150:45:2) to afford the title compound (6.6 mg, 22.2 mol, 78%) as a colorless solid.</p><p>Rf = 0.41 (n-pentane/EtOAc, 1:1).</p><p>, 3H), 1.17 -1.12 (m, 1H), 0.93 (s, 3H), 0.90 -0.83 (m, 8H).</p><!><p>Ethyl bromoacetate (0.359 mL, 0.539 g, 3.23 mol, 600 eq.) was added to pyridine 7 (1.6 mg, 5.4 mol, 1.0 eq.) and stirred for 24 h at 23 °C. The reaction mixture was concentrated under reduced pressure. HBr (1.0 mL) was added and the reaction mixture heated to 60 °C for 2 h in a sand bath. HBr (1.0 mL) was added and the reaction mixture heated to 90 °C for 2 h and 16 h at 50 °C in a sand bath. The reaction mixture was concentrated under reduced pressure to afford the title compound (2.4 mg, 6.7 mol, quant.) as brown solid.  Comment on the comparison between the published NMR-data of the natural sample and the synthetic material: We observed a discrepancy, especially in the pyridinium ion moiety and the acetic acid substituent. We believe the unreported counterion of the pyridinium ion might cause the observed differences. The NMR-shift of the synthetic material obtained by Basabe and coworkers, which presumably has a bromide counterion to the pyridinium, is in good agreement with our material (only 13 C data available, Table 3). 6  Chloroiodopyridine 8</p><!><p>To a solution of N,N-dimethylaminoethanol (freshly distilled over KOH, 92.9 L, 82.3 mg, 923 mol, 8.0 eq.) in toluene (1.0 mL) at −78 °C was added n-BuLi (2.5 M, 739 L, 1.85 mmol, 16.0 eq.) dropwise. After 15 min, a solution of chloropyridine 1 (38.3 mg, 115 mol, 1.0 eq.) in toluene (2.0 mL) was added dropwise over 5 min. After 4 h a solution of I2 (264 mg, 1.04 mmol, 9.0 eq.) in THF (1.3 mL) was added dropwise. The reaction temperature was maintained at −78 °C for 1 h. Then the reaction mixture was stirred for 40 min at 0 °C (change of cooling baths). Water (3 mL) and EtOAc were added, and the phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, n-pentane/EtOAc 1:0 to 40:1 to 25:1 to 15:1) to afford the title compound (39.6 mg, 86.5 mol, 75%) as a slightly yellow solid. Rf = 0.29 (n-pentane/EtOAc, 50:1).</p><p>[] D 20 = −57.8 (c = 3.96, CHCl3). To a suspension of CuI (1.6 mg, 8.37 mol, 10 mol%) and Pd(PPh3)Cl2 (2.9 mg, 4.18 mol, 5 mol%) in THF (0.5 mL) was added NEt3 (69.6 L, 50.8 mg, 502 mol, 6.0 eq.) and propargyl alcohol (14.5 L, 14.1 mg, 251 mol, 3.0 eq.) sequentially. A solution of chloroiodopyridine 8 (38.3 mg, 83.7 mol, 1.0 eq.) in THF (3.0 mL) was added, and the reaction flask was stirred at 23 °C for 19 h in the dark. The reaction mixture was directly purified by flash column chromatography (SiO2, n-pentane/EtOAc 10:1 to 5:1 to 2:1) to afford the title compound (31.6 mg, 81.9 mol, 98%) as a slightly brown solid.</p><p>Rf = 0.74 (n-pentane/EtOAc, 1:1).</p><p>[] D 20 = −45.2 (c = 0.48, CHCl3).</p><!><p>A suspension of Pd/C (10 wt%, 81.6 mg, 76.7 mol, 2.0 eq.) and KOH (10.8 mg, 192 mol, 5.0 eq.) in MeOH (3 mL) was purged with H2 (balloon) for 2 min. A solution of alkyne 9 (14.8 mg, 38.3 mol, 1.0 eq.) in MeOH (5 mL) was added, and purging was continued for 2 min. After 23 h Pd/C (10 wt%, 122 mg, 115 mol, 3.0 eq.) and KOH (12.9 mg, 230 mol, 6.0 eq.) were added, and the reaction mixture was purged with H2 (balloon). After stirring under an H2 atmosphere for 16 h Pd/C (10 wt%, 122 mg, 115 mol, 3.0 eq.) and KOH (19.4 mg, 345 mol, 9.0 eq.) were added, and the reaction mixture was purged with H2 (balloon). After 16 h the H2 atmosphere was exchanged, and air was slowly introduced. After 3 d the suspension was filtered through a Celite ® pad with CHCl3. The mixture was concentrated under reduced pressure and purified by preparative TLC (SiO2, n-pentane/EtOAc 11:4) to afford the title compound (8.8 mg, 22.9 mol, 60%) as a colorless solid. Rf = 0.72 (EtOAc).</p><p>[] D 22 = −43.5 (c = 0.62, CHCl3).</p>