HETEROCYCLES

Paper | Special issue | Vol. 80, No. 1, 2010, pp. 219-227
Received, 2nd December, 2008, Accepted, 16th January, 2009, Published online, 19th January, 2009.
DOI: 10.3987/COM-08-S(S)1

■ Stereoselective Formal Total Synthesis of Novel Antibiotic (-)-Centrolobine

Debendra K. Mohapatra,* Rita Pal, Hasibur Rahaman, and Mukund K. Gurjar

Organic Chemistry Division I, Indian Institute of Chemical Technology, Hyderabad-500 007, India

Abstract

A concise and stereoselective formal total synthesis of (−)-centrolobine is achieved utilizing Mioskowski’s Lewis acid mediated epoxide opening followed by ring-closing metathesis as the key reaction.

INTRODUCTION
Syntheses of natural products and analogues thereof embodying substituted tetrahydropyrans are of substantial interest to organic chemistry and chemical biology.1,2 Several natural products possessing 2,6-disubstituted tetrahydropyran, tetrahydrofurans, and oxepanes such as (−)-centrolobine,3 de-O-methylcentrolobine, calyxins,4 diospongins,5 annonaceae acetogenins,6 ionophores,7 etc. exhibit a wide range of biological activities. Owing to the challenges posed by the substitution pattern as well as the widespread occurrence of substituted tetrahydropyran moieties in natural products with interesting biological activities,8 has inspired the development of numerous creative synthetic approaches to this important structural subunit.

(−)-Centrolobine, 6-[β-(p-hydroxyphenyl)ethyl]-2-(p-methoxyphenyl)tetrahydropyran, is a crystalline substance (Figure 1) isolated from the heartwood of Centrolobine robustum and from the stem of Brosinium potabile in the amazon rain forest in 1962. Although the basic structure of (−)-centrolobine was elucidated in 1964,1 its absolute configuration was only established in 2002 by an enantioselective total syntheis.9 Afterward several research groups have accomplished the total synthesis of (−)-centrolobine. A variety of approaches starting with optically active building blocks, obtained by well-established asymmetric reactions or the chiral pool method, have been devised to provide access to the cis-2,6-disubstituted tetrahydropyran rings. These include the Prins and related cyclizations10a,h,k,o reductive etherifications,9,10b one-pot cross metathesis–hydrogenation –lactonization procedure,10c radical cyclization,10e nucleophilic addition-stereoselective reduction protocol,10f intramolecular oxy-Michael reaction,10g diastereoselective ring rearrangement metathesis–isomerization sequence,10l FeCl3-mediated cyclization of 1,5-diol,10m hetero-Diels-Alder reaction.10n
In continuation of our research on the synthesis of biologically active natural products containing tetrahydrofuran and tetrahydropyran rings,11 we herein disclose a new strategy towards the synthesis of tetrahydropyran derivatives using Mioskowski’s Lewis acid12 catalyzed regioselective epoxide opening followed by ring-closing metathesis as the key steps. This novel strategy was applied for the synthesis of (−)-centrolobine. Retrosynthetic analysis of (−)-centrolobine (1), as depicted in Scheme 1, revealed two fragments 6 and 7.

RESULTS AND DISCUSSION
As summarized in Scheme 1, one of the stereogenic centers of (−)-centrolobine was established in a reagent-controlled fashion, whereas the other capitalized on a stereocontrolled asymmetric allylation. For synthesizing fragment 6, we followed Keck allylation on 4-tosyloxybenzaldehyde.13 Detosylation14 followed by selective methylation10a of phenolic hydroxy group accomplished the fragment 6 in 83% yield over two steps.

The other fragment 7 was synthesized starting from cis-2-butene-1,4-diol. Accordingly, the alcohol 10 was mono protected as its benzyl ether with NaH and benzyl bromide followed by Sharpless asymmetric epoxidation with L-(+)-DET, TBHP afforded the epoxy alcohol 11.15 IBX oxidation of the primary hydroxyl group to the corresponding aldehyde and Wittig reaction using methyltriphenylphosphonium bromide11 afforded vinyl substituted epoxide 7 in an overall yield of 86% in two steps.

After having enantiomerically pure homoallylic alcohol 6 and the vinyl epoxide derivative 7 in hand, we proceeded further for the Mioskowski’s Lewis acid mediated epoxide opening reaction. Accordingly, the two segments were treated with BF3.OEt2 in dichloromethane to afford the diene 5 in 67% yield. Barely detectable amounts of isomeric diene could be detected in the product by HPLC analysis or by NMR spectroscopy. Now, the stage is set to effect the ring-closing metathesis reaction. On exposure of 5 to Grubbs second generation catalyst16 furnished the pyran ring in 73% yield. The product was assigned by 1H, 13C NMR, mass and elemental analysis.

Double bond reduction as well as benzyl ether cleavage was accomplished in one pot by exposure of 4 to Pd/C catalyst under hydrogen atmosphere10g to afford the diol 12 in 75% yield. Compound 12 was then treated with NaIO4 impregnated over silica gel in dichloromethane to afford the aldehyde 3 in 92% yield. The analytical data were exactly matching with the reported values. Though this constitutes a formal synthesis of (−)-centrolobine, we were interested to complete its synthesis and compare the data with the natural product. The Wittig reaction between the 4-benzyloxybenzyltriphenylphosphonium bromide9b and the aldehyde 3 was carried out in the presence of n-BuLi to obtain 2 followed by simultaneous reduction of the double bond and deprotection of the benzyl ether by catalytic hydrogenation gave (−)-centrolobine (1) in 78% yield over two steps. 1H and 13C NMR spectra, IR, melting point, and optical rotation ([α]D25 –91.5 (c 1.2, CHCl3)) of 1 were in good agreement with the natural product.10

CONCLUSION
In summary, a new synthetic approach has been designed for the stereoselective formal synthesis of (−)-centrolobine following Lewis acid mediated epoxide opening followed by ring-closing metathesis reaction for the first time. Total syntheses of other pyran ring containing natural products are in progress in our laboratory following the above approach and will be reported in due course.

EXPERIMENTAL
General
All chemicals used in this study were purchased from Aldrich, Fluka or Lancaster and used as received. All the moisture-sensitive reactions were performed in an inert atmosphere of either N2 or Ar using dry solvents. The elemental analyses were recorded on Elmentar-Vario-EL (Heraeus Company Ltd. Germany). The NMR spectra were obtained on a Bruker 200, 400, or 500 Fourier transform spectrometer. Optical rotations were measured with a JASCO DIP 370 digital polarimeter. All reactions are monitored by Thin Layer Chromatography (TLC) carried out on 0.25 mm E- Merck silica gel plates (60F-254) with UV, I2 or anisaldehyde in ethanol as development reagents.
(2R,3S)-2-(Benzyloxymethyl)-3-vinyloxirane (7)
To a solution of IBX (6.5 g, 23.19 mmol) in DMSO (14 mL), was added pyridine (5 mL) followed by epoxy alcohol 11 (3.0 g, 15.46 mmol) in dry THF (20 mL) at rt and stirred for 4 h. After completion of the reaction (monitored by TLC), water (H2O) (30 mL) was added, and diluted with Et2O (50 mL). The solid was filtered through a pad of Celite and organic layer was separated. The aqueous layer was extracted with Et2O (2 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4, concentrated to give crude aldehyde (2.9 g, crude product) which was used immediately for the next reaction.
To a suspension of methyltriphenylphosphonium bromide salt (16.56 g, 46.39 mmol) in THF (50 mL) at 0 oC, was added NaHMDS (31.0 mL, 1M solution in toluene) drop-wise. The reaction mixture was stirred for 1 h and the crude aldehyde (2.9 g in 20 mL THF) was added slowly. After 2 h, the reaction was quenched with saturated solution of NH4Cl and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification of the crude product by silica gel (60-120 mesh) column chromatography afforded vinyl epoxide 7 (2.5 g, 86% over two steps) as a yellow color liquid. [α]D25 −1.95 (c 1.65, CHCl3); IR (CHCl3): 3030, 2989, 2920, 2860, 1639, 1496, 1453, 1387, 1148, 1096, 1028, 929, 739.cm-1; 1H NMR (200 MHz, CDCl3): δ 3.24 (dt, J = 4.4, 5.9 Hz, 1H), 3.38 (dd, J = 4.4, 6.7 Hz, 1H), 3.45-3.62 (m, 2H), 4.44 (d, J = 11.9 Hz, 1H), 4.53 (d, J = 11.9 Hz, 1H), 5.22-5.44 (m, 2H), 5.51-5.68 (m, 1H), 7.17-7.27 (m, 5H) ppm; 13C NMR (50 MHz, CDCl3): δ 56.0, 56.7, 67.8, 73.2, 120.8, 127.7, 128.38, 131.9, 137.8 ppm; ESI-MS m/z 213.2 [M+Na]+; Anal. Calcd for C12H14O2: C, 75.76; H, 7.42. Found: C, 75.59; H, 7.35.
(2S,3R)-1-(Benzyloxy)-3-((S)-1-(4-methoxyphenyl) but-3-enyloxy)pent-4-en-2-ol (5)
To a mixture of epoxide 7 (250 mg 1.31 mmol) and homoallyl alcohol 6 (350 mg, 1.97 mmol) in CH2Cl2 (20 mL) was added drop-wise a 19% solution of BF3·Et2O (0.4 mL, 0.065 mmol) in freshly dried CH2Cl2 at rt. After 45 minutes of stirring at rt, the solution was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (light petroleum/EtOAc: 9/1) to afford diene 5 (0.32 g, 67%) as a colorless liquid. [α]D25 +3.8 (c 2.6, CHCl3); IR (CHCl3): 3436, 3009, 2906, 2862, 1639, 1611, 1512, 1496, 1454, 1302, 1247, 1175, 1035, 923, 832, 755, 698 cm-1; 1H NMR (200 MHz, CDCl3): δ 2.24-2.58 (m, 2H), 3.30-3.65 (m, 3H), 3.71 (s, 3H), 3.84-3.96 (m, 1H), 4.24-4.48 (m, 3H), 4.88-5.25 (m, 4H), 5.40-5.76 (m, 2H), 6.72-6.80 (m, 2H), 7.07-7.25 (m, 7H) ppm; 13C NMR (50 MHz, CDCl3): δ 43.7, 55.1, 70.8, 72.9, 73.2, 77.4, 77.6, 113.6, 116.8, 118.0, 127.0, 127.6, 128.2, 133.0, 134.6, 134.8, 135.1, 159.1 ppm; ESI-MS m/z 391.48 [M + Na]+; Anal. Calcd for C23H28O4: C, 74.97; H, 7.66. Found: C, 74.79; H, 7.49.
(S)-2-(Benzyloxy)-1-((2R,6S)-6-(4-methoxyphenyl)-5,6-dihydro-2H-pyran-2-yl)ethanol (4). A mixture of compound 5 (0.31 g, 0.84 mmol) and Grubbs’ II catalyst (0.021 g, 0.025 mmol) in degassed toluene (60 mL) was heated at 70 oC for 12 h. After completion of the reaction (monitored by TLC), solvent was evaporated under reduced pressure and the crude purified on silica gel column chromatography by eluting with light petroleum: EtOAc (19:1) to afford 4 (0.21 g, 73%) as a colorless viscous liquid. [α]D25 +4.3 (c 1.4, CHCl3); IR (CHCl3): 3401, 2922, 2851, 1612, 1514, 1454, 1385, 1303, 1247, 1174, 1085, 829, 770 cm-1; 1H NMR (200 MHz, CDCl3): δ 2.19-2.31 (m, 2H), 2.58 (bs, 1H), 3.53-3.72 (m, 2H), 3.78 (s, 3H), 3.78-3.90 (m, 1H), 4.48-4.61 (m, 4H), 5.74-5.80 (m, 1H), 5.94-6.04 (m, 1H), 6.85 (d, J = 8.7 Hz, 2H), 7.22-7.33 (m, 7H) ppm; 13C NMR (50 MHz, CDCl3): δ 32.9, 55.2, 70.9, 72.3, 73.4, 75.2, 75.7, 113.7, 126.8, 126.8, 127.0, 127.7, 128.4, 134.5, 138.1, 159.0 ppm; ESI-MS m/z 363.4 (M + Na)+; Anal. Calcd for C21H24O4: C, 74.09; H, 7.11. Found: C, 73.97; H, 7.00.
(S)-1-((2R,6S)-6-(4-Methoxyphenyl)tetrahydro-2H-pyran-2-yl)ethane-1,2-diol (12). A solution of 4 (0.34 g, 1.0 mmol) in EtOH:EtOAc:water (25:5:5) was hydrogenated in the presence of 10% Pd/C (20 mg) under acidic condition (conc. HCl) at rt. After 1 h, the reaction mixture was filtered through a pad of Celite, concentrated and the residue purified on silica gel column chromatography using EtOAc: light petroleum (1:4) to afford 12 (0.19 g, 75%) as a colorless liquid. [α]D25 +4.8 (c 1.25, CHCl3); IR (CHCl3): 3392, 2932, 1613, 1514, 1384, 1246, 1175, 1035, 830, 771 cm-1; 1H NMR (400 MHz, CDCl3): δ 1.43-1.48 (m, 2H), 1.56 (m, 1H), 1.61 (m, 1H), 1.70-1.73 (m, 1H), 1.89-1.93 (m, 1H), 2.55 (bs, 2H), 3.52-3.57 (m, 2H), 3.59 (dd, J = 4.5, 11.7 Hz, 1H), 3.67 (dd, J = 11.7, 3.4 Hz, 1H), 3.73 (s, 3H), 4.28 (dd, J = 11.4, 2.1 Hz, 1H), 6.80 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H) ppm; 13C NMR (50 MHz, CDCl3): δ 23.3, 26.8, 33.2, 55.2, 63.6, 74.2, 79.1, 79.7, 113.6, 127.1, 134.9, 158.9 ppm; ESI-MS m/z 275.1 [M + Na]+; Anal. Calcd for C14H20O4: C, 66.65; H, 7.99. Found: C, 66.54; H, 7.80.
(2R,6S)-2-(4-(Benzyloxy)styryl)-6-(4-methoxyphenyl)tetrahydro-2H-pyran (2). Compound 12 (0.08 g, 0.32 mmol) in CH2Cl2 (5 mL) was stirred with sodium metaperiodate impregnated over silica gel (0.64 g, 2.0 g/ mmol) for 0.5 h. Silica was separated by filtration, organic layer concentrated under reduced pressure and the crude aldehyde 3 used for the next reaction without further purification.
To a stirred solution of p-benzyoxybenzyltriphenylphosphonium bromide (0.41 g, 0.95 mmol) in THF (5 mL) under nitrogen was added (0.63 mL, of 1.6 M solution in hexane) of n-butyllithium. After stirring for 0.5 h, crude aldehyde 3 was added with THF (3 mL) and the reaction mixture stirred for an additional 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl and diluted with Et2O. The organic layer was separated and washed with water, brine and dried over Na2SO4. Solvent was evaporated under reduced pressure and the crude product purified by silica gel column chromatography eluting with EtOAc: light petroleum (3:97) to afford product 2 (0.07 g, 55%) as a colorless liquid. [α]D25 +15.0 (c 1.2, CHCl3); IR (CHCl3): 3368, 2929, 2853, 1607, 1511, 1454, 1382, 1247, 1174, 1074, 1029, 834, 769 cm-1; 1H NMR (200 MHz, CDCl3): δ 1.51-2.24 (m, 6H), 3.71 (s, 3H), 4.03-4.13 (m, 0.27H), 4.27-4.35 (m, 1.63H), 4.97 (s, 0.55H), 4.99 (s, 1.42H), 5.58 (dd, J = 8.7, 11.6 Hz, 0.68H), 6.06 (dd, J = 5.9, 16.0 Hz, 0.27H), 6.41 (d, J = 11.8 Hz, 0.8H), 6.63 (d, J = 16.0 Hz, 0.17H), 6.76-7.37 (m, 13H) ppm; 13C NMR (100 MHz, CDCl3): δ 23.9, 24.1, 31.6, 31.8, 32.9, 33.4, 55.2, 69.9, 74.9, 78.8, 79.0, 79.6, 113.6, 114.5, 114.8, 127.2, 127.3, 127.4, 127.6, 127.9, 128.0, 128.5, 128.6, 129.0, 129.2, 129.9, 130.1, 130.8, 131.5, 135.4, 135.6, 137.0, 158.0, 158.3, 159.0 ppm; ESI-MS m/z 423.5 [M + Na]+; Anal. Calcd for C27H28O3: C; 80.97, H; 7.05. Found: C; 80.78, H; 6.89.
4-(2-((2R,6S)-6-(4-Methoxyphenyl)tetrahydro-2H-pyran-2-yl)ethyl)phenol (1). Compound 2 was hydrogenated by the same procedure as used for the transformation of 4 to 12. The crude product was purified by silica gel column chromatography eluting with EtOAc: light petroleum (1:10) to obtain (−)-centrolobine (1) (0.02 g, 89%). [α]D25 −91.5 (c 1.2, CHCl3), lit.,3 [α]D25 −92.2 (c 1.0, CHCl3); IR (CHCl3): 3420, 2930, 1650, 1490, 1220, 1110 cm-1; 1H NMR (200 MHz, CDCl3): δ 1.42-1.58 (m, 4H), 1.61-1.69 (m, 2H), 1.78-1.89 (m, 2H), 2.54-2.69 (m, 2H), 3.34-3.39 (m, 1H), 3.73 (s, 3H), 4.22 (dd, J = 1.9, 11.1 Hz, 1H), 6.67 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H) ppm; 13C NMR (50 MHz, CDCl3): δ 24.0, 30.7, 31.3, 33.3, 38.3, 55.3, 77.1, 79.1, 113.6, 115.1, 127.1, 129.6, 134.7, 135.9, 153.5, 158.7 ppm; ESI-MS m/z 344.4 [M + Na]+; Anal. Calcd for C20H24O3: C; 76.89, H; 7.74. Found: C; 76.66, H; 7.67.

ACKNOWLEDGEMENT
RP and HR thank CSIR, New Delhi for financial support in the form of research fellowship. We thank Dr. Ganesh Pandey, HOD, Organic Chemistry Division, for his constant support and encouragement. We also thank Dr. P. R. Rajmohanan for the NMR data.

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