Chapter Bielschowskysin: A Structurally and Biologically Interesting Class of Diterpene Natural Product. 1.1 Introduction and Background to Bielschowskysin. 1.1.1 Isolation and Structural Characterisation. In 2004, the Rodríguez group at the University of Puerto Rico reported the isolation and structural elucidation of a new cembrane diterpene, as a colorless crystalline solid from 1.07 Kg of specimen of the sea plume, Pseudopterogorgia kallos, during an expedition to the South Western Caribbean Sea near the Old Province Island of Columbia. Me HO H H O Me OH O OH O O OAc CH Figure 1.1 Structure of Bielschowskysin This new diterpene was named bielschowskysin (1, Figure 1.1)1a after Bielschowsky, the 1918 discoverer of Pseudopterogorgia kallos. About Kg of selected specimens of the sea plume Pseudopterogorgia kallos was partially air dried, frozen, lyophilized, cut into small pieces and homogenised using methanol and dichloromethane (1:1). Subsequent concentration, standard solvent partitioning, silica gel chromatography and HPLC purification yielded bielschowskysin (39.6 mg, 0.024% yield). The structure of was identified as a highly oxygenated hexacyclic diterpene, as fully characterised by NMR and single-crystal X-ray analysis, to possess an unprecedented cembrane carbon skeleton.1 The molecular formula C22H26O9of bielschowskysin and m/z 374.1368 [M-AcOH] implied ten-degrees of unsaturation. The 13 C NMR spectrum showed four olefinic resonances and two carbonyl resonances accounted for four sites of unsaturation and the remaining six sites of unsaturation must be accounted by the rings. HMBC, HMQC, NOESY, COSY, 1H, 13 C and 13C-DEPT NMR experiments provided the key connectivities, relative stereochemistry of the 10 chiral centres, and X-ray crystal analysis proved the [9.3.3.0] tetradecane core of 1.1 The absolute stereochemistry is currently unproven, although may be predicted as shown in Figure 1.1 by comparison with other cembrane family members. 1.1.2 Biological Activity The interesting ring-structure of bielschowskysin (1) is matched by its ability to exhibit significant antiplasmodial activity against three chloroquine-resistant strains of Plasmodium falciparum at an IC50 of 10 µg/mL1a. As such, the terpene represents a [5-4-9] novel structural archetype to fight against malaria with a yet undefined mechanism with which to harness and understand. Unfortunately, the characterization studies of have exhausted all supplies of bielschowskysin for more in-depth and diverse biological evaluations. Due to its unique structural properties, biosynthesis and biological activity, we embarked on the total synthesis of bielschowskysin (1). 1.1.2.1 Antimalarial Agents and Continuing Needs. According to the WHO report, around 243 million cases of malaria are clinically registered every year causing over 880,000 deaths1b,2. This disease likely originated in Africa and has widely spread in tropical and subtropical regions over the last several decades. Figure 1.2 Structure of Antimalarial Drugs There are four main parasites responsible for malaria. These are Plasmodium falciparum, P. vivax, P. ovale, and P. malariae, of which P. falciparum and P. vivax accounts for 95% of the world cases; one death every 30 seconds. Malaria is re-emerging as the biggest infectious killer and ranked third among the major disease in causing deaths after pneumococcal acute respiratory infections (pneumonia) and tuberculosis (TB). Natural sources have been the choice for a long period to cure the disease. Chloroquinine (3) is largely used in most parts of the world because it is cheap and effective (Figure 1.2). Artemisinin (2) is a natural product and has been known for 2000 years3. Its current usage is FDA restricted solely for complicated cerebral malaria cases. In the past 30 years, only one new synthetic material, mefloquine, has been successfully developed. Plasmodium falciparum is rapidly increasing its resistance to many of the drugs. Chloroquine is particularly ineffective and the search for new antimalarial leads has gained more importance. While a number of targets have been suggested for antimalarial design, there is a continued need to expand our understanding of Plasmodium infection. In recent years, researchers have developed techniques such as fluorescent-labelling or GFP fusion analysis to study the host-parasite. Due to drug resistance, there have been no new classes of antimalarial drugs in the clinical trial since 1996. Recently, the screening of million compounds from GlaxoSmithKline’s library for the inhibitors of P. falciparum, highlighted around 13000 compounds to show parasite inhibition by at least 80%, and 8000 compounds against multidrug resistant strains. 1.1.3 Proposed Biosynthesis The geranylgeranyl diphosphate (GGPP) biosynthetic pathway is a well known source of the cembrane family of natural products (Schem 1.1). Initial C1→C14 cyclisation of GGPP 17 affords the 14 membered macrocycle of cembrane 18. Ring contraction or cyclisation of C7→C11 then furnishes the verrillane family4b 21 and C6→C12 cyclisation would generate the bielschowskyane skeleton 22, a novel class of diterpene. The intricarene skeleton 19 can be derived via a C6→C11 and C2→C12 cyclisation of cembrane (18) while the providenciane 20 could have originated via a C2→C17 cyclisation1a, 4a, 5. Scheme 1.1 Proposed biosynthesis of bielschowskyane skeleton and related cembranes 1.1.4 Related Diterpene Natural Products Rodríguez and his co-workers have investigated extensively the Pseudopterogorgia kallos6 sea plume. The octocoral fauna of West Indies is unique in its profusion of gorgonian corals. These corals are rich in producing acetogenins, prostanoids, sesquiterpenoids, diterpenoids and steroids, which are largely unknown from terrestrial sources. Typically the natural products isolated from these corals display significant antimalarial, anti-inflammatory, analgesic, and anticancer activities. The common structural features among the genus Pseudopterogorgia include substituted furans, butenolides, epoxy butenolides, macrocyclic, ring architectures and substituted isopropenyl groups (Figure 1.3). Figure 1.3 Related Diterpene Natural Products from Pseudopterogorgia species. In recent years, there have been many reports of isolation and structural characterisation from the sea plumes Pseudopterogorgia, for example, intricarene (23), kallolide A (24), lophotoxin (25) rubifolide (31), bipinnatin J (26), ciereszkolide (27), providencin (28), verrillin (29), kallosin A (30), rubifolide (31) and other natural products from the same source. Scheme 1.2 Rodríguez’s chemical isomerisation of bipinnatin J to kallolides and pinnatins The diterpenes 23 to 31 all show rearranged carbon skeletons that depend on how a carbocation precursor is trapped. The Rodríguez group has shown, for example, that irradiation of bipinnatin J 26 in acetonitrile produces kallolide A 24, pinnatin A 32 and pinnatin C 33 in a 120:1:6 ratio10 (Scheme 1.2). Similarly the biosynthesis of plumarellide, bielschowskysin and verrillin could have originated from bipinnatin J or rubifolide9 (Scheme 1.3). Oxidation of rubifolide or bipinnatin J may lead to the potential intermediates 35, 38, 40, and [4+2] cycloaddition of diene 35 may produce plumarellide 36 or transannular [2+2] cycloaddition of 38 for bielschowskysin or intramolecular hetero Michael addition of 40 could be explained for verrillin11. Trauner and Pattenden independently unveiled the synthesis of intricarene through biosynthetic pathway12. Retrosynthetic analysis of intricarene shows that it could be prepared via bipinnatin J followed by 1,3-dipolar cycloaddition of possible biosynthetic relevance. HO OH H O O OH H O O 35 H plumarellide (36) OH OH [O] OH O H O O OH O HO O O O [O] O H [4+2] HO H HO HO [2+2] HO 38 O OH O H H O OH H O O OAc Bielschowskysin (1 ) bipinnatin J (26) [O] OH OH HO O O O Michael Cyclisation H O O OH 40 OH O O H O O O H H O verrillin (29) Scheme 1.3 Biosynthetic conjecture to plumarellide, bielschowskysin and verrillin. Treating bipinnatin J 26 with m-CPBA followed by acetylation produced the pyranone acetate 41. Heating the pyranone acetate 41 in DMSO with tetramethyl piperidine yielded intricarene 23 (Scheme 1.4). 12 Scheme 1.4 Trauner’s biomimetic evidence to the biosynthesis of intricarene. A proposed biosynthesis of providencin is shown in the Scheme 1.1. The formation of the cyclobutane ring in providencin appears to involve a Norrish type II rearrangement of bipinnatin E. This proposed biosynthesis has recently been validated synthetically by the Pattenden group13. Irradiation of unsaturated aldehyde 43 in benzene produced the cyclobutanol 44 in 19% yield by a C-H insertion reaction (Scheme 1.5). Scheme 1.5 Pattenden’s cyclobutanol synthesis of providencin. It is difficult to determine an all-encompassing biosynthetic pathway or propose an exact chemical sequence to each of these natural products. Clearly, there appears to be considerable structural diversity (e.g., induced by seasonal or chemotype variations in the sea plumes) by way of concerted cycloadditions, photochemical oxidations, rearrangements and singlet-O2 oxidations. 1.1.5 Relevant Synthetic Efforts 1.1.5.1 Butenolide Construction Butenolides are oxidised derivatives of furans. Apart from the direct oxidation of furans by using traditional methods, there is interest in making butenolides 47 in optically pure form (Scheme 1.6). Marshall adopted allenic esters 46 to construct the butenolide moiety in the total synthesis of kallolide A16 and rubifolide17. Other methods include selenoxide elimination18,19,20 of butyrolactone 49, Wittig reaction21, alkylation of silyloxy furan22 and ring closingmetathesis23 (RCM) of vinyl esters 50. Pd(PPh3 )4 OMs CO, ROH R2 R1 R1 PhSeBr, LHMDS R2 60-80% yield R1 70-90% yield O O RCM O R2 47 R2 R1 H 2O 2, THF O 49 R1 O 1. Hydrolysis 2. AgNO3, Hexanes 46 SePh O 48 O R2 O 45 O H RO 75-85% yield R1 O R1 O R2 47 R1 R2 O O 50 R2 47 Scheme 1.6 Stereo-defined syntheses of chiral γ-butenolides 1.1.5.2 Furan Construction The strategy for constructing the furan moiety was reported by Paquette in his first synthesis of psuedopterolide19. The furan in question was constructed by condensing glyceraldehyde 51 and a β-keto ester to produce the 2,3,5-substituted furan 52 (Scheme 1.7). Careful extension of side chains and macrocyclisation led to the furanocembranes. The disadvantage of this approach was to carry the reactive furan ring throughout the synthesis. Alternatively, the macrocycle could be constructed first and the furan ring formed later in the synthesis. O O O O 51 PhS O CO2Me OMe HOAc, H 2O, EtOH 80 °C SPh OH O 52 Scheme 1.7 Paquette’s synthesis of the furan moiety of acersolide. 10 81.64, 81.42, 73.20, 63.37, 51.52, 39.28, 26.98, 26.76, 26.54, 25.74, 19.37, 18.02, -5.67, 5.74. To a solution of TBS ether (2.0 g, 3.17 mmol) in 20 mL of MeOH was added CSA (812 mg, 3.50 mmol, 1.1 eq.) and the reaction mixture stirred at room temperature for hrs. Methanol was removed on a rotary evaporator and the residue was used in the next step. To a solution of crude alcohol (2.0 g, 3.88 mmol, 1.0 eq.) in CH2Cl2 (20 mL) was added pyridine (1 mL) and the Dess-Martin reagent (2.0 g, 4.74 mmol, 1.5 eq.) at °C. The solution was stirred at room temperature for hrs and saturated solutions of Na2S2O3 and NaHCO3 were added. After stirring for ½ hr, the separated aqueous layer was extracted with CH2Cl2 (3x 20 mL). The combined organic layers were washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by column chromatography (5:1 hexane/ethyl acetate) to provide aldehyde (71%) as colorless oil4-12. 1H NMR (CDCl3, 500 MHz) : δ 9.58 (s, 1H), 7.65 (m, 6H), 7.36 (m, 4H), 5.65 (d, 1H), 4.69 (t, 1H), 3.99 (dd, 1H), 3.71 (m, 2H), 3.61 (s, 3H), 3.13 (dd, 1H), 2.58 (m, 1H), 2.54 (dd, 1H), 2.34 (dd, 1H), 1.42 (s, 3H), 1.30 (s, 3H), 1.08 (s, 9H), 0.80 (s, 9H), -0.09 (s, 3H), -0.14 (s, 3H). OH To a solution of aldehyde (1.20 g, 2.34 mmol) in anhydrous THF (24 OTBDPS mL) at –78 °C was added ethynyl magnesium bromide (7.00 mL, O O O CO2 CH3 311 3.51 mmol, 1.5 eq.) and the solution was stirred at this temperature for hrs. The reaction mixture was quenched with saturated NH4Cl solution, diluted with water and extracted with ether (2x 20 mL). The organic layers were dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (4:1 hexane/ethyl acetate = eluant) to provide diastereomeric alkynol (70%) as colorless oil (1.5:1). 142 To a solution of alkynol (2.00 g, 3.71 mmol) in CH2Cl2 (10 mL) was OTBS OTBDPS added 2,6-lutidine (2.14 mL, 18.5 mmol, eq.) and cooled to °C. O O TBSOTf (1.02 mL, 4.45 mmol, 1.22 eq.) was added at °C and O CO2CH stirred for 30 min. After addition of water (5 mL), the mixture was 312 extracted with CH2Cl2 (2 x 20 mL), and the combined organic extracts were dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (5:1 hexanes/ethyl acetate as eluant) to provide disilyl ether (75%) as colorless oil. OTBS OTBDPS was added NIS (344 mg, 1.53 mmol) and AgNO3 (26 mg, 0.153 O I To a solution of alkyne (1.00 mg, 1.53 mmol) in acetone (10 mL) O O CO2 CH3 mmol). After stirring for hrs, water was added and evaporated acetone. The product was extracted with AcOEt. The combined 313 organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, evaporation of solvent and purification through silica gel column chromatography (ethyl acetate/hexane = 1/4) gave the alkynyl iodide in 84% yield as pale yellow oil (101 mg). 1H NMR (CDCl3, 500 MHz): δ 9.61 (s, 1H), 5.47 (d, 1H), 4.65 (d, 1H), 4.63 (t, 1H), 4.05 (m, 2H), 2.76 (m, 1H), 2.50 (dd, 1H), 2.35 (dd, 1H), 1.30 (s, 3H), 1.23 (s, 3H), 1.10 (s, 9H), 0.87 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3, 125 MHz) : δ 200.16, 136.34, 136.17, 133.60, 133.26, 129.66, 129.54, 127.64, 127.48, 111.17, 104.53, 94.62, 82.06, 80.64, 75.66, 66.40, 39.89, 37.44, 27.10, 26.52, 26.38, 25.84, 19.63, 18.15, 4.37, -4.38, -4.79; OTBS OTBDPS was treated with DIBAL-H (0.38 mL, 0.385 mmol, M in O I To a solution of ester (200 mg, 0.256 mmol) in CH2Cl2 (10 mL) O O O 314 cyclohexane, 1.5 eq.) at –78 °C and stirred for 50 min. The reaction mixture was quenched by pouring into a saturated aqueous sodium potassium tartrate solution (10 mL) and was diluted with ether (25 mL). The 143 organic phase was dried (Na2SO4) and concentrated to afford lactol (77%). 1H NMR (CDCl3, 500 MHz): δ 9.61 (s, 1H), 5.47 (d, 1H), 4.65 (d, 1H), 4.63 (t, 1H), 4.05 (m, 2H), 2.76 (m, 1H), 2.50 (dd, 1H), 2.35 (dd, 1H), 1.30 (s, 3H), 1.23 (s, 3H), 1.10 (s, 9H), 0.87 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H); 13 C NMR (CDCl3, 125 MHz) : δ 200.16, 136.34, 136.17, 133.60, 133.26, 129.66, 129.54, 127.64, 127.48, 111.17, 104.53, 94.62, 82.06, 80.64, 75.66, 66.40, 39.89, 37.44, 27.10, 26.52, 26.38, 25.84, 19.63, 18.15, 4.37, -4.38, -4.79; To a solution of lactone (85 mg, mmol) in dioxane (2.5 mL) and water (2.5 mL) was added aldehyde (140 mg, 0.5 mmol, 0.5 eq.) followed by DABCO (113 mg, mmol, 100 mol%) at room temperature. The reaction was stirred for 20 hrs and then extracted with ether. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated. The crude material was purified by flash-chromatography (hexane/ethyl acetate 1:1) to afford non separable mixtures of aldehyde and adducts (25% of 322 and 75% of 323). H NMR (CDCl3, 300 MHz): δ 7.58 (m, 1H), 7.46 (m, 1H), 7.32 (m, 10H), 6.13 (m, 1H), 4.88 (m, 1H), 4.77 (m, 1H), 4.56 (s, 4H), 3.84 (m, 1H), 3.72 (m, 1H), 1.88-1.61 (m, 8H), 1.40 (m, 12H); To a solution of lactone (185 mg, mmol) in dioxane (5.5 mL) and water (5.5 mL) was added aldehyde (306 mg, 0.5 mmol, 0.5 eq.) followed by DABCO (246 mg, mmol, 100 mol%) at room temperature. The reaction was stirred for 20 hrs and then extracted with ether. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated. The crude material was purified by flash144 chromatography (hexane/ethyl acetate 1:1) to afford non separable mixtures of BaylisHillman adducts (4 diastereomers, 8% yield of 325) and aldehyde. H NMR (CDCl3, 300 MHz): δ 7.71 (m, 1H), 7.52 (m, 1H), 7.32 (m, 10H), 5.28 (m, 1H), 5.11 (m, 1H), 4.91 (m, 1H), 4.85 (m ,2H), 4.58 (s, 2H), 4.21 (m, 2H), 3.85 (m, 2H), 3.60 (m, 2H), 3.54 (m, 2H), 1.98 (m, 4H), 1.78 (m, 2H), 1.42 (s, 6H), 1.40 (s, 12H) ; To a solution of the butyrolactone (93 mg, 1.077 mmol, eq.) in dry THF (4 mL) at −78 ◦C was added dropwise a solution of LHMDS (1.0 mL, 1.077 mmol, 1.0 M in THF, eq.) at −78 ◦C. The mixture was stirred at −78 ◦C for 15 and then a solution of the aldehyde (100 mg, 0.359 mmol) in THF (4 mL) was added dropwise over 10 min. The mixture was stirred at −78 ◦C for 50 and then quenched with saturated aqueous NH4Cl. The solution was allowed to warm to room temperature and then diluted with water (30 mL) and Et2O (50mL). The separated aqueous layer was extracted with Et2O (3 × 50 mL) and the combined organic extracts were dried and concentrated to afford the furanolactone (265 mg, 71%) as yellow oil. H NMR (CDCl3, 300 MHz): δ 7.38 (m, 5H), 4.58 (s, 2H), 4.34 (m, 1H), 4.17 (m, 1H), 3.86 (m, 3H), 3.57 (m, 2H), 2.61 (m, 1H), 2.30 (m, 1H), 2.05 (m, 1H), 1.74 (m, 2H), 1.64 (m, 2H), 1.41 (s, 3H), 1.39 (s, 3H); 13 C NMR (CDCl3, 125 MHz) : δ 179.42, 137.98, 127.71, 127.69, 127.69, 108.9, 79.89, 78.45, 73.57, 71.5, 70.43, 67.00, 44.65, 31.37, 28.84, 27.30, 25.76, 22.06 To a solution of the lactone (58 mg, 0.144 mmol, 1.0 eq.) in dry THF (5 mL) at −78 ◦C was added dropwise a solution of LHMDS (0.22 mL, 0.216 mmol, 1.0 M in THF, 1.5 eq.) at −78 ◦C. The mixture was stirred at −78 ◦C for 15 and then a solution of the aldehyde (60 mg, 0.144 mmol, 1.0 eq.) in THF (5 145 mL) was added dropwise over 10 min. The mixture was stirred at −78 ◦C for 50 and then quenched with saturated aqueous NH4Cl. The solution was allowed to warm to room temperature and then diluted with water (20 mL) and Et2O (50mL). The separated aqueous layer was extracted with Et2O (3 × 50 mL) and the combined organic extracts were dried and concentrated to afford the furanolactone (major isomer, 65 mg, 55%) as colorless oil. IR (neat, cm-1): 4043, 3443, 2930, 2105, 1758, 1641, 1463, 1364, 1253, 1102; H NMR (CDCl3, 300 MHz): δ 7.32 (m, 5H), 5.03 (m, 1H), 4.85 (m, 1H), 4.52 (s, 2H), 3.93 (m, 1H), 3.69 (m, 5H), 3.55 (m, 2H), 3.35 (m, 5H), 2.56 (m, 2H), 2.11 (m, 3H), 2.18-2.08 (4H), 1.811.59 (m, 10H), 1.24 (s, 3H), 1.12 (m, 3H), 0.88 (3xs, 27H), 0.08 (6xs, 18H); 13 C NMR (CDCl3, 125 MHz) : δ 178.89, 138.43, 128.24, 127.58, 102.68, , 86.15, 76.15, 75.10, 73.29, 72.27, 72.21, 71.03, 71.00, 62.25, 45.03, 44.78, 39.92, 38.18, 33.36, 32.13, 25.89, 24.93, 18.20, 15.00, –2.04, –2.13, –4.42, –4.82, –5.44, –5.51; To a solution of the lactone (100 mg, 0.248 mmol, 1.0 eq.) in dry THF (5 mL) at −78 ◦C was added dropwise a solution of LHMDS (0.37 mL, 0.372 mmol, 1.0 M in THF, 1.5 eq.) at −78 ◦C. The mixture was stirred at −78 ◦ C for 15 and then a solution of the aldehyde (126 mg, 0.248 mmol, 1.0 eq.) in THF (5 mL) was added dropwise over 10 min. The mixture was stirred at −78 ◦C for 50 and then quenched with saturated aqueous NH4Cl. The solution was allowed to warm to room temperature and then diluted with water (20 mL) and Et2O (50mL). The separated aqueous layer was extracted with Et2O (3 × 50 mL) and the combined organic extracts were dried and concentrated to afford the furanolactone (major isomer, 120 mg, 53%) as colorless oil. 1H NMR (CDCl3, 300 MHz): δ 7.32 (m, 5H), 5.48 (dd,1H, J=4.72 Hz, 1.90 Hz and 1.25 Hz), 4.85 (m, 1H), 4.51 (d, 2H, J=2.50 Hz), 3.93 (q, 1H, J=5.42 Hz, 146 3.80 Hz and 3,25 Hz), 3.84 (m, 2H), 3.75 (m, 1H), 3.57 (dd, 1H, J=9.45 Hz and 5.65Hz), 3.49 (dd, 1H, J=9.80 Hz, 6.30 Hz and 5.70Hz), 3.34 (m, 3H), 2.57 (m, 2H), 2.11 (m, 3H), 1.811.59 (m, 8H), 1.24 (s, 3H), 0.88 (4xs, 36H), 0.08 (4xs, 24H); 13 C NMR (CDCl3, 125 MHz) : δ 179.31, 138.38, 128.23, 127.63, 127.39, 99.29, 84.52, 76.11, 75.06, 73.38, 72.58, 72.40, 70.82, 70.77, 44.82, 44.68, 40.23, 40.08, 34.34, 31.93, 25.93, 25.87, 25.85, 25.79, 25.04, 18.24, 18.20, 18.19, 17.88, –2.03, –2.13, –4.21, –4.32, –4.80, –5.27, –5.42, –5.52; MS (ESI): calcd-910.57; found [M + Na] 933.6 CeCl3 (670 mg, 2.69mmol) was dried at 100 °C under vacuo for h. To the resultant powder of CeCl3 at °C was added THF (50 ml), and the mixture was vigorously stirred at room temperature for h and LHMDS (2.52 mL, 2.514 mol, 28 eq.) was added at °C. The resultant solution was stirred at °C for h, then cooled to –45 °C and added the alkyne (40 mg, 0.00089 mmol) in THF. The suspension was allowed to warm to °C over hr with vigorous stirring and cooled back to –45 °C. To this mixture was added a solution of aldehyde (50 mg, 0.00089 mmol, 1.0 eq.) in THF (10 ml) at –45 °C. The mixture was kept at this temperature for 60 min, and then allowed to warm to °C. After being stirred at °C for 30 min, the reaction mixture was quenched with aqueous pH phosphate buffer. The solution was diluted with EtOAc, and filtered through a pad of Celite. The filtrate was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified with flash column chromatography to give alkynol as non-separable mixtures of diastereomer (30%). IR (neat, cm-1): 3459, 3308, 2951, 2892, 2117, 1740, 1465, 1372, 1253, 1097; 1H NMR (CDCl3, 500 MHz): δ 7.60 (m, 12H), 7.35 (m, 8H). 4.21 (m, 2H), 4.05 (m, 2H), 3.65 (m, 2H), 3.58 (m, 1H), 2.52 (m, 2H), 1.73 (m, 2H), 1.42 (m, 6H), 1.28 (2xs, 6H), 1.25 (2xs, 147 18H), 1.02 (2xs, 18H), –0.03 (4xs, 12H); 13 C NMR (CDCl3, 125 MHz) : δ 174.56, 136.35, 136.18, 135.62, 133.61, 133.24, 129.62, 129.55, 129.33, 128.95, 127.65, 127.46, 127.05, 113.21, 107.5, 99.86, 83.85, 71.10, 70.84, 69.90, 69.52, 68.99, 68.16, 51.39, 42.66, 31.49, 31.17, 29.68, 29.10, 27.06, 27.04, 27.00, 26.94, 25.65, 25.53, 19.34, 19.31, 19.25, 18.70, – 4.50, –4.56, –5.34, –5.39 To a solution of the lactone (100 mg, 0.179 mmol, 1.0 eq.) in dry THF (5 mL) at −78 ◦C was added dropwise a solution of LHMDS (0.18 mL, 0.179 mmol, 1.0 M in THF, 1.0 eq.) at −78 ◦C. The mixture was stirred at −78 ◦ C for 15 and then a solution of the aldehyde (120 mg, 0.161 mmol, 0.9 eq.) in THF (5 mL) was added dropwise over 10 min. The mixture was stirred at −78 ◦C for 50 and then quenched with saturated aqueous NH4Cl. The solution was allowed to warm to room temperature and then diluted with water (20 mL) and Et2O (50mL). The separated aqueous layer was extracted with Et2O (3 × 50 mL) and the combined organic extracts were dried and concentrated to afford the furanolactone (102 mg, 52%) as colorless oil. 1H NMR (CDCl3, 500 MHz): δ 7.75 (m, 4H), 7.67 (m, 2H), 7.40 (m, 6H), 7.32 (m, 3H), 5.52 (d, 1H), 4.76 (m, 2H), 4.36 (t, 1H), 4.05 (m, 2H), 3.73 (s, 2H), 2.72 (m, 1H), 2.33 (m, 2H), 1.83 (m, 2H), 1.74 (m, 2H), 1.28 (3xs, 9H), 1.10 (s, 9H), 0.87 (s, 9H), 0.86 (2xs, 18H), 0.10 (s, 3H), 0.08 (3xs, 9H), 0.03 (s, 6H); 13 C NMR (CDCl3, 125 MHz) : δ 177.23, 136.34, 136.17, 135.66, 133.60, 133.26, 129.66, 129.54, 129.36, 128.98, 127.64, 127.48, 127.07, 111.17, 104.52, 98.31, 82.06, 80.64, 76.49, 76.52, 75.07, 71.14, 66.30, 45.52, 39.92, 38.15, 37.44, 37.29, 27.10, 26.52, 26.38, 25.84, 25.88, 24.65, 19.63, 18.26, 18.19, 18.15, 4.35, –2.06, –2.13, -4.38, -4.79, –5.46, –5.55 148 To a selenolactone (70 mg, 0.125 mmol) in THF (3.0 mL) was added LHMDS (0.14 mL, 0.138 mmol, 1.1 eq.) in THF (3 mL) at −78 ◦C under inert atmosphere. The mixture was stirred at −78 ◦C for 10 and then a solution of the aldehyde (94 mg, 0.125 mmol, 1.0 eq.) in THF (2.0 mL) was added dropwise over 10 min. The mixture was stirred at −78 ◦C for hr and then quenched by the addition of a sat.NH4Cl. The mixture was diluted with water, extracted with Et2O and concentrated under reduced pressure. The residue was purified by column chromatography to afford the non-separable mixture of diastereoisomers (70%). 1H NMR (CDCl3, 500 MHz): δ 7.75 (m, 4H), 7.40 (m, 6H), 7.11 (br s, 1H), 5.52 (d, 1H), 5.33 (m, 1H), 4.36 (m, 1H), 4.05 (m, 2H), 3.73 (s, 2H), 2.72 (m, 1H), 2.33 (m, 2H), 1.83 (m, 2H), 1.74 (m, 2H), 1.28 (3xs, 9H), 1.10 (s, 9H), 0.87 (s, 9H), 0.86 (2xs, 18H), 0.10 (s, 3H), 0.08 (3xs, 9H), 0.03 (s, 6H); 13 C NMR (CDCl3, 125 MHz) : δ 177.23, 136.34, 136.17, 135.66, 133.60, 133.26, 129.66, 129.54, 129.36, 128.98, 127.64, 127.48, 127.07, 111.17, 104.52, 98.31, 82.06, 80.64, 76.49, 76.52, 75.07, 71.14, 66.30, 45.52, 39.92, 38.15, 37.44, 37.29, 27.10, 26.52, 26.38, 25.84, 25.88, 24.65, 19.63, 18.26, 18.19, 18.15, 4.35, –2.06, –2.13, -4.38, -4.79, –5.46, –5.55 To iodomethytriphenylphosphonium iodide (2.58 g, 4.87 mmol, 2.5 eq.) in THF (25 ml) at room temperature was added NaHMDS (1.95 mL, 1.95 mmol, 1.0 eq.) and stirred for 10 min. Then, it was cooled to −78 °C, and HMPA (1.5 ml) and the aldehyde (1.0 g, 1.95 mmol) in THF (10 ml) were added. The reaction mixture was slowly warmed to room temperature and the solids were removed by filtration. The filtrate was concentrated, and the residue was purified by chromatography eluting with (5:1 hexanes/ethyl acetate) to give cis149 vinyl iodide along with trans-isomer (14%) as colourless oil (870 mg, 70%). H NMR (CDCl3, 500 MHz) : δ 7.75 (m, 4H), 7.40 (m, 6H), 6.40 (t, 1H, J=7.55 Hz), 6.32 (d, 1H, J=7.55 Hz), 5.76 (d, 1H, J=3.80 Hz), 4.73 (m, 1H), 4.55 (m, 1H), 3.85 (m, 1H), 3.67 (s, 3H), 2.40 (m, 1H), 2.13 (m, 1H), 1.44 (s, 3H), 1.31 (s, 3H), 1.11 (s, 9H); 13C NMR (CDCl3, 125 MHz) : δ 172.19, 139.53, 135.91, 134.76, 133.48, 133.35, 129.76, 129.75, 127.70, 127.65, 111.74, 105.05, 83.79, 80.86, 75.77, 51.61, 39.94, 29.70, 26.92, 26.62, 26.53, 19.20 To a solution of acetonitrile (2.5 mL) contains vinyl iodide (158 mg, 0.249 mmol, 0.83 eq.), Pd(PPh3)4 (17 mg, 0.025 mmol, 0.05 eq.), CuI (2.8 mg, 0.015 mmol, 0.05 eq.), and triethylamine (49 mg, 0.493 mmol, 1.64 eq.) was added alkyne (50 mg, 0.300 mmol, 1.0 eq.). The reaction was stirred at ambient temperature for 24 hrs. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (85:15 hexanes/ethyl acetate) to yield 85 mg (42%) of 17 as pale yellow oil. H NMR (CDCl3, 500 MHz) : δ 7.68-7.66 (m, 4H), 7.37-7.34 (m, 6H), 7.48 (dd, 1H, J=5.7 Hz and 1.9 Hz), 6.05 (m, 2H), 5.68 (d, 1H, J=3.80 Hz), 5.51 (d, 1H, J=11.35 Hz), 5.22 (m, 1H), 4.76 (m, 1H), 4.66 (m, 1H), 3.79 (m, 1H), 3.65 (s, 3H), 2.38 (m, 1H), 2.24 (m, 1H), 2.04 (m, 1H), 1.86 (m, 1H), 1.82 (m, 1H), 1.40-1.33 (3xs, 9H), 1.07 (s, 9H); 13 C NMR (CDCl3, 125 MHz) : δ 176.77, 172.80, 156.88, 142.17, 135.90, 133.51, 129.79, 127.60, 121.87, 111.66, 110.01, 104.96, 84.43, 81.11, 81.06, 80.71, 80.63, 71.55, 66.22, 51.90, 45.75, 40.14, 29.65, 27.00, 26.87, 26.81, 26.62, 19.21. 150 To a solution of enyne (45 mg, 0.0666 mmol) in CH2Cl2 (2 mL) was added m-CPBA (12 mg, 0.0733 mmol, 1.1 eq.) and the mixture was stirred at room temperature for 24 hrs. The reaction was incomplete and the crude was purified by column chromatography using (85:15 hexanes/ethyl acetate) to yield 12 mg (60%) of 17 as pale yellow oil. 1H NMR (CDCl3, 500 MHz) : δ 7.68-7.66 (m, 4H), 7.37-7.34 (m, 6H), 7.48 (dd, 1H, J=5.7 Hz and 1.9 Hz), 6.05 (m, 1H), 5.68 (d, 1H, J=3.80 Hz), 5.22 (m, 1H), 4.76 (m, 1H), 4.66 (m, 1H), 3.79 (m, 1H), 3.65 (s, 3H), 3.07 (dd, 1H, J=17.65 Hz and 6.3 Hz), 2.38 (m, 1H), 2.24 (m, 1H), 2.04 (m, 1H), 1.86 (m, 1H), 1.82 (m, 1H), 1.40-1.33 (3xs, 9H), 1.07 (s, 9H); 151 References 1. (a) Marrero, J.; Rodríguez, A. D.; Baran, P.; Raptis, R. G.; Sanchez, J. A.; OrtegoBarria, E.; Capson, T. L. Org. Lett. 2004, 6, 1661-1664. (b) W. Armand Guiguemde, Anang A. Shelat, David Bouck, Sandra Duffy, Gregory J. Crowther, Paul H. Davis, David C. Smithson, Michele Connelly, Julie Clark, Fangyi Zhu, Marı´a B. Jime´nezDı´az, Marı´a S. Martinez, Emily B. Wilson, Abhai K. Tripathi, Jiri Gut, Elizabeth R. Sharlow, Ian Bathurst, Farah El Mazouni, Joseph W. 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Soc. 1994, 116, 10310-10311 157 [...]... methods to natural products, we have begun studies towards the total synthesis of 1 Our approach is to mimic the biosynthesis of 1 by the [2+ 2] photo-cycloaddition of allenyl -2( 5H)furanone 157 under high stereocontrol to form the tricyclic core27 (Figure 2. 1) Figure 2. 1: Proposed model study of the tricyclic core of bielschowskysin 2. 2 Model Study: [2+ 2] Cycloaddition of Allene-Butenolide As an intramolecular... O THF/pentane O -78 °C 64 Pd 2dba 3, PPh 3, lutidine HOCH2 CH2 TMS HO 1 02 1 PPh3 , CH3 CN O MsCl, Et 3 N, -78 °C CO, THF O MsCl, LiCl, 2, 6-lutidine CO2 Et Me PhCH3 OH 100 O 2 TBAF, DMF, THF H 3 AgNO 3, acetone CO 2CH2 CH2 TMS 103 O O Kallolide B (104) Scheme 1.19 Marshall’s synthesis of kallolide B23 20 1 .2. 3 Wipf Approach Wipf developed24 a new method for synthesising 2- alkenylfurans using Pd mediated... HO H 3CO CH2 N2 , Et2O BuOOH 93 O 94 H2 C 1-bromo -2- butyne C CH 3 95 (COCl) 2, DMSO CH 2 Cl2 , Et3 N, -78 °C HO DIBAL-H O AgNO3 , acetone SnCl2 , NaI, DMPU H 3CO2 C H 3CO2 C 96 97 CBr 4 , PPh3 OHC O Et 3N, CH 2Cl2 O PhCH3 sec-BuLi n-BuLi, THF, -78 °C, O DMF, -78 °C (CH2 O) n ,-78 °C to rt OHC 98 OH KHMDS, 18-C-6 O THF, -78 °C (F 3CH2 CO )2 O P 99 HO DIBAL-H, CH2 Cl2 , -78 °C CO 2Et OH 101 Cl NaH, 18-C-6... rings 25 Scheme 1 22 Trauner’s synthesis of bipinnatin J, rubifolide and isoepilophodione12a Retrosynthetic analysis of intricarene 23 (Scheme 1.4) showed a possible biosynthetic 1,3dipolar cycloaddition of bipinnatin J In order to explore this biosynthetic possibility, a hydroxy pyranone would be good candidate for the synthesis of intricarene Typically, a hydroxypyranone would form via a [4 +2] cycloaddition... H2O2/Py/CH2Cl2, to give the butenolide 65 23 Scheme 1 21 Pattenden’s synthesis of deoxylophotoxin16 24 Arsenine mediated Stille macrocyclisation yielded the furanocembranoid 130 as mixture of epimeric alcohol Acetylation followed by TBS deprotection and subsequent DMP oxidation gave the bis-deoxylophotoxin 131 with major α isomer (α:β / 2: 1) 1 .2. 4 Trauner Approach Trauner reported the first total synthesis. .. exchange of dioxolane to dioxane rings leaving the primary alcohol in 1 62 unprotected (Scheme 2. 2) CO2Me O O N O N ( R) ( S) OH CO 2Me CH(OMe )2 O CSA, CH 2Cl2 rt, 75% 161 O ( S) ( S) OH O Mes 1 62 Scheme 2. 2: Dioxolane/dioxane exchange with mesitaldehyde acetal Adopting this acetal/acetonide exchange concept30, we elected to use the benzaldehyde dimethyl acetal and benzaldehyde (Scheme 2. 3) Treatment of the... intramolecular [2+ 2] photocycloaddition product 78 in 50% yield as a single stereoisomer 14 Scheme 1.16 Sulikowski’s synthesis of the tetracyclic core of bielschowskysin2 5 1 .2 Approaches toward related diterpenes 1 .2. 1 Leo Paquette Approach The Paquette group was the first to synthesize a furanocembranoid with the synthesis of dihydropseudopterolide in 199019 Their synthesis began with the substituted furan 52 and... natural products 1.3 Retrosynthetic Analysis 1.3.1 Introduction: First Generation In the previous chapter, we highlighted various synthetic studies that could, in principle, aid in the retrosynthetic analysis of bielschowskysin (1) Biosynthetically, 1 susggests a plausible transannular [2+ 2] cycloaddition of a cembranoid framework Figure 1.3 : Structural features of bielschowskysin 29 Besides potential... retrosynthetic analysis of bielschowskysin to left and right fragments were also proposed The following chapters detail subsequent strategies and synthetic studies on bielschowskysin 33 Chapter 2 Bielschowskysin: A Biomimetic Model Study 2. 1 Introduction Apart from the fascinating structural complexity, we are interested in unravelling the biological activity of bielschowskysin (1) In the course of developing... product acersolide 92 in 1993 (Scheme 1.18) 16 Scheme 1.17 Paquette’s synthesis of dihydropseudopterolide and gorgiacerone17 17 Scheme 1.18 Paquette’s synthesis of acersolide26 1 .2. 2 Marshall Approach Along with Leo Paquette, the Marshall group was actively involved toward the synthesis of furanocembranoids Their group strategy was to make the macrocyclic propargylic ether followed by [2, 3]-Wittig rearrangement . Marshall’s synthesis of kallolide B 23 . OH O HO O H 3 CO O H 3 CO 2 C HO CH 3 C H 2 C H 3 CO 2 C O OHC O O O OHC O CO 2 E t O Cl HO O H 3 C O O HO V O(acac) 2 CH 2 N 2 , Et 2 O 1-bromo -2- butyne (COCl) 2 ,. Marshall’s synthesis of furan moiety from an alkynone β-ketoester TMS BzO CO 2 Me O O CO 2 Me TMS K 2 CO 3 , Pd(OAc) 2 , dppf 53 54 CH 3 CN:H 2 O, 84 °C O CO 2 t Bu O O O CO 2 t Bu SiO 2 57 58 12 . 97 98 99 100 101 1 02 63 64 t BuOOH H 5 IO 6 S nCl 2 , NaI, DMPU CH 2 Cl 2 , Et 3 N, -78 °C P hCH 3 Et 3 N, CH 2 Cl 2 CBr 4 , PPh 3 (CH 2 O) n ,-78 °C to rt (F 3 CH 2 CO) 2 P O CO 2 Et Me THF, -78