Synthesis and use of novel drimane sesquiterpenoids of khamkhaine type from thai basidiomycota

Abstract

The present invention refers to a method for the preparation of a compound according to formula (45), its enantiomers, diastereomers, a racemic mixture, and the pharmaceutically acceptable salts thereof. Furthermore the invention refers to a compound of formula (45) prepared by said method for use in treatment of neurodegenerative disorders and to pharmaceutical compositions.

Description

[0001] Synthesis and use of Novel Drimane Sesquiterpenoids of Khamkhaine Type from Thai Basidiomycota

[0002] Neurodegenerative disorders (NDDs) represent a significant global concern, corresponding to a massive health burden and costing healthcare systems billions annually. According to the World Health Organization (WHO, 2016), these disorders impact up to one billion people worldwide each year. NDDs are a range of disorders of the nervous system characterized by progressive degradation of neuronal structures and their function in the brain and spinal cord, resulting in neuronal damage and death. Examples are Alzheimer's disease, Parkinson's disease and Amyotrophic lateral sclerosis.

[0003] A novel drimane sesquiterpenoid isolated from Thai Basidiomycota (IIIPAC name: (S)-2-((R)-2-(((1 S,5S,5aS,9aS,9bS)-2-(3-carboxypropyl)-1 ,9b-dihydroxy-6,6,9a-tri- methyl-2,3,5,5a,6,7,8,9,9a,9b-decahydro-1 / - / -benzo[e]isoindol-5-yl)oxy)-2-oxo-1 - (((1 S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)meth- oxy)ethyl)succinic acid, (+)-45, provides an interesting modulation of neurotrophic activity. Researchers at HZI in Braunschweig reported that this promising new neurotrophic sesquiterpenoid induces expression of neurotrophic factors (NGFs) in Astrocytoma cells and enhances NGF-induced neurite outgrowth in PC-12 cells.

[0004] The object of the present invention is to provide the naturally occurring drimane sesquiterpenoid (+)-45 by performing the method of preparation according to the invention.

[0005] Furthermore, it is an object of the present invention to provide a novel enantiomer and diastereomers of the naturally occurring drimane sesquiterpenoid (+)-45 by modifying the building blocks used in the method of preparation in respect of their stereochemistry.

[0006] The object of the present invention is a method for the preparation of a compound according to formula 45, its enantiomers, diastereomers, a racemic mixture, and the pharmaceutically acceptable salts thereof.

[0007] P9599PC00

[0008]

[0009] 45 wherein the following steps are performed: reacting a compound of formula 20, in the form of a single enantiomer, a racemic mixture or a diastereomer thereof with a compound of formula 33, in the form of a single enantiomer, a racemic mix- to give a compound according to formula 42, in the form of a single enantiomer, a racemic mixture or a diastereomer thereof

[0010] P9599PC00

[0011] reacting the compound of formula 42, in the form of a single enantiomer, a racemic mixture or a diastereomer thereof, to a compound of formula 43, in the form of a single enantiomer, a racemic mixture or a diastereomer thereof

[0012] 43 reacting the compound of formula 43, in the form of a single enantiomer, a racemic mixture or a diastereomer thereof, to a compound of formula 44 in the form of a single enantiomer, a racemic mixture or a diastereomer thereof

[0013] P9599PC00 and reacting the compound of formula 44, a single enantiomer, a racemic mixture or a diastereomer thereof, with a compound of formula 41 , in the form of a single enantiomer, a racemic mixture or a diastereomer thereof

[0014] 41 to give the compound of formula 45 in the form of a single enantiomer, a racemic mixture or a diastereomer thereof.

[0015] Especially preferred is the method according the invention, wherein the compound of formula 45 is compound (+)-45 or compound (-)-45 or the racemic mixture thereof.

[0016] In a preferred embodiment the compound prepared by the method according to the invention is for use in the treatment of neurodegenerative disorders (NDDs), namely of disorders of the nervous system characterized by progressive degradation of neuronal structures and their function in the brain and spinal cord, resulting in neuronal damage and death.

[0017] Especially preferred is the compound prepared according to the invention for use in the treatment of Alzheimer's disease, Parkinson's disease and Amyotrophic lateral sclerosis.

[0018] P9599PC00 Another object of the invention is a pharmaceutical composition comprising at least one compound prepared by a method according to the invention in the form of a single enantiomer, the racemic mixture, the diastereomers or the pharmaceutically acceptable salts or the mixtures thereof.

[0019] In particular preferred is that the pharmaceutical composition according to the invention further comprises components like solid or liquid vehicle substances, dilution agents and pharmaceutical-technical adjuvants corresponding to the desired type of application.

[0020] It is furthermore preferred that the pharmaceutical composition according to the invention is provided for oral, buccal, sublingual, nasal, rectal, subcutaneous, intravenous or intramuscular application as well as for inhalation, provided as a liposomal formulation, as a spray, in the form of tablets, sucking tablets, film tablets, dragees, capsules, pills, powders, solutions, aerosols or suspensions or slow-release forms.

[0021] In an especially preferred embodiment the pharmaceutical composition according to the invention is for use in the treatment of neurodegenerative disorders (NDDs), namely of disorders of the nervous system characterized by progressive degradation of neuronal structures and their function in the brain and spinal cord, resulting in neuronal damage and death.

[0022] Especially preferred is the pharmaceutical composition according to the invention wherein the disorder is selected from Alzheimer's disease, Parkinson's disease and Amyotrophic lateral sclerosis.

[0023] The present invention provides entries to the following general structural motifs of Khamkhaines.

[0024] Based on that highly interesting biological profile the applicant developed a synthetic entry to synthesize this novel natural product and can offer a general strategy to synthesize structural analogues for biological studies - this provides a new lead to treat NDDs.

[0025] P9599PC00 Depending on the selected enantiomers or diastereomers of the below described building blocks selected stereoisomers of the compound of interest of formula 45 can be prepared.

[0026] In the present application a retrosynthetic analysis is presented, wherein three key fragments have been produced. These key fragments are a tricycle (-)-20, a linker (+)-33, and a bicycle (±)-41 compound shown below.

[0027] Furthermore, the three compounds are synthesized with a Yamaguchi esterifica- tion and a Williamson esterification as shown herein. In the following the synthesis of the compound of formula 45 is described.

[0028] P9599PC00 The synthesis of the tricycle (-)-20 is as follows:

[0029] The synthesis of reduced tricycle (— )-20. Reagents and conditions are as follows: (a) MePPhsBr, n-BuLi, THF, 90%; (b) 110°C, 80%; (c) BH3THF, THF, 0°C, then

[0030] 2N NaOH, H2O2, 0°C, 60%; (d) (R)-2-methoxy-2-phenylacetic acid, EDCI, DMAP, CH2CI2, r.t. , 39% (+)-7 and 29% (-)-8; (e) K2CO3, CH3OH, r.t. , 85%; (f) TESCI, imidazole, DMF, 0°C, 99%; (g) DIBAL-H, THF, 0°C, 68%; (h) mCPBA, CH2CI2, 0°C, 99%; (i) BAIB, TEMPO, CH2CI2, 0°C, 75%; (j) TBD, 4-((tert-

[0031] P9599PC00 butyldimethylsilyl)oxy)butan-1 -amine, toluene, 110°C, 80%; (k) Dess-Martin perio- dinane, CH2CI2, O°C-r.t., 70%; (I) Ac2O, NEt3, CH2CI2, O°C-r.t, 99%; (m) TBAF, THF, 0°C, 99%; (n) Dess-Martin periodinane, CH2CI2, O°C-r.t., 85%; , (o) DBU, toluene, 0°C, 90%, two steps; (p) NaBH4, CeCI37H2O, 0°C, 48% (-)-20 and 45% (— )-21.

[0032] The synthesis of the linker (+)-33 is as follows: The synthesis of tricarboxy linker (+)-33. Reagents and conditions are as follows: (a) BnBr, NaH, DMF, O°C-r.t., 99%; (b), (c) LDA, Et2O, -78°C-r.t., then (±)-25, CH3CN, 55°C, 60% two steps; (d) 10% Pd / C, CH3OH, H2, r.t., 99%; (e) (-)-

[0033] P9599PC00 Camphanic chloride, DMAP, Py, CH2CI2, O°C-r.t., 45% (+)-29 and 40% (-)-30; (f) K2CO3, CH3OH, r.t., 60%; (g) Ac2O, NEt3, CH2CI2, O°C-r.t, 80%; (h) TFA, CH2CI2, r.t., 99%.

[0034] The synthesis of the bicycle (±)-41 is as follows:

[0035] The synthesis of bicycle (±)-41. Reagents and conditions are as follows: (a) AC2O, Py, DMAP, CH2CI2, r.t., 99%; (b) NBS, THF / H2O, 0°C, then DBU, THF, 0°C, 60%;

[0036] (c) Cp2TiCl2, Mn-dust, THF, 2,4,6-collidine, TMSCI, r.t., 35%; (d) TCDI, DMAP, tol. , 80 °C, 90%; (e) Bu3SnH, AIBN, tol., 125 °C, 90%; (f) K2CO3, CH3OH, r.t., 99%; (g)

[0037] PPh3, SOCI2, CCI4, CH2CI2, , 60%.

[0038] P9599PC00 The synthesis of the final strategy for the total synthesis is as follows: The final strategy for the total synthesis. Reagents and conditions are as follows:

[0039] (a) (+)-33, Et3N, TCBC, THF, r.t., then (-)-20, tol., DMAP, r.t., 60%; (b) TBAF,

[0040] P9599PC00 THF, 0°C, 99%; (c) Dess-Martin periodinane, CH2CI2, 0°C-r.t.,99%; (d) NaCIC , NaH2PO4, 2-methyl-2-butene, H2O / t-BuOH, r.t., 99%; (e) CH2N2, Et2O, O°C-r.t., 70%; (f) K2CO3, CH3OH, r.t., 99%; (g) Nal, (±)-41 , acetone; (h) LiOH, THF, 90% 3 steps.

[0041] Experimental procedures and Analytical Data General Methods

[0042] Solvents were dried by standard procedures and redistilled under N2 atmosphere prior to use. All reactions were run under nitrogen unless otherwise stated. For reactions that require heating, an oil bath was used. For reaction that require cooling, ice (for reaction condition at 0°C) or dry ice and acetone (for reaction condition at -78°C) were used. The products were purified by flash chromatography on Merck silica gel 60 (40-63 pm); in some cases, automated flash chromatography was performed using a Biotage Selekt system. POLYGRAM SIL G / UV254 prefabricated TLC plates with fluorescent indicator from Macherey-Nagel have been used for analytical thin layer chromatography (TLC). The separated substances were detected by irradiation with UV light with a wavelength of 254 nm or staining with vanillin or Cerium-Molybdate and subsequent warming with a heat gun. Electrospray ionization (ESI) and electron ionisation (El) mass spectra were recorded on Finnigan MAT 95 and Waters Xevo G2-TOF spectrometers.1H,13C and 2D (NOESY) NMR spectra were recorded on Broker AVIII 400 and Broker AVI 600 spectrometers. Chemical shifts (5) are reported in ppm from tetramethylsilane, referenced to the solvent resonance resulting from incomplete deuteration (1H NMR = CDCI3: 5 7.26, D2O: 5 4.79;13C NMR= CDCI3: 5 77.16). Data are reported as follows: chemical shift, multiplicity (s= singlet, d= doublet, t= triplet, br= broad, m= multiplet), coupling constants (Hz) and integration. Optical rotations were recorded on Perkin-Elmer 341 and Anton Paar MCP150 polarimeters. Melting points were recorded on Buchi Melting Point B-540 apparatus. (IR) spectra were recorded on Broker Vertex 70v. Bands are characterized as strong (s), medium (m), weak (w) or broad (br).

[0043] P9599PC00 Tricycle

[0044] 1, 3, 3-Trimethyl-2-vinyl-1 -cyclohexene:

[0045] A suspension of 1.5 eq of methyltriphenylphosphonium bromide (195.33 mmol, 69.78 g) in dry THF (200 mL) was treated with 1 ,75 eq (227.89 mmol, 91 mL) of a 2.5 M solution of n-butyll ithium in hexane at 0°C. The mixture was then stirred at room temperature for 1 h until all the solid had disappeared. A solution of |3-cy- clocitral (1 eq, 130.22 mmol, 19.82 g, 21 mL) in dry THF (15 mL) was added dropwise at -78°C and stirring was continued for a further 3 h at room temperature. The reaction was quenched with NH4CI (sat. aq. solution) and extracted with Et20, filtered through a Na2SO4 plug, rinsed with Et20, and carefully concentrated to give the crude alkene product. Flash chromatography with Biotage Selekt (hexane 100%) afforded the diene 3 (90%, 117.20 mmol, 17.61 g, colorless oil).

[0046] General Data: C11 His; FW: 150.14; TLC: Rf = 0.9 (hexane); UV (+); Cerium-Molyb- date Phosphoric acid reagent: blue.

[0047] 1H-NMR (400 MHz, CDCI3): 6 (ppm): 6.21 (dd, J = 17.8, 11.3 Hz, 1 H), 5.23 (d, J = 11.3, 2.6 Hz, 1 H), 4.96 (d, J = 17.7, 2.8 Hz, 1 H), 1.98 (t, J = 6.2 Hz, 2H), 1.69 (s, 3H), 1.57-1.64 (m, 2H), 1.43-1.47 (m, 2H), 1.00 (s, 6H).

[0048] 13C-NMR (100 MHz, CDCI3): 6 (ppm): 138.4, 135.6, 128.6, 118.0, 39.6, 33.9, 32.9, 28.9, 21.5, 19.4.

[0049] IR (neat): 2958 (s), 2925 (s), 2864 (s), 1456 (m), 1374 (m), 1359 (m), 1189 (w), 971 (s), 707 (w) cm’1.

[0050] HRMS (ESI): calculated for C11H19 [M+H]+: 151 .1487; found: 151.1481.

[0051] P9599PC00 Dimethyl 5,5,8a-trimethyl-3,5,6,7,8,8a-hexahydronaphthalene-1,2-dicarbox- ylate:

[0052] A mixture of 1 .50 g (2 eq, 10 mmol) of 3 and 1 eq of the known alkyne dienophile dimethylacetylenedicarboxylate (5 mmol, 0.61 mL) was mechanically stirred and heated at 110 °C for 72 h. After cooling, purification with flash column chromatography (Biotage Selekt), EtOAc in hexane, 0 to 20 %) yielded the Diels-Alder adduct (±)-5 in 70% yield (3.5 mmol, 1 .02 g, clear, light-yellow oil) and 15% of dimethyl 5,5-dimethyl-5,6,7,8-tetrahydronaphthalene-1 ,2-dicarboxylate 5a (0.75 mmol, 207 mg, light oil). Starting material 3 was recovered in 14%.

[0053] General Data (±)-5. C17H24O4; FW: 292.17; TLC: Rf= 0.5 (hexane / EtOAc 7:1 ); UV (+); Cerium-Molybdate Phosphoric acid reagent: blue.

[0054] 1H-NMR (400 MHz, CDCI3): 5 (ppm): 5.69 (dd, J = 5.7, 2.2 Hz, 1 H), 3.79 (s, 3H), 3.72 (s, 3H), 3.14 (dd, J = 22.3, 5.6 Hz, 1 H), 2.77 (dd, J = 22.5, 2.2 Hz, 1 H), 1 .24- 1.84 (m, 6H), 1.41 (s, 3H), 1.17 (s, 3H), 1.13 (s, 3H).

[0055] 13C-NMR (100 MHz, CDCI3): 5 (ppm): 169.8, 166.5, 150.8, 147.7, 125.6, 117.0, 52.2, 52.0, 40.2, 39.0, 36.0, 35.9, 32.6, 31.3, 26.7, 26.2, 18.3.

[0056] IR (neat): 2938 (m), 1720 (s), 1433 (m), 1249 (s), 1125 (m), 1022 (s), 767 (m), 738 (m) cm’1.

[0057] HRMS (ESI): calculated for Ci7H25O4[M+H]+: 293.1753; found: 293.1755.

[0058] General Data 5a C16H20O4; FW: 276.14; TLC: Rf= 0.35 (hexane / EtOAc 7:1 ); UV (+); Cerium-Molybdate Phosphoric acid reagent: blue.

[0059] 1H-NMR (400 MHz, CDCI3): 5 (ppm): 7.78 (d, J = 8.4 Hz, 1 H), 7.43 (d, J = 8.4 Hz, 1 H), 3.94 (s, 3H), 3.87 (s, 3H), 2.72 (t, J = 6.4 Hz, 2H), 1.68-1.80 (m, 2H), 1.63- 1.66 (m, 2H), 1.29 (s, 6H).

[0060] 13C-NMR (100 MHz, CDCI3): 5 (ppm): 170.5, 166.3, 152.0, 135.8, 133.5, 127.9, 127.4, 124.5, 52.6, 52.5, 38.4, 34.7, 31.8, 27.4, 19.1.

[0061] IR (neat): 2938 (m), 1720 (s), 1601 (w), 1433 (m), 1249 (s), 1125 (m), 1022 (s), 846 (w), 767 (m), 738 (m) cm’1.

[0062] P9599PC00 HRMS (ESI): calculated for C16H21O4 [M+H]+: 277.1440; found: 277.1451.

[0063] Dimethyl 4-hydroxy-5, 5, 8a-trimethyl-3,4,4a, 5, 6, 7, 8, 8a-octahydronaphthalene- 1 ,2-dicarboxylate:

[0064] A 1 .0 M solution of BH3 THF in THF (1 .5 eq, 28.73 mmol, 28.7 mL) was added at 0°C to a solution of (±)-5 (1 eq, 19.15 mmol, 5.60 g) in dry THF (30 mL). The reaction mixture was stirred at room temperature for 8 h. Water (3 mL), a 2N aqueous NaOH solution (6 mL) and 35% aqueous H2O2 (4 mL) were added to the reaction mixture, and stirring was continued for 16 h at 0°C. The reaction mixture was poured into H2O and extracted with Et20. The organic layer was washed, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel. Elution with pentane / Et2O (2:1 ) gave alcohol +)-6 (60%, 11.50 mmol, 3.57 g, colorless needles).

[0065] General Data: C17H26O5; FW: 310.18; TLC: Rf= 0.4 (hexane / EtOAc 2:1 ); UV (+); Cerium-Molybdate Phosphoric acid reagent: blue; Mp 80-85 °C.

[0066] 1H-NMR (400 MHz, CDCI3): 5 (ppm): 4.16-4.23 (m, 1 H), 3.76 (s, 3H), 3.70 (s, 3H), 2.85 (dd, J = 18.2, 6.7 Hz, 1 H), 2.37 (dd, J = 18.3, 8.1 Hz, 1 H), 1.35-1.59 (m, 6H), 1.33 (d, J = 11.04 Hz, 1 H), 1.26 (s, 3H), 1.16 (s, 3H), 1.06 (s, 3H).

[0067] 13C-NMR (100 MHz, CDCI3): 5 (ppm): 169.3, 166.6, 152.9, 124.5, 67.7, 55.1 , 52.3, 52.1 , 43.3, 40.5, 37.4, 36.6, 36.2, 34.0, 22.2, 21.2, 18.5.

[0068] IR (neat): 3523 (br), 2931 (m), 1712 (s), 1644 (w), 1424 (m), 1246 (s), 1203 (m), 1069 (m), 837 (w), 758 (w) cm’1.

[0069] HRMS (ESI): calculated for C17H27O5 [M+H]+: 311.1858; found: 311.1858.

[0070] P9599PC00 Dimethyl 4-(2-methoxy-2-phenylacetoxy)-5, 5, 8a-trimethyl-3,4,4a, 5, 6, 7, 8, 8a-oc- tahydronaphthalene-1,2-dicarboxylate:

[0071] To a stirred solution of the racemic mixture of compound (±)-6 (1 eq, 12.06 mmol, 3.74 g) in CH2CI2 (236 mL) was added (R)-(-)-a-methoxyphenylacetic acid (2 eq, 23.12 mmol, 4 g), EDC HCI (2 eq, 23.12 mmol, 4.62 g), and DMAP (0.2 eq, 2.41 mmol, 294 mg) at 23 °C. After 3 h, water (~100 mL) was added to the reaction mixture, and the layers were separated. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography using hexane / EtOAc (5:1 ), affording the diastereoisomers (+)-7 (39%, 4.70 mmol, 2.16 g, oil) and (-)-8 (29%, 3.50 mmol, 1.60 g, oil).

[0072] H-7:

[0073] General Data: C26H34O7; FW: 458.23; TLC: Rf= 0.35 (hexane / EtOAc 4:1 ); UV (+);

[0074] Cerium-Molybdate Phosphoric acid reagent: blue; =+9.5 (c 0.76, CHCI3).1H-NMR (400 MHz, CDCI3): 5 (ppm): 7.30-7.44 (m, 5H), 5.37 (dt, J = 10.9, 6.9 Hz, 1 H), 4.74 (s, 1 H), 3.76 (s, 3H), 3.61 (s, 3H), 3.43 (s, 3H), 2.77 (dd, J = 18.4, 7.0 Hz, 1 H), 2.04 (dd, J = 18.5, 6.7 Hz, 1 H), 1.39-1.60 (m, 7H), 1.27 (s, 3H), 1.01 (s, 3H), 0.93 (s, 3H).

[0075] 13C-NMR (100 MHz, CDCI3): 5 (ppm): 170.3, 168.9, 166.0, 152.7, 135.9, 128.8, 128.7, 127.2, 123.9, 83.0, 70.7, 57.6, 52.2, 52.1 , 52.0, 42.9, 39.8, 36.3, 35.4, 33.7, 32.1 , 22.2, 20.6, 18.2.

[0076] IR (neat): 3523 (w), 2931 (w), 1723 (s), 1424 (m), 1249 (s), 1172 (m), 1203 (m), 1066 (m), 697 (m) cm’1.

[0077] HRMS (ESI): calculated for C26H35O7 [M+H]+: 476.2648; found: 476.2646.

[0078] (~)-8

[0079] P9599PC00 General Data: C26H34O7; FW: 458.23; TLC: Rf= 0.25 (hexane / EtOAc 4:1 ); UV (+);

[0080] Cerium-Molybdate Phosphoric acid reagent: blue; = -89.2 (c 0.66, CHCI3).1H-NMR (400 MHz, CDCI3): 5 (ppm): 7.20-7.34 (m, 5H), 5.18 (dt, J = 10.8, 6.8 Hz, 1 H), 4.58 (s, 1 H), 3.67 (s, 3H), 3.59 (s, 3H), 3.28 (s, 3H), 2.87 (dd, J = 18.3, 7.0 Hz, 1 H), 2.31 (dd, J = 18.4, 6.6 Hz, 1 H), 1.39-1.57 (m, 7H), 1.14 (s, 3H), 0.51 (s, 3H), 0.40 (s, 3H).

[0081] 13C-NMR (100 MHz, CDCI3): 5 (ppm): 170.3, 168.9, 166.1 , 152.9, 135.4, 129.2, 128.8, 128.2, 124.0, 83.2, 71.3, 57.2, 52.3, 52.1 , 52.0, 42.5, 39.9, 36.3, 34.5, 33.3, 32.7, 21.7, 20.5, 18.1.

[0082] IR (neat): 3518 (w), 2940 (w), 1720 (s), 1515 (w), 1396 (m), 1259 (s), 1168 (m), 1210 (m), 1067 (m), 684 (m) cm’1.

[0083] HRMS (ESI): calculated for C26H35O7 [M+H]+: 476.2648; found: 476.2651.

[0084] Dimethyl (4S,4aS, 8aS)-4-hydroxy-5, 5, 8a-trimethy!-3,4,4a, 5, 6, 7, 8, 8a-octahy- dronaphthalene-1 ,2-dicarboxylate:

[0085] Compound (+)-7 (1 eq, 4.11 mmol, 1 .90 g) was dissolved in CH3OH (50 mL), and finely powdered K2CO3 (1 eq, 4.11 mmol, 568 mg) was added. The mixture was stirred at room temperature for 16 h, then it was partitioned between Et20 and H2O, and the aqueous layer was extracted with Et20. The combined organic extracts were passed through a plug of silica / Na2SO4, and the solvents were evaporated. Compound (+)-9 (85 %, 3.50 mmol, 1 .08 g) was obtained as a colorless oil. General Data: C17H26O5; FW: 310.18; TLC: Rf= 0.4 (hexane / EtOAc 2:1 ); UV (+);

[0086] Cerium-Molybdate Phosphoric acid reagent: blue; = +71.94 (c = 0.36, CHCI3).

[0087] P9599PC001H-NMR (400 MHz, CDCh): 6 (ppm): 4.16-4.23 (m, 1 H), 3.76 (s, 3H), 3.70 (s, 3H), 2.85 (dd, J = 18.2, 6.7 Hz, 1 H), 2.37 (dd, J = 18.3, 8.1 Hz, 1 H), 1.35-1.59 (m, 6H), 1.33 (d, J = 11.04 Hz, 1 H), 1.26 (s, 3H), 1.16 (s, 3H), 1.06 (s, 3H).

[0088] 13C-NMR (100 MHz, CDCh): 5 (ppm): 169.3, 166.6, 152.9, 124.5, 67.7, 55.1 , 52.3, 52.1 , 43.3, 40.5, 37.4, 36.6, 36.2, 34.0, 22.2, 21.2, 18.5.

[0089] IR (neat): 3523 (br), 2931 (m), 1712 (s), 1644 (w), 1424 (m), 1246 (s), 1203 (m), 1069 (m), 837 (w), 758 (w) cm’1.

[0090] HRMS (ESI): calculated for C17H27O5 [M+H]+: 311.1858; found: 311.1858.

[0091] Dimethyl (4S,4aS, 8aS)-5, 5, 8a-trimethyl-4-((triethylsilyl)oxy)-3,4,4a, 5, 6, 7, 8, 8a- octahydronaphthalene-1,2-dicarboxylate:

[0092] (+)-10

[0093] To a solution of (+)-9 (1 eq, 8.05 mmol, 2.5 g) in dry DMF (40 mL) with imidazole (6 eq, 48.30 mmol, 3.3 g) was added TESCI (3 eq, 24.15 mmol, 4.1 mL) at 0°C and the reaction was stirred for 2 h at this temperature. The mixture was poured into water and extracted with Et20. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel using pentane / Et2O (10:1 ), yielding (+)-10 (99%, 7.97 mmol, 3.4 g) as a sticky oil.

[0094] General Data: C23H4o05Si; FW: 424,26; TLC: Rf= 0.8 (hexane / EtOAc 4:1 ); UV (+);

[0095] Cerium-Molybdate Phosphoric acid reagent: blue; = +61.5 (c = 0.4, CHCh).1H-NMR (600 MHz, CDCh): 5 (ppm): 4.24 (ddd, J = 10.7, 8.7, 6.2 Hz, 1 H), 3.76 (s, 3H), 3.71 (s, 3H), 2.73 (dd, J = 18.0, 6.2 Hz, 1 H), 2.37 (dd, J = 18.1 , 8.9 Hz, 1 H), 1.14-1.58 (s, 6H), 1.37 (d, J = 10.7 Hz, 1 H), 1.27 (s, 3H), 1.14 (s, 3H), 1.03 (s, 3H), 1 .00 (t, J = 7.9 Hz, 9H), 0.66 (q, J = 8 Hz, 6H).

[0096] P9599PC0013C-NMR (151 MHz, CDCh): 6 (ppm): 169.4, 166.7, 152.5, 124.8, 68.2, 54.7, 52.3, 52.0, 43.7, 40.4, 38.0, 37.0, 36.1 , 33.8, 22.2, 21.5, 18.4, 7.2, 5.6.

[0097] IR (neat): 1724 (s), 1649 (w), 1246 (s), 1086 (m), 1006 (m), 818 (w), 726 (s) cm’1. HRMS (ESI): calculated for C23H44NO5Si [M+NH4]+: 442.2989; found: 442.2987.

[0098] ((4S,4aS, 8aS)-5, 5,8a-trimethyl-4-((triethylsilyl)oxy)-3,4,4a, 5, 6, 7, 8, 8a-octahy- dronaphthalene-1 ,2-diyl) dimethanol:

[0099] To a solution of (+)-10 (1 eq, 12.7 mmol, 5.4 g) in dry THF (200 mL) was added 1 M DIBAL-H in hexane (6 eq, 76.2 mmol, 76.2 mL) dropwise at 0°C for 3 h. The reaction mixture was quenched with CH3OH, poured into a saturated aqueous Rochelle’s salt solution, and extracted with Et20. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel. Elution with pentane / Et2O (2:1 ) gave (+)-11 (68%,

[0100] 8.64 mmol, 3.2 g) as a sticky oil.

[0101] General Data: C2i H4o03Si; FW: 368.27; TLC: Rf= 0.2 (hexane / EtOAc 2:1 ); UV (-); Cerium-Molybdate Phosphoric acid reagent: blue; [«.c= +83.0 (c = 0.46, CHCI3).1H-NMR (600 MHz, CDCh): 5 (ppm): 4.00-4.20 (m, 5H), 2.52 (dd, J = 17.4, 5.9 Hz, 1 H), 2.29 (dd, J = 17.4, 9.2 Hz, 1 H), 2.04 (s, 1 H), 1.80 (d, J = 12.7 Hz, 1 H), 1.12-

[0102] 1.64 (m, 5H), 1.31 (d, J =10.7 Hz, 1 H), 1.15 (s, 3H), 1.04 (s, 3H), 1.03 (s, 3H), 0.98 (t, J = 8 Hz, 9H), 0.65 (q, J = 7.6 Hz, 6H).

[0103] 13C-NMR (151 MHz, CDCh): 6 (ppm): 146.0, 134.1 , 69.0, 63.6, 57.9, 56.2, 43.8, 43.0, 41.0, 36.9, 36.2, 33.6, 22.3, 21.8, 18.8, 7.3, 5.7.

[0104] IR (neat): 3321 (br), 2929 (m), 1121 (m), 1085 (s), 1001 (s), 981 (s), 834 (m), 724 (s) cm’1.

[0105] P9599PC00 HRMS (ESI): calculated for C23H4iO3Si [M+H]+: 369.2825; found: 369.2817.

[0106] (( 1aS,3S,3aS, 7 aS, 7bR)-4,4, 7a-trimethyl-3-((triethylsilyl)oxy) octahydronaph- tho[1,2-b] oxirane-1a,7b-diyl) dimethanol:

[0107] To a stirred solution of (+)-11 (1 eq, 18.4 mmol, 6.8 g) in CH2CI2 (260 mL) was added 1 eq of m-CPBA (ca. 77%, 18.4 mmol, 4.12 g), and stirring was continued at 0°C for 3 h. The reaction mixture was poured into a 5% aqueous Na2S2O3 solution and extracted with CH2CI2. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel. Elution with pentane / Et2O (2:1 ) gave (+)-12 (99%, 18.2 mmol, 7 g, white powder).

[0108] General Data: C2i H4o04Si; FW: 384.27; TLC: Rf= 0.4 (hexane / EtOAc 2:1 ); UV (-);

[0109] Vanillin: brown; WD = +37.2 (c = 0.44, CHCI3); Mp 85-90°C.

[0110] 1H-NMR (600 MHz, CDCI3): 5 (ppm): 4.09 (d, J = 11 .6 Hz, 1 H), 3.99 (ddd, J =

[0111] 10.7, 8.9, 6.9 Hz, 1 H), 3.67 (d, J = 11.6 Hz, 1 H), 3.62 (d, J = 11.8 Hz, 1 H), 3.55 (d, J = 11.3 Hz, 1 H), 2.46 (dd, J = 14.7, 6.8 Hz, 1 H), 1.87 (dd, J = 14.9, 8.9 Hz, 1 H), 1.70 (d br, J = 12.7 Hz, 1 H), 1.18-1.59 (m, 5H), 1.48 (d, J = 10.6 Hz, 1 H), 1.17 (s, 3H), 1 .09 (s, 3H), 1 .00 (s, 3H), 0.99 (t, J = 7.9 Hz, 9H), 0.64 (q, J = 8 Hz, 6H).

[0112] 13C-NMR (151 MHz, CDCI3): 5 (ppm): 71 .4, 67.6, 65.8, 64.8, 61 .8, 49.0, 43.5,

[0113] 38.8, 37.9, 36.3, 35.6, 33.2, 22.6, 18.5, 18.3, 7.2, 5.6.

[0114] IR (neat): 3344 (br), 2927 (s), 1458 (m), 1239 (m), 1117 (m), 1086 (s), 1016 (s), 838 (m), 723 (s) cm’1.

[0115] HRMS (ESI): calculated for C2i H4iO4Si [M+H]+: 385.2774; found: 385.2769.

[0116] P9599PC00 (3aR, 5S, 5aS, 9a S, 9bR)-6, 6, 9a-trimethyl-5-((triethylsilyl)oxy) octahydro-1 H,3H- 3a,9b-epoxynaphtho[ 1,2-c] furan-3-one:

[0117] Compound (+)-12 (1 eq, 0.52 mmol, 200 mg) was dissolved in CH2CI2 (5 mL) and cooled to 0°C. TEMPO (0.1 eq, 0.05 mmol, 8 mg) and Phl(OAc)2 (2 eq, 1.04 mmol, 335 mg) were added and the reaction mixture was continued at this temperature. After 24 h, saturated aqueous Na2S20s was added for quenching. The reaction was stirred for 15 min and extracted with CH2CI2. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel using hexane / EtOAc (30:1 ), yielding the desired compound (+)-13 (75%, 0.40 mmol, 148.4 mg, light-yellow powder) and its regioisomer (-)-13b (8%, 0.04 mmol, 16 mg, colorless sticky oil).

[0118] (+)-13:

[0119] General Data: C2i H3eO4Si; FW: 380.24; TLC: Rf = 0.64 (hexane / EtOAc 4:1 );

[0120] UV (-); Vanillin: brown; N? = +37.0 (c = 0.3, CHCI3).

[0121] 1H-NMR (600 MHz, CDCI3): 5 (ppm): 4.30 (d, J = 10.7 Hz, 1 H), 4.25 (d, J = 10.7 Hz, 1 H), 4.02 (ddd, J = 10.6, 8.9, 6.9 Hz, 1 H), 2.57 (dd, J = 15.4, 7.0 Hz, 1 H), 2.00 (dd, J = 15.3, 8.9 Hz, 1 H), 1 .66 (d, J = 10.7 Hz, 1 H), 1 .45-1 .58 (m, 4H), 1 .35-1 .40 (m, 1 H), 1.19-1.24 (m, 1 H), 1.26 (s, 3H), 1.12 (s, 3H), 1.03 (s, 3H), 0.97 (t, J = 7.8 Hz, 9H), 0.64 (q, J = 7.9 Hz, 6H).

[0122] 13C-NMR (151 MHz, CDCI3): 6 (ppm): 172.5, 73.0, 67.2, 67.1 , 58.3, 48.1 , 43.7, 37.1 , 36.4, 36.1 , 33.1 , 30.8, 22.4, 19.8, 17.9, 7.1 , 5.5.

[0123] IR (neat): 2915 (s), 1776 (s), 1091 (s), 1075 (s), 1017 (s), 811 (m), 800 (m), 743 (m), 724 (m) cm’1.

[0124] HRMS (ESI): calculated for C2i H37O4Si [M+H]+: 381 .2461 ; found: 381.2455.

[0125] (-)-13b:

[0126] P9599PC00 General Data: C2i H3eO4Si; FW: 380.24; TLC: Rf = 0.84 (hexane / EtOAc 4:1 );

[0127] UV (-); Vanil line: blue; = -7.4 (c = 0.8, CHCh).1H-NMR (600 MHz, CDCI3): 6 (ppm): 4.33 (d, J = 10.8 Hz, 1 H), 4.07-4.13 (m, 1 H), 4.04 (d, J = 11 .0 Hz, 1 H), 2.33 (d br, 1 H), 2.30 (dd, J = 15.0, 6.8 Hz, 1 H), 2.10 (dd, J = 14.7, 9.2 Hz, 1 H), 1.60 (d, J = 10.6 Hz, 2H), 1.45-1.53 (m, 1 H), 1.39-1.44 (m, 1 H), 1.32-1.38 (m, 1 H), 1.28 (s, 3H), 1.22-1.27 (m, 1 H), 1.10 (s, 3H), 1.01 (s, 3H), 0.98 (t, J = 8.1 Hz, 9H), 0.63 (q, J = 8.1 Hz, 6H).

[0128] 13C-NMR (151 MHz, CDCI3): 5 (ppm): 170.8, 70.3, 67.2, 65.0, 64.2, 48.7, 43.9, 36.2, 35.0, 34.6, 33.8, 33.2, 22.4, 18.3, 17.7, 7.2, 5.6.

[0129] IR (neat): 2980 (s), 1770 (s), 1075 (s), 1063 (s), 1016 (s), 824 (m), 800 (m), 737 (m), 723 (m) cm’1.

[0130] HRMS (ESI): calculated for C2i H37O4Si [M+H]+: 381 .2461 ; found: 381.2463.

[0131] 4-((Tert-butyldimethylsilyl) oxy) butan-l-amine:

[0132] 46

[0133] To a solution of 4-Amino-1 -butanol (1 eq, 2.24 mmol, 200 mg) and imidazole (3 eq, 6.72 mmol, 457 mg) in 2.5 mL of CH2CI2, TBSCI (1 .2 eq, 2.69 mmol, 405 mg) was added at 0°C and the reaction mixture was stirred overnight at room temperature. The mixture was poured in water and extracted with CH2CI2. The organic layer was washed with a saturated solution of NaHCOs and then with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was diluted in EtOAc and the filtration through a short pad of silica with EtOAc gave after evaporation in 99% yield (2.22 mmol, 451 mg, oil) the desired compound 46.

[0134] General Data: CioH25NOSi; FW: 203.17.

[0135] 1H-NMR (600 MHz, CDCI3): 5 (ppm): 3.59 (t, J = 632 Hz, 2H), 2.80 (t, J = 7.2 Hz, 2H), 1.59-1.65 (m, 2H), 1.51 -1.57 (m, 2H), 0.85 (s, 9H), 0.01 (s, 6H).

[0136] 13C-NMR (151 MHz, CDCI3): 5 (ppm): 62.8, 41 .0, 30.1 , 27.7, 26.0, 18.4, -5.2. IR (neat): 2929 (m), 1253 (m), 1097 (s), 833 (s), 773 (s), 662 (M) cm’1.

[0137] HRMS (ESI): calculated for CioH26NOSi [M+H]+: 204.1783; found: 204.1783.

[0138] P9599PC00 (1aR,3S,3aS,7aS,7bR)-N-(4-((tert-butyldimethylsilyl) oxy) butyl)-7b-(hy- droxymethyl)-4,4, 7a-trimethyl-3-((triethylsilyl)oxy) octahydronaphtho[ 1,2-b] oxirane-1a(2H)-carboxamide:

[0139] To a solution of (+)-13 (1 eq, 0.33 mmol, 124 mg) in toluene (4.8 mL), TBD (0.1 eq, 0.03 mmol, 5 mg) and compound 46 (2 eq, 0.66 mmol, 134 mg) were added and the reaction mixture was refluxed at 110°C. After 24 h, the solvent was evaporated and the crude was partitioned between brine and Et20. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (hexane / EtOAc 4:1 ) to afford +j-74 (80%, 0.26 mmol, 154 mg) as a sticky oil.

[0140] General Data: C3i H6i NO5Si2; FW: 583.40; TLC: Rf= 0.36 (hexane / EtOAc 4:1 ); UV (-); Vanillin: brown; l«]Z>2= +21.4 (c = 0.28, CHCh).

[0141] 1H-NMR (400 MHz, CDCI3): 6 (ppm): 6.46 (t, J = 6.1 Hz, 1 H), 4.00-4.10 (m, 1 H), 3.56-3.73 (m, 2H), 3.18-3.38 (m, 2H), 2.77 (dd, J = 15.1 , 7.1 Hz, 1 H), 1.85 (dd, J = 15.1 , 7.6 Hz, 1 H), 1.78 (d, J = 12.2 Hz, 1 H), 1.46-1.61 (m, 6H), 1.12-1.39 (m, 6H), 1 .21 (s, 3H), 1 .08 (s, 3H), 1 .00 (s, 3H), 0.96 (t, J = 9 Hz, 9H), 0.89 (s, 9H), 0.63 (q, J = 8 Hz, 6H), 0.05 (s, 6H).

[0142] 13C-NMR (100 MHz, CDCI3): 5 (ppm): 170.2, 72.7, 67.0, 66.9, 62.8, 60.8, 49.4, 43.5, 39.1 , 38.7, 36.2, 36.1 , 36.0, 33.3, 30.1 , 26.2, 26.1 , 22.5, 19.0, 18.5, 18.2, 7.2, 5.6, -5.2.

[0143] IR (neat): 3456 (br), 2928 (m), 1637 (s), 1462 (w), 1079 (s), 1006 (m), 853 (s), 721 (s), 618 (w) cm’1.

[0144] HRMS (ESI): calculated for C3i H62NO5Si2 [M+H]+: 584.4166; found: 584.4169.

[0145] P9599PC00 (1S,3aR, 5S, 5aS, 9a S, 9bS)-2-(4-((tert-butyldimethylsilyl) oxy) butyl)-1 -hydroxy- 6,6, 9a-trimethyl-5-((triethylsilyl)oxy) decahydro-3H-3a,9b-epoxybenzo[e]iso- indol-3-one:

[0146] To a stirred solution of (+)-14 (1 eq, 0.21 mmol, 121 mg) in CH2CI2 (4.2 ml) was added Dess-Martin periodinane (2 eq, 0.42 mmol, 178 mg) at 0°C, and stirring was continued at room temperature for 1 h. The white solution was poured into a mixture of saturated aqueous Na2S2O3 and saturated aqueous NaHCOs and extracted with CH2CI2. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel. Elution with hexane / EtOAc (5:1 ) gave (+)-15 (75%, 0.16 mmol, 93 mg) as a clear -sticky oil.

[0147] General Data: C3i H59NO5Si2; FW: 581.39; TLC: Rf= 0.58 (hexane / EtOAc 4:1 ); UV

[0148] (-); Vanillin: violet; = +22.94 (c = 0.34, CHCI3).

[0149] 1H-NMR (600 MHz, CDCI3): 5 (ppm): 4.98 (d, J = 13.0 Hz, 1 H), 3.93- 4.00 (m, 1 H), 3.60 (t, J = 6.3 Hz, 2H), 3.30-3.38 (m, 1 H), 3.06-3.13 (m, 1 H), 2.58 (dd, J = 15.4, 6.8 Hz, 1 H), 2.55 (d, J = 12.9 Hz, 1 H), 1.96 (dd, J = 15.4, 8.9 Hz, 1 H), 1.82 (d br, J = 12.1 Hz, 1 H), 1.41 -1.65 (m, 7H), 1.22-1.37 (m, 3H), 1.21 (s, 3H), 1.11 (s, 3H), 1.02 (s, 3H), 0.96 (t, J = 7.9 Hz, 9H), 0.88 (s, 9H), 0.64 (q, J = 8.1 Hz, 6H), 0.04 (s, 6H).

[0150] 13C-NMR (151.MHZ, CDCI3): 5 (ppm): 169.7, 78.5, 70.9, 67.2, 62.9, 62.7, 48.6,

[0151] 43.8, 39.7, 36.4, 36.3, 35.9, 33.2, 30.8, 30.3, 26.1 , 24.2, 22.4, 19.3, 18.5, 17.9,

[0152] 7.8, 5.5, -5.2.

[0153] IR (neat): 3258 (br), 2929 (m), 1668 (s), 1460 (w), 1252 (w), 1083 (s), 1006 (m), 853 (s), 729 (s) cm’1.

[0154] HRMS (ESI): calculated for C3i H6oN05Si2 [M+H]+: 582.4010; found: 582.4015.

[0155] P9599PC00 (1S,3aR, 5S, 5aS, 9a S, 9bS)-2-(4-((tert-butyldimethylsilyl) oxy) butyl)-6, 6, 9a-tri- methyl-3-oxo-5-((triethylsilyl) oxy) decahydro-1 H-3a,9b-epoxybenzo[e]isoin- dol-1-yl acetate:

[0156] To a solution of (+)-15 (1 eq, 0.53 mmol, 310 mg) in CH2CI2 (7 mL) were added at 0°C NEts (3 eq, 1 .60 mmol, 220 pL) and AC2O (3 eq, 1 .60 mmol, 150 pL), and the mixture was stirred overnight at room temperature for 1 h. The reaction mixture was poured into a saturated NH4CI solution and extracted with CH2CI2. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel using pen- tane / Et2O (8:1 ), yielding the desired compound (+)-16 as a sticky oil in 99% yield (0.52 mmol, 327 mg).

[0157] General Data: C33H6i NO6Si2; FW: 623.40; TLC: Rf= 0.69 (hexane / EtOAc 4:1 ); UV (-); Vanillin: brown; Ms? = +25.45 (c = 0.33, CHCI3).

[0158] 1H-NMR (400 MHz, CDCI3): 5 (ppm): 6.40 (s, 1 H), 3.97 (ddd, J = 10.4, 9.02, 6.9 Hz, 1 H), 3.58 (td, J = 7.7, 6.1 , 1.6 Hz, 2H), 3.29-3.39 (m, 1 H), 2.83-2.92 (m, 1 H), 2.57 (dd, J = 15.2, 6.9 Hz, 1 H), 2.14 (s, 3H), 1.99 (dd, J = 15.6, 9.1 Hz, 1 H), 1.61 (d, J = 10.8 Hz, 1 H), 1.28-1.59 (m, 10H), 1.24 (s, 3H), 1.10 (s, 3H), 1.01 (s, 3H), 0.96 (t, J = 7.8 Hz, 9H), 0.87 (s, 9H), 0.64 (q, J = 7.5 Hz, 6H), 0.03 (s, 6H).

[0159] 13C-NMR (100 MHz, CDCI3): 6 (ppm): 170.6, 170.0, 77.4, 68.3, 67.1 , 62.7, 60.6,

[0160] 48.4, 43.6, 40.2, 36.4, 36.2, 35.7, 33.1 , 30.5, 30.2, 26.1 , 24.3, 22.4, 21.2, 19.5,

[0161] 18.5, 17.9, 7.2, 5.5, -5.2.

[0162] IR (neat): 2929 (m), 2321 (w), 1721 (s), 1419 (w), 1218 (m), 1096 (s), 1014 (s), 853 (s), 724 (s) cm’1.

[0163] HRMS (ESI): calculated for C33H62NO6Si2 [M+H]+: 624.4115; found: 624.4118.

[0164] P9599PC00 (1S,3aR, 5S, 5aS, 9a S, 9bS)-2-(4-((tert-butyldimethylsilyl) oxy) butyl)-5-hydroxy- 6, 6, 9a-trimethyl-3-oxodecahydro-1H-3a, 9b-epoxybenzo[e]isoindol-1-yl acetate:

[0165] To a solution of (+)-16 (1 eq, 0.10 mmol, 60 mg) in THF (1 .7 mL) at 0°C, TBAF (1 M in THF, 1 eq, 0.10 mmol, 100 pL) was added and the stirring was continued at the same temperature. After 1 h, the reaction mixture was poured into a saturated solution of NH4CI and extracted with Et20. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude was purified by flash chromatography. Elution hexane / EtOAc (3:1 ) afforded in 99% yield the deprotected compound (+)-17 (0.10 mmol, 51 mg) as a sticky oil.

[0166] General Data: C27H47NO6Si; FW: 509.32; TLC: Rf= 0.35 (hexane / EtOAc 3:1 ); UV

[0167] (-); Vanillin: green; = +20.93 (c = 0.33, CHCI3).

[0168] 1H-NMR (400 MHz, CDCI3): 5 (ppm): 6.43 (s, 1 H), 3.89 (ddd, J = 15.6, 8.5, 6.9 Hz, 1 H), 3.58 (td, J = 8.9, 6.3, 2.7 Hz, 2H), 3.33-3.39 (m, 1 H), 2.84-2.91 (ddd, J = 13.57.7, 5.1 Hz, 1 H), 2.63 (dd, J = 16.7, 7.1 Hz, 1 H), 2.16 (dd, J = 14.8, 6.1 Hz, 1 H), 2.15 (s, 3H), 1.56 (d, J = 9.6 Hz, 1 H), 1.21-1.52 (m, 10H), 1.19 (s, 3H), 1.10 (s, 3H), 1.03 (s, 3H), 0.87 (s, 9H), 0.02 (s, 6H).

[0169] 13C-NMR (100 MHz, CDCI3): 5 (ppm): 170.5, 169.6, 76.7, 68.0, 66.0, 62.6, 60.5, 51.3, 42.8, 40.1 , 36.1 , 35.9, 35.0, 33.4, 30.2, 30.1 , 26.1 , 24.2, 22.4, 21.1 , 19.2, 18.5, 18.0, -5.2.

[0170] IR (neat): 3458 (br), 2929 (m), 1713 (s), 1423 (m), 1217 (s), 1017 (s), 835 (s), 755 (s) cm’1.

[0171] HRMS (ESI): calculated for C27H48NO6Si [M+H]+: 510.3251 ; found: 510.3248.

[0172] P9599PC00 (1S, 5a S, 9a S, 9bS)-2-(4-((tert-butyldimethylsilyl) oxy) butyl)-9b-hydroxy-6, 6, 9a- trimethyl-3, 5-dioxo-2,3, 5,5a, 6, 7, 8, 9, 9a, 9b-decahydro- 1H-benzo[ e]isoindol-1-yl acetate:

[0173] To a stirred solution of (+)-17 (1 eq, 1 .0 mmol, 510 mg) in CH2CI2 (20 mL) was added Dess-Martin periodinane (2 eq, 2 mmol, 849 mg) at 0°C, and stirring was continued at room temperature for 2 h. The white solution was poured into a mixture of saturated aqueous Na2S2O3 and saturated aqueous NaHCOs and extracted with CH2CI2. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel. Elution with hexane / EtOAc (5:1 ) gave the corresponding ketoaldehyde (+)-18 (85%, 0.85 mmol, 432 mg) and (+)-19 (10%, 0.10 mmol, 51 mg). Compound and (+)-18 was dissolved in toluene (20 mL) and DBU (0.1 eq, 0.2 mmol, 25 pL) was added at 0°C. After stirring the solution for 1 h, the solvent was evaporated under vacuum, the reaction mixture was poured into a saturated aqueous NaCI solution and then extracted with Et20. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (hexane / EtOAc 3:1 ) to afford (+)-19 (80%, 0.7 mmol, 345 mg, white needles based on (+)-18, for a total yield of 90% of (+)-19).

[0174] General Data: C27H45NO6Si; FW: 507.30; TLC: Rf= 0.38 (hexane / EtOAc 3:1 ); UV

[0175] (+); Vanillin: green; = +12.60 (c = 0.23, CHCI3); Mp 136-138 °C.1H-NMR (400 MHz, CDCI3): 5 (ppm): 6.48 (s, 1 H), 6.37 (s, 1 H), 3.60 (t, J = 6.2 Hz, 2H), 3.04-3.14 (m, 2H), 2.25 (s, 3H), 1.59 (s, 1 H), 1.34-1.80 (m, 8H), 1.06-1.23 (m, 2H), 1.20 (s, 3H), 1.14 (s, 3H), 1.01 (s, 3H), 0.88 (s, 9H), 0.03 (s, 6H).

[0176] 13C-NMR (100 MHz, CDCI3): 5 (ppm): 199.8, 168.9, 164.8, 145.7, 127.1 , 78.8, 74.6, 62.5, 56.1 , 45.6, 42.8, 40.8, 33.7, 32.4, 30.8, 30.2, 26.1 , 24.3, 21.5, 21.1 , 19.2, 18.5, 17.4, -5.2.

[0177] P9599PC00 IR (neat): 3245 (w), 2928 (m), 1752 (m), 1687 (s), 1219 (s), 1044 (s), 939 (w), 836 (s), 774 (s) cm’1.

[0178] HRMS (ESI): calculated for C27H46NO6Si [M+H]+: 508.3094; found: 508.3096.

[0179] (1S, 5S, 5a S, 9a S, 9bS)-2-(4-((tert-butyldimethylsilyl) oxy) butyl)-5, 9b-dihydroxy- 6, 6, 9a-trimethyl-3-oxo-2,3,5, 5a, 6, 7, 8, 9, 9a, 9b-decahydro-1H-benzo[ e]isoindol- 1-yl acetate:

[0180] To a solution of (+)-19 (1 eq, 0.2 mmol, 100 mg) in CH3OH (2 mL) was added CeCl3'7H2O (2 eq, 0.4 mmol, 150 mg) and NaBH4(3 eq, 0.6 mmol, 23 mg) at 0 °C. After stirring the mixture at this temperature for 1 h, the reaction mixture was poured into a saturated NH4CI solution, extracted with Et20. The organic layer was washed with a saturated NaHCOs aqueous solution and brine, dried over anhydrous Na2SO4and concentrated in vacuo. Purification with flash chromatography (hexanes / EtOAc 2:1 , then 1 :1 ) of the residue afforded (-)-20 (48%, 0.1 mmol, 51 mg, colorless oil) and (-)-21 (45%, 0.09 mmol, 46 mg, white powder).

[0181] (~)-20:

[0182] General Data: C27H47NO6Si; FW: 509.32; TLC: Rf= 0.32 (hexane / EtOAc 1 :1 ); UV

[0183] (+); Cerium-Molybdate Phosphoric acid reagent: blue; = -25.8 (c = 0.2, CHCI3).

[0184] 1H-NMR (600 MHz, CDCI3): 5 (ppm): 6.99 (d, J = 1 .9 Hz, 1 H), 6.55 (s, 1 H), 4.70 (dd, J = 10.2, 2.4 Hz, 1 H), 3.58-3.63 (m, 2H), 3.01-3.07 (m, 2H), 2.62 (d, J = 9.8 Hz, 1 H), 2.20 (s, 3H), 1.21 -1.62 (m, 10H), 1.19 (s, 3H), 1.10 (s, 3H), 1.03 (s, 3H), 0.87 (s, 9H), 0.02 (s, 6H).

[0185] IR (neat): 3442 (br), 2926 (s), 1661 (s), 1461 (m), 1253 (m), 1076 (s), 834 (s), 773 (s) cm’1.

[0186] P9599PC00 HRMS (ESI): calculated for C27H47NO6SiNa [M+Na]+: 532.3070; found: 532.3068.

[0187] 65.2 (c = 0.2, CHCI3).

[0188] 1H-NMR (600 MHz, CDCI3): 5 (ppm): 6.99 (d, J = 4.0 Hz, 1 H), 6.57 (s, 1 H), 4.75 (dt, J = 4.6, 4.0 Hz, 1 H), 3.56-3.64 (m, 2H), 3.01 -3.06 (m, 2H), 2.21 (s, 3H), 2.20 (d, J = 4.5 Hz, 1 H), 1.20-1.56 (m, 10H), 1.19 (s, 3H), 1.10 (s, 3H), 1.04 (s, 3H), 0.88 (s, 9H), 0.03 (s, 6H).

[0189] IR (neat): 3445 (br), 2944 (s), 1610 (s), 1452 (m), 1222 (m), 1078 (s), 835 (s), 777 (s) cm’1.

[0190] HRMS (ESI): calculated for C27H47NO6SiNa [M+Na]+: 532.3070; found: 532.3072.

[0191] Linker

[0192] Tert-butyl 2-(benzyloxy)acetate:

[0193] 23

[0194] To a stirred suspension of NaH (1.1 eq, 4.58 mmol, 110 mg, 60 % dispersion in mineral oil) in DMF (30 mL) at 0 °C was added dropwise tert-butyl glycolate (1 eq, 4.16 mmol, 534 pL). Effervescence was observed and after stirring for 30 min BnBr (1.1 eq, 4.58 mmol, 450 pL) was added dropwise. After stirring at room temperature for 5 h, TLC indicated complete consumption of starting material. The mixture was added to an Et2O / H2O bilayer and the aqueous layer was extracted with Et20. The organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated in vacuo. The residue was chromatographed on silica gel. Elution with pentane / Et2O (6:1 ) gave 23 in 99% yield (4.12 mmol, 916 mg, oil).

[0195] General Data: C13H18O3; FW: 222.13; TLC: Rf= 0.75 (hexane / EtOAc 3:1 ); UV (+); Vanillin: green.

[0196] P9599PC001H-NMR (600 MHz, CDCI3): 5 (ppm): 7.33-7.39 (m, 4H), 7.28-7.31 (m, 1 H), 4.62 (s, 2H), 3.99 s, (s, 2H), 1.49 (s, 9H).

[0197] 13C-NMR (151 MHz, CDCI3): 5 (ppm): 170.0, 137.5,128.6, 128.2, 127.0, 81.7,

[0198] 73.3, 67.9, 28.2.

[0199] IR (neat): 1743 (s), 1225 (m), 1160 (m), 1122 (s), 736 (m), 698 (m) cm’1.

[0200] HRMS (ESI): calculated for C13H22NO3 [M+NH4]+: 240.1600; found: 240.1591.

[0201] 1 -(tert-butyl) 2,3-diethyl (Z)-1 -(benzyloxy) prop-1-ene-1,2,3-tricarboxylate:

[0202] Compound 23 (1 eq, 0.68 mmol, 151 mg) was dissolved in 2.5 mL of dry Et20, and the solution was cooled to -78°C. LDA (1 .2 eq, 0.82 mmol, 410 pL) was added dropwise and the mixture was stirred for 1 h at this temperature. After adding dropwise 24 (1 eq, 0.68 mmol, 100 pM) at - 78°C, the stirring was continued at room temperature for 16 h. The reaction was quenched by dropwise addition of saturated aqueous NH4CI solution, and the organic layer was separated, and the aqueous phase was extracted with Et20. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude (±)-25 was used for the next step without purification. The crude product (±)-25 (1 eq, 0.54 mmol, 175 mg) was added to a solution of triphenylphosphonium ethoxycarbonylmethylide (26) (1 .5 eq, 0.81 mmol, 282 mg) in 2.5 mL of CH3CN. The solution was heated to 55°C for 1 h. After the mixture was cooled to room temperature, the acetonitrile was removed in vacuo and the residue was diluted with Et20. The solution was filtered through a silica plug and eluted with additional Et20. Purification of the crude oil by flash chromatography (pentane / Et2O 7:1 ) yielded the E-27 (60% over 2 steps, 0.41 mmol, 160 mg) and Z-27 (10% over 2 steps, 0.07 mmol, 27 mg).

[0203] E-27:

[0204] P9599PC00 General Data: C21 H28O7; FW: 392.18; TLC: Rf= 0.25 (pentane / Et2O 6:1 ; UV (+); Cerium-Molybdate Phosphoric acid reagent: blue.

[0205] 1H-NMR (600 MHz, CDCI3): 5 (ppm): 7.28-7.39 (m, 5H), 5.00 (s, 2H), 4.18 (q, J = 7.1 Hz, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.33 (s, 2H), 1 .56 (s, 9H), 1 .24 (t, J = 7.2 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H).

[0206] 13C-NMR (151 MHz, CDCI3): 6 (ppm): 170.9, 166.3, 162.4, 157.3, 135.8, 128.7, 128.6, 127.8, 106.7, 84.1 , 71.9, 60.8, 60.7, 31.3, 28.0, 14.4, 14.3.

[0207] IR (neat): 2979 (w), 1728 (s), 1716 (s), 1369 (m), 1307 (m), 1150 (s), 1108 (s), 1027 (m), 843 (w), 698 (w) cm’1.

[0208] HRMS (ESI): calculated for C21 H29O7 [M+H]+: 393.1913; found: 393.1906.

[0209] Z-27:

[0210] General Data: C21 H28O7; FW: 392.18; TLC: Rf= 0.16 (pentane / Et2O 6:1 ); UV (+); Cerium-Molybdate Phosphoric acid reagent: blue.

[0211] 1H-NMR (600 MHz, CDCI3): 5 (ppm): 7.28-7.43 (m, 5H), 4.93 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H), 3.55 (s, 2H), 1 .52 (s, 9H), 1 .25 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H).

[0212] 13C-NMR (151 MHz, CDCI3): 6 (ppm): 170.5, 167.0, 162.4, 151.6, 136.5, 128.5, 128.3, 128.0, 117.2, 83.9, 74.1 , 61.2, 61.1 , 34.5, 28.1 , 14.3, 14.2.

[0213] IR (neat): 2970 (w), 1728 (s), 1700 (s), 1350 (m), 1312 (m), 1148 (s), 1106 (s), 1015 (m), 843 (w), 690 (w) cm’1.

[0214] HRMS (ESI): calculated for C21 H29O7 [M+H]+: 393.1913; found: 393.1909.

[0215] 10% Pd / C (1.2 eq, 0.61 mmol, 65 mg) was added to a solution of E-27 (1 eq, 0.51 mmol, 200 mg) in CH3OH (5 mL). After two vacuum / H2 cycles to remove air from

[0216] P9599PC00 the reaction flask, the reaction was stirred under hydrogen atmosphere at room temperature for 24 h. The reaction mixture was filtered through a Celite pad with CH2CI2 to remove catalyst and concentrated in vacuo. The crude product was purified by flash chromatography (hexane / EtOAc 10:1 ) to afford the racemic (±)-28 in 99% yield (0.61 mmol, 154 mg, oil).

[0217] General Data: C14H24O7; FW: 304.15; TLC: Rf= 0.4 (hexane / EtOAc 3:1 ); UV (-); Cerium-Molybdate Phosphoric acid reagent: blue.

[0218] 1H-NMR (600 MHz, CDCI3): 5 (ppm): 4.25 (d, J = 2.7 Hz, 1 H), 4.12-4.17 (m, 4H), 3.42-3.46 (m, 1 H), 2.85 (dd, J = 16.9, 8.9 Hz, 1 H), 2.57 (dd, J = 16.8, 5.6 Hz, 1 H), 1.50 (s, 9H), 1.21 -1.27 (m, 6H).

[0219] 13C-NMR (151 MHz, CDCI3): 5 (ppm): 172.2, 172.0, 170.9, 83.5, 70.9, 61.3, 60.9, 45.1 , 32.4, 28.0, 14.3, 14.2.

[0220] IR (neat): 3025 (br), 1723 (s), 1156 (s), 1108 (s), 1096 (s), 1027 (m), 846 (w) cm’1. HRMS (ESI): calculated for Ci4H24O7Na [M+Na]+: 327.1419; found: 327.1414.

[0221] 1 -(tert-butyl) 2,3-diethyl (1R,2S)-1-(((1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicy- clo [2.2.1] heptane-1 -carbonyl) oxy) propane-1, 2, 3-tricarboxylate:

[0222] To a stirred solution of (±)-28 (1 eq, 1 .31 mmol, 400 mg) in CH2CI2 (10 mL) with NEts (4.5 eq, 6.00 mmol, 0.8 mL) and DMAP (0.35 eq, 0.46 mmol, 56 mg), (-)- (1 S,4R)-camphanic chloride (2 eq, 2.63 mmol, 570 mg) ws added at 0°C. The stirring was continued overnight at room temperature. The reaction mixture was poured into a saturated aqueous NaHCOs solution and extracted with CH2CI2. The

[0223] P9599PC00 combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (pen- tane / Et2O 1 :1 ) affording (+)-29 in 45% yield (0.59 mmol, 286 mg, sticky oil) and (-)-30 in 40% yield (0.52 mmol, 254 mg, clear oil).

[0224] (+)-29:

[0225] General Data: C24H36O10; FW: 484.23; TLC: Rf= 0.45 (pentane / Et2O 1 :1 ); UV (-);

[0226] Vanillin: light-blue; = +2.8 (c = 1 .45, CHCI3).

[0227] 1H-NMR (600 MHz, CDCI3): 5 (ppm): 5.36 (d, J = 3.6 Hz, 1 H), 4.12-4.17 (m, 4H), 3.55-3.59 (m, 1 H), 2.81 (dd, J = 16.7, 9.7 Hz, 1 H), 2.51 (dd, J = 17.1 , 5.0 Hz, 1 H), 2.44-2.49 (m, 1 H), 2.03-2.08 (m, 1 H), 1 .88-1 .94 (m, 1 H), 1 .65-1 .71 (m, 1 H), 1 .47 (s, 9H), 1.26 (t, J = 7.2 Hz, 6H), 1.11 (s, 3H), 1.06 (s, 3H), 1.04 (s, 3H).13C-NMR (151 MHz, CDCI3): 5 (ppm): 178.2, 171.2, 169.8, 166.7, 165.7, 91.1 ,

[0228] 83.6, 72.9, 61.7, 61.2, 55.1 , 54.6, 42.8, 32.1 , 30.8, 28.9, 28.0, 16.8, 16.7, 14.3, 14.2, 9.9.

[0229] IR (neat): 2978 (w), 1791 (m), 1735 (s), 1252 (m), 1229 (m), 1156 (s), 1105 (s), 1061 (s), 1019 (m), 934 (w), 843 (w), 735 (w) cm’1.

[0230] HRMS (ESI): calculated for C24H37O10 [M+H]+: 485.2386; found: 485.2384.

[0231] (~)-30

[0232] General Data: C24H36O10; FW: 484.23; TLC: Rf= 0.35 (pentane / Et2O 1 :1 ); UV (-); Vanillin: light-blue; [«c= -12.4 (c = 0.8, CHCI3).

[0233] 1H-NMR (600 MHz, CDCI3): 5 (ppm): 5.33 (d, J = 3.6 Hz, 1 H), 4.14-4.19 (m, 4H), 3.55-3.59 (m, 1 H), 2.81 (dd, J = 16.9, 9.6 Hz, 1 H), 2.47 (dd, J = 16.9, 4.9 Hz, 1 H), 2.39-2.44 (m, 1 H), 2.04-2.10 (m, 1 H), 1.90-1.96 (m, 1 H), 1.67-1.73 (m, 1 H), 1.48 (s, 9H), 1.26 (td, J = 8.5, 7.1 , 1.3 Hz, 6H), 1.11 (s, 3H), 1.10 (s, 3H), 1.03 (s, 3H).13C-NMR (151 MHz, CDCI3): 5 (ppm): 178.0, 171.2, 169.9, 166.4, 165.7, 91.0,

[0234] 83.7, 72.7, 61.7, 61.2, 55.0, 54.8, 42.8, 32.4, 30.8, 29.2, 28.1 , 16.6, 16.4, 14.3, 14.2, 9.8.

[0235] IR (neat): 2978 (w), 1786 (m), 1730 (s), 1253 (m), 1245 (m), 1140 (s), 1102 (s), 1052 (s), 1018 (m), 935 (w), 843 (w), 736 (w) cm’1.

[0236] HRMS (ESI): calculated for C24H37O10 [M+H]+: 485.2386; found: 485.2383.

[0237] P9599PC00

[0238] Compound (+)-29 (1 eq, 0.10 mmol, 50 mg) was dissolved in was dissolved in CH3CH2OH (2 mL), and finely powdered K2CO3 (1 eq, 0.10 mmol, 14 mg) was added. The mixture was stirred at room temperature for 4 h, then it was partitioned between Et20 and H2O. The aqueous layer was extracted with Et20, and the combined organic extracts were passed through a plug of silica / Na2SO4. The solvents were evaporated, and the residue was purified by flash chromatography (hex- ane / EtOAc 15:1 ), yielding compound (+)-31 (60%, 0.06 mmol, 18 mg) as a colorless oil.

[0239] General Data: C14H24O7; FW: 304.15; TLC: Rf= 0.4 (hexane / EtOAc 3:1 ); UV (-);

[0240] Cerium-Molybdate Phosphoric acid reagent: blue; = +32 (c = 0.10, CHCI3).1H-NMR (600 MHz, CDCI3): 5 (ppm): 4.25 (d, J = 2.7 Hz, 1 H), 4.12-4.17 (m, 4H), 3.42-3.46 (m, 1 H), 2.85 (dd, J = 16.8, 8.9 Hz, 1 H), 2.57 (dd, J = 16.8, 5.5 Hz, 1 H), 1.49 (s, 9H), 1.21 -1.26 (m, 6H).

[0241] 13C-NMR (151 MHz, CDCI3): 6 (ppm): 171.9, 171.6, 170.8, 83.5, 70.8, 61.3, 60.9, 45.1 , 32.3, 28.0, 14.3, 14.2.

[0242] IR (neat): 3015 (br), 1723 (s), 1156 (s), 1108 (s), 1096 (s), 1027 (m), 846 (w) cm’1. HRMS (ESI): calculated for Ci4H24O7Na [M+Na]+: 327.1419; found: 327.1414.

[0243] P9599PC00

[0244] To a solution of (+)-31 (1 eq, 0.164 mmol, 50 mg) in CH2CI2 (2.5 mL), NEts (3 eq, 0.5 mmol, 70 pL), DMAP (0.05 eq, 0.01 mmol, 1 mg), and AC2O (3 eq, 0.5 mmol, 50 pL) were added at 0°C. The mixture was stirred at room temperature for 5 h. The reaction mixture was poured into a 1 M HCI solution and extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (pentane / Et2O 3:1 ), yielding the desired compound (+)-32 (80%, 0.131 mmol, 45 mg, sticky oil).

[0245] General Data: CI6H26O8; FW: 346.16; TLC: = 0.6 (hexane / EtOAc 3:1 ); UV (-); Ce- hum -Molybdate Phosphoric acid reagent: blue; MB = +11 .8 (c = 1 .4, CHCI3).1H-NMR (400 MHz, CDCI3): 5 (ppm): 5.30 (d, J = 3.5 Hz, 1 H), 4.13-4.20 (m, 4H), 3.47-3.54 (m, 1 H), 2.78 (dd, J = 17.2, 9.4 Hz, 1 H), 2.50 (dd, J = 17.2, 4.8 Hz, 1 H), 2.12 (s, 3H), 1 .46 (s, 9H), 1 .26 (td, J = 8.8, 7.2, 1 .6 Hz, 6H).

[0246] 13C-NMR (100 MHz, CDCI3): 6 (ppm): 171.1 , 170.4, 169.7, 166.2, 83.0, 71.6, 61.4, 61.0, 42.8, 32.0, 28.0, 20.6, 14.2, 14.1.

[0247] IR (neat): 1721 (s), 1703 (s), 1152 (s), 1107 (s), 1063 (s), 1014 (m), 846 (w) cm’1. HRMS (ESI): calculated for C ^eOsNa [M+Na]+: 369.1525; found: 369.1524.

[0248] P9599PC00

[0249] Compound (+)-32 (1 eq, 0.144 mmol, 50 mg) was dissolved in CH2Cl2 (0.5 mL), followed by slow addition of 100 pL of TFA. After complete consumption of starting material, as monitored by TLC, the reaction was diluted with toluene, and the solvent along with TFA were removed by evaporation. The resulting crude product (+)-33, yielded in 90% (0.143 mmol, 41 mg) a colorless oil, was used for next step without purification.

[0250] General Data: C12H18O8; FW: 290.10; TLC: = 0.1 (hexane / EtOAc 3:1 );

[0251] UV (-); Cerium-Molybdate Phosphoric acid reagent: blue; [-T]DC= +6.0 (c = 1 .05, CHCI3). 3.42-3.46 (m, 1 H)

[0252] 1H-NMR (400 MHz, CDCI3): 5 (ppm): 5.42 (d, J = 3.6 Hz, 1 H), 4.12-4.17 (m, 4H), 3.60-3.66 (m, 1 H), 2.86 (dd, J = 17.0, 9.0 Hz, 1 H), 2.54 (dd, J = 16.9, 5.4 Hz, 1 H), 2.14 (s, 3H), 1.23-1.27 (m, 6H).

[0253] 13C-NMR (100 MHz, CDCI3): 6 (ppm): 173.0, 171.3, 170.6, 170.0, 71.3, 61.9, 61.2, 42.8, 32.4, 20.6, 14.2, 14.0.

[0254] IR (neat): 2982 (br), 1730 (s), 1446 (w), 1373 (m), 1216 (s), 1176 (s), 1027 (m), 956 (w), 857 (w), 734 (w), 615 (w) cm’1.

[0255] HRMS (ESI): calculated for C^H OsNa [M+Na]+: 313.0899; found: 313.0891.

[0256] P9599PC00 Bicycle

[0257] (2E,6E) -3,7,11-trimethyldodeca-2,6,10-trien-1-yl acetate:

[0258] AII-trans-F arnesol 34 (1 eq, 11 .24 mmol, 2.82 mL) was dissolved in CH2CI2 (60 mL) at room temperature. Pyridine (4 eq, 45 mmol, 3.6 mL), AC2O (6 eq, 67.44 mmol, 6.4 mL), and DMAP (0.05 eq, 0.56 mmol, 69 mg) were added sequentially. The mixture was stirred for 1 h at this temperature, after which 1 M HCI solution was added, and the layers were separated. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (pentane / Et2O 75:1 ) to afford all- frans-Farnesyl Acetate 35 in 99% yield (11.13 mmol, 2943 mg) as a colorless oil. General Data: C17H28O2; FW: 264.21 ; TLC: Rf= 0.7 (hexane / EtOAc 9:1 ); UV (+); Vanillin: brown.

[0259] 1H NMR (600 MHz, CDCI3): 5 (ppm): 5.33 (tq, J = 7.1 , 1.3 Hz, 1 H), 5.07-5.10 (m, 2H), 4.58 (d, J = 7.1 Hz, 2H), 2.08-2.13 (m, 2H), 2.04 (s, 3H), 2.02-2.07 (m, 4H), 1 .95-1 .98 (m, 2H), 1 .69-1 .71 (m, 3H), 1 .66-1 .68 (m, 3H), 1 .57-1 .60 (m, 6H).13C NMR (151 MHz, CDCI3): 5 (ppm): 171.2, 142.4, 135.6, 131.4, 124.4, 123.7, 118.4, 61.5, 39.8, 39.7, 26.8, 26.3, 25.8, 21.2, 17.8, 16.6, 16.1.

[0260] IR (neat): 2920 (w), 1739 (s), 1443 (w), 1366 (w), 1229 (s), 1022 (m), 954 (w) cm’1.

[0261] HRMS (ESI): calculated for C17H29O2 [M+H]+: 265.2167; found: 265.2162.

[0262] (2E,6E)-9-(3,3-dimethyloxiran-2-yl)-3,7-dimethylnona-2,6-dien-1-yl acetate:

[0263] / V-bromosuccinimide (1.2 eq, 46.80 mmol, 8.3 g) was added to an ice-cool solution of trans, trans-farnesyl acetate 35 (1 eq, 39 mmol, 10.2 g) in a mixture of THF / H2O

[0264] P9599PC00 (225 mL / 75 mL). The mixture was stirred at this temperature for 3h. Afterward, brine was added, and the layers were separated. The aqueous layer was extracted with Et2O. The combined organic layers were washed, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude was used for next step without purification. The crude residue was dissolved in THF (130 mL) and cooled to 0°C. DBU (1 .3 eq, 50.70 mmol, 7.6 mL) was then added, and the reaction was stirred at this temperature for 3h. After warming reaction at room temperature, the crude product was suspended in pentane and washed with brine. The aqueous layer was extracted with pentane and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel. Elution with pentane / Et2O (16:1 ) gave the desired compound +)-36 in 75% yield (29.3 mmol, 8.2 g) as a colorless oil.

[0265] General Data: C17H28O3; FW: 280.20; TLC: Rf= 0.6 (hexane / EtOAc 4:1 ); UV (+); Vanillin: brown.

[0266] 1H NMR (400 MHz, CDCI3): <5 (ppm): 5.32 (tq, J = 7.2, 1.2 Hz, 1 H), 5.13 (tq, J = 6.9, 1.2 Hz, 1 H), 4.56 (d, J = 7.1 Hz, 2H), 2.68 (t, J = 6.2 Hz, 1 H), 2.04-2.14 (m, 5H), 2.03 (s, 4H), 1.66-1.70 (m, 3H), 1.54-1.66 (m, 5H), 1.28 (s, 3H), 1.24 (s, 3H).13C NMR (100 MHz, CDCI3): 5 (ppm): 171.2, 142.2, 134.7, 124.4, 118.5, 64.2, 61.5, 58.4, 39.5, 36.4, 27.6, 26.3, 25.0, 21.2, 18.9, 16.6, 16.1.

[0267] IR (neat): 3022 (w), 2921 (m), 2850 (w), 1738 (s), 1445 (w), 1337 (w), 1229 (s), 1022 (m), 733 (w) cm’1.

[0268] HRMS (ESI): calculated for C17H29O3 [M+H]+: 281 .2116; found: 281 .2097.

[0269] (6-hydroxy-5, 5, 8a-trimethyl-2-methylenedecahydronaphthalen-1-yl) methyl acetate:

[0270] P9599PC00 A mixture of Mn dust (8 eq, 11 .44 mmol, 629 mg) and Cp2TiCl2 (0.2 eq, 0.29 mmol, 71 mg) was suspended in THF (20 mL) at room temperature. After 15-20 min, the color of the reaction mixture changed from reddish to greenish. A solution of trimethylsilyl chloride (4.5 eq, 6.44 mmol, 0.82 mL) in THF (1 mL) and a solution of 2 ,4,6-col lid ine (7 eq, 10 mmol, 1 .32 mL) in THF (0.5 mL) were added simultaneously. After 5 min, compound (±)-36 (1 eq, 1 .43 mmol, 400 mg) was added, and the mixture was stirred for 20 h. Excess Mn was dissolved by adding HCI (2M,

[0271] I .5 mL). H2O was added, and the reaction mixture was extracted with Et20. The combined organic extracts were evaporated and the resulting highly viscous, brownish oil was dissolved in CH3CN (1.5 mL), and HF (40% in H2O; 0.1 mL) was added. After 1 h, KHCO3 (2 eq, 2.86 mmol, 286 mg) and H2O (0.5 mL) were slowly added. The mixture was partitioned between CH2CI2 and H2O, the aqueous layer was extracted with CH2CI2, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography (pentane / Et2O 40:1 ) yielding (±)-37 in 37% (0.53 mmol, 148 mg) as a colorless oil.

[0272] General Data: C17H28O3; FW: 280.20; TLC: Rf= 0.7 (hexane / EtOAc 3:1 ); UV (+); Vanillin: green.

[0273] 1H NMR (400 MHz, CDCI3): 5 (ppm): 4.86 (d, J =1 .4 Hz, 1 H), 4.55 (d, J = 1 .5 Hz, 1 H), 4.33 (dd, J = 11.2, 3.8 Hz, 1 H), 4.17 (dd, J = 11.3, 8.9 Hz, 1 H), 3.23 (dd, J =

[0274] I I .4, 4.2 Hz, 1 H), 2.40 (ddd, J = 13.0, 4.2, 2.3 Hz, 1 H), 2.00-2.01 (m, 2H), 1.74- 2.00 (m, 4H), 1.67-1.72 (m, 2H), 1.35 -1.57 (m, 3H), 1.10 (dd, J = 12.5, 2.7 Hz, 1 H), 0.98 (s, 3H), 0.75 (s, 3H), 0.74 (s, 3H).

[0275] 13C NMR (100 MHz, CDCI3): 5 (ppm): 171.0, 145.9, 107.0, 78.8, 60.9, 54.0, 53.9, 39.0, 38.9, 37.0, 36.5, 28.1 , 27.6, 23.2, 20.7, 15.4, 14.7.

[0276] IR (neat): 3105 (br), 2952 (w), 1739 (s), 1610 (m), 1443 (w), 1367 (m), 1239 (s), 1095 (s), 893 (s), 838 (s), 749 (w) cm’1.

[0277] HRMS (ESI): calculated for C17H29O3 [M+H]+: 281.2116; found: 281.2105.

[0278] P9599PC00 (6-((1H-imidazole-1-carbonothioyl) oxy)-5,5,8a-trimethyl-2-methylenedecahy- dronaphthalen-1-yl) methyl acetate:

[0279] Compound (±)-37 (1 eq, 0.52 mmol, 146 mg) was dissolved in toluene (12 mL), and TCDI (2.7 eq, 1.40 mmol, 250 mg) and DMAP (1.1 eq, 0.57 mmol, 70 mg) were added and at room temperature. The reaction mixture was stirred at 80 °C for 48 h. The mixture was partitioned between CH2CI2 and H2O, and the aqueous layer was extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (pentane / Et2O 2:1 , then 1 :1 ) to afford (±)-38 in 80% yield (0.42 mmol, 162 mg) as a light-yellow crystalline solid.

[0280] General Data: C21 H30O3N2S; FW: 390.20; TLC: Rf= 0.6 (hexane / EtOAc 3:2); UV (+); Vanillin: black; Mp 110-115 °C.

[0281] 1H NMR (400 MHz, CDCI3): 5 (ppm): 8.4 (s, 1 H), 7.6 (d, J = 1 .5 Hz, 1 H), 7.2 (d, J = 1 .5 Hz, 1 H), 5.26 (dd, J = 11 .9, 4.2 Hz, 1 H), 4.88 (d, J = 1 .5 Hz, 1 H), 4.54 (d, J = 1.5 Hz, 1 H), 4.29 (dd, J = 11.5, 4.3 Hz, 1 H), 4.17 (dd, J = 11.5, 8.5 Hz, 1 H), 2.42 (ddd, J =13.0, 4.0, 2.2 Hz, 1 H), 2.03-2.05 (m, 4H), 2.00 (s, 3H), 1 .82 (ddd, J =

[0282] 13.1 , 3.6 Hz, 1 H), 1.30-1.74 (m, 4H), 0.98 (s, 3H), 0.96 (s, 3H), 0.84 (s, 3H).

[0283] 13C NMR (100 MHz, CDCI3): <5 (ppm): 181.4, 171.4, 145.4, 135.0, 132.6, 118.6, 108.5, 93.2, 61.4, 54.5, 54.3, 39.0, 38.6, 37.2, 36.5, 28.5, 23.2, 23.0, 21.2, 17.6,

[0284] 15.2.

[0285] IR (neat): 2942 (w), 1735 (s), 1370 (m), 1228 (s), 1099 (w), 1030 (w), 896 (w), 730 (s), 644 (w), 606 (w) cm-1.

[0286] HRMS (ESI): calculated for C21 H31O3N2S [M+H]+: 391.2055; found: 391.2056.

[0287] P9599PC00 (5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl) methyl acetate:

[0288] Thiocarbamate (±)-38 (1 eq, 0.51 mmol, 200 mg), BusSnH (3 eq, 1.53 mmol, 0.4 mL), and AIBN (0.2 eq, 0.10 mmol, 17 mg) were dissolved in toluene (75 mL). The reaction mixture was stirred at 160 °C for 3 h, then the oil-bath temperature was reduced to 125°C, and stirring continued for an additional 2 h. The mixture was cooled to room temperature using a water bath, then all the volatiles were evaporated. The crude product was purified by flash chromatography (pentane / Et2O 20:1 ), yielding (±)-39 (85%, 0.43 mmol, 115 mg) as a colorless oil.

[0289] General Data: C17H28O2; FW: 264.21 ; TLC: Rf= 0.8 (hexane / EtOAc 3:1 ); UV (-); Vanillin: black.

[0290] 1H NMR (400 MHz, CDCI3): 5 (ppm): 4.85 (d, J = 1 .4 Hz, 1 H), 4.48 (d, J = 1 .5 Hz, 1 H), 4.33 (dd, J = 11 .3, 3.8 Hz, 1 H), 4.19 (dd, J = 11 .3, 9.1 Hz, 1 H), 2.40 (ddd, J = 13.1 , 4.1 , 2.2 Hz, 1 H), 2.03-2.06 (m, 2H), 2.01 (s, 3H), 1.73-1.76 (m, 1 H), 1.12- 1.72 (m, 8H), 0.88 (s, 3H), 0.80 (s, 3H), 0.76 (s, 3H).

[0291] 13C NMR (100 MHz, CDCI3): 5 (ppm): 171.4, 145.4, 108.5, 61.4, 54.5, 54.3, 42.1 , 39.1 , 39.0, 37.2, 33.8, 33.7, 23.2, 21.2, 19.3, 17.6, 15.2.

[0292] IR (neat): 2952 (m), 1739 (s), 1610 (m), 1443 (w), 1367 (w), 1230 (s), 1095 (m), 1031 (m), 893 (m), 838 (s), 749 (w) cm’1.

[0293] HRMS (ESI): calculated for C17H29O2 [M+H]+: 265.2167; found: 265.2151.

[0294] P9599PC00 (5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl) methanol:

[0295] Finely powdered K2CO3 (2.5 eq, 0.85 mmol, 118 mg) was added to a solution of Albicanyl acetate (±)-39 (1 eq, 0.34 mmol, 90 mg) in CH3OH (4 mL), and the reaction was stirred at room temperature overnight. The mixture was partitioned between Et20 and H2O, the aqueous layer was extracted with Et20, the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by flash chromatography (pentane / Et2O 10:1 ) afforded compound (±)-40 (90 %, 0.31 mmol, 68 mg) as a colorless oil.

[0296] General Data: C15H26O; FW: 222.20; TLC: Rf= 0.4 (hexane / EtOAc 3:1 ); UV (-); Vanillin: brown.

[0297] 1H NMR (400 MHz, CDCI3): 5 (ppm): 4.94 (d, J = 1 .4 Hz, 1 H), 4.64 (d, J = 1 .5 Hz, 1 H), 3.83 (dd, J = 11 .3, 3.8 Hz, 1 H), 3.75 (dd, J = 11 .0, 9.7 Hz, 1 H), 2.42 (ddd, J = 12.9, 4.5, 2.5 Hz, 1 H), 2.02 (td, J = 18.4, 13.0, 5.0 Hz, 2H), 1.72-1.77 (m, 2H), 1.64-1.68 (m, 2H), 1.45-1.58 (m, 2H), 1.30-1.44 (m, 2H), 1.10-1.14 (m, 1 H), 0.87 (s, 3H), 0.80 (s, 3H),0.72 (s, 3H).

[0298] 13C NMR (100 MHz, CDCI3): <5 (ppm): 148.1 , 106.5, 59.3, 59.0, 55.3, 42.1 , 39.1 , 39.0, 38.0, 33.8, 33.6, 24.4, 21.9, 19.4, 15.4.

[0299] IR (neat): 3353 (br) , 2919 (s), 2846 (m), 1458 (m), 1384 (m), 1363 (w), 1113 (w), 1088 (w), 1023 (s), 969 (s), 913 (s), 822 (w), 770 (w), 674 (w) cm’1.

[0300] HRMS (ESI): calculated for C15H27O [M+H]+: 223.2062; found: 223.2057.

[0301] P9599PC00 (4aS,5S)-5-(bromomethyl)-1,1,4a-trimethyl-6-methylenedecahydronaphtha- lene:

[0302] To a solution of (±)-40 (1 eq, 0.03 mmol, 6 g) in dry CH2CI2 (0.3 mL) was added PPhs (1.1 eq, 0.033 mmol, 9 mg) and CCI4 (1 .1 eq, 0.033 mmol, 3 pL), and then the reaction was stirred at 0°C. To the reaction mixture was added SOCI2 (1.2 eq, 0.036 mmol, 3 pL), and the reaction was stirred for 1 h at room temperature. The mixture was partitioned between CH2CI2 and saturated solution of NaHCOs, the aqueous layer was extracted with CH2CI2, the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The alogenated compound (±)-41 was obtained in 60% yield (0.02 mmol, 4 mg) as a colorless oil.

[0303] General Data: C15H25CI; FW: 240.1645.

[0304] HRMS (ESI): calculated for C15H25 [M-CI]+: 205.1951 ; found: 205.1953.

[0305] Final Strategy

[0306] 1-((1S, 5S, 5a S, 9a S, 9bS)-1-acetoxy-2-(4-((tert-butyldimethylsilyl) oxy)butyl)-9b- hydroxy-6, 6, 9a-trimethyl-3-oxo-2,3,5, 5a, 6, 7, 8, 9, 9a, 9b-decahydro-1 H- benzo[e]isoindol-5-yl) 2,3-diethyl (1 R,2S)-1-acetoxypropane-1 ,2,3-tricarbox- ylate:

[0307] P9599PC00

[0308] H-42

[0309] The crude acid (+)-33 (1.5 eq, 0.03 mmol, 9mg) was dissolved in THF (0.3 mL) and treated at room temperature with NEts (6 eq, 0.12 mmol, 17 pL) and 2,4,6-tri- chlorobenzoyl chloride (4 eq, 0.08 mmol, 12 pL). The turbid solution was stirred for 2 h at room temperature and then diluted with toluene (0.3 mL) and added dropwise to a solution of alcohol (-)-20 (1 eq, 0.02 mmol, 10 mg) and DMAP (6 eq, 0.12 mmol, 15 mg) in toluene (0.5 mL). The mixture was stirred 3 h at room temperature and then quenched with saturated aqueous NH4CI solution. The aqueous phase was extracted with Et20. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (hexane / EtOAc 1 :1 ) to afford (-)-42 (60%, 0.12 mmol, 9 mg) as a sticky yellow oil.

[0310] General Data: CsoHesNO Si; FW: 781.41 ; TLC: Rf= 0.45 (hexane / EtOAc 1 :1 ); UV (+); Cerium-Molybdate Phosphoric acid reagent: blue; Ms' = -24 (c = 0.25, CHCI3).

[0311] 1H-NMR (600 MHz, CDCI3): 5 (ppm): 6.99 (d, J = 2.0 Hz, 1 H), 6.50 (s, 1 H), 5.40 (d, J = 3.7 Hz, 1 H), 5.36 (dd, J = 9.8, 2.3 Hz, 1 H), 4.05-4.19 (m, 4H), 3.55-3.76 (m, 3H), 2.70-2.81 (m, 3H), 2.60 (d, J = 9.6 Hz, 1 H), 2.51 (dd, J = 17.0, 6.4 Hz, 1 H), 2.12 (s, 3H), 2.12 (s, 3H), 1 .34-1 .80 (m, 6H), 1 .26 (t, J = 7.2 Hz, 6H), 1 .06-1 .23 (m, 4H), 1.20 (s, 3H), 1.14 (s, 3H), 1.01 (s, 3H), 0.88 (s, 9H), 0.03 (s, 6H).

[0312] 13C-NMR (151 MHz, CDCI3): 5 (ppm): 171.6, 171.4, 170.8, 170.1 , 170.0, 167.4, 140.5, 135.3, 87.3, 71.8, 71.5, 65.8, 61.8, 61.2, 61.1 , 48.7, 45.9, 42.9, 40.2, 36.0,

[0313] P9599PC00 34.4, 34.2, 34.1 , 32.3, 30.5, 25.8, 22.8, 21.6, 20.7, 20.6, 19.2, 18.4, 17.6, 14.3, 14.0, -5.2.

[0314] IR (neat): 3380 (br), 2987 (w), 2931 (w), 2853 (w), 1730 (s), 1547 (m), 1373 (m), 1216 (m), 1162 (m), 1123 (m), 1027 (m), 843 (s), 820 (m), 803 (m), 734 (w), 537 (w) cm-1.

[0315] HRMS (ESI): calculated for C39H64NOi3Si [M+H]+: 782.4147; found: 782.4148.

[0316] 1-((1S, 5S, 5a S, 9aS, 9bS)-1-acetoxy-9b-hydroxy-2-(4-hydroxybuty / )-6, 6, 9a-tri- methyl-3-oxo-2, 3, 5, 5a, 6, 7, 8, 9, 9a, 9b-decahydro- 1H-benzo[e]isoindol-5-yl) 2, 3- diethyl (1 R,2S)-1-acetoxypropane-1 ,2,3-tricarboxylate:

[0317] H-43

[0318] To a solution of (-)-42 (1 eq, 0.012 mmol, 9 mg) in THF (2 mL) at 0°C, TBAF (1 M in THF, 1 eq, 0.08 mmol, 80 pL) was added and the stirring was continued at the same temperature. After 3 h, the reaction mixture was poured into a saturated solution of NH4CI and extracted with Et20. The organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated in vacuo. The crude material was purified with flash chromatography (hexane / EtOAc 1 :2) to afford (-)-43 in quantitative yield (0.012 mmol, 8 mg) as sticky oil.

[0319] General Data: C33H49NOi3; FW: 667.32; TLC: Rf= 0.40 (hexane / EtOAc 1 :2); UV

[0320] (+); Cerium-Molybdate Phosphoric acid reagent: blue; Me = -16 (c = 0.2, CHCI3).

[0321] P9599PC001H-NMR (600 MHz, CDCh): 5 (ppm): 6.99 (d, J = 2.1 Hz, 1 H), 6.51 (s, 1 H), 5.38 (d, J = 3.7 Hz, 1 H), 5.36 5.36 (dd, J = 9.5, 2.2 Hz, 1 H), 4.04-4.19 (m, 4H), 3.58-3.76 (m, 3H), 2.75-2.81 (m, 3H), 2.60 (d, J = 9.6 Hz, 1 H), 2.50 (dd, J = 17.0, 6.4 Hz, 1 H), 2.12 (s, 3H), 2.10 (s, 3H), 1.34-1.82 (m, 6H), 1.26 (t, J = 7.2 Hz, 6H), 1.06- 1.20 (m, 4H), 1.20 (s, 3H), 1.14 (s, 3H), 1.01 (s, 3H).

[0322] 13C-NMR (151 MHz, CDCh): 5 (ppm): 171.6, 171.4, 170.8, 170.1 , 170.0, 167.4, 140.5, 135.3, 87.3, 71.8, 71.5, 65.8, 62.6, 61.2, 61.1 , 48.7, 45.9, 42.9, 41.7, 36.0, 34.4, 34.2, 34.1 , 31.9, 31.0, 30.5, 21.6, 20.7, 20.6, 19.2, 17.6, 14.3, 14.0.

[0323] IR (neat): 3412 (br), 2980 (w), 2929 (w), 2880 (m), 2453 (w), 1690 (s), 1545 (m), 1363 (m), 1210 (m), 1153 (m), 1123 (m), 1027 (m), 843 (s), 803 (m), 734 (w), 535 (w) cm’1.

[0324] HRMS (ESI): calculated for C33H53N2O13 [M+NH4]+: 685.3548; found: 685.3546.

[0325] 1-((1S, 5S, 5a S, 9aS, 9bS)-1-acetoxy-9b-hydroxy-2-(4-methoxy-4-oxobuty / )-

[0326] 6, 6, 9a-trimethyl-3-oxo-2,3,5, 5a, 6, 7, 8, 9, 9a, 9b-decahydro-1H-benzo[ e]isoindol- 5-yl) 2,3-diethyl (1 R,2S)-1-acetoxypropane-1 ,2,3-tricarboxylate:

[0327] To a stirred solution of (-)-43 (1 eq, 0.012 mmol, 8 mg) in CH2CI2 (40 mL) was added Dess-Martin periodinane (2 eq, 0.024 mmol, 10 g) at 0°C, and stirring was continued at room temperature 3 h. The white solution was poured into a mixture of saturated aqueous Na2S20s and saturated aqueous NaHCOs and extracted with

[0328] P9599PC00 CH2CI2. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was used without further purification. NaCIO2 (2 eq, 0.024 mmol, 2 mg) and NaH2PO4 (4 eq, 0.05 mmol, 6 g) were dissolved in water (15 pL) at 0 °C and stirred for 1 h. The crude aldehyde (1 eq, 0.012 mmol, 8 mg) was dissolved in t- BuOH (50 pL) and 2-methyl-2-butene (8.1 eq, 0.1 mmol, 10 pL). The system was stirred for half an hour, then the aqueous NaCIC / NaH2PO4 aqueous was added slowly over 15 min at 0 °C. After the reaction was kept for 1 h at this temperature, saturated NH4CI was poured into the system. The aqueous layer was extracted with Et20, then the organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford in quantitative yield the oxidized product. The residue was dissolved in ether (0.2 mL) and the solution was cooled to 0 °C; a 2.0 M ethereal solution of diazomethane (1 .5 eq, 0.015 mmol, 7.5 pL) was added and the reaction was stirred for 30 min. The reaction was quenched by the dropwise addition of acetic acid (5 pL), followed by the subsequent addition of saturated aqueous Na- HCO3.The two phases were separated, and the aqueous phase was extracted with Et20. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography on silica gel (hexane / EtOAc 1 :2) afforded (-)-44 as sticky oil in 65% yield over 3 steps (0.01 mmol, 7 mg).

[0329] General Data: C34H49NO14; FW: 695.32; TLC: Rf= 0.45 (hexane / EtOAc 1 :2); UV (+); Cerium-Molybdate Phosphoric acid reagent: blue; Ms1= -19.5 (c = 0.20, CHCI3).

[0330] 1H-NMR (600 MHz, CDCI3): 5 (ppm): 6.69 (d, J = 7.8 Hz, 1 H), 6.40 (s, 1 H), 5.40 (d, J = 3.7 Hz, 1 H), 5.28-5.36 (m, 1 H), 4.05-4.19 (m, 4H), 3.65 (s, 3H), 3.49-3.52 (m, 1 H), 2.75-2.81 (m, 3H), 2.51 (dd, J = 17.0, 6.4 Hz, 1 H), 2.12 (s, 3H), 2.12 (s, 3H), 2.01 (d, J = 6.3 Hz, 1 H), 1 .34-1 .82 (m, 6H), 1 .26 (t, J = 7.2 Hz, 6H), 1 .06-1 .23 (m, 4H), 1.20 (s, 3H), 1.14 (s, 3H), 1.01 (s, 3H).

[0331] 13C-NMR (151 MHz, CDCI3): 5 (ppm): 171.5, 171.4, 170.7, 170.2, 170.0, 167.5, 166.5, 140.7, 135.3, 87.4, 71.8, 71.5, 65.9, 62.5, 61.2, 61.1 , 48.8, 46.0, 43.0, 41.7, 36.0, 34.3, 34.3, 34.1 , 31.9, 31.0, 30.6, 21.6, 20.7, 20.6, 19.1 , 17.6, 14.3, 14.1.

[0332] IR (neat): 3420 (br), 2981 (w), 2930 (w), 2880 (m), 2453 (w), 1690 (s), 1756 (s), 1545 (m), 1365 (m), 1222 (m), 1170 (m), 1125 (m), 1027 (m), 843 (s), 803 (m), 734 (w) cm’1.

[0333] P9599PC00 HRMS (ESI): calculated for C34H49N2Oi4Na [M+Na]+: 718.3050; found: 718.3051.

[0334] (S)-2-((R)-2-(((1S,5S,5aS,9aS,9bS)-2-(3-carboxypropyl)-1,9b-dihydroxy-6,6,9a- trimethyl-3-oxo-2,3, 5, 5a, 6, 7, 8, 9, 9a, 9b-decahydro-1H-benzo[ e]isoindol-5- yl)oxy)-2-oxo-1-(((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaph- thalen-1-yl)methoxy)ethyl)succinic acid:

[0335] Compound (-)-44 (1 eq, 0.014 mmol, 10 mg) was dissolved in was dissolved in CH3OH (0.2 mL), and finely powdered K2CO3 (2 eq, 0.03 mmol, 4 mg) was added. The mixture was stirred at room temperature for 16 h, then it was partitioned between Et2O and H2O, and the aqueous layer was extracted with Et2O. The combined organic extracts were passed through a plug of silica / Na2SO4, and the solvents were evaporated. Deacetylated compound was used for the next step without purification and was dissolved with 1 eq of (±)-41 (0.014 mmol, 3.4 mg) in 0.2 mL of acetone. An excess of Nal (2 eq, 0.03 mmol, 4 mg) was added and the mixture was heated at 60°C for 3 h. The reaction mixture was cooled and the precipitated NaCI was filtered off. After drying over Na2SO4, filtered and concentrating in vacuo, the product was dissolved in THF (0.3 mL) and treated at room temperature with LiOH (3 eq, 1 M in H2O, 0.042mmol, 42 pL). The mixture was stirred for 3 h at room temperature and neutralized with 1 M HCI. The aqueous phase was extracted with Et2O and the organic extracts were dried over Na2SO4, filtered and

[0336] P9599PC00 concentrated in vacuo to give final compound (+)-45 (45 % over 3 steps, 0.0065 mmol, 4.7 mg).

[0337] General Data: C40H59NO12; FW: 745.40.

[0338] HRMS (ESI): calculated for C4oH59NOi2Na [M+Na]+: 745.4037; found: 745.4040.

[0339] P9599PC00

Claims

1. Claims1. Method for the preparation of a compound according to formula 45, its enantiomers, diastereomers, a racemic mixture, and the pharmaceutically ac- ceptable salts thereof45 wherein the following steps are performed: reacting a compound of formula 20, in the form of a single enantiomer, a racemic mixture or a diastereomer thereofwith a compound of formula 33, in the form of a single enantiomer, a racemic mixture or a diastereomer thereofP9599PC0033 to give a compound according to formula 42, in the form of a single enantiomer, a racemic mixture or a diastereomer thereof42 reacting the compound of formula 42, in the form of a single enantiomer, a racemic mixture or a diastereomer thereof, to a compound of formula 43, in the form of a single enantiomer, a racemic mixture or a diastereomer thereofP9599PC00reacting the compound of formula 43, in the form of a single enantiomer, a racemic mixture or a diastereomer thereof, to a compound of formula 44 in the form of a single enantiomer, a racemic mixture or a diastereomer thereofand reacting the compound of formula 44, a single enantiomer, a racemic mixture or a diastereomer thereof, with a compound of formula 41 , in the form of a single enantiomer, a racemic mixture or a diastereomer thereofP9599PC00to give the compound of formula 45 in the form of a single enantiomer, a racemic mixture or a diastereomer thereof.

2. The method according to claim 1 , wherein the compound of formula 45 is compound (+)-45 or compound (-)-45 or the racemic mixture thereof.

3. A compound prepared by the method according to claim 1 or 2 for use in the treatment of neurodegenerative disorders (NDDs), namely of disorders of the nervous system characterized by progressive degradation of neuronal structures and their function in the brain and spinal cord, resulting in neuronal damage and death.

4. The compound according to claim 3, wherein the disorder is selected from Alzheimer's disease, Parkinson's disease and Amyotrophic lateral sclerosis.

5. A pharmaceutical composition comprising at least one compound prepared by a method according to claim 1 or 2 in the form of a single enantiomer, , the racemic mixture, the diastereomers or the pharmaceutically acceptable salts or the mixtures thereof.

6. The pharmaceutical composition according to claim 5 that further comprises components like solid or liquid vehicle substances, dilution agents and pharmaceutical-technical adjuvants corresponding to the desired type of application.

7. The pharmaceutical composition according to claim 5 or 6 that is provided for oral, buccal, sublingual, nasal, rectal, subcutaneous, intravenous or intramuscular application as well as for inhalation, provided as a liposomalP9599PC00formulation, as a spray, in the form of tablets, sucking tablets, film tablets, dragees, capsules, pills, powders, solutions, aerosols or suspensions or slow-release forms.

8. The pharmaceutical composition according to any of claims 5 to 7 for use in the treatment of neurodegenerative disorders (NDDs), namely of disorders of the nervous system characterized by progressive degradation of neuronal structures and their function in the brain and spinal cord, resulting in neuronal damage and death.

9. The pharmaceutical composition according to claim 8, wherein the disorder is selected from Alzheimer's disease, Parkinson's disease and Amyotrophic lateral sclerosis.P9599PC00

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