1.2. Pregunta de investigación
2.3.3. Autoestima
2.3.3.2. Modelos teóricos de la autoestima
Ketal (3.6 g, 20.4 mmol, 1 eq) was dissolved in MeCN (100 mL) and aq. HCl (0.2 N, 0.8 mL, 0.008 eq) was added, immediately turning the solution orange. After 2.5 h TLC indicated complete conversion and solid NaHCO3 (60 mg, 70 mmol, 0.035 eq) was added.
The solution was filtrated and the solvent removed at 50 mbar, giving 2.7 g of crude mixture, which was used for the next step without further purification.
Rf: 0.20 (100 % EtOAc)
HRMS for C6H10O3: [M+Na]+ calcd. 153.0528, found: 153.0523
[α]20 D= +10.6 (c = 1.0, CH2Cl2) 1H NMR (400 MHz, CDCl 3): = 3.88 (q, J = 5 Hz, 1H), 3.78 – 3.68 (m, 2H), 3.67 – 3.58 (m, 1H), 3.25 (m, 1H), 3.13 (bs, 2H), 2.90 (qd, J1 = 5.8 Hz, J2 = 2.8 Hz, 1H), 2.76 (qd, J1 = 5.7 Hz. J2 = 2.8 Hz, 1H), 2.50 (m, 1H) 13C NMR (100 MHz, CDCl 3): = 207.0, 66.1, 65.3, 59.5, 47.2, 30.9
Experimental Section - Monomethoxytrityl Pathway
6.3
Monomethoxytrityl Pathway
6.3.1 Monomethoxytrityl protection (94)
To a solution of crude diol 93 (1.4 g, 11 mmol, 1 eq) in dry DCM (10 mL) was added pyridine (20 mL), MMTrCl (7.1 g, 21 mmol, 1.9 eq) and imidazole (0.08 g, 1 mmol) and the mixture was stirred overnight. The reaction was quenched with sat. aq. NH4Cl and diluted with toluene (150 mL). The organic phase
was separated, washed with sat. aq. Na2CO3 and water, dried with MgSO4 and the solvent was removed
under reduced pressure. The crude product was purified by column chromatography (100 x silica, toluene/diethyl ether: 100/1) to give 3 (5.9 g, 77% over two steps) as a colorless oil.
Rf: 0.29 (hexanes/ethyl acetate: 15/1)
[α]20
D = + 14.8 (c = 1.0, CH2Cl2)
HRMS for C46H42O5: [M+Na]+ calcd. 697.2930, found: 697.2921
1H NMR (400 MHz, CDCl 3): = 7.36 – 7.29 (m, 8H), 7.24 – 7.10 (m, 16H), 6.76 – 6.70 (m, 4H), 3.69 (s, 3H), 3.68 (s, 3H), 3.37 (q, J = 4.7 Hz, 1H), 3.28 (q, J = 4.9 Hz, 1H), 3.20 – 3.11 (m, 3H), 3.01 (qd, J1 = 8.7 Hz, J2 = 2.4 Hz, 1H), 2.79 – 2.65 (m, 2H) 13C NMR (100 MHz, CDCl 3): = 208.8, 158.5, 144.5, 144.4, 144.3, 130.4, 130.3, 128.4, 127.8, 126.9, 113.1, 86.3, 86.2, 65.8, 63.2, 60.7, 55.2, 48.1, 28.4
6.3.2 Triflate Formation (95)
In a Schlenk flask, 0.6 N solution of NaHMDS in toluene (21.2 mmol, 1.6 eq) was diluted with anhydrous THF (70 mL) and cooled to -90 °C. Starting material (8.5 g, 13.1 mmol, 1 eq) dissolved in dry THF (30 mL) was added dropwise over 10 min. After 2.5 h, a solution of NPh(Tf)2 (8.0 g,
22.4 mmol, 1.7 eq) in THF (20 mL) was added fast and the reaction was warmed up to -78 °C. After TLC indicated complete conversion the reaction was warmed up to 0 °C, diluted with toluene (100 mL) and quenched with sat. aq. NaHCO3.
After stirring for 30 min, the organic phase was separated, washed with 3 x sat. aq. NaHCO3, water, and
brine and dried with Na2SO4.The solvent was evaporated in vacuo, giving 11 g of a crude orange oil.
The product was purified by flash column chromatography (50 x silica, toluene/ethyl acetate: 70/1), giving 8.55 g of colorless oil (81 %).
Rf: 0.66 (hexanes/ethyl acetate: 15/1)
HRMS for C47H41F3O7S: [M+Na]+ calcd. 829.2423, found: 829.2415
[α]20 D= +24.5 (c = 1.0, CH2Cl2) 1H NMR (400 MHz, CD 2Cl2): = 7.37 – 7.27 (m, 4H), 7.26 – 7.11 (m, 20H), 6.77 – 6.70 (m, 4H), 5.49 (s, 1H), 3.68 (d, J = 1.6 Hz), 3.26 – 3.00 (m, 4H), 2.96 (t, J = 5.2 Hz, 1H), 2.59 (t, J = 5.4 Hz, 1H) 13C NMR (100 MHz, CD 2Cl2): = 158.6, 144.4, 128.9, 128.1, 127.8, 119.1, 118.5, 86.6, 64.6, 40.9
Experimental Section - Monomethoxytrityl Pathway
6.3.3 Stille Reaction (97)
In a Schlenk flask, triflate 95 (3.0 g, 3.72 mmol, 1 eq) and stannane ( g, 4.82 mmol, 1.3 eq) were dissolved in degassed DMF (15 mL). Against a counterflow of argon, Pd(PPh3)4 (82 mg, 0.19 mmol,
0.05 eq), CuTCA (1.5 g, 7.44 mmol, 2 eq) and DIPEA (11.4 mL, 65 mmol, 17 eq) were added in one batch and the reaction was stirred vigorously for 1 h. When TLC indicated complete conversion of 1, the reaction was quenched with a mix of sat. aq. Na2CO3 (20 mL) and TMEDA (20 mL) and stirred for
15 min.
The mixture was diluted with toluene (150 mL) and washed with sat. aq. NH4Cl (6x 15 mL) until no
significant discoloration was observed in the aqueous phase and then washed with sat aq. NaHCO3 and
brine. The combined aqueous phases were reextracted with toluene (2x 200 mL) and the resulting organic phases washed again with NH4Cl, NaHCO3 and brine. The combined organic phases were dried
over Na2SO4 and the solvents removed in high vacuum, yielding 3 g of a brown oil which was used for
the next step without further purification.
Rf: 0.50 (Tol/Et2O : 20/1)
HRMS for C52H46O7: [M+Na]+ calcd. 805.3142, found: 805.3138
[α]20 D= +27.2 (c = 1.0, CH2Cl2) 1H NMR (400 MHz, CD 2Cl2): = 7.38 – 7.07 (m, 24H), 6.77 – 6.70 (m, 4H), 6.68 – 6.63 (m, 2H), 5.47 (s, 1H), 3.72 – 3.64 (m, 9H), 3.27 – 3.02 (m, 4H), 2.96 (t, J = 5 Hz, 1H), 2.69 – 2.58 (m, 1H) 13C NMR (100 MHz, CD 2Cl2): = 158.6, 144.4, 141.1, 136.0, 135.0, 133.5, 131.0, 130.3, 129.2, 128.3, 127.9, 127.3, 126.9, 117.3, 113.1, 86.3, 64.6, 61.7, 58.7, 55.2, 50.7, 38.8, 35.7
6.3.4 DIBAL-H Reduction (98)
In a Schlenk flask, ester 97 (2.2 g, 2.84 mmol, 1 eq) was dissolved in anhydrous toluene (50 mL) and cooled to -80 °C. DIBAL – H (1 N in hexanes, 8.5 mL, 8.5 mmol, 3 eq) was added dropwise to the dark red solution and stirring was continued for 2 h. After TLC showed complete consumption of the starting material, MeOH (2 mL) and sat. aq. NaK tartrate (10 mL) were added and the mixture was warmed to ambient temperature.
More toluene was added (50 mL), the phases were separated and the organic phase was washed with sat. aq. NaHCO3, H2O and brine. The aqueous phase was reextracted with toluene (2 x 50 mL), the
combined organic phases were dried over Na2SO4 and the solvent was evaporated in vacuo, giving 2.4
g of a biphasic dark brown mixture.
The crude mixture was washed with n-Hexane (2x 30 mL) to remove residual furanyl stannane, yielding 1.9 g of a dark brown oil, which was used for the next step without further purification.
Rf: 0.53 (hexanes/ethyl acetate: 1/1) HRMS not found [α]20 D= +33.6 (c = 1.0, CH2Cl2) 1H NMR (400 MHz, CDCl 3): = 7.36 (d, J = 7.6 Hz, 4H), 7.31 (t, J = 6.6 Hz, 4H) 7.25 – 7.10 (m, 17H), 6.70 (dd, J1 = 12.8 Hz, J2 = 8.8 Hz, 4H), 6.35 (d, J = 1.6 Hz, 1H), 6.13 (s, 1H), 4.40 (q, J = 9.6 Hz, 2H), 3.69 (s, 3H), 3.68 (s, 3H), 3.37 (q, J = 4.4 Hz, 1H), 3.26 – 3.20 (m, 1H), 3.16 (d, J = 6.3 Hz, 1H), 3.03 – 2.94 (m, 2H) 13C NMR (100 MHz, CDCl 3): = 158.5, 146.3, 144.8, 144.7, 136.8, 136.1, 130.4, 129.2, 138.5, 127.7, 126.8, 122.3, 113.0, 111.9, 86.0, 66.1, 63.9, 56.4, 55.2, 46.8, 45.6,
Experimental Section - Monomethoxytrityl Pathway
6.3.5 TIPS Protection (99)
In a Schlenk flask, alcohol 98 (2.5 g, 3.3 mmol, 1 eq) was dissolved in anhydrous DMF (6 mL). Imidazole (676 mg, 9.9 mmol, 3 eq) and TIPSCl (0.84 mL, 4.0 mmol, 1.2 eq) were added at once and the reaction mixture was stirred for 3 h. After TLC indicated complete conversion, the reaction was diluted with toluene (50 mL) and stirred with sat. aq. NaHCO3 (10 mL) overnight.
The phases were separated and the organic phase was washed with H2O (6x) and brine. The aqueous
phase was reextracted with toluene and the reextracted organic phase washed with H2O (3x) and brine.
The combined organic phases were dried over Na2SO4 and the solvents were evaporated in vacuo,
yielding 4.5 g of crude product.
The product was purified by DCVC (50 x silica, hexanes/ethyl acetate: 20/1), to give 1.7 g of a colorless oil (56 % over three steps).
Rf: 0.64 (hexanes/ethyl acetate: 3/1)
HRMS for C60H66O6Si: [M+Na]+ calcd. 933.4527, found: 933.4520
[α]20 D= +31.3 (c = 1.0, CH2Cl2) 1H NMR (400 MHz, CDCl 3): = 7.36 – 7.29 (m, 8H) 7.25 – 7.10 (m, 17H), 6.70 (dd, J1 = 12.8 Hz, J2 = 8.8 Hz, 4H), 6.40 (s, 1H), 5.98 (s, 1H), 4.56 (q, J = 13.2 Hz, 2H), 3.68 (s, 3H), 3.67 (s, 3H), 3.34 (q, J = 4.2 Hz, 1H), 3.21 (dd, J1 = 9.2 Hz, J2 = 6.4 Hz, 1H), 3.14 (d, J = 6.8 Hz, 2H), 3.02 – 2.94 (m, 2H), 0.98 – 0.93 (m, 21H) 13C NMR (100 MHz, CDCl 3): = 158.4, 144.9, 140.1, 137.2, 136.1, 130.4, 128.5, 128.0, 127.7, 126.7, 126.6, 124.1, 113.0, 112.9, 111.7, 85.9, 85.7, 66.6, 66.3, 64.0, 57.5, 56.8, 55.2, 47.0, 45.4, 18.1, 17.9, 17.8, 12.0
6.3.6 Hydroboration - Oxidation (99 / 100)
In a Schlenk flask, cyclobutene 98 (1260 mg, 1.41 mmol, 1 eq) was dissolved in anhydrous THF (16 mL). Borane tetrahydrofuran complex (1 N in THF, 2 mL, 2 mmol, 1.4 eq) was added dropwise and the mixture stirred until TLC indicated 90 % consumption of the starting material (5.5 h).
The boranes were oxidized by adding sat. aq. K2CO3 (2 mL) and 35 % aq. H2O2 (2 mL) and stirring for
30 min. The mixture was quenched by cooling to 0° C, adding sat. aq. Na2S2O3 (6 mL, exothermic!) and
stirring for 15 min. Toluene (100 mL) and solid NaCl were added and the phases were separated. The organic phase was washed with sat. aq. NaHCO3, H2O and brine and dried over Na2SO4. Solvents were
evaporated under reduced pressure to give 1.65 g of crude Product.
Purification was performed by flash chromatography over the 100-fold amount of silica and a gradient of hexanes/ethyl acetate (product at 20-30 % EE), to give 740 mg of a colorless oil (57 %, isomers not separated).
Rf: 0.54 (hexanes/ethyl acetate: 3/1)
HRMS for C60H68O7Si: [M+Na]+ calcd. 951.4632, found: 951.4627
Experimental Section - Monomethoxytrityl Pathway
6.3.7 Dess-Martin Oxidation
In a round bottom flask, DMP (285 mg, 6.7 mmol, 1.25 eq) and NaHCO3 (550 mg) were suspended in
DCM (10 mL) and a drop of water was added. After stirring vigorously for 15 min, a solution of cyclobutanol(500 mg, 5.4 mmol, 1 eq) in 5 mL of DCM was added. Stirring was continued until TLC indicated complete conversion (30 min) and the whole mixture was filtered over silica (7.5 g, 100 % DCM). After solvent evaporation, ketones were isolated as a colorless oil (450 mg, 90 %).
Rf: 0.60 (PE/EE : 3/1)
HRMS for C60H66O7Si: [M+Na]+ calcd. 949.4476, found: 949.4469
6.3.8 Equilibration (101)
In a round bottom flask, ketones (400 mg, 0.43 mmol, 1 eq) were dissolved in a degassed mixture of MeOH (20 mL) and MeCN (4 mL). To the slightly yellow solution, K2CO3 (50 mg) was added,
immediately giving a strong yellow color. After 60 min, the reaction was quenched with sat. aq. NH4Cl
until a precipitate formed. The mixture was diluted with EtOAc (150 mL), washed with brine (2x) and dried over Na2SO4. After evaporation, 380 mg of a yellow resin were isolated, which was used for the
next step without further purification.
Rf: 0.60 (PE/EE : 3/1)
HRMS for C60H66O7Si: [M+Na]+ calcd. 949.4476, found: 949.4469
1H NMR (400 MHz, CD 2Cl2): = 7.37 (d, J = 7.6 Hz, 4H), 7.29 – 7.08 (m, 21H), 6.70 (dd, J1 = 11.8 Hz, J2 = 8.8 Hz, 4H), 6.33 (d, J = 1.6 Hz, 1H), 4.49 (d, J = 2.8 Hz, 2H), 4.33 (d, J = 8.8 Hz, 1H) 3.68 (d, J = 2.8 Hz, 1H), 3.41 – 3.10 (m, 6H), 0.95 (s, 21H) 13C NMR (100 MHz, CDCl 3): = 204.4, 158.5, 144.4, 144.0, 135.6, 135.5, 130.4, 130.2, 128.5, 128.3, 127.8, 126.9, 126.8, 122.3, 113.1, 110.9, 86.4, 86.3, 64.7, 60.3, 60.0, 57.4, 56.9, 34.7, 28.9, 27.2, 18.0, 12.0,
Experimental Section - Monomethoxytrityl Pathway
6.3.9 Stereoselective Reduction (102)
In a Schlenk flask, LiAlH4 (12 mg, 0.32 mmol, 2 eq) was suspended in anhydrous THF (0.6 mL). The
grey suspension was cooled to -80 °C and ketone 101 (150 mg, 0.16 mmol, 1eq) in THF (2 mL) was added dropwise. TLC showed complete conversion after 2 h and the reaction was quenched with MeOH (0.3 mL). Saturated aqueous solutions of NaK tartrate (1 mL) and NaHCO3 (0.3 mL) were added, the
mixture was diluted with toluene (10 mL), warmed to ambient temperature, and stirred overnight. The phases were separated and the organic fraction washed with sat. aq. NaHCO3 and brine. The
volatiles were removed in vacuo, to give 140 mg of crude product.
Purification was performed by flash column chromatography (hexanes/ethyl acetate: 10 / 1) and yielded 112 mg (75 %) of a slightly yellow resin.
Rf: 0.54 (hexanes/ethyl acetate: 3/1)
HRMS for C60H68O7Si: [M+Na]+ calcd. 951.4632, found: 951.4627
[α]20 D= -8.1 (c = 1.0, CH2Cl2) 1H NMR (400 MHz, CD 2Cl2): = 7.37 (d, J = 6.1 Hz, 4H), 7.30 – 7.05 (m, 21H), 6.69 (t, J = 8.6 Hz, 4H), 6.30, (s, 1H), 4.48 (s, 2H), 3.68 (s, 6H), 3.40 (m, 2H), 3.24 – 3.05 (m, 4H), 2.88 (d, J = 2 Hz, 1H), 2.49 (m, 1H), 0.97 (s, 21H) 13C NMR (100 MHz, CD 2Cl2): = 158.4, 149.2, 144.7, 141.3, 136.3, 130.3, 129.3, 128.5, 127.7, 127.2, 126.7, 113.2, 113.0, 111.4, 70.4, 65.5, 61.8, 57.3, 55.2, 41.3, 39.8, 39.3, 18.0, 12.0
6.3.10
MMTr Deprotection (104)
In a round bottom flask, alcohol 102 (50 mg, 0.054 mmol, 1eq) was suspended in MeOH (2 mL) and THF (30 drops) was added dropwise until a homogenous solution was achieved. Solid para- toluenesulfonic acid (1 mg) and a drop of water were added and the reaction was stirred for 20 min, quenched with NaHCO3 and filtered over silica (chloroform/ethyl acetate/methanol: 47/47/6).
Rf: 0.30 (chloroform/ethyl acetate/methanol: 47/47/6)
HRMS for C20H36O5Si: [M+Na]+ calcd. 407.2230, found: 407.2222
1H NMR (400 MHz, CD
2Cl2): = 7.04 (s, 1H), 6.24 (s, 1H), 4.40 (m, 2H), 3.84 (m, 2H), 3.68 (dd, J1 =
Experimental Section - Monomethoxytrityl Pathway
6.3.11
PMB Acetal (105)
In a Schlenk flask, triol 104 (5 mg, 0.013 mmol, 1 eq) was dissolved in dry chloroform (0.5 mL). Anisaldehyde dimethyl acetal (2 drops) and ZnCl2 (0.5 N in dry THF, 40 µL, 1.5 eq) were added and
the mixture was stirred for 1 h.
The reaction mixture was diluted with DCM (10 mL) and washed with sat. aq. NaHCO3 and brine. The
volatiles were removed under high vacuum, to give 3.4 mg of crude product.
Rf: 0.74 (EE)
HRMS for C28H42O6Si: [M+Na]+ calcd. 525.2649, found: 525.2643
1H NMR (400 MHz, C
6D6): = 7.55 (d, J = 6.0 Hz, 2H), 7.14 (s, 1H) 6.80 (d, J = 6.0 Hz, 2H), 6.46 (s,
1H), 5.14 (s, 1H), 4.86 (d, J = 8.4 Hz, 1H), 4.69 (d, J = 8.5 Hz, 1H), 4.44 (t, J = 3.2 Hz, 1H), 3.80 (d, J = 8.1 Hz, 1H), 3.67 (sept, J = 3.2 Hz, 1H), 3.56 (dd, J1 = 8.4 Hz, J2 = 2.8 Hz), 3.47 (q, J = 3.5 Hz), 3.37 (t, J = 3.0 Hz, 1H), 3.26 (s, 3H), 1.11 ppm (s, 21H)
6.4
Trityl Pathway
6.4.1 Trityl Protection
In a Schlenk flask, diol 93 (2.7 g, 20.8 mmol, 1 eq) was dissolved in anhydrous DCM (100 mL). Trityl chloride (12.2 g, 43.6 mmol, 2.1 eq) and dry DIPEA (10.2 mL, 60 mmol, 3 eq) were added at once and the yellow mixture heated to reflux for 24 h.
After TLC indicated complete conversion, the reaction was cooled to ambient temperature and diluted with DCM (200 mL). The organic phase was washed with sat. aq. NaHCO3, H2O, and brine and the
solvent was removed under reduced pressure, giving 15 g of a dark red oil.
The product was purified by MPLC (100x silica, Tol/MTBE: 50/1), giving 7.1 g of yellowish oil (56 % over two steps).
Rf: 0.76 (Tol/Et2O: 20/1)
HRMS for C44H38O3: [M+Na]+ calcd. 637.2719, found: 637.2712
[α]20 D= -16.9 (c = 1.0, CH2Cl2) 1H NMR (400 MHz, CDCl 3): = 7.37 – 7.27 (m, 12H), 7.25 – 7.05 (m, 18H), 3.34 (q, J = 4.5 Hz, 1H), 3.28 (q, J = 4.6 Hz, 1H), 3.15 (m, 3H), 3.01 (m, 1 H), 2.80 – 2.66 (m, 2H) 13C NMR (100 MHz, CDCl 3): = 208.7, 144.3, 144.0, 143.9, 129.1, 128.8, 127.9, 127.1, 125.3, 86.7, 86.5, 65.9, 63.2, 60.8, 48.1, 28.4,
Experimental Section - Trityl Pathway
6.4.2 Triflate Formation (90)
In a Schlenk flask, 0.6 N solution of NaHMDS in toluene (11.72 mmol, 1.5 eq) was diluted with anhydrous THF (40 mL) and cooled to -90 °C. Starting material (4.8 g, 7.81 mmol, 1 eq) dissolved in dry THF (30 mL) was added dropwise over 10 min. After 2.5 h, a small sample was quenched with D2O
and complete deprotonation was confirmed by NMR. A Solution of NPH(Tf)2 (4330 mg, 12.11 mmol,
1.55 eq) in THF (20 mL) was added fast and the reaction was warmed up to -78 °C. After TLC indicated complete conversion
The phases were separated and the organic phase was washed with H2O (6x) and brine. The aqueous
phase was reextracted with toluene and the resulting organic phase washed with H2O (3x) and brine.
The combined organic phases were dried over Na2SO4 and the solvents were evaporated in vacuo,
yielding 4.5 g of crude product.
The product was purified by DCVC (50x silica, hexanes/diethyl ether: 20/1), giving 2.4 g of colorless oil (52 % over three steps).
Rf: 0.75 (hexanes/ethyl acetate: 3/1)
HRMS for C45H37F3O5S: [M+Na]+ calcd. 769.2212, found: 769.2204
[α]20 D= -27.6 (c = 1.0, CH2Cl2) 1H NMR (400 MHz, C 6D6): = 7.37 – 7.26 (m, 12H), 7.25 – 7.11 (m, 18H), 5.49 (s, 1H), 3.21 (m, 2H), 3.13 (m, 1H), 3.04 (m, 1H), 2.95 (t, J = 4.1 Hz, 1H), 2.60 (t, J = 4.2 Hz, 1H) 13C NMR (100 MHz, CDCl 3): = 158.5, 141.1, 130.2, 128.2, 127.8, 126.9, 117.5, 113.0, 86.1, 64.6, 55.1, 50.6, 38.7
6.4.3 Stille Reaction (106)
In a Schlenk flask, triflate 90 (3.8 g, 5.1 mmol, 1 eq) and stannane 89 ( g, 7.63 mmol, 1.5 eq) were dissolved in degassed DMF (20 mL). Against a counterflow of argon, Pd(PPh3)4 (110 mg, 0.25 mmol,
0.05 eq), CuTCA (1.94 g, 10 mmol, 2 eq) and DIPEA (4 mL, 23 mmol, 4.5 eq) were added in one batch and the reaction was stirred vigorously for 1 h. When TLC indicated complete conversion of 1, the reaction was quenched with a mix of sat. aq. Na2CO3 (20 mL) and TMEDA (20 mL) and stirred for 15
min.
The mixture was diluted with toluene (150 mL) and washed with sat. aq. NH4Cl (6x 15 mL) until no
significant discoloration was observed in the aqueous phase and then washed with sat aq. NaHCO3 and
brine. The combined aqueous phases were reextracted with toluene (2x 200 mL) and the resulting organic phases washed again with NH4Cl, NaHCO3 and brine. The combined organic phases were dried
over Na2SO4 and the solvents removed in high vacuum, to give 3 g of a brown oil which was used for
the next step without further purification.
Rf: 0.50 (Tol/Et2O: 20/1)
HRMS for C50H42O5: [M+Na]+ calcd. 745.2930, found: 745.2921
[α]20 D= -29.2 (c = 1.0, CH2Cl2) 1H NMR (400 MHz, C 6D6): = 7.43 – 7.04 (m, 31H), 6.69 (s, 1H), 6.62 (s, 1H), 3.70 (s, 3H), 3.40 (bs, 1H), 3.24 (t, J = 8.4 Hz, 1H), 3.19 (d, J = 8 Hz, 2H), 3.07 (bs, 2H) 13C NMR (100 MHz, C 6D6): = 163.6, 153.1, 144.3, 140.9, 135.5, 128.8, 127.7, 126.8, 114.3, 112.0, 66.0, 63.6, 51.4, 47.0, 45.2
Experimental Section - Trityl Pathway
6.4.4 DIBAL-H Reduction
In a Schlenk flask, crude ester 106 (5 mmol, 1 eq) was dissolved in anhydrous toluene (50 mL) and cooled to -80 °C. DIBAL – H (1 N in hexane, 20 mL, 20 mmol, 4 eq) was added dropwise to the dark- red solution and stirring was continued for 2 h. After TLC showed complete consumption of starting material, MeOH (5 mL) and sat. aq. NaK tartrate (30 mL) were added and the mixture was warmed to ambient temperature.
More toluene was added (150 mL), the phases were separated and the organic phase was washed with sat. aq. NaHCO3, H2O and brine. The aqueous phase was reextracted with toluene (2x 150 mL), the
combined organic phases were dried over Na2SO4 and the solvents were evaporated in vacuo, giving 4.5
g of a biphasic dark brown mixture.
The crude product was washed with n-Hexane (2x 50 mL) yielding 4 g of a dark brown oil, which was used for the next step without further purification.
Rf: 0.21 (hexanes/diethyl ether: 3/1)
HRMS for C49H42O4: [M+Na]+ calcd. 717.2981, found: 717.2972
[α]20 D= -35.0 (c = 1.0, CH2Cl2) 1H NMR (400 MHz, CDCl 3): = 7.36 (d, J = 7.6 Hz, 4H), 7.31 (t, J = 6.6 Hz, 4H) 7.25 – 7.10 (m, 17H), 6.70 (dd, J1 = 12.8 Hz, J2 = 8.8 Hz, 4H), 6.35 (d, J = 1.6 Hz, 1H), 6.13 (s, 1H), 4.40 (q, J = 9.6 Hz, 2H), 3.69 (s, 3H), 3.68 (s, 3H), 3.37 (q, J = 4.4 Hz, 1H), 3.26 – 3.20 (m, 1H), 3.16 (d, J = 6.3 Hz, 1H), 3.03 – 2.94 (m, 2H) 13C NMR (100 MHz, CDCl 3): = 158.5, 146.3, 144.8, 144.7, 136.8, 136.1, 130.4, 129.2, 138.5, 127.7, 126.8, 122.3, 113.0, 111.9, 86.0, 66.1, 63.9, 56.4, 55.2, 46.8, 45.6,
6.4.5 TIPS Protection (107)
In a Schlenk flask, crude alcohol (5.0 mmol, 1 eq) was dissolved in anhydrous DMF (20 mL). Imidazole (1020 mg, 15 mmol, 3 eq) and TIPSCl (1.28 mL, 6 mmol, 1.2 eq) were added at once and the reaction mixture was stirred for 3 h. After TLC indicated complete conversion, the reaction was diluted with toluene and stirred with sat. aq. NaHCO3 (20 mL) overnight.
The phases were separated and the organic phase was washed with H2O (6x) and brine. The aqueous
phase was reextracted with toluene and the resulting organic phase washed with H2O (3x) and brine.
The combined organic phases were dried over Na2SO4 and the solvents were evaporated in vacuo,
yielding 4.5 g of crude product.
The product was purified by DCVC (50x silica, hexanes/diethyl ether: 20/1), giving 2.4 g of a colorless oil (52 % over three steps).
Rf: 0.75 (hexanes/ethyl acetate: 3/1)
HRMS for C58H62O4Si: [M+Na]+ calcd. 873.4315, found: 873.4309
[α]20 D= - 41.0 (c = 1.0, CH2Cl2) 1H NMR (400 MHz, C 6D6): = 7.40 – 7.25 (m, 12H), 7.25 – 7.05 (m, 18H), 6.42 (s, 1H), 6.00 (s, 1H), 4.55 (q, J = 13.1 Hz, 2H), 3.33 (m, 1H), 3.23 – 3.09 (m, 4H), 2.96 (m, 1H), 0.96 (s, 21H) 13C NMR (100 MHz, CDCl 3): = 144.8, 144.4, 141.0, 137.1, 128.7, 128.6, 127.9, 127.6, 126.8, 124.1, 111.7, 86.2, 86.0, 66.3, 64.0, 57.5, 46.9, 45.3, 18.0, 12.0
Experimental Section - Trityl Pathway
6.4.6 Hydroboration – Oxidation (108 + 109)
In a round bottom flask, 107 (2.4 g, 3 mmol, 1 eq) was dissolved in anhydrous THF (60 mL). Borane dimethyl sulfide complex (2N in THF, 3.3 mL, 6.6 mmol, 2.2 eq) was added dropwise and the mixture stirred until TLC indicated 90 % consumption of the starting material (9 h).
The boranes were oxidized by adding sat. aq. K2CO3 and 35 % aq. H2O2 (12 mL) and stirring for 30 min.
The mixture was quenched by cooling to 0° C, adding sat. aq. Na2S2O3 (50 mL, exothermic!) and stirring
for 15 min. Toluene (300 mL) and solid NaCl were added and the phases were separated. The organic phase was washed with sat. aq. NaHCO3, H2O and brine and dried over Na2SO4. Solvents were
evaporated under reduced pressure to give 2.6 g of crude product.
Purification was performed by flash chromatography over the 100-fold amount of silica and a gradient of hexanes/diethyl ether (product at 20-30 % Et2O), giving 1.2 g of a colorless oil (49 %).
Minor Isomer (108) Rf: 0.67 (toluene/diethyl ether: 20/1) [α]20 D= -5.7 (c = 1.0, CH2Cl2) 1H NMR (400 MHz, C 6D6): = 7.50 – 7.31 (m, 6H), 7.31 – 7.05 (m, 24H), 7.03 (s, 1H), 6.23 (s, 1H), 4.57 (q, J = 6.8 Hz, 1H), 4.44 (s, 2H), 3.53 (t, J = 7.6 Hz, 1H), 3.38 (m, 2H), 3.03 (t, J = 8.9 Hz), 2.89 (t, J = 2 Hz, 1H), 2.68 – 2.44 (m, 3H), 0.95 (s, 21H) 13C NMR (100 MHz, C 6D6): = 144.3, 144.0, 140.6, 128.6, 128.5, 128.4, 127.6, 127.1, 126.8, 120.8, 111.0, 87.2, 86.3, 69.8, 64.0, 62.9, 57.3, 42.6, 41.2, 36.7, 17.9, 12.0 Major Isomer (109) Rf: 0.63 (toluene/diethyl ether: 20/1) [α]20 D= +13.7 (c = 1.0, CH2Cl2)
1H NMR (400 MHz, C 6D6): = 7.43 – 7.05 (m, 31H), 6.33 (s, 1H), 4.64 (q, J = 8.5 Hz, 2H), 4.06 (s, 1H), 3.17 – 3.06 (m, 4H), 2.97 (t, J = 7.2 Hz, 1H), 2.34 (bs, 1H), 2.24 (bs, 1H), 2.11 (bs, 1H), 0.96 (s, 21H) 13C NMR (100 MHz, C 6D6): = 150.7, 144.3, 140.5, 120.0, 111.3, 86.2, 71.2, 65.4, 64.0, 57.1, 45.7, 43.7, 34.6, 17.8, 12.0
Experimental Section - Trityl Pathway
6.4.7 IBX Oxidation
In a round bottom flask, the crude mixture of 108 and 109 (740 mg, 0.8 mmol, 1 eq) were dissolved in DMSO (not dry, 10 mL). IBX (740 mg, 2.64 mmol, 3.3 eq) was added in one batch and the mixture was stirred until TLC indicated complete conversion (90 min). The solution was diluted with Et2O (50 mL),
leading to precipitation of IBX as a white solid, and washed with water (3 x 1.5 mL). Then, n-hexane (5 mL) was added, leading to precipitation of more IBX and the solution was washed again with water (3 x 1,5 mL). This process was repeated three times (until no further precipitation of IBX was observed), followed by washing with brine (2 x 2 mL). The organic phase was dried over Na2SO4 and the solvents
were removed under reduced pressure, yielding 750 mg of a colorless viscous oil.
The product was purified by flash chromatography (50 x silica, hexanes/diethyl ether: 10/1), giving 650 mg of a colorless oil (88 %). The product decays rapidly at room temperature to form a yellow oil. The mixture of isomers was not separated, for analytics see chapter 6.4.8.
6.4.8 Equilibration (110)
In a round bottom flask, cyclobutanone (880 mg, 0.95 mmol, 1 eq) was dissolved in DCM (200 mL). The slightly yellow solution was cooled to 0 °C and Et3N (5 mL) was added dropwise. After 75 min, the
reaction was quenched with sat. aq. NH4Cl. The phases were separated and the organic fraction washed
with sat. aq. NaHCO3 and brine. Volatiles were removed in vacuo, yielding 870 mg of crude Product,
which was used for the next step without further purification. The product decays rapidly at room temperature to form a yellow oil.
For analytical purposes, the compound was purified by flash column chromatography (100 x silica, n- hexane/diethyl ether: 5:1)
Rf: 0.60 (hexanes/ethyl acetate: 3/1)
HRMS for C58H62O5Si: [M+Na]+ calcd. 889.4265, found: 889.4258
[α]20 D= -3.2 (c = 1.0, CH2Cl2) 1H NMR (400 MHz, CD 2Cl2): = 7.40 – 7.35 (m, 6H), 7.30 – 7.25 (m, 6H), 7.22 – 7.10 (m, 19H), 6.33 (s, 1H), 4.50 (d, J = 4.0 Hz, 2H), 4.33 (d, J = 8.0 Hz, 1H), 3.42 – 3.10 (m, 6H), 0.96 (s, 21H) 13C NMR (100 MHz, CD 2Cl2): = 149.5, 144.3, 140.8, 128.6, 127.7, 126.9, 120.4, 111.5, 70.1, 65.6, 61.9, 57.2, 41.1, 39.7, 39.3, 29.7, 17.8, 12.0
Experimental Section - Trityl Pathway
6.4.9 Diastereoselective Reduction (111)
In a Schlenk flask, LiAlH4 (60 mg, 1.6 mmol, 1.75 eq) was suspended in anhydrous THF (10 mL). The
grey suspension was cooled to -80 °C and cyclobutanone 110 (830 mg, 0.9 mmol, 1 eq) in THF (10 mL) was added dropwise. TLC showed complete conversion after 2 h and the reaction was quenched with MeOH (1 mL). Saturated aqueous solutions of NaK tartrate (6 mL) and NaHCO3 (1.5 mL) were added,
the mixture was diluted with toluene (30 mL), warmed to ambient temperature, and stirred overnight. The phases were separated and the organic fraction washed with sat. aq. NaHCO3 and brine. The
volatiles were removed in vacuo, yielding 800 mg of crude product.
Purification was performed by DCVC (hexanes/diethyl ether: 10 / 1) and yielded 650 mg (69 %) of a slightly yellow viscous resin.
Rf: 0.50 (PE/EE : 3/1)
HRMS for C58H62O5Si: [M+Na]+ calcd. 891.4421, found: 891.4416
[α]20 D= +1.9 (c = 1.0, CH2Cl2) 1H NMR (400 MHz, CD 2Cl2): = 7.38 – 7.32 (m, 6H), 7.28 – 7.22 (m, 6H), 7.21 – 7.08 (m, 19H), 6.31 (s, 1H), 4.48 (s, 2H), 3.42 (t, J = 8.0 Hz, 1H), 3.32 (t, J = 8.1 Hz, 1H), 3.18 – 3.01 (m, 4H), 2.77 (d, J = 5.2 Hz, 1H), 2.47 (m, 1H), 0.96 (s, 21H) 13C NMR (100 MHz, CD 2Cl2): = 149.5, 144.2, 140.8, 128.6, 127.7, 126.8, 120.4, 111.5, 86.6, 86.2, 70.1, 65.6, 61.9, 57.2, 41.1, 39.7, 39.3, 29.7, 17.8, 12.0