1.2 [3+2] Annulation Reaction
Scheme 3. 44 Future work towards biselide E
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To complete the total synthesis of biselde E would then involve investigation of the Suzuki-Miyaura coupling reaction between the two fragments, followed by side-chain installation via a Nozaki-Hiyama-Kishi reaction and some protecting group manipulation.
3.7 Summary
In summary, we have developed efficient syntheses towards several fragments of biselide A, which could be used to explore both ring closing metathesis and relay ring closing metathesis to construct the 14-membered macrolactone. The trans-THF ring found in each northern component (3-97 and 3-98) was furnished by using our second generation Co(nmp)2 catalyst in a Mukaiyama oxidative cyclization, while the
chloroalkene moiety was introduced with a chloropalladation reaction. Key steps in the synthesis of the southern fragment 3-107 included a Sharpless asymmetric kinetic resolution, while a diastereoselective aldol reaction was utilized in our studies towards fragment 3-134.
Significant synthetic efforts toward biselide E have also been reported. We have designed an efficient method to access the western fragment using our second generation Co(nmp)2 catalyst in a Mukaiyama oxidative cyclization to furnish the trans-THF ring (3-
185). We have also developed a proficient method to an advanced intermediate of the eastern fragment (3-163) involving a Suzuki coupling reaction as the key step.
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3.8 Experimental
3.8.1 General Considerations
General experimental procedures were the same as provided in Chapter 1.
3.8.2 Experimental Procedures
(Z)-2-Hydroxy-5,5-dimethyl-1-(4-methylpiperazin-1-yl)hex-2- ene-1,4-dione (nmp ligand, 3-15)
A 500-mL round-bottomed one neck flask is charged with N- methylpiperazine (8.90 mL, 80.0 mmol), diluted with 200 mL of CH2Cl2, and cooled to 0
°C. To the cooled solution was added Et3N (11.2 mL, 80.0 mmol). Ethyl oxalyl chloride
(8.90 mL, 80.0 mmol) is added dropwise via syringe over 10 min to the vigorously stirred solution. After the addition, the heterogeneous solution is stirred at room temperature for 16 h, and then poured slowly into a rapidly stirred solution of half saturated sodium bicarbonate (200 mL). The solution is transferred to a 500 mL separatory funnel and the aqueous layer is extracted with CH2Cl2 (2 x 100 mL). The combined organic layers are
washed with 100 mL of brine, dried over anhydrous MgSO4, filtered through a pad of
Celite and concentrated by rotary evaporation (35 °C, 40 mmHg). The residue is then evacuated at 1.5 mmHg for 30 min to afford the title compound as colorless oil (99 % yield, 15.8 g). Rf 0.10 (66% EtOAc/Hex); 1H NMR (400 MHz, CDCl3) δ 4.30 (q, J = 7.2
Hz, 2H), 3.64-3.61 (m, 2H), 3.43-3.41 (m, 2H), 2.42-2.40 (m, 4H), 2.29 (s, 3H), 1.33 (t, J
= 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 162.7, 160.0, 62.0, 54.8, 54.1, 41.9, 41.2,
14.0. IR (neat, cm-1): 2973, 2798, 1646, 1599, 1463, 1293, 1262, 1001, 737. HRMS [m/z+H+] 200.1163 (calcd for C9H16N2O3, 200.1161).
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Ethyl 2-(4-methylpiperazin-1-yl)-2-oxoacetate (3-18)
A 500-mL round-bottomed flask equipped with a 3-cm egg shaped stir bar containing glyoxyalate 3-15 (12.0 g, 60.0 mmol), was diluted with 50.0 mL of THF, pinacolone (7.50 mL, 60.0 mmol) was added and the flask cooled to 0 °C. A separate 500-mL round-bottomed flask was charged with tBuOK (13.4 g, 120 mmol) and diluted with 250 mL of THF. The tBuOK solution was added to the cooled glyoxyalate/pinacolone solution via cannula over 10 min. After the addition, the solution was stirred at room temperature for 16 h. A solution of AcOH in CH2Cl2 (1.00 M, 150
mL, 150 mmol) was added in one portion and the reaction was stirred for an additional 30 min. The reaction mixture was filtered through Celite and concentrated by rotary evaporation (35 °C, 40 mmHg). The residue was then evacuated at 1.5 mmHg for 30 min to afford the title compound as pale yellow oil (90 % yield, 13.7 g). Rf 0.15 (5% MeOH/EtOAc); 1H NMR (400 MHz, CDCl3) δ 5.95 (s, 1H), 3.66-3.58 (m, 4H), 2.46-2.43 (m, 4H), 2.31 (s, 3H), 1.19 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 200.9, 185.3, 163.8, 95.3, 55.1, 54.3, 45.8, 41.6, 27.2. IR (neat, cm-1): 3445, 2965, 2362, 1649, 1560, 1540, 1458, 1108. HRMS [m/z+H+] 254.1644 (calcd for C13H22N2O3, 254.1630). (S,E)-N-(2-Chloroethylidene)-2-methylpropane-2-sulfinamide (3-57) 2-Methyl-2-propanesulfinamide (1.00 g, 8.25 mmol) in 16.5 mL CH2Cl2
was added CuSO4 (8.22 g, 51.5 mmol) followed by chloroacetaldehyde
(777 mg, 9.90 mmol). The solution was allowed to stir for 24 h at RT, and then filtered through a pad of Celite and concentrated under reduced pressure. Purification by flash chromatography on silica gel using EtOAc-hexanes for elution provided the title compound as colorless oil (82% yield, 1.23 g). Rf 0.58 (50% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 8.03 (t, J = 4.5, 1H), 4.31 (d, J = 4.7, 2H), 1.21 (s, 9H); 13C NMR
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(R)-4-Mesitylthiazolidine-2-thione (3-58)
To a solution of 1.34 M mesitylmagnesium bromide in Et2O (25.0 mL, 33.6
mmol) at −78 °C was added imine 3-57 as a solution in 22.0 mL toluene over 45 min. The reaction mixture was then stirred for 3 h at −78 °C, quenched with 4.00 M HCl (16.8 mL, 67.3 mmol), warmed to RT and stirred for 3 h. The organic layer was then extracted with H2O (2 x 30.0 mL), and the combined aqueous
layers were cooled to 0 °C, and 2.00 M NaOH solution was added until pH 11 was achieved. The aqueous layers were then extracted with EtOAc (3 x 50.0 mL), and the combined organic layers were washed with brine, dried (MgSO4), filtered through Celite
and concentrated under reduced pressure. The residue was then dissolved in 33.7 mL of 1.00 M KOH (33.7 mmol), and carbon disulfide (2.03 mL, 33.7 mmol) was added dropwise while stirring. The solution was heated to reflux for 16 h. Upon cooling to RT, 30.0 mL CH2Cl2 was added. The aqueous layer was then extracted with CH2Cl2 (3 x 20.0
mL), and the combined organic layers were washed with brine, dried (MgSO4), filtered
through Celite and concentrated under reduced pressure. Purification by flash chromatography on silica gel using EtOAc-hexanes for elution provided the title compound as a white solid (58% yield over two steps, 925 mg). Rf 0.53 (50% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 7.70 (bs, 1H), 6.86 (s, 2H), 5.82 (t, J =
10.4, 1H), 3.63 (d, J = 3.6, 2H), 2.39 (s, 6H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) 199.3, 138.5, 136.6, 130.7, 129.4, 63.6, 37.5, 20.7, 20.5.
(S)-4-Isopropylthiazolidine-2-thione (3-61)
L-Valinol (16.2 g, 0.16 mol) in 715 mL of 5.00 M KOH (3.57 mol), was added carbon disulfide (76.0 mL, 1.26 mol) dropwise while stirring. The solution was heated to reflux for 3 days. Upon cooling to RT, 300 mL CH2Cl2 was added. The aqueous
layer was then extracted with CH2Cl2 (3 x 100 mL), and the combined organic layers
were washed with brine, dried (MgSO4), filtered through Celite and concentrated under
reduced pressure. Purification by flash chromatography on silica gel using EtOAc- hexanes for elution provided the title compound as a white solid (70% yield, 17.7 g). Rf 0.62 (50% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 8.66 (bs, 1H), 4.07−4.02 (m,
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1H), 3.48−3.43 (m, 1H), 3.28−3.23 (m, 1H), 0.97 (d, J = 7.0 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) 200.5, 69.9, 35.5, 31.7, 18.5, 17.9.
(S)-4-tert-Butylthiazolidine-2-thione (3-62)
The title compound was obtained from L-tert-leucinol using the same procedure that was used to obtain compound 3-61. This procedure provided the title compound as a white solid (68% yield). Rf 0.63 (50% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 7.22 (bs, 1H), 4.00 (t, J = 8.8 Hz, 1H), 3.41 (dd, J = 8.9, 1.6 Hz,
2H), 1.00 (s, 9H); 13C NMR (100 MHz, CDCl3) 201.7, 73.3, 34.5, 34.4, 25.9.
(R)-1-(4-Mesityl-2-thioxothiazolidin-3-yl)ethanone (3-63)
The title compound was obtained from thiazolidin-2-thione 3-58 after an acylation reaction, as described above in the procedure to obtain compound 3-64. This procedure provided the title compound as pale yellow solid (85% yield). Rf 0.73 (50% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 6.84 (s, 2H), 6.34
(t, J = 9.9, 1H), 3.54 (d, J = 11.3, 10.6, 1H), 3.33 (d, J = 11.3, 10.2, 1H), 2.69 (s, 3H) 2.39 (bs, 6H), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3) 201.4, 171.9, 137.8, 132.6, 128.8,
127.2, 67.9, 32.4, 27.7, 20.8.
(S)-1-(4-Isopropyl-2-thioxothiazolidin-3-yl)ethanone (3-64)
Thiazolidin-2-thione 3-61 (4.00 g, 20.2 mmol) dissolved in 100 mL THF at −78 °C was added nBuLi (9.25 mL, 22.2 mmol, 2.40 M in hexanes) and stirred at −78 °C for 30 min. Acetyl chloride (1.58 mL, 22.2 mmol) was added dropwise and the solution was allowed to stir for 1 h at −78 °C, and then at RT for 30 min. The reaction mixture was then quenched with 100 mL half saturated aqueous NH4Cl solution. The solution was allowed to warm to RT and the aqueous layer was then
extracted with EtOAc (3 x 50.0 mL), and the combined organic layers were washed with brine, dried (MgSO4), filtered through Celite and concentrated under reduced pressure.
Purification by flash chromatography on silica gel using EtOAc-hexanes for elution provided the title compound as yellow oil (97% yield, 3.90 g). Rf 0.74 (50% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 8.66 (bs, 1H), 5.15−5.12 (m, 1H), 3.50
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(dd, J = 11.3, 7.8 Hz, 1H), 3.00 (d, J = 11.3 Hz, 1H), 2.76 (s, 3H), 2.36 (dq, J = 13.5, 6.8 Hz, 1H), 1.05 (d, J = 7.0 Hz, 3H), 0.96 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) 203.2, 170.7, 71.3, 30.8, 30.4, 26.9, 19.0, 17.7.
(S)-1-(4-tert-Butyl-2-thioxothiazolidin-3-yl)ethanone (3-65)
The title compound was obtained from thiazolidin-2-thione 3-62 after an acylation reaction, as described above in the procedure to obtain compound 3-64. This procedure provided the title compound as yellow oil (94% yield). Rf 0.75 (50% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 5.30 (d, J = 8.2 Hz, 1H),
3.52 (dd, J = 11.7, 8.2 Hz, 1H), 3.09 (d, J = 11.7 Hz, 1H), 2.77 (s, 3H), 1.02 (s, 9H); 13C NMR (100 MHz, CDCl3) 205.3, 170.3, 72.0, 37.9, 30.4, 26.8.
3-(tert-Butyldimethylsilyloxy)propan-1-ol (3-67a)
To a flask containing dry NaH (1.10 g, 45.9 mmol) and 100 mL THF at 0 °C was added freshly distilled propanediol (3.50 g, 45.9 mmol) dropwise. After stirring for 45 min at RT, TBSCl (6.93 g, 45.9 mmol) was added slowly dropwise and allowed to stir for another 45 min. The solution was quenched with 100 mL 10% aqueous Na2CO3. The
aqueous layer was then extracted with EtOAc (3 x 50.0 mL), and the combined organic layers were washed with brine, dried (MgSO4), and filtered through Celite. The solution
was then concentrated under reduced pressure to give the title compound as colorless oil (100% yield, 8.75 g). Rf 0.50 (40% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 3.86-
3.79 (m, 4H), 2.61−2.59 (m, 1H), 1.77 (quin, J = 5.6 Hz, 2H), 0.89 (s, 9H), 0.07 (s, 6H);
13
C NMR (100 MHz, CDCl3) 62.9, 62.5, 34.2, 25.9, 18.2, −5.5.
3-(tert-Butyldimethylsilyloxy)propanal (3-67)
To a solution of oxalyl chloride (452 μL, 5.25 mmol) in 5.00 mL CH2Cl2
at −78 °C, DMSO (747 μL, 10.5 mmol) as a solution in 3.00 mL CH2Cl2 was added over
10 min. The solution was stirred at −78 °C for 40 min. A solution of alcohol 3-67a (500 mg, 2.63 mmol) in 3.00 mL CH2Cl2 was then added over 15 min, and stirred at −78 °C
for 40 min. After the slow addition of Et3N (2.56 mL, 18.4 mmol) over 15 min, the
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The reaction mixture was diluted with 10.0 mL CH2Cl2 and then poured into a half
saturated solution of NaCl (20.0 mL). The heterogeneous mixture was separated and the aqueous layer was extracted with CH2Cl2 (5 x 10.0 mL). The combined organic layers
were dried (MgSO4) and filtered through Celite. After the solution was concentrated
under reduced pressure, the title compound was isolated as pale yellow oil (96% yield). Rf 0.72 (40% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 9.79 (t, J = 2.2 Hz, 1H),
3.97 (t, J = 6.1 Hz, 1H), 2.59 (td, J = 6.0, 2.2 Hz, 1H), 0.87 (s, 9H), 0.05 (s, 6H); 13C NMR (100 MHz, CDCl3) 202.0, 57.4, 46.6, 25.8, 18.2, -5.5.
(R)-5-(tert-Butyldimethylsilyloxy)-3-hydroxy-1-((S)-4- isopropyl-2-thioxothiazolidin-3-yl)pentan-1-one (3-68)
TiCl4 (148 μL, 1.36 mmol) and NEt(iPr)2 (473 μL, 2.72 mmol)
are added sequentially to a solution of auxilliary 3-64 (254 mg, 1.25 mmol) in 5.00 mL CH2Cl2 at −40 °C. After 1.5 h at −40 °C, the solution was cooled to −78 °C, and the
aldehyde 3-67 (144 mg, 0.76 mmol) is added slowly dropwise. After 10 min at −78 °C, the reaction is quenched with the addition of 5.00 mL 1.00 M NaH2PO4·H2O and the
solution was allowed to warm to RT. The aqueous layer was then extracted with CH2Cl2
(3 x 10.0 mL), and the combined organic layers were washed with brine, dried (MgSO4),
filtered through Celite and concentrated under reduced pressure. Purification by flash chromatography on silica gel using EtOAc-hexanes for elution provided the title compound as pale yellow oil (87% yield, 7:1 dr, 259 mg). Rf 0.53 (66% EtOAc/hexanes).
1 H NMR (400 MHz, CDCl3) 5.16−5.13 (m, 1H), 4.40−4.34 (m, 1H), 3.88−3.77 (m, 2H), 3.53−3.46 (m, 3H), 3.29 (dd, J = 17.6, 8.9 Hz, 1H), 3.00 (d, J = 11.3 Hz, 1H), 2.40−2.32 (m, 1H), 1.80−1.67 (m, 2H), 1.04 (d, J = 6.6 Hz, 3H), 0.96 (d, J = 7.0 Hz, 3H), 0.87 (s, 9H), 0.05 (s, 6H); 13C NMR (100 MHz, CDCl3) 202.9, 172.4, 71.5, 67.3, 61.4, 45.6, 38.1, 30.8, 30.6, 25.9, 19.0, 17.7, −5.5. HRMS [m/z+H+] 392.8066 (calcd for C17H33NO3S2Si, 391.1671).
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(R)-5-(tert-Butyldimethylsilyloxy)-3-hydroxy-N-methoxy-N- methylpentanamide (3-69)
Imidazole (85.0 mg, 1.25 mmol) and N,O- dimethylhydroxylamine hydrochloride salt (49.0 mg, 0.50 mmol) were added sequentially to a stirred solution of alcohol 3-68 (97.0 mg, 0.25 mmol) in 3.00 mL CH2Cl2. The solution was allowed to stir for 20 h and then quenched with 10.0 mL half
saturated aqueous NH4Cl solution. The aqueous layer was then extracted with CH2Cl2 (3
x 10.0 mL), and the combined organic layers were washed with brine, dried (MgSO4),
filtered through Celite and concentrated under reduced pressure. Purification by flash chromatography on silica gel using EtOAc-hexanes for elution provided the title compound as colorless oil (92% yield, 67.0 mg). Rf 0.25 (50% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 4.27−4.20 (m, 1H), 3.95 (d, J = 2.7 Hz, 1H), 3.86−3.77 (m, 2H),
3.68 (s, 3H), 3.18 (s, 3H), 2.66−2.57 (m, 2H), 1.77−1.57 (m, 2H), 0.88 (s, 9H), 0.06 (s, 6H); 13C NMR (100 MHz, CDCl3) 173.4, 66.6, 61.2, 60.8, 38.7, 38.6, 31.8, 25.8, 18.2,
−5.5. HRMS [m/z+H+] 292.1937 (calcd for C13H29NO4Si, 291.1866).
(R)-7-(tert-Butyldimethylsilyloxy)-5-hydroxyhept-1-en-3-one (3-70)
A 1.00 M solution of vinylmagnesium bromide in THF (1.53 mL, 1.53 mmol) was added to a solution of amide 3-69 (147 mg, 0.51 mmol) in 5.00 mL THF at −40 °C. After 4 h at 0 °C, the reaction was quenched with 10.0 mL half saturated aqueous NH4Cl solution.
The aqueous layer was then extracted with EtOAc (3 x 10.0 mL), and the combined organic layers were washed with brine, dried (MgSO4), filtered through Celite and
concentrated under reduced pressure. Purification by flash chromatography on silica gel using EtOAc-hexanes for elution provided the title compound as colorless oil (77% yield, 100 mg). Rf 0.67 (50% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 6.36 (dd, J = 17.6, 10.6 Hz, 1H), 6.36 (dd, J = 17.6, 10.6 Hz, 1H), 6.23 (d, J = 17.6 Hz, 1H), 5.87 (d, J = 10.2 Hz, 1H), 4.35−4.28 (m, 1H), 3.88−3.75 (m, 2H), 3.63 (d, J = 2.7 Hz, 1H), 2.85−2.72 (m, 2H), 1.73−1.58 (m, 2H), 0.88 (s, 9H), 0.06 (s, 6H); 13 C NMR (100 MHz, CDCl3) 200.5, 136.9, 128.9, 67.2, 61.5, 46.3, 38.3, 25.9, 18.3, −5.5. HRMS [m/z+H+]
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(3R,5R)-3-(tert-Butyldimethylsilyloxy)hept-6-ene-1,5-diol (3-71)
(3R,5R)-7-(tert-Butyldimethylsilyloxy)hept-1-ene-3,5-diol (3-72)
Ketone 3-70 (50.0 mg, 0.19 mmol) in 2.00 mL THF and 0.50 mL MeOH was cooled to −78 °C, and Et2B(OMe) (213 μL, 1.00 M in THF, 0.21 mmol) was added. After stirring
for 1 h at −20 °C, the solution was cooled to −78 °C, and NaBH4 (8.00 mg, 0.21 mmol)
was added in portions. After stirring for 3 h at −78 °C, the reaction was quenched with 5.00 mL half saturated aqueous NaHCO3 solution. The solution was allowed to warm to
RT and the aqueous layer was then extracted with EtOAc (3 x 10.0 mL), and the combined organic layers were washed with brine, dried (MgSO4), filtered through Celite
and concentrated under reduced pressure. Purification by flash chromatography on silica gel using EtOAc-hexanes for elution provided the title compound as a white solid (96% yield, 1:1 mixture of isomers, 48.0 mg). Desired isomer (3-72): Rf 0.48 (50% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) 5.82 (ddd, J = 16.9, 10.5, 5.3 Hz, 1H),
5.30 (d, J = 16.9 Hz, 1H), 5.11 (d, J = 10.5 Hz, 1H), 4.44−4.42 (m, 1H), 4.15−4.11 (m, 1H), 3.84−3.80 (m, 1H), 3.75−3.72 (m, 1H), 1.96 (dt, J = 14.0, 2.9 Hz, 1H), 1.72−1.64 (m, 2H), 1.41 (dt, J = 14.1, 11.4 Hz, 1H), 0.89−0.87 (m, 12H), 0.68 (q, J = 8.0 Hz, 1H), 0.05 (s, 6H); 13C NMR (100 MHz, CDCl3) 139.1, 114.5, 114.5, 71.9, 67.9, 58.9, 40.2,
39.1, 25.9, 18.4, 7.8, −5.5. HRMS [m/z+H+] 261.1893 (calcd for C13H28O3Si, 260.1808).
(R)-3-Hydroxy-1-((S)-4-isopropyl-2-thioxothiazolidin-3- yl)hept-6-yn-1-one (3-74)
The title compound was obtained from auxilliary 3-64 and pent- 4-ynal using the aldol reaction conditions described above in the procedure to obtain compound 3-68. This procedure provided the title compound as pale yellow oil (27% yield, 6:1 dr). Rf 0.43 (50% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 5.15 (t, J = 6.6 Hz, 1H), 4.28-4.24 (m, 1H), 3.64 (dd, J = 17.8, 2.5 Hz, 1H),
3.51 (dd, J = 11.5, 8.0 Hz, 1H), 3.15 (dd, J = 17.6, 9.4 Hz, 1H), 3.02 (d, J = 11.7 Hz, 1H), 2.92 (bs, 1H), 2.39−2.30 (m, 3H), 1.95 (t, J = 2.5 Hz, 1H), 1.80−1.66 (m, 2H), 1.05 (d, J
131
83.8, 71.3, 68.9, 68.2, 66.6, 45.3, 34.7, 30.8, 30.6, 14.8. HRMS [m/z+H+] 286.0934 (calcd for C13H19NO2S2, 285.0857).
5-(Trimethylsilyl)pent-4-yn-1-ol (3-76a)
4-Pentyn-1-ol (5.20 g, 56.0 mmol) dissolved in 200 mL THF at 0 °C was added nBuLi (56.0 mL, 123 mmol, 2.19 M in hexanes) over 30 min. The solution was allowed to stir for 3 h at 0 °C, and then TMSCl (15.7 mL, 123 mmol) was added to the reaction mixture dropwise. After stirring for 16 h at RT, 1 M HCl (200 mL, 200 mmol) was added and the solution was allowed to stir at RT for another 16 h. The aqueous layer was then extracted with EtOAc (3 x 50.0 mL), and the combined organic layers were washed with 5 % NaHCO3, brine, dried (MgSO4), filtered through Celite and
concentrated under reduced pressure which provided the title compound as colorless oil (100% yield, 8.75 g). 1H NMR (400 MHz, CDCl3) 3.79−3.73 (m, 2H), 2.34 (t, J = 6.8
Hz, 2H), 1.81−1.73 (m, 2H), 1.55 (bs, 1H), 0.14 (s, 9H); 13
C NMR (100 MHz, CDCl3)
106.6, 85.3, 63.3, 61.9, 31.2, 16.6, 0.1
5-(Trimethylsilyl)pent-4-ynal (3-76)
Alcohol 3-76a (5.00 g, 32.0 mmol) in 200 mL EtOAc was added IBX (17.9 g, 64.0 mmol) and heated to reflux for 3 h. After allowing the solution to cool to room temperature, the solution was filtered through Celite and concentrated under reduced pressure, which provided the title compound as colorless oil (92% yield, 4.50 g). Rf 0.76 (50% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 9.78
(s, 1H) 2.69−2.65 (m, 2H), 2.55−2.51 (m, 2H), 0.13 (s, 9H); 13C NMR (100 MHz, CDCl3) 200.4, 104.7, 42.5, 13.1, 0.0, −3.5.
(R)-3-Hydroxy-1-((S)-4-isopropyl-2-thioxothiazolidin-3- yl)-7-(trimethylsilyl)hept-6-yn-1-one (3-77)
The title compound was obtained from auxilliary 3-64 and aldehyde 3-76 using the aldol reaction conditions described above in the procedure to obtain compound 3-68. This procedure provided the title compound as pale yellow oil (85% yield, 6:1 dr). Rf 0.47 (50% EtOAc/hexanes). 1H
132 NMR (400 MHz, CDCl3) 5.13−5.10 (m, 1H), 4.22−4.18 (m, 1H), 3.58 (dd, J = 17.8, 2.5 Hz, 1H), 3.49 (dd, J = 11.5, 8.0 Hz, 1H), 3.11 (dd, J = 17.8, 9.2 Hz, 1H), 2.99 (d, J = 11.7 Hz, 1H), 2.96 (bs, 1H), 2.37−2.27 (m, 3H), 1.75−1.62 (m, 2H), 1.02 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 7.0 Hz, 3H), 0.09 (s, 9H); 13C NMR (100 MHz, CDCl3) 202.8, 172.6, 106.5, 71.2, 66.8, 45.3, 34.9, 30.7, 30.5, 19.0, 17.7, 16.2, 0.0. HRMS m/z 357.1246 (calcd for C16H27NO2S2Si, 357.1252). (R)-1-((S)-4-tert-Butyl-2-thioxothiazolidin-3-yl)-3- hydroxy-7-(trimethylsilyl)hept-6-yn-1-one (3-78)
The title compound was obtained from auxilliary 3-65 and aldehyde 3-76 using the aldol reaction conditions described above in the procedure to obtain compound 3-68. This procedure provided the title compound as pale yellow oil (86% yield, 10:1 dr). Rf 0.50 (50% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 5.31 (d, J = 8.2 Hz, 1H), 4.23−4.21 (m, 1H), 3.62 (dd, J = 17.6, 2.3 Hz, 1H), 3.54 (dd, J = 11.7, 8.2 Hz, 1H), 3.15 (dd, J = 17.6, 8.9 Hz, 1H), 3.11 (d, J = 11.7 Hz, 1H), 2.97 (d, J = 3.5 Hz, 1H), 2.39 (td, J = 7.2, 2.3 Hz, 1H), 1.76−1.69 (m, 2H), 1.03 (s, 9H), 0.13 (s, 9H); 13 C NMR (100 MHz, CDCl3) 205.1, 172.4, 106.6, 85.1, 72.1, 67.2, 45.0, 37.9, 35.0,
30.6, 26.9, 16.4, 0.1. HRMS m/z 371.1410 (calcd for C17H29NO2S2Si, 371.1409).
(R)-3-Hydroxy-1-((R)-4-mesityl-2-thioxothiazolidin-3-yl)- 7-(trimethylsilyl)hept-6-yn-1-one (3-79)
The title compound was obtained from auxilliary 3-63 and aldehyde 3-76 using the aldol reaction conditions described above in the procedure to obtain compound 3-68. This procedure provided the title compound as pale yellow oil (52% yield, 5:1 dr). Rf 0.69 (50% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 6.90−6.84 (m, 2H), 6.36 (t, J = 9.9 Hz, 1H), 4.00−3.94 (m,
1H), 3.60−3.51 (m, 2H), 3.32 (dd, J = 11.1, 9.6 Hz, 1H), 3.19 (dd, J = 17.4, 2.54 Hz, 1H), 2.94 (bs, 1H), 2.39−2.25 (m, 8H), 2.24 (s, 3H), 1.70−1.59 (m, 2H), 0.11 (s, 9H).
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(S)-1,1,2-Triphenylethane-1,2-diol (3-81)
(S)-Mandelate (37.0 g, 220 mmol) in 200 mL Et2O is added dropwise to a
0 °C solution of phenylmagnesium bromide (300 mL, 880 mmol, 2.93 M in Et2O), such that the temperature stayed below 10 °C. The solution was
stirred for 2 h at 0 °C and then brought to reflux for 3 h. After allowing to stand for 16 h at RT, the solution was poured onto 400 g of ice. Concentrated HCl was then added until the solution reached pH 4 and then stirred at RT for 1 h. The aqueous layers were then extracted with CH2Cl2 (3 x 200 mL), and the combined organic layers
were washed with brine, dried (MgSO4), filtered through Celite and concentrated under
reduced pressure. The yellow solid was then recrystallized from MeOH to give the title compound as a white solid (62% yield, 39.6 g, mp 125 °C). Rf 0.13 (50% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 7.69-7.67 (m, 2H), 7.42−7.38 (m, 2H),
7.32−7.29 (m, 1H), 7.18−7.04 (m, 10H), 5.61 (d, J = 2.34 Hz, 1H), 3.15 (s, 1H), 2.47 (d,
J = 3.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) 145.1, 143.3, 138.8, 128.4, 128.1, 127.7,
127.6, 127.5, 127.4, 126.9, 126.7, 126.2, 80.8, 78.0.
(S)-2-hydroxy-1,2,2-triphenylethyl acetate (3-82)
Diol 3-81 (12.7 g, 43.7 mmol) in 170 mL MeCN was added acetic anhydride (6.69 g, 65.6 mmol) followed by a solution of Sc(OTf)3 (430
mg, 0.87 mmol) in 40 mL MeCN over 30 min. After 4 h of stirring at RT, the precipitate was filtered, washed with 50.0 mL cold MeCN, and dried under reduced pressure to give the title compound as a white solid (77% yield, 11.2 g). Rf 0.45 (50% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 7.56-7.54 (m, 2H),
7.37−7.33 (m, 2H), 7.29−7.27 (m, 1H), 7.17−7.03 (m, 10H), 6.67 (s, 1H), 2.81 (s, 1H), 1.98 (s, 3H); 13C NMR (100 MHz, CDCl3) 169.7, 144.8, 142.7, 135.8, 128.4, 128.3,
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(R)-((S)-2-Hydroxy-1,2,2-triphenylethyl)-3- hydroxy-7-(trimethylsilyl)hept-6-ynoate (3-84) LDA (prepared by adding nBuLi (1.09 mL, 2.29 M in hexanes, 2.50 mmol), dropwise to a solution of
iPr2NH (367 μL, 2.60 mmol) in 5.00 mL THF at −78
°C and allowing the solution to warm to 0 °C) was added to a stirring suspension of auxiliary 3-82 (331 mg, 1.00 mmol) in 9.00 mL THF −78 °C. The reaction mixture was allowed to warm to 0 °C to give a clear solution, which was added to a solution of MgBr2·OEt2 (516 mg, 2.00 mmol) in 15.0 mL Et2O at −78 °C. After 1 h, the reaction
mixture was cooled to −115 °C using a EtOH/liquid N2 bath, and aldehyde 3-76 (247 mg,
1.60 mmol) was slowly added as a solution in 2.00 mL THF. After stirring at −115 °C for 40 min, the reaction was quenched with 30.0 mL half saturated aqueous NH4Cl solution.
The solution was allowed to warm to RT and the aqueous layer was then extracted with EtOAc (3 x 20.0 mL), and the combined organic layers were washed with brine, dried (MgSO4), filtered through Celite and concentrated under reduced pressure. Purification
by flash chromatography on silica gel using EtOAc-hexanes for elution provided the title compound as colorless oil (53% yield, >20:1 dr, 150 mg). Rf 0.61 (50% EtOAc/hexanes).
1 H NMR (400 MHz, CDCl3) 7.59−7.56 (m, 2H), 7.39−7.35 (m, 2H), 7.30−7.26 (m, 1H), 7.20−7.06 (m, 10H), 6.73 (s, 1H), 3.99−3.96 (m, 1H), 2.87 (bs, 1H), 2.44−2.39 (m, 2H), 2.27 (t, J = 7.0 Hz, 2H), 1.55−1.49 (m, 2H), 0.15 (s, 9H); 13C NMR (100 MHz, CDCl3) 171.0, 144.5, 142.4, 135.4, 128.4, 128.4, 128.1, 127.8, 127.6, 127.5, 127.1, 126.2, 126.1, 106.4, 85.3, 80.2, 79.0, 67.0, 41.6, 34.7, 16.2, 0.1. (S)- and (R)-4-Benzyloxazolidin-2-one (3-86)
(S)-4-Benzyloxazolidin-2-one was obtained from (S)-phenylalanine using the procedure described by Evans (70% yield).8 (R)-4- Benzyloxazolidin-2-one was prepared in the same fashion, but starting from (R)- phenylalanine (72% yield). Rf 0.15 (40% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3)
7.35−7.16 (m, 5H), 5.01 (bs, 1H), 4.48 (t, J = 8.4, 1H), 4.17−4.06 (m, 2H), 2.92−2.81 (m, 2H); 13C NMR (100 MHz, CDCl3) 159.4, 136.0, 129.0, 129.0, 127.2, 69.6, 53.8, 41.4.
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(S)- and (R)-4-Benzyl-3-(2-chloroacetyl)oxazolidin- 2-one (3-87)
Oxazolidine-2-one 3-86 (3.54 g, 20.0 mmol) in 300 mL THF at −78 °C was added nBuLi (9.09 mL, 20.0 mmol, 2.20 M in hexanes) and allowed to stir for 15 min. The solution was then allowed to warm to RT and stirred for 2.5 h. After cooling the reaction mixture to −78 °C, chloroacetyl chloride (1.59 mL, 22.0 mmol) was added dropwise, allowed to stir for 15 min and then warmed to RT for 30 min. The reaction mixture was then quenched with 10.0 mL half saturated aqueous NH4Cl solution.
The aqueous layer was then extracted with EtOAc (3 x 10.0 mL), and the combined organic layers were washed with brine, dried (MgSO4), filtered through Celite and
concentrated under reduced pressure. Purification by flash chromatography on silica gel using EtOAc-hexanes for elution provided the title compound as a white solid (90-95% yield, 4.71 g). Rf 0.34 (30% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 7.36−7.19 (m, 5H), 4.74 (s, 2H), 4.72−4.67 (m, 1H), 4.31−4.23 (m, 2H), 3.34 (dd, J = 13.3, 3.1, 1H), 2.81 (dd, J = 13.3, 9.4, 1H); 13C NMR (100 MHz, CDCl3) 166.1, 153.2, 134.7, 129.4, 129.1, 127.6, 67.0, 55.4, 43.8, 37.6. (S)-4-Benzyl-3-((2S,3R)-2-chloro-3-hydroxy-7- (trimethylsilyl)hept-6-ynoyl)oxazolidin-2-one (3-88)
EtN(iPr)2 (776 μL, 4.44 mmol) and Bu2BOTf (3.99 mL, 3.99
mmol, 1.00 M in CH2Cl2) were added sequentially to a stirring solution of auxiliary (S)-
3-87 (845 mg, 3.33 mmol) in 11.0 mL CH2Cl2 (dried and degassed) at −78 °C. After the
solution was allowed to stir at RT for 1.5 h, it was cooled to −78 °C, and aldehyde 3-76 (342 mg, 2.22 mmol) was added dropwise as a solution in 2.00 mL CH2Cl2. The solution
was then allowed to stir for 30 min at −78 °C followed by 2 h at 0 °C. The solution was then washed with 1.00 M NaHSO4 (4.00 mL, 4.00 mmol) and concentrated under
reduced pressure (rotary evaporator followed by 5 min under 0.1 mm Hg vacuum). The resulting residue was dissolved in 25.0 mL MeOH, cooled to 0 °C, and 2.00 mL 30% H2O2 aqueous solution was added and allowed to stir for 1 h. After adding 15.0 mL H2O
and 15.0 mL EtOAc, the aqueous layer was then extracted with EtOAc (3 x 15.0 mL),
8
136
and the combined organic layers were washed with brine, dried (MgSO4), filtered through
Celite and concentrated under reduced pressure. Purification by flash chromatography on silica gel using EtOAc-hexanes for elution provided the title compound as pale yellow oil (78% yield, >20:1 dr, 705 mg). Rf 0.50 (40% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 7.35−7.29 (m, 3H), 7.21 (d, J = 7.0 Hz, 2H), 5.67 (d, J = 2.9 Hz, 1H), 4.74−4.70 (m, 1H), 4.28−4.23 (m, 3H), 3.31 (dd, J = 13.5, 3.5 Hz, 1H), 2.86−2.81 (m, 2H), 2.44−2.41 (m, 2H), 1.94−1.88 (m, 1H), 1.81−1.78 (m, 1H), 1.53 (bs, 1H), 0.13 (s, 9H); 13C NMR (100 MHz, CDCl3) 168.2, 152.5, 134.6, 129.4, 129.0, 127.5, 105.8, 85.5, 70.2, 66.5, 59.4, 55.4, 37.2, 32.7, 16.2, 0.0. HRMS m/z 407.1305 (calcd for C20H26ClNO4Si, 407.1320). (S)-4-Benzyl-3-((R)-3-hydroxy-7-(trimethylsilyl)hept-6- ynoyl)oxazolidin-2-one (3-89)
Alcohol 3-88 (1.62 g, 3.98 mmol) in 35.0 mL reagent grade MeOH was added Zn powder (1.04 g, 15.9 mmol) and solid NH4Cl (850 mg, 15.9 mmol).
After 5 min of stirring at RT, the solution was filtered through Celite and concentrated under reduced pressure. Purification by flash chromatography on silica gel using EtOAc- hexanes for elution provided the title compound as colorless oil (96% yield, 1.42 g). Rf 0.50 (40% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) 7.35−7.19 (m, 5H), 4.73−4.67 (m, 1H), 4.26−4.16 (m, 4H), 3.27 (dd, J = 13.3, 3.5 Hz, 1H), 3.13−3.09 (m, 2H), 2.80 (dd, J = 13.7, 9.4 Hz, 1H), 2.41 (t, J = 7.0 Hz, 2H), 1.83−1.69 (m, 2H), 0.14 (s, 9H); 13C NMR (100 MHz, CDCl3) 172.4, 153.3, 134.9, 129.3, 129.0, 127.3, 106.5, 85.0, 66.6, 66.3, 54.9, 42.5, 37.7, 35.1, 16.2, 0.0. HRMS [m/z+H+] 374.1775 (calcd for C20H27NO4Si, 373.1709).
(R)-3-Hydroxy-N-methoxy-N-methyl-7- (trimethylsilyl)hept-6-ynamide (3-90)
N,O-Dimethylhydroxylamine hydrochloride salt (725 mg, 7.43 mmol) in 40.0 mL THF at 0 °C was added Me3Al (3.71 mL, 7.43 mmol, 2.00 M in
hexanes). After 30 min at 0 °C, the solution was stirred at RT for another 20 min. The mixture was cooled to −15 °C and alcohol 3-89 (923 mg, 2.47 mmol) in 15.0 mL THF
137
was added dropwise and stirred for 4 h at 0 °C. The reaction mixture was then quenched with 50.0 mL 0.50 M HCl. The aqueous layer was then extracted with EtOAc (3 x 25.0 mL), and the combined organic layers were washed with brine, dried (MgSO4), filtered
through Celite and concentrated under reduced pressure. Purification by flash chromatography on silica gel using EtOAc-hexanes for elution provided the title