Reaction SMILES: [Si]([O:8][CH:9]([C:14]1([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:17][CH2:16][CH2:15]1)CCCO)(C(C)(C)C)(C)C.[Si]([O:29]C(C1(CCCC)CCC1)CCC=O)(C(C)(C)C)(C)C.C(Cl)(=O)C(Cl)=O.CS(C)=O.CCN(CC)CC.Cl>CO.C(Cl)Cl.[Pd]>[CH2:18]([C:14]1([C:9]([OH:8])=[O:29])[CH2:17][CH2:16][CH2:15]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC1(C(CCC=O)O[Si](C)(C)C(C)(C)C)CCC1
Reactant: CCCCC1(C(CCCO)O[Si](C)(C)C(C)(C)C)CCC1
Agent: [Pd]
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCC1(C(=O)O)CCC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of lithium di-isopropylamide (100 mL, 2.0 M, 200 mmol) in heptane/tetrahydrofuran/benzene was diluted with 100 mL of anhydrous THF. To the LDA solution at 0° C. was added dropwise 10 g (100 mmol) of cyclobutanecarboxylic acid in 15 mL of anhydrous THF over 20 minutes under Argon. The mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 11.4 mL (100 mmol) of butyl iodide at 0° C. The reaction mixture was warmed to RT and stirred overnight. HCl (2N) was used to adjust the pH to 2˜3. The mixture was extracted with EtOAc (3×200 mL). The combined organic phase was washed with 100 mL of brine, dried (MgSO4) and concentrated. Thus obtained crude product was used directly for next step. Intermediate 15.2: (1-Butylcyclobutyl)methanol. To a solution of lithium aluminum hydride (120 mL, 1.0 M, 150 mmol) in THF was added dropwise at RT a solution of intermediate 15.1 synthesized above in THF (25 mL). The mixture was heated at reflux for 30 minutes, and allowed to cool to it overnight Water was added dropwise at 0° C. until no bubbles corning off. The mixture was filtered through a Celite pad, washed with ether (3×150 mL). The filtrate was concentrated. Flash chromatography of the crude product over silica gel, eluting with EtOAc/hexanes (1:10) afforded 8.83 g (62% 2 steps) of the pure product as a colorless oil. Rf 0.5 (EtOAc/hexanes 1:4). 1HNMR (CDCl3) δ 3.53 (s, 2H), 1.65˜1.90 (m, 4H), 1.40˜1.55 (m, 2H), 1.15˜1.35 (m, 4H), 0.95 (t, J=7.3 Hz, 3H). Intermediate 15.3: 1-butylcyclobutanecarbaldehyde To 31.6 mL of 2.0 M (63.3 mmol) of oxalyl chloride in dichloromethane was added 100 mL of DCM followed by 9.0 mL (126 mmol) of dimethylsulfoxide under Ar at −78° C. The mixture was stirred at −78° C. for 30 min. To this mixture was added 6.00 g (42.2 mmol) of (1-butylcyclobutyl)methanol in 10 mL of DCM. The temperature was allowed to warm to −40° C. over 40 minutes. To this mixture was added 35.3 mL (253 mmol) of Et3N dropwise. After the addition was completed, the temperature was allowed to warm to 0° C. over 1 hr. Water (30 mL) was added to the reaction mixture. The pH of the mixture was adjusted to ˜6 using 2N HCl. After extraction with DCM (2×100 mL), the combined organic phase was combined, washed with brine, dried (Na2SO4). Concentration afforded 6.0 g of the crude product as colorless oil, which was used directly for next step. Intermediate 15.4: 1-(1-Butylcyclobutyl)prop-2-yn-1-ol To 253 mL of 0.5 M (126 mmol) of ethynylmagnesium bromide solution in THF was added 5.92 g (42.2 mmol) of crudel-butylcyclobutanecarbaldehyde synthesized above in 10 mL of THF at −60° C. The reaction mixture was allowed to warm to 0° C. over 1.5 hr. The mixture was cooled again to −60° C., 50 mL of saturated aqueous NH4Cl was added dropwise to quench the reaction. After warmed to rt, the mixture was extracted with EtOAc (3×100 mL). The combined organic phase was washed with 50 mL of brine, dried (MgSO4), concentrated. The crude product (6.26 g) was obtained as colorless oil, which was used directly in the next step. Intermediate 15.5: tert-Butyl(dimethyl){[1-(1-butylcyclobutyl)prop-2-ylnyl]oxy}silane To 6.26 g (37.6 mmol) of crude 1-(1-butylcyclobutyl)prop-2-yn-1-ol in DMF (20 mL) were added imidazole (3.1 g, 45.2 mmol) and tert-butyldimethylsilyl chloride (6.8 g, 45.2 mmol). The reaction mixture was stirred at RT overnight, then concentrated to remove DMF, diluted with 100 ml of EtOAc, and added 100 mL of sat aq. NH4Cl. After separation, the aq. phase was extracted with EtOAc (2×100 mL). The combined organic phase was washed with 50 mL of brine, dried (Na2SO4), concentrated. Flash chromatography over silica gel of the crude product (eluted with hexanes) afforded the title intermediate (6.82 g, 58% 3 steps) as colorless oil. Intermediate 15.6: 4-{[tert-Butyl(dimethyl)silyl]oxy}-4-(1-butylcyclobutyl)but-2-yn-1-ol To a solution of intermediate 15.5 (6.82 g, 24.3 mmol) in THF (150 mL) was added dropwise at −78° C. a solution of n-BuLi in hexanes (18.2 mL, 1.6 M, 29.2 mmol). The mixture was stirred at the same temperature for 40 min, after which of paraformaldehyde (1.82 g, 60.8 mmol) was added in one portion under. After stirring at −78° C. for 10 min., the bath was removed, and the mixture was allowed to warm to RT overnight. Sat. aq. NH4Cl (100 mL) was added, followed by 200 mL of EtOAc. The organic phase was separated and the aq. phase was extracted with 2×100 mL of EtOAc. The combined organic phase was washed with 100 mL of brine, dried (Na2SO4), and concentrated under vacuum. Chromatography (silica gel, 1:15 EtOAc/hexanes) of the crude product afforded the title intermediate (4.15 g, 55%) as colorless oil. Rf 0.3 (1:15 EtOAc/hexanes). 1HNMR (CDCl3) δ 4.29 (s, 2H), 4.24 (s, 1H), 1.95˜2.10 (m, 2H), 1.74˜1.82 (m, 2H), 1.40˜1.70 (m, 4H), 1.20˜1.35 (m, 4H), 0.93 (s, 3H), 0.90 (s, 9H), 0.14 (s, 3H), 0.09 (s, 3H). Intermediate 15.7: 4-{[tert-Butyl(dimethyl)silyl]oxy}-4-(1-butylcyclobutyl)butan-1-ol To a solution of Intermediate 15.6 (2.00 g, 6.44 mmol) in MeOH (100 mL) was added of 10% Pd/C (340 mg, 0.32 mmol). The mixture was subjected to Parr hydrogenation for 2 hr. The reaction mixture was filtered through a celite pad, washed with MeOH, and concentrated in vacuo. The crude product (1.91 g) was used in the next step without further purification. Intermediate 15.8: 4-{[tert-Butyl(dimethyl)silyl]oxy}-4-(1-butylcyclobutyl)butanalde-hyde A solution of oxalyl chloride in dichloromethane (4.6 mL, 2.0 M, 9.2 mmol) cooled at −78° C. was diluted with DCM (12 mL) then a solution of DMSO (1.30 mL, 18.4 mmol) in DCM (5 mL) was added dropwise. The solution was stirred at −78° C. for 30 mm then a solution of intermediate 15.7 (1.91 g, 6.07 mmol) in DCM (2 mL) was added dropwise. The temperature was allowed to warm to −40° C. over 30 minutes. To this mixture was added dropwise Et3N (5.1 mL, 36.4 mmol). After the addition was completed, the temperature was allowed to warm to 0° C. over 1 hr. The pH of the mixture was adjusted to ˜6 using 2N HCl. After extraction with DCM (3×50 mL), the combined organic phase was combined, washed with brine, dried (Na2SO4). Concentration afforded of the crude product, which was subjected to chromatography (silica gel, 1:15 EtOAc/Hexanes). The desired product oil (0.96 g, 48%, 2 steps) was obtained as colorless oil. 1HNMR (CDCl3) δ 9.77 (s, 1H), 3.50˜3.55 (m, 1H), 2.40˜2.50 (m, 1H), 2.08˜2.16 (m, 2H), 1.15˜1.95 (m, 15H), 0.93 (s, 3H), 0.90 (s, 9H), 0.05 (s, 6H). Intermediate 15.9: Methyl(5Z)-7-{(trans-2,3)-1-[4-{[tert-butyl(dimethyl)silyl]oxy}-4-(1-butylcyclobutyl)butyl]-3-chloropyrrolidin-2-yl}hept-5-enoate To a mixture of intermediate 1.9 (100 mg, 0.407 mmol) and intermediate 15.8 (128 mg, 0.407 mmol) in anhydrous MeOH (5 mL) was added dropwise a solution of NaCNBH3 in THF (0.82 mL, 1.0 M) in THF. After 4 hrs at RT, the reaction mixture was concentrated, and diluted with 15 mL of EtOAc, washed with 10 mL of sat. aq. solution NaHCO3. The aq. phase was extracted with 2×10 mL of EtOAc. Combined organic phase was washed with 10 mL of brine, dried (Na2SO4), concentrated. Flash chromatography over silica gel (eluted with 1:15 EtOAc/Hexanes) afforded 30 mg (14%) of the mixed distereomeric products as a colorless oil. Rf 0.37 (1:9 EtOAc/hexanes). MS (m/z) 542.5 (M+1). Intermediate 15.10 and Intermediate 12.11: Methyl(5Z)-7-{(trans-2,3)-3chloro-1-[(4S and 4R)-4-hydroxy-4-(1-butylcyclobutyl)butyl]pyrrolidin-2-yl}hept-5-enoate(1st isomer) To the distereomeric mixtures of intermediate 15.9 (30 mg, 0.06 mmol) was added 2.5 mL of 4.0 M of HCl in dioxane. The reaction mixture was stirred at RT for 2 hr. It was then concentrated, diluted with EtOAc (5 mL), washed with 5 mL of sat aq. NaHCO3. The aq. phase was extracted with 3×5 mL of EtOAc. The combined organic phase was washed with 5 mL of brine, dried (Na2SO4), concentrated. After chromatography, the 1st diastereoisomer (Intermediate 15.10: 4 mg, 16%) 4 mg, 16%)) and 4 mg of the second diastereoisomer (Intermediate 15.11: 4 mg, 16%) were isolated both as colorless oil. Intermediate 15.10:1 HNMR (CDCl3) δ 5.40˜5.55 (m, 2H), 3.67 (s, 3H), 3.45 (broad, 1H), 3.25 (broad, 1H), 2.35˜2.30 (m, 2H), 2.25˜1.50 (m, 21H), 1.20˜1.45 (m, 8H), 0.90˜0.95 (m, 3H). MS (m/z) 428.3. Intermediate 12.11 1HNMR (CDCl3) δ 5.40˜5.55 (m, 2H), 3.67 (s, 3H), 3.45 (broad, 1H), 3.25 (broad, 1H), 2.35˜2.30 (m, 2H), 2.25˜1.50 (m, 21H), 1.20˜1.45 (m, 8H), 0.90˜0.95 (m, 3H). MS (m/z) 428.3.