Design and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1

Spongistatin 1 is among the most potent anti-proliferative agents ever discovered rendering it an attractive candidate for development as a payload for antibody–drug conjugates and other targeted delivery approaches. Unfortunately, it is unavailable from natural sources and its size and complex stereostructure render chemical synthesis highly time- and resource-intensive. As a result, the design and synthesis of more acid-stable and linker functional group-equipped analogs that retain the low picomolar potency of the parent natural product requires more efficient and step-economical synthetic access. Using uniquely enabling direct complex fragment coupling crotyl- and alkallylsilylation reactions, we report a 22-step synthesis of a rationally designed D-ring modified analog of spongistatin 1 that is characterized by GI50 values in the low picomolar range, and a proof-of-concept result that the C(15) acetate may be replaced with linker functional group-bearing esters with only minimal reductions in potency.


Supplementary Figures
The synthesis of aldehyde 14 is described in Supplementary Figure 1. The one pot asymmetric hydroformylation-allylation reaction to produce S1 is modeled after a similar reaction we employed in our synthesis of zincophorin methyl ester. 1

Supplementary Figure 1. Synthesis of aldehyde 14.
The synthesis of silyl enol ether 15 is described in Supplementary Figure 2. The asymmetric alkylation to produce S8 and the reductive auxiliary removal to produce S9 follow the Myers protocol. 2 The Wacker oxidation of S10 to S11 was carried out using Sigman's method.  To a solution of alcohol S9 (37.2 g, 152 mmol) in CH 2 Cl 2 (1.2 L) were sequentially added Et 3 N (32.0 mL, 228 mmol), TBDPSCl (50.4 mL, 193 mmol), and DMAP (3.71 g, 30.4 mmol). The resulting mixture was stirred for 12 h. MeOH (8.0 mL) was added to quench unreacted TBDPSCl and the resulting mixture was concentrated. The residue was resuspended in hexanes and the resulting precipitated Et 3 N•HCl salts were removed by filtration. The filtrate was washed with water (1 x 200 mL) and saturated NH 4 Cl (2 x 150 mL). The aqueous layers were extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give S10 as a pale yellow oil (70.6 g, 146 mmol, 96% yield) which was used without further purification. Purification for a characterization sample was achieved by silica gel column chromatography eluting with 2:98 EtOAc:Hexanes to give pure S10 as a pale yellow oil. Wacker oxidation of alkene S10 was performed using Sigman's protocol. 3 To a suspension of AgSbF 6 (3.35 g, 9.8 mmol) in CH 2 Cl 2 (200 mL) was added Pd(Quinox)Cl 2 (1.47 g, 3.9 mmol). The resulting mixture was stirred for 15 min and then diluted with CH 2 Cl 2 (400 mL). 70% aqueous tert-butyl hydrogenperoxide (340 mL, 2.3 mol) was added and the resulting mixture was stirred for 10 min. The reaction mixture was cooled to 0 °C and alkene S10 (47.1 g, 97.5 mmol) was added, rinsing with minimal CH 2 Cl 2 . The resulting mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was re-cooled to 0 °C and carefully quenched by the slow addition of saturated aqueous Na 2 SO 3 (800 mL). The layers were separated and the aqueous layer was extracted with hexanes (3 x 200 mL). The combined organic layers were washed with H 2 O (1 x 500 mL), dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 3:97  8:92 EtOAc:Hexanes to give S11 as a pale yellow oil (44. 6
Synthesis of aldehyde 9b from 14 and 15 Supplementary Figure 35. Synthesis of 15. To a cooled (-78 °C) solution of iPr 2 NH (99 μL, 0.70 mmol) in THF (3 mL) was added n-BuLi (240 μL, 0.60 mmol, 2.5 M in hexanes). After 5 min the solution was warmed to 0 °C, held at that temperature for 10 min, and then re-cooled to -78 °C. A solution of S11 (250 mg, 0.50 mmol) in THF (1 mL) was added slowly, with a THF rinse (1 mL). After 20 min, TMSCl (102 μL, 0.80 mmol) was added slowly. After 1 h, the mixture was warmed to room temperature and concentrated to give a thick cloudy oil. [CAUTION: over concentration will result in isomerization of the enol ether product]. The residue was resuspended in pentane and the iPr 2 NH•HCl salts were removed by filtration. The filtrate was concentrated to give enol ether 15 as a pale yellow oil that was used immediately in the next step without further purification.

Supplementary Figure 36. Synthesis of 16.
To a cooled (-78 °C) solution of the enol ether 15 and aldehyde 14 (90 mg, 0.35 mmol) in CH 2 Cl 2 (5 mL) was added BF 3 •Et 2 O (51 μL, 0.39 mmol) over 20 min by syringe pump. After 1 h the reaction was quenched by the addition of saturated aqueous NaHCO 3 (2.5 mL). The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (3 x 15 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated. Analysis of the residue by 1 H NMR spectroscopy revealed a 9:1 dr for the reaction. The residue was purified by silica gel column chromatography eluting with 0:100  40:60 EtOAc:Hexanes to give 16 as a colorless oil in 9:1 dr (170 mg, 0.25 mmol, 70% yield).  Figure 42. Synthesis of 9b. To a cooled (-78 °C) solution of alcohol 18 (8 mg, 0.0136 mmol) in CH 2 Cl 2 (200 µL) was added 2,6-lutidine (12 µL, 0.136 mmol) and TESOTf (3.2 µL, 0.014 mmol). After 4h, TMSOTf (6 µL, 0.0325 mmol) was added, and the reaction mixture was warmed to 0 °C. After 3h, the reaction mixture was quenched by the addition of water (150 µL). The mixture was stirred vigorously for 2h, and then the layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (5 x 0.5 mL). The combined organic layers were dried over Na 2 SO4, filtered, and concentrated. The crude product was purified by chromatography with pH 7.0 buffered silica gel eluting with 0:100  15:85 EtOAc:Hexanes to provide aldehyde 9b (8 mg, 0.011 mmol, 82% yield) as a colorless oil.  Figure 44. Synthesis of S12. Alcohol S12 was prepared using a modified literature procdure. 5 To a cooled (0 °C) solution of (S,S)-22 (20.3 g, 70.0 mmol) in CH 2 Cl 2 (250 mL) was added DBU (31.4 mL, 210 mmol). Allyltrichlorosilane (11.2 mL, 77 mmol) was then added slowly. The ice/water bath was removed and after 1 h the mixture was re-cooled to 0 °C. 3-((4-methoxybenzyl)oxy)propanal (13.6 g, 70.0 mmol, prepared as described here 8 ) was added and the resulting mixture was stirred at 0 °C for 1 h. The mixture was concentrated and the residue was suspended in Et 2 O (250 mL). The mixture was stirred vigorously for 20 min to ensure complete precipitation of the DBU•HCl salts. The mixture was then filtered through a frit, and the filtrate was treated with TBAF (70.0 mL, 70.0 mmol, 1 M in THF). After 2.5 h, 1 M HCl (350 mL, 350 mmol) was added and the mixture was transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with Et 2 O (3 x 100 mL). The combined organic layers were washed with H 2 O (2 x 50 mL) and saturated aqueous NaHCO 3 (1 x 100 mL), dried over MgSO 4 , filtered and concentrated. The residue was purified by chromatography on silica gel to provide pure S12 as a pale yellow oil ( 9 The enantiomeric excess was determined by chiral HPLC analysis: OD-H column, 98:2 hexanes:iPrOH, 1 mL/min, 254 nm, where the desired Renantiomer S12 has been established to elute second. 9 To recover (S,S)-22, the combined aqueous layers from above were treated with 3 M NaOH (240 mL) and extracted with CH 2 Cl 2 (5 x 100 mL). The combined organic layers were washed with water (2 x 100 mL), dried over MgSO 4 , filtered, and concentrated. The residue was dissolved in minimal hot 9:1 MeOH:H 2 O (during the dissolution process the temperature should not be allowed to exceed 80 °C, as the ligand may start to undergo decomposition at higher temperatures). The hot saturated solution was allowed to cool to room temperature, and distilled water (10.0 mL) was added to ensure complete crystallization of 22. The white solid was collected by filtration through a frit with a cold 1:1 MeOH:H 2 O rinse and then dried in vacuo at 45 °C to give recovered diaminophenol 22. Figure 45. Synthesis of S13. To a cooled (0 °C) solution of S12 (17.8 g, 75.2 mmol) in CH 2 Cl 2 (225 mL) was added Et 3 N (13.6 mL, 97.7 mmol) followed by the slow addition of TESCl (12.6 mL, 75.2 mmol) and DMAP (0.28 g, 2.2 mmol). The resulting solution was stirred at room temperature for 2 h. MeOH (3.0 mL) was added to quench unreacted TESCl and the resulting mixture was concentrated. The residue was suspended in hexanes and the Et 3 N•HCl salts were removed by filtration. The filtrate was concentrated to give crude S13 as a pale orange oil (26.6 g, 76 mmol), which was used without further purification. To a solution of unpurified S13 (15.5 g, 44.2 mmol) in dioxane:H 2 O (330 mL:110 mL) were sequentially added 2,6-lutidine (6.7 mL, 57.5 mmol), OsO 4 (168 mg, 0.66 mmol), and NaIO 4 (21.7 g, 102 mmol). The resulting reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was cooled to 0 ºC and carefully quenched with saturated aqueous Na 2 S 2 O 3 (250 mL). The layers were separated and the aqueous layer was extracted with Et 2 O (3 x 100 mL). The combined organic layers were dried over MgSO 4 , filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 5:95  15:85 EtOAc:Hexanes to give S14 as a pale yellow oil (13.5 g, 38.3 mmol, 87% yield from S12 over 2 steps).  Figure 48. Synthesis of S15. Diol S14 was prepared using a modified literature procdure. 5 To a cooled (0 °C) solution of (S,S)-22 (8.02 g, 27.6 mmol) in CH 2 Cl 2 (100 mL) was added DBU (12.4 mL, 82.8 mmol). The cis-crotyltrichlorosilane (4.6 mL, 30.4 mmol, prepared as described here 5 ) was then added slowly. The ice/water bath was removed and after 1 h the mixture was re-cooled to 0 °C. Aldehyde S14 (9.13 g, 25.9 mmol) was added and the resulting solution was stirred at 0 °C for 1 h. The mixture was concentrated and the residue was resuspended in Et 2 O (100 mL). The mixture was stirred vigorously for 20 min to ensure complete precipitation of the DBU•HCl salts. The mixture was then filtered through a frit, and the filtrate was treated with TBAF (52.0 mL, 52.0 mmol, 1 M in THF). After 2.5 h, 1 M HCl (140 mL, 140 mmol) was added and the mixture was transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with Et 2 O (3 x 50 mL). The combined organic layers were washed with H 2 O (2 x 25 mL) and saturated aqueous NaHCO 3 (1 x 50 mL), dried over MgSO 4 , filtered, and concentrated. The residue was purified by chromatography on silica gel to provide S15 as a pale yellow oil (7.24 g, 24.6 mmol, 95% yield, 15:1 dr).

3.34
Me OH OH OPMB
Supplementary Figure 50. Synthesis of S16. To a solution of S15 (9.27 g, 31.5 mmol) in dimethoxypropane (210 mL) was added camphor sulfonic acid (0.37 g, 1.6 mmol). The resulting solution was stirred at room temperature for 1 h. Saturated aqueous NaHCO 3 (75 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with H 2 O (1 x 75 mL), dried over Na 2 SO 4 , filtered, and concentrated to give crude S16 as a pale yellow oil (10.4 g, 31.2 mmol) that was used without further purification. Purification for a characterization sample was achieved by silica gel column chromatography eluting with 0:100  10:90 EtOAc:Hexanes to give S16 as a pale yellow oil.  Supplementary Figure 52. Synthesis of S17. To a solution of unpurified PMB ether S16 (4.00 g, 12.0 mmol) in CH 2 Cl 2 (106 mL) was added pH 7 buffer solution (14 mL). The resulting mixture was cooled to 0 °C. DDQ (4.07 g, 17.9 mmol) was added in 3 portions at a rate of 1 portion per 3 min. The resulting mixture was stirred at 0 °C for 5 min and then at room temperature for 1 h. The reaction mixture was filtered through celite, onto pH 7 buffer solution (100 mL), rinsing with CH 2 Cl 2 . The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (3 x 50 mL). The combined organic layers were washed with saturated NaHCO 3 solution (1 x 100 mL) and H 2 O (1 x 100 mL), dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by chromatography with pH 7 buffered silica gel eluting with 10:90  30:70 EtOAc:Hexanes to give S17 as a pale yellow oil (2.46 g, 11.4 mmol, 95% yield from S15 over 2 steps). Supplementary Figure 53. 1 H NMR and 13 C NMR of S17.

OR
Supplementary Figure 54. Synthesis of S18. To a cooled (-78 °C) solution of oxalyl chloride (4.4 mL, 52.4 mmol) in CH 2 Cl 2 (175 mL) was added DMSO (7.4 mL, 105 mmol). After 20 min a solution of S17 (5.61 g, 26.2 mmol) in CH 2 Cl 2 (90 mL) was added slowly. After 20 min Et 3 N (24.5 mL, 175 mmol) was added dropwise, and the mixture was then allowed to warm to room temperature. After 30 min the reaction mixture was quenched with water (100 mL) and the mixture was concentrated to remove the bulk of the CH2Cl2, and the residue was extracted with Et 2 O (3 x 100 mL). The combined ether layers were washed with water (1 x 100 mL), dried over Na 2 SO 4 , filtered, and concentrated to give S18 as a pale yellow oil (5.6 g, 26 mmol) which was used without further purification.
Supplementary Figure 56. Synthesis of 15. To a cooled (-78 °C) solution of i-Pr 2 NH (4.5 mL, 32.1 mmol) in THF (170 mL) was added n-BuLi (11.1 mL, 27.8 mmol, 2.5 M in hexanes). After 5 min the solution was warmed to 0 °C, held at that temperature for 10 min, and then re-cooled to -78 °C. A solution of S11 (10.7 g, 21.4 mmol) in THF (25 mL) was added slowly, with a THF rinse (15 mL). After 20 min TMSCl (4.6 mL, 36.4 mmol) was added slowly. After 1 h the reaction mixture was warmed to room temperature and concentrated to give a thick cloudy oil. [CAUTION: over concentration will result in isomerization of the enol ether product]. The residue was resuspended in pentane and the iPr 2 NH•HCl salts were removed by filtration. The filtrate was concentrated to give the enol ether as a pale yellow oil that was used immediately in the next step without further purification. Figure 57. Synthesis of S19. To a cooled (-78 °C) solution of the enol ether 15 and unpurifed aldehyde S18 (4.13 g, 19.5 mmol) in CH 2 Cl 2 (200 mL) was added BF 3 •Et 2 O (2.52 mL, 20.4 mmol) over 20 min by syringe pump. After 1 h the reaction was quenched by the addition of saturated aqueous NaHCO 3 (100 mL). The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (3 x 50 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated. Analysis of the residue by 1 H NMR spectroscopy revealed a 7:1 dr for the reaction. The residue was purified by silica gel column chromatography eluting with 5:95  20:80 EtOAc:Hexanes to give S19 as a colorless oil (10.8 g, 15.2 mmol, 78% yield from S17 over 2 steps, 7:1 dr). Supplementary Figure 58. 1 H NMR and 13 C NMR of S19.

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Supplementary Figure 59. Synthesis of S20. To a solution of S19 (10.8 g, 15.2 mmol) in CH 2 Cl 2 (150 mL) was added 4 Å MS (11.0 g), proton sponge (32.6 g, 152 mmol) and Me 3 O•BF 4 (18.1 g, 122 mmol). After 5 h the mixture was filtered through celite, with EtOAc rinses. The filtrate was washed with 1 M AcOH (1 x 500 mL) and saturated aqueous NaHCO 3 (1 x 300 mL), dried over MgSO 4 , filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 5:95  20:80 EtOAc:Hexanes to give S20 (7:1 dr) as a colorless oil (10.20 g, 14.1 mmol, 93% yield).  After 20 h additional PPTS (25 mg, 0.1 mmol) was added. After 2 h the reaction mixture was quenched by the addition of saturated aqueous NaHCO 3 (3.0 mL). The mixture was extracted with CH 2 Cl 2 (3 x 2.0 mL). The combined organic layers were dried over MgSO 4 , filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 5:95  20:80 EtOAc:Hexanes. The product S21 was isolated as a colorless oil and was diastereomerically pure (42 mg, 0.075 mmol, 78% yield).  The resulting mixture was warmed to room temperature and stirred 15 h. Excess TESCl was quenched by the addition of MeOH (0.80 mL) and the reaction mixture was concentrated. The residue was resuspended in hexanes and the Et 3 N•HCl salts were removed by filtration. The filtrate was concentrated and the residue purified by silica gel column chromatography eluting with 5:95 EtOAc:Hexanes to give S22 as a colorless oil (  7 mmol) in CH 2 Cl 2 (17 mL) was sparged with O 2 for 5 min. Ozone was then bubbled through the solution until it turned blue (~8 min.). The solution was sparged with O 2 for 5 min resulting in a cloudy white mixture. PPh 3 (0.54 g, 2.1 mmol) was added and the resulting mixture was warmed to room temperature. After 12h, the mixture was concentrated [CAUTION!!!! It is imperative to make sure that the ozonides have been completely reduced before concentration]. The residue was resuspended in hexanes and residual PPh 3 O was removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with 5:95  15:85 EtOAc:Hexanes to give 9a as a colorless oil (1.07 g, 1.6 mmol, 94% yield). To a solution of compound S23 6 (4.89 g, 28.4 mmol) in EtOH (82 mL), was added 2hydroxy-3-methylbenzaldehyde (4.13 mL, 34.1 mmol). After 12 h the mixture was concentrated and the residue was recrystallized from minimal boiling EtOH to give imine S24 as yellow crystals (6.70 g, 23.0 mmol, 81% yield).  Figure 69. Synthesis of (R,R)-24. A 500 mL roundbottom flask equipped with an addition funnel was charged with LiAlH 4 (4.10 g, 108 mmol) and THF (110 mL) and the resulting mixture was cooled to 0 °C. A solution of S24 (6.70 g, 27.0 mmol) in THF (110 mL) was added slowly via the addition funnel, with THF rinses (3 x 20.0 mL). The mixture was warmed to room temperature and stirred for 2 h. The addition funnel was replaced with a reflux condenser and the mixture was heated at reflux for 12 h. The mixture was cooled to 0 °C, and the reaction was quenched by the slow sequential addition of water (4.1 mL), 15% aq. NaOH (4.1 mL) and water (12.3 mL). The resulting mixture was stirred for 10 min at room temperature. The mixture was dried by stirring with excess MgSO 4 for an additional 20 min. The fine white solids were removed filtration and the filtrate was concentrated. The resulting beige solid was purified by recrystallization from minimal boiling hexanes to give diaminophenol (R,R)-24 as colorless crystals (6.  A 100 mL-capacity, septum-adapted pressure tube was charged with Pd(PPh 3 ) 4 (24 mg, 0.02 mmol), evacuated, and then back-filled with N 2 . A solution of diene 12 10 (1.19 g, 2.1 mmol) in benzene (24 mL) was added followed by trichlorosilane (0.43 mL, 4.2 mmol) and the tube was tightly sealed. The tube was heated with an oil bath set at 70 °C. After 15 h the oil bath was removed and the sealed tube was allowed to cool to room temperature. The resulting light brown solution was transferred by cannula into a 250 mL round bottom flask, rinsing with benzene (3 x 5 mL). The flask was attached to a vacuum line equipped with a manometer and a -78 °C cold finger, and then placed in a warm (~35 °C) water bath. All volatiles were evaporated by application of vacuum until a viscous oil remained.

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The residue was dissolved in CH 2 Cl 2 (21.0 mL) and (R,R)-19 11 (1.11 g, 2.11 mmol) was added. The resulting white slurry was cooled to 0 °C and DBU (1.26 mL, 8.4 mmol) was added over 10 min. After 5 min, the mixture was warmed to room temperature. After 2 h, the flask was attached to a vacuum line equipped with a manometer and a -78 °C coldfinger, and then placed in a room temperature water bath. All volatiles were removed by careful application of vacuum, and the residue was treated with Et 2 O (25.0 mL). The mixture was stirred vigorously for 3 h during which time to precipitate the DBU•HCl. The DBU•HCl salts were removed by syringe transfer on to an oven-dried, air-free filter frit and filtering into a 250 mL round bottom flask. The residual DBU•HCl salts were rinsed with Et 2 O (3 x 5.0 mL) and the resulting supernatants were again filtered through the air-free frit into the flask. The flask was attached to a vacuum line equipped with a manometer and a -78 °C coldfinger, and then placed in a room temperature water bath. All volatiles were removed by careful application of vacuum until the resulting yellow oil became opaque and foamy. The residue was dissolved in CH 2 Cl 2 (11.0 mL) and used without further purification.
To the above solution (cooled to 0 °C) was added aldehyde 9a (1.06 g, 1.58 mmol) as a solution in CH 2 Cl 2 (5.0 mL) rinsing with CH 2 Cl 2 (2 x 2.5 mL). Sc(OTf) 3 (78 mg, 0.16 mmol) was added in one portion. The N 2 inlet was removed and the septum was parafilmed. The reaction solution was stirred for 15 h during which time the ice/water bath was allowed to warm to room temperature. The reaction mixture was re-cooled to 0 ºC and TBAF•3H 2 O (0.50 g, 1.6 mmol) was added. After 45 min the mixture was concentrated. Analysis of the residue by 1 H NMR spectroscopy revealed that the product was formed with > 15:1 diastereoselectivity. The residue was purified by silica gel column chromatography eluting with 5:95  100:0 EtOAc:Hexanes to give pure 21 as a beige foam (1.50 g, 1.21 mmol, 57% from 12, 77% from 9a).  To a solution of diene 12 (838 mg, 1.49 mmol) in C 6 H 6 (15 mL) in a 100 mL-capacity, septum-adapted pressure tube was added Pd(PPh 3 ) 4 (34 mg, 0.029 mmol). The tube was evacuated and back-filled with N 2 (3x). HSiCl 3 (0.40 mL, 3.0 mmol) was added and the reaction vessel was sealed with a teflon lined screw cap and heated at 80 °C for 12 h. The reaction mixture was cooled to room temperature. The reaction vessel was attached to a vacuum line equipped with a manometer and a -78 °C cold finger, and then placed in a warm (~35 °C) water bath. All volatiles were evaporated by application of vacuum until a viscous oil remained.
The resulting hydrosilylated product was dissolved in CH 2 Cl 2 (11.0 mL) and the solution was cooled to 0 °C. A solution of diaminophenol (R,R)-24 (351 mg, 1.41 mmol) and DBU (0.63 mL, 4.2 mmol) in CH 2 Cl 2 (2.0 mL) was added, rinsing with CH 2 Cl 2 (2 x 1 mL). The mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was cooled back to 0 °C and aldehyde 9b (850 mg, 1.27 mmol) was added as a solution in CH 2 Cl 2 (2.0 mL), rinsing with CH 2 Cl 2 (3 x 0.5 mL). The N 2 inlet was removed and the septum was parafilmed. The mixture was stirred for 12 h during which time the ice/water bath was allowed to warm to room temperature. The reaction mixture was cooled to 0 °C and treated with TBAF•3H 2 O (400 mg, 1.3 mmol). After 1.5 h the reaction mixture was filtered through a plug of silica gel, rinsing with EtOAc. The filtrate was concentrated, and analysis of the residue by 1 H NMR spectroscopy revealed that the product was formed with ≥20:1 diastereoselectivity. The residue was purified by silica gel column chromatography eluting with 0:100  60:40 EtOAc:Hexanes to give 25 as a beige foam (1.27 g, 1.03 mmol, ≥20:1 dr, 69% from 12, 81% from 9b).     1.01 g, 3.7 mmol), and the vial containing the TASF was rinsed with DMF (2.0 mL). After 15 min the reaction mixture was heated to 50 °C (oil bath, external temperature). After 10 h, TLC analysis indicated complete conversion to product. The reaction mixture was cooled to room temperature and the excess TASF was quenched by the addition of pH 7 buffer (8.0 mL). The mixture was extracted with EtOAc (5 x 3 mL) and the combined organic layers were washed with H 2 O (1 x 3 mL), dried over Na 2 SO 4 , filtered, and concentrated. Filtration through a plug of silica gel eluting with 0:100  10:90 MeOH:CH 2 Cl 2 gave a beige foam, which was azeotroped with toluene (4 x) before being used immediately in the next step.

OR
To a solution of this material in CH 2 Cl 2 (3.0 mL) was added Et 3 N (60 μL, 0.43 mmol) and TIPSCl (68 μL, 0.32 mmol). After 20 min saturated aqueous NaHCO 3 (3 mL) was added. The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (3 x 1 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0:100  To a solution of S26 (102 mg, 0.115 mmol) in CH 2 Cl 2 (7.7 mL) was added Dess-Martin periodinane (147 mg, 0.35 mmol). After 1.5 h the reaction mixture was cooled to 0 °C and 10 mL of a 1:1 solution of saturated aqueous NaHCO 3 and saturated aqueous Na 2 S 2 O 3 was added slowly. The mixture was warmed to room temperature and after 30 min the layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (3 x 5.0 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was filtered through a plug of pH 7 buffered silica gel with 0:100  70:30 EtOAc:Hexanes to give a beige foam (88 mg), which was used immediately in the next step without further purification.
To a solution of 61 mg of this product in CH 2 Cl 2 (1.4 mL) was added 2,6-di-tertbutylpyridine (155 μL, 0.69 mmol). The mixture was cooled to -78 °C and TESOTf (78 μL, 0.35 mmol) was added slowly. After 2h, the reaction mixture was quenched by the addition of saturated aqueous NaHCO 3 (3.0 mL) and the mixture was warmed to room temperature over 10 minutes. The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (3 x 2 mL). The combined organic layers were dried over MgSO 4 , filtered, and concentrated. The residue was purified by silica gel column chromatography with pH 7 buffered silica gel eluting with 0:100  60:40 EtOAc:Hexanes to give 6a as a beige foam (58 mg, 0.058 mmol, 72% yield over 2 steps from S26).  To a solution of S27 (3.00 g, 16.3 mmol) in DMF (50 mL) was added NaN 3 (2.11 g, 32.5 mmol). The mixture was heated at 80 °C for 12 h and the cooled to room temperature. Water (30 mL) was added to the reaction vessel and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgSO 4 , filtered, and concentrated. The crude product was purified by silica gel column chromatography eluting with 0:100  70:30 EtOAc:Hexanes to afford the desired product S28 as a pale yellow solid (2.37 g, 79% yield). The 1 H NMR spectroscopic data is in agreement with data reported in literature. To a cooled (-20 °C) solution of 3,3-dimethylglutaric anhydride S29 (5.00 g, 35.0 mmol) in THF (175 mL) was added a LiAlH 4 (0.80 g, 21 mmol) in 3 equal portions in 5 min increments. The reaction mixture was slowly warmed to 0 °C and stirred for 1 h. Excess LiAlH 4 was quenched by the slow addition of 6 M HCl (45.0 mL), and the mixture was warmed to room temperature. After 20 min the mixture was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over MgSO 4 , filtered, and concentrated to provide crude S30, which was used without additional purification. A mixture of lactone S30 (205 mg, 1.6 mmol) and 33% HBr in AcOH (0.46 mL) was stirred at 75 °C for 1 h. Upon cooling to room temperature, MeOH (0.60 mL) was added and the resulting mixture was stirred for 48 h. All volatiles were removed in vacuo and the resulting residue was dissolved in EtOAc (5.0 mL) and washed with saturated NaHCO 3 (3 x 2.0 mL). The organic layer was dried over Mg 2 SO 4 , filtered, and concentrate to afford crude S31 as a colorless oil. NMR analysis of the crude indicated an 85:15 mixture of product S31 to side products (S30 and bromoacid) that was used without further purification.
To a solution of crude S31 in DMF (4 mL) was added NaN 3 (210 mg, 3.2 mmol) and the resulting mixture was stirred at 70 °C for 2 h. The reaction mixture was quenched by the addition of H 2 O (4 mL) and extracted with EtOAc (3 x 2 mL). The combined organic layers were dried over MgSO 4 , filtered, and concentrated to provide the crude product S32, which was used without further purification. To a solution of crude S32 in MeOH (0.4 mL) was added 1 M NaOH (2.4 mL, 2.4 mmol). The resulting reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated in vacuo and the resulting residue was treated with 1 M HCl until pH 1. The product was extracted with EtOAc (3 x 2 mL) and the combined organic layers were dried over MgSO 4 , filtered, and concentrated. The crude product was purified by silica gel column chromatography eluting with 0:100  50:50 EtOAc:Hexanes to afford the desired product S33 as a colorless oil (138 mg, 50% yield over 4 steps). To a cooled (0 °C) solution of alcohol 25 (400 mg, 0.324 mmol) in toluene (6.5 mL) was sequentially added benzoic acid S28 (309 mg, 1.6 mmol), Et 3 N (0.27 mL, 1.9 mmol), DMAP (198 mg, 1.6 mmol), and 2,4,6-trichlorobenzoyl chloride (278 μL, 1.8 mmol). The reaction mixture immediately became thick and cloudy upon addition of the 2,4,6-trichlorobenzoyl chloride. The mixture was warmed to room temperature. After 12 h the reaction mixture was quenched by the addition of saturated aqueous NaHCO 3 (10 mL). The mixture was extracted with EtOAc (3 x 3 mL) and the combined organic layers were dried over MgSO 4 , filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0:100  50:50 EtOAc:Hexanes to afford the desired product S34 as a beige foam (378 mg, 0.268 mmol, 83% yield).  To a solution of S34 (378 mg, 0.268 mmol) in DMF (5.4 mL) was added pH 7 buffer (150 μL) followed by tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) (740 mg, 2.69 mmol). After 23 h the reaction mixture was quenched by the addition of pH 7 buffer (10 mL). The mixture was extracted with EtOAc (5 x 5 mL) and the combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated. Filtration through a plug of silica gel eluting with 0:100  10:90 MeOH:CH 2 Cl 2 gave a beige foam (166 mg), which was used immediately in the next step.

OR
To a solution of this material in CH 2 Cl 2 (3.9 mL) was added Et 3 N (50 μL, 0.36 mmol) and TIPSCl (45 μL, 0.21 mmol). After 45 min the reaction mixture was quenched by the addition of saturated aqueous NaHCO 3 (5 mL). The product was extracted with CH 2 Cl 2 (3 x 2 mL) and the combined organic layers were dried over MgSO 4 , filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0:100  10:90 MeOH:CH 2 Cl 2 to afford the desired product S35 as a beige foam (190 mg, 0.187 mmol, 70% yield over 2 steps from S34).  To a solution of S35 (190 mg, 0.187 mmol) in CH 2 Cl 2 (12 mL) was added Dess-Martin periodinane (229 mg, 0.540 mmol). After 1.5 h the reaction mixture was cooled to 0 °C and 40 mL of a 1:1 solution of saturated aqueous NaHCO 3 and saturated aqueous Na 2 S 2 O 3 was added slowly. The mixture was warmed to room temperature and after 30 min the layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue (189 mg) was used immediately in the next step without further purification.
To a solution of this product (189 mg) in CH 2 Cl 2 (3.7 mL) was added 2,6-di-tertbutylpyridine (356 μL, 1.86 mmol). The mixture was cooled to -78 °C and TESOTf (210 μL, 0.93 mmol) was added dropwise. After 1 h the mixture was warmed to -45 °C. After 1 h excess TESOTf was quenched by the addition of saturated aqueous NaHCO 3 (10 mL). The mixture was warmed to room temperature and extracted with CH 2 Cl 2 (3 x 10 mL). The combined organic layers were washed with saturated CuSO 4 (10 mL), dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by column chromatography using pH 7 buffered silica gel and eluting with 0:100  5:95 acetone:CH 2 Cl 2 to afford the desired product 6b as a beige foam (119 mg, 0.106 mmol, 57% yield over 2 steps from S35).   (167 μL, 1.1 mmol). The reaction mixture immediately became thick and cloudy upon addition of 2,4,6-trichlorobenzoyl chloride. The mixture was warmed to room temperature. After 1.5 h the reaction mixture was quenched by the addition of saturated aqueous NaHCO 3 (10 mL). The mixture was extracted with EtOAc (3 x 3 mL) and the combined organic layers were dried over MgSO 4 , filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0:100  50:50 EtOAc:Hexanes to afford the desired product S36 as a beige foam (439 mg, 0.316 mmol, 98% yield).  To a solution of S36 (439 mg, 0.316 mmol) in DMF (6.3 mL) was added pH 7 buffer (0.17 mL) followed by tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) (0.87 g, 3.2 mmol). After 23 h the reaction mixture was quenched by the addition of pH 7 buffer (10 mL). The mixture was extracted with EtOAc (5 x 5 mL) and the combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated. Filtration through a plug of silica gel eluting with 0:100  10:90 MeOH:CH 2 Cl 2 gave a beige foam (228 mg), which was used immediately in the next step.

OR
To a solution of this material in CH 2 Cl 2 (5.4 mL) was added Et 3 N (70 μL, 0.50 mmol) and TIPSCl (64 μL, 0.30 mmol). After 45 min the reaction mixture was quenched by the addition of saturated aqueous NaHCO 3 (6 mL). The product was extracted with CH 2 Cl 2 (3 x 3 mL) and the combined organic layers were dried over MgSO 4 , filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0:100  6:94 MeOH:CH 2 Cl 2 to afford the desired product S37 as a beige foam (250 mg, 0.251 mmol, 79% yield over 2 steps from S34).  To a solution of S37 (154 mg, 0.154 mmol) in CH 2 Cl 2 (10 mL) was added Dess-Martin periodinane (190 mg, 0.447 mmol). After 1.5 h the reaction mixture was cooled to 0 °C and 35 mL of a 1:1 solution of saturated aqueous NaHCO 3 and saturated aqueous Na 2 S 2 O 3 was added slowly. The mixture was warmed to room temperature and after 30 min the layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue (152 mg) was used immediately in the next step without further purification.

Synthesis of 33
Supplementary Figure 98. Synthesis of 27. To a solution of 3-methyl-1,4-pentadiene 26 (5.62 mL, 45 mmol, 1 equiv) in t-butyl acrylate (135 ml, 0.9 mol, 20 equiv) was added Hoveyda-Grubbs 2nd Generation catalyst (65.6 mg, 0.105 mmol, 0.23 mol %). The flask was fitted with a dry-ice condenser under constant nitrogen flow and the reaction mixture was heated to 50 °C. After 1.5 h, an additional portion of the HG-II catalyst (65.6 mg, 0.105 mmol, 0.23 mol %) was added. After 1.5 h, an additional portion of the HG-II catalyst (65.6 mg, 0.105 mmol, 0.23 mol %) was added. After 2 h, the reaction mixture was cooled to ambient temperature and concentrated. The residue was treated with toluene (100 mL) and the mixture was concentrated. The residue was purified by silica gel flash column chromatography (4% EtOAc/Hexanes) to yield dienoate 27 (7.55 g, 26.7 mmol, 58%) as a pale yellow oil. Dienoate 27 was previously characterized, 13  To a mechanically-stirred solution of K 3 Fe(CN) 6 (148 g, 450 mmol, 6 equiv), K 2 CO 3 (62.1 g, 450 mmol, 6 equiv), NaHCO 3 (37.8 g, 450 mmol, 6 equiv) and CH 3 SO 2 NH 2 (14.3 g, 150 mmol, 2 equiv) in H2 O (750 mL) was added a solution of (DHQD) 2 PHAL (3.00 g, 3.85 mmol, 0.05 equiv) in t-BuOH (500 mL). The mixture was cooled to 0 °C and K 2 OsO 4 •2H 2 O (1.10 g, 3.00 mmol, 0.04 equiv) was added, followed 10 minutes later by a solution of dienoate 27 (21.2 g, 74.9 mmol) in t-BuOH (250 mL). The bright orange suspension was stirred vigorously at 0 °C for 18 h. Solid Na 2 SO 3 (94 g, 749 mmol, 10 equiv) was added and the reaction mixture was stirred for a further 45 min. The layers of the cold reaction mixture were separated, and the aqueous layer was extracted with EtOAc (3 x 150 mL). The combined organic layers were stirred with solid NaCl, the resulting brine layer was removed. The organic phase was washed with additional brine (350 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel flash column chromatography (50% EtOAc/Hexanes) to yield tetraol 28 (16.4 g, 46.7 mmol, 62%) as the major product of a 4.5:1 mixture of diastereomers as a colorless gum that solidified to a colorless solid on standing. This mixture was used as is in the next step, but for the purposes of characterization, an analytically pure sample was obtained by careful flash chromatography. Tetraol 28 was previously characterized, 13  64 mmol) was added. After 18 h 1M NaOH (45 mL) was added and the mixture was stirred for 10 minutes. The reaction mixture was diluted with CH 2 Cl 2 (450 mL) and filtered through Celite. The filtrate was washed with 1M NaOH (2 x 100 mL) and brine (150 mL), dried over Na 2 SO 4 , filtered, and concentrated. Purification of the residue by flash column chromatography (5%  10%  20%  30% EtOAc/Hexanes) on silica gel gave lactone 30 as a pale yellow oil (18.6 g, 36.8 mmol, 62% yield over two steps) as well as a mix of doubly benzylated lactones (1.9 g, 4.58 mmol, 9% yield).   Figure 102. Synthesis of 31. To a solution of lactone 30 (918 mg, 1.82 mmol) in toluene (15 mL) in a sealed-tube pressure apparatus was added Cp 2 TiMe 2 (5.77 g of a 24% w/w solution in toluene, 6.38 mmol) and ethyl pivalate (0.14 mL, 0.91 mmol). The pressure apparatus was sealed and heated at 80 °C (oil bath, external temperature) for 12 h. [CAUTION!!! Always use a blast shield and proper personal protective equipment when running reactions in sealed tubes.] The reaction mixture was cooled to room temperature and hexane (100 mL) was added to precipitate the titanocene oxide byproduct. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated. Purification of the residue by silica gel flash column chromatography 0%  10% EtOAc/Hexanes gave enol ether 31 as a yellow oil (501 mg, 1.00 mmol, 55% yield).

Synthesis of aldehyde 34
A synthesis of aldehyde 34 has been reported by Crimmins. 16 We devised our own route involving crotylation 5 of aldehyde S41 16 as the key step: Supplementary Figure 106. Synthesis of S42. To a cooled (0 °C) solution of (R,R)-22 (25.24 g, 86.90 mmol) in CH 2 Cl 2 (278 mL) was added DBU (39.00 mL, 260.7 mmol), followed by the dropwise addition of cis-crotyl trichlorosilane 5 (14.6 mL, 95.60 mmol). The reaction mixture was warmed to room temperature. After 1 h the reaction mixture was re-cooled to 0 °C and aldehyde S41 16 (15.87 g, 82.60 mmol) was added dropwise. After 3 h the reaction mixture was concentrated, the residue was resuspended in Et 2 O (40 mL), and the resulting mixture was stirred for 1 h to precipitate the DBU•HCl salts. The reaction mixture was filtered, and the filtrate was treated with n-Bu 4 NF (95 mL, 1M in THF). After 2 h 1 M HCl (400 mL) was added and the mixture was extracted with Et 2 O (3 x 400 mL). The combined organic layers were washed with H 2 O (2 x 100 mL) and saturated aqueous NaHCO 3 (100 mL). The organic layer was dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by flash column chromatography (0%  30% EtOAc/Hexanes) on silica gel to give alcohol S42 as a clear oil (16.2 g, 65.3 mmol, 79% yield, 97% ee).
The aqueous layers were combined and treated with 1 M NaOH (400 mL) and the mixture was then extracted with CH 2 Cl 2 (3 x 400 mL). The combined organic layers were washed with H 2 O (100 mL) and brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated to give recovered ligand (R,R)-22 which could be recrystallized according to the literature procedure. 5  To a cooled (-78 °C) solution of methyl ketone 33 (5.23 g, 8.24 mmol) in Et 2 O (33 mL) was added Cy 2 BCl (3.6 mL, 16.48 mmol), followed by Et 3 N (3.42 mL, 24.72 mmol). The reaction mixture was warmed to 0 °C and stirred for 3 h to give an off-white slurry. The mixture was recooled to -78 °C and a solution of aldehyde 34 (9.01 g, 24.72 mmol) in Et 2 O (9 mL) was added. After 4 h the reaction mixture was warmed to -60 °C. After 14 h the reaction mixture was warmed to 0 °C. After 1 h the reaction mixture was quenched by the addition of saturated aqueous NH 4 Cl (150 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated down to a volume of ~100 mL. pH 7 buffered silica gel was added and the yellow mixture was stirred at room temperature for 30 min, then filtered with EtOAc rinses (3 x 100 mL) of the filter cake. The filtrate was concentrated. Purification of the residue by flash column chromatography (5%  20% EtOAc/Hexanes) on pH 7 buffered silica gel gave 35 as a pale yellow oil (6.89 g, 6.88 mmol, 84% yield, 11:1 dr).   Figure 114. Synthesis of 36. To a solution of alcohol 35 (6.89 g, 6.90 mmol) in dry MeOH (138 mL) was added trimethylorthoformate (13.8 mL, 124 mmol) and pyridinium p-toluene sulfonate (PPTS) (607 mg, 2.42 mmol). After 2 h the reaction mixture was quenched by the slow addition of saturated aqueous NaHCO 3 (175 mL) and the mixture was extracted with EtOAc (3 x 125 mL). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered, and concentrated. Purification of the residue by flash column chromatography (10  25% EtOAc/Hexanes with 1% Et 3 N) on silica gel afforded hemiketal 36 as a clear oil (4.47 g, 5.00 mmol, 70% yield).  Figure 118. Synthesis of S44. Lithium di-tert-butylbiphenylide (LiDBB) was prepared as follows: a cooled (0 °C) solution of Li granules (415 mg, 29.61 mmol) and 4,4-di-tert-butyl-biphenyl (7.28 g, 27.33 mmol) in THF (57 mL) was sonicated for 3.5 h, and then used as is.

OR
To a cooled (-78 °C) solution of TBS ether 37 (960 mg, 0.949 mmol) in THF (57 mL) was added the LiDBB solution slowly by syringe. After 2 h the reaction mixture was warmed to -30 °C. After 16 h the reaction mixture was quenched by the addition of saturated aqueous NH 4 Cl (150 mL). The mixture was diluted with ethyl acetate (150 ml) and warmed to room temperature. The layers were separated and the aqueous layer was extracted with ethyl acetate (75 ml) and methylene chloride (2 x 75 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated. Purification of the residue by flash column chromatography (1%  10% MeOH/CH 2 Cl 2 ) on silica gel afforded pentaol S44 as an amorphous white solid (460 mg, 0.819 mmol, 86% yield).  Figure 122. Synthesis of 13. To a solution of diol S45 (392 mg, 0.432 mmol) in CH 2 Cl 2 (9 ml) was added Et 3 N (0.60 ml, 4.32 mmol), PPh 3 (566 mg, 2.16 mmol) and CCl 4 (0.84 ml, 8.64 mmol). After 14 h the reaction mixture was quenched by the addition of saturated aqueous NaHCO 3 (10 mL). The layers were separated and the aqueous layer was extracted with Et 2 O (2 x 7 ml). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated. Purification of the residue by flash column chromatography (0  2% EtOAc/Hexanes with 1% Et 3 N) on silica gel afforded dichloride 13 as a colorless oil (357 mg, 0.379 mmol, 87% yield).  Figure 124. Synthesis of 39.

OR
In an argon-atmosphere glovebox, copper (I) bromide (2.5 mg, 0.017 mmol) was placed in a vial with a stir bar. The vial was capped with a septum and transferred out of the glove box. The vial was charged with CH 2 Cl 2 (0.3 mL) and Et 3 N (13.5 μL, 0.097 mmol, 1.4 equiv) and then cooled to 0 °C. To a cooled (0 °C) solution of dichloride 13 (65 mg, 0.069 mmol) in CH 2 Cl 2 (0.3 mL) in a separate vial under an Ar atmosphere was added 2,6-di-t-butyl pyridine (89.5 μL, 0.414 mmol) and Cl 3 SiH (8.4 μL, 0.083 mmol). This solution was mixed thoroughly by gentle swirling of the vial, and then was added dropwise by syringe to the CuBr/Et 3 N solution with a 0.1 mL CH 2 Cl 2 rinse. After 5 h an additional portion of Cl 3 SiH (1.4 μL, 0.014 mmol) was added dropwise to the reaction vial. After 4 h a pre-prepared solution of (R,R)-24 (17.1 mg, 0.069 mmol), n-Bu 4 NBr (4.5 mg, 0.014 mmol) and DBU (31 μL, 0.207 mmol) in CH 2 Cl 2 (0.2 mL) was then added dropwise by syringe to the reaction mixture with a 0.1 mL CH 2 Cl 2 rinse. After 2 h the reaction mixture was then cooled to -78 ºC and a solution of freshly prepared chlorodiene aldehyde 11 17 (48.3 mg, 0.414 mmol) in CH 2 Cl 2 (0.25 mL) was added dropwise by syringe with a 0.1 mL CH 2 Cl 2 rinse. The reaction mixture was then warmed to -10 °C and maintained at that temperature for 12 h. The reaction mixture was warmed to 0 °C and n-Bu 4 NF3H 2 O (83 μL, 1M in THF) was added. After 2 h, the mixture was then filtered through a plug of pH 7 buffered silica gel with EtOAc washes. The filtrate was concentrated. Purification of the residue by flash column chromatography on pH 7 buffered silica (0%  5% EtOAc/Hexanes) gave allyl chloride 13 as a clear oil ( Figure 126. Synthesis of S46. To a cooled (-78 °C) solution of alcohol 39 (238 mg, 0.23 mmol) in THF (23 mL) was added a pre-prepared solution of 2,6-lutidine (268 μL, 2.30 mmol) and TBSOTf (121 μL, 0.69 mmol) in THF (4.6 mL) slowly by syringe with a 0.5 mL THF rinse. The reaction mixture was warmed to 0 °C. After 3 h the reaction mixture was quenched by the addition of saturated aqueous NaHCO 3 (50 mL) and extracted with Et 2 O (3 x 50 mL). The combined extracts were washed with brine (50 mL), dried over Na 2 SO 4 , filtered, and concentrated. Purification by flash column chromatography (0%  2% EtOAc/Hexanes) on pH 7 buffered silica gel gave TBS ether S46 as a colorless oil (237 mg, 90% yield). To a solution of chloride S46 (235 mg, 0.206 mmol) in MeCN (11.1 mL) and MeOH (1.2 mL) was added i-Pr 2 NEt (72 μL, 0.413 mmol), NaI (458 mg, 3.08 mmol), and PPh 3 (2.16 g, 8.23 mmol). The resulting mixture was heated at reflux for 12 h. The reaction mixture was cooled to room temperature and an additional portion of PPh 3 (1.08 g, 4.12 mmol) was added. The reaction mixture was heated at reflux for 8 h. The reaction mixture was cooled to room temperature and concentrated. The residue was suspended in CH 2 Cl 2 and filtered through a cotton plug, washing with CH 2 Cl 2 . The filtrate was concentrated. Purification of the residue by flash column chromatography (0%  5% MeOH/CH 2 Cl 2 ) on pH 7 buffered silica gel afforded phosphonium salt 7 as a yellow foam (274 mg, 0.184 mmol, 92% yield). Spectroscopic data was consistent with that previously reported for this compound. Synthesis of 5a from 7 and 6a Supplementary Figure 130. Synthesis of 40a. Phosphonium salt 7 (90 mg, 0.060 mmol) was azeotroped with dry benzene (3x) and placed under vacuum for 24 h. Aldehyde 6a (90 mg, 0.090 mmol) was azeotroped with dry benzene (3x) and placed under vacuum for 24 h. The dried Wittig salt was charged with dry 10% HMPA/THF solution (0.63 mL) and cooled to -78 ºC. LiHMDS (66 μL, 0.066 mmol) was added dropwise and the resultant orange solution was stirred 30 min at this temperature. A solution of the dried aldehyde in 10% HMPA/THF (0.45 mL) was added dropwise to the reaction mixture. The yellow solution was allowed to warm to 0 ºC over 1 h and stirred at 0 ºC for 1 h. The reaction was quenched by the addition of a 4:1 mixture of NH 4 Cl (sat. aq.) and Na 2 S 2 O 3 (sat. aq.) (5 mL). Et 2 O (7 mL) was added the layers were separated. The aqueous layer was extracted with Et 2 O (3 x 4 mL) and the combined organic layers were washed with NaHCO 3 (sat. aq) (5 mL) and brine (5 mL), dried over MgSO 4 , filtered and concentrated. Purification by flash column chromatography (10%  40% EtOAc/Hexanes, then 0%  10% MeOH/CH 2 Cl 2 ) on pH 7 buffered silica gel afforded Wittig product 40a as a white solid (75 mg, 0.036 mmol, 60% yield). Supplementary Figure 134. Synthesis of 42a. Seco-acid 41a (40 mg, 0.023 mmol) was dissolved in toluene (2.3 mL) and i-Pr 2 NEt (0.24 mL, 1.38 mmol) and 2,4,6-trichlorobenzoyl chloride (72 μL, 0.46 mmol) were added. This was stirred for 4 h at rt, then diluted with toluene (6.9 mL). The mixture was taken up into a 12 mL gas-tight syringe and added to a 90 ºC solution of DMAP (141 mg, 1.15 mmol) in toluene (34 mL) over 24 h by syringe pump. The vial containing starting material which was sealed and stored at 0 ºC was rinsed with toluene (2.3 mL) and added to the reaction at over 8 h by syringe pump. The starting material vial was rinsed with an additional portion of toluene (2.3 mL) and added to the reaction over 4 h by syringe pump. The reaction mixture was allowed to stir at 90 ºC for 20 h. The reaction mixture was cooled to rt and diluted with Et 2 O (50 mL). This was washed with NaHCO 3 (sat. aq) (50 mL) and brine (50 mL). The combined aqueous layers were extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. Purification by flash column chromatography (10%  40% EtOAc/Hexanes) on silica gel afforded lactone 42a as a white solid (31 mg, 0.0186 mmol, 81% yield).