Synthesis of Spirastrellolide A Fragments for Structure Elucidation

Abstract

A stereocontrolled synthesis of two diastereomeric C₁-C₂₂ fragments of spirastrellolide A consistent with reported spectroscopic data has been achieved to aid in a complete configurational assignment of this structurally novel and potent antimitotic natural product. A highly convergent coupling of two enantiomeric C₁-C₁₀ methyl ketone fragments with an enantiopure C₁₁-C₂₂ spiroketal ­aldehyde produced the C₁-C₂₂ fragments with a longest linear sequence of 13 steps from commercially available starting materials.

Key words

total synthesis - natural products - spiro compounds - asymmetric synthesis - structure elucidation

References and Notes

• 1 Williams DE. Roberge M. Van Soest R. Andersen RJ. J. Am. Chem. Soc.  2003,  125:  5296 
• 2 Williams DE. Lapawa M. Feng X. Tarling T. Roberge M. Andersen RJ. Org. Lett.  2004,  6:  2607 
• 3 Paterson and coworkers have recently reported the synthesis of two diastereomeric C₁-C₂₅ fragments, see: Paterson I. Anderson EA. Dalby SM. Loiseleur O. Org. Lett.  2005,  7:  4125 
• For other synthetic studies, see:
• 4a Paterson I. Anderson EA. Dalby SM. Loiseleur O. Org. Lett.  2005,  7:  4121 
• 4b Paterson I. Anderson EA. Dalby SM. Synthesis  2005,  3225 
• 4c Liu J. Hsung RP. Org. Lett.  2005,  7:  2273 
• 4d

  Wang, C.; Forsyth, C. J. Abstracts of Papers, 229th ACS National Meeting, San Diego, CA, United States, March 13-17, 2005, ORGN-414.

• 6 Brown HC. Randad RS. Bhat KS. Zaidlewicz M. Racherla US. J. Am. Chem. Soc.  1990,  112:  2389 
• Compound 9 was an intermediate in our synthesis of SCH 351448, see:
• 7a Bhattacharjee A. Soltani O. De Brabander JK. Org. Lett.  2002,  4:  481 
• 7b Soltani O. De Brabander JK. Org. Lett.  2005,  7:  2791 
• 8 Kubota K. Leighton JL. Angew. Chem. Int. Ed.  2003,  42:  946 
• 12 Prepared in three steps from commercially available 1,3-propanediol, see: Theodorakis EA. Drouet KE. Chem. Eur. J.  2000,  6:  1987 
• 13a Ohira S. Synth. Commun.  1989,  19:  561 
• 13b Müller S. Liepold B. Roth GJ. Bestmann HJ. Synlett  1996,  521 
• Prepared in two steps from commercially available divinyl carbinol, see:
• 14a Romero A. Wong C.-H. J. Org. Chem.  2000,  65:  8264 
• 14b Okamoto S. Kobayashi Y. Kato H. Hori K. Takahashi T. Tsuji J. Sato F. J. Org. Chem.  1988,  53:  5590 
• 15a Ko S. Na Y. Chang S. J. Am. Chem. Soc.  2002,  124:  750 
• 15b Wang L. Floreancig PE. Org. Lett.  2004,  6:  569 
• 15c Wang L. Floreancig PE. Org. Lett.  2004,  6:  4207 
• 18 Evans DA. Dart MJ. Duffy JL. Yang MG. J. Am. Chem. Soc.  1996,  118:  4322 
• 20 The absolute stereochemistry at C₁₁ was confirmed via Mosher ester derivatization (R- and S-esters) according to: Ohtani I. Kusumi T. Kashman Y. Kakisawa H. J. Am. Chem. Soc.  1991,  113:  4092 
• 21 Evans DA. Chapman KT. Carreira EM. J. Am. Chem. Soc.  1988,  110:  3560 

5

All new compounds gave spectroscopic data in agreement with the assigned structures.

9

2- ^d Icr₂Ball is enantiocomplimentary to 4- ^d Icr₂Ball, the enantiomer of which is not available, see ref. 6.

10

Paterson and coworkers have prepared the ethyl ester analogue of ent-9 based on our [7a] route to 9 using 2- ^d Icr₂Ball in 90% ee, see ref. 3.

11

For ee determination, see Supporting Information of ref. 7a.

16

To a solution of 11 (0.158 g, 0.444 mmol) in anhyd THF (3 mL) at -78 °C under nitrogen was added n-BuLi (2.5 M in hexane, 0.19 mL, 0.48 mmol) and the solution turned bright yellow. The reaction mixture was stirred at r.t. for 10 min before being cooled to -78 °C. A solution of the Weinreb amide 12 (0.229 g, 0.488 mmol) in THF (1.5 mL) was added dropwise, after which the mixture was warmed to r.t. and stirred for an additional 1.5 h. The reaction was quenched with sat. aq NH₄Cl (15 mL) and extracted with EtOAc (3 × 15 mL). The organic layers were combined, dried over Na₂SO₄ and concentrated. The residue was puri-fied by column chromatography (hexanes-EtOAc, 20:1 to 15:1) to give the product 18 as a colorless oil (0.278 g, 82%). [α]_D ²⁵ -4.9 (c 2.7, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.24 (2 H, d, J = 8.8 Hz), 6.86 (2 H, d, J = 8.8 Hz), 4.43 (2 H, s), 3.93 (1 H, dt, J = 8.0, 4.0 Hz), 3.83 (1 H, dd, J = 9.6, 4.8 Hz), 3.79 (3 H, s), 3.62-3.69 (2 H, m), 3.37-3.48 (2 H, m), 3.32 (3 H, s), 3.19 (1 H, dt, J = 8.0, 4.0 Hz), 2.73-2.80 (1 H, m), 2.54-2.70 (2 H, m), 1.76-1.87 (3 H, m), 1.66 (1 H, td, J = 13.6, 6.0 Hz), 1.20 (3 H, d, J = 7.2 Hz), 0.95 (9 H, t, J = 8.0 Hz), 0.92 (9 H, t, J = 8.0 Hz), 0.88 (9 H, s), 0.63 (6 H, q, J = 8.0 Hz), 0.58 (6 H, q, J = 8.0 Hz), 0.03 (6 H, s). ¹³C NMR (100 MHz, CDCl₃): δ = 188.1, 159.3, 130.5, 129.5, 113.9, 95.3, 82.4, 81.6, 73.2, 72.8, 71.9, 70.8, 59.7, 58.4, 55.4, 41.9, 37.0, 32.9, 26.1, 24.4, 18.4, 14.9, 7.1, 7.0, 5.2, 5.1, -5.2, -5.2. IR: 2955, 2877, 1676, 1514, 1249, 1108, 834, 742 cm^-1. MS (ESI): m/z = 773.60 (C₄₀H₇₄O₇Si₃Na).

17

Product 19 (colorless oil): [α]_D ²⁵ +55.8 (c 2.18, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.25 (2 H, d, J = 8.0 Hz), 6.84 (2 H, d, J = 8.0 Hz), 5.71 (1 H, d, J = 10.0 Hz), 5.58 (1 H, dd, J = 10.0, 2.4 Hz), 4.52 (1 H, d, J = 12.0 Hz), 4.48 (1 H, d, J = 12.0 Hz), 3.85-3.90 (1 H, m), 3.77 (3 H, s), 3.67-3.76 (4 H, m), 3.53 (1 H, dd, J = 10.0, 6.0 Hz), 3.27 (3 H, s), 3.15 (1 H, td, J = 9.6, 4.8 Hz), 2.11 (1 H, td, J = 7.2, 2.0 Hz), 2.02-2.06 (1 H, m), 1.92-1.99 (1 H, m), 1.79-1.82 (1 H, m), 1.54-1.73 (3 H, m), 0.95 (3 H, d, J = 7.2 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 159.2, 135.4, 130.4, 129.5, 128.5, 113.7, 94.0, 74.8, 73.5, 73.0, 71.6, 69.4, 59.4, 56.4, 55.3, 35.1, 34.0, 33.6, 24.4, 16.7. IR: 3467, 2935, 1514, 1456, 1248, 1100, 1037, 985, 820 cm^-1. MS (ESI): m/z = 415.15 (C₂₂H₃₂O₆Na).

19

To a solution of ent-5 (36.7 mg, 0.171 mmol) and 2,6-lutidine (140 µL, 1.20 mmol) in anhyd CH₂Cl₂ (1.2 mL) at -78 °C was added dropwise trimethylsilyl trifluoro-methanesulfonate (186 µL, 1.03 mmol). After stirring for 1.5 h at -78 °C, the reaction was quenched with sat. aq NaHCO₃ (5 mL) and the aqueous phase was extracted with hexane (3 × 5 mL). The organic layers were combined, dried over Na₂SO₄ and concentrated to give a colorless oil (46.0 mg). This crude silylenol ether and aldehyde 6 (66.9 mg, 0.172 mmol) were dissolved in anhyd CH₂Cl₂ (1.1 mL) and cooled to -78 °C. BF₃·OEt₂ (27.5 µL, 0.223 mmol) was slowly added and the solution was stirred for 2 h at -78 °C. The reaction was quenched with sat. aq NaHCO₃ (5 mL) and the aqueous phase was extracted with CH₂Cl₂ (3 × 5 mL). The organic layers were combined, dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography (hexanes-EtOAc, 2:1 to 2:3) to give, in order of elution, the recovered methyl ketone ent-5 (12.3 mg), the minor 1,3-syn aldol product (6.0 mg, 8.7% based on recovered starting material) and the 1,3-anti aldol product 21 (46.2 mg, 76% based on recovered starting material).
Compound 21: [α]_D ²⁵ +24.3 (c 1.1, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.26 (2 H, d, J = 8.4 Hz), 6.86 (2 H, d, J = 8.4 Hz), 5.71 (1 H, d, J = 9.6 Hz), 5.60 (1 H, dd, J = 9.6, 2.0 Hz), 4.55 (1 H, d, J = 12.0 Hz), 4.47 (1 H, d, J = 12.0 Hz), 4.39-4.45 (1 H, m), 3.80 (3 H, s), 3.77-3.84 (4 H, m), 3.66 (3 H, s), 3.64-3.68 (1 H, m), 3.55-3.60 (2 H, m), 3.28 (3 H, s), 3.18-3.23 (1 H, m), 2.62-2.69 (3 H, m), 2.36-2.52 (3 H, m), 2.10-2.14 (1 H, m), 2.01-2.05 (1 H, m), 1.51-1.84 (9 H, m), 1.15-1.23 (2 H, m), 0.97 (3 H, d, J = 7.2 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 209.6, 171.9, 159.2, 135.3, 130.6, 129.6, 128.6, 113.8, 94.1, 74.8, 74.7, 74.5, 73.4, 73.1, 70.7, 69.3, 64.1, 56.4, 55.4, 51.9, 50.9, 50.4, 41.6, 39.6, 34.2, 33.8, 31.2, 30.9, 24.3, 23.3, 16.8. IR: 3490, 2933, 1739, 1514, 1248, 1100, 1036, 985, 821, 728 cm^-1. MS (ESI): m/z = 627.30 (C₃₃H₄₈O₁₀Na).
Compound 20 was prepared using the same procedure in 59% yield and 11:1 dr; [α]_D ²⁵ +27.0 (c 0.22, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.26 (2 H, d, J = 8.4 Hz), 6.86 (2 H, d, J = 8.4 Hz), 5.71 (1 H, dd, J = 10.0, 1.6 Hz), 5.59 (1 H, dd, J = 10.0, 1.6 Hz), 4.55 (1 H, d, J = 12.0 Hz), 4.46 (1 H, d, J = 12.0 Hz), 4.39-4.45 (1 H, m), 3.80 (3 H, s), 3.75-3.83 (4 H, m), 3.65 (3 H, s), 3.62-3.69 (2 H, m), 3.58 (1 H, dd, J = 10.4, 5.6 Hz), 3.28 (3 H, s), 3.18-3.24 (1 H, m), 2.58-2.68 (3 H, m), 2.33-2.52 (3 H, m), 2.09-2.13 (1 H, m), 2.01-2.06 (1 H, m), 1.50-1.84 (9 H, m), 1.16-1.26 (2 H, m), 0.96 (3 H, d, J = 7.2 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 209.5, 171.9, 159.3, 135.3, 130.7, 129.6, 128.64, 113.8, 94.1, 74.7, 74.7, 74.6, 73.4, 73.1, 70.7, 69.3, 64.0, 56.4, 55.5, 51.9, 51.1, 50.4, 41.6, 39.6, 34.2, 33.8, 31.2, 31.0, 24.3, 23.3, 16.8. IR 3464, 2934, 1738, 1514, 1248, 1100, 1037, 985, 736 cm^-1. MS (ESI): m/z = 627.30 (C₃₃H₄₈O₁₀Na).

22

Compound 3: [α]_D ²⁵ +43.8 (c 0.16, CHCl₃). ¹H NMR (400 MHz, benzene-d ₆): δ = 5.57-5.63 (2 H, m, H₁₅, H₁₆), 4.66 (1 H, app t, J = 7.6 Hz, H₁₁), 4.17-4.21 (3 H, m, H₉, H₁₃, H₂₁), 4.06 (1 H, dd, J = 11.6, 1.2 Hz, H_22b), 3.86 (1 H, dd, J = 10.8, 5.6 Hz, H_22a), 3.53-3.58 (1 H, m, H₃), 3.45 (3 H, s, CO₂Me), 3.20 (1 H, app t, J = 10.4 Hz, H₇), 3.02 (3 H, s, OMe), 3.00-3.05 (1 H, m, H₂₀), 2.22 (1 H, dd, J = 14.8, 8.8 Hz, H_2b), 1.98-2.11 (2 H, m, H_2a, H₁₄), 1.84-1.94 (3 H, m, H_12b, H_18b, H_19b), 1.72-1.76 (1 H, m, H_19a), 1.60-1.69 (4 H, m, H_8a, H_8b, H_10b, H_12a), 1.48-1.52 (1 H, m, H_18a), 1.36-1.39 (1 H, m, H_5b), 1.21 (1 H, d, J = 14.0 Hz, H_10a), 1.06-1.12 (3 H, m, H_4b, H_5a, H_6b), 0.85-1.00 (2 H, m, H_4a, H_6a), 0.81 (3 H, d, J = 7.2 Hz). ¹³C NMR (75 MHz, benzene-d ₆): δ = 171.3 (C₁), 135.2 (C₁₅), 129.3 (C₁₆), 94.0 (C₁₇), 79.4 (C₇), 75.7 (C₂₀), 74.7 (C₃), 74.4 (C₂₁), 71.1 (C₁₃), 70.0 (C₉), 65.2 (C₁₁), 63.2 (C₂₂), 55.8 (20-OMe), 51.4 (-CO₂Me), 44.3 (C₁₀), 43.1 (C₈), 41.3 (C₂), 40.9 (C₁₂), 34.9 (C₁₄), 34.3 (C₁₈), 31.5 (C₄), 30.9 (C₆), 24.4 (C₂), 23.2 (C₅), 16.7 (14-Me). IR: 3450, 2933, 1738, 1438, 1090, 1044, 982 cm^-1. MS (ESI): m/z = 509.5 (C₂₅H₄₂O₉Na).
Compound 4: [α]_D ²⁵ +46.7 (c 0.18, CHCl₃). ¹H NMR (400 MHz, benzene-d ₆): δ = 5.59 (2 H, app s, H₁₅, H₁₆), 4.62 (1 H, app t, J = 8.8 Hz, H₁₁), 4.36 (1 H, br s, H₉), 4.12-4.17 (2 H, m, H₁₃, H₂₁), 4.05 (1 H, dd, J = 11.2, 1.6 Hz, H_22b), 3.82 (1 H, dd, J = 11.2, 6.0 Hz, H_22a), 3.61-3.66 (1 H, m, H₃), 3.51-3.55 (1 H, m, H₇), 3.47 (3 H, s, CO₂Me), 3.01 (3 H, s, 20-OMe), 2.96-3.01 (1 H, m, H₂₀) 2.33 (1 H, dd, J = 14.8, 8.8 Hz, H_2b), 2.01-2.09 (2 H, m, H_2a, H₁₄), 1.80-1.93 (3 H, m, H_12b, H_18b, H_19b), 1.66-1.74 (2 H, m, H_10b, H_19a), 1.50-1.60 (3 H, m, H_8a, H_8b, H_12a), 1.45-1.50 (2 H, m, H_5b, H_18a), 1.33-1.39 (1 H, m, H_10a), 1.08-1.19 (3 H, m, H_4b, H_5a, H_6b), 0.86-0.96 (2 H, m, H_4a, H_6a), 0.81 (3 H, d, J = 6.8 Hz, 14-Me). ¹³C NMR (75 MHz, benzene-d ₆): δ = 171.7 (C₁), 135.3 (C₁₅), 129.2 (C₁₆), 94.0 (C₁₇), 75.9 (C₂₀), 75.7 (C₇), 74.6 (C₃), 74.4 (C₂₁), 71.0 (C₁₃), 66.0 (C₉), 65.1 (C₁₁), 63.4 (C₂₂), 55.7 (20-OMe), 51.4 (CO₂Me), 44.4 (C₁₀), 43.0 (C₈), 41.4 (C₂), 40.6 (C₁₂), 34.8 (C₁₄), 34.2 (C₁₈), 31.2 (C₄), 31.0 (C₆), 24.3 (C₁₉), 23.6 (C₅), 16.7 (14-Me). IR: 3440, 2933, 1738, 1440, 1200, 1091, 983 cm^-1. MS (ESI): m/z = 509.5 (C₂₅H₄₂O₉Na).

23

A referee pointed out that an intact C₁-C₂₂ fragment is potentially available from degradation of the natural product. At this point, we have not yet contacted the isolation group to explore the possibility for such degradation studies on very limited amounts of natural spirastrellolide.