A Silicon-Centred Tetrafunctionalised Reagent for the Cyclopropylmethylsilane-Terminated Prins Reaction and a Concise Synthesis of Lyngbic Acid

Abstract

A novel silicon-centred tetrafunctionalised reagent, tetra(2-ethenylcyclopropylmethyl)silane, has been prepared as a mixture of all possible 19 diastereoisomers. It reacts with TMSOTf-activated acetals via initial Prins reaction of the olefin and ‘termination’ by the cyclopropylmethylsilane groups. In this manner it smoothly transfers three of its groups to form skipped diene ether products. The reaction is under stereoelectronic control and gives exclusively E-skipped dienes regardless of the initial cis/trans configuration of each of the reacting vinyl cyclopropanes, or the relative configurations of the other vinylcyclopropane groups in the silane. The synthetic utility of the reagent is demonstrated by its use in a concise synthesis of marine natural product Lyngbic acid.

carbocations - ring-opening - silicon - stereoelectronic - skipped diene

References

1 Braddock DC. Badine DM. Gottschalk T. Synlett  2001,  1909 ; and leading references cited therein for Prins reactions

2 Braddock DC. Badine DM. Gottschalk T. Matsuno A. Rodriguez-Lens M. Synlett  2003,  345 

3

One possible solution would be to employ cis- and trans-1-trimethylsilylmethyl-2-vinylcyclopropanes. Unfortunately, attempted synthesis of these trimethylsilyl derivatives revealed that they were too volatile to be readily handled. See ref. [1]

4

Procedures and Data for Compounds 5, 7-9.
Tetraester 7: EDA (2.0 mL, 20.5 mmol) was added dropwise via syringe pump (0.2 mL/h) to a mixture of tetraallylsilane 6 (1.0 g, 5.2 mmol) and Cu(NCCH₃)₄BF₄ (160 mg, 0.70 mmol) heated at 110 °C under nitrogen. After 20 h, the reaction mixture was allowed to cool, poured into sat. aq NaCl solution (50 mL) and extracted with Et₂O (150 mL). The organic layer was washed with sat. aq NaCl solution (3 × 50 mL), dried over MgSO₄, filtered and evaporated under reduced pressure to give a yellow oil. The oil was re-subjected to the above procedure to give a brown oil, from which diethylmaleate and diethylfumarate were removed by distillation under vacuum at 150 °C. The resulting brown residue was chromatographed (petroleum ether-Et₂O 1:1) to give tetraester 7 (2.78 g, 43%) as a yellow oil: R_f = 0.42 (Et₂O-petroleum ether 1:1). IR (thin film, NaCl plates): 2982, 1724 cm^-1. ¹H NMR (270 MHz, CDCl₃): δ = 4.33-4.02 (m, 8 H), 1.78-0.45 (m, 36 H). ¹³C NMR (68 MHz, CDCl₃): δ = 174.2, 172.7, 172.6, 68.2, 61.0, 60.4, 60.3, 22.5, 19.3, 18.4, 17.6, 17.5, 17.3, 14.4, 14.3, 10.2, 10.04, 10.0, 9.9. MS (CI⁺): m/z = 554 [M + NH₄ ⁺]. HRMS (CI⁺): m/z calcd for C₂₈H₄₅O₈Si: 537.2884 [M + H⁺]. Found: 537.2885 [M + H⁺]. Anal. Calcd for C₂₈H₄₄O₈Si: C, 62.66; H, 8.26. Found: C, 62.69; H, 8.07.
Tetrol 8: Tetraester 7 (1.2 g, 1.9 mmol) was added dropwise to a suspension of LiAlH₄ (710 mg, 19 mmol) in THF (15 mL) at 0 °C under nitrogen. The mixture was stirred for 2 h at r.t. and quenched by the sequential addition of H₂O (40 mL) and aq NaOH solution (4.0 M, 10 mL). The mixture was filtered and the collected white solid was triturated with hot Et₂O (10 × 50 mL). The combined organics were dried over MgSO₄, filtered and evaporated under reduced pressure to give tetrol 8 (580 mg, 85%) as a light yellow oil: R_f = 0.32 (MeOH-petroleum ether 1:5). IR (thin film, NaCl plates): 3550-3350, 3056, 2979, 2929, 2873 cm^-1. ¹H NMR (270 MHz, CD₃OD): δ = 3.76-3.52 (m, 4 H), 3.40-3.34 (m, 4 H), 1.18 to -0.09 (m, 24 H). ¹³C NMR (68 MHz, CD3OD): δ (major peaks only): 65.7, 61.8, 22.8, 17.8, 17.2, 12.0, 11.9, 10.9. MS (CI⁺): m/z = 386 [M + NH₄ ⁺].
Silane 5: Dess-Martin periodinane (9.2 g, 21.7 mmol) was added portion-wise to a solution of tetrol 8 (2.0 g, 5.43 mmol) in CH₂Cl₂ (50 mL) at 0 °C under nitrogen. The solution was heated to 40 °C for 2 h, allowed to cool to r.t., quenched with aq NaOH solution (20 mL, 1.3 M), and stirred for a further 10 min. To this solution, CH₂Cl₂ (100 mL) was added and the organics were washed with aq NaOH solution (20 mL, 1.3 M), H₂O (50 mL), sat. aq NaCl solution (50 mL), dried over MgSO₄, filtered and evaporated to give crude tetraaldehyde 9 (2.0 g, 100%) as a yellow oil. The aldehyde was used immediately in the next step: n-BuLi (8.9 mL, 2.5 M in hexanes, 22.1 mmol) was added dropwise to suspension of MePPh₃Br (7.9 g, 22.1 mmol) in THF (50 mL) under nitrogen. The yellow solution was cooled to r.t. and tetraaldehyde 9 (2.0 g, 5.43 mmol) as a solution in THF (5 mL) was added dropwise. The solution was allowed to warm to r.t. and stirred for 20 h. The brown mixture was diluted with Et₂O (250 mL), washed with H₂O (2 × 100 mL), brine (100 mL), dried over MgSO₄, filtered, evaporated under reduced pressure and chromatographed (petroleum ether) to give silane 5 (780 mg, 41%) as a colourless oil: R_f = 0.57 (petroleum ether). IR (thin film, NaCl plates): 3065, 2995, 2873, 1633 cm^-1. ¹H NMR (270 MHz, CDCl₃): δ = 5.66-5.40 (2.4 H, m), 5.33-5.22 (2.8 H, m), 5.11-4.95 (4 H, m), 4.81-4.78 (2.8 H, m), 1.66-0.46 (20 H, m), 0.17-0.14 (4 H, br s). ¹³C NMR (68 MHz, CDCl₃): δ = 142.1, 138.7, 137.7 (min), 137.6 (min), 134.0, 133.7, 132.9 (min), 132.3 (min), 132.1 (min), 132.0(min), 128.6, 128.5, 114.1, 111.1, 25.0, 20.7, 17.8, 16.6, 16.5, 15.0, 12.3. Anal. Calcd for C₂₄H₃₆Si: C, 81.75; H, 10.29. Found: C, 81.51; H, 9.95.

5 Cardellina JH. Dalietos D. Marner F.-J. Mynderse JS. Moore RE. Phytochemistry  1978,  17:  2091 

6 Gerwick WH. Reyes S. Alvarado B. Phytochemistry  1987,  26:  1701 

7 Cardellina JH. Marner F.-J. Moore RE. J. Am. Chem. Soc.  1979,  101:  240 

8 Fryhle CB. Williard PG. Rybak CM. Tetrahedron Lett.  1992,  33:  2327 

9 Müller C. Voss G. Gerlach H. Liebigs Ann.  1995,  673 

10 Samkaranarayaran S. Sharma A. Chattopadhyay S. Tetrahedron: Asymmetry  1996,  7:  2639 

11

Procedures and Data for Compounds 2 (R = C ₇ H ₁₅ , R′ = Me), 11 and 10.
Skipped diene 2 (R = C₇H₁₅, R′ = Me): TMSOTf (181 µL, 1.0 mmol) was added dropwise to a stirred solution of 1,1-dimethoxyoctane (204 µL, 1.0 mmol), silane 5 (88 mg, 0.25 mmol) and 2,6-di-tert-butylpyridine (240 µL, 1.1 mmol) in CH₂Cl₂ (4.0 mL) at -78 °C under nitrogen. The mixture was allowed to warm to r.t. and stirred for 18 h. The resulting mixture was quenched with H₂O (20 mL), and the aqueous layer was separated and extracted with CH₂Cl₂ (3 × 30 mL) and washed with H₂O (50 mL). The combined organics were dried over MgSO₄, filtered, evaporated under reduced pressure and chromatographed to give skipped diene 2 (R = C₇H₁₅, R′ = Me; 150 mg, 67%) as a pale yellow oil: R_f = 0.69 (CH₂Cl₂-petroleum ether 1:4). IR (thin film, NaCl plates): 3079, 2927, 2856 cm^-1. ¹H NMR (270 MHz, CDCl₃): δ = 5.86 (ddt, J = 17.2, 10.2, 6.8 Hz, 1 H), 5.50-5.40 (m, 2 H), 5.00 (dd, J = 17.2, 2.6 Hz, 1 H), 4.91 (dd, J = 10.2, 2.6 Hz, 1 H), 3.30 (s, 3 H), 3.15 (quint., J = 5.9 Hz, 1 H), 2.77 (t, J = 5.1 Hz, 2 H), 2.19 (t, J = 5.1 Hz, 2 H), 1.43 (m, 2 H), 1.50-1.30 (m, 10 H), 0.85 (t, J = 5.9 Hz, 3 H). ¹³C NMR (68 MHz, CDCl₃): δ = 137.3, 130.2, 127.6, 115.0, 81.0, 56.6, 36.9, 36.6, 33.5, 32.0, 29.9, 29.4, 25.4, 22.8, 14.2. MS (CI⁺): m/z 242 [M + NH₄]⁺. HRMS (CI⁺): m/z calcd for C₁₅H₃₂NO: 242.2484 [M + NH₄]⁺. Found: 242.2481 [M + NH₄]⁺.
Alcohol 11: Diene 2 (R = C₇H₁₅, R′ = Me; 300 mg, 1.38 mmol) was added dropwise to a stirred solution of 9-BBN in THF (5.3 mL, 0.5 M, 2.75 mmol) at 0 °C under nitrogen. After 18 h stirring at r.t. aq NaOH solution (5.5 mL, 1.0 M, 5.5 mmol) and 30% aq H₂O₂ solution (6 mL) was added at 0 °C. The mixture was stirred for 6 h, and the THF evaporated under reduced pressure. The aqueous residue was extracted with Et₂O (3 × 30 mL) and the combined organics dried over MgSO₄, filtered, evaporated under reduced pressure and chromatographed (Et₂O-petroleum ether 1:1) to give alcohol 11 (223 mg, 67%) as a colourless oil: R_f = 0.35 (Et₂O-petroleum ether 1:1). IR (thin film, NaCl plates): 3600-3100, 2929, 2856 cm^-1. ¹H NMR (270 MHz, CDCl₃): δ = 5.49-5.37 (m, 2 H), 3.55 (t, J = 6.5 Hz, 2 H), 3.26 (s, 3 H), 3.09 (quint, J = 5.8 Hz, 1 H), 2.36 (br s, 1 H), 2.13 (t, J = 5.6 Hz, 2 H), 2.04-1.99 (m, 2 H), 1.69-1.14 (m, 14 H), 0.82 (t, J = 6.2 Hz, 3 H). ¹³C NMR (68 MHz CDCl₃): δ = 132.2, 126.7, 80.9, 62.2, 56.4, 36.4, 33.3, 32.3, 31.9, 29.8, 29.3, 29.2, 25.3, 22.7, 14.1. MS (CI⁺): m/z 243 [M + H]⁺. HRMS (CI⁺): m/z calcd for C₁₅H₃₁O₂: 243.2324 [M + H]⁺. Found: 243.2319 [M + H]⁺.
Lyngbic acid 10: PDC (310 mg, 0.83 mmol) was added to a stirred solution of alcohol 11 (50 mg, 0.21 mmol) in DMF (3 mL) at 0 °C. The mixture was stirred for 18 h at r.t. and poured into H₂O (50 mL). The mixture was extracted with Et₂O (3 × 30 mL) and the combined organics were washed with sat. aq NaCl solution (40 mL), dried over MgSO₄, filtered, evaporated and chromatographed (Et₂O-petroleum ether 1:1) to give acid 10 (28 mg, 54%) as a colourless oil: R_f = 0.52 (Et₂O-petroleum ether 2:1). IR (thin film, NaCl plates): 3500-2800, 3018, 2930, 2858, 1711 cm^-1. ¹H NMR (270 MHz, CDCl₃): δ = 5.47 (m, 2 H), 3.31 (s, 3 H), 3.13 (quint, J = 5.7 Hz, 1 H), 2.44-2.35 (m, 2 H), 2.35-2.32 (m, 2 H), 2.20-2.10 (m, 2 H), 1.41-1.26 (m, 12 H), 0.86-0.84 (t, J = 6.8 Hz, 3 H). ¹³C NMR (68 MHz, CDCl₃): δ = 178.2, 130.2, 127.9, 80.8, 56.6, 36.4, 33.9, 33.4, 31.9, 29.8, 29.4, 27.7, 25.4, 22.7, 14.2. MS (CI⁺): m/z = 274 [M + NH₄]⁺. HRMS (CI⁺): m/z calcd for C₁₅H₃₂NO₃: 274.2382 [M + NH₄]⁺. Found: 274.2373 [M + NH₄]⁺. This data is identical to the data previously reported (ref. [5] ).