Synthesis of Nemorosone via a Difficult Bridgehead Substitution Reaction

Abstract

The synthesis of nemorosone, a polyprenylated acyl­phloroglucinol isolated from Clusia rosea, was achieved by means of a bridgehead substitution process, involving initial iodination and subsequent lithium-iodine exchange followed by acylation. The difficulties in the bridgehead substitution are discussed, and a probable explanation proposed, based on molecular modelling.

Key words

nemorosone - bridgehead substitution - iodine-lithium exchange - B3LYP calculations

References and Notes

• For a comprehensive review, see:
• 1a Ciochina R. Grossman RB. Chem. Rev.  2006,  106:  3963 
• 1b See also: Verotta L. Phytochem. Rev.  2002,  1:  389 
• For syntheses, see:
• 2a Kuramochi A. Usuda H. Yamatsugu K. Kanai M. Shibasaki M. J. Am. Chem. Soc.  2005,  127:  14200 
• 2b Siegel DR. Danishefsky SJ.
  J. Am. Chem. Soc.  2006,  128:  1048 
• 2c Rodeschini V. Ahmad NM. Simpkins NS. Org. Lett.  2006,  8:  5283 
• 2d Ahmad NM. Rodeschini V. Simpkins NS. Ward SE. Blake AJ. J. Org. Chem.  2007,  72:  4803 
• 2e Nuhant P. David M. Pouplin T. Delpech B. Marazano C. Org. Lett.  2007,  9:  287 
• 2f Qi J. Porco JA. J. Am. Chem. Soc.  2007,  129:  12682 
• 2g Tsukano C. Siegel DR. Danishefsky SJ. Angew. Chem. Int. Ed.  2007,  46:  840 
• For very recent synthetic efforts, and further leading references, see:
• 3a Couladouros EA. Dakanali M. Demadis KD. Vidali VP. Org. Lett.  2009,  11:  4430 
• 3b Mitasev B. Porco JA. Org. Lett.  2009,  11:  2285 
• 3c See also: Rodeschini V. Simpkins NS. Wilson C.
  J. Org. Chem.  2007,  72:  4265 
• 4 Ahmad NM. Rodeschini V. Simpkins NS. Ward SE. Wilson C. Org. Biomol. Chem.  2007,  5:  1924 
• Nemorosone - corrected structure:
• 5a Cuesta-Rubio O. Velez-Castro H. Frontana-Uribe BA. Cárdenas J. Phytochem.  2001,  57:  279 
• Cytotoxicity studies:
• 5b Cuesta-Rubio O. Frontana-Uribe BA. Ramirez-Apan T. Cárdenas J. Z. Naturforsch., C: Biosci.  2002,  57:  372 
• 5c Diaz-Carballo D. Malak S. Bardenheuer W. Freistuehler M. Reusch HP. J. Cell. Mol. Med.  2008,  12:  2598 
• 5d Diaz-Carballo D. Malak S. Freistuehler M. Elmaagacli A. Bardenheuer W. Reusch HP. Int. J. Clin. Pharm. Ther.  2008,  46:  428 
• 5e Diaz-Carballo D. Seeber S. Strumberg D. Hilger RA. Int. J. Clin. Pharm. Ther.  2003,  41:  622 
• 6a Schönwälder K.-H. Kollat P. Stezowski JJ. Effenberger F. Chem. Ber.  1984,  117:  3280 
• 6b Our approach was inspired by a paper from the Stoltz group, see: Spessard SJ. Stoltz BM. Org. Lett.  2002,  4:  1943 
• 11 Hayes CJ. Simpkins NS. Kirk DT. Mitchell L. Baudoux J. Blake AJ. Wilson C. J. Am. Chem. Soc.  2009,  131:  8196 
• 12 Computational Methods Geometry optimisations were performed using the B3LYP/6-31G* level of theory using Spartan 04 (Windows), and zero-point vibrational energies were calculated for all structures, and the absence of imaginary frequencies was used to characterise the structures as minima on their potential energy surfaces. NBO calculations were performed on all anionic species using the NBO keyword in Spartan 04 (Windows): Kong J. White CA. Krylov AI. Sherrill D. Adamson RD. Furlani TR. Lee MS. Lee AM. Gwaltney SR. Adams TR. Ochsenfeld C. Gilbert ATB. Kedziora GS. Rassolov VA. Maurice DR. Nair N. Shao Y. Besley NA. Maslen PE. Dombroski JP. Daschel H. Zhang W. Korambath PP. Baker J. Byrd EFC. Van Voorhis T. Oumi M. Hirata S. Hsu C.-P. Ishikawa N. Florian J. Warshel A. Johnson BG. Gill PMW. Head-Gordon M. Pople JA. J. Comput. Chem.  2000,  21:  1532 

7

Preparation of 10
LTMP (22.6 mL of a freshly prepared 0.5 M solution in THF, 11.3 mmol) was added dropwise to a solution of O-methylated trione 9 (1.95 g, 5.7 mmol) in THF (60 mL) at
-78 ˚C. The reaction mixture was stirred for 5 min before addition of TMSCl (2.87 mL, 22.6 mmol). The reaction mixture was stirred and allowed to warm to -40 ˚C over 2 h. The reaction was quenched with NH₄Cl solution (30 mL), and the product was extracted with Et₂O (3 × 40 mL). The combined organic extracts were dried (MgSO₄), and the solvent was removed under reduced pressure. Purification of the residue by flash column chromatography (10% Et₂O in PE) afforded vinylsilane 10 as a white solid (2.21 g, 94%); mp 46-48 ˚C; R _f  = 0.34 (10% EtOAc in PE). ^¹H NMR (500 MHz, CDCl₃): δ = 4.96-4.92 (m, 2 H), 3.73 (s, 3 H), 3.22 (s, 1 H), 2.40 (dd, J = 14.3, 7.7 Hz, 1 H), 2.32 (dd, J = 14.3, 7.7 Hz, 1 H), 2.04 (dd, J = 13.2, 5.1 Hz, 1 H), 1.91 (dd, J = 13.2, 4.0 Hz, 1 H), 1.66 (s, 3 H), 1.63 (s, 3 H), 1.60 (t, J = 13.2 Hz, 1 H), 1.59 (s, 3 H), 1.53 (s, 3 H), 1.54-1.51 (m, 1 H), 1.28 (app. t, J = 12.8 Hz, 1 H), 1.09 (s, 3 H), 0.94 (s, 3 H), 0.16 (s, 9 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 208.4, 201.9, 177.9, 133.6, 133.2, 123.5, 122.3, 119.6, 63.7, 61.1, 55.8, 42.8, 41.0, 39.4, 29.6, 27.9, 25.8, 25.73, 25.72, 20.9, 18.0, 17.8, 0.33. ESI-HRMS (TOF): m/z calcd for C₂₅H₄₀O₃Si [M + H]⁺: 417.2820; found: 417.2823. IR: ν = 2975 (s), 2911 (s), 1731 (s), 1641 (s), 1560 (s), 1447 (m), 1219 (s), 1057 (w), 842 (s) cm^-¹.
Preparation of 11
LDA (4.9 mL of a freshly prepared 0.5 M solution in THF, 2.44 mmol) was added dropwise to a solution of TMS-protected enone 10 (253 mg, 0.61 mmol) and TMSCl (0.31 mL, 2.44 mmol) in THF (2 mL) at -78 ˚C. The reaction mixture was stirred at -78 ˚C for 10 min before removal of the cold bath and warming to 0 ˚C over 30 min. The reaction mixture was then cooled to -78 ˚C, and a solution of iodine (709 mg, 5.5 mmol) in THF (2 mL) was added. The reaction mixture was stirred at -78 ˚C for 10 min before stirring at 0 ˚C for 30 min. The reaction mixture was diluted with EtOAc (20 mL) before washing with Na₂SO₃ solution (3 × 10 mL) and brine (3 × 10 mL). The organic layer was separated, and the solvent was removed under reduced pressure. The residue was subjected to flash column chromatography (5% EtOAc in PE) to afford bridgehead iodide 11 as a white solid (214 mg, 65%); mp 59-61 ˚C; R _f  = 0.5 (10% EtOAc in PE). ^¹H NMR (500 MHz, CDCl₃): δ = 5.04 (t, J = 7.2 Hz, 1 H), 4.95 (t, J = 7.2 Hz, 1 H), 3.92 (s, 3 H), 2.46-2.38 (m, 2 H), 2.17 (dd, J = 13.4, 5.3 Hz, 1 H), 1.80-1.73 (m, 2 H), 1.69-1.63 (m, 1 H), 1.62 (s, 3 H), 1.60 (s, 3 H), 1.51 (s, 6 H), 1.39 (app. t, J = 14.3 Hz, 1 H), 1.23 (s, 3 H), 0.88 (s, 3 H), 0.22 (s, 9 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 200.0, 199.9, 178.9, 134.0, 133.4, 125.2, 122.2, 119.6, 86.0, 65.6, 65.5, 47.7, 40.9, 38.9, 30.4, 30.2, 29.0, 25.8, 25.6, 20.6, 17.9, 17.8, 0.3. ESI-HRMS (TOF): m/z calcd for C₂₅H₃₉IO₃Si [M + H]⁺: 543.1791; found: 543.1779. IR: ν = 2976 (m), 1734 (s), 1654 (s), 1548 (s), 1437 (m), 1250 (s), 1034 (w), 848 (s), 758 (s) cm^-¹.
Preparation of 12
n-BuLi (0.17 mL of a 2.5 M solution in hexanes, 0.43 mmol) was added dropwise to a solution of bridgehead iodide 11 (196 mg, 0.36 mmol) in THF (3 mL) at -78 ˚C. The reaction mixture was stirred at -78 ˚C for 5 min before adding benzoyl chloride (50 µL, 0.43 mmol) dropwise at this temperature. The reaction mixture was stirred for 1 h at -78 ˚C and at r.t. for 30 min. The reaction was quenched with NH₄Cl solution (10 mL), and the product was extracted into Et₂O (3 × 15 mL). The combined organic layers were dried (MgSO₄), and the solvent was removed under reduced pressure. Purification of the residue by flash column chromatography (10% Et₂O in PE) gave the bridgehead benzoylated product, ready for the desilylation (117 mg, 63%). A solution of TBAF (0.33 mL of a 1 M solution in THF, 0.33 mmol) was added to a solution of the product obtained above (117 mg, 0.22 mmol) in THF (3 mL) at -78 ˚C. The reaction mixture was allowed to warm to r.t. over 1.5 h before quenching with NH₄Cl solution (10 mL). The product was extracted into Et₂O (3 × 15 mL), and the combined organic layers were dried (MgSO₄). Removal of the solvent under reduced pressure and purification of the residue by flash column chromatography (100% CH₂Cl₂) gave the benzoylated product 12 as a white solid (80 mg, 81%); mp 141-142 ˚C (subl.); R _f  = 0.40 (20% EtOAc in PE). ^¹H NMR (500 MHz, CDCl₃): δ = 7.59 (d, J = 7.3 Hz, 2 H), 7.42 (t, J = 7.3 Hz, 1 H), 7.27 (app. t, J = 7.9 Hz, 2 H), 5.94 (s, 1 H), 5.00 (t, J = 7.0 Hz, 1 H), 4.96 (t, J = 7.0 Hz, 1 H), 3.50 (s, 3 H), 2.56 (dd, J = 14.3, 7.0 Hz, 1 H), 2.44 (dd, J = 14.2, 7.2 Hz, 1 H), 2.12 (dd, J = 13.2, 5.1 Hz, 1 H), 1.98 (dd, J = 13.2, 4.4 Hz, 1 H), 1.79-1.72 (m, 1 H), 1.71-1.62 (m, 1 H), 1.66 (s, 3 H), 1.65 (s, 3 H), 1.64 (s, 3 H), 1.55 (s, 3 H), 1.45 (app. t, J = 13.0 Hz, 1 H), 1.34 (s, 3 H), 1.18 (s, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 207.3, 196.1, 192.5, 173.8, 137.0, 134.4, 133.3, 132.1, 127.92, 127.91, 122.3, 119.5, 106.5, 72.4, 65.6, 56.5, 47.5, 42.6, 42.5, 29.0, 27.7, 25.9, 25.8, 24.3, 18.1, 17.8, 15.8. ESI-HRMS (TOF): m/z calcd for C₂₉H₃₆O₄ [M + H]⁺: 449.2692; found: 449.2691. IR: ν = 2931 (m), 1720 (s), 1655 (s), 1606 (s), 1445 (w), 1344 (m), 1237 (s), 1218 (s) cm^-¹.
Preparation of Nemorosone (4)
LTMP (5.8 mL of a freshly prepared 0.1 M solution in THF, 0.58 mmol) was added to a solution of enone 12 (130 mg, 0.29 mmol) in THF (8 mL) at -78 ˚C. The reaction mixture was stirred for 30 min before addition of Li(2-Th)CuCN (5.8 mL of a freshly prepared 0.1 M solution in THF, 0.58 mmol). The reaction mixture was stirred at -78 ˚C for 5 min and at -40 ˚C for 30 min. The reaction mixture was then cooled
to -78 ˚C and prenyl bromide (0.17 mL, 1.45 mmol) was added. The reaction mixture was warmed to -30 ˚C over 1.5 h before quenching with NH₄Cl/NH₄OH solution (10% w/w, 20 mL). The product was extracted with Et₂O (3 × 20 mL), and the combined organic layers were dried (MgSO₄) and concentrated under reduced pressure. Purification by flash column chromatography (CH₂Cl₂-PE, 1:1) afforded O-methylated nemorosone as a white solid (83 mg, 55%). This intermediate (41 mg, 79 µmol) and LiCl (29 mg, 0.68 mmol) were dissolved in DMSO-d ₆ (0.75 mL) and heated to 120 ˚C for 2 h. The reaction mixture was then cooled to r.t., diluted with H₂O (5 mL) and extracted with Et₂O (3 × 5 mL). The combined organic layers were washed with brine (5 mL) and dried (MgSO₄). The solvent was removed under reduced pressure to afford nemorosone (4), which did not require further purification (39 mg, quant.). ^¹H NMR (500 MHz, MeOH-d ₄): δ = 7.58 (d, J = 8.4 Hz, 2 H), 7.47 (t, J = 7.3 Hz, 1 H), 7.29 (t, J = 7.7 Hz, 2 H), 5.12 (t, J = 7.3 Hz, 1 H), 5.06-5.02 (m, 2 H), 3.17 (dd, J = 14.7, 7.3 Hz, 1 H), 3.12 (dd, J = 14.7, 7.3 Hz, 1 H), 2.57 (dd, J = 14.3, 7.0 Hz, 1 H), 2.52 (dd, J = 14.3, 7.0 Hz, 1 H), 2.21-2.17 (m, 1 H), 2.06 (dd, J = 13.6, 3.7 Hz, 1 H), 1.82-1.74 (m, 2 H), 1.72 (s, 3 H), 1.693 (s, 3 H), 1.685 (s, 9 H), 1.63 (s, 3 H), 1.47 (app. t, J = 13.2 Hz, 1 H), 1.37 (s, 3 H), 1.14 (s, 3 H). The resonance for the hydroxy proton could not be identified in the ^¹H NMR spectrum. ^¹³C NMR (125 MHz, MeOH-d ₄): δ = 209.5, 195.1, 138.4, 135.3, 134.3, 133.7, 133.2, 129.7, 128.9, 124.1, 122.4, 121.3, 121.0, 78.2, 62.1, 49.1 (masked by MeOH signal), 44.8, 42.4, 30.6, 28.4, 26.4, 26.18, 26.16, 24.5, 22.5, 18.5, 18.3, 18.1, 16.4. The resonances for C-2 and C-4 could not be identified in the ^¹³C NMR spectrum (tautomeric exchange). ESI-HRMS (TOF): m/z calcd for C₃₃H₄₂O₄ [M + H]⁺: 503.3161; found: 503.3159.

8

The Danishefsky group reported a low yield for their final
O-demethylation leading to nemorosone, and noted the ‘chemical frailty’ of the natural product. We found nemorosone to be considerably more stable in either MeOH or DMSO than in CHCl₃, making these the solvents of choice for NMR work.

9

Our synthesis is about the same length as the Danishefsky route and proceeds in similarly modest overall yield of about 1-2%.

10

Typical Procedure - Preparation of 13
t-BuLi (160 µL of a 1.7 M solution in pentane) was added dropwise to a solution of bridgehead iodide 11 (75 mg, 0.14 mmol) in THF (2 mL) at -100 ˚C. The resulting strongly yellow reaction mixture was stirred at -100 ˚C for 20 min before adding dropwise the electrophile methyl chloro-formate (53 µL, 0.69 mmol) followed by warming of the reaction mixture to -78 ˚C. After 2 h the reaction was quenched at -78 ˚C using NH₄Cl solution (15 mL). The product was extracted into Et₂O (3 × 20 mL), and the combined organic layers were washed with H₂O (3 × 10 mL) and brine (3 × 10 mL) then dried (MgSO₄). The solvent was removed under reduced pressure, and purification of the residue by flash column chromatography (5% EtOAc in PE) gave bridgehead ester 13 as a colourless oil (33 mg, 50%); R _f  = 0.39 (10% EtOAc in PE). ^¹H NMR (300 MHz, CDCl₃): δ = 5.06 (t, J = 6.9 Hz, 1 H), 4.97 (t, J = 7.9 Hz, 1 H), 3.86 (s, 3 H), 3.74 (s, 3 H), 2.39 (app. d, J = 6.8 Hz, 2 H), 2.12 (dd, J = 11.2, 5.6 Hz, 1 H), 1.76 (dd, J = 13.0, 4.0 Hz, 1 H), 1.68-1.58 (overlapping m, 2 H), 1.65 (s, 6 H), 1.63 (s, 3 H), 1.54 (s, 3 H), 1.43 (app. t, J = 12.8 Hz, 1 H), 1.27 (s, 3 H), 1.10 (s, 3 H), 0.27 (s, 9 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 204.4, 199.9, 179.5, 168.0, 133.7, 133.4, 125.7, 122.3, 119.9, 74.9, 64.9, 64.8, 51.8, 45.1, 42.8, 40.0, 29.3, 27.6, 25.9, 25.7, 24.1, 18.0, 17.8, 16.0, 0.5. ESI-HRMS (TOF): m/z calcd for C₂₇H₄₂O₅Si [M + Na]⁺: 497.2699; found: 497.2694. IR: ν = 2951 (w), 1755 (m), 1728 (s), 1651 (m), 1565 (s), 1247 (s), 844 (s), 752 (s) cm^-¹.
Data for Compounds 14-16
Compound 14 was obtained using TFAA as the electrophile. Colourless oil (25 mg, 59%); R _f  = 0.32 (5% EtOAc in PE). ^¹H NMR (300 MHz, CDCl₃): δ = 5.02-4.88 (m, 2 H), 3.96 (s, 3 H), 2.54-2.31 (m, 2 H), 2.19-2.04 (m, 1 H), 1.86 (dd, J = 13.2, 3.9 Hz, 1 H), 1.70-1.52 {m, 14 H, including [1.67 (s, 3 H), 1.63 (s, 6 H), 1.55 (s, 3 H)}, 1.41 (app. t, J = 12.9 Hz, 1 H), 1.25 (s, 3 H), 1.07 (s, 3 H), 0.30 (s, 9 H). ^¹9F NMR (282 MHz, CDCl₃): δ = -74.7 (s). ^¹³C NMR (100 MHz, CDCl₃): δ = 205.8, 199.4, 188.9 (q, ^² J _C-F = 33.8 Hz), 176.3, 134.2, 133.9, 122.2, 121.9, 119.2, 115.0 (q, J _C-F = 294.8 Hz), 75.5, 64.9, 64.1, 46.6, 42.7, 40.9, 29.1, 27.4, 25.8, 25.7, 23.9, 18.0, 17.8, 15.8, 1.1. ESI-HRMS (TOF): m/z calcd for C₂₇H₃₉O₄F₃Si [M + Na]⁺: 535.2467; found: 535.2473. IR: ν = 2917 (m), 1768 (m), 1723 (m), 1655 (s), 1561 (s), 1233 (s), 1163 (s), 844 (s), 720 (s) cm^-¹.
Compound 15 was obtained as a single diastereomer using acetaldehyde as the electrophile. Colourless oil (48.4 mg, 58%); R _f  = 0.47 (20% EtOAc in PE). ^¹H NMR (500 MHz, CDCl₃): δ = 5.00 (t, J = 6.6 Hz, 1 H), 4.95 (t, J = 5.9 Hz, 1 H), 4.50 (app. sext, J = 6.3 Hz, 1 H), 3.95 (s, 3 H), 3.65 (d, J = 12.0 Hz, 1 H), 2.42 (dd, J = 14.5, 7.7 Hz, 1 H), 2.34 (dd, J = 14.5, 6.4 Hz, 1 H), 2.10-2.07 (m, 1 H), 1.82 (dd, J = 13.2, 4.2 Hz, 1 H), 1.66 (s, 3 H), 1.64 (s, 3 H), 1.62 (s, 3 H), 1.70-1.58 (overlapping m, 1 H), 1.54 (s, 3 H), 1.52-1.48 (overlapping m, 1 H), 1.40 (dd, J = 13.0 Hz, 1 H), 1.28 (d, J = 6.3 Hz, 3 H), 1.23 (s, 3 H), 1.11 (s, 3 H), 0.22 (s, 9 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 214.6, 200.2, 185.0, 133.9, 133.1, 124.8, 122.5, 119.8, 69.0, 67.5, 65.2, 63.3, 46.2, 44.1, 41.2, 29.9, 27.7, 25.9, 25.8, 23.9, 21.8, 18.4, 18.0, 17.9, 0.8. ESI-HRMS (TOF): m/z calcd for C₂₇H₄₄O₄Si [M + Na]⁺: 483.2907; found: 483.2902. IR: ν = 3529 (w), 2969 (m), 1710 (m), 1649 (m), 1227 (s), 1107 (w), 843 (s), 754 (s) cm^-¹.
Compound 16 was obtained as a single diastereomer using isobutyraldehyde as the electrophile. Colourless oil (18.8 mg, 51%); R _f  = 0.52 (20% EtOAc in PE). ^¹H (300 MHz, CDCl₃): δ = 4.92 (br s, 2 H), 4.56 (d, J = 11.8 Hz, 1 H), 4.26 (dd, J = 11.8, 2.0 Hz, 1 H), 3.95 (s, 3 H), 2.45 (dd, J = 14.0, 8.3 Hz, 1 H), 2.31 (dd, J = 14.0, 5.8 Hz, 1 H), 2.07 (d, J = 12.3 Hz, 1 H), 1.88 (dd, J = 12.2, 3.4 Hz, 2 H), 1.73-1.51 {m, 14 H, including [1.66 (s, 6 H), 1.58 (s, 3 H), 1.53 (s, 3 H)}, 1.34 (dd, J = 12.5 Hz, 1 H), 1.25 (s, 3 H), 1.15 (s, 3 H), 1.02 (d, J = 6.8 Hz, 3 H), 0.65 (d, J = 6.9 Hz, 3 H), 0.22 (s, 9 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 216.2, 199.9, 185.0, 134.0, 133.1, 124.0, 122.5, 119.7, 65.7, 65.6, 63.0, 48.0, 44.3, 42.7, 32.0, 30.0, 29.7, 27.8, 25.9, 25.8, 24.3, 22.2, 18.7, 18.0, 17.9, 17.3, 0.7. ESI-HRMS (TOF): m/z calcd for C₂₉H₄₈O₄Si [M + Na]⁺: 511.3220; found: 511.3228. IR: ν = 3484 (w), 2958 (m), 1707 (m), 1649 (s), 1548 (s), 1421 (w), 1229 (s), 1017 (w), 844 (s), 756 (s) cm^-¹.