‘One-pot’ Reactions: Total Synthesis of the Spirocyclic Marine Sesquiterpene, (+)-Axenol

Abstract

The marine sesquiterpene alcohol (+) axenol was prepared in a very short way from (+)-menthone using a one-pot olefination-ring closing metathesis.

Key words

domino reaction - methylenation - metathesis - organometallic - natural products

References

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• 2 Nicolaou KC. Aktuelle Entwicklungen in der Naturstofforschung   14. Irseer Naturstofftage der DECHEMA e.V.; Irsee: 2002. 
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• 3b Improved catalysts see also: Aeilts SL. Cefalo DR. Bonitatebus PJ. Houser JH. Hoveyda AH. Schrock RR. Angew. Chem.  2001,  113:  1500 
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• For alternative syntheses of this class of compounds:
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• 9b

  Triketon 2a was used as a 2:1 mixture of diastereomers, which could not be separated. The desired (2R)-diastereomer is the major isomer in the mixture.

• 10a

  We considered the McMurry coupling (17 equiv TiCl₃/35 equiv C₈K, DME, 85 °C) for the spiro ring closure which would have led directly to the spiro ketone 3 (and 4) but we could not detect the formation of these products by GC-MS analysis.

• 10b Clive DLJ. Zhang C. Keshava Murthy KS. Hayward WD. Daigneault S. J. Org. Chem.  1991,  56:  6447 
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• 15b

  We are indebted to Professor J. W. Blunt, Univ. of Canterbury, New Zealand, for providing the ¹H and ¹³C NMR spectra of (+)-1.

13

Domino reaction: To a stirring solution of 5.01 g (13.8 mmol) MoOCl₃(THF)₂(5) in THF (30 mL) under Ar at
-80 °C was added 15.8 mL of a solution of 1.6 M MeLi in diethyl ether. Stirring was continued at -80 °C for 10 min after which a solution of 1.07 g (4.2 mmol) of the ketone 2a (2:1) in THF (5 mL) was added slowly using a syringe. The reaction mixture was slowly warmed to r.t. over night. To the brown reaction mixture was added 179 mg (0.2 mmol) of the catalyst {[MesIm][(Cy)₃P]RuCl₂CHPh}(6) and stirring was continued at r.t. for additional 24 h (monitoring by GC). The reaction mixture was diluted with petrol ether/diethyl ether, (10 + 1) and the suspension filtered through silica gel. The concentrated filtrate was distilled. Kugelrohr (110-120 °C/0.06 Torr); yield (3 + 4, as 2:1-mixture): 0.510 g (60%), colorless oil. The mixture was chromatographed on silica gel/10% AgNO₃, eluent CH₂Cl₂. IR (Film): ν = 2956, 2930, 2955, 2870 (CH), 1704 (C=O), 1652 (C=C), 1460, 1376, 1130 cm^-1. C₁₅H₂₄O: HRMS: Calcd 220.1827. Found: 220.1821. 3: ¹H NMR (CDCl₃): δ = 0.89 (d, J = 8.4 Hz, 3 H, CH ₃), 0.92 (d, J = 6.6 Hz, 6 H, CH ₃), 1.37 (ddd, J = 12.8 Hz, J = 12.8 Hz, J = 3.8 Hz, 1 H, 8-H), 1.50-1.75 (m, 4 H, 10-H, 9-H,
4-H), 1.75 (br s, 3 H, allylic-CH ₃), 2.05-2.40 [m, 5 H, 3-H, 8-H, 7-H, CH(CH₃)₂], 2.84 (ddd, J = 13.4 Hz, J = 9.4 Hz, J = 5.2 Hz, 1 H, 4-H), 5.35 (s, 1 H, 1-H). ¹³C NMR (CDCl₃): δ = 16.9 (q, CH₃), 17.2 (q, CH₃), 19.0 (q, CH₃), 21.7 (q, CH₃), 26.5 [d, CH(CH₃)₂], 28.4 (t, C-4), 28.8 (t, C-8), 32.0 (t, C-9), 36.3 (t, C-3), 43.8 (d, C-10), 53.6 (d, C-7), 69.9 (s, C-5), 123.3 (d, C-1), 145.1 (s, C-2), 212.8 (s, CO). GC-EI-MS: m/z (%) = 220 (25) [M⁺], 192 (14) 149 (12), 121 (100), 108 (62). CD (methanol): λ_max(Θ/Δε) = 296 nm (+4.56 × 10³/+1.38). 4: ¹H NMR (CDCl₃): δ = 0.86-0.91 (3 × d, 9 H, 3 Me), 1.54-1.6 (m, 1 H), 1.61-1.68 (m, 1 H), 1.76 (d, J = 1.1 Hz, 3 H, allyl. CH ₃ ), 1.84-1.91 (m, 1 H), 1.96-2.07 (m, 3 H), 2.08-2.15 (m, 2 H), 2.16-2.24 (m, 2 H), 2.25-2.34 (1 H), 5.50 (s, 1 H, 1-H). ¹³C NMR (CDCl₃): δ = 15.9 (q), 16.8 (q), 19.1 (q), 21.3 (q), 24.6 (t, C-8), 26.1 (d, C-10), 29.2 (t, C-4), 34.5 (t, C-9), 35.5 (t, C-3), 41.4 [d, CH(CH₃)₂] 53.9 (d, C-7), 68.0 (s, C-5), 126.4 (d, C-1), 141.3 (s, C-2), 215.7 (s, CO). GC-EI-MS: m/z (%) = 220 (20) [M⁺], 192 (10) 149 (10), 121 (100), 108 (60). CD (methanol): λ_max(Θ/Δε) = 296 nm (-3.48 × 10³/-1.05).
(+)-1: A solution of 88 mg (0.4 mmol) of ketone 3 in THF (10 mL) at r.t. was added 2 mL (2 mmol) of l-Selectride
[1.0 M LiBH(s-Bu)₃ in THF] with stirring. Stirring was continued over night. After this time 0.5 g of solid pyridine-1-oxide was added and stirring was continued for another
1 h. The solution was concentrated and the remaining oil dissolved in diethyl ether (50 mL), the etheral solution washed with 2 N HCl (15 mL), water (3 × 10 mL), dried (MgSO₄), concentrated, and the residue purified on silica gel (petroleum ether/diethyl ether, 10 +1). Yield 75 mg (84%). IR(film): ν = 3470 (OH), 2950 (CH) cm^-1. ¹H NMR (CDCl₃): δ = 0.73 (d, J = 6.7 Hz, 3 H, CH ₃), 0.92 [d, J = 6.6 Hz, 3 H, CH(CH)₃], 0.93 [d, J = 6.6 Hz, 3 H, CH(CH)₃], 1.05 (dddd, J = 3.7 Hz, J = 12.8 Hz, J = 12.8 Hz, J = 12.8 Hz, 1 H, 9-H), 1.15 (m, 1 H, 7-H), 1.26 (dddd, J = 3.7 Hz, J = 12.8 Hz, J = 12.8 Hz, J = 12.8 Hz, 1 H, 8-H), 1.45 (m, 1 H, 9-H), 1.55 [m, 1 H, CH(CH₃)₂], 1.65 (m, 1 H, 8-H), 1.70 (m, 1 H, 10-H), 1.75 (q, J = 1.5 Hz, 3 H, allylic-CH ₃), 1.78 (ddd, J = 12.5 Hz, J = 8.0, J = 8.0 Hz, 1 H, 4-H), 1.88 (ddd, J = 12.5 Hz, J = 8.0, J = 8.0 Hz, 1 H, 4-H), 2.21 (m, 2 H,
3-H), 3.52 (br s, 1 H, 6-H), 5.18 (m, 1 H, 1-H). ¹³C NMR (CDCl₃): δ = 16.2 (q, CH₃), 16.9 (q, allylic-CH₃), 20.7 and 21.2 [q, CH(CH₃)₂], 24.4 (t, C-8), 29.3 [d, CH(CH₃)₂], 31.7 (t, C-4), 33.9 (t, C-9), 34.0 (d, C-10), 36.3 (t, C-3), 45.3 (d, C-7), 58.9 (s, C-5), 76.4 (d, C-6), 125.5 (d, C-1), 142.8 (s,
C-2). GC-MS (70 eV): m/z (%) = 222 (70), 204 (20), 121 (100). [α]_D ²⁵ +23 (c 0.6, CHCl₃). [Lit. [15] : +1.3 (c 0.6, CHCl₃, 589 nm); lit. [5b] : [α]_D ³² -17 (c 0.5, CHCl₃) for (-)-1].