The Catalytic Asymmetric Claisen Rearrangement (CAC) in Natural Product Synthesis: Synthetic Studies Toward (-)-Ecklonialactone B

Abstract

A catalytic asymmetric Claisen rearrangement (CAC) in concert with a ring-closing metathesis (RCM) has been utilized in the enantioselective synthesis of the C10-C18 segment of ecklonialactone B.

total synthesis - natural products - asymmetric catalysis - pericyclic reactions - Lewis acids

References and Notes

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<A NAME="RG14107ST-5">5</A> Ecklonialactones have also been isolated from the brown alga Eisenia bicyclis, see: Kousaka K. Ogi N. Akazawa Y. Fujieda M. Yamamoto Y. Takada Y. Kimura J. J. Nat. Prod.  2003,  66:  1318 

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Synthesis of (3 R ,4 R )-4
A stock solution of {Cu[(S,S)-tert-Bu-box]}(H₂O)₂(SbF₆)₂ (10) in CF₃CH₂OH (1 mL, 0.1 M, 86 mg, 0.1 mmol, 0.05 equiv) was dissolved in CH₂Cl₂ (5 mL). The allyl vinyl ether (E,Z)-5 (0.59 g, 2.0 mmol, 1 equiv) was then added and the solution was stirred over night at r.t. At this point, additional {Cu[(S,S)-tert-Bu-box]}(H₂O)₂(SbF₆)₂ (0.5 mL, 0.1 M in CF₃CH₂OH, 43 mg, 0.05 mmol, 0.025 equiv) was added. The reaction mixture was stirred for 3 d at r.t. and then concentrated under reduced pressure. The catalyst was removed by filtering the crude product mixture through a short path silica gel column. Subsequent flash chromatography (hexane-EtOAc, 50:1) afforded the α-keto ester 4 (0.54 g, 1.8 mmol, 92%) as a light yellow oil. TLC: R _f = 0.72 (hexane-EtOAc, 5:1). ¹H NMR (400 MHz, CDCl₃): δ = 2.32-2.36 (m, 2 H), 2.83 (ddd, J ₁ = 19.1 Hz, J ₂ = 9.5 Hz, J ₃ = 4.8 Hz, 1 H), 3.32 (dd, J ₁ = J ₂ = 9.7 Hz, 1 H), 3.39-3.47 (m, 2 H), 3.54 (s, 3 H), 4.27 (d, J = 12.1 Hz, 1 H), 4.31 (d, J = 12.1 Hz, 1 H), 4.90-4.97 (m, 2 H), 5.13-5.17 (m, 2 H), 5.52 (ddd, J ₁ = 17.4 Hz, J ₂ = J ₃ = 9.5 Hz, 1 H), 5.64 (dddd, J ₁ = 17.1 Hz, J ₂ = 10.0 Hz, J ₃ = 7.1, J ₄ = 7.0 Hz, 1 H), 7.19-7.31 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 34.7 (CH₂), 48.2 (CH), 48.2 (CH), 52.4 (CH₃), 72.5 (CH₂), 72.6 (CH₂), 117.2 (CH₂), 118.9 (CH₂), 127.5 (3 × CH), 128.2 (2 × CH), 134.7 (CH), 135.4 (CH), 137.3 (C), 161.2 (C), 194.7 (C). IR (in substance): 3080-2860, 1730, 1640 cm^-1. Anal. Calcd for C₁₈H₂₂O₄: C, 71.5; H, 7.3. Found: C, 71.5; H, 7.1. [α]_D ²⁵ +46.8 (c 0.68, CHCl₃).

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<A NAME="RG14107ST-19">19</A>

Synthesis of 3
Diene 11 (36.4 mg, 0.12 mmol, 1 equiv) was dissolved in DCE (2.5 mL) in a septum-sealed round-bottomed flask. The flask was twice evacuated (20 mbar, 2 min) and ventilated with argon. The Grubbs catalyst 12 (1.0 mg, 1.2 µmol, 0.01 equiv) was then added to the solution and the flask was again twice evacuated and ventilated with argon. The reaction mixture was then stirred for 5 h at 40 °C. Silica gel (120 mg) was subsequently added and the heterogeneous mixture was stirred for several minutes. The solid was then removed by filtration and the solvents were evaporated at reduced pressure. The crude product was purified by flash chromatography (hexane-EtOAc, 20:1 to 10:1) to afford the cyclopentenoid 3 (27.6 mg, 0.10 mmol, 84%) as a light yellow oil. TLC: R _f = 0.17 (hexane-EtOAc, 5:1). ¹H NMR (400 MHz, CDCl₃): δ = 2.32 (ddd, J ₁ = 15.9 Hz, J ₂ = 6.0 Hz, J ₃ = 2.1 Hz, 1 H), 2.41 (ddd, J ₁ = 15.1 Hz, J ₂ = J ₃ = 6.3 Hz, 1 H), 2.51 (ddd, J ₁ = 15.8 Hz, J ₂ = J ₃ = 2.3 Hz, 1 H), 2.96-2.98 (m, 1 H), 3.20 (dd, J ₁ = J ₂ = 8.7 Hz, 1 H), 3.51 (dd, J ₁ = 8.8 Hz, J ₂ = 5.0 Hz, 1 H), 3.66 (s, 3 H), 4.10 (d, J = 6.8 Hz, 1 H), 4.50 (d, J = 12.2 Hz, 2 H), 4.55 (d, J = 12.2 Hz, 1 H), 5.50 (ddd, J ₁ = 3.8 Hz, J ₂ = J ₃ = 1.9 Hz, 1 H), 5.70 (dd, J ₁ = 5.5 Hz, J ₂ = 2.3 Hz, 1 H), 7.25-7.35 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 35.7 (CH₂), 45.9 (CH), 48.8 (CH), 52.0 (CH₃), 73.2 (CH₂), 73.5 (CH₂), 74.0 (CH), 127.7 (3 × CH), 128.4 (2 × CH), 130.1 (CH), 130.9 (CH), 137.6 (C), 174.4 (C). IR (in substance): 3445, 3060-2855, 1738 cm^-1. Anal. Calcd for C₁₆H₂₀O₄: C, 69.5; H, 7.3. Found: C, 69.3; H, 7.6. [α]_D ²⁵ -58.9 (c 0.56, CHCl₃).

<A NAME="RG14107ST-20">20</A> Hicks DR. Fraser-Reid B. Synthesis  1974,  203 

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<A NAME="RG14107ST-22">22</A>

Synthesis of 2
To a solution of the olefin 17 (79.6 mg, 0.32 mmol, 1 equiv) in CH₂Cl₂ (12 mL) was added Na₂HPO₄ (137.7 mg, 0.97 mmol, 3 equiv) and MCPBA (77% purity, 108.7 mg, 0.49 mmol, 1.5 equiv) at 0 °C. The reaction mixture was then stirred for 7 h at r.t. and subsequently quenched with sat. aq Na₂SO₃ solution. The layers were separated and the aq phase was extracted three times with CH₂Cl₂. The combined organic phases were dried with MgSO₄ and concentrated under reduced pressure. Flash chromatography (hexane-EtOAc, 20:1 to 10:1) afforded the epoxide 2 (56 mg, 0.21 mmol, 66%) and its diastereomer 18 (22 mg, 0.08 mmol, 26%). TLC (hexane-EtOAc, 2:1): R _f (18) = 0.41, R _f (2) = 0.31.
Compound 2: ¹H NMR (400 MHz, CDCl₃): δ = 0.92 (dd, J ₁ = J ₂ = 7.4 Hz, 3 H), 1.26 (ddq, J ₁ = 14.2, J ₂ = 7.3 Hz, J ₃ = 7.1 Hz, 1 H), 1.41 (ddd, J ₁ = 13.9 Hz, J ₂ = 9.1 Hz, J ₃ = 0.7 Hz, 1 H), 1.47-1.59 (m, 2 H), 2.12-2.19 (m, 2 H), 3.26 (ddd, J ₁ = 8.5 Hz, J ₂ = 8.3 Hz, J ₃ = 1.9 Hz, 1 H), 3.40-3.41 (m, 2 H), 3.53 (dd, J ₁ = 9.3 Hz, J ₂ = 9.1 Hz, 1 H), 3.81 (dd, J ₁ = 9.1 Hz, J ₂ = 4.5 Hz, 1 H), 4.15 (OH, 1 H), 4.54 (d, J = 12.1 Hz, 1 H), 4.62 (d, J = 12.1 Hz, 1 H), 7.26-7.29 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 9.2 (CH₃), 28.0 (CH₂), 32.4 (CH₂), 44.7 (CH), 45.6 (CH), 55.6 (CH), 59.1 (CH), 71.5 (CH₂), 73.5 (CH₂), 75.8 (CH), 127.8 (3 × CH), 128.4 (2 × CH), 137.0 (C). IR (in substance): 3430, 3090-2875, 1715 cm^-1. Anal. Calcd for C₁₆H₂₂O₂: C, 73.3; H, 8.5. Found: C, 72.9; H, 8.6. [α]_D ²⁵ -55.1 (c 0.55, CHCl₃).

The stereochemical result of the epoxidation may be explained by assuming a favorable hydroxyl directed (12Si,13Si)-attack of the peracid, see:

<A NAME="RG14107ST-23A">23a</A> Hoveyda AH. Evans DA. Fu GC. Chem. Rev.  1993,  93:  1307 ; and literature cited therein

Alternatively and or additionally, the (12Si,13Si)-approach of the peracid from the face opposite to the benzyloxymethyl group on C11 should be favorable. For recent peracid epoxidations of highly substituted cyclopentenoids in the context of the total synthesis of oxylipins, see for example:

<A NAME="RG14107ST-23B">23b</A> Ghosh S. Sinha S. Drew MGB. Org. Lett.  2006,  8:  3781 

<A NAME="RG14107ST-23C">23c</A> Miyaoka H. Hara Y. Shinohara I. Kurokawa T. Yamada Y. Tetrahedron Lett.  2005,  46:  7945