Enantioselective Synthesis of 6-nor-Fluvirucinin B1

Anne W.  Baltrusch; Franz  Bracher

doi:10.1055/s-2002-34214

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Synlett 2002(10): 1724-1726
DOI: 10.1055/s-2002-34214

LETTER

Enantioselective Synthesis of 6-nor-Fluvirucinin B₁

Anne W. Baltrusch^a, Franz Bracher*^b
^a Institut für Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstr. 55, 38106 Braunschweig, Germany
^b Department für Pharmazie-Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13,81377 München, Germany
Fax: +49(89)21807802; e-Mail: Franz.Bracher@cup.uni-muenchen.de;

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Publication History

Received 8 August 2002
Publication Date:
23 September 2002 (online)

Abstract
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Abstract

An enantioselective synthesis of the 6-nor-derivative 3 of the antiviral macrocyclic lactam fluvirucinin B₁ (2) is presented. Key steps are two regioselective ring opening reactions of chiral epoxides, and a ring-closing metathesis with Grubbs’ catalyst. The choice of appropriate protective groups was essential for the success and efficiency of the synthesis.

Key words

asymmetric synthesis - epoxides - fluvirucin - natural products - metathesis

References

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11

The corresponding trityl ether was also examined, but gave ring opening products only in yields <10%. Similar observations with bulky protective groups have already been described. [13]

18

Ring-closing metathesis: A solution of diene 18 (30 mg, 0.075 mmol) and Ti(i-PrO)₄ (6 mg, 0.02 mmol) in 50 mL anhydrous CH₂Cl₂ was refluxed under N₂ for 1 hour. Then 2 mg (0.002 mmol) benzylidene-bis(tricyclohexylphos-phine)dichlororuthenium, dissolved in 0.5 mL CH₂Cl₂, was added and the mixture was refluxed for 4 days. Purification by flash column chromatography (silica, hexanes-ethyl acetate 5:2) gave 20 mg (72%) 19 as colorless crystals, mp 176 °C. [α]_D ²⁰ = +35.4 (CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.84 (t, J = 7.4 Hz, 3 H), 0.90 (t, J = 7.5 Hz, 3 H), 1.20-1.60 (m, 13 H), 2.00 (m, 2 H), 2.08 (m, 1 H), 2.39 (m, 1 H), 2.65 (m, 1 H), 3.21 (m, 1 H), 3.50 (m, 1 H), 3.75 (m, 1 H), 4.42 (d, J = 11.1 Hz, 1 H), 4.54 (d, J = 11.1 Hz,
1 H), 5.38 (m, 1 H), 5.42 (m, 2 H), 7.30 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 11.0, 12.2, 21.9, 23.4, 24.8, 25.1, 26.9, 29.7, 31.5, 35.3, 39.4, 42.5, 50.3, 72.1, 81.5, 127.4, 127.8 (2 C), 128.3 (2 C), 131.5, 131.7, 139.0, 175.0. MS (EI, 70 eV): m/z 371 (6, M⁺), 280 (100), 263 (12), 100 (12), 91 (91).

19

Analytical data of 3: Mp 208 °C. [α]_D ²⁰ = +50.8 (CHCl₃); ¹H NMR (400 MHz, CDCl₃-CD₃OD 1:1) δ (ppm) 0.88 (t, J = 7.5 Hz, 3 H), 0.89 (t, J = 7.1 Hz, 3 H), 1.20-1.75 (m, 22 H), 2.15 (m, 1 H), 2.71 (dt, J = 4.4 and 13.7 Hz, 1 H), 3.48 (m, 1 H), 3.65 (m, 1 H), 5.40 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃/CD₃OD 1:1) δ (ppm) 10.9, 12.3, 21.7, 22.1, 26.0 (2 C), 26.3, 26.4, 27.4, 27.6, 32.4, 33.5, 39.6, 44.9, 52.9, 73.7, 178.2. MS (EI, 70 eV): m/z 283 (44, M⁺), 265 (51), 212 (22), 184 (30), 171 (49), 156 (26), 128 (51), 115 (43), 100 (38), 81 (29), 69 (46), 55 (100), 43 (50).