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Synlett 2008(16): 2417-2420  
DOI: 10.1055/s-2008-1078170
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Cross-Metathesis Approach to the Synthesis of Key Precursor of the Macrolide Core of Rhizoxin D [¹]

Srinivas Padakantia,b, Bukkapattanam R. Sreekantha, Velisoju Mahendara, Manojit Pala, Khagga Mukkantib, Javed Iqbala, Parthasarathi Das*a
a Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500049, AP, India
Fax: +91(40)23045438; e-Mail: parthasarathi@drreddys.com;
b Chemistry Division, Institute of Science & Technology, JNT University, Kukatpally, Hyderabad 500072, AP, India
Further Information

Publication History

Received 15 April 2008
Publication Date:
10 September 2008 (online)

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Abstract

The synthesis of key precursor 5 of the macrolide core of rhizoxin D has been achieved by cross metathesis between two olefinic fragments 6 and 7. Both the olefinic fragments are easily synthesized in a diastereoselective manner from the common precursor 1-benzyloxy-2-methylhex-5-ene-3-ol (8).

Keywords

rhizoxin D - Keck allylation - Crimmins aldol - Takai ­olefination - cross metathesis

1

DRL Publication No. 691.

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1

DRL Publication No. 691.

17

Crystal Data for Fragment 17
C40H50O4Si1, M = 622.92, monoclinic, space group P2 1 , a = 14.79 (2) Å, b = 9.29 (1) Å, c = 15.09 (2) Å, β = 102.33 (2)˚, V = 2026 (4) ų, Z = 2, D c = 1.021 g cm-³, reflections collected = 20735, unique reflections = 4637, [R int = 0.0682], final R indices [I > 2σ(I)]: R 1 = 0.065, wR 2 = 0.114, CCDC-662327 contains the supplementary crystallographic data for this letter. These data can be obtained free of charge from The Cambridge Crystallo-graphic Data Centre via www.ccdc.cam.ac.uk./data_request/cif.

19

Spectral Data for 6
[α]D ²³ -21.6 (c 0.5, CHCl3). IR (neat): 2918, 1722, 1614, 1514 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 0.92 (d, 3 H, J = 6.8 Hz), 1.72 (ddd, 1 H, J = 14.0, 10.4, 3.6 Hz), 1.77 (d, 3 H, J = 1.2 Hz), 1.89 (ddd, 1 H, J = 12.0, 9.6, 2.4 Hz), 2.14 (ddd, 1 H, J = 11.6, 6.4, 4.8 Hz), 3.29 (dd, 1 H, J = 9.2, 6.4 Hz), 3.46 (dd, 1 H, J = 10.0, 6.4 Hz), 3.78 (s, 3 H), 3.82 (dd, 1 H, J = 9.2, 4.0 Hz), 4.11 (d, 1 H, J = 10.8, Hz), 4.30 (d, 1 H, J = 10.8 Hz), 4.46 (m, 2 H), 5.29 (ddd, 1 H, J = 7.2, 4.8, 2.4 Hz), 5.79 (dd, 1 H, J = 10.4, 1.6 Hz), 6.05 (dd, 1 H, J = 17.2, 10.4 Hz), 6.20 (s, 1 H), 6.34 (dd, 1 H, J = 17.2, 1.2 Hz), 6.83 (d, 2 H, J = 8.8 Hz), 7.22 (d, 2 H, J = 8.4 Hz), 7.28 (m, 5 H). ¹³C NMR (50 MHz, CDCl3): δ = 13.0, 19.1, 35.7, 37.3, 55.2, 70.3, 71.9, 72.6, 72.9, 79.2, 80.0, 113.8, 127.4, 127.5, 128.3, 129.4, 129.6, 130.0, 130.5, 138.4, 148.0, 159.1, 165.5. ESI-HRMS: m/z calcd for C27H33IO5Na [M + Na]+: 587.1270; found: 587.1277.

20

Synthetic Procedure and Spectroscopic Data of 5
A mixture of a solution of 6 (0.035 g, 0.06 mmol) and 7 (0.024 g, 0.123 mmol) in DCE (0.3 mL) was treated with Grubbs second-generation catalyst (5.25 mg, 0.0056 mmol) and the dark purple solution stirred at reflux temperature for 48 h. The reaction mixture was then loaded directly on top of a wet column packed with SiO2 and purified by flash chromatography (EtOAc-hexane, 1:3) to afford the product 5 (0.036 g, 80%) as light brown oil; [α]D ²³ -22.0 (c 0.1, CHCl3). IR (neat): 3468, 2924, 1712, 1414, 1247 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 0.92 (d, 3 H, J = 6.8 Hz), 0.97 (d, 3 H, J = 7.2 Hz), 1.42 (m, 1 H), 1.72 (m, 1 H), 1.77 (s, 3 H), 1.88 (m, 2 H), 2.18 (m, 6 H), 2.71 (dd, 1 H, J = 12.0, 2.0 Hz), 3.30 (dd, 1 H, J = 9.2, 6.4 Hz), 3.45 (dd, 1 H, J = 9.6, 6.4 Hz), 3.62 (dd, 1 H, J = 10.4, 5.2 Hz), 3.71 (dd, 1 H, J = 10.8, 7.6 Hz), 3.78 (s, 3 H), 3.82 (dd, 1 H, J = 8.8, 4.4 Hz), 4.12 (m, 2 H), 4.30 (d, 1 H, J = 10.8), 4.57 (s, 2 H), 5.26 (ddd, 1 H, J = 7.2, 4.8, 2.8 Hz), 5.81 (d, 1 H, J = 15.6 Hz), 6.20 (s, 1 H), 6.79 (m, 1 H), 6.83 (d, 2 H, J = 8.4 Hz), 7.21 (d, 2 H, J = 8.8 Hz), 7.38 (m, 5 H). ¹³C NMR (50 MHz, CDCl3): δ = 10.4, 12.4, 19.0, 30.9, 32.0, 35.4, 35.9, 37.2, 38.5, 39.6, 55.1, 63.9, 70.2, 71.9, 72.6, 72.8, 79.3, 80.0, 80.2, 113.7, 123.9, 127.4, 128.2, 129.2, 129.5, 129.9, 138.3, 144.5, 147.8, 159.0, 165.4, 170.9. ESI-HRMS: m/z calcd for C36H47IO8Na [M + Na]+: 757.2213; found: 757.2210.