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

Srinivas Padakanti; Bukkapattanam R. Sreekanth; Velisoju Mahendar; Manojit Pal; Khagga Mukkanti; Javed Iqbal; Parthasarathi Das

doi:10.1055/s-2008-1078170

LETTER

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

Srinivas Padakanti^a,b, Bukkapattanam R. Sreekanth^a, Velisoju Mahendar^a, Manojit Pal^a, Khagga Mukkanti^b, Javed Iqbal^a, 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

Abstract

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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

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References

References and Notes

DRL Publication No. 691.

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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) Å^³, 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.

<A NAME="RD12208ST-18">18</A> Takai K. Nitta K. Utimoto K. J. Am. Chem. Soc. 1986, 108: 7408

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.

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.