Stereoselective Synthesis of the C13–C28 Subunit of (–)-Laulimalide Utilizing an α-Chlorosulfide Intermediate

Sadagopan Raghavan; Pradip Kumar Samanta

doi:10.1055/s-0033-1339493

Synlett, Table of Contents

Synlett 2013; 24(15): 1983-1987
DOI: 10.1055/s-0033-1339493

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Stereoselective Synthesis of the C13–C28 Subunit of (–)-Laulimalide Utilizing an α-Chlorosulfide Intermediate

Sadagopan Raghavan*

Division of Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India Fax: +91(40)27160512 Email: sraghavan@iict.res.in

,

Pradip Kumar Samanta

Division of Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India Fax: +91(40)27160512 Email: sraghavan@iict.res.in

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Abstract

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Abstract

A stereoselective route to the C13–C28 subunit of (–)-laulimalide is described. l-Tartaric acid is the source of the hydroxy groups at C19 and C20. An α-chlorosulfide is employed as the key intermediate for the creation of the C17–C18 bond and the C16–C17 double bond was introduced using the Mislow–Braverman rearrangement and Hutchin’s dexoxygenation with concomitant double bond transposition reaction. The C15 and C23 stereogenic centers were created using catalytic asymmetric reactions. The trisubstituted and trans-disubstituted alkenes were created stereoselectively by taking advantage of ring-closing metathesis and the Julia–Kocienski olefination reaction, respectively.

Key words

laulimalide - α-chloro sulfide - Julia–Kocienski olefination - Mislow–Braverman rearrangement - ring-closing metathesis

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References

References and Notes

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26 Compound 4: To a solution of sulfone 5 (54 mg, 0.17 mmol, 1.5 equiv) in anhyd DMF (0.2 mL) and HMPA (64 μL) cooled at –60 °C was added KHMDS (192 μL, 15% in toluene, 1.2 equiv) via syringe. The reaction was stirred for 15 min and cooled to –78 °C. A solution of aldehyde 6 (80 mg, 0.12 mmol, 1 equiv) in anhyd DMF (0.2 mL) and HMPA (64 μL) was added dropwise. The reaction was stirred at the same temperature for 1 h and allowed to warm to ambient temperature for over a period of 12 h. The reaction mixture was quenched by adding sat. aq NH₄Cl solution (2 mL), the layers were separated and the aqueous layer was extracted with CH₂Cl₂ (3 × 15 mL). The combined organic layers were washed with brine, dried over anhyd Na₂SO₄, filtered and concentrated under reduced pressure to furnish the crude product. Purification of the crude residue via flash chromatography on silica gel using 12% EtOAc–hexane as the eluent afforded 4 as a colorless oil (56 mg, 0.09 mmol) in 75% yield. TLC (SiO₂): R_f 0.6 (EtOAc–hexane, 3:7); [α]²⁵ _D –21° (c = 0.98 in CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 7.58–7.70 (m, 4 H), 7.24–7.34 (m, 6 H), 5.74 (dt, J = 14.8, 5.0 Hz, 1 H), 5.52–5.64 (m, 2 H), 5.23–5.38 (m, 2 H), 4.56 (d, J = 7.0 Hz, 1 H), 4.37 (d, J = 7.0 Hz, 1 H), 4.08–4.16 (m, 1 H), 4.00–4.09 (m, 2 H), 3.87–3.96 (m, 1 H), 3.67–3.74 (m, 1 H), 3.62–3.66 (m, 1 H), 3.56–3.61 (m, 1 H), 3.20 (s, 3 H), 2.13–2.31 (m, 2 H), 1.91–2.04 (m, 1 H), 1.69–1.87 (m, 2 H), 1.60–1.68 (m, 4 H), 1.30 (s, 6 H), 0.98 (s, 9 H). ¹³C NMR (75 MHz, CDCl₃): δ = 135.6, 134.8, 133.9, 133.1, 131.2, 129.6, 128.9, 127.7, 127.0, 119.9, 108.6, 93.5, 81.1, 80.1, 73.4, 72.7, 65.6, 60.4, 55.3, 38.7, 35.8, 34.3, 27.3, 27.0, 23.1, 19.3. IR (neat): 2930, 2858, 1155, 1106, 1033, 704 cm^–1. MS (ESI): m/z = 643 [M + Na]⁺. HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₇H₅₂SiO₆Na: 643.3430; found: 643.3444.

Supplementary Material

Supporting Information