Enantioselective Total Synthesis of (-)-Dibromophakellstatin

Michael Zöllinger; Peter Mayer; Thomas Lindel

doi:10.1055/s-2007-986664

LETTER

Enantioselective Total Synthesis of (-)-Dibromophakellstatin

Michael Zöllinger^a, Peter Mayer^a, Thomas Lindel*^,a,b
^a Department of Chemistry and Biochemistry, Faculty of Chemistry and Pharmacy, Ludwig Maximilian University, Butenandtstr. 5-13, 81377 Munich, Germany
^b Institute of Organic Chemistry, Faculty of Life Sciences, TU Braunschweig, Hagenring 30, 38106 Brunswick, Germany
Fax: +49(531)3917744; e-Mail: th.lindel@tu-bs.de;

Abstract

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Abstract

The antitumor active pyrrole-imidazole alkaloid (-)-dibromophakellstatin from the marine sponge Phakellia mauritiana was synthesized enantioselectively in ten steps, starting from hydroxyproline. The key step is the diastereoselective three-component imidazolidinone annulation to a chiral dipyrrolopyrazinone. Deoxygenation of a hydroxyphakellstatin precursor was achieved by Appel reaction, followed by reduction with SmI₂.

Key words

hydroxyproline - imidazolidinone - marine natural products - N-oxycarbamates - pyrrole-imidazole alkaloids

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References

References and Notes

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CCDC-623847 (12) and CCDC-623846 (15) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB21EZ, UK; fax: +44 (1223)336033; or deposit@ccdc.cam.ac.uk].

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Compound (+)-16: [α]_D ²⁵ +46.1 (c 1.2 mg/10.0 mL, MeOH). TLC (silica, EtOAc): R _f = 0.83. ¹H NMR (600 MHz, CDCl₃): δ = 1.40 (t, 3 H, ³ J = 7.1 Hz, OCH₂CH ₃), 2.42 (s, 3 H, ArCH₃), 2.90-3.00 (m, 2 H, CCH₂), 3.63 (dd, 1 H, ² J = 11.7 Hz, ³ J = 9.9 Hz, NCHH), 4.12-4.18 (m, 1 H, CHBr), 4.42 (dq, 1 H, ² J = 11.5 Hz, ³ J = 7.1 Hz, OCHH), 4.44 (dq, 1 H, ² J = 11.5 Hz, ³ J = 7.1 Hz, OCHH), 4.53 (dd, 1 H, ² J = 11.7 Hz, ³ J = 7.5 Hz, NCHH), 6.05 (s, 1 H, NCHN), 6.36 (dd, 1 H, ³ J = 3.6, 3.1 Hz, CHCHCHN), 6.87 (dd, 1 H, ³ J = 2.7 Hz, ⁴ J = 1.6 Hz, CHCHCHN), 7.07 (dd, 1 H, ³ J = 3.9 Hz, ⁴ J = 1.5 Hz, CHCHCHN), 7.22 [d, 2 H, ³ J = 8.3 Hz, MeC(CH)₂], 7.61 [d, 2 H, ³ J = 8.3 Hz, O₂SC(CH)₂]. ¹³C NMR (150 MHz, CDCl₃): δ = 14.1 (OCH₂ CH₃), 21.9 (PhCH₃), 35.5 (CHBr), 41.7 (CCH₂), 53.5 (NCH₂), 65.2 (OCH₂), 66.3 (NCHN), 83.5 (CCH₂), 112.1 (CHCHCHN), 115.3 (CHCHCHN), 123.0 (CHCHCHN), 123.4 (CCHCHCHN), 129.4 [2 C, O₂SC(CH)₂], 129.5 [MeC(CH)₂], 129.9 [2 C, MeC(CH)₂], 146.9 [SO₂ C(CH)₂], 149.0 [O(CO)N], 151.0 [N(CO)N], 154.2 [(CO)N]. MS (ESI⁺, FTMS): m/z (%) = 553/555 (100/94.5) [M + H⁺]. HRMS (ESI⁺): m/z calcd for [C₂₁H₂₁ ⁷⁹BrN₄O₇S + H]: 553.0393; found: 553.0375.

Reduction of secondary alkyl bromides by SmI₂ has rarely been reported:

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Compound 17 had also been obtained as the (+)-enantiomer by Romo (ref. 5) and as the racemate by Austin (ref. 9).

Compound (-)-1: [α]_D ²⁰ -75.7 (c 0.14 mg/mL, MeOH). TLC (silica, MeOH-CHCl₃, 1:9): R _f = 0.52. ¹H NMR (600 MHz, DMSO-d ₆): δ = 1.95-2.00 (m, 1 H, NCHHCHH), 2.08-2.15 (m, 2 H, NCHHCHHCHH), 2.27-2.33 (m, 1 H, NCHHCHHCHH), 3.40-3.45 (m, 1 H, NCHH), 3.54-3.57 (m, 1 H, NCHH), 5.98 (s, 1 H, NCHN), 6.91 (s, 1 H, CBrCH), 7.97 (s, 1 H, NH), 8.26 (s, 1 H, NH). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 18.8 (NCH₂ CH₂), 39.7 (CCH₂), 44.1 (NCH₂), 68.6 (NCHN), 78.9 (CCH₂), 101.0 (CBrCH), 105.5 (NCBr), 113.7 (CBrCH), 125.3 (CBrCHC), 154.0 [N(CO)N], 157.8 [N(CO)]. MS (ESI⁺, FTMS): m/z (%) = 389/391/393 (40.9/100/39.1) [M + H⁺]. CD (MeOH): λ_max (Δε) = 260 nm (-1.1, tr, sh), 233 (-2.7, tr.). HRMS (ESI⁺): m/z calcd for [C₁₁H₁₀ ⁷⁹Br₂N₄O₂ + H⁺]: 388.9249; found: 388.9255.