Download PDF
Synlett 2004(1): 131-133  
DOI: 10.1055/s-2003-43361
LETTER
© Georg Thieme Verlag Stuttgart · New York

Regio- and Stereoselective Synthesis of α-Chiral 2-Substituted 4-Bromo­thiazoles from 2,4-Dibromothiazole by Bromine-Magnesium Exchange. ­Building Blocks for the Synthesis of Thiazolyl Peptides and Dolabellin

Alexandra Spieß, Golo Heckmann, Thorsten Bach*
Lehrstuhl für Organische Chemie I, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Fax: +49(89)28913315; e-Mail: thorsten.bach@ch.tum.de;
Further Information

Publication History

Received 9 September 2003
Publication Date:
26 November 2003 (online)

   Permissions and Reprints All articles of this category

Abstract

Fragment 6 of thiazolyl peptide GE 2270 D2 and fragment 11 of dolabellin were synthesized stereoselectively from 2,4-dibromothiazole (1) in three (6, 44% overall yield) and five synthetic steps (11, 63% overall yield). Key to the success of the strategy was a bromine-magnesium exchange, which proceeds with excellent regio- and chemoselectivity at carbon atom C-2 of 1.

Key words

asymmetric synthesis - magnesium - metalations - natural products - thiazoles

14

Procedure for the Conversion 1→4: At 0 °C, 6.60 mL (12.0 mmol) of a 1.80 M i-PrMgBr solution in Et2O was added dropwise to a solution of 2.92 g (12.0 mmol) 2,4-dibromothiazole in 30 mL of THF and the solution was stirred for 15 min at 0 °C. Neat TBS-protected mandelo-nitrile [12] (2.47 g, 10.0 mmol) was added dropwise. The mixture was stirred for 30 min at 0 °C and for another 30 min at r.t. After adding 10 mL of EtOH the reaction mixture was cooled to -78 °C and NaBH4 (0.76 g, 20.0 mmol) was added carefully in small portions. The mixture was stirred for 2 h at -78 °C and - after removing the cooling bath - over night at r.t. The reaction mixture was quenched with 25 mL of sat. aq NH4Cl solution and diluted with 200 mL Et2O. The organic layer was washed with 200 mL H2O and 100 mL brine and it was subsequently dried over Na2SO4. GC analysis indicated a facial diastereoselectivity of 79:21. After filtration the solvent was removed and the residue was purified by flash chromatography (pentane/Et2O: 75:25→50:50). Compound 4 (2.55 g, 6.18 mmol, 62%) was obtained as a yellow liquid. [α]D 20 -47.9 (c 1.5, CHCl3). 1H NMR (360 MHz, CDCl3): δ = -0.21 (s, 3 H), -0.06 (s, 3 H), 0.82 (s, 9 H), 2.02 (br s, 2 H), 4.41 (d, 3 J = 5.9 Hz, 1 H), 5.04 (d, 3 J = 5.9 Hz, 1 H), 7.09 (s, 1 H), 7.19-7.26 (m, 5 H). 13C NMR (90 MHz, CDCl3): δ = -5.3, -4.8, 18.0, 25.7, 60.6, 78.2, 117.0, 124.3, 127.0, 128.0, 128.1, 140.1, 173.9. Anal. Calcd for C17H25BrN2OSSi (413.45): C, 49.39; H, 6.09; N, 6.78. Found: C, 49.45; H, 6.11; N, 6.71. The erythro-diastereoisomer (0.47g, 1.13 mmol, 11%) was obtained as a yellow liquid.

15

The relative configuration was proven by converting the aminoalcohol 4 and its erythro-diastereoisomer into the corresponding cyclic N-Boc protected N,O-acetals which were studied independently by 1H NMR spectroscopy. In addition, a known acetal [11] was prepared by carboxylation of product 5 at carbon atom C-4 (t-BuLi, CO2 in Et2O), transformation into the corresponding ester (EtI in DMF), TBS-deprotection (TBAF in THF) and acetal formation (2,2-dimethoxypropane, TsOH in CH2Cl2). The enantiomeric excess (95% ee) was determined by HPLC analysis of the N-Boc protected product 5 (column: Machery-Nagel, Nucleodex β-OH, 200 × 4.00 mm; eluent: H2O/MeCN 20:80→0:100 over 30 min; flow rate: 1.0 mL/min).

18

Analytical data of compound 8: [α]D 20 +27.5 (c 0.80, CHCl3). 1H NMR (360 MHz, CDCl3): δ = 0.92 (d, 3 J = 6.8 Hz, 3 H), 1.02 (d, 3 J = 6.8 Hz, 3 H), 2.14-2.30 (m, 1 H), 2.60 (br s, 1 H), 4.80 (d, 3 J = 4.8 Hz, 1 H), 7.19 (s, 1 H). 13C NMR (90 MHz, CDCl3): δ = 16.2, 18.8, 34.9, 76.4, 116.7, 124.3, 175.6. Anal. Calcd for C7H10BrNOS (236.13): C, 35.61; H, 4.27; N, 5.93. Found: C, 35.81; H, 4.38; N, 5.87.

19

Analytical data of compound 11: [α]D 20 +26.9 (c 1.15, CHCl3). 1H NMR (360 MHz, CDCl3): δ = 0.93 (d, 3 J = 6.6 Hz, 3 H), 1.03 (d, 3 J = 7.0 Hz, 3 H), 2.08 (br s, 1 H), 2.20-2.35 (m, 1 H), 3.94 (s, 3 H), 4.82 (d, 3 J = 4.8 Hz, 1 H), 8.16 (s, 1 H). 13C NMR (90 MHz, CDCl3): δ = 16.2, 18.9, 35.0, 52.4, 76.7, 127.6, 146.4, 161.9, 175.7. Anal. Calcd for C9H13NO3S (215.27): C, 50.21; H, 6.09; N, 6.51. Found: C, 49.91; H, 6.20; N, 6.29.