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

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.

asymmetric synthesis - magnesium - metalations - natural products - thiazoles

References

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<A NAME="RG23503ST-14">14</A>

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.

<A NAME="RG23503ST-15">15</A>

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).

<A NAME="RG23503ST-16">16</A> Sone H. Kondo T. Kiryu M. Ishiwata H. Ojika M. Yamada K. J. Org. Chem.  1995,  60:  4774 

<A NAME="RG23503ST-17">17</A> Corey EJ. Shibata S. Bakshi RK. J. Org. Chem.  1988,  53:  2861 

<A NAME="RG23503ST-18">18</A>

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.

<A NAME="RG23503ST-19">19</A>

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.