Efficient Asymmetric Synthesis of Reissert Compounds

Abstract

Asymmetric synthesis of Reissert compounds 5, 12 was achieved using chiral acyl halides such as amino acid fluorides or (-)-(R)-menthylchloroformate and TMSCN. These are the first cases of asymmetric synthesis of unsubstituted isoquinoline-derived Reissert compounds with high stereoselectivities. The chiral Reissert compound 12 could be alkylated in position 1 affording 1-substituted Reissert compound 13 highly stereoselectively. The products are potential starting materials for unnatural amino acids and alkaloid analogues.

Key words

Reissert compounds - asymmetric synthesis - isoquinol­ines - amino acid fluorides - menthylchloroformate

References

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• 1b Popp FD. In Advances in Heterocyclic Chemistry   Vol. 9:  Katritzky AR. Academic Press; London: 1968.  p.1 
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• 4 Surygina O. Ehwald M. Liebscher J. Tetrahedron Lett.  2000,  41:  5479 
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• All quantum chemical calculations have been performed with the TURBOMOLE suite of programs:
• 12a

  TURBOMOLE (Vers. 5.5): Ahlrichs, R.; Bär, M.; Baron, H.-P.; Bauernschmitt, R.; Böcker, S.; Ehrig, M.; Eichkorn, K.; Elliott, S.; Furche, F.; Hase, F.; Häser, M.; Horn, H.; Huber, C.; Huniar, U.; Kattannek, M.; Kölmel, C.; Kollwitz, M.; May, K.; Ochsenfeld, C.; Öhm, H.; Schäfer, A.; Schneider, U. Treutler, O.; von Arnim, M.; Weigend, F.; Weis, P.; Weiss, H. Universität Karlsruhe 2002. The structures of 5 (Ph substituent replaced by a methyl group) and 12 have been fully optimised at the density functional (DFT) level employing the BP86 functional (b), a Gaussian AO basis of valence-double-zeta quality including polarisation functions (SVP) (c)and the RI-approximation for the two-electron integrals (d). The structures have been used in subsequent calculations of the frequency-dependent optical rotatory dispersion ([α]) at the sodium-d-line wavelength. These calculations have been performed in the framework of time-dependent DFT (e)as described in detail in (f). In the TDDFT approach the SVP basis sets augmented with diffuse basis functions (C, O: [1s1p1d], H: [1s1p]) have been used.

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Liebscher, J.; Surygina, O. presented at ICOS, Christchurch, New-Zealand, 2002.

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Reissert Compound 5a: Anhyd AlCl₃ (30 mg, 0.2 mmol) was added to a solution of (S)-N-cbz-alanoyl fluoride (500 mg, 2.22 mmol) in anhyd CH₂Cl₂ (50 mL) at -40 °C. A solution of isoquinoline (300 mg, 2.32 mmol) in anhyd CH₂Cl₂ (10 mL) was added at -40 °C over a period of 30 min. After stirring at this temperature for 2 h, the temperature was lowered to -78 °C and a solution of TMSCN (230 mg, 2.32 mmol) in anhyd CH₂Cl₂ (10 mL) was added at this temperature over a period of 1 h. After 4 h stirring at -78 °C and combining with ice water (100 mL) the mixture was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layers were washed with sat. aq NH₄Cl and 5% aq NaHCO₃, dried (MgSO₄) and concentrated under vacuum. Yield 830 mg (93%). Further purification by flash chromatography (CH₂Cl₂-MeOH) is possible but causes decomposition of a part of the product. [α] _D ²⁰ -118.7 (c 1, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 1.40 (d, J = 7.16 Hz, 3 H, CH₃), 4.72 (q, J = 7.16 Hz, 1 H, CH₃CH), 5.00 (s, 2 H, CH₂), 6.06 (d, J = 7.54 Hz, 1 H, CHCH-N), 6.57 (s, 1 H, CH-CN), 7.11 (d, J = 7.54 Hz, 1 H, CHCH-N), 7.20 (m, 1 H, NH), 7.25 (m, 5 H, CH_ar), 7.32-7.27 (m, 4 H, CH_ar). ¹³C NMR (75 MHz, CDCl₃): δ = 18.3 (CH₃), 43.7 (CH), 46.9 (CH), 67.1 (CH₂), 112.2 (CH), 116.1 (CN), 124.3 (C_q), 126.1 (CH), 126.7 (CH), 128.0 (CH), 128.2 (CH), 128.2 (CH), 128.4 (CH), 128.5 (CH), 128.8 (CH), 129.4 (C_q), 130.2 (CH), 151.8 (CO), 170.7 (CO). HRMS calcd for C₂₁H₁₉N₃O₃: 361.1426. Found: 361.1420.

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Observed [α]_D ²⁰ +27.4 (c 1.05, Et₂O), reference sample provided from Catalogue Special amino acids, building blocks of Neosystem groupe SNPE, Strasbourg, France: [α]_D ²⁰ 25.8 (c 1, DMF)

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Preparation of Reissert Compounds 12: The isoquinoline 9 (2.0 mmol) dissolved in CH₂Cl₂ (50 mL) was slowly added to a solution of (-)-(R)-menthylchloroformate (2.2 mmol) and AlCl₃ (20 mol%) in CH₂Cl₂ (20 mL) under argon at
-40 °C. After 30 min the yellow solution was cooled to
-78 °C and a solution of TMSCN (2.0 mmol) in CH₂Cl₂
(1 mL) was slowly added. After stirring for 3 h, the colourless solution was brought to r.t. and poured onto ice/water. The organic phases were separated, dried over MgSO₄ and concentrated. Crude products could be purified by column chromatography (silica, dichloromethane). 12a: [α]_D ²⁰ -59.6 (c 1, CH₂Cl₂).