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DOI: 10.1055/s-2003-37118
Efficient Asymmetric Synthesis of Reissert Compounds
Publication History
Publication Date:
07 February 2003 (online)

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
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1a
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Funabashi K.Takamura M.Kanai M.Shibasaki M. Abstract of Papers, 18th International Congress of Heterocyclic Chemistry ICHC; Yokohama: 2001. ; Abstract number 30-PO-56: 203 - 4
Surygina O.Ehwald M.Liebscher J. Tetrahedron Lett. 2000, 41: 5479 - 5
Itoh T.Nagata K.Miyazaki M.Kameoka K.Ohsawa A. Tetrahedron 2001, 57: 8827 -
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Stephens PJ.Devlin FJ.Cheeseman JR.Frisch MJ. J. Phys. Chem. A 2001, 105: 5356 - All quantum chemical calculations have been performed with the TURBOMOLE suite of programs:
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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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References
Liebscher, J.; Surygina, O. presented at ICOS, Christchurch, New-Zealand, 2002.
7Reissert 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, CHar), 7.32-7.27 (m, 4 H, CHar). 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 (Cq), 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 (Cq), 130.2 (CH), 151.8 (CO), 170.7 (CO). HRMS calcd for C21H19N3O3: 361.1426. Found: 361.1420.
8Observed [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)
10
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).