Application of Polymer-Supported Enzymes and Reagents in the Synthesis of γ-Aminobutyric Acid (GABA) Analogues

Abstract

Polymer-supported pig liver esterase was used for the resolution of meso-diesters. The enzyme can be recovered quantitatively from the reaction mixture by filtration and reused without significant loss of activity. Further transformation of the resulting enantiomerically enriched carboxylic acids through the application of polymer-supported reagents and scavengers provides a number of GABA-analogues.

polymer-supported enzymes - pig liver esterase - polymer-supported reagents - GABA-analogues - desymmetrisation

References

<A NAME="RD11602ST-1A">1a</A> Mohr P. Waespe-Sarcevic N. Tamm C. Gawronska K. Gawronski JK. Helv. Chim. Acta  1983,  66:  2501 

<A NAME="RD11602ST-1B">1b</A> Walser P. Renold P. N’Goka V. Hosseinzadeh F. Tamm C. Helv. Chim. Acta  1991,  74:  1941 

<A NAME="RD11602ST-1C">1c</A> Schneider M. Engel N. Hönicke P. Heinemann G. Görisch H. Angew. Chem., Int. Ed. Engl.  1984,  23:  67 

<A NAME="RD11602ST-2A">2a</A> Mosbach K. FEBS Lett.  1976,  62:  E80 

<A NAME="RD11602ST-2B">2b</A> Worsfold P. Pure Appl. Chem.  1995,  67:  597 

For recent reviews see:

<A NAME="RD11602ST-3A">3a</A> Ley SV. Baxendale IR. Bream RN. Jackson PS. Leach AG. Longbottom DA. Nesi M. Scott JS. Storer RI. Taylor SJ. J. Chem. Soc., Perkin Trans. 1  2000,  3815 

<A NAME="RD11602ST-3B">3b</A> Kirschning A. Monenschein H. Wittenberg R. Angew. Chem. Int. Ed.  2001,  40:  650 

<A NAME="RD11602ST-3C">3c</A> Guino M. Brule E. De Miguel YR. Chimica Oggi-Chem. Today  2002,  20:  23 

<A NAME="RD11602ST-3D">3d</A> Ley SV. Baxendale IR. Brusotti G. Caldarelli M. Massi A. Nesi M. Farmaco  2002,  57:  321 

<A NAME="RD11602ST-4A">4a</A> Allan RD. Curtis DR. Headley PM. Johnston GAR. Lodge D. Twitchin BJ. J. Neurochem.  1980,  34:  652 

<A NAME="RD11602ST-4B">4b</A> Kusama T. Spivak CE. Whiting P. Dawson VL. Schaeffer JC. Uhl GR. Br. J. Pharmacol.  1993,  109:  200 

<A NAME="RD11602ST-4C">4c</A> Kusama T. Wang T.-L. Guggino WB. Cutting GR. Uhl GR. Eur. J. Pharmacol.  1993,  245:  83 

<A NAME="RD11602ST-5">5</A> Allan RD. Johnston GAR. Med. Res. Rev.  1983,  3:  91 

<A NAME="RD11602ST-6A">6a</A> Kennewell PD. Matharu SS. Tazlor JB. West-wood R. Sammes PG. J. Chem. Soc., Perkin Trans. 1  1982,  2563 

<A NAME="RD11602ST-6B">6b</A> Paulini K. Reissig H.-U. Liebigs Ann. Chem.  1991,  455 

<A NAME="RD11602ST-6C">6c</A> Morikawa T. Sasaki H. Hanai R. Shibuya A. Taguchi T. J. Org. Chem.  1994,  59:  97 

<A NAME="RD11602ST-6D">6d</A> Galeazzi R. Mobili G. Orena M. Tetrahedron: Asymmetry  1997,  8:  133 

<A NAME="RD11602ST-6E">6e</A> Duke RK. Allan RD. Chebib M. Greenwood JR. Johnston GAR. Tetrahedron: Asymmetry  1998,  9:  2533 

<A NAME="RD11602ST-6F">6f</A> Forti L. Ghelfi F. Levizzani S. Pagnoni UM. Tetrahedron Lett.  1999,  40:  3233 

<A NAME="RD11602ST-6G">6g</A> Bonnaud B. Cousse H. Mouzin G. Briley M. Stenger A. Fauran F. Couzinier J.-P. J. Med. Chem.  1987,  30:  318 

<A NAME="RD11602ST-6H">6h</A> Galeazzi R. Mobili G. Orena M. Tetrahedron  1999,  8:  261 

<A NAME="RD11602ST-7">7</A>

Purchased from Fluka Cat. No. 46064; solid support: methacrylamide/allyl glycidylether/methylene-bis-acrylamide; loading: ˜500 U/g.

<A NAME="RD11602ST-8">8</A>

Enantiomeric ratio of 2 using non-immobilized pig liver esterase: 100% ee. [1a]

<A NAME="RD11602ST-9">9</A> Born M. Tamm C. Synthesis  1991,  435 

<A NAME="RD11602ST-10">10</A> Purchased from Aldrich Cat. No. 21,644-5

<A NAME="RD11602ST-11">11</A>

Purchased from Fluka Cat. No. 81393; solid support: poly(4-vinylpyridine)/25% DVB.

<A NAME="RD11602ST-12">12</A>

Purchased from Aldrich Cat. No. 36,834-2; solid support: styrene/DVB; loading: 3.8 mmol/g.

<A NAME="RD11602ST-13">13</A>

Purchased from Fluka Cat. No. 57895; solid support: styrene/>20% DVB; loading: 2.9 mmol/g.

<A NAME="RD11602ST-14">14</A>

Purchased from Fluka Cat. No. 93093; solid support: styrene/2% DVB; loading: 3 mmol/g.

<A NAME="RD11602ST-15">15</A>

Purchased from Novabiochem Cat. No. 01-64-0178; solid support: styrene/1% DVB; loading 2.0-3.5 mmol/g.

<A NAME="RD11602ST-16">16</A>

Lit. value 8: [α]_D ²⁵ = -38.1 (c 1, 1 N HCl). [6d]

<A NAME="RD11602ST-17">17</A>

Enantiomeric ratios of 10a-d using non-immobilized pig liver esterase: 10a: 100% ee, 10b: 90% ee, 10b: 9% ee, 10c: 78% ee. [1a]

<A NAME="RD11602ST-18">18</A>

For the observed inconsistencies compare reported optical rotation in references 1a and 1c. We wish to report the following rotation 10a: [α]_D ²⁵ = -17.4 (c 0.8, CHCl₃). Crystallographic data of the amide formed from 12a and
(+)-(R)-α-methylbenzylamine have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication No. CCDC-189257. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: [phone]; [e-mail]).

<A NAME="RD11602ST-19">19</A>

For compound 10b we measured [α]_D ²⁵ = -3.6 (c 0.95, CHCl₃), which is the opposite of the rotations published in references 1a,c.

<A NAME="RD11602ST-20">20</A>

According to the ¹³C NMR spectrum the ratio of the diastereomers is 1:1.7.

<A NAME="RD11602ST-21">21</A>

Purchased from Novabiochem Cat. No. 01-64-0177; solid support: styrene/2% DVB; loading: 2.0-3.0 mmol/g.

<A NAME="RD11602ST-22">22</A>

Lit. values: 13a·HCl: [α]_D ²⁵ = -38.1 (c 1, 1 N HCl); [6d] 13b·HCl: [α]_D ²⁵ = 24.1 (c 0.4, MeOH); [6h] analytical data for 13d: ¹H NMR (400 MHz, D₂O): δ = 1.25-1.71 (m, 8 H), 2.08-2.19 (m, 1 H), 2.43-2.50 (m, 1 H), 2.97 (dd, J = 12.8, 5.9 Hz, 1 H), 3.05 (dd, J = 12.8, 7.7 Hz, 1 H); ¹³C NMR (100 MHz, D₂O): δ = 21.9, 24.5, 26.5, 27.3, 35.6, 40.6, 47.6, 183.6; 13d·HCl: [α]_D ²⁵ = 3.3 (c 1.1, MeOH).

<A NAME="RD11602ST-23">23</A>

Purchased from Novabiochem Cat. No. 01-64-0170; solid support: styrene/1% DVB; loading: 2.2 mmol/g.

<A NAME="RD11602ST-24">24</A>

Lit. value 15: [α]_D ²⁵ = 49.2 (c 1, CHCl₃). [6h]

<A NAME="RD11602ST-25">25</A> Soai K. Yokoyama S. Mochida K. Synthesis  1987,  647