Practical Syntheses of Enantiomerically Pure Key Intermediates of Opioid Receptor-like 1 (ORL1) Antagonists

Abstract

Practical syntheses of enantiomerically pure key intermediates of opioid receptor-like 1 (ORL1) antagonists are described. Our synthetic methodology features the preparation of multigram quantities of seven-membered key intermediate (-)-3 and six-membered one (-)-4 without the use of toxic tin reagents. In the case of (-)-3, the key step involved diastereoselective reduction using a sterically hindered reducing reagent. Our methodology allows for facile scale-up to afford the products in multigram quantities [in the case of (-)-4, >100-g quantities). These convenient approaches facilitate structure-activity relationship studies including in vivo cardiovascular adverse effects.

ORL1 antagonist - multigram-scale preparation - asymmetric synthesis - cycloalkano[1,2-b]pyridines - stereoselective reduction

References

<A NAME="RF22608SS-1A">1a</A> Mollereau C. Parmentier M. Mailleux P. Butour J. Moisand C. Chalon P. Caput D. Vassart G. Meunier J.-C. FEBS Lett.  1994,  341:  33 

<A NAME="RF22608SS-1B">1b</A> Fukuda K. Kato S. Mori K. Nishi M. Takeshima H. Iwabe N. Miyata T. Houtani T. Sugimoto T. FEBS Lett.  1994,  343:  42 

<A NAME="RF22608SS-1C">1c</A> Chen Y. Fan Y. Liu J. Mestek A. Tian M. Kozak CA. Yu L. FEBS Lett.  1994,  347:  279 

<A NAME="RF22608SS-1D">1d</A> Pan Y.-X. Cheng J. Xu J. Rossi G. Jacobson E. Ryan-Moro J. Brooks AI. Dean GE. Standifer KM. Pasternak GW. Mol. Pharmacol.  1995,  47:  1180 

<A NAME="RF22608SS-1E">1e</A> Reinsceid RK. Nothacker H.-P. Bourson A. Ardati A. Henningsen RA. Bunzow JR. Grady DK. Langen H. Monsma FJ. Civelli O. Science  1995,  270:  792 

<A NAME="RF22608SS-1F">1f</A> Meunier J.-C. Mollereau C. Toll L. Suaudeu C. Moisand C. Alvinerie P. Butour J.-L. Guillemot J.-C. Ferrara P. Monsarrat B. Mazarguil H. Vassart G. Parmentier M. Constentin J. Nature  1995,  377:  532 

<A NAME="RF22608SS-2A">2a</A> Mogil JS. Grisel JE. Reinscheid RK. Civelli O. Belknap JK. Grandy DK. Neuroscience  1996,  75:  333 

<A NAME="RF22608SS-2B">2b</A> Manabe T. Noda Y. Mamiya T. Katagiri H. Houtani T. Nishi M. Noda T. Takahashi T. Sugimoto T. Nabeshima T. Takeshima H. Nature (London)  1998,  394:  577 

<A NAME="RF22608SS-2C">2c</A> Jenck F. Moreau J.-L. Martin JR. Kilpatrick GJ. Reinscheid RK. Monsma FJ. Nothacker H.-P. Civelli O. Proc. Natl. Acad. Sci. U.S.A.  1997,  94:  14854 

<A NAME="RF22608SS-2D">2d</A> Champion HC. Katwitz PJ. Life Sci.  1997,  60:  241 

<A NAME="RF22608SS-2E">2e</A> Gumusel B. Hao Q. Hyman A. Chang J.-K. Kapusta DR. Lippton H. Life Sci.  1997,  60:  141 

Reviews:

<A NAME="RF22608SS-3A">3a</A> Chiou L.-C. Liao Y.-Y. Fan P.-C. Kuo P.-H. Wang C.-H. Riemer C. Prinssen EP. Curr. Drug Targets  2007,  8:  117 

<A NAME="RF22608SS-3B">3b</A> Bignan GC. Connolly PJ. Middleton S. Expert Opin. Ther. Patents  2005,  15:  357 

<A NAME="RF22608SS-3C">3c</A> Zaveri N. Life Sci.  2003,  73:  663 

<A NAME="RF22608SS-3D">3d</A> Ronzoni S. Peretto I. Giardina GAM. Expert Opin. Ther. Patents  2001,  11:  525 

<A NAME="RF22608SS-4">4</A> Yoshizumi T. Takahashi H. Miyazoe H. Sugimoto Y. Tsujita T. Kato T. Ito H. Kawamoto H. Hirayama M. Ichikawa D. Azuma-Kanoh T. Ozaki S. Shibata Y. Tani T. Chiba M. Ishii Y. Okuda S. Tadano K. Fukuroda T. Okamoto O. Ohta H. J. Med. Chem.  2008,  51:  4021 

<A NAME="RF22608SS-5A">5a</A> Yoshizumi T. Miyazoe H. Sugimoto Y. Takahashi H. Okamoto O. Synthesis  2005,  1593 

<A NAME="RF22608SS-5B">5b</A> Takahashi H, Sugimoto Y, Yoshizumi T, Kato T, Asai M, and Miyazoe H. inventors; WO  2005085228. 

<A NAME="RF22608SS-6">6</A> Faull AW. Brewster AG. Brown GR. Smithers MJ. Jackson R. J. Med. Chem.  1995,  38:  686 

<A NAME="RF22608SS-7">7</A> Evans DA. Urpi F. Somers TC. Clark JS. Bilodeau MT. J. Am. Chem. Soc.  1990,  112:  8215 

<A NAME="RF22608SS-8">8</A>

^¹H NMR and RP-HPLC analyses of the reaction mixture indicated that the diastereoselectivity was >99:1.

<A NAME="RF22608SS-9">9</A> Schmid G. Fukuyama T. Akasaka K. Kishi Y. J. Am. Chem. Soc.  1979,  101:  260 

<A NAME="RF22608SS-10A">10a</A> Shorey BJ. Lee V. Baldwin JE. Tetrahedron  2007,  63:  5587 

<A NAME="RF22608SS-10B">10b</A> Kiehne U. Bunzen J. Lützen A. Synthesis  2007,  1061 

<A NAME="RF22608SS-10C">10c</A> Kaiser EM. Petty JD. Synthesis  1975,  705 

Reviews:

<A NAME="RF22608SS-11A">11a</A> Tsuji J. Palladium Reagent and Catalysts. Innovation in Organic Synthesis   John Wiley; New York: 1995. 

<A NAME="RF22608SS-11B">11b</A> Beletskaya IP. Cheprakov AV. Chem. Rev.  2000,  100:  3009 

<A NAME="RF22608SS-11C">11c</A> de Meijere A. Meyer FE. Angew. Chem., Int. Ed. Engl.  1994,  33:  2379 

<A NAME="RF22608SS-12">12</A> Shibata I. Baba A. Curr. Org. Chem.  2002,  6:  665 

<A NAME="RF22608SS-13">13</A>

The most stable conformer was investigated at the B3LYP/6-31G* level. All calculations were performed with the package SPARTAN’ 06 (Wavefunction, Inc. Irvine, CA).

<A NAME="RF22608SS-14">14</A> Abbiati G. Arcadi A. Bianchi G. Giuseppe SD. Marinelli F. Rossi E. J. Org. Chem.  2003,  68:  6959 

<A NAME="RF22608SS-15">15</A>

This levorotatory optical rotation for the (R)-isomer {[α]_D ^²6 -6.3 (c 1.00, CHCl₃)} was not in agreement with the reported data for the (S)-isomer {[α]_D -24.4 (c 2.67, CHCl₃)}.^¹6 However, the levorotatory optical rotation of the corresponding ester, methyl (2R)-2-[(benzyloxy)meth­-yl]pent-4-enoate {[α]_D ^²4 -5.9 (c 4.0, CHCl₃)}, which we prepared from (R)-21, was reasonable, compared to the dextrorotatory optical rotation of the (S)-isomer {[α]_D +3.2 (c 4.0, CHCl₃)}.^¹6

<A NAME="RF22608SS-16">16</A> Sime JT. Barnes RD. Elson SW. Jarvest RL. O’Toole KJ. J. Chem. Soc., Perkin Trans. 1  1992,  1653 ; although (S)-enriched samples, {[α]_D -24.4 (c 2.67, CHCl₃)} of 21 and {[α]_D +3.2 (c 4.0, CHCl₃)} of methyl 2-[(benz-yloxy)methyl]pent-4-enoate, were prepared, the ee values were not reported