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.
Key words
ORL1 antagonist - multigram-scale preparation - asymmetric
synthesis - cycloalkano[1,2-b ]pyridines - stereoselective reduction
References
1a Mollereau C.
Parmentier M.
Mailleux P.
Butour J.
Moisand C.
Chalon P.
Caput D.
Vassart G.
Meunier
J.-C.
FEBS Lett.
1994,
341:
33
1b Fukuda K.
Kato S.
Mori K.
Nishi M.
Takeshima H.
Iwabe N.
Miyata T.
Houtani T.
Sugimoto T.
FEBS Lett.
1994,
343:
42
1c Chen Y.
Fan Y.
Liu J.
Mestek A.
Tian M.
Kozak CA.
Yu L.
FEBS Lett.
1994,
347:
279
1d 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
1e 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
1f 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
2a Mogil JS.
Grisel JE.
Reinscheid RK.
Civelli O.
Belknap JK.
Grandy DK.
Neuroscience
1996,
75:
333
2b 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
2c 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
2d Champion HC.
Katwitz PJ.
Life Sci.
1997,
60:
241
2e Gumusel B.
Hao Q.
Hyman A.
Chang J.-K.
Kapusta DR.
Lippton H.
Life Sci.
1997,
60:
141
3a 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
3b Bignan GC.
Connolly PJ.
Middleton S.
Expert Opin. Ther. Patents
2005,
15:
357
3c Zaveri N.
Life
Sci.
2003,
73:
663
3d Ronzoni S.
Peretto I.
Giardina GAM.
Expert Opin. Ther. Patents
2001,
11:
525
4 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
5a Yoshizumi T.
Miyazoe H.
Sugimoto Y.
Takahashi H.
Okamoto O.
Synthesis
2005,
1593
5b Takahashi H, Sugimoto Y, Yoshizumi T, Kato T, Asai M, and Miyazoe H. inventors; WO 2005085228.
6 Faull AW.
Brewster AG.
Brown GR.
Smithers MJ.
Jackson R.
J. Med. Chem.
1995,
38:
686
7 Evans DA.
Urpi F.
Somers TC.
Clark JS.
Bilodeau MT.
J. Am. Chem. Soc.
1990,
112:
8215
8
¹ H NMR and RP-HPLC
analyses of the reaction mixture indicated that the diastereoselectivity
was >99:1.
9 Schmid G.
Fukuyama T.
Akasaka K.
Kishi Y.
J. Am. Chem. Soc.
1979,
101:
260
10a Shorey BJ.
Lee V.
Baldwin JE.
Tetrahedron
2007,
63:
5587
10b Kiehne U.
Bunzen J.
Lützen A.
Synthesis
2007,
1061
10c Kaiser EM.
Petty JD.
Synthesis
1975,
705
11a Tsuji J.
Palladium Reagent and Catalysts. Innovation
in Organic Synthesis
John Wiley;
New
York:
1995.
11b Beletskaya IP.
Cheprakov AV.
Chem.
Rev.
2000,
100:
3009
11c de Meijere A.
Meyer FE.
Angew. Chem.,
Int. Ed. Engl.
1994,
33:
2379
12 Shibata I.
Baba A.
Curr. Org. Chem.
2002,
6:
665
13 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).
14 Abbiati G.
Arcadi A.
Bianchi G.
Giuseppe SD.
Marinelli F.
Rossi E.
J. Org. Chem.
2003,
68:
6959
15 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
16 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
