Pergamon (cid:9)
`
`Bioorganic & Medicinal Chemistry Letters, Vol. 5, No. 23, pp. 2821-2824, 1995
`Copyright 0 1995 Elsevier Science Ltd
`Printed in Great Britain. All rights reserved
`0960-894X/95 $9.50+0.00
`
`0960-894X(95)00483-1
`
`Asymmetric Synthesis of FR165914: A Novel 33-
`Adrenergic Agonist with a Benzocycloheptene Structure
`
`Kenji Hattori,a* Masanobu Nagano,a Takeshi Kato,a Isao Nakanishi,b Keisuke
`
`Imai,c Takayoshi Kinoshita,b and Kazuo Sakanea
`
`New Drug Research Laborcuories,a Basic Research Laboratories!' Exploratory Research
`
`Laboratories,c Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Kashima, Yodogawa-ku, Osaka 532,
`
`faPal
`
`Abstract: The asymmetric synthesis of a novel 133-adrenergic agonist FR165194 is described.
`The critical steps involve preparation of an optically active amine via stercosclective reduction of a
`chiral imine prepared from a-methylbenzylamine and synthesis of a chiral epoxide via the
`Sharpless asymmetric dihydroxylation.
`
`In 1967,I3-adrenoreceptors were classified into two subtypes 131 and 132.1 Recently, atypical p-
`adrenoreceptors, that is, those which do not fit into either the pi- or the 32- classification, have been
`discovered and have been called I33-adrenoreceptors.2 They appear to be widely distributed among various
`tissues and co-occur with other receptors which complicates their classification.3 In particular, they are
`found on the cell surface of both white and brown adipocytes where their stimulation promotes both
`lipolysis and energy expenditure.4 A Beecham group5 and a number of other laboratories6 have reported
`research directed towards the discovery of potent agonists for 133-Adrenoreceptors, and have identified
`several new structural phenethanolamines. In this paper, we would like to describe the asymmetric
`synthesis of a novel and potent 133-Adrenoreceptor agonist FR165914 and its derivatives having a
`benzocycloheptene ring. The stereochemistry of the phenethanolamine has a crucial influence on the
`potency and selectivity, therefore, our synthetic plan required that both fragments; amino-
`benzocycloheptenes and epoxides be optically active (Scheme 1).
`
`Scheme 1
`
`Ck ICO2Na
`
`0 CO2Na
`
`Cl
`
`2821
`
`CI
`
`1: FR165914
`
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`2822 (cid:9)
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`K. HATTORI et al.
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`The requiste chiral amines were prepared via stereoselective reduction of imines containing a chiral
`auxiliary. The starting 2-benzosuberones 2 were prepared from commercially available 1-tetralones by
`ring expansion according to a modified literature procedure.7 Conversion to the chiral imines with (5)-a-
`methylbenzylamine in the presence of a catalytic amount of p-toluenesulfonic acid under Dean-Stark
`conditions followed by reduction of the resulting imines with Raney nickel (W-2) in methanol furnished
`amines 3 having a S configuration,8 with good selectivity, These results on the asymmetric reduction of
`imines are summarized in Scheme 2.10
`
`Scheme 2
`
`1) S-methylbenzylamine (cid:9)
`cat. Ts0H / toluene
`2) Raney Ni / Me0H; H2, 50 psi
`
`Ph
`
`2a: X,Y: OMe
`b: X: OMe, Y: H
`c: X: H, Y: OMe
`
`3a (cid:9)
`
`yield (%) (cid:9)
`61 (cid:9)
`50 (cid:9)
`70 (cid:9)
`
`ratio
`14 : 1
`12 : 1
`12 : 1
`
`The intermediate imines exist as an equilibrium mixture of E and Z isomers.11 Figure 1
`illustrates the most stable comformation of the E and Z isomers obtained by calculation using QUANTA
`It is reasonable to assume that reduction occurs
`
`(Version 3.3) and PM3 (MOPAC Version 6)12-14 . (cid:9)
`preferentially from the re face of the E-imines by taking into account steric hindrence of both faces of the Z-
`imines. Thereby the predicted absolute configuration of the adducts is in accord with the experimental
`findings.
`
`Figure 1
`
`E -isomer
`
`Z-isomer
`
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`Asymmetric synthesis of FR165914 (cid:9)
`
`2823
`
`The required optically active epoxides were obtained via the Sharpless AD reaction and
`epoxidation. Oxidation of 4 by the standard procedure with commercial available AD-mix-[315 provided the
`diols 5 in 95-98% yield. The diols 5 were easily converted to the epoxides 6 using the method involving a
`cyclic acetoxonium intermediate,16 and had 98-99% ee as determined by HPLC analysis with a chiral
`column (Chiralcel AD). Ring opening of epoxide bd with amine 3a (14:1 mixture) in ethanol under reflux
`for 48 h afforded the phenethanolamine 7 containing a small amount of the undesired diastereomer that was
`easily removed by column chromatography on silica gel. Treatment of enantiomerically pure 7 with BBr3
`followed by alkylation with diethyl dibromomalonate gave the diester compound. Hydrogenolysis of the
`benzyl group employing chlorobenzene as a co-solvent to inhibit reduction of the m-chlorogroup followed
`by hydrolysis furnished FR165914 in 23% overall yield from 7.
`The in vitro effects on p-adrenoreceptors mediated processes are shown in Table 1. FR165914
`possesses potent f33-agonist activity and especially low affinity for pi- and 32-adrenoreceptors.
`
`Scheme 3
`
`OH
`
`AD-mix-13
`/tau0H-H20; 0°C
`95-98% yield
`
`OH 1) TMSCI, MeC(OMe)3
`2) K2CO3
`
`85-97% yield
`
`4d:111: Cl, R2: H
`e:
`Cl
`f: R1: CF3, R2: H
`
`6d
`
`6d: 98% ee
`e: 99% ee
`f: 98% ee
`
`b,c,d,e
`
`OMe
`
`OMe
`
`7
`reagents and conditions: a) 3a, Et0H, 94% yield b) BBr3, CH2Cl2 c) diethyl dibromomalonate,
`K2CO3, DMF d) H2,Pd/C, Et0H-chlorobenzene(1:10) e) NaOH, Et0H, 23% yield (from 7)
`
`Cl (cid:9)
`
`Table 1.
`
`Rat colon (33)
`Icy)
`
`Rat uterus (32)
`1050
`
`Guinea-pig atrium (131)
`EC50
`
`6.0x10-9 (cid:9)
`
`>1.0x10-5 (cid:9)
`
`>1.0x10-5
`
`IC50 and EC50 concentration (M) producing half-maximal effect.
`
`In summary, we have disclosed a stereoselective synthesis for a novel 33-agonist FR165914.
`This method is easily applied to related structures, and is especially attractive for large-scale synthesis. The
`detailed structure-activity investigations will be published in due course.
`
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`2824 (cid:9)
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`K. HATTORI et al.
`
`Acknowledgment. We express our thanks to Dr. D. Barrett for his critical reading of the
`manuscript.
`
`References and Notes
`
`1. Lands, A. M.; Arnold, A.; McAuliff, J. P.; Luduena, F. P.; Brown, T. G., Jr. Nature 1967,
`
`4.
`
`6.
`
`214, 597,
`2. Tan, S.; Curtis-Prior, P. B. Int. J. Obesity 1983, 7, 409.
`(a) Arch, J. R. S.; Kaumann, A. J. Med. Res. Rev. 1993, 13(6), 663. (b) Howe, R. Drugs
`3.
`Fut. 1993, /8(6), 529.
`(a) Arch, J. R. S. Proc. Nutrition Soc. 1989, 48, 215. (b) Lafonate, M.; Berlan, M. J. Lipid
`Res. 1993, 34, 1057,
`5. Arch, 3. R. S.; Ainsworth, A. T.; Cawthorne, M.A.; Piercy, V.; Sennitt, M. V.; Thody, V. E.;
`Wilson, C.; Wilson, S. Nature 1984, 309, 163.
`(a) Bloom, J. D.; Dutia, M. D.; Johnson, B. D.; Wissner, A.; Burns, M. G.; Largis, E. E.; Dolan,
`J. A.; Claus, T. H. J. Med. Chem. 1992, 35, 3081. (b) Badone, D.; Guzzi, U. Bioorg. Med.
`Chem. Lett, 1994, 4, 1921. (c) Cecchi, R.; Croci, T.; Boigegrain, R.; Boveri, S.; Baroni, M.;
`Boccardi, G.; Guimbard, JP.; Guzzi, U. Ear. .1. Med. Chem, 1994, 29, 259. and ref 3.
`(a) Dauben, H. J.; Ringold, H. J.; Wade, R. H.; Pearson, D. L.; Anderson, A. G. Org. Syn.
`Coll. Vol. 4, 221. (b) Evans, D. A.; Carroll, G. L.; Truesdale, L. K. J. Org. Chem. 1974, 39,
`914.
`8. The assignment of the absolute configuration of 3a was determined by X-ray structural analysis.
`9. Goodman reported asymmetric reduction of imine prepared from acyclic ketone and a-
`methylbenzylamine using Raney nickel with good selectivity: Leftheris, K.; Goodman, M. J.
`Med. Chem. 1990, 33, 216.
`10. Ratio was determined by 1H-NMR.
`11. E: Z -Ratio of imines could not be determined.
`12. The most stable conformation for E and Z isomers were determined as follows. The conformation
`of the seven membered ring portions of both compounds were determined using systematic search
`analysis in QUANTA (Version 3.3).13 Next, based on the obtained stable ring conformations of
`each compound, the heat of formation of the rotamers around the N-C bonds were calculated using
`PM3.14 The rotamers which gave the minimum heat of formation were chosen as the most stable
`conformations and are shown in Fig I.
`13. Molecular Simulations Inc. 16 New England Executive Park Burlington, Massachusetts USA
`14. MOPAC Ver.6 (QCPE No.455), Stewart, J. J. P. QCPE Bull. 1989, 9, 10.
`15. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K-S.;
`Kwong, H-L.; Morikawa, K.; Wang, Z-M.; Xu, D.; Zhang, X-L. J. Org. Chem. 1992, 57,
`2768.
`16. Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515.
`
`7.
`
`(Received in Japan 13 October 1995; accepted 16 October 1995)
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