"”“L"I|25B-xi-r 37;;-=2% E{1n3zi‘:£,*E2.FlZ5E| mi namssqasmsn $3fi.§fi1i4z.%‘.’.’nT ISSN 0009-2363
`
`§__|4fl’|_|_QA_L.§.,.,
`
`Mylan Ex. 1020
`Mylan v. Novartis
`|PR2015-00265
`
`Page 1 of 5
`
`Page 1 of 5
`
`Mylan Ex. 1020
`Mylan v. Novartis
`IPR2015-00265
`
`

`
`Editor-in-Chief
`
`Associate Editors
`Editorial Board
`M. ltoh.
`M. Kurata,
`Y. Okadu,
`T. Tsuchiya,
`
`President
`Vice-President
`K. Tsuda
`
`T, Kawasaki
`K. Morita, M. l-lirobc,
`
`S. Tejima
`
`A. Tsuji
`U. Sankawa,
`H. Irie,
`K. Inoue,
`A. lchikawa,
`K. Fuji,
`K. Achiwa,
`T. Komori,
`Y. Kawashima, T. Kinoshita,
`H, Kaneto,
`H. Itokawa,
`T- Ohmolov
`N. Nanbu,
`H. 0&3-W
`M. Mochizuki, S. Muranishi,
`T. Sato,
`S. Shimomura, S. Tzikano,
`J_ Okuda,
`T. Sam),
`T. Tsuruo,
`K. Watanabe, M. Yoshioka
`
`Y. Takase,
`M. Shindo,
`M. Shimada.
`r. Asami,
`Staff
`N. Anrakll,
`F. Sato,
`H. Watanabe,
`Y. Enomoto.
`T. lmai,
`S. Shimizu
`R. I-larada,
`T. Sakamoto,
`K. Yokoyzimzi, T. Kato,
`Oflice of Secretary Pharmaceutical Society of Japan, 1245-501, Sbibuya 2-CIIOITIC. 5hibU)’a‘kU- Tokyo
`150, Japan
`
`Y. Nagai. _
`Y- Ikegilmh
`
`Secretary T. lmai
`Staff of Editorial and Publication Department Y. Maru (Chief), M. Fujita, M. Sato, K. Kubonoyil,
`T. Kuroiwa
`
`The publication of this Journal was supported in part by it Grant-in-Aid for Publication of Scientific Research Result from the
`Ministry of Education, Science and Culture, which is gratefully acknowledge.
`FOREIGN INl')IVII)LlAL, DOMESTIC MEMBER, AND DOMESTIC BODY SUBSCRIPTIONS FOR I989
`including postage:
`
`}'Yakiiga/(14 Za.i.i‘Iii (J. Plmrm. Soc. Japan) (monthly)
`l C'/1(‘niiL'u/ & P/mr'n1u('eurt't‘u/ Bullciliri (monthly)
`
`[Foreign]
`lndividual*
`
`Besides
`membership fee.
`Ordinary
`Student
`¥23,l()0
`‘t‘6_300
`¥4,800
`US$69.00
`’t‘-‘£0,000
`'Yl0.000
`“F7900
`I_}5S9‘),0{)
`*The foicigii individual subscriber is enrolled as it mem-
`ber of the Society.
`Foreign individual, domestic member. and domestic body subscriptions should be addressed to the Pharmaceutical Society of
`Japan. 12 l5—50l, Shibuya 2—chomci Shibuya-ku, Tokyo 150, JAPAN.
`D0.VlESTIC NON-MEMBER RATES FOR 1989 including postage:
`Y1//citgultu Zr/.i'5'/ii (J. Pharm. Sur. ./upzm) (monthly)
`('/mniwl & P/mrniaceutiazl Bu//min (monthly)
`FOREIGN l\'Ol\'-MEMBER RATES:
`inquire directly to the undermciitioncd agencies,
`DOMESTIC AND FOREIGN NON-MEMBER SLBSCRIPTIONS of the Journal and Bulletin are handled solely by:
`Japan Publication Trading Co., (U.S.A) Inc.. I255 Howard St, San Francisco. Calif. 94|03. U.S.A. and 175 Fifth Avenue. New
`York, N.Y. 10010, U.S.A.
`Japan Publications Trading Co., Ltd., Central P.0, Box 5030 Tokyo International, Tokyo, JAPAN.
`Kyowzt Book C0,. Inc.. Akimoto Bldg.. 38. Jimho~cho l-chome. Kainda, Chiyodzi-kn. Tokyo, JAPAN.
`Maruzen Co., Ltd., P.O. Box 5050, Tokyo Internatlonetl
`l00—3l, JAPAN,
`NOTICES T0 AUTHORS
`
`[Domestic]
`
`Bod)’
`
`per copy
`Pm Copy
`
`‘£52,300
`€54,000
`
`Page charges Regular Articles and Notcs- ‘i"4_0(J0/printed page. Communications to the Editor: ¥S.l00/printed page.
`correction charge: ¥700/printed page. Photographic Flutes and Blocks: cu. ¥l,7t)0/50cm’.
`Reprints
`50 reprints: free ofchargc. Over 50 reprints: ’l‘60/COPY
`See CONTRIBUTION RULES. printed in Fm'zmi(I.i‘/ii'u, 1‘) (1), 81 (1983), 2| (8), 797 (I985), 24 (5), 510 (1988), or C/zem. P/iurm.
`Bu//_, 37(1), ] ([989). before writing at paper for Client. P/mrm. Bull. The RULES collected together into a pamphlet: ’i‘950 (including
`pOSl'(1gCl/C0p_V.
`
`I_aiigu-age
`
`Page 2 of 5
`
`Page 2 of 5
`
`

`
`3033
`
`Chem. Phurm_ Bull. 37(2) 308-310 (1989)
`
`Vol. 37, No. 2
`
`,_._..~g;"
`
`Photochemical Iron(III)-Mediated Autoxidation of Dextromethorphan
`
`Giovanni BOCCARDI,*‘a Piergiorgio MEZZANZANICA,“ Umberto Guzzi,“ Giordano LEsMA," and Giovanni PALM1sA_No*-"
`Centre Ricerclie Midy S_p_A.,“ SANOFI Recherche, I 20137 Milaw, Izczly and Diparrimento dz‘ Chimiczz Organica e Industriale, Facolrd dz‘ Scierize_
`Universitd degli Studi,” I 20133 Mz'Iana,_IlaIy. Received August I, 1988
`
`The photochemical reaction of dextromethorphan 1, a widely used anti-tussive drug, in hydrochloric acid and in the
`presence of irou('III) salts leads to the 101%-hydroxyderivative 3 as a major product in a_d,fi@ EiY§2-
`The product composition of this reaction is strongly dependent on the experimental conditions and the effects of solvents
`are presented.
`Keywords
`
`photochemistry; heavy metal catalysis; autoxidation; stability; dextromethorphan
`Q
`
`-
`
`Dextromethorphan [3—methoxy-l 7-methyl-(9oc, 1 3:2, 141)-
`morphinan, 1) is a valuable non-narcotic anti—tussive drug
`in oral pharmaceutical form and its hydrobromide (la) is
`described in several official Pharmacopeias. It has been
`known since 1956' that (la) is moderately stable when
`exposed (3 d) in aqueous solution to direct sunlight, fur-
`nishing in a remarkably regioselective reaction the cor-
`responding l0-ketoderivative (2)“; however, in our hands,
`we observed a fast photochemical reaction which was hard
`to reproduce. In accordance with the results of Brossi et
`al,,“ Proska et al. have also recently reported the isolation
`of the 10-ketocompound from the oxygenated solutions of
`morphine.“
`I
`‘
`On the basis of some evidence, in particular the finding of
`traces of iron in glassware, we assumed that the reaction
`required catalysis by suitable inorganic ‘ions.
`It
`is well
`known that l<'e(III) ions and other higher valence metals act
`as efficient one-electron photo-oxidants in hydrochloric
`solutions, whereas" photolysis of aqueous s_olutions of
`Fe(III) bromide produces bromine.” Here an interesting
`example has been reported by Barbier, who found that
`Fe{III)—induced photo-oxidationvof benzylic methylenes in
`aqueous acetone occurs to yield the corresponding ketc-
`compounds.“
`In an effort to define the role of trace metals in these
`reactions, we have examined and report here the photo-
`chemical behavior of(1a) in the presence of Fe(III) in acidic
`solutions,
`and a
`plausible mechanistic
`sequence is
`proposed.
`
`in the C— and D-rings since these are encompassed by
`fragment mg’: 150 which remains undisplaced in the MS,
`whereas the peak at m/z 230 is displaced by 16 amu as
`compared to m/z 214 for 1.5’ Accordingly, the infrared (IR)
`spectrum was devoid of any carbonyl absorption but had a
`discrete hydroxyl band at 3400 cm".
`In the 200-MHz
`proton nuclear magnetic resonance (1 H-NMR) spectrum of
`3,
`the methine proton at C-9 was centered at 2.90ppm
`(sharp doublet, J =2.5 Hz) whereas the signal of H—lD
`appeared as a singlet at 4.72 ppm. The remarkable low-field
`chemical shift position for this proton provided evidence
`for oxygen substitution at this site. The stereochemistry at
`C-10 as depicted in 3 was assigned by application of
`Karplus analysis“ and the lack of any coupling for H-10
`(dihedral angle of approximately 90 °) indicated that the
`newly introduced OH group and aminomethylene bridge
`are trans to one another.
`When we carried out the reaction on la under the above
`conditions, no other hydroxy compound could be detected
`by ‘H-NMR spectroscopy, suggesting that 3 was being
`produced with complete control over
`the regio- and
`stereochemistry.
`Evidence in support of the structure of the minor photo-
`product (2) was secured by comparison with an authentic
`sample prepared according to Brossi et al."
`Additionally, we confirmed that the presence of exter-
`nally added chloride ions (as hydrochloric acid) affected the
`efficiency of the photo degradation of la induced by Fe(Ill)
`chloride in neutral or acidic solution. In the light of these
`results, the mechanism of the formation of 2 and 3 can be
`Results and Discussion
`interpreted in terms of an initial benzylic hydrogen abstrac-
`tion by Cl' (Eq. 1) to generate the carbon-centered radical
`The irradiation of an aqueous or acidic solution of (la) in
`(5) (Eq. 2). Although the role of Cl" as a radical initiator in
`the absence of Fe(III) ions did not induce any decom-
`photo-oxidation of organic compounds has been somewhat
`position, irrespective of the presence or absence of molec-
`controversial,” the lack of reactivity in sulfuric acid so-
`ular oxygen. By comparison,
`the irradiation (22 h) of a
`lutions indicated that at least the‘ formation of an Fe(I11)'
`2.68 mM solution of (la) in lM hydrochloric acid in the
`chloro complex is necessary for the reaction to take place
`‘presence of 6.2mM Fe(III) chloride produced (at 85%
`(Eq. 1). Subsequent reaction of 5 with molecular oxygen
`conversion; high performance liquid chromatography
`leads, to the secondary hydroperoxide (6) (Eqs. 3, 4) and this
`(HPLC) analysis) a mixture of 10/3-hydroxydextromethon
`reactive transient species_ has several options of being
`phan (3) (61%) and the known l0-oxoderivative (2) (26%).
`transformed into final products. Thus, 6 can unde1'g0
`Compound 3 gave a molecular peak at m/: 287 by
`dehydration,
`through O—O— bond cleavage, to give the
`"electron impact mass spectrum (El-MS) andithis value is in
`oxoderivative (2) (Eq. 5). However, thismechanisrn may
`» agreement with the molecular formula CIBHHNOZ, indi-
`only count for a minor part ofthe observed photodegradation
`cating the presence of an additional oxygen atom. An
`and the formation of 3 could be rationalized by an alter-
`inspection of the MS of 3 in comparison with that of 1
`native mechanism. The common intermediate (6) can under‘
`showed that the new oxygenated function cannot be -located
`© 1989 Pharmaceutical Society of Japan A
`
`7.|
`
`Page 3 of 5
`
`Page 3 of 5
`
`

`
`
`
`February 1989
`
`[1-‘eX,.(H20)s 4.13 ‘" —"L[FeX.-.<Hzo)..-.r‘"+x" 1
`1+c1'——-.5+HC1
`,
`’5+'3O2"*5
`-
`1+6—>5+7
`7.» 2+ H10 ‘
`7'+H+~s+H.o.
`s+H20—~3+H*
`s+MeoH—.4+r-1+
`
`,
`
`1
`
`’
`
`5
`
`,
`
`(1)
`(2)
`<3)
`(4)
`,(5)
`(6)
`(7)
`(8)
`
`—;—
`
`-
`
`,
`
`'
`Chart 1
`
`
`
`CR1, R2, R3=H
`ZR1=H; R2, R3=0
`SR1, R3‘=l-I; R-2:01-l
`2R1, R3=l-1; Rz=OMe
`
`>IsQoI:n—-
`
`5*
`3*
`
`61 R1, R3=H; R2=00.
`'7 I R1, R3=H; R:=00H
`9 '. R1, Rz=H; Rs=OH
`10 I R1=Br; R2, R3=H
`Fig.
`1
`
`\
`
`go ionic decomposition via attack at the 3-oxygen atom of
`the hydroperoxide function (C-0 bond fission) with loss of
`a molecule of hydrogen peroxide (Eq. 6). This reaction
`predominates,
`in that
`the stability of the resulting cat'-
`benium ion (8) provides the driving force for this reaction,
`and subsequent quenching by a suitable nucleophilic sol-
`vent (e.g., water) leads to 3. Finally, carbocation trapping
`experiments were performed under the above conditions in
`the presence of 0.6 mM Fe(III) chloride in 1 : 1 methanol—2 M
`hydrochloric acid mixture and the corresponding methyl
`ether (4) was isolated in good yield (Eq. 8).
`It is quite reasonable that the introduction of OH or
`OMe groups proceeded by entry from the sterically more
`accessible top face and a similar stereochemical outcome
`has
`recently been reported on morphinandienonessl
`Bottomside oxygen entry would be rather restricted es-
`pecially because of the aminomethylene bridge. An un-
`ambiguous stereochemical assignment for 3 was accom-
`plished by reduction of 2 with LiAlH4 in refluxing tetrahy-
`drofuran (THF). The sole isomer formed in this process is
`assigned the oz-hydroxyl stereochemistry depicted in 9 since
`this is the expected result of hydride delivery from the least
`encumbered face of the carbonyl function in 2.“ Ac-
`cordingly,_the methine hydrogen at C-10 in 9 appears at
`4.88 ppm [ vs. 4.72 ppm in 3] as a doublet (J=6.0Hz) (i.e.,
`H-9 and-H.--1.0 a—r:e—cis-or.iented.)_and this assignment agrees
`With the generalization that an equatorial proton resonates
`at lower field than its axial epimer.9’
`in lM aqueous hy-
`By exposure of , 1a to sunlight
`drobromic acid in the presence of Fe(III) ions we observ-
`ed a rapid and clean transformation to 2-bromo-dextro-
`methorphan (10) in 62% yield as the sole product. Com-
`pound 10 [M+' 351/349(3‘Br/_’9Br)] was identified by spec-
`tral methods and unambiguous synthesis. In particular,
`the two aromatic protons appeared as singlets at 7.28 ppm
`(H-1) and 6.85 ppm (H-4) in the 1H—NMR, thus confirming
`
`309
`
`that substitution had occurred at the 2-position.)
`The difference in reactions between Cl' and Br" may be
`explained on the basis of frontier orbital theory; in the
`hydrogen-abstraction reactions, generally S'Ol\7fO"(s'irigl'y
`occupied molecular orbital)/HOMO interaction—control-
`led,
`the SOMO energy of ‘X" lies between that of the
`HOMO (U orbital of C—H bond) and the radical with the
`higher-energy SOMO will be less reactive than the one with
`the lower—energy SOM0.‘°‘ This explains why the elec-
`trophilic Cl'
`radical (SOMO energy:
`-13 eV)“’ reacts
`faster in hydrogen abstraction of the benzylic methylene
`than the Br‘ radical (SOMO energy: — 11.8 eV). In the light
`of these arguments, two bromine radicals would recombine
`to yield bromine and the expected electrophilic substitution
`at the A-ring of dextromethorphan would be cleanly ob-
`served as the exclusive reaction channel.
`Experimental
`Melting points were determined on a Buechi 510 apparatus and are
`uncorrected. The ‘H-NMR spectra were recorded on a Bruker WP-80 CW
`or on a Varian XL-200 spectrometer in CDC13 solutions with tetramethyl-
`silane as an internal standard. Chemical shifts are reported in ppm (6) and
`signal described as s (singlet), d (doublet), rn (multiplet) or br (broad).
`Ultraviolet (UV) absorption spectra were recorded on a Beckman DU 6
`spectrophotometer. E1-MS were measured or. a Varian MAT 112 spectro-
`meter. Silica gel chromatography (thin layer chromatography, TLC) was
`carried out on Merck pre-coated 60F354 plates. Preparative silica gel
`chromatography was performed on Merck pre-coated 60F2,4 (thickness:
`1 mm, 20 x 20). HPLC analysis was performed on a Varian M 6000 pump,
`M 440 UV detector and 840 integrator system with 10 pm micro
`Bondapack C-18 column (i.d. 3.9x 300mm, Waters). The mobile phase
`was prepared by dissolving 5.8 g of dioctyl sulfosuccinate in water, MeOH,
`THF and concentrated H3PO4 330:630:37:1 and adjusting the pH to
`3.30 with concentrated amm0nia.”"
`Irradiation of la in HC1 in the Presence of FeCl3 Dextromethorphan
`hydrobromide (1a) (1.0 g, 2.68 mmol) was dissolved in 1 M HC1 (1000 ml)
`containing FeCl3 (1.0 g, 6.2mmol) in ten different borosilicate vessels and
`irradiated with tungsten light (500 W, Philips PF 308 13/21) at 50 cm from
`the reaction vessels after saturation with oxygen. After 22 h, disodiurn
`ethylenediaminetetraacetic acid (EDTA) was added and the mixture was
`made alkaline with 10% ammonia and extracted with EtOAc (500 ml). The
`organic layer was washed with water (200 ml), dried and concentrated in
`mono; Preparative TLC. (benzene—EtOH—10“/, ammonia, 89: 10: 1, one
`development, recovery with acetone) afiforded the known 10-ketoderiv-
`ative (2)1) (Rf 0.45; 213mg, 26%),
`the starting material (1) (Rf 0.29;
`125 mg) and the amorphous 10fi-hydroxydextromethorphan (3) (Rf 0.16;
`500 mg, 61%). 10-Keto-3-rnethoxy-17-methyl-(9ot,13ot,l4oz)-morphinan (2):
`mp 188-189 “C (MeOH). UV 1;‘_f,‘;‘"°'nm (logs): 287 (4.18), 231.(4.05).
`[o:],2,° —139° (c=3, CHCl,). IR (KBr): 2930, 2850, 1665 cm“. ‘H-NMR:
`l.0—2.8 (13H, m), 2.34 (3H, s.C1-1,—N), 2.97 (1H, c1,J= 3.0 Hz, H-9), 3.88
`(3H, s, CH3—O), 6.90 (2H, m), 8.00 (1H, m). Anal. Calcd. for C,51-IHNOZ:
`C, 75.76; H, 8.12: N, 4.91. Found: C, 75.54; 11, 8.19; N, 4.85.
`10/3-Hydroxy-3-methoxy-17-rnethyl-(901,l3rx,14a<)-morphinan (3): UV
`}Lf,};‘,‘,‘"°‘ nrn (logs): 284 (3.20), 277 (3.22), 234 (3.92). 1R(KBr): 3400, 2929,
`2830c_m“. ‘H-NMR: l.l—2.5 031-1, 111), 2.49 (3H, s, N-CH3), 2.90 (1H,
`d, J=2.5 Hz, H-9), 3.81 (3H, s, C1-13-0), 4.72 (1H, s, 1-I-10), 6.80 (2H, m,
`H-2 and H-4),
`7.42 (1H, m, H-1). MS m/z 287
`(M*' ‘),
`230
`(M*" —C2N4NCH3), 150, 143.5 (M“).
`.
`(-9)- Hydrochloride: mp 184 ‘C (MeOH-).—-IR (KBr): 3200,
`1609,
`1023 cm”. ‘H-NMR: 0.8-2.9 (141-1, m), 2.96 (3H, s, C1-13-3‘), 3.5 (1H, m,
`H-9), 3.72 (3H, s, O£H3), 4.88 (1H, br d, J=6.0Hz, 1-1-10), 6.54 (1H, d,
`J=2.0 Hz, H-4), 6.88 (1H, dd, J: 8.0, 2.0 Hz, H-2), 7.49 (1H, d, J=8.0 Hz,
`H-1). Anal’. Calcd for C,8H2_.-_NO‘HCl- 1/2H2O: C, 65.02; H, 8.19; N, 4.21.
`Found: C, 65.10; H, 8.22; N, 4.16.
`'
`1a (1.5 g,
`Irradiation of la in HCl and MeOH in the Presence of FeC13
`4mn1o1) in a 1 : 1 mixture of .\’leOH and 2M HC1 (30rn1) containing FeCl3
`(3.2mg, 0.02 mmol)
`in a borosilicate vessel .was set aside at
`room
`temperature under direct sunlight for 24 h. After evaporation of half of the
`solvent, water (100 ml) was added and the mixture was made alkaline with
`10% ammonia at 0°C and extracted with dichloromethane (50m1). The
`extract was washed with aqueous sodium potassium tartrate solution
`
`Page 4 of 5
`
`Page 4 of 5
`
`

`
`
`
`310
`
`Vol. 37, No_ 2
`
`(50 ml) and water (50m1) and dried. Filtration and evaporation afforded ’a
`syrup (1.08 g), which was shown by TLC (benzene—EtOH—l0% ammonia,.
`89: 10: l) to contain the starting material, the 10-ketoderiyative (2) and 3,
`together with a new compound (Rf 0.38). Separation of this was achieved
`by careful preparative TLC using the same eluaut and 250mg (20%: 42%
`based on the recovered starting material) of pure 10fi-methoxydextro-
`methorphan (4) was isolated as an amorphous glass. UV Af;,‘,‘j“°‘nm (loge)
`284 (3.23), 277 (3.25). 11-LNMR: 1.8~2.8 (131-I, m), 2.49 (3H, s, CH3~N),
`3.51 (3H, s, O—CH3), 3.78 (3H, s, O—CH3), 4.12 (1H, s, H-10), 6.8 (2H, m),
`7.3 (1H, in). Ms m/z 301 (M*‘), 271 (M*‘ —ocH,), 150.5 (M“), 150
`(M*'—l5l).
`...
`Photochemical Synthesis of 2-Bromo-3-methoxy-17-methyl-(91,13a1,14z)—
`morphinan (10)
`1a (150 mg, 0.4mmo1) in 1M HBr (100ml) containing
`FeC13 (65 mg, 0.4 mmol) in a borosilicate vessel was exposed to direct
`sunlight for 4h. The mixture was made alkaline with 10% ammonia and
`extracted with dichloromethane (50ml). The extract was washed with 2°/0
`aqueous sodium EDTA solution (50ml) and water (50 ml), dried and
`evaporated. The solid obtained was subjected to preparative TLC
`(Cl-12C1z—Me0H—10"/D ammonia, 85: 15 : 0.1) to give 93 mg (62%) of pure
`title compound (10). mp 130 “C (MeOH—H,O). IR (KBr): 2906, 2855,
`1595, 727, 712crn"‘. ‘H—NMR: 1.0—3.0 (l4H, m), 2.43 (3H, s, Cl-13-N),
`3.90 (3H, s, O-CH3), 6.85 (1H, s, I-17-74), 7.26 (1H.7s, H~1). Anal. Calcd for
`Cm!-I:,,BrNO: C, 61.72; H, 6.90; N, 4.00. Found: C, 61.56; H, 6.88; N,
`3.92.
`.
`The same compound was obtained in 38% yield according to the
`following procedure: 1a (2.1 g, 5.6 mmol) was dissolved in 1 M HBr (50 ml)
`and water (200 ml) and bromine (2 g, 12 mmol) were added dropwise under
`stirring. After 4 h the solution was filtered and sodium bisulfite was added
`
`until the color disappeared. The solution was extracted with ethyl acetate
`(2><300 ml), dried and evaporated. The solid was dissolved in MeOH
`(40 ml) and precipitated with water (40ml) giving 750 mg of a colorless
`crystalline solid (38%). This compound was identical with that obtm'ned by
`the photochemical procedure.
`
`References and Notes
`1) Q. Haefiger, A. Brossi, L. H. Chopard-dit-Jean, M. Walter and Q_
`Schnider, Helv. Chim. Acta, 39, 2053 (1956).
`
`2)
`13- Proska. Z. Votic.ky..L Mo1ana:J._1’1Jte1<_ai2d..\./I._S_t;=_f_ek. Chem
`Zvestii, 32, 710 (1978).
`S. N. Chen, N. N. Lichtinand and G. Stein, Science, 190, 879 (1975),
`V 3)
`4) M. Barbier, Helv. Chim. Acid, 67, 866 (1984).
`5) C. Koeppel, J. Tenczer and K. Ibe, Arzneim. Forsch., 37, 1304 (1987).
`6) M. Karplus, J. Chem. Phys., 30, 11 (1959); M. Kat-plus, J. Am. Chem,
`Soc., 85, 2870 (1963); S. Stemhell, Quart. Rev. (London), 23. 235
`(1969).
`7) A. Cox and T. J. Kemp, J. Chem. Sac., Faraday Trans. 1, 71, 2490
`(1975).
`'
`8) T. W. Bentley and S. J. Morris, J. Org. Chem., 51, 5005 (1987).
`9) L. M. Jackman, “Application of Nuclear Magnetic Resonance
`Spectroscopy in Organic Chemistry,” Pergamon Press, Ine., New
`York, 1959.
`'
`'
`1. Fleming, “Frontier Orbitals and Organic Chemical Reactions,"
`10)
`Wiley, New York, 1976.
`'
`11) R. W. Henderson, .1. Am. Chem. Soc., 97, 213 (1975).
`12) G. W. Halstead, J. Pharm. Soil, 71, 1108 (1932).
`
`1..
`
`Page 5 of 5
`
`Page 5 of 5