SAR teeJ. Med. Chem. 1998, 98, 8313-8931 Phosphinic Acid Analogues of GABA. 2. Selective, Orally Active GABAg Antagonists* 3313 Wolfgang Froestl,* Stuart J. Mickel, Georg von Sprecher, Peter J. Die’ Roger G. Hall,’ Ludwig Maier;t Dietrich Strub, Vito Melillo, Peter A. Baumann, Raymond Bernasconi, Conrad Gentsch, Kathleen Hauser, Joachim Jackel, Goeril Karisson,* Klaus Klebs, Laurent Maitre, Christian Marescaux,* Mario F. Pozza, Markus Schmutz, Martin W. Steinmann, Henk van Riezen, Annick Vassout, Cesare Mondadori, Hans-Rudolf Olpe, Peter C. Waldmeier, and Helmut Bittiger Research and Development and Medicine and Clinical Development Departments, Pharmaceuticals Division, and Crop Protection Division, CIBA-GRIGY AG, CH-4002 Basel, Switzerland, and Clinique Neurologique, C.41.U, F-67091 Strasbourg Cedex, France Received October 11, 1994° In 1987, 25 years after the synthesis of the potent and selective GABAx agonist baclofen (1), Kerr et’ al. described the first GABAx antagonist phaclofon 2. However, phaclofen and structurally similar derivatives 3-5 did not cross the blood~brain barrier and hence were inactive in vivo as central nervous system agents. As a consequence, the therapeutic potential of GABAs antagonists remained unclear. In exploring GABA and baclofen derivatives by replacing the carboxylic acid residue with various phosphinie acid groups, we discovered more potent and water soluble GABAg antagonists. Electrophysiological experiments in. vivo demonstrated that some of the new compounds were capable of penetrating the blood—brain barrier after oral administration, Neurotransmitter release experiments showed that they interacted with several presynaptic GABAg receptor subtypes, enhancing the release of GABA, glutamate, aspartate, and somatostatin. ‘The new GABAs antagonists interacted also with postsynaptic ;ABAs receptors, as they blocked late inhibitory postsynaptic potentials. They facilitated the induction of long-term potentiation in vitro and in vivo, suggesting potential cognition enhancing effects. Fifteen compounds were investigated in various memory and learning paradigms in rodents, Although several compounds were found to be active, only 10 reversed the age-related deficits of old rats in a multiple-trial one-way active avoidance test after chronic treatment. ‘The eognition facilitating effects of 10 were confirmed in learning experiments in Rhesus monkeys. The novel GABAs antagonists showed also protective effects in various animal models of absence epilepsy. Introduction ‘The most abundant inhibitory neurotransmitter in the mammalian brain, GABA (y-aminobutyrie acid)! interacts with two types of receptors designated GABA, and GABAg by Hill and Bowery in 19812" They reported that GABAs receptors are stereoselectively activated by the (R).(—)-enantiomer of the antispastic agent and muscle relaxant baclofen 1 (Figure 1),! a lipophilic derivative of GABA first synthesized in 1962. Surprisingly, it took 25 years until the first selective GABaAs antagonist, the phosphonic acid analogue of 1, phaclofen 2 (Figure 1), was described by Kerr et al.° Two sulfonic acid derivatives of baclofen, saclofen®? (3, Figure 1) and 2-hydroxy-saclofen®-1 (4, Figure 1), were more potent than 2 by factors of 6 and 10, respectively, showing comparable affinities to 3-benzo(b|furan-2-yl- GABA derivatives 5 (Figure 1) reported by Berthelot et alu-is ‘None of these compounds, however, was able to penetrate the blood—brain barrier, Therefore it was not possible to investigate the pharmacology of selective TW. Prost ould like to dedicate ths work this highly respected teacher, Pro. Jose Fried, The University of Chieago, on the aeeasion of his Bbth birthday. Address correspandence to Dr. W. Froest, Research and Develop ment. Department, Pharmaceuticals Division, CIBA-GEIGY AG, 138.6.26, CH-(062 Basel, Switzerland. Crop Protection Division. ‘ Medicinal and Clinieal Development Department, £ Clinique Neurologique © Abstract published in Advance ACS Abstracts, August 1, 1996 GABAs antagonists under in vivo conditions or to explore their therapeutic potential. Anew series of orally active GABAs receptor antago- nists was discovered during the course of a medicinal chemistry program designed to improve upon the phar- macology of substituted (3-aminopropyl)phosphinic ac- ids, some of which were very potent GABAs agonists. Electrophysiological experiments in hippocampal pyra- midal neurons revealed that (3-aminopropyl)phosphinic acid (6, CGP27492, Figure 1) and (3-aminopropyl> methylphosphinic acid (7, CGP35024, identical to SK&F9T541, Figure 1) displayed properties of GABAp agonists, whereas all higher homologues starting from (G-aminopropylJethylphosphinic acid (8, CGP36216, Fig- ure 1) showed effects of GABAp antagonists, ie., they antagonized various biological effects of baclofen. An example of the effects of the new GABAs antagonists is shown in Figure 2. A 10 MI solution of baclofen caused inhibition of cell firing of rat hippocampal neurons. This offect was fully and reversibly antagonized by a 30 j.M solution of 9 (CGP35348, Figure 1). Further electro- physiological studies in vivo showed that some of the novel GABAs antagonists were able to penetrate the blood brain barrier after oral administration, e.g., (3- aminopropyl)n-butylphosphinic acid (10, CGP36742, Figure 1. ‘These findings prompted us to investigate the struc- ture-activity relationships of this class of compounds (0022-2628/95/1838-3813809.00/0 © 1995 American Chemical Society (gnc reece8814 Journal of Medicinal Chemistry, 1995, Vol. 38, No. 17, -j i be eee ees R oY WN coor 5 s4Benzctoyuran- 2) GABA CGABAy antagonists CGP 27492, GABAy agonist CGP 95024 GABA agonist CGP 96216 GABA antagonist dy 9 R=CHOEH, COP35348 GABA, antazonst 40 R=nBu CGP26742 GABAy antagonist Figure 1. Structures of GABAy agonists and GABAp antago nists, Sain Dyett Figure 2, Intracellular recordings from two different rat CAL pyramidal neurons in vitro. Bath application of 10 pM solu tions of baclofen (B) induced hyperpolarization of the mem: brane potential in both neurons, ‘This effect was attenuated by 80 yM solutions of 9 and 600 pM solutions of 2 in a reversible manner (reproduced with permistion of authors and editor of rf 28). in a systematic way and to explore the in vivo pharma: cology and therapeutic potential of the new GABAs antagonists. Chemistry ‘The syntheses of phosphinic acid derivatives of GABA, without substituents in the 3-aminopropyl side chain (Table 1) started from two valuable reagents, either ethyl (diethoxmethylphosphinate 11 or its higher homologue ethyl (2,1-diethoxyethylphospinate 12.18 ‘The acetal or ketal group, respectively, are protecting groups for the P-H bond. P=C bond formation can be achieved at the site of the P—H bond of 11 or 12 under a variety of reaction conditions after which the acetal or ketal groups are cleaved. The nevly generated P-H bond permits further functionalization, thus allowing the syntheses of unsymmetrically substituted phos- phinic acids. Froestl et al ‘Table 1. Inhibition of Binding of HJCGP27492 to GABA Receptors of Rat Cortex and Enhancement of Electrically indeed Release of HIGABA from Rat Cortical Slices (Stimulation Frequency 2 Hz) ° Hat Bor aa on GABA binding _ release compa R IC dM) BCrs0 4) 6 oH 0.008 agonist 7 ly 0.016 agonist 8 Ge 2 118 9 CHOP 2 20 10 n-Caify 38 38 15 n-CaHly 16 30 16 CRICH» OH 2 15 17 i-CiBly rm 98 18 LCi 2B ae 19 CHCaHe 37 3a 20 n-Cetlae 20 4 21 Cally 135 at 22 ChiCeHle 40 8 23 CH.CiF sant 10 24 CHCaihy 4 3 25 (ClipCslle 10 os 26 (CHpiCeHla 2 13 27 °. a 89 2% 9 ua O 41 ~Y 2 30 32 m 6 30 38 CH(OH-n-Caliy 18 3 CHOH Cal, 8 38 CH,CH(OH)-CH»NPhthal 2 38 (Ciicoctt 1 2 iis 50 43 (CHpaNiy ont 44 (CHpNTis 29 49 CHO-n-Pry 2a 50 CHOA-Prie 18% 51 CHO Bu zoe 300 "nt = not tested, ”Persent inhibition at a concentration of 10 M.«Percent inerease ata concentration of 10-* M. Percent ‘increase at a concentrations of 10°? M. ‘Scheme 1 shows a typical procedure for the prepara- tion of (B-aminopropyl)alkyl- or arylalkylphosphinic acids, Deprotonation of 11 or 12 by treatment with sodium hydride and alkylation with various alkyl halides yielded the protected phosphinates 18, the reaction occurring at the phosphorus atom only. Cleav- age of the acetal protecting group (18, R’ = H) required reflux with 4 M hydrochloric acid and gave the corre- sponding phosphinic acids, which were then re-esterified with an alkyl chloroformate to give esters 14. Cleavage of the ketal protecting group (13, R’ = CHs) was achieved under very mild conditions using anhydrous HCI generated from the reaction of trimethylsilyl chlor ride with ethanol in dichloromethane. This latter process gave the esters 14 directly and is to be reco™ mended for compounds bearing acid labile substituents In some cases the residue R in 14 cannot be intto- duced via alkylation of precursors 11 or 12, as in 14Phosphinie Avid Analogues of GABA Scheme 1" sane? R——— oR’ Maco viviisoni | i HAR on 8, 10, 1-19, 24,22, 26-29 | © Reagents and conditions: (i) NaH, THR, room temperature, | ah, RX, room temperature, 24, or reflux, 24 h R= CHC {i or 190: Na, EtOH, 12, CH=CHN, 10 °C, 30 min, room temperature, 1.8 hy reflux, 3, HOAG; (il) for R= He (a) 4M Hl, reflux, 24; (b) CICO", BtgN, DOM, 10 °C — room temperature, 2b; (iv) for R’ = CH! 1.5 equiv of PMSC1, 10% BiOH | in DCM, room temperature, 24h; (w) ROH, Et, temperature, 24 b, 40 °C, 45 min; (vi) Na, ROK, CHy—CHN, | 10°C! 1h; room temperature; 1 hy reflux, 1h; (il) Ha Raney nickel, 10% NH in EtOH, 70 °C, 100 bar, 2 h; (ei) 8M HCI, rellux, 24 h; propylene oxide, MeOH, 4 °C, 24 by (ix) MesSIBr, DOM, room temperature, 24h; 1% HzO/MeOH, room temperature, 1h; propylene oxide, MeOH, room temperature, 24 h. Substitu centa for 18: a, R= Cif, R= Cal by R’ = H, R= n-CoHn;e, SH, R= n-Cify d, R= CH, R= SCH; g, R= H, R= CH Catt: CH, R= CH,CsHhy, ke, P= Cis, R 1 (CH) CoH, m, Re = H, R= tetrabydrofuran-2:yl (etrabydropyran-2 Zeyenoathyl; p, R= H, R= Qpyridylmethyl, “Substituents for ME a R= CoH, RY = Cole; by t= n-Cally, RY = Calls nsGiH, RY = Calle; d, R= CRACHahCHy, R" = Cals eR = S.CUHy, R” = Calg: f= Cale, RY = Cally: gy R= CH BY S Cig Ie= Cee, RY = CoH |, R= CHaCall, Re J, R= CHCgHl, R= Oils: ke, R= CHACHCeH ly, R= CoH |S CH.CHiCeltn, RY = CaF: m, R = tetrahydrofuran-2-y, Calle; n, R= (tetrabydropyran-2-ylmethyl, R” = CoH: 0, R Zeyanoethyl, R’ = CaF | (R= tert-butyl) or in 14h (R= pheny), In these cases the appropriate alkyl or aryldichlorophosphines were reacted with an alcohol in the presence of 1 equiv of triethylamine in dry diethyl ether (reaction v in Scheme ». ‘The introduction ofthe 8-aminopropyl side chain was achieved via base-catalyzed conjugate addition of the various alkyl phosphinates 14 to acrylonitrile followed by hydrogenation over Raney nickel in the presence of ammonia. ‘The phosphinic acid esters were then hy- drolysed under acidic or basic conditions to give 8, 10, 15-19, 21, 22, and 24-29, ‘A variation’ of Scheme 1 was necessary for the 2pyridyl derivative 18p due to the incompatibility of the pyridine ring with ethyl chloroformate, which is required for the re-esterification step (Scheme 2). Acidic | hydrolysis of 18p produced (2-pyridylmethyl)phosphinic acid 30, which was persilylated in refluxing hexameth- yidisilazane generating a reactive P{III) intermediate. Reaction with acrylonitrile gave the (2-cyanoethyl)- phosphinic acid derivative 31. Hydrogenation over Raney nickel yielded 92. Journal of Medicinal Chemistry, 1996, Vol. 38, No. 17 3815 Scheme 2 e 1 30 ems ae. wnt te nAR4 on No Or 2 Ea « Reagents and conditions: (i) 12.M HCI, reflu, 24 h(i) HMDS, reflux, 24h acrylonitrile, room temperature, 24h; (ii) Hp, Raney nickel, 55% NH In BO] (5°C, 1 bar, 18, Scheme 3° 20,23, 26, 93-96 438 «= Reagents and conditions: (i) HMDS, reflux, 24h, Hunig’s base, digiyme, reflux, 30 min, RX (or RCHO, epoxide ora unsaturated ketone) (i) 2 M HCI; propylene oxide, MeOH, 4°C, 24h, An alternative approach to the synthesis of ( ‘aminopropyl)alkyl- or arylalkylphosphinic acids is shown in Scheme 3, Thus, persilylation of 6" in refluxing hexamethyldisilazane and reaction of the reactive P(ID) intermediate with alkyl halides, aldehydes, ketones, a,f- unsaturated Ketones, or epoxides gave a large variety of substituted phosphinie acids as 20, 23, 26, or 33~ 36, ‘This route can also be applied to phosphinic acids bearing substitutents in the 3-aminopropyl side chain a8 87, providing access to compounds such as 88 (Table 2), ‘Although the route shown in Scheme 3 provided rapid access to a multitude of structurally diverse derivatives of (3-aminopropyl)phosphinie acids, we do not recom- mend this synthetic sequence for the following reason: Discrepancies were observed between the [Cio values of compounds prepared by either Schemes 1 or 3. Compounds prepared via the latter toute showed higher affinities to GABAs receptors in comparison to the affinities of the same compounds prepared via Scheme 1. As the starting material 6 for Scheme 3 is a very potent GABAp agonist (ICs = 5 nM), any contamina: tion by trace amounts of 6, even below the limit of detection by TLC, 'H NMR, or microanalysis, may produce compounds displaying artificially low ICso values, P-C bond formation can also be achieved via radical reactions with terminal alkenes (Scheme 4). Reaction of I4o with 2-vinyltetrahydropyran 39 in refluxing dioxane containing eatalytie amounts of dibenzoyl per- oxide gave disubstituted phosphinic acid ester 40. Hydrogenation and ester hydrolysis completed the synthesis of 41. The syntheses of (aminoalkyl)(3-aminopropyl)phos- phinie acids 42-44 (Table 1) have been described previously.!#20 (3-Aminopropyl)(dialkoxymethyl)phosphinic acids were prepared as shown in Scheme 6, Reaction of hypophos- ee8816. Journal of Medicinal Chemistry, 1998, Vol. 38, No. 17 Table 2, Inhibition of Binding of HICGP27492 to GABAg Receptors of Rat Cortex and Enhancement of Bleetreally induced Release of HJGABA from Rat Cortical Slices (Stimolation Frequency 2 He) GABA binding release compd Ri Re Re Ian Mb) BC 38 Hs Hal, Bx 5a on HL HO Came one 60 Ho 4CiGde HO 9 2am G1 CHIORN, Ho £CIGH) Ho 21 nL 6 nCiHy H OHH 29 aa 67 CHC, HOH oH 4 68 CHG; H (S}0H 4 5 69 CHG HOH H n 70 CHGH HOOK oH 8 71 CHG; Ho (S}OH 2 2 CHCl; HOH H 4 73 CHOBE); HOOK 9 84 CHOBE; H (S-OH n 89 nCiHe | Ho 4CICsH, OH 45m 96 CH; Ho 4-CIGH, OH 30 99 nC oH Ci," | OW at 106 nC oH Rpt Rr 0. ea" 107 CHiCas HO Re+Rr 0. 108 CHiCsly HO Rs+Rr 0. “Percent Increase at concentrations of 10~* M,* Pereent in crease at concentrations of 10-* M, Percent inhibition at concen- teations of 10"? M,# Pereent inhibition at concentrations of 10°° M, "nt = not tested a 0 «Reagents and conditions: () 20 mol % dibensoyl peroxide, dioxane, reflux, 1; (i) Hp, Raney nickel, 4% NH in BtOH, $8 *C, L bat, 19 hy Gi) concentrated HC, ret, 24h; propylene oxide, MEOH, room temperature, 24, phorus acid with trialkyl orthoformates in the presence of a Lewis acid catalyst gave acetal esters 45-48, Base- catalyzed addition to acrylonitrile followed by hydroge- nation of the resulting 2-cyanoethyl derivatives to the G-aminopropyl)phosphinie acid esters and saponifica- tion with lithium hydroxide gave 9 and 49-51. Different synthetic methodology was necessary for the preparation of phosphinie acid derivatives of GABA. ‘carrying substituents Ri, Ra, or Ry’ in the $-aminopropyl side chain (Table 2), For compounds with Ri equal to hydroxy, benzyloxy- carbonyl-protected 3-aminopropanal was condensed with ethyl phosphinates (e.., 14¢) under mildly basic eondi- tions (Scheme 6). Simultaneous hydrolysis of the ester and carbamate groups of 62 was carried out using strong mineral acid at reflux to give I-hydroxy-substi- tuted 53. ‘Scheme 7 outlines the preparation of the methyl- and re g i 2 or why 1 we mi ARS _| 40-61 Reagents and conditions: (i) HC(OR"), CR,COOH, room temperature, 72h; (ii) CHe~CHCN, NaOR”, ROH, 70 °C, 4 hy (i) Ha, Raney nickel, 10% NH in R“OH, 70 C, 100 bar, 4b; Gv) LiOH, ELOH/HLO, 1:4, reflux, 24 h, HsPOs, Substituents: in 4 and 9, R= CyHy; 46 and 49, R= n-C3lt; 47 and 60, RY = -C3H 48 and 51, RY = n-Caly Scheme 6 i Is ame the [— 82 Ne, RY=EL K+ 69 en, RI=H « Roagents and conditions: (i) EtyN, ZNH(CH:]:CHO, 100°C, 4; (li. 8 M HCI, reflux, 24 b; propylene oxide, MeOH, room temperature, 16 b, Scheme 7# ° A cu fee ~ © oR" g R. Ber ReCHOeY, Reet S7R=CHIOED, R'=NO, R'=Et SER=OHy REN, R=I-BU o SOR=CH(OED, xNHpRT* Et 8 ew agents and conditions: (i) LDA, THR, ~78 °C, 1 hy 4-ClCsH,CH=CHNO;, ~78 °C, 30 min; (i) Hp, Raney nickel, 10% [Nii EtOH, room temperature, 1 bar, 3h; i) concentrated FIC 4300 °C, 24h; propylene oxide, EtOH, room temperature 24 hi i) LIOH, ELOHMH,O 1:4, reflux, 24 h, NyPO,, Dowex 50 W x 8H" form) (diethoxymethy)phosphinic acid analogues of baclofen Conjugate addition of the anions of methylalkylphos phinic esters 54 or 55, prepared by deprotonation with LDA, to 4-chloro-f-nitrostyrene gave (3-nitropropy!)- phosphinie acid esters 56 and 7, respectively. Reduc tion of the nitro group was achieved in good yield vie hydrogenation over Raney nickel to give amino ester 58 and 59. Ester 58 was hydrolyzed under acidic conditions to yield 60, while the acid-sensitive di- ethoxymethyl-derivative 59° was hydrolyzed under basic conditions to furnish 61. Scheme 8 shows the syntheses of derivatives bearing a substituent Ry equal to hydroxy: Ethyl phosphinatesPhosphinic Acid Analogues of GABA Scheme & ei I i RY 0et Rop-H + r oe [ osite, | " | # ww The = OF yt © Reagents and conditions: (i) TMSCL, BtaN, THR, room tem perature, 24 hy Gi) 10 mol o ZaC,, N<2,3-¢poxypropytiphthalim: ‘We, room temperature ~ ‘10 *C, 24 h; (ii) 1% HOAe in MeOH, roulm temperature, 24h; iv) concentrated HCI, reflux, 24h; (¥) = CH(ORt)- (a) NaBH, f-PrOH, HO, room temperature, 24h, HOAc; (b) LIOH, H,0, 24 b, room temperature, HPO, Substit. wuents: in 62 and G6, R= n-Cilly GB and 67, R= CH;C3Hy: 64 and 70, R= CH.CgHy; 65 and 73, R= CHORD», 11, Ide, 14i, or 14] were converted into their corre- sponding highly reactive silylated P(III) intermediates by reaction with trimethylsilyl chloride in the presence of triethylamine under anhydrous conditions. Reaction with N-(2,3-epoxypropyl)phthalimide catalyzed by zine chloride in the absence of solvent gave, regiospecifcally, the trimethylsilyl ethers of ethyl (2-hydroxy-3-phthal- imidopropyl)phosphinates 62-65 as 1:1 mixtures of diastereoisomers. Under these conditions the trimeth- ylsilyl group is transferred from the intermediate ethyl (trimethylsilyl)phosphonite to the newly formed hydroxy group. Acidic hydrolysis of 62-64 furnished 2-hydroxy- substituted alkyl- or arylalkylphosphinic acids 66, 67, and 70, Cleavage of phthalimide 65 via sodium boro: hydride reduction and basie hydrolysis ofthe resulting amide provided (diethoxymethyl)phosphinic acid 7. cheme 9 shows the reaction of silylated PID intermediates derived from 11, 14e, 14i, or 14j with (R)- or (S)-epichlorohydrin yielding the trimethylsilyl ethers of 74-78, which were hydrolyzed under very mild conditions by stinving in methanolic solutions containing 1% acetic acid at room temperature providing chloro hydrins 74~78. No ring closure to an epoxide occurred. Nucleophilie displacement of the chlorine atom with ethanolic ammonia proceecled via a clean Sy2 process to give amino esters 79-83 with complete retention of, the stereochemistry at the carbon atom bearing the secondary hydroxyl group (see also part 1 of ‘this series"), Acid hydrolysis of 79-82 yielded chiral (3- amino-2-hydroxypropy})phosphinic acids 68, 69, 71, and 72. Basic hydrolysis of ester 83 gave chiral (diethoxym- ethyl)phosphinic acid 84 ‘Two synthetic routes for the preparation of phosphinie acid analogues of 2-hydroxysaclofen (4, Figure 1) are outlined in Schemes 10 and 11. Condensation of ep- oxide 85 with the reactive PUI) species prepared via silylation of ethyi n-butylphosphinate I4e gave hydroxy ester 86, which was converted to the primary amide 87 by reaction with ammonia catalyzed by sodium eya- nide.”" ‘The reduction of the primary amide 87 to the amino ester 88 using borane dimethyl sulfide complex proceeded with a yield of only 40%, ‘This may be due to concomitant reduction of the phosphinic acid moiety. After hydrolysis of ester 88 with sodium hydroxide, the crystalline sodium salt of 89 was obtained after reverse- phase chromatography. Journal of Medicinal Chemistry, 1995, Vol. 88, No. 17 Scheme 9" i RP ort tao, 18,14) " 68,69, 74,72,04 «Reagents and conditions: (i) TMSCI, BtsN, THE, room tem: perature, 24h; (i) 10 mol % ZnCl, (R)- or (Si-epichlorobydrin, oom temperatare ~~ 70-°C, 24h (ii) 1% HOAc in MeOH, room temperature, 4 h; (iv) 20 equiv of NHs in EtOH, room tempera ture, 96 b; (») (a) concentrated HCI, reflux, 2h; propylene oxide, ‘MeOH, or (b) LiOH, BtOH/H,O 1:4, reflux, 24 h:!HsPO,. Substit: uuents:'in 74, = CHsCyHe, 208)-O; 98, R= CHsCaHle, 28) (OH; 76, R='CHyCeH,, 218-0H; 77, R ~ CH,CoH{, 28-08, 7B, R = CHOBE, 28).0H, Substituents in 79 and 68, R= CHisCel, 215-0! 80 and 68, R= CHCeHs, 202)-0H; 81 and ‘71, R= CHC, 28)-O11; 89 and 72, R= CHsCaths, R/O, 83 and 84, CHIOHE, 218)-OH, Scheme 10¢ q ¢ i C 9 Roc’ 7 roc 85 R=08t roogt a5 R=08t Le or wenn, —* BigN, THF, room temperature, 2b; (il) 10 mal Seale relusbh ) Nl 10 ol % NACN, EeOH, sealed tube, 50°C, 10 h; (v) BHeMesS, THF, reflux, 3 h; MeOH, room temperature; (vi) NaOH, EtOWH,O, 2:1, 60°C, 24 h A more versatile route is shown in Scheme 11. Deprotection of 90—the preparation of which is de- scribed in part 1 of this series!—by reaction with anhydrous HCI generated from the reaction of trimeth- ylsilyl chloride with ethanol in dichloromethane pro- @uced phosphinate 91, which was deprotonated by treatment with n-butyllithium at ~78 °C and alkylated with either methyl iodide or n-butyl bromide to give the allylic phosphinates 92 and 98, respectively. No isomer- ea ——e—e—e—e—e—ee—e——e—~™~™~™~™i~™i™~i~iw~—iCCEeeeeeeeeee8818 Journal of Medicinal Chemistry, 1995, Vol. 38, No. 17 Scheme 11" a oO me Abs anon a Cay o 7 7 wv @ Ss, — an HW, oe 9OR=CHy © Roagents and conditions: (i) MeySiCl, 10% ELOH/DCM, room temperature, 24h; i) n-Buli, THF, ~78°C, 10 min, RX, 78°C, 5 min; NH.CVH.0, ~78 °C > room temperature; (it) BocNH, C, 16 min, NaOH, MeOH, 0 °C — room 8 mal % 050%, t-BuOH, Hs0, room temperature; AgNO, MeC! temperature, 24 h; (iv) MesSiBr, CH.Cl, toom temperature, 24 hi; propylene oxide, MoOH, room temperature, 24h, Scheme 12 wr won 9 or Q Ww q wether ot me bf is * Regents and conditions: (0) (Boc)sO, DCM, BtaN, 20 °C, 1h; (ii)