Pergamon PH: S0040-4020(97)00988-5 Tetrahedron, Vol. 53, No. 43, pp. 14773-14792, 1997 O 1997 Elsevier Science Lid All rights
`
`reserved. Printed in Great Britain 0040-4020/97 $17.00 + 0.00 Synthesis of (2S, 3R, 4S)-3,4-Methanoproliae and Analogues by Cyclopropylidene Insertion Viacheslav V. Tverezovsk3/b, Mark S. Baird =* and Ivan G. Bolesov ~ • Department of Chemistry, University of Wales, Bangor b Department of Chemistry, State University of Moscow, Moscow Abstract:. latramolecnlar h~ttioa of single emmtiomea's of oyclopropylideaes into 5,6-related C-H bcmds adjacent to nitrogea has been used to obtain emmtiomnrk~y pure metlumoproline and a mnnber of analogues with ahighdegreeofoae- or two-foldasymmetricinducfion. © 1997 Elsevier Science Ltd. Although methanoproline (1) was isolated some years ago from the American horse ehesnut, Aesculus parviflora, t it is still attracting considerable attention, z~ It was shown to be a potent inhibitor of proline metabofimz;' as such it was targeted as a potential chemical control agent in the production of hybrid wheats. 5 In addition, methanoproline inhibits the proline transport system of Escherichia coil, 6 while amide derivatives of methanoproline are inhibitors of angiotensin converting enzyme. ~ Although a number of routes to racemic methanoproline have been reported, S only one synthesis of enanfiomerically pure ( 1 )9 and one synthesis of the N- Boc derivative have appeared, t° The first involves the cyelopropanation of dehydroproline in a reaction which is not very diastereoseleetive and from which the major product is the trans-isomer (2).
`
`COOH
`
`(1)
`
`COOH
`
`.802Ph
`OTHP
`
`H
`
`(2)
`
`BocNH H
`
`(3)
`
`The second involves the coupling of two ehiral starting materials, (3) and (2R)-glycidyl triflate, followed by eydisation and functional group interconvertion to give N-Boe protected (1) in seven steps with overall yield of less then 25 %. We reported some years ago that 2-dialkylaminomethyl-l,l-dibromocyelopropanes such as (4) react with methyllithium to give 3-azabicyelo[3.1.0]hexanes (5) by a formal insertion of the derived cyelopropyli- dene or a related carbenoid into the CH-bond adjacent to nitrogen and 5,6-related to the carbene centre: tt MeLI H H e R (5) /\ . (4) /\ . II " It has also been shown that a similar insertion of cyelopropylidenes derived from the ethers (6a) and (6b) 14773
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`AstraZeneca Exhibit 2038
` Mylan v. AstraZeneca
` IPR2015-01340
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`
`H
`
`Me
`
`H
`
`Me
`
`Br
`
`(6a-(~, R = Vinyl)
`(6b-(~), R = t-PhCH=CH)
`
`-90oC ~ ÷ R
`
`14774 V.V. TVEREZOVSKY et al. by reaction with methyllithium leads to the 3-oxabicyclo[3.1.0]hexanes (7a) and (7b) with a moderate to high diastereoselectivity for the endo-R isomer. 12 R•r•o .~Me
`(7a, R = Vinyl, 73 %, endo/m¢o = 17:1) (Tb, R = t-PhCH=CH, 41%, endo/exo = 7:1 ) We now report the application of the insertion reaction to the synthesis of methanoproline and of a number of related compounds each as a single enantiomer. The method has the advantage that, although involving a number of steps, the starting materials are cheap and readily available on a large scale and the reactions involved are gmcxally extremely high yielding moreover it may be varied to produce in principle any required stereoisomer and a range of analogues. Reaction of methyl methacrylate with bromoform and base leads very readily to 2,2-dibromo-l- methylcyelopropane carboxylic acid, 13 this is simply resolved using dehydroabietylamine in methanol to give (8, R) and its enantiomer, and the absolute stereochemistry of the amide of(8, R) has been established by X-ray crystallography. ~* The corresponding non-methylated acid (9, R) and its enantiomer were readily obtained on a multi-gram scale by oxidation of 1,1-dibromo-2-vinylcyclopropane with potassium permanganate to give 2,2- dibromocyclopropane carboxylic acid followed by resolution of this with debydroabietylamine.t4 ~
`chloride, and this was reduced to the alcohol (11) by reaction with lithium aluminium hydride. This route was chosen in order to avoid competing reduction of the dibromocyclopropane to the corresponding isomeric mono- bromides. It was necessary to add a solution of the acid chloride in ether to lithium aluminium hydride in ether at - 80 °C, as addition of the hydride to the acid chloride led to up to 30 % of an ester derived by reaction of the product alcohol with the acid chloride. At higher temperatures monobromides were formed in addition to dibromi- des. The alcohol (11) was converted into the corresponding bromide (12) by reaction with 1,2-bis(diphenyl- phosphino)ethane and ~ and reaction ofthis with either allyiamine or benzylamine gave the amines (13) and (14).* Attempted direct reduction of amides of acid (8, S) to amines with LAH, NaBI-I4 or BI-Ij'SMe z led to mixtures of products. Attempts to make the tosylate from the alcohol (11 ) led to only a moderate yield.
`
`Br
`
`H O~H __Br
`
`COOH Br
`
`(8, R)
`
`r
`
`(9, R)
`
`The acid (8, S) (>99% e.e.) was converted into the corresponding acid chloride by reaction with thionyl
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`8OCl2
`
`OQ
`(8, S) (10, 95 %)
`
`.800C
`
`Br . Me (11, 89 %)
`
`~ D~hoe, Br,
`
`Me
`Br
`Br--//~/~
`
`-'~ K;co3B°c;O
`
`Br _ Me
`~¢- ~ RCI-hNH2
`
`(13, R = Vinyl, 98 %)
`(18, R = Vinyl, 96 %)
`(16, R = Ph, 95 %) (14, R = Ph, 90 %)
`
`(I~ 99 %1 By a similar sequence of reactions, the acid (9, R) (93 % e.e.) was converted into the dibenzylamine (17) in an overall yield of 86 %. Attempts to prepare (17) from 1,1-dibromo-2-bromomethylcyclopropane derived from (9, R) directly by reaction with dibenzylamine led to only 80 % yield of (17) after 4 days at 50 °C. (i) ~3C1~ H___~ HA_B r (ii) LiAIH 4 - - (iii) cLi1~hos , Br 2
`ROOC Br (iv) BnNH 2 1~n--~N--~ 1171 19, RI Iv) ram= The amines (13) and (14) were protected as their Boc derivatives (159 and (16), reaction of these with methyl lithium led to a mixlm'e of products, the major component of which was the azabicyclo[3.1.0]hexane (lga) or (18b) respectively. The yields of each of the products were highly dependent on the reaction conditions (Table 1 ). The stereochaags~ of the allyl and phenyl groups in (18a) or (18b) was assigned on the basis of the fact that the signal for H-4 in the proton NMR spectrum in each case appeared as a singlet rather than the doublet expected for the epima. '~'s Moreover, in each case these compounds showed the signals for two rotamers about the amide bond by IH and '3C NMR; deprotection gave the amines (21a) and (21b) which showed only the expected number of signals in 'H and '3C NIVlR.
`
`(18, R= Vinyl)
`(18, R : Ph)
`
`MeLi ~
`- 90QC, 30 min~
`
`H,,~._Me
`
`/,~fe
`
`'4'
`
`._-
`H/~~N y e
`Br
`
`"("
`
`(llL R = Vinyl)
`--
`.~,~
`(=IL R = Vi.yl)
`(21b, R = P~) R ;.] 118b, R = Ph)
`
`R
`(19~ R = Vinyl)
`
`(20a, R = Vinyl)
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`Synthesis of (2S,3R,4S)-3,4-methanoproline 14775
`R R
`(19b, R = Ph) (20b, R = Ph)
`

`
`14776 V.V. TVEREZOVSKY et aL Reactiem of (IS) and (16) with methyl lithium
`st, m~
`material
`
`Tempemure dur~ reamiea, °C" 20 -30 -60 -90 20 -90 C~mnds de~=u~naJ by ~ in rc~'tm mix.'e, ~lds, % b (zz) 09) (20) ° 40 45 9 50 19 17 61 8 16 49 8 29 40 d 27 7 25 d 8 17 unknown substmacee starting m lterid 2 7 3 2 l 8 l 1 II 3 24 a) Additi~ lime was 5 rain; stirring time was 30 main; b) these data wc~e oeaafirmed by glo; o) stereoobemistry of mmtobromidas was not determined; d) isolated yield; e) this mi~,ht be the diastereomaac of monobromide c. Although the purified
`
`06)
`
`~dd of(lga) obtained in this way was only 47 %, it could readily be converted into the methanoproline analogue (23) by oxidation with ruthenium tetroxide, generated in situ from RuCI3, followed by deprotection. Attempted ozonolysis also led to (22) but in this case a second product was the lactam (24).
`
`H~_Me
`"~
`"--
`HOOC H
`
`H/~N~-Me [RuO4]:=~; x. I H'~s~e
`C F'~O-~H ~ HsIOe "'1~ N /I
`HOOC BOO
`BOO
`
`03
`~
`
`H/~Me
`
`HC~-Me
`"IF
`HOOC BOC
`
`BOC
`
`(23, 89 %) (22, 90 %) (18a) (24, 46 %) (2.3, 41%) The amine (14) was be~zylated by reaction with benzyl bromide to give (25). In contrast to (16), the diben- zylamine (25) reacted with methyllithium to give the endo-phenyl isomer (26) as the major product (Table 2):
`
`Br
`"~
`"-'-
`MeLI ÷ 4" 4, Br ~ Br -90~ 30rain ~ Ph L,"
`
`
`
`
`
`L
`
`(25) ~'Ph (26) Ph (27) Ph (29) Ph Table 2. Reaction of compound (25) with methyl lithium. Temperature during Cmnpounds dctmmined by NMR in re, aotion mixtm¢, yiekls, % b rcaotion, °Ca (26) (27) (28) (29) o,f 20 56 5 d 33 -90 90 1.8 d 2 6 a, b, o, d see Table 1; f) stmoure assigned ett the basis of oyok~pi~ne siEqmalg in the ~H lqMR of the mixtm-e o~'(26), (28) and (29). The an~ (26) could be separated from its bicyclic isomer (27) by chromatography (96 %, >90 % pure).
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`(is)
`Me H Me H Me • .Me H~?e
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`Synthesis of (2S,3R,4S)-3,4-methanoproline 14777 It oouid be obtair~ pure by removal oftbe impurities (28) and (29) by selective debenzylafion with hydrogen and a catalyst (5 % Pd/C, 0.01 mol.eq., 1 h) followed by flash chromatography. The =ude amine (76) was debenzybted to (30) unde~ more vigorous conditions (0.05 mol.eq, of the same catalyst, 15 h). Protection by trifluoroacetylafion, then oxidation of the phenyl group by reaction with ruthenium tetroxide at 80 ~C for 3 h gave (32), and then deprotection gave the aminoacid (33), a second methylated analogue of methanoproline. It is interesting to note the remarkable stability of CH and CH 2 groups near nitrogen to oxidation under these conditions. It is well known that ethers RCH2OMe (R=Ph or AIk) can readily be oxidised to esters with ruthenium tetroxide even at room temperature. ]~ Attempts to oxidise (31) with ruthenium tetroxide at 20 °C even using more c~_~yst and for 1 day were unsuccessful. In the case of the Boc - protected amine (34), ruthenium tetroxide oxidation at room temperature led to ring opening, to give (35).
`
`~ M e
`
`Ph
`
`Pd/C
`
`~
`
`Ph
`
`H
`
`Me
`
`Boc20
`~ Ph
`
`H
`
`Me
`
`~sMe
`
`[RuO4]
`r
`1"lsIOa p~ COOH
`
`(26)
`
`Ph
`
`(C~O)20/
`
`H
`(30, 95 %)
`
`Boc
`(34, 61%)
`
`(35, 44 %)
`
`-~'
`
`Ph
`
`COCR
`
`[Ru04]
`1"lslOe
`
`HOOC
`
`(31, 98 %) H Me H Me KOH
`(32, 93 %) (33, 91%) Reaction of (17) with methyl lithium gave one major product (36) together with a number of minor products with structures typical of those usually obtained in similar reactions of non-functionalised dihalo- cyclopropanes.17 H Br H H H H H
`
`~
`MeOH
`
`HOO
`
`H
`
`COCF3
`
`oC,
`30min
`
`h
`
`J
`P
`
`p
`
`Ph
`
`4"
`
`4.
`
`Ph
`
`j
`p
`
`h
`
`4.5 %)
`
`4. p. Ph p. x_ _..
`
`Ph
`
`(41, 1.8 %)
`
`(40, 3.6 %)
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`H Me
`r -90
`(17) (~, 84 %) (37, 1.8 %) (38,
`

`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`14778 V.V. TVEREZOVSKY et al. The stermdamfistry of the bicyclopropylidenes (40) and (41) is not certain, while that of (39) is assigned on the basis of NOE studies. The use of modified reaction conditions to increase the yields of the novel optically active bicyclopropylidenes is being examined. The reason for the reversal in the stereochemistry of the major azabicycles (26) and (36) compared to that of(Ilia) and (llib) is not yet clear, but may reflect the increased steric demand of the Boc group compared to benzyl, or more probably the steric and electronic effect of the N-CO bond of the intermediates leading to (Ilia) and (llib) compared to the N-CH 2 bond of those leading to (26) and (36). Indeed, the NMR spectra of the products (18a) and (llib) are characterised by the presence of two rotamers about this bond. Debenzyiation of(36) (93 % e.e.) followed by protection as a trifluoroacetate gave crystalline (42) (81% yield, 100% e.e. by chiral gl.c., with baseline resolution, see acknowledgement). Oxidation as before and deprotec- tion gave the final aminoacid ( 1 ) with an NMR spectrum which was identical to that in the literature. 9 The [tt ]D 2° (- 141.8 °) was also in good agreement with the literature value ([~x]D 2° - 144°). 9 The overall yield of(l) from (9, R) was 41%.
`The reactions described above indicate that the insertion of cyclopropylidenes into C-H bonds can occur in a highly stereocontrolled manner and may offer a valuable route to a number of optically active mono- and polycyclic systems. Aeknowled|ement: This work was carried out in Bangor with the support of the INTAS programme. We thank Dr. Nikolay S. Ikonnikov, Nesmeyanov Institute of Organoelemeat Compmmds, 117813, 28 Vavilov, Moscow, for kindly supplying a chiral g.l.c, column which provided excellent resolutina. Experimental Section Reagents were obtained from comme~ial suppliers and were used without further purification unless stated, Dichloromethane was distilled over calcium hydride. Diethyl ether and tetrahydrofuran were distilled over sodium wire. Petroleum was either of boiling point 40 - 60 °C or 60 - 80 ° C and was distilled. Reactions requiring anhydrous conditions were performed using oven dried glassware (250 °C) that was cooled under either dry nitrogen or argon and the ~ were conducted under a positive atmosphere of one of these gases. Organic solutions were dried over anhydrous magnesium sulphate, and, unless stated, were evaporated at 14 mmHg. Yields quoted are for the pmJtied compounds unless stated. All new compounds were homogeneous by tic or by glc. Glc was conducted using a Perkin-Elmer Model F17 F.ID. on a capillary column (30 m x 0.32 mm id Phase, DB5 split ratio of 50:1) using nitrogen as carrier gas.
`
`H
`(1.79%)
`
`(I) 1"12, Pd/C
`
`(It) TFAA
`
`Ph
`
`[Ru~]
`
`~
`1"lsIOe ~
`
`COCFs
`
`COCF3
`
`COOH
`
`KOH
`
`aeOH
`
`COOH
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`(36, 93 % e.e.)
`(42, 81%, 100% e.e.) (43, 88 %)
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`Synthesis of (2S,3R,4S)-3,4-methanoproline 14779 Chiral gic was conducted u~n8 a 2,6-diamyi-3-trifluoroacetyl-K-cyclodextrin fused silica column (40 m x 0.23 mm ID, film 0.12 rmn), using beih~m as a carrier gas at 2 bar pressure (see acknowledgement). Tic was performed using Aldrich silica gel 60 plates (F254). Compounds were visualised either by examination under an ultraviolet source or by exposure to iodine vapour. Column chromatography was conducted with Merck 7736 silica gel under medium pressure. Melting points are uncorrected. Infiared spectra were obtained on a Perkin-Elmer 1600 FTIR spectrometer as liquid films unless otherwise stated. Low resolution mass spectra were obtained usin 8 a Finnigan Mat 1020 spectrometer. Mass meamr~ refer to 79Br and 3sCi isotopes unless stated and were obtained from the Swansea Mass Spectrometry Service. Mieroanalyses were performed with a Carlo-Erba Model 1106 CHN analyser. NMR spectra were recorded in CDC13 unless otherwise stated on a Bruker AC250 at 250 MHz for protons and 62.9 MHz for carbons and in the latter ease were broad-band decoupled. In most cases DEPT spectra were also run and the signs of signals (+ for CH, CH£ - for CH2) are indicated on the data for the broad-band decoupled spectrum. Those signals with no sign in such a spectrum are quaternary. (S)-(+)-2,2-Dibromo- l-methylcyclopropanecarbonyl chloride. Thionyl chloride (25 ml, 0.34 mole) was added to (S)-(-)-2,2-dibromo-l-methylcyclopropane carboxylie acid (4, S), [a]D 2° -55.1 ° (c 1.015, CHC13), >99% e.e. ~4 (26.4 g, 102.4 mmole) and the mixture was refluxed for 2 h. The excess of thionyl chloride was removed by distillation and the residue was distilled at 39 - 40 °C (0.8 mmHg) to give (S)-(+)-2,2-dibromo-l-methylcyclopropanecarbonyl chloride (10) (27.2 g, 98.4 mmole, 96 %) (for racemate see re£ 18), [tx]n 2° +0.3 ° (e 1.104, CHC13), m.p. -15 °C, which showed 8H: 1.77 (3H, S), 1.78 (IH, d, J 8.0 Hz), 2.52 (1H, d, J 8.0 I-Iz); 66 21.76+, 27.61, 34.37-, 42.97, 156.35; Vm~: 1783 S, 1451 m, 1421 m, 1384 m, 1297 m, 1240 m, 1088 m, 1056 m, 1029 m, 951 s, 931 m, 790 s, 721 m, 655 m, 626 m cm "1. (S)-(+)-2,2-Dibromo-l-hydroxymethyi-l-methylcyciopropane. A solution of (S)-(+)-2,2-dibromo-l-methylcyclopropanecarbonyl chloride (24.7 g, 89.4 mmole) in dry ether (20 ml) was added with stirring to lithium aluminium hydride (3.66 g, 89.4 mmole) in dry ether (400 ml) at -85 °C under nitrogen over 20 rain. After 10 rain at -85 °C, ethyl acetate (40 ml) was slowly added and the mixture was warmed to 0 °C and sat.aq, ammonium chloride (100 mi) was added. The aqueous layer was extracted with ether (100 ml). The combined organic layers were dried and solvent was removed to give crude product (21.7 g), which was sublimed at 5 mmH 8 and 70 °C to yield (S)-(+)-2,2-dibromo-]-hydroxymethyl-]-methyl- cyclopropane (11) (19.5 g, 80.0 mmole, 89 %) (Found: C 24.41, H 3.50. Calculated for C4I-IsBr20: C 24.62, H 3.31), m.p. 53 - 54 °C, [¢t] 2° +18.8 ° (e 1.050, CHCI3) (for racemate see ref.19) which showed 6a: 1.47 (1H, d, J 7.6), 1.51 (3H, s), 1.62 (1H, d, J 7.6), 1.89 (1H, dd, J 8.3, 3.9), 3.70 (1H, dd, J 11.9, 3.9), 3.86 (1H, dd, J 11.9, 8.3), 6c: 20.52+, 31.39, 32.55-, 35.75, 69.84-; Vm~: 3258 br.s, 2931 m, 1453 m, 1050 s, 1037 s, 1023 s, 787 s, 763 s, 691 sem "l. (S)-(+)-2,2-Dibromo-l-bromomethyl-l-methylcyclopropane. A solution of bromine (0.55 mi, 16.5 mmole) in dichloromethane (2 mi) was slowly added to diphos (3.44 g, 8.63 mmole) in dichlorometlume (25 ml) at 0 °C. (S)-(+)-2,2-Dibromo-l-hydroxymethyl-l-methylcyclopropane (3.66 g, 15.0 mmole) in dichloromethane (15 ml) was then added at 0 °C and the mixture was stirred for 3 h. Ether
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`14780 V.V. TVEREZOVSKY et al. (50 ml) was added, the solution was filtered and solvent was removed to give crude product which was purified by short column cJwomatograpby over silica eluting with petrol and ether (4:1 ) to yield (S)-(+)-2, 2.dibromo-1- bromomethyi-l-methylcyclopropane (12) (4.54 g, 14.8 mmole, 99 %), [a]v 2° +26.4 ° (c 0.884, CHCI 3 ) (for racemate see ref.20) which showed ~i: 1.57 (3H, s), 1.66 (1H, d, J 7.8 Hz), 1.70 (1H, d, J 7.8 Hz), 3.55 (1H, d, J 10.5 Hz), 3.73 (1H, d, J 10.5 Hz); 6¢: 22.21+, 30.31, 35.68-, 36.68, 41.97-; Vm~: 2994 S, 2965 S, 2929 S, 2868 m, 1451 s, 1427 s, 1381 s, 1320 m, 1270 m, 1227 s, 1150 m, 1078 s, 1048 s, 1026 s, 959 s, 900 m, 866 m, 839 m, 703 s, 642 s cm q. (S)-(-)-N-AUyl-2,2-dibromo-l-methylcydopropylmethylamine. ( S )-(+)-2,2-Dibromo- 1 -bromomcthyl- 1 -methylcyclopropane ( 1.53 g, 5.0 mmole) was added to allylamine (3.8 ml, 50 rmnole) in benzene (5 ml) and refluxed for 15 h, then extracted with 5 % aq. sodium hydroxide (5 ml, 6 mmole) and washed with brine (5 ml). The organic layer was dried and the solvent was removed to give (S)-(-)- N-altyl-2,2-vflbromo-l-methylcyclopropylmethylamine (13) (1.38 g, 4.88 mmole, 98 %), [a]v 2~ -15.4 ° (C 0.968, CHCIa) which showed ~h~: 1.40 (IH, s), 1.43 (1H, d, J 7.4 Hz), 1.48 (3H, s), 1.53 (1H, d, J 7.4 Hz), 2.75 (1H, d, J 12.4 Hz), 2.86 (1H, d, J 12.4 Hz), 3.28 (1H, ddd, J 6.0, 1.6, 1.0 Hz), 5.11 (1H, ddt, J 10.2, 1.6, 1.0 Hz), 5.20 (1H, ddt, J 17.1, 1.6, 1.6 Hz), 5.91 (1H, ddt, J 17.1, 10.2, 6.0 Hz); tic: 21.78+, 29.90, 33.55-, 37.31, 52.39-, 57.13-, 116.04-, 136.77+; v~: 3076 m, 2967 s, 2927 s, 2849 s, 2820 s, 1643 m, 1455 s, 1428 m, 1381 m, 1148 m, 1114 s, 1071 s, 1040 s, 1020 s, 993 s, 919 s, 759 m, 690 s cm q. (S)-(-)-N-Benzyl-2,2-dibromo-l-methylcyclopropylmethylamine. A solution of (S)-(+)-2,2-dibromo- 1-bromomethyl- 1-methylcyclopropane (1.84 g, 6.0 mmole) in DMSO (5 ml) was added to benzylamine (1.93 g, 18.0 mmole) in DMSO (10 ml) and stirred for 20 h. It was diluted with water (60 ml) and extracted with ether (3 x 25 ml) and the organic layers were combined and dried. After removing the solvent, the crude product was purified by column chromatography over silica to give starting material (0.14 g, 0.5 mmole) and (S)-(-)-N-benzyl-2,2-dibromo-l-methylcyclopropylmethylamine (14) ( 1.80 g, 5.41 mmole, 98 %, based on starting material consumed), [a]D 2° -8.0 ° (C 0.934, CHC13) which showed 6H: 1.41 (1H, d, J 7.5 Hz), 1.48 (3H, s), 1.49 (1H, d, J 7.5 Hz), 1.58 (1H, s), 2.72 (1H, d, J 12.4 Hz), 2.86 (lI-I, d, J 12.4 Hz), 3.81 (2H, s), 7.20-7.37 (5H, m); bc: 21.87+, 30.05, 33.53-, 37.45, 53.93-, 57.31-, 127.03+, 128.11+, 128.41+, 140.29; vm~: 3026 m, 2989 m, 2927 m, 2890 m, 2842 m, 1494 m, 1453 s, 1113 m, 1071 m, 1042 m, 1027 m, 739 s, 698 s cm q. (S)-(+)-N-t-ButoxycarbonyI-N-allyl-2,2-dibromo-l-methylcyciopropylmethylamine. Potassium carbonate (0.74 g, 7.0 mmole) was added to (S)-(-)-N-allyl-2,2-dibromo-l-methylcyclo- propylmethylamine (0.99 g, 3.50 mmole) and t-butoxycarbonylanhydride (0.96 g, 4.38 mmole) in THF (10 ml). The n~mre was vigorously stirred for 2 h, then filtered and THF was evaporated. A solution of sodium hydroxide (0.12 g, 3 tranole) in ethanol (10 ml) was added to the residue and the mixture was stirred for 1 h. The solvent was removed and the crude product was purified by short column chromatography over silica eluting with petrol and ether (3:1 ) to yield (S)-(+)-N-t-~taDcarbonyl-N-al!yl-2, 2-dibromo- l-methylcyclopropylmethylamine (15) ( 1.29 g, 3.37 mmole, 96 %), [a]v z° +22.6 ° (c 1.116, CHCI3) wldch showed ~H: 1.36 (3H, s), 1.49 (10H, s), 1.54 (1H, d, J 8.5 H_z), 3.30-3.90 (3H, br.m), 3.99 (114_, dd, J 10.2, 5.5 Hz), 5.11-5.19 (2H, m), 5.82 (IH, ddt, J 17.0, 10.4, 5.5 Hz); bc: 21.00+, 28.38+, (33.24, 33.80)-, 37.27, 48.98-, (51.90, 52.37)-, 79.86, 116.25-, 133.63+; v,==: 2975 s, 2931 m, 1698 s, 1455 s, 1408 s, 1365 s, 1319 m, 1245 s, 1172 s, 1148 s, 955 m, 923 m, 873 m, 774 m, 694 m cm q.
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`SAXA-DEF-00417
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`Page 8 of 20
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`Synthesis of (2S,3R,4S)-3,4-methanoproline 14781 (S)-(+)-N-t-Butoxycarbonyl-N-benzyl-2,2-dibromo- 1 -methylcyclopropylmethylamine- Potassium bicarbonate (0.34 g, 4.0 mmole) was added to (S)-(-)-N-benzyl-2,2-dibromo-l-metbyl- cycl~ (0.27 g, 0.81 mmole) and t-butoxycarbonylanhydride (0.22 g, 1.01 mmole) in THF (5 ml). The mixture was vigorously stirred for 18 h, then filtered and THF was evaporated. Work up as above and short column chromaIography over silica elufing with petrol and ether (2:1) gave (S)-(+)-N-t-butoxycarbonyl-N-benzyi- 2,2-~bromo-l-methyicyclopropyimethylmnine (16) (0.33 g, 0.77 mmole, 95 %), [a]D 2° +16.0 ° (c 1.373, CHCI3) which showed ~h~: 1.34 - 1.50 (14H, m), 3.20 - 3.70 (2H, br.m), 4.43 (1H, br.d, J 15.8 I-Iz), 4.57 (1H, d, J 15.8 Hz), 7.18 - 7.58 (5H, m), ~c: 21.07+, 28.40+, (33.46, 33.90)-, 36.02, (49.85, 49.98)-, 52.38-, 80.29, 127.11+, 127.22+, 128.48+, 138.37, (156.06, 156.36), v~: 3064 m, 3030 m, 2969 s, 2929 s, 1700 br.s, 1496 m, 1454 s, 1416 s, 1366 s, 1309 s, 1250 s, 1180 s, 1122 s, 1082 m, 1066 m, 1028 m, 960 m, 902 m, 879 m, 768 m, 698 s cm "~. (R)-(+)-2,2-Dibromocyclopropanecarbonyl chloride. Thionyl chloride (12 ml, 164 mmole) was added to (R)-(+)-2,2-<libromocyclopropanecarboxylie acid (5, R), ([Ct]D~ +129.4 ° (e 1.036, CHC13), 92.5% e.eJ4), (10.00 g, 41.0 mmole) and the mixture was refluxed for 2 h. The excess of thionyl chloride was removed by distillation to give (R)-(+)-2,2-dibromocyclopropanecarbonyl chloride (10.72 g, 40.9 mmole, 100 %), [c~]D 2° +109.7 ° (c 1.068, CHC13) which showed 6 a 2.18 (1H, dd, J 9.2, 7.9 Hz), 2.27 (IH, dd, J 7.9, 7.6 Hz), 3.12 (1H, dd, J 9.2, 7.6 Hz), 6c: 19.34, 31.18-, 42.63+, 168.06; Vm~: 1779 hr. s, 1417 m, 1347 s, 1104 m, 1069 s, 1001 s, 940 m, 836 s, 741 m, 689 s em "~. (R)-(+)-2,2-Dibromo-l-hydroxymethylcyclopropane. A solution of(R)-(+)-2,2-dibromocyclopropylcarbonyl chloride (10.68 g, 40.7 mmole) in dry ether (20 ml) was added to a stirred solution of lithium aluminium hydride (1.64 g, 40 mmole) in dry ether (150 ml) at -85 °C under nitrogen over 30 min. After 10 min at -85 °C, work up as for (6) and removal of the solvent gave (R)-(+)- 2,2-dibromo-l-hydroxymethylcyclopropane (9.02 g, 39.2 mmole, 96 %) as colourless oil, [a]D 2° +2.4 ° (C 1.234, CHCI3) (for racemate see ref. 21) which showed 6H: 1.43 (IH, dd, J 7.5, 7.3 Hz), 1.82 (IH, dd, J 10.4, 7.3 Hz), 1.97 (1H, dddd, J 10.4, 8.5, 7.5, 5.1 Hz), 2.33 (1H, s), 3.62 (IH, dd, J 12.2, 8.5 Hz), 3.91 (1H, dd, J 12.2, 5.1 I-Iz), ~c: 26.01, 26.45-, 32.33+, 64.84-, Vm~ : 3346 hr. s, 2934 m, 2879 m, 1462 m, 1432 m, 1390 m, 1240 m, 1103 s, 1042 s, 682 s em "1. (R)-(-)-2,2-Dibromo-l-bromomethylcyciopropane. A solution of bromine (2.21 ml, 42.9 mmole) in dichloromethane (5 ml) was slowly added to a solution of diphos (8.93 g, 22.4 mmole) in dichloromethane (150 ml) at 0 °C. (g)-(+)-2,2-Dibromo-l-bydroxymetbyl- cyclopropane (8.99 g, 39.1 mmole) in dichloromethane (30 ml) was then added at 0 °C and the reaction mixture was stirred for 3 h. The solution was evaporated to a volume of 100 ml and ether (100 ml) was added, and the solution was separated from a solid. The solid was dissolved in dichloromethane (50 ml) and ether (100 ml) was added. The solution was separated from precipitate and the last procedure was repeated 4 times, until there was no product in the organic layer by glc. All solutions were combined and the solvent was removed to give a crude product which was purified by short colunm chromatography over silica eluting with petrol and ether (4:1) to yield (R)-(-)-2,2-dibromo-l-bromomethylcyclopropane (11.08 g, 37.8 mmole, 97 %), [a]D 2° -15.9 ° (c 0.962, CHCI3) (for racemate see refs. 20, 22) which showed 8 u" 1.46 (1H, dd, J 7.7, 7.4 Hz), 1.95 (1H, dd, J 10.1, 7.4 Hz), 2.10
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`SAXA-DEF-00418
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`Page 9 of 20
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`14782 V.V. TVEREZOVSKY et al. (1H, ddt, J 10.1, 7.7, 7.5 Hz), 3.48 (2H, d, J 7.5 Hz); 8c: 20.62, 23.58-, 25.61% 26.84-; vu: 1430 s, 1366 s, 1230 m, 1215 s, 1191 m, 1106 s, 1047 m, 1011 m, 937 m, 690 s, 621 m cm "t. (R)-(+)-N-Bemefl-2,2-dibremoeydopropylmethylamine. A solution of (R)-(-)-2,2-dibromo-l-bromomethylcyclopropane (5.86 g, 20.0 mmole) in DMSO (20 ml) was added to benzylang-~ (6.43 g, 60.0 mmole) in DMSO (20 ml). The mixture was sfrred for 4 h at 60 °C, diluted with water (100 ml), and 5 % aq. of sodium hydroxide (20 ml, 25 mmole) was added and the mixture was extracted with ether (3 x 100 ml). The organic layers were combined and dried. After removing the solvent, the crude product was purified by chromatography over silica (petrol-ether, 1:1) to give (R)-(+)-N-benzyl-2,2-dibromo- cyclopropyimethylamine (6.01 g, 18.8 rnmole, 94 %), (Found: M ÷, 318.9394. Calculated for CnHt3N79BrUBr: 318.9394), [ct]v ~ +1.5° (c 1.348, CHCI3) which showed 8H: 1.34 (1H, dd, J 7.1, 6.8 Hz), 1.75 (1H, s), 1.78 (1H, dd, J 10.4, 6.8 Hz), 1.86 (1H, dddd, J 10.4, 8.0, 7.1, 5.2 Hz), 2.72 (1H, dd, J 12.8, 8.0 Hz), 2.89 (1H, dd, J 12.8, 5.2 I-Iz), 3.87 (1H, d, J 13.1 Hz), 3.89 (1H, d, J 13.1 Hz), 7.26 - 7.38 (5H,m), 6¢: 15.34, 27.29-, 30.94+, 52.00-, 53.67-, 127.13+, 128.16+, 128.50+, 139.92; Vm~: 3061 m, 3026 s, 2891 m, 2830 s, 1494 m, 1454 s, 1358 m, 1108 s, 1044 m, 1028 m, 734 s, 698 s, 679 s cm'l; (m~., %): 321, 2, 320, 2, 319, 3; 318, 3; 317, 2 (M+); 316, 2; 255, 2, 146, 20, 100, 24; 91,100. (R)-(+)-N,N-Dibenzyl-2,2-dibromocyclopropylmethylamine. Sodium carbonate (3.71 g, 35.0 mmole) in water (20 ml) was added to (R)-(+)-N-benzyl-2,2- dihromocyclopropylmethylamine (5.42 g, 17.0 mmole) and benzylbromide (6.0 g, 35 mmole) in dichloromethane (20 ml) and the mixture was refluxed and stirred for 15 h.The water layer was extracted with dichloromethane (2 x 5 ml). The organic layers were combined, dried and the solvent was removed. Most of the benzylbromide was evaporated in vacuo (100 °C, 1 mmHg). The residue was purified by chromatography over silica (petrol - ether, 2:98) to give (R)-(+)-N,N-dibenzyl-2,2-dibromocyclopropylmethylamine (17) (6.80 g, 16.6 mmole, 98 %) as colourless, very viscous oil (Found: M +, 408.9864. Calculated for CnHtgN79BrSlBr: 408.9864), [CC]D z° +17.0 ° (C 1.024, CHCI3) which showed 8H: 1.23 (IH, dd, J 7.2, 5.8 Hz), 1.81 (IH, dd, J 10.6, 5.8 Hz), 1.83 (1H, dddd, J 10.6, 7.2, 6.4, 5.1 Hz), 2.66 (1H, dd, J 13.7, 5.1 Hz), 2.81 (lI-I, dd, J 13.7, 6.4 Hz), 3.65 (2H, d, J 13.6 I-Iz), 3.80 (2H, d, J 13.6 Hz), 7.25 - 7.45 (10I-I, m); 8c: 27.60 -, 28.43, 29.09 +, 55.77 -, 58.30 -, 127.03 +, 128.30 +, 128.80 +, 139.41, vm: 3084 m, 3061 m, 3026 s, 2925 m, 2801 s, 1494 s, 1453 s, 1368 s, 1247 m, I 110 s, 1074 m, 1028 s, 973 m, 746 s, 698 s, 678 s, cm 1, (m~, %): 411, 3,410, 3; 409, 4, 408, 4; 407, 3 (M+); 406, 1; 210, 30, 149, 4; 92, 12; 91, 100. (IR, 4,5, 5S)-N-t-Butoxycarbonyl-l-methyl-4-vinyl-3-azabicydo[3.1.0]hexane. A 1.5 M solution ofmethyilithium in e~her (3.03 ml, 4.55 mmole) was added to (S)-(+)-N-t-butoxycarbonyl- N-allyl-2,2-dibromo- 1-methylcyclopropylmethylamine (1.66 g~ 4.33 mmole) in dry ether (50 ml) under nitrogen at - 60 ~C over 5 min. The solution was stirred for 30 min then sat. aq. ammonium chloride (20 ml) was added. The water layer was extracted with ether (50 ml). The combined organic layers were evaporated and purified by chromatography over silica (ether-petrol, 1:9) to give (IK 4S, 5S)-N-t-butoxycarbonyl-l-methyl-4-vinyl-3- azabicyclo[3.1.0]hexane (lga), (453 rag, 2.03 mmole, 47 %) as mixture of two rotamers in ratio 1.5:1, [a]n 2° -38.2° (c 0.976, CHCI3)which showed vmx: 2976 m, 1699 s, 1449 m, 1405 s, 1388 s, 1366 m, 1176 m, 1123 m,
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`SAXA-DEF-00419
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`Page 10 of 20
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`Synthesis of (2S,3R,4S)-3,4-methanoproline 14783 883 m ¢m ~, (m/z, %): 213, 9, 212, 10 (M+), 198, 12, 197, 14, 169, 44, 168, 59, 167, 38, 142, 27, 141, 38, 140, 13, 108, 20; 96, 24; major rotamer, ~: 0.39 (1H, m), 0.54 (IH, m), 1.07 (1H, In), 1.25 (3H, s), 1.41 (9H, s), 3.16 (IH, d, J 10.6 Hz), 3.61 (1H, d, J 10.6 Hz), 4.17 (1H, d, J 6.5 I-Iz), 5.03-5.18 (2H, m), 5.69-5.88 (1H, in), 8c: 15.39-, 18.64+, 22.07, 27.51+, 28.49+, 51.78-, 62.20+, 79.21, 114.22-, 138.00+, 154.73, minor rotamer, ~x: 0.39 (1H, In), 0.54 (1H, m), 1.07 (1H, m), 1.23 (3H, s), 1.43 (9H, s), 3.17 (1H, d, J 10.6 I-Iz), 3.55 (1H, d, J 10.6 Hz), 4.32 (1H, d, J 5.9 Hz), 5.03-5.18 (2H, m), 5.69-5.88 (1H, m), 8c: 15.31-, 18.55+, 22.78, 26.91+, 28.43+, 52.41-, 61.51+, 79.21, 114.31-, 137.53+, 154.51. Also were isolated N-al~l-N-t-butoxyccwbonyl-N-2-methylbuta-2,3-~enylamine (19a) (58 mg, 0.26 mmole, 6 %) (which showed 8a: 1.48 s (9H), 1.68 (3I-I, t, J 3.1), 3.72 (4H, br. s), 4.65 (2H, m), 5.12 (2H, m), 5.75 (1H, m), 8c: 15.91+, 28.34+, 48.74-, 75.23-, 79.53, 95.62, 116.20-, 116.63-, 133.76+, 155.52, 206.44; vm~: 2978 m, 2929 m, 1698 s, 1456 rn, 1407 s, 1366 m, 1244 s, 1167 s cm'~; N-allyl-N-t-butoxycarbonyl-N-(2-bromo-1- methylcyclopropylmethyl)amine (20a) (188 mg, 0.62 mmole, 14 %) which showed 5H: 0.69 (1H, dd, J 6.4, 4.5 Hz), 0.87 (1H, dd, J 7.4, 6.4 Hz), 1.25 (3H, s), 1.47 (9H, s), 2.95 (1H, br. s), 3.30 - 4.00 (4H, br. m), 5.07 - 5.17 (2H, m), 5.74 (1H, ddt, J 17.0, 10.5, 5.6 Hz), v~: 3079 w, 2977 m, 2930 m, 1694 s, 1456 m, 1410 m, 1366 m, 1246 m, 1172 s cm "t. (IR, 4S, SS)-N-t-Butoxyearbonyl-l-methyi-4-phenyl-3-azabiolclo[3.1.0]hexane. A 1.5 M solution of methyUithium in ether (0.44 rni, 0.66 mmole) was added to (S)-(+)-N-t-butoxy- carbonyl-N-benzyl-2,2-ch'bromo-l-methyloyclopropylmethylm~e (260 rag, 0.60 mmole) in dry ether (10 ml) under nitrogen at 20 °C over 5 min. The solution was stirred 30 rain then sat.aq, ammonium chloride (5 mi) was added. The water layer was extracted with ether (10 ml). Evaporation of the combined organic layers and chromatography over silica (ether-petrol, 3:17) gave (1I~ 4S, 5S)-N-t-butoxycarbonyl-l-methyl-4-phenyl-3-azabicyclo[J.l.O]- hexcme (lgb), (65 rag, 0.24 mmole, 40 %) as a mixture of two rotamers in ratio 2:1, [a]D 2° -98.2 ° (C 0.708, CHCI3) which showed Vm~: 2978 m, 2929 m, 2868 m, 2250 m, 1684 s, 1478 m, 1455 m, 1408 s, 1390 s, 1367 m, 1172 s, 1127 s, 908 s, 879 m, 731 s, 699 m, 649 m cm "1, major rotamer, 8H: 0.52 (1H, m), 0.69 (1H, m), 1.25 (1H, m), 1.27 (9H, s), 1.35 (3H, s), 3.44 (1H, d, J 10.7 8z), 3.75 (1H, d, J 10.7 Hz), 4.69 (1H, s), 7.19 - 7.36 (5H, m), 8c: 16.80,18.77+, 22.91, 28.28+, 30.14+, 53.26-, 64.32+, 79.38, 126.54+, 128.28+, 143.85, 154.56, minor rotamer, ~i: 0.52 (lI-I, m), 0.69 (1H, m), 1.25 (1H, m), 1.32 (3H, s), 1.41 (98, s), 3.37 (18, d, J 10.8 I-Iz), 3.69 (1H, d, J 10.8 Hz), 4.89 (1H, s), 7.19 - 7.36 (5H, m); 8c: 16.35-, 18.56+, 23.49, 28.28+, 29.19+, 53.46-, 63.45+, 79.38, 126.97+, 128.47+, 143.17, 154.33. Also isolated was a mixture of(19b), (20b) and starting material (90 nag, 27:7:11 based on ~H NMR of Boo-deprotected mixture) which showed vm: 3030 m, 2976 s, 2930 s, 1961 m, 1694 s, 1496 m, 1454 s, 1413 s, 1365 s, 1242 s, 1169 s, 1124 s, 877 m, 768 m, 699 s cm "~, N-benzyl-N-t-butoxycarbonyl-N-2-methylbuta-2,3- deny/amine (19b)showed (f~om this mixture)~: 1.51 (9H, In), 1.68 (3H, m), 3.80 (2H, m), 4.45 (2H, m), 4.73 (2H, In), 7.21-7.39 (514, m), 8c: 15.95, 28.39, 48.62, 75.37, 95.41, 127.09, 128.36, 128.58, 137.53, 156.31, 206.83. This mixture (90 nag) was deproteeted by reaction with trifluoroacetic acid to give 69 nag of amines which were separated by column chromatography to yield N-bemyl-N-2-methyibuta-2,3-a~enylamine (31 nag, 0.18 tranole, 27 %) which showed 8n: 1.70 0H, t, J 3.1 Hz), 3.