Contents
`
`6973
`
`Contributors to this Issue
`
`M. Adamczyk, J. C. Gebler and
`J. Grote
`
`G.-X. He and N. Bischofberger
`
`D. W. Phife, R. W. Patton, R. L. Berrie,
`R. Yarborough, M. S. Puar, M. Patel,
`W. R. Bishop and S. J. Coval
`P. Zhang and J. M. Cook
`
`T. A. Engler, W. Chai and
`K. 0. Lynch, Jr
`
`D. H. R. Barton, B. M. Chabot,
`N. C. Delanghe, B. Hu,
`V. N. Le Gloahec and R. U. Rojas Wahl
`D. Choi and H. Kohn
`
`C. T. Baker, M. N. Mattson and
`P. Helquist
`
`J. E. Macor
`
`S. D. Burke, G. Zhang and
`J. L. Buchanan
`
`6987
`
`6975 Graphical Abstracts
`Cherne-enzymatic transformations of sensitive systems. Preparation of
`digoxigenin haptens via regioselective lipase mediated hydrolysis
`A convenient preparation of protected 3'-deoxyguanosine from guanosine
`
`6991
`
`6995
`
`SCH 58450, a novel famesyl protein transferase inhibitor possessing a
`6a, 12a:7, 12-diepoxybenz[a)anthracene ring system
`
`6999
`
`7003
`
`7007
`
`7011
`
`7015
`
`7019
`
`7023
`
`A successful acid promoted asymmetric Pictet-Spengler reaction of Na·
`BOC protected tryptophans. Effect of the BOC group on reactivity and
`stereoselectivity
`Switchable regioselectivity in Lewis acid-promoted reactions of 1,4·
`benzoquinone monoimides with styrenyl systems: selective syntheses of
`either 2-aryl-2,3·dihydrobenzofurans or 2-aryl-2,3-dihydroindoles
`Further evidence for the Fell-FelV and Fe111-FeV manifolds in the sub(cid:173)
`stitution of saturated hydrocarbons
`
`Trimethylsilyl halides: effective reagents for the synthesis of p-halo amino
`acid derivatives
`·
`Mechanistic test for carbocationic alkene cyclization initiated by cationic
`iron carbene complex formation
`An unusual by-product in a concise synthesis of a rotationally restricted
`phenolic analog of serotonin
`Enantiosele:tive synthesis of a halichondrin B C(20)-+C(36) precursor
`
`[Continued on outside back coverj
`
`~Pergamon
`
`Breckenridge Exhibit 1010
`Breckenridge v. Research Corporation Technologies, Inc.
`
`

`
`Pergamon
`
`Tetrahedron
`
`Letters Vol 36 No 39 pp 7011-7014 1995
`Elsevier Science Ltd
`
`Printed
`
`in Great Britain
`
`0040-4039/95
`
`59.500.00
`
`0040-40399501451-9
`
`Trimethylsilyl Halides Effective Reagents for the Synthesis of
`3-Halo Amino Acid Derivatives
`
`Daeock Choi and Harold Kohn
`Department of Chemistry University of Houston Houston Texas 77204-5641
`
`Abstract
`
`corresponding
`
`alanine derivatives are prepared in moderate yields in one step from the
`13-Halogen
`serine compound and trimethylsilyl halide
`
`p-Halogen-substituted amino acid derivatives j-ç have been used as irreversible inactivators of
`
`enzymatic processes2 and are reagents for the construction of functionalized unnatural amino acids.3-5 Most
`
`current methods
`
`for
`
`the synthesis of j-c proceed through the corresponding serine analogue
`
`thereby
`
`generating
`
`optically pure derivatives.3
`
`Established
`
`routes for the synthesis of 13-chloro adduct
`
`.i
`
`include
`
`treatment of J.i1 with either phosphorous pentachloride36
`
`or triphenylphosphine and carbon tetrachloride78
`
`whereas the reaction of jj with triphenyiphosphine and carbon tetrabromide produces 1k.8 The most
`
`common synthesis for f3-iodo adduct
`conversion of the serine hydroxy group to the tosylate
`requires initial
`mesylate le then displacement with Na.39t0 In this letter we report
`
`one-step versatile method for the
`
`synthesis of 13-halogen
`
`amino acid derivatives
`
`The method has been shown to proceed without
`
`racemization
`
`and effectively introduces
`
`13-halogen
`
`substituent
`
`into peptides
`
`RNH--R
`
`H3CNJ1NC
`
`XCI
`XBr
`XI
`XOH
`XOTs
`
`2a XCI
`XBr
`cXl
`XOH
`XF
`
`For an ongoing project
`
`to prepare bioactive amino acid derivatives11 we needed the 13-halogen
`have advanced trimethylsilyl bromide and iodide14 as effective
`Jung and coworkers1213
`
`compounds
`
`reagents for the conversion
`
`of primary alcohols to bromides and iodides respectively Use of trimethylsilyl
`
`chloride in their procedure
`
`did not afford the alkyl chloride Recently Snyder
`
`reported that dimethyl
`
`sulfoxide catalyzed the trimethylsilyl chloride conversion of
`
`and
`
`alcohols to the corresponding
`
`7011
`
`

`
`7012
`
`chlorides.15
`
`Employing the Jung protocol and commercially available trimethylsilyl halides RS-N
`was converted to -2 in acetonitrile 1718 Attempts to convert 24 to
`acetylserine-N-benzylamidei6
`and gave dihydrooxazole
`
`fluoro
`
`with trimethylsilyl
`in 46% yield.9
`
`fluoride were unsuccessful
`
`room temperature 24
`
`H3CcjN HCH21
`
`The trimethylsilyl halide reactions were accomplished within
`
`at reflux temperatures
`
`The isolated
`
`yields were from 74% for
`
`to 20% for
`
`These decreased yields have been attributed in part to the
`
`sensitivity of
`
`the p-halogen product
`
`to the reflux conditions
`
`Significantly the hydroxy to chloride
`Treatment of R-24
`interchange within the serine derivative 24 proceeded without apparent
`racemization
`with trimethylsilyl chloride in acetonitrile gave only R-2 NMR analysis.20 The utility of this procedure
`the introduction of jI-halogen substituents within peptides was demonstrated by the conversion of
`to l-chloro aducts 4k2 and b22 respectively in 40-52% yields
`
`for
`
`dipeptides
`
`and
`
`H3C
`
`NOCH2CH3
`
`H3C
`
`4aXOH
`xCI
`
`NOCH3
`XOH
`kXCI
`
`In conclusion trimethylsilyl halides are effective
`
`reagents for the installation of n-halo substituents
`
`proceeds in one step and in moderate yields The
`within N-acyl serine containing peptides
`conversion of serine derivatives 24 4. and
`4k and
`
`respective
`
`to -chloro derivatives
`
`with
`
`The reaction
`
`trimethylsilyl chloride in the absence of dimethyl sulfoxide was unexpected.12.35
`
`The mechanism for this
`
`transformation is under
`
`investigation
`
`Acknowledgments
`of Texas Advanced Technology Program
`
`This work was funded in part by the Robert
`
`Welch Foundation
`
`and the State
`
`REFERENCES AND NOTES
`
`Silverman R.B Levy M.A Org Chem 1980 45 815
`Hornsperger J.M Heydt J.G
`Ducep J.B Baltzer
`Bey
`Piriou Wagner
`Schirlin
`Chem Soc Perkin Trans
`Jung M.J Danzin
`De Cian
`Weiss
`1053
`1992
`
`Mitschler
`
`Fischer
`
`

`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`7013
`
`Coppola G.M Schuster HF Asymmetric Synthesis Construction of Chiral Molecules Using Amino
`Acids Wiley New York 1987 pp 127-145
`Dunn M.J Jackson R.F.W Pietruszka
`Bajgrowicz J.A El Hallaoui
`2759
`
`Turner
`
`Org Chem 1995 60 2210
`
`Jacquier
`
`Pigière
`
`Viallefont
`
`Tetrahedron Lett 1984 25
`
`Miller M.J Mattingly PG Morrison MA Kerwin Jr J.F Am Chem Soc 1980 102 7026
`Snyder E.I Org Chem 1972 37 1466
`Synthesis 1975 708
`Org Chem 1985 50 3676
`Tetrahedron Len 1985 26 347
`Mizutani
`Itaya
`Sawhney K.N Bardel
`Robertson D.W Leander J.D
`Kohn
`Jung M.E Ornstein P.L Tetrahedron Lett 1977 18 2659
`Jung M.E Hatfield G.L Tetrahedron Lett 1978 19 4483
`Schmidt A.H Aidrichimica Acta 1981 14 31
`Snyder D.C Org Chem 1995 60 2638
`LeGall M.S Thesis University of Houston 1982
`spectral data 111 and 13C NMR IR low and high resolution MS were obtained for all new
`
`Gruber
`
`TOmdskOzi Radics
`
`Butera
`
`Rini
`
`Heiquist
`
`Satisfactory
`
`compounds
`
`Med Chem 1993 36 3350
`
`General Procedures
`
`for the Preparation of 2a-2
`To CH3CN suspension of
`mmol 20 mL/mmol of
`mmol under N2 The reaction mixture was heated at reflux 2-8
`11 mixture of CHC13 and H20 and the organic
`
`was added trimethylsilyl halide 2.5
`
`and then the solvent was removed
`
`under
`
`reduced pressure The residue was dissolved in
`
`layer was extracted with CHC13 and the combined organic layers
`layer was separated
`The aqueous
`were dried Na2SO4 and evaporated in vacuo The residue was triturated with Et20 to give the desired
`
`product
`
`COCH3 3.72 dd
`6.3 11.1 Hz CHHCl
`1H NMR CDCI3 62.06
`mp 143- 144
`6.3 11.1 Hz CHHCI 4.48
`5.7 Hz NHCH2 4.72-4.81
`3.94 dd
`CII 6.36 br
`6.3 Hz NH 6.49 br NH 7.22-7.35
`PhH 13C NMR DMSO-d6 22.45 COCH3 42.16
`CH2N or CH2C1 44.62 CH2N or CH2CI 53.89 CH 126.70 C4 127.03 2Cr or 2C3 128.16
`2C2 or 2C3 138.39 Ci 168.38 COCH3 or CONH 169.52 COCH3 or CONH ppm MS
`CI 257 M1 28 255 M1 81 222 100 Mr CI 255.09085
`C12H16C1N2O2 255.090 03
`2.04 COCH3 3.59 dd
`1H NMR CDCI3
`mp 123-125
`4.8 10.5 Hz CHHBr 4.47
`5.7 Hz NHCH2 4.79-4.83
`3.74 dd
`CII 6.42 br
`6.6 Hz NH 6.47 br NH 7.29-7.37
`PhIl 13C NMR CDC13 23.07 COCH3 32.19
`CH2BF 43.79 CHN 53.57 CH 127.62 C4 127.71 2C2 or 2C3 128.70 2C2 or 2C3 137.37
`C1 168.58 COCH3 or CONH 170.37 COCH3 or CONH ppm MS CI 301
`51 22072 219 100 Mr CI 299.039 22
`
`299
`
`51
`
`calcd for C12H16BrN2O2
`
`299.039
`
`calcd for
`
`4.8 10.5 Hz CHIIBr
`
`

`
`7014
`
`19
`
`35
`
`2.05 COCH3 4.38-4.51
`2c mp 169-170C dcc 1H NMR CDCI3
`C1121 4.48
`7.2 Hz NH 6.87 br NH 7.30-7.35
`5.7 Hz NHCH2 4.63-4.70
`CII 6.52 br
`PhH 3C NMR CDCI3 4.83 CH2I 22.75 COCH 43.44 CH2N 53.31 CH 127.29 C4
`127.42 2C2 or 2Cy 128.33 2Cr or 2C3 136.87 C1 168.39 COCH3 or CONH 169.80
`COCH3 or CONH ppm MS -4-Cl ni/e rd intensity 220 20 219 100 Mr CI 347.025 81
`calcd for C12H161N202 347.025 65
`CR3 4.21-4.38
`1H NMR DMSO-d6
`NHCH2
`mp 129-130
`Compound
`CH 7.22-7.33
`5.7 Hz NH 13C NMR CQ3OD
`PhH 843
`OCII2CH 4.55-4.61
`69.67 CH 71.87 OCH2CH 128.32 C4 128.60 2C2 or 2C3
`13.64 CH3 44.12 NHCH2
`129.56 2C2 or 2C3 139.60 C1 170.65 CNO or CO 173.66 CNO or CO ppm MS CI
`rd intensity 219 M1 100 141 41 Mr -4-Cl 219.112 64
`
`1.93
`
`caled for Ci2H15N2O2 219.113
`
`20
`
`saturated CDCI3 solution containing R--- mandelic
`acid to R-Za gave only one signal
`Addition of
`in the 1H NMR spectrum for the acetyl methyl protons while the corresponding
`peaks of equal height For the previous
`use of this method for the assessment of enantiomeric purity
`
`racemate gave two
`
`1.17
`
`see reference 11
`1H NMR DMSO-d6
`6.9 Hz OCH2CH3 1.88
`21 Compound
`mp 107-108
`COCH3 3.67 dd
`7.1 11.1 Hz CHHC1 3.77 dd
`5.1 11.1 Hz CFl11Cl 3.83
`CR 8.31
`8.4 Hz NH 8.58
`Hz NHCH2 4.07
`6.9 Hz OCR2CH3 4.61-4.68
`6.0 Hz NH 13C NMR DMSO-d6 14.02 OCH2CH3 22.45 COCH3 40.82 NHCH2 or CH2CI
`44.55 NHCH2 or CH2CI 53.57 CH 60.43 OCH2CH3 169.01 169.33
`169.53 COCH3
`intensity 253 Ml 57 251 Ml 100 215 41
`CONH COOCH2CH3 ppm MS CI rel
`calcd for C9H16C1N204 251.079 86
`Mr 4-Cl 251.080 55
`1.84 COCH3 3.67 OCH3 3.75
`NMR DMSO-d6
`22 Compound
`mp 133-134
`CH 8.12
`59 Hz NH 8.50 dJ 7.8
`5.9 Hz NHCH2 3.81-3.91
`CH2CI 4.71-4.77
`Hz NH 13C NMR CD3OD 22.38 COCH3 43.26 NI-CH2 or CH2C1 44.97 NHCH2 or CH2CI
`53.21 CII 55.02 OCH3 170.58 171.65 173.80 COCH3 CONH COOCH3 ppm MS CI
`rd intensity 239 M4I 41 237 M4-l 100 Mr --CI 237064 37 fM4-4-l calcd for C8H14C1N204
`237.064 21
`
`6.0
`
`Received
`
`in USA 30 June 1995 accepted 28 July 1995