Tetrahedron
`Letters
`
`Contents
`
`Contributors to this issue
`
`Graphical Abstracts
`
`Chemoenzymatic transformations of sensitive systems. Preparation of
`digoxigenin haptens via regioselective lipase mediated hydrolysis
`
`A convenient preparation of protected 3'~deoxyguanosine from guanosine
`
`SCH 58450, a novel tarnesyl protein transferase inhibitor possessing a
`6a,12a:7,12-diepoxybenz[a}anthracene ring system
`
`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 Fe"—FelV and Fe'“—FeV manifolds in the sub-
`stitution of saturated hydrocarbons
`
`Trimethylsilyl halides: effective reagents for the synthesis of 13~halo amino
`acid derivatives
`
`Mechanistic test for carbocationic alkene cyclization initiated by cationic
`iron carbene complex formation
`
`in a concise synthesis of a rotationally restricted
`An unusual by—prodLict
`phenolic analog of serotonin
`
`Enantioselective synthesis of a halichondrin B C(20)—eC(36) precursor
`
`[Continued on outside back cover]
`
`MYLAN — EXH1B1Tj010
`
`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. O. 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
`
`6973
`
`6975
`
`6987
`
`6991’
`
`6995
`
`6999
`
`7003
`
`7007
`
`7011
`
`7015
`
`7019
`
`7023
`
`Pergamon
`
`
`
`
`'99:»,
`
`
`
`MYLAN - EXHIBIT 1010
`
`

`
`Pergamon
`
`Tetrahedron Letters. Vol. 36. No. 39. pp. 701 l-7014, 1995
`Elsevier Science Ltd
`Printed in Great Britain
`0040-4039/95 $9.50-+0.00
`
`0040-4039(95)0l451-9
`
`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
`
`[3-Halogen alanine derivatives are prepared in moderate yields in one step from the
`Abstract:
`corresponding serine compound and trimethylsilyl halide.
`
`B-Halogen-substituted amino acid derivatives _Q—_c_ have been used as irreversible inactivators of
`
`enzymatic processes‘»2 and are reagents for the construction of functionalized unnatural amino acids.3'5 Most
`
`current methods for the synthesis of 1_a-_<_: proceed through the corresponding serine analogue _1_d, thereby
`
`generating optically pure derivatives.3 Established routes for the synthesis of |3—chloro adduct g include
`
`treatment of _Ig with either phosphorous pentachloride3-5 or triphenylphosphine and carbon tetrachloride,l»7-3
`
`whereas the reaction of lg with triphenylphosphine and carbon tetrabromide produces 112.1-3 The most
`
`common synthesis for [3-iodo adduct 1;, requires initial conversion of the serine hydroxy group to the tosylate
`
`(mesylate) l_e, then displacement with NaI.3-9-10 In this letter we report a one-step, versatile method for the
`
`synthesis of B-halogen amino acid derivatives. The method has been shown to proceed without racernization
`
`and effectively introduces a [5-halogen substituent into peptides.
`
`0
`
`RNH—c—c_n'
`O
`H
`
`H30
`
`fi
`
`x
`
`o
`
`E X=C|
`_b_ X=Br
`Q X=l
`g X=OH
`g X=OTs
`
`gg X=C|
`l_) X=Bl’
`Q X=l
`Q X=OH
`g X=F
`
`For an ongoing project to prepare bioactive amino acid derivatives,“ we needed the B—halogen
`
`compounds Za-29. Jung and coworkerslzv” have advanced trimethylsilyl bromide and iodide” as effective
`
`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 1° and 3“ alcohols to the corresponding
`
`70]]
`
`

`
`7012
`
`chlorides. ‘ 5 Employing the Jung protocol and commercially available trimethylsilyl halides, (R,S)-N-
`acetylserine—N-benzylamide'5 (251) was convened to 2_a—2_e in acetonitrile. 17-13 Attempts to convert 2_d to B-
`fluoro 2_e with trimethylsilyl fluoride were unsuccessful (room temperature, 24 h) and gave dihydrooxazole 3
`in a 46% yield. ‘9
`
`~ac4:}<e.~H<=++=—©
`
`O 3
`
`.
`
`The trimethylsilyl halide reactions were accomplished within 8 h at reflux temperatures. The isolated
`
`yields were from 74% for 2_a to 20% for 2;. These decreased yields have been attributed in part to the
`
`sensitivity of the B-halogen product to the reflux conditions. Significantly, the hydroxy to chloride
`
`interchange within the serine derivative 251 proceeded without apparent racemization. Treatment of (R)-2d
`
`with trimethylsilyl chloride in acetonitrile gave only (R)-23 (NMR analysis)?-0 The utility of this procedure
`
`for the introduction of B-halogen substituents within peptides was demonstrated by the conversion of
`
`dipeptides Ag and is, to [3-chloro aducts £121 and 512,22 respectively, in 40-52% yields.
`
`><
`
`X=OH
`X=Cl
`
`.§_§
`D
`
`In conclusion, trimethylsilyl halides are effective reagents for the installation of B—halo substituents
`
`within N—acyl serine containing peptides. The reaction proceeds in one step and in moderate yields. The
`
`respective conversion of serine derivatives 2g, 93, and 11 to B-chloro derivatives 2;, ;4_h, and Qb with
`
`trimethylsilyl chloride in the absence of dimethyl sulfoxide was unexpected.”-‘3v'5 The mechanism for this
`
`transformation is under investigation.
`
`Acknowledgments. This work was funded, in part, by the Robert A. Welch Foundation and the State
`
`of Texas Advanced Technology Program.
`
`REFERENCES AND NOTES
`
`1.
`
`2.
`
`Silverrnan, R.B.; Levy, M.A. J. Org. Chem. 1980, 45, 815.
`
`Schirlin, D.; Ducep, J.B.; Baltzer, S.; Bey, P.; Piriou, F.; Wagner, L; Homsperger, J.M.; Heydt, J.G.;
`
`J ung, M.J.; Danzin, C.; Weiss, R.; Fischer, 1; Mitschler, A.; De Cian, A. J. Chem. Soc. Perkin Trans.
`1992.1, 1053.
`
`

`
`7013
`
`S"
`
`—>—r-—-r---u-au—-r—-u—p---\O®\lO\.°°.".°‘!~":"‘E-*’.'°5“S3""
`
`Coppola, G.M.; Schuster, H.F. Asymmetric Synthesis. Construction of Chiral Molecules Using Amino
`Acids; Wiley: New York, 1987, pp 127-145.
`
`Dunn, M.J.; Jackson, R.F.W.; Pietruszka, J .; Turner, D. J. Org. Chem. 1995, 60, 2210.
`
`Bajgrowicz, J.A.; El Hallaoui, A.; Jacquier, R.; Pigiére, C.; Viallefont. P. Tetrahedron Lett. 1984, 25,
`2759.
`
`Miller, M.J.; Mattingly, P.G_; Morrison. M.A.; Kerwin, Jr., LF. 1. Am. Chem. Soc 1980, 102, 7026.
`
`Snyder, E.I. J. Org. Chem. 1972, 37, 1466.
`
`Gruber, L.; Tomfiskiizi, I; Radics, L. Synthesis 1975, 708.
`
`Butcra, J .; Rini, J.; Helquist, P. J. Org. Chem. 1985, 50, 3676.
`
`Itaya, T.; Mizutani, A. Tetrahedron Lett. 1985, 26, 347.
`
`Kohn, H.; Sawhney, K.N.; Bardel, P.; Robertson, D.W.; Leander, J .D. J. Med. Chem. "1993, 36, 3350.
`
`Jung. M.E.; Omstein, P.L. Tetrahedron Lett. 1977, 18, 2659.
`
`Jung, M.E.; Hatfield, G.L. Tetrahedron Lett. 1978, 19, 4483'.
`Schmidt, A.H. Aldrichimica Acta. 1981, I4, 31.
`
`Snyder, D.C. J. Org. Chem. 1995, 60, 2638.
`
`LeGall, P. M.S. Thesis, University of Houston, 1982.
`
`Satisfactory spectral data (‘H and 13C NMR, IR, low and high resolution M8) were obtained for all new
`
`compounds.
`
`General Procedures for the Preparation of 2_a-2_e:
`
`To a CH3CN suspension of 251 (1 mmol) (20 ml./mmol of 2_d) was added trimethylsilyl halide (2.5
`
`mmol) under N2. The reaction mixture was heated at reflux (2-8 h) and then the solvent was removed
`
`under reduced pressure. The residue was dissolved in a 1:1 mixture of CHCI3 and H20, and the organic
`
`layer was separated. The aqueous layer was extracted with CHCI3, and the combined organic layers
`
`were dried (NagSO4) and evaporated in vacuo. The residue was triturated with Et2O to give the desired
`
`product.
`
`23: mp 143-144 °C; 11-1 NMR (CDCl3) 8 2.06 (s, C(O)CH3), 3.72 (dd, J = 6.3, 11.1 Hz, CHH'Cl),
`
`3.94 (dd, J = 6.3, 11.1 Hz, CHH'Cl). 4.48 (d, J = 5.7 Hz, NHCH2), 4.72-4.81 (m, CH), 6.36 (br d, J =
`
`6.3 Hz, NH), 6.49 (br 5, NH), 7.22-7.35 (m, 5 PhH); 13C NMR (DMSO-d(,) 22.45 (C(O)CH3), 42.16
`
`(Cl-l2N or CH2Cl), 44.62 (CH2N or CH2Cl), 53.89 (CH), 126.70 (Ctr), 127.03 (2C2v or 2C3‘), 128.16
`
`(2C2- or 2C3'). 138.39 (C1-). 168.38 (C(O)CH3 or C(O)NH). 169.52 (C(O)CH3 or C(O)NH) ppm; MS
`
`(+CI) 257 (M'*’+l, 28), 255 (M"'+1, 81) 222 (100); M; (+CI) 255.090 85 [M++1] (calcd for
`
`C12H16C1N2O2 255.090 03).
`
`2_b: mp 123-125 °C; 1H NMR (CDCI3) 5 2.04 (s, C(0)CH3), 3.59 (dd, J = 4.8, 10.5 Hz, CHH'Br),
`
`3.74 (dd, J = 4.8, 10.5 Hz, CHH'Br), 4.47 (d, J = 5.7 Hz, NHCH2), 4.79-4.83 (m, CH), 6.42 (br d, J =
`
`6.6 Hz, NH), 6.47 (br s, NH), 7.29-7.37 (m, 5 Phil); 13C NMR (CDCl3) 23.07 (C(O)CH3), 32.19
`
`(CH2Br), 43.79 (CH2N), 53.57 (CH), 127.62 (Cm), 127.71 (2C2- or 2C3-), 128.70 (2C;' or 2C3'). 137.37
`
`(C1-), 168.58 (C(0)CH3 or C(O)NH), 170.37 (C(O)CH3 or C(O)NH) ppm; MS (+CI) 301 [M++1, 5].
`299 [M‘*+1, 5], 220 (72), 219 (100); Mr (+CI) 299.039 22 [M'*+1] (calcd for C12H15BrN2O2 299.039
`
`51).
`
`

`
`7014
`
`2;; mp 169-170 °C (dec); 1H NMR (CDC13) 8 2.05 (s, C(O)CH3), 4.38-4.51 (m, CHZI), 4.48 (d, J
`
`= 5.7 Hz, NHCH2), 4.63-4.70 (m, CH). 6.52 (br d, J = 7.2 Hz, NH), 6.87 (br s, NH), 7.30-7.35 (m, 5
`PhH)'. 13c NMR (CDC13) 4.83 (CH2I), 22.75 (C(O)CH3), 43.44 (C1-I2N), 53.31 (CH), 127.29 (C4-).
`127.42 (2C;- or 2C3-), 128.33 (2C2v or 2C3v), 136.87 (Cr), 168.39 (C(O)CH3 or C(O)NI-I), 169.80
`(C(O)CH3 or C(O)NH) Pllm; MS (+CI) In/e (rel intensity) 220 (20), 219 (100); M; (+CI) 347.025 81
`
`[M++1] (calcd for C12H15lN202 347.025 65).
`
`Compound 3: mp 129- 130 °C; ‘H NMR (DMSO-:15) 5 1.93 (s. CH3). 4.21-4.38 (m, N1-ICH2,
`
`OCHzCH), 4.55-4.61 (m, CH), 7.22-7.33 (In, 5 Phil), 8.43 (t, J: 5.7 Hz, NH); 13C NMR (CD_;OD)
`
`13.64 (CH3), 44.12 (NHCH2 ), 69.67 (CH), 71.87 (OCHZCH), 128.32 (C49, 128.60 (2C2' or 2C3»),
`
`129.56( 2C9; or 2C3~), 139.60 (C1-), 170.65 (C(N)O or C(O)), 173.66 (C(N)O or CO)) ppm; MS CI(+)
`(rel intensity) 219 (M*+1, 100), 141 (41); Mr (+CI) 219.1 12' 64 [M“’+1] (calcd for C121-115N202 219.113
`
`35).
`
`20.
`
`22.
`
`Addition of a saturated CDCl3 solution containing (R)-(-)- mandelic acid to (R)-,2_a gave only one signal
`
`in the 1H NMR spectrum for the acetyl methyl protons, while the corresponding racemate gave two
`
`peaks of equal height. For the previous use of this method for the assessment of enantiomeric purity,
`see reference 11.
`
`Compound 41;: mp 107-108 °C; ‘H NMR (DMSO—d5) 8 1.17 (t, J = 6.9 Hz, OCHZCH3), 1.88 (s,
`
`C(O)CH3), 3.67 (dd, J = 7.1, 11.1 Hz, CHH'Cl), 3.77 (dd, J = 5.1, 11.1 Hz, CHH‘Cl), 3.83 (d, J = 6.0
`
`Hz, NHCH2), 4.07 (q, J = 6.9 Hz, 0CH;CH3), 4.61-4.68 (m, CH), 8.31 (d, J = 8.4 Hz, NH), 8.58 (t, J =
`
`6.0 Hz, NH); 13C NMR (DMSO-d5) 14.02 (OC1-12CH3), 22.45 (C(O)CH3), 40.82 (NHCH2 or CH2C1),
`
`44.55 (N1-[CH2 or CH2C1), 53.57 (CH), 60.43 —(OCH2CH3), 169.01, 169.33, 169.53 (C(O)CH3,
`
`C(O)NH, C(O)OCH2CH3) ppm; MS CI(+) (rel intensity) 253 (M++1, 57), 251 (M++1, 100), 215 (41);
`
`M, (+CI) 251.080 55 [M++1] (calcd for C9H15C1N2O4 251.079 86).
`
`Compound 51;: mp 133-134 °C; ‘H NMR (DMSO-d6) 6 1.84 (s, C(0)CH3), 3.67 (s, OCH3), 3.75 (d, J
`
`= 5.9 Hz, NHCH2), 3.81-3.91 (m, CH2C1), 4.71-4.77 (m, CH), 8.12 (t, J = 5.9 Hz, NH), 8.50 (d,J = 7.8
`
`Hz, NH); 13C NMR (CD3OD) 22.38 (C(O)CH3), 43.26 (NHCH2 or CH2C1), 44.97 (NHCH2 or CH2C1),
`
`53.21 (CH), 55.02 (OCH3), 170.58, 171.65, 173.80 (C(O)CH3, C(O)NH, C(0)OCH3) ppm; MS CI(+)
`
`(rel intensity) 239 (M++1, 41), 237 (M++1, 100); M, (+CI) 237.064 37 [M++1] (calcd for C311 14C1N2O4
`
`237.064 21).
`
`(Received in USA 30 June 1995; accepted 28 July 1995)