PROTECTIVE GROUPS IN
`ORGANIC SYNTHESIS
`
`THIRD EDITION
`
`Theodora W. Greene
`The Rowland Institute for Science
`
`and
`Peter G. M. Wuts
`· Pharmacia and Upjohn Company
`
`A WILEY-INTERSCIENCE PUBLICATION
`
`JOHN WILEY & SONS, INC.
`
`Illumina Ex. 1075
`IPR Petition - USP 10,435,742
`
`

`

`This book is printed on acid-free paper. @)
`Copyright © 1999 by John Wiley & Sons, Inc.
`All rights reserved. Published simultaneously in Canada.
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`o;erwise except as permitted under Sections 107 or 108 of the 19:6 Umted States
`~opyright A~t, without either the prior written permission of the Pubhsher, ~r
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`Clearance Center 222 Rosewood Drive, Danvers, MA 01923, (978) 750-840 ' ax
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`Library of Congress Cataloging in Publication Data:
`Protective groups in organic synthesis. -
`I Theodora W.
`3rd ed.
`Greene and Peter G.M. Wuts.
`P·
`cm.
`·
`·
`th
`· 2 d d
`Rev. ed. of: Protective groups m or,gamc syn esis. n e .
`Theodora W. Greene and Peter G. M. Wuts. c1991.
`Includes index.
`ISBN 0-471-16019-9 (cloth)
`.
`1 Organic compounds-Synthesis. 2. Protective groups (Chemistry)
`I
`.Greene Theodora W., 1931-
`II. Wuts, Peter_G. M ..
`.
`III. Gree~e, Theodora W., 1931- Protective groups m orgamc
`synthesis.
`QD262. G665. 1999
`547.2-dc21
`
`98-38182
`
`Printed in the United States of America.
`
`10 9 8 7
`
`PREFACE TO THE THIRD
`EDITION
`
`Organic synthesis has not yet matured to the point where protective groups are
`not needed for the synthesis of natural and unnatural products; thus, the develop(cid:173)
`ment of new methods for functional group protection and deprotection conti(cid:173)
`nues; The new methods added to this edition come from both electronic searches
`and a manual examination of all the primary journals through the end of 1997.
`We have found that electronic searches of Chemical Abstracts fail to find many
`new methods that are developed during the course of a synthesis, and issues of
`selectivity are often not addressed. As with the second edition, we have
`attempted to highlight unusual and potentially useful examples of selectivity for
`both protection and deprotection. In some areas the methods listed may .seem
`rather redundant, such as the numerous methods for THP protection and depro(cid:173)
`tection, but we have included them in an effort to be exhaustive in coverage. For
`comparison, the first edition of this book contains about 1500 references and 500
`protective· groups, the second edition introduces an additional 1500 references
`and 206 new protective groups, and the third edition adds 2349 new citations and
`348 new protective groups.
`Two new sections on the protection of phosphates and the alkyne-CH are
`included. All other sections of the book have been expanded, some more than
`others. The section on the protection of alcohols has increased substantially,
`reflecting the trend of the nineties to synthesize acetate- and propionate-derived
`natural products. An effort was made to include many more enzymatic methods
`of protection and deprotection. Most of these are associated with the protection
`of alcohols as esters and the protection of carboxylic acids. Here we have not
`attempted to be exhaustive, but hopefully, a sufficient number of cases are pro(cid:173)
`vided that illustrate the true power of this technology, so that the reader will
`examine some of the excellent monographs and review articles cited in the refer(cid:173)
`ences. The Reactivity Charts in Chapter 10 are identical to those in the first
`edition. The chart number appears beside the name of each protective group
`when it is first introduced. No attempt was made to update these Charts, not only
`because of the sheer magnitude of the task, but because it is nearly impossible in
`
`V
`
`

`

`16
`
`THE ROLE OF PROTECTIVE GROUPS IN ORGANIC SYNTHESIS
`
`(b) P. J. Kocienski, Protecting Groups, Georg Theime Verlag, Stuttgart and New
`York, 1994; (c) J. F. W. McOmie, Ed., Protective Groups in Organic Chemistry,
`Plenum, New York and London, 1973.
`28. Organic Syntheses, Wiley-Interscience, New York, Collect. Vols. I-IX, 1941-1998,
`75, 1997; W. Theilheimer, Ed., Synthetic Methods of Organic Chemistry, S. Karger,
`Basel, Vols 1-52, 1946-1997; E. Mtiller, Ed., Methoden der Organischen Chemie
`(Houben-Wey!), Georg Thieme Verlag, Stuttgart, Vols. l-21f, 1958-1995; Spec.
`Period. Rep.: General and Synthetic Methods, Royal Society of Chemistry, 1-16
`(1978-1994); S. Patai, Ed., The Chemistry of Functional Groups, Wiley(cid:173)
`Interscience, Vols. 1-51, 1964-1997.
`29. (a) H. Waldmann and D. Sebastian, "Enzymatic Protecting Group Techniques,"
`Chem. Rev., 94,911 (1994); (b) K. Drauz and H. Waldmann, Eds., Enzyme Catalysis
`in Organic Synthesis: A Comprehensive Handbook, VCH, 1995, Vol. 2, 851-889.
`30. T. D. Nelson and R. D. Crouch, "Selective Deprotection of Silyl Ethers," Synthesis,
`1031 (1996).
`31. (a) K.-S. Lam, G. A. Hesler, J.M. Mattel, S.W. Mamber, and S. Forenza, J. Antibiot.,
`43, 956 (1.990); (b) J. E. Leet, D.R. Schroeder, B. S. Krishnan, and J. A. Matson,
`ibid., 43, 961 (1990); (c) J.E. Leet, D.R. Schroeder, J. Golik, J. A. Matson, T. W.
`Doyle, K. S. Lam, S. E. Hill, M. S. Lee, J. L. Whitney, and B. S. Krishnan, ibid. 49,
`299 (1996); (d)T. M. Kamenecka and S. J. Danishefsky, "Studies in the Total
`Synthesis of Himastatin: A Revision of the Stereochemical Assignment," Angew.
`Chem., Int. Ed. Engl., 37, 2993 (1998).
`32. T. M. Kamenecka and S. J. Danishefsky, "The Total Synthesis of Himastatin:
`Confirmation of the Revised Stereostructure," Angew. Chem., Int. Ed. Engl., 37,
`2995 (1998). We thank Professor Danishefsky for providing us with preprints of the
`himastatin communications here and in ref. 3l(d).
`33. (a) J. M. Humphrey and A. R. Chamberlin, Chem. Rev., 97, 2241 (1997); (b)
`A. Ehrlich, H.-U. Heyne, R. Winter, M. Beyermann, H. Haber, L.A. Carpino, and
`M. Bienert, J. Org. Chem., 61, 8831 (1996).
`34. HOAt, 7-aza-1-hydroxybenzotriazole; HATU (CAS Registry No. 148893-10-1),
`N-[ ( dimethylamino) (3H- I ,2,3-triazolo( 4,5-b )pyridin-3-yloxy )methylene ]-N-methyl(cid:173)
`methanaminium hexafluorophosphate, previously known as O-(7-azabenzotriazol-
`1-yl)-I, 1,3,3-tetramethyluronium hexafluorophosphate.
`[Note: Assignment of
`structure to HATU as a guanidinium species rather than as a uronium species, i.e.,
`attachment of the (Me2NC=NMe2f unit to N3 of 7-azabenzotriazole 1-N-oxide
`instead ofto the 0, is based on X-ray analysis (ref. 33b)].
`35. R. W. Armstrong, J.-M. Beau, S. H. Cheon, W. J. Christ, H. Fujioka, W.-H. Ham,
`L. D. Hawkins, H. Jin, S. H. Kang, YOSHITO KISHI, M. J. Martinelli, W. W.
`McWhorter, Jr., M. Mizuno, M. Nakata, A. E. Stutz, F. X. Talamas, M. Taniguchi,
`J. A. Tino, K. Ueda, J.-i. Uenishi, J. B. White, and M. Yonaga, J. Am. Chem. Soc.,
`111, 7530-7533 (1989). [See also idem., ibid., 111, 7525-7530 (1989).]
`
`2
`
`PROTECTION FOR THE
`HYDROXYL GROUP, INCLUD(cid:173)
`ING 1,2- AND 1,3-DIOLS
`
`ETHERS
`Methyl, 23
`
`Substituted Methyl Ethers
`Methoxymethyl, 27
`Methylthiomethyl, 33
`(Phenyldimethylsilyl)methoxymethyl, 35
`Benzyloxymethyl, 36
`p-Methoxybenzyloxymethyl, 37
`p-Nitrobenzyloxymethyl, 38
`o-Nitrobenzyloxymethyl, 38
`(4-Methoxyphenoxy)methyl, 38
`Guaiacolmethyl, 39
`t-Butoxymethyl, 39
`4-Pentenyloxymethyl, 40
`Siloxymethyl, 41
`2-Methoxyethoxymethyl, 41
`2,2,2-Trichloroethoxymethyl, 44
`Bis(2-chloroethoxy)methyl, 44
`2-(Trimethylsilyl)ethoxymethyl, 45
`Menthoxymethyl, 48
`Tetrahydropyranyl, 49
`3-Bromotetrahydropyranyl, 54
`Tetrahydrothiopyranyl, 54
`1-Methoxycyclohexyl, 54
`4-Methoxytetrahydropyranyl, 54
`4-Methoxytetrahydrothiopyranyl, 55
`
`23
`
`27
`
`17
`
`

`

`18
`
`PROTECTION FOR THE HYDROXYL GROUP, INCLUDING 1,2- AND 1,3-DIOLS
`
`4-Methoxytetrahydrothiopyranyl S,S-Dioxide, 55
`1-[(2-Chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, 55
`1-(2-Fluorophenyl)-4-methoxypiperidin-4-yl, 56
`1,4-Dioxan-2-yl, 57
`Tetrahydrofuranyl, 57
`Tetrahydrothiofuranyl, 58
`2,3,3a,4,5,6, 7, 7a-Octahydro-7 ,8,8-trimethyl-4, 7-methanobenzofuran-2-yl, 58
`
`Substituted Ethyl Ethers
`1-Ethoxyethyl, 59
`1-(2-Chloroethoxy)ethyl, 60
`1-[2-(Trimethylsilyl)ethoxy]ethyl, 61
`1-Methyl-1-methoxyethyl, 61
`1-Methyl-1-benzyloxyethyl, 62
`1-Methyl-1-benzyloxy-2-fluoroethyl, 62
`1-Methyl-1-phenoxyethyl, 63
`2,2,2-Trichloroethyl, 63
`1, 1-Dianisyl-2,2,2-trichloroethyl, 63
`1, 1, 1,3,3,3-Hexafluoro-2-phenylisopropyl, 64
`2-Trimethylsilylethyl, 64
`2-(Benzylthio)ethyl, 65
`2-(Phenylselenyl)ethyl, 65
`t-Butyl, 65
`Allyl,67
`Propargy, 7 4
`p-Chlorophenyl, 74
`p-Methoxyphenyl, 75
`p-Nitrophenyl, 76
`2,4-Dinitrophenyl, 76
`2,3,5,6-Tetrafluoro-4-(trifluoromethyl)phenyl, 76
`Benzyl, 76
`
`Substituted Benzyl Ethers
`p-Methoxybenzyl, 86
`3,4-Dimethoxybenzyl, 91
`o-Nitrobenzyl, 93
`p-Nitrobenzyl, 93
`p-Halobenzyl, 95
`2,6-Dichlorobenzyl, 95
`p-Cyanobenzyl, 96
`p-Phenylbenzyl, 96
`2,6-Difluorobenzyl, 97
`p-Acylaminobenzyl, 97
`p-Azidobenzyl, 97
`4-Azido-3-chlorobenzyl, 98
`2-Trifluoromethylbenzyl, 98
`p-(Methylsulfinyl)benzyl, 98
`2- and 4-Picolyl, 99
`3-Methyl-2-picolyl N-Oxido, 99
`2-Quinolinylmethyl, 100
`
`59
`
`86
`
`1-Pyrenylmethyl, 100
`Diphenylmethyl, 100
`p,p'-Dinitrobenzhydryl, 101
`5-Dibenzosuberyl, 102
`Triphenylmethyl, 102
`cx-Naphthyldiphenylmethyl, 104
`p-Methoxyphenyldiphenylmethyl, 105
`Di(p-methoxyphenyl)phenylmethyl, 105
`Tri(p-methoxyphenyl)methyl, 105
`4-( 4' -Bromophenacyloxy)phenyldiphenylmethyl, 106
`4,4' ,4"-Tris(4,5-dichlorophthalimidophenyl)methyl, 106
`4,4' ,4" -Tris(levulinoyloxyphenyl)methyl, 107
`4,4' ,4" -Tris(benzoyloxyphenyl)methyl, 107
`4,4'-Dimethoxy-3"-[N-(imidazolylmethyl)]trityl, 107
`4,4'-Dimethoxy-3"-[N-(imidazolylethyl)carbamoyl]trityl, 107
`1, 1-Bis(4-methoxyphenyl)-1 '-pyrenylmethyl, 108
`4-(17-Tetrabenzo[a,c,g,i ]fluorenylmethyl)-4,4"-dimethoxytrityl, 108
`9-Anthryl, 109
`9-(9-Phenyl)xanthenyl, 109
`9-(9-Phenyl-10-oxo )anthryl, 110
`1,3-Benzodithiolan-2-yl, 112
`Benzisothiazolyl S,S-Dioxido, 113
`
`Silyl Ethers
`Migration of Silyl Groups, 114
`Trimethylsilyl, 116
`Triethylsilyl, 121
`Triisopropylsilyl, 123
`Dimethylisopropylsilyl, 125
`Diethylisopropylsilyl, 126
`Dimethylthexylsilyl, 127
`t-Butyldimethylsilyl, 127
`t-Butyldiphenylsilyl, 141
`Tribenzylsilyl, 144
`Tri-p-xylylsilyl, 144
`Triphenylsilyl, 144
`Diphenylmethylsilyl, 145
`Di-t-butylmethylsilyl, 146
`Tris(trimethylsilyl)silyl: Sisyl, 146
`(2-Hydroxystyryl)dimethylsilyl, 147
`(2-Hydroxystyryl)diisopropylsilyl, 14 7
`t-Butylmethoxyphenylsilyl, 14 7
`t-Butoxydiphenylsilyl, 148
`
`Conversion of Silyl Ethers to other Functional Groups
`
`ESTERS
`Formate, 149
`Benzoylformate, 149
`
`ETHERS
`
`19
`
`113
`
`148
`
`149
`
`

`

`20
`
`PROTECTION FOR THE HYDROXYL GROUP, INCLUDING 1,2· AND 1,3-DIOLS
`
`ETHERS
`
`21
`
`Acetate, 150
`Chloroacetate, 160
`Dichloroacetate, 163
`Trichloroacetate, 163
`Trifluoroacetate, 164
`Methoxyacetate, 165
`Triphenylmethoxyacetate, 165
`Phenoxyacetate, 165
`p-Chlorophenoxyacetate, 166
`Phenylacetate, 166
`p-P-Phenylacetate, 166
`Diphenylacetate, 167
`Nicotinate, 167
`3-Phenylpropionate, 167
`4-Pentenoate, 167
`4-Oxopentanoate (Levulinate), 168
`4,4-(Ethylenedithio)pentanoate, 168
`5-[3-Bis( 4-methoxyphenyl) hydroxymethylphenoxy ]levuli nate, 169
`Pivaloate, 170
`1-Adamantoate, 172
`Crotonate, 173
`4-Methoxycrotonate, 173
`Benzoate, 173
`p-Phenylbenzoate, 178
`2,4,6-Trimethylbenzoate (Mesitoate ), 178
`Carbonates
`Methyl, 179
`Methoxymethyl, 180
`9-Fluorenylmethyl, 180
`Ethyl, 181
`2,2,2-Trichloroethyl, 181
`1, 1-Dimethyl-2,2,2-trichloroethyl, 181
`2-(Trimethylsilyl)ethyl, 182
`2-(Phenylsulfonyl)ethyl, 182
`2-(Triphenylphosphonio)ethyl, 183
`lsobutyl, 183
`Vinyl, 183
`Allyl, 184
`p-Nitrophenyl, 185
`Benzyl, 186
`p-Methoxybenzyl, 186
`3,4-Dimethoxybenzyl, 186
`o-Nitrobenzyl, 186
`p-Nitrobenzyl, 186
`Carbonates Cleaved by J3-Elimination
`2-Dansylethyl, 187
`2-(4-Nitrophenyl)ethyl, 187
`
`179
`
`187
`
`2-(2,4-Dinitrophenyl)ethyl, 187
`2-Cyano-1-phenylethyl, 188
`S-Benzyl Thiocarbonate, 188
`4-Ethoxy-1-naphthyl, 188
`Methyl Dithiocarbonate, 189
`Assisted Cleavage
`2-lodobenzoate, 189
`4-Azidobutyrate, 190
`4-Nitro-4-methylpentanoate, 190
`o-(Dibromomethyl)benzoate, 190
`2-Formylbenzenesulfonate, 190
`2-(Methylthiomethoxy)ethyl Carbonate, 191
`4-(Methylthiomethoxy)butyrate, 191
`2-(Methylthiomethoxymethyl)benzoate, 191
`2-(Chloroacetoxymethyl)benzoate, 191
`2-[(2-Chloroacetoxy)ethyl]benzoate, 192
`2-[2-(Benzyloxy)ethyl]benzoate, 192
`2-[2-(4-Methoxybenzyloxy)ethyl]benzoate, 192
`Miscellaneous Esters
`2,6-Dichloro-4-methylphenoxyacetate, 193
`2,6-Dichloro-4-(1, 1,3,3-tetramethylbutyl)phenoxyacetate, 193
`2,4-Bis(1, 1-dimethylpropyl}phenoxyacetate, 193
`Chlorodiphenylacetate, 193
`lsobutyrate, 193
`Monosuccinoate, 193
`(E)-2-Methyl-2-butenoate (Tigloate), 193
`o-(Methoxycarbonyl}benzoate, 193
`p-P-Benzoate, 193
`a-Naphthoate, 193
`Nitrate, 193
`Alkyl N,N,N',N'-Tetramethylphosphorodiamidate, 193
`2-Chlorobenzoate, 193
`4-Bromobenzoate, 193
`4-Nitrobenzoate, 193
`3'5' -Dimethoxybenzoin, 194
`A Wild and Woolly Photolabile Fluorescent Ester, 195
`N-Phenylcarbamate, 195
`Borate, 196
`Dimethylphosphinothioyl, 196
`2,4-Dinitrophenylsulfenate, 196
`Sulfonates
`Sulfate, 197
`Allylsulfonate, 198
`Methanesulfonate (Mesylate), 198
`Benzylsulfonate, 198
`Tosylate, 199
`2-[(4-Nitrophenyl)ethyl]sulfonate, 199
`
`189
`
`193
`
`197
`
`

`

`22
`
`PROTECTION FOR THE HYDROXYL GROUP, INCLUDING 1,2- AND 1,3-DIOLS
`
`PROTECTION FOR 1,2· AND 1,3-DIOLS
`
`Cyclic Acetals and Ketals
`Methylene, 201
`Ethylidene, 204
`t-Butylmethylidene, 205
`1-t-Butylethylidene, 205
`1-Phenylethylidene, 205
`1-( 4-Methoxyphenyl)ethylidene, 205
`2,2,2-Trichloroethylidene, 206
`Acrolein, 206
`Acetonide (lsopropylidene), 207
`Cyclopentylidene, 215
`Cyclohexylidene, 215
`Cycloheptylidene, 215
`Benzylidene, 217
`p-Methoxybenzylidene, 224
`2,4-Dimethoxybenzylidene, 227
`3,4-Dimethoxybenzylidene, 227
`2-Nitrobenzylidene, 228
`4-Nitrobenzylidene, 228
`Mesitylene, 228
`1-Naphthaldehyde Acetal, 229
`Benzophenone Ketal, 229
`o-Xylyl Ether, 230
`
`Chiral Ketones
`Camphor, 230
`Menthone, 230
`
`Cyclic Ortho Esters
`Methoxymethylene, 231
`Ethoxymethylene, 231
`Dimethoxymethylene, 232
`1-Methoxyethylidene, 232
`1-Ethoxyethylidine, 232
`Methylidene, 233
`Phthalide, 233
`1 ,2-Dimethoxyethylidene, 234
`a-Methoxybenzylidene, 234
`1-(N,N-Dimethylamino)ethylidene Derivative, 234
`a-(N,N-Dimethylamino)benzylidene D'erivative, 234
`2-Oxacyclopentylidene, 234
`Butane-2,3-bisacetal, 235
`Cyclohexane-1,2-diacetal, 235
`Dispiroketals, 236
`
`Silyl Derivatives
`Di-t-butylsilylene Group, 237
`
`201
`
`201
`
`Dialkylsilylene Groups, 238
`1,3-(1, 1,3,3~Tetraisopropyldisiloxanylidene) Derivative, 239
`1, 1,3,3-Tetra-t-butoxydisiloxanylidene Derivative, 240
`
`Cyclic Carbonates
`
`Cyclic Boronates
`Ethyl Boronate, 243
`Phenyl Boronate, 244
`o-Acetamidophenyl Boronate, 244
`
`ETHERS
`
`ETHERS
`
`23
`
`241
`
`243
`
`Hydroxyl groups are present in a number of compounds of biological and syn(cid:173)
`thetic interest, including nucleosides, carbohydrates, steroids, macrolides, poly(cid:173)
`ethers, and the side chain of some amino acids. 1
`• During oxidation, acylation,
`halogenation with phosphorus or hydrogen halides, or dehydration reactions of
`these compounds, a hydroxyl group must be protected. In polyfunctional mole(cid:173)
`cules, selective protection becomes an issue that has been addressed by the
`development of a number of new methods. Ethers are among the most used
`protective groups in organic synthesis and vary from the simplest, most stable
`methyl ether to the more elaborate, substituted trityl ethers developed for use in
`nucleotide synthesis. Ethers are formed and removed under a wide variety of
`conditions. Some of the ethers that have been used extensively to protect alco(cid:173)
`hols are included in Reactivity Chart L la,b
`
`L (a) See references 23 (Oligonucleotides) and 24 (Oligosaccharides) in Chapter 10;
`(b) see also C. B. Reese, "Protection of Alcoholic Hydroxyl Groups and Glycol
`Systems," in Protective Groups in Organic Chemistry, J, F. W. McOmie, Ed., Plenum,
`New York and London, 1973, pp, 95-143; H. M. Flowers, "Protection of the
`Hydroxyl Group," in The Chemistry of the Hydroxyl Group, S. Patai, Ed., Wiley(cid:173)
`Interscience, New York, 1971, Vol. 10/2, pp. 1001-1044; C. B, Reese, Tetrahedron,
`34, 3143-3179 (1978), see pp. 3145-3150; V. Amarnath and A. D. Broom, Chem.
`Rev., 77, 183-217 (1977), see pp. 184-194; M. Lalonde and T. H. Chan, "Use of
`Organosilicon Reagents as Protective Groups in Organic Synthesis," Synthesis, 817
`(1985); and P. Kocienski, Protecting Groups, Thieme Medical Publishers, New York,
`1994, seep. 21.
`
`'
`
`Methyl Ether: ROMe (Chart 1)
`
`Formation
`1. Me2SO4, NaOH, Bu4N+i-, org. solvent, 60-90% yield. 1
`2 NaH or KH, THF. This is the standard method for intro(cid:173)
`2. Mel or Me2SO4,
`ducing the methyl ether function onto hindered and unhindered alcohols.
`
`230
`
`231
`
`237
`
`

`

`24
`
`PROTECTION FOR THE HYDROXYL GROUP, INCLUDING 1,2- AND 1,3-DIOLS
`
`3. CH2N2, silica gel, 0-10°, 100% yield.3
`
`I \
`
`H9~
`Moko
`OH
`
`CH2N2, Et20
`Silica gel
`
`83%
`
`I \
`s
`s
`CH39-n
`~oko
`CHO
`H
`Ref.4
`3
`4. CH2N2, HBF4, CH2Cl2, Et3N, 25°, 1 h, 95% yield.5·6 Hydroxyl amines will
`O-alkylate without the acid catalyst.7 TMSCHN2 serves as a safe and sta(cid:173)
`ble alternative to diazomethane (74-93% yield).8
`5. Mel, solid KOH, DMSO, 20°, 5-30 min, 85-90% yield.9
`6. (MeO)2POH, cat. TsOH, 90-100°, 12 h, 60% yield. 10
`7. Me3O+BF4 - , 3 days, 55% yield. 11 A simple, large-scale preparation of this
`reagent has been described. 12
`8. CF3SO3Me, CH2Cl2, Pyr, 80°, 2.5 h, 85-90% yield. 13·14 The use of 2,6-di(cid:173)
`t-butyl-4-methylpyridine as a base is also very effective.15
`9. Because of the increased acidity and reduced steric requirement of the
`carbohydrate hydroxyl, t-BuOK can be used as a base to achieve ether
`formation. 16
`
`t-BuOK,MeI
`
`THF, 100%
`
`10. Mel, Ag2O, 93% yield. 17
`
`HO .... u::C02Bn
`I
`,,,,,,~OTBDMS
`
`I
`.
`CH30, .. ,u::co2Bn
`'•,~OTBDMS
`11. Me2SO4, DMSO, DMF, Ba(OH)2, Bao, rt, 18 h, 88% yield.18
`
`ETHERS
`
`25
`12. From an aldehyde: MeOH, Pd-C, H2, 100°, 40 bar, 80-95% yield. 19 Other
`alcohols can be used to prepare other ethers.
`13. AgOTf, Mel, 2,6-di-t-butylpyridine, 39-96% yield. This method can be
`used to prepare alkyl, benzyl, and ally! ethers.20
`14. From a MOM ether: Zn(BH4)2, TMSCI, 87% yield.21
`15
`
`· AOA'c --Bn_E_l3_N_+_rM_o_(C_0_)5_C_ll_
`MeOH, CH2Cl2
`30°, AgOTf
`
`93%
`
`Ref. 22
`
`Cleavage23
`1. Me3Sil, CHC13, 25°, 6 h, 95% yield.24 A number of methods have been
`reported in the literature for the in situ formation of Me3Sil,25 since
`Me3Sil is somewhat sensitive to handle. This reagent also cleaves many
`other ether-type protective groups, but selectivity can be maintained by
`control of the reaction conditions and the inherent rate differences
`between functional groups.
`2. BBr3, Nal, 15-crown-5.26 Methyl esters are not cleaved under these condi(cid:173)
`tions.27
`3. BBr3, EtOAc, 1 h, 95% yield.28
`4. BBr3, CH2Cl2, high yields.29
`
`-78° (cid:157)
`
`12°
`
`This method is probably the most commonly used one for the cleavage of
`methyl ethers, because it generally gives excellent yields with a variety of
`structural types. The solid complex BBr3-Me2S that is more easily han(cid:173)
`dled can also be used.30 BBr3 will cleave ketals.
`5. BF3·EtiO, HSCH2CH2SH, HCI, 15 h, 82% yield.31·32
`6. MeSSiMe3 or PhSSiMe3, Znl2, Bu4N+1- .33 In this case, the 6-O-methyl
`ether was cleaved selectively from permethylated glucose.
`7. SiC14, Nal, CH2Cl2, CH3CN, 80-100% yield.34
`8. AlX3 (X = Br, Cl), EtSH, 25°, 0.5-3 h, 95-98% yield.35
`9. t-BuCOCl or AcCl, Nal, CH3CN, 37 h, rt, 84% yield.36 In this case, the
`methyl ether is replaced by a pivaloate or acetate group that can be
`hydrolyzed with base.
`10. Ac2O, FeC13, 80°, 24 h.37 In this case, the methyl ether is converted to an
`
`

`

`26
`
`PROTECTION FOR THE HYDROXYL GROUP, INCLUDING 1,2· AND 1,3-DIOLS
`
`ETHERS
`
`27
`
`acetate. The reaction proceeds with complete racemization. Benzyl and
`ally! ethers are also cleaved.
`11. AcCl, Nal, CH3CN. 38
`12. Me2BBr, CH2Cl2, 0-25°, 3-18 h, 75-93% yield. Tertiary methyl ethers
`give the tertiary bromide.39
`13. Bl3-Et2NPh, benzene, rt, 3-4 h, 94% yield. 40
`14. TMSCI, cat. H2SO4, Acp, 71-89% yield.41
`15. AIC13, Bu4N+i-, CH3CN, 83% yield.42·43
`BzO ... _:A.,,:oH
`cYOH
`
`OH
`
`BzO,,,_:A,,,,OH
`
`cYOH
`
`OCH3
`
`AlCl3, Bu4N"'"r(cid:173)
`
`CH3CN, 83%
`
`16. Treatment of a methyl ether with RuC13, NalO4 converts the ether into a
`ketone. 44
`
`I. A. Merz, Angew. Chem., Int. Ed. Engl., 12,846 (1973).
`2. M. E. Jung and S. M. Kaas, Tetrahedron Lett., 30,641 (1989).
`3. K. Ohno, H. Nishiyama, and H. Nagase, Tetrahedron Lett., 4405 (1979).
`4. T. Nakata, S. Nagao, N. Mori, and T. Oishi, Tetrahedron Lett., 26, 6461 (1985).
`5. M. Neeman and W. S. Johnson, Org. Synth., Collect. Vol. V, 245 (1973).
`6. A. B. Smith, III, K. J. Hale, L. M. Laakso, K. Chen, and A. Riera, Tetrahedron Lett.,
`30, 6963 (1989).
`7. M. Somei and T. Kawasaki, Heterocycles, 29, 1251 (1989).
`8. T. Aoyama and T. Shioiri, Tetrahedron Lett., 31, 5507 (1990).
`9. R. A. W. Johnstone and M. E. Rose, Tetrahedron, 35, 2169 (1979).
`10. Y. Kashman, J. Org. Chem., 37,912 (1972).
`11. H. Meerwein, G. Hinz, P. Hofmann, E. Kroning, and E. Pfeil, J. Prakt. Chem., 141,
`257 (1937).
`12. M. J. Earle, R. A. Fairhurst, R. G. Giles, and H. Heaney, Synlett, 728 (1991).
`13. J. Arnarp and J. Uinngren,Acta Chem. Scand., Ser. B, 32,465 (1978).
`14. R. E. Ireland, J. L. Gleason, L. D. Gegnas, and T. K. Highsmith, J. Org. Chem., 61,
`6856 (1996).
`15. J. A. Marshall and S. Xie, J. Org. Chem., 60, 7230 (1995).
`16. P. G. M. Wuts and S. R. Putt, unpublished results.
`17. A. E. Greene, C. L. Drian, and P. Crabbe, J. Am. Chem. Soc. 102, 7583 (1980).
`18. J. T. A. Reuvers and A. de Groot, J. Org. Chem., 51, 4594 (1986).
`19. V. Bethmont, F. Fache, and M. Lemai,.,,e, Tetrahedron Lett., 36, 4235 (1995).
`20. R. M. Burk, T. S. Gae, and M. B. Roof, Tetrahedron Lett., 35, 8111 (1994).
`
`21. H. Kotsuki, Y. Ushio, N. Yoshimura, and M. Ochi, J. Org. Chem., 52, 2594 (1987).
`22. H. Dvorakova, D. Dvorak, J. Srogl, and P. Kocovsky, Tetrahedron Lett., 36, 6351
`(1995).
`23. For a review of alkyl ether cleavage, see B. C. Ranu and S. Bhar, Org. Prep. Proced.
`Int., 28,371 (1996).
`24. M. E. Jung and M.A. Lyster, J. Org. Chem., 42, 3761 (1977).
`25. M. E. Jung and T. A. Blumenkopf, Tetrahedron Lett., 3657 (1978); G. A. Olah,
`A. Husain, B. G. B. Gupta, and S. C. Narang, Angew. Chem., Int. Ed. Engl., 20, 690
`(1981); T.-L. Ho and G. Olah, Synthesis, 417 (1977). For a review on the uses of
`M~Sil, see A.H. Schmidt,AldrichimicaActa, 14, 31 (1981).
`26. H. Niwa, T. Hida, and K. Yamada, Tetrahedron Lett., 22, 4239 (1981).
`27. M. E. Kuehne and J.B. Pitner, J. Org. Chem., 54, 4553 (1989).
`28. H. Shimomura, J. Katsuba, and M. Matsui,Agric. Biol. Chem., 42, 131 (1978).
`29. M. Demuynck, P. De Clercq, and M. Vandewalle, J. Org. Chem., 44, 4863 (1979);
`P.A. Grieco, M. Nishizawa, T. Oguri, S. D. Burke, and N. Marinovic, J. Am. Chem.
`Soc., 99, 5773 (1977).
`30. P. G. Williard and C. B. Fryhle, Tetrahedron Lett., 21, 3731 (1980).
`31. G. Vidari, S. Ferrino, and P.A. Grieco, J. Am. Chem. Soc., 106, 3539 (1984).
`32. M. Node, H. Hori, and E. Fujita, J. Chem. Soc., Perkin Trans. 1, 2237 (1976).
`33. S. Hanessian and Y. Guindon, Tetrahedron Lett., 21, 2305 (1980); R. S. Glass,
`J. Organomet. Chem., 61, 83 (1973); I. Ojima, M. Nihonyangi, and Y. Nagai,
`J. Organmet. Chem., 50, C26 (1973).
`34. M. V. Bhatt and S.S. El-Morey, Synthesis, 1048 (1982).
`35. M. Node, K. Nishide, M. Sai, K. Ichikawa, K. Fuji, and E. Fujita, Chem. Lett., 97
`(1979).
`36. A. Oku, T. Harada, and K. Kita, Tetrahedron Lett., 23,681 (1982).
`37. B. Ganem and V. R. Small, Jr., J. Org. Chem., 39, 3728 (1974).
`38. T. Tsunoda, M. Amaike, U.S. F. Tambunan, Y. Fujise, S. Ito, and M. Kodama, Tetra-
`hedron Lett., 28, 2537 (1987).
`39. Y. Guindon, C. Yoakim, and H. E. Morton, Tetrahedron Lett., 24, 2969 (1983).
`40. C. Narayana, S. Padmanabhan, and G. W. Kabalka, Tetrahedron Lett., 31, 6977 (1990).
`41. J. C. Sarma, M. Borbaruah, D. N. Sarma, N. C. Barua, and R. P. Sharma, Tetra-
`hedron, 42, 3999 (1986).
`42. T. Akiyama, H. Shima, and S. Ozaki, Tetrahedron Lett., 32, 5593 (1991).
`43. E. D. Moher, J. L. Collins, and P. A. Grieco, J. Am. Chem. Soc., 114, 2764 (1992).
`44. L. E. Overman, D. J. Ricca, and V. D. Tran, J. Am. Chem. Soc., 119, 12031 (1997).
`
`Substituted Methyl Ethers
`
`Methoxymethyl (MOM) Ether: CH3OCH2-OR (Chart 1)
`
`Formation
`1. CHpCH2Cl, 1 NaH, THF, 80% yield.2
`
`

`

`28
`
`PROTECTION FOR THE HYDROXYL GROUP, INCLUDING 1,2· AND 1,3-DIOLS
`
`ETHERS
`
`29
`
`In the case of allylic or propargylic diols, the nonallylic (propargylic)
`alcohol is protected. 14
`
`25°, 8 h, 86% yield.3 This is the most
`2. CH3OCH2Cl, i-Pr2NEt, 0°, 1 h (cid:157)
`commonly employed procedure for introducing the MOM group. The
`reagent chloromethylmethyl ether is reported to be carcinogenic, and
`dichloromethylmethyl ether, a by-product in its preparation, is consid(cid:173)
`ered even more toxic. A preparation that does not produce any of the
`dichloro ether has been reported. 4
`5
`3. MOMBr, DIPEA, CH2Cl2, 0°, 6 h, 72% yield. 3
`•
`4. Nal increases the reactivity of MOMCl by the in situ preparation of
`MOMI, which facilitates the protection of tertiary alcohols. 6
`
`MOMCl,Nal
`DIPEA, DME, reflux
`OH
`12
`O2CH2CH2 TMS
`OCH2SCH3
`
`h, BB%
`
`O
`
`5. For the selective protection of diols: Bu2SnO, benzene, reflux; MOMCl,
`Bu4N+i-, rt, 87% yield.7
`6. CHi(OMe)2, Nafion H. 8
`7. CHi(OMe)2, CH2Cl2, TfOH, 4 h, 25°, 65% yield.9 This method is suitable
`for the formation of primary, secondary, allylic, and propargylic MOM
`ethers. Tertiary alcohols fail to give a complete reaction. 1,3-Diols give
`methylene acetals (89% yield).
`8. CHi(OMe)2, CH2=CHCH2SiMe3, Me3SiOTf, Pp5, 93-99% yield. 10 This
`method was used to protect the 2'-OH of ribonucleosides and deoxyri(cid:173)
`bonucleosides, as well as the hydroxyl groups of several other carbohy(cid:173)
`drates bearing functionality, such as esters, amides, and acetonides.
`9. CHi(OEt)2, Montmorillonite clay (H+), 72-80% for nonallylic alcohols,
`56% for a propargylic alcohol. 11
`10. Selective formation of MOM ethers has been achieved in a diol svstem. 12
`/2
`/2
`
`Bn-~r, -
`MOMCI,NaH Bn-~r,
`OH
`OMOM
`=
`0
`0
`61%
`/ ,,,
`!,,,,
`"'
`"''
`OH
`OH
`11. Mono MOM derivatives of diols can be prepared from the ortho esters by
`diisobutylaluminum hydride reduction (46-98% yield). In general, the
`most hindered alcohol is protected. 13
`
`COH
`
`OH
`
`(MeOlJCH
`CSA, CH2CI2
`rt, 24 h
`
`DIBAH, -78°
`30min
`
`O°, 10 min COMOM
`
`OH
`
`1. TMOF,CSA
`2. DIBAH
`
`10-96% yield
`
`I
`
`MOM~
`
`R
`
`I
`
`=
`OH
`
`~ R
`=
`OH
`12. CHPCH2OCH3, anhydrous FeC13-ms (3A), 1-3 h, 70-99% yield. 15
`13. MOMCl, Al2O3, ultrasound, 68-92% yield. 16
`'
`14. CHi(OMe)i, TsOH, LiBr, 9 h, rt, 71-100% yield. 17
`15. MoOi(acac)2, CHi(OMe)2, CHC13, reflux, 63-95% yield. 18
`16. MOMCl, CH2Cl2, Na-Y Zeolite, reflux, 70-91 % yield. 19
`17. From a PMB ether: SnC12, CH2Cl2, rt, 24 h, 13-81 % yield.20
`18. From a stannylmethyl ether: electrolysis, MeOH, 90% yield.21
`19. From a trimethylsilyl glycoside: TMSOTf or TFA or BF3-EtiO,
`CHPCH2OCH3, 54-66% yield.22
`20. CHi(OMe)2, cat. P2O5, CHC13, 25°, 30 min, 95% yield.23
`21. CHi(OMe)2, Me3Sil or CH2=CHCH2SiMe3, 12, 76-95% yield.24
`22. CHi(OMe)2 , TsOH, LiBr, 9 h, rt, 71-100% yield. 17
`23. From a PMB ether: CHi(OMe)i, MOMBr, SnBr2, ClCH2CH2Cl; rt,
`57-81 % yield. Phenolic PMB ethers were not converted efficiently. A
`BOM ether was prepared using this method.20
`
`Cleavage
`
`1. Trace coned. HCl, MeOH, 62°, 15 min. 25
`2. 6 M HCI, aq. THF, 50°, 6-8 h, 95% yield. 26 An attempt to cleave the
`MOM group with acid in the presence of a dimethyl acetal resulted in the
`cleavage of both groups, probably by intramolecular assistance.27
`3. Coned. HCl, isopropyl alcohol (IPA), 65% yield. 28
`Other methods attempted for the cleavage of this MOM group were
`unsuccessful.
`
`OPMB
`
`coned. HCI
`
`IPA, 65%
`
`TIPSO
`
`TIPSO
`
`4. 50%AcOH, cat. H2SO4, reflux, 10-15 min, 80% yield. 29
`5. PhSH, BF3·Et2O, 98% yield.30
`
`

`

`30
`
`PROTECTION FOR THE HYDROXYL GROUP, INCLUDING 1,2· AND 1,3-DIOLS
`
`ETHERS
`
`31
`
`OCO2Ph
`
`Ph3C+BF4 -, CH2CI2
`2,6-di-t-Bu-pyr
`
`OHC
`
`N-CO2Me 0-22°, 15-30 min
`75% yield
`
`R=MOM
`
`R=H
`
`Ref. 32
`
`7. Pyridinium p-toluenesulfonate, t-BuOH or 2-butanone, reflux, 80-99%
`yield.33 This method is useful for allylic alcohols. MEM ethers are also
`cleaved under these conditions.
`
`(lo
`
`"BBr Catechol boron halides-particularly the bromide-are
`0/
`
`8.
`
`effective reagents for the cleavage of MOM ethers. The bromide also
`cleaves the following groups in the order shown: MOMOR "" MEMOR >
`t-BOC > Cbz "" t-BuOR > BnOR > allylOR > t-BuO2CR"" 2° alkylOR >
`BnO2CR > 1 ° alkylOR >> alkylO2CR. The
`t-butyldimethylsilyl
`(TBDMS), t-butyldiphenylsilyl (TBDPS), and PMB groups are stable to
`this reagent.34 The chloride is less reactive and thus may be more useful
`for achieving selectivity in multifunctional substrates. Yields are generally
`> 83%.35
`9. (i-PrS)2BBr, MeOH, 94% yield.36 This method has the advantage that 1,2-
`and 1,3-diols do not give formyl acetals, as is sometimes the case in cleav(cid:173)
`ing MOM groups with neighboring hydroxyl groups.37 The reagent also
`cleaves MEM groups and, under basic conditions, affords
`the
`i-PrSCH2OR derivatives.
`
`TIPS = triisopropylsilyl
`
`TIPSO
`
`OH
`
`(i-PrS)iBBr
`CO2Me ------(cid:173)
`MeOH, 94%
`;yY~
`6H 6H
`10. Me2BBr, CH2Cl2, -78°, then NaHCO/H2O, 87-95% yield.38 This
`reagent also cleaves the MEM, MTM, and acetal groups. Esters are stable
`to this reagent.
`11. Me3SiBr, CH2Cl2, 0°, 8-9 h, 80-97% yield.39 This reagent also cleaves the
`acetonide, THP, trityl, and t-BuMe2Si groups. Esters, methyl and benzyl
`ethers, t-butyldiphenylsilyl ethers, and amides are reported to be stable.
`
`TMSBr,-30°
`25min
`
`R=H
`
`OTBDMS
`
`R=MOM
`
`13. LiBF4, CH3CN, H2O, 72°, 100% yield.41
`OSEM
`
`((JCH~
`
`CH30y
`0
`0
`H
`
`LiBF4, CH3CN
`
`14. MgBr2, ether, BuSH, rt, 40-97% yield. Tertiary and allylic MOM deriva(cid:173)
`tives give low yields. MTM and SEM ethers are also cleaved, but MEM
`ethers are stable.42
`15. Dowex-50W-X2, aq. MeOH, 42-97% yield.43
`
`O~ H
`
`OMOM
`
`0
`~OH
`
`Dowex-S0W
`MeOH
`93%
`
`~ H o
`MeO2C
`C 2Me
`CO2 Me
`Other methods resulted in skeletal rearrangement. This study also showed
`that the rate of acid-catalyzed MOM cleavage increases in the following
`
`~ MeOzC
`
`

`

`32
`
`PROTECTION FOR THE HYDROXYL GROUP, INCLUDING 1,2· AND 1,3-DIOLS
`
`ETHERS
`
`33
`
`order: primary (30 h) < secondary (8 h) < tertiary (0.5-2 h). Tertiary
`alcohols are cleaved in excellent yields (94-97% yield).
`16. A1Cl3, Nal, CH3CN, CH2Cl2, 0°, 25 min, >70% yield. 44
`
`1. For a review of a-monohalo ethers in organic synthesis, see T. Benneche, Synthesis,
`1 (1995).
`2. A. F. Kluge, K. G. Untch, and J. H. Fried, J. Am. Chem. Soc., 94, 7827 (1972).
`3. G. Stork and T. Takahashi, J. Am. Chem. Soc., 99, 1275 (1977).
`4. R. J. Linderman, M. Jaber, and B. D. Griedel, J. Org. Chem., 59, 6499 (1994).
`5. D. Askin, R. P. Volante, R. A. Reamer, K. M. Ryan, and I. Shinkai, Tetrahedron Lett.,
`29, 277 (1988).
`6. K. Narasaka, T. Sakakura, T. Uchimaru, and D. Guedin-Vuong, J. Am. Chem. Soc.,
`106, 2954 (1984).
`7. S. David, A. Thieffry, and A. Veyrieres, J. Chem. Soc., Perkin Trans. 1, 1796 (1981).
`8. G. A. Olah, A. Husain, B. G. B. Gupta, and S. C. Narang, Synthesis, 471 (1981).
`9. M. P. Groziak and A. Koohang, J. Org. Chem., 57, 940 (1992).
`10. S. Nishina and Y. lshido, J. Carbohydr. Chem., 5,313 (1986).
`11. U. A. Schaper, Synthesis, 794 (1981).
`12. M. Ihara, M. Suzuki, K. Fukumoto, T. Kametani, and C. Kabuto, J. Am. Chem. Soc.,
`110, 1963 (1988).
`13. M. Takasu, Y. Naruse, and H. Yamamoto, Tetrahedron Lett., 29, 1947 (1988).
`14. R. W. Friesen and C. Vanderwal, J. Org. Chem., 61, 9103 (1996).
`15. H.K. Patney, Synlett, 567 (1992).
`16. B. C. Ranu, A. Majee, and A. R. Das, Synth. Commun., 25,363 (1995).
`17. J.-L. Gras, Y.-Y. K. W. Chang, and A. Guerin, Synthesis, 74 (1985).
`18. M. L. Kantam and P. L. Santhi, Synlett, 429 (1993).
`19. P. Kumar, S. V. N. Raju, R. S. Reddy, and B. Pandey, Tet