PROTECTIVE GROUPSIN ORGANIC SYNTHESIS

PREFACE TO THE THIRDEDITION Organic synthesis has not yet matured to the point where protective groups arenot needed for the synthesis of natural and unnatural products; thus, the develo

PROTECTIVE GROUPS IN ORGANIC SYNTHESIS

JOHN WILEY & SONS, INC.

New York / Chichester / Weinheim / Brisbane / Toronto / Singapore

PREFACE TO THE THIRD

EDITION

Organic synthesis has not yet matured to the point where protective groups arenot needed for the synthesis of natural and unnatural products; thus, the develop-ment of new methods for functional group protection and deprotection conti-nues The new methods added to this edition come from both electronic searchesand 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 ofselectivity are often not addressed As with the second edition, we haveattempted to highlight unusual and potentially useful examples of selectivity forboth protection and deprotection In some areas the methods listed may seemrather redundant, such as the numerous methods for THP protection and depro-tection, but we have included them in an effort to be exhaustive in coverage Forcomparison, the first edition of this book contains about 1500 references and 500protective groups, the second edition introduces an additional 1500 referencesand 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 areincluded All other sections of the book have been expanded, some more thanothers The section on the protection of alcohols has increased substantially,reflecting the trend of the nineties to synthesize acetate- and propionate-derivednatural 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 notattempted to be exhaustive, but hopefully, a sufficient number of cases are pro-vided that illustrate the true power of this technology, so that the reader willexamine some of the excellent monographs and review articles cited in the refer-ences The Reactivity Charts in Chapter 10 are identical to those in the firstedition The chart number appears beside the name of each protective groupwhen it is first introduced No attempt was made to update these Charts, not onlybecause of the sheer magnitude of the task, but because it is nearly impossible in

a two-dimensional table to address adequately the effect that electronic andsteric controlling elements have on a particular instance of protection or depro-tection The concept of fuzzy sets as outlined by Lofti Zadeh would be ideallysuited for such a task.

The completion of this project was aided by the contributions of a number ofpeople I am grateful to Rein Virkhaus and Gary Callen, who for many years for-warded me references when they found them, to Jed Fisher for the information

he contributed on phosphate protection, and to Todd Nelson for providing me apreprint of his excellent review article on the deprotection of silyl ethers Iheartily thank Theo Greene for checking and rechecking the manuscript—all 15

cm of it—for spelling and consistency and for the arduous task of checking allthe references for accuracy I thank Fred Greene for reading the manuscript, forhis contribution to Chapter 1 on the use of protective groups in the synthesis ofhimastatin, and for his contribution to the introduction to Chapter 9, on phos-phates I thank my wife, Lizzie, for encouraging me to undertake the third edi-tion, for the hours she spent in the library looking up and photocopying hundreds

of references, and for her understanding while I sat in front of the computer nightafter night and numerous weekends over a two-year period She is the greatest!

Kalamazoo, Michigan PETER G M WUTS June 1998

PREFACE TO THE SECOND

EDITION

Since publication of the first edition of this book in 1981, many new protectivegroups and many new methods of introduction or removal of known protectivegroups have been developed: 206 new groups and approximately 1500 newreferences have been added Most of the information from the first edition hasbeen retained To conserve space, generic structures used to describe Formation/Cleavage reactions have been replaced by a single line of conditions, sometimeswith explanatory comments, especially about selectivity Some of the new infor-

mation has been obtained from on-line searches of Chemical Abstracts, which have limitations For example, Chemical Abstracts indexes a review article about

protective groups only if that word appears in the title of the article rences are complete through 1989 Some references, from more widelycirculating journals, are included for 1990

Refe-Two new sections on the protection for indoles, imidazoles, and pyrroles andprotection for the amide -NH are included They are separated from the regularamines because their chemical properties are sufficiently different to affect thechemistry of protection and deprotection The Reactivity Charts in Chapter 8 areidentical to those in the first edition The chart number appears beside the name

of each protective group when it is first discussed

A number of people must be thanked for their contributions and help in pleting this project I am grateful to Gordon Bundy, who loaned me his card file,which provided many references that the computer failed to find, and to BobWilliams, Spencer Knapp, and Tohru Fukuyama for many references on amineand amide protection I thank Theo Greene who checked and rechecked the man-uscript for spelling and consistency and for the herculean task of checking all thereferences to make sure that my 3's and 8's and 7's and 9's were not inter-changed—all done without a single complaint I thank Fred Greene who read themanuscript and provided valuable suggestions for its improvement My wifeLizzie was a major contributor to getting this project finished, by looking up andphotocopying references, by turning on the computer in an evening ritual, and by

com-typing many sections of the original book, which made the changes and tions much easier Without her understanding and encouragement, the volumeprobably would never have been completed.

addi-Kalamazoo, Michigan PETER G M WUTS May 1990

PREFACE TO THE FIRST

EDITION

The selection of a protective group is an important step in synthetic methodology, andreports of new protective groups appear regularly This book presents information onthe synthetically useful protective groups (-500) for five major functional groups:-OH, -NH,-SH,-COOH, and >C=O References through 1979, the best method(s)

of formation and cleavage, and some information on the scope and limitations of eachprotective group are given The protective groups that are used most frequently andthat should be considered first are listed in Reactivity Charts, which give an indica-tion of the reactivity of a protected functionality to 108 prototype reagents

The first chapter discusses some aspects of protective group chemistry: theproperties of a protective group, the development of new protective groups, how toselect a protective group from those described in this book, and an illustrative exam-ple of the use of protective groups in a synthesis of brefeldin The book is organized

by functional group to be protected At the beginning of each chapter are listed thepossible protective groups Within each chapter protective groups are arranged inorder of increasing complexity of structure (e.g., methyl, ethyl, ?-butyl, , benzyl).The most efficient methods of formation or cleavage are described first Emphasishas been placed on providing recent references, since the original method may havebeen improved Consequently, the original reference may not be cited; my apologies

to those whose contributions are not acknowledged Chapter 8 explains the ship between reactivities, reagents, and the Reactivity Charts that have beenprepared for each class of protective groups

relation-This work has been carried out in association with Professor Elias J Corey, whosuggested the study of protective groups for use in computer-assisted syntheticanalysis I appreciate his continued help and encouragement I am grateful to Dr

J F W McOmie (Ed., Protective Groups in Organic Chemistry, Plenum Press, New

York and London, 1973) for his interest in the project and for several exchanges ofcorrespondence, and to Mrs Mary Fieser, Professor Frederick D Greene, and

IX

Professor James A Moore for reading the manuscript Special thanks are also due toHalina and Piotr Starewicz for drawing the structures, and to Kim Chen, RuthEmery, Janice Smith, and Ann Wicker for typing the manuscript.

Harvard University THEODORA W GREENE September 1980

Abbreviations xiii

1 The Role of Protective Groups in Organic Synthesis 1

2 Protection for the Hydroxyl Group, Including

1,2-and1,3-Diols 17

Ethers, 23

Esters, 149

Protection for 1,2- and 1,3-Diols, 201

3 Protection for Phenols and Catechols 246

Protection for Phenols, 249

Ethers, 249

Esters, 276

Protection for Catechols, 287

Cyclic Acetals and Ketals, 287

Cyclic Esters, 290

4 Protection for the Carbonyl Group 293

Acetals and Ketals, 297

Miscellaneous Derivatives, 348

Monoprotection of Dicarbonyl Compounds, 364

5 Protection for the Carboxyl Group 369

Esters, 373

Amides and Hydrazides, 442

XI

6 Protection for the Thiol Group 454

Special -NH Protective Groups, 573

Protection for Imidazoles, Pyrroles, and Indoles, 615

Protection for Amides, 632

8 Protection for the Alkyne -CH 654

9 Protection for the Phosphate Group 660

10 Reactivities, Reagents, and Reactivity Charts 701

Reactivities, 701

Reagents, 702

Reactivity Charts, 705

1 Protection for the Hydroxyl Group: Ethers, 708

2 Protection for the Hydroxyl Group: Esters, 712

3 Protection for 1,2- and 1,3-Diols, 716

4 Protection for Phenols and Catechols, 720

5 Protection for the Carbonyl Group, 724

6 Protection for the Carboxyl Group, 728

7 Protection for the Thiol Group, 732

8 Protection for the Amino Group: Carbamates, 736

9 Protection for the Amino Group: Amides, 740

10 Protection for the Amino Group:

Special -NH Protective Groups, 744

Index 749

PROTECTIVE GROUPS

In some cases, several abbreviations are used for the same protective group Wehave listed the abbreviations as used by an author in his or her original paper,including capital and lowercase letters Occasionally, the same abbreviation hasbeen used for two different protective groups This information is also included.ABO 2,7,8-trioxabicyclo[3.2.1]octyl

Adpoc 1 -(1 -adamantyl)-1 -methylethoxycarbonyl

Alloc or AOC allyloxycarbonyl

Als allylsulfonyl

AMB 2-(acetoxymethyl)benzoyl

AN 4-methoxyphenyl or anisyl

Anpe 2-(4-acetyl-2-nitrophenyl)ethyl

AOC or Alloc allyloxycarbonyl

p-AOM /7-anisyloxymethyl or (4-methoxyphenoxy)methylAzb p-azidobenzyl

benzyloxymethyl

1 -methyl-1 -(4-biphenyl)ethoxycarbonylbenzoSTABASE

1,1 -dioxobenzo[b]thiophene-2-ylmethoxycarbonylbenzothiazole-2-sulfonyl

2-/-butylsulfonylethylf-butoxymethyll-(3,5-di-r-butylphenyl)-l-methylethoxycarbonyl

?-butylsulfonylbenzoyl2-[(2-chloroacetoxy)ethyl]benzoylcarboxamidomethyl

2-(chloroacetoxymethyl)benzoylbenzyloxycarbonyl

cyclohexane-1,2-diacetal2-cyano-1,1 -dimethy lethyl2-cyanoethyl

1 -(2-chloroethoxy)ethylcyclohexyl

2-chloro-3-indenylmethoxycarbonylcarboxymethylsulfenyl

2-cyanoethylcinnamyloxycarbonyl2-(cy ano-1 -phenyl )ethoxycarbonyl4,4',4"-tris(4,5-dichlorophthalimido)triphenylmethyll-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-ylcysteine

di-p-anisylmethyl or bis(4-methoxyphenyl)methyl

1, l-di-/j-anisyl-2,2,2-trichloroethyll,l-dimethyl-2,2-dibromoethoxycarbonyl2,7-di-r-butyl[9-( 10,10-dioxo-10,10,10,10-tetra=hydrothioxanthyl)]methoxycarbonyl

dibenzosuberyl2-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyll-methyl-l-(3,5-dimethoxyphenyl)ethoxycarbonyldiethoxymethyl

diethylisopropylsilyl2-oxo-1,2-diphenylethyl1,3-dithianyl-2-methyl

2-(2,4-dinitrophenyl)ethyl2-(2,4-dinitrophenyl)ethoxycarbonyl2,4-dinitrobenzenesulfonyl

2-dansylethoxycarbonyl/7-(dihydroxyboryl)benzyloxycarbonyl2,4-dimethylpent-3-yloxycarbonyldimethyl[l,l-dimethyl-3-(tetrahydro-2//-pyran-2-y loxy)propyl] silyl

diphenylacetyldiphenylisopropylsilyldiphenylmethyldiphenylmethylsilyldiphenylphosphinyl2-(diphenylphosphino)ethyl(diphenyl-4-pyridyl)methyl2-(methyldiphenylsilyl)ethyldiphenylphosphinothioyldiphenyW-butoxysilyl ordiphenyl-f-butylsilyldi-f-butylmethylsilyldi-f-butylsilylene2-(hydroxyethyl)dithioethyl or "dithiodiethanol"

dithiasuccinimidyl1-ethoxy ethylethoxymethylferrocenylmethyl9-fluorenylmethyl9-fluorenylmethoxycarbonylguaiacolmethyl

2-hydroxybenzyl1,1,1,3,3,3-hexafluoro-2-phenylisopropyl

1 -isopropy lally loxycarbonylisopinocamphenyl

isopropyldimethylsilyllevulinoyl

4,4-(ethylenedithio)pentanoyllevulinoyldithioacetal ester2-(9,10-anthraquinonyl)methyl or 2-methylene-anthraquinone

1 -methyl-1 -benzy loxyethyl2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl

jp-methoxybenzenesulfonyl2,6-dimethyl-4-methoxybenzenesulfonylα-methylcinnamyl

2-methoxyethoxymethylα-methylnitropiperonyloxycarbonylp-methoxybenzyloxycarbonylmesityl or 2,4,6-trimethylphenylmethoxyisopropyl or 1 -methyl- 1-methoxyethylmenthoxymethyl

/j-methoxyphenyldiphenylmethylp-methoxyphenyldiphenylmethylmethoxymethyl

methoxymethoxyp-methoxybenzyloxycarbonylp-methoxyphenyl

/7-methoxypheny lmethyl or /?-methoxybenzylp-methoxyphenylsulfonyl

dimethylphosphinothioylmethanesulfonyl or mesyl4-(methylsulfinyl)benzyl4-methylsulfinylbenzyloxycarbonyl2,4,6-trimethoxybenzenesulfonyl2,3,5,6-tetramethyl-4-methoxybenzenesulfonyl4-methoxytetrahydropyranyl

methylthiomethyl4-(methylthiomethoxy)butyryl

2-nitroethyl4-nitrocinnamyloxycarbonyl2- or 4-nitrobenzenesulfonyl2-(nitrophenyl)ethyl

2-(4-nitrophenyl)ethoxycarbonyl2-(4-nitrophenyl)ethylsulfonyl2-nitrophenylsulfenyl

2-[(2-nitrophenyl)dithio]-1 -phenylethoxycarbonyl

3 -nitro-2-pyridinesulfeny 12- or 4-nitrobenzenesulfonyl3,4-dimethoxy-6-nitrobenzyloxycarbonylor6-nitroveratryloxycarbonyl

2,6,7-trioxabicyclo[2.2.2]octylo-nitrobenzyl

/7-acylaminobenzyl2- [2-(benzyloxy )ethy 1] benzoyl2-[2-(4-methoxybenzyloxy)ethyl]benzoyl3-(3-pyridyl)allyloxycarbonyl or

3-(3-pyridyl)prop-2-enyloxycarbonyl2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl2-phosphonioethoxycarbonyl

2-(triphenylphosphonio)ethoxycarbonyl2-(2'-pyridyl)ethyl

9-phenylfluorenylphenylacetamidomethyl4-methoxyphenacyloxycarbonylphthalimidomethyl

9-(9-phenyl)xanthenylp-methoxybenzyl or p-methoxyphenylmethylp-methoxybenzyloxymethyl

2,2,5,7,8-pentamethylchroman-6-sulfonylpentamethylbenzenesulfonyl

p-methoxyphenylp-methylbenzylsulfonylp-nitrobenzyl

p-nitrophenyl2-(4-nitrophenyl)ethyl4-pentenyloxymethylpivaloyloxymethyl

pivaloyl9-(9-phenyl)xanthenyll-(a-pyridyl)ethyl2-(2'- or 4'-pyridyl)ethoxycarbonyl2-quinolinylmethyl

S-acetylthioethylS-carboxymethylsulfenyll-[2-(trimethylsilyl)ethoxy]ethyl2-(trimethylsilyI)ethoxymethyl2-(trimethylsilyl)ethanesulfonyltris(trimethylsilyl)silyl

(phenyldimethylsilyl)methoxymethylS-(N'-methyl-/V'-phenylcarbamoyl)sulfenyl1,1,4,4-tetramethyldisilylazacyclopentanetrimethylacetamidomethyl

f-butyldimethylsilylf-butyldiphenylsilyl4-(17-tetrabenzo[a,c,g,/]fluorenylmethyl-4',4"-dimethoxytrityl

17-tetrabenzo[a,c,g,i]fluorenylmethoxycarbonyltetra-f-butoxydisiloxane-1,3-diylidene

f-butylmethoxyphenylsilylf-butyldimethylsilyl4,4',4"-tris(benzyloxy)triphenylmethyl2,2,2-trichloro-1,1 -dimethylethyl1,1 -dimethyl-2,2,2-trichloroethoxycarbonylN-tetrachlorophthalimido

2-(trifluoromethyl)-6-chromonylmethyleneoxycarbonyl2-(trifluoromethyl)-6-chromonylmethylene

(2,2,2-trifluoro-1,1 -diphenyl)ethylthexyldimethylsilyl

2-(trimethylsilyl)ethoxycarbonyltriethylsilyl

trifluoromethanesulfonyltrifluoroacetyl

4,4,4-trifIuoro-3-oxo-1 -butenyl2,3-dimethyl-2-butyl

tetrahydrofuranyl

XIXTHP tetrahydropyranyl

benzotriazol-1 -yloxytris(dimethylamino)phosphoniumhexafluorophosphate

bis(2-oxo-3-oxazolidinyl)phosphinic chloridebromotris(dimethylamino)phosphoniumhexafluorophosphate

benzotriazol-1 -yl or 1 -benzotriazolylbenzyltriethylammonium chloride

Candida antarctica lipase

eerie ammonium nitrate2-chloro-1 -methylpyridinium iodidecyclooctadiene

cyclooctatetraenecamphorsulfonic acid1,4-diazabicyclo[2.2.2]octanedi-/-butyl azodicarboxylatel,5-diazabicyclo[4.3.0]non-5-ene

DBU l,8-diazabicyclo[5.4.0]undec-7-ene

DCC dicyclohexylcarbodiimide

DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DEAD diethyl azodicarboxylate

DIAD diisopropyl azodicarboxylate

DIBAL-H diisobutylaluminum hydride

DMSO dimethyl sulfoxide

EDCI or EDC l-ethyl-3-(3-(dimethylaminopropyl)carbodiimide

EDTA ethylenediaminetetraacetic acid

HATU yV-[(dimethylamino)(3//-l,2)

3-triazolo(4,5-&)pyridin-3-phosphate, previously known as 0(7-azabenzotriazol-l-yl)-1,1,3»3-tetramethyluronium hexafluorophosphateHMDS 1,1,1,3,3,3-hexamethyldisilazane

yloxy)methylene]-Af-methylmethanaminiumhexafluoro-HMPA hexamethylphosphoramide

HMPT hexamethylphosphorous triamide

HOAt 7-aza-1 -hydroxybenzotriazole

HOBT 1 -hydroxybenzotriazole

Im imidazol-1 -yl or 1 -imidazolyl

IPA isopropyl alcohol

IPCF (=IPCC) isopropenyl chloroformate (isopropenyl chlorocarbonate)KHMDS potassium hexamethyldisilazide

LAH lithium aluminum hydride

LDBB lithium 4,4'-di-f-butylbiphenylide

MAD methylaluminumbis(2,6-di-f-butyl-4-methylphenoxide)MCPBA m-chloroperoxybenzoic acid

/V-methylmorpholine N-oxide

JV-methylpyrrolidinonepolymer supportphthalocyaninepyridinium chlorochromatedichlorobis[tris(2-methylphenyl)phosphine]palladiumtris(dibenzylideneacetone)dipalladium

protective group[hydroxy(tosyloxy)iodo]benzeneporcine pancreatic lipasepyridinium p-toluenesulfonatel,8-bis(dimethylamino)naphthalenepyridine

rhodium perfluorobutyratemethoxycarbonylsulfenyl chloridesodium bis(2-methoxyethoxy)aluminum hydridesuccinimidyl

tris(dimethylamino)sulfonium difluorotrimethylsilicatetetrabutylammonium fluoride

triethylaminetriethylbenzylammonium chloridetriethylbenzylammonium chloridetriethylsilane

trifluoromethanesulfonyltrifluoroacetic acidtrifluoroacctic anhydridetrifluoromethanesulfonic acidtrifluoromethanesulfonic acidtetrahydrofuran

tetrahydropyran

N, A^A^N'-tetramcthylethylenediaminetri methyl orthoformate

tetrapropylammonium perruthenatetetraphenylporphyrin

sulfonated triphenylphosphinetriisopropylbenzensulfonyl chloridetriphenylcarbenium tetrafluoroboratetetrabutylammonium triphenylmethanethiolatetoluenesulfonyl

PROTECTIVE GROUPS IN ORGANIC SYNTHESIS

THE ROLE OF PROTECTIVE

GROUPS IN ORGANIC

SYNTHESIS

PROPERTIES OF A PROTECTIVE GROUP

When a chemical reaction is to be carried out selectively at one reactive site in amultifunctional compound, other reactive sites must be temporarily blocked.Many protective groups have been, and are being, developed for this purpose Aprotective group must fulfill a number of requirements It must react selectively

in good yield to give a protected substrate that is stable to the projected tions The protective group must be selectively removed in good yield by readilyavailable, preferably nontoxic reagents that do not attack the regenerated func-tional group The protective group should form a derivative (without the genera-tion of new stereogenic centers) that can easily be separated from side productsassociated with its formation or cleavage The protective group should have aminimum of additional functionality to avoid further sites of reaction All thingsconsidered, no one protective group is the best Currently, the science and art oforganic synthesis, contrary to the opinions of some, has a long way to go before

reac-we can call it a finished and reac-well-defined discipline, as is amply illustrated bythe extensive use of protective groups during the synthesis of multifunctionalmolecules Greater control over the chemistry used in the building of nature'sarchitecturally beautiful and diverse molecular frameworks, as well as unnaturalstructures, is needed when one considers the number of protection and deprotec-tion steps often used to synthesize a molecule

HISTORICAL DEVELOPMENT

Since a few protective groups cannot satisfy all these criteria for elaborate strates, a large number of mutually complementary protective groups are neededand, indeed, are available In early syntheses, the chemist chose a standard deriv-ative known to be stable to the subsequent reactions In a synthesis of callis-tephin chloride, the phenolic—OH group in 1 was selectively protected as anacetate.1 In the presence of silver ion, the aliphatic hydroxyl group in 2 displacedthe bromide ion in a bromoglucoside In a final step, the acetate group wasremoved by basic hydrolysis Other classical methods of cleavage include acidichydrolysis (eq 1), reduction (eq 2) and oxidation (eq 3):

exten-describes the selective protection of primary and secondary hydroxyl groups in asynthesis of gentiobiose, carried out in the 1870s, as triphenylmethyl ethers

DEVELOPMENT OF NEW PROTECTIVE GROUPS

As chemists proceeded to synthesize more complicated structures, they oped more satisfactory protective groups and more effective methods for the for-mation and cleavage of protected compounds At first a tetrahydropyranyl acetalwas prepared,4 by an acid-catalyzed reaction with dihydropyran, to protect ahydroxyl group The acetal is readily cleaved by mild acid hydrolysis, but forma-tion of this acetal introduces a new stereogenic center Formation of the4-methoxytetrahydropyranyl ketal5 eliminates this problem

devel-Catalytic hydrogenolysis of an O-benzyl protective group is a mild, selectivemethod introduced by Bergmann and Zervas6 to cleave a benzyl carbamate(>NCO-OCH2C6H5 —> >NH) prepared to protect an amino group during peptidesyntheses The method has also been used to cleave alkyl benzyl ethers, stablecompounds prepared to protect alkyl alcohols; benzyl esters are cleaved by cat-alytic hydrogenolysis under neutral conditions

DEVELOPMENT OF NEW PROTECTIVE GROUPS 3

Three selective methods to remove protective groups have received attention:

"assisted," electrolytic, and photolytic removal Four examples illustrate

"assisted removal" of a protective group A stable allyl group can be converted to

a labile vinyl ether group (eq 4)7; a β-haloethoxy (eq 5)8 or a β-silylethoxy(eq 6)9 derivative is cleaved by attack at the /3-substituent; and a stable o-nitro-phenyl derivative can be reduced to the o-amino compound, which undergoescleavage by nucleophilic displacement (eq 7):1 0

(4) ROCH2CH=CH2 f~B"° » [ROCH=CHCH3] H3° ROH

(5) RO-CH2-CC13 + Zn • RO" + CH2=CC12

(6) RO-CH2-CH2-SiMe3 — £ — - RO + CH2=CH2 + FSiMe3

R = alkyl, aryl, R'CO-, or

R'NHCO-NH

The design of new protective groups that are cleaved by "assisted removal" is achallenging and rewarding undertaking

Removal of a protective group by electrolytic oxidation or reduction is useful

in some cases An advantage is that the use and subsequent removal of chemicaloxidants or reductants (e.g., Cr or Pb salts; Pt- or Pd-C) are eliminated.Reductive cleavages have been carried out in high yield at —1 to —3 V (vs.SCE), depending on the group; oxidative cleavages in good yield have been real-ized at 1.5-2 V (vs SCE) For systems possessing two or more electrochemi-cally labile protective groups, selective cleavage is possible when the half-wavepotentials, E1/2, are sufficiently different; excellent selectivity can be obtainedwith potential differences on the order of 0.25 V Protective groups that havebeen removed by electrolytic oxidation or reduction are described at the appro-priate places in this book; a review article by Mairanovsky11 discusses electro-chemical removal of protective groups.12

Photolytic cleavage reactions (e.g., of o-nitrobenzyl, phenacyl, and phenylsulfenyl derivatives) take place in high yield on irradiation of the pro-tected compound for a few hours at 254-350 nm For example, the o-nitrobenzylgroup, used to protect alcohols,13 amines,14 and carboxylic acids,15 has beenremoved by irradiation Protective groups that have been removed by photolysisare described at the appropriate places in this book; in addition, the reader maywish to consult five review articles.l6~20

nitro-One widely used method involving protected compounds is solid-phasesynthesis21"24 (polymer-supported reagents) This method has the advantage ofrequiring only a simple workup by filtration such as in automated syntheses,especially of polypeptides, oligonucleotides, and oligosaccharides.

Internal protection, used by van Tamelen in a synthesis of colchicine, may beappropriate:25

SELECTION OF A PROTECTIVE GROUP FROM THIS BOOK

To select a specific protective group, the chemist must consider in detail all thereactants, reaction conditions, and functionalities involved in the proposed syn-thetic scheme First, he or she must evaluate all functional groups in the reactant

to determine those that will be unstable to the desired reaction conditions andthat, accordingly, require protection Then the chemist should examine the reac-tivities of possible protective groups, listed in the Reactivity Charts, to determinewhether the protective group and the reaction conditions are compatible A guide

to these considerations is found in Chapter 10 (The protective groups listed inthe Reactivity Charts in that chapter were the most widely used groups at thetime the charts were prepared in 1979 in a collaborative effort with othermembers of Professor Corey's research group.) The chemist should consult thecomplete list of protective groups in the relevant chapter and consider theirproperties It will frequently be advisable to examine the use of one protectivegroup for several functional groups (e.g., a 2,2,2-trichloroethyl group to protect ahydroxyl group as an ether, a carboxylic acid as an ester, and an amino group as

a carbamate) When several protective groups are to be removed simultaneously,

it may be advantageous to use the same protective group to protect differentfunctional groups (e.g., a benzyl group, removed by hydrogenolysis, to protect

an alcohol and a carboxylic acid) When selective removal is required, differentclasses of protection must be used (e.g., a benzyl ether cleaved by hydrogenoly-sis, but stable to basic hydrolysis, to protect an alcohol, and an alkyl estercleaved by basic hydrolysis, but stable to hydrogenolysis, to protect a carboxylicacid) One often overlooked issue in choosing a protective group is that the elec-tronic and steric environments of a given functional group will greatly influencethe rates of formation and cleavage As an obvious example, a tertiary acetate ismuch more difficult to form or cleave than a primary acetate

If a satisfactory protective group has not been located, the chemist has anumber of alternatives available: rearrange the order of some of the steps in the

synthetic scheme, so that a functional group no longer requires protection or aprotective group that was reactive in the original scheme is now stable; redesignthe synthesis, possibly making use of latent functionality26 (i.e., a functionalgroup in a precursor form, e.g., anisole as a precursor of cyclohexanone);include the synthesis of a new protective group in the overall plan; or, better yet,design new chemistry that avoids the use of a protective group.

Several books and chapters are associated with protective group chemistry.Some of these cover the area;27,28 others deal with more limited aspects.Protective groups continue to be of great importance in the synthesis ofthree major classes of naturally occurring substances—peptides,22 carbohy-drates,23 and oligonucleotides24—and significant advances have been made insolid-phase synthesis,22"24 including automated procedures The use of enzymes

in the protection and deprotection of functional groups has been reviewed.29

Special attention is also called to a review on selective deprotection of silylethers.30

SYNTHESIS OF COMPLEX SUBSTANCES:TWO

EXAMPLES (AS USED IN THE SYNTHESIS OF HIMASTATIN AND PALYTOXIN) OF THE SELECTION, INTRODUCTION, AND REMOVAL OF PROTECTIVE GROUPS

Synthesis of Himastatin

Himastatin, isolated from an actinomycete strain (ATCC) from the HimachalPradesh State in India and active against gram-positive microorganisms and avariety of tumor probe systems, is a C72H104Nl4O20 compound, I.31 It has a novelbisindolyl structure in which the two halves of the molecule are identical Eachhalf contains a cyclic peptidal ester that contains an L-tryptophanyl unit, D-threo-nine, L-leucine, D-[(7?)-5-hydroxy]piperazic acid, (S)-2-hydroxyisovaleric acid,and D-valine The synthesis of himastatin,32 which illustrates several importantaspects of protective group usage, involved the preparation of the pyrroloindo-line moiety A, its conversion to the bisindolyl unit A'2, synthesis of the peptidalester moiety B, the subsequent joining of these units (A'2 and two B units), andcyclization leading to himastatin The following brief account focuses on theprotective-group aspects of the synthesis

Unit A (Scheme 1)

The first objective was the conversion of L-tryptophan into a derivative that could

be converted to pyrroloindoline 3, possessing a cis ring fusion and a syn

relation-ship of the carboxyl and hydroxyl groups This was achieved by the conversions

shown in Scheme 1 A critical step was e Of many variants tried, the use of the

trityl group on the NH2 of tryptophan and the f-butyl group on the carboxyl

resulted in stereospecific oxidative cyclization to afford 3 of the desired cis-syn

stereochemistry in good yield

Himastatin 1

Bisindolyl Unit A'2 (Schemes 2 and 3)

The conversion of 3 to 8 is summarized in Scheme 2 The trityl group (too largeand too acid sensitive for the ensuing steps) was removed from N, and both N'swere protected by Cbz (benzyloxycarbonyl) groups Protection of the tertiary

OH specifically as the robust TBS (r-butyldimethylsilyl) group was found to benecessary for the sequence involving the electrophilic aromatic substitution step,

5 to 6, and the Stille coupling steps (6 + 7 -> 8)

The TBS group then had to be replaced (two steps, Scheme 3: a and b) by themore easily removable TES (triethylsilyl) group to permit deblocking at the laststep in the synthesis of himastatin Before combination of the bisindolyl unitwith the peptidal ester unit, several additional changes in the state of protection

at the two nitrogens and the carboxyl of 8 were needed (Schemes 2 and 3) TheCbz protective groups were removed from both N's, and the more reactive pyrro-lidine N was protected as the FMOC (fluorenylmethoxycarbonyl) group At thecarboxyl, the f-butyl group was replaced by the allyl group [The smaller allylgroup was needed for the later condensation of the adjacent pyrrolidine nitrogen

of 15 with the threonine carboxyl of 24 (Scheme 5); also, the allyl group can be

L-tryptophan

H

2 a) TMSC1, ETOAc (RCO;T -> RCO 2 TMS) b) TrCl, Et 3 N (-NH 3+ H> NHTr)

c) MeOH (-CO 2 TMS H> CO 2 H) d) /-BuOH, condensing agent (-CO 2 H to -CO 2 -f-Bu)

(a) TBAF, THF(91%) (TBSO- -> HO-)

(b) TESC1, DBU, DMF (92%) ( HO- -» TESO-)

(c) H2,Pd/C, EtOAc(100%) (both NCbz's->NH)

(d) FMOC-HOSU, pyridine, CH2C12 (95%) (NH -> NFMOC)

(e) TESOTf, lutidine, CH2C12 (-CO2-f-Bu -> -CO2H)

(f) allyl alcohol, DBAD, Ph3P, CH2C12 (90% from 12) (-CO2H -» -CO2-allyl(g) piperidine, CH3CN (74%) (NFMOC -> NH)

Scheme 3

NaHMDS THF, -78°C BOCN=NBOC

(a) TFA (both -NBOC's -> NH)

(b) TeocCl, pyridine (-NH -^ NTeoc)

(c) LiOH (lactone -> - C O2' + HO-)

(d) TBSOTf, lutidine (-OH -^ -OTBS)

Scheme 4

Peptidal Ester Unit B (Schemes 4 and 5)

Several of these steps are common in peptide synthesis and involve standardprotective groups Attention is called to the 5-hydroxypiperazic acid Its syn-thesis (Scheme 4) has the interesting feature of the introduction of the twonitrogens in protected form as BOC (f-butoxycarbonyl) groups in the same step.Removal of the BOC groups and selective conversion of the nitrogen furthestfrom the carboxyl group into the N-Teoc (2-trimethylsilylethoxycarbonyl)group, followed by hydrolysis of the lactone and TBS protection of the hydroxyl,

NHFMOC AllylO2C

I NH2 several TBSO steps

17 (a) EDCI, DMAP, CH 2 C1 2

(b) piperidine, CH 3 CN (NHFMOC to -NH 2 )

FMOC-L-Leucine

AllylO2C O

jsjj_j piperazic acid 16 (from Scheme 4)

XT |' HATU, HOAt, collidine, CH 2 C1 2

D-Threonine

HN

Teoc.N

(b H> e: 72% yield)

Scheme 5

neces-In the following step (19 + 20 —> 21), this somewhat hindered piperazyl -NH is

condensed with the acid chloride 20 Note that the hydroxyl in 20 is protected bythe FMOC group—not commonly used in hydroxyl protection A requirementfor the protective group on this hydroxyl was that it be removable (for the nextcondensation: 21 + Troc-D-valine 22 —> 23) under conditions that would leaveunaltered the -COO-allyl, the N-Teoc, and the OTBS groups The FMOC group(cleavage by piperidine) met this requirement The choice of the Troc (2,2,2-trichloroethoxycarbonyl) group for N-protection of valine was based on therequirements of removability, without affecting the OTBS and OTES groups,and stability to the conditions of removal of allyl from -COO-allyl [easily met

by the use of Pd(Ph3P)4 for this deblocking]

Himastatin 1 (Scheme 6)

Of special importance to the synthesis was the choice of condensing agentsand conditions.33 HATU-HOAt34 was of particular value in these final stages.Condensation of the threonine carboxyl of 24 (from Scheme 5) with the pyrroli-dine N's of the bisindolyl compound 15 (from Scheme 3) afforded 25 Removal

15

24

25 R = allylR' = Troc

NHTBSO

OTBS

(a) HATU, HO At, collidine, CH 2 C1 2) -10°C

(b) Pd(Ph 3 P) 4 , PhSiH 3 , THF (-CO 2 -allyl -s

(c) Pb/Cd, NH 4 OAc, THF (N-Troc -> NH)

(d) HATU, HO At,

j-Pr 2 NEt, DMF

(e) TBAF, THF, HOAc

(-OTBS and -OTES

-> it (65%) -CO 2 H)

SYNTHESIS OF COMPLEX SUBSTANCES 11

of the allyl groups from the tryptophanyl carboxyls and the Troc groups from thevaline amino nitrogens, followed by condensation (macrolactamization), gave

27 Removal of the six silyl groups (the two quite hindered TES groups and thefour, more accessible, TBS groups) by fluoride ion afforded himastatin

Synthesis of Palytoxin Carboxylic Acid

Palytoxin carboxylic acid, Cl23H2l3NO53, Figure 1 (R1 - R8 = H), derived frompalytoxin, C129H223N3O54, contains 41 hydroxyl groups, one amino group, oneketal, one hemiketal, and one carboxylic acid, in addition to some double bondsand ether linkages

The total synthesis35 was achieved through the synthesis of eight differentsegments, each requiring extensive use of protective group methodology, fol-lowed by the appropriate coupling of the various segments in their protectedforms

The choice of what protective groups to use in the synthesis of each segmentwas based on three aspects: (a) the specific steps chosen to achieve the synthesis

of each segment; (b) the methods to be used in coupling the various segments,and (c) the conditions needed to deprotect the 42 blocked groups in order to

84

OR 3 OR- ,

1: R1 = OMe, R2 = Ac, R3 = (f-Bu)Me2Si, R4 = 4-MeOC6H4CH2, R5 = Bz,

R6 = Me, R7 = acetonide, R8 = Me3SiCH2CH2OCO

2: Palytoxin carboxylic acid: R1 = OH, R2-R8 = H

Figure 1 Palytoxin carboxylic acid.

liberate palytoxin carboxylic acid in its unprotected form (These conditionsmust be such that the functional groups already deprotected are stable tothe successive deblocking conditions.) Kishi's synthesis employed only eightdifferent protective groups for the 42 functional groups present in the fullyprotected form of palytoxin carboxylic acid (Figure 1,1) A few additional protec-tive groups were used for "end group" protection in the synthesis and sequentialcoupling of the eight different segments The synthesis was completed byremoval of all of the groups by a series of five different methods The selection,formation, and cleavage of these groups are described next.

For the synthesis of the C.1-C.7 segment, the C.I carboxylic acid was tected as a methyl ester The C.5 hydroxyl group was protected as the f-butyl-dimethylsilyl (TBS) ether This particular silyl group was chosen because itimproved the chemical yield and stereochemistry of the Ni(II)/Cr(II)-mediatedcoupling reaction of segment C.1-C.7 with segment C.8-C.51 Nine hydroxylgroups were protected as p-methoxyphenylmethyl (MPM) ethers, a group thatwas stable to the conditions used in the synthesis of the C.8-C.22 segment.These MPM groups were eventually cleaved oxidatively by treatment with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)

pro-The C.2 hydroxyl group was protected as an acetate, since cleavage of ap-methoxyphenylmethyl (MPM) ether at C.2 proved to be very slow An acetylgroup was also used to protect the C.73 hydroxyl group during synthesis of theright-hand half of the molecule (C.52-C.115) Neither a /7-methoxyphenyl-methyl (MPM) nor a f-butyldimethylsilyl (TBS) ether was satisfactory at C.73:dichlorodicyanobenzoquinone (DDQ) cleavage of a /?-methoxyphenylmethyl

(MPM) ether at C.73 resulted in oxidation of the cis-trans dienol at C.78-C.73

to a cis-trans dienone When C.73 was protected as a f-butyldimethylsilyl (TBS)

ether, Suzuki coupling of segment C.53-C.75 (in which C.75 was a vinyliodide) to segment C.76-C.115 was too slow In the synthesis of segmentC.38-C.51, the C.49 hydroxyl group was also protected at one stage as anacetate, to prevent benzoate migration from C.46 The C.8 and C.53 hydroxylgroups were protected as acetates for experimental convenience A benzoateester, more electron withdrawing than an acetate ester, was used to protect theC.46 hydroxyl group to prevent spiroketalization of the C.43 and C.51 hydroxylgroups during synthesis of the C.38-C.51 segment Benzoate protection of theC.46 hydroxyl group also increased the stability of the C.47 methoxy group (part

of a ketal) under acidic cleavage conditions Benzoates, rather than acetates,were used during the synthesis of the C.38-C.51 segment, since they were morestable and were better chromophores in purification and characterization.Several additional protective groups were employed in the coupling of theeight different segments A tetrahydropyranyl (THP) group was used to protectthe hydroxyl group at C.8 in segment C.8-C.22, and a f-butyldiphenylsilyl(TBDPS) group for the hydroxyl group at C.37 in segment C.23-C.37 TheTBDPS group at C.37 was later removed by Bu4N+F~/THF in the presence ofnine p-methoxyphenylmethyl (MPM) groups After the coupling of segmentC.8-C.37 with segment C.38-C.51, the C.8 THP ether was hydrolyzed with

pyridinium/7-toluenesulfonate (PPTS) in methanol-ether, 42°, in the presence ofthe bicyclic ketal at C.28-C.33 and the cyclic ketal at C.43-C.47 (As notedpreviously, the resistance of this ketal to these acidic conditions was due to theelectron-withdrawing effect of the benzoate at C.46.) A cyclic acetonide (a 1,3-dioxane) at C.49-C.51 was also removed by this step and had to be reformed(acetone/PPTS) prior to the coupling of segment C.8-C.51 with segmentC.1-C.7 After the coupling of these segments to form segment C.1-C.51, thenew hydroxyl group at C.8 was protected as an acetate, and the acetonide atC.49-C.51 was, again, removed without alteration of the bicyclic ketal atC.28-C.33 or the cyclic ketal at C.43-C.47, still stabilized by the benzoate atC.46.

The synthesis of segment C.77-C.115 from segments C.77-C.84 andC.85-C.115 involved the liberation of an aldehyde at C.85 from its protectedform as a dithioacetal, RCH(SEt)2, by mild oxidative deblocking (I2/NaHCO3,acetone, water) and the use of the p-methoxyphenyldiphenylmethyl (MMTr)group to protect the hydroxyl group at C.77 The C.77 MMTr ether was sub-sequently converted to a primary alcohol (PPTS/MeOH-CH2Cl2, rt) withoutaffecting the 19 f-butyldimethylsilyl (TBS) ethers or the cyclic acetonide atC.lOO-C.lOl

The C.lOO-C.lOl diol group, protected as an acetonide, was stable to the

Wittig reaction used to form the cis double bond at C.98-C.99 and to all of the

conditions used in the buildup of segment C.99-C.115 to fully protected toxin carboxylic acid (Figure 1,1)

paly-The C.I 15 amino group was protected as a trimethylsilylethyl carbamate(Me3SiCH2CH2OCONHR), a group that was stable to the synthesis conditions,and cleaved by the conditions used to remove the ?-butyldimethylsilyl (TBS)ethers

Thus, the 42 functional groups in palytoxin carboxylic acid (39 hydroxylgroups, one diol, one amino group, and one carboxylic acid) were protected byeight different groups:

1 methyl ester -COOH

(dichlorodi-(2) To cleave the acetonide: 1.18 NHC1O 4 -THF, 25°, 8 days.

(3) To hydrolyze the acetates and benzoates: 0.08 N LiOH/H2 THF, 25°, 20 h.

O-MeOH-(4) To remove r-butyldimethylsilyl (TBS) ethers and the carbamoyl ester (Me 3 SiCH 2 CH 2 OCONHR): Bu 4 N + F~, THF, 22°, 18 h -» THF-DMF, 22°,

1 A Robertson and R Robinson, J Chem Soc, 1460 (1928).

2 E Fischer, Ber., 28, 1145-1167 (1895); see p 1165.

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17 P G Sammes, Quart Rev., Chem Soc, 24, 37-68 (1970); see pp 66-68.

18 B Amit, U Zehavi, and A Patchornik, Isr J Chem., 12, 103-113 (1974).

19 V N R Pillai, "Photolytic Deprotection and Activation of Functional Groups," Org Photochem., 9, 225-323 (1987).

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21 (a) R B Merrifield, J Am Chem Soc, 85, 2149 (1963); (b) P Hodge, Chem lnd (London), 624 (1979); (c) C C Leznoff, Ace Chem Res., 11, 327 (1978); (d) E C Blossey and D C Neckers, Eds., Solid Phase Synthesis, Halsted, New York, 1975;

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E Uhlmann, Angew Chem., Int Ed Engl, 28, 716 (1989); (c) S L Beaucage and

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26 D Lednicer, Adv Org Chem., 8, 179-293 (1972).

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75, 1997; W Theilheimer, Ed., Synthetic Methods of Organic Chemistry, S Karger, Basel, Vols 1-52, 1946-1997; E Miiller, Ed., Methoden der Organischen Chemie (Houben-Weyl), Georg Thieme Verlag, Stuttgart, Vols 1 —21f, 1958-1995; Spec.

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34 HO At, 7-aza-l-hydroxybenzotriazole; HATU (CAS Registry No 148893-10-1), N-[(dimethylamino) (3//-l,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene]-/V-methyl- methanaminium hexafluorophosphate, previously known as 0-(7-azabenzotriazol- l-yl)-l,l,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 (Me 2 NC=NMe 2 ) + unit to N 3 of 7-azabenzotriazole 1-TV-oxide

instead of to the O, 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,

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