protecting groups m.s

REVIEWS

Protecting Group Strategies in Organic Synthesis

Michael Schelhaas and Herbert Waldmann" Dedicated to Projessor Leopold Horner on the occasion of his 85th birthday

f The choice of protecting groups is one of the decisive factors in the successful realization of a complex, demanding synthetic project. The protecting groups used influence the length and efficiency of the synthesis and are often responsi- ble for its success or failure. A wide range of blocking groups are currently available for the different functional groups; however, an overall strategy combining these different masking techniques in an advantageous and reliable

'

manner has never been proposed or at best only for individual cases. This review attempts to make a contribution to filling this gap. First a very short overview of the most commonly used protecting groups will be given, in which they are classified according to their lability and not according to the functional group they protect. This classifi- cation clarifies coherent concepts for the development of blocking strategies. On the basis of this brief summary reliable

strategies will then be illustrated and developed with selected examples from the recent literature by which protecting groups may be combined successfully and advantageously in synthetic projects of differing degrees of complexity and difficulty.

Keywords: protecting groups * retrosynthetic analyses - synthetic methods - total syntheses

1. Introduction

Today, organic synthesis has reached a remarkable level of competence and even the most complex molecules are accessible.['] The prerequisites for this success are both the availability of a wide range of efficient synthetic methods['] and reagents,f3f and the fact that "retrosynthetic analysis"[41 can provide a framework for the design of a synthetic strategy leading to the desired product in the most efficient and logical way.

These strategies include tactics for the construction of the molecular framework, for the establishment of the absolute configuration of any stereocenters present, for the efficient formation of rings, and for the reduction of the number of synthetic steps. The complex synthetic intermediates and products contain, in general, a multiplicity of functional groups, most of which must be blocked and, at an appropriate point in the synthesis, liberated. The correct choice of protecting groups is often decisive for the realization of the overall operation. This is exemplified by the recently published total synthesis of the mitomycin analog FR-900482. In model studies Danishefsky et a]. had shown that the basic skeleton of this natural product can be accessed by FeC1,-mediated opening of the epoxide in 1 (Scheme 1 ).Is1 However, the synthesis could not be concluded successfully. because cleavage of the methyl ether was accompa-

[*] Prof. Dr. H. Wdldmann. DipLChem. M. Schelhads lnstitut fur Orgdnische Chemle der Universitdt Karlsruhe Richard-Willstiitter-Allee 2. D-76128 Karlsruhe (Germany) F a x : I n t . code +(721)608-4825 e-mail . waldmannkr ochhddes.chemie.uni-karlsruhe.de

a m e Me0 CHO

Me02C " MeO& " N-C02Me N-CO,Me

1

OMOM !???#.+

Me02C

2 Scheme 1. Protecting group problems in the synthesis of mitomycin analog FR-900482 by S. Danishefsky et al. [ 5 ] . MOM = methoxymethyl, Bzl = benzyl.

nied by decomposition of the aziridine. To avoid this problemat- ic situation, the hydroxyl groups in 2 were not protected as methyl ethers but rather as benzyl and methoxymethyl ethers. Unfortunately, after this seemingly innocuous"I alteration in the protecting group pattern, the selective FeC1,-mediated cleavage of the oxirane failed owing to the higher lability of the newly introduced ether functions. The authors were forced to find an entirely new reagent to complete the synthesis.'6]

Another unexpected protecting group problem appeared during the total synthesis of taxol, again by Danishefsky et aL1'] The advanced intermediate 3 was converted into the epoxide 4, but the robust tot-butyldimethylsilyl (TBDMS) ether could not be removed in the next steps (Scheme 2). Thus the TBDMS in 3 was replaced by the more labile triethylsilyl (TES) ether. Com- pound 5 was converted into the corresponding epoxide 6, which was then successfully transformed into the complex natural

Angrit.. c'hcwi. In t . Ed. Eiigl 1996. 35. 2056-2083 \T: VCH Ver.lu~sgesellsr/7u/t inhH. 0-69451 Weinheim, 1996 0570-0833:Y6~3518-2057 $ I S OO+ .25/0 2057

REVIEWS M . Schelhaas and H . Waldinann

only for isolated The protecting groups will be classi- ficd according t o their lability (for ii inore comprehensive treat- incnt sec rets. [9 1 I ] ) instead according to the functional group they block. This has the advantage that the sensitivity of thc compounds to be protected and the required reaction conditions can be accountcd for in the planning of 21 synthesis.

Experience shows that the critical paramcters ;ire generally the stability and thecleavage ofthe protecting group rather than its introduction. For most of the typically required functional groups, protecting groups are known that are labile under different. often alternative. conditions. Furthermore. unified concepts for the development of new blocking possibilities become clear a s it consequence of this approach. As an example, the N-fri.t-butyloxycarbony1 (Boc) gro~ip. the trrt-butyl ester. and the twt-butyl ether can be cleaved under acidic conditions. the trimethylsilylethoxycarbonyl (Tcoc) group and the trimethyl-

OBzl OBzl

O 3 4

J iEtL > 0

OAc

0 OBzI

O 5 ' 6 Schcmc 2 . I'l-otcc[tn~ group prohieins ~n :lie \~i i ihcsts 01' t i ixol h> S l);inlslieS\k! c: a1 171.

product. The TES group was removed only after construction of the correctly functionalized polycycle.

These examples make it obvious that a successful synthesis requires both basic retrosynthetic planning and a separate protecting group strategy that takes into account different requirements such as the lability of the intermediates and of the reagents to be used.

As a consequence of the great importance of protecting groups in organic chemistry. a multitude of blocking techniques have been developed for a wide range of functional groups. Here the chemist has numerous choices. However. when giving ;I

detailed description of a successfully completed total synthesis.

silylethyl (TMSE) ether are cleaved by fluoride ions through /Mimination. and allyloxycarbonyl (Aloc) urethane, ally1 (All) ester. ally1 ether, and 5-methylene-1.3-dioxane acetal,['3J which is used for the protection ofcarbony1 groups, can all be removed by noble metal catalyzed reactions. Following this short overview. selected examples from the irecent literature will be used to illustrate proven strategies for the successful and advantageous combination of protecting groups in synthetic projects of varying complexity and difficulty. This review should provide simple guidelines for the the development of successful tactics and strategies foi- organic synthesis.

authors rarely comment on why they selected particular protecting group patterns.[81 Similarly. in the monographs"). '01 and

2. Lability and Cleavage of Protecting Groups

reviews" ' I concerning protecting group chemistry, the empha- sis lies in the presentation of the various possibilities that exist for the blocking and deprotection of the function in question.

For 21 protecting group to find wide application in organic synthesis, it must fulfill several criteria. In particular. it must

Strategies that can be used to combine protecting groups in appropriate ways and that have proved their capability and reliability in complex syntheses have never been published or

be introduced into the molecule to be protected under mild conditions in a selective manner and in high yield; functional groups other than that to be protected must not be attacked.

Protecting Group Chemistry REVIEWS

be stable under all the conditions used during the synthesis, including rhose of the purification steps, up to the step in which the protecting group is removed, it should, as Par as possible, have a stabilizing effect on the molecule and should suppress racemization or epimerization.

~ be cleavable under very mild conditions in a highly selective manner and in high yield; other protecting groups present in the molecule and unprotected functionalities should not be affected by the cleavage conditions.

In addition to these minimum requirements, the protecting group should also

~ be introduced and removed with the help of readily available reagents. such that in both transformations the products can be easily purified.

- introduce no additional stereocenters. - lend the protected intermediates advantageous physical prop-

erties; for example the compounds should be easily crystal- lized and/or readily soluble.

Only a few protecting groups meet all of these demands, and in most cases a compromise must be found, in which the most important criteria are addressed. In most cases guaranteeing that the protecting group is very stable and, at the same time, readily liberated (an apparent contradiction) is the crucial problem and overshadows the requirements for efficient introduction and the provision of desirable physical and chemical properties. In the next sections the most important protecting groups will be presented briefly according to their lability and their ease of cleavage.

2.1. Acid-Labile Protecting Groups['-

The cleavage of protecting groups by acid-mediated hydrolysis is one of the best established methods in protecting group chemistry and forms one of the central pillars of the subject. Nevertheless. only those protecting groups that can be removed under sufficiently mild (but not too mild) conditions find wide- spread use.

2.1.1. Acetal Protecting Groups

Acetals are formed and cleaved under acid catalysis. They are generally stable towards nucleophiles and bases, and are thus suitable for the protection of alcohols, diols, and carbonyl compounds. Furthermore, N,N- and N,O-acetals are utilized for the protection of amino groups.

Cyclic 0,O-acetals can be considered as protecting groups for either carbonyl groups or diols, depending on which component is of interest. Carbonyl groups are normally protected as the 1,3-dioxolane or -dioxane by condensation with ethylene glycol or propylene glycol (Scheme 3). Similarly, 1.2- and 1.3-diols are masked by reaction with acetone, (substituted) benzaldehyde, and cyclic ketones (cyclopentanone, cyclohexanone, cyclohep- tanone) as rsopropylidene, (substituted) benzylidene, and cy- cloalkylidene acetals. Recently, the dispiroketal (DISPOKE)1'41 and the cyclohexane-I ,2-diacetal (CDA) groups1151 have been proposed as two promising new acetal protecting groups (see Section 5 ) .

Acyclic 0.0-acetals are normally used for the protection of alcohols. Most commonly used are the tetrahydropyranyl (THP),

Protecting Groups for Diols

n = 1 , 2

isopropylidene cyclopentylidene cyclohexylidene

benzylidene pmethoxy- opdirnethoxy- benzylidene benzylidene

Protecting Groups for Carbonyls

n O x 0 R R '

n x 0 0

R R'

1,3-dioxane 1,3-dioxolane

Scheme 3. Examples of cyclic 0.0-acetals as protecting groups for 1.2-diols, 1.3-diols. and carbonyl compounds.

the methoxymethyl (MOM), the benzyloxymethyl (BOM), and the methoxyethoxymethyl (MEM) protecting groups (Scheme 4). They can be cleaved readily under mildly acid conditions, and their complexing ability can also be used to control the stereochemical course of a transformation (see Section 3.5).

tetrahydropyranyl rnethoxymethyl methoxyethoxyrnethyl (ThP) (MOM) (MEW

benzyloxyrnethyl ( B O W

rnethylthiomethyl (MTM)

Scheme 4. Examples of acyclic 0.0-acetals and 0.S-acetals ns protecting groups for alcohols.

2.1.2. Formation of Stabilized Cations

The second large class of acid-labile protecting groups is char- acterized by the formation of stabilized cations upon cleavage. The tert-butyl ether along with the corresponding ester and urethane (Boc protecting group) are examples of this class, which find use in the protection of alcohols, thiols, amines, and carboxylic acids (Scheme 5 ) . In each case, their cleavage liberates the tert-butyl cation. By analogy, benzyl cations are gener- ated on the cleavage of benzyl protecting groups, which are also common blocking groups for hydroxyl groups, thiols, esters, and amino groups. By introduction of additional substituents,

2059

REVIEWS M. Schelhaas and H. Waldmann

p G i q X=O,NH

PG =

felt-butyl felt-butyloxycarbonyl adarnantyloxycarbonyl 0 Bu) (Adoc)

t O K /

NO*

benzylox ycarbon yl para-methoxy- para-nitro- (Z, Cbz) benzyloxycarbonyl benzyloxycarbonyl

(MOZ) (4-NO,-Z)

Scheme 5. Examples of acid-labile protecting groups that are cleaved with formation of stabilized cations.

the stability of the cation can be increased or reduced, and thereby the acid sensitivity of the protecting group can be fine- tuned. Thus, the adamantyloxycarbonyl (Adoc) and the para- methoxybenzyloxycarbonyl (MOZ) groups are more acid-labile than the respective parent Boc and Z groups. The 4-N02-Z group is, however, significantly more stable than the Z-urethane. It should be noted that the silyl ether protecting groups, which are usually removed by treatment with fluoride ion (see Section 2.3), are also labile under mild acidic conditions.

2.2. Base-Labile Protecting GroupsTg- ''I

The removal of protecting functions under basic conditions is also one of the tried-and-true methods in protecting group chemistry. On the basis of mechanistic considerations, two cat- egories can be distinguished : basic hydrolysis and based- induced p-elimination.

2.2.1. Basic Hydrolysis

This method applies to practically all esters, with the exception of the tert-butyl ester mentioned in Section 2.1.2. Car- boxylic acids are typically protected as (substituted) alkyl esters. Alcohols are often esterified with acetic acid, benzoic acid, or pivalic acid (Scheme 6). The rate of hydrolysis can be modified by adjusting steric and electronic factors. For example, tri-

I R-0-PG 1 PG =

acetyl benzoyl (Bz)

pivaloyl (Piv)

Scheme 6. Examples of base-labile acyl protecting groups.

horvaeetate can be removed selectively in the presence of acetate, and acetate can be cleaved in the presence of pivalate.

Basic cleavage of amides to liberate amines is only seldom used on account of the generally harsh conditions required. The phthaloyl group is one exception; it can be cleaved with hydrazine under mildly basic conditions. Again, it should be noted that the silyl ethers can be removed by basic hydrolysis (however, see Section 2.3).

2.2.2. Cleavage by Base-Induced 8-Elimination

Protecting groups such as the fluorenylmethoxycarbonyl (Fmoc) urethane, which has established itself as one of the stan- dard protecting functions for amino groups in solution-phase and solid-phase peptide synthesis, and the phenylsulfonylethyl group are cleaved by the abstraction of an acidic proton and subsequent 8-elimination, with the formation of a vinyl system (Scheme 7). Direct attack of the base on a carbonyl function is thus avoided. This type of protecting group has found many applications.

X=O,NH

PG =

9-fluorenylmethoxycarbonyl 2-(phenylsulfonyl)ethoxycarbonyl (Fmoc)

Scheme 7. Examples of protecting groups that are cleaved by a-elimination

2.3. Fluoride-Labile Protecting Groups[' 'I

Silyl protecting groups can be cleaved by treatment with fluoride ion under conditions that affect nearly no other functionalities. They thus make up a n essential chapter in protecting group chemistry (Scheme 8). Variation of the substituents on silicon allows modification of their stability towards acids and bases, as well as the selectivity of the cleavage with fluoride ion (see Section 3.2.2 and Scheme 37). A simple rule of thumb holds-the greater the steric demand, the higher the stability. Alcohols are typically protected as trialkylsilyl ethers; the order of stability for the ethers is TMS < TES < TBDMS < TIPS[161 z thexyl. For particularly challenging cases, a further level of fine-tuning can be achieved with, for example, isopropyl- dimethylsilyl,[171 diisopropylmethylsilyl,['81 and diethylisopropylsilyl (DEIPS)[191 groups. I,3-Diols can be masked as silanediyl derivatives (see also Scheme 44) or by introduction of the tetraisopropyldisiloxane-l,3-diyl (TIPDS) group. Silyl groups are rarely used for the protection of esters and amines due to the high lability of the resulting derivatives (the STABASE protecting group[201 for amines is an exception, see Scheme 8). For this purpose, trialkylsilylethyl esters and carbamates have been

2060 Angew. Chenr. In!. Ed. Engl. 1996. 35, 2056-2083

Protecting Gram Chemistry REVIEWS

R', R', R3 = Me: TMS R' , R', R3 = Et: TES R', R', R3 = i Pr: TIPS R' = t Bu, R', R3 = Me: TBDMS R' = t Bu, R', R3 = Ph: TBDPS

R = peptide, nucleoside, X=O,NH

nucleotide. carbohvdrate. R-X

1 ,

plactarn antibiotic [2'-231 I Denicillin G acvlase I 0

Me 1 ,Me

R.oz/Si, Me

R = peptide, lipopeptide P41

I acetyl esterase I trirnethylsilyl- trirnethylsilyl-

ethox ycarbonyl ethoxyrnethyl (Teoc) ( S W

X=NH,O

trirnethylsilyl- ethyl

(TMSE) 0 0 0 R K O - ~ ( ~ e ) 3 ~r

butyrylcholine esterase

R = peptide, lipopeptide [''I

M,e ,Me ,Si

Si I \

Me Me

R-N\ 3 0

RKO- R = pepttde, glycopeptide

llipasej STABASE di-t-butyl- 1 , I ,3,3-tetraisopropyl-

silanedryl disiloxane-l,3-diyl (DTBS) (TIPDS) R = peptide, glycopeptide P7I

R = carbohydrate [212']

I 1

Scheme 8. Examples of protecting groups that are cleaved with fluoride ions

R'OKMe R = carbohydrate, steroid,

nucleoside, phenol ['12'2J developed, which can be removed by fluoride ion promoted fragmentation analogous to the previously described p-elimination (Section 2.2.2; Scheme 8). The same principle is also behind the trimethylsilylethyl (TMSE) and trimethylsilylethoxymethyl (SEM) protecting groups for alcohols.

Scheme 9. Selected enzyme-labile protecting groups

polyfunctional carbohydrates, nucleosides, steroids, alkaloids, and phenolic natural products, often with astonishingly high regioselectivity not achievable with classical chemical techniques. The ability of enzymes to function in organic solvents opens up new possibilities for the introduction of protecting groups.

2.4. Enzyme-Labile Protecting Groups"'. "I

In many cases the selective removal of different acyl protecting groups from amines and alcohols and the targeted deblocking of carboxylic acids under mild conditions is most readily achieved with biocatalysts. Enzymes typically function in the p H range 5 - 9 and at room temperature; they may display a high specificity for the structures they recognize and the reactions they catalyze, and at the same time they may tolerate a wide range of substrates. Thus enzymes enable the targeted removal of protecting groups (which may in principle also be removed by classical chemical methods) under mild conditions and with a chemo- and regioselectivity that is hardly, if a t all, possible by classical chemical techniques. Although the development of enzymatic protecting group techniques has been inten- sively studied only in the last few years. a number of interesting enzyme-labile protecting groups have been developed for organic synthesis (Scheme 9). Thus, for example. the phenylacet (PhAc) amide['31 and the 4-acetoxybenzyloxycarbonyl (AcOz)

have been used as enzyme-labile protecting functions for amino groups, and carboxylic acids can be selectively dernasked through enzyme-mediated cleavage of heptyl[251 and choline esters.[261 Hydroxyl groups protected as the acetate, benzoate. butyrate, and even pivalate can be liberated enzymatically.[" 221 In this way such conversions can be carried out in

2.5. Reduction-Labile Protecting Groups['

Reductive conditions can be used to cleave a variety of protecting groups that are used more or less frequently in organic synthesis.

2.5.1. Cleavage by Hydrogenolysis

Benzyl groups, which can be present as ethers, esters, urethanes, carbonates, or benzylidene acetals, and are used for the protection of alcohols, carboxyk acids, amines, and diols, can be removed under mild conditions by hydrogenolysis. The rate of hydrogenolysis can be influenced by introducing electron- donating or -accepting substituents in the aromatic ring. Benzyl groups are frequently used.

2.5.2. Cleavage by Reductive Elimination

Protecting groups of the 2-haloethyl type can be cleaved by a mechanism involving the donation of electrons into the carbon - halogen bond, leading to a fragmentation corresponding to the p-elimination discussed in Sections 2.2.2 and 2.3 (Scheme 10).

2061

REVIEWS M . Schelhaas and H. Waldmann

R - 0 = ether, ester, urethane eQ = Zn", electrochemical X = Br, CI Y = H, Br. CI

ScI1c111c 10 '-Haloelll!l prolccl l l l~ gr<Iup, 111'11 i.11, IhC cIc;I\cd h\ rcdUCIIOI1

Zinc is the preferred electron donor. but electi-ochemical meth-

The reduction of. for instance. ester protecting groups with complex hydrides. reagents that also will attack ii pivalate ester. is rarely used. owing to thc poor selectivity ofthese reagents. An exception worth mentioning is the regioselcctive opening of ben- xylidene acetals in carbohydi-ate (Scheme 1 1 ) . The

ods are also successfully used.

,OAc (OAc ,OAc ,OAc

reductive cleavage of disulfides with thiols o r complex hydi-ides i s also seldom used. However. an interesting application of this deblocking technique for the libel-ation of amino groups from dithiasuccinimides (Dts protecting group) i n saccharide synthe- s is was I-ecently published['"' (Scheme I I ) .

2.6. Oxidation-Labile Protecting GroupsLU ' I

The choice of oxidation-labile protecting groups is vci-y l i m i t - ed. The 4-methoxybenzyl (Mpm) and the more labile 2.4- dimethoxybenzyl (Dmpm) ethers have proved their worth 21s reagents in the synthesis of complex molecules. Both of these functions are easily removed under mild conditions with dichlorodicyanoquinone (DDQ) or with cerium(rv) ammonium nitratc (CAN) (Scheme 12). or under acidic conditions (sec SCC- tion 2.1.1).

I t is also worth mentioning that S.S-acetals of carbonyl compounds, such as 1.3-dithianes. can he cleaved after oxidation of the sulfur (Scheme 12).

OMe

1 1 DDQ or CAN

OMe

r 1

2.7. Cleavage of Protecting Groups Assisted by Heavy Metal Salts or Complexes"' ' I

The activation of protecting groups with noble metals often o ffe r s a n ad van t a geo us a 1 t e I-n a t I ve tor the t a rge t ed deblock i ng of functional groups. Thus. carbonyl compounds masked a s 1 ..i-dithiancs can be hydrolyticallq regenerated easily by treat- nicnt with stoichiomcti-ic amounts of Hg". Ag'. Cu". or TI"' salts o r alternativelq bq 1-caction with other electi-ophiles o r by oxidu- tion o f thc sulfur (see Section 7.6) .

Catalytic iunotints of Khl. I]-". and Pd" complexes and even Pd -C suffice for the removal of protecting groups containing the ally1 group. Thus. ally1 cthel-s in carbohydrates and peptides can be selectively isomerized to the acid-labile prop-l -enyl system through the action ofcalalytic quantities of Pd C 01- Kh'. o r I r" complexes. Hydrolysis of this g ro~ip is achieved under inild conditions. (Schemc 1 3 ) . T h t allyloxycarbonyl ( Aloc)

or Pd C

R = alkyl, acyl cod= 0

2062

Protecting Group Chemistry

group. allyl esters, and ally1 phosphates can be cleaved under mild conditions by Pdo-mediated allyl transfer to a variety of nucleophiles such as amines and C-H-acidic compounds (Scheme 13). As a consequence of its ready removal and its compatibility with a range of other functional groups, the allyl protecting group has become established in protecting group chemistry and is finding increasing application in the synthesis of complex natural products (see Sections 3.1.3, Schemes 23-27). 1,3-Dithianes and allyl protecting groups can also be viewed “two-stage” protecting groups (see Section 2.9).

2.8. Photolabile Protecting Groupsr9 -

Photolabile protecting groups contain a chromophore of high chemical stability that can be selectively activated by irradiation with light of a suitable wavelength. Of the many known photolabile protecting groups, the o-nitrobenzyl has been used repeatedly in the form of ethers, esters, carbonates, carbamates. and acetals (Scheme 14, see also Section 3.1.5). Two

R-0-PG I PG =

onitrobenzyl o-hydroxystyry- Z-oxo-l,2-diphenylethyl ( O W dirnethylsilyl (Desyl)

Scheme 14. Examples of photolabile protecting groups.

further interesting photolabile protecting groups are the 2-0x0- 1.2-diphenylethyl (Desyl) and the o-hydroxystyryl- dimethylsilyl (Scheme 14). Photolabile protecting groups can be cleaved under mild conditions with light of a suitable wavelength. and highly selective cleavage in the presence of other functional groups is possible by the choice of an appropriate chromophore. Despite these advantages, photolabile protecting groups are used much less frequently than other types of protecting groups.

2.9. “Two-Stage” and “Safety-Catch” Protecting Groups

The inherent (and deliberately employed) reactivity of, for example, acid- and base-labile protecting groups is often the source of undesired side reactions. Thus, masking can be (partially) lost at the wrong point in the synthesis. If several protecting groups of comparable reactivity are present in one molecule, selective removal of a single protecting group can be difficult. This problem can be avoided by the use of protecting functions that initially exist in a chemically stable form and can be converted into a labile group when their cleavage is required; these are the “two-stage” protecting groups.[331 Examples include the methylthioethyl (Mte) and the 1,3-dithianylmethoxycarbonyl (Dmoc) groups, which are insensitive towards acid and base, but which, after oxidation of the sulfur to sulfone. fragment by

REVIEWS

Stable Form - Labile Form - Cleavage

OdR base f‘ + m R oxidation ~9 - Me ,s=o \\ ,s=o 0 Me0’ Me

U rnethylthioethyl (Mte)

H N ‘ ~ H N ‘ ~

(1,3-dithiane-2-yl)methoxy- carbonyl (Dmoc)

pyridylethyl (Pyet, Pyoc)

2-brornoethyl ester choline ester (Cho)

acetoxypropyl

Scheme 15. Selected ”two-stage” protecting groups

base-induced ,&elimination (Scheme 15). The same principle applies to the 2- and 4-pyridylethyl protecting groups, which, after alkylation of the pyridine nitrogen, can be cleaved even with morpholine (Scheme 15). 2-Bromoethyl esters can be transformed into salts of the corresponding choline esters by reaction with trimethylamine. The protecting group can then be cleaved either with base or under milder conditions with the enzyme butyrylcholine esterase (see Sections 2.4 and 3.1.4). Removal of another interesting protecting group, the acetoxypropyl protecting group for amines, requires hydrolysis of the acetate, subsequent oxidation of the liberated hydroxyl group to give the aldehyde, and finally base-induced elimination (Scheme 15). This proved to be a useful alternative to classical acyl protecting groups in the total synthesis of mitomycin C.[341 Other examples of this method of protecting group cleavage are 1) the removal of 1,3-dithianes by reaction with electrophiles (or oxidation of sulfur) and subsequent hydrolysis (see Sections 2.6 and 2.7), and 2) the removal of allyl groups by a ) isomerization of the allyl system followed by acid hydrolysis or by b) formation of a ~-allylpalladium complex and subsequent reaction with a nucleophile (see Sections 2.7 and 3.1.3).

Closely related to the two-stage protecting groups are the “safety-catch” protecting groups.[351 In these systems a chemi-

2063

REVIEWS

cally stable precursor is introduced, which is converted into an activated intermediate directly before cleavage. In this case no additional reagent, such as a base or a nucleophile, is required in order to remove the protecting groups. The activated intermediate itself carries a reactive functional group, typically a nucleophile, which intramolecularly attacks the bond to the blocked function and thus causes the cleavage of the protecting group. Several examples of this technique are presented in Scheme 16. Thus, reduction of the nitro-substituted aromatic

3-(oNitrophenyl)acetyl or -propionyi X=O,NH n = 1 , 2 H

4-azidobutvrvl

4-oxoacyl

2-chloracetyl 0 NH, 0

Scheme 16. Selected "safely-catch" protecting groups.

precursor generates the aniline derivative, which then cyclizes to give the amide with liberation of the deprotected functional group. The same principle applies for azidobutyrates. Crotyl and 4-oxoacyl protecting groups react with hydrazine by addition to the a,fl-unsaturated system and by formation of a hydra- zone, respectively, thereby placing the nucleophile in the correct position. Analogously, chloroacetates are converted to substituted a-thioacetates by reaction with thiourea; subsequent cy- clization releases the unprotected functional group.

3. Strategies for the Choice of Protecting Groups

When a synthesis is planned, the choice of suitable protecting groups i s inseparable from the consideration of how one will construct the basic structure of the target molecule and how the stereochemistry will be established. The first step in planning a synthesis is the retrosynthetic analysis of the target molecule, which designates the fragments containing the groups to be protected. On the basis of the inherent lability of these intermediates one can, even at this early stage, already exclude certain

M. Schelhaas and H. Waldmann

protecting group strategies. For example, if a fragment contains a C-C double bond, one would not consider using benzyl ethers or esters as protecting groups, which must be removed by hydrogenolysis. After a successful analysis, concrete reactions, the required reagents, and protecting groups are chosen simuIta- neously. Functional groups, which, after they are introduced or formed, should remain blocked throughout the entire synthesis, will be protected with permanent protecting groups, whereas those that will be liberated at an early stage in the synthesis will be blocked with temporary protecting groups. In practice, it is often neccessary to try out alternative approaches in the course of the synthesis. One must remain alert to the fact that in such cases other protecting groups may be required. For example, if an aldol reaction is planned and strong base is required to de- protonate the carbonyl compound, any protecting groups required should be base-stable but may be acid-labile. However, if this aldol reaction does not prove satisfactory, for example because of low or undesired stereoselectivity, an alternative would be Mukaiyama's variant of the aldol reaction, in which the corresponding silyl enol ether is activated by a Lewis acid (such a case has been described by Reetz et al.[36]). Now the requirements for successful protecting groups would be completely reversed, and exchange of the previously used protecting groups for others might thus be required. It should be noted that the type of blocking can also affect the course of the planned synthesis (see Section 3.5). This example illustrates that each synthetic alternative (here an aldol reaction under basic or acidic conditions) can require its own pattern of protecting groups (base-stable or acid-stable as the case may be).

In the development of a protecting group strategy two fundamental concepts are available (Scheme 17):

- the use of orthogonally stable protecting groups - the use of protecting groups with modulated lability

The principle of orthogonal stability[371 requires that only those protecting functions should be used that can be cleaved under (as a rule totally) different reaction conditions without affecting the other functions present (Scheme 17). For example, three protecting groups A, B, and C, which are attacked by acid, by base, and by hydrogenolysis, respectively, could therefore be selectively removed in any sequence at any point in a synthesis.

In following the principle of modulated lability, the protecting groups are all sensitive to one set of conditions, but to differing extents. Consider three protecting groups A', A" and A"', all of which are acid-labile. The most acid-sensitive group, A', can be removed without affecting the other two. However, the least labile A"' cannot be removed selectively in the presence of one or both of the others (Scheme 17).

A strategy based upon the concept of orthogonal stability guarantees a great degree of flexibility in the execution of a synthesis. However, it is often not possible to find and use the requisite number of orthogonally stable protecting groups, particularly in the case of multifunctional molecules, since cleavage of one protecting group requires not only the stability of all the other protecting groups but also of the masked molecule itself under a wide range of reaction conditions. Additionally, in the last steps of a synthesis it is often not necessary that all protecting groups have strictly orthogonal stability, since only a few groups must be selectively liberated and a series of selective

2064 A n p v . Chern In!. Ed. Engl. 1996, 35, 2056-2083


1 Orthogonal Stability I

Y Y ? A B C

Modulated Lability

WWLT-rf X Y f X Y Z

A " X l f

A S A

w Y Y ? A' A" A"'

x y z T Y f y v z A" A ' A A

Scheme 17. Orthogonal stability and moldulated lability as basic concepts for the development of protecting group strategies.

deblockings extend the synthesis significantly. These disadvan- tages do not exist if one uses a set of protecting groups of similar but modulated stability. In practice, a combination of the two strategies is often employed, in which the earlier stages rely more heavily on orthogonal stability and in the latter stages the concept of similar lability is more important.

These two fundamental strategies can be augmented by auxil- iary strategies, including: - the earliest possible unification of a protecting group pattern - the introduction of "stand-ins" - the use of protecting groups to direct reactions.

3.1. The Use of Orthogonally Stable Protecting Groups

The protecting groups discussed in Section 2 of differing lability can be used in a wide variety of combinations. In this case again. there are numerous possibilities. A general answer to the question of the most convenient combinations is not available. However. from the many published syntheses one can sift out some combinations that have proved effective time and again.

3. I . I . Acid Hydrolysis/ Base HydvolysislHydvogenolysis

The combination of acid-labile, base-labile, and hydro- genolytically labile protecting groups is a frequently used protecting group strategy. In oligonucleotide chemistry, for instance, the acid-labile dimethoxytrityl ether is typically used to protect hydroxyl functions, base-labile amides mask the amino

REVIEWS

groups of the nucleobases, and base-labile phosphate esters block the phosphate groups (Scheme 18). Similarly, in solid-

Y mNH

-1base-labileJ 0 A /VNH

n A mNH

. I DMTo@ CN ' I c,

Scheme 18. Oligonucleotide synthesis with acid-labile alcohol protecting groups and base-labile linkers and amino protecting groups. R = phenyl. isobutyl. etc.

phase peptide synthesis the base-labile Fmoc group is frequently used to block the N-terminus, while an acid-sensitive function links the C-terminal carboxylic acid and the polymeric carrier (that is, an acid-labile, polymeric protecting group). The orthogonal stability of all three types of protecting groups has, for example, been employed in the synthesis of a precursor of the dolastatin cytostatics by R. C. Kelly et al. (Scheme 19).[38a1

+ ,Cost BU Pd-C,

MeOH/ THF + % - v b - , ..,

HI\, MI\, Fmoc 5"C, quant. Fmoc 7 8

U

I Dolastatin 3 ] = 11

Scheme 19. The Combination of acid-labile, base-labile, and reduction-labile protecting groups in the synthesis of a precursor of dolastatin 3 (11) by R. C Kelly et al. [38a]

2065

M. Schelhaas and H. Waldmann REVIEWS

selectively protected glutamic acid derivative 7 the a-benzyl ester was selectively removed by hydrogenolysis and then the desired bisthiazole unit was constructed. Acid-mediated cleavage of the y-tert-butyl ester in 9 opened up the possibility of converting the y-carboxyl group of glutamic acid into the amide. In both steps the Fmoc group remained intact. This group can be removed under basic conditions, if required, and the amino acid N-terminus can be

Among the classical combinations of protecting groups is the simultaneous use of acid-labile acetals for the protection of car- bony1 groups or 1,2-diols, base-labile esters, and reductively cleavable benzyl groups. This strategy is often used, particularly in the field of carbohydrate chemistry, as illustrated by the synthesis of the dimeric Lewis" antigen described by R. R. Schmidt et al. (Scheme 20).[391 In this case, the isopropylidene group of

R

/pA-\ CF3C02H CHzC12

O-CO2Me 98% OBzHo OBz

AcO 12 I OAc

HO$O-$&, * HO OBzHo OBz BF3.Etz0, CH&/ hexane, 71%

13

AcO

AcO 15 I OAc

L .

64%

M e p O B z l - 1) CF3COzH, CH,CI,, 95% 2) NaOMe, MeOH; Ac,O, pyr, 87%

4) Pd-C, H,, MeOH: NaOMe, MeOH, quant 3) HS-(CH&-SH. py / Hz0; AcZO, py, 93% I OAc

AcO 16

Galp(l-4)GlcNAcS(1-3)Galp(l-4)GlcNAc~(l-3)Gal~(1-4)Glc~1-O)-R I I Fuca(1-3) 17 Fuca(1-3)

Scheme 20. Synthesis of the dimeric Lewis" antigen by R. R. Schmidt et al. [39].

the lactoside 12 was initially removed by acid hydrolysis. Of the two liberated hydroxyl groups present in 13, only the equatorial reacts in the subsequent glycosylation with the activated trisaccharide 14. A combination of base-labile esters (acetate and benzoate), a benzyl ether, and, again an acid-labile acetal are present in the resulting pentasaccharide 15. The benzyl group in the fucose unit of 15 ensures that the correct stereochemistry is produced in the introduction of this monosaccharide (see also Section 3.5); the acetates increase the stability of the 0-fucosidic bond towards acidic The acetal protecting group was again selectively removed from the complex pentasaccha-

ride 15 by acidic hydrolysis. This made possible repeated glycosylation with the trisaccharide unit 14, leading to the complete octasaccharide 16. Finally, all the protecting groups were suc- cessively removed from 16.

As demonstrated in this example, acetals are commonly employed as temporary protecting groups, whereas benzyl and acyl protecting functions are preferred as permanent protecting groups. When all such groups are removed to give the target compound, the acyl groups are typically removed before the benzyl ethers, in order to minimize steric hindrance in the final heterogeneous catalytic hydrogenolysis. For this reason, it can be advisable to exchange benzyl for acyl protecting groups as early in the synthesis as possible (see Section 3 . 3 ) .

Examples of alcohols protected as acyclic 0,O-acetals are given in Schemes 40,45, and 5O.Oxidation-labile and acid-labile protecting groups can also be advantageously combined. In the example in Scheme 41 the oxidatively cleavable (but also acid- labile) Mpm and Dmpm ethers were combined with an acid- labile dimethyl acetal.

3.1.2. Fluoride-Labile Protecting Croups in Combination with Oxidation-Labile Functions

The 4-methoxybenzyl (Mpm) and 2,4-dimethoxybenzyl (Dmpm) ether groups, which are cleaved by oxidation to quinone methides, can be favorably combined with a range of different protecting groups. Their combination with fluoride- labile silyl ethers has proved to be particularly effective. This combination rarely gives problems, since the substituted benzyl ethers are completely inert towards the fluoride ion. The

MeO.,, OTBC

HFI CH CN 3

Scheme 21. Final transformations in the synthesis of the immunosuppressant FK506 (21) by S . L. Schreiber et al. [41].

2066 Anger,,. Chem. Int. Ed. Engl. 1996.35, 2056-2083

REVIEWS Protecting Group Chemistry

oxidants DDQ and CAN (see Section 2.3), which are used for the oxidative cleavage of the Mpm and Dmpm groups, can in the worst case attack only the most labile silyl ethers such as the TMS group. which is seldom used in any case due to its high hydrolytic lability.

An illustration of the use of Mpm ethers in concert with various silyl ethers is provided by the synthesis of the immunosuppressant FK506 (21) by S. L. Schreiber et al. (Scheme 21 ) . I 4 ' ' Two hydroxyl groups are masked as substituted benzyl ethers and four others as different silyl ethers in the advanced intermediate 18. Oxidation with DDQ cleaved the alkoxybenzyl ethers selectively, and the hydroxyl group thus liberated was then oxidized with Dess- Martin periodinane to give the corresponding diketone 19. Of the various silyl groups in 19 (for a discussion of their relative stabilities see Sec- tion 3.2.2). the most labile was removed by treatment with acid and the selectively demasked hydroxyl group was then oxidized to give triketone 20 (see Section 3.4 for the strategy of masking carbonyl groups by the temporary introduction of hydroxyl groups as "stand-ins"). The synthesis was completed by the simultaneous cleavage of the remaining silyl groups.

The combination of Mpm and silyl ethers also proved its worth in the synthesis of the immunosuppressant rapamycin by K. C. Nicolaou et al. (Scheme 22).[421 In this case, the hydroxyl

MpmO 0 MpmO OTBDMS -+ + '+ Me Me OMe Me Me

22 23

TIPS Morn0 6 Mom0 OTBDMS

1) CrCI2, DMSO, 83% 2) TIPSOTf, 98%

t

24

TIPS I ) HFI Py. 97% 2) (COCI),, DMSO

NEt,, 97% H t

25

TIPS - A ____)

26

TIPS OH

DDQ, CHCI, I H,O 25"C, 1 h, 98%

Me Me 6MeMe Me

27

TIPS 0

\ - 0 0 __I)

1- - \* Me Me OMeMe Me

28 Scheme 22. Sections of the synthesis of the immunosuppressant rapamycin by K. C. N~colaou et iil. [42].

group in the product obtained from the Cr"-mediated addition of vinyl iodide 23 to aldehyde 22 was blocked as a TIPS ether. The TBDMS group was cleaved selectively (see Section 3.2.2) and the deblocked hydroxyl group was oxidized to give aldehyde 25. which enabled a subsequent aldol reaction (25 -+ 26). Intermediate 26carries both Mpm groups and a TIPS ether, and the methoxybenzyl ethers were selectively removed by oxidation. The resulting diol 27 was oxidized to provide the dicarbonyl compound 28. The TIPS ether remained intact in this reaction sequence and was removed only at the end of the synthesis.

3.1.3. Ally1 Croups with Acid- and Base-Labile Protecting Croups

Ally1 groups can be profitably utilized in combination with a wide variety of other protecting groups, in particular acid- and base-labile blocking groups, as they are readily cleaved by means of Pd-, Rh-, and Ir-catalyzed reactions (see Section 2.7). Carboxylic acids, amines, and alcohols can be blocked as allyl esters, allyl urethanes, allyl ethers, and allyl carbonates. In the past ten years the increasing number of examples in which allylic groups are removed in crucial deblocking steps proves that this protecting group has assumed a permanent position in protecting group chemistry.

One of the first demonstrations of the effectiveness of allyl protecting groups in the synthesis of complex molecules was provided by the synthesis of glycopeptide 32 by H. Kunz et al. (Scheme 23).L431 The allyl group in the glycosylated allyl ester of asparagine 29 was transferred to morpholine in almost quantitative yield in a Pdo-catalyzed reaction. Neither the acid-labile tert-butylurethane, nor the glycosidic bond, nor the base-labile

29

H-Phe-Thr-OAII * EEDQ, 81%

30

quant.

31 D

32 Scheme23. Application of allyl esters in a glycopeptide synthesis by H. Kunz et a]. [43]. EEDQ = ethyl-2-ethoxy-I .2-d1hydroquinoline-l-carboxylate.

Angrpi . Clioi? Inr Ed En,ql 1996, 35, 2056-2083 2067


acetates of the carbohydrate moiety were attacked under these conditions.

The especially mild conditions for the cleavage of allyl esters were also used to advantage by S. Danishefsky et al. in the synthesis of the immunosuppressant r a p a m y ~ i n [ ~ ~ I (Scheme 24). Attempts to activate the carboxyl group in the advanced intermediate 33 prior to a condensation reaction resulted in lac- tonization at the tertiary OH group of the tetrahydropyranyl

11 U

Me.,,& 33

OMe

Me

All

35

Scheme 24. Section of the synthesis of rapamycin by S. Danishefsky et dl. [44]

ring. The OH group therefore had to be protected. To avoid side reactions, it was necessary to mask the carboxylic acid as an allyl ester and then to silylate the remaining free hydroxyl group in 34, leading to the doubly protected 35. At this point the carboxyl group could be deprotected. The Pdo-mediated removal of the allyl ester in 35 proceeded under such gentle conditions that neither the complex molecular framework (including the z-keto- amide) nor the acid- and base-labile TMS ether were lost or damaged.

R. Noyori et al. relied on ally1 groups to protect amines and phosphates in the preparation of oligonucleotide^^^^^ (Scheme 25). They employed 0-allyl-masked phosphoro- amidites as condensation reagents and allyloxycarbonyl (Aloc) protected nucleobases for the construction of oligonucleotides 37 on the solid phase. When the synthesis was complete, all of the allyl protecting groups in the polymer-bound oligonucleotide were removed in a single step. The DNA oligomers 38 thus obtained, which are still bound to the polymer carrier, can be used directly for biological tests or can be cleaved from the solid phase. In one example, the simultaneous cleavage of 104 allyl groups led to the 60mer 39 in an overall yield of 25 YO and in high purity. (When conventional protecting groups were used an overall yield of 6 % was obtained.)

Blechert et al. incorporated the targeted cleavage of an allyl carbonate into the synthesis of a biologically active analog of the antitumor alkaloid taxol r461 (Scheme 26). The ally1 carbonate in 40 was cleaved in almost quantitative yield without attack at the ketal or ring expansion by fragmentation of the base- labile B-hydroxyketone unit.

H

[Pd2(dba)J, PPh,, CHCI, n C4H9NH2 I HC02H

50"C, l h *

H K

completely deprotected DNA

0'

polymer-bound DNA

Scheme 25. Application of allyl protectlng groups in the synthesis of oligonucleotides by R. Noyori et al. [45]. dbd = dibenzyhdeneacetone.

41 Scheme 26. Cleavage of an ally1 carbonate in the synthesis of a taxol analog by S . Blechert et 81. 1461.

The selective cleavage of an allyl ether was employed by D. A. Evans in the synthesis of van~ornycin[~'] (Scheme 27). The Boc group in peptide 42 was specifically removed with retention of

OAll 1) CF~COZH thioanisole

HO.,

0 81-90%

I 42 OBzl

45 OBzl OBzl 44

Scheme 27. Section of the synthesis of vancomycin by D. A. Evans et al 1471. DIC = diisopropylcarbodiimide. HOBt = 1-hydroxybenzotriazole

2068 Angel<.. Chem. h i , Ed. Enai. 1996. 35. 2056-2083

Protectin& Group Chemistry - ~

the phenolic allyl ether, thus enabling selective extension of the amino acid chain to give 43. Removal of the allyl group under mild conditions provided phenol 44, and subsequent oxidative ring closure yielded the cyclic product 45.

3.1.4. Enzyme- Labile Protecting Gvoups with Acid- and Base-Labile Groups

Owing to the often distinct chemo-, regio-, and stereoselectivity of enzyme-mediated transformations, enzyme-labile protecting groups can be combined with other protecting groups that can be removed by classical chemical techniques (see Section 2.4). Enzyme-catalyzed reactions are invaluable especially when

- the substrate is so labile that only the most gentle deblocking methods are tolerated.

- the chemo-. regio-. and stereoselectivity of the .enzyme im- parts orthogonality to protecting groups which, under classical deblocking methodology, would have similar or even in- verted lability.

Both principles were utilized in the chemoenzymatic synthesis of the S-palmitoylated and S-funesylated C-terminal lipo-

@ choline A l o ~ - C y s - M e t - G l y - O - ~ ( ~ ~ ) ~ esterase Aloc-Cys-Met-Gly-OH

I B r a - I S S-pal

n-

"---Y-- 46 Pal H-Leu-Pro-Cys-OMe 47

48 '.F/

0- 49

t Aloc-Cys-OH I

50 '-Pal

H-Met-Gly-Leu-Pro-Cys-OMe I

51 '.Far

I 48 '-Far

1) AcOZ-Met-Gly-OH

2) lipase carbodamide

H-Leu-Pro-Cys-OMe

1 I r

J I O O e O d L e u - P r o - C y s - O M e I

0 '.Far

4 iipase 1

0 Leu-Pro-Cys-OMe

M e P o e o d I 52 S m

w AcOZ Far

Scheme 28. ChemoenLymatic synthesis of the S-palm~toylated and S-farnesylated C-terminal Iipohexapeptide of the human N-Rds protein by H. Waldmann et al. [24. 261

REVIEWS

hexapeptide of the human N-Ras protein 49[24, 261 (Scheme 28). This type of modified lipoprotein cannot be deblocked under basic conditions because the labile palmitic acid thioester group would be preferentially hydrolyzed. Under acidic conditions the double bonds of the farnesyl moiety are attacked. However, the C-terminus of the peptide chain was successfully deprotected by selective enzymatic hydrolysis of the choline ester in 46 without attack on the palmitic acid thioester. The observed chemoselec- tivity here is exactly opposite to that found in the nonenzymatic conversion. Extension of the peptide chain in 47 with the farnesylated tripeptide 48 yielded the desired lipopeptide 49. Alterna- tively, the N-terminal AcOZ protecting group in 52 could be removed by lipase-initiated spontaneous fragmentation under neutral conditions and without attack on the C-C double bonds. After extension of the peptide chain in 48 with a further AcOZ-protected dipeptide and enzymatic deprotection, the lipopentapeptide 51 was obtained, which afforded the acid- and base-labile Ras peptide 49 after treatment with the S-palmitoylated cysteine 50. In these enzyme-catalyzed deprotections of urethane protecting groups, the biocatalyst differentiates between the C-terminal methyl ester and the aryl acetate incorporated in the urethane group.

The advantageous properties of the enzyme-labile protecting groups also makes possible the chemoenzymatic synthesis of base- and acid-sensitive O-gly~opeptides.[~*~ 491 Thus, the C-terminal heptyl ester of the glycosylated serine derivative 53 could be selectively cleaved by lipase-mediated hydrolysis[481 (Scheme 29). Glycopeptide 54 was condensed with an N-terminal deblocked glycodipeptide to give 55, and enzymatic removal of the heptyl ester was still efficient. Compound 56, accessible in this way in high yield, was subsequently extended to provide the glycohexapeptide 57. This compound represents a characteristic

E

2-Ser-OH

54 53 - Hep

AcO OAC

4~0%

0 AcHN

AcO OAC

A c O q AcHN

b a s e M ? I Z-ker-Thr-Ala-OHep I PH 37%, 7.0 76% Z-Ser-Thr-Ala-OH 1

___t

A c O S o A c O B o

Act) 'OAc Acb b A c

AcO OAc

AcO+

56 55

AcHN H-Pro-Pro-Ala-OHep I

carbodiirnide, 62% I * Z- Ser -Thr-Ala-Pro-Pro-Ala-OHep

AcHN

57 AcO OAc

Scheme 29. C-terminal enzymatic deprotection of glycopepfide heptyl esters by H. Waldmann and H. Kunz et al. [48].

Angric Clicrn Inr Ed Engl 1996. 35. 2056- 2083 2069


fragment of a tumor-associated antigen that appears on the surface of human breast cancer cells.

Selective N-terminal cleavage of a phenylacetoxybenzyloxy- carbonyl (PhAcOZ) urethane group (analogous to the AcOZ group) in 0-glycopeptides was accomplished by action of penicillin G a c y i a ~ e [ ~ ~ ~ (Scheme 30). The enzymatic cleavage of this

0 u o penicillin G acylase N d - o r B u pH 7.5, RT, 78% * pow

L v PhAcOZ 58 AcO

PhAcOZ-Ser-Pro-OH 1

H-Ser-Of Bu (Ac),GlcNAc PhAcOZ-Ser-Pro-Ser-Of Bu I I I

(Ac)3GlcNAc condensation * (Ac)~GIcNAc GlCNAC(AC),

59 60

penicillin G acylase H-Ser-Pro-Ser-Of Bu t I I

pH 7.5, RT, 74% (Ac)~GIcNAc G~cNAc(Ac)~

61

Aloc-Ser-Pro-Thr-Ser-Pro-Ser-Of Bu __t I I I ___) O=P-OAII (AC)~GICNAC GlCNAC(AC),

62 OAll

Scheme 30. Use of the enzyme-labile PhAcOZ group in the synthesis of a hexdpep- tide sequence of a partially processed RNA polymerase by H. Wdldmann et al. [49]. RT = room temperature.

urethane protecting group in 58 yielded 59, which was condensed with a further glycosylated dipeptide to give 60. The N-terminal protecting group in 60 was removed enzymatically in a selective manner, and the peptide 61 thus liberated was finally converted into the phosphorylated and glycosylated peptide conjugate 62, a characteristic sequence of a partially processed RNA polymerase. In the enzymatic transformations described in Schemes 29 and 30, no undesired attack on the acetate esters in the carbohydrates was observed, and neither b-elimination of the carbohydrate moiety nor anomerization of the glycosidic bonds take

The stereoselectivity of enzyme-mediated reactions can also be used advantageously for the preparation of specifically functionalized and protected synthetic intermediates. An example of this is the desymmetrization of the meso diacetate 63 in the enantioselective synthesis of the indole alkaloid (-)-anthirin (66) by G. Lesma et al.[511 (Scheme 31). Diester 63 was convert-

OH - 0-Ac ---+

lipase from 0 . ~ ~ porcine pancreas

O-Ac 96%; 99% ee ti

65 u

66

Scheme 31. Example of an enzymatic conversion in the synthesis of ( - (66) by G. Lesma et al. [Sl] .

)-anthirin

ed into the monoprotected diol 64 with essentially complete selectivity by treatment with porcine pancreatic lipase. The configuration remained intact throughout the construction of the target compound 66 via intermediate 65. Further applica- t i o n ~ [ ~ ~ ~ of such biocatalyzed transformations include syntheses of s h o w d ~ m y c i n ~ ~ ~ ~ biotin,[541 an analog of thromboxane A, ,i551 r h i~ox in , [~~] neplanocin A,r571 ni~ardipin,[~*] chrysan- themic acid, permethric acid and caronic acid,[591 rifamycin,[601 compactin,[6'1 (+ )-disparlure,r621 and aphan~rph in . '~~]

3.1.5. Photolabile Protecting Groups with Other Protecting Groups

The cleavage of protecting groups by irradiation with light of a suitable wavelength lends itself well to an orthogonal protection strategy.[641 Many other protecting groups are not affected by these conditions, and thus no particularly advantageous combinations have emerged. One of the most impressive applications of this technique is found in the synthesis of the enediyne antitumor antibiotic calicheamicin 7: by K. C. Nicolaou et aLf6'] (Scheme 32). To activate the complex oligosaccharide of

67

I 1 hv, 82%

t

Scheme 32. Application of a photolabile o-nitrobenzyl protecting group in the synthesis of calichearnicin y: by K. c. Nicolaou et al. [65].

the natural product towards the coupling reaction with the aglycone, the anomeric center of the terminal carbohydrate part of the fully protected intermediate 67 had to be liberated. The o-nitrobenzyl ether function proved to be a suitable protecting group. Due to its high stability, it could be introduced at an early point in the synthesis and remained intact even under drastic conditions such as treatment with methoxide, tetrabutylammonium fluoride, bromine, and diisobutylaluminum hy- dride. However, it was easily cleaved from 67 in high yield by photolytic conditions, under which the oxime group, the glycosidic bond, the thioester, the Fmoc group, and the silyl ether all remained intact.

The rate and selectivity of the photochemical deblocking is also an integral part of the "caging" technique used in biological studies[661 (Scheme 33). In this context a inactive substrate such as 69 having a photolabile protecting group is introduced into a biological system, for example, a cell. The protecting group is removed by an intense flash of light and the active compound, in this case 70, is thereby liberated. The advantage of this method is the precise triggering of the deprotection and libera-

2070 Anpen-. Chem. Int. Ed. E n d 1996, 35. 2056-20X3


m P h + HO-P 11.0 OH \

0

Ic-AMP I 70

Scheme 3 3 . Application of a photolabile protecting group in the "caging" method. A = adenine.

tion of the active species, making pharmacokinetics measure- able, even for fast processes. The prerequisite for the use of the "caging" technique is that the photodecomposition products have minimal toxicity. The required excitation wavelength and intensity should also not damage the cell. The photolabile protecting group most frequently employed in synthesis is the o-nitrobenzyl group. Since the photochemical cleavage of this species leads to the production of the toxic o-nitrobenzaldehyde, other photolabile groups such as l-pyrenylethyl[671 and the ben- zoin are commonly used for biological applications (see Scheme 33). An exception was described by W. Mantele et al.,[691 who monitored the progress of a reaction by following the decomposition of an mi-nitro intermediate by IR spec- troscopy.

Although photochemically cleavable protecting groups offer many advantages, their use is restricted since the substance to be deblocked may not itself contain any photoexcitable functional groups. For this reason this protecting group strategy was not widely applied for a long time. In more recent developments, for example the establishment of anchor groups in combinatorial chemistry (see Section 5), photolabile protecting groups may play an increasingly important role.

3.2. Protecting Groups with Modulated Lability

Protecting groups with modulated lability are often utilized in organic synthesis, although they d o not provide the same degree of safety offered by orthogonally stable functions. In particular, this strategy is applied when several of the same type of functional group are present in the molecule to be protected for which an insufficient number of orthogonal groups is available, or when the removal of the most stable protecting group could lead to undesired side reactions. In principle, protecting groups of modulated lability can be developed for each of the classes discussed in Section 2. Acid-labile, base-labile, and fluoride- labile protecting groups have proved to be particularly suitable; oxidatively cleavable functions have more limited scope. The modulated lability of many protecting groups can be referred to in, for example, ref. [9].

3.2.1. Modulated Acid- or Base-Lability

In many cases acetals have different labilities towards acids. For instance, acyclic acetals are more sensitive than their cyclic equivalents to acidic conditions. This property was utilized by

R. Ellison et al. in the synthesis of a prostaglandin precursor[7o1 (Scheme 34). The selective removal of the dimethyl acetal in 71 proceeded in almost quantitative yield and provided the liberated aldehyde 72, which was used in chain extension. After the removal of the dithiane group, 73 was ready for ring closure, which yielded the desired functionalized prostaglandin precursor 74.

n n 5% CF&O2H I ~ :v3

__t - , :93 CHC13,0°C,

Me-0 0-Me O H

71 72

1 ) OsO,, NalO, 2) NaOH, H20 I

dioxane

AcO HO 73 74

Scheme 34. Use of acid-labile protecting groups with modulated lability In the synthesis of a prostaglandin precursor by R. Ellison et al. [70]

The principle of using protecting groups with modulated acid-lability has found repeated application in peptide chemistry (see Sections 2 and 4). This is exemplified by the synthesis of human insulin carried out by P. Sieber et al." and sketched in Scheme 35. Compound 75 bears three protecting groups of

0

m O ' E - O t Bu CF3CH2OH I

\ - HCI. pH 3.5 I lllr

Y Bpoc 75 Trt

Ot Bu Bpoc-Ot Bu

coupling s o ___t S

76 H ' 'I OfBu

90% aq.

60°C Bpoc~-Ot BU CF3CHzOH

? - S-Acm s i

S-Acm $ p

Or Bu Boc 77

coupling H-------rOt Bu - S

Ot Bu Boc ' 78

s-s 1 ) 95% aq.

S-Acm S-Acm S i 2) 12/AcOH I

I CF3C02H Boc I OtBu 8 .

Boc Ot Bu 79

s-s H I OH I ?

OH s-s ? ;

H ' 80

Scheme 35. Use of acid-labile protecting groups with modulated lability in the synthesis of human insulin by P. Sieber et al. [71].

2071


varying lability-the tert-butyl ester and the Bpoc and trityl (Trt) groups. First the trityl group was removed selectively in the presence of the Bpoc group, which is likewise very acid-sensitive. After extension of the B chain (76 -+77), the Bpoc group was selectively removed. The A chain was completed by coupling 78 with a similarly Boc-protected peptide. All the tert-butyl protecting groups in 79 were then simultaneously cleaved. After the cysteine side chain was deblocked, ring closure provided insulin 80.

While the synthesis shown in Scheme 35 proves that this methodology can be quite successful, it has not found wide- spread use in peptide chemistry due to the potential of losing protecting groups required later in the synthesis. Owing to their greater reliability, orthogonal protecting strategies are generally preferred.

The modulated based-lability of two urethane protecting groups was used by K. C. Nicolaou et al. in the synthesis of a calicheamicin-dynemicin hybrid1721 (Scheme 36) . The 2-fluo-

Me 82

Scheme 36. Use of amino protecting groups of differing lability in the synthesis of a calicheamicin-dynemicin hybrid by K . C. Nicolaou et al. 1721.

renylmethoxycarbonyl (Fmoc) group was removed from the complex glycoside 81 by treatment with diethylamine, without attack at the similarly base-labile 2-phenylsulfonylethoxycar- bony1 (Psec) group. The cleavage of this group under basic conditions later triggered the liberation of the "warhead", which is buried in the dynemicin aglycone of 82.

3.2.2. Modulated Lability of Silyl Protecting Groups

The lability of silyl groups towards acids, bases, and fluoride ions can be specifically tuned by varying the substituents on silicon. Scheme 37 indicates the relative rates of hydrolysis of

Relative stability of silyl ethers R-O-SiRS3

Actdol ysis: R3Si: Me3Si (1) < Et$i (64) < t BuMe,Si (20000) < i Pr3Si (700000)< t BuPh,Si (5000000)

Basic solvolysis: R',Si: Me3Si (1) < Et3Si (10-100) c t BuMe,Si = t BuPh,Si (20000) < i Pr3Si (100000)

Scheme 37. Relative rates of hydrolysis for silyl ethers R - 0 -SIR; (!ir;,').

various silyl ethers under acidic and basic conditions. (The order of the cleavage rates on treatment with fluoride ions is similar.) As a consequence of this range of activities, silyl ethers with modulated solvolytic activity are now commonly used in synthesis.

tert-Butyldimethylsilyl (TBDMS) ethers can be cleaved with, for example, tetrabutylammonium fluoride (TBAF), while the cleavage of the more stable triisopropylsilyl (TIPS) and the terf- butyldiphenylsilyl (TBDPS) protecting groups requires solu- tions of HF in pyridine, acetonitrile, or even water.

These clear differences in reactivity were employed by Danishefsky et al. in the synthesis of the immunosuppressant r a p a m y ~ i n ~ ~ ~ ] (Scheme 38). When intermediate 83, which con-

I ) TBAFI HOAc 2) Dess-Martin

periodinane

0 Me..,& I o e ; M e , OTlPS Me

/ -

Me OMe Me Me OTBDMS

83

Me

1) TiCl,(Oi Pr) 2) HF 1 PY *

84

Me

I Rapamycin 1 = 85

Scheme 38. Use of silyl protecting groups of modulated lability in the synthesis of rapamycin (85) by S Danishefsky et al. [44].

2012 Anpew. Chem. l n t . Ed Enyl. 1996.35. 2056-2083


tains a TMS. a TBDMS, and a TIPS ether, was treated with TBAF, the TMS and the TBDMS ethers were cleaved, but the TIPS ether remained intact. After oxidation of the liberated secondary hydroxyl group, the macrocyclic ring was closed, and finally the TIPS ether in the cyclohexane moiety in 84 was cleaved with a solution of H F in pyridine to yield the natural product 85.

The different stabilities of silyl ethers was also utilized by K. C. Nicolaou et al.[421 in their synthesis of rapamycin. Scheme 22 indicates that treatment of 24 with HF/pyridine removed only the TBDMS protecting group, while the TIPS-protected secondary hydroxyl group remained intact. A similar strategy was used in the last steps of this synthesis (Scheme 39).

TIPSO F c c o

86

TIPSO

aq. HF, CH3CN b

Me OMe Me Me

Me .,

88 Scheme 39. Use ofsilyl protecting groups of modulated lability in the synthesis of rapamycin by K. C. Nicolaou et al. [42].

Of the five silyl protecting groups present in 86, only the TES ethers were cleaved by HF/pyridine. Thus the selective oxidation of the liberated secondary hydroxyl groups to give the corresponding carbonyl groups could be carried out. The remaining, more stable silyl ethers were cleaved by treatment with H F in CH,CN/H,O, and the synthesis was subsequently concluded by Pdo-mediated coupling of the two vinyl iodides.

The differing acid sensitivity of silyl ethers allowed S. Schreiber et at. to selectively deblock an advanced intermediate

REVIEWS

in the synthesis of FK505[411 (Scheme 21). Macrocycle 19 contains TIPS, TBDMS, and TES protecting groups, of which only the TES group was removed by treatment with aqueous tri- fluoroacetic acid, allowing the selective oxidation of only one of the four hydroxyl groups.

R. A. Holton et al. took advantage of the varying lability of silyl ethers towards both bases and different sources of fluoride ions in the synthesis of the antitumor agent tax01"~~ (Scheme 40). Thus, treatment of 89 with acetic acid cleaved only

0 91

0 92

93 94

0 0 TASF: (Et2N)$ Me,SiF,

Scheme 40. Use of silyl protecting groups of modulated lability in the synthesis of taxol by R. A. Holton et al. 1731.

the TMS ether; the other acid-labile groups, the BOM acetal and the other silyl groups, remained intact. After transformation of 90 into the oxetane 91, the TES group was selectively removed by treatment with HF/pyridine. The central eight- membered ring was oxygenated as required in the position adjacent to the free hydroxyl group. Finally, the remaining TBDMS protecting group was removed with the reagent TASF (see Scheme 40; this conversion failed with TBAF) to allow the at- tachment of the side chain.

3.2.3. Modulated Oxidation-Lability

The oxidation-labile Mpm and Dmpm ethers (see Section 2.6) are attacked at different rates by dichlorodicyanoquinone (DDQ) at 0-5°C. This modulated lability can be employed advantageously in the synthesis of polyfunctional target compounds, including those containing C-C double bonds. Thus, in the course of a total synthesis of methynolide (98), 0. Yone- mitsu et al. cleaved the more electron-rich, and therefore more easily oxidized Dmpm group in 95 in the presence of an Mpm group by treatment with DDQ at 0 "C (Scheme 41).[74, 7s1

The hydroxyl group in 96 thus liberated was then oxidized to the

A n g w . (%em in l Ed Engl. 1996. 35, 20.56 -2083 2013


h

0

0

' 96

HO &:o>OH ' "., - , MpmO &"'* "0

DDQ

RT 97 1''' 0 "OH CH,CI, 1." 0 "OH

_.

(Methynolidel E 98 0

DDQ= "OcN CI CN

0

Scheme 41. Selective oxidative cleavage of the Dmpm group in the presence of the Mpm group in the synthesis of methynolide (98) by 0. Yonemitsu et al. [74,75]. PDC = pyrrdinium dichromate. RT = room temperature.

aldehyde, which cyclized to give the hemiacetal97 following the acid-catalyzed hydrolysis of the adjacent acetal protecting group. Finally, the desired natural product was obtained by oxidative cleavage of the Mpm ether at room temperature.

Such fine-tuning of lability through the introduction of substituents can also be achieved for other types of protecting groups. Thus, for example, when a nitrophenyl substituent is attached to the allyl system of an allyloxycarbonyl (Aloc) group, cleavage of the resulting 4-nitrophenylallyl (Noc) urethane with Pdo and Rh' catalysts is significantly slower than that of the simple unsubstituted allyl protecting groups.[761 As can be seen from Scheme 42, the allyl ester in dipeptide 99 can be cleaved selectively without attack on the Noc group.

Noc

Scheme42. Selective cleavage of an unsubstituted allyl ester in the presence of a nitrophenylallyl group by H. Kunr et al. 1761.

3.3. Unification of Protecting Groups

In the construction of polyfunctional molecules the tactic of using several protecting groups that must be removed under drastically different reaction conditions can lead to problems in the late stages of a synthesis, for example after successful construction of the molecular framework. First, the molecule must be stable under all of the conditions used for deblocking. This stipulation must be made in the selection of protecting groups for each subunit in the whole molecule. It is thus possible that

only a few- and under certain circumstances too few--of the available protecting groups fulfill this criterium. Second, such a strategy can lead to a significant increase in the number of steps required at the end of the synthesis, even to the point that the associated losses become crippling.

To avoid these problems, the following strategy is often followed, in particular in complex multistep syntheses. As early as possible in the synthesis, protecting groups are used that can be removed under the same conditions in order to unify the protecting group pattern as much as possible. For example, intermediates having a single type of protecting group can be de- signed and used from the beginning of a synthesis, thus automatically simplifying the problem. This strategy cannot be used if specific reactivities in the intermediates are eliminated in the course of the synthesis, or the directing effect of particular protecting groups is required (see Section 3.5). Then protecting groups in the intermediates must be removed and replaced with others that correspond to the type remaining in the molecule. Under certain conditions this can increase the length of the

0 8- TBDMSO CH(SEt), (Ph),F TBDMSO.,,

C o \ ' " Z M S

102

OTBDMS ,..OTBDMS

TBDMSO

/' 103 OMMTr

~ O T B D M S

'"OTBDMS

OTBDMS

OTBDMS

HO TBDMSO

Me0 =

t ' 0

TBDMSO OTBDMS OTBDMS

'"OTBDMS

OTBDMS

OTBDMS M p m q oM:,:~pm

Me0 w q , . , & O M p m ~

OAc ' OAc

OTBDMS

M e ~ " s d ~ ~ ~ m ~ '.OTBDMS

1) - 5)

Scheme43. Part of the synthesis of palytoxln by Y. Kishi et al. [77]. 1 ) DDQ, rBuOH/CH,CI,, room temperature (RT), then Ac,O. DMAP in pyridine; 2) HCIO, (1.18 N) inTHF, 25°C. 8d; 3 ) 0 . 0 8 ~ LiOH, H,O/THF (t:2:8), 25°C 20h; 4) nBu,NF in THF. 22°C. 2Oh; 5) AcOH/H,O (1:9), RT. 12h

2074 A n p w Chem lnr. Ed. Enql 1996, 35, 2056-2083


synthesis; however, the risk of losses is shifted toward earlier stages in the synthesis with the simpler and more readily available early intermediates.

The strategy of creating the uniformly protected intermediates, which can be completely deblocked in only a few steps at the end of the synthesis, was followed by Y Kishi et al. in the synthesis of the marine natural product palyt~xin[’~] (Scheme 43). The size of the molecule, sheer number of groups needing protection, and the long list of synthetic problems to be overcome made it very difficult to use only one type of protecting group. Intermediate 109 (Scheme 43) contains the complete and still completely protected molecular framework of palytoxin, which was formed by the coupling of fragments 101 -108. In 101, 102, 103. and 104 the protecting groups are almost exclusively fluoride-labile. 105 and 108 incorporate esters of differing base- lability. and in 107 the hydroxyl groups are protected as oxidation-labile Mpm ethers. In addition, it was necessary to protect the hemiacetal at C-47 and the diol unit a t C-100 and C-101 as acid-labile acetals. This significant unification of the types of protecting groups enabled efficient deblocking in only five steps at the end of this extremely arduous synthesis (Scheme 43).

Me

Me “Me ,t Bu

t Bu

OTES I I , 112

t Bu TBDMSO

113

1) DDQ, CH& 2) Dess-Martin Deriodinane

Me

0 ,tBu f Bu TBDMSO

114

OH

= 115

Scheme44. Synthesis of cytovaricin (115) by D. A. Evans et al. [78]. DEIPS = diethylisopropylsilyl. TCEM = trichloroethoxymethyl.

REVIEWS

The strategy of choosing all the permanent protecting groups from the same class was demonstrated by D. A. Evans et al. in the synthesis of cytovaricin (115)[781 (Scheme 44). The intermediates 110-112 used to construct the protected form of the natural product 114 carried exclusively silyl protecting groups, all of which were removed in high yield in a single step at the end of the synthesis. The conditions required were so mild that the hemiacetal formed at C-17 remained stable and did not lose water and form a diene.

S. Danishefsky et al. used the same principle in the synthesis of the enediyne antibiotic dynemicin (Scheme 45). Thus

MOM?

@O+

MOMO OLi

116 0 117

MgBr,. 0.24%. 36h *

MO#cozMoM \ / / \ OMe 15% (4 steps)

MOMO 0 OH

H O 0 O H

119 Scheme 45. Use of a single type of protecting group in the synthesis of dynemicin by S. Ddnishefsky et al. [79]. MOM = methoxymethyl.

116 and 117 were fused to give compound 118 with three MOM acetal protecting groups, from which the sensitive natural product 119 was liberated.

The protecting group pattern of an advanced intermediate was changed by K. C. Nicolaou et al. in the synthesis of calicheamicin y’, [651 (Scheme 46). The complex glycoside 123 was formed from the predominantly acyl-protected unit 120 and the intermediates 121 and 122. After the coupling, the acetates were transformed into silyl ethers, which were cleaved in the same step as the silyl ethers originating from 121 and 122 by treatment with HF/pyridine in almost quantitative yield.

In the synthesis of the glycosphingolipid Gb, (130). K. C. Nicolaou et a1.[801 swapped the reduction-sensitive benzyl ethers for the base-labile acetates and thus unified the pattern of protecting groups (Scheme 47). Because the gdlactosylfluoride 125 carried benzyl groups, its coupling with the partially deblocked glycosyl acceptor 126 yielded the trisaccharide 127 predominantly as the a-anomer. Intermediate 126 carried acyl protecting groups, guaranteeing a high degree of P-selectivity in the introduction of the sphingosine group (see also Section 3.5). At the stage of trisaccharide 127 the benzyl protecting groups were

2075


. -v

AcO 01

Fmoc . 4 Meofi oMe 123 Et'MeO TESO Me

PY THF/ CHzCIz (5:l) 96%

124 E f M e O

Scheme46. Change in the pattern of protecting groups in the synthesis calicheamicin $, by K. C. Nicolaou et al. [80] NB = nitrobenzyl.

125 126

127

1) NBS, HF/ py, 89% 2) Hz, Pd(OH)z/C

3) Ac~O, DMAP, py *

91% (2 steps)

128

?H

PivO HNK(CHZ),&H3

Pglycoside 129

HO

NaOMe, MeOH 90%

of

removed by hydrogenolysis and the hydroxyl groups thus liberated were immediately protected as acetates. The complete trisaccharide unit thus contained exclusively base-labile acyl protecting groups, which, a t the end of the synthesis, were removed simultaneously in high yield. This strategy also proved to be very effective in the construction of the trimeric Lewis" nonasaccharide.[*'I

3.4. Introduction of "Stand-Ins"

In the synthesis of polyfunctional compounds, two factors can make the choice of protecting group strategy particularly difficult: the lability of the intermediates and the fact that sufficiently different enough protecting groups might not be available for a given type of functional group. Aldehydes and ketones are generally protected as thioacetals or 0,O-acetals. An example of this is given by the synthesis of FK506 by S. Schreiber et al.,[411 a section of which is shown in Scheme 48. The terminal aldehyde was masked as a 1,3-dithiane in 131; however, all attempts to liberate the protected carbonyl group by established methods afforded the desired product in very low

Phl(OCOCF3)z MeOH / CHzCIz 84% *

.OMpm

HC(0H)ZCOzH AcOH I CHzCIz 70% *

?)Me

"'OMe OMe

130 133

Scheme 47. Unification of the protecting group pattern in the synthesis of the glycosphingolipid Gb, (130) by K. C. Nicolaou el al. [Sl] .

Scheme 48. Application of 1.3-dithiane and dimethyl acetal protecting groups in the synthesis of the immunosuppressant FK506 by S . L. Schreiber et al. [41].

2076 An.qew. Chem. Int. Ed. Engl. 1996, 35, 2056--2083

Protecting G r o w Chemistry REVIEWS

yields. Only dethioacetalization employing a hypervalent iodine reagent as a mild oxidant gave satisfactory results. Even so, the aldehyde thus liberated was not isolated directly in the free state. but rather as the dimethyl acetal 132. This very sensitive compound yielded 133 with the free aldehyde group after transac- etalization with glyoxylic acid under mildly acidic conditions. This approach is practically identical to that employed by T. K. Jones et al. in the synthesis of FK506.[821

The example just given illustrates that, despite the effectiveness of thioacetals and acetals as protecting groups, the conditions necessary for their removal often hinder their use. 1,3-Di- 01s can also be protected as silylene derivatives, which are useful replacements for the acid-labile acetals (see 114 in Scheme 44). When such choices are not available, a completely different tactic must be used.

In one increasingly popular alternative strategy a “stand-in” is introduced for the required functional group. In the case of a carbonyl group, a masked alcohol can be used, which can be deprotected and subsequently oxidized to give the required aldehyde or ketone. Although a further protecting group must be introduced in following this strategy, many more masking groups are established for the hydroxyl function.

This methodology is illustrated by the synthesis of FK506 by S. Schreiber et al.14’] sketched out in Scheme 21. The very sensitive and reactive tricarbonyl unit in 20 was constructed right a t the end of the synthesis by the deprotection and oxidation of the corresponding hydroxyl groups. The successive deblocking and oxidation prevented the formation of mixtures of products resulting from incomplete oxidation. TES- and Mpm-protected hydroxyl groups were employed as the “stand-ins” for the car- bony1 groups. while the hydroxyl groups found in the final product (20) were masked as TIPS and TBDMS ethers.

Similarly, in the synthesis of rapamycin by S. Danishefsky et al.‘441 (Scheme 38) a t a step close to the end of the synthesis, one of the three protected hydroxyl groups in 83 is selectively deblocked and oxidized to give a carbonyl group.

D. A. Evans et al. also used this strategy in the synthesis of cyt~varicin’~’] (Scheme 44). The hydroxyl group to be oxidized in 113 was present as the Mpm ether, whereas all other alcohols were blocked as silyl ethers. After cleavage of the benzylic protecting group with DDQ, the required carbonyl group was formed and finally the silyl groups removed. This approach was necessary because the hemiacetal formed in the last step is very sensitive (see Section 3.3.).

3.5. The Influence of Protecting Groups on the Course of Syntheses

One factor that should always be taken into account when planning a protecting group strategy is the potential of the protecting group, under certain circumstances, to actively influence the course of the synthesis.

For example, the ability (or lack of) of a protecting function to complex metal ions can be utilized to direct the stereochemical course of a reaction. This use of “(non)chelating” protecting groups is one of the best established tools of asymmetric synthesis.[83] Such an effect was used by J. Mulzer et in the synthesis of erythronolide B (Scheme 49). The diastereomeric

PGO OH - Me Me Me Me

134 135 + PGO OH

PG = BzI 135 : 136 = 2:l 1 B z l o ~ PG = TBDMS 135 : 136 = 5:l

Me Me

136

137 138 Scheme 49. Stereochemical directing effects of protecting groups in the synthesis of erythronolide B by J. Mulzer et al. [84].

ratio of 135 and 136 formed from the addition of propenylrnag- nesium bromide to the aldehyde 134 was dependent upon the type of ether function present in 134. When the secondary hydroxyl group was protected as its benzyl ether, this ratio was 2 : l ; however, the corresponding silyl ether led to a 5 : l ratio of 135 and 136. The silyl group hindered the formation of a 1,3-chelate leading to anti-136 and favored the development of a Felkin-Anh transition state leading to the s.vn-diol. The diastereomeric ratio could be increased further by manipulation of the protecting groups. The mixture of 135 and 136 was converted to the acetonides 137 and 138. An unfavorable 1,3-diaxial interaction of the ketone with one of the methyl groups of the acetal protecting group came into play in 138, which meant that 138 could be equilibrated to the more stable 137 by treatment with K,CO, in methanol.

BOM, MOM, and MEM ethers are typically used as chelating protecting groups (see Section 2.1 .I .). Thus, for example, M. Isobe et al. employed the directing effect of a MEM group for the stereoselective construction of a precursor to may- t a n ~ i n ‘ ~ ~ ] (Scheme 50). In the reaction of 139 with methyllithi- um, the oxygen atoms of the protecting group complex the lithium cation and thus force the attack of the organometallic reagent onto the Re side of the double bond in the vinyl sulfone.

The directing effect of protecting groups is typically used in the synthesis of oligosaccharides, where the course of the glyco-

Me3Si> S02Ph ?+ lM:\Tp] 0 - 0 7 <o!.ii-Me

Ph Me’ Ph02S SiMe,

139 SO2Ph

0 Ph Me‘

Scheme 50. Directing influence of the MEM protecting group in the synthesis of a precursor of maytansin by M. Isobe et al. [85].

2077

REVIEWS

sylation can be affected. In glycosyl donors such as 140 (Scheme 51) the ester function in the 2-position shields the un- derside of the glycosyl cation 142 formed during the glycosylation reaction. Thus, the glycosyl acceptor 143 attacks from above to form the /I-glycoside 144.[861 If the 2-position of the

CICH2C00

140

CICH2C00

68% 142 yo

Me

82% 146 Y 145

BzlO ,oBZl

B z l 0 9 ; % & BzlO 4

AcHN OBzl 147

a-glycoside OAc 1

148 B Z I O ~ % ~ G 0

OBzl I I , OH ++I

1 Tetrasaccharide I Scheme 51. Control over zip-selectivity by choice of suitable protecting groups in the synthesis of the blood group B tetrasaccharide by B. Fraser-Reid et al. [86]. Pn = pentenyl, NIS = N-iodosuccinimide.

glycosyl donor is not blocked by an acyl group capable of neigh- boring group participation, as is the case in the benzyl-protected donor 145, then the a-glycoside, in this case 147, is preferentially formed. This directing effect was used highly effectively by B. Fraser-Reid et al. in the synthesis of 147, en route to the tetrasaccharide characteristic of the human blood group B. A further example is given in the preparation of the Gb, glycol- ipid by K. C. Nicolaou et al. sketched in Scheme 47.

The type of protecting group determines not only the stereochemical course of glycoside synthesis, but also affects the reactivity of the glycosyl donor. Since esters are better electron ac- ceptors than ethers, the formation of glycosyl cations is less favored from an acyl-protected glycosyl donor like 140 than from an alkyl-protected donor such as 145. The nucleophilicity

M. Schelhaas and H. Waldmann

of the leaving group at the anomeric center is also less in the ester case than in the alkyl-protected system. To characterize this finding, B. Fraser-Reid et al. described these acyl-masked glycosyl donors as “disarmed” with respect to activation by electrophiles, while alkyl-masked donors were viewed as being “armed”.187] This concept of armed/disarmed groups has proved useful for a wide variety of different glycosyl donors.

4. The Best Protecting Group Is No Protecting Group

The examples discussed in the foregoing sections illustrate the capabilities of the protecting group techniques available today and indicate that protecting groups can also be used to influence the course of reactions. Nevertheless, an unavoidable consequence of the introduction and removal of protecting groups is that the synthesis is lengthened, and that the use of protecting groups is thus often seen as “unproductive”.r841

The number of protecting group manipulations can be kept to a minimum through the use of the differences in reactivity of similar or identical functional groups. In certain cases this can determine the course of the entire synthesis and the chosen protecting group pattern. This approach is chosen again and again in the synthesis of glycosides, for example, because reliable in- formation is available concerning the reactivity of the various hydroxyl groups in carbohydrates. R. R. Schmidt et al. applied this strategy in the synthesis of the dimeric Lewis” determinant illustrated in Scheme 20.r39] In 12 and 15. the hydroxyl groups at C-3 and C-4 of the terminal carbohydrate were protected together as an acetal. After cleavage of the isopropylidene acetals of 12 and 15, the glycosyl donor 14 reacted regioselec- tively in both cases with the equatorial groups at C-3 to give the pentasaccharide 15 and the octasaccharide 15, respectively. The introduction of a protecting group at C-4 was thus unneccessary. R. R. Schmidt et al.E881 also utilized the difference in reactivity of the C-3 and C-4 hydroxyl groups in the syntheses of the tri- and tetrameric Lewis” glycosphingolipids.

Differences in the reactivity of functional groups have also been utilized in the synthesis of oligopeptides. An example of this tactic of “minimal protection” was also used in impressive fashion by R. Hirschmann and D. F. Veber et aI.IE9’ in the synthesis of the S-protein of ribonuclease A. This peptide consists of 103 amino acids and contains all of the trifunctional amino acids with the exception of tryptophan. As indicated in Scheme 52 for the masked 21 -40 fragment 149, only the c-amino groups of lysine and the p-mercapto group of the cysteine were masked, while the side chains of arginine, aspartic acid, and the hydrox- yamino acids serine, threonine, and tyrosine remained unprotected. This strategy stands in contrast to the concept of “maximum protection”, in which the maximum number of functional groups are masked in order to avoid side reactions. E. Wiinsch et al. followed this strategy in the synthesis of the peptide hor- mone glUCdg0nrgo1 and protected the side chains of all the hy- droxyamino acids. histidine, lysine, and aspartic acid with acid- labile protecting groups. The resulting 7- 15 intermediate 150 (Scheme 52) indicates that a distinctly greater effort must be made to prepare such synthetic intermediates than is demanded by the “minimal protection” tactic.

2078 Angcic. Chrm. lnt . Ed Engl. 1996, 35. 2056-2083


Acm Z I

Boc-Ser-Ser-Ser-Asn-Tyr-Cys-Asn-Gln-Met-Met-Lys-Ser

H,N-Cys-Arg-Asp-Lys-Thr-Leu-Asn- Arg I Z

21

40 I 149 Acm

fBu f B u O t B u f B u tBu Boc t6u OfBu I I I I I I I I

NPS-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-OH 7 15

150

0 Acm. MepN? NPS:

H

Scheme 52. The "minimal protection" tactic In the synthesis of the S-protein of ribonuclease A (11 40 fragment 149) by R. Hirschmann and D. F. Veber el al. [89] and the "maximum protection'. tactic in the synthesis of glucagon (7-15 fragment 150) by E. Wiinsch et al. [90] .

While the danger of side reactions is greater when one uses minimal protection, and the number of compatible coupling techniques is reduced, the tactic of maximum protection has the disadvantage that losses in yield can occur during the removal of protecting groups, and that the protected peptide fragments are often poorly soluble or difficult to purify.

5. New Developments

Most of the protecting groups discussed in Sections 2 through 4 have been known for some time. Their usefulness has been demonstrated in a multitude of complex syntheses and they can be considered to be well-established[lO. ' (this conclusion cannot yet be drawn for the enzyme-labile protecting groups). Nev- ertheless, the development of new protecting group techniques and the improvement of existing methods continues to be the subject of intensive research in organic synthesis. The following trends can be distinguished from the large number of new developments.

5.1. Development of Protecting Groups with New Lability/Stability

New developments on protecting groups with modulated reactivity have been described for silyl ethers, in particular (see Section 2.3). but new acid-labile groups have also been successfully developed and applied. An example is the triazone protecting group for amines developed by s. Knapp et al.,[911 which blocks two N -H positions and can be easily cleaved with dilute acid. This protecting group was essential in studies by L. E. Overman et on the synthesis of the strychnine alkaloids, as illustrated by the synthesis of strychnine itself (Scheme 53) . In the precursor 151 the amino group of the aniline was masked as a triazone. which, after a domino sequence consisting of Man- nich reaction and aza-Claisen rearrangement, could be removed from 152, enabling the subsequent ring closure to give 153. If the tert-butylurethane (Boc) group or a pivalinamide is used in place of the triazone, the selective cleavage is not successful.

The application of biocatalysts has given the area of orthogo-

nally stable protecting groups new impetus. An example of this is given in Scheme 54. Peptides such as 154, which carry a

Of Bu

1) (CHzO),, 98% ~ aoH ffpy0 2) LDA, NCC02Me CN) C0,Me

MeN K NMe

HO

, N-NMe

\ ' 151 152 0

153 Scheme 53. Use of the triazone protecting group in the synthcsis of strychnine by L. E. Overman et at. [92].

H H-Phe-Trp-Gly, !*No laccase, p~ 4, o2

154

H-Phe-Trp-Gly,N,N H-Phe-Trp-Gly-OH + N2

155

Scheme 54. Enzymatic cleavage of phenylhydrazides from peptides by A. N. Semonov et al. [93].

phenylhydrazide at the C-terminus, are oxidized by the enzyme laccase to give the diimide, in this case 155, which spontaneously hydrolyzes and liberates the desired p e ~ t i d e . ~ ~ ~ ] Phenylhydrazides can be cleaved by classical chemical methods only under much more drastic conditions.

5.2. Development of Protecting Groups that Induce Alternative Selectivities in Reactions

The number of blocking/deblocking steps in a synthesis can be reduced by employing protecting groups which, upon introduction, can distinguish between several functional groups of similar reactivity. Examples of such protecting groups are the recently developed dispiroketal (DISPOKE) and cyclohexane- 1,2-diacetal (CDA) protecting groups,[14. '. 941 which selectively mask diequatorial 1 ,2-diols. In the synthesis of the trisaccharide unit 161 of a streptococcal antigen, the two OH groups in the 3- and 4-positions of the glycosyl acceptor 156 were selectively blocked and thus the axial hydroxyl group at C-2 was made available for the coupling reaction with the glycosyl donor 158 (Scheme 55).*15' The disaccharide 159 thus formed was ready for a further glycosylation; its coupling with 160 and subsequent cleavage of the CDA and the benzyl groups completed an efficient synthesis of the trisaccharide 161.

The development of reagents for the introduction of protecting groups under alternative conditions is of great interest. Re- cent resuits in this area include the introduction of allyl, benzyl, and tert-butyl ethers via the corresponding trichloroacetimi- date[951 under acidic, rather than the usual basic, conditions. The formation of benzylidene acetals, normally introduced under acidic conditions, with the help of benzylidene-l,2-dibro- mide under basic conditions[961 is also a valuable alternative.

A i i , q m . (%cni In,. Ed Enxi. 1996, 35. 2056-2083 2079


OMe E'S one would have a very effective tool for the svnthesis of EtS B d O W oligomers. T. Ogawa et al.[991 have recently described such a

system for the construction of oligosaccharides. They exploited the possibility of orthogonally activating thioglycosides and gly- cosy1 fluorides (Scheme 57). The thioglycosides 165 and 169

OBzl EtS OM. M e 0

Hod :;,LZCO2H* Ho OH HC(OMe)3 O M e

Me? 156 157

EtS

O M e I

159

Me0

1) NIS, CF,CO,H

2) AcOH / HzO t

3) HP, Pd-C H O M

Ho OH 161

Scheme 55. Synthesis of a rhamnotrisaccharide by S. V. Ley et al. [15] using the CDA protecting group. NIS = N-iodosuccinimide.

5.3. Development of Protecting Groups that Can Be Converted into Activated Groups

If it is possible to use a protecting group that can be converted into a form that actually activates the molecule for the next transformation, then protecting groups become more than just a "necessary evil" and can be seen to play a n active, positive role.

An example of the successful realization of such a principle is given by the use of protecting groups based on o-phenylenedi- a m i t ~ e ' ~ ~ ] in peptide synthesis (Scheme 56). Under basic condi-

a0 K k!JNQ pH=9-10

0 HN-0 162 I

x

164 Scheme 56. Use of protecting groups capable of activation based on o-phenylene- diamine in the synthesis of peptides by R. Pascal et a]. [97].

tions peptide derivatives such as 162 react a t the urethane function to form 1 -acylbenzimidazolin-2-ones such as 163. These activated compounds can then be coupled directly with amino acid esters and peptide esters. A further example is the use of n-pentenyl groups in carbohydrate chemistry'981 (see Section 3.5, Scheme 51). In 140 and 145 the anomeric center is protected as a pentenyl ether. Treatment with N-iodosuccinimide and triethylsilyl triflate converts the stable, protected 140 and 145 into the activated glycosyl donors 141 and 146, respectively.

If the principle of converting protecting groups to activating groups can also be applied to doubIy orthogonal systems, then

HO-(-'&F 166 Roosph+ I NIS /TfOH (AgOTf)

1 HOG;:

165

R O - O O O F 167 - l"."clzHo~;o AgC104

R O ~ O ~ O ~ S P h ---t 1 NIS / TfOH 169 (AsO-rf)

~o-(-Jo~o~o~F

171

Scheme 57. Construction of oligsaccharides by T. Ogawa et al. [99] using orthogonal activation. NIS = N-iodosuccinimde, TfOH = trifluoromethanesulfonic acid.

were converted into reactive glycosyl donors with N-iodosuccinimide and trifluoromethane sulfonic acid or with silver(1) tri- fluoroacetate. The configuration of the anomeric center of the fluorosugar remained stable under these conditions. However, when bis(cyclopentadieny1)hafnium dichloride and silver(1) perchlorate were used, only the glycosyl fluorides 167 and 171 were activated. This switchable activation and direct glycosylation allows a rapid and elegant synthesis of oligosaccharides. The strategy is highly efficient, and it can be expected that further combinations of protecting groups capable of orthogonal activation will find use.

5.4. Development of New Anchor Groups for Solid-Phase Synthesis

In the synthesis of oligopeptides and nucleotides on polymeric supports, the terminal monomer is attached to the solid phase by an anchor group. The anchor groups are generally derived from protecting groups developed for solution-phase applications. Solid-phase synthesis can thus be understood as synthesis with polymer-modified protecting groups.

Synthesis on polymeric supports has found particular interest due to the development of combinatorial chemistry."001 The anchor groups used in solid-phase oligopeptide and nucleotide

chemistry often cannot be directly applied to the synthesis of other types of compounds. With the growing application of combinatorial techniques, the demand for new anchor groups will increase, which will be defined by the requirements of combinatorial chemistry in general, as well as by the properties of the target compounds. A representative example is given by the

2080 Angel,.. Chem. In!. €<I. Engl. 1996. 3s. 205C-2083


work of S. Fodor et al.,['o'l who have combined modern protecting group chemistry with photolithographic methods for the parallel synthesis of oligopeptides and oligonucleotides on spa- tially well-defined regions of a solid support (Scheme 58) . The

lhVl

YG YG YG YG - deprotection ? ? ? ? A-PG

YG YG NH NH NH NH photo- NHz NHZ NH NH

\ \ \ \ \ \ \ \ - \\\\T\\\-

m

Scheme 58. Light-directed parallel synthesis of oligomers developed by S P. A Fodor et al. [ lo l l .

surface of the support was initially derivatized with photolabile protected amino functions. Certain areas of the surface were then covered with a mask and the whole was then irradiated. Only the protecting groups in uncovered areas of the surface were removed, leaving free amino functions. These were chemically coupled with photolabile animo acid derivatives. By using another mask, other regions can be selectively deblocked and converted. This process allows a defined sequence to be pre- pared on a given x e d of the surface.

6. Outlook

The continuous development of new protecting group techniques over the last decades resulted in most of the strategies discussed in this review and has contributed substantially to the impressive achievements in organic synthesis today. The successful applications of the silyl and ally1 protecting groups in complex syntheses are particularly good examples. The authors are of the opinion that the potential of biocatalysts is equally vast. Basic methods relying on these systems have been developed in many areas and all that is lacking is definitive proof of their performance in demanding synthesis.

The development of more efficient protecting group techniques, relying, for example, on differences in reactivity between similar functional groups (see Section 4) and on new reagents with alternative reactivities, stabilities, and selectivities, continues to be the focus of attention (see Section 5 ) and will certainly lead to new protecting group strategies. Protecting group chemistry will thus continue to provide organic synthesis with great impetus in the future and open up new possibilities.

The basis and motivation ,for this review was research carried out at the Universities of Mainz, Bonn, und Kurlsruhe aimed at developing and establishing enzymatically cleavable protecting groups (see re6 / 21 ] ) . Active participants in this work were (in alphabetic order) : Peter Braun, Alain CottP, Stephanie Gabold, Simone Glonisda, Axel Heuser, Yolker Jungmunn, Thomas Kappes, Bruno Klaholz, Karsten Kuhn, Edgar Niigele, Torsten Pohl, Armin Reidel, Jorg Sander, Bernd Sauerbrei, Michael Schelhaas, Dagmar Sebastian, and Paul Stiiber. We are grateful to the Deutsche Forschungsgemeinschaft, the Fonds der Chemis- chen Industrie, the Bundesministeriurn fur Bildung und Forschung, BASF AG, Boehringer Mannheim GmbH, and Degussa AG ,for funding our research.

Received: December 15. 1995 Revised version March 11. 1996 [A14SIE]

German version: Angew. Chem 1996, 108, 2192-2219 Translated by Dr. D. Macqudrrie, York (UK)

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[XI Peptide and nucieotide chemistry are, however, exceptions The most advantageous combinations of protecting groups and strategies for the synthesis of oligopeptides and oligonucleotides have often been commented on in the relevant publications and textbooks (for examples see Schemes 35 and 52). Because the types of functions requiring protection in these classes of compounds is limited and the number of reactions to be carried out is restricted, the problem IS more easily defined in this area of synthesis than in the stereoselective synthesis of a complex natural product. For discussions of protecting group strategy in peptide synthesis see for examples refs. [35, 371, and refer- ences therein, or J. Jones, The Chemical Svnrhrsis of Pi,ptii/cs, Clarendon, Oxford. 1992; Meihod in Moleculur Eiolog!, Vol 35 Pqt ide Synrhesis Prorocols (Eds.. M. W. Pennington. B. M. Dunn). Humana Press, Totowa, NJ (USA), 1994: S. Sakakibara. 5iopolymer.s lPepIid~~ Scimcc,) 1994. 37, 17-28.

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