Polymeric Reagents

3 Polymeric Reagents ERICH C. BLOSSEY Rollins College, Winter Park, FL, USA WARREN T. FORD Oklahoma State University, Stillwater, OK, USA 3.1 INTRODUCTION

81

3.2 POLYMER SUPPORTS

82 82 82

3.2.1 Structure and Morphology 3.2.2 Functionalization of Polymers 3.2.3 Experimental Methods

85

3.3 PEPTIDE AND NUCLEOTIDE SYNTHESIS 3.3.1 Solid Phase Peptide Synthesis 3.3.2 Oligonucleotide Synthesis

87 87

3.4 POLYMERIC REAGENTS

92 92

90

3.4.1 Analogues of Hygroscopic, Pyrophoric and Explosive Reagents 3.4.2 Analogues of Toxic Reagents 3.4.3 Analogues of Odorous Reagents 3.4.4 Recyclable Reagents 3.4.5 Reagents and Catalysts for Stereoselectiue Reactions 3.5 ION EXCHANGE RESINS, ACIDS AND BASES 3.5.1 Ion Exchange Resin Reagents 3.5.2 Acidic Ion Exchange Resins As Catalysts 3.5.3 Tertiary Amine Catalysts 3.5.4 Polymeric 4-( N,N- Dialkylamino)pyridines 3.5.5 Phase Transfer Catalysts

93 95 96

97 99

99 101 102 102 10$

3.6 REACTIONS PROMOTED BY POLYMERIC ENVIRONMENTS

3.6.1 Kinetically Isolated Sites of Reaction 3.6.2 Polymeric Protecting Groups

107 107 110

3.7 CONCLUSIONS

111

3.8 REFERENCES

111

3.1 INTRODUCTION Polymeric reagents and catalysts have evolved from the polymers used in ion exchange and in solid phase peptide synthesis. Most ion exchange resins are prepared by functionalization of crosslinked polystyrenes, and are used for water purification and as acidic and basic catalysts.' Peptides are synthesized on similar polystyrene supports." 3 Multistep modifications of polymers are used to produce non-commercial reagents and catalysts. 4 - 1 3 However, peptide and nucleotide syntheses still provide the best-developed examples of polymeric reagents, and ion exchange resins are the most widely used polymer-supported catalysts. This chapter describes principles and applications of polymeric reagents with emphasis on reagents and catalysts that are commercial, or can be prepared quickly from commercial materials. Only the most widely used peptide and oligonucleotide syntheses are described, although there is a wealth of other useful reagents in those fields. Uses of functional polymers for chemical separation 81

82

Polymeric Reagents

processes, for immobilization of enzymes and for controlled release of drugs have been omitted, as have most polymer-supported analogues of homogeneous transition metal catalysts. 10- 13 The primary advantage of most polymer-supported reagents and catalysts is ease of separation. Polymer beads are filtered from batch reaction mixtures and can be used in flow reactors, thus avoiding the need for product isolation by extraction or chromatography. Polymeric analogues of toxic and odorous reagents are safer and easier to handle. Some polymeric reagents and catalysts give chemical selectivity quite different from the soluble analogues. Improved understanding of the polymers and the reagents has improved the design of polymeric reagents for specific reactions. The major disadvantages of polymeric reagents are their greater expense, due to extra synthetic steps required to make and use them, and the difficulty of analysis of polymeric species. This chapter stresses examples in which the ease of separation, safety, or selectivity of the polymeric reagent provides advantages over soluble reagents. First the nature of the polymer supports will be described to provide a foundation for understanding of polymeric reagents.

3.2 POLYMER SUPPORTS 3.2.1 Structure and Morphology The most common supports are insoluble particles of polystyrenes (PS), cross-linked with divinylbenzene (DVB), and silica gel (SG). Soluble polymers have been used as supports and separated by precipitation or by ultrafiltration. 14, 15 Insoluble PS beads are prepared by suspension polymerization. They can be either microporous or macroporous (synonymous with macroreticular).16-18 Typical average particle diameters are 50/-lm for peptide synthesis and 500/-lm for ion exchange. PS beads are used in the form of solvent-swollen gels. The micropores are created by solvent, and removal of solvent collapses the pores. A macroporous polymer retains pores in the dry state and may have as much as 700 m 2 g-1 of internal surface. The macropores are created during polymerization by a solvent from which the polymer precipitates as it is formed. A macroporous polymer is usually, but not necessarily, highly cross-linked. In a good solvent, the polymer phase of a macroporous PS also becomes a microporous, solvent-swollen gel. Silica gel is a macroporous polymer that precipitates from water or aqueous alcohol as it is formed from silicic acid, Si(OH)4' or tetraethyl orthosilicate, Si(OEt)4.19,20 The network structure is completed by removal of water and ethanol after gelation. The dried silica is more highly crosslinked than PS-DVB, because each silicon atom is tetrafunctional. It swells even less than poly-DVB resins, and commonly has 300-700 m 2 g-l of internal surface.l? In a swollen, microporous PS reagent the functional groups are mostly within the gel phase. In a macroporous PS they may lie only on the internal surface or both on the surface and within the gel phase. The functional groups are only on the surface of silica gel. Silica-supported heterogeneous catalysts are used at 400-500°C for petroleum cracking and reforming. Polystyrene begins thermal decomposition at 250°C, 21 but that does not affect its utility as a support that is normally used at < 150 °C.

3.2.2 Functionalization of Polymers PS has been functionalized with many different reactive groups. Schemes 1 and 2 show the most common methods. Table 1 lists PS resins that have been offered commercially. Most are beads crosslinked with 1% or 20/0 DVB. The common sulfonic acid, quaternary ammonium and tertiary amine ion exchange resins are available in macroporous form with up to 200/0 DVB cross-linking. Table 2 lists other commercial polymers that have been used as reagents or catalysts. Table 3 lists other polymers that have been used as reagents or catalysts after modifications in research laboratories. Polystyrene has been the most widely used support for reagents because it is available in bead form from suspension polymerization, is easily functionalized by aromatic substitutions, and contains no other reactive sites that could interfere with subsequent uses. Many other methods of functionalization of PS in addition to those in Schemes 1 and 2 are known.t": 8,9,24 - 30 Most PS reagents contain 1.0-4.0 mmol g-1 (DF 0.1-0.7) of functional groups. A high degree of functionalization (DF) does not necessarily mean an efficient reagent, because all functional groups may not be reactive. In the first solid phase peptide syntheses chloromethylated PS (1; Scheme 1) was converted to the polymeric benzyl ester of an N-protected amino acid.' ' More elaborate attachments are used now,

o

Polymeric Reagents

0 S

1

0

# DVB

m +P CH

m+p

2

83

+ S +DVB /

/(ref.23)

CICH 20Me Lewis acid (ref. 22)

It

!

Me 3 N

(ref. 1)'

0-CH2NMe2

0-CH2NMeJCl-

(2)

(3)

weakly basic anion exchange resin

strongly basic (in OH- form) anion exchange resin

Scheme 1

+ S + DVB

I

H 2C=CH(CH 2)"Br, n = 9,15,21

CF 3S03 H (ref. 25)

9 SOJH ~

.. H,SO, (ref. I)

(5)

strongly acidic cation exchange resin

Br

TI(OAch (ref. 26)

BunLi

~

Me2NCH2CH2NMe2 (ref. 26)

0(6)

BunLi

\

LiPPh,

,,\or.28)

(ref. 27)

,

L 0-

Li

C1PPh, (ref. 26)

(7)

•

f;;\ PPh ~

, 2

(8)

Scheme 2

such as benzhydrylamine resins (9, 10; Table 1) and acyloxymethylphenylacetamidomethyl (acyloxymethyl-Pam) resin (14). Peptide syntheses with PS supports in batch reactors are automated. 2,3

RC02CH20H2CONHCH2----0 (14)

Silica gel surfaces are modified for reagents and catalysts with silane coupling agents as in Scheme 3.3 2 , 3 3 Each silane could be bound to the SG surface with one, two, or three Si-O bonds, but the exact structures of the linkages usually are not known. DNA syntheses are performed with SG or controlled pore glass (CPG) supports.

Polymeric Reagents

84

Table 1 Commercial Functionalized Polystyrenes -(CH 2CH)n-

616~~ 5

.

~

3

4

Structure 4-CH 2CI (1) 3- and 4-CH 2CI (1) 4-CH 20H 4-CH 2NH 2 4-CHPhNHtCI- (9) 4-CH(4/-MeC 6H 4)NHtCI- (10)

Uses Reagents, catalysts Reagents, catalysts Reagents, catalysts Reagents, catalysts Peptide synthesis Peptide synthesis Peptide synthesis

4-Br (6) 4-Cl 4-S0 3H (5) 4-S0 3Na 4-CH 2NMe 2 (2) and complex with BH 3 4-CH 2NR2

Reagents, catalysts Reagents, catalysts Catalysts, ion exchange Ion exchange Reagents, catalysts, ion exchange Reagents, catalysts, ion exchange

1\ "----J°

N

Catalyst 4-CH 2NMetX- (3) X - = F-, CI-, Br-, 1-, CN-, SCN-, MeCOS -, CO~-, Br; , BHi, BH 3CN-, HFe(C0 4 ) - , HCrO~-, IOi, NO; 4-CH 2NMe 2CH2CH20H CI-

Ion exchange

4-CH2NHCOCH20COCH2Br

Peptide synthesis

4-CH 2NBu 3 CI4-CH 2PBu 3 CI4-(CH 2)6 NBu 3 Br4-CH2(OCH2CH2)nOH 3- and 4-PPh 2 (8), and modified with RhCI(PPh 3 h, RhBr(PPh 3 h, Pd(PPh 3 )4 ' RuCI(PPh 3 h Rose Bengal AICI3 (structure in resin unknown)

Phase transfer catalyst Phase transfer catalyst Phase transfer catalyst Catalyst Reagents, catalysts

Reagents, catalysts, ion exchange

Photosensitizer for 10 2 formation Catalyst

Table 2 Commercial Polymeric Reagents and Catalysts

Structure -{CH2CH)n~ (11), and modified with HCI, HBr

6

Uses Reagents, catalysts

Reagents, catalysts

Polymeric Reagents

85

Table 2 (continued)

Uses

Structure Poly(4-vinylpyridine-co-styrene)

Reagents, catalysts Reagents, catalysts

Poly(N -vinylpyrrolidinone)

-f(CF2CF 2)nCFCF 2-1x

I

[(OCF2CF)mOCF2CF2S03H] (Nation) (13)

I

CF 3

Reagents, catalysts

(CH 2CH2)n, surface oxidized, with C0 2H, CI, or S02CI groups (CH 2CH2NH)n, Pd HO(CH 2CH20)nH MeO(CH 2CH20)nMe -(CH 2CH)n-

trl\o)

Reagents, Catalysts Reagents, Reagents, Reagents,

catalysts catalysts catalysts catalysts

c:> LJ

rO~

H2~.~0

6 I

~O ? ~OV

Me

Me

Me

H-~iO-(~iO)n-~i-H I

Me

I

Me

Reagents

I

Me

Cellulose: 2-carboxymethyl, 2-diethylaminoethyl, 2-triethylammonioethyl Agarose: 2-carboxymethyl, 2-diethylaminoethyl, 2-triethylammonioethyl -(CH

Reagents, catalysts

21H)nC0

Chromatography, ion exchange Chromatography, ion exchange Ion exchange

2H

Me

I

-(CH 2C)n-

I

Ion exchange

C0 2H -(CH 2CH)nI C0 2CH2CH2NMe 2, and complex with BH 3

Reagents, catalysts, ion exchange

Ion exchange

3.2.3 Experimental Methods Reactions with insoluble polymeric reagents are conducted as stirred mixtures in the same manner as reactions with soluble reagents. A microporous polymer usually is swollen for efficient use. Macroporous PS and SG with lipophilic surfaces may require wetting with a water miscible organic solvent before use in water. After reaction the polymer usually is filtered with a glass frit. The frit can

Polymeric Reagents

86 Table 3

Other Polymer Supports for Reagents and Catalysts

Ref

Structure, use

Poly(3-alkoxycarbonyl-2-oxazolones), amino protecting reagents Polyamides with bound imidazole and phenylhydroxamic acid as catalysts Copolyesteramides with poly(ethylene oxide) segments as phase transfer catalysts Polybutadiene, transition metal catalysts Epoxy resins, chloromethylated Polyethylene oligomers with terminal functional groups Polyethylene single crystals, catalysts Poly(ethyleneimine), branched Poly(ethyleneimine), branched, silica composites Poly(ethyleneimine), linear Poly(ethylene oxide), terminal functional groups, linear 2,4-,2,6- and 2,10-ionenes [(NMe 2(CH2hNMe2(CH 2)n)], 20H-, n=4, 6, 10, soluble Poly(isocyanides), -{C},;-, R, R' = groups in amino acids and peptides

II

NCHRC0 2R' Polyphosphazenes, substituted with steroids or transitional metal complexes, reagents, catalysts Polyu.-Iysine)

Poly(2,6-dimethyl-l,4-phenylene oxide), chloromethylated Poly(p-phenyleneterephthalamide) (Kevlar), impregnated transition metal catalyst Polypropylene, isotactic, radiation grafted, transition metal catalyst Poly(styrene-co-2-hydroxyethyl methacrylate) and similar copolymers with chiral ligands, catalysts Polysulfone (from di(4-hydroxyphenyl) sulfone and bisphenol A), chloromethylated Polyureas based on 2,2'-bipyridyl and on dibenzo[18]crown-6-ether Polyurethanes based on 2,2'-bipyridyl Poly(vinyl alcohol), transition metal catalysts Poly(vinylamine) Poly(vinyl chloride), transition metal catalyst Poly(benzimidazole), transition metal catalyst aT. Kunieda, T. Higuchi, Y. Abe and M. Hirobe, Chern. Pharm. Bull., 1984, 32, 2174. b T. Kunitake and Y. Okahata, Macromolecules, 1976, 9, 15. C F. Montanari, M. Penso, G. Della Fortuna and A. Re, Gazz. Chim. Ital., 1985, 115,427. d K. G. Allum, R. Hancock, I. Howell, R. Pitkethly and P. Robinson, J. Organomet. Chern., 1975,87, 189. e W. H. Daly, Makromol, Chern.. Suppl., 1979,2,3. f D. E. Bergbreiter, ACS Symp. Ser., 1986, 308, 17. g B. Gordon, III, 1. S. Butler and I. R. Harrison, J. Polym. Sci., Polyrn. Chern. Ed., 1985, 23, 19. h W. M. Brouwer, P. Piet and A. L. German, J. Mol. Catal., 1985,31,169. i G. P. Royer, W.-S. Chow and K.-S. Hatton, J. Mol. Catal., 1985,31,1. j T. Saegusa,A. Yamada and S. Kobayashi, Polymer J., 1979,11, 53. k K. Geckeler, V. N. R. Pillai and M. Mutter, Adv. Polym. Sci., 1981, 39, 65. I H. G. J. Visser, R. J. M. Nolte, 1. W. Zwikker and W. Drenth, J. Org. Chern., 1985, 50, 3133, 3138. mH. R. Allcock, Chern. Eng. News, 1985, 63, 22. n G. Cum, R. Gallo, S. Ipsale and A. Spadaro, J. Chern. Soc., Chern. Cornrnun., 1985, 1571. OF. L. Hartley, Br. Polym. J., 1984, 16, 199. P R. Deschenaux and J. K. Stille, J. Org. Chern., 1985, 50, 2299. q K. Zhang, S. Kumar and D. C. Neckers, J. Polym. Sci., Polyrn. Chern. Ed., 1985, 23,1293. r N. H. Li and 1. M. J. Frechet, J. Chern. Soc., Chern. Commun., 1985, 1100.

@-OH

+

(ROhSi(CH 2 ). X or

@-OJi(CH 2h X

I

ROSi(Meh(CH 2)"X

= Me, Et; n = 2,3; . /~\ X = NH2,NR2,NCO,CI,Br,I,SH,PPh2,-OCH2CH-CH2' R

Scheme 3

a b c d e f g h j k h I m

h e n o

p e q q d h d

Polymeric Reagents

87

become clogged with powdered bead fragments. Faster filtration is attained by use of pressure instead of vacuum, and by agitation of the mixture to prevent settling of powder into the filter pores. Washing of the particles with a good solvent for the polymer removes adsorbed compounds. A swellable polymer may require alternate washing with good and poor solvents. Isolation of dry polymeric reagent is aided by use of a poor solvent for the last wash; a good solvent may be retained even under vacuum at a temperature above its boiling point at atmospheric pressure. Reaction mixtures should be stirred or shaken. A magnetic stirring bar sometimes crushes PS beads to powder against the wall of the flask. Both PS beads and SG can be used in flow reactors. The rates of many polymer-supported reactions are limited by mass transport processes as well as chemical reactivity.': 34 Even with efficient mixing, the rate of reaction can be controlled by either of two limiting mechanisms.V (a) In a process limited by intrinsic reactivity, the reagent diffuses into the particle much faster than reaction occurs. Reacted sites are distributed uniformly throughout the particle. (b) In an intraparticle diffusion-limited process reaction occurs as the reagent diffuses into the particle. Partially reacted particles consist of a reacted shell on the outside and an un reacted core. Analogous mechanisms apply to polymer-supported catalysts. There are active sites throughout the gel phase in a reaction controlled by intrinsic reactivity, but the active sites are only on the surface in the limit of fast reaction with slow diffusion. In a cross-linked polymer not all chemically identical structures are equally reactive. Polymeric reagents may contain some completely unreactive sites.:" To overcome this problem excess polymeric reagent is used in a reaction that forms a soluble product, and excess soluble reagent is used with a polymeric reagent that is only partly functionalized to drive to completion the formation of a polymer-bound product. Structures of polymeric reagents and catalysts are assigned by analogy to low molecular weight compounds. The extent of reaction may be determined by elemental analysis of a heteroatom in the functional group, expressed as mmol of functional group per gram of dry polymer. It is useful also to consider the DF of PS, the fraction of aromatic rings functionalized, or the percent ring substitution (%RS). DF of starting material and DF of product are required for calculation of the yield of conversion of one polymer-bound group to another. Weight changes of the insoluble polymer have been used to calculate yields by attributing all changes to the desired chemical reaction, but the method is fraught with errors due to incomplete recovery of the polymer and to incomplete removal of adsorbed solvents. The most accurate methods of determination of polymer-bound functional groups are based on specific quantitative chemical reactions. For example, chloromethyl PS (1) is analyzed with ± 1% accuracy by reaction with pyridine or trimethylamine and titrimetric determination of the liberated chloride ion. IR and UVjVIS spectra of polymeric reagents are obtained with KBr pellets and solvent mulls. Liquid state I3C NMR spectra with line widths as small as 5 Hz (at 25 MHz) can be obtained with swollen gels.?" All common magnetic nuclei can be detected, but the range of chemical shifts in 1 H spectra often is too narrow to overcome the loss of resolution due to broad lines. Less swellable polymers can be analyzed by cross-polarization and magic angle sample spinning (CP-MAS) solid state NMR spectroscopy." Functional groups bound to SG and to macroporous PS can be detected by liquid state NMR methods if they are highly solvated and tethered to the support by a long chain. Otherwise the CP-MAS method is required.

3.3 PEPTIDE AND NUCLEOTIDE SYNTHESIS 3.3.1 Solid Phase Peptide Synthesis The synthetic method most often used with polymer supports is solid phase peptide synthesis (SPPS),2,3 first described by Merrifield." and by Letsinger t" in 1963. Merrifield's original premise is that amino acids can be added one at a time to form a peptide of any desired sequence when one end of the polypeptide chain is attached to an insoluble gel support. After assembly of the desired sequence of amino acids in the gel, cleavage of the chain from the gel provides a solution of the finished peptide. Production of a homogeneous peptide with no sequence deletions or chain truncations requires that each step of the synthesis proceed in 100% yield. Insoluble polymersupported peptides allow the use of large excesses of the reactants in the solution to drive the deprotection and coupling reactions to very high yields and allow the recovery of unused reagents by filtration from the gel. The method avoids time-consuming purifications of intermediates, since the resin-peptide is simply isolated by filtration from the starting materials. The method permits synthesis in a single reaction vessel, and repetitive steps can be performed on a semi or totally automated basis. 2,3 Up to six residues can be synthesized per 24 h. PS 6-0*

88

Polymeric Reagents

Scheme 4 shows the general principles of SPPS using the original 1-2% DVB-cross-linked chloromethyl resin (1).3 Typical resins for peptide synthesis contain 0.20-0.75 mmol Cl s" (DF 0.02-0.08). The chloride of (1) is displaced by a trialkylammonium or cesium salt of the first Nprotected amino acid. The N-protecting group B' most often is t-butoxycarbonyl (Boc). If the amino acid side chain, R x , contains another functional group, such as hydroxyl, amino, thiol or carboxyl, that function is also protected by a group B, which must be stable during the coupling reaction, yet be labile at the conclusion of the synthesis to permit liberation of the completed peptide. Often B is a benzyl group. The Boc group is removed by treatment with acid, such as 250/0 trifluoroacetic acid in dichloromethane, in which the protecting groups on the side chains (B) are stable. The second amino acid with blocking groups is coupled via its carboxyl group to the free amino group of the polymersupported amino acid, normally with the aid of a dehydrating agent such as dicyclohexylcarbodimide (DCC). The cycle is repeated by deblocking the terminal amino group and coupling the third, and subsequent, amino acids to the support. Failure to obtain 100% yield in either the deprotection or the coupling step results in incomplete peptides. A sequence deletion occurs when one or more amino acids are omitted due to incomplete deprotection or to incomplete coupling of an amino acid. The synthetic cycle normally resumes after one or more such deletions. Truncated peptides arise when deprotection of a terminal amino acid fails, or when some of the peptide chains become inaccessible for further reactions. Completion of the amino acid sequence is followed by cleavage of the peptide from the polymer. The usual cleavage reagents, such as HF, may also remove blocking groups (B) from the side chain.

+

B'NHCHR t (B)COOH

----@

CICH 2

attachmentl

B'NHCHR, (B)COOCHcB deprotection

1

CF,CO,H, CH,Cl,

H 2NCHR 1 (B)COOCH2-G coupling

1

B'NHCHR,IB)CO,H, DCC

B'NHCHR 2(B)CONHCHR 1 (B)COOCH2-G repealed deprotection and coupling

1

B'[NHCHRx(B)CO].OCH2~

1

cleavage and deprotection HF

H[NHCHRxCO]nOH polypeptide Scheme 4

The acidic conditions of the deblocking steps may cause loss of up to 1% of the peptide from the support in each cycle. For syntheses of long polypeptides a larger difference in reactivities toward acid of the N-blocking group and the resin-peptide bond is required. Solutions to this problem involve a more labile amino-blocking group2, 3 or a more stable peptide-to-polymer bond."? More labile amino-blocking groups include 2-(4-biphenylyl)propyloxycarbonyl (Bpop; 15), 2-(3,5-dimethoxyphenyl)propyloxycarbonyl (Ddz; 16),or 2-phenylpropyl-2-oxycarbonyl (Poe; 17). These groups permit the use of more dilute acid solutions for deprotection. A support that provides a more stable peptide-polymer linkage is the Pam resin (14).40,41 Another solution to the problem of premature cleavage of the peptide from the support is the use of an amino blocking group, such as 9-fluorenylmethyloxycarbonyl (Fmoc; 18),42 that is base labile, along with an anchoring bond thatis. cleaved by acid, such as in (19). This method is called an orthogonal approach." 3since the side chain

Polymeric Reagents

89

(16) Ddz

(15) Bpop

(17) Poe

o H

"

C·H20C-

(18) Fmoe

groups and the anchoring bond are totally resistant to the basic conditions used to cleave the aminoblocking group B'. In the early work in SPPS there were assumed to be support-imposed steric restrictionsf' to the stepwise synthesis, based on closeness of the.peptide to the polymer backbone.t" or temporary steric occlusion of the terminal amino acid with the polymer chain/" A thorough study'" showed no significant effect of distance from the support or of peptide loading on the synthetic efficiency of peptide chain lengths of up to 60 residues and peptide-to-polymer ratio of 4:1. Couplingdeprotection steps had an average yield of 99.6% per cycle, based on a complete analysis of deletion (and truncation) peptides.t" Several large, complex peptides have been synthesized with PS supports. Examples include the biologically active murine interleukin-3 (a 140 amino acid peptide that has two disulfide bridgesj,"? rat and human TGF-a (50 amino acid peptide with three disulfide bridgesj.r" and murine EGF (53 amino acid peptide with three disulfide bridgesj.t" All of the foregoing discussion of SPPS concerns PS gels. PS and polypeptides have dissimilar solvation properties. If the support and the peptide are not both well solvated, some peptide chains may become unreactive, because reagents cannot diffuse to the reaction sites. Poly(N,N-dimethylacrylamide) (PA) supports such as (20), shown in Scheme 5, have been successfully used in a number of syntheses of peptides. 51 - 55 The PA supports have a volume-swelling factor of approximately 10 in most polar organic solvents. The more polar PA allows the synthesis to be performed entirely in N,N-dimethylformamide, a good solvent for both the gel support and the peptide. Dichloromethane, a good ~ CONMe2

+

~

CO~CH2C02Me

+

~ ;== CONHCH 2CH2NHCO

Me

1 Me02CCH27C(Ol-@

PA = backbone of poly(N,N-dimethylacrylamidel

Me H'NCH'CH'NH'!

H2NCH2CH2NHCOCH27Co-@ Me

00.I Cl

Me,COCONHCHRCO'CH,OCH,CO'

Cl

Me3COCONHCHRC02CH20H2CO NHCH2CH2NHCOCH27c0---8 Me

(20)

Scheme 5

90

Polymeric Reagents

solvent for PS but not for peptides, is used in some steps with PS supports. In the only difficult peptide synthesis for which direct comparison of PS and PA supports has been made, good yields were obtained with both supports.t" After attachment of a benzyl alcohol derivative as shown in Scheme 5, the remaining steps and reagents used with the polyamide support are essentially the same as in the PS-based SPPS. The PA method has been adapted to low pressure, continuous flow SPPS. 5 6 , 5 7 The soft, gelatinous polyamide supports are unsuitable for pumped flow systems due to changes in bed volume and bead instability. These problems were overcome by adsorbing and incorporating the polyamide support onto Kieselguhr."? This composite has high physical stability and produces negligible back pressure at flow rates of 3 ml min - 1 in a packed column reactor. Standard methods were employed with the column reactor except for the use of Fmoc-protected amino acid pentafluorophenyl esters, in place of symmetrical Boc amino acid anhydrides, for greater stability and ease of deprotection of the amino blocking group. The method also allows for monitoring of the steps in the synthesis by UV spectroscopy and for feedback control through the use of a computer. 58 A pentadecapeptide repeating unit in adenovirus fiber was synthesized in a flow reactor in 82% crude recovered yield. 5 7 Conventional solution phase peptide synthesis, as with any multistep synthesis, is tedious and time consuming because of the large number of separation and purification steps needed. Expensive amino-blocked amino acids cannot be easily recovered. SPPS has the advantage of ease of separation of the product from excess reactant. SPPS flow methods are easily automated and enable analysis of reactants in solution.

3.3.2

Oligonucleotide Synthesis

Chemical synthesis of oligonucleotides was not practical until the late 1970s. The major breakthrough for both solution and supported synthesis of DNA was the phosphite triester method '? with deoxynucleotide phosphoramidites.s'':"! which gave high yields in internucleotide coupling, permitted reactions to be run at room temperature and gave greater stability to hydrolysis. Another improvement was the use of silica gel or controlled pore glass as a support. 6 2 , 6 3 SG provides greater rigidity and more efficient mass transfer of polar reagents and solvents than does polystyrene, and is ideal for automated synthesizers and flow systems.P" SG of 50-100 nm average pore diameter is used; otherwise yields decrease when DNA of more than 100 bases is synthesized. A typical linkage of the nucleoside to SG is shown in Scheme 6. The synthesis, as shown in Scheme 7, consists of the removal of the dimethoxytrityl protecting group from the 5'-hydroxyl of the silicabound nucleoside with an acid reagent, coupling with an appropriately protected deoxynucleoside 3'-phosphoramidite,- acylation (called capping) of unreacted deoxynucleoside and oxidation of the phosphite triester to the phosphate.?" Once the sequence of deoxynucleotides has been completed, the methyl triester phosphate bond is cleaved with triethylammonium thiophenoxide in dioxane. Protecting groups are removed at the same time as cleavage of the chain from the silica by treatment with concentrated ammonia solution. The oligonucleotides are purified by reversed phase HPLC or polyacrylamide gel electrophoresis. DNA can be synthesized at a rate of 15 min per base manually or 7-10 min per base by machine. 6 4 , 6 5 Using these methods, condensation yields of 99.5-99.8% per step and DNA of more than 100 bases have been attained.?" Since only small amounts of DNA are required for subsequent applications, the typical scale of the synthesis is 5-10 Jlmol of DNA per gram of SG, although 50-100 Jlmol g-l has been used for short DNA segments. Synthetic deoxyoligonucleotides have been used for sequencing cloned, kilo base-sized DNA segments as primers, as probes for genomic libraries and in directed mutagenesis.P" An example of sequencing DNA segments (such as those found in the M13 vector system}"? involves the sequencing of a short, cloned fragment. Then a new segment of 10-15 nucleotides near the 3'-terminus is synthesized by the SG-supported technique and

I

(MeOhTr?

§-o--fi(CH2hNHCOCH2CH2COO B = base; (MeOhTr

= 4,4'-dimethoxytriphenylmethyl Scheme 6

-p

Polymeric Reagents

p

DMT

DMT

2-

i

4

---+

=

iii

--;---+ IV

o I

1J

MeO-P

B = base, purine or pyrimidine, DMT

91

G

dimethoxytriphenylmethyl;

p

IOCH v, vi

---+

o

+

+

@-OH

MeOH

+

DMT-QH

J

-O-P=O

~1J--o---.l~·_l OH

p

i, CHCI 2C02H; ii,DMT-0

?

Me-O-P-N

/CHMe 2

-,

CHMe2'

iii, 4-(N,N-dimethylamino)pyridine (DMAP), THF:lutidine (6:90: 10) 0.1 ml AC20 (capping); iv, 0.1 M 12 in THF:lutidine:H 20 (2:2: 1) + v, Et 3NH -SPh; vi, NH 40H (conc.)

(oxidation);

Scheme 7

is used to prime a second round of sequencing. This cycle is repeated until the complete fragment has been sequenced. This new method avoids the subcloning and ordering of small fragments, both very time-consuming processes. Synthetic DNA is also used to probe genomic libraries for unique DNA sequences."? Short, synthetic deoxyoligonucleotides of 11-17 units per segment that correspond to all possible gene sequences for a given peptide fragment are produced with a 32p-phosphate label and are used to locate unique genes under exact hybridization conditions/" Directed mutagenesis'" with synthetic DNA segments involves the change in the sequence of bases at a predetermined site and the expression of this change in the amino acid residues of the corresponding protein, either by deletion of many amino acids (such as in proinsulin 70) or a change in the composition of a single amino acid (tyrosyl RNA synthetasej."! The synthetic DNA segments are derived from trivalent phosphorus which is oxidized to the P" state and hydrolyzed to the natural dideoxyribophosphate. This pili intermediate permits the synthetic variation to form unusual analogues, such as alkyl phosphonates and chiral derivatives that are due to stable isotopes of oxygen or sulfur.P"

Polymeric Reagents

92 3.4 POLYMERIC REAGENTS

3.4.1 Analogues of Hygroscopic, Pyrophoric and Explosive Reagents Aluminum chloride has many advantages as a Lewis acid catalyst, but rapid hydrolysis by atmospheric moisture precludes its use for many reactions. The catalyst can be incorporated into PS by swelling the PS in carbon disulfide and adding aluminum chloride.72,73 After thorough washing with various solvents, including water, the dried polymer-reagent catalyzes ether formation from dicyclopropylmethanol as in equation (1). This alcohol is very sensitive to acid-catalyzed rearrangement, yet the symmetrical ether is formed in high yield, and no rearranged product is detected. PS-aluminum chloride is also an effective catalyst for ester and acetal formation.?": 75 2 C[:>r-CHOH

Ps-AICI,.

[c[:>1;- -t-o CH

(1)

Pyridine bromide is a useful reagent for halogenation of alkenes and ketones, but both pyridine and bromine are noxious reagents, and the solid pyridinium perbromide complex is dangerous to handle. Poly(vinylpyridine perbromide). (21) quantitatively produces «-bromo ketones from cyclohexanone and propiophenone and is easy to handle.?" Bromination of (Z)-stilbene and (E)- and (Z)1-phenylpropene77 gave 98-1000/0 anti addition, as in equation (2),while bromine in solution yielded dibromophenylpropanes with 25-920/0 anti addition, depending ·upon the solvent. -(CH 2CH)n

6 I

H

+

H

H

Ph

Ph

H1Br BryPh

>=<

Br)

(2)

H

(21)

N -Chloropolymaleimide (22) chlorinates alkylaromatic compounds on the aromatic ring in preference to the alkyl side chains as in equation (3) in yields of 70-88 %. 78 The solution analogue, N -chlorosuccinimide, gives both aromatic and alkyl chlorination in lower yields.

~ +OR-r\R

"F

oANA o I

(3)

CI

CI

(22)

p-Toluenesulfonyl (tosyl) azide converts active methylene groups into diazo groups, but it is reported to detonate."? A PS-tosyl azide (23) converted fJ-diketones and p-keto esters into diazo groups as in equation (4) in 68-97% yields and showed no tendency to detonate on shock treatment. 79 @-S02N3

+ RCOCH 2COR' -

RCOC(N 2)COR'

+ @-S02NH2

(4)

(23)

Poly(styryldiphenylphosphine) (8) in carbon tetrachloride converts alcohols to alkyl chlorides up to 20 times faster than does triphenylphosphine, as shown in equation (5).80 The phosphine oxide by-product is easily separated by filtration, but it cannot be recycled due to concurrent formation of a dichloromethylidinephosphorane. Yields are about 900/0 from primary and 40-70% from secondary alcohols. Reagent (8) in carbon tetrachloride also dehydrates primary carboxamides and oximes to amines, and secondary carboxamides and oximes to imidoyl chlorides.v' 0-PPh2

+ CC14 + ROH -

RCI

(5)

(8)

Poly(styryldiphenylphosphine}-halogen.. complexes are formed by addition of the halogen to a dichloromethane-swollen resin. The complexes react with epoxides to give trans-halohydrins in

Polymeric Reagents

93

>90% yield, as shown with cholesterol epoxide in equation (6).82 The iodine complex promotes esterification of carboxylic acids as shown in equation (7).83 Two structures of triphenylphosphineiodine complexes have been identified as [(PPh3I)213]I3 from 1,2-dichloroethane solution and (PPh 3I)I3 from 1,2-dichloroethane solution and (PPh 3I)I3 from toluene solution.P" VV\J

&PPh2(X2).

\J\..JV

~

+

------+

\

(6)

Ac vvv

&PPh 2(I 2).

+

Me(CH 2 ) 16 C0 2H

\JV\.J

~

+

~

-----.

H

Me(CH 2 ) 16 CO (7)

A diphenylpolystyryldiethoxyphosphorane (24), prepared from a DF = 1.0 PS-diphenylphosphine and diethyl peroxide, was more stable and easier to handle than the diethoxytriphenylphosphorane/" The polymeric reagent cyclodehydrated diols to three-, five- and six-membered ethers in yields as high as the solution reagent, and converted 1,2-diols to epoxides stereoselectively. For example, S( + )-phenylethane-l,2-diol gives 68% enantiomeric excess (ee) S( + )-styrene oxide as shown in equation (8), whereas only the racemic product was obtained from the soluble reagent.

/0\

H 2C-C\'I"'!H

~

(8)

Ph

(24)

Perfluoroalkanesulfonic acids are noxious to handle and cause severe burns on contact. Nafion-H

(13) is a polymeric strong acid used extensively in many synthetic applications.t" An example of its

selectivity, high" catalytic activity and ease of regeneration is the de-t-butylation of aromatic compounds.P" 88 Simply refluxing the t-butyl aromatic compound with Nafion-H in toluene results in nearly quantitative transfer of the t-butyl groups to toluene as in equation (9). The catalyst can be regenerated by washing the polymer with acetone and water, followed by drying. The use of expensive, corrosive and hard-to-recover trifluoromethanesulfonic acid in perfluoroalkylations of aromatic compounds is avoided by the use of a Nafion analogue as shown in Scheme 8.89 Me MeOMe

1.0

Me Nation-" (13) • PhMe

MeOMe I

+

(9)

~

But

PhH,80 pyridine

CC

•

n-CsF 17 C6HS 89%

Scheme 8

3.4.2

Analogues of Toxic Reagents

Polymer-bound oxidizing agents, such as chromium(VI) species, have many applications.?? Chromium in all oxidation states has been identified as carcinogenic.?! Poly(vinylpyridinium dichromate) (25) in cyclohexane at 70°C gave high yields bf aldehydes from primary alcohols, as in

Polymeric Reagents

94

equation (10), when the polymeric reagent was slightly wet. 9 2 For example, the oxidation of benzyl alcohol with 1.1 mol ratio ofchromium(VI) to alcohol gave >990/0 yield ofbenzaldehyde after 18 h with no detectable benzoic acid. The reaction time could be reduced .to 1 h with no change in the yield by the use of a 1.7 ratio of Cr to alcohol. Reagent (25) could be recycled five times with no loss of oxidizing capacity by a simple washing-preactivation procedure. Fast reaction rates were obtained when a four-fold excess of oxidant was used. The superior yields obtained using non-polar, non-swelling solvents such as cyclohexane, and a trace amount of water are puzzling.

----.. PhCH-CHCHO

(10)

A quaternary ammonium trifluoroacetochromate(VI) polymer (26), prepared from Amberlyst A-26 with Cr0 3 and trifluoroacetic acid, showed greater activity than (25) for oxidation of secondary alcohols. Reaction of 2-octanol in cyclohexane at 70°C with 3.8 molar equivalents of (26) gave 82% yield of 2-octanone in 4 h as shown in equation (11).93 A major advantage of the polymeric chromium reagents is the ease of isolation of the oxidation product from chromium salts. The major drawbacks are the initial expense of the polymer support and the relatively large amounts of polymer that must be used. OH .

I

MeCH(CH 2hMe

o

~

~H2NMeJ(CrOJ).

+

/I

-OCOCF J -

MeC(CH 2hMe

(11)

(26)

Advantages of polymeric peracid over a homogeneous reagent are that the supported system is more stable (making handling of toxic material easier) can be recycled, and may be more selective. Lithiation of 1% cross-linked PS followed by treatment with triethoxyarsine and hydrogen peroxide gave the polymer-bound arsonic acid (27).94,95 The peracid (28) was generated (Scheme 9) by addition of either 90% or 300/0 aqueous hydrogen peroxide and used as a catalyst with hydrogen peroxide in dioxane for Baeyer-Villiger oxidations of ketones. For example, 2-methylcyclohexanone reacted with a mixture of hydrogen peroxide, polymeric arsonic acid (28) and ketone (1:0.033:5)for 5 h at 80°C in dioxane to form the corresponding lactone in 78% conversion with no detectable carboxylic acid. Catalyst (27) could also be used to oxidize alkenes to epoxides.

0)-Li

(EtOhAs

--+ 'H 202

o

o all ~ts-OH

1I r::::L ~ts-OOH

OH

U

OH (28)

(27)

6 0

Me

(28)

dioxane,~

Me

+

(27)

recycle to (28)

Scheme 9

A PS-peroxyselenic acid (29) was prepared by treatment of PS-mercury(II) chloride (30) with selenium dioxide followed by 300/0 hydrogen peroxide (Scheme 10).96 In a triphase system, consisting of (29) (1.5 mol 0/0), 1.5-1.8 equivalents of 30% aqueous hydrogen peroxide and dichloromethane, alkenes were oxidized to 1,2-diols, and ketones to esters or lactones. The polymeric seleninic acid (31) could be reoxidized to the PS-peroxyseleninic acid (29) and recycled with no apparent loss of activity. A poly(styryltellurinic) acid (32), prepared from PS and tellurium tetrachloride followed by hydrolysis, as in· equation (12), catalyzed the epoxidation of alkenes with hydrogen peroxide in

Polymeric Reagents i, HgO, CF 3C0 2 H . ii,CI-

~-HgCl

~ii, Se~2.

V

95

Q-Se0

IV,H

V-

2H

v, H 20 2 •

Q - Se0 3 H

V-

(31)

(30)

(29)

Scheme 10 i,OH-

(12)

ii, HCl

dioxane or t-butyl alcohol."? Soluble tellurinic acids (either phenethyl or anisyl) showed no catalytic activity under the same conditions. Polymeric percarboxylic acids (33) have been prepared from PS analogues of benzoic acid and benzoyl chloride as in equation (13).98,99 Expoxides are formed from di- and tri-substituted alkenes with (33) at 40°C. The PS-peracids also oxidized sulfides to mixtures of sulfoxide and sulfone, and with penicillins and deacetoxycephalosporins gave sulfoxides in high yield.'?"

a

~C02H

70%H 2 0

2

~

a

~C03H

(13)

~

(33)

Poly(methylhydroxiloxane) (PMHS) serves as the hydride source for reduction of aldehydes and ketones to alcohols with 2 mol % of the catalyst bis(dibutylacetoxytin) oxide, thus· avoiding large quantities of toxic organotin hydrides. 10 1 PMHS in the presence of Pd-on-charcoal in ethanol also reduces nitrobenzene to aniline, benzaldehyde to toluene, 1-alkenes to alkanes, and only the cis isomer of an isomeric mixture of 2-nonenes to nonane.!"!

3.4.3

Analogues of Odorous' Reagents

Many synthetic procedures require odorous reagents such as organosulfur compounds.Methylation of a PS-methyl sulfide (34) gives a PS-dimethylsulfonium fluorosulfonate (35) that reacts with ketones and aldehydes under phase transfer conditions to form epoxides in near quantitative yield as in equation (14).102 The corresponding. solution reagent gave lower yields with ketones. The polymeric reagent could be recycled five times with no loss of activity, and it has no odor.

&SMe

MeSO,F.

8-

SMe2 FSOi

0

RR'CO CH 2CI 2 , NaOH(aq), Bu2 NOH •

(34)

+ RR'U

(14)

(35)

(34)

Thiamine and thiazole, which are coenzyme mimics, have bad odors and give by-products that are difficult to remove from reaction mixtures. A polymer-supported thiazolium salt (36), which incorporates the major structural features of thiamine, catalyzes the benzoin condensation of furaldehyde to furoin as in equation (15).103 The polymeric thiazolium ion was 12.6 times as productive at 50°C in 24 h as thiamine in solution.

OCHO o

~H-C-D 0 I II 0

(15)

OH 0

(36)

A trifluoroacetyl PS-thiol ester gives convenient, high yield trifluoroacetylation of primary amines, including amino acids, with no thiol odor, as shown in Scheme 11.104 HNRR' ~

dioxane

Scheme 11

RR'NCOCF 3

+

(4)

Polymeric Reagents

96 3.4.4

Recyclable Reagents

Wittig reagents bound to PS allow easy separation and recycling of the phosphine oxide byproduct with yields of alkenes as high as from reactions with soluble Wittig reagents. 1 05 Even bulky ketones such as 10-nanadecanane and cholest-4-en-3-one react with PS-methyHdenephosphorane to give> 90% yields of 1,1-disubstituted alkenes.i'" Such high yields have heen obtained only when the poly(styryldiphenylphosphine) (8) is prepared by phosphination of a brominated PS (6), and the solvent-base mixture used in the Wittig reaction both swells the PS and solvates the phosphonium ion sites. A generally useful Wittig reaction sequence is shown in Scheme 12.

+

RCH 2X - - @-PPh 2CH2RX-

(37)

(8)

R=H~

X=I·

(38) R=Ph; X=Br (37)

+

(38)

+ R'CHO

R'R"CO

- - . . . . R'R"C=CH 2 +@-POPh 2 - - . . . R'CH='CHR

@-POPh 2

iii

•

+

&POPh 2

@-PPh 2 (8)

i, NaCH 2S(O)Me, Me2S0, THF~ ii, NaOEt, HOEt, THF; iii, HSiC13 , benzene Scheme 12

Alkenes are formed with high stereoselectivity from PS-Wittig reagents under Li-salt and Li-free conditions, similar to results with soluble Wittig reagents.'?" A triphase method is convenient for reactions of PS-benzyl- and PS-allyl-phosphonium salts with aldehydes using solid potassium carbonate as base and THF as solvent.l?" Dicyclohexylcarbodiimide (DeC) and similar condensing agents are used extensively for amide bond formation in peptide synthesis. DCC also is used in esterifications and as a component in the Moffatt oxidation. One of the major difficulties with DCC is that its by-product, N,N'-dicyclohexylurea, frequently cocrystallizes or cochromatographs with the desired product. The PS-diimide (39) overcomes this recovery problem since the product urea (40) is attached to the polymer, is readily removed by filtration and is recycled to (39), as shown in Scheme 13.1 0 9 , 110 0-cH2N=C

NCHMe2

+

H 2N-peptide

+

BocNHCHRC0 2H

•

(39)

BocNHCHRCONH-peptide

+

@-CH 2NHCONHCHMe2 (40)

MeOSO,CI, NEt,

Recycle: (40)

- - - - - - -.. ~

(39)

Scheme 13

The reaction of alkyl bromides with alcohols to form ethers, promoted by silver salts of dicarboxylic acids, the Koenigs-Knorr synthesis, is sometimes complicated by the recovery of the ether from the dicarboxylic acid. A copolymer network of maleic acid and 1,4-bis(vinyloxy)butane was transformed into the silver salt (41) and used for the reaction of 2,3,4,6-tetra-O-acetyl-1abromoglucopyranose with cholesterol to give the cholesteryl ether in 55% yield as shown in Scheme 14. 1 1 1 The polymeric by-product dicarboxylic acid was filtered easily from the product solution.

Polymeric Reagents

97

AcO

(41)

+

AcO

o

AcO AcO

-(CH--CH--CH 2-CH)-,-

I

C0 2Ag

I

I

C0 2Ag

m

O(CH 2)40

I

-(rH--
C0 2Ag

(41) Scheme 14

3.4.5 Reagents and Catalysts for Stereoselective Reactions Few chiral reagents bound to polymers have succeeded in asymmetric syntheses with high enantiomeric excess (ee). Chiral amino alcohol reagent (42), prepared from (S)-tyrosine, and 2.0 molar equivalents ofborane in THF at 30°C, reduced alkyl phenyl ketones to secondary alcohols in 76-97% ee and quantitative yield 1 1 2 , 1 1 3 and reduced acetophenone O-methyloxime to l-phenylethylamine in 990/0 ee and 85-950/0 yield 114 as shown in Scheme 15. Reagent (42) was easily recycled.

o

OH

II

/

PhCBu n

Ph-Cf1fltttBun

~

97%ee OH

/

Ph-C\',ff'CH 2CI H

84%ee NOMe

II

NH 2

(42)'2BH 3

PhCMe

~ Ph_~,\\\\\\'-lH \ Me

99% ee Ph Ph

\

H'\\\\\

NH 2

0H

(42)

Scheme 15

Polymeric Reagents

98

Hydrogenation of N-acyl a-amino acids in 87-91 % ee has been accomplished with Rh' bound to copolymers (43) with chiralphosphine ligands, as shown in Scheme 16.1 1 5 The same % ee was obtained with Rh catalysts prepared from analogous soluble ligands. Hydrophilic poly(2-hydroxyethyl methacrylate) and poly(N,N-dimethylacrylamide) provided polar environments for the hydrogenations. The chiral polymeric catalyst can be recycled. Earlier studies with polymers based on chiral biphosphine monomer (44) showed that polar comonomers were required for high % ee catalysis.l!" Ar

NHAc

H

C0 2H

>=<

Ar = Ph, 4-AcOC 6H 4 , 3-MeO-4-AcOC 6H 3

(43) i, H 2 , Rh I-(43), EtOH, Et 3N

Scheme 16

(44)

0.9-x

0.1

(45)

x

= 0, 0.1

Scheme 17

99

Polymeric Reagents

Chiral biphosphine Pt II complexes (45) with SnCl 2 catalyze hydroformylations of styrene, vinyl acetate and N-vinylphthalimide in 56-650/0 ee, almost as high as with analogous soluble catalysts, as shown in Scheme 17.117 The polymer supports can be either soluble or cross-linked. Lower branched-to-normal product ratios were obtained with the polymeric catalysts, especially with the cross-linked ones. Reuse of the catalyst showed no loss in rate or selectivity with precipitated soluble polymer, and slight loss in rate but no loss in selectivity with the cross-linked polymer. Polymer (46) with SnCl 2 catalyzed hydroformylation of styrene in a mixture of benzene and triethyl orthoformate in 98% ee, but only 22% conversion was attained in 10 d (Scheme 18), compared with 98% ee and 1000/0 conversion in < 150 h using the soluble analogue of (46).118 The triethyl orthoformate converted the product aldehyde to an enantiomerically stable acetal, whereas the aldehyde racemized slowly under reaction conditions. Since the reaction proceeds much faster in benzene than in triethyl orthoformate, polymer (46) might be used in a flow reactor with benzene as solvent, continuous separation of aldehyde, and recycling of the styrene.

PhCH 2CH 2CH(OEth 2

Ph~

0.1

Scheme 18

Chiral PS-bound amino alcohol (47) reacts with diethylzinc to form catalyst (48), which promotes addition of diethylzinc to benzaldehyde to give 92 % ee (R)-I-phenylpropanol in 91% yield as shown in Scheme 19.119

1 8

Me -,

~ \

~~n---l

OR (47)

PhCHO

(48)

+

ZnEt 2

i,(48)

ii,

OH

H'~ Ph~:t

Scheme 19

3.5 ION EXCHANGE RESINS, ACIDS AND BASES 3.5.1

Ion Exchange Resin Reagents

Commercial ion exchange resins make convenient reagents because the large beads are easily filtered and packed into columns.P? Reagents in quaternary ammonium anion exchange resins (AER) are prepared as in equations (16) and (17). Both microporous and macroporous resins have

Polymeric Reagents

100

been used successfully, but macroporous resins generally provide higher yields of reactions in organic solvents. (16)

@-CH 2NMe 3 CI-

+

excessNaX -

§ - C H 2NMe3 X"

+

NaCi

(17)

(3)

Percolation of an ether solution of benzoic acid through a column ofa macroporous AER in OHform put the resin in benzoate form. Stirring of the resin with 4 molar equivalents of ethyl bromoacetate at room temperature produced 990/0 of ethyl benzoyloxyacetate as shown in equation (18).121 Similar displacement reactions of alkyl halides have been used to form esters from other carboxylate ions,121-123 alkyl fluorides from F-,124 phenyl sulfones from PhS02" ,125 N,N'dialkylureas and urethanes from NCO-,126 alkyl thiocyanates from NCS-,126,127 aldehydes from HFe(CO)i,128 alkyl phenyl ethers from PhO-,129 «-nitrocarboxylate esters from N02",129 alkylated p-diketones and fJ-keto esters. " alkyl cyanides from CN- ,127 p-nitrophenyl-tetraO-acetyl-p-D-glycopyranosides from 0-, m- and p-02NC6H40-,130 a-nitro esters from methyl nitroacetate,131 and alkyl phenyl selenides from PhSe - .132 Similarly arenesulfonyl fluorides 133 or isothiocyanates 12 7 can be produced from arenesulfonyl chlorides and F - or SCN -, and arenecarboxylic acid cyanides and isothiocyanates from arenecarboxylic acid chlorides and CN - or SCN- .127

+

@-CH 2NMe 3 PhCO;

BrCH 2C02Et - - - - PhC0 2CH 2C02Et

(18)

Addition of HF to cyano- and carbonyl-activated triple bonds gives the p-fluoroalkenes from H 2F 3 in a macroporous quaternary ammonium ion resin.P" Fluoride ions resins also are used as bases for alkylations of 2,4-pentanedione and phenols, addition of thiophenol to 3-buten-2-one, and autooxidative sulfenylation of 2,4-pentanedione as shown in equation (19).135 @--cH 2NMe3 F-

+

PhSH

+

(MeCOhCH 2

+

O2

-

(MeCOhCHSPh

(19)

Reductions of aldehydes and ketones to alcohols proceed at slower rates with AERs in BHi form than with NaBH 4 in ethanol.'?" a,p-Unsaturated carbonyl compounds are reduced by BHi in a gel AER to the allylic alcohols.P? Cyanoborohydride ion in a macroporous AER effects reductive aminations of ketones and ammonia to primary amines, reductive methylations of primary amines to the N,N-dimethyl tertiary amines with aqueous formaldehyde, reductions of N-alkyl- and N-acylpyridinium ions to tetrahydropyridines, and reductions of primary alkyl halides to alkanes.l " Nitroarenes are reduced to amines.P" the bromide of o-bromocarbonyl compounds is replaced by hydride.V" and 1,2-dibromoalkanes give alkenes'r" by treatment with HFe(CO)i in a macroporous AER. The complex of BH 3 with poly(2-vinylpyridine) in the presence of BF 3·OEt 2 in boiling benzene reduced aldehydes and ketones to alcohols.l '? The analogous poly(4-vinylpyridine)· BH 3 was effective for the same reductions only when half of the pyridine units were quaternized with l-bromododecane.P? Borane with 0.5 molar equivalent of chiral polymeric amino alcohol (49) reduces an equimolar mixture of benzaldehyde and acetophenone to 100% benzyl alcohol and no l-phenylethanol.vP Under conditions of complete reduction of acetophenone with (49)· borane, PhC(Me)=NOCH 2Ph and PhC(O)NMe 2 are not reduced at all. 113

Phosphonate carbanions, formed by percolation of a dilute ether solution of the diethyl phosphonate through a macroporous AER in HO- form, react with carbonyl compounds in Horner-Wittig syntheses of alkenes (Scheme 20).140 a,p-Unsaturated nitriles are formed from both aldehydes and ketones, but a,p-unsaturated esters are formed only from aldehydes. The reactions

Polymeric Reagents

101

succeed in diverse solvents (hexane, methanol, benzene, or THF-water), unlike many other polymersupported syntheses. Sequential reactions of two polymer-bound reagents allow use of dioxolanes rather than aldehydes and ketones as starting materials. The carbonyl compound is generated by hydrolysis catalyzed by a sulfonic acid .ion exchange resin (Scheme 20). G-CH2

NMe

3HO-

+

(EtOhP(OlCH 2X -

G - C H2

X=CN

(51)

X=C0 2Et

+

RR'CO - - .

RR'=CHCN

(51)

+

RCHO

RCH=CHC0 2 Et

a~S03H

PHh

+

XOo-.-Ji

----+

3

(50)

(50)

---.

NMe (EtOhP(OlCHX

PhCHO

(5)

Scheme 20

An example of three different reagents made from a macroporous AER in one synthesis of the fJ-adrenergic receptor antagonist propranolol is shown in Scheme 21.1 4 1 The key step was the iodocyclization of an allylic amine with carbonate ion.

2@-CH 2 N Me 3

CO~

@-CH 2 N Me, AcO-

I 2.CHCI 3

i, K 2 C0

3,

EtOH

•

~

ii, MeS02C1, Et 3 N , CH 2 Cl 2

i,@-CH 2

NMe,

.~

ii,KOH

OH

HN-<

Scheme 21

'3.5.2 Acidic Ion Exchange Resins As Catalysts Commercial poly(styrenesulfonic acid) ion exchange resins catalyze hydrolyses of carboxylic acid derivatives, acetal and ketal formation, esterification, condensations, alkylations and rearrangements. 14 2 The catalyst is filtered from reaction mixtures. In examples such as the dimerization of ' o-methylstyrene in equation (20), higher yields and cleaner products have been obtained than with p-toluenesulfonic acid or sulfuric acid as the catalyst.V:'

(20)

Methyl t-butyl ether is manufactured in at least 30 plants world-wide for use as a gasoline antiknock additive by addition of methanol to isobutylene catalyzed by a macroporous poly(styrenesulfonic acid). 144 Stich resins have also been used as catalysts in the manufacture of alkylated

102

Polymeric Reagents

benzenes and phenols, isopropyl alcohol by hydration of propylene, and bisphenol A from phenol and acetone.v'? The polymeric superacid Nafion has been used successfully as a catalyst for a wide range of reactions, some of which failed with the weaker poly(styrenesulfonic acid) catalysts.I"

3.5.3 Tertiary Amine Catalysts Polymeric amines can be proton acceptors, acyl transfer agents, or ligands for metal ions. The 2- and 4-isomers of poly(vinylpyridine) (11) and (12) and the weakly basic ion exchange resins, p-dimethylaminomethylated PS (2) and poly(2-dimethylaminoethyl acrylate), are commercial. The ion exchange resins are catalysts for aldol condensations, Knoevenagel condensations, Perkin reactions, cyanohydrin formation and redistributions of chlorosilanes.l '" The poly(vinylpyridine)s have been used in stoichiometric amounts for preparation of esters from acid chlorides and alcohols, and for preparation of trimethylsilyl ethers and trimethylsilylamines from chlorotrimethylsilane and alcohols or amines. 14 6 , 1 4 7 Polymer-suppored DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (52) in stoichiometric amounts promotes dehydrohalogenation of alkyl bromides and esterification of carboxylic acids with alkyl halides.l " The protonated tertiary amine resins are converted to free base form by treatment with aqueous sodium hydroxide.

8-(

CH

(52) n

2)nJ . \

>-~

U

= 1, 4, 7

Polymer-bound Cinchona alkaloids (53) are catalysts for asymmetric Michael additions of carbanions and thiols to a,fJ-unsaturated ketones, esters and nitro compounds as shown in Scheme 22. Attachment of the alkaloids to the polymer through the remote vinyl group by copolymerization with acrylonitrile or by addition of a polymeric thiol to the vinyl group was required for catalytic activity and stereoselectivity.Y'
R

C-8

C-9

Quinine

OMe

S

R

Quininidine

OMe

R

S

Cinchonine

H

R

S

Cinchonidine

H

S

R

Alkaloid

Scheme 22

3.5.4 Polymeric

4~(N,N~Dialkylamino)pyridines

Several polymeric analogues of 4-(N,N-dimethylamino)pyridine (DMAP) have been used as catalysts for esterification of tertiary alcohols, hydrolyses of active esters and other substitutions

Polymeric Reagents Table 4

103

4-(N,N-Dialkylamino)pyridine Monomers and Polymers Structure

Ref

HZC=CHO(CHzl"N(MelO ' n = 1,2, 3

a, b

(54)

c

HZC=CHOCHZO(CHzhN(MelO (55)

~

6

d

N

I

HCI-

(56)

e

@--(CHzl"N(Mel-Q n = 1, 2, 3, 4, 7 (58)

G-CHzNHCoO-cN

g

(59)

h

ii, LiAIH4

R = H, Ph, H 2C =CH, n-C 16H 3 3 , MeO aM. Tomoi, Y. Akada and H. Kakiuchi, Makromol. Chem., Rapid Commun., 1982,3,537. A. Deretani, G. D. Darling, D. Horak and J. M. J. Frechet, Macromolecules, 1987, 20, 767. C W. Storck and G. Manecke, J. Mol. Catal., 1985, 30, 145. dR. A. Vaidya and L. J. Mathias, J. Am. Chem. Soc., 1986,108,5514. e E. J. Delaney, L. E. Wood and I. M. Klotz, J. Am. Chem. Soc., 1982, 104, 799. f M. Tomoi, M. Goto and H. Kakiuchi, Makromol. Chem., Rapid Commun., 1985,6,397. g F. Guendouz, R. Jacquier and J. Verducci, Tetrahedron Lett., 1984, 25, 4521. h S. C. Narang andR. Ramharack, J. Polym. Sci., Polym. Lett. Ed., 1985,23, 147. b

104

Polymeric Reagents

at acyl carbon. The catalysts have been prepared both by polymerizations of substituted DMAP monomers (54) and (55) and by modifications of preformed polymers. Examples are in Table 4. Rates of hydrolysis of p-nitrophenyl esters of alkanecarboxylic acids in the pH range 7.2-9.2 increased with chain length up to 27 times faster for the dodecanoic ester with soluble polymeric catalyst (56) than with 4-(1-pyrrolidinyl)pyridine as catalyst.P" Enhanced activity is attributed to the lower pK a (7.8) of the conjugate acid of the polymer than of the soluble analogue (pK a 10.5), and to attraction of the lipophilic substrate to the polymer in an aqueous solution. Catalyst (57) bound to poly(ethyleneimine) was 2000 times more active than its monomeric analogue for hydrolysis of p-nitrophenyl caproate at pH 7.3.157 The DMAP analogues bound to cross-linked PS are active in non-polar solvents for esterification of sensitive tertiary alcohols as in equations (21) and (22),158, 159 dimerization of phenyl isocyanate as in equation (23),160 nucleophilic acyl rearrangements as in equation (24),161 and synthesis of dipalmitoylphosphatidylcholine from palmitic anhydride as in equation (25).162,163 The polymeric catalysts are slightly less active than DMAP, but they have been recovered and recycled three times with no loss of activity.P": 159, 161-163 The spacer chain catalyst (58; n = 3, DF = 0.16-0.48, 2% DVB) was more active than catalyst (58; n= 1) for acetylation of l-rnethylcyclohexanol.P? Spacer chains (n = 4,7) and DF 0.15-0.20 gave highest activity for acyl rearrangements.l"! A mixture of catalyst (58) and cross-linked poly(N,N-diethylaminomethylstyrene), as a proton acceptor, was more active for acetylation of linalool (equation 21), than catalyst (58) alone.I''"

~

(21)

OH

cx

Me

CX

Me

+

Ac20 _

OH

(22)

OAc

o

2PhNCO

-----+

PhN

A Yo

NPh

(23)

(24)

H~

H

L

0

/I

+

(25)

OPOCH2CH2NMe3

I

0-

(59)

+

PhCOCI

PhCOSON0 2

---+

+

Scheme 23

(S9)'HCI

Polymeric Reagents

105

Catalyst (59) in a circulating fixed bed reactor served as an acyl transfer agent for reactions of acetyl chloride, isobutyl chloroformate, p-toluenesulfonyl chloride and isopropyl o-chlorophenyl phosphoryl chloride with nucleophiles such as alcohols, carboxylic acids, HF, thiols and amines.':" For example, excess benzoyl chloride in dichloromethane was circulated through a Teflon column containing 1-4 ml of polymer at 0 DC, followed by pure dichloromethane to remove excess benzoyl chloride. Circulation of p-nitrophenol through the column gave p-nitrophenyl thiobenzoate in quantitative yield as shown in Scheme 23. Oxidation of poly(4-vinylpyridine) with hydrogen peroxide in acetic acid produced a pyridine N-oxide catalyst (60) that is useful for synthesis of mixed formic anhydrides as in equation (26).166

PhCH=CHCOCl

+ HC0 2Na (60~MeCN .. PhCH=CHC0 2CHO

(26)

3.5.5 Phase Transfer Catalysts Quaternary ammonium (3) and phosphonium ions (61), crown ethers such as (62), cryptands such as (63)and poly(ethylene glycol) ethers (64) bound to PS are catalysts for reactions of water insoluble organic compounds with organic insoluble inorganic salts.167-169 Silica gel,170,171 alumina.l"! polystyrene-polypropylene composite fibers, 172 nylon capsule membranes, 173,174 and polyethylene (M n 1000-3000)175 have also been used as supports. The reactions are called phase-transfercatalyzed because one or both of the reactants are transported from the normal liquid or solid phase into a polymer phase, where the reaction proceeds.

@-(CH2).PBUJ Br-

(61) n = 1,4,7

@-CH2(OCH2CH2)nOMe (64)

The reaction of aqueous sodium cyanide with 1-bromooctane, shown in equation (27), is catalyzed by tri-n-butylpbosphonium ions (61; n = 1, DF 0.17, 20/0 DVB) as shown in Scheme 24. 176 Reaction rates in heterogeneous mixtures can be limited by mass transport steps as well as intrinsic reactivity. Mass transfer of the cyanide ion from water to the particle surface, mass transfer of the 1bromooctane from organic liquid to the particle surface and intraparticle diffusion of both reactants from the particle surface to the active sites within the gel polymer are required. 168,169 Reaction occurs without stirring the triphase mixture because the polymer beads rest at the organic-aqueous interface. Stirring increases the reaction rates by promoting mass transfer from bulk liquid phases to the particle surface, The rates of reaction increase as catalyst particle size decreases in the range 200-20 J-lm because the time required for diffusion of reactants from the particle surface to the active sites is proportional to particle diameter. Slow mass transfer and intraparticle diffusion make

Polymeric Reagents

106

polymer-supported phase transfer catalysts less active by a factor of two or more compared with the analogous soluble quaternary ammonium salts and crown ethers, but the polymeric catalysts can be recovered and reused. (27)

Br-

AQUEOUS PHASE CN-

Masstransfer

j

RCN Mass transfer

CN-

Intraparticle \diffUSion

~PR3

Mass transfer

RCN

CN- + RBr

!

React ion

Intraparticle diffusion

~PR3 Br- + RCN CATALYST

Scheme 24 (reproduced with permission from M. Tomoi and W. T. Ford, 'Synthesis and Separations Using Functional Polymers', ed. D. C. Sherrington and P. Hodge, Wiley, Chichester, 1988.

Catalytic activity for nucleophilic displacement reactions with hard anions such as cyanide, acetate and chloride is promoted bt low DF (0.1-0.2), lipophilic quaternary onium ions, spacer chains between the active site and the polymer backbone, good swelling solvents and high concentration of the inorganic reactant in the aqueous phase. 1 6 7 , 1 6 8 Butylation of phenylacetonitrile with aqueous NaOH, as shown in Scheme 25, proceeds faster by use of high DF (> 0.5) anion exchange resins.!"?: 178 The strongly alkaline conditions degrade the quaternary ammonium ions of the catalyst. Catalyst (64) (1% DVB) is active for alkylation of phenylacetonitrile and benzyl phenyl ketone, and for Williamson ether synthesis, and it is much more stable in base than AERs. 1 7 9 AERs in OH- form are catalysts for dichlorocyclopropane syntheses from alkenes, chloroform and solid sodium hydroxide, and for dehydration of amides to nitriles.l"? AERs in the appropriate hydroxide, acetate, or cyanide form are catalysts for aldol condensations, Michael reactions, Knoevenagel condensations, cyanoethylations and cyanohydrin syntheses. 145, 168

PhCH 2CN PhCHCN Na +

+

NaOH~PhCHCNNa+

+ H 20

+ n-C4H 9Br ~ PhCHCN + NaBr I C4H 9 Scheme 2S

Phase transfer catalysis can be effective in triphase solid/solid/liquid mixtures. Solid potassium phenoxide ' P ! and solid sodium iodide'P? react with alkyl halides in the presence of (64). The solid/solid/liquid method also succeeds for hypochlorite oxidation of secondary alcohols'V and periodate oxidation of glycols 108,152 catalyzed by commercial AERs (3)... . Continuous flow phase-transfer-catalyzed reactions of 1-bromooctane In o-dichlorobenzene WIth aqueous KI have been performed in packed beds of PS bead~ beari.ng lipophilic quater~ary phosphonium ions. 1 8 3 Activity was as high as 0.4 times that attained with the same catalyst In a stirred reaction mixture. Poly(tetrafluoroethylene) membrane reactors have been used for phasetransfer-catalyzed reactions of 1-bromooctane in chlorobenzene with aqueous potassium iodide using tetra-n-butylammonium bromide as catalyst.i'"

107

Polymeric Reagents 3.6 REACTIONS PROMOTED BY POLYMERIC ENVIRONMENTS 3.6.1

Kinetically Isolated Sites of Reaction

Polymers can be used either to promote or to retard bimolecular reactions. 185, 186 Reactants that have greater affinities for the polymer than for surrounding solution can be concentrated into a polymer gel or into polymer random coils in solution. Reactants that normally diffuse freely in solution can be semi-immobilized by binding to a polymer network. In solution aliphatic esters are acylated or alkylated at the a position by treatment with a hindered organolithium base at dry ice temperature to generate an enolate, followed by addition of a carboxylic acid chloride or an alkyl bromide. At higher temperatures the ester self-condenses rapidly during the time of enolate generation. When the ester is bound to a slightly swellable 10-20% crosslinked PS, acylations and alkylations proceed at room temperature with 73-90% yields and little or no competing self-condensation of the ester as shown in Scheme 26. Self-condensation is retarded because it requires reaction of two polymer-bound species with each other.187-189

acylation self-condensation

Scheme 26

Two different carboxylic esters, the first enolizable and having low DF and the second nonenolizable and having high DF, have been immobilized in the same 20/0 cross-linked polystyrene and cross-condensed in 85% yield (vs. 20% in solution) as shown in Scheme 27.190 When each of the esters was bound to a different support, and the two supported esters were treated with triphenylmethyllithium in 'one flask at the same time, only the starting carboxylic acids were recovered, indicating that no condensation occurs in solution. CH 2CI

~CH2CI CH 2CI

j

HO'CO

•

+

i, PhJCLi ii, HBr,CFJCOzH iii,.1. -COz

Cl.

excess

°2CC6H4CI

&-02CCH2CH2 Ph °2CC6H4CI

Scheme 27

Two different polymers bearing a triaryllithium and an active carboxylic ester can be mixed in solvent with no reaction. Addition of an enolizable ketone, nitrile, or amide gives acylation in 88-96% yield by sequential reactions with the triaryllithium polymer and the active ester polymer as shown in Scheme 28.191 Yields of the corresponding solution reactions were 27-480/0. The triarylmethane polymer is easily recycled.

108

Polymeric Reagents

Scheme 28

Most syntheses of medium and large ring compounds are carried out under high dilution conditions in which the reagents are added slowly to a large volume of solvent to permit only low concentrations of reactants. Bimolecular dimerization competes with unimolecular cyclization. Low concentration favors unimolecular cyclization as shown in equations (28H30). d[macrocyc1e]/dt d[dimer]/dt

=

[macrocyc1e]/[dimer]

k 1 [reactant]

=

(28)

k 2[reactant] 2 =

(29) (30)

k 1 / k2[reactant]

The cyclization of compound (65) to a 17-membered lactone with a PS-bound z-allyl palladium catalyst, shown in Scheme 29, was carried out with 0.7 u substrate, a concentration 100 times higher than in most high dilution syntheses.l'" The competing intermolecular reaction of one polymerbound disulfonyl carbanion with a second polymer-bound z-allyl palladium is severely retarded.

o

o

OH

Scheme 29

Polymer supports also can enable high yields in the synthesis of cyclic peptides. Cyclo-Kily-His), was produced in 420/0 overall yield from attachment, five deprotection-coupling sequences, and cleavage from the resin.l":' It was isolated by chromatography with no detectable amounts of oligomeric linear or cyclic peptides. The oxidation of thiols to disulfides by dioxygen is catalyzed by cobalt phthalocyanine derivatives. The activity of cobalt phthalocyaninetetrasulfonate (66) is much higher when it is bound to a cationic polymer than it is in water. 1 9 4 , 1 9 5 Cross-linked and soluble poly(vinylamine) added to aqueous (66) give rate enhancements by factors of 16 and 106 for oxidation of 2-mercaptoethanol.

Polymeric Reagents

109

Likely reasons for the rate enhancement are that the polymer binds the thiolate ion close to the anionic catalyst, whereas reactions between species. of like charge in solution usually are slow because of electrostatic repulsion. Competitive kinetic experiments show that PS gels increase the lifetimes of reactive intermediates from seconds to minutes. Generation of benzyne in solution produces the dimer, biphenylene, if no reagent is present trap the benzyne. The polymer-bound benzyne in Scheme 30 either dimerizes or is trapped by tetraphenylcyclopentadienone."'" Sequential addition of iodobenzene diacetate and tetraphenylcyclopentadienone to the polymer gave yields of the tetraphenylnaphthalene that decreased as the time between addition of the two reagents increased. The lifetime r ofbenzyne in the 2% cross-linked, DF 0.11 PS was established as 0.6 < r < 15 min.

Scheme 30

Delayed trapping of a radiolabeled 2-~itrophenyl ester of glycine with acetic anhydride as in equation (31) gave a similar lifetime of a few minutes for the reactive polymer-bound free amine, DF 0.12 in 40/0 cross-linked PS. 1 9 7 i, EtJN,DMF ii AC20 iii, PhCH 2NH 2

Nt~ yNH

+

oligomers

°

(31)

The use of only 0.01-0.02 mmol of chlorodibutyltin per gram of 20% cross-linked macroporous polystyrene led to successful synthesis of bis(di-n-butylchlorotin)tetracarbonylosmium as shown in Scheme 31.1 9 8 In solution only a cyclic diosmium compound could be formed.

HCI

---~) CISn(BuhOs(CO)4Sn(BuhCI

Scheme 31

Polymeric Reagents

110

Detailed mechanisms of Dieckmann cyclizations on PS have been elucidated by isotopic labeling experiments. 187,199-201 In many cases scrambling of 14C-carbonyl carbon atoms by reversible condensations accompanies formation of the desired products, as shown in equation (32). Yields of six-membered fJ-keto esters from cyclization of PS-bound unsymmetrical diesters have been good, but attempts at PS-bound synthesis of the nine-membered fJ-keto ester failed, as have attempts to perform that cyclization in solution. Small amounts of cyclodimers were formed as shown in equation (33). 0

@-CH 202*qCH2)5C02CEt3

6C02CEt3 +

KOCEt 3 ~

&

0

CH 0 2 2*c6

(32)

36%

0

@--CH202C(CH2)SC02BUI

KOCEt 3

•

But 0 2C C0 2Bu t 0

+

@-

0

CH 20 2C

(33)

C0 2But 0

3.6.2 Polymeric Protecting Groups Polystyrene gels have been used as protecting groups for the synthesis of unsymmetrical derivatives of symmetrical difunctional compounds in higher yields than in solution. 202,203 A DF 0.14 triarylmethyl chloride in PS (2% DVB) gave 70% single binding of 1,4-, 1,7- and 1,10-alkanediols as shown in Scheme 32. Acetylation and acidic cleavage from the polymer gave the diol monoacetates in 600/0 recovered yield."?" The monoprotection method has been used for the synthesis of insect pheromones.i'" However, it appears to be limited to small scale laboratory syntheses because use of higher DF PS gives more double binding of difunctional reagents.F'" Polymeric chlorosilanes such as (67) have also been used for monoprotection of symmetrical diols.'"?

Scheme 32

@-Si(Phh C1 (67)

A PS-tin dihydride (68) reduced terephthaldehyde in 91% yield to an 86: 14 mixture of monoalcohol and diol, as shown in Scheme 33.27 The selectivity can be attributed to limited mobility of the first-formed alkoxytin intermediate (69). Other polymeric protecting groups that have been used are alcohols for the protection of symmetrical dicarboxylic acids as the monoesters.i?" arylboronic acids for the protection of vicinal

Polymeric Reagents @-snBunH 2

+

OHCOHO -

111

+

HOCH20CHO

HOCH20CH20H

86:14

(68)

H

@-tn-oCH20HO Bu (69)

Scheme 33

diols as the cyclic boronates.i'" vicinal diols for the protection of symmetrical dialdehydes as the monoacetals.i?": 210 and p-nitrophenyl carbonates for the protection of symmetrical primary diamines as the monocarbamate.i"!

3.7 CONCLUSIONS Polymeric reagents and catalysts offer advantages of ease of separation from reaction mixtures, lesser odor and toxicity, and sometimes different chemical selectivity compared with low molar mass analogues. Many are commercial, such as resins for peptide synthesis and ion exchange resins, and many others can be prepared easily from commercial monomers or polymers. The most elaborate and widely used applications have been polypeptide and oligonucleotide syntheses. The number of industrial uses of polymeric reagents has been limited because they cost more than low molar mass reagents. Industrial uses should increase as more emphasis is placed on the production of expensive fine chemicals and on reduction of the volume of chemical wastes.

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112 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97.

Polymeric Reagents 1. M. 1. Frechet, Tetrahedron, 1981, 37, 663. R. B. Merrifield, J. Arn. Chern. Soc., 1963, 85, 2149.

D. E. Leuyden and W. T. Collins (eds.), 'Silylated Surfaces', Gordon and Breach, New York, 1980. K. K. Unger, J. Chrornatogr. Libr., 1979, 16, 57. C. N. Satterfield, 'Mass Transfer in Heterogeneous Catalysis', MIT Press, Cambridge, MA, 1970. G. Schmuckler and S. Goldstein, in 'Ion Exchange and Solvent Extraction', ed. J. A. Marinsky and Y. Marcus, Dekker, New York, 1977, vol. 7, p. 1. S. Pan and H. Morawetz, Macrornolecules, 1980, 13, 1157. W. T. Ford, S. Mohanraj and M. Periyasamy, Br. Polyrn. J., 1984,16,179. C. A. Fyfe, 'Solid State NMR for Chemists', CFC Press, Guelph, Ontario, Canada, 1983. R. L. Letsinger and M. 1. Kornet, J. Arn. Chern. Soc., 1963,85,3045. A. R. Mitchell, S. B. H. Kent, M. Englhard and R. B. Merrifield, J. Org. Chern., 1978,43,2845. J. P. Tam, S. B. H. Kent, T. W. Wong and R. B. Merrifield, Synthesis, 1979,955. L. A. Carpino and G. Y. Han, J. Org. Chern., 1972,37,3404. E. Bayer, H. Eckstein, K. Hagele, W. A. Konig, W. Bruning, H. Hagenmaier and W. Parr, J. Arn. Chern. Soc., 1970,92, 1735. E. Wunsch, Angew. Chern., Int. Ed. Eng!., 1971,10,786. P. Fankhauser and M. Brenner, in 'The Chemistry of Polypeptides', ed. P. G. Katsoyannis, Plenum Press, New York, 1973, p. 389. V. K. Sarin, S. B. H. Kent, A. R. Mitchell and R. B. Merrifield, J. Arn. Chern. Soc., 1984,106,7845. I. Clark-Lewis, R. Aebersold, H. Ziltener, J. W. Schrader, L. E. Hood and S. B. H. Kent, Science, 1986, 231, 134. 1. P. Tam, M. A. Scheikh, D. S. Solomon and L. Ossowski, Proc. Natl. Acad. Sci. USA, 1986, 83, 8082. W. F. Heath and R. B. Merrifield, Proc. Nat/. Acad. Sci. USA, 1986,83,6367. E. Atherton, R. C. Sheppard and P. Ward, J. Chern. Soc., Perkin Trans. 1, 1985, 2065. E. Atherton, M. Pinori and R. C. Sheppard, J. Chern. Soc., Perkin Trans. 1, 1985,2057. E. Brown, R. C. Sheppard and B. J. Williams, J. Chern. Soc., Perkin Trans. 1, 1983, 1161. E. Brown, R. C. Sheppard and B. J. Williams, J. Chern. Soc., Perkin Trans. 1, 1983, 75. E. Atherton, M. Caviezel, H. Fox, D. Harkiss, H. Over and R. C. Sheppard, J. Chern. Soc., Perkin Trans. 1, 1983, 65. R. Arshady, E. Atherton, D. L. 1. Clive and R. C. Sheppard, J. Chern. Soc., Perkin Trans. 1, 1981,529. E. Atherton, E. Brown, R. C. Sheppard and A. Rosevear, J. Chern. Soc., Chem. Commun., 1981, 1151. A. Dryland and R. C. Sheppard, J. Chern. Soc., Perkin Trans. 1, 1986, 125. L. Cameron, M. Meldal and R. C. Sheppard, J. Chern. Soc., Chem. Commun., 1987, 270. R. L. Letsinger and W. B. Lunsford, J. Arn. Chern. Soc., 1976, 98, 3655. L. J. McBride and M. H. Caruthers, Tetrahedron Lett., 1983, 24, 245. S.L. Beaucage and M. H. Caruthers, Tetrahedron Lett., 1981, 22, 1859. M. D. Matteucci and M. H. Caruthers, Tetrahedron Lett., 1980, 21,719. M. D. Matteucci and M. H. Caruthers, J. Arn. Chern. Soc., 1981, 103, 3185. M. H. Caruthers, Science, 1985, 230, 281. M. Hunkapiller, S. Kent, M. H. Caruthers, W. Dreyer, 1. Firca, C. Griffin, S. Horvath, T. Hunkapillar, P. Tempst and L. Hood, Nature (London), 1984, 310, 105. 1. W. Efcavitch and C. Heiner, Nucleosides Nucleotides, 1985, 4, 267. M.Smith, in 'Methods of DNA and RNA Sequencing', ed. S. M. Weissman, Praeger, New York, 1983, p. 23. W. I. Wood, 1. Gitschier, L. A. Lasky and R. M. Lawn, Proc. Natl. Acad. Sci. USA, 1985,82, 1585. C. A. Hutchinson, III, S. Phillips, M. H. Edgell, S. Gillam, P. Jahnke and M. Smith, J. Bioi. Chern., 1978,253,6551. R. Wetzel, D. G. KJeid, R. Crea, H. L. Heyneker, D. G. Yansura, T. Hirose, A. Kraszewski; A. D. Riggs, K. Itakura and D. V. Goeddel, Gene, 1981, 16, 63. P. J. Carter, G. Winter, A. J. Wilkinson and A. R. Ferscht, Cell, 1984, 38, 835. D. C. Neckers, D. A. Kooistra and G. W. Green, J. Arn. Chern. Soc., 1972,94, 9284. H. liirai, H. Wakabayashi and M. Komiyama, Chern. Lett., 1983, 1047. E. C. Blossey, L. M. Turner andD. C. Neckers, J. Org. Chem., 1975, 40, 959. E. C. Blossey, L. M. Turner and D. C. Neckers, Tetrahedron Lett., 1973, 1823. 1. M. 1. Frechet, M. 1. Farrall and L. 1. Nuyens, J. Macromol. Sci., Chem., 1977, All, 507. Y. Johat. M. Zupan and B. Sket, J. Chern. Soc., Perkin Trans. 1, 1982, 2059. C. Yaroslavsky and E. Katchalski, Tetrahedron Lett., 1972, 5173. W. R. Roush, D. Feitler and J. Rebek, Tetrahedron Lett., 1974, 1391. C. R. Harrison, P. Hodge, B. 1. Hunt, E. Khoshdel and G. Richardson, J. Org. Chern., 1983, 48, 3721. C. R. Harrison, P. Hodge and W. 1. Rogers, Synthesis, 1977, 41. R. Caputo, C. Ferreri, S. Noviello and G. Palumbo, Synthesis, 1986,499. R. Caputo, E. Corrado, C. Ferreri and G. Palumbo, Synth. Commun., 1986,16, 1081. F. A. Cotton and P. A. Kibala, J. Arn. Chern. Soc., 1987, 109, 3308. 1. W. Kelly, P. L. Robinson and S. A. Evans, Jr., J. Org. Chern., 1985, 50, 5007. F. J. Waller, ACS Symp. Ser., 1986, 308, 42. G. A. Olah, G. K. S. Prakash, P. S. Iyer, M. Tashiro and T. Yamato, J. Org. Chem., 1987,52, 1881. G. A. Olah, P. S. Iyer and G. K. S. Prakash, Synthesis, 1986,513. T. Umemoto, Tetrahedron Lett., 1984, 25, 81. R. T. Taylor, ACS Syrnp. Ser., 1986,308, 132. P. H. Con net and K. E. Wetterhahn, Struct. Bonding (Berlin), 1983, 54, 93. 1. M. 1. Frechet, P. Darling and M. 1. Farrall, J. Org. Chem., 1981, 46, 1728. T. Brunelet, C. Jouitteau and G. Gelbard, J. Org. Chern., 1986, 51, 4016. S. E. Jacobson, F. Mares and P. M. Zambri, J. Arn. Chern. Soc., 1979, 101, 6938. S. E. Jacobson, F. Mares and P. M. Zambri, J. Arn. Chern. Soc., 1979, 101, 6946. R. T. Taylor and L. A. Flood, J. Org. Chern., 1983,48,5160. W. F. Brill, J. Org. Chern., 1986,51, 1149.

Polymeric Reagents 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112.

113

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