A Y

RX = BnCI, C13H27Br, Mel Scheme 4.108. The backbone amide-anchoring mode of the T2 linker [194].

Me3SiCI, CH2CI2 s

W N R1 rt.M0mln RKkiXk,.R2

507 508

Scheme 4.109. Synthesis of thioureas using the T2 linker [194].

fpO^N or R1X

509 510

Scheme 4.110. Synthesis of isothioureas using the T2 linker [514].

ful pharmacologically active compounds and the synthesis of guanidines in liquid phase has found widespread application in organic chemistry [515].

The T2 linker [193, 194] and the improved T2*-linker [183, 198] offer a unique possibility to immobilize and modify amine derivatives on solid support. Starting from immobilized amines, a three-step sequence based on coupling with isothio-cyanates, conversion to guanidines with amines, and subsequent cleavage presents an approach to the formation of guanidines in which all three substituents can be varied to a wide extent (Scheme 4.111) [195]. In addition, various other linkers for guanidines are available [85, 427, 516-524].

rvnan-r2

TFA CH2CI2 rt, 5 min r2

SYNH AgNOscrHgO n nh ___ ____ I\k N , MeCN,45°C, 12 h M ki

513 514

Scheme 4.111. Synthesis of functionalized guanidines [195].

Linkers for amidines Several techniques enable the synthesis of amidines on solid support. In most cases, benzyl-type linkers such as the indole linker [85], the Wang linker [525], or a carbamate system on the Wang linker [525] have been used.

Linkers for hydroxamic acids Hydroxamic acids are important building blocks in metalloproteinase inhibitors. Therefore, various linkers have been developed to satisfy these requirements.

The Wang linker is, for example, suitable for the detachment of hydroxamic acids as demonstrated in a cascade carbopalladation reaction [526] (Scheme 4.112).

515 516

5 examples

515 516

5 examples

Scheme 4.112. Carbonylation cascade on solid support toward hydroxamic acids according to Grigg et al. [526].

Alternatively, the THP, the Wang resin [527, 528], the Rink linker [529], trityl resin [530], PAL resin [528, 531], oxime resins [532], and others [285, 437, 533537] are suitable linkers for hydroxamic acids.

4.6.2.5 Linkers for Hydrazides and Semicarbazones

Only a few linkers have been used for the synthesis of hydrazides and semicarbazones, including a phthalamide linker cleavable with hydrazines [538] and the

T2 linker (Sect. 4.14.3.8) [466] (Scheme 4.113). Hydrazides can be cleaved from solid support using the trityl linkers, for example.

518 519

Scheme 4.113. Cleavage of semicarbazones from triazene resins [466].

4.6.2.6 Linkers for Cyclic Amides and Related Structures

Cyclic amide structures have found widespread application in the synthesis of biologically active compounds. Most of the linkers mentioned above for tertiary and secondary amide structures, ureas, and so forth, are suitable for the synthesis of cyclic amidic moieties; however, the most widespread applications are dedicated to the cyclative cleavage from the bead (Sect. 4.5.2).

Linkers for lactams The synthesis of b-lactams has been achieved using the hy-droxyaniline linker [508] (Scheme 4.114).

H N0 522

520 521

Scheme 4.114. Linker for b-lactams and secondary amides [508].

Linkers for other heterocycle-containing amidic structures Various techniques have been used for the synthesis of hydantoins [307, 308-313, 319], thiohydantoins [315], oxazolidinones [320, 321], diketopiperazines, frequently the ''byproducts'' of peptide synthesis [322-331], benzodiazepines and benzodiazepinones [306, 318, 332, 333], pyrazolones [335, 336], diketomorpholines [323], tetramic acids [337340], quinazolinediones [341], dihydropyrimidine-2,4-diones [342], quinolinones [343], tetrahydrocarbolines [326], thiazoles [317], and perhydrodiazepinones [327]. Sulfahydantoins (1,2,5-thiadiazolidin-3-one 1,1-dioxides) were prepared from ester-bound amino acids, which were first reductively alkylated, then reacted with sulfa-moyl chloride, and finally cleaved from the resin using 1,8-diazabicyclo[5.4.0]-undecene-7 (DBU) [344].

144 | 4 Linkers for Solid-phase Synthesis 4.6.3

Linkers for Ketones and Aldehydes

The anchoring of carbonyl compounds is generally based on established protecting groups. For example, alkyl hydrazones (Scheme 4.74) [449], sulfonyl hydrazones [539], and semicarbazones [540] can be used as linkers for aldehydes and ketones. Cleavage is conducted with acids, preferably in the presence of formaldehyde. In addition, aldehydes and ketones can be synthesized using photo-labile linkers, reduction of or nucleophilic additions to Weinreb amides [541-543], nucleophilic addition to thioesters [115, 544], oxidative cleavage (ozonolysis) of alkenes [545, 546], hydrolysis of enamines [419], and using various other methods [547].

Since their introduction some 20 years ago by Leznoff and coworkers [101, 102], acetal linkers have been used in the solid-phase synthesis of ketones and aldehydes [104, 548] (Scheme 4.115). Recently, it was demonstrated that even sterically hindered ketones could be attached to this support using scandium triflate and trime-thylorthoformate by acetal exchange reaction [104]. Similarly, thioketal structures are also suitable linkers for ketones [105] (Sect. 4.3.7.1).

1) RB(OH)2 (R = Aryl or Hetaryl) Pd(PPh3)4, Na2C03, DME, reflux, 24-48 h

Scheme 4.115. Cleavage of an acetal resin by Snieckus and coworkers [548].

Linkers for Alcohols, Phenols, Ethers, and Ketals 4.6.4.1 Linkers for Alcohols

Various linkers are suitable for the anchoring and release of alcohols; in particular, silyl ethers have been frequently used [20]. An early example of this type was provided by Farrall and Frechet [549]. Furthermore, these linkers are suitable for gly-copeptides [550], oligosaccharides [20], and prostaglandins (511) [123] (Scheme 4.116).

A direct loading of alcohols onto a silyl resin is possible using a hydridosilane [133], which might be better than the procedure described using silyl chloride [135]. A SEM (2-trimethylsilylethoxymethyl) linker is also suitable for the attachment and detachment of sterically encumbered alcohols. In this case, cleavage is conducted by tetrabutylammonium fluoride [21]. In addition to the silyl linkers, various ketal-based methods have been reported recently [23, 49, 69, 543, 551-553] (for a review, see [554]). The method of choice for various applications are the THP-type linkers [99,

C0/ C6H13-9-BBN

I - Na2C03,65 °C ^-v 1) Functionalization gj_0 -► (j . 2) 17.5 % HF/pyridine <jl

509 510 511

Scheme 4.116. Synthesis of prostaglandin by Ellman and coworkers [123].

108-114] (Sect. 4.3.3), as demonstrated in the synthesis of indolactams on solid support [555] (Scheme 4.117). However, other acetal linkers [100, 106] (Sect. 4.3.3) (Scheme 4.118) have also been used in this context. In addition, alcohols can be attached to a Wang or trityl resin, and can be cleaved in turn by the action of mild acids [533].

Alternatively, the benzyl group can be attached to the solid support, and hy-drogenolytic cleavage has been used to detach the molecules which are then usu-

R2 OUo^X

R2 OUo^X

THP type linker r2 = h

R1 1) r2cho

NaBH(OAc)3 n nh dMF/AoOH, rt 2) \2, 0 °c Pyr/dioxane

Et3N, dioxane, rt

Et3N, dioxane, rt

529 R3 530

Scheme 4.117. Synthesis of indolactam analogs according to Waldmann and coworkers [555].

Pd(PPh3)4, Na2C03

Ar = Ph, p-MeC6H4 Scheme 4.118. Synthesis of benzyl alcohols on solid support [100].

ally left with an oxygen or nitrogen functionality (cleavage of C-O Bn and C-N bond respectively) [29, 447]. The polymers in these cases are formally immobilized Z or Cbz groups. Interestingly, TentaGel and polystyrene give similar yields under identical conditions. Benzylic linkers can also be used advantageously in the presence of other benzylic protecting groups, since they can be removed in the same step [29] (Scheme 4.119).

NPhttk_ ^ 533 DOX PEG-OMe

67% OAcV

Acu NPhth

Scheme 4.119. Detachment of saccharides from polymeric benzyl-type protecting groups [29].

Finally, alcohols can be released from ester [117, 556], thioester [115], and amide resins using reductive methods (Sect. 4.4.2, Table 4.13). Furthermore, the reaction of Grignard reagents with thioesters has been reported to give tertiary alcohols [115]. Other anchoring groups are enzyme-labile linkers [285] and fluoride-sensitive linkers [557]. Cyclic ethers (tetrahydrofurans) are accessible via an iodo-lactonization approach [558, 559].

4.6.4.2 Linkers for Phenols

Similar to alcohols, phenols have been linked to anchors such as Wang [560], Rink [82], trityl [561], 2-chlorotrityl [562], and modified trityl [563] linkers. However, since these linkers are more acid stable, simple hydroxymethyl polystyrene can serve as a linker when cleaved by triflic acid [549, 557, 564, 565] (Scheme 4.120).

A direct method for the synthesis of phenol acetates has been demonstrated with the triazene T1 linker. An in situ cleavage and acylation proceeds with good yields when cleaved by acetic acid/acetic anhydride (Scheme 4.121) [186].

Linkers for Sulfur Compounds

4.6.5.1 Linkers for Thiols and Thioethers

Thiols can be synthesized using disulfides as remarkably stable linkers. The detachment proceeds in the presence of certain phosphines [232-235] or by exchange

-rR2

538 539

Scheme 4.120. Synthesis of quinolones from flavilylium salts according to Sato et al. [564].

-rR2

538 539

Scheme 4.120. Synthesis of quinolones from flavilylium salts according to Sato et al. [564].

or N^ph

N OAc

540 541

Scheme 4.121. Synthesis of phenol acetates (541) [186].

with thiols [566]. However, other suitable linkers are the Wang linker, cleavable by HF [33], Rink-type linkers [82, 567], thiocarbamates, cleavable by bases [568], dini-troaryl linker, cleavable by nucleophiles [229]; and others [569, 570]. Because thiols are prone to oxidation to give symmetrical disulfides, the latter were frequently found during cleavage if oxygen had not been strictly excluded.

4.6.5.2 Linkers for Sulfonamides

The synthesis of sulfonamides is similar to the strategies used for carboxamides. Therefore, primary sulfonamides were synthesized using, for example, the Rink resin (Scheme 4.122) [67].

The indole resin [85], the SASRIN linker [41, 44], and a reductively aminated acetophenone linker [54] are also suitable for the detachment for sulfonamides [24, 41, 67, 415, 571-574].

4.6.5.3 Linkers for Sulfonic Acids

Aryl and alkyl sulfonic acids have been detached from both Wang resin and SASRIN-type resins under mild conditions (20% TFA in CH2Cl2) after being at-

148 I 4 Linkers for Solid-phase Synthesis I

SnBu3

Rink amide resin

542 543

Scheme 4.122. Detachment of sulfonamides from the Rink resin [67].

tached to a solid support using the corresponding benzyl alcohol resins and sul-fonyl chlorides [575].

4.6.5.4 Linkers for Sulfones and Sulfoxides

Only one example has been presented so far for the synthesis of sulfones [405]. Starting from Merrifield resin, attachment of enantiopure sulfoximines and subsequent aldol-type coupling gives access to highly substituted sulfoximines. Cleavage proceeds under oxidative conditions using meta-chloroperbenzoic acid (mCPBA) to give sulfones (Scheme 4.123) [405].

3 545 547

Scheme 4.123. A linker for sulfones according to Gais and Hachtel [405].

4.6.5.5 Linkers for Sulfoximines

A linker for sulfoximines is the triazene T2 linker. The cleavage can be conducted under mild condition using 10% trimethylchlorosilane solution in dichloro-methane with retention of configuration [466].

Linkers for Hydrocarbons

Linkers for hydrocarbons are important tools in combinatorial chemistry for the synthesis of the lipophilic compounds required for modern drug research. As described above, access to hydrocarbons can proceed via the formation of either a C-C bond or a C-H bond. The latter strategy has been discussed in detail in Sect. 4.5.5 (traceless linkers), since the introduction of a hydrogen atom clearly is the prototype for this kind of linker.

4.6.6.1 Linkers for Alkanes

Alkanes have been synthesized on solid support, mostly by reduction of a C-X bond to a C-H functionality. This concept has been demonstrated using the selenium [165], sulfur [120], and stannane linkers. The formation of C-C bonds for the synthesis of alkanes has been described by Schiemann and Showalter [576]. Beginning with an aryl fragment attached to an immobilized benzotriazole, cleavage and subsequent C-C bond formation are achieved using organomagnesium compounds.

4.6.6.2 Linkers for Arenes and Heteroarenes

Alternatively, C-aryl bonds were formed using various cross-coupling methods, including stannanes [163, 169, 577], triazenes [187, 188] (Scheme 4.34), and boro-nates [148] as precursors.

Naphthalene derivatives are accessible via an electrocyclic ring opening of ben-zocyclobutane derivatives and a subsequent Diels-Alder reaction with dienophiles [578]. Hydrogenolytic removal of substrates from the solid support is important as it cleaves the substrate to form a C-H bond at the former binding site of the polymer. These types of linkers are also called traceless linkers (Sect. 4.5.5) [183].

The detachment of substituted arylsulfonates in the presence of a reducing agent such as formic acid provides a traceless cleavage. In this case, it is important that the arene core is substituted with electron-withdrawing substituents to enhance the yields [152]. This approach has been described previously (without experimental details) quite early in a patent and includes the possible derivatization of the intermediate s-aryl palladium aryl complex [579].

4.6.6.3 Linkers for Alkenes

Most of the linkers for alkenes are traceless linkers, such as those described in Sect. 4.5.5. Besides these, classical double-bond-forming reactions, such as the Wittig-Horner-Emmons [304, 305] or the Wittig reaction, can be used for the formation of C=C bonds [364]. Syntheses via metathesis (Sect. 4.4.4.2), for example the ring-closing metathesis of olefins [277, 580], have been used for the preparation of alkenes on solid support. In addition, multifunctional cleavage (Sect. 4.5.6) can be achieved using cross-metathesis.

Allylic groups can be attached to solid support via a sulfone, which is prepared by lithiation of polystyrene and subsequent treatment with sulfur dioxides and an allylbromide. After modification on the bead, cleavage proceeds with the action of a Grignard reagent in the presence of copper iodide. This overall SN2' alkylation provides a route to substituted alkenes [581] (Scheme 4.124).

The b-elimination generating alkenes has been used in the chemistry of the sulfone and selenium linkers [164, 582, 583] (Scheme 4.22). Similarly, polymer-bound 1-alkenylcyclobutylsulfones [274] (Scheme 4.33) or pentadienol carboxylates [273] (Scheme 4.32) were cleaved from a resin in the presence of suitable nucleo-philes and palladium catalysts to give substituted cyclobutylidene derivatives or di-enes, respectively.

RR R

548 549

Scheme 4.124. Nucleophilic substitution of an allylic sulfone [581].

4.6.6.4 Linkers for Alkynes

Two linkers have been used for the detachment of alkynes from solid support. Gibson and coworkers [355] have described the immobilization of alkynes onto polymer-bound triphenyl phosphine via a dicobaltoctacarbonyl arm. The detachment was conducted using air as the final oxidant.

Alkynes were obtained by the cleavage cross-coupling strategy of the T1 triazene resin (Scheme 4.26). In contrast to the Heck cleavage, these cleavage conditions give rise to di- and trimerization, thus making a chromatographic separation necessary [187] (Scheme 4.38).

Linkers for Aryl and Alkyl Halides

Aryl iodides have been synthesized by Moore et al. [179], starting from triazene resin by the action of methyl iodide (Sect. 4.14.3.8) (Scheme 4.125). Aryl iodides, bromides, and chlorides are also accessible from the triazene T1 linker using the corresponding trimethylsilyl halide (Scheme 4.126) [190].

SiMe3

550 R' 551

Scheme 4.125. The use of triazene anchoring groups in the synthesis of iodo arenes by Moore and coworkers [179].

SiMe3

The cleavage of triazene T2-linked primary amines with trimethylsilyl chloride, bromide, or iodide proceeds smoothly to give alkyl halides. This reaction proceeds presumably via the aliphatic diazonium ion. In some cases, a rearrangement was observed (Scheme 4.127).

Arylbromides and -iodides are accessible from silicon or germanium-linked arene fragments (Sect. 4.3.5). The released can be conducted with either bromine/ pyridine [126, 131] or iodochloride [126, 138].

Me3SiX

X = I, Br, CI 180-CI: X = CI 180-Br: X = Br 180-1: X= I

Scheme 4.126. Synthesis of aryl halides via the T1 triazene resin [190].

80:20-65:35

80:20-65:35

Scheme 4.127. Synthesis of alkyl halides via the triazene T2 linker [183, 196, 197].

The nucleophilic substitution of alkylsulfonates was used for the synthesis of alkyl iodides. Starting from the corresponding alcohols, attachment to a sulfonyl chloride and subsequent release from the bead was performed using sodium iodide [382, 465]. Allyl bromides can be released from a trityl linker if cleaved with hydrobromic acid in acetic acid [74]. Other methods start from with trityl linkers [74, 163, 382, 559].

Linkers for Heterocycles

Various methods are applicable in the synthesis of heterocycles [361, 362, 384, 584]. The cyclofragmentation of a certain class of sulfones leads to 3-arylbenzo-furans [160].

Linkers for Reactive Intermediates

Reactive intermediates cleaved from a solid support can be used for a subsequent functionalization. Thus, radicals, carbanions, and carbocations might then react with additional building blocks. This multifunctional cleavage mode (Sect. 4.14.5.6) has, for example, been used with the stannane, selenium (Sect. 4.14.3.7), and triazene linkers (Sect. 4.14.3.8).

152 | 4 Linkers for Solid-phase Synthesis 4.6.10

Linkers for Other Functional Groups 4.6.10.1 Linkers for Phosphonates

Phosphonates can be released from the resin using trimethylsilyl iodide (Scheme 4.128) [585]. They have been attached to a solid support using the Wang linker [586, 587, 588].

Ar = Ph, p-F-C6H4 Scheme 4.128. Synthesis of phosphonates using noncrosslinked polystyrene (NCPS) as support [585].

4.6.10.2 Linkers for Boronates

Diols are suitable anchors for boronic acids, as shown in the synthesis of hepatitis C virus proteinases [589].

4.6.10.3 Linkers for Silanes and Silanols

Silanols are accessible from silyl ether linker [127]. The silicon-oxygen bond can be cleaved with TFA via a protio-ipsodesilylation.

Overview for Linkers for Functional Groups

Table 4.20 gives a short overview of the different linker families, as described in Chapter X.

Conclusion, Summary and Outlook

In recent years, various new types of linkers have emerged. The design of a new anchoring group can be essential for the success of a synthesis, especially for small molecules on a solid support. Linker, cleavage conditions, and functional groups are associated with each other. Therefore, the decision to use one specific linker type has to be balanced with the requirements of the library to be synthesized.

Although the "perfect" or "universal" linker has not yet been developed, and will prove unattainable, interesting new developments increase the flexibility of solid-phase synthesis by traceless (Sect. 4.5.5) and multifunctional cleavage (Sect.

Ar = Ph, p-F-C6H4 Scheme 4.128. Synthesis of phosphonates using noncrosslinked polystyrene (NCPS) as support [585].

NCPS

NCPS

Tab. 4.20. Short overview for various linker types.

Functional group Benzyl- Ketal/ Esters/ Silane Triazene Selenium/

type acetal amide linkers linkers sulfur/ linkers linkers linkers stannyl linkers

Functional group Benzyl- Ketal/ Esters/ Silane Triazene Selenium/

type acetal amide linkers linkers sulfur/ linkers linkers linkers stannyl linkers

r3n

P

P

P

P

P

ROH

P

P

P

P

R2NCOR

P

P

P

RH (traceless) (Sect. 4.5.5)

P

P

P

P

P

RCO2H

P

P

Heterocycles

P

P

P

BAL

P

P

RX

P

P

Safety-catch option

P

P

P

Multifunctional cleavage

P

P

P

Photo cleavage

P

4.5.6). While traceless linkers provide access to unsubstituted compounds with ''no memory'' of solid-phase synthesis, multifunctional cleavage allows the introduction of various new functionalities during cleavage from the resin. Backbone amide linkers present new opportunities for solid-phase synthesis of small amidic structures, and cyclization-release strategies provide an opportunity to create novel carbo- and heterocyclic structures upon cleavage.

An anchor for traceless linking can also be a safety-catch linker (Sect. 4.5.1), or it can be suitable for multifunctional cleavage. Linker systems allow the introduction of certain atoms or molecule fragments and will play an important role in the development of diverse organic substance libraries. It is important to point out that the final diversification is achieved in the cleavage step and not in an additional solution-phase reaction step after the cleavage. However, only a few linker systems that are applicable to a wider range of substrates have been developed so far. As these linker systems offer the widest possibilities for the final diversification of a synthesized library, they will be the subject of increasing attention in the future.

References

1 E. M. Gordon, R. W. Barrett, W. J. Dower, S. P. A. Fodor, M. A. Gallop, J. Med. Chem. 1994, 37, 1385-1401.

3 R. W. Armstrong, A. P. Combs, P. A. Tempest, S. D. Brown, T. A.

4 F. Balkenhohl, C. von dem Bussche-HUnnefeld, A. Lansky, C. Zechel, Angew. Chem. Int. Ed. 1996, 35, 2289-2337; Angew. Chem. 1996, 108, 2436-2488.

5 J. S. FrUchtel, G. Jung in: Combi natorial Peptide and Nonpeptide Libraries: A Handbook. Jung, G. (ed.), VCH, Weinheim 1996, pp. 19-78.

6 P. H. H. Hermkens, H. C. J. Otrenheijm, D. Rees, Tetrahedron 1996, 52, 4527-4554.

7 I. W. James, Tetrahedron 1999, 55, 4855-4946.

8 F. Guillier, D. Oram, M. Bradley, Chem. Rev. 2000, 100, 2091-2157.

9 A. C. Comely, S. E. Gibson, Angew. Chem. Int. Ed. 2001, 40, 1012-1032; Angew. Chem. 2001, 113, 1043-1063.

10 F. Zaragoza Dorwald, Organic Synthesis on Solid-phase: Supports, Linkers, Reactions, Wiley-VCH, Weinheim 2000.

11 B. Carboni, F. Carreaux, J. F. Pilard, Actual. Chimique 2000, 9-13.

12 D. Maclean, J. J. Baldwin, V. T. Ivanov, Y. KaTo, A. Shaw, P. Schneider, E. M. Gordon, Pure Appl. Chem. 1999, 71, 2349-2365.

13 B. J. Backes, J. Ellman, Curr. Opin. Chem. Biol. 1997, 1, 86-93.

14 C. T. Bui, F. A. Rasoul, F. Ercole, Y. Pham, N. J. Maeji, Tetrahedron Lett. 1998, 39, 9279-9282.

15 W. Rapp, in: Combinatorial Peptide and Nonpeptide Libraries: A Handbook. Jung, G. (ed.), VCH, Weinheim 1996, pp. 425-464.

16 A. Svensson, T. F ex, J. Kihlberg, J. Comb. Chem. 2000, 2, 736-748.

17 J. R. Hauske, P. Dorf, Tetrahedron Lett. 1995, 36, 1589-1592.

18 K. Akaji, Y. Kiso, L. A. Carpino, J. Chem. Soc., Chem. Commun. 1990, 584-586.

19 T. H. Chan, W. Q. Huang, J. Chem. Soc., Chem. Commun. 1985, 909911.

20 J. T. Randolph, K. F. McClure, S. J. Danishefsky, J. Am. Chem. Soc. 1995, 117, 5712-5719.

22 R. B. Merrifield, J. Am. Chem. Soc. 1963, 85, 2149-2154.

23 S.-S. Wang, J. Am. Chem. Soc. 1973, 95, 1328-1333.

24 B. Yan, N. Nguyen, L. Liu, G. Holland, B. Raju, J. Comb. Chem. 2000, 2, 66-74.

25 M. Mergler, R. Tanner, J. Gosteli, P. Grogg, Tetrahedron Lett. 1988, 22, 4005-4008.

26 M. Mergler, J. Gosteli, P. Grogg, P. Nyfeler, R. Tanner, Chimia 1999, 53, 29-34.

27 F. Albericio, G. Barany, Tetrahedron Lett. 1991, 32, 1015-1018.

28 E. Atherton, C. J. Logan, R. C. Sheppard, J. Chem. Soc., Perkin Trans. 1 1981, 538-546.

29 S. Manabe, Y. Ito, T. Ogawa, Synlett 1998, 628-630.

30 G.-s. Lu, S. Mojsov, J. P. Tam, R. B. Merrifield, J. Org. Chem. 1981, 46, 3433-3436.

31 T. L. Deegan, O. W. Gooding, S. Baudart, J. A. Porco, Abstr., Pap. Am. Chem Soc. 1997, 214, 238-ORGN.

32 S. Kobayashi, Y. Aoki, Tetrahedron Lett. 1998, 39, 7345-7348.

33 D. R. Englebretsen, B. G. Garnham, D. A. Bergman, P. F. Alewood, Tetrahedron Lett. 1995, 36, 8871-8874.

34 G. Barany, R. B. Merrifield in: The Peptides. Gross, E., Meienhofer, J. (eds), Academic Press, New York 1979.

35 A. R. Mitchell, B. W. Erickson, M. N. Ryabtsev, R. S. Hidges, R. B. Merrifield, J. Am. Chem. Soc. 1976, 98, 7357-7362.

36 D. Seebach, A. Thaler, D. Blaser, S. Ko, Helv. Chim. Acta 1991, 74, 11021119.

37 J. V. Aldrich, S. C. Story, Int. J. Pept. Protein Res. 1992, 39, 87-92.

38 R. C. Sheppard, B. Williams, Int. J. Pept. Protein Res. 1982, 20, 451-454.

39 R. M. Valerio, A. M. Bray, N. J. Maeji, Int. J. Pept. Protein Res. 1994, 44, 158-165.

40 F. Albericio, G. Barany, Int. J. Pept. Protein Res. 1985, 26, 92-97.

41 A. M. Fivush, T. M. Willson, Tetrahedron Lett. 1997, 38, 7151-7154.

42 X. Ouyang, N. Tamayo, A. S. Kiselyov, Tetrahedron 1999, 55, 28272834.

43 D. Sarantakis, J. J. Bicksler, Tetrahedron Lett. 1997, 38, 7325-7328.

44 E. E. Swayze, Tetrahedron Lett. 1997, 38, 8465-8468.

46 F. Albericio, N. Kneib-Coedoniee, S. Biancalana, L. Gera, R. I. Masada, D. Huson, G. Baeany, J. Org. Chem. 1990, 55, 3730-3743.

47 C. G. Boojamra, K. M. Burow, J. A. Ellman, J. Org. Chem. 1995, 60, 5742-5743.

48 K. Barlos, O. Chatzi, D. Geatos, G. Stavropulos, Int. J. Pept. Protein Res. 1991, 37, 513-520.

49 V. KrchNAk, L. Szabo, J. Vagner, Tetrahedron Lett. 2000, 41, 2835-2848.

50 K. J. Jensen, J. Alsina, M. F. Songstee, J. Vagner, F. Albericio, G. Baeany, J. Am. Chem. Soc. 1998, 120, 5441-5452.

51 L. S. Harikrishnan, H. D. H. Showaltee, Synlett 2000, 1339-1341.

52 R. Ramage, C. A. Barron, S. Bidecki, D. W. Thomas, Tetrahedron Lett. 1987, 28, 4105-4108.

53 R. Ramage, C. A. Barron, S. Bielecki, R. Holden, D. W. Thomas, Tetrahedron 1992, 48, 499-514.

54 C. T. Bui, A. M. Bray, F. Eecole, Y. Pham, F. A. Rasoul, N. J. Maeji, Tetrahedron Lett. 1999, 40, 3471-3474.

55 H. Chao, M. S. Bernatowicz, G. R. Matsueda, J. Org. Chem. 1993, 58, 2640-2644.

56 H. G. Chao, M. S. Bernatowicz, P. D. Reiss, C. E. Klimas, G. R. Matsueda, J. Am. Chem. Soc. 1994, 116, 1746-1752.

57 P. G. Pietta, G. R. Marshall, J. Chem. Soc. D 1970, 650-651.

58 G. R. Matsueda, J. M. Stewart, Peptides 1981, 22, 45-50.

59 M. E. Theoclitou, J. M. Osteesh, V. Hamashin, R. A. Houghten, Tetrahedron Lett. 2000, 41, 20512054.

60 R. C. Orlowski, R. Waltee, D. Winklee, J. Org. Chem. 1976, 41, 3701-3705.

61 D. S. Brown, J. M. Revill, R. E. Shute, Tetrahedron Lett. 1998, 39, 8533-8536.

63 J. P. Tam, R. D. DiMaechi, R. ß. Merrifield, Tetrahedron Lett. 1981, 22, 2851-2854.

64 M. Patek, M. Lebl, Tetrahedron Lett. 1991, 32, 3891-3894.

65 Y. Kiso, T. Fukui, S. Tanaka, T. Kimuea, K. Akaj, Tetrahedron Lett. 1994, 35, 3571-3574.

66 H. Rink, Tetrahedron Lett. 1987, 28, 3787-3790.

67 K. A. Beaver, A. C. Siegmund, K. L. Spear, Tetrahedron Lett. 1996, 37, 1145-1148.

68 A. L. Marzinzik, E. R. Felder, Tetrahedron Lett. 1996, 37, 1003-1006.

69 A. Routledge, H. T. Stock, S. L. Flitsch, N. J. Turner, Tetrahedron Lett. 1997, 38, 8287-8290.

70 P. Sieber, Tetrahedron Lett. 1987, 28, 2107-2110.

71 Y. X. Han, S. L. Bontems, P. Hegyes, M. C. Munson, C. A. Minor, S. A. Kates, F. Albericio, G. Baeany, J. Org. Chem. 1996, 61, 6326-6339.

72 W. C. Chan, S. L. Melloe, J. Chem. Soc., Chem. Commun. 1995, 14751477.

73 M. Noda, M. Yamaguchi, E. Ando, K. Takeda, K. Nokihaea, J. Org. Chem. 1994, 59, 7968-7975.

74 J. M. J. Frechet, L. Nuyens, Can.J. Chem. 1976, 54, 926-934.

75 T. M. Fyles, C. C. Leznoff, Can. J. Chem. 1976, 54, 935-942.

76 K. Barlos, D. Gatos, J. Kallitsis, D. Papaioannou, P. Sotieiu, Liebigs Ann. Chem. 1988, 1079-1081.

77 K. Barlos, D. Gatos, J. Kallitsis, G. Papaphotiu, W. Yao, W. SchAfee, Tetrahedron Lett. 1989, 30, 3943-3946.

78 S. Eleftheriou, D. Gatos, A. Panagopoulos, S. Stathopoulos, K. Barlos, Tetrahedron Lett. 1999, 40, 2825-2828.

79 C. C. Zikos, N. G. Feedieeigos, Tetrahedron Lett. 1994, 35, 17671768.

80 L. Leondiadis, I. Vassiliadou, C. Zikos, N. Feedeeigos, E. Livaniou, D. S. Ithakissios, G. P. Evan-geiatos, J. Chem. Soc., Perkin Trans 11996, 10, 971-975.

81 T. Wieiand, C. Bier, P. Fleckenstein, Liebigs Ann. Chem. 1972, 756, 14-19.

82 R. S. Garigipati, Tetrahedron Lett. 1997, 38, 6807-6810.

84 N. Thieriet, F. Guibe, F. Albericio, Org. Lett. 2000, 2, 1815-1817.

85 K. G. Estep, C. E. Neipp, L. M. S. Stramiellü, M. D. Adam, M. P. Allen, S. Robinson, E. J. Roskamp, J. Org. Chem. 1998, 63, 5300-5301.

86 H. Kunz, B. Dombo, Angew. Chem. Int. Ed. Engl. 1988, 12, 711-712; Angew. Chem. 1988, 100, 732-734.

87 H. Kunz, W. Kosch, J. MArz (Orpegen GmbH), Patent No. US5214195, 1990.

88 C. Schumann, L. Seyfarth, G. Greiner, S. Reissmann, J. Pept. Res. 2000, 55, 428-435.

89 T. Johnson, R. C. Sheppard, J. Chem. Soc., Chem. Commun. 1991, 1653-1655.

90 O. Seitz, H. Kunz, J. Org. Chem. 1997, 62, 813-826.

91 O. Seitz, Tetrahedron Lett. 1999, 40, 4161-4164.

92 O. Seitz, C. H. Wong, J. Am. Chem. Soc. 1997, 119, 8766-8776.

93 B. Biankemeyer-Menge, R. Frank, Tetrahedron Lett. 1988, 29, 58715874.

94 K. Kaljuste, A. Unden, Tetrahedron Lett. 1996, 37, 3031-3034.

95 F. GuibE, O. Dangles, G. Baiavoine, A. Loffet, Tetrahedron Lett. 1989, 30, 2641-2644.

96 X. H. Zhang, R. A. Jones, Tetrahedron Lett. 1996, 37, 3789-3790.

97 K. C. Nicoiaou, N. Winssinger, R. Hughes, C. Smethurst, S. Y. Cho, Angew. Chem. Int. Ed. 2000, 39, 10841089; Angew. Chem. 2000, 112, 11261130.

98 O. Seitz, H. Kunz, Angew. Chem. Int. Ed. 1995, 34, 803-805; Angew. Chem. 1995, 107, 901-904.

99 L. A. Thompson, J. A. Ellman, Tetrahedron Lett. 1994, 35, 9333-9336.

100 S.-e. Yoo, Y.-D. Gong, M.-Y. Choi, J.-s. Seo, K. Y. Yi, Tetrahedron Lett. 2000, 41, 6415-6418.

101 C. C. Leznoff, J. Y. Wong, Can. J. Chem. 1973, 51, 3756-3764.

102 C. C. Leznoff, S. Greenberg, Can. J. Chem. 1976, 54, 3824-3829.

104 R. Maltais, M. Berube, O. Marion, R. Labrecque, D. Poirier, Tetrahedron Lett. 2000, 41, 1691-1694.

105 C. M. Huwe, H. KUnzer, Tetrahedron Lett. 1999, 40, 683-686.

106 G. T. Wang, S. Li, N. Wideburg, G. A. Krafft, D. J. Kempf, J. Med. Chem.

1995, 38, 2995-3002.

107 S. Q. Chen, K. D. Janda, Tetrahedron Lett. 1998, 39, 3943-3946.

1996, 61, 4494-4495.

109 E. K. Kick, J. A. Ellman, J. Med. Chem. 1995, 38, 1427-1430.

110 G. Wess, K. Bock, H. Kleine, M. Kurz, W. Guba, H. Hemmerle, E. Lopez-Calle, K. H. Baringhaus, H. Glombik, A. Enhsen, W. Kramer, Angew. Chem. Int. Ed. 1996, 35, 22222224; Angew. Chem. 1996, 108, 23632366.

111 W. H. Pearson, R. B. Ciark, Tetrahedron Lett. 1997, 38, 7669-7672.

112 S. E. Yoo, J. S. Seo, K. Y. Yi, Y. D. Gong, Tetrahedron Lett. 1997, 38, 1203-1206.

113 J. H. Ryu, J. H. Jeong, Arch. Pharm. Res. 1999, 22, 585-591.

114 M. Ramaseshan, J. W. Ellingboe, Y. L. Dory, P. Deslongchamps, Tetrahedron Lett. 2000, 41, 4743-4749.

115 P. J. May, M. Bradley, D. C. Harrowven, D. Pallin, Tetrahedron Lett. 2000, 41, 1627-1630.

116 Y. Kondo, T. Komine, M. Fujinami, M. Uchiyama, T. Sakamoto, J. Comb. Chem. 1999, 1, 123-126.

117 L. F. Tietze, A. Steinmetz, Angew. Chem. Int. Ed. 1996, 35, 651-652; Angew. Chem. 1996, 108, 682-683.

118 U. Grether, H. Waldmann, Angew. Chem. Int. Ed. 2000, 39, 1629-1632; Angew. Chem. 2000, 112, 16881691.

119 C. R. Millington, R. Quarrel, G. Lowe, Tetrahedron Lett. 1998, 39, 7201-7204.

120 J. R. Horton, L. M. Stamp, A. Routledge, Tetrahedron Lett. 2000, 41, 9181-9184.

121 P. Soucy, Y. L. Dory, P. Deslongchamps, Synlett 2000, 1123-1126.

122 D. G. Mullen, G. Barany, J. Org. Chem. 1988, 53, 5240-5248.

123 L. A. Thompson, F. L. Moore, Y. C. Moon, J. A. Ellman, J. Org. Chem. 1998, 63, 2066-2067.

124 B. Chenera, J. A. Finkelstein, D. F. Veber, J. Am. Chem. Soc. 1995, 117, 11999-12000.

125 M. J. Plunkett, J. A. Ellman, J. Org. Chem. 1995, 60, 6006-6007.

126 Y. Han, S. D. Walker, R. N. Young, Tetrahedron Lett. 1996, 37, 27032706.

127 T. L. Boehm, H. D. H. Showalter, J. Org. Chem. 1996, 61, 6498-6499.

128 C. A. Briehn, T. Kirschbaum, P. BAuerle, J. Org. Chem. 2000, 65, 352359.

129 T. Kirschbaum, C. A. Briehn, P. BAuerle, Perkin 1 2000, 1211-1216.

130 F. X. Woolard, J. Paetsch, J. A. Ellman, J. Org. Chem. 1997, 62, 6102-6103.

131 M. J. Plunkett, J. A. Ellman, J. Org. Chem. 1997, 62, 2885-2893.

132 NovaBiochem, Catalog and Peptide Synthesis Handbook 2000.

1998, 39, 2711-2714.

134 K. A. Newlander, B. Chenera, D. F. Veber, N. C. F. Yim, M. L. Moore, J. Org. Chem. 1997, 62, 6726-6732.

135 Y. H. Hu, J. A. Porco, J. W. Labadie, O. W. Gooding, B. M. Trost, J. Org. Chem. 1998, 63, 4518-4521.

136 N. D. Hone, S. G. Davies, N. J. Devereux, S. L. Taylor, A. D. Baxter, Tetrahedron Lett. 1998, 39, 897-900.

137 R. Maltais, M. R. Tremblay, D. Poirier, J. Comb. Chem. 2000, 2, 604-614.

138 S. D. Brown, R. W. Armstrong, J. Org. Chem. 1997, 62, 7076-7077.

1999, 1611-1616.

140 Y. Lee, R. B. Silverman, J. Am. Chem. Soc. 1999, 121, 8407-8408.

141 S. Curtet, M. Langlois, Tetrahedron Lett. 1999, 40, 8563-8566.

142 A. Studer, S. Hadida, R. Ferritto, S. Y. Kim, P. Jeger, P. Wipf, D. P. Curran, Science 1997, 275, 823-826.

144 M. Schuster, N. Lucas, S. Blechert, Chem. Commun. 1997, 823-824.

145 L. S. Harikrishnan, H. D. H. Showalter, Tetrahedron 2000, 56, 515-519.

146 J. M. J. Frechet, L. J. Nuyens, E. Seymour, J. Am. Chem. Soc. 1979, 101, 432-436.

147 C. Pourbaix, F. Carreaux, B. Carboni, H. Deleuze, Chem. Commun. 2000, 1275-1276.

148 W. Li, K. Burgess, Tetrahedron Lett.

1999, 40, 6527-6530.

149 H. S. Overkleeft, P. R. Bos, B. G. Hekking, E. J. Gordon, H. L. Ploegh, B. M. Kessler, Tetrahedron Lett. 2000, 41, 6005-6009.

150 D. L. Marshall, I. E. Liener, J. Org. Chem. 1970, 35, 867-868.

151 Z. Timar, T. Gallagher, Tetrahedron Lett. 2000, 41, 3173-3176.

152 S. J. Jin, D. P. Holub, D. J. Wustrow, Tetrahedron Lett. 1998, 39, 3651-3654.

153 K. C. Nicolaou, P. S. Baran, Y. L. Zhong, J. Am. Chem. Soc. 2000, 122, 10246-10248.

154 C. Vanier, F. LorgE, A. Wagner, C. Mioskowski, Angew. Chem. Int. Ed.

2000, 39, 1679-1683; Angew. Chem. 2000, 112, 1745-1749.

155 K. W. Jung, X. Y. Zhao, K. D. Janda, Tetrahedron 1997, 53, 6645-6652.

156 K. W. Jung, X. Y. Zhao, K. D. Janda, Tetrahedron Lett. 1996, 37, 6491-6494.

157 X. Zhao, K. D. Janda, Bioorg. Med. Chem. Lett. 1998, 8, 2439-2442.

158 X. Y. Zhao, K. D. Janda, Tetrahedron Lett. 1997, 38, 5437-5440.

159 H. C. Zhang, K. K. Brumfield, B. E. Maryanoff, Tetrahedron Lett. 1997, 38, 2439-2442.

160 K. C. Nicolaou, S. A. Snyder, A. Bigot, J. A. Pfefferkorn, Angew. Chem. Int. Ed. 2000, 39, 1093-1096; Angew. Chem. 2000, 112, 1135-1138.

161 I. Sucholeiki, Tetrahedron Lett. 1994, 35, 7307-7310.

162 F. W. Forman, I. Sucholeiki, J. Org. Chem. 1995, 60, 523-528.

163 K. C. Nicolaou, N. Winssinger, J. Pastor, F. Murphy, Angew. Chem.

Int. Ed. 1998, 37, 2534-2537; Angew. Chem. 1998, 110, 2677-2680.

164 K. C. NicoiAou, J. Pastor, S. Barluenga, N. Winssinger, Chem. Commun. 1998, 1947-1948.

165 T. Ruhiand, K. Andersen, H. Pedersen, J. Org. Chem. 1998, 63, 9204-9211.

166 B. Chenera (Smithkline Beecham Corporation), Patent No. WO PCT. 98/17695, 1995.

167 G. Marchand, J. F. Piiard, J. Simonet, Tetrahedron Lett. 2000, 41, 883-885.

168 C. Garcia-Echeverria, Tetrahedron Lett. 1997, 38, 8933-8934.

170 R. Michels, M. Kato, W. Heitz, Makromol. Chem. 1976, 177, 23112320.

171 H. E. Russell, R. W. A. Luke, M. Bradley, Tetrahedron Lett. 2000, 41, 5287-5290.

172 K. C. NicoiAou, J. A. Pfefferkorn, A. J. Roecker, G. Q. Cao, S. Barluenga, H. J. Mitchell, J. Am. Chem. Soc. 2000, 122, 9939-9953.

173 K. C. NicoiAou, J. A. Pfefferkorn, H. J. Mitchell, A. J. Roecker, S. Barluenga, G. Q. Cao, R. L. Affleck, J. E. Lillig, J. Am. Chem. Soc. 2000, 122, 9954-9967.

174 K. C. NicoiAou, J. A. Pfefferkorn, G. Q. Cao, Angew. Chem. Int. Ed. 2000, 39, 734-739; Angew. Chem. 2000, 112, 750-755.

175 K. C. NicoiAou, G. Q. Cao, J. A. Pfefferkorn, Angew. Chem. Int. Ed. 2000, 39, 739-743; Angew. Chem. 2000, 112, 755-759.

176 K. C. NicoiAou, A. J. Roecker, J. A. Pfefferkorn, G. Q. Cao, J. Am. Chem. Soc. 2000, 122, 2966-2967.

177 K. C. NicoiAou, H. J. Mitchell, K. C. Fyiaktakidou, H. Suzuki, R. M. Rodríguez, Angew. Chem. Int. Ed. 2000, 39, 1089-1093; Angew. Chem. 2000, 112, 1131-1135.

178 K. C. NicoiAou, C. N. C. Boddy, S. BrAse, N. Winssinger, Angew. Chem. Int. Ed. 1999, 38, 2096-2152; Angew. Chem. 1999, 111, 2230-2287.

180 J. K. Young, J. C. Nelson, J. S. Moore, J. Am. Chem. Soc. 1994, 116, 10841-10842.

181 L. Jones, J. S. Schumm, J. M. Tour, J. Org. Chem. 1997, 62, 1388-1410.

182 S. Brase, D. Enders, J. Kobberling, F. Avemaria, Angew. Chem. Int. Ed. 1998, 37, 3413-3415; Angew. Chem.

1998, 110, 3614-3616.

183 S. Brase, S. Dahmen, Chem. Eur. J. 2000, 6, 1899-1905.

184 M. Lormann, S. Dahmen, S. Brase, Tetrahedron Lett. 2000, 41, 38133816.

185 S. Schunk, D. Enders, Org. Lett. 2000, 2, 907-910.

186 M. Lormann, S. Brase, unpublished.

187 S. Brase, M. Schroen, Angew. Chem. Int. Ed. 1999, 38, 1071-1073; Angew. Chem. 1999, 111, 1139-1142.

188 A. de Meijere, H. NUske, M. EsSayed, T. Labahn, M. Schroen, S. Brase, Angew. Chem. Int. Ed. 1999, 38, 3669-3672; Angew. Chem. 1999, 111, 3881-3884.

189 F. Avemaria, V. Zimmermann, S. Brase, Org. Lett. 2001, submitted.

190 S. Brase, M. Lormann, J. Heuts, Chem. Eur. J. 2001, in preparation.

191 S. Brase, S. Dahmen, J. Heuts, Tetrahedron Lett. 1999, 40, 62016203.

192 M. E. P. Lormann, C. H. Walker, S. Brase, Chem. Commun. 2001, submitted.

193 S. Brase, J. Kobberling, D. Enders, M. Wang, R. Lazny, S. Brandtner, Tetrahedron Lett. 1999, 40, 21052108.

194 S. Brase, S. Dahmen, M. Pfefferkorn, J. Comb. Chem. 2000, 2, 710717.

195 S. Dahmen, S. Brase, Org. Lett. 2000, 2, 3563-3565.

196 a) C. Pilot, Maitrise de Chimie

1999, RWTH Aachen/Universite Strasbourg. b) C. Pilot, S. Dahmen, F. Lauterwasser, S. Brase, Tetrahedron Lett. 2001, 42, 9179-9181.

Int. Ed. 2000, 39, 3681-3683; Angew. Chem. 2000, 112, 3827-3830.

199 J. Heuts, S. Brase, unpublished.

200 J. Rademann, J. Smerdka, G. Jung, P. Grosche, D. Schmid, Angew. Chem. Int. Ed. 2001, 40, 381-385.

201 S. Brase, S. Dahmen, M. Schroen, unpublished.

202 S. Brase, S. Dahmen, C. Popescu, M. Schroen, F.-J. Wortmann, Polym. Degr. Stab. in press.

203 W. D. F. Meutermans, P. F. Alewood, Tetrahedron Lett. 1995, 36, 7709-7712.

204 R. B. Merrifield, L. D. Vizioli, H. G. Boman, Biochemistry 1982, 21, 5020-5031.

205 J. P. Tam, W. F. Heath, R. B. Merrifield, J. Am. Chem. Soc. 1983, 105, 6442-6455.

206 H. Yaijima, N. Fujii, H. Ogawa, H. Kawatani, J. Chem. Soc., Chem. Commun. 1974, 107-108.

207 A. R. Mitchell, S. B. H. Kent, M. Engelhard, R. B. Merrifield, J. Org. Chem. 1978, 43, 2845-2852.

208 K. C. Nicoiaou, N. Winssinger, J. Pastor, F. DeRoose, J. Am. Chem. Soc. 1997, 119, 449-450.

209 A. Mazurov, Tetrahedron Lett. 2000, 41, 7-10.

210 D. R. Englebretsen, C. T. Choma, G. T. Robillard, Tetrahedron Lett. 1998, 39, 4929-4932.

211 P. R. Hansen, C. E. Olsen, A. Holm, Bioconj. Chem. 1998, 9, 126-131.

212 Y. X. Han, G. Barany, J. Org. Chem. 1997, 62, 3841-3848.

213 M. C. Munson, G. Barany, J. Am. Chem. Soc. 1993, 115, 10203-10210.

214 G. Mezo, N. Mihaia, G. Koczan, F. Hudecz, Tetrahedron 1998, 54, 67576766.

215 D. Limai, J. P. Briand, P. Dalbon, M. Jolivet, J. Pept. Res. 1998, 52, 121-129.

216 B. Yan, H. Gstach, Tetrahedron Lett. 1996, 37, 8325-8328.

217 J. Biake, C. H. Li, J. Am. Chem. Soc. 1968, 90, 5882-5884.

218 E. G. Mata, Tetrahedron Lett. 1997, 38, 6335-6338.

219 J. D. Winkler, W. McCoull, Tetrahedron Lett. 1998, 39, 4935-4936.

220 M. J. Plater, A. M. Murdoch, J. R. Morphy, Z. Rankovic, D. C. Rees, J. Comb. Chem. 2000, 2, 508-512.

221 J. R. Morphy, Z. Rankovic, D. C. Rees, Tetrahedron Lett. 1996, 37, 32093212.

222 P. H. Toy, T. S. Reger, K. D. Janda, J. Comb. Chem. 2000, 2, 2205-2207.

223 A. R. Brown, D. C. Rees, Z. Rankovic, J. R. Morphy, J. Am. Chem. Soc. 1997, 119, 3288-3295.

224 X. H. Ouyang, R. W. Armstrong, M. M. Murphy, J. Org. Chem. 1998, 63, 1027-1032.

225 X. H. Ouyang, A. S. Kiselyov, Tetrahedron Lett. 1999, 40, 58275830.

226 W. Bannwarth, J. Huebscher, R. Barner, Bioorg. Med. Chem. Lett. 1996, 6, 1525-1528.

227 S. R. Chhabra, H. Parekh, A. N. Khan, B. W. Bycroft, B. Kellam, Tetrahedron Lett. 2001, 42, 2189-2192.

228 S. R. Chhabra, A. N. Khan, B. W. Bycroft, Tetrahedron Lett. 2000, 41, 1099-1102.

229 J. D. Giass, A. Taiansky, Z. Gronka, I. L. Schwartz, R. Walter, J. Am. Chem. Soc. 1974, 96, 6476-6480.

230 A. M. Bray, N. J. Maeji, A. G. Jhingran, R. M. Valerio, Tetrahedron Lett. 1991, 32, 6163-6166.

231 G. Faita, A. Paio, P. Quadrelli, F. Rancati, P. Seneci, Tetrahedron Lett. 2000, 41, 1265-1269.

232 A. J. Souers, A. A. Virgilio, S. S. SchUrer, J. A. Ellman, T. P. Kogan, H. E. West, W. Ankener, P. Vanderslice, Bioorg. Med. Chem. Lett. 1998, 8, 2297-2302.

233 K. Kurokawa, H. Kumihara, H. Kondo, Bioorg. Med. Chem. Lett. 2000, 10, 1827-1830.

234 A. A. Virgilio, S. C. SchUrer, J. A. Ellman, Tetrahedron Lett. 1996, 37, 6961-6964.

235 A. J. Souers, A. A. Virgilio, A. Rosenquist, W. Fenuik, J. A. Ellman, J. Am. Chem. Soc. 1999, 121, 1817-1825.

236 F. Berst, A. B. Holmes, M. Ladlow, P. J. Murray, Tetrahedron Lett. 2000, 41, 6649-6653.

Waldmann, Angew. Chem. Int. Ed. 1999, 38, 1073-1077; Angew. Chem.

1999, 111, 1142-1145.

238 D. H. Rich, S. K. Gurwara, J. Am. Chem. Soc. 1975, 97, 1575-1579.

239 S. J. Teague, Tetrahedron Lett. 1996, 37, 5751-5754.

240 R. P. Hammer, F. Albericiü, E. Giralt, G. Barany, Int. J. Pept. Protein Res. 1990, 28, 31-45.

241 C. P. Holmes, D. G. Jones, J. Org. Chem. 1995, 60, 2318-2319.

242 S. Peukert, B. Giese, J. Org. Chem. 1998, 63, 9045-9051.

244 H. B. Lee, S. Baiasubramanian, J. Org. Chem. 1999, 64, 3454-3460.

246 J. P. Tam, R. D. Dimarchi, R. B. Merrifield, Int. J. Pept. Protein Res. 1980, 16, 412-425.

247 D. H. Rich, S. K. Gurwara, J. Chem. Soc., Chem. Commun. 1973, 610-611.

248 A. Aiyaghosh, V. N. R. Piliai, Tetrahedron 1988, 44, 6661-6666.

249 U. Zehavi, A. Patchornik, J. Am. Chem. Soc. 1973, 95, 5673-5677.

250 D. L. Whitehouse, S. N. Savinov, D. J. Austin, Tetrahedron Lett. 1997, 38, 7851-7852.

251 D. J. Yoo, M. M. Greenberg, J. Org. Chem. 1995, 60, 3358-3364.

252 M. Rinnova, M. Novakova, V. Kasicka, J. Jiracek, J. Pept. Sci. 2000, 6, 355-365.

253 A. Ajayagosh, V. N. R. Piliai, J. Org. Chem. 1990, 55, 2826-2829.

254 C. P. Holmes, J. Org. Chem. 1997, 62, 2370-2380.

255 M. Smet, L. X. Liao, W. Dehaen, D. V. McGrath, Org. Lett. 2000, 2, 511513.

256 B. B. Brown, D. S. Wagner, H. M. Geysen, Mol. Diversity 1995, 1, 4-12.

257 R. Rodebaugh, B. Fraser-Reid, H. M. Geysen, Tetrahedron Lett. 1997, 38, 7653-7656.

258 S. M. Sternson, S. L. Schreiber, Tetrahedron Lett. 1998, 39, 7451-7454.

259 J. J. Baldwin, J. J. Burbaum, I. Henderson, M. H. J. Ohlmeyer, J. Am. Chem. Soc. 1995, 117, 5588-5589.

260 A. Ajayagosh, V. N. R. Piliai, J. Org. Chem. 1987, 52, 5714-5717.

261 P. Lloyd-Williams, M. Gairi, F. Albericio, E. Giralt, Tetrahedron 1993, 49, 10069-10078.

262 H. Venkatesan, M. M. Greenberg, J. Org. Chem. 1996, 61, 525-529.

263 P. Lloyd-Williams, M. Gairi, F. Albericio, E. Giralt, Tetrahedron 1991, 49, 9867-9880.

1996, 61, 1526-1529.

265 J. C. Sheehan, K. Umezawa, J. Org. Chem. 1973, 38, 3771-3774.

266 A. Routledge, C. Abell, S. Balasubramanian, Tetrahedron Lett.

1997, 38, 1227-1230.

267 T. D. Ryba, P. G. Harran, Org. Lett. 2000, 2, 851-853.

268 S. C. McKeown, S. P. Watson, R. A. E. Carr, P. Marshall, Tetrahedron Lett. 1999, 40, 2407-2410.

270 C. Deliaquiia, J. L. Imbach, B. Rayner, Tetrahedron Lett. 1997, 38, 5289-5292.

271 E. B. Akerblom, A. S. Nygren, K. H. Agback, Mol. Diversity 1998, 3, 137148.

272 M. R. Trembiay, D. Poirier, Tetrahedron Lett. 1999, 40, 1277-1280.

1998, 166-168.

274 W. C. Cheng, C. Halm, J. B. Evarts, M. M. Olmstead, M. J. Kurth, J. Org. Chem. 1999, 64, 8557-8562.

275 J. U. Peters, S. Blechert, Synlett 1997, 348-350.

276 J. Pernerstorfer, M. Schuster, S. Blechert, Chem. Commun. 1997, 1949-1950.

277 K. C. Nicoiaou, N. Winssinger, J. Pastor, S. Ninkovic, F. Sarabia, Y. He, D. Vourloumis, Z. Yang, T. Li, P. Giannakakou, E. Hamel, Nature 1997, 387, 268-272.

278 A. D. Piscopio, J. F. Miller, K. Koch, Tetrahedron Lett. 1997, 38, 7143-7146.

279 A. D. Piscopio, J. F. Miller, K. Koch, Tetrahedron Lett. 1998, 39, 2667-2670.

Koch, Tetrahedron 1999, 55, 81898198.

281 J. H. Van Maarseveen, J. A. J. den Hartog, V. Engelen, E. Finner, G. Visser, C. G. Kruse, Tetrahedron Lett. 1996, 37, 8249-8252.

282 J. J. N. Veerman, J. H. Van Maarseveen, G. M. Visser, C. G. Kruse, H. E. Schoemaker, H. Hiemstra, F. P. J. T. Rutjes, Eur. J. Org. Chem. 1998, 2583-2589.

283 L. G. Melean, W.-C. Haase, P. H. Seeberger, Tetrahedron Lett. 2000, 41, 4329-4333.

284 B. Sauerbrei, V. Jungmann, H. Waldmann, Angew. Chem. Int. Ed. 1998, 37, 1143-1146; Angew. Chem. 1998, 110, 1187-1190.

285 G. Böhm, J. Dowden, D. C. Rice, I. Burgess, J. F. Piiard, B. Guilbert, A. Haxton, R. C. Hunter, N. J. Turner, S. L. Flitsch, Tetrahedron Lett. 1998, 39, 3819-3822.

286 B. J. Backes, J. A. Ellman, J. Am. Chem. Soc. 1994, 116, 11171-11172.

287 B. J. Backes, J. A. Ellman, J. Org. Chem. 1999, 64, 2322-2330.

288 B. J. Backes, A. A. Virgilio, J. A. Ellman, J. Am. Chem. Soc. 1996, 118, 3055-3056.

289 G. W. Kenner, J. R. McDermott, R. C. Sheppard, J. Chem. Soc., Chem. Commun. 1971, 636-637.

290 C. Hulme, J. Peng, G. Morton, J. M. Salvino, T. Herpin, R. Labaudiniere, Tetrahedron Lett. 1998, 39, 7227-7230.

291 R. Soia, R. Saguer, M. L. David, R. Pascal, J. Chem. Soc., Chem. Commun. 1995, 1786-1788.

292 R. Soia, J. Mery, R. Pascal, Tetrahedron Lett. 1996, 37, 9195-9198.

293 M. H. Todd, S. F. Oliver, C. Abell, Org. Lett. 1999, 1, 1149-1151.

294 A. Link, S. Vancalenbergh, P. Herdewijn, Tetrahedron Lett. 1998, 39, 5175-5176.

295 A. Golisade, J. C. Bressi, S. Van Calenbergh, M. H. Gelb, A. Link, J. Comb. Chem. 2000, 2, 537-544.

296 M. H. Lyttle, D. Hudson, R. M. Cook, Nucl. Acids Res. 1996, 24, 27932798.

P. S. Gilbert, B. G. Main, K. PlE, J. Org. Chem. 2001, 66, 2240-2245.

298 S. Hoffmann, R. Frank, Tetrahedron Lett. 1994, 35, 7763-7766.

299 O. Lorthioir, S. C. McKeown, N. J. Parr, M. Washington, S. P. Watson, Tetrahedron Lett. 2000, 41, 8609-8613.

300 T. Masquelin, N. Meunier, F. Gerber, G. Rosse, Hetrocycles 1998, 48, 2489-2505.

301 L. Yang, Tetrahedron Lett. 2000, 41, 6981-6984.

302 H. Zhang, H. Ye, A. Moretto, K. Brumfield, B. Maryanoff, Org. Lett. 2000, 2, 89-92.

303 C. Atrash, M. Bradley, Chem. Commun. 1997, 1397-1398.

304 K. C. Nicoiaou, J. Pastor, N. Winssinger, F. Murphy, J. Am. Chem. Soc. 1998, 120, 5132-5133.

305 C. R. Johnson, B. R. Zhang, Tetrahedron Lett. 1995, 36, 9253-9256.

306 F. Camps, J. Castells, J. Pi, Ann. Quim. 1974, 70, 848-849.

307 Y. D. Gong, S. Najdi, M. M. Olmstead, M. J. Kurth, J. Org. Chem. 1998, 63, 3081-3086.

308 S. H. LEE, S. H. CHUNG, Y. S. LEE, Tetrahedron Lett. 1998, 39, 9469-9472.

309 K. H. Park, E. Abbate, S. Najdi, M. M. Olmstead, M. J. Kurth, Chem. Commun. 1998, 1679-1680.

310 K. H. Park, M. M. Olmstead, M. J. Kurth, J. Org. Chem. 1998, 63, 65796585.

311 S. Hanessian, R. Y. Yang, Tetrahedron Lett. 1996, 37, 5835-5838.

312 L. J. Wilson, M. Li, D. E. Portlock, Tetrahedron Lett. 1998, 39, 51355138.

313 S. W. KIM, J. S. KOH, E. J. LEE, S. RO, Mol. Diversity 1998, 3, 129-132.

314 S. W. Kim, S. Y. Ahn, J. S. Koh, J. H. Lee, S. Ro, H. Y. Cho, Tetrahedron Lett. 1997, 38, 4603-4606.

315 J. Matthews, R. A. Rivero, J. Org. Chem. 1997, 62, 6090-6092.

316 B. A. Dressman, L. A. Spangle, S. W. Kaldor, Tetrahedron Lett. 1996, 37, 937-940.

317 J. Stadlwieser, E. P. Ellmerer-MUller, A. Tako, N. Maslouh, W. Bannwarth, Angew. Chem. Int. Ed.

1998, 37, 1402-1404; Angew. Chem. 1998, 110, 1487-1489.

318 S. H. DeWitt, J. K. Kiely, C. J. Stankovic, M. C. Schroeder, D. M. R. Cody, M. R. Pavia, Proc. Natl. Acad. Sci. USA 1993, 90, 6909-6913.

319 A. Boeijen, J. A. W. Kruijtzer, R. M. J. Liskamp, Bioorg. Med. Chem. Lett. 1998, 8, 2375-2380.

320 H. P. Buchstaller, Tetrahedron 1998, 54, 3465-3470.

321 P. ten Holte, L. Thijs, B. Zwanen-burg, Tetrahedron Lett. 1998, 39, 7407-7410.

322 V. S. Goodfellow, C. P. Laudeman, J. I. Gerrity, M. Burkard, E. Strobel, J. S. Zuzack, D. A. McLeod, Mol. Diversity 1996, 2, 97-102.

323 A. K. Szardenings, T. S. Burkoth, H. H. Lu, D. W. Tien, D. A. Campbell, Tetrahedron 1997, 53, 6573-6593.

324 J. Kowalski, M. A. Lipton, Tetrahedron Lett. 1996, 37, 5839-5840.

325 A. Van Loevezijn, J. H. Van Maarseveen, K. Stegman, G. M. Visser, G. J. Koomen, Tetrahedron Lett. 1998, 39, 4737-4740.

326 P. P. Fantauzzi, K. M. Yager, Tetrahedron Lett. 1998, 39, 1291-1294.

327 R. A. Smith, M. A. Bobko, W. Lee, Bioorg. Med. Chem. Lett. 1998, 8, 2369-2374.

328 W. R. Li, S. Z. Peng, Tetrahedron Lett. 1998, 39, 7373-7376.

329 A. K. Szardenings, D. Harris, S. Lam, L. H. Shi, D. Tien, Y. W. Wang, D. V. Patel, M. Navre, D. A. Campbell, J. Med. Chem. 1998, 41, 2194-2200.

330 B. O. Scott, A. C. Siegmund, C. K. Marlowe, Y. Pei, K. L. Spear, Mol. Diversity 1996, 1, 125-134.

331 A. Golebiowski, S. R. Klopfenstein, J. J. Chen, X. Shao, Tetrahedron Lett. 2000, 41, 4841-4844.

332 D. A. Goff, R. N. Zuckermann, J. Org. Chem. 1995, 60, 5744-5745.

333 J. P. Mayer, J. W. Zhang, K. Bjergarde, D. M. Lenz, J. J. Gaudino, Tetrahedron Lett. 1996, 37, 8081-8084.

334 L. Moroder, J. Lutz, F. Grams, S. Rudolph-Bohner, G. Osapay, M.

Goodman, W. Kolbeck, Biopolymers 1996, 38, 295-300.

335 L. F. Tietze, A. Steinmetz, Synlett

1996, 667-668.

336 L. F. Tietze, A. Steinmetz, F. Balkenhohl, Bioorg. Med. Chem. Lett.

337 T. T. Romoff, L. Ma, Y. W. Wang, D. A. Campbell, Synlett 1998, 13411342.

338 L. Weber, P. Iaiza, G. Biringer, P. Barbier, Synlett 1998, 1156-1158.

339 J. Matthews, R. A. Rivero, J. Org. Chem. 1998, 63, 4808-4810.

340 B. A. Kulkarni, A. Ganesan, Tetrahedron Lett. 1998, 39, 4369-4373.

341 A. L. Smith, C. G. Thomson, P. D. Leeson, Bioorg. Med. Chem. Lett. 1996, 6, 1483-1486.

342 S. A. Kolodziej, B. C. Hamper, Tetrahedron Lett. 1996, 37, 5277-5280.

343 M. M. Sim, C. L. Lee, A. Ganesan, Tetrahedron Lett. 1998, 39, 6399-6402.

344 F. Albericio, J. Garcia, E. L. Michelotti, E. Nicoias, C. M. Tice, Tetrahedron Lett. 2000, 41, 3161-3163.

345 W. L. Huang, R. M. Scarborough, Tetrahedron Lett. 1999, 40, 26652668.

346 C. Le Hetet, M. David, F. Carreaux, B. Carboni, A. Sauleau, Tetrahedron Lett. 1997, 38, 5153-5156.

347 J. F. Pons, Q. Mishir, A. Nouvet, F. Brookfield, Tetrahedron Lett. 2000, 41, 4965-4968.

348 E. J. Guthrie, J. Macritchie, R. C. Hartley, Tetrahedron Lett. 2000, 41, 4987-4990.

349 A. Mazurov, Bioorg. Med. Chem. Lett. 2000, 10, 67-70.

350 S. BrAse, R. Lazny, unpublished.

351 B. K. Lorsbach, R. B. Miller, M. J. Kurth, J. Org. Chem. 1996, 61, 87168717.

352 B. A. Lorsbach, J. T. Bagdanoff, R. B. Miller, M. J. Kurth, J. Org. Chem. 1998, 63, 2244-2250.

353 S. E. Gibson, N. J. Hales, M. A. Peplow, Tetrahedron Lett. 1999, 40, 1417-1418.

354 M. F. Semmelhack, G. Hilt, J. H. Colley, Tetrahedron Lett. 1998, 39, 7683-7686.

Hales, Chem. Commun. 1999, 20752076.

356 M. A. Gallop (Glaxo Wellcome Inc., USA), US Patent No. 6057465 A, 2000.

357 A. C. Comely, S. E. Gibson, N. J. Hales, M. A. Peplow, PCT Int. Appl. WO 0007966,

Was this article helpful?

0 0

Post a comment