Merrifield, resin

In cases where Noyori s reagent (see p. 102f.) and other enantioselective reducing agents are not successful, (+)- or (—)-chlorodiisopinocampheylborane (Ipc BCl) may help. This reagent reduces prochiral aryl and tert-alkyl ketones with exceptionally high enantiomeric excesses (J. Chandrasekharan, 1985 H.C. Brown, 1986). The initially formed boron moiety is usually removed hy precipitation with diethanolamine. Ipc2BCl has, for example, been applied to synthesize polymer-supported chiral epoxides with 90% e.e. from Merrifield resins (T. Antonsson, 1989). 

Polypeptide Synthesis and Analysis. Sihca or controUed-pore glass supports treated with (chloromethyl)phenylethyltrimethoxysilane [68128-25-6] or its derivatives are replacing chloromethylated styrene—divinylbenzene (Merrifield resin) as supports in polypeptide synthesis. The sdylated support reacts with the triethyl ammonium salt of a protected amino acid. Once the initial amino acid residue has been coupled to the support, a variety of peptide synthesis methods can be used (34). At the completion of synthesis, the anchored peptide is separated from the support with hydrogen bromide in acetic acid (see Protein engineering Proteins). 

The adaptation of the Bischler-Napieralski reaction to solid-phase synthesis has been described independently by two different groups. Meutermans reported the transformation of Merrifield resin-bound phenylalanine derivatives 32 to dihydroisoquinolines 33 in the presence of POCI3. The products 34 were liberated from the support using mixtures of HF/p-cresol. In contrast, Kunzer conducted solid-phase Bischler-Napieralski reactions on a 2-hydroxyethyl polystyrene support using the aromatic ring of the substrate 35 as a point of attachment to the resin. The cyclized products 36 were cleaved from the support by reaction with i-butylamine or n-pentylamine to afford 37. 

Metal ion complexes. These classic CSPs were developed independently by Davankov and Bernauer in the late 1960s. In a typical implementation, copper (II) is complexed with L-proline moieties bound to the surface of a porous polymer support such as a Merrifield resin [28-30]. They only separate well a limited number of racemates such as amino acids, amino alcohols, and hydroxy acids. 

A number of studies have recently been devoted to membrane applications [8, 100-102], Yoshikawa and co-workers developed an imprinting technique by casting membranes from a mixture of a Merrifield resin containing a grafted tetrapeptide and of linear co-polymers of acrylonitrile and styrene in the presence of amino acid derivatives as templates [103], The membranes were cast from a tetrahydrofuran (THF) solution and the template, usually N-protected d- or 1-tryptophan, removed by washing in more polar nonsolvents for the polymer (Fig. 6-17). Membrane applications using free amino acids revealed that only the imprinted membranes showed detectable permeation. Enantioselective electrodialysis with a maximum selectivity factor of ca. 7 could be reached, although this factor depended inversely on the flux rate [7]. Also, the transport mechanism in imprinted membranes is still poorly understood. 

A short and efficient synthetic approach to hydroxy-substituted ( )-stil-benoids, as exemplified by the natural compound resveratrol (371b) via solid-phase CM, was reported by a Korean group (Scheme 71) [154]. When two different stilbenes were allowed to couple by catalyst C, all three kinds of possible stilbenes were obtained as an inseparable mixture. Anchoring 4-vinylphenol to Merrifield resin, followed by exposing the supported styrenyl ether 368 and diacetoxy styrene 369 (10 equiv) to the catalyst, inhibited self-metathesis of the supported substrate. Sequential separation of the homodimer formed from 369 by washing and subsequent cleavage of the resin 370 with acid provided (E)-stilbene 371a with complete stereocontrol in 61% yield. 

A cross-coupling reactions of terminal alkynes with terminal alkenes 32 supported on Merrifield-resin (Scheme 4.5) in the presence of Grubs ruthenium initiator [Cl2(PCy3)2Ru = CHPh] provided efficient access to supported 1,3-dienes 33 which were transformed into octahydrobenzazepinones 34 via MeAlCl2 catalyzed Diels-Alder reaction [27]. 

The resolution of racemic ethyl 2-chloropropionate with aliphatic and aromatic amines using Candida cylindracea lipase (CCL) [28] was one of the first examples that showed the possibilities of this kind of processes for the resolution of racemic esters or the preparation of chiral amides in benign conditions. Normally, in these enzymatic aminolysis reactions the enzyme is selective toward the (S)-isomer of the ester. Recently, the resolution ofthis ester has been carried out through a dynamic kinetic resolution (DKR) via aminolysis catalyzed by encapsulated CCL in the presence of triphenylphosphonium chloride immobilized on Merrifield resin (Scheme 7.13). This process has allowed the preparation of (S)-amides with high isolated yields and good enantiomeric excesses [29]. 

Tetrahydroisoquinolines have been synthesized on the Merrifield resin in good yields and high purity via the Bischler-Napieralski approach <95TL(36)7709>. 

P 10] The reaction was performed on 100 mg of Merrifield resin [75]. Absolute tetrahydrofuran was used as solvent and 4 h of agitation was employed. No other details are given in the reference. Generally, about 2 min were needed to perform a complete washing cycle. 

The Kumada-Corriu reaction is characterized by mild conditions and clean conversions [2]. A disadvantage of previous Kumada-Corriu reactions was due to the use of homogeneous catalysts, with more difficult product separation. Recently, an unsymmetrical salen-type nickel(II) complex was synthesized with a phenol functionality that allows this compound to be linked to Merrifield resin polymer beads (see original citation in [2]). By this means, heterogeneously catalyzed Kumada-Corriu reactions have become possible. 

A solid-phase version of the palladium-catalyzed carbonyl allylation of aldehydes by allylic alcohol has been described. Thus, allylation of resin-bound aldehyde (P = Merrifield resin) with allylic alcohols (e.g., MeCH=CHCH2OH) in the presence of SnCl2 afforded the homoal-lylic alcohols under different solvent conditions, in DMSO and aqueous DMSO respectively (Eq. 8.45).102... 

Benzyloxybenzylamine (BOBA) 48 is a new class of an amine support and was prepared from Merrifield resin in two steps [56]. BOBA resin was treated with an aldehyde in the presence of an acid to give an imine that subsequently reacted with Yb(OTf)3-catalyzed silyl enolates (Scheme 18). Cleavage with trimethylsilyl triflate (TMSOTf) or 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) gave either phenols or amines, respectively. 

A variety of cleavage conditions have been reported for the release of amines from a solid support. Triazene linker 52 prepared from Merrifield resin in three steps was used for the solid-phase synthesis of aliphatic amines (Scheme 22) [61]. The triazenes were stable to basic conditions and the amino products were released in high yields upon treatment with mild acids. Alternatively, base labile linker 53 synthesized from a-bromo-p-toluic acid in two steps was used to anchor amino functions (Scheme 23) [62]. Cleavage was accomplished by oxidation of the thioether to the sulfone with m-chloroperbenzoic acid followed by 13-elimination with a 10% solution of NH4OH in 2,2,2-trifluoroethanol. A linker based on l-(4,4 -dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) primary amine protecting group was developed for attaching amino functions (Scheme 24) [65]. Linker 54 was stable to both acidic and basic conditions and the final products were cleaved from the resin by treatment with hydrazine or transamination with ra-propylamine. 

Acetal handle 78 synthesized from Merrifield resin and 4-hydroxy-benzaldehyde was applied to the solid-phase synthesis of carbohydrates and 1-oxacephams (Scheme 41) [90]. For the latter, a 1,3-diol was initially anchored to the support to form a cyclic acetal. A ring opening reaction with DIBAL generated a resin-bound alcohol which was converted to the corresponding triflate for A-alkylation with 4-vinyl-oxyazetidin-2-one. A Lewis acid catalyzed ring closure released 1-oxa-cephams from the support. 

Devaky and Rajasree have reported the production of a polymer-bound ethylenediamine-borane reagent (63) (Fig. 41) for use as a reducing agent for the reduction of aldehydes.87 The polymeric reagent was derived from a Merrifield resin and a 1,6-hexanediol diacrylate-cross-linked polystyrene resin (HDODA-PS). The borane reagent was incorporated in the polymer support by complexation with sodium borohydride. When this reducing agent was used in the competitive reduction of a 1 1 molar mixture of benzaldehyde and acetophenone, benzaldehyde was found to be selectively reduced to benzyl alcohol. 

The concept for the synthesis of4-hydroxy-4,5-dihydroisoxazoles by Righi and coworkers was discussed earlier, in Chapter 7. Here, an extension of this methodology by utilizing polymer-bound nitroacetate (hydroxylated Merrifield resin) is described [10], Thus, the one-pot domino oxidation/nitroaldol cyclization of aziridine 10-28 with immobilized nitroacetate 10-29 furnished 10-30 which, after detachment from the resin, led to the desired product 10-31 in good yield and excellent trans-selectivity (Scheme 10.7). 

Preparation of Merrifield resin-bound nitro acetates, which is a suitable building block for the development of combinatorial solid phase synthesis, is reported.4 The anion of ethyl nitro acetate is generated in DMF by an electrochemical method using Pt cathode, magnesium rod anode, and tetrabutylammonium bromide as an electrolyte. Alkylaton of this anion with alkyl halides gives mono-alkylated products in 80% yield.5... 

Libraries of /3-turn mimetics have been prepared by solid-phase syntheses. The synthesis of the chiral saturated pyrazino[l,2- ]pyrazine 243 starts from Merrifield resin-bound a-iV-BOC-/3-./V-Fmoc-L-diaminopropionic acid as the central framework. The variable substituents are introduced during the synthesis (Scheme 43) <20000L2615>. The scope and limitations of the method are described <2002JC0584>. 

Solution-phase enantioselective synthesis of 437 and 438 thus achieved was also translated into solid-phase synthesis <2002TL8981>. The oxazolidinone 441 prepared from L-tyrosine methyl ester via 440 was attached to Merrifield resin to produce 442. Resin-bound 442 was converted to 443 (Scheme 98). 

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