SASRIN resin

Table 9.1 shows the method s versatility across several solid-support types. Care must be taken to dry the tentagel resins by lyophilization for 24 h before subjecting them to the reaction conditions. In the examples shown, quantitative conversions were obtained as determined by elemental analysis and 13C NMR. The mild reaction conditions are most evident by the quantitative conversion of SASRIN resin to its corresponding chloromethyl... 

Preparation of AMEBA Resin A from SASRIN Resin,... 

A total of 10.0 g (8.9 mmol) SASRIN resin2 (note 1) was washed with N,N-dimethyIfonnamide (DMF 2 x 25 mL), methanol (MeOH 2 x 25 mL), and dichloromethane (DCM note 2 2 x 25 mL), and dried under vacuum (0.5 torr) at 70°C overnight. To a suspension of the dried SASRIN resin in lOOmL of methyl sulfoxide (DMSO note 2) and 25 mL of DCM was added 12.4 mL (89 mmol, 10.0 Eq.) triethylamine (note 2) followed by 7.1 g (44.5 mmol, 5.0 Eq.) sulfur trioxide-pyridine complex (note 2). The suspension was shaken on a radial arm at room temperature overnight (note 3) filtered on a glass frit and washed with DCM (3 x 100mL), DMSO (3 x lOOmL), DCM (3 x lOOmL), and tetrahydrofuran (THF 3 x 100 mL) and dried under vacuum (0.5 torr) at room temperature to give 10.0 g Ameba resin (notes 4 and 5). 

SASRIN resin (0.89 mmol/g) was obtained from Bachem Bioscience, Inc., Product D-1295, Lot 507127. Checkers... 

Ameba resin A loading was assumed to be 0.89 mmol/g, based on the loading of the starting SASRIN resin. 

Solid-phase synthesis of pyrido[2,3 pytirtiidines 514 was achieved by Hantzsch condensation of Wang resin-supported Knoevenagel derivative 513 with 6-aminouracil derivatives 512 as an a-oxo enamine component in the presence of ceric ammonium nitrate (CAN) in DMA followed by hydrolysis with TFA in CH2GI2. Compound 513 was prepared by treatment of a hydroxylated polymer, such as Wang or Sasrin resin, with diketene, followed by condensation with benzaldehyde (Equation 41) <1996TL4643>. 

The linear decapeptide was synthesized on Fmoc-Lys(Boc)-SASRIN-resin (2.0 g, substitution 0.6 mmol-g1) applying standard Fmoc strategy based on DIC/HOBt activation with DIPEA as base. After removal of the last Fmoc group, the peptide was cleaved from the resin and cyclized as described in Section 13.1.1.1.1 yield 0.671 g (68%) ESI-MS 1646.3 [M + H]+, 823.8 [M/2+H]+. 

Method B Alternatively, the branched peptide-resin was synthesized using HBTU/HOBt as coupling reagents. The above mentioned Fmoc amino acids (1.95 mmol) were coupled to Fmoc-Gly-SASRIN-resin (lg, sub. level =0.65 mmol-g1) with HOBt (0.26g, 1.95mmol), HBTU (0.67g, 1.76mmol), and DIPEA (0.63 mL, 3.71 mmol) in DMF without preactivation. The coupling was complete within 1 to 2 h. 

Scheme 9 Use of Sasrin resin bound amino acid for the preparation of 3-lactam via [2+2] cycloaddition...

The linear precursor of, for example, 34 [51] was obtained by solid-phase peptide synthesis performed on an SASRIN -resin applying the Fmoc/ Bu strategy. This allowed the preparation of a protected peptide with both free amino and carboxylic acid termini, which were head-to-tail cyclized using diphenylphosphorylazide, leading to the protected cyclic peptide. Removal of side chain protecting groups afforded 34. 

Racemization occurring during esterification of protected amino acids to hydroxymethyl polymers is a well-recognized problem.PP l This reaction is promoted by the use of DMAP as catalyst,P l and racemization is particularly pronounced in the case of cysteine.P By the use of optimized esterification methods racemization can be reduced, but not totally sup-pressed.P l When starting with halomethyl-functionalized resins, such as 2-chlorotrityl chloride resin,P l bromo-SASRIN resin,P l or 4-(bromomethyl)phenoxyacetamide res-in,P l racemization levels are significantly lowered. Alternatively, racemization is largely prevented by using the TDO esters without DMAP,f P°l or PyAOP in the presence of DIPEA at low temperature.P l... 

SASRIN resin (super acid sensitive resin)... 

Other highly acid-labile functionalized solid supports and handles incorporate one or two additional electron-donating substituents, such as methoxy groups in 4-alkoxybenzyl alcohol-base-resins. Among these systems, SASRIN resin (super acid sensitive resin, 11),[4 " ] 4-(4-hydroxymethyl-3-methoxyphenoxy)butanoic acid (HMPB, 12),t4 and 2,4,5-trichlorophenyl 5-(4-hydroxymethyl-3,5-dimethoxyphenoxy)valerate (13)f4 l handles are the most widely used. 

Fmoc-D-cycloserine (4-aminoisoxazolidine-3-one) and its enantiomer were immobilized on SASRIN resin or 2-chlorotrityl linker resins using Mitsunobu-type reaction or direct tritylation, respectively. The loading of the resulting resins (0.59-0.69 mmol g) was determined by spectrophotometry of the in rr/ -generated piperidine-dibenzofulvene... 

R=H Wang resin OS analog R= OMe Sasrin resin OS analog... 

Hoveyda et al. [262] prepared different N-aryhnaleimidobenzoic acids linked to SASRIN resin, whose double bond present in the maleimido moiety could act as a convenient dipolarophile in cycloaddition reactions. Thus, solution-generated a-iminoesters (from different aromatic aldehydes and aminoesters) were reacted vdth the supported maleimides (158) under Tsuge [263] conditions. Formation of the expected syn-endo cycloadduct (160) was observed after only 1 h at room temperature (Scheme 33). From structure-reactivity analysis, the authors concluded that the cycloaddition reaction is more sensitive to steric then to electronic factors on the azomethine yhde counterpart. The advantage of this procedure stems essentially from the fact that the iminoesters (159) are formed in situ. Aldehydes containing a-hydrogens could also be employed. Moreover, the resin in this case also plays the role of a protective group, because, in contrast with N-alkyl and N-aryl (see above) maleimides, N-unsubstituted maleimide is not suitable for 1,3 dipolar cycloadditions. 

The majority of reported solid-phase combinatorial syntheses of the lactam core utilize a [2-i-2] cycloaddition reaction of ketenes with resin-bound imines [33-41]. A further development of the Staudinger reaction was reported by Mata and coworkers using Mukaiyama s reagent [42]. In addition, a stereoselective synthesis of chi-rally pure P-lactams has been performed as a first utilization of polymer-supported oxazolidine aldehydes [43]. Other strategies include an ester enolate-imine condensation [44], an Hg(OCOCF3)2-mediated intramolecular cydization [45], and Miller hydroxamate synthesis [46]. Because of the variability derived from the scaffold synthesis, not many attempts have been made to derivatize the resin-bound lactam template [47]. One of the most detailed descriptions of a versatile (3-lactam synthesis on a resin employed amino acids tethered as esters on Sasrin resin [48]. 

A patent application describes the synthesis of 2,4-quinazolinediones from either immobilized amine reagents or immobilized isocyanates [206]. Utilizing the amine route (Method A in Scheme 36), an Fmoc-protected amino acid immobilized on Sasrin resin [207] was treated with piperidine to provide the free amine derivative. Reaction of a resin-bound amino acid with 2-carboxymethyl phenyl-isocyanate and cyclization of the resulting urea upon treatment with DBU afforded a support-bound 2,4-quinazolinedione. Treatment of the resin with a reactive alkylating agent in the presence of DBU for 10-48 h at 20-70 °C provided the N -alkylated quinazolinedione. The compounds were released from the resin with TFA/CH2CI2. 

Ms CN O DBU [56J thiophene Resins/linkers used Wang resin. Moderate to high yields. 4-thiazolidinone, thiazole thiazolidine thiazanone Tentagel or Sasrin resin one-pot reaction good yields [56] [241] [200] [204] [205] [242]... 

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