Continuing studies into the utility of poly(ethylene glycol) (PEG)-supported triarylphosphines as functional polymer reagents in liquid-phase organic synthesis (LPOS) are being pursued. This report describes the synthesis and NMR characterization of an aryl−alkyl ether-linked PEG-triarylphosphine derivative (2) and its subsequent application in LPOS. The utility of 2 as a mild stoichiometric reagent for ozonide reduction has been demonstrated, and a direct comparison between 2, a Merrifield resin-bound triarylphosphine derivative, and a solution-phase triphenylphosphine reagent revealed that the highest observed yields occur under liquid-phase conditions. Transformation of phosphine 2 into a phosphonium salt (3) then allowed the inherent aqueous solubility of PEG-functionalized moieties to be exploited by enabling a Wittig reaction, between a range of aldehydes and 3, to occur under mildly basic aqueous conditions. This led to the generation of substituted stilbenes in good to excellent yields. Finally, regeneration of 2 was achieved by reduction of the PEG-supported triphenylphosphine oxide byproduct 4 with alane (100% conversion, 75% yield). This combination of reaction, recovery, and regeneration expands the utility of PEG-supported triarylphosphine reagents across the spectra of both organic chemistry and solution-phase combinatorial strategies.

No abstract

[Chemical reaction: See text] 29G12 is a murine monoclonal antibody programmed to catalyze the regio- and enantioselective 1,3-dipolar cycloaddition reaction between 4-acetamidobenzonitrile N-oxide 1a and N,N-dimethylacrylamide 2a (Toker, J. D.; Wentworth, P., Jr.; Hu, Y.; Houk, K. N.; Janda, K. D. J. Am. Chem. Soc. 2000, 122, 3244). Given the unique nature of 29G12 as a protein biocatalyst for this chemical reaction, we have investigated both the substrate specificity and mechanistic parameters of the 29G12-catalyzed process. These studies have shown that while 29G12 is specific for its dipole substrate 1a, the antibody is highly promiscuous with respect to the dipolarophiles it can process. 29G12 accepts a bulky hydrophobic dipolarophile cosubstrate, with rates of product formation up to 70-fold faster than with the original substrate 2a. In all cases, the respective isoxazoline products are produced with exquisite regio- and stereochemical control (78-98% ee). Comparison between the steady-state kinetic parameters from the 29G12-catalyzed reaction of 1a with the most efficient versus the original dipolarophile cosubstrate (2m and 2a, respectively), reveals that while the effective molarities (EM)s are almost identical (EM(2m)) 26 M; EM((2a)) 23 M), the affinity of 29G12 for the larger dipolarophile 2m is more than 1 order of magnitude higher than for 2a [Km(2m) 0.44 +/- 0.04 mM; Km(2a) 5.8 +/- 0.4 mM]. Furthermore, when 2m is the cosubstrate, the affinity of 29G12 for its dipole 1a is also greatly improved [Km(1a) 0.82 +/- 0.1 mM compared to Km(1a) 3.4 +/- 0.4 mM when 2a is the cosubstrate]. An analysis of the temperature dependence of the 29G12-catalyzed reaction between 1a and 2m reveals that catalysis is achieved via a decrease in enthalpy of activation (DeltaDeltaH 4.4 kcal mol(-1)) and involves a large increase in the entropy of activation (DeltaDeltaS 10.4 eu). The improved affinity of 29G12 for the nitrile oxide 1a in the presence of 2m, coupled with the increase in DeltaDeltaS during the 29G12-catalyzed reaction between 1a and 2m supports the notion of a structural reorganization of the active site to facilitate this antibody-catalyzed reaction.