length distributions (M w /M n < 1.20) and controlled molecular weights (500 < M n
< 500,000) [25]. These polymerizations can be conducted in a variety of solvents
(e.g., THF, DMF, EtOAc, dioxane, MeCN, DMAc, nitrobenzene) and over a broad
range of temperatures (i.e., 10–100
C) with no loss of polymerization control and
with dramatic increases in polymerization rate as temperature is increased. By
addition of different NCA monomers, the preparation of block copolypeptides of
defined sequence and composition is feasible [7, 26].
This polymerization system is general, and gives controlled polymerization of a
wide range of NCA monomers as pure enantiomers (D or L configuration) or as
racemic mixtures. In addition to commonly used NCA monomers, such as protected
lysine, glutamate, aspartate, and arginine, many hydrophobic amino acid monomers
(e.g., leucine, valine, alanine, isoleucine, phenylalanine) as well as other reactive
amino acids (e.g., methionine, cysteine, tyrosine, DOPA) have been successfully
polymerized in a controlled manner using cobalt and nickel initiators. There is
much current interest in functional and reactive polypeptides, and NCAs bearing
more complex functionality have also been polymerized using this methodology.
The earliest examples were controlled polymerizations of oligoethylene glycolfunctionalized lysines [27] and serines [28], which were later followed by
polymerization of lysine-based NCAs containing side-chain attached liquid
crystal-forming mesogens [29]. Thermoresponsive oligoethylene glycol-modified
glutamate NCAs have also been reported by Li and coworkers to polymerize
effectively using a nickel initiator [30].
Recently, the Deming laboratory has used cobalt initiators to polymerize
sugar-containing NCAs based on lysine [31] and cysteine [32], which yield fully
glycosylated, high molecular weight glycopolypeptides that can adopt different
chain conformations. Li and coworkers have also used a nickel initiator to
polymerize lysine-based NCAs that contain side-chain activated alkyl bromide
functionalities, which are useful for growth of vinyl polymers off the polypeptide
side chains using atom transfer radical polymerization (ATRP) [33]. It is notable
that the active metal centers do not react with the alkyl halide functionalities, which
could be problematic if amine initiators were used instead. A key challenge in these
recent examples was purification of the highly functional NCAs, which could not be
purified by recrystallization. To solve this problem, Kramer and Deming developed
an anhydrous flash column chromatography method for NCA purification that
enables one to obtain a wide range of difficult-to-crystallize NCAs in suitable
purity for controlled polymerization [34], and has made possible the preparation
of many new highly functional NCAs [35].
One potential limitation of using zerovalent metal initiators is in the preparation
of chain-end functionalized polypeptides because the active propagating species
are generated in situ and the C-terminal end of the polypeptide is derived from
the first NCA monomer. Consequently, this method does not allow easy incorporation
of functionality (e.g., polymer or small molecule) to the carboxyl chain
end. For this reason, Deming and coworkers pursued alternative methods for
direct synthesis of the amido-amidate metallacycle propagating species and
developed allyloxycarbonylaminoamides as universal precursors to amido-amidate
8
T.J. Deming
< 500,000) [25]. These polymerizations can be conducted in a variety of solvents
(e.g., THF, DMF, EtOAc, dioxane, MeCN, DMAc, nitrobenzene) and over a broad
range of temperatures (i.e., 10–100
C) with no loss of polymerization control and
with dramatic increases in polymerization rate as temperature is increased. By
addition of different NCA monomers, the preparation of block copolypeptides of
defined sequence and composition is feasible [7, 26].
This polymerization system is general, and gives controlled polymerization of a
wide range of NCA monomers as pure enantiomers (D or L configuration) or as
racemic mixtures. In addition to commonly used NCA monomers, such as protected
lysine, glutamate, aspartate, and arginine, many hydrophobic amino acid monomers
(e.g., leucine, valine, alanine, isoleucine, phenylalanine) as well as other reactive
amino acids (e.g., methionine, cysteine, tyrosine, DOPA) have been successfully
polymerized in a controlled manner using cobalt and nickel initiators. There is
much current interest in functional and reactive polypeptides, and NCAs bearing
more complex functionality have also been polymerized using this methodology.
The earliest examples were controlled polymerizations of oligoethylene glycolfunctionalized lysines [27] and serines [28], which were later followed by
polymerization of lysine-based NCAs containing side-chain attached liquid
crystal-forming mesogens [29]. Thermoresponsive oligoethylene glycol-modified
glutamate NCAs have also been reported by Li and coworkers to polymerize
effectively using a nickel initiator [30].
Recently, the Deming laboratory has used cobalt initiators to polymerize
sugar-containing NCAs based on lysine [31] and cysteine [32], which yield fully
glycosylated, high molecular weight glycopolypeptides that can adopt different
chain conformations. Li and coworkers have also used a nickel initiator to
polymerize lysine-based NCAs that contain side-chain activated alkyl bromide
functionalities, which are useful for growth of vinyl polymers off the polypeptide
side chains using atom transfer radical polymerization (ATRP) [33]. It is notable
that the active metal centers do not react with the alkyl halide functionalities, which
could be problematic if amine initiators were used instead. A key challenge in these
recent examples was purification of the highly functional NCAs, which could not be
purified by recrystallization. To solve this problem, Kramer and Deming developed
an anhydrous flash column chromatography method for NCA purification that
enables one to obtain a wide range of difficult-to-crystallize NCAs in suitable
purity for controlled polymerization [34], and has made possible the preparation
of many new highly functional NCAs [35].
One potential limitation of using zerovalent metal initiators is in the preparation
of chain-end functionalized polypeptides because the active propagating species
are generated in situ and the C-terminal end of the polypeptide is derived from
the first NCA monomer. Consequently, this method does not allow easy incorporation
of functionality (e.g., polymer or small molecule) to the carboxyl chain
end. For this reason, Deming and coworkers pursued alternative methods for
direct synthesis of the amido-amidate metallacycle propagating species and
developed allyloxycarbonylaminoamides as universal precursors to amido-amidate
8
T.J. Deming