Trifluoroacetyl as an orthogonal protecting group for guanidines

The trifluoroacetyl moiety has been used as a new protecting group for guanidine functionality. The protecting group is easily cleaved under mild basic conditions and is complementary to the Boc, Cbz, and Ddpe protecting groups. The protecting group can be applied to peptide synthesis in solution as well as on a solid phase as it is orthogonal to a Boc and Cbz strategy and semiorthogonal to an Fmoc strategy.     

Solid-phase synthesis of asymmetrically branched sequence-defined poly/oligo(amidoamines)

We present for the first time the synthesis of asymmetrically branched sequence-defined poly/oligo(amidoamines) (PAAs) using solid-phase synthesis with the capability of introducing diversity at the side chains. We introduce two new versatile (diethylenetriamine) building blocks for solid-phase synthesis bearing Fmoc/Boc and Fmoc/Alloc protecting groups expanding recently used Fmoc/Boc protecting group strategy for linear PAAs to an Fmoc/Alloc/Boc strategy. This allows for orthogonal on-resin cleavage of Fmoc and Alloc protecting groups during solid-phase synthesis of PAAs with backbones differing in chain length and sequence. With these structures we then demonstrate the potential for generating asymmetrical branching by automated multiple on-resin cleavage of Alloc protecting groups as well as the introduction of side chains varying in length and number. Such systems have high potential as nonviral vectors for gene delivery and will allow for more detailed studies on the correlation between the degree of branching of PAAs and their resulting biological properties.     

Synthesis of a β-glycoside functionalized GΛC motif for self-assembly into rosette nanotubes with predefined length

Progress toward the synthesis of guanine-cytosine (GΛC) oligonucleotides for the spontaneous self-assembly of rosette nanotubes (RNTs) with predefined length is described. Highlighted is the synthesis of the β-glycoside functionalized GΛC base along with a new nitrogen protecting group strategy that is compatible with Boc and Bn groups.     

Synthesis of Boc protected block copolymers based on para-hydroxystyrene via NMRP

Nitroxide mediated free radical polymerization (NMRP) was used for the preparation of orthogonally protected block copolymers based on para-hydroxystyrene. The polymers have a low polydispersity and an active chain end. By a series of polymer analogous reactions, a partly deprotected block copolymer was synthesized consisting of a block with unprotected phenolic OH groups and a further block which is protected by the thermolabile Boc group.     

An optimized method for the synthesis of amino-functionalized phosphatidylcholine

Phosphatidylcholine analogues were synthesised as affinity ligands for the capture of membrane proteins. Several protecting group strategies were investigated to synthesize the amino-functionalized phosphatidylcholine: 11-aminoundecyl 2-(trimethylammonio)ethyl phosphate (4). The acid-mediated deprotection of the Boc group generated a mixture of the target products which could only be purified by HPLC. However, an alternative strategy, using the hydrazine-labile phthalimide group route, followed by a gel filtration step proved straightforward to afford the desired amino-functionalized phosphatidylcholine product in high yield and purity.     

Synthesis of Fragment Derivatives of Delta Sleep-inducing Peptide （1-4） Catalyzed by Enzymes in Organic Solvents

Synthesis of two fragment derivatives of delta sleep-inducing peptide (DSIP) (1-4), Boc-Trp-Ala-Gly-GlyNHNHPh (1) and Boc-Trp-Ala-Gly-GlyOEt (2), catalyzed by proteases via 2 2 or 1 3 synthetic routes with different protecting groups at C-terminal in organic solvents was reported. The yield of N-Boc tetrapeptide with phenylhydrazinyl protecting carboxyl group at C-terminal (1) was higher than that of N-Boc tetrapeptide ethyl ester (2) by 2 2 route. The factors influencing the synthetic yield of the fragments of DSIP (1-4) were discussed.     

An Organocatalytic Mannich/Denitration Reaction for the Asymmetric Synthesis of 3‐Ethylacetate‐Substitued 3‐Amino‐2‐Oxindoles: Formal Synthesis of AG‐041R

The highly enantioselective organocatalytic addition of ethyl nitroacetate to isatin‐derived N‐Boc ketimines (Boc=tert‐butoxycarbonyl), followed by the removal of the nitro group, is described. The scalable reaction sequence leads to the title compounds as important intermediates of pyrroloindoline alkaloids and related drugs in excellent yields and enantioselectivities. The synthesis of the hexahydrofurano[2,3‐b]indole skeleton, the spirocarbamate oxindole unit, and the formal synthesis of AG‐041R have been carried out to demonstrate the synthetic utility of this protocol.     

Boc和Fmoc保护氨基酸与M树脂和王氏树脂结合率的比较

M树脂与Boc保护的亮氨酸、甘氨酸或苯丙氨酸的铯盐成酯反应摩尔比1:1.2,时间31h,其产物用重量法和水杨醛法测得的结合率均值分别为87.3%、89.1%和89.6%。王氏树脂与Fmoc保护的亮氨酸、甘氨酸或苯丙氨酸反应48h,树脂:Fmoc氨基酸:DCC:DMAP摩尔比为1:3:4:1,其产物结合率的均值分别为44.2%、30.4%和56.2%。结果表明,前者产物结合率高于后者。另外,重量法与水杨醛法测得的结合率相差不超过2.7%,但重量法更方便,易行。     

An expedient synthesis of peptidyl N-alkylamides by "HOPE" strategy

We have developed an expedient approach,"HOPE"(hybrid orthogonal protocol with ease) strategy for the synthesis of peptidyl N-alkylamides.This new strategy was characterized by following points:incorporating Boc and Fmoc protocols together on Merrifield resin,removal of SPG(side-chain protecting groups) without the damage of linker structure on the resin,and the ammonolysis of linker as the last step could achieve the introducing N-alkylamide structure into C-terminal and releasing product from resin-support simultaneously.In present work,eight peptidylamides with different alkylsubstitution at C-terminal were conveniently synthesized by HOPE strategy.     

The Use of Intermediates with Preformed Disulfide Bridge for the Synthesis of Oxytocin and Deamino-oxytocin

The disulfide-bridged hexapeptides 6a and 6b have been prepared from benzyl-protected intermediates. Coupling of 6a and 6b with prolyl-leucyl-glycine amide afforded deamino-oxytocin ( 7a ) and the protected oxytocin derivative 7b , respectively; the latter was converted to oxytocin ( 7c ) by removal of the Boc protecting group.     

Fluorous Boc ((F)Boc) carbamates: new amine protecting groups for use in fluorous synthesis

The first fluorous variants of the Boc (tert-butyloxycarbonyl) group have been prepared and tested for their suitability as nitrogen protecting groups. A group with two fluorous chains and an ethylene spacer, (RfCH2CH2)2(CH3)COC(O)-, was readily attached to a representative amine but was difficult to cleave. In contrast, groups with two fluorous chains and a propylene spacer, (RfCH2CH2CH2)2(CH3)COC(O)-, or one fluorous chain and an ethylene spacer, (RfCH2CH2)(CH3)2COC(O)-, were readily formed and cleaved. The fluorous alcohol component of the (F)Boc group can be removed by evaporation and can be recovered and reused. The utility of the new (F)Boc group (C8F17CH2CH2)(CH3)2COC(O)- was demonstrated in 16 and 96 compound library synthesis exercises. Separations can be achieved either by manual, parallel fluorous solid-phase extraction, or automated, serial fluorous chromatography. The results provide additional confirmation of the value of "light" fluorous synthesis techniques, and the new fluorous Boc groups expand the applicability of fluorous synthesis techniques to many classes of nitrogen-containing organic compounds.     

Aryldithioethyloxycarbonyl (Ardec): a new family of amine protecting groups removable under mild reducing conditions and their applications to peptide synthesis

The development of phenyldithioethyloxycarbonyl (Phdec) and 2-pyridyldithioethyloxycarbonyl (Pydec) protecting groups, which are thiol-labile urethanes, is described. These new disulfide-based protecting groups were introduced onto the epsilon-amino group of L-lysine; the resulting amino acid derivatives were easily converted into N alpha-Fmoc building blocks suitable for both solid- and solution-phase peptide synthesis. Model dipeptide(Ardec)s were prepared by using classical peptide couplings followed by standard deprotection protocols. They were used to optimize the conditions for complete thiolytic removal of the Ardec groups both in aqueous and organic media. Phdec and Pydec were found to be cleaved within 15 to 30 min under mild reducing conditions: i) by treatment with dithiothreitol or beta-mercaptoethanol in Tris.HCl buffer (pH 8.5-9.0) for deprotection in water and ii) by treatment with beta-mercaptoethanol and 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) in N-methylpyrrolidinone for deprotection in an organic medium. Successful solid-phase synthesis of hexapeptides Ac-Lys-Asp-Glu-Val-Asp-Lys(Ardec)-NH2 has clearly demonstrated the full orthogonality of these new amino protecting groups with Fmoc and Boc protections. The utility of the Ardec orthogonal deprotection strategy for site-specific chemical modification of peptides bearing several amino groups was illustrated firstly by the preparation of a fluorogenic substrate for caspase-3 protease containing the cyanine dyes Cy 3.0 and Cy 5.0 as FRET donor/acceptor pair, and by solid-phase synthesis of an hexapeptide bearing a single biotin reporter group.     

A highly directional fourfold hydrogen-bonding motif for supramolecular structures through self-assembly of fullerodendrimers

Supramolecular dendrimers resulting from the dimerization of fullerene-functionalized dendrons through a quadruple hydrogen-bonding motif were prepared. The synthetic strategy is based on the esterification of a tert-butoxycarbonyl (Boc)-protected 2-ureido-4-[1H]pyrimidinone precursor possessing an alcohol function with fullerodendrons bearing a carboxylic acid unit at the focal point. Subsequent acidic treatment to cleave the protecting group and reaction of the resulting amine with octylisocyanate affords the targeted compounds. As demonstrated by the results of MALDI-TOF mass spectrometry and 1H NMR spectroscopy, both of the 2-ureido-4-[1H]pyrimidinone derivatives form self-assembled dimers spontaneously through hydrogen-bonding interactions, thus leading to supramolecular structures containing two or ten fullerene moieties.     

Selective acidolytic cleavage of aralkyl carbonyl amino protecting groups

The acidolytic cleavage of a series of new N-aralkyloxycarbonyl protecting groups has been found to proceed as a first-order reaction, the rate of cleavage being dependent on the stability of the corresponding aralkyl carbonium ions. Some of the groups are cleaved at much the same rate as the N-trityl residue and up to 60000 times faster than the t-butyloxycarbonyl (Boc) group. The rate is also strongly influenced by the acidity of the reaction media. The relative rates at which aralkyloxycarbonyl and Boc groups are split off can be largely controlled by appropriate selection of the reaction conditions. The implications of these findings for peptide syntheses are discussed and the use of the 2-(p-diphenyl)-isopropyloxycarbonyl residue as an especially suitable N-protecting group is proposed.     

Expanding the Scope of PNA‐Encoded Synthesis (PES): Mtt‐Protected PNA Fully Orthogonal to Fmoc Chemistry and a Broad Array of Robust Diversity‐Generating Reactions

Nucleic acid‐encoded libraries are emerging as an attractive and highly miniaturized format for the rapid identification of protein ligands. An important criterion in the synthesis of nucleic acid encoded libraries is the scope of reactions that can be used to introduce molecular diversity and devise divergent pathways for diversity‐oriented synthesis (DOS). To date, the protecting group strategies that have been used in peptide nucleic acid (PNA) encoded synthesis (PES) have limited the choice of reactions used in the library synthesis to just a few prototypes. Herein, we describe the preparation of PNA monomers with a protecting group combination (Mtt/Boc) that is orthogonal to Fmoc‐based synthesis and compatible with a large palette of reactions that have been productively used in DOS (palladium cross‐couplings, metathesis, reductive amination, amidation, heterocycle formation, nucleophilic addition, conjugate additions, Pictet–Spengler cyclization). We incorporate γ‐modifications in the PNA backbone that are known to enhance hybridization and solubility. We demonstrate the robustness of this strategy with a library synthesis that is characterized by MALDI MS analysis at every step.     

Intramolecular cyclization assistance for fast degradation of ornithine‐based poly(ester amide)s

Inspired by the spontaneous cyclization of ornithine in peptides, polyesters containing protected ornithine (Orn) side chains along the backbone were synthesized and shown to degrade rapidly upon deprotection through intramolecular cyclization. A new ornithine‐based poly(ester amide) PEA 1 and a lysine‐based control PEA 2, both bearing the light‐sensitive protecting group o‐nitrobenzyl alcohol (ONB), were synthesized. Tert‐butyl carbamate (Boc)‐protected versions 1‐Boc and 2‐Boc were also synthesized for proof of concept. GPC confirmed that 1‐Boc degrades over 40 times faster than 2‐Boc following deprotection into the designed intramolecular cyclization products. Finally, TEM visualization of particles made from 1 encapsulating iron oxide nanoparticles reveals complete disruption of nanoparticles and release of payload within a day upon UV irradiation. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 3783–3790     

Convergent solid phase peptide synthesis. v. synthesis of the 1-4, 32-34, and 53-59 protected segments of the toxin ii of androctonus australis hector.

Two protected peptide segments corresponding to the sequence 32-34 and 53-59 of toxin II of the north African scorpion Androctonus australis Hector have been synthesized on a photolabile Nbb-resin using the TFA-labile Boc -amino protection and HF-labile side chain protecting groups. A third protected peptide corresponding to segment 1-4 has been synthesized on the same resin but with a t-butyl group for β protection of aspartic acid and a Z group on the lysine side chain. For this last segment a combination of Boc and Fmoc groups for -amino protection has been used successfully on the Nbb-resin. After photolysis the crude peptides have been treated by solvent extraction and semi-preparative HPLC to yield highly purified segments. These syntheses show the flexibility of the convergent solid phase approach and how segments with different and independent protecting groups can be assembled by solid phase peptide procedure.     

Photoactive Chiral Metal-Organic Frameworks for Light-Driven Asymmetric α-Alkylation of Aldehydes

Chiral metal-organic frameworks (MOFs) with porous and tunable nature show promise as heterogeneous asymmetric catalysts. Through incorporating the stereoselective organocatalyst l- or d-pyrrolidin-2-ylimidazole (PYI) and a triphenylamine photoredox group into a single framework, we have developed two enantiomeric MOFs, Zn-PYI1 and Zn-PYI2, to prompt the asymmetric α-alkylation of aliphatic aldehydes in a heterogeneous manner. The strong reductive excited state of the triphenylamaine moiety within these MOFs initiated a photoinduced electron transfer, rendering an active intermediate for the α-alkylation. The chiral PYI moieties acted as cooperative organocatalytic active sites to drive the asymmetric catalysis with significant stereoselectivity. Control experiments using the lanthanide-based metal-organic frameworks Ho-TCA and MOF-150, assembled from 4,4',4″-nitrilotribenzoic acid, as catalysts suggested that both the photosensitizer triphenylamine moiety and the chiral organocatalyst d-/l-PYI moiety were necessary for the light-driven α-alkylation reactions. Further investigations demonstrated that the integration of both photocatalyst and asymmetric organocatalyst into a single MOF makes the enantioselection superior to that of simply mixing the corresponding MOFs with the chiral adduct. The easy availability, excellent stereoselectivity, great separability, and individual components fixed with their well-defined porous and repeating structures make the MOF a versatile platform for a new type of tandem catalyst and cooperative catalyst.     

Asymmetric Disulfonimide‐Catalyzed Synthesis of δ‐Amino‐β‐Ketoester Derivatives by Vinylogous Mukaiyama–Mannich Reactions

An organocatalytic asymmetric synthesis of δ‐amino‐β‐ketoester derivatives has been developed. A chiral disulfonimide (DSI) serves as a highly efficient precatalyst for a vinylogous Mukaiyama–Mannich reaction of readily available dioxinone‐derived silyloxydienes with N‐Boc‐protected imines, delivering products in excellent yields and enantioselectivities. The synthetic utility of this reaction is illustrated in various transformations, including a new C? C bond‐forming reaction, which provide useful enantioenriched building blocks. The methodology is applied in a formal synthesis of (?)‐lasubin.     

Aza-Morita-Baylis-Hillman-type reactions: highly enantioselective organocatalytic addition of unmodified α,β-unsaturated aldehydes to N-Boc protected imines

Highly enantioselective catalytic routes to Boc protected aza-Morita-Baylis-Hillman-type products are presented. The organocatalytic asymmetric reactions between unmodified α,β-unsaturated aldehydes and N-Boc protected aryl imines proceed with excellent chemo- and enantioselectivity to give the corresponding compounds in good yields with 97-99% ee.