N-Boc Group Research Articles

Controlled synthesis of chiral polymers for the kinetic resolution of racemic amino acids

A novel lysine bearing vinyl monomer, (S)-2-(tert-butoxycarbonylamino)-6-(4′-vinylbenzamido)hexanoic acid, was designed and synthesized. It underwent reversible addition–fragmentation chain transfer polymerization induced by azobisisobutyronitrile in the presence of 2-cyano-2-propyl dodecyl trithiocarbonate in dioxane at 65 °C. The number-average molecular weights of the resultant polymers increased linearly with the monomer conversion and the molecular weight distribution indices kept relatively low, indicating a well-controlled chain growth process. After deprotection of N-Boc groups, the monomer and the polymers were used as stereospecific inhibitors in the fractional crystallization of racemic glutamic acid monohydrochloride (rac-Glu·HCl). The polymers showed much better performance than the monomer. At a polymer concentration above 0.5 wt%, the R-enantiomer was obtained with an enantiomeric excess (ee%) over 97%, independent of the molecular weights of the polymer additives. In contrast, 10 wt% of the monomer was required to achieve the same result under identical conditions. However, with an addition of 0.1 wt% polymeric inhibitors, the ee% of the resolved R-Glu·HCl crystals increased initially and then decreased with an increased molecular weight of polymer additives, and for the polymer with a moderate Mn of 5800 Dalton, R-Glu·HCl with ee% over 97% was yielded. Because of the large absorption difference in the UV-Vis range between the polymer inhibitor and the resolved molecules, the residual fraction of additives in the resolved crystals was evaluated by means of UV-Vis spectrophotometry, and all results showed that there were very low fractions of polymer residues (<0.1%). Moreover, the polymers were also efficient for the kinetic resolution of rac-threonine and rac-asparagine monohydrate conglomerates at concentrations of 0.5 and 1.0 wt%, respectively, yielding preferentially R-enantiomers with ee% ∼98%.

Construction of Pyrrolidinyl Spirooxindoles via a 1,3-Dipolar Cycloaddition Reaction of (E)-N-Boc-3-Alkylidene-Indolin-2(3H)ones with Azomethine Ylides

A mild and efficient method for the construction of pyrrolidinyl spirooxindoles via a 1,3-dipolar cycloaddition reaction of (E)-N-Boc-3-alkylidene-indolin-2(3H)ones with azomethine ylides has been established. The presence of an N-Boc group in the indolin-2(3H)ones obviously increased the activity and stereoselectivity of the reaction, affording the desired pyrrolidinyl spirooxindoles 4 with up to 85% yield and up to >99/1 dr value. Furthermore, the antibacterial activity of these compounds against Staphylococcus aureus (ATCC-25825) has been tested at minimum concentration, and some of them exhibit moderate antibacterial activity. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]

ChemInform Abstract: Synthesis of Spirocarbamate Oxindoles via Intramolecular Trapping of a β‐Silyl Carbocation by an N‐Boc Group.

We report the Lewis acid catalyzed additions of allylsilanes to N-Boc-iminooxindoles and the formation of novel silicon-containing spirocarbamates via intramolecular trapping of a β-silyl carbocation by an N-Boc group. Several transformations display the synthetic utility of these spirocarbamate oxindoles, including a reductive cyclization to access new silylated furoindoline derivatives.

Synthesis of Spirocarbamate Oxindoles via Intramolecular Trapping of a β-Silyl Carbocation by an N-Boc Group

We report the Lewis acid catalyzed additions of allylsilanes to N-Boc-iminooxindoles and the formation of novel silicon-containing spirocarbamates via intramolecular trapping of a β-silyl carbocation by an N-Boc group. Several transformations display the synthetic utility of these spirocarbamate oxindoles, including a reductive cyclization to access new silylated furoindoline derivatives.

Activation and regioselectivity of five-membered cyclic thionocarbamates to nucleophilic attack

The cyclic thionocarbamate of alaninol undergoes nucleophilic attack by sulfur nucleophiles at 5-C to give 1-thiopropyl-2-amine derivatives when derivatised on nitrogen with a Boc group. Iodide under microwave conditions causes a rearrangement to the isomeric thiazolidinone, while “hard” nucleophiles react at the thione group to yield a variety of product types by subsequent C–N or C–O cleavage. X-ray crystallography studies showed that the N-Boc group reduces delocalisation of electron density from nitrogen into the thione group, and thus promotes activation of the ring to nucleophilic attack.

ChemInform Abstract: Synthesis of Novel 2‐Phenyl‐5‐substituted Dihydropyrimidines Using 2‐Phenyl‐1,3‐diaza‐1,3‐butadienes and Electron‐Deficient Olefins.

Abstract A novel synthetic method for 2,5-disubstituted dihydropyrimidines was developed. The cyclization of 1,3-diaza-4-dimethylamino-1,3-butadienes having a N-protecting group (N-Boc, N-Cbz, N-n-C4H9, N-Bn or N-Ph) with electron-deficient olefins, such as α,β-unsaturated carbonyl compounds, phenyl vinyl sulfone, and acrylonitrile was studied in detail. The cyclization smoothly proceeded to afford 4-dimethylamino-1,4,5,6-tetrahydropyrimidines or 1,6-dihydropyrimidines in good yields. The isolated 4-dimethylamino-1,4,5,6-tetrahydropyrimidines were converted to 2,5-disubstituted-1,6-dihydropyrimidines through the β-elimination of the dimethylamino group. 2,5-Disubstituted-1,4(6)-dihydropyrimidines were obtained after removal of the N-Boc or N-Cbz group. Independent tautomers of the resulting dihydropyrimidines were observed.

Preparation of bifunctional isocyanate hydroxamate linkers: synthesis of carbamate and urea tethered polyhydroxamic acid chelators

Two novel bifunctional N-methylhydroxamate–isocyanate linkers 20 and 21 were prepared in good yield and high purity from the corresponding amine salts using a biphasic reaction with phosgene. The facile ring opening reaction of N-Boc lactams using the anion of O-benzylhydroxylamine gave the protected amino hydroxamates 6a and 6c in good yields. The selective methylation of the hydroxamate nitrogen in the presence of the N-Boc group in these intermediates could be readily accomplished. The utility of the linkers was clearly demonstrated by the synthesis of the carbamate-tethered trishydroxamic acid 27 and the urea-tethered 29.

Stereocontrolled Total Synthesis of (+)‐trans‐Dihydronarciclasine

A highly stereoselective and efficient total synthesis of trans-dihydronarciclasine from a readily available chiral starting material was developed. The synthesis defines two of the five stereogenic centers of the natural product by an amino acid ester-enolate Claisen rearrangement. The other three stereogenic centers are created in a highly stereocontrolled fashion via a six-ring vinylogous ester intermediate, which is generated from the γ,δ-unsaturated ester functional group of the Claisen rearrangement product in an efficient three-step sequence. This concise total synthesis exemplifies the use of a highly regioselective Friedel-Crafts-type cyclization to form the B ring via an isocyanate intermediate derived from an N-Boc group, which is superior to the conventional method using an imino triflate intermediate. This same N-Boc group is employed to give high selectivity in the Claisen rearrangement earlier in the sequence.

A Simple and Efficient Green Method for the Deprotection of N-Boc in Various Structurally Diverse Amines under Water-mediated Catalyst-free Conditions

A simple, efficient and eco-friendly protocol has been developed for the deprotection of N-Boc on structurally diverse amines. Selective removal of N-Boc groups was achieved with excellent yields using water around reflux temperatures. In the absence of any additional reagents, this method represents a reasonable alternative to previously reported deprotection procedures.

Polymeric membranes composed of polystyrenes tethering amino acids for preferential CO2 separation over H2

Various N-tert-butoxycarbonyl (N-Boc) amino acids, such as glycine, valine, and serine, were combined to 4-chloromethylstyrene. The resulted monomers were readily polymerized to give polystyrenes tethering an amino acid by a conventional free radical polymerization technique. After deprotection of the N-Boc group with trifluoroacetic acid, the obtained polystyrene derivatives were soluble in ethanol and spin-coated on a commercial poly(ether sulfone) porous membrane to fabricate a composite membrane for CO2 separation over H2. The CO2 selective layer of synthesized PSt was ca. 200 nm thick, and the composite membranes showed preferential CO2 separation over H2, while parent polystyrene passed through H2 rather than CO2. Especially, the separation factor \( \alpha_{{{\text{CO}}_{ 2} /{\text{H}}_{ 2} }} \) was raised after alkaline treatment to form free primary amine on the terminus of graft chain. Serine tethered polystyrene showed the highest \( \alpha_{{{\text{CO}}_{ 2} /{\text{H}}_{ 2} }} \) (16) among them, which suggested the hydroxyl group would enhance the CO2 affinity of primary amine.

Synthesis of novel 2-phenyl-5-substituted dihydropyrimidines using 2-phenyl-1,3-diaza-1,3-butadienes and electron-deficient olefins

A novel synthetic method for 2,5-disubstituted dihydropyrimidines was developed. The cyclization of 1,3-diaza-4-dimethylamino-1,3-butadienes having a N-protecting group (N-Boc, N-Cbz, N-n-C4H9, N-Bn or N-Ph) with electron-deficient olefins, such as α,β-unsaturated carbonyl compounds, phenyl vinyl sulfone, and acrylonitrile was studied in detail. The cyclization smoothly proceeded to afford 4-dimethylamino-1,4,5,6-tetrahydropyrimidines or 1,6-dihydropyrimidines in good yields. The isolated 4-dimethylamino-1,4,5,6-tetrahydropyrimidines were converted to 2,5-disubstituted-1,6-dihydropyrimidines through the β-elimination of the dimethylamino group. 2,5-Disubstituted-1,4(6)-dihydropyrimidines were obtained after removal of the N-Boc or N-Cbz group. Independent tautomers of the resulting dihydropyrimidines were observed.

Formation of Unusual Seven-Membered Heterocycles Incorporating Nitrogen and Sulfur by Intramolecular Conjugate Displacement

Baylis-Hillman alcohols derived from methyl acrylate or acrylonitrile and carrying an N-Boc group β to the hydroxyl (CH(OH)CHNBoc) can be converted into unusual seven-membered heterocycles containing both nitrogen and sulfur by O-acylation (AcCl or EtOCOCl), N-deprotection (CF(3)CO(2)H), and reaction with CS(2). In a modification of this process, when the original nitrogen is substituted in the form PhSCH(2)CON(Me), an azepine derivative is then generated. The ring closures occur by intramolecular conjugate displacement.

ChemInform Abstract: Stereoselective Alkylation of N-Boc-2-pyrrolidinones and N-Boc-2-piperidinones. Synthesis and Characterization of Disubstituted Lactams.

Abstract Alkylation of enolates of monosubstituted N-Boc lactams 4–6 afforded trans-disubstituted lactams as the major isomer. In the pyrrolidinone series, 1,3-induction seems to be ruled by steric interactions and the diastereoselection is low for the alkylation of enolates with small substituents at C-5 (e.g., Me) and methyl iodide. The trans selectivity improves with bulkier substituents at C-2 and/or bulkier electrophiles. The formation of 3,6-trans-disubstituted piperidinones benefits from the axial orientation of the substituent at C-2 due to the A1,3 strain with the N-Boc group and excellent trans preference is observed even in the alkylation of the lithium enolate of N-Boc-6-methyl piperidinone with methyl iodide.

ChemInform Abstract: Design and Synthesis of Isoxazole Containing Bioisosteres of Epibatidine as Potent Nicotinic Acetylcholine Receptor Agonists.

An efficient synthesis of isoxazole containing isosteres of epibatidine is described. The synthesis proceeded from N-tert-butoxycarbonyl (Boc)-exo-2-(methoxycarbonyl)-7-azabicyclo[2.2.1]heptane (9). Compound 9 was reacted with the dilithium salt of an appropriately substituted oxime in tetrahydrofuran (THF). Cyclodehydration of the resultant β-keto oxime and deprotection of the N-Boc group in 5N aqueous HCl afforded the isoxazole containing isosteres of epibatidine (6-8). The binding affinities of these compounds were determined at the nicotinic acetylcholine receptor for the displacement of [3H]cytisine. The unsubstituted isoxazole containing isostere (6) showed the lower binding potency compared to the 3'-methylisoxazole isostere (7). Substitution with a phenyl group at the 3'-position of the isoxazole significantly reduced the binding potency. The in vivo toxicological studies of these analogs were also performed. The LD50 of the analogs ranged in the order : Me>H>Ph.

ChemInform Abstract: A Mild Procedure for the Clay Catalyzed Selective Removal of the tert-Butoxycarbonyl Protecting Group from Aromatic Amines.

Abstract The application of solid acidic catalysts for the selective removal of N-Boc protection is presented in this report. Montmorillonite K10 was found to be an effective catalyst in removing aromatic N-Boc groups while leaving aliphatic N-Boc amines untouched.

ChemInform Abstract: Synthesis of Ethyl 2-Acetamido-6-S- (5-amino-5-deoxy-β-D-arabinopyranosyl) -2-deoxy-1,6-dithio-β-D-glucopyranoside: A Sulfur-Linked 5-Amino-5-deoxyglycopyranosyl Disaccharide.

Abstract A novel pseudo-disaccharide having an imino sugar residue at the non-reducing end, namely, a sulfur-linked 5-amino-5-deoxyglycopyranosyl disaccharide, which is a potential specific inhibitor for glycosidases that recognize not only the glycosidic linkage but also the aglycone moiety, was synthesized. Glycosidation of N-Boc-5-amino-5-deoxy- d -arabinose with ethyl 2-acetamido-3,4-di-O-acetyl-2-deoxy-1,6-dithio-β- d -glucopyranoside in the presence of TsOH gave exclusively the corresponding 1,2-cis-linked thioglycoside. The interglycosidic linkage proved stable enough under conditions for the deprotection of the N-Boc group with TFA. This pseudodisaccharide was unstable at pH>5, but stable at lower pH. The sulfur-linked 5-amino-5-deoxyglycopyranosyl disaccharide was shown to be formed from 5-amino-5-deoxy- d -arabinose and ethyl 2-acetamido-2-deoxy-1,6-dithio-β- d -glucopyranoside in an acidic buffer solution.

The Asymmetric Synthesis of Sitagliptin, a Selective Dipeptidyl Peptidase IV Inhibitor for the Treatment of type 2 diabetes

An efficient asymmetric synthesis of Sitagliptin, a new DPP-IV inhibitor for the treatment of type 2 diabetes mellitus has been developed. The beta-amino acid fragment of Sitagliptin was prepared by asymmetric Michael addition of the corresponding α, β-unsaturated ester to (R)-(α-methylbenzyl)benzylamine followed by a two-step elaboration to obtain N-boc beta-amino ester. Hydrolysis of the ester and coupling with the triazolopiperazine afforded Sitagliptin after cleavage of the N-boc group and salt formation. The overall yield was 31% over nine steps.

Novel and Practical Synthesis of Candesartan Cilexetil

A novel and convergent synthetic route of candesartan cilexetil (API of Atacand), an effective angiotensin II receptor blocker, is described. Cleavage of the N-Boc and N-trityl protective group are implemented simultaneously and formation of the benzimidazole ring is conducted at the last step of this route, which gives candesartan cilexetil in 55% yield over six steps with 99.1% purity (HPLC).

Synthesis and preliminary biological evaluation of new derivatives of the marine alkaloid leucettamine B as kinase inhibitors

New derivatives of the marine alkaloid leucettamine B were prepared in five steps with overall yields ranging from 23 to 30%. The key step of our strategy has been the sulfur/nitrogen displacement under solvent-free microwave irradiation of (5Z) 5-benzo[1,3]-dioxo-5-ylmethylene-2-ethylsulfanyl-3,5-dihydroimidazol-4-one 3 with a mono-protected ethylenediamine 2. After deprotection of the N-Boc group, the amino derivative of leucettamine B 5 was subjected to reductive amination in two steps with retention of configuration of the double bond, to lead to eight new analogs of leucettamine B. The effect of these compounds on CK1α/β, CDK5/p25, and GSK-3α/β were investigated.

Synthesis, Structure, and Reactions of NH-Bridged Calix[m]arene[n]pyridines

NH-bridged calix[1]arene[3]pyridine and calix[2]arene[2]pyridine were synthesized readily from efficient deprotection of N-Boc groups of NBoc-bridged calix[m]arene[n]pyridine derivatives which were prepared by a macrocyclic coupling reaction between NBoc-linked trimers and 1,3-phenylenediamine. In the solid state, calix[2]arene[2]pyridine adopted the flattened saddle conformation, while NH-bridged calix[1]arene[3]pyridine gave a slightly twisted 1,3-alternate conformer. In both cases, all NH bridges formed partial conjugation with both pyridine and benzene rings, whereas in solution they gave symmetric conformational structures in which the conjugation of bridging NH units with pyridine ring was stronger than with benzene ring. In the presence of NaH, NH-bridged calix[2]arene[2]pyridine reacted efficiently with methyl iodide and allyl bromide to afford the corresponding N-alkylated products in almost quantitative yield. Upon treatment of NH- and NMe-bridged calix[2]arene[2]pyridines with CF3CO2D and CuBr2, deuteration and bromination reactions took place selectively on the pyridine ring, producing respectively the pyridine ring-deuterated and -brominated macrocyclic products.