Novel route to azobenzenes via Pd-catalyzed coupling reactions of aryl hydrazides with aryl halides,followed by direct oxidations

[reaction: see text] N-Boc aryl hydrazines undergo Pd-catalyzed coupling reactions with aryl halides to provide N-Boc diaryl hydrazines in excellent yields. The resulting N-Boc diaryl hydrazines were directly oxidized with NBS/pyridine in CH(2)Cl(2) at room temperature to the azobenzenes.     

Reactivity series for s-BuLi/diamine-mediated lithiation of N-Boc pyrrolidine: applications in catalysis and lithiation of N-Boc piperidine

Using competition experiments between a range of ligands and (-)-sparteine, a reactivity series for N-Boc pyrrolidine lithiation using s-BuLi/diamines has been constructed; the results indicate that the s-BuLi/(+)-sparteine surrogate complex is more reactive than s-BuLi/(-)-sparteine and this has been exploited in the selection of ligand pairs for ligand exchange catalytic asymmetric lithiation of N-Boc pyrrolidine and lithiation of N-Boc piperidine.     

N-Boc ethyl oxamate: a new nitrogen nucleophile for use in Mitsunobu reactions

N-Boc ethyl oxamate can be directly coupled with primary and secondary alcohols under Mitsunobu conditions to afford various N-Boc amines after mild deprotection.     

Synthesis of diazahexathia-24-crown-8 derivatives and structures of Ag+ complexes

Diazahexathia-24-crown-8 (2) has been isolated from the reaction mixture during the preparation of monoazatrithia-12-crown-4 (1). When N-Boc protected bis(2-chloroethyl)amine was employed as a starting material, N-Boc protected monoazatrithia-12-crown-4 (3) and N-Boc protected diazahexathia-24-crown-4 (4) were separated easily. Double-armed diazahexathia-24-crown-8 having two 3',5'-dichlorobenzyl groups (5a) or two 2-phenylethyl groups (5b) were also prepared using reductive amination. The stoichiometry and detailed structures of the Ag+ complexes with and were investigated by 1H NMR titration experiments and X-ray crystallography.     

Improved synthesis of paroxetine hydrochloride propan-2-ol solvate through one of metabolites in humans, and characterization of the solvate crystals

Paroxetine, a potent and selective inhibitor of 5-hydroxytryptamine (serotonin) uptake, was prepared through a piperidine derivative, which was reported to be one of the paroxetine metabolites in humans. Thus, the piperidine derivative was converted to its N-tert-butoxycarbonyl (N-Boc) derivative, which was then converted to N-Boc paroxetine. Paroxetine hydrochloride propan-2-ol (isopropyl alcohol (IPA)) solvate crystals were directly obtained from the N-Boc paroxetine by adding hydrogen chloride to the N-Boc paroxetine IPA solution. The amount of IPA content in the crystals was reduced by drying with a continuous change of powder X-ray diffraction patterns. Other characterizations of the solvate crystals were also conducted.     

手性膦肽核酸单体的合成

肽核酸是一种潜在的反义和反基因药物。膦肽结构的引入克服了肽核酸低水溶性和低细胞膜通透性等缺点,有利于肽核酸的应用。本研究报道手性磷肽核酸单体的合成。还原氨化方法被用于实现N-Boc,N-Fmoc保护的丙氨醛与甘氨膦酸二酯的偶联,BBC-Cl,FEP等缩合剂被用于实现碱基侧链和母链的高效缩合。     

Pd(0)-catalyzed cross-coupling reactions of boron derivatives with a lactam-derived N-Boc enol triflate

[formula: see text] The cross-coupling reaction of 2-(1-alkenyl)-1,3,2-benzodioxaboroles, obtained from alkynes and catecholborane, and other boron derivatives with a lactam-derived N-Boc enol triflate occurred under very mild conditions in a THF-water medium employing (Ph3P)2PdCl2 as a catalyst, providing the corresponding 6-substituted N-Boc 3,4-dihydro-2H-pyridines in high yields.     

Partial reduction of pyrroles: application to natural product synthesis

The partial reduction of N-Boc pyrroles has been explored giving stereoselective routes to disubstituted pyrrolines in good yields and with excellent diastereoselectivities. A novel methodology has been developed to carry out reductive aldol reactions on 2-substituted N-Boc pyrroles; use of aldehydes under reductive aldol conditions gave the anti aldol product in good selectivity. This chemistry was used as the key transformation in a synthesis of omuralide, which was achieved in 13 steps and 14% overall yield. We also report a methodology for selectively forming either cis or trans 2,5-disubstituted pyrrolines via a partial reduction of an electron-deficient N-Boc pyrrole. The trans pyrroline formed using this route was utilized in the syntheses of the polyhydroxylated pyrrolizidine natural products hyacinthacine A1 and 1-epiaustraline. Further investigation has led to the development of routes to enantiopure substituted pyrroline compounds. This has been achieved via a chiral protonation approach using easily accessible chiral acids, such as ephedrine and oxazolidinones, to quench enolates formed during the partial reduction process. Alternatively, enzymatic desymmetrization of symmetrical diol compounds formed from the partial reduction products of substituted pyrroles is also reported. This leads to formation of both enantiomers of 2,2- and 2,5-disubstituted N-Boc pyrrolines in excellent ee and yields.     

A One-Pot Selective Synthesis of N-Boc Protected Secondary Amines: Tandem Direct Reductive Amination/N-Boc Protection

A one-pot tandem direct reductive amination of aldehydes with primary amines resulting in N-Boc secondary amines using a (Boc)(2)O/sodium triacetoxyborohydride (STAB) system is reported. The tandem procedure is efficient, selective, and versatile, giving excellent yields of N-Boc protected secondary amines even in those cases where the products are prone to intramolecular lactamization.     

Synthesis of alpha-kainic acid from a 7-azabicyclo[2.2.1]heptadiene by tandem radical addition-homoallylic radical rearrangement

Reductive radical addition of 2-iodoethanol to N-Boc 2-tosyl-7-azabicyclo[2.2.1]heptadiene gives N-Boc syn-7-(2-hydroxyethyl)-4-tosyl-2-azabicyclo[2.2.1]hept-5-ene, which is converted into the neuroexcitants 3-(carboxymethyl)pyrrolidine-2,4-dicarboxylic acid and alpha-kainic acid. [structure: see text]     

N-carbamate protected alpha-amidoalkyl-p-tolylsulfones: convenient substrates in the aza-Morita-Baylis-Hillman reaction

An efficient and practical one-pot approach to aza-Morita-Baylis-Hillman adducts has been developed. The reaction occurs between N-Boc or N-Cbz imines, generated in situ from stable and easy to handle N-Boc or N-Cbz protected alpha-amidoalkyl-p-tolylsulfones, and electron-deficient alkenes in the presence of DABCO. The presented procedure eliminates the use of the relatively unstable N-carbamate imines prior to the coupling reaction. The reaction is limited to alpha-amidosulfones derived from aromatic and heteroaromatic aldehydes.     

Enantioselective synthesis of bio-relevant 3,5-diaryl pyrazolines

The straightforward asymmetric construction of bio-relevant Δ(2)-pyrazolines having either N-(thio)amide or N-acetyl functional groups and flanked by aryl substituents such as phenol at C3 and C5 has been achieved through an enantioselective phase transfer organocatalytic addition of N-Boc hydrazine to chalcones followed by a transprotection sequence allowing N-Boc transformation into N-CXNHR (X = S, O) or N-Ac functional groups. This approach was applied to a straightforward elaboration of chiral monoamine oxidase inhibitor derivatives.     

2,2-Difunctionalization of alkenes via Pd(II)-catalyzed aza-Wacker reactions

N-Ts and N-Boc derivatives of 1,2-diamines and 1,2-amino alcohols are shown to undergo efficient Pd(II)-catalyzed aza-Wacker reactions with a large range of electron-deficient alkenes. The resulting enamine intermediate generally undergoes cyclization with the second heteroatom to form 1,3-heterocycles. The sequence facilitates the rapid synthesis of saturated oxazolidines, imidazolidines, and their derivatives. Use of N-L-valinol derivatives results in highly diastereoselective reactions, where the net stereochemical outcome diverges between N-Ts and N-Boc.     

Organocatalytic asymmetric Mannich reactions with N-Boc and N-Cbz protected alpha-amido sulfones (Boc: tert-butoxycarbonyl, Cbz: benzyloxycarbonyl)

Different malonates and beta-ketoesters can react with N-tert-butoxycarbonyl- (N-Boc) and N-benzyloxycarbonyl- (N-Cbz) protected alpha-amido sulfones in an organocatalytic asymmetric Mannich-type reaction. The reaction makes use of a simple and easily obtained phase-transfer catalyst and proceeds under very mild and user-friendly conditions. The optimised protocol avoids the preparation and the isolation of the relatively unstable N-Boc and N-Cbz imines that are generated in situ from the bench-stable alpha-amido sulfones. The corresponding Mannich bases are generally obtained in good yields and enantioselectivities, and can be readily transformed into key compounds, such as optically active beta3-amino acids in one easy step. Enantioenriched N-Boc and N-Cbz protected beta-amino acids that are suitable for peptide synthesis are also available from the Mannich adducts through simple manipulations. Control experiments showed the dual role of the enolate-catalyst ion pair in this reaction, as well as the crucial role of the presence of water to achieve high enantioselectivities.     

Enantioselective, palladium-catalyzed α-arylation of N-Boc pyrrolidine: in situ react IR spectroscopic monitoring, scope, and synthetic applications

A comprehensive study of the enantioselective Pd-catalyzed α-arylation of N-Boc pyrrolidine has been carried out. The protocol involves deprotonation of N-Boc pyrrolidine using s-BuLi/(-)-sparteine in TBME or Et(2)O at -78 °C, transmetalation with ZnCl(2) and Negishi coupling using Pd(OAc)(2), t-Bu(3)P-HBF(4) and the aryl bromide. This paper reports several new features including in situ React IR spectroscopic monitoring of the process; use of (-)-sparteine and the (+)-sparteine surrogate to access products with opposite configuration; development of a catalytic asymmetric lithiation-Negishi coupling reaction; extension to a wide range of heteroaromatic bromides; total synthesis of (R)-crispine A, (S)-nicotine and (S)-SIB-1508Y via short synthetic routes; and examples of α-vinylation of N-Boc pyrrolidine using vinyl bromides exemplified by the total synthesis of naturally occurring (+)-maackiamine (thus establishing its configuration as (R)). In this way, the full scope and limitations of the methodology are delineated.     

Asymmetric synthesis of enantioenriched (+)-elaeokanine A

The key transformation in the total synthesis of (+)-elaeokanine A was accomplished by asymmetric deprotonation of N-Boc pyrrolidine, followed by the reaction of the in situ generated enantioenriched stereogenic cuprate reagent with (E)-4-bromo-1-iodo-1-trimethylsilyl-1-butene with retention of configuration. N-Boc deprotection, followed by a one-pot olefin isomerization and intramolecular amine alkylation afforded a bicyclic vinyl bromide that was converted into (+)-elaeokanine A by sequential halogen metal exchange and reaction of the organolithium reagent with N-butanoylmorpholine.     

N-Boc and N-CBz Ethyl Oxamates: New Gabriel Reagents

N-Boc and N-CBz ethyl oxamates can be directly coupled with various halides under Gabriel conditions which afford the corresponding N-protected amines after mild deprotection with LiOH.     

Total synthesis of lepadiformine alkaloids using N-Boc α-amino nitriles as trianion synthons

Lepadiformine A, B, and C were synthesized in an enantiomerically pure form using a reductive cyclization strategy. N-Boc α-amino nitriles were deprotonated and alkylated with enantiomerically pure dibromides to afford the first ring. The products were manipulated to introduce phosphate leaving groups, and subsequent reductive lithiation followed by intramolecular alkylation formed the second ring with high stereoselectivity. The third ring was formed by intramolecular displacement of a mesylate by the deprotected amine. Lepadiformine A and B contain a hydroxymethyl group adjacent to the amine. This appendage was introduced in a sequence using a Polonovski-Potier reaction as the key step. The synthetic strategy is stereoselective and convergent and demonstrates the utility of N-Boc α-amino nitriles as linchpins for alkaloid synthesis.     

Stereocontrolled syntheses of kainoid amino acids from 7-azabicyclo[2.2.1]heptadienes using tandem radical addition-homoallylic radical rearrangement

[reaction; see text] N-Boc syn-7-(2-hydroxyethyl)-4-(alkyl or aryl)sulfonyl-2-azabicyclo[2.2.1]hept-5-enes serve as precursors in syntheses of the neuroexcitants 3-(carboxymethyl)pyrrolidine-2,4-dicarboxylic acid 43, alpha-kainic acid 12, alpha-isokainic acid 14, and alpha-dihydroallokainic acid 77. The key step in these syntheses is the intermolecular radical addition of 2-iodoethanol to a N-Boc 2-(alkyl or aryl)sulfonyl-7-azabicyclo[2.2.1]heptadiene 7 to induce nitrogen-directed homoallylic radical rearrangement. Oxidative cleavage of the resulting 2-azabicyclo[2.2.1]hept-5-enes provide straightforward access to polysubstituted pyrrolidines and, in particular, an efficient entry to the kainoid amino acids.     

Introduction of a substituent at the 5"-position of N-Boc neomycin B under Mitsunobu reaction conditions

Because of the peculiar reactivity of the idose part of N-Boc neomycin B , special care must be exercised to introduce a substituent at the 5"-position of the antibiotic when using Mitsunobu reaction conditions.