Hydroxyl Protective Groups Research Articles

Enantioselective Total Synthesis of (+)-Alstilobanine C, (+)-Undulifoline, and (-)-Alpneumine H.

We report herein the enantioselective total synthesis of three monoterpene indole alkaloids, namely, (+)-alstilobanine C, (+)-undulifoline, and (-)-alpneumine H. The key features of our synthesis include: a) introduction of chirality via enantioselective deprotonation of a prochiral 4-substituted cyclohexanone; b) use of methoxymethyl (MOM) ether as both a hydroxyl protective group and a latent oxonium species for the formation of bridged oxepane and c) domino double reductive cyclization to build both the indole and the piperidine ring at the end of the synthesis. The synthesis confirmed the absolute configuration of these natural products assigned based on the biogenetic hypothesis.

Enantioselective Total Synthesis of (+)‐Alstilobanine C, (+)‐Undulifoline, and (−)‐Alpneumine H

AbstractWe report herein the enantioselective total synthesis of three monoterpene indole alkaloids, namely, (+)‐alstilobanine C, (+)‐undulifoline, and (−)‐alpneumine H. The key features of our synthesis include: a) introduction of chirality via enantioselective deprotonation of a prochiral 4‐substituted cyclohexanone; b) use of methoxymethyl (MOM) ether as both a hydroxyl protective group and a latent oxonium species for the formation of bridged oxepane and c) domino double reductive cyclization to build both the indole and the piperidine ring at the end of the synthesis. The synthesis confirmed the absolute configuration of these natural products assigned based on the biogenetic hypothesis.

Innovative 2'-O-Imino-2-propanoate-Protecting Group for Effective Solid-Phase Synthesis and 2'-O-Deprotection of RNA Sequences.

The implementation of protecting groups for the 2'-hydroxyl function of ribonucleosides is still challenging, particularly when RNA sequences must be of the highest purity for therapeutic applications as nucleic acid-based drugs. A 2'-hydroxyl-protecting group should optimally (i) be easy to install; (ii) allow rapid and efficient incorporation of the 2'-O-protected ribonucleosides into RNA sequences to minimize, to the greatest extent possible, the formation of process-related impurities (e.g., shorter than full-length sequences) during solid-phase synthesis; and (iii) be completely cleaved from RNA sequences without the production of alkylating side products and/or formation of mutagenic nucleobase adducts. The reaction of 2'-O-aminoribonucleosides with ethyl pyruvate results in the formation of stable 2'-O-imino-2-methyl propanoic acid ethyl esters and, subsequently, of the fully protected ribonucleoside phosphoramidite monomers, which are required for the solid-phase synthesis of two chimeric RNA sequences (20-mers) containing the four canonical ribonucleosides. Upon treatment of the RNA sequences with a solution of sodium hydroxide, the 2'-O-imino-2-methyl propanoic acid ethyl ester-protecting groups are saponified to their sodium salts, which after ion exchange underwent quantitative intramolecular decarboxylation under neutral conditions at 65 °C to provide fully deprotected RNA sequences in marginally better yields than those obtained from commercial 2'-O-tert-butyldimethylsilyl ribonucleoside phosphoramidites under highly similar conditions.

Synthesis of N-Pyridyl Hydroxylamines via Copper-Catalyzed Cross-Coupling

N-Pyridyl hydroxylamine derivatives were prepared via copper-catalyzed cross-coupling of orthogonally functionalized hydroxylamines with iodopyridines. Various amino- and hydroxyl-protecting groups were tolerated. A total of 20 examples were synthesized in 28–90% yield.

Expanding the scope of methyl xanthate esters - From Barton-McCombie reaction auxiliary to versatile protective group

The methyl xanthate ester is presented as a versatile protective group for alcohols. Hydroxyl groups can easily be transformed into methyl xanthate esters by several methods and are commonly used as an auxiliary in the Barton-McCombie reaction. We show that these methyl xanthate esters can readily and chemoselectively be cleaved under mild conditions by the action of diethylenetriamine using microwave heating. This method is orthogonal to many common hydroxyl protective groups that can be introduced and cleaved in the presence of methyl xanthate ester.

Automated electrochemical assembly of the protected potential TMG-chitotriomycin precursor based on rational optimization of the carbohydrate building block.

The anomeric arylthio group and the hydroxyl-protecting groups of thioglycosides were optimized to construct carbohydrate building blocks for automated electrochemical solution-phase synthesis of oligoglucosamines having 1,4-β-glycosidic linkages. The optimization study included density functional theory calculations, measurements of the oxidation potentials, and the trial synthesis of the chitotriose trisaccharide. The automated synthesis of the protected potential N,N,N-trimethyl-d-glucosaminylchitotriomycin precursor was accomplished by using the optimized building block.

Ring-Contraction vs Ring-Expansion Reactions of Spiro-cyclopropanecarboxylated Sugars

Electrophilic ring opening of spiro-cyclopropanecarboxylated sugars followed by reaction with DBU revealed interesting ring-contraction and ring-expansion reactions depending on the substrate and the kind of hydroxyl protective group present adjacent to the spiro center. A stereoselective method for accessing a new class of carbon chain extended keto-furanoses and C-glycosylated bicyclic compounds is reported.

Development of hydrophilic photolabile hydroxyl protecting groups

Hydrophilic photolabile protecting groups (PPGs) for hydroxyl protection have been developed. The new PPGs are derived from 3-(dimethylamino)trityl (DMATr) by replacing the two methyl groups with two hydrophilic butyryl groups. The new PPG reagents can be readily prepared and installed. They are stable in the dark but can be removed cleanly and efficiently in aqueous environments upon irradiation with a UV lamp or sunlight.

Streamlined Process for the Chemical Synthesis of RNA Using 2′-O-Thionocarbamate-Protected Nucleoside Phosphoramidites in the Solid Phase

An improved method for the chemical synthesis of RNA was developed utilizing a streamlined method for the preparation of phosphoramidite monomers and a single-step deprotection of the resulting oligoribonucleotide product using 1,2-diamines under anhydrous conditions. The process is compatible with most standard heterobase protection and employs a 2'-O-(1,1-dioxo-1λ(6)-thiomorpholine-4-carbothioate) as a unique 2'-hydroxyl protective group. Using this approach, it was demonstrated that the chemical synthesis of RNA can be as simple and robust as the chemical synthesis of DNA.

Facilitated photochemical cleavage of benzylic C–O bond. Application to photolabile hydroxyl-protecting group design

A new photolabile hydroxyl-protecting group has been developed by introducing a dimethylamino group to the meta position of an aromatic ring of the traditional trityl (Tr) protecting group.

An Improved Preparation Process for Gemcitabine

An improved, cost-effective, and convenient process, using cinnamoyl as hydroxyl protective group and tosyl as the leaving group for gemcitabine (1) is described. The overall yield obtained from this newly developed process is around 10%, including two stereospecific crystallizations, and the quality of the product complies with the requirements of USP30.

Reappraisal of the diastereoselectivity of intramolecular Diels–Alder reactions of some o-quinodimethanes generated by benzocyclobutene thermolysis: some complementary results and an improvement

In a synthetic approach to 19-nor steroids and in order to compare the diastereoselectivities observed for the intramolecular Diels–Alder reactions of o-quinodimethanes generated either from 1 or 2, the thermolysis of benzocyclobutenes such as 2 was reexamined. The IMDA diastereoselectivity was highly dependent on the nature of the protective group of the hydroxyl substituent at the unique chiral stereocentre of the o-quinodimethane intermediate, in a position α to the double bond of the dienophile. Consistently with previous results reported for benzocyclobutenes 2, the trans-fused cycloadducts were the major products, the trans syn or trans anti predominant isomer being determined by the hydroxyl protective group. In contrast with these previous reports, the cis-fused cycloadducts were always formed competitively, although as minor products. In the present work, the diastereoselectivity was improved by achieving the thermolysis of a benzocyclobutene 2 having a lithium alkoxide which afforded the trans syn adduct in high yield.

Mild generation of o-quinodimethanes via fluoride induced 1,4-elimination of α-( o-trimethylsilylmethyl)benzylesters: stereoselective synthesis of 19-nor steroids and RU486 precursors

19-Nor steroids and RU486 tricyclic synthetic intermediates were stereoselectively prepared by an intramolecular Diels–Alder reaction involving an o-quinodimethane possessing a pro-17 unique chiral stereocenter, substituted by a protected hydroxyl group. The o-quinodimethane was generated in mild conditions by fluoride induced 1,4-elimination of α-( o-trimethylsilylmethyl)benzylesters and the present methodology allows a flexible access to α,α′-disubstituted o-quinodimethanes, as shown by the 11β-substituted steroid approach. The IMDA diastereoselections reported herein were highly dependent on the nature of the hydroxyl protective group and the diastereoselectivities superior to those observed with the thermolysis of the corresponding benzocyclobutenes.

Chemoselective Deprotection of Acid Labile Primary Hydroxyl Protecting Groups under CBr4‐Photoirradiation Conditions.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Chemoselective deprotection of acid labile primary hydroxyl protecting groups under CBr 4-photoirradiation conditions

The CBr 4-photoirradiation in methanol generates a controlled source of HBr, which can chemoselectively deprotect commonly used hydroxyl-protecting groups in saccharides and nucleosides, such as tert-butyldimethylsilyl, isopropylidene, benzylidene and triphenyl ethers in the presence of other acid-labile functional groups.

Highly Efficient and Versatile Acetylation of Alcohols Catalyzed by Cerium(III) Triflate.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Highly efficient and versatile acetylation of alcohols catalyzed by cerium(III) triflate

Cerium(III) triflate is a powerful catalyst for the acetylation of alcohols. The reaction works well for a large variety of simple and functionalized alcohols, without isomerisation of chiral centres. Changes of hydroxyl protective groups are possible in a one-pot procedure. The catalyst can be easily recycled.

Protection of 2′‐Hydroxy Functions of Ribonucleosides

The main purpose of this article is to discuss 2'-protection in the context of effective oligoribonucleotide synthesis. Emphasis is placed on the 2'-protecting groups of choice in the synthesis of oligo-and polyribonucleotides, and the requirements that a protective group must satisfy to become the 2'-hydroxyl-protecting group of choice. Finally, the unit discusses the issue of 2'-O-acyl and 2'-O-silyl group migration to the 3'-hydroxy function of ribonucleosides during protection, along with the consequences of the conditions used for their removal on the stability of internucleotide linkages.

A new set of orthogonal-protecting groups for oligosaccharide synthesis on a polymeric support

The hydroxyl-protecting groups, levulinoyl (Lev) and 9-fluorenylmethoxycarbonyl (Fmoc), and the amino-protecting group 2,2,2-trichloroethoxycarbonyl (Troc), offer an ideal set of orthogonal-protecting groups which are compatible with oligosaccharide synthesis on a methylpolyethyleneglycol (MPEG) support using a p-alkyloxybenzyl-type linker.

Synthesis and ring-opening polymerization of new 1,4-anhydro-glucopyranose derivatives

Three new 1,4-anhydro-glucopyranose derivatives having different hydroxyl protective groups such as 1,4-anhydro-2,3,6-tri-O-methyl-α-D-glucopyranose (AMGLU), 1,4-anhydro-6-O-benzyl-2,3-di-O-methyl-α-D-glucopyranose (A6BMG), and 1,4-anhydro-2,3-di-O-methyl-6-O-trityl-α-D-glucopyranose (A6TMG) were synthesized from methyl α-D-glucopyranoside in good yields. Their polymerizability was compared with that of 1,4-anhydro-2,3,6-tri-O-benzyl-α-D-glucopyranose (ABGLU) reported previously. The trimethylated monomer, AMGLU, was polymerized by a PF5 catalyst to give 1,5-α-furanosidic polymer having number-average molecular weights (M̄n) in the range of 2.8 × 103 to 6.8 × 103. The 13C-NMR spectrum was compared with that of methylated amylose and cellulose. Other anhydro monomers, A6BMG and A6TMG, gave the corresponding 1,5-α furanosidic polymers having M̄n = 17.1 × 103 and 1.8 × 103, respectively. Thus, the substituents at the C2 and C6 positions were found to play an important role for the ring-opening polymerizability of the 1,4-anhydro-glucose monomers. In addition, debenzylation of the tribenzylated polymer gave free (1 → 5)-α-D-glucofuranan. © 1998 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 36: 841–850, 1998