Hai-Ming Guo

CuI Controlled C–C and C–N Bond Formation of Heteroaromatics through C(sp3)–H Activation

A new method for C-C and C-N bond formation of heteroaromatics and C(sp(3))-H alkanes was developed with high regioselectivity. The reaction occurred on C8 to give 8-cylcoakylpurines by C-C bond formation only promoted by tBuOOtBu, while it occurred on the amino group to give N6-alkylated purines by C-N bond formation when 2 equiv of CuI were added. A reaction mechanism was also proposed based on our preliminary experimental data.

Metal catalyzed C(sp3)-H bond amination of 2-alkyl azaarenes with diethyl azodicarboxylate.

Metal-catalyzed direct C(sp(3))-H bond amination of 2-alkyl azaarenes with N=N double bonds has been developed, which expands the scope of C(sp(3))-H bond activation reactions and provides a new access to medicinally important azaarene derivatives.

Copper-catalysed addition of α-alkyl azaarenes to ethyl glyoxylate via direct C(sp3)–H activation

A novel protocol for the copper-catalysed direct C(sp3)–H bond functionalisation of 2-alkyl azaarenes to CO double bonds has been developed, which expands the scope of C(sp3)–H bond activation reactions and provides new access to medicinally important azaarene derivatives.

Highly Enantioselective Synthesis of Designed Chiral Acyclonucleosides and Acyclonucleotides by Organocatalytic Aza‐Michael Addition

Acyclonucleoside and acyclonucleotide analogues are currently used as antiviral drugs with a broad spectrum of activities. The discovery of acyclovir as an antiherpes agent stimulated the search for new antiviral nucleosides with an acyclic carbohydrate-mimicking chain. Some nucleosides and nucleotides with chiral carbons in the acyclic side chain, such as (S)-HPMPC (Cidofovir), (S)-HPMPA, (R)PMPA (Tenofovir), and (S)-DHPA, have been shown to possess various medicinal activities (Scheme 1). It is noteworthy that the absolute configuration of these compounds has a significant influence on their biological potency. For example, S enantiomers of DHPA and HPMPA exhibit antiviral activities, whereas the R enantiomers are markedly less active. Hence, there is considerable interest in the development of effective methods for the synthesis of optically active acyclonucleoside and acyclonucleotide analogues because of their significance in medicinal and nucleic acid research. There are two routes that are mainly employed for the synthesis of chiral acyclonucleoside and acyclonucleotide analogues. One route is based on the introduction of a chiral side chain to purine or pyrimidine bases, which involves alkylation and aza-Michael addition reactions of modified bases with the desired functionalized chiral side chains, or the ring-opening reaction of propylene oxide with a chiral carbon center. Unfortunately, the functionalized chiral side chains usually need to be prepared by lengthy or difficult processes, which thus limits these methodologies to particular types of substrates. The second route is based on the generation of chiral acyclonucleoside products selectively from achiral starting materials. Though this route opens an exceedingly valuable protocol for the synthesis of new, versatile chiral acyclonucleosides, only two examples of such asymmetric catalytic processes are known in the literature up to now. First, Jacobsen and Gandelman have shown that [(salen)Al] complexes can catalyze the conjugate addition of purine bases to a,b-unsaturated enones or imides, and that the products can be further reduced to chiral acyclonucleoside analogues. Second, Hartwig and Stanley have described how the N-allylation of purine bases catalyzed by metallacyclic iridium complexes gives the desired product, which can be converted to chiral acyclonucleoside analogues by reduction or dihydroxylation. These two methods both give chiral acyclonucleosides in high enantioselectivities, but their applications are restricted by the use of highly toxic and expensive organometallic complexes that are difficult to prepare, and by the multiple conversion steps to give the nucleosides. In addition, neither of the two examples gives acyclonucleotide analogues. These limitations prompted us to develop a method for the synthesis of optically pure acyclonucleoside and acyclonucleotide analogues from achiral starting materials. Organocatalysis has expanded widely over the last few years. To date, however, there has been no report on the organocatalytic synthesis of chiral acyclonucleoside and acyclonucleotide analogues. During our studies on the synthesis of purine analogues and taking into consideration reports [a] Prof. Dr. H.-M. Guo, Dr. T.-F. Yuan, J.-Y. Liu, R.-Z. Mao, D.-Y. Li, Prof. G.-R. Qu College of Chemistry and Environmental Science Key Laboratory of Green Chemical Media and Reactions of Ministry of Education, Henan Normal University 46 Jianshe Road, Xinxiang, 453007 (P. R. China) Fax: (+86) 373-332-9276 E-mail : guohm518@hotmail.com quguir@sina.com [b] Dr. H.-Y. Niu School of Chemistry and Chemical Engineering Henan Institute of Science and Technology 1 Hualan Avenue, Xinxiang 453003 (P. R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201100435. Scheme 1. Structures of some acyclonucleosides and acyclonucleotides possessing antiviral activities.

Microwave-promoted efficient synthesis of C6-cyclo secondary amine substituted purine analogues in neat water

The synthesis of C6-cyclo secondary amine-substituted purine analogues in neat water was achieved with the aid of microwave irradiation, providing a rapid, efficient and convenient method for the preparation of acyclic nucleosides in high yields.

Nickel catalyzed alkylation of N-aromatic heterocycles with Grignard reagents through direct C-H bond functionalization.

A novel protocol for nickel-catalyzed direct sp(2) C-H bond alkylation of N-aromatic heterocycles has been developed. This new reaction proceeded efficiently at room temperature using a Grignard reagent as the coupling partner. This approach provides new access to a variety of alkylated N-aromatic heterocycles which are potentially of great importance in medicinal chemistry.

Synthesis of novel 6-[N,N-bis(2-hydroxyethyl)amino]purine nucleosides under microwave irradiation in neat water

Novel 6-[N,N-bis(2-hydroxyethyl)amino]purine nucleosides were prepared in one step by nucleophilic substitution reaction of 6-choloropurine nucleosides with diethanolamine. Shorter reaction times and higher yields were achieved under microwave irradiation conditions in neat water.

Nickel-catalyzed sp2 C–H bonds arylation of N-aromatic heterocycles with Grignard reagents at room temperature

A novel protocol for nickel-catalyzed direct sp(2) C-H bond arylation of purines has been developed. This new reaction proceeded efficiently at room temperature using Grignard reagent as the coupling partner within 5 hours in good to high yields. This approach provides a new access to a variety of C8-arylpurines which are potentially of great importance in medicinal chemistry.

The synthesis of tenofovir and its analogues via asymmetric transfer hydrogenation.

A series of tenofovir analogues with potential antiviral and immunobiologically active compounds were synthesized through an asymmetric transfer hydrogenation reaction from achiral purine derivatives. Up to 97% ee and good to excellent yields were achieved under mild conditions through short reaction steps. The present report suggests an efficient process to acquire tenofovir and its analogues.

Microwave irradiated C6-functionalization of 6-chloropurine nucleosides with various mild nucleophiles under solvent-free conditions

An efficient method for the synthesis of C6-functionalized purine nucleosides was developed via the direct nucleophilic substitution reaction of 6-chloropurine derivatives with various mild nucleophiles. The eco-friendly solvent-free process gave good to high isolated yields within a short reaction time (5 min) under microwave irradiated conditions.