Chemistry and Biochemistry
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Dr. Guigen Li

Title:

Professor

Education:

Ph.D., University of Arizona, 1995; Postdoctoral Study, The Scripps Research Institute, 1995-97

Research Area:

Organic, Medicinal and Bioorganic Chemistry

Office:

Phone:

Email:

Chemistry 300-A

806-742-3015

Guigen.Li@ttu.edu

 

Research Group

Principal Research Interests

Professor Li is interested in the development of new reagents, new reactions and their asymmetric versions. He is also interested in bioorganic and medicinal chemistry, especially, in the study of new analgesic and anti-inflammatory agents, peptide and peptidomimetic drug design, synthesis and structure-activity-relationship (SAR) studies which are important in treating diseases such as AIDS, cancer and diabetes.

So far, Professor Li and his coworkers/collaborators have achieved 130 publications based on his research. Recently, the Li group has established novel chiral phosphoramide and N-phosphonyl imine chemistry, and has successfully utilized chiral N-phosphonyl imines for many asymmetric reactions of chemically and biomedically importance. Professor Li's research has been supported by the National Institutes of Health (NIH), the Robert Welch Foundation, South Plains Foundation, TTU REF grants and National Science Foundation (NSF, as Co-PI). The major research conducted by the Li group at Texas Tech University is summarized below.

1. New chiral reagents for asymmetric synthesis

Novel chiral phosphoramide and N-phosphonyl imine chemistry has proven to be powerful in controlling many asymmetric reactions of chemically and biomedically importance (Scheme 1). Most of these asymmetric reactions resulted in excellent diastereoselectivity and good to high chemical yields. The chiral phosphoramides can be readily synthesized by using convenient procedures in nearly quantitative overall yields without the use of chromatographic purification. The chiral diamine auxiliaries can readily removed and recycled without racemization by treating with various acids under concise conditions.

Scheme 1. Novel chiral phosphoramide and N-phosphonyl imine chemistry

2. Halo Aldol Reactions

(a) X-C(sp3)/C(sp3)-C(sp3) Bond Formations

The asymmetric halo aldol reaction (AHA) results in chiral halogenated aldol products which can be used for the synthesis of extended aldols and other numerous important building blocks. The first AHA reaction was conducted by carefully adding the solution of diethylaluminum iodide into the mixture of a,b-unsaturated N-acetyl-4-phenyl-oxazolidinone (in excess) and aldehyde in dichloromethane stirring at -20 °C. The absolute stereochemistry has been unambiguously confirmed by the X-ray structural analysis.

Scheme 2. Asymmetric X-C(sp3)/C(sp3)-C(sp3) Bond Formations

The second new AHA reaction was established by using cyclopropyl carbonyl derived enolates as nucleophiles.  Good yields and excellent diastereoselectivity (>95%) were obtained.  The resulting products can be readily cyclized to give chiral 2,3-disubstituted tetrahydrofuran derivatives which exist in many biologically important molecules.

Scheme 3. Asymmetric X-C(sp3)/C(sp3)-C(sp3) Bond Formations

(b) X-C(sp2)/C(sp2)-C(sp3) Bond Formations

The first catalytic AHA reaction of silyl allenolates with aldehydes was achieved by using N-C3F7CO oxazaborolidine as the catalyst. The fluoroacyl group of the catalyst was found to be crucial for the control of enantioselectivity. The reaction provides the first enantioselective approach to b-halo Morita-Baylis-Hillman (MBH)-type adducts.

Scheme 4. Asymmetric catalytic halo aldol reaction for MBH ketone synthesis

The asymmetric catalytic halo aldol reaction of b-iodo allenoate with aldehydes was also established. The reaction was successfully achieved by using (R,R)-SalenAlCl as the chiral catalyst and LiI as an additive at 0 °C in dichloromethane. Moderate to good yields and up to 62% ee were obtained. The new system showed a good scope of substrates in which both aromatic aldehydes and aliphatic aldehydes can be employed. The reaction provided the first catalytic and enantioselective approach to chiral b-iodo Baylis-Hillman ester adducts.

Scheme 5. Asymmetric catalytic halo aldol reaction for MBH ester synthesis

(c) X-C(sp2)/C(sp3)-C(sp3) Bond Formations

The TMS-I based halo aldol reaction was also developed for the tandem formations of I-C/C-C bonds by activating the a',b-positions of a,b-acetylenic ketones. The key intermediates, 1-iodo-3-siloxy-1,3-butadienes, were generated from allenolates and were directly monitored by 1H-NMR spectroscopic analysis.  Excellent geometric selectivity (>95%) and good yields (65 - 82%) have been achieved.

Scheme  6. X-C(sp2)/C(sp3)-C(sp3) Bond Formations

(d) X-C(sp3)/C-C Double Bond Formations

Highly stereoselective vicinal difuctionalization of ,-unsaturated ketones for the synthesis of multifunctionalized tri-substituted alkenes is described.  The new reaction employs titanium (IV) halides (0.5 eq) as promoters and inexpensive commercial chemicals as starting materials.  The reaction can be performed at room temperature in any convenient vials without the protection of inert gases.  Good to excellent yields and complete Z/E stereoselectivity have been realized in most cases presented.

Scheme 7. X-C(sp3)/C-C Double Bond Formations

3. Electrophilic Aminohalogenation of Alkenes

The aminohalogenation was achieved by using ZnCl­2 and Cu(OTf)2 as catalysts and TsNCl2 as the nitrogen source. The NsNCl2-based aminohalogenation was developed by using the combination of 2-NsNCl2/2-NsNHNa as the nitrogen and halogen sources. When 2-NsNCl2 was used to react with olefins in acetonitrile in the absence of 2-NsNHNa, the a,b-differentiated diamines were produced predominantly which resulted in a novel diamination reaction. These aminohalogenation and diamination reactions are believed to occur through the formation of unprecedented aziridinium intermediates.

Scheme 8. Aminohalogenation and diamination of alkenes

The asymmetric aminohalogenation of functionalized alkenes has been established. The ionic liquid, [bmim][BF4], was found to be the only effective media for success while normal organic solvents failed to give any product for this reaction. The reaction is also very convenient to perform by simply mixing the three reactants, cinnamates, N,N-dichloro-p-toluenesulfonamide and catalyst together with 4 Å molecular sieves at room temperature in [bmim][BF4] in any convenient vial of appropriate size without special protection from inert gases.

Scheme 9. Asymmetric aminohalogenation reaction

The novel multiple-site activation of alkynes with amine/halogen functionalities was discovered by treating alkyne with N,N-dichlorobenzenesulfonamide at 80 °C in the presence of palladium acetate catalyst.  A new mechanism was proposed which involves the novel formation of b-halovinyl palladium and p-allylpalladium species. Excellent regio and stereoselectivities were achieved with the absolute structure determined by X-ray structural analysis.

Scheme 10. Aminohalogenation of alkynes

3. Electrophilic Diamination Reaction of Alkenes

The new electrophilic diamination of alkenes was developed by taking the advantage of inexpensive petroleum olefins as the substrates, readily accessible TsNCl­2 or 2-NsNCl­2 and acetonitrile as the nitrogen sources. The resulting imidazolidines have been conveniently converted into 1,2-diffrentiated diamines which can mimic both a- and b-amino acids.  Excellent regio-, stereoselectivity and up to 84% yield have been obtained for a,b-unsaturated ester and ketone substrates.

Scheme 11. Imidazolidination and diamine formations

Recently, N,N-Dichloro-o-nitrobenzenesulfonamide (2-NsNCl2) was found to be effective electrophilic nitrogen source for the direct diamination of a,b-unsaturated ketones without the use of any metal catalysts. The reaction is very convenient to carry out without the protection of inert gases. 4 Å Molecular sieves and temperature were found to play key roles to control the formations of 3-trichloromethyl and dichloromethyl imidazoline products. 2-Ns-protection group of the resulting diamine products can be easily cleaved under mild Fukuyama's conditions. New mechanism hypothesis of [2+3] cyclization and N-chlorination has been proposed to explain the product structures, particularly, their regio and stereochemistry.

Scheme 12. Chemoselective imidazolination of alkenes

The new combination of 2-NsNH2/NCS was found to be as the effective electrophilic nitrogen source for the regio-, stereo- and chemoselective imidazolination of alkenes. The reaction is very convenient to carry out simply by mixing olefin, 2-NsNH2, NCS and 4 Å molecular sieves in freshly distilled acetonitrile at room temperature. The aziridinium ion formed from the reaction of 2-NsNCl with olefins and the corresponding [2+3] cycloaddition are proposed during the reaction process to control regio- and stereoselectivity.

Scheme 13. Novel [2+3] cycloaddition mechanism

 

Representative Publications

(from a total of 130 publications)