Texas Tech University

Dr. Guigen Li

Li Guigen

Title: Paul W. Horn Distinguished Professor

Education: Ph.D., University of Arizona (Victor Hruby), 1995
PostDoc, The Scripps Research Institute (Barry Sharpless), 1995-97
Associate Editor, Molecules
Associate Editor, ISRN-Organic Chemistry
Board Member, CHEMTRACTS-Organic Chemistry
Board Member, Chemical Biology & Drug Design
Editorial Advisory Board, Natural Products Against Cancer
Honorary Editorial Board Member, Reports in Organic Chemistry

Research Area: Organic, Medicinal and Bioorganic Chemistry

Office: Chemistry 300-A

Phone: 806-834-8755

Email: guigen.li@ttu.edu

Webpage: Research Group

Journal Cover Arts of Li's work

Chemical Communication cover art
Chemical Communications, Issue 6, 2012

2012 Outstanding Researcher Award
2012 Outstanding Researcher Award
Texas Tech University

Organic & Biomolecular Chemistry cover art
Organic & Biomolecular Chemistry, Issue13, 2012

Recent Invitation Talks Given at

  1. University of South Florida
  2. University of Göttingen
  3. Indiana Univ.-Purdue Univ
  4. University of Pennsylvania
  5. Columbia University
  6. University of California at Berkeley
  7. Southern Methodist University
  8. Emory University
  9. Georgia State University
  10. Georgia Institute of Technology

Principal Research Interests

  • Asymmetric Synthesis
  • Asymmetric Catalysis
  • Bioorganic and Medicinal Chemistry
Professor Li is interested in the development of new concepts, new achiral and chiral reagents, new reactions, their asymmetric versions and applications. 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 that are important for treating diseases, such as AIDS, cancer and diabetes.

So far, Professor Li and his coworkers/collaborators have achieved nearly 320 publications (H-index of 52). Recently, Li group has established a new concept called GAP chemistry (Group-Assistant-Purification chemistry), new phosphoramides and phosphinamides, N-phosphonyl and N-phosphinyl imine chemistry. His group has successfully utilized chiral N-phosphonyl and N-phosphinyl imines to 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, the South Plains Foundation, TTU REF grants and National Science Foundation (NSF as Co-PI). Some of the research conducted by the Li group at Texas Tech University is summarized below.

The GAP chemistry concept

The GAP chemistry means Group-Assistant-Purification chemistry. It is well-known that the development of efficient syntheses that combine economic, environmental and green aspects constitutes a great challenge in modern organic chemistry. It has been extremely difficult to find general achiral and chiral reagents that enable organic synthesis, particularly, asymmetric synthesis and catalysis, to be performed without the use of traditional purifications of chromatography or recrystallization. So far, such a chemistry concept with atom economic advantages has not been established. However, this new concept would encourage the synthetic community to search for efficient reagents and related reactions to better serve for academic and pharmaceutical industry with minimized use of energy, materials and manpower.

As shown below that the Li group has discovered that a series of reactions involving chiral N-phosphonyl and N-phosphinyl imines can meet the requirements of GAP chemistry, i.e. the pure chiral amino isomeric products attached with chiral N-phosphonyl or N-phosphinyl group can be obtained simply by washing the solid crude products with hexane or the mixture solvent of hexane-EtOAc. Furthermore, the achiral or chiral N-phosphonyl auxiliary can be easily cleaved under mild conditions, and can be quantitatively recycled by a one-time extraction with n-butanol.

GAP chemistry Pictorial Description

Fig 1. GAP chemistry Pictorial Description

GAP chemistry is the first concept which connects chemical reactions and reagents with separation and purification techniques.

Advantages of GAP chemistry:

(1) Decrease waste production (e. g., a 15 people-group may need 500 kg silica gels and 1000 L solvents annually);
(2) Reduce synthesis expenses (silica gels, solvents, manpower, energy, apparatus, etc.);
(3) Accelerate synthesis processes;
(4) Avoid shortcomings of both solid-phase-peptide and liquid-phase-peptide synthesis (SPPS and LPPS).

Requirements of GAP Chemistry: well-designed groups are crucial for GAP Chemistry. These groups should be able to:

(1) generate adequate reactivity for their attached reagents;
(2) control diastereoselectivity (for chiral GAP reagents);
(3) control enantioselectivity (for achiral GAP reagents in asymmetric catalysis);
(4) control solubility of resulting products (insoluble or nearly insoluble in some solvents such as hexane, petroleum ethers, their co-solvents with EtOAc, etc.; but soluable in common synthetic solvents such THF, DCM, etc.);
(5) be recovered and recycled for re-use;
(6) be adjusted readily to reach the aims of 1-5 above.

GAP washing was proven to be able to increase %ee of enantio mixtures, e.g., 85% ee mixtures can be enhanced to >99%ee by GAP washing of solid crude products (not crystals from recrystalization, J. Org. Chem., 2013, 78, 4006−4012), which is against textbooks knowledge.

1.1. The GAP chemistry in asymmetric reactions of N-phosphonyl imines

The N-phosphonyl imine chemistry has been proven to be powerful in controlling many asymmetric reactions as shown in Scheme 1. Most of these asymmetric reactions have resulted in excellent diastereoselectivity and 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 be readily removed and recycled without racemization by treating with various acids under concise conditions. All of the products were obtained via the GAP chemistry process.

GAP Chemistry of Chiral N-Phosphonyl Imines

Scheme 1. GAP Chemistry of Chiral N-Phosphonyl Imines

Very recently, the asymmetric Umpolung reaction of chiral N-phosphonyl imines with 2-lithio-1,3-dithianes has be performed to give good chemical yields (up to 82%) and good to excellent diastereoselectivities of > 99:1 (Scheme 2). The addition manner by which chiral N-phosphonyl imines were slowly added into the solution of 2-lithio-1,3-dithiane was found to be crucial for achieving excellent diastereoselectivity. The GAP chemistry process enabled a series of α-amino-1,3-dithianes to be readily obtained by washing the solid crude products with hexane.

Asymmetric Umpolung Reaction of N-Phosphonyl Imines

Scheme 2. Asymmetric Umpolung Reaction of N-Phosphonyl Imines

1.2. The GAP chemistry in asymmetric reactions of N-phosphinyl imines

To expend the scope of chiral N-phosphonyl imine chemistry, N-phosphinyl imines have been designed and synthesized through regional structure design (Scheme 3). N-Phosphinyl imines were applied to asymmetric aza-Henry reaction to give excellent chemical yields (92% - quant.) and diastereoselectivity (91% - >99%de). The reaction showed a great substrate scope in which aromatic/aliphatic aldehyde and ketone-derived N-phosphonyl imines can be employed as electrophiles. The chiral N-phosphinamide can be stored at r.t. for more than two months without inert gas protection; and chiral N-phosphinyl imines were also proven to be highly stable at r.t. for a long period under inert gas protection. The N-phosphinyl group also enabled the purification to follow the GAP chemistry process simply by washing crude product with EtOAc and hexane.

Asymmetric Henry Reaction of N-Phosphinyl Imines

Scheme 3. Asymmetric Henry Reaction of N-Phosphinyl Imines

1.3. TheGAPchemistry in asymmetric catalysis of achiral N-phosphonyl imines

The new asymmetric catalytic Strecker reaction of achiral N-phosphonyl imines has been established (Scheme 4). Excellent enantioselectivities and yields have been achieved by using several catalysts, such as primary free natural primary amino acids, amino alcohol and BINOLs. Et2AlCN was used as the nucleophile for this reaction which presents the new use of non-volatile Et2AlCN instead of HCN and TMS-CN in asymmetric catalysis. N,N'-Protection groups on achiral N-phosphonyl imine were found to play an important role for this success, and enabled the GAP chemistry purification. It can also be readily cleaved and recycled under mild condition to give a quantitative recovery of N,N'-bis(naphthalen-1-ylmethyl)ethane-1,2-diamine. A new mechanism has been proposed that is consistent with experimental observations (Fig 1 and Scheme 5).

Asymmetric Catalytic Strecker Reaction

Scheme 4. Asymmetric Catalytic Strecker Reaction

In the mechanism, the first step is to form the complex of amino acid-Al-CN species (B). The Lewis acidic center of this species can activate the oxygen of N-phosphonyl group of the imine substrate before species (B) delivers cyanide onto the C=N bond from its Si-face to afford intermediate (C) (Figure 1). During the reaction process, Et2AlCN reacts with i-PrOH additive to give species Et(i-PrO)AlCN, its activation of the imine nitrogen is anticipated prior to C=N addition. At the third step, the catalyst (B) is regenerated via the homotransmetallation between species (C) and Et(i-PrO)AlCN; simultaneously, the actual catalytic complex (D) was generated, which was followed by deprotonation and quenching to afford the final product.

Working model of asymmetric induction

Figure 1. Working model of asymmetric induction

Mechanism of Asymmetric Catalytic Strecker Reaction

Scheme 5. Mechanism of Asymmetric Catalytic Strecker Reaction

1.4 The GAP chemistry in multi-component domino reactions

A new four-component domino reaction has been discovered and was found to follow the GAP procedure without the need of chromatography or recrystallization. The reaction is easy to perform simply by mixing four common reactants and K2CO3 in ethylene glycol under microwave irradiation. The reaction proceeds at a fast speed and can be finished within 10-24 min with water as the major byproduct, which makes work-up convenient. Four stereogenic centers with one quaternary carbon-amino function have been controlled very well; and the stereochemistry has been unequivocally determined by X-ray structural analysis. The resulting pyrido[3,4-i]quinazoline derivatives would be of importance for organic and medicinal research.

(X = CH2, n = 0, 1, 2; X =N-Me, N-Bn, n = 1)

(X = CH2, n = 0, 1, 2; X =N-Me, N-Bn, n = 1)

One-pot Domino Reaction using Aromatic Aldehydes and Mechanism

Scheme 6. One-pot Domino Reaction using Aromatic Aldehydes and Mechanism

It was interesting to find that when the above reaction was conducted by using aliphatic aldehydes to replace their aromatic counterparts, the quinazoline derivatives were not generated (Scheme 7). Instead, the reaction occurred to another direction to form multi-functionalized tricyclo[,6]dodecanes that belong to another family of important scaffolds for organic synthesis and drug design in pharmaceutical sciences (Scheme 7). These two reactions are believed to go through the mechanisms as shown in Schemes 6 and 7.

Multicomponent Domino Reaction and their Asymmetric Versions

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

Scheme 7. One-pot Domino Reaction using Aliphatic Aldehydes and Mechanism

2. Multicomponent Domino Reaction and their Asymmetric Versions

2.1 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 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 and aldehyde in dichloromethane stirring at -20 ˚C. The absolute stereochemistry has been unambiguously confirmed by the X-ray structural analysis.

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

Scheme 8. Asymmetric X-C(sp3)/C(sp3)-C(sp3) Bond Formations

The second new multicomponent domino 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 and cyclic amine derivatives which exist in many biologically important molecules.

Asymmetric 2,3-disubstituted tetrahydrofuran and amine formations

81% yield 96% yield
>95% de

Scheme 7. Asymmetric 2,3-disubstituted tetrahydrofuran and amine formations

2.2. X-C(sp2)/C(sp2)-C(sp3) Bond Formations

The first catalytic multicomponent domino 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.

Asymmetric catalytic halo aldol reaction for MBH ketone synthesis

Scheme 8. 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 Morita-Baylis-Hillman esters.

Asymmetric catalytic halo aldol reaction for MBH ester synthesis

Scheme 9. Asymmetric catalytic halo aldol reaction for MBH ester synthesis

2.3. 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.

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

Scheme 10. X-C(sp2)/C(sp3)-C(sp3) Bond Formations

2.4. X-C(sp3)/C-C Double Bond Formations

Highly stereoselective vicinal difuctionalization of a,b-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 that were examined.

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

Scheme 11. X-C(sp3)/C-C Double Bond Formations

3. Electrophilic Aminohalogenation of Alkenes

The aminohalogenation was achieved by using ZnCl¬2 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 reactions are believed to occur through the formation of unprecedented aziridinium intermediates.

Aminohalogenation and diamination of alkenes

Scheme 12. Aminohalogenation and diamination of alkenes

The first 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.

Asymmetric aminohalogenation reaction

Scheme 13. 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.

Aminohalogenation of alkynes

Scheme 14. Aminohalogenation of alkynes

4. Multicomponent Diamination of Alkenes

The new multicomponent electrophilic diamination of alkenes was developed by taking the advantage of inexpensive petroleum olefins as the substrates, readily accessible TsNCl¬2 or 2-NsNCl¬2 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.

Imidazolidination and diamine formations

Scheme 15. Imidazolidination and diamine formations

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.

Chemoselective imidazolination of alkenes

Scheme 16. Chemoselective imidazolination of alkenes

A 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.

Novel [2+3] cycloaddition mechanism

Scheme 17. Novel [2+3] cycloaddition mechanism.

Representative Publications

(from a total of 254 publications)

  • Jiang, B.; Tu, X. J.; Wang, X.; Tu, S. J.; Li, G. G. Copper(I)-Catalyzed Multicomponent Reaction Providing a New Access to Fully Substituted Thiophene Derivatives Org. Lett. 2014, 16, 3656.
  • Ma, G. H.; Jiang, B.; Tu, X. J.; Ning, Y.; Tu, S. J.; Li, G. G. Synthesis of Isocoumarins with Different Substituted Patterns via Passerini-Aldol Sequence Org. Lett. 2014, 16, 4504.
  • Wu, J. B.; An, G. H.; Lin, S. Q.; Xie, J. B.; Zhou, W.; Sun, H.; Pan, Y.; Li, G. G. Solution-Phase-Peptide Synthesis via the Group-Assisted Purification (GAP) Chemistry Without Using Chromatography and Recrystallization Chem. Comm. 2014, 50, 1259.
  • Chen, Z. Z.; Liu, S.; Hao, W. J.; Xu, G.; Wu, S.; Miao, J. N.; Jiang, B.; Wang, S. L.; Tu, S. J.; Li, G. G. Catalytic Arylsulfonyl Radical-Triggered 1,5-Enyne-Bicyclizations and Hydrosulfonylation of Alpha, Beta-Conjugates Chem. Sci. 2015, 6, 6654.
  • Qiu, J. K.; Jiang, B.; Zhu, Y. L.; Hao, W. J.; Wang, D. C.; Sun, J.; Wei, P.; Tu, S. J.; Li, G. G. Catalytic Dual 1,1-H-Abstraction/Insertion for Domino Spirocyclizations J. Am. Chem. Soc. 2015, 137, 8928.
  • Seifert, C. W.; Pindi, S.; Li, G. Asymmetric Carbamoyl Anion Additions to Chiral N-Phosphonyl Imines via the GAP Chemistry Process and Stereoselectivity Enrichments J. Org. Chem. 2015, 80, 447.
  • Wu, H. M.; Zi, W. W.; Li, G. G.; Lu, H. J.; Toste, F. D. Gold(I)-Catalyzed Desymmetrization of 1,4-Dienes by an Enantioselective Tandem Alkoxylation/Claisen Rearrangement Angew. Chem.-Int. Edit. 2015, 54, 8529.
  • Wu, X. S.; Yang, K.; Zhao, Y.; Sun, H.; Li, G. G.; Ge, H. B. Cobalt-Catalysed Site-Selective Intra- and Intermolecular Dehydrogenative Amination of Unactivated sp(3) Carbons Nat. Commun. 2015, 6, 10.
  • Gao, Q.; Hao, W.-J.; Liu, F.; Tu, S.-J.; Wang, S.-L.; Li, G.; Jiang, B. Unexpected Isocyanide-Based Three-Component Bicyclization for the Stereoselective Synthesis of Densely Functionalized Pyrano[3,4-c]Pyrroles Chem. Comm. 2016, 52, 900.
  • Zhu, Y.-L.; Jiang, B.; Hao, W.-J.; Wang, A.-F.; Qiu, J.-K.; Wei, P.; Wang, D.-C.; Li, G.; Tu, S.-J. A New Cascade Halosulfonylation of 1,7-Enynes Toward 3,4-Dihydroquinolin-2(1H)-ones via Sulfonyl Radical-Triggered Addition/6-Exo-Dig Cyclization Chem. Comm. 2016, 52, 1907.

Department of Chemistry & Biochemistry