In the past seven years, Professor Li and his coworkers have discovered several new organic reactions and their practical asymmetric versions of chemically and biomedically importance. These reactions include asymmetric C(sp2)-C(sp3) bond formations, asymmetric halo aldol reaction (AHA) and corresponding cyclizations, regio- and stereoselective electrophilic aminohalogenation and diamination (imidazolination) of alkenes that are common petroleum chemicals. Professor Li’s synthesis methodologies can convert inexpensive starting materials in very useful and expensive products under convenient conditions.

1.     

1.  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 1

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 2

(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 3

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 4

(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  5

(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 6

2. 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 7

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 8

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 9

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 10

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 11

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 12

Several new other asymmetric reaction processes developed by Professor Li and coworkers in the first two years at Texas Tech University can be found in the publication list below. Meanwhile,  Professor Li is also interested in bioorganic and medicinal chemistry, especially in peptide and peptidomimetic drug design, synthesis and structure-activity-relationship (SAR) studies which are important in treating diseases such as AIDS, cancer and diabetes.  Opioid and organ-selective address peptides will also be studied. Professor Li's research has been supported by the National Institutes of Health, the Robert Welch Foundation and South Plains Foundation.

Selected Publications (from a total of 109):

• "The Asymmetric Catalytic Aldol Reaction of Allenolates with Aldehydes using N-Fluoroacetyl Oxazaborolidine as the Catalyst". Li, G.;  Wei, H.-X.; Phelps, B. S.; Purkiss, D. W.; Kim, S. H. Org. Lett   2001, 3, 823-826.

• "A Novel Three-Component Olefinic Reaction". Li, G.; Wei, H.-X.; Kim, S. H.; Carducci, M. Angew. Chem. Int. Ed., 2001, 40, 4277-4280.

• "A Novel Three-Component Reaction via 1,4-Robust Activation of a,b-Acetylenic Ketones for Stereoselective Formations of Versatile Aldol Adducts", Wei, H.-X.; Kim, S. H.; Li, G. Org. Lett 2002, 3691-3693.

• "Electrophilic Diamination of Alkenes by using FeCl3-PPh3 Complex as the Catalyst"; Wei, H.-X.; Kim, S. H.; Li, G. J. Org. Chem. 2002, 67, 4777-4781.

•  “A catalytic reaction of alkynes via multiple-site functionalization”, Karur, S.; Kotti, S. R. S. S.; Xu, X.; Cannon, J. F.; Headley, A.; Li, G. J. Am. Chem. Soc. 2003, 125, 13340-13341.

• “Direct Electrophilic Diamination of Functionalized Alkenes without the Use of any Metal Catalysts”, Chen, D. J.; Timmons, C.; Wei, H.-X.; Li, G. J. Org. Chem. 2003, 68, 5742-5745.

• “N,N-Dichloro-2-nitrobenzenesulfonamide as the electrophilic nitrogen source for direct diamination of enones”, Pei, W.; Wei, H. X.; Chen, D. J.; Li, G. J. Org. Chem. 2003, 68, 8404-8408.

• “Asymmetric Halo Aldol Reaction (AHA)” Li, G.; Xu, X.; Chen, D.; Timmons, C.; Carducci, M.; Headley, A. Org. Lett. 2003, 5, 329-331.

• “Efficient nucleophilic substitution reactions of highly functionalyzed allyl halides in ionic liquid media” Kotti, S. R. S. S.; Xu, X.; Li, G.; Headley, A. D. Tetrahedron Lett. 2004, 45,1427-1431.

• “New Asymmetric Halo Aldol Reaction Provides a Novel Approach to Biologically Important Chiral Cyclothers and Cycloamines” Timmons, C.; Cannon, J. F.; Headley, A. D.; Li, G. Org. Lett. 2004, 6, 2075-2078.

•  “MgI₂-Catalyzed Halo Aldol Reaction: a Practical Approach to (E)-b-Iodovinyl-b'-hydroxyketones” Wei, H.-X.; Timmons, C.; Farag, M. A.; Paré, P. W.; Li, G. Org. & Biomol. Chem. 2004, 2 (20), 2893-2896.

• “Ionic Liquid Media Resulted in the First Asymmetric Aminohalogenation Reaction of Alkenes” Xu, X.; Kotti, S.R.S.S.; Liu, J.; Cannon, J. F.; Headley, A. D.; Li, G. Org. Lett. 2004, 6, 4877-4879.

• “Functionalization of -Unsaturated Esters and Ketones: A Facile and Highly Stereoselective One-Pot Approach to N-Protected a,b-Dehydroamino Acid Derivatives” Chen, D.; Guo, L.; Liu, J.; Kirtane, S.; Cannon, J. F.; Li, G. Org. Lett. 2005, 7, 921-924.

• “Asymmetric Halo Mannich Type Reaction Provides Access to Pyrrolidines and b-Proline Derivatives” Timmons, C.; Guo, L.; Liu, J.; J. F. Cannon; Li, G. J. Org. Chem. 2005, 70, 7634-7639.

• “Aza Diels-Alder Reaction Utilizing 4-iodo-2-trimethylsilyloxy-butadiene” Timmons, C.; McPherson, L.; Mills, J.; Li, G. Tetrahedron, 2005, 61, 11837-11842.

• “The Design and Synthesis of C-2 Substituted Chiral Imidazolium Ionic Liquids from Amino Acid Derivatives” Bukuo Ni, Allan D. Headley, Guigen Li. J. Org. Chem. 2005, 70, 10600-10602.

• “Regio and stereoselective synthesis of anti 3-chloro-1,3-diaryl-2-(o-nirobenzenesulfonamido)-3-propan-1-ones through catalytic aminohalogenation reaction of a,b-unsaturated ketones” Liu, J.-Y.; Wang, Y.-N.; Li, G. Eur. J. Org. Chem. 2006, 14, 3112-3115.

•  “FeCl₃-Catalyzed Aminohalogenation of Arylmethylenecyclopropanes and Arylvinylidenecyclopropanes and the Corresponding Mechanism Studies” Li; Q.-J.; Shi, M; Timmons, C.; Li, G. Org. Lett. 2006, 8, 625-628.

•  “Novel Approach to Multifunctionalized Homoallylic Alcohols via Regioselective Ring Opening of Aryl Oxiranes with 3-Iodo Allenoates” Kattuboina, A.; Kaur, P.; Timmons, C.; Li, G. Org. Lett. 2006, 8, 2771-2774.