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Lee's Group-UIC-ChemistrytResearch Overview

Synthetic chemistry is a key component of chemical science, which deals with three major issues; structure, reactivity and synthesis. The most unique aspect of synthetic chemistry stems from its capacity to create molecules crucial to addressing problems ranging from fundamental science to human health. From the perspective of providing practical solutions to these problems, the synthesis of molecules containing desirable structure and properties in an efficient and practical manner is a prerequisite, which often requires the advent of new knowledge through developing new reactions, discovering new reactivities, and harboring new insights into structure and reaction mechanism. Also, due to the increasing concerns for environmental issues, the precept of green chemistry needs to be incorporated into new strategy and reaction development as well as in the practice of synthetic chemistry.

Having the tenets of practical synthesis, we are exploring the reactivity of transition metals to discover new coupling reactions of alkynes with alkenes and to improve the selectivity of existing metal-catalyzed reactions. It is generally accepted that transition metal-catalyzed carbon–carbon bond forming reactions are one of the most powerful and efficient arsenals in synthetic chemistry because they are normally; (1) catalytic in metal so that only small amount of precious metal is required, (2) atom-economical to make use of every atom in the starting materials to make products, (3) step-economical to form multiple bonds per synthetic operation, thereby increasing molecular complexity relevant to target structures within short synthetic sequence, and (4) environmentally-benign because only limited quantity of by-products are formed from these reactions. Although powerful, certain limitations including chemo-, regio-, and stereoselectivity often narrow the scope of metal-catalyzed reactions.

Our research is focused on the study of enyne metathesis, metallotropic [1,3]-shift, the ruthenium-catalyzed Alder ene reaction, and electrophilic transition metal carbenoids and the application of these reactions to the synthesis of natural products of biological relevance. We expect that the availability of more efficient new synthetic tools would allow us to develop innovated strategies for total synthesis of complex molecular targets including zampanolide, guanacastepene A, tartrolon B, panaxytriol, tricholomenyn A, and enediyne natural products.

UIC_chemistry_mainreserch

Lee's Group-UIC-ChemistrytCurrent Research Interests

UICEnyne Metathesis:
UICTandem Enyne RCM of Silaketal-Based Dienynes:
UICTotal Synthesis of Tartrolon B
UICTandem Enyne RCM for a Total Synthesis of Guanacastepene A
UICMetallotropic [1,3]-Shift
UICRCM of Diynes and Metallotropic [1,3]-Shift
UICMetathesis and Metallotropy (M&M)
UICMetallotropic [1,3]-Shift of Metal Carbenes Generated from Alkynes and Electrophilic Metals
UICRu-Catalyzed Alder Ene Reaction



Lee's Group-UIC-ChemistrytEnyne Metathesis

The reaction of metal carbene complexes with triple bonds has the characteristics of achieving tandem reactions effectively because the bond formation and cleavage in the first step will generate a vinyl metal carbene product, which is the reactive intermediate to enter into the second step, and the same process would repeat itself multiple times. The recent advent of reactive yet a wide range of functional group-tolerant Schrock and Grubbs type carbene complexes has revolutionized the olefin metathesis whereby cyclic and acyclic alkene-containing compounds can be made with atom- and step-economy. However, a closely related metathesis process between alkyne and alkene has not been studied thoroughly.
Enyne metathesis, which redistributes unsaturated functionalities between an alkene and an alkyne substrate is a powerful contemporary synthetic tool. It is the only metathesis process to generate a new functionality different from that of starting material whereas diene and diyne metathesis simply regenerate the functionality residing in the starting material. In addition, the enyne metathesis is, in nature, a tandem bond forming-reaction that produces two carbon-carbon double bonds consecutively in any given reaction setting. This unique aspect of enyne metathesis could be broadly exploited in organic synthesis. Despite its significant potential, enyne metathesis is relatively underdeveloped compared to diene counterpart because of the unpredictable nature of substrate reactivity, low regio- and stereoselectivity as well as the poorly understood reaction mechanism. To improve the utility of enyne metathesis as a synthetic tool, we set out to systematically explore the exo/endo-mode selectivity in ring-closing metathesis (RCM), group selectivity in tandem RCM, and regio- and stereoselectivity in cross metathesis (CM) by developing appropriate substrate platforms and reaction conditions. [Top]



Lee's Group-UIC-Chemistryt
Tandem Enyne RCM of Silaketal-Based Dienynes

An important ramification of the development of silicon-tethered enyne RCM is the efficient synthesis of 1,4-substituted 1,3-dienes. Depending on the regioselectivity of bond formation between the reacting alkene and alkyne, either a 1,2- or 1,3-substituted 1,3-diene can be formed. However, no mechanism within enyne metathesis for regio- and stereoselective generation of 1,4-substituted 1,3-dienes is known.

Tandem Enyne RCM of Silaketal-Based Dienynes

Given that 1,4-substitution is more frequently found in many natural products and synthetic intermediates, the limitation of typical enyne metathesis that generates only 1,3-disubstituted 1,3-diene is serious. We envisioned that this restriction could be eliminated if a temporary tether strategy is integrated into enyne metathesis as shown. This process formally combines an enyne RCM and a diene RCM to constitute tandem dienyne metathesis. Removal of the tethered silicon would then provide a 1,4-substituted cis,trans-diene functionality. Implementation of this RCM strategy for the total synthesis of natural products will be one of the ultimate goal of this research. [Top]



Lee's Group-UIC-Chemistryt
Total Synthesis of Tartrolon B

The silaketal-tethered tandem enyne RCM should constitute an effective synthetic method not only for stereoselective synthesis of long chain polyketide sub-structures but also for the construction of macrolides and carbocycles having cis,trans-1,4-di-substituted 1,3-diene functionality found in many biologically active compounds. To exploit the utility of this novel and powerful carbon–carbon bond-forming reaction, we envisioned a total synthesis of tartrolon B via a tandem enyne RCM of an unsymmetrical silaketal derived from two consecutive exchange reactions with two different secondary alcohols on phenyl triethynylsilane. Based on the retrosynthsis and the model study, the major polyketide-like framework was designed to be synthesized starting from glyceraldehyde acetonide via well-established synthetic transformations including asymmetric crotylation. The key RCM has been successfully implemented to synthesize the entire acyclic chain of tartrolon B. Currently, we are trying to work out the late stage details for the completion of tartrolon B. [Top]

Total Synthesis of Tartrolon B



Lee's Group-UIC-Chemistryt
Tandem Enyne RCM for a Total Synthesis of Guanacastepene A

Our previous effort to build the guanacastepene skeleton involving SmI­2-mediated reductive coupling between enone and enal provided an access to an advanced intermediate, which could be elaborated to a pentacyclic epoxy lactone shown below. To explore the synthetic utility of tandem enyne metathesis, we redesigned our synthesis relying on the enyne RCM for the construction of the tricyclic core of guanacastepenes. An enatioselective total synthesis of guanacastepene A is envisioned utilizing two terpene molecules, citronellal and carvone as the starting building blocks.[Top]
Tandem Enyne RCM for a Total Synthesis of Guanacastepene A



Lee's Group-UIC-Chemistryt
Metallotropic [1,3]-Shift

From a mechanistic standpoint, enyne RCM and metallotropic [1,3]-shift are the same class of chemical transformations. Thus, enyne RCM can be viewed as a metallotropic [1,n]-shift while the metallotropic [1,3]-shift can be considered as a special case of enyne RCM with no tether (m = 0) between the ene and the yne counterparts. Notwithstanding the similarity, the kinetic and thermodynamic details between the two transformations are expected to be substantially different. For example, based on a theoretical investigation, the enyne RCM is not fully reversible yet the metallotropic [1,3]-shift is expected to be reversible.[Top]

Metallotropic [1,3]-Shift




Lee's Group-UIC-Chemistryt
RCM of Diynes and Metallotropic [1,3]-Shift

We have demonstrated that the RCM of different enediynes provided products either with or without the involvement of metallotropic [1,3]-shift depending on the nature of the substituents on the alkyne. We believe that the divergent reaction manifolds were the consequence of the equilibrium of the metallotropic [1,3]-shifting alkylidenes. The alkylidene possessing a less hindered alkyl group at the terminal position of diyne underwent [1,3]-shift to generate a more conjugated alkylidene whereas the bulky silyl substituent does not allow the [1,3]-shift. Another plausible scenario for the formation of these divergent products could be a consequence of a kinetic barrier in the final turnover step. We have been trying to sort out the details of these two reaction pathways by employing density functional theory (DFT)-based calculations.[Top]

RCM of Diynes and Metallotropic [1,3]-Shift



Lee's Group-UIC-Chemistryt
Metathesis and Metallotropy (M&M)

On the basis of the metallotropic shift of Ru-carbenes, we developed tandem metathesis and metallotropy (M&M) sequence for the formation of oligoenynes. This tandem bond-forming strategy has been demonstrated to be a powerful reaction for the synthesis of oligoenynes. This tandem process can be extended to 1,3,5-triynes, 1,3,5,7,-tertraynes and their higher homologues to generate polytriacetylene, and polytetraacetylene etc.

Metathesis and Metallotropy (M&M)

Synthetic Application: From the synthetic standpoint, the combined use of enyne metathesis and metallotropic [1,3]-shift can be applied to the synthesis of a variety of natural products possessing enyne and enediyne functionality. We envisioned that a strategic placement of the required unsaturated functional units would render an efficient construction of panaxatriol and tricholomenyne A as shown below.  [Top]

Synthetic Application



Lee's Group-UIC-Chemistryt
Metallotropic [1,3]-Shift of Metal Carbenes Generated from Alkynes and Electrophilic Metals

The use of an alkyne as the precursor for the formation of metal carbenes has recently been a subject of intense study. On the basis of the metallotropic shift behavior of ruthenium carbenes generated during the enyne metathesis of diynes, we are interested in generating gold and platinum alkynyl carbenes from diynes and exploring their metallotropic  [1,3]-shift behavior.  This hypothesis was explored by using 1,3-diynes possessing propargylic acetate groups catalyzed by several Au and Pt complexes. Ring-closure with 1,6-endiynes is also an effective method to generate an intermediate carbene species. The initially formed metal carbene species then undergoes [1,3]-shift followed by cyclopropanation to give the final product. The incorporation of two different nucleophilic functionalities such as propargylic acetate and a tethered alkene show a general reactivity trend: an acetate is more reactive initiating functionality whereas an alkene is more reactive terminating functionality. This novel bond reorganization process will be extended to other heteroatom-based systems to generate a variety of heterocycles.[Top]

Metallotropic [1,3]-Shift of Metal Carbenes Generated from Alkynes and Electrophilic Metals



Lee's Group-UIC-Chemistryt
Ru-Catalyzed Alder Ene Reaction

Vinylboronates play a prominent role as versatile substrates for various coupling reactions such as the Suzuki-Miyaura coupling and Heck type reactions. Thus, the development of efficient and stereo-controlled syntheses of vinyl boronates is an important goal in organic chemistry. In this regard, we have developed Z-selective Alder ene reaction utilizing boronylated alkynes. The preferred formation of branched isomer with unusual cis-stereochemistry of the b,b-disubstituted vinyl boronate moiety is highly unusual and contrary to the normal trend of this type of reaction.
Although it is very powerful, this reaction has a significant limitation in terms of natural product synthesis due to the lack of capacity to introduce heteroatom substituent at the homoallylic position in the product. To relieve this functional group constraint, we intended to develop a strategy to generate a cyclic vinyl boronic acid via the allylic hydroxyl group transposition. We envision that the b,b-disubstituted vinyl boronates carrying the cis-stereochemistry is the prerequisite to control the equilibrium of the allylic rearrangement of the hydroxyl group by trapping the rearranged regioisomeric allylic alcohol when catalyzed by a certain type of transition metal catalyst such as Re2O7. The overall sequence of transformation turned out to be facile, providing a complete control of the equilibrium in the allylic transposition to give the expected cyclic vinyl boronic acid as a sole final product. This novel and efficient synthetic tool will be further developed and exploited in the context of natural products syntheses including that of dactylolide and zampanolide.[Top]

Ru-Catalyzed Alder Ene Reaction



Lee's Group-UIC-Chemistryt
Representative Publications:

  • Eric C. Hansen and Daesung Lee* “Macrocyclic Ring Closing Enyne Metathesis: Exo/Endo-Mode and Stereoselectivity Control” J. Am. Chem. Soc. 2004, 126, 15074–15080.
  • Mansuk Kim, Sangho Park, Sarah V. Maifeld and Daesung Lee* “Regio- and Stereoselective Cross Enyne Metathesis of Silylated Internal Alkynes” J. Am. Chem. Soc. 2004, 126, 10242–10243. 
  • Sangho Park, Mansuk Kim and Daesung Lee* “Regio- and Stereoselectivity Control in Cross Enyne Metathesis of Silylated Internal Alkynes” J. Am. Chem. Soc. 2005, 9410–9415.
  • Sarah V. Maifeld and Daesung Lee* “Group Selective Enyne Metathesis” Eur. J. Org. Chem. (Concept Article) 2005, 11, 6118–6126. 
  • Mansuk Kim, Reagan L. Miller and Daesung Lee* “Cross and Ring-Closing Metathesis of 1,3-Diynes: A Facile Metallotropic [1,3]-Shift” J. Am. Chem. Soc. 2005, 127, 12818–12819.
  • Mansuk Kim and Daesung Lee* “Metathesis and Metallotropy: A Versatile Combination for the Synthesis of Oligoenynes” J. Am. Chem. Soc. 2005, 127, 18024–18025. 
  • Eric C. Hansen and Daesung Lee* “Regio- and Stereoselctive Ruthenium-Catalyzed Alder Ene Reaction between Boronylated Alkynes and Alkenes” J. Am. Chem. Soc. 2005, 127, 3252–3253.
  • Eric C. Hansen and Daesung Lee* “Regiochemical Control in the Metal-Catalyzed Transposition of Allylic Silyl Ethers” J. Am. Chem. Soc. 2006, 128, 8142–8143. 
  • Eric C. Hansen and Daesung Lee* “Search for Solutions to the Reactivity and Selectivity Problems in Enyne Metathesis” Acc. Chem. Res. 2006, 39, 509–519.
  • Mansuk Kim and Daesung Lee* “Advances in the Metallotropic [1,3]-Shift of Alkynyl Carbenoides” Org. Biomol. Chem. 2007, DOI: 10.1039/b710379d