Research Prospectus

Robert M. Williams, University Distinguished Professor

Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523

Phone (970)-491-6747, FAX (970)-491-3944

Home page: http://rwindigo1.chm.colostate.edu/
Financial support for the Williams group has come from:
National Institutes of Health
National Science Foundation
Petroleum Research Fund
Ajinomoto Co., Japan
ELi Lilly
Merck & Co.
Xcyte Therapies

Organic and Biological Chemistry

Our research group, currently comprised of fourteen graduate students and ten postdoctoral fellows, makes extensive use of natural products synthesis to probe bio-mechanism and biosynthesis. Projects at the interface of chemistry and biology depend on a multi-disciplinary problem-solving approach that utilizes the tools and skills of complex molecule synthesis, physical organic chemistry, molecular biology, biochemistry, microbiology, computational chemistry and molecular structure determination.

The structures of some natural products of current interest in our group are shown below. It is Williams group tradition for each graduate student to have their own natural product “target” molecule. Within each project, the synthetic chemistry that is developed in the course of a total synthesis approach is harnessed to probe the biological chemistry of the natural substance. This may involve probing the mechanism of action of a biologically active natural product and the student’s thesis work will often entail working with the biological receptor when the designed analogs or probe molecules have been synthesized. Another focus is to study the biosyntheses of natural products. In this line of investigation, the total synthesis of intermediate metabolites on Nature’s biosynthetic pathway are synthesized, isotopically labeled and evaluated as pathway intermediates. The core training in all of these projects is organic synthesis. Our research efforts are currently supported by the NIH (3 grants), NSF, the USDA and several pharmaceutical companies.

CURRENT NATURAL PRODUCT “TARGETS” CURRENTLY UNDER STUDY IN THE WILLIAMS GROUP

I. DNA-REACTIVE ANTI-TUMOR NATURAL PRODUCTS

(a) Quinocarcin/Tetrazomine/Bioxalomycins/ET-743

Quinocarcin, Tetrazomine, and Bioxalomycin are potent, clinically important anti-tumor antibiotics, produced by various Streptomyces sp., have the capacity to damage nucleic acids by both a non-specific oxidative mechanism and by alkylation and/or cross-linking of DNA. Ecteinascidin 743, is a natural metabolite of a marine organism Ecteinascidia turbinate that is a potent DNA-alkylating agent and is currently in human clinical trials. The simple oxazolidine ring of these natural products constitute the biologically reactive pharmacophore which results in the reduction of molecular oxygen via an unusual auto-redox self-disproportionation (a Cannizzaro-type process) culminating in the production of superoxide. Our goal is to develop efficient syntheses of the natural products and mechanistically inspired analogs with altered modes of DNA-damaging properties.

We have elucidated an important stereoelectronic requirement for the auto-redox process of the oxazolidine through total chemical synthesis and detailed stereochemical structure determination of synthetic analogs. We have found that the lone pair on the oxazolidine nitrogen atom must be trans-antiperiplanar to the oxazolidine methine for the redox process to occur and consequently, superoxide production and DNA cleavage. We are continuing our mechanistic work on the Cannizzaro-type redox disproportionation reaction of quinocarcin and the newly discovered, more potent relatives, tetrazomine, the bioxalomycins and ecteinascidin 743, which is produced by a marine organism.

We have recently completed a total synthesis of quinocarcin and are actively engaged in pursuing total syntheses of the bioxalomycins, tetrazomine and ecteinascidin 743.

Major accomplishments:

1. A new mechanism for superoxide production from simple oxazolidines involving an auto-redox disproportionation of the natural products, has been elucidated. Slow, efficient release of superoxide causes Fenton-derived lesions in DNA with no sequence specificity; (see: J. Am. Chem. Soc., 1992, 114, 733~740).

2. A chemical synthesis of two stereochemically defined analogs of quinocarcin was exploited as a means for stereoelectronic control of the electron-transfer process from the oxazolidine nitrogen; this process is stereoelectronically similar to an E₂ elimination reaction (see: Tetrahedron 1991, 47, 2629~2642).

3. The total synthesis of quinocarcinamide was completed and featured a new method to generate azomethine ylids (see: J. Org. Chem., 1995, 60, 6791~6797).

4. The total synthesis and mechanism of DNA cleavage of a netropsin-quinocarcin conjugate that cleaves DNA in a superoxide-independent manner illustrated how the power of mechanistic insight coupled with organic synthesis can be harnessed to change bio-mechanism; see the inset below (see: Chemistry and Biology, 1995, 2, 147).

5. Bioxalomycin_a₂has been found to be a selective and potent DNA cross-linking agent (see Williams, R.M.; Herberich, B., J. Am. Chem. Soc., 1998, 120, 10272~10273).

File written by Adobe Photoshop® 4.0 Molecular model of a netropsin conjugate of a synthetic quinocarcin analog. The netropsin moiety binds to the sequence ^5’ATTT^3’ and positions the oxazolidinyl radical two bases to the 3’-side of the recognition sequence.

Robert M. Williams, Colorado State University

(b) FR900482: Total Synthesis and Mechanism of Action

FR900482 and FR66979 are natural products produced by Streptomyces sp. These clinically significant anti-tumor antibiotics function by cross-linking DNA and cross-linking DNA to DNA-binding proteins. These drugs must be reductively activated to produce a highly reactive, bis-electrophile (a mitosene) that cross-links DNA at 5'-CG steps.

We are engaged in the total synthesis of these anti-tumor drugs and mechanism-based analogs. We were the first to prepare the ring system of FR-900482 in the form of model compound and have recently synthesized the first photo-activated pro-mitosene, the active DNA cross-linking species formed from the natural drugs. The related pyrrolizidine alkaloids, such as the natural product monocrotaline, are also potent DNA-cross-linking agents that generate a similar mitosene-like core. We are engaged in developing new synthetic approaches to these natural alkaloids that will also exploit the latent triggering concept for improvement of their antitumor cytotoxicity.

The mechanism for reductive activation of these drugs is shown below. We are presently exploiting this mechanism to synthesize a new, potent class of "latent, triggerable" mitosenes for use in cancer chemotherapy. In addition, targeting of clinically relevant DNA-protein and RNA-protein cross-links by these drugs is under study with the objective of improving the selectivity of these agents toward cells of cancerous origin.

Major accomplishments:

1. The mechanism of reductive activation and the sequence selectivity of DNA cross-linking for these drugs have been elucidated; (see: Chemistry and Biology, 1997, 4, 127~137).

2. A concise synthesis of the FR900482 ring system and mechanistically inspired analogs has been devised; (see: Tetrahedron Lett., 1989, 30, 3397~3400).

3. Recent work on photo-triggered mitosenes has been completed; (see: Tetrahedron 2000, 56, 521~532 & Tetrahedron Lett., 1997, 38, 4033~4036).

4. Drug-DNA-protein cross-links have been formed with the binding domain of the High Mobility Group I/Y (HMG I/Y) DNA-binding proteins and are the subject of structural studies; (see: J. Am. Chem. Soc., 1998, 120, 2192~2193; Chem. Biol. 2000, 7, 805~812.).

5. Cross-linking of FR900482 to the natural, full-length HMG I/Y protein to human chromosomal DNA in Jurkat cells has been realized (Chem. Biol. 2000, 7, 805~812).

6. The asymmetric synthesis of FR900482 and the first photo-triggered pro-mitosene has been completed; the pro-mitosene cross-links DNA down to 1 mM concentration upon photo-activation has been demonstrated (Judd, T.; Williams, R.M., Angew. Chem. Int. Ed. Engl. 2002, 41, 4683~4685.; Judd, T.; Williams, R.M., Org. Lett. 2002, 4, 3711~3714.).

Pyrrolizidine alkaloids, such as monocrotaline, are found in numerous species of poisonous plants. The mechanism of activation of the natural alkaloid monocrotaline is shown below and involves the two-electron oxidation of the dihydropyrrole nucleus to the highly cytotoxic pyrrole (dehydromonocrotaline) which is a well-known DNA cross-linking agent. These agents are extremely hepatotoxic since, they are activated by liver P450 cytochrome oxidases. We have altered the chemical mechanism of activation of the pyrrolizidine alkaloids from the natural oxidative activation manifold to both reductive and photochemical mechanisms using chemical synthesis.

Our objectives are to re-engineer this ring system to provide a set of selectively triggerable progenitors to the cytotoxic agents, such as dehydromonocrotaline, by altering the chemical signal for releasing the agent. The general concept is shown below:

Major accomplishments:

1. The first photo-triggered progenitor of dehydromonocrotaline has been synthesized and demonstrated to cross-link DNA upon photochemical activation (see: J. Am. Chem. Soc., 1999, 121, 2951~2955).

2. The first reductively activated progenitor of dehydromonocrotaline has been synthesized as shown below. The pro-drug (box) incorporates the novel hydroxylamine-hemiacetal trigger that is found in the FR900482 series of natural antitumor drugs (see: Angew. Chemie Int. Ed Engl. 1999, 38, 3501~3503). The synthesis and mechanism of activation of this agent is shown below:

Robert M. Williams, Colorado State University

II. TOTAL SYNTHESIS AND BIOSYNTHESIS OF NATURAL PRODUCTS

The biosynthesis of complex, biologically active natural products is being pursued with the ultimate objectives of probing, understanding and manipulating the genetic machinery of complex, secondary metabolite construction in bacteria, fungi, and plants. In this area, we have targeted several biosynthetic pathways that have unusual intrigue and potential commercial importance. Extensive use of natural product total synthesis, stable and radioisotope synthesis of biosynthetic intermediates and biological methods are being employed to map and probe secondary metabolic pathways in detail.

(a) Paraherquamides/Brevianamides/Asperparaline: Total Synthesis and Biosynthesis

The paraherquamide family of alkaloids, produced by various Penicillium sp. and Aspergillus sp. molds, display a range of interesting biological activities including anti-parasitic and insecticidal properties. These substances are the result of "mixed" biosynthetic pathways conscripting proteinogenic a-amino acids and isoprene units as primary building blocks. We have completed the total synthesis of several members of the brevianamide/paraherquamide class of alkaloids. We are presently engaged in completing the total syntheses of other paraherquamides, asperparaline and a related metabolite, VM55599.

Major Accomplishments:

1. Asymmetric total syntheses of (-)-Brevianamide B (1988) and (+)-paraherquamide B (1993) plus several biosynthetic intermediates have been completed; (see: J. Am. Chem. Soc., 1996, 118, 557~579).

2. The asymmetric stereocontrolled total synthesis of paraherquamide A has been completed (see: Angew. Chem. Int. Ed. Engl. 2000, 39, 2540~2544).

3. The biomimetic total synthesis of d,l-VM55599 has been completed (see: J. Am. Chem. Soc., 2000, 122, 1675~1683) and an asymmetric synthesis of (-)-VM55599 has recently been completed (see: J. Am. Chem. Soc. 2002, 124, 2556~2559).

4. A ligand-assisted method to control the facial selectivity of the intramolecular S_N2' cyclization was devised to construct the bicyclo[2.2.2]ring system; (see: J. Am. Chem. Soc., 1990, 112, 808~821 & Angew. Chem. Int. Ed. Engl. 2000, 39, 2540~2544.).

5. Biogenetic implications: In search of the first Diels-Alderase. (J. Am. Chem. Soc. 1989, 111, 3064). demonstrated that brevianamide A and B are constructed in nature as optically pure diastereomers but from two distinct enantiomorphic groups. This finding supports the provocative hypothesis that the core bicyclo[2.2.2] nucleus of these metabolites (C) is produced by an unusual intramolecular Diels-Alder biosynthetic construction (A®B®C). Extensive use of the total syntheses to prepare isotopically labeled biosynthetic intermediates to establish biosynthetic pathway metabolites and isolate the Diels-Alderases are under study; (see: J. Am. Chem. Soc., 1993, 115, 347~348).

6. Studies on the biosynthesis of paraherquamide A have revealed that the biosynthetic building block of the b-hydroxy-b-methylproline ring is L-isoleucine; (see: J. Am. Chem. Soc., 1996, 118, 7008-7009).

7. The mechanism of reverse prenylation of the indole ring in the biosynthesis of these alkaloids has been studied and a facially indiscriminate SN2’ prenyl transfer has been implicated (see: Angew. Chem. Int. Ed Engl. 1999, 38, 786~789).

Robert M. Williams, Colorado State University

(b) Taxol Biosynthesis

The potent, commercially important natural product taxol (paclitaxel) has attracted considerable attention due to its excellent clinical activity against ovarian and breast cancers. Taxol is produced by the Pacific Yew tree (Taxus brevifolia) and related Yew species; these slow-growing trees grow in environmentally sensitive areas of the Pacific Northwest. It takes roughly three trees to obtain a gram of pure taxol and stripping the tree of it's bark, where most of the taxol is found, kills the Yew. As a result, alternative sources for taxol production are being vigorously pursued. Due to the complex nature of the taxol structure, total synthesis will not be a viable future source of taxol. Biological methods, which rely on a detailed understanding of taxol biosynthesis are being intensively pursued.

In collaboration with Prof. Rodney Croteau of Washington State University, we have the ultimate objective of identifying and cloning the genes responsible for the rate-limiting steps and enzymes involved in the biosynthesis of taxol. Toward this end, we are synthesizing isotopically labeled biosynthetic intermediates for cell-free incorporation experiments. Efforts are underway to map the complete series of hydroxylation reactions from taxa-4(5),11(12)-diene to taxol through the total chemical synthesis of the putative biosynthetic intermediates. The early stages in the biosynthetic elaboration of taxol are shown below and our collaboration with the Croteau lab have secured the first three steps of the pathway.

Major Accomplishments:

1. The first synthesis of the first committed biosynthetic intermediates in taxol biosynthesis (taxa-4(5), 11(12)-diene and taxa-4(20), 11(12)-diene-5-a-ol) has been completed. The synthesis was recently utilized to prepare tritium-, ¹³C- and deuterium-labeled compounds that are presently being used in collaboration with Prof. Rod Croteau to map the entire biosynthetic pathway from ggPP to taxol; (see: J. Org. Chem., 1995, 60, 7215-7223).

2. The first total synthesis of the first two hydroxylation products on the taxol biosynthetic pathway has been completed and was used to identify the natural metabolite and the cytochrome P450 taxadiene hydroxylase. Mechanistic studies are in progress to understand this unusual hydroxylation reaction; (see: Chemistry and Biology, 1996, 3, 479-489 & J. Org. Chem. 2000, 65, 7865~7869).

3. Tritium-labeled, synthetic taxa-4(20), 11(12)-dien-5-a-ol has been used in Pacific Yew to identify hydroxylation products downstream on the path to taxol. Cloning and expression of the biosynthetic enzymes on this pathway are being conducted in collaboration with the Croteau group. Current synthetic targets include lightly oxygenated taxoids on the pathway to taxol. (see: Chem. Biol. 2000, 7, 969~977).

Robert M. Williams, Colorado State University

III. DEVELOPMENT OF SYNTHETIC METHODOLOGY

The Asymmetric Synthesis of a-Amino Acids and Peptide Isosteres

We have developed a general, asymmetric synthesis of a-amino acids based on a variety of C-C bond-forming strategies to optically active glycinates. We are studying the construction of difficult classes of amino acids including the vancomycins, diaminopimelic acids, 1-aminocyclopropane carboxylic acids, vinyl glycines, and a,a-disubstituted amino acids. The optically active glycinates are now commercially available from Aldrich. This methodology is being applied to the total synthesis of various natural products containing or derived from unusual amino acids and numerous mechanism-based inhibitors of amino acid biosynthesis (ie., diaminopimelic acid) are being synthesized via the glycinate methodology. We are also engaged in utilizing this technology to provide unusual amino acids that will be useful for creating large combinatorial libraries of compounds for a wide range of biological screening projects.

A very recent area of investigation in this project has been devoted to a direct asymmetric synthesis of hydroxymethylene- and hydroxyethylene peptide isosteres. As shown below, we have developed an efficient method to access these substances including the natural product Statine.

Major accomplishments:

1. The design, synthesis and commercialization (Aldrich) of one of the most versatile templates for asymmetric amino acid synthesis has been developed. Numerous natural products have been synthesized with this methodology. (see: Williams, R.M., Aldrichimica Acta, 1992, 25, 11).

2. Exploitation of enolate, cation, radical, [1,3]dipolar cycloaddition, phosphonate and a,b-dehydro reactivity has been investigated for accessing a wide structural array of optically pure a-amino acids.

3. The N-t-BOC glycinates provide the only direct asymmetric synthesis of non-proteinogenic N-t-BOC- a-amino acids. While many methods exist for the synthesis of amino acids, and other chiral glycine templates have been developed, the strength of these glycine systems are their demonstrated versatility, ease of cleavage, and most significantly, the direct access to the t-BOC-protected non- proteinogenic amino acids. This work was a direct outgrowth of the total synthesis of bicyclomycin.

Application of the Williams’ Glycinates to Natural Products Synthesis

Ongoing methodology development is directed toward the total synthesis of natural products with structurally challenging functional group arrays such as spirotryprostatin, capreomycin and hapalosin, shown below.

A recently completed asymmetric total synthesis of spirotryprostatin B shown below, illustrates the power and versatility of these simple amino acid templates.

The Asymmetric, Stereocontrolled Total Synthesis of Spirotryprostatin B

Sebahar, P.; Williams, R.M., J. Am. Chem. Soc. 2000, 122, 5666~5667.

The Asymmetric Stereocontrolled Total Synthesis of Hypusine

Jain, R.P.; Albrecht, B.K.; DeMong, D.E.; Williams, R.M., Org. Lett. 2001, 24, 4287~4289.

IV. DEVELOPMENT OF NEW STRATEGIES TO TREAT DRUG-RESISTANT BACTERIA

(a) TAN-1057A-D

Takeda Pharmaceutical Co., Japan, recently isolated four new compounds identified as TAN-1057 A-D from a Flexibacter sp. PK-74 and PK-176. These compounds were found to be dipeptide antibiotics with potent activity against methicillin-resistant Staphylococcus aureus (MRSA). The development of drug resistance to many commonly used antibiotics has become an alarmingly acute problem in hospitals and the search for new antibiotics that have good activity against drug-resistant pathogens has become an extremely important endeavor. The search for new biochemical targets in bacteria appears to be the most promising avenue of exploration. We have chosen the TAN-1057 agents due to their unique chemical structure and excellent activity against MRSA in vivo.

Our objectives are to develop a general method to synthesize the TAN-1057 structural class and several analogs to probe the mechanism of antibacterial activity in this unique class of antibiotics. The mechanism of how these substances inhibit the growth of Gram-(+) microorganisms is currently unknown and is under study.

Major accomplishments:

1. The first total synthesis of TAN-1057A,B has been achieved. (see: J. Am. Chem. Soc. 1997, 119, 11,777~11,784). In addition, the synthesis of the seven-membered ring congeners, TAN-1057C,D has also been completed.

2. The synthesis of biologically active analogs of TAN-1057 (active against MRSA) has been completed and patents have been filed on this technology. (see: J. Antibiotics, 1998, 51, 189~201).

The total synthesis of TAN-1057A,B is shown below. The synthesis developed employed a new synthetic method to make amidinoureas, which is a unique functionality found in the natural antibiotics.

The Total Synthesis of TAN-1057A/B

Yuan, C.C.; Williams, R.M., J. Am. Chem. Soc. 1997, 119, 11,777~11,784.

(b) Capreomycin IB

Capreomycidine is a non-proteinogenic amino acid that is a constituent of the capreomycins and the tuberactinomycins. These cyclic pentapeptides are known for their unique tuberculostatic properties. First discovered by Herr et al. in 1960, the capreomycins have recently attracted attention due to their demonstrated effectiveness against resistant strains of Mycobacterium tuberculosis. Our goals are to develop a general synthetic approach to this class of antibacterial agents and to utilize this chemistry to further probe the mechanism of action of these agents and to explore their utility against INH-resistant strains of Mycobacterium tuberculosis.

Major accomplishments:

1. The first asymmetric synthesis of capreomycidine has been accomplished and is being utilized to complete a concise asymmetric total synthesis of capreomycin IB. (see: DeMong, D.E.; Williams, R.M., Tetrahedron Lett. 2001, 42, 3529~3532).

2. The first asymmetric synthesis of a-formylglycine, a precursor to the unsaturated amino acid constituent in the capreomycins, has been accomplished. (see: DeMong, D.E.; Williams, R.M., Tetrahedron Lett. 2002, 43, 2355~2357).

The Asymmetric Synthesis of Capreomycin IB

DeMong, D.E.; Williams, R.M., J. Am. Chem. Soc. 2003, 125, 8561

Robert M. Williams, Colorado State University

Total Synthesis of Natural Products

Below, is a representative compilation of natural product total syntheses carried out by individual graduate students in the Williams group. It has been a long-standing group tradition for graduate students to tackle the total synthesis of a complex natural product individually. The chemistry developed in the course of such a Ph.D. dissertation is typically utilized to study the biochemistry, biology or biosynthesis of these biologically active natural substances. Our overall goal is to utilize and develop new tools in synthetic organic chemistry to penetrate the chemical & biological secrets of Nature’s biologically active natural products. The syntheses outlined below give only the most superficial picture of the stories behind each molecular system and the new fundamental knowledge this approach has harnessed.

Total Syntheses of Natural Products by Individual Graduate Students from the Williams Group

1. Bicyclomycin (Robert W. Armstrong)

Williams, R.M.; Armstrong, R.W.; Dung, J-S., J. Am. Chem. Soc., 1984, 106, 5748~5750.

Williams, R.M.; Armstrong, R.W.; Dung, J-S., J. Am. Chem. Soc., 1985, 107, 3253~3266.

2. Showdomycin (Andrew O. Stewart)

Stewart, A.O.; Williams, R.M., J. Am. Chem. Soc., 1985, 107, 4289~4296.

3. b-Carboxyaspartic Acid (Asa) (Peter J. Sinclair)

Williams, R.M.; Sinclair, P.J.; Zhai, W., J. Am. Chem. Soc., 1988, 110, 482~483.

4. 6-Hydroxymethyl-2,6-diaminopimelic acid (Myeong Im)

Williams, R.M.; Im, M-N.; Cao, J., J. Am. Chem. Soc., 1991, 113, 6976~6981.

(6-hydroxymethyl-2,6-diaminopimelic acid or 6-HMDAP, a natural amino acid from Micromonospora chalcea)

5. Coronamic acid and norcoronamic acid (Glenn J. Fegley)

Williams, R.M.; Fegley, G.J., J. Am. Chem. Soc., 1991, 113, 8796~8806.

6. Cucurbitine (Glenn J. Fegley)

Williams, R.M.; Fegley, G.J., Tetrahedron Lett., 1992, 33, 6755~6758.

7. Aspirochlorine (Greg Miknis)

Williams, R.M.; Miknis, G.F., J. Am. Chem. Soc., 1993, 115, 536~547.

8. Quinocarcinamide (Mark E. Flanagan)

Flanagan, M.E.; Williams, R.M., J. Org. Chem., 1995, 60, 6791~6797.

9. Paraherquamide B (Timothy D. Cushing)

10. d,l-VM55599 (Emily Stocking)

Stocking, E.M.; Sanz-Cervera, J.F., Williams, R.M., J. Am. Chem. Soc. 2000, 122, 1675~1683

11. Taxa-4(5), 11(12)-diene (Steven M. Rubenstein)

Rubenstein, S.M.; Williams, R.M., J. Org. Chem., 1995, 60, 7215~7223.

12. Taxa-4(20), 11(12)-dien-5-a-ol (Steven M. Rubenstein)

Hefner, J.; Rubenstein, S.M.; Ketchum, R.E.B.; Gibson, D.M.; Williams, R.M., Croteau, R. Chem. Biol., 1996, 3, 479~489.

13. (-)-Paraherquamide A (Jeff Cao)

Williams, R.M.; Cao, J.; Tsujishima. H., Angew. Chem. 2000, 39, 2540~2544.

14. Capreomycidine (Duane E. DeMong)

DeMong, D.E.; Williams, R.M., Tetrahedron Lett. 2001, 42, 3529~3532.

15. Capreomycin IB (Duane E. DeMong)

DeMong, D.E.; Williams, R.M., J. Am. Chem. Soc. 2003, 125, 8561~8565.

16. Spirotryprostatin B (Paul Sebahar)

Sebahar, P.; Williams, R.M., J. Am. Chem. Soc. 2000, 122, 5666~5667.

17. Brevianamide B (Kathleen Halligan)

Williams, R.M.; Sanz-Cervera, J.F.; Sancenon, F., Marco, J.A.; Halligan, K.; J. Am. Chem. Soc., 1998, 120, 1090~1091.

18. TMC-95A/B (Brian K. Albrecht)

Albrecht, B.K.; Williams, R.M., Org. Lett. 2003, 5, 197~200.

Albrecht, B.K., Williams, R.M. PNAS 2004 (in press).

19. TAN-1057A&B (Chester Yuan)

Yuan, C.C.; Williams, R.M., J. Am. Chem. Soc. 1997, 119, 11,777~11,784.

20. TAN-1057C&D (Chester Yuan)

Yuan, C.C.; Williams, R.M., J. Am. Chem. Soc. 1997, 119, 11,777~11,784.

21. (-)-Tetrazomine (Jack D. Scott)

Scott, J.D.; Williams, R.M. Angew. Chem. Int. Ed. Engl. 2001, 40, 1463~1465.

22. g-D-Glutamyl-L-meso-DAP (Chester Yuan)

Williams, R.M.; Yuan, C., J. Org. Chem., 1994, 59, 6190~6193.

23. FR900482 (Ted Judd)

Judd, T.; Williams, R.M., Angew. Chem. Int. Ed. Engl. 2002, 41, 4683~4685.

24. (-)-Reneiramycin G (Wei Jin)

Jin, W.; Williams, R.M. (submitted for publication)

25. 7-epi-cylindrospermopsin (Ryan E. Looper)

Total Syntheses of Natural Products by Post-doctoral Associates from the Williams Group

(-)-Brevianamide B (Dr. Tomasz Glinka and Dr. Ewa Kwast)

R. M. Williams, T. Glinka, E. Kwast, H. Coffman and J.K. Stille, J.Am.Chem.Soc., 1990, 112, 808~821

Statin (Dr. Pierre-Jean Colson)

Williams, R.M.; Colson, P-J.; Zhai, W., Tetrahedron Lett., 1994, 35, 9371~9374

S-(+)-Carnitine (Dr. Rajendra P. Jain)

Jain, R.P.; Williams, R.M., Tetrahedron 2001, 57, 6505~6509.

R-(-)-Carnitine (Dr. Rajendra P. Jain)

Jain, R.P.; Williams, R.M., Tetrahedron Lett. 2001, 42, 4437~4440.

Hypusine (Dr. Rajendra P. Jain)

Jain, R.P.; Albrecht, B.K.; DeMong, D.E.; Williams, R.M., Org. Lett. 2001, 24, 4287~4289.

Negamycin (Dr. Rajendra P. Jain)

Jain, R.P.; Williams, R.M., J. Org. Chem. 2002, 67, 6361~6365.

Taxa-4(20), 11(12)-dien-2a, 5a-diol (Dr. Alfredo Vazquez)

Vazquez, A.; Williams, R.M., J. Org. Chem. 2000, 65, 7865~7869.

(-)-VM55599 (Dr. Juan F. Sanz-Cervera)

Sanz-Cervera, J.F.; Williams, R.M., J. Am. Chem. Soc. 2002, 124, 2556~2559.

Natural Products Total Syntheses Completed in the Williams Group

Robert M. Williams

Colorado State University


(+)-Bicyclomycin	(+)-Showdomycin	(-)-b-Carboxyaspartic Acid
J. Am. Chem. Soc. 1984, 106, 5748~5750 J. Am. Chem. Soc. 1985, 107, 3253~3266	J. Am. Chem. Soc. 1985, 107, 4289~4296	J. Am. Chem. Soc. 1988, 110, 482~483

(+)-6-HMDAP	Thienamycin (formal synthesis)	(-)-Brevianamide B
J. Am. Chem. Soc. 1991, 113, 6976~6981	Carbohydrate Res. 1984, 135, 167~173	J. Am. Chem. Soc. 1988, 110, 5927~5929 J. Am. Chem. Soc. 1990, 112, 808~821

(-)-Cucurbitine	Norcoronamic Acid	Coronamic Acid
Tetrahedron Lett. 1992, 33, 6755~6758	J. Am. Chem. Soc. 1991, 113, 8796~8806	J. Am. Chem. Soc. 1991, 113, 8796~8806

Statine	(+)-FR900130	Verruculotoxin
Tetrahedron Lett. 1994, 35, 9371~9374	JCS. Perkin Trans I 1990, 171~172	Synthesis 1988, 963~966

(+)-Aspirochlorine	(+)-Quinocarcin	(+)-Paraherquamide B
J. Am. Chem. Soc. 1993, 115, 536~547	J. Org. Chem. 1995, 60, 6791~6797	J. Am. Chem. Soc. 1993, 115, 9323~9324 J. Am. Chem. Soc. 1996, 118, 557~579

(+)-Taxa-4(5), 11(12)-diene	(+)-Taxa-4(20), 11(12)-dien-5a-ol	(+)-Taxa-4(20), 11(12)-dien-2a,5a-ol
J. Org. Chem. 1995, 60, 7215~7223	J. Org. Chem. 1995, 60, 7215~7223	J. Org. Chem. 2000, 65, 7865~7869

(S)-TAN-1057A/B	(S)-TAN-1057C/D	(+)-Brevianamide B (biomimetic synthesis)
J. Am. Chem. Soc. 1997, 119, 11,777~11,784	J. Am. Chem. Soc. 1997, 119, 11,777~11,784	J. Am. Chem. Soc. 1998, 120, 1090~1091 Bioorg. Med. Chem. 1998, 6, 1233~1241

(-)-Spirotryprostatin B	(-)-Paraherquamide A	(+)-VM55599
J. Am. Chem. Soc. 2000, 122, 5666~5667	Angew. Chem. Int. Ed. 2000, 39, 2540~2544	J. Am. Chem. Soc. 2000, 122, 1675~1683

(-)-Tetrazomine Angew. Chem. Int. Ed. Engl. 2001, 40, 1463~1465	(2S,3R)-Capreomycidine Tetrahedron Lett. 2001, 42, 3529~3532	Pre-paraherquamide Angew. Chem. Int. Ed. Engl. 2001, 40, 1296~1298

(S)-(+)-Carnitine Tetrahedron 2001, 57, 6505~6509	(R)-(-)-Carnitine Tetrahedron Lett. 2001, 42, 4437~4440	Hypusine Org. Lett. 2001, 24, 4287~4289