Williams Research Group

Research

Williams Group Research Interests

The Williams laboratory studies and exploits natural products syntheses to uniquely address fundamental questions regarding the bio-mechanism and the biosyntheses of natural compounds. Much of Williams’ work is based on his development of the first asymmetric electrophilic glycine template to synthesize alpha-amino acids based on diphenyl oxazinones; a technology commercialized by Aldrich in 1988. The group then established the broadest range of reaction diversity of any glycine template for asymmetric alpha-amino acids and peptide isostere syntheses. Laboratories world-wide utilize this reliable method to synthesize amino acids and derivatives. A broad repertoire of natural products were synthesized by  the Williams laboratory using this technology including spirotryprostatin, cylindrospermopsin, cribrostatin and capreomycin.

Bio-organic Chemistry: Williams discovered a new redox disproportionation reaction of oxazolidines responsible for the oxidative damage to DNA inflicted by quinocarcin, tetrazomine and bioxalomycin.He’s the first to demonstrate chromosomal DNA cross-linking of FR900482 to HMG-A1 oncoproteins in human cells. The Williams lab developed concise asymmetric syntheses of numerous natural antitumor drugs and has harnessed these syntheses to penetrate their mode of action.

Biosynthesis: The Williams lab reported the first experimental data supporting the azadiene IMDA biosynthetic pathway producing the bicyclo[2.2.2]diazaoctane core common to paraherquamide, and stephacidin. They exploited this biogenetic insight in imaginative, concise total syntheses of stephacidin A and marcfortine C. Williams discovered a new biosynthetic pathway to beta-methylproline from S-isoleucine. Williams’ studies revealed that biosynthetic reverse prenylations of tryptophan at the 2-position are non-stereospecific and proposed a non-selective intermolecular SN2´ mechanism. Williams has elucidated significant aspects of taxol biosynthesis including an unprecedented mechanism for taxadiene synthase and taxadiene 5-alpha-hydroxylation. Williams’ total syntheses of isotopically labeled biosynthetic intermediates made these advances possible.

Completed Natural Products Total Syntheses

(+)-Bicyclomycin

J. Am. Chem. Soc., 1984, 106, 5748~5750

J. Am. Chem. Soc., 1985, 107, 3253~3266

Other Structures Synthesized of Interest

(+)-Showdomycin

J. Am. Chem. Soc., 1985, 107, 4289~4296

B-Carboxyaspartic Acid

J. Am. Chem. Soc., 1988, 110, 482~483

(+)-6-HMDAP

J. Am. Chem. Soc., 1991, 113, 6976~6981

Thienamycin (formal synthesis)

Carbohydrate Res., 1984, 135, 167~173

(-)-Brevianamide B

J. Am. Chem. Soc., 1988, 110, 5927~5929

J. Am. Chem. Soc., 1990, 112, 808~821

(-)-Cucurbitine

Tetrahedron Lett., 1992, 33, 6755~6758

Norcoronamic Acid

J. Am. Chem. Soc., 1991, 113, 8796~8806

Coronamic Acid

J. Am. Chem. Soc., 1991, 113, 8796~8806

Statine

Tetrahedron Lett., 1994 35, 9371~9374

d,l-FR900130

JCS. Perkin Trans I 1990, 171~172

Verruculotoxin

Synthesis 1988, 963~966

d,l-Aspirochlorine

J. Am. Chem. Soc., 1993, 115, 536~547

d,l-Quinocarcin

J. Org. Chem., 1995, 60, 6791~6797

(+)-Paraherquamide B

J. Am. Chem. Soc. 1993, 115, 9323~9324

J. Am. Chem. Soc. 1996, 118, 557~579

d,l-Taxa-4(5), 11(12)-diene

J. Org. Chem. 1995, 60, 7215~7223

d,l-Taxa-4(20), 11(12)-dien-5a-ol

J. Org. Chem. 1995, 60, 7215~7223


d,l-Taxa-4(20), 11(12)-dien-2a, 5a-ol

J. Org. Chem. 2000, 65, 7865~7869


(S)-TAN-1057A/B

J. Am. Chem. Soc., 1997, 119, 11,777~11,784

(S)-TAN-1057C/D

J. Am. Chem. Soc., 1997, 119, 11,777~11,784

d,l-Brevianamide B

(biomimetic synthesis)

J. Am. Chem. Soc., 1998, 120, 1090~1091

Bioorg. Med. Chem. 1998, 6, 1233~1241

(-)-Spirotryprostatin B

J. Am. Chem. Soc. 2000, 122, 5666~5667

(-)-Paraherquamide A

Angew. Chem. Int. Ed. 2000, 39, 2540~2544

d,l-VM55599

J. Am. Chem. Soc. 2000, 122, 1675~1683

d,l(-)-Tetrazomine

Angew. Chem. Int. Ed. 2001, 40, 1463~1465

(2S,3R)-Capreomycidine

Tetrahedron Lett. 2001, 42, 3529~3532

d,l-Pre-paraherquamide

Angew. Chem. Int. Ed. 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

(-)-VM55599

J. Am. Chem. Soc. 2002, 124, 2556~2559

(+)-Negamycin

J. Org. Chem. 2002, 67, 6361~6365

(+)-FR900482

Angew. Chem. Int. Ed. 2002, 41, 4683~4685

(+)-TMC-95A/B

Org. Lett. 2003, 5, 197~200

PNAS 2004, 101, 11949-11954.


(-)-Capreomycin IB

J. Am. Chem. Soc. 2003, 125, 8561~8565

(-)-Spirotryprostatin A

Org. Lett. 2003, 5, 3135-3137.

(-)-7-epi-Cylindrospermopsin

Angew.Chem.Int.Ed. 2004, 43, 2930-2933

(+)-Cylindrospermopsin

Tetrahedron 2006, 62, 4549-4562

d,l-7-deoxy-Cylindrospermopsin

Angew.Chem.Int.Ed. 2005, 44, 3879-3881

(-)-Renieramycin G

J.Am.Chem.Soc. 2005, 127, 12684-12690

(-)-Jorumycin

J.Am.Chem.Soc. 2005, 127, 12684-12690

(-)-Cribrostatin 4 (Renieramycin H)

Angew. Chem.Int.Ed. 2007, 46, 1517

(+)-Notoamide C

Angew.Chem.Int.Ed. 2007, 46, 2257

(-)-Notoamide D

Angew.Chem.Int.Ed. 2007, 46, 2257

(-)-Notoamide E

Angew.Chem.Int.Ed.. 2007, 46, 2257


FR901228

Org. Lett. 2008, 10, 613-616.

(-)-Stephacidin A

Angew.Chem.Int.Ed.Engl. 2007, 46, 2262

J.Am.Chem.Soc. 2007, 129, 6336-6342

(-)-Notoamide B

Angew.Chem.Int.Ed.Engl. 2007, 46, 2262

J.Am.Chem.Soc. 2007, 129, 6336-6342


(+)-Stephacidin B

J.Am.Chem.Soc. 2007, 129, 6336-6342

(-)-Avrainvillamide

J.Am.Chem.Soc. 2007, 129, 6336-6342

d,l-Versicolamide B

Angew.Chem.Int.Ed. 2008, 47, 3573-3577

d,l-Marcfortine C

Tetrahedron 2007, 63, 6124-6130

d,l-Malbrancheamide

J. Org. Chem. 2008, 73, 3116-3119

d,l-Malbrancheamide B

J. Org. Chem. 2008, 73, 3116-3119

Pre-malbrancheamide

Org. Lett. 2008, 10, 4863-4866

Et-743 (formal synthesis)

J. Org. Chem. 2008, 73, 9594-9600


Largazole

J.Am.Chem.Soc. 2008, 130, 11219-11222


D,L-Oleocanthal

Tetrahedron Lett. 2009, 50, 2713-2715


(+)- and (-)-Versicolamide B

Nature Chemistry 2009, 1, 63-68


Notoamide J

J. Org. Chem. 2010, 75, 2785-2789


Geissoschizol

J. Org. Chem. 2010, 75, 7869-7876


Protoemetinol

J. Org. Chem. 2010, 75, 7869-7876


3-epi-Protoemetinol

J. Org. Chem. 2010, 75, 7869-7876


Hapalindole J

J. Org. Chem. 2012, 77, 519-524


Dihydrocorynantheidol

J. Org. Chem. 2010, 75, 7869-7876


Corynantheidol

J. Org. Chem. 2010, 75, 7869-7876

Hapalindole U

J. Org. Chem. 2012, 77, 519-524


Notoamide S

Heterocycles 2010, 82, 461-472


Notoamide T

Org. Lett. 2013, 15, 22-25.


Fawcettimine

J. Org. Chem. 2012, 77, 4801-4811


Lycoflexine

J. Org. Chem. 2012, 77, 4801-4811


Lycoposerramine B

J. Org. Chem. 2012, 77, 4801-4811


Fawcettidine

J. Org. Chem. 2012, 77, 4801-4811


“Carba-bicyclomycin”

J. Am. Chem. Soc., 1991, 113, 6621-6633

The First Anti-Bredt B-Lactam

J.Am.Chem.Soc. 1989, 111, 1073-1081

(R)-7-Hydroxyquinine

Org. Lett. 2006 8, 4051-4054


Peptide Isostere of FK228

J.Am.Chem.Soc. 2009, 131, 2900-2905

Netropsin-Quinocarcin Analog

Chem. Biol., 1995, 2, 147-156


C-19-epi-Malbrancheamide

Heterocycles 2006, 70, 249-259



Peptide Isostere of Largazole

J.Am.Chem.Soc. 2009, 131, 2900-2905

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