The Career of Larry E. Overman Pierce Group Meeting Presented by Yunlong Shi 4/7/2015

Awards / Honors ACS Arthur. C. Cope Award (2003) ACS Creative work in Synthetic Organic Chemistry (1995) UCI Medal, University of California, Irvine, American Chemical Society, Herbert C. Brown Award for Creative Research in Synthetic Methods, Tetrahedron Prize for Creativity in Organic Chemistry, The Nagoya Medal of Organic Chemistry, International Society of Heterocyclic Chemistry Senior Award, Ta-shue Chou Lectureship Award, American Chemical Society Arthur C. Cope Award, U.C. Irvine Distinguished Faculty Lectureship Award for Research, Yamada Prize Japan Society for the Promotion of Science Fellowship, - S. T. Li Prize for Achievements in Science and Technology, - Earlham College Distinguished Faculty Award, Centenary Medal, Chemical Society, U.K American Chemical Society Award for Creative Work in Synthetic Organic Chemistry, Guggenheim Fellowship, C.S. Hamilton Award, University of Nebraska Javits Neuroscience Investigator Award American Chemical Society Arthur C. Cope Scholar Award - Visiting Miller Research Fellow, U.C. Berkeley Alexander von Humboldt U.S. Senior Scientist Award, Camille and Henry Dreyfus Teacher-Scholar Award U.C. Irvine School of Physical Sciences Distinguished Teaching Award, U.C. Irvine Alumni Association Distinguished Research Award Alfred P. Sloan Foundation Fellow 164/129/457 * (under the name of Overman LE, as of 4/5/2015) Total synthesis / JACS / total entries on Web of Science Larry E. Overman Born in 1943 (Chicago, Illinois) B.A., Earlham College (-1965) Ph.D., University of Wisconsin (-1969) *Professor Howard W. Whitlock NIH postdoctoral fellowship Columbia University *Professor Ronald Breslow (-1971) Distinguished Professor of Chemistry, University of California, Irvine Editor-in-chief, Organic Reactions

“ M y fascination with rearrangement reactions is easily traced to the fall of 1965, just after I had begun graduate school in the Chemistry Department at the University of Wisconsin, Madison. I was in the office of Howard Whitlock, Jr. to discuss potential research opportunities in his laboratory. He outlined, gloriously as I remember with a fountain pen on white paper, the polyene cyclization and backbone rearrangement steps of the postulated biosynthesis of lanosterol from squalene oxide. As a potential dissertation project, Whitlock suggested examining in model systems whether or not backbone rearrangements take place in a concerted fashion. I was fascinated.” Tetrahedron 2009, 65, 6432

Method DevelopmentSelected Total Syntheses Overman Rearrangement Aza-cope Mannich Reaction Prins-Pinacol Rearrangement Intramolecular Heck Reaction Strychnine Sarain A Polycyclic Guanidine Alkaloids Contents of this talk...

Overman Rearrangement (1974) Catalytic Asymmetric Version (1997, 1999, 2003, 2012) J. Am. Chem. Soc. 1974, 96, 597. J. Org. Chem. 1997, 62, J. Am. Chem. Soc., 1999, 121, J. Am. Chem. Soc. 2003, 125, J. Org. Chem. 2012, 77, Difficulty: metal complexes the imidate nitrogen atom -- causing elimination Rearrangement of trichloroacetimidates

Overman Rearrangement: Applications Synthesis of amino acids Synthesis of glycosyl ureas J. Am. Chem. Soc., 2002, 124, J. Am. Chem. Soc. 2008, 130,

Overman Rearrangement: Applications Synthesis of amino acids J. Am. Chem. Soc., 2002, 124, J. Am. Chem. Soc. 2008, 130, Synthesis of glycosyl ureas

Aza-cope/Mannich Reaction (1979) Positive charge decreases the activation barrier Homoallylic amines w/ an allylic hydroxyl group  3-acylpyrrolidines J. Am. Chem. Soc. 1979, 101, 1310 J. Am. Chem. Soc. 1988, 110, 4329 Irreversibly traps the rearranged iminium ion Alternative mechanism Ruled out because: 1)Epimerization at C-(R 1 ) 2)Reaction works well when R 4 is EWG

Aza-cope/Mannich Reaction: Applications Total syntheses enabled by Aza-cope/Mannich reaction in Overman Lab: (±)-Gelsemine (2005) (±)-Dehydrotubifoline and (±)-Akuammicine (1993) (+) and (-)-Strychnine (1995, 1993) (±)-Deoxoapodine, (±)-Meloscine, (±)-Epimeloscine and 1-Acetylaspidoalbidine* (1991) (±)-6a-Epipretazettine (1990) (-)-Crinine (1985) and more... * Formal Syntheses 98%, multigram scale Construction of the DE ring in the enantioselective total synthesis of (+) and (-) strychnine J. Am. Chem. Soc., 1995, 117, 5776

Prins-Pinacol Rearrangement (1987) Allylic acetals  tetrahydrofurans J. Am. Chem. Soc., 1987, 109, 4748

Prins-Pinacol Rearrangement: Applications Example: (-)-Magellanine Synthesis (1993) J. Am. Chem. Soc. 1993, 115, 2992 Total syntheses enabled by Prins-Pinacol Rearrangement in Overman Lab (-)-Magellanine (+)-Shahamin K (-)-7-Deacetoxyalcyonin Acetate Briarellins E and F and more...

Asymmetic Intramolecular Heck Reactions (1989) First report (also see Shibasaki, M. J. Org. Chem. 1989, 54, 4738) J. Org. Chem. 1989, 54, 5846

Tandem Heck-πallyl reactions in total synthesis

Strychnine Isolation in pure form 1946/ Structure Determination (R. Robinson and R. B. Woodward) “For its molecular size it is the most complex substance known” -- R. Robinson (Nobel Prize for Chemistry, Alkaloid Chemistry, 1947) Woodward First Total Synthesis 28 Steps, % yield “If we can't make strychnine, we'll take strychnine!"” -- R. B. Woodward Colorless crystalline Pesticide (birds and rodents) Neurotoxin, acts as an antagonist of glycine and acetylcholine receptors LD 50 = 0.16 mg/kg in rats, 1-2 mg/kg orally in humans

Christopher D. VanderwalRacemicFormal synthesis2011 David W. C. MacMillanSingle enantiomerTotal synthesis2011 Hans-Ulrich ReissigRacemicFormal synthesis2010 Rodrigo B. AndradeRacemicTotal synthesis2010 Albert PadwaRacemicTotal synthesis2007 Tohru FukuyamaSingle enantiomerTotal synthesis2004 Graham J. BodwellRacemicFormal synthesis2002 Masakatsu ShibasakiSingle enantiomerTotal synthesis2002 Miwako MoriSingle enantiomerTotal synthesis2002 Stephen F. MartinRacemicFormal synthesis2001 Joan BoschSingle enantiomerTotal synthesis2000 Peter C. VollhardtRacemicFormal synthesis2000 Martin E. KuehneSingle enantiomerTotal synthesis1998 Viresh H. RawalRacemicFormal synthesis1994 Larry E. OvermanSingle enantiomerTotal synthesis1993 Martin E. KuehneRacemicTotal synthesis1993 Philip MagnusSingle enantiomerTotal synthesis1992 Robert B. WoodwardSingle enantiomerTotal synthesis1954 Source: Synarchive.com A List of Strychnine Total Syntheses

Overman Synthesis of Strychnine: Retrosynthetic Analysis

Overman Synthesis of Strychnine: Retrosynthetic Analysis (cont’d)

Syn dehydration Ketone reduction DIBAL-H ester reduction Enol triflate

Stille carbonylation Epoxidation from less hindered face

SN2SN2 Intramolecular epoxide opening Remove CF 3 CO Indoline formation

Reduction from β-faceBase-promoted epimerization DIBAL-H reduction Known transformation developed in 1950s Intermediate

Sarain A Two marcocycles, two sec-amines >5 partial syntheses before this work

Monoreduction of diester directed by α-hydroxyl group Oxazoline formation methyl benzimidate hydrochloride

> 20:1 dr (desired isomer) Thermolysis of Boc Allylation Amidation by AlMe 3 Oxazoline cleavage and translactamization Allylation

Two-step reduction of pyrrolidinone (DIBAL-H/NaBH 3 CN) Thermolysis of Boc (selective) Lactonization Reduction of lactone to lactol Tetracycle formation

Direct conversion to OTIPS enolate was not successful

N-Ts Removal Reductive amination

Selective removal of TBSRearrangement Goal – bulid the second (triene) marcocycle One of the challenges for previous formal synthesis

d.r. = 3-4 : 1 (chelation of the Grignard reagent) Dia. separated

Finally Forming the marcocycle by intramolecular Stille coupling End game – reveal the aldehyde- tertiary amine interaction

Biginelli Reaction and Polycyclic Guanidine Alkaloids “Biomimetic”synthesis (example: Snider ’ s synthesis of ptilomycalin A) Overman ’ s approach using tethered Biginelli reaction J. Am. Chem. Soc., 1994, 116, 549 J. Am. Chem. Soc., 1995, 117, 265 Review: Chem. Commun., 2004, 253

Tethered Biginelli Reaction: Tuning the Stereoselectivity Thermodynamically more stable How to control the stereochemistry? Chem. Commun., 2004, 253

Tethered Biginelli Reaction: Tuning the Stereoselectivity Cis selectivity Knoevenagel Pathway Morpholinium acetate - basic condition Trans selectivity Imminium Pathway PPE (Polyphosphate ester) - acidic dehydrating cond. Exception: when X=NH 2 + (guanidine) Iminium pathway Reason: Guanidine is more electron rich than urea and N-sufonylguanidine  Loss of HY more favorable  Favors iminium formation Chem. Commun., 2004, 253

Small-molecule Inhibitors of the HIV-1 Protein Nef. Missing Nef protein = fail to progress to AIDS Inhibition of protein-protein interaction (at 5 µ M) ★ ★ ★ PNAS 2004, 101, 14079

Summary Quaternary chiral centers Method DevelopmentStereoselection Overman ’ s work