Leo Armand Paquette 2011-08-20

Baran GM R.A. Rodriguez Leo Armand Paquette 2011-08-20

Born in Worcester, Mass., July 15, 1934 Syntheses Discussed B.S., Holy Cross College, 1956 Ph.D., MIT, 1959 synthesis of azasteroids and regioselectivity in Baeyer-Villiger (Adv. Norman A. Nelson) Upjohn, medicinal chemist, 1959-63 Prof. Ohio State University, 1969-present Honors and Awards [4]peristylane Elassovalene [22](1,5)Cyclo- Dodecahedron 1965 Alfred P. Sloan Fellow ctatetraenophane 1971 Morley Medalist Cleveland Section Me 1976 Guggenheim Fellow OH O H 1979 Columbus Section Award Me H H Me 1980 Senior Research Award, OSU 1981 Kimberly Professorship in Chemsitry Me Me 1987 Arthur C. Cope Scholar Me Me Me 1984 National Award for Creative Work Me Me OAc Me Salsolene oxide in Synthetic Organic Chemistry Pentalene 1989 Senior Humboldt Fellow 4aβ, 10β-doladiol acetate 1990 Sullivant Medal, OSU highest honor Me Me O 1992 Awardee of the Japanese Society for Me the Promotion of Science HO O Me 1992 Ernest Guenther Award Me Me O Me 2002 S.T. Li Prize Science and Technology Me Me H O O O OMe 3 1390 publications (111 reviews) HO 42 patents MeO (-)-Austalide B C(3) OH α; C(3) OH β 17 books 38 book chapters Timeline: Career in review Natural Product Synthesis 1979-present Gymnomitrol and Isocomene 1979 Research interests 55 total syntheses to date Heterocyclic chemistry Hydrocarbon chemistry Natural product synthesis Hydrocarbons 1974-1990 Dodecahedrane 1982 Synthetic methodology Catalytic asymmetric methods Heterocyclic chemsitry 1962-1975 Organoetallic chemistry Azepine 1962 Oxy-Cope RR 1978-2000 Organosulfur reagents Ag(I) cat. RR di-π−methane RR Squarate esters Indium reagents 1970-75 1975-1984 1993-97 1995-2000 Postdoctoral Researchers from the Paquette group: 1962 1968 Steven Ley (1972-1974) 1975 1981 1987 1993 2000 2006 2011 Louis Barriault (1997-1999) Organosulfur 1964-74 Silicon chemistry (-)-polycarvernoside A α-Halosulfones 1964 1977-1984 Polyspiro tetrahydrofurans 1981-2004 Baran GM R.A. Rodriguez Leo Armand Paquette 2011-08-20

Heterocyclic and Carbocycle Chemistry 1962-1975 MeO Upjohn and OSU N N Syntheses and derivatives: Syntheses and derivatives: MeO JACS 1962, 84, 4987 JACS 1965, 87, 1718 Azasemibullvalene Semibullvalene JACS 1963, 85, 4053 JACS 1965, 87, 3417 Azabullvalene Bullvalene N O 1969 H JACS 1964, 86, 4092 JACS 1968, 90, 6148 1967 Azepine JACS 1964, 86, 4096 Oxepin JACS 1972, 94, 6751 e.g. phenol and chloramine A Synthetic Entry into the Azasemibullvalene System Photochemistry of Carbocycles O Me Me Me Me Me ClO SN O O Me 2 H Me ClO2SN C O Me Me Me Me hv acyclic Me hv NSO2Cl α,β-cyclopropane Me Me Me Me H ester O Me Me 1/4 products trans-Bicyclo[6.1.0]nonan-2-ones 2,3 Homotropone O O JACS 1969, 91, 7108 Me JACS 1967, 89, 5633 Me Me Me ClO2SN HN + - Me NaOH 1. Me3O BF4 Me Me Me Me Me Me Me 2. K CO Me 2 3 N Identification of cationic species 1968 (collaboration with Olah) Me The Protonation of Hexamethyl Dewar Benzene and Hexamethylprismane Me Me Me Me MeO in FSO3H−SbF5−SO2 "magic acid" Me JACS 1969, 91, 6107; JACS 1967, 89, 5480; Me JACS 1975, 97, 6124; JACS 1970, 92, 4338 Me Me Me Me Me Me JACS 1968, 90, 7147 Novel aromatics 1976 Me Me Me Me The First 8C-6π Huckeloid System: 1,3,5,7- Tetramethylcyclooctatetraene Dication

Protonation of cis-Bicyclo[6.1.0]nona-2,4,6-trienes in superacidic media Me Me JACS 1976, 98, 1267 2 + H Me FSO3H−SO2ClF Me + + Me + −95 °C Me H initial trans cation Me Me JACS 1973, 95, 3386 JACS 1976, 98, 4327 Bis(tetramethylhomocyclopropenyl) Dication Baran GM R.A. Rodriguez Leo Armand Paquette 2011-08-20

Synthetic Methods: 3. di-π-methane RR 1975-80 1. Ramberg-Backlund 1964-74 1989 [3]peristylane Upjohn: Conversion of Mercaptans to Homologous Terminal Olefins HO O OH [O] hv SH SCH2Cl SO2CH2Cl 90% 97% O oxydi-π-methane Tetrahedron 1989, 45, 3099 OH- Cl 4. Silanes 1977-84 S S - cyclopentanone synthesis O O O O O Me Me O 1. PhSO2NHNH2 TMS Cl AlCl3 2. nBuLi + HO SO CH Cl O 2 2 X 3. TMSCl Me Me Me O O JACS 1964, 86, 4383 JOC 1980, 45, 3017 Me Chem. Rev. 1986, 86, 733 SnCl4 RR of α,α-Dichloromethyl Sulfones (silyl cylopropanes) R Cl Me Me Me Me base base -SO2 R CH SO CHCl 2 2 2 R TMS TMS -HCl S -HCl TMS O O JACS 1967, 89, 4487 Me Me Me α−Vetispirene Me Me Me Me 2. Ag I cat. RR 1970-75 Tet.Lett 1982, 23, 3227

Ag Ag Ag Ag+ Diels-Alder equivalents Phenyl Vinyl Sulfoxide as trans-1-(Phenylsulfonyl)-2-(TMS)ethylene as (AgBF ) H 4 Acetylene Equivalent Ethylene Equivalent

H vs >150 °C w/o Ag (I) O SO2Ph H H PhS Br Br H Ag+ TMS H H MeLi H * cis found to be less reactive 80% (AgBF4) via ene-type 40 °C quant. clean JACS 1978, 100, 1597 JACS 1980, 102, 4976 non-conjugated triene

JACS 1971, 93, 1288; JACS 1980, 102, 637 • Indium 1995 • Zr 2002 Baran GM R.A. Rodriguez Leo Armand Paquette 2011-08-20

Men of learning in ancient Greece took especial concern for "the putting together of cosmic figures.' their regular polyhedra whose mathematical elegance inspired considerable wonder. The heritage of that wonder inevitably passed into the realm of synthetic organic chemistry and attracted the practitioners of this science to apply their skills to the construction from carbon and hydrogen of such strained molecules...

A journey to dodecahedron: selected syntheses of hydrocarbons JACS, 1983, 105, 4113 T

e molecular modeling shows t • r a serious nonbonded steric strain h X e d r [3] peristylane [4] peristylane [5] peristylane o R

n [4] peristylane

Eaton and Muller , R "triaxane"

1 top view 9 8 9 ,

4 5 ,

3 H O 0

top view octahedrane decahedrane 9 1. SeO2 H

dodecahedrane 9 PhH, Δ mCPBA [8 faces] [10 faces] [12 faces] 2. Al2O3, H quinoline 98% 2 steps When first synthesized, trixane was viewed predominantly as a chemical curiosity. Ts Ts TS quant hv It was initially named "triaxane" in an effort to capture the C symmetry of its 3v 1. BF3, O + acetone 1.eth.gly., H O tetracyclic framework and to depict that the cyclopropane ring rests on three Et3SiH O O 2. Li, EtNH O HIO4, axial pillars fixed to a cyclohexane chair. 2 2. TsCl, py 3.H O+ 10%aq After successful preparation of one of these hydrocarbons, Eaton named it 3. LAH, Δ 3 69% 3 steps MeOH "peristylane" after a Greek word hat alludes to the similarity to "a group of 64% 3 steps 95% Ts columns arranged about an open space in a manner designed to support a roof". Ts

Several years later, Garratt and White noted that the top row (vide supra) N OH HO2C Me O O O O hydrocarbons constitutes a series of compounds characterized by the NaOEt, 1. interconnection of a smaller n-memberd ring to one twice the original size at EtONO O alternate carbons of the latter and the community decided to generalize the HO Eaton nomenclature. 77% 2. OH TsOH OH Hypostrophene N I O 1. hv 63% 2 steps [3] peristylane OH OH O O NaK-alloy "triaxane" 2. I2, PPh3 54% quant [5 gram] 1. hv O wurtz-type O MsCl/TEA 0 C; O ° 76% 2. H+,Δ I S rt NO GOOD!! H O Δ Δ I 1. sulfene [3+2] N NHTs N NHTs 85% OH LAH O wurtz N N H 2. NaI 84% SOCl2 H 90% H HO O Cl Cl I I O CO H O CO2H Cl O 80% 2 Br Tet. Lett., 1974, 17, 1615 Baran GM R.A. Rodriguez Leo Armand Paquette 2011-08-20

JACS, 1990, 112, 1258; Tetrahedron, 1981, 37, 4521 B

Br A B Br

45 ° A E

[22](1,5)Cyclooctatetraenophane The Weiss-Cook reaction: E R E E R O R - 4CO2 E aq. buffer O O O O O + 2 equiv O R E R E R E cis-bicyclo[3.3.0] CO2Me octanedione 1.LAH Br SiO2 E 2. DHP/H+ (10X weight) E E 3.Ph3PBr2 ether, rt O - 4CO2 O pH = 5.6 O O O O 66% 3 steps two-fold + HCl, Br Δ CO Me cation-olefin O 85% 2 E E 92% cyclization 83% 2 equiv E 1. OsO4 2.HO 83% OH TsOH Br H Br O H AgClO E Me Me 4 H 1.LAH 1. H O O O PhH/pentane Br 2.NaH, O HO OH 1.LAH O O CS2, MeI; (COCl)2, 2.NaH, CS2 Br Δ 2 eq E DMSO MeI; Δ Bu3SnH 70% 2. HCl, Δ 69% 3.TsOH 85% 56% O all mixtures A + all mixtures B NBS 4 eq O AIBN/CCl 4 minor (~ 1:2) major Br Br B Ni(CO)4 H , Pt [3,3] 500 °C 2 DMF EtOAc 34% 40% bicyclo bicyclo Br 2 steps brsm Br A [3.2.1]octane [2.2.2]octane all mixtures JACS, 1979, 101, 4773 Baran GM R.A. Rodriguez Leo Armand Paquette 2011-08-20

Elassovalene Used in studies towards the evaluation of homoaromaticity-special [4.4.4]Propella-2,4,7,9,12-pentaene & [4.4.4]Propellahexaene case of aromaticity in which conjugation is interrupted by a single luche/ sp3 hybridized carbon atom. Although this sp3 center disrupts the Br burgess Br continuos overlap of p-orbitals, considerable thermodynamic O O O stability and many other properties or aromatics are still observed. Br Br Ph Ph O N O N O O N O N Ag I CO2Me N N Me O RR S Cl O O CN Me O OH O CO2Me CO2Me O

O 120 °C, 12h O sealed vessel O O O O O O S O JACS, 1977, 99, 6935 O O O O Org. Reactions, 1977, 25

R* R* R* N N N NHSO2Ph N N O O O O O O Br N triple shapiro NHSO2Ph H2 N N N N N N N (-) Pd-C Br 4,5-Diazatwist-4-ene N Br Br JACS, 1986, 108, 3731 NHSO2Ph JACS, 1979, 101, 2131 COT / Br2 JACS, 1987, 109, 3174

Ramberg Ph bromination/ Backlund CO2Me elimination CO2Me Isotriquinacene Ph JOC, 1984, 49, 1445 2,8 Tricyclo[5.3.0.02,8]deca-3,5,9-triene Tricyclo[5.5.0.0 ]dodecatetraene study of bridgehead olefins JACS, 1987, 109, 2857 JACS, 1986, 108, 1986 Baran GM R.A. Rodriguez Leo Armand Paquette 2011-08-20

Syntheses of dodecahedrane Norrish II Trost Corey σ−bond radical Wurtz/Acyloin E annulation/ E lactonization/ E metathesis stitching desymmetrization Ring expansion O Oxidation

O

E E E Dodecahedrane Polyhedron Faces Edges Vertices Symmetry Group C2-symmetric 1982 Tetrahedron 4 6 4 Td 1974 Domino DA Hexahedron 6 12 8 Oh Oxidative E Domino 90 1976 Annulation/expansion Octahedron 8 12 6 Oh dimerization Diels-Alder °

1978 Hexaquinacene route Dodecahedron 12 30 20 Ih abandoned Icosahedron 20 30 12 I E 1979 Desymmetrization E E *Shenvi Platonic Hydrocarbons GM

O CO Me O Ph Ph 2 CO2Me E O CO2Me O I CO2Me S 1. NaOH, P O , MsOH O O O 4 10 KOH, MeOH; MeOH H2O2 O MeOH O 83% 2 steps I2, NaHCO3 2. Jones [O] 77% O O O I 3. Zn/Cu, MeOH 94% CO Me + E O O 2 O CO2Me 78% CO2Me CO2Me O H2, Pd/C quant. EtOAc - cannot attack ester (sterics) O OMe O O OMe O O OMe O OMe O OMe O Cl Cl H MeO2C Cl Cl Cl - Cl- NH3, Li HCl, fragmentation - MeO- Cl MeOH H NaBH4 Cl then OH O O O MeOH PhOCH Cl 62% O 2 81% 48% MeO CHO β−keto ester MeO O CO2Me O 1,4 diester O PhOCH2Cl blocking group O OMe O OMe chemoselective Cl Cl alkylation prevents wurtz-type? H [gram-scale]? over [O]... Norrish II: O OH O unstable Li 1. KOH, EtOH OPh PhO retro-aldol Pd/C OPh PhO MeO O O OPh HO OPh MeO2C Cl MeO C 1. Li, O 50% MeO2C 2 MeO2C CHO 37% 4 steps 250 °C hv NH3 + Norrish II TsOH 1.HN NH hv 2. H3O 2. hv O OH O 3. TsOH 2.DIBAL 36% 3. PCC -78 °C 4. HN NH JACS, 1982, 104, 4504; JACS, 1981, 103, 228 65% 3 steps Baran GM R.A. Rodriguez Leo Armand Paquette 2011-08-20

O 5. Squartate esters OMe O O R RO MeO RO N R N HO R MeO O R R RO Z RO OMe O OAc N R OAc MeO BF OEt O 3• 2 Z RO OMe Bu3Sn gloiosiphone A OH N O O O O RO O R Li 1 R1 R2 R2 RO R2 X = Pb(OAc)3 O O RO RO O RO RO O R RO O OAc RO OH OH O R1 O R R OH O RO 1 RO O O O RO RO R1 R2 X = I, Br, Cl O X R1 R2 R R1 1 O

RO RO R3 RO R3 RO R1 O O OH R O OH O RO 1 R O R R2 1 O R1 RO RO [2+2] R H RO X O X O OH RO RO X = I, Br, Cl RO R Tetrahedron 1997, 53, 8913 OR OR

OH O H O H Achieving high complexity in a single step: selected examples HO Me H Me Me O H O H Me Me Me Oi-Pr Me O Me Me OH Me H i-PrO i-PrO OH O O O O Hypnophilin Coriolin Ceratopicanol HO H Me i-PrO O i-PrO Me steps Me Li O N RO O 1. O OH Me H i-PrO O i-PrO Me Me 38% 35% 38% RO O 2. Me Li Me i-PrO OH Pentalene mechanism JACS 2002, 124, 9199; Org. Lett. 2002, 4, 4547 Baran GM R.A. Rodriguez Leo Armand Paquette 2011-08-20

6. Oxy-Cope RR 1978-2000 then Claisen RR Enolate trapping: kinetic, thermodynamic and electrophiles H 1964 "oxy-Cope" O H 320 °C α H = kinetic protonation gas phase β H = thermodynamic epimerization H H O H OH 1975 Evans Me Me H Me H H HO KH, O O O O PhSeCl KH, 18-cr-6 Me Me 18-cr-6 THF, 0 °C; H H H H O 80 °C - - 2 Me O O O Me Me Me Me Me Me SePh Rate accelerations up to 1015 !!! O Me Me Me Me MeO OMe OMe OMe CCl , NaH O MeO OH MeO 4 Δ KN(TMS) H O Me OH 2 H H via Me H THF, Δ; 18-cr-6 Me Me retro ene Me H O Me Me 2 O2, THF O Me OH Me HO

High basicity of "naked" potassium alkoxide vs less basic sodium salt Aromatic participants MeO OMe OMe Me KH, Me - H O OMe 18-cr-6 NaH Me O OH OH Δ, 1h, 18-cr-6, THF H THF, -25 °C; THF, Δ; O H2O KH, THF O H2O O 88% H prostaglanins, retro [4+2] - Me (algal sperm attractant) multifidene O O + Me preparation of 1,5-Diene-3-ols -addition of vinyl organometallics to β,γ−unsat aldehydes or ketones Me Jung, M. E. et. al. JACS, 1980, 102, 2463-2464 -condensation of allyl anions with conjugated carbonyl compounds

Alkyne, Allene and Diene participation Et Et Me Me MeO OMe MeO H HO Me Me O H MeO O [3,3] KOH H OH [3,3] O MeOH OH O O O OMe O H2O H Me Me O O OMe Baran GM R.A. Rodriguez Leo Armand Paquette 2011-08-20

Besides trapping with electrophiles: Ultimate TANDEM Oxy-Copes Oxy-Cope in total synthesis 1. i. H2, Pt Me ii. O A. Cope-ene (as well as Cope-aldol-not shown) 3 O O O H O H H Me 2. NaBH , H 4 Me aq NaOH; o-DCB Me + Me H3O Δ ene mechanism Me Me Me Me [3,3] Me Salsolene oxide (R)-(−)-carvone 46% 2 steps OH Br O OH Br Br 1. DIBAL, -78 °C B. Cope-ene: a more programmed approach CO2Et SPh SPh 2. PhSH, TiCl • Acidity of allylic hydrogen 4 88% 2 steps Me Me Me H O H Me KH Me Me Me Me [2+2] ketene-olefin factoids: O 0 °C ene O OEt 1. NaI, acetone • trans olefin = retention of stereochem [3,3] 65% • cis olefins = nonstereospecific OEt 2. CO2Me OH H OEt 2 steps • nucleophilic alkenes best O OH LDA, HMPA -78 °C • unsat. ketenes prefer criss-cross behavior • Silane anion promoter: two step process when matched with nucleophilic alkenes TMS TMS H O OMe 1. 14M KOH; H O H KH, I2 TBAF + H3O Δ rt O THF, rt 2. (COCl) , SPh 2 Me [2+2] Me SPh SPh OH O HO TEA Me Me 57% H C. Cope-S 2' N Me Me Li O THF, -78 °C H NOE Cl OH Cl OH Me H Me Δ - HCl H H LAH H MeI [3,3] OH H SN2' H O-Li+ H Me H O kinetic H Me K. Foo JACS YIR H Me Me SPh H 87% Me SPh SPh D. Cope-retro oxy-michael Me 1. Li, EtNH H 2 78% 2 steps 2. Ac O, py O CHO 2 O KH, Me HO Me NOE 18-cr-6 H+ H Me Me H Martin O H H H 1. mCPBA, O H H Me diglyme H H Sulfurane - NaHCO3 O O H H Me 100 °C Me Me Me Me Me Me AcO H 2. LAH Me HO 78% Me Me 3 steps Me Pallescensin A. JOC 1992, 57, 7118 Me Me H NOE Salsolene oxide Baran GM R.A. Rodriguez Leo Armand Paquette 2011-08-20

Recognizing the cope transform within cyclic systems: Its all about the vinyl grignard + O H H H H XM O OH OH OH O OH H 1995_vulgarolide acidic, conjugation + O MX H H H H H XM Ikarugamycin & cis Spinosyn A Relay H H H O H H O OH

JACS 1989, 111, 8037 OH [3,3] O JACS 1990, 112, 9292 JACS 1989, 112, 9284 H H + O XM Alternatives.... H H OH H O H OH H H O OH (E) Cerorubenic Acid 3 OH MX O H H H H H H H (E) H H H bridgehead olefin H H H O OH

possible pre-cope H HO OH O H OH OH O Me H O O H H Me H XM H O O H ∗ H H H H O H Me H H O SePh OH O H Me O O N O Cyathins studies towards OH O H H O O Me O O S [Li] SPh NH 1. SPh + MX OH H Δ (or) S Me H H O H O H 2. Dibal-H, Ikarugamycin HO S cis required for norbornane MeCN, chlor- S system trans is too strained HMPA/THF amine-T Baran GM R.A. Rodriguez Leo Armand Paquette 2011-08-20

Recognizing the claisen RR within cyclic systems: Find the γ - vinyl ketone A Me Me Me Me Me H Me H H Me H H I2, PhI(OAc)2 Me Me Me Me Me Me CycHex B O H H H H C 6 Me Me O Me Me Me O O hv, 50 C HO B H H H H 95% H A O D Me Me OAc OAc H Me Epoxydictymene A) Keep in mind where O-alkylation will take place O H Me B) Move unsaturation into one another H Me C) Break bond were unsaturation meets OMe Me D) Rotate bond to connect oxygen to carbon Me Me O + O Me H Me O Me O Me O MeO C H Me H 2 H Me 1. LDA, TMSCl Me Me Me MX O O 2. O3, MeOH; Me Me Me Me DMS 12 steps from 7,8-Epoxy-2-basmen-6-one H Me Me H 3. CH2N2, rt (R)-carvone

O H H O Me JACS 1993, 115, 1676 H H OH H H 4 7 1 7 Me Me H O AcO Me Me C6H15 O O 3 H H H H 1 H Me 3 4 H O O O Me MeO OAc PO O Acetoxycrenulide Me Me Me Ceroplastol I Me Me O O Me Me O H Me O Cl CuLi O R O O OMe 2 O O O H Cl O H SePh O O H SePh O MeO Me Me O H O H O H PO PO Me Me O O OMe Me N O mCPBA, NaHCO , P O 3 MeO MeO O O N CH2Cl2, reflux HO (S) H (S) Me OH O O Me [Li] O MeO Me O 91% O O MeO MeO H H H Me Me via epoxy lactone PO PO Me Me asymm. (R)-citronellol (zwitterionic or biradical) michael Baran GM R.A. Rodriguez Leo Armand Paquette 2011-08-20

Selected examples using cope RR controlled by facial TMS approach of vinyl, OPMB OPMB which is fixed H O OAc H Me H O H H OH O H O H H Wieland Me H Me O O Me H Me O Miescher TMS Me Me O ketone Me OMe Me Me O SePh O PMBO O Me TMS PMBO Me Me Me O-methylshikoccin H OR Me Me restricted reactivity to JACS 1997, 119, 9662 OH boat conformation

O Me Me O OH 1. LAH OH O O O Si 2. Me Me Me Me O Me O H2O2, KF Me Me HSi Cl Me Me Me Me Me Me Me Me Me BnO Me BnO Me H Me H Me HO H BnO 3. H2PtCl6, H Me H Me HMDS Me Me O Me Me OH Me Jatrophatrione Me Cope-ene OH H H Me i. tBuOK, THF Me Me O HO OH Me OH Me O 18-c-6, 0 °C Me Me Me Me Cl Me ii. MeI Me Me Et OMe BnO BnO Me H Cl H 98% H Me Me BnO OMe O JACS 2002, 124, 6542; JOC 1999, 64, 3244

O Ozaonlysis/ Jones[O] Me I CO2Et KN(TMS)2 O Me Me HMPA Me THF, Δ O O Me OH O O HO O SEMO O Me O CO2Et OSEM Me HO HO O SEMO O (see Cerorubenic acid synthesis) Vulgarolide JACS 1996, 118, 5620; Tet. Lett. 1995, 36, 673 Baran GM R.A. Rodriguez Leo Armand Paquette 2011-08-20

Selected examples using Cope RR JACS 1998, 120, 5953 OTBS H H H H H KN(TMS)2 Me Me H H THF, Δ H H O O H OH Me CO2H Me CO2Me H Me Me Me Me Cerorubenic Acid 3 (studies towards) Me O O O O O HO O 1. O H , 1. CH (CO Et) vinyl 1. LDA (2 eq) 2 2 2 1. cuprate TsOH PPA Na, EtOH O O O THF, -78 C O O 2. ozonolysis 2. BH3-THF OH HOAc, OH 2. KOH; HCl 100 °C 2. FeCl3 Me 3. Jones [O] Me Me via acylium Me DMF, -78 C Me Me (inverse addition) Me Me AcO OAc Me Me Me Me Me Me O Me OAc Me Me OAc O • dihydroxylation O Me Me Me [3,3] Me • pinacol shift Me Me OH Me H Me AcO H H AcO OAc H O H H H H H OR OAc O RO Taxusin RO

Me Me Me Me Me Me Me Me flagpole Me Me Me Me Me Me Me Me O O- - O O- O O O - Me H O Me H H Me Me H H H H H H H H endo vinyl = E H H E, trans H H RO H H Z, trans RO Z, syn RO exo-chair RO endo-chair chair CycHex = syn endo-boat exo-boat

Me Me Me Me Me Me Me Me Me Me Me Me H2SO4 CH2N2, OH * product TEA grignard Δ OH OH Ac2O crystallize out of soln Et2O, 0 °C Me mechanism O O O O O O S SO3H SO2Cl 2 RO JACS 1998, 120, 5203; Org.Syn. v.45, p12 (1965); coll.v. 5, p194 (1973), Org.Syn. v.48, p106 (1968); coll.v. 5, p877 (1973) Baran GM R.A. Rodriguez Leo Armand Paquette 2011-08-20

O Selected syntheses O protection/deprotection C3 selective Me Me O 4 3 1.i. NaH, PhMe, Me Me HO O O H OH 110° Me 30% Me Me Me O 4 steps Me 2 ii. Br 1 Me Me Me 64% CO2Et 2. decarboxylate O O O O Hagemann's MeLi 93% OMe O Me Me 98% ee OAc Ester Me O Li-NH3/MeI, then MeO (-)-Austalide B 67% tBuOK, MeI 4aβ, 10β-doladiol acetate OH alk./Robinson HO H Me O O O Me Me O Me SEMO SEMO Me Me O H 1. OsO4 Me Me Me Me 1. mCPBA Me Me 2. SEMCl Me Me 1. NaH, Cl Me Cl 53%, 4 steps Me Me 2. Me O+BF - Me 80% Me Cl Me O O 3 4 OH CO Me 51% 2 steps O 2. Ba(OH)2, Δ 2 O O Me 3. NaHMDS, MeO 1. Hg(OAc) , eliminates 2 MeI O 1. mCPBA 80% hydrolysis/ HOAc Me with NH4Cl 82% 3 steps H 2. BF3•Et2O Me Me Robinson SEMO O OTf 3. K CO , Δ SEMO O O 1. Me3Sn 2 3 1. LDA, O Me Me 37% 3 steps Me Me NCCO Me 2 Pd (dba) Me Me Me Me 2 3 O Me Me 1. hν 2. KN(TMS ) , CO2Me H2O2, 2. Ac O, py O O 3 2 O O 71% NaOH 2 PhTf2 33% + 52% rsm MeO 84% MeO O O 2 steps * low tendancy to aromatize due to conformational bias of neighboring rings Me Me O Me H Me H Me Me Me Me SEMO O SEMO O i-PrMgBr, KN(TMS3)2 Me Me O Me CuCN n-BuSH, HOAc Me O Me 89% Me CO Me 78% SBu 66% O O O H O 2 O O O O Me Me O OAc KN(TMS ) , HMPA, MeO 46% 3 2 Me2SO4, 80 °C MeO Me Me Me Me Me Me 1 OH 1. DIBAL Me 1. O2, SEMO O HO O 2. Ac2O, py 4aβ, 10β- 1.TBAF MeOH/DCM Me doladiol Me Me O 2. TPAP [O] Me O Me 2. P(OEt) Me 92% acetate Me 3 Me 3. NaBH 66% 4 O O O Me O Me Me Me O O O OMe 2 steps O OMe 65% 3 steps (-)-Austalide B MeO MeO JACS 1996, 88, 3408; JOC 1986, 51, 4807; Org.Biomol.Chem 2007, 5, 1522 JACS 1994, 116, 11323; JACS 1994, 116, 2665 * nice redox economy Baran GM R.A. Rodriguez Leo Armand Paquette 2011-08-20

Me O Me Me Me Ozonolysis/ O Me [3+2] Robinson Me Robinson Stork-Danheiser Me Me Me Me H Me Me Me Me HO 3 Me H Me i-BuO C(3) OH α; C(3) OH β HO O O Hydroxykempenones

Me Me Me Me Me Li, NH ; 3 KOH, Δ tBuOH; MeOH/H2O Li, NH3; Me NH Cl Me Me TMS Me 4 TMS Me Me Me TMS Me Me 80% 42% Me Me 4 steps Me - + O O Me O O Li O H OH O O NaH, DME Δ 81% Me (MeO)2CO Me Me Me

TMS OAc 1. LAH Me Me Me DDQ Me Me MeO C Me Me TsO MeO2C Me 2 Pd(OAc) , P(OEt) , 2. TsCl, py 77% 2 3 H THF, Δ MeO2C H DMAP O 60% 2 steps HO HO O 98% H H H H

1. LiBHEt3 88% 2. TBSOTf 2 steps Me Me Me Me O Me Me O O O H O Me Me KOH, O3; Me Me HF Me Me Me Me + Me MeOH Me Me2S Me MeCN Me Me Me H Me H Me H 60 % 63% Me H Me H O HO TBSO TBSO H H H H TBSO TBSO Not responsive to [3+2] (5:1) H H JACS. 1992, 114, 7375 Me O OH Me Me H H OMe Me OR O Me O O H Me O Me Me Me Me H H H Me Me Me Me Me Me OH O OH Silphinene

7,8-Epoxy-2-basmen-6-one Me Me Sclerophytin A; R = OH O JACS 1983, 104, 7352 Cherney JACS 1981 GM Sclerophytin B; R = OAc 11, O (3)-Dihydropseudopterolide JACS 1990, 112, 3252 JACS 1991, 113, 2610 Org. Lett. 2000, 2, 1875 JACS 1990, 112, 4078 Newhouse Cembranoid GM α Vetispirene Org. Lett. 2000, 2, 1879 Newhouse Cembranoid GM Me JACS 2001, 123, 9021 Me Tetrahedron Lett. 1982, 23, 3227 Org. Lett. 2001, 3, 135 (w/ Overman) O O Me JOC 1984, 49, 3610 Maimone Cladiellin GM Me OMe Burns Vetivane GM H Me Me O Me Pentalenene Me O Me Me JACS 1983, 104, 7358 Me OH Cherney JACS 1981 GM O O R O O Cleomeolide Me R 2 1 O Tetrahedron Lett. 1993, 34, 3523 Modhephene (R1 = H, R2 = Me) O JACS 1994, 116, 3367 Me Epimodhephene (R1 = Me, R2 = H) Gorgiacerone Newhouse Cembranoid GM OH CO Me JACS 1981, 103, 722 O H 2 JACS 1992, 114, 3926 H Me Rodriguez JACS 1981 GM Pentalenolactone P Newhouse Cembranoid GM HO2C Me O H Methyl Ester Me O Me Me Me OH O JACS 1991, 113, 9384 OH OH OMe Me JACS 1992, 114, 7387 Me Sterpuric Acid Coriolin DeMartino Pentalenolactone GM Me O Tetrahedron Lett. 1987, 28, 5017 JACS 2002, 124, 9199 Gymnomitrol Me O Me JACS 1988, 110, 5818 Gallagher Coriolin GM O JACS 1981, 103, 1831 McKerrall JACS 1988 Rodriguez JACS 1981 GM O O HO Me H O H Me CO Me Me 2 HO O Me Me Me O H Me Acerosolide H Me Me Me OH Me H Pentalenolactone E JOC 1993, 58, 165 OH Ceratopicanol Methyl Ester Newhouse Cembranoid GM Hypnophilin HO Me Punctatin A JACS 2002, 124, 9199 JACS 2002, 124, 9199 JACS 1981, 103, 6526 JACS 1986, 108, 3841 Gallagher Coriolin GM Org. Lett. 2002, 4, 71 DeMartino Pentalenolactone GM Gutekunst JACS 1986 Gallagher Coriolin GM Me Me Me Me H Me Me Me Me Me Me Me O Me Me Me H O Me Me Me Me H H Me Me Me Laurenene Isocomene Capnellene Me Me Multifidene Zingiberene Dactyloxene B and Dactyloxene C Me Me O MeO H Me Me Tandem michael/aldol H Ph N O Co chemoselective [H] H Me O O N H H H H O Me Me Me OH Me CO2H Me Me Me N Me N Me Me Me H OH H O 7 -Amino-7 -methoxy-3-methyl- Africanol β, α 18-Oxo-3-virgene 1-oxacephalosporin Magellanine and Magellaninone CHO Me O Me OH Me O RCM Me Me Ring expansion Upial H strategy Me H CO2H O Me O N Me H H H H H O Me Me Me O Me Me O Me H HO C NH 2 Me O Me Dactylol Subergoric acid O O Me H Me H O H H sugar [Zr] contraction O HO * good step count Ikarugamycin Me H strategy RuO4 H OH Asteriscanolide Retigeranic acid A O O Fomannosin Me CO H 2 Me Me Me O Me R1O OH Me O Me Me Me H prins pinacol [Zr] contraction HO O O HO HO2C O R 2 strategy strategy HO2C O AcO O O Trixikingolide Me Me OH CO2H Me H H OH Me Me O Me O Zaragozic Acid Me ent-Grindelic Acid HO OMe Me N O MeO Me 2 O Me H Me O MeO O Me Me OMe H OH O O O O OMe Me O Pestalotiopsin OMe H Me O O (studies towards) OMe OH O Pleuromutillin H Senoxydene O O Me Me (studies towards) Me (synthesis of Me H H OH O H H proposed structure) Me Polycavernoside A (w/ Barriault) Spinosyn A Relay Me HO Me H H O OH OH OHC OH H O HO OHC Me RCM O O H Me Me Me HO H Me Me Me OH O Me HO OH O Me HO AcO O O O O AcO Me Me Me O Kalmanol (studies towards) Me Me Me Me Me O O OH O O [4+2] with tropone Teubrevin G and Teubrevin H Cyathins (studies towards) oxy cope strategy Me HO O Me Cl HO O O O Me H H H Me O O O O O OMe H O OH O O HO O HO claisen strategy OH Me OH O H O Me Me Me OH cis-Lauthisan and trans-Lauthisan O O H H O O Me Me Spongistatin 1 (Altohyrtin A) O H H Me O Me Me Pectenotoxin-2 (PTX2) Me AcO OH (-)-Sanglifehrin A Stille Me Me OH H Me Me Me OH Me OH OAc OH O Me Evans aldol HO Me OH H Me HWE Me Me Me O OH O Me Me O O OH O O O HN O Me NH H H I OH H N N Me O Mangicol A Macrolactonization O N O OTBS Me H O Me HO O OH E Boron Me enolate Cochleamycin A OH

O O Cross Radical Me metathesis O Enyne RCM OTBS Me cyclization Me B-alkyl suzuki Me O OH Me H Negishi coupling Me O H O Oxy-michael/ H H O Me lactonization H O O O OTBS O OMe HO H OH O H Me Me BnO TBDPSO H O Me H O Pinacol Lancifodilactone G