Baran Group Meeting Derek H. R. Barton Will Gutekunst

Quick Timeline

- Born Derek Harold Richard Barton on Sept. 18, 1918 - Father died in 1935 and had to take over the family wood business. - In 1937 decided to leave family business and enrolled at London University. - Entered Imperial College in 1938 after passing entrance exams and graduated two years later. Graduate work focused on the synthesis of vinyl chloride - Completed his Ph.D. 1942 and started working with military intelligence developing nonaqueous secret inks. - At the end of the war he started work with Albright and Wilson, Ltd. on the synthesis of organophosphorus compounds. - In 1946 he took the "most junior position" at Imperial College as an assistant lecturer. - From 1949-1950 he was a visiting lecturer at Harvard - In 1950 he was appointed reader at Birkbeck College, then to professor in 1953. - 1955 he moved to University of Glasgow - In 1957 he moved (yet again) to Imperial College - Received the Nobel Prize with Odd Hassel in 1969 for his development of Conformational Analysis - Knighted in 1972 (but only known as "Sir" in Britain) - Moved to France in 1978 to become director of ICSN - Gif Sur-Yvette - Forced to retire, moved to Texas A&M in 1986 - Died 1998 at the age of 79 Flour Beetle Study Main Areas of Research: 6 days Flour + dead beetle pink (and unpalatable) flour surrounding beetle - Conformational Analysis - Stucture Elucidation - Phenol Oxidation Compound isolation: - Biosynthesis (lignans, phenolic 500-1000 adult beetles (ca. 5 mL) are placed in a distilling flask. A stream of dry air alkaloids, steroids, triterpenes) is passed through the flask for 6 hours. Every 2 hours, cool to 0° C for 20 minutes. - Radical Chemistry The excretion condensed long yellow needles on the cold finger (0.5 mg). Return beetles to flour for 3 days and repeat. Yields reduce with each interation. After 3 or - Photochemistry - Fluorine Chemistry 4 operations the insects were too feeble for further excretion. - Organometallics - Much, much more O Biochem. J. 1943, 37, 463-465 In all of these fields Barton made important contributions, if now start the field altogether. He frequently changed fields stating" O "... I have worked in many fields, but as ethylquinone! soon as these fields became popular, I have moved on. I have made the joke After a battey of tests, Barton determined that the compound was ethylquinone and of saying that if you cannot remember when the paper was submitted the journal's editor initially thought it was a joke. This all the published papers in the field you early study was performed during his free time when he was working for military are working in, then it is time to move intelligence, stating, "I though then, as now, that chemistry is more interesting that on." Gap Jumping, page 111. spare time." Gap Jumping, page 9. Baran Group Meeting Derek H. R. Barton Will Gutekunst

Method of Molecular Rotation Differences Vinyl chlorides Me Me Studied the thermal decomposition of various polychlorinated hydrocarbons and found that can J. Chem. Soc. 1945, 813-819 occur through three different pathways.

Me Cl ~300–500° C H Cl H cis-elimination + H Cl H Cl Me H

H H RO Cl Cl + H Cl cholesterol radical chain Cl H Cl Cl

Cl Cl + Cl Cl

R R R H H H H R Cl "surface" Me H Me H Me Me H Cl surface catalyzed + H Cl H Cl H H H H H H RO RO RO RO H H H J. Chem. Soc. 1949, 155. R H H R H R Notably, 1,1 dichloroethane cannot participate in radical chain processes

Me Me Me H Cl Cl Cl Cl Me + Cl H H H H HCl Me H RO RO RO H H H Established "rules" for the decomposition of any chlorinated hydrocarbon.

Cl Later extended to polyunsaturated compounds, hormones and bile acids ! Cl Me Cl + H Cl J. Chem. Soc. 1946, 512 Cl Cl J. Chem. Soc. 1946, 1116 At a given temperature and surface area/volume ratio, all three mechanisms operate at the same rate. This method, while empirical, was accurate. Barton used to correct numerous structures in the literature - even one assigned by Nobel laureate Leopold Ruzicka! "It was perhaps unwise for a young J. Am. Chem. Soc. 1950, 72, 988. man to criticize a distinguished professor at the prestigious ETH... I showed that L. Ruzicka had made an error in the assignment of configuration at the C-3 position in ring A of triterpenoid alcohols. Ruzicka, one of the greatest organic chemists of the day, had received the Nobel Prize just before the war. He was a passionate and fiery man. Our relations for some years were confied to print and somewhat strained" Baran Group Meeting Derek H. R. Barton Will Gutekunst

cis-Elimination

Me Me Δ H AcO OBz AcO H H

Originally reported by Plattner (ETH), refuted by MMRD

Me Me Δ H H AcO OBz AcO H H

Inspired by previous work, realizes it is requisite cis-elimination!

J. Chem. Soc. 1949, 2174. J. Chem. Soc. 1949, 2459.

Me Me Me

Δ + Using this analysis, he was able to rationalize the relative rates of esterification of Cl unimolecular equatorial and axial (polar) alcohols, thermodynamic isomerizations, anti-periplanar geometries for elimination, neighboring group participation, etc. Me Me Me Me Me Me "Conformational Analysis for the sutdy of the stability and reactivity of saturate or partly saturated cyclic systems promises to have the same degree of importance as Further support with menthyl chloride pyrolysis J. Chem. Soc. 1953, 453. the use of resonance in aromatic systems." – Arthur J. Birch, 1951

Conformational Analysis "Conformational Transmission"

Insprired by Odd Hassl's paper on decalin conformation, Barton became interested in calculating Remote conformational effects drastically change the relative rates of aldol reaction. the preferred conformations using force field calculations (logarithmic tables and slide rule!) Nature 1946, 157, 765. J. Chem. Soc. 1948, 340. Me H Me Me H H H H H H H H H H H or ? or H H ? O O O H H H H 4 H H H H 1 645 preferred!

J. Chem. Soc. 1960, 1297. This eventually led to the application of these concepts to steroid conformation Experientia 1950, 6, 316. Baran Group Meeting Derek H. R. Barton Will Gutekunst

Structure Elucidation O Me O Me O Me O Me Me O Me Me H Me O Me O O O O Me O O Me Me Me Me H glauconic acid byssochlamic acid H Me caryophyllene J. Chem. Soc. 1965, 1769. H Me Me J. Chem. Soc. 1951, 2988. J. Chem. Soc. 1952, 2210. !-amyrin J. Chem. Soc. 1953, 1027. OMe Cl Me O Me Me O Me Me Me Cl Me Me Me RO2C O OH H H OH OH Me Me Me H R = Me; geodin Me Me culmorin R = H; erdin Me Me J. Chem. Soc. (C) 1968, 1148. J. Chem. Soc. 1958, 1767. HO HO H H Me Me Me Me cycloartenol lanosterol O J. Chem. Soc. 1951, 1444. H O J. Chem. Soc. 1953, 576. O H O H Me H Me O Me O Me Me Me H O Me HO O O H O Me Me O OAc H AcO Me H OH H AcO O Me N Me HO Me clerodin limonin O OAc OH HO Me H J. Chem. Soc. 1961, 5061. J. Chem. Soc. 1961, 255. HO OH Me Me OH Me H Me OH Me O H OH Me HO Me H HO Me Me H VO5, HNO3 OH MeO H meso compound onocerin cevine "good yield" fusicoccin H J. Chem. Soc. 1955, 2639. J. Chem. Soc. 1954,3950. ` HO2C Me J. Chem. Soc. 1971, 1259; 1265. abietic acid Baran Group Meeting Derek H. R. Barton Will Gutekunst

Structure Elucidation O Me O Me O Me O Me Me O Me Me H Me O Me O O O O Me O O Me Me Me Me H glauconic acid byssochlamic acid H Me caryophyllene J. Chem. Soc. 1965, 1769. H Me Me J. Chem. Soc. 1951, 2988. J. Chem. Soc. 1952, 2210. !-amyrin J. Chem. Soc. 1953, 1027. OMe Cl Me O Me Me O Me Me Me Cl Me Me Me RO2C O OH H H OH OH Me Me Me H R = Me; geodin Me Me culmorin R = H; erdin Me Me J. Chem. Soc. (C) 1968, 1148. J. Chem. Soc. 1958, 1767. HO HO H H Me Me Me Me cycloartenol lanosterol O J. Chem. Soc. 1951, 1444. H O J. Chem. Soc. 1953, 576. O H O H Me H Me O Me O Me Me Me H O Me HO O O H O Me Me O OAc H AcO Me H OH H AcO O Me N Me HO Me clerodin limonin O OAc OH HO Me H J. Chem. Soc. 1961, 5061. J. Chem. Soc. 1961, 255. HO OH Me Me OH Me H Me OH Me O H OH Me HO Me CO H H HO 2 Me Me H VO5, HNO3 Me OH MeO H onocerin cevine "good yield" fusicoccin CO2H ` HO C H J. Chem. Soc. 1955, 2639. J. Chem. Soc. 1954,3950. 2 Me HO2C Me J. Chem. Soc. 1971, 1259; 1265. abietic acid Baran Group Meeting Derek H. R. Barton Will Gutekunst

Oxidative Phenol Couping and Biosynthetic Implications

These studies were initiated by a disbelief of the proposed structure of "Pummerer's ketone," despite being commonly held as true for 25 years. OH O OH J. Chem. Soc. 1956, 530.

K3[Fe(CN)6] Me Me NMe high dilution LAH NMe H O NMe O K [Fe(CN) ] O OH 3 6 HO O 1.4% Me O O MeO MeO MeO Me Me narwedine galanthamine "Pummer's ketone" J. Chem. Soc. 1962, 806. OH K [Fe(CN) ] H OH 3 6 O Me Me Me O Me O Me MeO MeO MeO

Barton's Proposal AcO SeO2; HO NaBH , H+ hydrolysis 4 O NMe NMe OH NMe O H H H+ MeO MeO MeO O Me OH OH O Me Me acetylreticuline salutaridine thebaine Me MeO

OH Ac OH Ac Na CO , H O O Ac H 2 3 2 O O K3[Fe(CN)6] HO O H2SO4 HO O NMe H H HO OH 15% Me Me Me Ac Me Ac HO Me OH HO OH HO methylphloractophenone usnic acid Proc. Chem. Soc. 1963, 189. morphine J. Chem. Soc. 1965, 2423.

The natural extension of these concepts led to the formalization of modern phenolic alkaloid and lignan Barton was also actively engaged in elucidating the biosynthesis of many of these phenolic alkaloids biosynthesis, and Barton even proposed compounds as necessary biosynthetic intermediates that were though the use of radiolabelling studies. later isolated (e.g. crotonosine, reticuline). Festschrift Arthur Stoll 1957, 117. Chem. Brit. 1967, 330. HO HO HO NH MeO H MeO NH MeO NH HO O HO crotonosine Baran Group Meeting Derek H. R. Barton Will Gutekunst

This allowed for an expedient synthesis of dimethylcrocetin Photochemistry Chem. Ber. 1977, 110 3582. OH Me Me Me Br O O Me Initially thought that irradiation would result in racemization of the quaternary center via: Br

Me Me Me Me Me Br Br Br Me O AcO O AcO O AcO O Me Me O Me Me h!, MeOH; Me Me Me Me CO Me 2 base Me Me MeO2C Me Br Me Me J. Chem. Soc. 1957, 929. dimethylcrocetin But only a single new product was formed whose identity was unknown. To investigate Br the reaction, a simpler and more readily available model substrate, santonin, was studied. Nitrite Ester Photolysis

Me Me Me OH Synthesis of aldosterone acetate H h OAc OAc OAc H ! H AcOH H Me H H ON O O Me O ON O Me OH NOCl O O h! OH O Me O Me O H H H Me O O O Me H py. Me H toluene Me H O Me H H H H H H Me O O O O H corticosterone acetate Me J. Chem. Soc. 1958, 140. O

O OAc OH OAc OH N O O O AcOH OH HNO Me Me H 2 H h! Me H Me H 15% overall J. Chem. Soc. 1961, 1215. H H AcO O AcO O H H Me Me Me Me O O aldosterone acetate As a natural extension, the photochemistry of linear cyclohexadienones were studied and were found to also have interesting behavior. J. Am. Chem. Soc. 1961, 83, 4083. Rearrangement to 18-nor-D-homosteroids

O O R O R 1 R O 4 h! 4 Nu: R4 Me R2 Nu ONO HO O h! R2 R2 H H toluene R3 R3 R1 R3 R1 H H H H

J. Chem. Soc. 1960, 1. J. Am. Chem. Soc. 1961, 83, 4481. Baran Group Meeting Derek H. R. Barton Will Gutekunst

Converstion of lanosterol into cycloartenol J. Chem. Soc. (C) 1969, 332. Even higher oxidations states! O Me NH Me 2 CO2H Me Pb(OAc)4 HO2C I , h!; H Me R R 2 Me Me H H Me HO O I basic reductive workup Me Me H H H H Me h!, I2; 44% H H MsO MsO HO H Me H Me H H2CrO4 Me Me BzO H BzO Me H Me Me Me lanosterol J. Chem. Soc. (C) 1968, 2283. KOt-Bu t-BuOH Me Me Me R Steroid Biosynthesis H O Barton some work on the biosynthesis of steroids in the 1970's (feeding studies, etc) but due to H Me LiAlH4 H time (and my knowledge of the subject) it will not be discussed. Me Me dioxane Me Ecdysone Synthesis J. Chem. Soc. C. 1970, 1584. HO BzO H R Me H R R Me Me Me Me Me a. TsCl, py. Me cycloartenol b. KHCO , H O 3 2 TsOH; Me Me acetone Me Modification for directed oxygenation LiBr, DMF J. Chem. Soc., Perkins Trans. 1 1973, 2402. H H H H c. MnO H H Me 2 HO 57–64% H Me O Me ergosterol O H Me R = C9H17 Me H Me H h!, O Me AgOAc, I Me 2 Me H 2 AcOH; H Me Me HO Me 44% H Ac2O AcO ONO ONO2 Me H OH cat. HClO4 Me Me AcO OH Me R H H Me Me R Me Me Me Me Me CO3H AcO AcO Me AcO H OH H OH CO2H H O2 N O AcO H AcO H Et2O AcO O Me OH OH O OH O O O H O O NO ecdysone OAc

Light Free Oxygen [4+2] R Me Me R Lactone synthesis J. Chem. Soc. 1965, 181. O , Ar NSbCl Me 2 3 6 Me H O h!, I2 dark, -78 C O Me H H ° H t-BuOCl; DCM, 5 min O Me NH AcO 2 O quant. AcO hydrolysis Me ergosterol acetate O Me R = C9H17 J. Chem. Soc., Chem. Comm. 1972, 447. Baran Group Meeting Derek H. R. Barton Will Gutekunst

Tetracycline Studies Fluorination O O H At the time, most fluorine chemistry was perfomed electrochemically, with the only known OMe OMe electrophilic fluorine reagent known being the explosive FClO4. Barton developed a number of h!, benzene hypofluorite reagent, especially CF3OF for this purpose H CO2Me benzoic acid CO2Me Me O O O O OAc Me O OMe 35% O OMe Me OAc AcO Me O Me H F COF, CFCl Me 3 3 Me H OH H -75 C ° F H AcO "good yield" H AcO CONH2 H OH OH OH OH O Me O Me 6-methylpretetramid F H H same J. Chem. Soc., Perkins Trans. 1 1973, 2402. H H H H O O MeO O H OH h!, benzene OH H F Me OH Me CO Me LHMDS 2 CO2Me same O S S 60%, [gram-scale] S S Me Me F O OH O OH O Me O H Me OH benzeneselenic OCF anhydride same 3 64% CO Me H 2 F O O OH O O J. Chem. Soc., Perkins Trans. 1 1981, 1840. same Olefin migrations with RhCl 3 F

O O O cat. RhCl3 Me O Me EtOH/CHCl3 Me H Me H 48 hr, 70° C same quant H H H F

F CO C F3CO2C 3 2 Br Br J. Chem. Soc., Perkins Trans. 1 1977, 359. Br Br "Acid-sensitive substrates have been protected by the inclusion of CaO, MgO, or NaF. Use of pyridine "the major effort on tetracycline synthesis convinced me that this sort of work should for this purpose led to the formation of a highly explosive by-product and is therefore discouraged." be left to Industrial friends who have the money and the resources to finish any multi- step synthesis, if it is economically justified. So it is the originality in the reactions Additionally, he discovered that these reagents add to olefins with exclusively Markovnikov cis-addition. and the reagents and any new principles that finally justify academic effort in The current process for manufacturing 5-fluorouracil is still the one he developed in 1972. synthesis. We are far away from the Woodwardian dogma of completely planned synthesis" Reason and Imagination, page 407 Chem. Comm. 1968, 804. Chem. Comm. 1968, 806. Nouveau J. Chimie 1980, 4, 239 Baran Group Meeting Derek H. R. Barton Will Gutekunst

Me Me Vitamin D Syntheses Me Me

J. Am. Chem. Soc. 1973, 95, 2748. Me Me Me H Me 1. SO2, PhH/H2O H 2. EtOH, NaHCO Me Me 3 Me Me heat H H 90% Me 1. DDQ Me 1. TBSCl Me 2. NaOH Me 2. SeO2, NMO H H H2O2 MeOH, DCM Me H 55% O Me H HO 45% OH H H Li/NH , NH Cl H H 3 4 cholecalciferol THF Me Me HO O 60% Me Me cholesterol

Me Me Me Me Me Me Me Me H H Me Me 1. Ac2O, DMAP 1. h!, acridine Me Me 2. TBAF H 2. DMDBH H H H AcO HO Me Me H 71% 3. P(OMe)3 34% h! H H H H AcO HO HO OH HO OTBS

Me Me Me Me 1"-Hydroxy vitamin D3 J. Am. Chem. Soc. 1986, 51, 1637. Me Me Me 1. 75° C Me H 2. MeOH, KOH H AcO Me

H H AcO

HO OH

1"-Hydroxy vitamin D3 Baran Group Meeting Derek H. R. Barton Will Gutekunst

Barton Olefin Synthesis Phenylselenic Anhydride Phenylselenic anhydride proved to be a highly efficient reagent for ketone dehydrogenation and Since many of the olefin forming methods of the time were adversely affected by steric hindrance, could also be used in catalytic amounts with hypervalent iodine reagents acting as the reoxidant. Barton decided to develop a new olefin synthesis through the use of a two-fold extrusion process. This J. Chem. Soc. Perkin Trans. I 1982, 1947. would allow the C–C formation ot be intramolecular, and therefore less affected by sterics. Tetra t- Butyl ethylene was viewed as the holy grail olefin, but was never successfully prepared. Me Me Me Me J. Chem. Soc. Perkin Trans. I 1972, 305. Concept: Me Me

R1 X R3 R1 R3 H 3 mol% BSA H + X + Y H 4 eq H R2 Y R4 R2 R4 Me H Me H 73% Systems considered: H H H H HO O O O S H R1 S R3 S S R1 R3 R1 R3 O S R1 R3 R1 R3 R S R 2 4 R S R O2 R2 S R4 2 4 S S R2 R4 R2 R4 CO2Me O2 CO2Me Me Me HO O Me cat. BSA Me N N H m-iodoxybenzoic acid H R N N R R N N R R N N R R R 1 3 1 3 1 3 1 3 Me H Me H S S S 64% R2 R4 R2 R4 R2 R4 R2 R4 O O O2 H H H O HO O H Preparation J. Chem. Soc. Perkin Trans. I 1976, 2079. Application to the degradation of the Cholic Acid side chain N N HN NH N N R1 R3 R R [o] R R S N2 1 3 1 3 + J. Chem. Soc. Perkin Trans. I 1985, 1865. Me R R S S N Me 2 4 R2 R4 R2 R4 R1 R2 R3 R4 H2S CO2H Me O Me Me NH Me Me Me 2 Me Me Me Me O O H Ph PPh3, ! H OH Me H N2 Me H 90% B(OH)3, xylene Ph Me Ph Me S H H H H Ph 96% HO HO H H Me Me Me Me t-Bu PBu3, ! BSA, py. N2 quant. 64% O O t-Bu Me t-Bu Me S Me Me t-Bu Me N Me Me N Me COCl3 Me Me Me O O H Cl3CCOCl H Me Me H Me H t-Bu Me Me PBu3, ! Me N2 H H H H t-Bu 64% Me Se Me Me Cl3OCO HO H H Me Baran Group Meeting Derek H. R. Barton Will Gutekunst

Radical Revolution O Me Due to the strong UV absorption of xanthates, Barton reasoned that they may be photochemically Me susceptible and lead to bond fissions products. He was pretty much correct. Me N Me O COCl3 O ; Me Me 3 O H Acyl xanthates to form acyl radicals. O saponification H Me H S Me H 80% S OEt h! S OEt - CO H H S OEt H H HO O S Et2O O S Cl3OCO H 97% H J. Chem. Soc. 1961, 1967.

O Thiobenzoate Photolysis (Game-of-Bridge Reaction) Me Me Me N Me Me O Me Me Me Me Me O H O H BSA Me H Me H iodoxybenzene Me ambient light Me H H H H H 35-40% H 5 days H AcO H AcO H Me H H quant. Me H S H H H H Amines can also be oxidized (primary amines to nitriles, secondary amines to imines, hyroxylamines to Ph O nitroso, hydrazines to azo and amides to imides). Nitrogen containing heterocycles can also be oxidized. Tetrahedron 1985, 41,4727. S OH J. Chem. Soc. Perkin Trans. I 1990, 707. S Me h! Application to lysergol synthesis Ph Ph Me Ph Me Ph O DCM Ph HOH2C HOH2C NMe NMe 55% 10% H 0.5 eq. BSA H SePh 3 eq. indole J. Chem. Soc. Perkin Trans. I 1973, 1580. H THF, 40° C N In the mid 1970's, there was a need to replace the secondary hydroxyl groups in amino-glycoside H N 97% N antibiotics with a hydrogen. Since traditional methods were ineffective, Barton devised a plan to H H use radicals to deoxygenate the substrate inspired by the Game-of-Bridge reaction. lysergol Deoxygenation J. Chem. Soc. Perkin Trans. I 1975, 1574. Phenol Oxidations J. Chem. Soc. Chem. Comm. 1975, 301. O O OH Me H Bu3SnH Me H O O Me OH Toluene reflux Me Me Me Me O O Me O O NaH, BSA O OH Me Me S 80–90% O O 55% O Me H Me Me O MeS Me Me Me J. Chem. Soc. Chem. Comm. 1977, 147. J. Am. Chem. Soc. 1993, 115, 948. Selenobenzoates were also examined, but were too reactive and gave large amounts of the free alcohol. The tellurium analogs, on the other hand, behaved differently during preparation. O OH Ph Me Me NSePh NMe BSA, HMDS Se N Ph 2 N Se NMe2 Cl Ph NaHTe 65% Se N R OH RO Ph RO Ph Ph N Se Me Me Ph Baran Group Meeting Derek H. R. Barton Will Gutekunst

The deoxygenation method could also be extended to deamination using isonitrile and thioformates as substrates. J. Chem. Soc. Perkin Trans. I 1980, 2657. OAc OAc Instead of reduction, the formed alkyl radical can also react with a variety of coupling partners Bu3SnH S AcO O AcO O O O Br AcO > 81% AcO N BrCCl N 3 OAc OAc 110 C C °

This method is now a staple of organic synthesis and many modifications have been made. Olefins 98% can be made from 1,2 dixanthates and less toxic alternatives to tin have been demonstrated (hypophosphorous acid being especially cheap and benign). In the presence of oxygen hydroperoxides are formed, nitroolefins give nitrosulfides, allyl Radical Anion Deoxygenation J. Chem. Soc. Perkin Trans. I 1981, 1501. sulfides to allylated products, sulfur dioxide to thiosulfonates, white phosphorus to J. Chem. Soc. Perkin Trans. I 1981, 1510. phosphonic acids, diazirines, etc. See Reason and Imagination pages 597-696.

Me Me Me Me In a strange example, these radicals also react with arsenic, antimony and bismuth phenylsulfides. Upon exposure to air, these intermediate species immediately oxidize to the corresponding alcohols. Me Me H K, 18-crown-6 H H t-BuNH2/THF H Me Me H Me H (PhS)3Sb O S air, water OH 86% DCM Sb(SPh)2 S N H H H H O S 12 hr, 79% Et2N O H H

This method is particularly well suited to sugar synthesis. Simple bulky ester reduce in a similar manner, though are less efficient.

Radical Decarboxylation S CO NH NH 2 2 O 2 SPh O Me Me O N Me Me O N O adenine h! O H S H S t-BuSH CbzHN 62% CbzHN h! O O O toluene, 3hrs CO2Bn Me Me N Me Me H CO2Bn 45% Me Me O 85% H Me H Me NH2 O AcO AcO N NH2 H H NH N Me Me 2 H OAc OAc O O adenine N N CbzHN These ideas led to the deoxygenation of tertiary alcohols (these substrates were previously H2N inaccessible due to rapid Chugaev elimination) O O HO OH CO2Bn CO2H Me Me Me O Et CSH Me 3 sinefungin J. Chem. Soc. Perkin Trans. I 1991,981. O N benzene O O S 70% Baran Group Meeting Derek H. R. Barton Will Gutekunst

Sodium Hydrogen Telluride OH Ph Bi O 5 Ph Nucleophilic opening of epoxides and reduction of quaternary ammonium salts Me Me benzene Me Me Tetrahedron Lett. 1985, 26, 6197. 83% Me Me Me Me TsCl, py. Me 15 Enolates were also reactive, again under basic conditions C-arylation predominated. Free enols NaHTe OH 92% can be O-arylated under acidic or neutral conditions, but normal ketones are unreactive. O EtOH Me Me TeH Nitronates, ester enolates and sulfinates were also viable substrates for arylation under basic Ni B conditions. 15 15 2 OH J. Chem. Soc. Perkin Trans. I 1985, 2667. 78% Me Me O Ph Bi O 15 5 KH, 60° C Ph Ph NaHTe Ph Ph Me EtOH Me 93% Bn N Me OH Bn N Me 97% Me

Reactions with olefins 2.5 eq NaHTe Ph CO Et N N CO2Et EtOH 2 HO 2.5 eq. Ph3BiCO3 O DCM reflux 73% 92% MeO N 2.5 eq NaHTe MeO N EtOH Me 100% Ph Ph BiCO Ph K 3 3 Ph Me 2.5 eq NaHTe Ph Ph 44% Ph Ph Me EtOH no reaction Me Later it was found that copper catalyzed these reactions and now anilines and amines were viable substrates for N-arylation. Similar results were seen with aryl lead (IV) reagents as well.

3 eq NaHTe R1 EtOH Ni2B HO C R2 HO2C HO2C 2 Me 8 1.1 eq Ph Bi(TFA) 8 8 Me 3 2 Me R1 = H, R2 = Te-alkyl quant. 0.1 eq Cu Tetrahedron Lett. 1986, 27, 3619. NH2 NHPh R1 = Te-alkyl, R2 = H DCM Tetrahedron Lett. 1986, 27, 3615. Tetrahedron Lett. 1987, 28, 3111. 95% Tetrahedron Lett. 1996, 53, 4137. Organobismuth Chemistry Me Me Me Me Barton initally investigated bismuth chemistry to explore its potential as an oxidant (which it does well), but also discovered its exceptional ability to arylate a variety of substrates. Phenol Arylation These bismuth reagents also proved to be effective at cleaving alpha glycols, even trans-diols. Phenols can provide either O-or C- arylated products depending on the bismuth reagent and the pH of the reaction. 0.1 eq Ph3Bi 0.1 eq Ph3Bi Ph OH NBS O NBS OH Ph BiOCOCF Ph BiOCOCF 4 3 OH 4 3 OH MeCN/H2O MeCN/H2O OPh cat. Cl3COOH BTMG OH 2.5 hr, 72% 3.7 hr, 77% 91% 94% O OH J. Chem. Soc. Perkin Trans. I 1985, 2657. Baran Group Meeting Derek H. R. Barton Will Gutekunst

Miscellaneous Chemistry A Tropone Synthesis Tetrahedron 1987, 43, 5031. Sterically Hindered Guanidine Bases; Barton's Base

A number of bulky guanidine bases were prepared from the corresponding ureas or thioureas. OH CHCl3 O O Bu SnH This resulted in the strongest organic bases known at the time and Barton employed them PTC Me 3 Me Me frequently in his chemistry. Me Me aq NaOH Me AIBN, PhH J. Chem. Soc. Perkin Trans. I 1982, 2085. CHCl2 X 80° C, quant. Cl NR 59% COCl2 Cl RNH2 R N NR Me Me Me 2 2 R2HN NR2 R2N NR2 X = O,S Ergosterol Isomerization with Chromium Synthesis 1979, 4, 265. Nt-Bu Nt-Bu N R R Me N NMe Me Me 2 2 (i-Pr)2N N(i-Pr)2 N Cr(CO)6 Barton's Base (BTMG) Me octane Me pKa = 14 DBN pKa = 13.5 H H 81% H AcO AcO H Synthesis of Vinyl Iodides from Hydrazones Tetrahedron 1988, 44, 147. R Me Me R

Me Cr(CO) 2.5 eq I2 NNH2 SePh 6 Me NNH2 I octane Me 3.5 eq BTMG 10 eq PhSeBr THF Me H 6 eq BTMG 78% Me Me AcO AcO 88% THF H H 88% Interestingly, Fe(CO)5 performs the reverse process. Also vinyl selenides!

Rhenium Catalyzed Silylation Tetrahedron Lett. 1992, 33, 5041. Synthesis of a Stable Dithiet J. Chem. Soc. Perkin Trans. I 1977, 515. Ph H 1.5 mol% Re2(CO)10 Si OSiH Ph O OH 4 eq. PhSiH3 Me 2 O Me R Me Me R Me Me H Me Me Me quant. Me Me Me H Me Me 86-88% 12-14% hν Me Me S heptane S AcO AcO H S H S Me Me Me Me

R R Me Me Me R

POCl3 py. hν Me Me S Me AcO AcO S H S AcO S Me Me Me Me S Me Me S Baran Group Meeting Derek H. R. Barton Will Gutekunst

p-Dimethylamino-N-thiosulphinylaniline J. Chem. Soc. Perkin Trans. I 1974,1245. Another Side Chain Degradation Tetrahedron 1989, 45, 3741.

S P4S10 O DCM S Me O N OH Me O Me N N Me2N N 3 eq. SOCl2 Me 2 S OMe O rt S H py.; CSA; Ac2O OMe H SO crystalline purple compound MeOH H O

Me2N Me O cat. Cu(OAc)2-bipy Trifluoronitrosomethane J. Chem. Soc. Perkin Trans. I 1974, 2344. H DABCO, O2, DMF 75-80% from acid ONO h ! F3C CF3 N N Barton-Zard Pyrrole Synthesis Tetrahedron 1989, 46, 7587. F CNO 3 AdO OAd

R R R1 2 R O 1 base + R R2 C N N O2N O H another pyrrole synthesis

R R R2 R3 R 2 3 PhSSPh R2 3 Bu3P R1 R4 R1 R4 F C CF "wet" MeOH R1 3 3 HS CO H N R4 2 F3C NOAd O NO2 O NH N N DIPEA NaOMe H NH AdO NH AdO OAd 2 " AdO F F

Things I did not cover: Enolate Anions as Protecting Groups for Ketones J. Chem. Soc. Perkin Trans. I 1977, 1075. - hundreds and hundreds of papers - Penicillin research Me O Me - Gif chemistry (see alkane hydroxylation group meeting) Me O O Me 2 eq Ph3CLi, rt; HO Me H LAH, -78° C Me H "...I found my true role in chemistry as an inventor of chemical reactions. Although, like an artist, I seek elegance and personal satisfaction, I am still pleased when I do something useful. I realize H H 50% H H that there is a direct relationship between the utility of chemistry and how much academic research O can be funded. It is strange that the same restrictions do not seem to apply for physics or O molecular biology." Gap Jumping, page 109 11-oxo-progesterone

Barton also mentions the potential use of this method in Grignard additions, Wittig reactions, etc.