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The Life and Achievements of Woodward

Long Literature Seminar July 13, 2009 Erika A. Crane “The structure known, but not yet accessible by synthesis, is to the what the unclimbed mountain, the uncharted sea, the untilled field, the unreached planet, are to other men. The achievement of the objective in itself cannot but thrill all , who even before they know the details of the journey can apprehend from their own experience the joys and elations, the disappointments and false hopes, the obstacles overcome, the frustrations subdued, which they experienced who traversed a road to the goal. The unique challenge which provides for the creative imagination and the skilled hand ensures that it will endure as long as men write books, paint pictures, and fashion things which are beautiful, or practical, or both.”

“Art and in the Synthesis of Organic Compounds: Retrospect and Prospect,” in Pointers and Pathways in Research (Bombay:CIBA of India, 1963).

• Graduated from MIT with his Ph.D. in at the age of 20 Woodward taught by example and captivated • A tenured at Harvard by the age of 29 the young... “Woodward largely taught principles and values. He showed us by • Published 196 papers before his death at age example and precept that if anything is worth 62 doing, it should be done intelligently, intensely • Received 24 honorary degrees and passionately.”

• Received 26 medals & awards including the -Daniel Kemp National Medal of Science in 1964, the in 1965, and he was one of the first recipients of the Arthur C. Cope Award in 1973 RBW: The Early Years

• Robert Burns Woodward was born to Arthur and Margaret Woodward in , on April 10, 1917

• In 1918, Robertʼs father, Arthur, died in the great influenza pandemic

• Robertʼs mother, Margaret, remarried but was soon abandoned to raise Robert on her own

Courtesy of Archives RBW: The Early Years

• Robert grew up and was educated in Quincy, Massachusetts

• When Robert was 8 years old in 1925, he received his first chemistry set

• By the age of 12 in 1929, Robert had completed all of the experiments in Ludwig Gattermannʼs Practical Methods of (1894)

Courtesy of Harvard University Archives

“I fell in love with the field [of ] when I was a small boy and the affair is still going on.” -RBW

“Opening Remarks,” in Organic Synthesis (Robert A. Welch Foundation Conference on Chemical Research, 12, 1969). Bridging into Academia: RBW at MIT

• Woodward enrolled at MIT in 1933, at the age of 16

• After his freshman year, he was given his own laboratory

• At the end of the first semester of his sophomore year, Robert was advised to withdrawal from college due to his neglect of his classes

Courtesy of MIT Museum Bridging into Academia: RBW at MIT

• Robert spent a semester as an employee of the MIT biology department

• He was permitted to re-enroll in school through the good offices of James F. Norris

• RBW earned a B.S. and a PhD from MIT in only four years, graduating in 1937 at the age of 20

James F. Norris, professor of organic chemistry at MIT and president of the American Chemical Society (1925-1926)

Courtesy of MIT Museum Bridging into Academia: RBW at MIT

“We saw we had a person who possessed a very unusual mind in our midst. We wanted to let it function at its best. If red tape which was necessary for other less brilliant students had to go, we cut it. We did for Woodward what we have done for no other student in the department. And we think he will make a name for himself in the scientific world.” -James F. Norris

From the interview of James F. Norris at RBWʼs graduation by the Boston Globe 8 June 1937 James F. Norris, professor of organic chemistry at MIT and president of the American Chemical Society (1925-1926)

Courtesy of MIT Museum Love & Marriage

• In 1937, Robert married a high school classmate, Irja Pullman

• They had two children in their 10 years together: Siiri Anne and Jean Kirsten

Courtesy of Harvard University Archives A Summer at the University of

Courtesy of C&EN News

Professor Carl “Speed” Marvel University of Illinois (1915-1961)

Courtesy of the University of Illinois

• RBW spent the summer of 1937 teaching of University of Illinois Professor , Chemistry Department Chair, • He “managed through his intelligence and impatience to alienate University of Illinois (1926-1957) several of the leading figures of organic chemistry in the ”.

• , a colleague and friend, said he believed “that Bob failed to conceal adequately that he was much brighter than the Illinois .” Moving to Harvard

Courtesy of the National Academy of

• In fall of 1937 through 1938, Robert worked as an Research Assistant to Elmer P. Kohler

• In 1938, RBW was appointed as a Junior in the Society of until 1940

• In 1941, Robert was made an official instructor of chemistry

Professor Elmer P. Kohler, Harvard (1912-1938)

“That marvelous institution was founded, at Harvard, by A. Lawrence Lowell, whose conviction it was that scholars should be gentleman, entirely free to follow their intellectual interests...One could read, learn, cogitate–even work, if one felt the urge–and plan the future, however unconsciously.” -RBW

Address on receiving the American Chemical Societyʼs Arthur C. Cope Award in Organic Chemistry, 28 August 1973. Woodwardʼs Inspiration

“From the first awakening of • Woodward was particularly drawn to the work of my interest in Friedrich August Kekule and chemistry, I Archibald Scott Cooper have found its history absorbing, and have been particularly entranced by Friedrich August Kekule the concept of bonding in the most general sense.” -RBW

Address on receiving the American Chemical Societyʼs Arthur C. Cope Award in Organic Chemistry, 28 August 1973.

Archibald Scott Cooper Woodwardʼs Inspiration

Friedrich August Kekule

Kekule structures Woodwardʼs Inspiration

O OH C C O OH O2 O2 H C H O OH – H2O C O2 O OH C H C H O2 2 C O O OH C O OH tartaric acid

Archibald Scott Cooper Woodwardʼs Inspiration

• In 1927, at the age of 10, RBW proposed his own structure of

• He later realized that this was simply a 2D representation of the prism structure proposed by Albert Ladenburg 50 years prior

• However it was Kekuleʼs structures that inspired Woodward to propose that benzene could be made by adding a olefin to a diene

In the Nr. 1 issue of Liebigʼs Annalen for 1928 was “Synthesen in der hydroaromatischen Reine” by and The Woodward Rules (1941-1942)

• The Woodward Rules (also known as the Woodward- O Fieser rules) were proposed in 4 papers in 1941-1942 α • In his first paper, he founds that generalizations could R be made between spectra if the absorption effects of different solvents was accounted for β β • He also found that the extent of substitution at the α and β positions of a α,β-unsaturated could be determined from the UV spectra absorbs in the 230-250 mμ region

Woodward, R. B. Structure and absorption of α,β-unsaturated , J. Am. Chem. Soc. 1941, 63, 495-498. The Woodward Rules (1941-1942)

O • The first article was based solely on the experimental work of others, citing more than forty papers α R • In particular, the work by Heinz Dannenburg was pertinent to Woodwardʼs evaluation β β • His rules concentrated on numerical analysis and built support for these rules with many examples absorbs in the 230-250 mμ region

Woodward, R. B. Structure and absorption of α,β-unsaturated ketones, J. Am. Chem. Soc. 1941, 63, 495-498. The Woodward Rules (1941-1942)

O α • The last three papers adapted the rules to α,β- unsaturated ketones and conjugated dienes within and external to ring structures β

Woodward, R. B.; Clifford, A. F. Structure and absorption spectra. II. 3-acetoxy-Δ5-(6)-norcholestene-7-, J. Am. Chem. Soc. 1941, 63, 2727-2729. Woodward, R. B. Structure and absorption spectra. III. Normal conjugated dienes. J. Am. Chem. Soc. 1942, 64, 72-75. Woodward, R. B. Structure and absorption spectra. IV. Further observation of α,β-unsaturated ketones, J. Am. Chem. Soc. 1942, 64, 76-77. The Woodward Rules (1941-1942)

Me C8H17

Me

• Woodward provided evidence against the then- accepted structure of 3-acetoxy-6-keto-7-hydroxy-Δ4- OR chloestene O • The compound had a λmax of 230 mμ when it should be at 239 ± 5 mμ with a small intensity band at 300 mμ too R = H or COC6H5

5 • Proposed the structure of 3-acetoxy-Δ -(6)- Me norcholestene-7-carboxylic instead Me C8H17

CO2H

Woodward, R. B.; Clifford, A. F. Structure and absorption spectra. II. 3-acetoxy-Δ5-(6)-norcholestene-7-carboxylic acid, J. Am. Chem. Soc. 1941, 63, 2727-2729. The Woodward Rules (1941-1942)

• In 1949, the rules were extended by Louis and Mary Fieser • UV was later superseded by newer structure determination techniques such as nuclear magnetic spectroscopy, spectroscopy and X-ray

• The use of physicochemical measurements in structural organic chemistry was a major landmark

O O α α R

β β β

The elucidation of these rules demonstrated RBWʼs remarkable power of analysis and his passion for scientific order Synthesis of 1943-1944

H H HO N MeO

Quinine N

• Quinine was discovered by the Quechua Indians of Peru in the 17th century in the bark of trees

• Jesuits recognized itʼs ability to treat and sent it back to Europe

• The cinchona bark was ground up in put in sweetened water to offset the bitter taste–known as tonic water today

A cinchona tree Synthesis of Quinine 1943-1944

H H HO N MeO

Quinine N

• Natural sources were being exhausted by the nineteenth century

• In William Henry Perkinʼs attempts to synthesize it in 1856, he made the first synthetic dye, mauveine

• Quinine became the “Holy Grail” of organic chemistry

William Henry Perkin Synthesis of Quinine 1943-1944

• During World War II in March of 1942, the Japanese invaded Java and cut off the major supply of quinine, the most effective antimalarial agent at the time

• Edwin Land of the hired Woodward to find a light polarizer replacement for quinine

• Land agreed to finance Woodward and a new Harvard Ph.D., William Doering, in the synthesis of quinine Edwin Herbert Land, owner of the Polaroid Corporation Woodward, R. B.; Doering, W. E. The of quinine. J. Am. Chem. Soc. 1944, 66, 849. Synthesis of Quinine 1943-1944

H H H HO Rabe and Kindler N 1918 O HN MeO MeO

N N quinine quinotoxine Kenner, Prelog and Zalan OH N

7-hydroxyisoquinoline

O OEt

MeO Prelog and Prostenik

N

ethyl quininate

O H O H

H EtO N HO H N H COC6H5

N-benzoylhomomeroquinene homomeroquinene ethyl

Woodwardʼs genius lied in his ability to see what others had not seen already in the known. Woodward, R. B.; Doering, W. E. The total synthesis of quinine. J. Am. Chem. Soc. 1944, 66, 849. Synthesis of Quinine 1943-1944

N 80% H SO OH N 2 4 N EtO OH benzene OEt Δ OH 7-hydroxyisoquinoline 5-hydroxyisoquinoline 60% yeild 5% yield work by Fritsch

CH2O, 62% yeild , MeOH inital attempts to induce reductive cleavage of the piperidino group failed

Me N NaOMe, MeOH OH N OH N 220 ºC 64% yield these conditions are essential in AcOH, Adamʼs order to obtain desired selectivity H2, Pt catalyst without loss of

Me Me Me H , Raney Ni Ac O, MeOH Ac OH 2 Ac OH 2 OH N N HN EtOH, 150 ºC, 95% yield 3000 psi over 2 steps mixture of cis and 50 % yield trans Woodward, R. B.; Doering, W. E. The total synthesis of quinine. J. Am. Chem. Soc. 1944, 66, 849. Synthesis of Quinine 1943-1944

H H H O Me Me Me H2CrO4, AcOH Ac OH OH H N H N H Ac N H 70% yield Ac

EtONO, cis configuration essential for the desired 68% yield NaOEt, cis-3,4-disubstitution of the piperdine ring EtOH

I– H H H N(Me) AcOH, 3 NH2 NOH O excess MeI O H2, Pt O H Me H Me H Me N OEt N * OEt N OEt Ac K2CO2, EtOH Ac Ac 90% yield mixture of isomers Hoffmann 60% K/NaOH elimination NEt3, 140 ºC

H H O H O O KCN, H2O H HO H HO H N N N OH H 42% yield H NH2 over 5 steps O homomeroquinene Woodward, R. B.; Doering, W. E. The total synthesis of quinine. J. Am. Chem. Soc. 1944, 66, 849. Synthesis of Quinine 1943-1944

O H H O O H 1. 0.1 N aq. HCl, Δ 1. HCl, EtOH EtO H N HO H N H HO N COC H H 6 5 NH2 2. benzoyl chloride, O 2. Ag2O then H2S K2CO3 N-benzoylhomomeroquinene 96% yield ethyl ester over 4 steps

O OEt

dry NaOEt MeO resolved as H H Δ dibenzoyl-d-tartrate N COC H 6 N HCl 6 5 O HN O N ethyl quininate

CO2Et MeO 50% yield MeO over 2 steps Claisen N N condensation quinotoxine

Rabe and Kindler 1918

H H HO N MeO

N quinine Synthesis of Quinine 1943-1944

H H H HO Rabe and Kindler N 1918 O HN MeO MeO

N N quinine quinotoxine

• Woodward worked with William von E. Doering for fourteen months on the and isolated 30 mg of d-quinotoxine

• However, they were not able to successfully convert quinotoxine to quinine leading to the Stork/Woodward controversy

Doering and Woodward in 1944, shortly after the quinotoxine synthesis Courtesy of Harvard University Archives Woodward, R. B.; Doering, W. E. The total synthesis of quinine. J. Am. Chem. Soc. 1944, 66, 849. Synthesis of Quinine 1943-1944

• This synthesis was hailed by the Times and featured in Life Magazine

• In this cartoon from the Oregon Journal, synthetic chemistry is displayed as Americaʼs hero in the loss of supplies of oil, rubber and quinine

• However, this route was not commercially viable • $3,000 per pound as opposed to $16 per pound for natural quinine

Courtesy of the Library of Congress Moving Up

• RBW was promoted to Assistant Professor at Harvard in 1944, at the age of 27 • In 1945, Woodward received the John Scott Medal of the along with Doering for the total synthesis of quinine

• In 1946, Robert was promoted again to Associate Professor at Harvard

The John Scott Medal

Fox, R. The John Scott Medal. Proceedings of the American Philosophical Society 1968, 112, 416-430. Love & Marriage

• In 1946, RBW divorced Irja Pullman and married Eudoxia Muller, an artist and technician whom he met at the Polaroid Corporation

• They had two children together: Crystal Elizabeth and Eric Richard Arthur

(1948) Eudoxia with Crystal and the children from RBWʼs first marriage, Jean and Siiri

Courtesy of Eudoxia Woodward Structure elucidation (1945-1956)

O H N O Me S Me • Starting in 1945, Woodward focused a lot on S Me R Me O structure elucidation N O R N N CO H CO H H 2 • He proposed structures for , patulin, 2 , (terramycin), penicillin proposed oxazolone carbomycin (magnamycin), santonic acid, structure of penicllin calycanthine, and aureomycin. O O O OH OH OH OH O O OH OH OH H N N 2 H2N HO H H OH O H N OH Me H H OH Me Me OH N OH Me Cl N Me Me H O Me oxytetracycline O aureomycin O H O Me strychnine O O patulin O O O Me Me N Me O H Me OH N N Me santonic acid N HO O OH O O Me Me MeO HN O O Me O O Me Me O OAc Me O calycanthine Me carbomycin Synthesis (1951)

Me Me Me

Me H Me

H H HO • The chemistry of become a “hot” area in organic chemistry in the 1940s and early 1950s because of their potential therapeutic value OH • Cholesterol was first isolated in 1769 by French O physicist/chemist François Poulletier de la Salle Me O OH from gallstones Me H • was isolated in 1930ʼs by a group of by Tadeua Reichstein (Zurich), H H Edward, C. Kendall (Mayo Clinic, MN), and Oskar O Wintersteiner () from the cortisone adrenal glands of cattle Steroid Synthesis (1951)

Me O

• Woodwardʼs interest in steroidʼs stemmed from his H desire to construct them utilizing a Diels-Alder reaction H H • He unsuccessful in his attempts to make HO using a Diels-Alder reaction in his PhD research in estrone 1947 Woodward, R. B.; Sondheimer, F.; Taub, D. The total synthesis of a steroid. J. Am. Chem. Soc. 1951, 73, 3548.

Steroid Synthesis (1951) Me Me Me

Me H Me

• Woodward chose a H H “relay” approach to the cholesterol HO synthesis of the steroids OH by first making the etiocholatrienate O Me intermediate, which O OH contained the core Me H structure and could be further functionalized H H MeO cortisone O O Me Me O Me H Me

H Me H O H H methyl dl-3-keto-Δ4,9(11),16-etiocholatrienate O

Me OH

Me H

H H O Woodward, R. B.; Sondheimer, F.; Taub, D. The total synthesis of a steroid. J. Am. Chem. Soc. 1951, 73, 3548. Steroid Synthesis (1951)

The B ring was added by a Robinson MeO O C Me Rings C and D were assembled Me H D by a Diels-Alder reaction The A ring was appended on by a H Michael addition of acrylonitrile A B O

methyl dl-3-keto-Δ4,9(11),16-etiocholatrienate O O O Me Me Me + benzene NaH then H

MeO MeO 40% yield MeO H over 2 steps H O O O

LiAlH4

OH Me Me Me Ac2O, Zn mineral acid xylenes, Δ O O H MeO O H 45% yield OH H over 3 steps OH H OEt Me O Me Me

O H O O cat. tBuOK, BuOH O H H Me H O O HO KOH, Me dioxane, 50% yield H over 3 steps Me H O Woodward, R. B.; Sondheimer, F.; Taub, D. The total synthesis of a steroid. J. Am. Chem. Soc. 1951, 73, 3548. prepared previously by Steroid Synthesis (1951) Orchin and Butz in O O O 1943 Me Me Me + benzene NaH then H C MeO MeO 40% yield MeO H over 2 steps H O Diels-Alder O O

LiAlH4

OH Me Me Me Ac2O, Zn mineral acid

xylenes, Δ O O H MeO O H 45% yield OH H over 3 steps OH H OEt Me O base Me Me

O H O O cat. tBuOK, BuOH O H H Me H O O HO Michael addition KOH, dioxane, the more thermodynamically Me 50% yield stable product H over 3 steps Me H cyclization & B deformylation O Woodward, R. B.; Sondheimer, F.; Taub, D. The total synthesis of a steroid. J. Am. Chem. Soc. 1951, 73, 3548.

stable Steroid Synthesis (1951) carried on Need to protect olefin Me Me Me for formation of A ring OH O Me H OsO4 H H Me Me Me Me OH O H H CuSO4 (anhydrous) H O O O two isomers 1 H2, Pd/SrCO3, Me benzene O Me Me H Me O Me Me 1. ethyl formate, O Me 1. base O base Me Me H H Me H Me Me O O O H 2. tBuOH/benzene/H2O, 2. PhNHMe, H HO2C MeOH Triton B, CN Me O N O Ac O, cyanoethylation protect the most 2 Ph AcOH, Δ base-sensitive center intramolecular Me Me Me O O Me Me CHO Me H 1. MeMgBr Me H HIO4 Me H Me Me CHO O O H 2. base A H dioxane/H2O H O O O O mixture of isomers MeO H piperdine O O acetate, Me Me Δ, benzene, 65% yield Me H 1. Na2Cr2O7, AcOH Me H D Dieckmann-like H 2. CH N H 2 2 condensation O O methyl dl-3-keto-Δ4,9(11),16-etiocholatrienate Woodward, R. B.; Sondheimer, F.; Taub, D. The total synthesis of a steroid. J. Am. Chem. Soc. 1951, 73, 3548. Steroid Synthesis (1951) MeO O MeO HO Me O O Me Me

Me H 1. H2, reduced Pt 1. NaBH4 Me H Me H

H 2. H2CrO4, AcOH 2. H H O 3. Ac2O, pyr O AcO H H methyl dl-3-keto-Δ4,9(11),16-etiocholatrienate 1. SOCl2 2. MeCd

to effect dehydration at C20 OH BrMg Me and acetylate at C3 Me O Me Me Me 1. Ac2O, AcOH, Δ Me Me Me H Me H Me 2. H2, PtO2 H H H HO AcO H H

Me Me Me Me Me hydrolysis Me Me H Me Me H Me routes from cholestanol, to

H H H H cholestanol cholesterol already described AcO HO H H Me Me Me

Me H Me

H H cholesterol HO Woodward, R. B.; Sondheimer, F.; Taub, D. The total synthesis of a steroid. J. Am. Chem. Soc. 1951, 73, 3548. Steroid Synthesis (1951) MeO MeO MeO O O O alpha isomer Me Me Me O perbenzoic acid 1. NaOMe, NaOH Me H Me O Me H 2. Na Cr O H H 2 2 7 O H 3. CrO3–H2O AcO AcO HO H H H Heymann & Feiser dry HBr

MeO MeO MeO O O Br O Me Me dehalogenation Me O O O 1. NaBH4, EtOH 1. NaI, acetone Me H Me H Me H 2. Ac O, pyr H H 2 H H 2. KOAc, Δ H H AcO O O H H H installing Lardon & Reichstein 1. KOH 4. KOH the α- 2. SOCl 5. Ac O hydroxy 2 2 3. CH2N2 6. CrO3 ketone at C19 oxidize the OAc OAc cyanohydrin OH O intermediate O Me Me O O 1. KCN, AcOH O OH Me 1. Br2 O OH Me H Me H Me H 2. OsO4, pyr 2. H H then Na2SO3 H H 3. hydrolysis H H O Sarett O cortisone H H O Moving Up

• RBW was promoted to Full Professor at Harvard in 1951, at the age of 34

(1951) Woodward and Sir Robert Robinson of MIT; two chemists who were often in competition

Courtesy of John D. Roberts Kealy, T. and Paulson, P. A New Type of Organo- Compound. . 1951, 168, 1039. Structure Elucidation of (1951)

• Peter Pauson and his student, Tom Kealy, of Duquesne University in Pittsburgh were trying to make fulvalene by MgBr FeCl3 adding ferric chloride to cyclopentadienyl bromide

• On August 7, 1951, they reported the new organometallic compound in Nature

• On January 30, 1952 both and Robert Woodward read the Nature article and Fe determined that the proposed structure was incorrect

• Woodward and Wilkinson agreed to work together on the project Woodward, R. B.; Wilkinson, G.; Rosenblum, M.; Whiting, M. C. The structure of iron biscyclopentadienyl. J. Am. Chem. Soc. 1951, 74, 2125-2126. Structure Elucidation of Ferrocene (1951)

Fe vs. Fe

• They argued that the proposed structure was likely incorrect because its isolation stood “in striking contrast to the failure of previous investigators”

Fe Fe • Obtained UV spectra and proved the compounds dimagnetism and lack of a moment

• Determined later that summer by Fischer that the structure was antiprismatic prismatic antiprismatic

The discovery of ferrocene initiated a revolution in organotransition metal chemistry Moving Up

Woodward and his son, Eric, at home in Belmont

Courtesy of Rolf Huisgen

• RBW was promoted to Morris Loeb Professor at Harvard in 1953, at the age of 36 • That year he was also elected into the National Academy of Science Synthesis of Strychnine (1954)

N VI 50 mg is lethal for V • Strychnine was first isolated in 1818 by Pierre- an adult human! Joseph Pelletier and Joseph Bienaimé Caventou I IV II H In 1838, Victor Regnaut determined its molecular N VII • H formula of C21H22N2O2 O H O III • 1898: Julius Tafel proposed the left-hand side of strychnine the molecule as an aromatic ring attached to a N • 1910-1932: William H. Perkin and Robert Robinson published a series of papers about the south face of the molecule, including correctly identifying it as an derivative

• 1932: Robinson and a competitor, Hermann Leuchs, mapped out the structure of the lower two rings

• The structure of ring V remained in debate however

• 1945: proved that ring VI was a 6- Seeds of the Strychnoe nux vomica tree membered ring Woodward, R. B.; Brehm, W. J.; Nelson, A. L. The structure of strychnine. J. Am. Chem. Soc. 1947, 69, 2250. Woodward, R. B.; Brehm, W. J. The structure of strychnine. Formulation of the neo bases. J. Am. Chem. Soc. 1948, 70, 2107-2115. Synthesis of Strychnine (1954)

N VI V I IV II H N H VII O H O III • 1948: Using Prelogʼs conclusion, Woodward strychnine proved that ring V was a five-membered ring, contrary to what Robinson thought

• Made biogenetic arguments and based rationale on his own experiments

• J. B. Hendrickson once called Strychnine the “Mount Everest of structural organic chemistry”

• In 1952, Robert Robinson claimed, “For its molecular size it is the most complex substance known”

Seeds of the Strychnoe nux vomica tree Woodward, R. B.; Cava, M. P.; Ollis, W.D.; Hunger, A.; Daniker, H. U. The total synthesis of strychnine. J. Am. Chem. Soc. 1954, 76, 4749-4751. Synthesis of Strychnine (1954)

N VI V N H O I IV H II H H N H N VII H H O O O III H 24 strychnine 7 rings 6 contiguous chiral centers

OMe open ring with O3 N to form ring III H 2-veratrylindole OMe

blocking the α position for form ring V Woodward, R. B.; Cava, M. P.; Ollis, W.D.; Hunger, A.; Daniker, H. U. The total synthesis of strychnine. J. Am. Chem. Soc. 1954, 76, 4749-4751. Synthesis of Strychnine (1954) I– NH 1. CH O, HNMe , 2 I 2 2 NMe3 OMe aq. dioxane, AcOH 1. NaCN, DMF II OMe OMe N H 2. MeI N 2. LiAlH4, THF, N OMe H H OMe Δ OMe

O H the two other aromatic rings O Me should be deficient unknown O benzene enough to inert to oxidation at formed center V N Ts N Ts N CO Et TsCl 2 OMe 1. NaBH4, EtOH CO Et CO Et 2 OMe 2 OMe N 2. Ac2O, pyr N pyridine N OMe H OMe OMe O Me only one isomer obtained 1. O3, aq. AcOH 2. HCl, MeOH, Δ 5-membered lactam will not form due to E geometry of enoate

N Ts N Ts

CO2Et CO2Et CO2Me N-phenylpyridone N -MeOH N CO2Me H III confirmed by UV and IR MeO C 2 O isomerization from α,β−unstaturated ester to a β,γ−unsaturated ester already established Woodward, R. B.; Cava, M. P.; Ollis, W.D.; Hunger, A.; Daniker, H. U. The total synthesis of strychnine. J. Am. Chem. Soc. 1954, 76, 4749-4751. Synthesis of Strychnine (1954)

O Dieckmann condensation N Ts NH 1. NaOMe, MeOH N Me OH CO2Et HI, Δ CO H 2. Ac O, pyr 2 2 IV N CO2Me N CO2H CO2Me red 3. NaOMe, MeOH, N phosphorus Δ O confirmed O O multiple acidic structure by UV werenʼt expecting the product sites present could 1. TsCl, pyr pose a problem in enol form, but were able to 2. NaSCH2C6H7 compound isolated in utilize it in the synthesis degredation studies addition- O O O elimination Ac O, pyr, N 1. Raney Ni, N Me 2 N Me Δ Me EtOH, Δ S O CO2H N 2. Pd/C, H CO2Me N –CO2 2 N Me 3. hydrolysis O O O cis ester obtained as major Dakin & West 1. aq. HCl, AcOH 2. SeO , EtOH product but easily converted 1928 2 into the more stable trans ester

O N VI

O N goes through a glyoxal intermediate O Woodward, R. B.; Cava, M. P.; Ollis, W.D.; Hunger, A.; Daniker, H. U. The total synthesis of strychnine. J. Am. Chem. Soc. 1954, 76, 4749-4751. Synthesis of Strychnine (1954)

iBu O O O N N N H Al LiAlH , EtOH, iBu 1. N a C C H , THF OH 4 H O N N 2. Lindlar's, H2 N Δ OAlR2 O O need to reduce the pyridone ring on the concave side the is without touching the carbonyl delivered strychnine intramolecularly N Prelog 1948 N N

OH H KOH, EtOH 1. HBr, AcOH

N N N H VII 2. aq. H2SO4, O Δ O H O OH O isostrychnine isomerization of the tertiary allylic carbinol with mild acid failed N H O H H N H

O H obtained 8 mg!

Courtesy of Harvard University Archives University Harvard of Courtesy

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10tSI UE

- I SzvlrNJH av0u. Hst0NlAvS 8I S't-10 0t/lV0 ri 80 Synthesis of Strychnine (1954) Strychnine of Synthesis Synthesis of (1956)

• Extract from Indian snake root, or Rauwolfia serpentina, had been used by traditional A doctors to treat insect or reptile bites MeO C N B H N D O OMe 1930s: Scientists discovered it could be used H H • E to treat hypertension, nervous disorders or H O OMe even schitzophrenia MeO2C OMe OMe • 1952: Emil Schlittler isolated reserpine at CIBA in and coined the name reserpine

• By 1955 the structure was fully elucidated

A Rauwolfia serpentina plant Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R. W. The total synthesis of reserpine. J. Am. Chem. Soc. 1956, 78, 2023-2025. Synthesis of Reserpine (1956) O OMe O

MeO N OMe OMe H N O OMe H OMe MeO C N N H H H H N MeO2C H H H O reserpine OMe H NH H OAc MeO2C OMe OMe MeO2C OMe aimed to get the most chiral centers into the molecule as early as possible OMe

6-methoxytryptamine

MeO A NH2 N H OHC H MeO B O RO C N D 2 H N H OAc E OAc H H MeO2C OMe MeO2C OMe

benzoquinone O Diels-Alder

O

MeO2C methyl vinylacrylate Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R. W. The total synthesis of reserpine. J. Am. Chem. Soc. 1956, 78, 2023-2025. Synthesis of Reserpine (1956) Meerwein-Pondorf reduction O Diels-Alder OH O O Al(i-OPr)4, H benzene H IPrOH O O O CO2Me O H Δ H E MeO C MeO C 2 2 O

endo transtition state 3 chiral centers set! Br2

Br E1cb mechanism O HO H H O NaOMe, O H OH2 aq. NBS MeOH O O O O O O H H H H2SO4, 70 ºC H H H H Br δ+ O OMe O Br O OMe bromonium formation on H2CrO7, AcOH bottom face formation of the 6-membered confirmed a quasi-axial conformation of the Diels-Alder cycloadduct Br H O H O H H H O H HO2C CO2H O Zn, AcOH O OH H O H H OH H H H HO2C OH quasi-equatorial quasi-axial OMe O OMe Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R. W. The total synthesis of reserpine. J. Am. Chem. Soc. 1956, 78, 2023-2025. Synthesis of Reserpine (1956)

OH O lose ! H O O OH H 1. CH2N2 H 2. Ac2O, pyr H 1. aq. HIO4 MeO2C H H H 3. OsO4, then 2. CH N , CH Cl HO2C OH 2 2 2 2 MeO2C OH NaClO3 MeO2C OH OMe OMe OMe reductive prepared in 1930 by MeO NH2 1. benzene Akabori and Saito 2. NaBH4, MeOH N H

OMe OAc N MeO A H POCl3 B O OMe N D H OAc N H NH H

MeO2C MeO2C OMe H

NaBH4, MeOH

MeO C N H need to invert newly N H H formed ! H OAc

MeO2C OMe Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R. W. The total synthesis of reserpine. J. Am. Chem. Soc. 1956, 78, 2023-2025. Synthesis of Reserpine (1956)

most stable conformation–canʼt isomerize center with acid very strained intermediate OMe OMe OAc N MeO O H 1. KOH, MeOH N OMe H OMe H N O H N NH H H OAc 2. DCC, pyr NH MeO2C MeO2C H OMe H H H

, isomerization driven by strain relief xylene, Δ O OMe O O O OMe OMe N H OMe H N H OMe 1. methanolysis H H MeO C NH 2 2. pyr, OMe H NH OMe reserpine

Cl OMe OMe OMe Synthesis of Reserpine (1956)

MeO N H N O OMe H H

H O OMe

MeO2C OMe OMe reserpine • This synthesis was Woodwardʼs favorite and is arguably one of the best of Woodwardʼs array of landmark syntheses

• 1958: the French company, Roussel-Uclaf took Woodwardʼs synthetic route to industrial scale

It was the first time was maintained throughout a long synthetic sequence in such a particularly elegant manner Synthesis of (1960) “Man cannot give a true reason for the grass under his feet, why it should be green rather than red or any other color.”

-Sir Walter Raleigh

• Chlorophyll was first isolated in 1818 by Pierre-Joseph Pelletier and Joseph Bienaimé Caventou

• 1905-1914: Richard Willstätter demonstrated that magnesium Me was contained in chlorophyll, he purified chlorophyllʼs a and b, and isolated the phytyl side chain Me I II Et N N • He won the Nobel Prize in 1915 for this work Mg 1930s: performed chemical studies and later N N • proposed a structure in 1936 Me IV III Me chlorophyll-a • He won the Nobel Prize in 1930 for synthesizing MeO C O 2 Me O • 1950s: R. P. Linstead also performed chemical studies and O Me proposed the structure that later RBW was skeptical of but Me accepted and turned out to be correct Me

Me Synthesis of Chlorophyll (1960)

R R

N R R NH HN R R Me N

Me I II Et N N R R Mg porphyrin ring N N Me IV III Me chlorophyll-a

MeO C O 2 Me O Chlorophyll contained an extra ring O Me • Me fused to ring III Me • It also possessed two “extra” Me in ring IV Woodward, R. B.; Ayer, W. A.; Beaton, J. M.; Bickelhaupt, F.; Bonnett, R.; Buchschacher, G. L.; Closs, G. L.; Dutler, H.; Hannah, J.; Hauck, F. P.; Ito, S.; Langemann, A.; Goff, E. L.; Leimgruber, W.; Lwowski, W.; Sauer, J.; Valenta, Z.; Volz, H. The total synthesis of chlorophyll. J. Am. Chem. Soc. 1960, 82, 3800-3802. Synthesis of Chlorophyll (1960)

the other α position is too CN masking CN NC Me CN NC Me electron deficient to react Me group! NC Et Et O Et HN aq. HCl HN HN Cl CO2Me

HN CH2Cl HN EtOH, Δ HN anhy. ZnCl2 O Me Me Me

CO2Et CO2Et CO2Et MeO2C

work by Triebs, Schmidt & 1. 33% aq. NaOH, Δ Zinsmeister in 1957 2. CH2N2

NH CN 2 Me NC Me goes through a N- Me Me S O Et ethylimino intermediate I Et Et NH II HN H H HN HN CH2Cl 1. EtNH O 2 HN HN H O 2. H2S, MeOH/ O NH HN benzene IV III Me Me Me Me CO2Me CO2Me CO Me CO Et MeO2C MeO2C 2 2 the thioaldehyde was a new concept! Woodward, R. B.; Ayer, W. A.; Beaton, J. M.; Bickelhaupt, F.; Bonnett, R.; Buchschacher, G. L.; Closs, G. L.; Dutler, H.; Hannah, J.; Hauck, F. P.; Ito, S.; Langemann, A.; Goff, E. L.; Leimgruber, W.; Lwowski, W.; Sauer, J.; Valenta, Z.; Volz, H. The total synthesis of chlorophyll. J. Am. Chem. Soc. 1960, 82, 3800-3802. Synthesis of Chlorophyll (1960) NH NH2 2 NH2

Me Me Me I the use of the thioaldehyde O NH HBr NH aq. NaBH4 NH doubled the yield of this H process! NH NH MeOH NH Me S Me IV Me Me Et CO Me H II CO2Me 2 CO2Me HN

Schiff base formed HN NH3 O Me Me III N Me Me Me Et Et CO2Me NH HN N MeO C 12 N HCl, H HN 2 phlorin salt MeOH Me NH NH HN HN O Me Me Me it was known that CO Me CO Me 2 phlorin salts can 2 CO2Me be readily oxidized MeO C MeO2C 2 CO2Me by air NHAc Me NHAc Me

Me Et Me Et oxidation N HN N HN

1. I2 AcOH NH N NH N 2. Ac O, pyr air 2 Me Me Me Me and no other 50% yield contaminant! over 5 steps CO2Me CO2Me

MeO C MeO C a porphyrin 2 CO2Me 2 CO2Me Woodward, R. B.; Ayer, W. A.; Beaton, J. M.; Bickelhaupt, F.; Bonnett, R.; Buchschacher, G. L.; Closs, G. L.; Dutler, H.; Hannah, J.; Hauck, F. P.; Ito, S.; Langemann, A.; Goff, E. L.; Leimgruber, W.; Lwowski, W.; Sauer, J.; Valenta, Z.; Volz, H. The total synthesis of chlorophyll. J. Am. Chem. Soc. 1960, 82, 3800-3802. Synthesis of Chlorophyll (1960)

steric compression is most likely driving this process NHAc Me NHAc Me

Me Et Me Et N HN AcOH, 100 ºC N HN

NH N H N HN Me Me under N2 Me Me MeO C CO2Me 2 CO2Me MeO C MeO2C 2 CO2Me 3: 5 porphyrin : purpurin

“This remarkable reaction represents the first instance ever observed of reversible interconversion of a porphyrin and a chlorin.” -RBW Woodward, R. B.; Ayer, W. A.; Beaton, J. M.; Bickelhaupt, F.; Bonnett, R.; Buchschacher, G. L.; Closs, G. L.; Dutler, H.; Hannah, J.; Hauck, F. P.; Ito, S.; Langemann, A.; Goff, E. L.; Leimgruber, W.; Lwowski, W.; Sauer, J.; Valenta, Z.; Volz, H. The total synthesis of chlorophyll. J. Am. Chem. Soc. 1960, 82, 3800-3802.

elimination of Synthesis of Chlorophyll (1960) trimethyl- NHAc Me Me Me species Me Et Me Et Me Et keto-aldehyde 1. 1 N HCl, MeOH HN N HN N HN light & N 2. Me2SO4 air formation most likely N HN H N HN H H N HN 3. NaOH, MeOH Me strain driven Me Me Me Me Me MeO C MeO2C Hofmann MeO C 2 2 O CO Me CO2Me CO Me CHO 2 Elimination 2 MeO C MeO2C MeO C 2 2 KOH, MeOH –CO2, –CO

Me Me Me

Me Et Me Et Me Et N HN N HN HCN, NEt3, N HN unexpected 1. Zn, AcOH CH Cl 2 2 methoxy- 2. CH N H N HN 2 2 H N HN H N HN lactone Me Me Me Me Me Me formation MeO2C MeO2C MeO2C H CO2Me H H NC NC O O MeO O O HCl, MeOH Me Et Dieckmann Me Me condensation N Me Et Me Me Et N NH N Mg chlorin e6 N HN NaOMe 1. phytol N Me trimethyl ester N H N HN chlorophyll-a H N HN 2. Mg (OH)Cl Me Me Me Me Me O Me Me H MeO C Me MeO2C Willstätter & 2 Me H CO2Me Me MeO2C O Fischer MeO2C Me MeO2C O O Woodward, R. B.; Ayer, W. A.; Beaton, J. M.; Bickelhaupt, F.; Bonnett, R.; Buchschacher, G. L.; Closs, G. L.; Dutler, H.; Hannah, J.; Hauck, F. P.; Ito, S.; Langemann, A.; Goff, E. L.; Leimgruber, W.; Lwowski, W.; Sauer, J.; Valenta, Z.; Volz, H. The total synthesis of chlorophyll. J. Am. Chem. Soc. 1960, 82, 3800-3802.

elimination of Synthesis of Chlorophyll (1960) trimethyl- NHAc ammonium Me Me Me species Me Et Me Et Me Et keto-aldehyde 1. 1 N HCl, MeOH HN N HN N HN light & N 2. Me2SO4 air formation most likely N HN H N HN H H N HN 3. NaOH, MeOH Me strain driven Me Me Me Me Me MeO C MeO2C Hofmann MeO C 2 2 O CO Me CO2Me CO Me CHO 2 Elimination 2 MeO C MeO2C MeO C 2 2 KOH, MeOH –CO , –CO The synthesis took 4 years and 2 Me Me Me

Me 17 Epostt docsMe in groupsEt of 3 Mtoe 6 Et N HN N HN HCN, NEt3, N HN unexpected 1. Zn, AcOH CH Cl at a time to complete2 2 methoxy- 2. CH N H N HN 2 2 H N HN H N HN lactone Me Me Me Me Me Me formation MeO2C MeO2C MeO2C H CO2Me H H NC NC O O MeO O O HCl, MeOH Me Et Dieckmann Me Me condensation N Me Et Me Me Et N NH N Mg chlorin e6 N HN NaOMe 1. phytol N Me trimethyl ester N H N HN chlorophyll-a H N HN 2. Mg (OH)Cl Me Me Me Me Me O Me Me H MeO C Me MeO2C Willstätter & 2 Me H CO2Me Me MeO2C O Fischer MeO2C Me MeO2C O O Synthesis of Chlorophyll (1960)

The practical execution of the synthesis “might as well have been impossible without his resource, his awareness, his sensitivity to the slightest clues and his insistence on obtaining the maximum information.” -John Cornforth

Courtesy of Harvard University Archives Moving up

• RBW was promoted to a Donner Professor of Science in 1960, at the age of 43

Courtesy of John D. Roberts Moscowitz, A.; Mislow, K.; Glass, M. A. W.; Djerassi, C. Optical Rotatory Dispersion Associated with Dissymmetric Non-conjugated Chromophores. An Extension of the Octant Rule. J. Am. Chem. Soc. 1962, 84, 1945-1955. The Octant Rule (1961)

positive Cotton effect

Me Me • In 1895, Aimé August Cotton Me observed that the changed dramatically when measured around the wavelength O absorbed by the chiral molecule chrysanthenone in isooctane • If the partial rotation curve became strongly positive and then sharply negative, it was a positive Cotton negative Cotton effect effect

H • A negative Cotton effect is observed when the curve Me HO OH becomes negative and then O H O O O positive H OH O OMe OH verbenalin in water Moscowitz, A.; Mislow, K.; Glass, M. A. W.; Djerassi, C. Optical Rotatory Dispersion Associated with Dissymmetric Non-conjugated Chromophores. An Extension of the Octant Rule. J. Am. Chem. Soc. 1962, 84, 1945-1955. The Octant Rule (1961)

positive Cotton effect

Me Me • From 1952-1957 at Me in applied optical rotatory dispersion to organic O chrysanthenone in • In 1957 William Klyne showed that isooctane introduction of a α to a ketone in the equatorial position of a steroid caused a small change in the Cotton effect compared to the parent negative Cotton effect compound

H • However, introduction of a halogen in the axial position caused a large Me HO OH O H O change in the Cotton effect O O H OH O OMe OH verbenalin in water Moscowitz, A.; Mislow, K.; Glass, M. A. W.; Djerassi, C. Optical Rotatory Dispersion Associated with Dissymmetric Non-conjugated Chromophores. An Extension of the Octant Rule. J. Am. Chem. Soc. 1962, 84, 1945-1955. The Octant Rule (1961)

positive Cotton effect

Me Me Me

O chrysanthenone in isooctane • In 1958, Djerassi gave a seminar at Harvard and met Woodward, Moffitt and Moscowitz who were working on a theory of optical activity negative Cotton effect

H

Me HO OH O H O O O H OH O OMe OH verbenalin in water The Octant Rule (1961)

“The connection was clear because every prediction by Moffitt and Moscowitz was immediately supported by my production some experimental verification. The octant rule explained virtually all of our published and unpublished results.”

-Carl Djerassi X “Steroids Made It Possible”

Z b C a O Y Woodward, R. B.; Moffitt, W.; Moscowitz, A.; Klyne, W.; Djerassi, C. Structure and optical rotatory dispersion of saturated ketones. J. Am. Chem. Soc. 1961, 83, 4013-4018. The Octant Rule (1961)

Absolute configurations can be assigned using this method!

X

The space around a carbonyl of an asymmetric ketone can Z be divided into octants b a C a not in the Z O Y plane of the will contribute to the chiral ketoneʼs asymmetry The octants are assigned signs based on empirical Djerassi & Klyne evidence of the contribution of each in a given octant toward the Cotton effect Woodward, R. B.; Moffitt, W.; Moscowitz, A.; Klyne, W.; Djerassi, C. Structure and optical rotatory dispersion of saturated ketones. J. Am. Chem. Soc. 1961, 83, 4013-4018. The Octant Rule (1961)

how the cyclohexanone must be drawn on the diagram:

X

Me Z H

O Y The Octant Rule (1961)

• Even though this rule was established in 1958, the results werenʼt published until 1961

• Unfortunately Moffitt passed away unexpectedly in December 1958

• Moffitt introduced Woodward to theory and if he had remained alive the Woodward-Hoffmann Rules may have been the Woodward-Moffitt Rules

(1958) Woodward and William Moffitt reenacting the afternoon when the octant rule was discovered

Courtesy of Carl Djerassi The Woodward Research Institute (1963)

• In 1963, the Woodward Research Institute was established by CIBA limited in Basel,

• RBW was allowed to carry out his research of choice “in the field of chemical compounds or processes associated in some way with living ”

• CIBA had hoped that the advances Woodward made at this institute would benefit the company

The door to the Woodward Research Institute at CIBA-Geigy in Basel, Switzerland

Courtesy of Harvard University Archives The National Medal of Science (1964)

RBW received the National Medal of Science Award in the physical sciences in 1964 for

“an imaginative new approach to the synthesis of complex organic molecules and, especially, for [his] brilliant syntheses of strychnine, reserpine, lysergic acid and chlorophyll.”

(1965) Woodward accepting the National Medal of Science from President Lyndon Johnson

Courtesy of Harvard University Archives Woodward, R. B. The mechanism of the Diels-Alder reaction. J. Am. Chem. Soc. 1942, 64, 3058-3059. The Woodward-Hoffmann Rules (1964-69)

• There was much debate during the 1930s over O O O OMe O OMe whether the mechanism of the Diels-Alder reaction O O Me heat Me was concerted or stepwise H H N N Me Me Me OH Me OH • In 1942, Woodward had proposed an ionic MeO2C MeO2C mechanism involving electron transfer and an ion CN CN pair hν • Woodward felt as though he fully understood and heat could predict the outcome of the Diels-Alder reaction until his endeavors in the B12

synthesis O O O OMe O OMe O O Me Me heat Working with his post doc, Subramania H H • N N Ranganathan, RBW discovered that he did not in MeO2C MeO2C Me Me fact make the expected product when trying the Me OH OH NC following Diels-Alder reaction CN CN The Woodward-Hoffmann Rules (1964-69)

O O O OMe O OMe O O Me heat Me H H N N Me Me Subramania Ranganathan described that Me OH Me OH MeO2C MeO2C when RBW “had discovered that his CN CN predictions relating to stereochemistry had gone awry...his enormous and rightful hν heat self-confidence would not accept the outcome meekly, and the result was, of O O course, the Woodward-Hoffmann rules.” O OMe O OMe O O Me Me heat H H N N MeO2C MeO2C Me Me Me OH OH NC CN CN The Woodward-Hoffmann Rules (1964-69)

e–

• It was already accepted that possessed both particle-like and wave-like properties and that these wave-like properties can change with energy level

• It was also accepted that these electrons occupy orbitals which can be calculated by quantum (wave) mechanics

• Bonding was visualized by orbitals overlapping, enabling the electron to spread over two or more atoms

The significant detail that Woodward and Hoffmann established was that the orbitals must be in the same phase in order to bond Woodward, R. B.; Hoffmann, R. Stereochemistry of electrocyclic reactions. J. Am. Chem. Soc. 1965, 87, 395-397. The Woodward-Hoffmann Rules (1964-69)

• In the first paper, Woodward and Hoffmann found that under thermal conditions cyclobutenes underwent a conrotatory ring closure, while hexatrienes underwent a disrotatory ring closure

disrotation Δ Me Me Me Me

conrotation Me Me Δ Me Me

“...the steric course of the electrocyclic transformation is determined by the of the highest occupied molecular orbital of the open-chain partner.” Woodward, R. B.; Hoffmann, R. Stereochemistry of electrocyclic reactions. J. Am. Chem. Soc. 1965, 87, 395-397. The Woodward-Hoffmann Rules (1964-69) In a 4n π-electron system, the symmetry of the HOMO must allow for a bonding interaction between “orbital envelopes on opposite faces of the system”, or via a conrotatory closure

Me H conrotation Me H Me H Δ H Me

In a 4n+2 π-electron system, the symmetry of the HOMO must allow for a bonding interaction between “orbital envelopes on the same face of the system”, or via a disrotatory closure

disrotation H H Δ H H Me Me Me Me

Under photochemical conditions, the 4n π-electron system will undergo a disrotatory closure and the 4n+2 π-electron system will undergo a conrotatory closure Me Me disrotation controtation hν hν Me Me Me Me Me Me Woodward, R. B.; Hoffmann, R. Selection rules for concerted reactions. J. Am. Chem. Soc. 1965, 87, 2046-2048. The Woodward-Hoffmann Rules (1964-69) • In the second paper, Woodward and Hoffmann introduce orbital correlation diagrams and explain how they can be used to predict whether a given electrocyclic reaction will undergo a conrotatory or a disrotatory closure under thermal or photochemical conditions

Classify whether the orbitals in the starting materials and product are symmetric or antisymmetric with respect to the selected symmetry element

Correlate the orbitals with the same symmetry

If the energy of the correlation between the HOMOs of the starting material and the product decreases in energy, then the process is favorable

photochemically allowed! Woodward, R. B.; Hoffmann, R. Selection rules for concerted cycloaddition reactions. J. Am. Chem. Soc. 1965, 87, 2046-2048. The Woodward-Hoffmann Rules (1964-69) • In the second paper, Woodward and Hoffmann introduce orbital correlation diagrams and explain how they can be used to predict whether a given electrocyclic reaction will undergo a conrotatory or a disrotatory closure under thermal or photochemical conditions

photochemically allowed! thermally allowed! Woodward, R. B.; Hoffmann, R. Selection rules for sigmatropic reactions. J. Am. Chem. Soc. 1965, 87, 2511-2513. The Woodward-Hoffmann Rules (1964-69) • In the third paper, Woodward and Hoffmann introduce the selection rules for sigmatropic [1,3], [1,5] and [1,7] shifts

1,3 sigmatropic shifts :

Proton 1S (LUMO) bonding H antibonding bonding

X Y X Y H Ψ2 (allyl anion HOMO)

bonding Suprafacial Geometry Antarafacial Geometry

bonding bonding 1S (LUMO) bonding H

Y X Y X Ψ2 (allyl anion HOMO) H antibonding Suprafacial Geometry Antarafacial Geometry Hoffmann, R. A Claim on the Development of the Frontier Orbital Explanation of Electrocyclic Reactions. Angew. Chem. Int. Ed. 2004, 43, 6586-6590. The Woodward-Hoffmann Rules (1964-69) the controversy...

Elias J. Corey

• In his 2004 Priestly Medal address, E. J. Corey claimed that he has provided RBW with the idea of the conservation of orbital symmetry

• That same year, Hoffmann published a tell-all account of what he knew and what he didnʼt know about Coreyʼs contribution to the Woodward-Hoffmann rules R. B. Woodward Hoffmann, R. A Claim on the Development of the Frontier Orbital Explanation of Electrocyclic Reactions. Angew. Chem. Int. Ed. 2004, 43, 6586-6590. The Woodward-Hoffmann Rules (1964-69) the controversy...

“I believe that E. J. Coreyʼs perception of the consequences of what he told R. B. Woodward is just that–what he, Corey, believes.” -Roald Hoffmann

Elias J. Corey Roald Hoffmann

“Woodward had a habit of posing to people “In 1963-64, E. J. Corey and A. G. Hortmann problems of great interest. And also of accomplished the total synthesis of posing such problems as puzzles, even if dihydrocostunolide. A crucial step involved a he had the solution...I think that May 4 stereospecific electrocyclic reaction. The two conversation [between RBW and EJC] papers on the work do not have any reference perhaps might have prompted Woodward to an electronic factor in the stereoselectivity.” to push on, and to ask for my assistance with calculations supporting the frontier orbital approach.”

R. B. Woodward Hoffmann, R. A Claim on the Development of the Frontier Orbital Explanation of Electrocyclic Reactions. Angew. Chem. Int. Ed. 2004, 43, 6586-6590. The Woodward-Hoffmann Rules (1964-69) the controversy...

“I believe that E. J. Coreyʼs perception of the consequences of what he told R. B. Woodward is just that–what he, Corey, believes.” -Roald Hoffmann “I asked him directly if Corey had a role in this work. He said “no”–this Elias J. Corey Roald Hoffmann was our (R.B.W. and R.H.) work.” -Roald Hoffmann“Woodward had a habit of posing to people “In 1963-64, E. J. Corey and A. G. Hortmann problems of great interest. And also of accomplished the total synthesis of posing such problems as puzzles, even if dihydrocostunolide. A crucial step involved a he had the solution...I think that May 4 stereospecific electrocyclic reaction. The two conversation [between RBW and EJC] papers on the work do not have any reference perhaps might have prompted Woodward to an electronic factor in the stereoselectivity.” to push on, and to ask for my assistance with calculations supporting the frontier orbital approach.”

R. B. Woodward Synthesis of C (1965)

Cephalosporin C Lecture The Nobel Prize (1965)

“It is sometimes said that organic synthesis is at the same time an exact science and a fine art. Here Nature is the uncontested master, but I dare say the the prize-winner of this year, Professor Woodward, is a good second.”

-Arne Fredga Les Prix Nobel en 1965 (Stockholm: Almquist & Wiksell, 1966)

Woodward reading the telegram announcing that he had won the Nobel Prize with his loyal secretary, Dolores “Dodie” Dyer looking on

From Aldrichimica Acta 10:1 (1977) The Nobel Prize (1965)

Courtesy of Eudoxia Woodward

The Nobel Prize winners in Stockholm for the ceremony in 1965: Robert B. Woodward (chemistry); and Richard P. Feynman (); François Jacob, André Lwoff, and ( or ); and (literature) for his “meritorious contributions to the art of organic synthesis” Love & Marriage

• Robert and his second wife, Eudoxia Miller, were divorced in 1972 The Arthur C. Cope Award (1973)

“[I]n chemistry, oneʼs ideas, however beautiful, logical, elegant, imaginative they may be in their own right, are simply without value unless they are actually applicable to the one physical environment we have–in short, they are only good if they work! I personally very much enjoy the challenge which this physical restraint on fantasy presents.”

-RBW From RBWʼs address upon receiving the American Chemical Societyʼs Arthur C. Cope Award in Organic Chemistry, 28 August 1973.

Hoffmann, Herman Bloch (chairman of the board of the ACS), Harriet Cope and Woodward after Woodward and Hoffmann had received the first Arthur C. Cope Award for outstanding achievement in organic chemistry

Courtesy of Harvard University Archives Synthesis (1960-76)

O O NH2 O H NH Me 2 H2N Me B N H NC Me O Co Me A N N C Me H2N Me N H D H NH H Me Me 2 In 1926, George Minot (a Harvard • H2N O professor of medicine) successfully O used liver to treat pernicious anemia O NH

N Me • In 1928, Eli Lilly & Co. introduced Me liver extract to the market HO H O O N P Me H • Ed Rickus of Merck was finally able O O O to isolate the red crystals of vitamin Vitamin B12 H B12 OH Vitamin B12 Synthesis (1960-76) O O NH2 O H NH Me 2 O H2N Me O Vitamin B12 NH2 N O H NC H Me NH2 O Co Me Me N H2N Me N Me H2N Me N N H H H NC Me O Co NH Me N Me Me 2 N Me H OH H2N O H2N Me N O H H O NH NH H Me Me 2 H2N O N Me O Me cobryic acid HO H O O OH O N P Me H O O O H • In 1956, was able OH to obtain and solve the X-ray crystal structure of vitamin B12

• Wilhelm Friedrich and Konrad Bernhauer from successfully converted cobryic acid to vitamin B12 Dorothy Hodgkin Won the Nobel Prize in 1964 for her advancement of X-ray crystallographic techniques in the structural determination of biological molecules Vitamin B12 Synthesis (1960-76)

O O NH2 O H NH Me 2 H2N Me The corrin system B is the porphyrin N H NC Me ring system of the O Co Me A N N C Me molecule without H N Me N 2 H the • In 1959, began H D working on the synthesis of the corrin NH H Me Me 2 system of vitamin B12 O H2N O

• During 1960-61, Woodward began O NH working on rings A and D, or the western portion of the molecule N Me Me HO H Also in 1960, Eschenmoser began working on the O O N • P Me eastern portion of the molecule, rings B and C H O O O Vitamin B12 By 1964, Eschenmoser had finished the corrin system H • OH • Eschenmoser and Woodward finally agreed to collaborate and finish the molecule together in 1965 Vitamin B12 Synthesis (1960-76)

The molecule contains 9 O , which means it O has 512 possible stereoisomers NH2 O H NH This type of corrin system had never been Me 2 H2N Me made before–needed to pioneer a route B N H NC Me O Co Me A N N C Me H2N Me N H H The direct link between the A and D rings with D NH no intervening was going to be a H Me Me 2 O challenge H2N O

O NH

N Me Me In this synthesis they needed to master the HO H O O N stereochemical complexity as well as master the P Me H O O complexity inherent in large, macrocyclic, highly O Vitamin B12 unsaturated, -containing chromophore H OH structures Woodward, R. B.; Recent advances in the chemistry of natural products. Pure Appl. Chem. 1968, 17, 519-547.

resolved by urea formation Vitamin B12 Synthesis (1960-76) with (+)-α- the transition state with the methyl groups phenylethyl syn to one another is lower in energy

Me Me OMe HgO OMe 1. MeMgI Me OMe BF3, HgO OMe O A Me N 2. propargyl N N Me Me N Me H H H bromide Me took 16 steps total O Me Cl Me

Me

Me Me Me O OMe O OMe OMe Me Me Me Li, NH3 (l), HO O O t-BuOH, THF O 1. H+, OH H N H N H N

OEt OEt + – O Me Me 2. Et3O BF4 Me 3. NaOMe Me Me Me Me Me 4. toluene, Δ Me

H+

CO2Me Me Me O HO O Me HO H O H 1. NH2OH N H 1. O3, MeOH O 2. HNO2, AcOH 2. HIO4 N H N H N Me Me H N Me O O 3. CH N Me Me Me 2 2 O Me Me Me Me Me Me O O Woodward, R. B.; Recent advances in the chemistry of natural products. Pure Appl. Chem. 1968, 17, 519-547.

Vitamin B12 Synthesis (1960-76)

Me Me Me OMe OMe OMe Me S OMe O O N S N N N Me Me Me Me H O O O

"ozonization"

Me CO2H Me NH Me Me O NH CO H H H 2 O degraded through chloride, azide and isocyanate

Me Me Me CO2H Me NHCO2Me Me H N O Me Me Me Me O O O O H H H H (+)–camphor Woodward, R. B.; Recent advances in the chemistry of natural products. Pure Appl. Chem. 1968, 17, 519-547.

Vitamin B12 Synthesis (1960-76)

Me Me OMe HgO OMe 1. MeMgI Me OMe BF3, HgO OMe O A Me N 2. propargyl N N Me Me N Me H H H bromide Me

O O Me Me Me Me CO2Me Me OH Cl O Me Me Me Me

H Me (–)-camphor Me Me

Me Me Me O OMe O OMe OMe Me Me Me Li, NH3 (l), HO O O t-BuOH, THF O 1. H+, OH H N H N H N

OEt OEt 2. Et O+BF – O Me Me 3 4 Me get one ! 3. NaOMe Me Birch reduction Me Me Me Me 4. toluene, Δ Me

H+ need to protect both carbonyls

CO2Me Me Me O HO O Me HO H O H 1. NH2OH N H 1. O3, MeOH O 2. HNO2, AcOH 2. HIO4 N H N H N Me Me H N Me O O 3. CH N Me cyclohexene and Me get oximation of both Me 2 2 O Me cyclopentene ring Me Me Me ketones but can remove Me Me O are opened! unfavored oximino group O Woodward, R. B.; Recent advances in the chemistry of natural products. Pure Appl. Chem. 1968, 17, 519-547.

Vitamin B12 Synthesis (1960-76)

CO2Me OH2 CO2Me CO Me O 2 Me Me Me Me MsO H MsO H HO H N N O 1. O3, wet MeOAc N O O N 1. MeOH, 2. HIO4 H N O H N H N Me Me Me Me Me 2. MsCl, NEt3 Me O 3. CH2N2 Me O O Me Me specific conditions MeO2C Me O O necessary to get desired cyclization of the diketones O polystyrene Beckmann sulphonic acid, rearrangement MeOH, 170 ºC confirmed by X-ray crystallography!

CO2Me CO2Me CO2Me CO2Me Me Me Me D ring formed H O H O H hesperimine HCl, MeOH 1. strong base, Δ through a Me O Me O Me O N N N N N N intramolecular H H 2. CH2N2 H MeO H O H O D H Michael CO2Me CO2Me CO2Me Me Me Me addition beta-corrnorsterone alpha-corrnorsterone

CO2Me CO2Me CO2Me

MeO2C Me H MeO2C MeO2C Me H Me H O 1. O3, MeOH O O Me 1. NaBH , MeOH MeO C NH 2. SMe2 Me 4 Me A 2 H NH NH MeO2C H MeO2C H western N N 2. MsCl, pyr N fragment Me 3. LiBr, DMF D Me Me complete

CHO CH2Br

CO2Me CO2Me OMe Woodward, R. B.; Recent advances in the chemistry of natural products. Pure Appl. Chem. 1968, 17, 519-547.

Vitamin B12 Synthesis (1960-76) The original route to eastern fragment developed by Eschenmoser but several routes were developed by both Zurich and Cambridge for this fragment

Ring B is formed -extrusion coupling method mechanism unknown of through a Diels- developed by Zurich in 1965 sulfur–extrusion but suspect O that an episulphide involved Alder cyclization O O and a Arndt-Eistert O Me Me homologation O Me O Me Me Me B CO2Me B BnOOH N 1. POEt , N HN CO2Me 3 CO2Me CH Cl xylene, Δ 2 2 S S Me Me + – HN Me 2. Me3O BF4 , HN Me C Me HN then H2S eastern C Me S O fragment O complete Ring C is derived CO2Me CO2Me from (+)-camphor CO2Me mechanism involves oxidation to the disulphide and then attack by the eneamide Eschenmoser, A.; Wintner, C. E. Synthesis and Vitamin B12. Science. 1977, 196, 1410-1420.

Vitamin B12 Synthesis (1960-76) O MeO2C O MeO2C O

CO2Me Me Me H O H S O Me Me MeO2C O S Me H MeO2C Me Me MeO2C Me Me Me B CO2Me P S O N N 2 5 HN 1. KOt-Bu, NH picoline (cat.) N Me A Me CO2Me Me CO2Me MeO2C H NH H H Me MeO2C N MeO2C N HN HN N N 2. PPh3, BF3, Me Me C Me benzene Me D Me Me S Me Me CH Br 2 eastern CO2Me CO2Me CO2Me fragment CO2Me western CO2Me CO2Me fragment Me2NH MeO2C MeO2C MeO2C CONMe CONMe CONMe 2 Me 2 Me 2 H H H Me S Me S Me MeO2C Me MeO2C Me CoCl, MeO2C Me 1. BnOOH aq. KCN, CN N CN N HN N CO Me CH2Cl2 N N Me 2 Me CO2Me air Me CO2Me H Co H Co H MeO2C N MeO2C N MeO2C N NC N NC N N Me 2. POEt3, Me Me Me xylene, Δ Me Me Me Me Me CO2Me CO2Me CO2Me block the C10 position CO2Me by formation of the CO2Me CO2Me I2, AcOH, DMA lactone from undesired O MeO2C O methylation 1. AgBF4, NH2 MeO2C O O H Me O NH2 H Me N Me Me H2N Me H MeO2C Me CO2Me O MeO C Cl 1. PhSH 2 Me N N CN N H NC 2. Zn(Hg), AcOH O Me Me N CN N Me N Co Co CO2Me Me H Me N Me MeO2C N Co CO2Me NC MeO C H 2. 0.1 N HCl OH N 3. CH2N2 2 N H2N Me N Me NC N H H 4. conc. H2SO4 3. Me2NH, i-PrOH Me Me separated 4. NH3, NH4Cl Me Me Me NH2 Me H Me O Me separated H2N O MeO C cobryic acid by HPLC 2 CO Me 2 MeO2C diastereomers by HPLC O CO2Me OH Eschenmoser, A.; Wintner, C. E. Natural Product Synthesis and Vitamin B12. Science. 1977, 196, 1410-1420.

Vitamin B12 Synthesis (1960-76)

O O NH2 Bernhauer-Friedrich pathway O H NH Me 2 H N O 2 Me B O Vitamin B12 NH2 N O H NC H Me NH2 O Co Me Me A N H2N Me N C Me H2N Me N N H H H NC D Me O Co NH Me N Me Me 2 N Me H OH H2N O H2N Me N O H H O NH NH H Me Me 2 H2N O N Me O Me cobryic acid HO H O O OH O N P Me H O O O H OH

Eschenmoser was able to successfully link together the A and D rings through a photochemical sigmatropic [1,16] H- shift on the basis of the Woodward-Hoffmann rules Vitamin B12 Synthesis (1960-76)

Woodward and Mark Wuonola on March 17, 1976, the day that the total synthesis of vitamin B12 was completed

• The synthesis of this molecule began in 1960 and involved over 100 chemists from 20 different nations

Courtesy of Mark Wuonola

This synthesis serves as an example of the role of natural product synthesis in generating fundamental knowledge in organic chemistry Vitamin B12 Synthesis (1960-76)

Woodward and Eschenmoser admiring the “marvelous B12 machine” at the Zurich symposium

“What really grew out of the decision to join forces in the B12 venture was the fine and delicate art of ʻcollaborative competitionʼ...In practice this partnership entailed a continuous and rigorously open discussion of the projectʼs present and future, an immediate exchange of information about anything that happened to succeed or fail in either of the two laboratories...On a more personal level it meant rejoicing wholeheartedly in the partnerʼs success. Perhaps above all it meant basic harmony between our attitudes toward our science...”

-Albert Eschenmoser

Courtesy of Dorothy Felix The “Woodward Lectures” • In later years, Woodward ran a notorious research seminar on Thursday nights for faculty, postdoctoral students and other students • He would start by lining up his cigarettes and colored chalk on 2 white handkerchiefs and he would write on the board from memory starting at the upper left-hand corner of the board and ending in the lower right-hand corner • RBW would often drink and entire pitcher of daiquiris while he lectured without noticeable affect and would smoke all of his cigarrettes using the old one to light the next one • The lectures would last three hours or more and would often run past 1:00 am • Roald Hoffmann used to joke that he measured lecture time in “milliwoodwards”

“I teach all the time so that I donʼt have to teach formal courses.” -RBW Death

• Woodward passed away on July 9, 1979 in his sleep from a heart attack

“All in all Bob was bigger than life. His chemistry and the great impact that he had on other peopleʼs chemistry survive him and stand as a monument to his achievements. His friends are the poorer now that he is no longer needling us, while the entire field of organic chemistry will benefit forever because he converted synthesis into a much more highly rational procedure.”

-Frank Westheimer “Woodward in his role as a pioneer of modern natural-product synthesis did not exert his influence on synthetic chemistry through any explicit proposition of principles and rules that could be used as recipes for designing a synthetic plan. He reached his contemporaries through teaching by example. It was not his way to routinize and ʻtechnifyʼ his art of synthetic design by giving such recipes; what he did was to put up one masterpiece after the other, masterpieces that were universally recognized as such by his fellow chemists, achievements that not only were chemically inspiring but also captivated the young.”

-Albert Eschenmoser Resources

• Main resource: Robert Burns Woodward: Architect and Artist in the World of Molecules; Benfey, O. T.; Morris, P. J. T., Eds.; Chemical Heritage Foundation: , PA, 2001.

• Bowden, M. E. and Benfey, T. Robert Burns Woodward and the Art of Organic Synthesis; The Beckman Center for : Philadelphia, PA, 1992.

• Blout, E. In Robert Burns Woodward. National Academy of Sciences Biographical Memoirs, Vol. 80; National Academy Press: Washington D. C., 2001.

• And all of the references included herin