the life and achievements of robert burns woodward

The Life and Achievements of Robert Burns Woodward

Long Literature SeminarJuly 13, 2009Erika A. Crane

“The structure known, but not yet accessible by synthesis, is to the chemist 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 chemists, 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 chemical synthesis 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 Science in the Synthesis of Organic Compounds: Retrospect and Prospect,” in Pointers and Pathways in Research (Bombay:CIBA of India, 1963).

Robert Burns Woodward

• Graduated from MIT with his Ph.D. in chemistry at the age of 20

• A tenured professor at Harvard by the age of 29

• Published 196 papers before his death at age 62

• Received 24 honorary degrees

• Received 26 medals & awards including the National Medal of Science in 1964, the Nobel Prize in 1965, and he was one of the first recipients of the Arthur C. Cope Award in 1973

Woodward taught by example and captivated the young... “Woodward largely taught principles and values. He showed us by example and precept that if anything is worth doing, it should be done intelligently, intensely and passionately.”

-Daniel Kemp

RBW: The Early Years

• Robert Burns Woodward was born to Arthur and Margaret Woodward in Boston, Massachusetts 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 Harvard University Archives

RBW: The Early Years

“I fell in love with the field [of organic synthesis] 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).

• 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 Organic Chemistry (1894)


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


• 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)



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

“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

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


A Summer at the University of Illinois

• RBW spent the summer of 1937 teaching of University of Illinois

• He “managed through his intelligence and impatience to alienate several of the leading figures of organic chemistry in the United States”.

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

Professor Roger Adams,Chemistry Department Chair,

University of Illinois (1926-1957)

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

Courtesy of C&EN News

Courtesy of the University of Illinois

Moving to Harvard

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

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

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

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

Courtesy of the National Academy of Sciences

“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.”

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

Woodwardʼs Inspiration

“From the first awakening of my interest in chemistry, I have found its history absorbing, and have been particularly entranced by the concept of bonding in the most general sense.”

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

• Woodward was particularly drawn to the work of Friedrich August Kekule and Archibald Scott Cooper

Friedrich August Kekule

Archibald Scott Cooper


Kekule structures

Friedrich August Kekule


C

C

C

C

OO2

O2

OH

O OH

HO OH

HO OH

C

C

C

C

OO2

O2

OH

O OH

H

H

O2– H2O

tartaric acid

Archibald Scott Cooper

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

• 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

Otto Diels and Kurt Alder

The Woodward Rules (1941-1942)

• The Woodward Rules (also known as the Woodward-Fieser rules) were proposed in 4 papers in 1941-1942

• In his first paper, he founds that generalizations could be made between spectra if the absorption effects of different solvents was accounted for

• He also found that the extent of substitution at the α and β positions of a α,β-unsaturated ketone could be determined from the UV spectra

R

O

ββ

α

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 first article was based solely on the experimental work of others, citing more than forty papers

• In particular, the work by Heinz Dannenburg was pertinent to Woodwardʼs evaluation

• His rules concentrated on numerical analysis and built support for these rules with many examples

R

O

ββ

α

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

O

β

α

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.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.


• Woodward provided evidence against the then-accepted structure of 3-acetoxy-6-keto-7-hydroxy-Δ4-chloestene

• 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

• Proposed the structure of 3-acetoxy-Δ5-(6)-norcholestene-7-carboxylic instead

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.

Me

Me C8H17

OOR

R = H or COC6H5

Me

CO2H

Me �C8H17


• In 1949, the rules were extended by Louis and Mary Fieser

• UV spectroscopy was later superseded by newer structure determination techniques such as nuclear magnetic resonance spectroscopy, mass spectroscopy and X-ray crystallography

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

O

β

αR

O

ββ

α

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

Synthesis of Quinine 1943-1944

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

• Jesuits recognized itʼs ability to treat malaria 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

N

MeO

HON

H H

A cinchona tree

Quinine


• 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

N

MeO

HON

H H

Quinine

William Henry Perkin


• 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 Polaroid Corporation 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


Woodwardʼs genius lied in his ability to see what others had not seen already in the known.

N

MeO

HON

H H

quinineN

MeO

O HN

H

Rabe and Kindler1918

quinotoxine

N

MeO

O OEt

ethyl quininate

NCOC6H5

H

H

O

EtO

N-benzoylhomomeroquinene ethyl ester

NH

H

H

O

HO

homomeroquinene

Woodward, R. B.; Doering, W. E. The total synthesis of quinine. J. Am. Chem. Soc. 1944, 66, 849.

N

7-hydroxyisoquinoline

OH

Kenner, Prelog and Zalan

Prelog and Prostenik

Synthesis of Quinine 1943-1944Woodward, R. B.; Doering, W. E. The total synthesis of quinine. J. Am. Chem. Soc. 1944, 66, 849.

work by Fritsch

these conditions are essential in order to obtain desired selectivity without loss of hydroxy group

mixture of cis and trans isomers

Adamʼs catalyst

inital attempts to induce reductive cleavage of the piperidino group failed

N

7-hydroxyisoquinoline60% yeild

OH

N

OEt

EtO80% H2SO4

benzeneΔ

OH N

OH

5-hydroxyisoquinoline5% yield

CH2O,piperidine,MeOH

62% yeild

NOH

N

NOH

MeNaOMe, MeOH

220 ºC64% yield

HNOH

Me

NOH

MeAc

NOH

MeAc

AcOH,H2, Pt

Ac2O, MeOH

95% yieldover 2 steps

H2, Raney Ni

EtOH, 150 ºC,3000 psi

50 % yield


cis configuration essential for the desired cis-3,4-disubstitution of the piperdine ring

mixture of isomers Hoffmannelimination

NH

H

H

O

HO

homomeroquinene

NOH

MeAc

NH

Ac

H

OHMe

H NH

Ac

Me

H

O

NMeH

Ac

H H

HO

OEt

NOH

NMeH

Ac

HO

OEt

NH2

NMeH

Ac

HO

OEt

N(Me)3

I–

NH

H

HO

OH

H2CrO4, AcOH

70% yield

EtONO,NaOEt,EtOH

68% yield

AcOH,H2, Ptexcess MeI

K2CO2, EtOH90% yield

60% K/NaOHNEt3, 140 ºC

*

N

H

H

O

HO

ONH242% yield

over 5 steps

KCN, H2O


resolved as dibenzoyl-d-tartrate

N

MeO

HON

H H

N

MeO

O HN

H

quinine

quinotoxine

N

MeO

O OEt

ethyl quininate

NH

H

H

O

HON

H

H

O

HO

ONH2 2. Ag2O then H2S

1. HCl, EtOH

2. benzoyl chloride, K2CO3 96% yield over 4 steps

NCOC6H5

H

H

O

EtO

N-benzoylhomomeroquinene ethyl ester

1. 0.1 N aq. HCl, Δ

dry NaOEtΔ

N

MeO

O N

H

COC6H5

CO2Et

6 N HCl



Claisen condensation


• Woodward worked with William von E. Doering for fourteen months on the molecule 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


N

MeO

HON

H H

quinineN

MeO

O HN

H


quinotoxine


Courtesy of the Library of Congress

Woodward, R. B.; Doering, W. E. The total synthesis of quinine. J. Am. Chem. Soc. 1944, 66, 849.

• This synthesis was hailed by the New York 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

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 Franklin Institute 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.

• 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

Love & Marriage

Courtesy of Eudoxia Woodward

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

Structure elucidation (1945-1956)• Starting in 1945, Woodward focused a lot on

structure elucidation

• He proposed structures for penicillin, patulin, strychnine, oxytetracycline (terramycin), carbomycin (magnamycin), santonic acid, calycanthine, and aureomycin.

O

O

OH

O

patulin

N

N

OH

H

HO

strychnine

OO

HO

OH OHO

H2NOH

HOH

HMeN

MeMeOH

oxytetracycline

O

O

O

O

Me OAc

MeOO

OMe

OHON

MeMeOMe

O

OH

Me

MeO

OMe

Mecarbomycin

OO

O

OH OHOH

H2NOH

HOH

HMeN

MeMeOH

Cl

aureomycin

HN

O

Me

MeO

OH

O

Me

santonic acid

N

HN

N

Me

Me

calycanthine

N

S

O

HN

R

O

MeMe

CO2H

O

NR

O

NH

S MeMe

CO2H

penicillin proposed oxazolone structure of penicllin

Steroid Synthesis (1951)

Me H

Me

HHO

O

OH

OOH

cortisone

Me H

MeMe

Me

Me

HHHO

cholesterol • The chemistry of steroids become a “hot” area in organic chemistry in the 1940s and early 1950s because of their potential therapeutic value

• Cholesterol was first isolated in 1769 by French physicist/chemist François Poulletier de la Salle from gallstones

• Cortisone was isolated in 1930ʼs by a group of scientists lead by Tadeua Reichstein (Zurich), Edward, C. Kendall (Mayo Clinic, MN), and Oskar Wintersteiner (Columbia University) from the adrenal glands of cattle


• Woodwardʼs interest in steroidʼs stemmed from his desire to construct them utilizing a Diels-Alder reaction

• He unsuccessful in his attempts to make estrone using a Diels-Alder reaction in his PhD research in 1947

H

Me O

HHHO

estrone


• Woodward chose a “relay” approach to the synthesis of the steroids by first making the etiocholatrienate intermediate, which contained the core structure and could be further functionalized

Woodward, R. B.; Sondheimer, F.; Taub, D. The total synthesis of a steroid. J. Am. Chem. Soc. 1951, 73, 3548.

Me H

MeMe

Me

Me

HHHO

cholesterol

Me H

Me

HHO

O

OH

OOH

cortisone

Me H

Me

HO

OMeO

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

Me H

Me

HHO

MeO

progesterone

Me H

Me

HHO

OH

testosterone

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

Me H

Me

HO

OMeO


C

DBA

Rings C and D were assembled by a Diels-Alder reaction

The B ring was added by a Robinson annulation

The A ring was appended on by a Michael addition of acrylonitrile


prepared previously by

Orchin and Butz in 1943O

OMeO

Me

MeO

O

O

Me

H

benzene

MeO

O

O

Me

H

NaH then H+


MeO

OHMe

HOH

LiAlH4

O

Me

HOH

mineral acidAc2O, Zn

xylenes, Δ45% yield

over 3 steps

O

Me

H

O

Me

HO

O

Me

HHO

O

Me

HO

HO

Me

H OEt

O

O

cat. tBuOK, BuOH

Me

HMe

O

H

KOH,dioxane,50% yield over 3 steps

base

Michael addition

cyclization &deformylation

the more thermodynamically stable product

Diels-Alder

O

OMeO

Me

MeO

O

O

Me

H

benzene

MeO

O

O

Me

H

NaH then H+


MeO

OHMe

HOH

LiAlH4

O

Me

HOH

mineral acidAc2O, Zn

xylenes, Δ45% yield

over 3 steps

O

Me

H

O

Me

HO

O

Me

HHO

O

Me

HO

HO

Me

H OEt

O

O

cat. tBuOK, BuOH

Me

HMe

O

H

KOH,dioxane,50% yield over 3 steps

base

C

B


two isomers

stable isomer carried on

Need to protect olefin for formation of A ring

protect the most base-sensitive center

mixture of isomers

intramolecular aldol reaction

Dieckmann-likecondensation

D

A

cyanoethylation

Me H

Me

HO

OH


Me

HMe

O

H OsO4 acetone

CuSO4 (anhydrous)

Me

HMe

O

HOH

OH

Me

HMe

O

HO

O

MeMe

1 H2,Pd/SrCO3,benzene

Me

HMe

O

HO

O

MeMe

Me

HMe

O

HO

O

MeMe

NPh

Me2. tBuOH/benzene/H2O, Triton B,

1. base

CN

Me

HO

HO

O

MeMe

Me

HO2C

Me

H

HO

O

MeMe

OO

Me

Ac2O,AcOH, Δ

Me

H

HO

O

MeMe

O

MeCHOCHO

Me

H

H

O

Me1. MeMgBr

2. base dioxane/H2O

piperdine acetate, Δ,benzene,65% yieldMe H

Me

HO

OMeO

1. Na2Cr2O7, AcOH

2. CH2N2

HIO4

2. PhNHMe, MeOH

1. ethyl formate, base


routes from cholestanol, to cholesterol already described

Me H

MeMe

Me

HHHO

cholesterol


Me H

Me

HO

OMeO

Me H

Me

HO

OMeO

1. H2, reduced Pt 1. NaBH4

2. hydrolysis3. Ac2O, pyr

Me H

Me

HAcO

OHO

2. H2CrO4, AcOH

H

Me H

Me

HAcO

OMe

1. SOCl22. MeCd

Me

Me

BrMg

Me H

MeMe

Me

HHAcO

1. Ac2O, AcOH, Δ

MeOH

2. H2, PtO2

Me

Me H

MeMe

Me

HHHO

Me

hydrolysis

Me H

MeMe

Me

HHHO

MeHH

H

H

H

cholestanol

to effect dehydration at C20 and acetylate at C3


alpha isomer

Heymann & Feiser

Lardon & Reichstein

Sarett

dehalogenation

installing the α-

hydroxy ketone at

C19 oxidize the cyanohydrin intermediate

Me H

Me

HHO

O

OH

OOH

cortisone

Me H

Me

HAcO

OMeO

H

Me

Me

HAcO

OMeO

H

O Me

Me

HHO

OMeO

H

perbenzoic acid 1. NaOMe, NaOHO

O

dry HBr

H

Me

Me

HO

OMeO

H

OH

Br

Me

Me

HO

OMeO

H

OH

HH

1. NaI, acetone

1. KOH2. SOCl23. CH2N2

Me

Me

H

O

H

OH

H

OAc

Me

Me

H

O

H

OH

H

OAc

OH

2. Na2Cr2O73. CrO3–H2O

2. KOAc, Δ

4. KOH5. Ac2O6. CrO3

1. KCN, AcOH

O

1. NaBH4, EtOH

2. Ac2O, pyrMe

Me

H

OMeO

H

OH

HAcO

O

1. Br2

2. pyridine3. hydrolysis

2. OsO4, pyrthen Na2SO3

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

Structure Elucidation of Ferrocene (1951)

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

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

Fe

MgBr FeCl3

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

• Woodward and Wilkinson agreed to work together on the project

Kealy, T. and Paulson, P. A New Type of Organo-Iron Compound. Nature. 1951, 168, 1039.

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

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

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

Fe Fe

prismatic antiprismatic

Fe Fevs.

Woodward, R. B.; Wilkinson, G.; Rosenblum, M.; Whiting, M. C. The structure of iron biscyclopentadienyl. J. Am. Chem. Soc. 1951, 74, 2125-2126.

The discovery of ferrocene initiated a revolution in organotransition metal chemistry

Structure Elucidation of Ferrocene (1951)

Moving Up

• 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

Woodward and his son, Eric, at home in Belmont

Courtesy of Rolf Huisgen

Synthesis of Strychnine (1954)

N

N

OH

H

HO

strychnine

Seeds of the Strychnoe nux vomica tree

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

• In 1838, Victor Regnaut determined its molecular formula of C21H22N2O2

• 1898: Julius Tafel proposed the left-hand side of 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 indole 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: Vladimir Prelog proved that ring VI was a 6-membered ring

V VI

I II

III

VII

IV50 mg is lethal for an adult human!


N

N

OH

H

HO

strychnine

Seeds of the Strychnoe nux vomica tree

• 1948: Using Prelogʼs conclusion, Woodward 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”

V VI

I II

III

VII

IV

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.


N

N

OH

H

HO

strychnine

V VI

I II

III

VII

IV

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.

2-veratrylindole

blocking the α position for form

ring V

open ring with O3to form ring III

NO

N

O

HH

H

H

H

NH

OMe

OMe

24 atoms7 rings

6 contiguous chiral centers

stereochemistry unknown at formed center

only one isomer obtained

the two other aromatic rings should be electron deficient enough to inert to oxidation

5-membered lactam will not form due to E geometry of enoate

isomerization from α,β−unstaturated ester to a β,γ−unsaturated ester already established

N-phenylpyridone confirmed by UV and IR

Synthesis of Strychnine (1954)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.

I II

V

III

NH

OMe

OMeNH

OMe

OMe

NMe3

I–

NH

NH2

NH

NCO2Et

N

OMe

OMe

NCO2Et

Ts

N

OMe

OMe

NCO2Et

Ts

O Me

NH

NCO2Et

Ts

CO2MeN

NCO2Et

Ts

O

1. CH2O, HNMe2, aq. dioxane, AcOH

2. MeI

1. NaCN, DMF

2. LiAlH4, THF, Δ

-MeOH

benzene

TsCl

pyridine

1. NaBH4, EtOH

2. Ac2O, pyr

1. O3, aq. AcOH2. HCl, MeOH, Δ

MeO2C

OMe

OMe

OMe

OMe

HO

O

O

Me

CO2Me

Dieckmann condensation


multiple acidic sites present could

pose a problem

confirmed enol structure by UV

werenʼt expecting the product in enol form, but were able to

utilize it in the synthesis addition-

elimination

compound isolated in degredation studies

cis ester obtained as major product but easily converted

into the more stable trans ester

N

N

O

OH

CO2Me

N

N

O

N

N

O

O

MeCO2H

N

N

O

O

Me

O

O

HI, Δ

red phosphorus

N

NHCO2H

O

1. NaOMe, MeOH2. Ac2O, pyr

3. NaOMe, MeOH, Δ

N

NCO2Et

Ts

O

CO2Me CO2H

O

Me

1. TsCl, pyr2. NaSCH2C6H7

1. Raney Ni, EtOH, Δ

2. Pd/C, H23. hydrolysis N

N

O

S

CO2Me

O

MeAc2O, pyr,Δ

–CO2

1. aq. HCl, AcOH2. SeO2, EtOH

Me

O

goes through a glyoxal intermediate

Dakin & West 1928

IV

VI


need to reduce the pyridone ring on the concave side

without touching the carbonylthe hydride is

delivered intramolecularly

isomerization of the tertiary allylic carbinol

with mild acid failed

isostrychnine

strychnine

obtained 8 mg!

VII

Prelog 1948

N

N

OH

H

HO

NO

N

O

HH

H

H

H

N

N

O

O

O

N

N

O

O

OH

N

N

O

OH

N

N

O OH

KOH, EtOH

LiAlH4, EtOH,

N

N

OAlR2

H

O

H AliBu

iBu

Δ

NaC CH1. , THF

2. Lindlar's, H2

1. HBr, AcOH

2. aq. H2SO4, Δ

.selrr{JJv dlrsJ:,\ru,l _ _-dsa1"rno3 'esJnoJJo ,an1q

tsa.t eqt .:_

eJntJnJls eql,eB euruqclrls s.pi.,.

's{lo PI^BC .\\

.,..

'slseqluls :uruq;,,futs oLlJ Jo uoll)lc .

uo sreqrreeser.i\rollej srq pue s{lo p-":ol prE.t|poo^\ dq ruas rurr8alat cne.-

-f,- dq.^s iqr qqtRdn'N.u!r

lsto ortEdu*.q HmqlbHublr rq!.I/o t,.pJo lqJo r oFr urq q.p qy,il! ro,.f,rrronr snwcira.r", *.,|#r; il;l;;6'F wdd; d{+ dnou3 vNtsu38 lNV0NV|1t103 (uvs000s s u

sN0 | tv-t0lvu9N03 tsSy{uvq

sun0 3uv ,\tHt qNv ,\t43N3 lHt l.lfr IAVH l$

- 10tS I UE

t

I

SzvlrNJH av0u. Hst0NlAvS 8I S't-10 0t/lV0 ri 80


“The beauty of the strychnine synthesis resides principally in the flexible strength of its master plan, and especially in the seemingly effortless disposal of one stereochemical problem after another.”

-John Cornforth

Woodwardʼs blue strychnine tie with the structure in white


Synthesis of Reserpine (1956)

A Rauwolfia serpentina plant

NH

NMeO

MeO2C OMe

O

O OMe

OMe

OMe

H

H

H

reserpine

• Extract from Indian snake root, or Rauwolfia serpentina, had been used by traditional doctors to treat insect or reptile bites

• 1930s: Scientists discovered it could be used to treat hypertension, nervous disorders or even schitzophrenia

• 1952: Emil Schlittler isolated reserpine at CIBA in Basel and coined the name

• By 1955 the structure was fully elucidated

A B CD

E

Synthesis of Reserpine (1956)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.

aimed to get the most chiral centers into the molecule as early as possible

A B

C

DE

Diels-Alder

MeO2C

NH

NMeO

MeO2COMe

O

O OMe

OMe

OMe

H

H

H

reserpine

N

H

HOMe

O

O

OMeOMe

OMe

H

NH

OMe

NH

NMeO

MeO2C OMe

OAc

H

H

O

NH

NMeO

MeO2COMe

OAc

H

H

H

NH

MeO NH2

RO2COHC

MeO2C OMe

OAc

H

H

6-methoxytryptamine

O

O

MeO2C

methyl vinylacrylate

benzoquinone


endo transtition state

O

O

MeO2C

benzene

Δ

O

O CO2Me O

O

H

H

MeO2C

OH

H

HO

O

Al(i-OPr)4, IPrOH

H

HO

O

Br2

O

Br

H

HO

O

O

OMe

NaOMe,MeOH

H

HO

O

O

OMe

aq. NBS

H2SO4, 70 ºC

HOBr

O

O

HH

O

HHBr

OH2

δ+

H2CrO7,AcOH

H

H

HO2COMe

O

OHH

HO

O

O

OMe

OBr

Zn, AcOH

Diels-Alder

bromonium ion formation on bottom face

3 chiral centers set!

Meerwein-Pondorf reduction

HHHO2C

HOHH

O

quasi-equatorial

H

H

H

CO2HO

OHH

quasi-axial

formation of the 6-membered lactone confirmed a quasi-axial conformation of the Diels-Alder cycloadduct

E

E1cb mechanism


lose formaldehyde!

reductive aminationprepared in 1930 by Akabori and Saito

need to invert newly formed stereocenter!

H

HOMe

NNH

OMeOAc

MeO2C �

NH

NMeO

MeO2C OMe

OAc

H

H

O

NH

MeO NH2

H

H

HO2COMe

O

OHH

H

MeO2COMe

O

OH

1. CH2N22. Ac2O, pyr

3. OsO4, then NaClO3

OHOH

H

H

MeO2COMe

OH

OH

MeO2C1. aq. HIO4

2. CH2N2, CH2Cl2

1. benzene2. NaBH4, MeOH

POCl3

NH

NMeO

MeO2COMe

OAc

H

H

H

NaBH4,MeOH

A B D

C


most stable conformation–canʼt isomerize center with acid

MeO2C

reserpine

N

H

HOMe

O

O

OMeOMe

OMe

H

NH

OMe

NH

NMeO

MeO2COMe

OAc

H

H

H

H

HOMe

NNH

OMe

1. KOH, MeOH

HOMe

O

NO

OAc

MeO2C �

pivalic acid,xylene, Δ

2. DCC, pyr

1. methanolysis

2. pyr, OMeOMe

OMeCl

N HOMe

H

NH

OMe

O

O

NH

OMe

HHH

H

very strained intermediate

isomerization driven by strain relief

Synthesis of Reserpine (1956)

NH

NMeO

MeO2C OMe

O

O OMe

OMe

OMe

H

H

H

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 stereoselectivity was maintained throughout a long synthetic sequence in such a particularly elegant manner

Synthesis of Chlorophyll (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 was contained in chlorophyll, he purified chlorophyllʼs a and b, and isolated the phytyl alcohol side chain

• He won the Nobel Prize in 1915 for this work

• 1930s: Hans Fischer performed chemical studies and later proposed a structure in 1936

• He won the Nobel Prize in 1930 for synthesizing heme

• 1950s: R. P. Linstead also performed chemical studies and proposed the structure that later RBW was skeptical of but accepted and turned out to be correct

N N

NN

Me

EtMe

Me Me

OO

MeMe

Me

Me

Me

OMeO2C

Mg

chlorophyll-a

I II

IIIIV

Synthesis of Chlorophyll (1960)

N

HN

N

NH

R R

R

R

R R

R

R

porphyrin ring

• Chlorophyll contained an extra ring fused to ring III

• It also possessed two “extra” hydrogen in ring IV

N N

NN

Me

EtMe

Me Me

OO

MeMe

Me

Me

Me

OMeO2C

Mg

chlorophyll-a

I II

IIIIV


I II

IIIIV

HN

Me

CO2Et

HN

Et

Me

CH2Cl

CNNC

aq. HCl

EtOH, Δ

HN

Et

MeCNNC

HN

Me

CO2Et

anhy. ZnCl2

Cl

O

CO2MeHN

Et

MeCNNC

HN

Me

CO2Et

O

MeO2C

1. 33% aq. NaOH, Δ2. CH2N2

HN

Et

MeO

HN

Me

CO2Me

O

MeO2C

H

1. EtNH2

2. H2S, MeOH/ benzene

HN

Et

MeS

HN

Me

CO2Me

O

MeO2C

HNH

Me

NH2

NH

Me

CO2Me

H

O

HN

Me

CO2Et

HN

Et

Me

CH2Cl

CNNC

work by Triebs, Schmidt & Zinsmeister in 1957

aldehyde masking group!

the other α position is too electron deficient to react

the thioaldehyde was a new concept!

goes through a N-ethylimino intermediate

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)I

II

III

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.

Schiff base formed

phlorin salt

the use of the thioaldehyde doubled the yield of this process!

oxidation

NH

Me

NH2

NH

Me

CO2Me

H

O

HN

Et

MeS

HN

Me

CO2Me

O

MeO2C

H

HBr

MeOH

aq. NaBH4

12 N HCl,MeOH

1. I2

2. Ac2O, pyr 50% yield over 5 steps

AcOH

air

NH

Me

NH2

NH

Me

CO2Me

NH

Me

NH2

NH

Me

CO2Me

NH

Me

NHMe

CO2Me

HN

Et

Me

HN

Me

CO2Me

O

N

MeO2C

NH HN

HNNH

Me

EtMe

Me Me

NH3

CO2Me

CO2MeMeO2C

NH N

HNN

Me

EtMe

Me Me

NHAc

CO2Me

CO2MeMeO2C

NH N

HNN

Me

EtMe

Me Me

NHAc

CO2Me

CO2MeMeO2C

and no other contaminant!

it was known that phlorin salts can

be readily oxidized by air

a porphyrin

Synthesis of Chlorophyll (1960)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.

“This remarkable reaction represents the first instance ever observed of reversible interconversion of a porphyrin and a chlorin.”

-RBW

NH N

HNN

Me

EtMe

Me Me

NHAc

CO2Me

CO2MeMeO2C

N HN

HNN

Me

EtMe

Me Me

NHAc

CO2MeMeO2C

H

MeO2C

3: 5porphyrin : purpurin

AcOH, 100 ºC

under N2

steric compression is most likely driving this process


elimination of trimethyl-ammonium species

Hofmann Elimination


keto-aldehyde formation most likely strain driven

NN

NN

MeEt

Me

Me

Me

OO

Me Me Me

Me

MeOMeO2C

Mg

N HN

HNN

Me

EtMe

Me Me

NHAc

CO2MeMeO2C

H

MeO2C

1. 1 N HCl, MeOH2. Me2SO4

3. NaOH, MeOH N HN

HNN

Me

EtMe

Me Me

CO2MeMeO2C

H

MeO2C

light &air

N HN

HNN

Me

EtMe

Me Me

CO2MeMeO2C

H

MeO2CCHOO

N HN

HNN

Me

EtMe

Me MeH

MeO2C

O OMeOH

KOH, MeOH–CO2, –CO

N HN

HNN

Me

EtMe

Me MeH

MeO2C

O ONCH

HCN, NEt3,CH2Cl21. Zn, AcOH

HCl, MeOH

2. CH2N2N HN

HNN

Me

EtMe

Me MeH

MeO2C

NCH CO2Me

N HN

HNN

Me

EtMe

Me MeH

MeO2C

MeO2CH CO2Me

N HN

NNH

Me

EtMe

Me Me

Me OMeO2CMeO2C

H

H

NaOMe 1. phytol

2. Mg (OH)Cl chlorophyll-a

chlorin e6 trimethyl ester

Willstätter & Fischer

unexpected methoxy-lactone formation


elimination of trimethyl-ammonium species

Hofmann Elimination


keto-aldehyde formation most likely strain driven

NN

NN

MeEt

Me

Me

Me

OO

Me Me Me

Me

MeOMeO2C

Mg

N HN

HNN

Me

EtMe

Me Me

NHAc

CO2MeMeO2C

H

MeO2C

1. 1 N HCl, MeOH2. Me2SO4

3. NaOH, MeOH N HN

HNN

Me

EtMe

Me Me

CO2MeMeO2C

H

MeO2C

light &air

N HN

HNN

Me

EtMe

Me Me

CO2MeMeO2C

H

MeO2CCHOO

N HN

HNN

Me

EtMe

Me MeH

MeO2C

O OMeOH

KOH, MeOH–CO2, –CO

N HN

HNN

Me

EtMe

Me MeH

MeO2C

O ONCH

HCN, NEt3,CH2Cl21. Zn, AcOH

HCl, MeOH

2. CH2N2N HN

HNN

Me

EtMe

Me MeH

MeO2C

NCH CO2Me

N HN

HNN

Me

EtMe

Me MeH

MeO2C

MeO2CH CO2Me

N HN

NNH

Me

EtMe

Me Me

Me OMeO2CMeO2C

H

H

NaOMe 1. phytol

2. Mg (OH)Cl chlorophyll-a

chlorin e6 trimethyl ester

Willstätter & Fischer

unexpected methoxy-lactone formation

The synthesis took 4 years and 17 post docs in groups of 3 to 6

at a time to complete



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

Moving up

Courtesy of John D. Roberts

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

The Octant Rule (1961)

• In 1895, Aimé August Cotton observed that the optical rotation changed dramatically when measured around the wavelength absorbed by the chiral molecule

• If the partial rotation curve became strongly positive and then sharply negative, it was a positive Cotton effect

• A negative Cotton effect is observed when the curve becomes negative and then positive

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.

positive Cotton effect

negative Cotton effect

chrysanthenone in isooctane

verbenalin in water

Me

O

Me Me

O

OMeO

O

H

MeH

H

O OHO OH

OH

OH


• From 1952-1957 Carl Djerassi at Wayne State University in Detroit applied optical rotatory dispersion to organic molecules

• In 1957 William Klyne showed that introduction of a halogen α to a ketone in the equatorial position of a steroid caused a small change in the Cotton effect compared to the parent compound

• However, introduction of a halogen in the axial position caused a large change in the Cotton effect

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.




verbenalin in water

Me

O

Me Me

O

OMeO

O

H

MeH

H

O OHO OH

OH

OH

The Octant Rule (1961)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.




verbenalin in water

Me

O

Me Me

O

OMeO

O

H

MeH

H

O OHO OH

OH

OH

• In 1958, Djerassi gave a seminar at Harvard and met Woodward, Moffitt and Moscowitz who were working on a theory of optical activity

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“Steroids Made It Possible”

CO

b a

Z

X

Y

The Octant Rule (1961)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 space around a carbonyl of an asymmetric ketone can

be divided into octants

The octants are assigned signs based on empirical

evidence of the contribution of each atom in a given

octant toward the Cotton effect

CO

b a

Z

X

Ya substituent not in the Z

plane of the carbonyl group will contribute to the chiral

ketoneʼs asymmetry

Absolute configurations can be assigned using this method!

Djerassi & Klyne

The Octant Rule (1961)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.

O

H

MeZ

X

Y

how the cyclohexanone must be drawn on the diagram:


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

Courtesy of Carl Djerassi

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

The Woodward Research Institute (1963)

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


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

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

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

The National Medal of Science (1964)

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


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.”

The Woodward-Hoffmann Rules (1964-69)

• There was much debate during the 1930s over whether the mechanism of the Diels-Alder reaction was concerted or stepwise

• In 1942, Woodward had proposed an ionic mechanism involving electron transfer and an ion pair

• Woodward felt as though he fully understood and could predict the outcome of the Diels-Alder reaction until his endeavors in the vitamin B12 synthesis

• Working with his post doc, Subramania Ranganathan, RBW discovered that he did not in fact make the expected product when trying the following Diels-Alder reaction

Woodward, R. B. The mechanism of the Diels-Alder reaction. J. Am. Chem. Soc. 1942, 64, 3058-3059.

N

OH

CN

MeO2CMe

O OMe

Me

Me

OO

H

N

OH

CN

MeMeO2C

O OMe

Me

Me

OO

H

N

OH

CNMeO2C

Me

O OMe

Me

Me

OO

H

N

OH

CNNC

MeO2C

O OMe

Me

Me

OO

H

heat

heat

heathν


N

OH

CN

MeO2CMe

O OMe

Me

Me

OO

H

N

OH

CN

MeMeO2C

O OMe

Me

Me

OO

H

N

OH

CNMeO2C

Me

O OMe

Me

Me

OO

H

N

OH

CNNC

MeO2C

O OMe

Me

Me

OO

H

heat

heat

heathν

Subramania Ranganathan described that when RBW “had discovered that his predictions relating to stereochemistry had gone awry...his enormous and rightful self-confidence would not accept the outcome meekly, and the result was, of course, the Woodward-Hoffmann rules.”


• It was already accepted that electrons 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 density to spread over two or more atoms

e–

The significant detail that Woodward and Hoffmann established was that the orbitals must be in the same phase in order to bond

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

“...the steric course of the electrocyclic transformation is determined by the symmetry 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.

MeMeMe Me

conrotationΔ

Me Me Me Me

disrotationΔ

The Woodward-Hoffmann Rules (1964-69)Woodward, R. B.; Hoffmann, R. Stereochemistry of electrocyclic reactions. J. Am. Chem. Soc. 1965, 87, 395-397.

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

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

conrotationMe H H Me

H

MeH

Me

Δ

disrotation

HMe

H MeMe

H

Me

HΔ

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

MeMe

Me controtationdisrotationhν hν

Me Me Me Me

The Woodward-Hoffmann Rules (1964-69)Woodward, R. B.; Hoffmann, R. Selection rules for concerted cycloaddition reactions. J. Am. Chem. Soc. 1965, 87, 2046-2048.

• 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!

The Woodward-Hoffmann Rules (1964-69)Woodward, R. B.; Hoffmann, R. Selection rules for concerted cycloaddition reactions. J. Am. Chem. Soc. 1965, 87, 2046-2048.

• 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!


1,3 sigmatropic shifts :

• In the third paper, Woodward and Hoffmann introduce the selection rules for sigmatropic [1,3], [1,5] and [1,7] shifts

Antarafacial GeometrySuprafacial Geometrybonding

Ψ2 (allyl anion HOMO)

antibondingbonding bonding

Y X YX

Proton 1S (LUMO)H

H

Antarafacial GeometrySuprafacial Geometry

bonding

antibonding

bonding bonding

Y X YX

H

H

Ψ2 (allyl anion HOMO)

Proton 1S (LUMO)

Woodward, R. B.; Hoffmann, R. Selection rules for sigmatropic reactions. J. Am. Chem. Soc. 1965, 87, 2511-2513.

The Woodward-Hoffmann Rules (1964-69)the controversy...

Hoffmann, R. A Claim on the Development of the Frontier Orbital Explanation of Electrocyclic Reactions. Angew. Chem. Int. Ed. 2004, 43, 6586-6590.

Elias J. Corey Roald Hoffmann

R. B. Woodward

• 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

“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

“In 1963-64, E. J. Corey and A. G. Hortmann accomplished the total synthesis of dihydrocostunolide. A crucial step involved a stereospecific electrocyclic reaction. The two papers on the work do not have any reference to an electronic factor in the stereoselectivity.”

“Woodward had a habit of posing to people problems of great interest. And also of posing such problems as puzzles, even if he had the solution...I think that May 4 conversation [between RBW and EJC] perhaps might have prompted Woodward to push on, and to ask for my assistance with calculations supporting the frontier orbital approach.”




R. B. Woodward

“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

“In 1963-64, E. J. Corey and A. G. Hortmann accomplished the total synthesis of dihydrocostunolide. A crucial step involved a stereospecific electrocyclic reaction. The two papers on the work do not have any reference to an electronic factor in the stereoselectivity.”

“Woodward had a habit of posing to people problems of great interest. And also of posing such problems as puzzles, even if he had the solution...I think that May 4 conversation [between RBW and EJC] perhaps might have prompted Woodward to push on, and to ask for my assistance with calculations supporting the frontier orbital approach.”

“I asked him directly if Corey had a role in this work. He said “no”–this was our (R.B.W. and R.H.) work.”

-Roald Hoffmann

Synthesis of Cephalosporin 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 FredgaLes 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)

The Nobel Prize winners in Stockholm for the ceremony in 1965: Robert B. Woodward (chemistry); Julian Schwinger and Richard P. Feynman (physics); François Jacob, André Lwoff, and Jacques Monod (physiology or medicine); and Mikhail Sholokhov (literature)

Courtesy of Eudoxia Woodward

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.”

-RBWFrom 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


Vitamin B12 Synthesis (1960-76)

N

O

H2N

H2N

OMeH

N

N

ONH2

Me NH2

O

H

NMeMe

NH2O

H

H2N OH Me

NHO

OP

O

O OO

OHH

HN

NHHO

Me

Me

Me

Co

Me

HMe

Me

NCA

B

CD

Vitamin B12

• In 1926, George Minot (a Harvard professor of medicine) successfully used liver to treat pernicious anemia

• In 1928, Eli Lilly & Co. introduced liver extract to the market

• Ed Rickus of Merck was finally able to isolate the red crystals of vitamin B12


• In 1956, Dorothy Hodgkin was able to obtain and solve the X-ray crystal structure of vitamin B12

• Wilhelm Friedrich and Konrad Bernhauer from Stuttgart 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

N

O

H2N

H2N

OMeH

N

N

ONH2

Me NH2

O

H

NMeMe

NH2O

H

H2N OH Me

NHO

OP

O

O OO

OHH

HN

NHHO

Me

Me

Me

Co

Me

HMe

Me

NC

N

O

H2N

H2N

OMeH

N

N

ONH2

Me NH2

O

H

NMeMe

NH2O

H

H2N OH Me

OHO

Me

Co

HMe

Me

NC

OH

Vitamin B12

cobryic acid


N

O

H2N

H2N

OMeH

N

N

ONH2

Me NH2

O

H

NMeMe

NH2O

H

H2N OH Me

NHO

OP

O

O OO

OHH

HN

NHHO

Me

Me

Me

Co

Me

HMe

Me

NCA

B

CD

Vitamin B12

• In 1959, Albert Eschenmoser began working on the synthesis of the corrin system of vitamin B12

• During 1960-61, Woodward began working on rings A and D, or the western portion of the molecule

• Also in 1960, Eschenmoser began working on the eastern portion of the molecule, rings B and C

• By 1964, Eschenmoser had finished the corrin system

• Eschenmoser and Woodward finally agreed to collaborate and finish the molecule together in 1965

The corrin system is the porphyrin ring system of the molecule without the cobalt


N

O

H2N

H2N

OMeH

N

N

ONH2

Me NH2

O

H

NMeMe

NH2O

H

H2N OH Me

NHO

OP

O

O OO

OHH

HN

NHHO

Me

Me

Me

Co

Me

HMe

Me

NCA

B

CD

Vitamin B12

The direct link between the A and D rings with no intervening carbon was going to be a challenge

The molecule contains 9 stereocenters, which means it has 512 possible stereoisomers

In this synthesis they needed to master the stereochemical complexity as well as master the complexity inherent in large, macrocyclic, highly unsaturated, nitrogen-containing chromophore structures

This type of corrin system had never been made before–needed to pioneer a route


A

the transition state with the methyl groups syn to one another is lower in energy

resolved by urea formation with (+)-α-phenylethyl isocyanate

NH

Me

Me

OMe 1. MeMgI

2. propargyl bromide

N

Me

Me

OMe

NH

OMe

O

Me

Me

Me

Me

MeCl

O

N

OMe

O

Me

Me

H

Me

MeMe

O

N

O

N

Me

MeH

Me

MeMe

O

HHO

NON

Me

MeH

O

HHO

CO2Me

Me

Me O O

Me

1. O3, MeOH2. HIO4

3. CH2N2

BF3, HgO

NHMe

Me

HgOOMe

1. H+,

2. Et3O+BF4–

3. NaOMe4. toluene, Δ

OHHO

N

OMeMe

Me

H

Me

MeMe

OEt

O

OLi, NH3 (l),t-BuOH, THFN

OMeMe

Me

H

Me

MeMe

OEt

O

O

H+

N

O

O

Me

MeH

Me

MeMe

O

H 1. NH2OH2. HNO2, AcOH

took 16 steps total

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


Me

NH

OMe

O

Me

Me

N

OMe

O

Me

MeN

OMeMe

Me

S

S N

OMeMe

Me

NH

O O O

OH

MeCO2HMe Me NH

H CO2H

O

"ozonization"

Me

Me HN

H

OMe

Me NHCO2Me

HOO

Me

Me CO2H

HO

Me

Me Me

H(+)–camphor

O

degraded through chloride, azide and isocyanate



A

Birch reduction

need to protect both carbonyls

cyclohexene and cyclopentene ring are opened!

get oximation of both ketones but can remove unfavored oximino group

NH

Me

Me

OMe 1. MeMgI

2. propargyl bromide

N

Me

Me

OMe

NH

OMe

O

Me

Me

Me

Me

MeCl

O

N

OMe

O

Me

Me

H

Me

MeMe

O

N

O

N

Me

MeH

Me

MeMe

O

HHO

NON

Me

MeH

O

HHO

CO2Me

Me

Me O O

Me

1. O3, MeOH2. HIO4

3. CH2N2

BF3, HgO

NHMe

Me

HgOOMe

1. H+,

2. Et3O+BF4–

3. NaOMe4. toluene, Δ

OHHO

N

OMeMe

Me

H

Me

MeMe

OEt

O

OLi, NH3 (l),t-BuOH, THFN

OMeMe

Me

H

Me

MeMe

OEt

O

O

H+

N

O

O

Me

MeH

Me

MeMe

O

H 1. NH2OH2. HNO2, AcOH

get one enantiomer!


Me

Me

MeOH

O

Me

Me

Me CO2Me

Me

Me Me

H(–)-camphor

O


specific conditions necessary to get desired cyclization of the diketones Beckmann

rearrangementconfirmed by X-ray crystallography!

alpha-corrnorsteronebeta-corrnorsterone

hesperimine

OH2

A

D

D

D ring formed through a intramolecular Michael addition

western fragment complete

NON

Me

MeH

O

HMsO

CO2Me

MeMe

O

NH

O

MeH

CO2Me

N

O

H

Me

CO2MeMe

ONH

O

MeH

CO2Me

N

O

H

Me

CO2MeMe

ONH

O

MeH

CO2Me

NH

Me

CO2MeMe

MeO

CO2Me

NH

OMe H

CO2Me

N

HMeMeO2C

Me

OMe

MeO2C

NH

OMe H

CO2Me

N

CHOCO2Me

HMeMeO2C

Me

MeO2C

NH

OMe H

CO2Me

N

CH2BrCO2Me

HMeMeO2C

Me

MeO2C

NON

Me

MeH

O

HHO

CO2Me

Me

Me O O

Me

1. MeOH,N

OMe

2. MsCl, NEt3

polystyrenesulphonic acid,MeOH, 170 ºC

NON

Me

MeH

O

HMsO

CO2Me

1. O3, wet MeOAc2. HIO4

3. CH2N2 Me

O

MeMeO2C

1. strong base, Δ

2. CH2N2

HCl, MeOH

1. O3, MeOH2. SMe2 1. NaBH4, MeOH

2. MsCl, pyr3. LiBr, DMF



B

C

Ring B is formed through a Diels-Alder cyclization and a Arndt-Eistert homologation

Ring C is derived from (+)-camphor

The original route to eastern fragment developed by Eschenmoser but several routes were developed by both Zurich and Cambridge for this fragment

mechanism involves oxidation to the disulphide and then attack by the eneamide

mechanism unknown of sulfur–extrusion but suspect that an episulphide involved

B

C eastern fragment complete

HN

O

O

MeMe

SCO2Me

HN

O

CO2Me

Me

Me

N

O

O

MeMe

CO2MeS

HN

O

CO2Me

MeMe

BnOOHCH2Cl2

N

O

O

Me

Me CO2Me

HN

S

CO2Me

Me

Me

1. POEt3, xylene, Δ

2. Me3O+BF4–,

then H2S

sulfur-extrusion coupling method developed by Zurich in 1965


Vitamin B12 Synthesis (1960-76)B

Ceastern fragment

A

D

western fragment

Eschenmoser, A.; Wintner, C. E. Natural Product Synthesis and Vitamin B12. Science. 1977, 196, 1410-1420.

NH

OMe H

CO2Me

N

CH2BrCO2Me

HMeMeO2C

Me

MeO2C

N

O

O

Me

Me CO2Me

HN

S

CO2Me

Me

Me

1. KOt-Bu,

2. PPh3, BF3, benzene

NH

OMeH

MeO2C

N

CO2Me

HMe

MeO2C

Me

MeO2CN

O

O

MeMe

CO2Me

HN

CO2Me

Me

Me

CoCl,aq. KCN,

air

N

MeH

MeO2C

N

CO2Me

HMe

MeO2C

Me

MeO2CHN

S

O

MeMe

CO2Me

N

CO2Me

Me

Me

SMe

P2S5picoline (cat.)

N

MeH

MeO2C

N

CO2Me

HMe

MeO2C

Me

MeO2CHN

Me

CO2Me

N

CO2Me

Me

Me

SMe

CONMe2

Me2NH

N

MeH

MeO2C

N

CO2Me

HMe

MeO2C

Me

MeO2CN

Me

CO2Me

N

CO2Me

Me

Me

SMe

CONMe2

CoCN

NC

1. BnOOH CH2Cl2

2. POEt3, xylene, Δ

N

MeH

MeO2C

N

CO2Me

HMe

MeO2C

Me

MeO2C

N

Me

CO2Me

N

CO2Me

Me

Me

CONMe2

CoCN

NC

N

MeH

MeO2C

N

MeO2C

HMe

MeO2C

Me

MeO2C

N

Me

CO2Me

N

CO2Me

Me

Me

CoCN

NC

O

O

1. AgBF4,

I2, AcOH, DMA

1. PhSH 2. Zn(Hg), AcOH N

MeH

MeO2C

N

MeO2C

HMe

MeO2C

Me

MeO2C

N

Me

CO2Me

N

CO2Me

Me

Me

CoCN

NC

CO2Me

3. CH2N24. conc. H2SO4

2. 0.1 N HCl3. Me2NH, i-PrOH4. NH3, NH4Cl

N

O

H2N

H2N

OMeH

N

N

ONH2

Me NH2

O

H

NMe

Me

NH2

O

H

H2N OH Me

OHO

Me

Co

HMe

Me

NC

OH

Me

ClN

OMe

Mecobryic acidseparated

diastereomers by HPLC

separated diastereomers by HPLC

block the C10 position by formation of the lactone from undesired methylation


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

Eschenmoser, A.; Wintner, C. E. Natural Product Synthesis and Vitamin B12. Science. 1977, 196, 1410-1420.

N

O

H2N

H2N

OMeH

N

N

ONH2

Me NH2

O

H

NMeMe

NH2O

H

H2N OH Me

NHO

OP

O

O OO

OHH

HN

NHHO

Me

Me

Me

Co

Me

HMe

Me

NC

N

O

H2N

H2N

OMeH

N

N

ONH2

Me NH2

O

H

NMeMe

NH2O

H

H2N OH Me

OHO

Me

Co

HMe

Me

NC

OH

Vitamin B12

cobryic acid

Bernhauer-Friedrich pathway

A

B

CD


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

This synthesis serves as an example of the role of natural product synthesis in generating fundamental knowledge in organic chemistry

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

Courtesy of Mark Wuonola

Vitamin B12 Synthesis (1960-76)Woodward and Eschenmoser admiring the

“marvelous B12 machine” at the Zurich symposium

Courtesy of Dorothy Felix

“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

The “Woodward Lectures”

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

-RBW

• 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”

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: Philadelphia, PA, 2001.

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

the life and achievements of robert burns woodward

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