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William S. Knowles

June 28, 2012

Extended molecules, especially those built from a carbon atom backbone, have various options as to how their molecules are arranged in space. The formula unit is the same, but the shape of the molecule is different, and it may have different chemical properties. Molecules can exist in one form, or a mirror image form, a property called chirality, from, χειρ, the Greek word for hand.

Living things favor one of these forms, one enantiomer over the other. Amino acids, the primitive building blocks of proteins, are left-handed (L, for Levo-), and sugars are "right-handed" (D, for dextro-). The D and L designations refer to the optical rotation caused by the molecules in solution.

The interesting thing is that when you make chemical compounds by the usual methods, you get what's called a racemic mixture, a product that has equal quantities of right- and left-handed molecules. Why living things prefer one handedness over the other is a mystery, but there are a few conjectures.

One of these conjectures is that the choice was made randomly at early stages of evolution, and it was then "locked-in." Another conjecture is that the initial amino acid "seeds" came from meteors that were exposed to cosmic radiation. The partial circular polarization of this radiation might have selectively destroyed one amino acid enantiomer, leaving the other.[1]

The chirality of molecules can be important in drug discovery. One enantiomer may have desired therapeutic properties, while the other might be toxic. This was the case for 3,4-dihydroxyphenylalanine (DOPA), which comes in an "L" form, L-DOPA, and an "D" form, D-DOPA. L-DOPA is useful in the treatment of Parkinson's disease, while R-DOPA is both ineffective for this, and also toxic.

William Standish Knowles, who died on June 13, 2012, at age 95, shared the 2001 Nobel Prize in Chemistry for developing methods for the synthesis of one enantiomer over the other.[2-9] Knowles and his team at Monsanto applied his techniques to the synthesis of L-DOPA. His daughter revealed that the cause of death was amyotrophic lateral sclerosis (ALS; a.k.a., Lou Gehrig's disease).[5]

William S. Knowles

William Standish Knowles

June 1, 1917 - June 13, 2012

(Courtesy of the National Academy of Sciences))


William Standish Knowles (June 1, 1917 - June 13, 2012) was an American chemist who received his Bachelor's degree from Harvard in 1939; and his Ph.D. from Columbia University in 1942. Knowles spent most of his career at the Monsanto Chemical Company in St. Louis, Missouri.

In his Nobel Foundation autobiography, Knowles writes that he was the first of his relatives to become a scientist.[2] Knowles excelled at academics, and he won easy admittance to Harvard. He was advised, however, that he was too young to be a college student, so he spent an additional senior year of high school at Andover Academy.[2]

The summer between high school and college, Knowles was a crewman aboard 75-foot schooner, where he sailed across the Atlantic from Gloucester, Massachusetts, eventually arriving at Stockholm, Sweden, where, later in life, he received his Nobel Prize.[2] At Harvard, he excelled in mathematics and physical chemistry, but he became enamored with organic chemistry after taking a course from the Harvard organic chemist, Louis Fieser.[9] While at Columbia, he had a laboratory explosion while distilling diazomethane, but no one was hurt.[2]

During the war years, chemists were put on a fast track to their Ph.D., so Knowles obtained his in three years, and he went to work for a Monsanto laboratory in Dayton, Ohio, making hexamethylenetetramine for explosives.[2] After two years at Dayton, he was transferred to St. Louis, synthesizing such things as benzyl benzoate, which acted as a mite repellent.[2] He helped devise a synthesis for vanillin, but the process was not economically viable; and chloramphenicol, an antibiotic that was later found to have an unfortunate side-effect. Knowles used his laboratory antibiotic to cure his dog of a fungal infection.[2]

Knowles worked also on the synthesis of cortisone with Harvard's Robert Burns Woodward, Nobel Chemistry Laureate for 1965. Knowles simplified Woodward's original fifty-step cortisone synthesis to 36 steps.[9]. As it turned out, the Mexican yam had a high content of diosgenin which could be used in a simpler synthesis.[2] Monsanto had a "technical ladder" through which scientist could advance without becoming managers, so Knowles was happily a productive scientist for all his working years.[2]

Knowles' process for production of L-DOPA was based on asymmetric hydrogenation using the catalyst, methylcyclohexyl-o-anisylphosphine (CAMP). The original efficiency in terms of the L-DOPA product was 88%;[9] but with tweaking it jumped to 97.5 percent.[6-7] Knowles shared the 2001 Nobel Prize in Chemistry with K. Barry Sharpless of the Scripps Research Institute (La Jolla, CA), and Ryoji Noyori of Nagoya University, Japan.[3-4], with half the monetary award going to Sharpless.[5] This division may have been because of Sharpless later work producing beta blockers, anti-inflammatory drugs, and other pharmaceuticals using the same technique.[4]

The Nobel Prize was a complete surprise to Knowles. In 2001, he had been retired for fifteen years. Knowles thought that his award was a consequence of Alfred Nobel's intention that his prize would be for things of certain benefit to mankind. He had created an invention that immediately helped people.[9] Said his co-Nobel Laureate, Barry Sharpless, "What I think is so cool about Knowles is that he's such a gentleman... And he came out of no-where, actually. He was surprised, I think (to win the Nobel Prize)."[9]

Although the Nobel Prize was awarded to just three individuals, the number limited to three by custom, Knowles always cited Henri Kagan of the Université Paris-Sud (Orsay, France), who discovered a similar asymmetric synthesis about six months after Knowles. Kagan received the Wolf Prize in Chemistry, along with Noyori and Sharpless, the same year as the award of the Nobel Prize. The Wolf Prize is considered to be the most prestigious chemistry award after the Nobel Prize.[9]

Knowles was a member of the National Academy of Sciences and the American Chemical Society (ACS).[3] He was given the 1982 ACS Award for Creative Invention.[2]

Knowles loved nature, and he was a dedicated conservationist. He and his wife fought against construction of a highway through the 100-acre farm that they had inherited and restored native prairie grasses, and they won.[6-7] This farm will be ceded to the St. Charles County. Missouri, Parks Department upon their death for use as a nature park.[3]

Knowles daughter, Elizabeth Knowles, said her father did not keep any of the more than $200,000 monetary award of his Nobel Prize. He gave a portion to two Monsanto collaborators on the L-dopa research. The rest, he donated to his two almae matres, Harvard and Columbia.[6-8]

References:

  1. Daniel P. Glavin and Jason P. Dworkin, "Enrichment of the amino acid l-isovaline by aqueous alteration on CI and CM meteorite parent bodies," Proc. Natl. Acad. Sci., vol. 106, no. 14 (April 7, 2009), pp. 5487-5492.
  2. William S. Knowles, Autobiography, Nobel Prize Web Site
  3. Obituary, William Standish Knowles Ph.D., 95, South Coast Today, June 17, 2012.
  4. Tim O'Neil, "William S. Knowles dies at 95; Nobel Prize-winning chemist," LA Times, June 18, 2012.
  5. Martin Weil, "William S. Knowles dies; Nobel Prize-winning chemist was 95," Washington Post, June 18, 2012.
  6. Kenneth Chang, "William Knowles, Nobel Winner in Chemistry, Dies at 95," The New York Times, June 15, 2012.
  7. Kenneth Chang, "William Knowles, Nobel Winner in Chemistry, Dies at 95," Pittsburgh Post Gazette, June 16, 2012
  8. William S. Knowles 1917-2012, Monsanto Blog.
  9. Oliver Yun, "Profile of William S. Knowles," Proc. Natl. Acad. Sci., vol. 102 no. 47 (November 22, 2005), pp. 16913-16915.

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Linked Keywords: Molecule; carbon; atom; empirical formula; formula unit; chemical property; mirror image; chirality; Greek language; hand; life; Living things; enantiomer; amino acid; protein; Levo-; sugar; dextro-; dextrorotation and levorotation; optical rotation; racemic mixture; conjecture; random; evolution; meteorite; meteor; cosmic radiation; circular polarization; drug discovery; toxicity; toxic; DOPA; 3,4-dihydroxyphenylalanine; L-DOPA; D-DOPA; Parkinson's disease; William Standish Knowles; Nobel Prize in Chemistry; enantioselective synthesis; Monsanto; amyotrophic lateral sclerosis; United States; American; chemist; bachelor's degree; Harvard; Ph.D.; Columbia University; Monsanto Chemical Company; St. Louis, Missouri; Nobel Foundation; autobiography; scientist; college student; senior year; high school; Phillips Academy; Andover Academy; schooner; Atlantic Ocean; Gloucester, Massachusetts; Stockholm, Sweden; Nobel Prize; mathematics; hysical chemistry; organic chemistry; Louis Fieser; laboratory; explosion; diazomethane; Dayton, Ohio; hexamethylenetetramine<; explosive; St. Louis; benzyl benzoate; vanillin; economics; economically viable; chloramphenicol; antibiotic; side-effect; dog; drmatophytosis; fungal infection; cortisone; Robert Burns Woodward; Nobel Chemistry Laureate; Dioscorea mexicana; Mexican yam; diosgenin; enantioselective synthesis; asymmetric hydrogenation; catalyst; Nobel Prize in Chemistry; Karl Barry Sharpless; Scripps Research Institute (La Jolla, CA); Ryoji Noyori; Nagoya University; beta blocker; non-steroidal anti-inflammatory drug; anti-inflammatory drug; pharmaceutical; Alfred Nobel; Henri Kagan; Université Paris-Sud (Orsay, France); Wolf Prize in Chemistry; National Academy of Sciences; American Chemical Society; ACS Award for Creative Invention; nature; conservation movement; conservationist; acre; prairie grass; St. Charles County. Missouri.

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