William Standish Knowles (1917–2012)

Bill Knowles passed away on June 13, 2012 at hishome in Chesterfield, Missouri at the age of 95. HisNobel Prize brought the importance of industrialand applied chemistry to the forefront.

William was born on June 1, 1917 in Taunton,Massachusetts and grew up in nearby New Bed-ford. His father was the owner of a cotton mill andhe could have gone into the family business butdidn�t want to do that. He was educated at privateschools and thinking that he was too young to go tocollege, spent a year at Phillips Academy in And-over, Massachusetts, where he won the Boylstonprize (US$50) in chemistry. After this, Knowleswent to Harvard where he specialized in organicchemistry, even though his ability to do mathemat-ics had led his advisors to suggest a physicalchemistry pathway. Louis Fieser was the maininfluence in the move to organic chemistry. Heobtained his AB degree in 1939.

Bill obtained his PhD from Columbia Univer-sity in 1942, working on steroid chemistry withRobert Elderfield. While performing one experi-ment, which required the distillation of diazo-methane, he had an explosion that destroyed ahard-fought intermediate and he had to remake it.The war aided the short time to get his degree.

He then joined the Monsanto Company at theirfacility in Dayton, Ohio, moving to St. Louis in1944. The reason he chose Monsanto was because itwas the farthest west of the companies that offeredhim a job. Chemists were in short supply during thewar. The work at Monsanto covered many topics,starting with the manufacture of hexamethylene-tetramine for the explosive cyclonite and miterepellents, and benzyl benzoate for soldier�s cloth-ing. Another project involved the synthesis ofvanillin from catechol, and this was to have aninfluence later in Bill�s career, even though thischemical route was superseded by an isolation oflignin from paper waste. He also studied a manu-facturing route to the antibiotic chloramphenicol,which was taken off the market because of aplasticanaemia developing in a few patients. However,this did not stop him from mixing some of thisantibiotic with an ointment of other drugs that werebeing administered to his dog suffering from afungal infection. The dog was better in two daysand lived to be 17. Monsanto also looked at thesynthesis of cortisone, and Bill was nominated tojoin this effort from his PhD work on steroids. Thisallowed him to return to Harvard and work in thelabs of Professor R. B. Woodward, whom he grewto admire for his encyclopedic knowledge ofchemistry and ability to look at problems fromnew angles. The first manufacturing project Bill hadthat involved a hydrogenation was the reduction of

para-nitrophenetol. Nickel was the catalyst beingused but the reaction was capricious owing to thehydrogen supply. The use of the more expensivepalladium on carbon gave a much more reliablereaction, which was cheaper in the long term.

The research area that led to the Nobel Prizewas asymmetric hydrogenation. Monsanto becameinterested in the manufacture of the Parkinson�sdrug l-Dopa, and to make it as a single enantiomer.Even in the 1960s, it was realized that the d-isomerwas inactive and just baggage for the patient totake. As noted in his Nobel Lecture, naivety can beuseful and lead to inventions. In a rather academicinvestigation, a new PhD, Jerry Sabacky, was giventhe task of reducing a-phenylacrylic acid in ahomogeneous hydrogenation reaction with rho-dium and a chiral phosphine. The resultant enan-tiomeric excess was 15 %. At this time, Monsantowas selling vanillin to Hoffman–LaRoche, whothen made racemic Dopa and resolved it. Knowlesfound out that the method being used involved theErlenmeyer azlactone procedure, something in thepublic domain, but not simple to find out through“official” channels. As he put it, “the less you haveto hide, the more secretive you become.” Use of therhodium catalyst with the CAMP ligand gave an88% ee of the amino acid derivative, and this wasgood enough to use in a commercial process, as theunwanted enantiomer was rejected in downstreampurifications.

Kagan�s work with DIOP led to an investigationwhere the phosphines were dimerized, and this ledto DIPAMP. As this was easier to make thanCAMP, gave a higher ee in the Dopa synthesis(95 %), and was a crystalline air-stable solid, themanufacturing process moved to the use of [Rh-(DIPAMP)], which is still used today on a com-mercial scale.

The reduction of enamides to make a variety ofa-amino acids and esters was continued by NSCTechnologies, part of Monsanto, to make a widevariety of intermediates used in the pharmaceuticalindustry. Bill regretted the fact that he did not pushharder to get Monsanto to make l-phenylalanineby an asymmetric hydrogenation, as this is a keycomponent of the sweetener aspartame. Nutra-Sweet was the parent company of NSC Technolo-gies, and some of Bill�s colleagues, especially BillyVineyard, were key in working out a crystallizationfor the isolation of the correct isomer of aspartameat commercial scale.

After retiring in 1986, Bill continued to act as aconsultant and interacted with many of us whowere looking to apply asymmetric hydrogenationson an industrial scale to a variety of compounds.These included a new route to the NSAID,naproxen, and the synthesis of unnatural aminoacids using, what was then affectionately known asKnowles� catalyst. John Talley was very impressed

W. S. Knowles

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that he saw this retired scientist sitting in theMonsanto library still reading the literature andmaking notes on 3 � 5 cards.

Working in industry, interactions on researchare not as public as in academia. There is not theturnover of students and many workers can spend aconsiderable time on a single project. Bill was agentle but challenging mentor with an easygoingattitude. He did like to challenge the management.He was excited to talk about science and newpossibilities during these consulting sessions. DrScott Laneman, who was a postdoc at Monsanto atthe time, cherishes one of these sessions where heand Knowles were discussing possible new phos-phine ligands on a chalkboard. Both were coveredin chalk dust with the lab radio blasting out AC/DC.This “older generation meets young” illustratesthat Bill was interested in the science and workingwith others to solve a problem and was not put offby other, albeit rather loud, factors.

Bill chose to follow the technical ladder, ratherthan the managerial one, and was a MonsantoDistinguished Fellow. This acknowledged not onlyhis contributions to the scientific field but also hiscontributions in making products for the company.Even after retirement, he continued to provideexpertise on projects and provide insight into thearea of asymmetric hydrogenations. He took pridein the knowledge that he had helped start animportant and useful area of chemistry. In his ownwords, “industry does too little exploratoryresearch.” His group�s Nobel Prize-winning projecton asymmetric catalysis is “an excellent example ofhow a modest and inexpensive exploratory effort inindustry can produce significant results.” Indeedmuch of the early work was just done just by JerrySabacky. Billy Vineyard then became a member ofthe team. Their work was recognised by Monsantoin 1981 when they won the Charles A. Thomas &Carroll A. Hochwalt Award. Of course, manyothers were involved in moving the technologyinto the plant and this was highlighted when Billwas not invited to the plant celebration when themillionth pound of l-Dopa was produced.

Even before the Nobel Prize, the asymmetrichydrogenation work had gained the attention ofacademics. Jack Halpern (University of Chicago)and John Brown (University of Oxford) bothstudied the mechanism of the hydrogenation reac-tion. Even Barry Sharpless, who won the NobelPrize along with Knowles and Noyori, said thatKnowles had inspired him to work in the area ofasymmetric catalysis.

Bill was a keen outdoorsman, even though headmitted he was terrible at athletics while growingup. He was raised by the sea and took a trip toEurope on a sailing ship before starting his under-graduate work at Harvard. The trip ended up inStockholm, but not before getting arrested inTallinn, Estonia. His return to Stockholm manyyears later certainly saw a different form of traveland no arrest.

He enjoyed fly-fishing, hiking, and cycling. TheKnowles family spent time in their cabin in JacksonHole, Wyoming, which is ideal for skiing andsummer activities. The love of a challenge showedup in his recreational pursuits. Professor AlbertChan remembers being taught how to ski inColorado where Bill, who was over 70 at the time,took him to the more difficult black diamondslopes. Although this was a large challenge forAlbert, on getting down, he felt more confidentwith himself and fell in love with skiing. The lessonwas to be well prepared all of the time formeaningful challenges.

Bill Knowles was able to look back on his careerand at what is being done now. Asymmetric hydro-genation is now a key tool for the manufacture ofmolecules used in the life science industry. He sawmonodentate phosphorus ligands being used forasymmetric hydrogenations after a hiatus of over30 years. His vanillin method was surpassed by anextraction method from a cheap, renewableresource; with the move to green this trend seemsto be continuing. He was allowed to performindependent research in an industrial environmentthat paid back manyfold over. As former employ-ees of the Monsanto group of companies, we willcherish the memories of our interactions with him.Bill knew that it took a team to solve a problem andmove a project forward. Overall, he was a jollygood fellow who will be sadly missed but neverforgotten.

David AgerDSM Innovative Synthesis BVAlbert ChanHong Kong Baptist UniversityScott LanemanDigital Specialty ChemicalsJohn TalleySARmont LLC

DOI: 10.1002/anie.201205394

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Obituary

D. Ager,* A. Chan, S. Laneman,J. Talley &&&&—&&&&

William Standish Knowles (1917–2012)

William S. Knowles, who received the2001 Nobel Prize in Chemistry for hiswork on asymmetric catalysis, and par-ticular hydrogenation reactions, passedaway in June 2012.

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