Sharpless was born April 28, 1941, in Philadelphia, Pennsylvania. His childhood was filled with summers at his family cottage on the Manasquan River in New Jersey. This is where Sharpless developed a love for fishing that he would continue throughout his life, spending summers in college working on fishing boats.^[1] He graduated from Friends' Central School in 1959,^[2] and continued his studies at Dartmouth College, earning an A.B. in 1963. Sharpless originally planned to attend medical school after his undergraduate degree, but his research professor convinced him to coninute his education in chemistry.^[3] He earned his Ph.D. in Organic Chemistry from Stanford University in 1968 under Eugene E. Tamelen.^[4] He continued post-doctoral work at Stanford University (1968–1969) with James P. Collman, working on organometallic chemistry. Sharpless then moved to Harvard University (1969–1970), studying enzymology in Konrad E. Bloch's lab.^[3]

Sharpless was a professor at the Massachusetts Institute of Technology (1970–1977, 1980–1990) and Stanford University (1977–1980).^[5] While at Stanford, Sharpless discovered Sharpless asymmetric epoxidation, which was used to make (+)-disparlure. This chemical is a gypsy moth phermone and was used by Sharpless to perform demonstrations that showed the efficacy of the reaction after he returned to MIT.^[3] He has held the W. M. Keck professorship in chemistry at The Scripps Research Institute since 1990.

Sharpless developed stereoselective oxidation reactions, and showed that the formation of an inhibitor with femtomolar potency can be catalyzed by the enzyme acetylcholinesterase, beginning with an azide and an alkyne. He discovered several chemical reactions which have transformed asymmetric synthesis from science fiction to the relatively routine, including aminohydroxylation, dihydroxylation, and the Sharpless asymmetric epoxidation.^[6]

In 2001 he won a half-share of the Nobel Prize in Chemistry for his work on chirally catalysed oxidation reactions (Sharpless epoxidation, Sharpless asymmetric dihydroxylation, Sharpless oxyamination). The other half of the year's Prize was shared between William S. Knowles and Ryōji Noyori (for their work on stereoselective hydrogenation).^[7]

His group has also successfully epoxidized (using racemic tartaric acid) a C-86 Buckminster Fullerene ball, employing p-Cresol as solvent.

The term "click chemistry" was coined by Sharpless in 1998, and was first fully described by Sharpless, Hartmuth Kolb, and M.G. Finn at The Scripps Research Institute in 2001.^[8][9] This involves a set of highly selective, exothermic reactions which occur under mild conditions; the most successful example is the azide alkyne Huisgen cycloaddition to form 1,2,3-triazoles.^[10]

As of 2022^[update], Sharpless has an h-index of 180 according to Google Scholar^[11] and of 124 according to Scopus.^[12]

Sharpless was a recipient of the 2001 Nobel Prize in Chemistry for his work on "chirally catalysed oxidation reactions".^[13]

In 2019, Sharpless was awarded the Priestley medal, the American Chemical Society's highest honor, for “the invention of catalytic, asymmetric oxidation methods, the concept of click chemistry and development of the copper-catalyzed version of the azide-acetylene cycloaddition reaction.”.^[2][3]

He holds honorary degrees from the KTH Royal Institute of Technology (1995), Technical University of Munich (1995), Catholic University of Louvain (1996) and Wesleyan University (1999).^[5]

Sharpless married Jan Dueser in 1965 and they have three children.^[6] He was blinded in one eye during a lab accident in 1970 where an NMR tube exploded, shortly after he arrived at MIT as an assistant professor. After this accident, Sharpless stresses "There's simply never an adequate excuse for not wearing safety glasses in the laboratory at all times.”^[14]

• K. Barry Sharpless at The Scripps Research Institute
• Karl Barry Sharpless on Nobelprize.org   including the Nobel Lecture December 8, 2001 The Search for New Chemical Reactivity
• Karl Barry Sharpless publications indexed by Google Scholar