Corey in 2007
Elias James Corey
July 12, 1928
Methuen, Massachusetts, United States
|Alma mater||Massachusetts Institute of Technology|
|Known for||Retrosynthetic analysis|
|Institutions||University of Illinois at Urbana–Champaign|
|Doctoral advisor||John C. Sheehan|
Elias James "E.J." Corey (born July 12, 1928) is an American organic chemist. In 1990, he won the Nobel Prize in Chemistry "for his development of the theory and methodology of organic synthesis", specifically retrosynthetic analysis. Regarded by many as one of the greatest living chemists, he has developed numerous synthetic reagents, methodologies and total syntheses and has advanced the science of organic synthesis considerably.
E.J. Corey (the surname was anglicized from the Lebanese Arabic Khoury, meaning priest) was born to Christian Lebanese immigrants in Methuen, Massachusetts, 50 km (31 mi) north of Boston. His mother changed his name to "Elias" to honor his father, who died eighteen months after Corey's birth. His widowed mother, brother, two sisters and an aunt and uncle all lived together in a spacious house, struggling through the Great Depression. As a young boy, Corey was independent and enjoyed sports such as baseball, football, and hiking. He attended a Catholic elementary school and Lawrence High School in Lawrence, Massachusetts.
At the age of 16 Corey entered MIT, where he earned both a bachelor's degree in 1948 and a Ph.D. under Professor John C. Sheehan in 1951. Upon entering MIT, Corey's only experience with science was in mathematics, and he began his college career pursuing a degree in engineering. After his first chemistry class in his sophomore year he began rethinking his long-term career plans and graduated with a bachelor's degree in chemistry. Immediately thereafter, at the invitation of Professor John C. Sheehan, Corey remained at MIT for his Ph.D. After his graduate career he was offered an appointment at the University of Illinois at Urbana–Champaign, where he became a full professor of chemistry in 1956 at the age of 27. He was initiated as a member of the Zeta chapter of Alpha Chi Sigma at the University of Illinois in 1952. In 1959, he moved to Harvard University, where he is currently an emeritus professor of organic chemistry with an active Corey Group research program. He chose to work in organic chemistry because of "its intrinsic beauty and its great relevance to human health". He has also been an advisor to Pfizer for more than 50 years.
Among numerous honors, Corey was awarded the National Medal of Science in 1988, the Nobel Prize in Chemistry in 1990, and the American Chemical Society's greatest honor, the Priestley Medal, in 2004.
E.J. Corey has developed several new synthetic reagents:
One of these advantages is that the compound is available as an air-stable yellow solid that is not very hygroscopic. Unlike other oxidizing agents, PCC can accomplish single oxidations with only about 1.5 equivalents (scheme 1). The alcohol performs nucleophilic attack to the electropositive chromium(VI) metal displacing chlorine. The chloride anion then acts as a base to afford the aldehyde product and chromium(IV). The slightly acidic character of PCC makes it useful for cyclization reactions with alcohols and alkenes (Scheme 2).
The initial oxidation yields the corresponding aldehyde, which can then undergo a Prins reaction with the neighboring alkene. After elimination and further oxidation, the product is a cyclic ketone. If this product is undesired, powdered sodium acetate can be used as a buffer to achieve only initial oxidation. The robustness of PCC as an oxidizing agent has also rendered it useful in the realm of total synthesis (Scheme 3). This example illustrates that PCC is capable of performing a Dauben oxidative rearrangement with tertiary alcohols through a [3,3]-sigmatropic rearrangement.
In the field of complex molecule synthesis, TBS has been widely used as one of the most versatile of the silicon-based protecting groups (scheme 4). The use of CSA provides selective removal of a primary TBS ether in the presence of tertiary TBS ether and TIPS ethers. Other means of TBS deprotection include acids (also Lewis acids), and fluorides. TIPS protecting groups were also pioneered by Corey and provide increased selectivity of primary alcohol protection over secondary and tertiary alcohol protection. TIPS ethers are more stable under acidic and basic conditions, the disadvantage of this protecting group over TBS ethers being that the group is less labile for deprotection. The most common reagents used for cleavage employ the same conditions as TBS ether, but longer reaction times are generally needed.
Usually TBS ethers are severed by TBAF, but the hindered TBS ether above survives the reaction conditions upon primary TIPS removal (scheme 5). The MEM protecting group was first described by Corey in 1976. This protecting group is similar in reactivity and stability to other alkoxy methyl ethers under acidic conditions. Cleavage of MEM protecting groups is usually accomplished under acidic conditions, but coordination with metal halides greatly enhances lability via assisted cleavage (scheme 6).
The pKa of dithianes is approximately 30, allowing deprotonation with an alkyl lithium reagent, typically n-butyllithium. The reaction with dithianes and aldehydes is now known as the Corey-Seebach reaction. The dithiane once deprotonated serves as an acyl anion used to attack incoming electrophiles. After deprotection of the dithiane, usually with HgO, a ketone product is observed from the masked acyl dithiane anion. The utility of such reactions has expanded the field of organic synthesis by allowing synthetic chemists to use Umpolung disconnections in total synthesis (scheme 8). 1,3-dithianes are also used as protecting groups for carbonyl compounds expressing the versatility and utility of this functional group.
Several reactions developed in Corey's lab have become commonplace in modern synthetic organic chemistry. At least 302 methods have been developed in the Corey group since 1950. Several reactions have been named after him:
Later, Corey demonstrated that substituted boranes were easier to prepare and much more stable. The reduction mechanism begins with the oxazoborolidine being only slightly basic at [nitrogen], coordinating with the stoichiometric borane of the boron amine complex(scheme 10). Lack of donation from the nitrogen to the boron increases its Lewis acidity, allowing coordination with the ketone substrate. The complexation of the substrate occurs from the most accessible lone pair of the oxygen leading to restricted rotation around the B-O bond due to the sterically neighboring phenyl group.
Migration of the hydride from borane to the electrophilic ketone center occurs via a 6-membered ring transition state, leading to a four-membered ring intermediate ultimately providing the chiral product and regeneration of the catalyst. The reaction has also been of great use to natural products chemists (scheme 11). The synthesis of dysidiolide by Corey and co-workers was achieved via an enantioselective CBS reduction using a borane-dimethylsulfide complex.
On treatment with two equivalents of n-buLi, lithium halogen exchange and deprotonation yields a lithium acetylide species that undergoes hydrolysis to yield the terminal alkyne product (scheme 12). More recently, a one-pot synthesis using a modified procedure has been developed. This synthetic transformation has been proven successful in the total synthesis (+)-taylorione by W.J. Kerr and co-workers (scheme 13).
The alkoxy sulfonium salt is deprotonated at the alpha position with triethylamine to afford the oxidized product. The reaction accommodates a wide array of functional groups, but allylic and benzylic alcohols are typically transformed into allylic and benzylic chlorides. Its application in synthesis is based on the mild protocol conditions and functional and protecting group compatibility. In the total synthesis of ingenol, Kuwajima and co-workers exploited the Corey-Kim oxidation by selectively oxidizing the less hindered secondary alcohol(scheme 15).
This transition state likely occurs because of favorable pi-stacking with the phenyl substituent. The enantioselectivity of the process is facilitated from the diene approaching the dienophile from the opposite face of the phenyl substituent. The Diels-Alder reaction is one of the most powerful transformations in synthetic chemistry. The synthesis of natural products using the Diels-Alder reaction as a transform has been applied especially to the formation of six-membered rings(scheme 18).
The reaction occurs in the presence of 2,2'-dipyridyl disulfide and triphenylphosphine. The reaction is generally refluxed in a nonpolar solvent such as benzene. The mechanism begins with formation of the 2-pyridinethiol ester (scheme 19). Proton-transfer provides a dipolar intermediate in which the alkoxide nucleophile attacks the electrophilic carbonyl center, providing a tetrahedral intermediate that yields the macrolactone product. One of the first examples of this protocol was applied to the total synthesis of zearalenone (scheme 20).
Based on their reactivity, another distinct advantage of these two variants is that kinetically they provide a difference in diastereoselectivity. The reaction is very well established, and enantioselective variants (catalytic and stoichiometric) have also been achieved. From a retrosynthetic analysis standpoint, this reaction provides a reasonable alternative to conventional epoxidation reactions with alkenes (scheme 22). Danishefsky utilized this methodology for the synthesis of taxol. Diastereoselectivity is established by 1,3 interactions in the transition state required for epoxide closure.
His 1969 total syntheses of several prostaglandins are considered classics. Specifically the synthesis of Prostaglandin F2α presents several challenges. The presence of both cis and trans olefins as well as five asymmetric carbon atoms renders the molecule a desirable challenge for organic chemist. Corey's retrosynthetic analysis outlines a few key disconnections that lead to simplified precursors (scheme 23).
Molecular simplification began first by disconnecting both carbon chains with a Wittig reaction and Horner-Wadsworth Emmons modification. The Wittig reaction affords the cis product, while the Horner-Wadsworth Emmons produces the trans olefin. The published synthesis reveals a 1:1 diastereomeric mixture of the carbonyl reduction using zinc borohydride. However, years later Corey and co-workers established the CBS reduction. One of the examples that exemplified this protocol was an intermediate in the prostaglandin synthesis revealing a 9:1 mixture of the desired diastereomer (scheme 24).
The iodolactonization transform affords an allylic alcohol leading to a key Baeyer-Villiger intermediate. This oxidation regioselectively inserts an oxygen atom between the ketone and the most electron-rich site. The pivotal intermediate leads to a straightforward conversion to the Diels-Alder structural goal, which provides the carbon framework for the functionalized cyclopentane ring. Later Corey developed an asymmetric Diels-Alder reaction employing a chiral oxazoborolidine, greatly simplifying the synthetic route to the prostaglandins.
Other notable syntheses:
E.J. Corey has more than 1100 publications. In 2002, the American Chemical Society (ACS) recognized him as the "Most Cited Author in Chemistry". In 2007, he received the first ACS Publications Division "Cycle of Excellence High Impact Contributor Award" and was ranked the number one chemist in terms of research impact by the Hirsch Index (h-index). His books include:
Among the hundreds of graduate students supervised by Corey was Jason Altom. Altom's suicide caused controversy because he explicitly blamed Corey, his research advisor, for his suicide. Corey was devastated and bewildered by Altom's death. Altom cited in his 1998 farewell note "abusive research supervisors" as one reason for taking his life. Altom's suicide note also contained explicit instructions on how to reform the relationship between students and their supervisors. Corey is quoted as stating: "That letter doesn't make sense. At the end, Jason must have been delusional or irrational in the extreme." Corey also is on record as stating that he never questioned Altom's intellectual contributions. "I did my best to guide Jason as a mountain guide would to guide someone climbing a mountain. I did my best every step of the way," Corey states. "My conscience is clear. Everything Jason did came out of our partnership. We never had the slightest disagreement."
As a result of Altom's death, the Department of Chemistry accepted a proposal allowing graduate students to ask two additional faculty members to play a small advisory role in preparing a thesis.
The American Foundation for Suicide Prevention (AFSP) cited The New York Times article on Altom's suicide as an example of problematic reporting, and suggested that Corey was unfairly scapegoated. According to The Boston Globe, Altom's suicide note indicated fear that his career hopes were doomed, but The Globe also cited students and professors as saying that Altom actually retained Corey's support.
As of 2010, approximately 700 people have been Corey Group members. A database of 580 former members and their current affiliation was developed for Corey's 80th birthday in July, 2008.
"On May 4, 1964, I suggested to my colleague R. B. Woodward a simple explanation involving the symmetry of the perturbed (HOMO) molecular orbitals for the stereoselective cyclobutene → 1,3-butadiene and 1,3,5-hexatriene → cyclohexadiene conversions that provided the basis for the further development of these ideas into what became known as the Woodward–Hoffmann rules."
This was Corey's first public statement on his claim that starting on May 5, 1964 Woodward put forth Corey's explanation as his own thought with no mention of Corey and the conversation of May 4. Corey had discussed his claim privately with Hoffmann and close colleagues since 1964. Corey mentions that he made the Priestley statement "so the historical record would be correct".
Corey's claim and contribution were publicly rebutted by Roald Hoffmann in the journal Angewandte Chemie. In the rebuttal, Hoffmann states that he asked Corey over the course of their long discussion of the matter why Corey did not make the issue public. Corey responded that he thought such a public disagreement would hurt Harvard and that he would not "consider doing anything against Harvard, to which I was and am so devoted." Corey also hoped that Woodward himself would correct the historical record "as he grew older, more considerate, and more sensitive to his own conscience." Woodward died suddenly of a heart attack in his sleep in 1979.
E.J. Corey has received more than 40 major awards including the Linus Pauling Award (1973), Franklin Medal (1978), Tetrahedron Prize (1983), Wolf Prize in Chemistry (1986), National Medal of Science (1988), Japan Prize (1989), Nobel Prize in Chemistry (1990), Golden Plate Award of the American Academy of Achievement (1991), Roger Adams Award (1993), and the Priestley Medal (2004). He was inducted into the Alpha Chi Sigma Hall of Fame in 1998. As of 2008, he has been awarded 19 honorary degrees from universities around the world including Oxford University (UK), Cambridge University (UK), and National Chung Cheng University. In 2013, the E.J. Corey Institute of Biomedical Research (CIBR) opened in Jiangyin, Jiangsu Province, China.
Corey was elected a Foreign Member of the Royal Society (ForMemRS) in 1998.
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