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.
E. J. Corey and his research group have completed many total syntheses. At least 265 compounds have been synthesized in the Corey group since 1950.
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.
When awarded the Priestley Medal in 2004, E. J. Corey created a controversy with his claim to have inspired Robert Burns Woodward prior to the development of the Woodward–Hoffmann rules. Corey wrote:
"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.
An enamine is an unsaturated compound derived by the condensation of an aldehyde or ketone with a secondary amine. Enamines are versatile intermediates.
Organolithium reagents are organometallic compounds that contain carbon – lithium bonds. They are important reagents in organic synthesis, and are frequently used to transfer the organic group or the lithium atom to the substrates in synthetic steps, through nucleophilic addition or simple deprotonation. Organolithium reagents are used in industry as an initiator for anionic polymerization, which leads to the production of various elastomers. They have also been applied in asymmetric synthesis in the pharmaceutical industry. Due to the large difference in electronegativity between the carbon atom and the lithium atom, the C-Li bond is highly ionic. Owing to the polar nature of the C-Li bond, organolithium reagents are good nucleophiles and strong bases. For laboratory organic synthesis, many organolithium reagents are commercially available in solution form. These reagents are highly reactive, and are sometimes pyrophoric.
The Simmons–Smith reaction is an organic cheletropic reaction involving an organozinc carbenoid that reacts with an alkene to form a cyclopropane. It is named after Howard Ensign Simmons, Jr. and Ronald D. Smith. It uses a methylene free radical intermediate that is delivered to both carbons of the alkene simultaneously, therefore the configuration of the double bond is preserved in the product and the reaction is stereospecific.
In retrosynthetic analysis, a synthon is a hypothetical unit within a target molecule that represents a potential starting reagent in the retroactive synthesis of that target molecule. The term was coined in 1967 by E. J. Corey. He noted in 1988 that the "word synthon has now come to be used to mean synthetic building block rather than retrosynthetic fragmentation structures". It was noted in 1998 that the phrase did not feature very prominently in Corey's 1981 book The Logic of Chemical Synthesis, as it was not included in the index. Because synthons are charged, when placed into a synthesis a neutral form is found commercially instead of forming and using the potentially very unstable charged synthons.
The Claisen rearrangement is a powerful carbon–carbon bond-forming chemical reaction discovered by Rainer Ludwig Claisen. The heating of an allyl vinyl ether will initiate a [3,3]-sigmatropic rearrangement to give a γ,δ-unsaturated carbonyl.
The Corey–Itsuno reduction, also known as the Corey–Bakshi–Shibata (CBS) reduction, is a chemical reaction in which an achiral ketone is enantioselectively reduced to produce the corresponding chiral, non-racemic alcohol. The oxazaborolidine reagent which mediates the enantioselective reduction of ketones was previously developed by the laboratory of Itsuno and thus this transformation may more properly be called the Itsuno-Corey oxazaborolidine reduction.
Aflatoxin total synthesis concerns the total synthesis of a group of organic compounds called aflatoxins. These compounds occur naturally in several fungi. As with other chemical compound targets in organic chemistry, the organic synthesis of aflatoxins serves various purposes. Traditionally it served to prove the structure of a complex biocompound in addition to evidence obtained from spectroscopy. It also demonstrates new concepts in organic chemistry and opens the way to molecular derivatives not found in nature. And for practical purposes, a synthetic biocompound is a commercial alternative to isolating the compound from natural resources. Aflatoxins in particular add another dimension because it is suspected that they have been mass-produced in the past from biological sources as part of a biological weapons program.
A chiral auxiliary is a stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. The chirality present in the auxiliary can bias the stereoselectivity of one or more subsequent reactions. The auxiliary can then be typically recovered for future use.
Silyl ethers are a group of chemical compounds which contain a silicon atom covalently bonded to an alkoxy group. The general structure is R1R2R3Si−O−R4 where R4 is an alkyl group or an aryl group. Silyl ethers are usually used as protecting groups for alcohols in organic synthesis. Since R1R2R3 can be combinations of differing groups which can be varied in order to provide a number of silyl ethers, this group of chemical compounds provides a wide spectrum of selectivity for protecting group chemistry. Common silyl ethers are: trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS/TBDMS) and triisopropylsilyl (TIPS). They are particularly useful because they can be installed and removed very selectively under mild conditions.
The Johnson–Corey–Chaykovsky reaction is a chemical reaction used in organic chemistry for the synthesis of epoxides, aziridines, and cyclopropanes. It was discovered in 1961 by A. William Johnson and developed significantly by E. J. Corey and Michael Chaykovsky. The reaction involves addition of a sulfur ylide to a ketone, aldehyde, imine, or enone to produce the corresponding 3-membered ring. The reaction is diastereoselective favoring trans substitution in the product regardless of the initial stereochemistry. The synthesis of epoxides via this method serves as an important retrosynthetic alternative to the traditional epoxidation reactions of olefins.
The Holton Taxol total synthesis, published by Robert A. Holton and his group at Florida State University in 1994 was the first total synthesis of Taxol.
The Corey–Kim oxidation is an oxidation reaction used to synthesise aldehydes and ketones from primary and secondary alcohols. It is named for American chemist and Nobel Laureate Elias James Corey and Korean-American chemist Choung Un Kim.
Umpolung or polarity inversion in organic chemistry is the chemical modification of a functional group with the aim of the reversal of polarity of that group. This modification allows secondary reactions of this functional group that would otherwise not be possible. The concept was introduced by D. Seebach and E.J. Corey. Polarity analysis during retrosynthetic analysis tells a chemist when umpolung tactics are required to synthesize a target molecule.
Schwartz's reagent is the common name for the organozirconium compound with the formula (C5H5)2ZrHCl, sometimes called zirconocene hydrochloride or zirconocene chloride hydride, and is named after Jeffrey Schwartz, a chemistry professor at Princeton University. This metallocene is used in organic synthesis for various transformations of alkenes and alkynes.
The Rubottom oxidation is a useful, high-yielding chemical reaction between silyl enol ethers and peroxyacids to give the corresponding α-hydroxy carbonyl product. The mechanism of the reaction was proposed in its original disclosure by A.G. Brook with further evidence later supplied by George M. Rubottom. After a Prilezhaev-type oxidation of the silyl enol ether with the peroxyacid to form the siloxy oxirane intermediate, acid-catalyzed ring-opening yields an oxocarbenium ion. This intermediate then participates in a 1,4-silyl migration to give an α-siloxy carbonyl derivative that can be readily converted to the α-hydroxy carbonyl compound in the presence of acid, base, or a fluoride source.
The oxidation of primary alcohols to carboxylic acids is an important oxidation reaction in organic chemistry.
In chemistry, bis(oxazoline) ligands (often abbreviated BOX ligands) are a class of privileged chiral ligands containing two oxazoline rings. They are typically C2‑symmetric and exist in a wide variety of forms; with structures based around CH2 or pyridine linkers being particularly common (often generalised BOX and PyBOX respectively). The coordination complexes of bis(oxazoline) ligands are used in asymmetric catalysis. These ligands are examples of C2-symmetric ligands.
(R)-2-Methyl-CBS-oxazaborolidine is an organoboron catalyst that is used in organic synthesis. This catalyst, developed by Itsuno and Elias James Corey, is generated by heating (R)-(+)-2-(diphenylhydroxymethyl) pyrrolidine along with trimethylboroxine or methylboronic acid. It is an excellent tool for the synthesis of alcohols in high enantiomeric ratio. Generally, 2-10 mol% of this catalyst is used along with borane-tetrahydrofuran (THF), borane-dimethylsulfide, borane-N,N-diethylaniline, or diborane as the borane source. Enantioselective reduction using chiral oxazaborolidine catalysts has been used in the synthesis of commercial drugs such as ezetimibe and aprepitant.
Metal-catalyzed C–H borylation reactions are transition metal catalyzed organic reactions that produce an organoboron compound through functionalization of aliphatic and aromatic C–H bonds and are therefore useful reactions for carbon–hydrogen bond activation. Metal-catalyzed C–H borylation reactions utilize transition metals to directly convert a C–H bond into a C–B bond. This route can be advantageous compared to traditional borylation reactions by making use of cheap and abundant hydrocarbon starting material, limiting prefunctionalized organic compounds, reducing toxic byproducts, and streamlining the synthesis of biologically important molecules. Boronic acids, and boronic esters are common boryl groups incorporated into organic molecules through borylation reactions. Boronic acids are trivalent boron-containing organic compounds that possess one alkyl substituent and two hydroxyl groups. Similarly, boronic esters possess one alkyl substituent and two ester groups. Boronic acids and esters are classified depending on the type of carbon group (R) directly bonded to boron, for example alkyl-, alkenyl-, alkynyl-, and aryl-boronic esters. The most common type of starting materials that incorporate boronic esters into organic compounds for transition metal catalyzed borylation reactions have the general formula (RO)2B-B(OR)2. For example, bis(pinacolato)diboron (B2Pin2), and bis(catecholato)diborane (B2Cat2) are common boron sources of this general formula.
Proline organocatalysis is the use of proline as an organocatalyst in organic chemistry. This theme is often considered the starting point for the area of organocatalysis, even though early discoveries went unappreciated. Modifications, such as MacMillan’s catalyst and Jorgensen's catalysts, proceed with excellent stereocontrol.
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