Reagents Corey has developed several new synthetic reagents: •
Pyridinium chlorochromate (PCC), also known as the Corey–Suggs reagent, is widely used for the oxidation of
alcohols to corresponding
ketones and
aldehydes.
CSA (Camphorsulfonic acid) selectively removes a primary TBS ether in the presence of TIPS and tertiary TBS ethers. Other TBS deprotection methods include acids (also Lewis acids), and
fluorides. TIPS protecting groups provide increased selectivity of primary over secondary and tertiary alcohol protection. Their ethers are more stable under acidic and basic conditions than TBS ethers, but less labile for deprotection. The most common cleavage reagents employ the same conditions as TBS ether, but longer reaction times. Usually TBAF severs TBS ethers, but the hindered TBS ether above survives 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. Acidic conditions usually accomplish cleavage of MEM protecting groups, but coordination with metal halides greatly enhances lability (scheme 6). • 1,3-
Dithianes are a temporary modification of a
carbonyl group that reverses their reactivity in displacement and addition reactions. Dithianation introduced
umpolung chemistry, now a key concept in organic synthesis. The pKa of dithianes is approximately 30, allowing deprotonation with an alkyl lithium reagent, typically
n-butyllithium. The reaction between dithianes and aldehydes is now known as the
Corey-Seebach reaction. The dithiane, once deprotonated, serves as an acyl anion, attacking incoming
electrophiles. Dithiane deprotection, usually with HgO, constructs a ketone product. • Corey also commenced detailed studies on cationic polyolefin cyclizations utilized in enzymatic production of
cholesterol from simpler plant terpenes. Corey established the details of the remarkable cyclization process by first studying the biological synthesis of sterols from squalene.
Methodology 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:
Corey-Itsuno reduction, also known as the Corey-Bakshi-Shibata reduction, is an enantioselective reduction of ketones to alcohols through an oxazaborolidine
catalyst, with various boranes as the stoichiometric reductant. The Corey group first demonstrated
the catalyst's synthesis using borane and the chiral amino acid
proline (scheme 9). Later, Corey demonstrated that substituted boranes were easier to prepare and much more stable. The reduction mechanism begins with the oxazaborolidine, only slightly basic at
nitrogen, coordinating to a borane reductant (scheme 10). 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 synthesis of dysidiolide by Corey and co-workers was achieved via an enantioselective CBS reduction using a borane-dimethylsulfide complex.
Corey-Fuchs alkyne synthesis is the synthesis of terminal
alkynes through a one-carbon homologation of aldehydes using
triphenylphosphine and carbon tetrabromide. The mechanism is similar to that of a combined
Wittig reaction and
Appel reaction. Reacting a phosphorus ylide formed
in situ with the aldehyde substrate yields a dibromoolefin. On treatment with two equivalents of
n-butyllithium, lithium halogen exchange and deprotonation yields a lithium acetylide species that undergoes hydrolysis to yield the terminal alkyne product (scheme 12). This synthetic transformation has been proven successful in the total synthesis (+)-taylorione by W.J. Kerr and co-workers (scheme 13). The
Corey–Kim oxidation was a new conversion of alcohols into corresponding aldehydes and ketones. This combination of
N-chlorosuccinimidosulfonium chloride (NCS), dimethylsulfide (DMS), and
triethylamine (TEA) offers a less toxic alternative to chromium-based oxidations. The Corey-Kim reagent is formed in
situ when the succinimide and sulfide react to form a dimethylsuccinimidosulfonium chloride species (scheme 14).
Corey-Winter olefination is a stereospecific transformation of 1,2-diols to alkenes involving the diol substrate, thiocarbonyldiimidazole, and excess trialkylphosphite. The exact mechanism is unknown, but has been narrowed down to two possible pathways. The thionocarbonate and trialkylphosphite either form a phosphorus ylide or carbenoid intermediate. The reaction is stereospecific for most substrates unless the product would lead to an exceedingly strained structure, as discovered when Corey
et al attempted to form sterically hindered
trans alkenes in certain 7-membered rings. Stereospecfic alkenes are present in several natural products as the method continues to be exploited to yield a series of complex substrates. Professor T.K.M Shing
et al used the Corey-Winter olefination reaction to synthesize (+)-Boesenoxide (scheme 16). CBS-type enantioselective
Diels–Alder reaction has been developed using a similar scaffold to the enantioselective CBS reduction. 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).
Corey-Nicolaou macrolactonization provides the first method for preparing medium-to-large-size
lactones. Previously, intermolecular outcompeted intramolecular lactonization even at low concentrations. One big advantage of this reaction is that it is performed under neutral conditions allowing the presence of acid and base-labile functional groups. As of 2016, rings of 7–44 members have been successfully synthesized using this method. The reaction occurs in the presence of 2,2'-dipyridyl disulfide and triphenylphosphine with reflux of 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. The
Johnson-Corey-Chaykovsky reaction synthesizes
epoxides and
cyclopropanes. Two sulfur ylide variants have been employed that give different chemoselective products (scheme 21).The dimethylsulfoxonium methylide provides epoxides from ketones, but yields the cyclopropanes when enones are employed. Dimethylsulfonium methylide transforms ketones and enones to the corresponding epoxides. Dimethylsulfonium methylide is much more reactive and less stable than dimethylsulfoxonium methylide, so it is generated at low temperatures. 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.
Total syntheses E. J. Corey and his research group have completed many
total syntheses. At least 265 natural 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 chemists. 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). •
Ginkgolides A and B •
Lactacystin •
Miroestrol •
Ecteinascidin 743 •
Salinosporamide A Computer programs Corey and his research group created
LHASA, a program that uses
artificial intelligence to discover sequences of reaction which may lead to total synthesis. The program was one of the first to use a graphical interface to input and display chemical structures.
Publications 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: • • • • • ==Altom suicide==