![]() | |
Names | |
---|---|
Preferred IUPAC name (1aR,2R,5R,6R,6aS)-6-Hexyl-2,6-dihydroxy-2,5,6,6a-tetrahydrooxireno[2,3-f] [2]benzofuran-3(1aH)-one | |
Other names (+)-Integrasone | |
Identifiers | |
| |
3D model (JSmol) | |
ChEMBL | |
ChemSpider | |
PubChem CID | |
UNII | |
CompTox Dashboard (EPA) | |
| |
| |
Properties | |
C14H20O5 | |
Molar mass | 268.309 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
Integrasone is a polyketide natural product, isolated from an unknown fungus, that has been shown to inhibit the HIV-1 integrase enzyme. [1]
Integrasone occurs naturally in an unidentified sterile fungus. This fungus has been given the label MF6836 by Merck researchers, and was grown on a vermiculite-based solid media, AD2. The methyl ethyl ketone extract of the fungal growth on Sephadex LH 20 (a liquid chromatography medium designed for the separation of small natural products) was then run through both gel permeation chromatography and high performance liquid chromatography to isolate integrasone, which was separated as an amorphous powder at a concentration of 1.8 g/L. [1]
Integrasone inhibits HIV-1 integrase, the viral enzyme responsible for integrating the HIV provirus into the host genome. [2] Integrase accomplishes this using two reactions: 3-prime end processing, and the strand transfer reaction. In the first of these two reactions, the viral DNA is processed by the removal of two deoxynucleotides. In the strand transfer reaction, these processed 3-prime viral DNA ends are covalently bound to the host chromosomal DNA. [3] Integrasone inhibits HIV integrase activity by interfering with the strand transfer reaction, with an IC50 (half maximal inhibitory concentration) of 41 μM.[ citation needed ]
Due to its high mutation rate and systematic elimination of key immune system cells, HIV is a very difficult virus for which to make a vaccine. In some trials, groups given experimental HIV vaccines have actually had higher incidence of HIV infection than groups given a placebo. [4] As vaccination, the traditional method of fighting viral diseases, is largely unavailable, chemotherapy becomes a better option. Unfortunately, the extraordinarily high mutation rate of HIV allows it to evolve in order to evade both the human immune system and the effect of anti-viral drugs. For this reason, new antiviral HIV-1 drugs are necessary to continue the fight against HIV. The method of inactivation which integrasone uses shows promise for halting the spread of HIV in its host, though it will not eliminate the virus entirely.[ citation needed ]
The total laboratory synthesis of integrasone has been worked out, starting with a commonly available Diels-Alder adduct of p-benzoquinone and cyclopentadiene. Using a base mediated epoxidation reaction, structure 3 was achieved, which led to structure 4 after exhaustive hydroxymethylation in the presence of DBU. The formation of structure 4 is particularly impressive – it not only forms two important C-C bonds in one step, but also occurs in quantitative yield. Using a retro Diels-Alder reaction, structure 5 was formed in near quantitative yield. [5] Structure 5 was desymmetrized through an enzymatic transesterification process, using an immobilized lipase PS 30 enzyme to give structure 6, which was formed with a 99% enantiomeric excess. [6]
The stereochemistry of the hydroxyl group at carbon 6 in the final integrasone molecule (3) was determined by reduction, which was both regio and stereo selective due to the directing effects of the primary hydroxyl group (carbon 8) and the epoxide ring (carbons 4 and 5). The hydroxy group on carbon 8 is then selectively protected with as the triethylsilyl (TES) ether to give structure 8. With the hydroxyl groups on both carbons 1 and 8 protected, it is then relatively straightforward to stereoselectively reduce the carbonyl group on carbon 3 with sodium borohydride to give the diol depicted in structure 9. Before any oxidation reactions could be used, the two newly formed hydroxyl groups were protected with as acetate esters, forming structure 10. The TES protecting group on the carbon 8 hydroxyl was removed without deprotecting any of the other groups, and then the carbon 8 hydroxyl was oxidized with PCC [7] to give the aldehyde shown in structure 11.
The next step involved the installation of a hexyl chain at the aldehyde carbon (carbon 8). This was accomplished using the Grignard reagent hexylmagnesium bromide, and was highly stereoselective – so much so that the chemists reporting this reaction express their “delight”. [8] It is speculated that this stereoselectivity for product 12 is due to the directing influence of the acetate group attached to carbon 6, which migrates during the reaction to carbon 8. Unfortunately, in 42% of the product, the alkyl chain was not installed, and instead the aldehyde was reduced with an accompanying acetate migration to form a triacetate (structure 14). Efforts to improve this step of the synthesis were made by attempting to vary the temperature and solvent. At high temperatures, more of the triacetate 14 was formed, while at low temperatures, the reaction was sluggish. [8]
Structure 12 is very close to the target molecule, 1 – all that remains is to close the 5-membered ring and form a carbonyl. Base hydrolysis was used to remove the remaining acetate protecting groups, resulting in the tetrol depicted in structure 15. Integrasone (1) is then formed in a single step by oxidation of the primary hydroxyl groups and concerted electron cyclization to form the ring, using sodium chlorite catalyzed by TEMPO and bleach. [9] Structure 16 is a transition state proposed to explain the concerted electrocyclic reaction and the carbonyl formation. [10]
Elias James Corey 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.
The aldol reaction is a means of forming carbon–carbon bonds in organic chemistry. Discovered independently by the Russian chemist Alexander Borodin in 1869 and by the French chemist Charles-Adolphe Wurtz in 1872, the reaction combines two carbonyl compounds to form a new β-hydroxy carbonyl compound. These products are known as aldols, from the aldehyde + alcohol, a structural motif seen in many of the products. Aldol structural units are found in many important molecules, whether naturally occurring or synthetic. For example, the aldol reaction has been used in the large-scale production of the commodity chemical pentaerythritol and the synthesis of the heart disease drug Lipitor.
The 1,3-dipolar cycloaddition is a chemical reaction between a 1,3-dipole and a dipolarophile to form a five-membered ring. The earliest 1,3-dipolar cycloadditions were described in the late 19th century to the early 20th century, following the discovery of 1,3-dipoles. Mechanistic investigation and synthetic application were established in the 1960s, primarily through the work of Rolf Huisgen. Hence, the reaction is sometimes referred to as the Huisgen cycloaddition. 1,3-dipolar cycloaddition is an important route to the regio- and stereoselective synthesis of five-membered heterocycles and their ring-opened acyclic derivatives. The dipolarophile is typically an alkene or alkyne, but can be other pi systems. When the dipolarophile is an alkyne, aromatic rings are generally produced.
Dess–Martin periodinane (DMP) is a chemical reagent used in the Dess–Martin oxidation, oxidizing primary alcohols to aldehydes and secondary alcohols to ketones. This periodinane has several advantages over chromium- and DMSO-based oxidants that include milder conditions, shorter reaction times, higher yields, simplified workups, high chemoselectivity, tolerance of sensitive functional groups, and a long shelf life. However, use on an industrial scale is made difficult by its cost and its potentially explosive nature. It is named after the American chemists Daniel Benjamin Dess and James Cullen Martin who developed the reagent in 1983. It is based on IBX, but due to the acetate groups attached to the central iodine atom, DMP is much more reactive than IBX and is much more soluble in organic solvents.
The Henry reaction is a classic carbon–carbon bond formation reaction in organic chemistry. Discovered in 1895 by the Belgian chemist Louis Henry (1834–1913), it is the combination of a nitroalkane and an aldehyde or ketone in the presence of a base to form β-nitro alcohols. This type of reaction is also referred to as a nitroaldol reaction. It is nearly analogous to the aldol reaction that had been discovered 23 years prior that couples two carbonyl compounds to form β-hydroxy carbonyl compounds known as "aldols". The Henry reaction is a useful technique in the area of organic chemistry due to the synthetic utility of its corresponding products, as they can be easily converted to other useful synthetic intermediates. These conversions include subsequent dehydration to yield nitroalkenes, oxidation of the secondary alcohol to yield α-nitro ketones, or reduction of the nitro group to yield β-amino alcohols.
In stereochemistry, 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.
The Petasis reaction is the multi-component reaction of an amine, a carbonyl, and a vinyl- or aryl-boronic acid to form substituted amines.
The Dakin oxidation is an organic redox reaction in which an ortho- or para-hydroxylated phenyl aldehyde or ketone reacts with hydrogen peroxide in base to form a benzenediol and a carboxylate. Overall, the carbonyl group is oxidized, and the hydrogen peroxide is reduced.
In stereochemistry, asymmetric induction describes the preferential formation in a chemical reaction of one enantiomer or diastereoisomer over the other as a result of the influence of a chiral feature present in the substrate, reagent, catalyst or environment. Asymmetric induction is a key element in asymmetric synthesis.
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 Fleming–Tamao oxidation, or Tamao–Kumada–Fleming oxidation, converts a carbon–silicon bond to a carbon–oxygen bond with a peroxy acid or hydrogen peroxide. Fleming–Tamao oxidation refers to two slightly different conditions developed concurrently in the early 1980s by the Kohei Tamao and Ian Fleming research groups.
Organoindium chemistry is the chemistry of compounds containing In-C bonds. The main application of organoindium chemistry is in the preparation of semiconducting components for microelectronic applications. The area is also of some interest in organic synthesis. Most organoindium compounds feature the In(III) oxidation state, akin to its lighter congeners Ga(III) and B(III).
The α-ketol rearrangement is the acid-, base-, or heat-induced 1,2-migration of an alkyl or aryl group in an α-hydroxy ketone or aldehyde to give an isomeric product.
Benzylic activation and stereocontrol in tricarbonyl(arene)chromium complexes refers to the enhanced rates and stereoselectivities of reactions at the benzylic position of aromatic rings complexed to chromium(0) relative to uncomplexed arenes. Complexation of an aromatic ring to chromium stabilizes both anions and cations at the benzylic position and provides a steric blocking element for diastereoselective functionalization of the benzylic position. A large number of stereoselective methods for benzylic and homobenzylic functionalization have been developed based on this property.
Hydrogen auto-transfer, also known as borrowing hydrogen, is the activation of a chemical reaction by temporary transfer of two hydrogen atoms from the reactant to a catalyst and return of those hydrogen atoms back to a reaction intermediate to form the final product. Two major classes of borrowing hydrogen reactions exist: (a) those that result in hydroxyl substitution, and (b) those that result in carbonyl addition. In the former case, alcohol dehydrogenation generates a transient carbonyl compound that is subject to condensation followed by the return of hydrogen. In the latter case, alcohol dehydrogenation is followed by reductive generation of a nucleophile, which triggers carbonyl addition. As borrowing hydrogen processes avoid manipulations otherwise required for discrete alcohol oxidation and the use of stoichiometric organometallic reagents, they typically display high levels of atom-economy and, hence, are viewed as examples of Green chemistry.
The Enders SAMP/RAMP hydrazone alkylation reaction is an asymmetric carbon-carbon bond formation reaction facilitated by pyrrolidine chiral auxiliaries. It was pioneered by E. J. Corey and D. Enders in 1976, and was further developed by D. Enders and his group. This method is usually a three-step sequence. The first step is to form the hydrazone between (S)-1-amino-2-methoxymethylpyrrolidine (SAMP) or (R)-1-amino-2-methoxymethylpyrrolidine (RAMP) and a ketone or aldehyde. Afterwards, the hydrazone is deprotonated by lithium diisopropylamide (LDA) to form an azaenolate, which reacts with alkyl halides or other suitable electrophiles to give alkylated hydrazone species with the simultaneous generation of a new chiral center. Finally, the alkylated ketone or aldehyde can be regenerated by ozonolysis or hydrolysis.
Fétizon oxidation is the oxidation of primary and secondary alcohols utilizing the compound silver(I) carbonate absorbed onto the surface of celite also known as Fétizon's reagent first employed by Marcel Fétizon in 1968. It is a mild reagent, suitable for both acid and base sensitive compounds. Its great reactivity with lactols makes the Fétizon oxidation a useful method to obtain lactones from a diol. The reaction is inhibited significantly by polar groups within the reaction system as well as steric hindrance of the α-hydrogen of the alcohol.
Dynamic kinetic resolution in chemistry is a type of kinetic resolution where 100% of a racemic compound can be converted into an enantiopure compound. It is applied in asymmetric synthesis. Asymmetric synthesis has become a much explored field due to the challenge of creating a compound with a single 3D structure. Even more challenging is the ability to take a racemic mixture and have only one chiral product left after a reaction. One method that has become an exceedingly useful tool is dynamic kinetic resolution (DKR). DKR utilizes a center of a particular molecule that can be easily epimerized so that the (R) and (S) enantiomers can interconvert throughout the reaction process. At this point the catalyst can selectively lower the transition state energy of a single enantiomer, leading to almost 100% yield of one reaction pathway over the other. The figure below is an example of an energy diagram for a compound with an (R) and (S) isomer.
In organic chemistry, carbonyl allylation describes methods for adding an allyl anion to an aldehyde or ketone to produce a homoallylic alcohol. The carbonyl allylation was first reported in 1876 by Alexander Zaitsev and employed an allylzinc reagent.
The Krische allylation involves the enantioselective iridium-catalyzed addition of an allyl group to an aldehyde or an alcohol, resulting in the formation of a secondary homoallylic alcohol. The mechanism of the Krische allylation involves primary alcohol dehydrogenation or, when using aldehyde reactants, hydrogen transfer from 2-propanol. Unlike other allylation methods, the Krische allylation avoids the use of preformed allyl metal reagents and enables the direct conversion of primary alcohols to secondary homoallylic alcohols.