Grob Fragmentation Research Articles

Palladium-catalyzed selective activation of allyl alcohols as allyl cations, allyl anions, and zwitterionic trimethylenemethanes

Abstract Pd-Et3B catalytic system promotes the generation of allyl cations, allyl anions, and zwitterionic trimethylenemethane species from the corresponding allylic alcohols. Allyl cations react with a wide variety of nucleophiles, e.g., amines, active methylene compounds, 1,3,5-trihydroxybenzene, indoles, aldehydes (at the α-position). The reaction is extended to dehydrative Grob fragmentation of 1,3-diols. Allyl anions react with aldimines to give homoallyl amines. Zwitterionic trimethylenemethane, generated from 2-methylene-1,3-propanediol, reacts with aldehydes and aldimines to provide 3-methylenecyclopentanols and 3-methylenepyrrolidines, respectively. Vinyl epoxide can be utilized as a synthetic equivalent of 3-butenyl 2-anion-1-cation.

Aspects of the chemistry of 8-azabicyclo[3.2.1]octanes

Mesylation and elimination from dimethyl 3-hydroxy-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate gave a conjugated alkenyl ester. Reduction of the mesyloxy ester by di-isobutylaluminium hydride was also accompanied by elimination giving an unsaturated aldehyde. Treatment of the mesylate of the corresponding monoprotected diol with potassium tert-butoxide gave a 2-unsubstituted alkene via a Grob fragmentation but a different alkene was obtained using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile. Epoxidation of both the protected hydroxy-alkene and the free hydroxy-alkene was stereoselective in favour of epoxidation from the exo-face, and ring-opening of the hydroxy-epoxide using hydrogen bromide gave the diaxial bromohydrin. Treatment of a 2-iodomethyl-3-oxo-8-azabicyclo[3.2.1]octane with tert-butyllithium gave a cyclopropane, whereas the corresponding iodo-alcohol gave the 1-azatricyclo[5.3.0.0 4,10]decan-2-one as the major product.

Stable Carborane Biradicals

Building on previously developed chemistry to functionalize the carba-closo-dodecaborate anion, Michl and co-workers report the synthesis of two neutral, isolable biradicals. In the key synthetic step, a Grob fragmentation converts 7 into carbocation 8, which can then react with 4 or 6 to form the dianion biradical precursors 9 and 10. Oxidation with PbO2 and extraction into pentane provides the neutral biradicals 11 and 12.

Synthesis of Bicyclic Pyroglutamic Acid Featuring the Ugi Reaction and a Unique Stereoisomerization at the Angular Position by Grob Fragmentation Followed by a Transannular Ketene [2+2] Cycloaddition Reaction

A stereoisomerization at the angular position of N-acylindoles during basic hydrolysis was discovered to give only the syn-bicyclic pyroglutamic acid, proceeding through a transannular [2+2] cycloaddition of a ketene-ketone intermediate generated by a Grob fragmentation.

Carbohydrate pyrolysis mechanisms from isotopic labeling: Part 1: The pyrolysis of glycerin: Discovery of competing fragmentation mechanisms affording acetaldehyde and formaldehyde and the implications for carbohydrate pyrolysis

The flash pyrolysis of glycerin was investigated by the use of isotopic labeling with 13C, in conjunction with GC/MS analysis of the products. The formation of acetaldehyde and acrolein was shown to occur by unimolecular reaction. Acetaldehyde was found to be produced by at least two competing mechanisms. Mechanism “A” delivered C-2 of glycerin to the carbonyl group of acetaldehyde, whereas mechanism “B” delivered C-2 of glycerin to the methyl group of acetaldehyde. Formaldehyde was exclusively derived from C-1 or C-3 by either mechanism. The partition between the two mechanistic paths was found to be influenced by the presence of potassium salts and acids, but not by the presence of benzoyl peroxide or galvanoxyl. Mechanism “A” is postulated to be a concerted cyclic version of the Grob Fragmentation, proceeding through an intermediate which is hydrogen-bonded between the 1- and 3-hydroxyl groups to simultaneously generate enol-acetaldehyde, formaldehyde and H 2O. Mechanism “B” as favored by the presence of alkali is postulated to involve hydrogen-bonding between adjacent hydroxyl groups and to be an alkaline version of the pinacol rearrangement followed by retro-aldol fragmentation of the intermediary 3-oxopropoxide anion. These mechanistic classes are both fundamentally important, not only for their effect on glycerin, but for being able to provide numerous means of initial pyrolytic carbon–carbon bond breakage along carbohydrate carbon-chains, given the numerous 1,2,3-triol interactions that are possible. Further nomenclature is introduced to refine the distinctions among isotopomers and isotopologs (ipsomer, ipsolog, naturalomer, “nominal” isotopolog, ubiquilog), as extensions of a concept previously adopted by IUPAC.

First Efficient Synthesis of Enantiopure Homoketopinic Acid

The first efficient synthesis of enantiopure homoketopinic acid, an interesting camphor derivative is firstly reported. The synthetic procedure uses 10-(triflyloxy)camphor as key electrophilic intermediate. The ability of 10-(triflyloxy)camphor to react selectively with a charged C-nucleophile (cyanide anion) without undergoing Grob fragmentation of the norbornane framework is also demonstrated. Keywords: Bicyclic compounds, camphor derivatives, carboxylic acid, chiral agents

Origin of Structural Diversity in Natural Triterpenes: Direct Synthesis of seco-Triterpene Skeletons by Oxidosqualene Cyclase

At1g78500, one of the oxidosqualene cyclase (OSC) homologues from Arabidopsis thaliana, was expressed in a lanosterol synthase-deficient yeast strain and the products were analyzed. In addition to the known triterpenes, this OSC was found to produce two new triterpenes, the structures of which were determined by NMR and MS analyses. The new triterpenes are C-ring-seco-beta-amyrin (1) and C-ring-seco-alpha-amyrin (2) and named beta-seco-amyrin and alpha-seco-amyrin, respectively. beta-seco-Amyrin is produced from the oleanyl cation through bond cleavage between C8 and C14, and alpha-seco-amyrin is produced from the ursanyl cation in the same manner. Together with Grob fragmentation catalyzed by another OSC (marneral synthase) from A. thaliana, the formation of seco-amyrins by this OSC revealed that OSCs not only catalyze carbon-carbon bond formations and Wagner-Meerwein rearrangements but also cleave preformed ring systems in cationic intermediates. Based on this information, direct production of other natural seco-triterpenes by OSCs is proposed.

Synthesis of Medium Sized Rings from the Cycloadducts of 3,5-Dibromo-2-pyrone via a Radical Mediated Fragmentation Reaction

Medium sized macrocycles, natural or unnatural, are important synthetic targets because of a wide spectrum of their intriguing biological activity. Various synthetic strategies have been developed, most of which utilize ring closure of α,ω-bifunctional linear precursors. Despite many examples in the literature, the formation of medium sized rings is not a trivial task, owing to the unfavourable entropic change associated with. Moreover, the requisite employment of high dilution conditions renders the preparative scale synthesis arduous. Also reported were various methods based on ring expansion including the Wharton/Grob fragmentation as alternatives. We have previously reported the synthesis of structurally novel tricyclolactones 1 from the Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone with cyclic enol ethers. Envisioning the potency of mesylates 2, readily accessible from 1, for the ensuing the Wharton/Grob type fragmentation, we decided to investigate the synthetic manipulation of 1 to medium sized rings 3 (Scheme 1). The cycloadduct 1a was first converted into triol 4a upon debrominations with 2 equiv of Bu3SnH and reductive opening of the lactone bridge with excess LiAlH4 (Scheme 2). Deprotection of TMS followed by selective protection of the primary alcohol with TBS afforded 5a. Subsequent mesylation of the secondary hydroxyl group of 5a would set the stage for the Wharton/Grob fragmentation reaction. However, the attempted mesylation of 5a furnished aromatized product 6a in quantitative yield instead of the desired ketone 3a. Evidently, the initially formed putative mesylate 2a further underwent β-elimination and dehydration reaction. Running the mesylation reaction at lower temperatures produced similar results. Triol 5a was then hydrogenated into 7a before the mesylation, envisioning the removal of the double bond may suppress the ensuing β-elimination reaction (Scheme 3). Treatment of 7a with MsCl indeed provided mesylate 8a in good yield. However, subjection of mesylate 8a into the Wharton/ Grob fragmentation conditions resulted in the formation of alkene 9a, rather than the fragmentation product (Scheme 3). During the investigation, Marko and coworkers reported an efficient radical fragmentation protocol for the Wharton/ Grob type ring expansion reactions of bicyclic tertiary hydroxyl ketones, providing 9-, 10-, and 11-membered

Total Synthesis of (±)‐Pallavicinin and (±)‐Neopallavicinin

Through a biomimetic pathway, (+/-)-pallavicinin and (+/-)-neopallavicinin were synthesized from (+/-)-Wieland-Miescher ketone via Grob fragmentation, intramolecular aldol cyclization, and intramolecular Michael reaction. The synthesis was stereocontrolled efficiently and followed the stereochemistry of the Wieland-Miescher ketone, and could provide opportunities for access to analogues of pallavicinin, neopallavicinin, and other related bioactive diterpenoids.

Synthesis of D-seco-13α-Androst-5-ene Derivatives

3β-Hydroxy-16,17-seco-13α-androsta-5,16-dien-17-al was obtained from 3β-acetoxyandrost-5-en-17-one in six steps with a Grob fragmentation as the key step. This seco-steroid, containing a formyl group and an unsaturated side-chain in a sterically favourable cis position, is a useful synthon for the synthesis of novel heterocycles condensed to the 3β-hydroxy-13α-androst-5-en-17-one skeleton.

A Pauson−Khand and Ring-Expansion Approach to the Aquariane Ring System

[Structure: see text] The carbocyclic ring system of the aquariolide diterpenes has been synthesized by two routes involving a diastereoselective Pauson-Khand reaction and subsequent ring expansion. In one route, a tetracyclic enone was elaborated to generate the nine-membered ring by Grob fragmentation. In the second approach, a spirocyclic tricycle underwent a facile anionic oxy-Cope rearrangement to complete the synthesis of the desired ring system.

Solvolysis of a Tetrahydropyranyl Mesylate: Mechanistic Implications for the Prins Cyclization, 2-Oxonia-Cope Rearrangement, and Grob Fragmentation

[reaction: see text] A solvolysis reaction is used to demonstrate that a tetrahydropyranyl cation is a common intermediate for Prins cyclizations, 2-oxonia-Cope rearrangements, and Grob fragmentations of tetrahydropyran rings.

An Arabidopsis Oxidosqualene Cyclase Catalyzes Iridal Skeleton Formation by Grob Fragmentation

Mechanistic and phylogenetic surprises: A triterpene synthase (MRN1) from Arabidopsis invokes a Grob fragmentation in the cyclization of oxidosqualene. The enzymatic product is the elusive carbocyclic precursor of iridals, unusual triterpenoids known only in the distant Iris family. The results demonstrate the power of genome mining and exemplify the facile evolution of cyclases to generate diverse triterpene skeletons.

Oxidation of 3‐Hydroxypiperidines with Iodosylbenzene in Water: Tandem Oxidative Grob Fragmentation—Cyclization Reaction

AbstractFor Abstract see ChemInform Abstract in Full Text.

A New Type of Intermediate, C+(BCH3)11-↔ C(BCH3)11, in a Grob Fragmentation Coupled with Intramolecular Hydride Transfer. A Nonclassical Carbocation Ylide or a Carbenoid?

In solvolysis of alkyl halides Hal-(CH(2))(n)-C(BCH(3))(11)(-) (n = 2, 5, 6, but not 3, 4, or 7) and protonation of alkenes CH(2)=CH-(CH(2))(n)(-)(2)-C(BCH(3))(11)(-) (n = 3, 6, 7, but not 4 or 5) carrying the icosahedral electrofuge -C(BCH(3))(11)(-) attached through its cage carbon atom, generation of incipient positive charge on C(alpha) (as shown in Scheme 1 in the article) leads to simultaneous cleavage of the C(beta)-C(BCH(3))(11)(-) bond. The products are a C(alpha)=C(beta) alkene and a postulated intermediate C(+)(BCH(3))(11)(-) <--> C(BCH(3))(11), trapped as the adduct Nu-C(BCH(3))(11)(-) by one of the nucleophiles (Nu(-)) present. The reaction kinetics is E1, first order in the haloalkylcarborane and zero order in [Nu(-)], and the elimination appears to be concerted, as in the usual E2 mechanism. The process is best viewed as a Grob fragmentation. The loss of the longer chains involves intrachain hydride transfer from the C(alpha)-H bond to an incipient carbocation on C(delta)(') or C(epsilon)(') via a five- or six-membered cyclic transition state, respectively. The electronic structure of the postulated intermediate is believed to lie between those of a nonclassical carbonium ylide C(+)(BCH(3))(11)(-) and a carbenoid C(BCH(3))(11) whose electronic ground state resembles the S(2) state of ordinary carbenes.

Acid‐Promoted Retro‐Mannich Reaction of N‐Protected Tropenones to 2‐Substituted Pyrroles.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The synthesis of functionalized 13,14-seco-steroids via Grob fragmentation

A synthetic methodology for the synthesis of 13,14-seco-steroids with substituents at C-14 and C-17 is described. The approach involves Grob fragmentation of 14β-hydroxy-17β-tosylates, hydroboration–oxidation of the intermediate Δ 13(17)-olefin, and hydride reduction of the 14-ketone. An unambiguous structural assignment of (13 R,14 S,17 S)-14,17-diacetoxy-3-methoxy-7α-methyl-13,14-secoestra-1,3,5(10)-triene was determined by X-ray analysis.

Synthetic studies of the HIV-1 protease inhibitive didemnaketals: stereocontrolled synthesis of an ester side chain

The stereocontrolled synthesis of the C 1–C 8 portion, the ester side chain of the HIV-1 protease inhibitive didemnaketals from the ascidian Didemnum sp., has been carried out through 15 steps starting from ( S)-carvone as the chiral template. This approach involved the diastereoselective construction of three conjoint chiral centers by intramolecular chiral inducement, and generation of allylic alcohol intermediate through a key Grob fragmentation reaction.

Oxidation of 3-Hydroxypiperidines with Iodosylbenzene in Water: Tandem Oxidative Grob Fragmentation-Cyclization Reaction

Oxidation of 3-hydroxypiperidine with iodosylbenzene in water afforded 2-pyrrolidinone directly in good yields. The reaction probably involves oxidative Grob fragmentation yielding imino aldehyde, which upon hydrolysis produces 2-pyrrolidinone via a cyclization-oxidation sequence.

Synthesis of chiral methyl-branched linear pheromones starting from (+)-aromadendrene. Part 7

Ethyl (7 S)-10-hydroxy-7-methyldecanoate ( 4 ), a linear methyl-branched intermediate with its chiral center at C7, and with two different functional groups at the ends of the chain, has been synthesized from (+)-aromadendrene in nine steps. A Baeyer–Villiger oxidation and a Grob fragmentation are the key reactions in this transformation. Intermediate 4 has been applied in the synthesis of three linear methyl-branched pheromones, (i) ( R)-10-methyl-2-tridecanone, the active pheromone of the southern corn rootworm Diabrotica undecimpunctata howardi Barber, (ii) ( S)-9-methylnonadecane, one of the sex pheromones of the cotton leafworm Alabama argillacea, and (iii) ( meso)-13,23-dimethylpentatriacontane, the sex pheromone of the tse tse fly Glossina pallidipes.