Three-carbon Unit Research Articles

Direct anabolic metabolism of three-carbon propionate to a six-carbon metabolite occurs in vivo across tissues and species

Anabolic metabolism of carbon in mammals is mediated via the one- and two-carbon carriers S-adenosyl methionine and acetyl-coenzyme A. In contrast, anabolic metabolism of three-carbon units via propionate has not been shown to extensively occur. Mammals are primarily thought to oxidize the three-carbon short chain fatty acid propionate by shunting propionyl-CoA to succinyl-CoA for entry into the TCA cycle. Here, we found that this may not be absolute as, in mammals, one nonoxidative fate of propionyl-CoA is to condense to two three-carbon units into a six-carbon trans-2-methyl-2-pentenoyl-CoA (2M2PE-CoA). We confirmed this reaction pathway using purified protein extracts provided limited substrates and verified the product via LC-MS using a synthetic standard. In whole-body in vivo stable isotope tracing following infusion of 13C-labeled valine at steady state, 2M2PE-CoA was found to form via propionyl-CoA in multiple murine tissues, including heart, kidney, and to a lesser degree, in brown adipose tissue, liver, and tibialis anterior muscle. Using ex vivo isotope tracing, we found that 2M2PE-CoA also formed in human myocardial tissue incubated with propionate to a limited extent. While the complete enzymology of this pathway remains to be elucidated, these results confirm the in vivo existence of at least one anabolic three- to six-carbon reaction conserved in humans and mice that utilizes propionate.

Unified Total Syntheses of Rhamnofolane, Tigliane, and Daphnane Diterpenoids.

Rhamnofolane, tigliane, and daphnane diterpenoids are structurally complex natural products with multiple oxygen functionalities, making them synthetically challenging. While these diterpenoids share a 5/7/6-trans-fused ring system (ABC-ring), the three-carbon substitutions at the C13- and C14-positions on the C-ring and appending oxygen functional groups differ among them, accounting for the disparate biological activities of these natural products. Here, we developed a new, unified strategy for expeditious total syntheses of five representative members of these three families, crotophorbolone (1), langduin A (2), prostratin (3), resiniferatoxin (4), and tinyatoxin (5). Retrosynthetically, 1-5 were simplified into their common ABC-ring 6 by detaching the three-carbon units and the oxygen-appended groups. Intermediate 6 with six stereocenters was assembled from four achiral fragments in 12 steps by integrating three powerful transformations, as follows: (i) asymmetric Diels-Alder reaction to induce formation of the C-ring; (ii) π-allyl Stille coupling reaction to set the trisubstituted E-olefin of the B-ring; and (iii) Eu(fod)3-promoted 7-endo cyclization of the B-ring via the generation of a bridgehead radical. Then 6 was diversified into 1-5 by selective installation of the different functional groups. Attachment of the C14-β-isopropenyl and isopropyl groups led to 1 and 2, respectively, while oxidative acetoxylation and C13,14-β-dimethylcyclopropane formation gave rise to 3. Finally, formation of an α-oriented caged orthoester by C13-stereochemical inversion and esterification with two different homovanillic acids delivered 4 and 5 with a C13-β-isopropenyl group. This unified synthetic route to 1-5 required only 16-20 total steps, demonstrating the exceptional efficiency of the present strategy.

Azide-Functionalized Derivatives of the Virulence-Associated Sugar Pseudaminic Acid: Chiral Pool Synthesis and Labeling of Bacteria.

Pseudaminic acid (Pse) is a significant prokaryotic monosaccharide found in important Gram‐negative and Gram‐positive bacteria. This unique sugar serves as a component of cell‐surface‐associated glycans or glycoproteins and is associated with their virulence. We report the synthesis of azidoacetamido‐functionalized Pse derivatives as part of a search for Pse‐derived metabolic labeling reagents. The synthesis was initiated with d‐glucose (Glc), which served as a cost‐effective chiral pool starting material. Key synthetic steps involve the conversion of C1 of Glc into the terminal methyl group of Pse, and inverting deoxyaminations at C3 and C5 of Glc followed by backbone elongation with a three‐carbon unit using the Barbier reaction. Metabolic labeling experiments revealed that, of the four Pse derivatives, ester‐protected C5 azidoacetamido‐Pse successfully labeled cells of Pse‐expressing Gram‐positive and Gram‐negative strains. No labeling was observed in cells of non‐Pse‐expressing strains. The ester‐protected and C5 azidoacetamido‐functionalized Pse is thus a useful reagent for the identification of bacteria expressing this unique virulence‐associated nonulosonic acid.

Palladium-Catalyzed [3 + 2] Cycloaddition via Twofold 1,3-C(sp3)-H Activation.

Cycloaddition reactions provide an expeditious route to construct ring systems in a highly convergent and stereoselective manner. For a typical cycloaddition reaction to occur, however, the installation of multiple reactive functional groups (π-bonds, leaving group, etc.) is required within the substrates, compromising the overall efficiency or scope of the cycloaddition reaction. Here, we report a palladium-catalyzed [3 + 2] reaction that utilizes twofold C(sp3)-H activation to generate the three-carbon unit for formal cycloaddition. The initial β-C(sp3)-H activation of aliphatic amide, followed by maleimide insertion, triggers a relayed, second C(sp3)-H activation to complete a formal [3 + 2] cycloaddition. The key to success was the use of weakly coordinating amide as the directing group, as previous studies have shown that Heck or alkylation pathways are preferred when stronger-coordinating directing groups are used with maleimide coupling partners. To promote the amide-directed C(sp3)-H activation step, the use of pyridine-3-sulfonic acid ligands is crucial. This method is compatible with a wide range of amide substrates, including lactams, which lead to spiro-bicyclic products. The [3 + 2] product is also shown to undergo a reductive desymmetrization process to access chiral cyclopentane bearing multiple stereocenters with excellent enantioselectivity.

Asymmetric Total Synthesis of Crotophorbolone: Construction of the 5/7/6-Fused Ring System via an α-Alkoxy Bridgehead Radical Reaction

Abstract This account describes the development of a synthetic route to crotophorbolone (1). Compound 1 is classified as a derivative of the tigliane diterpenoids, and possesses a highly oxygenated 5/7/6-fused ABC-ring system. First, the six-membered C-ring fragment with five contiguous stereocenters was stereoselectively constructed from (R)-carvone. Nucleophilic addition of the three-carbon unit to the C-ring and stereoselective attachment of the five-membered A-ring through a π-allyl Stille coupling reaction provided the substrate for the key radical cyclization. Next, treatment of the O,Se-acetal with V-40 and (TMS)3SiH in refluxing toluene generated the α-alkoxy bridgehead radical, which participated in the endo-cyclization of the seven-membered B-ring with formation of the sterically congested bond in C9-stereospecific and C10-stereoselective manners. The C11-methyl group controlled the C10-stereochemical outcome via a long-range steric interaction, which was supported by the calculated transition state of the abbreviated α-alkoxy bridgehead radical structure. Finally, the functional groups on the 5/7/6-membered ring system were manipulated by Rh-catalyzed C2-olefin isomerization, C13-decarboxylative oxidation and C4-hydroxylation, completing the first total synthesis of 1 in 33 steps from (R)-carvone.

ChemInform Abstract: Two‐Directional Carbon Chain Elongation via the Consecutive 1,4‐Addition of Allyl Malononitrile and the Cope Rearrangement on an Alkynoate Platform.

A one-pot procedure for the regioselective introduction of two different three-carbon units, allyl and malononitrile functionalities, to C–C triple bonds was established. The transformation proceeds through the phosphine-catalyzed 1,4-addition of allyl malononitrile to the alkynoate and the Cope rearrangement with microwave heating, achieving two-directional carbon chain elongation on the alkynoate platform. The operational simplicity, succinct carbon skeletal construction, and high atom economy should make the present procedure appealing for the synthesis of structurally complex organic molecules.

Two-directional carbon chain elongation via the consecutive 1,4-addition of allyl malononitrile and the Cope rearrangement on an alkynoate platform

A one-pot procedure for the regioselective introduction of two different three-carbon units, allyl and malononitrile functionalities, to C–C triple bonds was established. The transformation proceeds through the phosphine-catalyzed 1,4-addition of allyl malononitrile to the alkynoate and the Cope rearrangement with microwave heating, achieving two-directional carbon chain elongation on the alkynoate platform. The operational simplicity, succinct carbon skeletal construction, and high atom economy should make the present procedure appealing for the synthesis of structurally complex organic molecules.

ChemInform Abstract: Rhodium(III)‐Catalyzed Transannulation of Cyclopropenes with N‐Phenoxyacetamides Through C—H Activation.

An efficient rhodium(III)-catalyzed synthesis of 2H-chromene from N-phenoxyacetamides and cyclopropenes has been developed. The reaction represents the first example of using cyclopropenes as a three-carbon unit in rhodium(III)-catalyzed C(sp(2))-H activations.

Computational protein design enables a novel one-carbon assimilation pathway.

We describe a computationally designed enzyme, formolase (FLS), which catalyzes the carboligation of three one-carbon formaldehyde molecules into one three-carbon dihydroxyacetone molecule. The existence of FLS enables the design of a new carbon fixation pathway, the formolase pathway, consisting of a small number of thermodynamically favorable chemical transformations that convert formate into a three-carbon sugar in central metabolism. The formolase pathway is predicted to use carbon more efficiently and with less backward flux than any naturally occurring one-carbon assimilation pathway. When supplemented with enzymes carrying out the other steps in the pathway, FLS converts formate into dihydroxyacetone phosphate and other central metabolites in vitro. These results demonstrate how modern protein engineering and design tools can facilitate the construction of a completely new biosynthetic pathway.

Electron-withdrawing group effect in aryl group of allyl bromides for the successful synthesis of indolizines via a novel [3+3] annulation approach

A new synthetic approach to 6,7-disubstituted indolizines has been developed from pyrrole-2-carboxaldehydes and allyl bromides via two successive base-mediated reactions. As three-carbon units for formation of pyridine moiety of indolizines, allyl bromides easily derived from Morita–Baylis–Hillman (MBH) adducts were employed. We found that positioning electron-withdrawing group(s) at the aromatic ring of allyl bromides was a key to successful ring closure to allow access to indolizines with unique substitution style. Structurally relevant imidazo[1,2-a]pyridine and pyrido[1,2-a]indole were assembled by this method as well.

The alkaloids of the madangamine group.

This chapter is focused on madangamines, a small group of complex diamine alkaloids isolated from marine sponges of the order Haplosclerida, and covers their isolation, characterization, biogenesis, biological activity, and synthesis. Structurally, madangamines are pentacyclic alkaloids with an unprecedented skeletal type, characterized by a common diazatricyclic core and two peripheral macrocyclic rings. The isolation of these alkaloids from Xestospongia ingens (madangamines A-E) and Pachychalina alcaloidifera (madangamine F) is described in detail. Physical and complete spectroscopic 1H and 13C NMR data are included. The proposed biogenesis of madangamines from ammonia, a functionalized three-carbon unit, and saturated or unsaturated linear long-chain dialdehydes, via partially reduced bis-alkylpyridine macrocycles, is discussed. The synthesis of alkaloids of the madangamine group has been little explored, with only one total synthesis reported so far, that of (+)-madangamine D. This review also describes several model synthetic approaches to the diazatricyclic ABC core of these alkaloids, as well as model studies on the construction of the (Z,Z)-unsaturated 11-membered E macrocycle common to madangamines A-E, the 13- and 14-membered D rings of madangamines C-E, and the all-cis-triunsaturated 15-membered D ring of madangamine A. Some members of this group have shown significant in vitro cytotoxicity against a number of cancer cell lines.

Rhodium(III)-catalyzed transannulation of cyclopropenes with N-phenoxyacetamides through C-H activation.

An efficient rhodium(III)-catalyzed synthesis of 2H-chromene from N-phenoxyacetamides and cyclopropenes has been developed. The reaction represents the first example of using cyclopropenes as a three-carbon unit in rhodium(III)-catalyzed C(sp(2))-H activations.

Synthesis of Poly-Substituted Benzene Derivatives via [3+3] Annulation Protocol from Morita-Baylis-Hillman Adducts and Glutaconates

Morita-Baylis-Hillman (MBH) adducts 1 have been used for the synthesis of various aromatic compounds including poly-substituted benzenes 2 and phenols. 3 The reaction of MBH adduct and 1,3-dimethylacetone dicarboxylate has been used for the synthesis of poly-substituted phenols bearing 2,6-dicarboxylates via the [3+3] annulation protocol (vide infra, Scheme 1). 3a 1,3-Dimethylacetone dicarboxylate served a three-carbon unit with 1,3-dicarboxylates and 2keto functionality in the reaction. The corresponding polysubstituted benzene 3a has been synthesized in low yield (23%) 2a by DBU-mediated dehydrogenation of the cyclohexene intermediate which was prepared from MBH adduct and diethyl malonate (vide infra, Scheme 1). 4 Glutaconates have been used in organic synthesis in order to introduce a three-carbon unit bearing two carboxylates at the 1,3-position. 5,6 In these respects, we presumed that the reaction of MBH adduct and diethyl glutaconate could be used for the preparation of poly-substituted benzene derivatives bearing 1,3-dicarboxylates such as 3a, as shown in Scheme 1. At the outset of our experiment, the reaction of MBH bromide 1a and diethyl glutaconate (2a) was examined in CH3CN in the presence of Cs2CO3 at 50 o C for 2 h. To our delight, desired product 3a was obtained in moderate yield (61%). 7 The nucleophilic substitution of 1a with the anion of 2a would produce a resonance-stabilized carbanion intermediate I, 8 and the following cyclization, dehydration and a base-catalyzed 1,3-H shift produced 3a via an overall [3+3] annulation approach, as shown in Scheme 2. The reaction in refluxing CH3CN gave a similar yield of 3a (60%). After some trials, we found that the reaction in DMF at 90 o C produced 3a in good yield (72%) in short time (1 h), and we

Asymmetric Formal [3 + 2] Cycloaddition Reaction of Succinaldehyde via Diarylprolinol-mediated Domino Aldol–Acetalization Reaction for the Construction of Tetrahydrofuran

Abstract Highly enantioselective synthesis of tetrahydrofurans was accomplished via a formal [3 + 2] cycloaddition reaction of succinaldehyde, which acts as a three-carbon unit. The reaction consists of the domino reaction of the diarylprolinol-mediated aldol reaction of succinaldehyde followed by an intramolecular acetalization reaction.

Biosynthesis of tetronate antibiotics: A growing family of natural products with broad biological activities

Tetronate antibiotics, a growing family of natural products featuring a characteristic tetronic acid moiety, are of importance and of particular interest for their typical structures, especially the spirotetronate structure, and corresponding versatile biological activities. Considerable efforts have persistently performed since the first tetronate was isolated, to elucidate the biosynthesis of natural tetronate products, by isotope-labeled feeding experiments, genetical characterization of biosynthetic gene clusters, and biochemical reconstitution of key enzymatic catalyzed reactions. Accordingly, the biosynthesis of spirotetronates has been gradually determined, including biosynthesis of a polyketide-derived backbone for spirotetronate aglycone, incorporation of a glycerol-derived three-carbon unit into tetronic acid moiety, formation of mature aglycone via Diels-Alder-like reaction, and decorations of aglycone with various deoxysugar moieties. In this paper, the biosynthetic investigations of natural tetronates are well documented and a common biosynthetic route for this group of natural products is summarized accordingly.

ChemInform Abstract: A Novel Synthetic Approach to Steroids via Intramolecular 1,3-Dipolar Cycloaddition. A Highly Stereocontrolled Synthesis of Testosterone.

A new synthetic methodology for construction of the A/B ring system of steroids was developed consisting of a 1,3-dipolar cycloaddition, followed by incorporation of a three-carbon unit; a facile total synthesis of (+)-testosterone was achieved via this strategy

An Unexpected Phosphine‐Catalyzed Regio‐ and Diastereoselective [4+1] Annulation Reaction of Modified Allylic Compounds with Activated Enones

Nucleophilic phosphines are known to be useful mild catalysts for the synthesis of cyclic and heterocyclic compounds. Generally, tertiary-phosphine-mediated annulations are triggered by nucleophilic addition of phosphines to activated compounds. The resultant zwitterionic intermediates can react with various electrophiles such as aldehydes, imines, and activated polarized C=C bonds to furnish cyclic compounds. Herein, we report a phosphine-catalyzed highly diastereoselective synthesis of tetrasubstituted 2,3-dihydrofurans, which are subunits of a range of biologically active compounds (e.g., aflatoxin B1 and clerodin), [4] via [4+1] annulations of Morita–Baylis–Hillman carbonates with activated enones. In these annulations, Morita–Baylis– Hillman carbonates act as the one-carbon unit, which is distinguished from the modified allylic compounds reported by Lu et al. as the three-carbon units, such as in [3+2], [3+3], [3+4], and [3+6] annulation reactions. In recent years, Morita–Baylis–Hillman adducts have been illustrated as suitable starting materials for the synthesis of a variety of multifunctional compounds. During our study of the new chemistry of electron-deficient enynes, we became interested in the annulation between Morita– Baylis–Hillman carbonate 1a and conjugated yne-enone 2a. We were pleased to find that the reaction proceeded smoothly in toluene at room temperature under catalysis with 10 mol% PPh3, leading to a [4+1] adduct, 2,3-dihydrofuran 3a, in 72% yield of isolated product with 20:1 diastereoselectivity (Table 1, entry 1). The structure of 3a was established by X-ray crystallography analysis of the analogous product 3f (R=p-BrC6H4; Figure 1). [7] To improve the yield of 3a, various solvents and tertiary phosphines were tested and the results are summarized in Table 1. A higher product yield was obtained when the reaction was performed in CH2Cl2, while the selectivity was slightly decreased (Table 1, entry 2). Good yields with high selectivity were also obtained in DCE, Et2O, and 1,4-dioxane, albeit the reactions require a longer time to go to completion (Table 1, en-

Platinum(II)-Catalyzed Intermolecular [3 + 2] Cycloaddition of Propadienyl Silyl Ethers and Alkenyl Ethers

A Pt(II)-catalyzed [3 + 2] cycloaddition reaction of silyl propadienyl ethers and alkenyl ethers has been developed as the first example of the utilization of allenes as a three-carbon unit in a transition-metal-catalyzed intermolecular cycloaddition reaction. Pt(II)-containing 1,3-dipole equivalents generated by electrophilic activation of silyl propadienyl ethers using a Pt(II) catalyst reacted with various electron-rich alkenes to give synthetically useful functionalized cyclopentene derivatives in high yield with wide generality.

Total synthesis of epothilones B and D: stannane equivalents for beta-keto ester dianions.

Studies leading to a total synthesis of epothilones B and D are described. The overall synthetic plan was based on late-stage fragment assembly of two segments representing C(1)-C(9) and C(10)-C(21) of the structure. The C(1)-C(9) fragment was prepared by elaboration of commercially available (2R)-3-hydroxy-2-methylpropanoate at both ends of the three-carbon unit. Introduction of carbons 1-4 containing the gem-dimethyl unit was achieved in a convergent manner using a diastereoselective addition of a stannane equivalent of a beta-keto ester dianion. An enantioselective addition of such a stannane equivalent for a beta-keto ester dianion was also used to fashion one version of the C(10)-C(21) subunit; however, the fragment assembly (using bimolecular esterification followed by ring-closing metathesis) with this subunit failed. Therefore, fragment assembly was achieved using a Wittig reaction; this was followed by macrolactonization to close the macrocycle. The C(10)-C(21) subunit needed for this approach was prepared in an efficient manner using the Corey-Kim reaction as a key element. Other key reactions in the synthesis include a stereoselective SmI(2) reduction of a beta-hydroxy ketone and a critical opening of a valerolactone with aniline which required extensive investigation.

Living Ring-Opening Polymerization of 2-Alkoxy-1-methylenecyclopropanes Initiated by Pd Complexes

Pd complexes with a chelating diimine ligand promote ring-opening polymerization of 2-alkoxy-1-methylenecyclopropanes to produce the polymers having vinylidene and alkoxy substituents for every three-carbon unit. 13C{1H} NMR spectra of the produced polymers show the well-regulated structures with head-to-tail connection of the repeating units. [(π-Allyl)PdCl]2 initiates living polymerization of 2-alkoxy-1-methylenecyclopropanes (alkoxy: OBu, OtBu, OMe) to afford the polymers with narrow molecular weight distribution. Molecular weight of the polymer was controlled over a wide range by changing the initial monomer-to-initiator molar ratio. Direct measurement of the growing polymer of 2-butoxy-1-methylenecyclopropane by NMR and GPC indicates that the polymer molecule has a dimer structure with a Pd2Cl2 core and two π-allyl−Pd bonds. Treatment of the growing polymer with nucleophilic reagents, such as NaOH/MeOH, NaOH/H2O, AgOAc, and NaCMe(COOEt)2−PPh3, cleaves the π-allyl−Pd bonds and forms the polymers havin...