Chiral Pool Strategy Research Articles

Asymmetric Synthesis of Taiwaniaquinone H via a Late-Stage Oxidative Decarboxylation.

The asymmetric syntheses of naturally occurring biologically relevant abeo-abietane diterpenoids, (-)-taiwaniaquinone G (1a), and H (1b) have been reported via a chiral pool strategy starting from commercially available abietic acid. A ring contraction of the middle ring of the [6,6,6]-carbotricyclic abietane diterpenoid core was carried out under the Wolff rearrangement. Finally, the synthesis of (-)-taiwaniaquinone H (1b) was completed via a one-pot CAN-mediated oxidative decarboxylation.

The first enantioselective total synthesis of the eremophilane-type sesquiterpenoid (−)-peniroqueforin C

Herein, we report the first stereoselective total synthesis of the eremophilane-type sesquiterpenoid (−)-peniroqueforin C using a chiral-pool strategy. This synthetic route features the use of readily available (S)-(+)-carvone as a chiral building block, Robinson annulation to construct the decalin system, substrate-controlled stereoselective methylation, single-step annulative construction of a tricyclic γ-ylidene-butenolide with concomitant alkene transposition, and direct lactone-to-lactam conversion as key transformations.

K3PO4–Mediated Synthesis of Chromeno–[3,4‐c]isoxazole from 3–Nitro–2H–chromene and α–Chloro Aldehyde via Michael Addition/C−Cl Bond Cleavage/Deformylation as Key Fragmentation Sequences

AbstractHere we report a transition metal– and oxidant–free annulation cascade method for the synthesis of chromeno–isoxazoles. The annulation reaction involves easily accessible starting materials, 3‐nitro‐2H‐chromene and α‐chloro aldehyde, yielding the structurally intriguing framework, chromeno[3,4‐c]isoxazoles employed by tripotassium phosphate as a base. The isoxazole ring construction over the 2H–chromene unit is believed to occur via a series of multiple reaction sequences. Here, the enolate generation/Michael addition/C−Cl bond cleavage/oxy–anionic addition to reactive tethered‐aldehyde/deformylation via retro–C−C and N−O bond cleavages are the most possible sequences which furnish the desired end–product in good chemical yields. The multiple reaction sequences occur in one‐pot at mild conditions, supported by experimental results and a few control experiments including DFT studies. This process exhibits a broad substrates scope illustrating good functional group compatibility towards both the nitrochromenes and aldehydes, and thus prove to be a general and efficient protocol for the synthesis of chromeno[3,4–c]isoxazoles. Overall, the use of nitrochromene as the limiting reagent, noteworthy functional group tolerance, scalability including great applications like chiral pool strategy towards the synthesis of enantioenriched chromeno‐isoxazole are the additional features.

Cover Picture

The cover image portrays the asymmetric synthesis of dihydrospirotryprostatin B, achieved through a chiral pool strategy utilizing readily available tryptamine‐ynamide. This tryptamine‐ynamide was constructed from three synthetic building blocks: L‐tryptophan, methyl‐L‐proline ester, and bromoalkyne. For a comprehensive understanding of this process, refer to the article authored by Liu et al., pages 1355—1359.image

A Chiral Pool Strategy for the Synthesis of a SMARCA2 Degrading PROTAC

A Chiral Pool Strategy for the Synthesis of a SMARCA2 Degrading PROTAC

Synthesis and Anti-Inflammatory Evaluation of a Library of Chiral Derivatives of Xanthones Conjugated with Proteinogenic Amino Acids.

In recent decades, the relationship between drug chirality and biological activity has been assuming enormous importance in medicinal chemistry. Particularly, chiral derivatives of xanthones (CDXs) have interesting biological activities, including enantioselective anti-inflammatory activity. Herein, the synthesis of a library of CDXs is described, by coupling a carboxyxanthone (1) with both enantiomers of proteinogenic amino esters as chiral building blocks (2-31), following the chiral pool strategy. The coupling reactions were performed at room temperature with good yields (from 44 to 99.9%) and very high enantiomeric purity, with most of them presenting an enantiomeric ratio close to 100%. To afford the respective amino acid derivatives (32-61), the ester group of the CDXs was hydrolyzed in mild alkaline conditions. Consequently, in this work, sixty new derivatives of CDXs were synthetized. The cytocompatibility and anti-inflammatory activity in the presence of M1 macrophages were studied for forty-four of the new synthesized CDXs. A significant decrease in the levels of a proinflammatory cytokine targeted in the treatment of several inflammatory diseases, namely interleukin 6 (IL-6), was achieved in the presence of many CDXs. The amino ester of L-tyrosine (X1AELT) was the most effective in reducing IL-6 production (52.2 ± 13.2%) by LPS-stimulated macrophages. Moreover, it was ≈1.2 times better than the D-enantiomer. Indeed, enantioselectivity was observed for the majority of the tested compounds. Thus, their evaluation as promising anti-inflammatory drugs should be considered.

Asymmetric total synthesis of (1S,2S,4S)-β-elemene.

Elemenes are sesquiterpene natural products extracted from Chinese medicinal herbs and have been used as an important antitumor drug in China. Here, we report the first stereoselective total synthesis of (1S,2S,4S)-β-elemene using (R)-carvone as a chiral pool starting material. The isopropenyl moiety was achieved in a highly stereoselective manner through 1,4-Michael conjugate addition. The following transformations like regio- and stereoselective aldol condensation, Wittig olefination have been employed as the key steps, resulting in a concise total synthesis of (1S,2S,4S)-β-elemene. Our accomplishment will allow further biological investigations of this natural product and open opportunities for developing a new potentially promising antitumor drug.

An alternative process for the synthesis of the key intermediate of ritlecitinib

An alternative synthetic route towards the key intermediate of ritlecitinib has been developed. Stereochemistry of intermediate 10 was introduced based on chiral pool strategy by employing d-pyroglutamate derivative 20 as starting material and chiral salt resolution strategy by using safer resolving agents without exothermic risk. The economical cost was lowered by avoiding noble metals catalyzed hydrogenation while maintaining a high-quality delivery of key intermediate 10 with excellent selectivity and purity. From process operability perspectives, all chromatographic purifications were eliminated and the process is readily scalable.

Cover Feature: Synthesis of Pyrrolo[2,1‐a]isoquinoline Class of Natural Product Crispine A (Eur. J. Org. Chem. 35/2021)

The Cover Feature shows naturally occurring (2S,3S)- and (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furan dicarboxylic acid bearing, chemically amenable functional groups that are an ideal choice for the enantiopure synthesis of the (−)- and (+)-Crispine A, respectively. The diastereomeric natural products are conveniently converted to desirable enantiomers of Crispine A through the chiral pool strategy. This exciting and efficient strategy is one of the well-explored trends in synthetic organic chemistry, especially regarding molecules procured from tropical plant material (Nature) and serves as key step in the enantiopure synthesis of small-molecule natural products. More information can be found in the Minireview by C. Mohan, I. Ibnusaud et al.

Evolution of a Strategy for the Total Synthesis of (+)-Cornexistin.

Herein is given a full account of the evolution of the first total synthesis of (+)‐cornexistin. Initial efforts were based on masking the reactive maleic anhydride moiety as a 3,4‐substituted furan and on forming the nine‐membered carbocycle in an intramolecular Conia‐ene or Nozaki–Hiyama–Kishi (NHK) reaction. Those strategies suffered from low yields and were jeopardized by a late‐stage installation of the Z‐alkene, as well as the stereocenters along the eastern periphery. These issues were addressed by employing a chiral‐pool strategy that involved construction of the crucial stereocenters at C2, C3 and C8 at an early stage with installation of the maleic anhydride as late as possible. The successful approach featured an intermolecular NHK coupling to install the Z‐alkene, a syn‐Evans‐aldol reaction to forge the stereocenters along the eastern periphery, an intramolecular allylic alkylation to close the nine‐membered carbocycle, and a challenging stepwise hydrolysis of a β‐keto nitrile to furnish the maleic anhydride.

A New Asymmetric Synthesis of (S)-14-Methyl-1-Octadecene, the Sex Pheromone of the Peach Leafminer Moth

An asymmetric synthesis of 14-methyl-1-octadecene, the sex pheromone of the peach leafminer moth, has been efficiently achieved. A key chiral intermediate, ( R)−4-(benzyloxy)−3-methylbutanal, which has been developed as the resource chemical, can be obtained in large quantities from the steroid industry. 1,11-Undecanediol is selectively masked, and then converted into a phosphonium salt derivative, thereby effectively constructing a carbon skeleton. The target molecule is synthesized in 8 linear steps, with a 42% yield. The key characteristic of our synthesis lies in its chiral-pool strategy.

Chiral benzimidazole derived bis‐phenyl triazoles as chiroptical sensors for iodide and chiral amines

AbstractA series of chiral 2‐hydroxy ethyl/benzyl benzimidazole based aryl triazole tweezers have been prepared using click chemistry in high yields. Chiral pool strategy has been used to obtain the benzimidazole‐based tweezers in very high enantiomerically enriched form. The aryl triazole tweezers, S‐(−)‐5a and S‐(+)‐8a displayed a high degree of selectivity for iodide anion over other anions, including other halides. The aryl triazole tweezers, S‐(−)‐5a and S‐(+)‐8a display significant enantio‐discrimination for chiral amines. The chiral recognition studies were carried out using UV and circular dichroism (CD) spectroscopy. NMR analysis has been used for establishing the sites for ligation of the iodide anion.

First total synthesis of the pro-resolving lipid mediator 7(S),12(R),13(S)-Resolvin T2 and its 13(R)-epimer

The first total synthesis of the pro-resolving lipid mediator 7(S),12(R),13(S)-Resolvin T2 [7(S),12(R),13(S)-RvT2] and its 13(R)-epimer, derived from n-3 docosapentaenoic acid (n-3 DPA), are described. 7(S),12(R),13(S)-RvT2 and its 13(R)-epimer were obtained by total synthesis using a chiral pool strategy to introduce the chiral centers. C7 was generated from S-(−)-1,2,4-butanetriol in both molecules and the C12 and C13 centers were generated from L-(+)-ribose and D-(−)-arabinose respectively. Cis and trans-selective Wittig reactions, selective deprotections, and Dess-Martin periodinane oxidation were the key steps in the syntheses.

Stereoselective synthesis of MaR2n-3 DPA

The first total synthesis of the n-3 docosapentaenoic derived oxygenated product MaR2n-3 DPA has been achieved. The 13R and 14S stereogenic centers were introduced using 2-deoxy-d-ribose in a chiral pool strategy. The geometry of the Z,E,E-triene moiety was prepared using highly E-selective Wittig- and Takai-olefination reactions as well as the Z-stereoselective Lindlar reduction. LC/MS-MS data of synthetic MaR2n-3 DPA matched data for the biosynthetic formed product that enabled the configurational assignment of this oxygenated natural product to be (7Z,9E,11E,13R,14S,16Z,19Z)-13,14-dihydroxydocosa-7,9,11,16,19-pentaenoic acid.

First total syntheses of the pro-resolving lipid mediators 7(S),13(R),20(S)-Resolvin T1 and 7(S),13(R)-Resolvin T4

The first total syntheses of the pro-resolving lipid mediators 7(S),13(R),20(S)-Resolvin T1 [7(S),13(R),20(S)-RvT1] and 7(S),13(R)-Resolvin T4 [7(S),13(R)-RvT4], derived from n-3 docosapentaenoic acid (n-3 DPA), are described. 7(S),13(R),20(S)-RvT1 was prepared from 7(S),13(R)-RvT4 via an enzymatic lipoxidase reaction. 7(S),13(R)-RvT4 was obtained by total synthesis where the chiral centers at C7 and C13 where introduced by a Noyori transfer hydrogenation and a chiral pool strategy respectively. Wittig reactions, Sonogashira coupling and Boland Zn(Cu/Ag) reduction were the key steps in the synthesis.

First total synthesis of the anti-inflammatory and pro-resolving lipid mediator 16(R),17(S)-diHDHA

The first total synthesis of the anti-inflammatory and pro-resolving lipid mediator 16(R),17(S)-diHDHA, derived from docosahexaenoic acid (DHA), and its 16-epimer have been achieved. Two synthetic approaches are described for the synthesis of 16(R),17(S)-diHDHA. The first strategy started from DHA and used an enzymatic reaction, a vanadium catalyzed allylic epoxidation and a base-promoted epoxide isomerization. The second approach utilized a chiral pool strategy starting from 2-deoxy-d-ribose to establish the chiral centers; Wittig reactions, mild acetonide cleavage and ester hydrolysis were the key steps in the synthesis.

Asymmetric synthesis, molecular modeling and biological evaluation of 5-methyl-3-aryloxazolidine-2,4-dione enantiomers as monoamine oxidase (MAO) inhibitors

Single enantiomers of the new 5-methyl-3-aryloxazolidine-2,4-diones have been obtained either by an asymmetric synthesis using the chiral pool strategy or by a semipreparative resolution of the racemic compound by HPLC on an optically active stationary phase. The single enantiomers were assayed for their in vitro monoamine oxidase (hMAO) inhibitory activity and selectivity. The most potent inhibitor among the studied compounds has been found as (5R)-3-phenyl-5-methyl-2,4-oxazolidinedione (compound 1-R) which appeared to be a good antidepressant drug candidate since it inhibited hMAO-A selectively, competitively and reversibly with Ki values in the micromolar range (0.16 ± 0.01 μM). To better understand the enzyme-inhibitor interaction and to explain the efficiency and selectivity of the compounds toward hMAOs, molecular modeling studies were carried out on new, high resolution hMAO-A and hMAO-B crystallographic structures. According to binding energies and inhibition constants obtained from molecular docking calculations, compound 1-R has been found as the most selective MAO-A inhibitor and its weak binding affinities to MAO-B (large Ki values) led to the enhancement in MAO-A selectivity. It bounded in close proximity to FAD in the active site of MAO-A and situated near the aromatic cage by means of π-alkyl interactions with Tyr407 and Phe352 whereas its position in MAO-B was 10 Å far from FAD and it was situated outside the Ile199 gate of the active site. None of the studied compounds showed any cytototoxicity on HepG2 cells at 1 and 5 µM concentrations.

First total synthesis of pro-resolving and tissue-regenerative resolvin sulfido-conjugates

The first total synthesis of the pro-resolving and tissue-regenerative resolvin sulfido-conjugates: 7S,8R,17S-RCTR1, 7S,8R,17S-RCTR2 and 7S,8R,17S-RCTR3, derived from docosahexaenoic acid, has been achieved. Two synthetic approaches are described. Chiral centers 7S and 8R were introduced in both approaches via a chiral pool strategy starting from 2-deoxy-d-ribose. The 17S chiral center was introduced either by a chiral pool strategy or by an enzymatic hydroxylation with lipoxidase. Wittig reactions, selective epoxide formation and epoxide opening with glutathione, l-cysteinylglycine and l-cysteine respectively, were the key steps in the synthesis.

Synthesis of (2-mercaptoacetyl)-L-[2-14 C]tryptophan as a selective metallo-β-lactamase inhibitor via [2-14 C]indole based on chiral pool strategy.

Metallo-beta-lactamase enzymes make bacteria resistant to a broad range of commonly used beta-lactam antibiotics. Several thiol derivatives of L-amino acids have been shown their inhibitory effects against the metallo-β-lactamase IMP-1. In this study, (2-mercaptoacetyl)-L-tryptophan as a new inhibitor of metallo-β-lactamases labeled with carbon-14 in the 2-position of the indole ring was prepared from [2-14 C]indole as a key synthetic intermediate based on chiral pool strategy. The overall synthesis was performed in 10 steps with the overall radiochemical yield 3.6% on the basis of the barium [14 C]carbonate as a starting material.

Chiral pool approach for the synthesis of functionalized amino acids: synthesis of antiepileptic drug (R)-lacosamide

An efficient total synthesis of (R)-lacosamide 1 has been achieved from N-Boc-N,O-isopropylidene-l-serinol 2 which could easily be obtained from natural l-serine. Our synthesis of 1 starting from 2 using chiral pool strategy resulted in 54% overall yield.