Recent advances of desymmetrization protocol applied in natural product total synthesis

Desymmetrization synthesis strategy has simplified and improved the efficiency of synthesis, which attracted great attention in the past few decades. Since the strategy has been developed rapidly and got a wide range of applications in natural product total synthesis, the rules are urgent to be summarized. In this Letter, the recent developments of desymmetrization protocol in natural product total synthesis were summarized.     

Recent topics of the stereodivergent synthesis of natural products

A variety of natural products, a valuable source of drug lead compounds, coexist with their stereoisomers as congeners. For pursuing the structural elucidation and the structure–activity relationship study of natural products, it is needed to establish the streamlined synthetic route to supply natural products and their stereoisomers. Divergent pathway is one of the synthetic strategies to deliver more than one target compound. In this digest, selected examples of the stereodivergent approach toward the synthesis of natural products are described. Especially, this digest focuses on common synthetic intermediates and stereodiversification steps from the common intermediates to reach the target compounds.     

Asymmetric total syntheses of heliannuol E and epi-heliannuol E

Asymmetric total syntheses of heliannuol E and epi-heliannuol E were achieved in 10 and 13 steps, respectively, from the commercially available starting materials. The syntheses feature an intramolecular attacking on the sulfate to form the dihydropyran ring of heliannuol E and an acyl transfer-secondary carbocation capture sequence to construct the dihydropyran ring of epi-heliannuol E.     

Total syntheses of cyclitol based natural products from myo-inositol: brahol and pinpollitol

Inositol and their derivatives are important class of biologically active natural products. Among the nine theoretically possible inositols, six are known to occur in nature. Interestingly one or more methyl ethers of these inositols have been isolated from plants and these methyl inositols are presumed to have important functions in plant biology. Brahol and pinpollitol are two naturally occurring methylated inositols reported to have allo-inositol and chiro-inositol configurations, respectively. Adopting our sulfonate inversion strategies for synthesizing protected chiro- and allo-inositols from cheaply available myo-inositol in combination with new methods we have achieved the total syntheses of these methylated inositols. The proposed structure of brahol has been synthesized in six steps from myo-inositol. We have not only disproved the proposed structure of brahol but also established its correct structure. Also, we have efficiently synthesized pinpollitol and its positional isomer from myo-inositol. These works involve several selective protection-deprotection strategies of inositol hydroxyl groups.     

One-pot total syntheses of natural products containing a THP-ring backbone: (±)-centrolobine and (±)-civet cat secretion

A one-pot strategy is devised and applied to the total syntheses of natural products with a THP-ring backbone. A special feature of this one-pot synthesis is the recyclability of the indium complex byproduct generated from the indium-mediated allylation reaction for concurrent catalysis in subsequent steps. Centrolobine and civet cat secretion are synthesized via this new method in overall yields of 58% and 23%, respectively.     

Recent topics in application of selective Rh(II)-catalyzed CH functionalization toward natural product synthesis

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Total syntheses of the proposed structures of cuevaene A

Two proposed structures of cuevaene A were synthesized and the NMR spectra of both structures are proved to be inconsistent with those of the natural product. The structure of cuevaene A is still unclear and needs to be revised.     

Total syntheses via cyclopropanols

Cyclopropanols are readily available via the Kulinkovich cyclopropanation, the Simmons-Smith reaction, and other synthetic methods. Due to their intrinsic ring stains, cyclopropanols and their derivatives are highly reactive and can be converted to different structural scaffolds which are frequently found in many natural products. In this review, we highlight the applications of various cyclopropanol ring opening/expansion/fragmentation reactions in the total syntheses of natural products.     

Recent progress toward the total synthesis of humulanolides

The humulanolides are a series of sesquiterpene lactones, most of which have unique and challenging structure. The humulanolides have exhibited anticancer activity. The combinations of fascinating structural motifs and promising pharmacological properties have prompted significant interest in the synthetic community. In this review, we provide a summary of recent progress regarding the total synthesis of humulanolides.     

Total syntheses of bupleurynol and its analog

An efficient route to the natural products bupleurynol and its analog (RB-2), isolated from Bupleuri Radix, was established based on versatile intermediate (15). In this synthetic route, Sonogashira and Cadiot-Chodkiewicz coupling as well as Julia-Kocienski olefination are utilized as key steps. The highly efficient synthetic route provides opportunities to explore the biological behavior of bupleurynol and RB-2.     

A novel and efficient total synthesis of shikonin

A novel and efficient synthesis of shikonin was accomplished with excellent enantiomeric excess (99.3% ee) and high overall yield (47%) in only six steps. The synthetic strategy involved an efficient Ru(II)-catalyzed asymmetric hydrogenation employing C₂-symmetric planar chiral ruthenocene phosphinooxazoline ligand (L-3), followed by the subsequent removal of the methyl protecting groups. Meanwhile, it could be preliminarily confirmed that the chiral side chain of shikonin was difficult to be constructed in one step with both stereoselectivity and α-regioselectivity.     

Recent applications of gold-catalyzed cascade reactions in total synthesis of natural product

From the point of the view of the synthetic efficiency, the concept ‘step economy’ was required in total synthesis of natural product. Recently, versatile gold-catalyzed cascade reactions have been developed, and relating reports on practical applications in total synthesis has increased. This digest focuses and summarizes the gold-catalyzed reaction cascades in natural product synthesis during last five years with brief discussion on the reaction mechanism of the key gold-catalyzed cascade transformations.     

The first total syntheses of (±)-Preussomerins K and L using 2-arylacetal anion technology

The first syntheses of newly isolated members of the Preussomerin family, Preussomerins K and L, are reported. Key steps include the functionalisation of a 2-arylacetal anion, one-pot Friedel-Crafts cyclisation-deprotection and reductive opening of epoxides.     

Chemistry of renieramycins. Part 9: Stereocontrolled total synthesis of (±)-renieramycin G

A 25-step stereocontrolled total synthesis of (±)-renieramycin G (1g) from readily available 2-hydroxy-3-methyl-4,5-dimethoxybenzaldehyde (3) is described. This synthesis features the concise construction of the pentacyclic framework using the stereoselective Pictet-Spengler type cyclization reaction of lactam (14) with ethyl diethoxyacetate, followed by the base-catalyzed isomerization of the C-1 stereo center.     

Total syntheses of the sesquiterpenoids (+)-trans-dracunculifoliol and (+)-4-hydroxyoppositan-7-one

Sesquiterpenoids (+)-trans-dracuncuflifoliol (1) and (+)-4-hydroxyoppositan-7-one (2) were prepared stereoselectively from enantiomerically pure (7aR)-7a-methyl-1,2,5,6,7,7a-hexahydro-4H-inden-4-one ((−)-6), whose synthesis was described herein. Conjugate addition of the organocopper (I) reagent 10 to (−)-6, followed by epimerization of the ring junction, generated 3 of the 4 contiguous chiral centers of both natural products.     

An expeditious total synthesis of kalkitoxins: determination of the absolute stereostructure of natural kalkitoxin

Kalkitoxin, a potent neurotoxin isolated from the marine cyanobacteria Lyngbya majuscula, and its congeners (1-7) were efficiently synthesized utilizing Hruby's diastereoselective 1,4-addition and the Wipf's oxazoline-thiazoline conversion as key steps. These synthetic efforts in combination with spectral studies of natural kalkitoxin clearly determined the absolute stereostructure of kalkitoxin to be 7.