Efficient Enantioselective Total Synthesis Research Articles

Research on the Efficient Enantioselective Total Synthesis of Useful Bioactive Polycyclic Compounds

Abstract Useful bioactive polycyclic natural products are important targets in academic research, wherein their mechanisms of action and total syntheses are commonly investigated. In addition, polycyclic compounds that exhibit highly selective biological activities through multipoint recognition are valuable as biochemical reagents and lead compounds for pharmaceuticals. However, when such compounds are difficult to obtain, their supply depends on appropriate chemical preparations. Unfortunately, polycyclic natural products pose difficult synthetic problems, such as the construction of distorted ring structures, contiguous stereogenic centers, and quaternary asymmetric carbon atoms in their fused ring moieties. Moreover, since polycyclic natural products have a large number of bonds, their total syntheses inevitably become multi-step procedures, and when enantioselective total synthesis is required, the number of steps tends to increase, since such routes require the use of commercially available chiral compounds. Hence, their efficient total synthesis is challenging. In our group, we have demonstrated the preparation of chiral synthetic intermediates, especially those bearing a quaternary stereogenic center, through novel asymmetric catalysis procedures, as well as the incorporation of logically designed cascade reactions to reduce the number of transformations. This route can ultimately lead to the efficient enantioselective total syntheses of useful bioactive polycyclic natural products.

Total Synthesis and Antibiotic Properties of Amino‐Functionalized Aromatic Terpenoids Related to Erogorgiaene and the Pseudopterosins

AbstractFollowing a concept recently introduced by Hergenrother,[6] the present study addresses the question of whether certain antimicrobially active aromatic (marine) natural products can be converted into more potent broad‐spectrum antibiotics by introducing an aminoalkyl side chain. To this end, phenolic mono‐ and sesquiterpenoids (incl. carvacrol, xanthorrhizol, and 7‐hydroxycalamene) as well as the diterpenes 7‐hydroxyerogorgiaene and 9‐deoxypseudopterosin A were converted into amino‐functionalized analogs that display either an amino‐methyl or a 2‐amino‐ethoxy substituent in place of (or next to) the OH group. This was achieved either by Pd‐catalyzed nitromethylation/reduction of the aryltriflates, by O‐alkylation of the phenols with bromoacetonitrile and subsequent reduction, or by ortho‐hydroxymethylation/amination. During the study, an efficient enantioselective total synthesis of 7‐hydroxyerogorgiaene (8 steps, 29 % overall yield) and 9‐deoxypseudopterosin A (9 steps, 30 % overall yield) was elaborated using an asymmetric cobalt‐catalyzed hydrovinylation (91 % ee) of 3‐methoxy‐4‐methyl‐styrene as the chirogenic step. Other important C−C bond forming steps include a Pd‐catalyzed Suzuki cross‐coupling and diastereoselective Lewis acid‐mediated cyclization reactions. A total of 16 amino derivatives of natural products were prepared and subsequently tested for their antibacterial properties. Some of the diterpene‐derived amines showed high efficacy, not only against Gram‐positive (S. aureus SG511, S. aureus HG003, B. subtilis 168; MIC=0.5 to 2 μg/ml), but also against Gram‐negative bacterial strains (E. coli K12; E. coli I‐11276b; MIC=8 to 32 μg/ml). This clearly supported the underlying working hypothesis.

Versatile and Enantioselective Total Synthesis of Naturally Active Gnetulin

AbstractA versatile and efficient enantioselective total synthesis of natural isorhapontigenin dimers (−)‐gnetulin, (+)‐gnetulin, and (±)‐gentulin was proposed. By using this method, we were able to synthesize the dimers from commercial available achiral materials in 13 steps, and achieve a 7%–9% overall yield with >98% enantiomeric excess. The key features of the method include the stereocontrolled enantioselective conjugate reduction of 3‐arylindenone catalyzed by methyloxazaborolidine (Me‐CBS) and the α‐arylation of 3‐aryl‐1‐indanones. Benzylic sulfide was accessed in excellent yield through the InCl3‐catalyzed thio‐etherification reaction between 2,3‐diarylindanol and bezylic thiol. The method is practical and might thus be useful in the enantioselective synthesis of the optical antipodes of natural indane derivatives with or without methoxy groups at aromatic rings.magnified image

Enantioselective synthesis of cis-hydrobenzofurans bearing all-carbon quaternary stereocenters and application to total synthesis of (\u2012)-morphine

(‒)-Morphine, which is selected as an essential medicine by World Health Organization, is widely applied in the treatment of the pain-related diseases. Due to its synthetically challenging molecular architecture and important clinical role, extensive synthetic studies of morphine-type alkaloids have been conducted. However, catalytic asymmetric total synthesis of (‒)-morphine remains a long-standing challenge. Here, we disclose an efficient enantioselective total synthesis of (‒)-morphine in a longest linear sequence of 16 steps. The key transformation features a highly enantioselective Robinson annulation enabled by our spiro-pyrrolidine catalyst to rapidly construct the densely functionalized cis-hydrodibenzofuran framework containing vicinal stereocenters with an all-carbon quaternary center. This asymmetric approach provides an alternative strategy for the synthesis of (‒)-morphine and its analogues.

Enantioselective total synthesis of pyrrolo-[2,1-c][1,4]-benzodiazepine monomers (S)-(−)-barmumycin and (S)-(+)-boseongazepine B

An efficient enantioselective total synthesis of pyrrolo-[2,1-c][1,4]benzodiazepine (PBD) monomers (S)-(−)-barmumycin and (S)-(+)-boseongazepine B was achieved through a stereocontrolled strategy, which relies on a proline catalysed asymmetric α-amination and ester α-ethylenation.

Efficient Organocatalytic Construction of C4-Alkyl Substituted Piperidines and Their Application to the Synthesis of (+)-α-Skytanthine.

Chiral piperidines which contain an alkyl group at C4 positions are one of the important architectures because it is appeared in several natural products. An efficient protocol for the preparation of C4-alkyl substituted chiral piperidines using secondary amine catalyzed formal aza [3+3] cycloaddition reaction with aliphatic α,β-unsaturated aldehydes and thiomalonamate derivatives is reported. In our reaction system, thiomalonamate is an excellent nucleophile and the addition of suitable acid and its amount is an important factor for the acceleration effect in organocatalytic reaction. Furthermore, water and MeOH also have an acceleration effect. These efforts lead to only 0.1 mol % catalyst loading in multigram scale synthesis for suitable reaction time. In addition, the efficient enantioselective total synthesis of (+)-α-skytanthine by using our developed reaction as key step was achieved in total 15 % yield. All carbon and nitrogen units were introduced by one step with high enantioselectivity.

Catalytic asymmetric synthesis of (S,4E,15Z)-docosa-4,15-dien-1-yn-3-ol, an antitumor marine natural product

An efficient enantioselective total synthesis of an antitumor marine natural product (S,4E,15Z)-docosa-4,15-dien-1-yn-3-ol 1 with 96% ee and 15% overall yield has been achieved; this is the first preparation of 1 via asymmetric catalytic strategy. The key steps involve the asymmetric addition of trimethylsilylacetylene to a diolefinc aldehyde using a (R,R)-ProPhenol ligand and a zipper reaction of an alkyne.

Synthesis of EFdA via a Diastereoselective Aldol Reaction of a Protected 3-Keto Furanose

An efficient enantioselective total synthesis of EFdA, a remarkably potent anti-HIV nucleoside analogue with various favorable pharmacological profiles, has been achieved in 37% overall yield from diacetone-D-glucose by a 14-step sequence that features a highly diastereoselective installation of the tetrasubstituted stereogenic center at the C4' position, direct oxidative cleavage of an acetonide-protected diol derivative to an aldehyde, and one-pot 2'-deoxygenation of a ribonucleoside intermediate.

Efficient Enantioselective Total Synthesis of (−)‐Horsfiline

A new efficient and concise enantioselective synthetic method for (-)-horsfiline is reported. (-)-Horsfiline could be obtained from diphenylmethyl tert-butyl malonate in 9 steps (32%,>99% ee) by using the enantioselective phase-transfer catalytic allylation (91% ee) as the key step. This approach can be applied as a practical route for the large-scale synthesis of spirooxindole natural products, which enables a systematic investigation of their biological activity to be performed.

Three Rings in One Step: A Quick Approach to IKD‐8344

A highly efficient enantioselective total synthesis of the natural antibiotic IKD-8344 is achieved through a convergent route. This route features an otherwise impossible concurrent formation of the THF rings from a linear polyketide precursor through intramolecular O alkylations of mesylates in competition with normally rather facile β elimination and/or α racemization reactions (see scheme, Ms=methanesulfonyl).

Formal Total Synthesis of (–)‐Raphidecursinol B

AbstractAn efficient enantioselective formal total synthesis of antimalarial natural product (–)‐raphidecursinol B along with its all stereoisomers is described from commercially available 3,4,5‐trimethoxybenzaldehyde using the Sharpless asymmetric dihydroxylation, regioselective α‐tosylation, epoxide opening and Mitsunobu reaction as the key reaction steps.

Target-Directed Synthesis of Antibacterial Drug Candidate GSK966587

An efficient enantioselective total synthesis of the potent antibiotic GSK966587 was accomplished. Highlights of the synthesis include two innovative Heck reactions, a highly selective zincate base directed ortho-metalation, Sharpless asymmetric epoxidation, and a fully convergent final step fragment coupling.

ChemInform Abstract: An Efficient and Concise Enantioselective Total Synthesis of Lactacystin.

A selective, irreversible inhibitor of proteasome function, lactacystin (1) is an important experimental tool in cell biology. An efficient and direct enantioselective synthesis of lactacystin proceeds via the intermediates shown below. This process allows for the first time easy access to analogues of lactacystin in which the isopropyl substituent is replaced by other lipophilic groups. PMB=p-methoxybenzyl.

Organocatalytic Asymmetric Total Synthesis of (R)-Rolipram and Formal Synthesis of (3S,4R)-Paroxetine

An efficient enantioselective total synthesis of (R)-rolipram and an efficient enantioselective formal synthesis of (3S,4R)-paroxetine has been achieved using the highly enantioselective Michael addition of malonate nucleophiles as key steps in both cases.

A Short Enantioselective Total Synthesis of (-)-Linderol A

An efficient short enantioselective total synthesis of (-)-linderol A was achieved via a five-step reaction with 30% overall yield, starting from 4-methoxyphloroacetophenone.

Stereoselective Heck—Matsuda Arylations of Chiral Dihydrofurans with Arenediazonium Tetrafluoroborates: An Efficient Enantioselective Total Synthesis of (‐)‐Isoaltholactone.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Stereoselective Heck-Matsuda Arylations of Chiral Dihydrofurans with Arenediazonium Tetrafluoroborates; An Efficient Enantioselective Total Synthesis of (-)-Isoaltholactone

The Heck-Matsuda arylation of chiral 2-( S)-hydroxy-methyl dihydrofurans (endocyclic enolethers) and its derivatives, employing arenediazonium tetrafluoroborates, was developed into a highly efficient, practical and diastereoselective synthetic process. This methodology was applied to the total synthesis of the styryllactone (-)-isoaltholactone in seven steps with an overall yield of ~25%, from the readily available chiral 2-hydroxymethyldihydrofuran. The strategy permits the synthesis of several other aromatic analogues of isoaltholactone.

Enantioselective total syntheses of (−)-clasto-lactacystin β-lactone and 7-epi-(−)-clasto-lactacystin β-lactone

An alkylidene carbene 1,5-CH insertion has been used as a key step in an efficient enantioselective total synthesis of (-)-clasto-lactacystin beta-lactone, and its C7-epimer. An additional noteworthy feature of the synthesis is the use of a novel oxidative deprotection procedure, utilizing DMDO, for the conversion of a late-stage benzylidene acetal into a primary alcohol and a secondary benzoate ester.

Total Synthesis of the Tricyclic Marine Alkaloids (‐)‐Lepadiformine, (+)‐Cylindricine C, and (‐)‐Fasicularin via a Common Intermediate Formed by Formic Acid‐Induced Intramolecular Conjugate Azaspirocyclization.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Total Synthesis of the Tricyclic Marine Alkaloids (−)-Lepadiformine, (+)-Cylindricine C, and (−)-Fasicularin via a Common Intermediate Formed by Formic Acid-Induced Intramolecular Conjugate Azaspirocyclization

A very short and efficient enantioselective total synthesis of the tricyclic marine alkaloids (-)-lepadiformine (3), (+)-cylindricine C (1c), and (-)-fasicularin (4) has been developed utilizing the formyloxy 1-azaspiro[4.5]decane 5 as a common intermediate. The key strategic element for the synthesis was the formic acid-induced intramolecular conjugate azaspirocyclization, which proved to be a highly efficient and stereoselective way to rapid construction of the 1-azaspirocyclic substructure of these natural products in a single operation. Thus, the common intermediate 5, synthesized in two steps with 70% overall yield starting from the known (S)-N-Boc-2-pyrrolidinone 7 via the conjugate spirocyclization using an acyclic ketoamide 6, was utilized for the concise and stereoselective total synthesis of (-)-lepadiformine (3), which was accomplished in seven steps with 45% overall yield from 5 (31% yield from 7). The developed strategy based on the conjugate spirocyclization was also applied to the stereoselective total synthesis of (+)-cylindricine C (1c), which was achieved in 10 steps from 5 in 18% overall yield (12% yield from 7). Further application of this approach using 5 led to the synthesis of (-)-fasicularin (4), wherein an extremely efficient method for the introduction of the thiocyanato group via an aziridinium intermediate at the last step was developed. Thus, the highly efficient first enantioselective total synthesis of (-)-fasicularin was accomplished in nine steps with an overall yield of 41% from 5 (28% yield from 7).