Iminium ion-enamine cascade reaction enables the asymmetric total syntheses of aspidosperma alkaloids vincadifformine and ervinceine

Asymmetric total synthesis of (+)-vincadifformine and (+)-ervinceine is reported by utilizing an iminium ion triggered cascade reaction using chiral 3,3-disubstituted piperidine imine and 2,3-disubstituted indole derivatives coupling partner. In the first generation total synthesis, the pivotal imine is prepared in excellent stereoselectivity but in moderate yield involving a Birch reduction-alkylation strategy. Furthermore, to improve upon the synthesis of the decisive imine, the more practical second generation route is devised through a Johnson-Claisen rearrangement to access chiral 3,3-disubstituted piperidinone in excellent yield and stereoselectivity. Apart from synthesizing (+)-vincadifformine, this strategy is also exploited for the first asymmetric total synthesis of (+)-ervinceine employing an iminium ion mediated cascade reaction. This distinctive strategy simultaneously sets up two new rings, two new stereogenic centers, and three new sigma bonds in a single operation.     

Copper-catalyzed methylenation reaction: total synthesis of (+)-desoxygaliellalactone

The enantioselective total synthesis of (+)-desoxygaliellalactone was achieved in six steps starting from 4-tert-butyldimethylsilyloxybutanal. This synthesis featured a one-pot copper-catalyzed methylenation-Diels-Alder cyclization. The challenging methylenation of aldehyde 4 was studied under various reaction conditions. Whereas Wittig reaction conditions led to byproducts resulting from decomposition of the sensitive butenolide moiety, the mild copper-catalyzed methylenation reaction produced the desired triene in good yield.     

A Negishi cross-coupling reaction enables the total synthesis of (+)-stachyflin

We present a full account on the development of the total synthesis of the antiviral meroterpenoid (+)-stachyflin. The decalin subunit is rapidly accessed by an exo-selective Diels–Alder reaction, whereas the isonindolinone was synthesized via a highly efficient and practical de novo route starting from dimedone. A challenging sp²–sp³ Negishi cross-coupling reaction enabled construction of the crucial C15–C16 bond that connects the arene with the decalin subunit. For the final installation of the cis-decalin framework, a Lewis acid-catalyzed cyclization was applied.     

Regiocontrol in an intramolecular Schmidt reaction: total synthesis of (+)-aspidospermidine

[reaction--see text] A total synthesis of (+)-aspidospermidine (1) is described, featuring an intramolecular Schmidt reaction as the key step. The effects of stereochemistry and protecting group status on the regio- and chemoselectivity of this reaction were examined.     

Iminium ion catalysis: use of the alpha-effect in the acceleration of the Diels-Alder reaction

The alpha-effect can be used in the acceleration of the Diels-Alder reaction between a series of dienes and electron deficient dienophiles using iminium ion catalysis, providing a novel molecular scaffold capable of performing this class of catalytic process.     

Iminium ion cyclizations. Highly stereoselective synthesis of substituted tetrahydroisoquinoline derivatives

Cationic cyclizations of acyliminium ions $\text{2}$ (R₁  phenyl) occur with high stereo-selectivity, which is suggested to originate in the intermediate arenium ions.     

Concise asymmetric total synthesis of lycopodine and flabelliformine via cascade cyclization reaction

The shortest asymmetric total synthesis of lycopodine (3) and the first asymmetric total synthesis of flabelliformine (4) were accomplished by a strategy that features a cascade cyclization of linear substrate (5) to construct tetracyclic structure (6).     

Enantioselective total synthesis of (+)-gigantecin: exploiting the asymmetric glycolate aldol reaction

The enantioselective synthesis of the potent, selective, cytotoxic, annonaceous acetogenin, (+)-gigantecin, has been completed. An asymmetric glycolate aldol serves to establish the stereocenters at C13,14 and at C21,22. A Carreira asymmetric acetylide addition is used to establish the C17 stereocenter.     

The total synthesis of (+)-hapalindole Q by an organomediated Diels-Alder reaction

The total synthesis of (+)-hapalindole Q has been achieved. The key step is a Diels-Alder reaction mediated by MacMillan's organocatalyst to provide the critical intermediate with high enantioselectivity (93% ee). This step establishes the proper arrangement of the required four contiguous stereocenters, including the quaternary center, and represents the first successful application of an enantioselective organomediated Diels-Alder reaction in total synthesis.     

Stereoselective total synthesis of (+)-Scyphostatin via a pi-facially selective Diels-Alder reaction

A stereoselective total synthesis of scyphostatin is described. The hydrophilic moiety was stereoselectively synthesized via (i) a highly pi-facially selective Diels-Alder reaction of a spirolactone generated from L-tyrosine and (ii) a hydroxy group directed epoxidation as key reactions. The hydrophilic moiety was combined with the hydrophobic side chain in the final stage. Total synthesis was achieved by overcoming the instability of the C5-C6 epoxide ring with carefully executed mild reactions. In the course of this work, it was revealed that we had mistakenly assigned the relative stereochemistry of the C5-C6 epoxide ring of the end product in our previous model study. Revision of the stereochemical assignment in the model study is described. A diastereomer of (+)-scyphostatin epimeric at C5 and C6 (the epoxide region) was also synthesized.     

Semisynthesis of (+)- and (−)-goniomitine from (−)- and (+)-vincadifformine

The first biomimetic semisynthesis of goniomitine has been accomplished in nine steps with 11% overall yield starting from vincadifformine. Natural (?)- and unnatural (+)-goniomitine were prepared from (+)- and (?)-vincadifformine, respectively. The evaluation of the antiproliferative effect of both enantiomers proved unnatural (+)-goniomitine to be more potent, but this enantiomer as well as some close derivatives displayed a moderate activity only.     

Exploration of cascade cyclizations terminated by tandem aromatic substitution: total synthesis of (+)-schweinfurthin A

The termination of epoxide-initiated cascade cyclizations with a range of "protected" phenols is described. When the protecting group can be lost as a stabilized electrophile, the cascade process continues beyond ring closure to afford products which have undergone a tandem electrophilic aromatic substitution. A number of groups have proven viable in this process and the regiochemistry of their substitution reactions has been studied. Application of this methodology in the first total synthesis of (+)-schweinfurthin A, a potent antiproliferative agent, has been achieved.     

Asymmetric total synthesis of (+)-curcutetraol and (+)-sydonol

The asymmetric total syntheses of (+)-curcutetraol and (+)-sydonol, phenolic bisabolane-type sesquiterpenoids having chiral tertiary alcohol moiety in the o-position of a phenol, were achieved in high enantiomeric excesses (99% ee). The chiral tertiary benzylic alcohol moiety of these compounds was constructed by an asymmetric synthesis using an easily available chiral aminal, (−)-(2R,5S)-2-methoxycarbonyl-3-phenyl-1,3-diazabicyclo[3.3.0]octane. The absolute configurations of both (+)-curcutetraol and (+)-sydonol have been assumed to be S-configuration based on the stereochemical course of the well established asymmetric synthesis used in the syntheses.     

Asymmetric total synthesis of (+)-cannabisativine

The asymmetric total synthesis of natural (+)-cannabisativine 1 was completed in 19 steps and 7% overall yield. The key synthetic intermediate 29 was prepared with a high degree of stereocontrol in 12 steps starting from chiral 1-acylpyridinium salt 10. Addition of zinc enolate 11 to pyridinium salt 10 furnished dihydropyridone 12 containing two contiguous stereocenters of the correct absolute configuration. Luche reduction of ketone 16 afforded diol 17 in high yield (96%) and excellent diastereoselectivity. The Mukaiyama-Michael reaction of pyridones 27a/b with O-silyl ketene acetal 32 gave phenyl selenyl ketones 33a/b with complete stereoselectivity. Elimination of cis-beta-hydroxyselenides 34 and 35 effected the regiocontrolled preparation of tetrahydropyridine derivative 29. Several approaches to the macrocyclic ring closure of the 13-membered ring were investigated, ultimately leading to the completion of an asymmetric synthesis of the target compound with a high degree of stereocontrol.     

Stereocontrolled total synthesis of (+)-pederine

A mild one-pot method for the synthesis of acyclic N-(1-methoxyalkyl)amides starting from carboxylic acid and methyl imidates has been developed and applied to the first total synthesis of (+)-pederine (1), a potent insect poison. Furthermore, the stereocontrolled total synthesis of 1 was also achieved by employing acid catalyzed double alkoxy-exchange reaction of N-(1 -methoxylakyl)amide group as key step.     

Enantioselective total synthesis of (+)-tricycloclavulone

The first total synthesis of (+)-tricycloclavulone having a unique tricyclo[5,3,0,01,4]decane skeleton and six chiral centers was achieved in a highly stereoselective manner. It includes a catalytic enantioselective [2+2]-cycloaddition reaction using novel chiral copper catalyst, extremely effecting an intramolecular ester transfer reaction, and asymmetric reduction of the carbonyl group on the alpha-chain using Noyori's chiral ruthenium catalyst.     

Asymmetric total synthesis of (+)-fostriecin

[structure: see text] The title compound, a potent protein phosphatase inhibitor and anticancer agent, was prepared by an efficient, multiconvergent asymmetric synthesis. Key transformations include a ring forming olefin metathesis leading to the alpha,beta-unsaturated lactone and creation of the triene moiety via Suzuki cross-coupling.     

Stereoselective total synthesis of (+)-cardiobutanolide

Stereoselective synthesis of styryllactone (+)-cardiobutanolide was accomplished in good overall yield from d-(-)-tartaric acid. Key features of the synthesis include the elaboration of a gamma-hydroxy butyramide obtained from the dimethylamide of tartaric acid, involving a combination of the addition of 1,3-dithian-2-yllithium and stereoselective reduction.