The application of vinylogous iminium salt derivatives to efficient formal syntheses of the marine alkaloids lamellarin G trimethyl ether and ningalin B

Studies directed at the synthesis of lamellarin G trimethyl ether and ningalin B via vinylogous iminium salt derivatives are described. The successful strategy relies on the formation of a 2,4-disubstituted pyrrole or a 1,2,3,4-tetrasubstituted pyrrole from a vinylogous iminium salt or vinylogous iminium salt derivative. Subsequent transformations of these highly substituted pyrroles lead to efficient and regiocontrolled formal syntheses of the respective pyrrole containing natural products.     

Catalytic asymmetric vinylogous Mannich-type (AVM) reaction of nonactivated α-angelica lactone

A direct highly diastereo- and enantioselective asymmetric vinylogous Mannich-type (AVM) reaction of aldimines with nonactivated natural α-angelica lactone has been successfully developed. It was demonstrated that the nonactivated natural α-angelica lactone is a useful vinylogous nucleophile to give the chiral δ-amino γ,γ-disubstituted butenolide carbonyl derivatives. The N,N'-dioxide L2-Sc(III) complex is efficient toward the obtention of a range of corresponding products with adjacent quaternary and tertiary stereocenters in excellent dr and ee values.     

Application of vinylogous carbamates and vinylogous aminonitriles to the regiospecific synthesis of uniquely functionalized pyrroles and quinolones

Pyrroles and quinolones represent core structures, which are routinely found in both natural and synthetic bioactive substances. Consequently, the development of efficient and regiospecific methods for the preparation of such heterocycles with unique functionality is of some importance. We describe herein the regiospecific synthesis of 1,2,3,4-tetrasubstituted pyrroles containing polar substituents and such products are prepared from vinylogous carbamates and vinylogous aminonitriles. We also describe the regiospecific synthesis of 3-aryl containing 1,3,6-trisubstituted quinolones from vinylogous carbamates. The use of an amine exchange reaction to prepare precursors for the pyrrole and quinolone forming cyclizations represents a key factor in the strategy.     

The application of vinylogous iminium salt derivatives to the synthesis of Ningalin B hexamethyl ether

A vinylogous iminium salt derivative has been used to prepare a 2,3,4-trisubstituted pyrrole synthon in a regioselective, efficient and convenient manner. This pyrrole synthon was subsequently converted to the multidrug-resistant (MDR) reversal agent, Ningalin B hexamethyl ether, via alkylation, hydrolysis and oxidative lactonization steps. This methodology provides an alternative pathway to this important class of pyrrole containing marine natural products.     

Remote asymmetric induction with vinylketene silyl n,o-acetal

A highly regio- and diastereoselective TiCl4-mediated vinylogous Mukaiyama aldol reaction using the chiral vinylketene silyl N,O-acetal has been developed. The present vinylogous Mukaiyama aldol reaction provides a unique and effective means of controlling remote asymmetric induction. The methyl group at the alpha-position is important in achieving a high level of stereoselectivity. From a synthetic point of view, this methodology can provide a one-step construction of delta-hydroxy-alpha,gamma-dimethyl-alpha,beta-unsaturated carbonyl unit that is seen in many natural polyketide products.     

One-pot Eschenmoser episulfide contractions in DMSO: applications to the synthesis of fuligocandins A and B and a number of vinylogous amides

Practical total syntheses of the natural products fuligocandin A (2a) and fuligocandin B (3) have been achieved through a convergent strategy depending on the Eschenmoser episulfide contraction as a key step. Conducting the reaction in DMSO proved to be an efficient and general method for the synthesis of a variety of vinylogous amides, such as azepan-2-ylidenepropan-2-one.     

The Application of Vinylogous Iminium Salt Derivatives and Microwave Accelerated Vilsmeier-Haack Reactions to Efficient Relay Syntheses of the Polycitone and Storniamide Natural Products

Studies directed at the synthesis of polycitone and storniamide natural products via vinylogous iminium salts and microwave accelerated Vilsmeier-Haack formylations are described. The successful strategy relies on the formation of a 2,4-disubstituted pyrrole or a 2,3,4-trisubstituted pyrrole from a vinamidinium salt or vinamidinium salt derivative followed by formylation at the 5-position of the pyrrole. Subsequent transformations of the selectively formylated pyrroles lead to efficient and regiocontrolled relay syntheses of the respective pyrrole containing natural products.     

Asymmetric total synthesis and structural elucidation of NFAT-68

Total synthesis of NFAT-68 (7) has been achieved and its relative stereochemistry has been determined. A key step thereof is the utilization of the chelation-controlled vinylogous Mukaiyama aldol reaction (VMAR) to stereoselectively synthesize the syn-aldol product 8. This developed chemistry is anticipated to have wider application in total syntheses of many other natural products.     

Further studies on the application of vinylogous amides and β-halovinylaldehydes to the regiospecific synthesis of unsymmetrical,polyfunctionalized 2,3,4- and 1,2,3,4- substituted pyrroles

Highly functionalized pyrroles with appropriate regiochemical functionality represent an important class of marine natural products and potential drug candidates. We describe herein a detailed study of the reaction of α-aminoacid esters with vinylogous amides and also β-halovinylaldehydes for the regiospecific synthesis of 2,3,4-trisubstituted and 1,2,3,4-tetrasubstituted pyrroles. Since the vinylogous amides and β-halovinylaldehydes are readily available precursors, rapid access to a wide variety of unsymmetrically substituted pyrroles is accomplished via this methodology.     

Recent progress on direct catalytic asymmetric vinylogous reactions

Direct catalytic asymmetric vinylogous reaction serves as a powerful tool to introduce stereocenter(s) at the γ- or/and even more remote position(s) of the vinylogous products in an atom-economical and efficient way. A variety of direct catalytic asymmetric vinylogous reactions with broad substrate scope and mild reaction conditions has been developed. Both metal catalysis and organocatalysis contributed in this field and led to the vinylogous products in high stereoselectivity. These vinylogous reactions provided efficient pathways for the synthesis of highly functionalized optically pure compounds, especially these with potential biological activity and pharmacological activity. This digest paper mainly focuses on the most recent developments in this field, including both nucleophilic addition and nucleophilic substitution.     

A mild and efficient method for the synthesis of vinylogous carbamates from alkyl azides

A mild and efficient one-pot method for the synthesis of vinylogous carbamates is reported starting from alkyl azides under a hydrogen atmosphere using 10% Pd/C. The resulting products are useful intermediates for the synthesis of heterocyclic compounds, natural products, and in peptidomimetics.     

Synthetic studies towards marmycins A and B: development of the vinylogous aldol-aza-Michael domino reaction

The vinylogous aldol-aza-Michael domino reaction between 2-aminobenzaldehydes and prenal was developed to build up the core of natural products marmycin A and B without the need of protective groups.     

Palladium-Catalyzed Asymmetric Alkylation in the Synthesis of Cyclopentanoid and Cycloheptanoid Core Structures Bearing All-Carbon Quaternary Stereocenters

General catalytic asymmetric routes toward cyclopentanoid and cycloheptanoid core structures embedded in numerous natural products have been developed. The central stereoselective transformation in our divergent strategies is the enantioselective decarboxylative alkylation of seven-membered β-ketoesters to form α-quaternary vinylogous esters. Recognition of the unusual reactivity of β-hydroxyketones resulting from the addition of hydride or organometallic reagents enabled divergent access to γ-quaternary acylcyclopentenes through a ring contraction pathway or γ-quaternary cycloheptenones through a carbonyl transposition pathway. Synthetic applications of these compounds were explored through the preparation of mono-, bi-, and tricyclic derivatives that can serve as valuable intermediates for the total synthesis of complex natural products. This work complements our previous work with cyclohexanoid systems.     

Enantioselective total synthesis of convolutamydines B and E

[reaction: see text] The first enantioselective total synthesis of convolutamydines B and E has been achieved using our vinylogous Mukaiyama aldol reaction. The synthesis features highly diastereoselective vinylogous Mukaiyama aldol reaction with isatin instead of aldehydes to construct a chiral center of convolutamydines. Additionally, the absolute configuration of natural convolutamydine B has been determined as R by its CD spectrum.     

A unified strategy for the asymmetric total syntheses of diversonol and lachnone C

A unified synthetic strategy for the asymmetric syntheses of the natural products diversonol and lachnone C was developed by using the domino vinylogous aldol-oxa-Michael reaction as the enantioselective key step. Further transformations include dihydroxylation, lactol-opening by a Wittig-reaction, and lactonization. The obtained chromone lactones, a class of mycotoxins, can further be converted to tetrahydroxanthones by a Dieckmann condensation. This general method allows for the first time the enantioselective access to these classes of natural products and should be applicable to other members of the tetrahydroxanthone and chromone lactone families.     

Silyldienolates in Organocatalytic Enantioselective Vinylogous Mukaiyama-Type Reactions: A Review

Mukaiyama aldol, Mannich, and Michael reactions are arguably amongst the most important C–C bond formation processes and enable access to highly relevant building blocks of various natural products. Their vinylogous extensions display equally high potential in the formation of important key intermediates featuring even higher functionalization possibilities through an additional conjugated C–C double bond. Hence, it is much desired to develop highly selective vinylogous methods in order to enable unconventional, more efficient asymmetric syntheses of biologically active compounds. In this regard, silyl-dienolates were discovered to display high regioselectivities due to their tendency toward γ-additions. The control of the enantio- and diastereoinduction of these processes have been for a long time dominated by transition metal catalysis, but it received serious competition by the application of organocatalytic approaches since the beginning of this century. In this review, the organocatalytic applications of silyl-dienolates in asymmetric vinylogous C–C bond formations are summarized, focusing on their scope, characteristics, and limitations.     

Synthesis of the azaphilones (+)-sclerotiorin and (+)-8-O-methylsclerotiorinamine utilizing (+)-sparteine surrogates in copper-mediated oxidative dearomatization

Enantioselective syntheses of the azaphilone natural products (+)-sclerotiorin and (+)-8-O-methylsclerotiorinamine that possess the natural R-configuration at the quaternary center are reported. The syntheses were accomplished using copper-mediated asymmetric dearomatization employing bis-μ-oxo copper complexes prepared from readily available (+)-sparteine surrogates. Of note, site-selective O-methylation of a vinylogous pyridone was used to access the isoquinolin-6(7H)-one core of (+)-8-O-methylsclerotiorinamine.     

The application of vinylogous iminium salt derivatives to an efficient synthesis of the pyrrole containing alkaloids Rigidin and Rigidin E

Studies directed on the synthesis of the pyrrole containing marine natural products Rigidin and Rigidin E via vinylogous iminium salts are described. The successful strategy relies on the formation of a 2,4-disubstituted pyrrole from a vinamidinium salt followed by acylation at the 5-position of pyrrole. Halogenation and aminocarbonylation at the 3-position of pyrrole followed by hydrolysis of the ester group at C-2 and subsequent Curtius rearrangement generates the pyrrolopyrimidine skeleton. A final deprotection step completes the synthesis of Rigidin and Rigidin E.     

Indolizinones as synthetic scaffolds: fundamental reactivity and the relay of stereochemical information

Indolizinones are under-explored N-heterocycles that react with exquisite chemo- and stereoselectivity. An exploration of the fundamental reactivity of these azabicycles demonstrates the potential to relay stereochemical information from the ring-fusion to newly formed stereocenters on the bicyclic core. The indolizinone diene undergoes selective hydrogenation and readily participates in Diels-Alder cycloadditions as well as ene reactions. The vinylogous amide embedded in the five-membered ring is resistant to reaction when the diene is in place. However, removal of the diene allows for diastereoselective hydrogenation of, and 1,4-additions to, the vinylogous amide. These fundamental reactions with indolizinones have provided a structurally diverse array of products that hold promise in the context of natural product synthesis.     

Intramolecular cyclization and subsequent rearrangements of alkyne-tethered N-heterocyclic carbenes

Alkyne-tethered imidazole and 1,2,4-triazole-based N-heterocyclic carbene precursors have been prepared and studies of the intramolecular reactions of carbenes are performed. Products consistent with intramolecular cyclizations and subsequent rearrangements were observed. Mechanistic studies using crossover experiments showed that the products did arise from intramolecular carbene additions. The reactions are proposed to go through vinylogous diaminocarbene intermediates similar to vinylogous dialkoxycarbenes formed during Boger cycloaddition reactions. Imidazole substituted dienes were observed to be the major products of tandem cyclization and elimination reactions that were observed for imidazole-based N-heterocyclic carbenes.