Towards routine organic structure determination using Raman microscopy.

Raman microscopy can reveal a compound-specific vibrational "fingerprint" from micrograms of material with no sample preparation. We expect this increasingly available instrumentation to routinely assist synthetic chemists in structure determination; however, interpreting the information-dense spectra can be challenging for unreported compounds. Appropriate theoretical calculations using the highly efficient r2SCAN-3c method can accurately predict peak positions but are less precise in matching peak heights. To limit incorrect biases while comparing experimental and theoretical spectra, we introduce a user-friendly software that gives a match score to assist with structure determination. The capabilities and limitations of this approach are demonstrated for several proof-of-concept examples including the characterization of intermediates in the total synthesis of deoxyaspidodispermine.

Iodanes as multi-tools for the total synthesis of complex natural products.

Hypervalent iodine reagents are among the most fascinating reagents described in the last 30 years since they allow a plethora of different transformations and are environmentally friendly compounds that avoid the use of toxic heavy metals in most cases. Hence, their versatility has been widely used in multi-step syntheses for the formation of complex structures. In particular, the use of iodanes can easily generate complexity from simple substrates, leading to polyfunctionalized systems that allow the rapid formation of natural products or related intricate architectures. In this review, we describe a plethora of recent routes and strategies to produce complex natural products based on several key steps mediated by hypervalent iodines that help in building the desired molecule framework, highlighting the numerous advantages of these key reactants yet not hiding their possible limitations.

Synthesis of Deoxyaspidodispermine Based on a Functional Protecting Group Strategy.

A synthesis of deoxyaspidodispermine was produced from homotyramine. This approach is based on the application of a functional protecting group strategy that not only masks the reactivity of sensitive groups during crucial steps but also possesses a moiety desired in the final target, which is transferred to the substrate at the time of deprotection. This synthesis highlights an aza-Michael-Smiles ring-closure cascade, which enables the formation of a tetracyclic system from a nosylamide protecting group.

Common Strategy for the Synthesis of Some Strychnos Indole Alkaloids.

Indole alkaloids are important natural compounds with interesting bio-activities that can be found in various species belonging to the Amaryllidaceae, Apocynaceae, or Strychnaceae families. Although these compounds have different connections, substituents, and functionalities, their main core can be produced via the formation of a common functionalized tetracyclic subunit, which is rapidly obtained by an oxidative de-aromatization process mediated by a hypervalent iodine reagent from an inexpensive phenol containing a lactate moiety as the chiral auxiliary. A subsequent stereoselective aza-Michael addition and an intramolecular Heck-type reaction lead to the formation of a common key intermediate. This approach provides a solid foundation for the further elaborations of several natural products. The asymmetric syntheses of (-)-strychnopivotine and the polycyclic main cores of (-)-strychnosplendine, (+)-isosplendine, and (+)-malagashanol, three other indole alkaloids, are reported.

Elaboration of Functionalized Organophosphates.

In this study, the rapid transformation of inexpensive phenols into polyfunctionalized cyclohexenones containing a phosphonate in one pot is described. Such systems readily obtained from simple aromatic compounds could open up a multitude of synthetic possibilities. For example, this scaffold was easily and stereoselectively transformed into the corresponding enol functionality in the same pot by the addition of sodium borohydride.

Rapid transformation of sulfinate salts into sulfonates promoted by a hypervalent iodine(III) reagent.

An alternative method for forming sulfonates through hypervalent iodine(III) reagent-mediated oxidation of sodium sulfinates has been developed. This transformation involves trapping reactive sulfonium species using alcohols. With additional optimization of the reaction conditions, the method appears extendable to other nucleophiles such as electron-rich aromatic systems or cyclic ethers through a ring opening pathway.

Carbon-Phosphorus Bond Formation on Anilines Mediated by a Hypervalent Iodine Reagent.

Substituted anilines containing a sulfonyl group may be oxidized in situ in the presence of methanol and a hypervalent iodine reagent to form an active iminium species. Subsequent addition of phosphines or phosphites in the same pot produces meta-substituted anilines in good yields. This formal C-H bond functionalization is a direct and efficient means of selectively substituting the meta-position of anilines to produce aromatic phosphonium ions or phosphonates.

One-step formation of dihydrofuranoindoline cores promoted by a hypervalent iodine reagent.

Treatment of various substituted anilines containing a sulfonyl group in the presence of a hypervalent iodine reagent, a perfluorinated alcohol and furan promotes a formal dearomatizing [2 + 3] cycloaddition process, leading to a dihydrofuranoindoline core in useful yields. Thereafter, these functionalized systems can be used for further transformations, yielding potential key intermediates for the total synthesis of complex natural products.

A Stereoselective Arylative-Cyclopropanation Process.

A new stereoselective arylative cyclopropanation process involving treatment of halogenated dienone systems in the presence of a Michael donor containing a nitro-aryl-sulfone has been developed. This transformation enables production of an arylated cyclopropane under mild conditions and occurs via a Michael-Smiles ring closure cascade process, reflecting the concepts of green chemistry and atom economy.

Use of the Nosyl Group as a Functional Protecting Group in Applications of a Michael/Smiles Tandem Process.

Concise preparations of elaborated polycyclic and heterocyclic systems present in natural products were obtained using the nosyl group as a functional protecting group not only to mask the reactivity of a sensitive moiety but also to provide a structure desired in the final target. The group is transferred to the substrate during deprotection through a novel extension of the Truce-Smiles rearrangement in tandem with a 1,4-addition. This strategy provides access to a ring system laden with valuable functionalities for subsequent manipulations and can serve as a versatile building block for the construction of more complex molecular architectures such as indoles in a manner compatible with the concepts of green chemistry and atom economy.

Asymmetric synthesis of (+)-17-epi-methoxy-kauran-3-one through tandem oxidative polycyclization-pinacol process.

A synthesis of (+)-17-epi-methoxy-kauran-3-one, an O-methylated isomer of the natural diterpene 17-hydroxy-kauran-3-one, has been achieved. The strategy is based on a diastereoselective oxidative polycyclization-pinacol tandem process consisting of transforming a functionalized phenol into a compact and complex tetracycle, which represents the main core of kaurane family members. The synthesis also includes an enantioselective Yamamoto's allylation, a diastereoselective Ru-catalyzed hydrocyanation, a ring-closing metathesis and a reductive isomerization process as key steps. The structure of our synthetic substrate was determined through comparison with an O-methylated derivative of the natural compound.

Synthesis of the Strychnos Alkaloid (-)-Strychnopivotine and Confirmation of its Absolute Configuration.

The first enantioselective synthesis of (-)-strychnopivotine from a known and inexpensive phenol has been achieved in 15 steps. The strategy is based on a new diastereoselective aza-Michael-enol-ether cascade desymmetrization of a dienone, guided by a removable lactic acid-derived chiral auxiliary. Synthesis involves a phenol dearomatization, a conjugated silicon addition, a stereoselective double reductive amination, and two Heck-type carbopalladations as key steps. The absolute configuration of the natural compound, which, to date, has been uncertain, was confirmed by using circular dichroism (CD) spectroscopy and X-ray analyses.

Ferrocene-Modified Phospholipid: An Innovative Precursor for Redox-Triggered Drug Delivery Vesicles Selective to Cancer Cells.

Controlled payload release is one of the key elements in the creation of a reliable drug delivery system. We report the discovery of a drug delivery vessel able to transport chemotherapeutic agents to target cancer cells and selectively trigger their release using the electrochemical activity of a ferrocene-modified phospholipid. Supported by in vitro assays, the competitive advantages of this discovery are (i) the simple one step scalability of the synthetic process, (ii) the stable encapsulation of toxic drugs (doxorubicin) during transport, and (iii) the selective redox triggering of the liposomes to harness their cytotoxic payload at the cancer site. Specifically, the redox-modified giant unilamellar vesicle and liposomes were characterized using advanced methods such as scanning electrochemical microscopy (SECM), transmission electron microscopy (TEM), dynamic light scattering (DLS), and fluorescent imaging.

Rearrangements Induced by Hypervalent Iodine.

This chapter describes advances in hypervalent iodine(III)-induced rearrangements reported between 2004 and 2015, beginning with Hofmann-type rearrangements and aliphatic aryl transpositions. In both reactions the iodine(III) reagent may be off-the-shelf or catalytically generated in situ. A number of stereoselective transformations are discussed, followed by transpositions triggered through phenol dearomatization, including Wagner-Meerwein-type rearrangements, Prins-pinacol transpositions, and a tandem polycylization-pinacol process. Other rearrangements such as an iodonio-Claisen rearrangement, an ipso-rearrangement, and rearrangements performed using iodine(V) are also described.

Formation of the Main Cores Present in Natural Products by Tandem Additions.

A rapid route to 5,5- and 5,6- bicyclic systems is provided by an 1,3-alkyl-shift process mediated by a hypervalent iodine reagent on aromatics. The structures obtained contain several unsaturations with different behaviors and reactivities. Such diversity allows further elaborations for the rapid formation of compact systems present in a variety of natural products. The potential for further transformations has been demonstrated by performing a double Michael addition. This cyclization process is regio- and stereoselective due to the presence of a former benzylic substituent. Furthermore, an extension of this approach has been accomplished on indole derivatives.

Isostrychnine synthesis mediated by hypervalent iodine reagent.

Althought there are several reported synthetic routes to strychnine, one of the most widely recognized alkaloids, we report an unexplored route with an oxidative dearomatizing process mediated by hypervalent iodine as the key step. The new syntheses of isostrychnine and strychnine have been achieved from an readily available phenol in nine and ten steps. In addition to the key step, these syntheses involve an aza Michael-ether-enol tandem transformation, two heck type cyclizations, a reductive isomerization, and a double reductive amination in cascade leading to the alkaloid main core.

Asymmetric synthesis of the main core of kaurane family members triggered by an oxidative polycyclization-pinacol tandem process.

Polycyclization processes represent expeditious routes used in both nature and the laboratory to produce complex polycyclic molecules. A new stereoselective oxidative variant of such a polycyclization has been developed in which the cascade is triggered by a phenol dearomatization and is concluded by a pinacol transposition. This unprecedented avenue combines the synthetic power of a polycyclization and a transposition in tandem and enables the rapid formation of the tetracyclic main core of kaurane diterpenes containing several asymmetric and quaternary carbon centers in a single step from a simple phenol derivative.

Synthesis of the erythrina alkaloid erysotramidine.

A concise synthesis of erysotramidine (an alkaloid belonging to the erythrina family) was achieved starting with an inexpensive phenol and amine derivative. The synthesis is based on oxidative phenol dearomatizations mediated by a hypervalent iodine reagent and includes a novel route to a key indolinone moiety.

Asymmetric synthesis of fortucine and reassignment of its absolute configuration.

A convergent and enantioselective synthesis of fortucine was achieved from the starting materials tyrosine methyl ester and 3-hydroxy-4-methoxybenzaldehyde. The synthesis is based on two key steps mediated by a hypervalent iodine reagent. This work has enabled us to reassign the absolute configuration of the natural product reported in the literature.