Synthesis of Stereodefined Polysubstituted Bicyclo[1.1.0]butanes.

We report a highly diastereoselective synthesis of polysubstituted bicyclobutanes possessing up to three stereodefined quaternary centers and five substituents. Our strategy involves a diastereoselective carbometalation of cyclopropenes followed by a cyclization to furnish the bicyclobutane ring system. This straightforward approach allows for the incorporation of a diverse range of substituents and functional groups, notably without the need for electron-withdrawing functionalities.

Stereoinvertive SN1 Through Neighboring Group Participation.

Neighboring group participation, the assistance of non-conjugated electrons to a reaction center, is a fundamental phenomenon in chemistry. In the framework of nucleophilic substitution reactions, neighboring group participation is known to cause rate acceleration, first order kinetics (SN1), and retention of configuration. The latter phenomenon is a result of double inversion: the first one when the neighboring group displaces the leaving group, and the second when a nucleophile substitutes the neighboring group. This powerful control of stereoretention has been widely used in organic synthesis for more than a century. However, neighboring group participation may also lead to inversion of configuration, a phenomenon which is often overlooked. Herein, we review this unique mode of stereoinversion, dividing the relevant reactions into three classes with the aim to introduce a fresh perspective on the different modes of stereoinversion via neighboring group participation as well as the factors that control this stereochemical outcome.

Stereoselective Nucleophilic Halogenation at CF3-Substituted Nonclassical Carbocation.

CF3-substituted cyclopropyl carbinol derivatives undergo regioselective and diastereoselective nucleophilic halogenation at the quaternary carbon center to provide acyclic products as a single diastereomer. The selectivity of the substitution is rationalized by the formation of a nonclassical cyclopropylcarbinyl cation intermediate, reacting at the most-substituted carbon center. Tertiary alkyl chlorides, bromides, and fluorides adjacent to a stereogenic C-CF3-motif are diastereomerically pure and can be obtained in few catalytic steps from commercially available alkynes.

Highly Diastereoselective Preparation of Tertiary Alkyl Thiocyanates en Route to Thiols by Stereoinvertive Nucleophilic Substitution at Nonclassical Carbocations.

An effective InBr3-catalyzed nucleophilic thiocyanation of cyclopropyl alcohols has been developed. The reaction takes place at the quaternary carbon stereocenter of the cyclopropyl carbinol with a complete inversion of configuration, offering a novel pathway for the creation of complex tertiary alkyl thiocyanates with high diastereopurity. These substitution reactions proceed under mild reaction conditions and tolerate several functional groups. Additionally, thiocyanates were converted to thiols using lithium aluminum hydride.

Selective Terminal Functionalization of Linear Alkanes.

A two-step sequential strategy involving a biocatalytic dehydrogenation/remote hydrofunctionalization, as a unified and versatile approach to selectively convert linear alkanes into a large array of valuable functionalized aliphatic derivatives is reported. The dehydrogenation is carried out by a mutant strain of a bacteria Rhodococcus and the produced alkenes are subsequently engaged in a remote functionalization through a metal-catalyzed hydrometalation/migration sequence that subsequently react with a large variety of electrophiles. The judicious implementation of this combined biocatalytic and organometallic approach enabled us to develop a high-yielding protocol to site-selectively functionalize unreactive primary C-H bonds.

Tetrazole Diversification of Amino Acids and Peptides via Silver-Catalyzed Intermolecular Cycloaddition with Aryldiazonium Salts.

Selective structural modification of amino acids and peptides is a central strategy in organic chemistry, chemical biology but also in pharmacology and material science. In this context, the formation of tetrazole rings, known to possess significant therapeutic properties, would expand the chemical space of unnatural amino acids but has received less attention. In this study, we demonstrated that the classic unimolecular Wolff rearrangement of α-amino acid-derived diazoketones could be replaced by a faster intermolecular cycloaddition reaction with aryldiazonium salts under identical practical conditions. This strategy provides an efficient synthetic platform that could transform proteinogenic α-amino acids into a plethora of unprecedented tetrazole-decorated amino acid derivatives with preservation of the stereocenters. Density functional theory studies shed some light on the reaction mechanism and provided information regarding the origins of the chemo- and regioselectivity. Furthermore, this diazo-cycloaddition protocol was applied to construct tetrazole-modified peptidomimetics and drug-like amino acid derivatives.

Highly Diastereoselective Preparation of Tertiary Alkyl Isonitriles by Stereoinvertive Nucleophilic Substitution at a Nonclassical Carbocation.

A highly efficient SnCl4-catalyzed nucleophilic isocyanation of cyclopropyl ethers has been developed. The reaction proceeds at the quaternary carbon stereocenter of the cyclopropane with a complete inversion of configuration, providing a new avenue for the construction of synthetically challenging tertiary alkyl isonitriles with high diastereopurity. The diversity of the incorporated isocyanide group has been demonstrated by the transformation of tertiary alkyl isonitriles into the corresponding tertiary alkyl amines, amides, and cyclic ketoimines.

Stereoselective Construction of Tertiary Homoallyl Alcohols and Ethers by Nucleophilic Substitution at Quaternary Carbon Stereocenters.

An efficient method for the stereoselective construction of tertiary C-O bonds via a stereoinvertive nucleophilic substitution at the quaternary carbon stereocenter of cyclopropyl carbinol derivatives using water, alcohols and phenols as nucleophiles has been developed. This substitution reaction proceeds under mild conditions and tolerates several functional groups, providing a new access to the stereoselective formation of highly congested tertiary homoallyl alcohols and ethers.

Stereoselective Preparation of CF3-Containing Cyclopropanes.

A regio- and diastereoselective carbometalation of easily accessible CF3-substituted cyclopropenes is developed with a diastereoselectivity of the addition opposite to the CF3 group. This simple strategy allows the preparation of polysubstituted (up to penta-) cyclopropyl rings possessing two adjacent quaternary carbon stereocenters with excellent diastereoselectivities.

Directed Diastereoselective Cyclopropanation and Epoxidation of Alkenyl Cyclopropyl Carbinol Derivatives.

We report the directed diastereoselective Simmons-Smith cyclopropanation and vanadium-catalyzed epoxidation reactions of alkenyl cyclopropyl carbinol derivatives. The reaction furnished densely substituted stereodefined bicyclopropanes and cyclopropyl oxiranes as a single diastereomer in each case. The remarkable selectivity is obtained thanks to the rigidity of the cyclopropyl core, allowing diastereoselective reactions on the alkenyl moiety. This emphasizes the uniqueness of the cyclopropyl ring as a central platform in stereoselective synthesis.

Synthesis and Functionalization of Tertiary Propargylic Boronic Esters by Alkynyllithium-Mediated 1,2-Metalate Rearrangement of Borylated Cyclopropanes.

Implementing the use of alkynyllithium reagents in a stereospecific 1,2-metalate rearrangement-mediated ring opening of polysubstituted cyclopropyl boronic esters provides a variety of tertiary pinacol boranes bearing adjacent tertiary or quaternary carbon stereocenters with high levels of diastereomeric purity. The potential of this strategy was demonstrated through a selection of α- and γ-functionalization of the propargyl boronic esters.

Regio- and Diastereoselective Carbometalation Reaction of Cyclopropenes.

The various facets of the chemistry of cyclopropane derivatives, the smallest carbocycle, are amazingly diverse and continue to fascinate theoreticians, synthetic or structural chemists having interest in fundamental physical, medicinal chemistry, and natural product synthesis. The challenges generated by this intriguing cyclic arrangement of only three tetravalent carbons represent a wide area of the chemical spectrum. From fundamental aspects of bonding through the synthesis of highly strained molecules, the understanding of the mode of action in biological systems to the selective cleavage into acyclic substrates makes the chemistry of these small rings fascinating. Therefore, efficient routes to prepare differently polysubstituted cyclopropanes have always been of a primordial importance. In the past decade, we and others have expanded the scope of the carbometalation reaction of cyclopropenes as a broad and general method to the formation of stereodefined cyclopropane derivatives. Although cyclopropenes, with their even higher strain energy, easily undergo addition reactions of organometallic reagents, their carbometalation reactions generate new regio-, diastereo-, and enantioselectivity issues that needed to be addressed. These various stereochemical aspects accompanied our research from its origins to today, and we are proposing in this Account, a didactic overview of the different ways by which cyclopropenes can lead to the formation of polysubstituted cyclopropanes or open-products possessing several stereogenic centers as a single regio- and diastereomer.We initially launched our research campaign on the chemistry of these strained three-membered rings by the regio- and diastereoselective copper-catalyzed carbomagnesiation of enantiomerically enriched cyclopropenyl carbinols. The directing alcohol governed both the regio- and diastereoselectivity of the addition and also served as a good leaving group as it undergoes a selective 1,2-elimination reaction to provide enantioenriched alkylidenecyclopropanes in excellent yields and enantiomeric excesses. Then, we turned our attention to the regio- and stereoselective synthesis of stereodefined tri- and tetrasubstituted cyclopropanes through the diastereoselective addition to sp2- monosubstituted cyclopropenyl ester derivatives. With the aim to further expand this concept to the formation of penta- and hexa-substituted cyclopropanes as single isomer, we had first to design the preparation of the required 1,2-disubstituted cyclopropenes that would control the regioselective addition of the organometallic derivatives. The synthesis of penta- and hexa-substituted cyclopropanes was then reported for the first time as a single regio- and diastereomer. It should be noted that the in situ formed cyclopropyl-metal intermediate is configurationally stable and can be subsequently functionalized with pure retention of the configuration by addition of electrophiles. Then, the enantioselective-catalyzed carbometalation reaction of achiral cyclopropenes allowed the synthesis of several new classes of cyclopropane derivatives in high enantiomeric ratios. Finally, by combining the regio- and diastereoselective carbometalation reaction of a cyclopropene with a subsequent reaction of the resulting cyclopropylmetal species, a selective carbon-carbon bond cleavage was observed to lead to the preparation of acyclic substrates possessing several stereocenters including a quaternary carbon stereogenic center. Our original vision of using strain within an embedded double bond in a three-membered ring has provided new routes to the stereoselective synthesis of polysubstituted cyclopropanes and has been extremely successful, as it represents a current new tool for the synthesis of persubstituted cyclopropanes as a single diastereomer.

Stereoselective Synthesis of Polysubstituted Spiropentanes.

A new approach to polysubstituted spiropentanes is developed through a regio- and diastereoselective carbometalation of sp2-disubstituted cyclopropenes. The control of selectivity originates from a combined syn-facial diastereoselective carbometalation with a regio-directed addition. The regio-controlling element subsequently serves as a leaving group in an intramolecular nucleophilic substitution. This method allows the preparation of various polysubstituted spiropentanes with up to five contiguous stereocenters.

Borylated Cyclopropanes as Spring-Loaded Entities: Access to Vicinal Tertiary and Quaternary Carbon Stereocenters in Acyclic Systems.

Herein, we present the formation of acyclic frameworks bearing two consecutive stereocenters of either tertiary or quaternary nature starting from easily accessible cyclopropenes. This holistic approach involves a regio- and diastereoselective hydro- or carboborylation of substituted cyclopropenyl esters. Formation of boronate complexes of the latter via the addition of nucleophiles and subsequent stereospecific 1,2-migration with carbon-carbon bond cleavage delivered the title compounds.

Preparation of Distant Quaternary Carbon Stereocenters by Double Selective Ring-Opening of 1,1-Biscyclopropyl Methanol Derivatives.

The diastereoselective double carbometalation reaction of cyclopropenes provides, in a single-pot operation, two ω-ene-[1,1]-bicyclopropyl ester derivatives. One regioisomer then undergoes a Pd-catalyzed addition of aryl iodide to provide skipped dienes possessing several distant stereocenters including two congested quaternary carbon centers with excellent diastereoselectivity.

Stereoinvertive Nucleophilic Substitution at Quaternary Carbon Stereocenters of Cyclopropyl Ketones and Ethers.

A highly regio- and diastereoselective nucleophilic substitution at the quaternary carbon stereocenter of cyclopropyl ketones and cyclopropyl carbinol derivatives using TMSBr, DMPSCl and TMSN3 as nucleophiles has been developed. A variety of acyclic tertiary alkyl bromides, chlorides and azides were therefore prepared with excellent diastereopurity. The substitution occurs at the most substituted quaternary carbon center in a stereoinvertive manner, which may be attributed to the existence of a bicyclobutonium species.

Mechanistic Insights on the Selectivity of the Tandem Heck-Ring-Opening of Cyclopropyldiol Derivatives.

The preparation of a new class of alkenyl cyclopropyl diols, easily available through a copper-catalyzed carbometalation reaction of cyclopropenes, has enabled the study of key mechanistic aspects of the tandem Heck-cyclopropane ring-opening reaction. Utilizing these substrates containing two distinct hydroxyl groups allowed us to examine parameters affecting the reaction outcome and selectivity. The combination of these experimental results with detailed DFT studies shed light on the mechanism governing the regio- and stereoselectivity of the cyclopropane ring-opening. A thorough investigation displayed the dual roles fulfilled by the hydroxyl group during the reaction, which is key to this remarkable transformation. In addition to its mechanistic implication, the reaction granted access to various lactones possessing up to four stereocenters as a single diastereomer, conveniently prepared in only two catalytic steps from easily accessible achiral cyclopropenes.

Stereospecific Construction of Quaternary Carbon Stereocenters from Quaternary Carbon Stereocenters.

Organoaluminum species promote a smooth nucleophilic substitution at the quaternary carbon stereocenter of stereodefined polysubstituted cyclopropyl methyl phosphate with a complete inversion of configuration, even when more reactive functional groups are present. The regio- and diastereoselectivity of the substitution is attributed to the existence of a bicyclobutonium intermediate.

Stereodivergent Access to Trisubstituted Alkenylboronate Esters through Alkene Isomerization.

We report an efficient method for the preparation of synthetically valuable trisubstituted alkenylboronate esters through alkene isomerization of their readily available 1,1-disubstituted regioisomeric counterparts. Either stereoisomer of the target alkenylboronate motif can be obtained at will from the same starting material by employing different isomerization catalysts.