Varinder K. Aggarwal

Enantiodivergent conversion of chiral secondary alcohols into tertiary alcohols

From receptors in the nose to supramolecular biopolymers, nature shows a remarkable degree of specificity in the recognition of chiral molecules, resulting in the mirror image arrangements of the two forms eliciting quite different biological responses. It is thus critically important that during a chemical synthesis of chiral molecules only one of the two three-dimensional arrangements is created. Although certain classes of chiral molecules (for example secondary alcohols) are now easy to make selectively in the single mirror image form, one class—those containing quaternary stereogenic centres (a carbon atom with four different non-hydrogen substituents)—remains a great challenge. Here we present a general solution to this problem which takes easily obtainable secondary alcohols in their single mirror image form and in a two-step sequence converts them into tertiary alcohols (quaternary stereogenic centres). The overall process involves removing the hydrogen atom (attached to carbon) of the secondary alcohol and effectively replacing it with an alkyl, alkenyl or aryl group. Furthermore, starting from a single mirror image form of the secondary alcohol, either mirror image form of the tertiary alcohol can be made with high levels of stereocontrol. Thus, a broad range of tertiary alcohols can now be easily made by this method with very high levels of selectivity. We expect that this methodology could find widespread application, as the intermediate tertiary boronic esters can potentially be converted into a range of functional groups with retention of configuration.

Application of Chiral Sulfides to Catalytic Asymmetric Aziridination and Cyclopropanation with In Situ Generation of the Diazo Compound

Imines and alkenes can be converted into the corresponding aziridines and cyclopropanes (see scheme, PTC=phase-transfer catalyst, Ts=toluene-4-sulfonyl) in good yield with moderate to high d.r. and high ee values using tosylhydrazone salts with catalytic quantities of chiral sulfide (5-20 mol %) and metal catalyst (1 mol %). The process is particularly suited to the synthesis of conformationally locked cyclopropyl amino acids, which can now be prepared in only three steps from commercially available material in 100 % ee.

Unexpected side reactions of imidazolium-based ionic liquids in the base-catalysed Baylis–Hillman reactionElectronic supplementary information (ESI) available: NMR data; details of conditions employed by Afonso and integrations and calculations. See http://www.rsc.org/suppdata/cc/b2/b203079a/

Low yields are obtained when the Baylis-Hillman reaction is conducted in the presence of an imidazolium-based ionic liquid due to direct addition of the deprotonated imidazolium salt to the aldehyde. Ionic liquids are evidently not inert.

Protodeboronation of Tertiary Boronic Esters: Asymmetric Synthesis of Tertiary Alkyl Stereogenic Centers

While tertiary boranes undergo efficient protodeboronation with carboxylic acids, tertiary boronic esters do not. Instead, we have discovered that CsF with 1.1 equiv of H2O (on tertiary diarylalkyl boronic esters) or TBAF·3H2O (on tertiary aryldialkyl boronic esters) effect highly efficient protodeboronation of tertiary boronic esters with essentially complete retention of configuration. Furthermore, substituting D2O for H2O provides ready access to deuterium-labeled enantioenriched tertiary alkanes. The methodology has been applied to a short synthesis of the sesquiterpene, (S)-turmerone.

Catalytic asymmetric synthesis of epoxides from aldehydes using sulfur ylides with in situ generation of diazocompounds

A practical, general, and convergent route to epoxides with control of the relative and absolute stereochemistry has been achieved by generating the reactive intermediate (the diazo compound) in situ from tosylhydrazone salts (see scheme, PTC=phase-transfer catalyst, Ts=toluene-4-sulfonyl). High yields (58-82 %), high d.r. (88:12-98:2), and high ee values (87-94 %) have been obtained using a new class of stable chiral sulfides at low catalyst loading (5 mol %) and [Rh2 (OAc)4 ] (0.5 mol %).

Assembly-line synthesis of organic molecules with tailored shapes

Molecular assembly lines, where molecules undergo iterative processes involving chain elongation and functional group manipulation are hallmarks of many processes found in Nature. We have sought to emulate Nature in the development of our own molecular assembly line through iterative homologations of boronic esters. Here we report a reagent (α-lithioethyl triispopropylbenzoate) which inserts into carbon-boron bonds with exceptionally high fidelity and stereocontrol. Through repeated iteration we have converted a simple boronic ester into a complex molecule (a carbon chain with ten contiguous methyl groups) with remarkably high precision over its length, its stereochemistry and therefore its shape. Different stereoisomers were targeted and it was found that they adopted different shapes (helical/linear) according to their stereochemistry. This work should now enable scientists to rationally design and create molecules with predictable shape, which could have an impact in all areas of molecular sciences where bespoke molecules are required.Molecular ‘assembly lines’, in which organic molecules undergo iterative processes such as chain elongation and functional group manipulation, are found in many natural systems, including polyketide biosynthesis. Here we report the creation of such an assembly line using the iterative, reagent-controlled homologation of a boronic ester. This process relies on the reactivity of α-lithioethyl tri-isopropylbenzoate, which inserts into carbon–boron bonds with exceptionally high fidelity and stereocontrol; each chain-extension step generates a new boronic ester, which is immediately ready for further homologation. We used this method to generate organic molecules that contain ten contiguous, stereochemically defined methyl groups. Several stereoisomers were synthesized and shown to adopt different shapes—helical or linear—depending on the stereochemistry of the methyl groups. This work should facilitate the rational design of molecules with predictable shapes, which could have an impact in areas of molecular sciences in which bespoke molecules are required.

Enantiospecific sp2–sp3 coupling of secondary and tertiary boronic esters

The cross-coupling of boronic acids and related derivatives with sp(2) electrophiles (the Suzuki-Miyaura reaction) is one of the most powerful C-C bond formation reactions in synthesis, with applications that span pharmaceuticals, agrochemicals and high-tech materials. Despite the breadth of its utility, the scope of this Nobel prize-winning reaction is rather limited when applied to aliphatic boronic esters. Primary organoboron reagents work well, but secondary and tertiary boronic esters do not (apart from a few specific and isolated examples). Through an alternative strategy, which does not involve using transition metals, we have discovered that enantioenriched secondary and tertiary boronic esters can be coupled to electron-rich aromatics with essentially complete enantiospecificity. As the enantioenriched boronic esters are easily accessible, this reaction should find considerable application, particularly in the pharmaceutical industry where there is growing awareness of the importance of, and greater clinical success in, creating biomolecules with three-dimensional architectures.

Highly Enantioselective Synthesis of Tertiary Boronic Esters and their Stereospecific Conversion to other Functional Groups and Quaternary Stereocentres

Organoboron compounds are useful in asymmetric synthesis. We have developed an efficient methodology for the highly enantioselective synthesis of tertiary boronic esters from the corresponding secondary benzylic alcohols. Further stereospecific transformations of the boronic ester moiety are described including the preparation of tertiary alcohols, C-tertiary amines and tertiary arylalkanes. Several homologations of tertiary boronic esters have also been developed for the construction of quaternary stereocentres.

An Annulation Reaction for the Synthesis of Morpholines, Thiomorpholines, and Piperazines from β‐Heteroatom Amino Compounds and Vinyl Sulfonium Salts

The nitrogen-containing heterocycles comprising morpholines, thiomorpholines, and piperazines are some of the most important pharmacophores in medicinal chemistry. However, the direct synthesis of such compounds by alkylation of b-amino alcohols/thiols/amines with 1,2-dihalo derivatives is often fraught with low yields and side reactions. 1,2Dihalogen derivatives are generally poor electrophiles and reactions are often accompanied by competing elimination processes. A solution to this problem is to carry out a threestep sequence employing an a-halogen acid halide as the electrophile. Following amide formation and intramolecular alkylation, reduction finally furnishes the required heterocycles. Herein, we describe the application of a novel concept to prepare these pharmacologically important heterocycles from b-amino alcohols/thiols/amines in one step and high yield. We reasoned that soft electrophiles operating under less basic conditions would minimize competing elimination pathways and therefore considered the possibility of employing Michael acceptors. This led us to vinyl onium salts (e.g., 1). We expected that, following conjugate addition of one of the heteroatoms, an ylide 4 would be generated that could undergo proton transfer with the other heteroatom (Scheme 1). The heteroatom anion generated, 5, would then attack the onium ion electrophile to effect ring-closure and produce the required heterocycle. Although vinyl onium salts have been employed in three-component coupling reactions with nucleophiles and electrophiles, their potential to react according to the pathway shown in Scheme 1 has not previously been recognized. Of the readily available vinyl onium salts, it was thought that sulfonium and phosphonium would be better at promoting the conjugate addition step than ammonium since the ylide intermediate is better stabilized. However, to promote cyclization leaving group ability of the onium is critical and this falls in the order S>N @ P. These considerations led us to examine vinyl sulfonium salts, and in particular diphenyl vinyl sulfonium salt 1. This salt was easily prepared through a modified procedure as shown in Scheme 2. In this

Application of the Lithiation-Borylation Reaction to the Preparation of Enantioenriched Allylic Boron Reagents and Subsequent In Situ Conversion into 1,2,4-Trisubstituted Homoallylic Alcohols with Complete Control over All Elements of Stereochemistry

The reactions of Hoppes lithiated carbamates with vinylboranes and boronic esters give allylic boranes/boronic esters, and subsequent addition of aldehydes provides a new route to enantioenriched homoallylic alcohols with high enantiomeric ratios and diastereomeric ratios. Specifically, reactions of sparteine-complexed lithiated carbamates with trans-alkenyl-9-BBN derivatives followed by addition of aldehydes gave (Z)-anti-homoallylic alcohols in greater than 95:5 er and 99:1 dr. However, in the special case of the methyl-substituted lithiated carbamate, diamine-free conditions were required to achieve high selectivity. Reactions of sparteine-complexed lithiated carbamates with (Z)-alkenyl pinacol boronic esters and (E)-alkenyl neopentyl boronic esters gave (E)-syn- and (E)-anti-homoallylic alcohols, respectively, in greater than 96:4 er and 98:2 dr. In these reactions, a Lewis acid (MgBr(2) or BF(3) x OEt(2)) was required to promote both the 1,2-metalate rearrangement and the addition of the intermediate allylic boronic ester to the aldehyde. This methodology provides a general route to each of the three classes of homoallylic alcohols with high selectivity.