Asymmetric Synthesis of Chiral Atropisomeric Bis‐Aryl Organophosphorus from Menthyl H‐Phosphinate

This review describes new methods for the synthesis of chiral monophosphine ligands with menthyl phenylphosphinate as a chiral auxiliary through asymmetric Suzuki‐Miyaura cross‐coupling reactions and asymmetric C–H functionalization. The chiral menthyl phenylphosphinate as a chiral auxiliary is easy to prepare and the menthyl group can easily be transformed into other functional groups, with the chiral center synchronously remaining. These methodologies provide highly efficient and practical strategies for the synthesis of novel axially chiral biaryl monophosphine oxides and their corresponding phosphines. Meanwhile, these reactions are easy to handle and exhibit wide scope for substrates with excellent diastereomeric ratios.     

Asymmetric Diels-Alder reactions with a chiral spirodione, (6S, 7S, 10R)-7-Isopropyl-10-methyl-1-oxaspiro[5.5]undec-3-ene-2,5-dione

The synthesis of the title spirodione, a new class of auxiliary based chiral synthon, using (−)-menthone having a unique carbon-carbon bond is described. Diels-Alder reactions were carried out with variety of dienes using the title auxiliary as a chiral dienophile in the presence of diethyl aluminium chloride as Lewis acid catalyst to afford the cycloadduct with good diastereoselectivity. The configurations of the chiral synthon and cycloadducts were determined by X-ray crystallography. Methodology for detachment of the chiral auxiliary from the cycloadducts has been developed.     

Diastereoselective aziridination of chiral electron-deficient olefins with N-chloro-N-sodiocarbamates catalyzed by chiral quaternary ammonium salts

Chiral quaternary ammonium salt-catalyzed diastereoselective aziridination of electron-deficient olefins that possess a chiral auxiliary with N-chloro-N-sodiocarbamates was developed. The key to high stereoselectivity was found to be the employment of the "matching" stereochemical combination of chiral auxiliary/ammonium salt. For example, when 3-phenyl-(4R,7S)-4-methyl-7-isopropyl-4,5,6,7-tetrahydroindazole (L-menthopyrazole) as a chiral auxiliary and a cinchonidine-derived chiral ammonium salt as a catalyst were applied to the reaction system, perfect diastereoselectivity was realized. Furthermore, the preparation of enantiomerically pure aziridines by removal of the chiral auxiliary was demonstrated.     

Chiral Photochemistry in a Confined Space: Torquoselective Photoelectrocyclization of Pyridones within an Achiral Hydrophobic Capsule

Chiral induction during the photoelectrocyclization of pyridones included within octa acid (OA) capsule has been established. Chiral induction is brought about by a chiral auxiliary appended to the reactive pyridone moiety. Importantly, the same chiral auxiliary while ineffective in acetonitrile solution is found to be effective within the confined space of OA capsule. The diastereomeric excess of 92% obtained here is comparable only to that in solid state. OA capsule, we believe, provides restriction to the rotational motions of the reactant pyridone and chiral auxiliary and thus places the chiral auxiliary in a selective conformation with respect to the reactive pyridone part. A correlation between the position of the methyl group on the pyridone ring and diastereoselectivity was noted. Structures of the host-guest complexes were examined by ¹H NMR and the data were used to obtain preliminary information concerning the mechanism of chiral induction within the confined spaces of OA capsule.     

Chemoenzymatic synthesis and application of a new,easily chiral auxiliary for the synthesis of peptidomimetics via an Ugi reaction

A new chiral auxiliary derived from α-phenylethylamine, α-(2,4-dimethoxyphenyl)ethylamine is presented. It significantly expands upon the application of α-phenylethylamine derivatives used as chiral auxiliaries. A straightforward, chemoenzymatic synthesis of non-racemic α-(2,4-dimethoxyphenyl)ethylamine is described and the new chiral auxiliary applied to an asymmetric Ugi reaction. The mild conditions used for the cleavage of the auxiliary allowed to obtain chiral, non-racemic peptidomimetics possessing reactive α,β-unsaturated double bonds.     

New perspective for natural products synthesis: concise synthesis of (+)-sch 642305 by chiral auxiliary multiuse methodology

The synthesis of (+)-Sch 642305 is an example of chiral auxiliary multiuse methodology, which shows a new perspective for the synthesis of compounds with multiple asymmetric centers. Thus, (+)-Sch 642305 was concisely synthesized from the known compound. Every reaction is stereoselective, and the chiral nonracemic hydrobenzoin worked as chiral auxiliary for desymmetrization of diene, as a template for attaining regio- and stereoselective reactions, as an oxygen source at the C4-position, and as a protecting group of hydroxyl functions. Namely, the chiral auxiliary played a role in every step throughout the synthesis. Furthermore, the synthesis contains a new protocol for obtaining alpha'-alkylated enone compounds.     

Non-cross-linked Polystyrene Supported Cyclosulfamide:A New Chiral Auxiliary for Highly Stereoselective Alkylation Reactions

The asymmetric alkylation reactions induced by non-cross-linked polystyrene supported cyclosulfamide chiral auxiliary occurred in moderate to good yields with a very high stereoselectivity（e.e.〉99%）. Compared to non-supported cyclosulfamide chiral auxiliary, this chiral auxiliary can be recovered by simple precipitation and filtration, and could be reused at least four cycles without appreciable reduction in the yield or stereoselectivity.     

Use of chirally modified zeolites and crystals in photochemical asymmetric synthesis

Three different approaches to asymmetric induction in the cis-to-trans photoisomerization of a number of 1-benzoyl-2,3-diphenylcyclopropane derivatives are reported: the use of chiral inductors and covalent chiral auxiliaries in MY zeolites and the use of ionic chiral auxiliaries in crystals. High levels of asymmetric induction were achieved using the latter two methods-up to 71% through the use of covalent chiral auxiliaries in zeolites and a remarkable 99% via the solid state ionic chiral auxiliary approach. In the zeolite method, the diastereomeric excess was found to depend strongly on the nature of the zeolite cation, M(+), and in the ionic chiral auxiliary approach, evidence is presented that it is the fixed orientation of the benzoyl group with respect to the cyclopropane ring that controls enantioselectivity in the crystalline state-a finding that is directly relevant to theoretical work on this topic.     

Chiral auxiliary based approach toward the synthesis of C-glycosylated amino acids

[reaction in text] In a chiral auxiliary based method C-glycosylated amino acids can be obtained by a 1,3-dipolar cycloaddition of a chiral glycine equivalent and C-1 allyl- or vinyl-derived carbohydrate building blocks as the key step. The products are formed regio- and diastereoselectively. Reductive cleavage of the N-O bond of the isoxazolidine and of the chiral auxiliary leads to C-glycosylated amino acids. The use of (-)-menthone to (+)-menthone as the auxiliary leads to the corresponding diastereomers.     

Indene-based thiazolidinethione chiral auxiliary for propionate and acetate aldol additions

An indene-based thiazolidinethione chiral auxiliary was prepared in two steps from trans-1-amino-2-indanol. Chlorotitanium enolates of this chiral auxiliary delivered excellent diastereoselectivities in propionate and acetate aldol additions. The chiral auxiliary was easily removed to deliver several valuable functionalities.     

Preparation and Reactions of Amino Acid Ester Sulfones as New Remote Asymmetrical Induced Reagents

The development of chiral auxiliary-controlled asymmetric synthesis has been receiving increasing interest in recent yearsfi,2] Various chiral auxiliary reagents have been observed[3] and a lot of results showed that variation of the chiral auxiliary could influence asymmetric induction. Recently, it has been reported the reaction of the aminated sulfones as a remote chiral auxiliary with α,β-unsaturated carbonyl compounds.[4] Here we would like to report the preparation of amino acid ester sulfones as new remote asymmetrical induced reagents and their reactions with α,β-unsaturated esters.     

C(2)-Symmetric bis-sulfoxide: A novel chiral auxiliary for asymmetric desymmetrization of cyclic meso-1,2-diols

A new heterocyclic compound, C(2)-symmetric bis-sulfoxide 1, has been found to be an efficient chiral auxiliary for asymmetric desymmetrization of cyclic meso-1,2-diols via diastereoselective acetal fission. Both (R,R)- and (S,S)-1 are readily synthesized with high optical purity via asymmetric oxidation of 1, 5-benzodithiepan-3-one (2). After acetalization of meso-1,2-diols 6a-e and a mono-TMS ether 6f with this chiral auxiliary 1, the resulting acetals 7a-f were subjected to base-promoted acetal fission upon treatment with potassium hexamethyldisilazide (KHMDS) followed by acetylation or benzylation to give the desymmetrized diol derivatives 8a-f with high diastereoselectivity. The chiral auxiliary 1 is readily removed by acid-promoted hydrolysis and can be recovered without a loss in enantiomeric excess.     

Cleavage of a chiral auxiliary using RCM on an especially sterically crowded alkene: Syntheses of chiral carbo- and heterocycles

Chiral 1,5-, 1,6-, and 1,7-dienes generated in 3–4 steps from chiral auxiliary p-menthane-3-carboxaldehyde undergo RCM with notable discrepancies in reactivity depending on the nature and number of substituents flanking the central double bond. The chiral auxiliary is thus cleaved releasing a carbo- or heterocycle in the process. Special features concerning the RCM on these especially crowded systems are discussed.     

4 + 2] cycloadditions of nitroalkenes in water. Highly asymmetric synthesis of functionalized nitronates.

The [4 + 2] cycloadditions of (E)-2-aryl-1-cyano-1-nitroalkenes 1 with achiral and enantiopure vinyl ethers 2 and 3 carried out in sole water are reported. These reactions occur in a heterogeneous phase under mild conditions and are fast and highly stereoselective. By using (-)-N,N-dicyclohexyl-(1S)-isoborneol-10-sulfonamide as a chiral auxiliary, the cycloadditions are totally asymmetric. The face selectivity is discussed in terms of the shape of the chiral auxiliary and the reactive conformation of vinyl ether.     

Asymmetric Eschenmoser-Claisen rearrangement for anti-beta-substituted gamma,delta-unsaturated amino acids

Optically active anti-beta-substituted gamma,delta-unsaturated amino acids are important synthetic building blocks in organic synthesis and for peptidomimetics. A novel asymmetric Eschenmoser-Claisen rearrangement with use of a C2-symmetric chiral auxiliary was developed to generate this type of amino acid. Excellent diastereoselectivities and high enantioselectivities (87-93% ee) were obtained after the chiral auxiliary was removed via iodolactonization/zinc reduction.     

Application of acyclic chiral auxiliaries on alkylation reactions

The application in alkylation reactions of an acyclic chiral auxiliary is described. The synthesis is straightforward from a chiral primary amine and a double acylation. A characteristic of this auxiliary is its modular design formed by an achiral part (acyl) and a chiral component (primary amine) so it can be tuned for different reactions without difficulty. The alkylation proceeds with excellent diastereoselectivity because the conformational flexibility of the enolate is restricted by the formation of a chelate and the allylic 1,3-strain.     

Asymmetric synthesis via acetal templates. 9. Further studies of the allylation reaction. Preparation of (−)-dihydromyoporone

A procedure has been developed for the high-yield coupling of chiral acetals 1 with allyltrimethylsilane (2, R′=H) as well as with methallyltrimethylsilane (2,R′=ME) to afford the hydroxy ethers 3 in which the new chiral center is formed highly enantioselectively. Homoallylic alcohols 4 of high ee are produced by removal of the chiral auxiliary.     

Synthesis of novel chiral spirodione, (6R,7R)-7-phenyl-1-oxaspiro[5.5]undec-3-ene-2,5-dione: application to the asymmetric Diels-Alder reaction with high π-facial selectivity

The synthesis of the title spirodione, a new class of auxiliary based chiral synthon using (−)-trans-2-phenylcyclohexanol and its application to the asymmetric Diels-Alder reaction are described. Methodology for detachment of the chiral auxiliary from the cycloadduct has been developed.     

Chiral Auxiliary Approach for Gold(I)-Catalyzed Cyclizations

Two different classes of stereoselective cyclizations have been developed using a chiral auxiliary approach with commercially available [JohnPhosAu(MeCN)SbF₆] as catalyst. First, a stereoselective cascade cyclization of 1,5-enynes was achieved using the Oppolzer camphorsultam as chiral auxiliary. In this case, a one-pot cyclization-hydrolysis sequence was developed to directly afford enantioenriched spirocyclic ketones. Then, the stereoselective alkoxycyclization of 1,6-enynes was mediated by an Evans-type oxazolidinone. A reduction-hydrolysis sequence was selected to remove the auxiliary to give enantioenriched β-tetralones. DFT studies confirmed that the steric clash between the chiral auxiliary and alkene accounts for the experimentally observed diastereoselective cyclization through the Si face.     

Sterically biased 3,3-sigmatropic rearrangement of chiral allylic azides: application to the total syntheses of alkaloids

We describe a tandem Mitsunobu/3,3-sigmatropic rearrangement of allylic azides on a chiral auxiliary system that favors one regioisomer thanks to its exceptional steric bias. The sequence may be completed by the oxidative cleavage of the auxiliary or by a ring-closing metathesis reaction that produces a carbo- or heterocycle directly and a recyclable form of the chiral auxiliary. Applications of the methodology to the total synthesis of (+)-coniine, (+)-lentiginosin, and (+)-pumiliotoxin C are reported.