A highly enantio- and diastereoselective catalytic intramolecular Stetter reaction

A highly enantio- and diastereoselective intramolecular Stetter reaction has been developed. Subjection of alpha,alpha-disubstituted Michael acceptors to an asymmetric intramolecular Stetter reaction results in a highly enantioselective conjugate addition and a diastereoselective proton transfer. Available evidence suggests the diastereoselective protonation occurs via intramolecular delivery to the sterically more hindered face of the enolate. The scope of the trisubstituted Michael acceptors has been examined and found to be broad with respect to the size of the alpha-substituent and nature of the Michael acceptor. Aliphatic and aromatic aldehydes were examined and found to afford the desired product in good overall yield with high enantio- and diastereoselectivity.     

Diastereoselective synthesis of alpha,beta'-disubstituted aminomethyl(2-carboxyethyl)phosphinates as phosphinyl dipeptide isosteres

A new and efficient method has been developed for the diastereoselective synthesis of unnatural dipeptide analogues containing the metabolically stable phosphinic moiety, NH 2XaaPsi[P(O)OHCH 2]XaaOH, which mimics the transition state of tetrahedral geometry of a scissile peptide bond in hydrolysis by protease. The method is based upon stereospecific Michael addition of stereodefined alpha-aminoalkyl- H-phosphinates to acrylates and subsequent diastereoselective alkylation at the beta'-position of the resulting Michael adducts.     

Quinine-derived thiourea promoted enantioselective Michael addition reactions of 3-substituted phthalides to maleimides

A highly diastereoselective and enantioselective Michael addition/desymmetrization reaction of maleimides with prochiral 3-substituted phthalides catalyzed by quinine-derived bifunctional thiourea was realized. A broad range of the 3,3′-disubstituted phthalides bearing vicinal quaternary-tertiary stereogenic centers were synthesized in moderate to good yields(up to 96%) with high diastereoselectivities(up to 19:1 dr) and enantioselectivities(up to 96:4 er).     

Highly diastereoselective four-component synthesis of polysubstituted 2-piperidinones with three and four stereogenic centers

Research on Chemical Intermediates - A novel four-component diastereoselective synthesis of polysubstituted 2-piperidinones is reported. The Michael addition–Mannich cascade of...     

Total synthesis of (-)-nakadomarin A

A highly diastereoselective bifunctional organocatalyst controlled Michael addition, a nitro-Mannich/lactamization cascade, a furan N-acyliminium cyclisation, a sequential alkyne RCM/syn-reduction and an alkene RCM has allowed a 19 step, highly stereoselective synthesis of (-)-nakadomarin A.     

Recyclable cinchona alkaloid catalyzed asymmetric Michael addition reaction

A highly enantioselective and diastereoselective Michael addition reaction of α-fluoro-β-ketoesters with maleimides is catalyzed by fluorous cinchona alkaloid to afford two adjacent chiral centers. The catalyst attached with a perfluroalkyl tag can be recovered by fluorous solid-phase extraction (F-SPE).     

Total synthesis of (-)-nakadomarin A

A concise diastereoselective total synthesis of (-)-nakadomarin A has been completed in 21 steps from D-pyroglutamic acid. Key steps include an enecarbamate Michael addition/furan-N-acyliminium ion cascade cyclization to provide the tetracyclic core and ring-closing alkyne and alkene metatheses to construct the fifteen- and eight-membered azacycles, respectively.     

Selective Michael Reaction Controlled by Supersilyl Protecting Group

Selective Michael reaction of organolithium reagents to supersilyl methacrylate is reported. The method was able to control a single and double Michael addition. The successful termination of the process using the supersilyl protecting group allows for the controlled, chemoselective, and diastereoselective Michael reaction.     

First asymmetric synthesis of (un)substituted bridged tetrahydro-2-benzazepines

A new and flexible route for the asymmetric synthesis of a variety of alkylated bridged tetrahydro-2-benzazepines has been developed. The key steps are the highly diastereoselective Michael addition of metalated SAMP-hydrazones to α,β-unsaturated esters combined with cyclomethylenation/Mitsunobu coupling reactions to secure the formation of the seven-membered azaheterocycle and of the bridged unit, respectively.     

Synthesis of the C(29)-C(45) bis-pyran subunit (E-F) of spongistatin 1 (Altohyrtin A)

A synthesis of the C(29)-C(45) bis-pyran subunit 2 of spongistatin 1 (1a) is described. The synthesis proceeds in 19 steps from the chiral aldehyde ent-7, and features highly diastereoselective alpha-alkoxyallylation reactions using the gamma-alkoxy substituted allylstannanes 17 and 19, as well as a thermodynamically controlled intramolecular Michael addition to close the F-ring pyran. The E ring was assembled via the Mukaiyama aldol reaction of F-ring methyl ketone 3 and the 2,3-syn aldehyde 4.     

Antibody-catalyzed asymmetric intramolecular Michael addition of aldehydes and ketones to yield the disfavored cis-product

The development of new catalytic asymmetric reactions continues to be a major goal in organic chemistry. Here we report a novel antibody-catalyzed intramolecular Michael addition of aldehydes and ketones to enones. The reaction is enantioselective and diastereoselective with a high ee value and cis/trans ratio. This is the first example of asymmetric intramolecular Michael addition of ketones. Antibody 38C2 is the only catalyst to date capable of generating this selectivity in Michael addition products.     

Asymmetric synthesis of 3,5-disubstituted indolizidines by intermolecular addition of an allylsilane on an N-acyliminium ion

A diastereoselective synthesis of 3,5-disubstituted indolizidines based on an intermolecular addition of an allylsilane on an acyliminium ion derived from (S)-pyroglutamic acid is described. The synthetic potential of this methodology is demonstrated by the enantioselective synthesis of (−)-indolizidine 195B, (−)-indolizidine 223AB, (+)-monomorine and (−)-3-butyl-5-propyl indolizidine.     

Chiral Guanidine Catalyzed Annulation to the Core Structure of （－）－Huperzine A

A bridged bicydic compound (7), the key intermediate for the synthesis of ( - )-huperzine A (1), was prepared by diastereoselective Michael-aldol annulatlon of β-keto ester (4) catalyzed by chiral guanidine (2). A variety of chiral catalysts, substrates and reaction conditions were tested.     

Tandem Michael addition/ylide epoxidation for the synthesis of highly functionalized cyclohexadiene epoxide derivatives

A highly efficient diastereoselective synthesis of cyclohexadiene epoxide derivatives with a multi-stereocenter has been developed via a tandem ylide Michael addition/epoxidation. By employing a chiral sulfonium ylide, up to 96% ee can be achieved in good yields.     

A flexible approach toward trisubstituted piperidines and indolizidines: synthesis of 6-epi-indolizidine 223A

2,5,6-Trisubstituted piperidines are readily prepared by a combination of an aza-Achmatowicz oxidation of a furyl-substituted benzenesulfonamide followed by a conjugate addition to the resulting 2H-pyridone and subsequent addition of various nucleophiles to a transient N-sulfonyliminium ion. The stereochemistry of the conjugate addition product is the result of axial attack from the face opposite the diaxial substituents at C(2) and C(6). This can be attributed to steric hindrance between the pseudoaxially oriented 2,6-substituents and the equatorially approaching nucleophile, thereby leading to the exclusive formation of the kinetically favored axial 1,4-adduct. Indolizidine alkaloid 223A was isolated from a skin extract of a Panamanian population of the dendrobatid Dendrobates pumilio Schmidt (Dendrobatidae). Synthesis of the originally proposed structure of this alkaloid was achieved in 13 steps in 13.1% overall yield by using an aza-Achmatowicz oxidative rearrangement and a diastereoselective 1,4-conjugate addition as the key steps. The structure of the natural 223A alkaloid (5b) differs from that of the epi-isomer 5a synthesized in this study in the configuration at the 6-position of the indolizidine ring.     

Enantioselective Total Synthesis of 3β‐Hydroxy‐7β‐kemp‐8(9)‐en‐6‐one,a Diterpene Isolated from Higher Termites

The first total synthesis of the title diterpene was accomplished starting from the Wieland–Miescher ketone. A diastereoselective sulfa‐Michael addition enabled the generation of the delicate β,γ‐unsaturated ketone moiety, while the tetracyclic kempane skeleton was readily constructed through domino metathesis.     

Stereoselective cascade reactions for construction of polyfunctionalised octahydroquinolines via [2C+2C+1C,1N] cyclisation

A conceptually unifying approach for a highly enantio- and diastereoselective synthesis of polyfunctionalised octrahydroquinolines incorporating three contiguous chiral centres is reported. The synthesis involves diphenylprolinol silyl ether-catalysed Michael addition of 1,3-cyclohexanedione to nitroalkenes followed by potassium carbonate-promoted aza-Henry reaction with N-tosyl aldimines, intramolecular hemiaminalisation and dehydration reaction cascade in a one-pot operation.     

Simple diamine- and triamine-protonic acid catalysts for the enantioselective Michael addition of cyclic ketones to nitroalkenes

Simple, chiral, pyrrolidine-based diamine and triamine derivatives that incorporate the secondary-secondary diamine motif are efficient catalysts for the highly diastereoselective and enantioselective Michael addition of cyclic ketones to 2-nitrovinyl arenes. The highest selectivities are obtained when these catalysts are used in conjunction with protonic acids. Steric factors in the substrate and the size of the acid additive play an important role in stereoselection.     

Synthetic approaches to bicyclomycin I. Prepration of monocylic intermediates by retrograde Michael cleavage of 6-alkyl-6-methoxyhexahydro-3H-thiazolo [3,4-a]pyrazine-5,8-diones.

The syntheses of N-protected-3-(hydroxypropyl)-3-methoxy-6-alkylidine piperazine-2,5-diones are described, in relation to an approach to bicyclomycin. A chemoselective Grignard reaction and a novel diastereoselective retrograde Michael cleavage highlight the sequence.     

Total Synthesis of the Tetracyclic Antimalarial Alkaloid (±)‐Myrioneurinol

The first total synthesis of the tetracyclic antimalarial Myrioneuron alkaloid (±)‐myrioneurinol has been accomplished using three highly diastereoselective reactions as pivotal steps: 1) an intramolecular Michael addition of a benzyloxycarbonyl‐protected lactam titanium enolate to an α,β‐unsaturated ester for construction of the spirocyclic C5 quaternary center and the a/d rings, 2) a malonate anion conjugate addition to a transient nitrosoalkene to install the requisite functionality and configuration at the C7 position, and 3) an intramolecular sulfonyliminium aza‐Sakurai reaction to form the b ring and the attendant C9/C10 configuration of the natural product.