Cuprate Addition Research Articles

Formal Total Synthesis of Neopeltolide

A concise synthesis of the core structure of the macrolide neopeltolide was developed featuring a Prins cyclization to fashion the pyran ring. Key steps in the synthesis of aldehyde 16 were a Leighton allylation and a Feringa-Minnaard asymmetric methyl cuprate addition to an unsaturated thioester. For lactonization, a classical Yamaguchi macrolactonization was used. The longest linear sequence consists of 17 steps providing lactone 26 with an overall yield of 23%.

Alkyl C−O Ring Cleavage of Bicyclic β-Lactones with Normant Reagents: Synthesis of a Merck IND Intermediate

Highly diastereoselective Cu(I)-mediated, bicyclic beta-lactone ring cleavage reactions with either alkyl or aryl cuprates proceeded with inversion of stereochemistry to give optically active trans-substituted cyclopentanes and cyclohexanes. Optimization of typically problematic aryl cuprate additions was made possible by minimization of a competing bromide-induced ring cleavage process. The utility of this process was demonstrated by an efficient synthesis of a Merck investigational new drug (IND) intermediate for an anti-HIV CCR5 antagonist.

Synthesis of C2-symmetric trans-2,6-diarylpiperidinones via aryl cuprate addition: an unexpected stereochemical outcome

An efficient procedure for the preparation of trans-2,6-diaryl piperidinones has been developed. Addition of aryl Grignard reagents to 2-aryl dihydropyridones under catalytic copper promoted conditions generates the trans isomer exclusively, an unprecedented stereochemical event. The X-ray structures of both starting material and product have been solved and shed light on the steric constraints and substrate geometry leading to the observed product. The reaction conditions tolerate a variety of aromatic nucleophiles to generate C 2-symmetric products in good overall yields.

Regioselective Cuprate Additions to Tethered Allylic Phosphates

The method allows the preparation of enantiopure alkyl-substituted homoallylic alcohols. The phosphate group is used both as a tether to ensure the Z-conformation of the alkene from two allylic alcohols, and as diastereotopic leaving group. In the case of non-symmetrical bis-allylic phosphates 4 and 6, the most substituted phosphate C-O bond is the leaving group. The allylic phosphates can be prepared in three steps and offer the advantage that different bis-allylic alcohols can be easily prepared.

Stereoselective syntheses of piperidinones and their modification by organometallic coupling reactions

Dehydropiperidinones stereoselectively obtained from N-arabinosyl imines were iodinated at the enaminone structure. Knochel iodine-magnesium exchange afforded Grignard compounds of these piperidinone derivatives which reacted, either directly or after transmetalation to zinc or copper intermediates, with alkyl-, aryl- or acylhalides to give correspondingly substituted piperidinones. Stereoselective conjugate allyl cuprate addition to a thus obtained 5-allyl dehydropiperidinone and ring-closing metathesis of the product gave a hydroquinolinone containing three stereogenic centers.

Total Synthesis and Comparative Analysis of Orlistat, Valilactone, and a Transposed Orlistat Derivative: Inhibitors of Fatty Acid Synthase

Concise syntheses of orlistat (Xenical), a two-carbon transposed orlistat derivative, and valilactone are described that employ the tandem Mukaiyama aldol-lactonization (TMAL) process as a key step. This process allows facile modification of the alpha-side chain. Versatile strategies for modifying the delta-side chain are described, involving cuprate addition and olefin metathesis. Comparative antagonistic activity of these derivatives toward a recombinant form of the thioesterase domain of fatty acid synthase is reported along with comparative activity-based profiling.

Iterative Synthesis of Deoxypropionate Units: The Inductor Effect in Acyclic Conformation Design

Conjugate addition of lithium dimethylcuprate to acyclic alpha,beta-unsaturated esters of varying lengths bearing terminal alkyl or phenyl groups leads to a preponderance of syn 1,3-adducts when one methyl is already present. Conversion to enoates, and iteration of cuprate additions also favors syn adducts to give contiguous deoxypropionate units in a growing chain. The effect of end-group variation (Me, i-Pr, phenyl, tert-butyl) in conjunction with the nature of the ester group (Me, tert-butyl, etc.) on the diastereoselectivity of syn and anti products was studied. The results are rationalized in terms of inductor effects related to the minimization of the 1,5-pentane interactions in energetically favored folded conformations and corroborated by homodecoupling NMR studies.

Enantioselective Catalysis on the Solid Phase: Synthesis of Natural Product‐Derived Tetrahydropyrans Employing the Enantioselective Oxa‐Diels–Alder Reaction

AbstractAliphatic aldehydes were synthesized on a solid support and subjected to an enantioselectively catalyzed oxa‐Diels–Alder reaction with Danishefsky’s diene. Employing 5 mol % of a Cr(III)‐salen catalyst enantiomeric ratios up to>99 % and yields up to 40 % over five steps were achieved. Further elaboration of the polymer‐bound dihydropyrones was performed by subsequent conjugate cuprate addition, reduction of the ketone and transformation of the resulting alcohol to a carbamate yielding 2,4,6‐trisubstituted tetrahydropyrans after cleavage from the solid support.

Stereoselective synthesis of chiral piperidine derivatives employing arabinopyranosylamine as the carbohydrate auxiliary

Stereoselective synthesis of 2-substituted dehydropiperidinones and their further transformation to variously disubstituted piperidine derivatives was achieved employing D-arabinopyranosylamine as the stereodifferentiating carbohydrate auxiliary. A domino Mannich–Michael reaction of 1-methoxy-3-(trimethylsiloxy)butadiene (Danishefsky's diene) with O-pivaloylated arbinosylaldimines furnished N-arabinosyl dehydropiperidinones in high diastereoselectivity. Subsequent conjugate cuprate addition gave 2,6-cis-substituted piperidinones, while enolate alkylation furnished 2,3-trans-substituted dehydropiperidinones. Electrophilic substitution at the enamine structure afforded 5-nitro- and 5-halogen dehydropiperidinones of which the latter were applied in palladium-catalyzed coupling reactions. The absolute configuration of the obtained products was proven by NMR and X-ray structure analysis as well as by syntheses of the alkaloids (+)-coniine and (+)-dihydropinidine.Key words: piperidine alkaloids, carbohydrate auxiliary, domino Mannich–Michael reaction, conjugate cuprate and hydride addition, electrophilic substitution of enamines.

The Synthesis and Preliminary Biological Evaluation of a Novel Steroid with Neurotrophic Activity: NGA0187

[structure, reaction: see text] A full account of the total synthesis of neurotrophic compound NGA0187 is provided. A key feature of the synthesis involved the direct selective oxidation of 6alpha,7beta-diol to install the unusual 6,7-ketol moiety and stereoselective conjugate addition of vinyl cuprate to enone. A preliminary evaluation of its ability to stimulate the neurite outgrowth was also evaluated with PC12 cell.

Regio‐ and Diastereoselective Conjugate Addition to 4,4‐Dimethylcyclohexadienones

AbstractConjugate addition of vinyl cuprate and dimethyl malonate to 4,4‐dimethylcyclohexa‐2,5‐dienones has allowed facile access to mono‐ and bis‐adducts in satisfactory yields. While the high diastereoselectivity of such processes to afford trans‐bis‐adducts was predictable, an unprecedented regioselectivity was observed with 2,4,4‐trimethylcyclohexa‐2,5‐dienone, with the first addition occurring exclusively at the C‐5 carbon atom (distal from the methyl group) and with the second addition of a bulky nucleophile such as dimethyl malonate even prevented. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Total Synthesis of Guanacastepene A: A Route to Enantiomeric Control

[reaction: see text] The goal of the total synthesis of guanacastepene A served as a focus to bring together several chemical inquiries. One involved the synthesis of fused 5,7-hydrazulenones (see structure 20). Another issue had to do with the mechanistic intermediates in reductive cyclizations (see 17 to 18 and 19). The total synthesis required a mastery of an intramolecular Knoevenagel condensation of a beta,gamma-unsaturated ketone (see compound 41). Actually, cyclization was best accomplished when the terminal double bond of 41 was first converted to an epoxide. Further issues related to the stereochemistry at C5 and, rather surprisingly, the propensity for beta-face acetoxylation at C13. Crystallographic verification of the assigned beta-stereochemistry at C13 is provided. Finally, a route to optically active material is provided (see compound 20). A key element in this construction was an enantioselective addition of isopropenyl cuprate to 2-methylcyclopentenone (see compound 99).

New synthesis of cis 5‐tert‐butyl‐L‐proline via cuprate. Evaluation as a cis proline mimetic in a biological active octapeptide

cis 5-tert-butyl-L-proline (Cbp) was prepared rapidly and efficiently by the addition of low-valent tert-butyl cuprate to an aminal derived from proline. [Cbp(2), D-Leu(5)]-OP was then synthesized, showing a predominant cis peptide bond conformation, as confirmed by NMR.

Synthesis of 4-Substituted-3-aminopiperidin-2-ones: Application to the Synthesis of a Conformationally Constrained TetrapeptideN-Acetyl-Ser-Asp-Lys-Pro

A new and practical synthetic strategy is developed for the synthesis of six-membered lactam-bridged dipeptides, 4-substituted-3-aminopiperidin-2-ones, featuring two key steps: (a) a diastereoselective addition of cuprate to (E)-alpha,beta-unsaturated ester (3) and (b) racemization-free reductive amination. On the basis of this methodology, conformationally constrained tetrapeptide N-acetyl-Ser-Asp-Lys-Pro (AcSDKP) (2) has been successfully synthesized from 3-amino-4-vinylpiperidin-2-one (22).

Synthesis of the Putative Structure of Tridachiahydropyrone

[reaction: see text] A short total synthesis of the putative structure of the marine natural product tridachiahydropyrone as a single enantiomer is described. Novel steps include a cuprate addition and cyclization to form a cyclohexanone ring and formation of the bicyclic pyrone with P(2)O(5) on Celite. The spectroscopic data obtained for compound 1 do not match those reported for tridachiahydropyrone; therefore, revision of the assigned natural product structure is warranted.

Enantioselective Approaches to Potential MetAP-2 Reversible Inhibitors

[reaction: see text] Enantioselective deprotonation of 4-substituted cyclohexanones and highly stereoselective conjugate addition of higher order mixed cuprates were the key steps in a concise synthesis of fumagalone-related molecules. The origin of the (low) biological activity of the new compounds as compared to fumagalone is briefly discussed.

The Synthesis of (−)-Isodomoic Acid C

The neuroactive algal metabolite (-)-isodomoic acid C, a kainoid amino acid, has been synthesized for the first time. Asymmetric dearomatizing cyclization of an aromatic amide using a chiral lithium amide base generates a bicyclic enone containing a pyrrolidinone ring with the relative and absolute stereochemistry of the target. A further 15 synthetic steps, including conjugate cuprate addition to the enone of a side chain precursor, a Ru-promoted oxidation of the phenyl ring to the C2-carboxylic acid substituent, a regioselective Baeyer-Villiger reaction, and an E-selective Horner-Wadsworth-Emmons reaction, elaborate the cyclization product into the target molecule.

Synthesis of the A,B,C‐Ring System of Hexacyclinic Acid.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of latanoprost diastereoisomers

A new synthesis of latanoprost diastereoisomers is described which utilizes a highly stereoselective Michael addition of higher-order cuprate to a chiral cyclopentenone derived from G-lactone in the crucial skeleton-forming step.

Synthesis of the hamigeran skeleton through an electro-oxidative coupling reaction

The tricyclic core of the hamigerans has been prepared through the use of a two-step electrochemical benzannulation reaction. The annulation proceeds through an initial conjugate addition of a phenethyl cuprate to 3-methylcyclopentenone with in situ silylation of the resulting enolate. Anodic oxidation effectively couples the pendant arene and the silyl enolether to produce a key intermediate for the synthesis of the natural products. Careful optimization revealed that the use of ‘alcohol-free’ conditions during the electrolysis was critical to obtain high yields of the annulated product. This method allowed the preparation of the tricyclic core of hamigeran A and B in just four steps from commercially available starting materials.