A FISCHER INDOLIZATION STRATEGY TOWARD THE TOTAL SYNTHESIS OF (-)-GONIOMITINE.

A Fischer indolization strategy toward the core of (-)-goniomitine is reported. Initial investigations into the Pd-catalyzed asymmetric allylic alkylation of dihydropyrido[1,2-a]indolone (DHPI) substrates are also discussed.

Enantioselective Pd-Catalyzed Allylic Alkylation Reactions of Dihydropyrido[1,2-a]indolone Substrates: Efficient Syntheses of (-)-Goniomitine, (+)-Aspidospermidine, and (-)-Quebrachamine.

The successful application of dihydropyrido[1,2-a]indolone (DHPI) substrates in Pd-catalyzed asymmetric allylic alkylation chemistry facilitates rapid access to multiple alkaloid frameworks in an enantioselective fashion. Strategic bromination at the indole C3 position greatly improved the allylic alkylation chemistry and enabled a highly efficient Negishi cross-coupling downstream. The first catalytic enantioselective total synthesis of (-)-goniomitine, along with divergent formal syntheses of (+)-aspidospermidine and (-)-quebrachamine, are reported herein.

Construction of Tertiary Chiral Centers by Pd-catalyzed Asymmetric Allylic Alkylation of Prochiral Enolate Equivalents.

The palladium-catalyzed decarboxylative allylic alkylation of enol carbonates derived from lactams and ketones is described. Employing these substrates with an electronically tuned Pd catalyst system trisubstituted chiral centers are produced. These stereocenters have been previously challenging to achieve using Pd complex/chiral P-N ligand systems.

Identification of alpha-substituted acylamines as novel, potent, and orally active mGluR5 negative allosteric modulators.

This Letter describes the identification of a series of novel non-acetylenic mGluR5 negative allosteric modulators based on the alpha-substituted acylamine structure. An initial structure-activity relationship study suggested that (R)-19b and (R)-19j might have good in vitro activity. When administered orally, these compounds were found to have an anxiolytic-like effect in a mouse model of stress-induced hyperthermia.

Selective syntheses of leuconolam, leuconoxine, and mersicarpine alkaloids from a common intermediate through regiocontrolled cyclizations by Staudinger reactions†Electronic supplementary information (ESI) available: Experimental details and procedures, compound characterization data, copies of 1H and 13C NMR spectra for new compounds. See DOI: 10.1039/c4qo00312hClick here for additional data file.

Selective syntheses of leuconolam, leuconoxine, and mersicarpine alkaloids bearing distinctive core structures were achieved through Staudinger reactions using a common intermediate. In the key cyclization step, water functioned like a switch to control which core structure to produce. The chemistry allowed for selective syntheses of the group of alkaloids from a simple intermediate through straightforward chemical operations.

Enantioselective synthesis of dialkylated N-heterocycles by palladium-catalyzed allylic alkylation.

The enantioselective synthesis of α-disubstituted N-heterocyclic carbonyl compounds has been accomplished using palladium-catalyzed allylic alkylation. These catalytic conditions enable access to various heterocycles, such as morpholinone, thiomorpholinone, oxazolidin-4-one, 1,2-oxazepan-3-one, 1,3-oxazinan-4-one, and structurally related lactams, all bearing fully substituted α-positions. Broad functional group tolerance was explored at the α-position in the morpholinone series. We demonstrate the utility of this method by performing various transformations on our useful products to readily access a number of enantioenriched compounds.

Enantioselective synthesis of α-quaternary Mannich adducts by palladium-catalyzed allylic alkylation: total synthesis of (+)-sibirinine.

A catalytic enantioselective method for the synthesis of α-quaternary Mannich-type products is reported. The two-step sequence of (1) Mannich reaction followed by (2) decarboxylative enantioselective allylic alkylation serves as a novel strategy to in effect access asymmetric Mannich-type products of "thermodynamic" enolates of substrates possessing additional enolizable positions and acidic protons. Palladium-catalyzed decarboxylative allylic alkylation enables the enantioselective synthesis of five-, six-, and seven-membered ketone, lactam, and other heterocyclic systems. The mild reaction conditions are notable given the acidic free N-H groups and high functional group tolerance in each of the substrates. The utility of this method is highlighted in the first total synthesis of (+)-sibirinine.

An Efficient Protocol for the Palladium-catalyzed Asymmetric Decarboxylative Allylic Alkylation Using Low Palladium Concentrations and a Palladium(II) Precatalyst.

Enantioselective catalytic allylic alkylation for the synthesis of 2-alkyl-2-allylcycloalkanones and 3,3-disubstituted pyrrolidinones, piperidinones and piperazinones has been previously reported by our laboratory. The efficient construction of chiral all-carbon quaternary centers by allylic alkylation was previously achieved with a catalyst derived in situ from zero valent palladium sources and chiral phosphinooxazoline (PHOX) ligands. We now report an improved reaction protocol with broad applicability among different substrate classes in industry-compatible reaction media using loadings of palladium(II) acetate as low as 0.075 mol % and the readily available chiral PHOX ligands. The novel and highly efficient procedure enables facile scale-up of the reaction in an economical and sustainable fashion.

Solid-phase total synthesis of (-)-apratoxin A and its analogues and their biological evaluation.

Two approaches for the solid-phase total synthesis of apratoxin A and its derivatives were accomplished. In synthetic route A, the peptide was prepared by the sequential coupling of the corresponding amino acids on trityl chloride SynPhase Lanterns. After cleavage from the polymer-support, macrolactamization of 10, followed by thiazoline formation, provided apratoxin A. This approach, however, resulted in low yield because the chemoselectivity was not sufficient for the formation of the thiazoline ring though its analogue 33 was obtained. However, in synthetic route B, a cyclization precursor was prepared by solid-phase peptide synthesis by using amino acids 13-15 and 18. The final macrolactamization was performed in solution to provide apratoxin A in high overall yield. This method was then successfully applied to the synthesis of apratoxin analogues. The cytotoxic activity of the synthetic derivatives was then evaluated. The epimer 34 was as potent as apratoxin A, and O-methyl tyrosine can be replaced by 7-azidoheptyl tyrosine without loss of activity. The 1,3-dipolar cycloaddition of 38 with phenylacetylene was performed in the presence of a copper catalyst without affecting the thiazoline ring.

Total synthesis of (-)-apratoxin A, 34-epimer, and its oxazoline analogue.

A concise and convergent total synthesis of the highly cytotoxic marine natural product apratoxin A is accomplished by an 18-step linear sequence. The high sensitivity of the thiazoline, bearing an adjacent beta-hydroxyl group at the C35-position, results in the assembly process requiring the inclusion of appropriate protecting groups and the careful optimization of all individual transformations. In the synthesis of 3,7-dihydroxy-2,5,8,8-tetramethylnonanoic acid (Dtena), the three reagent-controlled asymmetric reactions enables us to introduce four chiral carbon centers in a dihydroxylated fatty acid moiety. Formation of the hindered ester and sterically-unfavorable N-methylamide bonds were successfully demonstrated. The thiazoline in apratoxin A was constructed by Tf(2)O and Ph(3)PO-mediated dehydrative cyclization, and final macrocyclization was achieved between N-methylisoleucine and proline residues. Moreover, an oxazoline analogue and a C34 epimer of apratoxin A have also been elaborated in a similar approach. This synthetic route would enable assembly of other analogues differing in stereocenters of Dtena and their amino acids.

Total synthesis of apratoxin A.

[reaction: see text]. We have achieved a total synthesis of apratoxin A in which thiazoline formation was accomplished from the moCys containing amide 4 using PPh3(O)/Tf2O. Deprotection of the Troc and allyl ester in 17, coupling with tripeptide 3, and deprotection of the allyl ester and the Fmoc, followed by macrolactamization provided apratoxin A (1).