Search

The first total synthesis of aeruginosin 98B (1) was accomplished. The key step includes a highly diastereoselective Pd-catalyzed intramolecular asymmetric allylic alkylation (AAA) reaction of a diastereomeric mixture of allylic carbonates, which is enabled by the use of racemic phosphine ligand L1.

A six step synthesis and resolution of (±)-2,2′-bis(di-2-furylphosphino)-1,1′-binaphthalene 4 (TetFuBINAP) is described along with its use in asymmetric inter- and intramolecular Heck reactions.

The synthesis of (R)- and (S)-7,7′-dimethoxy-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene 5a and 5b is described. The phosphorus atoms in (S)-(−)-5b are shown to be slightly more basic than the phosphorus atoms in (S)-BINAP by comparing the magnitude of the 1J (31P–77Se) coupling constant in their respective diselenide derivatives. (S)-(−)-5b behaved similarly to (S)-BINAP in asymmetric Heck reactions.

This paper describes the chemistry presented during the Merck Frosst Centre for Therapeutic Research Lecture Award given at the 79th Chemistry in Canada Conference held in St. John's, Newfoundland in June 1996. The first section describes the synthesis of (+)-xestoquinone using an asymmetric palladium-catalyzed polyene cyclization as the key step that creates the C and D rings and the stereogenic centre (68% ee) in one step. Extensions of the work involving an in situ Suzuki reaction are presented. The synthesis of C2-symmetric biaryls and the synthesis of a recently isolated binaphthyl natural product is described using this new method. A new one-pot desilylation–oxidation procedure of silyl ethers is described in detail for the preparation of aldehydes and ketones directly without the need for the isolation of the alcohol intermediate. Finally, a highly diastereoselective (>97%) Diels–Alder reaction is presented using (+)-cis,cis-spiro[4.4]nonane-1,6-diol as a new chiral auxiliary. One of the alcohols is attached to a pivalate, the other to an acrylate, and the Diels–Alder reaction with cyclopentadiene provides only one adduct (by 1H NMR and HPLC) with the endo stereochemistry. Keywords: (+)-xestoquinone, asymmetric palladium-catalyzed polyene cyclization, in situ Suzuki reaction, desilylation–oxidation reaction, spirodiols, chiral auxiliaries.

The first total asymmetric synthesis of (+)-xestoquinone (1) has been accomplished in 68% ee by a palladium(0)-catalyzed polyene cyclization of naphthyl triflate 44 using (S)-(+)-BINAP as the chiral ligand. Attempts at an asymmetric polyene cyclization using the corresponding naphthyl bromide 41 gave poor enantioselectivities even in the presence of silver salts, thus exemplifying the effect of the coordination state of palladium on the enantioselectivity. A new method for the preparation of 6,7-dihydroisobenzofurans is also described using a [1,2]-Wittig rearrangement on a seven-membered cyclic ether precursor.

(±)-2,2′-Bis(diphenylphosphino)-3,3′-binaphtho[2,1-b]furan (BINAPFu) was synthesized from 2-naphthoxyacetic acid in a five-step sequence in 62% overall yield. A variety of reported resolution procedures for biaryl bisphosphines did not work with (±)-BINAPFu; thus, a new resolution method was developed, involving the Staudinger reaction of the aforementioned racemate of BINAPFu with an enantiopure camphor sulfonyl azide derivative. The resulting diastereomeric phosphinimines were separated by flash chromatography. Subsequent hydrolysis to the corresponding bis-phosphine oxide and trichlorosilane reduction provided enantiopure BINAPFu. The absolute stereochemical configuration of BINAPFu was established by X-ray crystallography. BINAPFu was compared with commercially available 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP) in Pd(0)-catalyzed intermolecular Heck reactions. Investigation of the Heck arylation of 2,3-dihydrofuran showed BINAPFu to be more efficacious than BINAP in dioxane at 30 °C. A variety of phosphorus selenides were prepared, and the 1JP-Se coupling constants measured, to obtain a comparative scale of parent phosphine basicity. The phosphorus atoms in BINAPFu were found to be electron deficient when compared with BINAP but slightly more electron rich than trifurylphosphine. Key words: naphthofurans, atropisomers, electron-deficient phosphines, asymmetric Heck reactions, Staudinger reaction.

[figure: see text] This paper demonstrates that both 1,2,2,6,6-pentamethylpiperidine (PMP) and 1,4-dioxane can act as hydride donors in palladium-catalyzed polyene cyclizations of 2 and 3. Studies using PMP-d3 and dioxane-d8 either incorporate a deuterium atom into the monosubstituted product or completely inhibit the hydride transfer so that the second ring closure occurs in high yield. Dabco is the best substitute for PMP.

Tipranavir, an important antiviral agent in clinical development for the treatment of HIV, is synthesized in 15 linear steps from readily available starting materials in 25% overall yield by utilizing Pd- and Mo-catalyzed DYKAT reactions to control the quaternary and tertiary stereogenic centers, respectively.