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The benzoxazepine core is present in several kinase inhibitors, including the mTOR inhibitor 1. The process development for a scalable synthesis of 7-bromobenzoxazepine and the telescoped synthesis of 1 are reported. Compound 1 consists of three chemically rich, distinct fragments: the tetrahydrobenzo[f][1,4]oxazepine core, the aminopyridyl fragment, and the substituted (methylsulfonyl)benzoyl fragment. Routes were developed for the preparation of 3-fluoro-2-methyl-4-(methylsulfonyl)benzoic acid (17) and tert-butyl 7-bromo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (2). The processes for the two compounds were scaled up, and over 15 kg of each starting material was prepared in overall yields of 42% and 58%, respectively. A telescoped sequence beginning with compound 2 afforded 7.5 kg of the elaborated intermediate 5-(2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-2-amine dihydrochloride (6) in 63% yield. Subsequent coupling with benzoic acid 17 gave 7.6 kg of the target compound 1 in 84% yield. The pref...

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 variety of N-tert-butanesulfinyl imines were reduced with NaBH4 in THF containing 2% water to provide the corresponding secondary sulfinamides in high yield and diastereoselectivity. By using the same sulfinyl imine starting materials and changing the reductant to L-Selectride, the stereoselectivity could be efficiently reversed to afford the opposite product diastereomer in high yield and selectivity.

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.

The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated (R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide, showed EC50 of 10.3 nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described.

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.

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 ...

A new general route for preparing enantiomerically pure P-stereogenic phosphine oxides has been developed by exploiting the Staudinger reaction between racemic tertiary phosphines and an enantiomerically pure organoazide. The resulting phosphinimines are easily resolved by either crystallization or flash chromatography and serve as synthetic intermediates toward enantiomerically pure phosphine oxides.

(±)-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.

The resolution of a variety of (+/-)-P-stereogenic phosphines is achieved by exploiting the Staudinger reaction of a (+/-)-phosphine with enantiopure (1S,2R)-O-(tert-butyldimethylsilyl)isobornyl-10-sulfonyl azide. The resulting mixtures of diastereomeric phosphinimines are generally separable by fractional crystallization or flash chromatography. Subsequent acid-catalyzed hydrolysis provides the corresponding optically pure phosphine oxides in high yields.

[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.

A short five-step synthesis of (±)-2,2‘-bis(diphenylphosphino)-3,3‘-binaphtho[2,1-b]furan (BINAPFu, 1) starting from 2-naphthoxyacetic acid is reported. The resolution of BINAPFu 1 was possible using our newly developed resolution procedure for phosphines wherein (1S)-camphorsulfonyl azide was used to prepare the bisphosphinimine of BINAPFu via the Staundinger reaction. BINAPFu consistently outperformed BINAP in an asymmetric Heck reaction between 2,3-dihydrofuran and phenyl triflate.

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.

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.