Intramolecular thermal stepwise [2 + 2] cycloadditions: investigation of a stereoselective synthesis of [n.2.0]-bicyclolactones

A new method for the synthesis of highly functionalised cyclobutenes.

are reported relative to an internal reference (tetramethylsilane) or residual proton signals of the solvent. Multiplets are indicated as s, singlet; d, doublet; t, triplet; q, quartet; qn, quintet; m, multiplet; br broad; app apparent. Coupling constants (J) are expressed in Hertz (Hz). With the exception of sidechains and protecting groups, atoms have been identified using the numbering system in the systematic name of the compound (ie. H1 is the hydrogen atom or atoms bonded to C1 of the skeletal structure). 13 C NMR chemical shifts are reported relative to the signal of the solvent. Routine mass spectra were carried out by the University of Bradford Centre for Chemical and Structural Analysis (Mr Andrew Healey) and were run on a Micromass Quattro Ultima spectrometer in the electron impact (EI), chemical ionisation (AP) or electrospray (ES) mode as stated. High resolution mass spectrometry (HRMS) was carried out by the EPSRC National Mass Spectrometry Facility, Swansea University. Optical rotations where carried out on a Perkin Elmer polarimeter, model 341. All moisture sensitive reactions were carried out under an inert atmosphere using dry argon or nitrogen. LCMS analysis was performed on a Waters e2695 Separation module using a HICHROM column (3.5RPB,15cm × 2.1mm), with a flow rate of 0.25 ml/min and mobile phase of water:MeOH:formic acid (5:5:0.1 at T=O mins,→1:9:0.1 at T=7mins, →5:5:0.1 at T=13 mins); eluting compounds were analysed by Waters 2998 PDA Detector (uv spectroscopy 210-400 nm) and QDA Detector (mass spectrometry).

Synthesis of Unbranched Alcohols and Amines (6a-f)
General procedure for protection of diols 1 Diol (1.4 eq) was added to a stirred suspension of NaH (60% dispersion in oil, 1 eq) in THF at 0 °C under a blanket of N 2 . The resultant mixture was stirred for 40 minutes, TBSCl (1 eq) was added and the reaction mixture stirred for a further 1 hour 45 minutes. The mixture was poured into saturated aqueous ammonium chloride solution and extracted with diethyl ether. The combined organic layers were dried (MgSO 4 ) and concentrated in vacuo to give the crude protected diols that were used without further purification. HO OH TBSO OH

General Procedure for Addition to Aldehyde
A solution of organo-lithium/Grignard reagent (1.3 eq) was added to a stirred solution of 4-((tertbutyldimethylsilyl)oxy)butanal (1 eq) in THF at -78 °C under a blanket of argon and stirred for 1-3 hour. The reaction was quenched with saturated aqueous ammonium chloride, extracted with EtOAc, washed with H 2 O, dried (MgSO 4 ) and concentrated in vacuo. The crude residue was purified via column chromatography.

Synthesis of Fumarates and Fumaramides
General procedure for coupling with fumarate EDCI (1.25 eq) was added to a stirred solution of ethyl or t butyl hydrogen fumarate (1.1 eq), alcohol/amine 6a-f (1 eq), DIPEA (1.25 eq) and DMAP (0.1 eq) in DCM under a blanket of N 2 and the reaction mixture stirred for 24 hours. The reaction mixture was washed with 5% aqueous HCl and saturated aqueous sodium bicarbonate, dried (MgSO 4 ) and concentrated in vacuo to give the crude material (that was purified via column chromatography to give the fumarates).

Boc Protection of Fumaramides
(Boc) 2 O (2 eq) was added to a stirred solution of fumaramide (1 eq), NEt 3 (1 eq) and DMAP (1 eq) in DCM and stirred at RT under a blanket N 2 for 16-24 hours. The reaction mixture was washed with 5% aqueous HCl and saturated aqueous sodium bicarbonate, dried (MgSO 4 ) and concentrated in vacuo. The crude residue was purified via column chromatography.

General Procedure for Enamine [2+2] cyclisation
Diethylamine (2 eq) was added to a stirred solution of aldehyde 7a-g (1 eq) and K 2 CO 3 (2 eq) in MeCN and stirred at RT under a blanket of N 2 for 24-48 hours. The reaction mixture was then filtered through Celite® and concentrated in vacuo. The crude cyclobutane 8 was dissolved in MeCN and MeI (5 eq) was added and the reaction mixture stirred at RT under a blanket of N 2 for 16-72 hours. The reaction mixture was concentrated in vacuo and the crude residue dissolved in MeCN and K 2 CO 3 (2 eq) was added and the reaction mixture heated at 60 °C for 24 hours. The reaction mixture was cooled and concentrated in vacuo. The crude residue was purified via column chromatography.