Easy access to cis -1,3-disubstituted cyclopentane 1,4-diphosphines

cis -1-(Diphenylphosphino)-3-(diphenylphosphinomethyl)cyclopentane ( 13a ) and the corresponding dicyclopentylphosphino derivative 13b have been readily obtained in high yield from 2-cyclopentenone by a five-step sequence which takes advantage of the electrophilic character of positions 1 and 3 of 2-cyclopentenone to introduce the substituents, while their relative cis -configuration is established by diastereoselective hydrogenation of the mixture of isomeric alkenes 12a or 12b .


Introduction
As part of our current interest on the synthesis of carbocyclic analogs of cis-MCCPM (Figure 1), 1 we have recently described the synthesis of bisphosphinoyl compounds 5a-c in racemic form (Scheme 1). 2 Also, compound (6a) was prepared by dehydroxylation of 5a by using the Barton procedure.However, the synthesis of these compounds has serious drawbacks: (a) multi-step reaction sequence; (b) low overall yield; and (c) stereoselectivity problems in the crucial step (nucleophilic opening of epoxide 4 with the lithium derivative of methyldiphenylphosphine oxide, and (d) column chromatography of the acetates derived from the mixture of 5 and 7 was required to isolate the desired minor cis-stereoisomers.

Results and Discussion
Herein we describe a straightforward diastereoselective synthesis of 6a and the corresponding 3-(dicyclopentylphosphinoyl) derivative (6b), starting from 2-cyclopentenone (1) (Scheme 2) and their conversion into the corresponding diphosphines, 13a and 13b, respectively.Since positions 1 and 3 of 2-cyclopentenone are electrophilic, both substituents of the desired diphosphines (13) could be introduced by appropriate nucleophilic addition reactions.It is known that chlorodiphenylphosphine reacts with acyclic α,β-unsaturated ketones in anhydrous acetic acid to give a β-(diphenylphosphinoyl)ketone, 3 while we have recently described 2 the synthesis of 10a and 10b by using the same kind of reaction.Also, configurationally stable lithiated P-chiral disubstituted phosphine oxides have been added (Michael reaction) with high diastereoselectivity to 2-cyclopentenone. 4 Moreover, examples of nucleophilic additions of the lithium derivative of methyldiphenylphosphine oxide (9) and related derivatives to ketones are also known. 5nitial attempts to carry out the nucleophilic addition of the lithium derivative of 9 to cyclopentanone (10a) failed, probably due to the water present in compound (10a).When 10a was made anhydrous by azeotropic distillation of water with toluene and then it was reacted with the lithium derivative of 9, the corresponding addition product (11a) was obtained in high yield.
Only one stereoisomer, probably the one derived from the attack of the nucleophile on the less hindered carbonyl face, was observed.Once the diphenylphosphinoyl and diphenylphosphinoylmethyl substituents were introduced, the hydroxyl group of compound 11a was removed in order to establish the relative cisconfiguration of the substituents.To this end, compound 11a was dehydrated, which required quite drastic conditions (2 mol of concentrated H 2 SO 4 per mol of 11a, in THF under reflux for 3 days).The product thus obtained (93% yield) consisted of a mixture of regio-and stereo-isomers (12a) which was submitted without separation to hydrogenation under standard conditions.Fortunately, from the hydrogenation, only compound 6a was obtained in 83% yield.The relative cis-configuration of this compound was assigned by comparison of its 1 H and 13 C NMR data with those of a reference sample of 6a, prepared by the synthetic sequence of scheme 1, whose relative cis-configuration had unequivocally been established by X-ray diffraction analysis. 2oreover, the 1 H and 13 C NMR data of 6a differ from those of the corresponding transstereoisomer (8a, scheme 1). 2 Similarly, reaction of 10b 2 with the lithium derivative of 9 gave in good yield a mixture of 11b and its stereoisomer in an approximate ratio of 5:1, respectively.The main component was assumed to be 11b.Dehydration of the mixture of 11b and its stereoisomer gave a regio-and stereo-isomeric mixture of alkenes 12b, which on hydrogenation gave 6b, as a highly hygroscopic solid, whose melting point could not be determined.The relative cis-configuration of 6b was established by comparison of its 1 H and 13 C NMR spectra with those of 6a.Compounds 6a and 6b were reduced in high yield to the corresponding diphosphines 13a and 13b by reaction with trichlorosilane.
The new compounds 11a, 11b + stereoisomer, and 6b have been fully characterized by spectroscopic means (IR, 1 H, 13 C and 31 P NMR, MS) and elemental analysis, while diphosphines 13a and 13b have been characterized by NMR spectroscopy ( 1 H, 13 C and 31 P).In general, assignment of the NMR spectra has been carried out with the aid of COSY 1 H/ 1 H, HETCOR 1 H/ 13 C and NOESY experiments.
In conclusion, the unexpected stereoselective hydrogenation of the mixture of alkenes 12a and 12b to the cis-derivatives 6a and 6b, opens the way to the synthesis of a new family of cis-1,3disubstituted cyclopentane 1,4-diphosphines, which might be of interest to prepare new chiral catalysts.Work is in progress to prepare and isolate Rh (I) complexes derived from diphosphines 13a and 13b, to study their catalytic activity in hydrogenation reactions.

Experimental Section
General Procedures.Melting points were determined with a MFB 595010 M Gallenkamp melting point apparatus.500 MHz 1 H NMR spectra were recorded on a Varian VXR 500 spectrometer, 75.4 MHz 13 C NMR spectra were taken on a Varian Gemini 300 and 121.4 MHz 31 P NMR on a Varian Unity 300 Plus, always in CDCl 3 solution. 1H and 13 C NMR chemical shifts (δ) are reported in ppm with respect to internal tetramethylsilane (TMS) and 31 P NMR chemical shifts (δ) are reported in ppm relative to 85% H 3 PO 4 as external standard.The multiplicity of the signals is: s, singulet; d, doublet; t, triplet; m, multiplet.For the different compounds, the terms H α or H β are assigned to hydrogen atoms which are cis or trans relative to the reference substituent (usually at position 1), respectively.IR spectra were recorded on a FT/IR Perkin−Elmer spectrometer, model 1600; only significant absorption bands are given.Routine MS spectra were taken on a Hewlett−Packard 5988A spectrometer, the sample was introduced directly or through a gas chromatograph, Hewlett−Packard model 5890 Series II, equipped with a 30−meter HP-5 (5% diphenyl−95% dimethyl-polysiloxane) column and the electron impact technique (70 eV).Only significant ions are given: those with higher relative abundance, except for the ions with higher m/z values.NMR and routine MS spectra were performed at the Serveis Científico-Tècnics of the University of Barcelona, while elemental analyses were carried out at the Microanalysis Service of the IIQAB (CSIC, Barcelona, Spain).

c-3-(Diphenylphosphinoyl)-1-[(diphenylphosphinoyl)methyl]-r-1-cyclopentanol (11a).
To a cold (ice-bath) solution of methyldiphenylphosphine oxide (98%, 580 mg, 2.63 mmol) in anhydrous THF (15 mL) was added dropwise n-butyllithium (2.36 mL, 1.6M in hexanes, 3.78 mmol) and the suspension was stirred at 0ºC for 45 min.The suspension was cooled to -78ºC and a solution of anhydrous ketone 10a (747 mg, 2.63 mmol, azeotropic distillation of the water content with toluene in a Dean-Stark equipment) in THF (25 mL) was added dropwise.After 3 h at room temperature, the mixture was heated under reflux for 15 h.The mixture was allowed to cool to room temperature, saturated aqueous solution of NH 4 Cl (19 mL) was added, and the organic phase was separated and evaporated to dryness in vacuo.The residue was taken in H 2 O (35 mL) and the solution was extracted with CH 2 Cl 2 (3×37 mL).The combined organic phases were dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give 11a (950 mg, 72% yield) as an orange-brown viscous oil.The analytical sample of 11a was obtained as a colorless solid by crystallization (ethyl acetate), m.p. 179−180ºC.IR (KBr) 3425 (OH st), 1197, 1158, 1119 (P=O

cis-1-(Diphenylphosphinoyl)-3-[(diphenylphosphinoyl)methyl]cyclopentane (6a). a) Dehydration
of 11a to the mixture of alkenes 12a.To a solution of 11a (1.46 g, 2.92 mmol) in THF (60 mL), concentrated H 2 SO 4 (0.32 mL, 5.84 mmol) was added and the mixture was stirred under reflux for 3 days.The mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo.The residue was dissolved in CH 2 Cl 2 (30 mL), washed with NaHCO 3 (saturated aqueous solution, 3×20 mL), dried (Na 2 SO 4 ), filtered and concentrated to dryness in vacuo to give the mixture of alkenes 12a as a brown foamy solid (1.31 g, 93% yield).b) Hydrogenation of the mixture of alkenes 12a.To a solution of the mixture of alkenes 12a (557 mg, 1.16 mmol) in methanol (25 mL), Pd-C (5% Pd, 54% water content, 223 mg) was added and the mixture was vigorously stirred under hydrogen (1 atm) for 3 days.The suspension was filtered and the filtrate was concentrated to dryness in vacuo to give 6a (464 mg, 83% yield) as a pale yellow foamy solid, whose 1 H and 13 C NMR spectra coincide with those of a sample of 6a, previously obtained by a different synthetic procedure. 2