Enantioselective synthesis of a substituted cyclopentanone with all-carbon quaternary stereocenter

The enantioselective synthesis of a substituted cyclopentanone with an all-carbon quaternary stereocenter was performed using an asymmetric nitroaldol condensation involving metal-complex catalysis and stereocontrolled silyl nitronate intramolecular [3+2] cycloaddition reaction in the key steps of the synthesis.


Introduction
Enantioselective construction of all-carbon quaternary stereocenters, i.e. centers in which the carbon atom bears four different carbon substituents, remains one of the most challenging subjects in modern synthetic chemistry because creation of such centers is complicated by steric repulsion between the carbon substituents. 1However there is a strong demand for the development of effective methods for the asymmetric synthesis of organic compounds containing such structural units which were revealed in a variety of natural compounds and bioactive molecules.In particular, many terpenoids, 1-5 alkaloids 1,6,7 and prostaglandin analogs 8 contain substituted cyclopentane fragments containing such chiral centers.
Currently, there are few direct C-C bond formation reactions that have been successfully applied for the construction of all-carbon quaternary stereocenters. 1,9,10Among them the enantioselective catalysis for allylic alkylation, 1,9-13 conjugation addition, 14,15 Diels-Alder reactions 16 and some other reactions have been used. 17,180][21] Nevertheless, using the substrate-controlled stereo-induction of an easily accessible stereogenic center is a very attractive strategy to create another one that is more difficult to establish by conventional methods.We surmised that the advantages of this approach could additionally be shown using an annulation reaction by intramolecular dipolar [3+2] cycloaddition of silyl nitronates generated from chiral unsaturated nitro compounds.Previously we have demonstrated 22,23 a strong stereocontrol of the formation of substituted cyclopentane and cyclohexane rings in such cycloadditions directed by a substituent on the corresponding nitronate derived from the starting nitroolefin (cf.refs 24,25) (Scheme 1).

Scheme 1
Herein we describe an application of the intramolecular silyl nitronate cycloaddition reaction in the synthesis of a highly enantioenriched ( ~96 % ee) substituted cyclopentanone with an all-carbon quaternary stereocenter in the molecule.

Results and Discussion
The key unsaturated nitroalcohol 1 (96 % ee, HPLC data) in the synthesis of the target compound was obtained by enantioselective Henry reaction of 4-methylpentenal 2 with nitromethane promoted by a catalytic system proposed earlier 26 for a similar process (Scheme 2).The absolute configuration of the newly obtained compound 1 was assigned by analogy with that of its homologue synthesized under the same reaction conditions. 26For further measurement of the enantiomeric excess by chiral HPLC, racemic nitroalcohol (±)-1 was obtained by a convenient procedure.

Scheme 2
The nitroalcohol 1 thus obtained was converted into silyl ether 3. Heating the latter with 1,1,1,3,3,3hexamethyldisilazane at 115 o C yields (via formation of nitronate 4) a rather labile cyclopentaisoxazolidine 5.The intramolecular cycloaddition proceeds highly stereoselectively with formation of the sole stereoisomer with trans-disposition of the OTBS substituent relative to the annulated isoxazolidine ring (cf.refs.22-25).Further transformation of cyclopentaisoxazolidine 5 consisted in isoxazolidine fragment opening upon the action of sodium methoxide as described earlier for related compounds (cf.ref. 23).In this case it gives a mixture of isomeric oximes 7a,b (anti-/syn-≈ 12 : 1, 1 H NMR data) through initial formation of plausible nitroso intermediate 6.The configuration of the C=N double bond in isomers 7a and 7b was established from 13 C NMR spectroscopic data, because it is known 27,28 that the oxime hydroxyl group exerts a substantial shielding effect on the adjacent α-carbon atom.
Deoximination of oximes 7a and 7b was carried out in the absence of a solvent by triturating with HIO4•2H2O in a mortar for a short time (cf.ref. 29) to give desired cycloalkanone 8 in moderate yields in both cases.Enantiomeric excess of ketone 8 is apparently not less than 96 % ee since chiral center which was initially in the starting nitroalcohol 1 and the newly induced quaternary stereocenter was not affected during the subsequent stages of the synthesis.
The relative configuration of cyclopentanone 8 substituents was additionally confirmed by 1D NOE experiment.Methyl group at C(2) shows considerable NOE with H-4 α-hydrogen (Fig. 1).Its trans-orientation to H-5 was established by comparison of coupling constants between hydrogens H-4 and H-5 and these constants values calculated by DFT method using B3LYP functional and aug-cc-pvtz basis set.

Conclusions
In summary, we have developed a highly diastereoselective and enantioselective synthesis of a substituted cyclopentanone containing an all-carbon quaternary stereocenter.To the best of our knowledge, this is the first example of the construction of a cyclopentane core with such a structural feature using an intramolecular [3+2] cycloaddition reaction of silyl nitronate generated from an available enantioenriched nitro compound.
We believe this methodology has potential to be utilized for the synthesis a number of natural cyclopentanoids.

Experimental Section
General.All reactions involving moisture-sensitive chemicals were carried out under pressure of argon with magnetic stirring.Commercially available chemicals were used without further purification.Solvents, including petroleum ether with bp 40-70 o C, were purified and dried using standard procedures.Starting 4-methylpent-4-enal was prepared according to known procedure. 30Melting points were measured with a Kofler hot-stage apparatus.HRMS spectra (ESI) were obtained with a Bruker micrOTOF II mass spectrometer.IR spectra were recorded with Bruker ALPHA-T spectrometer.Optical rotation values were measured on a Jasco P-2000 polarimeter. 1 H and 13 C NMR spectra were recorded in CDCl3 or C6D6 at 303 K on a Bruker AM-300 spectrometer.Chemical shifts were reported relative to CHCl3 (δH = 7.27 and δC = 77.0)or C6H6 (δ H = 7.17 and δ C = 128.6).TLC was performed on silica-coated glass plates (Merck, silica gel 60 F254).Visualization was accomplished by the plates with KMnO4 (0.5% in H2O).Flash chromatography performed on silica gel 60 (Merck, 230-400 mesh) with the indicated eluents.For analytical HPLC a chiral phase Kromasil  3 CelluCoat (column 4.6×150 mm) was used.Sonication was performed with an ultrasonic bath UZV-1/100-TN at 44 kHz (75 W).