Asymmetric Synthesis of the Epimeric (3S)-3-((E)-Hex-1-enyl)- 2-methylcyclohexanones

The asymmetric rhodium-catalysed 1,4-addition of alkenylzirconium reagents to 2-cyclohexenone can be useful in the synthesis of 3-alkenyl-2-methylcyclohexanones, provided that formaldehyde is used in trapping the intermediate zirconium enolates. In this manner a four-step sequence leading to the two epimeric 3-hexenyl-2-methylcyclohexanones in enantiomeric form was developed.


Introduction
In the context of the development of CD-ring modified structural analogs of calcitriol, the hormonally active metabolite of vitamin D 3 [1], we required the epimeric ketones 4a and 4b (Scheme 1) in enantiopure form.Both cyclohexanones are being converted to derivatives in which the bicyclic CD-entity is replaced by a single six-membered D-ring and in which the hexenyl substituent serves as a latent aldehyde for the introduction of the A-ring [2].We describe herein in detail a synthesis of 4a and 4b featuring a highly enantioselective 1,4-addition of alkenylzirconocene to 2-cyclohexenone catalysed by the chiral rhodium complex generated from [Rh(cod)Cl] 2 and (R)-BINAP [3], followed by trapping of the O-enolate with formaldehyde.

Results and Discussion
The synthesis of the two epimeric cyclohexanones 4a and 4b rests on the asymmetric 1,4introduction of the hexenyl side chain on 2-cyclohexenone followed by trapping of the resulting metal O-enolate with an electrophilic reagent.Among several known enantioselective 1,4-additions of organometallic reagents to α,β-unsaturated ketones, we obtained the best results with the recently reported rhodium(I)-catalysed addition of alkenylzirconocene chlorides with BINAP as chiral ligand [3,4].This result also follows Nicolaou's report of the tandem reaction of the rhodium-catalysed asymmetric additions of alkenylzirconium reagents followed by trapping of the zirconium enolate by aldehydes [5].In our case, the 1,4-addition was performed on 2-cyclohexenone using (E)-1-hexenylzirconocene chloride [6], prepared from 1-hexyne and bis(cyclopentadienyl)zirconium chloride hydride (Cp 2 Zr(H)Cl or Schwartz reagent) in the presence of a catalytic amount of the Rh(I)-complex [Rh(cod)Cl] 2 and (R)-BINAP as a chiral ligand.As previously observed by Schwartz, we were unable to directly alkylate the intermediate zirconium O-enolate [7]; however, reaction with gaseous formaldehyde at -78 °C led, after acid work-up, to a 2.7:1 mixture (89% yield) of 1a and 1b, respectively [8], with an excellent ee (better than 96%) [9].The obtained mixture was readily separated by flash chromatography.The assignment of the transand cis-relationship to the alkyl substituents in the a-and b-series, respectively, rests on the analysis of NMR spectral data of 1a.The diequatorial orientation in 1a follows from the large vicinal J-value of 11. 7 Hz for the coupling between H a and H b .The same coupling in epimer 1b (5.3 Hz) is indicative of a cis-relationship (Figure 1).The absolute configuration was assigned on the basis of the results obtained by Oi and Inoue [3].The further conversion of 1a and 1b to 4a and 4b, respectively, first involves the reduction of the mesylates 2a and 2b, obtained by treatment with mesyl chloride and triethylamine in dichloromethane, to afford a mixture of the two epimeric alcohols.From 2a there was obtained in 95% yield a 1:4 mixture of 3aa and 3ab; from 2b there was obtained in 98% yield a 1:4 mixture of 3ba and 3bb, respectively.Again the structural assignment of the four isomeric alcohols rested on 1 H-NMR analysis (Figure 3).Within the trans-series distinction between 3aa and 3ab readily follows from the coupling constant pattern of the H a proton, which indicates an axial hydroxyl group in 3aa (cf.smaller sum of vicinal J-values for H a ) and an equatorial one in 3ab (cf.larger sum of vicinal J-values for H a ).Furthermore a characteristic long range W coupling is observed between H a and H b in 3aa.The structural assignment in the cis-series (3ba and 3bb) on the other hand rests on the observed nOe's in both derivatives, in particular between H a and the olefinic proton of the hexenyl side-chain in 3ba.Finally, Swern oxidation of both mixtures led to the desired cyclohexanones 4a and 4b [10].

Conclusions
The two epimeric cyclohexanones 4a and 4b have been obtained in four steps starting from 2cyclohexenone.The synthesis was based on the very efficient asymmetric 1,4-introduction of the 1hexenyl chain using alkenylzirconocene and a chiral rhodium complex.

(2R,3S)-3-((E)-Hex-1-enyl)-2-(hydroxymethyl)cyclohexanone (1a) and (2S,3S)-3-((E)-hex-1-enyl)-2-(hydroxylmethyl)cyclohexanone (1b).
Dry formaldehyde was prepared as follows: paraformaldehyde is predried overnight in vacuo at 60 °C in a three-necked 100-mL, round-bottom flask.The flask is equipped with an inlet for N 2 (dried over molecular sieves) and is connected via Teflon tubing to the reaction flask.The latter is then equipped with a CaCl 2 drying tube.The entire system is evacuated, filled with N 2 and the dried paraformaldehyde is depolymerised in a stream of N 2 by heating at 180 °C.To a suspension of Cp 2 ZrHCl (6.20 g, 24 mmol) in dry THF (80 mL) under Ar was added 1-hexyne (2.76 mL, 24 mmol) and the mixture was stirred at rt for 45 minutes to give a solution of 1-hexenyl-zirconocene chloride.In a two-necked 250-mL flask under Ar, [Rh(cod)Cl] 2 (247 mg, 1 mmol) and (R)-BINAP (749 mg, 1.2 mmol) were dissolved in dry THF (40 mL) and the solution was stirred at rt for 0.5 h.To the solution of rhodium catalyst, cyclohexenone (1.94 mL, 20 mmol) and the solution of 1-hexenylzirconocene chloride were added and the mixture was stirred at rt for 3 h.The reaction mixture was cooled to -78 °C and quenched with gaseous dry formaldehyde (see above).After warming up the mixture to rt, an aqueous saturated NH 4 Cl solution (3 mL) was added and the resulting mixture was stirred for 0.5 h.t-Butylmethyl ether (MTBE; 200 mL) was added and the precipitate formed was removed by filtration.
After removal of the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel (n-pentane/EtOAc, 83:17 to 75:25) to give cyclohexanones 1a (2.70 g) and 1b (