Oxidative allylic rearrangement of cycloalkenols: Formal total synthesis of enantiomerically pure trisporic acid B

Enantiomerically highly enriched unsaturated β-ketoesters bearing a quaternary stereocenter can be utilized as building blocks for the synthesis of natural occurring terpenes, i. a., trisporic acid and its derivatives. An advanced building block has been synthesized in a short reaction sequence, which involves an oxidative allylic rearrangement initiated by pyridinium dichromate (PDC) as the key step.

The enantiomeric excess of (−)-1c was monitored during the reaction, and after completion of the reaction the enantiomeric excess was determined to be >99% by GLC using a cyclodextrin modified stationary phase (LIPODEX E). The R-configuration at the stereocenter was established by chemical correlation [10,14].
The first step towards the synthesis of cyclohexenone (+)-7, which is the key building block in our synthesis, was the Scheme 3: Synthesis of key building block (+)-7.
incorporation of a C 2 unit into β-ketoester (−)-1c (Scheme 3). This was achieved by adding ethynyl magnesium bromide in THF at room temperature. The cyclohexenol (+)-6 can be isolated in 79% yield with a diastereomeric ratio of 96:4. However, the configuration at the newly created stereogenic centre need not be determined since it is destroyed in the next step, the PDC-catalyzed rearrangement to (+)-7. After 7 h, no starting material was detected by TLC, allowing the isolation of the desired cyclohexenone 7 in 91% yield. Although steric interference was believed to be a major obstacle of this process, this factor turned out to be unimportant. It is assumed, that the transition state during [3,3]-sigmatropic rearrangement is as shown in Scheme 3 [23,24], where the hydroxyl group is fixed in a pseudo-axial orientation, any other orientation would cause severe steric interaction with the 3-methyl group.
In conclusion, the key intermediate R-(+)-7, which can be utilized as an enantiomerically pure starting material in Suzuki's elegant protocol [25] towards the synthesis of racemic (9E)-trisporic acid B methyl ester (9E)-4, has been synthesized enantiomerically pure in a two step procedure starting from optically pure β-ketoester (−)-1c in an overall yield of 65%. Furthermore, we have shown that the oxidative allylic rearrangement of cycloalkenols can be carried out easily despite a high degree of functionalization and steric interactions. Therefore, this method should be applicable additionally to the synthesis of a great number of natural products such as cassiol [26,27].

Experimental
General. All air-and moisture-sensitive reactions were performed under an argon atmosphere in oven-dried glassware.
All solvents were dried over standard drying agents; THF was freshly distilled over sodium prior to use. Enzymatic reactions were monitored by Methrom 702 SM Titrino titrator, chiral GLC was performed with a LIPODEX E column (12 m), provided by Macherey&Nagel, Germany. Pig liver esterase (PLE) was purchased from Sigma. Reactions were monitored by TLC on silica gel 60 F254. Column chromatography was performed on silica gel 60 (70-230 mesh, ASTM). Melting points were determined with a Gallenkamp melting point apparatus in open capillaries and are uncorrected. Optical rotations were measured in solution at 589 nm with a PerkinElmer 241 polarimeter on a 1.00 dm cell. 1 H (200 MHz) and 13 C (50 MHz) NMR spectra were recorded with a Bruker AMX-200 with TMS as internal reference. Coupling constants J are given in Hz, the carbon multiplicities were assigned by DEPT 135 pulse sequence techniques (s = singlet, d = doublet, t = triplet, q = quadruplet). IR spectra were recorded with a Nicolet 510 FT-IR spectrometer, and GC-MS analysis was performed with a Finnigan MAT Magnum System 240, Varian GC 3400 DB 5. Elemental analysis was carried out with a PerkinElmer elemental analysator 240 at the University of Paderborn, Germany.

Methyl (−)-(1R)-1,3-dimethyl-2-oxocyclohex-3-ene-1carboxylate (1c).
Methyl 2-methyl-3-oxopentanoate (5) (3.42 g, 24.0 mmol) was added dropwise to a solution of sodium methoxide prepared from sodium (0.02 g, 0.9 mmol) and methanol (30 mL). The reaction mixture was cooled to 0 °C (ice bath), after which freshly distilled acrolein (1.34 g, 24.0 mmol) in methanol (8 mL) was added dropwise. Stirring was continued at 20 °C for approx. 12 h. The mixture was cooled in ice, and HCl (gas) introduced until the color changed to red (approximately after 2-3 h); stirring was then continued at 20 °C for about 12 h. The reaction mixture was filtered and evaporated to dryness. After the addition of a catalytic amount of hydroquinone the dark brown residue was heated at 180 °C for 1 h and then purified by distillation under reduced pressure to give (±)-1c (1.70 g, 40%). The kinetic resolution was carried out as follows: To phosphate buffer (pH 7.0, 0.1 M, KH 2 PO 4 / K 2 HPO 4 , 200 mL) was added (±)-1c (1.50 g, 8.2 mmol) and PLE (100 µL) and the resulting mixture stirred at 20 °C. The pH was maintained constant by periodic addition of NaOH (2 N). During the reaction, the ee value was monitored by GLC (LIPODEX E). After the reaction was complete, the mixture was acidified with aqueous HCl to pH 2 and extracted overnight using a continuous liquid/liquid extractor with Et 2 O. After drying of the organic layer (MgSO 4 ), the solvent was evaporated and the remaining oily residue distilled in a Kugelrohr apparatus to afford (−)-1c (590 mg, 39%); bp 88 °C/1.

Methyl (+)-(1R)-2-ethynyl-1,3-dimethyl-4-oxocyclohex-2ene-1-carboxylate (7)
. PDC (0.72 g, 1.90 mmol) was added to a solution of 6 (0.20 g, 0.90 mmol) in abs CH 2 Cl 2 (5 mL) in the presence of a catalytic amount of hydroquinone. The resulting suspension was heated under reflux in an argon atmosphere for 7 h. At the end of the reaction, ethyl acetate (1 mL) was added and the product separated from the chromium salts by passage through a short column of silica gel (petroleum/ethyl acetate 9:1) to give 7 (0.18 g, 91%) as a colorless oil. The product required storage in a freezer to prevent polymerization.