Synthesis of (2 S , 3 R )-2-allyl-3-furyl cyclopentanone. An enantioselective strategy towards the synthesis of phorbol

(1 S , 5 R )-5-(2-furyl)-2-oxocyclopentanecarboxylate 10 was synthesised by asymmetric conjugate addition of lithium difurylcyanocuprate to the chiral substrate 9 in high diastereoisomeric excess (>95 %). After transesterification, allylation and subsequent decarbomethoxylation, (2 S , 3 R )-2- allyl-3-furyl cyclopentanone 13 was obtained in >86 % ee.


Introduction
Phorbol 1 and its derivatives are toxic diterpenes found in the sap of plants of the family Euphorbiaceae. 1 The extracts and sap of these plants have been used in folkloric medicine as purgatives but their toxicological properties are very harsh 2 and tetradecanoyl phorbol acetate has been found to be a potent tumour promoter. 3Wender has succeeded in total synthesis of phorbol, 4 while other routes have yet to be completed. 5Thus far only Wender 6a and Shibasaki 6b have reported enantioselective strategies.
To date, we have made substantial progress in a synthetic approach to phorbol utilising the diastereocontrolled ultra-high pressure promoted intramolecular Diels-Alder reaction of furan (IMDAF) 7 to provide tricyclic adducts 2 with relative stereochemistry at 6 stereocentres and disposed functionality rendering them amenable to access phorbol.
The relative stereocontrol in the cycloaddition is a consequence of the trans-2, 3 relative configuration at the cyclopentanone and endo cycloaddtion of the Z-dienophile in the precursor 4 under high pressure conditions and subsequent regiocontrolled epimerisation of the cycloadducts 3 at standard pressure to furnish the desired relative stereochemistry (Figure 1).Thus, stereochemical information in the trans-2-substituted-3-furyl cyclopentanone precursor 4 is relayed and amplified during the sequence and, therefore, development of an enantiocontrolled approach to substrates of general structure 5 could provide precursors suitable for elaboration to the natural antipode of phorbol and its analogues.
The 1H NMR spectrum showed keto and enol tautomers in a ratio of 4:1 but the alternative diastereisomer could not be detected.X-ray crystallographic analysis confirmed that the 5-(2furyl) substituent and the ester group were trans to each other and that the adduct had the required absolute stereochemistry at C-1 and C-5 to access the natural antipode of phorbol (Figure 2). 12dduct 10 was efficiently transesterified using methanol in a sealed-tube at 100 °C, following Ikegami's method 13 to furnish the corresponding (1S, 5R) methyl ester 11 cleanly in good yield (91%) without epimerisation at C5 (Scheme 2) as confirmed by X-ray crystallographic analysis (Figure 2). 12In addition, this procedure allowed recovery of the chiral auxiliary in 85 % yield with >95 % ee.Subsequently, 11 was allylated following the procedure of Urban 14 to produce (1R, 5R) methyl-1-allyl-5-(2-furyl)-2-oxocyclopentanecarboxylate 12 as a single diastereoisomer in high yield (89 %), X-ray crystallographic analysis showing that the allyl group was trans to the furyl group (Figure 2  In conclusion, an experimentally straightforward enantioselective synthesis of (2S, 3R)-2allyl-3-(2-furyl)cyclopentanone (13) has been accomplished.This methodology will be applied to our enantioselective synthetic approach to phorbol.

Experimental Section
General Procedures.Preparation of chiral ester 7. A mixture of (1R)-5 (3 g, 7.54 mmol), methyl-2-oxocyclopentane 6 (1.06 mL, 8.54 mmol) and vanadyl (IV) acetate (212.5 mg, 1.16 mmol) in toluene (80 mL) was refluxed for 18 h.The reaction mixture was then filtered through Celite ® and the filtrate was concentrated in vacuo.The crude solid was recrystallised (DCM : light petroleum ether) to give the desired product as a colourless needles and the mother liquors were further purified by flash column chromatography (hexane : EtOAc, 1:1) to give an additional quantity of the desired product (3.6