Enantioselective approach to the asymmetric synthesis of (6 R )- hydroxymethyl-5,6-dihydro-2 H -pyran-2-one. A formal synthesis of ( R )-argentilactone and total synthesis of ( R )-goniothalamin

The asymmetric synthesis of the (6 R )-hydroxymethyl-5,6-dihydro-2 H -pyran-2-one, a key intermediate in the formal synthesis of ( R )-argentilactone, and the total synthesis of ( R )- goniothalamin are described. Our aproach involved the Lemieux-Johnson oxidative cleavage, enantioselective Keck allylation, ring-closing metathesis and Wittig olefination.


Introduction
In 1977, Rúveda and coworkers reported the isolation of (R)-argentilactone (1) from Aristolochia argentia (Figure 1) 1 .Later, this natural pyranone was shown to have antileishmanial activity equivalent to the reference drug N-methylglucamine antimonate against Leishmania amazonensis 2 , as well as cytotoxic activity against mouse leukaemia cells (P-388) 3 .
(R)-Goniothalamin (2) was isolated in 1967 from the dried bark of Cryptocarya caloneura (Figure 1) 4 .It is a potential cytotoxic compound that has been demonstrated to have antiproliferative activities in a number of transformed cell lines including MCF-7 (breast carcinoma) and HeLa cells (human cervical carcinoma) 5,6 .Recent studies have indicated that gonithalamin induced apoptosis in JurKat T-cells from activation of two members of the family of cysteine proteases, caspases-3 and -7.Deregulation of apoptosis has now been implicated in the onset or progression of cancer 7 .Consequently, apoptosis represents an innate cellular defense against carcinogen-induced cellular damage by removing and inhibiting survival and growth of altered cells at different stages of carcinogenesis 7 .1) and (R)-goniothalamin (2).
Due to the interesting biological activity displayed by (R)-argentilactone ( 1) and (R)goniothalamin (2), several successful aproaches to these natural products have been reported 8 .Both substances contain the 5,6-dihydro-2H-pyran-2-one moiety and bear the (R)-configuration in their natural form.In this work, we describe the formal synthesis of (R)-argentilactone and the total synthesis of (R)-goniothalamin from benzyl alcohol featuring Lemieux-Johnson oxidative cleavage, enatioselective Keck allylation, ring-closing metathesis and Wittig reactions as the key steps (Scheme 1).

Results and Discussion
Our approach to these natural products centered around the olefin ring-closing metathesis reaction 9 of 7 that was planned to be prepared in enantiomerically enriched form from allylic alcohol 6 available in good yield and enantiomeric excess from benzyloxyacetaldehyde (5)  according to the catalytic asymmetric allylation protocol developed by Keck and coworkers 10 .
Benzyloxyacetaldehyde (5) was obtained in 78% overall yield from benzyl alcohol by treatment with sodium hydride and allyl bromide, followed by oxidative cleavage according to the Lemieux-Johnson protocol 11 .In the event, reaction of benzyloxyacetaldehyde (5) with allyltributyltin, under the influence of chiral (R)-BINOL/Ti(O i Pr) 4 complex generated in situ in CH 2 Cl 2 and in the presence of molecular sieves at -20 o C for 72 h afforded 6 in 78% yield and 94% ee 10 .Enantiomeric excess was determined by chiral GC (column Chirasil-DEX CB) after conversion of the 6 to acrylate ester 7 (acrylolyl chloride, Et 3 N and catalytic amount of DMAP in CH 2 Cl 2 at -23 o C, 86% yield).Ring-closing metathesis of 7 with Grubbs' catalyst 9 (10 mol%) in refluxing CH 2 Cl 2 for 12 h furnished the corresponding α,β-unsaturated δ-lactone 8 in 69% yield from 6 (Scheme 1).
At this point, our efforts were directed to the selective removal of the benzyl group in 8.While no reaction was observed with lithium naphthalenide 12 , lithium tert-butyldiphenyl (LiDBB) 13 and tin(IV) chloride 14 , hydrogenolysis with Pd(OH)/C 15 (1 atm of H 2 ) promoted the reduction of the α,β-unsaturated bond.Low yield was obtained using titanium(IV) chloride 16 , chromium(II) chloride/lithium iodide 17 and boron tribromide 18 .In our hands, utilization of ferric chloride 19 in CH 2 Cl 2 at rt achieved debenzylation of 8 to give 9 in 88% yield.The preparation of (6R)-hydroxymethyl-5,6-dihydro-2H-pyran-2-one (9) in 6 steps and 42% overall yield, starting from benzyl alcohol, constitutes a formal synthesis of both (R)-argentilactone (1) and (R)goniothalamin (2) as Tsubuki and coworkers have previously described the total synthesis of these natural pyranones from 9 which was prepared in 13 steps and 11% yield overall from (R)isopropylideneglyceraldehyde 20 .

Scheme 1
The efficient access to dihydropyranone 9 and our interest in the biological evaluation of (R)-goniothalamin (2) and some of its congeners led us to explore the route described by Tsubuki and coworkers to (R)-goniothalamin (2) 20 .Wittig olefination of the corresponding aldehyde (prepared from 9 by Swern oxidation and employed in the next step without further purification) with a solution of benzylidenetriphenylphosphorane (prepared by treatment of the corresponding triphenyl phosphonium chloride with n-BuLi in THF) afforded, after column chromatography on silica gel, a 1:3 molar ratio (53% yield) of (R)-goniothalamin (2) (13% yield) and its corresponding Z-isomer 10 (40% yield).In Table 1 are presented the 1 H-NMR and 13 C-NMR data of natural 4b and synthetic (R)-goniothalamin (2).For 1 H NMR, the chemical shifts were followed by multiplicity (s, singlet; d, doublet; dd, double dublet; ddd, double double dublet; t, triplet; q, quartet; m, multiplet) and coupling constant, J, reported in Hertz (Hz).
The stereochemistry of the olefination products was assigned based on the coupling constants between the olefinic hydrogens H-1' and H-2' (15.9 Hz for the minor isomer and 11.3 Hz for the major one) as well as by comparison of the 1 H-and 13 C-NMR data of the synthetic and natural 4b (R)-goniothalamin (2).
Despite the low level of diastereoselection found in the Wittig olefination, Tsubuki and coworkers 20 have already shown that the yield of (R)-goniothalamin (2) could be enhanced by photochemical isomerization of (Z)-10 in the presence of diphenyldisulfide to afford a 2:1 ratio of (R)-goniothalamin ( 2) and (Z)-10 in 65% yield.Additionally, recent results by Enders and coworkers 8c and Kalesse and coworkers 8f have demonstrated that the use o tributylphosphonium bromide and potassium tert-butoxide provides a better solution for the preparation of E isomer via Wittig olefination.
In this work, we have performed the formal synthesis of (R)-argentilactone (1) and the total synthesis of (R)-goniothalamin (2) which was obtained in 7 steps and 6% overall yield together with the correspondent (Z)-10 isomer (18% overall yield).This approach illustrates the utility of the enantioselective catalytic allylation to provide rapid access to synthetically useful α,βunsaturated δ-lactone from commercially available starting materials.

Experimental Section
General Procedures.Reagents and solvents are commercial grade and were used as supplied, with the following exceptions: a) ether and THF were destilled from sodium benzophenone ketyl; b) dichloromethane and triethylamine were distilled from calcium hydride and c) oxalyl chloride and dimethyl sulfoxide were distilled prior to use.Chromatographic separations were performed using 70-230 Mesh silica gel.Thin-layer chromatography was carried out on Macherey-Nagel precoated silica plates (0.25 mm layer thickness).IR spectra were obtained on Nicolet Impact 410 FT (film on KBr plates or KBr pellets).Melting points were measured with an Eletrothermal AZ9003 MK3 apparatus and are uncorrected. 1H NMR and 13 C-NMR data were recorded on a Varian Gemini 300 (7.0 T) or Varian Inova (11.7 T) spectrometer.Chemical shifts are reported in δ [ppm relative to (CH 3 ) 4 Si] for 1 H and CDCl 3 for 13 C-NMR.For 1 H-NMR, the chemical shifts were followed by multiplicity (s, singlet; d, doublet; dd, double dublet; ddd, double double dublet; t, triplet; q, quartet; m, multiplete) and coupling constant J reported in Hertz (Hz).High resolution mass spectra (HRMS) were measured on a VG Autospec-Micromass spectrometer.Chiral GC analyses were performed with capillary column CP-Chirasil-DEX CB fused silica WCOT (25m x 0.25 mm x 0.25 µm) and chiral HPLC analyses were performed with Welk-O 2 column (25 cm x 10 mm i.d.).Optical rotations were measured at 25 o C with Perkin-Elmer 241 instrument.
The organic layer was separated and the aqueous layer was extracted with dichloromethane (5 x 20 mL).The combined organic layers were dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure.The crude product was purified by column chromatography (ethyl acetate) to give (R)-6-hydroxymethyl-

Table 1 a
13H-NMR and13C-NMR spectral data of natural 4b and synthetic (R)-goniothalamin a Chemical shifts are reported in δ [ppm relative to (CH 3 ) 4 Si] for 1 H and CDCl 3 for 13 C NMR.