Two simple and alternative approaches for the synthesis of anticancer active goniothalamin

Two alternative and straightforward routes were developed for the construction of ( R )-goniothalamin, a natural anticancer agent. The first method starts with ( R )-glycidol involving stereoselective (partial) reduction of alkyne and sulfoxide Julia-Lythgoe olefination as key steps. Second method deals with the synthesis of ( R )- goniothalamin from 2,3-O -isopropylidene- D -glyceraldehyde with partial reduction of nitrile and Still-Gennari stereoselective olefination as critical steps. These two methods with simple sequence of standard organic reactions may be adopted for the sophomore or junior's courses in organic chemistry


Introduction
Nature is the source for several bio-potent natural products and are the base for the development of numerous medicinally or pharmaceutically active compounds. 1Natural products with styryl δ-lactones possess interesting biological activities such as anticancer, antimicrobial, antimalarial, antilarvicidal and etc. 5,6 The genus Goniothalamus is a rich source of styryl 5-or 6-membered lactones. 6,7Goniothalamin (1) is prototypical example of styryl δ-lactones, was initially isolated in 1967 from dried bark of Cryptocarya caloneura (Scheff.). 8ater it was found in several plants, for example in Goniothalamus velutinus, 9 Cryptocarya moschata, 10 Bryonopsis laciniosa, 11 and Alyxia schlechteri. 12Goniothalamin was assigned initially (S)-configuration, 8 but, revised as (R)-configuration after the synthesis of both the enantiomers. 13Goniothalamin shows a variety of biological activities such as anti-cancer, 14,15,16 anti-microbial, 17,18 anti-inflammatory and antinociceptive, 19,20 antiproliferative, 20,21 plant growth inhibition activity, 22 larvae antifeedant or larvicidal, 23 etc. activities.The activity studies of 1 and its related compounds was revealed by the presence of their side chain. 7,21ince it was reported the synthesis of 1 in 1979 by Meyer 13 several reports appeared 16,21,[24][25][26][27][28][29][30][31][32] because of its significant biological properties.Some of the reported syntheses suffers from the requirement of large quantity of hazardous reagents 24,25 or expensive catalysts/auxiliaries 26 or with low overall yields 31,32 etc. Although, some efficient protocols were developed, it is still in demand to develop new/improved synthetic protocols to enhance the scope and possibility of starting materials with simple reactions.In this process we report here, two alternative routes for the synthesis of 1, involving simple reaction sequences.
The retrosynthetic approach (Scheme 1) revealed that the target compound 1 may be achieved in two different ways.In the first route lactone 2 is the key intermediate to furnish goniothalamin (1).The lactone 2 could be obtained from ester 3, and is possible to derive from the commercially available (R)-glycidol, 4. In another route, 1 may be obtained from the aldehyde 6, which in turn obtained from the 2,3-O-isopropylidine-D-glyceraldehyde 9. Scheme 1. Retrosynthetic analysis of (R)-goniothalamin (1).
At the beginning of the first route (Scheme 2) we have conducted the protection reaction of (R)glycidol (4) with p-methoxybenzyl bromide (PMB-Br) in the presence of NaH 33 and obtained PMB ether, 10 in 95% yield.Then the compound 10 was subjected for nucleophilic ring opening of epoxide with ethyl propiolate in the presence of n-BuLi and BF 3 •Et 2 O, 34 to give homopropargilic alcohol, 3 in an yield of 90%.
Compound 2 was converted into 1 by Swern oxidation followed by olefin synthesis in one-pot.In this connection several attempts were made for the preparation of 1.In one attempt, we have oxidized 2 under Swern oxidation conditions [(COCl) 2 , CH 2 Cl 2 , DMSO, Et 3 N, −78 °C, 30 min)] into its corresponding aldehyde A (Figure 1), and added a solution of B (Figure 1) in THF and KHMDS at −78 °C to afford 1 with only 20% yield (Julia-Kocienski olefination). 28,38In another attempt we have used sulfoxide modified Julia-Lythgoe procedure 39 to react Swern oxidation product (A) with benzyl phenyl sulfone (C) (Figure 1) to give goniothalamin (1) in 80% yield.This step revealed that the final step of the reported procedure for the construction of 1, by Pospíšil and Markó. 28We have started the second route (Scheme 3) by a Wittig olefination 40 reaction of 2,3-Oisopropylidene-D-glyceraldehyde (9) with benzyltriphenylphosphonium bromide in the presence of n-BuLi to obtain olefin, 8 in 90% yield as 8:2 ratio of E:Z isomers and the E-isomer has been separated by column chromatography was used for further step.The acetonide function of E-isomer (8) was uninstalled to 1,2-diol, 13 (96% yield) with 2M HCl in a mixture of H 2 O and THF (2:8) was subjected for selective protection (tosylation) of primary alcoholic function using (n-butyl) 2 SnO (catalytic amount), tosyl chloride and triethylamine (TEA) 41 to furnish compound 14 in 82% yield.Tosylate, 14 was used for nucleophilic substitution reaction with KCN in aq.ethanol 42 to furnish β-cyanohydrin, 7 (90% yield), was used to react with tertbutyldimethylsilyl chloride (TBS-Cl) in the presence of imidazole 40 to give TBS protected cyanohydrin, 15 in 95% yield.Scheme 3. Synthesis of 1 from 2,3-O-isopropylidene-D-glyceraldehyde (9).
The first method has been developed with the reaction sequence; etherification (protection), epoxide ring opening, partial and stereoselective reduction (Lindlar's alkyne hydrogenation), lactonization (ester formation), deprotection, oxidation and stereoselective (sulfone) olefin synthesis.The second method involves the Wittig olefination, ketal hydrolysis, tosylation (protection), nucleophilic replacement, silyl ether formation (protection), nitrile partial reduction, stereoselective (Still-Gennari) olefination and cyclic ester formation (lactonization).These straightforward sequences may be used as the teaching exercise for sophomore or junior's courses in organic chemistry to educate on anti-cancer agents.

Conclusions
In summary, we have developed two independent routes for the synthesis of goniothalamin, a significant anticancer agent.Simple reactions with high yields in each step, use of commercially available chiral starting materials and inexpensive reagents are the notable advantages of the present methods.These methods with simple sequence of a variety of organic transformations may be adopted for the sophomore or junior's courses in organic chemistry.
General.Solvents were dried over standard drying agents and distilled prior to their use.The reagents and starting materials were purchased from Aldrich and Acros were used without further purification unless otherwise stated.All moisture-sensitive reactions were carried out under nitrogen.Organic portion after workup was dried over anhydrous Na 2 SO 4 and concentrated below 40 °C in vacuo.All column chromatographic separations were performed using silica gel (Acme's 60-120 mesh). 1 H NMR (200 MHz & 300 MHz) and 13 C NMR (50 MHz and 75 MHz) spectra were measured with a Varian Gemini FT-200 MHz & Bruker Avance 300 MHz with tetramethylsilane (TMS) as an internal standard in CDCl 3 .Coupling constant (J) values were given in Hz.IR spectra were recorded on a Perkin-Elmer IR-683 spectrophotometer with NaCl optics.Optical rotations were measured with Horiba high sensitive polarimeter SEPA-300 at 25 o .Mass spectra were recorded on Agilent Technologies 1100 Series (Agilent Chemistation Software).

Goniothalamin [(R)-5,6-dihydro-6-styrylpyran-2-one] (1).
Compound 1 was synthesized from 2 by the reported procedure 28 as follows.To a stirred solution of oxalyl chloride (93 µl, 1.25 mmol) in CH 2 Cl 2 (5 ml) was added a solution of dimethylsulfoxide (132 µl, 1.87 mmol) in CH 2 Cl 2 (2 ml) at −78 o C under nitrogen atmosphere.After 15 min, (R)-5,6-dihydro-6-(hydroxymethyl)pyran-2-one (2) (80 mg, 0.63 mmol) was added and the reaction mixture was stirred for further 30 min at the same temperature.In another flask a solution of sulfoxide (benzyl phenyl sulfone) (110 mg, 0.62 mmol) in dry THF (6.2 ml, 0.1M solution) was cooled to −78 o C and lithium diisopropylamide (LDA) (340 µl, 2M solution in THF, 0.672 mmol) was added drop wise.The color of the reaction mixture changed from light yellow to orange red.After stirring the mixture at −78 o C for 30 min, aldehyde (A) obtained in Swern oxidation in THF was added drop wise and the mixture was stirred for an additional 2h at −78 o C. Benzoyl chloride (78 µl, 0.672 mmol) in dry THF (0.5 mL) was added.The resultant mixture was stirred for 30 min at −78 o C and then allowed to warm to r.t.over 1h and stirred for additional 30 min at r.t.Me 2 N(CH 2 ) 3 NH 2 (119 µl, 0.672 mmol) was added to this and the resultant suspension was stirred for 10 min at r.t.The mixture was diluted with 6 ml of Et 2 O/H 2 O (1:1) and the layers formed were separated.The aqueous layer was extracted with Et 2 O (3 x 10 ml).The combined organic layer was washed with brine, dried over Na 2 SO 4 and evaporated under reduced pressure to give the crude product, which was used without purification for the next step (reductive elimination).To a solution of SmI 2 (24.5 ml, 0.1M THF solution, 4 eq.) was added HMPA (425 µl, 2.48 mmol) and the mixture was cooled to −78 o C. The crude product (246 mg, 0.612 mmol) in dry THF (0.5 mL) was added drop wise and the resulting mixture was stirred at −78 o C for additional 30 min.Then, saturated aq.NH 4 Cl (15 ml) was added and the whole mixture was allowed to warm to r.t.The layers were separated and the aqueous phase was extracted with Et 2 O (3 x 20 ml).The combined organic layers were washed with 10% aq.Na 2 S 2 O 3 (15 ml), water (15 ml) and brine (15 ml), dried over Na 2 SO 4 and evaporated under reduced pressure.The crude product was then purified by silica gel CC using AcOEt:PE (2:8) as eluent to afford compound 1 as white solid with 80% yield in two sequential steps (Swern oxidation followed by sulfoxide Julia-Lythgoe olefination reaction).[α] D 25 = +168.2o (c = 1.5, CHCl 3 ) [lit. 48 Goniothalamin [(R)-5,6-dihydro-6-styrylpyran-2-one] (1).To a stirred solution of compound 5 (0.2 g, 0.86 mmol) in benzene (15 ml) was added a catalytic amount of p-toluenesulfonic acid (0.014 mg, 0.08 mmol) under nitrogen atmosphere and reaction mixture was refluxed at 90 o C for 1h.Then the reaction mixture was cooled to r.t., quenched by an addition of solid NaHCO 3 , the mixture was filtered and the solvent was evaporated under vacuum to obtain the crude residue, which was purified by flash CC on silica gel by eluting with AcOEt:PE (4:6) to afford goniothalamin (1) (0.134g, 78% yield) as a white solid.The spectroscopic data were identical with the data given at Section 2.6.

Figure 1 .
Figure 1.Structures of compounds A, B and C.