Asymmetric synthesis of (–)-leiocarpin A via (–)-(S)-goniothalamin employing Julia–Kocienski olefination

ABSTRACT A concise and enantioselective syntheses of antileukemic natural products such as (–)-(S)-goniothalamin and (–)-leiocarpin A has been accomplished in excellent yields. By employing reported conditions on suitable substrates via Julia–Kocienski olefination, intramolecular lactonization, and subsequently dehydroxylative olefination, (–)-(S)-goniothalamin was synthesized. Then Sharpless asymmetric dihydroxylation–intramolecular Michael addition on (–)-(S)-goniothalamin provided (–)-leiocarpin A. GRAPHICAL ABSTRACT

However, we aim for the synthesis of 3a from 2 and optimize the reaction conditions and the isolated compound subjected for characterization considering that the obtained compound might be 3a. Based on the single-cell x-ray crystallographic data, it was confirmed as (-)-leiocarpin A (3b). Compound 3b could be obtained by the in situ enantioselective dihydroxylation-intramolecular Michael addition methodology with 2 under the Sharpless asymmetric dihydroxylation conditions. [39] The key precursor (-)-(S)-goniothalamin (2) required for the synthesis could be obtained from β-hydroxy lactone 7. The stereocontrolled Julia-Kocienski olefination [40] of the aldehyde 11 with sulfone 10 [41][42] followed by a series of transformations involving ester hydrolysis, acetonide deprotection, and intramolecular lactonization would afford the β-hydroxy lactone 7.
The synthesis of (-)-(S)-goniothalamin (2) begins with Julia-Kocienski olefination of sulfone 10 and benzaldehyde (11). The sulfone 10 was prepared as per the literature procedure with minor modifications. [41] We have reported the synthesis 9 using Julia-Kocienski olefination [42] and it was studied in detail to get high E/Z selectivity under various conditions (Scheme 2). The Julia-Kocienski reaction was performed at various conditions: Barbier conditions [40] using LiHMDS and LDA and premetallic conditions with other bases such as NaH, KO t Bu, NaHMDS, and KHMDS (Table 1).
During the optimization of the suitable conditions for Julia-Kocienski olefination reaction we have concluded that the lithium enolate of sulfone 10 is stable at À 70°C. If the temperature is above À 5°C the sulfone 10 was undergone self-degradation. In the case of sodium or potassium enolates of sulfone were more stable. This might lead us to conclude that when the Barbier conditions with lithium are used, there is more E isomer than Z isomer. The Julia-Kocienski olefination reaction, when carried out with NaHMDS, causes the olefin to be formed in good yield (80%) but with diminished E/Z ratio. The use of bases such as LDA and NaH in the olefination reaction resulted in low conversion as well as deteriorated E/Z ratios. Though the use of KO t Bu, KHMDS provided the olefinic ester 9 with improved yields and diminished E/Z ratio were observed. However, when the olefination reaction was carried out with LiHMDS in THF, the product was formed in 90% (by HPLC) with 11.5:1 E/Z ratios. The crude olefinic ester 9 thus obtained was then purified by column chromatography and the required E olefin was isolated in 85% yield. Scheme 2. Synthesis of 9.

Scheme 1. Retrosynthetic scheme for (-)-leiocarpin A (3b).
After the synthesis of olefin in good yield, we have converted 9 to lactone 7 [43][44][45] via stepwise process involving acetonide deprotection (12a), hydrolysis of ester and intramolecular lactonization. When the reaction was carried out using TFA in acetonitrile/water 10:2 ratios, due to the extended conjugation epimerization [41,42] of C5-OH group, the acetonide deprotection of 9 was observed. The epimerization is inconsistent and always resulted in a mixture of 12a and 12b. The acetonide deprotection of 9, when attempted with other acids such as pyridine para-toluenesulfonate, trichloroacetic acid, PTSA, and 0.05 N HCl in solvents such as acetonitrile, THF, and toluene, gave greater content (range 4 to 10%) of epimer. However, when the acetonide deprotection is attempted with oxalic acid, the rate of reaction is very slow and about 20% of 9 was remained unreacted (Scheme 3) although the epimerization was well below 3% (by HPLC).
To circumvent the aforementioned issues, we altered the reactions and performed hydrolysis of olefinic ester 9 first under basic conditions, followed by acetonide deprotection and subsequent lactonization. Thus 9 was subjected for ester hydrolysis using aqueous NaOH solution in MeOH at reflux temperature followed by pH adjustment to afford the crude acid 8a. The crude acid 8a thus obtained was taken for acetonide deprotection using oxalic acid in aqueous acetonitrile to yield the dihydroxy olefinic acid 8. The 6-exo-trig cyclization of the crude dihydroxy olefinic acid 8 to lactone 7 is carried out in toluene at its boiling temperature, and the lactone 7 was isolated in overall 58% yield starting from 9. Our efforts to isolate pure 8a and 8 were not successful, as these products always contaminated with some percentages of lactone 7. Finally the elimination of hydroxyl group in 7 was done smoothly to yield (-)-(S)-goniothalamin (2) as per the reaction conditions reported by Kaneko and coworkers (Scheme 4). [46] The (-)-(S)-goniothalamin (2) thus obtained was purified by column chromatography, and the product was obtained in 80% yield. The spectral and analytical data of (-)-(S)goniothalamin (2) thus synthesized was found to be in accordance with the reported values  [2h] After the successful completion of (-)-(S)-goniothalamin (2) synthesis in overall good yield, we have directed our effort towards the conversion of 2 to (-)-leiocarpin A (3b). As described in our retrosynthetic strategy, the Sharpless asymmetric dihydroxylation on (-)-(S)-goniothalamin (2) followed by intramolecular hydroxylative Michael addition and heteroannulation reaction yielded (-)-leiocarpin A (3b) in a single-pot operation. Lin and coworkers [11b] reported the synthesis of (þ)-9-deoxygoniopypyrone (3a) by employing the dihydroxylation conditions on (þ)-(R)-goniothalamin (1) with AD-mix-α and obtained enantiomer of 6 and subsequently obtained the 3a. Similarly when employed the AD-mix-β on (þ)-(R)-goniothalamin (1) obtained the 6-Epi-goniodiol (6) under the Sharpless conditions. Intrigued by this literature report, we have attempted the Sharpless dihydroxylation of (S)-goniothalamin (2) with AD-mix-β under various conditions for the synthesis of (-)-leiocarpin A (3b).
The in situ Sharpless dihydroxylation-intramolecular hydroxylative Michael additionheteroannulation reaction initially was carried out using 1 mmol of olefin, 0.86 mmol of AD-mix-β, and 1 mmol of methane sulfonamide, and the required product (-)-leiocarpin A (3b) was obtained in about 5% after maintaining the reaction mixture over a period of 24 h at 0°C in a mixture of tert-butanol and water. However, when the reaction was carried out at 30°C for 24 h, by keeping the same molar ratio of substrate to reagents as described previously, the required product 3b was obtained in 25% yield. When this reaction was conducted with greater equivalents of AD-mix-β (1.24 mmol) and 1.25 mmol of methane sulfonamide, the complete consumption of the starting material was observed over a period of 20 h at 30°C and the isolated product was 65% yield (Scheme 5), characterized by spectral and analytical methods.
Then structure of (-)-leiocarpin (3b) is confirmed by spectral and analytical methods and compared with literature reported data. The specific optical rotation of 3b was recorded using ethanol and specific optical rotation is ½a� 25 D ¼ À 9:8 (c, 0.2 w/v, EtOH); further the structural elucidation was carried out with 2D-spectroscopic experiments such as nuclear Overhauser effect spectroscopy (NOESY), correlation spectrometry (COSY), and heteronuclear single quantum coherence (HSQC). Finally the single crystal of (-)-leiocarpin (3b) was generated from CHCl 3 and single-cell x-ray crystallography was recorded. The ORTEP diagram [47] of the product thus obtained conclusively proved the stereochemical orientation of the product, with configuration 1S,5S,7R,8S and confirmed the structure of 3b as (-)-leiocarpin A (Figure 2).

3.1]nonan-3one [(-)-leiocarpine A] (3b)
A 25-mL round-bottomed flask, equipped with a magnetic stirrer, was charged with 5 mL of tert-butyl alcohol, 5 mL of water, and AD-mix-β (2.0 g, 1.23 mmol), and methane sulfonamide (125 mg, 1.25 equiv based on 1 mmol of olefin) was added. The mixture was cooled to 0°C whereupon some of the dissolved salts precipitated. Goniothalamin (0.2 g, 1 mmol) was added at once, and the heterogeneous slurry was stirred vigorously at 0°C for 2 h and then allowed to reach room temperature, and it was stirred at that temperature for 20 h. Progress was monitored by TLC. Solid sodium sulfite (1.5 g) was added at room temperature and stirred for 30-60 min. Ethyl acetate (10 mL) was added to the reaction mixture, and after separation of the layers, the aqueous phase was further extracted with ethyl acetate (5 mL). The combined organic layers were washed with 2 N KOH. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give the crude product. This crude product purified by flash column chromatography (230-to 400-mesh silica gel) and eluted with 40% EtOAc/hexanes to afford 3b. Yield: 65%; white crystalline solid, mp 214-219°C.