Abstract
The 4-oxofurofuran lignan, (＋)-aptosimon (1), was synthesized from g-butyrolactone (9). To construct the two benzylic chiral center of (＋)-aptosimon (1), highly erythro selective aldol condensation and stereoconvergent SN1 intramolecular cyclization were used as the key reactions.

(＋)-Aptosimon has been isolated from Aptosimum spinescens 1) and its structure corrected to that of 1.

2) Since 4-oxofurofuran lignan is a small group in the furofuran series, 3) onlyˆve synthetic studies on the racemate have been reported. [4] [5] [6] [7] [8] Though many types of biological activity for furofuran lignan have been reported, 9, 10) e.g. antioxidative activity, antitumor activity, phosphodiesterase inhibition activity, and the eŠect on the central nervous system, the structure-activity relationship is unknown. To contribute to this biological research, and particularly to study the relationship between activity and degree of oxygenation of the furofuran structure, 1,2-oxygenated furofuran lignan has been synthesized. 11) As a continuation of this research, the 4-oxofurofuran lignan, (＋)-aptosimon (1), has been selected as the target compound in this work.

In this synthetic study, erythro or threo selectivity in the aldol condensation of b-[(aryl)(silyloxy) methyl]-g-butyrolactone 2 with piperonal via potassium enolate is also interesting. In our previous study, aldol condensation using the potassium enolate of bbenzyl-g-butyrolactone 3 and benzaldehydes showed erythro selectivity. 12 ) As a new substrate for this aldol condensation, oxygenated b-benzyl-g-butyrolactone 2 is employed. The erythro selectivity in this aldol condensation with 2 is very important in this project ( Fig.) .

The retrosynthetic analysis of (＋)-aptosimon (1) is shown in Scheme 1. (＋)-Aptosimon (1) could be obtained by the cyclization of 4 followed by oxidation. Tetrahydrofuran derivative 4 could be obtained from triol 5 by employing stereoconvergent SN 1 cyclization between oxygen at the 4 position and 1?-benzylic position of 5 in the presence of a catalytic amount of acid. Erythro aldol product 6 could be converted to triol 5 by protection, reduction, and selective removal of R1. The high erythro selectivity in the aldol condensation between g-butyrolactone 7 and piperonal would be required to give 6. Aldol product 8 could be converted to g-butyrolactone 7. This aldol product 8 would be obtained from gbutyrolactone 9 and piperonal; however, the erythro or threo selectivity would not be necessary in this step. g-Butyrolactone 9 can be obtained from L-glutamic acid. 13) The chiral center at the 2 position of (＋)-aptosimon (1) could be converted from the 2? position of 6, which could be obtained by erythro selective aldol condensation, and the other chiral center at the 6 position could be obtained by the stereoconvergent cyclization of triol 5.
Results and Discussion
The enantiomeric excess of the starting material was determined before tritylation to 9 as 99z ee by Mosher's method. The aldol condensation of gbutyrolactone 9 13) with piperonal, using lithium diisopropylamide, gave erythro aldol product 10 (43z) and threo aldol product 11 (43z). Although the erythro or threo selectivity at this stage was not important, the next step was performed from separated erythro aldol product 10 and threo aldol product 11. The erythro and threo isomers were determined by the coupling constant between 2-H and the benzylic proton. 14) After the hydroxy group of erythro 10 had been protected as a triisopropylsilyl ether (85z), resulting Scheme 1. Retrosynthetic Analysis of (＋)-Aptosimon (1). lactone 12 was subjected to LiAlH4 reduction and subsequent cleavage of the trityl ether in formic acidether to give triol 13 in 69z yield in 2 steps. NaIO 4 followed by Ag2CO3-celite oxidation of triol 13 gave g-butyrolactone 14 in 71z yield in 2 steps. This lactone 14 was exposed to the important aldol condensation requiring erythro selectivity. This erythro selectivity was achieved by using potassium bis(trimethylsilyl)amide as a base, giving erythro aldol product 15 as a single isomer in 84z yield. This erythro conˆguration was conˆrmed by the coupling constant between 2-H and benzylic 2?-H. 14) After the hydroxy group had been protected as a methoxymethyl ether in a quantitative yield, lactone 16 was transformed to triol 17 by LiAlH4 reduction and then by cleavage of the silyl ether with (n-Bu)4NF in 75z yield in 2 steps (Scheme 2).
Results and Discussion
Threo aldol product 11 was converted to lactone 20 in 54z overall yield by the same method as that described for the preparation of lactone 14. Aldol condensation of the potassium enolate of lactone 20 with piperonal also gave erythro aldol product 21 as a single isomer in 86z yield. These results show that the presence of a silyloxy group at the benzylic position of b-benzyl-g-butyrolactone did not reduce the erythro selectivity and that the stereochemistry at this benzylic position did not eŠect the erythro selectivity in the aldol condensation via potassium enolate.
Results and Discussion
After protecting the hydroxy group as a methoxymethyl ether in 82z yield, resulting lactone 22 was treated with diisobutylaluminum hydride and NaBH4 and then by (n-Bu) 4 NF to give triol 23 in a quantitative yield in 3 steps. The treatment of 22 with LiAlH4 gave a desilylated product (scheme 3).
Results and Discussion
SN1 intramolecular etheriˆcation of triols 17 and 23 was carried out by employing 10-camphorsulfonic acid as a catalyst, giving stereoconvergently tetrahydrofuran derivative 24 as a single isomer in 61z and 57z yield, respectively. The conversion of 17 to 24 proceeded smoothly, although that of 23 took a long time. At this stage, the construction of two benzylic chiral centers of (＋)-aptosimon (1) was accomplished. After pyridinium chlorochromate oxidation of 24 to aldehyde 25 in 73z yield, subsequent cleavage of the methoxymethyl ether in a 6 M aqueous HCl solution and tetrahydrofuran gave hemiacetal 26 in 82z yield. Finally, hemiacetal 26 was subjected to pyridinium chlorochromate oxidation to give (＋)-aptosimon (1) in 84z yield. The existence of NOE between the two benzylic protons and 8b-H supports this absolute conˆguration (Scheme 4).
Results and Discussion
(＋)-Aptosimon (1) was thus synthesized from gbutyrolactone 9, involving 14-15 steps in 6-10z overall yield. This is theˆrst synthesis of optically active 4-oxofurofuran lignan, and highly erythro selective aldol condensation of b-[(aryl)(silyloxy) methyl]-g-butyrolactone with piperonal, using KHMDS, was observed. The two benzylic chiral centers of (＋)-aptosimon (1) were constructed by this erythro selective aldol condensation and stereoconvergent SN1 intramolecular cyclization. 
840
S. YAMAUCHI and M. YAMAGUCHI
Experimental
All melting point (mp) data are uncorrected. NMR data were measured by a JNM-EX400 spectrometer, IR spectra were determined with a Shimadzu FTIR-8100 spectrophotometer, FABMS data were measured with a JMS-MS700V spectrometer, and optical rotation values were evaluated with a HORIBA SEPA-200 instrument. The silica gel used was 
(2 S,4 S )-2-[( S )-(3,4-Methylenedioxyphenyl) (triisopropylsilyloxy)methyl]-5-trityloxy-4-pentanolide (12).
To an ice-cooled solution of erythro10 (13.0 g, 0.026 mol) and 2,6-lutidine (6.56 ml, 0.057 mol) in CH2Cl2 (100 ml) was added TIPSOTf (7.69 ml, 0.029 mol). The reaction solution was stirred at 09 C for 1 h before addition of a sat. aq. NaHCO3 solution. The organic solution was separated, washed with a sat. aq. CuSO4 solution, sat. aq. NaHCO3 solution, and brine, and dried (Na2SO4 To an ice-cooled suspension of LiAlH4 (0.98 g, 0.026 mol) in THF (20 ml) was added a solution of lactone 12 (17.3 g, 0.026 mol) in THF (80 ml). The reaction mixture was stirred at 09 C for 1 h before additions of a sat. aq. MgSO4 solution and K2CO3. The mixture was stirred at room temperature for 30 min and thenˆltered. Theˆltrate was concentrated to give a crude diol. To a solution of this crude diol in ether (1000 ml) was added formic acid (1000 ml) at -109 C. After the reaction solution was stirred at -109 C for 10 min, EtOAc and H 2 O were added. The organic solution was separated, washed with a sat. aq. NaHCO3 solution and brine, and dried (Na2SO4) 
( 3 R ) -3 -[ ( S ) -( 3 , 4 -M e t h y l e n e d i o x y p h e n y l ) (triisopropylsilyloxy)methyl]-4-butanolide (14)
. A reaction mixture of triol 13 (3.51 g, 8.23 mmol) and NaIO 4 (1.93 g, 9.04 mmol) in MeOH (30 ml) was stirred at room temperature for 2 h. After its concentration, the resulting residue was dissolved in H2O and EtOAc. The organic solution was separated, washed with brine, and dried (Na2SO4). Concentration gave a crude hemiacetal. A reaction mixture of this crude hemiacetal and Ag2CO3-celite (9.04 g, containing ca. 9.04 mmol of Ag2CO3) in toluene (80 ml) was heated under re‰ux for 1 h. After the mixture wasˆltered, theˆltrate was concentrated. The residue was applied to silica gel column chromatography (EtOAc W hexane＝1 W 4) to give lactone 14 (2.28 g, 5.81 mmol, 71z) as a colorless oil. [ 50 g, 9 .99 mmol) in THF (10 ml) was added. The reaction solution was stirred at -759 C for 1 h, and then a sat. aq. NH 4 Cl solution was added. The organic solution was separated, washed with brine, and dried (Na2SO4). Concentration followed by silica gel column chromatography (EtOAc W hexane＝1 W 9) gave erythro aldol product 15 (2.90 g, 5.34 mmol, 84z) as a colorless oil. [ 
( 2 S , 3 R ) -2 -[ ( S ) -( M e t h o x y m e t h o x y ) ( 3 , 4 -m e th yle n e d io xy p h en y l)m e t h yl] -3-[( S )-(3 ,4 -methylenedioxyphenyl)(triisopropylsilyloxy)methyl]-4-butanolide (16).
A reaction mixture of alcohol 15 (2.56 g, 4.72 mmol), DIPEA (12.8 ml, 73.5 mmol), and MOMCl (2.80 ml, 36.9 mmol) in CH2Cl2 (5 ml) was stirred at room temperature for 16 h before the additons of MeOH, H2O, and CH2Cl2. The organic solution was separated, washed with 1 M aq. HCl solution, sat. aq. NaHCO3 solution, and brine, and dried (Na2SO4). Concentration followed by silica gel column chromatography (EtOAc W hexane＝1 W 9) gave MOM ether 16 (2.77 g, 4.72 mmol, 100z) as colorless crystals, mp 108-1099 C (MeOH). To an ice-cooled suspension of LiAlH 4 (0.18 g, 4.74 mmol) in THF (10 ml) was added a solution of lactone 16 (2.80 g, 4.77 mmol) in THF (20 ml). The resulting reaction mixture was stirred at 09 C for 30 min before additions of a sat. aq. MgSO4 solution and K 2 CO 3 . After stirring at room temperature for 30 min, the mixture wasˆltered, and the resultinĝ ltrate was concentrated to give a crude diol. To an ice-cooled solution of this crude diol in THF (30 ml) was added (n-Bu)4NF (5.25 ml, 1 M in THF, 5.25 mmol). After the reaction solution was stirred at 09 C for 1 h, a sat. aq. NH4Cl solution was added. The organic solution was separated, washed with brine, and dried (Na2SO4). Concentration followed by silica gel column chromatography (EtOAc W hexane ＝1 W 1) gave triol 17 (1.56 g, 3.59 mmol, 75z) as colorless crystals, mp 93-949 C (MeOH W iso-Pr2O＝1 W 4). To an ice-cooled solution of threo-11 (10.3 g, 0.020 mol) and 2,6-lutidine (5.16 ml, 0.045 mol) in CH2Cl2 (100 ml) was added TIPSOTf (5.96 ml, 0.022 mol). The reaction solution was stirred at 09 C for 1 h before addition of sat. aq. NaHCO3 solution. The organic solution was separated, washed with a sat. aq. CuSO4 solution, sat. aq. NaHCO3 solution, and brine, and dried (Na2SO4 To an ice-cooled suspension of LiAlH4 (0.68 g, 0.018 mol) in THF (10 ml) was added a solution of lactone 18 (12.1 g, 0.018 mol) in THF (60 ml). The reaction mixture was stirred at 09 C for 1 h before additions of a sat. aq. MgSO4 solution and K2CO3. The mixture was stirred at room temperature for 30 min andˆltered. The resultingˆltrate was concentrated to give a crude diol. To a solution of this crude diol in ether (900 ml) was added formic acid (900 ml) at -109 C. After the reaction solution was stirred at -109 C for 10 min, EtOAc and H2O were added. The organic solution was separated, washed with a sat. aq. NaHCO 3 solution and brine, and dried (Na 2 SO 4 ). Concentration followed by silica gel column chromatography (EtOAc W hexane＝1 W 1) gave triol 19 (4.69 g, 0.011 mol, 61z) as a colorless oil. [ (20) . A reaction mixture of triol 19 (2.30 g, 5.39 mmol) and NaIO4 (1.27 g, 5.94 mmol) in MeOH (30 ml) was stirred at room temperature for 2 h. After its concentration, the resulting residue was dissolved in H2O and EtOAc. The organic solution was separated, washed with brine, and dried (Na2SO4). Concentration gave a crude hemiacetal. A reaction mixture of this crude hemiacetal and Ag2CO3-celite (5.86 g, containing ca. 5.86 mmol of Ag2CO3) in toluene (80 ml) was heated under re‰ux for 1 h. After the mixture wasˆltered, theˆltrate was concentrated. The residue was applied to silica gel column chromatography (EtOAc W hexane＝1 W 4) to give lactone 20 (2.10 g, 5.35 mmol, 99z) as a colorless oil. [ To a solution of lactone 22 (2.11 g, 3.60 mmol) in toluene (20 ml) was added DIBAL-H (3.84 ml, 1 M in toluene, 3.84 mmol) at -759 C. After stirring at -759 C for 1 h, a 1 M aq. HCl solution was added. The organic solution was separated, washed with a sat. aq. NaHCO 3 solution and brine, and dried (Na2SO4). Concentration gave a crude hemiacetal. To an ice-cooled solution of this crude hemiacetal in EtOH (20 ml) was added NaBH4 (0.15 g, 3.97 mmol). The reaction mixture was stirred at room temperature for 2 h before addition of a 1 M aq. HCl solution. After neutralization with a sat. aq. NaHCO3 solution, the mixture was concentrated. The resulting residue was dissolved in EtOAc and H2O. The organic solution was separated, washed with brine, and dried (Na2SO4). Concentration gave a crude diol. To an ice-cooled solution of this crude diol in THF (20 ml) was added (n-Bu)4NF (3.80 ml, 1 M THF, 3.80 mmol). The reaction solution was stirred at 09 C for 1 h before addition of a sat. aq. NH4Cl solution. The organic solution was separated, washed with brine, and dried (Na2SO4 

{'paper_id': '28752580', 'title': 'Synthesis of (+)-aptosimon, a 4-oxofurofuran lignan, by erythro selective aldol condensation and stereoconvergent cyclization as the key reactions.', 's2_url': 'https://api.semanticscholar.org/CorpusID:28752580', 'source': 'S2ORC'}