(+)-Inophyllum B and (+)-Calanolide A by Application of (−)-Quinine

Oct 13, 1993 - systems in the context of the asymmetric synthesis of anti-HIV-1 active Calophyllum coumarins. Combination of the IMA and MgI2-assisted...
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Concise Synthesis of Anti-HIV-1 Active (+)-Inophyllum B and (+)-Calanolide A by Application of (-)-Quinine-Catalyzed Intramolecular Oxo-Michael Addition Etsuko Sekino, Takuya Kumamoto, Tomohiro Tanaka, Tomoko Ikeda, and Tsutomu Ishikawa* Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan [email protected] Received November 30, 2003

(-)-Quinine-catalyzed intramolecular oxo-Michael addition (IMA) of 7-hydroxy-5-methoxy-8tigloylcoumarins was developed for the enantioselective construction of 2,3-dimethyl-4-chromanone systems in the context of the asymmetric synthesis of anti-HIV-1 active Calophyllum coumarins. Combination of the IMA and MgI2-assisted demethylation of the 5-methoxy group along with isomerization of the formed chromanone systems as key steps successfully led to the concise synthesis of (+)-inophyllum B and (+)-calanolide A, possible candidates for AIDS drugs. Further examination of the asymmetric IMA with cinchona alkaloids lacking a methoxy group on the quinoline skeleton suggested the influence of the methoxy substituent on stereoselectivity at the stereogenic centers of the chromanone systems. Introduction In 1992 Boyd and co-workers1 isolated (+)-calanolide A [(+)-1] as a strong anti-HIV-1 active coumarin, which has recently been under investigation as a possible candidate for an AIDS drug at the clinical level in the United States,2 together with its related 4-propylcoumarins from Calophyllum lanigerum var. austrocoriaceum (Guttiferae). Nearly at the same time Patil et al.3 reported the isolation of (+)-inophyllum B [(+)-2], a structurally related 4-phenylcoumarin to (+)-1, from C. inophyllum as the most active component for inhibition against HIV-reverse transcriptase among the isolated coumarins. These Calophyllum coumarins were basically composed of three skeletal rings, coumarin, 2,2dimethylchromene, and 2,3-dimethyl-4-chromanol (or 2,3dimethyl-4-chromanone).4 Among the three the chromanol ring, especially with three sequential (R,S,S) stereochemistries at the 10, 11, and 12 positions in (+)-1 and (+)-2, has been suggested to be mostly responsible for the antiviral activity.1,3,5

Although no reports have appeared on the enantioselective total synthesis6 of (+)-inophyllum B [(+)-2], (+)-

calanolide A [(+)-1] had been successfully synthesized by either the chiral borane-participated allylation7 of 8-formylcoumarin derivative or by enzymatic optical resolution8 of 8-(3-hydroxy-2-methylpropionyl)coumarin. Furthermore, (-)-calanolide A [(-)-1] had been prepared through the Pd-catalyzed asymmetric O-allylation9 of 7-hydroxycoumarin, in addition to the above chiral boraneparticipated synthesis.7 It would be expected that 2,3dimethyl-4-chromanol systems can be easily obtained from the corresponding chromanone systems by hydride reduction.10 Thus, we planned the enantioselective total synthesis of these coumarins through chiral chromanone(1) Kashman, Y.; Gustafson, K. R.; Fuller, R. W.; Cardellina, J. H., II; McMahon, J. B.; Currens, M. J.; Buckheit, R. W., Jr.; Hughes, S. H.; Cragg, G. M.; Boyd, M. R. J. Med. Chem. 1992, 35, 2735-2743; 1993, 36, 1110. (2) Xu, Z.-Q.; Hollingshead, M. G.; Borgel, S.; Elder, C.; Khilevich, A.; Flavin, M. T. Bioorg. Med. Chem. Lett. 1999, 9, 133-138. Rouhi, A. M. Chem. Eng. News 2003, Oct. 13, 93. (3) Patil, A. D.; Freyer, A. J.; Eggleston, D. S.; Haltiwanger, R. C.; Bean, M. F.; Taylor, P. B.; Caranfa, M. J.; Breen, A. L.; Bartus, H. R.; Johnson, R. K.; Hertzberg, R. P.; Westley, J. W. J. Med. Chem. 1993, 36, 4131-4138. (4) Ishikawa, T. Heterocycles 2000, 53, 453-474. (5) Zembower, D. E.; Liao, S.; Flavin, M. T.; Xu, Z.-Q.; Stup, T. L.; Buckheit, R. W., Jr.; Khilevich, A.; Mar, A. A.; Sheinkmann, A. K. J. Med. Chem. 1997, 40, 1005-1017 and references therein. (6) (a) Palmer, C. J.; Josephs, J. L. Tetrahedron Lett. 1994, 35, 5363-5366. Palmer, C. J.; Josephs, J. L. J. Chem. Soc., Perkin Trans. 1 1995, 3135-3152. (b) Gao, Q.; Wang, L.; Liang, X. T. Chin. Chem. Lett. 2002, 13, 714-716. (7) Deshpande, P. P.; Tagliaferri, F.; Victory, S. F.; Yan, S.; Baker, D. C. J. Org. Chem. 1995, 60, 2964-2965. Deshpande, P. P.; Baker, D. C. Synthesis 1995, 630-632. (8) Khilevich, A.; Mar, A.; Flavin, M. T.; Rizzo, J. D.; Lin, L.; Dzekhtser, S.; Brankovic, D.; Zhang, H.; Chen, W.; Liao, S.; Zembower, D. E.; Xu, Z.-Q. Tetrahedron: Asymmetry 1996, 7, 3315-3326. (9) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 90749075. (10) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 54545459. 10.1021/jo035753t CCC: $27.50 © 2004 American Chemical Society

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Synthesis of (+)-Inophyllum B and (+)-Calanolide A SCHEME 1. Synthetic Plan of Calophylum Coumarins through IMA of 7-Hydroxy-8-tigloylcoumarins 4

coumarins 5, which could be prepared by intramolecular oxo-Michael addition (IMA)11 of 7-hydroxy-8-tigloylcoumarins 4 derived from appropriate 4-substituted 5,7dioxygenated coumarins 3 in the presence of a chiral amine such as (-)-quinine, as a key step (Scheme 1). In the preliminary communications12,13 we reported that (-)-quinine effectively catalyzed the IMA of 7hydroxy-8-tigloylcoumarins to afford cis-2,3-dimethyl-4chromanone systems with high enantioselectivity and moderate diastereoselectivity, especially when chlorobenzene (PhCl) was used as a solvent.13 Total synthesis of (+)-calanolide A [(+)-1] was, thus, achieved by application of the (-)-quinine-catalyzed asymmetric IMA;14 however, the synthetic route was not practical because of the long path from 1,3,5-trimethoxybenzene (6) (13 steps in 3.5% overall yield, see Scheme 2). In the course of our synthetic approaches to (+)-inophyllum B [(+)-2] we observed the possibility of shortening the original route by application of magnesium iodide (MgI2)-assisted demethylation. In addition, examination of the asymmetric IMA with use of other cinchona alkaloids suggested that the stereoselectivity in the chromanone construction could be influenced by not only the presence of a methoxy group in the catalyst used but also the acidity of their conjugated acids. In this paper we present the concise synthesis of both (+)-inophyllum B [(+)-2] and (+)-calanolide A [(+)-1], and the catalytic ability of cinchona alkaloids to form the asymmetric IMA. Results and Discussion We at first planned to use a methoxy group for the protection of a phenolic function (R1 ) Pr; R2 ) R3 ) Me in Scheme 1) in the synthesis of (+)-calanolide A [(+)-1]. However, as mentioned in the previous communication,14 failure in trials for the preliminary demethylation of the 5-methoxy group in a chromanone-coumarin 9 to the (11) At the start of our synthetic study racemic 1 had been synthesized under the same strategy [see ref 6b and: Chenera, B.; West, M. L.; Finkelstein, J. A.; Dreyer, G. B. J. Org. Chem. 1993, 58, 5605-5606]. (12) Ishikawa, T.; Oku, Y.; Tanaka, T.; Kumamoto, T. Tetrahedron Lett. 1999, 40, 3777-3780. (13) Tanaka, T.; Kumamoto, T.; Ishikawa, T. Tetrahedron: Asymmetry 2000, 11, 4633-4637. (14) Tanaka, T.; Kumamoto, T.; Ishikawa, T. Tetrahedron Lett. 2000, 41, 10229-10232.

SCHEME 2. Previous Total Synthesis of (+)-Calanolide A [(+)-1] Using the TIPS Group as a Phenol Protection14

5-hydroxycoumarin 10 had obliged a change in the original strategy to an alternative route (Scheme 2). Thus, an unsymmetrical butyrophenone 11 protected with the triisopropylsilyl (TIPS) group at one ortho phenolic position was prepared from 6. Successive reactions of selective deprotection of the o-methoxy group of 11, cyclization to coumarin, and 2,2-dimethylchromene ring construction after cleavage of the TIPS function afforded the chromene-coumarin 12. Demethylation of the methoxy group in 12 afforded the 7-hydroxy-8tigloylcoumarin, which was subjected to the (-)-quininecatalyzed asymmetric IMA to give the desired chromenechromanone-coumarin 13. After isomerization of the cis2,3-dimethyl-4-chromanone system in 13 to the trans system, the hydride reduction of the formed transchromanone system afforded (+)-calanolide A [(+)-1] with correct stereochemistries at the stereogenic centers.14 Total Synthesis of (+)-inophyllum B [(+)-2]. Historically, (+)-inophyllum B [(+)-2] and its related 4-phenylcoumarins were isolated as anti-piscicidal principles from C. inophyllum 25 years ago15 before their isolation from the same plant as anti-HIV-1 active coumarins by Patil et al.3 We had planned to synthesize (+)-2 according to the original retrosynthetic strategy using a methoxy function as the phenol protection (R1 ) Ph, R2 ) R3 ) Me) as shown in Scheme 1. Thus, 7-hydroxy-5-methoxy4-phenyl-8-tigloylcoumarin (16) as a precursor for (-)quinine-catalyzed IMA was prepared from phloroglucinol (14) by successive reactions of the Pechmann reaction of 14 with ethyl 3-phenyl-3-oxopropionate in the presence of triflic acid, conventional methylation, the FriedelCrafts acylation of 5,7-dimethoxycoumarin 15 with tigloyl chloride, and regioselective demethylation at the 7-posi(15) Kawazu, K.; Ohigashi, H.; Mistui, T. Tetrahedron Lett. 1968, 2383-2385. Kawazu, K.; Ohigashi, H.; Takahashi, N.; Mistui, T. Bull. Inst. Chem. Res. Kyoto Univ. 1972, 50, 160-167; Chem. Abstr. 1973, 78, 13744f.

J. Org. Chem, Vol. 69, No. 8, 2004 2761

Sekino et al. SCHEME 3. Preparation of 7-Hydroxy-5methoxy-4-phenyl-8-tigloylcoumarin (16)a

a Reagents and conditions: (a) (i) ethyl 3-phenyl-3-oxopropionate/TfOH, rt, 18 h, (ii) Me2SO4/K2CO3/acetone, rt, 16 h (71% in 2 steps); (b) tigloyl chloride/SnCl4/CH2Cl2, 8 °C, 3 days (67%); (c) MgI2/K2CO3/PhH, reflux, 4 h (84%).

SCHEME 4. (-)-Quinine-Catalyzed IMA of 16 and Chemical Correlation of the Demethylated Productsa

a Reagents and conditions: (a). (-)-quinine/PhCl, 4 °C, 33 h [cis(+)-17 (70%, 97% ee), trans-(-)-17 (23%, 52% ee)]; (b) MgI2/K2CO3/ PhH, reflux, 14 days: [cis-18 (37%), trans-18 (42%)]; (c) CH2N2 (62%, 96% ee on trans-18; 64%, 95% ee on cis-18).

tion with MgI2 in the presence of potassium carbonate (K2CO3) in 40% overall yield (Scheme 3). Next, we examined the asymmetric IMA of the tigloylcoumarin 16 (Scheme 4). Treatment of 16 with a catalytic amount (10 mol %) of (-)-quinine in PhCl13 at 4 °C for 33 h gave cis-(+)-chromanone-coumarin cis-(+)-17 and trans-(-)-derivative trans-(-)-17 in 3:1 ratio in 93% overall yield. The stereochemistries of the 2,3-dimethyl4-chromanone system in these cyclized products were determined by coupling constants between the methine protons at C2 and C3 positions in the chromanone system (J ) 3.4 Hz in cis-(+)-17; J ) 11.2 Hz in trans-(-)-17) in the 1H NMR spectra. Their enantiopurities could be established by chiral HPLC analysis. Excellent asymmetric induction (97% ee) was, as expected, observed in cis-(+)-17, whereas trans-(-)-17 showed moderate enantiopurity (52% ee). We had already reported the MgI2-assisted epimerization of the cis-2,3-dimethyl-4-chromanone system to the trans system in the total synthesis14 of (+)-calanolide A [(+)-1] nearly without loss of enantiopurity. However, trials for epimerization on the 2,3-dimethyl-4-chromanone system in cis-(+)-17 led to inconsistent results in the absence of an acid scavenger, in which phenolic chromanone-coumarins 18 were detected as over-reaction products even in minute amounts in some cases of 2762 J. Org. Chem., Vol. 69, No. 8, 2004

prolonged reactions. These findings gave us an important clue for the concise synthesis of Calophyllum coumarins using a methoxy function as a possible protecting group. We, thus, precisely examined simultaneous demethylation of the 5-methoxy group in cis-(+)-17 and the epimerization of the cis-chromanone system. Refluxing cis-(+)-17 in benzene for a longer time (14 days) with MgI2 in the presence of K2CO3 gave the desired phenolic trans-chromanone-coumarin trans-18 and the corresponding cis-derivative cis-18 in 42% and 37% yields, respectively. Estimation of their enantiopurities (96% ee on trans-18 and 95% ee on cis-18) after methylation with diazomethane indicated that no racemization occurred during the reaction. Interestingly, coumarin obtained in the methylation of the trans phenolic coumarin trans-18 was found to be an enantiomer of the trans-chromanone-coumarin trans(-)-17 produced in the (-)-quinine-catalyzed IMA of 16. We had reported that (2R,3S)-configuration at the stereogenic centers was predominantly produced in the enantioselective construction of cis-2,3-dimethyl-4-chromanone systems by (-)-quinine-catalyzed asymmetric IMA of 7-hydroxy-8-tigloylcoumarins.13,14 These facts allowed us to assign the same absolute configurations in cis-(+)-17, which could be supported by the following reaction sequences to (+)-inophyllum B [(+)-2] (vide infra). The MgI2-assisted epimerization of a 2,3-dimethyl-4-chromanone system should occur at the C3 position. Therefore, the formation of enantiomeric trans-chromanone systems between those in the IMA and in the epimerization indicated that the absolute stereochemistries of the IMA-derived trans-chromanone trans-(-)-17 could be (2S,3S)-configuration.16 For 2,2-dimethylchromene ring construction we, at first, tried stepwise cyclization through 1,1-dimethylpropargylation of the phenolic function in trans-18 and then Claisen rearrangement according to our synthetic procedure14 for (+)-calanolide A [(+)-1]; however, ineffective etherification (9%) in the former reaction was observed despite satisfactory cyclization (80%) in the latter step. Thus, we alternatively examined phenylboronic acid-assisted chromene ring formation reported by Lau et al.17 (Scheme 5). Treatment of trans-18 with senecioaldehyde in the presence of phenylboronic acid and propionic acid under reflux in toluene gave the expected cyclized product trans-(+)-19 in 51% yield along with an isomerized cis-(+)-19 (23% yield).18 They were obtained with 90% ee and 84% ee, respectively, when cis5-methoxychromanone-coumarin cis-(+)-17 with 93% ee was used as the starting material. Their spectral data were identical with those of natural (+)-inophyllum C and (+)-inophyllum E.3,15 Synthetic coumarins showed [R]23D +35 (c 1.10, CHCl3) in trans-(+)-19 and [R]23D +59 (c 0.92, CHCl3) in cis-(+)-19, whereas specific rotations of (+)-inophyllum C and (+)-inophyllum E had been (16) In the previous paper of the synthesis of (+)-calanolide A [(+)1],14 the incorrect stereochemical illustration of (2R,3R)-configuration was given for the IMA-derived trans-2,3-dimethyl-4-chromanone system (trans-9 from 19 in the literature14). (17) Chembers, J. D.; Crawford, J.; Williams, H. W. R.; Dufresne, C.; Scheigetz, J.; Bernstein, M. A.; Lau, C. K. Can. J. Chem. 1992, 70, 1717-1720. (18) cis-(+)-19 could be reused as the source of trans-(+)-19 in the MgI2-assisted isomerization as shown in the synthesis of (+)-calanolide A [(+)-1].14

Synthesis of (+)-Inophyllum B and (+)-Calanolide A SCHEME 5. Preparation of (+)-Inophyllum B [(+)-2] and Its Related Coumarinsa

a Reagents and conditions: (a) senecioaldehyde, PhB(OH) , 3 EtCO2H/PhMe, reflux, 2 h [trans-(+)-19: 51% (90% ee), cis-(+)t 19: 23% (84% ee) from trans-18 (93% ee)]; (b) LiAlH4/ BuOH/THF, -20 °C, ca. 3 min [(+)-inophylum B [(+)-2]: 91%, (+)-inophylum P (20): 9%].

SCHEME 6. Preparation of (+)-Calanolide A (1) and Its Related Coumarinsa

a Reagents and conditions: (a) (-)-quinine/PhCl, 20 °C, 25 h [cis-(+)-9 (67%, 98% ee); trans-(-)-9 (21%, 39% ee)]; (b) MgI2/ K2CO3/PhH, reflux, 15 days (77%); (c) senecioaldehyde, PhB(OH)3, EtCO2H/PhMe, reflux, 1.5 h [trans-(+)-13 (61%, 91% ee), cis-(+)13 (23%, 84% ee)]; (d) LiAlH4/tBuOH/THF, -20 °C, ca. 3 min [(+)calanolide A [(+)-1] (88%); (+)-calanolide B (21) (12%)].

reported to be [R]24D +13 (c 1.1, CHCl3) and [R]20D +70 (c 1.2, CHCl3), respectively.15 These data suggested that natural (+)-inophyllum C contained 30% of the (-)-enantiomer, whereas natural (+)-inophyllum E was isolated as an enantiopure form. The final stage for the synthesis of (+)-inophyllum B [(+)-2] is the stereoselective reduction of the trans2,3-dimethyl-4-chromanone function of trans-(+)-19 [(+)-inophyllum C] into a trans,trans-2,3-dimethyl-4chromanol system. Treatment of trans-(+)-19 with lithium tri(tert-butoxy)aluminum hydride (LBAH), freshly prepared from lithium aluminum hydride and tert-butyl alcohol, in tetrahydrofuran (THF) at -20 °C immediately yielded (+)-inophyllum B [(+)-2] in 91% yield. The specific rotation of the synthetic inophyllum B was [R]24D +54 (c 0.37, CHCl3), whereas natural coumarin15 showed [R]20D +36 (c 0.72, CHCl3). The trans,cis-(+)-2,3-dimethyl4-chromanol, (+)-inophyllum P (20), was also produced as a minor reduction product (9% yield). Nearly the same specific rotations were observed in the synthetic, [R]24D +33 (c 0.09, CHCl3), and natural (+)-inophyllum P, [R]20D +35 (c 0.25, CHCl3).19 Total Synthesis of (+)-Calanolide A [(+)-1]. Next, we applied the concise preparation method for (+)inophyllum B [(+)-2] described above to the synthesis of (+)-calanolide A [(+)-1] (Scheme 6). The starting tigloylphenol 8 was prepared from phloroglucinol (14) through 5,7-dimethoxycoumarin 7 according to the preparation method described in the above 4-phenylcoumarin series (see Scheme 3). The yield of 5,7-dimethoxycoumarin 7 slightly increased (75% yield in 2 steps, see Supporting Information) compared to the previous yield (in 67% yield in 3 steps) starting from 1,3,5-trimethoxylbenzene (6) through coumarin construction by Wittig reaction.14

As reported previously, the (-)-quinine-catalyzed IMA of 8 in PhCl13 afforded cis-(+)-5-methoxychromanonecoumarin cis-(+)-9 in 67% yield with 98% ee and trans(-)-derivative trans-(-)-916 in 21% yield with lower enantioselectivity (39% ee).20 The MgI2-assisted isomerization of cis-(+)-9 accompanied by demethylation followed by treatment of the formed diastereomeric mixture of phenol 10, without separation, with senecioaldehyde in the presence of phenylboronic acid under the same conditions for the 2,2-dimethylchromene construction described in the synthesis of (+)-inophyllum B [(+)-2], as expected, afforded trans-cyclized product trans-(+)13 with 91% ee as a major product (61% yield). The cisisomer cis-(+)-13, corresponding to natural (+)-calanolide D,1 was also produced as a minor product (in 23% yield with 84% ee). These products were identical with the samples previously prepared through the TIPS protection method.14 In the preliminary communication14 (+)-calanolide A [(+)-1] was obtained in the hydride reduction of trans(+)-13 with LBAH in moderate yield (41%), in which only one trial for the reduction had been examined because of the limited amount of starting chromanone-coumarin. Retrial for the reduction of trans-(+)-13 led to a reasonable production of (+)-calanolide A [(+)-1] (88% yield). (+)-Calanolide B (21)1 with a trans,cis-2,3-dimethyl-4chromanol system was also given as a minor reduction product (12% yield). Effect of Cinchona Alkaloids on the Asymmetric IMA. As mentioned above, (-)-quinine effectively catalyzed asymmetric IMA of 7-hydroxy-5-methoxy-8-tigloylcoumarins. We were interested in the influence of other commercially available cinchona alkaloids such as (-)hydroquinine, (-)-cinchonidine, and (+)-cinchonine on

(19) In the Experimental Section of the literature3 the value of +19.8 had been given as the [R]D of natual inophyllum P.

(20) In the stage of the previous paper13 the ee had not been determined.

J. Org. Chem, Vol. 69, No. 8, 2004 2763

Sekino et al. TABLE 1. Cinochona Alkaloid-Catalyzed IMA of 7-Hydroxy-5-methoxy-8-tigloylcoumarins 8 or 16

yield (%) of chromanones (ee%) run

8 or 16

catalyst

temp (°C)

time (h)

product

cis

trans

total

1 2 3 4 5 6

8 8 8 8 16 16

(-)-quinine (-)-hydroquinine (-)-cinchonidine (+)-cinchonine (-)-quinine (-)-cinchonidine

20 17 17 17 4 4

25 14 14 14 33 42

9 9 9 ent-9 17 17

67 (98) 64 (97) 33 (66) 47 (42) 72 (97) 30 (55)

21 (39) 23 (26) 64 (86) 52 (70) 21 (52) 68 (84)

88 87 97 97 93 98

stereoselectivities in the asymmetric IMA (Table 1). In the calanolide series with 8, (-)-hydroquinine, as expected, led to effective asymmetric induction [97% ee and 50% de for cis-(+)-9] (run 2) comparable to the case of (-)-quinine (run 1), indicating that the vinyl group in a catalyst is replaceable by an ethyl group. However, the use of (-)-cinchonidine and (+)-cinchonine, lacking a methoxy function on the quinoline skeleton, as catalyst resulted in major cyclization to enantiomeric trans-2,3dimethyl-4-chromanone systems with relatively high ee, but lower de. Thus, (-)-cinchonidine predominantly afforded trans-(-)-9 in 64% yield with 86% ee (run 3), which was produced as a minor isomer in the (-)-quininecatalyzed IMA (see run 1). In contrast, an enantiomeric trans-chromanone ent-trans-9 was obtained in 52% yield with 70% ee when (+)-cinchonine was used as a catalyst (run 4). These results are comparable to those obtained with (-)-quinine and (+)-quinidine.12 A similar tendency for asymmetric induction was also observed in the inophyllum series. Thus, trans-(-)-2,3-dimethyl-4-chromanone trans-(-)-17 was produced as a major product (in 68% yield with 84% ee) in the (-)-cinchonidinecatalyzed IMA of 16 (run 6).

A conjugate addition is generally accepted as a mode of the Michael addition reaction, in which an enolate should be formed under base-catalyzed conditions after initial bond formation. Therefore, if asymmetric induction occurs at the first addition step, the same absolute configuration at the 2 position in the chromanone ring system and complimentary enantioselectivities must be observed in both diastereoisomers of cis- and trans-2,3dimethyl-4-chromanones produced by the asymmetric IMA of 7-hydroxy-8-tigloylcoumarins. However, in the (-)-quinine-catalyzed IMA of 7-hydroxy-8-tigloylcoumarins, the diastereoisomers with an opposite 2764 J. Org. Chem., Vol. 69, No. 8, 2004

absolute configuration at the 2 position [(2R,3S)- and (2S,3S)-chromanones]21 were predominantly produced. Furthermore, effective asymmetric induction was generally observed in the construction of one diastereoisomer compared to the alternative, that is, a cis-chromanone system in the use of the methoxy-substituted cinchona alkaloids while a trans-chromanone system in the use of the methoxy-free cinchona alkaloids. These facts strongly indicate that the cinchona alkaloid-catalyzed IMA of 7-hydroxy-8-tigloylcoumarins should be kinetically controlled by two independent reaction paths, but not a simple 1,4-addition mode. We had proposed a concerted syn-addition in the diastereoselective trans-chromanone construction by the CsF-induced IMA of 3.22 In the cinchona alkaloidcatalyzed IMA trans-chromanones were also produced by similar syn-addition through a transition state like T-1, while cis-chromanones were produced by anti-addition through an alternative transition state like T-2 (see Figure 1). The asymmetric induction of (2S,3S)- and (2R,3S)-stereochemistries at the stereogenic centers in trans- and cis-chromanone construction, respectively, in the use of (-)-cinchona alkaloids such as (-)-quinine, (-)hydroquinine, or (-)-cinchonidine, could be reasonably explained by supposing complex formation in the transition state due to (1) a hydrogen bonding between an alcoholic function in the catalyst and a carbonyl group in the tigloyl group like the transition state in the (-)quinine-catalyzed thio-Michael addition reaction proposed by Wynberg et al.23 and (2) nonbonding π-π stacking interaction between each aromatic ring of the catalyst and the 7-hydroxy-8-tigloylcoumarins, in which an electron-deficient pyridine unit in the quinoline skeleton directs to an electron-rich dimethoxybenzene unit of the coumarin one, while the remaining benzene unit in the quinoline skeleton directs to a lactone unit in (21) The use of 8-angeloyl-7-hydroxy-5-methoxycoumarin, a geometrical isomer of the tigloylcoumarin 8, as a substrate of the (-)quinine-catalyzed asymmetric IMA, a (2R,3R)-enantiomer, had been predominantly formed in the trans-chromanone system obtained as a major cyclization product.13 (22) Ishikawa, T.; Oku, Y.; Kotake, K.-I.; Ishii, H. J. Org. Chem. 1996, 61, 6484-6485. Ishikawa, T.; Oku, Y.; Kotake, K.-I. Tetrahedron 1997, 53, 14915-14928. (23) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417430.

Synthesis of (+)-Inophyllum B and (+)-Calanolide A

Conclusions In conclusion, we have succeeded in the concise enantioselective synthesis of anti-HIV-1 active (+)-inophyllum B [(+)-2] and (+)-calanolide A [(+)-1] using a methoxy group as a phenol protecting group. The overall reaction comprised eight steps from phloroglucinol (14). Thus, (+)inophyllum B [(+)-2] and (+)-calanolide A [(+)-1] were synthesized from 14 in 5%25 and 16% yields, respectively. In these reaction sequences the key steps for the effective creation of correct absolute configurations at the new stereogenic centers are the (-)-quinine-catalyzed asymmetric IMA of 7-hydroxy-5-methoxy-8-tigloylcoumarins and the simultaneous MgI2-assisted demethylation of the 5-methoxy group and isomerization of the cis-2,3-dimethyl-4-chromanone systems to the trans ones. Although long reaction time was needed in some reaction steps, the preparation method described here would be applicable to a large-scale experiment under simple operation. In addition, examination of the asymmetric IMA by using other cinchona alkaloids suggested that stereoselectivity of the chromanone cyclization could be influenced by the methoxy substituent in the catalyst used and the acidity of their conjugated acids.

Experimental Section

the coumarin one, as shown in Figure 1. Transition state T-1, in which syn-addition could be controlled by effective π-π interaction, can play an important role for the trans selectivity in the use of the methoxy-free cinchona alkaloids. In contrast, incrementing the electron density in the quinoline skeleton of the catalyst, acting as an electron acceptor in the π-π interaction, by substitution with the methoxy group may make the interaction replusive, resulting in the preferential anti situation of ionic reactants (oxygen anion and proton) to a tigloyl double bond like T-2. The conjugated acids of the methoxy-substituted cinchona alkaloids such as (-)-quinine (pK1 ) 5.07), (-)hydroquinine (pK1 ) 5.33), and (+)-quinidine (pK1 ) 5.4) are more acidic than the corresponding ones without a methoxy group, (-)-cinchonidine (pK1 ) 5.8) and (+)cinchonine (pK1 ) 5.85), even a small difference.24 Higher stereoselectivity in both ee and de in the use of the methoxy-substituted alkaloids than in those of the methoxy-free alkaloids may be dependent upon easier proton transfer from the ammonium nitrogen of the more acidic conjugated acids to the tigloyl function through an ion pair complex like T-2. Thus, stereochemical profiles observed in the cinchona alkaloid-catalyzed IMA of 7-hydroxy-8-tigloylcoumarins could be reasonably explained by either the presence or the absence of a methoxy group on the quinoline skeleton in the catalysts in addition to the acidity of their conjugated acids.

The (-)-Quinine-Catalyzed IMA of 7-Hydroxy-5-methoxy-4-phenyl-8-tigloylcoumarin (16). A suspension of 16 (0.140 g, 0.40 mM) in PhCl (2.5 mL) in the presence of (-)quinine (0.013 g, 0.041 mM) was stirred at 4 °C for 33 h under argon. After evaporation, water (5 mL) was added. The aqueous mixture was extracted with CHCl3 (3 × 20 mL). The organic solution was successively washed with 10% HCl aq (20 mL), water (20 mL), and brine (20 mL), dried over MgSO4, and evaporated. Purification of the residue by column chromatography on SiO2 (benzene:ethyl acetate ) 10:1) gave trans(-)-17 (0.032 g, 23%) and cis-(+)-17 (0.098 g, 70%). (8S,9S)8,9-Dihydro-8,9-dimethyl-5-methoxy-4-phenyl-2H,10Hbenzo[1,2-b;5,6-b′]dipyran-2,10-dione [trans-(-)-17]: Colorless prisms, mp 193-194 °C; IR 1716, 1694 cm-1; 1H NMR δ 1.24 (3H, d, J ) 7.0 Hz, 9-Me), 1.53 (3H, d, J ) 6.4 Hz, 8-Me), 2.58 (1H, dq, J ) 11.2, 7.0 Hz, 9-H), 3.45 (3H, s, OMe), 4.32 (1H, dq, J ) 11.2, 6.4 Hz, 8-H), 6.07 (1H, s, 3- or 6-H), 6.20 (1H, s, 6- or 3-H), 7.20-7.22 (2H, m, ArH), 7.33-7.37 (3H, m, ArH); 13C NMR δ 10.5, 19.6, 47.2, 55.6, 79.7, 95.5, 103.7, 104.1, 113.6, 126.9, 127.5, 127.9, 139.7, 154.9, 156.0, 159.5, 161.8, 165.3, 189.8; EIMS m/z 350 (M+, 32%). Anal. Calcd for C21H18O5: C, 71.99; H, 5.18. Found: C, 71.84; H, 5.34. [R]20D -25.2 (c 0.745, CHCl3). (8R,9S)-8,9-Dihydro-8,9-dimethyl5-methoxy-4-phenyl-2H,10H-benzo[1,2-b;5,6-b′]dipyran2,10-dione [cis-(+)-17]: Colorless prisms, mp 219-221 °C; IR 1718 cm-1; 1H NMR δ 1.18 (3H, d, J ) 7.3 Hz, 9-Me), 1.42 (3H, d, J ) 6.8 Hz, 8-Me), 2.71 (1H, dq, J ) 7.3, 3.4 Hz, 9-H), 3.47 (3H, s, OMe), 4.72 (1H, dq, J ) 6.8, 3.4 Hz, 8-H), 6.08 (1H, s, 3- or 6-H), 6.21 (1H, s, 6- or 3-H), 7.20-7.23 (2H, m, ArH), 7.35-7.38 (3H, m, ArH); 13C NMR δ 9.2, 15.6, 45.9, 55.6, 77.3, 95.6, 103.1, 104.1, 113.5, 126.8, 127.5, 127.9, 139.7, 154.9, 156.2, 159.5, 161.8, 165.2, 191.3; EIMS m/z 350 (M+, 32%). Anal. Calcd for C21H18O5: C, 71.99; H, 5.18. Found: C. 71.70; H, 5.15. [R]20D +112.9 (c 0.255, CHCl3). Demethylation of cis-(+)-2,3-Dimethyl-4-chromanone (cis-(+)-17). A suspension of cis-(+)-17 (0.122 g, 0.35 mM, 98% ee), MgI2 (0.237 g, 2.39 mM), and K2CO3 (0.0257 g, 0.19 mM) in dry benzene (12 mL) was refluxed for 14 days under argon. After quenching with 10% HCl aq (20 mL) under ice-cooling,

(24) Budavari, S. The Merck Index, 11th ed.; Merck Co. Ltd: Rahway, NJ, 1989.

(25) This yield could be improved by skipping separation of a mixture of diastereomeric phenols 18.

FIGURE 1. Supposed mechanism for the (-)-cinchona alkaloidcatalyzed IMA of 7-hydroxy-8-tigloylcoumarins.

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Sekino et al. the mixture was extracted with ethyl acetate (3 × 20 mL). The organic solution was washed with water (20 mL) and brine (20 mL), dried over MgSO4, and evaporated. Purification of the residue by column chromatography (with benzene:ethyl acetate ) 10:1) gave trans-18 (0.047 g, 42%) and cis-18 (0.043 g, 37%). trans-18: Colorless powder, mp 224-226 °C; IR 3443, 1733, 1690 cm-1; 1H NMR δ 1.24 (3H, d, J ) 6.8 Hz, 9-Me), 1.50 (3H, d, J ) 6.4 Hz, 8-Me), 2.58 (1H, dq, J ) 11.2, 6.8 Hz, 9-H), 4.31 (1H, dq, J ) 11.2, 6.4 Hz, 8-H), 6.00 (1H, s, 5-OH), 6.06 (1H, s, 3-H), 6.25 (1H, s, 6-H), 7.43-7.45 (2H, m, ArH), 7.57-7.59 (3H, m, ArH); 13C NMR δ 10.6, 19.6, 47.3, 79.4, 100.6, 102.6, 103.7, 113.2, 127.4, 129.2, 129.9, 136.8, 153.8, 155.9, 159.7, 159.8, 165.3, 190.3; EIMS m/z 336 (M+, 100%). Anal. Calcd for C20H16O5: C, 71.42; H, 4.79. Found: C. 70.93; H, 4.78. cis-18: Colorless powder, mp 227-230 °C; IR 3404, 1692 cm-1; 1H NMR δ 1.18 (3H, d, J ) 7.1 Hz, 9-Me), 1.41 (3H, d, J ) 6.6 Hz, 8-Me), 2.72 (1H, dq, J ) 7.1, 3.4 Hz, 9-H), 4.70 (1H, dq, J ) 6.6, 3.4 Hz, 8-H), 5.60 (1H, s, 5-OH), 6.07 (1H, s, 3-H), 6.25 (1H, s, 6-H), 7.43-7.48 (2H, m, ArH), 7.577.60 (3H, m, ArH); 13C NMR δ 9.2, 16.0, 46.0, 100.8, 100.9, 102.4, 103.5, 113.4, 127.5, 129.7, 130.4, 136.2, 152.8, 156.2, 159.1, 159.3, 165.1, 191.6; EIMS m/z 336 (M+, 44%). Anal. Calcd for C20H16O5: C, 71.42; H, 4.79. Found: C. 71.49; H, 4.73. Chromene Cyclization of the Chromanone trans-18. A mixture of trans-18 (0.227 g, 0.61 mM, 93% ee), senecioaldehyde (0.770 g, 9.15 mM), phenylboronic acid (0.610 g, 4.85 mM), and propionic acid (0.068 g, 0.91 mM) in toluene (20 mL) was refluxed for 2 h. After quenching with water (20 mL) the mixture was extracted with ethyl acetate (3 × 20 mL). The organic solution was washed with brine (20 mL), dried over MgSO4, and evaporated. Purification of the residue by column chromatography (benzene:ethyl acetate ) 5:1) gave trans-(+)19 (0.126 g, 51%) and cis-(+)-19 (0.056 g, 23%). (10R,11R)10,11-Dihydro-4-phenyl-6,6′10,11-tetramethyl-2H,6H,12Hbenzo[1,2-b;3,4-b′;5,6-b′′]tripyran-2,12-dione [(+)-Inophyllum C] [trans-(+)-19]: A pale yellow solid, mp 178-182 °C (lit.15 mp 188-191 °C); IR 1737, 1689 cm-1; 1H NMR δ 0.94 (3H, s, Me), 0.98 (3H, s, Me), 1.24 (3H, d, J ) 7.0 Hz, 11-Me), 1.55 (3H, d, J ) 6.2 Hz, 10-Me), 2.57 (1H, dq, J ) 11.0, 7.0 Hz, 11-H), 4.31 (1H, dq, J ) 11.0, 6.2 Hz, 10-H), 5.42 (1H, d, J ) 10.1 Hz, 7-H), 6.05 (1H, s, 3-H), 6.55 (1H, d, J ) 10.1 Hz, 8-H), 7.20-7.24 (2H, m, ArH), 7.36-7.40 (3H, m, ArH); 13C NMR δ 10.5, 19.6, 27.2, 27.4, 47.2, 78.6, 79.6, 103.4, 103. 9, 105.4, 113.5, 115.2, 127.2, 127.5, 127.7, 133.6, 135.6, 139.9, 155.0, 155.1, 155.6, 159.5, 190.1; FABMS m/z 403 (MH+); HRFABMS m/z 403.1548, calcd for C25H23O5 403.1545; [R]23D +35 (c 1.10, CHCl3). (10R,11S)-10,11-Dihydro-4-phenyl6,6′10,11-tetramethyl-2H,6H,12H-benzo[1,2-b;3,4-b′;5,6-b′′]tripyran-2,12-dione [(+)-Inophyllum E] [cis-(+)-19]: A pale yellow oil (lit.15 mp 149-151 °C); IR 1735 cm-1; 1H NMR δ 0.96 (3H, s, Me), 0.98 (3H, s, Me), 1.18 (3H, d, J ) 7.1 Hz, 11-Me), 1.43 (3H, d, J ) 6.6 Hz, 10-Me), 2.71 (1H, dq, J ) 7.1, 3.5 Hz, 11-H), 4.72 (1H, dq, J ) 6.6, 3.5 Hz, 10-H), 5.42 (1H, d, J ) 10.1 Hz, 7-H), 6.05 (1H, s, 3-H), 6.55 (1H, d, J ) 10.1 Hz, 8-H), 7.20-7.24 (2H, m, ArH), 7.36-7.40 (3H, m, ArH); EIMS m/z 402 (M+, 34%); HRFABMS m/z 403.1565, calcd for C25H23O5 403.1545; [R]23D +59 (c 0.92, CHCl3). Reduction of trans-Chromene-Chromanone-Coumarin trans-(+)-19. To a suspension of LiAlH4 (0.025 g, 0.6 mM) in THF (2 mL) was added abs tert-butyl alcohol (0.1445 g, 1.95 mM) in THF (2 mL) at -20 °C during 5 min under argon. To this solution was added a solution of trans-(+)-19 (0.113 g, 0.28 mM) in THF (4 mL). After immediate quenching with water (10 mL) and 10% aq HCl (10 mL) the mixture was extracted with Et2O (3 × 10 mL). The organic solution was washed with water (10 mL) and brine (10 mL), dried over MgSO4, and evaporated. Purification of the residue by preparative TLC (CHCl3:ethyl acetate ) 40:1, 3 times development) gave trans, trans-2,3-dimethyl-4-chromanol (+)-2 (0.100 g, 91%) and trans, cis-2,3-dimethyl-4-chromanol 20 (0.010 g, 9%). (10R,11S,12S)10,11-Dihydro-12-hydroxy-4-phenyl-6,6′10,11-tetramethyl-

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2H,6H,12H-benzo[1,2-b;3,4-b′;5,6-b′′]tripyran-2-one [(+)Inophyllum B] [(+)-2]: A pale yellow solid, mp 58-62 °C; IR 3448, 1718 cm-1; 1H NMR δ 0.91 (3H, s, Me), 0.97 (3H, s, Me), 1.17 (3H, d, J ) 6.7 Hz, 11-Me), 1.47 (3H, d, J ) 6.4 Hz, 10-Me), 1.95 (1H, ddq, J ) 9.1, 7.9, 6.7 Hz, 11-H), 3.51 (1H, d, J ) 2.7 Hz, 12-OH), 4.77 (1H, dd, J ) 7.9, 2.7 Hz, 12-H), 5.37 (1H, d, J ) 9.9 Hz, 7-H), 5.96 (1H, s, 3-H), 6.52 (1H, d, J ) 9.9 Hz, 8-H), 7.23-7.25 (2H, m, ArH), 7.36-7.38 (3H, m, ArH); 13C NMR δ 15.1, 19.0, 26.6, 27.0, 40.5, 67.2, 67.2, 103.6, 106.2, 106.4, 111.5, 111.6, 115.9, 126.0, 127.5, 127.7, 140.0, 150.9, 153.7, 154.1, 156.5, 160.2; FABMS m/z 405 (MH+); HRFABMS m/z 405.1676, calcd for C25H25O5 405.1702; [R]24D +53.7 (c 0.37, CHCl3). (10R,11S,12R)-10,11-Dihydro-12-hydroxy-4-phenyl-6,6′10,11-tetramethyl-2H,6H,12H-benzo[1,2-b;3,4-b′;5,6b′′]tripyran-2-one [(+)-Inophyllum P] (20): A pale yellow solid, mp 102-105 °C; IR 3448, 1718 cm-1; 1H NMR δ 0.93 (3H, s, Me), 0.94 (3H, s, Me), 1.17 (3H, d, J ) 7.0 Hz, 11-Me), 1.44 (3H, d, J ) 6.2 Hz, 10-Me), 1.77 (1H, ddq, J ) 10.5, 7.0, 3.5 Hz, 11-H), 2.84 (1H, br s, 12-OH), 4.28 (1H, dq, J ) 10.8, 6.2 Hz, 10-H), 5.02 (1H, d, J ) 3.5 Hz, 12-H), 5.36 (1H, d, J ) 10.0 Hz, 7-H), 5.96 (1H, s, 3-H), 6.53 (1H, d, J ) 10.0 Hz, 8-H), 7.23-7.25 (2H, m, ArH), 7.37-7.38 (3H, m, ArH); FABMS m/z 405 (MH+); HRFABMS m/z 405.1666, calcd for C25H25O5 405.1702; [R]23D +33 (c 0.09, CHCl3). The (-)-Quinine-Catalyzed IMA of 7-Hydroxy-5-methoxy-4-propyl-8-tigloylcoumarin (8). A solution of 8 (3.00 g, 9.49 mM) and (-)-quinine (0. 309 g, 0.95 mM) in PhCl (60 mL) was stirred at room temperature for 25 h under argon. After evaporation, 10% aq HCl (20 mL) was added and then extracted with CHCl3 (3 × 150 mL). The organic solution was washed with water (150 mL) and brine (150 mL), dried over MgSO4, and evaporated. Purification of the residue by column chromatography on SiO2 (benzene:ethyl acetate ) 10:1) gave trans-(-)-9 (0.637 g, 21%) and cis-(+)-9 (2.013 g, 67%). (8S,9S)8,9-Dihydro-8,9-dimethyl-5-methoxy-4-propyl-2H,10Hbenzo[1,2-b;5,6-b′]dipyran-2,10-dione [trans-(-)-9]: Colorless prisms, mp 149-152 °C; IR 1728, 1687 cm-1; 1H NMR δ 1.00 (3H, t, J ) 7.3 Hz, CH2Me), 1.22 (3H, d, J ) 7.0 Hz, 9-Me), 1.52 (3H, d, J ) 8.6 Hz, 8-Me), 1.58 (2H, dif tq, J ) 7.5, 7.5 Hz, CH2CH2Me), 2.55 (1H, dq, J ) 6.6, 6.6 Hz, 9-H), 2.84 (2H, t, J ) 6.7 Hz, (C)CH2CH2), 3.93 (3H, s, OMe), 4.30 (1H, dq, J ) 6.6, 6.6 Hz, 8-H), 6.05 (1H, s, 3-H), 6.31 (1H, s, 6H); 13C NMR δ 10.6, 14.0, 19.6, 22.8, 38.8, 47.3, 56.1, 79.6, 95.5, 103.8, 104.9, 111.9, 156.2, 157.2, 159.8, 162.3, 164.1, 189.8. Anal. Calcd for C18H20O5: C, 68.34; H, 6.37. Found: C, 68.22; H, 6.24. [R]24D -18.1 (c 0.498, CHCl3). (8R,9S)-8,9Dihydro-8,9-dimethyl-5-methoxy-4-propyl-2H,10H-benzo[1,2-b;5,6-b′]dipyran-2,10-dione [cis-(+)-9]: Colorless prisms, mp 63-65 °C; IR 1725, 1687 cm-1; 1H NMR δ 1.00 (3H, t, J ) 7.5 Hz, CH2Me), 1.16 (3H, d, J ) 7.3 Hz, 9-Me), 1.41 (3H, d, J ) 6.6 Hz, 8-Me), 1.59 (2H, tq, J ) 7.1, 7.1 Hz, CH2CH2Me), 2.68 (1H, dq, J ) 7.3, 7.3 Hz, 9-H), 2.84 (2H, t, J ) 7.5 Hz, (C)CH2CH2), 3.93 (3H, s, OMe), 4.69 (1H, dq, J ) 6.6, 3.3 Hz, 8-H), 6.06 (1H, s, 3-H), 6.31 (1H, s, 6- H); 13C NMR δ 9.2, 14.0, 16.1, 22.8, 38.8, 46.0, 56.2, 77.2, 95.6, 103.2, 105.0, 111.9, 156.5, 157.3, 159.9, 162.4, 164.6, 191.4. Anal. Calcd for C18H20O5: C, 68.34; H, 6.37. Found: C, 68.42; H, 6.26. [R]23D +79.6 (c 1.36, CHCl3). Demethylation of cis-2,3-Dimethyl-4-chromanone cis(+)-9. A suspension of cis-(+)-9 (0.431 g, 1.36 mM, 97% ee), MgI2 (0.924 g, 3.26 mM), and K2CO3 (0.188 g, 1.36 mM) in dry benzene (20 mL) was refluxed for 15 days under argon. After quenching with 10% aq HCl (40 mL) under ice-cooling the mixture was extracted with ethyl acetate (3 × 40 mL). The organic solution was washed with water (40 mL) and brine (40 mL), dried over MgSO4, and evaporated. Purification of the residue by column chromatography (benzene:ethyl acetate ) 5:1) gave a 1:1 mixture of trans-10 and cis-10 (0.317 g, 77%) as colorless powder, which was used in the next step without further separation. Chromene Cyclization of the Chromanone trans-10 and cis-10. A mixture of trans-10 and cis-10 (0.274 g, 0.90

Synthesis of (+)-Inophyllum B and (+)-Calanolide A mM), senecioaldehyde (1.158 g, 13.8 mM), phenylboronic acid (0.910 g, 7.24 mM), and propionic acid (0.103 g, 1.38 mM) in toluene (20 mL) was refluxed for 1.5 h. After being quenched with water (20 mL) the mixture was extracted with ethyl acetate (3 × 20 mL). The organic solution was washed with brine (20 mL), dried over MgSO4, and evaporated. Purification of the residue by column chromatography (CHCl3:ethyl acetate ) 100:1) gave trans-(+)-13 (0.202 g, 61%) and cis-(+)-13 (0.076 g, 23%). (10R,11R)-10,11-Dihydro-4-propyl-6,6′10,11-tetramethyl-2H,6H,12H-benzo[1,2-b;3,4-b′;5,6-b′′]tripyran-2,12dione [trans-(+)-13]: A pale yellow solid, mp 175-180 °C (lit.10 mp 130-132 °C for (()-derivative); IR 1685 cm-1; 1H NMR δ 1.03 (3H, t, J ) 7.3 Hz, CH2Me), 1.22 (3H, d, J ) 6.9 Hz, 9-Me), 1.51 (3H, s, Me) and 1.55 (3H, s, Me), 1.54 (3H, d, J ) 7.5 Hz, 10-Me), 1.65 (2H, tq, J ) 7.3, 7.3 Hz, CH2CH2Me), 2.55 (1H, dq, J ) 11.4, 6.9 Hz, 11-H), 2.88 (2H, m, (C)CH2CH2), 4.29 (1H, dq, J ) 11.4, 6.4 Hz, 10-H), 5.59 (1H, d, J ) 10.1 Hz, 7-H), 6.05 (1H, s, 3-H), 6.65 (1H, d, J ) 10.1 Hz, 8-H); 13 C NMR δ 10.5, 13.9, 19.6, 23.2, 28.0, 28.4, 38.8, 47.4, 79.2, 79.6, 103.6, 104.5, 105.5, 112.1, 115.9, 127.0, 155.6, 156.0, 157.1, 159.1, 159.8, 190.0; FABMS m/z 369 (MH+); HRFABMS m/z 369.1668, calcd for C21H25O5 369.1702. (10R,11S)-10,11Dihydro-4-propyl-6,6′10,11-tetramethyl-2H,6H,12H-benzo[1,2-b;3,4-b′;5,6-b′′]tripyran-2,12-dione [(+)-Calanolide D] [cis-(+)-13]: A pale yellow solid, mp 52-54 °C (lit.10 mp 130131 °C); IR 1735, 1689 cm-1; 1H NMR δ 1.03 (3H, t, J ) 7.3 Hz, CH2Me), 1.16 (3H, d, J ) 7.1 Hz, 11-Me), 1.42 (3H, d, J ) 6.6 Hz, 10-Me), 1.536 (3H, s, Me), 1.541 (3H, s, Me), 1.64 (2H,

m, CH2CH2Me), 2.68 (1H, dq, J ) 7.1, 3.3 Hz, 11-H), 2.88 (2H, m, (C)CH2CH2), 4.70 (1H, dq, J ) 6.6, 3.3 Hz, 10-H), 5.59 (1H, d, J ) 10.1 Hz, 7-H), 6.04 (1H, s, 3-H), 6.65 (1H, d, J ) 10.1 Hz, 8-H); FABMS m/z 369 (MH+); HRFABMS m/z 369.1704, calcd for C21H25O5 369.1702. Reduction of trans-Chromanone-Chromanone-Coumarin trans-(+)-13. To a suspension of LiAlH4 (0.0094 g, 0.25 mM) in THF (0.5 mL) was added abs tert-butyl alcohol (0.553 g, 0.75 mM) in THF (1.5 mL) at -20 °C during 5 min under argon. To this solution was added a solution of trans-(+)-13 (0.040 g, 0.11 mM) in THF (2 mL). After immediate quenching with water (4 mL) and 10% aq HCl (4 mL), the mixture was extracted with Et2O (3 × 4 mL). The organic solution was washed with water (4 mL) and brine (4 mL), dried over MgSO4, and evaporated to give a pale yellow oil (0.04 g, quant), which contained calanolide A (1) and calanolide B (21) in 7.3:1.

Acknowledgment. We thank the Shorai Foundation for Science and Technology for partial financial support to this study. Supporting Information Available: Experimental procedures for the starting materials for (-)-quinine-catalyzed IMA and the conditions of chiral HPLC for determination of enantiopurites of chiral coumarins. This material is available free of charge via the Internet at http://pubs.acs.org. JO035753T

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