Chemical Transformation of an Intermediate in the Synthesis of Huperzine A, Leading to a Diverse Array of Molecules

1528 Chem. Pharm. Bull. 64, 1528–1531 (2016) Vol. 64, No. 10 Note

Satoshi Yokoshima,* Masatsugu Ishikawa, Youko Beniyama, and Tohru Fukuyama* Graduate School of Pharmaceutical Sciences, Nagoya University; Furo-cho, Chikusa-ku, Nagoya 464–8601, Japan. Received June 23, 2016; accepted July 11, 2016

Chemical transformation of an early intermediate in our synthesis of huperzine A provided a diverse array of molecules in which a variety of functional groups could be embedded. Key words natural product; total synthesis; synthetic intermediate; chemical library; screening

Total synthesis of natural products provides a reliable entry synthesis of huperzine A,16) was chosen for efficient chemical to their derivatives in drug development.1–9) Since interme- transformations. diates at a later stage of the synthesis tend to have similar We first prepared the key intermediate 1 according to the structures to the target natural products, they could be used reported procedure.16) Chart 2 summarizes the synthesis. Tri- for the structure–activity relationship studies. On the other cyclic lactone 217,18) was successively treated with potassium hand, intermediates at an early or middle stage of the syn- hexamethyldisilazide (KHMDS, 2.5 eq) and then methallyl thesis may have scaffolds that are significantly different from bromide to furnish 3. The vanadium-mediated epoxidation of the target natural products. These intermediates, however, 3 proceeded stereoselectively,19,20) giving 4, which was sub- may have some advantageous structural features for drug jected to Swern oxidation to afford γ-hydroxy-α,β-unsaturated development; for example, they may be rich in stereogenic ketone 5. Upon treatment with trifluoromethanesulfonic acid centers, have a fused or bridged ring system, or have non-flat (TfOH), 5 underwent cation-olefin cyclization to give 1. three-dimensional structures. These structural features appear With a sufficient amount of 1 in hand, the chemical elabo- to contribute to the clinical success of drug candidates.10–15) ration of the bicyclo[3.3.1] nonane core in 1 was carried out Intermediates even at the early or middle stage of total syn- (Chart 3). An attempted reduction of the ketone moiety in 1 thesis could, therefore, form the basis of a fine library for drug with sodium borohydride in methanol afforded a 3 : 1 mixture discovery. In order to demonstrate an easy access to drug-like of 6 and its diastereomer. To promote chelation to the second- scaffolds, compound 1 (Chart 1), an early intermediate in our ary hydroxy group, the reaction with sodium borohydride was performed in acetic acid, in which sodium triacetoxyborohy- dride was formed in situ.21) Under such conditions, the diaste- reoselectivity was improved to 16 : 1, and the desired alcohol 6 was obtained in 72% yield. Treatment of 6 with TfOH induced the formation of an oxaadamantane skeleton,22–24) and the sub- sequent methanolysis of the lactone ring in 7 occurred under mild basic conditions to give diol 8. The primary alcohol moiety in 8 was selectively tosylated according to Tanabe’s Chart 1. Synthesis of Huperzine A via Intermediate 1 protocol.25) Heating of the resulting tosylate facilitated the formation of a tetrahydrofuran ring to furnish 9 in 92% yield. For further functionalization, the methyl ester was hydrolyzed under basic conditions. The resulting carboxylic acid 10 and pyrrolidine were coupled via the formation of the correspond- ing acid chloride 11 to produce amide 12 in 86% yield. On the other hand, Curtius rearrangement of 10 using diphenyl- phosphoryl azide (DPPA) and benzyl alcohol furnished 14.26) Cleavage of the benzyloxycarbonyl (Cbz) group in 14 by hy- drogenolysis gave primary amine 15. In conclusion, compound 1, an early intermediate in our synthesis of huperzine A, was efficiently converted to diverse molecules bearing three different ring systems in which a variety of functional groups were embedded. These compounds have been deposited in a chemical library and are currently employed in screening assays for drug discovery. The results of the screening assays will be reported in due course.

Experimental 1 Chart 2. Preparation of Intermediate 1 General Remarks Nuclear magnetic resonance ( H-NMR

trate was concentrated in vacuo, and the residue was purified using flash column chromatography (60–100% ethyl acetate in hexane) to give 6 (479 mg, 72.0%) as a white solid. IR (neat, −1 1 cm ) 3394, 2914, 1749, 1219, 1065, 984; H-NMR (CDCl3) δ: 5.67 (d, J=5.2 Hz, 1H), 4.42 (dd, J=8.8, 8.8 Hz, 1H), 4.17 (dd, J=9.6, 8.8 Hz, 1H), 4.09 (d, J=4.0 Hz, 1H), 3.89 (m, 1H), 2.81 (d, J=17.6 Hz, 1H), 2.61 (ddd, J=9.6, 8.8, 2.0 Hz, 1H), 2.50 (m, 1H), 2.33 (ddd, J=14.6, 5.2, 5.2 Hz, 1H), 1.99 (d, J=17.6 Hz, 13 1H), 1.75 (s, 3H), 1.69 (d, J=14.6 Hz, 1H); C-NMR (CDCl3) δ: 180.2 (C), 134.8 (C), 126.2 (CH), 70.0 (CH), 69.3 (CH2), 64.3 (CH), 49.2 (CH), 46.3 (C), 41.0 (CH2), 34.2 (CH), + 28.4 (CH2), 22.8 (CH3); HR-MS (ESI ) 247.0945 (Calcd for C12H16NaO4 247.0946). (3aS*,4R*,6R*,8S*,9aS*,10R*)-10-Hydroxy-8-methyloctahydro-1H-4,8-epoxy-6,9a-methanocycloocta[c]furan- 1-one (7) To a stirred solution of 6 (112 mg, 0.499 mmol) in 1,2-dichloroethane (1.7 mL) was added trifluoromethanesulfonic acid (4.4 µL, 0.050 mmol) at room temperature, and the reaction mixture was heated at 50°C. After stirring for 1 h, the reaction mixture was quenched with aqueous sodium hydrogen carbonate. The resulting solution was extracted with dichloromethane and then with 10% methanol in chloroform. The combined organic phases were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and the residue was purified using flash column chromatography (50% ethyl acetate in hexane) to give 7 (101 mg, 89.9%) as a white solid. IR (neat, cm−1) 3375, 2928, 1765, 1453, 1362, 1228, 1126, 1067, 1011, 820; 1 H-NMR (CDCl3) δ: 4.62 (dd, J=12.4, 7.7 Hz, 1H), 4.35 (dd, J=7.7, 7.7 Hz, 1H), 4.28 (m, 1H), 4.10 (br s, 1H), 2.78 (m, 1H), Chart 3. Chemical Transformation of 1 2.32 (br s, 1H), 2.23 (m, 1H), 2.11 (d, J=12.4 Hz, 1H), 1.95 (d, J=12.8 Hz, 1H), 1.93–1.87 (m, 2H), 1.74 (dd, J=12.4, 2.8 Hz, 13 13 (400 MHz), C-NMR (100 MHz)) spectra were determined 1H), 1.68 (d, J=12.8 Hz, 1H), 1.22 (s, 3H); C-NMR (CDCl3) using a JEOL-ECS400 instrument. The chemical shifts in δ: 179.2 (C), 72.8 (CH), 70.5 (C), 70.2 (CH2), 68.2 (CH), 45.6 1 the H-NMR spectra are reported in parts per million (ppm) (CH), 45.4 (C), 42.8 (CH2), 40.7 (CH2), 33.4 (CH), 27.9 (CH3), + downfield of the tetramethylsilane (δ) signal, which provided 23.4 (CH2); HR-MS (ESI ) 247.0957 (Calcd for C12H16NaO4 the internal standard. Coupling constants are reported in hertz 247.0946). (Hz). The chemical shifts in the C-NMR spectra are reported (1S*,3R*,4S*,5S*,6R*,7R*)-Methyl 6-Hydroxy-4-(hydroxy- in ppm relative to the centerline of the triplet at 77.0 ppm, cor- methyl)-1-methyl-2-oxaadamantane-5-carboxylate (8) To responding to deuteriochloroform. IR spectra were recorded a stirred solution of 7 (74.0 mg, 0.330 mmol) in methanol using a JASCO FT/IR-4100 Fourier Transform Infrared Spec- (1.1 mL) was added potassium carbonate (91.2 mg, 0.660 mmol) trophotometer and are reported in wavenumbers (cm−1). High- at room temperature. After stirring for 2 h, the reaction mix- resolution (HR)-MS were obtained using a JEOL JMS-T100LP ture was quenched with water. The resulting solution was ex- AccuTOF LC-plus in positive electrospray ionization (ESI) tracted with dichloromethane and then with 10% methanol in method, using sodium trifluoroacetate as the internal stan- chloroform. The combined organic phases were washed with dard. Flash chromatography separations were performed on brine, dried over sodium sulfate, and filtered. The filtrate was KANTO CHEMICAL Silica Gel 60 (spherical, 40–100 mesh) concentrated in vacuo, and the residue was purified with flash unless otherwise noted. Reagents were commercial grade and column chromatography (70–100% ethyl acetate in hexane) to were used without purification. All reactions sensitive to oxy- give 8 (58.8 mg, 69.6%) as a white solid. IR (neat, cm−1) 3405, gen or moisture were conducted under an argon atmosphere. 2930, 1721, 1444, 1374, 1258, 1130, 1072, 1034, 803; 1H-NMR

(3aS*,7R*,9R*,9aS*,10R*)-9,10-Dihydroxy-5-methyl- (CDCl3) δ: 4.23 (s, 1H), 4.18 (br s, 1H), 3.89–3.80 (m, 2H), 7,8,9,9a-tetrahydro-1H-3a,7-methanocycloocta[c]furan- 3.78 (s, 3H), 2.51 (m, 1H), 2.27 (m, 1H), 2.19 (d, J=13.6 Hz, 3(4H)-one (6) To a stirred solution of 1 (660 mg, 2.97 mmol) 1H), 2.05 (dd, J=12.8, 2.8 Hz, 1H), 1.88 (ddd, J=13.2, 2.8, in acetic acid (10 mL) was added sodium borohydride (669 mg, 2.8 Hz, 1H), 1.74 (d, 13.6 Hz, 1H), 1.66 (d, J=12.8 Hz, 1H), 13 17.7 mmol) portionwise at room temperature. After stirring 1.63 (d, J=13.2 Hz, 1H), 1.17 (s, 3H); C-NMR (CDCl3) δ: for 12 h, additional sodium borohydride (112 mg, 2.96 mmol) 176.3 (C), 72.8 (CH), 69.7 (CH), 69.4 (C), 62.2 (CH2), 52.1 was added. After stirring for another 3 h, the reaction mix- (CH3), 47.5 (C), 47.0 (CH), 44.9 (CH2), 41.0 (CH2), 32.2 (CH), + ture was quenched with water. The resulting solution was 28.0 (CH3), 24.6 (CH2); HR-MS (ESI ) 279.1198 (Calcd for extracted with dichloromethane and then with 10% methanol C13H20NaO5 279.1208). in chloroform. The combined organic phases were washed (3S*,3aS*,5S*,7R*,7aR*,9R*)-Methyl 5-Methyloctahydro- with brine, dried over sodium sulfate, and ﬁltered. The ﬁl- 5,3,7-(epoxyethane[1,1,2]triyl)benzofuran-3a-carboxylate 1530 Chem. Pharm. Bull. Vol. 64, No. 10 (2016)

(9) To a stirred solution of 8 (178 mg, 0.696 mmol) in aceto- 1H), 4.08 (d, J=2.8 Hz, 1H), 3.84 (dd, J=8.3, 4.2 Hz, 1H), nitrile (2.3 mL) were added N,N,N′,N′-tetramethylpropane-1,3- 3.63 (d, J=8.2 Hz, 2H), 3.55 (br, 3H), 3.10 (dd, J=4.6, 4.6 Hz, diamine (0.250 mL, 1.50 mmol) and p-toluenesulfonyl chloride 1H), 2.35 (s, 1H), 2.08–1.76 (m, 8H), 1.61–1.56 (m, 2H), 1.25 13 (160 mg, 0.837 mmol) at 0°C. The reaction mixture was then (s, 3H); C-NMR (CDCl3) δ: 171.1 (C), 77.1 (CH), 71.0 (CH), allowed to warm to room temperature. After stirring for 69.0 (CH2), 67.9 (C), 52.2 (C), 47.8 (CH2), 42.1 (CH), 38.7 30 min, the reaction mixture was heated at 50°C. After stir- (CH2), 38.7 (CH2), 34.0 (CH), 30.3 (CH2), 28.1 (CH3), 27.2 (br), + ring for 2 h, the reaction mixture was quenched with water. 22.9 (br); HR-MS (ESI ) 300.1576 (Calcd for C16H23NNaO3 The resulting solution was extracted with dichloromethane 300.1576). and then with 10% methanol in chloroform. The combined Benzyl ((3S*,3aS*,5S*,7R*,7aR*,9R*)-5-Methyloctahydro- organic phases were washed with brine, dried over sodium 5,3,7-(epoxyethane[1,1,2]triyl)benzofuran-3a-yl)carbamate sulfate, and filtered. The filtrate was concentrated in vacuo, (14) To a solution of 10 (57 mg, 0.25 mmol) in benzene and the residue was purified using flash column chromatog- (0.8 mL) were added triethylamine (0.11 mL, 0.79 mmol) and raphy (40% ethyl acetate in hexane) to give 9 (152 mg, 91.8%) DPPA (82 µL, 0.38 mmol) at room temperature. After stir- as a pale yellow oil. IR (neat, cm−1) 2931, 1733, 1450, 1252, ring for 50 min, the mixture was concentrated in vacuo. The 1 1169, 1036, 972, 878; H-NMR (CDCl3) δ: 4.56 (d, J=5.6 Hz, residue was dissolved in benzene (0.8 mL), and the resulting 1H), 4.08 (m, 1H), 3.82 (dd, J=8.8, 4.0 Hz, 1H), 3.74 (s, 3H), solution was heated at 80°C for 2 h. After cooling to room 3.67 (d, J=8.8 Hz, 1H), 2.88 (m, 1H), 2.33 (m, 1H), 2.04 (dd, temperature, benzyl alcohol (52 µL, 0.50 mmol) and triethyl- J=12.8, 2.8 Hz, 1H), 1.97 (m, 1H), 1.86 (d, J=12.8 Hz, 1H), amine (0.10 mL, 0.72 mmol) were added. The resulting mixture 1.77 (ddd, J=13.2, 3.2, 3.2 Hz, 1H), 1.61–1.55 (m, 2H), 1.18 was heated at 80°C for 1.5 h before it was concentrated in 13 (s, 3H); C-NMR (CDCl3) δ: 174.5 (C), 78.0 (CH), 70.5 (CH), vacuo. The residue was partitioned between dichloromethane 69.0 (CH2), 67.9 (C), 52.2 (CH3), 52.0 (C), 41.4 (CH), 39.4 and aqueous sodium hydrogen carbonate, and the aqueous (CH2), 38.5 (CH2), 33.7 (CH), 30.0 (CH2), 27.9 (CH3); HR-MS phase was extracted with dichloromethane. The combined + (ESI ) 261.1103 (Calcd for C13H18NaO4 261.1103). organic phases were washed with brine, dried over sodium (3S*,3aS*,5S*,7R*,7aR*,9R*)-5-Methyloctahydro-5,3,7- sulfate, and filtered. The filtrate was concentrated in vacuo, (epoxyethane[1,1,2]triyl)benzofuran-3a-carboxylic Acid (10) and the residue was purified with flash column chromatog- To a solution of 9 (146 mg, 0.613 mmol) in methanol (2.1 mL) raphy (30–100% ethyl acetate in hexane) to give 14 (63 mg, −1 was added an aqueous solution of sodium hydroxide (3 M, 76%) as an amorphous solid. IR (neat, cm ) 3301, 2930, 1712, 1 2.1 mL, 6.3 mmol) at room temperature. The resulting solution 1527, 1282, 1240, 1113, 1035, 969; H-NMR (CDCl3) δ: 7.35 was heated at 70°C for 2 h before it was quenched with aque- (s, 5H), 5.07 (s, 2H), 4.85 (s, 1H), 4.19 (s, 1H), 4.10 (s, 1H), ous hydrochloric acid. The resulting mixture was extracted 3.99–3.95 (m, 1H), 3.68 (d, J=8.7 Hz, 1H), 2.75 (s, 1H), 2.49 with diethyl ether. The combined organic phases were washed (d, J=12.8 Hz, 1H), 2.36 (s, 1H), 2.05 (d, J=12.8 Hz, 1H), 1.97 with brine, dried over sodium sulfate, and filtered. The filtrate (d, J=13.3 Hz, 1H), 1.73 (d, J=13.3 Hz, 1H), 1.61–1.56 (m, 2H), 13 was concentrated in vacuo to give carboxylic acid 10 (129 mg, 1.20 (s, 3H); C-NMR (CDCl3) δ: 165.2 (C), 136.3 (C), 128.6 94.0%) as a white solid. IR (neat, cm−1) 2931, 1727, 1454, (CH), 128.2 (CH), 128.1 (CH), 79.9 (CH), 71.3 (CH), 70.4 1 1376, 1244, 1171, 1030, 961, 872, 773; H-NMR (CDCl3) δ: (C), 68.6 (CH2), 66.4 (CH2), 59.6 (C), 44.3 (CH), 40.2 (CH2), + 9.98 (br, 1H), 4.58 (d, J=5.5 Hz, 1H), 4.10 (d, J=3.2 Hz, 1H), 38.5 (CH2), 34.4 (CH), 29.8 (CH2), 27.9 (CH3); HR-MS (ESI ) 3.92 (dd, J=8.7, 4.1 Hz, 1H), 3.70 (d, J=8.7 Hz, 1H), 2.87 (dd, 352.1534 (Calcd for C19H23NNaO4 352.1525). J=5.0, 5.0 Hz, 1H), 2.35 (br, 1H), 2.11 (dd, J=12.8, 2.8 Hz, (3S*,3aS*,5S*,7R*,7aR*,9R*)-5-Methyloctahydro-5,3,7- 1H), 1.97 (ddd, J=13.3, 1.8, 1.8 Hz, 1H), 1.91 (d, J=12.8 Hz, (epoxyethane[1,1,2]triyl)benzofuran-3a-amine (15) To a 1H), 1.79 (ddd, J=13.3, 2.7, 2.7 Hz, 1H), 1.63–1.58 (m, 2H), flask charged with benzyl carbamate 14 (40 mg, 0.12 mmol) 13 1.20 (s, 3H); C-NMR (CDCl3) δ: 179.4 (C), 77.9 (CH), 70.4 and palladium on carbon (10%, 26 mg, 0.012 mmol) was (CH), 69.0 (CH2), 68.1 (C), 51.8 (C), 41.2 (CH), 39.2 (CH2), added methanol (0.5 mL). The solution was then purged with + 38.5 (CH2), 33.6 (CH), 29.9 (CH2), 27.8 (CH3); HR-MS (ESI ) hydrogen gas. After stirring for 2 h, the reaction mixture was 247.0947 (Calcd for C12H16NaO4 247.0946). filtered through a pad of celite. The filtrate was concentrated ((3S*,3aS*,5S*,7R*,7aR*,9R*)-5-Methyloctahydro-5,3,7- in vacuo, and the residue was purified using flash column

(epoxyethane[1,1,2]triyl)benzofuran-3a-yl)(pyrrolidin-1- chromatography (NH2 silica gel, dichloromethane) to give yl)methanone (12) To a solution of 10 (45 mg, 0.20 mmol) in 15 (22 mg, 94%) as an oil. IR (neat, cm−1) 3456, 2927, 1375, 1 dichloromethane (0.6 mL) were added oxalyl chloride (34 µL, 1031, 966; H-NMR (CDCl3) δ: 4.08–4.04 (m, 2H), 3.81 (d, 0.40 mmol) and a small amount of N,N-dimethylformamide J=5.5 Hz, 1H), 3.68 (d, J=8.7 Hz, 1H), 2.33 (s, 1H), 2.16 (d, at 0°C. After stirring for 1 h, the mixture was concentrated in J=4.6 Hz, 1H), 1.91 (ddd, J=12.8, 12.8, 2.8 Hz, 2H), 1.71 vacuo. The residue was dissolved in dichloromethane (0.5 mL), (dd, J=17.0, 13.3 Hz, 2H), 1.56–1.49 (m, 2H), 1.20 (s, 3H); 13 and pyrrolidine (41 µL, 0.49 mmol) and pyridine (32 µL, C-NMR (CDCl3) δ: 83.2 (CH), 71.8 (CH), 70.3 (C), 68.5 0.40 mmol) were added. After stirring for 1 h at room tempera- (CH2), 56.7 (C), 48.6 (CH), 43.6 (CH2), 39.1 (CH2), 34.5 (CH), + ture, the reaction was quenched with water, and the resulting 29.2 (CH2), 28.1 (CH3); HR-MS (ESI ) 196.1332 (Calcd for mixture was extracted with dichloromethane. The combined C11H18NO2 196.1338). organic phases were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo, Acknowledgments This work was financially supported and the residue was purified using flash column chromatog- by JSPS KAKENHI (Grant Numbers 25221301, 26713001, raphy (5% methanol in dichloromethane) to give 12 (47 mg, 16H01141), the Tokyo Biochemical Research Foundation, and 85%) as a white solid. IR (neat, cm−1) 3489, 2928, 1615, 1412, the Platform Project for Supporting in Drug Discovery and 1 1189, 1038, 967, 877; H-NMR (CDCl3) δ: 4.79 (d, J=6.0 Hz, Life Science Research (Platform for Drug Discovery, Infor- Vol. 64, No. 10 (2016) Chem. Pharm. Bull. 1531 matics, and Structural Life Science) from the Japan Agency (2010). for Medical Research and Development (AMED). 13) Schreiber S. L., Proc. Natl. Acad. Sci. U.S.A., 108, 6699–6702 (2011). 14) Lachance H., Wetzel S., Kumar K., Waldmann H., J. Med. Chem., Conflict of Interest The authors declare no conflict of 55, 5989–6001 (2012). interest. 15) Lovering F., Med. Chem. Commun., 4, 515–519 (2013). 16) Koshiba T., Yokoshima S., Fukuyama T., Org. Lett., 11, 5354–5356 References and Notes (2009). 1) Wilson R. M., Danishefsky S. J., J. Org. Chem., 71, 8329–8351 17) Wilson N. H., Jones R. L., Marr C. G., Muir G., Eur. J. Med. (2006). Chem., 23, 359–364 (1988). 2) Wender P. A., Verma V. A., Paxton T. J., Pillow T. H., Acc. Chem. 18) While a racemic sample was used for this study, asymmetric syn- Res., 41, 40–49 (2008). thesis of 2 has been reported. See ref. 16. 3) Jackson K. L., Henderson J. A., Phillips A. J., Chem. Rev., 109, 19) Evans J. M., Kallmerten J., Synlett, 1992, 269–271 (1992). 3044–3079 (2009). 20) Nicolaou K. C., Harrison S. T., J. Am. Chem. Soc., 129, 429–440 4) Danishefsky S., Nat. Prod. Rep., 27, 1114–1116 (2010). (2007). 5) Wilson R. M., Danishefsky S. J., Angew. Chem. Int. Ed., 49, 6032– 21) Evans D. A., Chapman K. T., Carreira E. M., J. Am. Chem. Soc., 6056 (2010). 110, 3560–3578 (1988). 6) Wetzel S., Bon R. S., Kumar K., Waldmann H., Angew. Chem. Int. 22) Krishnamurthy V. V., Fort R. C., Jr., J. Org. Chem., 46, 1388–1393 Ed., 50, 10800–10826 (2011). (1981). 7) Irie K., Yanagita R. C., Chem. Rec., 14, 251–267 (2014). 23) Kozikowski A. P., Campiani G., Tückmantel W., Heterocycles, 39, 8) Wender P. A., Quiroz R. V., Stevens M. C., Acc. Chem. Res., 48, 101–116 (1994). 752–760 (2015). 24) Dixon D. D., Sethumadhavan D., Benneche T., Banaag A. R., Tius 9) Crane E. A., Gademann K., Angew. Chem. Int. Ed., 55, 3882–3902 M. A., Thakur G. A., Bowman A., Wood J. T., Makriyannis A., J. (2016). Med. Chem., 53, 5656–5666 (2010). 10) Nielsen T. E., Schreiber S. L., Angew. Chem. Int. Ed., 47, 48–56 25) Yoshida Y., Shimonishi K., Sakakura Y., Okada S., Aso N., Tanabe (2008). Y., Synthesis, 1999, 1633–1636 (1999). 11) Lovering F., Bikker J., Humblet C., J. Med. Chem., 52, 6752–6756 26) Shioiri T., Ninomiya K., Yamada S., J. Am. Chem. Soc., 94, 6203– (2009). 6205 (1972). 12) Drewry D. H., Macarron R., Curr. Opin. Chem. Biol., 14, 289–298