ㅪ⛯ᔕࠍ⚻↱ߔࠆ ↢‛ᵴᕈᄙⅣᑼᄤὼ‛ߩല₸⊛ోวᚑ⎇ⓥ Research on Efficient Total Synthesis of Bioactive Polycyclic Natural Products via Cascade Reaction 2014 ᐕ 2 ⮮ ඳ Tomohiro FUJII
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(2) ㅪ⛯ᔕࠍ⚻↱ߔࠆ ↢‛ᵴᕈᄙⅣᑼᄤὼ‛ߩല₸⊛ోวᚑ⎇ⓥ Research on Efficient Total Synthesis of Bioactive Polycyclic Natural Products via Cascade Reaction. 2014 ᐕ 2 ᣧⒷ↰ᄢቇᄢቇ㒮 వㅴℂᎿቇ⎇ⓥ⑼ ൻቇ↢ൻቇኾ ൻቇวᚑᴺ⎇ⓥ ⮮ ඳ Tomohiro FUJII.
(3)
(4) ⇛⺆. Ac. :. acetyl. AIBN. :. 2,2’-azobisisobutyronitrile. 9-BBN. :. 9-borabicyclo[3.3.1]nonane. Bn. :. benzyl. BOM. :. benzyloxymethyl. Bz. :. benzoyl. cat.. :. catalytic amount. conv.. :. conversion. dba. :. dibenzylideneacetone. DBU. :. 1,8-diazabicyclo[5.4.0]undec-7-ene. DCC. :. dicyclohexylcarbodiimide. DIBAL-H. :. diisobutylaluminium hydride. DIPEA. :. N,N-diisopropylethylamine. DMAP. :. N,N-dimethyl-4-aminopyridine. DMF. :. N,N-dimethylformamide. DMPU. :. N,N'- dimethylpropyleneurea. DMSO. :. dimethyl sulfoxide. dr. :. diastereomeric ratio. EDCI. :. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. equiv. :. equivalent. Et. :. ethyl. FAB. :. fast atom bombardment. HRMS. :. high resolution mass spectrometry. HMPA. :. hexamethylphosphoric triamide. HWE. :. Horner-Wadsworth-Emmons. IMDA. :. intramolecular Diels-Alder. IR. :. infrared spectroscopy. KHMDS. :. potassium bis(trimethylsilyl)amide. KPB. :. potassium phosphate buffer. LDA. :. lithium diisopropylamide. Me. :. methyl.
(5) mp. :. melting point. MS. :. molecular sieves. NBS. :. N-bromosuccinimide. NMO. :. N-methylmorpholine N-oxide. NMR. :. nuclear magnetic resonance. NOE. :. nuclear Overhauser effect. NOESY. :. NOE correlated spectroscopy. NR. :. no reaction. Ph. :. phenyl. PMB. :. p-methoxybenzyl. PPTS. :. pyridinium p-toluenesulfonate. Pr. :. propyl. PTLC. :. preparative thin-layer chromatography. PTSA. :. p-toluenesulfonic acid. Py. :. pyridine. quant.. :. quantitative. Rf. :. retention factor. rt. :. room temperature. TBAF. :. tetrabutylammonium fluoride. TBHP. :. t-butyl hydroperoxide. TBS. :. t-butyldimethylsilyl. temp. :. temperature. TES. :. triethylsilyl. TFA. :. trifluoroacetic acid. Tf. :. trifluoromethanesulfonyl. THF. :. tetrahydrofuran. TIPS. :. triisopropylsilyl. TMS. :. trimethylsilyl. TPAP. :. tetrapropylammonium perruthenate.
(6) ⋡ᰴ ╙㧝┨ ᐨ⺰㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯. 3. ╙㧞┨ 1,4-ࡅ࠼࠼ㆶరࠍὐߣߔࠆㅪ⛯ Michael ᔕߩ㐿⊒ ╙1▵. ⎇ⓥ⢛᥊㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯. 4. ╙2▵. ,-ਇ㘻ࠛࠬ࠹࡞(㧱)ߦኻߔࠆᔕᬌ⸛㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯. 6. ╙3▵. ,-ਇ㘻ࠛࠬ࠹࡞(Z )ߦኻߔࠆᔕᬌ⸛㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯. 9. ╙㧟┨ ᷰⅣဳㅪ⛯ Michael ᔕߩ㐿⊒ ╙1▵. ⎇ⓥ⢛᥊㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯. 12. ╙2▵. ၮ⾰วᚑ㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯. 14. ╙3▵. ᔕᬌ⸛㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯. 17. ╙㧠┨ Liebeskind-Srogl ࠞ࠶ࡊࡦࠣ́ಽሶౝ Diels-Alder ㅪ⛯ᔕߩ㐿⊒ ╙1▵. ⎇ⓥ⢛᥊㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯. 21. ╙2▵. ၮ⾰วᚑ㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯. 24. ╙3▵. ᔕᬌ⸛㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯. 27. ╙㧡┨ ent-kauranoid ࠹࡞ࡍࡁࠗ࠼ߩోวᚑ⎇ⓥ ╙1▵. ⎇ⓥ⢛᥊㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯. 35. ╙2▵. Phyllostachysin F ߩวᚑ⎇ⓥ㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯. 36. ╙3▵. ਇᢧട᳓ಽ⸃ߦࠃࠆ A Ⅳㇱಽߩਇᢧวᚑ㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯. 43. ╙㧢┨ ✚㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯. 47. ╙㧣┨ ታ㛎㗄㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯. 49. ෳ⠨ᢥ₂㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯㨯. 104. ⻢ㄉ⎇ޔⓥᬺ❣. .
(7) ᐨᢥ ᯏวᚑൻቇߪᣂⷙ⚛᧚ߩ㐿⊒߿ක⮎ຠวᚑߥߤߦ߅ߡ㊀ⷐߥᓎഀࠍᨐߚߒߡ߈ ߚ‛↢ߦ․ޕᵴᕈᄤὼ‛ߩ᭴ㅧቯ߿᭴ㅧᵴᕈ⋧㑐⎇ⓥ⎇ࠫࡠࠝࠗࡃ࡞ࠞࡒࠤޔⓥߩ ಽ㊁ߦ߅ߡᯏวᚑൻቇߪᔅⷐਇนᰳߢࠅ⥄ޔὼ߆ࠄዋ㊂ߒ߆ᓧࠄࠇߥ↪ߥᄤ ὼ‛ߩ㊂⊛ଏ⛎ߦ߽⽸₂ߒߡࠆ⥄ޔߚ߹ޕὼ⇇ߦ߅ߌࠆ↥‛ߢࠆᄤὼ‛ࠍวᚑߔࠆ ߎߣߪੱޔ㘃ߦ߅ߡᚢ⊛߆ߟ⍮⊛ߥᵴേߢࠆߣࠆߔ৻ޕᄤὼ‛ߩోวᚑߪᣢሽ ߩᔕߩ⚵ߺวࠊߖߦㆊ߉ߥߣ್ᢿߐࠇ߆ߨߕࠬࠪ࠲ࡔޔᔕࠣࡦࡊ࠶ࠞޔᔕ ߩ᭽ߥᣂᔕߦᵈ⋡߇㓸߹ࠆะ߇ࠆ߇ޔᱧผ⊛ߦߡ߽ࡆ࠲ࡒࡦ B12 ߩోวᚑ߆ࠄ Woodward-Hoffmann ೣ߇⺀↢ߒߚࠃ߁ߦޔᄤὼ‛ߩోวᚑߩㆊ⒟߆ࠄߐࠇߚᣂߚߥ ⍮ߪ⏕ታߦൻቇࠍㅴൻߐߖߡࠆޕ ᄤὼ‛ߩోวᚑߪޔᐲ⊓ޘጊߦ߃ࠄࠇࠆోޕวᚑߩ㆐ᚑࠍጊߩ㗂ߣߒޔ⊒‛ߢ ࠆ⊒ὐ߆ࠄ㜞ല₸ߥ࡞࠻ࠍߒߡߊߦ߆ޕ⍴ᦼ㑆ߦᦨ⍴࡞࠻ߢጊ㗂߹ߢ ㄡࠅ⌕ߊ߆ޔ㜞₸ߣ⍴Ꮏ⒟ᢙߢൻว‛วᚑࠍ⋡ᜰߔోวᚑߣ㉃ૃߒߡࠆޕᯏ วᚑൻቇ߇⊒㆐ߒߚᣣߢߪޔ㜞₸ޔ⍴Ꮏ⒟ߦട߃ߡ␠ޔળ⊛ⷐ⺧ߢ߽ࠆ⋭⾗Ḯޔ ⋭ࠛࡀ࡞ࠡ⋭ޔജൻޔⅣႺ⽶⩄ૐᷫ߇ోวᚑߦ᳞ࠄࠇߡ߅ࠅޔวᚑല₸ะߦ߁ޔ ൻว‛ߩోวᚑࠍὐߣߔࠆቇ㓙㗔ၞ⎇ⓥ߿Ꮏᬺ⊛↢↥߳ߩዷ㐿߽ᦼᓙߐࠇߡࠆߎޕ ߁ߒߚⷰὐ߆ࠄ╩⠪ߪ⸅ᇦᔕߣㅪ⛯ᔕߦ⌕⋡ߒߚ⸅ޕᇦᔕޔㅪ⛯ᔕߪᎿ⒟ᢙ ᷫߦലߢޔ⸥ߩ␠ળ⊛ⷐ⺧ߦኻᔕน⢻ߢࠅⶄޔᢙߩਇᢧὐ߿ᄙⅣᑼ㛽ᩰߩ᭴▽ࠍ ⴕ߁ߢวℂ⊛ߢࠆߣ⠨߃ߚ߆ࠄߢࠆޕએਅߦߘߩ⎇ⓥߦߟߡ⸥ߔޕ. .
(8) ╙㧝┨ ᐨ⺰. HO. O. HO Me. H Me. COOMe. HO Me. O. H HO. O. H. H O. O. bruceantin. H Me. H. O HO. H Me OAc. CO2H OAc. Me O. fusidic acid. HO Me H H. H OH O OH. phyllostachysin F. Figure 1.1. Bioactive terpenes. ࠹࡞ࡍࡁࠗ࠼ߦߪఝࠇߚ↢‛ᵴᕈࠍᜬߟൻว‛߇ᄙߊሽߔࠆ(Figure 1.1)߫߃ޕ bruceantin ߪ quassinoids ߣߒߡಽ㘃ߐࠇࠆ࠻࠹࡞ࡍࡁࠗ࠼ߢࠅੱޔ㑆ߩฦ⒳߇ࠎ⚦ ⢩ߦኻߒߡ㜞Ⴧᱺ㒖ኂᵴᕈࠍ␜ߔ 1ޕFusidic acid ߪ fusidane ࠹࡞ࡍࡁࠗ࠼ߦዻߒޔ᛫ ↢‛⾰ߣߒߡ⚦⩶ߩჇᱺ㒖ኂᵴᕈࠍ␜ߔ 2ޕPhyllostachysin F ߪ ent-kauranoid ߣ߫ࠇࠆ ࠫ࠹࡞ࡍࡁࠗ࠼ߢࠅޔbruceantin ߣห᭽ߦੱ㑆ߩ߇ࠎ⚦⢩ߦኻߒߡჇᱺ㒖ኂᵴᕈࠍ␜ ߔ 3ߩࠄࠇߎޕൻว‛ࠍ↢‛ᵴᕈൻว‛ߪⶄᢙߩਇᢧὐࠍᄙⅣᑼ㛽ᩰࠍߒߡ ࠆޕഃ⮎ߩᣂⷙ࠼ൻว‛ߦᚑࠅᓧࠆ߶ߤఝࠇߚ↢‛ᵴᕈࠍᜬߟߦ߽߆߆ࠊࠄߕ᭴ ㅧ⊛ⶄ㔀ߐ߆ࠄోวᚑ߇㆐ᚑߐࠇߡ߅ࠄߕ᭴ㅧᵴᕈ⋧㑐⎇ⓥߦ⥋ߞߡߥൻว‛߽ ᄙޕFigure 1.1 ߦ␜ߒߚ fusidic acid, phyllostachysin F ߽ߘߩߢࠆޕ ߘߎߢߩࠄࠇߎޔൻว‛ߩోวᚑࠍⷞ㊁ߦࠇޔല₸⊛ߥ㛽ᩰ᭴▽ߩ㐿⊒ࠍ⋡⊛ߣߒ ߡ⎇ⓥߦ⌕ᚻߒߚޕല₸⊛ߥ㛽ᩰ᭴▽ࠍⴕ߁ߢㅪ⛯ᔕߦ⌕⋡ߒߚޕㅪ⛯ᔕߪ৻ᐲ ߩᠲߢⶄᢙߩਇᢧὐ߅ࠃ߮Ⅳ᭴▽ࠍⴕ߁ߎߣ߇น⢻ߥߚޔᎿ⒟ᢙߩᷫߪ߽ߜࠈࠎ ߩߎߣ⋭⾗Ḯޕࠆ߇ߥߟ߽ߦࠡ࡞ࡀࠛ⋭ޔ ㅪ⛯ᔕߦߪ cascade ᔕޔdomino ᔕޔtandem ᔕߥߤ᭽ߥޘ⒓߇ߟߌࠄࠇߡ ࠆ߇↪ߩߘޔᕈ߆ࠄᐢߊ⎇ⓥ߇ߥߐࠇߡ߅ࠅޔᄤὼ‛วᚑߦ߽↪ࠄࠇߡ߈ߚ 4ޕ એਅߩ┨ߢߪޔᣂⷙㅪ⛯ᔕߩ㐿⊒ߣߘߩᔕ↪ߦߟߡ⚦ࠍ⸥ߔޕ. .
(9) ╙㧞┨ 1,4-ࡅ࠼࠼ㆶరࠍὐߣߔࠆㅪ⛯ Michael ᔕߩ㐿⊒ ╙㧝▵ ⎇ⓥ⢛᥊ ᒝ᛫⣲≌ᵴᕈࠍ␜ߔ bruceantin ߥߤᄙߊߩ↢‛ᵴᕈᄤὼ‛ߦߪోޔ⚛྾⚖ਇᢧਛ ᔃࠍ❗Ⅳㇱߦ࠻ࡦࠬ-1,2-⟎឵ࠪࠢࡠࡋࠠࠨࡦⅣࠍߔࠆൻว‛߇ᄙߊሽߔ ࠆ ߫߃ޕFigure 2.1 ߦ␜ߔࠃ߁ߦ bruceantin ߿ helvolic acid ߩ A Ⅳㇱಽߪ 1 ߦ⋧ᒰߔ ࠆޕ. HO Me 1 R. O. R2. HO. HO Me A. H 1. O. H Me. H. H O. O. Me. Me. O. H. CO2H. H. COOMe. A. O. O. H. H Me OAc. bruceantin. OAc. Me O. helvolic acid. Figure 2.1. Structures of 1 and bruceantin, helvolic acid. ┙ㆬᛯ⊛ߦ᭴▽ߔࠆലᨐ⊛ߥᚻᴺߣߒߡ[4+2]ઃടⅣൻᔕ߇ߍࠄࠇࠆߒ߆ߒޕ ߥ߇ࠄోޔ⚛྾⚖ਇᢧਛᔃࠍ᭴▽ߔࠆߚߦߪടᾲ߿࡞ࠗࠬ㉄ߩᷝടߥߤỗߒ᧦ઙ ߿ᤨ㑆ࠍⷐߒޔᔕᕈߩ㜞ࠫࠛࡦ߿ࠫࠛࡁࡈࠖ࡞ࠍ↪ࠆᔅⷐ߇ࠆ(Scheme 2.1)ޕ ߹ߚ৻ޔᣇߢޔಽሶౝ Michael ᔕߪᔕᤨ㑆߇⍴ߊޔૐ᷷ਅߢᔕࠍⴕ߁ߎߣ߇น⢻ ߥߚో⚛྾⚖ਇᢧਛᔃࠍ᭴▽ߔࠆߢലᨐ⊛ߢࠆ 5ޔߢߎߘޕಽሶౝ Michael ᔕࠍ↪ߚ 1 ߩ᭴▽ᬌ⸛ࠍⴕߞߚޕ Scheme 2.1. The proposed method to synthesize the trans-stereodiad including an all-carbon quaternary stereogenic center. Intramolecular Michael reaction R1. [4+2]. Me 1 R. Me R2. R2 H. R1. + R2. H. 1. Bruceantin ߿ helvolic acid ߩోวᚑࠍⷞ㊁ߦࠇ࠻ࡦࠬ-1,2-⟎឵ࠪࠢࡠࡋࠠࠨࡦⅣ 5 ࠍᮡ⊛ൻว‛ߣߒޔ᭴▽ߦ 1,4-ࡅ࠼࠼ㆶరࠍὐߣߔࠆㅪ⛯ Michael ᔕ↪ࠆߎߣ ࠍ⠨߃ߚ (Scheme 2.2)ޕၮ⾰ߣߒߡಽሶౝߦ ,-ਇ㘻ࠛࠬ࠹࡞ࠍੑߟᜬߟ 2 ࠍ⸳ቯߒ ߚޕੑߟߩ ,-ਇ㘻ࠛࠬ࠹࡞ߩౝ৻ޔᣇࠍᔕᕈߩ㜞 -ࡔ࠴ࡦࠛࠬ࠹࡞ߦߔࠆߎ .
(10) ߣߢޔ⟎ㆬᛯ⊛ߦ 1,4-ࡅ࠼࠼ㆶరࠍⴕߊ⛯ޔಽሶౝ Michael ᔕߦࠃߞߡ࠻ࡦ ࠬ-1,2-⟎឵ࠪࠢࡠࡋࠠࠨࡦⅣ 5 ࠍ┙ㆬᛯ⊛ߦ᭴▽ߔࠆߎߣ߇น⢻ߛߣ⠨߃ߚޕὐߣ ߥࠆ 1,4-ࡅ࠼࠼ㆶరߩࠃࠅ㜞⟎ㆬᛯᕈߩ⊒ࠍᦼᓙߒ࡞࠹ࠬࠛޔㇱࠍᵴᕈߩ㜞 ࡈࠚ࠾࡞ࠛࠬ࠹࡞ߦߒߚޔࠅࠃߦࠇߎޕⅣൻᓟߦౝߔࠆੑߟߩࠛࠬ࠹࡞߇ൻߐ ࠇࠆߚߩߘޔᓟߩᄌ឵ࠍㆬᛯ⊛ߦⴕ߁ߎߣ߇น⢻ߣߥࠆޕ Scheme 2.2. Concept of the Michael reduction/intramolecular Michael reaction cascade. CO2Ph. OPh Me O CO2Et. reducing reagent. R1. TIPSO. TIPSO. R2. Me. Me 3. 2E: R1=CO2Et, R2=H 2Z: R1=H, R2=CO2Et. Me CO2Ph. Me OPh O. TIPSO Me. H. CO2Et. TIPSO. O OEt. H Me 5. 4. ᧄᔕߩࠃ߁ߥ 1,4-ࡅ࠼࠼ㆶరࠍὐߣߔࠆㅪ⛯ Michael ᔕߪએ೨ߦ߽ႎ๔ߐࠇ ߡࠆ 5,6ޕၳࠄߪ Scheme 2.3 ߦ␜ߔᔕࠍႎ๔ߒߚ 6ޕMichael ฃኈߣߥࠆਇ㘻ࠛ ࠬ࠹࡞ߩǫߦੑߟߩࡔ࠴࡞ၮࠍᜬߟၮ⾰ࠍ↪ࠆߎߣߢ 1,4-ࡅ࠼࠼ㆶరࠍ⟎ㆬ ᛯ⊛ߦⴕޔ྾⚖⚛ࠍⅣൻࠍ㜞┙ㆬᛯ⊛ߦวᚑߒߡࠆޔߒ߆ߒޕ࿁ߩࠃ ߁ߦࠛࠠ࠰ࡔ࠴ࡦㇱߩᔕᕈࠍ↪ߒߡ 1,4-ࡅ࠼࠼ㆶరߩ⟎ㆬᛯᕈࠍ⊒ߐ ߖߡࠆߪߥߚޔㅪ⛯ߒߡ┙ㆬᛯ⊛ߦⅣൻ߇ㅴⴕߒోޔ⚛྾⚖ਇᢧਛᔃࠍ᭴ ▽ߢ߈ࠇ߫ޔวᚑൻቇ⊛ߦ߽ᣂⷙߢ↪ߣߥࠆޕ Scheme 2.3. Hori’s study of the Michael reduction/intramolecular Michael reaction cascade. CO2Me CO2t-Bu Me Me. Me. H. THF A:B= 79 : 21 (72%). Me. H Me A. Me. Me. H Me. . H Me B. CO2t-Bu Me. CO2t-Bu Me. Me CO2Me. L-Selectride THF, 82%. CO2Me. CO2t-Bu +. CO2Me. CO2t-Bu. H. CO2Me. L-Selectride.
(11) ╙㧞▵ ,-ਇ㘻ࠛࠬ࠹࡞(㧱)ߦኻߔࠆᔕᬌ⸛ ߹ߕޔMichael ฃኈ߇ E ߩ ,-ਇ㘻ࠛࠬ࠹࡞ߢࠆၮ⾰ 2E ߩวᚑߦขࠅ߆߆ ߞߚޕᏒ⽼ߩ propargyl alcohol 6 ߦኻߒ࡛࠙⚛ൻࠍⴕࠕ࡞ࠦ࡞ 7 ߳ᄌ឵ߒ 7ޔ7 ߦኻ ߒ Johnson-Claisen ォࠍⴕ߁ߎߣߢࠛࠬ࠹࡞ 8 ࠍวᚑߒߚޕ ↢ߓߚࠛࠬ࠹࡞ࠍ DIBAL-H ߦࠃߞߡㆶరߒࠕ࡞࠺ࡅ࠼ 9 ࠍวᚑߒߚ(Scheme 2.4)ޕ Scheme 2.4. Preparation of aldehyde 9. OH. a. I. b. I. 6. I. c. OH. CO2Et. 7. CHO. 8. 9. Reagents and conditions: (a) TMSCl, NaI, H2O, MeCN, rt, 2 h, 61%; (b) (EtO)3CCH3, propionic acid, reflux, 6 h, 72%; (c) DIBAL-H, CH2Cl2, –78 °C, 2 h, 76%.. วᚑߒߚࠕ࡞࠺ࡅ࠼ 9 ߣ(S)-valinol ↱᧪ߩᣢ⍮ൻว‛ 10 ߣߩ non-Evans aldol ᔕ 8 ࠍ ⴕ 11 ߳ߣᄌ឵ߒߚޔߡ⛯ޕ᳓㉄ၮߩ⼔߅ࠃ߮ࠝࠠࠨ࠱ࠫࡦ࠴ࠝࡦߩ㒰ࠍⴕ ߁ߎߣߦࠃࠅࠕ࡞࠺ࡅ࠼ 12 ࠍวᚑߒޔHorner-Wadsworth-Emmons (HWE)ᔕߦࠃࠅ ㎮ߩિ㐳ޔPd ⸅ᇦࠍ↪ߚࠞ࡞ࡏ࠾࡞ൻࠍⴕၮ⾰ 2E ࠍวᚑߒߚ(Scheme 2.5)ޕ Scheme 2.5. Synthesis of substrate 2E. O I + CHO 9. I. S N. I. a. b, c. O. HO. O Me S. N. Me. 11. 10. CHO. TIPSO O. 12. CO2Ph. I d. e CO2Et. TIPSO Me 13. CO2Et. TIPSO Me 2E. Reagents and conditions: (a) TiCl4, DIPEA, CH2Cl2, –78 °C to rt, 1 h, 83%; (b) TIPSOTf, 2,6-lutidine, CH2Cl2, rt, 10 h; (c) DIBAL-H, CH2Cl2, –78 °C, 15 min, 95% (2 steps); (d) (EtO)2P(O)CH2CO2Et, NaH, THF, rt, 1 h, 93%, (e) Pd(PPh3)4, PhOH, triethylamine, CO, THF, 50 °C, 20 h, 72%.. Ⅳൻ೨㚟 2E ߩวᚑߦᚑഞߒߚߩߢ 1,4-ࡅ࠼࠼ㆶరࠍὐߣߔࠆㅪ⛯ Michael ᔕߦࠃࠆⅣൻߩᬌ⸛ࠍⴕߞߚ(Table 2.1)ޕㆶరߣߒߡ L-Selectride ࠍ↪ޔṁᇦ╬᧦ઙ ᬌ⸛ࠍⴕߞߚޔߕ߹ޕtoluene ṁᇦࠍ↪ޔᔕ᷷ᐲࠍᄌ߃ߡᔕࠍⴕߞߚ (entries 1-3)ޕ ߘߩ⚿ᨐޔᚲᦸߩ┙㈩⟎ࠍߔࠆ 5 ߇ਥ↢ᚑ‛ߣߒߡᓧࠄࠇߡߊࠆ߽ߩߩࠕࠫߩߘޔ .
(12) ࠬ࠹ࠝࡑߢࠆ 5’߽ᓧࠄࠇߚ ߡ⛯ޕCH2Cl2ޔEt2O ࠍṁᇦߣߒߡ↪ߚ߇ㆬᛯᕈ ߩะߪࠄࠇߥ߆ߞߚ (entries 4 and 5)ޕEntry 6 ߢߪⅣൻߩ㓙ߦࠠ࠻߇ᒻᚑߐࠇ ࠆߎߣࠍᦼᓙߒߡ LiClO4 ࠍᷝടߒߚ߇ᄌൻߪࠄࠇߥ߆ߞߚޕEntry 7 ߢߪ㜞ᭂᕈṁᇦ ߢࠆ THF ࠍṁᇦߣߒߡ↪ߚ⚿ߩߘޕᨐޔㆬᛯᕈ߇ㅒォߒࡑࠝ࠹ࠬࠕࠫޔ5’߇ ㆬᛯ⊛ߦᓧࠄࠇߚޕEntries 8,9 ߢߪ HMPA ߿ DMF ࠍᷝടߒߚޔߣࠆߔޕDMF ࠍᷝടߒ ߚ㓙ߦᚲᦸߩ 5 ߪᓧࠄࠇߕ┙ޔㆬᛯ⊛ߦ 5’ߩߺ߇ᓧࠄࠇߚߩࠄࠇߎޕᬌ⸛ߩ⚿ᨐޔૐ ᭂᕈṁᇦਛߢߪ 5 ߇ㆬᛯ⊛ߦᓧࠄࠇࠆ৻ᣇߢޔ㜞ᭂᕈṁᇦਛߢߪࠫࠕࠬ࠹ࠝࡑߢ ࠆ 5’߇ㆬᛯ⊛ߦᓧࠄࠇࠆߎߣ߇ಽ߆ߞߚޕ Table 2.1. Michael reduction/intramolecular Michael reaction of 2E. CO2Ph CO2Et. TIPSO Me. Me CO2Ph. L-Selectride (1.2 equiv.) 2h conditions. 2E. entry. CO2Et. TIPSO. H Me 5 (desired). Me CO2Ph + H Me. 5' (undesired). yield (%). temp (°C). solvent/ additive (equiv.). CO2Et. TIPSO. 5. 5’. 1. toluene. –78. 31. 31. 2. toluene. 0. 40. 27. 3. toluene. rt. 39. 24. 4. CH2Cl2. –78. 30. 25. 5. Et2O. –78. 22. 10. 6. Et2O, LiClO4 (2.0). –78. 29. 12. 7. THF. –78. 20. 50. 8. THF, HMPA (10.0). –78. 26. 31. 9. THF/DMF (1/2). 0. 0. 82. ↢ᚑߒߚ 5 ߩ⋧ኻ┙㈩⟎ߪᢙᎿ⒟ߩᄌ឵ࠍ⚻ߡᓧࠄࠇࠆ࠻ࠝ࡞ 14 ߩ X ✢⚿᥏ ᭴ㅧ⸃ᨆߦࠃߞߡቯߒ(Figure 2.2)9ޔ5’ߩ⋧ኻ┙㈩⟎ߪᢙᎿ⒟ߩቭ⢻ၮᄌ឵ߦࠃࠅว ᚑߒߚ 15 ߩ NOESY ࠬࡍࠢ࠻࡞᷹ቯߦࠃߞߡቯߒߚ(Figure 2.3)ޕ. .
(13) Me OH HO. OH H Me 14 R factor = 0.0431 wR factor = 0.1039. Figure 2.2. X-ray crystallographic structure of 14.. Me CHO HO. H. O. H. CO2Et. HMe. HO. H Me. H. 15. CO2Et. Figure 2.3. NOESY experiment on 15. ᓧࠄࠇߚ⍮ࠍၮߦᧄᔕߩㆫ⒖⁁ᘒࠍ⠨ኤߒߚ(Scheme 2.6)ޕChamberlin ߪ -ࡔ࠴ ࡦࠤ࠻ࡦߦኻߒߡ L-Selectride ߦࠃࠆ 1,4-ࡅ࠼࠼ㆶరࠍⴕ߁ߣ E-enolate ߇↢ᚑߔࠆ ߎߣࠍႎ๔ߒߡࠆ 10ᧄޔߢߎߘޕᔕߩㆊ⒟ߢ↢ߓࠆࠛࡁ࠻ߪ E ߢࠆߣផ᷹ ߒߚޕૐᭂᕈṁᇦਛߢߪ↢ߓߚࠛࡁ࠻ߣ Michael ฃኈߢࠆਇ㘻ࠛࠬ࠹࡞ߣߩ 㑆ߦࠠ࠻߇↢ߓޔㆫ⒖⁁ᘒ TS 1 ࠍ⚻↱ߒᔕ߇ㅴⴕߒᚲᦸߩ┙ࠍߔࠆ 5 ߇ㆬ ᛯ⊛ߦᓧࠄࠇߚߣ⠨߃ߚ৻ޕᣇߢޔ㜞ᭂᕈṁᇦਛߢߪṁᇦߩߚࠠ࠻߇↢ߓߕ┙ ⊒ߩᓇ㗀ߦࠃࠅޔㆫ⒖⁁ᘒ TS 2 ࠍ⚻↱ߒ 5’߇ఝవߒߡᓧࠄࠇߚߣផ᷹ߒߚޕ Scheme 2.6. Proposed transition states of the Michael reduction/intramolecular Michael reaction cascade of 2E. Me CO2Ph CO2Et. TIPSO. Me. OO. Me. TIPSO Li. 2E. TIPSO. OPh Me. Me. O OEt. TS 2. . CO2Et H Me 5 (desired). TS 1 Li O. . Me CO2Ph. OPh OEt. TIPSO. Me CO2Ph TIPSO. CO2Et H Me. 5' (undesired).
(14) ╙㧟▵ ,-ਇ㘻ࠛࠬ࠹࡞(Z )ߦኻߔࠆᔕᬌ⸛ E ߩ ,-ਇ㘻ࠛࠬ࠹࡞ࠍᜬߟၮ⾰ߩㅪ⛯ Michael ᔕߪᚲᦸߢߪߥࠫࠕࠬ࠹ ࠝࡑ5’ࠍ┙ㆬᛯ⊛ߦਈ߃ߚߚޔᚲᦸߩ┙㈩⟎ࠍߔࠆ 5 ࠍਥ↢ᚑ‛ߣߒߡᓧࠆ ߴߊޔၮ⾰ࠍ E ߆ࠄ Z ߦߒߚߩߘޕℂ↱ࠍㆫ⒖⁁ᘒ߆ࠄ⺑ߔࠆ(Scheme 2.7)ޕㆫ ⒖⁁ᘒߪ TS 1-4 ߇⠨߃ࠄࠇࠆ߇ TS 3,4 ߢߪࡔ࠴࡞ၮߣ Michael ฃኈߢࠆࠛ࠴࡞ࠛࠬ ࠹࡞ߣߩ㑆ߦ 1,3-ࠕ࡞⊒߇↢ߓਇቯൻߐࠇࠆޕవߩ⍮߆ࠄ㜞ᭂᕈṁᇦਛߢߪ ┙㓚ኂ߇ᄢ߈ߥᓇ㗀ࠍਈ߃ࠆߎߣ߇␜ໂߐࠇߚߚޔTS 1,2 ߢߪࠃࠅ┙㓚ኂߩዊߐ ߥ TS 2 ߇ቯߢࠆߣ⠨߃ࠄࠇࠆޕTS 2 ࠍ⚻↱ߒߡᔕ߇ㅴⴕߔࠇ߫ᚲᦸߩ┙ࠍ ߔࠆ 5 ߇ᓧࠄࠇࠆޕ Scheme 2.7. Proposed transition states of the Michael reduction/intramolecular Michael reaction cascade of 2Z. O O. Me. TIPSO Me. TIPSO Me. H. Me CO2Ph. Me O OEt OPh. OPh OEt. H. TIPSO. O. CO2Et H Me 5. TS 1. TS 2 (favored). O. Me. OPh. OPh. TIPSO. Me. TIPSO. O. O. O. OEt. OEt TS 4. TS 3. Michael ฃኈ߇ Z ߩ ,-ਇ㘻ࠛࠬ࠹࡞ߢࠆၮ⾰ 2Z ߩวᚑߦขࠅ߆߆ߞߚޕ ⮮ࠄ߇㐿⊒ߒߚ 17 ࠍ↪ࠆ HWE ᔕ 11 ࠍⴕޔ2E ߩวᚑਛ㑆ߢࠆࠕ࡞࠺ࡅ࠼ 12 ࠍ 16 ߦᄌ឵ߒߚߩߘޕᓟ Pd ⸅ᇦࠍ↪ߚࠞ࡞ࡏ࠾࡞ൻࠍⴕ 2Z ࠍวᚑߒߚ(Scheme 2.8)ޕ Scheme 2.8. Synthesis of substrate 2Z. I. I a TIPSO. O Me 12. CO2Ph b. TIPSO. TIPSO Me. CO2Et. Me. 16. 2Z. CO2Et. O o-MeC6H4O P. O OEt. o-MeC6H4O 17. Reagents and conditions: (a) Triton B, 17, THF, 0 °C, 20 min, 93% (Z/E = 10/1); (b) Pd(PPh3)4, PhOH, triethylamine, CO, THF, 50 °C, 20 h, 78%.. .
(15) ၮ⾰ 2Z ߇ᓧࠄࠇߚߩߢㅪ⛯ Michael ᔕߩᬌ⸛ࠍⴕߞߚ(Table 2.2)ޕૐᭂᕈṁᇦࠍ↪ ߚ entries 1-4 ߢߪⅣൻߪᓧࠄࠇߕޔ1,4-ࡅ࠼࠼ㆶరߩߺ߇ㅴⴕߒߚޕEntries 5,6 ߢ ߪᭂᕈߩ㜞 THF ࠍṁᇦߣߒᔕࠍⴕߞߚ⚿ߩߘޕᨐޔਛ⒟ᐲߩ₸ߢߪࠆ߇ᚲᦸ ߩ┙ࠍߔࠆ 5 ߇┙ㆬᛯ⊛ߦᓧࠄࠇߚޕEntry 7 ߢߪ DMF ṁᇦߢᔕࠍⴕߞߚ߇ ₸ߩૐਅ߇ࠄࠇߚޕ2E ߩᔕ߇┙ㆬᛯ⊛ߦㅴⴕߒߚ THF ߣ DMF ߩᷙวṁᇦࠍ⹜ ߒߚ(entries 8 and 9)⚿ߩߘޕᨐ߇ࠆߪߢ߆ߕࠊޔ₸ߦะ߇ࠄࠇߚޕEntries 10,11 ߢ THF ṁᇦਛ HMPA ࠍᷝടߒߚߣߎࠈޔᄢߦ₸߇ะߒ 78㧑ߩ₸ߢ 5 ߇┙ㆬ ᛯ⊛ߦᓧࠄࠇߚޕHMPA ߦᲧߴᲥᕈߩૐ DMPU ࠍᷝടߒޔᔕࠍⴕߞߚ߇Ⅳൻߪㅴ ⴕߒߥ߆ߞߚ(entry 12)ޕ Table 2.2. Michael reduction/intramolecular Michael reaction cascade of 2Z. CO2Ph TIPSO Me. CO2Et. Me CO2Ph. L-Selectride (1.2 equiv.) 2h conditions. TIPSO. 2Z. entry. CO2Et H Me 5. Me CO2Ph + TIPSO. yield (%). temp (°C). solvent/ additive (equiv.). CO2Et H Me 5'. 5. 5’. 1. toluene. –78 to 0. 0. 0. 2. CH2Cl2. –78 to 0. 0. 0. 3. Et2O. –78 to 0. 0. 0. 4. Et2O, LiClO4 (2.0). –78 to 0. 0. 0. 5. THF. –78. 45. 0. 6. THF. 0. 40. 0. 7. DMF. 0. 24. 0. 8. THF/DMF (1/2). –78. 22. 0. 9. THF/DMF (1/2). 0. 61. 0. 10. THF, HMPA (10.0). –78. 78. 0. 11. THF, HMPA (10.0). 0. 57. 0. 12. THF, DMPU (10.0). 0. 0. 0. ኻࠞ࠴ࠝࡦߩᓇ㗀ࠍ⺞ߴࠆߚߦ K-Selectride ࠍㆶరߣߒߡ↪ᬌ⸛ࠍⴕߞߚ (Table 2.3)ޕL-Sectride ࠍ↪ߚ㓙ߦⅣൻ߇ㅴⴕߒߚṁᇦࠍ↪ߡᬌ⸛ࠍⴕߞߚ߇ߕޔ ࠇ߽ L-Selectride ࠃࠅ߽₸߇ૐਅߒߚޕ. .
(16) Table 2.3. Michael reduction/intramolecular Michael reaction cascade of 2Z. CO2Ph TIPSO Me. CO2Et. Me CO2Ph. K-Selectride (1.2 equiv.) 2 h, -78 oC conditions. TIPSO. 2Z. CO2Et. Me CO2Ph + TIPSO. H Me 5. CO2Et H Me 5'. yield (%) entry. solvent/ additive (equiv.) 5. 5’. 1. THF. 38. 0. 2. THF/DMF (1/2). 48. 0. 3. THF, HMPA (10.0). < 20. 0. ߎߩࠃ߁ߦ Michael ฃኈߢࠆ ,-ਇ㘻ࠛࠬ࠹࡞ߩᐞ㈩⟎ࠍᄌ߃ࠆߎߣߦࠃࠅ ੑߟߩ࠻ࡦࠬ-1,2-⟎឵ࠪࠢࡠࡋࠠࠨࡦⅣࠍ┙ㆬᛯ⊛ߦ᭴▽ߔࠆߎߣߦᚑഞߒߚࠛޕ ࠠ࠰ࡔ࠴ࡦㇱߩᔕᕈࠍ↪ߒో⚛྾⚖ਇᢧਛᔃߩ᭴▽ߦᚑഞߒߡࠆὐߢᣂ ⷙᕈ߇㜞ߣ⸒߃ࠆޕ. .
(17) ╙㧟┨ ᷰⅣဳㅪ⛯ Michael ᔕߩ㐿⊒ ╙㧝▵ ⎇ⓥ⢛᥊ ᄤὼߦߪ fusidane ࠻࠹࡞ࡍࡁࠗ࠼ߣ߫ࠇࠆ࠹࡞ࡍࡁࠗ࠼߇ሽߔࠆ(Figure 3.1)12ޕ ߎߩൻว‛⟲ߪߦ⊛⥸৻ޔ⍮ࠄࠇߡࠆࠬ࠹ࡠࠗ࠼㛽ᩰߣߪ⇣ߥࠅޔchair-boat-chair ߩ ਃⅣᑼ㛽ᩰࠍߒߡࠆߩ߇․ᓽߢࠆޔߚ߹ޕઍߐࠇࠆൻว‛ helvolic acid13 ߿ fusidic acid2 ߪ᛫↢‛⾰ߣߒߡ⚦⩶ߩჇᱺࠍ㒖ኂߔࠆߎߣ߇⍮ࠄࠇߡࠆޕHelvolic acid ߿ fusidic acid ߪఝࠇߚ↢‛ᵴᕈ࡙߮࠾ࠢߥ᭴ㅧࠍߒߡࠆߚࠄ߆ߡߨ߆ޔวᚑ ⎇ⓥ߇ⴕࠊࠇߡ߈ߚ߇ fusidic acid ߩᒻᑼోวᚑߩႎ๔߇৻ઙࠆߩߺߢࠆ 14ޕ ߘߎߢޔ fusidane ࠹࡞ࡍࡁࠗ࠼ߩਇᢧోวᚑࠍⷞ㊁ߦࠇ ߥࠢ࠾࡙ޔchair-boat-chair ߩਃⅣᑼ 㛽ᩰ㧔ABC Ⅳ㧕ߩ᭴▽ᬌ⸛ߦขࠅ߆߆ߞߚޕ. H H. Me H Me. H. Me H. H. Me. O. H fusidane. Me. H Me OAc. chair-boat-chair ABC-ring. Me O. helvolic acid. CO2H HO Me. OAc. H Me. H HO. H Me OAc. CO2H OAc. Me O. fusidic acid. Figure 3.1. Fusidane triterpenes. ߎߩ㛽ᩰࠍ᭴▽ߔࠆߢᄙߊߩวᚑᚢ⇛ࠍขࠅᓧࠆ߇ᷰⅣဳᔕ߇ᦨ߽ലᨐ⊛ߢ ࠆߣ⠨߃ߚ 15ޔࠄߥߗߥޕᷰⅣဳᔕߪᄢຬⅣߩ․ᕈߩࡦ࡚ࠪࡔࠜࡈࡦࠦޔ⚂ࠍ ฃߌޔ㜞┙ㆬᛯᕈߩ⊒߇ㄟࠆ߆ࠄߢࠆޕ ᷰⅣဳ Diels-Alder ᔕߦࠃࠆ chair-boat-chair ߩਃⅣᑼ㛽ᩰ㧔ABC Ⅳ㧕ߩ᭴▽ߪႎ ๔ߐࠇߡࠆ߽ߩߩ 16ޔᷰⅣဳ Michael ᔕߦࠃࠆ᭴▽ߪ╩⠪߇⍮ࠆ㒢ࠅ߹ߢߦ ߥߩߎޔߢߎߘޕਃⅣᑼ㛽ᩰࠍᷰⅣဳㅪ⛯ Michael ᔕߦࠃߞߡ᭴▽ߔࠆߎߣߦߒߚ (Scheme 3.1)ޕ ⅣߦੑߟߩࠛࡁࡦࠍᜬߟਛຬⅣ 19 ࠍၮ⾰ߣߒߡ⸳ቯߒߚ৻ޕᣇࠍᔕᕈߩ㜞ࠛ ࠠ࠰ࡔ࠴ࡦࠤ࠻ࡦߦߔࠇ߫ޔ⟎ㆬᛯ⊛ߥ Michael ᔕ߇ㅴⴕߒ࠻ࡁࠛߚߓ↢ޔ ߇߽߁৻ᣇߩࠛࡁࡦߦኻߒߡᷰⅣဳ Michael ᔕ߇ㅴⴕߔࠆߎߣߦࠃࠅߩ⊛⋡ޔⅣൻ 18 ߇ᓧࠄࠇࠆߣ⠨߃ߚޕਛຬⅣ 19 ߪ೨ㅀߩ 1,4-ࡅ࠼࠼ㆶరࠍὐߣߔࠆㅪ⛯ Michael ᔕߦࠃߞߡᓧߚ 5 ߆ࠄวᚑߢ߈ࠆ߽ߩߣߒߚޕ. .
(18) Scheme 3.1. Concept of the intermolecular/transannular Michael reaction cascade. O Nu Me H O. Me TIPSO. H TIPSO. Me. O. H Me 18. O. H. Nu. O Me CO2Ph. Me. Nu TIPSO. TIPSO. O. H Me 19. CO2Et H Me 5. ߎࠇ߹ߢᷰⅣဳ Michael ᔕߪᄤὼ‛วᚑߦᐲ(ߚ߈ߡࠇࠄ↪ޘScheme 3.2)17߆ߒޕ ߒߥ߇ࠄޔScheme 3.2 ߩਅᲑߦ␜ߔࠃ߁ߥ᳞ᩭߩ Michael ᔕࠍὐߣߒߚㅪ⛯ Michael ᔕߩႎ๔ߪዋߥ 17cޕ Scheme 3.2. Application of the transannular Michael reaction. O O O. Me O. TBAF. BOMO. O. Me O MeO. OMe. O. DMF/THF (2/1) -78 to 5 oC, 2 h 99% (dr > 95 : 5). BOMO. Me. Me. Me H. O. LiOAllyl. H Me. O. Salvinorin A Me. MeO O. O. H. Me Me H. Me OMe. O OH. Evans's total synthesis of salvinorin A17e. Me H. H AllylOH, rt ovn, 73%. Me OAllyl. Yamamura's synthetic study of leuphoreppinol17c. ߎߩᚻᴺߪߩࡦ࠴ࡔ࠰ࠠࠛޔᔕᕈࠍ↪ߒޔ⟎ㆬᛯᕈࠍ⊒ߐߖࠆὐ߮ࠃ߅ޔ ᳞ᩭߩ Michael ᔕࠍὐߣߒߚᷰⅣဳᔕߢࠆὐߢᣂⷙᕈ߇㜞ߊޔ ᚢ⊛ߢࠆޕ ߎߩᚻᴺߦࠃߞߡ chair-boat-chair ߩਃⅣᑼ㛽ᩰࠍ᭴▽ߔࠆߎߣ߇น⢻ߣߥࠇ߫ޔᷰⅣဳ ㅪ⛯ Michael ᔕߩᣂߚߥน⢻ᕈࠍߔߎߣ߇ߢ߈ࠆޕ. .
(19) ╙㧞▵ ၮ⾰วᚑ ၮ⾰ߣߥࠆਛຬⅣ 19 ߩวᚑߦขࠅ߆߆ߞߚ(Scheme 3.3)ޕ೨ㅀߩ 1,4-ࡅ࠼࠼ㆶరࠍ ὐߣߔࠆㅪ⛯ Michael ᔕߦࠃߞߡᓧࠄࠇߚ 5 ߦኻߒߡޔᵴᕈߩ㜞ࡈࠚ࠾࡞ࠛࠬ࠹ ࡞ࠍࡌࡦࠫ࡞࠴ࠝ࡞ߣㆬᛯ⊛ߦࠛࠬ࠹࡞឵ߒ 20 ࠍᓧߚߩߘޕᓟޔጊㆶర. 18. ߦࠃ. ߞߡ࠴ࠝࠛࠬ࠹࡞ࠍࠕ࡞࠺ࡅ࠼ߦㆶరߒޔㅜวᚑߒߚࡎࠬࡎࡀ࠻ 23(Scheme 3.4)ࠍ ↪ߡ HWE ᔕࠍⴕ 22 ࠍวᚑߒߚޕᔕߪ↢ᚑ‛ࠍਈ߃ࠆߎߣߥߊㅴⴕߔࠆ߽ ߩߩޔᔕὐߢࠆࠕ࡞࠺ࡅ࠼߇ࡀࠝࡍࡦ࠴࡞ߦ⟎ߔࠆߚޔ㜞᷷ࠍⷐߒ₸ߪਛ ⒟ᐲߦߣߤ߹ߞߚޕ Scheme 3.3. Synthesis of enone 22. O Me. Me CO2Ph TIPSO. a. CO2Et. SBn CO2Et. TIPSO. H Me. O Me b TIPSO. H Me. 5. 20. H CO2Et H Me 21. O I. Me. c. TIPSO. I H Me CO2Et. O 23. OMe P OMe O. 22. Reagents and conditions: (a) BnSH, K2CO3, DMF, 70 ºC, 4 h, 76%; (b) Pd(OAc)2, Et3SiH, acetone, rt, 5 min, 90%; (c) 23, NaH, 1,4-dioxane, reflux, 4 h, 68%.. Scheme 3.4. Preparation of phosphonate 23. n-BuLi dimethyl methylphosphonate. I CO2Et. I. THF, -78 oC, 2 h, quant.. 8. O. OMe P OMe O. 23. ࠛࡁࡦ 22 ߇ᓧࠄࠇߚߚ ࠍࡦ࠻ࠤ߮ࠃ߅࡞࠹ࠬࠛޔDIBAL-H ߦࠃߞߡㆶరߒࠫࠝ ࡞ 24 ߳ ߣ ᄌ ឵ ᓟ ㉄ ޔൻ ߔ ࠆ ߎ ߣ ߢ 25 ࠍ ว ᚑ ߒ ߚ (Scheme 3.5) ޕ25 ߩ ಽ ሶ ౝ Nozaki-Hiyama-Kishi(NHK)ᔕ. 19. ࠍⴕߞߚߣߎࠈਛຬⅣ 26 ߪᒻᚑߐࠇߕޔಽሶౝ. Michael ᔕ߇ㅴⴕߔࠆߎߣߢ↢ߓࠆ↢ᚑ‛߇ᓧࠄࠇߚޕ. .
(20) Scheme 3.5. Attempted construction of the ten-membered ring. OH. O Me. TIPSO. Me. a. I. O. TIPSO. Me. b. I. H Me CO2Et. H Me. 22. 24. O. TIPSO OH. Me I. H Me CHO. TIPSO. H Me. 25. OH. 26. Reagents and conditions: (a) DIBAL-H, CH2Cl2, 0 ºC, 2 h, 89%; (b) Dess-Martin periodinane, CH2Cl2, rt, 1 h, 90%.. ߘߎߢޔಽሶౝ Michael ᔕࠍ㒐ߋߚࠛࡁࡦࠍ⼔ߔࠆߎߣߣߒߚޕ22 ࠍࠫࡔ࠴࡞ ࠕ࠲࡞ 27 ߳ߣᄌ឵ߒޔDIBAL ㆶరࠍⴕޔ28 ࠍวᚑߒߚ(Scheme 3.6)ޕ Scheme 3.6. Preparation of aldehyde 28. O. MeO. Me. TIPSO. Me. a. I. OMe. TIPSO. H Me CO2Et 22. MeO Me. b. I H Me CO2Et 27. OMe. TIPSO. I H Me CHO 28. Reagents and conditions: (a) CH3C(OMe)3, PTSA, MeOH, reflux, 10 min, 79%; (b) DIBAL-H, CH2Cl2,. –78 ºC, 2 h, 77%. ࠕ࡞࠺ࡅ࠼ 28 ߇ᓧࠄࠇߚߚޔಽሶౝ NHK ᔕߦࠃࠆਛຬⅣߩวᚑࠍᬌ⸛ߒߚ (Table 3.1)ޕTHF/DMF ṁᇦߢᔕࠍⴕߞߚߣߎࠈᗐቯߒߡߚ 29 ߢߪߥߊࠍࡦࡁࠛޔ ⼔ߒߡߚࠫࡔ࠴࡞ࠕ࠲࡞ߩ⣕⼔ࠍߞߚ 26 ߇ᓧࠄࠇߚ(entry 1)ޕṁᇦࠍ DMSO ߦᄌ߃ᔕࠍⴕߞߚߣߎࠈⅣൻߩߺ߇ㅴⴕߒߚ 29߮ࠃ߅ޔ⣕⼔ࠍߞߚ 26 ߇ ᓧࠄࠇߚ(entry 2)ޕEntries 1,2 ߩ㆑ߪṁᇦߩ࡞ࠗࠬႮၮᕈᐲߩ㆑ߦࠃࠆ߽ߩߛߣ⠨߃ ࠄࠇࠆᧄޕᔕߩࠃ߁ߦⅣౝߦⶄᢙߩ sp2 ⚛ࠍᜬߟ 10 ຬⅣࠍಽሶౝ NHK ᔕߦࠃߞ ߡ᭴▽ߒߡࠆߪ߶ߣࠎߤߥޕ. .
(21) Table 3.1. Intramolecular Nozaki-Hiyama-Kishi reaction. MeO. OMe. Me. MeO. O. OMe. Me. conditions. Me +. TIPSO. I. TIPSO. H Me CHO. H Me. 28. entry. OH. TIPSO. 29. Reagents (equiv.). solvent. H Me 26. OH. temp. time. yield (%). (°C). (h). 29. 26. 1. CrCl2 (15.0), NiCl2 (0.15). THF/DMF (2/1). 50. 15. 0. 70. 2. CrCl2 (15.0), NiCl2 (0.15). DMSO. 50. 15. 36. 16. ಽሶౝ Nozaki-Hiyama-Kishi ᔕߦࠃߞߡᓧࠄࠇߚ 26 ࠍ㉄ൻߒⅣൻ೨㚟 19 ࠍวᚑ ߒߚ(Scheme 3.7)ޕ Scheme 3.7. Preparation of substrate 19. O. O Dess-Martin periodinane. Me. TIPSO. H Me 26. OH. CH2Cl2 rt, 1 h, 86% TIPSO. . Me. H Me 19. O.
(22) ╙㧟▵ ᔕᬌ⸛ ၮ⾰ߣߥࠆਛຬⅣ 19 ߇ᓧࠄࠇߚߩߢᷰⅣဳㅪ⛯ Michael ᔕߩᬌ⸛ࠍⴕߞߚޕ ߹ߕޔ ᳞ᩭߣߒߡ L-Selectride ࠍ↪ߡᬌ⸛ࠍⴕߞߚ(Table 3.2)ޕṁᇦߩᬌ⸛ࠍ⒳ޔ߇ߚߞⴕޘ ߕࠇߦ߅ߡ߽ޔේᢱ߇ᶖᄬߔࠆ߽ߩߩࠛࠠ࠰ࡔ࠴ࡦㇱߪㆶరߐࠇߕޔ⟎ㆬᛯ ⊛ߥ 1,4-ࡅ࠼࠼ㆶరߩㅴⴕߪ⏕ߐࠇߥ߆ߞߚޕ Table 3.2. Intermolecular/transannular Michael reaction cascade with L-Selectride. O. O. Me. Me. L-Selectride (1.1 equiv.) -78 oC, 1 h. TIPSO. H. O. H Me. Me. TIPSO. 19. H Me. O. 30. entry. solvent. additive (equiv.). yield (%). 1. THF. -. 0. 2. THF/DMF (1/2). -. 0. 3. THF. HMPA (5.0). 0. 4. CH2Cl2. -. 0. ࡅ࠼࠼ㆶరߦࠃࠆᷰⅣဳᔕ߇ㅴⴕߒߥ߆ߞߚߚࠍ࡞ࠦ࡞ࠕޔ᳞ᩭߣߒߡ ↪ߡᬌ⸛ࠍⴕߞߚ(Table 3.3)ޕPMB ࠕ࡞ࠦ࡞ ߿࡞ࠦ࡞ࠕ࡞ࠕޔp-(MeO)C6H4OH ࠍ᳞ᩭߣߒߡ↪ߡޔႮၮ߿ṁᇦߩᬌ⸛ࠍ⒳ߩ⊛⋡߇ߚߞⴕޘⅣൻߪᓧࠄࠇߥ߆ߞ ߚߩߘޕේ࿃ߣߒߡޔὐߣߥࠆ Michael ᔕࠃࠅ߽ࠛࡁ࠻ൻߥߤ߇ㅴⴕߒߡࠆ ߎߣ߇⠨߃ࠄࠇࠆޕ. .
(23) Table3.3. Intermolecular/transannular Michael reaction cascade with alcohol. O. RO. Me. TIPSO. H Me 19. Me. conditions. O. O. TIPSO. H Me 31. O. entry. reagents (equiv.). solvent. temp (°C). time (h). yield (%). 1. PMBOH (2.0), n-BuLi (1.5). THF. –78. 4. 0. 2. PMBOH (2.0), K2CO3 (5.0). THF. –78. 4. 0. 3. K2CO3 (5.0). allylOH. rt. 3. 0. THF. –78. 8. 0. 4. p-(MeO)C6H4OH (2.0), KHMDS (1.5). 5. p-(MeO)C6H4OK (1.5). THF. rt. 8. 0. 6. p-(MeO)C6H4OK (1.5). THF. 50. 8. 0. 7. p-(MeO)C6H4OK (1.5). THF/DMF (1/2). rt. 8. 0. 8. p-(MeO)C6H4OLi (1.5). THF. rt. 8. 0. ㅀߩࠃ߁ߦࡅ࠼࠼߿ࠕ࡞ࠦ࡞ࠍ᳞ᩭߣߒߡ↪ߚ㓙ޔⅣൻ߇ᓧࠄࠇߥේ ࿃ߣߒߡὐߣߥࠆ᳞ᩭߩ Michael ᔕ߇㚂የࠃߊㅴⴕߒߡߥߎߣ߇ߍࠄࠇࠆޕ ߘߎߢޔὐߣߥࠆ Michael ᔕ߇ߎࠅ߿ߔ࠰ࡈ࠻ߥ᳞ᩭࠍ↪ࠆߎߣߣߒ࠴ޔ ࠝ࡞ࠍ↪ߚᷰⅣဳㅪ⛯ Michael ᔕߩᬌ⸛ࠍⴕߞߚ(Table 3.4)ޕEntries 1,2 ߢߪ࠴ࠝ ࡈࠚࡁ࡞ߣ㉄ࠞ࠙ࡓࠍ↪ߡᔕࠍⴕߞߚ⚿ߩߘޕᨐࡑࠝ࠹ࠬࠕࠫޔ32’߇ ࠊߕ߆ߦᓧࠄࠇߡߊࠆ߽ߩߩޔ32 ߇ਥ↢ᚑ‛ߣߒߡᓧࠄࠇߚޕEntry 3 ߢߪ࠴ࠝࡈࠚࡁ ࡞ߣ DBU ࠍ↪ߚߣߎࠈ 73㧑ߣ㜞₸߆ߟ㜞┙ㆬᛯ⊛ߦ 32 ߇ᓧࠄࠇߚޕEntries 4,5 ߢߪ࠴ࠝࡈࠚࡁ࡞ߩࠞ࠙ࡓႮࠍ᳞ᩭߣߒߡ↪ߚߣߎࠈޔ32 ߇┙ㆬᛯ⊛ߦᓧ ࠄࠇߚޕኻࠞ࠴ࠝࡦߩᓇ㗀ࠍขࠅ㒰ߊߚ 18-crown-6 ࠍᷝടߒߚߣߎࠈⅣൻߪ߶ߣ ࠎߤᓧࠄࠇߥ߆ߞߚ(entry 6)ޕ. .
(24) Table 3.4. Intermolecular/transannular Michael reaction cascade with benzenethiol. O. O. PhS. Me. Me. Me. conditions. + H. TIPSO. entry. TIPSO. O. H Me 19. reagents (equiv.). O. PhS. H O. H Me 32. O. H Me 32'. yield (%). temp (°C). solvent. TIPSO. time (h) 32. 32’. 1. PhSH (3.0), K2CO3 (5.0). MeOH. 50. 2. 30. 9. 2. PhSH (3.0), K2CO3 (5.0). MeOH. 0. 3. 54. 8. 3. PhSH (3.0), DBU (5.0). MeOH. 0. 3. 73. 13. 4. PhSK (2.0). THF. –78. 1. 43. 0. 5. PhSK (2.0). MeOH. –78. 1. 41. 0. 6. PhSK (2.0), 18-crown-6 (1.0). THF. rt. 5. trace. trace. ᓧࠄࠇߚⅣൻߩ⋧ኻ┙㈩⟎ߩቯߪੑ⚖᳓㉄ၮࠍ⼔ߒߡࠆ TIPS ၮࠍ⣕⼔ ߔࠆߎߣߢᓧࠄࠇߚ 33ޔ33’ߩ NOESY ࠬࡍࠢ࠻࡞᷹ቯߦࠃߞߡቯߒߚ(Figure 3.2)ޕ. PhS. O. PhS Me H. Me HO. H HO. H Me 33. O. Me. O. O. HO. H. O. HO. H SPh. H Me 33'. SPh O. Me H. Me. O. Me. H. H. O. Figure 3.2. NOESY experiments on 33 and 33’. ᷰⅣဳ Michael ᔕߩㆬᛯᕈࠍㆫ⒖⁁ᘒ߆ࠄ⠨ኤߒߚ(Figure 3.3)ޕᚲᦸߩ┙ࠍߔ ࠆ 32 ߪㆫ⒖⁁ᘒ TS 3 ࠍ⚻↱ߔࠆߎߣߢᓧࠄࠇࡑࠝ࠹ࠬࠕࠫޔ32’ߪ TS 1 ࠍ⚻↱ߔ ࠆߎߣߢᓧࠄࠇࠆޕTS 2,4 ߪ┙⊒߇ᄢ߈ߚਇቯߢࠆޕTS 1 ߪ TS 2,4 ⒟ߩ┙ ⊒ߪή߇ axial ߦ㈩ะߔࠆࡔ࠴࡞ၮߣࠛࠠ࠰ࡔ࠴ࡦ↱᧪ߩࡔ࠴ࡦㇱߣߩ 㑆ߢ 1,3-diaxial ⊒߇↢ߓࠆ⚿ߩߘޕᨐ┙ޔ⊒߇ᦨ߽ዊߐ TS 3 ࠍ⚻↱ߒᔕ߇ㅴ ⴕߒޔਥ↢ᚑ‛ߣߒߡ 32 ߇ᓧࠄࠇߚߣ⠨߃ࠄࠇࠆޔߡߒߘޕᰴߦ⊒ߩዋߥ TS 1 ࠍ ⚻↱ߒࠫࠕࠬ࠹ࠝࡑ32’߇ࠊߕ߆ߦᓧࠄࠇߚߣ⠨߃ࠄࠇࠆޕ. .
(25) SPh O. Me. O. Me O TIPSO. TIPSO Me. H. H. Me. H. O. SPh. TS 1. TS 2 Me O. H. Me. O. TIPSO Me. SPh H. TIPSO Me. H SPh. TS 3 (favored). H. O O. TS 4. Figure 3.3. Proposed transition states of the transannular Michael reaction. ਥ↢ᚑ‛ߣߒߡᓧࠄࠇߚ 32 ࠍ Raney Ni ߦࠃࠅ⣕⎫ߔࠆߎߣߢ 30 ࠍᓧߚ(Scheme 3.8)ޕ 30 ߩ┙㈩⟎ߪ᛫↢‛⾰ helvolic acid ߩ ABC Ⅳߩ┙㈩⟎ߣ৻⥌ߔࠆޕᓧࠄࠇߚਃⅣ ᑼൻว‛ 30 ߪ PM3 ඨ⚻㛎⊛ᚻᴺࠍ↪ߚ⸘▚ߦࠃࠅ chair-boat-chair ਃⅣᑼ㛽ᩰࠍߒ ߡࠆߎߣ߇␜ໂߐࠇߚޕ Scheme 3.8. Desulfurization of 32. O. O. Me H TIPSO. H Me 32. Me. Raney Ni SPh O. CH2Cl2, rt 56%. H TIPSO. H Me 30. Me O. ߎߩࠃ߁ߦᷰⅣဳㅪ⛯ Michael ᔕߦࠃࠅࠬ࠹ࡠࠗ࠼㛽ᩰߣߒߡߪ⒘ߥ chair-boat-chair ਃⅣᑼ㛽ᩰߩ┙ㆬᛯ⊛ߥ᭴▽ߦᚑഞߒߚࠅࠃߦࠇߎޕᷰⅣဳᔕߩᣂ ߚߥᄙⅣᑼ㛽ᩰ᭴▽ᴺߣߒߡߩน⢻ᕈࠍߒߚࠆߥᦝޕᄌ឵ߦࠃࠅ helvolic acid ߿ fusidic acid ߩోวᚑ߳ߣዷ㐿ߢ߈ࠆޕ. .
(26) ╙㧠┨ Liebeskind-Srogl ࠞ࠶ࡊࡦࠣ́ಽሶౝ Diels-Alder ㅪ⛯ᔕߩ㐿⊒ ╙㧝▵ ⎇ⓥ⢛᥊ ಽሶౝ Diels-Alder ᔕߪ৻ᐲߦⶄᢙߩⅣ᭴ㅧ߅ࠃ߮ਇᢧὐࠍ᭴▽ߒ߁ࠆߚޔᄤὼ ‛วᚑߦ㗫❥ߦ↪ࠄࠇߡ߈ߚ(Scheme 4.1)20ోޔߒ߆ߒޕ⚛྾⚖ਇᢧਛᔃߩ᭴▽ࠍ ߁Ⅳൻᔕߪ㜞ᾲ߿ᒝ࡞ࠗࠬ㉄ߩᷝടߥߤỗߒ᧦ઙࠍᔅⷐߣߔࠆߎߣ߽ᄙߊޔૐ ₸ߦ⇐߹ࠆߎߣ߽ࠆޕ Scheme 4.1. Application of the intramolecular Diels-Alder reaction. Me TIPSO OTES Me. Me. Me. O MnO2. TBSO TIPSO H. CO2Me. 80 oC, 2 days OH. CHO. OTIPS Me. Me. Me H. OTBS. OTES. H H Me. OTES. 28% Me. FR 182877. CO2Me H. Nakada's total synthesis of FR 182877. OTBS. ᔕᕈࠍ㜞ࠆߚߦᵴᕈߥࠫࠛࡦ߿ࠫࠛࡁࡈࠖ࡞ࠍ↪ࠆᔅⷐ߇ࠆߦ․ޕఝࠇߚ ࠫࠛࡁࡈࠖ࡞ߩ৻ߟߣߒߡ -ࠕ࡞ࠠ࠺ࡦ -ࠤ࠻ࠛࠬ࠹࡞߇ߍࠄࠇࠆޕ-ࠕ࡞ࠠ࠺ ࡦ -ࠤ࠻ࠛࠬ࠹࡞ߪࠕ࡞ࠤࡦ߇ੑߟߩ㔚ሶ᳞ᒁᕈၮߦࠃࠅᵴᕈൻߐࠇߡࠆߚࠛࠫޔ ࡦߣㅦ߿߆ߦ Diels-Alder ᔕࠍߎߒోޔ⚛྾⚖ਇᢧਛᔃߩ᭴▽߽น⢻ߢࠆ (Scheme 4.2)ޕ Scheme 4.2. Intramolecular Diels-Alder reaction of -alkylidene -ketoester. Intramolecular Diels-Alder (IMDA) reaction. RO2C. CO2R O. O. D-alkylidene E-ketoester. . .
(27) ߒ߆ߒߥ߇ࠄޔ㜞ᔕᕈࠁ߃ߦขᛒ߅ࠃ߮᭴▽߇࿎㔍ߢࠆ♽ޔߢߎߘޕਛߢ ࠕ࡞ࠠ࠺ࡦ -ࠤ࠻ࠛࠬ࠹࡞ࠍวᚑߒޔන㔌ߖߕߦㅪ⛯ߒߡ Diels-Alder ᔕࠍⴕ߁⸘ ↹ࠍ┙ߡߚ(Scheme 4.3)ౕޕ⊛ߦߪขᛒ߇ኈᤃߥ࠴ࠝࠛࠬ࠹࡞ 36 ߣࠕ࡞ࠤ࠾࡞ࠬ࠭ ൻว‛ 37 ߩࠞ࠶ࡊࡦࠣᔕ㧔Liebeskind-Srogl ࠞ࠶ࡊࡦࠣᔕ㧕ߦࠃࠅޔ-ࠕ࡞ࠠ ࠺ࡦ -ࠤ࠻ࠛࠬ࠹࡞ 35 ࠍวᚑߔࠆߎߣ߇ߢ߈ࠇ߫↢ޔᚑᓟߦㅦ߿߆ߦㅪ⛯ߒߡಽሶ ౝ Diels-Alder ᔕ߇ㅴⴕߒⅣൻ 34 ࠍਈ߃ࠆߣ⠨߃ߚޕ Scheme 4.3. Concept of the Liebeskind-Srogl/intramolecular Diels-Alder reaction cascade. Liebeskind-Srogl coupling reaction CO2R2 Me H TIPSO. H Me 34. 37 SnBu3. Me CO2R2 O. TIPSO. Intramolecular Diels-Alder reaction (IMDA reaction). H Me 35. CO2R2 O. Me O TIPSO. H Me 36. SR1. Liebeskind-Srogl ࠞ࠶ࡊࡦࠣᔕߪࠕ࡞ࠤ࠾࡞ࠬ࠭ൻว‛߽ߒߊߪࠕ࡞ࠤ࠾࡞ࡎ࠙ ⚛ൻว‛ߣ࠴ࠝ࡞ࠛࠬ࠹࡞ߣߩ Pd ⸅ᇦࠍ↪ߚࠞ࠶ࡊࡦࠣᔕߢࠆ(Scheme 4.4)21ޕ1 ଔߩ㌃Ⴎࠍᷝടߔࠆߎߣߢ᷷ߥ᧦ઙਅࠞ࠶ࡊࡦࠣᔕ߇ㅴⴕߔࠆߎߣ߇⍮ ࠄࠇߡࠆޔߚ߹ޕਛᕈ᧦ઙߢᔕ߇ㅴⴕߔࠆߎߣ߆ࠄ㉄Ⴎၮߦ⣀ᒙߥൻว‛ߦኻߒ ߡᔕࠍⴕ߁ߎߣ߇ߢ߈ࠆ․ߥ߁ࠃߩߎޕᓽࠍᜬߟߚޔขᛒ߇࿎㔍ߥ -ࠕ࡞ࠠ࠺ ࡦ -ࠤ࠻ࠛࠬ࠹࡞ߩ᭴▽ߦ Liebeskind-Srogl ࠞ࠶ࡊࡦࠣᔕࠍ↪ࠆߎߣࠍ⠨߃ߚޕ Scheme 4.4. Liebeskind-Srogl coupling reaction. O R1. S. R'. +. R2. O 1. S. R. R'. O R1. S. p-tolyl. +. +. R2. B(OH)2. Pd2(dba)3 (10 mol%) TFP (3 mol%) CuTC THF, 50 oC. 9-BBN. n-Bu3Sn. CuP(O)Ph2 THF, 45 - 50 oC. S CO2Cu. R2. 57-93%. Cu(I) thiophene-2-carboxylate (CuTC). O 1. R2. R. 21-90%. Pd2(dba)3 (1 mol%) TFP (8 mol%). . R1. Pd(PPh3)4 (5 mol%) Cs2CO3 CuTC THF, 45 oC. R2. O. O. P O. O R1. O. R2. 61-97%. tri-2-furylphosphine (TFP).
(28) ಽሶౝ Diels-Alder ᔕߪᄤὼ‛วᚑߦᐲޔ߇ߚ߈ߡࠇࠄ↪ޘLiebeskind-Srogl ࠞ࠶ ࡊࡦࠣᔕߣ IMDA ᔕߩㅪ⛯ᔕߪ೨߇ߥߩߎޕᚻᴺࠍ⏕┙ߢ߈ࠇ߫ޔᔕ ᕈ߇㜞ߚߦන㔌߇࿎㔍ߥਛ㑆 35 ࠍᔕ♽ਛߢ⊒↢ߐߖ߇ߣߎࠆ↪ޔน⢻ߣߥ ࠆߚޔಽሶౝ Diels-Alder ᔕߩᄤὼ‛วᚑ߳ߩㆡ↪ߩ߇ᐢ߇ࠆޕ. .
(29) ╙㧞▵ ၮ⾰วᚑ ᔕᬌ⸛ࠍⴕ߁ߚၮ⾰วᚑߦขࠅដ߆ߞߚޕ೨ㅀߩࠕ࡞࠺ࡅ࠼ 21 ߆ࠄวᚑࠍⴕߞ ߚࡦࠛࠫޔߕ߹ޕㇱࠍ᭴▽ߔࠆߎߣߣߒޔHorner-Wittig ᔕ߿ Julia-Kocienski ᔕߥ ߤࠍ⹜ߺߚ߇┙㓚ኂߩᓇ㗀߆ߕࠇ߽ࠫࠛࡦ 38 ߪᓧࠄࠇߥ߆ߞߚ(Scheme 4.5)ޕ໑৻ޔ Takai ᔕߦࠃࠅ࡛࠼ࠝࡈࠖࡦ߳ߣ㜞₸ߦߡᄌ឵ߢ߈ߚߚ ߊ⛯ޔStille ࠞ࠶ࡊ ࡦࠣᔕߦࠃࠅࠫࠛࡦ 38 ߳ߣᄌ឵ߒߚޕ Scheme 4.5. Attempted construction of diene 38. a). S SO2 N. Me CHO TIPSO. CO2Et H Me. Me. KHMDS, DME b) (EtO)2. O P. TIPSO. 21. CO2Et H Me 38. n-BuLi, THF c. d. I Me O TIPSO. H Me. OEt. 39. Reagents and conditions: (c) CHI3, CrCl2, THF/1,4-dioxane (1/1), rt, 8 h, 68%; (d) PdCl2(MeCN)2, tributylvinylstannane, DMF, rt, 1 h, quant... ᰴߦߩ߳࡞࠹ࠬࠛ࡞ࠝ࠴ޔᄌ឵ࠍᬌ⸛ߒߚ(Scheme 4.6)࡞࠹ࠬࠛޕㇱߪࠫࠛࡦߩ ┙㓚ኂ߽ߒߊߪ㔚ሶ⊛ⷐ࿃ߦࠃࠅᔕᕈ߇⪺ߒߊૐߊ⋥ߩࠄ߆࡞࠹ࠬࠛޔធ⊛ߥ࠴ࠝ ࡞ࠛࠬ࠹࡞߳ߩᄌ឵ߪᚑഞߒߥ߆ߞߚޔߚߩߘޕᎿ⒟ᢙࠍⷐߔࠆ߽ߩߩㆶరߒ㉄ޔ ൻߔࠆߎߣߢࠞ࡞ࡏࡦ㉄߳ߣዉ߈❗ޔวߦࠃࠅ࠴ࠝ࡞ࠛࠬ࠹࡞ࠍวᚑߔࠆߎߣߦߒߚޕ ࠛࠬ࠹࡞ 38 ߩ LiAlH4 ㆶరߦࠃࠅᓧࠄࠇߚࠕ࡞ࠦ࡞ࠍ TPAP ㉄ൻߦࠃࠅࠕ࡞࠺ࡅ࠼߳ ᄌ឵ߒޔPinnick ㉄ൻࠍⴕࠞ࡞ࡏࡦ㉄ 40 ࠍวᚑߒߚޕၮ⾰ߢࠆ⒳࠹ࠬࠛ࡞ࠝ࠴ޘ ࡞ߪ❗วߦࠃࠅวᚑߒߚޕ. .
(30) Scheme 4.6. Preparation of thiol esters 36. Me. Me. a, b, c. O TIPSO. TIPSO. OEt. H Me 38. Me. Me d. O H Me. OH. H Me 40. Me. TIPSO. O. SPh. e. O TIPSO. 36a. TIPSO. OH. H Me. O. 40 g. Me. Me O. H Me. N. 36b. f. TIPSO. S. H Me. O TIPSO. SEt. H Me. 36c. St-Bu. 37d. Reagents and conditions: (a) LiAlH4, THF, 0 °C, 4 h; (b) TPAP, NMO, MS 4A, CH2Cl2, rt, 12 h; (c) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O (1/1), rt, 4 h, 68% (3 steps); (d) PhSH, DCC, DMAP, CH2Cl2, rt, 30 min, 87%; (e) 2-PySH, EDCI, DMAP, CH2Cl2, rt, 1 h, 98%; (f) EtSH, DCC, DMAP, CH2Cl2, rt, 1 h, 12%; (g) t-BuSH, DCC, DMAP, CH2Cl2, rt, 1 h, 35%.. ࠫࠛࡦߩၮ⾰৻⥸ᕈࠍ⏕ߔߴߊࠫࠛࡦᧃ┵ߦ⟎឵ၮࠍዉߒߚၮ⾰ߩวᚑ߽ⴕߞ ߚ(Scheme 4.7)ޕScheme 4.5-6 ߣห᭽ߦࠞ࡞ࡏࡦ㉄߹ߢ⺃ዉߒߚޕ Scheme 4.7. Preparation of 43. I Me. TIPSO. CO2Et H Me 39. OTBS. Me. a TIPSO. OTBS. Me. b, c CO2Et. TIPSO. H Me 41. CHO H Me 42. OTBS. Me d TIPSO. CO2H H Me. Bu3Sn. OTBS 44. 43. Reagents and conditions: (a) PdCl2(MeCN)2, 44, DMF, rt, 1 h, quant.; (b) LiAlH4, THF, 0 °C, 8 h; (c) TPAP, NMO, MS 4A, CH2Cl2, rt, 12 h; (d) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O (1/1), rt, 4 h, 55% (3 steps). . .
(31) ࠞ࡞ࡏࡦ㉄ 43 ߦኻߒߡ࠴ࠝ࡞ࠍ❗วߐߖࠆߎߣߦࠃࠅ࠴ࠝ࡞ࠛࠬ࠹࡞ࠍวᚑߒ ߚ(Scheme 4.8)ޕ Scheme 4.8. Preparation of thiol esters. OTBS. Me O TIPSO. H Me 45a. SPh. OTBS. Me. a. O TIPSO. OH. H Me 43. OTBS. Me. b. O TIPSO. S. H Me. N. 45b. Reagents and conditions: (a) PhSH, DCC, DMAP, CH2Cl2, rt, 30 min, 56%; (b) 2-PySH, EDCI, DMAP, CH2Cl2, rt, 1 h, 85%.. .
(32) ╙㧟▵ ᔕᬌ⸛ ၮ⾰ߢࠆ࠴ࠝ࡞ࠛࠬ࠹࡞߇ᓧࠄࠇߚߚᔕᬌ⸛ࠍⴕߞߚ࠭ࠬ࡞࠾ࠤ࡞ࠕޕൻว ‛ߣߒߡ 4622 ࠍ↪ߚ(Table 4.1)ޕEntries 1,2 ߢߪࠕ࡞ࠠ࡞࠴ࠝ࡞ࠛࠬ࠹࡞ࠍၮ⾰ߣߒ ߡᔕࠍⴕߞߚޕቶ᷷ߢߪᔕ߇ㅴⴕߖߕޔടᾲ᧦ઙਅߦᔕࠍⴕߞߚ߇ലᨐߪࠄࠇ ߕේᢱ߇࿁ߐࠇߚ ࡞࠹ࠬࠛ࡞ࠝ࠴࡞࠾ࠚࡈޕ36a ࠍၮ⾰ߣߒߡ↪ࠆߣਛ⒟ᐲߩ ₸ߢߪࠆ߇Ⅳൻࠍ┙ㆬᛯ⊛ߦᓧߚ(entry 3)ޕ2-ࡇࠫࡦ࠴ࠝ࡞ࠛࠬ࠹࡞ 36b ߪ 0 °C ߢߪⅣൻ 47 ࠍࠊߕ߆ߦਈ߃ࠆߩߺߛߞߚ߇ޔቶ᷷ਅߢ 81%ߣ㜞₸┙ޔㆬᛯ ⊛ߦⅣൻࠍਈ߃ߚ(entries 4 and 5)ޕ Table 4.1. Liebeskind-Srogl coupling/intramolecular Diels-Alder reaction cascade. Me. SnBu3. O TIPSO. H Me 36. Pd2(dba)3 (10 mol%) AsPh3 (30 mol%) CuTC (3.0 equiv.). Me. + CO2Me. SR. H. THF TIPSO. H Me. 46 (2.0 equiv.). CO2Me O. 47 °. entry. R. temp ( C). time (h). yield (%). 1. Et (36c). rt to 50. 2 to 12. trace. 2. t-Bu (36d). rt to 50. 1 to 12. NR. 3. Ph (36a). rt. 3. 58. 4. 2-Py (36b). 0. 4. 19. 5. 2-Py (36b). rt. 0.5. 81. ᧄᔕߦ߅ߡߪޔਛ㑆ߢࠆ -ࠕ࡞ࠠ࠺ࡦ -ࠤ࠻ࠛࠬ࠹࡞ߩ↢ᚑ߇⏕ߢ߈ ߥ߶ߤޔㅦ߿߆ߦ IMDA ᔕ߇ㅴⴕߒߚᧄޕᔕߦࠃߞߡ┙ㆬᛯ⊛ߦᓧࠄࠇߚൻ ว‛ߩ⋧ኻ┙㈩⟎ߪ 48 ߩ NOESY ࠬࡍࠢ࠻࡞⸃ᨆߦࠃࠅቯߒߚ(Figure 4.1)ޕᔕߩ ┙ㆬᛯᕈߪㆫ⒖⁁ᘒ߆ࠄ⺑ߢ߈ࠆ(Figure 4.2)ޕTS 2 ߦ߅ߡ axial ߦ㈩ะߒߡ ࠆࡔ࠴࡞ၮߣࡔ࠴࡞ࠛࠬ࠹࡞ߣߩ㑆ߢ 1,3-diaxial ⊒߇↢ߓਇቯൻߐࠇ┙ࠅࠃޔ㓚 ኂߩዋߥ TS 1 ࠍ⚻↱ߒߚߎߣߦࠃࠅ 47 ߇┙ㆬᛯ⊛ߦᓧࠄࠇߚ߽ߩߣ⠨߃ࠄࠇࠆޕ. Me H O. Me H HO. H Me. CO2Me O. H H. HO Me. H H. CO2Me. 48. Figure 4.1. NOESY experiment on 48.. .
(33) Me O. OMe. O. TIPSO. TIPSO. Me. CO2Me. H. Me. O. H. TS 1. TS 2. Figure 4.2. Proposed transition states of the intramolecular Diels-Alder reaction. ᧄᔕߩၮ⾰৻⥸ᕈࠍ⺞ߴࠆߚࡦࠛࠫޔ߮ࠕ࡞ࠤ࠾࡞ࠬ࠭ൻว‛ߩᧃ┵ߦ⟎឵ၮ ࠍዉߒߚၮ⾰ߢㅪ⛯ᔕߩᬌ⸛ࠍⴕߞߚޕవߩ⍮ࠃࠅࠕ࡞ࠠ࡞࠴ࠝ࡞ࠛࠬ࠹࡞ߪ ࠞ࠶ࡊࡦࠣᔕ߇ㅴⴕߒߥߎߣ߇್ߒߚߚޔએਅߩᬌ⸛ߢߪࡈࠚ࠾࡞࠴ࠝ࡞ ࠛࠬ࠹࡞ 36a ߣ 2-ࡇࠫࡦ࠴ࠝ࡞ࠛࠬ࠹࡞ 36b ߩߺࠍၮ⾰ߣߒߡ↪ߚޕᆎߦࠕ ࡞ࠤ࠾࡞ࠬ࠭ൻว‛ߩၮ⾰৻⥸ᕈࠍ⏕߆ࠆߎߣߦߒޔE ߦ⟎឵ၮࠍߔࠆࠕ࡞ࠤ࠾ ࡞ࠬ࠭ൻว‛ 4923 ࠍ↪ߡᬌ⸛ࠍⴕߞߚ(Table 4.2)ޕ Table 4.2. Liebeskind-Srogl coupling/intramolecular Diels-Alder reaction cascade. O TIPSO. H Me 36. Pd2(dba)3 (10 mol%) AsPh3 (30 mol%) CuTC (3.0 equiv.). SnBu3. Me. CO2Me. +. Me H. THF. SR. TIPSO. OTBS. H Me. 49 (2.0 equiv.). CO2Me O. OTBS. 50 °. entry. R. temp ( C). time (h). yield (%). 1. Ph (36a). rt. 2. 66. 2. 2-Py (36b). 0. 0.5. 28. 3. 2-Py (36b). rt. 0.5. 44. ߘߩ㓙ޔ೨ㅀߩ Table 4.1 ߣߪ⇣ߥࠅࡈࠚ࠾࡞࠴ࠝ࡞ࠛࠬ࠹࡞ 36a ࠍၮ⾰ߣߒߡ↪ ߚᔕ߇⦟ᅢߥ₸ࠍਈ߃ߚ(entry 1)ޕᓧࠄࠇߚൻว‛ߩ┙㈩⟎ߪ 50 ߆ࠄᢙᎿ⒟ࠍ ⚻ߡᄌ឵ߒߚ 51 ߩ NOESY ⸃ᨆߦࠃࠅቯߒߚ(Figure 4.3)ޕᔕߩ┙ㆬᛯᕈߪ Figure 4.4 ߦ␜ߔㆫ⒖⁁ᘒ߆ࠄ⺑ߢ߈ࠆޕ. H Me H. Me H RO. H Me. O OO. Me. H. H O. R=diNO2Bz. 51. Figure 4.3. NOESY experiment on 51.. . O. RO O.
(34) Me O. H. TIPSO Me. H. OTBS. CO2Me. Figure 4.4. Proposed transition state of the intramolecular Diels-Alder reaction. ᰴߦޔZ ߩࠕ࡞ࠤ࠾࡞ࠬ࠭ൻว‛ 5224 ࠍ↪ߚᔕࠍᬌ⸛ߒߚ(Table 4.3)ޕ2-ࡇࠫ ࡦ࠴ࠝ࡞ࠛࠬ࠹࡞ 36b ࠍၮ⾰ߣߒߡ↪ߚᔕߢߪⅣൻߪᓧࠄࠇߥ߆ߞߚ߇ (entries 2 and 3) ࡞࠹ࠬࠛ࡞ࠝ࠴࡞࠾ࠚࡈޔ36a ࠍ↪ߚᔕߢߪૐ₸ߢߪࠆ߇Ⅳ ൻ߇ᓧࠄࠇߚ(entry 1)ޕ Table 4.3. Liebeskind-Srogl coupling/intramolecular Diels-Alder reaction cascade. CO2Et. Me O TIPSO. SnBu3. +. Pd2(dba)3 (10 mol%) AsPh3 (30 mol%) CuTC (3.0 equiv.). H. THF. SR. H Me. Me. TIPSO. OPMB. H Me. 52 (2.0 equiv.). 36. CO2Et O. OPMB. 53 °. entry. R. temp ( C). time (h). yield (%). 1. Ph (36a). rt. 2. 31. 2. 2-Py (36b). 0. 0.5. 0. 3. 2-Py (36b). rt. 0.5. trace. ᓧࠄࠇߚൻว‛ߩ┙㈩⟎ߪ 53 ߆ࠄᢙᎿ⒟ࠍ⚻ߡᄌ឵ߒߚ 54 ߩ NOESY ⸃ᨆߦࠃࠅ ቯߒߚ(Figure 4.5)ޕᔕߩ┙ㆬᛯᕈߪ Figure 4.6 ߦ␜ߔㆫ⒖⁁ᘒߦࠃࠅ⺑ߢ߈ࠆޕ. H Me H O. Me H RO. H Me. OR CO2Et O R=diNO2Bz. RO Me. H H. H H H CO2Et. OR. 54. Figure 4.5. NOESY experiment on 54.. Me O. OPMB. TIPSO Me. H. H CO2Me. Figure 4.6. Proposed transition state of the intramolecular Diels-Alder reaction.. .
(35) ࠕ࡞ࠤ࠾࡞ࠬ࠭ൻว‛ߩᧃ┵ߦ⟎឵ၮࠍዉߒߚ႐ว߽Ⅳൻ߇ㅴⴕߔࠆߎߣࠍ ߒߚߚߩࡦࠛࠫߡ⛯ޔၮ⾰৻⥸ᕈࠍ⏕߆ࠆߴߊᬌ⸛ࠍⴕߞߚޕ೨ㅀߒߚ 45 ࠍၮ ⾰ߣߒߡ↪ߚ࠭ࠬ࡞࠾ࠤ࡞ࠕޔߕ߹ޕൻว‛ 46 ߣߩ Liebeskind-Srogl ࠞ࠶ࡊࡦࠣ́ ಽሶౝ Diels-Alder ㅪ⛯ᔕߩᬌ⸛ࠍⴕߞߚ(Table 4.4)ޕ Table 4.4. Liebeskind-Srogl coupling/intramolecular Diels-Alder reaction cascade. SnBu3. O TIPSO. H Me. Pd2(dba)3 (10 mol%) AsPh3 (30 mol%) CuTC (3.0 equiv.). OTBS. Me. + CO2Me. SR. H. THF TIPSO. H Me. 46 (2.0 equiv.). 45. OTBS. Me. CO2Me O. 55 °. entry. R. temp ( C). time (h). yield (%). 1. Ph (45a). rt. 10. 33. 2. 2-Py (45b). 0. 2. 62. 3. 2-Py (45b). rt. 1. 37. 2-ࡇࠫࡦ࠴ࠝ࡞ࠛࠬ࠹࡞ 45b ࠍ↪ 0 °C ߢᔕࠍⴕ߁ߎߣߢ 62%ߩ₸ߢⅣൻ ࠍ┙ㆬᛯ⊛ߦᓧߚ(entry 2)ߩߢ߹ޕᬌ⸛ߣห᭽ߦࠞ࠶ࡊࡦࠣߩ↢ᚑࠍ⏕ߔ ࠆߎߣߥߊⅣൻ߇ㅴⴕߒߚޕᓧࠄࠇߚൻว‛ߩ┙㈩⟎ߪ 55 ߆ࠄᢙᎿ⒟ࠍ⚻ߡᄌ឵ߒ ߚ 56 ߩ NOESY ⸃ᨆߦࠃࠅቯߒߚ(Figure 4.7)ޕᔕߩ┙ㆬᛯᕈߪ Figure 4.8 ߦ␜ߔ ㆫ⒖⁁ᘒߦࠃࠅ⺑ߢ߈ࠆޕ. H RO. H Me 56. H. Me H O. OR. Me. RO. CO2Me O. Me. H H. OR H. H. CO2Me. R=diNO2Bz. Figure 4.7. NOESY experiment on 56.. Me O. OTBS. TIPSO Me. CO2Me. H. Figure 4.8. Proposed transition state of the intramolecular Diels-Alder reaction.. .
(36) ᰴߦ࠭ࠬ࡞࠾ࠤ࡞ࠕޔൻว‛ 49 ࠍ↪ߡᬌ⸛ࠍⴕߞߚ(Table 4.5)࡞ࠝ࠴࡞࠾ࠚࡈޕ ࠛࠬ࠹࡞ 45a ߣ 2-ࡇࠫࡦ࠴ࠝ࡞ࠛࠬ࠹࡞ 45b ߩਔၮ⾰ߦ߅ߡࠞ࠶ࡊࡦࠣߩߺ ߇ㅴⴕߒߚ 58 ߇ᓧࠄࠇߚࡦࠛࠫޕ߮ࠫࠛࡁࡈࠖ࡞ߩᧃ┵ߦ⟎឵ၮࠍዉߒߚߎߣߦ ࠃࠅ┙㓚ኂߩᓇ㗀߇ᄢ߈ߊߥࠅޔಽሶౝ Diels-Alder ᔕ߇ㅴⴕߒߠࠄߊߥߞߚߚ ߛߣ⠨߃ࠄࠇࠆޕ Table 4.5. Liebeskind-Srogl coupling/intramolecular Diels-Alder reaction cascade. OTBS. Me H TIPSO Me O TIPSO. SnBu3. OTBS. CO2Me. +. H Me. Pd2(dba)3 (10 mol%) AsPh3 (30 mol%) CuTC (3.0 equiv.). OTBS. 57 +. THF. SR. H Me 45. CO2Me O. OTBS. OTBS. Me. Z. 49 (2.0 equiv.) TIPSO. CO2Me O. H Me. OTBS. 58. entry. temp (°C). R. Yield (%) time (h) 57. 58. 1. Ph (45a). rt. 3. 0. 58. 2. 2-Py (45b). 0. 2. 0. < 44. 3. 2-Py (45b). rt. 0.5. 0. < 53. ᓧࠄࠇߚࠞ࠶ࡊࡦࠣ 58 ߦኻߒߡടᾲ߿ߩ㉄ࠬࠗ࡞ޔᷝടࠍⴕⅣൻࠍ⹜ߺߚ߇ Ⅳൻ 57 ߪᓧࠄࠇߕⶄᢙߩ↢ᚑ‛ࠍਈ߃ߚ(Scheme 4.9)ޕ Scheme 4.9. Intramolecular Diels-Alder reaction of 58. Me. TIPSO. OTBS Z CO2Me O. H Me. OTBS. Me2AlCl, BF3OEt2 etc. or heat. OTBS. Me H. TIPSO. 58. H Me. CO2Me O. 57. ᦨᓟߦࠕ࡞ࠤ࠾࡞ࠬ࠭ൻว‛ 52 ࠍ↪ߡᬌ⸛ࠍⴕߞߚ(Table 4.6)ޕ. . OTBS.
(37) Table 4.6. Liebeskind-Srogl coupling/intramolecular Diels-Alder reaction cascade. EtO2C OTBS. Me O TIPSO. 45. Pd2(dba)3 (0.1 equiv.) AsPh3 (0.3 equiv.) CuTC (3.0 equiv.). +. TIPSO. TIPSO. O. H Me. OPMB. CO2Et O. H Me. 59. 59'. H TIPSO. OPMB. CO2Et O. H Me. temp (oC). OTBS. Me. OPMB. H TIPSO. OPMB. CO2Et O. H Me. 60. 52 (2.0 equiv.). R. OTBS. Me. SnBu3. 60'. yield (%) time (h) 59. 59’. 60. 60’. 1. 2-Py (45b). 0. 4. 10. trace. 0. 0. 2. 2-Py (45b). rt. 4. trace. trace. 0. 0. 3. Ph (45a). rt. 4. 46. 5. 0. 0. a. Ph (45a). rt. 4. 36. 14. 0. 0. 5. Ph (45a). rt to 50. 2 to 2. 0. 0. 0. -b. 6a. Ph (45a). rt to 50. 2 to 2. 0. 0. 0. 38. 4. a. OTBS Z. THF. CO2Et. entry. Me. E OPMB. SR. H Me. OTBS. Me. Pd(PPh3)4 (20 mol%) was used as catalyst. b no reproducibility. 2-ࡇࠫࡦ࠴ࠝ࡞ࠛࠬ࠹࡞ 45b ࠍ↪ߚ㓙ߪⅣൻߩߺߥࠄߕࠞ࠶ࡊࡦ߽ࠣ߶ ߣࠎߤᓧࠄࠇߥ߆ߞߚ(entries 1 and 2)ߩߎޕ㓙↢ࠅࠃߦࠣࡦࡊ࠶ࠞޔᚑߒߚ -ࠕ࡞ࠠ ࠺ࡦ -ࠤ࠻ࠛࠬ࠹࡞߇⇣ᕈൻߒߚ 59’߇∥〔㊂ᓧࠄࠇߚ(Scheme 4.10)ࠝ࠴࡞࠾ࠚࡈޕ ࡞ࠛࠬ࠹࡞ 45a ࠍ↪ࠆߣࠞ࠶ࡊࡦࠣߩߺ߇ㅴⴕߒߚ 59 ߣ 59’߇ਛ⒟ᐲߩ₸ߢᓧ ࠄࠇߚ(entry 3)⸅ޕᇦߣߒߡ↪ߚ Pd2(dba)3 ↱᧪ߩ dba ߣࠞ࠶ࡊࡦࠣ 59ޔ59’ߩಽ 㔌߇࿎㔍ߛߞߚߚ Pd(PPh3)4 ࠍ⸅ᇦߣߒߡ↪ߚ(entry 4)⚿ߩߘޕᨐ⇣ޔᕈൻߒߚࠞ࠶ ࡊࡦࠣ 59’ߩഀว߇Ⴧടߒߚ┙ޕ㓚ኂߩᓇ㗀ߢಽሶౝ Diels-Alder ᔕ߇ㅴⴕߒߠ ࠄߊߥߞߡࠆߎߣ߇⠨߃ࠄࠇߚߚߩࠣࡦࡊ࠶ࠞޔㅴⴕࠍ⏕ߒߚᓟޔടᾲࠍⴕߞ ߚޕPd2(dba)3 ࠍ⸅ᇦߣߒߡ↪ߚ㓙ߪⅣൻߩ↢ᚑ߇⏕ߐࠇߚ߇ౣᕈߦਲߒ߆ߞߚ (entry 5)ޕPd(PPh3)4 ࠍ↪ߡห᭽ߩ᧦ઙࠍ⹜ߒߚ⚿ᨐޔ38%ߣૐ₸ߢߪࠆ߇Ⅳൻ ߇ᓧࠄࠇߚ(entry 6)ޕᓧࠄࠇߚⅣൻߪᢙᎿ⒟ߩᄌ឵ߩᓟᓧࠄࠇࠆ 61 ߩ NOESY ࠬࡍࠢ ࠻࡞⸃ᨆߦࠃࠅ(Figure 4.9)ޔⅣൻ೨ߦടᾲߣ Pd ⸅ᇦߩᓇ㗀ߦࠃࠅ -ࠕ࡞ࠠ࠺ࡦ -ࠤ ࠻ࠛࠬ࠹࡞߇ 59’ߦ⇣ᕈൻߒߩߘޔᓟߦⅣൻ߇ㅴⴕߒߚ 60’ߢࠆߎߣ߇ಽ߆ߞߚ (Scheme 4.10)ޕⅣൻߩㆬᛯᕈߪ Figure 4.10 ߦ␜ߔㆫ⒖⁁ᘒࠃࠅ⺑ߢ߈ࠆޕ. .
(38) Scheme 4.10. Isomerization of -alkyliden -ketoester of 59. CO2Et OTBS. Me. TIPSO. Me. OTBS. TIPSO. OPMB. CO2Et O. H Me. 59. H TIPSO. H Me. 59'. H RO. CO2Et O. H Me. OPMB. RO H H H H H H OPMB MeH H CO2Et. OPMB RO Me. R=diNO2Bz. CO2Me O. 60'. OR. Me. OTBS. Me. heat. Z. OPMB. E O. H Me. isomerization. H O. H. 61. Figure 4.9. NOESY experiment on 61.. Me O. OPMB. TIPSO. OTBS Me. H. H CO2Me. Figure 4.10. Proposed transition state of intramolecular Diels-Alder reaction. ᓧࠄࠇߚࠞ࠶ࡊࡦࠣ 59 ߇Ⅳൻߒ 60 ߇ᓧࠄࠇࠆߎߣࠍᦼᓙߒޔടᾲ᧦ઙਅࠗ࡞ޔ ࠬ㉄ߩᷝട᧦ઙਅߦⅣൻߩᬌ⸛ࠍⴕߞߚ(Scheme 4.11)ޕടᾲߦࠃࠅ 60’ߣ⇣ߥࠆⅣൻ ߩ↢ᚑ߇⏕ߢ߈ߚ߽ߩߩޔౣᕈ߇ਲߒߊߘߩ᭴ㅧቯߦߪ⥋ࠄߥ߆ߞߚޕ Scheme 4.11. Intramolecular Diels-Alder reaction of 59. CO2Et OTBS. Me. TIPSO. E O. H Me. toluene, 100 oC. OPMB TIPSO. 59. CO2Et O. H Me 62. . OTBS. Me. OPMB.
(39) ࠫࠛࡦ߮ࠕ࡞ࠤ࠾࡞ࠬ࠭ൻว‛ߩਔᣇߦ⟎឵ၮࠍዉߒߚၮ⾰ߦ߅ߡߪ┙㓚 ኂߩᓇ㗀ߦࠃࠅⅣൻ߇ㅴⴕߖߕࠞ࠶ࡊࡦࠣߩߺ߇ᓧࠄࠇࠆߎߣ߆ࠄ┙ޔ㓚ኂߦࠃ ࠆㆡ↪㒢⇇ߪ⏕ߐࠇߚ߽ߩߩޔ ᓥ᧪ߩᣇᴺߢߪขᛒ߇࿎㔍ߢࠆ -ࠕ࡞ࠠ࠺ࡦ ࠤ࠻ࠛࠬ࠹࡞ࠍᵴ↪ߔࠆ Liebeskind-Srogl ࠞ࠶ࡊࡦࠣ́ಽሶౝ Diels-Alder ㅪ⛯ᔕߩ 㐿⊒ߦᚑഞߒߚޕ. .
(40) ╙㧡┨ ent-kauranoid ࠹࡞ࡍࡁࠗ࠼ߩోวᚑ⎇ⓥ ╙㧝▵ ⎇ⓥ⢛᥊ ᄤὼߦߪࠫ࠹࡞ࡍࡁࠗ࠼ߣߒߡ ent-kauranoid ߣ߫ࠇࠆൻว‛⟲߇ሽߔࠆ. 25. ޕ. ent-kauranoid ߦዻߔࠆൻว‛ߩ᭴ㅧ⊛․ᓽߣߒߡ Figure 5.1 ߦ␜ߔ྾Ⅳᑼ㛽ᩰߢࠆ ent-kaurane 㛽ᩰࠍߒߡࠆߎߣ߇ߍࠄࠇࠆߩࠄࠇߎޕൻว‛⟲ߦߪ 600 ࠍ߃ࠆห ᣖ߇ሽߒߩߘޔᄙߊߪఝࠇߚ↢‛ᵴᕈੱߌࠊࠅߣޔ㑆ߩฦ⒳߇ࠎ⚦⢩ߦኻߒߡ㜞 Ⴧᱺ㒖ኂᵴᕈࠍ␜ߔߎߣ߇⍮ࠄࠇߡࠆ ߇ߟ৻ߩߘޕphyllostachysin F3 ߢࠆ(Figure 5.1)ޕ. HO Me H. H. H. H. H OH O OH. phyllostachysin F. ent-kaurane scaffold. Figure 5.1. Structure of ent-kaurane scaffold and phyllostachysin F. Phyllostachysin F ߪਛ⪇ੱ᳃࿖㔕ධ⋭ߦ⥄↢ߔࠆ Isodon Phyllostachys ߆ࠄ 2006 ᐕ ߦන㔌ߐࠇߚൻว‛ߢࠆޕޔㆡ↪▸࿐ߩᐢߐ߆ࠄ᛫߇ࠎᴦ≮ߦ߅ߡਛᔃ⊛ߥ ᓎഀࠍᜂߞߡࠆࠪࠬࡊ࠴ࡦࠃࠅ߽ᒝജߥ⚦⢩Ⴧᱺ㒖ኂᵴᕈࠍ␜ߔࡊࠬࠪޔߚ߹ޕ ࠴ࡦߪ㜞⣲≌❗ዊലᨐࠍᜬߟ߽ߩߩ࠽࠴ࡊޔ㍲ࠁ߃ߦ⣢Ქᕈࠍ␜ߔߚޔ⣢ਇో ߥߤ⢄⤳ᯏ⢻ߩ㓚ኂߣߞߚ㊀◊ߥ↪߇↢ߓࠆߣߞߚ⍴ᚲࠍᜬߟࠄ߆ߣߎߩߎޕ ࠪࠬࡊ࠴ࡦߣห⒟ᐲࠆߪߘࠇࠍಒ㚧ߔࠆ᛫߇ࠎᵴᕈࠍߒߟߟޔ↪߇ዋߥ ↪ߥ᛫߇ࠎߩត⚝ߪ㕖Ᏹߦ㊀ⷐߢࠅޔphyllostachysin F ߪߘࠇࠄࠍߨ߃ߚ᛫ ߇ࠎߩᣂߚߥ࠼ൻว‛ߢࠆ ߦ߁ࠃߩߎޕphyllostachysin F ߪᓟߩ᛫߇ࠎ ᴦ≮ࠍᦼᓙߒ߁ࠆ߶ߤߩఝࠇߚ↢‛ᵴᕈࠍ␜ߔ߇ߩߘޔ᭴ㅧ⊛ⶄ㔀ߐߩߚวᚑߪᧂ ߛ৻ઙ߽ႎ๔ߐࠇߡ߅ࠄߕޔ᭴ㅧᵴᕈ⋧㑐⎇ⓥ߽ⴕࠊࠇߡߥޔߚ߹ޕphyllostachysin F ߦ⇐߹ࠄߕޔent-kauranoid ߦዻߔࠆൻว‛ߩోวᚑߩႎ๔ߪ߈ࠊߡዋߥ 26ߞࠃޕ ߡࠄࠇߎޔൻว‛⟲ߦㅢߒߡሽߔࠆ ent-kaurarene 㛽ᩰߩല₸⊛᭴▽ᴺߩ⏕┙߅ࠃ߮ ߘߩᔕ↪ߦࠃࠆ phyllostachysin F ߩోวᚑ⎇ⓥߪቇⴚ㕙ߦ߅ߡ↪ᕈ߇ࠆߩߺߥࠄ ߕޔ᭴ㅧᵴᕈ⋧㑐⎇ⓥࠍᣂⷙ᛫߇ࠎߩត⚝⎇ⓥߦ߅ߡᭂߡ㊀ⷐߢࠆߚޔ ᧄ⎇ⓥࠍ㐿ᆎߒߚޕ. .
(41) ╙㧞▵ Phyllostachysin F ߩวᚑ⎇ⓥ ߹ߕࡒޔߢߩ phyllostachysin F ߩోวᚑߦ⌕ᚻߒߚޕㅒวᚑ⸃ᨆࠍ Scheme 5.1 ߦ␜ߔޕPhyllostachysin F ߩ D Ⅳࠍࠫࠞ࡞Ⅳൻߦࠃߞߡ᭴▽ߒޔABC ⅣߩਃⅣᑼ㛽 ᩰߪ೨ㅀߩ Liebeskind-Srogl ࠞ࠶ࡊࡦࠣ́ಽሶౝ Diels-Alder ㅪ⛯ᔕߦࠃߞߡ᭴▽ߔ ࠆ߽ߩߣߒߚޕㅪ⛯ᔕߩၮ⾰ 65 ߪ⺰ᢥᣢ⍮ߩᚻᴺߢࠆ 1,4-ࡅ࠼࠼ㆶరࠍὐߣ ߔࠆㅪ⛯ࡑࠗࠤ࡞ᔕ 6 ߦࠃߞߡ᭴▽น⢻ߥ A Ⅳ 66 ߆ࠄᄌ឵ߢ߈ࠆ߽ߩߣ⠨߃ߚޕ Scheme 5.1. Retrosynthetic analysis of phyllostachysin F. H. HO Me. Intramolecular radical reaction. RO Me. OH O OH. H. Me OR OH OR. H H. H phyllostachysin F. O. H. Me CO2Et CO2t-Bu. SnBu3. SR. H. 64. RO2C. +. CO2R O. H. 63 Me. Liebeskind-Srogl coupling/ Intramolecular Diels-Alder reaction cascade. I. H. 65. 37. 66. ߹ߕޔA Ⅳ 66 ߩวᚑߦขࠅដ߆ߞߚ(Scheme 5.2)ޕᢥ₂ᣢ⍮ൻว‛ 6727 ߆ࠄ৻⚖ࠕ ࡞ࠦ࡞ࠍ㉄ൻߒࠕ࡞࠺ࡅ࠼ 68 ߳ޔ7228 ߣߩ Wittig ᔕߦࠃࠅਇ㘻ࠛࠬ࠹࡞ 69 ߳ ߣᄌ឵ߒߚ᧦㉄ࠍ࡞࠲ࠕޕઙߦߡ⣕⼔ߒޔ7329 ߣ HWE ᔕࠍⴕ߁ߎߣߢ 71 ࠍ วᚑߒߚޕ71 ߦኻߒߡ L-Selectride ࠍㆶరߣߒߡ↪ޔⅣൻᔕࠍⴕߞߚޕᔕ᧦ઙ ߩᦨㆡൻߦࠃࠅ 87%ߣ㜞₸ߦߡⅣൻ 66 ࠍ┙ㆬᛯ⊛ߦᓧߚޕ Scheme 5.2. Preparation of A-ring moiety 66. Me. OH a O. OO. Me. CO2Et. c O. O. O. O. O. 67. Me. CO2Et. b. 68. CO2Et. d. e CO2t-Bu 71. 69. Me CO2Et CO2t-Bu. 70. CO2Et PPh3. H 66. 72. O CO2t-Bu P MeO OMe 73. Reagents and conditions: (a) Dess-Martin periodinane, CH2Cl2, rt, 2 h, 73%; (b) 72, CH2Cl2, rt, 2 h, 88%; (c) PTSA, acetone/H2O (1/1), 50 °C, 1.5 h; (d) 73, NaH, THF, rt, 1 h, 97% (2 steps); (e) L-Selectride, THF,. –78 °C to –40 °C, 2 h, 87%. .
(42) ⛯ߡޔ㎛ᔕߢࠆ Liebeskind-Srogl ࠞ࠶ࡊࡦࠣ́ಽሶౝ Diels-Alder ㅪ⛯ᔕߩ ၮ⾰วᚑߦขࠅដ߆ߞߚ(Scheme 5.3) ࡞࠹ࠬࠛࠫޕ66 ߦኻߒߡૐ᷷ਅߢ DIBAL ㆶరࠍ ⴕ߁ߎߣߢㆬᛯ⊛ߦࠛ࠴࡞ࠛࠬ࠹࡞ࠍㆶరߒߚ৻ޕㇱߢ߹࡞ࠦ࡞ࠕޔㆊㆶరߐࠇߚ ߚޔᓟಣℂᓟ㉄ߕߖࠍ♖ޔൻࠍ߅ߎߥ߁ߎߣߢࠕ࡞࠺ࡅ࠼ 74 ߳ߣᄌ឵ߒߚ࡞ࠕޕ ࠺ࡅ࠼ 74 ߦኻߒߡ Takai ᔕࠍⴕ࡛࠼ࠕ࡞ࠤࡦ 75 ߳ߣᄌ឵ߒޔStille ࠞ࠶ࡊࡦ ࠣᔕߦࠃࠅࠫࠛࡦ 76 ࠍวᚑߒߚޕ ࠛࠬ࠹࡞ㇱࠍ࠴ࠝ࡞ࠛࠬ࠹࡞߳ߣᄌ឵ߔߴߊޔ ㉄ᕈ᧦ઙൻߢ t-ࡉ࠴࡞ࠛࠬ࠹࡞ߩട᳓ಽ⸃ࠍ⹜ߺߚ߇⋡⊛ߩࠞ࡞ࡏࡦ㉄ߪᓧࠄࠇߥ߆ ߞߚߢ߹࡞ࠦ࡞ࠕޔߢߎߘޕㆶరߒ㉄ൻߔࠆߎߣߢࠞ࡞ࡏࡦ㉄߳ᄌ឵ߒߚޕLiAlH4 ㆶరࠍടᾲ᧦ઙਅⴕ߁ߎߣߢࠕ࡞ࠦ࡞߳ߣᄌ឵ߒޔTPAP ㉄ൻ ߊ⛯ޔPinnick ㉄ൻߦ ࠃࠅࠞ࡞ࡏࡦ㉄ 77 ߳ߣᄌ឵ߒߚޕ Scheme 5.3. Preparation of carboxylic acid 77. Me CO2Et. a. Me CHO. CO2t-Bu H. I Me. b. CO2t-Bu. CO2t-Bu. H 66. H 74. 75. c. Me. d,e,f. Me. CO2t-Bu H. CO2H H. 76. 77. Reagents and conditions: (a) DIBAL-H, CH2Cl2, –78 °C , 2 h; Dess-Martin periodinane, CH2Cl2, rt, 10 min, 72%; (b) CrCl2, CHI3, THF/DMF (1/1), rt, 4 h, 73%; (c) PdCl2(MeCN)2, dibutylvinylstannane, DMF, rt, 3 h; (d) LiAlH4, THF, 50 °C, 16 h; (e) TPAP, NMO, MS 4A, CH2Cl2, rt, 24 h; (f) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O (1/1), rt, 2 h, 61% (4 steps).. Liebeskind-Srogl ࠞ࠶ࡊࡦࠣ́ಽሶౝ Diels-Alder ㅪ⛯ᔕࠍⴕ߁ߦᒰߚࠅޔ⒳ߩޘ ࠴ࠝ࡞ࠛࠬ࠹࡞ࠍวᚑߒߚ(Scheme 5.4)ޕ. .
(43) Scheme 5.4. Preparation of thiol esters. Me. Me. a. O SPh. H. b. O OH. H. 65a. Me O S. H. 77. N. 65b. c. Me. Cl. O S. H. 65c. Reagents and conditions: (a) PhSH, DCC, DMAP, CH2Cl2, rt , 1 h, quant.; (b) 2-PySH, EDCI, DMAP, CH2Cl2, rt , 1 h, 52%; (c) 4-ClPhSH, DCC, DMAP, CH2Cl2, rt, 30 min, 86%.. ࠴ࠝ࡞ࠛࠬ࠹࡞ 65 ߩวᚑߦᚑഞߒߚߚ Liebeskind-Srogl ࠞ࠶ࡊࡦࠣ́ಽሶౝ Diels-Alder ㅪ⛯ᔕߩᬌ⸛ࠍⴕߞߚ(Table 5.1)࠭ࠬ࡞࠾ࠤ࡞ࠕޕൻว‛ߣߒߡ 46 ࠍ↪ ߚޕ2-ࡇࠫࡦ࠴ࠝ࡞ࠛࠬ࠹࡞ 65b ࠍၮ⾰ߣߒߡ↪ߚ߇ޔⅣൻ 78 ߪ∥〔㊂ᓧ ࠄࠇࠆߩߺߛߞߚ(entry 1) ࡞࠹ࠬࠛ࡞ࠝ࠴࡞࠾ࠚࡈޕ65a ࠍ↪ߚߣߎࠈޔේᢱ߇ᱷ ࠅૐ₸ߢߪࠆ߇Ⅳൻ߇ᓧࠄࠇࠆߎߣࠍߒߚ(entry 2)ޕᓧࠄࠇߚⅣൻߪੑ⒳ 㘃ߩࠫࠕࠬ࠹ࠝࡑߩᷙߓࠅߢࠫࠕࠬ࠹ࠝㆬᛯᕈߪ⚂ 2:1 ߛߞߚޕਥ↢ᚑ‛ߣߒ ߡᓧࠄࠇߚൻว‛ߩ⋧ኻ┙㈩⟎ߪᄌ឵ߒߚ 79 ߩ NOESY ⸃ᨆߦࠃߞߡቯߒߚ (Figure 5.2)ޕ Table 5.1. Liebeskind-Srogl/intramoloecular Diels-Alder reaction cascade. 46 SnBu3 (2.0 equiv.) Me. CO2Me. O SR. H. Pd2(dba)3 (10 mol%) AsPh3 (30 mol%) CuTC (3.0 equiv.). Me H. THF, rt, conditions. CO2Me O. H. 65. 78. Entry. R. time (h). 1. 2-Py (65b). 2. 2. Ph (65a). 4. results 65 remained, 78 (trace) 65 (ca. 10%), 78 (< 24%, dr 2:1). ┙ㆬᛯᕈߪㆫ⒖⁁ᘒࠃࠅ⺑ߢ߈ࠆ(Figure 5.3)ߩߎޕᔕߪ TS 1 ࠍ⚻↱ߔࠆߎߣ ߢᦸߺߩⅣൻࠍਈ߃ࠆޔࠄ߇ߥߒ߆ߒޕTS 1 ߦ߅ߡߪ axial ߦ㈩ะߔࠆࡔ࠴࡞ၮ ߣࠫࠛࡁࡈࠖ࡞ߣߩ㑆ߢ 1,3-diaxial ⊒߇↢ߓࠆ৻ޕᣇޔTS 2 ߦ߅ߡ߽ axial ߦ㈩ ะߒߡࠆࡔ࠴࡞ၮߣࡔ࠴࡞ࠛࠬ࠹࡞ߣߩ㑆ߢ 1,3-diaxial ⊒߇↢ߓࠆ⚿ޕᨐߣߒߡ TS 1 ߣ TS 2 ߣߩ㑆ߦࠛࡀ࡞ࠡᏅ߇ࠇߥ߆ߞߚߚૐㆬᛯᕈߦߟߥ߇ߞߚߣ⠨߃ߚޕ .
(44) Me. H CO2Me OH. H H. H H CO2Me H. H. Me. Me Me HO. 79. Figure 5.2. NOESY experiment on 79.. H O. Me. H. H. Me. Me CO2Me. O. Me CO2Me. TS 1 (favored). TS 2. Figure 5.3. Proposed transition states of the intramolecular Diels-Alder reaction. ḩ⿷ߩߊ┙ㆬᛯᕈ߇ᓧࠄࠇߥ߆ߞߚߚޔㆬᛯᕈߩะࠍᗧ࿑ߒ┙⊛ߦ㜞 ࠕ࡞ࠤ࠾࡞ࠬ࠭ൻว‛ 80 ࠍᬌ⸛ߦ↪ߚ(Table 5.2)ޕ 80 ߪ⺰ᢥᣢ⍮ൻว‛ߢࠆ 8130 ߆ࠄวᚑߒߚ(Scheme 5.5)ࠍ࡞࠹ࠬࠛ࡞ࠝ࠴࡞࠾ࠚࡈޕၮ⾰ߣߒߡ↪ߚ entry 1 ߢߪ ේᢱ߇ᱷࠅޔ↢ᚑ‛ߩ↢ᚑ߇⏕ߐࠇߚ߽ߩߩⅣൻ߇ᓧࠄࠇߚޕⅣൻߩࠫࠕࠬ ࠹ࠝㆬᛯᕈߪ 3:1 ߹ߢะߒߚޕ↢ᚑ‛ߩ᭴ㅧߪቯߢ߈ߥ߆ߞߚ߇ޔේ࿃ߣߒ ߡ࠻ࡦࠬࡔ࠲࡞ൻߩㅴⴕ߇ㆃߎߣ߇⠨߃ࠄࠇߚ࡞࠲ࡔࠬࡦ࠻ޔߢߎߘޕൻߩㅴ ⴕࠍଦㅴߔࠆ⋡⊛ߢ TBAF ߩᷝടࠍⴕߞߚ(entry 2)31⚿ߩߘޕᨐޔ↢ᚑ‛ߩ↢ᚑߪ⏕ ߐࠇߕ⋡⊛ߩⅣൻߣࠊߕ߆ߥ߇ࠄᱷߞߚේᢱߩߺ߇ᓧࠄࠇߚޕේᢱ߇ᶖᄬߒߥ ℂ↱ߣߒߡ㔚ሶ⊛ߥⷐ࿃ߦࠃࠅ㉄ൻ⊛ઃട߇㚂የࠃߊㅴⴕߒߡߥߎߣ߇⠨߃ࠄࠇ ߚߚޔ ࠃࠅᔕᕈߩ㜞࠴ࠝ࡞ࠛࠬ࠹࡞ 65b,65c ࠍ↪ߚ(entries 3 and 4)ޕ ߔࠆߣޔ ේᢱߪᶖᄬߒ↢ᚑ‛ߪ↢ᚑߖߕⅣൻߩߺࠍਈ߃ߚޕⅣൻߩࠫࠕࠬ࠹ࠝࡑᲧ ߪ࠴ࠝ࡞ࠛࠬ࠹࡞ߩ⒳㘃߿ᷝട‛ߦᓇ㗀ࠍฃߌࠆߎߣߪߥ߆ߞߚޕⅣൻ 82 ߪࠕ࡞ ࠤ࠾࡞ࠬ࠭ൻว‛↱᧪ߩਇ⚐‛ߣߩಽ㔌߇ࠞࡓߢߪ࿎㔍ߛߞߚߚޔNaBH4 ㆶరࠍ ⴕ㧞Ꮏ⒟ߢߩ₸ࠍ᳞ߚ(Scheme 5.6)ޕਥ↢ᚑ‛ߣߒߡᓧࠄࠇߚⅣൻߩ┙㈩⟎ ߪᄌ឵ߒߚ 83 ߩ NOESY ⸃ᨆߦࠃࠅቯߒߚ(Figure 5.4)ޕ Scheme 5.5. Synthesis of alkenylstannane 80. I. Pd2(dba)3, Bu3SnSnBu3 CO2t-Bu. DMF, rt, 3 h, 53%. 81. CO2t-Bu 80. . SnBu3.
(45) Table 5.2. Liebeskind-Srogl coupling/intramolecular Diels-Alder reaction cascade. 80 SnBu3 Me. (2.0 equiv.). CO2t-Bu. O. Me H. THF, rt, conditions. SR. H. Pd2(dba)3 (10 mol%) AsPh3 (30 mol%) CuTC (3.0 equiv.) additive (2.0 equiv.). CO2t-Bu O. H. 65. 82. entry. R. additive. time (h). results. 1. Ph (65a). -. 4. 2. Ph (65a). TBAF. 1. 65 (ca. 10%), 82 (dr 3:1). 3. 2-Py (65b). TBAF. 1. 82 (dr 3:1). 4. 4-ClPh (65c). TBAF. 1. 82 (dr 3:1). 65 (ca. 10%), 82 (dr 3:1), byproduct was observed.. Me. H. H. O OH. H. H H. Me. Me Me HO. 83. H O. H H. Figure 5.4. NOESY experiment on 83. Scheme 5.6. Synthesis of alcohol 84. 1) SnBu3 Me O. Me H. S. H. (2.0 equiv.). CO2t-Bu. Pd2(dba)3 (10 mol%) AsPh3 (30 mol%) CuTC (3.0 equiv.) TBAF (2.0 equiv.) THF, rt, 1 h. 2) NaBH4, MeOH, 0 oC, 10 min, 38% (2 steps). N. H 84. 65b 1) SnBu3 Me. Cl. O H. S. CO2t-Bu OH. (2.0 equiv.). CO2t-Bu. Pd2(dba)3 (10 mol%) AsPh3 (30 mol%) CuTC (3.0 equiv.) TBAF (2.0 equiv.) THF, rt, 1 h. 2) NaBH4, MeOH, 0 oC, 10 min, 45% (2 steps). 84. 65c. ᦝߥࠆ┙ㆬᛯᕈߩะ߇ᔅⷐߢߪࠆ߇ޔวᚑߦะߌߡᬌ⸛ࠍⴕߞߚޕC Ⅳߩੑߟ ߩ㉄⚛ේሶࠍశᾖߦࠃࠆ৻㊀㗄㉄⚛ߣߩ[4+2]ઃടⅣൻᔕߦࠃߞߡዉߔࠆߎߣࠍ ⠨߃ߚ(Scheme 5.7)ޕ. .
(46) Scheme 5.7. [4+2]cycloaddition with O2. Me OR OR. H H. O O. Me. O2, hQ. OR OR. H H. ၮ⾰ߣߥࠆࠫࠛࡦߩวᚑߦขࠅដ߆ߞߚ(Scheme 5.8)ޕIMDA ᔕߦࠃߞߡᓧࠄࠇߚ 84 ߩ᳓㉄ၮࠍ⼔ߒߡ 85 ߦᄌ឵ߒߚޕ85 ߦኻߒߡ NBS ߣ AIBN ࠍട߃ߡടᾲߒߚߣ ߎࠈࠢ࠻ࡦ 86 ߇ᓧࠄࠇߚ┙ߪࡦ࠻ࠢߩߎޕ⊛ⷐ࿃ߩߚ߆ࡅ࠼࠼એᄖߩ᳞ ᩭߢߪ㐿Ⅳߒߥ߆ߞߚߚޔDIBAL-H ߦࠃߞߡㆶరߒ ࡞ࠝࠫޔ87 ߦᄌ឵ߒߚߘޕ ߩᓟޔੑ⚖᳓㉄ၮߩ⣕⼔ ߢߣߎࠆߔ⼔ߡߞࠃߦ࠼ࠗ࠽࠻ࠕޔ88 ࠍวᚑߒߚޕ88 ߦኻߒߡ Burgess ⹜⮎ࠍ↪ࠆߎߣߦࠃࠅࠫࠛࡦ 89 ߩวᚑߦᚑഞߒߚޕ Scheme 5.8. Preparation of diene 89. OH Me. Me. a. H. CO2t-Bu OH. H. b. H. CO2t-Bu OTBS. H. 84. Me. O. H. OH. H. O OTBS. H. 85. c. Me. H. 86. OTBS 87. OH d,e. Me. f. H H. Me O. H. O O. O. H. 88. 89. Reagents and conditions: (a) TBSOTf, 2,6-lutidine, CH2Cl2, rt , 20 min, quant.; (b) NBS, AIBN, CCl4, reflux , 1 h, 72%; (c) DIBAL-H, CH2Cl2, 0 oC, 30 min, 70%; (d) TBAF, THF, rt, 30 min; (e) 2,2-dimethoxypropane, PPTS, THF, rt, 30 min, 92% (2 steps); (f) Burgess reagent, THF, 50 oC, 3 h, 78%.. ࠫࠛࡦ 89 ߩวᚑߦᚑഞߒߚߚ㉄⚛ሽਅశᾖࠍⴕߞߚ(Scheme 5.9)߇ߥߒ߆ߒޕ ࠄޔᔕߪㅴⴕߒߥ߆ߞߚ࠼ࠗ࠽࠻ࠕޕㇱߦࠃࠆ┙㓚ኂߩᓇ㗀߇⠨߃ࠄࠇߚߚޔ ⣕⼔ߒߚ 91 ߦኻߒߡห᭽ߩ᧦ઙߢᔕࠍⴕߞߚ߇┙ޔ㓚ኂߩᓇ㗀߇シᷫߐࠇߥ߆ ߞߚߚ߆ᔕߪㅴⴕߒߥ߆ߞߚޕ. .
(47) Scheme 5.9. Installation of oxygen atoms. Rose bengal O2. Me H. O. H. H. i-PrOH, hQ, rt 5 h, NR. O. O O. Me. H. 89. O O. 90. PTSA (cat.) THF/H2O (10/1) rt, 12 h, quant.. Me OH. H. OH. H. Rose bengal O2. O O. Me H. i-PrOH, hQ, rt 5 h, NR. H. 91. OH OH. 92. శᔕߦࠃࠆ㉄⚛ේሶߩዉߪ࿎㔍ߛߞߚߚ㉄ޔൻᐲࠍᓢߦޘߍߡߊߎߣࠍ⠨ ߃ߚ(Scheme 5.10)ޕ Scheme 5.10. Oxidation of C-ring. OH Me. H. Me. a OH. H. O. O b. H. Me. 94. O. O OAc. e. H. 95. OTBS 96. O OH OAc. Me. OAc. H. OTBS. O. OTBS. Me. d. H. OTBS. H. 93. O. H. OH. OTBS. H. 87. c. OH. H. OTBS. O. Me. H H. OTBS 97. Reagents and conditions: (a) MnO2, CH2Cl2, rt , 3 days, 88%; (b) TBHP, Triton B, THF, 0 oC , 1 h; (c) Ac2O, Py, DMAP, CH2Cl2, rt, 30 min,77% (2 steps); (d) DBU, TBSOTf, CH2Cl2, rt, 16 h, 92%; (e) mCPBA, CH2Cl2, rt, 16 h, 56%.. ೨ㅀߩࠕ࡞ࠕ࡞ࠦ࡞ 87 ࠍ MnO2 ߦࠃࠅࠛࡁࡦ 93 ߦ㉄ൻߒࠪࠠࡐࠛޔൻߦࠃࠅ 94 ࠍวᚑߒߚޕ᳓㉄ၮࠍ Ac ၮߢ⼔ߒ 95 ߳ᄌ឵ߒޔ95 ࠍࠪ࡞ࠛࡁ࡞ࠛ࠹࡞ߦߒ ߚᓟޔRubottom ㉄ൻࠍⴕޔ᳓㉄ၮߩዉࠍⴕߞߚޕ วᚑߒߚ 97 ߪ phyllostachysin F ߩᜬߟߔߴߡߩ㉄⚛ේሶࠍߒߡ߅ࠅ࠻ࠤࠪࠠࡐࠛޔ ࡦࠍ㐿ⅣߒޔD Ⅳࠍ᭴▽ߔࠆߎߣߢ phyllostachysin F ߩోวᚑ߇㆐ᚑߐࠇࠆޕ. .
(48) ╙㧟▵ ਇᢧട᳓ಽ⸃ߦࠃࠆ A Ⅳㇱಽߩਇᢧวᚑ ㉂⚛ᔕߪޔᲥᕈߩ㜞⹜⮎ࠍࠊߕޔቶ᷷ߦㄭ᷷ᐲߥߤ᷷ߥ᧦ઙߢᔕࠍⴕ߁ ߎߣ߇ߢ߈ࠆὐ߿ޔᲥᕈᑄ᫈‛ޔ↢ᚑ‛ࠍ↥ߺߐߥߣ߁ὐߢૐⅣႺ⽶⩄ဳᔕ ߢࠆ 32߇ࡊ࠶ࠕ࡞ࠤࠬޔߚ߹ޕኈᤃߥߚᎿᬺ⊛ࠬࠤ࡞ߦዷ㐿ߢ߈ࠆߥߤߩࡔ ࠶࠻߇ࠆ৻ޕᣇߢޔ㉂⚛ᔕߪၮ⾰․⇣⊛ߢࠆߣ߁㗴ὐߪࠆ߇ޔlipase ߿ࡉ ࠲⢄⤳㉂⚛㧔PLE㧕ߩࠃ߁ߦၮ⾰․⇣ᕈ߇ૐߊࠠ࡞ൻว‛ߩวᚑߦᐢߊ↪ࠄࠇߡ ࠆ߽ࠆ ߦ․ޕPLE ߪၮ⾰․⇣ᕈ߇ૐߊࡊࡠࠠ࡞ߥࠫࠛࠬ࠹࡞ߩਇᢧട᳓ಽ⸃ ߿ࡒߩࠛࠬ࠹࡞ࠍㅦᐲ⺰⊛ಽഀߢ߈ࠆߎߣ߇⍮ࠄࠇߡࠆ 33ޕ ࠫࡔ࠴࡞ࡑࡠࡀ࠻↱᧪ߩࡊࡠࠠ࡞ߥၮ⾰ 100 ߦኻߒߡ PLE ࠍᷝടߔࠆߎߣߢਇ ᢧട᳓ಽ⸃߇ㅴⴕߔࠆߣ੍ᗐߒߚ৻ޕᣇߩࠛࠬ࠹࡞ߩߺട᳓ಽ⸃ߐࠇࠆߚޔቭ⢻ၮㆬ ᛯ⊛ߦᄌ឵ࠍⴕࡦࠖࡈࠝޔㇱࠍㆶరߔࠆߎߣߢ xerophilsin B ߿ macrocalin B ߥߤ ߩ ent-kauranoid 㘃 33 ߩ A Ⅳ߳ߣᄌ឵น⢻ߛߣ⠨߃ߚ(Scheme 5.11)ᧄޕᔕߦࠃߞߡࠠ ࡞ߥࠢ࠻ࡦ 98 ࠍ᭴▽ߔࠆߎߣ߇ߢ߈ࠇ߫ߡߒߣࠢ࠶ࡠࡉࠣࡦࠖ࠺࡞ࡆ࡞ࠠޔ ent-kauranoid 㘃ߩߺߥࠄߕઁߩᄤὼ‛ߩਇᢧวᚑߦኻߒߡ㕖Ᏹߦ↪ߢࠆޕ Scheme 5.11. Retrosynthetic analysis of xerophilsin B and madrocalin B. R. HO. O O H. PLE-catalyzed asymmetric hydrolysis. H. CO2Me CO2Me. O. O OH. OH. CO2H CO2Me. O. 98. 99. 100. xerophilsin B (R=H ) macrocalin B (R=OH). ၮ⾰ߣߥࠆࠫࠛࠬ࠹࡞ 100 ߩวᚑߦขࠅ߆߆ߞߚ(Scheme 5.12)ޕᢥ₂ᣢ⍮ൻว‛ 6727 ߩ᳓㉄ၮࠍ࡛࠙⚛ൻߒࠍ࡞࠲ࠕޔᄖߔߎߣߢ 102 ߦᄌ឵ߒߚߦ࠼ࡅ࠺࡞ࠕߚߓ↢ޕ ኻߒߡ Ohira-Bestmann ⹜⮎ࠍ↪ߡࠕ࡞ࠠࡦ 103 ߳ ߩߣ࠻ࡀࡠࡑ࡞࠴ࡔࠫޔSN2 ᔕ ߦࠃࠅⅣൻ೨㚟 104 ࠍวᚑߒߚޕ 104 ߦኻߒߡ Conia-ene ᔕ 35 ࠍⴕ߁ߎߣߢ 6-exo-dig ߩⅣൻ߇ㅴⴕߒ 100 ࠍᓧߚޕ. .
(49) Scheme 5.12. Preparation of diester 100. OH I O. a O. I. b. c O. O. O 67. 102. 101. I. CO2Me CO2Me. d. 103. 104. e. CO2Me CO2Me. 100. Reagents and conditions: (a) imidazole, PPh3, I2, CH2Cl2, 0 °C , 2 h, 85%; (b) PTSA, acetone/H2O (1/1), 50 °C, 10 h, 80%; (c) Ohira-Bestmann reagent, K2CO3, MeOH, rt, 12 h, 68%; (d) NaH, dimethyl malonate, THF, 50 °C, 4 h, 85%; (e) triethylamine, SnCl4, CH2Cl2, rt, 14 h then THF, 5.5M H2SO4 aq., rt, 1 h, 87%.. ࡊࡠࠠ࡞ࠫࠛࠬ࠹࡞ 100 ߇ᓧࠄࠇߚߩߢ PLE ࠍ↪ߚਇᢧട᳓ಽ⸃ࠍⴕߞߚ 36. (Scheme 5.13)ޕᔕߪ 97%ߣ⦟ᅢߥ₸ߢㅴⴕߒߚޕᓧࠄࠇߚࠠ࡞ൻว‛ߩਇᢧ. ₸ߪࠕ࠾࠼ 105 ߦᄌ឵ߒ HPLC ߦߡ᷹ቯࠍⴕߞߚ⚿ߩߘޕᨐ 99% ee ߣ㜞ࠛ࠽ࡦ࠴ࠝ ㆬᛯ⊛ߦട᳓ಽ⸃߇ㅴⴕߒߡࠆߎߣ߇ಽ߆ߞߚ⛘ޕኻ㈩⟎ߩቯࠍⴕ߁ߚߦࠕ࠾ ࠼ 106 ߳ߣᄌ឵ߒ X ✢⚿᥏⸃ᨆࠍⴕߞߚ(Figure 5.5)37⚿ߩߘޕᨐ࠻ࡀࡠࡑ࡞࠴ࡔࠫޔ ߩ -ࡔ࠴࡞ࠛࠬ࠹࡞߇ࠛ࠽ࡦ࠴ࠝㆬᛯ⊛ߦട᳓ಽ⸃ߐࠇߡࠆߎߣ߇್ߒߚޕ Scheme 5.13. PLE-catalyzed asymmetric hydrolysis of 100. CO2Me CO2Me. PLE. CO2H CO2Me. KPB 8, 30 oC, 6 h 97%, 99 % ee 100. 99. Br. O CONHPh CO2Me. NH CO2Me 106. 105. R factor = 0.0496 wR factor = 0.1413. Figure 5.5. Determination of absolute configuration. .
(50) ࠠ࡞ߥࠞ࡞ࡏࡦ㉄ 99 ߇ᓧࠄࠇߚߩߢ┙ߩࡦࠖࡈࠝޔㆬᛯ⊛ߥᄌ឵ࠍᬌ⸛ߒߚ (Scheme 5.14)ޕട᳓ಽ⸃ߦࠃߞߡ↢ߓߚࠞ࡞ࡏࡦ㉄ 99 ࠍㆶరߒ ࡞ࠦ࡞ࠕޔ107 ߳ߣ ᄌ឵ߒߚᓟ⚛࠙ࡎࡠ࠼ࡅޔൻࠍⴕߞߚޕᔕߪ┙ㆬᛯ⊛ߦㅴⴕߒ ࡦ࠻ࠢޔent-98 ࠍਈ߃ߚޕ᳓㉄ၮߩ directing effect ߦࠃࠅ┙ㆬᛯᕈ߇⊒ߒߚ߽ߩߣ⠨߃ࠄࠇࠆޕᓧ ࠄࠇߚࠢ࠻ࡦߪ ent-kauranoid 㘃ߩวᚑࠍⴕ߁ߢᚲᦸߩ┙㈩⟎ߣߪ⇣ߥࠆࠛ࠽ࡦ ࠴ࠝࡑߛߞߚߚᦝߥࠆᬌ⸛ࠍⴕߞߚ(Scheme 5.15)ޕ Scheme 5.14. Synthesis of lactone ent-98. CO2H CO2Me. OH CO2Me. a. HO. O. b O. 107. 99. ent-98. Reagents and conditions: (a) (COCl)2, DMF, CH2Cl2, –78 °C , 9 h; 18-crown-6, K2CO3, NaBH4, CH2Cl2/H2O (2/1), 0 °C, 1 h, 81%; (b) BH3㨯SMe2, THF, rt, 10 h; 2M NaOH aq., H2O2, rt, 2 h, 73%.. ࠠ࡞ߥࠞ࡞ࡏࡦ㉄ 99 ߦኻߒߡ N,N’-diisopropyl-O-tert-butyl isourea38 ࠍ↪ࠆߎߣߢ tert-ࡉ࠴࡞ࠛࠬ࠹࡞ 108 ߳ߣᄌ឵ߒߚࠇߎޕએᄖߩ᧦ઙ߽ᬌ⸛ߒߚ߇⣕㉄߇ㅴⴕߒ tert-ࡉ࠴࡞ࠛࠬ࠹࡞ߪᓧࠄࠇߥ߆ߞߚࠍ࡞࠹ࠬࠛ࡞࠴ࡔޔߡ⛯ޕട᳓ಽ⸃ߒࡂࡈࠛ ࠬ࠹࡞ 109 ߳ᄌ឵ߒߚ 39ࠍ࡞࠹ࠬࠛࡈࡂޕㆶరߔࠆߎߣߢ ent-107 ࠍᓧࠃ߁ߣ⹜ߺߚ ߇⣕㉄߇ㅴⴕߒߚߚࠍ㉄ࡦࡏ࡞ࠞޔㆬᛯ⊛ߦࠕ࡞ࠦ࡞ߦㆶరߒޔtert-ࡉ࠴࡞ࠛࠬ ࠹࡞ࠍ㉄ᕈ᧦ઙߢട᳓ಽ⸃ߒ࡞࠹ࠬࠛ࡞࠴ࡔޔൻߔࠆߎߣߢ ent-107 ࠍวᚑߒߚޕ೨ㅀ ߩᚻᴺ(Scheme 5.14)ߦ୮ᄌ឵ߔࠆߎߣߢޔent-kauranoid 㘃ߩวᚑࠍⴕ߁ߢᔅⷐߣߥ ࠆࠢ࠻ࡦ 98 ࠍᓧࠆߎߣ߇ߢ߈ࠆޕ Scheme 5.15. Synthesis of ent-107. CO2H CO2Me. 99. O a. Ot-Bu CO2Me. O b. 108. Ot-Bu CO2H. 109. O. Ot-Bu. c. OH. 110. O d. OMe OH. ent-107. Reagents and conditions: (a) N,N’-diisopropyl-O-tert-butyl isourea, CH2Cl2, 50 °C , 3 h, 90%; (b) t-BuOK, H2O, Et2O, rt, 46 h, 95%; (c) triethylamine, ClCO2i-Pr, 0 °C, 1 h; NaBH4, MeOH, 0 °C, 2 h, 60%; (d) TFA, CH2Cl2, rt, 3 h; conc. H2SO4, MeOH, 70 °C, 20 h, 72%.. .
(51) ߎߩࠃ߁ߦ PLE ࠍ↪ߚਇᢧട᳓ಽ⸃ߦࠃࠅ㜞₸߆ߟ㜞ࠛ࠽ࡦ࠴ࠝㆬᛯ⊛ߦࠠ ࡞ࠞ࡞ࡏࡦ㉄ 99 ࠍวᚑߔࠆߎߣߦᚑഞߒߚ┙ޔߚ߹ޕㆬᛯ⊛ߥㆶరࠍⴕ߁ߎߣߢࠠ ࡞ࡆ࡞࠺ࠖࡦࠣࡉࡠ࠶ࠢ 98 ߣ ent-98 ߩวᚑߦ߽ᚑഞߒߚޔࠅࠃߦࠇߎޕent-kauranoid 㘃ߩਇᢧวᚑ߳ߣዷ㐿ߢ߈ࠆ⿷߇߆ࠅ߇ߢ߈ߚޕPLE ࠍ↪ߚࡊࡠࠠ࡞ൻว‛ߩਇᢧ ട᳓ಽ⸃ߦߪᄙߊߩ߇ࠆ߇ޔᣂߚߥၮ⾰ߩ࠺ࠩࠗࡦߦࠃࠅࠠ࡞ࡆ࡞࠺ࠖࡦࠣࡉࡠ ࠶ࠢഃߩലߥᚻᲑߣߥࠆน⢻ᕈ߇ᱷߐࠇߡࠆߎߣ߇␜ߐࠇߚޕᓟߩዷ㐿߇ᦼᓙ ߐࠇࠆޕ. .
(52) ╙㧢┨ ✚ ᧄ⺰ᢥࠍએਅߩࠃ߁ߦ✚ߔࠆޕ 㧝㧚1,4-ࡅ࠼࠼ㆶరࠍὐߣߔࠆㅪ⛯ Michael ᔕߦࠃࠅ Michael ฃኈߩᐞ㈩⟎ࠍ ᄌ߃ࠆߎߣߦࠃࠅੑߟߩ࠻ࡦࠬ-1,2-⟎឵ࠪࠢࡠࡋࠠࠨࡦⅣࠍࠅಽߌࠆߎߣߦᚑഞ ߒߚࡦ࠴ࡔ࠰ࠠࠛޕㇱߩᔕᕈࠍ↪ߒో⚛྾⚖ਇᢧਛᔃࠍ᭴▽ߒߡࠆὐߢᣂ ⷙᕈ߇㜞ޕ CO2Ph. L-Selectride (1.2 equiv.) HMPA (10.0 equiv.). CO2Et. THF -78 C, 2 h, 78%. CO2Ph. L-Selectride (1.2 equiv.). TIPSO Me. Me CO2Ph TIPSO. o. 2Z. CO2Et. TIPSO Me 2E. THF/DMF (1/2) 0 oC, 2 h, 82%. CO2Et H Me 5. Me CO2Ph TIPSO. CO2Et H Me 5'. 㧞㧚ᷰⅣဳㅪ⛯ Michael ᔕߦࠃࠅ chair-boat-chair ߦ❗ⅣߒߚਃⅣᑼ㛽ᩰߩ┙ㆬᛯ⊛ ߥ᭴▽ߦᚑഞߒߚޕᷰⅣဳ Michael ᔕߦࠃߞߡ chair-boat-chair ߦ❗ⅣߒߚਃⅣᑼ㛽ᩰ ࠍ᭴▽ߒߡࠆ೨ߪߥޕ O. a) PhSH, DBU MeOH, 0 oC 86% (dr 5.6/1). Me. TIPSO. O. H Me 19. b) PhSK, THF, -78 oC 43% (dr 1/0). PhS. O. Me H TIPSO. H Me 32. O. 㧟㧚Liebeskind-Srogl ࠞ࠶ࡊࡦࠣ́ಽሶౝ Diels-Alder ㅪ⛯ᔕߦࠃߞߡ trans-cis ߦ❗ ⅣߒߚਃⅣᑼ㛽ᩰߩ┙ㆬᛯ⊛ߥ᭴▽ߦᚑഞߒߚޕLiebeskind-Srogl ࠞ࠶ࡊࡦࠣᔕ ߣಽሶౝ Diels-Alder ᔕࠍㅪ⛯ߒߡⴕߞߡࠆ೨ߪߥޕ. Me. SnBu3. O TIPSO. H Me 36b. Pd2(dba)3 (10 mol%) AsPh3 (30 mol%) CuTC (3.0 equiv.). S. N. CO2Me. H. THF, rt, 30 min, 81% TIPSO. 46 (2.0 equiv.). . Me. + H Me. 47. CO2Me O.
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