JP6476396B2 - Cyclization catalyst, method for producing chromans, and method for producing pyrrolidines - Google Patents
Cyclization catalyst, method for producing chromans, and method for producing pyrrolidines Download PDFInfo
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- JP6476396B2 JP6476396B2 JP2015047543A JP2015047543A JP6476396B2 JP 6476396 B2 JP6476396 B2 JP 6476396B2 JP 2015047543 A JP2015047543 A JP 2015047543A JP 2015047543 A JP2015047543 A JP 2015047543A JP 6476396 B2 JP6476396 B2 JP 6476396B2
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- cyclization
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- pyrrolidines
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- 238000007363 ring formation reaction Methods 0.000 title claims description 50
- 239000003054 catalyst Substances 0.000 title claims description 46
- 238000004519 manufacturing process Methods 0.000 title claims description 29
- 150000003235 pyrrolidines Chemical class 0.000 title claims description 23
- -1 diester amide Chemical class 0.000 claims description 73
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
- 125000005843 halogen group Chemical group 0.000 claims description 19
- 229930184489 Iodoether Natural products 0.000 claims description 16
- 239000002841 Lewis acid Substances 0.000 claims description 16
- VSHDHKDWBUMJIJ-UHFFFAOYSA-N iodo hypoiodite Chemical compound IOI VSHDHKDWBUMJIJ-UHFFFAOYSA-N 0.000 claims description 16
- 150000007517 lewis acids Chemical class 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 14
- 229910052740 iodine Inorganic materials 0.000 claims description 14
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 14
- 239000012336 iodinating agent Substances 0.000 claims description 12
- 239000011630 iodine Substances 0.000 claims description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 125000004437 phosphorous atom Chemical group 0.000 claims description 9
- 229910052698 phosphorus Inorganic materials 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical group C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 claims description 5
- 125000005106 triarylsilyl group Chemical group 0.000 claims description 4
- 230000003287 optical effect Effects 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 2
- 229910052794 bromium Inorganic materials 0.000 claims 2
- 239000000460 chlorine Substances 0.000 claims 2
- 150000002430 hydrocarbons Chemical group 0.000 description 40
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 25
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 20
- 239000000758 substrate Substances 0.000 description 20
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- 125000001424 substituent group Chemical group 0.000 description 12
- 125000003545 alkoxy group Chemical group 0.000 description 11
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- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
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- 125000000217 alkyl group Chemical group 0.000 description 9
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 9
- 239000012230 colorless oil Substances 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 101000652482 Homo sapiens TBC1 domain family member 8 Proteins 0.000 description 4
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- 239000004215 Carbon black (E152) Substances 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
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- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical group C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
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- 229910052757 nitrogen Inorganic materials 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
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- XRLZJXZLLUTPEI-UHFFFAOYSA-N 2-(iodomethyl)-1-(4-methylphenyl)sulfonyl-2-phenylpyrrolidine Chemical compound ICC1(N(CCC1)S(=O)(=O)C1=CC=C(C)C=C1)C1=CC=CC=C1 XRLZJXZLLUTPEI-UHFFFAOYSA-N 0.000 description 1
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- 239000001257 hydrogen Substances 0.000 description 1
- 238000005657 iodolactonization reaction Methods 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- XVDBWWRIXBMVJV-UHFFFAOYSA-N n-[bis(dimethylamino)phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)N(C)C XVDBWWRIXBMVJV-UHFFFAOYSA-N 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Landscapes
- Pyrane Compounds (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
本発明は、環化触媒、クロマン類の製法、ピロリジン類の製法及びリン酸ジエステルアミドに関する。 The present invention relates to a cyclization catalyst, a process for producing chromans, a process for producing pyrrolidines, and a phosphoric diester amide.
本発明者らは、既に、キラルなリン酸トリエステルが４−置換−４−ペンテン酸のヨードラクトン化反応を促進し、対応するヨードラクトンを高収率且つ高いエナンチオ選択性で得られることを報告した（非特許文献１）。一例として、下記スキームに示すように、ヨード化剤としてＩ2 、ルイス酸としてＮ−クロロフタルイミド、触媒としてリン酸トリエステルを使用した場合、４−ベンジル−４−ペンテン酸から対応するヨードラクトンを収率９５％、９３％ｅｅで得られることを報告した。 The present inventors have already shown that chiral phosphoric acid triesters promote the iodolactonization reaction of 4-substituted-4-pentenoic acid, and the corresponding iodolactone can be obtained in high yield and high enantioselectivity. Reported (Non-Patent Document 1). As an example, as shown in the following scheme, when I 2 is used as an iodinating agent, N-chlorophthalimide is used as a Lewis acid, and phosphoric acid triester is used as a catalyst, the corresponding iodolactone is obtained from 4-benzyl-4-pentenoic acid. The yield was reported to be 95% and 93% ee.
ところで、天然には、クロマン骨格を有する生理活性物質が数多く存在する。また、ピロリジン骨格を有する生理活性物質も数多く存在する。そこで、本発明者らは、キラルなリン酸トリエステルがクロマン類やピロリジン類の合成触媒として有用か否かを検討した。すなわち、上記スキームにおいて、触媒のフェノール部分の２，６位にｎ−ブチルを導入したリン酸トリエステルを用いて、２−アルケニルフェノール類のヨードエーテル環化反応を試みた。同様に、Ｎ−アルケニルスルホンアミド類のヨードアミノ環化反応を試みた。そうしたところ、いずれにおいても目的とする環化物は得られたものの、収率が不十分であったり、エナンチオ選択性が低かったりした。 By the way, many physiologically active substances having a chroman skeleton exist in nature. There are also many physiologically active substances having a pyrrolidine skeleton. Therefore, the present inventors examined whether chiral phosphoric acid triesters are useful as synthesis catalysts for chromans and pyrrolidines. That is, in the above scheme, an iodoether cyclization reaction of 2-alkenylphenols was attempted using a phosphoric acid triester in which n-butyl was introduced at positions 2 and 6 of the phenol moiety of the catalyst. Similarly, an iodoamino cyclization reaction of N-alkenylsulfonamides was attempted. As a result, in either case, the desired cyclized product was obtained, but the yield was insufficient or the enantioselectivity was low.
本発明はこのような課題を解決するためになされたものであり、ヨードエーテル環化反応又はヨードアミノ環化反応に適した触媒を提供することを主目的とする。 The present invention has been made to solve such problems, and has as its main object to provide a catalyst suitable for an iodoether cyclization reaction or an iodoamino cyclization reaction.
上述した目的を達成するために、本発明者は、ヨードエーテル環化反応又はヨードアミノ環化反応を促進する触媒として、種々のリン酸エステルを試したところ、ある種のリン酸ジエステルアミドがリン酸トリエステルよりも優れた触媒活性を有することを見いだし、本発明を完成するに至った。 In order to achieve the above-mentioned object, the present inventors have tried various phosphate esters as catalysts for promoting the iodoether cyclization reaction or the iodoamino cyclization reaction. It has been found that it has a catalytic activity superior to that of triesters, and the present invention has been completed.
即ち、本発明の環化触媒は、ヨードエーテル環化反応又はヨードアミノ環化反応に用いられる、式（１）で表されるリン酸ジエステルアミドからなる触媒である。 That is, the cyclization catalyst of the present invention is a catalyst comprising a phosphoric diester amide represented by the formula (1) used for an iodoether cyclization reaction or an iodoamino cyclization reaction.
（Ｒ1は、水素原子か炭化水素基であり、
Ｒ2は、炭化水素基であり、
Ｒ1とＲ2は、互いに結合して炭化水素鎖を形成していてもよく、
Ｚは、１，１’−ビアリール骨格又は１，１’−ジアリールメチル骨格を含む基であり、リン原子に結合した２つの酸素原子は１，１’−ビアリール骨格又は１，１’−ジアリールメチル骨格の２，２’位で結合している）
(R 1 is a hydrogen atom or a hydrocarbon group,
R 2 is a hydrocarbon group,
R 1 and R 2 may be bonded to each other to form a hydrocarbon chain,
Z is a group containing a 1,1′-biaryl skeleton or a 1,1′-diarylmethyl skeleton, and two oxygen atoms bonded to a phosphorus atom are a 1,1′-biaryl skeleton or a 1,1′-diarylmethyl. It is bonded at the 2 'and 2' positions of the skeleton
本発明のクロマン類の製法は、ヨードエーテル環化反応により２−アルケニルフェノール類からクロマン類を製造する方法であって、ヨード化剤としてヨウ素（Ｉ2 ）、ルイス酸としてハロイミド類又はハロヒダントイン類（ハロゲン原子は塩素原子、臭素原子又はヨウ素原子）、触媒として上述した環化触媒を使用するものである。 The method for producing chromans according to the present invention is a method for producing chromans from 2- alkenylphenols by iodoether cyclization reaction, wherein iodine (I 2 ) is used as an iodinating agent, haloimides or halohydantoins are used as Lewis acids. (The halogen atom is a chlorine atom, a bromine atom or an iodine atom), and the cyclization catalyst described above is used as a catalyst.
本発明のピロリジン類の製法は、ヨードアミノ環化反応によりＮ−アルケニルスルホンアミド類からピロリジン類を製造する方法であって、ヨード化剤としてヨウ素（Ｉ2 ）、ルイス酸としてハロイミド類又はハロヒダントイン類（ハロゲン原子は塩素原子、臭素原子又はヨウ素原子）、触媒として上述した環化触媒を使用するものである。 The method for producing pyrrolidines of the present invention is a method for producing pyrrolidines from N-alkenylsulfonamides by iodoamino cyclization reaction, wherein iodine (I 2 ) is used as an iodinating agent, haloimides or halohydantoins as Lewis acids (The halogen atom is a chlorine atom, a bromine atom or an iodine atom), and the cyclization catalyst described above is used as a catalyst.
本発明の環化触媒は、２−アルケニルフェノール類からクロマン類へのヨードエーテル環化反応やＮ−アルケニルスルホンアミド類からピロリジン類へのヨードアミノ環化反応において、高い反応促進効果を発現したり、高いエナンチオ選択性を発現したりする。そのため、本発明によれば、クロマン類やピロリジン類（特に光学活性なもの）を効率よく合成することができる。 The cyclization catalyst of the present invention exhibits a high reaction promoting effect in an iodoether cyclization reaction from 2-alkenylphenols to chromans and an iodoamino cyclization reaction from N-alkenylsulfonamides to pyrrolidines, Express high enantioselectivity. Therefore, according to the present invention, chromans and pyrrolidines (particularly optically active) can be synthesized efficiently.
本発明の環化触媒は、上述した式（１）で表されるリン酸ジエステルアミドからなる触媒である。 The cyclization catalyst of the present invention is a catalyst comprising a phosphoric diester amide represented by the above formula (1).
Ｒ1は、水素原子か炭化水素基であり、Ｒ2は、炭化水素基であり、Ｒ1とＲ2は、互いに結合して炭化水素鎖を形成していてもよい。炭化水素基とは、炭素と水素とで構成された基であり、例えば、アルキル基、シクロアルキル基、アリール基、アラルキル基などが挙げられる。アルキル基としては、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、ｓｅｃ−ブチル基、イソブチル基、ｔｅｒｔ−ブチル基などが挙げられる。シクロアルキル基としては、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基などが挙げられる。アリール基としては、フェニル基、ナフチル基、アントラニル基、フェナンスリル基、トリル基、ジアルキルフェニル基、トリアルキルフェニル基などが挙げられる。このうち、ジアルキルフェニル基としては、キシリル基、ジエチルフェニル基、ジ−ｎ−プロピルフェニル基、ジイソプロピルフェニル基、ジ−ｎ−ブチルフェニル基、ジイソブチルフェニル基、ジ−ｓｅｃ−ブチルフェニル基、ジ−ｔｅｒｔ−ブチルフェニル基などが挙げられる。トリアルキルフェニル基としては、トリメチルフェニル基、トリエチルフェニル基、トリイソプロピルフェニル基などが挙げられる。アラルキル基とは、アルキル基の水素原子の１つがアリール基で置換されたものであり、ベンジル基やフェネチル基などが挙げられる。アラルキル基中のアリール基には、更にアルキル基やアルケニル基が結合されていてもよい。炭化水素基は、１以上の置換基を有していてもよい。炭化水素基が有する置換基としては、ハロゲン原子、シアノ基、ニトロ基、アルコキシ基などが挙げられる。ハロゲン原子としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子などが挙げられる。アルコキシ基としては、メトキシ基、エトキシ基、ｎ−プロポキシ基、イソプロポキシ基、ｎ−ブトキシ基、ｓｅｃ−ブトキシ基、イソブトキシ基、ｔｅｒｔ−ブトキシ基などが挙げられる。Ｒ1とＲ2とが互いに結合して炭化水素鎖を形成する場合、炭化水素鎖は−（ＣＨ2）n−（ｎは１〜７の整数）としてもよい。こうした炭化水素鎖は、置換基を有していてもよい。この場合の置換基としては、ハロゲン原子、シアノ基、ニトロ基、アルキル基、シクロアルキル基、アリール基、アラルキル基、アルコキシ基などが挙げられる。なお、ハロゲン原子やアルキル基、シクロアルキル基、アリール基、アラルキル基、アルコキシ基の具体例は、上述した通りである。 R 1 is a hydrogen atom or a hydrocarbon group, R 2 is a hydrocarbon group, and R 1 and R 2 may be bonded to each other to form a hydrocarbon chain. The hydrocarbon group is a group composed of carbon and hydrogen, and examples thereof include an alkyl group, a cycloalkyl group, an aryl group, and an aralkyl group. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group. Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Examples of the aryl group include a phenyl group, a naphthyl group, an anthranyl group, a phenanthryl group, a tolyl group, a dialkylphenyl group, and a trialkylphenyl group. Among these, as the dialkylphenyl group, xylyl group, diethylphenyl group, di-n-propylphenyl group, diisopropylphenyl group, di-n-butylphenyl group, diisobutylphenyl group, di-sec-butylphenyl group, di- Examples thereof include a tert-butylphenyl group. Examples of the trialkylphenyl group include a trimethylphenyl group, a triethylphenyl group, and a triisopropylphenyl group. An aralkyl group is a group in which one of hydrogen atoms of an alkyl group is substituted with an aryl group, and examples thereof include a benzyl group and a phenethyl group. An alkyl group or an alkenyl group may be further bonded to the aryl group in the aralkyl group. The hydrocarbon group may have one or more substituents. Examples of the substituent that the hydrocarbon group has include a halogen atom, a cyano group, a nitro group, and an alkoxy group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, an isobutoxy group, and a tert-butoxy group. When R 1 and R 2 are bonded to each other to form a hydrocarbon chain, the hydrocarbon chain may be — (CH 2 ) n — (n is an integer of 1 to 7). Such hydrocarbon chains may have a substituent. Examples of the substituent in this case include a halogen atom, a cyano group, a nitro group, an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, and an alkoxy group. Specific examples of the halogen atom, the alkyl group, the cycloalkyl group, the aryl group, the aralkyl group, and the alkoxy group are as described above.
Ｒ1、Ｒ2は、一方が水素原子で他方がアリール基であるか、一方が水素原子で他方がアラルキル基であるか、互いに結合して炭素数５〜８の炭化水素鎖を形成していることが好ましい。アリール基やアラルキル基の具体例は、上述した通りであるが、アリール基としては、２，６−ジアルキルフェニル基が好ましい。アラルキル基としては、ベンジル基のほか、ベンジル基中のフェニル基にハロゲン原子、アルキル基又はアリール基を有していてもよい。 R 1 and R 2 are either a hydrogen atom and the other is an aryl group, or one is a hydrogen atom and the other is an aralkyl group, or are bonded to each other to form a hydrocarbon chain having 5 to 8 carbon atoms. Preferably it is. Specific examples of the aryl group and the aralkyl group are as described above, and the aryl group is preferably a 2,6-dialkylphenyl group. As the aralkyl group, in addition to the benzyl group, the phenyl group in the benzyl group may have a halogen atom, an alkyl group or an aryl group.
Ｚは、１，１’−ビアリール骨格又は１，１’−ジアリールメチル骨格を含む基であり、リン原子に結合した２つの酸素原子は１，１’−ビアリール骨格又は１，１’−ジアリールメチル骨格の２，２’位で結合している。Ｚはキラルでもアキラルでもよい。キラルなＺとしては、２つのアリール基の回転障害に起因する軸不斉を持つ１，１’−ビアリール骨格を含む基やスピロ型１，１’−ジアリールメチル骨格を含む基などが挙げられる。下記式のうち、左側は前者の骨格の一例であり、右側は後者の骨格一例である。式中、Ｒ11〜Ｒ18は同じでも異なっていてもよく、水素原子、ハロゲン原子、炭化水素基、有機シリル基、シアノ基、ニトロ基又はアルコキシ基であり、これらのうち２つが互いに結合して炭化水素鎖を形成していてもよい。また、Ｒ21〜Ｒ24は同じでも異なっていてもよく、水素原子、ハロゲン原子、炭化水素基、有機シリル基、シアノ基、ニトロ基又はアルコキシ基であり、これらのうち２つが互いに結合して炭化水素鎖を形成していてもよい。なお、ハロゲン原子、炭化水素基、アルコキシ基、炭化水素鎖の具体例は、上述した通りである。有機シリル基としては、トリアルキルシリル基、トリアリールシリル基、アルキルとアリールとを有するシリル基、トリアラルキルシリル基、トリアルコキシシリル基などが挙げられる。トリアルキルシリル基としては、トリメチルシリル基、トリエチルシリル基、トリイソプロピルシリル基、イソプロピルジメチルシリル基、イソプロピルジエチルシリル基、エチルジメチルシリル基、ｔｅｒｔ−ブチルジメチルシリル基等が挙げられる。トリアリールシリル基としては、トリフェニルシリル基、トリキシリルシリル基などが挙げられる。アルキルとアリールとを有するシリル基としては、ｔｅｒｔ−ブチルジフェニルシリル基、メチルジフェニルシリル基などが挙げられる。トリアラルキルシリル基としては、トリベンジルシリル基などが挙げられる。トリアルコキシシリル基としては、トリメトキシシリル基、トリエトキシシリル基などが挙げられる。他にも嵩高いシリル基としてトリス（トリメチルシリル）シリル基を挙げることができる。 Z is a group containing a 1,1′-biaryl skeleton or a 1,1′-diarylmethyl skeleton, and two oxygen atoms bonded to a phosphorus atom are a 1,1′-biaryl skeleton or a 1,1′-diarylmethyl. Bonded at the 2,2 'position of the skeleton. Z may be chiral or achiral. Examples of the chiral Z include a group containing a 1,1′-biaryl skeleton having axial asymmetry resulting from a rotation hindrance of two aryl groups, a group containing a spiro-type 1,1′-diarylmethyl skeleton, and the like. In the following formula, the left side is an example of the former skeleton, and the right side is an example of the latter skeleton. In the formula, R 11 to R 18 may be the same or different and are a hydrogen atom, a halogen atom, a hydrocarbon group, an organic silyl group, a cyano group, a nitro group, or an alkoxy group, and two of these are bonded to each other. To form a hydrocarbon chain. R 21 to R 24 may be the same or different and are a hydrogen atom, a halogen atom, a hydrocarbon group, an organic silyl group, a cyano group, a nitro group, or an alkoxy group, and two of these are bonded to each other. A hydrocarbon chain may be formed. Specific examples of the halogen atom, hydrocarbon group, alkoxy group, and hydrocarbon chain are as described above. Examples of the organic silyl group include a trialkylsilyl group, a triarylsilyl group, a silyl group having alkyl and aryl, a triaralkylsilyl group, and a trialkoxysilyl group. Examples of the trialkylsilyl group include a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, an isopropyldimethylsilyl group, an isopropyldiethylsilyl group, an ethyldimethylsilyl group, and a tert-butyldimethylsilyl group. Examples of the triarylsilyl group include a triphenylsilyl group and a trixylsilyl group. Examples of the silyl group having alkyl and aryl include a tert-butyldiphenylsilyl group and a methyldiphenylsilyl group. Examples of the triaralkylsilyl group include a tribenzylsilyl group. Examples of the trialkoxysilyl group include a trimethoxysilyl group and a triethoxysilyl group. In addition, a tris (trimethylsilyl) silyl group can be exemplified as a bulky silyl group.
Ｚが軸不斉を持つ１，１’−ビアリール骨格を含む光学活性な基である場合、そのような基としては、例えば、下記式に示すものが挙げられる。ビフェニルのＨｉは２つのフェニル基が自由に軸回転するのを拘束する置換基である。なお、これらは基本骨格を表すものであるため、適当な位置に置換基を１以上有していてもよい。置換基としては、ハロゲン原子、炭化水素基、有機シリル基、シアノ基、ニトロ基、アルコキシ基などが挙げられる。ハロゲン原子や炭化水素基、有機シリル基、アルコキシ基の具体例は、上述した通りである。 When Z is an optically active group containing a 1,1'-biaryl skeleton having axial asymmetry, examples of such a group include those represented by the following formulae. Hi of biphenyl is a substituent that constrains the two phenyl groups to rotate freely. Since these represent basic skeletons, they may have one or more substituents at an appropriate position. Examples of the substituent include a halogen atom, a hydrocarbon group, an organic silyl group, a cyano group, a nitro group, and an alkoxy group. Specific examples of the halogen atom, hydrocarbon group, organic silyl group, and alkoxy group are as described above.
Ｚは、式（２）で表される光学活性な基であることが好ましい。式（２）中、Ｒ3、Ｒ4は、同じでも異なっていてもよく、炭化水素基又は有機シリル基であり、Ｘ1、Ｘ2は、同じでも異なっていてもよく、水素原子、ハロゲン原子又は炭化水素基であり、１，１’−ビ−２−ナフトール部位はＲかＳの光学異性体である。炭化水素基、有機シリル基、ハロゲン原子の具体例は、上述した通りである。式（２）において、Ｒ3、Ｒ4は、両方ともアリール基又はトリアリールシリル基であり、Ｘ1、Ｘ2は、両方とも水素原子であることが好ましく、Ｒ3、Ｒ4は、両方とも９−アントラセニル基又はトリフェニルシリル基であり、Ｘ1、Ｘ2は、両方とも水素原子であることがより好ましい。 Z is preferably an optically active group represented by the formula (2). In the formula (2), R 3 and R 4 may be the same or different, and are a hydrocarbon group or an organic silyl group, and X 1 and X 2 may be the same or different, and are a hydrogen atom, halogen It is an atom or a hydrocarbon group, and the 1,1′-bi-2-naphthol moiety is an optical isomer of R or S. Specific examples of the hydrocarbon group, the organic silyl group, and the halogen atom are as described above. In the formula (2), R 3 and R 4 are both aryl groups or triarylsilyl groups, X 1 and X 2 are preferably both hydrogen atoms, and R 3 and R 4 are both It is more preferable that both are 9-anthracenyl groups or triphenylsilyl groups, and X 1 and X 2 are both hydrogen atoms.
本発明のクロマン類の製法は、ヨードエーテル環化反応により２−アルケニルフェノール類からクロマン類を製造する方法であって、ヨード化剤としてヨウ素（Ｉ2 ）、ルイス酸としてハロイミド類又はハロヒダントイン類（ハロゲン原子は塩素原子、臭素原子又はヨウ素原子）、触媒として上述した環化触媒を使用するものである。 The method for producing chromans according to the present invention is a method for producing chromans from 2- alkenylphenols by iodoether cyclization reaction, wherein iodine (I 2 ) is used as an iodinating agent, haloimides or halohydantoins are used as Lewis acids. (The halogen atom is a chlorine atom, a bromine atom or an iodine atom), and the cyclization catalyst described above is used as a catalyst.
本発明のクロマン類の製法において、２−アルケニルフェノール類は、ヨードエーテル環化反応によりクロマン類へ変換されるものであればよく、例えば、アルケニル基として−ＣＨ2ＣＨ2Ｃ（＝ＣＨＲa）Ｒb（Ｒa、Ｒbは同じでも異なっていてもよく、水素原子又は炭化水素基であり、幾何異性体がある場合はシスでもトランスでもよい）又は−ＣＨ2ＣＨ＝ＣＨＲc（Ｒcは炭化水素基であり、幾何異性体がある場合はシスでもトランスでもよい）を有しているものが好ましい。なお、炭化水素基の具体例は、上述した通りである。また、２−アルケニルフェノール類のフェノールの芳香環は置換基を有していてもよい。置換基としては、ハロゲン原子、炭化水素基、ニトロ基、シアノ基、アルコキシ基などが挙げられる。これらの具体例は、上述した通りである。 In the method for producing the chromans of the present invention, the 2-alkenylphenols may be any one that can be converted into chromanes by an iodoether cyclization reaction. For example, as the alkenyl group, —CH 2 CH 2 C (═CHR a ) R b (R a , R b may be the same or different and each represents a hydrogen atom or a hydrocarbon group, and may be cis or trans when there is a geometric isomer) or —CH 2 CH═CHR c (R c Is a hydrocarbon group, and when there is a geometric isomer, it may be cis or trans). Specific examples of the hydrocarbon group are as described above. Moreover, the aromatic ring of the phenol of 2-alkenylphenols may have a substituent. Examples of the substituent include a halogen atom, a hydrocarbon group, a nitro group, a cyano group, and an alkoxy group. Specific examples of these are as described above.
本発明のクロマン類の製法において、ヨード化剤であるヨウ素（Ｉ2 ）は、２−アルケニルフェノール類に対して０．５倍モル以上使用するのが好ましく、０．５５〜１．１倍モルの範囲で使用するのがより好ましい。Ｉ2 は、分子を構成する２つのヨウ素原子がヨード化に用いられるため、理論的には０．５倍モル使用すれば十分である。 In the process for producing chromans according to the present invention, iodine (I 2 ) as an iodinating agent is preferably used in an amount of 0.5-fold mol or more, based on 2-alkenylphenols, 0.55-1.1-fold mol. It is more preferable to use in this range. As for I 2 , it is theoretically sufficient to use 0.5 times mole because two iodine atoms constituting the molecule are used for iodination.
本発明のクロマン類の製法において、ルイス酸として使用するハロイミド類としては、Ｎ−クロロスクシンイミド（ＮＣＳ）、Ｎ−ブロモスクシンイミド（ＮＢＳ）、Ｎ−ヨードスクシンイミド（ＮＩＳ）、Ｎ−クロロフタルイミド（ＮＣＰ）、Ｎ−ブロモフタルイミド（ＮＢＰ）、Ｎ−ヨードフタルイミド（ＮＩＰ）、Ｎ−クロロマレイミド、Ｎ−ブロモマレイミド、Ｎ−ヨードマレイミドなどが挙げられる。ルイス酸として使用するハロヒダントイン類は、１，３−ジクロロ−５，５−ジメチルヒダントイン（ＤＣＨ）、１，３−ジブロモ−５，５−ジメチルヒダントイン（ＤＢＨ）、１，３−ジヨード−５，５−ジメチルヒダントイン（ＤＩＨ）などが挙げられる。こうしたルイス酸は、２−アルケニルフェノール類に対して等モル以上使用するのが好ましく、１〜１．５倍モルの範囲で使用するのがより好ましい。 In the process for producing the chromans of the present invention, haloimides used as Lewis acids include N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), and N-chlorophthalimide (NCP). N-bromophthalimide (NBP), N-iodophthalimide (NIP), N-chloromaleimide, N-bromomaleimide, N-iodomaleimide and the like. The halohydantoins used as Lewis acids are 1,3-dichloro-5,5-dimethylhydantoin (DCH), 1,3-dibromo-5,5-dimethylhydantoin (DBH), 1,3-diiodo-5, And 5-dimethylhydantoin (DIH). Such Lewis acid is preferably used in an equimolar amount or more with respect to 2-alkenylphenols, and more preferably in the range of 1 to 1.5 times mole.
本発明のクロマン類の製法において、環化触媒は、２−アルケニルフェノール類に対して、０．１〜３０ｍｏｌ％の範囲で使用するのが好ましく、１〜１０ｍｏｌ％の範囲で使用するのがより好ましい。 In the method for producing chromans of the present invention, the cyclization catalyst is preferably used in the range of 0.1 to 30 mol%, more preferably 1 to 10 mol%, based on the 2-alkenylphenol. preferable.
本発明のピロリジン類の製法は、ヨードアミノ環化反応によりＮ−アルケニルスルホンアミド類からピロリジン類を製造する方法であって、ヨード化剤としてヨウ素（Ｉ2 ）、ルイス酸としてハロイミド類又はハロヒダントイン類、触媒として上述した環化触媒を使用するものである。 The method for producing pyrrolidines of the present invention is a method for producing pyrrolidines from N-alkenylsulfonamides by iodoamino cyclization reaction, wherein iodine (I 2 ) is used as an iodinating agent, haloimides or halohydantoins are used as Lewis acids. The cyclization catalyst described above is used as the catalyst.
本発明のピロリジン類の製法において、Ｎ−アルケニルスルホンアミド類は、アルケニル基として−ＣＨ2ＣＨ2ＣＨ2Ｃ（＝ＣＨＲd）Ｒe（Ｒd、Ｒeは同じでも異なっていてもよく、水素原子又は炭化水素基であり、幾何異性体がある場合はシスでもトランスでもよい）を有していことが好ましい。スルホンアミド部位は、−ＮＨＳＯ2Ｒf （Ｒf は炭化水素基である）と表すことができる。なお、炭化水素基の具体例は、上述した通りである。また、アルケニル基は置換基を有していてもよい。また、アルケニル基の炭化水素鎖の一部が芳香環骨格に組み込まれていてもよい。例えば、−ＣＨ2ＣＨ2ＣＨ2Ｃ（＝ＣＨＲd）Ｒeのうちの１位と２位の炭素原子が芳香環（例えばベンゼン環）の２つの炭素原子を構成していてもよいし、２位と３位の炭素原子が芳香環の２つの炭素原子を構成していてもよい。その場合、芳香環に置換基がついていても構わない。置換基としては、ハロゲン原子、ニトロ基、シアノ基、アルコキシ基などが挙げられる。これらの具体例は、上述した通りである。 In the method for producing pyrrolidines of the present invention, N-alkenylsulfonamides may be the same or different as the alkenyl group —CH 2 CH 2 CH 2 C (═CHR d ) R e (R d , R e , It is preferably a hydrogen atom or a hydrocarbon group, and when there is a geometric isomer, it may be cis or trans. The sulfonamide moiety can be represented as —NHSO 2 R f (R f is a hydrocarbon group). Specific examples of the hydrocarbon group are as described above. Moreover, the alkenyl group may have a substituent. Further, a part of the hydrocarbon chain of the alkenyl group may be incorporated into the aromatic ring skeleton. For example, the first and second carbon atoms in —CH 2 CH 2 CH 2 C (═CHR d ) R e may constitute two carbon atoms of an aromatic ring (for example, a benzene ring), The carbon atoms at the 2nd and 3rd positions may constitute two carbon atoms of the aromatic ring. In that case, the aromatic ring may have a substituent. Examples of the substituent include a halogen atom, a nitro group, a cyano group, and an alkoxy group. Specific examples of these are as described above.
本発明のピロリジン類の製法において、ヨード化剤であるヨウ素（Ｉ2）は、Ｎ−アルケニルスルホンアミド類に対して、０．５倍モル以上使用するのが好ましく、０．５５〜１．１倍モルの範囲で使用するのがより好ましい。Ｉ2 は、分子を構成する２つのヨウ素原子がヨード化に用いられるため、理論的には０．５倍モル使用すれば十分である。 In the process for producing pyrrolidines of the present invention, iodine (I 2 ), which is an iodinating agent, is preferably used in an amount of 0.5 times mol or more with respect to N-alkenylsulfonamides, 0.55 to 1.1. It is more preferable to use in the range of double mole. As for I 2 , it is theoretically sufficient to use 0.5 times mole because two iodine atoms constituting the molecule are used for iodination.
本発明のピロリジン類の製法において、ルイス酸として使用するハロイミド類やハロヒダントイン類の具体例は、クロマン類の製法で説明したとおりである。こうしたルイス酸は、Ｎ−アルケニルスルホンアミド類に対して、等モル以上使用するのが好ましく、１〜１．５倍モルの範囲で使用するのがより好ましい。 Specific examples of haloimides and halohydantoins used as Lewis acids in the method for producing pyrrolidines of the present invention are as described in the method for producing chromans. Such Lewis acid is preferably used in an equimolar amount or more with respect to N-alkenylsulfonamides, and more preferably in a range of 1 to 1.5 times mole.
本発明のピロリジン類の製法において、環化触媒は、Ｎ−アルケニルスルホンアミド類に対して、０．１〜３０ｍｏｌ％の範囲で使用するのが好ましく、１〜１０ｍｏｌ％の範囲で使用するのがより好ましい。 In the process for producing pyrrolidines of the present invention, the cyclization catalyst is preferably used in the range of 0.1 to 30 mol%, preferably 1 to 10 mol%, based on the N-alkenylsulfonamides. More preferred.
本発明のクロマン類の製法及びピロリジン類の製法において、反応溶媒は、環化反応に影響しない溶媒であれば特に限定されないが、例えば炭化水素系溶媒やニトリル系溶媒、ニトロ系溶媒、エーテル系溶媒、アミド系溶媒、ハロゲン系溶媒が好ましい。炭化水素系溶媒としては、ヘキサン、ヘプタン、オクタン、ノナン、ベンゼン、トルエン、キシレンなどが挙げられる。ニトリル系溶媒としては、ブチロニトリル、プロピオニトリルなどが挙げられる。ニトロ系溶媒としては、ニトロメタン、ニトロエタンなどが挙げられる。エーテル系溶媒としては、フェニルメチルエーテル、ジイソプロピルエーテル、ｔｅｒｔ−ブチルメチルエーテルなどが挙げられる。アミド系溶媒としては、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチルピロリドン、Ｎ−ブチルピロリドンなどが挙げられる。ハロゲン系溶媒としては、ジクロロメタン、１，２−ジクロロエタン、クロロベンゼン、α，α，α−トリフルオロトルエン、フルオロベンゼンなどが挙げられる。また、これらの混合溶媒を用いてもよい。 In the method for producing chromans and the method for producing pyrrolidines of the present invention, the reaction solvent is not particularly limited as long as it does not affect the cyclization reaction. For example, hydrocarbon solvents, nitrile solvents, nitro solvents, ether solvents An amide solvent and a halogen solvent are preferable. Examples of the hydrocarbon solvent include hexane, heptane, octane, nonane, benzene, toluene, xylene and the like. Examples of the nitrile solvent include butyronitrile and propionitrile. Examples of the nitro solvent include nitromethane and nitroethane. Examples of the ether solvent include phenyl methyl ether, diisopropyl ether, tert-butyl methyl ether and the like. Examples of amide solvents include N, N-dimethylacetamide, N-methylpyrrolidone, N-butylpyrrolidone and the like. Examples of the halogen solvent include dichloromethane, 1,2-dichloroethane, chlorobenzene, α, α, α-trifluorotoluene, fluorobenzene and the like. Moreover, you may use these mixed solvents.
本発明のクロマン類の製法及びピロリジン類の製法において、反応温度は反応速度などを考慮して適宜設定すればよいが、例えば、−８０〜−４０℃の範囲で設定するのが好ましい。また、反応時間は、反応基質、反応温度などに応じて適宜設定すればよいが、通常は数分間〜数１０時間である。なお、環化反応は反応基質が完全に消費されるまで行ってもよいが、反応が進むにつれて反応基質の消失速度が極端に遅くなる場合には反応基質が完全に消費されなくても反応を終了して環化物（クロマン類やピロリジン類）を取り出した方が好ましい場合もある。 In the method for producing chromans and the method for producing pyrrolidines of the present invention, the reaction temperature may be appropriately set in consideration of the reaction rate and the like, but for example, it is preferably set in the range of −80 to −40 ° C. The reaction time may be appropriately set according to the reaction substrate, reaction temperature, etc., but is usually from several minutes to several tens of hours. The cyclization reaction may be performed until the reaction substrate is completely consumed. However, when the reaction substrate disappears at an extremely slow rate as the reaction proceeds, the reaction can be performed even if the reaction substrate is not completely consumed. In some cases, it may be preferable to remove the cyclized product (chromans or pyrrolidines) after completion.
本発明のクロマン類の製法及びピロリジン類の製法において、目的とする環化物を単離するには、通常知られている単離手法を適用すればよい。例えば、反応混合物中の反応溶媒を減圧濃縮した後、カラムクロマトグラフィーや再結晶などで精製することにより、目的とする環化物を単離することができる。 In the method for producing chromans and the method for producing pyrrolidines of the present invention, a generally known isolation method may be applied to isolate the desired cyclized product. For example, the target cyclized product can be isolated by concentrating the reaction solvent in the reaction mixture under reduced pressure and then purifying it by column chromatography or recrystallization.
本発明のクロマン類の製法は、クロマン骨格を有する医薬品又はその中間体の合成に用いることができる。例えば、α−トコフェノールの中間体の合成に用いることができる。また、本発明のピロリジン類の製法は、ピロリジン骨格を有する医薬品又はその中間体の合成に用いることができる。 The method for producing chromans of the present invention can be used for the synthesis of a pharmaceutical having a chroman skeleton or an intermediate thereof. For example, it can be used for the synthesis of an intermediate of α-tocophenol. Further, the method for producing pyrrolidines of the present invention can be used for the synthesis of a pharmaceutical having a pyrrolidine skeleton or an intermediate thereof.
本発明のリン酸ジエステルアミドは、式（３）で表される化合物である。式（３）中、Ｒ1は、水素原子か炭化水素基であり、Ｒ2は、炭化水素基であり、Ｒ1とＲ2は、互いに結合して炭化水素鎖を形成していてもよく、Ｒ3、Ｒ4は、同じでも異なっていてもよく、炭化水素基又は有機シリル基であり、１，１’−ビ−２−ナフトール部位はＲかＳの光学異性体である。なお、炭化水素基や炭化水素鎖、有機シリル基の具体例は上述した通りである。 The phosphoric diester amide of the present invention is a compound represented by the formula (3). In Formula (3), R 1 is a hydrogen atom or a hydrocarbon group, R 2 is a hydrocarbon group, and R 1 and R 2 may be bonded to each other to form a hydrocarbon chain. , R 3 and R 4 may be the same or different, and are a hydrocarbon group or an organic silyl group, and the 1,1′-bi-2-naphthol moiety is an optical isomer of R or S. Specific examples of the hydrocarbon group, hydrocarbon chain, and organic silyl group are as described above.
以下、実験例を挙げて本発明を更に詳細に説明するが、本発明はこれらの実験例に限定されるものではない。 EXAMPLES Hereinafter, although an experiment example is given and this invention is demonstrated in detail, this invention is not limited to these experiment examples.
［実験例Ａ］リン酸ジエステルアミドの合成
下記スキームにしたがってリン酸ジエステルアミドを合成した。まず、市販のＢＩＮＯＬにトリス（ジメチルアミノ）ホスフィンとテトラゾールを作用させ、ジメチルホスホラミダイトへと導いた。その後、アミンとフェニルイミダゾリウムトリフラートを作用させた後、ｔｅｒｔ−ブチルヒドロペルオキシドを作用させてリン酸ジエステルアミドへ導いた。合成したリン酸ジエステルアミドのＲ1〜Ｒ4を下記スキームと共に示した。
[Experimental example A] Synthesis of phosphoric acid diester amide A phosphoric acid diester amide was synthesized according to the following scheme. First, tris (dimethylamino) phosphine and tetrazole were allowed to act on commercially available BINOL to lead to dimethyl phosphoramidite. Thereafter, amine and phenylimidazolium triflate were allowed to act, and then tert-butyl hydroperoxide was allowed to act to lead to phosphoric acid diester amide. R 1 to R 4 of the synthesized phosphoric diester amide are shown together with the following scheme.
主なリン酸ジエステルアミド１ａ〜１ｅのスペクトルデータを以下に示す。 The spectrum data of main phosphoric acid diester amides 1a to 1e are shown below.
リン酸ジエステルアミド１ａ（実験例Ｂ１−３等で使用）：無色の結晶；1H NMR (400 MHz, CDCl3) δ8.07 (s, 1H), 7.89 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 6.0 Hz, 6H), 7.40 (d, J = 7.4 Hz, 6H), 7.50-7.06 (m, 21H), 6.87 (t, J = 7.3 Hz, 1H), 6.61 (d, J = 7.8 Hz, 2H), 1.78-1.60 (m, 2H), 1.60-1.45 (m, 2H), 0.52 (t, J = 6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ152.3 (d, JC-P = 10.5 Hz), 151.2 (d, JC-P = 10.5 Hz), 142.4, 141.9, 141.1 (2C), 136.5 (6C), 136.2 (6C), 134.8, 134.5, 133.4 (3C), 133.3 (3C), 132.1, 130.9, 129.7 (3C), 129.0 (3C), 128.6, 128.0 (6C), 127.5, 127.4 (6C), 126.8, 126.6, 126.5, 126.02, 125.95, 125.31, 125.27, 124.6(2C) , 121.4, 121.0, 23.1 (2C), 13.2 (2C); 31P NMR (162 MHz, CDCl3) δ4.1. Phosphoric acid diester amide 1a (used in Experimental Example B1-3 etc.): colorless crystals; 1 H NMR (400 MHz, CDCl 3 ) δ8.07 (s, 1H), 7.89 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 6.0 Hz, 6H), 7.40 (d, J = 7.4 Hz, 6H), 7.50-7.06 (m, 21H), 6.87 (t, J = 7.3 Hz, 1H), 6.61 (d, J = 7.8 Hz, 2H), 1.78-1.60 (m, 2H), 1.60-1.45 (m, 2H), 0.52 (t, J = 6.9 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ152.3 (d, J CP = 10.5 Hz), 151.2 (d, J CP = 10.5 Hz), 142.4, 141.9, 141.1 (2C), 136.5 (6C), 136.2 (6C), 134.8, 134.5, 133.4 (3C), 133.3 (3C), 132.1, 130.9, 129.7 (3C), 129.0 (3C), 128.6, 128.0 (6C), 127.5, 127.4 (6C ), 126.8, 126.6, 126.5, 126.02, 125.95, 125.31, 125.27, 124.6 (2C), 121.4, 121.0, 23.1 (2C), 13.2 (2C); 31 P NMR (162 MHz, CDCl 3 ) δ4.1.
リン酸ジエステルアミド１ｂ（実験例Ｂ３−２等で使用）：無色の結晶；1H NMR (400 MHz, CDCl3) δ8.12 (s, 1H), 7.94 (s, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.66 (d, J = 6.9 Hz, 6H), 7.57 (d, J = 6.9 Hz, 6H), 7.53-7.38 (m, 1H), 7.46-7.17 (m, 22H), 7.07 (d, J = 8.7 Hz, 1H), 2.35-2.25 (m, 2H), 1.80-1.63 (m, 2H), 0.98-0.83 (m, 2H), 0.81-0.62 (m, 6H); 13C NMR (100 MHz, CDCl3) δ153.0 (d, JC-P = 10.5 Hz), 151.2 (d, JC-P = 8.6 Hz), 142.2, 141,6, 136.7 (6C), 136.5 (6C), 134.2, 134.0 (3C), 133.6 (3C), 130.7, 130.0, 129.5 (3C), 129.3 (3C), 128.9, 128.6, 128.4, 128.1, 127.8 (6C), 127.6 (6C), 127.4, 127.3, 126.6, 126.4, 126.2, 126.1, 125.1, 46.2 (2C), 28.5 (2C), 26.4 (2C); 31P NMR (162 MHz, CDCl3) δ9.6. Phosphoric acid diester amide 1b (used in Experimental Example B3-2 etc.): colorless crystals; 1 H NMR (400 MHz, CDCl 3 ) δ8.12 (s, 1H), 7.94 (s, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.66 (d, J = 6.9 Hz, 6H), 7.57 (d, J = 6.9 Hz, 6H), 7.53-7.38 (m, 1H), 7.46-7.17 (m, 22H), 7.07 (d, J = 8.7 Hz, 1H), 2.35-2.25 (m, 2H), 1.80-1.63 (m, 2H), 0.98-0.83 (m, 2H) , 0.81-0.62 (m, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ153.0 (d, J CP = 10.5 Hz), 151.2 (d, J CP = 8.6 Hz), 142.2, 141,6, 136.7 (6C), 136.5 (6C), 134.2, 134.0 (3C), 133.6 (3C), 130.7, 130.0, 129.5 (3C), 129.3 (3C), 128.9, 128.6, 128.4, 128.1, 127.8 (6C), 127.6 (6C), 127.4, 127.3, 126.6, 126.4, 126.2, 126.1, 125.1, 46.2 (2C), 28.5 (2C), 26.4 (2C); 31 P NMR (162 MHz, CDCl 3 ) δ9.6.
リン酸ジエステルアミド１ｃ（実験例Ｂ５−４で使用）：無色の結晶；1H NMR (400 MHz, CDCl3) δ8.10 (s, 1H), 8.02 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.67-7.55 (m, 6H), 7.49-7.37 (m, 2H), 7.37-7.10 (m, 28H), 6.62 (t, J = 8.2 Hz, 2H), 6.44-6.33 (m, 2H); 13C NMR (100 MHz, CDCl3) δ161.6 (d, JC-F = 244.4 Hz), 152.1 (d, JC-P = 11.5 Hz), 151.0 (d, JC-P = 8.6 Hz), 142.4, 141.6, 136.8 (6C), 136.7 (6C), 134.4, 134.3, 134.2 (d, JC-F = 1.9 Hz), 133.9 (3C), 133.4 (3C), 130.8, 130.5, 129.8 (3C), 129.5 (3C), 128.8, 128.74 (2C), 128.67, 128.0 (6C), 127.6 (6C), 127.5, 126.9, 126.6, 126.3 (d, JC-P = 2.9 Hz), 126.0 (d, JC-P = 3.8 Hz), 125.5, 125.4, 121.2, 121.1, 114.5 (d, JC-F = 114.5 Hz), 44.9; 31P NMR (162 MHz, CDCl3) δ8.6. Phosphoric acid diester amide 1c (used in Experimental Example B5-4): colorless crystals; 1 H NMR (400 MHz, CDCl 3 ) δ8.10 (s, 1H), 8.02 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.67-7.55 (m, 6H), 7.49-7.37 (m, 2H), 7.37-7.10 (m, 28H), 6.62 (t, J = 8.2 Hz, 2H), 6.44-6.33 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ161.6 (d, J CF = 244.4 Hz), 152.1 (d, J CP = 11.5 Hz) , 151.0 (d, J CP = 8.6 Hz), 142.4, 141.6, 136.8 (6C), 136.7 (6C), 134.4, 134.3, 134.2 (d, J CF = 1.9 Hz), 133.9 (3C), 133.4 (3C) , 130.8, 130.5, 129.8 (3C), 129.5 (3C), 128.8, 128.74 (2C), 128.67, 128.0 (6C), 127.6 (6C), 127.5, 126.9, 126.6, 126.3 (d, J CP = 2.9 Hz) , 126.0 (d, J CP = 3.8 Hz), 125.5, 125.4, 121.2, 121.1, 114.5 (d, J CF = 114.5 Hz), 44.9; 31 P NMR (162 MHz, CDCl 3 ) δ8.6.
リン酸ジエステルアミド１ｄ（実験例Ｃ１−３等で使用）：黄色の結晶；1H NMR (400 MHz, CDCl3) δ8.47 (s, 2H), 8.15 (d, J = 6.0 Hz, 2H), 8.07-7.89 (d, J = 8.7 Hz, 7H), 7.81 (d, J = 8.7 Hz, 1H), 7.78-7.57 (m, 6H), 7.56-7.46 (m, 2H), 7.44-7.20 (m, 8H), 1.80-1.65 (m, 2H), 1.54-1.38 (m, 2H), 0.50-0.38 (m, 4H), 0.36-0.17 (m, 4H); 13C NMR (100 MHz, CDCl3) δ147.8 (d, JC-P = 11.5 Hz), 146.0 (d, JC-P = 8.6 Hz), 133.8, 133.5, 132.8, 132.7, 131.6, 131.6, 131.4, 131.3, 131.2 (2C), 131.2, 131.0, 130.9, 130.7, 130.57, 130.47, 130.2, 128.7, 128.6, 128.5, 128.4, 128.1, 127.9, 127.7, 127.6, 127.5, 127.4, 127.1, 126.9, 126.8 (2C), 126.7, 126.4, 126.1, 126.0, 125.8, 125.5, 125.43, 125.36, 125.26, 125.0, 124.6, 124.5, 122.5, 122.1, 48.14, 48.11, 28.6 (2C), 25.2 (2C); 31P NMR (162 MHz, CDCl3) δ12.0. Phosphoric acid diester amide 1d (used in Experimental Example C1-3 etc.): yellow crystals; 1 H NMR (400 MHz, CDCl 3 ) δ 8.47 (s, 2H), 8.15 (d, J = 6.0 Hz, 2H) , 8.07-7.89 (d, J = 8.7 Hz, 7H), 7.81 (d, J = 8.7 Hz, 1H), 7.78-7.57 (m, 6H), 7.56-7.46 (m, 2H), 7.44-7.20 (m , 8H), 1.80-1.65 (m, 2H), 1.54-1.38 (m, 2H), 0.50-0.38 (m, 4H), 0.36-0.17 (m, 4H); 13 C NMR (100 MHz, CDCl 3 ) δ147.8 (d, J CP = 11.5 Hz), 146.0 (d, J CP = 8.6 Hz), 133.8, 133.5, 132.8, 132.7, 131.6, 131.6, 131.4, 131.3, 131.2 (2C), 131.2, 131.0, 130.9 , 130.7, 130.57, 130.47, 130.2, 128.7, 128.6, 128.5, 128.4, 128.1, 127.9, 127.7, 127.6, 127.5, 127.4, 127.1, 126.9, 126.8 (2C), 126.7, 126.4, 126.1, 126.0, 125.8, 125.5, 125.43, 125.36, 125.26, 125.0, 124.6, 124.5, 122.5, 122.1, 48.14, 48.11, 28.6 (2C), 25.2 (2C); 31 P NMR (162 MHz, CDCl 3 ) δ12.0.
リン酸ジエステルアミド１ｅ（実験例Ｂ１−３等で使用）：無色の結晶；1H NMR (400 MHz, CDCl3) δ8.13 (s, 1H), 8.10 (s, 1H), 7.82 (t, J = 8.7 Hz, 2H), 7.67 (d, J = 6.9 Hz, 6H), 7.53 (d, J = 7.3 Hz, 6H), 7.46-7.24 (m, 23H), 7.19-7.11 (m, 1H), 1.50 (s, 3H), 1.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ153.1 (d, JC-P = 10.5 Hz), 151.0 (d, JC-P = 10.5 Hz), 141.7 (2C), 141.6 (2C), 136.8 (6C), 136.8 (6C), 134.6 (3C), 134.0, 133.9, 133.7 (3C), 130.7, 130.1, 129.6 (3C), 129.2 (3C), 128.64 (2C), 128.57 (2C), 127.8 (6C), 127.5 (6C), 127.4 (2C), 127.3, 126.9, 126.5 (2C), 126.27, 126.26, 125.26, 125.23, 121.2, 120.9, 36.26, 36.22; 31P NMR (162 MHz, CDCl3) δ10.8. Phosphoric acid diester amide 1e (used in Experimental Example B1-3 etc.): colorless crystals; 1 H NMR (400 MHz, CDCl 3 ) δ8.13 (s, 1H), 8.10 (s, 1H), 7.82 (t, J = 8.7 Hz, 2H), 7.67 (d, J = 6.9 Hz, 6H), 7.53 (d, J = 7.3 Hz, 6H), 7.46-7.24 (m, 23H), 7.19-7.11 (m, 1H), 1.50 (s, 3H), 1.47 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ153.1 (d, J CP = 10.5 Hz), 151.0 (d, J CP = 10.5 Hz), 141.7 ( 2C), 141.6 (2C), 136.8 (6C), 136.8 (6C), 134.6 (3C), 134.0, 133.9, 133.7 (3C), 130.7, 130.1, 129.6 (3C), 129.2 (3C), 128.64 (2C) , 128.57 (2C), 127.8 (6C), 127.5 (6C), 127.4 (2C), 127.3, 126.9, 126.5 (2C), 126.27, 126.26, 125.26, 125.23, 121.2, 120.9, 36.26, 36.22; 31 P NMR ( 162 MHz, CDCl 3 ) δ10.8.
［実験例Ｂ］クロマン類の合成
［実験例Ｂ１］
出発原料（基質）である２−（３−ベンジル−３−ブテニル）フェノールを下記のスキームにしたがって合成した。市販の３−（２−メトキシフェニル）プロピオン酸を塩化チオニルで酸クロリドへと変換した後、ワインレブアミドに導いた。グリニャール（Grignard）試薬を作用させてケトンへと導き、ウィティッヒ（Wittig）反応によりオレフィンへと変換した後、エタンチオール、水素化ナトリウムによりメトキシ基を脱保護し、２−（３−ベンジル−３−ブテニル）フェノールを合成した。
[Experiment B] Synthesis of chromans [Experiment B1]
The starting material (substrate) 2- (3-benzyl-3-butenyl) phenol was synthesized according to the following scheme. Commercially available 3- (2-methoxyphenyl) propionic acid was converted to acid chloride with thionyl chloride and then led to wine levamide. A Grignard reagent is allowed to act to lead to a ketone, which is converted to an olefin by a Wittig reaction, and then the methoxy group is deprotected with ethanethiol and sodium hydride to give 2- (3-benzyl-3- Butenyl) phenol was synthesized.
表１の上段に示した反応式にしたがってヨードエーテル環化反応を行った。シュレンク管に、触媒（０．００５ｍｏｌ)及びトルエン（０．５ｍＬ）を加え、窒素を充填した。−７８℃でルイス酸としてＮＩＳ（０．１１ｍｏｌ）及びヨード化剤としてＩ2（０．１１ｍｏｌ）を加えた後、トルエン（０．５ｍＬ）に溶かした２−（３−ベンジル−３−ブテニル）フェノール（０．１ｍｏｌ）を滴下した。１５時間攪拌後、チオ硫酸ナトリウムの飽和水溶液を加え、酢酸エチルで３度分液を行い、ろ液をエバポレータを用いて濃縮した。残渣をシリカゲルカラムクロマトグラフィーを用いてヘキサン−酢酸エチル混合溶媒で分離・精製した。その結果、目的の２−ヨードメチル−２−ベンジルクロマンが油状物質として得られた。 The iodoether cyclization reaction was performed according to the reaction formula shown in the upper part of Table 1. A catalyst (0.005 mol) and toluene (0.5 mL) were added to a Schlenk tube and filled with nitrogen. 2- (3-benzyl-3-butenyl) dissolved in toluene (0.5 mL) after adding NIS (0.11 mol) as a Lewis acid and I 2 (0.11 mol) as an iodinating agent at −78 ° C. Phenol (0.1 mol) was added dropwise. After stirring for 15 hours, a saturated aqueous solution of sodium thiosulfate was added, liquid separation was performed three times with ethyl acetate, and the filtrate was concentrated using an evaporator. The residue was separated and purified with a hexane-ethyl acetate mixed solvent using silica gel column chromatography. As a result, the desired 2-iodomethyl-2-benzylchroman was obtained as an oily substance.
実験例Ｂ１−１ではＲが２，６−ジエチルフェニル基のリン酸トリエステルアミドを触媒として用いたのに対して、実験例Ｂ１−２ではＲが２，６−ジエチルアニリノ基のリン酸ジエステルアミド１ａを触媒として用いた。その結果、実験例Ｂ１−２は、実験例Ｂ１−１に比べて反応促進効果もエナンチオ選択性も格段に高かった。また、実験例Ｂ１−３ではＲがジメチルアミノ基のリン酸ジエステルアミド１ｅを触媒として用いたところ、エナンチオ選択性は更に向上した。以上の結果から、リン酸ジエステルアミドはリン酸トリエステルに比べてヨードエーテル環化触媒としての活性が高いと判断した。 In Experimental Example B1-1, phosphoric acid triester amide having R of 2,6-diethylphenyl group was used as a catalyst, whereas in Experimental Example B1-2, phosphoric acid having R of 2,6-diethylanilino group was used. Diester amide 1a was used as a catalyst. As a result, Experimental Example B1-2 was significantly higher in both the reaction promoting effect and enantioselectivity than Experimental Example B1-1. In Experimental Example B1-3, when phosphoric acid diester amide 1e having R as a dimethylamino group was used as a catalyst, the enantioselectivity was further improved. From the above results, it was determined that phosphoric diester amide had higher activity as an iodoether cyclization catalyst than phosphoric triester.
２−ベンジル−２−ヨードメチルクロマンのスペクトルデータは以下の通り。無色のオイル; 1H NMR (400 MHz, CDCl3) δ 7.46-7.23 (5H, m), 7.18-7.04 (2H, m), 6.92 - 6.81 (2H, m), 3.25 (d, J = 10.5 Hz, 1H), 3.18 (d, J = 10.5 Hz, 1H), 3.16 (d, J = 14.2 Hz, 1H), 3.09 (d, J = 14.2 Hz, 1H), 2.81-2.74 (m, 2H), 2.27-2.15 (m, 2H), 1.96-1.84 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 152.9, 135.9, 130.6 (2C), 129.5, 128.1, 127.6, 126.8, 120.7, 120.4, 117.5, 75.9, 42.8, 28.3, 21.3, 11.9; eeはHPLC分析により決定した(Daicel Chiralpack IC-3 column, hexane-iPrOH = 1000:1, flow rate = 0.5 mL/min) tR= 18.6 (minor enantiomer), 27.4 (major enantiomer) min. The spectrum data of 2-benzyl-2-iodomethylchroman are as follows. Colorless oil; 1 H NMR (400 MHz, CDCl 3 ) δ 7.46-7.23 (5H, m), 7.18-7.04 (2H, m), 6.92-6.81 (2H, m), 3.25 (d, J = 10.5 Hz , 1H), 3.18 (d, J = 10.5 Hz, 1H), 3.16 (d, J = 14.2 Hz, 1H), 3.09 (d, J = 14.2 Hz, 1H), 2.81-2.74 (m, 2H), 2.27 -2.15 (m, 2H), 1.96-1.84 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 152.9, 135.9, 130.6 (2C), 129.5, 128.1, 127.6, 126.8, 120.7, 120.4, 117.5 , 75.9, 42.8, 28.3, 21.3, 11.9; ee was determined by HPLC analysis (Daicel Chiralpack IC-3 column, hexane- i PrOH = 1000: 1, flow rate = 0.5 mL / min) t R = 18.6 (minor enantiomer ), 27.4 (major enantiomer) min.
［実験例Ｂ２］
表２の上段に示した反応式にしたがってヨードエーテル環化反応を行った。基質の合成手順や環化反応の手順は、実験例Ｂ１に準じて行った。ここでは、実験例Ｂ１−２で用いた触媒（リン酸ジエステルアミド１ａ）のもと、基質一般性について検討した。その結果、実験例Ｂ２−１〜Ｂ２−４に示すように、Ｒ’がオクチル基、シクロヘキシル基、メチル基の基質でもベンジル基の基質と同様に高収率で目的物が得られると共に、エナンチオ選択性も高かった。一方、Ｒがフェニル基の基質では、高収率で目的物が得られたものの、エナンチオ選択性は中程度であった。
[Experiment B2]
The iodoether cyclization reaction was performed according to the reaction formula shown in the upper part of Table 2. The synthesis procedure of the substrate and the procedure of the cyclization reaction were performed according to Experimental Example B1. Here, the generality of the substrate was examined under the catalyst (phosphoric diester amide 1a) used in Experimental Example B1-2. As a result, as shown in Experimental Examples B2-1 to B2-4, even when R ′ is an octyl group, cyclohexyl group, or methyl group substrate, the target product can be obtained in a high yield in the same manner as a benzyl group substrate. The selectivity was also high. On the other hand, with the substrate in which R is a phenyl group, the target product was obtained in high yield, but the enantioselectivity was moderate.
実験例Ｂ２−１で得られた２−ヨードメチル−２−オクチルクロマンのスペクトルデータは以下の通り。淡黄色のオイル; 1H NMR (400 MHz, CDCl3) δ 7.14-7.01 (m, 2H), 6.90-6.78 (m, 2H), 3.34 (d, J = 11.9 Hz, 1H), 3.31 (d, J = 11.9 Hz, 1H), 2.80-2.65 (m, 2H), 2.20-2.03 (m, 1H), 2.00-1.88 (m, 1H), 1.49-1.18 (m, 12H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 153.3, 129.4, 127.4, 120.8, 120.1, 117.4, 75.9, 37.5, 31.8, 29.8, 29.5, 29.2, 28.1, 22.7, 21.5, 14.1, 12.1. eeはHPLC分析により決定した(Daicel Chiralpack IB-3 column, hexane-iPrOH = 1000:1, flow rate = 0.5 mL/min) tR= 11.1 (major enantiomer), 11.8 (minor enantiomer) min. The spectrum data of 2-iodomethyl-2-octylchroman obtained in Experimental Example B2-1 are as follows. Pale yellow oil; 1 H NMR (400 MHz, CDCl 3 ) δ 7.14-7.01 (m, 2H), 6.90-6.78 (m, 2H), 3.34 (d, J = 11.9 Hz, 1H), 3.31 (d, J = 11.9 Hz, 1H), 2.80-2.65 (m, 2H), 2.20-2.03 (m, 1H), 2.00-1.88 (m, 1H), 1.49-1.18 (m, 12H), 0.88 (t, J = 6.9 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 153.3, 129.4, 127.4, 120.8, 120.1, 117.4, 75.9, 37.5, 31.8, 29.8, 29.5, 29.2, 28.1, 22.7, 21.5, 14.1, 12.1 ee was determined by HPLC analysis (Daicel Chiralpack IB-3 column, hexane- i PrOH = 1000: 1, flow rate = 0.5 mL / min) t R = 11.1 (major enantiomer), 11.8 (minor enantiomer) min.
実験例Ｂ２−２で得られた２−シクロヘキシル−２−ヨードメチルクロマンのスペクトルデータは以下の通り。無色のオイル; 1H NMR (400 MHz, CDCl3) δ 7.17-6.99 (2H, m), 6.93-6.78 (2H, m), 3.45 (d, J = 10.5 Hz, 1H), 3.38 (d, J = 10.5 Hz, 1H), 2.90-2.60 (m, 2H), 2.13-1.97 (m, 2H), 1.94-1.76 (m, 5H), 1.76-1.74 (m, 2H), 1.41-1.02 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 153.4, 129.3, 127.4, 120.9, 120.0, 117.5, 76.8, 43.6, 26.6, 26.51, 26.48, 26.4 (2C), 21.4, 12.2; eeはHPLC分析により決定した(Daicel Chiralpack IB-3 column, hexane-iPrOH = 1000:1, flow rate = 0.5 mL/min) tR= 11.5 (major enantiomer), 12.3 (minor enantiomer) min. The spectrum data of 2-cyclohexyl-2-iodomethylchroman obtained in Experimental Example B2-2 are as follows. Colorless oil; 1 H NMR (400 MHz, CDCl 3 ) δ 7.17-6.99 (2H, m), 6.93-6.78 (2H, m), 3.45 (d, J = 10.5 Hz, 1H), 3.38 (d, J = 10.5 Hz, 1H), 2.90-2.60 (m, 2H), 2.13-1.97 (m, 2H), 1.94-1.76 (m, 5H), 1.76-1.74 (m, 2H), 1.41-1.02 (m, 5H ); 13 C NMR (100 MHz, CDCl 3 ) δ 153.4, 129.3, 127.4, 120.9, 120.0, 117.5, 76.8, 43.6, 26.6, 26.51, 26.48, 26.4 (2C), 21.4, 12.2; ee determined by HPLC analysis (Daicel Chiralpack IB-3 column, hexane- i PrOH = 1000: 1, flow rate = 0.5 mL / min) t R = 11.5 (major enantiomer), 12.3 (minor enantiomer) min.
実験例Ｂ２−３で得られた２−ヨードメチル−２−メチルクロマンのスペクトルデータは以下の通り。淡黄色のオイル; 1H NMR (400 MHz, CDCl3) δ 7.16-7.02 (m, 2H), 6.92-6.75 (m, 2H), 3.35 (d, J = 10.1 Hz, 1H), 3.32 (d, J = 10.1 Hz, 1H), 2.84-2.67 (m, 2H), 2.24-2.12 (m, 1H), 1.98-1.83 (m, 1H), 1.49; 13C NMR (100 MHz, CDCl3) δ 153.1, 129.3, 127.4, 120.5, 120.2, 117.2, 74.1, 30.0, 25.2, 21.7, 14.1; eeはHPLC分析により決定した(Daicel Chiralpack IA-3 column, hexane-iPrOH = 1000:1, flow rate = 0.5 mL/min) tR= 13.4 (minor enantiomer), 15.1 (major enantiomer) min. The spectrum data of 2-iodomethyl-2-methylchroman obtained in Experimental Example B2-3 are as follows. Pale yellow oil; 1 H NMR (400 MHz, CDCl 3 ) δ 7.16-7.02 (m, 2H), 6.92-6.75 (m, 2H), 3.35 (d, J = 10.1 Hz, 1H), 3.32 (d, J = 10.1 Hz, 1H), 2.84-2.67 (m, 2H), 2.24-2.12 (m, 1H), 1.98-1.83 (m, 1H), 1.49; 13 C NMR (100 MHz, CDCl 3 ) δ 153.1, 129.3, 127.4, 120.5, 120.2, 117.2, 74.1, 30.0, 25.2, 21.7, 14.1; ee was determined by HPLC analysis (Daicel Chiralpack IA-3 column, hexane- i PrOH = 1000: 1, flow rate = 0.5 mL / min) t R = 13.4 (minor enantiomer), 15.1 (major enantiomer) min.
実験例Ｂ２−４で得られた２−ヨードメチル−２−フェニルクロマンのスペクトルデータは以下の通り。無色のオイル; 1H NMR (400 MHz, CDCl3) δ7.39-7.23 (5H, m), 7.18-7.12 (1H, m), 7.07-7.02 (2H, m), 6.96-6.92 (1H, m), 6.85-6.79 (1H, m), 3.63 (d, J = 11.0 Hz, 1H), 3.60 (d, J = 11.0 Hz, 1H), 2.74-2.60 (m, 2H), 2.51-2.33 (m, 1H), 2.46 - 2.40 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 153.5, 141.1, 129.2, 128.6, 127.7, 127.6, 125.6, 121.3, 120.5, 117.0, 77.9, 30.5, 22.5, 18.3; eeはHPLC分析により決定した(Daicel Chiralpack IB-3 column, hexane-iPrOH = 1000:1, flow rate = 0.5 mL/min) tR= 23.7 (major enantiomer), 26.7 (minor enantiomer) min. The spectrum data of 2-iodomethyl-2-phenylchroman obtained in Experimental Example B2-4 are as follows. Colorless oil; 1 H NMR (400 MHz, CDCl 3 ) δ 7.39-7.23 (5H, m), 7.18-7.12 (1H, m), 7.07-7.02 (2H, m), 6.96-6.92 (1H, m ), 6.85-6.79 (1H, m), 3.63 (d, J = 11.0 Hz, 1H), 3.60 (d, J = 11.0 Hz, 1H), 2.74-2.60 (m, 2H), 2.51-2.33 (m, 1H), 2.46-2.40 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 153.5, 141.1, 129.2, 128.6, 127.7, 127.6, 125.6, 121.3, 120.5, 117.0, 77.9, 30.5, 22.5, 18.3 ee was determined by HPLC analysis (Daicel Chiralpack IB-3 column, hexane- i PrOH = 1000: 1, flow rate = 0.5 mL / min) t R = 23.7 (major enantiomer), 26.7 (minor enantiomer) min.
［実験例Ｂ３］
表３の上段に示した反応式にしたがってヨードエーテル環化反応を行った。環化反応の手順は実験例Ｂ１に準じて行った。ここでは、実験例Ｂ２−４で用いた基質について、触媒の最適化を検討した。実験例Ｂ３−１に示すようにジメチルアミノ基がリン原子に結合したリン酸ジエステルアミド１ｅを用いた場合、目的物が高収率で得られたが、エナンチオ選択性は向上しなかった。これに対して、実験例Ｂ３−２，Ｂ３−３に示すように、含窒素７員環がリン原子に結合したリン酸ジエステルアミド１ｂや含窒素８員環がリン原子に結合したリン酸ジエステルアミドを用いた場合、目的物が高収率で得られると共に、エナンチオ選択性が向上した。表３においては、リン酸ジエステルアミド１ｂが触媒として最適であると判断した。
[Experiment B3]
The iodoether cyclization reaction was performed according to the reaction formula shown in the upper part of Table 3. The procedure of the cyclization reaction was performed according to Experimental Example B1. Here, optimization of the catalyst was examined for the substrate used in Experimental Example B2-4. As shown in Experimental Example B3-1, when the phosphoric acid diester amide 1e having a dimethylamino group bonded to a phosphorus atom was used, the target product was obtained in high yield, but the enantioselectivity was not improved. In contrast, as shown in Experimental Examples B3-2 and B3-3, phosphoric acid diester amide 1b in which a nitrogen-containing 7-membered ring is bonded to a phosphorus atom and phosphoric acid diester in which a nitrogen-containing 8-membered ring is bonded to a phosphorus atom When an amide was used, the target product was obtained in a high yield and the enantioselectivity was improved. In Table 3, it was judged that phosphoric diester amide 1b was optimal as a catalyst.
［実験例Ｂ４］
表４の上段に示した反応式にしたがってヨードエーテル環化反応を行った。環化反応の手順は実験例Ｂ１に準じて行った。ここでは、内部にオレフィンを有する基質を用いて検討を行った。実験例Ｂ４−１，Ｂ４−２に示すように、リン酸ジエステルアミド１ｂを用い、ルイス酸としてＮＢＳやＤＢＨを用いた場合に反応が進行した。特に、実験例Ｂ４−３に示すように、ＤＢＨとリン酸ジエステルアミド１ａ（実験例Ｂ１−２で用いた触媒）とを組み合わせると、高収率で目的物が得られると共に、エナンチオ選択性も高くなった。
[Experiment B4]
The iodoether cyclization reaction was performed according to the reaction formula shown in the upper part of Table 4. The procedure of the cyclization reaction was performed according to Experimental Example B1. Here, examination was performed using a substrate having olefin inside. As shown in Experimental Examples B4-1 and B4-2, the reaction proceeded when phosphoric acid diester amide 1b was used and NBS or DBH was used as the Lewis acid. In particular, as shown in Experimental Example B4-3, when DBH and phosphoric diester amide 1a (catalyst used in Experimental Example B1-2) are combined, the target product is obtained in high yield, and the enantioselectivity is also high. It became high.
［実験例Ｂ５］
α−トコフェノールをはじめとする生理活性を有するクロマン類の合成に利用可能な中間体を合成した。まず、下記スキームにしたがって基質を合成した。すなわち、入手容易なラクトンの水酸基を保護し、その後、ワインレブアミン（Weinreb amine）を用いて開環し、水酸基をベンジル基で保護した。グリニャール（Grignard）試薬によりメチルケトンとした後、Ｐｄ−Ｃでベンジル保護を脱保護し、ウィティッヒ（Wittig）反応によりケトンをオレフィンに変換し、基質を合成した。
[Experiment B5]
Intermediates that can be used for the synthesis of chromans having physiological activity including α-tocophenol were synthesized. First, a substrate was synthesized according to the following scheme. That is, the hydroxyl group of an easily available lactone was protected, and then the ring was opened using Weinreb amine to protect the hydroxyl group with a benzyl group. After making methyl ketone with Grignard reagent, benzyl protection was deprotected with Pd-C, and the ketone was converted to olefin by Wittig reaction to synthesize the substrate.
合成した基質のスペクトルデータは以下の通り。1H NMR (400 MHz, CDCl3) δ 4.79 (s, 2H), 4.52 (s, 1H), 3.62 (s, 3H), 2.82-2.67 (m, 2H), 2.23 (s, 3H), 2.20 (s, 3H), 2.14 (s, 3H), 2.30-2.08 (m, 2H), 1.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 150.5, 147.8, 146.3, 127.6, 126.8, 124.9, 120.3, 110.0, 60.3, 37.1, 25.9, 22.7, 12.7, 12.1, 11.9. The spectrum data of the synthesized substrate is as follows. 1 H NMR (400 MHz, CDCl 3 ) δ 4.79 (s, 2H), 4.52 (s, 1H), 3.62 (s, 3H), 2.82-2.67 (m, 2H), 2.23 (s, 3H), 2.20 ( s, 3H), 2.14 (s, 3H), 2.30-2.08 (m, 2H), 1.81 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 150.5, 147.8, 146.3, 127.6, 126.8, 124.9 , 120.3, 110.0, 60.3, 37.1, 25.9, 22.7, 12.7, 12.1, 11.9.
合成した基質を用いて、表５の上段に示した反応式にしたがってヨードエーテル環化反応を行った。手順は実験例Ｂ１に準じて行った。実験例Ｂ５−１〜Ｂ５−４に示すように、Ｒがベンジルアミノ基などのアラルキルアミノ基のリン酸ジエステルアミドを用いたところ、良好なエナンチオ選択性が得られた。表５においては、実験例Ｂ５−４のリン酸ジエステルアミド１ｃが触媒として最適であると判断した。 Using the synthesized substrate, iodoether cyclization reaction was performed according to the reaction formula shown in the upper part of Table 5. The procedure was performed according to Experimental Example B1. As shown in Experimental Examples B5-1 to B5-4, when R was an aralkylamino group phosphoric diesteramide such as a benzylamino group, good enantioselectivity was obtained. In Table 5, it was judged that the phosphoric diester amide 1c of Experimental Example B5-4 was optimal as a catalyst.
合成した２−ヨードメチル−６−メトキシ−２，５，７，８−テトラメチルクロマンのスペクトルデータは以下の通り。無色のオイル; 1H NMR (400 MHz, CDCl3) δ 3.63 (3H, s), 3.32 (s, 2H), 2,66-2.50 (2H, m), 2.19 (s, 3H), 2.14 (s, 3H), 2.11 (s, 3H), 2.17-2.07 (m, 1H), 1.96 - 1.84 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 150.0, 147.1, 128.3, 125.9, 123.4, 117.1, 73.0, 60.5, 30.2, 25.4, 20.6, 15.3, 12.7, 12.0, 11.8; eeはHPLC分析により決定した(Daicel Chiralpack IB-3 column, hexane-iPrOH = 98:2, flow rate = 0.5 mL/min) tR= 9.04 (major enantiomer), 10.5 (minor enantiomer) min. The spectrum data of synthesized 2-iodomethyl-6-methoxy-2,5,7,8-tetramethylchroman are as follows. Colorless oil; 1 H NMR (400 MHz, CDCl 3 ) δ 3.63 (3H, s), 3.32 (s, 2H), 2,66-2.50 (2H, m), 2.19 (s, 3H), 2.14 (s , 3H), 2.11 (s, 3H), 2.17-2.07 (m, 1H), 1.96-1.84 (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 150.0, 147.1, 128.3, 125.9, 123.4, 117.1, 73.0, 60.5, 30.2, 25.4, 20.6, 15.3, 12.7, 12.0, 11.8; ee was determined by HPLC analysis (Daicel Chiralpack IB-3 column, hexane- i PrOH = 98: 2, flow rate = 0.5 mL / min) t R = 9.04 (major enantiomer), 10.5 (minor enantiomer) min.
［実験例Ｃ］ピロリジン類の合成
［実験例Ｃ１］
出発原料（基質）であるＮ−（４−シクロヘキシルメチル−４−ペンテニル）−４−メチルベンゼンスルホンアミドを下記のスキームにしたがって合成した。市販のエチルスクシニルクロリドにグリニャール（Grignard）試薬とヨウ化銅を作用させてケトエステルへと導いた。その後、Yeungらの合成法に従い、ウィティッヒ（Wittig）反応によりオレフィンへと導き、水素化アルミニウムリチウムを作用させ、エステルを還元した後、メチルクロリドとトリエチルアミンによりメシル化し、トシルアミンと水素化ナトリウムを作用させて目的とするＮ−アルケニルスルホンアミドを合成した。
[Experimental example C] Synthesis of pyrrolidines [Experimental example C1]
The starting material (substrate), N- (4-cyclohexylmethyl-4-pentenyl) -4-methylbenzenesulfonamide, was synthesized according to the following scheme. A commercially available ethyl succinyl chloride was reacted with a Grignard reagent and copper iodide to lead to a keto ester. Then, according to the synthesis method of Yeung et al., It led to olefin by Wittig reaction, reacted with lithium aluminum hydride, reduced ester, mesylated with methyl chloride and triethylamine, reacted with tosylamine and sodium hydride The target N-alkenylsulfonamide was synthesized.
表６の上段に示した反応式にしたがってヨードアミノ環化反応を行った。シュレンク管に、リン酸ジエステルアミド（０．００５ｍｏｌ)及びトルエン（０．５ｍＬ）を加え、窒素を充填した。−７８℃でＮＩＳ（０．１１ｍｏｌ）及びＩ2（０．１１ｍｏｌ）を加えた後、トルエン（０．５ｍＬ）に溶かしたＮ−アルケニルスルホンアミド（０．１ｍｏｌ）を滴下した。１５時間攪拌後、チオ硫酸ナトリウムの飽和水溶液を加え、酢酸エチルで３度分液を行い、ろ液をエバポレータを用いて濃縮した。残渣をシリカゲルカラムクロマトグラフィーを用いてヘキサン−酢酸エチル混合溶媒で分離・精製した。その結果、目的の２−ヨードメチルピロリジン誘導体が無色透明の油状物質として得られた。 The iodoamino cyclization reaction was performed according to the reaction formula shown in the upper part of Table 6. To the Schlenk tube, phosphoric diesteramide (0.005 mol) and toluene (0.5 mL) were added and filled with nitrogen. After adding NIS (0.11 mol) and I 2 (0.11 mol) at −78 ° C., N-alkenylsulfonamide (0.1 mol) dissolved in toluene (0.5 mL) was added dropwise. After stirring for 15 hours, a saturated aqueous solution of sodium thiosulfate was added, liquid separation was performed three times with ethyl acetate, and the filtrate was concentrated using an evaporator. The residue was separated and purified with a hexane-ethyl acetate mixed solvent using silica gel column chromatography. As a result, the desired 2-iodomethylpyrrolidine derivative was obtained as a colorless and transparent oily substance.
実験例Ｃ１−１，Ｃ１−２に示すように、含窒素７員環がリン原子に結合したリン酸ジエステルアミド１ｂや含窒素８員環がリン原子に結合したリン酸ジエステルアミドを触媒として用いたところ、高収率で目的物が得られると共に、中程度のエナンチオ選択性が発現した。実験例Ｃ１−１で反応温度を−７８℃に下げて１５時間反応させたところ、エナンチオ選択性が７０％に向上した。実験例Ｃ１−３では、含窒素７員環がリン原子に結合しＢＩＮＯＬの３，３’位に９−アントラセニル基を持つリン酸ジエステルアミド１ｄを触媒とし、−７８℃で１５時間反応させたところ、収率及びエナンチオ選択性が大幅に向上した。したがって、表６においては、リン酸ジエステルアミド１ｄが触媒として最適であると判断した。 As shown in Experimental Examples C1-1 and C1-2, phosphoric acid diester amide 1b in which a nitrogen-containing 7-membered ring is bonded to a phosphorus atom and phosphoric acid diester amide in which a nitrogen-containing 8-membered ring is bonded to a phosphorus atom are used as catalysts. As a result, the target product was obtained in a high yield, and a moderate enantioselectivity was exhibited. In Experimental Example C1-1, the reaction temperature was lowered to −78 ° C. and reacted for 15 hours. As a result, the enantioselectivity was improved to 70%. In Experimental Example C1-3, phosphoric diester amide 1d having a 9-anthracenyl group at the 3,3′-position of BINOL with a nitrogen-containing 7-membered ring bonded to a phosphorus atom was used as a catalyst, and reacted at −78 ° C. for 15 hours. However, the yield and enantioselectivity were greatly improved. Therefore, in Table 6, it was judged that phosphoric acid diester amide 1d was optimal as a catalyst.
実験例Ｃ１−３で得られた２−ヨードメチル−２−シクロヘキシルメチル−１−トシルピロリジンのスペクトルデータは以下の通り。無色のオイル; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 3.92 (d, J = 10.5 Hz, 1H), 3.65 (d, J = 10.5 Hz, 1H), 3.43-3.32 (m, 1H), 3.31-3.19 (m, 1H), 2.42 (s, 3H), 2.21-1.50 (m, 11H), 1.38-0.98 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 143.2, 138.0, 129.5, 127.6, 71.0, 49.4, 44.6, 38.1, 354, 35.2, 34.8, 26.5, 26.4, 26.0, 22.9, 21.5, 19.4. ｅｅはＨＰＬＣ分析により決定した (Daicel Chiralpack AD-3 column, hexane-EtOH = 98:2, flow rate = 1.0 mL/min) tR= 20.4 (minor enantiomer), 22.8 (major enantiomer) min. The spectral data of 2-iodomethyl-2-cyclohexylmethyl-1-tosylpyrrolidine obtained in Experimental Example C1-3 are as follows. Colorless oil; 1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 3.92 (d, J = 10.5 Hz, 1H) , 3.65 (d, J = 10.5 Hz, 1H), 3.43-3.32 (m, 1H), 3.31-3.19 (m, 1H), 2.42 (s, 3H), 2.21-1.50 (m, 11H), 1.38-0.98 (m, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 143.2, 138.0, 129.5, 127.6, 71.0, 49.4, 44.6, 38.1, 354, 35.2, 34.8, 26.5, 26.4, 26.0, 22.9, 21.5, 19.4 ee was determined by HPLC analysis (Daicel Chiralpack AD-3 column, hexane-EtOH = 98: 2, flow rate = 1.0 mL / min) t R = 20.4 (minor enantiomer), 22.8 (major enantiomer) min.
［実験例Ｃ２］
表７の上段に示した反応式にしたがってヨードアミノ環化反応を行った。基質の合成手順や環化反応の手順は、実験例Ｃ１に準じて行った。ここでは、触媒として、リン酸ジエステルアミド１ｄを用いて、実験例Ｃ１の基質のシクロヘキシルメチル基の代わりにフェニル基、オクチル基やベンジル基を有するものを基質として用いたところ、中程度から高収率で目的物が得られ、中程度から良好のエナンチオ選択性が発現した（実験例Ｃ２−１〜Ｃ２−３）。
[Experimental example C2]
The iodoamino cyclization reaction was performed according to the reaction formula shown in the upper part of Table 7. The substrate synthesis procedure and the cyclization reaction procedure were performed in accordance with Experimental Example C1. Here, when phosphoric acid diester amide 1d was used as a catalyst and a substrate having a phenyl group, an octyl group or a benzyl group was used instead of the cyclohexylmethyl group of the substrate of Experimental Example C1, the medium to high yield was obtained. The target product was obtained at a moderate rate, and moderate to good enantioselectivity was exhibited (Experimental Examples C2-1 to C2-3).
実験例Ｃ２−１で得られた２−ヨードメチル−２−フェニル−１−トシルピロリジンのスペクトルデータは以下の通り。無色のオイル; 1H NMR (400 MHz, CDCl3) δ 7.37-7.29 (m, 2H), 7.28-7.15 (m, 5H), 7.07-7.05 (m, 2H), 4.36 (d, J = 10.1 Hz, 1H), 4.19 (d, J = 10.1 Hz, 1H), 3.80-3.69 (m, 1H), 3.65-3.53 (m, 1H), 2.64-2.54 (m, 1H), 2.13-1.90 (m, 2H)；13C NMR (100 MHz, CDCl3) δ142.6, 140.5, 137.0, 129.0 (2C), 128.0 (2C), 127.4 (3C), 127.0(2C), 70.6, 50.4, 44.2, 23.1, 21.5, 16.3. ｅｅはＨＰＬＣ分析により決定した (Daicel Chiralpack AD-3 column, hexane-iPrOH = 9:1, flow rate = 1.0 mL/min) tR= 14.5 (minor enantiomer), 15.3 (major enantiomer) min. The spectrum data of 2-iodomethyl-2-phenyl-1-tosylpyrrolidine obtained in Experimental Example C2-1 are as follows. Colorless oil; 1 H NMR (400 MHz, CDCl 3 ) δ 7.37-7.29 (m, 2H), 7.28-7.15 (m, 5H), 7.07-7.05 (m, 2H), 4.36 (d, J = 10.1 Hz , 1H), 4.19 (d, J = 10.1 Hz, 1H), 3.80-3.69 (m, 1H), 3.65-3.53 (m, 1H), 2.64-2.54 (m, 1H), 2.13-1.90 (m, 2H ); 13 C NMR (100 MHz, CDCl 3 ) δ 142.6, 140.5, 137.0, 129.0 (2C), 128.0 (2C), 127.4 (3C), 127.0 (2C), 70.6, 50.4, 44.2, 23.1, 21.5, 16.3. Ee was determined by HPLC analysis (Daicel Chiralpack AD-3 column, hexane- i PrOH = 9: 1, flow rate = 1.0 mL / min) t R = 14.5 (minor enantiomer), 15.3 (major enantiomer) min.
実験例Ｃ２−２で得られた２−ヨードメチル−２−オクチル−１−トシルピロリジンのスペクトルデータは以下の通り。無色のオイル; 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.8 Hz, 2H), 7.27 (d, J = 7.8 Hz, 2H), 3.81 (d, J = 10.5 Hz, 2H), 3.67 (d, J = 10.5 Hz, 2H), 3.37 (d, J = 6.9 Hz, 1H), 3.36 (d, J = 6.9 Hz, 1H), 2.40 (s, 3H), 2.12-1.91 (m, 4H), 1.91-1.79 (m, 1H), 1.77-1.63 (m, 1H), 1.38-1.05 (m, 14H), 0.87 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ143.0, 138.0, 129.8, 129.4, 70.3, 50.0, 38.1, 29.9, 29.5, 29.2, 25.2, 22.9, 22.6, 21.4, 19.3, 14.1. ｅｅはＨＰＬＣ分析により決定した (Daicel Chiralpack AD-3 column, hexane-iPrOH = 20:1, flow rate = 1.0 mL/min) tR= 19.1 (minor enantiomer), 25.6 (major enantiomer) min. The spectrum data of 2-iodomethyl-2-octyl-1-tosylpyrrolidine obtained in Experimental Example C2-2 are as follows. Colorless oil; 1 H NMR (400 MHz, CDCl 3 ) δ 7.76 (d, J = 7.8 Hz, 2H), 7.27 (d, J = 7.8 Hz, 2H), 3.81 (d, J = 10.5 Hz, 2H) , 3.67 (d, J = 10.5 Hz, 2H), 3.37 (d, J = 6.9 Hz, 1H), 3.36 (d, J = 6.9 Hz, 1H), 2.40 (s, 3H), 2.12-1.91 (m, 4H), 1.91-1.79 (m, 1H), 1.77-1.63 (m, 1H), 1.38-1.05 (m, 14H), 0.87 (t, J = 6.9 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ143.0, 138.0, 129.8, 129.4, 70.3, 50.0, 38.1, 29.9, 29.5, 29.2, 25.2, 22.9, 22.6, 21.4, 19.3, 14.1.ee was determined by HPLC analysis (Daicel Chiralpack AD-3 column , hexane- i PrOH = 20: 1, flow rate = 1.0 mL / min) t R = 19.1 (minor enantiomer), 25.6 (major enantiomer) min.
実験例Ｃ２−３で得られた２−ヨードメチル−２−ベンジル−１−トシルピロリジンのスペクトルデータは以下の通り。無色のオイル; 1H NMR (400 MHz, CDCl3) δ7.83 (d, J = 8.2 Hz, 2H), 7.33-7.23 (m, 8H), 3.89 (d, J = 10.1 Hz, 1H), 3.75 (d, J = 10.1 Hz, 1H), 3.49-3.33 (m, 3H), 3.22-3.11 (m, 1H), 2.42 (s, 3H), 2.10 (ddd, J = 12.8, 7.3, 3.7 Hz, 1H), 1.87 (ddd, J = 13.3, 10.5, 7.3 Hz, 1H), 1.68-1.56 (m, 11H), 1.32-1.15 (m, 1H)；13C NMR (100 MHz, CDCl3) δ143.2, 137.9, 136.9, 130.8, 129.5, 128.3, 127.5, 126.8, 70.6, 49.8, 43.0, 37.9, 22.3, 21.5, 18.5. ｅｅはＨＰＬＣ分析により決定した (Daicel Chiralpack AD-3 column, hexane-iPrOH = 20:1, tR= 18.6 (minor enantiomer), 25.2 (major enantiomer) min. The spectrum data of 2-iodomethyl-2-benzyl-1-tosylpyrrolidine obtained in Experimental Example C2-3 are as follows. Colorless oil; 1 H NMR (400 MHz, CDCl 3 ) δ7.83 (d, J = 8.2 Hz, 2H), 7.33-7.23 (m, 8H), 3.89 (d, J = 10.1 Hz, 1H), 3.75 (d, J = 10.1 Hz, 1H), 3.49-3.33 (m, 3H), 3.22-3.11 (m, 1H), 2.42 (s, 3H), 2.10 (ddd, J = 12.8, 7.3, 3.7 Hz, 1H ), 1.87 (ddd, J = 13.3, 10.5, 7.3 Hz, 1H), 1.68-1.56 (m, 11H), 1.32-1.15 (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ143.2, 137.9, 136.9, 130.8, 129.5, 128.3, 127.5, 126.8, 70.6, 49.8, 43.0, 37.9, 22.3, 21.5, 18.5.ee was determined by HPLC analysis (Daicel Chiralpack AD-3 column, hexane- i PrOH = 20: 1, t R = 18.6 (minor enantiomer), 25.2 (major enantiomer) min.
なお、上述した実験例のうち実験例Ｂ１−１以外のものが本発明の実施例に相当する。 Of the experimental examples described above, those other than the experimental example B1-1 correspond to the examples of the present invention.
本発明は、主に薬品化学産業に利用可能であり、例えば医薬品や農薬、化粧品の中間体などを製造する際に利用することができる。 The present invention can be used mainly in the pharmaceutical and chemical industries, and can be used, for example, in producing pharmaceuticals, agricultural chemicals, cosmetic intermediates, and the like.
Claims (10)
Ｒ2は、炭化水素基であり、
Ｒ1とＲ2は、互いに結合して炭化水素鎖を形成していてもよく、
Ｚは、１，１’−ビアリール骨格又は１，１’−ジアリールメチル骨格を含む基であり、リン原子に結合した２つの酸素原子は１，１’−ビアリール骨格又は１，１’−ジアリールメチル骨格の２，２’位で結合している） A cyclization catalyst comprising a phosphoric diester amide represented by the formula (1), which is used for an iodoether cyclization reaction or an iodoamino cyclization reaction.
R 2 is a hydrocarbon group,
R 1 and R 2 may be bonded to each other to form a hydrocarbon chain,
Z is a group containing a 1,1′-biaryl skeleton or a 1,1′-diarylmethyl skeleton, and two oxygen atoms bonded to a phosphorus atom are a 1,1′-biaryl skeleton or a 1,1′-diarylmethyl. It is bonded at the 2 'and 2' positions of the skeleton)
Ｘ1、Ｘ2は、同じでも異なっていてもよく、水素原子、ハロゲン原子又は炭化水素基であり、
１，１’−ビ−２−ナフトール部位はＲかＳの光学異性体である） The cyclization catalyst according to claim 1, wherein Z is an optically active group represented by the formula (2).
X 1 and X 2 may be the same or different and each represents a hydrogen atom, a halogen atom or a hydrocarbon group,
1,1′-bi-2-naphthol moiety is an optical isomer of R or S)
ヨード化剤としてヨウ素（Ｉ2 ）、ルイス酸としてハロイミド類又はハロヒダントイン類（ハロゲン原子は塩素原子、臭素原子又はヨウ素原子）、触媒として請求項１〜４のいずれか１項に記載の環化触媒を使用する、
クロマン類の製法。 A method for producing chromans from 2-alkenylphenols by iodoether cyclization reaction,
The cyclization according to any one of claims 1 to 4, wherein iodine (I 2 ) is used as an iodinating agent, haloimides or halohydantoins are used as Lewis acids (halogen atoms are chlorine, bromine or iodine atoms), and catalysts are used. Use catalyst,
Method for producing chromans.
ヨード化剤としてヨウ素（Ｉ2 ）、ルイス酸としてハロイミド類又はハロヒダントイン類（ハロゲン原子は塩素原子、臭素原子又はヨウ素原子）、触媒として請求項１〜４のいずれか１項に記載の環化触媒を使用する、
ピロリジン類の製法。 A method for producing pyrrolidines from N-alkenylsulfonamides by iodoamino cyclization reaction, comprising:
The cyclization according to any one of claims 1 to 4, wherein iodine (I 2 ) is used as an iodinating agent, haloimides or halohydantoins are used as Lewis acids (halogen atoms are chlorine, bromine or iodine atoms), and catalysts are used. Use catalyst,
Production method of pyrrolidines.
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