JP2006016351A - Method for selective deprotection of acetal - Google Patents
Method for selective deprotection of acetal Download PDFInfo
- Publication number
- JP2006016351A JP2006016351A JP2004196870A JP2004196870A JP2006016351A JP 2006016351 A JP2006016351 A JP 2006016351A JP 2004196870 A JP2004196870 A JP 2004196870A JP 2004196870 A JP2004196870 A JP 2004196870A JP 2006016351 A JP2006016351 A JP 2006016351A
- Authority
- JP
- Japan
- Prior art keywords
- acetal
- group
- derived
- compound containing
- aldehyde
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 title claims abstract description 46
- 238000010511 deprotection reaction Methods 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims abstract description 35
- 125000004036 acetal group Chemical group 0.000 claims abstract description 48
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract description 30
- STMPXDBGVJZCEX-UHFFFAOYSA-N triethylsilyl trifluoromethanesulfonate Chemical compound CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F STMPXDBGVJZCEX-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000007530 organic bases Chemical class 0.000 claims abstract description 10
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 24
- 125000006241 alcohol protecting group Chemical group 0.000 claims description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 claims description 5
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 claims description 5
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 claims description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 27
- 238000006243 chemical reaction Methods 0.000 abstract description 20
- 125000003172 aldehyde group Chemical group 0.000 abstract 3
- 150000002576 ketones Chemical class 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- -1 acetal compound Chemical class 0.000 description 12
- 125000006239 protecting group Chemical group 0.000 description 10
- 125000000524 functional group Chemical group 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000005580 one pot reaction Methods 0.000 description 4
- 238000006884 silylation reaction Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 1
- 238000006227 trimethylsilylation reaction Methods 0.000 description 1
Images
Landscapes
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
本発明は、有機合成分野において特定の官能基に結合された保護基を選択的に脱保護する方法に関する。 The present invention relates to a method for selectively deprotecting a protecting group bonded to a specific functional group in the field of organic synthesis.
複数の官能基を持つ有機分子を用いて有機合成を行う場合、目的の官能基のみを選択的に反応させるために、その他のより反応性の高い官能基を保護基と呼ばれる反応性の低い原子団に変換して一時的に不活性化することが多い。これを官能基の「保護」といい、例えばカルボニル基はアセタール基に、水酸基はシリルエーテル基によってしばしば保護される。
また、保護基は対象とする官能基を安定に保護するだけでなく、必要に応じて容易に除去できることが重要である。このように、反応終了後に不要となった保護基を外すことを「脱保護」といい、合成を進める上で保護基によって不活性化した官能基のうち特定のものだけを反応させる必要が生じた際には、それらに結合した保護基を独立に除去する必要がある。従って、特定の官能基に結合した保護基のみを緩和な条件下で脱保護することは有機合成において有用である。
When organic synthesis is carried out using organic molecules with multiple functional groups, other reactive groups that are more reactive, called protective groups, are used to selectively react only the desired functional group. Often converted to a group and temporarily inactivated. This is called “protection” of a functional group. For example, a carbonyl group is often protected by an acetal group, and a hydroxyl group is often protected by a silyl ether group.
Further, it is important that the protecting group not only stably protects the target functional group, but also can be easily removed as necessary. In this way, removing a protecting group that is no longer necessary after completion of the reaction is called `` deprotection '', and it is necessary to react only a specific functional group inactivated by the protecting group in order to proceed with the synthesis. In this case, it is necessary to remove the protecting group bonded to them independently. Therefore, it is useful in organic synthesis to deprotect only a protecting group bonded to a specific functional group under mild conditions.
カルボニル基の保護基として用いられるアセタール基は、中性及び塩基性条件下で安定であり、通常、酸性条件下で加水分解により脱保護される。このとき、アルデヒド由来のアセタールよりも、安定なカチオン中間体を経るケトン由来のアセタールの方が脱保護化されてケトンへと変換されやすいことが知られている。それに対し、ケトン由来のアセタール存在下でアルデヒド由来のアセタールを選択的に脱保護する方法は未だ知られていない。
本発明はこのような課題を解決するために成されたものであり、その目的とするところは、緩和な条件下でアルデヒド由来のアセタールを選択的に脱保護する方法を提供することにある。
Acetal groups used as protecting groups for carbonyl groups are stable under neutral and basic conditions and are usually deprotected by hydrolysis under acidic conditions. At this time, it is known that an acetal derived from a ketone that passes through a stable cation intermediate is more easily deprotected and converted to a ketone than an acetal derived from an aldehyde. On the other hand, a method for selectively deprotecting an aldehyde-derived acetal in the presence of a ketone-derived acetal is not yet known.
The present invention has been made to solve such problems, and an object of the present invention is to provide a method for selectively deprotecting an acetal derived from an aldehyde under mild conditions.
本願発明者らは上記課題の解決のため鋭意研究を行った結果、有機塩基、及びトリフルオロメタンスルホン酸トリメチルシリル（TMSOTf）又はトリフルオロメタンスルホン酸トリエチルシリル（TESOTf）によってアセタール基を脱保護できることを発見し、更に該脱保護法が特にアルデヒド由来のアセタール基に対して高い選択性を有することを見いだし、本願発明に至った。 As a result of diligent research to solve the above problems, the present inventors have found that an acetal group can be deprotected with an organic base and trimethylsilyl trifluoromethanesulfonate (TMSOTf) or triethylsilyl trifluoromethanesulfonate (TESOTf). Furthermore, the inventors have found that the deprotection method has high selectivity particularly for an aldehyde-derived acetal group, and have reached the present invention.
すなわち、上記課題を解決するために成された本発明に係るアセタールの脱保護法は、アセタール基を含む化合物に対し、有機塩基、及びトリフルオロメタンスルホン酸トリメチルシリル又はトリフルオロメタンスルホン酸トリエチルシリルを加えて反応させることにより、該アセタール基をカルボニル基に変換することを特徴とする。 That is, the method for deprotecting an acetal according to the present invention made to solve the above-described problem is to add an organic base and trimethylsilyl trifluoromethanesulfonate or triethylsilyl trifluoromethanesulfonate to a compound containing an acetal group. The acetal group is converted to a carbonyl group by reacting.
また、本発明の別の態様のものは、一分子中に水酸基及びアセタール基を含む化合物、又は水酸基を含む化合物とアセタール基を含む化合物の混合物に対し、上記脱保護法を適用することにより、該アセタール基をカルボニル基に変換すると共に、該水酸基をシリル化することを特徴とする。 In another embodiment of the present invention, by applying the above deprotection method to a compound containing a hydroxyl group and an acetal group in a molecule, or a mixture of a compound containing a hydroxyl group and a compound containing an acetal group, The acetal group is converted into a carbonyl group, and the hydroxyl group is silylated.
上記の手段を用いることによりアルデヒド由来のアセタール基を選択的に脱保護することができるため、例えばアルデヒド由来のアセタール基を有する化合物とケトン由来のアセタール基を有する化合物の混合物や、一分子中にアルデヒド由来のアセタール基及びケトン由来のアセタール基を有する化合物のような、ケトン由来のアセタール存在下において、アルデヒド由来のアセタールのみを選択的に脱保護することができる。 Since the aldehyde-derived acetal group can be selectively deprotected by using the above means, for example, a mixture of a compound having an aldehyde-derived acetal group and a compound having a ketone-derived acetal group, or in one molecule In the presence of an acetal derived from a ketone such as a compound having an acetal group derived from an aldehyde and an acetal group derived from a ketone, only the acetal derived from the aldehyde can be selectively deprotected.
また、上記反応により水酸基はシリル化（トリメチルシリル化又はトリエチルシリル化）されるため、アセタールの脱保護及び水酸基の保護をワンポット(one-pot)の反応によって実現することができる。 In addition, since the hydroxyl group is silylated (trimethylsilylation or triethylsilylation) by the above reaction, acetal deprotection and hydroxyl group protection can be realized by a one-pot reaction.
また、本発明の脱保護法は非常に緩和な反応であるため、OAc, OTBS, オレフィン、アルコールやアリルアルコールなど他の官能基に影響を与えることなくアセタールの脱保護を行うことができる（但し、アルコールやアリルアルコールの水酸基はシリルエーテルになる）。 In addition, since the deprotection method of the present invention is a very mild reaction, acetal can be deprotected without affecting other functional groups such as OAc, OTBS, olefin, alcohol and allyl alcohol (however, The hydroxyl group of alcohol or allyl alcohol becomes silyl ether).
なお、上記脱保護法はアセタール基の内、特にアルデヒド由来のものを高選択的に脱保護するものであるが、反応条件を適宜選択することにより、ケトン由来のアセタール基を脱保護することもできる。 In addition, although the said deprotection method deprotects an acetal group especially highly from an aldehyde, it can also deprotect a ketone-derived acetal group by selecting reaction conditions suitably. it can.
以上のように、本発明において脱保護の対象となる化合物は、アセタール基又はアセタール型アルコール保護基を含む化合物であればいかなるものでも良く、更に、同一分子内にアセタール基及び／又はアセタール型アルコール保護基と水酸基とを含む化合物に本発明を適用し、アセタールの脱保護と水酸基のシリル化をワンポットで行うようにしてもよい。なお、これらのアセタール基、アセタール型アルコール保護基、及び水酸基は必ずしも同一分子内に存在している必要はなく、これらの基を個別に含む化合物を混合したものに対して本発明の脱保護法を適用しても良い。 As described above, the compound to be deprotected in the present invention may be any compound containing an acetal group or an acetal type alcohol protecting group, and further, an acetal group and / or an acetal type alcohol in the same molecule. The present invention may be applied to a compound containing a protecting group and a hydroxyl group, and deprotection of the acetal and silylation of the hydroxyl group may be performed in one pot. The acetal group, the acetal type alcohol protecting group, and the hydroxyl group are not necessarily present in the same molecule, and the deprotection method of the present invention is applied to a mixture of compounds containing these groups individually. May be applied.
本発明の脱保護法に用いられる有機塩基としては特に限定されないが、コリジン, 2,6-ルチジン, トリエチルアミンのいずれかを用いるのが望ましい。 The organic base used in the deprotection method of the present invention is not particularly limited, but it is preferable to use one of collidine, 2,6-lutidine, and triethylamine.
反応溶媒としては、反応に悪影響を与えない限り特に制限はなく、例えば塩化メチレンなどを用いることができる。 The reaction solvent is not particularly limited as long as it does not adversely influence the reaction, and for example, methylene chloride can be used.
反応温度には特に限定はないが、0℃付近で反応を行うことが望ましい。また、反応時間は、アセタール化合物の種類や、脱保護に用いる試薬や溶媒の種類に応じて適宜選択する。 The reaction temperature is not particularly limited, but it is desirable to perform the reaction at around 0 ° C. The reaction time is appropriately selected according to the type of acetal compound and the type of reagent or solvent used for deprotection.
本発明のアセタールの脱保護法によって得られた生成物は、通常の有機化合物の単離・精製に用いられる方法により単離・精製することができる。例えば、反応混合物を食塩水又は水で処理し、ジエチルエーテル、酢酸エチル、塩化メチレンなどの有機溶媒で抽出する。抽出液を無水硫酸マグネシウム、無水硫酸ナトリウムなどで乾燥し、濃縮して得られる粗生成物を必要に応じて蒸留、クロマトグラフィー、再結晶などにより精製する。
［実施例］
The product obtained by the deprotection method of an acetal of the present invention can be isolated and purified by a method used for usual isolation and purification of organic compounds. For example, the reaction mixture is treated with brine or water and extracted with an organic solvent such as diethyl ether, ethyl acetate, methylene chloride. The extract is dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., and concentrated, and the crude product obtained by purification is purified by distillation, chromatography, recrystallization or the like, if necessary.
[Example]
以下に、本発明の実施例を示すが、本発明はこれらに限定されるものではない。 Examples of the present invention are shown below, but the present invention is not limited thereto.
colorless oil;IR(KBr): 1724cm-1;1H NMR(300MHz, CDCl3)δ:9.77(t,J=1.8 Hz, 1H),3.94-3.92(doublet like, 4H),2.44-2.39(m, 2H),1.65-1.60(m, 2H),1.31(s, 3H),1.42-1.28(m, 16H); 13C NMR (75 MHz, CDCl3)δ:21.83, 23.45, 23.84, 28.90, 29.07, 29.23, 29.22, 29.30, 29.59, 38.93, 43.66, 64.34, 109.96, 202.72.
colorless oil; IR (KBr): 1724 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ: 9.77 (t, J = 1.8 Hz, 1 H), 3.94-3.92 (doublet like, 4H), 2.44-2.39 (m , 2H), 1.65-1.60 (m, 2H), 1.31 (s, 3H), 1.42-1.28 (m, 16H); 13 C NMR (75 MHz, CDCl 3) δ: 21.83, 23.45, 23.84, 28.90, 29.07 , 29.23, 29.22, 29.30, 29.59, 38.93, 43.66, 64.34, 109.96, 202.72.
colorless oil;IR(KBr): 1720cm-1;1H NMR(300MHz, CDCl3)δ:9.82(dd,J=2.7, 3.2 Hz, 1H), 5.76(dt, J=3.6, 10.0 Hz, 1H),5.57(dt, J=1.8, 10.0 Hz, 1H),3.89(dd, J=2.0, 14.5 Hz, 1H),2.63(dd, J=3.2, 15.9 Hz, 1H), 2.31(dd, J=2.7, 15.9 Hz, 1H), 2.30-2.19(m, 2H), 1.82-1.92(m, 1H), 1.54-1.64(m, 1H), 0.85-1.07(m, 18H), 0.94(t, J= 7.8 Hz, 6H), 0.88(s, 9H), 0.62(q, J=7.8 Hz, 6H), 0.08(s, 6H); 13C NMR (75 MHz, CDCl3)δ:-4.0, 7.2, 18.0, 23.1, 25.9, 28.2, 51.4, 75.8, 129.5, 130.9, 202.6.
colorless oil; IR (KBr): 1720 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ: 9.82 (dd, J = 2.7, 3.2 Hz, 1H), 5.76 (dt, J = 3.6, 10.0 Hz, 1H) , 5.57 (dt, J = 1.8, 10.0 Hz, 1H), 3.89 (dd, J = 2.0, 14.5 Hz, 1H), 2.63 (dd, J = 3.2, 15.9 Hz, 1H), 2.31 (dd, J = 2.7 , 15.9 Hz, 1H), 2.30-2.19 (m, 2H), 1.82-1.92 (m, 1H), 1.54-1.64 (m, 1H), 0.85-1.07 (m, 18H), 0.94 (t, J = 7.8 Hz, 6H), 0.88 (s, 9H), 0.62 (q, J = 7.8 Hz, 6H), 0.08 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ: -4.0, 7.2, 18.0, 23.1, 25.9, 28.2, 51.4, 75.8, 129.5, 130.9, 202.6.
以下、本発明の脱保護法に関するその他の実施例について簡単に説明する。なお、これらの実施例は以下の基本操作法に従って実施した。 Hereinafter, other examples relating to the deprotection method of the present invention will be briefly described. In addition, these Examples were implemented according to the following basic operation methods.
基本操作法：窒素雰囲気下、アセタールの無水塩化メチレン溶液（0.1モル濃度）に0℃で2,6-ルチジン（反応部位がアセタールのみの場合は3.0当量、分子内にアセタールと水酸基がある場合は4.0当量）とTMSOTf又はTESOTf（反応部位がアセタールのみの場合は2.0当量、分子内にアセタールと水酸基がある場合には3.0当量）を加え、撹拌した。原料の消失を薄層クロマトグラフィーで確認し、水を加えて塩化メチレンで抽出し、有機層をNa2SO4で乾燥、減圧濃縮した。粗生成物をシリカゲルフラッシュカラムクロマトグラフィーで精製し、生成物を得た。 Basic operation method: Acetal in anhydrous methylene chloride (0.1 molar concentration) in nitrogen atmosphere at 0 ° C, 2,6-lutidine (3.0 equivalents if the reaction site is only acetal, and if there are acetals and hydroxyl groups in the molecule) 4.0 equivalents) and TMSOTf or TESOTf (2.0 equivalents when the reaction site is only acetal, and 3.0 equivalents when there are acetals and hydroxyl groups in the molecule) were added and stirred. The disappearance of the raw materials was confirmed by thin layer chromatography, water was added and the mixture was extracted with methylene chloride. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography to give the product.
種々のアルデヒド由来のアセタール基を含む化合物及びケトン由来のアセタール基を含む化合物に対して、本発明の脱保護法を適用した例を図１に示す。アルデヒド由来のアセタール化合物（run1-6, 9-15)では殆どの場合において高い収率でアルデヒドが得られた。
一方、ケトン由来のアセタール化合物に本発明を適用した場合（run7,8)は、TESOTfを用いた場合（run8）に殆ど脱保護が起こっておらず、本発明の脱保護法が高い選択性を持つことが分かる。但し、TMSOTfを用いた場合（run7）には、ケトン由来のアセタール基の脱保護化が見られた。
The example which applied the deprotection method of this invention with respect to the compound containing the acetal group derived from various aldehydes and the compound containing the acetal group derived from a ketone is shown in FIG. Aldehyde derived acetal compounds (run 1-6, 9-15) yielded aldehydes in high yields in most cases.
On the other hand, when the present invention is applied to a ketone-derived acetal compound (run 7, 8), almost no deprotection occurs when TESOTf is used (run 8), and the deprotection method of the present invention has high selectivity. I understand that I have it. However, when TMSOTf was used (run 7), deprotection of the ketone-derived acetal group was observed.
同一分子内に水酸基とアルデヒド由来のアセタール基を含む化合物に対して、本発明の脱保護法を適用した例を図２に示す。その結果、第1アルコール型（run 1,2）、第2アルコール型（run 3）、第3アルコール型（run 4）、及びステロイド型（run 5）のいずれのアセタール化合物においても、アセタール基が脱保護されると共に水酸基がシリル化された生成物が高い収率で得られた。
FIG. 2 shows an example in which the deprotection method of the present invention is applied to a compound containing a hydroxyl group and an aldehyde-derived acetal group in the same molecule. As a result, in any of the acetal compounds of the first alcohol type (
本発明の脱保護法の高い選択性を証明するため、アルデヒド由来のアセタール基を含む化合物とケトン由来のアセタール基を含む化合物の混合物、及び同一分子内にアルデヒド由来のアセタール基とケトン由来のアセタール基を併せ持つ化合物に対して本発明の脱保護法を適用した。その結果、図３に示すように、どちらの場合においても、アルデヒド由来のアセタールのみが選択的に脱保護され、ケトン由来のアセタールはそのまま残っていた。
一方、同一分子内にアルデヒド由来のアセタール基とケトン由来のアセタール基を併せ持つ化合物に対して、従来の代表的なアセタールの脱保護法であるp-TsOH処理又はTMSI処理を施した場合（run 2,3）には、このような選択性は見られなかった。
In order to prove the high selectivity of the deprotection method of the present invention, a mixture of a compound containing an aldehyde-derived acetal group and a compound containing a ketone-derived acetal group, and an aldehyde-derived acetal group and a ketone-derived acetal in the same molecule The deprotection method of the present invention was applied to a compound having a group. As a result, as shown in FIG. 3, in both cases, only the aldehyde-derived acetal was selectively deprotected, and the ketone-derived acetal remained as it was.
On the other hand, when a compound having both an acetal group derived from an aldehyde and an acetal group derived from a ketone in the same molecule is subjected to p-TsOH treatment or TMSI treatment, which is a typical conventional acetal deprotection method (run 2 3) did not show such selectivity.
更に、図４に示すように、同一分子内にアルデヒド由来のアセタール基とケトン由来のアセタール基を併せ持つ種々の化合物に対して、本発明の脱保護法を適用したところ、いずれの場合もアルデヒド由来のアセタール基の選択的な脱保護が見られた。また、同一分子内のアセチル基やメトキシル基などはそのまま残っており、本発明における脱保護反応が緩和な反応であることが分かる。 Furthermore, as shown in FIG. 4, the deprotection method of the present invention was applied to various compounds having both an aldehyde-derived acetal group and a ketone-derived acetal group in the same molecule. A selective deprotection of the acetal group was observed. In addition, acetyl groups and methoxyl groups in the same molecule remain as they are, and it can be seen that the deprotection reaction in the present invention is a mild reaction.
アセタール化合物の代わりに、アセタール型アルコール保護基を含む化合物に対して本発明の脱保護法を適用したところ、図５に示すように、MOMエーテル、THPエーテル、アセトニドのいずれの保護基も脱保護されると共に、シリルエーテル化された生成物が得られた。 When the deprotection method of the present invention was applied to a compound containing an acetal type alcohol protecting group instead of an acetal compound, as shown in FIG. 5, any protecting groups of MOM ether, THP ether, and acetonide were deprotected. As a result, a silyl etherified product was obtained.
種々のシリル化試薬を用いてアルデヒド由来アセタールの脱保護を試みた。その結果、図６に示すように、TMSOTf又はTESOTf以外ではアルデヒド由来アセタールの脱保護化は見られなかった（図中の“n.r.”は“反応なし（no reaction）”を意味する）。 Attempts were made to deprotect aldehyde-derived acetals using various silylation reagents. As a result, as shown in FIG. 6, deprotection of the aldehyde-derived acetal was not observed except for TMSOTf or TESOTf (“n.r.” in the figure means “no reaction”).
種々の有機塩基を用いてアルデヒド由来のアセタールの脱保護を試みた結果を図７(a)に示す。その結果、2,6-ルチジン、トリエチルアミン（Et3N）の順に効果が高いことが分かった。更に、図７(b)に示すように有機塩基として2,6-ルチジンを用いた場合と、コリジンを用いた場合とで比較を行ったところ、コリジンを用いた場合の方が、より高収率でアルデヒド由来のアセタールが脱保護された生成物が得られた。 FIG. 7 (a) shows the results of attempts to deprotect aldehyde-derived acetals using various organic bases. As a result, it was found that 2,6-lutidine and triethylamine (Et 3 N) were effective in this order. Furthermore, as shown in FIG. 7 (b), when 2,6-lutidine was used as the organic base and when collidine was used, higher yields were obtained when collidine was used. A product with a deprotected aldehyde-derived acetal was obtained.
Claims (6)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004196870A JP4729752B2 (en) | 2004-07-02 | 2004-07-02 | Selective deprotection of acetal |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004196870A JP4729752B2 (en) | 2004-07-02 | 2004-07-02 | Selective deprotection of acetal |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2006016351A true JP2006016351A (en) | 2006-01-19 |
| JP4729752B2 JP4729752B2 (en) | 2011-07-20 |
Family
ID=35790926
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2004196870A Expired - Lifetime JP4729752B2 (en) | 2004-07-02 | 2004-07-02 | Selective deprotection of acetal |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4729752B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2021026053A (en) * | 2019-07-31 | 2021-02-22 | 日東電工株式会社 | Photosensitive composition, device, and method for manufacturing device |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6296438A (en) * | 1985-10-22 | 1987-05-02 | Teijin Ltd | 4-hydroxy-2-cyclopentenone and production thereof |
| JPS6393796A (en) * | 1986-10-09 | 1988-04-25 | Shin Etsu Chem Co Ltd | Agent for eliminating protecting group in peptide synthesis |
| JP2003267930A (en) * | 2002-03-14 | 2003-09-25 | Shionogi & Co Ltd | Immunopotentiater and antitumor agent |
-
2004
- 2004-07-02 JP JP2004196870A patent/JP4729752B2/en not_active Expired - Lifetime
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6296438A (en) * | 1985-10-22 | 1987-05-02 | Teijin Ltd | 4-hydroxy-2-cyclopentenone and production thereof |
| JPS6393796A (en) * | 1986-10-09 | 1988-04-25 | Shin Etsu Chem Co Ltd | Agent for eliminating protecting group in peptide synthesis |
| JP2003267930A (en) * | 2002-03-14 | 2003-09-25 | Shionogi & Co Ltd | Immunopotentiater and antitumor agent |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2021026053A (en) * | 2019-07-31 | 2021-02-22 | 日東電工株式会社 | Photosensitive composition, device, and method for manufacturing device |
| JP7395278B2 (en) | 2019-07-31 | 2023-12-11 | 日東電工株式会社 | Photosensitive composition, device, and device manufacturing method |
Also Published As
| Publication number | Publication date |
|---|---|
| JP4729752B2 (en) | 2011-07-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5440057A (en) | Access to taxol analogs | |
| JP2009522227A (en) | Epoxide intermediates in the synthesis of Tamiflu | |
| DE69617425T2 (en) | PACLITAXEL SYNTHESIS FROM PRECURSOR CONNECTIONS AND METHOD FOR THE PRODUCTION THEREOF | |
| US20100249415A1 (en) | Process for preparation of temsirolimus | |
| JP4729752B2 (en) | Selective deprotection of acetal | |
| JP4237490B2 (en) | Methods for preparing taxane derivatives | |
| JP3878204B2 (en) | Oxidation of glycoside-substituted paclitaxels leading to paclitaxel and paclitaxel precursors and novel taxane compounds formed as intermediates | |
| Dai et al. | Structures and total syntheses of the plecomacrolides | |
| RU2326876C2 (en) | Method of paclitaxel preparation | |
| Kaburagi et al. | 4-(tert-Butyldimethylsilyloxy) benzylidene acetal: a novel benzylidene-type protecting group for 1, 2-diols | |
| Mihovilovic et al. | An Efficient and Simple Procedure for the Preparation of α‐Keto‐β‐lactams | |
| KR100796396B1 (en) | Process for Preparing Discodermolide and Analogues Thereof | |
| RU2434014C2 (en) | Method of producing taxane derivatives | |
| Tori et al. | Synthesis and the absolute configuration of the sesquiterpene aldehyde tridensenal from the Taiwanese liverwort Bazzania tridens | |
| Mahrwald et al. | Prostaglandins and prostaglandin intermediates. Part 26. A novel route to PGF2α using triisopropoxy‐hept‐1‐ynyl‐titanium as precursor for the β‐side chain | |
| JP2001322994A (en) | Method for manufacturing mercapto group-containing alkoxysilane compound | |
| JP4428086B2 (en) | Method for producing 1-acetoxy-3- (3,4-methylenedioxyphenyl) propene derivative | |
| JP3773578B2 (en) | Taxol synthetic intermediate | |
| JP3712077B2 (en) | Hydroindan-4-ol derivative and method for producing the same | |
| JP2000256244A (en) | Production of 4-methyltetrafluorobenzyl alcohol derivative | |
| Raubo et al. | Enantioselective Silicon-Mediated Synthesis of Glyceraldehyde Derivatives from Propargyl Alcohol | |
| Mallya et al. | Cis-hydroxylation of cyclic vinylsilanes using cetyltrimethylammonium permanganate | |
| JP2006206552A (en) | Method for recovering silicon component in stereoselective synthesis process | |
| JP4075923B2 (en) | 1-acetoxy-3- (substituted phenyl) propene compound | |
| JP2002308864A (en) | Production method for 5-propargylfurfuryl alcohol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20070702 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20100519 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20100525 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20100726 |
|
| RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20100726 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20100726 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20100831 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20101027 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20101116 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20110105 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20110125 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20110331 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140428 Year of fee payment: 3 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 Ref document number: 4729752 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| EXPY | Cancellation because of completion of term |