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Process of making alpha-aminooxyketone/alpha-aminooxyaldehyde and alpha-hydroxyketone/alpha-hydroxyaldehyde compounds and a process making reaction products from cyclic alpha, beta-unsaturated ketone substrates and nitroso substrates

外国特許コード F110005360
整理番号 B12-03US
掲載日 2011年9月5日
出願国 アメリカ合衆国
出願番号 57883609
公報番号 20100099915
公報番号 8252941
出願日 平成21年10月14日(2009.10.14)
公報発行日 平成22年4月22日(2010.4.22)
公報発行日 平成24年8月28日(2012.8.28)
国際出願番号 US2005005426
国際公開番号 WO2005090294
国際出願日 平成17年2月18日(2005.2.18)
国際公開日 平成17年9月29日(2005.9.29)
優先権データ
  • 特願2004-044540 (2004.2.20) JP
  • 11/506,590 (2006.10.25) US
  • 2005US005426 (2005.2.18) WO
  • 60/564,048P (2004.4.20) US
発明の名称 (英語) Process of making alpha-aminooxyketone/alpha-aminooxyaldehyde and alpha-hydroxyketone/alpha-hydroxyaldehyde compounds and a process making reaction products from cyclic alpha, beta-unsaturated ketone substrates and nitroso substrates
発明の概要(英語) The present invention is directed to a process of making α-aminooxyketone and α-hydroxyketone compounds.
The synthetic pathway generally involves reacting an aldehyde or ketone substrate and a nitroso substrate in the presence of a catalyst of the formula (IV): wherein Xa—Xc represent independently nitrogen, carbon, oxygen or sulfur and Z represents a 4 to 10-membered ring with or without a substituent and optionally a further step to convert the α-aminooxyketone compound formed to the α-hydroxyketone compound.
The present invention results in α-aminooxyketone and α-hydroxyketone compounds with high enantioselectivity and high purity.
The present invention is also directed to a catalytic asymmetric O-nitroso Aldol/Michael reaction.
The substrates of this reaction are generally cyclic α,&bgr;-unsaturated ketone substrate and a nitroso substrate.
This methodology generally involves reacting the cyclic α,&bgr;-unsaturated ketone substrate and the nitroso substrate in the presence of a proline-based catalyst, to provide a heterocyclic product.
従来技術、競合技術の概要(英語) BACKGROUND OF THE INVENTION
alpha -Hydroxyketone compounds are found in natural products and frequently in the molecule framework of pharmaceutical compounds.
They are synthetic equivalents for aldose compounds, e.g. pentoses and hexoses, and are very important synthetic building blocks which can lead to various physiologically active materials, medicines and intermediates in the synthesis of liquid crystalline materials.
alpha -Hydroxyketones can be obtained readily with high purity by asymmetric oxidation of carbonyl compounds.
However, asymmetric oxidation of the alpha -position of the carbonyl group by the usual methods requires a two-step process.
First, the preparation and isolation of an enolate, and second, the use of a relatively expensive oxygen-introducing reagent, which have the problem of low atom efficiency.
Other methods for direct preparation of chiral alpha -hydroxyketones without isolation of an enolate have been reported.
These methods generally involve synthesizing enantioenriched alpha -aminooxyketones, which are precursors to alpha -hydroxyketones.
Previously disclosed were methods which used the amino acid proline as a catalyst and nitrosobenzene as an oxygen-introducing reagent to prepare alpha -aminooxyketones (see e.g. Brown, S. P., Brochu, M. P., Sinz, C. J. & MacMillan, D. W. C. (2003) J. Am. Chem. Soc. 125, 10808-10809; Zhong, G. (2003) Angew.
Chem. Int. Ed. 42, 4247-4250; Hayashi, Y., Yamaguchi, J., Hibino, K. & Shoji, M. (2003) Tetrahedron Lett. 44, 8293-8296).
However, many problems remain unsolved with this method, including a lack of catalytic efficiency (10 to 20 mol % catalyst is needed) and an inability to consistently reproduce results.
Moreover, it is known that a second unwanted oxygen atom may be introduced via a side reaction with a second equivalent of nitrosobenzene.
Alternatively, it was reported that alpha -aminooxyketone could be obtained in high yield from an alkylsilyl ether and nitrosobenzene with alkylsilyl triflate as a Lewis Acid catalyst (see e.g. Momiyama, N., Yamamoto, H. (2002) Angew.
Chem. Int. Ed. 41, 2986-2987) and also from an alkyltin enolate and nitrosobenzene with Ag-BINAP as a catalyst (see e.g. Momiyama, N., Yamamoto, H. (2003) J. Am. Chem. Soc. 125, 6038-6039).
Additionally, other methods have been disclosed to produce aldol products from the condensation reaction of carbonyl compounds by: (1) using a substrate with an ether or alcohol unit in the molecule with liquid CO2, or supercritical CO2 as a solvent (see e.g. Japanese Patent 2002-No. 284729); (2) running the reaction in water using boronic acid or a phase transfer catalyst or Brönsted acid (see e.g. Japanese Patent 2002-No. 275120); or (3) using a lanthanide triflate with a chiral crown ether (see e.g. Japanese Patent 2002-No. 200428).
Despite these methods for synthesizing alpha -aminooxyketone or alpha -hydroxyketone compounds, there is still a need in the art for a process which can produce alpha -aminooxyketone or alpha -hydroxyketone compounds with sufficient enantioselectivity, purity and/or reproducibility of results to enable these compounds to be suitable for use as synthetic building blocks or intermediates in a synthetic process.
One of the most intensely studied areas in chemical synthesis at present is the development of new enantioselective processes which are catalyzed by simple organic molecules.
By using a proline-based chiral catalyst, we have discovered a reaction process which provides a method for the catalytic asymmetric synthesis of alpha -aminooxyketones via an O-nitroso Aldol reaction between an aldehyde or ketone and a nitroso compound.
These compounds are easily converted into the synthetically important enantioenriched alpha -hydroxyketones.
Furthermore, we have developed a process for producing bicyclo ketones which contain nitrogen and oxygen heteroatoms via an asymmetric O-nitroso Aldol/Michael reaction between an alpha ,beta -unsaturated cyclic ketone with a nitroso compound.
The product generated from this reaction is a Diels-Alder adduct that usually is formed through a typical Diels-Alder reaction.
However, in the tandem O-Nitroso Aldol/Michael reactions described herein, the regiochemistry of the Diels-Alder adduct is opposite that of the normal nitroso Diels-Alder reaction.
Owing to the ability to control both regiochemistry and stereochemistry, these catalytic asymmetric Aldol/Michael reactions provide novel routes to important or previously unaccessible heterocyclic compounds.
Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.

特許請求の範囲(英語) [claim1]
1. A process of making an enantioenriched alpha -aminooxyketone comprising reacting a ketone of formula (II):
with a nitroso compound of formula (IIIa) or (IIIb):
in the presence of a solvent and a catalyst of formula (IVa):
wherein:
R1 and R2 independently represent either hydrogen; a substituted or unsubstituted alkyl group; a substituted or unsubstituted alkoxy group; a substituted or unsubstituted alkoxycarbonyl group; a substituted or unsubstituted aryl group; or
R1 and R2 together form a cycloalkyl ring;
R3 is each independently selected from the group consisting of:
hydrogen, halogen, -- OR5, -- OC(O)R5, -- CN, -- C(O)R5, -- CO2R5, -- C(O)NR5R5', -- NO2, -- NR5R5', -- NRC(O)R5, -- NR5CO2R5', -- NR5S(O)2R5', -- SR5, -- S(O)R5, -- S(O)2R5, -- S(O)2NR5R5', C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl; wherein each R5 and R5' may be independently selected from the group consisting of hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl;
n is an integer from 0-5;
R4 is substituted or unsubstituted alkyl;
the configuration of the stereogenic carbon alpha to the nitrogen on the pyrolidine ring is the (L) or optionally (D) configuration.
[claim2]
2. The process of claim 1 wherein: R1 and R2 independently represent either hydrogen; a substituted or unsubstituted C1-C8 alkyl group; a substituted or unsubstituted C1-C8 alkoxy group; a substituted or unsubstituted C1-C8 alkoxycarbonyl group; a substituted or unsubstituted aryl group, wherein the groups when substituted are substituted by the group consisting of hydrogen, halogen, -- OR4, -- OC(O)R4, -- CN, -- C(O)R4, -- CO2R4, -- C(O)NR4R5, -- NO2, -- NR4R5, -- NRC(O)R4, -- NR4CO2R5, -- NR4S(O)2R5, -- SR4, -- S(O)R4, -- S(O)2R4, -- S(O)2NR4R5, C1-8 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl; or
R1 and R2 together form a C3-C8 cycloalkyl ring;
R3 is each independently selected from the group consisting of: hydrogen, halogen, -- OR5, -- OC(O)R5, -- CN, -- C(O)R5, -- CO2R5, -- C(O)NR5R5', -- NO2, -- NR5R5', -- NRC(O)R5, -- NR5CO2R5', -- NR5S(O)2R5', -- SR5, -- S(O)R5, -- S(O)2R5, -- S(O)2NR5R5', C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl; wherein each R5 and R5' may be independently selected from the group consisting of hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl;
R4 is a substituted or unsubstituted C1-C8 alkyl, wherein when substituted are substituted by the group consisting of halogen, -- OR5, -- OC(O)R5, -- CN, -- C(O)R5, -- CO2R5, -- C(O)NR5R5', -- NO2, -- NR5R5', -- NRC(O)R5, -- NR5CO2R5', -- NR5S(O)2R5', -- SR5, -- S(O)R5, -- S(O)2R5, -- S(O)2NR5R5', C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl; wherein each R5 and R5' may be independently selected from the group consisting of hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl;
n is an interger from 0-3; and
the configuration of the stereogenic carbone alpha to the nitrogen on the pyrolidine ring is the (L) or optionally (D) configuration.
[claim3]
3. The process of claim 1 wherein the enantioselectivity is greater than 99% enantiomeric excess (ee).
[claim4]
4. The process of claim 1 wherein the catalyst has the following structure:
  • 発明者/出願人(英語)
  • MOMIYAMA NORIE
  • TORII HIROMI
  • SAITO SUSUMU
  • YAMAMOTO HISASHI
  • YAMAMOTO YUHEI
  • JAPAN SCIENCE AND TECHNOLOGY AGENCY
国際特許分類(IPC)
米国特許分類/主・副
  • 548/250
参考情報 (研究プロジェクト等) SORST Selected in Fiscal 2000
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