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WO2008020007A2 - Process for the preparation of 5-hydroxyisoxazolidines, 5-isoxazolidinones, b-amino acids, b-amino aldehydes and derivatives thereof - Google Patents

Process for the preparation of 5-hydroxyisoxazolidines, 5-isoxazolidinones, b-amino acids, b-amino aldehydes and derivatives thereof Download PDF

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WO2008020007A2
WO2008020007A2 PCT/EP2007/058362 EP2007058362W WO2008020007A2 WO 2008020007 A2 WO2008020007 A2 WO 2008020007A2 EP 2007058362 W EP2007058362 W EP 2007058362W WO 2008020007 A2 WO2008020007 A2 WO 2008020007A2
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alkyl
amino
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WO2008020007A3 (en
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Armando CÓRDOVA
Jonas Fredrik Hafren
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Organoclick AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member

Definitions

  • the present invention relates to a process for the preparation of 5-hydroxyisoxazolidines, 5- isoxazolidinones, ⁇ -amino acids, ⁇ -amino aldehydes and derivatives thereof.
  • the present invention relates to a process for the metal-free chemo selective preparation of 5- hydroxyisoxazolidines, 5-isoxazolidinones, ⁇ -amino acids, ⁇ -amino aldehydes and derivatives thereof.
  • the present invention relates to a process for the preparation of 5- hydroxyisoxazolidines, 5-isoxazolidinones, ⁇ -amino acids, ⁇ -amino aldehydes and derivatives thereof in the presence of a particular catalyst.
  • ⁇ -Amino acids have merged in recent years as substances of considerable biological interest.
  • Examples are reported for instance in: "Enantioselective Synthesis of ⁇ -amino acids", E. Juaristi, Wiley- VCH, New York, 1997). See also: E. Juaristi, H. Lopez-Ruiz, Curr. Med. Chem. 1999, 6, 983.
  • ⁇ -Amino acids have a wide variety of use in the industry, particularly in the pharmaceutical industry. They are, for instance, components of a growing list of antibiotics and used as precursors for ⁇ -lactam synthesis. In addition, ⁇ -amino acids have gained attention as building blocks for oligomers with well defined folding behavior (foldamers). Some examples are reported in: S. H. Gellman, Ace. Chem. Res. 1998, 31, 173; K. Gademann, Thintermann, J. V. Schreiber, Curr. Med. Chem. 1999, 6, 905.
  • the present invention in its more general definition, relates to a process for the preparation of 5-hydroxyisoxazolidines, 5-isoxazolidinones, ⁇ -amino acids, ⁇ -amino aldehydes and derivatives thereof, said process being based on the use of particular amino compounds as catalysts for the reaction between hydroxyl amines or hydroxyl carbamates and ⁇ , ⁇ -unsaturated aldehydes or ketones under environmentally benign reaction conditions.
  • the present invention relates to a process for the preparation of 5- hydroxyisoxazolidines, 5-isoxazolidinones, ⁇ -amino acids, ⁇ -amino aldehydes and derivatives thereof, said process being based on the use of non-toxic natural amino acids, peptides and derivatives thereof, chiral pyrrolidines, protected diarylprolinol derivatives and acyclic and cyclic amines as catalysts for the reaction between hydroxyl amines or hydroxyl carbamates and ⁇ , ⁇ -unsaturated aldehydes or ketones.
  • amino compounds used as catalyst in the process according to the invention are: natural amino acids, peptides and derivatives thereof, chiral pyrrolidines, protected diarylprolinol derivative and acyclic and cyclic amines.
  • PG suitable protective group
  • R2 H or alkyl in the presence of an amine or amino acid derivative as Catalyst,
  • PG suitable protective group
  • R2 H or alkyl in the presence of an amine or amino acid derivative as Catalyst, which could be chiral.
  • PG suitable protective group
  • PG suitable protective group
  • R COOH, COOR', alkyl, aryl, aromatic, CF3, OMe
  • OR CH2X', CHX'2 ,CHX
  • PG suitable protective group
  • R COOH, COOR', alkyl, aryl, aromatic, CF3, OMe, OR, CH2X
  • Another aspect of the invention is to convert the ⁇ -amino aldehydes derived from Scheme 7 to ⁇ -amino acids and amino alcohols by oxidation and reduction, respectively, according to Scheme 8.
  • Another aspect of the invention is to link the chiral amine, including protected diary lpro lino 1, or amino acid derivative catalyzed reaction in Scheme 7 in situ or in two-steps with other reaction such as ⁇ -amination, ⁇ -oxidation, Wittig reactions and Mannich reactions according to Scheme 9.
  • Example 1 Typical experimental procedure for the synthesis of racemic hy droxyisoxazo lidine .
  • Example 2 Typical experimental procedure for the asymmetric synthesis of hydroxyisoxazolidines.
  • Example 3 Typical experimental procedure for the direct catalytic enantioselective synthesis of 5-isoxazolidinones.
  • suitable organic catalyst including protected arylprolinols, (20 mol %) in chloroform or other suitable solvent (0.5 rnL) at 4 0 C was added ⁇ , ⁇ -unsaturated aldehyde 2 (1.0 equiv. 0.25 mmol) and hydroxycarbamate 1 (1.2 equiv. 0.3 mmol). The reaction was vigorously stirred for 3 hours.
  • Example 5 Experimental procedure for the one-pot synthesis of amino alcohols.
  • the catalyst including protected diarylprolinols (20 mol %) in CHCI3 or other suitable solvent (1 mL) was added ⁇ , ⁇ -unsaturated aldehyde (0.25 mmol) and protected hydroxylamine (0.3 mmol).
  • the reaction was vigorously stirred at room temperature or 4 0 C for 4 hours.
  • the reaction mixture was diluted with MeOH (1 mL) and cooled to O 0 C followed by addition Of NaBH 4 (19 mg, 0.5 mmol).
  • the mixture was then stirred for 10 min., quenched with HCl (1 N), and extracted with EtOAc.
  • ⁇ , ⁇ -unsaturated aldehyde 1.0 equiv. 0.25 mmol
  • O-protected hydroxycarbamate 1.2 equiv. 0.3 mmol
  • the reaction was vigorously stirred for 3 hours or 16 hours.
  • the reaction mixture was directly loaded upon a silica-gel column and immediate chromatography (pentane:EtOAc-mixtures or toluene:EtOAc-mixtures) furnished the pure ⁇ -amino aldehyde.
  • the ⁇ -amino aldehyde can also be reduced or oxidized in situ to the corresponding amino alcohol and ⁇ -amino acid, respectively, as described above.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

A process for the preparation of for the preparation of 5-hydroxyisoxazolidines, 5- isoxazo lidinones, β-amino acids, β-amino aldehydes and derivatives thereof, by reacting hydroxyl amines or hydroxyl carbamates with an α,β-unsaturated aldehyde or ketone in the presence of an amino compound as catalysts. The catalyst is preferably selected from amino acids, peptides and derivatives thereof, chiral pyrrolidines, protected diarylprolinol derivatives and acyclic and cyclic amines.

Description

PROCESS FOR THE PREPARATION OF 5-HYDROXYISOXAZOLIDINES, 5- ISOXAZOLIDINONES, β-AMINO ACIDS, β-AMINO ALDEHYDES AND
DERIVATIVES THEREOF DESCRIPTION
The present invention relates to a process for the preparation of 5-hydroxyisoxazolidines, 5- isoxazolidinones, β-amino acids, β-amino aldehydes and derivatives thereof. In particular, the present invention relates to a process for the metal-free chemo selective preparation of 5- hydroxyisoxazolidines, 5-isoxazolidinones, β-amino acids, β-amino aldehydes and derivatives thereof. More in particular, the present invention relates to a process for the preparation of 5- hydroxyisoxazolidines, 5-isoxazolidinones, β-amino acids, β-amino aldehydes and derivatives thereof in the presence of a particular catalyst.
It is well known that 5-hydroxyisoxazolidines and 5-isoxazolidinones are important chiral building blocks, which are readily converted to the corresponding amino alcohols and β- amino acids. In this regard, see for instance: J. E. Baldwin, L. M. Harwood, M. J. Lombard, Tetrahedron 1984, 40, 4363; M. P. Sibi, N. Prabagaran, S. G. Ghorpade, G. P. Jasperse, J. Am. Chem. Soc. 2003, 125, 11796; M.P. Sibi, M. Liu, Org. Lett. 2001, 3, 4181; S. Mukherjee, A. K. Prasad, V. S. Parmar, O. W. Howarth, Biorg. Med. Chem. Lett. 2001, 11, 2117; D. Keirs, D. Moffat, K. Overton, R. Tomanek, J. Chem. Soc. Perkin Trans. 1999, 1, 1041; I. Panfil, S. Maciejewski, C. Belzecki, M. Chielewski, Tetrahedron Lett. 1989, 30, 1527; M. Shindo, K. Itoh, C. Tsuchiya, K. Shishido, Org. Lett. 2002, 4, 3119; R. Luisi, V. Capriati, S. Florio, T. Vista, J. Org. Chem. 2003, 2961; H. S. Lee, J. S. Park, B. M. Kim, S. H. Gellman, J. Org. Chem. 2003, 68, 1575; Y. Xiang, H. J. Gi, D. Mu, R. F. Schinazi, K. Zhao J. Org. Chem. 1997, 62, 7429. For a review, see also M. Liu, M.P. Sibi, Tetrahedron 2002, 58, 7439. Thus, asymmetric methods have been developed for their preparation. For instance, optically active 5-acetoxyisoxazolines can be converted in two steps to the corresponding isoxazolidinones. Moreover, utilization of chiral auxiliaries enables the asymmetric synthesis of 5-isoxazolidinones.
Recently, 5-isoxazolidinones were prepared by Lewis-acid catalyzed enantioselective conjugate addition of hydroxyl amines to α,β-unsaturated amide derivatives. For examples of catalytic coniugate aminations see: M. P. Sibi, J. J. Shay, M. Liu, C. P. Jasperse, J. Am. Chem. Soc. 2001, 123, 9708; T. E. Hortsmann, D. J. Guerin, S. J. Miller, Angew. Chem. Int. Ed. 2000, 39, 3635; H. Doi, T. Sakai, M. Iguchi, K. Yamada, K. Tomioka, J. Am. Chem. Soc. 2003, 125, 2886; J. K. Myers, E. N. Jakobsen, J. Am. Chem. Soc. 1999, 121, 8959; W. Zhuang, R. G. Hazell, K. A. Jorgensen, Chem. Commun. 2001, 1240; Y. K. Chen, M. Yoshida, D. W. C. MacMillan, J. Am. Chem. Soc. 2006, 128, 9328; N. Yamagiwa, H. Qin, S. Matunaga, M. Shibasaki, J. Am. Chem. Soc. 2005, 127, 13419. β-Amino acids have merged in recent years as substances of considerable biological interest. (Examples are reported for instance in: "Enantioselective Synthesis of β-amino acids", E. Juaristi, Wiley- VCH, New York, 1997). See also: E. Juaristi, H. Lopez-Ruiz, Curr. Med. Chem. 1999, 6, 983. See also: R. A. Barrow, T. Hemscheidt, J. Liang, S. Paik, R. e: Moore, M. A. Tius, J. Am. Chem. Soc. 1995, 117, 2479; P. E. Floreancing, S. E. Swalley, J. W. Rauger, P. B. Dervan, J. Am. Chem. Soc. 2000, 122, 6342; M. Werden, H. Hausre, S. AeIe, D. Seebach, HeIv. Chem. Acta 1999, 82, 1774; E. A. Porter, X. Wang, H. S. Lee, B. weisblum, S. H. Gellman, Nature 2000, 404, 565. β-Amino acids have a wide variety of use in the industry, particularly in the pharmaceutical industry. They are, for instance, components of a growing list of antibiotics and used as precursors for β-lactam synthesis. In addition, β-amino acids have gained attention as building blocks for oligomers with well defined folding behavior (foldamers). Some examples are reported in: S. H. Gellman, Ace. Chem. Res. 1998, 31, 173; K. Gademann, Thintermann, J. V. Schreiber, Curr. Med. Chem. 1999, 6, 905.
In the field of organocatalysis, amine catalyzed reactions that involve catalytic domino, tandem or cascade reaction pathways were recently developed. Examples are reported in: P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 2001, 40, 3726; B. List, Chem. Comm. 2006, 819; R. O. Duthaler, Angew. Chem. Int. Ed. 2003, 42, 975; P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 2004, 116, 5138. Selected examples are reported also in: N. Halland, P. S. Aburell, K. A. Jorgensen, Angew. Chem. Int. Ed. 2004, 43, 1272; Y. Huang, A. M. Walji, C. H. Larsen, D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127, 15051; J. W. Yang, M. T. Hechavarria Fonsenca, B. List, J. Am. Chem. Soc. 20055, 117, 15036; M. Marigo, T. Schulte, J. Franen, K. A. Jorgensen, J. Am. Chem. Soc. 2005, 127, 15710; Y. Yamamoto, N. Momiyama, H. Yamamoto, J. Am. Chem. Soc. 2004, 126, 5962; D. B. Ramachary, N. S. Chowdari, C. F. Barbas III, Angew. Chem. Int. Ed. 2003, 42, 4233; H. Sunden, I. Ibrahem, L. Eriksson, A. Cordova, Angew. Chem. Int. Ed. 2005, 44, 4877; D. Enders, M. R. M. Huttl, C. Grondaal, G. Raabe, Nature 2006, 441, 861. For a summary on the concept of domino reaction see: L. F. Tietze, Chem. Rev. 1996, 96, 115.
It has now been found that chiral pyrrolidines catalyze the formation of 1,2-dihydroquinoline derivatives via an asymmetric domino amine-conjugate/aldol reaction pathway between 2- aminobenzaldehyde and enals according to Equation 1 reported below.
Figure imgf000004_0001
Nudeophile only
Despite all the chemo selectivity issues that could arise in the amine conjugate addition step, such as non-productive imine formation and racemic back ground reaction, the subsequent intramolecular aldol addition kinetically controls the desired reaction pathway and pushes the equilibrium towards product formation. It has therefore been found that the chiral amine- catalyzed reaction between //-protected hydroxylamines and enals is be a simple asymmetric entry to 5-hydroxyisoxazolidines where the subsequent tandem intramolecular hemiacetal formation is an important driving force for product formation (Scheme 1). The employment of a chiral catalyst would make the reaction asymmetric.
Figure imgf000004_0002
Figure imgf000004_0003
Scheme 1.
Thus, the present invention in its more general definition, relates to a process for the preparation of 5-hydroxyisoxazolidines, 5-isoxazolidinones, β-amino acids, β-amino aldehydes and derivatives thereof, said process being based on the use of particular amino compounds as catalysts for the reaction between hydroxyl amines or hydroxyl carbamates and α,β-unsaturated aldehydes or ketones under environmentally benign reaction conditions. In particular, the present invention relates to a process for the preparation of 5- hydroxyisoxazolidines, 5-isoxazolidinones, β-amino acids, β-amino aldehydes and derivatives thereof, said process being based on the use of non-toxic natural amino acids, peptides and derivatives thereof, chiral pyrrolidines, protected diarylprolinol derivatives and acyclic and cyclic amines as catalysts for the reaction between hydroxyl amines or hydroxyl carbamates and α,β-unsaturated aldehydes or ketones.
It has been found, for instance, that the employment of chiral pyrrolidine derivatives as catalyst for the asymmetric reactions between hydroxylamines and α,β-unsaturated aldehydes proceed with high chemo- and enantio selectivity to give the corresponding 5- hydroxyisoxazolidines or β-amino aldehydes in high yields with 90-99% ee. The reaction was also applied to the reaction between hydroxylamines and α,β-unsaturated ketones. The products are readily converted to 5-oxazolidinones, β-amino acids and γ-amino alcohols with excellent enantio selectivity
Examples of amino compounds used as catalyst in the process according to the invention are: natural amino acids, peptides and derivatives thereof, chiral pyrrolidines, protected diarylprolinol derivative and acyclic and cyclic amines.
In a first embodiment the present invention relates to a process for the preparation of 5- hydroxyisoxazolidine derivatives according to Scheme 2, in which R1 = suitable protective group (PG) such as Boc, Fmoc, Cbz and other suitable amine protective group (benzyl, dibenzyl and allyl) or Rl = H and alkyl; R = COOH, COOR', alkyl, aryl, aromatic, CF3, OMe, OR, CH2X, CHX2, CX3 (X = Cl, F, Br); R2 = H or alkyl in the presence of an amine or amino acid derivative as Catalyst, which could be chiral.
- H
Figure imgf000005_0001
Scheme 2. Another aspect of the invention relates to a process for the preparation of 5-isoxazolidinone derivatives according to Scheme 3 in which: R1 = suitable protective group (PG) such as Boc, Fmoc, Cbz and other suitable amine protective group (benzyl, dibenzyl and allyl) or Rl = H and alkyl; R = COOH, COOR', alkyl, aryl, aromatic, CF3, OMe, OR, CH2X, CHX2 ,CX3 (X = Cl, F, Br) in the presence of an amine or amino acid derivative as Catalyst, which could be chiral.
R
Figure imgf000006_0001
Scheme 3
Another aspect of the invention relates to a process for the preparation of amino alcohol derivatives according to Scheme 4 in which: R1 = suitable protective group (PG) such as Boc, Fmoc, Cbz and other suitable amine protective group (benzyl, dibenzyl and allyl) or Rl = H and alkyl; R = COOH, COOR', alkyl, aryl, aromatic, CF3, OMe, OR, CH2X, CHX2, CX3 (X = Cl, F, Br); R2 = H or alkyl in the presence of an amine or amino acid derivative as Catalyst, which could be chiral.
Ar
Ar
OPG
ΓΛ R5
Q*z or Rξ V.γ
O H W
Rl OH
N-O in situ R ^.
RV H (Catalyst) N /" OH
H 0H R Jj$» R2
Suitable solvent reduction
Scheme 4
Another aspect of the invention relates to a process for the preparation of β-amino acid derivatives according to Scheme 5, in which: R1 = suitable protective group (PG) such as Boc, Fmoc, Cbz and other suitable amine protective group (benzyl, dibenzyl and allyl) or Rl = H and alkyl; R = COOH, COOR', alkyl, aryl, aromatic, CF3, OMe, OR, CH2X, CHX2, CX3 (X =
Cl, F, Br) in the presence of an amine or amino acid derivative as Catalyst, which could be chiral.
RV H
Figure imgf000007_0001
NaCIO2
Scheme 5.
Another aspect of the invention is to use nucleophiles similar to protected hydroxyl amines such as hydrazines (X = NH2, NHR, SH) to form heterocycles, amino acid and amino alcohol derivatives according and similar to Scheme 2, 3, 4, 5 and 6, in which: Rl = suitable protective group (PG) such as Boc, Fmoc, Cbz and other usable amine protective group (benzyl, dibenzyl and allyl) or Rl = H and alkyl; R = COOH, COOR', alkyl, aryl, aromatic, CF3, OMe, OR, CH2X', CHX'2 ,CHX'3 (X' = Cl, F, Br) in the presence of an amine or amino acid derivative as Catalyst, which could be chiral.
Ar
Ar
Rb
Q- or R?>γ
O H
RV l_l (Catalyst) ^N-X
OH
H X
Suitable solvent
Scheme 6.
Still another aspect of the invention is to use protected hydroxyl amines with a protective group at the oxygen as well, said protective group X being, for instance, a suitable protective group such as SiR3, Alkyl, Me and similar, to form β-amino aldehyde derivatives according to Scheme 7, in which: Rl = suitable protective group (PG) such as Boc, Fmoc, Cbz and other usable amine protective group (benzyl, dibenzyl and allyl) or Rl = H and alkyl; R = COOH, COOR', alkyl, aryl, aromatic, CF3, OMe, OR, CH2X', CHX'2, CHX'3 (X' = Cl, F, Br); R2 = H and alkyl, in the presence of an amine or amino acid derivative as Catalyst, which could be chiral.
R
Figure imgf000008_0001
Scheme 7
Another aspect of the invention is to convert the β-amino aldehydes derived from Scheme 7 to β-amino acids and amino alcohols by oxidation and reduction, respectively, according to Scheme 8.
R
Figure imgf000008_0002
Scheme 8
Another aspect of the invention is to link the chiral amine, including protected diary lpro lino 1, or amino acid derivative catalyzed reaction in Scheme 7 in situ or in two-steps with other reaction such as α-amination, α-oxidation, Wittig reactions and Mannich reactions according to Scheme 9. R
Figure imgf000009_0001
acetone ArNH Mannich
1 OX
"N' NHArO
Scheme 9
Detailed Description.
EXAMPLES
Example 1. Typical experimental procedure for the synthesis of racemic hy droxyisoxazo lidine .
To a stirred solution of pyrrolidine or other suitable amine catalyst (20 mol%) in chloroform or other suitable solvent (1.0 mL) was added α,β-unsaturated aldehyde (1 equiv) and hydroxycarbamate (1.2 equiv). The reaction was vigorously stirred overnight. Next, the crude product was purified by silica gel chromatography (pentane (toluene):EtOAc-mixtures) to give the corresponding hy droxyisoxazo lidine.
Example 2. Typical experimental procedure for the asymmetric synthesis of hydroxyisoxazolidines.
To a stirred solution of suitable catalyst, including protected diarylprolinols, (20 mol %) in chloroform or other suitable solvent (0.5 mL) at 4 0C was added α,β-unsaturated aldehyde 2
(1.0 equiv. 0.25 mmol) and hydroxycarbamate 1 (1.2 equiv. 0.3 mmol). The reaction was vigorously stirred for 3 hours or 16 hours. Next, the reaction mixture was directly loaded upon a silica-gel column and immediate chromatography (pentane:EtOAc-mixtures or toluene: EtO Ac-mixtures) furnished the pure 5 -hydroxyisoxazolidines.
Example 3. Typical experimental procedure for the direct catalytic enantioselective synthesis of 5-isoxazolidinones. To a stirred solution of suitable organic catalyst, including protected arylprolinols, (20 mol %) in chloroform or other suitable solvent (0.5 rnL) at 4 0C was added α,β-unsaturated aldehyde 2 (1.0 equiv. 0.25 mmol) and hydroxycarbamate 1 (1.2 equiv. 0.3 mmol). The reaction was vigorously stirred for 3 hours. Upon completion (a small aliquot was removed for ee determination) The reaction temperature was increased to room temperature, isobutene (0.1 mL), tert-butanol (0.4 mL), H2O (0.2mL) KH2PO4 (54.4 mg, 4 mmol), and NaClO2 (36 mg, 4mmol) were added sequentially. After 16h, the crude product was purified by column chromatography (pentane/EtOAC mixtures) to afford the desired 5-isoxazolidinones. Example 4. β-amino acid synthesis.
To a stirred solution of Cbz-protected isoxazolidinones in MeOH (0.1 M), was added 10% (in weight) of Pd/C (10%). The reaction was stirred under 90 atm of Hydrogen overnight. Then the cude reaction was filtered through a plug of Celite®. The solvent was removed under reduced pressure to afford the pure β-aminoacid 11.
Example 5. Experimental procedure for the one-pot synthesis of amino alcohols. To a stirred solution of the catalyst, including protected diarylprolinols (20 mol %) in CHCI3 or other suitable solvent (1 mL) was added α,β-unsaturated aldehyde (0.25 mmol) and protected hydroxylamine (0.3 mmol). The reaction was vigorously stirred at room temperature or 4 0C for 4 hours. Then the reaction mixture was diluted with MeOH (1 mL) and cooled to O0C followed by addition Of NaBH4 (19 mg, 0.5 mmol). The mixture was then stirred for 10 min., quenched with HCl (1 N), and extracted with EtOAc. The organic layer was separated, dried over Na2SO4 and the solvent was removed. The residue was purified by silica gel (pentane: ethyl acetate = 4:1) to give the pure amino alcohol product. Example 6. Typical experimental procedure for the asymmetric synthesis of -amino aldehydes (Scheme 7 and 8).
To a stirred solution of suitable catalyst, including protected diarylprolinols, (20 mol %) and suitable organic acid (20 mol%) in chloroform or other suitable solvent (0.5 mL) at 4 0C was added α,β-unsaturated aldehyde (1.0 equiv. 0.25 mmol) and O-protected hydroxycarbamate (1.2 equiv. 0.3 mmol). The reaction was vigorously stirred for 3 hours or 16 hours. Next, the reaction mixture was directly loaded upon a silica-gel column and immediate chromatography (pentane:EtOAc-mixtures or toluene:EtOAc-mixtures) furnished the pure β-amino aldehyde. The β-amino aldehyde can also be reduced or oxidized in situ to the corresponding amino alcohol and β-amino acid, respectively, as described above.

Claims

A process for the preparation of for the preparation of 5-hydroxyisoxazolidines, 5- isoxazolidinones, β-amino acids, β-amino aldehydes and derivatives thereof, by reacting hydroxyl amines or hydroxyl carbamates with an α,β-unsaturated aldehyde or ketone in the presence of an amino compound as catalysts.
The process according to claim 1, characterized in that said amino compound is selected form the group consisting of amino acids, peptides and derivatives thereof, chiral pyrrolidines, protected diary lpro lino 1 derivatives and acyclic and cyclic amines.
The process according to claim 1 or 2, characterized in that said amino compound is a chiral amino compound.
The process according to one or more of previous claims, characterized in that said amino compound is selected form chiral pyrrolidines and protected diarylprolinol derivative.
The process according to one or more of previous claims, characterized in that 5- hydroxyisoxazolidine derivatives are prepared according to the reaction:
R
Figure imgf000011_0001
in which, R1 = suitable protective group (PG) such as Boc, Fmoc, Cbz and other suitable amine protective group (benzyl, dibenzyl and allyl) or Rl = H and alkyl; R = COOH, COOR', alkyl, aryl, aromatic, CF3, OMe, OR, CH2X, CHX2, CX3 (X = Cl, F, Br); R2 = H or alkyl in the presence of an amine or amino acid derivative as Catalyst.
6. The process according to claim 5, characterized in that said said Catalyst is chiral.
7. The process according to one or more of claims 1-4, characterized in that 5- hydroxyisoxazolidine derivatives are prepared according to the reaction:
R
Figure imgf000011_0002
in which R1 = suitable protective group (PG) such as Boc, Fmoc, Cbz and other suitable amine protective group (benzyl, dibenzyl and allyl) or Rl = H and alkyl; R = COOH, COOR', alkyl, aryl, aromatic, CF3, OMe, OR, CH2X, CHX2, CX3 (X = Cl, F, Br); R2 = H or alkyl in the presence of an amine or amino acid derivative as Catalyst.
8. The process according claim to 7, characterized in that said said Catalyst is chiral. 9. The process according to one or more of claims 1-4, characterized in that amino alcohol derivatives are prepared according to the reaction:
Ar
Ar
OPG
ΓΛ R5
STZ or Rξ V.γ O H W
Rl OH in situ
RV H (Catalyst) Rl. N OH
H 0H R Jj$» R2
Suitable solvent reduction
in which: R1 = suitable protective group (PG) such as Boc, Fmoc, Cbz and other suitable amine protective group (benzyl, dibenzyl and allyl) or Rl = H and alkyl; R = COOH, COOR', alkyl, aryl, aromatic, CF3, OMe, OR, CH2X, CHX2, CX3 (X = Cl, F, Br); R2 = H or alkyl in the presence of an amine or amino acid derivative as Catalyst.
10. The process according to claim 9, characterized in that said said Catalyst is chiral. 11. The process according to one or more of claims 1-4, characterized in that β-amino acid derivatives are prepared according to the reaction:
Ar
Ar
H I
OPG r\ R5
C>z or Rξ V.γ
O H W D1 N-O bond cleavage
R1- NH O
RV0H l_l (Catalyst)
H
Suitable solvent ,^>° AA OH
NaCIO2 in which: R1 = suitable protective group (PG) such as Boc, Fmoc, Cbz and other suitable amine protective group (benzyl, dibenzyl and allyl) or Rl = H and alkyl; R = COOH, COOR', alkyl, aryl, aromatic, CF3, OMe, OR, CH2X, CHX2, CX3 (X = Cl, F, Br) in the presence of an amine or amino acid derivative as Catalyst.
12. The process according to claim 11, characterized in that said said Catalyst is chiral. 13. The process according to one or more of claims 1-4, characterized in that nucleophiles similar are used to protected hydroxyl amines, such as hydrazines (X = NH2, NHR, SH) to form heterocycles, amino acid and amino alcohol derivatives according to the reaction:
Figure imgf000013_0001
in which: Rl = suitable protective group (PG) such as Boc, Fmoc, Cbz and other usable amine protective group (benzyl, dibenzyl and allyl) or Rl = H and alkyl; R = COOH, COOR', alkyl, aryl, aromatic, CF3, OMe, OR, CH2X', CHX'2 ,CHX'3 (X' = Cl, F, Br) in the presence of an amine or amino acid derivative as Catalyst.
14. The process according to claim 13, characterized in that said said Catalyst is chiral.
15. The process according to one or more of claims 1-4, characterized in that use is made of protected hydroxyl amines with a protective group X at the oxygen, said protective group X being SiR3, Alkyl, Me and similar, to form β-amino aldehyde derivatives according to the reaction:
Figure imgf000013_0002
in which: Rl = suitable protective group (PG) such as Boc, Fmoc, Cbz and other usable amine protective group (benzyl, dibenzyl and allyl) or Rl = H and alkyl; R = COOH, COOR', alkyl, aryl, aromatic, CF3, OMe, OR, CH2X', CHX'2, CHX'3 (X' = Cl, F, Br); R2 = H and alkyl, in the presence of an amine or amino acid derivative as Catalyst.
16. The process according to claim 15, characterized in that said said Catalyst is chiral.
17. The process according to claim 15, characterized in that said the β-amino aldehydes are converted to β-amino acids and amino alcohols by oxidation and reduction, respectively, according to the following reaction: RV H
Figure imgf000014_0001
18. 5-hydroxyisoxazolidines, 5-isoxazolidinones, β-amino acids, β-amino aldehydes and derivatives thereof obtained form a process according to one or more of claims 1-17.
PCT/EP2007/058362 2006-08-14 2007-08-13 Process for the preparation of 5-hydroxyisoxazolidines, 5-isoxazolidinones, b-amino acids, b-amino aldehydes and derivatives thereof Ceased WO2008020007A2 (en)

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JP2010083856A (en) * 2008-09-03 2010-04-15 Central Glass Co Ltd METHOD FOR PRODUCING alpha-TRIFLUOROMETHYL-beta-SUBSTITUTED-beta-AMINO ACIDS
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EP2327685A4 (en) * 2008-09-03 2011-10-12 Central Glass Co Ltd Process for production of -trifluoromethyl- -substituted- -amino acid
US8524913B2 (en) 2008-09-03 2013-09-03 Central Glass Company, Limited Process for production of α-trifluoromethyl-β-substituted-β-amino acid
CN102143938B (en) * 2008-09-03 2013-11-06 中央硝子株式会社 Process for production of alpha-trifluoromethyl-beta-substituted- beta-amino acid

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