A PROCESS FOR THE PREPARATION OF β-AMINO ALDEHYDES AND

DERIVATIVES THEREOF DESCRIPTION

The present invention relates to a process for the preparation of β-amino aldehydes and derivatives thereof. In particular, the present invention relates to a process for the metal-free chemoselective preparation of β-amino aldehydes and derivatives thereof, such as β-amino acids and γ-amino alcohols and derivatives thereof. More in particular, the present invention relates to a process for the preparation of β-amino aldehydes and derivatives thereof, such as β-amino acids and γ-amino alcohols and derivatives thereof, in the presence of a particular catalyst.

It is well known that the Mannich reaction has found a multitude of applications in organic chemistry. The resulting Mannich bases are of particular interest due to their utilization as synthetic building blocks and precursors of pharmaceutically valuable compounds. Examples in this regard are reported, e.g., in: Mannich, C, Krόsche, W. Arch. Pharm. 1912, 250, 647; Kleinmann, E. F., in Comprehensive Organic Synthesis, Trost, B. M.. Flemming, I. Eds., Pergamon Press: New York, 1991; Vol. 2, Chapter 4.1; Arend, M., Westerman, B., Risch, N., Angew. Chem. Int. Ed. 1998, 37, 1044; Denmark, S., Nicaise, O. J.-C, in Comprehensive Asymmetric Catalysis, Jacobsen, E. N., Pfaltz, A., Yamomoto, H., Eds. Springer: Berlin, 1999, Vol. 2, 93; Tramontini, M., Angiolini, L., Tetrahedron 1990, 46, 1791; Hellmann, H., Optiz, G., a-Aminoalkylierung, Verlag Chemie, Weinheim, 1960, p. 1; Enantios elective Synthesis of β-Amino Acids, Juaristi, E. Ed., Wiley-VCH, Weinheim, 1997; Risch, N., Esser, A., Liebigs Ann. 1992, 233; Risch, N., Arend, M., in Houben-Weyl: Methoden der Organischen Chemie, Vol. E21b, Mϋller, E. Ed., Thieme: Stuttgart, 1995, 1908; Vinkovic, V., Sunjic, V., Tetrahedron 1997, 55, 689.

Chemists have developed several stoichiometric indirect stereoselective Mannich transformations that utilize preformed enol equivalents or imines. See for example: Enders, D., Ward, D., Adam, J., Raabe, G., Angew. Chem. Int. Ed. 1996, 55, 981; Enders, D., Oberbόrsch, S., Adam, J., Ward, D., Synthesis 2002, 18, 1737. See also: Kober, R., Papadopoulos, K., Miltz, W., Enders, D., Steglich, W., Reuter, H., Puff, H., Tetrahedron 1985, 42, 1963; Enders, D., Oberbόrsch, S., Adam, J., Synlett 2000, 644; Seebach, D., Hoffmann, M., Eur. J. Org. Chem. 1998, 1337.; Aoyagi, Y., Jain, R. P., Williams, R. M., J. Am. Chem. Soc. 2001, 123, 3472 and references therein; Schόllkopf, U. in Topics in Current Chemistry, Boschke, F. L. Ed., Springer Verlag: Berlin, 1983, Vol. 109, pp 45-85; Evans, D. A., Urpi, F., Somers, T. C, Clark, J. S., Bilodeau, M. T., J. Am. Chem. Soc. 1990, 112, 8215;

Palomo, C, Oiarbide, M., Landa, A., Gonzales-Rego, M. C, Garcia, J. M., Gonzales, A., Odriozola, J. M., Martin-Pastor, M., Linden, A., J. Am. Chem. Soc. 2002, 124, 8637 and references therein.

The first successful examples of catalytic asymmetric additions of enolates to imines led to an intense study of catalytic indirect Mannich reactions, examples of which are reported, e.g., in: Kobayashi, S., Hamada, T., Manabe, K. J. Am. Chem. Soc. 2002, 124, 5640; Ishitani, H., Ueno, M., Kobayashi, S., Org. Lett. 2002, 4, 143; Ishitani, H., Ueno, S., Kobayashi, S., J. Am. Chem. Soc. 2000, 122, 8180; Hamashima, Y., Yagi, K., Tamas, H., Sodeoka, M., J. Am. Chem. Soc. 2002, 124, 14530; Hamashima, Y., Hotta, M., Sodeoka, M., J. Am. Chem. Soc. 2002, 124, 11240; Ferraris, D., Young, B., Cox, C, Drury III, W. J., Dudding, T., Lectka, T., J. Org. Chem. 1998, 63, 6090; Ferraris; D., Young, B., Cox, C, Dudding, T., Drury III, W. J., Ryzhkov, L., Taggi, T., Lectka, T., J. Am. Chem. Soc. 2002, 124, 67; Josephsohn, W. S., Snapper, M. L., Hoveyda, A. H., J. Am. Chem. Soc. 2004, 126, 3734.

Recently, heterodimetallic complexes and di-nuclear zinc organo-metallic complexes as catalysts for highly enantioselective direct Mannich-type reactions were reported in the following articles: Yamasaki, S., Iida, T., Shibasaki, M., Tetrahedron Lett. 1999, 40, 307; Matsunaga, S., Kumagai, N., Harada, N., Harada, S., Shibasaki, M., J. Am. Chem. Soc. 2003, 125, 4712; Trost, B. M., Terrell, L. M., J. Am. Chem. Soc. 2003, 125, 338. Moreover, chiral copper(II) bisoxazoline (BOX) complexes are also catalysts for direct asymmetric Mannich-type reactions, as reported in the articles: Juhl, K., Gathergood, N., Jørgensen, K. A., Angew. Chem. Int. Ed. 2001, 40, 2995; Marigo, M., Kjaersgaard, A., Juhl, K., Gathergood, N., Jørgensen, K. A., Chem. Eur. J. 2003, 9, 2359.

Recently, organocatalysis has been added to the synthetic repertoire for this important transformation, as reported in: Cordova, A. Ace. Chem Res. 2004, 37, 102. These direct asymmetric Mannich reactions are catalyzed by chiral Brønsted acids (see: Akiyama, T., Itoh, J., Yokota, K., Fuchibe, K., Angew. Chem. Int. Ed. 2004, 43, 1566; Uraguchi, D., Terada, M., J. Am. Chem. Soc. 2004, 126, 5356), chincona alkaloids (see: Lou, S., Taoka, B. M., Ting, A., Schaus, S., J. Am. Chem. Soc. 2005, 127, 11256), proline and its derivatives (For selected examples see: List, B., J. Am. Chem. Soc. 2000, 122, 9336; Cordova, A., Watanabe, S.-i., Tanaka, F., Notz, W., Barbas III, C. F., J. Am. Chem. Soc. 2002, 124, 1866; Munch, A., Wendt, B., Christmann, M., Synlett 2004, 2751; Zhuang, W., Saaby, S., Jørgensen, K. A., Angew. Chem.. Int. Ed. 2004, 43, 4476; Fustero, S., Jimenez, D., Sanz- Cervera, J. F., Sanchez-Rosello, M., Esteban, E., Simon-Fuentes, A., Org. Lett. 2005, 7, 3433; Cordova, A., Barbas, III, C. F., Tetrahedron Lett. 2002, 43, 1149; Westermann, B., Neuhaus,

C, Angew. Chem. Int. Ed. 2005, 44, AQIl; Ibrahem, L, Cordova, A., Tetrahedron Lett. 2005, 46, 3363; Enders, D., Grondal, C, Vrettou, M., Raabe G., Angew. Chem. Int Ed. 2005, 44, 4079; Cobb, A. J. A., Shaw, D. M., Ley, S. V., Synlett 2004, 558; Cobb, A. J. A., Shaw, D. M., Longbottom, D. A., Gold, J. B., Ley, S. V., Org. Biomol. Chem. 2005, 3, 84; Ibrahem, L, Cordova, A., Chem Commun. 2006, 1760; Ibrahem, L, Casas, J., Cordova, A., Angew. Chem. Int. Ed. 2004, 43, 6528; Ibrahem, L, Zou, W., Casas, J., Sunden, H., Cordova, A., Tetrahedron 2006, 62, 357; Chi, Y., Gellman, S., J. Am. Chem. Soc. 2006, 128, 6804; Ibrahem, L, Zhao, G. -L., Cordova, A., Chem. Eur. J. 2006, In press, DOI: 10.1002/chem.200600725; Rodriguez, B., BoIm, C, J. Org. Chem. 2006, 71, 2888), peptide derivatives (see: Wenzel, E. N., Jacobsen, E. N., J. Am Chem. Soc. 2002, 124, 12964) and amino acids (see: Ibrahem, L, Zou, W., Engqvist, M., Xu, Y. Chem. Eur. J. 2005, 11, 7024). In this context, it has also been reported (see: Cordova, A., Synlett 2003, 1651; Cordova, A., Chem. Eur. J. 2004, 10, 1987; Ibrahem, L, Cordova, A., Tetrahedron Lett. 2005, 46, 2839; Ibrahem, L, Samec, J. S. M., Backvall, J. -E., Cordova, A., Tetrahedron Letters 2005, 46, 3965; Liao, W. -W., Ibrahem, L, Cordova, A., Chem. Commun. 2006, 674; Hayashi, Y., Tsuboi, W., Ashimine, L, Urushima, T., Shoji, M., Sakai, K., Angew. Chem. Int. Ed. 2003, 42, 3677; Hayashi, Y., Urushima, T., Shoji, M., Uchimary, T., Shiina, L, Adv. Synth. Cat. 2005, 347, 1595) the amino acid catalyzed addition of unmodified aldehydes to aryl N-/?- methoxyphenyl (PMP) imines according to Equation 1. Equation 1 :

( ¹ >

The corresponding PMP-protected β-amino aldehydes are not very stable and are therefore reduced in situ to the corresponding γ-aldehydes. In addition, the removal of the PMP group requires oxidative conditions and could be low yielding.

It has now been found that carbamate-protected imines can be reacted with unmodified aldehydes in the presence of particular catalysts to produce β-amino aldehydes and derivatives thereof, in particular β-amino acids and γ-amino alcohols and derivatives thereof. In fact, the process according to the invention allows to prepare carbamate protected β-amino acids,

which can be used directly in peptide synthesis, as well as γ-amino alcohols according to Equation 2 reported below.

Equation 2:

Moreover, the process according to the invention allows preparing Boc-protected α-hydroxy- β-amino acids that are useful intermediates in the pharmaceutical industry. The side chain of Docetaxel (Taxotere) reported in formula I, one of the most important cancer chemotherapeutic substances, is an example of a Boc-protected α-hydroxy-β-amino acid that can be prepared with the process according to the invention. Formula I:

In general the reaction proceeds with high chemoselectivity. It has also been found that the employment of chiral pyrrolidine derivatives as catalyst for the asymmetric reactions between in situ generated or preformed carbamate imines and unmodified aldehydes proceed with high chemo- and enantioselectivity to give the β-amino aldehydes in high yields with 90-99% ee. The products are readily converted to the corresponding β-amino acids and γ-amino alcohols with excellent enantioselectivity

Thus, the present invention in its more general definition, relates to a process for the preparation of β-amino aldehydes having Formula II (in which: R ¹ = suitable protective group PG such as Boc, Fmoc, Cbz and other suitable amine protective group (benzyl, dibenzyl and allyl); R ² = aryl, furfuryl, pyridyl, aromatic, CO ₂ Me, CO ₂ Et, CO ₂ R, alkyl, CF ₃ , CH ₂ X, CHX ₂ , CX ₃ (X = Cl, F, Br); R ³ = Me, OSiR ₂ , OR, OBn, NHR, NHR ₂ or alkyl) and derivatives thereof, said process being based on the use of particular amino compounds as catalysts for

the reaction between carbamate-protected imines and unmodified aldehydes under environmentally benign reaction conditions. Formula II:

The employment of a chiral catalyst would make the reaction asymmetric. In particular, the present invention relates to a process for the preparation of β-amino aldehydes and derivatives thereof, said process being based on the use of non-toxic natural amino acids, (5)-proline, peptides and derivatives thereof, chiral pyrrolidines, protected diarylprolinol derivatives and acyclic and cyclic amines as catalysts for the reaction between carbamate-protected imines and unmodified aldehydes.

In a first embodiment the present invention relates to a process for the preparation of β-amino aldehydes according to Scheme 1, in which R ¹ = suitable protective group (PG) such as Boc, Fmoc, Cbz and other suitable amine protective group (benzyl, dibenzyl and allyl); R ² = aryl, furfuryl, pyridyl, aromatic, CO ₂ Me, CO ₂ Et, CO ₂ R, alkyl, CF ₃ , CH ₂ X, CHX ₂ , CX ₃ (X = Cl, F, Br); R ³ = Me, OSiR ₂ , OR, OBn, NHR, NHR ₂ or alkyl; in the presence of an amine or amino acid derivative such as (5)-proline, (i?)-proline, proline tetrazole, hydroxyprolines and their derivatives, which could be chiral.

Scheme 1.

Another aspect of the invention relates to a process for the preparation of β-amino acid derivatives according to Scheme 2, in which R ¹ = suitable protective group (PG) such as Boc, Fmoc, Cbz and other suitable amine protective group (benzyl, dibenzyl and allyl); R ² = aryl, furfuryl, pyridyl, aromatic, CF ₃ , CO ₂ Me, CO ₂ Et, CO ₂ R, alkyl, CH ₂ X, CHX ₂ , CX ₃ (X = Cl, F, Br); R ³ = Me, OSiR ₂ , OR, OBn, NHR, NHR ₂ or alkyl; in the presence of an amine or amino acid derivative such as (5)-proline, (i?)-proline, proline tetrazole, hydroxyprolines and their derivatives, which could be chiral. The oxidation step can either be performed as a one-pot procedure or in two steps.

oxidation

Scheme 2

Another aspect of the invention relates to a process for the preparation of γ-amino alcohol derivatives according to Scheme 3, in which R ¹ = suitable protective group (PG) such as Boc, Fmoc, Cbz and other suitable amine protective group (benzyl, dibenzyl and allyl); R ² = aryl, furfuryl, pyridyl, aromatic, CO ₂ Me, CO ₂ Et, CO ₂ R, alkyl, CF ₃ , CH ₂ X, CHX ₂ , CX ₃ (X = Cl, F, Br); R ³ = Me, OSiR ₂ , OR, OBn, NHR, NHR ₂ or alkyl; in the presence of an amine or amino acid derivative, such as (5)-proline, (i?)-proline, proline tetrazole, hydroxyprolines and their derivatives, which could be chiral. The reduction step can either be performed as a one -pot procedure or in two steps.

reduction

Scheme 3

Another aspect of the invention relates to a process for the preparation of β-amino aldehydes derivatives according, by combining the reaction of Scheme 1, in situ or in two-steps, with other C-C bond-forming reactions, such as nucleophilic additions Wittig, aldol and Mannich reactions according to Scheme 4

Mannich Carbonyl nucleophile

Rl , ^R 6

NH HN O

Scheme 4.

Detailed Description.

EXAMPLES

Example 1. Typical experimental procedure for the synthesis of racemic β-amino aldehydes.

To a stirred solution of pyrrolidine, (i?),(5)-proline or other suitable amine catalyst (20 mol%) and imine (1.0 equiv, 0.25 mmol) in DMF or other suitable solvent (1.0 mL) at was added the unmodified aldehyde (1.2 equiv, 0.30 mmol). The reaction was vigorously stirred for reported time. Next, the reaction was directly loaded upon a silica-gel column and immediate chromatography (pentane:EtOAc-mixtures or toluene:EtOAc-mixtures) furnished the corresponding β-amino aldehyde.

Example 2. Typical experimental procedure for the asymmetric synthesis of β-amino aldehyde.

To a stirred solution of suitable catalyst, (5)-proline or hydroxyproline, (20 mol %) in DMF or other suitable solvent such as CH ₃ CN, CHCl ₃ and NMP was added the unmodified aldehyde

(1.2 equiv, 0.30 mmol). The reaction was vigorously stirred until complete conversion occurred. Next, the reaction was directly loaded upon a silica-gel column and immediate chromatography (pentane:EtOAc-mixtures or toluene:EtOAc-mixtures) furnished the corresponding β-amino aldehyde. This procedure can also be scaled up to multigram scale.

Example 3. Typical experimental procedure for the asymmetric synthesis of β-amino acids.

To the solution of amino aldehyde (26 mg, 0.1 mmol) in chloroform (ImL) isobutene (0.1 mL), tert-butanol (0.4 mL), H ₂ O (0.2 mL), KH ₂ PO ₄ (54.4 mg, 4.0 mmol) and NaClO ₂ (36 mg,

4.0 mmol) were added sequentially at room temperature. After 16h, the crude product was

purified by column chromatography (pentane/EtOAc mixtures) to afford the desired β-amino acid. This procedure can also be scaled up to multigram scale. Example 4. Experimental procedure for the one-pot synthesis of amino alcohols. To a stirred solution of suitable catalyst, (5)-proline or hydroxyproline, (20 mol %) in DMF or other suitable solvent such as CH ₃ CN, CHCl ₃ and NMP was added the unmodified aldehyde (1.2 equiv, 0.30 mmol). The reaction was vigorously stirred until complete conversion occurred. Next, the reaction mixture was diluted with MeOH (1 mL) and cooled to O ⁰ C followed by addition OfNaBH ₄ (19 mg, 0.5 mmol). The mixture was then stirred for 10 min., quenched with NH ₄ Cl (1 N), and extracted with EtOAc. The organic layer was separated, dried over Na ₂ SO ₄ and the solvent was removed. The residue was purified by silica gel (pentane: ethyl acetate mixtures) to give the pure amino alcohol product. This procedure can also be scaled up to multigram scale.