WO2000010977A1

WO2000010977A1 - Catalytic asymmetric aminohydroxylation with amino-substituted heterocycles

Info

Publication number: WO2000010977A1
Application number: PCT/US1999/018998
Authority: WO
Inventors: K. Barry Sharpless; Lukas J. Goossen; Hong Liu; Klaus R. Dress
Original assignee: The Scripps Research Institute
Priority date: 1998-08-21
Filing date: 1999-08-20
Publication date: 2000-03-02
Also published as: WO2000010977A9; AU5682299A

Abstract

Amino-substituted heterocycles are disclosed to be suitable nitrogen sources for the osmium catalyzed asymmetric aminohydroxylation of olefins, achieving suprafacial, vicinal addition of a heterocycle moiety and a hydroxyl group. The enantioselectivities are strongly dependent on the nature of the heterocycles and are comparable to those of standard nitrogen sources. Instead of merely providing a route to protected aminoalcohols, the AA can now also be considered as a means to introduce complex substructures to hydrocarbon backbones.

Description

CATALYTIC ASYMMETRIC AMINOHYDROXYLATION WITH AMINO-SUBSTITUTED HETEROCYCLES

Description

Government Rights:

This invention was made with government support under Grant No. GM-28384 awarded by the National Institutes of Health and with government support under Grant No. CHE-9531152 awarded by the National Science Foundation. The U.S. government has certain rights in the invention.

Technical Field:

The present invention relates to the aminohydroxylation of olefins. More particularly, the present invention relates to the use of amino-substituted heterocycles as a nitrogen source for enantioselective aminohydroxylation reactions.

Background:

The β-aminoalcohol moiety appears in numerous biologically active compounds (G. Shaw in Comprehensive Heterocyclic Chemistry II, Vol. 7 (Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon, New York, 1996, pp. 397 - 429). To this end, the osmium-catalyzed asymmetric aminohydroxylation (AA) of olefins provides an efficient method for the enantioselective creation of this important functionality (G. Schlingloff, et al., in Asymmetric Oxidation Reactions: A Practical Approach (Ed.: T. Katsuki), Oxford University Press, Oxford, 1998; and H. C. Kolb, et al., in Transition Metals for Fine Chemicals and Organic Synthesis, Vol. 2 (Eds.: M. Beller, C. Bolm), Wiley- VCH, New York, 1998, pp. 243 - 260). A number of nitrogen sources have been employed for the AA reaction. Sulfonamides were one of the first nitrogen sources to be employed in the AA reaction (G. Li, et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 451 - 454). Subsequent to this initial report, there has been rapid improvement in both scope and selectivity. The use of amides as a nitrogen source was reported by M. Bruncko et al. (Angew. Chem. Int. Ed. Engl. 1997, 36, 1483 - 1486). The use of carbamates was reported by G. Li et al. (Angew. Chem. Int. Ed. Engl. 1996, 35, 2813 - 2815) and by K. L. Reddy et al. ( J. Am. Chem. Soc. 1998, 120, 1207 - 1217). The N-protected aminoalcohols obtained were usually converted to free aminoalcohols so that the development of a set of orthogonally cleavable protecting groups had been a major concern Current developments in combinatorial chemistry have stimulated the exploitation of this reaction for the direct introduction of biomedically relevant heterocyclic substructures to olefins. (F Balkenhohl, et al. Angew Chem. Int. Ed. Engl. 1996, 35, 2288 - 2337; and A Νefzi, et al Chem. Rev. 1997, 97, 449 - 472).

Attempts to extend the scope of the nitrogen sources in the AA to heterocyclic compounds had long been frustrated by very poor turnover and side reactions, e g. πng chloπnations (I Lengyel, et al , Synth Commun 1998, 28, 1891 - 1896, and references therein) This problem was then solved by Jeπna et al , when a breakthrough was achieved with the use of an adenine derivative as nitrogen source in the aminohydroxylation of a unique olefin (A. S Pilcher, et al., J. Am. Chem. Soc. 1998, 120, 3520 - 3521) Subsequently, a general procedure for this kind of transformation was developed (K R Dress, et al , Tetrahedron Lett 1998, 39, 7669 - 7672). However, no asymmetric inductions weie achieved.

Summary:

A new generation of nitrogen sources is disclosed which greatly extends the scope of the osmium-catalyzed asymmetric aminohydroxylation (AA). With these nitrogen souices, the AA can now be considered as a means for introducing complex heterocyclic fragments into hydrocarbon backbones when appropπate olefinic functionality is present.

One aspect of the invention is directed to an improved method for converting an olefin to a β-aminoalcohol using an osmium-catalyzed asymmetric aminohydroxylation reaction. More particularly, the olefin is enantioselectively aminohydroxylated using chiral hgands and an N-halo alkali salt of an ammo-substituted heterocycle as a nitrogen source for producing the β-aminoalcohol. The ammo group of the amino-substituted heterocycle is oxidized to form the N-halo alkali salt. The heterocycle of the ammo- substituted heterocycle includes a ring lmine conjugated with the amino group to form a planar imidamide system. The β-aminoalcohol produced by the catalytic asymmetric aminohydroxylation reaction has a β-amino group substituted with the heterocycle. The N-halo alkali salt of the amino-substituted heterocycle is represented by the following structure:

In the above structure, X is a halogen; Z⁺ is an alkali counter ion; -(Ν-X)^" Z⁺ represents the N-halo alkali salt, Ν=C represents the ring imine; N=C-N represents the planar imidamide system; Y together with the ring imine forms the heterocycle; and -R¹ is one or more radicals, each independently selected from of hydrogen, halogen, aryl, and alkyl groups. However, there is a proviso that Y does not include a fused imidazole ring that is coplanar with the planar imidamide system. It has been found that the sp² nitrogen of fused imidazole rings coplanar with the planar imidamide system coordinate with the osmium during catalysis and block or inhibit the enantioselective activity of chiral ligands. In a preferred mode, the N-halo alkali salt of the amino-substituted heterocycle is obtained by oxidation of the following amino-substituted heterocycles:

In the above structures, each R is independently selected from hydrogen, halogen, alkyl, aryl or, together with an adjacent R group, forms a fused aromatic ring.

Brief Description of Drawings:

Figure 1 illustrates an aminohydroxylation with a generalized amino-substituted heterocycle. Figure 2 illustrates the aminohydroxylation with exemplary amino-substituted heterocycles.

Figure3 illustrates the aminohydroxylation of stilbene with various amino- substituted-heterocycles. Footnotes therein are as follows: [a] Major product from the reaction using (DHQ)₂PHAL. [b] Isolated yields of pure products after chromatography on silica gel. [c] Determined by chiral HPLC. [d] Concentration in grams per 100 mL of EtOH/CHCl₃ 1:1.

Figure 4 illustrates the aminohydroxylation of various olefins with 2-amino-4,6- dimethyltriazine. Footnotes therein are as follows: [a] Major product from the reaction using (DHQ)₂PHAL. [b] Determined by Η NMR spectroscopy. [c] Determined by chiral HPLC. [d] Isolated yields from the reaction using the (DHQ)₂PHAL ligand, where regioisomers are possible, of mixture of both regioisomers. Similar yields and regioselectivities were obtained with the (DHQD)₂PHAL ligand.

Detailed Description:

Disclosed herein is an enantioselective procedure for the vicinal addition of a hydroxyl group and amino-substituted heterocycles to olefins (Scheme 1).

Scheme 1 Aminohydroxylation with aminosubstituted heterocycles; Het = heterocycle.

J. Rudolph, et al. disclosed that the size and particular placement of the heteroatoms in the adenine moiety favor "second cycle turnover"( Angew. Chem. Int. Ed. Engl. 1996, 35, 2810 - 2813). This would preclude the desired chirality transfer from the alkaloid ligand. Contrary to this teaching, it is disclosed herein that simple aminopyrimidines and aminotriazines function as excellent reagents for the asymmetric aminohydroxylation. With a few modifications to the original procedure, stilbene is converted to either enantiomer of the corresponding aminoalcohol in high ee with 2- aminopyrimidine as the nitrogen source (Scheme 2). 1. ^βuOCI, EtOH, 0^βC 2. aq. NaOH, 0°C

Scheme 2 Aminohydroxylation of traπs-stilbene with 2-aminopyrimidine.

It is imperative that the N-chlorination be performed in the absence of water to retard the electrophilic aromatic substitution. Deprotonation with aqueous ΝaOH affords the chloramine salts, which are relatively stable, especially under an inert atmosphere. A slight deficit of ΝaOH ensured the absence of excess OH even if some chloramine had been consumed by side reactions. The only suitable solvent systems turned out to be mixtures of primary alcohols and water (approx. 2: 1 ratio). No turnover was observed for mixtures of water and acetonitrile or tert-butanol. The use of highly polar protic solvents appears crucial to facilitate the rate of hydrolysis of the relatively electron rich osmium azaglycolate intermediate. Stilbene was chosen as an ideal test olefin for probing the reactivity of other heterocycles because of the mediocre enantioselectivities observed with standard nitrogen sources. The results are documented in Figure 3.

The enantiomeric excesses of 56 to 97% observed with these heterocyclic nitrogen sources are quite impressive when compared to earlier nitrogen sources for the AA. For instance, 62% ee with Chloramine-T (ibid, G. Li, et al. 1996); 75% ee with Chloramine-M (ibid, J. Rudolph, et al. 1996); 94% ee with N-bromoacetamide (ibid, M. Bruncko, et al. 1997); 91% ee with N-halocarbarmate, as disclosed by G. Li (ibid, G. Li 1996). The ee depends on both steric and electronic characteristics of the heterocycles. Smaller nitrogen sources seem to provide higher enantiomeric excesses than the more sterically demanding systems (entry 1, 2 versus 3, 5). There seems to be a modest ee advantage for less electron withdrawing substituents on the nitrogen (entry 1, 3 versus 2, 5). The chemical yields are reasonable to good, with ring chlorinated aminoalcohols as the major contaminants, e.g., entry 1 where 23% of aminoalcohol derived from 2-amino-5-chloropyrimidine was isolated. In order to map out the scope of this reaction on the olefin side, we screened a number of representative olefins with 2-amino-4,6-dimethyl-l,3,5-triazine as a nitrogen source, for the simple reason that it had shown midrange enantioselectivity with stilbene. A remarkably broad range of olefins gave good yields and enantioselectivities (Figure 4) when subjected to the reaction conditions. Cinnamate and fumarate (entry 1, 2) are among the best substrates, whereas the enantioselectivity for the trisubstituted olefin (entry 5) remains poor. In contrast to the highly regioselective adenine derivatives (ibid, K. R. Dress, 1998) , the simple heterocyclic nitrogen sources give modest regioselectivities, comparable to that of the earlier versions of the AA. For all unsymmetrical olefins, a strong preference for the isomer with nitrogen in the benzylic position was observed; isopropyl cinnamate gave only a single regioisomer. The regioisomers were separable by preparative TLC.

Experimental Section Representative procedure for the aminohydroxylations: Reaction of 2- aminopyrimidine with tra/ts-stilbene. All solvents were deoxygenated by three freeze pump / thaw cycles under nitrogen, all reactions were performed under an argon atmosphere. 2-aminopyrimidine (95.1 g mol^"1, 166 mg, 1.75 mmol) was dissolved in dry ethanol (20.0 mL). The solution was cooled in an ice bath. tert-Butylhypochlorite (108.5 g mol^"1, 190 mg, 1.75 mmol) was added. The solution was allowed to warm up to RT and was stirred for 30 min. Then it was cooled again to 0 °C and aqueous NaOH (1.00 M, 1.50 mL, 1.50 mmol) was added. The solution was again warmed to RT in a water bath and water (8.5 mL) was added. Finely divided trans-stilbene (180.2 g mol^~l, 90.1 mg, 0.50 mmol), (DHQ)2PHAL (778 g mol^"1, 23.3 mg, 30 μmol, 6 mol%), and K₂OsO₂(OH)₄ (368 g mol^"1, 9.2 mg, 25 μmol, 5 mol%) were added. The mixture was stirred at RT for 12 h. A saturated solution of NaHSO₃ (4 mL) and water (10 mL) was added and the mixture was stirred for 1 h at RT. The mixture was then placed in a separatory funnel and EtOAc (80 mL) was added. The organic phase was separated and washed with water (40 mL) and brine (40 mL). After drying over MgSO₄, the solvent was evaporated to leave a brownish residue. The product was purified by column chromatography (SiO₂, CH₂Cl₂/MeOH, 1-

5%) yielding 66 mg (45%) as an off-white solid. As a second band, small quantities of the corresponding ring chlorinated product were isolated. Melting point: 132°C (decomp); HRMS (FAB) [C₁₈H₁₇N₃O] calcd. for MH⁺ 292.1450, found 292.1460; Η NMR (400 MHz, CDCl_j, 25°C, TMS): δ=8.12 (d, V(H,H) = 8 Hz, 2H, N=CH), 7.37 - 7.21 (m, 10H, Ph-CH), 6.45 (t, ³J(H,H) = 8 Hz, 1H, py-CH), 6.28 (br d, V(H,H) = 13 Hz, 1H, NH), 5.29 (dd, V(H,H) = 13, 7 Hz, 1H, CHN), 5.07 (d, ³7(H,H) = 7 Hz, 2H, CHO), 4.08 (s, 1H, OH) ppm; ¹³C NMR (100 MHz, CDC1₃): δ = 162.2, 157.9, 141.4, 140.5, 128.5, 128.1, 127.5, 127.4, 127.1, 126.4, 111.0, 78.0, 61.7 ppm; [α]²⁰ _D = - 0.7° (c = 0.59, in EtOH/CHCl₃ 1:1, α = -0.4 °); HPLC: Chiralpak AS, 30% iPrOH/hexane, 1 mL min, 5.1 min (IS, 25), 7.2 (1R, 2R).

Assignment of the absolute configuation: (15, 25)-2-Amino-l,2-diphenylethanol was converted to an authentic sample of the (15, 25) enantiomer mentioned above by reaction with 2-bromopyrimidine (C. G. Overberger, et al., Org. Synth. Coll. Vol. 7V 1963, 336 - 337).

All other compounds were produced similarly. Regioisomers were usually separable by preparative TLC. It is advisable to keep the solvent polarity as high as possible, however, for some nonpolar olefins the addition of a small quantity of π-propanol was necessary to ensure the formation of homogeneous mixtures. A catalyst loading of 5% is sufficient for converting even heterocycles prone to electrophilic aromatic substitution. In most cases, however, it is possible to reduce the catalyst content to 1% without significant loss of ee; for example isopropyl cinnamate (Figure 4, entry 1) gave 96% ee and 51% yield after 24 h. It is also usually possible to reduce the excess of the chlorinated salt of the heterocyclic amine to two equivalents.

Claims

What is claimed is:

1. An improved method for converting an olefin to a ╬▓-aminoalcohol using an osmium catalyzed asymmetric aminohydroxylation reaction, wherein the improvement comprises:

in said catalytic asymmetric aminohydroxylation reaction, the olefin is enantioselectively aminohydroxylated using chiral ligands and an N-halo alkali salt of an amino-substituted heterocycle as a nitrogen source for producing the ╬▓- aminoalcohol, the amino group of the amino-substituted heterocycle being oxidized to form the N-halo alkali salt, the heterocycle of the amino-substituted heterocycle including a ring imine conjugated with the amino group to form a planar imidamide system, the ╬▓-aminoalcohol produced by said catalytic asymmetric aminohydroxylation reaction having a ╬▓-amino group substituted with the heterocycle;

wherein the N-halo alkali salt of the amino-substituted heterocycle is represented by the following structure:

wherein X is a halogen, Z⁺ is an alkali counter ion, -(╬¥-X)^" Z⁺ represents the N- halo alkali salt, ╬¥=C represents the ring imine, N=C-N represents the planar imidamide system, Y together with the ring imine forms the heterocycle, and -R¹ is one or more radicals, each independently selected from the group consisting of hydrogen, halogen, aryl, and alkyl groups;

with a proviso that Y does not include a fused imidazole ring coplanar with the planar imidamide system.

2. An improved method for converting an olefin to a ╬▓-aminoalcohol according to claim 1 wherein the N-halo alkali salt of the amino-substituted heterocycle is obtained by activation of amino-substituted heterocycles selected from the following group:

wherein each R is independently selected from a group consisting of hydrogen, halogen, alkyl, and aryl or, together with an adjacent R group, forms a fused aromatic ring.