An intramolecular amidation processes for substrates such as sulfamates using chiral and non-chiral metalloporphyrin complexes which can maximize catalytic activity, enhance efficiency, stereoselectivity and speed of amidation reactions is described. The chiral metalloporphyrin catalyzed amidation of sulfamates exhibits excellent cis-selectivity, affording cyclic sulfamidates with high enantiomeric excess values.

FIELD OF THE INVENTION

The invention relates to methods for direct intramolecular amidation of sulfamates affording cyclic sulfamidates. The method represents an example of asymmetric intramolecular amidation of sulfamate esters with high ee (enantiomeric excess) values, (typically 46–87% ee).

BACKGROUND OF THE INVENTION

Pioneering work by Breslow and co-workers in 1983 demonstrated catalytic intramolecular amidation of sulfonamides with either transition metal porphyrin complexes or rhodium acetate as catalysts gave cyclic sulfonamides in good yields (Breslow et al.J. Am. Chem. Soc. (1983), 105, 6728). Recent studies by Du Bois and co-workers reported rhodium acetate to be an efficient catalyst for intramolecular amidation of sulfamate esters, affording the corresponding cyclic sulfamidates in good to high yields (Du Bois et al.J. Am. Chem. Soc. (2001), 123, 6935). However, the challenge still remains to seek more stereoselective catalysts for the synthesis of optically active cyclic sulfamidates. To our knowledge, the asymmetric intramolecular amidation of such substrates using chiral catalysts is not known.

The present invention describes the first intramolecular amidation of sulfamates catalyzed by a metalloporphyrin and asymmetric intramolecular amidation of sulfamidates catalyzed by a transition metal complex supported by a porphyrin macrocycle. The target cyclic sulfamidates can be easily converted to α- or β-amino alcohols (Du Bois et al.J. Am. Chem. Soc. (2001), 123, 6935), which are important precursors for drug synthesis and for the synthesis of chiral ligands for asymmetric catalysis (Kajiro et al.Synlett(1998), 51; Davies et al.Tetrahedron Lett. (1996), 37, 813; Ghosh et al.J. Am. Chem. Soc. (1996), 118, 2527).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an intramolecular amidation process using a non-chiral metalloporphyrin catalyst and a chiral metalloporphyrin catalyst represented by structural formula:

wherein

each R1–R12is independently H, optionally substituted hydroxyl, optionally substituted amino, halogen, —CN, —NO2, optionally substituted C1-20alkyl, optionally substituted phenyl; optionally substituted naphthyl; optionally substituted anthracenyl, —SR13, —SO2R13, —CO2R13, and optionally substituted heteroatom-containing aromatic ring, in which the optional substitutents are independently selected from the foregoing alkyl, phenyl, naphthyl, anthracenyl and heteroatom-containing aromatic groups; R13is independently selected from the same groups as R1other than —SR13and —SO2R13; and L is CO or R1. The various R groups may be optically pure or can be stereo- and regioisomers.

In an embodiment of this invention, the metalloporphyrin is a transition metal porphyrin, such as ruthenium, manganese, iron, osmium, copper or cobalt porphyrin. In an embodiment of this invention, the porphyrin ligand is a tetraphenylporphyrin and the phenyl rings are attached at the meso-positions of the porphyrin. In an embodiment of the present invention, the catalysts are capable of exhibiting both regio- and stereo-selectivity. Two of the preferred catalysts are shown inFIG. 1. In an embodiment of the present invention, the catalyst is capable of selectively catalyzing intramolecular amidation of saturated C—H bonds. In an embodiment of the present invention, the catalyst is capable of catalyzing asymmetric intramolecular amidation of saturated C—H bonds. In an embodiment of this invention, the stereoselectivity is the formation of only cis-configuration cyclic sulfamidates.

Additionally, the present invention provides a method for the preparation of cyclic sulfamidates with the catalysts from sulfamates as starting materials. Further, the present invention provides a method for producing cis-cyclic sulfamidates with the catalyst. The present invention also provides a method for producing optically active cyclic sulfamidates with the catalyst. Preferably, the method involves the use of an oxidant which selectively alters the oxidation state of the substrate, preferably in the presence of a solvent and preferably in the the presence of a base. The solvent can be MeOH, MeCN, DMF, C4H4Cl2, CH2Cl2, and benzene. Typical oxidants include PhI(OAc)2, PhIO and NBS (N-bromosuccinimide). Bases, which scavenge by-products, include Al2O3, MgO, ZnO, K2CO3and NaOH. In an embodiment of this invention, the substrate is a sulfamate, a sulfamate derivative, or a hydrocarbon containing a sulfonylamide functional group. As shown in the figures, carbon to which the sulfonylamide moiety is attached can be a part of a cyclic or non-cyclic moiety, which in turn can be substituted with a functional group such as —CO2Me or by an aromatic or cycloaliphatic group.

As used herein, the term, “stereoselective” refers to selection of an optical isomer. “Enantioselectivity” represents the maximal asymmetric induction and minimal racemization of the optically active products. The term “turnover” refers to the relative number of molecules of products per number of molecules of catalyst prior to the exhaustion of a given reaction.

EXAMPLES

The invention relates to a direct method for the synthesis of cyclic sulfamidates using ruthenium porphyrin 1 (prepared according to: Murahashi et al.Tetrahedron Left. (1995), 36, 8059; Groves et al.J. Am. Chem. Soc. (1996), 118, 8961) as a general and effective catalyst for the direct intramolecular amidation of sulfamates.

Typical conditions employ 1.5 mol % of 1, 1 equiv. of sulfamate ester, 2 equiv. of PhI(OAc)2, 2.5 equiv. of anhydrous Al2O3(pH=7–7.4) in CH2Cl2(distilled from CaH2prior to use) under argon at 40° C. for 2 h. Commercially available Al2O3was dried to a constant weight at 250° C. for 12 h. The reaction mixture was cooled to 25° C., diluted with 5 mL of CH2Cl2, and filtered through a pad of Celite®. The filter cake was rinsed with 2×5 mL of CH2Cl2and the combined filtrates were evaporated under reduced pressure. The residue was purified by silica gel chromatography (Merck, 230–400 mesh) to afford the corresponding cyclic sulfamidates. AcOH generated as a by-product from PhI(OAc)2was scavenged from the reaction mixture by addition of base. Following a series of control experiments, Al2O3proved to be the best among MgO, ZnO, K2CO3, Al2O3and NaOH, in that it gave the highest product yields.

With only 1.5 mol % catalyst loading, sulfamates 5–10 were converted to the corresponding cyclic sulfamidates 11–16 in good to high yields (seeFIG. 4). The highest yield (88%) was achieved for the intramolecular amidations of 7 and 10. Catalyst 1 shows high catalytic efficiency and excellent cis-selectivity. For substrates 7, 8 and 10, only cis-cyclic sulfamidates 12, 13 and 16 were obtained, respectively. The trans-cyclic sulfamidates were undetected. This shows that ruthenium porphyrin 1 has better stereoselectivity than rhodium acetate (a 8:1 mixture of cis and trans isomers was obtained for the reaction of 8 catalyzed by rhodium acetate. See: Du Bois et al.J. Am. Chem. Soc. (2001), 123, 6935). The oxidant used in the catalytic reaction is PhI(OAc)2, which is commercially available. For substrates 5–7, and 10, six- rather than five-membered ring heterocycles 11–13 and 16 were formed in high yields (76–88%). For substrates 8 and 9, five-membered ring formation gave cycloadducts 14 and 15 in moderate yields of 61 and 56%, respectively.

Turnover number refers to the relative number of molecules of product per number of molecules of catalyst prior to the exhaustion of a given reaction and shows a very important aspect of catalyst efficiency. The turnover numbers for the analogous rhodium acetate catalyzed reactions do not exceed 50 (see: Du Bois et al.J. Am. Chem. Soc. (2001), 123, 6935). With electron-deficient ruthenium porphyrin 1 as catalyst, intramolecular amidation of 5 and 7 afforded turnover numbers of 290 and 301, respectively (FIG. 5). This shows that 1 is more robust catalyst than rhodium (II,II) dimmer complexes (the reaction conditions are almost the same as those for EXAMPLE 1, and with a lower catalyst loading in EXAMPLE 2. SeeFIG. 5footnote).

With chiral ruthenium porphyrin 2 as catalyst (prepared according to: Che et al.Chem. Commun. (1997), 1205), sulfamates 5, 8 and 9 undergo enantioselective C—H insertion to give the corresponding cyclic sulfamidates with high ee values (typically 46–87%,FIG. 6). As shown inFIG. 6, an ee (enantiomeric excess) of 46% or more can be achieved. In order to reduce the amount of by-products, the substrate to PhI(OAc)2ratio was decreased from 2 to 1.4. Solvent has a very important effect on ee values obtained. For example, reaction of sulfamate ester 5 in CH2Cl2gave 11 with 46% ee (entry 1). In comparison, the analogous reaction carried in C6H6gave 11 with an ee value of 79% (entry 2). Similar outcomes were obtained for substrates 8 and 9.

Similarly, reaction temperature has an effect on the ee values. With benzene as solvent, lowering the reaction temperature to 4° C. resulted in an increase in ee values (entries 2 and 3: from 79 to 84%; entries 5 and 6: from 82 to 87%; entries 8 and 9: from 81 to 82%).

The present invention provides an efficient method for the synthesis of chiral cyclic sulfamidates. These compounds are useful synthetic intermediates in the preparation of optically active α- or β-amino alcohols of biological importance. For example, optically active 17 is currently receiving considerable attention as a key component of the HIV protease inhibitor Indinavir 18 (see: Hiyama et al.Synlett(1998), 51.FIG. 7). Amino alcohol 17 can be prepared from (1S,2R)-14 upon hydrolysis (see: Du Bois et al.J. Am. Chem. Soc. (2001), 123, 6935). Using commercially available achiral 2-indanol, amino alcohol 17 can be obtained in 3 steps; optically active 17 requires 8 steps from the chiral amino acid (see: Hiyama et al.Synlett(1998), 51).