Catalytic, enantioselective synthesis of Boc-protected 1,2-amino alcohols through aminolysis of meso -epoxides with benzophenone imine

Aromatic meso -epoxides 3 have been ring-opened with benzophenone imine (2) using catalytic quantities of the chiral scandium bipyridine complex 1a to furnish Boc-protected 1,2-amino alcohols 5 in good yields and enantioselectivities after acidic hydrolysis and Boc-protection

The nucleophilic addition of amines to epoxides catalyzed by Lewis acids typically suffers from compatibility problems between the Lewis basic amine and the Lewis acid catalyst which tend to coordinate to one another irreversibly.A solution to this problem was first shown in the work of Crotti who found that lanthanide triflates such as Yb(OTf) 3 are effective catalysts for the aminolysis of 1,2-epoxides, presumably because they are able to exert their exceptional Lewis acidity even in the presence of the amine. 7ollowing this precedence Hou et al. discovered a Yb(OTf) 3 -R-BINOL-catalyst for the first catalytic, enantioselective aminolysis of cyclohexene oxide with aniline. 8Inaba et al. utilized a chiral titanium catalyst made from equimolar amounts of Ti(OiPr) 4 and (S)-BINOL (1 mol-%) for the addition of benzyl amine to a seven-membered cyclic epoxide containing a ketal moiety epoxide which proceeded in excellent yield and enantioselectivity. 9Both procedures, however, suffered from an extremely narrow substrate scope tolerating just the mentioned epoxides.A more broadly applicable catalyst was subsequently developed by Collin et al. who introduced a Sm III iodo-(S)-BINOL complex which gave rise to very high enantioselectivities of greater than 90% ee for a variety of cyclic meso-epoxides when treated with anilines. 10Very recently, Kobayashi et al. have devised a chiral niobium complex which displayed high enantioselectivity for a range of meso-epoxides. 11e have introduced the chiral scandium and indium bipyridine catalysts 1a and 1b for a variety of epoxide-opening reactions (scheme 1).Thus, 1,2-diol monoethers, 12 1,2-amino alcohols, 13 1,2-mercapto alcohols, 14 and 1,2-seleno alcohols 15 have been obtained in partly excellent enantioselectivities upon reaction of meso-epoxides with alcohols, amines, thiols, and selenols, respectively.Whereas aromatic substrates performed admirably in these ring-opening reactions and furnished products with well above 90% ee, aliphatic meso-epoxides typically gave rise to enantioselectivities not exceeding 75% ee.A combined Lewis acid-Brønsted acid catalysis model has been proposed to account for the reactivity as well as the enantioselectivity of this reaction.95% (93% ee) 80% (92% ee) 77% (93% ee) Scheme 1. Scandium-and indium-bipyridine-catalyzed, enantioselective ring-opening reactions of meso-epoxides.
One major drawback of our procedure for the aminolysis of meso-epoxides, however, stems from the necessity to employ anilines as amine components.If one wants to obtain the primary 1,2-amino alcohols as products a tedious oxidative deprotection of the N-aryl group typically with cerium ammonium nitrate 16 has to be performed.In our search for an alternative procedure that would obviate this additional operation we have found benzophenone imine (2) as a suitable ammonia surrogate that adds readily to epoxides and liberates the free amino group upon simple acidic hydrolysis in good yields and enantioselectivities when catalyzed with our scandium bipyridine catalyst 1a.

Results and Discussion
Based upon the well-known capacity of benzophenone imine to act as an ammonia surrogate in Buchwald-Hartwig amination reactions 17 we investigated its use as nucleophile in our scandiumbipyridine-catalyzed epoxide-opening process.We started our studies with the reaction of cisstilbene oxide (3a) and benzophenone imine (2) (2 eq.) in dichloromethane (0.2 M) catalyzed through 10 mol% of the scandium bipyridine catalyst 1a.After 3 d at rt we stopped the reaction by adding 1 N HCl-solution and heated the mixture to 60°C for 4 h to effect hydrolysis of the imine.Upon basification the desired 1,2-amino alcohol 4a was obtained in 36% yield and 88% ee as determined by HPLC-analysis along with 45% of the starting epoxide 3a which reflects the attenuated nucelophilicity of the ketimine relative to anilines (table 1, entry 1).In an attempt to increase conversion we doubled the amount of the nucleophile from 2 to 4 eq. of benzophenone imine (2) under otherwise identical reaction conditions.Indeed, 1,2-amino alcohol 4a was now obtained in 59% yield, but with a diminished 43% ee indicating a detrimental effect of the imine on the enantioselectivity of the reaction (entry 2).In a further attempt the overall concentration of the mixture was increased from 0.2 M to 0.5 M and the catalyst amount was increased from 10 mol% to 15 mol%.Gratifyingly, these changes led to the isolation of 4a in 75% yield and 80% ee after 5 d at rt (entry 3).Two other aromatic mesoepoxides 3b and 3c were subsequently converted into the corresponding 1,2-amino alcohols 4b and 4c, respectively, in good overall yields and enantioselectivities according to this protocol (entries 4 and 5).In some experiments it turned out, however, that the highly polar 1,2-amino alcohols 4 were frequently difficult to isolate.Accordingly, we developed an alternate procedure which involved the in situ protection of the amino group with the butyloxycarbonyl(Boc)-group.When we followed the sequence comprising the enantioselective ring-opening of meso-epoxides 3 with benzophenone imine (2), imine hydrolysis and Boc-protection we were able to obtain the Bocprotected 1,2-amino alcohol 5a-c in 48-56% overall yields and up to 82% ee (table 2).This procedure had the advantage that we could more reliably obtain the products in the indicated yields.

Conclusions
We have developed a novel protocol for the scandium-bipyridine-catalyzed, enantioselective aminolysis of aromatic meso-epoxides with benzophenone imine as ammonia surrogate.Upon imine hydrolysis either the free or the Boc-protected 1,2-amino alcohols were obtained in good overall yields and enantioselectivities without the need to oxidatively cleave off a nitrogen substituent.

Experimental Section
General Procedures.All reactions were performed in flame-dried glassware under an atmosphere of dry nitrogen.The following reaction solvents were distilled from the indicated drying agents: dichloromethane (CaH 2 ), tetrahydrofuran (LiAlH 4 , triphenylmethane), diethyl ether (Na, benzophenone), toluene (Na, benzophenone), N,N-dimethylformamide (Acros ACS grade), acetonitrile (Acros ACS grade), chloroform (Acros ACS grade).Diethyl ether, petroleum ether and ethyl acetate for chromatography were technical grade and distilled from KOH or CaCl 2 .All reactions were monitored by thin-layer chromatography (TLC) on precoated silica gel SIL G/UV254 plates (Machery, Nagel & Co.); spots were visualized by treatment with a solution of vanillin (0.5 g), conc.acetic acid (10 mL), and conc.H 2 SO 4 (5 mL) in methanol (90 mL) or molybdophosphoric acid (5 g) in ethanol (250 mL).Flash column chromatography was performed by using Merck silica gel 60 230-400 mesh.The meso-epoxides 3b and 3c were prepared according to the method of Burk et al. 18 The chiral bipyridine was best prepared according to the protocol developed by Kobayashi. 19All other chemicals were used as received from commercial suppliers. 1H and 13 C NMR spectra were recorded with VARIAN Gemini 200 (200 MHz), VARIAN Gemini 300 (300 MHz) spectrometers or an Bruker Avance DRX 400 (400 MHz) spectrometer in CDCl 3 at 25°C with TMS as internal standard.IR spectra were obtained with a FTIR spectrometer (Genesis ATI, Mattson/Unicam).UV spectra were obtained with a Beckmann DU-650 spectrometer.Melting points are uncorrected.Optical rotations were measured using a Polarotronic polarometer (Schmidt & Haensch).HPLC analyses were performed on a JASCO MD-2010 plus instrument with a chiral stationary phase column (Chiralcel AD-H column purchased from Daicel Co., Ltd.).Mass spectra were measured at 70 eV (EI) with a Finnigan MAT 95 A spectrometer.High-resolution mass spectra (HRMS; ESI/Na) were measured with a Bruker Daltonics APEX II FT-ICR spectrometer.
General procedure for the one-pot synthesis of Boc-protected 1,2-amino alcohols 38 mg (0.075 mmol) of Sc(OTf) 3 and 30 mg (0.08 mmol) of chiral bipyridine were stirred in CH 2 Cl 2 (1 ml, 0.5 M final solution relative to epoxide) for 5 min at rt whereupon 0.50 mmol of meso-epoxide 3 and 181 mg (1.00 mmol) of benzophenone imine (2) were added.The mixture was stirred at rt for 5 d.Subsequently, 1 N HCl solution was added and the mixture heated to 60°C for 4 h.After cooling to rt the phases were separated, the aqueous layer was extracted with dichloromethane (3 x 10 ml) and subsequently made alkaline through addition of 6 N NaOH solution.The basic solution was extracted with EtOAc (4 x 50 ml), the combined organic extracts were dried over MgSO 4 , filtered, and evaporated in vacuo.The crude product was dissolved in 2 ml of THF/H 2 O (3:1) and 106 mg (1.00 mmol) of Na 2 CO 3 and 130 mg (0.55 mmol) of Boc 2 O were added at 0°C.After 6 h stirring at rt 2 ml of water were added and the mixture was extracted with CH 2 Cl 2 (3 x 5 ml).The combined organic extracts were dried over MgSO 4 , filtered, and evaporated in vacuo.The crude products were purified through column chromatography over silica gel with ethyl acetate/hexane (1:4) to yield typically crystalline products 5.

Table 1 .
Optimization studies for the addition benzophenone imine (2) to cis-stilbene oxide (3) a Isolated yield of purified material.b Determined by HPLC-analysis on a chiral stationary phase.

Table 2 .
Sequential epoxide-opening and Boc-protection to furnish Boc-protected 1,2-amino alcohols 5 in a one-pot operation a Isolated yield of purified material.b Determined by HPLC-analysis on a chiral stationary phase.