Oxazaborolidines from boracycles through the intramolecular azide insertion 1

Optically active 2-azido alcohols react with boracycles such as 9-BBN-H and borinane to produce air stable oxazaborolidines, namely 3-oxa-6-aza-2-boratricyclo[5.3.3.0 2,6 ]tridecanes and 10-oxa-7-aza-1-borabicyclo[5.3.0]decanes, respectively. Nopyl azide reacts with 9-BBN-H forming a novel N -substituted-9-aza-10-borabicyclo[3.3.2]decane through a B-C nitrenoid insertion. This intermediate undergoes intramolecular hydroboration at 200 °C to produce a pinene-derived azaborapentacycle. These compounds were examined in the asymmetric reduction of acetophenone under the conditions employed for CBS-type catalytic processes. The enantioselectivities obtained were very low due to the lack of formation of the oxazaborolidine-borane complex, which is essential in orchestrating this process.


Introduction
In recent years, oxazaborolidines have proven to be useful chiral catalysts and reagents in for asymmetric transformations. 3Some examples of these oxazaborolidines are illustrated in Scheme 1. Asymmetric processes mediated by these reagents include the asymmetric borane reduction of prochiral ketones catalyzed by 1 and 2, 4 the asymmetric addition of alkynyldimethylborane to aldehydes via complexation with 3 (R 1 = CH 3 , R 2 = H), 5 the asymmetric addition of diethylzinc to aldehydes by 3 (R 1 = CH 3 or H, R 2 =CH 3 ), 6 the asymmetric Rh(I) catalyzed hydroboration of styrenes by 4, 7 the asymmetric Diels-Alder reaction catalyzed by 5, 8 and the asymmetric aldol reaction of aldehydes and silyl ketene acetals catalyzed by 6. 9 These oxazaborolidines are prepared by two methods.The B-H derivatives (e.g. 1 (R = H), 2, 3 (R 1 = H, R 2 =CH 3 ), 4-6) are prepared by the reaction of their corresponding β-amino alcohol or N-sulfonyl amino acid with BH 3 •L (L = THF or S(CH 3 ) 2 ).The B-alkyl and -aryl substituted oxazaborolidines (e.g. 1 ( R=CH 3 or Bu), 3 (R 1 = CH 3 , R 2 = H)) are prepared by the reaction of the amino alcohol or amino acid with the corresponding boronic acid followed by the azeotropic removal of H 2 O.The scrupulous exclusion of the water from these reagents and processes is critical because even the partial hydrolysis of the oxazaborolidines can dramatically lower both the yields and enantioselectivities obtained.For example, Merck scientists have encountered this problem in the reduction of prochiral ketones with (R)-Me-1. 10

Scheme 1
Shortly after our discovery of the selective ring B-C bond oxidation with trimethylamine Noxide in 9-BBN systems, 12 Brown and Midland reported the analogous process with organic azides and 9-BBN derivatives which give 9,10-azaborabicyclo [3.3.2]decanes. 11This process, which was not examined in detail, led us to investigate this process as a novel approach to chiral oxazaborolidines from the reaction of 9-BBN-H 7 with β-azido alcohols 8 (eq.1).
Several new representatives of 9-BBN derived oxazaborolidines 9 were prepared (Table 1).These compounds are thermally stable and are resistant toward oxidation in the open atmosphere.Moreover, they appear to be more resistant to hydrolysis in the open air than are other oxazaborolidines.

Scheme 2
In contrast to the boronic acid routes to oxazaborolidines, this new process involves no water by-products.Only hydrogen and nitrogen gases are formed in this reaction (eq.1).The β-azido alcohols used for the study were prepared by two well-documented methods.The first method involves the epoxide ring opening reaction with sodium azide in the presence of ammonium chloride. 13The second involves a methodology developed by Sharpless where a cyclic sulfate ring is opened by the reaction with sodium azide. 14These cyclic sulfates were available from their corresponding diols, which are either commercially available or were prepared through the asymmetric dihydroxylation of the alkene with OsO 4 .

Oxazaborolidines from borinanes
While less information is available on insertion processes for the borinane ring systems compared to the analogous processes for 9-BBN derivatives, they do appear to be more reactive.For example, the oxidation of B-tert-butylborinane with trimethylamine N-oxide (TMANO) at 0 °C proceeds instantaneously forming B-tert-butyl-1,2-oxaborepane.While this process is analogous to the general 9-BBN process, B-tert-butyl-9-BBN itself is inert to TMANO.This difference in reactivity can be understood on the basis of the attack of the borinane by TMANO giving a complex in which the tert-butyl group can occupy an equatorial position with the TMANO occupying an axial position.However, in the 9-BBN system, the related TMANO complex would force the tert-butyl group into an axial position with respect to one of the sixmembered rings, an intermediate which would be expected to be too high in energy to be reached in this process. 12In the present case, neither the alcohol nor azide functionalities are large enough to present major steric problems occupying an axial position.Therefore, we expected the borinane process to be more facile, but exhibit analogous behavior to that of the 9-BBN derivatives.

Scheme 3
The intramolecular azide insertion process was examined with the borinane 12 leading to the smooth formation of the bicyclic oxazaborolidines 13 from 12.The insertion occurs in a manner analogous to that observed for the 9-BBN systems (Scheme 3), where an alkoxyborinane intermediate 14 ( 11 B NMR: δ 54.6) is formed with the concomitant evolution of hydrogen gas.This intermediate is in equilibrium with the cyclic complex 15 ( 11 B NMR: δ 7.0) which collapses to the oxazaborolidine 13 ( 11 B NMR: δ32.6) through a 1,2-alkyl migration from boron to nitrogen producing the 1,2-azaborepane ring and nitrogen gas.

Pinene-derived azaborapentacycles through azide insertion and cyclic hydroboration
Midland prepared a series of terpenic azaboracyclohexanes and found that their BH 3 complexes reduce prochiral ketones in modest to good enantioselectivities (60-82%). 15Evans discovered, in work directed toward the synthesis of echinocandin D, that γ-olefinic azides react with 9-BBN-H 7 to produce an 9-aza-10-borabicyclo[3.3.2]decanethrough an intramolecular azide insertion process. 16In this B-R-9-BBN process, no B-R nitrogen insertion was observed, but rather, exclusive nitrogen insertion into a ring B-C bond.By contrast, the corresponding dicyclohexylborane adduct did exhibit B-C nitrogen insertion into the B-R moiety leading to the synthesis of pyrrolidines and piperidines. 17This process has been applied to the synthesis of the unnatural (R)-nicotine by the hydroboration-intramolecular azide insertion process. 18It is important to point out for both hydroborating agents, hydroboration was thought to precede the nitrenoid insertion process.We envisaged a new route to 9-BBN-derived terpenic azaborinane based upon this methodology.Thus, (-)-nopyl azide 17 was prepared from (-)-nopol 16 in an 84% overall yield and this was allowed to react with 9-BBN-H.This mixture was ultimately converted to the novel terpene-derived polycycle 19 which contains the 9-aza-10borabicyclo[3.3.2]decanering system.19 was prepared from (-)-nopol, 16, through the azide insertion-cyclic hydroboration of (-)-nopyl azide 17 with 9-BBN (Scheme 4).

Scheme 4
Contrary to what was expected, the reaction of 17 with 7 leads to the initial insertion of a nitrogen atom into the 9-BBN ring rather than hydroboration of the C=C double bond, forming an N-substituted 9-aza-10-borabicyclo[3.To further support the presence of the double bond, the N-nopyl azaborane 18 was allowed to react with BH 3 •SMe 2 to form an µ-aminodiborane adduct 20 (eq.2).These µ-aminodiboranes have been previously reported. 19Examples of B-substituted µ-aminodiboranes include µdimethylaminomethyldiborane 20 and the 9-BBN-derived 1,1,2,2-bis(cyclooctane-1,5-diyl)-µaminodiborane. 21 study of the oxazaborolidines 9, 13 and 19 in CBS-type reduction processes The 9-BBN derived oxazaborolidines 9b-d, bicyclic oxazaborolidine 13b and azaborapentacycle 19 were tested as asymmetric catalysts and reagents for the asymmetric reduction of acetophenone or propiophenone using BH 3 •THF as the reductant under CBS conditions (eq.3, Table 2).All these reductions are complete in less than 5 min, as observed by GC and all alcohols are isolated in moderate yields.At lower temperatures the reaction proceeded slower.For example, at 0 °C with 1 equiv of 9b, the reaction took 6 h to complete.Unfortunately, very poor enantioselectivities were obtained by using these oxazaborolidines.
To obtain a working model to explain these results and to help in the design of a catalyst that could improve these selectivities, it was necessary to take a deeper look at the mechanism of this reduction.As mentioned previously, 4 the CBS reduction of prochiral ketones catalyzed by Corey's oxazaborolidine ((R)-B-Me-1) is believed to occur through the formation of the oxazaborolidine-BH 3 complex (R)-B-Me-1•BH 3 .This delivers a hydride to the ketone carbon complexed to (R)-B-Me-1•BH 3 in which the endocyclic boron atom is complexed anti to the large aromatic group.The resulting alkoxyborate complex eventually collapses to the dialkoxyborane, regenerating the catalyst.The borane complex intermediate (R)-B-Me-1•BH 3 , structurally defined by NMR and X-Ray analysis, 22 is essential to orchestrate this very stereoselective process.The complexation of Corey's CBS B-Me-1 with BH 3 •THF (1:1) was reproduced and reveals that 85% of (R)-B-Me-1•BH 3 was formed in equilibrium by 11 B NMR analysis.Values of K = 73 M -1 and ∆G° = -2.53kcal / mol were calculated from this data.The asymmetric reduction of acetophenone with (S)-B-Me-1 was performed under catalytic conditions where (R)-sec-phenethyl alcohol was obtained in 94% ee in agreement with Corey's results.4e In contrast, the BH 3 complexation experiment with the 9-BBN-derived oxazaborolidines 9 and 19 revealed that neither of these boron-ring systems produced significant amounts of borane complexes analogous to 21 (eq.4).For example, in 9a and 9c less than 5% of 21 were observed to form.MMX calculations suggest that the nitrogen atom in 9 adapts a nearly planar geometry.In addition, the methylene carbons of the 9-aza-10-borabicyclo[3.3.2]decyl(ABBD) system imparts a steric interaction with the approaching BH 3 species.This methylene group makes this nitrogen more hindered toward borane complexation.These findings are analogous to other amine-borane complexes, where their complex stability and hence high reactivity toward hydroboration and carbonyl reduction is influenced by these steric effects. 23In addition, when propiophenone is added to either oxazaborolidines (R)-B-Me-1 or 9b, no oxazaborolidine-ketone complexed was observed to form by 11  Bicyclic oxazaborolidine 13a was evaluated in the borane complexation process where 50% of 22 complex was formed upon the addition of 1 mol / eq. of BH 3 •THF as observed by 11 B NMR (eq.5).From this, K = 3.3 M -1 and ∆G° = -0.71Kcal/ mol.Unfortunately, the chiral oxazaborolidine 13b produced only 10% ee in the sec-phenethyl alcohol from the CBS-type reduction of acetophenone.From the above, the greater basicity of the nitrogen atom and other structural features present in the CBS catalysts are critical to their success.The systems examined herein lack the ability to simultaneously complex borane and effectively direct the process.Further studies with these interesting new boron heterocycles in other asymmetric processes are underway.

Experimental Section
General Procedures.All experiments were carried out in pre-dried glassware (1 h, 250 °C) under nitrogen atmosphere.Standard handling techniques for air-sensitive compounds were employed through out this study.NMR spectra were obtained on a General Electric QE-300, a General Electric GN-300, a Bruker Advance DPX-300 and / or a Bruker Advance DRX-500 spectrometers. 1 H, 13 C and 11 B NMR were recorded in CDCl 3 or C 6 D 6 , unless otherwise used, and the chemical shifts were expressed in ppm relative to CDCl 3 (7.26 and 77.0 ppm in 1 H and 13 C NMR, respectively) or C 6 D 6 (7.15 and 128.0 ppm in 1 H and 13 C NMR, respectively) as the internal standard.Multiplicity assignments and sequence in 13 C NMR were made with the aid of DEPT and HETCOR experiments. 1 H NMR assignments were carried out with the aid of 1 H-1 H COSY experiment.Infrared spectra were obtained on a Nicolet Magna IR-750, a Perkin-Elmer 281 or a Nicolet Series 6000 FT-IR spectrophotometers.Mass spectral data were obtained with a Hewlett-Packard 5995A GC/MS spectrometer (70 eV).High resolution mass spectral data were obtained with a Micromass VG AutoSpec magnetic sector mass spectrometer (70 eV).Gas chromatographic analyses were performed with a Perkin-Elmer 8320 capillary or a Perkin-Elmer Autosystem XL gas chromatograph using 30 m X 0. 25  Elemental analyses were performed by Atlantic Microlabs, Norcross, Georgia.

Representative procedure for the asymmetric reduction of a prochiral ketone with BH 3 •THF and heterocycles 9, 13b and 19
Into a round bottomed flask containing BH 3 •THF (2.0 mL (1.0 M in THF), 2.0 mmol), 9c (0.04 g, 0.02 mmol) and THF (3.0 mL) at 25 °C was added acetophenone (0.36 g, 3.0 mmol) dropwise.When the addition was complete, the reaction mixture was stirred for 5 min at 0 °C.Water (2 mL) and ether (2 mL) were added and the resulting two phases were separated.The organic phase was washed with water (3 X 1 mL) and dried over magnesium sulfate.The organic phase was decanted, concentrated and Kugelrohr distilled to give 0.24 g (66%) of 1-phenylethanol.16), 107 (66), 79 (100), 77 (59).This enantiomeric alcohol mixture was converted to the corresponding Mosher esters under the conditions described above, where a diastereomeric 55 : 45 mixture of (R, R)and (R, S)-MTPA esters was observed as determined by integrating the 1 H NMR peaks of the sec-phenethoxy methyl group signals at 1.61 and 1.67 ppm, respectively as well as the 13 C NMR peaks of the methyl group signals at 21.6 and 22.0 ppm, respectively.Thus, the %ee of the alcohol obtained was determined to be 10%.The configuration of the alcohol obtained was determined to be R by comparing the NMR peaks of the diastereomeric Mosher ester mixture with the MTPA ester derived from authentic sample of (S)-(-)-sec-phenethyl alcohol.

a
Isolated yields.b Measured by the determination of the diastereomeric composition of their MTPA (Mosher) esters.c Yield and ee by using 1 equiv of 9b at 0 °C.d Determined by comparing the sign of rotation with the obtained in the literature.e The reaction was carried out by using 1 equiv of 19 at 0 °C.
B and 13 C NMR indicating the weak Lewis acidity of these oxazaborolidines.The Corey's oxazaborolidine-borane complex B-Me-1•BH 3 contains a more Lewis acidic boron than the uncomplexed catalyst B-Me-1.These species are possibly more reactive to ketone complexation than B-Me-1.Even though the reduction of ketones catalyzed by 9 are complete in 5 min, poor enantioselectivity in this process due to the ISSN 1424-6376 Page 51 © ARKAT USA, Inc oxazaborolidine-borane complex intermediate is observed.This lack of borane complexation by these 9-BBN-derived cyclic systems 9 explains why they do not function as effective asymmetric catalysts in the reduction of prochiral ketones.