Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 43 ? ARKAT USA, Inc Oxazaborolidines from boracycles through the intramolecular azide insertion1 Jorge Ramos2 and John A. Soderquist* Department of Chemistry, University of Puerto Rico San Juan, PR 00931-3346 E-mail: jas@janice.uprr.pr Dedicated to Professor Hassner on the occasion of his 70th birthday (received 11 Jun 01; accepted 07 Oct 01; published on the web 15 Oct 01) Abstract 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[5.3.3.02,6 ]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. Keywords: Oxazaborolidines, 9-borabicyclo[3.3.1]nonane, azido alcohols, azidesorganoboranes, boron heterocycles Introduction In recent years, oxazaborolidines have proven to be useful chiral catalysts and reagents in for asymmetric transformations.3 Some 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 (R1 = CH3, R2 = H),5 the asymmetric addition of diethylzinc to aldehydes by 3 (R1 = CH3 or H, R2 =CH3),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 (R1 = H, R2 =CH3), 4–6) are prepared by the reaction of their corresponding β-amino alcohol Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 44 ? ARKAT USA, Inc or N-sulfonyl amino acid with BH3·L (L = THF or S(CH3)2). The B-alkyl and -aryl substituted oxazaborolidines (e.g. 1 ( R=CH3 or Bu), 3 (R1 = CH3, R2 = H)) are prepared by the reaction of the amino alcohol or amino acid with the corresponding boronic acid followed by the azeotropic removal of H2O. 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 N- oxide 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.11 This 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). Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 45 ? ARKAT USA, Inc Results and Discussion It was found that 7 reacts with 8 to produce the 9-BBN-derived oxazaborolidines 9 (eq. 1). This reaction occurs by the initial formation of B-(2-azidoalkoxy)-9- BBNs 10 (11 B NMR: δ 54.0, Scheme 2) producing H2 gas. This intermediate 10 equilibrates to the cyclic "ate" complex 11 (11 B NMR: δ 7.0), which decomposes to insert the nitrogen moiety into the ring B-C bond, forming 9 (11 B NMR: δ 32.0) with nitrogen gas evolution. 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.13 The second involves a methodology developed by Sharpless where a cyclic sulfate ring is opened by the reaction with sodium azide.14 These cyclic sulfates were available from their corresponding diols, which are either commercially available or were prepared through the asymmetric dihydroxylation of the alkene with OsO4. Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 46 ? ARKAT USA, Inc Table 1. Oxazaborolidines 9 from 9-BBN-H 7 and β-azido alcohols 8 Entry R1 R2 R3 R4 Yielda (%) A H H H H 90 B H Ph H H 91 C H H H t-Bu 97 D Ph H Ph H 54 a Isolated yields 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 six- membered rings, an intermediate which would be expected to be too high in energy to be reached in this process.12 In 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. Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 47 ? ARKAT USA, Inc 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 BH3 complexes reduce prochiral ketones in modest to good enantioselectivities (60–82%).15 Evans 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]decane through an intramolecular azide insertion process.16 In 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.17 This process has been applied to the synthesis of the unnatural (R)-nicotine by the hydroboration-intramolecular azide insertion process.18 It 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 Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 48 ? ARKAT USA, Inc 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-10- borabicyclo[3.3.2]decane ring 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[3.3.2]decane 18 (11 B NMR: δ43.6), which was isolated in 64% yield by distillation under high vacuum. Intramolecular hydroboration with neat 18 at 200 °C led to the formation of 19 (11 B NMR: δ 47.0) in a 50 % overall yield from 17. The formation of 18 is supported by the presence of the vinylic proton (1 H NMR (300 MHz, CDCl3) δ 5.22 (dd , J = 1.4, 1.4 Hz, 1 H) and carbons (13 C NMR (75 MHz, CDCl3) δ 117.3 and 146.1). To further support the presence of the double bond, the N-nopyl azaborane 18 was allowed to react with BH3·SMe2 to form an ?-aminodiborane adduct 20 (eq. 2). These ?-aminodiboranes have been previously reported.19 Examples of B-substituted ?-aminodiboranes include ?- dimethylaminomethyldiborane20 and the 9-BBN-derived 1,1,2,2-bis(cyclooctane-1,5-diyl)-?- aminodiborane.21 Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 49 ? ARKAT USA, Inc A 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 BH3·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-BH3 complex (R)-B-Me-1·BH3. This delivers a hydride to the ketone carbon complexed to (R)-B-Me-1·BH3 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·BH3, 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 BH3·THF (1:1) was reproduced and reveals that 85% of (R)-B-Me-1·BH3 was formed in equilibrium by 11 B NMR analysis. Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 50 ? ARKAT USA, Inc Table 2. Asymmetric reduction of ketones with 9, 13b and 19 Heterocycle R Yielda (%) ee (%), Config.b 9b Et 64 (68)c 5 (12)c , Rd 9c Me 66 10, R 9d Me 78 15, R 13b Me 63 10,R 19 Me 69 19,Re 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. Values of K = 73 M–1 and ?G° = –2.53 kcal / 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 BH3 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 BH3 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.23 In addition, when propiophenone is added to either oxazaborolidines (R)-B-Me-1 or 9b, no oxazaborolidine-ketone complexed was observed to form by 11 B and 13 C NMR indicating the weak Lewis acidity of these oxazaborolidines. The Corey's oxazaborolidine-borane complex B-Me-1·BH3 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 Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 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. 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 BH3·THF as observed by 11 B NMR (eq. 5). From this, K = 3.3 M–1 and ?G° = –0.71 Kcal/ 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 CDCl3 or C6D6, unless otherwise used, and the chemical shifts were expressed in ppm relative to CDCl3 (7.26 and 77.0 ppm in 1 H and 13 C NMR, respectively) or C6D6 (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 mm I.D. 20% SE-30 vitreous silica open tubular columns. Optical rotation data were obtained using a Perkin-Elmer 243B Polarimeter. Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 52 ? ARKAT USA, Inc Elemental analyses were performed by Atlantic Microlabs, Norcross, Georgia. Preparation of azido alcohols 8 2-Azidoethanol 8a was prepared from 2-chloroethanol by the reaction with NaN3.25 (S)-(+)-2- azido-2-phenylethanol 8b26 was prepared from (R)-(+)-styrene oxide through the ring opening reaction with NaN3/NH4Cl.13 (2R)-(+)-3,3-Dimethyl-1-azido-2-butanol 8c27 and (1R, 2S)-(+)-1,2- Diphenyl-2-azidoethanol 8d28 were prepared from (2R)-(–)-3,3-dimethylbutane-1,2-diol29 and (R,R)-(+)-hydrobenzoin,30 respectively, through the reaction of their corresponding cyclic sulfates with NaN3.14, 31 3-Oxa-6-aza-2-bora tricyclo[5.3.3.02,6 ]tridecane (9a). Into a 2-necked-round bottom flask equipped with a reflux condenser and containing 7 (1.83 g , 15.0 mmol) in hexane (15.0 mL) was added 8a (1.31 g, 15.0 mmol). The reaction mixture was stirred at reflux temperature. After 1 h, an aliquot was taken, and by 11 B NMR analysis indicated the presence of B-(2-azidoethoxy)-9- BBN intermediate 10 (11 B NMR δ 57.4, 40%), oxazaborolidine 9a (11 B NMR δ36.2 , 40%) and the β-azidoethoxy cyclic "ate" complex 11 (11 B NMR δ 7.0 , 20%). After 12 h, when the reaction was complete (monitored by 11 B NMR), the solvent was removed by vacuum and the residue was distilled to obtain 2.42 g (90 %, bp 104–105 °C / 0.65 Torr) of 9a. 1 H-NMR (300 MHz, CDCl3): δ 1.37–1.43 (m, 5 H), 1.47–1.65 (m, 4 H), 3.20 (broad m, 1 H), 3.25 (t, J= 7.8 Hz, 2 H), 4.17 (t, J= 7.5 Hz, 2 H); 13 C-NMR (75 MHz, CDCl3) δ 17.1 (C 1), 22.2 (C 9, C 12), 26.7 (C 10, C 11), 30.6 (C 8, C 13), 49.8 (C 5), 56.4 (C 7), 66.9 (C 4); 11 B-NMR (96 MHz, CDCl3): δ36.1 (87 %), 9.76 (dimeric 9a, 13%); MS: m/z (rel. abundance) 179 (M+ , 7), 178 (3), 150 (100), 136, (30), 122 (70), 67 (25), 54 (30). HRMS (EI) exact mass calc. for C10H18BNO 179.1481, found 179.1484. (5S)-(+)-Phenyl-3-oxa-6-aza-2-boratricyclo[5.3.3.02,6 ]tridecane (9b). Into a 2-necked-round bottom flask equipped with a reflux condenser and containing 7 (3.66 g , 30.0 mmol) in hexane (45.0 mL) was added 8b (4.89 g, 30.0 mmol). The reaction mixture was stirred at 25 °C for 2 h and then at reflux temperature for 72 h. The solvent was removed by vacuum and the residue was distilled to obtain 6.98 g (91%, bp 145 °C / 0.04 Torr) of 9b. [α]25 D +125° (c 1.7, n-C6H14). 1 H-NMR (300 MHz, C6D6): δ 1.24–1.64 (m, 7 H), 1.75–1.90 (m, 6 H), 2.90 (s, 1 H), 3.97 (dd, J= 7.8, 7.8 Hz, 1 H), 4.35 (dd, J= 7.8, 7.8 Hz, 1 H), 4.42 (dd, J= 7.8, 7.8 Hz, 1 H), 7.20 (m 5 H); 13 C-NMR (75 MHz, C6D6) δ 17.2 (C 1), 22.4 (C 12), 22.9 (C 9), 26.4 (C 11), 26.5 (C 10), 29.9 (C 13), 31.4 (C 8 ), 47.4 (C 7), 65.0 (C 5), 75.5 (C 4), 127.2, 127.4, 128.4, 142.5 (o, p, m, i of Ph ring) ; 11 B-NMR (96 MHz, CDCl3) δ 37.0 ; IR (TF) 2900, 1950, 1875, 1810, 1750, 1700 (overtone mono subst. Ph) 1600 cm–1 ; MS: m/z (rel. abundance) 255 (M+ , 46), 226 (100), 212 (25), 198 (25), 146 (11), 115 (5), 105 (6), 95 (6), 77 (5), 59 (6). HRMS (EI) exact mass calc. for C16H22BNO 255.1794, found 255.1777. (4R)-(+)-(1,1-Dimethylethyl)-3-oxa-6-aza-2-boratricyclo[5.3.3.02,6 ]tridecane (9c). Into a 2- necked-round bottom flask equipped with a reflux condenser containing 7 (0.34 g , 2.80 mmol) in hexane (3.0 mL) was added 8c (0.40 g, 2.80 mmol). The reaction mixture was stirred at reflux temperature for 18 h. The solvent was removed under vacuum and the residue was distilled to Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 53 ? ARKAT USA, Inc obtain 0.64 g (97%, bp 93 °C/0.1 Torr) of 9c. [α]25 D +7.7° (c 3.0, n-C6H14). 1 H-NMR (300 MHz, C6D6): δ 0.90 (s, 9 H), 1.30–1.51 (m, 5 H), 1.53–1.75 (m, 8 H), 2.89 (d, J = 8.4 Hz, 2 H), 2.94– 3.00 (m, 1 H), 4.05 (t, J= 8.4 Hz, 1 H); 13 CNMR (75 MHz, C6D6) δ18.0 (C 1), 23.1 (C 12), 23.2 (C 9), 27.1 (C 11), 27.1 (C 10), 30.4 (C 13), 31.7 (C 8), 50.2 (C 7), 25.1 ((CH3)3C) , 34.1 ((CH3)3C), 51.3 (C 5), 86.0 (C 4); 11 B-NMR (96 MHz, CDCl3) δ32.1. MS: m/z (rel. abundance) 235 (M+ , 17), 206 (100), 192 (17), 178 (54), 67 (11), 55 (19). HRMS (EI) exact mass calc. for C14H26BNO 235.2107, found 235.2081. (4R,5S)-(+)-Diphenyl-3-oxa-6-aza-2-boratricyclo[5.3.3.02,6 ]tridecane (9d). Into a 2-necked- round bottom flask equipped with a reflux condenser containing 7 (0.61 g , 5.0 mmol) in THF (10.0 mL) was added 8d (1.20 g, 5.0 mmol). The reaction mixture was stirred at reflux temperature for 72 h. The solvent was removed under vacuum and the residue was chromatographed trough silica (eluting with 10% ether in pentane). The elutant was concentrated to obtain 0.90 g (54%) of 9d. [α]25 D +121° (c 1.4, n-C6H14). 1 HNMR (300 MHz, C6D6): δ1.22 (s, 1 H), 1.39–1.69 (m, 5 H), 1.71–2.00 (m, 7 H), 3.02 (broad m, 1 H), 5.04 (d, J = 9.0 Hz, 1 H), 5.77 (d, J = 9.0 Hz, 1 H), 6.93–7.12 (m, 10 H); 13 C-NMR (75 MHz, C6D6) δ 18.5 (C 1), 22.7 (C 12), 23.0 (C 9), 26.1 (C 11), 26.8 (C 10), 29.9 (C 13), 31.7 (C 8), 47.9 (C 7), 69.7 (C 5), 84.2 (C 4), 126.4, 126.6, 126.8, 139.4 (o, m, p, i of Ph ring at C 4), 127.2, 127.5, 128.4, 138.8 (o, p, m, i of Ph ring at C 5); 11 BNMR (96 MHz, CDCl3) δ 37.1. HRMS (EI) exact mass calc. for C22H26BNO 331.2107, found 331.2099. 10-Oxa-7-aza-1-borabicyclo[5.3.0]decane (13a). Into a 2-necked round-bottomed flask equipped with a reflux condenser containing 1 (0.36 , 4.4 mmol) in hexane (10.0 mL) was added 8a (0.38 g, 4.4 mmol). The reaction mixture was allowed to be stirred at reflux temperature. After 1 h, an aliquot was taken for 11 B NMR analysis revealing the presence of a β- azidoalkoxyborane intermediate (14, δ54.6), "ate" complex 15 (δ 7.0) and the product oxazaborolidine 13a (δ32.6). The reaction mixture was stirred for 60 h at reflux temperature. The solvent was removed in vacuo and the residue was fractionally distilled to obtain 0.40 g (66%, bp 93 °C / 0.7 Torr) of 13a. 1 H NMR (300 MHz, CDCl3): δ 0.81–0.93 (m, 2 H), 1.19–1.29 (m, 2 H), 1.51 (broad s, 2 H), 1.64–1.65 (broad s, 2 H), 3.33 (t, J = 4.8 Hz, 2 H), 3.76 (t, J = 6.7 Hz, 2 H), 3.98 (t, J =9.0 Hz, 2 H); 13 C NMR (75 MHz, CDCl3) δ 14.0 (C 2), 22.8 (C 3), 31.4 (C 4), 32.0 (C 5), 52.1 (C 6), 61.3 (C 8), 67.2 (C 9); 11 B-NMR (96 MHz, CDCl3) δ 32.6. (10S)-Phenyl-10-oxa-7-aza-1-borabicyclo[5.3.0]decane (13b). Into a 2-necked round- bottomed flask equipped with a reflux condenser containing B-methoxy-borinane (1.12 g, 10.0 mmol) in monoglyme (10.0 mL) was added BH3·SMe2 (0.5 mL (10.0 M), 5.0 mmol). The resulting mixture was stirred at reflux temperature for 2 h. The reflux condenser was replaced with a short-path distillation apparatus and the reaction mixture was distilled under N2 until a distillation temperature of 85 °C was reached, indicating the distillation of pure monoglyme. The mixture was cooled down to 25 °C and fresh monoglyme (10.0 mL) was added. The distillation apparatus was exchanged for a reflux condenser and 8b (1.30 g, 8.0 mmol) was added. The reaction mixture was stirred for 72 h at reflux temperature. The solvent was removed in vacuo and the residue was fractionally distilled to obtain 0.92 g (54 %) of 13b. Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 54 ? ARKAT USA, Inc 1 H NMR (300 MHZ, CDCl3): δ0.80–1.00 (m, 1 H), 1.07–1.10 (m, 1 H), 1.18–1.24 (m, 1 H), 1.41–1.56 (m, 5 H), 2.55 (broad s, 2 H), 3.89 (dd, J = 6.6, 9.0 Hz, 1 H), 4.11 (dd, J = 6.6, 6.6 Hz, 1 H), 4.33 (dd, J = 9.0, 9.0 Hz, 1 H), 7.10 - 7.15 (m, 5 H); 13 C NMR (75 MHz, CDCl3) δ 12.5 (C 6), 25.0 (C 4), 31.1 (C 5), 31.4 (C 3), 45.8 (C 2), 67.5 (C 10), 74.8 (C 9), 127.2, 127.4, 128.9, 143.5 (o, p, m, i of Ph ring); 11 B-NMR (96 MHz, CDCl3) δ 32.5. (1R,5S)-(–)-2-(2-Azidoethyl)-7,7-dimethylbicyclo[3.1.1]hept-2-ene ((–)-Nopyl azide, (17)). Into a round bottom flask containing 16 (13.9, 83.6 mmol) and triethylamine (13.5 g, 133 mmol) in CH2Cl2 (400 mL) at 0 °C was added methanesulfonyl chloride (14.3 g, 124.8 mmol) dropwise. The reaction mixture was warmed to room temperature slowly and stirred overnight and transferred into a separatory funnel with ice water. The aqueous phase was separated and the organic phase was washed with ice water (5 X 200 mL). The organic phase was dried over magnesium sulfate, decanted and concentrated to give 19.5 g (96%) of the crude nopyl mesylate. 1 H-NMR (300 MHz, CDCl3) δ 0.79 (s, 3H), 1.11 (d, J= 8.6 Hz, 1 H), 1.24 (s, 3 H), 2.02–2.07 (m, 2 H), 2.18–2.20 (m, 1 H), 2.31–2.39 (m, 3 H), 2.95 (s, 3 H), 4.14 (td, J= 7.1, 1.1 Hz, 2 H), 5.56 (broad m, 1 H); 13 C-NMR (75 MHz, CDCl3) δ20.9 (C 8), 26.0 (C 9), 31.3 (C 6), 36.1 (CH2 CH2OMs), 37.1 (CH3SO3), 37.8 (C 7), 40.4 (C 5), 45.4 (C 1), 67.8 (CH2OMs), 1196 (C 3), 142.4 (C 2). Note!: This mesylate decomposes explosively upon heating, and was used without further purification for the next reaction. This nopyl mesylate (19.3 g, 79 mmol) in DMF (200 mL) was added to a 1 L 2-neck round-bottomed flask containing sodium azide (39.7 g, 611 mmol). The reaction slurry was stirred and heated to ~ 90 °C for 1 h (followed by GC). After the reaction was complete, the mixture was cooled to room temperature and pentane (500 mL) and water (200 mL) were added. The aqueous phase was separated and the organic phase was washed with water (5 X 200 mL). The organic phase was dried over magnesium sulfate, decanted and concentrated. This concentrate was flash chromatographed over silica gel (eluting with pentane), concentrated and distilled to give 13.3 g (88%, bp 70 °C / 0.25 Torr) of 17. [α]25 D –47° (c 14.7, CCl4). 1 H-NMR (300 MHz, CDCl3) δ 0.86 (s, 3 H), 1.16 (d, J= 8.6 Hz, 1 H), 1.28 (s ,3 H), 2.01 (td, J= 5.6, 1.4 Hz, 1 H), 2.07–2.11 (m, 1 H), 2.22–2.27 (m, 4 H), 2.37 (dt, J= 8.6, 5.7 Hz, 1 H), 3.25 (ddt, J= 16.4, 12.7, 7.1 Hz, 2 H), 5.32 (dd, J= 2.8, 1.4 Hz, 1 H); 13 C-NMR (75 MHz, CDCl3) δ21.1 (C 9), 26.2 (C 8), 31.3 (C 4), 31.6 (C 6), 35.9 (C 7), 38.0 (CH2CH2N3), 40.7 (C 5), 45.6 (C 1), 49.3 (CH2N3), 118.9 (C 3), 144.2 (C 2); IR(TF) 2090 cm–1 (-N3); MS m/z (rel. abundance) 162 (M+ -29, 6), 148 (20), 120 (34), 91 (100), 77 (12), 67 (23); Anal. calc. for C11H17N3 : C, 69.07; H, 8.96; found: C, 68.96; H, 9.03. (1R,5S)-2-(2-(9-Aza-10-borabicyclo[3.3.2]dec-9-yl)ethyl)-7,7-dimethylbicyclo[3.1.1]hept-2- ene (18). Into a round bottomed flask containing 7 (6.10 g, 50.0 mmol) in hexane (50 mL) at 0 °C was added 17 (9.55 g, 50.0 mmol). The reaction mixture was stirred at 0 °C for 1 h and warmed to 25 °C and stirred for 12 h at this temperature. Concentration and distillation under high vacuum gave 9.6 g (64 %, bp 160 °C / 0.1 Torr) of 18. 1 H-NMR (300 MHz, CDCl3): δ 0.83 (s, 3 H), 1.14 (d, J = 8.4 Hz, 1 H), 1.27 (s, 3 H), 1.36–1.48 (m, 4 H), 1.53–1.59 (br m, 4 H), 1.60–1.64 (m, 4 H), 1.70– 1.80 (m , 3 H), 2.02–2.13 (m, 4 H), 2.19–2.22 (m, 1 H), 2.33–2.36 (m, 1 H), 3.06–3.12 (m , 2 H), 3.24 (br m, 1 H), 5.22 (dd , J = 1.4, 1.4 Hz, 1 H); 13 C-NMR (75 MHz, Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 55 ? ARKAT USA, Inc CDCl3) δ22.0, 23.2, 26.6, 31.2, 57.3 (ABBD ring), 21.2 (C 8), 26.3 (C 9), 31.3 (C 4), 31.6 (C 6), 38.0 (C 7), 39.2 (C 10), 40.8 (C 5), 45.8 (C 1), 57.9 (C 11), 117.3 (C 3), 146.1 (C 2) ; 11 B-NMR (96 MHz, CDCl3) δ 43.5. (5S, 6R, 8R)-7,7-Dimethyl-2-aza-11-borapentacyclo[10.3.3.16,8 .02,11 .05,10 ]nonadecane (19). Into a round bottomed flask containing 7 (3.05 g, 12.5 mmol) in THF (25.0 mL) at 0 °C was added 17 (4.78 g, 50 mmol). The reaction mixture was stirred at 0 °C for 1 h and warmed up to 25 °C and stirred for 5 h at this temperature. The solvent was removed under vacuum and the residue was stirred at 200 °C for 12 h. Distillation of the residue under high vacuum gave 7.72 g (52 % , bp 145 °C at 0.2 Torr) of 19. 1 H-NMR (300 MHz, CDCl3): δ 0.69 (d, J = 11.8 Hz, 1 H), 1.15 (s, 3 H), 1.25 (s, 3 H), 1.39–1.53 (m, 8 H), 1.65–1.83 (m, 8 H), 2.00–2.02 (m, 4 H), 2.49 (ddd, J = 14.9, 6.2, 2.3 Hz, 1 H), 3.01– 3.02 (m, 1 H), 3.10 (dd, J = 8.6, 6.8 Hz, 2 H); 13 C-NMR (75 MHz, CDCl3) δ 20.8 (C 12), 22.9 (C 17), 23.3 (CH3- attached to C 7), 23.6 (C 17), 26.4 (C 18), 27.3 (C 10), 27.3 (C 13), 29.9 (C 16), 30.3 (CH3- attached to C 7), 30.6 (C 4), 30.8 (C 2), 35.7 (C 9), 38.9 (C 7), 40.0 (C 19), 43.5 (C 8), 44.4 (C 5), 48.5 (C 6), 53.5 (C 3), 58.5 (C 1) ; 11 B-NMR (96 MHz, CDCl3) δ 47.0; MS: m/z (rel. abundance) 285 (6), 256 (7), 214 (5), 200 (15), 150 (61), 120 (23), 82 (72), 67 (100). Reaction of 18 with BH3·SMe2: Into a round bottom flask containing BH3·SMe2 (0.5 mL (10 M), 5 mmol) in THF (5.0 mL) at 25 °C was added 18 (1.43 g, 5.0 mmol) in THF (5.0 mL). After 1 h, a sample was taken for 11 B NMR analysis suggesting the complete formation of a nitrogen- and hydrogen-bridged diboryl species (two doublets at –6.9 and –14.6 ppm). The mixture was stirred for 12 h and concentrated under vacuum. A sample was taken for 1 H, 13 C, 11 B NMR and IR analysis, which indicated the formation of diboryl adduct 20. 1 H-NMR (300 MHz, CDCl3): δ 0.77 (d, J = 9.2 Hz, 1 H), 1.00–1.10 (m, 2 H), 1.13 (s, 3 H), 1.15–1.22 (m, 4 H), 1.23 (s, 3 H), 1.30–1.40 (m, 1 H), 1.44–1.48 (m, 6 H), 1.61–1.84 (m, 8 H), 1.93–2.12 (m, 4 H), 2.15–2.30 (m, 1 H), 2.42–2.55 (m, 1 H), 2.98–3.02 (m, 1 H), 3.14–3.16 (m, 1 H); 13 C-NMR (75 MHz, CDCl3) δ 19.7, 23.3, 23.7, 27.3, 27.9, 31.2, 32.1, 59.0 (ABBD ring moiety), 22.8 (CH3- attached to C 7), 27.3 (C 3), 28.1 (C 4), 29.8 (CH3- attached to C 7), 30.4 (C 6), 38.5 (C 10), 39.6 (C 7), 42.6 (C 2), 43.5 (C 5), 46.1 (C 1), 54.0 (C 11); 11 B-NMR (96 MHz, CDCl3) δ –14.4 (d, 1 JB-H = 116 Hz, B attached to C 3), –6.9 (d, 1 JB-H = 106 Hz, ABBD B); IR (TF) 2500, 2440 (B-H stretch), 1605 (B-H-B and B-N-B stretch)cm–1 . Representative procedure for the asymmetric reduction of a prochiral ketone with BH3·THF and heterocycles 9, 13b and 19 Into a round bottomed flask containing BH3·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. 1 H- NMR (300 MHz, CDCl3) δ 1.49 (d, J= 6.3 Hz, 3 H), 2.21 (broad s, 1 H), 4.87 (q, J= 6.3 Hz, 1 Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 56 ? ARKAT USA, Inc H), 7.22–7.47 (m, 5 H); 13 C-NMR (75 MHz, CDCl3) δ 25.1 (C 2), 70.3 (C 1), 125.3, 127.4, 128.4, 145.8 (o, p, m, i of phenyl ring); IR (TF): 3340 cm-1 MS m/z (rel. abundance) 122 (M+ , 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. Representative procedure for the BH3 complexation experiments with (S)-Me-1, 9, 13 and 19 A NMR tube was charged with (S)-Me-1 (0.12 g, 0.43 mmol). Sodium borohydride-free BH3·THF (0.37 mL (1.22 M in THF), 0.45 mmol) was added and C6D6 was added to reach a volume of 0.6 mL (the resulting inital concentration of (S)-Me-CBS and BH3·THF is 0.72 M and 0.75 M, respectively). A 11 B NMR (96 MHZ, C6D6) was taken (coupled and decoupled) where the oxazaborolidine ring boron and the (S)-Me-CBS-BH3 complex (δ 36.3), BH3·THF (δ –0.3 (q, J= 103 Hz)) and 94 (δ –14.1 (broad q), BH3 group in (S)-Me-CBS-BH3 in a 85:15 ratio with respect of BH3·THF signal determined by integration) was observed. From the integration of the signals and the initial concentration [(S)-Me-1·BH3] = (0.85)(0.75 M) = 0.64 M, [(S)-Me-1] = 0.72 M – 0.64 M = 0.08 M, [BH3·THF] = (0.15)(0.75 M) = 0.11 M, Keq. = 73 M-1 and ?G°exp. = – 2.54 kcal/mol (calculated from ?G° = –RT lnK where T = 298 °K and R = 1.987 kcal/°K ·mol). Representative procedure for the reaction of propiophenone with (R)-Me-1 and 9b An NMR tube was charged with (R)-Me-1 (0.40 mL (1.0 M in toluene), 0.40 mmol) and C6D6 (0.3 mL). A 11 B NMR was taken to check the oxazaborolidine boron chemical shift (δ 34.5). Propiophenone (0.06 g, 0.4 mmol) was added and 11 B and 13 C NMR spectra were taken where no oxazaborolidine-ketone complex was observed to form. 11 B NMR (96 MHz, C6D6) δ 34.5 (oxazaborolidine B); 13 C NMR (75 MHz, C6D6) δ 199.1 (C=O of pure propiophenone). Acknowledgements The support of the NIH-MBRS (SO6-GM08102), NSF (CHE9817550) and a NIH Pre-doctoral Fellowship (5 F31 GM18030-02) to JR are gratefully acknowledged. Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 57 ? ARKAT USA, Inc References and Notes 1. This work is dedicated to Professor Alfred Hassner on the occasion of his 70th birthday. 2. Graduate student supported by the NIH Predoctoral Fellowship for Minority Students (5 F31 GM18030-02) and by the NIH-MBRS Program (SO6-GM08122)Reviews: (a) Wallbaum, S.; Martens, J. Tetrahedron: Asymmetry 1992, 3, 1475. (b) Deloux, L.; Srebnik, M. Chem. Rev. 1993, 93, 763. 3. (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986. (b) Corey, E. J. Pure Appl. Chem. 1990, 62, 1209. (d) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551. (e) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V.; K. J. Am. Chem. Soc. 1987, 109, 7925. (f) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53, 2861. 4. Corey, E. J.; Cimprich, K. A. J. Am. Chem. Soc. 1994, 116, 3151. 5. Joshi, N. N.; Srebnik, M.; Brown, H. C. Tetrahedron Lett. 1989, 30, 5551. 6. Brown, J. M.; Lloyd-Jones, G. C. Tetrahedron: Asymmetry 1990, 1, 869. 7. Corey, E. J.; Loh, T.-P. J. Am. Chem. Soc. 1991, 113, 8966. 8. Parmee, E. R.; Tempkin, O.; Masamune, S. J. Am. Chem. Soc. 1991, 113, 9365. 9. Jones, T. K.; Mohan, J. J.; Xavier, L. C.; Blacklock, T. J.; Mathre, D. J.; Sohar, P.; Jones, E. T. T.; Reamer, R. A.; Roberts, F. E.; Grabowski, E. J. J. J. Org. Chem. 1991, 56, 763. 10. Brown, H. C.; Midland, M. M.; Levy, A. B.; Suzuki, A.; Sono, S.; Itoh, M. Tetrahedron 1987, 43, 4079. 11. Soderquist, J. A.; Najafi, R. M. J. Org. Chem. 1986, 51, 1330. 12. Ramachandran, P. V.; Gong, B.; Brown, H. C. J. Org. Chem. 1995, 60, 41. 13. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483. 14. Midland, M. M.; Kazubski, A. J. Org. Chem. 1992, 57, 2953. 15. Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1987, 109, 7151. 16. (a) Jego, J. M.; Carboni, B.; Vaultier, M. Bull. Soc. Chim. Fr. 1992, 129, 554. (b) Carboni, B.; Vaultier, M. Bull. Soc. Chim. Fr. 1992, 129, 554. (c) Salmon, A.; Carboni, B. J. Organomet Chem. 1998, 567, 31. 17. Girard, S.; Robins, R. J.; Villiéras, J.; Lebreton, J. Tetrahedron Lett. 2000, 41, 9245. 18. Schlessinger, H. I.; Ritter, D. M.; Burg, A. B. J. Am. Chem. Soc. 1938, 60, 2297. 19. Dobson, J.; Schaeffer, R. Inorg. Chem. 1970, 9, 2183. 20. K?ster, R.; Seidel, G. Liebigs Ann. Chem. 1977, 1837. 21. Corey, E. J.; Azimiohara, M.; Sarshar, S. Tetrahedron Lett. 1992, 33, 3429. 22. (a) Soderquist, J. A.; Medina, J. R.; Huertas, R. Tetrahedron Lett. 1998, 39, 6119. (b) Soderquist, J. A.; Huertas, R.; Medina, J. R. Tetrahedron Lett. 1998, 39, 6123. (c) Brown, H. C.; Bhaskar Kanth, J. V.; Zaidlewicz, M. J. Org. Chem. 1998, 63, 5154. (d) Brown, H. C.; Zaidlewicz, M.; Dalvi, P. V. Organometallics 1998, 17, 4202. (e) Brown, H. C.; Kanth, J. V. B.; Zaidlewicz, M. Organometallics 1999, 18, 1310. (f) Brown, H. C.; Kanth, J. V. B.; Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 58 ? ARKAT USA, Inc Dalvi, P. V.; Zaidlewicz, M. J. Org. Chem. 1999, 64, 6263. (g) Brown, H. C.; Kanth, J. V. B.; Dalvi, P. V.; Zaidlewicz, M. J. Org. Chem. 2000, 65, 4655. 23. Brown, H. C.; Midland, M. M.; Levy, L. V.; Kramer, G. W. Organic Syntheses via Boranes; Wiley-Interscience: New York, 1975. 24. Forster, M. O.; Fierz, H.E. J. Chem. Soc. 1988, 93, 1865. 25. Sutowardoyo, K. I.; Emziane, M.; Lhoste, P.; Sinou, D. Tetrahedron 1991, 47, 1435. 26. Foelsche, E.; Hickel, A.; H?nig, H.; Seufer-Wasserthal, P. J. Org. Chem. 1990, 55, 1749. 27. Ittah, Y.; Sasson, Y.; Shahak, I.; Tsaroom, S.; Blum, J. J. Org. Chem. 1978, 43, 4271. 28. This diol was made in a 89% ee by the Sharpless Asymmetric Dihydroxylation procedure: Crispino, G. A.; Jeong, K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu, D.; Sharpless, K. B. J. Org. Chem. 1993, 58, 3785. 29. This diol was made in a >99.5% ee by the Sharpless Asymmetric Dihydroxylation procedure: Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L J. Org. Chem. 1992, 57, 2768. 30. Oi, R.; Sharpless, K. B. Tetrahedron Lett. 1991, 32, 9
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Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 43 ? ARKAT USA, Inc Oxazaborolidines from boracycles through the intramolecular azide insertion1 Jorge Ramos2 and John A. Soderquist* Department of Chemistry, University of Puerto Rico San Juan, PR 00931-3346 E-mail: jas@janice.uprr.pr Dedicated to Professor Hassner on the occasion of his 70th birthday (received 11 Jun 01; accepted 07 Oct 01; published on the web 15 Oct 01) Abstract 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[5.3.3.02,6 ]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. Keywords: Oxazaborolidines, 9-borabicyclo[3.3.1]nonane, azido alcohols, azidesorganoboranes, boron heterocycles Introduction In recent years, oxazaborolidines have proven to be useful chiral catalysts and reagents in for asymmetric transformations.3 Some 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 (R1 = CH3, R2 = H),5 the asymmetric addition of diethylzinc to aldehydes by 3 (R1 = CH3 or H, R2 =CH3),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 (R1 = H, R2 =CH3), 4–6) are prepared by the reaction of their corresponding β-amino alcohol Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 44 ? ARKAT USA, Inc or N-sulfonyl amino acid with BH3·L (L = THF or S(CH3)2). The B-alkyl and -aryl substituted oxazaborolidines (e.g. 1 ( R=CH3 or Bu), 3 (R1 = CH3, R2 = H)) are prepared by the reaction of the amino alcohol or amino acid with the corresponding boronic acid followed by the azeotropic removal of H2O. 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 N- oxide 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.11 This 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). Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 45 ? ARKAT USA, Inc Results and Discussion It was found that 7 reacts with 8 to produce the 9-BBN-derived oxazaborolidines 9 (eq. 1). This reaction occurs by the initial formation of B-(2-azidoalkoxy)-9- BBNs 10 (11 B NMR: δ 54.0, Scheme 2) producing H2 gas. This intermediate 10 equilibrates to the cyclic "ate" complex 11 (11 B NMR: δ 7.0), which decomposes to insert the nitrogen moiety into the ring B-C bond, forming 9 (11 B NMR: δ 32.0) with nitrogen gas evolution. 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.13 The second involves a methodology developed by Sharpless where a cyclic sulfate ring is opened by the reaction with sodium azide.14 These cyclic sulfates were available from their corresponding diols, which are either commercially available or were prepared through the asymmetric dihydroxylation of the alkene with OsO4. Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 46 ? ARKAT USA, Inc Table 1. Oxazaborolidines 9 from 9-BBN-H 7 and β-azido alcohols 8 Entry R1 R2 R3 R4 Yielda (%) A H H H H 90 B H Ph H H 91 C H H H t-Bu 97 D Ph H Ph H 54 a Isolated yields 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 six- membered rings, an intermediate which would be expected to be too high in energy to be reached in this process.12 In 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. Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 47 ? ARKAT USA, Inc 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 BH3 complexes reduce prochiral ketones in modest to good enantioselectivities (60–82%).15 Evans 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]decane through an intramolecular azide insertion process.16 In 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.17 This process has been applied to the synthesis of the unnatural (R)-nicotine by the hydroboration-intramolecular azide insertion process.18 It 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 Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 48 ? ARKAT USA, Inc 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-10- borabicyclo[3.3.2]decane ring 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[3.3.2]decane 18 (11 B NMR: δ43.6), which was isolated in 64% yield by distillation under high vacuum. Intramolecular hydroboration with neat 18 at 200 °C led to the formation of 19 (11 B NMR: δ 47.0) in a 50 % overall yield from 17. The formation of 18 is supported by the presence of the vinylic proton (1 H NMR (300 MHz, CDCl3) δ 5.22 (dd , J = 1.4, 1.4 Hz, 1 H) and carbons (13 C NMR (75 MHz, CDCl3) δ 117.3 and 146.1). To further support the presence of the double bond, the N-nopyl azaborane 18 was allowed to react with BH3·SMe2 to form an ?-aminodiborane adduct 20 (eq. 2). These ?-aminodiboranes have been previously reported.19 Examples of B-substituted ?-aminodiboranes include ?- dimethylaminomethyldiborane20 and the 9-BBN-derived 1,1,2,2-bis(cyclooctane-1,5-diyl)-?- aminodiborane.21 Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 49 ? ARKAT USA, Inc A 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 BH3·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-BH3 complex (R)-B-Me-1·BH3. This delivers a hydride to the ketone carbon complexed to (R)-B-Me-1·BH3 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·BH3, 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 BH3·THF (1:1) was reproduced and reveals that 85% of (R)-B-Me-1·BH3 was formed in equilibrium by 11 B NMR analysis. Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 50 ? ARKAT USA, Inc Table 2. Asymmetric reduction of ketones with 9, 13b and 19 Heterocycle R Yielda (%) ee (%), Config.b 9b Et 64 (68)c 5 (12)c , Rd 9c Me 66 10, R 9d Me 78 15, R 13b Me 63 10,R 19 Me 69 19,Re 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. Values of K = 73 M–1 and ?G° = –2.53 kcal / 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 BH3 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 BH3 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.23 In addition, when propiophenone is added to either oxazaborolidines (R)-B-Me-1 or 9b, no oxazaborolidine-ketone complexed was observed to form by 11 B and 13 C NMR indicating the weak Lewis acidity of these oxazaborolidines. The Corey's oxazaborolidine-borane complex B-Me-1·BH3 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 Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 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. 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 BH3·THF as observed by 11 B NMR (eq. 5). From this, K = 3.3 M–1 and ?G° = –0.71 Kcal/ 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 CDCl3 or C6D6, unless otherwise used, and the chemical shifts were expressed in ppm relative to CDCl3 (7.26 and 77.0 ppm in 1 H and 13 C NMR, respectively) or C6D6 (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 mm I.D. 20% SE-30 vitreous silica open tubular columns. Optical rotation data were obtained using a Perkin-Elmer 243B Polarimeter. Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 52 ? ARKAT USA, Inc Elemental analyses were performed by Atlantic Microlabs, Norcross, Georgia. Preparation of azido alcohols 8 2-Azidoethanol 8a was prepared from 2-chloroethanol by the reaction with NaN3.25 (S)-(+)-2- azido-2-phenylethanol 8b26 was prepared from (R)-(+)-styrene oxide through the ring opening reaction with NaN3/NH4Cl.13 (2R)-(+)-3,3-Dimethyl-1-azido-2-butanol 8c27 and (1R, 2S)-(+)-1,2- Diphenyl-2-azidoethanol 8d28 were prepared from (2R)-(–)-3,3-dimethylbutane-1,2-diol29 and (R,R)-(+)-hydrobenzoin,30 respectively, through the reaction of their corresponding cyclic sulfates with NaN3.14, 31 3-Oxa-6-aza-2-bora tricyclo[5.3.3.02,6 ]tridecane (9a). Into a 2-necked-round bottom flask equipped with a reflux condenser and containing 7 (1.83 g , 15.0 mmol) in hexane (15.0 mL) was added 8a (1.31 g, 15.0 mmol). The reaction mixture was stirred at reflux temperature. After 1 h, an aliquot was taken, and by 11 B NMR analysis indicated the presence of B-(2-azidoethoxy)-9- BBN intermediate 10 (11 B NMR δ 57.4, 40%), oxazaborolidine 9a (11 B NMR δ36.2 , 40%) and the β-azidoethoxy cyclic "ate" complex 11 (11 B NMR δ 7.0 , 20%). After 12 h, when the reaction was complete (monitored by 11 B NMR), the solvent was removed by vacuum and the residue was distilled to obtain 2.42 g (90 %, bp 104–105 °C / 0.65 Torr) of 9a. 1 H-NMR (300 MHz, CDCl3): δ 1.37–1.43 (m, 5 H), 1.47–1.65 (m, 4 H), 3.20 (broad m, 1 H), 3.25 (t, J= 7.8 Hz, 2 H), 4.17 (t, J= 7.5 Hz, 2 H); 13 C-NMR (75 MHz, CDCl3) δ 17.1 (C 1), 22.2 (C 9, C 12), 26.7 (C 10, C 11), 30.6 (C 8, C 13), 49.8 (C 5), 56.4 (C 7), 66.9 (C 4); 11 B-NMR (96 MHz, CDCl3): δ36.1 (87 %), 9.76 (dimeric 9a, 13%); MS: m/z (rel. abundance) 179 (M+ , 7), 178 (3), 150 (100), 136, (30), 122 (70), 67 (25), 54 (30). HRMS (EI) exact mass calc. for C10H18BNO 179.1481, found 179.1484. (5S)-(+)-Phenyl-3-oxa-6-aza-2-boratricyclo[5.3.3.02,6 ]tridecane (9b). Into a 2-necked-round bottom flask equipped with a reflux condenser and containing 7 (3.66 g , 30.0 mmol) in hexane (45.0 mL) was added 8b (4.89 g, 30.0 mmol). The reaction mixture was stirred at 25 °C for 2 h and then at reflux temperature for 72 h. The solvent was removed by vacuum and the residue was distilled to obtain 6.98 g (91%, bp 145 °C / 0.04 Torr) of 9b. [α]25 D +125° (c 1.7, n-C6H14). 1 H-NMR (300 MHz, C6D6): δ 1.24–1.64 (m, 7 H), 1.75–1.90 (m, 6 H), 2.90 (s, 1 H), 3.97 (dd, J= 7.8, 7.8 Hz, 1 H), 4.35 (dd, J= 7.8, 7.8 Hz, 1 H), 4.42 (dd, J= 7.8, 7.8 Hz, 1 H), 7.20 (m 5 H); 13 C-NMR (75 MHz, C6D6) δ 17.2 (C 1), 22.4 (C 12), 22.9 (C 9), 26.4 (C 11), 26.5 (C 10), 29.9 (C 13), 31.4 (C 8 ), 47.4 (C 7), 65.0 (C 5), 75.5 (C 4), 127.2, 127.4, 128.4, 142.5 (o, p, m, i of Ph ring) ; 11 B-NMR (96 MHz, CDCl3) δ 37.0 ; IR (TF) 2900, 1950, 1875, 1810, 1750, 1700 (overtone mono subst. Ph) 1600 cm–1 ; MS: m/z (rel. abundance) 255 (M+ , 46), 226 (100), 212 (25), 198 (25), 146 (11), 115 (5), 105 (6), 95 (6), 77 (5), 59 (6). HRMS (EI) exact mass calc. for C16H22BNO 255.1794, found 255.1777. (4R)-(+)-(1,1-Dimethylethyl)-3-oxa-6-aza-2-boratricyclo[5.3.3.02,6 ]tridecane (9c). Into a 2- necked-round bottom flask equipped with a reflux condenser containing 7 (0.34 g , 2.80 mmol) in hexane (3.0 mL) was added 8c (0.40 g, 2.80 mmol). The reaction mixture was stirred at reflux temperature for 18 h. The solvent was removed under vacuum and the residue was distilled to Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 53 ? ARKAT USA, Inc obtain 0.64 g (97%, bp 93 °C/0.1 Torr) of 9c. [α]25 D +7.7° (c 3.0, n-C6H14). 1 H-NMR (300 MHz, C6D6): δ 0.90 (s, 9 H), 1.30–1.51 (m, 5 H), 1.53–1.75 (m, 8 H), 2.89 (d, J = 8.4 Hz, 2 H), 2.94– 3.00 (m, 1 H), 4.05 (t, J= 8.4 Hz, 1 H); 13 CNMR (75 MHz, C6D6) δ18.0 (C 1), 23.1 (C 12), 23.2 (C 9), 27.1 (C 11), 27.1 (C 10), 30.4 (C 13), 31.7 (C 8), 50.2 (C 7), 25.1 ((CH3)3C) , 34.1 ((CH3)3C), 51.3 (C 5), 86.0 (C 4); 11 B-NMR (96 MHz, CDCl3) δ32.1. MS: m/z (rel. abundance) 235 (M+ , 17), 206 (100), 192 (17), 178 (54), 67 (11), 55 (19). HRMS (EI) exact mass calc. for C14H26BNO 235.2107, found 235.2081. (4R,5S)-(+)-Diphenyl-3-oxa-6-aza-2-boratricyclo[5.3.3.02,6 ]tridecane (9d). Into a 2-necked- round bottom flask equipped with a reflux condenser containing 7 (0.61 g , 5.0 mmol) in THF (10.0 mL) was added 8d (1.20 g, 5.0 mmol). The reaction mixture was stirred at reflux temperature for 72 h. The solvent was removed under vacuum and the residue was chromatographed trough silica (eluting with 10% ether in pentane). The elutant was concentrated to obtain 0.90 g (54%) of 9d. [α]25 D +121° (c 1.4, n-C6H14). 1 HNMR (300 MHz, C6D6): δ1.22 (s, 1 H), 1.39–1.69 (m, 5 H), 1.71–2.00 (m, 7 H), 3.02 (broad m, 1 H), 5.04 (d, J = 9.0 Hz, 1 H), 5.77 (d, J = 9.0 Hz, 1 H), 6.93–7.12 (m, 10 H); 13 C-NMR (75 MHz, C6D6) δ 18.5 (C 1), 22.7 (C 12), 23.0 (C 9), 26.1 (C 11), 26.8 (C 10), 29.9 (C 13), 31.7 (C 8), 47.9 (C 7), 69.7 (C 5), 84.2 (C 4), 126.4, 126.6, 126.8, 139.4 (o, m, p, i of Ph ring at C 4), 127.2, 127.5, 128.4, 138.8 (o, p, m, i of Ph ring at C 5); 11 BNMR (96 MHz, CDCl3) δ 37.1. HRMS (EI) exact mass calc. for C22H26BNO 331.2107, found 331.2099. 10-Oxa-7-aza-1-borabicyclo[5.3.0]decane (13a). Into a 2-necked round-bottomed flask equipped with a reflux condenser containing 1 (0.36 , 4.4 mmol) in hexane (10.0 mL) was added 8a (0.38 g, 4.4 mmol). The reaction mixture was allowed to be stirred at reflux temperature. After 1 h, an aliquot was taken for 11 B NMR analysis revealing the presence of a β- azidoalkoxyborane intermediate (14, δ54.6), "ate" complex 15 (δ 7.0) and the product oxazaborolidine 13a (δ32.6). The reaction mixture was stirred for 60 h at reflux temperature. The solvent was removed in vacuo and the residue was fractionally distilled to obtain 0.40 g (66%, bp 93 °C / 0.7 Torr) of 13a. 1 H NMR (300 MHz, CDCl3): δ 0.81–0.93 (m, 2 H), 1.19–1.29 (m, 2 H), 1.51 (broad s, 2 H), 1.64–1.65 (broad s, 2 H), 3.33 (t, J = 4.8 Hz, 2 H), 3.76 (t, J = 6.7 Hz, 2 H), 3.98 (t, J =9.0 Hz, 2 H); 13 C NMR (75 MHz, CDCl3) δ 14.0 (C 2), 22.8 (C 3), 31.4 (C 4), 32.0 (C 5), 52.1 (C 6), 61.3 (C 8), 67.2 (C 9); 11 B-NMR (96 MHz, CDCl3) δ 32.6. (10S)-Phenyl-10-oxa-7-aza-1-borabicyclo[5.3.0]decane (13b). Into a 2-necked round- bottomed flask equipped with a reflux condenser containing B-methoxy-borinane (1.12 g, 10.0 mmol) in monoglyme (10.0 mL) was added BH3·SMe2 (0.5 mL (10.0 M), 5.0 mmol). The resulting mixture was stirred at reflux temperature for 2 h. The reflux condenser was replaced with a short-path distillation apparatus and the reaction mixture was distilled under N2 until a distillation temperature of 85 °C was reached, indicating the distillation of pure monoglyme. The mixture was cooled down to 25 °C and fresh monoglyme (10.0 mL) was added. The distillation apparatus was exchanged for a reflux condenser and 8b (1.30 g, 8.0 mmol) was added. The reaction mixture was stirred for 72 h at reflux temperature. The solvent was removed in vacuo and the residue was fractionally distilled to obtain 0.92 g (54 %) of 13b. Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 54 ? ARKAT USA, Inc 1 H NMR (300 MHZ, CDCl3): δ0.80–1.00 (m, 1 H), 1.07–1.10 (m, 1 H), 1.18–1.24 (m, 1 H), 1.41–1.56 (m, 5 H), 2.55 (broad s, 2 H), 3.89 (dd, J = 6.6, 9.0 Hz, 1 H), 4.11 (dd, J = 6.6, 6.6 Hz, 1 H), 4.33 (dd, J = 9.0, 9.0 Hz, 1 H), 7.10 - 7.15 (m, 5 H); 13 C NMR (75 MHz, CDCl3) δ 12.5 (C 6), 25.0 (C 4), 31.1 (C 5), 31.4 (C 3), 45.8 (C 2), 67.5 (C 10), 74.8 (C 9), 127.2, 127.4, 128.9, 143.5 (o, p, m, i of Ph ring); 11 B-NMR (96 MHz, CDCl3) δ 32.5. (1R,5S)-(–)-2-(2-Azidoethyl)-7,7-dimethylbicyclo[3.1.1]hept-2-ene ((–)-Nopyl azide, (17)). Into a round bottom flask containing 16 (13.9, 83.6 mmol) and triethylamine (13.5 g, 133 mmol) in CH2Cl2 (400 mL) at 0 °C was added methanesulfonyl chloride (14.3 g, 124.8 mmol) dropwise. The reaction mixture was warmed to room temperature slowly and stirred overnight and transferred into a separatory funnel with ice water. The aqueous phase was separated and the organic phase was washed with ice water (5 X 200 mL). The organic phase was dried over magnesium sulfate, decanted and concentrated to give 19.5 g (96%) of the crude nopyl mesylate. 1 H-NMR (300 MHz, CDCl3) δ 0.79 (s, 3H), 1.11 (d, J= 8.6 Hz, 1 H), 1.24 (s, 3 H), 2.02–2.07 (m, 2 H), 2.18–2.20 (m, 1 H), 2.31–2.39 (m, 3 H), 2.95 (s, 3 H), 4.14 (td, J= 7.1, 1.1 Hz, 2 H), 5.56 (broad m, 1 H); 13 C-NMR (75 MHz, CDCl3) δ20.9 (C 8), 26.0 (C 9), 31.3 (C 6), 36.1 (CH2 CH2OMs), 37.1 (CH3SO3), 37.8 (C 7), 40.4 (C 5), 45.4 (C 1), 67.8 (CH2OMs), 1196 (C 3), 142.4 (C 2). Note!: This mesylate decomposes explosively upon heating, and was used without further purification for the next reaction. This nopyl mesylate (19.3 g, 79 mmol) in DMF (200 mL) was added to a 1 L 2-neck round-bottomed flask containing sodium azide (39.7 g, 611 mmol). The reaction slurry was stirred and heated to ~ 90 °C for 1 h (followed by GC). After the reaction was complete, the mixture was cooled to room temperature and pentane (500 mL) and water (200 mL) were added. The aqueous phase was separated and the organic phase was washed with water (5 X 200 mL). The organic phase was dried over magnesium sulfate, decanted and concentrated. This concentrate was flash chromatographed over silica gel (eluting with pentane), concentrated and distilled to give 13.3 g (88%, bp 70 °C / 0.25 Torr) of 17. [α]25 D –47° (c 14.7, CCl4). 1 H-NMR (300 MHz, CDCl3) δ 0.86 (s, 3 H), 1.16 (d, J= 8.6 Hz, 1 H), 1.28 (s ,3 H), 2.01 (td, J= 5.6, 1.4 Hz, 1 H), 2.07–2.11 (m, 1 H), 2.22–2.27 (m, 4 H), 2.37 (dt, J= 8.6, 5.7 Hz, 1 H), 3.25 (ddt, J= 16.4, 12.7, 7.1 Hz, 2 H), 5.32 (dd, J= 2.8, 1.4 Hz, 1 H); 13 C-NMR (75 MHz, CDCl3) δ21.1 (C 9), 26.2 (C 8), 31.3 (C 4), 31.6 (C 6), 35.9 (C 7), 38.0 (CH2CH2N3), 40.7 (C 5), 45.6 (C 1), 49.3 (CH2N3), 118.9 (C 3), 144.2 (C 2); IR(TF) 2090 cm–1 (-N3); MS m/z (rel. abundance) 162 (M+ -29, 6), 148 (20), 120 (34), 91 (100), 77 (12), 67 (23); Anal. calc. for C11H17N3 : C, 69.07; H, 8.96; found: C, 68.96; H, 9.03. (1R,5S)-2-(2-(9-Aza-10-borabicyclo[3.3.2]dec-9-yl)ethyl)-7,7-dimethylbicyclo[3.1.1]hept-2- ene (18). Into a round bottomed flask containing 7 (6.10 g, 50.0 mmol) in hexane (50 mL) at 0 °C was added 17 (9.55 g, 50.0 mmol). The reaction mixture was stirred at 0 °C for 1 h and warmed to 25 °C and stirred for 12 h at this temperature. Concentration and distillation under high vacuum gave 9.6 g (64 %, bp 160 °C / 0.1 Torr) of 18. 1 H-NMR (300 MHz, CDCl3): δ 0.83 (s, 3 H), 1.14 (d, J = 8.4 Hz, 1 H), 1.27 (s, 3 H), 1.36–1.48 (m, 4 H), 1.53–1.59 (br m, 4 H), 1.60–1.64 (m, 4 H), 1.70– 1.80 (m , 3 H), 2.02–2.13 (m, 4 H), 2.19–2.22 (m, 1 H), 2.33–2.36 (m, 1 H), 3.06–3.12 (m , 2 H), 3.24 (br m, 1 H), 5.22 (dd , J = 1.4, 1.4 Hz, 1 H); 13 C-NMR (75 MHz, Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 55 ? ARKAT USA, Inc CDCl3) δ22.0, 23.2, 26.6, 31.2, 57.3 (ABBD ring), 21.2 (C 8), 26.3 (C 9), 31.3 (C 4), 31.6 (C 6), 38.0 (C 7), 39.2 (C 10), 40.8 (C 5), 45.8 (C 1), 57.9 (C 11), 117.3 (C 3), 146.1 (C 2) ; 11 B-NMR (96 MHz, CDCl3) δ 43.5. (5S, 6R, 8R)-7,7-Dimethyl-2-aza-11-borapentacyclo[10.3.3.16,8 .02,11 .05,10 ]nonadecane (19). Into a round bottomed flask containing 7 (3.05 g, 12.5 mmol) in THF (25.0 mL) at 0 °C was added 17 (4.78 g, 50 mmol). The reaction mixture was stirred at 0 °C for 1 h and warmed up to 25 °C and stirred for 5 h at this temperature. The solvent was removed under vacuum and the residue was stirred at 200 °C for 12 h. Distillation of the residue under high vacuum gave 7.72 g (52 % , bp 145 °C at 0.2 Torr) of 19. 1 H-NMR (300 MHz, CDCl3): δ 0.69 (d, J = 11.8 Hz, 1 H), 1.15 (s, 3 H), 1.25 (s, 3 H), 1.39–1.53 (m, 8 H), 1.65–1.83 (m, 8 H), 2.00–2.02 (m, 4 H), 2.49 (ddd, J = 14.9, 6.2, 2.3 Hz, 1 H), 3.01– 3.02 (m, 1 H), 3.10 (dd, J = 8.6, 6.8 Hz, 2 H); 13 C-NMR (75 MHz, CDCl3) δ 20.8 (C 12), 22.9 (C 17), 23.3 (CH3- attached to C 7), 23.6 (C 17), 26.4 (C 18), 27.3 (C 10), 27.3 (C 13), 29.9 (C 16), 30.3 (CH3- attached to C 7), 30.6 (C 4), 30.8 (C 2), 35.7 (C 9), 38.9 (C 7), 40.0 (C 19), 43.5 (C 8), 44.4 (C 5), 48.5 (C 6), 53.5 (C 3), 58.5 (C 1) ; 11 B-NMR (96 MHz, CDCl3) δ 47.0; MS: m/z (rel. abundance) 285 (6), 256 (7), 214 (5), 200 (15), 150 (61), 120 (23), 82 (72), 67 (100). Reaction of 18 with BH3·SMe2: Into a round bottom flask containing BH3·SMe2 (0.5 mL (10 M), 5 mmol) in THF (5.0 mL) at 25 °C was added 18 (1.43 g, 5.0 mmol) in THF (5.0 mL). After 1 h, a sample was taken for 11 B NMR analysis suggesting the complete formation of a nitrogen- and hydrogen-bridged diboryl species (two doublets at –6.9 and –14.6 ppm). The mixture was stirred for 12 h and concentrated under vacuum. A sample was taken for 1 H, 13 C, 11 B NMR and IR analysis, which indicated the formation of diboryl adduct 20. 1 H-NMR (300 MHz, CDCl3): δ 0.77 (d, J = 9.2 Hz, 1 H), 1.00–1.10 (m, 2 H), 1.13 (s, 3 H), 1.15–1.22 (m, 4 H), 1.23 (s, 3 H), 1.30–1.40 (m, 1 H), 1.44–1.48 (m, 6 H), 1.61–1.84 (m, 8 H), 1.93–2.12 (m, 4 H), 2.15–2.30 (m, 1 H), 2.42–2.55 (m, 1 H), 2.98–3.02 (m, 1 H), 3.14–3.16 (m, 1 H); 13 C-NMR (75 MHz, CDCl3) δ 19.7, 23.3, 23.7, 27.3, 27.9, 31.2, 32.1, 59.0 (ABBD ring moiety), 22.8 (CH3- attached to C 7), 27.3 (C 3), 28.1 (C 4), 29.8 (CH3- attached to C 7), 30.4 (C 6), 38.5 (C 10), 39.6 (C 7), 42.6 (C 2), 43.5 (C 5), 46.1 (C 1), 54.0 (C 11); 11 B-NMR (96 MHz, CDCl3) δ –14.4 (d, 1 JB-H = 116 Hz, B attached to C 3), –6.9 (d, 1 JB-H = 106 Hz, ABBD B); IR (TF) 2500, 2440 (B-H stretch), 1605 (B-H-B and B-N-B stretch)cm–1 . Representative procedure for the asymmetric reduction of a prochiral ketone with BH3·THF and heterocycles 9, 13b and 19 Into a round bottomed flask containing BH3·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. 1 H- NMR (300 MHz, CDCl3) δ 1.49 (d, J= 6.3 Hz, 3 H), 2.21 (broad s, 1 H), 4.87 (q, J= 6.3 Hz, 1 Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 56 ? ARKAT USA, Inc H), 7.22–7.47 (m, 5 H); 13 C-NMR (75 MHz, CDCl3) δ 25.1 (C 2), 70.3 (C 1), 125.3, 127.4, 128.4, 145.8 (o, p, m, i of phenyl ring); IR (TF): 3340 cm-1 MS m/z (rel. abundance) 122 (M+ , 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. Representative procedure for the BH3 complexation experiments with (S)-Me-1, 9, 13 and 19 A NMR tube was charged with (S)-Me-1 (0.12 g, 0.43 mmol). Sodium borohydride-free BH3·THF (0.37 mL (1.22 M in THF), 0.45 mmol) was added and C6D6 was added to reach a volume of 0.6 mL (the resulting inital concentration of (S)-Me-CBS and BH3·THF is 0.72 M and 0.75 M, respectively). A 11 B NMR (96 MHZ, C6D6) was taken (coupled and decoupled) where the oxazaborolidine ring boron and the (S)-Me-CBS-BH3 complex (δ 36.3), BH3·THF (δ –0.3 (q, J= 103 Hz)) and 94 (δ –14.1 (broad q), BH3 group in (S)-Me-CBS-BH3 in a 85:15 ratio with respect of BH3·THF signal determined by integration) was observed. From the integration of the signals and the initial concentration [(S)-Me-1·BH3] = (0.85)(0.75 M) = 0.64 M, [(S)-Me-1] = 0.72 M – 0.64 M = 0.08 M, [BH3·THF] = (0.15)(0.75 M) = 0.11 M, Keq. = 73 M-1 and ?G°exp. = – 2.54 kcal/mol (calculated from ?G° = –RT lnK where T = 298 °K and R = 1.987 kcal/°K ·mol). Representative procedure for the reaction of propiophenone with (R)-Me-1 and 9b An NMR tube was charged with (R)-Me-1 (0.40 mL (1.0 M in toluene), 0.40 mmol) and C6D6 (0.3 mL). A 11 B NMR was taken to check the oxazaborolidine boron chemical shift (δ 34.5). Propiophenone (0.06 g, 0.4 mmol) was added and 11 B and 13 C NMR spectra were taken where no oxazaborolidine-ketone complex was observed to form. 11 B NMR (96 MHz, C6D6) δ 34.5 (oxazaborolidine B); 13 C NMR (75 MHz, C6D6) δ 199.1 (C=O of pure propiophenone). Acknowledgements The support of the NIH-MBRS (SO6-GM08102), NSF (CHE9817550) and a NIH Pre-doctoral Fellowship (5 F31 GM18030-02) to JR are gratefully acknowledged. Issue in Honor of Prof. Alfred Hassner ARKIVOC 2001 (iv) 43-58 ISSN 1424-6376 Page 57 ? ARKAT USA, Inc References and Notes 1. This work is dedicated to Professor Alfred Hassner on the occasion of his 70th birthday. 2. 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