Resolution of Planar-Chiral Ferrocenylborane Lewis Acids: The Impact

Jun 2, 2009 - Reaction of 2 with 0.5 equiv of the (1S,2S)-derivative gave a ... methods for either their stereoselective preparation or separation by ...
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Organometallics 2009, 28, 4141–4149 DOI: 10.1021/om900303j

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Resolution of Planar-Chiral Ferrocenylborane Lewis Acids: The Impact of Steric Effects on the Stereoselective Binding of Ephedrine Derivatives :: Ramez Boshra, Krishnan Venkatasubbaiah, Ami Doshi, and Frieder Jakle* Department of Chemistry, Rutgers University Newark, 73 Warren Street, Newark, New Jersey 07102 Received April 21, 2009

Resolution of the planar-chiral bidentate Lewis acid Fc[B(Cl)Me][SnMe2Cl] (Fc = 1,2-ferrocenediyl) (1) by complexation with pseudoephedrine derivatives was studied. Compound 1 was first converted to the methoxy derivative Fc[B(OMe)Me][SnMe2Cl] (2) by treatment with Me3SiOMe. The latter was fully characterized by multinuclear NMR and single-crystal X-ray diffraction analysis, both of which suggest a significant interaction between the oxygen of the B(OMe)Me substituent and the neighboring tin center. Complexation with (1S,2S )-pseudoephedrine under release of MeOH proceeded smoothly at RT, but gave a 1:1 mixture of the Rp and Sp complexes, even when a deficiency of the pseudoephedrine was used. The complexes were separated by fractional crystallization and analyzed by multinuclear NMR, 2D NOESY, and X-ray crystallography. In contrast, with the sterically more demanding ligand N-methylpseudoephedrine (MPE) highly stereoselective complexation was achieved. Reaction of 2 with 0.5 equiv of the (1S,2S )-derivative gave a complex with Sp-2, leaving behind the uncomplexed isomer Rp-2, while treatment with 0.5 equiv of the (1R,2R)derivative furnished the isomeric complex of Rp-2 and uncomplexed Sp-2. The complex between (1S,2S )-MPE and Sp-2 was fully characterized, and the structure was examined by 2D NOESY and single-crystal X-ray analysis. In all cases the central chirality at boron was found to correlate with the chirality of the pseudoephedrine derivative; that is, with (1S,2S )-pseudoephedrine or (1S,2S )N-methylpseudoephedrine the SB isomer was formed, while (1R,2R)-pseudoephedrine led to RB chirality at boron. Finally, a sample of enantiomerically pure Rp-2 was reacted with (1S,2S )-MPE to answer the question why complexation is less favorable for this combination. Two species were detected in solution, corresponding to a mixture of the SB and RB isomers, which were found to be in fast equilibrium on the NMR time scale at RT. An X-ray diffraction analysis showed that in the solid state only the SB isomer was present. The crystal structure revealed a very unfavorable steric interaction between the NMe2 group and the free Cp ring of ferrocene, leading to major distortions in the structure. Introduction Chiral organoborane Lewis acids have been known for several decades.1 Since the early work on R-pinene derivatives by H. C. Brown,2 a variety of organoborane reagents and catalysts have been developed and commercialized.3

Among them are oxazaborolidines, introduced by E. J. Corey,4 which have been used as catalysts in a number of organic transformations,5 most notably in Diels-Alder reactions.6 More recently, Soderquist developed a highly versatile class of chiral borane reagents based on 10-R-9borabicyclo[3.3.2]decane (R = Me3Si, Ph).7,8 Arylboranes have garnered some recent interest due to their perceived enhanced stability. For instance, Hawkins introduced an interesting naphthylborane system that functions as a two-prong scaffold in asymmetric Diels-Alder reactions;9 the dienophile attacks at the boron center, while the naphthyl group provides a platform to which the dienophile is aligned.10 The related binaphthyl backbone has been

*Corresponding author. E-mail: [email protected]. (1) (a) Ishihara, K. Lewis Acids in Organic Synthesis, 1st ed.; WileyVCH: Weinheim, 2000; Vol. 1. (b) Nogradi, M. Stereoselective Synthesis: A Practical Approach, 2nd. ed.; Wiley-VCH: New York, 1994. (c) Midland, M. M. Chem. Rev. 1989, 89, 1553–1561. (2) (a) Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1961, 83, 486– 487. (b) Brown, H. C.; Ramachandran, P. V. Acc. Chem. Res. 1992, 25, 16–24. (c) Brown, H. C.; Ramachandran, P. V. J. Organomet. Chem. 1995, 500, 1–19. (3) Cho, B. T. Aldrichim. Acta 2002, 35, 3–14. (4) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551–5553. (5) (a) Deloux, L.; Srebnik, M. Chem. Rev. 1993, 93, 763–784. (b) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986– 2012. (c) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 5384– 5387. (d) Gnanadesikan, V.; Corey, E. J. Org. Lett. 2006, 8, 4943–4945. (6) (a) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650–1667. (b) Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 4800–4802.

(7) Soderquist, J. A. In Contemporary Boron Chemistry; Davidson, M., Hughes, A. K., Marder, T. B., Wade, K., Eds.; Royal Society of Chemistry: London, 2000. (8) (a) Burgos, C. H.; Canales, E.; Matos, K.; Soderquist, J. A. J. Am. Chem. Soc. 2005, 127, 8044–8049. (b) Canales, E.; Prasad, K. G.; Soderquist, J. A. J. Am. Chem. Soc. 2005, 127, 11572–11573. (9) Hawkins, J. M.; Loren, S. J. Am. Chem. Soc. 1991, 113, 7794– 7795. (10) (a) Hawkins, J. M.; Loren, S.; Nambu, M. J. Am. Chem. Soc. 1994, 116, 1657–1660. (b) Hawkins, J. M.; Nambu, M.; Loren, S. Org. Lett. 2003, 5, 4293–4295.

r 2009 American Chemical Society

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widely applied as a chiral scaffold, and especially binol is extensively used as a substituent for Lewis acid catalysts.11 More challenging is to attach the Lewis acid center directly to the binaphthyl backbone itself. Chiral borane-functionalized binaphthyl systems of this type have been used by Yamamoto12 and Piers13 as catalysts for Diels-Alder reactions and in the allylstannation of aldehydes, respectively. Owing to its rigid structure, ferrocene is known to provide an excellent environment for chiral synthesis. Hence, heteronuclear substituted ferrocenes, with their inherent planar and possible central chirality, have been widely used in stereoselective synthesis. Most of the chiral ferrocenes reported thus far relate to the electron-donating phosphorus,14 sulfur,15 or oxazoline16 ligands commonly used in transition metal chemistry. In addition, N-heterocyclic systems designed by Fu et al.17 are touted for their high enantioselectivities in nucleophilic catalysis. Fu is also credited for the synthesis of the first planarchiral Lewis acid, a (η6-borabenzene)Cr(CO)3 complex, which was prepared as an enantiopure borabenzene-ligand adduct, A, but the free Lewis acid could not be isolated.18 Planar-chiral (η5-1,2-azaborolyl)iron Lewis acids such as B have since been prepared by the Fu group in their free acid form and used in stereoselective aldol reactions and imine additions.19 Chart 1

We have been pursuing the development of ferrocenebased Lewis acids.20-22 We conjectured that planar-chiral bidentate Lewis acids C should be promising candidates for chiral synthesis and have recently described their successful use in the stereoselective allylation of carbonyl (11) (a) Faller, J. W.; Sams, D. W. I.; Liu, X. J. Am. Chem. Soc. 1996, 118, 1217–1218. (b) Du, H.; Long, J.; Hu, J.; Li, X.; Ding, K. Org. Lett. 2002, 4, 4349–4352. (c) Zhou, Y.; Wang, R.; Xu, Z.; Yan, W.; Liu, L.; Kang, Y.; Han, Z. Org. Lett. 2004, 6, 4147–4149. (d) Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 13760– 13761. (e) Teo, Y. C.; Goh, J. D.; Loh, T. P. Org. Lett. 2005, 7, 2743– 2745. (12) Ishihara, K.; Inanaga, K.; Kondo, S.; Funahashi, M.; Yamamoto, H. Synlett 1998, 1053–1056. (13) Morrison, D. J.; Piers, W. E.; Parvez, M. Synlett 2004, 13, 2429– 2433. (14) Colacot, T. J. Chem. Rev. 2003, 103, 3101–3118. (15) Bonini, B. F.; Fochi, M.; Ricci, A. Synlett 2007, 3, 360–373. (16) Dai, L. X.; Tu, T.; You, S. L.; Deng, W. P.; Hou, X. L. Acc. Chem. Res. 2003, 36, 659–667. (17) (a) Ruble, J. C.; Fu, G. C. J. Org. Chem. 1996, 61, 7230–7231. (b) Fu, G. C. Acc. Chem. Res. 2000, 33, 412–420. (c) Fu, G. C. Acc. Chem. Res. 2006, 39, 853–860. (18) (a) Tweddell, J.; Hoic, D. A.; Fu, G. C. J. Org. Chem. 1997, 62, 8286–8287. (b) Fu, G. C. J. Org. Chem. 2004, 69, 3245–3249. (19) (a) Liu, S.-Y.; Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 15352–15353. (b) Liu, S.-Y.; Lo, M. M.-C.; Fu, G. C. Tetrahedron 2006, 62, 11343–11349. (20) Gamboa, J. A.; Sundararaman, A.; Kakalis, L.; Lough, A. J.; :: Jakle, F. Organometallics 2002, 21, 4169–4181. (21) (a) Boshra, R.; Sundararaman, A.; Zakharov, L. N.; Incarvito, :: C. D.; Rheingold, A. L.; Jakle, F. Chem.;Eur. J. 2005, 11, 2810–2824. (b) Boshra, R.; Venkatasubbaiah, K.; Doshi, A.; Lalancette, R. A.; :: Kakalis, L.; Jakle, F. Inorg. Chem. 2007, 46, 10174–10186. :: (22) Boshra, R.; Doshi, A.; Jakle, F. Angew. Chem., Int. Ed. 2008, 47, 1134–1137.

Boshra et al. Scheme 1. Synthesis of 2a

a

Only one enantiomer of the racemate is shown.

compounds.22 Of critical importance for the further development of ferrocene-based chiral Lewis acids is to find effective methods for either their stereoselective preparation or separation by chiral resolution. We describe here the highly efficient resolution of planar-chiral ferrocene-based bidentate Lewis acids of type C by stereoselective complexation with pseudoephedrine derivatives. We also provide detailed structural studies by X-ray crystallography and NOESY NMR that shed light on the origin of the observed high stereoselectivity of the complexation process.

Results and Discussion The synthesis of the heteronuclear bidentate Lewis acid Fc [B(Cl)Me][SnMe2Cl] (1) in its racemic form has been previously reported.20 We decided to pursue a straightforward and effective approach for the chiral resolution of organoboranes that was introduced by Masamune et al. and relies on the selective chelation of methoxyboranes with optically active amino alcohols.8,23 Thus, we first converted 1 to the methoxy derivative Fc[B(OMe)Me][SnMe2Cl] (2) by treatment with an excess of Me3SiOMe (Scheme 1). Compound 2 was isolated in 90% yield as an orange crystalline solid and characterized by multinuclear NMR, single-crystal X-ray diffraction, and elemental analysis. The 11B NMR of 2 shows a broad signal at 50.3 ppm, which is considerably upfield shifted compared to 1 (61.5 ppm), reflecting the increased π character of the B-O bond.24 Interestingly, the 119Sn NMR signal for 2 at 69.0 ppm is also upfield shifted relative to that of 1 (103.0 ppm)20 and the related monofunctional species Fc(SnMe2Cl) (130.0 ppm).25 This indicates that the oxygen of the B-OMe moiety interacts to a significant extent with the tin atom in solution, and the molecular structure of 2 shows further evidence of this intramolecular interaction in the solid state (Figure 1). As a result, the tin center adopts a distorted trigonal-bipyramidal geometry, with a Sn(1) 3 3 3 O(1) bond distance of 2.593(2) A˚, which is well within the sum of the van der Waals radii of tin and oxygen (3.69 A˚).26 The tin-oxygen (23) (a) Masamune, S.; Kim, B. M.; Petersen, J. S.; Sato, T.; Veenstra, S. J.; Imai, T. J. Am. Chem. Soc. 1985, 107, 4549–4551. (b) Short, R. P.; Masamune, S. J. Am. Chem. Soc. 1989, 111, 1892-1894. More recently, Soderquist has reported the use of pseudoephedrine derivatives for the resolution of B-methoxy-10-trimethylsilyl-9-borabicyclo[3.3.2]decane and related compounds: (c) Hernandez, E.; Burgos, C. H.; Alicea, E.; Soderquist, J. A. Org. Lett. 2006, 8, 4089–4091. (d) Canales, E.; Gonzalez, A. Z.; Soderquist, J. A. Angew. Chem., Int. Ed. 2007, 46, 397–399. (e) Gonzalez, A. Z.; Soderquist, J. A. Org. Lett. 2007, 9, 1081– 1084. (24) Elschenbroich, C.; Salzer, A. Organometallics, 3rd ed.; VCH: Weinheim, NY, 2006. (25) Kabouche, Z.; Nguyen Huu, D. J. Organomet. Chem. 1989, 375, 191–195. (26) Haiduc, I.; Edelmann, F. T. Supramolecular Organometallic Chemistry, 1st ed.; Wiley-VCH: Weinheim, 2000.

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Scheme 2. Reaction of 2 with (1S,2S)-(+)-Pseudoephedrinea

Figure 1. Molecular structure of 2 (ORTEP 50% probability). Hydrogens are omitted for clarity. Selected bond lengths (A˚) and angles (deg): B(1)-C(2) 1.545(5), B(1)-C(11) 1.570 (5), B(1)-O(1) 1.374(4), O(1)-B(1)-C(11) 122.4(3), O(1)-B (1)-C(2) 111.8(3), C(11)-B(1)-C(2) 125.8(3), Sn(1)-C(1) 2.111(3), Sn(1)-C(13) 2.127(3), Sn(1)-C(12) 2.127(3), Sn(1)Cl(1) 2.4425(8), Sn(1) 3 3 3 O(1) 2.593(2), C(1)-Sn(1)-C(12) 120.28(13), C(1)-Sn(1)-C(13) 118.24(12), C(12)-Sn(1)-C (13) 113.26(13), C(12)-Sn(1)-Cl(1) 100.02(9), C(1)-Sn(1)Cl(1) 99.01(9), C(13)-Sn(1)-Cl(1) 99.86(9), Cl(1)-Sn(1) 3 3 3 O (1) 171.69(5).

interaction is also reflected in an elongation of the Sn(1)-Cl (1) bond in the trans-position, which measures 2.4425(8) A˚ in 2 (cf. 2.4026(12) A˚ in 1), and an O(1) 3 3 3 Sn(1)-Cl(1) bond angle of 171.69(5)°, which is close to the 180° expected for an ideal trigonal-bipyramidal arrangement. Resolution of 2 with Pseudoephedrine (PE). Our initial attempts at resolving 2 by addition of 0.5 equiv of (1S,2S )(+)-pseudoephedrine (1S,2S-PE) in toluene resulted in a 1:1 mixture of the planar-chiral complexes Rp-(1S,2S )-3 and Sp(1S,2S )-3 together with unreacted racemic 2 (Scheme 2). Hence, we repeated the reaction with 1 equiv of (1S,2S )-PE and attempted the separation of the two isomers by fractional crystallization. The isomer Rp-(1S,2S )-3 was obtained by crystallization from a mixture of toluene and hexanes (3:1) at -38 °C in 47% yield relative to the isomer Rp-2, followed by isolation of the Sp-(1S,2S )-3 isomer from the supernatant solution in 32% yield relative to the isomer Sp-2. The identity of the chelate complexes Rp-(1S,2S )-3 and Sp(1S,2S )-3 was confirmed by elemental analysis, single-crystal X-ray diffraction, multinuclear NMR, and 2D-NOESY 1 H NMR spectroscopy. The 11B NMR shifts of 7.1 and 7.5 ppm are similar to each other and consistent with tetracoordination of the boron center as a result of intramolecular coordination of the amino group (NH-Me),8,27,28 while the 119 Sn NMR spectra show distinct sharp signals at 17.8 and 30.3 ppm for the Rp and Sp isomer, respectively. The substantial upfield shift of the Sn NMR signals relative to that of 2 (69.0 ppm) is indicative of an enhancement of the tin-oxygen interaction. It is worth mentioning that due to the central (boron) chirality present in the complexes in addition to the planar chirality, two possible diastereomers could theoretically form from each enantiomer of 2. However, variable-temperature 1H NMR in CDCl3 showed only one set of signals for each complex over the range from -50 to 60 °C. :: (27) Hopfl, H.; Farfan, N.; Castillo, D.; Santillan, R.; Contreras, R.; Martinez-Martinez, F. J.; Galvan, M.; Alvarez, R.; Fernandez, L.; Halut, S.; Daran, J.-C. J. Organomet. Chem. 1997, 544, 175–188. (28) Unlike other boron pseudoephedrine chelates, which commonly display two signals in the 11B NMR in solution (indicating the existence of both open and closed forms), Rp-(1S,2S )-3 and Sp-(1S,2S )-3 display only one signal for the coordinated species; see ref 8.

a

1 h, RT, -MeOH.

The molecular structures for Rp-(1S,2S )-3 and Sp(1S,2S )-3 confirm the formation of a B-N heterocycle as a result of the intramolecular coordination of the NH-Me group to boron (Figure 2).27 The five-membered ring comprised of B(1), O(1), C(15), C(13), and N(1) is strongly puckered, and the nitrogen atom is displaced from the average plane made by the other four atoms by 0.539 and 0.584 A˚ in Rp-(1S,2S )-3 and Sp-(1S,2S )-3, respectively. The heterocycle in Rp-(1S,2S )-3 is pointing in the direction of the free Cp ring, while in Sp-(1S,2S )-3 it occupies the less crowded space above the plane of the substituted Cp ring. Consequently, in Rp-(1S,2S )-3 the B-Me group is located above the Cp plane, while in Sp-(1S,2S )-3 it points downward (in the direction of the iron center). These different spatial arrangements result also in an increase in the Cp tilt angle from 2.9° in Sp-(1S,2S )-3 to 4.9° in Rp-(1S,2S )-3. Moreover, the B-N bond distance in Rp-(1S,2S )-3 of 1.623(4) A˚ is slightly shorter than the 1.652(3) A˚ measured for Sp-(1S,2S )-3, which correlates well with the tetrahedral character (% THCDA29) of 76.9% and 68.3% and hence suggests stronger ligand binding in the Rp-isomer. The Sn (1) 3 3 3 O(1) bond distances in Rp-(1S,2S )-3 and Sp-(1S,2S )-3 of 2.556(2) and 2.523(2) A˚, respectively, are considerably shorter than in the precursor 2 (2.593(2) A˚). This again suggests an enhanced Sn 3 3 3 O interaction in the pseudoephedrine chelates in comparison to 2 and is consistent with the upfield shift of the 119Sn NMR signals in solution. We performed 2D-NOESY 1H NMR experiments to verify the different conformations of the complexes in solution and, in particular, to determine whether the chirality at boron is retained. The position of the five-membered ring in Rp-(1S,2S )-3 below the plane of the substituted Cp is evident from a strong cross-peak between the N-H(1) proton and the free Cp ring. The exo position of the B-Me group (SB chirality) was confirmed by cross-peaks between B-Me and Cp-3H (adjacent Cp proton) and the absence of any crosspeaks with the free Cp ring (Figure 3). In contrast, the B-Me (29)PThe degree of tetrahedral character % THCDA is defined as [1 - ( n=1-6|109.5° - θn|/90°)]  100%, where θn=1-6 are the bond :: angles at the boron center. See: Hopfl, H. J. Organomet. Chem. 1999, 581, 129–149.

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Figure 2. Molecular structures of (left) Rp-(1S,2S)-3 and (right) Sp-(1S,2S)-3 (ORTEP 50% probability). Only hydrogens attached to stereogenic carbon and nitrogen atoms are shown.

Figure 3. Methyl/Cp region of the NOESY spectrum of (left) Rp-(1S,2S)-3 and (right) Sp-(1S,2S)-3 (CDCl3, 25 °C).

group in Sp-(1S,2S )-3 displays cross-peaks with the free Cp ring, confirming its endo position (SB chirality). Noteworthy is also the unusual downfield shift of the N-H proton in Rp-(1S,2S )-3 to 4.71 ppm (cf. 3.10 ppm for Sp-(1S,2S )-3). This is attributed to ring currents imposed by the free Cp ring, and therefore further supports the endo orientation. We conclude that the planar chirality of the ferrocene moiety influences the orientation of the pseudoephedrine moiety above or below the plane of the substituted Cp ring. Thus, the five-membered ring resulting from the chelation of (1S,2S )-PE is situated above the Cp plane for the Sp isomer and below for the Rp isomer (the opposite is true for (1R,2R)PE). However, the central chirality at boron is predetermined by the chirality of the pseudoephedrine moiety, as the B-Me group adopts the most favorable orientation in each isomer to accommodate the steric strain imposed by the particular orientation of the pseudoephedrine moiety. Hence, for both Sp-(1S,2S )-3 and Rp-(1S,2S )-3 an SB chirality is realized at boron (see Figure 2). Resolution of 2 with N-Methylpseudoephedrine (MPE). Although we were able to separate 2 into the individual planar-chiral enantiomers by complexation with pseudoephedrine and subsequent fractional crystallization, largescale preparation proved more challenging. Hence, we directed our efforts at the use of N-methylpseudoephedrine as an alternative chiral resolving agent.30 The room-temperature (30) Beak, P.; Anderson, D. R.; Curtis, M. D.; Laumer, J. M.; Pippel, D. J.; Weisenburger, G. A. Acc. Chem. Res. 2000, 33, 715–727.

reaction of 0.5 equiv of (1S,2S )-(+)-N-methylpseudoephedrine ((1S,2S )-MPE) with 2 in toluene was followed by 1H, 11 B, and 119Sn NMR. The 1H NMR spectrum of the reaction mixture in CDCl3 showed only two sets of signals in a 1:1 ratio with one set matching that of the starting material 2. The latter was extracted from the mixture with hexanes and identified by 1H NMR comparison with the starting material. The chelated product (not hexanes-soluble; second set of signals) was isolated in 71% yield (relative to the isomer Sp-2) and identified by multinuclear NMR, 2D-NOESY, X-ray diffraction, and elemental analysis as the isomer Sp-(1S,2S )4 (Scheme 3). A similar procedure using (1R,2R)-MPE gave the corresponding isomer Rp-(1R,2R)-4.31 The characteristics of the Sp-(1S,2S )-4 enantiomer are described in the following, and similar considerations apply to the Rp-isomer. The room-temperature 1H NMR of Sp(1S,2S )-4 revealed a pattern similar to that of Sp-(1S,2S )-3 with an additional signal at 1.93 ppm, which was assigned to the second diastereotopic N-methyl group (N-Me).32 The 11 B and 119Sn NMR display signals at 10.2 and 22.4 ppm, (31) For large-scale preparations we used a slight excess of (1R,2R)(-)-N-methylpseudoephedrine (0.55 equiv) to ensure the optical purity of Sp-2, which was isolated in 85% yield. The residual material can then be converted to Rp-(1S,2S )-4 (65% isolated yield) by simple addition of a slight excess of racemic 2. A similar procedure was used for the reaction of (1S,2S )-(+)-N-methylpseudoephedrine with racemic 2. Optically pure Rp-2 and Sp-(1S,2S )-4 were isolated in 84% and 75% yield, respectively. (32) Two signals for the diastereotopic N-methyl groups are observed as a result of the central chirality of the boron center.

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Scheme 3. Resolution of 2 by Complexation with N-Methylpseudoephedrine (MPE)a

Figure 4. Molecular structure of one of two independent molecules of Sp-(1S,2S)-4 (ORTEP 30% probability). Only hydrogens attached to stereogenic carbon atoms are shown, and a cocrystallized toluene solvent molecule is omitted for clarity. a

(i) (1S,2S)-MPE, -MeOH; (ii) (1R,2R)-MPE, -MeOH.

Chart 2

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respectively. The B NMR signal is slightly downfield shifted in comparison to Sp-(1S,2S )-3 (7.4 ppm), which indicates a weaker B-N interaction and is likely due to the increased steric demand of the NMe2 group.33 The 119Sn signal is upfield shifted by 7.9 ppm, which suggests a further enhanced Sn 3 3 3 O interaction. Suitable X-ray quality crystals were obtained from a concentrated toluene solution left at -38 °C for several days. Two independent molecules with structural parameters that are very similar to one another were found in the unit cell, and only one of them will be discussed in detail here (for a plot of the second molecule see Figure S1 in the Supporting Information). Figure 4 displays the molecular structure of the chelate, confirming its identity to be that of the isomer Sp-(1S,2S)-4.34 The molecular structure of Sp-(1S,2S)-4 is similar to that of Sp-(1S,2S)-3 shown in Figure 2. Noteworthy is the decrease in the Sn(1) 3 3 3 O(1) bond distance to 2.467(3) A˚ compared with 2.523(2) A˚ in Sp-(1S,2S)-3, which is accompanied by a lengthening of the Sn(1)-Cl(1) bond distance from 2.4641(6) A˚ in Sp-(1S,2S)-3 to 2.4903(12) in Sp-(1S,2S)-4.35 These differences are attributed to the electronic effect of the additional N-Me group of the MPE derivative, which ultimately leads to an enhanced Sn 3 3 3 O interaction. The solution conformation adopted by Sp-(1S,2S)-4 is similar to that in the solid state according to 1H 2D-NOESY measurements (cf. Figure S2, Supporting Information) The above results clearly show that (1S,2S )-MPE reacts preferentially with Sp-2, while (1R,2R)-MPE binds to the Rp2 isomer. To gain further insight into the origin of the excellent stereoselectivity observed and to determine what factors make the reaction between (1S,2S )-MPE and Rp-2 less favorable, we also carried out a reaction with a 1:1 molar ratio of (1S,2S )-MPE using a previously isolated sample of enantiomerically pure Rp-2 (the isomer that did not bind to (1S,2S )-MPE at the 0.5:1 molar ratio using racemic 2). Surprisingly, a mixture of two species (75:25) was obtained as determined by 1H NMR in CDCl3 at RT. Given that the :: (33) Hopfl, H. J. Organomet. Chem. 1999, 581, 129–149. (34) Rp-(1S,2S )-4a crystallizes with two independent molecules in the unit cell with similar geometrical parameters and two dichloromethane molecules in the crystal lattice. (35) This decrease in bond distance is also reflected in the 119Sn NMR chemical shift of 22.4 ppm for Sp-2-(1S,2S )-PE vs 30.3 ppm for Sp-1(1S,2S )-PE.

11

B NMR showed only one signal at 10.3 ppm, a similar shift to that found for Sp-(1S,2S )-4, these were thought to be different isomers of the chelate product between (1S,2S )MPE and Rp-2, Rp-(1S,2S )-4. Indeed, two signals in approximately 3:1 ratio at 60.1 and 10.5 ppm were found in the 119 Sn NMR spectrum. The considerable variation in chemical shift suggests very different conformations for the two isomers with a different extent of Sn 3 3 3 O interaction. We assign these isomers to be Rp-(1S,2S )-4a and Rp-(1S,2S )-4b (Chart 2), which exhibit different central chirality at boron and hence a different orientation of the B-N heterocycle with respect to the Cp ring. In the 1H NMR, the major isomer Rp-(1S,2S )-4a gives rise to two distinguishable diastereotopic N-Me signals (3.20, 2.64 ppm), while the minor isomer features only one broad signal at 2.3 ppm with an area integration corresponding to six protons. In comparison to Sp-(1S,2S )-4 the B-Me group in the major isomer is strongly upfield shifted to -0.04 ppm (cf. Figure S3, Supporting Information). This shift is most likely due to a γ-gauche conformation assumed by the NMe2 group with respect to the B-Me on the basis of prior studies :: by Hopfl et al. on pseudoephedrine complexes of diphenyl(2-aminoethoxy)boranes.27 To further explore the identity of these isomers, we carried out multinuclear low-temperature NMR as well as variabletemperature 1H 2D NOESY. Unlike the room-temperature 1H NMR spectrum, the low-temperature spectrum (CDCl3, -15 °C) shows two well-resolved N-Me signals for the minor isomer at 2.49 and 2.18 ppm. These two resonances coalesce at 5 °C (Figure 5), clearly indicating a dynamic process in solution.36 (36) Toyota, S.; Futawaka, T.; Asakura, M.; Ikeda, H.; Oki, M. Organometallics 1998, 17, 4155–4163.

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Figure 5. Variable-temperature (1S,2S)-4a/b.

1

H NMR spectra for Rp-

Figure 6. Methyl/Cp region of the NOESY spectrum of Rp(1S,2S)-4a/b (CDCl3, -20 °C).

The signals in the low-temperature 119Sn NMR spectrum (CDCl3, -15 °C) are slightly upfield shifted to 55.9 and 7.3 ppm. However, the 11B NMR spectrum remained virtually unchanged. The room-temperature NOESY spectrum in CDCl3 revealed fast exchange between both isomers, which made complete peak assignment unattainable (cf. Figure S4, Supporting Information). Fortunately, at -20 °C exchange was slow enough so that individual NOE peaks could be observed for the two isomers (Figure 6).37 The five-membered ring in the major isomer is situated below the plane of the substituted Cp ring, as evident from strong cross-peaks between the NMe2 group and the free Cp ring. Moreover, for the major isomer a strong cross-peak was found between the B-Me group and the adjacent Cp proton, while no cross-peak was found with the free Cp ring, indicating its position above the substituted Cp plane. On the other hand, the B-Me signal for the minor isomer shows a strong cross-peak with the free Cp ring, suggesting its downward position (in the direction of the iron center). Importantly, unlike the other pseudoephedrine and methylpseudoephedrine chelates, the downward orientation of the B-Me group (37) The N-Me signals (belonging to the same isomers) are found to be exchanging even at low temperatures.

Boshra et al.

Figure 7. Molecular structure of Rp-(1S,2S)-4a (ORTEP 50% probability). Only hydrogens attached to stereogenic carbon atoms are shown, and a cocrystallized CH2Cl2 solvent molecule is omitted for clarity.

results in a boron chirality that is opposite of that of the (1S,2S )-(+)-N-methylpseudoephedrine moiety, i.e., RB. We isolated Rp-(1S,2S )-4 as a homogeneous crystalline solid from a dichloromethane/hexanes mixture at -38 °C in 91% yield, indicating that only one isomer (the major isomer) is present in the solid state.38 An X-ray crystal structure analysis confirmed the formation of Rp-(1S,2S )4a (Figure 7, Table 1) with the five-membered ring in the endo position. Some peculiar features that distinguish this structure from the previously described pseudoephedrine compounds are worth noting. Most importantly, the boryl group in Rp-(1S,2S )-4a is strongly bent upward above the plane of the Cp ring, and the bent angle (180° - angle(CpCent-C(2)B(1)), measures 16.1° compared to only 5.5° for Rp-(1S,2S )3 (see Figure 2). This highly unusual geometry is accompanied by lengthening of the Cp-B bond distance to 1.613(4) A˚, as well as an increase in the Fe(1) 3 3 3 B(1) distance from 3.316 to 3.515 A˚. These structural distortions are brought about by an unfavorable interaction between the NMe2 group and the free Cp ring in Rp-(1S,2S )-4a. The latter is also reflected in an exceptionally large Cp/Cp tilt angle of 8.7° (cf. Rp-(1S,2S )-3, 4.8°). On the basis of all these observations we conclude that the unfavorable interaction of the NMe2 group with the free Cp ring in the isomer Rp(1S,2S )-4a is directly responsible for the excellent selectivity observed in the binding of (1S,2S )-MPE to Sp-2 rather than Rp-2. Finally, we further investigated the dynamic behavior observed for Rp-(1S,2S )-4a and Rp-(1S,2S )-4b by variabletemperature 1H NMR studies. At -20 °C the minor isomer Rp-(1S,2S )-4b constitutes ca. 17% of the total mixture. This amount increases to ca. 30% upon heating to 50 °C. Thermodynamic parameters calculated from van’t Hoff analysis (Figure 8) show that the isomerization process has a ΔH = 9.0 ( 1.0 kJ mol-1 and a very small entropy change of ΔS = 21 ( 4.0 J mol-1 K-1. The dissociation process of the NfB bond for the minor isomer Rp-(1S,2S )-4b was studied by standard line-shape analysis techniques.39 The free energy barrier (ΔGq ) calculated from the Eyring plot shown in Figure 9 is 56.5 ( 1.0 kJ mol-1. This value is similar to that calculated for (38) NMR studies show that isolated Rp-(1S,2S )-4a re-equilibrates to form a 75:25 mixture with Rp-(1S,2S )-4b in solution. (39) (a) Kaplan, J. I.; Fraenkel, G. NMR of Chemically Exchanging :: Systems; Academic Press: New York, 1980. (b) Sandstrom, J. Dynamic NMR Spectroscopy; Academic Press: New York, 1982; pp 77-92.

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Table 1. Selected Bond Lengths (A˚), Interatomic Distances (A˚), and Angles (deg) for Rp-(1S,2S)-3, Sp-(1S,2S)-3, Sp-(1S,2S)-4, and Rp-(1S,2S)-4a Rp-(1S,2S)-3

Sp-(1S,2S)-3

Sp-(1S,2S)-4

Rp-(1S,2S)-4a

Sn(1)-Cl(1) 2.4680(8) 2.4641(6) 2.4903(12) 2.4932(7) Sn(1)-C(1) 2.106(3) 2.109(2) 2.104(5) 2.103(3) Sn(1) 3 3 3 O(1) 2.556(2) 2.523(2) 2.467(3) 2.431(2) B(1)-C(2) 1.589(5) 1.601(3) 1.608(8) 1.613(4) B(1)-C(11) 1.613(5) 1.602(3) 1.615(7) 1.620(4) B(1)-O(1) 1.514(4) 1.523(3) 1.511(7) 1.511(4) B(1)-N(1) 1.623(4) 1.652(3) 1.676(6) 1.647(4) Fe(1) 3 3 3 B(1) 3.316 3.399 3.347 3.515 C(2)-B(1)-C(11) 115.1(3) 118.6(2) 114.8(4) 109.2(2) C(2)-B(1)-O(1) 108.1(3) 107.73(17) 107.6(4) 107.1(2) C(2)-B(1)-N(1) 109.2(3) 106.85(16) 111.3(4) 117.8(2) C(11)-B(1)-N(1) 111.9(3) 110.82(18) 110.4(4) 110.8(2) 5.6 (up) 8.0 (up) 4.8 (up) 16.1 (up) 180-CpCent-C(2)-B(1) a 5.0 (dn) 7.9 (dn) 7.4 (dn) 5.7 (dn) 180-CpCent-C(1)-Sn(1) a (C1-C5)//(C6-C10) 4.9 2.9 3.5 8.7 a The position of the boryl group relative to the Cp ring is indicated as “dn” for bending toward Fe and as “up” for bending away from Fe; CpCent refers to the centroid of the substituted Cp ring.

Figure 8. van’t Hoff plot for the equilibrium between Rp(1S,2S)-4a and Rp-(1S,2S)-4b.

diphenyl[N,N-dimethyl-(1-(R)-phenyl-2-(R)-methyl-2-ami:: nomethoxy)]borane (52.7 kJ mol-1) by Hopfl et al.27 and reflects the weak binding due to the sterically unfavorable interaction between the NMe2 group and the boron center/ free Cp ring in Rp-(1S,2S )-4b. No substantial broadening was observed for the N-Me signals for the major isomer Rp-(1S,2S )-4a in the temperature range studied.

Conclusions Chiral resolution of the ferrocene-based bidentate Lewis acid 1 was accomplished by selective chelation with the appropriate pseudoephedrine reagents. We found that pseudoephedrine does not give any stereoselectivity in the binding to planar-chiral 1. In contrast, N-methylpseudoephedrine gives excellent stereoselectivity with preferential formation of the Sp-(1S,2S)-4 and Rp-(1R,2R)-4 isomers. Ultimately, this process allows for separation of the enantiomers Rp-2 and Sp-2, which can be converted back to the enantiomerically pure planar-chiral Lewis acids Rp-1 and Sp-1 by simple treatment with PhBCl2.22 Both the free acid 1 and the complexes 4 are promising precursors for other chiral Lewis acids, and further work in this regard is currently in progress. An investigation into the origin of the observed high stereoselectivity of the complexation of N-methylpseudoephedrine (but not pseudoephedrine) revealed that the additional methyl group on nitrogen leads to highly unfavorable interactions with the free Cp ring of the ferrocene moiety in the isomer Rp-(1S,2S )-4. In this context it is also important to emphasize that complexation of Sp-2 with (1S,2S )pseudoephedrine or (1S,2S )-N-methylpseudoephedrine results exclusively in formation of the isomers with SB central

Figure 9. Eyring plot for the isomerization kinetics of Rp(1S,2S)-4b in CDCl3; the N-Me protons were used.

chirality at boron. Similarly, reaction of Rp-2 with (1S,2S )pseudoephedrine leads to the SB isomer, suggesting that the chirality at boron is determined by the chiral information of the pseudoephedrine reagent rather than the ferrocene moiety. However, for the unfavorable combination of enantiomerically pure Rp-2 and (1S,2S )-N-methylpseudoephedrine, both the RB and SB isomers are in thermal equilibrium in solution and the free energy difference of ΔG298 = 2.7 kJ mol-1 is very small at RT. The isomer Rp(1S,2S)-4a with SB chirality at boron selectively crystallizes from solution. Its structure is highly distorted, as evidenced by a tilt angle of 8.7° between the two Cp rings and a bending of the boryl group away from the iron center by a remarkable 16.1°. This clearly demonstrates the importance of the steric effect of the NMe2 group.

Experimental Section Materials and Instrumentation. (1S,2S )-(+)-Pseudoephedrine, (1R,2R)-(-)-pseudoephedrine, and (1S,2S )-(+)-Nmethylpseudoephedrine were purchased from Sigma Aldrich and used without any further purification. (1R,2R)-(-)-NMethylpseudoephedrine40 and Fc[B(Cl)Me][SnMe2Cl] (1)20,41 were prepared according to literature procedures. Deuterated solvents were obtained from Cambridge Isotope Laboratories. Hydrocarbon and chlorinated solvents were purified using a solvent purification system (Innovative Technologies; alumina/ copper columns for hydrocarbon solvents), and the chlorinated solvents were subsequently distilled from CaH2 and degassed via several freeze-pump-thaw cycles. All reactions and manipulations (40) Woodruff, E. H.; Lambooy, J. P.; Burt, W. E. J. Am. Chem. Soc. 1940, 62, 922–924. :: (41) Jakle, F.; Lough, A. J.; Manners, I. Chem. Commun. 1999, 453– 454.

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were carried out under an atmosphere of prepurified nitrogen using either Schlenk techniques or an inert-atmosphere glovebox (Innovative Technologies). All 499.9 MHz 1H NMR, 125.7 MHz 13C NMR, 186.4 MHz 119 Sn NMR, and 160.3 11B NMR spectra were recorded on a Varian INOVA NMR spectrometer (Varian Inc., Palo Alto, CA) equipped with a 5 mm dual broadband gradient probe (Nalorac, Varian Inc., Martinez, CA). Two-dimensional NMR spectra were acquired on the Varian INOVA NMR spectrometer. All solution 1H and 13C NMR spectra were referenced internally to the solvent signals. 119Sn and 11B NMR spectra were referenced externally to SnMe4 (δ = 0) and BF3 3 Et2O (δ = 0) in C6D6, respectively. Splittings of NMR signals are abbreviated as pst (pseudotriplet), dpst (doublet of pseudotriplet), and nr (not resolved). Two-dimensional 1H NOESY42 measurements were obtained with the standard pulse sequence that was followed by a 90° pulse flanked by two 5 G/cm gradients for dephasing any residual transverse magnetization and suppressing potential artifacts, before the relaxation delay. Mixing times of 600 ms (Sp-(1S,2S )-3, Rp-(1S,2S )-3), 500 ms (Sp-(1S,2S )-4, Rp-(1S,2S )-4 at RT) or 300 ms (Rp-(1S,2S )-4 at -20 °C) were applied. Spectra were recorded in the phasesensitive mode by employing the TPPI improvement43 of the States-Haberkorn-Ruben Hypercomplex method.44 Typically, 256 t1 increments of 2K complex data points over 5.0 kHz spectral widths were collected with 32 scans per t1 increment, preceded by 16 or 32 dummy scans, and a relaxation delay of 2 s. Data sets were processed on a Sun Blade 100 workstation (Sun Microsystems Inc., Palo Alto, CA) using the VNMR software package (Varian Inc., Palo Alto, CA). In order to decrease t1 ridges arising from incorrect treatment of the first data point in the discrete Fourier transform (FT) algorithm, the spectrum corresponding to the first t1 value was divided by 2 prior to FT along t1.45 Unshifted sine bell window functions were used in both dimensions. Data sets were zero-filled in the t1 dimension, yielding 1000  1000 final matrices. Optical rotation analysis was performed on an Autopol II polarimeter, Rudolph Research Analytical, using a tungstenhalogen light source operating at λ=589 nm. Elemental analyses were performed by Quantitative Technologies Inc., Whitehouse, NJ. Synthesis of 2. Neat Me3SiOMe (218 mg; 2.09 mmol) was added to a solution of 1 (100 mg; 0.233 mmol) in CH2Cl2 (2 mL) via syringe. The reaction mixture was stirred at 40 °C for 48 h. Light orange crystals were obtained from a 2:1 mixture of hexanes/CH2Cl2 after two days at -38 °C and dried under vacuum for several hours. Yield: 88.7 mg (0.209 mmol, 90%). 1 H NMR (500 MHz, CDCl3, 25 °C): δ 4.81 (dd, J=1.0 Hz, 2.5 Hz, 1 H, Cp-H5), 4.73 (pst, J = 2.5 Hz, 1 H, Cp-H4), 4.61 (dd, J = 1.0 Hz, 2.5 Hz, 1 H, Cp-H3), 4.16 (s, 5 H, C5H5), 3.76 (s, 3 H, O-Me), 0.89 (s/d, J(117/119 Sn, H) = 64/66 Hz, 3 H, Sn-Me), 0.70 (s, 3 H, B-Me), 0.64 (s/d, J(117/119Sn, H) = 61/63 Hz, 3 H, SnMe). 13C NMR (125.7 MHz, CDCl3, 25 °C): δ 79.2 (s/d, J(117/ 119 Sn, C) = 63 Hz, Cp-C5), 77.6 (s/d, J(117/119Sn, C) = 59 Hz, Cp-C3), 76.3 (s/d, J(117/119Sn, C) = 59 Hz, Cp-C4), 68.8 (C5H5), 53.6 (O-Me), 1.9 (s/d, J(117/119Sn, C) = 466/487 Hz, Sn-Me), 0.9 (s/d, J(117/119Sn, C)=422/442 Hz, Sn-Me), 0.1 (br, B-Me), not observed Cp-C1, Cp-C2. 119Sn NMR (186.4 MHz, CDCl3, 25 °C): δ 69.0. 11B NMR (160.3 MHz, CDCl3, 25 °C): δ 50.3

(42) (a) Jeener, J.; Meier, B. H.; Bachmann, P.; Ernst, R. R. J. Chem. :: Phys. 1979, 71, 4546–4553. (b) Muller, L. J. Am. Chem. Soc. 1979, 101, 4481–4484. (43) (a) Redfield, A. G.; Kunz, S. D. J. Magn. Reson. 1975, 19, 250– :: 254. (b) Marion, D.; Wuthrich, K. Biochem. Biophys. Res. Commun. 1983, 113, 967–974. (44) States, D. J.; Haberkorn, R. A.; Ruben, D. J. J. Magn. Reson. 1982, 48, 286–292. :: (45) Otting, G.; Widmer, H.; Wagner, G.; Wuthrich, K. J. Magn. Reson. 1986, 66, 187–193.

Boshra et al. (w1/2 = 350 Hz). Anal. Calcd for C14H20BClFeOSn (425.13): C, 39.55; H, 4.74. Found: C, 39.69; H, 4.59. Synthesis of Rp-(1S,2S )-3 and Sp-(1S,2S )-3. A solution of (1S,2S )-(+)-pseudoephedrine (24.6 mg, 0.148 mmol) in toluene (2 mL) was added dropwise to a stirred solution of 1-OMe (62 mg, 0.146 mmol) in toluene (2 mL). The reaction mixture was left to stir at RT for 1 h. The reaction mixture was concentrated to approximately half of the original volume, and hexanes (0.5 mL) were added to the remaining solution. The reaction mixture was left at -38 °C for one week to give light orange crystals. The pure isomers were obtained by repeated crystallization from a 3:1 mixture of toluene/hexanes. Yields: Rp-(1S,2S )-3 19 mg (34 μmol, 47% relative to the isomer Rp-2); Sp-(1S,2S )-3 13 mg (23.2 μmol, 32% relative to the isomer Sp-2). For Rp-(1S,2S )-3: 1H NMR (500 MHz, CDCl3, 25 °C): δ 7.35-7.43 (overlapping, 5 H, aromat.), 4.71 (overlapping, 1H, N-H), 4.71 (overlapping, 1 H, Cp-H5), 4.70 (d, J = 9.0 Hz, 1 H, CHPh), 4.50 (pst/dpst J = 2.0 Hz, J(117/119Sn, H) = 11 Hz, 1 H, Cp-H4), 4.17 (s, 5 H, C5H5), 4.15 (dd/ddd J = 1.2 Hz, 2.5 Hz, J(117/119Sn, H) = 12 Hz, Cp-H3), 3.07 (m, 1 H, CHMe), 2.72 (d, J = 6.0 Hz, 3 H, N-Me), 1.41 (d, J = 6.5 Hz, 3 H, CHMe), 0.68 (s/d, J(117/119Sn, H) = 64/66 Hz, 3 H, Sn-Me), 0.49 (s/d, J(117/119Sn, H) = 66/69 Hz, 3 H, Sn-Me), 0.01 (s, 3 H, B-Me). 13C NMR (125.7 MHz, CDCl3, 25 °C): δ 140.2 (ipso-Ph), 129.0 (ortho-Ph), 128.8 (para-Ph), 126.7 (meta-Ph), 96.0 (br, Cp-C2), 83.4 (CHPh), 80.3 (Cp-C1), 74.7 (s/d, J(117/119Sn, C) = 77 Hz, Cp-C5), 73.4 (s/d, J(117/119Sn, C) = 59 Hz, Cp-C3), 71.0 (s/d, J(117/119Sn, C) = 72 Hz, Cp-C4), 67.4 (C5H5), 65.4 (CHMe), 32.1 (N-Me), 13.7 (CHMe), 5.8 (br, B-Me), 3.5 (s/d, J(117/119Sn, C) = 472/494 Hz, Sn-Me), 2.14 (s/d, J(117/119Sn, C) = 486/509 Hz, Sn-Me). 119Sn NMR (186.4 MHz, CDCl3, 25 °C): δ 17.8. 11B NMR (160.3 MHz, CDCl3, 25 °C): δ 7.1 (w1/2 = 280 Hz). For Sp-(1S,2S )-3: 1H NMR (500 MHz, CDCl3, 25 °C): δ 7.34-7.75 (overlapping, 5 H, aromat.), 4.55 (dd/ddd, J = 1.0 Hz, 2.5 Hz, J(117/119Sn, H) = 11 Hz, 1 H, Cp-H5), 4.49 (d, J = 9.0 Hz, 1 H, CHPh), 4.48 (pst/dpst, J = 2.0 Hz, J(117/119Sn, H) = 11 Hz, 1 H, Cp-H4), 4.34 (dd/ddd, J = 1.0 Hz, 2.0 Hz, J(117/119Sn, H) = 13 Hz, Cp-H3), 4.24 (s, 5 H, C5H5), 3.10 (br, 1 H, N-H), 3.00 (m, 1 H, CHMe), 2.51 (d, J = 5.5 Hz, 3 H, N-Me), 1.27 (d, J = 6.0 Hz, 3 H, CHMe), 0.74 (s/d, J(117/119Sn, H) = 68.5/71.5 Hz, 3 H, Sn-Me), 0.57 (s/d, J(117/119Sn, H) = 58.5/60.5 Hz, 3 H, Sn-Me), 0.28 (s, 3 H, BMe). 13C NMR (125.7 MHz, CDCl3, 25 °C): δ 140.8 (ipso-Ph), 128.9 (ortho-Ph), 128.5 (para-Ph), 126.4 (meta-Ph), 93.8 (br, CpC2), 82.5 (CHPh), 75.1 (Cp-C1), 74.3 (s/d, J(117/119Sn, C) = 74 Hz, Cp-C5), 72.7 (s/d, J(117/119Sn, C) = 62 Hz, Cp-C4), 72.7 (s/d, J(117/119Sn, C) = 72 Hz, Cp-C3), 68.9 (C5H5), 64.8 (CHMe), 31.7 (N-Me), 14.2 (CHMe), 6.6 (br, B-Me), 4.7 (Sn-Me), 2.2 (SnMe). 119Sn NMR (186.4 MHz, CDCl3, 25 °C): δ 30.3. 11B NMR (160.3 MHz, CDCl3, 25 °C): δ 7.5 (w1/2 = 255 Hz). Anal. Calcd for Rp-(1S,2S )-3 C23H31BClFeNOSn (558.32): C, 49.48; H, 5.60; N, 2.51. Found: C, 49.21; H, 5.37; N, 2.48. Synthesis of Sp-(1S,2S )-4 and Rp-2. A solution of (1S,2S )(+)-N-methylpseudoephedrine (45 mg, 0.25 mmol) in toluene (2 mL) was added dropwise to a stirred solution of racemic 2 (200 mg, 0.47 mmol) in toluene (2 mL). The reaction mixture was left to stir at RT for 2 h followed by removal of all volatile components. The residue was extracted three times with 3 mL of hexanes each to isolate the unreacted starting material. The solvent was removed from the combined extracts under vacuum, and the residue was recrystallized from CH2Cl2/hexanes at -38 °C and dried under high vacuum. Yield for Rp-2: 84 mg (0.195 mmol; 84%). The NMR data for Rp-2 are identical to those of racemic 2. For Rp2 [R]D22 = +104.4 (c 0.38, CH2Cl2). The residue left behind after hexane extraction was redissolved in toluene (2 mL), a small amount of racemic 2 (10 mg) was added, and the mixture was stirred for 1 h at RT. Toluene was removed under vacuum, and the residue washed with hexanes (3  1 mL) and dried under high vacuum. Yield for Sp-(1S,2S)-4: 95 mg (0.166 mmol, 71% relative to the isomer Sp-2). For Sp-(1S,2S)-4: [R]D22=49.9 (c 0.54, CH2Cl2).

Article H NMR (500 MHz, CDCl3, 25 °C): δ 7.36-7.44 (overlapping, 5 H, aromat.), 4.59 (br, 1 H, Cp-H), 4.48 (overlapped, 1 H, Cp-H), 4.48 (d, J = 10 Hz, 1 H, CHPh), 4.27 (br, 1 H, Cp-H), 4.23 (s, 5 H, Cp), 3.34 (m, 1 H, CHMe), 2.44 (br, 3 H, N-Me), 1.93(br, 3 H, N-Me), 1.12 (d, J = 6.5 Hz, 3 H, CHMe), 0.63 (s/d, J(117/119Sn, H) = 69/72 Hz, 3 H, Sn-Me), 0.60 (s/d, J(117/119Sn, H) = 57/59 Hz, 3 H, Sn-Me), 0.45 (s, 3 H, B-Me). 13C NMR (125.7 MHz, CDCl3, 25 °C): δ 140.5 (ipso-Ph), 128.9 (orthoPh), 128.6 (para-Ph), 126.8 (meta-Ph), 92.5 (br, Cp-C2), 81.4 (CHPh), 74.8 (Cp-C1), 74.4 (s/d, J(117/119Sn, C) = 78 Hz, Cp-C5), 72.7 (s/d, J(117/119Sn, C) = 64 Hz, Cp-C3), 72.3 (s/d, J(117/119Sn, C) = 74 Hz, Cp-C4), 69.0 (C5H5), 68.3 (CHMe), 43.1 (N-Me), 39.4 (N-Me), 9.4 (br, B-Me), 8.7 (CHMe), 5.1 (s/d, J(117/119Sn, C) = 518/539 Hz, Sn-Me), 1.4 (s/d, J(117/119Sn, C)=394/ 416 Hz, Sn-Me). 119Sn NMR (186.4 MHz, CDCl3, 25 °C): δ 22.4. 11 B NMR (160.3 MHz, CDCl3, 25 °C): δ 10.2 (w1/2 = 360 Hz). Anal. Calcd for C24H34BClFeNOSn (572.34): C, 50.28; H, 5.98, N 2.44. Found: C, 50.67; H, 5.75, N 2.37. Synthesis of Rp-(1R,2R)-4 and Sp-2. A solution of (1R,2R)(-)-N-methylpseudoephedrine (45 mg, 0.25 mmol) in toluene (2 mL) was added dropwise to a stirred solution of racemic 2 (200 mg, 0.47 mmol) in toluene (2 mL). Using a similar procedure as for the preparation of Sp-(1R,2R)-4 and Rp-2, compounds Rp-(1R,2R)-4 and Sp-2 were obtained as a yellow powdery material and orange crystals, respectively. Yield for Rp-(1R,2R)-4: 91 mg (0.159 mmol, 68% relative to the isomer Rp-2). Yield for Sp-2 after recrystallization from CH2Cl2/hexanes at -38 °C: 85 mg (0.20 mmol, 85%). The NMR data for Rp-(1R,2R)-4 are identical to those of Sp-(1S,2S )-4, and the data for Sp-2 are identical to those of racemic 2. For Sp-2: [R]D22 = -100.6 (c 0.36, CH2Cl2); for Rp-(1R,2R)-4: [R]D22 = 49.4 (c 0.52, CH2Cl2). Synthesis of Rp-(1S,2S )-4. A solution of (1S,2S )-(+)-Nmethylpseudoephedrine (2.2 mg, 12.3 μmol) in 2 mL of toluene was added dropwise to a stirred solution of Rp-2 (5.0 mg, 11.5 μmol) in 2 mL of toluene. The reaction mixture was left to stir at RT for 30 min followed by removal of all volatile components. The residue was washed with 3  1 mL of hexanes, and the remaining solid material was crystallized from a mixture of dichloromethane/hexanes (2:1) at -38 °C. Yield: 6.0 mg (10.5 μmol; 91%). For Rp-(1S,2S )-4a: 1H NMR (500 MHz, CDCl3, 25 °C): δ 7.36-7.42 (overlapping, 5 H, aromat.), 4.69 (br, 1 H, Cp-H), 4.62 (d, J = 10 Hz, 1H, CHPh), 4.56 (pst, J = 2.0 Hz, 1 H, Cp-H), 4.11 (s, 5 H, C5H5), 3.97 (br, 1 H, Cp-H), 3.44 (m, 1 H, CHMe), 3.20 (br, 3 H, N-Me), 2.64 (br, 3 H, NMe), 1.14 (d, J = 7 Hz, 3 H, CHMe), 0.71 (s/d, J(117/119Sn, H) = 68 Hz, 3 H, Sn-Me), 0.33 (s/d, J(117/119Sn, H) = 67 Hz, 3 H, Sn-Me), -0.04 (s, 3 H, B-Me). 13C NMR (125.7 MHz, CDCl3, 25 °C): δ 139.6 (ipso-Ph), 128.9 (para-Ph), 128.8 (ortho-Ph), 127.6 (meta-Ph), 94.5 (br, Cp-C2), 81.2 (CHPh), 73.8 (Cp-C), 72.7 (Cp-C), 70.3 (Cp-C), 70.0 (CHMe), 69.2 (C5H5), 45.5 (N-Me), 42.6 (N-Me), 12.4 (br, B-Me), 8.0 (CHMe), 3.3 (Sn-Me), 2.6 (Sn-Me). 119Sn NMR (186.4 MHz, CDCl3, 25 °C): δ 10.5. For Rp-(1S,2S )-4b: 1H NMR (500 MHz, CDCl3, 25 °C): δ 7.36-7.42 (overlapping, 5 H, aromat.), 4.81 (d, J=9.0 Hz, 1 H, CHPh), 4.50 (br, 1 H, Cp-H), 4.44 (br, 1 H, Cp-H), 4.24 (br, 1 H, 1

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Cp-H), 4.17 (s, 5 H, C5H5), 3.15 (m, 1 H, CHMe), 2.33 (br, 6 H, N-Me), 1.28 (d, J = 6.5 Hz, 3 H, CHMe), 0.66 (s/d, J(117/119Sn, H) = 70 Hz, 3 H, Sn-Me), 0.37 (s, 3 H, B-Me), 0.23 (s/d, J(117/119Sn, H) = 59 Hz, 3 H, Sn-Me). 119Sn NMR (186.4 MHz, CDCl3, 25 °C): δ 60.1. For mixture: 11B NMR (160.3 MHz, CDCl3, 25 °C): δ 10.3 (w1/2 = 320 Hz). Crystal Structure Determinations. Crystals of 2 and Rp(1S,2S )-4a were grown from CH2Cl2/hexanes, and those of Rp-(1S,2S )-3, Sp-(1S,2S )-3, and Sp-(1S,2S )-4 from toluene/ hexanes at -38 °C. X-ray data were collected on a Bruker SMART APEX CCD diffractometer using Cu KR (1.54178 A˚) radiation. SADABS46 absorption correction was applied, and the structures were solved using direct methods, completed by subsequent difference Fourier syntheses, and refined by full matrix least-squares procedures on F2. Non-hydrogen atoms were refined with anisotropic displacement coefficients. The hydrogen atoms were placed at calculated positions and were refined as riding atoms. All software and source scattering factors are contained in the SHELXTL program package.47 Crystallographic data and details of X-ray diffraction experiments and crystal structure refinements are given in the Supporting Information. Crystallographic data for the structures of 2, Sp-(1S,2S )-3, Rp-(1S,2S )-3, Sp-(1S,2S )-4, and Rp(1S,2S )-4a have been deposited with the Cambridge Crystallographic Data Center as supplementary publication no. CCDC-669585, CCDC-676750, CCDC-676749, CCDC669586, and CCDC-676748, respectively. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax: (+44)1223-336033; e-mail: [email protected]).

Acknowledgment. We gratefully acknowledge support by the Petroleum Research Fund, administered by the American Chemical Society, and the National Science Foundation (NSF CRIF-0443538). F.J. thanks the Alfred P. Sloan Foundation for a research fellowship. We thank Prof. Lalancette for advice in regard to the X-ray structure determinations and Dr. Kakalis for help with 2D NMR data acquisition, Prof. Malhotra for providing access to a polarimeter, and Prof. Soderquist and his group for helpful discussions during the BORAM X meeting in San Juan, Puerto Rico. Supporting Information Available: Crystal data and structure refinement details for all crystal structures; ORTEP plot of the second molecule of Sp-(1S,2S)-4; NOESY spectrum of Sp(1S,2S)-4; 1H NMR spectrum for the 1:1 reaction of Rp-2 and (1S,2S )-MPE; room-temperature NOESY spectrum of Rp(1S,2S)-4a/b. This material is available free of charge via the Internet at http://pubs.acs.org. (46) Sheldrick, G. M. SADABS, Version 2, Multi-Scan Absorption :: Correction Program; University of Gottingen: Germany, 2001. (47) Sheldrick, G. SHELXTL, Version 6.14; Bruker AXS Inc.: Madison, WI, 2004.