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Stereospecific synthesis of a twinned alanine ester† Cite this: Org. Biomol. Chem., 2013, 11, 8022
Jik Chin,*a,b Soon Ho Kwon,a,c Kimia Moozeh,a Soon Mog So,a,b Alan J. Lougha and B. Moon Kim*c
Received 2nd August 2013, Accepted 5th October 2013 DOI: 10.1039/c3ob41582a www.rsc.org/obc
Reaction between 1,2-bis(2-hydroxyphenyl)-ethylenediamine (hpen) and methyl pyruvate gives the diaza-Cope rearrangement product with good yield and excellent stereospecificity. The product containing two chiral quaternary carbon centers is characterized by high performance liquid chromatography and X-ray crystallography. DFT computation provides insight into why the diaza-Cope rearrangement takes place readily with methyl pyruvate but not with other ketones like acetone and substituted acetophenones.
Introduction About a decade ago, we showed that resonance assisted hydrogen bond directed diaza-Cope rearrangement can be used for stereospecific synthesis of a chiral vicinal diamine based on seminal work by Vögtle.1 Since then this method has been used to make a variety of chiral diamines2 including C2-symmetric aryl3 and alkyl4 substituted diamines as well as non-symmetrical chiral diamines.5 Wide ranging applications of this method have been reported including tuning of the reactivity and stereoselectivity of transition metal based catalysts (Ir(III),6 Ru(II),7 Rh(II),8 Ni(II),9 Pd(II)10) and organocatalysts11 as well as developing chiral auxiliary,12 sensors,13 molecular levers14 and microporous materials.15 In all of these rearrangement reactions, imine formation between hpen and aldehydes is a key reaction for making the chiral diamines. We a Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada. E-mail: [email protected]; Fax: +1 416 978 7113; Tel: +1 416 946 7335 b DiaminoPharm Inc., Toronto M2N 7B2, Canada. E-mail: [email protected]; Fax: +1 416 226 9565; Tel: +1 416 453 6778 c Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, Korea. E-mail: [email protected]; Fax: +82 2 872 7505; Tel: +82 2 880 6644 † Electronic supplementary information (ESI) available: General information, expermetal details, 1H NMR, 13C NMR spectra, of 1, 3, chiral HPLC spectra of 3; Calculation results of 2 to 9 and additional comments; Crystallographic data of 3 in ESI and CIF file. CCDC 953697. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ob41582a
8022 | Org. Biomol. Chem., 2013, 11, 8022–8025
Scheme 1
Stereospecific diaza-Cope rearrangement.
showed that mixed diimines formed between hpen and methyl pyruvate and aldehydes undergo diaza-Cope rearrangement.5a However, it has been a challenge to obtain diaza-Cope rearrangement from diimines formed exclusively from ketones. Here we report the first such example using methyl pyruvate as the ketone for the stereospecific synthesis of a twinned alanine ester with two quaternary chiral centers (Scheme 1). DFT computation provides interesting insights into the origin of stereospecificity as well as the rate and equilibrium constants for the facile rearrangement reaction. While other interesting methods have been developed for the synthesis of twinned alanine derivatives,16 stereospecific versions have not been reported.
Results and discussion In a typical experiment, (R,R)-hpen (0.5 g) was added to neat methyl pyruvate (2 mL, approx. 10 equiv.) and stirred for 14 h
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Fig. 2 Transition state of 4. Resonance assisted hydrogen bonds not shown for clarity. (A) Both carboxylate groups in equatorial position (4a). (B) One carboxylate group in equatorial position, and the other in axial position (4b). (C) Both carboxylate groups in axial position (4c).
Fig. 1
17
Crystal structure of chiral diimine 3.
at ambient temperature. The crude product (3) was purified by column chromatography and crystallized. 1H NMR of the crude product in CDCl3 shows that the diastereomeric purity of 3 is over 94%. The enantiopurity of 3 (>99% ee) is greater than its diastereopurity as determined by chiral HPLC analysis (ESI†) and also as expected from the computer modeling studies shown below. The crystal structure of 3 (Fig. 1) reveals that the two chiral centers are both R in configuration. Thus the diaza-Cope rearrangement with diimines formed from methyl pyruvate and hpen takes place stereospecifically as it does with diimines formed from aldehydes and hpen. Time dependent 1H NMR shows that the one pot reaction for the formation of 3 from hpen and methyl pyruvate proceeds by an initial formation of the imidazolidine intermediate (1) that can be isolated (ESI†). This five-membered ring forms cleanly within 2 h from the reaction of hpen and methyl pyruvate. The aminal carbon in the five-membered ring is not a stereogenic center due to the pseudo C2 symmetry of 1. Reaction of the imidazolidine ring with a second equivalent methyl pyruvate apparently gives the initial diimine (2) that rearranges to give 3. It is generally difficult to obtain diaza-Cope rearrangement of diimines formed between hpen and ketones as this will result in the formation of sterically hindered diimines with two quaternary carbons attached to each other. Furthermore, controlling the stereospecificity for the rearrangement is considerably more challenging with diimines formed with ketones than those formed with aldehydes. Interestingly, diimines formed from hpen and methyl pyruvate undergo diaza-Cope rearrangement smoothly and cleanly at ambient temperature with excellent stereospecificity. The diaza-Cope rearrangement of the diimine formed between hpen and methyl pyruvate is expected to go through a six-membered ring transition state 4a, 4b or 4c (Fig. 2). DFT computation (B3LYP at the 6-31G* level) shows that 4a is the most stable followed by 4b (ΔΔH‡ = 1.49 kcal mol−1) and 4c (ΔΔH‡ = 2.63 kcal mol−1). The most stable transition state (4a) with both carboxylate groups in equatorial positions leads to the formation of the product diimine with (R,R)
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configuration (3) as observed experimentally through X-ray crystallography (Fig. 1) and chiral HPLC analysis (ESI†). The second most stable transition state (4b) leads to the formation of the meso diimine product. The above transition state energy difference (1.49 kcal mol−1) translates to the formation of about 10% of the diimine in the meso form. Consistent with computation, 1H NMR of the crude rearrangement product indicates that about 3% of the rearranged diimine appears to be in the meso form. The least stable transition state (4c) with both carboxylate groups in axial positions leads to the formation of the diimine product with (S,S) configuration. DFT computation shows that the amount of the (S,S)-enantiomer formed from the least stable transition state (ΔΔH‡ = 2.63 kcal mol−1) would be less than 2%. Consistent with computation, we do not observe any of the (S,S)-enantiomer through chiral HPLC analysis. X-ray crystallography was used to determine the product configuration. The energies of the initial diimines leading to transition states 4a, 4b and 4c are provided in the ESI.† If the starting E and Z diimines are in rapid equilibrium, only the transition state energies determine the product distribution according to the Curtin–Hammett principle.18 We have not been able to synthesize the analogous diimines using hpen and acetone or acetophenone in place of methyl pyruvate. DFT computation provides some interesting insights into why methyl pyruvate is a particularly useful ketone for the rearrangement reaction. Rearrangement of 2 to 3 (Scheme 2) is a downhill reaction (ΔH = −6.61 kcal mol−1) with a relatively low energy barrier (ΔH‡ = 12.8 kcal mol−1). By comparison, rearrangement of the diimine formed between hpen and acetophenone (5a) to form the product diimine (6a) is an uphill reaction (ΔH = 5.09 kcal mol−1, Scheme 2). This thermodynamic barrier can be lowered with electron withdrawing substituents such as chloro (ΔH = 4.56 kcal mol−1, 5b), cyano (ΔH = 3.77 kcal mol−1, 5c) or nitro (ΔH = 3.52 kcal mol−1, 5d) groups. However, none of these reactions with substituted acetophenones are thermodynamically downhill reactions as the one with methyl pyruvate. While rearrangement of diimine formed between hpen and acetone (7) is thermodynamically favorable (ΔH = −4.20 kcal mol−1, Scheme 3), it has a relatively large energy barrier to form the product diimine (9). The energy barrier for the formation of 9 is about 8.68 kcal mol−1 greater than that for the
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with conjugated ketones like methyl pyruvate over alkyl ketones due to the greater steric crowding at the transition state in the latter case.
Acknowledgements This research was supported by the Natural Sciences and Engineering Research Council of Canada. B.M.K. thanks the Nano Material Development Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012M3A7B4049644).
Scheme 2 Comparison of the energy barrier following para-substituents on acetophenones.19
Scheme 3 Comparison of diimine formation from hpen with acetone/methyl pyruvate.19
rearrangement of the diimine formed with hpen and methyl pyruvate (2). The greater energy barrier translates to about 2 × 106-fold decrease in rate at room temperature. This slowing down of the rearrangement reaction may be due to the unfavorable steric effects of four sp3 hybridized carbon atoms (methyl groups) coming together at the transition state (see ESI†).
Conclusions A diamino diacid with two quaternary chiral centers has been synthesized with excellent stereospecificity under mild conditions by diaza-Cope rearrangement. This represents the first time that a ketone has been used exclusively for the rearrangement reaction. DFT computation shows that the rearrangement is thermodynamically more favorable with electron deficient ketones like methyl pyruvate over acetophenones. Furthermore, the rearrangement is kinetically more favorable
8024 | Org. Biomol. Chem., 2013, 11, 8022–8025
Notes and references 1 (a) F. Vögtle and E. Goldschmitt, Angew. Chem., Int. Ed. Engl., 1974, 13, 480–482; (b) H.-J. Kim, H. Kim, G. Alhakimi, E. J. Jeong, N. Thavarajah, L. Studnicki, A. Koprianiuk, A. J. Lough, J. Suh and J. Chin, J. Am. Chem. Soc., 2005, 127, 16370–16371. 2 (a) J. Chin, F. Mancin, N. Thavarajah, D. Lee, A. Lough and D. S. Chung, J. Am. Chem. Soc., 2003, 125, 15276–15277; (b) H. Kim, Y. Nguyen, A. J. Lough and J. Chin, Angew. Chem., Int. Ed., 2008, 47, 8678–8681; (c) H. Kim, S. M. So, J. Chin and B. M. Kim, Aldrichimica Acta, 2008, 41, 77–88; (d) D.-N. Lee, H. Kim, L. Mui, S.-W. Myung, J. Chin and H.-J. Kim, J. Org. Chem., 2009, 74, 3330–3334; (e) S. M. So, H. Kim, L. Mui and J. Chin, Eur. J. Org. Chem., 2012, 229– 241; (f ) S. M. So, L. Mui, H. Kim and J. Chin, Acc. Chem. Res., 2012, 45, 1345–1355. 3 (a) H. Kim, Y. Nguyen, C. P.-H. Yen, L. Chagal, A. J. Lough, B. M. Kim and J. Chin, J. Am. Chem. Soc., 2008, 130, 12184– 12191; (b) K. Kiss, T. Holczbauer, M. Czugler, P. Sohar, A. Bodor and A. Csampai, J. Organomet. Chem., 2012, 706–707, 46–51. 4 H. Kim, M. Staikova, A. J. Lough and J. Chin, Org. Lett., 2009, 11, 157–160. 5 (a) H. Kim and J. Chin, Org. Lett., 2009, 11, 5258–5260; (b) H.-J. Kim, W. Kim, A. J. Lough, B. M. Kim and J. Chin, J. Am. Chem. Soc., 2005, 127, 16776–16777; (c) S. H. Kwon, S. M. Lee, S. M. Byun, J. Chin and B. M. Kim, Org. Lett., 2012, 14, 3664–3667. 6 (a) O. Soltani, M. A. Ariger and E. M. Carreira, Org. Lett., 2009, 11, 4196–4198; (b) O. Soltani, M. A. Ariger, H. Vazquez-Villa and E. M. Carreira, Org. Lett., 2010, 12, 2893–2895. 7 (a) K. M. Steward, M. T. Corbett, C. G. Goodman and J. S. Johnson, J. Am. Chem. Soc., 2012, 134, 20197–20206; (b) K. M. Steward, E. C. Gentry and J. S. Johnson, J. Am. Chem. Soc., 2012, 134, 7329–7332. 8 Y. Tang, J. Xiang, L. Cun, Y. Wang, J. Zhu, J. Liao and J. Deng, Tetrahedron: Asymmetry, 2010, 21, 1900–1905. 9 Z. Lu, A. Wilsily and G. C. Fu, J. Am. Chem. Soc., 2011, 133, 8154–8157.
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Organic & Biomolecular Chemistry 10 C. A. Busacca and C. H. Senanayake, in Comprehensive Chirality, Editors-in-Chief E. M. Carreira and H. Yamamoto, Elsevier, Amsterdam, 2012, pp. 167–216. 11 H. Kim, C. Yen, P. Preston and J. Chin, Org. Lett., 2006, 8, 5239–5242. 12 T. Ai and G. Li, Bioorg. Med. Chem. Lett., 2009, 19, 3967–3969. 13 J. H. Lee, A. R. Jeong, I.-S. Shin, H.-J. Kim and J.-I. Hong, Org. Lett., 2010, 12, 764–767. 14 (a) M. J. Bojdys, M. E. Briggs, J. T. A. Jones, D. J. Adams, S. Y. Chong, M. Schmidtmann and A. I. Cooper, J. Am. Chem. Soc., 2011, 133, 16566–16571; (b) N. Giri, C. E. Davidson, G. Melaugh, M. G. Del Popolo, J. T. A. Jones, T. Hasell, A. I. Cooper, P. N. Horton, M. B. Hursthouse and S. L. James, Chem. Sci., 2012, 3, 2153–2157. 15 S. Akine, S. Hotate and T. Nabeshima, J. Am. Chem. Soc., 2011, 133, 13868–13871. 16 (a) K. K. Andersen, D. F. Gloster, D. D. Bray, M. Shoja and A. Kjær, J. Heterocycl. Chem., 1998, 35, 317–324; (b) O. Benson, G. Gaudiano, R. C. Haltiwanger and T. H. Koch, J. Org. Chem., 1988, 53, 3036–3045; (c) V. A. Burgess, C. J. Easton and M. P. Hay, J. Am. Chem. Soc., 1989, 111, 1047–1052; (d) D. Cież, Tetrahedron, 2007,
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Communication 63, 4510–4515; (e) D. Cież and J. Kalinowska-Tłuścik, Synthesis, 2012, 1736–1744; (f) D. Cież, J. KalinowskaTłuścik, S. Peyrat, E. P. Touko, B. Trzewik and K. Zwoliński, Synthesis, 2008, 3261–3266; (g) T. Nishio, J. Chem. Soc., Perkin Trans. 1, 1990, 565–570; (h) A. Sutherland and J. C. Vederas, Chem. Commun., 2002, 224–225. 17 Crystal structure of 3: C22H24N2O6, T = 147(2) K, monoclinic, P21, Z = 2, a = 6.9679(3) Å, b = 19.0540(9) Å, c = 7.6683(4) Å, a = 90°, b = 93.428(2)°, g = 90°, V = 1016.27(8) Å3, R1 = 0.0305, wR2 = 0.0761 for I > 2σ(I), GOF on F2 = 1.067. 18 (a) J. I. Seeman, Chem. Rev., 1983, 83, 83–134; (b) J. I. Seeman, J. Chem. Educ., 1986, 63, 42–48. 19 All calculations were carried out with Spartan’08 from Wavefunction Inc. DFT computation at the B3LYP/6-31G* level was used to calculate the optimized geometry and vibrational frequencies. A vibrational analysis was performed at each stationary point to confirm its identity as an energy minimum or a transition structure. The gas-phase enthalpy was calculated as ΔH298.15K = ΔZPVE + ΔΔH0→298.15K + ΔE0. Zero-point vibrational energy (ZPVE) and enthalpy change (ΔΔH0→298.15K) from 0 to 298.15 K at 1 atm were obtained from vibrational frequencies.
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Stereospecific synthesis of a twinned alanine ester† Cite this: Org. Biomol. Chem., 2013, 11, 8022
Jik Chin,*a,b Soon Ho Kwon,a,c Kimia Moozeh,a Soon Mog So,a,b Alan J. Lougha and B. Moon Kim*c
Received 2nd August 2013, Accepted 5th October 2013 DOI: 10.1039/c3ob41582a www.rsc.org/obc
Reaction between 1,2-bis(2-hydroxyphenyl)-ethylenediamine (hpen) and methyl pyruvate gives the diaza-Cope rearrangement product with good yield and excellent stereospecificity. The product containing two chiral quaternary carbon centers is characterized by high performance liquid chromatography and X-ray crystallography. DFT computation provides insight into why the diaza-Cope rearrangement takes place readily with methyl pyruvate but not with other ketones like acetone and substituted acetophenones.
Introduction About a decade ago, we showed that resonance assisted hydrogen bond directed diaza-Cope rearrangement can be used for stereospecific synthesis of a chiral vicinal diamine based on seminal work by Vögtle.1 Since then this method has been used to make a variety of chiral diamines2 including C2-symmetric aryl3 and alkyl4 substituted diamines as well as non-symmetrical chiral diamines.5 Wide ranging applications of this method have been reported including tuning of the reactivity and stereoselectivity of transition metal based catalysts (Ir(III),6 Ru(II),7 Rh(II),8 Ni(II),9 Pd(II)10) and organocatalysts11 as well as developing chiral auxiliary,12 sensors,13 molecular levers14 and microporous materials.15 In all of these rearrangement reactions, imine formation between hpen and aldehydes is a key reaction for making the chiral diamines. We a Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada. E-mail: [email protected]; Fax: +1 416 978 7113; Tel: +1 416 946 7335 b DiaminoPharm Inc., Toronto M2N 7B2, Canada. E-mail: [email protected]; Fax: +1 416 226 9565; Tel: +1 416 453 6778 c Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, Korea. E-mail: [email protected]; Fax: +82 2 872 7505; Tel: +82 2 880 6644 † Electronic supplementary information (ESI) available: General information, expermetal details, 1H NMR, 13C NMR spectra, of 1, 3, chiral HPLC spectra of 3; Calculation results of 2 to 9 and additional comments; Crystallographic data of 3 in ESI and CIF file. CCDC 953697. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ob41582a
8022 | Org. Biomol. Chem., 2013, 11, 8022–8025
Scheme 1
Stereospecific diaza-Cope rearrangement.
showed that mixed diimines formed between hpen and methyl pyruvate and aldehydes undergo diaza-Cope rearrangement.5a However, it has been a challenge to obtain diaza-Cope rearrangement from diimines formed exclusively from ketones. Here we report the first such example using methyl pyruvate as the ketone for the stereospecific synthesis of a twinned alanine ester with two quaternary chiral centers (Scheme 1). DFT computation provides interesting insights into the origin of stereospecificity as well as the rate and equilibrium constants for the facile rearrangement reaction. While other interesting methods have been developed for the synthesis of twinned alanine derivatives,16 stereospecific versions have not been reported.
Results and discussion In a typical experiment, (R,R)-hpen (0.5 g) was added to neat methyl pyruvate (2 mL, approx. 10 equiv.) and stirred for 14 h
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Fig. 2 Transition state of 4. Resonance assisted hydrogen bonds not shown for clarity. (A) Both carboxylate groups in equatorial position (4a). (B) One carboxylate group in equatorial position, and the other in axial position (4b). (C) Both carboxylate groups in axial position (4c).
Fig. 1
17
Crystal structure of chiral diimine 3.
at ambient temperature. The crude product (3) was purified by column chromatography and crystallized. 1H NMR of the crude product in CDCl3 shows that the diastereomeric purity of 3 is over 94%. The enantiopurity of 3 (>99% ee) is greater than its diastereopurity as determined by chiral HPLC analysis (ESI†) and also as expected from the computer modeling studies shown below. The crystal structure of 3 (Fig. 1) reveals that the two chiral centers are both R in configuration. Thus the diaza-Cope rearrangement with diimines formed from methyl pyruvate and hpen takes place stereospecifically as it does with diimines formed from aldehydes and hpen. Time dependent 1H NMR shows that the one pot reaction for the formation of 3 from hpen and methyl pyruvate proceeds by an initial formation of the imidazolidine intermediate (1) that can be isolated (ESI†). This five-membered ring forms cleanly within 2 h from the reaction of hpen and methyl pyruvate. The aminal carbon in the five-membered ring is not a stereogenic center due to the pseudo C2 symmetry of 1. Reaction of the imidazolidine ring with a second equivalent methyl pyruvate apparently gives the initial diimine (2) that rearranges to give 3. It is generally difficult to obtain diaza-Cope rearrangement of diimines formed between hpen and ketones as this will result in the formation of sterically hindered diimines with two quaternary carbons attached to each other. Furthermore, controlling the stereospecificity for the rearrangement is considerably more challenging with diimines formed with ketones than those formed with aldehydes. Interestingly, diimines formed from hpen and methyl pyruvate undergo diaza-Cope rearrangement smoothly and cleanly at ambient temperature with excellent stereospecificity. The diaza-Cope rearrangement of the diimine formed between hpen and methyl pyruvate is expected to go through a six-membered ring transition state 4a, 4b or 4c (Fig. 2). DFT computation (B3LYP at the 6-31G* level) shows that 4a is the most stable followed by 4b (ΔΔH‡ = 1.49 kcal mol−1) and 4c (ΔΔH‡ = 2.63 kcal mol−1). The most stable transition state (4a) with both carboxylate groups in equatorial positions leads to the formation of the product diimine with (R,R)
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configuration (3) as observed experimentally through X-ray crystallography (Fig. 1) and chiral HPLC analysis (ESI†). The second most stable transition state (4b) leads to the formation of the meso diimine product. The above transition state energy difference (1.49 kcal mol−1) translates to the formation of about 10% of the diimine in the meso form. Consistent with computation, 1H NMR of the crude rearrangement product indicates that about 3% of the rearranged diimine appears to be in the meso form. The least stable transition state (4c) with both carboxylate groups in axial positions leads to the formation of the diimine product with (S,S) configuration. DFT computation shows that the amount of the (S,S)-enantiomer formed from the least stable transition state (ΔΔH‡ = 2.63 kcal mol−1) would be less than 2%. Consistent with computation, we do not observe any of the (S,S)-enantiomer through chiral HPLC analysis. X-ray crystallography was used to determine the product configuration. The energies of the initial diimines leading to transition states 4a, 4b and 4c are provided in the ESI.† If the starting E and Z diimines are in rapid equilibrium, only the transition state energies determine the product distribution according to the Curtin–Hammett principle.18 We have not been able to synthesize the analogous diimines using hpen and acetone or acetophenone in place of methyl pyruvate. DFT computation provides some interesting insights into why methyl pyruvate is a particularly useful ketone for the rearrangement reaction. Rearrangement of 2 to 3 (Scheme 2) is a downhill reaction (ΔH = −6.61 kcal mol−1) with a relatively low energy barrier (ΔH‡ = 12.8 kcal mol−1). By comparison, rearrangement of the diimine formed between hpen and acetophenone (5a) to form the product diimine (6a) is an uphill reaction (ΔH = 5.09 kcal mol−1, Scheme 2). This thermodynamic barrier can be lowered with electron withdrawing substituents such as chloro (ΔH = 4.56 kcal mol−1, 5b), cyano (ΔH = 3.77 kcal mol−1, 5c) or nitro (ΔH = 3.52 kcal mol−1, 5d) groups. However, none of these reactions with substituted acetophenones are thermodynamically downhill reactions as the one with methyl pyruvate. While rearrangement of diimine formed between hpen and acetone (7) is thermodynamically favorable (ΔH = −4.20 kcal mol−1, Scheme 3), it has a relatively large energy barrier to form the product diimine (9). The energy barrier for the formation of 9 is about 8.68 kcal mol−1 greater than that for the
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with conjugated ketones like methyl pyruvate over alkyl ketones due to the greater steric crowding at the transition state in the latter case.
Acknowledgements This research was supported by the Natural Sciences and Engineering Research Council of Canada. B.M.K. thanks the Nano Material Development Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012M3A7B4049644).
Scheme 2 Comparison of the energy barrier following para-substituents on acetophenones.19
Scheme 3 Comparison of diimine formation from hpen with acetone/methyl pyruvate.19
rearrangement of the diimine formed with hpen and methyl pyruvate (2). The greater energy barrier translates to about 2 × 106-fold decrease in rate at room temperature. This slowing down of the rearrangement reaction may be due to the unfavorable steric effects of four sp3 hybridized carbon atoms (methyl groups) coming together at the transition state (see ESI†).
Conclusions A diamino diacid with two quaternary chiral centers has been synthesized with excellent stereospecificity under mild conditions by diaza-Cope rearrangement. This represents the first time that a ketone has been used exclusively for the rearrangement reaction. DFT computation shows that the rearrangement is thermodynamically more favorable with electron deficient ketones like methyl pyruvate over acetophenones. Furthermore, the rearrangement is kinetically more favorable
8024 | Org. Biomol. Chem., 2013, 11, 8022–8025
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Communication 63, 4510–4515; (e) D. Cież and J. Kalinowska-Tłuścik, Synthesis, 2012, 1736–1744; (f) D. Cież, J. KalinowskaTłuścik, S. Peyrat, E. P. Touko, B. Trzewik and K. Zwoliński, Synthesis, 2008, 3261–3266; (g) T. Nishio, J. Chem. Soc., Perkin Trans. 1, 1990, 565–570; (h) A. Sutherland and J. C. Vederas, Chem. Commun., 2002, 224–225. 17 Crystal structure of 3: C22H24N2O6, T = 147(2) K, monoclinic, P21, Z = 2, a = 6.9679(3) Å, b = 19.0540(9) Å, c = 7.6683(4) Å, a = 90°, b = 93.428(2)°, g = 90°, V = 1016.27(8) Å3, R1 = 0.0305, wR2 = 0.0761 for I > 2σ(I), GOF on F2 = 1.067. 18 (a) J. I. Seeman, Chem. Rev., 1983, 83, 83–134; (b) J. I. Seeman, J. Chem. Educ., 1986, 63, 42–48. 19 All calculations were carried out with Spartan’08 from Wavefunction Inc. DFT computation at the B3LYP/6-31G* level was used to calculate the optimized geometry and vibrational frequencies. A vibrational analysis was performed at each stationary point to confirm its identity as an energy minimum or a transition structure. The gas-phase enthalpy was calculated as ΔH298.15K = ΔZPVE + ΔΔH0→298.15K + ΔE0. Zero-point vibrational energy (ZPVE) and enthalpy change (ΔΔH0→298.15K) from 0 to 298.15 K at 1 atm were obtained from vibrational frequencies.
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