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Article

Synthesis of cis- and trans-3-Aminocyclohexanols by Reduction of β-Enaminoketones

Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Cuernavaca, Mor., CP 62209, Mexico
*
Author to whom correspondence should be addressed.
Molecules 2012, 17(1), 151-162; https://doi.org/10.3390/molecules17010151
Submission received: 25 October 2011 / Revised: 21 December 2011 / Accepted: 22 December 2011 / Published: 27 December 2011
(This article belongs to the Section Organic Chemistry)

Abstract

:
We describe a protocol developed for the preparation of β-enaminoketones derived from 1,3-cyclohexanediones, and their subsequent reduction by sodium in THF-isopropyl alcohol to afford cis- and trans-3-aminocyclohexanols.

1. Introduction

Amino alcohols are of great interest because of their biological and structural importance. For example, acyclic 1,3-amino alcohols are key structural components of numerous natural products [1,2,3,4,5,6], potent drugs [7,8], and components of numerous medicinal compounds such as HIV-protease inhibitors [9], μ-opioid receptor antagonists [10], potent antibiotic negamycin [11,12,13], serotonin reuptake inhibitor, and antidepressants [14]. Additionally, 1,3-amino alcohols are useful chiral building blocks in asymmetric synthesis functioning as chiral ligands and auxiliaries [15,16,17,18,19,20,21,22,23]. Despite their prevalence and the importance of acyclic 1,3-amino alcohols [24,25,26,27], there are only a few synthetic methods reported in the literature to access to this important class of compounds [28,29,30,31], and even fewer reports exist regarding the synthesis of 1,3-aminocyclohexanols [32,33,34]. We wish to report herein our results on the reduction of β-enaminoketones, leading to the synthesis of both cis- and trans-3-aminocyclohexanols.

2. Results and Discussion

Our method starts with the condensation reaction of 4,4-dimethyl-1,3-cyclohexanedione with either benzylamine or (S)-α-methylbenzylamine in toluene at reflux, conditions that lead to the β-enaminoketones 1 and 2 in 85 and 87% yield, respectively (Scheme 1) [35,36]. Both products were fully characterized by NMR spectroscopy and the stereochemistry was corroborated by their X-ray crystal structure [37] (Figure 1).
Scheme 1. Preparation of β-enaminoketones 1 and 2.
Scheme 1. Preparation of β-enaminoketones 1 and 2.
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Figure 1. X-Ray structure of β-enaminoketone 2.
Figure 1. X-Ray structure of β-enaminoketone 2.
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In a subsequent step, the reduction of β-enaminoketones 1 and 2 was carried out following a procedure described in the literature [38,39,40,41,42,43,44,45]. Thus, the reaction of 1 and 2 with sodium in a mixture of THF/isopropyl alcohol at room temperature afforded the corresponding diasteromeric mixture of amino alcohols 3 and 4 in 77 and 75% yield, respectively (Scheme 2).
Scheme 2. Reduction of β-enaminoketones 1 and 2.
Scheme 2. Reduction of β-enaminoketones 1 and 2.
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A percolation of the reaction mixture followed by GC-MS analysis using a cyclosil-B chiral column revealed the presence of four major stereoisomers in identical ratio for compound 3 and two stereoisomers for compound 4 (cis and trans in 89:11 ratio). The diastereoisomeric separation of 3 was not attempted; however, column chromatography separation of 4 afforded the cis-4 and trans-4 in 69 and 6% yield, respectively.
Considering the X-ray structure of β-enaminoketone 2, a reasonable explanation of the high cis:trans diastereoselectivity in its reduction step can be explained assuming that the allyl anion A obtained by successive electron-transfers from the sodium to the conjugate system of enaminone, is the more stable conformation, because it avoids the interaction of C-10 or Ph with C2-H observed in conformation B. Thus, protonation with isopropyl alcohol of the corresponding allyl anion in the conformation A takes place selectively from the bottom-face, since the top-face is hindered by the methyl group (Figure 2).
Figure 2. Plausible explanation of the diastereoselectivity in the reduction of 2.
Figure 2. Plausible explanation of the diastereoselectivity in the reduction of 2.
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Additionally, structural elucidation for cis-4 and trans-4 was accomplished through 1H- and 13C-NMR, as well as 2D NMR spectra like COSY, HSQC and NOESY. Spectra data for cis-4 and trans-4 are shown in Table 1. In the 1H-NMR spectra of compound cis-4, protons H1 and H3 exhibit a triplet of triplets multiplicity, with coupling constants of 11.2, 4.8 Hz and 11.6, 4.0 Hz, respectively. Analysis of these coupling constants confirms the axial disposition of both protons establishing then an equatorial distribution of the OH and NHR groups. Additionally, proton H2b presents a quadruple signal (J = 11.6 Hz) which determines its axial position whereas H2a is occupies an equatorial position. The multiplicity of H4a (ddt) shows three couplings constants 2J = 12.8 Hz, 3Jec/ax = 3.6 Hz and 4JH4a/H6a = 2 Hz, this scalar coupling establishes that H1 and H3 occupy axial positions (Figure 3).
Table 1. 1H And13C-NMR chemical shifts for the compounds cis-4 and trans-4.
Table 1. 1H And13C-NMR chemical shifts for the compounds cis-4 and trans-4.
cis-4trans-4
Proton1H δ(ppm), J (Hz)Carbon13C δ (ppm)1H δ(ppm), J (Hz)13C δ (ppm)
H13.65 (tt, J = 11.2, 4.8, 1H)C166.83.64 (tt, J = 10.8, 4.4, 1H)67.1
H2a2.13 (m, Jgem = 11.6, 1H)C243.32.35 (dddd, J = 11.6, 5.6, 4.2, 1H)42.6
H2b1.07 (q, J = 11.6, 1H) 0.94 (bq, J = 10.2, 1H)
H32.53 (tt, J = 11.6, 4.0, 1H)C349.52.59 (tt, J = 11.6, 4.0, 1H)49.3
H4a1.70 (ddt, J = 12.8, 3.6, 2.0, 1H)C444.71.50 (m, 1H)46.5
H4b0.97 (t, J = 12.0, 1H)0.99 (t, J = 12.0, 1H)
H5- -C531.8- -31.7
H6a1.63 (ddt, J = 12.4, 4.0, 2.0, 1H)C648.11.63 (ddt, J = 12.4, 4.0, 2.0, 1H)48.4
H6b0.97 (t, J = 11.8, 1H) 1.04 (bq, J = 12.0, 1H)
H70.97 (s, 3H)C733.30.93 (s, 3H)33.2
H80.70 (s, 3H)C826.00.75 (s, 3H)26.2
H94.00 (q, J = 6.4, 1H)C955.14.03 (q, J = 6.8, 1H)54.8
H101.42 (d, J = 6.4, 3H)C1024.31.40 (d, J = 6.8, 3H)24.9
C6H57.30–7.38 (m, 5H)Cipso144.3,7.32–7.35 (m, 5H)145.4, 128.7, 127.1, 126.7
Cmeta128.7,
Cortho127.3,
Cpara126.8
NH, OH2.37 (bs, 2H) - -2.01 (bs, 2H)- -
Figure 3. Conformation of the compound cis-4.
Figure 3. Conformation of the compound cis-4.
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The coupling pattern shown by compound cis-4 establishes a syn diequatorial distribution of the OH and NHR groups. A NOESY experiment (Figure 4) carried out on this compound, shows that H1 interacts with H3 and both protons are close to the equatorial H2a. In addition, H2b, H6b and H4b show dipolar couplings confirming the analysis of the coupling constants described previously.
The 1H-NMR spectra of the compound trans-4 displays similar data to those observed for the cis-4 stereoisomer, the main difference being the chemical shift for protons H2a, H2b, and H4a. On the other hand, its 13C-NMR data shows that C4 is shifted downfield by 2.0 ppm. This can be attributed to a lesser ring strain around this atom. In addition, the coupling pattern for proton H2a is different due to dihedral angles variations (Figure 5).
Figure 4. NOESY experiments for cis-4 (CDCl3, 400 MHz).
Figure 4. NOESY experiments for cis-4 (CDCl3, 400 MHz).
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Figure 5. Multiplicity of the protons H2ec for compounds cis-4 and trans-4.
Figure 5. Multiplicity of the protons H2ec for compounds cis-4 and trans-4.
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Compound trans-4 shows a triplet of triplets for the H1 and H3 protons (J = 11.8, 4.4 Hz and J = 11.6, 4.0 Hz respectively), which are similar to those observed for cis-4. However, in the NOESY experiment (Figure 6) these two protons do not interact spatially, suggesting an anti-arrangement of the hydroxyl and amino groups.
Figure 6. NOESY experiment for compound trans-4 (CDCl3, 400 MHz).
Figure 6. NOESY experiment for compound trans-4 (CDCl3, 400 MHz).
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In order to establish the relative configuration at C-1 and C-3 of compound 4, we also carried out a NOESY experiment (Figure 7). If a chair conformation is considered for compound trans-4 (A), the fact that H3 has a dihedral angle below 60° with respect to H2a, H2b, H4a and H4b, would generate coupling constants with magnitude around ~3–5 Hz according to the Karplus rule, however, this is not observed in the spectrum of this compound.
Figure 7. Proposed conformations for the compound trans-4 in solution.
Figure 7. Proposed conformations for the compound trans-4 in solution.
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These experimental data thus confirm that the compound trans-4 does not adopt a chair conformation as its isomer cis-4 does. Therefore, we carried out an additional NOESY experiment in order to establish the relative configurations at C-1 and C-3, analyzing the coupling constants and spatial interactions of the two possible conformations C and D (Table 2).
Table 2. NOE interactions for H1, H3, H4eq and H6eq.
Table 2. NOE interactions for H1, H3, H4eq and H6eq.
Protoncis-4trans-4
13, 2eq, 4eq, Meupfield2eq, 6eq
31, 2eq, 4eq, 7axMeupfield, 4eq
6eq- -6ax, Medownfield
4eq- -Me-7, Me-8
In conformation D, proton H3 shows a dihedral angle larger than 120° with H2a and H4a, this spatial arrangement exhibits coupling constants of ~12.0 Hz, and the coupling with H2b and H4b of 4.0 Hz. On the other hand the NOESY experiment shows the spatial proximity of H4b to both methyl groups at C5, and of proton H1 to both H2a and H6a. In addition the fact that proton H3 shows a proximity to H4b, suggests a boat conformation for compound trans-4. The shielding of H4a is caused by the proximity of the NHR substituent, the torsional effect and the steric hindrance of the boat conformation explains the variation of the chemical shift of C4 in comparison to that of compound cis-4.

3. Experimental

Reagents were obtained from commercial suppliers and were used without further purification. Melting points were determined in a Fischer-Johns apparatus and are uncorrected. NMR studies were carried out with a Varian Gemini 200 and Varian Inova 400 instruments using TMS as a standard (1H, 13C). Chemical shifts are stated in parts per million. IR spectra have been recorded on a Bruker Vector 22 FT spectrophotometer. The diastereoisomeric composition were determined by GC-MS on the HP 5989A, Cyclosil-B column, 30 m, 0.25 mm (ID), 0.25 μm (film), transfer line 220 °C, injection 220 °C, and HRMS in Jeol JMS 700 equipment. X-ray diffraction studies were performed on a Bruker-APEX diffractometer with a CCD area detector at 100 K (λMo = 0.71073 A, monochromator: graphite). Specific rotations were measured in a Perkin-Elmer 341 polarimeter at room temperature and λ = 589 nm.

3.1. General Experimental Procedures

5,5-Dimethyl-3-benzylaminocyclohexen-2-one (1). A solution of 4,4-dimethyl-1,3-cyclohexanedione (1.0 g, 7.13 mmole) and benzylamine (0.86 mL, 7.84 mmole) was refluxed in toluene (30 mL) for 3 h, while the water formed was azeotropically removed using a Dean-Stark trap. After this time, the solvent was removed under reduced pressure and the resulting yellow solid was purified by recrystallization (CH2Cl2/hexane) affording 1 (1.39 g, 85%), mp = 122–125 °C. IR (film CH2Cl2, cm−1): 3,252, 3,062, 1,800, 1,545. 1H-NMR (400 MHz, CDCl3): δ 1.05 (s, 6H), 2.14 (s, 2H), 2.25 (s, 2H), 4.23 (d, J = 10.8 Hz, 2H), 5.14 (s, 1H), 5.77 (bs, 1H), 7.30 (m, 5H). 13C-NMR (100 MHz, CDCl3): δ 28.5(2), 33.0, 43.5, 47.3, 50.2, 95.9, 127.6(2), 127.9(2), 128.9, 136.9, 163.5, 196.7. HRMS CI+ calcd. for C15H20NO (M++1): 230.1545. Found: 230.1538.
(S)-5,5-Dimethyl-3-(α-methylbenzylamino)cyclohexen-2-one (2). A solution of 4,4-dimethyl-1,3-cyclohexanedione (1.0 g, 7.13 mmole) and (S)-α-methylbenzylamine (1.0 mL, 7.84 mmole) was refluxed in toluene (30 mL) during 3.5 h, while the water formed was removed azeotropically using a Dean-Stark trap. After this time, the solvent was removed and the yellow solid obtained was purified by crystallization (CH2Cl2/hexane) to give compound 2 (1.51 g, 87%), mp = 135–137 °C. [α]D = −243.26 (c = 1, CHCl3). IR (KBr, cm−1): 3,270, 3,059, 1,750, 1,542 cm−1. 1H-NMR (200 MHz, CDCl3): δ 1.01 (s, 3H), 1.06 (s, 3H), 1.47 (d, J = 6.6 Hz, 3H), 2.12 (s, 2H), 2.23 (s, 2H), 4.47 (q, J = 6.6 Hz, 1H), 4.97 (s, 1H), 5.62 (d, J = 6 Hz, 1H), 7.26 (m, 5H). 13C-NMR (50 MHz, CDCl3): δ 23.6, 28.5(2), 33.1, 43.6, 50.1, 53.0, 97.1, 125.7(2), 127.5, 128.9(2), 142.9, 162.5, 196.5. HRMS CI+ calcd. for C16H22NO (M++1): 244.1701, found: 244.1695.

3.2. General Procedure for the Reduction of β-Enaminoketones 1 and 2

The β-enaminoketones (2.0 mmol) were dissolved in a mixture of isopropyl alcohol (2 mL) and THF (5 mL). The resulting solution was treated with an excess of small pieces of metallic sodium (0.27 g, 12.0 g-atoms) and stirred from 0 °C to room temperature until the reaction was complete (TLC). After removal of the unreacted sodium, the reaction mixture was poured into a saturated aqueous solution of NH4Cl and extracted with AcOEt. The organic layers were combined, dried over Na2SO4 filtered and evaporated under reduced pressure. The resulting materials were submitted to an initial percolation and then were submitted to HPLC-MS analysis. The materials were separated by column chromatography (silica gel, 230–400) eluting with 65:25:10 proportions of hexane/ethyl acetate/isopropyl alcohol or 95:5, CH2Cl2/CH3OH.
5,5-Dimethyl-3-benzylaminocyclohexanols (3a,b). Compound 3a: (97 mg, 48%). 1H-NMR (400 MHz, CDCl3): δ 0.85 (s, 3H), 0.99 (s, 3H), 1.09 (m, 3H), 1.67 (m, 2H), 2.31(m, Jgem = 11.6 Hz, 1H), 2.79 (tt, J = 11.6, 4 Hz, 1H), 2.95 (bs, 2H), 3.75 (tt, J = 11.2 4.4 Hz, 1H), 3.83 (d, J = 12.8 Hz, 1H), 3.85 (d, J = 13.2 Hz, 1H), 7.3 (m, 5H). 13C-NMR (50 MHz, CDCl3): δ 26.3, 31.8, 33.3, 42.7, 45.3, 48.2, 50.9, 51.7, 66.6, 127.2, 128.4, 128.6, 139.7. MS, CI+ (M++1): 234, 216, 162, 91. HRMS CI+ calcd. for C15H24NO (M++1): 234.1858, found 234.1891. Compound 3b: (59 mg, 29%). 1H-NMR (400 MHz, CDCl3): δ 0.89, (s, 3H), 0.99 (s, 3H), 1.04 (m, 3H), 1.6 (bs, 2H), 1.65 (ddt, J = 12.8, 4, 2 Hz, 1H), 1.70 (ddt, J = 12.8, 4, 2 Hz, 1H), 2.29 (dddd, J = 11.6, 4, 2 Hz, 1H), 2.76 (tt, J = 11.2, 4 Hz, 1H), 3.79 (m, 1H), 3.8 (d, J = 12.8 Hz, 1H), 3.84 (d, J = 12.8 Hz, 1H), 7.3 (m, 5H). 13C-NMR (100 MHz, CDCl3): δ 25.9, 31.8, 33.1, 41.3, 43.2, 47.8, 49.7, 51.7, 66.5, 128.2, 128.9, 129.3, 136.3. MS, CI+ (M++1): 234, 216, 174, 162, 108, 106, 91. HRMS calcd. for C15H24NO (M++1): 234.1858, found 234.1852.
5,5-Dimethyl-3-[(S)-α-methylbenzylamino]cyclohexanol (cis-4 and trans-4). Compound cis-4: (352 mg, 69%), [α]D = −48 (c = 3.26, CHCl3). IR (KBr, cm−1): 3439, 3257, 3028, 1646. 1H-NMR (400 MHz, CDCl3): δ 0.70 (s, 3H), 0.97 (s, 3H), 0.97 (t, J = 11.8 Hz, 1H), 0.97 (t, J = 12 Hz, 1H), 1.07 (q, J = 11.6 Hz, 1H), 1.42 (d, J = 6.4 Hz, 3H), 1.63 (ddt, J = 12.4, 4.2 Hz, 1H), 1,70 (ddt, J = 12.8, 3.6, 2.0 Hz, 1H), 2.13 (m, Jgem = 11.6 Hz, 1H), 2.37 (bs, 2H), 2.53 (tt, J = 11.6, 4.0 Hz, 1H), 3.65 (tt, J = 11.2, 4.8 Hz, 1H), 4.00 (q, J = 6.4 Hz, 1H), 7.30–7.38 (m, 5H). 13C-NMR (100 MHz, CDCl3): δ 24.3, 26.0, 31.8, 33.3, 43.3, 44.7, 48.1, 49.5, 55.1, 66.8, 126.8, 127.3, 128.7, 144.3. MS CI+ (M++1): 248, 247, 232, 230, 176, 105. HRMS CI+ calcd. for C16H26NO (M++1): 248.2014, found 248.2132. Compound trans-4: (32 mg, 6%) [α]D = −28 (c = 0.24, CHCl3). IR (KBr, cm−1): 3,376, 3,067, 3,029, 1,633. 1H-NMR (400 MHz, CDCl3): δ 0.75 (s, 3H), 0.93 (s, 3H), 0.94 (bq, J = 10.2 Hz, 1H), 0.99 (t, J = 12 Hz, 1H), 1.04 (bq, J = 12 Hz, 1H), 1.40 (d, J = 6.8 Hz, 3H), 1.50 (m, 1H), 1.63 (ddt, J = 12.4, 4.2 Hz, 1H), 2.01 (bs, 2H), 2.35 (dddd, J = 11.6, 5.6, 4.2 Hz, 1H), 2.59 (tt, J = 11.6, 4.1 Hz, 1H), 3.64 (tt, J = 10.8, 4.4 Hz, 1H), 4.03 (q, J = 6.8 Hz, 1H), 7.32–7.35 (m, 5H). 13C-NMR (50 MHz, CDCl3): δ 24.9, 26.2, 31.7, 33.2, 42.6, 46.5, 48.4, 49.3, 54.8, 67.1, 126.7, 127.1, 128.7, 145.4. MS CI+ (M++1): 248, 247, 232, 230, 176, 105. HRMS CI+ calcd. for C16H25NO (M++1): 248.2014, found 248.2341.

4. Conclusions

In conclusion, 1,3-amino alcohols 3 and 4 were obtained as diastereoisomeric mixtures in good yield by reduction of the corresponding β-enaminoketones 1 and 2, which were analyzed by gas chromatography/mass spectrometry using a chiral column. Two diastereomeric pairs were identified for compound 3 and two diasteromeric pairs, cis-4 and trans 4, for compound 4. Chromatographic techniques allowed the separation of cis-4 and trans-4. On the other hand, NMR NOESY experiments enabled us to establish a chair conformation and a syn-orientation of the hydroxyl and amino groups for cis-4 and a boat conformation with anti-orientation of the hydroxyl and amino groups for trans-4.

Acknowledgements

We are grateful to María Gregoria Medina Pintor for her technical support and PROMEP-SEP for economic support for this publication.

References and Notes

  1. Shibahara, S.; Kondo, S.; Maeda, K.; Umezawa, H.; Ohno, M. Total synthesis of negamycin and the antipode. J. Am. Chem. Soc. 1972, 94, 4353–4354. [Google Scholar]
  2. Kozikowski, A.P.; Chen, Y.-Y. Intramolecular nitrile oxide cycloaddition (INOC) reactions in the indole series. 2. Total synthesis of racemic and optically active paliclavine and 5-epi-paliclavine. J. Org. Chem. 1981, 46, 5248–5250. [Google Scholar] [CrossRef]
  3. Wang, Y.-F.; Izawa, T.; Kobayashi, S.; Ohno, M. Stereocontrolled synthesis of (+)-negamycin from an acyclic homoallylamine by 1,3-asymmetric induction. J. Am. Chem. Soc. 1982, 104, 6465–6466. [Google Scholar] [CrossRef]
  4. Hashiguchi, S.; Kawada, A.; Natsugari, H. Stereoselective synthesis of sperabillins and related compounds. J. Chem. Soc. Perkin Trans. 1 1991, 2435–2444. [Google Scholar]
  5. Knapp, S. Synthesis of complex nucleoside antibiotics. Chem. Rev. 1995, 95, 1859–1876. [Google Scholar] [CrossRef]
  6. Sakai, R.; Kamiya, H.; Murata, M.; Shimamoto, K. Dysiherbaine: A new neurotoxic amino acid from the micronesian marine sponge Dysidea herbacea. J. Am. Chem. Soc. 1997, 119, 4112–4116. [Google Scholar] [CrossRef]
  7. Kempf, D.J.; Marsh, K.C.; Denissen, J.F.; McDonald, E.; Vasavanonda, S.; Flentge, C.A.; Green, B.E.; Fino, L.; Park, C.H.; Kong, X.-P.; et al. ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. Proc. Natl. Acad. Sci. USA 1995, 92, 2484. [Google Scholar]
  8. Sham, H.L.; Zhao, C.; Li, L.; Betebenner, D.A.; Saldivar, A.; Vasavanonda, S.; Kempf, D.J.; Plattner, J.J.; Norbeck, D.W. Novel lopinavir analogues incorporating non-aromatic P-1 side chains-synthesis and structure-activity relationships. Bioorg. Med. Chem. Lett. 2002, 12, 3101–3103. [Google Scholar] [CrossRef]
  9. Haight, A.R.; Stuk, T.L.; Allen, M.S.; Bhagavatula, L.; Fitzgerald, M.; Hannick, S.M.; Kerdesky, F.A.J.; Menzia, J.A.; Parekh, S.I.; Robbins, T.A.; et al. Reduction of an enaminone: Synthesis of the diamino alcohol core of ritonavir. Org. Process Res. Dev. 1999, 3, 94–100. [Google Scholar] [CrossRef]
  10. Shi, Z.; Harrison, B.A.; Verdine, G.L. Unpredictable stereochemical preferences for Mu opioid receptor activity in an exhaustively stereodiversified library of 1,4-enediols. Org. Lett. 2003, 5, 633–636. [Google Scholar] [CrossRef]
  11. Kondo, S.; Shibahara, S.; Takahashi, S.; Maeda, K.; Umezawa, H.; Ohno, M. Negamycin, a novel hydrazide antibiotic. J. Am. Chem. Soc. 1971, 93, 6305–6306. [Google Scholar] [CrossRef]
  12. Raju, B.; Mortell, K.; Anandan, S.; O’Dowd, H.; Gao, H.; Gomez, M.; Hackbarth, C.; Wu, C.; Wang, W.; Yuan, Z.; et al. N- and C-terminal modifications of negamycin. Bioorg. Med. Chem. Lett. 2003, 13, 2413–2418. [Google Scholar]
  13. Naidu, S.V.; Kumar, P.A. Simple and efficient approach to 1,3-aminoalcohols: Application to the synthesis of (+)-negamicyn. Tetrahedron Lett. 2007, 48, 3793–3796. [Google Scholar] [CrossRef]
  14. Carlier, P.R.; Lo, M.M.-C.; Lo, P.C.-K.; Richelson, E.; Tatsumi, M.; Reynolds, I.J.; Sharma, T.A. Synthesis of a potent wide-spectrum serotonin-, norepinephrine-, dopamine-reuptake inhibitor (SNDRI) and a species-selective dopamine-reuptake inhibitor based on the gamma-amino alcohol functional group. Bioorg. Med. Chem. Lett. 1998, 8, 487–492. [Google Scholar] [CrossRef]
  15. Wang, X.-B.; Kodama, K.; Hirose, T.; Yang, X.-F.; Zhang, G.-Y. Chirality control in the enantioselective arylation of aromatic aldehydes catalized by cis-(1R,2S)-2-benzamidocyclo-hexanecarboxylic acid derived 1,3-aminoalcohols. Tetrahedron: Asymmetry 2010, 21, 75–80. [Google Scholar] [CrossRef]
  16. Geng, H.; Zhang, W.; Chen, J.; Hou, G.; Zhou, L.; Zou, Y.; Wu, W.; Zhang, X. Rhodium-catalized enantioselective and diastereoselective hydrogenation of β-ketoenamides: Efficient access to anti-1,3-amino alcohols. Angew. Chem. Int. Ed. 2009, 48, 6052–6054. [Google Scholar] [CrossRef]
  17. Davis, F.A.; Gaspari, P.M.; Nolt, B.M.; Xu, P. Asymmetric synthesis of acyclic 1,3-amino alcohols by reduction of N-sulfinyl β-amino ketones. Formal synthesis of (-)-pinidol and (+)-epipinidol. J. Org. Chem. 2008, 73, 9619–9626. [Google Scholar] [CrossRef]
  18. Menche, D.; Arikan, F.; Li, J.; Rudolph, S. Directed reductive amination β-hydroxy-ketones: Convergent assembly of the ritonavir/lopinavir core. Org. Lett. 2007, 9, 267–270. [Google Scholar] [CrossRef]
  19. Kochi, T.; Tang, T.P.; Ellman, J.A. Asymmetric synthesis of syn- and anti-1,3-amino alcohols. J. Am. Chem. Soc. 2002, 124, 6518–6519. [Google Scholar] [CrossRef]
  20. Keck, G.E.; Truong, A.P. Directed reduction of β-amino ketones to syn- or anti-1,3-amino alcohol derivatives. Org. Lett. 2002, 4, 3131–3134. [Google Scholar] [CrossRef]
  21. Vilaplana, M.J.; Molina, P.; Arques, A.; Andrés, C.; Pedrosa, R. Synthesis of the novel chiral 1,3-amino alcohol 8-N,N-bis(Ferrocenylmethyl)amino-menthol and its use as catalyst in the enantioselective addition of diethylzinc to aldehydes. Tetrahedron: Asymmetry 2002, 13, 5–8. [Google Scholar] [CrossRef]
  22. Panev, S.; Linden, A.; Dimitrov, V. Chiral aminoalcohols with a menthane skeleton as catalyst for the enantioselective addition of diethylzinc to benzaldehyde. Tetrahedron: Asymmetry 2001, 12, 1313–1321. [Google Scholar] [CrossRef]
  23. Andrés, C.; Duque-Soladana, J.P.; Iglesias, J.M.; Pedrosa, R. Diastereoselective 5-exo-trig radical cyclisation on N-acryloyl-tetrahydro-1,3-oxazines. A novel approach to enantiopure 3-substituted pyrrolidines. Tetrahedron Lett. 1996, 37, 9085–9086. [Google Scholar]
  24. Liu, D.; Gao, W.; Wang, C.; Zhang, X. Practical synthesis of practical enantiopure γ-aminoalcohols by rhodium-catalyzed asymmetric hydrogenation of β-secondary-amino ketones. Angew. Chem. Int. Ed. 2005, 44, 1687–1689. [Google Scholar] [CrossRef]
  25. Rice, G.T.; White, M.C. Allylic C-H amination for the preparation of syn-1,3-amino alcohol motifs. J. Am. Chem. Soc. 2009, 131, 11707–11711. [Google Scholar] [CrossRef]
  26. Millet, R.; Träff, A.M.; Petrus, M.L.; Bäckvall, J.-E. Enantioselective synthesis of syn and anti-1,3-aminoalcohols via β-aminoketones and subsequent reduction/dynamic kinetic asymmetric transformation. J. Am. Chem. Soc. 2010, 132, 15182–15184. [Google Scholar] [CrossRef]
  27. Solé, C.; Whiting, A.; Gulyás, H.; Fernández, E. Highly enantio and diastereoselective synthesis of γ-amino alcohols from α,β-unsaturated imines trough a one-pot β-boration/reduction/oxidation sequence. Adv. Synth. Catal. 2011, 353, 376–384. [Google Scholar] [CrossRef]
  28. Anzai, M.; Yanada, R.; Fujii, N.; Ohno, H.; Ibuka, T.; Takemoto, Y. Asymmetric synthesis of β2,3-amino acids by InI-Pd(0)-promoted metalation and addition of chiral 2-vinylaziridines. Tetrahedron 2002, 58, 5231–5239. [Google Scholar] [CrossRef]
  29. Raghavan, S.; Rajender, A. Stereoselective synthesis of (-)-allosedamine and (1R,3R)-HPA-12 from β-p-toluenesulfonamido-γ,δ-unsaturated sulfoxide. Tetrahedron 2004, 60, 5059–5067. [Google Scholar] [CrossRef]
  30. Patti, A.; Pedotti, S. Chemoenzymatic access to all four enantiopure stereoisomers of 1-ferrocenyl-1,3-butanediol. Tetrahedron: Asymmetry 2006, 17, 778–785. [Google Scholar] [CrossRef]
  31. Barbarotto, M.; Geist, J.; Choppin, S.; Colobert, F. SmI2-coupling reaction of chiral non-racemic α-bromo-α´-sulfinyl ketones with imines: Synthesis of enantiomerically pure 2-methyl-3-amino-1-ol moieties. Tetrahedron: Asymmetry 2009, 20, 2780–2787. [Google Scholar] [CrossRef]
  32. Olsson, C.; Helgesson, S.; Frejd, T. New bicyclic γ- and δ-aminoalcohols as catalyst for the asymmetric diethylzinc addition to benzaldehyde. Tetrahedron: Asymmetry 2008, 19, 1484–1493. [Google Scholar] [CrossRef]
  33. Levy, L.M.; de Gonzalo, G.; Gotor, V. Resolution of N-protected cis- and trans-3-aminocyclohexanols via lipase-catalyzed enantioselective acylation in organic media. Tetrahedron: Asymmetry 2004, 15, 2051–2056. [Google Scholar] [CrossRef]
  34. Bernardelli, P.; Bladon, M.; Lorthiois, E.; Manage, A.C.; Vergne, F.; Wrigglesworth, R. Resolution of trans-3-aminocyclohexanol. Tetrahedron: Asymmetry 2004, 15, 1451–1455. [Google Scholar] [CrossRef]
  35. Santos, E.; Padilla, J.; Crabbé, P. Optical properties dimedonyl derivatives of α-phenylethylamine. Can. J. Chem. 1967, 45, 2275–2277. [Google Scholar] [CrossRef]
  36. Dudek, G.O.; Holm, R.H. Nuclear magnetic resonance studies of keto-enol equilibria. III. α,β-unsaturated-β-ketoamines. J. Am. Chem. Soc. 1962, 84, 2691–2696. [Google Scholar] [CrossRef]
  37. Crystal data for C16H21NO (2), Mr = 243.34 gmol−1, 0.41 × 0.34 × 0.16 mm3, monoclinic, space group P2(1), a = 9.6513(16), b = 7.0546(11), c = 21.462(4) Å, α = 90, β = 93.259(3), γ = 90°, V = 1458.9(4) Å3, Z = 4, ρcalcd = 1.108 gcm−3, θmax=25°, 5149 independent reflections, R1 = 0.0700 for 14134 reflections with I > 2σ(I) and wR2 = 0.1455 for all data, 2 parameters. Crystallographic data for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 841749.
  38. Bartoli, G.; Cimarelli, C.; Palmieri, G. Convenient procedure for the reduction of β-enamino ketones: Synthesis of γ-amino alcohols and tetrahydro-1,3-oxazines. J. Chem. Soc. Perkin Trans. 1 1994, 537–543. [Google Scholar]
  39. San Martin, R.; Martínez de Marigorta, E.; Domínguez, E. A convenient alternative route to β-aminoketones. Tetrahedron 1994, 50, 2255–2264. [Google Scholar]
  40. Bartoli, G.; Cupone, G.; Dal Pozzo, R.; de Nino, A.; Mariuolo, L.; Procopio, A.; Tagarelli, A. Stereoselective reduction of enaminones to syn-γ-aminoalcohols. Tetrahedron Lett. 2002, 43, 7441–7444. [Google Scholar]
  41. Machado, M.A.; Harris, M.I.N.C.; Braga, A.C.H. Studies on the reduction of β-enamino ketones. J. Braz. Chem. 2006, 17, 1440–1442. [Google Scholar] [CrossRef]
  42. Cimarelli, C.; Giuli, S.; Palmieri, G. Stereoselective synthesis of enantiopure γ-aminoalcohols by reduction of chiral β-enaminoketones. Tetrahedron: Asymmetry 2006, 17, 1308–1317. [Google Scholar] [CrossRef]
  43. Cimarelli, C.; Palmieri, G.; Volpini, E. Regio- and stereoselective double alkylation of β-enamino esters with organolitium reagents followed by one-pot reduction: Convenient method for the synthesis of tertiary γ-amino alcohols. Tetrahedron 2006, 62, 9423–9432. [Google Scholar] [CrossRef]
  44. Elassar, A.-Z.A.; El-Khair, A.A. Recent developments in the chemistry of enaminones. Tetrahedron 2003, 59, 8463–8480. [Google Scholar] [CrossRef]
  45. Bartoli, G.; Cimarelli, C.; Marcantoni, E.; Palmieri, G.; Petrini, M. Chemo- and diastereoselective reduction of beta-enamino esters: A convenient synthesis of both cis- and trans-γ-amino alcohols and β-amino esters. J. Org. Chem. 1994, 59, 5328–5335. [Google Scholar] [CrossRef]
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MDPI and ACS Style

Balbás, I.M.; Mendoza, B.E.D.; Fernández-Zertuche, M.; Ordoñez, M.; Linzaga-Elizalde, I. Synthesis of cis- and trans-3-Aminocyclohexanols by Reduction of β-Enaminoketones. Molecules 2012, 17, 151-162. https://doi.org/10.3390/molecules17010151

AMA Style

Balbás IM, Mendoza BED, Fernández-Zertuche M, Ordoñez M, Linzaga-Elizalde I. Synthesis of cis- and trans-3-Aminocyclohexanols by Reduction of β-Enaminoketones. Molecules. 2012; 17(1):151-162. https://doi.org/10.3390/molecules17010151

Chicago/Turabian Style

Balbás, Iris Montoya, Blanca Eda Domínguez Mendoza, Mario Fernández-Zertuche, Mario Ordoñez, and Irma Linzaga-Elizalde. 2012. "Synthesis of cis- and trans-3-Aminocyclohexanols by Reduction of β-Enaminoketones" Molecules 17, no. 1: 151-162. https://doi.org/10.3390/molecules17010151

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