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Synlett 2009(7): 1136-1140  
DOI: 10.1055/s-0028-1088150
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Highly Functionalized Proline Derivatives via a One-pot Michael/Aldol Addition-Cyclization Approach

Uli Kazmaier*, Christian Schmidt
Institut für Organische Chemie, Universität des Saarlandes, 66123 Saarbrücken, Germany
Fax: +49(681)3022409; e-Mail: u.kazmaier@mx.uni-saarland.de;
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Publication History

Received 5 January 2009
Publication Date:
20 March 2009 (online)

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Abstract

Chelated enolates undergo Michael addition towards halogenated α,β-unsaturated esters in a highly stereoselective fashion. The enolates formed can be trapped with aldehydes in a stereoselective aldol reaction, before subsequent cyclization gives rise to substituted proline derivative. Up to for stereogenic centers can be formed in this new one-pot reaction.

Key words

aldol reaction - amino acids - chelates - cyclization - Michael addition - one-pot reaction

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17

In some cases the reactions of chelated enolates with aromatic aldehydes proceed with low diastereoselectivicity, probably because of the reversibility of the aldol process.

19

It should be mentioned, that NMR is not a suitable method for determination of the isomeric ratios, because in addition to the signals of the different isomers, in general a double set of signals is observed caused by rotamers (hindered rotation around the secondary amide bond).

21

General Procedure for Domino Michael-Aldol Additions-Cyclizations
In a Schlenk flask HMDS (0.3 mL, 1.42 mmol) was dissolved in THF (2 mL). The solution was cooled to -78 ˚C before n-BuLi (1.6 M, 0.78 mL, 1.25 mmol) was added. The cooling bath was removed and the solution was allowed to warm up for 15 min, before it was cooled again to -78 ˚C. In a second Schlenk flask ZnCl2 (80 mg, 0.57 mmol) was dried with a heat gun in high vacuum, before it was dissolved in THF (3 mL). After addition of TFA-Gly-Ot-Bu (115 mg, 0.5 mmol) the solution was cooled to -78 ˚C, before the fresh prepared LHMDS solution was added. Then, 15 min later, the Michael acceptor (0.45 mmol) was added in THF (2 mL). After 2 h the corresponding aldehyde (1-1.5 mmol) was added and the reaction mixture was allowed to r.t. overnight. The solution was diluted with Et2O before 1 N KHSO4 was added. The layers were separated, the aqueous phase was washed twice with CH2Cl2, and the combined organic layers were dried (Na2SO4). After evaporation of the solvent in vacuo the crude product was purified by flash chromatography (SiO2, hexanes-EtOAc).

22

Spectroscopic and Analytical Data of Selected Products 9
Compound 9a
Major rotamer, (2S,3S,4R,5R)-9a: ¹H NMR (500 MHz, CDCl3): δ = 0.91 (d, J = 6.6 Hz, 2 H), 1.00 (d, J = 6.5 Hz, 2 H), 1.45 (s, 9 H), 1.56 (m, 1 H), 1.94 (m, 1 H), 2.24 (m, 1 H), 2.54 (dd, J = 11.6, 2.6 Hz, 1 H), 3.01 (m, 1 H), 3.21 (ddd, J = 12.2, 9.9, 2.4 Hz, 1 H), 3.29 (br s, 1 H), 3.63 (m, 1 H), 3.75 (s, 3 H), 3.98 (dd, J = 9.8, 9.8 Hz, 1 H), 4.38 (d, J = 7.9 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 19.2, 19.8, 27.6, 27.7, 33.1, 40.2, 46.1 (J = 3.0 Hz), 47.5, 52.0, 62.9, 77.4, 83.0, 115.8 (J = 287.6 Hz), 157.3 (J = 37.4 Hz), 168.8, 172.2.
Minor rotamer (selected signals): ¹H NMR (500 MHz, CDCl3): δ = 1.44 (s, 9 H), 1.78 (m, 1 H), 2.53 (dd, J = 11.5, 2.5 Hz, 1 H), 3.12 (m, 1 H), 3.77 (s, 3 H), 3.83 (dd, J = 11.9, 10.0 Hz, 1 H), 4.48 (dd, J = 7.4, 1.4 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 24.4, 32.0, 42.8, 47.9, 52.0, 61.8 (J = 2.7 Hz), 83.3, 168.9, 172.5.
Major rotamer, (2S,3S,4R,5S)-9a: ¹H NMR (500 MHz, CDCl3): δ = 0.89 (d, J = 6.8 Hz, 2 H), 1.02 (d, J = 6.7 Hz, 2 H), 1.43 (m, 1 H) 1.44 (s, 9 H), 1.80 (m, 1 H), 2.04 (m, 1 H), 2.57 (dd, J = 7.8, 2.5 Hz, 1 H), 2.62 (br s, 1 H), 3.02 (m, 1 H), 3.56-3.65 (m, 2 H), 3.71 (s, 3 H), 3.98 (dd, J = 10.1, 9.4 Hz, 1 H), 4.61 (d, J = 7.8 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 19.1, 19.7, 27.9, 28.0, 34.2, 39.6, 46.0 (J = 3.5 Hz), 47.7, 51.9, 62.8, 75.6, 83.1, 168.1, 174.4.
Minor rotamer (selected signals): ¹H NMR (500 MHz, CDCl3): δ = 1.45 (s, 9 H), 3.11 (m, 1 H), 3.72 (s, 3 H), 4.65 (dd, J = 7.4,1.4 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 19.0, 19.7, 47.1, 61.6 (J = 2.8 Hz), 83.6, 168.0, 174.2. GC (isothermic, 170 ˚C): t R [(±)-(2S,3S,4R,5S)-9a] = 39.96 min; t R [(±)-(2S,3S,4R,5R)-9a] = 49.87 min. HMRS (CI): m/z [M + H]+ calcd for C18H29F3NO6: 412.1947; found: 412.1991. Anal. Calcd for C18H28F3NO6 (411.42): C, 52.55; H, 6.86; N, 3.40. Found: C, 52.37; H, 6.71; N, 3.42.
Compound 9b
Major rotatmer, (2S,3S,4R,5R)-9b: ¹H NMR (500 MHz, CDCl3): δ = 0.89 (s, 9 H, 15-H), 1.46 (s, 9 H, 7-H), 1.50 (br s, 1 H), 2.02 (m, 1 H), 2.29 (m, 1 H), 2.58 (dd, J = 11.2, 2.3 Hz, 1 H), 2.92 (m, 1 H), 3.32 (dd, J = 10.3, 2.1 Hz, 1 H), 3.64 (m, 1 H), 3.74 (s, 3 H), 3.97 (dd, J = 9.8, 9.8 Hz, 1 H), 4.34 (d, J = 7.6 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 26.0, 27.7, 27.8, 35.8, 42.1, 44.8, 46.0 (J = 3.5 Hz), 52.1, 62.8, 79.1, 82.9, 115.8 (J = 287.6 Hz), 157.3 (J = 37.4 Hz), 168.6, 174.4.
Minor rotamer (selected signals): ¹H NMR (500 MHz, CDCl3): δ = 0.89 (s, 9 H), 1.45 (s, 9 H), 1.87 (m, 1 H), 2.56 (dd, J = 11.3, 2.2 Hz, 1 H), 3.03 (m, 1 H), 3.35 (dd, J = 10.0, 2.0 Hz, 1 H), 3.75 (s, 3 H), 3.82 (dd, J = 11.5, 10.3 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 27.7, 35.8, 45.0, 45.4, 79.1, 83.3, 169.7, 174.2. GC (isothermic, 180 ˚C): t R [(±)-(2S,3S,4R,5S)-9b] = 32.33 min; t R [(±)-(2S,3S,4R,5R)-9b] = 35.17 min. Anal. Calcd for C19H30F3NO6 (425.44): C, 53.64; H, 7.11; N, 3.29. Found: C, 53.76; H, 6.85; N, 3.41.
Compound 9e
Major rotamer, (2S,3S,4R,5R)-9e: ¹H NMR (500 MHz, CDCl3): δ = 0.96 (t, J = 7.4 Hz, 3 H), 1.43 (s, 9 H), 1.50 (m, 2 H), 1.87 (br s, 1 H), 1.94 (m, 1 H), 2.25 (m, 1 H), 2.54 (dd, J = 11.6, 2.7 Hz, 1 H), 3.00 (m, 1 H), 3.59-3.66 (m, 2 H), 3.74 (s, 3 H), 3.97 (dd, J = 9.7, 9.7 Hz, 1 H), 4.45 (d, J = 8.0 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 10.5, 27.7, 27.8, 29.1, 39.7, 46.2 (J = 3.4 Hz), 49.9, 51.9, 62.9, 72.9, 83.0, 116.1 (J = 287.4 Hz), 155.9 (J = 37.4 Hz), 168.8, 172.3.
Minor rotamer (selected signals): ¹H NMR (500 MHz, CDCl3): δ = 1.42 (s, 9 H), 1.78 (m, 1 H), 2.33 (dd, J = 11.6, 2.7 Hz, 1 H), 3.11 (m, 1 H), 3.75 (s, 3 H), 3.82 (dd, J = 10.0, 10.0 Hz, 1 H), 4.50 (dd, J = 7.4, 1.0 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 42.7, 47.2, 61.8 (J = 2.7 Hz), 72.8, 83.4, 168.9, 172.2. The signals of the minor diastereomer could not be separated from these of the major isomers.
GC (155 ˚C, 60 min; 5˚/min; 180 ˚C, 3 min): t R [(±)-(2S,3S,4R,5S)-9e] = 66.10 min; t R [(±)-(2S,3S,4R,5R)-9e] = 75.16 min. Anal. Calcd for C17H26F3NO6 (397.39): C, 51.38; H, 6.56; N, 3.52. Found: C, 50.98; H, 6.37; N, 3.56.

23

Unfortunately the aldol products obtained with aromatic aldehydes could not be analyzed by GC; NMR has to be used in this case. Therefore, we were not able to determine exact ratios, but the NMR spectra indicated that the isomers were formed in comparable amounts.