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

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

References and Notes

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• 18 No epimerization of the ester 7a was observed. According to Seebach et al. LHMDS is not able to deprotonate amino acid esters except glycine and sarcosine, see: Seebach D. Beck AK. Studer A. In Modern Synthetic Methods   Vol. 7:  Ernst B. Leumann C. Verlag Helvetica Chimica Acta; Basel: 1995.  p.1-178  ; and references cited therein
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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.