Pauson-Khand Reaction of Amino Acid Derived 3-Pyrrolines: New Enantiopure Scaffolds for Diversity-Oriented Synthesis

Félix Cuevas; Carmen García-Granda; Helmut Buschmann; Antoni Torrens; Susana Yenes; Miquel A. Pericàs

doi:10.1055/s-2006-958408

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Synlett 2007(1): 0119-0122
DOI: 10.1055/s-2006-958408

LETTER

Pauson-Khand Reaction of Amino Acid Derived 3-Pyrrolines: New Enantiopure Scaffolds for Diversity-Oriented Synthesis

Félix Cuevas^a, Carmen García-Granda^a, Helmut Buschmann^b, Antoni Torrens^b, Susana Yenes^b, Miquel A. Pericàs*^a,c
^a Institute of Chemical Research of Catalonia (ICIQ), Avda. Països Catalans, 16, 43007 Tarragona, Spain
Fax: +34(977)920222; e-Mail: mapericas@iciq.es;
^b Laboratorios Dr. Esteve, S.A., Avda. Mare de Deu de Montserrat, 221, 08041 Barcelona, Spain
^c Departament de Química Orgànica, Universitat de Barcelona, 08028 Barcelona, Spain

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Publication History

Received 24 September 2006
Publication Date:
20 December 2006 (online)

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Abstract

Amino acid derived 3-pyrrolines can be readily prepared in a single step in enantiomerically pure form by cycloalkylation of the corresponding amino esters with (Z)-1,4-dichloro-2-butene. Enantiopure azabicyclo[3.3.0]octenones can be then easily obtained through an unprecedented Pauson-Khand reaction followed by diastereomer separation.

Key words

Pauson-Khand reaction - pyrrolines - amino acids - cyclization - alkynes

References and Notes

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5

The preparation of 2a-f can also be performed, albeit in somewhat decreased yield, by treating cis-1,4-dichloro-2-butene with 1.1 equiv of amino ester hydrochloride and 3.5 equiv of diisopropylethylamine in CH₂Cl₂ at r.t. for 24 h. In this way, 2d is obtained in 57% yield (vs. 65% yield with the standard procedure).

6

Representative Procedure for the Synthesis of 2a-f.
A mixture of cis-1,4-dichloro-2-butene (1 mmol) and amino ester 1a-f (3.5 mmol) in CH₂Cl₂ (1 mL) was stirred at r.t. for 24 h. Then, CH₂Cl₂ was added and the precipitated was filtered. The filtrate was washed with H₂O and sat. solution of NaCl, dried over Na₂SO₄, filtered and concentrated. The crude was purified by flash chromatography on silica gel with EtOAc and n-hexane, gradient 1:2 to 2:1.
Spectral Data for Selected Compounds.
Compound 2a: yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 5.76 (s, 2 H), 4.17 (q, J = 7 Hz, 2 H), 3.63 (m, 4 H), 3.46 (q, J = 7 Hz, 1 H), 1.36 (d, J = 7 Hz, 3 H), 1.26 (t, J = 7 Hz, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 173.86, 127.13, 60.35, 60.28, 56.55, 17.22, 14.26 ppm. MS (EI⁺): m/z = 170.1 [M + H⁺].
Compound 2b: yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 5.75 (s, 2 H), 4.10 (q, J = 7 Hz, 2 H), 3.70 (m, 2 H), 3.51 (m, 2 H), 2.98 (d, J = 7 Hz, 1 H), 1.95 (m, 1 H), 1.20 (t, J = 7 Hz, 3 H), 0.96 (d, J = 7 Hz, 3 H), 0.86 (d, J = 7 Hz, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 172.67, 127.08, 70.72, 59.70, 55.79, 29.16, 19.94, 19.07, 14.45 ppm. MS (EI⁺): m/z = 198.1 [M + H⁺].
Compound 2e: colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.48 (m, 2 H), 7.34 (m, 3 H), 5.75 (s, 2 H), 4.32 (s, 1 H), 3.69 (s, 3 H), 3.54 (m, 2 H), 3.52 (m, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 172.23, 137.31, 128.65, 128.52, 128.33, 127.20, 72.56, 58.09, 52.09 ppm. MS (EI⁺): m/z = 218.1 [M + H]⁺.

10

General Procedure for the Pauson-Khand Reaction of Amino Acid Derived 3-Pyrrolines.
A mixture of alkyne (0.60 mmol) and Co₂(CO)₈ (0.65 mmol) in 1,2-dichloroethane (2 mL) was stirred at r.t. for 2 h. A solution of 2a-f (0.50 mmol) in 1,2-dichloroethane (1 mL) and DMSO (1.75 mmol) was added and the mixture was heated at 83 °C for 24 h. The reaction mixture was cooled at r.t., filtrated through Celite^® and washed with CH₂Cl₂. The filtrate was concentrated and purified by flash chromatog-raphy on silica gel, gradient with neat n-hexane to n-hexane-EtOAc (1:2). Compounds 3 were obtained as mixture of two diastereomers that were purified by HPLC: Chiralcel^® OD-H (1 cm × 25 cm), n-hexane-2-PrOH, 5 mL/min.
Spectral Data for Selected Compounds.
Compound 3cp: white solid.
Diastereomer 1: (2S)-methyl 4-methyl-2-[(3aR,6aS)-4-oxo-5-phenyl-1,3a,4,6a-tetrahydrocyclo penta[c]pyrrol-2 (1H)-yl]pentanoate.¹H NMR (400 MHz, CDCl₃): δ = 7.67 (m, 2 H), 7.65 (d, J = 3.0 Hz, 1 H), 7.40-7.31 (m, 3 H), 3.68 (s, 3 H), 3.38 (m, 2 H), 3.16 (d, J = 9.0 Hz, 1 H), 2.89 (m, 1 H), 2.84 (m, 2 H), 2.77 (m, 1 H), 1.58-1.42 (m, 3 H), 0.85 (d, J = 6.5 Hz, 3 H) 0.80 (d, J = 6.5 Hz, 3 H) ppm. HPLC [Chiralcel^® OD-H (0.46 cm × 25 cm), n-hexane-2-PrOH (99:1), 0.5 mL/min, 254 nm]: r.t. 11.7 min. HRMS (ES⁺): m/z calcd for C₂₀H₂₅NO₃ + H⁺: 328.1913; found: 328.1923. [α]_D ²⁰ +46.1 (c 1, CHCl₃).
Diastereomer 2: (2S)-methyl 4-methyl-2-[(3aS,6aR)-4-oxo-5-phenyl-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2 (1H)-yl]pentanoate. ¹H NMR (400 MHz, CDCl₃): δ = 7.70-7.65 (m, 3 H), 7.40-7.30 (m, 3 H), 3.68 (s, 3 H), 3.37 (m, 2 H), 3.18 (d, J = 9.0 Hz, 1 H), 2.92 (m, 2 H), 2.82 (m, 2 H), 1.59-1.44 (m, 3 H), 0.86 (d, J = 6.5 Hz, 3 H), 0.80 (d, J = 6.5 Hz, 3 H) ppm. HPLC [Chiralcel^® OD-H (0.46 cm × 25 cm), n-hexane-2-PrOH (99:1), 0.5 mL/min, 254 nm]: r.t. 15.8 min. HRMS (ES⁺): m/z calcd for C₂₀H₂₅NO₃ + H⁺: 328.1913; found: 328.1922. [α]_D ²⁰ -79.2 (c 1, CHCl₃).
Compound 3ab: yellow oil.
Diastereomer 1: (2S)-ethy l2-[(3aR,6aS)-5-butyl-4-oxo-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2 (1H)-yl]propanoate.¹H NMR (400 MHz, CDCl₃): δ = 7.12 (m, 1 H), 4.14 (q, J = 7 Hz, 2 H), 3.26 (m, 1 H), 3.22 (m, 1 H), 3.06 (d, J = 9 Hz, 1 H), 2.76 (m, 2 H), 2.66 (m, 2 H), 2.16 (m, 2 H), 1.45 (m, 2 H), 1.32 (m, 2 H), 1.26 (d, J = 7 Hz, 3 H), 1.25 (t, J = 7 Hz, 3 H), 0.89 (t, J = 7 Hz, 3 H) ppm. HPLC [Chiralcel^® OD-H (0.46 cm × 25 cm), n-hexane-2-PrOH (99.5:0.5), 0.5 mL/min, 254 nm]: r.t. 14.46 min. HRMS (ES⁺): m/z calcd for C₁₆H₂₆NO₃ + H⁺: 280.1913; found: 280.1906. [α]_D ²⁰ +70.5 (c 1, CHCl₃).
Diastereomer 2: (2S)-ethyl 2-[(3aS,6aR)-5-butyl-4-oxo-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2 (1H)-yl]propanoate. ¹H NMR (400 MHz, CDCl₃): δ = 7.13 (m, 1 H), 4.14 (q, J = 7 Hz, 2 H), 3.26 (m, 2 H), 3.04 (m, 1 H), 2.78 (m, 2 H), 2.72 (m, 2 H), 2.16 (m, 2 H), 1.45 (m, 2 H), 1.33 (m, 2 H), 1.27 (d, J = 7 Hz, 3 H), 1.25 (t, J = 7 Hz, 3 H), 0.89 (t, J = 7 Hz, 3 H) ppm. HPLC [Chiralcel^® OD-H (0.46 cm × 25 cm), n-hexane-2-PrOH (99.5:0.5), 0.5 mL/min, 254 nm]: r.t. 15.80 min. HRMS (ES⁺): m/z calcd for C₁₆H₂₆NO₃ + H⁺: 280.1913; found: 280.1906. [α]_D ²⁰ -83.6 (c 1, CHCl₃).