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Synlett 2004(13): 2421-2424  
DOI: 10.1055/s-2004-832832
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© Georg Thieme Verlag Stuttgart · New York

Chiral Relay in Enantioselective Conjugate Radical Additions Using ­Pyrazolidinone Templates. How Does Metal Geometry Impact Selectivity?

Mukund P. Sibi*, Narayanasamy Prabagaran
Department of Chemistry, North Dakota State University, Fargo, ND 58105, USA
Fax: +1(701)2311057; e-Mail: Mukund.Sibi@ndsu.nodak.edu;
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Publication History

Received 5 July 2004
Publication Date:
24 September 2004 (online)

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Abstract

A novel class of achiral templates containing fluxional groups has been evaluated in conjugate radical additions. Magnesium and copper Lewis acids provide high enantioselectivity (>90% ee) for radical additions. The impact of the metal geometry on enantioselectivity using relay templates has also been assessed.

Key words

radical reactions - chiral Lewis acid - relay - conjugate additions - pyrazolidinones - enantioselectivity amplification

8

For the synthesis of pyrazolidinone templates see details in ref. [3] and ref. [5]

9

Typical Reaction Conditions: The chiral ligand (0.031 mmol) and Lewis acid (0.03 mmol) were dissolved in CH2Cl2 at r.t. under nitrogen and stirred for 30 min. The substrate (0.1 mmol) was added and the mixture was stirred for an additional 30 min. The reaction mixture was cooled to -78 °C and after 15 min, the reaction was initiated by sequential addition of 2-iodopropane (0.5 mmol), tributyltin hydride (0.2 mmol), triethyl borane (0.3 mmol) and oxygen (10 mL). After 2 h, the reaction was quenched with silica gel (5 g), evaporated, washed with hexane (50 mL) and extracted with EtOAc. The product was purified by column chromatography over silica gel.
Compound 5a (entry 1, Table [1] ): 1H NMR (500 MHz, CDCl3): d = 0.74 (d, 3 H, J = 6.5 Hz,), 0.79 (t, 3 H, J = 7.0 Hz,), 0.98 (s, 3 H), 0.99 (d, 3 H, J = 6.5 Hz), 1.13 (m, 4 H), 1.19 (s, 3 H), 1.89 (m, 1 H), 2.48 (m, 2 H), 2.67 (m, 2 H), 3.05 (m, 2 H), 3.58 (m, 1 H), 7.21 (m, 5 H). 13C NMR (125 MHz, CDCl3): d = 20.7, 21.0, 21.2, 21.3, 25.8, 26.1, 27.1, 33.5, 39.8, 43.7, 48.9, 60.6, 61.9, 126.3, 128.1, 128.8, 143.2, 170.2, 175.7. HRMS: m/z calcd for C21H32N2O2Na+: 367.2356; found: 367.2360. [a]D 25 -7.03 (c 1.18, CHCl3) ee 52% (Chiralcel AD, hexanes-i-PrOH 99:1, flow rate 0.5 mL/min; t R major enantiomer: 17.7 min, minor enantiomer: 21.2 min).
Compound 5b (entry 2, Table [1] ): 1H NMR (500 MHz, CDCl3): d = 0.74 (d, 3 H, J = 7.0 Hz,), 0.77 (d, 3 H, J = 2.0 Hz), 0.79 (d, 3 H, J = 2.0 Hz), 0.98 (d, 3 H, J = 7.0 Hz), 0.99 (s, 3 H), 1.17 (s, 3 H), 1.60 (m, 1 H), 1.88 (m, 1 H), 2.31 (m, 2 H), 2.48 (m, 2 H), 3.04 (m, 2 H), 3.52 (m, 1 H), 7.17 (m, 5 H). 13C NMR (125 MHz, CDCl3): d = 14.0, 20.7, 20.8, 21.0, 25.7, 29.5, 33.5, 39.5, 44.3, 48.9, 53.1, 60.2, 126.4, 128.1, 128.8, 143.2, 170.3, 175.5. HRMS: m/z calcd for C21H32N2O2Na+: 367.2356; found: 367.2359. [a]D 25 -6.4 (c 1.66, CHCl3) ee 58% (Chiralcel AS, hexanes-i-PrOH 99:1, flow rate 0.5 mL/min; t R minor enantiomer: 11.3 min, major enantiomer: 21.1 min).
Compound 5c (entry 1, Table [2] ): 1H NMR (500 MHz, CDCl3): d = 0.71 (d, 3 H, J = 6.5 Hz,), 0.93 (d, 3 H, J = 6.5 Hz), 1.00 (s, 3 H), 1.14 (s, 3 H), 1.85 (m, 1 H), 2.43 (m, 2 H), 2.89 (m, 1 H), 2.98 (m, 1 H), 3.42 (m, 1 H), 3.85 (s, 2 H), 7.24 (m, 10 H). 13C NMR (125 MHz, CDCl3): d = 20.6, 21.0, 26.1, 26.2, 33.4, 39.5, 44.0, 48.7, 56.7, 60.7, 126.4, 127.7, 128.2, 128.6, 128.8, 129.5, 137.7, 143.4, 169.9, 174.6. HRMS: m/z calcd for C24H30N2O2Na+: 401.2200; found: 401.2222. [a]D 25 -13.4 (c 1.0, CHCl3) ee 98% (Chiralcel AS, hexanes-i-PrOH 98:2, flow rate 0.5 mL/min; t R minor enantiomer: 25.3 min, major enantiomer: 31.0 min).
Compound 5d (entry 4, Table [1] ): 1H NMR (500 MHz, CDCl3): d = 0.47 (d, 3 H, J = 8.0 Hz,), 0.59 (d, 3 H, J = 8.0 Hz), 1.14 (s, 3 H), 1.19 (s, 3 H), 1.52 (m, 1 H), 2.65 (m, 5 H), 4.16 (d, 1 H, J = 16.0 Hz), 4.35 (d, 1 H, J = 16.0 Hz), 6.86 (d, 2 H, J = 9.0 Hz), 7.08 (m, 3 H), 7.36 (m, 1 H), 7.48 (m, 1 H), 7.55 (m, 2 H), 7.75 (d, 1 H, J = 10.5 Hz), 7.83 (d, 1 H, J = 10.5 Hz), 8.14 (d, 1 H, J = 11.0 Hz). 13C NMR (125 MHz, CDCl3): d = 20.2, 20.6, 25.8, 26.3, 32.9, 38.9, 43.4, 47.9, 54.9, 61.3, 123.5, 125.7, 125.9, 126.1, 126.5, 128.1, 128.7, 129.1, 132.1, 132.6, 133.8, 143.2, 170.8, 174.3. HRMS: m/z calcd for C28H32N2O2Na+: 451.2355; found: 451.2347. [a]D 25 -30.24 (c 1.64, CHCl3) ee 90% (Chiralcel AD, hexanes-i-PrOH 97:3, flow rate 1.0 mL/min; t R minor enantiomer: 14.4 min, major enantiomer: 19.0 min).

10

The absolute stereochemistry of the products 5a-d were determined by hydrolysis to the acid and comparison of their rotation with 3-phenyl-4-methyl-pentanoic acid.

12

Although the proximity will vary, the ligand will be orthogonal to the substrate so long as one of the ligand nitrogen occupies an apical position, whether that is in an octahedral, trigonal bipyramidal, square pyramidal, or tetrahedral complex.

13

The molecular graphics images in Figure [2] were produced using the UCSF Chimera package from the Computer Graphics Laboratory, University of California-San Francisco.

14

In cycloadditions the bulk of the pyrazolidinone templates can also influence regioselectivity (ref. [5b] ) or exo/endo diastereoselectivity (ref. [5a] ).

15

Magnesium iodide and magnesium triflimide both provide nearly identical results when used in combination with ligand 8; for example see entry 14 in Table [2] and entry 1 in Table [4] . The cheaper magnesium iodide was used for experiments in Table [4] .