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

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.

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

References

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2d Evans DA. Miller SJ. Lectka T. von Matt P. J. Am. Chem. Soc.  1999,  121:  7559 

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3 Sibi MP. Venkatraman L. Liu M. Jasperse CP. J. Am. Chem. Soc.  2001,  123:  8444 

4a For a mini review on this subject see: Corminboeuf O. Quaranta L. Renaud P. Liu M. Jasperse CP. Sibi MP. Chem.-Eur. J.  2003,  9:  28 

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6f See also: Radicals in Organic Synthesis   Vol. 1:  Renaud P. Sibi MP. Wiley-VCH; Weinheim: 2001. 

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Enantioselective conjugate radical reactions:

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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.

11a For a review on stereochemical reversal see: Sibi MP. Liu M. Curr. Org. Chem.  2000,  5:  735 

11b Evans DA. Johnson JS. Bergey CS. Campos KR. Tetrahedron Lett.  1999,  40:  2879 

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] .