Diastereoselective Heck Arylation of Spirolactams: An Approach to Spiroamine-Based Nicotinic Ligands

Abstract

The intermolecular Heck arylations of the cyclopentenyl based spirolactams 6a and 6c are stereoselective leading to adducts 7 and 8 derived by face-selective carbopalladation anti to the lactam carbonyl.

Key words

Heck reaction - spirocycles - lactams - metathesis - ste­reo­selectivity

References and Notes

• 1 Badio B. Daly JW. Mol. Pharmacol.  1994,  45:  563 
• 2a Wonnacott S. Gallagher T. In Marine Drugs and Ion Channels   Arias HR. MDPI; Basel: 2006.  p.in press 
• 2b For an overview of the role of natural products as nicotinic ligands, see: Daly JW. Cell. Mol. Neurobiol.  2005,  25:  513 
• 3a Holladay MW. Dart MJ. Lynch JK. J. Med. Chem.  1997,  40:  4169 
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• 4c Glennon RA. Dukat M. Liao L. Curr. Top. Med. Chem.  2004,  4:  631 
• 5a Wright E. Gallagher T. Sharples CGV. Wonnacott S. Bioorg. Med. Chem. Lett.  1997,  7:  2867 
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• 5c Sharples CGV. Karig G. Simpson GL. Spencer JA. Wright E. Millar NS. Wonnacott S. Gallagher T. J. Med. Chem.  2002,  45:  3235 
• 5d See also: Gohlke H. Gundisch D. Schwarz S. Seitz G. Tilotta MC. Wegge T. J. Med. Chem.  2002,  45:  1064 
• For reviews covering recent synthetic and mechanistic aspects of the Heck arylation reaction, see:
• 6a Amatore C. Jutand A. Acc. Chem. Res.  2000,  33:  314 
• 6b Whitcombe NJ. Hii KK. Gibson SE. Tetrahedron  2001,  57:  7449 
• 6c Beletskaya IP. Cheprakov AV. Chem. Rev.  2000,  100:  3009 
• 6d Dounay AB. Overman LE. Chem. Rev.  2003,  103:  2945 
• 7 A related sequence aimed at the spirocyclic core of spirolide marine toxins has been developed. See: Brimble MA. Trzoss M. Tetrahedron  2004,  60:  5613 
• 10a Jeffery T. J. Chem. Soc., Chem. Commun.  1984,  1287 
• 10b Jeffery T. Tetrahedron Lett.  1985,  26:  2667 
• 10c For the application of an improved procedure for arylation of simple cycloalkenes, see: Larock RC. Gong WH. Baker BE. Tetrahedron Lett.  1989,  30:  2603 
• 11 Hartung CG. Kohler K. Beller M. Org. Lett.  1999,  1:  709 
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• 13b Overman LE. Watson DA. J. Org. Chem.  2006,  71:  2600 
• 14 Ung AT. Pyne SG. Batenburg-Nguyen U. Davis AS. Sherif A. Bischoff F. Lesage ASJ. Tetrahedron  2005,  61:  1803 

8

All compounds reported in this paper are racemic. Nicotinic activity may only be associated with one enantiomeric series as is the case with anatoxin-a (2) and UB-165 (3). This is not the case with epibatidine (1) where both enantiomers are equipotent. As predicting the biologically active enantiomer is difficult and subject to pitfalls, our initial targets were racemates. All novel compounds were characterized by ¹H NMR and ¹³C NMR, IR, MS, and HRMS or elemental analysis. The numbering systems used for NMR assignments are indicated on the relevant structures.
¹H NMR and ¹³C NMR data in CDCl₃ for spirolactams 6a-d:
Compound 6a: ¹H NMR (300 MHz): δ = 2.00 (2 H, t, J = 6.5 Hz, 2 × H-4), 2.26 (2 H, d, J = 14.5 Hz, H-6, H-9), 2.82 (2 H, d, J = 14.5 Hz, H-6, H-9), 2.88 (3 H, s, CH₃), 3.30 (2 H, t, J = 6.5 Hz, 2 × H-3), 5.65 (2 H, br s, H-7, H-8). ¹³C NMR (75.5 MHz): δ = 30.0 (CH₃), 35.7 (C-4), 43.6 (C-6, C-9), 49.7 (C-5), 46.5 (C-3), 128.4 (C7, C-8), 179.1 (CO).
Compound 6b: ¹H NMR (400 MHz): δ = 1.42-1.51 (1 H, m, H-10), 1.76-1.91 (4 H, m, 2 × H-9, 2 × H-4), 2.06-2.16 (2 H, m, H-6, H-10), 2.32-2.42 (1 H, m, H-6), 2.86 (3 H, s, CH₃), 3.30 (2 H, td, J = 7.5, 2.0 Hz, 2 × H-3), 5.61-5.71 (2 H, m). ¹³C NMR (100 MHz): δ = 21.9 (C-10), 28.4 (C-4), 29.2 (C-9), 29.7 (CH₃), 32.3 (C-6), 42.8 (C-5), 46.2 (C-3), 126.3 and 124.6 (C-7, C-8), 179.0 (C-1).
Compound 6c: (300 MHz): δ = 1.75-1.89 (4 H, m, 2 × H-9, 2 × H-10), 2.23 (2 H, d, J = 14.5, H-1, H-4), 2.95 (3 H, s, CH₃), 2.99 (2 H, d, J = 14.5, H-1, H-4), 3.31 (2 H, t, J = 6, 2 × H-8), 5.61 (2 H, br s, H-2, H-3). ¹³C NMR (75.5 MHz): δ = 20.0 (C-9), 35.4 (C-10), 35.3 (CH₃), 46.2 (C-1, C-4), 47.8 (C-5), 50.4 (C-8), 128.1 (C-2, C-3), 176.0 (CO).
Compound 6d: ¹H NMR (300 MHz): δ = 1.55 (1 H, ddt, J = 12.5, 4.5, 2.0 Hz, H-11), 1.67 (1 H, dd, J = 9.0, 3.5 Hz, H-5), 1.76-1.85 (4 H, m, 2 × H-10, 1 × H-5, 1 × H-11), 1.89-1.93 (1 H, m, H-7), 2.00-2.07 (1 H, m, H-4), 2.09-2.12 (1 H, m, H-4), 2.64 (1 H, dd, J = 17.0, 13.0 Hz, H-7), 2.93 (3 H, s, CH₃), 3.24-3.32 (2 H, m, 2 × H-3), 5.60-5.66 (2 H, m, CH=CH). ¹³C NMR (100 MHz): δ = 19.1 (C-10), 21.6 (C-4), 29.1 (C-5), 30.5 (C-11), 33.6 (C-7), 35.4 (CH₃), 39.9 (C-6), 50.3 (C-3), 125.3 and 125.0 (C-8, C-9), 175.0 (C-1).

9

Three sets of Heck conditions were used: a) Pd(OAc)₂, NaOAc, n-Bu₄NCl, H₂O, PhI, DMF, 50 °C, 24 h; [10] b) Herrmann palladacycle catalyst (10 mol%), NaOAc, PhI, DMA, 100 °C, 24 h; [11] c) Pd₂(dba)₃ (0.1 mol%), 4 PCy₃, Na₂CO₃, PhI, DMA, 140 °C, 24 h [11] (Heck arylation of 6a and 6c was not observed under these latter conditions). A number of other conditions, including use of Ag(I) as an activator, were also evaluated.

12

Characterization data for Heck adducts 7a and 8a.
Compound 7a: colorless solid; mp 88 °C (EtOAc-cyclohexane). IR (neat): 3060, 3019, 2930, 2870, 1950, 1740, 1660, 1600, 1490, 1654 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.59 (1 H, dd, J = 13.0, 6.5 Hz, H-9), 1.97 (1 H, ddd, J = 13.0, 8.0, 6.0 Hz, H-4), 2.23 (1 H, ddd, J = 13.0, 8.0, 5.0 Hz, H-4), 2.88 (1 H, dd, J = 13.0, 8.5 Hz, H-9), 2.89 (3 H, s, CH₃), 3.31 (1 H, ddd, J = 10.0, 8.0, 5.0, H-3), 3.39 (1 H, ddd, J = 10.0, 8.0, 6.0 Hz, H-3), 4.27 (1 H, ddt, J = 8.5, 6.5, 2.0 Hz, H-8), 5.82 (1 H, dd, J = 5.5, 2.0 Hz, CH=CH), 5.94 (1 H, dd, J = 5.5, 2.0 Hz, CH=CH), 7.26 (1 H, d, J = 8.0 Hz, H-5′), 7.46 (1 H, dd, J = 8.0, 2.5 Hz, H-4′), 8.23 (1 H, d, J = 2.5 Hz, H-2′). ¹³C NMR (100 MHz, CDCl₃): δ_C = 30.3 (CH₃), 32.9 (C-4), 44.9 (C-9), 46.7 (C-3), 47.7 (C-8), 57.8 (C-5), 124.1 (C-5′), 135.2 (C-6, C-7), 137.7 (C-4′), 139.7 (C-3′), 148.8 (C-2′), 149.5 (C-6′), 176.9 (CO). MS (EI⁺): m/z (%) = 264, 262 (100) [M⁺]. HRMS (EI⁺): m/z calcd for C₁₄H₁₅ ³⁵ClN₂O: 262.0873; found: 262.0864. Anal. Calcd for C₁₄H₁₅ClN₂O: C, 64.10; H, 5.77; N, 10.68. Found: C, 64.15; H, 5.80; N, 10.60.
Compound 8a: mp 89 °C (EtOAc-cyclohexane). IR (neat): 3046, 2970, 2904, 1660, 1580, 1560, 1452, 1273, 1109, 808 cm^-1. ¹H NMR: (400 MHz, CDCl₃): δ = 1.44 (1 H, dd, J = 13.0, 7.5 Hz, H-4), 1.80-1.89 (2 H, m, H-9, H-10), 1.91-1.99 (2 H, m, H-9, H-10), 2.96 (1 H, dd, J = 13.0, 8.0 Hz, H-4), 2.97 (3 H, s, -CH₃), 3.34 (2 H, t, J = 6.0 Hz, 2 × H-8), 4.35 (1 H, ddt, J = 8.0, 7., 2.0 Hz, H-3), 5.91 (1 H, dd, J = 5.5, 1.5 Hz, -CH=CH-), 5.93 (1 H, dd, J = 5.5, 2.5 Hz, -CH=CH-), 7.26 (1 H, d, J = 8.0 Hz, H-5′), 7.46 (1 H, dd, J = 8.0, 2.5 Hz, H-4′), 8.23 (1 H, d, J = 2.5 Hz, H-2′). ¹³C NMR (100 MHz, CDCl₃): δ = 20.7 (C-9), 35.5 (-CH₃), 35.6 (C-10), 47.3 (C-4), 48.4 (C-3), 50.4 (C-8), 56.9 (C-5), 124.1 (C-5′), 136.9 and 134.8 (C-1, C-2), 137.7 (C-4′), 140.1 (C-6′), 148.9 (C-2′), 149.4 (C-3′), 174.0 (CO). MS (EI⁺): m/z (%) = 278, 276 (100) [M⁺]. HRMS (EI⁺): m/z calcd for C₁₅H₁₇ ³⁵ClN₂O: 276.1029; found: 276.1022. Anal. Calcd for C₁₅H₁₇ClN₂O: C, 65.19; H, 6.20; N, 10.14. Found: C, 65.25; H, 6.11; N, 10.24.

15

Alkene isomerisation under basic conditions (t-BuOK, DME, 60 °C) was observed but this could not be controlled and an inseparable 1:1 mixture of regioisomers was obtained.

16

¹H NMR and ¹³C NMR data for spirolactams 12a-d (all compounds were characterized by IR, microanalysis and/or HRMS).
Compound 12a: ¹H NMR (300 MHz, CDCl₃): δ = 2.05 (2 H, m), 2.39 (1 H, ddd, J = 17.0, 2.5, 2.5 Hz), 2.60 (1 H, d, J = 16.0 Hz), 3.00 (1 H, dddd, J = 17.0, 2.5, 2.5, 2.5 Hz), 3.25 (1 H, dddd, J = 16.0, 2.5, 2.5, 2.5 Hz), 3.32 (2 H, t, J = 6.5 Hz), 6.03-6.06 (1 H, m), 7.20-7.41 (5 H, m). ¹³C NMR (100 MHz, CDCl₃): δ = 30.0, 35.8, 43.8, 43.9, 46.4, 50.1, 123.1, 125.4, 127.0, 128.2, 135.9, 140.1, 178.5.
Compound 12b: ¹H NMR (400 MHz, CDCl₃): δ = 1.54 (1 H, ddt, J = 13.0, 6.5, 2.5 Hz), 1.88-1.98 (3 H, m), 2.18 (1 H, dt, J = 17.0, 2.5 Hz), 2.24-2.31 (1 H, m), 2.36-2.45 (1 H, m), 2.82 (1 H, dd, J = 17.0, 2.5 Hz), 2.90 (3 H, s), 3.32-3.34 (2 H, m), 3.34 (1 H, dd, J = 8.0, 2.0 Hz), 6.12 (1 H, dt, J = 5.0, 2.0 Hz), 7.20-7.37 (5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 22.5, 27.9, 29.3, 29.7, 34.4, 43.2, 45.9, 122.9, 125.3, 126.6, 128.0, 134.2, 141.8, 178.5
Compound 12c: ¹H NMR (400 MHz, CDCl₃): δ = 1.78-1.92 (4 H, m), 2.42 (1 H, ddd, J = 17.0, 2.5, 2.5 Hz), 2.58 (1 H, d, J = 15.5 Hz), 3.18 (1 H, dddd, J = 17.0, 2.5, 2.5, 2.5 Hz), 3.35 (2 H, t, J = 6.5 Hz), 3.42 (1 H, dddd, J = 15.5, 2.5, 2.5, 2.5 Hz), 6.02-6.06 (1 H, m), 7.20-7.40 (5 H, m). ¹³C NMR (100 MHz, CDCl₃): δ = 19.9, 35.5, 35.8, 46.3, 48.1, 50.2, 122.5, 125.5, 126.7, 128.2, 136.2, 139.6, 175.7.
Compound 12d: ¹H NMR (300 MHz, CDCl₃): δ = 1.63 (1 H, dddd, J = 9.0, 4.5, 2.0, 2.0 Hz), 1.67-1.74 (1 H, m), 1.76-1.85 (3 H, m), 2.15-2.20 (3 H, m), 2.28 (1 H, dt, J = 16.0, 2.0 Hz), 2.97 (3 H, s), 3.08 (1 H, dt, J = 16.0, 2.0 Hz), 3.27-3.32 (2 H, m), 6.07 (1 H, dt, J = 5.0, 2.0 Hz), 7.21-7.38 (5 H, m). ¹³C NMR (100 MHz, CDCl₃): δ = 19.2, 22.3, 29.0, 30.1, 35.4, 35.9, 40.5, 50.3, 122.5, 125.0, 126.7, 128.2, 134.7, 142.4, 175.8.