Stereoselective Synthesis of 8-Substituted 6-Azabicyclo[3.2.1]octan-3-ones

Abstract

The vinylogous imide photocycloaddition-retro-­Mannich-Mannich cascade leads to the stereoselective synthesis of 8-substituted azabicyclooctanones.

photochemistry - Mannich bases - annulations - asymmetric synthesis - bicyclic compounds

References and Notes

1 Kwak Y.-S. Winkler JD. J. Am. Chem. Soc.  2001,  123:  7429 

2a Cimino G. Mattia CA. Mazzarella L. Puliti R. Scognamiglio G. Spinella A. Trivellone E. Tetrahedron  1989,  45:  3863 

2b The first total synthesis of sarain A has recently been described: Garg NK. Hiebert S. Overman LE. Angew. Chem. Int. Ed.  2006,  45:  2912 

For recent approaches to the synthesis of the sarain alkaloids, see:

3a Ge CS. Hourcade S. Ferdenzi A. Chiaroni A. Mons S. Delpech B. Marazano C. Eur. J. Org. Chem.  2006,  4106 

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4

All new compounds were purified chromatographically (>95%) and were fully characterized by ^¹H NMR, ^¹³C NMR, IR, and HRMS.

5

Compound 14 (major): ^¹H NMR (500 MHz, CDCl₃, * de-notes rotamer peak): δ = 4.01 (s, 0.5 H), 3.89* (s, 0.5 H), 3.69 (s, 1.5 H), 3.68* (s, 1.5 H), 3.63 (ddd, J = 11.0, 5.3, 1.5 Hz, 0.5 H), 3.56* (ddd, 10.7, 5.0, 1.7 Hz, 0.5 H), 3.28 (d, J = 11.1 Hz, 0.5 H), 3.23* (d, J = 10.9 Hz, 0.5 H), 2.85 (ddd, J = 17.4, 2.4, 2.4 Hz, 0.5 H), 2.73* (ddd, J = 17.3, 2.2, 2.2 Hz, 0.5 H), 2.75-2.38 (m, 3), 2.34 (br s, 1 H), 2.28 (m, 1 H), 1.08 (d, J = 2.6 Hz, 1.5 H), 1.07* (d, J = 2.7 Hz, 1.5 H). ^¹³C NMR (125 MHz, CDCl₃, * denotes rotamer peak): δ = 209.0, 208.8*, 155.342, 59.3, 59.2*, 52.5, 52.4*, 49.9, 49.5*, 48.9, 48.8*, 47.6, 47.1*, 43.1, 42.3*, 41.8, 41.6*, 39.6, 38.7*, 29.7, 16.6, 16.5*. IR (neat): 2957, 1701, 1452, 1387, 1191, 1114 cm^-¹. HRMS (CI): m/z calcd for C₁₀H₁₅NO₃ [M⁺]: 197.1052; found: 197.1056.
Compound 15 (minor): ^¹H NMR (500 MHz, CDCl₃, * de-notes rotamer peak): δ = 4.13 (s, 0.5 H), 4.03* (s, 0.5 H), 3.67 (s, 1.5 H), 3.65* (s, 1.5 H), 3.50 (m, 0.5 H), 3.46* (m, 0.5 H), 3.33 (d, J = 10.6 Hz, 0.5 H), 3.28* (d, J = 10.4, 0.5 H), 2.72 (d, J = 17.8 Hz, 0.5 H), 2.61 (m, 1.5 H), 2.32-2.44 (m, 3 H), 1.22 (d, J = 3.0 Hz, 1.5 H), 1.21 (d, J = 3.0 Hz, 1.5 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 208.9, 208.8*, 155.0, 154.9*, 56.4, 56.3*, 52.9, 52.6*, 52.4, 52.3*, 43.1, 43.0*, 42.3, 41.8*, 37.7, 37.4*, 36.9, 36.8*, 11.4, 11.3*. IR (neat): 2960, 2921, 2853, 1705, 1451, 1393, 1350, 1311, 1258, 1190, 1118 cm^-¹. ESI-HRMS: m/z calcd for C₁₀H₁₄NO₃ [MH⁺]: 198.1130; found: 198.1123.

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11c

An improved synthesis of 22 will be reported separately.

12

Compound 28: ^¹H NMR (500 MHz, CDCl₃, * denotes rotamer peak): δ = 4.00 (d, J = 4.2 Hz, 0.5 H), 3.89 (m, 2.5 H), 3.76 (m, 2 H), 3.73 (s, 3 H), 3.69 (s, 3 H), 3.67 (d, J = 10.9 Hz, 0.5 H), 3.61 (d, J = 10.9 Hz, 0.5 H), 3.41 (m,
1 H), 2.83 (br, 1 H), 1.80-2.14 (m, 4 H), 1.31 (s, 3 H). ^¹³C NMR (125 MHz, CDCl₃, * denotes rotamer peak): δ = 174, 155.7, 107.0, 64.2, 63.2, 58.9, 58.8*, 53.1, 52.4*, 52.2, 51.9, 48.1, 47.9*, 39.5, 38.7*, 38.3, 38.0*, 36.4, 35.2*, 22.4, 22.3*. IR (neat): 2955, 2885, 1700, 1451, 1389, 1195, 1116, 1062, 1023 cm^-¹. HRMS (CI): m/z calcd for C₁₄H₂₁NO₆ [MH⁺]: 300.1447; found: 300.1445.

13 Garner P. Anderson JT. Dey S. Youngs WJ. Galat K. J. Org. Chem.  1998,  63:  5732