Enantioselective Approach to Tropane Skeleton: Synthesis of (1S,5S,6R)-6-Hydroxy-8-methyl-8-azabicyclo[3.2.1]octan-3-one

Abstract

The original and classical Mannich-type construct for the tropane skeleton, developed over half a century ago by Willstätter, Robinson and Schöpf as the first biomimetic synthesis, has been employed for the enantioselective construction of 6β-hydroxytropinone. The component compounds of this novel one-step Mannich-type condensation sequence are acetonedicarboxylic acid, methyl­amine hydrochloride and (2R)-hydroxy-1,4-butanedial, in turn prepared from tert-butyl (R)-3-hydroxy-4-pentenoate as the starting chiral synthon.

tropane alkaloids - kinetic resolution - stereoselective synthesis - multicomponent reactions - tropinones

References

<A NAME="RG40004ST-1">1</A> Singh S. Chem. Rev.  2000,  100:  925 

<A NAME="RG40004ST-2">2</A> Fodor G. Dharanipragada R. Nat. Prod. Rep.  1994,  11:  443 

<A NAME="RG40004ST-3">3</A> Lounasmaa M. Tamminen T. Alkaloids  1993,  44:  1 

<A NAME="RG40004ST-4">4</A> Isomura S. Hoffman TZ. Wirsching P. Janda KD. J. Am. Chem. Soc.  2002,  124:  3661 

<A NAME="RG40004ST-5">5</A> Willstätter R. Ber.  1896,  29:  936 

<A NAME="RG40004ST-6">6</A> Willstätter R. Liebigs Ann. Chem.  1903,  326:  23 

<A NAME="RG40004ST-7">7</A> Robinson R. J. Chem. Soc.  1917,  111:  762 

<A NAME="RG40004ST-8">8</A> Schöpf C. Lehman G. Liebigs Ann.  1935,  518:  1 

<A NAME="RG40004ST-9">9</A> Mikami K. Ohmura H. Chem. Commun.  2002,  2626 ; and references quoted therein

<A NAME="RG40004ST-10">10</A> Mans DM. Pearson WH. Org. Lett.  2004,  3305 ; and references quoted therein

<A NAME="RG40004ST-11">11</A> Albrecht U. Armbrust H. Langer P. Synlett  2004,  143 

<A NAME="RG40004ST-12">12</A> Majewski M. Lazny R. J. Org. Chem.  1995,  60:  5825 

<A NAME="RG40004ST-13">13</A> Majewski M. Lazny R. Ulaczyk A. Can. J. Chem.  1997,  75:  754 

<A NAME="RG40004ST-14">14</A> Chol Lee J. Lee K. Kun Cha J. J. Org. Chem.  2000,  65:  4773 

<A NAME="RG40004ST-15">15</A> Kozikowski AP. Simoni D. Manfredini S. Roberti M. Stoelwinder J. Tetrahedron Lett.  1996,  37:  5333 

<A NAME="RG40004ST-16">16</A> Stoll A. Becker B. Jucker E. Helv. Chim. Acta  1952,  35:  1263 

<A NAME="RG40004ST-17">17</A> Van Tamelen EE. Barth P. Lornitzo F. J. Am. Chem. Soc.  1956,  78:  5442 

<A NAME="RG40004ST-18">18</A> Dewar GH. Parfitt RT. Sheh L. Eur. J. Med. Chem.  1985,  228 

<A NAME="RG40004ST-19">19</A> He X.-S. Brossi A. J. Heterocycl. Chem.  1991,  28:  1741 

<A NAME="RG40004ST-20">20</A> Villacampa M. Martínez M. González-Trigo G. Söllhuber MM. J. Heterocycl. Chem.  1992,  29:  1541 

<A NAME="RG40004ST-21">21</A> Chen Z. Meltzer PC. Tetrahedron Lett.  1997,  38:  1121 

<A NAME="RG40004ST-22">22</A> Zhao L. Kozikowski AP. Tetrahedron Lett.  1999,  40:  4961 

<A NAME="RG40004ST-23">23</A> Zhao L. Johnson KM. Zhang M. Flippen-Anderson J. Kozikowski AP. J. Med. Chem.  2000,  43:  3283 

<A NAME="RG40004ST-24">24</A> Cramer N. Laschat S. Baro A. Synlett  2003,  2178 

<A NAME="RG40004ST-25A">25a</A> Keck GE. Palani A. McHardy SF. J. Org. Chem.  1994,  59:  3113 

<A NAME="RG40004ST-25B">25b</A> Breuilles P. Oddon G. Uguen D. Tetrahedron Lett.  1997,  38:  6607 

<A NAME="RG40004ST-25C">25c</A> Oddon G. Uguen D. De Cian A. Fischer J. Tetrahedron Lett.  1998,  39:  1149 

<A NAME="RG40004ST-26A">26a</A> Solladié G. Wilb N. Bauder C. Bonini C. Viggiani L. Chiummiento L. J. Org. Chem.  1999,  64:  5447 

<A NAME="RG40004ST-26B">26b</A> Solladié G. Wilb N. Bauder C. Tetrahedron Lett.  2000,  41:  4189 

<A NAME="RG40004ST-27A">27a</A> Kumar A. Dittmer DC. J. Org. Chem.  1994,  59:  4760 

<A NAME="RG40004ST-27B">27b</A> Song J. Hollingsworth RI. Tetrahedron: Asymmetry  2001,  12:  387 

<A NAME="RG40004ST-28">28</A> Zibuck R. Streiber JM. J. Org. Chem.  1989,  54:  4717 

<A NAME="RG40004ST-29">29</A> Vrielynck S. Vandewalle M. García AM. Mascareňas JL. Mouriňo A. Tetrahedron Lett.  1995,  36:  9023 

<A NAME="RG40004ST-30">30</A> Tan C.-H. Holmes AB. Chem.-Eur. J.  2001,  7:  1845 

<A NAME="RG40004ST-31">31</A> González-García E. Helaine V. Klein G. Schuermann M. Sprenger GA. Fessner W.-D. Reymond J.-L. Chem.-Eur. J.  2003,  9:  893 

<A NAME="RG40004ST-32">32</A>

Typical Procedure for the Synthesis of (+)-1.
A pentane solution of racemic alcohol (10.0 mmol) and vinyl acetate (20.0 mmol) was stirred at r.t. for 19 h in the presence of PS-C (Pseudomonas cepacia lipase immobilized on ceramic particles). The suspension was filtered to recover the supported enzyme (we found that it might be reused several times without loss of activity) and the solvent was evaporated. Column chromatography of the residue on silica gel (Et₂O-petroleum ether 2:8) yielded (+)-1 (4.6 mmol) with >95% ee.

<A NAME="RG40004ST-33">33</A>

All new compounds gave satisfactory analytical and spectroscopic data. Compound (+)-5: [α]_D ²⁵ +18.4 (c 2.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 1.71 (m, 1 H), 1.91 (m, 1 H), 2.67 (d, J = 2.0 Hz, 1 H), 3.34 (s, 3 H), 3.35 (s, 3 H), 3.42 (s, 3 H), 3.43 (s, 3 H), 3.80 (m, 1 H), 4.16 (d, J = 6.0 Hz, 1 H), 4.62 (dd, J = 5.2 and 6.5 Hz, 1 H). Compound (-)-6: ¹H NMR (400 MHz, CDCl₃): δ = 1.90-2.00 (m, 1 H), 2.00-2.05 (m, 1 H), 2.05-2.08 (m, 1 H), 2.14-2.19 (m, 1 H), 2.61 (s, 3 H), 2.60-2.68 (m, 2 H), 3.00 (br s, 1 H), 3.34 (d, J = 4.8 Hz, H-5), 3.56 (m, H-1), 4.03 (dd, J = 2.4 and 6.8 Hz, H-6). ¹³C NMR (100 MHz, CDCl₃): δ = 34.6, 41.0, 41.4, 43.4, 58.9, 68.2, 75.1, 207.8.

<A NAME="RG40004ST-34">34</A> Chen Z. Gonzalez MD. Blundell P. Meltzer PC. Tetrahedron Lett.  1997,  38:  6823 

<A NAME="RG40004ST-35">35</A> Barco A. Benetti S. De Risi C. Marchetti P. Pollini GP. Zanirato V. Tetrahedron  1999,  55:  5923 

<A NAME="RG40004ST-36">36</A> Justice DE. Malpass JR. Tetrahedron Lett.  1995,  36:  4689