A Flexible Carbanionic Approach to Protected trans-(2R,3S)-2-Substituted 3-Aminopyrrolidines: Application to the Asymmetric Synthesis of (+)-Absouline

Abstract

Based on the use of phenyl thioether (3S)-7 as a synthetic equivalent to the N- and α-dianions (3S)-2a, a new carbanionic approach to trans-(2R,3S)-2-substituted 3-aminopyrrolidines (10) is described. Application of the method to the asymmetric synthesis of 1-aminopyrrolizidine alkaloid (+)-absouline is also reported.

asymmetric synthesis - additions - pyrrolidine - carbanions - reductive lithiation

References

For reviews involving the generation and application of α-lithioamines, see:

<A NAME="RU28804ST-1A">1a</A> Gant TG. Meyers AI. Tetrahedron  1994,  50:  2297 

<A NAME="RU28804ST-1B">1b</A> Beak P. Basu A. Gallagher DJ. Park YS. Thayumanavan S. Acc. Chem. Res.  1996,  29:  552 

<A NAME="RU28804ST-1C">1c</A> Gawley RE. Curr. Org. Chem.  1997,  1:  71 

<A NAME="RU28804ST-1D">1d</A> Kessar SV. Singh P. Chem. Rev.  1997,  97:  721 

<A NAME="RU28804ST-1E">1e</A> Katritzky A. Qi M. Tetrahedron  1998,  54:  2647 

<A NAME="RU28804ST-1F">1f</A> Husson HP. Royer J. Chem. Soc. Rev.  1999,  28:  383 

<A NAME="RU28804ST-1G">1g</A> Rassu G. Zanardi F. Battistini L. Casiraghi G. Chem. Soc. Rev.  2000,  29:  109 

For representative approaches to optically active α-lithiopyrrolidines and α-lithiopiperidines, see:

<A NAME="RU28804ST-2A">2a</A> Meyers AI. Dickman DA. Bailey TR. J. Am. Chem. Soc.  1985,  107:  7974 

<A NAME="RU28804ST-2B">2b</A> Huang P.-Q. Arseniyadis S. Husson H.-P. Tetrahedron Lett.  1987,  28:  547 

<A NAME="RU28804ST-2C">2c</A> Gawley RE. Hart GC. Bartolotti LJ. J. Org. Chem.  1989,  54:  175 

<A NAME="RU28804ST-2D">2d</A> Pearson WH. Lindbeck AC. Kampf JW. J. Am. Chem. Soc.  1993,  115:  2622 

<A NAME="RU28804ST-2E">2e</A> Wu S. Lee S. Beak P. J. Am. Chem. Soc.  1996,  118:  715 

<A NAME="RU28804ST-2F">2f</A> Coldham I. Hufton R. Snowden D. J. Am. Chem. Soc.  1996,  118:  5322 

<A NAME="RU28804ST-2G">2g</A> Dearden MJ. Firkin CR. Hermet J.-PR. O’Brien P. J. Am. Chem. Soc.  2002,  124:  11870 

<A NAME="RU28804ST-2H">2h</A> Wiberg KB. Bailey WF. Angew. Chem. Int. Ed.  2000,  39:  2127 

<A NAME="RU28804ST-2I">2i</A> Watson RT. Gore VK. Chandupatla KR. Dieter RK. Snyder JP. J. Org. Chem.  2004,  69:  6105 

<A NAME="RU28804ST-3">3</A> For a racemic synthetic equivalent to synthon 2 (X = O), see: Thompson SHJ. Subramanian RS. Roberts JK. Hadley MS. J. Chem. Soc., Chem. Commun.  1994,  933 

For chiral non-racemic synthetic equivalents to synthon 2 (X = O), see:

<A NAME="RU28804ST-4A">4a</A> Huang P.-Q. Wu T.-J. Ruan Y.-P. Org. Lett.  2003,  5:  4341 

<A NAME="RU28804ST-4B">4b</A> Huang P.-Q. Deng J. Synlett  2004,  247 

<A NAME="RU28804ST-5">5</A> Beak P. Lee WK. J. Org. Chem.  1993,  58:  1109 

<A NAME="RU28804ST-6A">6a</A> Sunose M. Peakman TM. Charmant JPH. Gallagher T. Macdonald SJF. Chem. Commun.  1998,  1723 

<A NAME="RU28804ST-6B">6b</A> Pandey G. Chakrabarti D. Tetrahedron Lett.  1998,  39:  8371 ; and references cited therein

For approaches to optically active 2-substituted 3-aminopyrrolidines, see:

<A NAME="RU28804ST-7A">7a</A> Iwanami S. Takashima M. Hirata Y. Hasegawa O. Usuda S. J. Med. Chem.  1981,  24:  1224 

<A NAME="RU28804ST-7B">7b</A> Drugs Future  1991,  16:  95 

<A NAME="RU28804ST-7C">7c</A> Andres CJ. Lee PH. Nguyen TH. Meyers AI. J. Org. Chem.  1995,  60:  3189 

<A NAME="RU28804ST-7D">7d</A> Huang P.-Q. Wang SL. Ye JL. Ruan YP. Huang YQ. Zheng H. Gao J. Tetrahedron  1998,  54:  12547 

<A NAME="RU28804ST-7E">7e</A> Borthwick AD. Crame AJ. Davies DE. Exall AM. Jackson DL. Mason AM. Pennell AMK. Weingarten GG. Synlett  2000,  504 

<A NAME="RU28804ST-7F">7f</A> Cooke JWB. Berry MB. Caine DM. Cardwell KS. Cook JS. Hodgson A. J. Org. Chem.  2001,  66:  334 

<A NAME="RU28804ST-7G">7g</A> Andrews DM. Carey SJ. Chaignot H. Coomber BA. Gray NM. Hind SL. Jones PS. Mills G. Robinson JE. Slater MJ. Org. Lett.  2002,  4:  4475 

For approaches to racemic 2-substituted 3-aminopyrrolidines, see:

<A NAME="RU28804ST-8A">8a</A> MacDonald SJF. Clarke GDE. Dowle MD. Harrison LA. Hodgson ST. Inglis GGA. Johnson MR. Shah P. Upton RJ. Walls SB. J. Org. Chem.  1999,  64:  5166 

<A NAME="RU28804ST-8B">8b</A> Norton Matos MRP. Afonso CAM. Batey RA. Tetrahedron Lett.  2001,  42:  7007 

<A NAME="RU28804ST-8C">8c</A> Suero R. Gorgojo JM. Aurrecoechea M. Tetrahedron  2002,  58:  6211 

<A NAME="RU28804ST-9">9</A> Flynn DL. Zabrowski DL. Becker DP. Nosal R. Villamil CI. Gullickson GW. Moummi C. Yang D.-C. J. Med. Chem.  1992,  35:  1489 

<A NAME="RU28804ST-10A">10a</A> For a recent asymmetric synthesis of 1-aminopyrrolizidine, see: Giri N. Petrini M. Profeta R. J. Org. Chem.  2004,  69:  7303 

<A NAME="RU28804ST-10B">10b</A> For an approach to optically active 1-aminopyrrolizidin-3-one derivative, see: Langlois N. Radom M.-O. Tetrahedron Lett.  1998,  39:  857 

For approaches to racemic 1-aminopyrrolizidines, see:

<A NAME="RU28804ST-11A">11a</A> Suri KA. Suri OP. Sawhney RS. Gupta OP. Atal CK. Indian J. Chem., Sect. B  1977,  15:  972 

<A NAME="RU28804ST-11B">11b</A> Suri KA. Suri OP. Atal CK. Indian J. Chem., Sect. B  1983,  22:  822 

<A NAME="RU28804ST-11C">11c</A> Zabrowski DL. Becker DP. Nosal R. Villamil CI. Gullikson GW. Moummi C. Yang D.-C. J. Med. Chem.  1992,  35:  1486 

<A NAME="RU28804ST-11D">11d</A>

Ref. [13]

<A NAME="RU28804ST-12">12</A> Ikhiri K. Ahond A. Poupat C. Potier P. Pusset J. Sévenet T. J. Nat. Prod.  1987,  50:  626 

<A NAME="RU28804ST-13">13</A> For preparation of both enantiomers of absouline by racemic synthesis followed by chiral HPLC separation, see: Christine C. Ikhiri K. Ahond A. Mourabit AA. Poupat C. Potier P. Tetrahedron  2000,  56:  1837 

<A NAME="RU28804ST-14">14</A> Neuner-Jehle N. Nesvadba H. Spiteller G. Monatsh. Chem.  1965,  96:  321 

<A NAME="RU28804ST-15A">15a</A> Glass RS. Deardorff DR. Gains LH. Tetrahedron Lett.  1978,  2965 

<A NAME="RU28804ST-15B">15b</A> Wilson SR. Sawicki RA. Huffman JC. J. Org. Chem.  1981,  46:  3887 

<A NAME="RU28804ST-15C">15c</A> Tufariello JJ. Merckler H. Winzenberg K. J. Org. Chem.  1986,  51:  3556 

<A NAME="RU28804ST-16">16</A> Huang P.-Q. Zheng X. Wang S.-L. Ye J.-L. Jin L.-R. Chen Z. Tetrahedron: Asymmetry  1999,  10:  3309 

<A NAME="RU28804ST-17A">17a</A> Screttas CG. Micha-Screttas M. J. Org. Chem.  1978,  43:  1064 

<A NAME="RU28804ST-17B">17b</A> Freeman PK. Hutchinson LL. J. Org. Chem.  1980,  45:  1924 

<A NAME="RU28804ST-17C">17c</A> Cohen T. Matz JR. J. Am. Chem. Soc.  1980,  102:  6900 

<A NAME="RU28804ST-17D">17d</A> Tsunoda T. Fujiwara K. Yamamoto Y. Ito S. Tetrahedron Lett.  1991,  32:  1975 

<A NAME="RU28804ST-17E">17e</A> For reviews, see: Cohen T. Bhupathy M. Acc. Chem. Res.  1989,  22:  152 

<A NAME="RU28804ST-17F">17f</A> Yus M. Chem. Soc. Rev.  1996,  25:  155 

<A NAME="RU28804ST-17G">17g</A> Cohen T. Pure Appl. Chem.  1996,  68:  913 

For analogue glycosyl dianions, see:

<A NAME="RU28804ST-18A">18a</A> Hoffmann M. Kessler H. Tetrahedron Lett.  1994,  35:  6067 

<A NAME="RU28804ST-18B">18b</A> Urban D. Skrydstrup T. Riche C. Chiaroni A. Beau JM. Chem. Commun.  1996,  1883 

<A NAME="RU28804ST-18C">18c</A> Westermann B. Walter A. Diedrichs N. Angew. Chem. Int. Ed.  1999,  38:  3384 

<A NAME="RU28804ST-19">19</A> Tang T. Zhu C. Huang P.-Q. Heterocycles  2004,  64:  in press ; (http://www.heterocycles.jp/heterohtml/index.html)

<A NAME="RU28804ST-20">20</A> Wijberg JBPA. Schoemaker HE. Speckamp WN. Tetrahedron  1978,  34:  179 

<A NAME="RU28804ST-21">21</A>

All new compounds gave satisfactory analytical and spectral data.

<A NAME="RU28804ST-22">22</A>

General Procedure for the One-Pot Synthesis of Compounds 10a-h:
To a solution of phenyl thioether 7 (0.48 mmol) in anhyd THF (1.6 mL) at -78 °C was added successively n-BuLi (2.0 M solution in n-hexane, 0.69 mmol) and freshly prepared lithium naphthalenide (1.5 M solution in THF, 1.36 mmol). After being stirred for 30 min, an electrophile (0.70 mmol) was added. The stirring was maintained at -78 °C for 1 h, then allowed to warm to 0 °C. A sat. aq solution of NH₄Cl was added and the mixture was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. Flash chromatography (EtOAc-petroleum ether = 1:3) of the crude afforded the desired product 10b-i and a small amount of reduced product 10a.
Data for 10b: Electrophile used: acetone. Yield 86%; colorless oil; [α]_D ²⁰ -4.95 (c 1.0, CHCl₃). IR (film): ν_max = 3421, 3319, 2975, 1697, 1669, 1535, 1399, 1246, 1170, 1122 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ(rotamers) = 1.15 (br s, 3 H), 1.34 (br s, 3 H), 1.48 (s, 9 H), 1.68-1.78 (m, 1 H), 2.20-2.32 (m, 1 H), 3.28-3.36 (m, 1 H), 3.60-3.80 (m, 2 H), 4.10-4.20 (m, 1 H), 4.80-5.00 (m, 2 H), 5.10 (m, 2 H), 7.28-7.40 (m, 5 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ(rotamers) = 28.26 (1 C), 28.38 (1 C), 29.58 (3 C), 30.19, 30.66, 31.10 (1 C), 43.88, 44.15 (1 C), 49.89 (1 C), 50.38, 50.68 (1 C), 65.57, 65.70 (1 C), 72.22 (1 C), 78.51, 78.83 (1 C), 128.00, 128.06, 128.48, 128.57, 137.23, 137.38 (6 C), 153.72 (1 C), 155.68, 155.97 (1 C). MS (ESI): m/z (%) = 379 (100) [M + H⁺], 401 (60) [M + Na⁺]. HRMS: m/z calcd for [C₂₀H₃₀N₂O₅ + H]⁺: 379.2234; found: 379.2233.

<A NAME="RU28804ST-23">23</A> Rychnovsky SD. Skalitzky DJ. J. Org. Chem.  1992,  57:  4336 

<A NAME="RU28804ST-24">24</A> Sibi MP. Christensen JW. J. Org. Chem.  1999,  64:  6434 

<A NAME="RU28804ST-25">25</A>

In the reported ¹H NMR and ¹³C NMR spectral data of 1-aminopyrrolizidine and its derivatives (13, [10a] 14, [10a] [12] 4, [11] [12] and 5 [11] [12] ), some differences exist from one to the other. This may be due to conformational isomerism and/or H-bond formation in the 1-aminopyrrolizidine ring system. In addition, these molecules were shown to be labile.

<A NAME="RU28804ST-26">26</A>

We thank Dr. C. Poupat (Institut de Chimie des Substances Naturelles, CNRS, France) for sending us a sample of natural absouline.