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:

1a Gant TG. Meyers AI. Tetrahedron  1994,  50:  2297 

1b Beak P. Basu A. Gallagher DJ. Park YS. Thayumanavan S. Acc. Chem. Res.  1996,  29:  552 

1c Gawley RE. Curr. Org. Chem.  1997,  1:  71 

1d Kessar SV. Singh P. Chem. Rev.  1997,  97:  721 

1e Katritzky A. Qi M. Tetrahedron  1998,  54:  2647 

1f Husson HP. Royer J. Chem. Soc. Rev.  1999,  28:  383 

1g 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:

2a Meyers AI. Dickman DA. Bailey TR. J. Am. Chem. Soc.  1985,  107:  7974 

2b Huang P.-Q. Arseniyadis S. Husson H.-P. Tetrahedron Lett.  1987,  28:  547 

2c Gawley RE. Hart GC. Bartolotti LJ. J. Org. Chem.  1989,  54:  175 

2d Pearson WH. Lindbeck AC. Kampf JW. J. Am. Chem. Soc.  1993,  115:  2622 

2e Wu S. Lee S. Beak P. J. Am. Chem. Soc.  1996,  118:  715 

2f Coldham I. Hufton R. Snowden D. J. Am. Chem. Soc.  1996,  118:  5322 

2g Dearden MJ. Firkin CR. Hermet J.-PR. O’Brien P. J. Am. Chem. Soc.  2002,  124:  11870 

2h Wiberg KB. Bailey WF. Angew. Chem. Int. Ed.  2000,  39:  2127 

2i Watson RT. Gore VK. Chandupatla KR. Dieter RK. Snyder JP. J. Org. Chem.  2004,  69:  6105 

3 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:

4a Huang P.-Q. Wu T.-J. Ruan Y.-P. Org. Lett.  2003,  5:  4341 

4b Huang P.-Q. Deng J. Synlett  2004,  247 

5 Beak P. Lee WK. J. Org. Chem.  1993,  58:  1109 

6a Sunose M. Peakman TM. Charmant JPH. Gallagher T. Macdonald SJF. Chem. Commun.  1998,  1723 

6b Pandey G. Chakrabarti D. Tetrahedron Lett.  1998,  39:  8371 ; and references cited therein

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

7a Iwanami S. Takashima M. Hirata Y. Hasegawa O. Usuda S. J. Med. Chem.  1981,  24:  1224 

7b Drugs Future  1991,  16:  95 

7c Andres CJ. Lee PH. Nguyen TH. Meyers AI. J. Org. Chem.  1995,  60:  3189 

7d Huang P.-Q. Wang SL. Ye JL. Ruan YP. Huang YQ. Zheng H. Gao J. Tetrahedron  1998,  54:  12547 

7e Borthwick AD. Crame AJ. Davies DE. Exall AM. Jackson DL. Mason AM. Pennell AMK. Weingarten GG. Synlett  2000,  504 

7f Cooke JWB. Berry MB. Caine DM. Cardwell KS. Cook JS. Hodgson A. J. Org. Chem.  2001,  66:  334 

7g 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:

8a 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 

8b Norton Matos MRP. Afonso CAM. Batey RA. Tetrahedron Lett.  2001,  42:  7007 

8c Suero R. Gorgojo JM. Aurrecoechea M. Tetrahedron  2002,  58:  6211 

9 Flynn DL. Zabrowski DL. Becker DP. Nosal R. Villamil CI. Gullickson GW. Moummi C. Yang D.-C. J. Med. Chem.  1992,  35:  1489 

10a For a recent asymmetric synthesis of 1-aminopyrrolizidine, see: Giri N. Petrini M. Profeta R. J. Org. Chem.  2004,  69:  7303 

10b 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:

11a Suri KA. Suri OP. Sawhney RS. Gupta OP. Atal CK. Indian J. Chem., Sect. B  1977,  15:  972 

11b Suri KA. Suri OP. Atal CK. Indian J. Chem., Sect. B  1983,  22:  822 

11c Zabrowski DL. Becker DP. Nosal R. Villamil CI. Gullikson GW. Moummi C. Yang D.-C. J. Med. Chem.  1992,  35:  1486 

11d

Ref. [13]

12 Ikhiri K. Ahond A. Poupat C. Potier P. Pusset J. Sévenet T. J. Nat. Prod.  1987,  50:  626 

13 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 

14 Neuner-Jehle N. Nesvadba H. Spiteller G. Monatsh. Chem.  1965,  96:  321 

15a Glass RS. Deardorff DR. Gains LH. Tetrahedron Lett.  1978,  2965 

15b Wilson SR. Sawicki RA. Huffman JC. J. Org. Chem.  1981,  46:  3887 

15c Tufariello JJ. Merckler H. Winzenberg K. J. Org. Chem.  1986,  51:  3556 

16 Huang P.-Q. Zheng X. Wang S.-L. Ye J.-L. Jin L.-R. Chen Z. Tetrahedron: Asymmetry  1999,  10:  3309 

17a Screttas CG. Micha-Screttas M. J. Org. Chem.  1978,  43:  1064 

17b Freeman PK. Hutchinson LL. J. Org. Chem.  1980,  45:  1924 

17c Cohen T. Matz JR. J. Am. Chem. Soc.  1980,  102:  6900 

17d Tsunoda T. Fujiwara K. Yamamoto Y. Ito S. Tetrahedron Lett.  1991,  32:  1975 

17e For reviews, see: Cohen T. Bhupathy M. Acc. Chem. Res.  1989,  22:  152 

17f Yus M. Chem. Soc. Rev.  1996,  25:  155 

17g Cohen T. Pure Appl. Chem.  1996,  68:  913 

For analogue glycosyl dianions, see:

18a Hoffmann M. Kessler H. Tetrahedron Lett.  1994,  35:  6067 

18b Urban D. Skrydstrup T. Riche C. Chiaroni A. Beau JM. Chem. Commun.  1996,  1883 

18c Westermann B. Walter A. Diedrichs N. Angew. Chem. Int. Ed.  1999,  38:  3384 

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

20 Wijberg JBPA. Schoemaker HE. Speckamp WN. Tetrahedron  1978,  34:  179 

21

All new compounds gave satisfactory analytical and spectral data.

22

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.

23 Rychnovsky SD. Skalitzky DJ. J. Org. Chem.  1992,  57:  4336 

24 Sibi MP. Christensen JW. J. Org. Chem.  1999,  64:  6434 

25

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.

26

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