Total Synthesis of Sperabillin A and C

Abstract

The first total synthesis of sperabillin A and an improved total synthesis of sperabillin C have been achieved in 11 steps from N-Boc-O-methyl-l-tyrosine. The stereoselective pathway to the core (3R,5R)-3,6-diamino-5-hydroxyhexanoic acid involves an Arndt-Eistert homologation, an asymmetric Henry reaction and a ruthenium tetroxide-catalyzed oxidative degradation of a benzene ring as key steps.

sperabillins - antibiotics - pseudo-peptides - Henry reaction - ruthenium tetroxide

References

1 Hamada M. Takeuchi T. Kondo S. Ikeda Y. Naganawa H. Maeda K. Okami Y. Umezawa H. J. Antibiot.  1970,  23:  170 

2a Harada S, and Ono H. inventors; Eur. Pat. Appl.;  EP206068. 

2b Katayama N. Nozaki Y. Tsubotani S. Kondo M. Harada S. Ono H. J. Antibiot.  1992,  45:  10 

2c Hida T. Tsubotani S. Funabashi Y. Ono H. Harada S. Bull. Chem. Soc. Jpn.  1993,  66:  863 

For some recent examples see:

3a Raju B. Mortell K. Anandan S. O’Dowd H. Gao H. Gomez M. Hackbarth C. Wu C. Wang W. Yuan Z. White R. Trias J. Patel DV. Bioorg. Med. Chem. Lett.  2003,  13:  2413 

3b Jain RP. Williams RM. J. Org. Chem.  2002,  67:  6361 

3c Davies SG. Ichihara O. Tetrahedron: Asymmetry  1996,  7:  1919 

4 Hashiguchi S. Kawada A. Natsugari H. Synthesis  1992,  403 

Highly efficient asymmetric total syntheses of sperabillin B (3b) and D (3d) have been reported recently, see:

5a Davies SG. Kelly RJ. Price Mortimer AJ. Chem. Commun.  2003,  2132 

5b Davies SG. Haggitt JR. Ichihara O. Kelly RJ. Leech MA. Price Mortimer AJ. Roberts PM. Smith AD. Org. Biomol. Chem.  2004,  2:  2630 

5c For a previous chiral-pool synthesis of sperabillin D (3d) see: Hashiguchi S. Kawada A. Natsugari H. J. Chem. Soc., Perkin Trans. 1  1991,  2435 

6 Chen HG. Tustin JM. Wuts PGM. Sawyer TK. Smith CW. Int. J. Pept. Protein Res.  1995,  45:  1 

7 Jackson RFW. Dexter CS. J. Org. Chem.  1999,  64:  7579 

8a Ohtake N. Okamoto O. Mitomo R. Kato Y. Yamamoto K. Haga Y. Fukatsu H. Nakagawa S. J. Antibiot.  1997,  50:  598 

8b Rudolph J. Hanning F. Theis H. Wischnat R. Org. Lett.  2001,  3:  3153 

8c Paintner FF. Allmendinger L. Bauschke G. Klemann P. Org. Lett.  2005,  7:  1423 

9 Evans DA. Seidel D. Rueping M. Lam HW. Shaw JT. Downey CW. J. Am. Chem. Soc.  2003,  125:  12692 

10

The reaction of chiral aldehyde 6 with nitromethane in the presence of catalyst (+)-11 represents the matched case of double diastereoselection, since application of the enantiomeric catalyst (-)-11 gave the corresponding epimer of 5 with slightly lower stereoselectivity (91% de).

For recent examples see:

11a Emmer G. Grassberger MA. Meingassner JG. Schulz G. Schaude M. J. Med. Chem.  1994,  37:  1908 

11b Matsuura F. Hamada Y. Shioiri T. Tetrahedron  1994,  50:  9457 

11c Georgiadis D. Matziari M. Vassiliou S. Dive V. Yiotakis A. Tetrahedron  1999,  55:  14635 

11d Walker JR. Curley RW. Tetrahedron  2001,  57:  6695 

11e Moutevelis-Minakakis P. Sinanoglou C. Loukas V. Kokotos G. Synthesis  2005,  933 

11f For a recent review covering the oxidative degradation of benzene rings see: Mander LN. Williams CM. Tetrahedron  2003,  59:  1105 

12a Yoshifuji S. Tanaka K. Nitta Y. Chem. Pharm. Bull.  1985,  33:  1749 

12b Tanaka K. Yoshifuji S. Nitta Y. Chem. Pharm. Bull.  1988,  36:  3125 

13a

In addition to product 10, its N-formyl derivative 3-tert-butoxycarbonylformylamino-5-tert-butyldimethylsilyloxy-6-nitrohexanoic acid (5% yield) and trace amounts (<1%) of 4-tert-butoxycarbonylamino-2-tert-butyldimethyl-silyloxyhexanedioic acid, the latter indicating a Nef-type reaction at the nitromethyl group, were obtained. Application of the reaction conditions [2.2 mol% RuCl, NaIO₄ (18 equiv), CCl₄-MeCN-H₂O = 2:2:3, r.t.] previously developed by Sharpless and co-workers (see ref. 13b) gave the oxidation product 10 in a 41% yield together with 24% of the N-formyl derivative mentioned above.

13b Carlsen PHJ. Katsuki T. Martin VS. Sharpless KB. J. Org. Chem.  1981,  46:  3936 

14

In the absence of sodium hydrogen carbonate a somewhat lower yield (56%) of product 10 was obtained.

15

Spectroscopic data of compound 4: [α]_D ²⁰ +20.8 (c 0.95 in CH₂Cl₂). ¹H NMR (500 MHz, MeOH-d ₄): δ = 0.13 (3 H, s), 0.15 (3 H, s), 0.92 (9 H, s), 1.43 (9 H, s_br), 1.78 (2 H, m), 2.31 (1 H, dd, J = 14.9, 7.7 Hz), 2.39 (1 H, dd, J = 14.9, 4.7 Hz), 3.01 (1 H, dd, J = 13.0, 4.1 Hz), 3.06 (1 H, dd, J = 13.0, 4.9 Hz), 3.85 (1 H, m), 4.18 (1 H, m), 4.09 (1 H, m). ¹³C NMR (100 MHz, MeOH-d ₄): δ = -5.0, 18.4, 25.9, 28.3, 40.0, 43.5, 45.2, 45.8, 67.7, 79.6, 157.1, 178.6.

16 Rossi R. Carpita A. Quirici MG. Gaudenti ML. Tetrahedron  1982,  38:  631 

17

For an alternative stereoselective approach to (2E,4Z)-hexa-2,4-dienoic acid (14), see ref. 5b.

18 Smith AB. Pitram SM. Boldi AM. Gaunt MJ. Sfouggatakis C. Moser WH. J. Am. Chem. Soc.  2003,  125:  14435 

19a Barker PL. Gendler PL. Rapoport H. J. Org. Chem.  1981,  46:  2455 

19b Josse O. Labar D. Marchand-Brynaert J. Synthesis  1999,  404 

20 For a previous synthesis of 3-aminopropionamidine, starting from 3-aminopropionitril, see: Hilgetag G. Paul H. Günther J. Witt M. Chem. Ber.  1964,  97:  704 

21 Lee HK. Ten LN. Pak CS. Bull. Korean Chem. Soc.  1998,  19:  1148 

22

Spectroscopic data of sperabillin A (3a) [2c] : [α]_D ²³ -11.4 (c 0.4 in H₂O), lit. [2c] [α]_D ²³ -11 (c 1.1 in H₂O). ¹H NMR (500 MHz, D₂O): δ = 1.77 (1 H, ddd, J = 4.5, 10.0, 15.0 Hz), 1.87 (3 H, d, J = 7.2 Hz), 1.87 (1 H, m), 2.68 (2 H, t, J = 6.6 Hz), 2.74 (2 H, m), 3.33 (1 H, dd, J = 6.6, 14.0 Hz), 3.39 (1 H, dd, J = 4.5, 14.0 Hz), 3.55 (1 H, dt, J = 6.6, 14.0 Hz), 3.59 (1 H, dt, J = 6.7, 14.0 Hz), 3.86 (1 H, m), 4.00 (1 H, m), 6.02 (1 H, dq, J = 7.2, 10.8 Hz), 6.07 (1 H, d, J = 15.1 Hz), 6.23 (1 H, t, J = 10.8 Hz), 7.56 (1 H, dd, J = 11.8, 15.1 Hz). ¹³C NMR (100 MHz, D₂O): δ = 16.0, 35.3, 38.0, 39.2, 39.8, 47.8, 49.1, 69.1, 125.1, 129.6, 139.4, 139.5, 171.7, 172.4, 174.7.

23

Spectroscopic data of sperabillin C (3c) [2c] : [α]_D ²³ -10.2 (c 0.4 in H₂O), lit. [2c] [α]_D ²⁰ -11 (c 0.7 in H₂O). ¹H NMR (500 MHz, D₂O): δ = 1.75 (1 H, ddd, J = 4.7, 10.0, 15.0 Hz), 1.83 (3 H, d, J = 5.5 Hz), 1.87 (1 H, ddd, J = 3.1, 7.5, 15.0 Hz), 2.67 (2 H, t, J = 6.7 Hz), 2.73 (2 H, d, J = 7.0 Hz), 3.30 (1 H, dd, J = 6.5, 14.0 Hz), 3.37 (1 H, dd, J = 4.7, 14.0 Hz), 3.57 (2 H, m), 3.85 (1 H, m), 3.98 (1 H, m), 5.97 (1 H, d, J = 15.5 Hz), 6.26 (2 H, m), 7.13 (1 H, dd, J = 9.7, 15.5 Hz). ¹³C NMR (100 MHz, D₂O): δ = 20.7, 35.3, 38.0, 39.2, 39.8, 47.8, 49.1, 69.1, 122.9, 132.0, 143.2, 145.4, 171.6, 172.5, 174.7.