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.

Key words

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

References

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• 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.

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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).

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.

17

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

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.