Syntheses and evaluation of multicaulin and miltirone-like compounds as antituberculosis agents

Figures & data

Figure 1. Structures of abietane-type diterpenes 1–4, which include a quinone moiety in the C-ring.

Figure 2. Structures of aromatic norabietanes 5–8.

Figure 3. Four C-ring functionalised abietane-like compounds (9–12).

Scheme 1. Retrosynthetic analysis for compounds 9–12.

Scheme 2. Reaction conditions and reagents: (i) Me₂SO₄, NaOH (aq), 90 °C, 4 h, 93%; (ii) LiBr/(NH₄)₂Ce(NO₃)₆, CH₃CN, 20 °C, 2 h, 97%; (iii) CuCN, DMF, 140 °C, 12 h, 90%; (iv) EtOH, H₂SO₄, reflux, 12 h, 84%; (v) LiAlH₄, THF, 0 °C, 4 h, 91%; (vi) PBr₃, DCM, 0 °C, 12 h, 92%; (vii) PPh₃, CH₃CN, reflux, 24 h; (viii) NaH, DCM, 0 °C, 15 min; and 2-nitrobenzaldehyde (15), 20 °C, rt, 16 h; and (ix) H₂, Pd/C, MeOH, 20 °C, 2 h.

Scheme 3. Synthesis of 11 and 12^a. ^aReaction conditions and reagents: (i) isopentyl nitrite, H₂SO₄, acetone, 0–10 °C, 2 h, 24%; (ii) DDQ, toluene, reflux, 24 h, 70%; (iii) BBr₃, DCM, N₂ atm., 0 °C, 12 h, 93%; (iv) DMP, DCM, 0 °C, 12 h, 61%.

Table 1. In vitro antimycobacterial activity of synthesised compounds (9–12) expressed as the minimum inhibitory concentration (μm).

Chemical compounds	9	10	11	12	Streptomycin
M. smegmatis ATCC14468	>991.50	>999.40	>1058.80	499.98	2.68
M. bovis ATCC35734	991.50	249.90	>1058.80	>999.96	0.67
M. szulgai ATCC35799	>991.50	62.49	66.20	62.52	1.30
M. gastri ATCC15754	>991.50	62.49	33.03	62.52	0.17
M. simiae ATCC25275	>991.50	249.90	66.20	249.99	2.68
M. tuberculosis (H37Ra) ATCC25177	>991.50	NA	8.26	>999.96	0.84

NA: No assay. Streptomycin: Positive control.