Scalable, stereocontrolled total syntheses of (±)-axinellamines A and B

Abstract

The development of a simple, efficient, scalable, and stereocontrolled synthesis of a common intermediate en route to the axinellamines, massadines, and palau'amine is reported. This completely new route was utilized to prepare the axinellamines on a gram scale. In a more general sense, three distinct and enabling methodological advances were made during these studies: (1) an ethylene glycol-assisted Pauson-Khand cycloaddition reaction, (2) a Zn/In-mediated Barbier-type reaction, and (3) a TfNH(2)-assisted chlorination-spirocyclization.

Figure 1

Structures of axinellamines A & B, massadine, massadine chloride, and palau’amine and Retrosynthetic analysis.

Scheme 1

Stereocontrolled, gram-scale synthesis of the axinellamines (1 and 2). Reagents and Conditions: a) Co₂(CO)₈, NMO, ethylene glycol, 4Å molecular sieves, DCM, rt, 12 h, 46-58%; b) NaBH₄, CeCl₃·7H₂O, MeOH, 0 °C to rt, 12 h; c) PPh₃, NCS, DCM, 0 °C to rt, 12 h; d) Zn, In, 2,2,2-trifluoro-N-(2-oxoethyl)-acetamide, THF, 6% aq NH₄Cl, rt, 3 h, 61% for 3 steps; e) NaN₃, DMF, 85°C, 16 h; f) TFA, DCM, rt; then 21, Et₃N, DCM, rt, 12 h, 59% for 3 steps; g) ^tBuOCl, TfNH₂ (0.25 eq), DCM, 0 °C; then DMP, TFA:DCM=1:10, rt, 12 h, 81%; h) TFA:H₂O=1:1, 70 °C, 36 h, quantitative if isolated, carried to next step directly; i) H₂NCN, brine, NaOH (pH=5.5), 70 °C, 4 h, 75% for 2 steps; j) DMDO, TFA:H₂O=5:95; then TFA:DCM=1:1, rt, 24 h; k) Silver(II)picolinate, TFA:H₂O=1:9, rt, 1.5 h, 63% yield over 2 steps, 2.7:1 β:α; l) H₂, Pt₂O, TFA:H₂O=5:95, 1 h; then 2,3-dibromo-5-trichloroacetylpyrrole, DIEA (pH=8.0), MeCN, rt, 24 h, 56% and 37% over 2 steps for 1 and 2