3 research outputs found
Total Synthesis of (−)-Irciniastatin B and Structural Confirmation via Chemical Conversion to (+)-Irciniastatin A (Psymberin)
The total synthesis and structural confirmation of the marine sponge cytotoxin (−)-irciniastatin B has been achieved via a unified strategy employing a late-stage, selective deprotection/oxidation sequence that provides access to both (+)-irciniastatin A (psymberin) and (−)-irciniastatin B
Total Synthesis of (+)-Irciniastatin A (a.k.a. Psymberin) and (−)-Irciniastatin B
A unified synthetic strategy to access
(+)-irciniastatin A (a.k.a.
psymberin) and (−)-irciniastatin B, two cytotoxic secondary
metabolites, has been achieved. Highlights of the convergent strategy
comprise a boron-mediated aldol union to set the C(15)–C(17) <i>syn–syn</i> triad, reagent control to set the four stereocenters
of the tetrahydropyran core, and a late-stage Curtius rearrangement
to install the acid-sensitive stereogenic <i>N</i>,<i>O</i>-aminal. Having achieved the total synthesis of (+)-irciniastatin
A, we devised an improved synthetic route to the tetrahydropyran core
(13 steps) compared to the first-generation synthesis (22 steps).
Construction of the structurally similar (−)-irciniastatin
B was then achieved via modification of a late-stage (−)-irciniastatin
A intermediate to implement a chemoselective deprotection/oxidation
sequence to access the requisite oxidation state at C(11) of the tetrahydropyran
core. Of particular significance, the unified strategy will permit
late-stage diversification for analogue development, designed to explore
the biological role of substitution at the C(11) position of these
highly potent tumor cell growth inhibitory molecules
Design, Synthesis, and Evaluation of Irciniastatin Analogues: Simplification of the Tetrahydropyran Core and the C(11) Substituents
The
design, synthesis, and biological evaluation of irciniastatin
A (<b>1</b>) analogues, achieved by removal of three synthetically
challenging structural units, as well as by functional group manipulation
of the C(11) substituent of both irciniastatins A and B (<b>1</b> and <b>2</b>), has been achieved. To this end, we first designed
a convergent synthetic route toward the diminutive analogue (+)-<i>C</i>(8)-desmethoxy-<i>C</i>(11)-deoxy-<i>C</i>(12)-didesmethylirciniastatin (<b>6</b>). Key transformations
include an acid-catalyzed 6-<i>exo</i>-tet pyran cyclization,
a chiral Lewis acid mediated aldol reaction, and a facile amide union.
The absolute configuration of <b>6</b> was confirmed via spectroscopic
analysis (CD spectrum, HSQC, COSY, and ROESY NMR experiments). Structure–activity
relationship (SAR) studies of <b>6</b> demonstrate that the
absence of the three native structural units permits access to analogues
possessing cytotoxic activity in the nanomolar range. Second, manipulation
of the C(11) position, employing late-stage synthetic intermediates
from our irciniastatin syntheses, provides an additional five analogues
(<b>7</b>–<b>11</b>). Biological evaluation of
these analogues indicates a high functional group tolerance at position
C(11)