Synthesis of the <i>C</i>₂-Symmetric, Macrocyclic Alkaloid, (+)-Xestospongin A and Its C(9)-Epimer, (−)-Xestospongin C:  Impact of Substrate Rigidity and Reaction Conditions on the Efficiency of the Macrocyclic Dimerization Reaction

Abstract

Xestospongin A [also known as araguspongine D ( 1 )], a C 2 -symmetric macrocyclic alkaloid isolated from the sponge Xestospongia exigua ( Xestospongia sp.), and its C(9) epimer xestospongin C [also known as araguspongine E ( 2 )] have been synthesized. The route capitalizes on the facile condensation between 5-halovaleraldehydes and 1,3-aminoalcohols to produce an oxaquinolizidine ring system in which all proper relative stereochemical relationships are controlled by equilibration. A linchpin synthesis was used to construct one key monomeric precursor a 2,5-disubstituted thiophene derivative 26 [N≡CCH 2 CH(OH)-2-Th-5-CH 2 CH 2 CH(CH(OMe) 2 )CH 2 CH 2 CH 2 Cl]. A second precursor lacking the thiophene ring 38 [N≡CCH 2 CH(OH)(CH 2 ) 6 CH(CH(OMe) 2 )CH 2 CH 2 CH 2 Cl] was assembled in a similar fashion. The carbinol center in each of these precursors was efficiently resolved enzymatically; lipase (PS-30) hydrolysis of the racemic acetate derivative of the thiophenemethanol derivative 26 and SP-435-catalyzed esterification of the β-hydroxynitrile 38 proved effective. The initial macrocyclization strategy involved (i) hydrolysis of a portion of monomer (+)-26 to the corresponding aldehyde, (ii) reduction of the nitrile to a 1,3-aminoalcohol derivative with a second portion of the monomer, (iii) condensation of these two, end-differentiated monomers to give the “half-cyclized” oxaquinolizidine 30 that bears pendant nitrile and acetal groups, (iv) sequential reduction and acid-catalyzed hydrolysis to give the corresponding aldehyde ammonium ion 31, and v) dilution and elevation of pH leading to the macrocyclic bis-thiophene ( − )-32 . Final reductive removal of both thiophenes with Raney nickel proceeded smoothly to give (+)-xestospongin A/(+)-araguspongine D ( 1 ). The impact of pH-control, concentration effects, and monomer rigidity on the macrocyclic dimerization event are discussed. A more direct strategy involved sequential nitrile reduction and acetal hydrolysis within (+)-26 and direct, two-stage macrocyclic dimerization to ( − )-32 . Control of pH is important to the success of this cyclization. In an analogous fashion the non-thiophene monomer ( − )-38 was converted to the ammonium ion/aldehyde S -41 . This could be used to probe the effect of substrate rigidity on the efficiency of macrocycle formation. Substrate S -41 spontaneously dimerized to produce a mixture of xestospongin A ( 1 ) and xestospongin C ( 2 ) with similar efficiency to the thiophene-containing 33 .