Synthesis of the C-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

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 19-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=CCH2CH(OH)-2-Th-5-CH2CH2CH(CH(OMe)(2))CH2CH2CH2Cl]. A second precursor lacking the thiophene ring 38 [N=CCH2CH(OH)(CH2)(6)CH(CH(OMe)(2))CH2CH2CH2Cl] 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 beta-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.