SYNTHESIS OF THE C-2-SYMMETRICAL, 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 ma crocyclic alkaloid isolated from the sponge Xestospongia exigua (Xesto spongia sp.), and its C(9) epimer xestospongin C [also known as aragus pongine E (2)] have been synthesized. The route capitalizes on the fac ile condensation between 5-halovaleraldehydes and 19-aminoalcohols to produce an oxaquinolizidine ring system in which all proper relative s tereochemical relationships are controlled by equilibration. A linchpi n synthesis was used to construct one key monomeric precursor-a 2,5-di substituted thiophene derivative 26 CH2CH(OH)-2-Th-5-CH2CH2CH(CH(OMe)( 2))CH2CH2CH2Cl]. A second precursor lacking the thiophene ring 38 [N=C CH2CH(OH)(CH2)(6)CH(CH(OMe)(2))CH2CH2CH2Cl] was assembled in a similar fashion. The carbinol center in each of these precursors was efficien tly resolved enzymatically; lipase (PS-30) hydrolysis of the racemic a cetate derivative of the thiophenemethanol derivative 26 and SP-435-ca talyzed esterification of the beta-hydroxynitrile 38 proved effective. The initial macrocyclization strategy involved (i) hydrolysis of a po rtion 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 mo nomers to give the ''half-cyclized'' oxaquinolizidine 30 that bears pe ndant nitrile and acetal groups, (iv) sequential reduction and acid-ca talyzed hydrolysis to give the corresponding aldehyde ammonium ion 31, and v) dilution and elevation of pH leading to the macrocyclic bis-th iophene (-)-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 r igidity on the macrocyclic dimerization event are discussed. A more di rect strategy involved sequential nitrile reduction and acetal hydroly sis within (+)-26 and direct, two-stage macrocyclic dimerization to (- )-32. Control of pH is important to the success of this cyclization. I n an analogous fashion the non-thiophene monomer (-)-38 was converted to the ammonium ion/aldehyde S-41. This could be used to probe the eff ect of substrate rigidity on the efficiency of macrocycle formation. S ubstrate S-41 spontaneously dimerized to produce a mixture of xestospo ngin A (1) and xestospongin C (2) with similar efficiency to the thiop hene-containing 33.