Efficient Syntheses of Rugulosin Analogues

Abstract

Oxidation of 3b or 14c,d with Pb(OAc)4 in AcOH for 20 min at 25 degrees C and 1 h at 75 degrees C gave flavoskyrin-type dimers 6b and 15c,d in 53-86% yield. Heating a solution of 6b or 15c,d in pyridine under air for 1 h at 75-80 degrees C and then for 1-2 h at 110 degrees C afforded rugulosin-type dimers 10b and 17c,d in 61-88% yield. This two-step sequence provides a practical route to this unusual natural product skeleton.

Monomeric Dihydroanthraquinones: A Chemoenzymatic Approach and its (Bio)synthetic Implications for Bisanthraquinones

“…The proposal was based on a series of monomeric anthraquinones synthesized by Zahn and Koch almost 80 years ago, which tend to dimerize through a hetero‐Diels–Alder reaction into flavoskyrin‐type dimeric compounds . This has been reflected in the biomimetic synthetic strategies to bisanthraquinones, evident from the cascade syntheses of (+)‐rugulosin ( 7 ) and its analogues developed independently by the groups of Nicolaou and Snider, respectively . Interestingly, both approaches involved flavoskyrin‐type dimeric intermediates which are formed by dimerization of monomeric anthrahydroquinones, followed by a synthetic cascade .…”

“…Alternatively, we used Pb(OAc) 4 /AcOH, as employed by Seo et al ,. and later by Snider and Gao, for the selective oxidation of anthrahydroquinones. Addition of a suspension of Pb(OAc) 4 in AcOH to an ice‐cold suspension of 3 in AcOH and stirring for 20 minutes resulted in the formation of mainly two new products along with the expected chrysophanol ( 2 ), with no starting material remaining.…”

“…[15b, 16] This has been reflectedi nt he biomimetic synthetic strategies to bisanthraquinones,e videntf rom the cascade syntheses of (+ +)-rugulosin (7)a nd its analogues developed independently by the groups of Nicolaou [17] andS nider, respectively. [18] Interestingly,b otha pproaches involved flavoskyrin-type dimerici ntermediates which are formed by dimerization of monomeric anthrahydroquinones,f ollowed by as ynthetic cascade. [17] However,t he proposed monomeric intermediate, dihydroemodin (4a), and its naturallyo ccurring dimer,f lavoskyrin (5), could not be synthesized so far,o wing to the presence of sensitive b-hydroxy ketone groups [19] which may undergo elimination.…”

“…In this transformation,N ADPH was regenerated using ag lucose/glucose dehydrogenase system.T oo btain 4a from 3,w ef irst applied MnO 2 for oxidation, which mainly resulted in the formation of chrysophanol (2), with no trace of monomeric intermediate (4a). Alternative-ly,w eu sed Pb(OAc) 4 /AcOH, as employed by Seo et al [15a,b] and later by Snidera nd Gao, [18] for the selectiveo xidationo fa nthrahydroquinones. Addition of as uspension of Pb(OAc) 4 in AcOH to an ice-colds uspension of 3 in AcOH and stirring for 20 minutes resulted in the formation of mainly two new products along with the expected chrysophanol( 2), with no starting materialr emaining.…”

Cascade Reactions in Total Synthesis

“…The growing family of bisanthraquinone natural products includes a number of dimeric structures, such as rugulosin ( 47 , Scheme 9), in which the monomeric anthraquinone units are united by between one and four single bonds to form cagelike skeletons. Following the biosynthetic proposals and preliminary experimental results of Shibata and co‐workers,23 the groups of Nicolaou24 and Snider25 independently developed biomimetic approaches to this class of natural products by employing cascade sequences to prepare model systems and analogues. A major obstacle to the preparation of the natural compounds is the presence of β‐hydroxy or alkoxy ketone groups in both the monomeric tricyclic units (such as 39 ) and the dimeric intermediates, as these motifs are very prone to elimination and subsequent aromatization of the resulting cyclohexenone ring.…”