Synthesis of the Monomeric Unit of the Lomaiviticin Aglycon

Abstract

[3] In this communication, we describe the total synthesis of the monomeric aglycon unit (3, Figure 1) of the lomaiviticins, which is reminiscent of the kinamycins (i.e. kinamycin C, 4, Figure 1).The dimeric structure of the lomaiviticins renders itself to a symmetrical retrosynthetic dissection through the center of the molecule, revealing monomeric unit 3 (see Figure 2) as a possible precursor to both 1 and 2, a scenario that might not be so dissimilar to their biosynthetic pathway. Our approach to enantiopure pre-lomaiviticin structure 3 followed our general strategy towards the kinamycins[4] (defining bromo-aldehyde 5 and iodo-enone 7 as the possible building blocks as shown in Figure 2), and involved an Ullmann coupling reaction and a benzoin-type cyclization as the main processes to construct its molecular framework. However, it required special design features (e.g. substrate 6, vide infra, in order to achieve high regiocontrol) and the development of a novel samarium-mediated allylic hydroxyl group transposition (vide infra) that allowed significant shortening of the synthetic route.The required building blocks 6 and 7 were synthesized from starting materials 5 and 8, respectively, as summarized in Scheme 1. Thus, readily available bromo-aldehyde 5[4] was debenzylated (AlCl 3 , 80 % yield) [5] and selectively oxidized with PhI(CF 3 CO 2 ) 2 [6] to the expected p-quinone (97 % yield), which was reduced with Na 2 S 2 O 4 to the corresponding dihydroquinone and protected with SEM groups (SEMCl, iPr 2 NEt, 92 % yield for two steps) to afford bromo-aldehyde 6. On the other hand, and as shown in Scheme 1, enantioselective asymmetric dihydroxylation of enone 8[7] (AD-mix β, single recrystallization, 69 % yield, >95 % ee) [8] afforded the corresponding 1,2-diol, whose protection (2-methoxypropene, PPTS) furnished acetonide 9 in 94 % yield. Conversion of the latter to its TMS-enol ether (TMSOTf,

Development of Enantioselective Synthetic Routes to (−)-Kinamycin F and (−)-Lomaiviticin Aglycon

“…To date, several completed routes to the kinamycins 6 and studies toward the lomaiviticins 7 have been described. Our own efforts have resulted in an efficient synthesis of (–)-kinamycin F ( 9 ), 8d the first synthesis of (–)-lomaiviticin aglycon ( 6 ), 7i and the development of a general and versatile strategy to prepare diazofluorenes of wide structural variability.…”

“…Our own efforts have resulted in an efficient synthesis of (–)-kinamycin F ( 9 ), 8d the first synthesis of (–)-lomaiviticin aglycon ( 6 ), 7i and the development of a general and versatile strategy to prepare diazofluorenes of wide structural variability. We have discovered several new reactions during our investigations, have obtained insights into the factors influencing reductive activation of the diazofluorene, and have identified certain diazofluorenes as potent inhibitors of ovarian cancer stem cells.…”

Enantioselective Syntheses of (-)-Kinamycin F and (-)-Lomaiviticin Aglycon

“…14 Nicolaou has also reported the total synthesis of the monomeric lomaiviticin aglycon. 15 The 2,6-dideoxyaminosugar of the lomaiviticins is b-linked; the formation of such glycoside linkages is notoriously difficult. Shair and co-workers used this as motivation to develop a new method for the direct construction of such bonds.…”

Hypervalent iodine reagents in the total synthesis of natural products

“…Then, three oxidations were performed in a single step using DMP: the secondary alcohol was oxidized to the corresponding ketone, the hydrazone was transformed into a diazo derivative, and the bis-(SEM)-protected aromatic system gave the quinine moiety (Scheme 33). 280 The same group has employed PIFA with PMBOH as external nucleophile in an oxidative dearomatization toward (+)-sporolide B. 199 The preparation of 4-hydroxy dienones with DIB in MeCN/water has been reported in the synthesis of cleroindicins C, D, F 281 and in the formal synthesis of cortistatins.…”