Synthesis of the Monomeric Unit of the Lomaiviticin Aglycon

Abstract

Reported in 2001, lomaiviticins A (1) and B (2; Scheme 1) were isolated from Micromonospora lomaivitiensis and demonstrated striking molecular architectures and impressive antitumor and antibiotic activities against a variety of cancer cell lines and bacteria. [1] These natural products apparently exert their action through a novel mechanism involving the cleavage of DNA. [2] Their chemical synthesis presents a formidable challenge, and reports describing partial success have already appeared. [3] Herein, we describe the synthesis of the monomeric aglycon unit of the lomaiviticins (3; Scheme 1), which is reminiscent of the kinamycins (i.e. kinamycin C (4); Scheme 1).The dimeric structure of the lomaiviticins renders itself to a symmetrical retrosynthetic dissection through the center of the molecule. This dissection reveals monomeric unit 3 (Scheme 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 bromoaldehyde 5 and iodoenone 7 as the possible building blocks as shown in Scheme 2), and involved an Ullmann coupling reaction and a benzoin-type cyclization as the main processes to construct its molecular framework. However, the approach required special design features (e.g. substrate 6, see below, to achieve high regiocontrol) and the development of a novel samarium-mediated 1,3-allylic hydroxy group transposition (see below) 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 3. Thus, readily available bromoaldehyde 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 bromoaldehyde 6. Meanwhile, enantioselective asymmetric dihydroxylation of enone 8 [7] (AD-mix-b, 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 into its TMS enol ether (TMSOTf, Et 3 N), and subsequent exposure to O 2 in the presence of catalytic amounts of Pd(OAc) 2 , [9] led to enone 10 (83 % yield), whose iodination (I 2 , py) afforded iodoenone 7 in 91 % yield.Scheme 1. Structures of lomaiviticins A (1) and B (2), their monomeric unit (3), and kinamycin C (4).Scheme 2. Retrosynthetic analysis of lomaiviticin aglycon monomer 3. Bn = benzyl, SEM = 2-(trimethylsilyl)ethoxymethyl.

Anwendungen der Katalyse mit N‐heterocyclischen Carbenen in Totalsynthesen

“…[ (30). [22] Die strukturellen ¾hnlichkeiten zwischen dem Lomaiviticin-Aglykon und den Kinamycinen ermçglichte die Anwendung eines Ansatzes, welcher der Synthese der Kinamycine ähnelte. Allerdings führte der…”

Samarium Diiodide Mediated Reactions in Total Synthesis

“…This protocol was also applied by Nicolaou et al to improve the synthesis of kinamycin C (134; Scheme 32 b). [74,75] Thus, exposure of a-hydroxyketone 132 to the newly defined reaction conditions (SmI 2 , MeOH; then O 2 ; then Na 2 S 2 O 3 ) gave the desired isomeric product 133 as a single stereoisomer in 83 % yield. This constitutes a marked improvement over the previously reported four-step procedure, which generated the requisite alcohol 133 in 55 % overall yield from ahydroxyketone 132.…”

“…In a recent synthesis of the lomaiviticin aglycon monomeric unit 131 (Scheme 32 a), [74] Nicolaou et al developed an unusual SmI 2 -promoted isomerization. Treatment of ahydroxyketone 127 with SmI 2 in the presence of MeOH gave access to conjugated Sm III enolate 128, which was then treated with O 2 gas to generate hydroperoxide species 129.…”

“…[73] Scheme 32. a) A SmI 2 -mediated isomerization in the synthesis of monolomaiviticin aglycon (131) and b) application in the total synthesis of kinamycin C (134; ). [74,75] lead to an ionic reaction allowed an impressive propagation of the cascade. Thus, further reduction of secondary radical 136 afforded organosamarium species 137, which underwent a Barbier-type reaction with acetone to give tertiary alcohol 138 in 40 % overall yield for the cascade sequence.…”

A Continuum of Progress: Applications of N‐Hetereocyclic Carbene Catalysis in Total Synthesis

“…[20] In 2009, Nicolaou et al reported an enantioselective route to the monomeric unit of lomaiviticin aglycon (30). [22] The structural similarities between the lomaiviticin aglycon and the kinamycins allowed them to apply a similar synthetic approach that was employed for the kinamycins (see above). Unfortunately, the attempted NHC-catalyzed benzoin condensation with bromide 18 (Scheme 4) resulted in the Stetter product as the major component.…”