Synthetic and Biosynthetic Studies on FR900482 and Mitomycin C:  An Efficient and Stereoselective Hydroxymethylation of an Advanced Benzazocane Intermediate

Abstract

We report a simple, efficient, and stereoselective Mukaiyama aldol approach to install the key hydroxymethyl moiety into the benzazocane framework of FR900482. Synthetic investigations revealed that the reaction is highly dependent upon the electronics of the aromatic ring. This approach enabled the economical introduction of a [ 13 C]-label to study the biosynthesis of these structurally and biogenetically related natural products. Epimerization of the initially formed β-hydroxy ketone may enable access to mitomycin C or FR900482 biosynthetic congeners. FR900482 (2) and congeners FR66979 (3), FK973 (4), and FK317 (5) have enormous potential as anticancer agents (Figure 1). 1 These new prospective drugs are cytotoxic to tumors, but do not appear to exhibit the deleterious side effects characteristic of the structurally related drug mitomycin C (MMC, 1). 2 For example, myelo-suppression and hemolytic uremic syndrome have plagued the broad clinical utility of MMC since 1974. 3 The allure of less toxic and more active chemotherapeutic agents has spawned numerous total and formal syntheses of FR900482 and its congeners. 4 In particular, we recently described a stereoselective, convergent total synthesis of FR900482 (2) 5 as well as an improved synthesis of the benzazocane core of both FR900482 and mitomycin C. 4 Although our thirty-three-step asymmetric route is among the most concise syntheses of FR900482 (2) extant, our interest in exploring the biogenesis of 1 and 2 has mandated that we improve the unselective hydroxymethylation aldol condensation reaction (dr ≈ 1:1). 5 Throughout the course of our studies towards the synthesis of putative biosynthetic intermediates of both FR900482 and the mitomycins, it became necessary to investigate the hydroxymethylation of substrates such as 6 (Scheme 1). 6 Hydroxymethylation of benzazocane intermediates en route to FR900482 under basic conditions often resulted in undesired elimination of the initially formed hydroxymethylation product. In conjuction with their synthetic studies, Rapoport 7 and Danishefsky 8 demonstrated that epoxidation and reductive ring opening of the exo-methylene in their respective eight-or six-membered ring substrates afforded the requisite hydroxymethyl compound indirectly. In a recent full paper describing his total synthesis of FR-900482 (2), Fukuyama reported a one-step, stereoselective, basermw@lamar.colostate.edu. With benzazocane 6 in hand, we explored alternate hydroxymethylation conditions. We were especially intrigued by the lanthanide triflate-catalyzed Mukaiyama aldol reaction of enoxysilanes developed by Kobayashi. 11 Accordingly, treatment of benzazocane 6 with trimethylsilyl triflate provided the silyl enol ether which was used without purification in the hydroxymethylation step. Exposing the enoxysilane to a catalytic amount of ytterbium(III) triflate and five equivalents of formaldehyde over 48 hours provided alcohol 7 in 70% yield as a 84:16 ratio of diastereomers. Scandium(III) triflate was a superior catalyst and furnishe...

Biosynthesis of 3,5-AHBA-derived natural products

“…168 Recently, potential intermediates of mitomycin biosynthesis have been synthesized chemically. 170,171 However, investigations of the mitomycin assembly mechanism with these synthesized intermediates have not yet been reported.…”

Synthesis of Potential Early-Stage Intermediates in the Biosynthesis of FR900482 and Mitomycin C

“…10 Beyond these early investigations, little is known regarding the details of how these simple precursors are assembled into the complex architectures characteristic of these structurally unique agents. 11 A unified biogenesis for the formation of MMC and FR900482 has been partially formulated by Sherman and co-workers and is further elaborated herein (Scheme 1). 12 A preliminary step in the biogenesis of MMC and FR900482 likely involves MitE, an acyl AMP ligase, and MmcB, a discrete acyl carrier protein.…”

“…15 Once this substance is formed, N-glycosylation of activated D-glucosamine derivative 8 with ACP-bound amine 7 may afford the first committed biosynthetic intermediate, N-glycoside 9. 11 Another enzyme critical for mitomycin biosynthesis, MitB, has been implicated as the glycosyl transferase responsible for the in vivo assembly of N-glycoside 9. 12,13 Next, ring-opening and reduction of N-glycoside 9 would afford the corresponding amine 10.…”

“…Indeed, biogenetic studies revealed that these agents originate from 3-amino-5-hydroxybenzoic acid (AHBA) and d -glucosamine (Figure ) . Beyond these early investigations, little is known regarding the details of how these simple precursors are assembled into the complex architectures characteristic of these structurally unique agents …”

Mitomycins syntheses: a recent update

“…Unfortunately, all attempts to introduce the hydroxymethyl group at C9 by aldol-type strategies met with failure. Electronics seem to play a major role, as very similar substrates en route to FR-900482 underwent analogous reactions [ 66 ]. Solving this issue at the stage of the benzazocenol or at an earlier intermediate would constitute a major breakthrough.…”