A Macrocyclic β-Iodoallenolate Intermediate is Key: Synthesis of the ABD Core of Phomactin A

Abstract

An enantioselective strategy for the synthesis of phomactin natural products is described. The Lewis acid-triggered cyclization of a β-iodoallenolate embedded in a 12-membered macrocycle was used to obtain a highly functionalized bicyclo[9.3.1]pentadecane in good yield and high diastereoselectivity. This iodoenone contains the substituents of the AD ring system of the phomactin family of natural products, appropriate for further functionalization. Synthesis of the oxadecalin core of phomactin A from the AD iodoenone intermediate was achieved. In this unusual strategy, rings A and B are both fashioned within a macrocyclic precursor.

The phomactin natural products (Figure 1) were isolated from Phoma sp. [SANK 11486], a marine fungus that grows on the shell of a crab Chinoecetes opilioi, off the coast of Fukui prefecture, Japan.¹

Figure 1.

Phomactins A, D, and G

Interestingly, the phomactins were found to be platelet-activating factor (1-O-alkyl-2(R)-(acetylglyceryl)-3-phosphorylcholine, PAF) antagonists, inducing platelet aggregation and inhibiting the binding of platelet-activating factor to its receptor.^2,3 PAF is a highly potent phospholipid, and it is thought to be involved in a number of inflammatory and respiratory diseases.² Phomactin A is the most structurally intricate member of the family, and has thus triggered a variety of creative synthetic strategies over the past decade.⁴ It is characterized by a tetracyclic framework comprised of a bicyclo[9.3.1]pentadecane core, six stereocenters (three of which are quaternary), a reduced furanochroman, and an oxadecalin.

Our synthetic approach was focused on building the oxadecalin core of phomactin A from a macrocyclic precursor. To achieve this task, we intended to employ a β-iodoallenolate cyclization recently developed in our laboratory.⁵ As shown in Scheme 1, 1,4-addition of iodide to alkynone 1 generates β-iodoallenolate intermediate 2, which can be selectively converted into either cyclohexenyl alcohol 3 or oxadecalin 4, depending on the Lewis acid.^6,7 In this communication we describe the execution of this transformation within a carefully crafted 12-membered macrocycle, as a strategy for the synthesis of the framework of members of the phomactin family, including the tricyclic core of phomactin A.

Scheme 1.

β-Iodoallenolate Cyclization

The synthetic strategy is centered on cyclization of macrocycle 5 to produce target alcohol 6, which not only contains the framework of the phomactins, but also a vinyl iodide moiety that could act as a versatile linchpin (Scheme 2). An oxy-Michael ring closure of cyclohexenyl alcohol 6 would then give tricycle 7, containing the ABD ring system of phomactin A. Macrocycle 5 could come from a Nozaki-Hiyama-Kishi reaction with linear precursor 8, which, in a convergent manner, would come from the β-alkyl Suzuki coupling of vinyl iodide 9 and olefin 10.

Scheme 2.

Synthetic Strategy

The synthesis of the vinyl iodide 9 commenced with known nerol derived aldehyde 11 (Scheme 3).⁸ Then, using the Ohira-Bestmann⁹ modification of the Seyferth-Gilbert homologation,¹⁰ aldehyde 11 was transformed into terminal alkyne 12.

Scheme 3.

Synthesis of Vinyl Iodide 9

Alkylation with methyl iodide followed by regioselective silylcupration afforded vinyl silane 14 in high yield.¹¹ Iododesilylation of vinyl silane 14 was achieved using the conditions developed by Zakarian (N-iodosuccinimide (NIS), 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), and 2,6-lutidine).¹² Thus, the desired vinyl iodide 9 was generated in 4 steps and 63% overall yield from aldehyde 11.

The key challenge for the synthesis of olefin 10 was the diastereoselective installation of the C7 tertiary center adjacent to the C6 all-carbon quaternary center (Figure 1). To achieve this, we relied on the enantioselective palladium-catalyzed cycloisomerization protocol developed by Mikami.¹³ Accordingly, enyne 15 was converted into compound 16, with excellent yield and enantioselectivity (Scheme 4). Then, conjugate reduction of the α,β-unsaturated ester was accomplished by using Buchwald’s procedure to afford compound 17 in 63% yield as a 12:1 mixture of diastereomers.¹⁴ The ester was then reduced and protected as an acetate and the absolute and relative configuration of compound 18 was confirmed by X-ray crystallography of the corresponding p-nitrobenzoate derivative.¹⁵ Regioselective opening of the tetrahydrofuran moiety using NaI and AcCl gave rise to iodide 19.¹⁶ The selectivity can be attributed to iodide attack at the least hindered, more reactive allylic carbon, which is expected to be more favorable than attack at the neopentylic carbon. Radical reduction of the alkyl iodide with n-Bu₃SnH and subsequent cleavage of the acetates with K₂CO₃ in methanol provided the diol. Finally, protection of both alcohols with tert-butyldimethylchlorosilane (TBSCl) gave the desired olefin 10 in 43% overall yield over 8 steps.

Scheme 4.

Synthesis of Olefin 10

Coupling of 9 and 10 was accomplished by hydroboration of olefin 10 with 9-borabicyclo[3.3.1] nonane (9-BBN) followed by in situ β-alkyl Suzuki coupling¹⁷ with vinyl iodide 9 to furnish compound 20 in good yield (Scheme 5). Desilylation of the coupling product followed by selective monoprotection of the primary alcohol with TBSCl gave neopentylic alcohol 21. Oxidation with pyridinium chlorochromate (PCC) and subsequent homologation with the Ohira-Bestmann reagent produced alkyne 22. Then, the p-methoxybenzyl ether was oxidatively cleaved with DDQ and the terminal alkyne was iodinated with NIS in the presence of silver nitrate. Finally, oxidation with the Dess-Martin periodinane (DMP) gave macrocyclization precursor 8.

Scheme 5.

Synthesis of Macrocycle 5

Iodoalkyne 8 was cyclized to afford the corresponding macrocycle via an intramolecular Nozaki-Hiyama-Kishi Cr(II)/Ni(II) coupling (Scheme 5).¹⁸ Oxidation of the resulting alcohol with MnO₂ gave the desired ketone 23 in a 3.6:1.0 ratio of Z and E isomers.¹⁹ Fortunately, these isomers were easily separable via flash chromatography. After separation of the E and Z-isomers, the Z-isomer was desilylated using a HF-pyridine solution in tetrahydrofuran. Oxidation of the primary alcohol with the Ley-Griffith reagent²⁰ afforded aldehyde 5 in just 4 steps from iodoalkyne 8.

Next, we examined the β-iodoallenolate cyclization with aldehyde 5 (Scheme 6). The first attempts with the conditions previously reported (BF₃·OEt₂ and TiCl₄; Scheme 1) failed to provide the corresponding oxadecalin or even the cyclohexenyl alcohol. These conditions gave either complex mixtures or degradation, indicating that these conditions were too harsh. So, we turned our attention to MgI₂, a milder Lewis acid.^6e,7b,21 β-Iodoallenolate 24 was then generated in the presence of MgI₂ and cyclized smoothly to afford cyclohexenyl alcohol 6, in a 60% yield as a single diastereomer. The relative stereochemistry of the alcohol was assigned by nOe analysis.²²

Scheme 6.

β-Iodoallenolate Cyclization with Macrocycle 5

Cyclohexenyl alcohol 6 could serve as an intermediate for the synthesis of multiple members of the phomactin family (Figure 1). This versatility is a notable feature of our synthetic approach to the phomactins. In this study, we focused on generating the tricyclic core of phomactin A.

Mitsunobu inversion of the alcohol with p-nitrobenzoic acid using diethyl azocarboxylate (DEAD) and triphenylphosphine generated compound 26, whose structure was assigned by X-ray crystallography (Scheme 7). Removal of the p-nitrobenzoate ester followed by treatment of cyclohexenyl alcohol 25 with tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) and 2,6-lutidine in toluene triggered an oxy-Michael addition, producing tricycle 7. This oxadecalin derivative possesses all the stereogenic centers of the A, B and D rings of phomactin A, and was assembled using a highly diastereoselective synthetic strategy.

Scheme 7.

Synthesis of the Core of Phomactin A

In summary, we have developed a novel enantioselective approach to the central core of the phomactins, and synthesized the ABD ring system of phomactin A. The strategy features the efficient cyclization of a β-iodoallenolate intermediate, generating the AD ring system of the phomactin skeleton within a 12-membered macrocycle.