An Asymmetric Total Synthesis of Brevisamide

Abstract

An enantioselective synthesis of marine alkaloid brevisamide was accomplished in a convergent manner. The synthesis utilized an enantioselective hetero-Diels-Alder reaction which sets three chiral centers in compound 11. The synthesis also features a modified Wolff-Kishner reduction, Rubottom oxidation and Suzuki-Miyaura coupling to furnish brevisamide.

The bloom of dinoflagellates causing ‘Red Tide’ led to the massive death of a wide range of marine life and human food poisoning in the Florida Coast and Gulf of Mexico. ¹ Brevetoxins secreted by the dinoflagellate called Ptychodiscus brevis may have been responsible for this extensive natural calamity.² In 1981, Nakanishi and co-workers reported the structure of brevetoxin B, the first member of a new class of structurally extraordinary marine toxin.³ Brevetoxin consists of eleven contiguous trans-fused cyclic ether rings, spectacularly arranged in a ‘ladder-like’ rigid frame work. ³ Nakanishi and coworkers subsequently proposed an intriguing biogenetic scheme indicating that brevetoxins may be biosynthesized by a poly-epoxide cascade cyclization.⁴

Further search for ladder-frame polyethers led to the discovery of brevenal (1) from Karenia brevis. ⁵ Interestingly, this smaller polyether is antagonist to brevetoxins. Recently, Wright and co-workers have isolated a new marine alkaloid, brevisamide (2) from K. brevis, which appears to be the biogenetic template for the poly- epoxide cascade reaction leading to brevenal.⁶ It contains the same conjugated dienal side chain as brevenal (1) and a highly substituted tetrahydropyran similar to the first ring of brevenal. Thus, brevisamide appears to be an important biosynthetic precursor for the ladder-frame structures. Chemistry, biology and scarcity of natural abundance of brevisamide attracted our attention to its synthesis and subsequent design of molecular probes.⁷ Satake reported the first total synthesis based on a stepwise construction of the substituted tetrahydropyran ring and Suzuki-Miyaura coupling of the fragments. ^8a Very recently, Lindsley and co-worker reported another route to brevisamide.^8b Herein we disclose an asymmetric total synthesis of brevisamide based upon a strategic facile assembly of the highly substituted tetrahydropyran ring using Jacobsen’s asymmetric hetero-Diels-Alder reaction. ⁹ The strategy renders high convergence and flexibility to structural modulation.

The retrosynthesis of our route is shown in Figure 2. Strategic bond disconnection of brevisamide provides a coupling reaction.¹⁰ The functionalized tetrahydropyran moiety 3 can be assembled through an asymmetric hetero-Diels-Alder reaction between the diene 5 and aldehyde 6 using Jacobsen’s catalyst.^9a The resulting cycloadduct can be converted to 3 with a few additional steps of functional group manipulation. The other half of Suzuki-Miyaura coupling substrate is diene 4. It could be easily constructed using Negishi’s zirconium catalyzed carboalumination-iodination reaction ¹¹ from a known starting material 7.

Figure 2.

Retrosynthetic analysis of 2

The synthesis of functionalized tetrahydropyran moiety 3 is outlined in Scheme 1. The known aldehyde 8¹² is converted to enone 9 via addition of ethylmagnesium bromide followed by Swern oxidation to provide 9 in 84% yield in two steps. It was treated with TESOTf in the presence of Et₃N to afford triethylsilyl diene 5 in 84% yield. Jacobsen’s asymmetric catalytic hetero-Diels-Alder reaction of diene 5 and aldehyde 6 with 10 mol % Jacobsen’s chromium catalyst 10,^9a in the presence of molecular sieves 4 Å at 23 °C for 7 days afforded the desired cycloadduct 11 in 52% isolated yield. The Cycloadduct 11 was obtained with high diastereoselectivity (dr = 95%). The major diastereomer has shown high enantiomeric purity (ee = 96%). Of particular note, Jacobsen and co-workers have reported a very similar reaction with equally slow rate compared to other dienes.^9b Our synthetic strategy calls for the introduction of a hydroxyl group at the α position of the carbonyl group. This was achieved by Rubottom oxidation of 11 using m-chloroperoxybenzoic acid solution in toluene in the presence of aqueous NaHCO₃ buffer at 0 °C in 60% yield.¹³ Epoxidation proceeded from the less hindered side affording 12 as a single isomer. The stereochemical outcome of the Rubottom oxidation was confirmed by NOE experiment (see the supporting information).

Scheme 1.

Synthesis of dihydro-2H-pyranone 12.

The synthesis of functionalized tetrahydropyran derivative 3 is shown in Scheme 2. A modified Wolff-Kishner reduction¹⁴ protocol was utilized for the reduction of ketone 12. Accordingly, ketone 12 was first converted to its corresponding hydrazone with tosylhydrazine in ethanol. The resulting hydrazone was reduced with NaBH₃CN under pH 3 to provide the corresponding hydrazine. Treatment of this hyrazine with NaOAc in EtOH at 75 °C, afforded deoxygenated product 13 in 76% yield for the three steps. Protection of the alcohol as TBS ether followed by removal of the benzyl ether by catalytic hydrogenation over 10 % Pd-C provided the alcohol 14 in 82% yield for the two steps. Mitsunobu reaction of alcohol 14 using hydrazoic acid as the azide source afforded the azide 15 in 94% yield.¹⁵ Reduction of the azide by catalytic hydrogenation followed by acetylation of the resulting amine furnished the acetamide. Selective desilylation of primary TBS-ether in this intermediate with a catalytic amount of pyridinium p-toluenesulfonate in ethanol at 23 °C provided a primary alcohol 16 in 77% yield for the two steps. The hydroxy ethyl derivative was converted to olefin 3 in two-step sequence using Grieco’s protocol.¹⁶ Thus, alcohol 16 was reacted with o-nitrophenylselenic cyanide and n-Bu₃P in THF at 23 °C to provide the corresponding phenylselenide derivative. Oxidation of selenide with m-CPBA resulted in olefin 3 in 50% yield for the two steps.

Scheme 2.

Synthesis of tetrahydropyran 3.

The synthesis of diene 4 is as shown in Scheme 3. The E-bromocrotyl alcohol 7¹⁷ was reacted with trimethylsilylacetylene in DMF in the presence of diisopropylethylamine and a catalytic amount of Pd(PPh₃)₄ and CuI at 23 °C for 4 h to provide enyne derivative 17 in 96% yield.¹⁸ Desilylation of 17 with K₂CO₃ in methanol at 23 °C for 1 h afforded alkynol 18 in 82% yield. It was treated with trimethylaluminum in the presence of catalytic amount of dichlorozirconocene for 24 h. Subsequent treatment of the reaction mixture with elemental iodine provided the desired diene 19 in 39% yield. ¹⁹ Treatment of 19 with TBSCl and imidazole furnished silyl ether 4 in 87% yield.

Scheme 3.

Synthesis of diene 4.

Scheme 4 depicts the synthesis of brevisamide by assembly of tetrahydropyran 3 and vinyl iodide 4 using a Suzuki-Miyaura coupling reaction as the key step as utilized by Satake and co-workers.⁹ The requisite alkylborane was generated in situ by hydroboration of 3 with 9-BBN (5 equiv) in THF at 23 °C. After 3 h, the resulting solution containing the alkylborane was carefully treated with a degassed saturated aqueous Cs₂CO₃ solution. The cross-coupling of the resulting alkylborane and iodide 4 using a catalytic amount of PdCl₂(dppf)·CH₂Cl₂ at 45 °C in the presence of additional DMF yielded a TBS-ether intermediate. This intermediate was desilylated to give 20 in 40% yield for the two steps. Selective oxidation of the allylic alcohol in 20 was carried out using TEMPO in the presence of PhI(OAc)₂ in CH₂Cl₂ at 23 °C for 1 h. This has provided synthetic brevisamide 2 in 87% isolated yield. The spectroscopic data of synthetic brevisamide 2 [ ${[\alpha ]}_{\text{D}}^{20}=-14.5(c0.30,\text{MeOH})$] and those of natural brevisamide⁷ [ ${[\alpha ]}_{\text{D}}^{22}=-13(c0.18,\text{MeOH})$] are identical.

Scheme 4.

Synthesis of brevisamide 2.

In summary, we have reported an asymmetric total synthesis of (−)-brevisamide in 22 total synthetic steps, with an unoptimized yield of 1.7% in 18 longest linear steps from the readily prepared aldehyde 8. Substituted tetrahydropyran fragment of brevisamide was synthesized in enantiomerically pure form using Jacobsen’s asymmetric hetero-Diels-Alder reaction. This reaction has set three of the four stereocenters of brevisamide enantioselectively. The vinyl iodide fragment 4 was readily prepared using Negishi’s zirconium catalyzed carboalumination-iodination reaction. The synthesis also features Suzuki-Miyaura cross coupling and selective allylic oxidation using TEMPO. The present synthesis will provide access to a variety of structural analogues of brevisamide for further studies.

Figure 1.

Structures of brevenal (1) and brevisamide (2)