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Probing a Biomimetic Approach To Mycaperoxide B: Hydroperoxidation Studies

Eduarda M. P. Silva, Richard J. Pye, Christine Cardin, Laurence M. Harwood*

Department of Chemistry, University of Reading, Whiteknights, Reading RG6 6AH, U.K.

Fax: +44(0)118 378 6121; E-mail: l.m.harwood@reading.ac.uk

Received: The date will be inserted once the manuscript is accepted.

Dedicated to Gerry Pattenden on the occasion of his 70th birthday; an inspiring scientist and a genial companion.

Abstract: Hydroperoxidation studies on a series of alkene substrates demonstrate the introduction of the hydroperoxide functional group into the required position for a biosynthetiycall inspired synthesis of mycaperoxide B 1.

Key words: hydroperoxidation, cobalt catalyst, mycaperoxide, marine endoperoxide, Michael addition.

Mycaperoxide B 1 is a member of a group of eight structurally related terpene cyclic peroxides isolated from marine sponges of the genus Mycale. It was found to exhibit significant cytotoxicity against various cancer cell lines and antiviral activity.1 The isolation of a hydroperoxide containing norsesterterpene endoperoxide from a marine sponge of the genus Sigmosceptrella has prompted Capon to propose a biosynthetic pathway for the synthesis of these norsesterterpene cyclic peroxides that invokes an intramolecular hydroperoxide Michael type cyclisation.2,3 Our synthetic planning to access the mycaperoxides has been inspired by Capon’s proposal and is shown in Scheme 1.3

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Scheme 1

The proposed route would commence with the known decalone 5 and an organometallic species derived from 6. The key step in this sequence is the intramolecular Michael addition of the intermediate 2 to afford the cyclic peroxide that could be converted to the desired carboxylic acid 1.

The work described in this communication, following previous investigations within our group,4 is concerned with model studies of the Co(II)-catalysed peroxidation of alkenes related to the side-chain of the putative hydroperoxidation substrate in order to validate this approach and establish the scope and limitations of the key hydroperoxidation step.

The method chosen to introduce the hydroperoxide functionality utilises the methodology developed by Mukaiyama et al.5 The catalyst Co(modp)2 (modp = 1-morpholino-5,5-dimethyl-1,2,4-hexanetrione) was selected as the preferred catalyst for these reactions because of its reported high efficiency in the conversion of olefins into the corresponding triethylsilyl peroxide derivatives.5,6,7

Compound 78 (Scheme 2) was chosen as an initial model system. The hydroperoxidation of 7, using the reaction conditions described in the literature,9 led to the formation of two new compounds. Interpretation of the NMR data of the less polar component isolated led to it being identified as 9, with the protected peroxide on the most substituted carbon of the double bond and the primary alcohol also silylated. The 1H NMR spectrum of the more polar component exhibited a broad singlet at δ 2.00 ppm characteristic of a free hydroxyl and examination of the integration values of the triplet and quartet at δ 0.99 and 0.68 ppm, respectively, revealed that there was only one triethylsilyl protecting group present. Additionally, 13C NMR analysis revealed that a signal corresponding to the resonance of a quaternary carbon at δ 82.8 ppm was present leading to the conclusion that hydroperoxidation had occurred and that the expected compound 8 had been obtained in 43% yield.

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Scheme 2

The methodology was next tested on compound 17 (Scheme 3). Compound 17 was prepared in 6 steps in an overall yield of 34%. The free hydroxyl group in 11 was activated and displaced to form a new carbon-sulfur bond using a Mitsunobu substitution.10 Oxidation of the sulfide 12 to the sulfone 13 was achieved using MCPBA in 90% yield. Sulfone 13 and ketone 15 were subsequently reacted together in a one-pot Julia-Kocienski olefination reaction to furnish alkene 16 as a 1:1 mixture of E- and Z- isomers.11 Selective TBAF-mediated silyl deprotection of 16 allowed the isolation of a 2:1 mixture of isomeric alcohols 17 in 80% yield.

Following the previously established conditions for the hydroperoxidation protocol, reaction of unprotected alcohol 17 furnished a 1:1 mixture of isomeric triethylsilyl protected peroxides 18 in a disappointing 28% yield (Scheme 3), given its structural similarity to 7, although, the reaction again proceeded with high Markovnikov regioselectivity.

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Scheme 3

The synthetic approach to alkene 4, a substrate closer to that proposed in the synthetic pathway, relied upon selective delivery of the lithiated species of 6 equatorially onto the decalone 5 (Scheme 4). Decalone 5 was prepared using a modified version of the 4 step literature procedure starting from commercially available (-)-carvone.12 The synthesis of 1-(tert-butyldiphenylsilyl oxy)-6-iodo-3-methylhex-3-ene 6 was accomplished through conversion of the THP protected alcohol 16 to iodide 6 using iodine and DIPHOS in 75% yield as a 2:1 isomeric mixture (Scheme 4).

The coupling to form 4 was achieved via in situ organolithium generation by direct treatment of a mixture of 5 and 6, at -100(C with two equivalents of t-BuLi leading to the isolation of 4 in 52% yield as a 3:2 mixture of diastereoisomers (Scheme 4). The 13C NMR data of the decalin system of the coupled product 4 correlate well with those described in the literature for mycaperoxide B 1.1 In particular, the resonance of C-1 (observed at 76.9 and 77.1 ppm) for compound 4 compares favourably with that for the natural product (( 77.0 ppm). Desilylation of 4 with TBAF furnished the primary alcohol 19 in 91% yield (6:1 isomeric ratio).

When compound 19 (Scheme 4) was subjected to hydroperoxidation13 it gave rise to a 30% purified yield of hydroperoxide 21 as a 1:1 mixture of diastereoisomers with 12% of unreacted starting material being recovered. Following literature precedent that the hydroperoxation may be improved by protection of hydroxyl groups14 we repeated the reaction on substrate 4 which furnished compound 20 (R = TBDPS) in an excellent yield of 80% (Scheme 4). It is worth noting that this reaction took 5.5 hours, longer than with the other substrates, but that starting material 4 and product 20 were stable to the peroxidation conditions permitting reaction to be run until complete consumption of the starting material.

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Scheme 4

Attempted selective deprotection of the t-butyldiphenylsilyl protected alcohol in compound 20 with tetrabutylammonium fluoride led to both silyl protecting groups being removed and compound 22 was isolated in 86% purified yield as a 1:1 mixture of diastereoisomers (Scheme 5). Although this was not the desired outcome of the deprotection reaction, it was decided to attempt the oxidation of the primary hydroxyl of 22 using Dess-Martin periodinane. After work-up and purification of the complex reaction mixture, the major component was isolated and proton and carbon NMR spectroscopic analysis of this compound showed resonances supporting the formation of the hemiacetal 23 by spontaneous cyclisation of the intermediate hydroperoxy aldehyde in 38% yield (Scheme 5).15 Diagnostic of 23 were the characteristic hemiacetal proton signal at δ 5.25 ppm and the quaternary carbon signal at δ 93.4 ppm. The presence in the 13C NMR spectrum of two signals at δ 80.8 and 80.7 ppm revealed that compound 23 was obtained as a mixture of two diastereoisomers in a 1:1 ratio.

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Scheme 5

Guided by the encouraging result obtained with 4 (Scheme 4) and the unsuccessful selective deprotection of the primary t-butyldiphenylsilyl alcohol 20 (Scheme 5), dioxolane protected aldehyde analogue 29 was prepared in 4 steps in an overall yield of 44% (Scheme 6). Treatment of 24 with 2-mercaptobenzothiazole 25 in the presence of sodium hydride, in anhydrous tetrahydrofuran afforded the desired sulfide 26 in 69%. Oxidation of the sulfide 26 to the sulfone 27 was achieved using MCPBA in 90% yield. Sulfone 27 and ketone 15 were subsequently coupled in a one-pot Julia-Kocienski olefination reaction to furnish alkene 28 as a 2:1 mixture of E- and Z- isomers, respectively.11 The tetrahydropyran group in 28 was transformed in one step to the iodide 29 using iodine and DIPHOS in 70% yield as a 2:1 isomeric mixture. The synthesis of the trityl protected side chain analogue 30 (Scheme 7) was accomplished in 6 steps following the same procedure described previously in Scheme 3 in an overall yield of 38%.

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Scheme 6

Both iodide 29 and 30 were reacted with decalone 5 (Scheme 7) and subjected to Barbier lithiation conditions. Intermediate 31 was obtained as a 2:1 mixture of diasterioisomers in 57% yield while compound 32 was prepared as a 1:1 mixture of diasterioisomers in 32% yield.

[pic]

Scheme 7

When the peroxidation reaction was performed using substrate 31 (Scheme 7), analysis of the 1H NMR spectrum of the product enabled the assignment of the structure as 33, isolated in 55% yield as a 1:1 mixture of diastereoisomers. The presence of the triethylsilyl peroxyether was indicated by the loss of the olefin signal and the presence of a set of complex ethyl group signals, integrating to 9 and 6 protons. Furthermore, in the 13C NMR spectrum two signals were present at δ 84.4 and 84.3 ppm corresponding to the resonance of the quaternary carbon connected to the protected peroxide. Subsequently, compound 32 (Scheme 7) was subjected to the same established peroxidation conditions and gave a 16% purified yield of peroxide 34 as 1:1 mixture of diastereoisomers with 17% of unreacted starting material being recovered. It is proposed that this low yield is due to steric hindrance to the approach of the catalyst by the bulky trityl protecting group.

The deprotection of the acetal was not attempted by usual aqueous acid hydrolysis17 due to the presence of the acid labile triethylsilylperoxy group. Tanemura et al. reported in 1992 the successful hydrolysis of several acetals to their corresponding aldehydes or ketones using catalytic amounts of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) in aqueous acetonitrile under neutral conditions.18 It was decided to attempt the hydrolysis of the acetal 33 using DDQ (Scheme 8). The reaction of compound 33 proceeded smoothly at room temperature in aqueous acetonitrile to give only one product. Analysis of the 1H NMR spectrum revealed that removal of the triethylsilyl group had occurred and the two singlets at δ 9.28 and 9.10 ppm in a ratio of 1:1 were attributed to the resonances of the epimeric hydroperoxides, indicating no stereocontrol in the original hydroperoxidation. After purification, compound 35 was isolated in 72% yield.

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Scheme 8

The deprotection of the acetal 33 was also attempted with bismuth(III) chloride.19 This reaction led to the formation of the already known hemiacetal 23 and compound 35, both obtained as a mixture of diastereoisomers (Scheme 8). Crystallization using a mixture of petroleum ether (30-40(C) and diethyl ether afforded suitable crystals of single diastereoisomer 23a20 and subsequent X-ray crystallographic analysis confirmed the cyclic peroxyhemiacetal structure (Figure 1).21 This also allowed unambiguous determination of the stereochemistry at C-1 with the quaternary alcohol being in the correct axial position as required for the preparation of the natural product.

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Figure 1

In conclusion, we have demonstrated that introduction of a triethylsilylperoxy substituent into analogues of a potential synthetic precursor to the mycaperoxides is dependent on hydroxyl protection and this has led to the successful high yielding synthesis of a triethylsilylperoxide 20. The ease of cyclisation of the free hydroperoxy- group to form a cyclic peroxyhemiacetal lends support for the biosynthetic proposal and augers well for the proposed synthetic approach to Mycaperoxide B 1.

Acknowledgment

E.M.P.S. is grateful to the Portuguese Foundation for Science and Technology (ref SFRH/BD/22683/2005) for a PhD grant. We are also grateful to EPSRC for funding of the Oxford Gemini S Ultra Image Plate System.

References

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12) J. P. Gesson, J. C. Jacquesy and B. Renoux, Tetrahedron, 1989, 45, 5853.

13) Typical procedure for hydroperoxidation reaction: Into a flask flushed with oxygen were added 9,10-trans-1-[3’-methylhex-3’-en-6’-ol]-2(,5,5,9(-tetramethyldecahydronaphthalen-1(-ol 19 (53 mg, 0.16 mmol), bis(5,5-dimethyl-1-morpholino-1,2,4-hexanetrionato)cobalt (II) (4 mg, 0.008 mmol) and 1,2-dichloroethane (2 mL) and the flask was again charged with oxygen. Triethylsilane (0.052 mL, 0.32 mmol) and t-BuOOH (2 drops) were added via a 1.0 mL gas-tight syringe and the resulting green solution was stirred vigorously under an oxygen atmosphere at room temperature. After stirring for 2.5 h, the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica. Elution with hexane-acetone (9:1) gave pure 21 as a colourless oil (20 mg, 30 %). IR (thin film) ν(max) cm-1: 3 390, 2 929, 2 869, 1 461, 1 375, 1 051, 1 017, 801, and 729; 1H NMR (400 MHz, CDCl3) δ: 3.68-3.63 (2H, m, H-6’), 1.63-1.25 (20H, m, H 2,3,4,6,7,8,10 and H-1’,2’,4’,5’), 1.15 and 1.14 (3H, s, 3’-CH3), 0.97 (9H, t, J 7.4 Hz, SiCH2CH3), 0.93 and 0.92 (3H, s, 9-CH3), 0.858 (3H, d, J 6.4 Hz, 2-CH3), 0.860 (3H, s, 5(-CH3), 0.83 (3H, s, 5β-CH3), 0.67 (6H, q, J 7.4 Hz, SiCH2CH3); 13C NMR (100 MHz, CDCl3) δ: 84.6 and 84.5 (COOTES), 77.1 (C-1), 63.3 (C-6’), 46.2 (C-10), 43.5 and 43.4 (C-9), 41.8 and 41.7 (C-6), 36.6 and 36.3 (C-2), 33.8 (5(-CH3), 33.3 (C-5), 32.6 (C-1’), 32.55 and 32.46 (C-8), 32.2 and 32.0 (C-4’), 31.5 (C-2’), 27.6 and 27.5 (C-3), 27.21 and 27.17 (C-5’), 22.1 (5β-CH3), 22.0 (3’-CH3), 21.7 (C-4), 18.7 (C-7), 16.6 and 16.43 (2-CH3), 16.36 and 16.2 (9-CH3), 6.8 [Si(CH2CH3)3], 3.9 [Si(CH2CH3)3]; HRMS (CI) m/z: Calcd C27H54O4Si (M)+( 470.3791, found 470.3800.

14) X.-X. Xu and H.-Q. Dong, Tetrahedron Lett., 1994, 35, 9429.

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16) a) I. Smonou, S. Khan, C. S. Foote, Y. Elemes, I. M. Mavridis, A. Pantidou, and M. Orfanopoulos, J. Am. Chem. Soc., 1995, 117, 7081; b) P. L. Stotter and K. A. Hill, Tetrahedron Lett., 1975, 16, 1679; c) J.-L. Giner, Tetrahedron Lett., 2002, 43, 5457.

17) T. W. Green and P. G. M. Wuts in “Protective Groups in Organic Synthesis”, Wiley-Interscience, New York, 1981, 188.

18) K. Tanemura, T. Suzuki, and T. Horaguchi, J. Chem. Soc., Chem. Commun., 1992, 979.

19) G. Sabitha, R. S. Babu, E. V. Reddy, and J. S. Yadav, Chem Lett., 2000, 1074.

20) 6’(-(2’’-(1(-Hydroxy-9,10-trans-2(,5,5,9(-tetramethyldecahydronaphthalen-1-yl)ethyl)-6’(-methyl-1’,2’-dioxan-3’(-ol 23a: mp litt. 49-50 (C, IR (thin film) ν(max) cm-1: 3 402, 2 930, 2 863, 1 461, 1 451, 1 372, 1 137, 1 088, and 989; 1H NMR (400 MHz, CDCl3) δ: 5.26 (1H, q, J 4.0 Hz, H-3’), 3.04 (1H, d, J 4 Hz, OH), 2.07-1.17 (20H, m, H-4’,5’,1’’,2’’ and H-2,3,4,6,7,8,10), 1.15 (3H, s, 6’-CH3), 0.87 (3H, d, J 8.0 Hz, 2-CH3), 0.87 (3H, s, 5(-CH3), 0.83 (3H, s, 5β-CH3); 13C NMR (100 MHz, CDCl3) δ: 96.4 (C-3’), 80.9 (C-6’), 77.2 (C-1), 46.3 (C-10), 43.4 (C-9), 41.7 (C-6), 36.5 (C-2), 33.8 (5(-CH3), 33.3 (C-5), 32.1 (C-4’), 31.9 (C-5’), 31.4 (C-2’’), 27.8 (C-8 and C-3), 25.4 (C-1’’), 22.1 (6’-CH3), 22.03 (5β-CH3), 21.7 (C-4), 18.7 (C-7), 16.5 (2-CH3), 16.3 (9-CH3); HRMS (ESI) m/z: Calcd for C21H38O4Na (M+Na)+( 377.2662, found 377.2666.

21) Crystal data for 23a: C21H38O4 M = 354.51, centered monoclinic, C 2, a = 24.384 (3), b = 7.4398 (12), c = 11.0398 Å , V = 2000.5 (5) Å3, Z = 4, D = 1.177 g cm-3, F(000) = 784. 2586 Independent reflections were collected on an Oxford Gemini S Ultra Image Plate System. The structures was solved by direct methods and refined on F2 using SHELXL97. Final R = 0.0487, weighted R = 0.1345. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via dc.cam.ac.uk/data_request/cif quoting deposition no. CCDC 750510.

Probing a Biomimetic Approach To Mycaperoxide B: Hydroperoxidation Studies

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