The first total synthesis of (+)-mucosin has been completed allowing assignment of the absolute stereochemistry of the natural product. A zirconium induced co-cyclisation was utilised to install the correct stereochemistry of the four contiguous stereocentres around the unusual bicyclo[4.3.0]nonene core

Henderson, Alan R.

Owen, David R.

Stec, Jozef

Whitby, Richard J.

English

Southampton (e-Prints Soton)

The first total synthesis of (+)-mucosin   Alan R. Henderson, Jozef Stec, David R. Owen and Richard J Whitby  School of Chemistry, University of Southampton, Southampton UK SO17 1BJ. E-mail: rjw1@soton.ac.uk  Please cite this paper as:  Chemical Communications, 2012, 3409-3411  The publisher’s version of this paper is available here: http://dx.doi.org/10.1039/c2cc17915f Related articles by Prof Richard Whitby can be found below: T. Luker and R. J. Whitby, (1995) The Tandem Insertion of Lithium Chloroallylide and Electrophiles into Zirconacyclopentanes, Tetrahedron Lett., 36, 4109-4112. (doi: 10.1016/0040-4039(95)00650-2) D. R. Owen and R. J. Whitby,(2005)  Zirconocene-induced cocyclisation/elimination reactions of 2-heterosubstituted 1,6-dienes and 1,6-enynes, Synthesis, 2005, 2061-2074. (doi:10.1055/s-2005-870029). E. Thomas, S. Dixon and R. J. Whitby, (2007) The regiochemistry of zirconacycle elaboration Tetrahedron, 63, 11686-11701 (doi:10.1016/j.tet.2007.08.105). G. J. Gordon, T. Luker, M. W. Tuckett and R. J. Whitby, (2000)  The regiochemistry of carbenoid insertion into zirconacycles Tetrahedron, 56, 2113-2129. (doi:10.1016/S0040-4020(99)01094-7).  S. Dixon, S. M. Fillery, A. Kasatkin, D. Norton, E. Thomas and R. J. Whitby, (2004) Ring expansion of 5-to 6-member zirconacycles by carbenoid insertion  Tetrahedron, 60, 1401-1416. (doi:10.1016/j.tet.2003.09.056).  S. Dixon, G. J. Gordon, R. J. Whitby,(2005) Zirconium mediated total synthesis of crinitol, 9-hydroxyfarnesoic acid, 9-hydroxyfarnesol, 9-hydroxysargaquinone and the selectively-protected aglycone of moritoside and euplexide A, Chem. Commun.,  4303-4305. (doi:10.1039/B508524A)  I. R. Baldwin, R. J. Whitby, (2003) Total synthesis of (+/-)-acetoxyodontoschismenol using zirconium chemistry, Chem. Commun., 2786-2787. (doi:10.1039/b309848f)     Journal Name Cite this: DOI: 10.1039/c0xx00000x www.rsc.org/xxxxxx Dynamic Article Links ► ARTICLE TYPE  This journal is © The Royal Society of Chemistry [year] Journal Name, [year], [vol], 00–00  |  1 The first total synthesis of (+)-mucosin‡ Alan R. Henderson, Jozef Stec, David R. Owen and Richard J. Whitby* Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X DOI: 10.1039/b000000x The first total synthesis of (+)-mucosin has been completed 5 allowing assignment of the absolute stereochemistry of the natural product. A zirconium induced co-cyclisation was utilised to install the correct stereochemistry of the four contiguous stereocentres around the unusual bicyclo[4.3.0]nonene core. 10 In 1997 (−)-mucosin 1, a novel bicyclic eicosanoid was isolated from the marine sponge Reniera mucosa in the Mediterranean.1 The structure of its methyl ester 2 was determined using mass, infrared and high field NMR spectroscopy. The relative stereochemistry was determined using a series of 2D NMR 15 experiments. Mucosin is an interesting synthetic target given its unusual bicyclo [4.3.0]nonene core and close structural relation to the biologically important leukotrienes and  prostanoids, including PGE2 (3), thromboxane and prostacyclin, with which it presumably shares a common precursor in arachidonic acid (4).2  20 The only similar structure of which we are aware is the C22 compound dictyosphaerin (5).3 Herein we report the first total synthesis of (+)-mucosin and hence establish the absolute stereochemistry of the natural product.  25  Our synthetic strategy (Scheme 1) was to use the zirconocene(1-butene) induced cocyclisation of triene 6 to zirconacycle 7 to control the relative stereochemistry of the four contiguous chiral centres in mucosin.4 Further elaboration of the zirconacycle through allyl carbenoid insertion to afford 8 30 followed by 1,4-addition to an acrylate equivalent should provide a concise completion of the synthesis with control of the alkene stereochemistry.5  Scheme 1 Synthetic strategy for the synthesis of mucosin. 35  The synthesis of triene 6 was achieved in eight steps from the commercially available tetrahydrophthalic acid anhydride 9 (Scheme 2). The first step was the asymmetric ring opening of anhydride 9 for which there are wide variety of methods.6 We found that catalysis of methanolysis with a chiral amine 40 (alkaloid) as established by Bolm to be the simplest and cheapest.7 Use of quinidine gave the (1R,6S) enantiomer of acid ester 10 in 100% yield and 90% ee. To obtain the opposite enantiomer quinine could have been used as the catalyst.7 The selective reduction of acid ester 10 using Super-Hydride® 45 furnished lactone 11.8 Partial reduction of 11 using DIBAL-H gave a lactol which underwent Wittig methylenation to yield alcohol 12.9 The second alkene branch was installed by conversion of 12 to its mesylate followed by cyanide displacement to give nitrile 13. DIBAL-H reduction and 50 treatment of the resultant aldehyde with butylidenetriphenylphosphorane gave triene 6 as a 4 : 1 mixture of Z : E isomers.  Control of the four contiguous stereocentres of mucosin is challenging, but precedent is that 3-zirconabicyclo[3.3.0]octanes 55 form with trans-ring junction stereochemistry (thus controlling the relative stereocentres c and d – Scheme 3), and there is generally good trans-1,2-control  between adjacent substituents and the zirconacyclopentane ring, which would give the correct relative stereochemistry at centres b and c.4 The effect of the 60 stereocentre at a, and indeed of the fused 6-member ring was harder to predict.10 Energies from Density Function Theory calculations have been shown to be useful in predicting the relative stability of zirconacycles.11 The four most stable  2  |  Journal Name, [year], [vol], 00–00 This journal is © The Royal Society of Chemistry [year] zirconacycle structures 7a-d, which should form from 6 are shown in Scheme 3 with their calculated relative energies and indicate that the desired isomer 7a is favoured. There are four additional stereoisomers differing in the configuration of the propyl-substituent, but we have shown in other systems that this 5 centre is independent of the stereochemistry of the starting alkene due to rapid epimerisation via exocyclic β-hydride elimination/readdition.12 Only the more stable epimers are shown as the energy differences were calculated to be >16 kJ/mol.   10  Scheme 2 Synthesis of triene 6. Reagents and Conditions: (a) MeOH, quinidine, PhMe, −55 °C, 8 h, then −18 °C, 3 days then 2.0 M HCl; (b) Li(Et)3BH, THF, 0 °C, 1 h then rt, 15 h then 2.0 M HCl; (c) DIBAL-H (fast addition), PhMe, −78 °C, 1 h, then 3.0 M HCl; (d) MePh3P+Br−, 15 n-BuLi, THF, 0 °C → rt, 2 h, then 1.0 M HCl; (e) MsCl, Et3N, DMAP, THF, 0 °C, 2 h; (f) KCN, NaI, 18-crown-6, 90 °C, 66 h; (g) DIBAL-H (dropwise addition), THF, −78 °C → rt, 2 h, then MeOH, aq NaHCO3; (h) BuPh3P+Br−, n-BuLi, THF, 0 °C → rt, 2 h, then 1.0 M HCl.    20  Scheme 3 Zirconocene induced co-cyclisation of 6 and synthesis of alcohols 16.   It is known that the formation of zirconacyclopentanes is reversible and heating is sometimes needed to form the 25 thermodynamically more stable product.13 Zirconium induced cocyclisation of triene 6 was monitored by quenching aliquots to give the protonated compounds 14, which were assayed by GC. After 1.25 h at room temperature we observed a 26:68:4:2  ratio, in order of GC retention times, of isomers formed with around 30 34% of 6 uncyclised, whereas after heating for 0.5 h at 65 °C the cyclisation was complete and the corresponding isomer ratio was  63:24:11:2. Further heating did not change the ratio significantly and additional products started to form. In order to identify if the kinetic or thermodynamic isomer was needed for mucosin we 35 further elaborated the zirconacycles formed under each condition by insertion of 1-lithio-1-chloro-2-propene. The insertion occurred exclusively into the unsubstituted C-Zr bond to afford 15, followed by the BF3·Et2O promoted addition of benzaldehyde to give the alcohols 16.14 Chromatography gave samples of 16 40 comprising 3.1 : 1 and 1 : 1.5 of major diastereoisomers (ignoring the hydroxyl stereochemistry) from the thermodynamic and kinetic conditions, respectively. By comparing the spectral data of the obtained alcohols 16 with those of mucosin 1, we were able to establish that the major product obtained under 45 thermodynamic conditions was 16a derived from zirconacycle 7a with the desired stereochemistry. We speculate, but have not proven, that the major isomer under kinetic conditions is  the zirconacycle 7b.   With reasonable conditions for predominant formation of the 50 correct stereoisomer we examined introduction of the carboxy containing side chain. We have previously shown that allyl-zirconacycles similar to 15 react with the diethylacetal of acrolein to afford around 20% of the 1,4-addition product.15 However, despite extensive investigation of different acrylate equivalents 55 and conditions on model systems we were unable to achieve good yields of selective 1,4-addition.  An alternative stepwise approach was developed to complete the total synthesis. Insertion of the silyl carbenoid 1716 into zirconacycle mixture 7 formed under thermodynamic conditions  60 gave the zirconacyclohexane 18. Subsequent protonation and the Woerpel modification of the Fleming-Tamao oxidation17  yielded alcohol 19 as a 2.7:1 mixture of diastereoisomers in 75% overall yield from triene 6. The pure desired diasteroisomer 19a could be seperated by HPLC. Removal of the minor diastereoisomer was 65 also achieved by refluxing the mixture with iodine in benzene then purification by normal chromatography. We assume that the unwanted diastereoisomer was removed via iodoetherification although such a product was not isolated.  Unfortunately the pure alcohol 19a was only recovered in 39% yield.  Despite the low 70 recovery this method provided further evidence for the relative stereochemistry of the major diastereoisomer given that alcohol 19a cannot undergo iodoetherification, and some evidence that the minor isomer is 19b which can.  75  This journal is © The Royal Society of Chemistry [year] Journal Name, [year], [vol], 00–00  |  3  Scheme 4 Completion of the synthesis of mucosin. Reagents and conditions: (a) THF, −78 °C, 45 mins; (b) NaHCO3, MeOH, −78 °C → rt, 15 h; (c). KH, NMP, t-BuOOH, 0 °C → rt, 10 mins then TBAF, 70 °C, 14 h. (d) Me2SO, CH2Cl2, oxalyl chloride, −60 °C, 15 min then Et3N, −60 °C 5 → rt, 1 h; (e) CrCl2, DMF, THF, rt, 2.5 h; (f) TBAF, THF, rt, 3 h; (g) PDC, DMF, 0 °C → rt, 15 h. (h) CH2N2, Et2O, -78 °C → rt, 1 h.  Oxidation of the alcohol 19a to aldehyde 20 followed by Takai olefination18 with diiodide 21 and removal of the silicon protecting group with TBAF gave the alcohol 23 in 81% overall 10 yield. Finally alcohol 23 was oxidised to mucosin 1 in 84% yield using PDC in DMF (Scheme 4).19 Conversion of acid 1 to its methyl ester 2 using diazomethane allowed comparison with  the reported data demonstrating excellent agreement.1 The optical rotation of the synthetic mucosin methyl ester (90% ee) was 15 [α]26D  = +38.2° (c = 0.8, n-hexane) compared with that reported for the methyl ester of the natural product of [α]26D  =  −35.5 °C (n-hexane, c = 0.8) proving that the natural product is (E)-7-((1S,2R,3aS,7aS)-2-butyl-2,3,3a,4,7,7a-hexahydro-1H-inden-1-yl)hept-5-enoic acid. 20  In conclusion the absolute stereochemistry of the natural product (−)-mucosin has been established and the first total synthesis of its enantiomer (+)-mucosin has been completed in 14 steps and 7% overall yield. (−)-Mucosin could easily be made by using quinine in the enantioselective ring opening of 9. 25 Acknowledgements We thank GlaxoSmithKline, the EPSRC and ERDF (IS:CE-Chem & InterReg IVa program 4061) for funding this work. Notes and references * Chemistry, University of Southampton, Southampton, Hampshire, SO17 30 1BJ, UK. Fax: +44 238059 3781; Tel: +44 238059 2777; E-mail: R.J.Whitby@soton.ac.uk † Electronic Supplementary Information (ESI) available: Experimental procedures and characterisation data for all new compounds; comparison of data with that reported for the natural product; and additional 35 crystallographic evidence for the relative stereochemistry of the major isomer formed . See DOI: 10.1039/b000000x/ ‡ Dedicated to Prof. Phil Parsons on the occasion of his 60th birthday.  1 A. Casapullo, G. Scognamiglio and G. Cimino, Tetrahedron Lett., 40 1997, 38, 3643-3646. 2 F. Marks and G. 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The first total synthesis of (+)-mucosin

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