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Cite this: Org. Biomol. Chem., 2013, 11, 8026 Received 22nd August 2013, Accepted 11th October 2013

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Synthesis of rac-Lindenene via a thermally induced cyclopropanation reaction†‡ Thomas W. Fenlon, Michael W. Jones, Robert M. Adlington and Victor Lee*

DOI: 10.1039/c3ob41716f www.rsc.org/obc

The first synthesis of the sesquiterpene Lindenene is described. A novel non-catalysed intramolecular cyclopropanation reaction between a diazoketone and an unactivated alkene was utilised to construct the relatively labile ketone precursor with complete stereocontrol. This ketone was transformed in three steps into Lindenene.

Lindenene (1), a furansesquiterpene which possesses a lindenane skeleton, was isolated from the dried root of Lindera strychnifolia Vill in 1960 by Takeda.1 This plant is a constituent of the Chinese drug T’ien T’ai wu yao. Subsequently a group of similar but structurally more complex natural products, exemplified by Shizukaol A (2) here, were found in Chloranthus japonicas.2 Although Lindera strychnifolia and C. japonicas are not taxonomically related, one can speculate that the Shizukaol A (2) is biosynthetically derived from the Lindenene (1). We envisaged that in vivo oxidation of Lindenene (1) would give Lindenatriene (3), a putative biosynthetic precursor of Shizukaol A (2) (Fig. 1). In fact, Kawabata et al. observed that pyrolysis of Shizukaol A (2) gave Lindenatriene (3) as one of the products, via a retro-Diels-Alder reaction.2 Curiously, Lindenene (1) has been isolated from the extracts of the coral Acanthogorgia vague.3 The lindenane skeleton containing natural products have caught the attention of synthetic chemists and a number of publications on the synthesis or synthetic studies of these compounds have appeared in the literature.4–9 We are interested in examining the feasibility of the biosynthetic oxidation hypothesis and the intrinsic reactivities of Lindenatriene (3) (Fig. 1) so our first objective is to develop an efficient synthesis of Lindenene (1). Previously we have reported the attempted synthesis of Lindenene (1).10 In our initial investigation it was observed that intramolecular cyclopropanation of diazo

Chemistry Research Laboratory, 12 Mansfield Road, University of Oxford, Oxford, OX1 3TA, UK. E-mail: [email protected]; Fax: +44 (0)1856 285002; Tel: +44 (0)1865 275650 † Dedicated to Professor Sir Jack Baldwin on the occasion of his 75th birthday. ‡ Electronic supplementary information (ESI) available. CCDC 953764 and 953765. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ob41716f

8026 | Org. Biomol. Chem., 2013, 11, 8026–8029

Fig. 1 Possible biosynthetic relationship between Lindenene (1), Lindenatriene (3) and Shizukaol A (2).

compound 4 under transition metal complex catalysis gave a mixture of 5 and 6.10 Neither 5 nor 6 possessed the correct relative stereochemistry corresponding to Lindenene (1). Although this synthetic route did not lead to the successful preparation of (1), our effort did culminate in the synthesis of epi-Lindenene (7) and iso-Lindenene (8) (Scheme 1). Based on these results we hypothesised that the formation of the undesired isomers 5 and 6 in the intramolecular

Scheme 1

Synthesis of epi-Lindenene (7) and iso-Lindenene (8).10

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Table 1 Conditions used in the attempted cyclopropanation reactions of diazo-olefin

Scheme 2

Entry

Catalysta/solvent

Temp./ °C

Time/ hours

Yields/% 14, 15, 16/17

1 2 3 4 5 6 7 8 9 10

CuSO4/PhH CuSO4, Cu(acac)2/PhH Cu(acac)2/PhH Cu(acac)2/PhH Cu(acac)2/PhH Cu(OTf)2/PhH Pd(OAc)2/PhH Rh2(OAc)4/DCM Rh2(OAc)4/DCM Rh2(TFA)4/DCM

80 80 80 50 RT 50 80 40 RT 40

6 6 4 6 24 12 4 6 24 6

8, 38, 10 5, 42, 15 0, 51, 38 0, 64, 22 13, 56, 17 8, 20, 20 15, 25, 25 50, 27, trace 55, 25, trace 38, 30, trace

Retrosynthetic analysis of Lindenene (1).

cyclopropanation of 4 was due to the presence of the furan ring in precursor 4, which might impose extra strain in the transition state during the reaction. Following this conjecture, it was hoped that any unfavourable strain during the cyclopropanation process could be alleviated if the construction of the furan ring was implemented after the formation of the cyclopropane ring (Scheme 2). This new approach may change the selectivity of the metal complex catalysed reaction and favours the formation of the desirable diastereoisomer. Herein we report our successful synthesis of rac-(1) through a modified route. The synthesis of 1 commenced by protection of compound 9,10,11 which was previously utilised in the synthesis of 7 and 8, as its cyclic acetal derivative 10. Compound 10 was then converted directly into the corresponding Weinreb amide 11 using isopropylmagnesium chloride and N-methoxymethylamine hydrochloride.12 Reaction of 11 with excess methyllithium afforded ketone 12.13 Ketone 12 was then deprotonated with lithium bis(trimethylsilyl)amide to form the corresponding enolate, which was quenched with 1,1,1-trifluoroethyl trifluoroacetate to afford the corresponding mixed anhydride. This compound was not isolated but was immediately treated with a mixture of tosyl azide, triethylamine and water to deliver diazo-ketone 13 as product (Scheme 3).14,15 With compound 13 in hand the crucial intramolecular cyclopropanation reaction was next examined and the results are summarised in Table 1.

Scheme 3 Synthesis of compound 13. (a) ethylene glycol, TsOH, benzene, 80 °C, 20 h, quantitative; (b) HNMe(OMe)·HCl, iPrMgCl, THF, −30 °C, 3 h, quantitative; (c) MeLi, THF, −78 °C, 2 h, quantitative; (d) LHMDS, CF3CO2CH2CF3, THF, −78 °C, 1 h; (ii) H2O, Et3N, TsN3, MeCN, RT, 12 h, 88% over two steps.

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a

5 mol%; RT = room temperature.

Initially treating 13 with CuSO4 as catalyst in benzene for 6 hours at 80 °C delivered a mixture of four products 14, 15, 16 and 17. While compounds 13 and 14 could be isolated in 8 and 38% yield respectively, compounds 16 and 17 co-eluted as an inseparable mixture in a combined yield of 10% (entry 1). The use of a mixture of CuSO4–Cu(acac)2 as catalyst under the same conditions gave similar result (entry 2). When the reaction was conducted for a shorter duration with Cu(acac)2 as catalyst, the formation of 15 was favoured (51%) together with 16/17 in 38% yield and interestingly no compound 14 was found in the reaction mixture (entry 3). Performing the reaction for 6 hours at 50 °C further improved the yield of 15 (entry 4). Further lowering of the reaction temperature to ambient together with a longer reaction time still favoured the formation of 15, but now a small amount of 14 was also formed (entry 5). Switching the catalyst to Cu(OTf )2 and changing the reaction conditions to 50 °C for 12 hours resulted in low yields for all the products (entry 6). The use of Pd(OAc)2 as catalyst at 80 °C gave 14, 15 and 16/17 mixture in 15%, 25% and 25% yield respectively after 4 hours (entry 7). Changing the catalyst to Rh2(OAc)4 and solvent to dichloromethane afforded 14 and 15 in 50% and 27% yield respectively when the reaction was conducted at 40 °C for 6 hours while 16/17 was only formed in trace amounts (entry 8). Lowering the reaction temperature together with a longer reaction time did not make any significant change to the outcome of the reaction (entry 9). The use of Rh2(TFA)4 as catalyst gave a lower yield of 14 and 15 after 6 hours at 40 °C. Compound 15 formed colourless prisms and its X-ray crystal structure was obtained (Fig. 2).

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Fig. 3 Fig. 2

X-ray crystal structure of compound 15.§

Chart 1 Control experiment to investigate the possible epimerisation of compound 14.

At this stage we began to suspect that compound 13 initially underwent intramolecular cyclopropanation to give 14 which gradually epimerised to compound 15 under the reaction conditions. Indeed, heating a mixture of 14 and 15 with Cu(acac)2 in benzene at 80 °C for 12 hours resulted in complete isomerisation to 15 (Chart 1). This was a rather intriguing observation as the reaction was conducted under neutral conditions. Mechanistically in a transition metal catalysed cyclopropanation reaction, the metal complex will first undergo ligand dissociation to form a coordinationally unsaturated species. These dissociated anionic ligands may act as a weak base and catalyse the epimerisation of the trans- ring junction in 14 into the cis- isomer 15, which is more thermodynamically stable.16 Based on this assumption, we decided to explore the possibility of performing an uncatalysed thermally induced intramolecular cyclopropanation on 13. It was hoped that this would alleviate the undesirable epimerisation reaction as there would be no offending anionic ligands in the reaction. At the time of this study, there was no literature precedent for an uncatalysed intramolecular cyclopropanation reaction between a diazoketone and an unactivated olefin. Gratifyingly, after some experimentation, we discovered that by heating a solution of compound 13 in dichloromethane under reflux for 96 hours, an excellent yield of compound 14 was obtained (Chart 2). Single-crystal X-ray studies of the product confirms the structure of compound 14 (Fig. 3). It was observed that this reaction is very solvent sensitive. Attempts to increase the rate of this reaction by using higher boiling solvents as reaction medium at elevated temperature

Chart 2

X-ray crystal structure of compound 14.§

Thermal cyclisation of compound 13.

8028 | Org. Biomol. Chem., 2013, 11, 8026–8029

either resulted in decomposition of 13 or partial epimerisation of 14. With compound 14 being available we continued to investigate the synthesis of 1. First compound 14 was olefinated with compound 15 using a modified Julia–Kocienski protocol17 to afford 16. Next the acetal protecting group was removed. By stirring a solution of 16 in acetone at room temperature with catalytic amount of PdCl2(MeCN)2 18 for 12 hours, a 70% yield of volatile ketone 17 was obtained. It should be noted that if the duration of this reaction was prolonged (24 h), a significant degree of isomerisation of the exocyclic double bond to the endocyclic position was observed and compound 19 was formed as the major product. This outcome clearly demonstrated the inherent instability of this ring system. Ketone 17 was deprotonated by LDA and then transmetallated into its zinc enolate. This species was reacted with compound 18 to give a cross aldol product.19,20 This crude aldol product was treated with tosic acid19,20 in a mixture of THF and methanol to give Lindenene (1) in 48% yield over two steps (Scheme 4). As a final attempt to streamline the synthesis of Lindenene (1) we subjected compound 410 to the thermal cyclisation conditions what was effective for compound 13. When 4 was heated under reflux in dichloromethane for 96 hours no formation of 1 was observed (Chart 3) but instead, 4 was recovered unchanged. Changing the reaction medium to other higher boiling solvents and further elevating the reaction temperature only resulted in complete decomposition of the starting material. The failure of 4 to cyclise may be due to the presence of the furan ring, which imposed extra strain in the transition state as mentioned earlier.

Scheme 4 Reagents and conditions: (a) NaHMDS, THF, −78 °C to RT, 12 h, 79%; (b) PdCl2(CH3CN)2, acetone, RT, 12 h, 70%; (c) (i) LDA, ZnCl2, then 18, THF, −78 °C to −30 °C, 3 h; (ii) TsOH, THF–H2O (2 : 1), 50 °C, 12 h, 48% over two steps.

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Notes and references § The X-ray crystallographic data has been deposited with the Cambridge Crystallographic Data Centre (CCDC 953764 (14) and 953765 (15)). Chart 3

Attempted thermal cyclisation of compound 3.

Conclusions In summary we have achieved the first synthesis of the Lindenene (1). Through this investigation we realised the intrinsic instability of lindenane ring system in synthetic intermediate 14 and its tendency to epimerise in apparently neutral conditions under transitional metal catalysis. This problem was eventually overcome by using an unprecedented thermally induced intramolecular cyclopropanation reaction. With the availability of 1 its oxidation to Lindenatriene (2) will be investigated.

Experimental section Diazoketone 13 (500 mg) was dissolved in DCM (50 mL) and the solution heated to reflux for 96 h. The reaction was monitored by analysing aliquots of the solution by 1H NMR. Once the reaction was found to be complete, the solvent was removed under vacuum, furnishing title compound 14 as a colourless oil (440 mg, 99%) which crystallised after leaving on high vacuum for 24 hours. Rf 0.3 (P.E. 30–40 : Et2O; 1 : 1); νmax (KBr disc)/cm−1 2931s, 1716s, 1308s, 1008s, 932s; δH (400 MHz, CDCl3) 0.89 (3H, s, 1b-CH3), 1.06 (1H, ddd, J = 6.0 Hz, 7.5 Hz, 10.5 Hz, 1 × 1-CH), 1.20–1.24 (1H, m, 1 × 1-CH), 1.35 (1H, dq, J = 4.0 Hz, 13.0 Hz, 1 × 5-CH), 1.52 (1H, dt, J = 5.5 Hz, 13.0 Hz, 1 × 4-CH), 1.71– 1.79 (2H, m, 1a-CH, 1 × 4-CH), 1.87–1.94 (2H, m, 1 × 5-CH, 6aCH), 1.95 (1H, d, J = 13.0 Hz, 1 × 2-CH), 2.08 (1H, d, J = 13.0 Hz, 1 × 2-CH), 2.42 (1H, dd, J = 2.0 Hz, 12.0 Hz, 5a-CH), 3.87– 3.90 and 3.95–4.03 (4H, m, 2 × OCH2); δC(100.6 MHz, CDCl3) 14.6 (1-C), 16.9 (5-C), 19.4 (6a-C), 26.5 (1a-C), 28.8 (1b-CH3), 34.8 (1b-C), 35.8 (4-C), 48.5 (2-C), 63.6 and 64.7 (2 × OCH2), 68.2 (5a-C), 109.9 (3-C), 216.3 (6-C); m/z (ES)+ 223 [(M + H)+, 100%], 201 [34], 178 [23], 95 [10]; HRMS (CI)+ found 223.1335 (MH+), C13H19O3 requires 223.1334.

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Org. Biomol. Chem., 2013, 11, 8026–8029 | 8029

Synthesis of rac-Lindenene via a thermally induced cyclopropanation reaction.

The first synthesis of the sesquiterpene Lindenene is described. A novel non-catalysed intramolecular cyclopropanation reaction between a diazoketone ...
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