Gold(I)-catalyzed access to neomerane skeletons

Coralie Tugny a, Omar Khaled a, Etienne Derat a, Jean-Philippe Goddard b, Virginie Mouriès-Mansuy *a and Louis Fensterbank *a
aInstitut Parisien de Chimie Moléculaire, UPMC CNRS 8232, Sorbonne Universités UPMC Univ Paris 06. 4 Place Jussieu, CC 229, F-75252 Paris Cedex 05, France. E-mail: virginie.mansuy@upmc.fr; louis.fensterbank@upmc.fr; Etienne.derat@upmc.fr
bLaboratoire de Chimie Organique et Bioorganique EA4566, Université de Haute-Alsace, Ecole Nationale Supérieure de Chimie de Mulhouse, 3 rue Alfred Werner, F-68093 Mulhouse Cedex, France

Received 7th May 2017 , Accepted 10th June 2017

First published on 12th June 2017


The gold(I) catalyzed cycloisomerization of an enynyl propargylic ester, featuring a 1,2-acyloxy migration/intramolecular cyclopropanation sequence, opens a straightforward access to the 5,7,3-tricyclic skeleton of neomerane sesquiterpenes. The first total synthesis of 5-epi-valeneomerin B in 12 steps with an overall yield of 5.3% from the readily available hex-5-en-2-one is reported.


Introduction

Neomeranol (I) is one of the three brominated sesquiterpene alcohols which were isolated for the first time from the green alga Neomeris annulata. Besides its attractive structure of a marine halogenated metabolite, neomeranol exhibits phytotoxicity to johnsongrass and toxicity to brine shrimp.1 Its relative stereochemistry was determined by NMR analysis1a while its absolute configuration was elucidated by Horeau's method.2 More recently, the related neomerane-type sesquiterpenoid valeneomerin B (II) was isolated from the roots of Valeriana officinalis var. latifolia.3 This plant has been applied in Chinese medicine for centuries for the treatment of insomnia. The structure of valeneomerin B was determined by spectroscopic analysis and was fully confirmed by the X-ray diffraction analysis of a derivative (Fig. 1).3
image file: c7qo00360a-f1.tif
Fig. 1 Neomerane sesquiterpenes.

To date, no total synthesis of these two sesquiterpenoids has been described. As part of our ongoing interest in the total synthesis of natural products and more specifically using a gold catalyzed step,4,5 we have focused our attention on these two natural products. We planned to assemble the common 5,7,3-fused ring skeleton V in one step by a PtCl2 or gold(I) or (III) salt catalyzed 1,2-acyloxy migration/intramolecular cyclopropanation6 sequence from a propargyl acetate of type VI. The latter would originate from a diastereoselective alkylation of ketone 1. The previously described formation of IV from III was safe ground for this endeavor (Scheme 1).7


image file: c7qo00360a-s1.tif
Scheme 1 Retrosynthetic strategy.

Results and discussion

We investigated the synthesis of dione 1. Ketal 3a was first obtained in 59% yield by the reaction of the commercially available 6-methyl-5-hepten-2-one 2a with trimethyl orthoformate and p-toluenesulfonic acid (PTSA) in ethylene glycol. It was then submitted to a pinacol ring-enlarging annulation as described by Curran.8 However, the treatment of 3a with 1,2-bis(trimethylsilyloxy)cyclobutene in the presence of BF3·Et2O afforded a mixture of the expected compound 1a (35% yield) and diquinane 4 (19% yield) which originated from an intramolecular Prins reaction (Scheme 2).
image file: c7qo00360a-s2.tif
Scheme 2 Preparation of the starting ketone 1a. (a) HC(OMe)3, (CH2OH)2, PTSA, rt, 15 min, 3a 59%, 3b 65%; (b) −78 °C, 0.5 h then −10 °C, 2.5 h, 1a 35% and 4 19%; −78 °C, 3 h, 5 °C, 10 min, 1b 91%; (c) amylene (10 equiv.), Grubbs II (0.5 mol%), 40 °C, 18 h, 1a quant.

To circumvent this side reaction, we decided to introduce the prenyl moiety at the final stage of the synthesis. Following the same sequence, we obtained diketone 1b in 59% yield from 5-hexen-2-one, 2b. Careful control of the temperature allowed us to perform the reaction on a 10 mmol-scale. Cross-metathesis5f,9 then proved to be extremely efficient for the introduction of the prenyl moiety since ketone 1a was obtained quantitatively. Treatment of the latter with lithium trimethylsilylacetylide in the presence of anhydrous cerium(III) chloride afforded 5 as a single diastereomer almost quantitatively (95% yield). The subsequent desilylation of the alkyne with K2CO3 in methanol followed by acetylation of the tertiary alcohol yielded 6 in 79% yield over two steps. The relative configuration of 6 was confirmed by XRD analysis of the hydrazone derivative 7 (Scheme 3).


image file: c7qo00360a-s3.tif
Scheme 3 Preparation of precursors 6 and 9. (a) TMS-acetylene, n-BuLi, CeCl3 (3 equiv.), THF, −78 °C, 3 h, 95%; (b) K2CO3, MeOH, rt, 15 h, 81%; (c) DMAP, Et3N, Ac2O, DCM, 40 °C, 15 h, 98%; (d) DNPH, PTSA, toluene, 110 °C, 15 h, 58%; (e) LiBH4, THF, 0 °C, 1 h, 80%; (f) TBSCl, DMAP, imidazole, DMF, 15 h, 91%.

The diastereoselectivity of the addition of the acetylide carbanion on 1a leading to 5 could be rationalized by DFT calculations. Importantly, these calculations evidenced some metal–π interactions between the pendant prenyl group and CeCl3 which is also coordinated to one carbonyl group so that the other ketone can undergo nucleophilic attack from the opposite face (Fig. 2).


image file: c7qo00360a-f2.tif
Fig. 2 (a) Model for the diastereoselective addition leading to 5 done at the following DFT level: B3LYP-D3/def2-SV(P) (Turbomole Program). (b) NCI analysis highlighting the main weak interactions.

With the propargyl acetate derivative 6 in hand, we turned our attention to the formation of the basic core of the natural products. In the presence of platinum dichloride under typical conditions (toluene, 80 °C for 18 h), no reaction took place while decomposition unfortunately occurred in refluxing toluene. Thus, we screened a number of gold catalytic systems (Table 1).

Table 1 Au(I)-Catalyzed cycloisomerization of 6: [2 + 2] vs. [3 + 2] formal cycloaddition

image file: c7qo00360a-u1.tif

Entry Catalyst 2 mol% Reaction conditions Yield (%) 10 and 11 10[thin space (1/6-em)]:[thin space (1/6-em)]11 ratio Yield (%) (12)
2 Ph3PAuCl/AgSbF6 DCM, rt, 4 h 20 75[thin space (1/6-em)]:[thin space (1/6-em)]25
3 Au1/AgSbF6 DCM, rt, 1 h 28 40[thin space (1/6-em)]:[thin space (1/6-em)]60
4 Au2 DCM, rt, 1 h 44
5 Au2 DCM, rt, 20 h 22 25[thin space (1/6-em)]:[thin space (1/6-em)]75
6 Au3 DCM, rt, 2 h 76 55[thin space (1/6-em)]:[thin space (1/6-em)]45
image file: c7qo00360a-u2.tif image file: c7qo00360a-u3.tif image file: c7qo00360a-u4.tif


In most cases an inseparable mixture of formal [2 + 2] and [3 + 2] tricyclic products 10 and 11 was obtained.10 With PPh3AuCl, the cyclobutyl derivative 10 was formed as the major product. In contrast, the selectivity was reversed in favor of the angular triquinane 11 when using IPrAuCl (Au1) and Echavarren's catalysts (Au2). It is noteworthy that with catalyst Au2 a longer reaction time (20 h) was needed. Interestingly, only the intermediate allene 12 was obtained as a mixture of two diastereoisomers (1[thin space (1/6-em)]:[thin space (1/6-em)]1 ratio) after 1.5 h of reaction. The yield of these transformations was significantly increased by changing the catalyst to the phosphite complex Au3; however no selectivity was observed (Table 1).

The structures of 10 and 11 were confirmed by XRD analysis of the corresponding hydrazone derivatives 13 and 14, respectively (Fig. 3).


image file: c7qo00360a-f3.tif
Fig. 3 Structures of 13 and 14 obtained by X-ray diffraction analysis.

These findings could be explained following the mechanism manifold of Scheme 4. Electrophilic activation of the alkyne by a cationic gold(I) via intermediate A triggers a 1,3-acetate migration to form the 1-acetoxyallene complex B.11 Subsequent nucleophilic addition of the prenyl moiety would lead to the formation of the vinyl gold intermediate C[thin space (1/6-em)]12 which may evolve through a formal [2 + 2] cycloaddition process to form 10 or by a formal [3 + 2] process to give triquinane 11 (Scheme 4).10


image file: c7qo00360a-s4.tif
Scheme 4 Mechanistic proposal.

We surmised that the presence of the ketone function might perturb the reactivity of the propargyl acetate system and notably favor the formation of the allenylester intermediate B. So we decided to reduce the carbonyl group in order to install a C-sp3 center at that position. The reduction of 6 with LiBH4 at 0 °C afforded 8 in 80% yield as a single diastereomer and its relative stereochemistry was determined by H–H nOe spectroscopy (Scheme 3). The direct cationic gold(I)-catalyzed cyclization of alcohol 8 with Ph3PAuCl/AgSbF6 afforded a complex mixture of products so that protection of the secondary alcohol was envisioned. Treatment of 8 with tert-butyldimethylsilyl chloride (TBSCl) in the presence of imidazole led to 9 in 91% yield (Scheme 3). TBS-protected propargyl acetate 9 was then subjected to the metal-catalyzed cyclization step (Table 2). Gratifyingly, our design proved to be right since using a series of gold-based catalytic systems yielded a similar result consisting of the isolation of the expected 5,7,3-fused tricyclic product 15 in 30–70% yields as a single diastereomer whose relative configuration could be confirmed after derivatization as shown below. The reaction time was much shorter with cationic gold(I) catalysts than with gold(III). Depending on the reaction conditions, some side products (allenylesters notably) could be present and which rendered the purification by chromatography of 15 relatively difficult. Nevertheless, running the reaction with Echavarren's catalyst Au2 at 0 °C provided an optimized yield of 15. In all these reactions, no side product from a nucleophilic attack from the prenyl group was observed,13 presumably because it is too remote.

Table 2 Au(I)-Catalyzed cycloisomerization of TBS ether 9

image file: c7qo00360a-u5.tif

Entry Catalyst 2 mol% Reaction time Yield(%) 15
a The reaction was performed at 0 °C.
1 AuCl3 7.2 h 46
2 Ph3PAuCl/AgSbF6 5 min 41
3 Au2 5 min 48
4 Au2 1.5 h 70a
5 Au3/AgSbF6 5 min 33


We then decided to explore the post-functionalization of the cycloisomerization product 15. Since the precursor 15 could lead to both neomeranol and valeneomerin B depending on the reaction sequences, we turned our attention to the alkylation step. First, the methyl group was installed by the addition of methyllithium in the presence of hexamethyl-phosphoramide onto 15 to generate an enolate intermediate which could be trapped by methyliodide.14 A 4[thin space (1/6-em)]:[thin space (1/6-em)]1 mixture of both C- and O-alkylation products 16 and 17 was obtained in moderate yield (40%, Scheme 5). Characterization of these derivatives could be achieved after desilylation (see the ESI). Second, in order to favor the C-alkylation process, a zinc enolate15 was involved and a cycloisomerization–aldol reaction was performed from 9. The addition of two equivalents of methyllithium followed by the addition of anhydrous ZnCl2 and paraformaldehyde guaranteed the formation of the expected hydroxymethylated product 20 in 50% overall yield and as a single diastereomer. Fortunately, the stereochemistry of 20 was ascertained by X-ray analysis.


image file: c7qo00360a-s5.tif
Scheme 5 Post functionalization of the cycloisomerization product 15. (a) MeLi (1.6 M in Et2O), HMPA, MeI, 1,2-DME, −50 °C, 5 min; (b) TBAF (1.0 M, THF), 18 32%, 19 8% over two steps; (c) MeLi (1.6 M in Et2O), ZnCl2, (d) (CH2O)n, 20 50%.

In the perspective to access valeneomerin B, the reduction of the ketone was conducted next. First, in order to activate the ketone and block its Re face, a mixture of CeCl3 and sodium borohydride in methanol was used. No reaction occurred and we hypothesized that the size of the reducing agent formed was too sterically demanding. So we modified the reaction conditions and switched to lithium borohydride in THF. Nothing happened at room temperature, but keeping the reaction mixture at 50 °C overnight led to 21 in 30% yield. A better yield of 50% was obtained in refluxing DCM using diisobutylaluminium hydride (DIBALH) as a reducing agent. The reduction step was totally diastereoselective but we still obtained the undesired stereoisomer 21 whose stereochemistry was confirmed by XRD analysis (Scheme 6). The observed stereoselectivity in all these attempts can be explained by the fact that the attack of the carbonyl group from the Si face appears strongly disfavored, as judged from the XRD structure of 20. On the one hand, the dimethylcyclopropyl moiety exerts a strong unfavorable steric effect and on the other hand, both methylene groups of the cycloheptane ring block a Bürgi–Dunitz approach of the hydride.


image file: c7qo00360a-s6.tif
Scheme 6 Reduction of the ketone. (a) DIBALH (1.0 M, THF), DCM, 40 °C, 15 h, 50%; (b) TBAF (1.0 M in THF), THF, rt, 15 h, 64%; (c) LAH, THF, 0 °C to rt, 3 h, quant.

We also attempted to control the stereoselectivity of the reduction from diol 22 (obtained by desilylation of 20 in 64% yield). Its reduction using LAH led quantitatively to triol 23 with the same stereoselectivity, though.16

Following these results, we looked at the possibility of inverting the configuration of the hydroxyl group in position 5 in order to obtain the desired stereoisomer. First, we considered a Mitsunobu reaction. To prevent the free primary alcohol from interfering in the Mitsunobu process, the latter was selectively acylated with one equivalent of Ac2O to give 24 quantitatively. Of note, this acetate function is present in valeneomerin B. Following the Martin and Dodge17 procedure recommended for the inversion of relatively hindered secondary alcohols, we used p-nitrobenzoic acid as a nucleophile. Unfortunately the inversion failed; only the starting material was recovered. Moriarty et al. described the inversion of a very hindered secondary alcohol from the corresponding triflate with potassium nitrite in DMF in the presence of 18-crown-6.18 However, when alcohol 24 was treated by triflic anhydride in the presence of pyridine, a carbocationic rearrangement occurred leading to compound 25 in 34% yield.19 We also considered a mesylation of the secondary hydroxyl group followed by nucleophilic substitution using cesium carboxylate in DMF to introduce the hydroxyl group.20 However, the mesylation step, a seemingly straightforward reaction, proved to be troublesome since we obtained quantitatively diene 26, which originates from the opening of the cyclopropane ring (Scheme 7) through an E1-type of elimination. All these findings suggested to us that the introduction of a leaving group at that position could not be achieved without the opening of the cyclopropane moiety.


image file: c7qo00360a-s7.tif
Scheme 7 Attempted inversions of the secondary alcohol. (a) DMAP, Et3N, Ac2O, DCM, rt, 0.5 h, quant.; (b) 4-nitrobenzoic acid, PPh3, DIAD; (c) Tf2O, pyridine, DCM, rt, 1 h, 34%; (d) MsCl, DMAP, Et3N, quant.

Gratifyingly, the total synthesis of 5-epi-valeneomerin B could be accomplished in 73% yield from 23 by the selective acylation of the primary alcohol (Scheme 8).


image file: c7qo00360a-s8.tif
Scheme 8 Synthesis of 5-epi-valeneomerin B.

Conclusions

The gold-catalyzed 1,2-acetate migration of a propargyl ester to generate a carbenoid intermediate and its intramolecular trapping is a very nice tool to construct polycyclic derivatives in a highly diastereoselective fashion. As an illustration of this, we could efficiently assemble the complex 5,7,3-fused skeleton of neomerane sesquiterpenes and in a highly diastereoselective fashion. Further functionalizations of the cycloisomerization product could install diastereoselectively the critical C-substituent at the 5,7-ring junction but failed to deliver the hydroxyl function at position 5 with the proper configuration of the neomeranol and valeneomerin B natural products. Nevertheless, we have worked out the first total synthesis of 5-epi-valeneomerin B in 12 steps with an overall yield of 5.3% from readily available hex-5-en-2-one.

Experimental

All reactions were performed under an argon atmosphere. All solvents were freshly distilled prior to use, tetrahydrofuran over sodium and benzophenone, dichloromethane over calcium hydride. Silica gel (35–70 mm) was used for column chromatography. Thin-layer chromatography (TLC) was performed on silica gel and the chromatograms were visualized using a UV lamp (254 nm). 1H NMR and 13C NMR spectra were recorded at room temperature unless otherwise required on 300 and 400 MHz spectrometers with solvent resonance as the internal standard (1H NMR: CDCl3 at 7.26 ppm, 13C NMR: CDCl3 at 77.16 ppm). Chemical shifts (δ) are given in parts per million (ppm) and coupling constants (J) are given in Hertz (Hz). The letters m, s, d, t, and q stand for multiplet, singlet, doublet, triplet, and quartet, respectively. The letter b indicated that the signal is broad. Referenced high resolution mass spectra were obtained at UPMC using a mass spectrometer with an electron spray ion source (ESI) and a TOF detector. Melting points (mp) were recorded with a melting point apparatus. IR data are reported as characteristic bands (cm−1).

General procedure for the synthesis of acetal 3 (GP1)

Ketone 2 (1.0 equiv.) was added neat to a solution of ethylene glycol (71.2 mL, 1.3 mol, 7.0 equiv.) and trimethyl orthoformate (60.3 mL, 546 mmol, 3.0 equiv.), followed by the addition of p-toluenesulfonic acid (4.7 g, 27 mmol, 15 mol%). The mixture was quenched with saturated NaHCO3 solution (150 mL). The aqueous layer was extracted with Et2O (3 × 50 mL) and the combined organic extracts were washed with distilled water (2 × 100 mL) and brine (1 × 100 mL). The resulting organic layer was dried over MgSO4, filtered and solvent evaporation under reduced pressure gave crude acetal. The residue was purified by flash chromatography on silica gel to afford the desired product.
2-Methyl-2-(4-methylpent-3-en-1-yl)-1,3-dioxolane (3a). Following the general procedure GP1 using 6-methylhept-5-en-2-one 2a (6.1 g, 48.4 mmol, 1.0 equiv.), the crude product was purified by flash chromatography on silica gel (PE/Et2O, 95[thin space (1/6-em)]:[thin space (1/6-em)]5 to 50[thin space (1/6-em)]:[thin space (1/6-em)]50) to afford 3a as a yellow oil (4.85 g, 28.6 mmol, 59%). 1H NMR (CDCl3, 300 MHz): δ 5.12–5.05 (m, 1H), 3.96–3.86 (m, 4H), 2.04 (q, J = 8.1 Hz, 2H), 1.66 (s, 3H), 1.64–1.60 (m, 2H), 1.59 (s, 3H), 1.30 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 131.4, 124.1, 109.9, 64.6, 39.1, 25.6, 23.8, 22.8, 17.5; IR (neat) ν = 2924, 2866, 1667, 1449, 800.
2-(But-3-en-1-yl)-2-methyl-1,3-dioxolane (3b). Following the general procedure GP1 using hex-5-en-2-one 2b (21.3 mL, 182 mmol, 1.0 equiv.), the crude product was purified by flash chromatography on silica gel (n-Pent/Et2O, 90[thin space (1/6-em)]:[thin space (1/6-em)]10) to afford 3b (16.8 g, 118 mmol, 65%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ = 5.83 (ddt, J = 6.6 Hz, J = 10.3 Hz, J = 17.1 Hz, 1H), 5.07–4.98 (m, 1H), 4.97–4.89 (m, 1H), 4.00–3.91 (m, 4H), 2.19–2.12 (m, 2H), 1.78–1.69 (m, 2H), 1.33 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 138.6, 114.3, 109.9, 64.7, 38.4, 28.4, 24.0; IR (neat): ν = 3078, 2982, 2948, 2879, 1642, 1478, 1452, 1407, 1376, 996, 909.
2-(But-3-en-1-yl)-2-methylcyclopentane-1,3-dione (1b). To a solution of 3b (2.5 g, 17.6 mmol, 1.0 equiv.) in CH2Cl2 (176 mL) and cooled at −78 °C, BF3·Et2O (21.7 mL, 176 mmol, 10 equiv.) was added dropwise. After 10 min at this temperature, 1,2-bis(trimethylsilyloxy)cyclobutene (6.2 mL, 22.9 mmol, 1.3 equiv.) was added slowly. After 3 h of stirring of the resulting mixture at the same temperature, the mixture was placed at 5 °C for ten minutes. Then, the mixture was quenched with distilled water (200 mL). The aqueous layer was extracted with Et2O (3 × 100 mL) and the combined organic extracts were washed with brine (1 × 200 mL). The resulting organic layer was dried over MgSO4, filtered and evaporation of the solvent at room temperature under reduced pressure gave crude dione, which was purified by flash chromatography on silica gel (n-Pent/Et2O, 75[thin space (1/6-em)]:[thin space (1/6-em)]25) to afford 1b (2.64 g, 16 mmol, 91%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 5.60 (ddt, J = 6.7 Hz, J = 10.2 Hz, J = 17.0 Hz, 1H), 4.98–4.83 (m, 2H), 2.84–2.64 (m, 4H), 1.98–1.90 (m, 2H), 1.79–1.73 (m, 2H), 1.10 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 216.7, 137.5, 115.9, 56,4, 35.2, 34.3, 29.3, 20.2; IR (neat): ν = 3078, 2923, 2854, 1764, 1718, 1642, 1452, 1420, 1373, 993, 914.
2-Methyl-2-(4-methylpent-3-en-1-yl)cyclopentane-1,3-dione (1a) and 3α-hydroxy-6α-methyl-4-(prop-1-en-2-yl)hexahydropentalen-1(2H)-one (4). 3a (500 mg, 2.94 mmol, 1.0 equiv.) was dissolved in dichloromethane (32 mL). BF3·Et2O (3.6 mL, 29.4 mmol, 10.0 equiv.) was added dropwise at −78 °C. The reaction mixture was stirred at −78 °C for 30 min before the 1,2-bis(trimethylsilyloxy)cyclobutene (1.0 mL, 3.82 mmol, 1.3 equiv.) was added dropwise. The reaction mixture was allowed to warm up to −10 °C over 2.5 hours. Then, the reaction was quenched at −10 °C by the addition of water. The aqueous layer was extracted with Et2O (3 × 20 mL). The combined organic layers were dried over MgSO4, filtered in a glass frit and concentrated under vacuum to afford a mixture of 1a as yellow oil and 4. Purification by flash chromatography on silica gel (n-Pent/Et2O, 85[thin space (1/6-em)]:[thin space (1/6-em)]15) gave 1a (199 mg, 1.0 mmol, 35%) as a yellow oil and 4 (108 mg, 0.55 mmol, 19%). 1a: 1H NMR (CDCl3, 400 MHz): δ 4.81–4.76 (m, 1H), 2.68–2.50 (m, 4H), 1.76–1.70 (m, 2H), 1.61–1.57 (m, 2H), 1.49 (s, 3H), 1.39 (s, 3H), 0.96 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 216.4, 133.8, 123.3, 56.2, 35.5, 34.9 (2C), 25.4, 23.3, 19.92, 17.5; IR (neat): ν = 2922, 2858, 1722, 1454, 838.

4: 1H NMR (CDCl3, 300 MHz): δ 5.07 (s, 1H), 4.87 (s, 1H), 2.55–2.21 (m, 4H), 1.87 (s, 3H), 1.96–1.83 (m, 4H), 1.56–1.75 (m, 2H), 1.06 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 221.9, 143.8, 114.0, 86.2, 59.9, 54.6, 35.5, 33.4, 30.7, 28.2, 24.5, 17.1; IR (neat): ν = 3476, 2955, 2924, 2855, 1737, 1639, 1460, 1375, 1261, 1031, 891; MS (ES+): m/z (rel. intensity): 217 (100), 218 (10); HRMS (ES+) calcd for ([C12H18O2 + Na]+): 217.11990; found: 217.11979.

Synthesis of 1avia metathesis process. 1b (14.6 g, 88.0 mmol, 1 equiv.) was dissolved into 2-methyl-2-butene (94 mL, 88.0 mmol, 10 equiv.). A yellow solution was obtained, to which Grubbs II catalyst (374 mg, 0.440 mmol, 0.5 mol%) was added at room temperature, before the reaction mixture was heated to 40 °C overnight. Then, the reaction mixture was filtered through a short pad of silica, and concentrated under reduced pressure to afford a brown oil as a crude product. The latter was purified by flash column chromatography on silica gel (n-Pent/EtOAc, 90[thin space (1/6-em)]:[thin space (1/6-em)]10) to give 1a (17.1 g, 88.0 mmol, quant.%) as a yellow oil.
3-Hydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)-3-((trimethylsilyl)ethynyl)cyclopentanone (5). THF (16.0 mL) was added to anhydrous CeCl3 (2.2 g, 8.9 mmol, 3.5 equiv.). The resulting suspension was stirred at room temperature for 2 h. In another flask, to a solution of trimethylsilylacetylene (1.2 mL, 8.4 mmol, 3.3 equiv.) in THF (16.0 mL) cooled at −78 °C, n-BuLi (3.3 mL, 2.3 M in hexane, 7.7 mmol, 3.0 equiv.) was added dropwise. The resulting mixture was stirred at this temperature for 30 min to give a solution of 2-trimethylsilylethynyllithium, which was then cannulated to the prepared suspension of CeCl3 in THF cooled at −78 °C. After the stirring was continued at the same temperature for an additional 30 min, the diketone 1a (495 mg, 2.55 mmol, 1.0 equiv.) was introduced as a solution in THF (4 mL). After 3 h the mixture was quenched at room temperature with distilled water (40 mL). The aqueous layer was extracted with Et2O (3 × 15 mL) and the combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford a brown oil as the crude product, which was purified by flash chromatography on silica gel (n-Pent/Et2O, 85[thin space (1/6-em)]:[thin space (1/6-em)]15) to afford 5 (708 mg, 2.42 mmol, 95%) as an orange powder. 1H NMR (CDCl3, 300 MHz): δ 5.59–5.08 (m, 1H), 2.46–2.10 (m, 7H), 1.65 (s, 3H), 1.59–1.55 (m, 2H), 1.59 (s, 3H), 1.10 (s, 3H), 0.15 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ 219.2, 131.9, 124.8, 106.4, 91.8, 76.7, 56.3, 34.9, 33.5, 30.9, 25.7, 22.4, 19.0, 17.8, 0.12; mp = 70.5 °C; IR (neat): ν = 3433, 2962, 2925, 2857, 2164, 173, 1459, 1373, 839; MS (CI): m/z (rel. intensity): 315 (100), 316 (24), 317 (3); HRMS (CI) calcd for ([C17H28O2Si + Na]+): 315.17508; found: 315.17501.
1-Ethynyl-2-methyl-2-(4-methylpent-3-en-1-yl)-3-oxocyclopentyl acetate (6). To a solution of 5 (4.2 g, 14.3 mmol, 1.0 equiv.) in MeOH (14.4 mL) was added K2CO3 (4.0 g, 29 mmol, 2.0 equiv.). The heterogeneous mixture was stirred at room temperature for 18 h. Then, the reaction mixture was diluted with EtOAc (30 mL), washed with distilled water (30 mL) and brine (2 × 30 mL). The resulting organic layer was dried over Na2SO4, filtered and concentrated under vacuum. Purification by flash chromatography on silica gel (PE/Et2O, 70[thin space (1/6-em)]:[thin space (1/6-em)]30) afforded pure deprotected alkyne-5 (3-ethynyl-3-hydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)cyclopentanone) (2.6 g, 12 mmol, 81%) as a pale yellow powder. 1H NMR (CDCl3, 400 MHz): δ 5.14 (m, 1H), 2.65 (s, 1H), 2.54–2.17 (m, 6H), 2.02 (s, 1H), 1.68 (s, 3H), 1.65–1.53 (m, 2H), 1.62 (s, 3H), 1.15 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 218.9, 132.1, 124.6, 84.6, 76.5, 75.3, 56.2, 35.1, 33.5, 31.0, 25.8, 22.5, 19.0, 17.8; mp = 75.0 °C; IR (neat): ν = 3435, 3294, 2966, 2924, 2857, 1975, 1733, 1459, 1374, 1271, 1107, 835, 798, 651; MS (CI): m/z (rel. intensity): 243 (100), 244 (14); HRMS (CI) calcd for ([C14H20O2 + Na]+): 243.13555; found: 243.13570.

To a solution of the deprotected alkyne-5 (2.6 g, 12 mmol, 1.0 equiv.) and DMAP (966 mg, 7.8 mmol, 68.0 mol%) in CH2Cl2 (19.0 mL), Et3N (4.9 mL, 35 mmol, 3.0 equiv.) and acetic anhydride (4.4 mL, 46 mmol, 4.0 equiv.) were added. The resulting mixture was stirred for 20 h at reflux. The reaction mixture was warmed to room temperature and the mixture was quenched with distilled water (25 mL). The aqueous layer was extracted with CH2Cl2 (4 × 10 mL) and the combined organic extracts were washed with brine (2 × 20 mL), dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure, affording a crude residue, which was purified by flash chromatography on silica gel (n-Pent/Et2O, 20[thin space (1/6-em)]:[thin space (1/6-em)]10) to afford 6 (3.1 g, 11.8 mmol, 98%) as a pale yellow powder. 1H NMR (CDCl3, 400 MHz): δ 5.13–5.06 (m, 1H), 2.90–2.80 (m, 1H), 2.75 (s, 1H), 2.54–2.01 (m, 5H), 2.06 (s, 3H), 1.68 (s, 3H), 1.65–1.54 (m, 2H), 1.60 (s, 3H), 1.22 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 216.9, 169.0, 132.0, 124.3, 82.4, 80.4, 77.7, 56.7, 33.4, 31.5, 30.7, 25.7, 22.5, 21.7, 18.3, 17.7; mp = 80.2 °C; IR (neat): ν = 2962, 2925, 2855, 2117, 1735, 1454, 1371, 1307, 832, 609; MS (CI): m/z (rel. intensity): 285 (100), 286 (17), 288 (5); HRMS (CI) calcd for ([C14H20O2 + Na]+): 285.14612; found: 285.14669.

3-((2,4-Dinitrophenyl)imino)-1-ethynyl-2-methyl-2-(4-methylpent-3-en-1-yl)cyclopentyl acetate (7). To a solution of 6 (50 mg, 0.191 mmol, 1 equiv.) and 2,4-dinitrophenylhydrazine (57 mg, 0.287 mmol, 1.5 equiv.) in toluene (3 mL) PTSA was added. The resulting mixture was heated at reflux overnight. The reaction mixture was warmed to room temperature, then concentrated under vacuum to yield a red-orange powder that was purified by flash column chromatography on silica gel (n-Pent/Et2O, 80[thin space (1/6-em)]:[thin space (1/6-em)]20) to afford 7 (49 mg, 0.11 mmol, 58%) as a yellow oil. 1H NMR (CDCl3, 400 MHz): 9.13 (d, J = 2.4 Hz, 1H), 8.31 (bdd, J = 8.8, 2.0 Hz, 1H), 7.96 (d, J = 9.6 Hz, 1H), 5.14 (bt, J = 10.0 Hz, 1H), 2.87–2.79 (m, 1H), 2.73 (s, 1H), 2.70–2.53 (m, 3H), 1.85–1.56 (m, 2H), 1.71 (s, 3H), 1.63 (s, 3H), 1.40 (s, 3H).
1-Ethynyl-3-hydroxy-2-methyl-2-(4-methylpent-3-en-1-yl)cyclopentyl acetate (8). A solution of 6 (1.3 g, 4.96 mmol, 1 equiv.) in THF (50 mL) was prepared and cooled to 0 °C before LiBH4 (454 mg, 19.8 mmol, 4 equiv.) was added. The reaction mixture was then let stirring at 0 °C for 5 hours. The reaction was quenched by the slow addition of a diluted aqueous solution of hydrochloric acid (C = 0.1 M). The aqueous layer was extracted with dichloromethane (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered in a glass frit and concentrated under vacuum to give a thick yellow oil as the crude product. The latter was then purified by flash column chromatography on silica gel (n-Pent/EtOAc, 80[thin space (1/6-em)]:[thin space (1/6-em)]20 to 70[thin space (1/6-em)]:[thin space (1/6-em)]30) to afford 8 (1.05 g, 3.96 mmol, 80%) as a white paste. 1H NMR (CDCl3, 400 MHz): δ 5.16–5.12 (m, 1H), 4.13 (t, J = 8.1 Hz, 1H), 2.65 (s, 1H), 2.50–2.42 (m, 1H), 2.35–2.13 (m, 4H), 2.10 (s, 3H), 1.69–1.54 (m, 3H), 1.69 (s, 3H), 1.62 (s, 3H), 1.08 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 169.3, 132.0, 125.4, 84.9, 81.8, 78.1, 76.1, 52.1, 34.4, 33.4, 29.5, 25.8, 23.2, 22.0, 17.8, 14.9; mp = 57 °C; IR (neat): ν = 3458, 3304, 2967, 2921, 2859, 2113, 1744, 1444, 1369, 835, 625; HRMS (CI) calcd for ([C16H24O3 + Na]+): 287.1618; found: 287.1620.
3-((tert-Butyldimethylsilyl)oxy)-1-ethynyl-2-methyl-2-(4-methylpent-3-en-1-yl)cyclopentyl acetate (9). 8 (150 mg, 0.568 mmol, 1.0 equiv.) was dissolved in DMF (1 mL). Imidazole (94 mg, 1.36 mmol, 2.4 equiv.), DMAP (7 mg, 0.0568 mmol, 10 mol%) and TBSCl (106 mg, 0.682 mmol, 1.2 equiv.) were successively added at room temperature; then the reaction mixture was let stirring overnight. The reaction was quenched with distilled water (10 mL). After separation, the aqueous layer was extracted with Et2O (3 × 10 mL) and the combined organic extracts were washed with distilled water (2 × 10 mL), and brine (2 × 10 mL), then dried over MgSO4, filtered through a glass frit and concentrated under vacuum to afford a yellow oil as a crude product. The latter was purified by flash column chromatography on silica gel (n-Pent/Et2O, 75[thin space (1/6-em)]:[thin space (1/6-em)]25) to afford 9 (195 mg, 0.51 mmol, 91%) as a clear yellow oil. 1H NMR (CDCl3, 400 MHz): δ 5.12–5.08 (m, 1H), 4.03 (t, J = 8.2 Hz, 1H), 2.62 (s, 1H), 2.47–2.44 (m, 1H), 2.29 (m, 2H), 2.12–2.04 (m, 1H), 2.03 (s, 3H), 1.95–1.80 (m, 1H), 1.68 (s, 3H), 1.62 (s, 3H), 1.58–1.48 (m, 3H), 1.03 (s, 3H), 0.89 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 169.3, 131.1, 125.6, 84.2, 82.1, 78.7, 75.9, 52.5, 35.0, 33.7, 29.9, 26.0, 25.8, 23.2, 22.1, 18.1, 17.7, 15.2, −4.0, −4.8; IR (neat): ν = 3311, 2955, 2928, 2857, 1747, 1463, 1366, 1303, 834, 619; HRMS (ESI) calcd for ([C22H38O3Si + Na]+): 401.2482; found: 401.2494.

General procedure for catalyzed cycloisomerization of 6 (GP2)

To a solution of a gold-catalyst complex (0.02 equiv.) in dry and degassed dichloromethane (5 mL) was added when necessary AgSbF6 (0.02 equiv.). After 2 min stirring at room temperature, the formation of AgCl was observed as a white solid. Then, a solution of 6 was added (100 mg, 0.382 mmol, 1.0 equiv.) in dry and degassed dichloromethane (10 mL). The mixture was stirred at room temperature following a catalyst-dependent time. When the reaction was complete, the mixture was filtered through a short pad of silica (Et2O, 30 mL) then concentrated under reduced pressure. Subsequent purification by flash-chromatography on silica gel afforded the cycloizomerization products.
2-(2-Methyl-2-(4-methylpent-3-en-1-yl)-3-oxocyclopentylidene)vinyl acetate (12).
According to GP2 with Au2. Using Echavarren's catalyst (7 mg, 0.00764 mmol, 2 mol%). The reaction mixture was stirred for 1.5 h. Purification by flash chromatography on silica gel (n-Pent/Et2O, 95[thin space (1/6-em)]:[thin space (1/6-em)]5 to 90/10) yielded 12 (44 mg, 0.168 mg, 44%) as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ 7.56–7.49 (m, 1 H), 5.06–4.93 (m, 1 H), 2.81–2.70 (m, 2 H), 2.49–2.36 (m, 2 H), 2.11 (s, 3 H), 2.05–1.72 (m, 2 H), 1.63 (s, 3 H), 1.68–1.38 (s, 2 H), 1.56 (m, 3 H), 1.09 (s, 3 H); 13C NMR (CDCl3, 100 MHz): δ 219.3, 219.2, 187.0, 186.9, 168.5, 132.4, 132.2, 123.7, 123.6, 123.2, 122.6, 113.3, 113.2, 53.4, 53.3, 37.7, 37.6, 36.5, 25.7, 25.6, 23.4, 22.8, 21.0, 20.9, 17.7, 17.6; IR (neat): ν = 2966, 2925, 2857, 1980, 1743, 1450, 1409, 1369, 1293, 948, 796; HRMS (ES+) calcd for ([C16H22O3 + Na]+): 285.14612; found: 285.14650.
According to GP2 with Au2. Using Echavarren's catalyst (7 mg, 0.00764 mmol, 2 mol%). The reaction mixture was stirred for 20 h. Purification by flash chromatography on silica gel (n-Pent/Et2O: 95/5 to 90/10) yielded 10 and 11 in an inseparable mixture (20 mg, 0.084 mmol, 22%) in a 2.5/7.5 ratio.
According to GP2 with Ph3AuCl. Using Ph3PAuCl (3.9 mg, 0.00764 mmol, 2 mol%) and AgSbF6 (2.7 mg, 0.00764 mmol, 2 mol%). The reaction mixture was stirred for 3 h. Purification by flash chromatography on silica gel (Pent/Et2O: 95/5 to 90/10) yielded 10 and 11 in an inseparable mixture (22 mg, 0.076 mmol, 22%) in a 7.5/2.5 ratio.
According to GP2 with Au3. Using tris(2,4-di-terbutylphenyl)phosphite gold(I) chloride (7 mg, 0.00764 mmol, 2 mol%) and AgSbF6 (3 mg, 0.00764 mmol, 2 mol%). The reaction mixture was stirred for 1.5 h. Purification by flash chromatography on silica gel (n-Pent/Et2O, 90[thin space (1/6-em)]:[thin space (1/6-em)]10) yielded 10 and 11 in an inseparable mixture (76 mg, 0.29 mmol, 76%) in a 5.5/4.5 ratio.
(E)-(2,2,4a-Trimethyl-5-oxooctahydro-1H-cyclobuta[c]pentalen-1-ylidene)methyl acetate (10). 1H NMR (CDCl3, 400 MHz): δ 6.85 (s, 1H), 2.43–2.29 (m, 1H), 2.28–2.02 (m, 4H), 2.10 (s, 3H), 1.99–1.89 (m, 1H), 1.65–1.46 (m, 2H), 1.38–1.24 (m, 1H), 1.29 (s, 3H), 1.07 (s, 3H), 0.92 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 223.7, 167.8, 135.8, 129.2, 59.3, 57.9, 55.0, 38.9, 38.7, 36.3, 30.4, 29.8, 26.3, 20.8, 19.8, 16.9; IR (neat): ν = 2954, 2928, 2864, 1753, 1737, 1693, 1459, 1370, 1290, 1270, 827; HRMS (ES+) calcd for ([C16H22O3 + Na]+): 285.14612; found: 285.14647.
3,3,5a-Trimethyl-6-oxo-3,3a,4,5,5a,6,7,8-octahydrocyclopenta[c] pentalen-2-yl acetate (11). 1H NMR (CDCl3, 400 MHz): δ 5.33 (s, 1H), 2.41–2.22 (m, 2H), 2.22–1.83 (m, 3H), 2.13 (s, 3H), 1.70–1.54 (m, 1H), 1.46–1.26 (m, 2H), 1.12 (s, 3H), 0.95 (s, 3H), 0.91 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 224.8, 168.3, 156.0, 113.1, 63.2, 58.8, 57.8, 46.1, 38.2, 37.1, 32.4, 31.3, 27.7, 21.6, 21.3, 17.5; IR (neat): ν = 2957, 2868, 1754, 1736, 1651, 1458, 1369, 1346, 1308, 831; HRMS (ES+) calcd for ([C16H22O3 + Na]+): 285.1461; found: 285.1469.
(E)-(2,2,4a-Trimethyl-5-(2-(4-nitrophenyl)hydrazono)octahydro-1H-cyclobuta[c]pentalen-1-ylidene)methyl acetate (13). A mixture of 10 and 11 in a 7.5/2.5 ratio (29 mg, 0.11 mmol, 1 equiv.) and 2,4-dinitrophenylhydrazine (65 mg, 0.33 mmol, 3 equiv.) were dissolved in toluene (4.5 mL). An orange solution was obtained, to which PTSA (4 mg, 0.022 mmol, 20 mol%) was added. The reaction mixture was heated to reflux for 3 h. Then, the reaction mixture was concentrated under vacuum to yield a red-orange powder that was purified by flash column chromatography on silica gel (n-Pent/Et2O, 75[thin space (1/6-em)]:[thin space (1/6-em)]25). The major compound 13 was obtained as orange crystals (19 mg, 0.0428 mmol, 39%). 1H NMR (CDCl3, 400 MHz): δ 10.80 (s, 1H), 9.11 (d, J = 2.5 Hz, 1H), 8.29 (ddd, J = 9.6, 2.6, 0.8 Hz, 1H), 7.96 (d, J = 9.6 Hz, 1H), 6.91 (s, 1H), 2.69 (dd, J = 17.5, 9.4 Hz, 1H), 2.51–2.29 (m, 3H), 2.15 (s, 3H), 2.11–1.98 (m, 2H), 1.79 (td, J = 12.8, 7.1 Hz, 1H), 1.68 (dd, J = 13.9, 7.1 Hz, 1H), 1.53–1.39 (m, 1H), 1.34 (s, 3H), 1.16 (s, 3H), 1.14 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 171.7, 167.9, 145.2, 137.8, 135.2, 130.1, 129.4, 129.1, 123.7, 110.5, 59.6, 56.8, 54.5, 40.5, 38.7, 32.5, 29.8, 26.3, 26.2, 20.9, 20.7, 19.9; mp = 165 °C; IR (neat): ν = 3317, 2956, 2929, 2864, 1752, 1693, 1617, 1591, 1537, 1517, 1504, 1457, 1424, 1362, 1335, 1311, 1282, 884, 833; HRMS (ES+) calcd for ([C22H26N4O6 + Na]+): 441.1780; found: 441.1766.
3,3,5a-Trimethyl-6-(2-(4-nitrophenyl)hydrazono)-3,3a,4,5,5a,6,7,8-octahydrocyclopenta[c]pentalen-2-yl acetate (14). A mixture of 10 and 11 in a 2.5/7.5 ratio (66 mg, 0.252 mmol, 1 equiv.) and 2,4-dinitrophenylhydrazine (150 mg, 0.755 mmol, 3 equiv.) were dissolved in toluene (4.5 mL). An orange solution was obtained, to which PTSA (8 mg, 0.05 mmol, 20 mol%) was added. The reaction mixture was heated to reflux for 3 h. Then, the reaction mixture was concentrated under vacuum to yield a red-orange powder that was purified by flash column chromatography on silica gel (n-Pent/Et2O, 92[thin space (1/6-em)]:[thin space (1/6-em)]8). The major compound 14 was obtained as orange crystals (111 mg, 0.279 mmol, 99%). 1H NMR (CDCl3, 400 MHz): δ 10.8 (s, 1H), 9.10 (d, J = 2.6 Hz, 1H), 8.27 (dd, J = 9.6, 2.5 Hz, 1H), 7.96 (d, J = 9.6 Hz, 1H), 5.35 (s, 1H), 2.73 (ddd, J = 17.8, 7.0, 3.2 Hz, 1H), 2.53–2.39 (m, 1H), 2.18 (s, 3H), 2.11–1.95 (m, 4H), 1.74–1.50 (m, 2H), 1.50–1.35 (m, 1H), 1.16 (s, 3H), 1.15 (s, 3H), 1.01 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 171.6, 167.9, 145.2, 137.9, 135.2, 130.1, 129.5, 129.1, 123.7, 116.5, 59.6, 56.8, 54.5, 40.5, 38.7, 32.5, 29.8, 26.3, 26.2, 20.9, 20.7, 10.9; mp: degrades at T > 150 °C; IR (neat): ν = 3318, 2956, 2928, 2867, 1753, 1650, 1617, 1591, 1517, 1504, 1457, 1423, 1362, 1334, 1310, 1283, 889, 832; HRMS (ES+) calcd for ([C22H26N4O6 + Na]+): 465.1745; found: 465.1757.
5-((tert-Butyldimethylsilyl)oxy)-1,1,5a-trimethyl-1a,3,4,5,5a,6,7,7a-octahydro-1H-cyclopropa[f]azulen-2-yl acetate (15). A solution of 9 (75 mg, 0.198 mmol, 1.0 equiv.) in dichloromethane (7.9 mL) was cooled to 0 °C before Echavarren's catalyst was added (3.1 mg, 0.00397 mmol, 2 mol%). The solution turns yellow. After a 1.5 h stirring at 0 °C, the reaction was complete, as confirmed by TLC (n-Pent/EtOAc, 95[thin space (1/6-em)]:[thin space (1/6-em)]5). The reaction mixture was then filtered in a glass frit through a short pad of silica and the filtrate was concentrated under vacuum to give a yellow oil as the crude product. The latter was further purified by flash column chromatography on silica gel (n-Pent/EtOAc, 98[thin space (1/6-em)]:[thin space (1/6-em)]2) to afford 15 (53 mg, 0.140 mmol, 70%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 3.60 (dd, J = 9.6, 6.8 Hz, 1H), 2.17–2.13 (m, 2H), 2.08 (s, 3H), 1.77–1.69 (m, 3H), 1.55–1.42 (m, 3H), 1.05–1.02 (m, 2H), 1.03 (s, 3H), 1.02 (s, 3H), 0.90–0.85 (m, 12H), 0.02 (bs, 6H); 13C NMR (100 MHz, CDCl3): δ 169.0, 140.2, 134.4, 79.3, 46.6, 34.6, 29.8, 29.4, 28.2, 26.6, 26.0, 23.7, 21.9, 21.2, 20.8, 20.1, 18.2, 17.0, −4.1, −4.9; IR (neat): ν = 2954, 2928, 2857, 1751, 1701, 1461, 1366, 1250; HRMS (ES+) calcd for ([C22H38O3Si + Na]+): 401.2482; found: 401.2480.
5-Hydroxy-1,1,5a-trimethyl-1a,3,4,5,5a,6,7,7a-octahydro-1H-cyclo propa[f]azulen-2-yl acetate (18) and 2-methoxy-1,1,5a-trimethyl-1a,3,4,5,5a,6,7,7a-octahydro-1H-cyclopropa[f]azulen-5-ol (19). To a stirred solution of 15 (254 mg, 0.671 mmol, 1 equiv.) in DME (2.7 mL) cooled at −50 °C, MeLi (0.84 mL, 1.34 mmol, 1.6 M in Et2O, 2 equiv.) was added dropwise. The reaction mixture was stirred at −50 °C for 5 min before HMPA (0.23 mL, 1.34 mmol, 2 equiv.) was added dropwise, followed by the addition of MeI (1.05 mL, 16.8 mmol, 25 equiv.). The reaction mixture was stirred at −50 °C for 5 min more. Then the reaction mixture was poured into a saturated aqueous solution of NH4Cl cooled at 0 °C. The aqueous layer was extracted with Et2O (3 × 15 mL) and the resulting combined organic layers were dried over MgSO4, filtered through a glass frit and concentrated under vacuum to give the crude mixture of 16 and 17 as a pale yellow oil. Purification by flash column chromatography on silica gel (n-Pent/EtOAc, 98[thin space (1/6-em)]:[thin space (1/6-em)]2) afforded an inseparable mixture of 16 and 17 (62 mg). The latter was dissolved in THF (2 mL) to which TBAF (1.77 mL, 1.77 mmol, 1.0 M in THF, 10 equiv.) was added at room temperature. Then, the reaction mixture was heated to 50 °C and stirred at this temperature overnight. 10 mL water was added, and the aqueous layer was extracted with AcOEt (3 × 20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered in a glass frit and concentrated under vacuum to give the crude product as an orange oil that was purified by flash column chromatography on silica gel (n-Pent/Et2O, 55[thin space (1/6-em)]:[thin space (1/6-em)]45); 18 (50.8 mg, 0.215 mmol, 32%) and 19 (12.7 mg, 0.05 mmol, 8%) were obtained in mixture.

18 and 19: 1H NMR (CDCl3, 400 MHz): δ 0.87 (s, 3H), 0.91–0.94 (m, 3H), 1.00 (s, 3H), 1.02 (s, 3H), 1.03 (s, 3H), 1.10 (s, 3H), 1.18 (s, 3H), 1.25 (s, 3H), 1.29–1.52 (m, 11H), 1.61–1.83 (m, 6H), 2.14–2.21 (m, 3H), 3.52–3.65 (m, 3H), 3.74–3.79 (m, 1H). 13C NMR (100 MHz, CDCl3): 211.6, 145.4, 124.6, 81.2, 73.6, 60.7, 47.5, 45.0, 44.8, 34.3, 33.3, 30.8, 29.9, 29.8, 28.4, 28.3, 28.0, 27.8, 24.8, 23.4, 22.0, 20.6, 20.5, 20.3, 19.8, 17.8, 17.0, 16.7. HRMS (ES+) calcd for ([C15H24O2 + Na]+): 259.1669; found: 259.1663.

5-((tert-Butyldimethylsilyl)oxy)-2a-(hydroxymethyl)-1,1,5a-trimethyldecahydro-1H-cyclopropa[f]azulen-2-ol (20). ZnCl2 (1.4 g, 10 mmol) was dried under high vacuum by means of a heat gun and put in dry Et2O (20 mL). This solution was let stirring under argon and in the dark for 1 h. 15 (45 mg, 0.119 mmol, 1 equiv.) was introduced as a solution in Et2O (1.5 mL). A colourless solution was obtained, to which MeLi (0.24 mL, 0.238 mmol, 1.0 M in Et2O, 2 equiv.) was added dropwise at room temperature. After 10 min of stirring, a yellow solution was obtained. To it, ZnCl2 (0.5 M in Et2O, 0.48 mL, 0.238 mmol, 2 equiv.) was added dropwise at room temperature. Following this addition, a white precipitate was formed. The reaction mixture was let stirring for 10 min more at room temperature. Finally, dry paraformaldehyde (18 mg, 0.595 mmol, 5 equiv.) was added rapidly in one single portion at this temperature. After a further 10-min stirring at this temperature the reaction went to completion. The reaction mixture was quenched with distilled water. The aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic layers were then washed with distilled water (10 mL), dried over magnesium sulphate, filtered in a glass frit and concentrated under vacuum to give a yellow oil as the crude product. Purification by flash column chromatography (n-Pent/EtOAc, 98[thin space (1/6-em)]:[thin space (1/6-em)]2 to 70[thin space (1/6-em)]:[thin space (1/6-em)]30) afforded 20 as a white solid (22 mg, 0.06 mmol, 50%) as the pure product. 1H NMR (CDCl3, 300 MHz): δ 4.40 (bd, J = 12.0 Hz, 1H), 3.81 (d, J = 9.0 Hz, 1H), 3.70–3.65 (m, 1H), 2.42–2.35 (m, 1H), 2.07–2.00 (m, 1H), 1.87–1.82 (m, 2H), 1.70–1.58 (m, 1H), 1.49–1.39 (m, 4H), 1.23 (s, 3H), 1.08 (s, 3H), 0.92–0.87 (m, 14H), 0.00 (s, 3H), −0.04 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 209.9, 74.0, 67.0, 66.1, 47.5, 34.8, 34.0, 29.7, 28.5, 27.7, 27.6, 25.9, 23.0, 20.6, 18.5, 18.1, 17.1, −4.2, −5.0; mp: 140 °C (the product starts degrading at 110 °C); IR (neat): ν = 3400, 2954, 2926, 2896, 2856, 1692, 1461, 1451, 1437, 1377; HRMS (ES+) calcd for ([C21H38O3Si + Na]+): 389.2482; found: 389.2467.
5-((tert-Butyldimethylsilyl)oxy)-2a-(hydroxymethyl)-1,1,5a-trimethyl octahydro-1H-cyclopropa[f]azulen-2(1aH)-one (21). To a solution of 20 (146 mg, 0.400 mmol, 1 equiv.) in dichloromethane (10 mL) was added dropwise the first equivalent of DIBALH (0.44 mL, 0.439 mmol, 1.0 M in THF, 1.1 equiv.) at room temperature. After 5 min stirring at this temperature, no more H2 was released from the reaction mixture and the second equivalent of DIBALH was added dropwise. Then the reaction mixture was heated to reflux and let stirring at 40 °C overnight. The reaction was quenched by the addition of a diluted aqueous solution of hydrochloric acid (C = 1.0 M). After separation, the aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered in a glass frit and concentrated under vacuum to afford a yellow oil as the crude product. The latter was purified by flash column chromatography on silica gel (n-Pent/EtOAc, 85[thin space (1/6-em)]:[thin space (1/6-em)]15) to afford 21 (73 mg, 0.200 mmol, 50%) as a yellowish powder. 1H NMR (DMSO-d6, 400 MHz): δ 4.64 (t, J = 8.1 Hz, 1H), 4.39 (d, J = 6.5 Hz, 1H), 4.33 (dd, J = 6.5, 4.9 Hz, 1H), 4.23 (t, J = 4.8 Hz, 1H), 3.64 (dd, J = 10.3, 5.3 Hz, 1H), 3.40 (dd, J = 10.3, 4.4 Hz, 1H), 1.92–1.72 (m, 1H), 1.65–1.44 (m, 5H), 1.31–1.19 (m, 2H), 1.28 (s, 3H), 0.97 (s, 3H), 0.85 (s, 9H), 0.71–0.67 (m, 1H), 0.67 (s, 3H), 0.67–0.56 (m, 1H), −0.03 (s, 3H), −0.04 (s, 3H); 13C NMR (DMSO-d6, 100 MHz): δ 74.8, 74.1, 65.4, 54.7, 49.7, 34.4, 32.4, 30.9, 30.8, 28.8, 26.8, 25.8 (3C), 21.1, 19.6, 19.1, 17.7, 16.9, −4.4, −4.9; mp: 126 °C; IR (neat): ν = 3400, 2955, 2926, 2893, 2883, 2855, 1472, 1463, 1453, 1439, 1090, 1047, 1347, 1256; HRMS (ES+) calcd for ([C21H40O3Si + Na]+): 391.2639; found: 391.2639.
5-Hydroxy-2a-(hydroxymethyl)-1,1,5a-trimethyloctahydro-1H-cyclopropa[f]azulen-2(1aH)-one (22). To a solution of 20 (340 mg, 0.927 mmol, 1 equiv.) in THF (3.3 mL) was added TBAF (0.45 mL, 0.45 mmol, 1.0 M in THF, 1.5 equiv.) at room temperature. The solution turned yellow, and then was let stirring at room temperature overnight. 10 mL water was added, and the aqueous layer was extracted with AcOEt (3 × 20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered in a glass frit and concentrated under vacuum to give the crude product as a yellow oil that was purified by flash column chromatography on silica gel (n-Pent/EtOAc, 50[thin space (1/6-em)]:[thin space (1/6-em)]50) to yield 22 (149 mg, 0.593 mmol, 64%) as a white crystals. 1H NMR (acetone-d6, 300 MHz): δ 4.41 (dd, J = 10.4, 5.0 Hz, 1H), 3.89–3.78 (m, 1H), 3.77–3.62 (m, 2H), 3.57 (d, J = 5.7 Hz, 1H), 2.38–2.21 (m, 1H), 2.01–1.87 (m, 2H), 1.82–1.67 (m, 2H), 1.54–1.35 (m, 3H), 1.16 (s, 3H), 1.08–0.91 (m, 2H), 1.02 (s, 3H), 0.85 (s, 3H); 13C NMR (acetone-d6, 75 MHz): δ 209.8, 73.3, 67.2, 66.5, 47.3, 35.4, 34.6, 29.9, 28.7, 28.6, 28.1, 23.2, 21.2, 18.6, 17.4; mp = 180 °C; IR (neat): ν = 3378, 2951, 2921, 2864, 2852, 1692, 1483, 1454, 1438, 1377, 1324, 1284; HRMS (ESI) calcd for ([C15H24O3 + Na]+): 275.1618; found: 275.1627.
2a-(Hydroxymethyl)-1,1,5a-trimethyldecahydro-1H-cyclopropa [f]azulene-2,5-diol (23). To a suspension of LiAlH4 (30 mg, 0.783 mmol, 3 equiv.) in dry THF (6 mL) cooled at 0 °C was added dropwise a solution of 22 (66 mg, 0.261 mmol, 1 equiv.) in THF (2 mL). The reaction mixture was then warmed to room temperature and stirred for 3 h. The reaction was cooled at 0 °C and quenched by the addition of saturated aqueous Na2SO4 solution. The mixture was filtered through a pad of Celite® and the cake was washed with ethyl acetate (3 × 5 mL). The combined filtrates were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (n-Pent/EtOAc, 70[thin space (1/6-em)]:[thin space (1/6-em)]30) afforded 23 (66.5 mg, 0.261 mmol, quant.) as a white foam. 1H NMR (CDCl3, 300 MHz): δ 4.60 (t, J = 8.3 Hz, 1H), 4.51 (d, J = 4.0 Hz, 1H), 3.87 (d, J = 10.7 Hz, 1H), 3.69 (d, J = 10.7 Hz, 1H), 2.20–2.10 (m, 1H), 1.82–1.64 (m, 5H), 1.48–1.37 (m, 5H), 1.33 (s, 3H), 1.04 (s, 3H), 0.83 (s, 3H), 0.75–0.70 (m, 2H); 13C NMR (CDCl3, 75 MHz): δ 77.6, 75.8, 68.2, 55.6, 50.2, 35.0, 32.1, 31.0 (2C), 29.5, 27.8, 22.5, 19.9, 19.0, 17.0; mp = 63 °C; IR (neat): ν = 3380, 2954, 2923, 2894, 2859, 1484, 1465, 1441, 1375, 1344, 1279, 1261; HRMS (ESI) calcd for ([C15H26O3 + Na]+): 277.1774; found: 277.1774.
5-((tert-Butyldimethylsilyloxy)-2-hydroxy-1,1,5a-trimethyldecahydro-1H-cyclopropa[f]azulen-2a-yl)methyl acetate (24). To a solution of 21 (60 mg, 0.163 mmol, 1 equiv.) in CH2Cl2 (1.63 mL), DMAP (3 mg, 0.0245 mmol, 15 mol%), triethylamine (25 μL, 0.179 mmol, 1.1 equiv.) and acetic anhydride (17 μL, 0.179 mmol, 1.1 equiv.) were successively added at room temperature. The mixture was quenched by the addition of water (10 mL). The aqueous layer was extracted with CH2Cl2 (3 × 10 mL), and the combined organic layers were washed with brine (10 mL), with a 1 M aqueous solution of hydrochloric acid (3 × 10 mL), dried over MgSO4, filtered in a glass frit and concentrated under vacuum to afford 24 (67 mg, 0.163 mmol, quant.) as a white powder. 1H NMR (CDCl3, 400 MHz): δ 4.58 (t, J = 8.2 Hz, 1H), 4.44 (d, J = 5.0 Hz, 1H), 4.22 (d, J = 11.2 Hz, 1H), 4.17 (d, J = 11.2 Hz, 1H), 2.04 (s, 3H), 2.01–1.89 (m, 1H), 1.84–1.68 (m, 4H), 1.68–1.54 (m, 2H), 1.51–1.28 (m, 1H), 1.33 (s, 3H), 1.02 (s, 3H), 0.87 (s, 9H), 0.82 (s, 3H), 0.73 (td, J = 9.5, 5.9 Hz, 1H), 0.54–0.45 (m, 1H), −0.01 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 171.4, 77.6, 75.0, 69.9, 53.4, 51.0, 34.6, 32.5, 31.1, 31.0, 29.8, 27.6, 26.0, 22.5, 21.2, 20.0, 19.8, 18.2, 17.1, −4.2, −4.8; mp: 140 °C; IR (neat): ν = 3514, 2958, 2927, 2910, 2892, 2857, 1707, 1462, 1369, 1098, 1345, 1325, 1299, 1270; HRMS (ES+) calcd for ([C23H42O4Si + Na]+): 433.2745; found: 433.2740.
(3,3,7-Trimethyl-1,3,4,5,6,8,9,9a-octahydro-1,4-methanocyclopenta[c]oxocin-9a-yl)methyl acetate (25). To a solution of 24 (47 mg, 0.115 mmol, 1 equiv.) in DCM (2 mL), pyridine (19 μL, 0.230 mmol, 2 equiv.) and Tf2O (39 μL, 0.230 mmol, 2 equiv.) were successively added. A dark orange solution was obtained, which was stirred at room temperature for 24 h. A brown mixture was obtained. The reaction was quenched by the addition of water (10 mL). The aqueous layer was extracted with dichloromethane (3 × 10 mL). Then, the combined organic layers were washed with brine (2 × 10 mL), dried over MgSO4, filtered through a glass frit and concentrated under vacuum to give the crude product as an orange oil. The latter was purified by flash column chromatography on silica gel (n-Pent/EtOAc, 90[thin space (1/6-em)]:[thin space (1/6-em)]10) to yield 25 (11 mg, 0.0395 mmol, 34%) as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ 4.09 (d, J = 8.2 Hz, 1H), 4.00 (d, J = 9.8 Hz, 1H), 3.97 (d, J = 9.8 Hz, 1H), 2.38–2.16 (m, 4H), 2.14–1.99 (m, 2H), 2.02 (s, 3H), 1.89–1.76 (m, 1H), 1.76–1.65 (m, 3H), 1.65–1.53 (m, 1H), 1.63 (s, 3H), 1.18 (s, 3H), 1.06 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 171.5, 137.2, 133.4, 83.3, 81.8, 68.1, 58.4, 43.7, 36.5, 31.9, 29.4, 28.4, 25.7, 25.2, 21.6, 21.1, 14.2; IR (neat): ν = 2968, 2924, 2858, 1742, 1692, 1472, 1454, 1437, 1380, 1298; HRMS (ES+) calcd for ([C17H26O3 + Na]+): 301.1774; found: 301.1762.
1-((tert-Butyldimethylsilyloxy)-8a-methyl-6-(prop-1-en-2-yl)-1,2,3,3a,6,7,8,8a-octahydroazulen-3a-yl)methyl acetate (26). To a solution of 25 (20 mg, 0.0488 mmol, 1 equiv.) in DCM (2 mL) were successively added at 0 °C, triethylamine (136 μL, 0.976 mmol, 20 equiv.), DMAP (24 mg, 0.195 mmol, 4 equiv.) and MsCl (58 μL, 0.732 mmol, 15 equiv.). Then, the reaction mixture was let stirring at room temperature overnight. Then the reaction was quenched by the addition of a saturated aqueous solution of NaHCO3 (10 mL). After separation, the aqueous layer was extracted with EtOAc (3 × 10 mL). Then, the combined organic layers were washed with brine (1 × 10 mL), dried over MgSO4, filtered through a glass frit and concentrated under vacuum to afford a brown crude product that was purified by flash column chromatography on silica gel (n-Pent/EtOAc, 98[thin space (1/6-em)]:[thin space (1/6-em)]2) to yield 26 as a yellow oil (19 mg, 0.0488 mmol, quant.). 1H NMR (CDCl3, 300 MHz): δ 5.48 (dd, J = 12.3, 3.5 Hz, 1H), 5.23 (dd, J = 12.3, 2.7 Hz, 1H), 4.75–4.67 (m, 2H), 4.23 (t, J = 7.9 Hz, 1H), 4.17 (d, J = 10.9 Hz, 1H), 4.04 (d, J = 10.9 Hz, 1H), 2.98–2.89 (m, 1H), 2.06 (s, 3H), 2.00–1.89 (m, 1H), 1.88–1.62 (m, 4H), 1.60–1.36 (m, 3H), 1.73 (s, 3H), 0.90 (s, 3H), 0.88 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 171.2, 150.2, 137.4, 135.1, 109.6, 75.7, 69.2, 50.8, 47.8, 47.5, 35.9, 34.9, 29.1, 28.0, 26.0, 21.3, 20.4, 18.8, 18.1, −4.02, −4.8; IR (neat): ν = 2956, 2930, 2857, 1745, 1647, 1469, 1400, 1375, 889, 668; HRMS (ESI) calcd for ([C23H40O3 + Na]+):415.2639; found:415.2653.
2a-(Hydroxymethyl)-1,1,5a-trimethyldecahydro-1H-cyclopropa[f]azulene-2,5-diol (5-epi-valeneomerin B). To a solution of 23 (66 mg, 0.179 mmol, 1 equiv.) was added TBAF (0.27 mL, 0.269 mmol, 1.0 M in THF, 1.5 equiv.) at room temperature. The solution turned green, then brown, after a few minutes, and was let stirring at room temperature overnight. 10 mL water was added, and the aqueous layer was extracted with AcOEt (3 × 20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered in a glass frit and concentrated under vacuum to give the crude product as an oil that was purified by flash column chromatography on silica gel (n-Pent/EtOAc, 70[thin space (1/6-em)]:[thin space (1/6-em)]30) to give 5-epi-valeneomerin B (38 mg, 0.130 mmol, 73%) as a white foam. 1H NMR (CDCl3, 300 MHz): δ 4.64 (t, J = 8.4 Hz, 1H), 4.45 (d, J = 4.8 Hz, 1H), 4.21 (m ABX, 2H), 2.19–2.09 (m, 1H), 2.05 (s, 3H), 1.80–1.62 (m, 4H), 1.48–1.37 (m, 3H), 1.32 (s, 3H), 1.02 (s, 3H), 0.85 (s, 3H), 0.78–0.69 (m, 1H), 0.51 (dd, J = 9.0, 4.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ 77.6, 75.8, 68.2, 55.6, 50.2, 35.0, 32.1, 31.0, 29.5, 27.8, 22.5, 19.9, 19.0, 17.0; mp = 63 °C; IR (neat): ν = 3380, 2954, 2923, 2894, 2859, 1484, 1465, 1441, 1375, 1344, 1279, 1261; HRMS (ESI) calcd for ([C15H26O3 + Na]+): 277.1774; found: 277.1774.

Acknowledgements

The authors thank UPMC, CNRS and MRES (Ph.D. grant for CT). We thank L.-M. Chamoreau and G. Gontard (UPMC) for the X-ray structure determination analyses.

Notes and references

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Footnotes

Electronic supplementary information (ESI) available: 1H, 13C NMR, DFT and crystallography data. CCDC 1540872–1540876. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7qo00360a
CCDC 1540872 (7); 1540873 (13); 1540874 (14); 1540875 (20); 1540876 (21).

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