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Article

An Enantiospecific Synthesis of 5-epi-α-Bulnesene

by
Jiarui Zong
1 and
Jeremy Robertson
1,2,*
1
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
2
Oxford Suzhou Centre for Advanced Research, Ruo Shui Road, Suzhou Industrial Park, Suzhou 215123, China
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(9), 3900; https://doi.org/10.3390/molecules28093900
Submission received: 19 April 2023 / Revised: 2 May 2023 / Accepted: 3 May 2023 / Published: 5 May 2023
(This article belongs to the Special Issue Natural Compounds and New Analogs in Chemical Synthesis: A Themed Issue in Honor of Professor Dr. Mark Moloney)
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Abstract

:
As a result of its unique fragrance and wider role in traditional medicine, agarwood produced in Aquilaria spp. and certain other trees has been harvested to near extinction as a natural phenomenon. Artificially induced agarwood production in Aquilaria plantations has sated some of the demand although the product quality is variable. Synthetic chemistry may have a role to play in providing sustainable routes to many of the fragrant components identified in agarwood and its smoke when burnt as incense. In this work, we report efforts towards a total synthesis of the guaiane sesquiterpene α-bulnesene, which is found, along with its more fragrant oxidised derivatives, in agarwood. Following the ring-expansion of (R)-carvone using reported procedures, α-butenylation gave a substrate for samarium diiodide mediated reductive cyclisation, the two butenyl epimers of the substrate each leading to a single bicyclic alcohol (24 and 25). Overall homoconjugate hydride reduction of one of these alcohols was achieved by Lewis acid-mediated ionisation and then hydride transfer from triethylsilane to complete an overall seven-step synthesis of 5-epi-α-bulnesene. This new synthesis paves the way for short routes to both α-bulnesene enantiomers and a study of their aerial and enzymatic oxidation products.

1. Introduction

A variety of tree species from, notably, the Aquilaria and Gyrinops genera (Thymelaeaceae) react to stress by the production of an oleoresin, known inter alia as aloes or agar, that darkens the tree’s heartwood characteristically and progressively with time (years to decades) [1]. This dense, resinous heartwood—agarwood (oud, gahara, jinkoh and others)—has been revered for its unique fragrance for at least 3400 years. Burnt as incense or steam-distilled to form the essential oil, naturally occurring agarwood has become increasingly rare, exacerbated by a growing demand for agarwood objects [2]; the highest grades can sell to aficionados for USD 1000s per gram creating a vicious circle of spiralling demand and cost [3]. Some consequences of this include indiscriminate felling of potential agarwood-bearing trees, to the extent that South-East Asian Aquilaria and Gyrinops species are now protected under the Convention on International Trade in Endangered Species of Wild Fauna and Flora [4]; a black market of poached, smuggled, adulterated, or fake agarwood [5,6]; agarwood investment schemes (and scams) [7]; and the development of artificial methods of inducing agarwood production in Aquilaria plantations by physical, chemical, and biological (fungal inoculation) means [8,9,10,11,12].
The cultural importance, desirability, and high commercial value of agarwood stimulated extensive and ongoing research directed towards understanding the physiological and biochemical processes leading to its production [13] and identifying the chemical components chiefly responsible for the fragrance [14,15,16,17]. As expected, the number and distribution of secondary metabolites identified within different samples of agarwood—including the smoke from smouldering samples, the vapours of heated samples, and the essential oil—vary significantly but, in general, somewhere between 200–400 compounds are present within which sesquiterpenoids and 2-(2-phenylethyl)chromanones dominate [14]. Descriptions of the “characteristic” agarwood fragrance differ, in part due to the variety of sources but also due to inherent subjectivity and social context; typical descriptions include “rich, sweet woody, wet wood-like” [18], “warm, unique balsamic notes with sandalwood-ambergris tonalities” [17], “gorgeous, mysterious and elegant Oriental odor” [19]. The principal contributors to these properties are the relatively volatile sesquiterpenoids, of which 182 are listed in a recent review [14], that span a range of structural types including, especially, eudesmanes, eremophilanes, and guaianes.
Our interest in this area stemmed from two observations. First, the oxidation products of α-bulnesene 1 (Figure 1), present in agarwood essential oil and extracts, contribute to the complex fragrance properties; aldehyde 2 and lactone 3 are described in Naef’s influential review [17] as “pleasant, β-damascenone-like, woody, touch of camphor” and “powerful, long lasting, woody, sweet note”, respectively. Zviely and Boix-Camps are more effusive: “a beautiful note of β-damascenone; its woodiness […], almost having soul and spirit” and “its smell is very strong […], extremely long lasting […], clean, radiant, diffusive, bright, woody ambery”, respectively [20]. Second, in our collaborative research on employing engineered P450BM3 enzymes in synthesis, we have noted the kinetic resolution of racemic terpenoid substrates [21,22]. Putting these together led us to consider: (a) would the enantiomers of α-bulnesene be discriminated by the Oxford P450BM3 library, and (b) would the enantiomers of sesquiterpenoids 2 and 3 have different odours? To answer these questions, a source of both enantiomers of α-bulnesene was sought.
Τhe naturally occurring enantiomer of α-bulnesene is conveniently available by extraction from patchouli oil [23,24] and has been synthesised [25,26,27,28]. Of the total syntheses, only Heathcock’s route [27] from (±)-Wieland–Miescher ketone could, in principle, be modified to access the separate α-bulnesene enantiomers but, at around 18 steps overall, we aimed to find a shorter route that could be applied equally to both enantiomers. In this report we summarise our study of a free radical cyclisation route to the 7,5-fused ring system leading to 5-epi-α-bulnesene in just seven steps from (R)-carvone.

2. Results and Discussion

The synthetic strategy was shaped by our experience in constructing the pyrrolizidine ring system of heliotridane by a 1,5-hydrogen atom transfer/5-exo-trig cyclisation [29] which, in turn, had roots in the original work of Parsons [30,31,32] and Curran [33,34]. For α-bulnesene, the initial target was identified as vinyl iodide 3 (Figure 2), a precursor to radical intermediates 4 and then 5. The regiochemical outcome of the final cyclisation step was not fully predictable, given the lack of close precedent, but C–C bond formation at the methyl-bearing allyl radical terminus was considered to be less favourable on purely steric grounds. The stereochemical outcome was also unclear but the precedent for analogous 5,5- and 6,5-fused ring-forming processes supported the preferred production of the desired endo-methyl configuration; see also [35].
A short route was developed (Scheme 1) to vinyl radical precursor 3 that began with ring expansion [36] of dihydro-(R)-carvone 6 to afford the analogue 7 as an inconsequential mixture of diastereomers. Regioselective enolisation [37] and silylation, then sulfonylation [38] of the regenerated lithium enolate afforded enol triflate 9 with high (98:2) regioselectivity. The route was completed by employing Fürstner’s variant of the Kumada coupling [39,40] followed by nickel-catalysed hydroalumination and iodination [41]. The low yield in the Kumada coupling step may reflect a slow metal insertion into the C–OTf bond in enol triflate 9 which is co-planar with the adjacent methyl; the analogous reaction of the regioisomeric enol triflate (S1, Supplementary Materials) proceeded efficiently (76% yield) despite the volatility of the product.
All attempts to effect the 1,5-HAT/5-exo-trig sequence from iodide 3, or its cycloheptene regiosomer (S3, Supplementary Materials), using a variety of conditions based on R3SnH and AIBN, returned complex product mixtures whose 1H NMR spectra consistently showed resonances corresponding to RCH=CH2 [δH 5.89–5.77 (1H, m), 5.01 (1H, dd, J 17.0, 2.0 Hz), 4.94 (1H, dd, J 10.5, 2.0 Hz)], indicating simple reduction of the C–I bond (→11) as a dominant pathway. A reaction with Bu3SnD was considered, in order to identify which of the 1,5-HAT or cyclisation steps was problematic, but this was discarded in light of the complex product profile and poor mass recovery; instead, an unambiguous route to the allylic radical 5 was sought. The ring-expanded derivatives 13 and 14 (Figure 3) of (R)-carvone (and their enantiomers from (S)-carvone) are available on a multigram scale via efficient three- or four-step sequences. From these, enolate alkylation and carbonyl reduction would provide allylic alcohol 12 from which a variety of radical precursors could potentially be prepared.
Cycloheptenone derivative 14 was prepared from (R)-carvone as described [42,43] and a sample was isomerised into the conjugated enone isomer 13 under basic conditions (Scheme 2). Direct 3-butenylation of similar ketones has been reported [44] but none of many combinations of base (LHMDS, NaH, t-BuONa, KHMDS, t-BuOK), solvent (THF, DMF, toluene, t-BuOH), additive (DMPU, HMPA), temperature (−78 °C to RT), and electrophile (4-bromobutene, 4-iodobutene) gave acceptable yields of the alkylated product from either cycloheptenone 13 or 14 (Supplementary Materials, Tables S1 and S2). A solution was found in Lautens’ indirect method comprising alkylation with 1,4-dichlorobut-2-ene then Pd(0)-catalysed reductive isomerisation of the so-formed vinyl cyclopropane [45]. Applied to substrate 14, both stages of this method required much development. The alkylation step was best achieved using a mixed base system for the deprotonation [46] with 1,4-dibromobut-2-ene as an electrophile (Supplementary Materials, Table S3). The reductive rearrangement step was complicated by the presence of the endocyclic C=C bond that presumably stabilises the intermediate π-allyl palladium enol(ate) 16 leading to O-alkylation product 17, sometimes as the major component in the crude product mixture. Eventually, it was found that replacing ammonium formate in the reported procedure with an excess of formic acid and triethylamine eliminated this side reaction and the desired butenylated product 18 was thereby obtained in ~65% yield from ketone 14 (Supplementary Materials, Table S4). Alkene isomerisation (→19) and Luche reduction completed the route to alcohol 12.
The significant effort expended in achieving a reliable route to the alcohol was not rewarded by success in converting it into a suitable precursor to allylic radical 5. To summarise many attempts: O-thiocarbonyl derivatives showed a strong tendency to undergo [3,3]-shift leading to unreactive S-acyl isomers, and intermediates generated en route to the corresponding allylic halides or phenylselenides were generally unstable with respect to elimination leading to volatile cycloheptadienes.
At this stage in the project, ketones 18 and 19 were identified as candidates for a reductive cyclisation of the derived ketyl radical anion (Step A, Figure 4) for which there is ample precedent [47,48,49,50,51,52]. In the context of the synthesis of africanol and its isomers, the related approaches of Tai [53], Cossy [44], and Piers [54] gave confidence that this could be a reasonably efficient process, with the stereochemical outcome being controllable to a certain extent by the choice of reaction conditions. Following this cyclisation, an ambitious endgame was planned (Step B, Figure 4) which, mechanistically, would involve (a) activation of the bridgehead alcohol to initiate its departure (→21), then (b) [1,2]-H shift followed by (c) hydride reduction at the less substituted terminus of the so-formed allylic carbocation 22 leading to the fully substituted alkene 23. No direct precedent for such a process could be found but the combination of a Brønsted or Lewis acid activator coupled with a trialkylsilane reducing agent [55,56,57,58,59] was envisaged to achieve the transformation. Notable, Carey’s early work [57] with trifluoroacetic acid and trialkylsilanes showed that cations generated from 3°-alcohols are able to undergo stereospecific rearrangement prior to reductive quenching; see also [60].
Piers’ experimental conditions [54] for reductive cyclisation were used as the starting point for the analogous reaction of ketone 18 submitted as a mixture of inseparable diastereomers. With minor adjustments to the published procedure (freshly prepared samarium diiodide, less HMPA, a more concentrated solution, shorter reaction time), unwanted side-reactions were minimised and just two major products were isolated (24 and 25, Scheme 3), their structures being confirmed by extensive NMR spectroscopic analysis including the key NOE correlations shown (Figure 5; Supplementary Materials, pp. S11–S14). The reaction showed high stereocontrol, with one major product arising from each diastereomer of the starting ketone; notably, both products had the same trans-relative disposition of methyl and hydroxyl groups with respect to the fixed isopropenyl substituent. When the separated alcohol diastereomers were treated with boron trifluoride etherate at low temperatures in the presence of an excess of triethylsilane, the outcomes differed dramatically. In the case of trans-fused bicyclic alcohol 24, the reaction proceeded cleanly to deliver a single hydrocarbon 26, with the merely moderate isolated yield reflecting the high volatility of the product. In contrast, the analogous reaction with cis-fused bicyclic alcohol 25 gave no clear products. From these results, it seems reasonable to propose that the departure of the Lewis acid-complexed hydroxyl group in substrate 24 benefits from participation by the antiperiplanar C–H bond leading directly to a relatively long-lived allylic cation; for 25, no such participation can occur so the localised 3°-carbocation must form fully from which a variety of uncontrolled reactions compete to the exclusion of clean [1,2]-H shift.
The isolated hydrocarbon 26 is assigned as 5-epi-α-bulnesene on the basis of a full NMR spectroscopic analysis; however, very limited NMR data are reported for the epimers of α-bulnesene with which to corroborate the assigned structure. For 5-epi-α-bulnesene, 1H NMR resonances are available [26] for just =CH2 (δ 4.66) and the methyls at C-13 (δ 1.72), C-14 (δ 0.95), and C-15 (δ 1.67); the values obtained for compound 26 are, respectively: δ 4.73/4.70, 1.75, 0.98, and 1.58 with the resonance for CH3-15 differing by −0.09 ppm, out of line with the others that differ consistently by +0.03–0.05 ppm, potentially attributable to referencing methods. We considered a number of alternative structures that could reasonably arise from a more complex reductive rearrangement but none of these fit the COSY and HMBC data (Table 1 and Table 2; Supplementary Materials, pp. S15–S17) as well as the assigned structure; indeed, some of these are reported [61] and can be confidently excluded. Furthermore, apart from the C-7 resonance in the 13C NMR spectrum, all the 13C chemical shifts are within ~3 ppm of the values for authentic α-bulnesene (Figure 6); the aberrant C-7 resonance (43.5 vs. 51.0 for α-bulnesene in CDCl3; 43.8 vs. 51.2 for α-bulnesene in C6D6) is, however, not unreasonable when compared with that reported [62] for 4,5-di-epi-α-bulnesene (δ 43.5 in C6D6).

3. Materials and Methods

3.1. General Methods

All solvents for anhydrous reactions were obtained dry from Grubbs solvent dispenser units after being passed through an activated alumina column under argon. THF was additionally distilled from sodium/benzophenone ketyl under argon. Commercially available reagents were, in general, used as supplied; amines and dipolar aprotic solvents (HMPA and NMP) were purified by standard methods before use. “Petrol” refers to the fraction of light petroleum ether boiling in the range of 30–40 °C; “ether” refers to diethyl ether. All reactions were carried out in oven-dried glassware and under an inert atmosphere (N2 or Ar as specified). Thin layer chromatography (TLC) was carried out using Merck aluminium-backed DC60 F254 0.2 mm precoated plates. Spots were then visualised by the quenching of ultraviolet light fluorescence (λmax 254 nm) and then stained and heated with either anisaldehyde or KMnO4 solutions as appropriate. Retention factors (Rf) are reported along with the solvent system used in parentheses. Flash column chromatography was performed using Merck 60 silica gel (particle size 40–63 μm), and the solvent system used is reported in parentheses. Infrared spectra were recorded using a Bruker Tensor 27 FT-IR fitted with a diamond ATR module. Absorption maxima (νmax) are reported in wavenumbers (cm−1) and are described as strong (s), medium (m), weak (w) or broad (br). Proton (1H) and carbon-13 (13C) NMR spectra were recorded on Bruker NEO-600 or AVIIIHD-400 spectrometers. Chemical shifts (δH or δC) are reported in parts per million (ppm) downfield of tetramethylsilane, internally referenced (in MestReNova) to the appropriate solvent peak: CDCl3, 7.26/77.16; C6D6, 7.16/128.06; acetone-d6, 2.05/206.26. Peak multiplicities are described as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quin), multiplet (m), and broad (br) or a combination thereof. Coupling constants (J) are rounded to the nearest 0.5 Hz. Assignments are made on the basis of chemical shifts, integrations, and coupling constants, using COSY, HSQC, HMBC, and NOESY experiments where appropriate. High-resolution mass spectra (HRMS) were recorded by the staff at the Chemistry Research Laboratory (University of Oxford) using a Bruker Daltonics MicroTOF spectrometer; mass-to-charge ratios (m/z) are reported in Daltons. Melting points were recorded on a Griffin MFB-700-010U melting point apparatus and are uncorrected.

3.2. (2RS,5R)-2-Methyl-5-(prop-1-en-2-yl)cycloheptan-1-one (7)

BF3·OEt2 (3.76 mL, 30.0 mmol) was added dropwise to a stirred solution of (2RS,5R)-dihydrocarvone (3.28 mL, 20.0 mmol) in dry ether (80 mL) under N2 at 0 °C. A solution of ethyl diazoacetate (3.16 mL, 30.0 mmol) in dry ether (10 mL) was added over 15 min and the resulting solution was stirred at RT. When the reaction was complete (~2 h, TLC), the mixture was cooled to 0 °C and neutralised with saturated aqueous NaHCO3 solution (40 mL). The resulting mixture was extracted with chloroform (3 × 30 mL) then the combined extracts were washed with brine (30 mL), dried (MgSO4), filtered, and concentrated. The crude product was purified by flash column chromatography (pentane/ethyl acetate, 25:1) to obtain an intermediate ketoester mixture (4.52 g), which was dissolved in methanol (35 mL) and stirred. A solution of NaOH (1.90 g, 47.4 mmol) in water (40 mL) was added at RT then the mixture was heated at reflux for 3 h, then cooled to RT, diluted with hydrochloric acid (30 mL, 1.0 M), and extracted with ether (3 × 20 mL). The combined extracts were washed successively with water (20 mL) and brine (20 mL), then dried (MgSO4), filtered, and concentrated. The residue was purified by chromatography (pentane/ethyl acetate, 20:1) to give the title compound 7 (2.46 g, 74%) as a colourless oil and a 3:1 ratio of unassigned 2-methyl diastereomers. Rf0.40 (pentane/ethyl acetate, 20:1); νmax/cm−1 2926 m, 2854 m, 1702 s, 1456 m, 887 m; δH (400 MHz, CDCl3) 4.71–4.63 (2H, m), 2.67–2.41 (3H, m), 2.03–1.94 (1H, m), 1.94–1.78 (3H, m), 1.75–1.55 (4H, m), 1.50–1.36 (2H, m), 1.09 (0.75H, d, J = 7.0 Hz), 1.06 (2.25H, d, J = 7.0 Hz); δC (101 MHz, CDCl3) (major/minor) 216.5/216.0, 150.7/149.9, 109.0/109.6, 49.3/48.6, 47.0/45.8, 41.6/41.2, 35.0/30.3, 33.3/30.2, 29.9 (both), 20.6/20.9, 17.9/16.1; HRMS (ESI+) m/z [M + H]+ calcd for C11H19O, 167.1430; found, 167.1432.

3.3. (5R)-2-Methyl-5-(prop-1-en-2-yl)cyclohept-1-en-1-yl trifluoromethanesulfonate (9)

Methylmagnesium bromide (7.5 mL, 3.0 M in ether, 22.5 mmol) was added dropwise to a stirred suspension of FeCl3 (1.20 g, 7.40 mmol) in dry ether (40 mL) under Ar at 0 °C then the mixture was stirred at RT for 1 h. A solution of ketone 7 (830 mg, 5.00 mmol) in dry ether (5 mL) was added dropwise, the resulting suspension was stirred for 30 min and then trimethylsilyl chloride (1.90 mL, 15.0 mmol), triethylamine (2.10 mL, 15.1 mmol), and HMPA (0.870 mL, 5.00 mmol) were added sequentially. The mixture was stirred for 14 h at RT then diluted with ether (40 mL), washed with cold saturated aqueous NaHCO3 solution (2 × 10 mL), dried (MgSO4), filtered, and concentrated. The crude silyl enol ether was dissolved in dry THF (40 mL) and cooled to 0 °C under Ar. Methyllithium (4.4 mL, 1.6 M in ether, 7.0 mmol) was added dropwise then the mixture was allowed to warm to RT and stirred for 30 min. The solution was re-cooled to −78 °C, a solution of Comins’ reagent (3.1 g, 7.9 mmol) in THF (10 mL) was added dropwise, and then the mixture was allowed to warm slowly to RT and stirred for a further 2 h. The solvent was removed under vacuum and the residue was purified by chromatography (pentane) to give enol triflate 9 as a yellow oil (721 mg, 48%). Rf 0.38 (pentane); [α]D25 +3.8 (c 0.62, CHCl3); νmax/cm−1 2937 m, 1413 m, 1245 m, 1207 s, 1143 s; δH (400 MHz, CDCl3) 4.70 (1H, quin, J = 1.5 Hz), 4.68 (1H, br s), 2.58 (1H, br app t, J = 14.0 Hz), 2.46 (1H, dd, J = 16.0, 6.5 Hz), 2.26–2.15 (2H, m), 2.11 (1H, tt, J = 10.5, 4.0 Hz), 1.86–1.75 (2H, m) overlaying 1.81 (3H, d, J = 2.0 Hz), 1.71 (3H, s), 1.60–1.51 (1H, m), 1.46–1.39 (1H, m); δC (151 MHz, CDCl3) 150.2, 146.2, 131.6, 118.5 (q, J = 319.5 Hz), 109.3, 49.2, 32.0, 31.5, 30.1, 29.7, 21.1, 19.5; HRMS (APCI–) m/z [M–H+]− calcd for C12H16O3F3S, 297.0778; found, 297.0765.

3.4. (5R)-1-(But-3-yn-1-yl)-2-methyl-5-(prop-1-en-2-yl)cyclohept-1-ene (10)

A solution of [4-(trimethylsilyl)but-3-yn-1-yl]magnesium bromide in THF was prepared by adding (4-bromobut-1-yn-1-yl)trimethylsilane (156 mg, 0.760 mmol) into a stirred suspension of Mg (184 mg, 7.57 mmol) in dry THF (10 mL). After formation of the grey Grignard solution was complete, it was added into a −30 °C solution of enol triflate 9 (113 mg, 0.379 mmol), Fe(acac)3 (7.0 mg, 0.02 mmol), and NMP (0.30 mL, 3.1 mmol) in dry THF (10 mL) under N2, leading to an immediate colour change from orange to black. The mixture was stirred for 1 h at −30 °C and was then quenched with saturated aqueous NH4Cl solution (10 mL). The aqueous phase was extracted with ether (3 × 10 mL) then the combined organic extracts were dried (Na2SO4), filtered, and concentrated. The residue was dissolved in dry THF (5 mL) then TBAF (0.19 mL, 1.0 M in THF, 0.19 mmol) was added and the mixture stirred under N2 for 1 h at RT. Saturated aqueous NH4Cl solution (10 mL) was added and the aqueous layer was extracted with ether (3 × 10 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography (pentane) to give the title compound 10 as a colourless oil (19 mg, 25%). This volatile compound was used directly in the next step. Rf 0.42 (pentane); δH (400 MHz, CDCl3) 4.64–4.62 (2H, m), 2.37–2.16 (6H, m), 2.11 (1H, tt, J = 11.5, 3.5 Hz), 2.08–1.94 (2H, m), 1.92 (1H, t, J = 2.5 Hz), 1.75–1.65 (2H, m) overlaying 1.72 (3H, d, J = 1.5 Hz) and 1.68 (3H, t, J = 1.0 Hz), 1.25–1.12 (2H, m); δC (101 MHz, CDCl3) 151.9, 134.4, 134.0, 108.4, 84.8, 68.2, 51.7, 34.9, 34.4, 32.8, 32.0, 31.2, 21.1, 20.9, 17.7.

3.5. (5R)-1-(3-Iodobut-3-en-1-yl)-2-methyl-5-(prop-1-en-2-yl)cyclohept-1-ene (3)

DIBAL (0.72 mL, 1.2 M in toluene, 0.86 mmol) was added dropwise to a solution of Ni(dppp)Cl2 (47 mg, 0.087 mmol) in dry THF (10 mL) under Ar. The mixture was cooled to 0 °C and alkyne 10 (88.0 mg, 0.435 mmol) was added via syringe into the black solution; the mixture was warmed to RT and stirred for 1 h then cooled to 0 °C. A solution of N-iodosuccinimide (292 mg, 1.30 mmol) in dry THF (2 mL) was added dropwise, then the solution was warmed to RT and stirring continued for a further 1 h. The solution was quenched with saturated aqueous Rochelle’s salt solution (10 mL), the aqueous phase was extracted with ether (3 × 20 mL), and the combined organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography (pentane/triethylamine, 100:1) to give vinyl iodide 3 as a colourless oil (86.5 mg, 60%). Rf 0.25 (pentane); [α]D25 + 8.3 (c 0.29, CHCl3); νmax/cm–1 2981 s, 1382 m, 1252 m, 1151 m, 955 m; δH (400 MHz, CDCl3) 6.00 (1H, q, J = 1.5 Hz), 5.68 (1H, d, J = 1.5 Hz), 4.64 (2H, br s), 2.50–2.40 (2H, m), 2.33–2.20 (4H, m), 2.15–2.08 (1H, tt, J = 11.5, 3.5 Hz), 2.08–1.95 (2H, m), 1.75–1.65 (2H, m) overlaying 1.72 (3H, d, J = 1.5 Hz) and 1.68 (3H, t, J = 1.0 Hz), 1.21–1.08 (2H, m); δC (101 MHz, CDCl3) 151.8, 134.0, 133.8, 125.3, 112.3, 108.4, 51.7, 44.5, 35.5, 34.9, 33.1, 32.1, 31.3, 21.2, 21.0; HRMS (ESI+) m/z [M + H]+ calcd for C15H24I, 331.0917; found, 331.0916.

3.6. (6R)-3-Methyl-6-(prop-1-en-2-yl)cyclohept-2-en-1-one (13)

DBU (0.40 mL, 2.7 mmol) was added to a stirred solution of cycloheptenone derivative 14 (420 mg, 2.56 mmol) in dichloromethane (13 mL) at RT under N2. The mixture was stirred for 3 h and then quenched with the addition of hydrochloric acid (5 mL, 1.0 M). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 10 mL) then the combined organic portions were washed with brine (10 mL), dried (MgSO4), filtered, and concentrated to yield the title compound 13 (400 mg, 95%), a colourless oil, that was sufficiently pure to use in further steps. A sample was purified for analytical purposes by column chromatography (pentane/ether, 9:1). The analytical data are as reported in [63].

3.7. (6R)-9-Methyl-6-(prop-1-en-2-yl)-1-vinylspiro[2.6]non-8-en-4-one (15)

Potassium tert-butoxide (4.0 mL, 1.0 M in THF, 4.0 mmol) was added to a RT suspension of NaH (267 mg, 60% in mineral oil, 6.68 mmol) in dry toluene (80 mL) under Ar and the mixture was stirred for 1 h. A solution of ketone 14 (550 mg, 3.35 mmol) in dry toluene (10 mL) was added via syringe, stirring was continued for 1 h then the enolate solution was cooled to −78 °C and a solution of (E)-1,4-dibromo-2-butene (2.86 g, 13.4 mmol) in dry toluene (20 mL) was added dropwise over 10 min. The mixture was warmed slowly to RT and stirred for 2 h then quenched with saturated aqueous NH4Cl solution (20 mL) and extracted with ether (3 × 20 mL). The combined extracts were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated to give a residue that was purified by chromatography (pentane/ethyl acetate, 20:1), affording the product 15 as a yellow oil and as a pair of unassigned diastereomers (527 mg, 73%, dr = 1:1). Rf 0.54 (pentane/ethyl acetate, 20:1); νmax/cm–1 2966 m, 2917 m, 1686 s, 1645 m, 1439 m; δH (400 MHz, CDCl3) 5.85–5.71 (2H, m), 5.21 (0.5H, dd, J = 17.0, 2.0 Hz), 5.20 (0.5H, dd, J = 17.0, 2.0 Hz), 5.04 (0.5H, dd, J = 10.5, 2.0 Hz), 5.02 (0.5H, dd, J = 10.5, 2.0 Hz), 4.76–4.73 (1H, m), 4.73–4.68 (1H, m), 2.84–2.69 (1.5H, m), 2.64 (1H, d, J = 7.0 Hz), 2.51–2.43 (1H, m), 2.30–2.24 (1H, m), 2.21–2.11 (1H, m), 1.98 (0.5H, app. q, J = 8.5 Hz), 1.90 (0.5H, dd, J = 7.5, 4.5 Hz), 1.76 (0.5H, dd, J = 7.5, 5.0 Hz), 1.72 (1.5H, br s), 1.70 (1.5H, br s), 1.69 (1.5H, br s), 1.67 (1.5H, q, J = 1.0 Hz), 1.44 (0.5H, dd, J = 8.5, 5.0 Hz), 1.31 (0.5H, dd, J = 9.0, 4.5 Hz); δC (101 MHz, CDCl3) 209.3/208.7, 148.4/148.2, 137.5/136.0, 135.8/135.4, 126.4/125.9, 116.5 (both), 110.2/109.9, 46.5/45.9, 46.2/42.7, 42.9/42.2, 36.8/36.0, 31.2/29.4, 21.9/21.1, 21.2/21.0, 20.7 (two peaks); HRMS (ESI+) m/z [M + H]+ calcd for C15H21O, 217.1587; found, 217.1586.

3.8. (2RS,6R)-2-(But-3-en-1-yl)-3-methyl-6-(prop-1-en-2-yl)cyclohept-3-en-1-one (18)

Triethylamine (1.36 mL, 9.76 mmol) and then formic acid (1.29 mL, 34.2 mmol) were added to a RT solution of Pd2(dba)3 (45 mg, 0.049 mmol) and tributylphosphine (98 μL, 0.39 mmol) in dry toluene (35 mL) under Ar. The resulting suspension was stirred for 5 min and then heated to 105 °C. A solution of ketone 15 (526 mg, 2.43 mmol) in dry toluene (5 mL) was added dropwise into the heated mixture over 5 min and stirring was continued at 105 °C for 2 h. The mixture was cooled to RT and water (20 mL) was added. The resulting mixture was extracted with ether (3 × 20 mL), and the combined extracts were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by chromatography (pentane/ethyl acetate, 30:1) to give the title compound 18, a pair of diastereomers (468 mg, 89%, dr = 2:1), as a yellow oil. Rf 0.31 (pentane/ethyl acetate, 30:1); νmax/cm–1 2935 m, 2857 m, 1707 s, 1643 m, 1447 m; δH (400 MHz, CDCl3) (indicative integrals) 5.85–5.74 (1H, m), 5.69–5.57 (1H, m), 5.06–4.93 (2H, m), 4.80–4.67 (2H, m), 3.26 (0.67H, dd, J = 8.5, 4.5 Hz), 3.11 (0.33H, dd, J = 8.5, 5.0 Hz), 2.72–2.62 (2.67H, m), 2.55–2.48 (0.67H, m), 2.37–2.25 (0.67H, m), 2.26–2.13 (1.67H, m), 2.09–2.00 (1.67H, m), 2.00–1.92 (0.67H, m), 1.77 (1H, br s), 1.75 (2H, br s), 1.73–1.72 (3H, m) overlaying 1.82–1.60 (1H, m); δC (101 MHz, CDCl3) (major/minor) 209.5/210.1, 148.2/148.4, 138.4/138.2, 135.9/135.5, 125.3/124.9, 115.2/115.3, 110.0/110.2, 56.0/57.0, 48.9/46.9, 47.4/45.2, 31.9/31.8, 30.5/31.7, 26.9/27.7, 22.2/24.2, 20.6/20.8; HRMS (ESI+) m/z [M + H]+ calcd for C15H23O, 219.1743; found, 219.1745.

3.9. (6R)-2-(But-3-en-1-yl)-3-methyl-6-(prop-1-en-2-yl)cyclohept-2-en-1-one (19)

A solution of potassium tert-butoxide (0.030 mL, 1.0 M in THF, 0.030 mmol) was added to a RT solution of ketone 18 (22 mg, 0.10 mmol) in dry toluene (2 mL) under N2. The mixture was heated to 90 °C and stirred for 4 h. The resulting orange solution was cooled to RT and quenched with saturated aqueous NH4Cl solution (5 mL) then extracted with ether (3 × 5 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated. The residue was purified by chromatography (pentane/ethyl acetate, 30:1) to give the ketone 19 (7.0 mg, 32%) as a colourless oil and recovered ketone 18 (6.0 mg, 27%). Rf 0.22 (pentane/ethyl acetate, 10:1); [α]D25 +59.8 (c 0.22, CHCl3); νmax/cm–1 2980 s, 1660 s, 1447 m, 1376 m, 908s; δH (400 MHz, CDCl3) 5.76 (1H, ddt, J = 17.0, 10.0, 7.0 Hz), 4.97 (1H, dq, J = 17.0, 1.5 Hz), 4.91 (1H, br d, J = 10 Hz)), 4.73 (2H, br s), 2.61–2.56 (2H, m), 2.54–2.45 (2H, m), 2.44–2.31 (2H, m), 2.23 (1H, ddd, J = 16.5, 6.0, 3.0 Hz), 2.10–2.02 (2H, m), 1.92 (3H, s), 1.88–1.74 (1H, m), 1.72 (3H, br s), 1.66 (1H, dddd, J = 14.0, 7.5, 6.0, 4.0 Hz); δC (101 MHz, CDCl3) 205.4, 150.0, 148.0, 138.5, 137.9, 114.9, 109.9, 46.8, 40.2, 33.7, 33.5, 29.8, 28.4, 23.0, 21.1; HRMS (ESI+) m/z [M + H]+ calcd for C15H23O, 219.1743; found, 219.1743.

3.10. (1RS,6R)-2-(But-3-en-1-yl)-3-methyl-6-(prop-1-en-2-yl)cyclohept-2-en-1-ol (12)

NaBH4 (11 mg, 0.29 mmol) was added to a stirred solution of CeCl3·7H2O (109 mg, 0.293 mmol) and ketone 19 (58.0 mg, 0.268 mmol) in methanol (25 mL) at 0 °C under N2. Stirring was continued at 0 °C for 1 h by which time the reaction was complete (TLC). Water (10 mL) was added, and the mixture was extracted with ether (4 × 20 mL); the combined organic extracts were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by chromatography (pentane/ethyl acetate, 10:1) to give the title compound 12 (33 mg, 56%) as a colourless solid, and as a pair of unassigned diastereomers (dr~5:1). Rf 0.35 (pentane/ethyl acetate, 10:1); m.p. 41 °C; νmax/cm–1 3661w, 2981 s, 2890 m, 1461 m, 1153 m; δH (600 MHz, C6D6) (major diastereomer) 5.94 (1H, ddt, J = 17.0, 10.0, 6.5 Hz), 5.12 (1H, dq, J = 17.0, 1.5 Hz), 5.01 (1H, br d, J = 10.0 Hz), 4.74 (2H, br s), 4.28 (1H, d, J = 10.0 Hz), 2.45–2.35 (2H, m), 2.34–2.23 (2H, m), 2.11 (1H, tt, J = 12.0, 4.0 Hz), 2.07–2.01 (1H, m), 1.82 (1H, ddd, J = 14.5, 7.0, 1.5 Hz), 1.64 (3H, d, J = 1.5 Hz), 1.60 (3H, t, J = 1.0 Hz), 1.58–1.47 (3H, m), 1.04 (1H, dtd, J = 13.5, 12.0, 1.5 Hz); δC (151 MHz, C6D6) (major diastereomer) 150.7, 139.6, 138.8, 130.5, 114.5, 109.3, 72.0, 49.0, 43.1, 34.7, 33.9, 30.5, 28.0, 21.3, 20.6; HRMS (ESI+) m/z [M + H–H2O]+ calcd for C15H23, 203.1794; found, 203.1794.

3.11. (3S,3aR,5R,8aR)-3,8-Dimethyl-5-(prop-1-en-2-yl)-2,3,4,5,6,8a-hexahydroazulen-3a(1H)-ol (24); (3S,3aR,5R,8aS)-3,8-dimethyl-5-(prop-1-en-2-yl)-2,3,4,5,6,8a-hexahydroazulen-3a(1H)-ol (25)

1,2-Diiodoethane (387 mg, 1.37 mmol) was added to a stirred suspension of Sm powder (360 mg, 2.39 mmol) in dry THF (14 mL) under Ar. The resulting solution was stirred for 2 h to yield a deep blue SmI2 solution. Dry HMPA (1.0 mL, 5.7 mmol) was then added to generate a deep purple solution. A solution of ketone 18 (120 mg, 0.555 mmol) and dry tert-butanol (1.05 ml, 1.10 mmol) in dry THF (3 mL) was transferred into the HMPA/SmI2 solution dropwise by syringe over 5 min and the mixture was stirred for 30 min. Saturated aqueous NaHCO3 solution (10 mL) was added, the mixture was extracted with ether (3 × 10 mL), and the combined extracts were washed with brine (10 mL), then dried (MgSO4), filtered, and concentrated. The residue was purified by chromatography on basic alumina (pentane/ethyl acetate, 30:1) to give the trans-fused bicyclic alcohol 24 (43 mg, 35%) as a yellow oil. Rf 0.56 (pentane/ethyl acetate, 10:1); [α]D25 +30.7 (c 0.25, CH2Cl2); IR (film) νmax/cm–1 3567w, 2934 s, 2854 m, 1644 m, 1446 s; δH (600 MHz, acetone-d6) 5.74–5.70 (1H, m, H9), 4.68–4.67 (1H, m, H12), 4.64–4.62 (1H, m, H12′), 2.77 (1H, br t, J = 9.5 Hz, H1), 2.60 (1H, s, OH), 2.27 (1H, br t, J = 11.0 Hz, H7), 2.21–2.12 (1H, m, H8), 2.09–1.95 (3H, m, H3, H4, H8′), 1.92–1.84 (2H, m, H2, H6), 1.78–1.72 (1H, m, H2′), 1.71–1.70 (6H, m, H13, H15), 1.64 (1H, dd, J = 13.5, 12.0 Hz, H6′), 1.12 (1H, ddt, J = 12.0, 9.5, 7.0 Hz, H3′), 0.93 (3H, d, J = 7.0 Hz, H14); δC (151 MHz, acetone-d6) 153.0 (C11), 139.3 (C10), 126.3 (C9), 108.9 (C12), 79.3 (C5), 51.0 (C1), 47.6 (C4), 46.6 (C6), 39.8 (C7), 34.2 (C8), 33.8 (C3), 27.2 (C2), 23.7 (C15), 20.8 (C13), 17.6 (C14); HRMS (ESI+) m/z [M + H–H2O]+ calcd for C15H23, 203.1794; found, 203.1796. The cis-fused bicyclic alcohol 25 was also obtained as a yellow oil (33 mg, 27%). Rf 0.30 (pentane/ethyl acetate, 10:1); [α]D25 +46.5 (c 0.11, CH2Cl2); νmax/cm–1 3447w, 2923s, 1457m; δH (600 MHz, acetone-d6) 5.51 (1H, tq, J = 6.0, 1.5 Hz, H9), 4.68–4.65 (1H, m, H12), 4.61–4.60 (1H, m, H12′), 3.27 (1H, br s, OH), 2.55–2.49 (1H, m, H7), 2.43 (1H, dd, J = 12.5, 8.5 Hz, H1), 2.09–2.05 (2H, m, H8), 1.98–1.85 (3H, m, H2, H3, H4), 1.71 (3H, br s, H13) and 1.70 (3H, br s, H15) overlays 1.72–1.68 (1H, m, H6), 1.59 (1H, dd, J = 13.5, 11.5 Hz, H6′), 1.59–1.52 (1H, m, H2′), 1.29–1.21 (1H, m, H3′), 0.87 (3H, d, J = 6.5 Hz, H14); δC (151 MHz, acetone-d6) 153.5 (C11), 138.6 (C10), 123.8 (C9), 108.6 (C12), 78.8 (C5), 57.6 (C1), 47.4 (C4), 39.6 (C7), 38.8 (C6), 35.1 (C8), 29.0 (C3), 28.1 (C15), 26.6 (C2), 21.0 (C13), 14.1 (C14); HRMS (ESI+) m/z [M + H–H2O]+ calcd for C15H23, 203.1794; found, 203.1795.

3.12. (3S,3aR,5R)-3,8-Dimethyl-5-(prop-1-en-2-yl)-1,2,3,3a,4,5,6,7-octahydroazulene [5-epi-α-bulnesene] (26)

A solution of BF3·OEt2 (0.0152 mL, 0.120 mmol) in dry dichloromethane (1.52 mL) was added dropwise over 5 min to a −78 °C solution of alcohol 24 (39.0 mg, 0.177 mmol) and triethylsilane (0.168 mL, 1.05 mmol) in dry dichloromethane (2 mL) under N2. The resulting mixture was allowed to warm slowly to 0 °C and was then stirred for 1 h. Saturated aqueous NaHCO3 solution (10 mL) was added, and the mixture was extracted with ether (3 × 10 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated carefully under vacuum. The residue was purified by chromatography (pentane) to give the title compound 26 (19.5 mg, 54%) as a volatile, colourless oil. Rf 0.63 (pentane); [α]D25 + 40.8 (c 0.95, CH2Cl2); νmax/cm–1 2923 s, 2866 s, 1643 m, 1456 m, 1375 m; δH (600 MHz, CDCl3) 4.73 (1H, br s, H12), 4.70 (1H, br s, H12′), 2.35–2.30 (1H, m, H7), 2.25 (1H, dd, J = 16.5, 8.5 Hz, H2), 2.21–2.10 (3H, m, H2′, H9), 2.05 (1H, tq, J = 10.0, 2.5 Hz, H5), 1.89–1.82 (1H, m, H8), 1.82–1.77 (2H, m, H3, H6), 1.75 (3H, br s, H13), 1.72–1.65 (1H, m, H6′), 1.65–1.59 (1H, m, H8′), 1.58 (3H, br s, H15), 1.41–1.32 (1H, m, H4), 1.13 (1H, qd, J = 11.5, 8.5 Hz, H3′), 0.99 (3H, d, J = 6.5 Hz, H14); δC (151 MHz, CDCl3) 150.8 (C11), 140.8 (C1), 126.6 (C10), 108.5 (C12), 46.1 (C5), 43.5 (C7), 42.5 (C4), 34.7 (C6), 34.1 (C9), 33.8 (C3), 31.0 (C2), 29.6 (C8), 22.1 (C13), 21.6 (C15), 18.3 (C14); HRMS (EI) m/z [M]•+ calcd for C15H24, 204.1873; found, 204.1878.

4. Conclusions

This study set out to develop a short synthesis of both enantiomers of α-bulnesene in order to investigate their relative reactivity towards our local library of P450BM3 enzymes and the fragrance properties of oxidised derivatives in both enantiomeric series. The initially planned 1,5-HAT/cyclisation strategy was not productive but led to the exploration of a related ketyl radical anion cyclisation. During this project, optimised conditions were developed for overall butenylation of enone 14; a modified reductive cyclisation protocol led to increased efficiency and stereoselectivity compared with previously reported close precedents, and a new reductive rearrangement step completed the synthesis not of α-bulnesene itself but of the 5-epi-isomer. The overall route (Figure 7A) from carvone is short (seven steps) and sufficiently efficient (~15%) for the project’s purposes. Current work is exploring methods [64,65,66] to produce the “missing stereoisomer” 27 projected to lead to the natural product (Figure 7B) and, from (S)-carvone, its enantiomer.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28093900/s1. NMR spectra for compounds in Scheme 1, Scheme 2 and Scheme 3, reference NMR data for α-bulnesene 1, procedures and characterisation data for S1–S3, optimisation tables for the formation of butenyl ketone 18 (PDF).

Author Contributions

Conceptualisation, J.R.; investigation, J.Z.; methodology, J.R. and J.Z.; supervision, J.R.; writing—original draft preparation, J.R.; writing—review and editing, J.R. and J.Z. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are not available from the authors.

References

  1. Mohamed, R. (Ed.) Agarwood—Science Behind the Fragrance; Springer: Singapore, 2016. [Google Scholar]
  2. Thompson, I.D.; Lim, T.; Turjaman, M. Expensive, Exploited and Endangered—A Review of the Agarwood-Producing Genera Aquilaria and Gyrinops: CITES Considerations, Trade Patterns, Conservation, and Management. In Proceedings of the Nineteenth Meeting of the Conference of the Parties, Panama City, Panama, 14–25 November 2022. [Google Scholar]
  3. Kynam: The King of Agarwood. Available online: https://interactive.aljazeera.com/aje/2016/oud-agarwood-scent-from-heaven/scent-from-heaven-the-king-of-agarwood.html (accessed on 17 April 2023).
  4. CITES. Checklist of CITES Species. Available online: checklist.cites.org (accessed on 17 April 2023).
  5. Antonopoulou, M.; Compton, J.; Perry, L.S.; Al-Mubarak, R. The Trade and Use of Agarwood (Oudh) in the United Arab Emirates; TRAFFIC Southeast Asia: Petaling Jaya, Malaysia, 2010. [Google Scholar]
  6. Wyn, L.T.; Anak, N.A. Wood for the Trees: A Review of the Agarwood (Gaharu) Trade in Malaysia; TRAFFIC Southeast Asia: Petaling Jaya, Malaysia, 2010. [Google Scholar]
  7. Alternative Investment Report: Forestry—2014. Available online: https://intelligent-partnership.com/AiR/reports/Forestry-Report-2014/files/assets/common/downloads/publication.pdf (accessed on 7 April 2023).
  8. Shivanand, P.; Arbie, N.F.; Krishnamoorthy, S.; Ahmad, N. Agarwood—The Fragrant Molecules of a Wounded Tree. Molecules 2022, 27, 3386. [Google Scholar] [CrossRef] [PubMed]
  9. Wang, Y.; Hussain, M.; Jiang, Z.; Wang, Z.; Gao, J.; Ye, F.; Mao, R.; Li, H. Aquilaria Species (Thymelaeaceae) Distribution, Volatile and Non-Volatile Phytochemicals, Pharmacological Uses, Agarwood Grading System, and Induction Methods. Molecules 2021, 27, 7708. [Google Scholar] [CrossRef] [PubMed]
  10. Tan, C.S.; Isa, N.M.; Ismail, I.; Zainal, Z. Agarwood Induction: Current Developments and Future Perspectives. Front. Plant Sci. 2019, 10, 122. [Google Scholar] [CrossRef] [PubMed]
  11. Azren, P.D.; Lee, S.Y.; Emang, D.; Mohamed, R. History and Perspectives of Induction Technology for Agarwood Production from Cultivated Aquilaria in Asia: A Review. J. For. Res. 2019, 30, 1–11. [Google Scholar] [CrossRef]
  12. Chhipa, H.; Chowdhary, K.; Kaushik, N. Artificial Production of Agarwood Oil in Aquilaria sp. by Fungi: A Review. Phytochem. Rev. 2017, 16, 835–860. [Google Scholar] [CrossRef]
  13. Naziz, P.S.; Das, R.; Sen, S. The Scent of Stress: Evidence from the Unique Fragrance of Agarwood. Front. Plant Sci. 2019, 10, 840. [Google Scholar] [CrossRef]
  14. Li, W.; Chen, H.-Q.; Wang, H.; Mei, W.-L.; Dai, H.-F. Natural Products in Agarwood and Aquilaria Plants: Chemistry, Biological Activities and Biosynthesis. Nat. Prod. Rep. 2021, 38, 528–565. [Google Scholar] [CrossRef]
  15. Gao, M.; Han, X.; Sun, Y.; Chen, H.; Yang, Y.; Liu, Y.; Meng, H.; Gao, Z.; Xu, Y.; Zhang, Z.; et al. Overview of Sesquiterpenes and Chromones of Agarwood Originating from Four Main Species of the Genus Aquilaria. RSC Adv. 2019, 9, 4113–4130. [Google Scholar] [CrossRef]
  16. Kristanti, A.N.; Tanjung, M.; Amina, N.S. Secondary Metabolites of Aquilaria, a Thymelaeaceae Genus. Mini-Rev. Org. Chem. 2018, 15, 36–55. [Google Scholar] [CrossRef]
  17. Naef, R. The Volatile and Semi-volatile Constituents of Agarwood, the Infected Heartwood of Aquilaria Species: A Review. Flavour Fragr. J. 2011, 26, 73–89. [Google Scholar] [CrossRef]
  18. Niebler, J. Incense Materials. In Springer Handbook of Odor; Buettner, A., Ed.; Springer: Cham, Switzerland, 2017; pp. 63–86. [Google Scholar]
  19. Ishihara, M.; Tsuneya, T.; Uneyama, K. Components of the Volatile Concentrate of Agarwood. J. Essent. Oil Res. 1993, 5, 283–289. [Google Scholar] [CrossRef]
  20. Zviely, M.; Boix-Camps, A. Sesquiterpenoides—The Holy Fragrance Ingredients. Isr. Chem. Eng. 2015, 1, 27–31. [Google Scholar]
  21. Syntrivanis, L.-D.; Wong, L.L.; Robertson, J. Hydroxylation of Eleuthoside Synthetic Intermediates by P450BM3 (CYP102A1). Eur. J. Org. Chem. 2018, 2018, 6369–6378. [Google Scholar] [CrossRef]
  22. Harwood, L.A.; Wong, L.L.; Robertson, J. Enzymatic Kinetic Resolution by Addition of Oxygen. Angew. Chem. Int. Ed. 2021, 60, 4434–4447. [Google Scholar] [CrossRef]
  23. Rakotonirainy, O.; Gaydou, E.M.; Faure, R.; Bombarda, I. Sesquiterpenes from Patchouli (Pogostemon cablin) Essential Oil. Assignment of the Proton and Carbon-13 NMR Spectra. J. Essent. Oil Res. 1997, 9, 321–327. [Google Scholar] [CrossRef]
  24. Ishihara, M.; Tsuneya, T.; Uneyama, K. Guaiane Sesquiterpenes from Agarwood. Phytochemistry 1991, 30, 3343–3347. [Google Scholar] [CrossRef]
  25. Piers, E.; Cheng, K.F. Stereoselective Synthesis of α-Bulnesene. Chem. Commun. 1969, 52, 562–563. [Google Scholar] [CrossRef]
  26. Piers, E.; Cheng, K.F. Stereoselective Synthesis of α-Bulnesene, 4-epi-α-Bulnesene, and 5-epi-α-Bulnesene. Can. J. Chem. 1970, 48, 2234–2245. [Google Scholar] [CrossRef]
  27. Heathcock, C.H.; Ratcliffe, R. Stereoselective Total Synthesis of the Guaiazulenic Sesquiterpenoids α-Bulnesene and Bulnesol. J. Am. Chem. Soc. 1971, 93, 1746–1757. [Google Scholar] [CrossRef]
  28. Mehta, G.; Singh, B.P. Terpenes and Related Systems. XIII. Regiospecific Fragmentation of Patchoulol. Short Synthesis of α-Bulnesene. Tetrahedron Lett. 1975, 50, 4495–4498. [Google Scholar] [CrossRef]
  29. Robertson, J.; Peplow, M.A.; Pillai, J. The Synthesis of (±)-Heliotridane and (6S,7S)-Dihydroxyheliotridane via Sequential Hydrogen Atom Abstraction and Cyclisation. Tetrahedron Lett. 1996, 37, 5825–5828. [Google Scholar] [CrossRef]
  30. Lathbury, D.C.; Parsons, P.J.; Pinto, I. A Route to the Pyrrolizidine Ring System using a Novel Radical Cyclisation. Chem. Commun. 1988, 81–82. [Google Scholar] [CrossRef]
  31. Borthwick, A.D.; Caddick, S.; Parsons, P.J. 1,5 Allylic Abstraction, Cyclisation: A New Route to Five Membered Carbocycles. Tetrahedron Lett. 1990, 31, 6911–6914. [Google Scholar] [CrossRef]
  32. Borthwick, A.D.; Caddick, S.; Parsons, P.J. Approaches to Bicyclic Ring Systems via 1,5 Allylic Abstraction Cyclisation. Tetrahedron 1992, 48, 10655–10666. [Google Scholar] [CrossRef]
  33. Curran, D.P.; Kim, D.; Liu, H.T.; Shen, W. Translocation of Radical Sites by Intramolecular 1,5-Hydrogen Atom Transfer. J. Am. Chem. Soc. 1988, 110, 5900–5902. [Google Scholar] [CrossRef]
  34. Curran, D.P.; Shen, W. Radical Translocation Reactions of Vinyl Radicals: Substituent Effects on 1,5-Hydrogen-Transfer Reactions. J. Am. Chem. Soc. 1993, 115, 6051–6059. [Google Scholar] [CrossRef]
  35. Beaufils, F.; Dénès, F.; Becattini, B.; Renaud, P.; Schenk, K. Thiophenol-Mediated 1,5-Hydrogen Atom Abstraction: Easy Access to Mono- and Bicyclic Compounds. Adv. Synth. Catal. 2005, 347, 1587–1594. [Google Scholar] [CrossRef]
  36. Liu, H.J.; Majumdar, S.P. On the Regioselectivity of Boron Trifluoride Catalyzed Ring Expansion of Cycloalkanones with Ethyl Diazoacetate. Synth. Commun. 1975, 5, 125–130. [Google Scholar] [CrossRef]
  37. Krafft, M.E.; Holton, R.A. Preparation of a New, Highly Reactive Form of Iron(0) and its Use in Deprotonation of Carbonyl Compounds. J. Org. Chem. 1984, 49, 3669–3670. [Google Scholar] [CrossRef]
  38. Comins, D.L.; Dehghani, A. Pyridine-Derived Triflating Reagents: An Improved Preparation of Vinyl Triflates from Metallo Enolates. Tetrahedron Lett. 1992, 33, 6299–6302. [Google Scholar] [CrossRef]
  39. Fürstner, A.; De Souza, D.; Parra-Rapado, L.; Jensen, J.T. Catalysis-Based Total Synthesis of Latrunculin B. Angew. Chem. Int. Ed. 2003, 42, 5358–5360. [Google Scholar] [CrossRef]
  40. Scheiper, B.; Bonnekessel, M.; Krause, H.; Fürstner, A. Selective Iron-Catalyzed Cross-Coupling Reactions of Grignard Reagents with Enol Triflates, Acid Chlorides, and Dichloroarenes. J. Org. Chem. 2004, 69, 3943–3949. [Google Scholar] [CrossRef] [PubMed]
  41. Gao, F.; Hoveyda, A.H. α-Selective Ni-Catalyzed Hydroalumination of Aryl- and Alkyl-Substituted Terminal Alkynes: Practical Syntheses of Internal Vinyl Aluminums, Halides, or Boronates. J. Am. Chem. Soc. 2010, 132, 10961–10963. [Google Scholar] [CrossRef]
  42. Alves, L.D.C.; Desiderá, A.L.; de Oliveira, K.T.; Newton, S.; Ley, S.V.; Brocksom, T.J. A Practical Deca-gram Scale Ring Expansion of (R)-(−)-Carvone to (R)-(+)-3-Methyl-6-isopropenyl-cyclohept-3-enone-1. Org. Biomol. Chem. 2015, 13, 7633–7642. [Google Scholar] [CrossRef]
  43. Meng, Z.; Fürstner, A. Total Syntheses of Scabrolide A and Nominal Scabrolide B. J. Am. Chem. Soc. 2022, 144, 1528–1533. [Google Scholar] [CrossRef]
  44. Cossy, J.; BouzBouz, S.; Mouza, C. A Short Total Synthesis of (±)-Isoafricanol and Two of its Isomers. Synlett 1998, 1998, 621–622. [Google Scholar] [CrossRef]
  45. Hughes, G.; Lautens, M.; Wu, J. The Use of 1,4-Dichlorobut-2-ene as a Synthetic Equivalent of 4-Bromo-but-1-ene. Synlett 2000, 2000, 835–837. [Google Scholar]
  46. Chahboun, R.; Botubol-Ares, J.M.; Durán-Peña, M.J.; Jiménez, F.; Alvarez-Manzaneda, R.; Alvarez-Manzaneda, E. Deconjugative α-Alkylation of Cyclohexenecarboxaldehydes: An Access to Diverse Terpenoids. J. Org. Chem. 2021, 86, 8742–8754. [Google Scholar] [CrossRef]
  47. Corey, E.J.; Pyne, S.G. Conversion of Ketones Having δ,ε-π-Functions to Cyclopentanols by Zinc-Trimethylchlorosilane. Tetrahedron Lett. 1983, 24, 2821–2824. [Google Scholar] [CrossRef]
  48. Belotti, D.; Cossy, J.; Pete, J.P.; Portella, C. Photoreductive Cyclization of δ,ε-Unsaturated Ketones. Tetrahedron Lett. 1985, 26, 4591–4594. [Google Scholar] [CrossRef]
  49. Belotti, D.; Cossy, J.; Pete, J.P.; Portella, C. Synthesis of Bicyclic Cyclopentanols by Photoreductive Cyclization of δ,ε-Unsaturated Ketones. J. Org. Chem. 1986, 51, 4196–4200. [Google Scholar] [CrossRef]
  50. Molander, G.A.; Kenny, C. Stereocontrolled Intramolecular Ketone-Olefin Reductive Coupling Reactions Promoted by Samarium Diiodide. Tetrahedron Lett. 1987, 28, 4367–4370. [Google Scholar] [CrossRef]
  51. Jasperse, C.P.; Curran, D.P. Sequential Radical Cyclization Approach to Propellane Triquinanes. Total Synthesis of (±)-Modhephene. J. Am. Chem. Soc. 1990, 112, 5601–5609. [Google Scholar] [CrossRef]
  52. Molander, G.A.; McKie, J.A. Samarium(II) Iodide-Induced Reductive Cyclization of Unactivated Olefinic Ketones. Sequential Radical Cyclization/Intermolecular Nucleophilic Addition and Substitution Reactions. J. Org. Chem. 1992, 57, 3132–3139. [Google Scholar] [CrossRef]
  53. Sugimura, T.; Futagawa, T.; Tai, A. Synthetic Approach for (+)-Africanol. Chem. Lett. 1990, 19, 2295–2298. [Google Scholar] [CrossRef]
  54. Marques, F.A.; Ferreira, J.T.B.; Piers, E. Synthesis of (±)-Africanol. J. Braz. Chem. Soc. 2000, 11, 502–511. [Google Scholar] [CrossRef]
  55. Kursanov, D.N.; Parnes, Z.N.; Bassova, G.I.; Loim, N.M.; Zdanovich, V.I. Ionic Hydrogenation of the Ethylene Bond and the Double Bond of the Carbonyl Group. Tetrahedron 1967, 23, 2235–2242. [Google Scholar] [CrossRef]
  56. Carey, F.A.; Tremper, H.S. Carbonium Ion-Silane Hydride Transfer Reactions. I. Scope and Stereochemistry. J. Am. Chem. Soc. 1968, 90, 2578–2583. [Google Scholar] [CrossRef]
  57. Carey, F.A.; Tremper, H.S. Carbonium Ion-Silane Hydride Transfer Reactions. V. tert-Alkyl Cations. J. Org. Chem. 1971, 36, 758–761. [Google Scholar] [CrossRef]
  58. Adlington, M.G.; Orfanopoulos, M.; Fry, J.L. A Convenient One-Step Synthesis of Hydrocarbons from Alcohols through use of the Organosilane-Boron Trifluoride Reducing System. Tetrahedron Lett. 1976, 17, 2955–2958. [Google Scholar] [CrossRef]
  59. Doyle, M.P.; West, C.T.; Donnelly, S.J.; McOsker, C.C. Silane Reductions in Acidic Media VIII. Boron Trifluoride Catalyzed Organosilane Reductions. Selectivity and Mechanism. J. Organomet. Chem. 1976, 117, 129–140. [Google Scholar] [CrossRef]
  60. Aulenta, F.; Berndt, M.; Brüdgam, I.; Hartl, H.; Sörgel, S.; Reißig, H.-U. A New, Efficient and Stereoselective Synthesis of Tricyclic and Tetracyclic Compounds by Samarium Diiodide Induced Cyclisations of Naphthyl-Substituted Arylketones—An Easy Access to Steroid-Like Skeletons. Chem. Eur. J. 2007, 13, 6047–6062. [Google Scholar] [CrossRef]
  61. Srikrishna, A.; Pardeshi, V.H. Enantiospecific Total Synthesis of Aciphyllene. Tetrahedron 2010, 66, 8160–8168. [Google Scholar] [CrossRef]
  62. Tesso, H.; König, W.A.; Kubeczka, K.-H.; Bartnik, M.; Glowniak, K. Secondary Metabolites of Peucedanum tauricum Fruits. Phytochemistry 2005, 66, 707–713. [Google Scholar] [CrossRef] [PubMed]
  63. Brocksom, T.J.; Brocksom, U.; Pergentino de Sousa, D.; Frederico, D. Enantiopure Cycloheptenones from (R)-(−)-Carvone: Intermediates for Perhydroazulene Terpenoids. Tetrahedron Asymmetry 2005, 16, 3628–3632. [Google Scholar] [CrossRef]
  64. Hewlett, D.F.; Whitby, R.J. Intramolecular Cocyclisation of Carbonyl Groups and Unactivated Alkenes or Alkynes induced by a Low-valent Titanium Complex. Chem. Commun. 1990, 1684–1686. [Google Scholar] [CrossRef]
  65. Kablaoui, N.M.; Buchwald, S.L. Reductive Cyclization of Enones by a Titanium Catalyst. J. Am. Chem. Soc. 1995, 117, 6785–6786. [Google Scholar] [CrossRef]
  66. Quan, L.G.; Cha, J.K. Reductive Cyclization of Enones by Titanium(IV) Aryloxide and a Grignard Reagent. Tetrahedron Lett. 2001, 42, 8567–8569. [Google Scholar] [CrossRef]
Molecules 28 03900 g001 550
Figure 1. The guaiane sesquiterpene α-bulnesene, showing the accepted numbering system, and two representative fragrant oxidised derivatives found in agarwood.
Figure 1. The guaiane sesquiterpene α-bulnesene, showing the accepted numbering system, and two representative fragrant oxidised derivatives found in agarwood.
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Molecules 28 03900 g002 550
Figure 2. The key step in an initial proposal for the synthesis of α-bulnesene and its diastereomers by homolytic 1,5-hydrogen atom transfer (HAT) and 5-exo-trig cyclisation.
Figure 2. The key step in an initial proposal for the synthesis of α-bulnesene and its diastereomers by homolytic 1,5-hydrogen atom transfer (HAT) and 5-exo-trig cyclisation.
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Molecules 28 03900 sch001 550
Scheme 1. Synthesis of radical precursor 3. Reagents and conditions: (i) N2CHCO2Et, BF3·OEt2, Et2O, RT, 2 h; (ii) aq. NaOH, MeOH, reflux, 3 h then aq. HCl (74% from 6); (iii) MeMgBr, FeCl3, Et2O, RT, 1 h then 7, RT, 30 min then Me3SiCl, Et3N, HMPA, RT, 14 h; (iv) MeLi, THF, RT, 30 min then Comins’ reagent, −78 °C to RT, 2 h (48% from 7); (v) Me3SiC≡C(CH2)2MgBr, THF, Fe(acac)3, NMP, −30 °C, 1 h; (vi) TBAF, THF, RT, 1 h (25%); (vii) DIBAL, Ni(dppp)Cl2, THF, 0 °C to RT, 1 h then NIS, 0 °C to RT, 1 h (60%).
Scheme 1. Synthesis of radical precursor 3. Reagents and conditions: (i) N2CHCO2Et, BF3·OEt2, Et2O, RT, 2 h; (ii) aq. NaOH, MeOH, reflux, 3 h then aq. HCl (74% from 6); (iii) MeMgBr, FeCl3, Et2O, RT, 1 h then 7, RT, 30 min then Me3SiCl, Et3N, HMPA, RT, 14 h; (iv) MeLi, THF, RT, 30 min then Comins’ reagent, −78 °C to RT, 2 h (48% from 7); (v) Me3SiC≡C(CH2)2MgBr, THF, Fe(acac)3, NMP, −30 °C, 1 h; (vi) TBAF, THF, RT, 1 h (25%); (vii) DIBAL, Ni(dppp)Cl2, THF, 0 °C to RT, 1 h then NIS, 0 °C to RT, 1 h (60%).
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Molecules 28 03900 g003 550
Figure 3. Direct access to the translocated allylic radical 5 from enones 13 and 14, readily available from (R)-carvone.
Figure 3. Direct access to the translocated allylic radical 5 from enones 13 and 14, readily available from (R)-carvone.
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Molecules 28 03900 sch002 550
Scheme 2. Synthesis of alcohol 12. Reagents and conditions: (i) DBU, CH2Cl2, RT, 4 h (95%); (ii) (from 14) NaH, t-BuOK, THF/toluene, RT, 1 h then 1,4-dibromobut-2-ene, −78 °C to RT, 2 h (73%); (iii) Pd2(dba)3, Bu3P, Et3N, HCO2H, toluene, 105 °C, 2 h (89%); (iv) t-BuOK, THF, reflux, 4 h (32% + recovered 18, 27%); (v) NaBH4, CeCl3·7H2O, MeOH, 0 °C, 1 h (56%).
Scheme 2. Synthesis of alcohol 12. Reagents and conditions: (i) DBU, CH2Cl2, RT, 4 h (95%); (ii) (from 14) NaH, t-BuOK, THF/toluene, RT, 1 h then 1,4-dibromobut-2-ene, −78 °C to RT, 2 h (73%); (iii) Pd2(dba)3, Bu3P, Et3N, HCO2H, toluene, 105 °C, 2 h (89%); (iv) t-BuOK, THF, reflux, 4 h (32% + recovered 18, 27%); (v) NaBH4, CeCl3·7H2O, MeOH, 0 °C, 1 h (56%).
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Molecules 28 03900 g004 550
Figure 4. Proposal for a two-step synthesis of α-bulnesene diastereomers from ketone 18 comprising: A—reductive cyclisation; and B—reductive rearrangement.
Figure 4. Proposal for a two-step synthesis of α-bulnesene diastereomers from ketone 18 comprising: A—reductive cyclisation; and B—reductive rearrangement.
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Molecules 28 03900 g005 550
Figure 5. Diagnostic NOE correlations supporting the assigned configuration in reductive cyclisation products 24 and 25, and the α-bulnesene epimer 26.
Figure 5. Diagnostic NOE correlations supporting the assigned configuration in reductive cyclisation products 24 and 25, and the α-bulnesene epimer 26.
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Molecules 28 03900 sch003 550
Scheme 3. Synthesis of 5-epi-α-bulnesene 26. Reagents and conditions: (i) SmI2, t-BuOH, HMPA, THF, RT, 30 min (24, 35%; 25, 27%); (ii) Et3SiH, BF3·OEt2, CH2Cl2, –78 → 0 °C, 1 h (26, 54%).
Scheme 3. Synthesis of 5-epi-α-bulnesene 26. Reagents and conditions: (i) SmI2, t-BuOH, HMPA, THF, RT, 30 min (24, 35%; 25, 27%); (ii) Et3SiH, BF3·OEt2, CH2Cl2, –78 → 0 °C, 1 h (26, 54%).
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Molecules 28 03900 g006 550
Figure 6. 13C NMR resonances in CDCl3 for α-bulnesene (black), and 5-epi-α-bulnesene (blue).
Figure 6. 13C NMR resonances in CDCl3 for α-bulnesene (black), and 5-epi-α-bulnesene (blue).
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Molecules 28 03900 g007 550
Figure 7. (A)—Summary of the synthesis of 5-epi-α-bulnesene from (R)-carvone. (B)—Projected route to α-bulnesene.
Figure 7. (A)—Summary of the synthesis of 5-epi-α-bulnesene from (R)-carvone. (B)—Projected route to α-bulnesene.
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Table
Table 1. Observed 1H,1H-COSY correlations for compound 26.
Table 1. Observed 1H,1H-COSY correlations for compound 26.
ProtonCorrelated with
H2-2H2-3, H3-15
H2-3H2-2, H-4
H-4H2-3, H-5, H3-14
H-5H-4, H2-6, H3-15
H2-6H-5, H-7
H-7H2-6, H2-8, H3-15
H2-8H-7, H2-9 1
H2-9overlapped 1
H2-12H-7, H3-13
H3-13H2-12
H3-14H-4
H3-15H2-2, H-5
1 Ambiguous correlation between overlapping multiplets.
Table
Table 2. Observed 1H,1H-COSY and 1H,13C-HMBC correlations for compound 26 1.
Table 2. Observed 1H,1H-COSY and 1H,13C-HMBC correlations for compound 26 1.
CarbonExpected 2JC–HExpected 3JC–H
C-1H2-2, H-5H2-3, (H-4), 2 H2-6, H2-9, H-15
C-2H2-3(H-4), 2 (H-5) 3
C-3H2-2, H-4(H-5), 3 H3-14
C-4H2-3, H-5, H3-14H2-2, H2-6
C-5H-4, H2-6H2-2, H2-3, H-7, H3-14
C-6(H-5), 3 H-7H-4, H2-8
C-7H2-6, H2-8(H-5), 3 H2-9, H2-12, H3-13
C-8H-7, H2-9H2-6
C-9H2-8H-7, H3-15
C-10H2-9, H3-15H2-2, H-5, H2-8
C-11H-7, H2-12, H3-13H2-6, H2-8
C-12—H-7, H3-13
C-13—H-7, H2-12
C-14H-4 H2-3, (H-5) 3
C-15—H2-9
1 All expected correlations are observed except those in parentheses. Ambiguous correlations with overlapping 1H multiplets are italicised (this mainly concerns H2-9 that is wholly contained within an unresolved multiplet overlapping with one of H2-2). 2 C-4 shows expected correlation to H2-2. 3 C-5 shows expected correlations to H2-2, H2-3, H2-6, H-7, and H3-14.
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Zong, J.; Robertson, J. An Enantiospecific Synthesis of 5-epi-α-Bulnesene. Molecules 2023, 28, 3900. https://doi.org/10.3390/molecules28093900

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Zong J, Robertson J. An Enantiospecific Synthesis of 5-epi-α-Bulnesene. Molecules. 2023; 28(9):3900. https://doi.org/10.3390/molecules28093900

Chicago/Turabian Style

Zong, Jiarui, and Jeremy Robertson. 2023. "An Enantiospecific Synthesis of 5-epi-α-Bulnesene" Molecules 28, no. 9: 3900. https://doi.org/10.3390/molecules28093900

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