Asymmetric synthesis of trans-4,5-disubstituted γ-butyrolactones involving a key allylboration step. First access to (−)-nicotlactone B and (−)-galbacin

S. Henriona, A. Macéa, M. M. Vallejosb, T. Roisnela, B. Carbonia, J. M. Villalgordoc and F. Carreaux*a
aUniv Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes) – UMR 6226, F-35000 Rennes, France. E-mail: francois.carreaux@univ-rennes1.fr
bLaboratorio de QuÍmÍca Organica. Universidad Nacional del Nordeste. CONICET, FACENA, Avenida Libertad 5460, Corrientes, 3400, Argentina
cVillaPharma Research, Parque Tecnológico de Fuente Alamo, Ctra El Estrecho-Lobosillo, Av. Azul, 30320 Murcia, Spain

Received 12th January 2018 , Accepted 8th February 2018

First published on 8th February 2018


An efficient asymmetric synthesis of trans-4,5-disubstituted γ-butyrolactones from aldehydes and enantioenriched γ-carbamate alkenylboronates is reported. The cornerstone of this strategy is the implementation of sequential [3,3]-allyl cyanate rearrangement/allylboration/nucleophilic addition/cyclisation reactions. Diverse γ-butyrolactones such as the flavouring compounds, (+)-trans-whiskey lactone and (+)-trans-cognac lactone, as well as an advanced intermediate towards the first synthesis of natural products, (−)-nicotlactone B and (−)-galbacin, have thus been obtained.


Introduction

trans-4,5-Disubstituted-γ-butyrolactones represent a class of compounds whose structural units can be encountered in widespread naturally occurring substances as sex-attractant pheromones 1 as well as the flavouring components 2 and 3 (Fig. 1).1 Their structural motif can also be used as a construction platform to access biologically significant α-alkylidene γ-butyrolactones,2 such as the α-methylene derivative 4 which inhibits in vitro the growth of HL-60 myeloid leukemia cells by activating apoptosis with no obvious toxic side effects in T-lymphocytes or in murine splenocytes.3 In addition, the 4,5-disubstituted five-membered ring lactones were also considered as useful synthetic intermediates to prepare lignans having a 2,5-diaryl-3,4-disubstituted tetrahydrofuran scaffold by alkylation and subsequent introduction of an aromatic group, respectively, at the C3 and C2 positions.4 As an example, the biologically active natural product (+)-galbacin has been obtained by using this approach.5 To the best of our knowledge, the synthesis of its optical antipod, (−)-galbacin 5, has not been reported to date. For all these reasons, the development of new asymmetric syntheses of such compounds is always of interest and more specially when the sequential one-pot procedure is implemented in order to reduce the purification steps, and minimize time and efforts.
image file: c8ob00101d-f1.tif
Fig. 1 Structure of some biologically active substituted γ-butyrolactones and 2,5-diaryl-3,4-disubstituted tetrahydrofuran lignans.

Several strategies have been hitherto developed for the stereoselective synthesis of γ-lactones, but only a few allow access to a broad structural and stereochemical diversity.6 Taking into account the fact that functionalized homoallylic alcohols can be considered as potential building blocks for the preparation of a lactone skeleton, the stereoselective allylboration of carbonyl compounds has been successfully incorporated in various synthetic approaches.7 Regarding the preparation of trans-4,5-disubstituted-γ-butyrolactones, chiral unfunctionalized (E)-substituted allylboron reagents were used to give the final products with excellent enantioselectivities.8 However, it requires several steps since the resulting homoallylic alcohols must be converted into diols via a hydroboration-oxidation sequence followed by a selective oxidation of primary alcohols before obtaining the expected five membered-rings. The reaction of chiral (E)-α-sulfonamidocrotylboronate with aldehydes provides a more straightforward access to the disubstituted γ-lactones via the formation of γ-sulfonamido homoallyl alcohols which can be further easily cyclized into lactol ethers.9 Nevertheless, the reactivity of this boronic ester with aldehydes is lower than usual, which means that either heating at elevated temperature, or the use of high pressure at room temperature for several days to obtain good yields. In all cases, the purification of the key starting allylboronates can be tedious depending upon the nature of the chiral auxiliary located on the boron atom and (or) the presence of a functional group at the alpha position to the boronate ester.

Keeping this in mind, one-pot procedures in situ generating the allylboron reagents, before the subsequent addition to carbonyl compounds, have emerged as efficient synthetic tools to achieve such transformation. In this respect, Miyaura's group described an elegant and short synthesis of trans-4,5-disubstituted-γ-butyrolactones starting from (R,R)-tartrate allyl boronate.10 The reaction with methyl 3-butenoate under cross-metathesis conditions led to the stereoselective formation of the linear (E)-allylboronate, which is directly trapped with aldehydes before carrying out the last lactonization step. Unfortunately, this process suffers from low enantioselectivity.

As part of our efforts to develop sequential reactions involving an allylboration step,11 we recently reported a [3,3]-sigmatropic rearrangement/allylboration/cyclisation sequence allowing us to obtain optically pure functionalized seven-membered ring carbamates from enantioenriched compounds 6 (Fig. 2).12 From a similar approach and taking advantage of the fact that the homoallylic alcohols resulting from the addition of α-isocyanato allylboronic esters 7 to aldehydes are obtained as their protected O-Bpin form, we envisaged that such intermediates could be subjected to an intermolecular trapping by the addition of a nucleophile to afford the corresponding acyclic enecarbamates 8. An acid-catalyzed cyclization should lead to (tetrahydrofuran-2-yl)ethers 9 as precursors to the γ-lactone framework.13 In this paper, we report our efforts regarding the implementation of this new approach for a stereocontrolled synthesis of trans-4,5-disubstituted γ-butyrolactones 11. Asymmetric one-pot sequential transformations were employed permitting the synthesis of desired γ-butyrolactones without any purification of intermediates.


image file: c8ob00101d-f2.tif
Fig. 2 Strategy for the asymmetric synthesis of trans-4,5-disubstituted γ-butyrolactones from γ-carbamate alkenylboronates 6.

A large variety of compounds have thus been obtained as well as γ-butyrolactone natural products like the (+)-trans-whiskey lactone and (+)-trans-cognac lactone. As evidence for the efficiency of this strategy, the first total syntheses of (−)-nicotlactone B and (−)-galbacin were also described.

Results and discussion

The enantioenriched carbamate (S,E)-6a (98% ee) was first chosen as the starting material for the optimization of the strategy. This compound was prepared in multigram-scale quantities from (S)-but-3-yn-2-ol.12 The dehydration reaction of carbamate into cyanate groups can be performed mainly under two conditions.14 In our case, we favoured the use of trifluoroacetic anhydride (TFAA) as the reagent in place of triphenylphosphine in order to avoid the formation of the corresponding oxide which can be difficult to remove. After 1 h at room temperature in the presence of triethylamine, the formation of the α-isocyanato allylboronate 7a resulting from the domino dehydration/rearrangement sequence was evaluated as complete by NMR-spectroscopic analysis of the crude mixture (Scheme 1).15 The allyl boronate 7a was directly treated without purification with aromatic aldehydes, and then followed by addition of methanol. Using the 4-nitro benzaldehyde, the acyclic enecarbamate 8aa was formed as a single diastereomer (determined by 1H NMR) and obtained with 89% overall yield from 6a after chromatographic purification. In the case of the 4-fluoro benzaldehyde, an 1H NMR study of the crude product showed that the formation of the desired enecarbamate 8ab was accompanied by an important quantity of the five-membered ring 9ab (ratio of 16/84, respectively), which probably comes from 8ab via an intramolecular addition of the secondary alcohol to an iminium species. These two structurally isomeric compounds cannot be separated easily by purification on a silica gel. Fortunately, treatment under acidic conditions allowed the complete conversion of enecarbamates 8 into substituted 3-aminotetrahydrobenzofurans, 9.
image file: c8ob00101d-s1.tif
Scheme 1 Synthesis of carbamates 8 and 9 from (S,E)-6a.

The latter can be considered as suitable intermediates to access γ-butyrolactones. Indeed, the N,O-acetals 9aa and 9ab can be efficiently transformed into the corresponding γ-lactol methyl ethers 10 with methanol using a 4N hydrogen chloride solution in dioxane.16 Subsequent oxidation by m-CPBA in the presence of boron trifluoride etherate led to the expected lactones 11aa and 11ab (Scheme 2). At this point, the enantiomeric excess was measured by chiral HPLC to be 98% (see ESI). Compared to the starting material (S,E)-6a, we can conclude that during all these transformations, no loss of chirality occurred.17


image file: c8ob00101d-s2.tif
Scheme 2 Transformation of 9 into γ-butyrolactones 11.

On the basis of these experimental results, we assumed that there was still room for improvement of the procedure. In fact, using appropriate acidic conditions in the presence of methanol, the enecarbamate intermediates 8 could be directly transformed into the corresponding γ-lactol methyl ethers 10. After some adjustments, we selected the optimized protocol, shown in Scheme 3. Starting from (S,E)-6a, the γ-lactol methyl ethers 10 were easily obtained according to a one-pot sequence. After evaporation of volatile components, the crude mixture was directly engaged in an oxidation reaction for 1 h at 0 °C. The single purification stage of this multistep sequence was further carried out. Using this simplified protocol, a large variety of hithertho unknown trans-4,5-disubstituted-γ-butyrolactones 11 have been thus obtained from various aldehydes with modest to good overall yields (5 steps from (S,E)-6a) and in a highly diastereoselective manner (>95%, evaluated by 1H NMR before purification). It is interesting to note that this excellent diastereoselectivity was maintained even with aromatic aldehydes possessing strongly electron donating groups on the ring (+M effect).18 In order to highlight the versatility of this approach, other enantioenriched carbamates (R,E)-6a and 6b have been prepared and used as starting materials.12,19 In all cases, the corresponding γ-butyrolactones 11ba, 11bb and 11ca were obtained in a highly stereoselective way as previously observed, showing the good level of reliability and generalization of this approach.


image file: c8ob00101d-s3.tif
Scheme 3 Selected process for the asymmetric synthesis of trans-4,5-disubstituted γ-lactones 11.

This multi-stage procedure was also applied to the synthesis of γ-butyrolactone natural products, such as (+)-trans-whiskey lactone 11aj20 and (+)-trans-cognac lactone 11ak,21 giving compounds which showed NMR and optical properties in full agreement with those reported in the literature.

(−)-Galbacin is a natural product isolated, inter alia, from Talauma hodgsonii Hook, F & Thoms,22 which inhibits in particular the growth of several human tumor cell lines.23,24 Among all the γ-butyrolactones previously prepared, we speculated that compound 11ai could be a key intermediate for the asymmetric synthesis of (−)-galbacin, via several transformations on the scaffold such as a stereoselective alkylation step and an electrophilic aromatic substitution reaction (EArS) as reported in Fig. 3.


image file: c8ob00101d-f3.tif
Fig. 3 Strategy for the synthesis of (−)-galbacin from the advanced intermediate 11ai.

For the purpose of developing the first asymmetric synthesis of this tetrahydrofuran lignan, the methylation reaction of 11ai was tried under several basic conditions using MeI as the alkylating agent (Scheme 4). When the enolate was generated using LiHMDS as the base, the major product of alkylation was the stereoisomer 12 having a cis-configuration between C3 and C4. The origin of this π-facial stereoselectivity could be mainly attributed to the presence of the substituent at C5 favouring the anti-selectivity with respect to the aromatic group by a combination of different effects in the transition state already reported in the literature.25 A computational study on the alkylation of lithium enolate showed that the anti-transition structure is 0.6 kcal mol−1 more favourable than the syn-transition structure in Gibbs free energy, difference which corresponds quite exactly to the ratio observed experimentally (see ESI). The stereoselectivity was reversed when the alkylation reaction was performed employing KHDMS as the base under the same conditions of temperature, solvent and time. Unfortunately, the stereoisomer 13 with the required stereochemistry to access (−)-galbacin was obtained with a low yield and cannot be separated from 12 by purification.26


image file: c8ob00101d-s4.tif
Scheme 4 Diastereoselectivity of the alkylation reaction of 11ai using diverse bases.

To overcome this drawback, an epimerization of 12 under basic conditions was planned. Treatment of 12 (ratio 89/11) with MeONa in MeOH for 18 h at room temperature resulted in the inversion of configuration at chiral center C3 (ratio of 8/92 in favour of 13) (Scheme 5). It is interesting to note that 13, also named (−)-nicotlactone B,27 is a natural product present in the Australian endemic plant Austrobaileya scandens whose asymmetric synthesis had not yet been reported. The reduction of 13 with DIBAL-H, followed by an acidic treatment in the presence of methylorthoformate and para-toluenesulfonic acid (APTS) in methanol led to γ-lactol methyl ether 14 in 67% yield as an anomeric mixture. The final step of our synthesis is the crucial building of remaining chiral center C2 by the introduction of a 1,2-methylenedioxybenzene moiety. To this end, a Friedel-Craft type arylation was carried out in the presence of a stoichiometric quantity of SnCl4 in CH2Cl2 at −78 °C for 2 h. Under these conditions, the desired natural product 5 was obtained in good yield (85%) as a single stereoisomer. All the spectroscopic data of this synthetic compound are identical to those of natural (−)-galbacin.24 The relative configurations of all chiral centers of (−)-galbacin were afterwards confirmed by the analysis of its X-ray crystallographic structure.28


image file: c8ob00101d-s5.tif
Scheme 5 Asymmetric syntheses of (−)-nicotlactone B and (−)-galbacin with an X-ray crystallographic structure of 5.

Conclusion

We described in this paper a new asymmetric synthesis of trans-4,5-disubstituted-γ-butyrolactones through an approach based on sequential one-pot transformations including a [3,3] allyl cyanate rearrangement/allylboration/nucleophilic addition followed by a cyclization reaction and an oxidation step. The value and the efficiency of this method was clearly demonstrated by the synthesis of various lactone natural products, including (−)-nicotlactone B, as well as a bioactive tetrahydrofuran lignan, (−)-galbacin, whose synthesis had never been reported to date.

Experimental section

General information

Tetrahydrofuran (THF) was distilled over sodium/benzophenone, and dichloromethane (DCM) was distilled over P2O5. Amines were distilled over potassium hydroxide. Trifluoroacetic anhydride was distilled over P2O5. Alcohols were distilled over calcium hydride (CaH2). Triethylamine was distilled over KOH and stored under an argon atmosphere. All aldehydes used were distilled under vacuum. NMR spectra were recorded on Bruker apparatus at 300, 400 or 500 MHz for 1H and 75, 101 or 126 MHz for 13C. Chemical shifts of 1H and 13C NMR were referenced to Me4Si as internal reference. Data are represented as follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad), coupling constant J (Hz) and integration. All high-resolution mass spectra (HRMS) were recorded on a Bruker Micro-Tof-Q II or on a Waters Q-Tof 2 at the CRMPO (Centre Régional de Mesures de Physiques de l'Ouest – Rennes – France) using positive ion electrospray. Purifications on a silica gel were carried out on an Acros silica gel 0.006–0.200 mm, 60 A. Analytical thin layer chromatography was performed on Merck Silica gel 60 F254 plates. X-ray crystallographic data were collected on an APEXII crystal diffractometer. The optical rotations were measured on a PerkinElmer Model 341 polarimeter (sodium D-line: 589 nm and mercury I-line: 365 nm). Melting points were measured on a melting point apparatus Stuart SMP10. All analytical high-performance liquid chromatography (HPLC) were performed on an Agilent Technologies equipped with diode array UV detectors, using a Chiralcel OD-H column. Enantioenriched compounds 6 were prepared according to a literature procedure.12

A general experimental procedure for γ-butyrolactones synthesis

To a solution of carbamate 6a–c (1 eq.) in dry dichloromethane (0.10 M), under an argon atmosphere were added trifluoroacetic anhydride (3 eq.) and triethylamine (4.5 eq.). The solution was stirred at 0 °C for one hour and then, aldehyde was added. The resulting solution was stirred at 25 °C for 12 hours. Methanol was added and the solution was stirred at 25 °C for an additional 12 hours. Methanol (20 eq.) and HCl 4 N in dioxane (10 eq.) were added and the solution was stirred at room temperature for an additional 2 hours. The reaction medium was diluted with dichloromethane and neutralized with NaOH 2 M. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. To the crude reaction in dry dichloromethane (0.15 M), cooled at 0 °C, were added Et2O·BF3 (3 eq.) and a solution of m-CPBA (3 eq.) in dry dichloromethane (0.50 M). The mixture was stirred at 0 °C for 1 hour and quenched with a saturated solution of NaHCO3. The aqueous phase was extracted with Et2O. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography to give the desired lactone 11.
(4S,5S)-4-Methyl-5-(4-nitrophenyl)dihydrofuran-2(3H)-one (11aa). Yield: 87%, orange oil; [α]20D = +13 (c 1.60, CH2Cl2); 1H NMR (400 MHz, acetone-d6, δ ppm) 8.29 (d, J = 8.7 Hz, 2H), 7.73 (d, J = 8.7 Hz 2H), 5.21 (d, J = 8.5 Hz, 1H), 2.78 (dd, J = 16.3, 7.2 Hz, 1H), 2.61–2.52 (m, 1H), 2.47 (dd, J = 16.3, 10.5 Hz, 1H), 1.23 (d, J = 6.5 Hz, 3H); 13C NMR (101 MHz, acetone-d6, δ ppm) 175.8, 148.9, 147.2, 128.1, 124.5, 86.8, 40.7, 37.2, 16.1; HRMS (ESI) m/z calcd for C11H11NO4Na [M + Na]+ 244.0580; found 244.0579.
(4S,5S)-5-(4-Fluorophenyl)-4-methyldihydrofuran-2(3H)-one (11ab). Yield: 58%, yellow oil; [α]20I = +30 (c 1.05, CH2Cl2); 1H NMR (300 MHz, acetone-d6, δ ppm) 7.56–7.44 (m, 2H), 7.23–7.14 (m, 2H), 5.02 (d, J = 8.6 Hz, 1H), 2.74 (dd, J = 16.0, 7.2 Hz, 1H), 2.55–2.53 (m, 1H), 2.41 (dd, J = 16.0, 10.7 Hz, 1H), 1.15 (d, J = 6.4 Hz, 3H); 19F NMR (282 MHz, acetone-d6, δ ppm) −115.2; 13C NMR (75 MHz, acetone-d6, δ ppm) 176.0, 163.6 (d, J = 245.0 Hz), 135.8 (d, J = 3.1 Hz), 129.4 (d, J = 8.5 Hz), 116.2 (d, J = 21.8 Hz), 87.7, 40.6, 37.5, 16.0; HRMS (ESI) m/z calcd for C11H11FO2Na [M + Na]+ 217.0635; found 217.0636.
(4S,5S)-4-Methyl-5-phenyldihydrofuran-2(3H)-one (11ac)20c. Yield: 46%, colourless oil; [α]20D = −9 (c 0.75, CHCl3); 1H NMR (300 MHz, CDCl3, δ ppm) 7.45–7.34 (m, 5H), 5.01 (d, J = 8.5 Hz, 1H), 2.74 (dd, J = 16.0, 7.2 Hz, 1H), 2.60–2.46 (m, 1H), 2.40 (dd, J = 16.0, 10.6 Hz, 1H), 1.16 (d, J = 6.4 Hz, 3H); 13C NMR (75 MHz, acetone-d6, δ ppm) 176.1, 139.7, 129.4, 129.3, 127.2, 88.4, 40.6, 37.6, 16.1; HRMS (EI) m/z calcd for C11H12O2Na [M + Na]+ 199.0729; found 199.0729.
(4S,5S)-4-Methyl-5-(4-(trifluoromethyl)phenyl)dihydrofuran-2(3H)-one (11ad). Yield: 81%, orange oil; [α]20I = +15 (c 0.40, CH2Cl2); 1H NMR (300 MHz, acetone-d6, δ ppm) 7.78 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 5.15 (d, J = 8.3 Hz, 1H), 2.77 (dd, J = 15.9, 7.0 Hz, 1H), 2.64–2.50 (m, 1H), 2.45 (dd, J = 15.9, 10.4 Hz, 1H), 1.21 (d, J = 6.3 Hz, 3H); 19F NMR (282 MHz, acetone-d6, δ ppm) −63.1; 13C NMR (75 MHz, acetone-d6, δ ppm) 175.9, 144.5 (q, J = 1.3 Hz), 130.9 (q, J = 32.2 Hz), 127.8, 126.4 (q, J = 3.9 Hz), 125.2 (q, J = 271.3 Hz), 123.4, 87.3, 40.7, 37.3, 16.2; HRMS (ESI) m/z calcd for C12H11F3O2Na [M + Na]+ 267.0603; found 267.0604.
(4S,5S)-5-(4-Bromophenyl)-4-methyldihydrofuran-2(3H)-one (11ae). Yield: 64%, slight yellow oil; [α]20I = +41 (c 1.45, CH2Cl2); 1H NMR (300 MHz, acetone-d6, δ ppm) 7.60 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 5.02 (d, J = 8.4 Hz, 1H), 2.74 (dd, J = 15.7, 6.9 Hz, 1H), 2.58–2.46 (m, 1H), 2.41 (dd, J = 15.7, 10.7 Hz, 1H), 1.16 (d, J = 6.3 Hz, 3H); 13C NMR (75 MHz, acetone-d6, δ ppm) 175.9, 139.1, 132.5, 129.3, 122.8, 87.5, 40.6, 37.4, 16.0; HRMS (ESI) m/z calcd for C11H11BrO2Na [M + Na]+ 276.9835; found 276.9837.
(4S,5S)-4-Methyl-5-(p-tolyl)dihydrofuran-2(3H)-one (11af). Yield: 40%, orange oil; [α]20I = +30 (c 0.35, CH2Cl2); 1H NMR (400 MHz, CDCl3, δ ppm) 7.25–7.14 (m, 4H), 4.91 (d, J = 8.3 Hz, 1H), 2.78 (dd, J = 16.9, 7.6 Hz, 1H), 2.56–2.39 (m, 1H), 2.36 (s, 3H), 2.33 (dd, J = 16.9, 10.5 Hz, 1H), 1.18 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3, δ ppm) 176.3, 138.8, 135.0, 129.5, 126.1, 88.4, 39.9, 37.5, 21.3, 16.6; HRMS (ESI) m/z calcd for C12H14O2Na [M + Na]+ 213.0886; found 213.0887.
(4S,5S)-5-(4-Methoxyphenyl)-4-methyldihydrofuran-2(3H)-one (11ag)29. Yield: 47%, orange oil; [α]20D = +13 (c 0.75, CHCl3); litt.: [α]20D = +12 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3, δ ppm) 7.26 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 4.88 (d, J = 8.5 Hz, 1H), 3.82 (s, 3H), 2.78 (dd, J = 16.9, 7.7 Hz, 1H), 2.54–2.43 (m, 1H), 2.33 (dd, J = 16.9, 10.7 Hz, 1H), 1.16 (d, J = 6.5 Hz, 3H); 13C NMR (101 MHz, CDCl3, δ ppm) 176.2, 160.1, 129.8, 127.7, 114.2, 88.3, 55.5, 39.8, 37.6, 16.4. HRMS (ESI) m/z calcd for C12H14O3Na [M + Na]+ 229.0835; found 229.0836.
(4S,5S)-5-(3,4-Dimethoxyphenyl)-4-methyldihydrofuran-2(3H)-one (11ah). Yield: 30%, green oil; [α]20I = +37 (c 0.33, CH2Cl2); 1H NMR (400 MHz, CDCl3, δ ppm) 6.90–6.81 (m, 3H), 4.88 (d, J = 8.6 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 2.80 (dd, J = 16.9, 7.6 Hz, 1H), 2.53–2.43 (m, 1H), 2.34 (dd, J = 16.9, 10.8 Hz, 1H), 1.18 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3, δ ppm) 176.3, 149.6, 149.5, 130.3, 119.0, 111.1, 109.1, 88.5, 56.2, 56.1, 39.9, 37.6, 16.5; HRMS (ESI) m/z calcd for C13H16O4Na [M + Na]+ 259.0940; found 259.0940.
(4S,5S)-5-(Benzo[d][1,3]dioxolo-5-yl)-4-methyldihydrofuran-2(3H)-one (11ai). Yield: 42%, colourless oil; [α]20I = +94 (c 0.35, CH2Cl2); 1H NMR (400 MHz, CDCl3, δ ppm) 6.86–6.77 (m, 3H), 5.98 (s, 2H), 4.84 (d, J = 8.5 Hz, 1H), 2.78 (dd, J = 16.8, 7.6 Hz, 1H), 2.51–2.40 (m, 1H), 2.32 (dd, J = 16.8, 10.8 Hz, 1H), 1.16 (d, J = 6.5 Hz, 3H); 13C NMR (101 MHz, CDCl3, δ ppm) 176.0, 148.3, 148.2, 131.7, 120.2, 108.4, 106.5, 101.5, 88.4, 39.9, 37.5, 16.5; HRMS (ESI) m/z calcd for C12H12O4Na [M + Na]+ 243.0628; found 243.0628.
(4S,5R)-5-Butyl-4-methyldihydrofuran-2(3H)-one (11aj) [(+)-trans-whiskey lactone](2)20c. Yield: 40%, colourless oil; [α]20D = +50 (c 0.6, CHCl3); litt.: [α]25D = +59.6 (c 0.71, CHCl3); 1H NMR (400 MHz, CDCl3, δ ppm) 4.00 (ddd, J = 8.2, 7.3, 4.1 Hz, 1H), 2.71–2.61 (m, 1H), 2.25–2.12 (m, 2H), 1.73–1.54 (m, 3H), 1.41– 1.31 (m, 3H), 1.13 (d, J = 6.4 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3, δ ppm) 176.7, 87.6, 37.3, 36.2, 33.8, 28.0, 22.6, 17.6, 14.0. HRMS (ESI) m/z calcd for C9H16O2Na [M + Na]+ 179.1042; found 179.1043.
(4S,5R)-4-Methyl-5-pentyldihydrofuran-2(3H)-one (11ak) [(+)-trans-cognac lactone](3)20b. Yield: 40%, colourless oil; [α]20D = +70 (c 0.27, CHCl3); litt.: [α]25D = +72 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3, δ ppm) 4.05–3.96 (m, 1H), 2.75–2.61 (m, 1H), 2.31–2.13 (m, 2H), 1.73–1.60 (m, 4H), 1.38–1.28 (m, 4H), 1.15 (d, J = 6.4 Hz, 3H), 0.92 (t, J = 5.8 Hz, 3H); 13C NMR (75 MHz, CDCl3, δ ppm) 176.6, 87.5, 37.2, 36.1, 34.0, 31.6, 25.4, 22.5, 17.5, 14.0. HRMS (ESI) m/z calcd for C10H18O2Na [M + Na]+ 193.1198; found 193.1199.
(4R,5R)-5-Methyl-5-(4-nitrophenyl)dihydrofuran-2(3H)-one (11ba). Yield: 73%, orange oil; [α]20D = −12 (c 1.60, CH2Cl2); 1H NMR (400 MHz, acetone-d6, δ ppm) 8.29 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H), 5.21 (d, J = 8.5 Hz, 1H), 2.78 (dd, J = 16.3, 7.2 Hz, 1H), 2.61–2.52 (m, 1H), 2.47 (dd, J = 16.3, 10.5 Hz, 1H), 1.23 (d, J = 6.5 Hz, 3H); 13C NMR (101 MHz, acetone-d6, δ ppm) 175.8, 148.9, 147.2, 128.1, 124.5, 86.8, 40.7, 37.2, 16.1. HRMS (ESI) m/z calcd for C11H11NO4Na [M + Na]+ 244.0580; found 244.0581.
(4R,5R)-5-(3,4-Dimethoxyphenyl)-4-methyldihydrofuran-2(3H)-one (11bb). Yield: 32%, green oil; [α]20D = −35 (c 0.33, CH2Cl2); 1H NMR (400 MHz, CDCl3, δ ppm) 6.90–6.81 (m, 3H), 4.88 (d, J = 8.6 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 2.80 (dd, J = 16.9, 7.6 Hz, 1H), 2.53–2.43 (m, 1H), 2.34 (dd, J = 16.9, 10.8 Hz, 1H), 1.18 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3, δ ppm) 176.3, 149.6, 149.5, 130.3, 119.0, 111.1, 109.1, 88.5, 56.2, 56.1, 39.9, 37.6, 16.5. HRMS (ESI) m/z calcd for C13H16O4Na [M + Na]+ 259.0940; found 259.0941.
(4S,5S)-5-(4-Nitrophenyl)-4-pentyldihydrofuran-2(3H)-one (11ca). Yield: 66%, orange oil; [α]20D = +15 (c 0.50, CH2Cl2); 1H NMR (300 MHz, CDCl3, δ ppm) 8.26 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 5.10 (d, J = 7.3 Hz, 1H), 2.89–2.71 (m, 1H), 2.48–2.28 (m, 2H), 1.71–1.55 (m, 1H), 1.55–1.42 (m, 1H), 1.39–1.17 (m, 6H), 0.92–0.80 (m, 3H); 13C NMR (101 MHz, CDCl3, δ ppm) 175.3, 148.1, 145.7, 126.7, 124.1, 85.2, 53.4, 45.1, 34.9, 32.1, 31.6, 30.9, 22.4, 14.2, 13.9; HRMS (ESI) m/z calcd for C13H19NO4Na [M + Na]+ 300.1206; found 300.1207.
5,5′-((2S,3S,4S,5S)-3,4-Dimethyltetrahydrofuran-2,5-diyl)bis(benzo[d][1,3]dioxole), (−)-galbacin (5)24a. Yield from 14: 85%, colourless oil; [α]20D = −103 (c 0.88, CHCl3); litt.: [α]25D = −119 (c 0.02, CHCl3); 1H NMR (300 MHz, CDCl3, δ ppm) 6.91 (d, J = 1.6 Hz, 2H), 6.83 (dd, J = 8.0, 1.6 Hz, 2H), 6.77 (d, J = 7.9 Hz, 2H), 5.94 (s, 4H), 4.59 (d, J = 9.2 Hz, 2H), 1.83–1.67 (m, 2H), 1.02 (d, J = 6.1 Hz, 6H); 13C NMR (101 MHz, CDCl3, δ ppm) 147.9, 147.1, 136.5, 119.9, 108.1, 106.7, 101.1, 88.4, 51.2, 13.9. HRMS (ESI) m/z calcd for C20H20NaO5 [M + Na]+ 363.1202; found 363.1203.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the University of Rennes 1 and the Centre National de la Recherche Scientifique (CNRS). S. H. thanks the Region Bretagne and VillaPharma Research for a research fellowship. We also thank the CONICET y ANPCyT for funding a postdoctoral fellowship to M. M. V.

Notes and references

  1. (a) S. S. Canan Koch and A. R. Chamberlin, in Studies in Natural Products Chemistry, ed. Atta-ur-Rahman, Elsevier Science, 1995, vol. 16, pp. 687–725 Search PubMed; (b) M. Seitz and O. Reiser, Curr. Opin. Chem. Biol., 2005, 9, 285 CrossRef CAS PubMed.
  2. R. R. A. Kitson, A. Millemaggi and R. J. K. Taylor, Angew. Chem., Int. Ed., 2009, 48, 9426 CrossRef CAS PubMed.
  3. A. G. González, M. H. Silva, J. I. Padrón, F. León, E. Reyes, M. Álvarez-Mon, J. P. Pivel, J. Quintana, F. Estévez and J. Bermejo, J. Med. Chem., 2002, 45, 2358 CrossRef.
  4. For some examples, see: (a) T. Esumi, D. Hojyo, H. Zhai and Y. Fukuyama, Tetrahedron Lett., 2006, 47, 3979 CrossRef CAS; (b) P. Xue, L.-P. Wang, X.-Z. Jiao, Y.-J. Jiang, Q. Xiao, Z.-G. Luo, P. Xie and X.-T. Liang, J. Asian Nat. Prod. Res., 2009, 11, 281 CrossRef CAS PubMed; (c) H. Kim, A. C. Kasper, E. J. Moon, Y. Park, C. M. Wooten, M. W. Dewhirst and J. Hong, Org. Lett., 2009, 11, 89 CrossRef CAS PubMed; (d) T. S. Kaoud, H. Park, S. Mitra, C. Yan, C.-C. Tseng, Y. Shi, J. Jose, J. M. Taliaferro, K. Lee, P. Ren, J. Hong and K. N. Dalby, ACS Chem. Biol., 2012, 7, 1873 CrossRef CAS PubMed; (e) A. Theodorou and C. G. Kokotos, Green Chem., 2017, 19, 670 RSC.
  5. S. Hazra and S. Hajra, RSC Adv., 2013, 3, 22834 RSC.
  6. (a) B. Mao, M. Fañanas-Mastral and B. L. Feringa, Chem. Rev., 2017, 117, 10502 CrossRef CAS PubMed; (b) N. Kaplaneris, A. Bisticha, G. N. Papadopoulos, D. Limnios and C. G. Kokotos, Green Chem., 2017, 19, 4451 RSC; (c) I. Triandafillidi, M. Raftopoulou, A. Savvidou and C. G. Kokotos, ChemCatChem, 2017, 9, 4120 CrossRef CAS.
  7. For some selected examples, see: (a) E. Moret and M. Schlosser, Tetrahedron Lett., 1984, 25, 4491 CrossRef CAS; (b) P. V. Ramachandran, M. P. Krzeminski, M. V. R. Reddy and H. C. Brown, Tetrahedron: Asymmetry, 1999, 10, 11 CrossRef CAS; S. H. Yu, M. J. Ferguson, R. McDonald and D. G. Hall, J. Am. Chem. Soc., 2005, 127, 12808 Search PubMed; (c) V. Mamane, A. B. Garcia, J. D. Umarye, T. Lessmann, S. Sommer and H. Waldmann, Tetrahedron, 2007, 63, 5754 CrossRef CAS; (d) S. Mitra, S. R. Gurrala and R. S. Coleman, J. Org. Chem., 2007, 72, 8724 CrossRef CAS PubMed; (e) T. G. Elford, A. Ulaczyk-Lesandro, G. De Pascale, G. D. Wright and D. G. Hall, J. Comb. Chem., 2009, 11, 155 CrossRef CAS PubMed; (f) F. Hessler, A. Korotvička, D. Nečas, I. Valterová and M. Kotora, Eur. J. Org. Chem., 2014, 2543 CrossRef CAS.
  8. (a) H. C. Brown, S. V. Kulkarni and U. S. Racherla, J. Org. Chem., 1994, 59, 365 CrossRef CAS; (b) P. V. Ramachandran, K. J. Padiya, V. Rauniyar, M. V. R. Reddy and H. C. Brown, Tetrahedron Lett., 2004, 45, 1015 CrossRef CAS.
  9. A. Schlapbach and R. W. Hoffmann, Eur. J. Org. Chem., 2001, 323 CrossRef CAS.
  10. Y. Yamamoto, M. Takahashi and N. Miyaura, Synlett, 2002, 128 CrossRef.
  11. (a) F. Carreaux, F. Possémé, B. Carboni, A. Arrieta, B. Lecea and F. P. Cossio, J. Org. Chem., 2002, 67, 9153 CrossRef CAS PubMed; (b) X. Gao, D. G. Hall, M. Deligny, A. Favre, F. Carreaux and B. Carboni, Chem. – Eur. J., 2006, 12, 3132 CrossRef CAS PubMed; (c) F. Possémé, M. Deligny, F. Carreaux and B. Carboni, J. Org. Chem., 2007, 72, 984 CrossRef PubMed; (d) R. Hemelaere, F. Carreaux and B. Carboni, Chem. – Eur. J., 2014, 20, 14518 CrossRef CAS PubMed; (e) S. Touchet, A. Macé, T. Roisnel, F. Carreaux, A. Bouillon and B. Carboni, Org. Lett., 2013, 15, 2712 CrossRef CAS PubMed.
  12. A. Macé, S. Touchet, P. Andres, F. Cossio, V. Dorcel, F. Carreaux and B. Carboni, Angew. Chem., Int. Ed., 2016, 55, 1025 CrossRef PubMed.
  13. For a recent review about the enecarbamate chemistry, see: G. Kovura and H. Kagan, Chem. Rev., 2011, 111, 4599 CrossRef PubMed.
  14. For a review, see: P.-A. Nocquet, S. Henrion, A. Macé, B. Carboni, J. M. Villalgordo and F. Carreaux, Eur. J. Org. Chem., 2017, 1295 CrossRef CAS.
  15. At no moment the transient allyl cyanate was detected by 1H NMR.
  16. This transformation was also described using H2SO4 in MeOH, see: C. Gaul and D. Seebach, Helv. Chim. Acta, 2002, 85, 772 CrossRef CAS.
  17. This outcome is in complete agreement with those observed in the synthesis of seven-membered ring using a similar strategy, see: ref. 12.
  18. Under acidic conditions, the presence of a π-electron donating group at the 4-position of the aromatic ring favored the elimination of the hydroxyl functional group in the acyclic enecarbamate intermediate 8, thus forming a potential benzylic carbocation with loss of diastereoselectivity. For an example described in the literature, see: S. Chaimanee, M. Pohmakotr, C. Kuhakarm, V. Reutrakul and D. Soorukram, Org. Biomol. Chem., 2017, 15, 3985 CAS.
  19. For the compound 6b, the enantiomeric excess (97%) was determined by GC for the starting (R)-but-3-yn-2-ol.
  20. For syntheses of (+)-trans-whiskey lactone described in the last two decades, see: (a) X. Jiang, C. Fu and S. Ma, Eur. J. Org. Chem., 2010, 687 CrossRef CAS; (b) J. S. Yadav, C. V. Rao, A. R. Prasad and A. A. K. Al Ghamdi, Synthesis, 2011, 3894 CrossRef CAS; (c) T. Liang, W. Zhang, T.-Y. Chen, K. D. Nguyen and M. J. Krische, J. Am. Chem. Soc., 2015, 137, 13066 CrossRef CAS PubMed.
  21. For some recent syntheses of (+)-trans-cognac lactone, see: (a) F. Schleth, T. Vogler, K. Harms and A. Studer, Chem. – Eur. J., 2004, 10, 4171 CrossRef CAS PubMed; (b) D. A. Devalankar, P. V. Chouthaiwale and A. Sudalai, Tetrahedron: Asymmetry, 2012, 23, 240 CrossRef CAS.
  22. L. M. Vieira, A. Kijjoa, A. M. S. Silva, I.-O. Mondranondra and W. Herz, Phytochemistry, 1998, 48, 1079 CrossRef CAS.
  23. M. S. J. Nascimento, M. Pedro, F. Cerqueira, M. Bastos, L. M. Vieira, A. Kijjoa and M. M. M. Pinto, Pharm. Biol., 2004, 42, 449 CrossRef CAS.
  24. For other biological activities in which (−)-galbacin was tested, see: (a) G. Li, C.-S. Lee, M.-H. Woo, S.-H. Lee, H.-W. Chang and J.-K. Son, Biol. Pharm. Bull., 2004, 27, 1147 CrossRef CAS PubMed; (b) P. H. Nguyen, T. V. T. Le, H. W. Kang, J. Chae, S. K. Kim, K.-I. Kwon, D. B. Seo, S. J. Lee and W. K. Oh, Bioorg. Med. Chem. Lett., 2010, 20, 4128 CrossRef CAS PubMed.
  25. K. Ando, J. Am. Chem. Soc., 2005, 127, 3964 CrossRef CAS PubMed.
  26. This observation was also reported in the following paper, see: ref. 5.
  27. T. D. Tran, N. B. Pham, R. Booth, P. L. Forster and R. J. Quinn, J. Nat. Prod., 2015, 79, 1514 CrossRef PubMed.
  28. CCDC 1578065 contains the supplementary crystallographic data for compound 5.
  29. G. Mandville, M. Ahmar and R. Bloch, J. Org. Chem., 1996, 61, 1122 CrossRef CAS.

Footnote

Electronic supplementary information (ESI) available: Characterization and NMR spectra of all compounds. DFT and computational data. CCDC 1578065. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c8ob00101d

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