Stereospecific Hydrogenolysis of Lactones: Application to the Total

Apr 11, 2017 - Stereospecific Hydrogenolysis of Lactones: Application to the Total Syntheses of (R)-ar-Himachalene and (R)-Curcumene. Kim Spielmann, R...
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Stereospecific hydrogenolysis of lactones: Application to the total syntheses of (R)-ar-himachalene and (R)-curcumene Kim Spielmann, Renata Marcia de Figueiredo, and Jean-Marc Campagne J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00419 • Publication Date (Web): 11 Apr 2017 Downloaded from http://pubs.acs.org on April 11, 2017

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Stereospecific Hydrogenolysis of Lactones: Application to the Total Syntheses of (R)-arHimachalene and (R)-Curcumene Kim Spielmann, Renata Marcia de Figueiredo* and Jean-Marc Campagne* Institut Charles Gerhardt – UMR 5253 CNRS-UM-ENSCM Ecole Nationale Supérieur de Chimie de Montpellier 8, Rue de L'Ecole Normale F-34296 Montpellier Cedex 5, France E-mail: [email protected]; [email protected] Tel.: (+) 33 (0) 4 67 14 72 21 or (+) 33 (0) 4 67 14 72 24 Fax: (+) 33 (0) 4 67 14 43 22 ORCID Jean-Marc Campagne : 0000-0002-4943-047X Renata Marcia de Figueiredo: 0000-0001-5336-6071

ABSTRACT GRAPHIC

ABSTRACT A straightforward strategy for the syntheses of curcumene and ar-himachalene is reported. Synthetic highlights include a catalytic and asymmetric vinylogous Mukaiyama reaction and a stereospecific hydrogenolysis of a tertiary benzylic center using Pd/C or Ni/Raney catalysts. Notably, using Ni/Raney, the stereoselectivity outcome (inversion vs retention) of the hydrogenolysis depends on the tertiary benzylic alcohol substitution.

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1. INTRODUCTION Molecules bearing a tertiary (or quaternary) benzylic stereocenter are widely representated in natural products and pharmaceuticals (Figure 1). Curcumene 1, curcuhydroquinone 2, arturmerone 3 and congeners, members of the bisabolane sesquiterpenes family have been used in traditional medicine, exhibit anti-cancer / antimicrobial activities and they are also employed in cosmetics.1 (S)-ar-himachalene 4 is a key component in cedar woods essential oils whereas the (R)-enantiomer is a male specific pheromone of some flea beetles.2 Marine diterpene (+)-erogorgiaene 5 exhibits potent antibacterial activity against Mycobacterium tuberculosis H37Rv.3 Along with traditional ways involving stereoselective synthesis and the use of the chiral pool,4 the construction of stereogenic benzylic centers has become a benchmark for the evaluation of catalytic and asymmetric reactions.5

Figure 1. Natural products bearing a tertiary benzylic stereocenter We have recently launched a program to address the functionalization of lactones bearing a tertiary alcohol at the C6 position (Scheme 1). Indeed these compounds present a good leaving group at the benzylic position and their stereospecific transition metal catalyzed transformation could offer interesting synthetic application perspectives.6 Moreover lactones 2 ACS Paragon Plus Environment

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can readily be obtained in high enantioselectivities from the corresponding ketones using a catalytic and asymmetric vinylogous Mukaiyama reaction (CAVM).7,8

Scheme 1. Functionalization of lactones The hydrogenolysis (Scheme 1, Nu = H) of lactones 6 was first investigated because compounds bearing a methyl group at a stereogenic benzylic position are widely represented in natural products as illustrated in figure 1. The hydrogenolysis of chiral tertiary alcohols (and derivatives thereof) have been rather scarcely described and the stereoselective outcome (retention vs inversion) can finely depend on the nature of the oxygen substituent, on the metal used (Pd vs Ni) and on the presence of additives.9 In this paper, we would like to disclose the potential of this strategy for the construction of stereodefined benzylic groups, and its synthetic potential will be illustrated in the short syntheses of (R)-ar-himachalene and (R)-curcumene (Scheme 2).

Scheme 2. Synthetic approach toward (R)-ar-himachalene and (R)-curcumene 2. RESULTS AND DISCUSSION In order to check the viability of the approach, we thus embarked on the synthesis of α,βunsaturated lactone 6a (Table 1). In the presence of silyldienolate 7 and p3 ACS Paragon Plus Environment

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methylacetophenone 8, the corresponding lactone 6a was obtained in excellent yield and moderate enantioselectivity (70% ee) using (R)-Tol-BINAP [e.g. (R)-(+)-2,2′-Bis(di-ptolylphosphino)-1,1′-binaphthyl] as the ligand (Scheme-table 1, entry 1). In order to optimize the enantioselectivity, various ligands were next tried and the best results were observed with (S)-(−)-MeOBIPHEP

[e.g.

(S)-(−)-(6,6′-Dimethoxybiphenyl-2,2′-

diyl)bis(diphenylphosphine)] leading to an excellent 93% yield and a very good 87% ee (Table 1, entry 13).

Entry

Ligands

Yield

ee

1

(R)-Tol-BINAP

95%

70%

2

(R)-SEGPHOS

43%

79%

3

(R)-DTBM-SEGPHOS

70%

81%

4

(R)-DM-SEGPHOS

NR

ND

5

(R)-tBu-MeOBIPHEP

95%

84%

6

(R)-Furyl-MeOBIPHEP

NR

ND

7

(R)-p-Tol-MeOBIPHEP

80%

77%

8

(R)-3,5-iPr-4-NMe2-MeOBIPHEP

56%

84%

9

(R)-3,5-tBu-4-MeO-MeOBIPHEP

82%

82%

10

(R)-iPr-MeOBIPHEP

NR

ND

11

(R)-3,5-xyl-MeOBIPHEP

5%

63%

12

(R)-3,4,5-MeO-MeOBIPHEP

27%

58%

13

(S)-MeOBIPHEP

93%

−87%

14

(R)-SynPHOS

40%

80%

Table 1. Lactone 6a synthesis. Reaction conditions: Cu(OTf)2 (10 mol%), ligand L* (11 mol%), rt, 30 min, then TBAT (20 mol%) in THF, rt, 15 min, followed by the silyldienolate 7 4 ACS Paragon Plus Environment

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(2.00 equiv) and p-methylacetophenone 8 (1.00 equiv), rt, 16h. Cu(OTf)2 = Copper(II) trifluoromethanesulfonate;

L*

=

chiral

ligand,

TBAT

=

Tetrabutylammonium

difluorotriphenylsilicate; THF = tetrahydrofuran; NR = No reaction; ND = Not determined.

MeOBIPHEP is however quite expensive, and this point might be detrimental for its use on a larger scale. Fortunately, we found that lactone 6a can be easily purified by crystallization and the ee improved up to 95%.10 Thus, the reaction could be set-up on a 1 gram scale using (R)Tol-BINAP and the resulting lactone could be isolated, after recrystallization, in 60% yield and 95% ee (Scheme 3).

Scheme 3. Gram-scale synthesis of 6a The hydrogenolysis of enantioenriched unsaturated lactone 6a was next undertaken. In the presence of Pd/C, both hydrogenation of the C3-C4 double bond and hydrogenolysis proceed efficiently leading to compound 9a in quantitative yield (Scheme 4). After derivatization into the corresponding methyl ester 10a, a 91% ee could be determined by chiral HPLC (see supporting information for details). Slight erosion of the enantioselectivity and inversion of the chirality at C6 were observed (inversion of chirality determined by comparison with authentic samples, vide infra). In contrast, Ni/Raney mediated hydrogenolysis proved sluggish under various reaction conditions, mainly leading to the only hydrogenation of the C3-C4 double bond, and 9a was isolated in 16% yield and a marked erosion of the enantioselectivity (42% ee determined after conversion to methyl ester 10a).

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Scheme 4. Hydrogenolysis of 6a In order to get insights on the low conversion on the Ni-catalyzed process and to check the influence of the O-Acyl group on the outcome of the reaction, compound 11a was obtained in two steps (91% yield) after reduction of the C3-C4 double bond and transesterification (Scheme 5). In the presence of Pd/C, the 'inversion' product 10a was nicely obtained (quantitative yield, 86% ee) whereas in the presence of Ni/Raney the hydrogenolysis product ent-10a was stereospecifically obtained in high yield and with a 'clean' retention of configuration at the C6 stereocenter (94% ee). These results are consistent with previously described data.2c,9

Scheme 5. Stereochemistry outcome during the hydrogenolysis of benzylic alcohols These results prompt us to re-investigate the Ni-catalyzed hydrogenolysis of unsaturated lactone 6a in the presence of K2CO3 in order to ideally promote in a sequential one-pot

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procedure simultaneously the saponification of the lactone, the hydrogenation of the double bond and the C-O hydrogenolysis. The expected product was indeed obtained in 70% yield with however in this case inversion of configuration and 85% ee (Table 2, entry 3). The addition of K2CO3 in the Pd/C catalyzed reaction was thus next investigated leading to the same enantiomer without significant effect (Table 2, entry 4). Finally, suspecting that the generation of a carboxylic acid during the hydrogenolysis could have an impact on the enantioselectivity outcome, the Ni-catalyzed hydrogenolysis was next carried out in the presence of acetic acid (1.10 equiv). In this case, the same 'inversion' enantiomer 10a could be observed however in low yield (28%) and with a marked erosion (48% ee) of the enantioselectivity (Table 2, entry 5).11

(a)

Entry

Catalyst

Additive (1.1 eq.)

T° Time

1

Pd/C

-

rt, 1 h

2

Ni Raney

3

eea

Major isomer

Yielda

91% (R)-10a

95%

-

Reflux, 16 h 42% (R)-10a

16%

Ni Raney

K2CO3

Reflux, 16 h 85% (R)-10a

70%

4

Pd/C

K2CO3

5

Ni Raney

AcOH

rt, 1 h

91% (R)-10a

70%

Reflux, 16 h 48% (R)-10a

28%

Enantioselectivity and yield determined after conversion of the carboxylic acid to the corresponding methyl ester 10a

Table 2. Additives effects on the hydrogenolysis of lactone 6a Under Ni/Raney hydrogenolysis, the alcohol substitution thus appears to have a great impact on the reaction mechanism: Whereas retention of configuration is observed in the presence of 7 ACS Paragon Plus Environment

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a 'free' OH group (Scheme 5), inversion was observed starting from lactone 6a in the presence of K2CO3 (Scheme-table 2). This general behavior could be confirmed starting from substrate 12a bearing an acetate (Scheme 6). In this case, compound 10a was isolated in 77% yield with a marked erosion of the enantioselectivity (65% ee). In the presence of 1.10 equivalents of K2CO3 the same enantiomer was observed in 84% yield and an improved enantiopurity (84% ee).

Scheme 6. Hydrogenolysis of benzylic acetate 11a The influence of K2CO3 on the Ni-Raney mediated hydrogenolysis of 11a was finally investigated. In this case, the 'retention' product ent-10a was isolated in 48% yield and 94% ee (Scheme 7).12

Scheme 7. Influence of K2CO3 in the Ni/Raney hydrogenolysis of 11a These results highlight that hydrogenolysis reactions with Ni/Raney are highly sensitive and slight modifications of the reaction conditions / substrate absorption on the surface of the catalyst may have a profound impact on the stereoselective outcome of the reaction (dichotomy between two distinct mechanistic scenarios). Further investigations are currently underway to unveil these mechanistic aspects. With enantiomerically enriched 9a and ent-9a in hands, the syntheses of (R)-curcumene and (R)-ar-himachalene were next investigated. Starting from enantiomerically enriched 9a, 8 ACS Paragon Plus Environment

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himachalene could be easily synthesized in two steps. First, in the presence of the Eaton's reagent (P2O5 in MeSO3H), the corresponding Friedel-Crafts seven-membered acylated product 13 was isolated in 86% yield. The ketone could be then transformed to the corresponding gem-dimethyl product using the Me2TiCl2 Reetz reagent.13 (R)-ar-himachalene ent-4 was thus obtained in only four steps (35% overall yield) from p-methylacetophenone 8 (Scheme 8).

Scheme 8. (R)-ar-himachalene synthesis For the synthesis of (R)-Curcumene, compound 10a was treated by an excess of MeMgBr to give the corresponding tertiary alcohol 14 in 94% yield. Acid-catalyzed dehydration of this alcohol finally led to the formation of (R)-Curcumene (Scheme 9).14 This natural product was thus obtained in only 5 steps and 32% overall yield from p-methylacetophenone 8. OH CO2Me

MeMgBr THF 94% H2SO4 drops CH2Cl2, rt 52 %

( )-curcumene

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Scheme 9. (R)-curcumene synthesis 3. CONCLUSION In conclusion, we have developed an expeditive and protecting group free synthesis of two natural products: the (R)-curcumene, widely used in traditional medicine, and the (R)-arhimachalene, a pheromone of some flea beetles. Our strategy features i) a catalytic and asymmetric vinylogous Mukaiyama reaction on aryl ketones and ii) a stereospecific hydrogenolysis to construct the benzylic stereocenter. We have shown that the access to chiral lactone 6a, bearing a quaternary stereogenic center, could be successfully achieved using an efficient transformation from our laboratories. This compound, which was obtained in high yields and enantiomeric excess, was used as a common intermediate for both total syntheses. The studies that were undertaken toward the behavior of 6a under hydrogenolysis conditions, either in the presence of Pd- or Ni-based catalysts, displayed interesting outcomes. Indeed, the Ni/Raney mediated hydrogenolysis of 6a has highlighted a strong dependence of the benzylic OH group protection on the stereochemical outcome (inversion vs retention of configuration) whereas Pd/C, under different conditions, afforded 'inversion' products. These observations suggest different reaction pathways (Pd vs Ni) that are not yet clear enough to allow us to propose a mechanistic scenario for both ways. Further investigations are currently ongoing in our laboratories in order to disclose such mechanistic features. 4. EXPERIMENTAL SECTION General method. Unless otherwise specified (see paragraph below), all commercial products and reagents were used as purchased, without further purification. Reactions were carried out in round-bottom flasks and schlenks equipped with a magnetic stirring bar under argon atmosphere. Analytical thin-layer chromatography (TLC) of all reactions was performed on silica gel 60 F254 TLC plates. Visualization of the developed chromatogram was performed 10 ACS Paragon Plus Environment

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by UV absorbance (254nm), using p-anisaldehyde and/or KMnO4. Flash chromatography was carried out on silica gel 60 Å (35-70 nm). FT-IR spectra were recorded with a Perkin-Elmer Spectrum 1000; absorptions are given in wave numbers (cm-1). 1H (400 MHz),

13

C (100

MHz), NMR spectra were recorded with a Bruker Ultra Shield 400 Plus. 1H chemical shifts are reported in delta (δ) units in parts per million (ppm) relative to the singlet at 7.26 ppm for d-chloroform (residual CHCl3). 13C chemical shifts are reported in ppm relative to the central line of the triplet at 77.0 ppm for d-chloroform. Splitting patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; m, multiplet; and br, broad and combinations thereof. All coupling constants (J values) are reported in Hertz (Hz). Data are reported as follows: chemical shift (δ in ppm), multiplicity, coupling constants (Hz), integration and attribution. Enantiomeric excesses were measured on a Shimadzu® LC 20 A HPLC with a UV/visible detector at 254 nm. Optical rotations were measured with a Bellingham + Stanley® ADP 440 Polarimeter or a Perkin Elmer® Polarimeter with a sodium lamp at 589 nm. Low resolutions mass spectra were recorded on a Waters QTof-I spectrometer using electrospray ionization. High resolution mass spectra were obtained using the mass spectrometers operated by the “Laboratoire de Mesures Physiques of the University of Montpellier”. THF was dried by distillation over sodium metal and benzophenone under argon. Dichloromethane (CH2Cl2) and diethylether (Et2O) were dried by distillation over CaH2 under argon. Dimethylzinc solution (1.2 M in toluene) was purchased from Acros® and used without additional purification. Cu(OTf)2 was purchased from Aldrich®, kept under argon atmosphere, and dried over P2O5 before use. (Z)-((1-Ethoxybuta-1,3-dien-1-yl)oxy)trimethylsilane (7) a) Synthesis of β,γ-unsaturated and α,β-unsaturated esters derived from crotonyl chloride Crotonyl chloride (10.0 mL, 106 mmol, 1.00 equiv.) and anhydrous CH2Cl2 (40 mL) were added to a flame dried flask. The reaction mixture was cooled down with and ice bath and 11 ACS Paragon Plus Environment

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stirred. Then, dried EtOH (7.4 ml, 126 mmol, 1.20 equiv.) was added, followed by the dropwise addition of diisopropylethylamine (DIPEA) (21.4 mL, 126 mmol, 1.20 equiv.). The mixture turned orange and after 30 min of stirring at 0 °C, the reaction was warmed to room temperature, and the stirring was continued for another 2 h. A solution of HCl 1M (40 mL) was added to quench the reaction. The aqueous phase was extracted with Et2O (3x). The organic layers combined were washed once with brine, and then dried over MgSO4. Filtration was followed by solvent removal under reduced pressure (600 mbar, 35 °C) to yield the crude product as a yellow oil. Purification was performed by distillation (150 mbar, 100 °C) to afford a colorless oil (10.3 g, 90 mmol, 85%) corresponding at an inseparable mixture of β,γand α,β-unsaturated ester with a ratio of 7:3 in favor of the β,γ-unsaturated ester (NMR determination). β,γ-unsaturated ester: 1H NMR (400 MHz, CDCl3): δ 1.27 (t, J = 7.2 Hz, 3H), 3.10 (dt, J = 7.0 Hz, 2H), 4.17 (q, J = 7.2 Hz, 2H), 5.13-5.18 (m, 2H), 5.80-6.02 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 14.2, 39.2, 60.6, 118.4, 130.4, 171.5 ppm. α,β-unsaturated ester: 1H NMR (400MHz, CDCl3): δ 1.28 (t, J = 7.2 Hz, 3H), 1.87 (dd, J = 6.8 and 1.7 Hz, 3H), 4.18 (q, J = 7.2 Hz, 2H), 5.83 (dq, J = 15.5 and 1.7 Hz, 1H), 6.96 (dq, J = 15.5 and 6.9 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 14.2, 17.9, 60.1, 122.8, 144.4, 166.6 ppm. These data are in accordance with previously described analysis.15 b) Synthesis of the dienedioxysilane (7) Diisopropylamine (DIPA) (6.2 mL, 44.2 mmol, 1.20 equiv.) and freshly distilled THF (70 mL) were added to a flame dried flask at 0 °C. Then, n-BuLi (27.6 mL, 44.2 mmol, 1.20 equiv., 1.6 M in Et2O) was added dropwise over a period of 30 min. The pale yellow solution obtained was stirred for additional 15 min, then, cooled at −78 °C. Freshly distilled 1,3dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (6.0 mL, 44.2 mmol, 1.20 equiv.) was added dropwise to the reaction mixture, giving rise to a milky solution. After 30 min, freshly distilled ester was added (4.6 mL, 36.8 mmol, 1.00 equiv.), and the color turned to yellow. The resulting mixture was stirred at the same temperature for another hour. Thus, freshly distilled chlorotrimethylsilane (TMSCl) (5.5 mL, 58.9 mmol, 1.60 equiv.) was added dropwise over a period of 10 min. The milky solution obtained was stirred for 30 min at −78 °C and then, allowed to reach room temperature. The formation of a white suspension in an orange solution was observed. The suspension was filtered through oven dried anhydrous Na2SO4, and the solvent was removed under reduced pressure. The crude product obtained was diluted with pentane (150 mL), filtered off and the solvent was removed under vacuum; this step was performed twice. The crude product so obtained was diluted with pentane and washed with a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Purification of the residue was performed by distillation (100 °C, 0.7 mbar) yielding a colorless oil (5.7 g,

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30.5 mmol, 83%) corresponding to a mixture of the two inseparable Z/E isomers with a ratio of 8:2 in favor of the Z isomer (NMR determination). Z isomer: 1H NMR (400 MHz, CDCl3): δ 0.21 (s, 9H), 1.28 (t, J = 7.0 Hz, 3H), 3.78 (q, J = 7.0 Hz, 2H), 4.43 (d, J = 10.4 Hz, 1H), 4.58 (dd, J = 1.8 and 10.4 Hz, 1H), 4.80 (dd, J = 1.8 and 17.2 Hz, 1H), 6.46-6.58 (m, J = 10.4 and 17.2 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 0.3, 14.3, 63.3, 80.8, 106.4, 132.5, 157.6 ppm. E isomer: 1H NMR (400 MHz, CDCl3): δ 0.24 (s, 9H), 1.22 (t, J = 7.0 Hz, 3H), 3.89 (q, J = 7.0 Hz, 2H), 4.51 (d, J = 10.4 Hz, 1H), 4.58 (dd, J = 1.8 and 10.4 Hz, 1H), 4.80 (dd, J = 1.8 and 17.2 Hz, 1H), 6.46-6.58 (m, J = 10.4 and 17.2 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ −0.2, 14.8, 62.8, 88.4, 107.3, 132.1, 154.6 ppm. These data are in accordance with previously described one.16 (R)-6-Methyl-6-(p-tolyl)-5,6-dihydro-2H-pyran-2-one (6a) Cu(OTf)2 (0.10 equiv.) and ligand (0.11 equiv.) were added in a flame dried round bottom flask, dissolved in freshly distilled THF (c = 0.0035 M), and stirred at room temperature for 30 min. Then, a solution of tetrabutylammonium difluorotriphenylsilicate (TBAT) (0.20 equiv.) in freshly distilled THF (c = 0.02 M) was added in the reaction mixture. After stirring for 15 min, freshly distilled dienedioxysilane 7 (2.00 equiv.) was added dropwise, followed by freshly distilled p-methylacetophenone 8 (1.00 equiv.). After stirring at room temperature for additional 16 h, the solvent was removed under reduced pressure. The crude product obtained was purified by silica gel chromatography (eluent: Petroleum Ether/Et2O 1:1) to give the tittle compound as a pale yellow oil. Rf = 0.50 (eluent: Petroleum Ether/Et2O 1:1, UV and p-anisaldehyde staining); [α]D = +40.0 (c 1.10, CHCl3); Enantiopurity has been controlled by chiral HPLC analytical column CHIRALCEL® IC column (250 x 4.6 mm); nhexane/iPrOH 9:1, 1.0 mL/min, 25 °C): tR1 = 26.85 min (S) isomer and tR2 = 28.78 min (R) isomer; 1H NMR (400 MHz, CDCl3): δ 1.71 (s, 3H), 2.34 (s, 3H) 2.79 (ddd, J = 18.4, 3.6 and 2.2 Hz, 1H), 2.95 (ddd, J = 18.4, 5.1 and 1.6 Hz, 1H), 5.99 (ddd, J = 9.8, 2.2 and 1.6 Hz, 1H), 6.73 (ddd, J = 9.8, 5.1 and 3.6 Hz, 1H), 7.167.28 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3) δ 20.9, 30.3, 35.4, 83.2, 121.9, 124.5 (2C), 129.2 (2C), 137.4, 141.0, 143.4, 164.0; IR (cm-1): 2980.0, 1709.2, 1514.7, 1378.5, 1258.2, 1063.2, 810.2; HRMS (ASAP) (+) m/z: [M+H]+ calcd for C13H15O2 203.1072; found 203.1072. 5-(p-Tolyl)hexanoic acid (9a) To a solution of α,β-unsaturated lactone 6a (ee: 95%) in solvent at room temperature was added the additive (see table 2). Several vacuum/argon cycles were performed in the flask prior to the addition of the catalyst (Pd/C or Ni/Raney). Then, the argon atmosphere was replaced by H2 and the suspension was stirred at room temperature. After reaction completion (TLC control), the catalyst was filtered off and the solvent was removed under reduced pressure. The residue obtained was used for the next step without further purification. 13 ACS Paragon Plus Environment

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Rf = 0.40 (eluent: Petroleum Ether/Et2O 1:1, UV and p-anisaldehyde staining); [α]D = −25,9 (c 1.08, CHCl3) for (R) isomer; 1H NMR (400 MHz, CDCl3): δ 1.23 (d, J = 7.1 Hz, 3H), 1.451.65 (m, 4H), 2.27-2.32 (m, 5H), 2.66 (sext, J = 6.8 Hz, 1H), 7.06-7.12 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3) δ 21.0, 22.4, 22.9, 34.0, 37.6, 39.3, 126.8 (2C), 129.1 (2C), 135.4, 144.0, 179.5 ppm; IR (cm-1): 2956.7, 2924.0, 1703.8, 1514.7, 1412.0, 1243.1, 929.5, 814.9; HRMS (ASAP) (−) m/z: [M−H]+ calcd for C13H17O2 205.1229; found 205.1229. Methyl 5-(p-tolyl)hexanoate (10a) a) From 9a To a solution of carboxylic acid 9a (24 mg, 0.12 mmol, 1.00 equiv.) in anhydrous MeOH (5 mL) were added a few drops of concentrated H2SO4. After stirring overnight at room temperature, the reaction was diluted with Et2O (20 mL) and washed with saturated aqueous solution of NaHCO3 and brine. The organic layer was separated, dried over MgSO4 and the solvent was removed under reduced pressure to afford a pale yellow oil (25 mg, 0.11 mmol, 95%). b) From the hydrogenolysis of 11a and 12a To a solution of methyl ester 11a or 12a (ee: 95%) in solvent at room temperature was added the additive (see scheme 7). Several vacuum/argon cycles were performed in the flask prior to the addition of the catalyst. Then, the argon atmosphere was replaced by H2 and the suspension was stirred for 16 h at a room temperature or reflux. After reaction completion (TLC control), the catalyst was filtered off and the solvent was removed under reduced pressure. The expected compound was isolated by silica gel chromatography (eluent: Petroleum Ether/Et2O 9.5:0.5) as a pale yellow oil. Rf = 0.35 (eluent: Petroleum Ether/Et2O 9.5:0.5, UV and KMnO4 staining); [α]D = −15,4 (c 1.04, CHCl3) for (R) isomer, [α]D = +18,2 (c 1.54, CHCl3) for (S) isomer; Enantiopurity has been controlled by chiral HPLC (CHIRALCEL® IC column (250 x 4.6 mm), n-hexane/iPrOH 99.5:0.5, 1.0 mL/min): minor tR1 = 7.69 min (S) isomer, major tR2 = 8.46 min (R) isomer; 1H NMR (400 MHz, CDCl3): δ 1.22 (d, J = 7.1 Hz, 3H), 1.46-1.62 (m, 4H), 2.26 (t, J = 6.6 Hz, 2H), 2.32 (s, 3H), 2.66 (sext, J = 6.8 Hz, 1H), 3.64 (s, 3H), 7.05-7.11 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3) δ 21.0, 22.4, 23.1, 34.1, 37.8, 39.3, 51.4, 126.8 (2C), 129.0 (2C), 135.4, 144.1, 174.1 ppm. Data are in accordance with previously described one.17 Methyl (R)-5-hydroxy-5-(p-tolyl)hexanoate (11a) a) Reduction of the double bond of 6a To a solution of α,β-unsaturated lactone 6a (434 mg, 2.15 mmol, 1.00 equiv.) in MeOH (22 mL) was added NiCl2.6H2O (51 mg, 0.22 mmol, 0.10 equiv.) at 0 °C. After 10 min, NaBH4 (163 mg, 4.30 mmol, 2.00 equiv.) was added portionwise. At this stage, the mixture turned black and the reaction was warmed to room temperature for 1 h. A saturated aqueous solution 14 ACS Paragon Plus Environment

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of NH4Cl (20 mL) was added to quench the reaction and the resulting mixture was extracted with Et2O (3x 20 mL). The organic layers combined were successively washed with a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. Purification was performed through silica gel chromatography (eluent: Petroleum Ether/Et2O 1:1) to yield the title compound as a pale yellow oil (420 mg, 2.05 mmol, 95%). Rf = 0.42 (eluent: Petroleum Ether/Et2O 1:1, UV and p-anisaldehyde staining); [α]D = +39.3 (c 1.22, CHCl3); 1H NMR (400 MHz, CDCl3): δ 1.54-1.64 (m, 1H), 1.66 (s, 3H), 1.74-1.83 (m, 1H), 1.98 (ddd, J = 14.2, 11.4 and 4.4 Hz, 1H), 2.3 (dt, J = 14.3 and 4.9 Hz, 1H), 2.34 (s, 3H), 2.41-2.48 (m, 2H), 7.16-7.23 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3) δ 16.5, 20.9, 29.0, 31.4, 34.3, 85.3, 124.4 (2C), 129.3 (2C), 137.0, 141.6, 171.6 ppm; IR (cm-1): 2953.1, 1724.0, 1251.7, 1072.8, 1053.1, 816.5; HRMS (ESI-TOF) (+) m/z: [M+H]+ calcd for C13H17O2 205.1229; found 205.1227. b) Transesterification To a solution of the previously synthesized lactone (50 mg, 0.24 mmol, 1.00 equiv.) in MeOH (24 mL) at room temperature was added K2CO3 (37 mg, 0.27 mmol, 1.1 equiv.). The stirring was maintained for additional 16 h at the same temperature. Then, Et2O (20 mL) was added and the mixture was washed first with a saturated aqueous solution of NH4Cl and then brine. The organic layer was separated, dried over MgSO4 and the solvent was removed under reduced pressure to afford the title compound, without further purification, as colorless oil (55 mg, 0.23 mmol, 96%). Rf = 0.40 (eluent: Petroleum Ether/Et2O 1:1, UV and p-anisaldehyde staining); [α]D = +11.1 (c 1.22, CHCl3); 1H NMR (400 MHz, CDCl3): δ 1.55 (s, 3H), 1.57-1.66 (m, 2H), 1.75-1.88 (m, 2H), 2.26 (t, J = 7.5 Hz, 2H), 2.33 (s, 3H), 3.63 (s, 3H), 7.14-7.16 (m, 2H), 7.30-7.32 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 19.6, 20.9, 30.3, 34.0, 43.3, 51.5, 74.3, 124.7 (2C), 128.9 (2C), 136.2, 144.6, 174.0 ppm; IR (cm-1): 3477.8, 2952.7, 1723.0, 1436.9, 1170.3, 817.9; HRMS (ESI-TOF) (+) m/z: [M+Na]+ calcd for C14H20O3Na 259.1310; found 259.1311. Methyl (R)-5-acetoxy-5-(p-tolyl)hexanoate (12a) Compound 11a (81 mg, 0.34 mmol, 1.00 equiv.) and CH2Cl2 (5 mL) were added in a flame dried round bottom flask under argon atmosphere at 0 °C. Then, acetic anhydride (97 µL, 1.02 mmol, 3.00 equiv.) followed by 4-dimethylaminopyridine (DMAP) (46 mg, 0.38 mmol, 1.10 equiv.) were added. Then, the reaction mixture was warmed to room temperature and stirring was continued for 12 h. The reaction was quenched with a saturated aqueous solution of NH4Cl. The organic layer was separated and washed successively with a saturated aqueous solution of NH4Cl, a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. Purification of the crude compound was performed over silica gel chromatography (eluent: Petroleum Ether/Et2O 7:3) to afford the title compound (85 mg, 0.30 mmol, 90%) as a pale yellow oil.

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Rf = 0.35 (eluent: Petroleum Ether/Et2O 7:3, UV and p-anisaldehyde staining); αD = + 1.3 (c 1.35, CHCl3); 1H NMR (400 MHz, CDCl3): δ 1.52-1.56 (m, 2H), 1.82 (s, 3H), 1.97-2.00 (m, 2H), 2.05 (s, 3H), 2.25 (t, J = 7.6 Hz, 2H), 2.32 (s, 3H), 3.64 (s, 3H), 7.12-7.20 (m, 4H) ppm; 13 C NMR (100 MHz, CDCl3) δ 19.4, 21.0, 22.3, 24.9, 33.9, 41.8, 51.5, 83.6, 124.4 (2C), 128.9 (2C), 136.5, 141.7, 169.6, 173.7 ppm; IR (cm-1): 2951.1, 1732.4, 1366.6, 1237.6, 1016.7, 815.9; HRMS (ESI-TOF) (+) m/z: [M+Na]+ calcd for C16H22O4Na 301.1416; found 301.1415. (R)-2-Methyl-6-(p-tolyl)heptan-2-ol (14) To a solution of ester 10a (80 mg, 0.36 mmol, 1.00 equiv.) in freshly distilled THF (2.0 mL) was added dropwise the Grignard reagent MeMgBr (605 µL, 1.8 mmol, 5.00 equiv., 3 M in Et2O) at 0 °C. Then, the reaction mixture was warmed to room temperature and stirring was continued overnight. After reaction completion (TLC monitoring), it was quenched with the addition of HCl 1M solution until the pH became acidic, then the aqueous phase was extracted with Et2O (20 mL). The organic layer was separated, washed with saturated aqueous solution of NaHCO3 and brine, dried over MgSO4 and the solvent was removed under reduced pressure. Purification of the crude compound was performed over silica gel chromatography (eluent: Petroleum Ether/Et2O 1:1) and the title compound was isolated as a colorless oil (75 mg, 0.34 mmol, 94%). Rf = 0.50 (eluent: Petroleum Ether/Et2O 1:1, UV and p-anisaldehyde staining); 1H NMR (400 MHz, CDCl3): δ 1.16 (s, 6H), 1.22 (d, J = 7.1 Hz, 3H), 1.25-1.36 (m, 2H), 1.37-1.47 (m, 2H), 1.50-1.63 (m, 2H), 2.32 (s, 3H), 2.66 (sext, J = 6.8 Hz, 1H), 7.06-7.11 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3): δ 21.0, 22.4, 22.4, 29.2, 38.9, 39.4, 43.9, 71.0 126.7 (2C), 129.0 (2C), 135.2, 144.6 ppm. Data are in accordance with previously reported analysis.16 (R)-Curcumene (1) To a solution of 14 (32 mg, 0.15 mmol, 1.00 equiv.) in dried CH2Cl2 (15 mL) were added a few drops of concentrated H2SO4. After stirring overnight at room temperature, the reaction was diluted with Et2O (20 mL) and washed with saturated aqueous solution of NaHCO3 and brine. The organic layer was separated, dried over MgSO4 and the solvent was removed under reduced pressure to afford a colorless oil. Purification was performed over silica gel chromatography (eluent: Petroleum Ether 100%) to yield the title compound as a colorless oil (15 mg, 0.075 mmol, 50%) corresponding to a mixture of curcumene and its natural isomer with a ratio of 9/1 in favor of the (R)-curcumene according to NMR and GC/MS analysis. Rf = 0.70 (eluent: Petroleum Ether 100%, UV and p-anisaldehyde staining); 1H NMR (400 MHz, CDCl3): δ 1.23 (d, J = 7.0 Hz, 3H), 1.53 (s, 3H), 1.57-1.63 (m, 2H), 1.67 (s, 3H), 1.851.92 (m, 2H), 2.32 (s, 3H), 2.66 (sext, J = 6.8 Hz, 1H), 5.08-5.12 (m, 1H), 7.07-7.12 (m, 4 H) ppm; 13C NMR (100 MHz, CDCl3): δ 17.7, 21.0, 22.5, 25.7, 26.2, 38.5, 39.0, 124.6, 126.9 (2C), 128.9 (2C), 131.4, 135.1, 144.7 ppm. Data are in accordance with previously reported analysis.16 16 ACS Paragon Plus Environment

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(R)-3,9-Dimethyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (13) To the carboxylic acid 9a (175 mg, 0.85 mmol, 1.00 equiv.) was added Eaton’s reagent (24 mL, 7,7% weight of P2O5 in MsOH) at room temperature. The resulting solution was stirred at this temperature for 48 h. After reaction completion (TLC monitoring), the reaction mixture was poured on ice, then extracted with Et2O. The organic layer was further washed with a saturated aqueous solution of NaHCO3 (2x) and brine. The organic layer was separated, dried over MgSO4 and the solvent was removed under reduced pressure. Purification was performed over silica gel chromatography (eluent: Petroleum Ether/Et2O 9:1) to yield the title compound as a colorless oil (138 mg, 0.73 mmol, 86%). Rf = 0.40 (eluent: Petroleum Ether/Et2O 90:10, UV and p-anisaldehyde staining); [α]D = −90.0 (c 1.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 1.36 (d, J = 6.9 Hz, 3H), 1.51-1.57 (m, 1H), 1.61-1.71 (m, 1H), 1.86-2.03 (m, 2H), 2.35 (s, 3H), 2.59 (ddd, J = 18.2, 12.4 and 2.8 Hz, 1H), 2.78 (ddd, J = 18.0, 5.9 and 2.6 Hz, 1H), 3.06-3.14 (m, 1H), 7.15 (d, J = 7.9 Hz, 1H), 7.28 (dd, J = 7.9 and 2.3 Hz, 1H), 7.35 (d, J = 2.3 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 19.4, 20.4, 20.8, 34.0, 34.3, 41.2, 125.3, 128.4, 132.7, 136.1, 139.3, 140.4, 208.8 ppm; IR (cm-1): 2933.5, 1674.8, 1608.1, 1256.3, 1174.5, 822.1; HRMS (ASAP) (+) m/z: [M+H]+ calcd for C13H17O 189.1283; found 189.1279. (R)-ar-himachalene (4) Freshly distilled TiCl4 (161 µL, 1.47 mmol, 4.00 equiv.) and dry CH2Cl2 (1 mL) were placed in a flame dried round bottom flask under argon atmosphere. The solution was cooled to −40 °C and then Me2Zn (1.28 mL, 1.54 mmol, 4.20 equiv., 1.2 M in toluene) was added dropwise. After 10 min of stirring, the reaction mixture was cooled to −78 °C and compound 13 (69 mg, 0.37 mmol, 1.00 equiv., solubilized in 1 mL of dry CH2Cl2) was then added. The mixture was allowed to warm up to −40 °C over a period of 3 h and was stirred for additional 16 h. Afterwards, the reaction mixture was successively warmed up to −20 °C (over a period of 5 h) followed by warming up to room temperature (over a period of 2 h) and stirred for another 16 h. After reaction completion (TLC monitoring), the reaction mixture was poured on ice, then extracted with Et2O. The organic layer was washed (3x) with saturated aqueous solution of NaHCO3 and brine. The organic layer was separated, dried over MgSO4 and the solvent was removed under reduced pressure to afford a pale yellow oil corresponding at a mixture of two inseparable products: the expected one, and the dehydro byproduct with a ratio of 8.3/1.7 in favor of the (R)-ar-himachalene according to NMR and GC/MS analysis. The residue obtained was dissolved in CH2Cl2 (2.0 mL) and 3-chloroperbenzoic acid (mCPBA) (141 mg, 0.6 mmol, 0.40 equiv.) was added at room temperature. The resulting solution was stirred for 16 h at this temperature. Quenching was performed by the addition of a saturated aqueous solution of NaHCO3 and CH2Cl2, followed by an extraction. The organic layer was washed twice with a saturated aqueous solution of NaHCO3 and then brine. The organic layer was separated, dried over MgSO4, and the solvent was removed under reduced pressure. Purification was performed over silica gel chromatography (eluent: Petroleum 100%) to yield the title compound as a colorless oil (46 mg, 0.23 mmol, 62%). 17 ACS Paragon Plus Environment

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Rf = 0.75 (eluent: Pentane 100%, UV and p-anisaldehyde staining); [α]D = −4.8 (c 1.09, CHCl3); 1H NMR (400 MHz, CDCl3): δ 1.33-1.35 (m, 6H), 1.43 (s, 3H), 1.46-1.56 (m, 2H), 1.60-1.67 (m, 1H), 1.73-1.83 (m, 3H), 2.32 (s, 3H), 3.23-3.31 (m, 1H), 6.98 (dd, J = 8.0 and 1.6 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 1.9 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 21.0, 21.2, 24.0, 29.7, 33.9, 34.5, 36.5, 39.5, 41.1, 125.4, 126.5, 127.5, 134.9, 141.2, 147.69 ppm. Data are in accordance with previously reported analysis.2

ACKNOWLEDGMENTS We are grateful to ENSCM for a grant (K. S.) and to CNRS. We also thank Prof. M. T. Reetz for sharing information on the use of Me2TiCl2 and Prof. S. P. Chavan for helpful discussions. Special thanks to P. Guiffrey for her help in chiral HPLC analyses. ASSOCIATED CONTENT

The Supporting Information is available free of charge on the ACS Publications website at DOI : 1H, 13C NMR and Chiral HPLC chromatograms are provided.

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1

(a) Fuganti C.; Serra, S.; Dulio, A. J. Chem. Soc. Perkin Trans. 1 1999, 279. (b) Heathcock, C. H. Total Synthesis of Sequiterpenes. In Total Synthesis of Natural Products, Volume 2 (ed. J. ApSimon), John Wiley & Sons, Inc.: Hoboken, New Jersey, 1973. (c) Del Prete, D.; Millán, E.; Pollastro, F.; Chianese, G.; Luciano, P.; Collado, J. A.; Munoz, E.; Appendino, G.; Taglialatela-Scafati, O. J. Nat. Prod. 2016, 79, 267. 2 (a) Muto, S.; Bando, M.; Mori, K. Eur. J. Org. Chem. 2004, 1946. (b) Mori, K. Tetrahedron: Asymmetry 2005, 16, 685. (c) Chavan, S. P.; Khatod, H. S. Tetrahedron: Asymmetry 2012, 23, 1410. 3 Rodriguez, A. D.; Ramirez, C. J. Nat. Prod. 2001, 64, 100. 4 see Ref 4 in Aggarwal, V. K.; Ball, L. T.; Carobene, S.; Connelly, R. L.; Hesse, M. J.; Partridge, B. M.; Roth, P.; Thomas, S. P.; Webster, M. P. Chem. Commun., 2012, 48, 9230. 5 For a few selected references. Dual transition metal/organocatalysis: (a) Ibrahem, I.; Ma, G.; Afewerki, S.; Córdova, A. Angew. Chem. Int. Ed. 2013, 52, 878; Asymmetric hydrogenation: (b) Yang, S.; Zhu, S.-F.; Guo, N.; Song, S.; Zhou, Q.-L. Org. Biomol. Chem. 2014, 12, 2049; Kumada cross-coupling: (c) Wu, L.; Zhong, J.-C.; Liu, S.-K.; Liu, F.P.; Gao, Z.-D.; Wang, M.; Bian, Q.-H. Tetrahedron: Asymmetry 2016, 27, 78; Lithiation/borylation: (d) Elford, T. G.; Nave, S.; Sonawane, R. P.; Aggarwal, V. K. J. Am. Chem. Soc. 2011, 133, 16798; Metal catalyzed conjugated additions: (e) Drissi-Amraoui, S.; Morin, M.; Crévisy, C.; Baslé, O.; de Figueiredo, R. M.; Mauduit, M.; Campagne, J.-M. Angew. Chem. Int. Ed. 2015, 127, 11996. 6 (a) Tollefson, E. J.; Dawson, D. D.; Osborne, C. A.; Jarvo, E. R. J. Am. Chem. Soc. 2014, 136, 14951. (b) Dawson, D. D.; Jarvo, E. R. Org. Process Res. Dev. 2015, 19, 1356. (c) Tollefson, E. J.; Hanna, L. E.; Jarvo, E. R. Acc. Chem. Res. 2015, 48, 2344. 7 (a) Bluet, G.; Campagne, J. M. Tetrahedron Lett. 1999, 40, 5507. (b) Moreau, X.; BazanTejeda, B.; Campagne, J. M. J. Am. Chem. Soc. 2005, 127, 7288. (c) Bazan-Tejeda, B.; Bluet, G.; Broustal, G.; Campagne, J. M. Chem. Eur. J. 2006, 12, 8358. 8 For a comprehensive review see: Kalesse, M.; Cordes, M.; Symkenberg, G.; Lu, H.-H. Nat. Prod. Rep. 2014, 31, 563. 9 (a) Sullivan, H. R.; Beck, J. R.; Pohland, A. J. Org. Chem., 1963, 28, 2381. (b) Garbisch, E. W.; Schreader, L.; Frankel, J. J. J. Am. Chem. Soc. 1967, 89, 4233. (c) Ishibashi, H.; Maeki, M.; Yagi, J.; Ohba, M.; Kanai, T. Tetrahedron 1999, 55, 6075. (d) Wilsily, A.; Nguyen, Y.; Fillion, E. J. Am. Chem. Soc. 2009, 131, 15606. (e) Fillion, E.; Beaton, E.; Nguyen, Y.; Wilsily, A.; Bondarenko, G.; Jacq, J. Adv. Synth. Catal. 2016, 358, 3422. (f) Fessard, T. C.; Motoyoshi, H.; Carreira, E. M. Angew. Chem. Int. Ed. 2007, 46, 2078. 10 The racemic lactone recrystallizes and the enantioenriched one is recovered, after filtration of rac-6a, as a pale yellow oil. 11 In this latter case, a competitive SN1 reaction can be suspected to explain the erosion of the enantioselectivity. 12 Around 30% of the starting material was recovered in this reaction. 13

Reetz, M. T.; Westermann, J.; Kyung, S.-H. Chem. Ber. 1985, 118, 1050. Iso-α-curcumene is also identified as observed in the naturally derived extraction mixture, see ref 1b. 15 Lombardo, L. Tetrahedron Lett. 1985, 26, 381. 16 Hertler, W. R.; Reddy, G. S.; Sogah, D. Y. J. Org. Chem. 1988, 53, 3532. 17 Ehara, T.; Tanikawa, S.; Ono, M.; Akita, H. Chem. Pharm. Bull. 2007, 55, 1361. 14

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