Stereospecific Hydrogenolysis of Lactones: Application to the Total Syntheses of (R)-ar-Himachalene and (R)-Curcumene

Article abstract of DOI:10.1021/acs.joc.7b00419

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.

Full text of DOI:10.1021/acs.joc.7b00419

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Article
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)-ar-
Himachalene and (R)-Curcumene
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Kim Spielmann, Renata Marcia de Figueiredo* and JeanꢀMarc Campagne*
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Institut Charles Gerhardt – UMR 5253 CNRSꢀUMꢀENSCM
Ecole Nationale Supérieur de Chimie de Montpellier
8, Rue de L'Ecole Normale Fꢀ34296 Montpellier Cedex 5, France
Eꢀmail: renata.marcia_de_figueiredo@enscm.fr; jeanꢀmarc.campagne@enscm.fr
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
JeanꢀMarc Campagne : 0000ꢀ0002ꢀ4943ꢀ047X
Renata Marcia de Figueiredo: 0000ꢀ0001ꢀ5336ꢀ6071
ABSTRACT GRAPHIC
ABSTRACT
A straightforward strategy for the syntheses of curcumene and arꢀhimachalene 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
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Molecules bearing a tertiary (or quaternary) benzylic stereocenter are widely representated in
natural products and pharmaceuticals (Figure 1). Curcumene 1, curcuhydroquinone 2, arꢀ
turmerone 3 and congeners, members of the bisabolane sesquiterpenes family have been used
in traditional medicine, exhibit antiꢀcancer / antimicrobial activities and they are also
employed in cosmetics.1 (S)ꢀarꢀhimachalene 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
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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
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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
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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)ꢀarꢀhimachalene and (R)ꢀcurcumene (Scheme 2).
Scheme 2. Synthetic approach toward (R)ꢀarꢀhimachalene and (R)ꢀcurcumene
2. RESULTS AND DISCUSSION
In order to check the viability of the approach, we thus embarked on the synthesis of α,βꢀ
unsaturated lactone 6a (Table 1). In the presence of silyldienolate 7 and pꢀ
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methylacetophenone 8, the corresponding lactone 6a was obtained in excellent yield and
moderate enantioselectivity (70% ee) using (R)ꢀTolꢀBINAP [e.g. (R)ꢀ(+)ꢀ2,2′ꢀBis(diꢀpꢀ
tolylphosphino)ꢀ1,1′ꢀbinaphthyl] as the ligand (Schemeꢀtable 1, entry 1). In order to optimize
the enantioselectivity, various ligands were next tried and the best results were observed with
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(S)ꢀ(−)ꢀMeOBIPHEP
[e.g.
(S)ꢀ(−)ꢀ(6,6′ꢀDimethoxybiphenylꢀ2,2′ꢀ
diyl)bis(diphenylphosphine)] leading to an excellent 93% yield and a very good 87% ee
(Table 1, entry 13).
Entry
1
Ligands
(R)ꢀTolꢀBINAP
Yield
95%
43%
70%
NR
ee
70%
79%
81%
ND
2
(R)ꢀSEGPHOS
3
(R)ꢀDTBMꢀSEGPHOS
(R)ꢀDMꢀSEGPHOS
4
5
(R)ꢀtBuꢀMeOBIPHEP
(R)ꢀFurylꢀMeOBIPHEP
(R)ꢀpꢀTolꢀMeOBIPHEP
(R)ꢀ3,5ꢀiPrꢀ4ꢀNMe2ꢀMeOBIPHEP
(R)ꢀ3,5ꢀtBuꢀ4ꢀMeOꢀMeOBIPHEP
(R)ꢀiPrꢀMeOBIPHEP
(R)ꢀ3,5ꢀxylꢀMeOBIPHEP
(R)ꢀ3,4,5ꢀMeOꢀMeOBIPHEP
(S)-MeOBIPHEP
95%
NR
84%
ND
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7
80%
56%
82%
NR
77%
84%
82%
ND
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9
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13
14
5%
63%
58%
−87%
80%
27%
93%
40%
(R)ꢀSynPHOS
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
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(2.00 equiv) and pꢀmethylacetophenone 8 (1.00 equiv), rt, 16h. Cu(OTf)2 = Copper(II)
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trifluoromethanesulfonate; L*
=
chiral ligand, TBAT
=
Tetrabutylammonium
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difluorotriphenylsilicate; THF = tetrahydrofuran; NR = No reaction; ND = Not determined.
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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 setꢀup on a 1 gram scale using (R)ꢀ
TolꢀBINAP and the resulting lactone could be isolated, after recrystallization, in 60% yield
and 95% ee (Scheme 3).
Scheme 3. Gramꢀscale synthesis of 6a
The hydrogenolysis of enantioenriched unsaturated lactone 6a was next undertaken. In the
presence of Pd/C, both hydrogenation of the C3ꢀC4 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 C3ꢀC4
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 Niꢀcatalyzed process and to check the
influence of the OꢀAcyl group on the outcome of the reaction, compound 11a was obtained in
two steps (91% yield) after reduction of the C3ꢀC4 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
entꢀ10a 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 reꢀinvestigate the Niꢀcatalyzed hydrogenolysis of unsaturated
lactone 6a in the presence of K2CO3 in order to ideally promote in a sequential oneꢀpot
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procedure simultaneously the saponification of the lactone, the hydrogenation of the double
bond and the CꢀO 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 Niꢀcatalyzed 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
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Additive
(1.1 eq.)
ꢀ
T°
Time
rt, 1 h
Major
isomer
Entry Catalyst
eea
Yielda
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Pd/C
91% (R)ꢀ10a 95%
Ni Raney
ꢀ
Reflux, 16 h 42% (R)ꢀ10a 16%
Ni Raney K2CO3 Reflux, 16 h 85% (R)ꢀ10a 70%
Pd/C K2CO3 rt, 1 h 91% (R)ꢀ10a 70%
Ni Raney AcOH Reflux, 16 h 48% (R)ꢀ10a 28%
(a) 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
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a 'free' OH group (Scheme 5), inversion was observed starting from lactone 6a in the presence
of K2CO3 (Schemeꢀtable 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).
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Scheme 6. Hydrogenolysis of benzylic acetate 11a
The influence of K2CO3 on the NiꢀRaney mediated hydrogenolysis of 11a was finally
investigated. In this case, the 'retention' product entꢀ10a 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 entꢀ9a in hands, the syntheses of (R)ꢀcurcumene and
(R)ꢀarꢀhimachalene were next investigated. Starting from enantiomerically enriched 9a,
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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 FriedelꢀCrafts sevenꢀmembered acylated
product 13 was isolated in 86% yield. The ketone could be then transformed to the
corresponding gemꢀdimethyl product using the Me2TiCl2 Reetz reagent.13 (R)ꢀarꢀhimachalene
entꢀ4 was thus obtained in only four steps (35% overall yield) from pꢀmethylacetophenone 8
(Scheme 8).
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Scheme 8. (R)ꢀarꢀhimachalene 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. Acidꢀcatalyzed 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 pꢀmethylacetophenone 8.
OH
CO2Me
MeMgBr
THF
94%
H2SO4 drops
CH2Cl2, rt
52 %
(
)-curcumene
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Scheme 9. (R)ꢀcurcumene synthesis
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3. CONCLUSION
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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)ꢀarꢀ
himachalene, 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 Pdꢀ or Niꢀbased 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.
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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 roundꢀbottom flasks and schlenks equipped with a magnetic stirring bar under argon
atmosphere. Analytical thinꢀlayer chromatography (TLC) of all reactions was performed on
silica gel 60 F254 TLC plates. Visualization of the developed chromatogram was performed
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by UV absorbance (254nm), using pꢀanisaldehyde and/or KMnO4. Flash chromatography was
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carried out on silica gel 60 Å (35ꢀ70 nm). FTꢀIR spectra were recorded with a PerkinꢀElmer
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Spectrum 1000; absorptions are given in wave numbers (cmꢀ1). H (400 MHz), 13C (100
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1
MHz), NMR spectra were recorded with a Bruker Ultra Shield 400 Plus. H chemical shifts
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are reported in delta (δ) units in parts per million (ppm) relative to the singlet at 7.26 ppm for
13
dꢀchloroform (residual CHCl3). C chemical shifts are reported in ppm relative to the central
line of the triplet at 77.0 ppm for dꢀchloroform. 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 QTofꢀI 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)ꢀ((1ꢀEthoxybutaꢀ1,3ꢀdienꢀ1ꢀyl)oxy)trimethylsilane (7)
a) Synthesis of β,γꢀunsaturated and α,βꢀunsaturated 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
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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,γꢀ
and α,βꢀunsaturated ester with a ratio of 7:3 in favor of the β,γꢀunsaturated ester (NMR
determination).
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β,γꢀunsaturated 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), 5.13ꢀ5.18 (m, 2H), 5.80ꢀ6.02 (m, 1H) ppm; 13C NMR (100
MHz, CDCl3) δ 14.2, 39.2, 60.6, 118.4, 130.4, 171.5 ppm.
1
α,βꢀunsaturated ester: H 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, nꢀBuLi (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 1,3ꢀ
dimethylꢀ3,4,5,6ꢀtetrahydroꢀ2(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).
1
Z isomer: H 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), 6.46ꢀ6.58 (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.
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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), 6.46ꢀ6.58 (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)ꢀ6ꢀMethylꢀ6ꢀ(pꢀtolyl)ꢀ5,6ꢀdihydroꢀ2Hꢀpyranꢀ2ꢀone (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 pꢀmethylacetophenone 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 pꢀanisaldehyde 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), 7.16ꢀ
7.28 (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 (cmꢀ1): 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.
5ꢀ(pꢀTolyl)hexanoic acid (9a)
To a solution of α,βꢀunsaturated 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.
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Rf = 0.40 (eluent: Petroleum Ether/Et2O 1:1, UV and pꢀanisaldehyde staining); [α]D = −25,9 (c
1.08, CHCl3) for (R) isomer; H NMR (400 MHz, CDCl3): δ 1.23 (d, J = 7.1 Hz, 3H), 1.45ꢀ
1.65 (m, 4H), 2.27ꢀ2.32 (m, 5H), 2.66 (sext, J = 6.8 Hz, 1H), 7.06ꢀ7.12 (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 (cmꢀ1): 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.
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Methyl 5ꢀ(pꢀtolyl)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), nꢀhexane/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), 1.46ꢀ1.62 (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), 7.05ꢀ7.11 (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)ꢀ5ꢀhydroxyꢀ5ꢀ(pꢀtolyl)hexanoate (11a)
a) Reduction of the double bond of 6a
To a solution of α,βꢀunsaturated 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
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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%).
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Rf = 0.42 (eluent: Petroleum Ether/Et2O 1:1, UV and pꢀanisaldehyde staining); [α]D = +39.3
(c 1.22, CHCl3); H NMR (400 MHz, CDCl3): δ 1.54ꢀ1.64 (m, 1H), 1.66 (s, 3H), 1.74ꢀ1.83
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(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), 2.41ꢀ2.48 (m, 2H), 7.16ꢀ7.23 (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 (cmꢀ1): 2953.1,
1724.0, 1251.7, 1072.8, 1053.1, 816.5; HRMS (ESIꢀTOF) (+) 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 pꢀanisaldehyde staining); [α]D = +11.1
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(c 1.22, CHCl3); H NMR (400 MHz, CDCl3): δ 1.55 (s, 3H), 1.57ꢀ1.66 (m, 2H), 1.75ꢀ1.88
(m, 2H), 2.26 (t, J = 7.5 Hz, 2H), 2.33 (s, 3H), 3.63 (s, 3H), 7.14ꢀ7.16 (m, 2H), 7.30ꢀ7.32 (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 (cmꢀ1): 3477.8, 2952.7, 1723.0, 1436.9, 1170.3,
817.9; HRMS (ESIꢀTOF) (+) m/z: [M+Na]+ calcd for C14H20O3Na 259.1310; found 259.1311.
Methyl (R)ꢀ5ꢀacetoxyꢀ5ꢀ(pꢀtolyl)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 4ꢀdimethylaminopyridine (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 pꢀanisaldehyde staining); αD = + 1.3 (c
1.35, CHCl3); 1H NMR (400 MHz, CDCl3): δ 1.52ꢀ1.56 (m, 2H), 1.82 (s, 3H), 1.97ꢀ2.00 (m,
2H), 2.05 (s, 3H), 2.25 (t, J = 7.6 Hz, 2H), 2.32 (s, 3H), 3.64 (s, 3H), 7.12ꢀ7.20 (m, 4H) ppm;
13C 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 (cmꢀ1): 2951.1, 1732.4, 1366.6, 1237.6, 1016.7,
815.9; HRMS (ESIꢀTOF) (+) m/z: [M+Na]+ calcd for C16H22O4Na 301.1416; found 301.1415.
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(R)ꢀ2ꢀMethylꢀ6ꢀ(pꢀtolyl)heptanꢀ2ꢀol (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 pꢀanisaldehyde staining); 1H NMR (400
MHz, CDCl3): δ 1.16 (s, 6H), 1.22 (d, J = 7.1 Hz, 3H), 1.25ꢀ1.36 (m, 2H), 1.37ꢀ1.47 (m, 2H),
1.50ꢀ1.63 (m, 2H), 2.32 (s, 3H), 2.66 (sext, J = 6.8 Hz, 1H), 7.06ꢀ7.11 (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.
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Rf = 0.70 (eluent: Petroleum Ether 100%, UV and pꢀanisaldehyde staining); H NMR (400
MHz, CDCl3): δ 1.23 (d, J = 7.0 Hz, 3H), 1.53 (s, 3H), 1.57ꢀ1.63 (m, 2H), 1.67 (s, 3H), 1.85ꢀ
1.92 (m, 2H), 2.32 (s, 3H), 2.66 (sext, J = 6.8 Hz, 1H), 5.08ꢀ5.12 (m, 1H), 7.07ꢀ7.12 (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
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(R)ꢀ3,9ꢀDimethylꢀ6,7,8,9ꢀtetrahydroꢀ5Hꢀbenzo[7]annulenꢀ5ꢀone (13)
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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%).
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Rf = 0.40 (eluent: Petroleum Ether/Et2O 90:10, UV and pꢀanisaldehyde staining); [α]D = −90.0
(c 1.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 1.36 (d, J = 6.9 Hz, 3H), 1.51ꢀ1.57 (m, 1H),
1.61ꢀ1.71 (m, 1H), 1.86ꢀ2.03 (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), 3.06ꢀ3.14 (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
(cmꢀ1): 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)ꢀarꢀhimachalene (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)ꢀarꢀhimachalene according to NMR and GC/MS analysis.
The residue obtained was dissolved in CH2Cl2 (2.0 mL) and 3ꢀchloroperbenzoic 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%).
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Rf = 0.75 (eluent: Pentane 100%, UV and pꢀanisaldehyde staining); [α]D = −4.8 (c 1.09,
CHCl3); H NMR (400 MHz, CDCl3): δ 1.33ꢀ1.35 (m, 6H), 1.43 (s, 3H), 1.46ꢀ1.56 (m, 2H),
1.60ꢀ1.67 (m, 1H), 1.73ꢀ1.83 (m, 3H), 2.32 (s, 3H), 3.23ꢀ3.31 (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.
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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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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:
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3 Rodriguez, A. D.; Ramirez, C. J. Nat. Prod. 2001, 64, 100.
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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.
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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 crossꢀcoupling: (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) DrissiꢀAmraoui, S.;
Morin, M.; Crévisy, C.; Baslé, O.; de Figueiredo, R. M.; Mauduit, M.; Campagne, J.ꢀM.
Angew. Chem. Int. Ed. 2015, 127, 11996.
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(a) Tollefson, E. J.; Dawson, D. D.; Osborne, C. A.; Jarvo, E. R. J. Am. Chem. Soc. 2014,
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Tollefson, E. J.; Hanna, L. E.; Jarvo, E. R. Acc. Chem. Res. 2015, 48, 2344.
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(a) Bluet, G.; Campagne, J. M. Tetrahedron Lett. 1999, 40, 5507. (b) Moreau, X.; Bazanꢀ
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8 For a comprehensive review see: Kalesse, M.; Cordes, M.; Symkenberg, G.; Lu, H.ꢀH. Nat.
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10 The racemic lactone recrystallizes and the enantioenriched one is recovered, after filtration
of racꢀ6a, 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.
14 Isoꢀαꢀcurcumene 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.
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