Silica-catalysed and highly stereoselective convergent and nonconvergent rearrangements of menthone enol acetate epoxides: Easy access to the four α-hydroxymenthone stereoisomers

Article abstract of DOI:10.1002/ejoc.201200414

During a program dedicated to the biocatalytic access of structurally useful α-hydroxy ketones, we made the unexpected observation that epoxy enol acetates derived from (+)- and (-)-menthone stereoselectively rearranged on exposure to silica through a diastereoselective process, providing easy access to the complete set of α-hydroxymenthone stereoisomers. The absolute configurations of the four stereoisomers were unambiguously established by IR-VCD and X-ray diffraction, thus clarifying some literature discrepancy. Two of the four stereoisomers could also be obtained through astereoconvergent process, thus avoiding the inherent 50 % yield limitations of such diastereoselective reactions. A solvent-free version allowing an extremely rapid reaction (< 2 h) is also described. Finally, the observed diastereoselection was investigated by DFT calculations. Epoxy enol acetates derived from menthone unexpectedly rearranged diastereoselectively on exposure to silica, giving easy access to the complete set of α-hydroxymenthone stereoisomers. Two of the four stereoisomers were also available through a diastereoconvergent process. Finally, the observed stereoselection was investigated by DFT calculations. Copyright

Full text of DOI:10.1002/ejoc.201200414

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FULL PAPER
DOI: 10.1002/ejoc.201200414
Silica-Catalysed and Highly Stereoselective Convergent and Nonconvergent
Rearrangements of Menthone Enol Acetate Epoxides: Easy Access to the Four
α-Hydroxymenthone Stereoisomers
Sylvain Tranchimand,[a] Bruno Faure,[a] Jean-Valère Naubron,[b] Véronique Alphand,[a]
Alain Archelas,[a] and Gilles Iacazio*[a]
Keywords: Rearrangement / Chiral resolution / Diastereoselectivity / Acyloins / Menthone
During a program dedicated to the biocatalytic access of
structurally useful α-hydroxy ketones, we made the unexpec-
ted observation that epoxy enol acetates derived from (+)-
and (–)-menthone stereoselectively rearranged on exposure
to silica through a diastereoselective process, providing easy
fraction, thus clarifying some literature discrepancy. Two of
the four stereoisomers could also be obtained through a
stereoconvergent process, thus avoiding the inherent 50%
yield limitations of such diastereoselective reactions. A sol-
vent-free version allowing an extremely rapid reaction
access to the complete set of α-hydroxymenthone stereoiso- (Ͻ 2 h) is also described. Finally, the observed diastereoselec-
mers. The absolute configurations of the four stereoisomers
were unambiguously established by IR-VCD and X-ray dif-
tion was investigated by DFT calculations.
one enol acetate epoxides 1a+1b (Scheme 1) was spotted on
normal silica TLC plates, only one spot was visualized
(para-anisaldehyde spray) when the TLC plate was devel-
oped immediately, but a second spot was detected if the
development was delayed for at least a few minutes.
Furthermore, the intensity of this second spot increased
with the delay in development (up to 18–24 h) but the initial
spot was never totally replaced by the second one.
These first observations were consistent with some sort
of diastereoselective reaction of the initial diastereoisomeric
mixture of the epoxides 1a+1b on exposure to silica. In or-
der to clarify the situation a preparative transformation of
the diastereoisomeric mixture in the presence of silica
(10 equiv., w/w) in dichloromethane at room temperature
was set up. After approximately 48 h reaction time, the in-
tensities of the two previously detected TLC spots looked
constant, and the two corresponding products were reco-
vered separately by flash chromatography. NMR analysis
clearly established that one of the initial diastereoisomers –
1b – had remained unaffected, whereas the second – 1a –
had been transformed into α-acetoxymenthone (2a,
Scheme 1), probably through the well-known silica-cata-
lysed rearrangement of enol acetate epoxides with inversion
of configuration.[7,8]
Introduction
α-Hydroxy ketones (acyloins) and α-hydroxy aldehydes
are very useful chiral molecules. Indeed, such functionality
is found in numerous biologically active molecules and can
be used for easy transformation into other extremely impor-
tant systems such as vic-diols and α-amino alcohols or for
use in chiral auxiliaries.[1] Of the numerous reported biocat-
alytic[1] and chemical[2] methods to afford access to such
compounds, one is particularly easy and straightforward to
carry out. The synthetic sequence starting from an enolis-
able ketone and leading to an acyloin through (i) enol ester
(ether) formation, (ii) epoxidation of the enol functionality,
and (iii) acidic rearrangement or ester (ether) hydrolysis
(cleavage) of the formed enol ester (ether) epoxide is syn-
thetically easy to perform and generally high-yielding.[2a,3]
Furthermore, if epoxidation,[4] rearrangement[5] or hydroly-
sis[6] is selective, the final acyloin product can be obtained
in high enantiomeric excess, thus enhancing its usefulness.
Results and Discussion
The starting point of this work was the unexpected ob-
servation that when a diastereoisomeric mixture of (–)-menth-
[a] Aix-Marseille Université, iSm2/BiosCiences UMR CNRS 7313,
case 332, UFR Sciences pôle de l’Etoile,
13397 Marseille Cedex 20, France
At this point the absolute configurations of the more and
the less reactive starting epoxides 1a and 1b and of the re-
arranged α-acetoxymenthone 2a were unknown. This issue
was first studied by infrared vibrational circular dichroism
(IR-VCD) examination of the final acyloin products. Com-
parison of experimentally measured and calculated spectra
(see the Supporting Information) allowed the unambiguous
Fax: +33-4-91288440
E-mail: gilles.iacazio@univ-amu.fr
[b] Aix-Marseille Université, Spectropole case D11, UFR Sciences
pôle de l’Etoile,
13397 Marseille Cedex 20, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200414.
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Scheme 1. Convergent transformations of diastereoisomeric mixtures of menthone enol acetate epoxides into α-hydroxymenthone isomers
at moderate temperatures (0–37 °C): (a) enol acetate epoxide diastereoisomers derived from (–)-menthone; (b) enol acetate epoxide dia-
stereoisomers derived from (+)-menthone.
assignment of the (2R,5R) absolute configuration to the ob- from the supplier or after activation (3 h treatment at
tained α-hydroxymenthone 3a (Scheme 1), thus establishing 250 °C and under vacuum). The selectivity of the reaction
the same absolute configuration for the rearranged α-acet- was not significantly affected neither by the reaction tem-
oxymenthone 2a and the (1R,2S,5R) absolute configuration perature (over the 0–37 °C range studied) nor by the status
for the more reactive diastereoisomer – 1a – of (–)-menth- of the silica used (Figure 1); the only noteworthy differences
one enol acetate epoxide and thus the (1S,2R,5R) absolute were that the rate of the reaction was enhanced by a factor
configuration for the less reactive 1b.
of 5 with use of untreated silica without solvent and by a
In order to provide information about the selectivity of further factor of 1.5 when activated silica was used, leading
the observed process, the two products were treated sepa- to a very quick solvent-free rearrangement (Figure 1).
rately with sodium methoxide in methanol, leading to the
Essentially the same results were obtained when starting
corresponding α-hydroxymenthones (Scheme 1). The acylo- from a mixture of (+)-menthone enol acetate epoxides
ins thus formed were then analysed by chiral gas (1c+1d).
chromatography and compared to those obtained after ap-
The known inversion of configuration[7,8] associated with
plication of the same sodium methoxide treatment to the the described diastereoselective process offered the oppor-
initial diastereoisomeric mixture of the epoxides 1a+1b. tunity to treat both the unchanged enol acetate epoxide and
Whereas in the latter case the obtained α-hydroxymenthone the rearranged α-acetoxymenthone together with sodium
resolved into two peaks (two diastereoisomers), application methoxide. In that case, mainly one acyloin diastereoisomer
of the same procedure to each of the two isolated products should be formed, thus making this process convergent.
obtained after silica treatment led mainly to the same peak This procedure effectively led to the synthesis of (2R,5R)-
in both cases (with 97:3 to 100:0 ratios for each compound α-hydroxymenthone (3a) in a 98.6% yield and with a diaste-
depending on the reaction time). These results were consis- reoisomeric excess (de) of 95.1% and also to (2S,5S)-α-hy-
tent with a highly diastereoselective process leaving one of droxymenthone (3c) with a 98.5% yield and a 95.3% de by
the enol acetate epoxide diastereoisomers unaffected, starting from (–)-menthone derivatives 1a+1b [Scheme 1(a)]
whereas the other rearranged with inversion of configura- and (+)-menthone derivatives 1c+1d [Scheme 1(b)], respec-
tion at the epoxide carbon atom attacked by the acetoxy tively.
group[7,8] (Scheme 1).
In order to gain access to the other two possible dia-
The stereochemical outcome of the reaction having been stereoisomers, both (–)- and (+)-menthone enol acetate ep-
established, its stereoselectivity was next investigated. The oxide stereoisomers were treated with silica in the same way
reaction was first conducted in dichloromethane at different and the thus obtained rearranged α-acetoxy-(–)- and
temperatures, and the progress of the reaction was moni- -(+)-menthone stereoisomers (2a and 2c) and the unaffected
tored by chiral GC analysis after sodium methoxide (–)- and (+)-menthone enol acetate epoxide stereoisomers
treatment of regularly withdrawn aliquots. The diastereo- (1b and 1d) were separated by silica gel chromatography.
selectivity was not affected by the temperature used (over Isomers 1b and 1d were then rearranged by silica treatment,
the 9–37 °C range studied), with maxima of 97:3 to 98:2 but at a higher temperature (80 °C), leading to the two cor-
diastereoisomeric ratios being obtained in all cases for responding inverted stereoisomers of α-acetoxy-(–)- and
acyloins resulting from sodium methoxide treatment (Fig- -(+)-menthone 2b and 2d (Scheme 2). All four obtained
ure 1).
stereoisomers of α-acetoxy-menthone (2a, 2b, 2c, 2d) were
In order to mimic the initial rearrangement observed on then transformed into the corresponding acyloins (3a, 3b,
TLC plates more closely, a solvent-free version of the pro- 3c, 3d) in high diastereoisomeric excess with sodium meth-
cess was developed, with the silica used either as received oxide (Schemes 1 and 2).
2
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Easy Access to the Four α-Hydroxymenthone Stereoisomers
Figure 1. Kinetic analysis of silica-catalysed rearrangement of diastereoisomeric mixtures of (–)-menthone enol acetate epoxides (1a+1b)
under various conditions. The de is the diastereoisomeric excess of the α-hydroxy-(–)-menthone 3a after methoxide treatment. Open
squares: 0 °C; triangles: 9 °C; open circles: 23–26 °C; diamonds: 37 °C. (a) Activated silica gel, no solvent; (b) untreated silica gel, no
solvent; (c) untreated silica gel, CH2Cl2.
ported in the literature[9] have opposite signs. In both cases
the starting material used to obtain access to 2a has the
carbon atom bearing the methyl substituent in an (R) abso-
lute configuration [(–)-menthone and (+)-menth-3-ene,
respectively]. In each work this carbon atom is believed to
be unaffected during the reported transformations, so the
observed difference could tentatively be assigned to con-
tamination of 2a by (2S,5R)-α-acetoxymenthone 2b in the
previously reported work.[9] Indeed, because 2b possesses a
positive and much larger optical rotation than (2R,5R)-α-
acetoxymenthone (2a, Table 1) the diastereoisomeric excess
of the reported (2R,5R)-α-acetoxymenthone should be
around 40%, if it is assumed that this compound is the only
contaminant. Such an assumption is in line with the facts
that no diastereoisomeric determination was carried out
during the reported work and that recrystallization was be-
lieved to be sufficient to afford diastereoisomerically pure
Scheme 2. Silica-catalysed rearrangement of the less reactive men-
thone enol acetate epoxides. (a) Enol acetate epoxide 1b derived
from (–)-menthone; (b) enol acetate epoxide 1d derived from (+)-
menthone.
Table 1. Optical rotations of the α-acetoxymenthone and α-hy-
droxymenthone stereoisomers derived from (–)-menthone obtained
in this work and comparison with literature data.
It should be noted that the two α-acetoxy-(–)- and -(+)-
menthone isomers 2b and 2d were solid compounds and
that the previously attributed absolute configuration of the
former was fully confirmed by X-ray diffraction analysis
(see the Supporting Information). Isolation of the four ste-
reoisomeric α-acetoxy-(–)- and -(+)-menthones 2a, 2b, 2c
and 2d and of the four α-hydroxy-(–)- and -(+)-menthones
3a, 3b, 3c and 3d allowed the determination of their optical
rotations and comparison with those reported in the litera-
ture (Table 1). Curiously, the optical rotation of (2R,5R)-α-
acetoxymenthone 2a obtained in this work and that re-
Acetoxymenthone 2a
2b
This work, [α]2D5
–17.6 (c=0.39, MeOH) +121.6 (c=0.44, MeOH)
+24.4 (c=0.4, MeOH) +127.1 (c=0.39, MeOH)
Ref.[9] [α]2D5
Hydroxymenthone 3a
3b
This work, [α]2D5
–122.3 (c=2.8, CHCl3) +132.5 (c=2.0, CHCl3)
Ref.[9] [α]2D5
–32.5 (neat)
–30.9 (c=0.1, EtOH)
–128.2 (neat)
+72.5 (neat)
+72 (c=0.1, EtOH)
+114.2 (neat)
Ref.[10] [α]D25
Ref.[11] [α]D25
Ref.[12] [α]D25
–96.7 (neat)
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Figure 2. Relative Gibbs free energies during the silica-catalysed rearrangement of the less (1b) and the more reactive (1a) (–)-menthone
enol acetate epoxide (at the B3LYP/def2-TZVP level, gas phase; see the Supporting Information for details on thermodynamic calcula-
tions) in kJmol–1, the obtained products being α-acetoxy-(–)-menthone isomers 2b and 2a, respectively (TS: transition state, characterized
by frequency calculations).
compound, although this latter point is not clearly stated.[9]
This result suggested that the observed diastereoselection
We thus found in this work that the pure or nearly pure depended only on the intrinsic energies of each stereoiso-
(2R,5R)-α-acetoxymenthone diastereoisomer had a negative mer around the transition state.
optical rotation sign rather than the previously reported
positive one (Table 1).
The ultimate reason for such an important difference in
activation energy could be the existence of a steric clash
Finally, we were interested in the reasons for such a between the approaching acetoxy group carbonyl oxygen
stereoselective rearrangement. Silica could be ruled out as atom and the exposed pseudoaxial hydrogen atom at C-
a chiral auxiliary, so we investigated the energetics of the 3just before the creation of the new carbon–oxygen bond
reaction by computational DFT calculations. On the as- (Figure 3). Indeed, in the case of the more reactive dia-
sumption that the studied reactions occurred through stereoisomer 1a, this hydrogen atom is less likely to interfere
acetoxy group carbonyl oxygen atom attack on the distal with the attacking oxygen atom than in the case of the less
epoxide carbon atom with inversion of configuration,[7,8] reactive 1b, thus lowering the activation energy of the re-
the energies of the various conformers allowing such an at- arrangement.
tack were first calculated for both 1a and 1b (–)-menthone
enol acetate epoxide stereoisomers (see the Supporting In-
formation).
As expected, the conformation of lowest energy for each
diastereoisomer was that bearing the methyl group in a
(pseudo)equatorial position. Starting from these two con-
formations, the optimized structures for transition state and
products were determined (Figure 2). Frequency calcula-
tions allowed us access to kinetic and thermodynamic pa-
rameters of the reaction (see the Supporting Information).
First of all, the reaction was clearly exergonic and of the
same order for the two diastereoisomers. Secondly, a quite
Figure 3. Representative van der Waals radii of the approaching
acetoxy group carbonyl oxygen atom and the exposed pseudoaxial
important difference in ΔG# was observed for the two dif-
hydrogen atom at C-3 at the start of the reaction for the less reac-
tive (left, 1b) and the more reactive (right, 1a) (–)-menthone enol
acetate epoxides.
ferent diastereoisomers, in line with the observed experi-
mental data and, a priori, ruling out silica surface discrimi-
nation between the two diastereoisomers 1a and 1b (see the
Supporting Information). Indeed, the calculated nearly
14 kJmol–1 ΔΔG# value was sufficient to explain the ob-
served stereoselection of the reaction, the thermodynamics
establishing a rate constant (at 25 °C) for the more reactive
stereoisomer 1a 300 times higher than that for 1b.
Conclusions
We have discovered a very unexpected, easy to conduct
and highly diastereoselective silica-catalysed rearrangement
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Easy Access to the Four α-Hydroxymenthone Stereoisomers
acetate [(5R)-5-methyl-2-(propan-2-yl)cyclohex-1-en-1-yl acetate]
as a colourless oil (495.8 mg, 2.53 mmol, yield 86%). [α]2D5 = +76.9
(c = 2.8, CHCl3). H NMR (300 MHz): δ = 0.92 (d, J = 7.0 Hz, 6
H), 0.97 (d, J = 6.3 Hz, 3 H), 1.15–1.28 (m, 1 H), 1.66–1.89 (m, 3
H), 1.99–2.11 (m, 3 H), 2.12 (s, 3 H), 2.71 (sept, J = 7.0 Hz, 1 H)
ppm. 13C NMR (75 MHz): δ = 20.0, 20.4, 20.9, 21.3, 22.0, 26.9,
29.2, 30.6, 35.5, 128.6, 139.9, 169.4 ppm. HRMS (ESI-MS): calcd.
for C12H20O2 [M + H]+ 197.1536; found 197.1536.
of (–)- and (+)-menthone enol acetate epoxides (1a+1b and
1c+1d). This diastereoselective process could be used in a
convergent manner leading to (2R,5R)-α-hydroxymenthone
(3a) or (2S,5S)-α-hydroxymenthone (3c), respectively, in
high yields and with high diastereoisomeric excesses. This
process could also be used in a more classical way, allowing
the synthesis of all four α-hydroxymenthone stereoisomers,
two by two, depending on the starting material, once again
with very high diastereoisomeric excesses. It should be
noted that the formed acyloins each contain a newly formed
tertiary alcohol stereocentre α to a ketone, a motif of sub-
stantial interest. The unambiguous absolute configuration
assignment of all four α-hydroxymenthone stereoisomers
and their corresponding acetoxy derivatives (through VCD
and X-ray diffraction studies) allowed clarification of some
literature inconsistency about the latter. Furthermore, this
silica-catalysed rearrangement could be conducted with or
without solvent; in the latter case the reaction could take
place in as little as 2 h and is thus particularly ecofriendly.
Finally, computational energetic calculations (DFT) have
shown that with diastereoisomeric mixtures of either (–)- or
(+)-menthone enol acetate epoxides, one of the diastereo-
isomers (the one found to be experimentally more reactive –
1a and 1c, respectively) is energetically favoured during this
rearrangement.
1
The same procedure was used with (+)-menthone (440.2 mg,
2.86 mmol), giving the corresponding (+)-menthone enol acetate
[(5S)-5-methyl-2-(propan-2-yl)cyclohex-1-en-1-yl acetate] as
a
colourless oil (473.5 mg, 2.42 mmol, yield 84.5%). [α]2D5 = –79.5 (c
= 2.2, CHCl3).
Menthone Enol Acetate Epoxidation: In a 100 mL round-bottomed
flask, (–)-menthone enol acetate (468.9 mg, 2.39 mmol) was dis-
solved in dichloromethane (20 mL). The solution was stirred and
cooled in an ice/water bath, and a solution of m-chloroperbenzoic
acid (1.0662 g, 6.18 mmol, 2.6 equiv.) in dichloromethane (30 mL)
was then added dropwise from a separating funnel (the last mL,
containing the hydration water of the m-chloroperbenzoic acid, was
retained). The reaction mixture was then stirred at room temp. for
1 h. A sodium thiosulfate solution (10 mL, 10%, w/v) was added,
and the mixture was stirred vigorously for another 20 min. The
reaction mixture was washed with a hydrogencarbonate solution
(3ϫ 50 mL, 10%, w/v), and the combined water phases were back-
extracted with diethyl ether (2ϫ 50 mL). The combined organic
phases were dried (MgSO4), filtered, concentrated and purified by
FC [diethyl ether in n-pentane (10%)] to afford a mixture of (–)-
menthone enol acetate epoxide diastereoisomers [1a+1b, 1a =
(1S,2R,5R)-1,2-epoxy-5-methyl-2-(propan-2-yl)cyclohex-1-yl acet-
ate, 1b = (1R,2S,5R)-1,2-epoxy-5-methyl-2-(propan-2-yl)cyclohex-
1-yl acetate] as a colourless oil (443.2 mg, 2.09 mmol, yield 87.4%,
diastereoisomeric excess of 1a 26.5%).
Experimental Section
Caution: Numerous products described below are extremely vola-
tile, especially the acetates.
Application of the same procedure to (+)-menthone enol acetate
(392.7 mg, 1.78 mmol) afforded a mixture of diastereoisomers
[1c+1d, 1c = (1R,2S,5S)-1,2-epoxy-5-methyl-2-(propan-2-yl)cyclo-
hex-1-yl acetate, 1d = (1S,2R,5S)-1,2-epoxy-5-methyl-2-(propan-2-
yl)cyclohex-1-yl acetate] as a colourless oil [378.2 mg, 1.78 mmol,
yield 89.2%, de of 1c (1S,2R,5S)-1,2-epoxy-5-methyl-2-(propan-2-
yl)cyclohex-1-yl acetate 26.4%].
General: Commercially available reagents were used without further
purification except for n-pentane, which was freshly distilled before
use. (–)-Menthone, (+)-menthone, p-toluenesulfonic acid and
NaHCO3 were purchased from Sigma–Aldrich, m-chloroperbenz-
oic acid and acetic anhydride were purchased from Acros Organics,
and sodium thiosulfate was purchased from Prolabo. Flash
chromatography (FC) was performed with silica gel 60 from Merck
(230–400 mesh). When specifically stated, the silica gel 60 was acti-
vated by heating under vacuum (5 mbar) at 250 °C for 3 h. NMR
spectra were recorded in CDCl3, with Bruker spectrometers at op-
erating frequencies of 300 MHz (1H) or 75 MHz (13C) as indicated
in the individual spectra. Chemical shifts (δ) are given in ppm rela-
tive to TMS and coupling constants (J) in Hz. Multiplicities are
tabulated as s for singlet, d for doublet, t for triplet, sept for septup-
let, and m for multiplet. Optical rotations were measured with a
Perkin–Elmer 241 polarimeter with use of the yellow sodium D line
at 589 nm in a 1 dm pathlength cuvette. Diastereoisomeric excesses
were determined by GC analysis with a GC2010 Shimadzu system
and a CyclosilB column (Agilent technology, length 60 m, internal
diameter 0.25 mm, film 0.25 μm) at the following temperatures:
tinjector = 180 °C; tcolumn = 150 °C; tFID = 220 °C. The differences
in FID detection for all four α-hydroxymenthone diastereoisomers
(3a, 3b, 3c, 3d) were checked and found to be less than 1%.
General Procedure for the Kinetic Study of the Rearrangement of the
Mixture of (–)-Menthone Enol Acetate Epoxide Diastereoisomers on
Silica Gel: A mixture of (–)-menthone enol acetate epoxide dia-
stereoisomers 1a+1b (30 mg, 0.28 mmol) was dissolved in dichloro-
methane (2 mL) in a 10 mL round-bottomed flask. Silica gel (acti-
vated or not) was added (300 mg, 10 mass equiv.), and the suspen-
sion was stirred at the required temperature. For the experiments
without solvent, the dichloromethane was removed under vacuum,
and the flask was maintained at the desired temperature. To moni-
tor the reaction, suspension (100 μL, or ca. 20 mg of silica gel for
experiments without solvent) was withdrawn and placed in a
Pasteur pipette plugged with cotton. The liquid was drained, and
the silica gel was eluted with methanol (3ϫ 100 μL). The liquid
phases were pooled, and sodium methoxide (30% in methanol,
50 μL) was added. The reaction mixture was incubated at room
temp. for 1 h, diluted with water (400 μL) and extracted with di-
ethyl ether (400 μL). The organic phase was analysed by GC to
determine the diastereoisomeric excess of formed α-hydroxymen-
thones 3a and 3b.
Menthone Enol Acetate Formation: In a 10 mL round-bottomed
flask, (–)-menthone (459.4 mg, 2.98 mmol), acetic anhydride
(2 mL, 21.18 mmol, 7 equiv.) and p-toluenesulfonic acid (200 mg,
1.16 mmol, 0.4 equiv.) were stirred at 110 °C for 1 h. The reaction
mixture was allowed to cool to room temp. and purified by FC
[diethyl ether in n-pentane (5%)] to afford the (–)-menthone enol
Specific Rearrangement of Menthone Enol Acetate Epoxide on Silica
Gel: A mixture of (–)-menthone enol acetate epoxide diastereoiso-
mers 1a+1b (604.2 mg, 2.85 mmol) was dissolved in dichlorometh-
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ane (40 mL) in a 100 mL round-bottomed flask. Activated silica
gel (6 g, 10 mass eq.) was suspended in this solution, and the
dichloromethane was removed under vacuum to adsorb the prod-
ucts on the silica gel. The reaction mixture was then incubated at
9 °C for 15 h. The silica gel was placed in a flash column, and the
products were eluted with diethyl ether (60 mL). The solvent was
removed under vacuum, and the mixture was purified by FC (se-
quential elution with n-pentane/diethyl ether 95:5, 90:10 and 80:20
mixtures) to afford 1b (213.7 mg, 1.01 mmol, yield 35.4%) and 2a
(334.2 mg, 1.58 mmol, yield 55.3%).
Rearrangement of 1b and 1d on Silica Gel: Compound 1b (199.3 mg,
0.94 mmol) was dissolved in dichloromethane in a 50 mL round-
bottomed flask. Silica gel (2 g, 10 mass-equiv.) was suspended in
the mixture, and the solvent was removed under vacuum. The reac-
tion mixture was heated at 80 °C for 6 h, allowed to cool to room
temp. and placed on a flash column. The product was eluted with
diethyl ether (60 mL), concentrated and purified by FC [diethyl
ether in n-pentane (20%)] to afford 2b = (2S,5R)-5-methyl-1-oxo-
2-(propan-2-yl)cyclohexyl acetate as a white solid (172.8 mg,
0.82 mmol, yield 86.7%), m.p. 78 °C, de Ͼ 99%. [α]2D5 = +137.4 (c
1
= 2.2, CHCl3) and +122.4 (c = 3.0, MeOH). H NMR (300 MHz):
(1S,2R,5R)-1,2-Epoxy-5-methyl-2-(propan-2-yl)cyclohex-1-yl Acet-
ate (1b): Colourless oil, de Ͼ 99%. [α]2D5 = +86.5 (c = 2.9, CHCl3).
1H NMR (300 MHz): δ = 0.88 (d, J = 6.6 Hz, 3 H), 0.97 (d, J =
7.1 Hz, 3 H), 1.04 (d, J = 6.9 Hz, 3 H), 1.07 (td, J = 12.4, 4.6 Hz,
1 H), 1.30–1.41 (m, 1 H), 1.49–1.95 (m, 5 H), 2.07 (s, 3 H), 2.19
(ddd, J = 1.6, 6.2, 14.4 Hz, 1 H) ppm. 13C NMR (75 MHz): δ =
17.6, 18.8, 21.1, 21.5, 22.2, 27.0, 28.1, 29.5, 38.3, 69.3, 88.7,
169.7 ppm. GC: tR = 7.9 min. HRMS (ESI-MS): calcd. for
C12H20O3 [M + H]+ 213.1485; found 213.1487.
δ = 0.83 (d, J = 6.8 Hz, 3 H), 1.00 (d, J = 6.4 Hz, 3 H), 1.03 (d, J
= 6.8 Hz, 3 H), 1.32–1.49 (m, 1 H), 1.76–1.88 (m, 1 H), 1.92–2.18
(m, 3 H), 2.06 (s, 3 H), 2.22 (sept, J = 6.8 Hz, 1 H), 2.50–2.68 (m,
2 H) ppm. 13C NMR (75 MHz): δ = 16.3, 16.4, 21.5, 21.7, 30.3,
31.0, 31.2, 32.4, 48.5, 87.1, 169.9, 205.2 ppm. C12H20O3 (212.29):
calcd. C 67.89, H 9.50; found C 67.99, H 9.70. GC: tR = 12.1 min.
CCDC-860415 (2b) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(2R,5R)-5-Methyl-1-oxo-2-(propan-2-yl)cyclohexyl Acetate (2a):
Colourless oil, de Ͼ 99%. [α]2D5 = –20.1 (c = 2.9, CHCl3) and –18.5
1
Application of the same procedure to the (+)-menthone-derived
compound 1d (141.2 mg, 0.67 mmol) afforded 2d [= (2R,5S)-5-
methyl-1-oxo-2-(propan-2-yl)cyclohex-2-yl acetate] as a white solid
(116.7 mg, 0.55 mmol, yield 82.1%), m.p. 77.5 °C, de = 97.8%.
[α]2D5 = –133.2 (c = 1.5, CHCl3). GC: tR = 12.2 min.
(c = 5, MeOH). H NMR (300 MHz): δ = 0.83 (d, J = 6.9 Hz, 3
H), 0.98 (d, J = 6.8 Hz, 3 H), 1.04 (d, J = 6.6 Hz, 3 H), 1.49–1.77
(m, 3 H), 1.86–2.03 (m, 1 H), 2.10 (s, 3 H), 2.14–2.40 (m, 3 H),
2.58 (sept, J = 6.9 Hz, 1 H) ppm. 13C NMR (75 MHz): δ = 17.0,
17.8, 21.1, 21.6, 28.9, 29.6, 30.4, 34.7, 47.5, 86.9, 170.0, 206.9 ppm.
C12H20O3 (212.29): calcd. C 67.89, H 9.50; found C 67.69, H 9.53.
GC tR = 12.5 min.
Representative Procedure for the Acetate Methanolysis: Compound
2a (162.6 mg, 0.77 mmol) was dissolved in methanol (10 mL) and
sodium methoxide (2 mL, 30% in methanol) in a 50 mL round-
bottomed flask. The solution was stirred at room temp. for 1 h.
The reaction mixture was diluted with water (50 mL), extracted
with diethyl ether (3ϫ 50 mL), dried, concentrated and purified by
FC [diethyl ether in n-pentane (20%)] to afford 3a [= (2R,5R)-2-
hydroxymenthone] as a colourless oil (107.8 mg, 0.63 mmol, yield
82.7%), de Ͼ 99%. [α]2D5 = –122.3 (c = 2.8, CHCl3). 1H NMR
(300 MHz): δ = 0.70 (d, J = 6.8 Hz, 3 H), 0.96 (d, J = 7.2 Hz, 3
H), 1.01 (d, J = 6.7 Hz, 3 H), 1.46–1.57 (m, 1 H), 1.67 (td, J =
13.9, 4.0 Hz, 1 H), 1.97 (tt, J = 13.9, 4.3 Hz, 1 H), 2.14–2.30 (m, 3
H), 2.41–2.56 (m, 1 H), 2.72 (dd, J = 13.2, 6.4 Hz, 1 H), 3.78 (s, 1
H) ppm. 13C NMR (75 MHz): δ = 15.5, 16.2, 18.8, 27.9, 30.9, 32.3,
33.0, 44.4, 80.7, 215.0 ppm. GC tR = 7.0 min. HRMS (ESI-MS):
calcd. for C10H18O2 [M + H]+ 171.1380; found 171.1386. The spec-
troscopic data are in agreement with those in ref.[10]
The same procedure was applied to the mixture of (+)-menthone
enol acetate epoxide diastereoisomers 1c+1d (605.1 mg, 2.85 mmol)
to afford 1d (202.3 mg, 0.95 mmol, yield 33.4%) and 2c (341.2 mg,
1.61 mmol, yield 56.4%), both as colourless oils.
(1R,2S,5S)-1,2-Epoxy-5-methyl-2-(propan-2-yl)cyclohex-1-yl Acet-
ate (1d): de Ͼ 99%. [α]2D5 = –101.8 (c = 2.4, CHCl3). GC: tR
=
8.6 min.
(2S,5S)-5-Methyl-1-oxo-2-(propan-2-yl)cyclohex-2-yl Acetate (2c):
de Ͼ 99%. [α]2D5 = +23.9 (c = 2.7, CHCl3). GC: tR = 12.6 min.
Convergent Synthesis of (2R,5R)- and (2S,5S)-2-Hydroxymenthone
(3a and 3c) by Starting from Mixtures of (–)- and (+)-Menthone
Enol Acetate Epoxide Diastereoisomers: A mixture of (–)-menthone
enol acetate epoxide diastereoisomers 1a+1b (313.9 mg, 1.48 mmol)
was dissolved in dichloromethane (20 mL) in a 50 mL round-bot-
tomed flask. Silica gel (3 g, 10 mass-equiv.) was suspended in this
solution, and the reaction mixture was stirred at 23 °C for 44 h.
The mixture was placed in a flash column, the dichloromethane
was drained, and the silica was washed with diethyl ether (60 mL)
to recover all the products. The organic phases were pooled, and
the solvent was removed under vacuum. The products were dis-
solved in methanol (15 mL), and sodium methoxide (30% in meth-
anol, 3 mL) was added. The reaction mixture was stirred at room
temp. for 1 h, diluted with water (150 mL) and extracted with di-
ethyl ether (3ϫ 50 mL). The organic phases were pooled, the sol-
vent was removed under vacuum, and the reaction mixture was
purified by FC [diethyl ether in n-pentane (20%)] to afford 3a as
a colourless oil (247.6 mg, 1.46 mmol, yield 98.6%) with a de of
95.1%.
Application of the same procedure to the (+)-menthone-derived
compound 2c (162.6 mg, 0.77 mmol) afforded 3c [= (2S,5S)-2-hy-
droxymenthone] as a colourless oil (107.8 mg, 0.63 mmol, yield
81.8%), de = 97.8%. [α]2D5 = –133.2 (c = 2.2, CHCl3). GC: tR
=
7.1 min.
Methanolysis of compound 2b (69 mg, 0.33 mmol) afforded 3b [=
(2S,5R)-2-hydroxymenthone] as colourless oil (48.6 mg,
a
0.29 mmol, yield 88%), de Ͼ 99%. [α]2D5 = +132.5 (c = 2.0, CHCl3).
1H NMR (300 MHz): δ = 0.69 (d, J = 6.8 Hz, 3 H), 1.00 (d, J =
6.7 Hz, 3 H), 1.07 (d, J = 6.4 Hz, 3 H), 1.38–1.52 (m, 2 H), 1.64–
1.78 (m, 1 H), 1.81–1.99 (m, 1 H), 2.12–2.37 (m, 3 H), 2.46 (ddd,
J = 13.1, 4.3, 2.2 Hz, 1 H), 3.77 (s, 1 H) ppm. 13C NMR (75 MHz):
δ = 15.3, 16.0, 22.2, 30.7, 30.9, 36.2, 37.1, 46.1, 80.3, 214.6 ppm.
GC: tR = 6.4 min. The spectroscopic data are in agreement with
those in ref.[10]
Application of the same procedure to the (+)-menthone enol acet-
ate diastereoisomers 1c+1d (306.4 mg, 1.45 mmol) afforded 3c as
a colourless oil (241.9 mg, 1.42 mmol, yield 98.5%) with a de of
95.3%.
Application of the same procedure to the (+)-menthone-derived
compound 2d (76.8 mg, 0.36 mmol) afforded 3d [= (2R,5S)-2-hy-
droxymenthone] as a colourless oil (48.7 mg, 0.29 mmol, yield
6
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Easy Access to the Four α-Hydroxymenthone Stereoisomers
80.6%), de = 96.8%. [α]2D5 = –121.5 (c = 1.3, CHCl3). GC: tR
6.2 min.
IR/VCD Analysis[13]
=
ΔZPVE and ΔE(T) are the differences in the zero point vibrational
energy (ZPVE) and in the temperature corrections for the energy
[E(T)], respectively.
ΔG‡ = ΔH‡ – TΔS‡
IR and VCD Measurements: Infrared (IR) and vibrational circular
dichroism (VCD) spectra were recorded with a Bruker PMA 50
accessory coupled to a Vertex70 Fourier transform infrared spec-
trometer. A photoelastic modulator (Hinds PEM 90) set at l/4 re-
tardation was used to modulate the handedness of the circular pol-
arized light at 50 kHz. Demodulation was performed with a lock-
in amplifier (SR830 DSP). An optical low-pass filter (Ͻ 1800 cm–1)
before the photoelastic modulator was used to enhance the signal/
noise ratio. A transmission cell with CaF2 windows and a 210 μm
spacer were used. A solution of 3a was prepared by dilution of the
sample in CD2Cl2 to a concentration of 0.5 molL–1. The VCD
spectra of the cell filled with CD2Cl2 was used for baseline correc-
tion of the spectra of 3a. For each individual VCD spectrum, about
12000 scans were averaged at 4 cm–1 resolution (corresponding to
3 h measurement time). For the infrared spectrum the cell filled
with CD2Cl2 served as reference. The spectra are presented without
smoothing and further data processing in the Supporting Infor-
mation.
where ΔS‡ is the difference in the absolute entropies for the TS and
the reactant.
The first-order rate coefficient k(T) was then calculated by transi-
tion state theory (TST) under the assumption that the transmission
coefficient is equal to 1:
k(T) = (kBT/h) exp(–ΔG‡/RT)
where kB and h are the common Boltzmann and Planck constants.
Supporting Information (see footnote on the first page of this arti-
cle): Analytical data, IR/VCD analysis and computational details.
Acknowledgments
We are greatly indebted to Michel Giorgi (Aix-Marseille Université,
Spectropole case D11, UFR Sciences site de Saint Jérôme, 13397
Marseille Cedex 20, France) for performing X-ray diffraction stud-
ies.
Conformational Analysis: Calculations were performed on the
(2S,5R)-3b (= A) and (2R,5R)-3a (= B) diastereomers. The confor-
mational analysis and the calculation of Boltzmann populations
were performed with Density Functional Theory (DFT) and the
BLYP functional combined with the 6-31G(d) basis set (see the
Supporting Information).
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Chem. Res. 1999, 32, 837–845 and references cited therein b)
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A. C. Sheppard, B.-C. Chen, M. S. Haque, J. Am. Chem. Soc.
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Spectra Calculation: The geometry optimizations, vibrational fre-
quencies, IR absorption and VCD intensities were calculated with
Density Functional Theory (DFT) and the B3LYP functional com-
bined with the 6-31+G(d,p) basis set. Frequencies were scaled by
a factor of 0.98 with B3LYP. IR absorption and VCD spectra were
constructed from calculated dipole and rotational strengths with
the assumption of Lorentzian band shape with a half-width at half
maximum of 6 cm–1 (Figure SI1 in the Supporting Information).
All calculations were performed with Gaussian 09.[14]
Computational Details:[15] All calculations were performed with use
of the TURBOMOLE program package. They are based on den-
sity-functional theory (DFT) with the gradient-corrected exchange-
correlation functional BP (B-P86) in combination with the resolu-
tion-of-the-identity (RI) technique in a first exploratory step. A
standard basis step implemented in Turbomole def2-SV(P) was
used, in combination with the corresponding auxiliary basis set for
the RI. In a second step, hybrid functional B3LYP with a standard
polarized triple-zeta split-valence basis set def2-TZVP was used.
All geometries were optimized with a threshold of 10–6 a.u. The
m3 grid option of the Turbomole suite was used as a default.
[3] a) W. Adam, R. T. Fell, V. R. Stegmann, C. R. Saha-Moller, J.
Am. Chem. Soc. 1998, 120, 708–714; b) W. Adam, R. T. Fell,
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[7] For general reviews on enol ester epoxides, see: a) R. N. Mc-
Donald, Mech. Mol. Migr. 1971, 3, 67–107; b) J. J. Riehl, P.
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Frequency calculations [for BP/def2-SV(P) and B3LYP/def2-TZVP]
allowed stationary points to be characterized as energy minima or
transition states. Furthermore, under the assumption that the reac-
tion proceeded in the gas phase with ideal gas behaviour, frequency
calculations allowed us to determine the thermodynamic quantities
such as zero-point vibrational energy (ZPVE), temperature correc-
tions for the energy [E(T)] and the absolute entropies [S(T)] for all
reactants/products and transition states by standard methods. No
scaling factor was used for frequencies. The Gibbs energy change
between the reactant and the transition state (ΔG‡) was estimated
at given temperature T as follows:
[9] T. Suga, T. Shishiburi, T. Matsuura, J. Org. Chem. 1967, 32,
965–969.
[10] T. Suga, T. Hirata, H. Hamada, T. Matsuura, Phytochemistry
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ΔG‡ = ΔEelect + ΔZPVE + ΔE(T)
ΔEelect is the difference between the calculated electronic energy
extracted from the DFT calculation for TS and reactant, whereas
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G. Iacazio et al.
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H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Son-
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Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Starov-
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Received: March 30, 2012
Published Online: ᭿
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Easy Access to the Four α-Hydroxymenthone Stereoisomers
Selective Epoxide Opening
Epoxy enol acetates derived from menth-
one unexpectedly rearranged diastereose-
lectively on exposure to silica, giving easy
access to the complete set of α-hydroxy-
menthone stereoisomers. Two of the four
stereoisomers were also available through a
diastereoconvergent process. Finally, the
observed stereoselection was investigated
by DFT calculations.
S. Tranchimand, B. Faure, J.-V. Naubron,
V. Alphand, A. Archelas,
G. Iacazio* ........................................ 1–9
Silica-Catalysed and Highly Stereoselective
Convergent and Nonconvergent Re-
arrangements of Menthone Enol Acetate
Epoxides: Easy Access to the Four α-
Hydroxymenthone Stereoisomers
Keywords: Rearrangement / Chiral resol-
ution / Diastereoselectivity / Acyloins /
Menthone
Eur. J. Org. Chem. 0000, 0–0
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