Synthesis and characterization of atropisomers arising from 1,3-cyclohexanediones by intermolecular tandem-Michael/Michael additions

Article abstract of DOI:10.1002/ejoc.200700803

Intermolecular tandem-Michael/Michael addition reactions of alkyne acceptors and CH-acidic compounds such as 1,3-cyclohexanedione (2a) and dimedone (2b) under L-proline catalysis furnished four new products 1a-d with C ₂ axial chirality. Wiley-

Full text of DOI:10.1002/ejoc.200700803

FULL PAPER
DOI: 10.1002/ejoc.200700803
Synthesis and Characterization of Atropisomers Arising from 1,3-
Cyclohexanediones by Intermolecular Tandem-Michael/Michael Additions
Liliana E. Luna,[a] Gustavo Seoane,[b] and Raquel M. Cravero*[a]
Keywords: Tandem reactions / Michael addition / Cyclohexanediones / Alkynes / Chirality / Atropisomerism
Intermolecular tandem-Michael/Michael addition reactions
of alkyne acceptors and CH-acidic compounds such as 1,3-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
cyclohexanedione (2a) and dimedone (2b) under L-proline
catalysis furnished four new products 1a–d with C2 axial chi-
rality.
Introduction
tandem-1,4-additions mediated by phosphanes or aryl thio-
The double Michael reaction is a useful synthetic strat- lates were reported by Murphy and co-workers.[6]
egy in organic synthesis that allows the atom-economic con-
Perhaps the most familiar example was provided by the
struction of complex carbon frameworks through the for- pioneering work of Stork and Tomasz on the concise syn-
mation of two bonds in one step, for example, the trans- thesis of griseofulvin which they obtained from an active
decalins and trans-hydrindanes.[1,2] This reaction has also methylene compound and a cross-conjugated enynone.[7]
been applied to the construction of the carbon skeletons of However, intermolecular C2-symmetric tandem-Michael/
different natural products such as (Ϯ)-cedranediol,[3] (–)- Michael products 1a–d (Scheme 1) derived from the reac-
epibatidine,[4] and substituted piperidinones.[5] Recently, tions of β-dicarbonyl compounds 2 with alkynes are un-
Scheme 1. Preparation of 1 by a tandem-Michael/Michael process. Reagents and conditions: ϵ–C(O)R1 (R1 = CH3, OCH3), DMSO, cat.
-proline, room temp.
known and might prove to be valuable structures for asym-
metric synthesis.
[a] IQUIR (Instituto de Química de Rosario), Facultad de Ciencias
Bioquímicas y Farmacéuticas, Universidad Nacional de Rosa-
rio-Suipacha 531,
In connection with our study on the synthesis of polycy-
clic compounds of biological interest[8] we now report the
preparation, structural analysis, and properties of new atro-
pisomeric products 1. These compounds were obtained
from the chiral enaminones of 1,3-cyclohexanediones 2[9]
S2002LRK Rosario, Argentina
Fax: +54-341-4370477
E-mail: rcravero@fbioyf.unr.edu.ar
[b] Departamento de Química Orgánica, Facultad de Química,
Universidad de la República,
CC 1157, Montevideo, Uruguay
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L. E. Luna, G. Seoane, R. M. Cravero
FULL PAPER
with activated π systems like Michael acceptors (methyl The nucleophilic attack on A was assumed to take place on
propiolate and butynone). It is interesting to recall here the less hindered face of the double bond (Si face), anti to
that, as in compounds 1, a 1,3-dione motif is found in the carboxy substituent borne by the proline moiety.
cordypyridones A and B, two natural products that are
In the same manner as the alumina method (Scheme 2),
atropisomers of each other which exhibit potent in vitro it is evident that there is competition between two possible
antimalarial activity.[10]
reactions when a new Michael acceptor is generated and it
reacts with a second diketone (or the corresponding enami-
none) instead of methyl propiolate, directing the reaction
towards the preferential formation of 1a whenever 1–
Results and Discussion
At first we found that the treatment of 2a with methyl 10 mmol of dione were used.
propiolate and Cs2CO3[11] in THF/DMF (1:1) at room tem-
This hypothesis was supported by measurement of the
perature gave rise to the monoadducts 3, with the E isomer product concentration P versus reaction time by the per-
being predominant (18:1, E:Z ratio), after isolation by care- iodic spectral lecture NMR method. Thus, equivalent
ful column chromatography (Scheme 2). After that, based amounts of 2a and methyl propiolate in [D6]DMSO under
on our previous work on solid-support addition,[8b] we used catalysis with -proline were placed in a NMR tube and
methyl propiolate on alumina at room temperature. Thus, shaken at room temperature (Figure 1).
under magnetic stirring or sonication, an interesting tan-
In Figure 1 (top) it is possible to see that after 13 d (ap-
dem conjugate addition took place to give the chiral prod- prox. 350 h) of reaction, recording two sets of spectroscopic
uct 1a together with the minor adduct 3 (Scheme 2).
data a day, monitoring of the CH and OCH3 signals by
After several attempts the reaction of 2a with methyl pro- 1H NMR indicated a progressive conversion of the starting
piolate on a solid support gave the best results under sonic- material into P without detection of the monoadduct A. A
ation with a 1:1.1 ratio of 2a/alkyne; the pure products 1a time course for the reaction is illustrated in Figure 1 (bot-
1
and 3 were obtained in 25 and 6% yields, respectively. These tom) with the stack plot of H NMR spectra recorded dur-
results encouraged us to carry out the amine-catalyzed ad- ing the experiment. The product formation was determined
dition of 2a to methyl propiolate using -proline in DMSO by integration of the signals arising from the methine pro-
at room temperature under magnetic stirring;[12] compound ton and the methoxy group at δ = 4.50 and 3.70 ppm,
1a was generated in 65% yield as the sole isolated product. respectively. We also verified the proposed mechanism with
We rationalized that 1a was formed by means of an inter- the preparation and isolation of the enaminone resulting
molecular double Michael reaction via the sp2 acceptor A from the reaction of 2a with -proline,[13] showing that chi-
generated in situ, which then undergoes another addition ral induction involved a covalent bond and that this enami-
by a second molecule of the enaminone donor (Scheme 3). none then reacted with methyl propiolate to afford P.
Scheme 2. Michael addition of 2a to methyl propiolate in solution and on a solid support.
Scheme 3. Mechanism for the Michael/Michael addition of 2a.
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Atropisomers from 1,3-Cyclohexanediones
1
absorption peaks observed as duplicate signals in the H
NMR spectrum indicated a slow tautomeric interconver-
sion at room temperature (Figure 2). Hence, variable-tem-
perature NMR experiments carried out at temperatures
ranging from 37 to 52 °C showed us that the equilibrium is
so fast that the protons labeled with a and aЈ with of the
enol moieties are magnetically equivalent, whereas at lower
temperatures (from 7 to –23 °C) the experiment revealed
two sets of signals for Ha, HaЈ, and CH2, confirming the
two rings have different magnetic environments. The enolic
hydroxy proton peak at δ = 13 ppm, observed as a singlet
at 7 °C, was shifted upfield and became two singlets cen-
tered at 13 and 12.5 ppm at –43 °C.
Figure 2. Tautomerization process for the dicarbonyl compounds
1.
Figure 1. Top: concentration of P, as determined by methine signal
integration, vs. reaction time when tandem-Michael addition of 2a
was carried out by catalysis with -proline. Bottom: 1H NMR spec-
tral stack plot of the reaction 2aǞP recorded by the periodic spec-
tral lecture 1H NMR method. The behavior of the OCH3 (δ =
3.70 ppm) and CH (δ = 4.50 ppm) groups of P during the reaction
was considered in the calculation of the degree of conversion.
To gain more structural information we performed mo-
lecular modeling studies on 1a. The molecule was mini-
mized by using the B3LYP/6-31+G(d,p) basis set, as de-
scribed in the Exp. Section, and the result is shown in Fig-
ure 3 (bottom). As can be seen, it shows a 3D arrangement
with an out-of-plane anti orientation of the vinylogous
groups in both rings with an angle between them of –21°.
With regard to the molecular structure, 1a has restricted It also exhibits additional stabilization through two intra-
rotation around the C2(sp2)–C3(sp3) bond (Scheme 2, arbi- molecular hydrogen bonds. This structure has been super-
trary numbering) giving rise to conformational chirality, imposed with the recently published crystal structure of
that is, atropisomerism,[14] with the rings forced into dif- 2,2Ј-methylenebis(3-hydroxy-5,5-dimethylcyclohex-2-en-1-
ferent planes with all groups being maintained in a tetrahe- one), which shows a similar arrangement of the bicyclic sys-
dral arrangement in space with a C2 axis. Also, taking into tem.[17] Further evidence confirming the presence of a hy-
account the structural portion of the vinylogous acid (con- drogen bond is one broad and diffuse band at 3400 cm–1 in
jugate enol form), associated keto/enol tautomerism might the infrared spectra, which has been assigned to the pres-
be considered.[15,16] The structure of 1a was supported by ence of an enolic hydroxy group involved in intramolecular
1
IR spectroscopy, coupling constant analysis of the H and hydrogen-bonding.[18] Rotation around C1–C2–C3–H4 (cf.
13C NMR spectra, 2D NMR spectroscopy (HQBC and Scheme 2) was calculated to have a rotational barrier of
HMBC), selective irradiation, and mass spectrometry ex- 40 kcalmol–1 for the conformer with the lowest energy. The
periments. In the infrared spectra the absorption band at energy value determined for the conformer with the highest
1589 cm–1 and a hydroxy absorption band are strong evi- energy (at a dihedral angle of 210 °) is a consequence of the
dence for the presence of the enol form of the 1,3-dicar- strong steric hindrance between the carbonyl of the carbox-
1
bonyl compounds. In the H NMR spectrum recorded in ylate group and the carbonyl of one of the rings.
[D]chloroform the most significant signals, which fall at δ
All this evidence demonstrates the high stability of the
= 4.50 and 3.04 ppm, were assigned to the methine 3-H and minimum energy conformation. Also the high value found
the α-ester proton resonances, respectively, with an equiva- for the energy barrier permitted speculation about the pres-
3
lent coupling constant J = 7.5 Hz. Selective irradiation of ence of atropisomerism. In addition, these compounds
the doublet centered at δ = 3.04 ppm removed its coupling show low optical rotations [α]D which are also temperature-
effect with the neighboring 3-H to give a singlet. In ad- dependent.
1
dition, the presence of the signal at δ = 12 ppm in the H
The CD spectrum of 1a revealed the existence of one
NMR spectrum together with the signals of the sp2 carbons optically active species with a positive multiple Cotton ef-
at 196.9, 172.2, and 114.2 ppm in the 13C NMR spectra are fect near 245 and 300 nm which correlates with the πǞπ*
consistent with the vinylogous acid portion. Some of the UV absorption of an α,β-unsaturated ketone.[19]
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L. E. Luna, G. Seoane, R. M. Cravero
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Figure 3. Top: superimposed conformational energy diagram for
1a: single point (AM1), Hartree–Fock (HF), and (density func-
tional theory, DFT). Bottom: representation of the global mini-
mum energy conformation of 1a.
Figure 4. Top: ORTEP plot showing the structure of the derivative
4 in the solid state obtained from a single-crystal X-ray analysis.
Bottom: structure of 4.
An attempt at X-ray analysis of 1 failed due to the low this structure, corresponding to a substituted decahydrox-
quality of the crystals obtained. Also, several alkylsilyloxy anthene, is shown in Figure 4.
derivatives of 1 were prepared, but they were isolated as
The formation of tricyclic derivative 4 is consistent with
oils at room temperature. Finally, the reaction of 1a with a diazomethane-mediated vinylogous esterification followed
diazomethane and careful crystallization from ethanol gave by a 1,4-addition to the newly formed ester portion origi-
the methylated derivative 4 which was submitted to single- nating a new ring. The formation of this six-membered ring
crystal X-ray diffraction analysis.[20] An ORTEP drawing of (center ring of the xanthene skeleton) imposes new confor-
Scheme 4. Reaction mechanism for the transformation 1Ǟ4 with diazomethane in methanol.
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Eur. J. Org. Chem. 2008, 1271–1277

Atropisomers from 1,3-Cyclohexanediones
(Na2SO4), filtered, and concentrated. Flash chromatography of the
residue on silica gel (hexane/EtOAc) gave 62–68% of pure crystal-
line 1.
mational restraints causing the separation of the other car-
bonyl and enolic hydroxy groups. As a consequence, the
remaining hydrogen bond is broken and the isolated enol
group tautomerizes to the more stable ketone with the pro-
ton disposed to form a cis junction (Scheme 4).[21]
Thus, the structural characterization of derivative 4 lends
support to the proposed structure of parent compound 1a.
The presence of optical activity in derivative 4 indicated to
us that the transformation 1aǞ4 occurred through a selec-
tive mode of attack on one of the enolic forms thus pre-
venting racemization.
1-(3-Oxocyclohex-1-enyl)pyrrolidine-2-carboxylic Acid (Enami-
none): A solution of 2a (112 mg, 1 mmol) and -proline (115 mg,
1 mmol) in benzene (5 mL) was heated at reflux with azeotropic
removal of water using a Dean–Stark apparatus for 5 h. The sol-
vent was then evaporated and the residue distilled under vacuum
to give enaminone as a pale-yellow oil in quantitative yield after
purification by flash chromatography (EtOAc/EtOH, 50:50). [α]2D2
= +102.6 (c = 2.5, Cl CH), IR (film): ν = 3416 [–C(O)–OH], 2951,
˜
3
1718 [–C(O)–OH], 1580 (enaminone), 1542, 1534 (C=C), 1437,
1336, 1198, 1145, 668 cm–1. 1H NMR (CDCl3): δ = 10.1 (br. s, 1
H, acid H), 5.37 (s, 1 H, 2Ј-H), 4.26 (t, J = 4.4 Hz, 1 H, 2-H), 3.74
(m, 1 H, 5-H), 3.54 (m, 1 H, 5-H), 2.53 (m, 2 H, 6Ј-H), 2.31 (t, J
= 6.2 Hz, 2 H, 4Ј-H), 2.25 (m, 2 H, 3-H), 1.99 (m, 4 H, 4-H and
5Ј-H) ppm. 13C NMR (CDCl3): δ = 197.3 (C=O, enaminone), 173.1
(C=O acid), 166.8 (=C–N), 98.1 (C-2Ј), 61.9 (C-2), 49.2 (C-5), 34.1
(C-4Ј), 30.1 (C-6Ј), 27.8 (C-3), 23.5 (C-4), 21.5 (C-5Ј) ppm.
Compounds 1b–d exhibit similar behavior to that of 1a;
in the case of 1b, the side-chain permits the formation of a
hemiacetal.
Conclusions
In summary, we have developed a new route to the for-
mation of sp2–sp3 atropisomers by means of Michael ad-
dition reaction between 1,3-diones and alkynes. By catalysis
with -proline, an unusual intermolecular tandem process
was observed. Compounds 1a–d possess tautomerism as a
result of axial chirality around the C2–C3 bond (cf.
Scheme 2). We envision that this will allow us to design new
related compounds and to explore their applications in
asymmetric syntheses.
Compound P: To a solution of the enaminone (523 mg, 2.5 mmol)
in DMSO (1.8 mL) was added methyl propiolate (0.24 mL,
3 mmol). The reaction mixture was stirred at room temperature for
13 d. Water and EtOAc were added. The aqueous layer was ex-
tracted with EtOAc (5ϫ3 mL) and the organic layers were dried,
filtered, and concentrated. By flash chromatography compound P
was isolated in 75% yield as an oil. [α]2D5 = –3.30 (c = 0.72, Cl3CH).
IR (film): ν = 3400 [–C(O)–OH], 2945, 1736 [–C(O)–OMe], 1727
˜
[–C(O)–OH], 1654, 1609 (enaminone), 1436, 1398, 1172, 998 cm–1.
1H NMR (CDCl3): δ = 12.83 (br. s, 2 H, acid H), 4.46 (t, J =
7.6 Hz, 1 H), 3.86 (m, 2 H, 2-H), 3.70 (m, 4 H, 5-H), 3.67 (s, 3 H, –
OCH3), 3.03 (d, J = 7.6 Hz, 2 H, CH2CO2Me), 2.51–2.15 (complex
signal, 12 H), 2.00–1.88 (m, 8 H) ppm. 13C NMR (CDCl3): δ =
197.3 (C=O enaminone), 181.5 (–COOH), 172.0 (C=O ester), 168.7
(=C–N), 116.9 (=C–C=O), 52.7 (CH–COOH), 51.6 (–OCH3), 48.2
(CH2–N), 36.9 (CH2–C=O), 35.8 [CH2–C(O)–Me], 34.6 (CH2–
C=C–C=O), 28.4 (CH2–CH–N), 26.2 (–CH–CH2–CO2Me), 22.2
(CH2–CH2–N), 20.4 (CH2–CH2–C=O) ppm. MS (EI): m/z (%) =
502 (10) [M]+, 322 (25), 248 (23), 234 (27), 204 (82), 162 (93), 146
(50), 73 (100).
Experimental Section
General: Optical rotations: Jasco Model DIP 1000 polarimeter.
Melting points (uncorrected) were measured in open capillary tubes
with an Electrothermal 9100 apparatus. 1H and 13C NMR spectra:
NMR Bruker AC-200E and Bruker Avance 300 MHz spectrome-
ters in CDCl3. FTIR spectra: Shimadzu, Prestige 21 Model.
HPLCL Hewlett–Packard Series 1100 Model, LiChroCART® 250–
4 LiChrospher®100 RP-18 and ChiraDex® columns. A two-solvent
gradient elution was performed at a flow rate of 0.7–1 mLmin–1.
The solvent compositions used were (A) water/methanol and (B)
water/acetonitrile (v/v). All samples were microfiltered before injec-
tion. All solvents were HPLC grade. CD data were recorded in
MeOH (0.59ϫ10–6 ), absorbance 0.631 (λmax = 261 nm) on a Ja-
sco Model J-810 spectropolarimeter at the Department of Chemis-
try, University of Córdoba. HRMS: recorded at the UCR Mass
Spectrometry Facility, Department of Chemistry, University of
California, Riverside, USA. Ab initio calculations were performed
with Gaussian 98.[22] Rotational energy barrier calculation: a full
conformational search was performed on 1a by using the confor-
mation search algorithm as is implemented in Hyperchem® 6.0.[23]
The minimum was optimized by density functional calculations
using Gaussian 98[22] and the B3LYP/6-31+G(d,p) basis set and the
nature of the minimum was confirmed by vibrational analysis. The
energy barrier was calculated by single-point calculations every 30°
over the dihedral angle C1–C2–C3–H4 (Scheme 2).
Methyl 3,3-Bis(2-hydroxy-6-oxocyclohex-1-enyl)propionate (1a):
Flash chromatography of the residue on silica gel (hexane/EtOAc,
60:40) furnished white crystals; m.p. 126–127 °C. [α]2D2 = –3.84 (c =
0.1, Cl3CH). CD: [Φ]243 = 3300 (c = 0.06 m, MeOH). IR (film):
ν = 3400 (OH), 2954, 2360, 1731 (C=O, ester), 1589 (C=C enol of
˜
diketone), 1435, 1387, 1197, 1100 cm–1. 1H NMR (CDCl3): δ =
12.00 (br. s, 1 H), 4.50 (t, J = 7.3 Hz, 1 H), 3.62 (s, 3 H, OCH3),
3.04 (d, J = 7.5 Hz, 2 H), 2.40 (m, 8 H), 1.88 (br. s, 4 H) ppm. 13C
NMR (CDCl3): δ = 196.9 (C=O ketone), 172.2* (=C–OH), 165.8*
(C=O ester), 114.2 (C=C–OH), 51.0 (OCH3), 36.9 (CH2), 36.8
(CH2–C=O), 27.0 (CH2–COH), 23.6 (CH), 20.3 (CH2–CH2–
CH2) ppm. Signals marked with * may be interchanged. HRMS:
calcd. for C16H20O6 308.1260: found 309.1327 [MH]+.
Methyl
2-[(4aR,9R,9aS)-4a-methoxy-1,8-dioxo-2,3,4,4a,5,6,7,8,-
9,9a-decahydro-1H-xanthen-9-yl]acetate (4): Compound 1a (30 mg,
0.1 mmol) was dissolved in methanol (1 mL) and cooled to 0 °C.
A solution of diazomethane in ethyl ether was added and the mix-
ture stirred for 1 h as the temperature gradually raised to 25 °C.
The solvent was removed in vacuo to afford 4 as white solid, recrys-
General Procedure for the Synthesis of 1: A solution of -proline
(3.4 mg, 1.5 mol-%), the corresponding alkyne (2 mmol) in DMSO
(1.8 mL), and 1,3-cyclohexanedione 2 (2 mmol) was stirred at room
temperature for 13 d. EtOAc (2 mL) and a saturated NH4Cl solu-
tion (4 mL) were added and the aqueous layer was extracted with
EtOAc (4ϫ3 mL). The combined organic layers were dried
tallized from EtOH in quantitative yield; m.p. 129–130 °C. [α]2D6
=
–1.35 (c = 0.94, Cl CH). IR (film): ν = 2947, 2850, 1725 (C=O
˜
3
ester), 1718 (C=O ketone), 1653 (α,β-unsaturated ketone), 1628,
1549, 1437, 1385, 1165, 1097, 1078, 950, 663 cm–1. 1H NMR [(CD3)2-
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L. E. Luna, G. Seoane, R. M. Cravero
CO]: δ = 3.75 (m, 1 H), 3.65 (s, 3 H, –OCH3), 3.30 (s, 3 H, –OCH3), raphy (hexane/EtOAc, 70:30) gave isomers E (235.3 mg, 60%) and
FULL PAPER
3.08 (m, 1 H), 2.83 (m, 2 H), 2.55–2.20 (m, 8 H), 2.10–1.80 (m, 4
H) ppm. 13C NMR (CDCl3): δ = 204.7 (C=O), 197.3 (α,β-unsatu-
rated C=O), 173.7 (C=O ester), 166.8 (=C–O–C), 113.6 (C=C–O–
C), 103.3 (O–C–OMe), 54.1 and 51.3 (–OCH3), 49.0 (CH–C=O),
40.2 (CH2–C–OMe), 37.1 (CH2–C=O), 35.5 (CH2–C=O), 31.7
(CH2–CO2Me), 28.2 (CH2–C–O–C), 20.7 and 20.1 (CH2CH2-
C=O) ppm.
Z (12 mg, 3%) in a ratio of 18:1, respectively, as oils.
3a: IR (film): ν = 3456 (=C–OH), 2926, 1745 (ester), 1681 (unsatu-
˜
rated C=O), 1631(C=C), 1564, 1412, 1306, 1058, 760 cm–1. 1H
NMR (CDCl3): δ = 7.83 (d, J = 9.9 Hz, 1 H), 6.23 (d, J = 9.5 Hz,
1 H), 3.75 (OCH3), 2.87–1.50 (m, 7 H) ppm. 13C NMR (CDCl3): δ
= 191.6 and 190.9 (C=O, keto-enol), 172.5 (ester), 139.7 (C=CH–
CO2Me), 116.8 (C=CH–CO2Me), 51.4 (OCH3), 36.4 (CH), 34.6,
33.3, 32.6, 28.1, 26.1, 19.8 ppm.
2,2Ј-(3-Oxobutane-1,1-diyl)bis(3-hydroxycyclohex-2-enone)
(1b):
Flash chromatography of residue on silica gel (hexane/EtOAc,
3b: IR (film): ν = 3419 (=C–OH), 2922, 1732 (ester), 1635 (unsatu-
˜
70:30) gave white and pure crystals; m.p. 123–124 °C. [α]2D9 = –8.4
1
rated C=O), 1620(C=C), 1450, 1379, 935 cm–1. H NMR (D2O): δ
(c = 0.1, Cl CH). IR (film): ν = 3390 (OH), 2944, 2360, 1720 (C=O
˜
3
= 7.79 (d, J = 14.6 Hz, 1 H), 6.57 (d, J = 15.7 Hz, 1 H), 3.62 (s, 3
H, OCH3), 3.10–1.70 (m, 7 H) ppm. 13C NMR (CDCl3): δ = 192.0
and 190.7 (C=O, keto-enol), 173.0 (ester), 139.5 (C=CH–CO2Me),
115.6 (=C–CO2Me), 51.8 (OCH3), 36.6 (CH), 34.8, 33.0, 32.8, 28.4,
26.8, 19.1 ppm.
ketone), 1618 (C=O enol of diketone), 1592 (C=C enol of dike-
1
tone), 1435, 1389, 1100 cm–1. H NMR (CDCl3): δ = 12.7 (br. s, 1
H), 4.56 (t, J = 7.1 Hz, 1 H), 3.20 (d, J = 7.1 Hz, 2 H), 2.43–2.15
(m, 12 H), 2.10 [s, 3 H, C(O)CH3], 1.75–1.50 (m, 8 H), 1.40 [s, 3
H, C(OH)CH3] ppm. 13C NMR (CDCl3): δ = 206.4 (C=O ketone,
side-chain), 196.8 (C=O ketone, hemiketal), 191.8 and 190.7 (C=O,
keto-enol), 166.7 (=C–OC, hemiketal), 117.4 (C=C–OH), 117.3
(C=C–O–C, hemiketal), 99.8 [q, C(OH)CH3], 43.8 [CH2–C(O)-
CH3], 39.0 [CH2–C(OH)CH3], 37.8 (CH, hemiketal), 37.1 and 36.5
(CH2–C=O, ketone), 34.3 (CH2C=O, hemiketal), 33.2 and 32.5
(CH2–C=O keto-enol), 29.8 [C(O)CH3], 27.8 (CH2–O–C, hemike-
tal), 24.2 [C(OH)CH3], 24.0 (CH), 20.6, 19.7, and 18.3 (CH2–CH2–
CH2) ppm. HRMS: calcd. for C16H20O5 292.1311; found 293.1324
[MH]+.
Acknowledgments
We would like to thank the Consejo Nacional de Investigaciones
Científicas y Técnicas (CONICET) and the Agencia Nacional de
Promoción Científica y Técnica (ANPCYT) for financial support.
We also wish to thank Lic. S. A. Tindiglia and Dr. M. González-
Sierra for recording all the NMR spectra and Dr. Labadie for dis-
cussion.
Methyl 3,3-Bis(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)propi-
onate (1c): Flash chromatography of the residue on silica gel (hex-
ane/EtOAc, 75:25) gave white crystals; m.p. 82–83 °C. [α]3D2 = –0.12
[1] R. B. Grossman, M. A. Varner, A. J. Skaggs, J. Org. Chem.
1999, 64, 340–341, and references therein.
(c = 1.1, Cl CH). IR (film): ν = 3390, 2957, 2871, 1738 (C=O ester),
˜
3
[2] T. Nakamura, N. Waizumi, K. Tsuruta, A. Horiguchi, I. Kuwa-
jima, Synlett 1994, 584–586.
1596 (C=C enol of diketone), 1472, 1388, and 1369 (gem-dimethyl),
1
1168 cm–1. H NMR (CDCl3): δ = 12.40 (br. s, 1 H), 4.51 (t, J =
[3] K. Makita, K. Fukumoto, M. Ihara, Tetrahedron Lett. 1997,
7.7 Hz, 1 H), 3.59 (s, 3 H, OCH3), 3.05 (d, J = 7.7 Hz, 2 H), 2.26
38, 5197–5200.
and 2.25 [s, 8 H, –CH2C(O), keto-enol], 1.02 (br. s, 12 H) ppm. 13
C
[4] Y. Hoashi, T. Yabuta, Y. Takemoto, Tetrahedron Lett. 2004, 45,
9185–9188.
NMR (CDCl3): δ = 190.1 and 189.5 (keto-enol), 172.5 (C=O ester),
115.7 (C=C–OH), 51.6 (OCH3), 46.8 and 46.1 (CH2–C=O, keto-
enol), 34.3 (CH2–CO2Me), 31.0 [C(CH3)2], 29.8 (CH), 25.8
(CH3) ppm. HRMS: calcd. for C20H28O6 364.1886; found
365.1971[MH]+.
[5] K. Takasu, N. Nishida, M. Ihara, Tetrahedron Lett. 2003, 44,
7429–7432.
[6] P. M. Brown, N. Käppel, P. J. Murphy, Tetrahedron Lett. 2002,
43, 8707–8710.
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S. Popich, L. E. Luna, R. M. Cravero, M. González Sierra, A.
Bardón, Chem. Biodivers. 2006, 3, 21–26.
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1615; b) Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974, 39,
1615–1622.
[10] a) M. Isaka, M. Tanticharoen, P. Kongsaeree, Y. Thebtar-
anonth, J. Org. Chem. 2001, 66, 4803–4808; b) Y. Fujita, H.
Oguri, H. Oikawa, J. Antibiot. 2005, 58, 425–427.
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[12] B. List, P. Pojarliev, H. J. Martin, Org. Lett. 2001, 3, 2423–
2425.
[13] H. Iida, Y. Yuasa, C. Kibayashi, Synthesis 1982, 6, 471–472.
[14] E. L. Eliel, S. H. Wilen, Stereochemistry of Organic compounds,
Wiley-Interscience, New York, 1994.
[15] V. Lacerda Jr, M. G. Constantino, V. J. Silva Gil, C. F. Tor-
mena, A. Cunha Neto, J. Mol. Struct. 2007, 828, 54–58.
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Soc. Perkin Trans. 2 1993, 6, 1067–1071.
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o668.
2,2Ј-(3-Oxobutane-1,1-diyl)bis(3-hydroxy-5,5-dimethylcyclohex-2-en-
one) (1d): Flash chromatography of residue on silica gel (hexane/
EtOAc, 70:30) gave white crystals; m.p. 169–170 °C. [α]3D1 = +0.78
(c = 0.35, Cl CH). IR (film): ν = 3412 (OH), 2960, 1714 (C=O,
˜
3
ketone), 1597 (C=C enol of diketone), 1471, 1382, and 1373 (gem-
dimethyl), 1140 cm–1. 1H NMR (CDCl3): δ = 12.40 (br. s, 1 H),
4.57 (t, J = 7.3 Hz, 1 H), 3.22 (d, J = 7.3 Hz, 2 H), 2.28 [br. s, 8
H, CH2C(O), keto-enol], 2.11 [s, 3 H, C(O)CH3], 1.05 and 1.04 (s,
12 H) ppm. 13C NMR (CDCl3): δ = 206.3 (C=O ketone), 190.1 and
189.4 (C=O, keto-enol), 116.1 (C=C–OH), 46.8 and 46.1 (CH2–
C=O, keto-enol), 43.4 [CH2–C(O)CH3], 31.1[C(CH3)2], 30.0 (CH),
26.4 [C(O)CH3], 24.0 [C(CH3)2] ppm. HRMS: calcd. for C20H28O5
348.1937; found 349.2017 [MH]+.
Methyl (Z)- and (E)-3-(2,6-Dioxocyclohexyl)acrylate (3a and 3b):
Solid Cs2CO3 (869 mg, 2.6 mmol) was added to a solution of 2a
(224 mg, 2 mmol) in THF/DMF (1:1, 10 mL) and the mixture was
stirred at room temperature for 20 min. After that methyl pro-
piolate (0.18 mL, 2 mmol) was slowly added dropwise and the mix-
ture was allowed to stand at room temperature for 1 h. The reaction
mixture was concentrated, the residue was dissolved in Et2O
(15 mL), and extracted with brine solution (3ϫ15 mL). The or-
ganic layers were washed with water (3ϫ5 mL), dried with anhy-
drous Na2SO4, filtered, and evaporated in vacuo. Flash chromatog-
[18] R. T. Conley, Infrared Spectroscopy, 2nd ed., Allyn and Bacon,
Boston, 1975.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1271–1277

Atropisomers from 1,3-Cyclohexanediones
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Tomasi, V. Barone, M. Cossi, R. Cammi, B. Mennucci, C. Pom-
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Komaromi, R. Gomperts, R. L. Martin, D. J. Fox, T. Keith,
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[20] R. Facci et al., unpublished results.
[21] We acknowledge the suggestion of this mechanism from the
referees. Alternatively, the formation of tricyclic derivative 4
through the nucleophilic attack of the hydroxy group on the
carbonyl to form a hemiacetal species, which is further methyl-
ated by the original diazomethane, cannot be ruled out. This
is in agreement with Patterson and Reusch’s report on the
transformation of a hemiacetal to a ketal bicyclic system in
excess diazomethane: J. W. Patterson Jr, W. Reusch, Synthesis
1971, 3, 155–156.
[22] Hyperchem® 6.0, Hypercube Inc., Gainesville, Florida.
[23] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Zakrzewski Jr, J. A. Mont-
Received: August 29, 2007
Published Online: January 7, 2008
Eur. J. Org. Chem. 2008, 1271–1277
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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