An enantioselective approach to furanoeremophilanes: (+)-9-oxoeuryopsin

Article abstract of DOI:10.1021/jo400399q

An enantioselective total synthesis of the furanoeremophilane sesquiterpene (+)-9-oxoeuryopsin 1 is reported. The synthesis involves as a key step a copper(II) triflate catalyzed tandem asymmetric conjugate addition of AlMe ₃ to 2-methyl-2-cyclohexen-1-one with the Feringa (S,R,R)-phosphoramidite binaphthol ligand, followed by aldol condensation of the resulting aluminum enolate with 4-methyl-3-furaldehyde 4. This tandem transformation has not been previously reported with a 2-substituted-2- cyclohexen-1-one. Conventional functional group manipulations completed the synthesis.

Full text of DOI:10.1021/jo400399q

Article
pubs.acs.org/joc
An Enantioselective Approach to Furanoeremophilanes:
(+)‑9‑Oxoeuryopsin
Ana L. Silva, Ruben A. Toscano, and Luis A. Maldonado*
́
́ ́ ́ ́
Instituto de Química, Universidad Nacional Autonoma de Mexico, Circuito Exterior, Ciudad Universitaria, Coyoacan, Mexico DF
04510, Mexico
S
* Supporting Information
ABSTRACT: An enantioselective total synthesis of the
furanoeremophilane sesquiterpene (+)-9-oxoeuryopsin 1 is
reported. The synthesis involves as a key step a copper(II)
triflate catalyzed tandem asymmetric conjugate addition of
AlMe3 to 2-methyl-2-cyclohexen-1-one with the Feringa
(S,R,R)-phosphoramidite binaphthol ligand, followed by aldol
condensation of the resulting aluminum enolate with 4-
methyl-3-furaldehyde 4. This tandem transformation has not
been previously reported with a 2-substituted-2-cyclohexen-1-
one. Conventional functional group manipulations completed the synthesis.
set of chemical reactions, was published in the same year by
White and Shanmugam with the synthesis of ( )-6β-
hydroxyeuryopsin.6 Now, we wish to present an asymmetric
version of our approach which led us to the first total synthesis
of a natural furanoeremophilane, (+)-9-oxoeuryopsin 1.7
INTRODUCTION
■
Members of the genera Senecio, Euryops, Ligularia, and
Psacalium of the Asteraceae family are globally distributed
plants rich in furanoeremophilane compounds.1 This group of
sesquiterpenes contains a linearly fused C6−C6−C4O tricyclic
(C12) framework with three Me groups attached at the 4, 5, and
11 positions (Figure 1). Oxygenated functional groups at C-3,
RESULTS AND DISCUSSION
■
Our synthetic route is shown in Scheme 1 and uses in the first
step as the key reaction the well-known tandem8 1,4 alkyl
Scheme 1. Synthesis Plan
Figure 1. Furanoeremophilane framework and the structure of (+)-9-
oxoeuryopsin.
C-6, and C-9 are very common in these compounds. Reported
biological profiles of furanoeremophilanes are diverse and
include cytotoxic, antifungal, antifeedant, phytotoxic, anti-
inflammatory, antibacterial, antihyperglycemic, and hepatotoxic
activities.2
Syntheses of these natural products began in the late 1970s
by Japanese researchers, but in particular Yamakawa and his
group, which in a 7-year period synthesized dozens of
furanoeremophilanes following a BC → ABC approach.3 At
present, all the known syntheses have been performed in the
racemic series, although transformations among some natural
furanoeremophilanes are also known.4 Our interest in the total
synthesis of these compounds started in 2004 with the
successful synthesis of ( )-13-nor-9-oxoeuryopsin based on a
convergent new approach by the novel A + C → A−C → A−
B−C route.5 The same strategy, but with a completely different
conjugate addition−enolate trapping reaction with an aldehyde
to construct the A−C aldol intermediate 2 with a regio- and
stereocontrolled introduction of the C-4 and C-5 methyl
groups. Free-radical removal of the alcohol, homologation to
the unsaturated carboxylic acid and a Friedel−Crafts cyclization
completes the synthesis. A few comments about this approach
are appropriate. First, it should be noted that for 9-
Received: February 28, 2013
© XXXX American Chemical Society
A
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oxoeuryopsin synthesis, the apparently most convenient 3-
halomethylfuran electrophiles in the enolate-trapping reaction
cannot be employed due to the poor stability of the required
electrophiles and the low yields (32−48%) and stereo-
selectivities (cis/trans ratios of 5.5−3.0:1 for the cyclohexane
methyl groups) observed in model studies in the racemic series.
Second, although the reaction is highly stereoselective, in the
racemic 13-nor series an unexpected stable conformer with an
axial furyl substituted chain was obtained,9 which at an
undetermined stage of the synthesis changed to an equatorial
conformation, allowing the construction of ring B. In spite of
the presence of the new methyl group in the furan ring, we
anticipate that similar behavior would be observed in the
present case. Finally, although a deoxygenation step is required
for the synthesis of 1 to remove the oxygen substituent at C-6,
other natural furanoeremophilanes containing an oxygen
substituent at this position are known, and are potential
synthetic targets for future studies.
The copper-catalyzed asymmetric conjugate addition of zinc
and aluminum reagents to enones in the presence of
phosphoramidite binaphthol (mainly) and other ligands have
been extensively investigated by Feringa, Alexakis, and
Woodward.10 The latter reagents are especially useful for α-
and β-substituted enones which are unreactive toward zinc
alkyls. Unfortunately, and in striking contrast to zinc enolates,
the extension of this reaction to include trapping of aluminum
enolates with aldehydes to form an additional C−C bond to
give an aldol has been difficult to achieve due to the low
reactivity of such species, as found by other authors.11
Nevertheless, Alexakis and co-workers could trap the aluminum
enolates from tandem conjugate addition of aluminum alkyls to
3-substituted enones only with oxyphilic electrophiles such as
TMSCl or acid chlorides/anhydrides (Scheme 2).12 The
resulting TMS enol ethers, enol acetates, or mixed alkyl enol
carbonates, though convenient enolate precursors require
further isolation, purification and an additional reaction to
form C−C bonds. For 2-methyl-2-cyclohexen-1-one, Vuag-
noux−d’Augustin and Alexakis12b reported high conversions
(>95%) and ee (90−93%) of (3R, 2S)-dimethylcyclohexanone
with Me3Al and the (R,S,S)-Feringa ligand ((R,S,S)-FL),13 but
trapping experiments with the intermediate aluminum enolate
were not reported. Perhaps, since the results obtained with β-
substituted enones were fruitless, the corresponding enolate
trapping experiments with 3 (R1 = H, R2 = Me) to form C−C
or C−O bonds were not attempted. Considering that the
success of this reaction was key in our plan for the
enantioselective synthesis of 1, we decided to study the
unreported trapping of the aforementioned intermediate
enolate 3 with 4-methyl-3-furaldehyde 4. However, it should
be noted that for this study, the (S,R,R)-FL ligand is required to
establish the 4S configuration of the natural product.
Aldehyde 4 is a known compound,14 but we were unable to
reproduce one of the most recent reported methods14a and a
mixture with its regioisomer 2-methyl-3-furaldehyde was
obtained. Hence, we designed a new method of synthesis of
4 based on previous work in our laboratory (Scheme 3).15 The
Scheme 3. New Synthesis of 4-Methyl-3-furaldehyde 4
Scheme 2. Conjugate Addition−Enolate Trapping of 2- and
3-Substituted Cyclohexen-1-ones
method starts from the known iodoketal 5 available in one step
and at 77% yield from commercial methacrolein,16 uses simple
reactions and is easily performed in medium-sized batches. The
volatile aldehyde 4 was obtained in 26% overall yield as a pale
yellow oil, which was freshly distilled (bp 70 °C/20 mmHg) for
the tandem reactions.
To our surprise and delight, even the first experiment
afforded evidence of a successful tandem reaction in low yield
and further experiments were needed for optimization (Scheme
4). Based on the assumption that conjugate addition of Me3Al
to 2-methyl-2-cyclohexen-1-one does not require any improve-
ment, our entire efforts were focused on the aldehyde trapping
step. We found it very important to dry the Cu(OTf)2
immediately before use (2 h at 130 °C/20 mmHg), employ
freshly distilled excess aldehyde (1.2 equiv) and inverse
quenching (aqueous saturated NH4Cl solution) of the reaction
mixture to minimize aldol reversal. Other factors that can also
be taken into account are thoroughly washing of the aluminum
hydroxide precipitate with ether during the isolation procedure
and the scale-up of the experiments. In this regard, in the 30
B
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Scheme 4. Asymmetric Conjugate Addition of Me3Al to
2‑Methyl-2-cyclohexen-1-one and Trapping of the
Aluminum Enolate with 4
Scheme 5. Thiocarbonylation of Aldols 10 and
Dedithiocarbonylation of 11b
the presence of the OH group in the chain is mandatory to
stabilize the axial substituent in crystalline anti-10. Previously,
Noyori and co-workers18 had prepared aldols related to 10
(syn- and anti-3-ethyl-2-hydroxybenzylcyclohexan-1-one) and
found by X-ray analyses that both diastereomers showed the
same trans diaxial disposition of substituents as we observed
with anti-10, which probably means this is a general
phenomenon for this type of aldol. According to these authors,
steric repulsion of the 2,3 substituents and multiple
intermolecular hydrogen bonds combine to give the observed
result. In our case, extensive intermolecular hydrogen bonding
was also observed in the X-ray crystal analysis of anti-10 (see
the Supporting Information).
In the thiocarbonylation reaction of syn-10, we could also
isolate and characterize the 1H-imidazol-1-yl S-carbothioate
11c (12%; IR 1683 cm−1, SCO; MS 346, M+), the 1H-
imidazol-1-yl carboxylate 11d (4%; IR 1759 cm−1; MS 330,
M+) and the 1H-imidazol-1-yl derivative 11e (13%; MS 286,
M+), but only the former was useful for the synthesis and could
be converted into ketone 12 by (1) free-radical reduction to the
thiol 13 (n-Bu3SnH, ACHN, 91% yield), (2) TCDI reaction to
11b (93% yield), and (3) free-radical hydrogen substitution of
the 1H-imidazol-1-yl carbodithioate group as mentioned above
(Scheme 6). To the best of our knowledge, the free radical
conversion of the S-alkyl carbothioate group into a thiol
(formally a deacylation) has no precedent in the literature. We
have some spectroscopic evidence that anti-10 gave a similar set
of byproducts (anti-11c−e) in the thiocarbonylation reaction,
last optimized experiments with 300−500 mg batches of 2-
methyl-2-cyclohexen-1-one (the limiting substrate), a reason-
ably constant 50−65% range of yields of the product was
obtained, while an experiment with 700 mg had a reduced yield
of 46%.
As in the 13-nor series, the aldol products could be separated
by flash chromatography as major less polar (syn-10) and minor
more polar (anti-10) products, the structures being assigned by
X-ray crystal diffraction analysis of the latter isomer which
shows the furyl containing substituent axially disposed. A
quantitative determination of the ratio of aldols was not
attempted, but isolated products were obtained in the range of
7−5:1. We believe that the real ratio is lower, because losses
during purification of anti-10 were higher compared with syn-
10, due to the two column chromatographies required for the
former.
The next step in the synthesis was removal of the OH
function of the separated aldols by the Barton−McCombie
protocol,17 but we found unusual behavior of these compounds
during preparation of the required substrates for the
deoxygenation step (thiocarbonyl diimidazole (TCDI) in
CH2Cl2 or ClCH2CH2Cl at rt) (Scheme 5). For both isomers,
the expected 1H-imidazol-1-yl O-carbothioates syn- and anti-
11a were not found and a mixture of products were obtained
instead in which the corresponding 1H-imidazol-1-yl carbodi-
thioates syn- and anti-11b (IR 1051 cm−1, CS; MS 362, M+)
were the major components (56% and 48% from the syn and
anti aldols, respectively). Although a search in SciFinder and
the extensive listings of substrates in a recent review on the
Barton−McCombie reaction17b revealed that alkyl 1H-
imidazol-1-yl carbodithioates have not been submitted to the
free radical conditions, from a mechanistic point of view it
seemed feasible. This was indeed the case and compounds syn-
and anti-11b were smoothly converted (n-Bu3SnH and 1,1′-
azobis(cyclohexanecarbonitrile) (ACHN) in toluene at 75 °C)
to a single crystalline ketone 12, mp 65−67 °C in 95% and 75%
yields, respectively. X-ray diffraction analysis of this ketone by
the anomalous dispersion method showed the expected
(2R,3S) absolute configuration with an equatorial furyl
containing chain as required for the synthesis (see the
Supporting Information). This experiment demonstrates that
Scheme 6. Byproducts of the Thiocarbonylation of syn-10
and Preparation of 13
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but the small amounts available of these compounds did not
allow their satisfactory purification.
Scheme 8. Exploration of the Shapiro Reaction on 12
As mentioned above, MS and IR spectroscopy were crucial
for the elucidation of structures of syn-11b-e, but chemical
shifts in 1H- and 13C NMR for the “benzylic” CH and carbonyl
or thiocarbonyl groups were also diagnostic for the assign-
ments. In particular, it should be noted the 13C chemical shift of
the dithioate carbon at δ ∼200.
With regard the reaction mechanism of these unusual
transformations we have speculated a ionization-recombination
process on the initially formed (but not found) O-alkyl 1H-
imidazol-1-yl carbothioate syn-11a, as depicted in Scheme 7. A
Scheme 7. Mechanistic Proposal for Formation of syn-11b−e
with aqueous 48% HBF4 as the catalyst in THF−MeCN.24
With anhydrous TsOH as the catalyst in THF, the yield of 14a
was only 8% with 33% recovered 12, and if no catalyst was
used, an 18% yield of 14a was obtained. Under AcOH catalysis
in EtOH, the azine derivative 14b was obtained in 29% yield.
The Shapiro reaction-CO2 trapping of the intermediate
carbanion was attempted with n-BuLi and t-BuLi alone or in
the presence of TMEDA, but no evidence of an acid product
was observed. It is conceivable that the acidity of the α
hydrogens of the furan ring interfered with the intermediate
vinyl carbanion formation. Hence, we abandoned this route and
turned our attention to the longer reaction sequence employed
successfully in the synthesis of ( )-13-nor-9-oxoeuryopsin.5
Ketone 12 was converted to a 3:1 mixture of O-
trimethylsilyl-protected cyanohydrins 15a,b by the method of
Greenlee and Hangauer,25 and the free cyanohydrins (10% HCl
in THF at rt) 16a and 16b could be separated by column
chromatography as crystalline solids mp 96−98 and 81 °C,
respectively (Scheme 9). The more abundant, higher melting
facile, furan-assisted Schonberg-type rearrangement19 of syn-
̈
Scheme 9. Preparation of Nitrile 17
11a gives syn-11c which is cleaved by imidazole to thiol 13 and
carbonyl diimidazole (CDI). TCDI reaction on 13 then gave
syn-11b and CDI reaction of starting aldol affords syn-11d. The
1H-imidazolyl compound syn-11e should be formed as an
alternative pathway (COS extrusion−imidazole recombination)
during the Schonberg-type rearrangement. Evidence for this
̈
mechanism are the isolation of small amounts of thiol 13 in
some of our experiments and the known precedent on the
preparation of type 11e compounds during thiocarbonylation
or carbonylation of ferrocenyl alcohols.20 Hence, the electron-
rich ferrocenyl and furyl substituents are key for the anomalous
observed results. Other electron-rich substituents from which
we can expect the formation of rearranged products are
conceivable and apparently this is the case for the bis 4-
methoxy benzhydryl alcohol used as substrate in a solid state O-
alkyl 1H-imidazol-1-yl carbothioate synthesis21 which is
reported to have a 1697 cm−1 band absorption in the IR.
Clearly, this band belongs to the Schonberg rearranged S-alkyl
̈
1H-imidazol-1-yl carbothioate isomer. From the above
discussion and since intermediates in the Barton-McCombie
deoxygenation are not always fully characterized, one can
conclude that at least for substrates with electron donating R
groups, perhaps many assumed ImC(S)OR compounds were
actually ImC(S)SR compounds.22
In our original synthesis plan, we contemplated the use of the
Shapiro reaction23 on ketone 12 to simultaneously introduce
the 1,10-double bond and C-9 as a carboxylic acid (Scheme 8).
The required 2,4,6-triisopropylbenzenesulfonylhydrazone 14a
was prepared in moderate yield (43% with 33% recovered 12)
point cyanohydrin 16a had an equatorial β-OH as determined
by single-crystal X-ray diffraction analysis. Both cyanohydrins
could be dehydrated under the same reaction conditions to a
single unsaturated nitrile 17 (70% and 31% yields,
respectively), although substantial amounts of the starting
cyanohydrins remained (13% and 43%, respectively) and
ketone 12 was also recovered (7% each). The higher recovery
of starting material and the lower yield of 17 obtained from 16b
is probably due to steric interference of the axial OH and the
D
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furyl group in the vicinal substituent, which makes it difficult to
form the bulky dichlorophosphate leaving group.
336 nm (nπ* transitions) and was compared with the simulated
ECD curves of (4S,5R)-1 and its enantiomer (4R, 5S)-1
acquired at the TD-PM6 theoretical level using Gaussian 09
software. The experimental curve is qualitatively similar to (4S,
5R)-1 and as expected, a mirror image of (4R, 5S)-1.
Since in the 13-nor series we had observed that alkaline
hydrolysis of the analogous unsaturated nitrile to the
corresponding carboxylic acid was very sluggish (three cycles
of 72 h reflux each, with KOH in diethyleneglycol−water), for
the preparation of acid 18a we first explored an alternative
method through the unsaturated aldehyde 19 (Scheme 10).
CONCLUSIONS
■
In summary, we accomplished the first asymmetric total
synthesis of a natural furanoeremophilane, (+)-9-oxoeuryopsin
1, in 7% overall yield from 2-methyl-2-cyclohexen-1-one in
seven relatively simple synthetic operations (conjugate
addition-enolate trapping, imidazoylthiocarbonylation, bisde-
thiocarbonylation, protected cyanohydrin formation-hydrolysis,
dehydration, alkaline hydrolysis, and Friedel−Crafts cycliza-
tion). To our knowledge, the key asymmetric copper-catalyzed
conjugate addition of AlMe3 to the poorly reactive 2-methyl-2-
cyclohexen-1-one in the presence of the (S,R,R) Feringa ligand
and trapping of the intermediate aluminum enolate with an
aldehyde have not been previously reported. A new preparation
of aldehyde 4 and the finding of unusual behavior of aldols 10
in the imidazoylthiocarbonylation reaction are also important
contributions of our work. Further progress toward the total
asymmetric syntheses of other furanoeremophilanes using this
potentially general approach will be reported in due course.
Scheme 10. Last Steps of the Synthesis
This compound was obtained by DIBALH reduction of 17, but
it was very unstable and decomposed very rapidly during silica
gel column chromatography. With basic alumina as the
adsorbent,6 an 85% yield of partially purified 19 was obtained,
which was submitted immediately to oxidation conditions
(NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH−THF−
H2O) and the crude acid fraction was treated with MeI and
anhydrous K2CO3 in hot Me2CO (35 °C), but only traces (2%)
of the methyl ester 18b were obtained. Fortunately, we were
able to find an improved procedure for the alkaline hydrolysis
of 17 (70% yield of 18a) which reduces the reaction time to 24
h with just ethylene glycol as the solvent and KOH as the base
(180 °C, 24 h). Some starting nitrile 17 was recovered (5.5%)
along with traces of the intermediate amide.
EXPERIMENTAL SECTION
■
General Methods. TLC was performed on silica gel 60 GF254, and
flash chromatography was carried out on handpacked columns of silica
gel 60 (230−400 mesh). The qualitative purity of all compounds was
determined by TLC analysis using a UV lamp, iodine vapors, or a
KMnO4 solution stains for detection purposes.
1H NMR spectra were recorded at 300, 400, or 500 MHz and 13C
NMR at 75, 100, or 125 MHz in CDCl3 using TMS as internal
standard (0.00 ppm). The signals in 1H NMR are reported as s
(singlet), d (doblet), t (triplet), q (quartet), h (heptuplet), m
(multiplet), or brs (broad signal), followed by coupling constant(s) in
Hz and integration. 13C NMR spectra were recorded with 1H
decoupling and DEPT-135 experiments were performed to assign CH,
CH2, and CH3. LRMS were carried out at 70 eV by electron-impact
(EI) and HRMS were obtained by the FAB technique with a double
sector mass spectrometer. Optical rotations were recorded on a digital
polarimeter at room temperature.
To complete the synthesis, the crude acid 18a was converted
into (+)-9-oxoeuyopsin 1 in 59% overall yield by an
intramolecular Friedel−Crafts cyclization (SnCl4 as the Lewis
acid) of the in situ formed acid chloride (PCl5 in C6H6, rt). The
mp of our synthetic sample was 124−125 °C (lit.7 mp 119−120
°C) and showed optical rotations of [α]20589 +6.5, [α]20578 +8.7,
[α]20 +16.9, [α]20 +158.5 (c 1.3 in CDCl3) (lit.7 [α]24
589
Diethyl ether was dried by distillation from sodium/benzophenone
ketyl. Commercial Cu(OTf)2 was dried at 130 °C/20 mmHg for 3 h
before use. 2-Methyl-2-cyclohexene-1-one was prepared by chlorina-
tion (SO2Cl2, CCl4) or bromination (NBS, CCl4) of 2-methylcyclo-
hexanone and dehydrohalogenation with 2,4,6-collidine neat or LiBr/
Li2CO3 in DMF, respectively.27
546
436
+0.35, [α]24 +2.8, [α]24 +7.1, [α]24 +9.65 (c 1.3 in
578
546
436
CDCl3)) and UV absorption at 291 nm (Et2O, ε 25898) (lit.7
λmax 291 nm (ε 16200)). The higher values obtained by us
suggest a higher purity of the synthetic material but
unfortunately, a sample of natural 9-oxoeuryopsin for direct
comparison is apparently no longer available. In order to
conciliate the observed differences, we submitted our sample to
X-ray diffraction analysis by the anomalous dispersion method,
thus confirming the (4S,5R) assignment.
2-(1-Nitropropan-2-yl)-1,3-dioxolane 6.28 A solution of
iodoketal 516 (17.4 g, 0.072 mol) in dry DMSO (5 mL) was added
dropwise under Ar to a mixture of dry phloroglucinol (11 g, 0.087
mol) and dry NaNO2 (9.9 g, 0.14 mol) in dry DMSO (70 mL). The
dark solution was stirred at rt for 24 h, water/ice (∼100 g) was added,
extracted with CH2Cl2, dried (Na2SO4), and concentrated at reduced
pressure to give 18.37 g of a reddish oil. Column chromatography (8:2
hexane/AcOEt) gave nitroketal 6 (9.46 g, 82%) and 2-(propan-1-ol-2-
yl)-1,3-dioxolane (1.55 g, 16%) which can be recycled through 5 (I2,
PPh3, imidazole, CH2Cl2, 70%) or the corresponding p-toluenesulfo-
nate (TsCl, Et3N, CH2Cl2, 92%).
The electronic circular dichroism (ECD) spectroscopy is a
widely used chiroptical method for assigning absolute
configurations of synthetic or natural products. Unfortunately,
ECD curves of furanoeremophilanes containing a cisoid enone
system such as 1 have not (to our knowledge) been reported.26
Hence, it was important for our future synthetic studies in this
area to record the ECD curve of synthetic (4S, 5R)-1. The
experimental curve in MeOH showed strong negative peaks at
213 and 267 nm (ππ* forbidden and allowed transitions,
respectively) and medium intensity positive peaks at 307 and
6: colorless oil; 1H NMR (300 MHz, CDCl3) δ 4.84 (d, J = 3.3 Hz,
1H), 4.57 (dd, J = 12.5, 5.6 Hz, 1H), 4.22 (dd, J = 12.5, 7.9 Hz, 1H,),
4.0−3.83 (m, 4H), 2.8−2.65 (m, 1H), 1.1 (d, J = 7.2 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 104.6 (CH), 76.5 (CH2), 65.3 (CH2), 65.2
(CH2), 36.2 (CH), 12.8 (CH3); IR (film) ν 1553, 1379, 1117, 1070
cm−1; LRMS (EI) m/z 161 (M+), 73 (100), 45 (39); HRMS (FAB)
m/z calcd for C6H12NO4 (M + H)+ 162.0766, found 162.0769.
E
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2-[1-(1,3-Dioxolan-2-yl)ethyl]-2-nitropropan-1,3-diol 7. A
stirred mixture of nitroketal 6 (9.94 g, 0.062 mol) and 37% formalin
(30 mL, 0.37 mol) was treated with Ba(OH)2 (0.86 g, 2.7 mmol). An
exothermic reaction was noted, and stirring was continued for 2 h at rt.
It was extracted with AcOEt, washed with brine, dried (Na2SO4), and
concentrated to dryness at reduced pressure to give the crude product
(16.65 g). Column chromatography (50% → 60% → 70% AcOEt in
hexane) afforded diol 7 (13.64 g, 100%).
thoroughly washed with CH2Cl2. The solvent was removed at reduced
pressure, and the crude aldehyde (2.47 g) was freshly distilled before
use. Recovery of pure aldehyde after distillation was 70−72% yield
independently of using pure 9 or more conveniently, crude furan
alcohol precursor. (b) Swern oxidation: To oxalyl chloride (0.06 mL,
0.64 mmol) in dry CH2Cl2 (2 mL) cooled at −50 °C was added dry
DMSO (0.09 mL, 1.26 mmol). After the solution was stirred for 2 min,
a solution of 9 (0.062 g, 0.55 mmol) in dry CH2Cl2 (0.7 mL) was
added, and after 15 min dry Et3N (0.4 mL, 2.9 mmol) was added. The
resulting mixture was then allowed to reach rt, H2O (5 mL) was
added, and the mixture was extracted with CH2Cl2 (3 × 5 mL). The
combined organic layers were washed (5 mL each) with brine, 1%
HCl, H2O, 5% aqueous Na2CO3, and H2O. After drying (Na2SO4), the
solvent was removed at reduced pressure (150 mmHg), and the
residual dark brown oil was distilled in a Kugelrohr apparatus (68−70
°C/20 mmHg) to provide 0.041 g (0.37 mmol, 66%) of pure 4.
7: clear viscous oil; 1H NMR (300 MHz, CDCl3) δ 4.92 (d, J = 3.9
Hz, 1H), 4.27 (d, J = 13.2 Hz, 2H), 4.14 (d, J = 13.2 Hz, 2H), 4.01−
3.8 (m, 4H), 3.15−2.90 (brs, exchangeable 2 OH), 2.77 (dc, J = 7.2,
3.9 Hz, 1H), 1.02 (d, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
103.2 (CH), 95.5 (C), 65.3 (CH2), 65.0 (CH2), 63.5 (CH2), 63.2
(CH2), 40.8 (CH), 9.3 (CH3); IR (film) ν 3500−2900, 1545, 1351,
1114, 1053, 946 cm−1; LRMS (EI) m/z 220 (M-1)+, 73 (100), 45
(25); HRMS (FAB) m/z calcd for C8H16NO6 (M + H)+ 222.0978,
found 222.0977.
1
4: pale yellow oil; H NMR (300 MHz, CDCl3) δ 9.98 (d, J = 0.6
2-Hydroxy-4-hydroxymethyl-3-methyl-4-nitrotetrahydro-
furan 8. A mixture of diol 7 (9.35 g, 0.04 mol) and 5% HCl (70 mL)
in Me2CO (300 mL) was heated under reflux for 27 h. It was cooled at
0 °C, a saturated solution of NaHCO3 (80 mL) was added dropwise,
and then solid NaHCO3 in small portions until neutralization was
complete. After removal of Me2CO at reduced pressure, it was
extracted with CH2Cl2 (3 × 50 mL) and AcOEt (3 × 50 mL). Each
organic extract was separately dried (Na2SO4) and concentrated at
reduced pressure to give 1.59 and 5.86 g of crude materials,
respectively. Column chromatography (1:1 hexane/AcOEt) from the
CH2Cl2 extract afforded cyclic hemiketal 8 (0.48 g). From the AcOEt
extraction, after column chromatography (1:1 hexane/AcOEt) 4.8 g
(71%) of 8 and 0.41 g (4.3%) of a cyclic mixed ketal which was not
fully characterized, were obtained. As expected, the 1H NMR spectrum
of 8 (mixture of four diastereoisomers) is very complex, but we could
assign the signals for one of the two major isomers (8a).
Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.26−7.23 (m, 1H), 2.24 (d, J = 1.2
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 185.5 (C), 152.8 (CH),
141.9 (CH), 127.8 (C), 119.2 (C), 8.8 (CH3); IR (film) ν 1688, 3139,
1538, 1145, 1043, 875, 824, 754 cm−1; LRMS (EI) m/z 110 (M+,
100), 109 (99), 81 (9), 53 (31).14c
Tandem Conjugate Addition−Aldol Formation. Preparation
of syn-10 and anti-10. A Schlenk type tube flask was charged with
freshly dried (130 °C/20 mmHg, 1−2 h) Cu(OTf)2 (0.014 g, 0.04
mmol) and (S,R,R)-FL (0.041 g, 0.076 mmol). The system was
evacuated and filled with dry Ar (three cycles), and dry Et2O (10 mL)
was added. The mixture was stirred 1 h at rt and cooled at −30 °C,
and a 2 M solution of Me3Al in toluene (3.2 mL, 6.4 mmol) was
added. After the mixture was stirred for 15 min, a solution of 2-methyl-
2-cyclohexen-1-one (0.36 g, 3.2 mmol) in dry Et2O (4 mL) was added
(3 mL of dry Et2O was used for rinsing). The reaction mixture was
stirred at −30 °C for 18 h, and a solution of aldehyde 4 (0.43 g, 3.8
mmol) in dry Et2O was added (3 mL of dry Et2O for rinsing). The
mixture was stirred at −20 °C for 2 h and at −5 °C for 30 min, and the
green solution poured into saturated NH4Cl solution (18 mL). After 4
h of stirring at rt, the color of the solution changed to white and finally
blue. The suspension was filtered, the cake thoroughly washed with
Et2O and after the usual workup the crude material was obtained (0.87
g). Column chromatography (10% → 15% → 20% → 30% AcOEt in
hexane) gave syn-10 (0.45 g, 60%) and impure anti-10 (0.091 g). Final
purification of anti-10 required another column chromatography
(85:15 hexane/Me2CO) to get the pure product (0.064 g, 8%). Other
compounds isolated were the phosphoramidate ligand (67%) and the
chiral binaphthol (7%).
8: colorless oil; 1H NMR (300 MHz, CDCl3, only the signals due to
8a are given) δ 5.26 (t, J = 4 Hz, 1H), 4.64 (d, JAB = 10.8 Hz, 1HA),
4.49−3.80 (m, 2H), 4.37 (d, JAB = 10.8 Hz, 1HB), 3.75−3.65 (brs,
exchangeable OH), 2.60−2.40 (brs, exchangeable OH), 2.29 (dq, J =
7.1, 3.9 Hz,1H), 1.06 (d, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3,
all signals are given) δ 104.2 (CH), 104.1 (CH), 100.2 (CH), 99.4
(C), 99.9 (CH), 98.3 (C), 97.8 (C), 96.6 (C), 72.3 (CH2), 71.3
(CH2), 71.1 (CH2), 69.9 (CH2), 65.0 (CH2), 64.9 (CH2), 63.0 (CH2),
63.1 (CH2), 47.5 (CH), 47.3 (CH), 46.9 (CH), 44.5 (CH), 11.6
(CH3), 11.5 (CH3), 8.8 (CH3), 7.9 (CH3); IR (film) ν 3700−3000,
1546, 1073, 1014, 938 cm−1; LRMS (EI) m/z 160 (2), 130 (6), 113
(14), 101 (33), 83 (62), 67 (100), 55 (40); HRMS (FAB) m/z calcd
for C6H11NO5 (M+) 177.0637, found 177.0640.
4-Methyl-3-furanmethanol 9. To a solution of cyclic hemiketal 8
(5 g, 0.028 mol) in dry DME (96 mL) was added DABCO (3.81 g,
0.034 mol) and the mixture heated at reflux for 24 h. Solvent was
removed at reduced pressure, water was added, and the product was
extracted with CH2Cl2 and washed with 10% HCl, a saturated solution
of NaHCO3, and brine. After drying (Na2SO4), the solvent was
removed to afford a quantitative yield of 9 (3.16 g). Column
chromatography (75:25, hexane/AcOEt) of 1.21 g of crude alcohol
gave the pure product (1 g, 77%). In small batches, purification of
crude 9 by Kugelrohr distillation (90 °C/20 mmHg) affords yields up
to 82% yield, but in large batches extensive decomposition was
observed even at 70°/5 mmHg. Even in the freezer, pure
furanmethanol 9 is unstable if kept neat but is stable in acetone
solution for months.
(2S,3S)-2-((R)-Hydroxy(4-methylfuran-3-yl)methyl)-2,3-dimethyl-
cyclohexanone (syn-10): colorless solid; mp 30−32 °C; Rf = 0.50
1
(7:3, hexane/AcOEt); [α]21 = +42.2 (c 1.46 in CHCl3); H NMR
D
(400 MHz, CDCl3) δ 7.17−7.14 (m, 2H), 4.40 (d, J = 11 Hz, 1H),
3.94 (d, J = 11 Hz, exchangeable OH), 2.54−2.44 (m, 1H), 2.37−2.28
(m, 1H), 2.02 (d, J = 0.8 Hz), 1.99−1.89 (m, 2H), 1.65−1.54 (m, 3H),
1.38 (s, 3H), 0.86 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
219.9 (C), 140.6 (CH), 139.2 (CH), 126.1 (C), 120.4 (C), 70.7
(CH), 55.8 (C), 39.4 (CH2), 36.9 (CH), 29.7 (CH2), 24.0 (CH2),
17.1 (CH3), 15.1 (CH3), 8.2 (CH3); IR (KBr) ν 3600−3100, 1692,
1456, 1051, 1012, 807, 787 cm−1; LRMS (EI) m/z 236 (M+, 2), 126
(77), 111 (100); HRMS (FAB) m/z calcd for C14H21O3 (M + H)+
237.1491, found 237.1490.
(2S,3S)-2-((S)-Hydroxy(4-methylfuran-3-yl)methyl)-2,3-dimethyl-
cyclohexanone (anti-10): colorless solid; mp 83−84 °C; Rf = 0.43
1
(7:3, hexane/AcOEt); [α]21 = +41.2 (c 1.0 in CHCl3); H NMR
9: colorless oil; 1H NMR (300 MHz, CDCl3) δ 7.37−7.35 (m, 1H),
7.20−7.17 (m, 1H), 4.50 (s, 2H), 2.05 (d, J = 0.9 Hz, 3H), 1.48−1.40
(brs, exchangeable OH); 13C NMR (75 MHz) δ 140.6 (CH), 140.2
(CH), 125.2 (C), 120.0 (C), 55.4 (CH2), 7.8 (CH3); IR (film) ν
3600−3000, 1550, 1451, 1139, 1043, 1004, 873, 798, 756 cm−1; LRMS
(EI) m/z 112 (M+, 100), 95 (27), 94 (61), 55 (43), 32 (36).14c
4-Methyl-3-furaldehyde 4. (a) With MnO2: Commercial MnO2
(41.6 g, 0.48 mol) was added in portions to a stirred solution of 9
(3.16 g, 0.028 mol) in CH2Cl2 (120 mL) and the suspension stirred at
rt for 24 h. The suspension was filtered through Celite and the cake
D
(400 MHz, CDCl3) δ 7.38 (d, J = 1.6 Hz, 1 H), 7.15 (q, J = 1.2 Hz, 1
H), 4.66 (d, J = 8.4 Hz, 1 H), 3.0 (d, J = 8.4 Hz, exchangeable OH),
2.57 (ddd, J = 12.8, 11.2, 6.0 Hz, 1 H), 2.42- 2.3 (m, 2 H), 2.04−2.0
(m, 1 H), 2.02 (d, J = 0.8 Hz, 3 H), 1.87−1.54 (m, 3 H), 0.99 (d, J =
6.8 Hz, 3 H), 0.96 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 218.0
(C), 141.8 (CH), 139.0 (CH), 126.0 (C), 120.1 (C), 68.5 (CH), 57.1
(C), 39.3 (CH2), 38.6 (CH), 29.8 (CH2), 26.0 (CH2), 15.47 (CH3),
14.6 (CH3), 8.52 (CH3); IR (KBr) ν 3600−3300, 1692, 1455, 1058,
1034, 867, 800 cm−1; LRMS (EI) m/z 236 (M+, 8), 126 (67),111
F
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The Journal of Organic Chemistry
Article
(100); HRMS (FAB) m/z calcd for C14H20O3 (M+) 236.1412, found
236.1413.
129.8 (CH), 125.6 (CH), 117.5 (CH), 114.2 (C), 85.5 (CH), 54.5
(C), 41.9 (CH), 38.1 (CH2), 28.8 (CH2), 23.6 (CH2), 19.6 (CH3),
15.7 (CH3), 7.8 (CH3). syn-11e-2 δ 212.7 (C), 145.9 (CH), 141.1
(C), 136.5 (CH), 129.6 (CH), 127.5 (CH), 117.1 (CH), 114.0 (C),
84.3 (CH), 54.6 (C), 43.8 (CH), 38.6 (CH2), 28.7 (CH2), 23.1
(CH2), 18.9 (CH3), 15.0 (CH3), 7.7 (CH3); IR (film) ν 1702, 1069
cm−1; LRMS (EI) m/z 288 (M++2, 6), 287 (M+ + 1, 39), 286 (M+,
59), 219 (100), 161 (80), 95 (65); HRMS (FAB) m/z calcd for
C17H23N2O2 (M + H)+ 287.1760, found 287.1758.
(b) anti-10 as substrate: The same procedure as above was followed
with anti-10 (0.11 g, 0.46 mmol), TCDI (0.2 g, 1.13 mmol) and 1,2-
dichloroethane (1.5 mL) for 15 h. Column chromatography (30% →
40% → 50% AcOEt in hexane) gave recovered starting material (0.009
g, 9%) and anti-11b (0.081 g, 48%). In this case, the yield of anti-11b
was lower (40%) with CH2Cl2 as solvent.
Imidazoylthiocarbonylation Reactions. (a) syn-10 as substrate:
Two identical batches of a solution of syn-10 (0.21 g, 0.89 mmol) and
TCDI (0.4 g, 2.2 mmol) in dry CH2Cl2 (1.5 mL) were stirred at rt for
5 h. The solvent was removed at reduced pressure, and the residues
were combined and purified by column chromatography (30% → 40%
→ 50% AcOEt in hexane) to give (syn-11b) (0.36 g, 56%), (syn-11c)
(0.057 g, 9%), (syn-11d) (0.069 g, 12%) and (syn-11e) (0.055 g,
11%).With 1,2-dichloroethane as solvent yield of syn-11b was lower
(46%).
(ζ)-((1R,2S)-1,2-Dimethyl-6-oxocyclohexyl)(4-methylfuran-3-yl)-
methyl 1H-imidazole-1-carbodithioate (syn-11b): yellow solid; mp
147−148 °C; Rf = 0.50 (1:1, hexane/AcOEt); [α]20 = −453 (c 0.71
D
1
in CHCl3); H NMR (300 MHz, CDCl3) δ 8.52−8.50 (m, 1H), 7.81
(t, J = 1.5 Hz, 1H), 7.23 (d, J = 1.5 Hz, 1H), 7.12 (q, J = 1.5 Hz, 1H),
7.07 (dd, J = 1.5, 0.9 Hz, 1H), 5.66 (s, 1H), 2.51 (td, J = 14.4, 6.3 Hz,
1H), 2.42−2.33 (m, 1H), 2.04 (d, J = 1.5 Hz, 3H), 2.13−2.03 (m,
1H), 2.02−1.92 (m, 2H), 1.74−1.44 (m, 2H), 1.35 (s, 3H), 1.11 (d, J
= 6.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 214.1 (C), 201.7 (C),
143.5 (CH), 139.4 (CH), 136.0 (CH), 130.6 (CH), 124.0 (C), 120.2
(C), 118.0 (CH), 59.4 (C), 50.9 (CH), 38.2 (CH2), 37.7 (CH), 30.3
(CH2), 24.4 (CH2), 16.4 (CH3), 15.7 (CH3), 9.28 (CH3); IR (KBr) ν
1697, 1461, 1367, 1272, 1216, 1052, 997, 821 cm−1 ; LRMS (EI) m/z
362 (M+, 12), 219 (100); HRMS (FAB) m/z calcd for C18H23N2O2S2
(M + H)+ 363.1201, found 363.1198.
(epi-ζ)-((1R,2S)-1,2-Dimethyl-6-oxocyclohexyl)(4-methylfuran-3-
yl)methyl 1H-imidazole-1-carbodithioate (anti-11b): yellow oil; Rf =
1
0.54 (4:6, hexane/AcOEt); [α]20 = +71.8 (c 1.53 in CHCl3); H
D
NMR (500 MHz, CDCl3) δ 8.65−8.55 (m, 1H), 7.81 (t, J = 1.5 Hz,
1H), 7.60 (dd, J = 1.8, 0.3 Hz, 1H), 7.12−7.09 (m, 1H), 7.09 (dd, J =
1.5, 0.9 Hz, 1H), 5.42 (s, 1H), 2.56 (td, J = 13, 6 Hz, 1H), 2.35−2.29
(m, 1H), 2.29−2.21 (m, 1H), 2.17 (d, J = 1.2 Hz, 3H), 2.06−2.0 (m,
1H), 1.82−1.77 (m, 1H), 1.71−1.58 (m, 2H), 1.13 (d, J = 6.5 Hz,
3H); 1.1 (s, 3H), 13C NMR (125 MHz, CDCl3) δ 214.1 (C), 199.4
(C), 144.9 (CH), 138.8 (CH), 135.9 (CH), 130.6 (CH), 124.0 (C),
120.4 (C), 118.0 (CH), 59.0 (C), 49.2 (CH), 40.0 (CH), 38.3 (CH2),
30.3 (CH2), 25.8 (CH2), 16.8 (CH3), 16.3 (CH3), 9.1 (CH3); IR
(film) ν 1704, 1464, 1367, 1271, 1221, 1051, 1003, 826 cm−1; LRMS
(EI) m/z 362 (M+, 7), 219 (100), 95 (87); HRMS (FAB) m/z calcd
for C18H23N2O2S2 (M + H)+ 363.1201, found 363.1205.
S-(ζ)-((1R,2S)-1,2-Dimethyl-6-oxocyclohexyl)(4-methylfuran-3-
yl)methyl 1H-imidazole-1-carbothioate (syn-11c): brownish glassy
solid; Rf = 0.44 (4:6 hexane/AcOEt); [α]20D = −140 (c 0.8 in CHCl3);
1H NMR (500 MHz) δ 8.27−8.25 (m, 1H), 7.49 (t, J = 1.5 Hz, 1H),
7.21 (d, J = 2 Hz, 1H), 7.15−7.14 (m, 1H), 7.1−7.09 (m, 1H), 4.94 (s,
1H), 2.53 (td, J = 14.2, 6.5 Hz, 1H), 2.41−2.35 (m, 1H), 2.10−2.02
(m, 1H), 2.03 (d, J = 1 Hz, 3H), 2.02−1.95 (m, 1H), 1.73−1.59 (m,
2H), 1.61−1.48 (m, 1H), 1.36 (s, 3H), 1.02 (d, J = 7 Hz, 3H); 13C
NMR (125 MHz) δ 214.2 (C), 168.5 (C), 143.0 (CH), 139.4 (CH)
135.5 (CH), 130.3 (CH), 124.1 (C), 119.9 (C), 116.0 (CH), 58.0
(C), 44.7 (CH), 38.3 (CH2), 37.9 (CH), 30.3 (CH2), 24.6 (CH2),
17.2 (CH3), 15.5 (CH3), 8.2 (CH3); IR (film) ν 1702, 1683, 1467,
1364, 1292, 1270, 1218, 1099, 1055, 888 cm−1 ; LRMS (EI) m/z 346
(M+, 14), 219 (82), 95 (100); HRMS (FAB) m/z calcd for
C18H23N2O3S (M + H)+ 347.1429, found 347.1429.
(ζ)-((1S,2S)-1,2-Dimethyl-6-oxocyclohexyl)(4-methylfuran-3-yl)-
methyl) 1H-imidazole-1-carboxylate (syn-11d): brownish glassy
solid; Rf = 0.35 (4:6 hexane/AcOEt); [α]20 = −1.75 (c 1.2 in
CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.16−D8.15 (m, 1H), 7.45 (d,
J = 1.5 Hz, 1H), 7.43 (t, J = 1.5 Hz, 1H), 7.17 (q, J = 1.5 Hz, 1H), 7.06
(dd, J = 1.5, 0.5 Hz, 1H), 6.17 (s, 1H), 2.46 (ddd, J = 14.5, 10.0, 5.5
Hz, 1H), 2.37−2.30 (m, 1H), 2.12−2.04 (m, 1H), 2.08 (d, J = 1 Hz,
3H) 1.98−1.9 (m, 2H), 1.75−1.65 (m, 1H), 1.64−1.55 (m, 1H), 1.28
(s, 3H), 0.98 (d, J = 7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 211.5
(C), 148.5 (C), 143.3 (CH), 139.7 (CH), 137.2 (CH), 130.7 (CH),
120.8 (C), 120.2 (C), 117.2 (CH), 74.7 (CH), 56.8 (C), 39.6 (CH2),
36.9 (CH), 29.4 (CH2), 23.5 (CH2), 16.0 (CH3), 15.9 (CH3), 8.55
(CH3); IR (film) ν 1759, 1709, 1471, 1389, 1317, 1287, 1242, 1175,
1096, 1056, 1001, 948 cm−1 ; LRMS (EI) m/z 330 (M+, 5), 219 (77),
111 (66), 95 (100); HRMS (FAB) m/z calcd for C18H23N2O4 (M +
H)+ 331.1658, found 331.1662.
(2S,3S)-2-((ζ)-(1H-Imidazol-1-yl)(4-methylfuran-3-yl)methyl)-2,3-
dimethylcyclohexanone (syn-11e): colorless oil; 1H NMR (500
MHz, CDCl3, ∼5:1 diastereoisomer mixture of syn-11e-1 and syn-11e-
2): syn-11e-1 δ 7.53−7.52 (m, 1H), 6.98 (s, 1H), 6.89 (t, J = 1 Hz,
1H), 6.67 (d, J = 2 Hz, 1H), 6.55−6.53 (m, 1H), 5.34 (dd, J = 2.3, 1.0
Hz, 1H), 2.22−2.13 (m, 1H), 2.13−2.06 (m, 1H), 1.79−1.76 (m, 1H),
1.78 (d, J = 1.5 Hz, 3H), 1.60−1.54 (m, 1H), 1.48−1.22 (m, 2H), 1.12
(s, 3H), 0.84 (d, J = 7 Hz, 3H). syn-11e-2 δ 7.54 (s, 1H), 7.07 (s, 1H),
6.87 (t, J = 1 Hz, 1H), 6.55−6.53 (m, 1H), 6.31 (d, J = 2 Hz, 1H), 5.59
(dd, J = 2.3 1.0 Hz, 1H), 2.6−2.51 (m, 1H), 2.37−2.22 (m, 1H),
2.13−2.06 (m, 1H), 2.06−1.76 (2H), 1.82 (d, J = 1.5 Hz, 3H), 1.6−
1.42 (m, 1H), 1.12 (s, 3H), 0.82 (d, J = 7 Hz, 3H); 13C NMR (125
MHz): syn-11e-1 δ 213.0 (C), 145.8 (CH), 140.4 (C), 136.8 (CH),
(c) Thiol 13 as substrate: The same procedure as above was
followed with 13 (0.018 g, 0.07 mmol), TCDI (0.042 g, 0.24 mmol) in
CH2Cl2 (0.2 mL) for 9 h. Column chromatography gave syn-11b
(0.024 g, 93%).
Preparation of 12 and 13 by Dethiocarbonylation Reac-
tions. (a) syn-11b as substrate: ACHN (0.046 g, 0.19 mmol) was
suspended in a solution of syn-11b (0.22 g, 0.6 mmol) in toluene (2.2
mL) and sonicated while Ar was bubbled through the solution for 20
min. The reaction mixture was heated at 75 °C, n-Bu3SnH (0.032 mL,
1.2 mmol) was added, and heating was continued for 2h. The solvent
was removed at reduced pressure and the residue purified by column
chromatography (98:2 hexane/AcOEt) to give 12 (0.127 g, 95%) mp
65−67 °C.
(b) anti-11b as substrate: The same procedure as above was
followed with anti-11b (0.07 g, 0.2 mmol), ACHN (0.016 g, 0.065
mmol) and n-Bu3SnH (0.11 mL, 0.4 mmol) in dry toluene (0.7 mL).
After 3 h heating, removal of solvent and column chromatography
(98:2 hexane/AcOEt) afforded 12 (0.033 g, 75%).
(2R,3S)-2,3-Dimethyl-2-((4-methylfuran-3-yl)methyl)-
cyclohexanone (12): colorless prisms; mp 65−67 °C; Rf = 0.51
1
(85:15, hexane/AcOEt); [α]22 = +9.1 (c 1.01 in CHCl3); H NMR
D
(500 MHz, CDCl3) δ 7.13−7.12 (m, 1H), 7.06 (s, 1H), 2.83 (dd, J =
15, 0.75 Hz, 1H), 2.48 (d, J = 15 Hz, 1H), 2.42−2.37 (m, 2H), 2.01−
1.88 (m, 2H), 1.95 (d, J = 1.5, 3H), 1.85−1.79 (m, 1H), 1.7−1.61 (m,
1H), 1.6−1.5 (m, 1H), 1.03 (s, 3H), 0.95 (d, J = 7 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 215.7 (C), 141.4 (CH), 138.8 (CH), 121.3 (C),
121.9 (C), 53.5 (CH3), 38.4 (CH2), 37.7 (CH), 29.2 (CH2), 29.2
(ArCH2), 23.9 (CH2), 19.0 (CH3), 16.0 (CH3), 8.4 (CH3); IR (KBr)
ν 1701, 1456, 1144, 1047, 801 cm−1; LRMS (EI) m/z 220 (M+, 10),
96 (77), 95 (100); HRMS (FAB) m/z calcd for C14H21O2 (M + H)+
221.1542, found 221.1543.
(c) syn-11c as substrate: The same procedure as above was followed
with 11c (0.026 g, 0.076 mmol), ACHN (0.006 g, 0.023 mmol) and n-
Bu3SnH (0.04 mL, 0.15 mmol) in dry toluene (1.1 mL). After 9 h
heating, column chromatography (9:1 hexane/AcOEt) afforded 13
(0.017 g, 91%) as a white solid.
(2R,3S)-2-((ζ)-Mercapto(4-methylfuran-3-yl)methyl)-2,3-dime-
thylcyclohexanone (13): colorless solid; mp 78−80 °C; Rf = 0.50
(85:15, hexane/AcOEt); [α]20D = −79.1 (c 0.66 in CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.21−7.2 (m, 1H), 7.14−7.12 (m, 1H), 4.05 (d,
G
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1
J = 9.6 Hz, 1H), 2.41−2.28 (m, 2H), 2.28−2.19 (m, 1H), 2.2 (d, J =
9.6 Hz, exchangeable SH), 2.05 (d, J = 0.8 Hz, 3H), 2.0−1.83 (m, 2H),
1.81−1.69 (m, 1H), 1.65−1.51 (m, 1H), 1.37 (s, 3H), 0.86 (d, J = 6.8
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 214.3 (C), 140.5 (CH),
139.1 (CH), 125.9 (C), 119.3 (C), 56.6(C), 39.5 (CH), 39.1 (CH2),
39.0 (CH3), 29.2 (CH2), 24.2 (CH2), 17.4 (CH3), 15.0 (CH3), 8.2
(CH3); IR (KBr) ν 2594, 1701, 1461, 1434, 1146, 1046, 797 cm−1;
LRMS (EI) m/z 254 (M++2, 2), 253 (M++1, 7), 252 (M+, 44), 127
(78), 111 (100), 32 (100), 28 (100); HRMS (FAB) m/z calcd for
C14H21O2S (M + H)+ 253.1262, found 253.1255.
(2R,3S)-2,3-Dimethyl-2-((4-methylfuran-3-yl)methyl)-
cyclohexanone 2,4,6-Triisopropylbenzenesulfonylhydrazone 14a.
To 12 (51 mg, 0.23 mmol) in THF (0.5 mL) and CH3CN (1 mL)
was added 2,4,6-tri-i-Pr-benzenesulfonyl hydrazine (0.078 g, 0.26
mmol) and one drop of 48% aqueous HBF4. The reaction mixture was
stirred at rt for 2 h and cooled at 0 °C, solid NaHCO3 (0.04 g, 0.48
mmol) was added, and the volatiles were removed (oil pump) at rt.
Column chromatography (95:5 hexane/AcOEt) gave 17 mg of starting
material and 50 mg (43%) of 14a as a white foam. The yield of 14a in
THF at rt for 41 h without acid catalyst was 18% and with TsOH and
CHCl3); H NMR (300 MHz, CDCl3) δ signals common to both
diastereoisomers 2.73 (d, JAB = 15 Hz, HA), 2.67 (d, JAB = 15 Hz, HB),
1.92−1.18 (m, 7H); signals of major isomer δ 7.19 (s, 1H), 7.15−7.13
(m, 1H), 2.01 (d, J = 1.2 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H), 0.91 (s,
3H), 0.20 (s, 9H); signals of minor isomer δ 7.22 (s, CH), 7.17−7.15
(m, 1H), 2.0 (d, J = 1.2 Hz, 3H), 1.06 (s, 3H), 0.85 (d, J = 6.9 Hz,
3H), 0.26 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 141.1 (CH), 138.8
(CH), 122.0 (C), 121.7 (CN), 121.4 (C), 78.6 (C), 12.3 (CH3), 8.8
(CH3); signals for major isomer δ 45.5 (C), 37.2 (CH), 35.3 (CH2),
30.3 (CH2), 29.6 (CH2), 21.8 (CH2), 16.7 (CH3), 1.4 (3 CH3);
signals for minor isomer δ 44.5 (C), 35.1 (CH2), 33.7 (CH), 30.0
(CH2), 29.8 (CH2), 19.7 (CH2), 16.3 (CH3), 1.3 (3 CH3); IR (film) ν
1255, 1451, 1134, 1107, 1050, 936, 878, 845, 791, 759 cm−1; LRMS
(EI) m/z 320 (M++1, 4), 319 (M+, 13), 96 (100), 95 (51), 73 (38);
HRMS (FAB) m/z calcd for C18H30NO2Si (M + H)+ 320.2046, found
320.2048.
Preparation and Separation of Free Cyanohydrins β-OH 16a
and α-OH 16b. Two identical batches of crude protected
cyanohydrins 15a,b (0.28 g) obtained from ketone 12 (0.18 g, 8.1
mmol) were dissolved in THF (14 mL), 10% HCl (4 mL) was added,
and the reaction mixture was stirred at rt for 19 h. The volatiles were
removed at reduced pressure, diluted with brine, extracted with
CH2Cl2, dried (Na2SO4), and concentrated under reduced pressure to
give crude cyanohydrins (0.23 g). The crude material was combined
and after column chromatography separation (95:5 hexane/AcOEt)
gave the β-OH isomer 16a (0.25 g, 60% overall from 12) and the α-
OH isomer 16b (0.12 g, 28% overall from 12) as crystalline solids.
(1R,2R,3S)-1-Hydroxy-2,3-dimethyl-2-((4-methylfuran-3-yl)-
methyl)cyclohexanecarbonitrile (β-OH 16a): colorless solid; mp 96−
anhydrous MgSO4 in dry THF (84 h) was 8% (33% recovery of 12).
1
14a: white foam; [α]23 = −62.0 (c 1.28 in CHCl3); H NMR (300
D
MHz, Z and E isomers) δ 7.3−7.34 (broad signal, exchangeable NH),
7.14 (s, 2H), 6.99−6.96 (m, 1H), 6.47 (s, 1H), 4.2 (h, J = 6.6 Hz, 2H),
2.9 (h, J = 6.6 Hz, 1H), 2.72 (dd, J = 15, 0.9 Hz, 1H), 2.38 (d, J = 15
Hz, 1H), 2.28−2.09 (m, 2H), 1.82 (d, J = 1.2 Hz, 3H), 1.78−1.34 (m,
5H), 1.26 (d, J = 6.6 Hz, 6H), 1.25 (d, J = 6.6 Hz, 6H), 1.22 (d, J = 6.6
Hz, 6H), 1.20 (d, J = 6.6 Hz, 6H), 0.88 (s, 3H), 0.77 (d, J = 6.6 Hz,
3H); 13C NMR (75 MHz) δ 162.6 (C), 153.4 (C), 151.1 (2 C), 141.1
(CH), 138.1 (CH), 131.2 (C), 123.7 (2 CH), 120.8 (C), 120.5 (C),
46.7 (C), 37.0 (CH), 34.2 (CH), 30.4 (CH2), 29.8 (2 CH), 28.8
(CH2), 24.8 (4 CH3), 24.6 (4 CH3), 23.5 (2 CH3), 23.5 (2 CH3), 22.8
(CH2), 22.2 (CH2), 21.2 (CH3), 15.9 (CH3), 8.4 (CH3); IR (KBr) ν
3300−3100, 1601, 1459, 1384, 1052, 757, 1324, 1158 cm−1; LRMS
(EI) m/z 502 (M++2, 30), 501 (M++1, 50), 500 (M+, 42), 405 (26),
267 (57), 251 (57), 233 (100), 203 (57), 109 (58), 95 (61); HRMS
(FAB) m/z calcd for C29H45N2O3S (M + H)+ 501.3151, found
501.3159.
98 °C; Rf = 0.56 (85:15, hexane/AcOEt); [α]22 = +38.6 (c 1.04 in
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.26−7.24 (m,
1H), 2.90 (s, exchangeable OH), 2.77 (d, JAB = 15 Hz, HA), 2.71 (d,
JAB = 15 Hz, HB), 2.06 (d, J = 1.2 Hz, 3H), 1.91−1.85 (m, 1H,), 1.85−
1.65 (m, 4H), 1.56−1.45 (m, 1H), 1.35−1.23 (m, 1H), 1.05 (s, 3H),
1.0 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 141.9 (CH),
141.1 (CH), 122.4 (C), 121.8 (CN), 120.3 (C), 77.8 (C), 45.2 (C),
38.9 (CH), 33.9 (CH2), 32.1 (CH2), 29.7 (CH2), 22.2 (CH2), 16.0
(CH3), 11.4 (CH3), 8.8 (CH3); IR (KBr) ν 3365, 2236, 1452, 1416,
1102, 1051, 1020 cm−1; LRMS (EI) m/z 247 (M+, 6), 96 (100), 95
(100); HRMS (FAB) m/z calcd for C15H22NO2 (M + H)+ 248.1651,
found 248.1647.
(2R,3S)-2,3-Dimethyl-2-((4-methylfuran-3-yl)methyl)-
cyclohexanone Azine 14b. To 12 (0.04 g, 0.18 mmol) in EtOH (1
mL) were added 2,4,6-tri-i-Pr-benzenesulfonyl hydrazine (0.07 g, 0.24
mmol) and HOAc (4 microdrops added with a capillary tube). After
the mixture was stirred at rt for 21 h, the solvent was removed in the
pump oil and the residue purified by column chromatography (95:5
hexane/AcOEt) to give 23 mg (29%) of azine 14b as a viscous
colorless oil: [α]23D = −11.3 (c 0.23 in CHCl3); 1H NMR (300 MHz)
δ 7.12 (s, 2H), 2.82 (d, J = 14.5 Hz, 1H), 2.66 (d, J = 14.5 Hz, 1H),
2.30−2.21 (m, 2H), 1.96 (d, J = 0.9 Hz, 3H), 1.96−1.36 (3 m, 5 H),
1.06 (s, 3H), 0.92 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz) δ 165.4
(C), 140.8 (CH), 139.5 (CH), 121.7 (C), 121.2 (C), 46.5 (C), 37.9
(CH), 31.0 (CH2), 29.2 (CH2), 24.0 (CH2), 22.6 (CH2), 21.1 (CH3),
16.0 (CH3), 8.6 (CH3); IR (film) ν 1622, 1459, 1381, 1146, 1051, 873,
788, 757 cm−1; LRMS (EI) m/z 438 (M++2, 9), 437 (M++1, 32), 436
(M+, 69), 341 (39), 220 (63), 219 (30), 218 (100), 217 (76), 203
(54), 95 (100); HRMS (FAB) m/z calcd for C28H41N2O2 (M + H)+
437.3168, found 437.3172.
(1S,2R,3S)-1-Hydroxy-2,3-dimethyl-2-((4-methylfuran-3-yl)-
methyl)cyclohexanecarbonitrile (α-OH 16b): colorless solid; mp 81
°C; Rf = 0.53 (85:15, hexane/AcOEt); [α]22 = −9.6 (c 1.35 in
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.32 (s, 1H), 7.25−7.23 (m,
1H), 2.75 (d, JAB = 16 Hz, HA), 2.69 (d, JAB = 16 Hz, HB), 2.64 (d, J =
2 Hz, exchangeable OH), 2.11 (d, J = 1.5 Hz, 3H), 2.12−2.10 (m,
1H),1.96 (ddd, J = 13, 4.5, 2.0 Hz, 1H), 1.93−1.88 (m, 1H), 1.74−
1.63 (m, 1H), 1.55−1.49 (m, 2H), 1.39−1.29 (m, 1H), 1.14 (s, 3H),
1.0 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 141.7 (CH),
140.3 (CH), 121.9 (CN), 120.4 (C), 120.1 (C), 76.7 (C), 43.3 (C),
34.4 (CH2), 30.7 (CH), 30.0 (CH2), 29.4 (CH2), 19.4 (CH2), 18.3
(CH3), 16.4 (CH3), 8.44 (CH3); IR (KBr) ν 3600−3200, 2233, 1464,
1446, 1385, 1174, 1150, 1052, 1031, 998, 790 cm−1; LRMS (EI) m/z
247 (M+, 6), 96 (100), 95 (100); HRMS (FAB) m/z calcd for
C15H21NO2 (M+) 247.1572, found 247.1583.
(5S,6R)-5,6-Dimethyl-6-((4-methylfuran-3-yl))methyl)cyclohex-1-
enecarbonitrile 17. (a) From the β-OH cyanohydrin 16a:
Cyanohydrin 16a (0.25 g, 1 mmol) in dry pyridine (1.65 mL) was
cooled at 0 °C and POCl3 (0.3 mL, 3.25 mmol) was added dropwise.
After 30 min at 0 °C, 14 h at rt, and 2 h at 93 °C, the dark brown
solution was cooled at 0 °C, poured into ice, and extracted with t-
BuOMe. The organic layer was washed with saturated NaHCO3, brine,
dried (Na2SO4), and concentrated under reduced pressure. Column
chromatography (2% → 5% AcOEt in hexane) of the crude product
(0.26 g) gave the unsaturated nitrile 17 (0.16 g, 70%), saturated
ketone (0.015 g, 7%), and recovered starting cyanohydrin (0.031 g,
13%). (b) From the α-OH cyanohydrin 16b: The same procedure as
above was followed with cyanohydrin 16b (0.1 g, 0.4 mmol), dry
pyridine (0.7 mL) and POCl3 (0.12 mL, 1.3 mmol). Column
(1R,2R,3S)-1-Hydroxy-2,3-dimethyl-2-((4-methylfuran-3-yl)-
methyl)cyclohexanecarbonitrile trimethylsilyl Ether and (1S,2R,3S)-
1-Hydroxy-2,3-dimethyl-2-((4-methylfuran-3-yl)methyl)-
cyclohexanecarbonitrile Trimethylsilyl Ether 15a,b. To a solution of
ketone 12 (0.040 g, 0.18 mmol) in dry C6H6 (0.6 mL) was added
KCN (0.0027 g, 0.04 mmol), 18-crown-6 ether (0.0068 g, 0.026
mmol) and Me3SiCN (0.04 mL, 0.03 mmol) under Ar and the mixture
stirred for 3 h at rt. The reaction was quenched with brine and the
benzene layer separated. The aqueous layer was extracted with CH2Cl2
and the combined organic extracts washed with brine, dried (Na2SO4)
and concentrated at reduced pressure. Column chromatography (95:5
hexane/AcOEt) of the residue (0.07 g) gave a 3:1 mixture of
diastereoisomeric protected cyanohydrins (0.055 g, 97%) as a colorless
oil. 15a,b: Rf = 0.70 (9:1, hexane/AcOEt); [α]23 = +23.6 (c 0.44 in
D
H
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Article
chromatography purification of the crude product (0.12 g) gave the
unsaturated nitrile 17 (0.029 g, 31%), saturated ketone 12 (0.0065 g,
7%), and recovered starting cyanohydrin (0.044 g, 43%). Unsaturated
the cake thoroughly washed with Et2O. The filtrate was washed with
brine, dried (Na2SO4), and concentrated to give 0.06 g of crude
product. Column chromatography (98:2 hexane/AcOEt) afforded
pure 19 (0.021 g, 36%) as a white solid. Purification by column
chromatography (Et2O) with basic Al2O3 gave an 85% yield recovery
of impure 19 which was used in the oxidation experiments.
nitrile 17: colorless solid; mp 59−60 °C, Rf = 0.56 (85:15, hexane/
1
AcOEt); [α]22 = −88.3 (c 1.33 in CHCl3); H NMR (400 MHz,
D
CDCl3) δ 7.28 (s, 1H), 7.15−7.13 (m, 1H), 6.65 (ddd, J = 5.2, 3.2, 0.9
Hz, 1H), 2.71 (d, J = 15.2 Hz, 1H), 2.57 (d, J = 15.2 Hz, 1H), 2.14
(dtd, J = 19.8, 5.4, 3.2 Hz, 1H), 2.08−1.98 (m, 1H), 1.96 (d, J = 1.2
Hz, 3H), 1.73−1.63 (m, 1H), 1.63−1.54 (m, 1H), 1.46−1.34 (m, 1H),
1.12 (s, 3H), 0.95 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
146.2 (CH), 140.8 (CH), 139.0 (CH), 122.1 (C), 120.8 (C), 120.4
(C), 119.0 (CN), 40.8 (C), 32.0 (CH), 31.7 (CH2), 25.7 (CH2), 25.5
(CH2), 21.9 (CH3), 16.3 (CH3), 8.5 (CH3); IR (KBr) ν 2212, 1629,
1457, 1380, 1144, 1047, 871, 792 cm−1; LRMS (EI) m/z 230 (M++1,
5), 229 (M+, 28), 96 (32), 95 (100); HRMS (FAB) m/z calcd for
C15H20NO (M + H)+ 230.1545, found 230.1549.
19: unstable white solid; Rf = 0.60 (85:15 hexane/AcOEt); [α]20
=
D
1
−8.0 (c 1.24 in CHCl3); H NMR (300 MHz) δ 9.39 (s, 1H), 7.10−
7.70 (m, 1H), 6.92 (s, 1H), 6.81 (dd, J = 4.7, 3 Hz, 1H), 3.27 (d, J =
15.3 Hz, 1H), 2.53 (d, J = 15.3 Hz, 1H), 2.34 (m, 1H), 2.21 (m, 1H),
1.92 (d, J = 0.9 Hz, 3H), 1.79−1.67 (m, 1H), 1.64−1.54 (m, 1H),
1.48−1.33 (m, 1H), 1.15 (s, 3H), 0.94 (d, J = 6.6 Hz, 3H); 13C NMR
(100 MHz) δ 195.2 (C), 155.6 (CH), 147.2 (C), 140.0 (CH), 138.7
(CH), 122.0 (C), 121.1 (C), 40.2 (C), 33.4 (CH), 28.7 (CH2), 26.6
(CH2), 26.0 (CH2), 20.2 (CH3), 15.5 (CH3), 8.5 (CH3); IR (KBr)ν
1686, 1629, 1457, 1376, 1178, 1149, 1052, 869, 793 cm−1; LRMS (EI)
m/z 234 (M++2, 4), 233 (M++1, 25), 232 (M+, 82), 203 (31), 137
(87), 136 (63), 109 (87), 96 (71), 95 (100); HRMS (FAB) calcd for
C15H20O2 (M+) 232.1463, found 232.1465.
(5S,6R)-5,6-Dimethyl-6-((4-methylfuran-3-yl)methyl)cyclohex-1-
enecarboxylic Acid 18a. The unsaturated nitrile 17 (0.074 g, 0.32
mmol) and KOH (0.8 g, 14 mmol) in ethylene glycol (3.4 mL) were
heated at 180 °C (silicone oil bath) under Ar for 24 h. It was cooled in
an ice bath, water was added and extracted with t-BuOMe. The organic
layer was washed with brine, dried (Na2SO4), and concentrated at
reduced pressure to give 0.044 g (the “neutral” fraction). The aqueous
layer was cooled in an ice bath, acidified (pH∼1) with 18% HCl,
extracted with AcOEt, washed with brine, dried (Na2SO4) and
concentrated at reduced pressure. Column chromatography (8:2
hexane/Me2CO) of the residue (0.1 g) afforded acid 18a (0.05 g,
63%). An additional amount of acid (0.006g, 7%), recovered nitrile
(0.0024 g, 6%) and traces of the intermediate amide were obtained by
column chromatography (98:2 hexane/AcOEt→8:2 hexane/Me2CO)
(+)-9-Oxoeuryopsin 1. Acid 18a (0.03 g, 0.12 mmol) in dry C6H6
(1.6 mL) was cooled at 5 °C and under Ar was added PCl5 (0.028g,
0.12 mmol). The green solution was stirred at 5 °C for 25 min and at
rt for 1 h. It was cooled at 5 °C, and SnCl4 (0.03 mL, 0.25 mmol) was
added (0.1 mL C6H6 for rinsing). After 30 min, the red solution was
quenched with ice and 18% HCl (1 mL) and extracted with t-BuOMe.
The combined organic extracts were washed with 1 N HCl (2 mL),
water (2 mL), 5% Na2CO3 (3 × 2 mL), and brine (2 × 2 mL) and
dried (Na2SO4). After removal of solvent at reduced pressure the
yellow oily residue (0.030 g) was purified by column chromatography
(10% → 15% → 20% AcOEt in hexane) to afford synthetic (+)-9-
oxoeuryopsin as a white solid (0.016 g, 59%). 1: mp 124−125 °C; Rf =
of the “neutral fraction”. Acid 18a: viscous oil, Rf = 0.51 (7:3, hexane/
1
Me2CO); [α]22 = −20.8 (c 1.49 in CHCl3); H NMR (400 MHz,
D
0.54 (7:3, hexane/AcOEt); [α]20 = +6.5, [α]20 = +8.7, [α]20
=
546
589
578
CDCl3) δ 13−10 (brs, exchangeable CO2H), 7.19 (dd, 1 H, J = 4.8,
3.2 Hz, 1H), 7.12−7.09 (m, 1H), 7.06 (s, 1H), 3.13 (d, JAB = 15.2 Hz,
HA), 2.58 (d, JAB = 15.2 Hz, HB), 2.27−2.03 (m, 2H), 1.93 (d, J = 0.8
Hz, 3H), 1.81−1.69 (m, 1H), 1.61−1.51 (m, 1H), 1.50−1.35 (m, 1H),
1.21 (s, 3H), 0.93 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
173 (C), 144.7 (CH), 140.2 (CH), 138.6 (CH), 136.4 (C), 121.8 (C),
121.0 (C), 40.3 (C), 33.7 (CH), 29.8 (CH2), 25.8 (CH2), 25.6 (CH2),
21.1 (CH3), 15.9 (CH3), 8.4 (CH3); IR (film) ν 3500−2300, 1682,
1627, 1455, 1411, 1384, 1264, 1236, 1148, 1053, 940, 874, 792, 759
cm−1; LRMS (EI) m/z 250 (M++2, 2), 249 (M++1, 13), 248 (M+, 19),
153 (77), 152 (62), 107 (100), 96 (79), 95 (47); HRMS (FAB) m/z
calcd for C15H20O3 (M+) 248.1412, found 248.1406.
1
+16.9, [α]20 = +158.5 (c 1.3 in CDCl3) ; H NMR (500 MHz,
436
CDCl3) δ 7.42−7.41 (m, 1H), 6.99 (t, J = 4 Hz, 1H), 2.80 (d, JAB
=
16.5 Hz, HA), 2.48 (d, JAB = 16.5 Hz, HB), 2.32−2.26 (m, 2H), 2.0 (d, J
= 1.5 Hz, 3H), 1.87−1.78 (m, 1H), 1.63−1.46 (m, 2H), 1.05 (d, J = 7
Hz, 3H), 1.02 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 175.9 (C),
147.0 (C), 145.2 (CH), 142.5 (C), 137.3 (C), 136.6 (CH), 121.3 (C),
40.4 (C), 40.0 (CH), 34.2 (CH2), 26.3 (CH2), 26.1 (CH2), 20.5
(CH3), 15.6 (CH3), 7.7 (CH3); UV (λmax, Et2O) 291 nm (ε 24882),
UV (λmax, MeOH) 304 nm (ε 25898); IR (CCl4) ν 1674, 1626, 1607,
1537, 1461, 1420, 1347, 908, 874 cm−1; LRMS (EI) m/z 232 (M++2,
6), 231 (M+ + 1, 33), 230 (M+, 100); HRMS m/z calcd for C15H19O2
(M + H)+ 231.1385, found 231.1388.
Methyl (5S,6R)-5,6-Dimethyl-6-((4-methylfuran-3-yl)methyl)-
cyclohex-1-enecarboxylate 18b. Crude acid 18a (0.046 g) in
Me2CO (1 mL) was cooled at 0 °C, and excess ethereal solution of
CH2N2 was added. After 1 h at rt, the volatiles were removed at
reduced pressure and the residue purified by column chromatography
(98:2 hexane/AcOEt) to give methyl ester 18b (0.02 g, 41% overall
Lit.:7 colorless crystals; mp 119−120 °C; [α]589 = +0.35, [α]578
=
1
+2.8, [α]546 = +7.1, [α]436 = +9.65 (c 1.3 in CDCl3); H NMR (100
MHz, CDCl3) δ 7.31 (c, J = 1 Hz, 1H), 6.77 (t, J = 3.9 Hz, 1H), 2.74
(d, JAB = 16 Hz, HA), 2.38 (d, JAB = 16 Hz, HB), 1.98 (d, J = 1 Hz, 3H),
2.23 (m, 2H), 1.03 (s, 3H), 0.98 (s, 3H); UV λmax 291 nm (ε 16200);
IR (CCl4) ν 1675, 1625, 1605, 1540, 830 cm−1; MS (EI) m/z calcd for
C15H18O2 (M + H)+ 230.130, found 230.130, 215 (38), 202 (9), 188
(13), 173 (12), 159 (5).
yield from 17). 18b: colorless oil; Rf = 0.59 (9:1, hexane/Me2CO);
1
[α]22 = −12.6 (c 1.16 in CHCl3); H NMR (500 MHz, CDCl3) δ
D
7.11−7.10 (m, 1H), 6.97−6.95 (m, 1H), 6.96 (dd, J = 5, 3 Hz, 1H),
3.70 (s, 3H), 3.06 (dd, J = 15, 1.0 Hz, 1H), 2.59 (d, J = 15 Hz, 1H),
2.2−2.12 (m, 1H), 2.12−2.03 (m, 1H), 1.93 (dd, J = 1, 0.5 Hz, 3H),
1.79−1.7 (m, 1H), 1.59−1.53 (m, 1H), 1.47−1.38 (m, 1H), 1.21 (s,
3H), 0.92 (d, J = 6.5, 3H); 13C NMR (125 MHz) δ 167.9 (C), 141.4
(CH), 140.2 (CH), 138.6 (CH), 137.3 (C), 121.9 (C), 121.1 (C),
51.3 (CH3), 40.5 (C), 33.6 (CH), 30.0 (CH2), 25.9 (CH2), 25.3
(CH2), 21.3 (CH3), 16.0 (CH3), 8.4 (CH3); IR (film) ν 1712, 1633,
1455, 1434, 1251, 1225, 1088, 1052, 1034, 790, 760 cm−1; LRMS (EI)
m/z 264 (M++2, 4), 263 (M++1, 13), 262 (M+, 13), 231 (33), 167
(45), 166 (48), 135 (74), 107 (100), 96 (24); HRMS (FAB) m/z
calcd for C16H22O3 M+ 262.1569, found 262.1574.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of all compounds, crystal
data for compounds 1, anti-10, 12, and 16a, and experimental
and simulated ECD curves for 1. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
(5S,6R)-5,6-Dimethyl-6-((4-methyl-3-furan-3-yl)methyl)cyclohex-
1-enecarbaldehyde 19. Compound 17 (0.056 g, 0.24 mmol) in dry
toluene (4 mL) was cooled at 0 °C and under Ar was added a 1.5 M
solution of DIBALH in toluene (0.5 mL, 0.75 mmol). After the
mixture was stirred for 3 h, water (1 mL) was added, the mixture
stirred for 90 min to reach rt and filtered through a pad of Celite, and
Corresponding Author
*E-mail: lammg@unam.mx.
Notes
The authors declare no competing financial interest.
I
dx.doi.org/10.1021/jo400399q | J. Org. Chem. XXXX, XXX, XXX−XXX

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(b) Sugiura, S.; Toru, T.; Tanaka, T.; Hazato, A.; Okamura, N.;
Bannai, K.; Manabe, K.; Kurozumi, S.; Noyori, R. Chem. Pharm. Bull.
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ACKNOWLEDGMENTS
■
We thank PASPA-UNAM for a scholarship to A.L.S. and Dr.
Eugene A. Bratoeff (FQ-UNAM) and Dr. Gerardo L. Zepeda
(ENCB-IPN), members of the Tutorial Committee of A.L.S.,
for valuable suggestions to this research. The technical
́
(9) García, E.; Mendoza, V.; Guzman, J. A.; Maldonado, L. A.;
Hernandez-Ortega, S. Acta Crystallogr. 2002, C58, 336−338.
́
́
assistance of Q.F.B. Rocio Patino (IR, UV, ECD, and optical
(10) For reviews, see: (a) Jerphagnon, T.; Pizzuti, M. G.; Minnaard,
A. J.; Feringa, B. L. Chem. Soc. Rev. 2009, 38, 1039−1075. (b) Alexakis,
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H. Bull. Chem. Soc. Jpn. 1981, 54, 274−278. (e) Ertas, M.; Seebach, D.
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̃
rotations, Dr. Beatriz Quiroz, M.C. Elizabeth Huerta, and Q.
́
Ma. de los Angeles Pena (NMR) and I.Q. Luis Velasco and Dr.
̃
́
F. Javier Perez (MS) is also acknowledged. We also thank Dr.
Carlos Cerda (CINVESTAV-IPN) and Dr. Ignacio Regla (FES-
Zaragoza-UNAM) for the optical rotations of 1 at several
́
wavelengths, Dr. Fernando Cortes for computer calculations for
acquisition of the simulated ECD curves of (4S, 5R)-1 and (4R,
5S)-1, and Dr. Guillermo E. Delgado for stimulating
discussions.
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