Investigation of a new chiral auxiliary derived chemoenzymatically from toluene: Experimental and computational study

Article abstract of DOI:10.1139/cjc-2016-0327

A tricyclic chiral auxiliary, prepared from the enzymatically derived cis-arene dihydrodiol metabolite of toluene, was investigated as a means of asymmetric induction in several different reactions. The auxiliary was converted to an oxaziridine, and its u

Full text of DOI:10.1139/cjc-2016-0327

848
ARTICLE
Investigation of a new chiral auxiliary derived chemoenzymatically
from toluene: experimental and computational study
Ivan Šnajdr, Jordan Froese, Travis Dudding, Pavlína Horáková, and Tomáš Hudlicky´
Abstract: A tricyclic chiral auxiliary, prepared from the enzymatically derived cis-arene dihydrodiol metabolite of toluene, was
investigated as a means of asymmetric induction in several different reactions. The auxiliary was converted to an oxaziridine,
and its utility in hydroxylation, providing low levels of enantiomeric excess, was compared with that of Davis’s oxaziridine.
Insight into the origin of stereoinduction in this reaction is provided and is based on computational Monte Carlo Multiple
Minimum (MCMM) searches using the OPLS3 force field. The use of the auxiliary group in the alkylation of appended esters
proved disappointing. Diels-Alder cycloaddition of an acrylate, derived from the auxiliary group, with cyclohexadiene furnished
a mixture of diastereomeric adducts in essentially equal amounts. The adducts were separated and the corresponding enantio-
meric residues were isolated with good enantiomeric excess. Evidence of reasonable levels of asymmetric induction in the above
processes was lacking. Experimental and spectral data are provided for all key compounds.
Key words: chiral auxiliary, biocatalysis, computational study, Diels-Alder cycloaddition, Davis hydroxylation.
Résumé : Nous avons étudié l’utilisation d’un auxiliaire chiral tricyclique préparé a` partir d’un arène cis-dihydrodiol, un
métabolite dérivé du toluène par voie enzymatique, comme moyen d’induction asymétrique dans plusieurs réactions différen-
tes. Nous avons converti l’auxiliaire en oxaziridine et nous avons comparé son utilité dans la réaction d’hydroxylation avec celle
de l’oxaziridine de Davis, étant donné les faibles niveaux d’excès énantiomérique. Nous offrons également un point de vue sur
l’origine de la stéréo-induction dans cette réaction en nous basant sur des méthodes computationnelles de recherche Monte
Carlo (MCMM, Monte Carlo Multiple Minimum) dans lesquelles nous utilisons le champ de force OPLS3. L’emploi du groupement
auxiliaire dans l’alkylation des esters attachés s’est révélé décevant. La cycloaddition de Diels-Alder d’un acrylate dérivé du
groupement auxiliaire sur le cyclohexadiène a produit un mélange d’adduits diastéréomériques en quantités a` peu près égales.
Nous avons séparé les adduits et avons obtenu un bon excès énantiomérique après avoir isolé les résidus énantiomériques
correspondants. Les résultats ne démontrent pas des niveaux acceptables d’induction asymétrique dans les processus décrits
plus haut. Nous présentons également les données expérimentales et spectrales des composés clés. [Traduit par la Rédaction]
Mots-clés : auxiliaire chiral, biocatalyse, étude computationnelle, cycloaddition de Diels-Alder, hydroxylation de Davis.
Introduction
toluene further supported our expectations. In this paper we re-
port some rather disappointing results with regard to low level of
asymmetric induction for several common processes.
Almost two decades ago, we subjected several arene cis-dihydrodiols,
namely 1, 2, and 3, derived from styrene, toluene, and (2-bromoethyl)
benzene, respectively, to intramolecular Diels-Alder reactions. These
efforts led to the total synthesis of zeylena (5) and to an effective
model study for the synthesis of morphine fragments 7, and 9, as
shown in Fig. 1.
The model studies toward morphine eventually led to a very
efficient synthesis of ent-hydromorphone (12)4 by employing a
similar intramolecular cycloaddition strategy, shown in Fig. 1.
In addition, in 1992 we utilized compound 13 (Scheme 1),
derived from the enzymatic metabolite of styrene, in a proof of
absolute stereochemistry of new metabolites derived from o- and
m-chlorostyrenes (14). We suggested in 1993 that rigid struc-
tures of type 13 or 15 might be useful as auxiliary groups for
reactions such as Michael additions, alkylations, Diels-Alder
cycloadditions, hydroxylations, and as organocatalysts.
Results and discussion
1
2
3
Synthesis of auxiliary groups
We reasoned that the hindered exo-face of 15 would result in rigid
transition states and limited facial access for the functionalization
of groups attached to the core. We chose to examine Davis hy-
droxylation, alkylation of enolate anions, and intramolecular Diels-
Alder cycloadditions. The reactions were designed to produce known
substances for immediate comparison. The synthesis of the chiral
auxiliary group, shown in Scheme 2, begins with the enzymatic dihy-
droxylation of toluene with Escherichia coli JM109 (pDTG601A), a strain
5
6
7
that over-expresses toluene dioxygenase.
The synthesis started from enantiomericaly pure cis-dihydrodiol 2
8
obtained from the enzymatic dihydroxylation of toluene. The distal
We did not return to the investigation of compounds such as 15
until two decades later, with expectations of useful levels of asym-
metric induction that would be derived from its use as a chiral
auxiliary. The efficient and easily scalable synthesis of 15 from
hydroxyl in diol 2 was selectively protected with a bulky dimethyl-
thexylsilyl chloride (THSCI) to afford silyl ether 16 in 91% yield, as
shown in Scheme 2. When tert-butyldimethylsilyl chloride was used
instead of THSCl, migration of the protecting group was observed in
Received 22 June 2016. Accepted 23 July 2016.
I. Šnajdr, J. Froese, T. Dudding, P. Horáková, and T. Hudlick y´ . Department of Chemistry and Centre for Biotechnology, Brock University,
St. Catharines, ON L2S 3A1, Canada.
Corresponding author: Tomáš Hudlický (email: thudlicky@brocku.ca).
Copyright remains with the author(s) or their institution(s). Permission for reuse (free in most cases) can be obtained from RightsLink.
Can. J. Chem. 94: 848–856 (2016) dx.doi.org/10.1139/cjc-2016-0327
Published at www.nrcresearchpress.com/cjc on 4 August 2016.

Šnajdr et al.
849
Fig. 1. Synthesis of zeylena (5) and ent-hydromorphone (12) via intramolecular [4+2] cycloaddition.
5
Scheme 1. Proof of absolute stereochemistry of 14. Reagents and
sion. When the reaction mixture was heated to reflux, the conver-
sion was complete, but the yield after chromatography was only
42%. When the amount of TBAF was decreased to 1.4 equivalents,
the yield increased to 72% after 3 h of reflux in dry THF. Alcohol 15
was then oxidized with pyridinium chlorochromate in CH Cl to
conditions: (i) NaH, allyl bromide, THF, –20 °C; (ii) CCl , 80 °C;
4
(
iii) H , Pd/C, 45 psi.
2
2
2
provide ketone 20 in 91% yield.
Formation of imine 21 was rather complicated. Ketone 20 was
treated with tosylamine in the presence of various titanium cata-
lysts, and the use of TiCl or TiCl /Ti(O-iPr) , in refluxing CH Cl ,
4
4
4
2
2
1,2-DCE, or THF did not lead to any conversion. The use of Ti(O-iPr)4
in refluxing CH Cl provided 65% conversion with 35% of the
2
2
starting material recovered. The best results were obtained using
Ti(O-iPr) in refluxing THF, which resulted in complete conversion
4
after 5 days. Imine 21 was not stable to silica gel, decomposing to
ketone 20. Purification was accomplished by extraction and rapid
filtration through a short plug of silica, and the compound was used
immediately in the next step. Imine 21 was oxidized in a biphasic
TM
system of toluene and aqueous K CO using Oxone as an oxidant.
2
3
the subsequent step. Alcohol 16 was then alkylated with allyl bro-
mide, and the resulting allyl ether spontaneously underwent intra-
molecular Diels-Alder reaction upon work-up. To complete the
conversion, the crude reaction mixture was dissolved in THF and
heated to reflux. Column chromatography of the reaction mixture
provided tricyclic silyl ether 18 in 83% yield. The alkene in 18 was
then reduced using 10% Pd/C in a Parr shaker to afford compound 19
in 93% yield.
The resulting oxaziridine 22 was also not stable to silica gel, decom-
posing to ketone 20. Purification of an analytical sample was possi-
ble on deactivated silica gel (10% w/w H O).
2
Davis hydroxylation attempts
Deoxybenzoin 23 was selected as a model compound for enan-
tioselective hydroxylations. The use of (–)-Davis oxaziridine led to
9
the production of 24 in 85% yield with 95% ee. We followed the
The deprotection of the dimethylthexylsilyl group proved to be
problematic. The standard procedure, using 3 equivalents of TBAF
in dry THF at room temperature (RT), provided only 45% conver-
same procedure using NaHMDS and oxaziridine 22 in dry THF at
–78 °C (Scheme 3). Purification of the reaction mixture afforded
85% yield of 24 (R)- and 25 (S)-benzoin with a disappointing 16% ee
Published by NRC Research Press

850
Can. J. Chem. Vol. 94, 2016
Scheme 2. Synthesis of oxaziridine 22.
Scheme 3. Hydroxylation with oxaziridine 22.
Fig. 3. Lowest energy si- vs. re-stereofacial addition modes (si–23 and
re–23) and superimposition. [Colour online.]
Fig. 2. Imposed constraints for MCMM search. [Colour online.]
in favor of 25, which was the opposite enantiomer than the one
obtained from the reaction with (–)-Davis’s oxaziridine. This result
may be surprising in view of the similarity of the structure of oxaziri-
dine 22 to that of Davis’s oxaziridine. We have not assigned the
stereochemistry of 22 but assumed that the oxaziridine had the endo-
configuration. Modeling of the transition state for the hydroxylation
of 23 also assumed the endo-22, and the prediction is clearly in favor
of si-23 that would lead to (S)-25, which is in agreement with the
experimental results (see Fig. 3 and discussion of calculations below).
Alkylation attempts
To test enantioselective alkylation, we prepared phenylacetyl
ester 26 from alcohol 15 in 74% yield. Alkylation using lithium
diisopropylamide and methyl iodide at –78 °C provided ester 27 in
8
4% yield. Ester 27 was then hydrolyzed using LiOH in aqueous meth-
10
anol, affording 2-phenylpropanoic acid 28 in 86% yield (Scheme 4).
The analysis of the specific rotation revealed an essentially racemic
mixture of (R-) and (S-) enantiomers with 5% ee.
[
4+2] Cycloaddition attempts
To investigate the asymmetric induction in [4+2] cycloaddition
reactions, acryloyl ester 29 was prepared from alcohol 15 in 87%
yield by treatment with acryloyl chloride and triethylamine. The
subsequent [4+2] cycloaddition was performed in a sealed tube in
toluene at 155 °C (Scheme 5). Purification of the reaction mixture
Published by NRC Research Press

Šnajdr et al.
851
Scheme 4. Alkylation with auxiliary 15.
Scheme 5. [4+2] cycloaddition with auxiliary 15.
Scheme 6. Synthesis of rac-32.
by column chromatography provided two compounds, 30a and
From these results, we assumed that 32a and 32b each repre-
sent an individual enantiomer of the endo-isomer. To confirm this
hypothesis, chiral HPLC analysis of both samples 32a and 32b was
performed, and a racemic standard was prepared, as shown in
Scheme 6.
Chiral HPLC analysis of the racemate (rac-32) showed two peaks
at 22.3 min and 23.0 min, respectively, and a minor peak corre-
sponding to the exo-isomer (likely formed by partial epimerization
of the ester) at 23.8 min. The analysis of compound 32a displayed
one major peak at 22.7 min, whereas sample 32b showed a differ-
ent peak at 22.0 min, representing the other enantiomer.
Based on these chiral HPLC results, we prepared both endo-
isomers that were easily separated using standard column chro-
matography. Unfortunately, the nearly 1:1 ratio of 30a to 30b
indicates that no significant asymmetric induction was achieved
during the cycloaddition with enantiomeric excess estimated as <5%.
3
0b, in nearly equal amounts, indicating that almost no asymmet-
ric induction took place.
Initially, these compounds were separated and treated with so-
1
1
dium methoxide to obtain the known methyl esters (31a, 31b).
1
H-NMR spectrum of 31a showed a mixture of 95% endo- and 5%
exo-isomers. Similarly, 31b showed a mixture of 90% endo- and 10%
exo-isomers. The specific rotations were also different — 31a was
+
1.2 and 31b was –39.5. The literature value for 99% enantiomeri-
11
cally enriched sample of 31a is +95.6.
To determine the composition of the above-mentioned products,
and to ensure that no epimerization took place during methanolysis
of 30a/30b, each adduct was separately treated with Red-Al to obtain
12
starting alcohol 15 and alcohols 32a and 32b (Scheme 5). After
chromatographic separation of these alcohols, the specific rotation
of both was measured. The specific rotation of starting alcohol 15
remained unchanged, as expected. The values corresponding to the
new alcohols 32a and 32b however were different: 32a was –10.5 and
Computational studies
3
2b was +7.7. The literature value for 99% enantiomerically enriched
Disappointed by the outcomes of the three reactions studied,
namely alkylation, dihydroxylation, and Diels-Adler cycloaddition,
12
13
sample of 32a is +8.7 and for 32b is –10.7.
Published by NRC Research Press

852
Can. J. Chem. Vol. 94, 2016
we turned to computational modeling to gain insight into the factors
contributing to the low levels of asymmetric induction offered by
our tricyclic chiral auxiliary. To this end, we focused on understand-
ing the stereoselectivity conferred by oxaziridine 22 in the dihy-
droxylation reactions affording (S)-benzoin (25) in 16% ee, as opposed
to the alkylation or the Diels-Alder reactions. The basis for this deci-
sion stemmed from the rationale that little, if any, meaningful in-
sight into the origin of stereoselectivity could be gained by studying
the latter two cases because of the extremely low stereoselectivity
observed (see Supplementary data for additional information). Thus,
working under the conceptual framework of the Hammond–Leffler
postulate with the imposed caveat that oxaziridine oxygen transfer
occurred early on the reaction coordinate, Monte Carlo Multiple Min-
imum (MCMM) searches using the OPLS3 force field as implemented
in the Schrödinger MacroModel software program were used to ra-
tionalize the stereoinduction offered by 22.1 More specifically, we
performed a MCMM simulation initiated from a geometry conform-
ing to a CÊO bond forming precomplex for addition of an enolate
derived in situ from 23 to the oxaziridine ring of 22. Imposed on this
system were a CÊO bond distance constraint of 2.8 Å, while the
coordinates of the *C, *O, and *N of the oxaziridine ring were frozen,
as shown in Fig. 2.
Conclusions
The chiral auxiliary group 15, prepared from the homochiral
diene-diol (2), derived chemoenzymatically from toluene, was inves-
tigated for asymmetric induction in several reactions: Davis-
type hydroxylations utilizing its oxaziridine derivative, alkylation of
appended esters, and [4+2] cycloadditions of an appended acrylate
with cyclohexadiene. The very low levels of induction observed in
hydroxylation reactions were disappointing. No induction was ob-
served in alkylation or cycloaddition reactions, although enantiom-
ers of bicyclic alcohols 31a and 31b were isolated after separation of
the diastereomeric adducts. We attribute the lack of any reasonable
induction to the freely rotating side chain of appended functional-
ities. The expected structural similarity of 15 to chiral auxiliary
groups derived from camphor and other rigid bicyclic systems was
clearly not evident in the results obtained. The computational study
confirmed the reasons for the low levels of induction observed espe-
cially in the case of hydroxylation.
5
Experimental section
General experimental
All nonaqueous reactions were conducted under an inert (ni-
trogen or argon) atmosphere, using standard Schlenk techniques
for the exclusion of moisture and air. All solvents were distilled
unless otherwise noted. Analytical thin-layer chromatography was
performed on silica gel 60 Å 250 ␮m TLC plates with F-254 indicator.
Flash column chromatography was performed using silica gel (230–
This search provided a conformer distribution (5.02 kcal/mol
cut-off threshold) (1 cal = 4.184 J) that revealed a 0.35 kcal/mol
energetic difference between the lowest energy si- vs. re-stereofacial
addition modes (si-23 and re-23), which favored the formation of
16
(
S)-benzoin. Notably, this is in reasonable agreement with the ex-
400 mesh). Melting points are uncorrected. Optical rotation was mea-
perimental formation of (S)-benzoin in 16% ee (predicted = 29% ee),
shown in Fig. 3. Perhaps worth noting is the fact that the C-O-N
sured in 1 dm cell at 25 °C (unless otherwise stated) and 589 nm,
concentration in g/100 mL on PerkinElmer 341 polarimeter. IR spec-
tra were obtained on Bruker ALPHA FT-IR spectrometer. H and
spectra were recorded on Bruker 300 MHz and (or) 600 MHz spec-
trometers. All chemical shifts are referenced to TMS or residual non-
deuterated solvent. Data for proton spectra are reported as follows:
chemical shift (multiplicity [singlet (s), doublet (d), triplet (t), quartet
(bond-making/bond-breaking) angle in si-23 and re-23 was displaced
1
13
C
from the 180° metric that one might expect based on the theoretical
work of Bach, which is not at all surprising given the use of precom-
plexes vs. transition states for this analysis.17
As for the factors contributing to stereoselectivity, a superim-
position (maximum atom deviation = 0.5 Å) of these two stereofa-
cial addition modes offered visible clues (see si/re-23 overlay,
Fig. 3). Foremost in this regard was the flipped, circa 180°, orienta-
tions of the enolates relative to the oxaziridine ring, which resulted
in subtle differences in terms of negative van der Waals contacts (i.e.,
steric interactions). For instance, the displaced edge-to-face C–H/␲
aryl arrangement between the tosyl ring and the enolate phenyl
group of re-23 introduced an unfavorable C–HÊC contact measuring
(q), quintet (quint), and multiplet (m)], coupling constants [Hz], inte-
gration). Carbon spectra were recorded with complete proton decou-
pling and the chemical shifts are reported in ppm (C). Mass spectra
and high resolution mass spectra were performed by the analytical
division at Brock University. Combustion analyses were performed
by Atlantic Microlabs, Atlanta, Georgia, USA.
(–)-(3aS,7S)-3a-Methyloctahydro-3,6-methanobenzofuran-7-ol (15)
2
.67 Å, which is markedly below the summed radii of C and H (C =
18
1.7 Å, H = 1.2 Å). In addition, an unfavourable steric relationship
between a hydrogen of the tricyclic core of 22 and the nearby phenyl
of the enolate was also present in re-23 (C–HÊC, distance = 2.81 Å).
Conversely, the offset ␲-␲ alignment in si-23 did not result in a com-
parable steric interaction between the tosyl ring and the proximal
phenyl of the enolate, with the closest interaction being a C–HC
contact (distance = 2.89 Å). Meanwhile no unfavourable van der
Waals contacts were found between the tricyclic motif and enolate
in si-23. At that stage, to provide for a more evolved and in-depth
vision of the elements governing stereoselectivity, the optimization
of structures si-23 and re-23 to first-order saddle points at the density
functional theory (DFT) level was attempted, which were unfortu-
nately unsuccessful. Notwithstanding, despite the fact that our chi-
ral auxiliary did not provide good levels of asymmetric induction, it
is noteworthy that the conceptual understanding that has emerged
from this study offers some promise as a point of departure for
designing new chiral auxiliaries. Indeed, the MCMM modelling ap-
proach employed herein is fast (processing time on a standard PC
desktop computer = 2 min) and simple to execute. Accordingly, its
use as springboard for DFT studies and employment as a rapid
method for assessing stereoselective trends provided by chiral auxil-
iary oxaziridine reagents is ongoing and developments on this front
will be reported.
A solution of compound 19 (17.5 g, 56.3 mmol) in an anhy-
drous THF (80 mL) was cooled to 0 °C and tetrabutylammonium
fluoride [1 mol/L solution in THF (78.9 mL, 78.9 mmol)] was
added. The reaction mixture was heated to reflux for 3 h. The
reaction mixture was then quenched with H O (150 mL), and
2
extracted with CH Cl (3 × 100 mL). The combined organic ex-
2
2
tracts were dried (Na SO ) and concentrated under reduced
2
4
pressure to provide a yellow oil, which was purified by column
chromatography on silica gel eluting with [hexane/EtOAc (3:1)].
The alcohol 15 was obtained as white solid. Yield 6.82 g (72%).
15: R = 0.26 [hexane/EtOAc (3:1)]; mp 129–131 °C (hexane);
f
[␣]D2 = –8.8 (c = 0.5, CHCl ). IR (neat) ␯ 2924, 2867, 1069, 1048,
2
3
−
1 1
1039, 987, 923, 897, 760 cm . H-NMR (300 MHz, CDCl ) ␦ 4.16–
3
4.00 (m, 1H), 3.75 (d, J = 6.7 Hz, 1H), 3.66 (t, J = 6.8 Hz, 1H), 3.46
(dd, J = 7.4, 5.2 Hz, 2H), 1.91–1.43 (m, 9H), 0.99 (s, 3H); 1 C-NMR
3
(75 MHz, CDCl ) ␦ 80.8, 76.4, 71.5, 40.3, 40.1, 31.3, 30.2, 25.8,
3
24.3, 23.6. MS (EI) m/z (%) 186 (5), 150 (10), 133 (35), 107 (20),
93 (100), 91 (80), 79 (95), 77 (60), 55 (75). HRMS (EI) calcd. for
Published by NRC Research Press

Šnajdr et al.
853
C H O : 168.1154; found 168.1150. Anal. calcd. for C H O : C,
EtOAc (15:1)]. Product 18 was obtained as a yellow oil. Yield
1
0
16
2
10 16 2
7
1.39; H, 9.59. Found: C, 71.26; H, 9.52.
1.18 g (83%).
2
f 3
2
1
8: R = 0.61 [hexane/EtOAc (9:1)]; [␣]D = –61.8 (c = 0.5, CHCl ). IR
(1R,6S)-6-(((2,3-Dimethylbutan-2-yl)dimethylsilyl)oxy)-
(
neat) ␯ 3041, 2949, 2872, 1250, 1127, 1101, 912, 888, 860, 832,
76 cm . H-NMR (300 MHz, CDCl ) ␦ 6.23 (dd, J = 8.2, 6.9 Hz, 1H),
.66 (dd, J = 8.3, 1.4 Hz, 1H), 4.00 (dd, J = 7.5, 4.9 Hz, 1H), 3.61 (d, J =
.6 Hz, 1H), 3.46 (dt, J = 6.8, 2.0 Hz, 1H), 3.33 (d, J = 6.8 Hz, 1H),
.39–2.18 (m, 1H), 1.83–1.39 (m, 4H), 1.22 (s, 3H), 0.97–0.77 (m, 13H),
2
-methylcyclohexa-2,4-dienol (16)2
−1 1
7
5
7
2
0
3
1
3
.16- –0.02 (m, 6H). C-NMR (75 MHz, CDCl ) ␦ 134.8, 132.2, 77.6,
3
Diol 2 (0.9 g, 7.13 mmol) was recrystallized from EtOAc/pentane
74.4, 72.1, 45.9, 40.2, 36.8, 34.4, 34.0, 25.1, 21.2, 20.6, 20.2, 18.7, 18.5,
–2.7, –3.4; MS (EI) m/z (%) 223 (100), 205 (39), 193 (52), 131 (55), 91 (32),
75 (62), 73 (29). HRMS (EI) calcd. for C H O Si (loss of C H ):
and dissolved in dry DMF (20 mL). Imidazole (0.56 g, 8.28 mmol) was
added to the stirring mixture, followed by dimethylthexylchlorosi-
lane (1.65 mL, 8.42 mmol) and the mixture was allowed to react at
1
8
32
2
6 13
223.1154; found 223.1155. Anal. calcd. for C H O Si: C, 70.07; H,
1
8 32 2
–
20 °C for 23 h. The reaction mixture was then diluted with Et O
10.45. Found: C, 70.37; H, 10.45.
2
(
50 mL) and washed with brine (3 × 25 mL). The brine was back-
(
–)-(2,3-Dimethylbutan-2-yl)dimethyl(((3aS,7S)-3a-
extracted with Et O (3 × 25 mL), and the combined organic extracts
were washed with sat. CuSO (3 × 25 mL), water (30 mL) and brine
2
methyloctahydro-3,6-methanobenzofuran-7-yl)oxy)silane (19)
4
(
30 mL). The combined organic extracts were dried (Na SO ) and
2 4
concentrated under reduced pressure to give a yellow oil, which was
purified by column chromatography on silica gel (10% deactivated
with H O) with [hexane/based washed EtOAc (95:5)]. Product 16 was
2
obtained as yellow oil. Yield 1.73 g (91%). Spectral data were in agree-
2
The Diels-Alder adduct 18 (1.93 g, 6.25 mmol) was dissolved in
absolute ethanol (100 mL), and 10% Pd/C was added (250 mg,
0.23 mmol). The mixture was hydrogenated in Parr shaker at 20 psi of
ment with previously published data.
2
2
2
1
6: R = 0.72 [hexane/EtOAc (9:1)]; [␣]
= 69.5 (c = 0.5, CHCl ) (lit.
3
f
D
22
1
3 3
[
␣]D = 86.11 (c = 1.26, CHCl ). H-NMR (300 MHz, CDCl ) ␦ 5.87 (ddd,
TM
H for 3 h. The reaction mixture was then filtered through Celite
J = 9.6, 5.3, 1.6 Hz, 1H), 5.74 (d, J = 5.4 Hz, 1H), 5.62 (dd, J = 9.6, 2.6 Hz,
H), 4.56–4.39 (m, 1H), 3.89 (t, J = 5.3 Hz, 1H), 2.63 (d, J = 4.8 Hz, 1H),
.94 (s, 3H), 1.75–1.55 (m, 1H), 1.03–0.77 (m, 14H), 0.16 (d, J = 6.2 Hz, 7H).
2
and the solvent was removed under reduced pressure to provide
1
1
1.84 g of a colorless oil, which was purified by column chromatogra-
phy on silica gel, eluting with [hexane/EtOAc (15:1)]. Product 19 was
(
(
((1S,6R)-6-(Allyloxy)-5-methylcyclohexa-2,4-dien-1-yl)oxy)
2,3-dimethylbutan-2-yl)dimethylsilane (17)
obtained as a colorless oil. Yield 1.81 g (93%).
19: R = 0.65 [hexane/EtOAc (9:1)]; [␣]D = –17.7 (c = 0.5, CHCl ).
IR (neat) ␯ 2926, 2866, 1249, 1130, 1099, 830, 773 cm . H-NMR
2
f 3
2
−
1 1
(
300 MHz, CDCl ) ␦ 4.08–3.95 (m, 1H), 3.69 (d, J = 6.7 Hz, 1H), 3.57
3
(
0
d, J = 6.7 Hz, 1H), 3.41 (d, J = 7.5 Hz, 1H), 1.85–1.38 (m, 9H),
.99–0.70 (m, 15H), 0.18–0.01 (m, 6H). C-NMR (75 MHz, CDCl3)
1
3
A solution of silyl ether 16 (1.07 g, 3.99 mmol) in dry THF
30 mL) was added dropwise to a stirring slurry of NaH (0.28 g,
.98 mmol) in dry THF (10 mL) at 0 °C. The resulting mixture was
stirred for 10 min at this temperature, which was followed by
the rapid addition of allylbromide (0.45 mL, 5.19 mmol). The
mixture was allowed to warm to RT and after 5 h of stirring, the
␦ 81.8, 75.9, 73.9, 40.7, 40.0, 34.5, 32.2, 31.1, 26.0, 25.1, 24.5, 23.9,
20.6, 20.3, 18.7, 18.5, –2.6, –3.3; MS (EI) m/z (%) 226 (29), 225 (92),
223 (33), 196 (29), 195 (100), 133 (28), 119 (44), 91 (31), 75 (86), 73
(
6
(46), 59 (30). HRMS (EI) calcd. for C18
H
O
Si (loss of C
H13):
34
2
6
225.1311. Found: 225.1315. Anal. calcd. for C18
H, 11.04. Found: C, 70.05; H, 10.98.
H O
34 2
Si: C, 69.62;
reaction mixture was quenched with H O (10 mL) and extracted
2
(
7
–)-(3aS,6R)-3a-Methylhexahydro-3,6-methanobenzofuran-
(7aH)-one (20)
with Et O (3 × 25 mL). The combined organic extracts were
2
washed with H O (30 mL), brine (3 × 25 mL), and dried (Na SO ).
2
2
4
Concentration under reduced pressure provided a yellow oil,
which was purified by column chromatography on silica gel
(
10% deactivated with H O) eluting with [hexane/EtOAc (15:1)].
2
Product 17 was obtained as a yellow oil. Yield 0.88 g (65%).
1
1
7: H-NMR (300 MHz, CDCl ) ␦ 6.26 (dd, J = 8.2, 6.9 Hz, 1H), 5.96
3
Alcohol 15 (330 mg, 1.96 mmol) was dissolved in dry CH Cl2
30 mL), and pyridinium chlorochromate (2.11 g, 9.81 mmol) was
added. The mixture was allowed to stir for 20 h at RT. The
2
(
2
1
1
dd, J = 6.1, 4.9 Hz, 1H), 5.69 (dd, J = 8.3, 1.3 Hz, 1H), 4.14 (q, J = 7.1 Hz,
H), 4.03 (dd, J = 7.6, 4.8 Hz, 1H), 3.62 (s, 1H), 3.48 (dt, J = 6.8, 2.0 Hz,
H), 3.35 (d, J = 6.8 Hz, 1H), 2.28 (d, J = 3.9 Hz, 1H), 1.85–1.46 (m, 9H),
.41–1.13 (m, 17H), 0.99–0.69 (m, 25H), –0.01–0.26 (m, 11H).
(
reaction mixture was then diluted with Et O (30 mL) and fil-
2
tered through a short plug of silica gel. The solvent was re-
moved under reduced pressure, and the title compound was
recrystallized from hot hexane (20 mL) affording 20 as a white
solid. Yield 298 mg (91%).
(
2
–)-(2,3-Dimethylbutan-2-yl)dimethyl(((3aS,7S)-3a-methyl-
,3,3a,6,7,7a-hexahydro-3,6-methanobenzofuran-7-
yl)oxy)silane (18)
2
0: R = 0.43 [hexane/EtOAc (3:1)]; mp 105–106 °C (hexane);
f
2
2
[
1
␣]D = –25.7 (c = 0.5, CHCl ). IR (neat) ␯ 2955, 2931,2874, 1715,
237,1028, 1000, 884, 486 cm . H-NMR (300 MHz, CDCl ) ␦ 4.15
3
3
−
1 1
(
2
dd, J = 7.9, 4.3 Hz, 1H), 3.60–3.44 (m, 2H), 2.23 (d, J = 2.6 Hz, 1H),
.15 (dd, J = 9.5, 4.3 Hz, 1H), 2.04 (dd, J = 13.3, 9.5 Hz, 1H),
1
3
A solution of silyl ether 17 (1.43 g, 4.63 mmol) in dry THF
1.93–1.53 (m, 5H), 1.05 (s, 3H). C-NMR (75 MHz, CDCl ) ␦ 212.8,
3
(
30 mL) was heated to reflux for 2 h. After the reaction was
84.0, 76.2, 43.1, 39.9, 38.7, 31.4, 26.2, 23.2, 22.6; MS (EI) m/z (%)
166 (89), 138 (57), 120 (75), 109 (44), 107 (87), 105 (56), 96 (37), 95
(55), 93 (74), 92 (66), 91 (62), 83 (84), 82 (32), 81 (54), 80 (30), 79
(73), 77 (45), 68 (30), 67 (100), 55 (63), 53 (53). HRMS (EI) calcd. for
deemed to be complete, the solvent was removed under re-
duced pressure to give a light yellow oil, which was purified by
column chromatography on silica gel, eluting with [hexane/
Published by NRC Research Press

854
Can. J. Chem. Vol. 94, 2016
2
2
C H O : 166.0994. Found: 166.0986. Anal. calcd. for C H O :
C, 72.26; H, 8.49. Found: C, 72.23; H, 8.49.
24 + 25: R = 0.46 [hexane/EtOAc (5:1)]; [␣]
= 18.5 (c = 0.83,
CHCl ); ee = 16%. H-NMR (400 MHz, CDCl ) ␦ 7.91 (dd, J = 5.2,
3
(
7
1
0
14
2
10 14
2
f
D
1
3
3
1
3
.4 Hz, 2H), 7.66–7.09 (m, 8H), 5.96 (s, 1H), 4.56 (s, 1H). C-NMR
101 MHz, CDCl ) ␦ 199.0, 139.0, 133.9, 129.7, 128.7, 128.6, 127.8,
(E)-4-Methyl-N-(3a-methylhexahydro-3,6-methanobenzofuran-
3
7(7aH)-ylidene)benzenesulfonamide (21)
6.23.
The same reaction was run with (-) Davis Reagent for compari-
2
2
son. [␣]D = –78.5 (c = 0.83, CHCl ); ee = ϳ95% (estimated).
3
(7S,7aR)-3a-Methyloctahydro-3,6-methanobenzofuran-7-yl
2
-phenylacetate (26)
To a stirring solution of ketone 20 (20 mg, 0.1203 mmol) in dry THF
3 mL) was added titanium(IV) isopropoxide (102.57 mg, 0.361 mmol),
followed by the rapid addition of 4-toluenesulfonamide (22.66 mg,
.132 mmol). The mixture was heated to reflux for 89 h. The reaction
(
0
was then quenched with brine and extracted with EtOAc (3 × 30 mL).
The combined organic extracts were dried (Na SO ), concentrated un-
der reduced pressure, and the resulting residue was filtered through
a short plug of silica gel eluting with [hexane/EtOAc (3:1)]. The solvent
was evaporated under reduced pressure affording 21 as a colorless
oil.
Alcohol 15 (0.185 mg, 1.1 mmol) was dissolved in anhydrous
2
4
CH Cl (5 mL), and NaH (60% in oil dispersion, 48 mg, 1.2 mmol)
2
2
was added at 0 °C. The reaction mixture was stirred for 1 h
before phenylacetyl chloride (0.26 mL, 2.0 mmol) was added,
and the reaction mixture was then stirred for 16 h at RT. The
reaction mixture was then quenched with a saturated solution
(
3aS)-3a-Methyl-2=-tosylhexahydro-2H-spiro[3,6-
of NH Cl and extracted with EtOAc (3 × 25 mL). The combined
4
methanobenzofuran-7,3=-[1,2] oxaziridine] (22)
organic extracts were concentrated under reduced pressure,
and the residue was purified by column chromatography on
silica gel eluting with [hexane/EtOAc (6:1)] providing 26 as a
colorless oil. Yield 233 mg (74%).
2
2
2
6: R = 0.78 [hexane/EtOAc (3:1)]; [␣]D = –55.1 (c = 1.0, CHCl ). IR
f 3
1
(
(
neat) ␯ 2931, 2870, 1728, 1452, 1356, 1218, 1165, 1025, 702. H-NMR
400 MHz, CDCl ) ␦ 7.62–7.07 (m, 5H), 4.56 (d, J = 6.2 Hz, 1H), 3.90 (t,
3
Imine 21 (50 mg, 0.156 mmol) was dissolved in toluene (3 mL)
J = 24.7 Hz, 2H), 3.77–3.52 (m, 2H), 3.15 (d, J = 7.8 Hz, 1H), 1.94–1.06
and an aqueous solution of K CO (83.1 mg, 0.6 mmol) was added.
The mixture was stirred vigorously, and an aqueous solution of
Oxone (105.3 mg, 0.342 mmol) was added dropwise. The mix-
ture was stirred for 6 h at RT. The aqueous layer was separated,
extracted with toluene (3 × 3 mL), and the combined organic ex-
tracts were washed with 10% aqueous solution of Na SO , dried
2
3
1
3
(
m, 8H), 0.84 (d, J = 63.4 Hz, 3H). C-NMR (101 MHz, CDCl ) ␦ 171.2,
3
TM
134.5, 129.5, 129.4, 128.6, 128.4, 126.8, 78.7, 76.3, 76.0, 41.4, 40.9,
0.5, 39.8, 32.3, 27.2, 25.7, 24.1, 23.5. MS (EI) m/z (%) 286 (25), 167
15), 150 (20), 118 (45), 105 (20), 91 (100), 77 (20). HRMS (EI) calcd. for
C H O : 286.1569. Found: 286.1561; Anal. calcd. for C H O : C,
4
(
18 22
3
18 22 3
2
3
75.50; H, 7.74. Found: C, 75.36; H, 7.63.
over anhydrous MgSO , and purified by column chromatography
4
on silica gel (10% deactivated with H O) eluting with [hexane/
2
(
2
7S,7aR)-3a-Methyloctahydro-3,6-methanobenzofuran-7-yl
-phenylpropanoate (27)
EtOAc (4:1)]. Yield 30 mg (57%).
2
2
2
2: R = 0.21 [hexane/EtOAc (4:1)]; [␣]D = –63.6 (c = 1.285, CHCl3).
f
IR (neat) ␯ 2929, 2874, 1349, 1164, 1115, 892, 814, 709, 671, 659, 566,
1
5
5
3
29. H-NMR (300 MHz, CDCl ) ␦ 5.83 (ddd, J = 9.6, 5.3, 1.6 Hz, 1H),
3
.74–5.66 (m, 1H), 5.59 (dd, J = 9.6, 2.7 Hz, 1H), 4.48–4.35 (m, 1H),
.86 (t, J = 5.4 Hz, 1H), 2.59 (d, J = 4.9 Hz, 1H), 1.90 (s, 1H), 1.72–1.56
(
m, 1H), 0.94–0.78 (m, 2H), 0.14 (s, 3H). 13C-NMR (75 MHz, CDCl ) ␦
3
1
45.45, 145.25, 134.92, 129.79, 129.70, 128.82, 128.39, 97.89, 93.73,
A solution of freshly prepared LDA (0.82 mmol) in THF was added
8
3
6
4.60, 81.86, 76.12, 76.06, 41.77, 40.96, 39.46, 39.26, 31.71, 31.54,
1.50, 25.70, 24.84, 23.70, 23.20, 22.83, 22.75, 21.70. MS (EI) m/z (%)
79 (44), 662 (39), 661 (100), 360 (25), 358 (48), 342 (25), 320 (28).
dropwise to a solution of phenylacetyl ester 26 (0.21 g, 0.74 mmol) in
THF (7 mL) at –78 °C. The reaction mixture was stirred for 1 h before
the dropwise addition of methyl iodide (0.05 mL, 0.82 mmol). The
reaction mixture was then slowly warmed to –20 °C before being
Asymmetric hydroxylation
quenched with a saturated solution of NH Cl and extracted with
4
EtOAc (3 × 25 mL). The combined organic extracts were concentrated
under reduced pressure, and the resulting residue was purified by
column chromatography on silica gel eluting with [hexane/EtOAc
(6:1)] yielding 187 mg (84%) of 27 as a colorless oil.
Sodium bis(trimethylsilyl)amide (0.12 mL, 0.05 mmol) was
cooled in acetone/dry ice bath to –78 °C, and a solution of
deoxybenzoin 23 (18 mg, 0.092 mmol) in THF (1 mL) was added
dropwise. The mixture was stirred at this temperature for 30 min,
and a solution of oxaziridine 22 (46 mg, 0.138 mmol) in THF (1 mL)
was added. The reaction was monitored by TLC for 4 h, before being
27: R = 0.83 [hexane/EtOAc (3:1)]. IR (neat) ␯ 2930, 2870, 1729,
f
1
1493, 1376, 1205, 1165, 1063, 728. H-NMR (400 MHz, CDCl ) ␦ 7.41–
3
7.29 (m, 4H), 7.29–7.22 (m, 1H), 4.61–4.44 (m, 1H), 4.06–3.89 (m, 1H),
3.89–3.69 (m, 2H), 3.26 (d, J = 7.8 Hz, 1H), 2.82 (d, J = 7.9 Hz, 1H),
1.94–1.34 (m, 8H), 0.95 (d, J = 3.8 Hz, 3H), 0.91 (s, 3H). 1 C-NMR
3
(101 MHz, CDCl ) ␦ 174.2, 173.7, 140.90, 140.86, 129.5, 128.7, 128.4,
3
quenched with NH Cl, and the mixture was allowed to warm to RT.
128.3, 128.0, 127.8, 126.9, 126. 8, 78.83, 78.81, 76.3, 76.1, 75.7, 45.6,
45.5, 40.5, 39.8, 39.6, 32.3, 32.2, 27.2, 27.1, 25.6, 25.5, 24.2, 23.47,
23.45, 18.7, 18.0. MS (EI) m/z (%) 300 (10), 210 (10), 167 (10), 151 (20),
132 (20), 105 (100), 91 (75), 79 (20). HRMS (EI) calcd. for C H O :
4
The aqueous solution was extracted by Et O (3 × 5 mL), and the
2
combined organic extracts were dried (Na SO ), concentrated under
2
4
reduced pressure, and the resulting residue was purified by column
chromatography on silica gel eluting with [hexane/EtOAc (5:1)]. Yield
19 24 3
300.1725. Found: 300.1729. Anal. calcd. for C H O : C, 75.97; H,
1
9 24 3
17 mg (85%).
8.05. Found: C, 76.25; H, 8.01.
Published by NRC Research Press

Šnajdr et al.
855
-Phenylpropanoic acid (28)10
1
H-NMR (300 MHz, CDCl ) ␦ 6.31 (t, J = 6.9 Hz, 1H), 6.25–6.11 (m, 1H),
2
3
4
7
6
.49 (t, J = 7.1 Hz, 1H), 4.01 (ddd, J = 13.4, 8.1, 5.3 Hz, 1H), 3.91 (t, J =
.8 Hz, 1H), 3.47–3.31 (m, 1H), 2.94 (d, J = 3.7 Hz, 1H), 2.67 (ddd, J = 11.3,
.8, 3.8 Hz, 1H), 2.59 (dd, J = 10.0, 7.1 Hz, 1H), 1.91–1.81 (m, 2H), 1.74–1.67
13
(m, 2H), 1.67–1.39 (m, 14H), 1.00 – 0.90 (m, 4H). C-NMR (101 MHz,
Ester 27 (0.145 g, 0.48 mmol) was dissolved in 25% aqueous
CDCl ) ␦ 175.5, 134.9, 131.7, 79.0, 76.2, 75.6, 42.7, 40.5, 39.9, 32.5, 32.4,
3
MeOH (4 mL), lithium hydroxide monohydrate (100 mg, 2.4 mmol)
was added, and the reaction mixture was stirred at RT for 16 h. The
solvent was then removed under reduced pressure, and the result-
ing residue was purified by column chromatography on silica gel
eluting with [hexane/EtOAc (6:1)] yielding 62 mg (86%) of 28 as a
colorless oil. The spectroscopic data correspond to those previ-
ously reported in the literature.
3
(
0.0, 29.5, 27.4, 25.8, 25.5, 24.4, 24.2, 23.5. MS (EI) m/z (%) 167 (76), 151
67), 150 (26), 107 (61), 93 (28), 91 (25), 79 (100), 77 (28). HRMS (EI) calcd.
for C H O : 302.1882. Found: 302.1879. Anal. calcd. for C H O : C,
19
23
3
19 23 3
75.46; H, 8.67. Found: C, 75.21; H, 8.47.
30b: white solid; R = 0.46 [hexane/EtOAc (12:1)]; mp 97–99 °C
f
2
2
(hexane/EtOAc); [␣]D = –95.97 (c = 1.0, CHCl ). IR (neat) ␯ 3048,
2935, 2870, 1727, 1187, 1168, 1048, 913, 690 cm . H-NMR (300 MHz,
CDCl ) ␦ 6.38–6.24 (m, 1H), 6.18 (dd, J = 10.8, 3.7 Hz, 1H), 4.46 (d, J =
6.5 Hz, 1H), 4.09–3.96 (m, 1H), 3.93 (d, J = 6.5 Hz, 1H), 3.38 (d, J =
7.7 Hz, 1H), 2.96 (d, J = 3.4 Hz, 1H), 2.71–2.52 (m, 2H), 1.90–1.75 (m,
3H), 1.92–1.74 (m, 3H), 1.70 (ddd, J = 11.3, 6.0, 3.9 Hz, 2H), 1.67–1.56
3
1 1
−
2
2
2
8: R = 0.10 [hexane/EtOAc (1:1)]; [␣]
= –3.6 (c = 1.0, CHCl3)
f
D
22
3
10
(
(S)-(+)-2-phenylpropionic acid lit. [␣]D = +72.6 (c = 1.6, CHCl )).
3
1
H-NMR (300 MHz, CDCl ) ␦ 7.39–7.25 (m, 5H), 3.76 (q, J = 7.2 Hz,
3
13
1
1
H), 1.54 (d, J = 7.2 Hz, 3H). C-NMR (75 MHz, CDCl ) ␦ 180.8, 139.8,
3
1
3
28.7, 127.6, 127.4, 45.4, 18.1.
(m, 4H), 1.55–1.38 (m, 4H), 0.92 (d, J = 5.1 Hz, 3H). C-NMR (101 MHz,
CDCl ) ␦ 175.0, 134.6, 131.9, 79.0, 76.1, 75.7, 42.5, 40.5, 39.9, 32.7,
32.6, 29.7, 29.3, 27.4, 25.8, 25.7, 24.4, 24.2, 23.5. MS (EI) m/z (%) 167
(75), 151 (74), 121 (25), 107 (64), 93 (29), 81 (25), 79 (100), 77 (26).HRMS
3
(
7S,7aR)-3a-Methyloctahydro-3,6-methanobenzofuran-7-yl
acrylate (29)
(
EI) calcd. for C H O : 302.1882. Found: 302.1877. Anal. calcd. for
19 23 3
C H O : C, 75.46; H, 8.67. Found: C, 75.17; H, 8.67.
1
9 23 3
(
1S,4S)-Methyl bicyclo[2.2.2]oct-5-ene-2-carboxylate (31a)
1R,4R)-Methyl bicyclo[2.2.2]oct-5-ene-2-carboxylate (31b)11
(
Alcohol 15 (60 mg, 0.36 mmol) was dissolved in anhydrous THF
(5 mL) before triethylamine (0.08 mL, 0.54 mmol) and acryloyl
chloride (0.04 mL, 0.47 mmol) were added, and the reaction mixture
was stirred for 2 h at RT. The reaction mixture was then quenched
with a saturated aqueous solution of NH Cl and extracted with
4
EtOAc (3 × 25 mL). The combined organic extracts were concentrated
under reduced pressure, and the resulting residue was purified by
column chromatography on silica gel eluting with [hexane/EtOAc
Diels-Alder adduct 30a (53.5 mg, 0.18 mmol) was dissolved in
MeOH (2 mL) under an argon atmosphere. After the addition of so-
dium methoxide (0.7 mL 25% v/v in MeOH) the resulting mixture was
stirred for the next 4 h at RT. After the completion, acidic Dowex
exchange resin was added to neutralize the pH. The resin was filtered
out, and the solvent was removed under the reduced pressure. The
residue was purified using column chromatography on silica gel
eluting with [hexane/EtOAc (4:1)]. Ester 31a was obtained as light
yellow oil (14.7 mg) yield 59.12%. NMR analysis confirmed that the
ester is mixture of exo- and endo- (1:10). Identical procedure was ap-
plied to produce 31b from 30b.
(
6:1)] providing 29 as a colorless oil. Yield 69 mg (87%).
2
2
2
9: R = 0.68 [hexane/EtOAc (3:1)]; [␣]
= –111.5 (c = 1.0, CHCl ); IR
f
D
3
1
(neat) ␯ 2930, 2871, 1719, 1634, 1453, 1269, 1192, 1060, 860. H-NMR
(
300 MHz, CDCl ) ␦ 6.41 (dd, J = 17.3, 1.6 Hz, 1H), 6.15 (dd, J = 17.3,
3
1
1
1
1
0.3 Hz, 1H), 5.80 (dd, J = 10.3, 1.6 Hz, 1H), 4.64 (dd, J = 6.4, 1.6 Hz,
H), 4.06–3.99 (m, 1H), 3.97 (d, J = 6.5 Hz, 1H), 3.38 (d, J = 7.8 Hz, 1H),
.93–1.46 (m, 7H), 0.94 (s, 3H). 13C-NMR (75 MHz, CDCl ) ␦ 165. 9,
3
30.3, 128.6, 78.9, 76.3, 76.1, 40.5, 39.8, 32. 5, 27.3, 25.8, 24.2, 23.5;
MS (EI) m/z (%) 222 (5), 150 (40), 135 (10), 121 (25), 109 (35), 93 (55), 79
(
40), 55 (100). HRMS (EI) calcd. for C H O : 222.1256. Found:
13 18 3
2
0
3
f
1a: R = 0.86 [hexane/EtOAc (4:1)]; [␣]D = +1.2 (c = 0.5, CHCl3).
2
7
22.1254. Anal. calcd. for C H O : C, 70.24; H, 8.16. Found: C,
0.34; H, 8.23.
13 18 3
1
H-NMR (400 MHz, CDCl ) ␦ 6.33 (dd, J = 19.7, 12.2 Hz, 1H), 6.15 (t, J =
3
7
.3 Hz, 1H), 3.69 (s, 1H), 3.63 (s, 3H), 2.92 (d, J = 3.4 Hz, 1H), 2.68–2.53
(
1
m, 2H), 1.80–1.61 (m, 2H), 1.56 (ddd, J = 21.0, 9.6, 6.8 Hz, 2H),
(
7
(
1S, 2S, 4S)-(3aS,7S)-3a-Methyloctahydro-3,6-methanobenzofuran-
-yl bicyclo[2.2.2]oct-5-ene-2-carboxylate (30a) and (1R,2R,4R)-
3aS,7S)-3a-Methyloctahydro-3,6-methanobenzofuran-7-yl
.51–1.41 (m, 1H), 1.39–1.12 (m, 5H), 0.92–0.76 (m, 1H).
2
0
3
f
1b: R = 0.86 [hexane/EtOAc (4:1)]; [␣]D = –39.5 (c = 0.5, CHCl3).
1
H-NMR (400 MHz, CDCl ) ␦ 6.33 (dd, J = 19.7, 12.2 Hz, 1H), 6.15 (t, J =
bicyclo[2.2.2]oct-5-ene-2-carboxylate (30b)
3
7
.3 Hz, 1H), 3.69 (s, 1H), 3.63 (s, 3H), 2.92 (d, J = 3.4 Hz, 1H), 2.68–2.53
(
m, 2H), 1.80–1.61 (m, 2H), 1.56 (ddd, J = 21.0, 9.6, 6.8 Hz, 2H),
1.51–1.41 (m, 1H), 1.39–1.12 (m, 5H), 0.92–0.76 (m, 1H).This com-
pound was a mixture of 5% exo- and 95% endo-isomers.
(
1S,2S,4S)-Bicyclo[2.2.2]oct-5-en-2-ylmethanol (32a)12,14
Ester 29 (129 mg, 0.58 mmol) was dissolved in toluene (1 mL)
before the addition of 1,3-cyclohexadiene (0.7 mL, 7.2 mmol), and
the mixture was heated in a sealed tube for 15 h. The volatiles were
then removed under reduced pressure, and the resulting residue
was purified by column chromatography on silica gel eluting with
Diels-Alder adduct 30a (104 mg, 0.34 mmol) was dissolved in
anhydrous THF (5 mL). After the addition of Red-Al (0.43 g,
1.38 mmol), the resulting mixture was stirred for 3 h at RT. After
the reaction was deemed to be complete, a saturated aqueous
solution of Rochelle’s salt was added, and the mixture was ex-
tracted with EtOAc (3 × 25 mL). The combined organic extracts
[
hexane/EtOAc (12:1)]. Two isomers 30a (47.6 mg) and 30b (53.5 mg)
were obtained.
0a: light yellow oil; R = 0.37 [hexane/EtOAc (12:1)]; [␣]
2
2
3
= –45.7
f
D
−
1
(
c = 0.5, CHCl ). IR (neat) ␯ 2928, 2866, 1730, 1162, 1050, 899, 695 cm .
3
Published by NRC Research Press

856
Can. J. Chem. Vol. 94, 2016
were concentrated under reduced pressure, and the residue was
purified by column chromatography on silica gel eluting with
colorless oil. Spectral data were in agreement with previously pub-
14
lished results.
rac-32: R = 0.20 [hexane/EtOAc (4:1)]; [␣]
H-NMR (400 MHz, CDCl ) ␦ 6.28 (t, J = 7.4 Hz, 1H), 6.13 (t, J = 7.4 Hz, 1H),
22
[hexane/EtOAc (4:1)] yielding 40 mg (84%) of 32a as a colorless oil.
f
D
= –0.8 (c = 0.5, CHCl ).
3
1
The spectroscopic data correspond to those previously reported in
3
1
2,14
3.36–3.14 (m, 2H), 2.58 (d, J = 18.7 Hz, 1H), 2.51 (d, J = 2.7 Hz, 1H), 1.98–1.78
(m, 1H), 1.68 (ddd, J = 12.3, 9.7, 2.6 Hz, 1H), 1.62–1.39 (m, 3H), 1.39–1.14 (m,
the literature.
2a: R = 0.20 [hexane/EtOAc (4:1)]; [␣]
2
0
3
= –10.2 (c = 0.9, EtOH).
f
D
13
1
2H), 0.84–1.14 (m, 1H). C-NMR (75 MHz, CDCl ) ␦ 135.1, 131.7, 67.5, 40.5,
H-NMR (400 MHz, CDCl ) ␦ 6.27 (t, J = 7.4 Hz, 1H), 6.13 (t, J = 7.3 Hz,
3
3
3
1.3, 30.2, 29.7, 25.9, 24.7. t (HPLC, chiral column IA, 98:2 Hept/iPrOH,
1H), 3.37–3.16 (m, 2H), 2.61 (d, J = 3.9 Hz, 1H), 2.56–2.43 (m, 1H),
R
15 °C, 0.5 mL/min) 22.3 and 23.0 min.
2
3
.01–1.79 (m, 1H), 1.67 (ddd, J = 12.4, 9.7, 2.8 Hz, 1H), 1.62–1.40 (m,
H), 1.40–1.16 (m, 2H), 0.75 (ddt, J = 12.4, 5.4, 2.8 Hz, 1H). C-NMR
1
3
Supplementary material
(
75 MHz, CDCl ) ␦ 135.0, 131.7, 67.5, 40.5, 31.4, 30.2, 29.7, 25.9, 24.7.
3
For additional computational data, H-NMR and 13C-NMR spectra
for all key compounds, see Supplementary Information. Supplemen-
tary data are available with the article through the journal Web site
at http://nrcresearchpress.com/doi/suppl/10.1139/cjc-2016-0327.
1
tR (HPLC, chiral column IA, 98:2 Hept/iPrOH, 15 °C, 0.5 mL/min)
2.72 min.
2
(
1R,2R,4R)-Bicyclo[2.2.2]oct-5-en-2-ylmethanol (32b)13,14
Acknowledgements
The authors are grateful to the following agencies for financial
support of this work: Natural Sciences and Engineering Research
Council of Canada (NSERC) (Idea to Innovation and Discovery
Grants), Canada Research Chair Program, Canada Foundation for
Innovation (CFI), TDC Research, Inc., TDC Research Foundation, the
Ontario Partnership for Innovation and Commercialization (OPIC),
and The Advanced Biomanufacturing Centre (Brock University). PH,
a visiting exchange student from Palacky University in Olomouc,
Czech Republic, thanks the European Social Funds for funding by a
grant (CZ.1.07/2.4.00/31.0130).
Diels-Alder adduct 30b (103 mg, 0.34 mmol) was dissolved in
anhydrous THF (5 mL). After the addition of Red-Al (0.43 g,
.38 mmol), the resulting mixture was stirred for 3 h at RT. After
the reaction was deemed to be complete, a saturated aqueous
solution of Rochelle’s salt was added, and the mixture was ex-
tracted with EtOAc (3 × 25 mL). The combined organic extracts
were concentrated under reduced pressure, and the residue was
purified by column chromatography on silica gel eluting with
1
[
hexane/EtOAc (4:1)] yielding 38 mg (80%) of 32b as a colorless oil.
References
The spectroscopic data correspond to those previously reported in
(1) Hudlicky, T.; Seoane, G.; Pettus, T. J. Org. Chem. 1989, 54, 4239. doi:10.1021/
1
3,14
jo00278a052.
the literature.
2b: R = 0.20 [hexane/EtOAc (4:1)]; [␣]
(
2) Hudlicky, T.; Boros, C. H.; Boros, E. E. Synthesis 1992, 1992, 174. doi:10.1055/
2
0
3
= +7.7 (c = 0.9, EtOH).
f
D
s-1992-34161.
1
H-NMR (400 MHz, CDCl ) ␦ 6.28 (t, J = 7.3 Hz, 1H), 6.14 (t, J = 7.2 Hz,
(3) Butora, G.; Gum, A. G.; Hudlicky, T.; Abboud, K. A. Synthesis 1998, 1998, 275.
3
doi:10.1055/s-1998-4529.
4) Varghese, V; Hudlicky, T. Angew. Chem., Int. Ed. 2014, 53, 4355. doi:10.1002/
1
1
3
H), 3.36–3.14 (m, 2H), 2.58 (d, J = 18.7 Hz, 1H), 2.51 (d, J = 2.7 Hz, 1H),
(
.98–1.78 (m, 1H), 1.68 (ddd, J = 12.3, 9.7, 2.6 Hz, 1H), 1.62–1.39 (m,
anie.201400286.
13
H), 1.39–1.14 (m, 2H), 0.84–1.14 (m, 1H). C-NMR (75 MHz, CDCl ) ␦
3
(5) Hudlicky, T.; Boros, E. E.; Boros, C. H. Synlett 1992, 1992, 391. doi:10.1055/s-
1
35.1, 131.7, 67.5, 40.5, 31.3, 30.2, 29.7, 25.9, 24.7. tR (HPLC, chiral
1992-21355.
(
(
6) Hudlicky, T.; Boros, E. E.; Boros, C. H. Tetrahedron: Asymmetry 1993, 4, 1365.
doi:10.1016/S0957-4166(00)80247-5.
7) (a) Zylstra, G. J.; Gibson, D. T. J. Biol. Chem. 1989, 264, 14940; (b) For medium-
scale preparation of the metabolites, see Endoma, M. A.; Bui, V. P.; Hansen, J.;
Hudlicky, T.; Org. Process Res. Dev. 2002, 6, 525.
column IA, 98:2 Hept/iPrOH, 15 °C, 0.5 mL/min) 22.0 min.
Bicyclo[2.2.2]oct-5-en-2-ylmethanol (rac-32)14
(
8) Hudlicky, T.; Luna, H.; Barbieri, G.; Kwart, L. D. J. Am. Chem. Soc. 1988, 110,
4
735. doi:10.1021/ja00222a035.
9) Davis, F. A.; Sheppard, A. C.; Chen, B. C.; Haque, M. S. J. Am. Chem. Soc. 1990,
12, 6679. doi:10.1021/ja00174a035.
(
1
(
10) Milne, J. E.; Storz, T.; Colyer, J. T.; Thiel, O. R.; Dilmeghani, Seran, M.;
Larsen, R. D.; Murry, J. A. J. Org. Chem. 2011, 76, 9519. doi:10.1021/jo2018087.
11) (a) Brown, M. K.; Corey, E. J. Org. Lett. 2010, 12, 172. doi:10.1021/ol9025793; (b)
Ohwada, T.; Uchiyama, M.; Tsuji, M.; Okamoto, I.; Shudo, K. Chem. Pharm.
Bull. 1996, 44, 296. doi:10.1248/cpb.44.296.
Methyl acrylate (2.0 mL, 22 mmol) was dissolved in toluene
(
(5 mL) before the addition of 1,3-cyclohexadiene (3.5 mL, 31 mmol).
The mixture was then heated in a sealed tube for 15 h.Volatiles were
then removed under reduced pressure, and the resulting residue was
directly used in the subsequent step. The resultant methyl ester
(
12) Ishihara, K.; Fushimi, M. J. Am. Chem. Soc. 2008, 130, 7532. doi:10.1021/
ja8015318.
(13) Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi, A.; Taguchi, T.; Shiro, M. J. Org.
Chem. 1998, 63, 2634. doi:10.1021/jo9721711.
(0.2 g, 1.2 mmol) was dissolved in anhydrous THF (5 mL). After the
(
(
(
(
14) Arai, Y.; Takadoi, M.; Koizumi, T. Chem. Pharm. Bull. 1988, 36, 4162. doi:10.
248/cpb.36.4162.
15) Schrödinger Release 2016-2: MacroModel, version 11.2, Schrödinger, LLC,
New York, 2016.
16) Schrödinger Release 2016-2: Maestro, version 10.6, Schrödinger, LLC, New
York, 2016 was used to generate illustrations.
17) Bach, R. D.; Andres, J. L; Davis, F. A. J. Org. Chem. 1992, 57, 613. doi:10.1021/
jo00028a039.
addition of Red-Al (1.0 g, 3.20 mmol), the resulting mixture was
stirred for 3 h at RT. After the reaction was deemed to be complete, a
saturated aqueous solution of Rochelle’s salt was added, and the
mixture was extracted with EtOAc (3 × 40 mL). The combined organic
extracts were concentrated under reduced pressure, and the result-
ing residue was purified by column chromatography on silica gel
eluting with [hexane/EtOAc (4:1)] yielding 130 mg (80%) of rac-32 as a
1
(18) Bondi, A. J. Phys. Chem. 1964, 68, 441. doi:10.1021/j100785a001.
Published by NRC Research Press