Ruthenium-catalyzed asymmetric [2 + 2] cycloadditions between chiral acyl camphorsultam-substituted alkynes and bicyclic alkenes

Article abstract of DOI:10.1021/jo501594g

Ruthenium-catalyzed asymmetric [2 + 2] cycloadditions between chiral acyl camphorsultam-functionalized alkynes and bicyclic alkenes were examined, providing adducts with complete exo stereoselectivity in good overall yield and enantioselectivity (up to 99% and 166:1, respectively), as well as appreciable diastereoselectivity (up to 163:1). The diastereoselectivity showed dependence on the solvent and temperature, as well as on the substitution pattern of the reacting alkyne and bicyclic alkene components. In general, higher diastereoselectivities were observed for reactions conducted in ethereal solvents and at lower temperatures between N-propynoyl camphorsultams and bicyclic alkenes.

Full text of DOI:10.1021/jo501594g

Article
pubs.acs.org/joc
Ruthenium-Catalyzed Asymmetric [2 + 2] Cycloadditions between
Chiral Acyl Camphorsultam-Substituted Alkynes and Bicyclic Alkenes
Jordan Goodreid, Karine Villeneuve, Emily Carlson, and William Tam*
Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, Department of Chemistry, University of Guelph,
Guelph, Ontario Canada N1G 2W1
S
* Supporting Information
ABSTRACT: Ruthenium-catalyzed asymmetric [2 + 2]
cycloadditions between chiral acyl camphorsultam-function-
alized alkynes and bicyclic alkenes were examined, providing
adducts with complete exo stereoselectivity in good overall
yield and enantioselectivity (up to 99% and 166:1,
respectively), as well as appreciable diastereoselectivity (up
to 163:1). The diastereoselectivity showed dependence on the
solvent and temperature, as well as on the substitution pattern
of the reacting alkyne and bicyclic alkene components. In
general, higher diastereoselectivities were observed for
reactions conducted in ethereal solvents and at lower temperatures between N-propynoyl camphorsultams and bicyclic alkenes.
Scheme 1. Ruthenium-Catalyzed [2 + 2] Cycloadditions
between Chiral Alkynes 1 and Bicycloalkenes 2
INTRODUCTION
■
a
Transition-metal-catalyzed cycloaddition reactions allow for
facile and highly selective adduct formation between
unactivated alkynes, alkenes, or dienes which would otherwise
require high pressure, temperature or photochemical treatment
to be cyclized.1,2 This enhanced reactivity arises from
complexation of the metal to the reacting ene and yne
components, which transiently polarizes and activates them
toward cycloaddition.1 In particular, [2 + 2] cycloaddition
reactions between bicyclic alkenes and alkynes have been found
to proceed effectively with a large variety of transition-metal
catalysts, including ruthenium,3,4 rhodium,5 nickel,6,7 cobalt,8,9
and rhenium,10 demonstrating overall low catalyst loading and
broad functional group compatibility, allowing for asymmetric
transformations to be practiced.11 We and others have studied
various aspects of the transition-metal-catalyzed [2 + 2]
cycloaddition between bicyclic alkenes and alkynes, such as
the development of novel catalysts,12,13 studies on the reactivity
between different reacting partners,14−18 on regioselectivity
using unsymmetrical substrates,15,19−21 and on asymmetric
syntheses employing both chiral catalysts5 and chiral sub-
strates.11,22 In particular, we have reported the first asymmetric
induction study of ruthenium-catalyzed [2 + 2] cycloaddition
between chiral alkynes 1 and bicyclic alkenes 2 to afford fully
exo stereoselective chiral cyclobutenes 3/4 that were sub-
sequently reduced to 5 and its enantiomer in good yield and
excellent enantioselectivity (Scheme 1).11
a
For structures of Xc, see Table 2.
rhodium catalyst, [(Rh(cod)(H8-binap)]BF4.5 However, the
ability of rhodium to form stable [Rh(nbd)Ln]X complexes
with norbornadiene23−25 has largely detracted from the broader
applications of this method. For instance, when we tried to
perform a rhodium-catalyzed [2 + 2] cycloaddition reaction
between alkyne 6a and norbornadiene 2a under conditions
similar to those of Shibata’s work (Scheme 2), the reaction did
not proceed. We attributed this reactivity difference to the
localized π-electron density in norbornadiene which allows for
its coordination yielding complex 7, whereas in benzonorbor-
nadiene electronic delocalization of the aromatic ring prevents
coordination, thus allowing for cycloaddition to take place.
For the present investigation, we selected the [Cp*RuCl-
(cod)] catalyst, since its reactivity with both alkyne and
Since our report in 2004, there have been few examples of
asymmetric [2 + 2] cycloaddition reactions involving other
bicycloalkene derivatives: In 2006, Shibata and co-workers
demonstrated an enantioselective and high-yielding [2 + 2]
cycloaddition between benzonorbornadiene or norbornene and
selected alkynyl esters in the presence of a chiral cationic
Received: July 16, 2014
Published: October 10, 2014
© 2014 American Chemical Society
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Scheme 2. Formation of a [Rh(η4-norbornadiene)(binap)]BF4 Complex That Inhibits [2 + 2] Cycloaddition
a b c
, ,
Table 1. Synthesis of Racemic Cycloadducts
a
b
c
Isolated yield after column chromatography. Reaction was performed in Et3N. The methyl ester analogue was used.
bicycloalkene components is well understood,16,18 and it serves
as an effective catalyst under mild conditions with good
functional group compatibility.3,4 For the cycloaddition
partners, we chose to react a variety of bicycloalkenes 2 with
alkynes bearing the chiral acyl camphorsultam auxiliary 1c
(Scheme 1), which was highly successful in our previous work
and was also employed by Moyano and Pericas
̀
, showing high
levels of regioselectivity in the cobalt-mediated Pauson−Khand
[2 + 2 + 1] cycloaddition with norbornadiene.26 As addressed
in their work, we show that the diastereoselectivity of the
cycloaddition is influenced by multiple factors, including
temperature, solvent, and substitutent effects of both cyclo-
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addition partners. In addition, we have extended the scope of
the [2 + 2] cycloaddition reaction to encompass a broad class
of chiral alkynes bearing various aryl and alkyl acetylenic
substituents.
We suggest that the exceptionally high level of asymmetric
induction observed in the [2 + 2] cycloaddition between 1c and
2g is a result of coordination of the sulfone oxygen with
ruthenium,27 which could preferentially stabilize one of the two
possible transition states during formation of the high energy
ruthenacyclopentene intermediate postulated by Mitsudo et al.
(Scheme 3).3,4 Intermediate A shows how coordination of a
RESULTS AND DISCUSSION
■
To begin this study, we prepared a series of racemic
cycloadducts to which we could compare the outcomes of
our later trials using novel chiral auxiliaries. The racemic ester
cycloadducts 8a−q were prepared via ruthenium-catalyzed [2 +
2] cycloaddition between alkynyl esters 6a−k and bicyclic
alkenes 2a−g, and were further reduced to adducts 9a−q
(Table 1). Cycloaddition between the phenyl-substituted
alkynyl ester and bicyclic alkenes generally gave high yields of
the racemic cycloadduct (entries 1−7), whereas cycloadditions
of aryl-substituted alkynyl esters with norbornene resulted in
lower yields overall (entries 7−16).
Scheme 3. Possible Intermediates in the Mechanism of the
Ruthenium-Catalyzed [2 + 2] Cycloaddition between Chiral
Alkyne 1c and Norbornene 2g
With electron-donating methyl and methoxy aryl substituents
of the alkyne, the methoxy derivative produced noticeably
(≥20%) higher yields of 8 when substituents were present in
the 2-position (entries 11 and 12), whereas the exact opposite
was observed for the identical substituents at the 4-position
(entries 13 and 14). Heterocyclic aromatic alkynyl esters gave
excellent yields of cycloadducts (entries 15 and 16), and finally
cycloaddition of a propargylic alcohol with 2g occurred readily
at room temperature (entry 17).
Studies of the chiral alkyne component in asymmetric [2 +
2] cycloadditions with norbornene 2g showed that, albeit 1a
and 1b provided low levels of asymmetric induction in the
cycloadditions (entries 1 and 2), the analogous reaction using
1c was highly diastereoselective, producing diastereomers 3c
and 4c in a 131:1 ratio (Table 2).11 Upon removal of the
recoverable chiral auxiliary, compound 5g was obtained as the
major enantiomer in a ratio of 199:1.
sulfone oxygen of the sultam may stabilize the metal center,
which leads to the preferential formation of major diastereomer
3c. Intermediate B, in contrast, demonstrates how this
stabilization is not geometrically feasible as the sulfone oxygen
is too distant from the ruthenium center, and the acetylenic
substituent would also impede their interaction. Moreover,
there are unfavorable steric constraints between the sultam ring
and the acetylenic substituent that could explain why
diastereomer 4c is formed as the minor isomer. The structure
of the major diastereomer 3c was confirmed by X-ray
crystallography.28
Table 2. Ruthenium-Catalyzed [2 + 2] Cycloadditions
between Norbornene 2g and Alkynes Bearing Various Chiral
a b c d
, , ,
Auxiliaries
We then studied the temperature and solvent dependence on
the regioselectivity in the ruthenium-catalyzed [2 + 2]
cycloaddition between chiral alkyne 1c and 2g (Table 3).11
When the cycloadditions were performed in tetrahydrofuran
(THF), an increase in temperature from 25 to 50 °C led to a
substantial decrease in diastereoselectivity (entries 1 and 2),
although no additional loss of diastereoselectivity was noted
upon further increasing the temperature to 80 °C (entry 3).
Overall, ethereal solvents (THF, 1,2-dimethoxyethane (DME),
and diglyme) gave the best yields of cycloadducts and optimal
levels of asymmetric induction, whereas other solvents, such as
dimethyl sulfoxide (DMSO), dimethylformamide (DMF),
toluene, hexanes, and 1,2-dichloroethane (DCE), resulted in
low yields (<20%).
With the optimal conditions established, trials focusing on
the alkene component were carried out. Various bicycloalkenes,
including derivatives of norbornadiene (2a, 2b, 2c), benzo-
norbornadiene (2d, 2e), and norbornene (2f, 2g), were
investigated for their degree of asymmetric induction toward
a
b
Isolated yield after column chromatography. Determined by 1H
c
d
NMR. Determined by HPLC. Determined by HPLC on a chiral
phase (OJ-H) column.
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Table 3. Effect of Temperature and Solvent on the Ruthenium-Catalyzed [2 + 2] Cycloaddition of Chiral Alkyne 1c and
Norbornene 2g
a
b
c
entry
solvent
temp (°C)
yield (%)
dr 3c:4c
er 5:enant-5
1
2
3
4
5
6
THF
THF
THF
25
50
80
25
25
25
95
95
99
95
76
90
131:1
64:1
132:1
64:1
THF/Et3N (1:1)
DME
114:1
132:1
126:1
99:1
diglyme
a
b
c
Isolated yield after column chromatography. Determined by HPLC. Determined by HPLC on a chiral phase (OJ-H) column.
Table 4. Ruthenium-Catalyzed [2 + 2] Cycloadditions of Chiral Alkyne 1c and Bicyclic Alkenes 2a−g
a
b
c
entry
alkene
time (h)
yield (%)
dr 3:4
er 5:enant-5
1
2
3
2g
2f
70
168
168
168
168
70
95
73
131:1
35:1
8:1
132:1
39:1
7:1
d
2a
2a
2b
2c
2d
2e
27
e
4
89
5:1
5:1
d
5
6
7
8
44
24:1
10:1
33:1
163:1
19:1
11:1
32:1
166:1
85
78
98
70
70
a
b
1
Isolated yield after column chromatography. Determined by HPLC, H NMR, or indirectly from the ee value of the product obtained upon
c
d
e
removal of the chiral auxiliary. Determined by HPLC on a chiral phase (OJ-H) column. Starting material was recovered. Reaction was performed
at 65 °C.
Scheme 4. Synthesis of Alkynyl Acids 11b,d−l, Chiral N-Propynoyl Camphorsultams 12d−n, Chiral Alkynyl Bromide 12q, and
Chiral Propargylic Alcohol 12s
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Table 5. Ruthenium-Catalyzed [2 + 2] Cycloadditions of Chiral Alkynes and 2g
a
b
c
entry
R
alkyne
temp (°C)
time (h)
yield 3 + 4 (%)
dr 3:4
er 5:enant-5
1
2
3
4
5
6
7
8
9
Ph
1c
25
25
60
25
60
25
25
25
25
25
60
60
60
25
70
24
95
88
81
99
97
95
73
72
98
67
92
99
41
131:1
38:1
30:1
4:1
132:1
39:1
30:1
4:1
3-F-C6H4
12d
12e
12f
12g
12h
12i
3-Cl-C6H4
3,5-CF3-C6H3
2-Me-C6H4
2-OMe-C6H4
4-Me-C6H4
4-OMe-C6H4
3-thienyl
120
12
144
19
8:1
8:1
58:1
104:1
31:1
20:1
5:1
58:1
99:1
32:1
19:1
5:1
17
12j
24
12k
12l
18
d
10
2-pyridinyl
nPen
18
11
12
13
14
12m
12n
12q
12s
72
9:1
c
Hex
120
68
4:1
Br
2.4:1
49:1
e
f
CH2OH
22
32(39)
49:1
a
b
1
Isolated yield after column chromatography (3/4 are inseparable due to identical Rf). Determined by HPLC, H NMR, or from the ee of the
c
d
product obtained upon removal of the chiral auxiliary. Determined by HPLC on a chiral phase (OJ-H) column. Product obtained was cyclobutane
13 (see Scheme 6). Yield of chiral auxiliary recovered. Measured indirectly by protecting the alcohol as a p-methoxyphenyl ether before removal of
e
f
the chiral auxiliary.
cycloaddition with chiral alkyne 1c (Table 4).11 All alkenes
were readily transformed to the corresponding cycloadduct
with full exo stereoselectivity. For the norbornene series, the
reaction of 1c with 2g proceeded with high yield and high
diastereoselectivity at room temperature (entry 1), whereas,
under similar conditions, the electron-poor oxanorbornene 2f
showed moderate yield and reduced diastereoselectivity (entry
2). The norbornadiene derivatives on average were both less
effective and less selective in the cycloaddition compared to
norbornenes (entries 3−6), and as was noted previously (Table
3), increasing the temperature of the reaction showed improved
yields, although at the cost of reduced diastereoselectivity
(entries 3 and 4). While cycloaddition of 7-phenylnorborna-
diene 2b (entry 5) was less efficient than 2,3-dibromonorbor-
nadiene 2c (entry 6), a noticeably higher diastereoselectivity
was observed for the reaction of 2b. Moreover, cycloaddition
involving 2c was completely regioselective with adduct
formation only occurring on the less substituted π-bond. For
the oxabicycloalkenes, oxabenzonorbornadiene 2d showed
similar reactivity to that of the oxanorbornene 2f, giving
comparable yields and levels of asymmetric induction (entries 2
and 7). Remarkably, benzonorbornadiene 2e showed excellent
yield and diastereoselectivity (entry 8), and upon removal of
the chiral auxiliary, cyclobutene 5e was obtained as the major
enantiomer in 199:1 er.
Finally, with focus on the alkyne component, a large number
of aryl- and alkyl-substituted chiral alkynes were prepared from
the corresponding alkynyl acids (Scheme 4). Because of the
nature of the R group, the chiral acyl camphorsultam-
substituted alkynes with the alkynyl bromide and propargylic
alcohol functionalities were prepared by alternative methods:
Alkynyl bromide 12q was prepared from the corresponding
chiral TIPS alkyne 12o, which was deprotected to the chiral
terminal alkyne 12p using TBAF. The bromine was installed
under mild conditions by treatment of 12p with NBS in the
presence of a catalytic amount of silver nitrate.29 The chiral
propargylic alcohol 12s was instead prepared via THP
protection of the hydroxyl group on the alkynyl acid 11n to
give 11o, followed by incorporation of the chiral auxiliary to
give the chiral THP-protected alkyne 12r, which was
subsequently deprotected.
The chiral alkynes 12 were then each reacted with
norbornene 2g to probe the effects of acetylenic substitution
on asymmetric induction in the ruthenium-catalyzed [2 + 2]
cycloaddition reaction (Table 5). As with our initial racemic
trials (Table 1), the phenyl substituted alkyne underwent
cycloaddition, affording a slightly higher yield of cycloadducts
3/4 than the alkynes bearing electron-poor 3-fluoro and 3-
chloro acetylenic aromatic substituents, all of which showed
high levels of asymmetric induction (entries 1−3). Although
further trials with various acetylenic phenyl derivatives did not
display obvious substituent effects, all cycloadditions were high-
yielding and showed good to excellent asymmetric induction
(entries 4−8). In addition, cycloaddition proceeded reasonably
well with alkynes bearing heteroaromatic acetylenic substituents
(entries 9 and 10).
In contrast, both primary and secondary alkyl-based alkynes
were far less reactive and required heating for efficient
conversion to take place, although this afforded excellent yields
of 3/4 with moderate diastereoselectivity (entries 11 and 12).
Subjection of an alkynyl bromide to cycloaddition similarly
showed reduced reactivity for this species, resulting in a low
yield and poor diastereoselectivity even upon heating (entry
13). Finally, when a propargylic alcohol derivative was reacted,
cycloaddition took place smoothly at room temperature (entry
14), although much of the unreacted auxiliary was also
recovered. Through control experiments, we found that, in
the absence of norbornene 2g, the chiral propargylic alcohol
was in fact decomposed by the ruthenium catalyst. In addition,
as the diastereomeric ratio of the cycloadducts 3/4v from
reaction of the propargylic alcohol could not be discerned by
1H NMR, we chose to derivatize 3/4v and measure the ratio by
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Scheme 5. Protection of Alcohol via Mitsunobu-type Reaction
Scheme 6. Formation and Analysis of the cis−trans−cis Cyclobutane 13
HPLC. Of the protecting groups p-chlorophenyl ether,30 benzyl
ether,31 and p-methoxyphenyl ether,32 we found p-methoxy-
phenyl ether to be the most successful, and following a
Mitsunobu-type protection of 3/4v and cleavage of the chiral
auxiliary, the enantiomers 5r and enant-5r were obtained in a
ratio of 49:1 (Scheme 5). The identical protection-reduction
sequence was applied to the racemic ester adduct 8q, producing
the same alcohol. The high level of asymmetric induction
observed in this instance could arise from a stabilizing
intramolecular hydrogen-bonding interaction between the
alcohol oxygen of alkyne 12s and the chloride of the
Cp*RuCl(cod) catalyst, which has been investigated in
cycloaddition studies involving propargylic alcohols.33,34
Although removal of the chiral auxiliary was typically
achieved under reductive conditions with LAH/AlCl3, several
cycloadducts (3/4; Table 5 entries 2−4, 10) showed multiple
degradation products by TLC upon use of LAH/AlCl3, and
thus a milder reducing agent, DIBALH, was chosen for auxiliary
removal in these species. When we used an excess of DIBALH
to reduce the 2-pyridinyl cycloadducts 3/4r (entry 10) in THF
at −78 °C, we did not obtain the expected cyclobutene
product, but instead attained the enantiomeric pair of cis−
trans−cis cyclobutanes 13 and enant-13 in a ratio of 5:1. The
structure of the major adduct 13 was confirmed by NOE
experiments (Scheme 6). Reduction of the corresponding
racemic ester cycloadduct 8q under similar conditions also
yielded this cyclobutane, which demonstrates a broader
potential of the ruthenium-catalyzed [2 + 2] cycloaddition in
the preparation of bicycle-fused cyclobutanes, in addition to
cyclobutene derivatives.35
CONCLUSION
■
In conclusion, we have demonstrated asymmetric induction in
ruthenium-catalyzed [2 + 2] cycloadditions using the acyl
camphorsultam-substituted alkynes and bicycloalkenes, examin-
ing solvent and temperature effects, as well as effects of the
individual ene and yne components on the reaction. The
cycloadditions were found to be highly stereo- and
regioselective, exhibiting excellent levels of asymmetric
induction (up to er 166:1 after removal of the chiral auxiliary).
The present work demonstrates the versatility of ruthenium
catalysis in the [2 + 2] cycloaddition reaction, as this catalyst
shows compatibility with a broader class of bicyclic substrates,
including norbornadienes, which were not tolerated under
rhodium catalysis. We have shown that the four-membered ring
systems including both cyclobutenes and cyclobutanes can be
constructed via a mild and simple procedure using the chiral N-
propynoyl camphorsultam, which gives high to excellent yields
of cycloadduction products with an overall excellent degree of
asymmetric induction.
EXPERIMENTAL SECTION
■
General Experimental Methods. All reactions were carried out
in flame-dried glassware under dry nitrogen at ambient temperature.
Column chromatography was performed on 230−400 mesh silica gel
using flash column chromatography techniques.36 Analytical thin-layer
chromatography was performed on precoated silica gel 60 F254 plates.
1H and 13C NMR spectra were recorded on 300, 400, and 600 MHz
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spectrometers. Chemical shifts for NMR spectra are reported in parts
per million (ppm) from tetramethylsilane, with the solvent resonance
(m), 1471 (m), 1265 (s), 1219 (s), 1204 (s), 1133 (m), 1110 (m),
1030 (m), 746 (m) cm−1; 1H NMR (CDCl3, 300 MHz): δ 7.85−7.77
(m, 1H), 7.72 (d, 1H, J = 7.8 Hz), 7.36−7.27 (m, 1H), 7.03 (td, 1H, J
= 8.3 Hz, J = 2.1 Hz), 4.23 (q, 2H, J = 7.2 Hz), 2.76 (d, 1H, J = 3.4
Hz), 2.68 (d, 1H, J = 3.4 Hz), 2.36 (br s, 1H), 2.21 (br s, 1H), 1.69−
1.55 (m, 2H), 1.38−1.29 (m, 4H), 1.22−1.14 (m, 2H), 1.03 (d, 1H, J
= 10.5 Hz); 13C NMR (CDCl3, 75 MHz): δ 162.7, 153.7, 134.3 (2C),
130.3, 129.6, 129.5, 128.7, 126.8, 60.1, 46.6, 46.1, 34.6, 34.1, 30.5, 28.2
(2C), 14.3. HRMS (CI) calcd for C18H19ClO2 [M + H]+: 303.1152;
found: 303.1156.
1
as the internal standard (deuterochloroform, H: δ 7.26 ppm; 13C: δ
77.0 ppm). HRMS samples were ionized by chemical ionization (CI),
electron impact (EI) or electrospray ionization (ESI) as specified, and
detection of the ions was performed by time-of-flight (TOF).
Commercial reagents were used without purification. Solvents were
purified by distillation under dry nitrogen: 1,2-dichloroethane,
hexanes, DMF, and Et3N from from CaH2, toluene from sodium,
and THF from potassium/benzophenone. Alkyne 6a,37 chiral alkynes
1a−c,11 12d−o,26 7-substituted norbornadiene 2b,38 2,3-disubstituted
norbornadiene 2c,39 7-oxanorbornene 2f,40 and Cp*RuCl(COD)41
were prepared according to literature procedures. Bicyclic alkene 2e
was prepared from the commercially available 1,4-dihydro-1,4-
methanonaphthalene-5,8-diol diacetate via reduction with LiAlH4,
followed by methylation using methyl iodide. For experimental
procedures and characterization data for cycloadducts 3/4c−i, 5a−g
(or 9a−g; Table 1, entries 1−7, and Table 4), see the Supporting
Information section of our previous publication.11 Diastereomeric
ratios of 3/4j−r,v were measured indirectly from the ee value of the
product obtained upon removal of the chiral auxiliary, and ratios of 3/
4s−u were determined by 1H NMR. Alkynyl esters 6b−k were
prepared by deprotonation of the corresponding terminal alkyne and
trapping with the appropriate alkyl chloroformate.42
General Procedure for the Ruthenium-Catalyzed [2 + 2]
Cycloadditions of Chiral Alkyne 1 with Bicycloalkene 2 and
Subsequent Reduction of the Cycloadduct. A mixture of 2g (17.5
mg, 0.186 mmol), 1c (20.3 mg, 0.059 mmol), and THF (0.4 mL) in an
oven-dried vial was added via cannula to an oven-dried screw-cap vial
containing [Cp*RuCl(cod)] (weighed in a drybox, 4.4 mg, 0.012
mmol) under nitrogen. The residue in the first vial was transferred to
the reaction mixture with rinses of THF (0.1 mL). The reaction was
stirred in the dark at 25 °C for 70 h. The crude product was purified
by column chromatography (ethyl acetate/hexanes mixture) to give an
inseparable mixture of the cycloadducts 3c/4c (24.5 mg, 0.056 mmol,
95%).
rac-(1S,2R,5S,6R)-Ethyl 4-(3,5-Bis(trifluoromethyl)phenyl)-
tricyclo[4.2.1.02,5]non-3-ene-3-methanoate, 8j (Table 1, entry
10). 52% (61.9 mg); Orange-brown solid, mp: 48−51 °C. Rf 0.48
(5:95 EtOAc:hexanes); IR (KBr): 3081 (w), 2959 (m), 2876 (m),
1702 (m), 1383 (m), 1288 (s), 1278 (s), 1135 (s), 897 (m) cm−1; 1H
NMR (CDCl3, 400 MHz): δ 8.44 (s, 2H), 7.81 (s, 1H), 4.26 (q, 2H, J
= 7.2 Hz), 2.84−2.80 (m, 1H), 2.75 (d, 1H, J = 3.1 Hz), 2.29 (br s,
1H), 2.21 (br s, 1H), 1.69−1.62 (m, 2H), 1.36−1.29 (m, 4H), 1.26−
1.19 (m, 2H), 1.08 (d, 1H, J = 10.5 Hz); 13C NMR (CDCl3, 100
MHz): δ 162.4, 151.2, 134.3, 132.9, 131.8 (q, 2JC−F = 33.5 Hz), 128.6,
1
123.2 (q, JC−F = 272.7 Hz), 122.7, 60.6, 46.6 (2C), 34.4, 34.1, 30.6,
28.2 (2C), 14.2. HRMS (CI) calcd for C20H18F6O2 [M + H]+:
405.1289; found: 405.1295.
rac-(1S,2R,5S,6R)-Ethyl 4-(o-Tolyl)tricyclo[4.2.1.02,5]non-3-
ene-3-methanoate, 8k (Table 1, entry 11). 62% (78.7 mg);
Brown wax. Rf 0.54 (5:95 EtOAc:hexanes); IR (CH2Cl2): 3066 (w),
2953 (s), 2870 (s), 1709 (s), 1633 (m), 1459 (m), 1450 (s), 1128
(m), 1203 (s), 1125 (s), 1045 (m), 1023 (m), 747 (m), 720 (m)
cm−1; 1H NMR (CDCl3, 300 MHz): δ 7.46 (d, 1H, J = 7.4 Hz), 7.23−
7.00 (m, 3H), 4.20−4.08 (q, 2H, J = 7.2 Hz), 2.88 (d, 1H, J = 3.4 Hz),
2.71 (d, 1H, J = 3.4 Hz), 2.37 (s, 3H), 2.31 (br s, 1H), 2.05 (br s, 1H),
1.65−1.53 (m, 2H), 1.49 (d, 1H, J = 10.4 Hz), 1.21 (t, 3H, J = 7.1 Hz),
1.18−1.08 (m, 2H), 1.04 (d, 1H, J = 10.4 Hz); 13C NMR (CDCl3, 75
MHz): δ 162.9, 157.1, 136.6, 133.2, 131.6, 130.4, 129.2, 128.6, 125.2,
59.8, 50.4, 46.6, 35.0, 33.8, 30.7, 28.2, 28.1, 20.7, 14.2. HRMS (CI)
calcd for C19H22O2 [M + H]+: 283.1698; found: 283.1702.
Reduction by LAH/AlCl3. A solution of 3c/4c (20.0 mg, 0.0457
mmol) in THF (0.7 mL) was transferred via cannula to an oven-dried
vial containing a suspension of LAH (2.5 mg, 0.065 mmol) and AlCl3
(1.8 mg, 0.014 mmol) in THF (0.3 mL) under nitrogen at 0 °C. The
reaction was stirred for 45 min and then quenched slowly with water.
Ethyl acetate was added and the layers were separated. The aqueous
phase was extracted twice with ethyl acetate, and the combined organic
layers were washed with brine, dried over MgSO4, and concentrated to
dryness.
Reduction by DIBALH. A solution of 3j/4j (22.7 mg, 0.0498 mmol)
in THF (0.5 mL) was stirred in an oven-dried vial under nitrogen and
cooled to −78 °C. DIBALH (1.0 M in hexanes; 0.35 mL, 0.350 mmol)
was added dropwise over 5 min. The solution was left to stir at −78 °C
for 2 h, warmed to room temperature, and quenched gradually with
water. The crude product was extracted as described above.
rac-(1S,2R,5S,6R)-Ethyl 4-(o-Methoxyphenyl)tricyclo-
[4.2.1.02,5]non-3-ene-3-methanoate, 8l (Table 1, entry 12).
87% (65.1 mg); Brown oil. Rf 0.46 (1:9 EtOAc:hexanes); IR
(CH2Cl2): 3076 (w), 2954 (s), 2873 (m), 1699 (s), 1595 (s), 1485
(m), 1251 (s), 1214 (s), 1199 (s), 1164 (s), 1135 (s), 1114 (s), 1046
(s), 1028 (s), 750 (s) cm−1; 1H NMR (CDCl3, 300 MHz): δ 8.02 (dd,
1H, J = 7.7 Hz, J = 1.6 Hz), 7.32−7.21 (m, 1H), 6.92 (t, 1H, J = 7.3
Hz), 6.85 (d, 1H, J = 8.3 Hz), 4.18 (q, 2H, J = 7.1 Hz), 3.79 (s, 3H),
2.95 (d, 1H, J = 3.4 Hz), 2.66 (d, 1H, J = 3.3 Hz), 2.25 (br s, 1H), 2.10
(br s, 1H), 1.65−1.50 (m, 2H), 1.44 (d, 1H, J = 10.3 Hz), 1.26 (t, 3H,
J = 7.1 Hz), 1.20−1.07 (m, 2H), 0.96 (d, 1H, J = 10.4 Hz); 13C NMR
(CDCl3, 75 MHz): δ 163.3, 158.2, 153.3, 131.2, 130.6, 130.2, 121.9,
120.1, 110.8, 59.7, 55.1, 50.0, 47.2, 35.0, 34.3, 30.5, 28.2, 28.1, 14.3.
HRMS (CI) calcd for C19H22O3 [M + H]+: 299.1647; found:
299.1651.
rac-(1S,2R,5S,6R)-Ethyl 4-(m-Fluorophenyl)tricyclo-
[4.2.1.02,5]non-3-ene-3-methanoate, 8h (Table 1, entry 8).
86% (91.3 mg); Brown oil. Rf 0.57 (1:9 EtOAc:hexanes); IR
(CH2Cl2): 3072 (w), 2955 (s), 2871 (s), 1699 (s), 1608 (s), 1480
rac-(1S,2R,5S,6R)-Ethyl 4-(p-Tolyl)tricyclo[4.2.1.02,5]non-3-
ene-3-methanoate, 8m (Table 1, entry 13). 83% (81.2 mg);
Brown solid, mp: 50−52 °C. Rf 0.41 (1:9 EtOAc:hexanes); IR (KBr):
2955 (s), 2936 (s), 2905 (m), 2863 (m), 1704 (s), 1613 (s), 1562
(m), 1470 (m), 1223 (s), 1201 (s), 1179 (s), 1135 (s), 1135 (s), 1106
(s), 1062 (s), 821 (s), 783 (s) cm−1; 1H NMR (CDCl3, 300 MHz): δ
7.92 (d, 2H, J = 8.1 Hz), 7.17 (d, 2H, J = 8.0 Hz), 4.22 (q, 2H, J = 7.1
Hz), 2.76 (d, 1H, J = 3.3 Hz), 2.66 (d, 1H, J = 3.2 Hz), 2.35 (s, 3H),
2.24 (br s, 1H), 2.21 (br s, 1H), 1.68−1.52 (m, 2H), 1.41−1.27 (m,
4H), 1.22−1.12 (m, 2H), 1.00 (d, 1H, J = 10.4 Hz); 13C NMR
(CDCl3, 75 MHz): δ 163.2, 155.7, 140.1, 130.1, 129.0, 128.9, 127.6,
59.8, 46.5, 45.9, 34.8, 34.3, 30.6, 28.3 (2C), 21.5, 14.4. HRMS (CI)
calcd for C19H22O2 [M + H]+: 283.1698; found: 283.1689.
1
(s), 1580 (s), 1235 (s), 1206 (s), 1135 (s) 781 (s) cm−1; H NMR
(CDCl3, 300 MHz): δ 7.85−7.77 (m, 1H), 7.72 (d, 1H, J = 7.8 Hz),
7.37−7.27 (m, 1H), 7.01 (td, 1H, J = 8.3 Hz, J = 2.3 Hz), 4.23 (q, 2H,
J = 7.1 Hz), 2.76 (d, 1H, J = 3.4 Hz), 2.68 (d, 1H, J = 3.4 Hz), 2.25 (br
s, 1H), 2.21 (br s, 1H), 1.69−1.56 (m, 2H), 1.38−1.29 (m, 4H), 1.23−
1.13 (m, 2H), 1.03 (d, 1H, J = 10.4 Hz); 13C NMR (CDCl3, 75 MHz):
δ 162.8, 162.7 (d, 1JC−F = 245.7 Hz), 154.0, 134.6 (d, 3JC−F = 7.9 Hz),
3
4
130.1, 129.7 (d, JC−F = 8.4 Hz), 124.4 (d, JC−F = 2.2 Hz), 116.6 (d,
2JC−F = 21.3 Hz), 115.5 (d, JC−F = 22.0 Hz), 60.1, 46.6, 46.1, 34.6,
2
rac-(1S,2R,5S,6R)-Ethyl 4-(p-Methoxyphenyl)tricyclo-
[4.2.1.02,5]non-3-ene-3-methanoate, 8n (Table 1, entry 14).
63% (131.8 mg); Light brown solid, mp: 43−45 °C. Rf 0.47 (1:9
EtOAc:hexanes); IR (KBr): 3066 (w), 2954 (s), 2933 (s), 2866 (m),
1694 (s), 1603 (s), 1457 (w), 1509 (s), 1260 (m), 1220 (s), 1202 (s),
34.2, 30.5, 28.3, 28.2, 14.3. HRMS (CI) calcd for C18H19FO2 [M +
H]+: 287.1447; found: 287.1445.
rac-(1S,2R,5S,6R)-Ethyl 4-(m-Chlorophenyl)tricyclo-
[4.2.1.02,5]non-3-ene-3-methanoate, 8i (Table 1, entry 9). 67%
(219.8 mg); Brown oil. Rf 0.68 (5:95 EtOAc:hexanes); IR (CH2Cl2):
3065 (w), 2956 (s), 2871 (m), 1745 (m), 1703 (s), 1617 (m), 1562
1
1174 (s), 1138 (m) cm−1; H NMR (CDCl3, 300 MHz): δ 8.00 (d,
10008
dx.doi.org/10.1021/jo501594g | J. Org. Chem. 2014, 79, 10002−10012

The Journal of Organic Chemistry
Article
2H, J = 8.8 Hz), 6.89 (d, 2H, J = 8.8 Hz), 4.21 (q, 2H, J = 7.1 Hz),
3.81 (s, 3H), 2.73 (d, 1H, J = 3.5 Hz), 2.65 (d, 1H, J = 3.5 Hz), 2.23
(br s, 1H), 2.19 (br s, 1H), 1.67−1.51 (m, 2H), 1.37 (d, 1H, J = 10.6
Hz), 1.31 (t, 3H, J = 7.1 Hz), 1.22−1.11 (m, 2H), 1.00 (d, 1H, J = 10.4
Hz); 13C NMR (CDCl3, 75 MHz): δ 163.3, 160.8, 155.6, 130.8, 126.0,
125.9, 113.7, 59.8, 55.3, 46.5, 45.8, 34.8, 34.4, 30.6, 28.4 (2C), 14.4.
HRMS (CI) calcd for C19H22O3 [M + H]+: 299.1647; found:
299.1653.
tR (minor enantiomer): 31.50 min; IR (CH2Cl2): 3352 (br), 2950 (s),
2870 (s), 1610 (s), 1485 (m), 1445 (s), 1581 (s), 1267 (s), 1172 (s),
1155 (s), 1034 (s), 1005 (s), 870 (s), 783 (s), 686 (s) cm−1; 1H NMR
(CDCl3, 400 MHz): δ 7.30−7.20 (m, 1H), 7.09 (d, 1H, J = 7.6 Hz),
7.04−6.98 (m, 1H), 7.01 (td, 1H, J = 8.6 Hz, J = 2.5 Hz), 4.44 (d, 1H,
J = 14.3 Hz), 4.37 (d, 1H, J = 14.3 Hz), 2.68 (s, 1H), 2.57 (d, 1H, J =
3.3 Hz), 2.17 (br s, 1H), 2.12 (br s, 1H), 1.67−1.52 (m, 2H), 1.44 (br
s, 1H), 1.39 (d, 1H, J = 10.2 Hz), 1.21−1.04 (m, 2H), 1.01 (d, 1H, J =
10.2 Hz); 13C NMR (CDCl3, 75 MHz): δ 163.0 (d, 1JC−F = 244.7 Hz),
rac-(1S,2R,5S,6R)-Methyl 4-(3-Thienyl)tricyclo[4.2.1.02,5]non-
3-ene-3-methanoate, 8o (Table 1, entry 15). 93% (87.2 mg);
Light brown oil. Rf 0.69 (1:9 EtOAc:hexanes); IR (CH2Cl2): 3108
(w), 2949 (s), 2869 (s), 1701 (s), 1617 (s), 1304 (m), 1283 (m), 1232
4
3
142.2, 139.0 (d, JC−F = 2.2 Hz), 136.5 (d, JC−F = 7.5 Hz), 129.9 (d,
3JC−F = 8.0 Hz), 122.9 (d, 4JC−F = 2.1 Hz), 114.0 (d, 2JC−F = 21.7 Hz),
113.3 (d, 2JC−F = 21.4 Hz), 58.9, 46.6, 46.4, 34.5, 34.2, 30.7, 28.5, 28.2.
HRMS (EI) calcd for C16H17FO [M]+: 244.1263; found: 244.1269.
3-((1S,5R,7R)-10,10-Dimethyl-3,3-dioxo-3-thia-4-azatricyclo-
[5.2.1.01,5]decane-4-carbonyl)-(1S,2R,5S,6R)-4-(m-chloro-
phenyl)tricyclo[4.2.1.02,5]non-3-ene, 3/4k (Table 5, entry 3).
81% (73.6 mg); Beige solid. mp: 160−161 °C. Rf 0.51 (3:7
EtOAc:hexanes); IR (KBr): 3012 (w), 2949 (m), 1636 (s), 1585
(m), 1560 (m), 1338 (s), 1314 (m), 1068 (m), 788 (m) cm−1; dr 30:1
1
(s), 1203 (s), 1131 (s), 1065 (s), 864 (m), 779 (s) cm−1; H NMR
(CDCl3, 300 MHz): δ 8.00 (d, 1H, J = 2.3 Hz), 7.66 (dd, 1H, J = 5.0
Hz, J = 0.6 Hz), 7.26 (dd, 1H, J = 5.0 Hz, J = 3.0 Hz), 3.76 (s, 3H),
2.72 (d, 1H, J = 3.4 Hz), 2.68 (d, 1H, J = 3.4 Hz), 2.24 (br s, 1H), 2.20
(br s, 1H), 1.66−1.54 (m, 2H), 1.37 (d, 1H, J = 10.5 Hz), 1.22−1.09
(m, 2H), 1.02 (d, 1H, J = 10.5 Hz); 13C NMR (CDCl3, 75 MHz): δ
163.4, 150.4, 135.2, 133.0, 128.4, 128.0, 125.3, 51.0, 47.2, 46.4, 34.6,
34.3, 32.2, 30.6, 28.2. HRMS (CI) calcd for C15H16O2S [M]+:
260.0871; found: 260.0876.
1
for 3k/4k; H NMR (CDCl3, 300 MHz): δ 7.79−7.76 (m, 1H), 7.71
(td, 1H, J = 6.8 Hz, J = 1.9 Hz), 7.30−7.25 (m, 2H), 4.12−4.05 (m,
1H), 3.48 (d, 1H, J = 13.6 Hz), 3.41 (d, 1H, J = 13.6 Hz), 3.27 (d, 1H,
J = 3.7 Hz), 2.80 (d, 1H, J = 3.7 Hz), 2.24 (br s, 1H), 2.16 (br s, 1H),
2.10 (dd, 1H, J = 13.6 Hz, J = 7.6 Hz), 2.06−1.96 (m, 1H), 1.96−1.80
(m, 3H), 1.60 (m, 2H), 1.46−1.34 (m, 3H), 1.22−1.12 (m, 5H), 1.02
(d, 1H, J = 10.6 Hz), 0.98 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ
162.7, 154.8, 134.3, 134.1, 131.5, 129.7, 129.4, 128.2, 126.6, 65.7, 53.7,
48.2, 47.7 (2C), 46.9, 45.1, 38.7, 35.4, 34.3, 33.2, 30.7, 28.1, 28.0, 26.3,
21.3, 19.9. HRMS (CI) calcd for C26H30ClNO3S [M + H]+: 472.1713;
found: 472.1717.
rac-(1S,2R,5S,6R)-Ethyl 4-(2-Pyridyl)tricyclo[4.2.1.02,5]non-3-
ene-3-methanoate, 8p (Table 1, entry 16). 95% (86.0 mg); Light
brown solid. mp: 35−36 °C. Rf 0.51 (2:8 EtOAc:hexanes); IR
(CH2Cl2): 3047 (m), 2955 (s), 2870 (s), 1704 (s), 1618 (s), 1462 (s),
1580 (s), 1291 (s), 1256 (s), 1223 (s), 1201 (s), 1133 (s), 1098 (s),
1
1050 (s), 1030 (s), 779 (s), 743 (m) cm−1; H NMR (CDCl3, 300
MHz): δ 8.62 (d, 1H, J = 4.7 Hz), 8.58 (d, 1H, J = 8.0 Hz), 7.68 (td,
1H, J = 7.8 Hz, J = 1.6 Hz), 7.22−7.14 (m, 1H), 4.22 (q, 2H, J = 7.1
Hz), 2.94 (d, 1H, J = 3.3 Hz), 2.68 (d, 1H, J = 3.3 Hz), 2.36 (br s, 1H),
2.24 (br s, 1H), 1.66−1.52 (m, 2H), 1.37−1.27 (m, 4H), 1.24−1.15
(m, 2H), 1.00 (d, 1H, J = 10.4 Hz); 13C NMR (CDCl3, 100 MHz): δ
162.8, 155.6, 150.9, 149.4, 136.1, 132.0, 125.4, 123.6, 60.1, 47.0, 46.3,
34.5, 34.2, 30.5, 28.2 (2C), 14.2. HRMS (CI) calcd for C17H19NO2
[M]+: 269.1416; found: 269.1399.
(1S,2R,5S,6R)-3-Hydroxymethyl-4-(m-chlorophenyl)tricyclo-
[4.2.1.02,5]non-3-ene, 5i (Table 5, entry 3). 91% (14.1 mg); Yellow
oil. Rf 0.41 (2:8 EtOAc:hexanes); [α]2D6 −30.6 (c 0.46, CHCl3, 93.5%
ee, er 30:1 for 5i/enant-5i); HPLC (OJ-H column, 0.4 mL/min, 1%
iPrOH/99% hexanes, 254 nm), tR (major enantiomer): 28.70 min, tR
rac-(1S,2R,5S,6R)-Ethyl 4-(Hydroxymethyl)tricyclo[4.2.1.02,5]-
non-3-ene-3-methanoate, 8q (Table 1, entry 17). 88% (80.3
mg); Yellow oil. Rf 0.32 (2:8 EtOAc:hexanes); IR (CH2Cl2): 3416
(br), 2954 (s), 2871 (m), 1712 (s), 1681 (s), 1303 (s), 1285 (s), 1217
(s), 779 (w) cm−1; 1H NMR (CDCl3, 300 MHz): δ 7.43 (t, 1H, J = 5.2
Hz), 4.29−4.23 (m, 2H), 4.16 (q, 2H, J = 7.1 Hz), 2.58−2.51 (m, 1H),
2.40−2.35 (m, 1H), 2.16−2.10 (m, 1H), 2.03−1.97 (m, 1H), 1.62−
1.46 (m, 2H), 1.36−1.23 (m, 1H), 1.26 (t, 3H, J = 7.1 Hz), 1.11−0.96
(m, 3H); 13C NMR (CDCl3, 75 MHz): δ 164.4, 164.2, 130.2, 60.9,
60.7, 47.1, 46.1, 33.9, 33.5, 30.4, 28.0, 27.7, 14.1. HRMS (ESI) calcd
for C13H18O3 [M + H]+: 223.1334; found: 223.1340.
(minor enantiomer): 32.39 min; IR (CH2Cl2): 3423 (br), 2958 (s),
2933 (s), 2871 (s), 1592 (m), 1453 (m), 1299 (m), 690 (s) cm−1; 1H
NMR (CDCl3, 400 MHz): δ 7.30−7.27 (m, 1H), 7.26−7.14 (m, 3H),
4.43 (d, 1H, J = 14.3 Hz), 4.36 (d, 1H, J = 14.4 Hz), 2.67 (s, 1H), 2.56
(d, 1H, J = 3.3 Hz), 2.17 (br s, 1H), 2.12 (br s, 1H), 1.65−1.56 (m,
2H), 1.53 (br s, 1H), 1.38 (d, 1H, J = 10.2 Hz), 1.18−1.08 (m, 2H),
1.01 (d, 1H, J = 10.2 Hz); 13C NMR (CDCl3, 75 MHz): δ 142.5,
138.7, 136.1, 134.4, 129.7, 127.1, 126.5, 124.7, 58.9, 46.7, 46.3, 34.5,
34.2, 30.6, 28.5, 28.2. HRMS (CI) calcd for C16H17ClO [M − H]−:
259.0890; found: 259.0893.
3-((1S,5R,7R)-10,10-Dimethyl-3,3-dioxo-3-thia-4-azatricyclo-
[5.2.1.01,5]decane-4-carbonyl)-(1S,2R,5S,6R)-4-(3,5-bis-
(trifluoromethyl)phenyl)tricyclo[4.2.1.02,5]non-3-ene, 3/4l
(Table 5, entry 4). 99% (78.0 mg); Dark brown wax. Rf 0.54 (3:7
EtOAc:hexanes); IR (KBr): 3090 (w), 2959 (s), 2876 (m), 1652 (s),
1379 (s), 1349 (s), 1279 (s), 1223 (s), 1174 (s), 1135 (s), 900 (m),
761 (m), 739 (m), 701 (m), 681 (m) cm−1; dr 4:1 for 3l/4l; 1H NMR
(CDCl3, 400 MHz): δ 8.52 (s, 2H), 7.79 (s, 1H), 4.09 (dd, 1H, J = 7.4
Hz, 4.4 Hz), 3.50 (d, 1H, J = 13.6 Hz), 3.42 (d, 1H, J = 13.6 Hz), 3.33
(d, 1H, J = 3.5 Hz), 2.87 (d, 1H, J = 3.5 Hz), 2.23 (br s, 1H), 2.20 (br
s, 1H), 2.11 (dd, 1H, J = 13.6 Hz, 7.8 Hz), 2.04−1.78 (m, 4H), 1.58−
1.45 (m, 2H), 1.38−1.21 (m, 3H), 1.12 (s, 3H), 1.17−1.04 (m, 2H),
0.94 (d, 1H, J = 10.7 Hz), 0.88 (s, 3H); 13C NMR (CDCl3, 100 MHz):
3-((1S,5R,7R)-10,10-Dimethyl-3,3-dioxo-3-thia-4-azatricyclo-
[5.2.1.01,5]decane-4-carbonyl)-(1S,2R,5S,6R)-4-(m-fluoro-
phenyl)tricyclo[4.2.1.02,5]non-3-ene, 3/4j (Table 5, entry 2).
88% (60.6 mg); Yellow-brown solid. mp: 174−176 °C. Rf 0.60 (3:7
EtOAc:hexanes); IR (KBr): 3085 (w), 3005 (m), 2948 (s), 2871 (s),
1650 (s), 1578 (s), 1343 (s), 1284 (s), 1238 (s), 1212 (s), 1056 (m),
1
998 (m) cm−1; dr 38:1 for 3j/4j; H NMR (CDCl3, 300 MHz): δ
7.63−7.50 (m, 2H), 7.33−7.24 (m, 1H), 7.00 (td, 1H, J = 8.1 Hz, J =
2.1 Hz), 4.09 (dd, 1H, J = 7.4 Hz, J = 5.0 Hz), 3.58 (d, 1H, J = 13.7
Hz), 3.41 (d, 1H, J = 13.6 Hz), 3.27 (d, 1H, J = 3.4 Hz), 2.81 (d, 1H, J
= 3.5 Hz), 2.24 (br s, 1H), 2.16 (br s, 1H), 2.10 (dd, 1H, J = 13.7 Hz, J
= 7.7 Hz), 2.05−1.80 (m, 4H), 1.64−1.55 (m, 2H), 1.42−1.30 (m,
3H), 1.24 (s, 3H), 1.22−1.11 (m, 2H), 1.02 (d, 1H, J = 10.8 Hz), 0.98
(s, 3H); 13C NMR (CDCl3, 75 MHz): δ 162.5 (d, 1JC−F = 245.8 Hz),
2
δ 162.3, 152.5, 134.4, 134.1, 131.6 (q, JC−F = 33.3 Hz), 128.3, 123.2
1
(q, JC−F = 272.8 Hz), 122.8, 65.8, 53.7, 48.7, 48.3, 47.7, 46.8, 45.2,
3
3
162.7, 155.1, 134.6 (d, JC−F = 7.9 Hz), 131.3, 129.6 (d, JC−F = 8.0
38.6, 35.2, 34.2, 33.3, 30.7, 28.1, 28.0, 26.3, 21.3, 19.9. HRMS (CI)
calcd. for C28H29F6NO3S [M + H]+: 574.1851; found: 574.1849.
(1S,2R,5S,6R)-3-Hydroxymethyl-4-(3,5-bis(trifluoromethyl)-
phenyl)tricyclo[4.2.1.02,5]non-3-ene, 5j (Table 5, entry 4). 89%
(25.9 mg); Yellow oil. Rf 0.45 (2:8 EtOAc:hexanes); [α]2D6 −17.4 (c
1.4, CHCl3, 59.6% ee, er 4:1 for 5j/enant-5j); HPLC (OD-H column,
0.2 mL/min, 2% iPrOH/98% hexanes, 254 nm), tR (major
enantiomer): 35.76 min, tR (minor enantiomer): 34.67 min; IR
(CH2Cl2): 3330 (br), 2953 (s), 2874 (s), 1467 (m), 1452 (m), 1383
(s), 1277 (s), 1175 (s), 1130 (s), 1044 (s), 894 (s), 702 (s), 682 (s)
4
2
Hz), 124.1 (d, JC−F = 2.4 Hz), 116.7 (d, JC−F = 21.4 Hz), 115.2 (d,
2JC−F = 22.0 Hz), 65.7, 53.7, 48.24, 48.20, 47.7, 47.0, 45.1, 38.7, 35.4,
34.3, 33.3, 30.7, 28.1, 28.0, 26.4, 21.3, 19.9. HRMS (CI) calcd for
C26H30FNO3S [M + H]+: 456.2009; found: 456.2003.
(1S,2R,5S,6R)-3-Hydroxymethyl-4-(m-fluorophenyl)tricyclo-
[4.2.1.02,5]non-3-ene, 5h (Table 5, entry 2). 86% (10.4 mg);
Yellow oil. Rf 0.40 (2:8 EtOAc:hexanes). [α]2D6 −34.2 (c 0.81, CHCl3,
95% ee, er 39:1 for 5h/enant-5h); HPLC (OJ-H column, 0.4 mL/min,
1% iPrOH/99% hexanes, 254 nm), tR (major enantiomer): 33.31 min,
10009
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1
cm−1; H NMR (CDCl3, 300 MHz): δ 7.77 (m, 2H), 7.68 (s, 1H),
46.8, 34.8, 34.3, 30.6, 28.6, 28.3. HRMS (CI) calcd for C17H20O2
[M]+: 256.1463; found: 256.1470.
4.56−4.40 (m, 2H), 2.75 (s, 1H), 2.59 (d, 1H, J = 3.0 Hz), 2.18 (br s,
1H), 2.14 (br s, 1H), 1.67−1.58 (m, 2H), 1.56 (br s, 1H), 1.38 (d, 1H,
J = 10.4 Hz), 1.22−1.10 (m, 2H), 1.05 (d, 1H, J = 10.4 Hz); 13C NMR
3-((1S,5R,7R)-10,10-Dimethyl-3,3-dioxo-3-thia-4-azatricyclo-
[5.2.1.01,5]decane-4-carbonyl)-(1S,2R,5S,6R)-4-(p-tolyl)tricyclo-
[4.2.1.02,5]non-3-ene, 3/4o (Table 5, entry 7). 73% (58.9 mg);
White solid. mp: 186−189 °C. Rf 0.69 (3:7 EtOAc:hexanes); IR
(KBr): 3082 (w), 3006 (m), 2954 (s), 2867 (m), 1644 (s), 1586 (s),
1454 (m), 1505 (s), 1329 (s), 1286 (s), 1220 (s), 1108 (s), 1058 (s),
2
(CDCl3, 75 MHz): δ 145.3, 137.1, 136.1, 131.7 (q, JC−F = 33.4 Hz),
1
128.5, 123.3 (q, JC−F = 273.0 Hz), 120.3, 59.1, 46.8, 46.2, 34.6, 34.1,
30.6, 28.4, 28.1. HRMS (CI) calcd for C18H16F6O [M]+: 362.1105;
found: 362.1101.
1
992 (m), 764 (m), 570 (m), 548 (m) cm−1; dr 104:1 for 3o/4o; H
3-((1S,5R,7R)-10,10-Dimethyl-3,3-dioxo-3-thia-4-azatricyclo-
[5.2.1.01,5]decane-4-carbonyl)-(1S,2R,5S,6R)-4-(o-tolyl)tricyclo-
[4.2.1.02,5]non-3-ene, 3/4m (Table 5, entry 5). 97% (107.9 mg);
Dark brown oil. Rf 0.50 (3:7 EtOAc:hexanes); IR (CH2Cl2): 3065 (w),
2955 (s), 2873 (s), 2255 (w), 1652 (s), 1617 (m), 1485 (m), 1456
(m), 1335 (s), 1286 (s), 1236 (s), 1167 (s), 1128 (s), 1060 (s), 992
(s), 914 (s), 734 (s) cm−1; dr 8:1 for 3m/4m; 1H NMR (CDCl3, 300
MHz): δ 7.37 (d, 1H, J = 7.0 Hz), 7.20−7.00 (m, 3H), 3.99−3.92 (m,
1H), 3.46 (d, 1H, J = 13.7 Hz), 3.31 (d, 1H, J = 13.7 Hz), 3.25−3.21
(m, 1H), 2.79 (d, 1H, J = 3.0 Hz), 2.34−2.27 (m, 4H), 2.22 (br s, 1H),
2.04−1.96 (m, 2H), 1.93−1.75 (m, 3H), 1.70−1.50 (m, 3H), 1.40−
1.27 (m, 2H), 1.20- 1.15 (m, 4H), 1.15−1.04 (m, 2H), 0.95 (s, 3H);
13C NMR (CDCl3, 75 MHz): δ 162.3, 157.3, 136.4, 134.2, 133.3,
130.3, 128.3, 128.2, 125.2, 65.4, 53.5, 50.8, 48.8, 48.2, 47.6, 45.0, 38.6,
35.4, 34.8, 33.1, 30.7, 28.0 (2C), 26.3, 21.1, 20.7, 19.8. HRMS (CI)
calcd for C27H33NO3S [M + H]+: 452.2259; found: 452.2250.
(1S,2R,5S,6R)-3-Hydroxymethyl-4-(o-tolyl)tricyclo[4.2.1.02,5]-
non-3-ene, 5k (Table 5, entry 5). 77% (25.6 mg); White solid. mp:
41−43 °C. Rf 0.42 (2:8 EtOAc:hexanes); [α]2D4 −113.5 (c 1.2, CHCl3,
77.9% ee, er 8:1 for 5k/enant-5k); HPLC (OJ-H column, 0.4 mL/min,
5% iPrOH/95% hexanes, 210 nm), tR (major enantiomer): 17.86 min,
tR (minor enantiomer): 30.28 min; IR (KBr): 3298 (br), 3202 (m),
3054 (m), 3019 (m), 2952 (s), 2868 (m), 1486 (m), 1458 (m), 1448
(m), 1021 (m), 995 (m) cm−1; 1H NMR (CDCl3, 400 MHz): δ 7.16−
7.10 (m, 4H), 4.26 (d, 1H, J = 13.7 Hz), 4.19 (dd, 1H, J = 13.7 Hz, J =
2.4 Hz), 2.85−2.81 (m, 1H), 2.61−2.57 (d, 1H, J = 3.3 Hz), 2.36 (s,
3H), 2.18−2.13 (m, 1H), 2.04−2.00 (m, 1H), 1.61−1.55 (m, 2H),
1.55−1.49 (m, 1H), 1.31−1.25 (br m, 1H), 1.16−1.04 (m, 2H), 1.01
(d, 1H, J = 10.1 Hz); 13C NMR (CDCl3, 100 MHz): δ 142.3, 141.8,
135.9, 134.0, 130.5, 128.9, 127.3, 125.5, 58.9, 49.9, 46.7, 34.8, 34.3,
30.7, 28.4, 28.1, 20.7. HRMS (EI) calcd for C17H20O [M]+: 240.1514;
found: 240.1521.
NMR (CDCl3, 300 MHz): δ 7.75 (d, 2H, J = 8.1 Hz), 7.12 (d, 2H, J =
8.0 Hz), 4.09 (dd, 1H, J = 7.3 Hz, 5.1 Hz), 3.48 (d, 1H, J = 13.6 Hz),
3.41 (d, 1H, J = 13.6 Hz), 3.27 (d, 1H, J = 3.5 Hz), 2.80 (d, 1H, J = 3.5
Hz), 2.32 (s, 3H), 2.23 (br s, 1H), 2.16 (br s, 1H), 2.09 (dd, 1H, J =
13.7 Hz, J = 7.9 Hz), 2.05−1.80 (m, 4H), 1.57 (m, 2H), 1.46−1.32
(m, 3H), 1.24 (s, 3H), 1.23−1.11 (m, 2H), 1.02−0.95 (m, 4H); 13C
NMR (CDCl3, 100 MHz): δ 162.8, 157.5, 140.3, 130.0, 128.8, 128.7,
128.6, 65.7, 53.6, 48.1, 47.8, 47.6, 46.8, 45.1, 38.8, 35.5, 34.5, 33.2,
30.7, 28.2, 28.1, 26.4, 21.5, 21.3, 19.9. HRMS (CI) calcd for
C27H33NO3S [M + H]+: 452.2259; found: 452.2264.
(1S,2R,5S,6R)-3-Hydroxymethyl-4-(p-tolyl)tricyclo[4.2.1.02,5]-
non-3-ene, 5m (Table 5, entry 7). 83% (8.4 mg); Yellow oil. Rf 0.50
(2:8 EtOAc:hexanes); [α]2D4 −40.2 (c 0.26, CHCl3, 98% ee, er 99:1 for
i
5m/enant-5m); HPLC (OJ-H column, 0.4 mL/min, 5% PrOH/95%
hexanes, 254 nm), tR (major enantiomer): 21.81 min, tR (minor
enantiomer): 32.83 min; IR (CH2Cl2): 3435 (br), 3026 (m), 2952 (s),
2870 (s), 1608 (s), 1451 (s), 1510 (s), 1297 (s), 1265 (s), 1183 (s),
1
1039 (s), 993 (s), 820 (s), 737 (s) cm−1; H NMR (CDCl3, 400
MHz): δ 7.23 (d, 2H, J = 8.0 Hz), 7.12 (d, 2H, J = 7.9 Hz), 4.44 (dd,
1H, J = 13.9 Hz, J = 4.0 Hz), 4.36 (dd, 1H, J = 13.8 Hz, J = 5.0 Hz),
2.72−2.66 (m, 1H), 2.56 (d, 1H, J = 3.1 Hz), 2.32 (s, 3H), 2.17 (br s,
1H), 2.11 (br s, 1H), 1.65−1.51 (m, 2H), 1.41 (d, 1H, J = 10.2 Hz),
1.36 (br t, 1H, J = 5.4 Hz), 1.18−1.08 (m, 2H), 0.99 (d, 1H, J = 10.2
Hz); 13C NMR (CDCl3, 75 MHz): δ 140.2, 139.5, 137.1, 131.6, 129.1,
126.5, 59.0, 46.5, 46.3, 34.6, 34.3, 30.7, 28.6, 28.2, 21.3. HRMS (CI)
calcd for C17H20O [M + H]+: 241.1592; found: 241.1598.
3-((1S,5R,7R)-10,10-Dimethyl-3,3-dioxo-3-thia-4-azatricyclo-
[5.2.1.01,5]decane-4-carbonyl)-(1S,2R,5S,6R)-4-(p-methoxy-
phenyl)tricyclo[4.2.1.02,5]non-3-ene, 3/4p (Table 5, entry 8).
72% (96.0 mg); Light brown solid. mp: 170−172 °C. Rf 0.51 (3:7
EtOAc:hexanes); IR (KBr): 2951 (s), 1650 (m), 1603 (m), 1506 (s),
1
1332 (s), 1223 (s), 994 (m), 836 (m) cm−1; dr 31:1 for 3p/4p; H
3-((1S,5R,7R)-10,10-Dimethyl-3,3-dioxo-3-thia-4-azatricyclo-
[5.2.1.01,5]decane-4-carbonyl)-(1S,2R,5S,6R)-4-(o-methoxy-
phenyl)tricyclo[4.2.1.02,5]non-3-ene, 3/4n (Table 5, entry 6).
95% (50.0 mg); Gold-brown solid. mp: 135−136 °C. Rf 0.41 (3:7
EtOAc:hexanes); IR (KBr): 2952 (s), 2869 (m), 1685 (m), 1654 (m),
1623 (m), 1493 (m), 1457 (m), 1336 (s), 752 (m) cm−1; dr 58:1 for
NMR (CDCl3, 400 MHz): δ 7.88 (d, 2H, J = 8.9 Hz), 6.84 (d, 2H, J =
8.9 Hz), 4.14−4.06 (m, 1H), 3.80 (s, 3H), 3.48 (d, 1H, J = 13.6 Hz),
3.41 (d, 1H, J = 13.6 Hz), 3.26 (d, 1H, J = 3.5 Hz), 2.79 (d, 1H, J = 3.5
Hz), 2.21 (br s, 1H), 2.18 (br s, 1H), 2.09 (dd, 1H, J = 13.6 Hz, J = 7.8
Hz), 2.02−1.80 (m, 4H), 1.65−1.56 (m, 2H), 1.44−1.37 (m, 2H),
1.35 (d, 1H, J = 9.8 Hz), 1.25 (s, 3H), 1.21−1.12 (m, 2H), 1.04−0.96
(m, 4H); 13C NMR (CDCl3, 75 MHz): δ 162.8, 161.0, 158.0, 130.7,
127.0, 125.8, 113.5, 65.9, 55.2, 53.8, 48.1, 47.7, 47.6, 46.8, 45.3, 38.9,
35.7, 34.6, 33.3, 30.7, 28.19, 28.16, 26.4, 21.4, 19.9. HRMS (CI) calcd
for C27H33NO4S [M + H]+: 468.2209; found: 468.2217.
1
3n/4n; H NMR (CDCl3, 300 MHz): δ 7.42 (d, 1H, J = 7.5 Hz),
7.27−7.18 (m, 1H), 6.88 (t, 1H, J = 7.5 Hz), 6.82 (d, 1H, J = 8.2 Hz),
3.90 (dd, 1H, J = 6.9 Hz, J = 5.3 Hz), 3.77 (s, 3H), 3.40 (d, 1H, J =
13.6 Hz), 3.34 (d, 1H, J = 13.8 Hz), 2.98 (d, 1H, J = 2.1 Hz), 2.82 (d,
1H, J = 2.2 Hz), 2.29 (br s, 1H), 2.13−2.10 (m, 2H), 2.04−1.78 (m,
4H), 1.66 (d, 1H, J = 10.5 Hz), 1.58 (d, 2H, J = 9.2 Hz), 1.45−1.25
(m, 2H), 1.17 (s, 3H), 1.14 (d, 2H, J = 9.0 Hz), 1.02 (d, 1H, J = 10.5
Hz), 0.94 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 163.4, 158.1, 132.4,
130.2, 128.9, 122.0, 120.0, 110.7, 64.7, 54.7, 52.9, 49.1, 48.8, 48.3, 47.7,
44.9, 38.4, 35.6, 34.5, 33.0, 30.9, 28.2, 28.1, 26.4, 20.7, 19.9. HRMS
(CI) calcd for C27H33NO4S [M + H]+: 468.2209; found: 468.2215.
(1S,2R,5S,6R)-3-Hydroxymethyl-4-(o-methoxyphenyl)-
tricyclo[4.2.1.02,5]non-3-ene, 5l (Table 5, entry 6). 78% (7.3 mg);
Yellow oil. Rf 0.29 (2:8 EtOAc:hexanes); [α]2D4 −53.4 (c 0.46, CHCl3,
96.6% ee, er 58:1 for 5l/enant-5l); HPLC (OJ-H column, 0.4 mL/min,
5% iPrOH/95% hexanes, 254 nm), tR (major enantiomer): 21.93 min,
tR (minor enantiomer): 31.73 min; IR (CH2Cl2): 3438 (br), 3072 (w),
2950 (s), 2869 (m), 1643 (m), 1464 (s), 1599 (s), 1246 (s), 1180
(m), 1163 (m), 1053 (m), 1026 (s), 752 (s) cm−1; 1H NMR (CDCl3,
300 MHz): δ 7.30−7.10 (m, 2H), 7.00−6.75 (m, 2H), 4.33−4.16 (m,
2H), 3.84 (s, 3H), 2.71 (br s, 1H), 2.52 (br s, 1H), 2.12 (br s, 2H),
1.98 (br s, 1H), 1.65−1.54 (m, 2H), 1.49 (d, 1H, J = 10.2 Hz), 1.19−
1.05 (m, 2H), 0.97 (d, 1H, J = 10.2 Hz); 13C NMR (CDCl3, 75 MHz):
δ 156.2, 142.6, 136.0, 128.8, 128.6, 123.8, 120.8, 110.9, 60.1, 55.3, 47.4,
(1S,2R,5S,6R)-3-Hydroxymethyl-4-(p-methoxyphenyl)-
tricyclo[4.2.1.02,5]non-3-ene, 5n (Table 5, entry 8). 55% (8.7
mg); Yellow solid. mp: 41−43 °C. Rf 0.29 (2:8 EtOAc:hexanes); [α]D24
−30.6 (c 0.71, CHCl3, 94% ee, er 32:1 for 5n/enant-5n); HPLC (OJ-
H column, 0.4 mL/min, 5% iPrOH/95% hexanes, 254 nm), tR (major
enantiomer): 50.93 min, tR (minor enantiomer): 65.50 min; IR(KBr):
3398 (br), 2949 (s), 2868 (m), 1606 (m), 1509 (s), 1249 (s), 1174
1
(m), 1033 (m), 834 (s) cm−1; H NMR (CDCl3, 400 MHz): δ 7.28
(d, 2H, J = 8.8 Hz), 6.85 (d, 2H, J = 8.7 Hz), 4.41 (dd, 1H, J = 13.9
Hz, J = 5.4 Hz), 4.33 (dd, 1H, J = 13.7 Hz, J = 5.7 Hz), 3.79 (s, 3H),
2.67 (s, 1H), 2.54 (d, 1H, J = 3.0 Hz), 2.15 (br s, 1H), 2.10 (br s, 1H),
1.64−1.54 (m, 2H), 1.41 (d, 1H, J = 10.1 Hz), 1.29 (t, 1H, J = 5.7 Hz),
1.17−1.07 (m, 2H), 0.99 (d, 1H, J = 10.2 Hz); 13C NMR (CDCl3, 75
MHz): δ 158.8, 139.7, 138.1, 127.9, 127.4, 113.9, 58.9, 55.2, 46.4, 46.3,
34.5, 34.3, 30.6, 28.5, 28.2. HRMS (CI) calcd. for C17H20O2 [M + H]+:
257.1542; found: 257.1551.
3-((1S,5R,7R)-10,10-Dimethyl-3,3-dioxo-3-thia-4-azatricyclo-
[5.2.1.01,5]decane-4-carbonyl)-(1S,2R,5S,6R)-4-(3-thienyl)-
tricyclo[4.2.1.02,5]non-3-ene, 3/4q (Table 5, entry 9). 98% (65.0
mg); Brown solid, mp: 199−201 °C dec Rf 0.61 (3:7 EtOAc:hexanes);
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Article
IR (KBr): 3126 (w), 2963 (s), 2870 (m), 1633 (s), 1583 (s), 1326 (s),
1300 (s), 1222 (s), 1117 (s), 1056 (s), 998 (m), 913 (m), 808 (m),
(dd, 1H, J = 7.4 Hz, J = 5.0 Hz), 3.45 (d, 1H, J = 13.6 Hz), 3.39 (d,
1H, J = 13.6 Hz), 3.03 (br s, 1H), 2.55−2.46 (m, 1H), 2.42 (d, 1H, J =
3.1 Hz), 2.38−2.31 (m, 1H), 2.17 (br s, 1H), 2.10−1.98 (m, 3H),
1.96−1.80 (m, 3H), 1.56−1.50 (m, 2H), 1.50−1.24 (m, 9H), 1.22 (s,
3H), 1.15−1.00 (m, 2H), 0.99−0.93 (m, 4H), 0.87 (t, 3H, J = 6.9 Hz);
visible peaks for minor isomer: δ 3.96−3.80 (1H, m), δ 2.73 (br s,
1H); 13C NMR (CDCl3, 100 MHz): δ 168.2, 162.2, 131.2, 65.7, 53.7,
48.5, 48.1, 48.0, 47.6, 45.1, 38.8, 34.6, 34.3, 33.2, 32.0, 30.7, 29.5, 28.1,
27.9, 26.4, 26.3, 22.4, 21.2, 19.9, 14.0. HRMS (CI) calcd for
C25H37NO3S [M + H]+: 432.2572; found: 432.2578.
1
742 (m) cm−1; dr 20:1 for 3q/4q; H NMR (CDCl3, 300 MHz): δ
8.08 (dd, 1H, J = 2.9 Hz, J = 0.9 Hz), 7.56 (dd, 1H, J = 5.0 Hz, J = 1.0
Hz), 7.22 (dd, 1H, J = 5.1 Hz, J = 3.0 Hz), 4.09 (dd, 1H, J = 7.2 Hz, J
= 5.2 Hz), 3.48 (d, 1H, J = 13.6 Hz), 3.41 (d, 1H, J = 13.5 Hz), 3.29
(d, 1H, J = 3.6 Hz), 2.76 (d, 1H, J = 3.6 Hz), 2.22 (br s, 1H), 2.20 (br
s, 1H), 2.09 (dd, 1H, J = 13.4 Hz, J = 7.6 Hz), 2.04−1.80 (m, 4H),
1.62−1.55 (m, 2H), 1.45−1.30 (m, 3H), 1.25 (s, 3H), 1.23−1.10 (m,
2H), 1.10−0.94 (m, 4H); 13C NMR (CDCl3, 75 MHz): δ 162.1,
153.4, 135.3, 129.3, 128.2, 126.7, 125.0, 66.0, 53.8, 48.3, 48.1, 47.6,
47.3, 45.3, 38.9, 35.3, 34.7, 33.4, 30.8, 28.2, 28.0, 26.4, 21.4, 19.9.
HRMS (CI) calcd for C24H29NO3S2 [M]+: 443.1589; found: 443.1604.
(1S,2R,5S,6R)-3-Hydroxymethyl-4-(3-thienyl)tricyclo-
[4.2.1.02,5]non-3-ene, 5o (Table 5, enty 9). 95% (10.0 mg);
Orange liquid. Rf 0.40 (3:7 EtOAc:hexanes); [α]2D4 +13.1 (c 0.46,
CHCl3, 90.3% ee, er 19:1 for 5o/enant-5o); HPLC (OJ-H column, 0.4
3-((1S,5R,7R)-10,10-Dimethyl-3,3-dioxo-3-thia-4-azatricyclo-
[5.2.1.01,5]decane-4-carbonyl)-(1S,2R,5S,6R)-4-cyclohexyl-
tricyclo[4.2.1.02,5]non-3-ene, 3/4t (Table 5, entry 12). 99% (67.5
mg); Light brown oil. Rf 0.49 (2:8 EtOAc:hexanes); IR (CH2Cl2):
2927 (s), 2870 (s), 2852 (m), 1651 (s), 1617 (m), 1449 (m), 1335
(s), 1132 (s), 1282 (s), 1271 (s), 1236 (s), 1219 (s), 1193 (s), 1129
1
(s), 1113 (s), 993 (m), 769 (m), 734 (s) cm−1; dr 4:1 for 3t/4t; H
i
NMR (CDCl3, 600 MHz) major isomer: δ 3.97 (dd, 1H, J = 7.4 Hz, J
= 4.8 Hz), 3.44 (d, 1H, J = 13.6 Hz), 3.37 (d, 1H, J = 13.6 Hz), 2.98
(d, 1H, J = 3.4 Hz), 2.82−2.70 (m, 1H), 2.42 (d, 1H, J = 3.4 Hz), 2.10
(br s, 1H), 2.08 (br s, 1H), 2.03 (dd, 1H, J = 13.8 Hz, 7.8 Hz), 2.00−
1.95 (m, 1H), 1.93−1.79 (m, 5H), 1.77−1.58 (m, 5H), 1.53−1.45 (m,
2H), 1.43−1.27 (m, 3H), 1.27−1.14 (m, 3H), 1.19 (s, 3H), 1.09−0.97
(m, 2H), 0.95 (s, 3H), 0.94−0.91 (m, 1H); visible peaks for minor
isomer:δ 1.12 (s, 3H); 13C NMR (CDCl3, 100 MHz) major isomer: δ
171.2, 162.1, 129.7, 65.5, 53.7, 48.1, 47.7, 47.6, 47.3, 45.1, 39.2, 38.8,
35.1, 34.4, 33.2, 30.6, 30.5, 30.1, 28.1, 27.9, 26.4, 26.0, 25.9, 25.8, 21.2,
19.9; visible peaks for minor isomer: δ 67.2, 53.8, 44.2, 38.85, 32.7,
26.6, 20.4. HRMS (CI) calcd. for C26H37NO3S [M + H]+: 444.2572;
found: 444.2558.
mL/min, 5% PrOH/95% hexanes, 254 nm), tR (major enantiomer):
26.64 min, tR (minor enantiomer): 34.85 min; IR(neat): 3371 (br),
3103 (m), 2946 (s), 2868 (s), 1470 (m), 1448 (m), 1296 (s), 1079
(s), 1031 (s), 1003 (s), 910 (s), 853 (s), 779 (s), 733 (s), 648 (s)
cm−1; 1H NMR (CDCl3, 300 MHz): δ 7.28−7.21 (dd, 1H, J = 5.0 Hz,
J = 3.0 Hz), 7.21−7.17 (m, 1H), 7.15 (dd, 1H, J = 4.9 Hz, J = 1.0 Hz),
4.36 (d, 1H, J = 14.0 Hz), 4.29 (d, 1H, J = 14.0 Hz), 2.64 (s, 1H), 2.55
(d, 1H, J = 3.1 Hz), 2.16 (br s, 1H), 2.10 (br s, 1H), 1.65−1.53 (m,
2H), 1.42 (d, 1H, J = 10.2 Hz), 1.32 (br s, 1H), 1.17−1.07 (m, 2H),
1.00 (d, 1H, J = 10.3 Hz); 13C NMR (APT, CDCl3, 75 MHz): δ 138.2,
136.3, 135.7, 126.4, 125.7, 121.9, 59.0, 47.0, 46.9, 34.4, 34.2, 30.7, 28.4,
28.2. HRMS (CI) calcd. for C14H16OS [M + H]+: 233.1000; found:
233.1009.
3-((1S,5R,7R)-10,10-Dimethyl-3,3-dioxo-3-thia-4-azatricyclo-
[5.2.1.01,5]decane-4-carbonyl)-(1S,2R,5S,6R)-4-bromotricyclo-
[4.2.1.02,5]non-3-ene, 3/4u (Table 5, entry 13). 41% (20.5 mg);
Light brown wax. Rf 0.50 (3:7 EtOAc:hexanes); IR (CH2Cl2): 2958
(s), 2876 (m), 1679 (s), 1663 (s), 1335 (s), 1287 (s), 1172 (s) cm−1;
dr 2.4:1 for 3u/4u; 1H NMR (CDCl3, 400 MHz) major isomer: δ 4.02
(dd, 1H, J = 7.5 Hz, J = 5.0 Hz), 3.59 (d, 1H, J = 13.5 Hz), 3.43 (d,
1H, J = 13.7 Hz), 3.30 (d, 1H, J = 3.4 Hz), 2.76 (d, 1H, J = 3.5 Hz),
2.28 (br s, 1H), 2.17 (br s, 1H), 2.13−2.00 (m, 2H), 2.00−1.82 (m,
3H), 1.65−1.52 (m, 2H), 1.48−1.30 (m, 3H), 1.21 (s, 3H), 1.19−1.10
(m, 3H), 0.99 (s, 3H); visible peaks for minor isomer: δ 3.95 (dd, J =
7.5 Hz, J = 5.0 Hz, 1H), 3.02 (d, 1H, J = 3.4 Hz), 2.81 (d, 1H, J = 3.3
Hz), 1.24 (s, 3H), 0.97 (s, 3H); 13C NMR (CDCl3, 100 MHz) major
isomer: δ 159.8, 137.6, 131.9, 65.6, 55.0, 53.8, 51.5, 48.4, 47.7, 45.1,
38.7, 34.8, 34.1, 33.3, 30.4, 27.4, 27.0, 26.4, 21.5, 19.9; visible peaks for
minor isomer: 161.7, 139.5, 64.8, 55.5, 53.3, 52.1, 48.6, 47.8, 44.9, 38.4,
35.2, 34.4, 33.0, 30.5, 27.3, 27.2, 26.5, 21.0. HRMS (EI) calcd for
C20H26BrNO3S [M]+: 439.0817; found: 439.0811.
3-((1S,5R,7R)-10,10-Dimethyl-3,3-dioxo-3-thia-4-azatricyclo-
[5.2.1.01,5]decane-4-carbonyl)-(1S,2R,5S,6R)-4-(2-pyridinyl)-
tricyclo[4.2.1.02,5]non-3-ene, 3/4r (Table 5, entry 10). 67% (44.3
mg); Brown solid, mp: 190−191 °C dec Rf 0.37 (4:6 EtOAc:hexanes);
IR (KBr): 3002 (m), 2955 (s), 1656 (s), 1459 (s), 1336 (s), 1292 (s),
1
1269 (s), 1223 (s) cm−1; dr 5:1 for 3r/4r; H NMR (CDCl3, 400
MHz): δ 8.58 (d, 1H, J = 4.2 Hz), 8.05 (d, 1H, J = 7.9 Hz), 7.60 (dt,
1H, J = 7.7 Hz, J = 1.8 Hz), 7.17−7.11 (m, 1H), 4.07−4.00 (m, 1H),
3.46 (d, 1H, J = 13.7 Hz), 3.39 (d, 1H, J = 13.7 Hz), 3.22 (d, 1H, J =
3.4 Hz), 2.95 (d, 1H, J = 3.4 Hz), 2.38 (br s, 1H), 2.16 (br s, 1H), 2.06
(d, 2H, J = 6.3 Hz), 1.95−1.78 (m, 3H), 1.62−1.52 (m, 2H), 1.47 (d,
1H, J = 10.5 Hz), 1.43−1.27 (m, 2H), 1.22 (s, 3H), 1.22−1.16 (m,
2H), 1.01 (d, 1H, J = 10.5 Hz), 0.96 (s, 3H); 13C NMR (CDCl3, 100
MHz): δ 163.0, 155.0, 150.9, 149.4, 135.9, 133.5, 124.1, 123.5, 65.5,
53.5, 48.5, 48.3, 47.7, 47.2, 45.1, 38.6, 35.3, 34.4, 33.2, 30.8, 28.08,
28.06, 26.4, 21.2, 19.9. HRMS (CI) calcd for C25H30N2O3S [M + H]+:
439.2055; found: 439.2052.
(1S,2R,3S,4R,5S,6R)-3-Hydroxymethyl-4-(2-pyridinyl)tricy-
clo[4.2.1.02,5]nonane, 13 (Table 5 entry 10, Scheme 6). 25 %
(2.0 mg); Clear oil. Rf 0.30 (4:6 EtOAc:hexanes); [α]2D6 +60.5 (c 0.15,
CHCl3, 68% ee, er 5:1 for 13/enant-13); HPLC (OJ-H column, 0.4
3-((1S,5R,7R)-10,10-Dimethyl-3,3-dioxo-3-thia-4-azatricyclo-
[5.2.1.01,5]decane-4-carbonyl)-(1S,2R,5S,6R)-4-hydroxymethyl-
tricyclo[4.2.1.02,5]non-3-ene, 3/4v (Table 5, entry 14). 32% (15.7
mg); White solid. mp: 175−176 °C. Rf 0.38 (1:1 EtOAc:hexanes); IR
(KBr): 3432 (br), 2959 (s), 2870 (m), 1627 (m), 1614 (s), 1334 (s),
1134 (s), 1036 (m), 539 (s) cm−1; dr 49:1 for 3v/4v; 1H NMR
(CDCl3, 600 MHz): δ 4.48 (t, 1H, J = 5.5 Hz), 4.28 (d, 2H, J = 4.2
Hz), 4.00 (dd, 1H, J = 7.5 Hz, J = 5.0 Hz), 3.48 (d, 1H, J = 13.6 Hz),
3.42 (d, 1H, J = 13.6 Hz), 2.43 (d, 1H, J = 2.7 Hz), 2.21 (br s, 1H),
2.06 (br s, 1H), 2.05 (dd, 1H, J = 13.9 Hz, J = 6.2 Hz), 2.02−1.81 (m,
5H), 1.59−1.48 (m, 2H), 1.41−1.29 (m, 3H), 1.20 (s, 3H), 1.07−0.94
(m, 3H), 0.97 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 167.3, 163.2,
131.6, 65.9, 60.9, 53.8, 48.4, 48.3, 47.7, 47.5, 45.1, 38.8, 34.5, 34.2,
i
mL/min, 5% PrOH/95% hexanes, 254 nm), tR (major enantiomer):
15.53 min, tR (minor enantiomer): 22.91 min; IR (CH2Cl2): 3296
(br), 2948 (s), 2869 (m), 1594 (s), 1476 (m), 1430 (m), 1566 (m),
1
1034 (s), 1002 (m), 789 (m), 757 (m) cm−1; H NMR (CDCl3, 300
MHz): δ 8.42−8.35 (m, 1H), 7.61 (td, 1H, J = 7.7 Hz, J = 1.9 Hz),
7.11−7.02 (m, 2H), 6.49 (br s, 1H), 4.25−4.10 (m, 2H), 3.44 (dd, 1H,
J = 11.7 Hz, J = 4.9 Hz), 3.32−3.16 (m, 1H), 2.78−2.67 (m, 1H),
2.38−2.28 (m, 1H), 2.22−2.17 (m, 1H), 2.08 (d, 1H, J = 3.2 Hz),
1.51−1.35 (m, 2H), 1.35−1.27 (m, 1H), 1.11−1.00 (m, 2H), 1.00−
1.91 (m, 1H); 13C NMR (CDCl3, 75 MHz): δ 161.8, 147.6, 136.1,
123.0, 120.5, 58.6, 43.8, 43.0, 41.09, 41.06, 36.1, 35.9, 34.7, 29.3, 27.9.
HRMS (ESI) calcd for C15H19NO [M + H]+: 230.1545; found:
230.1530.
1
33.3, 30.6, 27.9, 27.8, 26.3, 21.3, 19.9. (Note: both the H and 13C
NMR spectra of 3/4v contain residual camphorsultam that could not
be separated by column chromatography). HRMS (ESI) calcd for
C21H29NO4S [M + Na]+: 414.1715; found: 414.1703.
(1S,2R,5S,6R)-3-Hydroxymethyl-4-(p-phenoxymethyl)tricy-
clo[4.2.1.02,5]non-3-ene, 5r (Scheme 5). 52% (21.3 mg); Yellow
oil. Rf 0.30 (4:6 EtOAc:hexanes); [α]2D6 +12.3 (c 0.65, CHCl3, 96.0%
ee, er 49:1 for 5r/enant-5r); HPLC (OD-H column, 1.0 mL/min, 1%
iPrOH/99% hexanes, 210 nm), tR (major enantiomer): 43.22 min, tR
3-((1S,5R,7R)-10,10-Dimethyl-3,3-dioxo-3-thia-4-azatricyclo-
[5.2.1.01,5]decane-4-carbonyl)-(1S,2R,5S,6R)-4-pentyltricyclo-
[4.2.1.02,5]non-3-ene, 3/4s (Table 5, entry 11). 92% (43.0 mg);
White solid. mp: 106−107 °C. Rf 0.50 (2:8 EtOAc:hexanes); IR
(CH2Cl2): 2952 (s), 2931 (s), 2866 (s), 1648 (s), 1337 (s) cm−1; dr
1
10:1 for 3s/4s; H NMR (CDCl3, 400 MHz) major isomer: δ 4.00
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dx.doi.org/10.1021/jo501594g | J. Org. Chem. 2014, 79, 10002−10012

The Journal of Organic Chemistry
Article
(minor enantiomer): 45.69 min; IR(CH2Cl2): 3416 (br), 2947 (s),
2868 (s), 2834 (m), 1507 (s), 1229 (s), 1181 (m), 1039 (s), 825 (s),
(29) Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, R. Angew.
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1
732 (m) cm−1; H NMR (CDCl3, 400 MHz): δ 6.87−6.77 (m, 4H),
4.47 (d, 1H, J = 14.0 Hz), 4.43 (d, 1H, J = 14.0 Hz), 4.18−4.03 (m,
2H), 3.74 (s, 3H), 2.61 (br s, 1H), 2.39 (s, 2H), 1.99 (br s, 2H), 1.60−
1.48 (m, 2H), 1.43 (d, 1H, J = 10.2 Hz), 1.10−0.99 (m, 2H), 0.97 (d,
1H, J = 10.2 Hz); 13C NMR (CDCl3, 100 MHz): δ 154.1, 152.2, 143.1,
136.7, 115.5, 114.6, 64.8, 59.1, 55.6, 46.9, 46.6, 38.8, 33.7, 30.5, 28.1
(2C). HRMS (ESI) calcd for C18H22O3 [M + H]+: 287.1647; found:
287.1653.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra and HPLC chromatograms of novel
cycloadducts. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: wtam@uoguelph.ca (W.T.).
■
(40) Millward, D. B.; Sammis, G.; Waymouth, R. M. J. Org. Chem.
2000, 65, 3902.
(41) Fagan, P. J.; Mahoney, W. S.; Calabrese, J. C.; Williams, I. D.
Organometallics 1990, 9, 1843.
Notes
The authors declare no competing financial interest.
(42) Lai, G.; Colon, C. Synth. Commun. 1999, 29, 3011.
ACKNOWLEDGMENTS
This work was supported by the Natural Sciences and
Engineering Research Council of Canada (NSERC).
■
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