Scalable synthesis of enantiomerically pure bicyclo[2.2.2]octadiene ligands

Article abstract of DOI:10.1021/jo3005638

An operationally simple and scalable synthesis of enantiomerically pure bicyclo[2.2.2]octadiene (bod) ligands relying on an organocatalytic one-pot Michael addition-aldol reaction with cheap 2-cyclohexenone and phenylacetaldehyde is presented. The crystalline bicyclic product 4a (6-hydroxy-5-phenylbicyclo[2.2.2]octan-2-one) is transformed into phenylbicyclo[2.2.2]oct-5-en-2-one 2, a versatile starting material for the 2-step synthesis of both symmetrical, such as Hayashi's Ph-bod* ligand, as well as novel unsymmetrical chiral dienes.

Full text of DOI:10.1021/jo3005638

Article
pubs.acs.org/joc
Scalable Synthesis of Enantiomerically Pure Bicyclo[2.2.2]octadiene
Ligands
Stefan Abele,*,† Roman Inauen,† Dirk Spielvogel,‡ and Christian Moessner‡
†Process Research Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland
‡Chemical Development and Catalysis, Solvias AG, Romerpark 2, CH-4303 Kaiseraugst, Switzerland
̈
S
* Supporting Information
ABSTRACT: An operationally simple and scalable synthesis
of enantiomerically pure bicyclo[2.2.2]octadiene (bod*)
ligands relying on an organocatalytic one-pot Michael
addition−aldol reaction with cheap 2-cyclohexenone and
phenylacetaldehyde is presented. The crystalline bicyclic
product 4a (6-hydroxy-5-phenylbicyclo[2.2.2]octan-2-one) is
transformed into phenylbicyclo[2.2.2]oct-5-en-2-one 2, a
versatile starting material for the 2-step synthesis of both
symmetrical, such as Hayashi’s Ph-bod* ligand, as well as novel
unsymmetrical chiral dienes.
10%, respectively.8 The key intermediate was racemic
bicyclo[2.2.2]octane-2,5-dione 1 that is difficult to prepare on
INTRODUCTION
■
Since 2003, chiral dienes have gained considerable interest in
metal-catalyzed asymmetric processes.1,2 They have not only
larger scales, as most intermediates are oils, thwarting a simple
and scalable purification.9
been successfully used for known catalytic enantioselective
transformations (mainly 1,4-addition of organoboronic acids to
The need for a more expeditious and simplistic synthesis of
bod* ligands has been explicitely expressed by several groups in
α,β-unsaturated carbonyl compounds and 1,2-additions to
order to stimulate wider acceptance and application of these
imines) but proved superior in reactions where other types of
versatile and powerful ligands.10 Herein, we report a concise
ligands led to inferior results in terms of selectivity and notably
catalytic activity.3 Besides other factors like stability and scope,
the widespread use of any new class of ligands is influenced by
the ease and cost of their synthesis. Specifically, Hayashi’s
bicyclo[2.2.2]octadiene (bod*) ligands,4 which display a broad
scope and excellent selectivities, are still lacking a straightfor-
ward access in terms of scalability and costs (Figure 1).5
Another type of chiral diene pioneered by Carreira is accessible
from the chiral pool.6,7 The Ph- and Bn-bod* ligands have been
synthesized following two resolution routes, either by fractional
crystallization of diastereomeric dihydrazones of (R)-5-(1-
phenylethyl)semioxamazides or by separation with chiral
HPLC, resulting in an overall yield of approximately 1% and
and scalable synthesis of enantiomerically pure bod* ligands
relying on an organocatalytic tandem Michael addition−aldol
reaction as the pivotal step and employing phenylbicyclo-
[2.2.2]oct-5-en-2-one 2 as the common chiral intermediate.
Besides the symmetrical bod* ligands known so far, unsym-
metrical bod*-type ligands are also accessible with this new
approach.
Recently, (R,R)-211 became readily accessible on a kilogram
scale in our laboratories (Scheme 1).12 Aldehyde 3 is easily
obtained on multi-kg scale in 63% yield, starting with the
Shibasaki reaction13 of 2-cyclohexenone and dimethyl
malonate. The key to success was the discovery of an
intramolecular crystallization-induced diastereomer transforma-
tion (CIDT)14 in the aldol reaction of the masked ketone
aldehyde 3, allowing the simple isolation of the highest melting
stereoisomer 4a from the crude reaction mixture among several
isomers.
Our new approach as discussed below is based on results
reported by Bella15 involving the reaction of 2-cyclohexenone
and phenylacetaldehydes in the presence of a cinchona alkaloid
and a chiral secondary amine as organocatalysts (Scheme 2).
The use of expensive cinchona alkaloids, a moderate dr
Figure 1. Hayashi’s bod* ligands and reported syntheses.4
Received: March 23, 2012
Published: May 2, 2012
© 2012 American Chemical Society
4765
dx.doi.org/10.1021/jo3005638 | J. Org. Chem. 2012, 77, 4765−4773

The Journal of Organic Chemistry
Article
Scheme 1. Synthesis of Pivotal Intermediate 212 as Starting Material for the Synthesis of Chiral Dienes
a
Scheme 2. Organocatalytic Synthesis of Bicyclic
Table 1. One-Pot Organocatalytic Michael−Aldol Reaction
Intermediate 4a (Example with Highest er with L-Proline)15
b
c
entry
1
scale
base
dr IPC
yield of 4a (%)
er 4a
25 g
0.5 kg
5 g
Et2-i-PrN
Et2-i-PrN
Et3N
n.a.
53
66
54
53
58
41
33
54
41
29
32
74:26
72:28
74:26
70:30
67:33
75:25
62:38
62:38
63:37
62:38
63:37
d
2
n.a.
3
4
5
6
7
8
n.a.
obtained with L-proline alone, and the required chromatog-
raphy were perceived as obstacles for immediate scale up. Since
the major isomer 4a was also the key intermediate in our
approach (Scheme 1), we were confident in capitalizing on our
findings related to the CIDT in order to find a more efficient
synthesis of the chiral bicycle 4a. In view of our projected
demands for this building block in one of our development
programs, the overall cost of this process had to be taken into
account in addition to the selectivity.16
5 g
n-Bu3N
n-Oct3N
DABCO
DBU
92:8
92:8
84:16
n.a.
5 g
5 g
5 g
5 g
pyridine
no base
no base
no base
94:6
d
e
9
5 g
n.a.
f
10
5 g
66:34
79:21
g
11
5 g
a
Conditions: 2-cyclohexenone, phenylacetaldehyde (1.1 equiv), L-
proline (0.25 equiv), toluene (6−7 vol), base (0.25 equiv or without
base), 45 °C, 3 d (entries 9−11) and 4 d (entries 1−8), water addition
(2 vol), filtration, washing (water, toluene). Product 4a was isolated
RESULTS AND DISCUSSION
■
Inspired by the encouraging enantiomeric ratios (er) reported
by Bella, the possibility to enrich and easily isolate 4a from an
isomeric mixture,12 and the low costs of the starting materials,17
we embarked on a screen of solvents, additives, organocatalysts,
and temperatures for this reaction. In total, 96 experiments
were run on a 96-well plate, followed by verification of selected
screening hits on the gram scale (Supporting Information). The
dr, i.e., the ratio of (4a+ent-4a)/(4b+ent-4b) in the reaction
mixture, started at approximately 50:50 and grew to 92:8 at the
end of the reaction. This could be explained by an equilibrium
between 4a and 4b as observed in the aldol reaction of 3 to 4a
(Scheme 1). Under all conditions screened, the major products
after some hours were the bicyclic alcohols 4 (40−60% a/a 4 by
GC). Many lower level impurities are detectable by GC−MS,
and their structure has been tentatively assigned on the basis of
their mass. One set was identified as Baylis−Hillman products,
and the other set could be conceivably derived from the
addition of a second equivalent of phenylacetaldehyde to the
Michael product followed by cyclization. It is noteworthy that
using an oily mixture of isomers of 4 of lower purity afforded
bicyclic ketone 2 that could not be purified by crystallization,
giving an oily product of low purity.12 The target was therefore
to have 4a accumulated in the reaction mixture. The best er
(86:14) was achieved at 0 °C; however, the dr was only 50:50,
more byproducts were formed, and the reaction took 21 days
for completion. The best results in terms of yield, dr, and er of
4a were obtained with 0.25 equiv of L-proline and 0.25 equiv of
b
with diastereomeric purity >99.5%. dr in reaction mixture after 4 d.
c
IPC (in-process control). Ratio of 4a:ent-4a of isolated product, chiral
d
e
HPLC. No water was added prior to filtration. dr of mother liquor:
f
g
approximately 50:50. TBME instead of toluene. EtOAc instead of
toluene.
in pure form by simple filtration of the reaction mixture. This
moderate enantioselectivity is counterbalanced not only by the
low cost of L-proline and the two starting materials but also by
the ease of upgrade of the enantiopurity by crystallization (vide
infra).18
Similar results were obtained with Et3N, n-Bu3N, n-Oct3N,
1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU), and pyridine (entries 3−8). The
dr of the reaction mixture was as high as 94:6, and the isolated
product was consistently diastereomerically pure, with isolated
yields and er’s ranging from 33% to 66% and from 62:38 to
75:25, respectively. The absolute configuration of both 4a and
4b was ascertained by comparison with pure samples derived
from our first enantioselective route (Scheme 1). It is
interesting to note that racemic 4a was produced in 32−36%
yield when these reactions were run in the presence of water.
Surprisingly, similar diastereoselectivities and enantioselec-
tivities were obtained when no base was used in toluene, TBME,
and EtOAc (entries 9−11) since virtually no conversion was
observed when the reaction of phenylacetaldehyde and 2-
cyclohexenone was run without base in the presence of L-
proline in toluene.15a In our hands, 4a of excellent
diastereomeric purity (>99.5%) was obtained by simple
filtration, starting with a reaction mixture with a dr of as low
as 66:34. The isomer distribution 4a:4b does not seem to be
Hunig’s base (i-Pr EtN) in toluene at 45 °C for 4 days (Table
̈
2
1, entry 1). As a testimony to the scalability of this process, 717
g of 4a (diastereomeric purity >99.5%, er 72:28) was obtained
from 500 g of 2-cyclohexenone in 66% yield by this exceedingly
simple and efficient process (entry 2): the product was isolated
4766
dx.doi.org/10.1021/jo3005638 | J. Org. Chem. 2012, 77, 4765−4773

The Journal of Organic Chemistry
Article
a
determined only by the steric and electronic factors governing
the organocatalysis of proline and its derivatives19,20 but also by
the thermodynamic stability of the products following the
intramolecular aldol reaction since we have shown that there is
an equilibrium between 4b and 4a by retro-aldol reaction,
accompanied by epimerization of the benzylic position through
an enolate.12 The predominance of isomer 4a over 4b could
hence result from the differences in solubility as discussed
above (CIDT). We speculate that a major driving force for this
reaction is the crystallization of 4a. We have no data indicating
reversibility of the Michael addition step, though we cannot
exclude it under modified reaction conditions.21 A higher
overall yielding process is conceivable if conditions are found to
decouple the two reactions, i.e., first optimizing the
enantioselectivity of the Michael addition prior subjecting the
isomers to the CIDT; keeping both major diastereoisomers in
solution until the end of the tandem sequence is a prerequisite
for this alternative target.22
Table 2. Synthesis of Chiral Dienes 5 (Diaryl)
b
5
Raryl
yield (%)
mp (°C)
a
Ph (Ph-bod)*
2-MeC6H4
65
33
76
44
30
72
12
30
52
4
74−77
47−48
103−104
95−98
80−81
69−72
b
c
d
e
f
4-FC6H4
4-MeOC6H4
4-C6H4OC6H4
2-thienyl
c
g
h
i
4-C6H4C6H4
1-naphthyl
142
resin
2-naphthyl
119−121
oil
d
j
3,5-difluoro-C6H3
a
The dehydration to 2 was performed as already described
Using phenylketone 2 with er >99.5:0.5. Purity of all dienes >99% a/a
(LC−MS). Yields after purification, unoptimized, er for all dienes
>99.5:0.5, (S,S)-diene was not detected, determined by chiral HPLC
(Scheme 3).12 Having reached a limit for the er in the
b
c
methods, see the Supporting Information. Melts with decomposition;
Scheme 3. Dehydration of the Bicyclic Alcohol 4a and
Upgrade of er12
d
DSC: peak temp 152 °C. Unstable.
regioisomeric elimination products (endo- and exo-methylene
products) upon treatment with MsCl and Et3N. Therefore, the
alkyl-substituted dienes 7 were accessed via the triflate 6, which
was cross-coupled with Grignard reagents, catalyzed by
iron(III) acetylacetonate (Table 3).10a The triflate 6 was
a
Table 3. Synthesis of Chiral Dienes 7 (Phenylalkyl)
organocatalytic step, recrystallization of bicyclic alcohol 4a or
ketone 2 led to an enrichment of the desired enantiomer. It is
favorable to proceed directly to ketone 2 giving slightly higher
yields. Hence, the crude mesylate 4a-Ms23 was reacted to 2
(with an er of approximately 70:30), which was crystallized
from heptane or TBME (on 36-g scale) to reach an er of >98:2
in 38% yield in a first crop. A second recrystallization delivers
an er of >99.5:0.5 in 87% recovery. In summary, starting from
2-cyclohexenone to enantiopure bicyclic ketone 2, six out of the
nine steps have been skipped, allowing for an efficient
production. The overall yield is 17%; only one intermediate
(4a) is isolated.
Having secured a practical access to enantiomerically pure
ketone 2, two methods were applied to synthesize chiral dienes
of the bod*-type. To access aryl-substituted dienes 5, aryl
Grignard reagents were added to ketone 2, forming a mixture of
tertiary alcohols that were dehydrated under mild conditions by
treatment with MsCl and Et3N at rt (Table 2). The yield of the
crude dienes was good and the main byproduct detected was
the arene derivative coming from Grignard hydrolysis. Because
of the unpolar nature of these compounds, different methods
were applied for their purification. Chromatography24 was
usually used on a gram scale, whereas a slurrying in methanol
became the favored operation on a larger scale.25
b
7
Ralkyl
Me
yield (%)
mp (°C)
a
45
51
35
oil
b
Bn
51−52
oil
c
c
isobutyl
a
Using phenyl ketone 2 with er >99.5:0.5. Purity of 7a and 7b > 98.8%
a/a (LC−MS). Yields after purification, unoptimized, er for both
dienes >99.5:0.5, other enantiomer not detected, determined by chiral
b
c
HPLC methods, see the Supporting Information. Purity 97% a/a
(LC−MS), unstable.
readily accessed by quenching the lithium enolate derived from
2 with Comins reagent.27 The yields from the ketone 2 to the
dienes 7a and 7b are comparable to the yields obtained by
Hayashi for the transformation of the bis-triflate of diketone 1
to Ph-bod* or Bn-bod*.4b
Cross-coupling triflate 6 with allyl-, vinyl-, and propargyl-
magnesium bromide led to low conversion and decomposition.
The chiral diene with R = H could not be isolated from the
reaction of triflate 6 with formic acid, n-Bu3N, and
PdCl2(PPh3)2, as the product degraded during aqueous
workup. The 3,5-difluorophenyl diene 5j (Raryl = 3,5-
difluorophenyl) and isobutyl diene 7c (Ralkyl = isobutyl) were
successfully synthesized and fully characterized. They proved to
be stable at rt for some days; however, after storage at −20 °C
Enantiomeric and chemical purities were consistently
excellent (er >99.5:0.5, >99% a/a LC−MS). The absolute
configuration was determined by spiking (R,R)-5a with a
commercial sample of (R,R)-5a (Ph-bod*). The quality of 5a
synthesized by this organocatalytic route is equal or superior to
that of a commercial sample of (1R,4R)-Ph-bod*.26
The addition of alkyl Grignard or lithium alkyl reagents to 2
proved to be difficult. n-BuLi afforded the carbinol as an endo/
exo mixture (dr 40:60, 58%, 90% a/a) leading to a mixture of
1
for 9 months both had degraded as judged by H NMR and
4767
dx.doi.org/10.1021/jo3005638 | J. Org. Chem. 2012, 77, 4765−4773

The Journal of Organic Chemistry
Article
temperatures, and yields are given as is, unless otherwise stated. All
reactions were run under an atmosphere of N2
LC−MS. All dienes in Tables 2 and 3 were stable as neat solids
or oils at rt for at least 12 months.28
(1R,4R,5S,6S)-6-Hydroxy-5-phenylbicyclo[2.2.2]octan-2-one
(4a). General Method: Organocatalytic Tandem Michael−aldol
Reaction (Table 1). L-Proline (0.25 equiv) and the base (0.25 equiv)
were added to a mixture of 2-cyclohexenone (1 wt, 1.00 equiv) and
phenylacetaldehyde (1.10 equiv) in toluene (7 vol) at 20−25 °C. The
mixture was stirred at 45 °C for 4 d. Preparation of a sample for in-
process-control (IPC by LC−MS): sampled well-stirred mixture,
evaporated sample to dryness at 20 °C under reduced pressure; 2 mg
of the residue was dissolved in water/acetonitrile 1:1 (1 mL) for LC−
MS. The suspension was cooled to 20−25 °C, water (2 vol) was
added, and the mixture was stirred at 20−25 °C for 15 min. The
suspension was filtered and washed with water (3 × 1 vol) and toluene
(3 × 1 vol). The filter cake was dried under reduced pressure at 45 °C
to yield 4a as colorless solid. Diastereomeric purity and er (ratio of
4a:ent-4a) were determined by chiral HPLC method (ChiralPak AS-H,
4.6 × 250 mm, 5 μm, heptane/2-propanol 60:40, 0.8 mL/min). LC−
In a holistic view of the process efficiency toward chiral
dienes 5, the moderate overall yield caused by the low ee (44%)
of the organocatalytic step is counterbalanced by the low cost
of the organocatalyst (L-Pro), the low number of isolated
intermediates (2 or 3), and the operational simplicity of the
enantioselective step.16 Acknowledging that good processes are
inherently green processes,29 the process mass intensity (PMI,
kg reagents/1 kg of product)30 was calculated for this new
approach to Ph-bod* ligand 5a. It was compared with the
published route relying on separation of diastereomeric
dihydrazones4b (Table 4).31 Even though the overall yield has
Table 4. Comparison of This Organocatalytic Route to 5a
with Published Route4b (PMI: Mass of All Material Used To
Make 1 kg of Product)
12
1
MS, H NMR, and 13C NMR data correspond to literature.
Large-Scale Run. In a 4-L double-jacketed reactor L-proline (146.0
g, 0.25 equiv) and N-ethyldiisopropylamine (217 mL, 0.25 equiv) were
added to a mixture of 2-cyclohexenone (496.5 g, purity 98%, 5.06 mol)
and phenylacetaldehyde (743.3 g, purity 90%, 1.10 equiv) in toluene
(3 L) at 23 °C. Note: addition of N-ethyldiisopropylamine led to an
exotherm. The mixture was stirred at 45 °C for 4 d. Note: the initial
cloudy yellow suspension turned into a thick, well-stirred suspension.
The suspension was cooled to 20 °C, stirred at 20 °C for 1 h, and
filtered. The filter cake was washed with water (3 × 500 mL, pH 9−
10) and toluene (3 × 400 mL). The filter cake was dried under air for
2 h to yield 4a as colorless solid (717 g, 66%): purity (LC−MS): 100%
a/a, tR = 1.19 min, [M − 18 + 1]+ = 199; chiral HPLC: er 72:28, tR =
14.8 min (R,R), (tR = 12.4 min (S,S)), 1H NMR (CDCl3) corresponds
to 4a.12
Recrystallization of 4a (er 72:28) in Acetonitrile (32 vol).
Compound 4a (5 g) was dissolved in acetonitrile (160 mL) at 82
°C. After being cooled to 23 °C, the suspension was filtered, washed
with acetonitrile (2 × 1 mL), and dried under reduced pressure to
afford 4a as white solid (0.47 g, 9%). Chiral HPLC: er >99.5:0.5.
Recrystallization of 4a (er 72:28) in Acetonitrile (16 vol).
Compound 4a (5 g) was dissolved in acetonitrile (80 mL) at 82 °C.
After being cooled to 50 °C, the suspension was filtered, washed with
acetonitrile (2 × 1 mL), and dried under reduced pressure to afford 4a
as a white solid (1.5 g, 30%). Chiral HPLC: er 91.6:8.4.
present
organocatalytic
route (%)
published
a
typical range for
pharmaceuticals32
route (%)
b
overall yield
11
5
1
(1.3)
n.a.
n.a.
n.a.
chemical steps
6 + 2 + 2 (5)
7 (4)
isolated
intermediates
2
b
PMI without
solvents and
water
36
1365 (1019)
n.a.
c
b
solvent usage
a
207
10174 (7646)
10−170
Numbers in parentheses refer to the published route excluding the
syntheses of the (cyclohexa-1,5-dien-1-yloxy)trimethylsilane, of 2-
acetoxyacrylonitrile, and of (R)-5-(1-phenylethyl)semioxamazide;
these starting materials are not readily available on a larger scale.
Starting from 2-cyclohexenone. Major contribution is heptane used
to crystallize the unpolar 2.
b
c
increased only by a factor of approximately 10, the PMI
regarding the reagents decreased by a factor of 38 (or 28),
paving the way to a much reduced cost for this class of ligands.
CONCLUSION AND OUTLOOK
Recrystallization of 4a (er 72:28) in THF (10 vol). Compound 4a
(5 g) was dissolved in THF (50 mL) at 66 °C. After cooling to 23 °C,
the suspension was filtered, washed with THF (2 × 1 mL), and dried
under reduced pressure to afford 4a as white solid (1.17 g, 23%).
Chiral HPLC: er 96.0:4.0.
(1S,4S,5R,6R)-6-Hydroxy-5-phenylbicyclo[2.2.2]octan-2-one
(ent-4a). 2-Cyclohexenone (10 mL, 0.10 mol) and phenylacetalde-
hyde (14.6 mL, 1.10 equiv) were added to a mixture of D-proline (2.93
g, 0.25 equiv) and DIPEA (4.36 mL, 0.25 equiv) in toluene (70 mL) at
20−25 °C. The mixture was stirred at 45 °C for 3 d. IPC according to
LC−MS indicated >99% conversion. The suspension was cooled to
20−25 °C and filtered. The filter cake was washed with water (3 × 10
mL) and toluene (3 × 10 mL). The filter cake was dried on the filter
by sucking air through the filter to afford ent-4a as colorless solid (13.2
g, 60%). Chiral HPLC: er 27:73 (4a:ent-4a, tR 14.8 min:12.4 min).
Purity (LC−MS): 100% a/a, tR 1.2 min. 1H NMR (CDCl3)
corresponds to 4a.
(1R*,4R*,5S*,6S*)-6-Hydroxy-5-phenylbicyclo[2.2.2]octan-2-
one (rac-4a). N-Diisopropylethylamine (6.6 mL, 0.25 equiv) and 20
mM sodium phosphate buffer solution (pH 8, 14 mL) were added to a
mixture of L-proline (5.87 g, 0.25 equiv), 2-cyclohexenone (20 g, 0.20
mol), and phenylacetaldehyde (29.9 g, 1.10 equiv) in toluene (140
mL) at 20−25 °C. The mixture was stirred at 45 °C for 10 d. The
suspension (pH 8−9) was filtered. The filter cake was washed with
water (3 × 10 mL), followed by toluene (3 × 20 mL). The filter cake
was dried at 45 °C under reduced pressure to afford rac-4a as a white
solid (15.7 g, 36%). Chiral HPLC: er 50:50, diastereoisomeric purity
■
In conclusion, we have developed a concise and flexible access
to various chiral dienes starting from cheap starting materials.
This approach also delivers unsymmetrical (C1-symmetrical)
dienes, not accessible with the standard route (Figure 1) that
affords the C2-symmetrical ligands.33 Since it was shown that
one substituent on related chiral dienes was sufficient to control
the enantioselectivity,10b application of our unsymmetrical
dienes is currently being investigated in asymmetric trans-
formations where known diene ligands gave only moderate
results.34 Fine-tuning properties such as stability, selectivity,
and activity of the asymmetric catalysts is straightforward since
our new synthetic route could deliver a large variety of ligands
in a short time.
EXPERIMENTAL SECTION
■
General remarks: 1 vol or 1 wt means 1 L of solvent or 1 kg of reagent,
respectively, with respect to the reference starting material. er and dr
reported in this paper have not been validated by calibration.
Therefore, we are reporting an er of >99.5:0.5 when the other
enantiomer was not detectable by the chiral HPLC methods.35
Compounds were characterized by mp (uncorrected), GC−MS, LC−
MS, 1H NMR (400 MHz), or 13C NMR (100 MHz). High-resolution
mass spectra (HRMS) were recorded for new compounds (ESI,
quadrupole time-of-flight, Q-TOF). Temperatures are internal
4768
dx.doi.org/10.1021/jo3005638 | J. Org. Chem. 2012, 77, 4765−4773

The Journal of Organic Chemistry
Article
1
100% (chiral HPLC). Purity (LC−MS): 100% a/a, tR = 1.2 min. H
NMR (CDCl3) corresponds to 4a.
General Method B. Alkylmagnesium bromide (commercially
available solution in Et2O or THF, 2−4 equiv) was added with
cooling to a mixture of triflate 6 (1.0 equiv) and iron(III)
acetylacetonate (0.05−0.2 equiv) in THF (10−20 vol) at 20−40 °C.
LC−MS was used for IPC. If full conversion was not obtained with
stirring at 30−50 °C after the indicated time, additional
alkylmagnesium bromide and iron(III) acetylacetonate were added,
followed by stirring at 30−50 °C for the indicated time. Water (4 vol)
was added with cooling, followed by TBME (6 vol). The organic phase
was concentrated to dryness under reduced pressure at 50 °C to afford
the crude diene.
(1R,4R)-5-Phenylbicyclo[2.2.2]oct-5-en-2-one (2). MsCl (46.5
mL, 1.3 equiv) was added to a suspension of bicyclic alcohol 4a (100 g,
er 72:28, 0.46 mol) and Et3N (97 mL, 1.5 equiv) in toluene (500 mL)
at 10−20 °C. After being stirred at 10−20 °C for 10 min, the mixture
was washed with water (2 × 250 mL) and concentrated to dryness
under reduced pressure to afford the mesylate 4a-Ms as a light-yellow
oil that solidified at rt (136 g, 100%). Purity (LC−MS): 100% a/a, tR =
1
1.4 min, [M − 96 + 1]+ = 199. H NMR data (CDCl3) in agreement
with structure.12 Half of the crude mesylate 4a-Ms (67.8 g, 0.23 mol)
was dissolved in 2,4,6-collidine (65 mL) and stirred at 140−145 °C for
80 min. HCl (2 N, 320 mL) and heptane (800 mL) were added, and
the layers were separated. The organic phase was washed with 2 N
HCl (2 × 170 mL) and water (170 mL) and filtered over MgSO4. The
filtrate was evaporated to dryness at 50 °C under reduced pressure to
afford crude 2 as red oil (36 g, 79%). Purity (LC−MS): 95.2% a/a, tR
= 1.54 min. This crude product (36 g) was dissolved in TBME (30
mL) at 50 °C. After cooling to 0 °C and stirring at 0 °C for 0.5−1 h,
the suspension was filtered, and the filter cake was washed with TBME
(3 × 3 mL). The product was dried at 50 °C under reduced pressure
to afford the first crop of 2 as a colorless solid (first crop: 11.95 g,
26%). Chiral HPLC (ChiralPak AS-H, 4.6 × 250 mm, 5 μm, heptane/
2-propanol 60:40, 0.8 mL/min): er 98.3:1.7, tR = 10.3 min (R,R) (tR =
28.3 min (S,S)). The mother liquor was diluted with heptane (30 mL)
and stirred at 0 °C for 0.5 h. The suspension was filtered, and the filter
cake was washed with TBME (3 × 1 mL). The product was dried
under reduced pressure at 50 °C to afford the second crop of 2 as a
colorless solid (second crop: 1.63 g, 4%). Chiral HPLC: er 97.9:1.2, tR
= 10.3 min (R,R) (tR = 28.3 min (S,S)). 1H NMR (CDCl3)
corresponds to the structure.12
Recrystallization of 2 (er 67:33) in Heptane. Compound 2 (8 g)
was dissolved in heptane (40 mL) at 40 °C, at which temperature seed
crystals (er >99.5:0.5) were added. After being cooled to 23 °C, the
suspension was filtered, washed with heptane (2 mL), and dried under
reduced pressure to afford 2 as white solid (2.41 g, 30%). Chiral
HPLC: er 97.6:2.4.
Recrystallization of 2 (er 98.3:1.7) in TBME. Compound 2 (3 g)
was dissolved in TBME (3 mL) at 55 °C. The yellow solution was
cooled to 20−25 °C, at which temperature crystallization occurred.
The suspension was aged at 0 °C for 30 min, diluted with TBME (1
mL), stirred at 0 °C for 10 min, and filtered. The filter cake was
washed with TBME (2 × 1 mL) and dried under reduced pressure at
45 °C to afford 2 as a white solid (2.6 g, 87%). Chiral HPLC: er
99.6:0.4.
Racemic Dienes 5 and 7. For determination of er by chiral HPLC,
the racemic dienes rac-5a−i and rac-7a,b were prepared in the same
manner as described below for the (R,R)-isomers 5 and 7.
(1R,4R)-2,5-Diphenylbicyclo[2.2.2]octa-2,5-diene (5a). Phe-
nylmagnesium bromide (1 M in THF, 100 mL, 2 equiv) was added
to a solution of 2 (10 g, 50.4 mmol) in THF (60 mL) at 5−15 °C. The
reaction was allowed to warm to 20 °C and stirred for 1 h. IPC by
LC−MS indicated full conversion. Cold water (30 mL) was added
dropwise at 0−20 °C with cooling. More water (100 mL) and TBME
(140 mL) were added. After phase separation, the aqueous phase was
washed with TBME (50 mL). The combined organic phases were
washed with 1/2-saturated NaCl solution (2 × 60 mL), filtered over
MgSO4, and concentrated to dryness under reduced pressure at 50 °C
to afford the intermediate tert-alcohol as a yellow oil (15.8 g, 113%);
this mixture of exo- and endo-alcohols was dissolved in CH2Cl2 (155
mL). Et3N (48 mL, 6.0 equiv) and MsCl (11.6 mL, 2.6 equiv) were
added at 0−10 °C. After the mixture was stirred at 20 °C for 2 h, IPC
by LC−MS indicated full conversion. Water (40 mL) was added
dropwise, followed by 1/2-saturated NaHCO3 solution (120 mL) at
10−20 °C. CH2Cl2 (120 mL) was added, the phases were separated,
and the organic phase was washed with 1/2-saturated NaHCO3
solution (120 mL), dried over MgSO4, and concentrated to dryness
under reduced pressure at 50 °C to afford crude 5a as red oil that
turned into a mixture of solid and oil overnight (crude: 17.6 g, 135%).
The crude product (15.5 g) was suspended in MeOH (20 mL) at 50
°C for 5 min. The suspension was cooled to 20 °C and filtered, and
the filter cake was washed with MeOH (3 × 8 mL) and dried at 45 °C
under reduced pressure to afford 5a as a colorless solid (7.44 g, 65%):
mp 74−77 °C (Aldrich sample (1R,4R)-Ph-bod*, no. 707171: mp
74−76 °C); [α]25D = −29.6 (c = 1.04, CHCl3) (lit.4a [α]20D = −30 (c
= 0.72, CHCl3); Aldrich sample no. 707171 [α]22D = −37.0 (c = 1.03,
CHCl3)); GC−MS 99.5% a/a, tR = 3.82 min, [M + 1]+ = 259;37 purity
(LC−MS) >99.5% a/a, tR = 2.1 min, [M + 1]+ = 259; chiral HPLC
(Chiralpak AD-H, 250 × 4.6 ID, 5 μm, heptane/EtOH 1:1, 0.8 mL/
min): er >99.5:0.5, tR = 5.7 min (R,R); spiked with rac-5a (tR = 9.0
1
min (S,S)); H NMR and 13C NMR (CDCl3) data and chiral HPLC
Recrystallization of 2 (er 69:31) in TBME. Compound 2 (36.2 g)
was dissolved in TBME (30 mL) at 50 °C. The solution was cooled to
0 °C. The suspension was aged at 0 °C for 30 min and filtered. The
filter cake was washed with TBME (3 × 3 mL) and dried under
reduced pressure at 45 °C to afford 2 as a white solid (11.95 g, 33%).
Chiral HPLC: er 98.3:1.7.
data correspond to literature4b and to a commercial sample of
(1R,4R)-Ph-bod* (Aldrich, 95%, No. 707171, [796966-15-9]).
Differential scanning calorimetry (DSC): endotherm 67−81 °C,
peak 78 °C, exotherm 192−159 °C (−114 J/g). HRMS (ESI) m/z
calcd for C20H19 259.1487 [M + H]+, found 259.1481.
Synthesis of Chiral Dienes 5 and 7. General Method A1.
Arylmagnesium bromide (as a commercially available solution in THF,
2 equiv) was added to a solution of 2 (1 equiv) in THF (6 vol) at 5−
15 °C. The reaction was allowed to warm to 20 °C and stirred for the
indicated time. In-process-control (IPC) by LC−MS or TLC. After
full conversion,36 cold water (2−3 vol) was added at 0−20 °C. More
water (10−30 vol) and TBME (10−40 vol) were added. The organic
layer was concentrated to dryness under reduced pressure at 50 °C to
afford the intermediate tert-alcohol as a mixture of endo/exo isomers.
General Method A2. The crude product obtained from general
method A1 was used as such or purified by chromatography prior to
the following dehydration step. Et3N (6.0 equiv) and MsCl (2.6 equiv)
were added to a solution of the tert-alcohol in CH2Cl2 (6−10 vol) at
0−10 °C. After the solution was stirred at 20−25 °C for the indicated
time, >90% conversion was observed (LC−MS). Water (6−20 vol)
was added at 10 °C, followed by CH2Cl2 (10−20 vol). The organic
layer was washed with water (10−20 vol) and concentrated to dryness
under reduced pressure at 40 °C to afford the crude chiral diene.
(1R,4R)-2-Phenyl-5-(o-tolyl)bicyclo[2.2.2]octa-2,5-diene (5b).
Phenyl ketone 2 (5 g, 25.2 mmol) was reacted with o-tolylmagnesium
bromide (2 M in THF) according to general method A1 for 50 min.
After aqueous workup, the crude tert-alcohol was obtained (7 g, 96%)
that was purified by chromatography on silica gel (30 g, eluent
heptane/EtOAc 9:1) to afford the tert-alcohol (5.3 g, 72%). This
intermediate was reacted with MsCl and Et3N according to general
method A2 for 80 min to afford crude 5b as yellow oil (crude: 5.1 g,
74%). The crude product was triturated with heptane at 50 °C. The
soluble part was separated from the insoluble red oil by decantation
and purified by chromatography on silica gel (20 g, eluent heptane) to
afford 5b as colorless oil that solidified at rt (2.25 g, 33%): mp 47−48
°C; [α]25 = +80.7 (c = 1.13, CHCl3); GC−MS 97.2% a/a, tR = 3.80
D
min, [M + 1]+ = 273; purity (LC−MS) 100% a/a, tR = 2.14 min, [M +
1]+ = 273; chiral HPLC (Chiralpak AZ-H, 250 × 4.6 i.d., 5 μm,
heptane (0.05% Et2NH)/EtOH (0.05% Et2NH) 1.1, 0.8 mL/min) er
>99.5:0.5, tR = 5.0 min (R,R) (tR = 5.2 min (S,S)); 1H NMR (CDCl3)
δ 7.48−7.53 (m, 2 H), 7.34−7.43 (m, 2 H), 7.13−7.32 (m, 5 H), 6.72
4769
dx.doi.org/10.1021/jo3005638 | J. Org. Chem. 2012, 77, 4765−4773

The Journal of Organic Chemistry
Article
(dd, J1 = 6.3 Hz, J2 = 1.8 Hz, 1 H), 6.33 (dd, J1 = 6.3 Hz, J2 = 1.7 Hz, 1
H), 4.24 (d, J = 6.0 Hz, 1 H), 3.89 (d, J = 6.0 Hz, 1 H), 2.32 (s, 3 H),
1.49−1.68 (m, 4 H); 13C NMR (CDCl3) δ 148.2, 147.0, 140.2, 138.4,
135.7, 131.1, 130.3, 129.3, 128.5, 128.2, 126.8, 125.6, 124.9, 43.3, 39.9,
25.7, 25.5, 20.8; HRMS (ESI) m/z calcd for C21H21 273.1643 [M +
H]+, found 273.1636.
H), 4.20−4.28 (m, 2 H), 1.59 (s, 4 H); 13C NMR (CDCl3) δ 157.5,
156.2, 147.0, 146.2, 138.2, 133.5, 129.7, 129.1, 128.5, 128.4, 126.8,
126.1, 124.8, 123.1, 119.1, 118.7, 40.2, 40.1, 25.8, 25.8; HRMS (ESI)
m/z calcd for C26H23O 351.1749 [M + H]+, found 351.1744.
2-((1R,4R)-5-Phenylbicyclo[2.2.2]octa-2,5-dien-2-yl)-
thiophene (5f). 2-Thienylmagnesium bromide (1 M in THF, 200
mL, 2 equiv) was added to a solution of phenyl ketone 2 (20 g, 0.101
mol) in THF (120 mL) at 5−15 °C. The reaction was allowed to
warm to 20 °C and stirred for 1 h. IPC by LC−MS indicated full
conversion. Cold water (80 mL) was added at 0−20 °C with cooling.
More water (170 mL) and TBME (200 mL) were added, and the
mixture was filtered over Celite. After phase separation, TBME (100
mL) was added to the aqueous phase, and the mixture was filtered
over Celite. The TBME phase was washed with 1/2-saturated NaCl
solution (2 × 100 mL), filtered over MgSO4, and concentrated to
dryness under reduced pressure at 50 °C to afford the intermediate
tert-alcohol as a brown oil (29.7 g, 113%); this intermediate mixture of
exo- and endo-alcohols was dissolved in CH2Cl2 (280 mL). Et3N (85
mL, 6.0 equiv) and MsCl (20.6 mL, 2.6 equiv) were added at 0−10
°C. After the mixture was stirred at 20 °C for 20 min, IPC by LC−MS
indicated full conversion. Water (50 mL) was added dropwise,
followed by 1/2-saturated NaHCO3 solution (120 mL) at 10−20 °C.
CH2Cl2 (100 mL) was added, the phases were separated, and the
organic phase was washed with 1/2-saturated NaHCO3 solution (120
mL), dried over MgSO4, and concentrated to dryness under reduced
pressure at 50 °C to afford crude 5f as a black oil (crude: 30.1 g,
113%). MeOH (40 mL) was added to the crude product (30.1 g), and
the supension was stirred at 50 °C for 10 min. The suspension was
cooled to 20 °C, stirred at 20 °C for 1 h, and filtered, and the filter
cake was washed with MeOH (4 × 5 mL) and dried at 45 °C under
reduced pressure to afford 5f as off-white solid (19.35 g, 72%): mp
(1R,4R)-2-(4-Fluorophenyl)-5-phenylbicyclo[2.2.2]octa-2,5-
diene (5c). Phenyl ketone 2 (5 g, 25.2 mmol) was reacted with 4-
fluorophenylmagnesium bromide (1 M in THF) according to general
method A1 for 30 min. After aqueous workup, the crude tert-alcohol
was obtained (7.74 g, 104%); 7.7 g thereof was reacted with MsCl and
Et3N according to general method A2 for 60 min to afford crude 5c as
a red oil (crude: 9.2 g, 132%). The crude product was triturated with
heptane at 50 °C. The soluble part was separated from the insoluble
red oil by decantation and purified by chromatography on silica gel (33
g, eluent heptane) to afford 5c as a colorless solid (5.25 g, 76%): mp
103−104 °C; [α]25D = −19.6 (c = 1.12, CHCl3); GC−MS 94.1% a/a,
tR = 3.77 min, [M + 1]+ = 277; purity (LC−MS) 100% a/a, tR = 2.13
min, [M + 1]+ = 277; chiral HPLC (Chiralpak ID, 250 × 4.6 i.d., 5 μm,
heptane/EtOH 9:1, 0.8 mL/min) er >99.5:0.5, tR = 5.0 min (R,R) (tR
= 6.7 min (S,S)); 1H NMR (CDCl3) δ 7.33−7.49 (m, 6 H), 7.23−7.30
(m, 1 H), 7.00−7.08 (m, 2 H), 6.66 (dd, J1 = 6.4 Hz, J2 = 1.8 Hz, 1 H),
6.60 (dd, J1 = 6.4 Hz, J2 = 1.7 Hz, 1 H), 4.25 (d, J = 6.4 Hz, 1 H), 4.20
(d, J = 6.5 Hz, 1 H), 1.55−1.62 (m, 4 H); 13C NMR (CDCl3) δ 162.0
(d, J = 245 Hz), 146.9, 146.0, 138.1, 134.4 (d, J = 3.6 Hz), 129.0, 128.9
(d, J = 2.2 Hz), 128.5, 126.9, 126.4, 124.8, 115.3 (d, J = 22 Hz), 40.3,
40.1, 25.7; HRMS (ESI) m/z calcd for C20H18F 277.1393 [M + H]+,
found 277.1396.
(1R,4R)-2-(4-Methoxyphenyl)-5-phenylbicyclo[2.2.2]octa-
2,5-diene (5d). Phenyl ketone 2 (5 g, 25.2 mmol) was reacted with 4-
methoxyphenylmagnesium bromide (0.5 M in THF) according to
general method A1 for 60 min. After aqueous workup, the crude tert-
alcohol was obtained (8.2 g, 106%); 7.64 g thereof was reacted with
MsCl and Et3N according to general method A2 for 15 min to afford
crude 5d as a beige solid (crude: 6.6 g, 98%). The crude product was
dissolved in EtOAc (35 mL) at 50 °C, and the insoluble, slimy part
was separated by decantation. The clear solution was stirred at rt, and
the white precipitate was filtered off and washed with heptane to afford
the first crop. The mother liquor was stirred at rt, filtered, and washed
with heptane to afford the second crop. This procedure was repeated a
second time to afford a third crop. All three crops were combined to
69−72 °C; [α]25 = −116.7 (c = 1.04, CHCl3); purity (LC−MS)
D
100% a/a, tR = 2.1 min, [M + 1]+ = 265; chiral HPLC (Chiralpak AD-
H, 250 × 4.6 ID, 5 μm, heptane (0.05% Et2NH)/EtOH (0.05%
Et2NH) 1:1, 0.8 mL/min) er >99.5:0.5, tR = 5.6 min (R,R), (tR = 9.5
min (S,S)); 1H NMR (CDCl3) δ 7.32−7.48 (m, 4 H), 7.22−7.28 (m,
1 H), 7.09−7.18 (m, 2 H), 6.98−7.03 (m, 1 H), 6.64 (d, J = 2.0 Hz, 1
H), 6.63 (d, J = 2.0 Hz, 1 H), 4.16−4.22 (m, 2 H), 1.56−1.65 (m, 4
H); 13C NMR (CDCl3) δ 147.1, 142.6, 141.1, 138.1, 128.6, 128.4,
127.9, 127.5, 126.9, 124.9, 123.6, 121.7, 41.0, 39.9, 26.0, 25.7. HRMS
(ESI) m/z calcd for C18H17S 265.1051 [M + H]+, found 265.1046.
(1R,4R)-2-([1,1′-Biphenyl]-4-yl)-5-phenylbicyclo[2.2.2]octa-
2,5-diene (5g). Phenyl ketone 2 (5 g, 25.2 mmol) was reacted with 4-
biphenylmagnesium bromide (0.5 M in THF) according to general
method A1 for 60 min. After aqueous workup, the crude product (15.3
g, 172%) was purified by chromatography on silica gel (40 g, eluent
CH2Cl2/heptane 1:1) to obtain crude tert alcohol (6.7 g, 76%) which
was reacted with MsCl and Et3N according to general method A2 for
30 min to afford crude 5g as beige solid (crude: 6.88 g, 81%): purity
(LC−MS); 91% a/a. The crude product was suspended in TBME (70
mL) and filtered, and the filter cake washed with TBME (2 × 20 mL).
The filtrate was concentrated under reduced pressure to approximately
30 mL. The suspension was filtered and washed with TBME to afford
a first crop of 5g. A second crop of 5g was obtained by a similar
treatment of the mother liquor. Both crops were combined to afford
5g as colorless solid (1.33 g, 16%): purity (LC−MS) 95.8% a/a, tR =
2.31 min, [M + 1]+ = 335. A sample (83 mg) was triturated in
acetonitrile/MeOH (5 mL) at reflux. The suspension was cooled to rt
and filtered. The filter cake was washed with acetonitrile (0.5 mL) and
dried at 50 °C under reduced pressure to afford a purified sample of 5g
as a white solid (sample: 64 mg, 12% overall from 2): mp 152 °C
(peak temp in DSC), 141 °C dec; [α]25D = −12.7 (c = 1.18, CHCl3);
purity (LC−MS) 100% a/a, tR = 2.31 min, [M + 1]+ = 335; chiral
HPLC (Chiralpak OJ-3, 100 × 4.6 i.d., 3 μm, heptane (0.05%
Et2NH)/EtOH (0.05% Et2NH) 1:1, 0.8 mL/min): er >99.5:0.5, tR =
afford 5d as a colorless solid (3.0 g, 44%): mp 95−98 °C; [α]25
=
D
−68.4 (c = 1.03, CHCl3); TLC (heptane/EtOAc 9:1) one spot for all
crops; GC−MS 97.1% a/a, tR = 4.29 min, [M + 1]+ = 289; purity
(LC−MS) 100% a/a, tR = 2.07 min, [M + 1]+ = 289; chiral HPLC
(Chiralpak ID, 250 × 4.6 i.d., 5 μm, heptane/EtOH 9:1, 0.8 mL/min)
1
er >99.5:0.5, tR = 6.0 min (R,R) (tR = 10.3 min (S,S)); H NMR
(CDCl3) δ 7.33−7.51 (m, 6 H), 7.23−7.30 (m, 1 H), 6.92 (d, J = 8.8
Hz, 2 H), 6.67 (dd, J1 = 6.4 Hz, J2 = 1.9 Hz, 1 H), 6.57 (dd, J1 = 6.4
Hz, J2 = 1.9 Hz, 1 H), 4.20−4.27 (m, 2 H), 3.85 (s, 3 H), 1.59 (s, 4
H); 13C NMR (CDCl3) δ 158.7, 147.0, 146.3, 138.3, 131.0, 129.2,
128.5, 127.2, 126.8, 125.9, 124.8, 113.9, 55.4, 40.1, 34.0, 25.9, 25.8;
HRMS (ESI) m/z calcd for C21H21O 289.1592 [M + H]+, found
289.1588.
(1R,4R)-2-(4-Phenoxyphenyl)-5-phenylbicyclo[2.2.2]octa-
2,5-diene (5e). Phenyl ketone 2 (5 g, 25.2 mmol) was reacted with 4-
phenoxyphenylmagnesium bromide (0.5 M in THF) according to
general method A1 for 40 min. After aqueous workup, the crude tert-
alcohol was obtained (14 g, 151%) that was reacted with MsCl and
Et3N according to general method A2 for 60 min to afford crude 5c as
a red oil (crude: 15.1 g, 171%). The crude product was purified by
chromatography on silica gel (45 g, eluent heptane) to afford 5e as
colorless solid (2.6 g, 30%): mp 80−81 °C; [α]25D = −15.9 (c = 1.06,
CHCl3); GC−MS 100% a/a, tR = 3.46 min; purity (LC−MS) 98.7%
a/a, tR = 2.29 min, [M + 1]+ = 351; chiral HPLC (Chiralpak AD-H,
250 × 4.6 i.d., 5 μm, heptane (0.05% Et2NH)/EtOH (0.05% Et2NH)
1:1, 0.8 mL/min) er >99.5:0.5, tR = 9.2 min (R,R) (tR = 15.0 min
(S,S)); 1H NMR (CDCl3) δ 7.42−7.50 (m, 4 H), 7.33−7.41 (m, 4 H),
7.22−7.28 (m, 1 H), 7.08−7.15 (m, 1 H), 6.98−7.07 (m, 4 H), 6.66
(dd, J1 = 6.3 Hz, J2 = 1.5 Hz, 1 H), 6.62 (dd, J1 = 6.4 Hz, J2 = 1.6 Hz, 1
1
7.4 min (R,R), (tR = 9.1 min (S,S)); H NMR (CDCl3) δ 7.52−7.66
(m, 6 H), 7.42−7.51 (m, 4 H), 7.34−7.41 (m, 3 H), 7.21−7.28 (m, 1
H), 6.73 (dd, J1 = 6.4 Hz, J2 = 1.9 Hz, 1 H), 6.68 (dd, J1 = 6.4 Hz, J2 =
1.9 Hz, 1 H), 4.26−4.32 (m, 2 H), 1.60−1.64 (m, 4 H); 13C NMR
(CDCl3) δ 146.9, 146.4, 140.9, 139.6, 138.2, 137.1, 129.4, 129.2, 128.8,
4770
dx.doi.org/10.1021/jo3005638 | J. Org. Chem. 2012, 77, 4765−4773

The Journal of Organic Chemistry
Article
128.5, 127.2, 127.2, 126.9, 126.9, 125.2, 124.8, 40.2, 40.0, 25.8; HRMS
(ESI) m/z calcd for C26H23 335.1800 [M + H]+, found 335.1804.
(1R,4R)-2-(Naphthalen-1-yl)-5-phenylbicyclo[2.2.2]octa-2,5-
diene (5h). Phenyl ketone 2 (1.25 g, 6.3 mmol) was reacted with 1-
naphthylmagnesium bromide (0.25 M in THF) according to general
method A1 for 16 h. After aqueous workup, the crude product (2.8 g,
136%) was purified by chromatography on silica gel (7 g, eluent
heptane/EtOAc 9:1) to obtain crude tert-alcohol (1.45 g, 75%).
Another run starting with phenyl ketone 5h (1.25 g) gave crude tert-
alcohol (0.75 g, 39%). Both batches were combined (2.2 g) and
reacted with MsCl and Et3N according to general method A2 for 5 h
to afford crude 5h as beige oil (crude: 2.5 g, 64%). The crude product
was purified by chromatography on silica gel (25 g, eluent heptane), to
purified by chromatography on silica gel (40 g, eluent heptane) to
yield a fraction (2.29 g) that was purified again by chromatography on
silica gel (30 g, eluent heptane) to afford 5j as colorless oil (0.28 g,
4%): GC−MS 94.3% a/a, tR = 3.66 min, [M + 1]+ = 295; purity (LC−
MS) 100% a/a, tR = 2.11 min; chiral HPLC (Chiralpak IA, 250 × 4.6
ID, 5 μm, heptane/EtOH 9:1, 0.8 mL/min) er >99.5:0.5, tR = 7.2 min
1
(R,R), (tR = 11.4 min (S,S)); H NMR (CDCl3) δ 7.44−7.48 (m, 2
H), 7.33−7.40 (m, 2 H), 7.22−7.30 (m, 1 H), 6.93−7.00 (m, 2 H),
6.62−6.75 (m, 3 H), 4.28 (dd, J1 = 6.5 Hz, J2 = 1.8 Hz, 1 H), 4.16 (dd,
J1 = 6.0 Hz, J2 = 1.4 Hz, 1 H), 1.53−1.62 (m, 4 H); 13C NMR
(CDCl3) δ 163.3 (dd, J1 = 247 Hz, J2 = 14 Hz), 146.7, 145.2 (t, J = 3
Hz), 141.5 (t, J = 10 Hz), 137.9, 131.8, 128.7, 128.6, 127.0, 124.8,
107.5 (dd, J1 = 18 Hz, J2 = 7 Hz), 101.9 (t, J = 26 Hz), 40.2, 39.9, 25.7,
25.5; HRMS (ESI) m/z calcd for C20H16F2: 295.1298 [M + H]+,
found 295.1303. After storage at −20 °C for 8 months, the sample had
degraded, purity (LC−MS): 80.4% a/a.
afford 5h as colorless resin (1.16 g, 30%): [α]25 = +83.4 (c = 1.00,
D
CHCl3); GC−MS 98.5% a/a, tR = 4.73 min, [M + 1]+ = 309; purity
(LC−MS) 100% a/a, tR = 2.24 min, [M + 1]+ = 309; chiral HPLC
(Chiralpak AD-H, 250 × 4.6 ID, 5 μm, heptane/EtOH 1:1, 0.8 mL/
min) er >99.5:0.5, tR = 4.9 min (R,R), (tR = 4.6 min (S,S)); 1H NMR
(CDCl3) δ 7.94−8.00 (m, 1 H), 7.84−7.90 (m, 1 H), 7.76−7.81 (m, 1
H), 7.54−7.60 (m, 2 H), 7.37−7.53 (m, 5 H), 7.25−7.36 (m, 2 H),
6.85 (dd, J1 = 6.3 Hz, J2 = 2.0 Hz, 1 H), 6.54 (dd, J1 = 6.3 Hz, J2 = 1.9
Hz, 1 H), 4.31−4.36 (m, 1 H), 4.01−4.06 (m, 1 H), 1.52−1.78 (m, 4
H); 13C NMR (CDCl3) δ 147.4, 147.3, 138.7, 138.4, 133.9, 132.3,
131.7, 129.2, 128.6, 128.3, 127.3, 126.9, 126.2, 125.8, 125.7, 125.4,
125.0, 124.9, 44.2, 40.1, 25.9; HRMS (ESI) m/z calcd for C24H21
309.1643 [M + H]+, found 309.1640.
(1R,4R)-5-Phenylbicyclo[2.2.2]octa-2,5-dien-2-yl Trifluoro-
methanesulfonate (6). n-Butyllithium in hexane (1.6 M, 70.3 mL,
1.5 equiv) was added to diisopropylamine (11.6 mL, 1.5 equiv) at −78
°C in THF (25 mL). The mixture was warmed to −20 °C and stirred
at −20 °C for 10 min. After the mixture was cooled to −78 °C, a
solution of phenyl ketone 2 (15 g, 75.7 mmol) in THF (44 mL) was
added at −78 °C. After the mixture was stirred at −78 °C for 1 h, a
solution of 1,1,1-trifluoro-N-(pyridin-2-yl)-N-((trifluoromethyl)-
sulfonyl)methanesulfonamide27 (40.6 g, 1.5 equiv) in THF (44 mL)
was added. The brown solution was allowed to warm to rt. LC−MS
indicated >99% conversion. Cold water (200 mL) was added, and
THF was removed under reduced pressure at 50 °C. The mixture was
extracted with TBME (500 mL). The organic phase was washed with
10% aqueous NaOH solution (600 mL) and water (190 mL) and
evaporated to dryness under reduced pressure at 50 °C to afford the
crude product 6 as dark-red resin (crude: 33 g, 132%). The crude
product was purified by plug filtration over silica gel (190 g) using
heptane/EtOAc 9:1, fraction size approximately 100 mL, to afford
crude 6 as yellow oil (22 g, 88%): [α]25D = −5.90 (c = 1.10, CHCl3);
purity (LC−MS) 98.6% a/a, tR = 2.02 min; 1H NMR δ 7.20−7.52 (m,
5 H), 6.57 (dd, J1 = 6.4 Hz, J2 = 2.1 Hz, 1 H), 6.19 (dd, J1 = 7.2 Hz, J2
= 2.7 Hz, 1 H), 4.20 (m, 1 H), 3.76 (m, 1 H), 1.42−1.96 (m, 4 H);
13C NMR (CDCl3) δ 155.1, 147.0, 137.1, 128.6, 127.5, 127.3, 124.9,
(1R,4R)-2-(Naphthalen-2-yl)-5-phenylbicyclo[2.2.2]octa-2,5-
diene (5i). For the preparation of the 2-naphthyl Grignard reagent,
magnesium (1.22 g, 50.4 mmol) in THF (10 mL) was treated with a
solution of 2-bromonaphthalene (2.07 g, 10.1 mmol, 2 equiv) in THF
(10 mL). A slight exotherm was observed, and the mixture became
turbid. Additional THF (20 mL) was added, and the mixture was
stirred at rt for 15 min. The 2-naphthyl Grignard solution was cooled
to 0 °C, and a solution of phenyl ketone 2 (er >99.5:0.5, 1.0 g, 5.04
mmol, 1 equiv) in THF (10 mL) was added such that the temp did
not exceed 15 °C. The reaction mixture was stirred at rt for 2 h. The
reaction was quenched by addition of water (10 mL), the mixture was
extracted twice with TBME (2 × 10 mL), and the combined organic
phases were washed with water, dried over MgSO4, filtered, and
evaporated to dryness under reduced pressure to afford the tert-alcohol
as red viscous oil (2.53 g, 120%). The crude intermediate was
dissolved in CH2Cl2 (60 mL), and Et3N (5.4 mL, 38.8 mmol) was
added. MsCl (1.6 mL, 20.2 mmol) was added at 5 °C over 20 min. A
slight exotherm was observed, and the reaction mixture turned brown-
red. The reaction mixture was stirred at rt for 16 h. Water (50 mL) was
added, and the organic phase was washed with water (3×), dried over
MgSO4, filtered, and evaporated to dryness under reduced pressure to
yield crude 5i (crude: 1.8 g, 116%). Purification by chromatography
(50 g silica gel, ⌀ 3 cm, eluent heptane → heptane/EtOAc 10:2)
afforded 5i as off-white solid (810 mg, 52%). For analytical purposes, a
sample (750 mg) was further purified by crystallization from heptane
to give 5i as white solid (210 mg, 28% recovery): mp 119−121 °C;
120.3, 117.0, 40.7, 39.6, 25.8, 24.7; HRMS (ESI, negative mode) m/z
calcd for C15H13O3F3S 329.0459 [M − H]−, found 329.0463.
(1R,4R)-2-Methyl-5-phenylbicyclo[2.2.2]octa-2,5-diene (7a).
Methylmagnesium bromide (3 M in Et2O, 4 mL, 2.00 equiv) was
added with cooling to a mixture of triflate 6 (2 g, 6.05 mmol) and
iron(III) acetylacetonate (0.106 g, 0.05 equiv) in THF (30 mL) at
22−30 °C. The mixture was stirred at 35−40 °C for 3 d. Additional
iron(III) acetylacetonate (0.32 g, 0.15 equiv) and methylmagnesium
bromide (3 M in Et2O, 12 mL, 6.00 equiv) were added, and the
mixture was stirred at 30−40 °C for 24 h. GC−MS showed 81%
conversion. Water (20 mL) was added with cooling, followed by
TBME (50 mL). The organic phase was concentrated to dryness
under reduced pressure at 50 °C to afford crude 7a (crude: 1.3 g,
109%): purity (LC−MS) 96.8% a/a, tR = 2.0 min. The crude product
was purified by chromatography on silica gel (4 g, eluent heptane), to
[α]25 = +65.4 (c = 1.00, CHCl3); TLC Rf (heptane) = 0.19; Rf
D
(heptane/EtOAc 10:2) = 0.63; purity (LC−MS) 100% a/a, tR = 2.08
min, [M + 1]+ = 309; chiral HPLC (Chiralpak IA, 250 × 4.6 i.d., 5 μm,
heptane/EtOH 9:1, 0.8 mL/min) er >99.5:0.5, tR = 5.8 min (R,R) (tR
= 6.9 min (S,S)); 1H NMR (300 MHz, CDCl3) δ 7.70−7.90 (m, 4 H),
7.55−7.60 (m, 2 H), 7.2−7.50 (m, 6 H), 6.80 (dd, J1= 3 Hz, J2 = 6 Hz,
1 H), 6.70 (dd, J1 = 3 Hz, J2 = 6 Hz, 1 H), 4.41 (d, J = 6 Hz, 1 H), 4.29
(d, J = 6 Hz, 1 H), 1.61 (s br, 4 H); 13C NMR (300 MHz, CDCl3) δ
129.9, 129.2, 128.5, 128.1, 127.6, 126.8, 126.1, 125.5, 124.8, 123.7,
122.8, 41.2, 39.9, 25.9, 25.8; HRMS (ESI) m/z calcd for C24H21
309.1643 [M + H]+, found 309.1637.
(1R,4R)-2-(3,5-Difluorophenyl)-5-phenylbicyclo[2.2.2]octa-
2,5-diene (5j). Phenyl ketone 2 (5 g, 25.2 mmol) was reacted with
3,5-difluorophenylmagnesium bromide (0.5 M in THF) according to
general method A1 for 105 min. After aqueous workup, the crude tert-
alcohol was obtained (8.7 g, 110%); 8.15 g thereof was reacted with
MsCl and Et3N according to general method A2 for 70 min to afford
crude 5j as red-brown oil (crude: 8.5 g, 122%). The crude product was
afford 7a as colorless oil (0.54 g, 45%): [α]25 = −20.7 (c = 1.11,
D
CHCl3); purity (LC−MS) 98.8% a/a, [M + 1]+ = 197; chiral HPLC
(Chiralpak AD-H, 250 × 4.6 i.d., 5 μm, heptane/EtOH 1:1, 0.8 mL/
min) er >99.5:0.5, tR = 4.4 min, (tR = 4.7 min (S,S)); 1H NMR
(CDCl3) δ 7.42−7.46 (m, 2 H), 7.30−7.37 (m, 2 H), 7.19−7.25 (m, 1
H), 6.56 (dd, J1 = 6.3 Hz, J2 = 1.9 Hz, 1 H), 4.00−4.04 (m, 1 H),
3.45−3.49 (m, 1 H), 1.87 (s, 3 H), 1.40−1.49 (m, 4 H); 13C (CDCl3)
δ 147.0, 144.4, 138.5, 129.0, 128.4, 126.7, 126.6, 124.7, 43.1, 39.5, 26.2,
25.1, 19.3; HRMS (ESI) m/z calcd for C15H17 197.1330 [M + H]+,
found 197.1326.
(1R,4R)-2-Benzyl-5-phenylbicyclo[2.2.2]octa-2,5-diene (7b).
Benzylmagnesium bromide (19% in THF, 12 mL, 2.00 equiv) was
added to a mixture of triflate 6 (1.9 g, 5.75 mmol) and
iron(III)acetylacetonate (200 mg, 0.05 equiv) in THF (35 mL) at
35−40 °C. After 20 min of stirring at 33−40 °C, LC−MS indicated
>99% conversion. Water (40 mL) was added with cooling, followed by
4771
dx.doi.org/10.1021/jo3005638 | J. Org. Chem. 2012, 77, 4765−4773

The Journal of Organic Chemistry
Article
TBME (60 mL). The organic phase was evaporated to dryness under
reduced pressure at 50 °C to afford crude 7b as yellow oil (crude: 1.94
g, 124%). The crude product was purified by chromatography on silica
gel (10 g, eluent heptane) to afford two fractions with 7b (1.55 g)
which were submitted to a second chromatography on silica gel (50 g,
eluent heptane), to afford 7b as a colorless oil which solidified at rt
(0.8 g, 51%): mp 51−52 °C; [α]25D = +33.9 (c = 1.01, CHCl3); GC−
MS 100% a/a, tR = 3.84 min, [M + 1]+ = 273; purity (LC−MS) 98.8%
a/a, tR = 2.19 min, [M + 1]+ = 273; chiral HPLC (Chiralcel OJ-H, 250
REFERENCES
■
(1) Seminal work: (a) Hayashi, T.; Ueyama, K.; Tokunaga, N.;
Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508−11509. (b) Fischer,
C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem. Soc. 2004,
126, 1628−1629.
(2) Reviews: (a) Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 3364−
3366. (b) Shintani, R.; Hayashi, T. Aldrichimia Acta 2009, 42, 31−38.
(c) Defieber, C.; Grutzmacher, H.; Carreira, E. M. Angew. Chem., Int.
̈
Ed. 2008, 47, 4482−4502. (d) Johnson, J. B.; Rovis, T. Angew. Chem.,
Int. Ed. 2008, 47, 840−871.
× 4.6 i.d., 5 μm, heptane/EtOH 9:1, 0.8 mL/min) er 99.8:0.2, tR
=
12.0 min (tR = 10.6 min (S,S)); 1H NMR (CDCl3) δ 7.41−7.46 (m, 2
H), 7.27−7.37 (m, 4 H), 7.15−7.26 (m, 4 H), 6.51 (dd, J1 = 6.2 Hz, J2
= 1.7 Hz, 1 H), 6.00 (d, J = 6.2 Hz, 1 H), 4.04−4.09 (m, 1 H), 3.52 (s,
2 H), 3.45−3.50 (m, 1 H), 1.23−1.55 (m, 4 H); 13C NMR (CDCl3) δ
147.2, 146.9, 139.5, 138.4, 129.3, 129.1, 128.4, 128.3, 128.2, 126.6,
126.0, 124.7, 41.6, 40.1, 39.6, 26.2, 25.6; HRMS (ESI) m/z calcd for
C21H21 273.1643 [M + H]+, found 273.1643.
(3) Examples of Rh-catalyzed asymmetric reactions: (a) Arylation of
N-tosylarylimines with aryl boroxines: Tokunaga, N.; Otomaru, Y.;
Okamoto, K.; Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc.
2004, 126, 13584−13585. (b) Addition of Me2Zn to N-
tosylarylimines: Nishimura, T.; Yasuhara, Y.; Hayashi, T. Org. Lett.
2006, 8, 979−981. (c) Addition of aryl boronic acids to 2-
cyclopentenone: Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira, E. M.
Org. Lett. 2004, 6, 3873−3876. (d) Addition of aryl boronic acids to
cinnamaldehydes: Paquin, J.-F.; Defieber, C.; Stephenson, C. R. J.;
Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 10850−10851.
(4) bod* Ligands: (a) Tokunaga, N.; Otomaru, Y.; Okamoto, K.;
Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126,
13584−13585. (b) Otomaru, Y.; Okamato, K.; Shintani, R.; Hayashi,
T. J. Org. Chem. 2005, 70, 2503−2508.
(1R,4R)-2-Isobutyl-5-phenylbicyclo[2.2.2]octa-2,5-diene (7c).
Isobutylmagnesium bromide (2 M in Et2O, 3 mL, 2.0 equiv) was
added with cooling to a mixture of triflate 6 (1 g, 3.03 mmol) and
iron(III) acetylacetonate (214 mg, 0.2 equiv) in THF (15 mL) at 22−
40 °C. After the mixture was stirred at 40−45 °C for 2.5 h, additional
isobutylmagnesium bromide (2 M in Et2O, 3 mL, 2.0 equiv) was
added, followed by stirring at 40−45 °C for 2.5 h. LC−MS indicated
>99% conversion. Water (20 mL) was added with cooling, followed by
TBME (30 mL). The organic phase was evaporated to dryness at 50
°C under reduced pressure to afford crude 7c as a yellow oil (crude:
0.65 g, 90%). The crude product was purified by chromatography on
silica gel (14 g, eluent heptane) to afford 7c as a colorless oil (0.25 g,
35%): purity (GC−MS) 95.7% a/a, tR = 3.00 min, [M + 1]+ = 239;
purity (LC−MS) 97.0% a/a, tR = 2.26 min; chiral HPLC (Chiralpak
AD-H, 250 × 4.6 i.d., 5 μm, heptane/EtOH 1:1, 0.8 mL/min) tR = 4.2
min, er >99.5:0.5;38 1H NMR (CDCl3) δ 7.40−7.47 (m, 2 H), 7.30−
7.38 (m, 2 H), 7.17−7.26 (m, 1 H), 6.55 (dd, J1 = 6.3 Hz, J2 = 2.0 Hz,
1 H), 5.96 (dd, J1 = 6.2 Hz, J2 = 1.4 Hz, 1 H), 4.00−4.07 (m, 1 H),
3.47−3.55 (m, 1 H), 2.04 (d, J = 7.0 Hz, 2 H), 1.76−1.89 (m, 1 H),
1.37−1.51 (m, 4 H), 0.90 (d, J = 6.6 Hz, 3 H), 0.86 (d, J = 6.6 Hz, 3
H); 13C NMR (CDCl3) δ 147.4, 147.0, 138.6, 129.4, 128.4, 127.5,
126.5, 124.7, 43.6, 42.0, 39.5, 26.6, 26.0, 25.4, 22.8, 22.6. HRMS (ESI)
m/z calcd for C18H23 239.1800 [M + H]+, found 239.1801. After
storage at −20 °C for 8 months the sample had degraded, purity (LC−
MS): 38.3% a/a.
(5) Aldrich No. 707171, (1R,4R)-Ph-bod*, CHF 676/500 mg.
(6) From cheap (R)- or (S)-carvone, see refs 1b and 3c.
(7) Another diene, emerging from (R)-(−)-α-phellandrene:
Okamoto, K.; Hayashi, T.; Rawal, V. H. Org. Lett. 2008, 10, 4387−
4389.
(8) See ref 4b for yield calculation. We assumed a 90% recovery for
the chiral separation on Chiralcel OJ.
(9) Funel, J.-A.; Schmidt, G.; Abele, S. Org. Process Res. Dev. 2011, 15,
1420−1427.
(10) (a) Berthon-Gelloz, G.; Hayashi, T. J. Org. Chem. 2006, 71,
8957−8960. (b) Genindreau, T.; Chuzel, O.; Eijsberg, H.; Genet, J.-P.;
Darses, S. Angew. Chem., Int. Ed. 2008, 47, 7669−7672. (c) Boyd, W.
C.; Crimmin, M. R.; Rosebrugh, L. E.; Schomaker, J. M.; Bergmann, R.
G.; Toste, F. D. J. Am. Chem. Soc. 2010, 132, 16365−16367. (d) Wang,
Y.; Hu, X.; Du, H. Org. Lett. 2010, 12, 5482−5485.
(11) (a) First enantioselective synthesis of 2 via racemic
bicyclo[2.2.2]oct-7-ene-2,5-dione, 0.2% yield: Kinoshita, T; Haga, K.;
Ikai, K.; Takeuchi, K. Tetrahedron Lett. 1990, 31, 4057−4060. (b)
Large-scale (180 kg) synthesis of rac-2; see ref 9.
(12) Practical enantioselective route to 2: Abele, S.; Inauen, R.;
Funel, J.-A.; Weller, T. Org. Process Res. Dev. 2012, 16, 129−140.
(13) Ohshima, T.; Xu, Y.; Takita, R.; Shibasaki, M. Tetrahedron 2004,
60, 9569−9588.
(14) (a) Brands, K. M. J.; Davies, A. J. Chem. Rev. 2006, 106, 2711−
2733.
(15) (a) Bella, M.; Scarpino Schietroma, D. M.; Cusella, P. P.;
Gasperi, T. Chem. Commun. 2009, 597−599. Best dr and er were
obtained with cinchona alkaloids: the highest dr (90:10) and er
(93.5:6.5) were obtained with (R)-2,2-dimethylthiazolidine-4-carbox-
ylic acid and quinine. (b) Piovesana, S.; Scarpino Schietroma, D. M.;
Bella, M. Angew. Chem., Int. Ed. 2011, 50, 6216−6232. (c) Scarpino
Schietroma, D. M.; Monaco, M. R.; Visca, V.; Insogna, S.; Overgaard,
J.; Bella, M. Adv. Synth. Catal. 2011, 353, 2648−2652.
(16) (a) Rationales for changing synthetic routes: Butters, M.;
Catterick, D.; Craig, A.; Curzons, A.; Dale, D.; Gillmore, A.; Green, S.
P.; Marziano, I.; Sherlock, J.-P.; White, W. Chem. Rev. 2006, 106,
3002−3027. (b) Holistic route selection: Leng, R. B.; Emonds, M. V.
M; Hamilton, C. T.; Ringer, J. W. Org. Process Res. Dev. 2012, 16, 415−
424.
(17) The prices as offered on a 20-kg scale. 2-Cyclohexenone Euro
50/kg (HIKAL). Phenylacetaldehyde Euro 21/kg (Symrise).
(18) It is conceivable that higher er’s could be achieved with other
organocatalysts. However, the cost of goods might be even higher due
to the usually high loading (0.25 equiv) and the high price of most
organocatalysts as compared to L-proline.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Details for the GC−MS, LC−MS, chiral HPLC methods, H
and 13C NMR spectra, chiral HPLC data of 4a, 2, 5 and 7, and
screening report for the organocatalytic reaction. This material
is available free of charge via the Internet at http://pubs.acs.
org/.
AUTHOR INFORMATION
■
Corresponding Author
*Tel: +41 61 565 67 59. E-Mail: stefan.abele@actelion.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Patrick Furer for the screening experiments, Rene
Vogelsanger for chiral HPLC, and Franco
́
̧
is Le Goff for HRMS.
We appreciate the donation of organocatalyst V (Supporting
Information) from Prof. Helma Wennemers and of 5i from Dr.
Roger Marti. We are indebted to Dr. Thomas Weller for
continuous support. Dr. Hans-Ulrich Blaser is acknowledged
for careful review of the manuscript. S.A. thanks Prof. Dieter
Seebach for mechanistic discussions.
4772
dx.doi.org/10.1021/jo3005638 | J. Org. Chem. 2012, 77, 4765−4773

The Journal of Organic Chemistry
Article
(19) Seebach−Eschenmoser model: Seebach, D.; Beck, A. K.; Badine,
D. M.; Limbach, M.; Eschenmoser, A.; Treasurywala, A. M.; Hobi, R.
Helv. Chim. Acta 2007, 90, 425−471.
enes: Luo, Y.; Carnell, A. J. Angew. Chem., Int. Ed. 2010, 49, 2750−
2754.
(35) Wernerova, M.; Hudlicky, T. Synlett 2010, 2701−2707.
(36) The mass of the dehydrated eliminated product (chiral diene)
was already detected in the LC−MS at the stage of the tertiary
alcohols, prior to the addition of MsCl and Et3N.
(37) In the GC−MS trace of the dienes, the largest mass signal
besides the [M + 1]+ peakwas [M − 28]+, indicative of an Alder−
Rickert reaction with release of ethylene to give the p-terphenyl
derivative.
(38) rac-7c was measured with a different chiral HPLC method. Still,
the er is reported to be >99.5:0.5, as the starting material, ketone 2,
was enantiomerically pure. A racemization is not deemed conceivable.
(20) List−Houk model: (a) List, B.; Lerner, R. A.; Barbas, C. F. J.
Am. Chem. Soc. 2000, 122, 2395−2396. (b) Mukherjee, S.; Yang, J. W.;
Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471−5569. (c) Bock, D.
A.; Lehmann, C. W.; List, B. Proc. Nat. Acad. Sci. U.S.A. 2010, 107,
20636−20641. (d) Clemente, F. F.; Houk, K. N. Angew. Chem., Int. Ed.
2004, 43, 5766−5768. (e) Hein, J. H.; Bures
M.; Houk, K. N.; Armstrong, A.; Blackmond, D. G. Org. Lett. 2011, 13,
5644−5647. (f) Cheong, P. H.-Y.; Legault, C. Y.; Um, J. M.; Celebi-
́
, J.; Lam, Y.-h.; Hughes,
̧
̈
Olcu̧ m, N.; Houk, K. N. Chem. Rev. 2011, 111, 5042−5137.
̈
(21) (a) A reaction at 45 °C, stopped after 24 h (instead of 4−5 d),
gave an isolated yield of 25% with a diastereomeric purity of 100% and
a similar er of 70:30. (b) Submitting pure 4a to the reaction
conditions of the organocatalytic step (Table 1) did not lead to any
isomerizationthe chiral HPLC only showed the presence of 4a.
(22) We acknowledge the reviewer for this proposal.
(23) Recrystallization of the mesylate 4a-Ms with an er 72:28 in
EtOAc/heptane led to an enrichment of the undesired minor
enantiomer.
(24) Either silica gel using heptane or reversed-phase HPLC using
water/acetonitrile (0.5% formic acid) as eluent was used. The silica gel
chromatographies were run as “plug filtrations” with low relative
amounts of SiO2 (approximately 5 wt).
(25) A slurry in MeOH was applied for the efficient purification of 5a
(79 g) and 5f (30 g).
(26) Analytical data of a commercial sample (1R,4R)-Ph-bod*
(Aldrich No. 707171) in parentheses: purity (GC−MS): 99.5% a/a
(98.1% a/a), purity (LC−MS): >99.5% a/a (97.4% a/a), enantiomeric
ratio (chiral HPLC): er >99.5:0.5 (>99.5:0.5), mp 74−77 °C (74−76
°C), see also the Experimental Section.
(27) (a) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33,
6299−6302. (b) Org. Synth. 1998, Coll. Vol. 9, 165.
(28) Samples reanalyzed by LC−MS after storage at rt under air for
12 months showed no decomposition. Stress tests data of diene 5a
(100% a/a LC−MS): stirring at rt for 3 weeks with aqueous HCl/
THF, silica gel in heptane, or aqueous NaOH/THF. Purity was
monitored by LC−MS and TLC. Result: only acidic conditions (HCl/
THF) led to decomposition.
(29) Laird, T. Org. Process Res. Dev. 2012, 16, 1−2.
(30) (a) The American Chemical Society Green Chemistry
Institute’s Pharmaceutical Roundtable has chosen PMI as the key
metric for evaluating processes with regard to their efficiency and
sutainability; see: Jimenez-Gonzalez, C.; Ponder, C.; Broxterman, Q.
B.; Manley, J. B. Org. Process Res. Dev. 2011, 15, 912−917. (b) Dunn,
P. J. In Pharmaceutical Process Development; Blacker, J. A., Williams, M.
T., Eds.; Royal Society of Chemistry: London, 2011; Chapter 6.
(31) To account for the fact that small-scale protocols are normally
not optimized with respect to solvent and waste, the most meaningful
PMI is given for the reagents, i.e., without considering solvents and
aqueous solutions. As the goal was to devise a route not relying on
preparative chiral HPLC separation, the published route using
resolution by chiral HPLC4b was not considered for this comparison.
The trend is similar when routes involving resolution by chiral HPLC
are compared, see refs 4b and 12.
(32) Derived from data submitted by several companies for for 21
products in phase 3 or commercial products. Published by the
Pharmaceutical Roundtable (13 pharmaceutical companies and the
American Chemical Society Green Chemistry Institute);30b see:
Henderson, R. K.; Kindervater, J.; Manley, J. M., III. International
Conference on Green and Sustainable Chemistry; Delft, Holland, July
2007.
(33) Bella has also used the 4-Cl-, 4-Br-, 4-OMe-phenylacetaldehyde
and the 2-naphthylaldehyde in the organocatalytic step,15a affording
bicyclic alcohols that would be ideal substrates for further C2-
symmetric dienes.
(34) For a study of eletronic effects of related dienes on catalytic
efficiency, see (R,R)-1,4-dimethyl-2,5-diarylbicyclo[2.2.2]octa-2,5-di-
4773
dx.doi.org/10.1021/jo3005638 | J. Org. Chem. 2012, 77, 4765−4773