Facile synthesis of isocampholenic acids by the rearrangement of camphor derivatives

Article abstract of DOI:10.1016/j.tet.2012.12.011

A variety of substituted isocampholenic acid derivatives were prepared by rearrangement of the camphor skeleton of a variety of tertiary alcohols derived from ketopinic acid. The reaction was highly reliable and retained the stereochemical information from the camphor scaffold. This rearrangement represents an efficient way to prepare synthetically useful isocampholenic acids. Mechanistic experiments show that a short-lived carbocation is implicated in the reaction.

Full text of DOI:10.1016/j.tet.2012.12.011

Tetrahedron 69 (2013) 1539e1545
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Facile synthesis of isocampholenic acids by the rearrangement of
camphor derivatives
*
Robyn Aryn Biggs, William W. Ogilvie
Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, ON K1N 6N5, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 October 2012
Received in revised form 3 December 2012
Accepted 4 December 2012
Available online 11 December 2012
A variety of substituted isocampholenic acid derivatives were prepared by rearrangement of the camphor
skeleton of a variety of tertiary alcohols derived from ketopinic acid. The reaction was highly reliable and
retained the stereochemical information from the camphor scaffold. This rearrangement represents an
efficient way to prepare synthetically useful isocampholenic acids. Mechanistic experiments show that
a short-lived carbocation is implicated in the reaction.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Rearrangement
Camphor-based
Isocampholenic acids
1. Introduction
2. Results and discussion
The use of camphor-based starting materials in the synthesis of
natural products, chiral auxiliaries, organocatalysts, and ligands is
a general strategy to exploit the stereochemical information from
nature’s chiral pool.1 Many syntheses of alkaloid natural products
employ rearrangements of the camphor skeleton to provide access
to complex intermediates while controlling stereochemistry. Rear-
rangement reactions have been utilized in the synthesis of natural
products, such as the zizaane sesquiterpenes,2 (ꢀ)-quadrone,3
(þ)-ophiobolin C,4 (þ)-norpatchoulenol,5 taxane diterpenes,6 and
the clavularanes.7 Most of these syntheses involve the conversion of
camphor derivatives into cyclopentanoid building blocks. Several
methods have been described for such transformations, including
those producing campholenic acid derivatives,8 isocampholenic
acids,9 campholanic acid intermediates,10 and cyclopentene car-
boxylic acids.11 One method of converting camphor-based starting
materials into isocampholenic acid derivatives involves the con-
densation of 9,10-dibromocamphor compounds with KOH.12,13 This
method has been employed in the synthesis of many natural
products,4,7,14 and chiral synthetic intermediates.15 The value of
cyclopentanoid compounds in the synthesis of alkaloid natural
products suggests that methods which facilitate access to these
derivatives have significant synthetic utility. Herein we disclose
a method that provides a three-step synthesis to a variety of
substituted isocampholenic acid derivatives.
During the synthesis of a potential organocatalyst, we attemp-
ted to condense ketone 1a with a benzoyl hydrazide to prepare
cyclic hydrazone 2 (Scheme 1). When this was done, the desired
product was not observed, instead, a significant amount of an un-
expected byproduct was obtained. This byproduct was formed
when a variety of protic acids were used as catalysts in the reaction,
however, it was exclusively obtained in quantitative yield when
BF3$OEt2 was employed. The structure of the unknown compound
was elucidated by INADEQUATE analysis and found to be iso-
campholenic acid 3a. This structural assignment was subsequently
confirmed by a single crystal X-ray structure (Fig. 1).
BF3•OEt2
H2NNHC(O)Ph
Byproduct (3a)
N
THF
rt
Ph
Ph
Ph
Ph
N
O
OH
1a
Ph
O
2
not observed
Scheme 1.
Because of the efficiency of this process, we decided to in-
vestigate if this was a general method for synthesizing cyclo-
pentanoid compounds. Toward this end, several diaryl-substituted
* Corresponding author. Tel.: þ1 613 562 5800; fax: þ1 613 562 5170; e-mail
addresses: wogilvie@uOttawa.ca, wogilvie@science.uottawa.ca (W.W. Ogilvie).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.011

1540
R.A. Biggs, W.W. Ogilvie / Tetrahedron 69 (2013) 1539e1545
Substituents located on the meta or ortho position of the aryl
ring did not significantly impair the reaction (entries 4, 8 and 9),
although the yield diminished slightly in the case of an ortho-
methoxy substituted derivative. Large aromatic groups, such as
naphthyl could also be present (entry 10), and the use of a hetero-
aromatic-substituted alcohol gave the rearranged product in ex-
cellent yield (entry 11).
The rearrangement likely proceeded via carbocationic in-
termediate 6, that subsequently rearranged to provide the car-
boxylic acids 3 via an acylium species (Scheme 3). This was
suggested by the fact that a differentially substituted alcohol (11)
gave a mixture of isomers (12) from the reaction (see below).
Fig. 1. X-ray ORTEP image of byproduct.
alcohols were prepared. Ketopinic acid16 4 was converted into
methyl ester 5 by treatment with thionyl chloride in methanol.17
This derivative was then converted into the alcohols 1aek by ex-
posure to the appropriate Grignard reagent at 0 ꢁC (Scheme 2).18
Treatment of the products obtained from these condensations
with BF3$OEt2 smoothly converted the tertiary alcohols 1 into the
rearranged isocampholenic acids 3 in high yields (Table 1).
BF3•OEt2
R
R
O
R
O
OH
R
6
1a-k
2 RMgBr
SOCl2
THF
0°C
42-81%
MeOH
0°C→rt
98%
R
O
O
O
O
O
OH
OH
OMe
R
4
5
1a-k
R
R
HO
Scheme 2.
R
R
O
O
7
3a-k
Table 1
BF3$OEt2 promoted rearrangements to obtain isocampholenic acid derivatives 3
Scheme 3.
from camphor derived tertiary alcohols 1a
To test this, a toluene solution of alcohol 1e and methanol
(5 equiv) was treated with BF3$OEt2. This resulted in the production
of the corresponding methyl ester in 91% yield, suggesting that the
process involved an intermolecular reaction.19 We also prepared
methyl ether 8, and performed a crossover experiment using a 1:1
mixture of 8 and 1d. This experiment gave an 81% combined yield
of a 1.1:1 mixture of the corresponding acids and esters. These re-
sults are consistent with the reaction proceeding by the rear-
rangement of a carbocationic intermediate, which then opens to
form an acylium.
Dialkyl substituted derivatives did not cleanly rearrange under
the reaction conditions. Although dimethyl alcohol 1l was com-
pletely consumed when treated with BF3$OEt2, an inseparable
mixture of products was obtained. The NMR spectrum of the ma-
terial obtained indicated that the desired product was present, but
the compound could not be satisfactorily purified.
R
BF3•OEt2
HO
R
Toluene
rt
62-96%
R
O
O
OH
R
1a-k
3a-k
Entry
R
Yieldb (%)
1
2
3
4
5
6
7
8
Ph (a)
4-FeC6H4 (b)
96
96
80
89
76
84c
80
79
62
65d
93
4-CH3eC6H4 (c)
3-CH3eC6H4 (d)
4-tBueC6H4 (e)
4-CF3eC6H4 (f)
4-OMeeC6H4 (g)
3-OMeeC6H4 (h)
2-OMeeC6H4 (i)
2-Naphthyl (j)
2-Thiophenyl (k)
9
10
11
a
Reaction conditions: BF3$OEt2 (1.2 equiv), toluene, room temperature, 15 min.
Isolated yield.
Reaction required 48 h to complete.
b
c
R
Me
O
O
d
OMe
OH
Me
Dichloromethane used in place of toluene.
R
t
1l
8 : R = 4- BuC6H4
The reactions proceeded in good to excellent yields and oc-
curred very rapidly and cleanly (Table 1). The presence of fluoro-
substituted aryl rings (entry 2) was tolerated and resulted in
a similar yield to that of the unsubstituted case (entry 1). Alkyl
substituents on the aryl rings also did not significantly alter the
efficiency of the reaction (entries 3e5). The effect of electronics on
the rearrangement reaction was investigated by employing an
electron withdrawing p-trifluoromethyl substituent (entry 6), and
an electron donating p-methoxy group (entry 7). Comparable yields
were obtained in both cases, however, the presence of the tri-
fluoromethyl substituent significantly slowed the rate of the
reaction.
To try to recover reactivity for alkyl-substituted derivatives, we
prepared and tested an alkyl, aryl substituted alcohol and subjected
it to the reaction conditions (Scheme 4). The required precursor, 11,
was prepared by converting methyl ester 5 into the corresponding
Weinreb amide 9.20 Treatment with excess PhMgBr in THF at
ꢀ78 ꢁC resulted in clean conversion to phenyl ketone 10. When this
substance was exposed to MeMgBr, alcohol 11 was obtained as
a single isomer.21 Exposing this material to BF3$OEt2 caused rapid
conversion to the carboxylic acid, which was immediately treated
with diazomethane to provide methyl ester 12,22 a material that
was obtained as a 3.7:1 mixture of isomers.23 This result was

R.A. Biggs, W.W. Ogilvie / Tetrahedron 69 (2013) 1539e1545
1541
consistent with the stepwise mechanism involving carbocationic
intermediates, such as 6 (Scheme 3).
spectrometer. High resolution mass spectra were obtained using an
Analytical Concept spectrometer. Melting points were determined
using an Electrothermal Meltemp apparatus and are uncorrected.
4.1.1. Methyl 7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylate
(5). Methanol (30 mL) was stirred in a 100 mL round bottom
flask and cooled to 0 ꢁC using an ice bath. Thionyl chloride (4 mL,
54.9 mmol) was then slowly added via syringe. To this solution was
introduced (S)-(þ)-ketopinic acid16 in four portions, waiting 5 min
between additions. The resulting reaction mixture was stirred at
CH3NH(OMe)•HCl
i-PrMgCl
THF
-20°C→rt
76%
O
O
O
MeO
O
N
OMe
5
9
0
ꢁC for 4 h, allowed to warm to room temperature over 18 h, and
PhMgBr
THF
-78°C
43%
then concentrated under reduced pressure using a rotary evapo-
rator. The resulting residue was diluted with ethyl acetate (50 mL).
Water (50 mL) was added and the phases were separated. The
aqueous phase was extracted once more with ethyl acetate
(2ꢂ50 mL). The combined organic extracts were washed with
saturated sodium bicarbonate solution (100 mL), and brine
(100 mL), dried over MgSO4, filtered, and concentrated in vacuo.
The crude material was purified by silica gel chromatography
(5e20% EtOAc in hexanes) to afford 4 as white needles (2.09 g, 98%).
MeMgBr
THF
0°C
87%
Ph
O
O
O
OH
Me
Ph
10
1H NMR (300 MHz, CDCl3)
d
3.73 (s, 3H), 2.51 (ddd, J¼18.3, 3.9,
11
3.9 Hz, 1H), 2.40e2.27 (m, 1H), 2.09 (dd, J¼4.2, 4.2 Hz, 1H),
2.07e1.95 (m, 1H), 1.93 (d, J¼18.3 Hz, 1H), 1.77 (ddd, J¼13.8, 9.6,
5.1 Hz, 1H), 1.39 (ddd, J¼12.3, 9.3, 4.2 Hz, 1H), 1.13 (s, 3H), 1.06 (s,
3H). Spectral data matched those previously reported.17
1) 2.0 BF3•OEt2
Toluene
rt
69%
2) CH2N2
THF
4.1.2. N-Methoxy-N-7,7-trimethyl-2-oxobicyclo[2.2.1]heptane-1-
carboxamide (9). To a solution of 5 (200 mg, 1.02 mmol) in dry THF
(10 mL) was added CH3NH(OMe)$HCl (160 mg, 1.63 mmol). The
resulting mixture was cooled to ꢀ20 ꢁC and iPrMgCl (2.6 mL,
5.10 mmol) was added via syringe. After warming to 0 ꢁC over 5 h, the
reaction was quenched by the addition of saturated ammonium
chloride (5 mL). The aqueous phase was then extracted twice with
methyl tert-butyl ether (20 mL portions), and the organic extracts
combined, dried over MgSO4, filtered, and concentrated on a rotary
evaporator. Column chromatography (15e30% EtOAc/hexanes) pro-
81%
Ph
MeO
Me
O
3.7:1
12
Scheme 4.
vided pure 9 as a white powder (153 mg, 67%). Mp 46e48 ꢁC; [
a]
D
3. Conclusions
The rearrangement of tertiary alcohols
þ26.5(c 0.62, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d 3.67 (s, 3H), 3.23 (s,
3H), 2.51 (ddd, J¼18.4, 5.2, 3.6 Hz, 1H), 2.38e2.28 (m, 1H), 2.15e1.98
1
to afford iso-
(m, 3H), 1.94 (d, J¼18.0 Hz, 1H), 1.46e1.39 (m, 1H), 1.21 (s, 3H), 1.14 (s,
campholenic acids 3 is an efficient way to prepare these syntheti-
cally useful intermediates. The rearrangement was highly reliable
and most products required no further purification. The products
retained the stereochemical information of the starting camphor
derivatives, and possessed a tetrasubstituted olefin. Functionality
suitable for further elaboration is also a key feature of these
products. Mechanistic experiments were consistent with ring
opening of a keto carbocation, such as 6 to give an acylium ion.
3H); 13C NMR (100 MHz, CDCl3)
d 211.1 (C), 169.9 (C), 67.5 (C), 60.6
(CH3), 50.1 (C), 43.8 (CH3), 43.7 (CH2), 32.6 (CH), 27.1 (CH2), 26.7 (CH2),
21.6 (CH3), 20.4 (CH3); IR (neat) 1741, 1623 cmꢀ1. MS (EI) 225.1 (Mþ);
HRMS (EI) calcd for C12H19NO3 (Mþ) 225.1365, found 225.1342.
4.1.3. 1-Benzoyl-7,7-dimethylbicyclo[2.2.1]heptan-2-one (10). To a
solution of amide 9 (128 mg, 0.57 mmol) in dry THF (5 mL) at ꢀ78 ꢁC
was added a freshly prepared solution of PhMgBr in THF (0.61 mL,
0.85 mmol). The resulting mixture was allowed to warm to room
temperature over 12 h, and then quenched by the addition of satu-
rated ammonium chloride (5 mL). The mixture was then diluted with
EtOAc (20 mL), washed with 10% HCl (10 mL), saturated NaHCO3
(10 mL), and brine (10 mL), dried over MgSO4, filtered, and concen-
trated on a rotary evaporator. Column chromatography (5% EtOAc/
hexanes) provided pure 10 as a white powder (59.3 mg, 43%). Mp
4. Experimental
4.1. General methods
Reactions were performed under nitrogen in oven-dried glass-
ware equipped witha magnetic stirbarand a rubber septum. Solvents
were freshly distilled prior to use as follows: THF over sodium/ben-
zophenone and toluene over calcium hydride. BF3$OEt2 was freshly
distilled before each use. All other reagents were used without further
purification unless otherwise indicated. Reactions were monitored by
60e62 ꢁC; [
a]
D
ꢀ23.1 (c 0.62, CH2Cl2); 1H NMR (300 MHz, CDCl3)
d
7.80e7.75 (m, 2H), 7.52e7.36 (m, 3H), 2.63 (ddd, J¼18.6, 4.8, 3.3 Hz,
1H), 2.32e1.98 (m, 4H), 2.06 (d, J¼18.3 Hz,1H),1.55e1.43(m,1H),1.24
(s, 3H), 1.12 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
213.1 (C), 200.2 (C),
TLC analysis using aluminum plates (250
m
m thickness) precoated
139.1 (C), 131.9 (CH), 128.9 (CH), 128.0 (CH), 73.2 (C), 50.0 (C), 44.4
(CH2), 44.3 (CH), 28.9 (CH2), 26.8 (CH2), 21.8 (CH3), 20.1 (CH3); IR
(neat) 1733, 1658 cmꢀ1; MS (EI) 242.1 (Mþ); HRMS (EI) calcd for
C16H18O2 (Mþ) 242.1307, found 242.1308.
with silica gel 60 F254. TLC plates were visualized using ultraviolet
light and potassium permanganate. Flash chromatography was car-
ried out on 230e400 mesh silica gel 60, or preparatory TLC glass
plates precoated with silica gel (Si250F).1H and 13C NMR spectra were
acquired on a 300 MHz, 400 MHz, or 500 MHz spectrometer in the
4.1.4. 1-(1-Hydroxy-1-phenylethyl)-7,7-dimethylbicyclo[2.2.1] hep-
specified solvent. Infrared spectra were acquired on
a
FTIR
tan-2-one (11). To a solution of ketone 10 (59 mg, 0.24 mmol) in dry

1542
R.A. Biggs, W.W. Ogilvie / Tetrahedron 69 (2013) 1539e1545
THF (5 mL) at 0 ꢁC was added a solution of 3.0 M MeMgBr in Et2O
(0.24 mL, 0.73 mmol). The reaction mixture was allowed to warm to
room temperature, and stirred at this temperature for 2 h. The
reaction was then quenched with saturated ammonium chloride
(5 mL), and the aqueous phase extracted twice with EtOAc (20 mL
portions). The combined organic phases were washed with brine
(20 mL), dried over MgSO4, filtered, and concentrated on a rotary
evaporator. Column chromatography (3% EtOAc/hexanes) provided
portions). The combined organic extracts were washed with brine
(50 mL), dried over MgSO4, filtered, and concentrated in vacuo. Pure
3a (924 mg, 60%) was obtained as clear crystals after re-
crystallization from 1:4 EtOAc/hexanes. 1H NMR (300 MHz, CDCl3)
d
7.53e7.15 (m, 10H), 3.82 (s, 1H), 2.57e2.45 (m, 2H), 2.29 (ddd,
J¼13.8, 9.6, 5.1 Hz, 1H), 1.99e1.87 (m, 1H), 1.97 (d, J¼18.6 Hz, 1H),
1.78 (dd, J¼4.8, 4.8 Hz,1H),1.42 (ddd, J¼12.0, 9.3, 3.9 Hz,1H),1.07 (s,
3H), 0.27 (s, 3H). Spectral data matched those previously
reported.18
11 as fine white needles (53.8 mg, 87%). Mp 79e81 ꢁC; [
0.74, CH2Cl2); 1H NMR (300 MHz, C6D6)
7.62e7.55 (m, 2H),
a
]
D ꢀ98.9 (c
d
7.19e7.05 (m, 3H), 4.07 (s,1H), 2.14e2.03 (m,1H),1.89e1.77 (m,1H),
1.71 (s, 3H), 1.45 (d, J¼18.3 Hz, 1H), 1.45e1.33 (m, 1H), 1.25e1.14 (m,
2H), 0.95 (s, 3H), 0.77 (ddd, J¼17.7, 9.0, 3.6 Hz, 1H), 0.00 (s, 3H); 13C
4.2.2. 1-(Bis(4-fluorophenyl)(hydroxy)methyl)-7,7-dimethylbicyclo
[2.2.1]heptan-2-one (1b). Prepared from 5 (100 mg, 0.51 mmol)
using a procedure similar to that described for 1a. Column chro-
matography (5% EtOAc/hexanes) provided the title compound as
NMR (100 MHz, C6D6) d 145.3 (C), 127.5 (CH), 126.9 (CH), 126.8 (CH),
74.6 (C), 67.3 (C), 48.1 (C), 44.7 (CH), 43.4 (CH2), 28.2 (CH3), 26.6
clear crystals (142 mg, 78%). Mp 138e140 ꢁC; [
a
]
ꢀ145.7 (c 1.03,
D
(CH2), 25.7 (CH2), 21.8 (CH3), 20.9 (CH3); IR (neat) 3393, 1717 cmꢀ1
;
CH2Cl2); 1H NMR (300 MHz, CDCl3)
d 7.48e7.28 (m, 4H), 7.02e6.86
MS (EI) 258.2 (Mþ); HRMS (EI) calcd for C17H22O2 (Mþ) 258.1620,
found 258.1617.
(m, 4H), 3.76 (s, 1H), 2.51 (ddd, J¼18.6, 5.1, 3.0 Hz, 1H), 2.48e2.37
(m, 1H), 2.21 (ddd, J¼13.5, 9.3, 4.8 Hz, 1H), 2.02e1.88 (m, 1H), 1.97
(d, J¼18.6 Hz, 1H), 1.79 (dd, J¼4.8, 4.8 Hz, 1H), 1.43 (ddd, J¼12.6, 9.6,
3.9 Hz, 1H), 1.03 (s, 3H), 0.32 (s, 3H); 13C NMR (100 MHz, CDCl3)
4.1.5. Methyl-2-((R)-2,2-dimethyl-3-(1-phenylethylidene)cyclo-
pentyl)acetate (12). To a solution of 11 (97 mg, 0.38 mmol) in dry
toluene (4 mL) was added a solution of 0.65 M BF3$OEt2 (0.10 mL,
0.76 mmol) under nitrogen. The mixture was stirred at room
temperature for 15 min, and the reaction was then quenched by the
addition of water (10 mL). The resulting mixture was extracted
twice with EtOAc (20 mL portions). The combined organic extracts
were washed with brine (20 mL) dried over MgSO4, filtered, and
concentrated in vacuo to provide compound the isocampholenic
acid without need for further purification (3.7:1 mixture of isomers,
67.6 mg, 69%) as a clear syrup. This product was immediately dis-
solved in dry THF (2 mL), and a solution of freshly prepared
diazomethane in Et2O (2.6 mL, 1.77 mmol) was added dropwise
until the yellow color persisted. The solvent was then evaporated,
and the resulting residue purified by column chromatography
(3e6% EtOAc/hexanes) to obtain the title compound as a 3.7:1
mixture of isomers (57 mg, 81%). 1H NMR (300 MHz, C6D6)
d
162.9 (d, J¼35 Hz, C), 160.4 (d, J¼35.4 Hz, C), 142.7 (d, J¼1.9 Hz, C),
140.3 (d, J¼2.7 Hz, C), 130.8 (d, J¼7.8 Hz, CH),129.8 (d, J¼7.4 Hz, CH),
114.1 (d, J¼2.2 Hz, CH),113.9 (d, J¼2.2 Hz, CH), 79.2 (C), 68.1 (C), 50.2
(C), 44.5 (CH), 43.5 (CH2), 26.8 (CH2), 25.6 (CH2), 22.7 (CH3), 21.9
(CH3); IR (neat) 3548, 1719 cmꢀ1; MS (EI) 260.1 (MþꢀC6H5F); HRMS
(EI) calcd for C16H17FO2 (MþꢀC6H5F) 260.1213, found 260.1237.
4.2.3. 1-(Hydroxydi-p-tolylmethyl)-7,7-dimethylbicyclo[2.2.1] hep-
tan-2-one (1c). Prepared from 5 (100 mg, 0.51 mmol) using a pro-
cedure similar to that described for 1a. Column chromatography (3%
EtOAc/hexanes) provided the title compound as clear needles
(118 mg, 67%). Mp 98e100 ꢁC; [
(300 MHz, CDCl3)
a
]
D ꢀ180.6 (c 0.96, CH2Cl2); 1H NMR
d
7.34 (d, J¼8.1 Hz, 2H), 7.25 (d, J¼8.4 Hz, 2H), 7.08
(d, J¼7.8 Hz, 2H), 7.02 (d, J¼8.4 Hz, 2H), 3.73 (s, 1H), 2.57e2.43 (m,
2H), 2.33 (s, 3H), 2.29 (s, 3H), 2.24 (ddd, J¼14.1, 9.3, 4.5 Hz, 1H), 1.95
(d, J¼18.6 Hz,1H),1.96e1.86 (m,1H),1.76 (dd, J¼4.8, 4.8 Hz,1H),1.40
(ddd, J¼12.3, 9.3, 3.9 Hz, 1H), 1.05 (s, 3H), 0.30 (s, 3H); 13C NMR
d
7.20e7.01 (m, 5.4H), 3.37 (s, 0.9H), 3.35 (s, 2.1H), 2.38e1.89 (m,
6.9H), 1.79 (dd, J¼1.5, 1.5 Hz, 2.4H), 1.36e1.21 (m, 0.6H), 1.23 (s,
(100 MHz, CDCl3) d 144.4 (C), 141.7 (C), 136.3 (C), 136.2 (C), 128.9
0.6H), 0.89 (s, 0.6H), 0.71 (s, 2.2H), 0.68 (s, 2.3H); 13C NMR
(CH), 128.1 (CH), 127.9 (CH), 127.7 (CH), 79.5 (C), 68.1 (C), 50.1 (C),
44.5 (CH), 43.5 (CH2), 26.9 (CH2), 25.6 (CH2), 22.7 (CH3), 21.8 (CH3),
20.9 (CH3), 20.8 (CH3); IR (neat) 3530, 1716 cmꢀ1; MS (EI) 348.2
(Mþ); HRMS (EI) calcd for C24H28O2 (Mþ) 348.2089, found 348.2070.
(100 MHz, C6D6)
d 173.2 (C), 145.0 (C), 144.7 (C), 128.8 (CH), 127.7
(CH), 126.0 (CH), 50.7 (CH3), 50.6 (CH3), 49.3 (CH), 48.5 (CH), 44.3
(C), 44.2 (C), 34.5 (CH2), 34.3 (CH2), 32.5 (CH2), 30.3 (CH2), 29.0
(CH2), 27.8 (CH2), 26.7 (CH3), 26.3 (CH3), 24.4 (CH3), 22.6 (CH3), 20.7
(CH3), 20.5 (CH3); IR (neat) 1735 cmꢀ1; MS (EI) 272.2 (Mþ); HRMS
(EI) calcd for C18H24O2 (Mþ) 272.1776, found 272.1773.
4.2.4. 1-(Hydroxydi-m-tolylmethyl)-7,7-dimethylbicyclo[2.2.1] hep-
tan-2-one (1d). Prepared from 5 (100 mg, 0.51 mmol) using a pro-
cedure similar to that described for 1a. Column chromatography
(3% EtOAc/hexanes) provided the title compound as clear crystals
4.2. General procedure for the synthesis of diaryl alcohols
(Table 1, compounds 1ael)
(116 mg, 66%). Mp 124e126 ꢁC; [
NMR (300 MHz, CDCl3)
a
]
ꢀ188.8 (c 0.99, CH2Cl2); 1H
D
d
7.45e7.00 (m, 8H), 3.86 (s, 1H), 2.61e2.46
4.2.1. 1-(Hydroxydiphenylmethyl)-7,7-dimethylbicyclo[2.2.1] heptan-
2-one (1a). Magnesium turnings (1.2 g, 51.2 mmol) and a few small
crystals of I2 were placed under a nitrogen atmosphere in a 100 mL
round bottom flask equipped with a condenser. The flask was then
warmed gently using a heat gun to vaporize the iodine, and the
apparatus allowed to stand until the color of the iodine vapor dis-
appeared. Into this flask was introduced one half of a solution of
bromobenzene (4.5 mL, 42.7 mmol) in dry THF (30 mL). The solu-
tion was stirred until an exothermic reaction was observed,
bringing it to reflux. As the reflux began to subside, the other half of
the bromobenzene solution was added, and the reaction was
heated to reflux for 1 h using a heating mantle, and then cooled to
(m, 2H), 2.37 (s, 3H), 2.35e2.23 (m, 1H), 2.31 (s, 3H), 1.99 (d,
J¼18.6 Hz, 1H), 1.99e1.89 (m, 1H), 1.79 (dd, J¼4.5, 4.5 Hz, 1H), 1.44
(ddd, J¼12.3, 9.3, 3.9 Hz, 1H), 1.09 (s, 3H), 0.30 (s, 3H); 13C NMR
(100 MHz, CDCl3)
d 147.1 (C), 144.3 (C), 136.7 (C), 136.6 (C), 129.7
(CH), 128.7 (CH), 127.5 (CH), 127.4 (CH), 127.0 (CH), 126.9 (CH), 126.1
(CH), 125.6 (CH), 79.8 (C), 68.1 (C), 50.2 (C), 44.5 (CH), 43.5 (CH2),
26.9 (CH2), 25.6 (CH2), 22.7 (CH3), 21.8 (CH3), 21.7 (CH3), 21.6 (CH3);
IR (neat) 3569, 1719 cmꢀ1; MS (EI) 348.2 (Mþ); HRMS (EI) calcd for
C24H28O2 (Mþ) 348.2089, found 348.2109.
4.2.5. 1-(Bis(4-tert-butylphenyl)(hydroxy)methyl)-7,7-
dimethylbicyclo[2.2.1]heptan-2-one (1e). Prepared from 5 (100 mg,
0.51 mmol) using a procedure similar to that described for 1a.
Column chromatography (3% EtOAc/hexanes) provided the title
0
ꢁC in an ice bath. Methyl ester 5 (1.37 g, 6.48 mmol) was then
introduced in one portion and the resulting mixture stirred at 0 ꢁC
for 1 h. The reaction was quenched with a saturated solution of
ammonium chloride (20 mL). Water (50 mL) was then added and
the resulting mixture was then extracted twice with EtOAc (50 mL
compound as white needles (127 mg, 58%). Mp 162e164 ꢁC; [
a]
D
ꢀ116.3 (c 1.02, CH2Cl2); 1H NMR (300 MHz, CDCl3)
d 7.49e7.21 (m,
8H), 3.82 (s, 1H), 2.58e2.45 (m, 2H), 2.25 (ddd, J¼13.8, 9.3, 4.5 Hz,

R.A. Biggs, W.W. Ogilvie / Tetrahedron 69 (2013) 1539e1545
1543
1H), 1.95 (d, J¼18.6 Hz, 1H), 2.00e1.85 (m, 1H), 1.76 (dd, J¼4.5,
4.5 Hz, 1H), 1.40 (ddd, J¼12.9, 9.6, 3.9 Hz, 1H), 1.32 (s, 9H), 1.29 (s,
2.66e2.58 (m, 1H), 2.45e2.38 (m, 1H), 2.17 (ddd, J¼14.0, 9.5, 5.0 Hz,
1H), 1.90e1.83 (m, 1H), 1.89 (d, J¼18.0 Hz, 1H), 1.72 (dd, J¼4.5, 4.5 Hz,
1H),1.36 (ddd, J¼11.5, 9.5, 4.0 Hz,1H),1.04 (s, 3H), 0.70 (s, 3H); 13CNMR
9H), 1.05 (s, 3H), 0.25 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 149.7 (C),
149.3 (C), 144.1 (C), 141.4 (C), 128.7 (CH), 127.8 (CH), 124.1 (CH),
123.9 (CH), 79.4 (C), 68.2 (C), 50.1 (C), 44.5 (CH), 43.6 (CH2), 34.3 (C),
34.2 (C), 31.4 (CH3), 31.3 (CH3) 26.9 (CH2), 25.6 (CH2), 22.5 (CH3),
21.4 (CH3); IR (neat) 3483, 1718 cmꢀ1; MS (EI) 432.3 (Mþ); HRMS
(EI) calcd for C30H40O2 (Mþ) 432.3028, found 432.3075.
(125 MHz, (CD3)2SO, 145 ꢁC)
d 213.4, 156.5, 156.4, 135.3, 134.9, 129.5,
128.5, 126.8, 126.3, 118.5, 118.1, 113.0, 112.6, 79.8, 68.1, 54.9, 54.7, 49.6,
44.2, 42.9, 25.4, 22.4, 21.7; IR (neat) 3517, 1734 cmꢀ1; MS (EI) 380.2
(Mþ); HRMS (EI) calcd for C24H28O4 (Mþ) 380.1988, found 380.2011.
4.2.10. 1-(Hydroxy(naphthalen-2-yl)(naphthalen-3-yl)methyl)-7,7-
dimethylbicyclo[2.2.1]heptan-2-one (1j). Prepared from 5 (100 mg,
0.51 mmol) using a procedure similar to that described for 1a. Col-
umn chromatography (3% EtOAc/hexanes) provided the title com-
4.2.6. 1-(Bis(4-(trifluoromethyl)phenyl)(hydroxy)methyl)-7,7-
dimethylbicyclo[2.2.1]heptan-2-one (1f). Prepared from 5 (500 mg,
2.55 mmol) using a procedure similar to that described for 1a.
Column chromatography (5% EtOAc/hexanes) provided the title
pound as a white fluffy powder (111 mg, 52%). Mp 228e230 ꢁC [
a]
D
compound as clear crystals (972 mg, 81%). Mp 148e150 ꢁC; [
a
]
ꢀ266.8 (c 0.40, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d 8.18e8.11 (m,
D
ꢀ137.9 (c 1.13, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
7.64e7.54 (m,
1H), 7.98e7.96 (m, 1H), 7.88e7.58 (m, 7H), 7.51e7.42 (m, 4H),
7.34e7.28 (m,1H), 4.04 (s,1H), 2.70e2.47 (m, 3H), 2.08 (d, J¼18.8 Hz,
1H), 2.01e1.89 (m,1H),1.81 (dd, J¼4.8, 4.8 Hz,1H),1.53e1.47 (m,1H),
4H), 7.49 (s, 4H), 3.86 (s, 1H), 2.53 (ddd, J¼18.8, 4.8, 2.8 Hz, 1H),
2.49e2.43 (m, 1H), 2.32e2.23 (m, 1H), 2.02e1.92 (m, 1H), 1.99 (d,
J¼18.8 Hz, 1H), 1.83 (dd, J¼4.8, 4.8 Hz, 1H), 1.47 (ddd, J¼12.8, 9.2,
3.6 Hz, 1H), 1.07 (s, 3H), 0.30 (s, 3H); 13C NMR (100 MHz, CDCl3)
1.18 (s, 3H), 0.22 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 143.8 (C),141.8
(C), 132.5 (C), 132.3 (C), 132.2 (C), 132.1 (C), 128.6 (CH), 128.5 (CH),
128.2 (CH), 127.4 (CH), 127.3 (CH), 127.2 (CH), 126.9 (CH), 126.7 (CH),
126.5 (CH), 126.0 (CH), 125.9 (CH), 125.7 (CH), 80.3 (C), 68.2 (C), 50.3
(C), 44.6 (CH), 43.5 (CH2), 26.9 (CH2), 25.8 (CH2), 22.9 (CH3), 22.0
(CH3); IR (neat) 3513, 1710 cmꢀ1; MS (EI) 420.2 (Mþ); HRMS (EI)
calcd for C30H28O2 (Mþ) 420.2089, found 420.2099.
d
150.3 (C), 147.7 (C), 129.2 (CH), 128.4 (CH), 124.5 (q, J¼3.7 Hz, CH),
124.3 (q, J¼3.7 Hz, CH), 79.5 (C), 67.9 (C), 50.3 (C), 44.4 (CH), 43.3
(CH2), 26.8 (CH2), 25.6 (CH2), 22.8 (CH3), 21.9 (CH3); IR (neat) 3542,
1716 cmꢀ1; MS (EI) 456.2 (Mþ); HRMS (EI) calcd for C24H22F6O2
(Mþ) 456.1524, found 456.1557.
4.2.7. 1-(Hydroxybis(4-methoxyphenyl)methyl)-7,7-dimethylbicyclo
[2.2.1]heptan-2-one (1g). Prepared from 5 (500 mg, 2.55 mmol)
using a procedure similar to that described for 1a. Column chro-
matography (7e10% EtOAc/hexanes) provided the title compound
4.2.11. 1-(Hydroxydi(thiophen-2-yl)methyl)-7,7-dimethylbicyclo
[2.2.1]heptan-2-one (1k). Prepared from 5 (140 mg, 0.71 mmol)
using a procedure similar to that described for 1a. Column chro-
matography (3% EtOAc/hexanes) provided the title compound as
as a clear syrup (614 mg, 63%). [
a
]
D ꢀ155.9 (c 1.29, CH2Cl2); 1H NMR
a charcoal powder (160 mg, 68%). Mp 112e114 ꢁC. [
a]D ꢀ147.8 (c 0.97,
(400 MHz, C6D6)
d
7.62e7.46 (m, 4H), 6.79e6.71 (m, 4H), 3.92 (s,
CH2Cl2); 1H NMR (300 MHz, CDCl3)
d 7.24e7.12 (m, 4H), 6.98e6.91
1H), 3.31 (s, 3H), 3.29 (s, 3H), 2.29e2.17 (m, 1H), 2.21 (ddd, J¼18.0,
4.8, 2.8 Hz, 1H), 1.99 (ddd, J¼14.0, 9.6, 4.8 Hz, 1H), 1.58 (d, J¼18.0 Hz,
1H), 1.60e1.51 (m, 1H), 1.30 (dd, J¼4.8, 4.8 Hz, 1H), 0.99 (s, 3H), 0.95
(ddd, J¼12.8, 9.2, 3.6 Hz, 1H), 0.31 (s, 3H); 13C NMR (100 MHz, C6D6)
(m, 2H), 4.33 (s, 1H), 2.63e2.41 (m, 2H), 2.09e1.94 (m, 2H), 1.90 (d,
J¼18.3 Hz,1H),1.83 (dd, J¼4.5, 4.5 Hz,1H),1.44e1.33 (m,1H), 0.98 (s,
3H), 0.58 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 151.5 (C), 148.2 (C),
126.5 (CH), 126.3 (CH), 125.5 (CH), 124.1 (CH), 124.0 (CH), 68.5 (C),
49.6 (C), 44.7 (CH), 43.3 (CH2), 26.6 (CH2), 26.2 (CH2), 21.5 (CH3), 21.2
(CH3); IR (neat) 3448, 1712 cmꢀ1; MS (EI) 332.1 (Mþ); HRMS (EI)
calcd for C18H20O2S2 (Mþ) 332.0905, found 332.0907.
d
159.0 (C), 158.8 (C), 140.2 (C), 138.0 (C), 131.0 (CH), 129.9 (CH),
112.8 (CH), 112.7 (CH), 79.6 (C), 68.4 (C), 54.7 (CH3), 54.6 (CH3), 50.0
(C), 44.7 (CH), 43.6 (CH2), 26.9 (CH2), 25.8 (CH2), 22.8 (CH3), 22.2
(CH3); IR (neat) 3527, 1719 cmꢀ1; MS (EI) 380.2 (Mþ); HRMS (EI)
calcd for C24H28O4 (Mþ) 380.1988, found 380.2008.
4.2.12. 1-(Bis(4-tert-butylphenyl)(methoxy)methyl)-7,7-
dimethylbicyclo[2.2.1] heptan-2-one (8). To a dry 25 mL round
bottom flask containing NaH (103 mg, 2.58 mmol) was added
a solution of 1e (223 mg, 0.52 mmol) in dry DMF (10 mL). Methyl
4.2.8. 1-(Hydroxybis(3-methoxyphenyl)methyl)-7,7-dimethylbicyclo
[2.2.1]heptan-2-one (1h). Prepared from 5 (100 mg, 0.51 mmol)
using a procedure similar to that described for 1a. Column chro-
matography (5% Et2O/toluene) provided the title compound as
iodide (97 mL,1.56 mmol) was then added and the resulting mixture
stirred at room temperature for 18 h. The reaction was quenched
with water (10 mL), and extracted twice with EtOAc (20 mL por-
tions). The combined organic phases were then washed with brine
(20 mL), dried over MgSO4, filtered, and concentrated in vacuo.
Flash chromatography (2% EtOAc in hexanes) provided the title
compound as a clear oil (73.5 mg, 32%). 1H NMR (400 MHz, C6D6)
a clear syrup (135 mg, 70%). [
(300 MHz, C6D6)
a
]
ꢀ153.7 (c 0.29, CH2Cl2); 1H NMR
D
d
7.53 (s, 1H), 7.40 (dd, J¼2.1, 2.1 Hz, 1H), 7.28e7.22
(m, 1H), 7.09e6.99 (m, 3H), 6.69e6.61 (m, 2H), 3.96 (s, 1H), 3.33 (s,
3H), 3.29 (s, 3H), 2.33 (ddd, J¼14.4, 12.0, 3.6 Hz, 1H), 2.13 (ddd,
J¼18.6, 5.1, 3.0 Hz,1H), 2.08e1.99 (m,1H),1.58e1.45 (m,1H),1.50 (d,
J¼18.3 Hz, 1H), 1.25 (dd, J¼4.5, 4.5 Hz, 1H), 0.97 (s, 3H), 0.87 (ddd,
J¼12.6, 9.3, 3.6 Hz, 1H), 0.32 (s, 3H); 13C NMR (100 MHz, C6D6)
d
7.79 (d, J¼8.4 Hz, 2H), 7.64 (d, J¼8.0 Hz, 2H), 7.31e7.24 (m, 4H),
2.95 (s, 3H), 2.24e2.13 (m, 1H), 2.03 (ddd, J¼13.6, 9.6, 5.2 Hz, 1H),
1.77e1.67 (m, 1H), 1.55 (d, J¼18.0 Hz, 1H), 1.32 (dd, J¼3.6, 3.6 Hz,
1H), 1.26 (s, 9H), 1.24 (s, 9H), 1.02e0.88 (m, 1H), 0.93 (s, 3H), 0.29 (s,
d
159.4 (C), 149.4 (C), 146.8 (C), 124.4 (CH), 128.1 (CH), 121.9 (CH),
121.5 (CH), 116.2 (CH), 114.9 (CH), 112.1 (CH), 111.9 (CH), 79.9 (C),
68.4 (C), 54.7 (CH3), 54.6 (CH3), 50.1 (C), 44.6 (CH), 43.3 (CH2), 26.9
3H); 13C NMR (100 MHz, C6D6)
d 212.7 (C), 150.1 (C), 149.7 (C), 138.5
(CH2), 25.9 (CH2), 22.8 (CH3), 21.9 (CH3); IR (neat) 3512, 1719 cmꢀ1
;
(C), 131.1 (CH), 130.5 (CH), 124.4 (CH), 124.2 (CH), 86.3 (C), 70.5 (C),
53.0 (CH3), 50.0 (C), 45.9 (CH), 44.4 (CH2), 34.4 (C), 34.3 (C), 31.5
(CH3), 31.4 (CH3), 27.5 (CH2), 26.6 (CH2), 22.2 (CH3), 22.1 (CH3); IR
(neat) 1740 cmꢀ1; MS (EI) 446.3 (Mþ); HRMS (EI) calcd for C31H42O2
(Mþ) 446.3185, found 446.3160.
MS (EI) 380.2 (Mþ); HRMS (EI) calcd for C24H28O4 (Mþ) 380.1988,
found 380.1997.
4.2.9. 1-(Hydroxybis(2-methoxyphenyl)methyl)-7,7-dimethylbicyclo
[2.2.1]heptan-2-one (1i). Prepared from 5 (200 mg, 1.02 mmol) using
a procedure similar to that described for 1a. Recrystallization from 3:1
hexanes/EtOAc provided the title compound as a clear crystals
4.3. General procedure for the synthesis of isocampholenic
acid derivatives (Table 1, compounds 3aek)
(164 mg, 42%). [
a
]
ꢀ43.1 (c 0.51, CH2Cl2); 1H NMR (500 MHz,
D
(CD3)2SO,145 ꢁC)
d
7.67e7.63 (m, 1H), 7.52e7.48 (m,1H), 7.18e7.08 (m,
4.3.1. 2-((R)-2,2-Dimethyl-3-(diphenylmethylene)cyclopentyl)acetic
2H), 6.92e6.75 (m, 4H), 5.00 (s, 1H), 3.40 (s, 3H), 3.25 (s, 3H),
acid (3a). To a solution of 1a (1.06 g, 3.31 mmol) in dry toluene

1544
R.A. Biggs, W.W. Ogilvie / Tetrahedron 69 (2013) 1539e1545
(30 mL) was added BF3$OEt2 (0.49 mL, 4.00 mmol). The mixture
was stirred at room temperature for 15 min, and the reaction was
then quenched by the addition of water (20 mL). The resulting
mixture was extracted twice with EtOAc (30 mL portions). The
combined organic extracts were washed with brine (20 mL) dried
over MgSO4, filtered, and concentrated in vacuo to provide com-
d 7.28e7.21 (m, 8H), 2.49e2.34 (m, 2H), 2.22e2.10 (m, 2H),
2.01e1.92 (m, 1H), 1.91e1.82 (m, 1H), 1.21e1.16 (m, 1H), 1.19 (s, 9H),
1.18 (s, 9H), 0.87 (s, 3H), 0.84 (s, 3H); 13C NMR (100 MHz, C6D6)
d
180.3 (C), 149.0 (C), 148.6 (C), 148.2 (C), 142.7 (C), 140.3 (C), 136.1
(C), 129.8 (CH), 128.4 (CH), 125.5 (CH), 124.9 (CH), 48.6 (CH), 44.8
(C), 34.8 (CH2), 34.4 (C), 34.3 (C), 32.2 (CH2), 31.5 (CH3), 28.4 (CH2),
27.0 (CH3), 23.1 (CH3); IR (neat) 1701 cmꢀ1; MS (EI) 432.3 (Mþ);
HRMS (EI) calcd for C30H40O2 (Mþ) 432.3028, found 432.3042.
pound 3a as a white powder (1.02 g, 96%). Mp 138e140 ꢁC; [
a]
D
ꢀ126.3 (c 0.51, CH2Cl2); 1H NMR (300 MHz, C6D6)
d 7.21e6.96 (m,
10H), 2.31e2.21 (m, 2H), 2.19e2.05 (m, 2H), 1.95 (dd, J¼14.7,
10.5 Hz, 1H), 1.89e1.76 (m, 1H), 1.24e1.09 (m, 1H), 0.78 (s, 3H), 0.76
4.3.6. 2-((R)-3-(Bis(4-(trifluoromethyl)phenyl)methylene)-2,2-
dimethylcyclopentyl)acetic acid (3f). Prepared from 1f (300 mg,
0.64 mmol) using a procedure similar to that described for 3a.
Column chromatography (15e30% EtOAc/hexanes) provided the
title compound as a pale yellow powder (253 mg, 84%). Mp
(s, 3H); 13C NMR (100 MHz, C6D6)
d 180.7 (C), 148.3 (C), 145.3 (C),
142.9 (C), 136.3 (C), 129.9 (CH), 128.6 (CH), 128.5 (CH), 126.5 (CH),
126.3 (CH), 48.5 (CH), 44.8 (C), 34.8 (CH2), 31.9 (CH2), 28.3 (CH2),
26.8 (CH3), 22.9 (CH3); IR (neat) 1693 cmꢀ1; MS (EI) 320.2 (Mþ);
HRMS (EI) calcd for C22H24O2 (Mþ) 320.1776, found 320.1791.
60e62 ꢁC; [
a
]
D
ꢀ89.3 (c 0.52, CH2Cl2); 1H NMR (400 MHz, C6D6)
d
7.35 (d, J¼8.0 Hz, 2H), 7.29 (d, J¼8.0 Hz, 2H), 6.92 (d, J¼8.0 Hz, 2H),
4 . 3 . 2 . 2 - ( ( R ) - 3 - ( B i s ( 4 - fl u o ro p h e nyl ) m e t hyl e n e ) - 2 , 2 -
dimethylcyclopentyl)acetic acid (3b). Prepared from 1b (25 mg,
0.07 mmol) using a procedure similar to that described for 3a to
6.83 (d, J¼8.0 Hz, 2H), 2.18 (dd, J¼14.8, 3.2 Hz, 1H), 2.11e1.91 (m,
4H), 1.86e1.76 (m, 1H), 1.18e1.05 (m, 1H), 0.61 (s, 3H), 0.59 (s, 3H);
13C NMR (100 MHz, C6D6)
d 180.7 (C), 150.7 (C), 147.6 (C), 145.5 (C),
obtain the title compound as a clear syrup (24.6 mg, 96%). [
a
]
133.4 (C), 130.2 (CH), 129.2 (q, J¼32.2 Hz, C), 128.8 (CH), 128.8 (q,
J¼32.0 Hz, C), 125.8 (q, J¼3.7 Hz, CH), 125.2 (q, J¼3.7 Hz, CH), 124.9
(q, J¼270.1 Hz, C), 124.8 (q, J¼270.2 Hz, C), 48.3 (CH), 44.9 (C), 34.7
(CH2), 31.7 (CH2), 28.1 (CH2), 26.6 (CH3), 22.7 (CH3); IR (neat)
1705 cmꢀ1; MS (EI) 456.2 (Mþ); HRMS (EI) calcd for C24H22F6O2
(Mþ) 456.1524, found 456.1523.
D
ꢀ108.6 (c 0.48, CH2Cl2); 1H NMR (400 MHz, C6D6)
d 6.88e6.69 (m,
8H), 2.21 (dd, J¼14.8, 3.2, 1H), 2.15e2.03 (m, 3H), 1.96 (dd, J¼14.8,
10.8, 1H), 1.88e1.78 (m, 1H), 1.21e1.08 (m, 1H), 0.69 (s, 3H), 0.67 (s,
3H); 13C NMR (100 MHz, C6D6)
d
180.3 (C), 163.0 (d, J¼28.8 Hz, C),
160.6 (d, J¼28.4 Hz, C), 149.6 (C), 140.8 (d, J¼3.2 Hz, C), 138.5 (d,
J¼3.3 Hz, C),133.9 (C),131.3 (d, J¼7.6 Hz, CH),130.0 (d, J¼7.7 Hz, CH),
115.4 (d, J¼21.0 Hz, CH), 114.9 (d, J¼21.0 Hz, CH), 48.5 (CH), 44.7 (C),
34.7 (CH2), 31.9 (CH2), 28.2 (CH2), 26.8 (CH3), 22.8 (CH3); IR (neat)
1701 cmꢀ1; MS (EI) 356.2 (Mþ); HRMS (EI) calcd for C22H22F2O2
(Mþ) 356.1588, found 356.1583.
4.3.7. 2-((R)-3-(Bis(4-methoxyphenyl)methylene)-2,2-
dimethylcyclopentyl)acetic acid (3g). Prepared from 1g (26 mg,
0.07 mmol) using a procedure similar to that described for 3a to
obtain the title compound as a pale yellow syrup (22 mg, 80%). [a]
D
ꢀ104.5 (c 1.09, CH2Cl2); 1H NMR (400 MHz, C6D6)
d 7.13e7.08 (m,
4.3.3. 2-((R)-2,2-Dimethyl-3-(di-p-tolylmethylene)cyclopentyl) ace-
tic acid (3c). Prepared from 1c (33 mg, 0.10 mmol) using a pro-
cedure similar to that described for 3a to obtain the title compound
4H), 6.00e6.72 (m, 4H), 3.30 (s, 3H), 3.28 (s, 3H), 2.47e2.33 (m, 2H),
2.24 (dd, J¼14.8, 3.2 Hz, 1H), 2.20e2.12 (m, 1H), 1.99 (dd, J¼14.4,
10.4 Hz, 1H), 1.95e1.86 (m, 1H), 1.28e1.16 (m, 1H), 0.88 (s, 3H), 0.83
as a white sticky solid (26.8 mg, 80%). Mp 80e82 ꢁC; [
a]
D ꢀ86.3 (c
(s, 3H); 13C NMR (100 MHz, C6D6)
d 180.3 (C), 158.6 (C), 158.4 (C),
0.41, CH2Cl2); 1H NMR (400 MHz, C6D6)
d
7.17e7.09 (m, 4H), 6.96 (d,
148.3 (C), 138.2 (C), 135.7 (C), 135.5 (C), 131.0 (CH), 129.7 (CH), 114.0
(CH), 113.6 (CH), 54.7 (CH3), 54.6 (CH3), 48.7 (CH), 44.8 (C), 34.9
(CH2), 32.2 (CH2), 28.4 (CH2), 27.0 (CH3), 23.1 (CH3); IR (neat)
1701 cmꢀ1; MS (EI) 380.2 (Mþ); HRMS (EI) calcd for C24H28O4 (Mþ)
380.1988, found 380.1982.
J¼7.6 Hz, 2H), 6.92 (d, J¼7.6 Hz, 2H), 2.40e2.33 (m, 2H), 2.22e2.11
(m, 2H), 2.10 (s, 3H), 2.07 (s, 3H), 1.94 (dd, J¼14.4, 10.4 Hz, 1H),
1.91e1.83 (m, 1H), 1.25e1.13 (m, 1H), 0.85 (s, 3H), 0.82 (s, 3H); 13C
NMR (100 MHz, C6D6)
d 180.6 (C), 148.0 (C), 142.8 (C), 140.4 (C),
136.2 (C), 135.7 (C), 135.4 (C), 129.9 (CH), 129.3 (CH), 128.8 (CH),
128.5 (CH), 48.6 (CH), 44.8 (C), 34.8 (CH2), 32.0 (CH2), 28.3 (CH2),
4.3.8. 2-((R)-3-(Bis(3-methoxyphenyl)methylene)-2,2-
dimethylcyclopentyl)acetic acid (3h). Prepared from 1h (87 mg,
0.23 mmol) using a procedure similar to that described for 3a to
26.7 (CH3), 22.7 (CH3), 20.8 (CH3), 20.7 (CH3); IR (neat) 1702 cmꢀ1
;
MS (EI) 348.2 (Mþ); HRMS (EI) calcd for C24H28O2 (Mþ) 348.2089,
found 348.2140.
obtain the title compound as a clear syrup (69 mg, 79%). [
a]
D ꢀ101.8
(c 1.20, CH2Cl2); 1H NMR (400 MHz, C6D6)
d
7.10e7.01 (m, 2H),
4.3.4. 2-((R)-2,2-Dimethyl-3-(di-m-tolylmethylene)cyclopentyl)ace-
tic acid (3d). Prepared from 1d (31 mg, 0.09 mmol) using a pro-
cedure similar to that described for 3a to obtain the title compound
6.99e6.96 (m, 2H), 6.91e6.82 (m, 2H), 6.64e6.58 (m, 2H), 3.28 (s,
3H), 3.26 (s, 3H), 2.43e2.29 (m, 2H), 2.19 (dd, J¼14.8, 3.6 Hz, 1H),
2.15e2.07 (m, 1H), 1.94 (dd, J¼14.8, 10.8 Hz, 1H), 1.88e1.80 (m, 1H),
1.23e1.10 (m, 1H), 0.86 (s, 3H), 0.81 (s, 3H); 13C NMR (100 MHz,
as clear needles (27.6 mg, 89%). Mp 100e102 ꢁC; [
a]
D ꢀ94.4 (c 0.50,
CH2Cl2); 1H NMR (400 MHz, C6D6)
d
7.13e7.02 (m, 6H), 6.85 (d,
C6D6) d 180.3 (C), 159.7 (C), 148.3 (C), 146.6 (C), 144.2 (C), 136.0 (C),
J¼7.6 Hz, 2H), 2.42e2.28 (m, 2H), 2.25e2.11 (m, 2H), 2.09 (s, 3H),
2.06 (s, 3H), 1.96 (dd, J¼14.8, 10.8 Hz, 1H), 1.91e1.83 (m, 1H),
1.27e1.14 (m, 1H), 0.85 (s, 3H), 0.83 (s, 3H); 13C NMR (100 MHz,
129.7 (CH), 129.0 (CH), 122.5 (CH), 120.9 (CH), 116.1 (CH), 114.7 (CH),
111.8 (CH), 111.6 (CH), 54.7 (CH3), 54.6 (CH3), 48.6 (CH), 34.8 (CH2),
31.9 (CH2), 28.2 (CH2), 26.8 (CH3), 22.9 (CH3); IR (neat) 1701 cmꢀ1
;
C6D6)
d
180.6 (C), 147.9 (C), 145.5 (C), 143.1 (C), 137.9 (C), 137.4 (C),
MS (EI) 380.2 (Mþ); HRMS (EI) calcd for C24H28O4 (Mþ) 380.1988,
found 380.1967.
136.5 (C), 130.6 (CH), 129.1 (CH), 128.6 (CH), 127.9 (CH), 127.3 (CH),
127.1 (CH), 127.0 (CH), 125.7 (CH), 48.6 (CH), 44.8 (C), 34.9 (CH2),
31.9 (CH2), 28.3 (CH2), 26.9 (CH3), 23.0 (CH3), 21.5 (CH3), 21.4 (CH3);
IR (neat) 1700 cmꢀ1; MS (EI) 348.2 (Mþ); HRMS (EI) calcd for
C24H28O2 (Mþ) 348.2089, found 348.2083.
4.3.9. 2-((R)-3-(Bis(2-methoxyphenyl)methylene)-2,2-
dimethylcyclopentyl)acetic acid (3i). Prepared from 1i (30 mg,
0.08 mmol) using a procedure similar to that described for 3a to
obtain the title compound as a white powder (19 mg, 62%). Mp
4.3.5. 2-((R)-3-(Bis(4-tert-butylphenyl)methylene)-2,2-
dimethylcyclopentyl)acetic acid (3e). Prepared from 1e (25 mg,
0.06 mmol) using a procedure similar to that described for 3a to
obtain the title compound as a white powder (19 mg, 76%). Mp
182e184 ꢁC; [
(CD3)2SO, 145 ꢁC)
a]
ꢀ24.6 (c 0.29, CH2Cl2); 1H NMR (500 MHz,
D
d
7.33e7.22 (m, 2H), 7.18e7.07 (m, 2H), 6.94e6.80
(m, 4H), 3.78 (s, 3H), 3.76 (s, 3H), 2.32e2.24 (m, 1H), 2.15e2.06 (m,
2H), 2.03e1.94 (m, 2H),1.84e1.75 (m,1H),1.35e1.24 (m,1H), 0.82 (s,
176e178 ꢁC; [
a]
ꢀ86.1 (c 0.53, CH2Cl2); 1H NMR (400 MHz, C6D6)
6H); 13C NMR (100 MHz, C6D6)
d 180.5 (C), 180.4 (C), 157.5 (C), 156.5
D

R.A. Biggs, W.W. Ogilvie / Tetrahedron 69 (2013) 1539e1545
1545
(C) 156.3 (C), 149.3 (C), 149.1 (C), 133.7 (C), 132.5 (CH), 132.2 (CH),
130.9 (CH), 130.5 (CH), 120.9 (CH), 120.7 (CH), 119.9 (CH), 119.7 (CH),
111.3 (CH),110.8 (CH),110.7 (CH), 55.0 (C), 54.9 (C), 54.6 (C), 54.5 (C),
48.7 (CH), 48.4 (CH), 44.9 (C), 44.6 (C), 35.1 (CH2), 34.8 (CH2), 31.5
(CH2), 31.3 (CH2), 28.3 (CH2), 27.9 (CH2), 24.3 (CH3), 22.5 (CH3), 22.4
(CH3), 21.2 (CH3),1.3 (CH3); IR (neat) 1707 cmꢀ1; MS (EI) 380.2 (Mþ);
HRMS (EI) calcd for C24H28O4 (Mþ) 380.1988, found 380.1975.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
CCDC 908239. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax:
þ44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk). Supple-
mentary data related to this article can be found online at http://
dx.doi.org/10.1016/j.tet.2012.12.011.
4.3.10. 2-((R)-2,2-Dimethyl-3-((naphthalen-2-yl)(naphthalen-3-yl)
methylene)cyclopentyl)acetic acid (3j). Prepared from 1j (35 mg,
0.08 mmol) using a procedure similar to that described for 3a to
References and notes
1. (a) Money, T. Nat. Prod. Rep. 1985, 2, 253; (b) Langlois, Y.; Kouklovsky, C. Synlett
2009, 3065; (c) McGarrigle, E. M.; Myers, E. L.; Illa, O.; Shaw, M. A.; Riches, S. L.;
Aggarwal, V. K. Chem. Rev. 2007, 107, 5841; (d) Boobalan, R.; Chen, C.; Lee, G. H.
Org. Biomol. Chem. 2012, 10, 1625; (e) Komarov, I. V.; Monsees, A.; Spannenberg,
A.; Baumann, W.; Schmidt, U.; Fischer, C.; Borner, A. Eur. J. Org. Chem. 2003, 138;
(f) Lemay, M.; Ogilvie, W. W. Org. Lett. 2005, 7, 4141.
obtain the title compound as a clear syrup (23 mg, 65%). [a]
D
ꢀ143.2 (c 0.60, CH2Cl2); 1H NMR (400 MHz, C6D6)
d 7.84e7.81 (m,
1H), 7.76e6.73 (m, 1H), 7.68e7.52 (m, 6H), 7.39e7.33 (m, 2H),
7.27e7.18 (m, 4H), 2.50e2.30 (m, 2H), 2.24e2.13 (m, 2H), 1.99 (dd,
J¼11.7, 8.4 Hz,1H), 1.93e1.84 (m, 1H),1.29e1.16 (m, 1H), 0.85 (s, 3H),
€
2. Liu, H. J.; Chan, W. H. Can. J. Chem. 1982, 60, 1081.
3. Liu, H. J.; Llinas-Brunet, M. Can. J. Chem. 1988, 66, 528.
0.82 (s, 3H); 13C NMR (100 MHz, C6D6)
d 179.7 (C), 149.5 (C), 142.6
4. Rowley, M.; Tsukamoto, M.; Kishi, Y. J. Am. Chem. Soc. 1989, 111, 2735.
5. Liu, H. J.; Ralitsch, M. J. Chem. Soc., Chem. Commun. 1990, 997.
6. (a) Paquette, L. A.; Zhao, M. J. Am. Chem. Soc. 1998, 120, 5203; (b) Paquette, L. A.;
Wang, H. L.; Su, Z.; Zhao, M. J. Am. Chem. Soc. 1998, 120, 5213.
7. Williams, D. R.; Coleman, P. J.; Henry, S. S. J. Am. Chem. Soc. 1993, 115, 11654.
8. (a) Stevens, R. V.; Gaeta, F. C. A.; Lawrence, D. S. J. Am. Chem. Soc. 1983, 105,
7713; (b) Lansbury, P. T.; Mazur, D. J.; Springer, J. P. J. Org. Chem. 1985, 50, 1632.
9. Knizhnikov, V. O.; Voitenko, Z. V.; Golovko, V. B.; Gorichko, M. V. Tetrahedron
2012, 68, 1972.
(C), 140.4 (C), 136.0 (C), 134.3 (C),133.6 (C), 132.6 (C), 132.6 (C),128.8
(CH),128.4 (CH),128.3 (CH),128.2 (CH),128.2 (CH),128.0 (CH),127.9
(CH), 127.8 (CH), 127.4 (CH), 127.2 (CH), 126.3 (CH), 126.2 (CH), 125.9
(CH), 125.8 (CH), 48.6 (CH), 45.0 (C), 34.6 (CH2), 32.1 (CH2), 28.4
(CH2), 26.9 (CH3), 23.1 (CH3); IR (neat) 1699 cmꢀ1; MS (EI) 420.2
(Mþ); HRMS (EI) calcd for C30H28O2 (Mþ) 420.2089, found
420.2106.
€
ꢀ
10. (a) Ruedi, G.; Nagel, M.; Hansen, H. J. Org. Lett. 2003, 5, 2691; (b) Groselj, U.;
ꢀ
Bevk, D.; Jakse, R.; Meden, A.; Stanovnik, B.; Svete, J. Tetrahedron: Asymmetry
4.3.11. 2-((R)-2,2-Dimethyl-3-(di(thiophen-2-yl)methylene)cyclo-
pentyl)acetic acid (3k). Prepared from 1k (47 mg, 0.14 mmol) using
a procedure similar to that described for 3a to obtain the title
2005, 16, 2187.
11. Martínez, A. G.; Vilar, E. T.; Fraile, A. G.; de la Moya Cerero, S.; Maroto, B. L.
Tetrahedron: Asymmetry 2001, 12, 189.
12. Hutchinson, J. H.; Money, T.; Piper, S. E. Can. J. Chem. 1986, 64, 854.
13. Ferguson, C. G.; Money, T.; Pontillo, J.; Whitelaw, P. D. M.; Wong, M. K. C. Tet-
rahedron 1996, 52, 14661.
14. (a) Hutchinson, J. H.; Money, T. Can. J. Chem. 1985, 63, 3182; (b) Money, T.;
Wong, M. K. C. Tetrahedron 1996, 52, 6307; (c) Mermet-Mouttet, M. P.; Gabriel,
K.; Heissler, D. Tetrahedron Lett. 1999, 40, 843; (d) Hiersemann, M.; Helmboldt,
H. Top. Curr. Chem. 2005, 243, 73.
15. (a) Clase, J. A.; Money, T. Can. J. Chem. 1992, 70, 1537; (b) Money, T.; Richardson,
S. R.; Wong, M. K. C. Chem. Commun. 1996, 667; (c) Clase, J. A.; Money, T.
Synthesis 1989, 934.
16. Bartlett, P. P.; Knox, L. H. Organic Syntheses; Wiley & Sons: New York, NY, 1973;
Collect. Vol. 5; 1965; 689; Vol. 45, p 55.
17. Gilbertson, S. R.; Fu, Z. Org. Lett. 2001, 3, 161.
18. Chu, Y. Y.; Yu, C. S.; Chen, C. J.; Yang, K. S.; Lain, J. C.; Lin, C. H.; Chen, K. J. Org.
Chem. 1999, 64, 6993.
compound as a turquoise powder (44 mg, 93%). Mp 76e78 ꢁC; [
a]
D
ꢀ130.5 (c 0.57, CH2Cl2); 1H NMR (400 MHz, C6D6)
6.89 (dd, J¼4.8,
d
0.8 Hz, 1H), 6.86 (dd, J¼5.2, 1.2 Hz, 1H), 6.78 (dd, J¼3.2, 1.2 Hz, 1H),
6.73 (dd, J¼4.0, 1.6 Hz, 1H), 6.70 (dd, J¼4.8 Hz, 2.8 Hz, 1H), 6.69 (dd,
J¼4.8, 2.8 Hz, 1H), 2.70e2.49 (m, 2H), 2.17 (dd, J¼14.8, 3.2 Hz, 1H),
2.11e2.01 (m, 1H),1.96e1.85 (m, 2H),1.28e1.16 (m,1H), 0.81 (s, 3H),
0.76 (s, 3H); 13C NMR (100 MHz, C6D6)
d 179.8 (C),154.2 (C),147.3 (C),
142.8 (C), 126.4 (CH), 126.3 (CH), 125.9 (CH), 125.5 (CH), 124.8 (CH),
121.2 (CH), 48.1 (CH), 46.2 (C), 34.4 (CH2), 33.7 (CH2), 28.1 (CH2), 25.8
(CH3), 22.2 (CH3); IR (neat) 1699 cmꢀ1; MS (EI) 332.1 (Mþ); HRMS
(EI) calcd for C18H20O2S2 (Mþ) 332.0905, found 332.0925.
19. Acid 3e was recovered intact when exposed to the same conditions, indicating
that the ester was not formed by the action of Lewis acid on the product.
20. Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling, U. H.;
Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.
Acknowledgements
We thank Glenn A. Facey and Ilia Korobkov for their technical
assistance. This research has been supported by NSERC, the Cana-
dian Foundation for Innovation, and by the University of Ottawa.
21. Compound 11 was isolated as a single isomer, but the relative configuration of
the exocyclic alcohol could not be established.
22. The methyl ester was synthesized in an attempt to separate the isomers.
23. Comparison of some characteristic resonances in the 1H NMR of the iso-
campholenic acid derivatives 3aek suggested that the major isomer was 13.
Supplementary data
Ph
Detailed experimental procedures and copies of 1H and 13C NMR
spectra of all new compounds. This material is available free of
charge via the Internet.
MeO
Me
O
13