Catalytic asymmetric synthesis of a tertiary benzylic carbon center via phenol-directed alkene hydrogenation

Article abstract of DOI:10.1021/jo200941r

An expeditious synthetic approach to chiral phenol 1, a key building block in the preparation of a series of drug candidates, is reported. The strategy includes a cost-effective and readily scalable route to cyclopentanone 3 from isobutyronitrile (10). The sterically hindered and enolizable ketone 3 was subsequently employed in a challenging Grignard addition mediated by LaCl ₃?2LiCl. A novel preparation of the lanthanide reagent required for this transformation is described. To complete the process, a highly enantioselective hydrogenation step afforded the target (1). The importance of the phenol group to the success of this asymmetric transformation is discussed.

Full text of DOI:10.1021/jo200941r

FEATURED ARTICLE
pubs.acs.org/joc
Catalytic Asymmetric Synthesis of a Tertiary Benzylic Carbon Center
via Phenol-Directed Alkene Hydrogenation
Seb Caille,* Rich Crockett, Krishnakumar Ranganathan, Xiang Wang, Jacqueline C. S. Woo, and
Shawn D. Walker
Chemical Process R&D, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
S Supporting Information
b
ABSTRACT:
An expeditious synthetic approach to chiral phenol 1, a key building block in the preparation of a series of drug candidates, is
reported. The strategy includes a cost-effective and readily scalable route to cyclopentanone 3 from isobutyronitrile (10). The
sterically hindered and enolizable ketone 3 was subsequently employed in a challenging Grignard addition mediated by
LaCl3 2LiCl. A novel preparation of the lanthanide reagent required for this transformation is described. To complete the process,
3
a highly enantioselective hydrogenation step afforded the target (1). The importance of the phenol group to the success of this
asymmetric transformation is discussed.
’ INTRODUCTION
The preparation of chiral benzylic stereocenters represents a
significant challenge in organic synthesis. Several methods
affording these structural motifs make use of functional handles
which must subsequently be removed if they are not part of the
target molecules (asymmetric conjugate addition to enones,
asymmetric arylation of ketones).1 During the course of a recent
development program, chiral phenol 1 emerged as a key building
block in the synthesis of a series of drug candidates (Figure 1).
Asymmetric hydrogenation of an alkene precursor would con-
stitute an attractive method to generate this type of chiral
compound without the use of a carbonyl-containing functional
handle. Such a method2 could also be applied to the preparation
of tolterodine3 (2, Detrol LA), a structurally related commercial
drug employed in the treatment of urinary bladder disorders. The
development of a short and practical synthesis of 1, including an
asymmetric hydrogenation step, became a primary focus of
our group.
The original synthesis of 1 employed by the Discovery
Chemistry team is depicted in Scheme 1. Boronate ester 6 was
prepared in two steps from 2,2-dimethylcyclopentanone (3) by
generation of vinyl triflate 4 and subsequent Pd-catalyzed
coupling with bis(pinacolato)diboron (5) (37% overall yield).
Bromide 8 was obtained from the commercially available car-
boxylic acid 7 by esterification and protection of the phenol
group as a tetrahydro-2H-pyran-2-yl (THP) ether. Suzu-
kiꢀMiyaura coupling of 6 and 8 produced alkene 9 (80%).
Solvolysis of the THP ether group of 9 was followed by
Figure 1. Chiral intermediate 1 and tolterodine.
hydrogenation of the alkene and the resulting racemic mixture
was separated by chiral chromatography to provide phenol 1.
This approach to 1 comprised several features that made it
unsuitable for large-scale application. First, cyclopentanone 3 is
an expensive starting material with limited availability.4 Conse-
quently, any route that employs 3 should involve a minimum
number of linear steps from 3 to 1. The linear sequence from 3 to
1 in the drug discovery sequence is rather long (six steps), and the
overall yield is low (12%). Additionally, the use of protecting
groups is not desirable for long-term application. Finally, the
benzylic stereogenic center should be generated enantioselec-
tively to improve the overall yield and avoid chiral separation of a
racemic mixture.
Received: May 9, 2011
Published: June 01, 2011
r
2011 American Chemical Society
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The Journal of Organic Chemistry
FEATURED ARTICLE
Scheme 1. Discovery Synthesis of Chiral Phenol 1
asymmetric hydrogenation of unfunctionalized alkenes employ-
ing iridium complexes and the BARF counterion.10 However, the
use of this counterion on manufacturing scale is prohibited by
cost,11 unless very low catalyst loadings (below 0.05 mol %) can
be achieved. On the other hand, it was conceived that the phenol
group could serve as a complexing agent in the asymmetric
hydrogenation, thus allowing the transformation to proceed with
high enantioselectivity employing rhodium catalysis as is the case
in the well documented rhodium catalyzed asymmetric hydro-
genation of enamides.12
Scheme 2. Proposed Approach to Chiral Phenol 1
’ RESULTS AND DISCUSSION
2,2-Dimethylcyclopentanone (3) was prepared via a simple,
three-step reaction sequence using inexpensive and readily
available starting materials and reagents (Scheme 3). Isobutyr-
onitrile (10) was deprotonated using LDA, and the resulting
lithium anion was alkylated with 1-bromo-3-chloropropane.
Byproduct 15 was obtained along with the desired adduct 14.
The amounts of 15 generated were observed to be dependent on
the temperature of the reaction, lower temperatures allowing for
a more selective transformation. Upon performing the transfor-
mation at ꢀ70 °C, the products (14/15) were obtained in a
>100/1 ratio; however, this ratio was 4.2/1 when the reaction
was conducted at ꢀ40 °C. Chloride 14 was isolated after aqueous
workup/distillation and converted to iodide 11 via a Finkelstein
reaction (NaI, acetone, reflux). The product (11), purified by
distillation, was prepared in 83% yield from starting material 10.
A solution of iodide 11 was added to n-hexyllithium in THF at
ꢀ5 °C to afford, after acidification using aqueous oxalic acid, 2,
2-dimethylcyclopentanone (3) in 81% yield (99% assay yield).
The addition of a THF solution of 11 to n-hexyllithium gave a
higher yield (99% assay yield) than the inverse mode of addition
(adding n-hexyllithium to a solution of 11, 83% assay yield). Two
equivalents of n-hexyllithium were utilized in this transformation
to maximize the yield of 3 since the equivalent of iodohexane
generated from lithium-halogen exchange immediately reacted
Our proposed alternative approach to phenol 1 is shown in
Scheme 2. Cyclopentanone 3 has been synthesized previously via
an intramolecular anionic cyclization process initiated by forma-
tion of an alkyl Grignard reagent from iodide 11.5,6 However, low
yields (<10%) of 3 were obtained in our hands using this
Grignard reagent and it was desired to improve on these results
by employing an alkyl lithium reagent as an alternative. An
additionꢀelimination sequence would constitute an attractive
method to obtain 13 from 3. This addition would ideally be
performed by preparing an aryl Grignard reagent directly from
unprotected phenol 12.7 The addition employing sterically
hindered cyclopentanone 3 was expected to be challenging due
to competing ketone enolization.8 Lanthanide salts have been
utilized in the literature to improve the yields of such
transformations.9 The development of an enantioselective hy-
drogenation of the alkene group of 13 would complete our
synthesis of 1. A lot of attention has recently been focused on the
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Scheme 3. Preparation of 2,2-Dimethylcyclopentanone (3)
Table 1. Grignard Addition To Generate Tertiary Alcohol 16a
entry
substrate
R
additive (x equiv)
lanthanide reagent (x equiv)
T (°C)
time (h)
16 (%)
17 (%)
1
2
12a
12a
12a
12a
12a
12a
12a
12b
12b
12c
12c
Me
Me
Me
Me
Me
Me
Me
i-Pr
i-Pr
t-Bu
t-Bu
LiCl (1)
LiCl (1)
LiCl (1)
LiCl (1)
LiCl (1)
LiCl (1)
LiOiPr (1)
none
none
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ10
ꢀ10
23
12
0
18
0
83
39
52
27
28
29
26
57
30
23
35
CeCl3 “rods” (1.3)
12
3
CeCl3 2LiCl (1.3)
12
3
4
CeCl3 2LiCl (1.3)
12
27
34
39
44
17
50
71
46
3
5
LaCl3 2LiCl (1.3)
12
3
6
LaCl3 2LiCl (1.3)
1.5
1.5
1.5
1.5
1.5
1.5
3
7
LaCl3 2LiCl (1.3)
3
8
LaCl3 2LiCl (1.3)
3
9
LiOiPr(1)
LiOiPr(1)
LiOiPr(1)
LaCl3 2LiCl (1.3)
3
10
11
LaCl3 2LiCl (1.3)
3
LaCl3 2LiCl (0.5)
23
3
a Reaction conditions: 18 mL of solvent per gram of 12 utilized. Assay yields determined by HPLC versus an authentic standard are reported except for
16 in entries 9 and 10.
with a second equivalent of alkyllithium reagent to afford
dodecane. The ketone 3 (bp 145 °C) was separated from
dodecane (bp 216 °C) via distillation.13,14
formed in this experiment and the only product of the reaction
was phenol 17a (83%, entry 1).15 This result was consistent with
the known propensity of cyclic ketones, particularly sterically
hindered R-substituted ketones, to undergo enolization rather
than carbonyl addition reactions. To help address this problem,
the use of rod-shaped CeCl3 THFꢀsolvate crystals has been
reported by Conlon and co-workers.16 Thus a suspension of
CeCl3 THFꢀsolvate “rods” was generated according to the
reported procedure and ketone 3 was added to the mixture at
23 °C. The suspension was agitated for 1 h and subsequently
added to a solution of the Grignard reagent prepared from 12a
(R = Me). The resulting mixture was aged at ꢀ20 °C for 12 h to
afford 16a in a disappointing 18% assay yield (entry 2).
With an efficient route to 2,2-dimethylcyclopentanone (3) in
hand, work focused on conversion of 3 to alkene 13. An aryl
Grignard reagent was generated from iodide 12a (R = Me)
according to the procedure reported by Knochel and co-workers.7
In this protocol, 1 equivalent of MeMgCl was employed to
deprotonate the phenol group of 12a and 1 equivalent of i-
PrMgCl was subsequently added to effect the desired MgꢀI
exchange. The transformation was carried out at ꢀ30 °C in the
presence of 1 equivalent of LiCl. We found that for substrate 12a
(R = Me), aging of the reaction mixture at ꢀ10 °C for 2.5 h after
addition of all the reagents was necessary to observe complete
conversion of the starting iodide. To the resulting aryl Grignard
reagent was added a solution of 3 in THF and the reaction
mixture was aged at ꢀ20 °C for 12 h. No desired alcohol 16a was
An alternative method to prepare lanthanum chloride reagents
was reported by Knochel and co-workers.9c This procedure
involves the use of solutions of CeCl3 2LiCl or LaCl3 2LiCl
3
3
in THF to improve the yield of desired carbonyl addition
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products. However, several features of the procedure described
to prepare these solutions were unattractive for application on
large scale including: (i) extended heat cycles up to 160 °C, (ii)
drying of nonstirrable CeCl3 2LiCl or LaCl3 2LiCl solid com-
for 12 h to afford alcohol 16a in 27% yield (Table 1, entry 4). The
same experiment performed with LaCl3 2LiCl instead of CeCl3
3
3
2LiCl afforded 16a in 34% yield (entry 5). One should note that
the order of addition is critical to the success of this transforma-
tion. Interestingly, when the order of addition was changed and a
3
3
plexes, (iii) low and variable concentrations of the final lantha-
nide solutions, (iv) time-consuming operations and the need for
multireactor processing to prepare the desired solutions. As a
result, we elected to prepare these reagents in a simplified
manner that should be suitable for larger scale application. We
used anhydrous LaCl3 or CeCl3 to prepare 0.125 M solutions of
CeCl3 2LiCl or LaCl3 2LiCl in THF by adding commercially
CeCl3 2LiCl solution was added to the aryl Grignard reagent,
3
followed by addition of ketone 3, no desired product 16a was
observed (entry 3). Owing to the ease of preparation of the
LaCl3 2LiCl reagent (no filtration step), we elected to pursue
3
the optimization of the Grignard addition using this reagent
rather than CeCl3 2LiCl. The reaction time after addition of
3
3
3
available solutions of LiCl (0.5 M in THF) to the lanthanide salt
and heating the resulting mixtures at reflux for 12 h. Undissolved
materials remained at the end of that heating period in the case of
CeCl3 and thus a filtration step was required to obtain a clear
solution.17 However, using LaCl3, a homogeneous solution was
conveniently obtained at the end of the heating period. After the
initial 0.125 M solutions were obtained, distillation of most of the
LaCl3 2LiCl and 3 was shortened to 1.5 h, and LiCl was replaced
3
with LiOiPr as an additive during Grignard formation. As a result,
the yield of 16a was increased from 34% to 44% (entry 5 vs entry 7).
Table 3. Reaction Screen for Asymmetric Hydrogenation of
13a Using Josiphos SL-J-210-1 as Liganda
THF was performed to produce solutions of CeCl3 2LiCl or
3
LaCl3 2LiCl with a concentration range of 0.7 M to 1.0 M.18
3
Ketone 3 was added at 23 °C to a solution of CeCl3 2LiCl thus
3
prepared, and the resulting mixture was aged for 1 h. This
solution was added to a cold (ꢀ20 °C) solution of the Grignard
reagent generated from iodide 12a, and the mixture was agitated
Table 2. Elimination To Generate Alkene 13ba
pressure Rh loading
conversion
(%)
entry solvent
(psi)
(%)
additiveb
ee (%)
1
2
3
4
5
6
7
8
9
MeOH
THF
200
200
200
200
200
200
50
5
5
95
100
99
79
94
77
96
95
97
95
EtOAc
Toluene
THF
5
5
98
1
NaCl
Et3N
Et3N
Et3N
Et3N
Et3N
75
THF
1
100
90
THF
1
entry
acid
time (h)
yield (%)
THF
50
0.5
0.1
0.1
40
1
2
3
methanesulfonic acid
1.5
3.0
1.0
90b
91
89b
THF
200
100
97
99c
HCl
10 THF
200
100
a Reaction Conditions: 13a (100 mg), catalyst/ligand added as stock
solution, 10 vol of THF. b 5 mol % of additive was used. c 97.7 g scale, 3
vol of THF.
H2SO4
a Reaction conditions: 4.7 mL of solvent per gram of 16b utilized. b Assay
yields determined by HPLC versus an authentic standard are reported.
Scheme 4. High-Throughput Screening Results for Asymmetric Hydrogenation of 13aa
a The enantiomer of 1a was obtained as major isomer using ligands L1 and L3.
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Scheme 5. Absolute Stereochemistry Determination for Phenols 1a and 1b
However, it was noted that the combined yields of products 16a
Scheme 6. Asymmetric Hydrogenation of a Substrate Lack-
ing the Phenol Moiety (21)
and 17a obtained utilizing methyl ester 12a and either LaCl3 2
3
LiCl or CeCl3 2LiCl in the Grignard addition ranged from 54%
3
to 70% (entries 4ꢀ7). The remaining mass balance was attrib-
uted to the formation of a number of other byproducts, as
indicated by HPLC analysis of the reaction mixtures. Some of
these byproducts corresponded to the methyl ester function of
12a reacting under these conditions (byproduct masses were
correlated by LCMS). Consequently, the same transformation
with bulkier ester derivatives was studied in order to suppress
nucleophilic addition to the ester group. The Grignard addition
withcorrespondingisopropylester(substrate12b) was conducted
higher enantiomeric excesses were observed using THF (94% ee,
entry 2) and toluene (96% ee, entry 4). It is well established that
trace amounts of impurities may inhibit Rh-catalyzed hydrogena-
tions by attenuating the activity of the catalyst.20 Accordingly, the
transformation failed to go to completion in the presence of small
amounts of NaCl (entry 5). In the presence of Et3N (5 mol %),
the catalyst loading could be reduced from 5 mol % (entry 2) to
0.1% (entry 9) and the hydrogenation ee increased from 94% to
97%. The optimized reaction conditions (0.1% Rh loading, 200
psi, 5 mol % Et3N, THF, entry 9) were used in an experiment
performed starting with 98 g of 13a (entry 10). The transforma-
tion proceeded in 1 h at 22 °C (98.7% ee). The crude reaction
mixture was filtered through silica gel, concentrated, triturated in
EtOAc/heptane, and filtered. Using this protocol, phenol 1a was
obtained as a crystalline white solid in 96% corrected yield and
99.5% ee (upgraded during trituration).
The hydrogenation conditions developed for 13a were ap-
plied to the corresponding isopropyl ester (13b) and phenol 1b
was obtained in 99% corrected yield and 99% ee (Scheme 5). The
absolute stereochemistry of the stereogenic center in 1a and 1b
was determined via single-crystal X-ray crystallographic analysis
of amide 20. This compound was synthesized by hydrolysis of 1b
under basic conditions (NaOH, MeOH, 50 °C, 84%) followed
by coupling of the resulting carboxylic acid (19) with commer-
cially available (1S,2R)-cis-1-amino-2-indanol (EDCI, HOBT,
NaHCO3, DMF, 45 °C, 74%). A crystal of 20 suitable for the
X-ray diffraction study was provided by recrystallization of the
material in EtOAc/hexane. Acid 19 was converted to 1a via
Fisher esterification. The enantiomer of 1a generated via this
sequence of reactions was the same as that obtained by asym-
metric hydrogenation of 13a. Consequently, the absolute
with LiOiPr as additive and LaCl3 2LiCl as lanthanide source and
3
tertiary alcohol 16b was generated in 50% yield (entry 9). It is
worth noting that the same experiment performed in the absence
of LiOiPr provided 16b in significantly reduced yield (17%, entry
8). Using tert-butyl ester 12c as starting material, the Grignard
addition could be conducted at 22 °C19 and 16c was isolated in
71% yield (entry 10). The transformation could be carried out
with substoichiometric amounts of LaCl3 2LiCl, though the yield
3
of 16c obtained in this instance was considerably reduced (46%,
entry 11 vs 71%, entry 10). The combined yields of products 16
and 17 generated using isopropyl ester 12b or tert-butyl ester 12c
in this transformation were 80% to 94% (entries 8ꢀ11). These
joint recoveries constitute a marked improvement relative to those
achieved utilizing methyl ester 12a for the same reaction.
The elimination to generate asymmetric hydrogenation pre-
cursor 13b proceeded uneventfully employing various acid sources
as described in Table 2. The reaction conditions described in entry
2 (Table 2) were utilized to perform the same transformation
starting with methyl ester 16a to afford 13a (87% yield).
A large collection of ligands (72) was evaluated for the
rhodium-catalyzed asymmetric hydrogenation of alkene 13a
using Rh(COD)2BF4 as catalyst. Four of the ligands provided
>85% conversion and >50% ee (Scheme 4), with Josiphos SL-
J-210-1 providing the highest enantiomeric excess (83%).
Thetransformationwasfurtherexploredwithregardtosolvents,
pressure, additives, and rhodium loadings employing Josiphos
SL-J-210-1 as ligand (Table 3). The choice of solvent proved to
have a significant impact on the enantioselectivity of the hydro-
genation. Relatively low enantiomeric excesses were obtained with
MeOH (79% ee, entry 1) and EtOAc (77% ee, entry 3), whereas
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configuration of the product obtained in this transformation was
shown to be independent of the nature of the ester function of
the starting material.
It is worth noting that the presence of the hydroxyl group in
13a and 13b was essential for the success of the asymmetric
hydrogenation. For example, when the transformation was
performed with a substrate lacking the phenol moiety (21) and
under the same experimental conditions, it failed to reach
completion after 24 h and the product was obtained in only
10% ee (Scheme 6).21
CDCl3) δ 5.3, 26.6, 29.1, 31.7, 41.8, 124.6; HRMS (ESI) calcd for
C7H12NI 237.0014, found 237.0005.
2,2-Dimethylcyclopentanone (3). To a cold (ꢀ20 °C) solution
of n-hexylithium (2.3 M in hexanes, 74.6 mL, 0.18 mol, 2.0 equiv) in
THF (40 mL) was added a solution of 11 (21.0 g, 0.9 mol) in THF
(89 mL) over a period of 20 min (the internal temperature was
maintained below ꢀ5 °C). The reaction mixture was agitated at
ꢀ5 °C for 1 h, and 1.6 M aqueous oxalic acid (112 mL, 0.18 mol, 2.0
equiv) was added over the course of 15 min while the temperature was
maintained below 20 °C. The mixture was agitated at 20 °C for 1 h.
MTBE (110 mL) and DI water (110 mL) were added to the reaction
mixture. The layers were separated. The organic layer was dried
(Na2SO4) and concentrated under reduced pressure. Purification of
the residue by distillation using a Snyder column (300 mmHg, head
temperature 110ꢀ112 °C) afforded 3 as an oil (11.92 g, 81% corrected
yield, 32.4 wt % dodecane in isolated oil): 1H NMR (400 MHz, CDCl3)
δ 1.04 (s, 6 H), 1.80 (t, J = 6.5 Hz, 2 H), 1.50 (quintet, J = 7.4 Hz, 2 H),
2.26 (t, J = 7.6 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 18.7, 23.7,
37.1, 38.5, 44.9, 123.8; HRMS (ESI) calcd for C7H12O 112.0888, found
112.0887.
tert-Butyl 4-Hydroxy-3-iodobenzoate (12c). To a solution of
4-hydroxy-3-iodobenzoic acid (2.5 g, 9.47 mmol) and DMAP (0.06 g,
0.47 mmol) in tert-butyl alcohol (60 mL) was added a solution of DCC
(2.15 g, 10.4 mmol) in THF (20 mL) over a period of 30 min at 22 °C.
The reaction mixture was agitated for 12 h and concentrated under
reduced pressure. Diethyl ether (200 mL) and oxalic acid (2.0 g, 27.0
mmol) were added, and the mixture was filtered through a short silica
pad. The filtrate was washed with saturated aqueous NaHCO3, water,
and brine. The solution was dried (Na2SO4) and concentrated under
reduced pressure. Chromatographic purification (15 g silica gel, 20%
EtOAc/hexanes) of the residual material yielded 2.7 g (89%) of 12c as a
solid: mp 126ꢀ128 °C; 1H NMR (400 MHz, CDCl3) δ 1.58 (s, 9 H),
6.13 (s, 1 H), 6.98 (d, J= 8.0 Hz, 1 H), 7.88 (d, J= 8.0 Hz, 1 H), 8.30 (s, 1 H);
13C NMR (100 MHz, CDCl3) δ 28.2, 81.5, 84.9, 114.5, 126.2, 131.8,
140.1, 158.5, 164.3; HRMS (ESI) calcd for C11H12IO3 318.9831, found
318.9824.
’ CONCLUSION
In summary, a rapid access to chiral phenol 1, a key building
block in the preparation of a series of drugs candidates, was
developed. The strategy includes six chemical steps, and the
target molecule was prepared in 31% overall yield from isobutyr-
onitrile (10). The sequence of reactions features a challenging
Grignard addition conducted in the presence of LaCl3 2LiCl
3
(50% yield using 12b as substrate, 70% yield using 12c as
substrate) as well as a highly enantioselective hydrogenation of
an aryl substituted alkene (99% yield, 99% ee). A novel prepara-
tion of the lanthanide reagent used for the Grignard addition was
developed. The importance of the phenol group to the success of
this asymmetric transformation was discussed.
’ EXPERIMENTAL SECTION
5-Chloro-2,2-dimethylpentanenitrile (14). To a solution of i-
Pr2NH (101.8 mL, 0.72 mol) in THF (680 mL) at 0 °C was added n-
BuLi (2.5 M in hexanes, 288 mL, 0.72 mol). The mixture was cooled to
ꢀ65 °C, and isobutyronitrile (10, 50.0 g, 0.72 mol) was added as a liquid
over the course of 10 min. The reaction mixture was warmed to ꢀ20 °C
over a period of 45 min and cooled to ꢀ78 °C. The resulting slurry was
added (via cannula) over the course of 3 h to an agitated solution of
1-bromo-3-chloropropane (113.9 g, 0.72 mol) in THF (300 mL) at
ꢀ78 °C (internal temperature was maintained below ꢀ68 °C). The
original vessel was rinsed using THF (200 mL), and the rinse solution
was added to the reaction mixture (via cannula). The mixture was
agitated for 10 min at ꢀ70 °C, and DI water (220 mL) was added.
Aqueous HCl (5 M, 215 mL) was added over a period of 10 min while
the internal temperature was maintained below 0 °C. MTBE (250 mL)
was added, the mixture was agitated vigorously, and the layers were
separated. The aqueous phase was extracted with MTBE (100 mL). The
combined organic extracts were washed with saturated aqueous NaH-
CO3 (250 mL), dried (Na2SO4), and concentrated under reduced
pressure. Purification of the residue by distillation (80 to 100 mmHg,
head temperature 175 to 200 °C) afforded 14 as an oil (101.0 g, 96.8%
corrected yield): 1H NMR (400 MHz, CDCl3) δ 1.37 (s, 6 H),
1.67ꢀ1.72 (m, 2 H), 1.94ꢀ2.01 (m, 2 H), 3.59 (t, J = 6.3 Hz, 2 H);
13C NMR (100 MHz, CDCl3) δ 26.6, 28.4, 32.0, 38.4, 44.5, 124.6;
HRMS (ESI) calcd for C7H12N 110.0970, found 110.0959.
5-Iodo-2,2-dimethylpentanenitrile (11). To a solution of 14
(35.4 g, 0.24 mol) in acetone (250 mL) was added NaI (79.8 g, 0.53
mol). The mixture was warmed to reflux, agitated for 18 h, and cooled to
22 °C. The suspension was filtered, and the filtrate was concentrated
under reduced pressure. MTBE (100 mL) was added, and the slurry was
filtered. The filtrate was washed twice with saturated aqueous Na2S2O3
(2 ꢁ 100 mL), dried (Na2SO4), and concentrated under reduced
pressure. Purification of the residue by distillation (1 mmHg, head
temperature 62 to 66 °C) afforded 11 as an oil (49.8 g, 86.2% corrected
yield): 1H NMR (400 MHz, CDCl3) δ 1.37 (s, 6 H), 1.63ꢀ1.67 (m, 2
H), 1.98ꢀ2.05 (m, 2 H), 3.22 (t, J = 6.6 Hz, 2 H); 13C NMR (100 MHz,
LaCl3 2LiCl Solution. To a commercial solution of LiCl (0.5 M in
3
THF, 300 mL) were added dry THF (300 mL) and anhydrous LaCl3
(18.4 g, 0.075 mol) under nitrogen. The suspension was warmed to
reflux and agitated for 12 h (a solution was obtained). The majority of
the THF was distilled (approximately 510 mL) at 760 mmHg. Dry THF
(100 mL) was added, the distillation was continued (another 100 mL of
THF was distilled), and the solution was cooled to 20 °C. The measured
LaCl3 concentration of the solution (volume ∼100 mL) was 0.808 M
(ICP-MS). The measured water content of the solution was 350
ppm (KF). The reagent was stored under nitrogen prior to use.
Methyl 4-Hydroxy-3-(1-hydroxy-2,2-dimethylcyclopentyl)-
benzoate (16a, Entry 7, Table 1). To a cold (ꢀ25 °C) solution of
methyl 4-hydroxy-3-iodobenzoate (12a, 5.0 g, 18.0 mmol) in THF
(30 mL) was added a solution of LiOiPr (2.0 M in THF, 9.9 mL, 19.8
mmol) over a period of 10 min, and the reaction mixture was agitated for
15 min. MeMgCl (2.5 M in THF, 7.9 mL, 19.8 mmol) was added over
the course of 30 min (the internal temperature was maintained below
ꢀ17 °C), and the mixture was agitated at ꢀ25 °C for 30 min. i-PrMgCl
(2.0 M in THF, 9.9 mL, 19.8 mmol) was added over a period of 10 min.
The reaction mixture was agitated for 2 h and cooled to ꢀ32 °C.
In a separate flask, 2,2-dimethylcyclopentanone (3, 2.5 mL, 19.8
mmol) was added to a solution of LaCl3 2LiCl (0.71 M in THF,
3
32.9 mL, 23.4 mmol) at 22 °C. The mixture was agitated for 1 h and
cooled to ꢀ10 °C. The LaCl3 2LiCl solution was added to the Grignard
3
solution via cannula over a period of 1 h (the internal temperature was
maintained below ꢀ20 °C). The reaction mixture was agitated for 1.5 h
at ꢀ20 °C (44% assay yield). Aqueous citric acid (1 M, 25 mL) was
added over the course of 30 min, and the reaction mixture was warmed
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FEATURED ARTICLE
to 22 °C. IPAc (300 mL) and aqueous HCl (1 M, 10 mL) were added
and the layers were separated. The aqueous layer was extracted with
IPAc (200 mL). The combined organic extracts were washed with water
and brine. The organic layer was dried (Na2SO4) and concentrated
under reduced pressure. Chromatographic purification (35 g silica gel,
0ꢀ15% MTBE/heptane) of the residual material was followed by
trituration of the chromatographed product in MTBE (5 mL) and
heptane (100 mL) to yield 16a as a white solid (1.54 g, 32% yield): mp
108ꢀ110 °C; 1H NMR (400 MHz, CDCl3) δ 0.70 (s, 3 H), 1.09 (s, 3
H), 1.59ꢀ1.61 (m, 1 H), 1.87ꢀ1.94 (m, 4 H), 2.79ꢀ2.82 (m, 1 H), 3.21
(s, 1 H), 3.83 (s, 3 H), 6.80 (d, J = 8.0 Hz, 1 H), 7.71 (s, 1 H), 7.76 (d, J =
8.0 Hz, 1 H), 10.19 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ 19.0, 22.3,
25.9, 38.3, 38.6, 47.4, 51.9, 90.4, 117.5, 120.2, 124.9, 130.0, 130.8, 161.8,
167.5; HRMS (ESI) calcd for C15H21O4 265.1440, found 265.1422.
Isopropyl 4-Hydroxy-3-(1-hydroxy-2,2-dimethylcyclopentyl)-
benzoate (16b, Entry 9, Table 1). To a cold (ꢀ5 °C) solution of
isopropyl 4-hydroxy-3-iodobenzoate (12b, 4.0 g, 13.0 mmol) in THF
(25 mL) was added a solution of LiOiPr (2.0 M in THF, 7.9 mL, 15.7
mmol) over a period of 10 min, and the reaction mixture was agitated for
15 min. MeMgCl (2.5 M in THF, 6.3 mL, 15.7 mmol) was added over
the course of 30 min (the internal temperature was maintained below
0 °C), and the mixture was agitated at ꢀ5 °C for 30 min. i-PrMgCl (2.0
M in THF, 9.5 mL, 15.7 mmol) was added over a period of 10 min. The
reaction mixture was agitated for 2 h and cooled to ꢀ20 °C.
added and the layers were separated. The aqueous layer was extracted
with IPAc (200 mL). The combined organic extracts were washed with
water and brine. The organic layer was dried (Na2SO4) and concen-
trated under reduced pressure. Chromatographic purification (25 g silica
gel, 0ꢀ15% MTBE/heptane) of the residual material afforded 16c as a
white solid (2.04 g, 71% yield): mp 154ꢀ156 °C; 1H NMR (400 MHz,
CDCl3) δ 0.73 (s, 3 H), 1.10 (s, 3 H), 1.56 (s, 9 H), 1.61ꢀ1.64 (m, 1 H),
1.86ꢀ1.94 (m, 4 H), 2.80ꢀ2.86 (m, 2 H), 6.81 (d, J = 8.0 Hz, 1 H),
7.73ꢀ7.77 (m, 2 H), 10.04 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ
19.0, 22.4, 25.9, 28.3, 38.3, 38.9, 47.4, 80.6, 90.7, 117.3, 122.3, 124.7,
129.8, 130.6, 161.4, 166.1; HRMS (ESI) calcd for C18H26O4Na
329.1723, found 329.1721.
Isopropyl 3-(5,5-Dimethylcyclopent-1-enyl)-4-hydroxyben-
zoate (13b, Entry 2, Table 2). To a solution of 16b (2.8 g, 9.4 mmol)
in IPAC (10 mL) at 22 °C was added HCl (5 M in IPA, 2.8 mL, 14.1
mmol). The reaction mixture was agitated for 1.5 h, and IPAC (200 mL)
was added. The mixture was washed with water and brine. The organic
layer was dried (Na2SO4) and concentrated under reduced pressure.
Chromatographic purification (25 g silica gel, 20% MTBE/heptane) of
the residual material afforded 13b as a colorless oil (2.3 g, 91% yield): 1H
NMR (400 MHz, CDCl3) δ 1.12 (s, 6 H), 1.35 (d, J = 8.0 Hz, 6 H), 1.92
(t, J = 8.0 H, 2 H), 2.49 (dt, J = 8.0 and 2.4 Hz, 2 H), 5.18ꢀ5.26 (m, 1 H),
5.79 (t, J = 2.4 Hz, 1 H), 6.01 (s, 1H), 6.93ꢀ6.99 (m, 1 H), 7.76ꢀ7.80
(m, 1 H), 7.85ꢀ7.92 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 22.0,
27.2, 30.1, 40.6, 48.3, 67.9, 114.7, 122.5, 123.5, 130.4, 130.9, 131.6, 146.9,
157.3, 166.0; HRMS (ESI) calcd for C17H23O3 275.1647, found
275.1630.
In a separate flask, 2,2-dimethylcyclopentanone (3, 2.0 mL, 15.7
mmol) was added to a solution of LaCl3 2LiCl (0.71 M in THF,
3
23.9 mL, 17.0 mmol) at 22 °C. The mixture was agitated for 1 h and
cooled to ꢀ10 °C. The LaCl3 2LiCl solution was added to the Grignard
Methyl 3-(5,5-Dimethylcyclopent-1-enyl)-4-hydroxybenzoate
(13a). The procedure reported to prepare 13b (entry 2, Table 2) was
utilized. 16a (1.50 g, 5.7 mmol) replaced 16b as starting material, and
13a was isolated as white solid (1.22 g, 87% yield): mp 92ꢀ94 °C; 1H
NMR (400 MHz, CDCl3) δ 1.12 (s, 6 H), 1.93 (t, J = 8.0 H, 2 H), 2.50
(dt, J = 8.0 and 2.4 Hz, 2 H), 3.88 (s, 3 H), 5.80 (t, J = 2.4 Hz, 1 H), 5.89
(s, 1H), 6.95ꢀ6.99 (m, 1 H), 7.76ꢀ7.80 (m, 1 H), 7.86ꢀ7.92 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 27.1, 30.0, 40.5, 48.2, 51.8, 114.7, 121.5,
123.5, 130.5, 130.9, 131.5, 146.7, 157.5, 166.9; HRMS (ESI) calcd for
C15H19O3 247.1334, found 247.1339.
3
solution via cannula over a period of 1 h (the internal temperature was
maintained below ꢀ10 °C). The reaction mixture was agitated for 1.5 h
at ꢀ10 °C. Aqueous citric acid (1 M, 20 mL) was added over the course
of 30 min, and the reaction mixture was warmed to 22 °C. IPAc
(300 mL) and aqueous HCl (1 M, 10 mL) were added, and the layers
were separated. The aqueous layer was extracted with IPAc (200 mL).
The combined organic extracts were washed with water and brine. The
organic layer was dried (Na2SO4) and concentrated under reduced
pressure. Chromatographic purification (30 g silica gel, 0ꢀ15% MTBE/
heptane) of the residual material was followed by trituration of the
chromatographed product in MTBE (5 mL) and heptane (100 mL) to
yield 16b as a white solid (1.90 g, 50% yield): mp 128ꢀ130 °C; 1H NMR
(400 MHz, CDCl3) δ 0.73 (s, 3 H), 1.11 (s, 3 H), 1.34 (d, J = 8.0 Hz, 6
H), 1.59ꢀ1.65 (m, 1H), 1.88ꢀ1.92 (m, 4H), 2.42 (s, 1H), 2.83ꢀ2.90
(m, 1 H), 5.14ꢀ5.24 (m, 1 H), 6.84 (d, J = 8.0 Hz, 1 H), 7.77 (s, 1 H),
7.83 (d, J = 8.0 Hz, 1 H), 9.96 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ
19.0, 22.0, 22.3, 25.9, 38.3, 38.8, 47.4, 68.1, 90.6, 117.4, 121.1, 124.8,
130.0, 130.6, 161.3, 166.4; HRMS (ESI) calcd for C17H25O4 293.1753,
found 293.1733.
(R)-Methyl 3-(2,2-Dimethylcyclopentyl)-4-hydroxybenzo-
ate (1a, Entry 10, Table 3). A solution of 13a (99.7 g, 0.41 mol),
Rh(COD)2BF4 (165 mg, 0.41 mmol), and Josiphos SL-J-210-1 (L4)
(364 mg, 0.44 mmol) in THF (300 mL) was charged to a Parr reactor.
The reactor was purged with argon once and with H2 three times (200
psig). The contents of the reactor were agitated at 20 °C for 30 min
under an atmosphere of H2 (200 psig). The solution was purged with
N2, filtered through silica gel (20 g), and concentrated under reduced
pressure. The residue was triturated (5% EtOAc/heptane, 120 mL) and
filtered to afford 1a as a solid (95.0 g, 96% yield, 99.5% ee): chiral SFC
analysis, OD-H column, 250 mm ꢁ 4.6 mm, 5 μm; MeOH, 252 nm, S
enantiomer at 3.07 min, R enantiomer (1a) at 3.38 min; mp
tert-Butyl 4-Hydroxy-3-(1-hydroxy-2,2-dimethylcyclopentyl)-
benzoate (16c, Entry 10, Table 1). To a cold (0 °C) solution of tert-
butyl 4-hydroxy-3-iodobenzoate (12c, 3.0 g, 9.4 mmol) in THF (20 mL)
was added a solution of LiOiPr (2.0 M in THF, 5.2 mL, 10.3 mmol) over
a period of 10 min, and the reaction mixture was agitated for 15 min.
MeMgCl (2.5 M in THF, 4.1 mL, 10.3 mmol) was added over the course
of 30 min (the internal temperature was maintained below 5 °C), and
the mixture was agitated at 0 °C for 30 min. i-PrMgCl (2.0 M in THF,
9.5 mL, 15.7 mmol) was added over a period of 10 min. The reaction
mixture was warmed to 22 °C, agitated for 2 h, and cooled to 0 °C.
In a separate flask, 2,2-dimethylcyclopentanone (3, 1.3 mL, 10.3
127ꢀ129 °C; [R]2D3 þ47.5 (c 1.00, MeOH); H NMR (400 MHz,
1
CDCl3) δ 0.70 (s, 3H), 1.04 (s, 3H), 1.38ꢀ2.21 (m, 6H), 3.12ꢀ3.26 (m,
1H), 3.89 (s, 3H), 6.08 (s, 1H), 6.83 (d, J = 8.4 Hz, 1H), 7.77 (dd, J = 8.3,
1.4 Hz, 1H), 7.90 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 22.0, 23.5,
29.0, 30.5, 41.6, 43.0, 47.2, 52.0, 115.2, 121.7, 128.7, 129.0, 131.2, 159.0,
167.8; HRMS (ESI) calcd for C15H21O3 249.1491, found 249.1467.
(R)-Isopropyl 3-(2,2-Dimethylcyclopentyl)-4-hydroxyben-
zoate (1b). The procedure reported to prepare 1a was utilized. 13b
(1.00 g, 3.6 mmol) replaced 13a as starting material, and 1b was isolated
as white solid (0.99 g, 99% yield, 99% ee): chiral HPLC analysis: OD-H
column, 250 mm ꢁ 4.6 mm, 5 μm; 1.5 mL/min; 5 μL; 25 °C; 3% IPA/n-
hexane, isocratic; 254 nm, S enantiomer at 7.40 min, R enantiomer (1b)
at 7.88 min; mp 135ꢀ137 °C; [R]2D3 þ55.0 (c 1.00, MeOH); 1H NMR
(400 MHz, CDCl3) δ 0.71 (s, 3H), 1.04 (s, 3H), 1.35 (dd, J = 6.2, 1.4 Hz,
6H), 1.52ꢀ1.68 (m, 2H), 1.68ꢀ1.91 (m, 2H), 1.92ꢀ2.17 (m, 2H), 3.17
mmol) was added to a solution of LaCl3 2LiCl (0.78 M in THF,
3
15.7 mL, 12.2 mmol) at 22 °C. The mixture was agitated for 1 h. The
LaCl3 2LiCl solution was added to the Grignard solution via cannula
3
over a period of 10 min. The reaction mixture was warmed to 22 °C and
agitated for 1.5 h. Aqueous citric acid (1 M, 20 mL) was added over the
course of 30 min. IPAc (300 mL) and aqueous HCl (1 M, 30 mL) were
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FEATURED ARTICLE
(dd, J = 8.0, 10.1 Hz, 1H), 5.22 (septet, J = 6.2 Hz, 1H), 5.83 (s, 1H),
6.81 (d, J = 8.4 Hz, 1H), 7.76 (dd, J = 2.1, 8.4 Hz, 1H), 7.90 (d, J = 2.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 22.0, 23.5, 29.0, 30.5, 41.6, 43.0,
47.3, 68.1, 115.0, 122.6, 128.5, 128.8, 131.1, 158.3, 166.66; HRMS (ESI)
calcd for C17H25O3 277.1804, found 277.1822.
’ ASSOCIATED CONTENT
Supporting Information. Copies of H and 13C NMR
1
S
b
spectra as well as the CIF for compound 20. This material is
available free of charge via the Internet at http://pubs.acs.org.
3-[(R)-2,2-Dimethylcyclopentyl]-4-hydroxy-N-[(1S,2R)-
2-hydroxy-2,3-dihydro-1H-inden-1-yl]benzamide (20). To a
solution of 1b (0.5 g, 1.8 mmol) in MeOH (5 mL) was added aqueous
NaOH (5 M, 3.7 mL, 18.1 mmol). The reaction mixture was warmed to
60 °C, agitated for 16 h, and cooled to 22 °C. Water (20 mL) and
aqueous HCl (5 M, 4 mL, 20 mL) were added (final pH = 1), and the
mixture was extracted with MTBE (2 ꢁ 75 mL). The combined organic
extracts were washed with water and brine. The organic layer was dried
(Na2SO4) and concentrated under reduced pressure.
The residue (crude 19) was dissolved in DMF (5 mL) at 22 °C.
NaHCO3 (0.7 g, 8.1 mmol), (1S,2R)-cis-1-amino-2-indanol (0.4 g, 2.7
mmol), EDCI (0.51 g, 2.7 mmol), and HOBt (0.13 g, 0.27 mmol) were
added to the solution. The mixture was warmed to 50 °C, agitated for 16
h, and cooled to 22 °C. EtOAc (100 mL) was added, and the mixture was
washed with saturated aqueous NaHCO3, aqueous HCl (5 M, 50 mL),
water (50 mL), and brine. The organic layer was dried (Na2SO4) and
concentrated under reduced pressure. Chromatographic purification
(10 g silica gel, 10ꢀ50% EtOAc/hexanes) of the residual material
afforded crude 20 as an oil. The oil was dissolved in EtOAc (5 mL),
and hexanes was added at 22 °C over the course of 45 min. The
suspension was filtered, and the cake was dried on frit to afford 20 as a
white solid (0.47 g, 62% yield): mp 204ꢀ206 °C; 1H NMR (400 MHz,
CD3OD) δ 0.74 (s, 3 H), 0.87ꢀ0.93 (m, 1 H), 1.06 (s, 3 H), 1.26ꢀ1.36
(m, 1 H), 1.57ꢀ1.68 (m, 2 H), 1.72ꢀ2.03 (m, 3 H), 2.09ꢀ2.20 (m, 1
H), 3.00 (d, J = 16.0 Hz, 1 H), 3.21 (dd, J = 20 and 8.0 Hz, 1 H),
3.39ꢀ3.42 (m, 1 H), 4.66 (t, J = 4 Hz, 1 H), 5.56 (d, J = 8.0 Hz, 1 H), 6.84
(d, J = 8.0 Hz, 1 H), 7.23ꢀ7.30 (m, 4 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.80
(d, J = 4.0 Hz, 1 H); 13C NMR (100 MHz, CD3OD) δ 23.2, 24.3, 29.6,
31.5, 41.0, 42.7, 43.9, 47.8, 59.1, 74.3, 115.6, 125.4, 125.5, 126.2, 127.2,
128.0, 129.0, 129.9, 130.7, 141.8, 142.6, 160.7, 170.6; HRMS (ESI) calcd
for C23H28NO3 366.2069, found 366. 2062.
Methyl 3-(5,5-Dimethylcyclopent-1-enyl)benzoate (21).
To a solution of i-Pr2NH (4.58 mL, 32.7 mmol) in THF (40 mL) at
ꢀ78 °C was added n-BuLi (13.1 mL, 32.7 mmol, 2.5 M in Hexanes) over
a period of 10 min. 2,2-Dimethylcyclopentanone (3, 3.5 g, 31.2 mmol)
was added over a period of 15 min, and the solution was agitated at
ꢀ78 °C for 30 min. N-Phenylbis(trifluoromethanesulfonimide) (11.1 g,
31.2 mmol) was added, and the reaction mixture was warmed to 20 °C
over a period of 3 h. The mixture was concentrated under reduced
pressure, and MTBE (100 mL) was added. The suspension was filtered,
and the filtrate was concentrated under reduced pressure. Chromato-
graphic purification (40 g silica gel, 2% EtOAc/hexanes) of the residual
material afforded 4 (3.8 g, 50% yield) as a colorless oil.
Vinyl trifluoromethanesulfonate 4 (1.2 g, 5 mmol) was dissolved in
dioxane (10 mL) and water (10 mL) at 20 °C. 3-(Methoxycarbonyl)-
phenylboronic acid (1.1 g, 6 mmol), K3PO4 (3.0 g, 15.0 mmol), and
PdCl2[(p-Me2NPh)P-t-Bu2]2 (71 mg, 0.1 mmol) were added, and the
suspension was degassed using argon. The reaction mixture was warmed
to 80 °C, agitated for 30 min, and cooled to 20 °C. MTBE was added
(30 mL), and the phases were separated. The organic layer was dried
(Na2SO4) and concentrated under reduced pressure. Chromatographic
purification (silica gel, 0ꢀ10% EtOAc/hexanes) of the residual material
afforded 21 (0.8 g, 89% yield) as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 1.20 (s, 6H), 1.87 (t, J = 7.0 Hz, 2H), 2.38 (td, J = 2.4, 7.0 Hz,
2H), 3.90 (s, 3H), 5.79 (t, J = 2.4 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.51
(t, J = 9.5 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.96ꢀ8.04 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 26.7, 28.8, 41.6, 46.0, 51.4, 127.0, 127.3,
127.8, 128.0, 129.2, 131.2, 137.6, 150.5, 166.5; HRMS (ESI) calcd for
C15H19O2 231.1385, found 231.1382.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: scaille@amgen.com.
’ ACKNOWLEDGMENT
We wish to dedicate this manuscript to the career and legacy of
Professor Edward Piers (1938ꢀ2010, University of British
Columbia). We thank Jack Hu, Kevin Turney, and Jenny Chen
for analytical support. We thank Richard Staples for performing
the single-crystal X-ray analysis included.
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(13) Under nonoptimized distillation conditions, dodecane was only
partially separated from 3 and the isolated material contained 32.4 wt%
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of dodecane. High purity 3 (>96 wt%) from Aldrich was utilized to
screen the lanthanide-catalyzed Grignard addition reaction.
(14) Although n-butyllithium was also a suitable mediator, the
byproduct octane (bp 126 °C) could not be readily separated from 3.
(15) When benzaldehyde was added to the Grignard reagent instead
of ketone 3, alcohol 18 was isolated in 72% yield.
(16) Conlon, D. A.; Kumbe, D.; Moeder, C.; Hardiman, M.; Hutson,
G.; Sailer, L. Adv. Synth. Catal. 2004, 346, 1307–1315.
(17) Due to the necessity to filter these solids, the stoichiometry of
Ce relative to that of Li in the final lanthanide solution cannot be
assessed with certainty.
(18) Concentrations of La and Ce were measured by ICP-MS.
(19) The Grignard addition performed at 23 °C with substrates 12a
and 12b produced complex mixtures of products.
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P. N.; Krska, S. W. J. Org. Chem. 2008, 73, 1639–1642.
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