Efficient and highly enantioselective aerobic oxidation-michael- carbocyclization cascade transformations by integrated Pd(0)-CPG nanoparticle/chiral amine relay catalysis

Article abstract of DOI:10.1055/s-0033-1340883

A series of highly diastereo- and enantioselective aerobic oxidation-Michael-carbocyclization cascade transformations by integrated heterogeneous Pd(0)-CPG nanoparticle/chiral amine relay catalysis are disclosed. The heterogeneous Pd(0)-CPG nanoparticle catalysts were efficient for both the sequential aerobic oxidation and dynamic kinetic asymmetric Michael- carbocyclization transformations, resulting in 1) oxidation of a variety of allylic alcohols to enals and 2) formation of cyclopentenes containing an all-carbon quaternary stereocenter in good to high yields with up to 20:1 dr and 99.5:0.5 er. Georg Thieme Verlag Stuttgart.New York.

Full text of DOI:10.1055/s-0033-1340883

SPECIAL TOPIC
▌1303
special topic
Efficient and Highly Enantioselective Aerobic Oxidation–Michael–Carbocy-
clization Cascade Transformations by Integrated Pd(0)-CPG Nanoparticle/
Chiral Amine Relay Catalysis
Integrated Heterogeneous Pd(0)-CPG Nanoparticle Catalysts
Luca Deiana,a Lorenza Ghisu,a Oscar Córdova,a Samson Afewerki,b Renyun Zhang,b Armando Córdova*a,b
a
Department of Organic Chemistry, The Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
b
Department of Applied Science and Design, Holmgatan 10, 851 70 Sundsvall, Sweden
Fax +46(15)4908; E-mail: armando.cordova@miun.se; E-mail: acordova@organ.su.se
Received: 08.01.2014; Accepted: 08.02.2014
highly selective fashion from simple alcohols using inte-
Abstract: A series of highly diastereo- and enantioselective aerobic
grated heterogeneous transition metal/chiral amine multi-
oxidation–Michael–carbocyclization cascade transformations by
ple relay catalysis (Scheme 1).9 Higher levels of
molecular complexity were defined as how many times
integrated heterogeneous Pd(0)-CPG nanoparticle/chiral amine re-
lay catalysis are disclosed. The heterogeneous Pd(0)-CPG nanopar-
ticle catalysts were efficient for both the sequential aerobic the heterogeneous metal catalyst was present or took part
oxidation and dynamic kinetic asymmetric Michael–carbocycliza-
tion transformations, resulting in 1) oxidation of a variety of allylic
alcohols to enals and 2) formation of cyclopentenes containing an
2 two steps, level 3 three steps, etc. The proof of concept
all-carbon quaternary stereocenter in good to high yields with up to
20:1 dr and 99.5:0.5 er.
in the one-pot catalytic cascade sequences. For example,
at level 1 the metal catalyst was present in one step, level
was demonstrated by using heterogeneous Pd(0)-amino-
propyl-mesocellular foam (AMP-MCF) nanoparticles10
Key words: asymmetric cocatalysis, aerobic oxidations, relay ca-
as the co-catalysts. However, the integrated heteroge-
talysis, integrated heterogeneous catalysis, integrated homogeneous
catalysis, quaternary stereocenters
neous metal/amine relay catalysis strategy is not only re-
stricted to this type of support. Thus, it is of high interest
to investigate and find other catalytic systems with good
activity and selectivity that are easy to separate and recy-
Typically, chemical synthesis operates through stepwise
processes where each product intermediate is isolated and
cle for this multi-catalysis concept.11
purified prior to the target product molecule.1 In compar-
ison, the biosynthesis of the cell’s molecules is performed
by multi-enzymatic cascade systems.2 This has inspired
researchers and led to the development of elegant tandem
and cascade synthesis.3 Recently, relay catalysis based on
multi-catalyst systems have been applied for these type of
transformations.2,4 However, a challenge is the develop-
ment of catalytic asymmetric relay catalysis (ARC). In
this context, the combination of metal and organic cata-
lysts has begun to receive increased attention.5,6 Here the
combined and sometimes synergistic catalysis by a metal
complex and an organic molecule is a powerful approach
that can improve and importantly enable transformations,5
which are not possible by a single catalytic entity. Yet
there are challenges and limitations related to compatibil-
ity problems such as different reactivity and inactivation.
A way to circumvent these obstacles would be as in Na-
ture by compartmentalization such as site-isolation via
heterogeneous reaction conditions and performing cataly-
sis in sequential steps.7 For example, if the metal co-cata-
lysts were supported on a solid support they could be
recycled, which would prevent contamination and allow
for ‘green’8 chemical synthesis. We recently demonstrat-
ed a versatile strategy for the eco-friendly synthesis of
valuable molecules and expansion of chemical space in a
Porous glasses have a high mechanical, chemical, and
thermal stability. They also have a variable manufacturing
of pore sizes with a small pore size distribution and can be
produced in different shapes. In this context, controlled
pore glass (CPG) is widely used as a carrier for solid-
phase synthesis of nucleotides.12 It is also used in formu-
lations of dental composites and as a carrier in affinity pu-
rification of antibodies. However, there are a few limited
examples of the use of CPGs as supports for a noncova-
lently bound Pd complex13 or Pd particles.14 Based on the
advantages of using CPG as a support in chemistry and
engineering and our research interest in sequential and
synergistic metal/amine catalysis,15 we became interested
in whether a CPG-supported Pd nanoparticle catalyst
could act in concert with a chiral amine co-catalyst for the
application in multiple ARC of complex molecules. In
particular, the enantioselective construction of com-
pounds with an all-carbon stereocenter would be chal-
lenging.16 Herein, we disclose efficient aerobic oxidation–
Michael–carbocyclization cascade reactions by integrated
heterogeneous Pd(0)-CPG nanoparticle/chiral amine mul-
tiple relay catalysis for the highly enantioselective synthe-
sis of cyclopentenes with adjacent tertiary and all-carbon
quaternary stereocenters.
In initial experiments, we prepared different Pd(0)-CPG
nanoparticles (see experimental for details). The amounts
of immobilized Pd species were determined by elemental
analysis using Inductively Coupled Plasma-Optical Emis-
sion Spectroscopy (ICP-OES) technique [e.g., Pd(0)-
Amp-CPG, Pd = 2.18 wt%]. The sizes of the Pd-nanopar-
SYNTHESIS 2014, 46, 1303–1310
Advanced online publication: 17.03.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1340883; Art ID: SS-2014-C0014-OP
© Georg Thieme Verlag Stuttgart · New York

1304
L. Deiana et al.
SPECIAL TOPIC
etc.
etc.
level X + 1
E2
O
increasing levels of
stereochemical diversity
E3
O
R
Nu1
Nu2
R
Nu
Nu
complex molecules
complex molecules
level X
cat. amine
Nu2 and E3
cat. amine
Nu
1 and E2
M
level X+1
level X
Nu
R2
O
R1
O
O
E
E
O
R
level 2
Nu
OH
Nu
R1
R
Nu
complex molecules
complex molecules
cat. amine
Nu
level 2
level 1
cat. amine
Nu and/or E
recycling
M
R
O
level 1
M
Nu = nucleophile
E = electrophile
R = alkyl, aryl, allyl or cinnamoyl
O2
R
OH
Scheme 1 Integrated heterogeneous metal/chiral amine multiple ARC
ticles were 3–5 nm as determined by transmission electron (Scheme 2). In comparison to Pd(0)-Amp-MCF (entry
microscopy (TEM). With these Pd(0)-CPG nanoparticles 8),9 significant rate acceleration was observed for both the
in hand, their ability to catalyze the aerobic oxidation of aerobic oxidation of 1a to 2a and conversion of 2a to 4a.
cinnamyl alcohol 1a in toluene at 70 °C to aldehyde 2a Thus, the reaction time for the whole aerobic oxidation–
followed by its co-catalytic Michael–carbocyclization17 Michael–carbocyclization cascade sequence could be re-
with propargylic ester 3 in the presence of chiral amine 518 duced with up to 20 hours (from 24 to 4 h). The Pd(0)-
were investigated (Table 1, Scheme 2, see Supporting In- Amp-CPG and Pd(0)-CPG-Hybrid VBC nanoparticles
formation for experimental details). The later cascade step catalyzed the aerobic oxidation with the fastest rates (en-
is
a
dynamic kinetic asymmetric transformation tries 3 and 5). We also found that using Pd(0)-CPG
(DYKAT), which proceeds via a reversible amine-cata- nanoparticles, which had been additionally washed with
lyzed Michael reaction via product intermediate 6a fol- MeOH and CH2Cl2 after their final preparation slightly
lowed by the irreversible synergistically metal/chiral improved the stereoselectivity of the cascade sequence
amine co-catalyzed carbocyclization to give 4a (Scheme (entries 4 and 6). A clear cooperative affect was observed
2).17
since no carbocyclization product 4a was formed without
both the presence of 5 and Pd-CPG (entries 9 and 10). The
results from the screening made us investigate the scope
of the integrated Pd(0)-CPG nanoparticle/chiral amine ca-
talysis for a set of alcohols 1 using Pd(0)-Amp-CPG,
To our delight, all of the investigated Pd(0)-CPG nanopar-
ticles were efficient catalysts for the conversion of 1a to
2a (Table 1, entries 1–7). Moreover, they were highly ef-
ficient co-catalysts for the synergistic carbocyclization of
chiral enyne Ia to 4a via Michael adduct 6a and 2a
Synthesis 2014, 46, 1303–1310
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Integrated Heterogeneous Pd(0)-CPG Nanoparticle Catalysts
1305
Table 1 Pd(0)-CPG-Nanoparticle Screeninga
Pd(0)
nanoparticles
(5–6 mol%)
5
O
(20 mol%)
r.t., 3.5–4 h
Ph
O
Ph
OH
Ph
O2, toluene
70 °C, 1–2 h
NC
CO2Me
2a
CN
1a
MeO2C
3
4a
Aerobic oxidation
Michael–carbocyclization
Entry
Pd(0)-nanoparticle
Pd(0)-CPG-Hybrid
Pd(0)-CPG-COPO
Pd(0)-Amp-CPG
Time (h)
Conv. (%)b
Time (h)
Yield (%)c
drb
erd
1
2
2
2
1
1
1
1
1
7
1
1
7
100
100
100
100
100
100
100
100
100
100
100
4
3
65
60
60
60
59
69
62
71
–
15:1
17:1
16:1
18:1
15:1
17:1
19:1
16:1
–
97.5:2.5
98:2
3
4
97:3
4
Pd(0)-Amp-CPGe
Pd(0)-CPG-Hybrid-VBC
Pd(0)-CPG-Hybrid-VBCe
Pd(0)-Amp-CPGe,f
Pd(0)-Amp-MCF
3.5
3
98.5:1.5
97.5:2.5
98:2
5
6
3
7
3.5
17
17g
17h
7
98:2
8
97:3
9
Pd(0)-Amp-CPGe
Pd(0)-Amp-CPGe
Pd(0)-Amp-CPGe,i
–
10
11
–
–
–
65
17:1
98.5:1.5
a To a suspension of Pd(0)-CPG-catalyst (5 mol% to the alcohol) in toluene (0.5 mL) placed in a vial was added 1a (0.24 mmol, 1.2 equiv). The
vial was capped, evacuated, and an O2 balloon was connected to the reaction vessel. The reaction mixture was stirred at 70 °C for the time shown
in Table 1. Next, the mixture was cooled to r.t., followed by the addition of 3 (0.2 mmol, 1 equiv) and 5 (20 mol%) and stirred for the time
shown in Table 1.
b Determined by 1H NMR analysis of the crude reaction mixture.
c Isolated yield of pure 4a.
d Determined by chiral-phase HPLC analysis.
e Further washed (3 × MeOH, 3 × CH2Cl2) and dried overnight under vacuum.
f Toluene: 1 mL.
g No chiral amine 5 was added.
h The Pd-CPG-catalyst was removed after formation of 2a.
i Pd(0)-CPG-catalyst (1 mol% to the alcohol).
which had been extra washed, and 5 as co-catalysts in tol- practical applications. Thus, we investigated the possibil-
uene. The results are depicted in Table 2.
ity of recycling the Pd(0)-Amp-CPG nanoparticle catalyst
after the completed multiple ARC (Table 3).
The Pd(0)/5-catalyzed aerobic oxidation–Michael–carbo-
cyclization cascade transformations were highly enantio- Satisfyingly, the catalytic relay sequences displayed ex-
selective for all the cases investigated and the cellent recyclability both in terms of yield and stereoselec-
corresponding cyclopentenes 4 with an all-carbon quater- tivity. It is noteworthy that no leaching of the metal
nary stereocenter were isolated in good to high yields with catalyst was observed. However, we noticed that the reac-
up to 20:1 dr and 99.5:0.5 er. The catalytic aerobic oxida- tion rates slightly decreased for cycles 4 and 5 while the
tion of enals 1 was finished within five hours except when yields of 4a somewhat increased. The latter could be due
1g and 1h were used as the starting materials (Table 2, en- to the grinding of the Pd-CPG particles during the vigor-
tries 7 and 9). In particular, the oxidation of 1g took time ous stirring with a magnetic stir-bar, which can result in
(entry 7). However, the aerobic oxidation of 1g with collapse of the pore structures of the CPG particles. In
Pd(0)-Amp-CPG as catalyst was significantly faster as fact, Prime Synthesis is not using this type of stirring in
compared with Pd(0)-Amp-MCF (entry 7 vs 11). The syn- their preparation of commercially available CPGs due to
ergistic Michael–carbocyclization step of the sequence this reason. The stereochemical outcome of the catalytic
was efficient and the reaction was complete within five relay sequence is in accordance with the homogeneous
hours at the selected reaction conditions. The recycling of Pd/chiral amine co-catalyzed dynamic Michael–carbocy-
heterogeneous catalysts is an important factor for their clization cascade reaction.17 Thus, the utilization of 5 as
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1303–1310

1306
L. Deiana et al.
SPECIAL TOPIC
CO2Me
NC
Ph
O
6a
CO2Me
X
N
M
NC
Ph
M
4a
N
Ph
CN
Ia
fast
X
M
MeO2C
cat. 5
+
IIa
2a
1a
3
O2
CN
X
MeO2C
Ph
N
M
M
N
ent-4a
Ph
slow
Ib
X
CO2Me
NC
IIb
CN
MeO2C
Ph
O
ent-6a
Scheme 2 The metal/chiral amine co-catalyzed aerobic oxidation–Michael–carbocyclization cascade synthesis of 4a from 1a
the amine catalyst in combination with the Pd(0)-Amp- They can also act as efficient nanoparticle catalysts for
CPG catalyst provides carbocycles (1R,2R)-4 (R = aryl) nonmulti-catalytic transformations in organic synthesis as
with an R-configuration at C-1 and C-2, respectively, demonstrated by the Pd(0)-CPG catalyzed aerobic oxida-
while the intermediate Michael adducts 6 were nearly ra- tion of allylic alcohols. Studies towards these research
cemic. Accordingly, we propose that the reaction proceed lines and the development of other heterogeneous metal
via synergistically Lewis acid and enamine dual-activated catalyst systems for integrated transition metal/chiral
transition state IIa over IIb (Scheme 2) followed by hy- amine multiple relay catalysis are ongoing in our labora-
drolysis, protonation, and isomerization to give 4a in ex- tories and will be reported in due course.
cellent ratios over ent-4a, respectively.
In conclusion, highly diastereo- and enantioselective aer-
obic oxidation–Michael–carbocyclization cascade se-
quences by integrated heterogeneous Pd(0)-CPG
nanoparticle/chiral amine relay catalysis were developed.
The heterogeneous Pd(0)-CPG nanoparticle catalysts
were excellent catalysts for both steps of the catalytic re-
lay sequence. Thus, different allylic alcohols were oxi-
dized to enals and directly converted to cyclopentenes
containing an all-carbon quaternary stereocenter in good
to high yields with up to 20:1 dr and 99.5:0.5 er in one pot.
Moreover, the metal catalyst can be recycled several times
without any significant decrease in stereoselectivity of the
reaction sequence, activity, or leaching of metal into solu-
tion, making the protocol highly stereoselective, econom-
ical, and environmentally friendly. Another important
aspect of this investigation is that the Pd(0)-CPG nanopar-
ticles that were prepared here are not only efficient cata-
lysts for the concept of integrated heterogeneous
transition metal/chiral amine multiple relay catalysis.
All chemicals, unless otherwise noted, were purchased from com-
mercial sources. The control pore glass supports were obtained
from Prime Synthesis Ltd. H NMR spectra were recorded on a
1
Bruker Avance 500 (500 MHz) spectrometer or Bruker Avance II
spectrometer (400 MHz). Chemical shifts are reported in ppm from
TMS with the solvent resonance resulting from incomplete deuteri-
um incorporation as the internal standard (CDCl3: δ = 7.26 ppm).
Data are reported as follows: chemical shift, multiplicity (standard
abbreviations), coupling constants (Hz), integration. 13C NMR
spectra were recorded on a Bruker Avance 500 (125.8 MHz) spec-
trometer or Bruker Avance II spectrometer (400 MHz) spectrometer
with complete proton decoupling. Chemical shifts are reported in
ppm from TMS with the solvent resonance as the internal standard
(CDCl3: δ = 77.26 ppm). High-resolution mass spectrometry was
performed on a Agilent Technologies 6520-Q-TOF ESI-MS (posi-
tive mode) at the Stockholm University or Mid-Sweden University
Mass Spectrometry Facility. Enantiomer ratios were determined by
HPLC [Chiral Agilent Technologies Chiralpak OD, OJ-H, AS col-
umn, or Chiralcel OD-R column (4.6 mm × 250 mm)] in compari-
son with authentic racemic materials. Optical rotations were
measured on a PerkinElmer 341 Polarimeter. Unless otherwise not-
ed, all reactions were performed with distilled solvents under an at-
mosphere of N2 in oven-dried (135 °C) or flame-dried glassware
Synthesis 2014, 46, 1303–1310
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Integrated Heterogeneous Pd(0)-CPG Nanoparticle Catalysts
1307
Table 2 The Scope of the Cocatalytic Aerobic Oxidation–Michael–Carbocyclization Relay Sequencea
5
Pd(0)-Amp-CPG
(6 mol%)
O
(20 mol%)
r.t., 2.3–5 h
R
R
OH
O
R
O2, toluene
70 °C, 1–48 h
NC
CO2Me
CN
2
1
MeO2C
3
4
Aerobic oxidation
Michael–Carbocyclization
Entry
1
R
Time (h)
Conv. (%)b
Product
4a
Time (h)
Yield (%)c
drb
erd
Ph
1
100
5
67
57
63
63
67
68
52
81
63
69
52
17:1
16:1
16:1
6:1
98.5:1.5
98:2
2
4-O2NC6H4
4-MeC6H4
2-ClC6H4
3-O2NC6H4
n-Bu
2
100
4b
4c
2.5
2.3
2.3
2.5
2.5
2
3
1
100
98:2
4
1.5
5
100
4d
4e
97.5:2.5
98:2
5
100
15:1
5:1
6e
7f
4
100
4f
98:2
4-BrC6H4
n-Pr
48
4.5
24
1
81
4g
12:1
4:1
99:1
8e
9e
10
11g
100
4h
4i
3
98.5:1.5
99.5:0.5
97.5:2.5
99.5:0.5
100
3
7:1
4-MeOC6H4
4-BrC6H4
100
4j
3
20:1
12:1
120
75
4g
16
a To a suspension of Pd(0)-Amp-CPG (6 mol% Pd to 1, 36 mg) in toluene (0.5 mL) placed in a microwave vial was added alcohol 1 (0.12 mmol,
1.2 equiv). The vial was capped, evacuated, and an O2 balloon was connected to the reaction vessel. The reaction mixture was stirred at 70 °C
for the time shown in Table 2. Next, the mixture was cooled to r.t. Propargyl derivative 3 (0.1 mmol, 1 equiv) and the chiral amine 5 (20 mol%)
were added and the reaction mixture was vigorously stirred for the time shown in Table 2.
b Determined by 1H NMR analysis of the crude reaction mixture.
c Isolated yield of pure 4.
d Determined by chiral-phase HPLC analysis.
e Compound 1 (0.14 mmol) and Pd(0)-Amp-CPG (5 mol%, 36 mg).
f Pd(0)-Amp-CPG (10 mol% to 1g).
g Pd(0)-Amp-MCF (10 mol% to 1g).
with standard vacuum line techniques. The Pd catalyst on the sup-
port was characterized for Pd loading by Inductively Coupled Plas-
ma (ICP; Mikroanalytisches Laboratorium Kolbe, Germany).
Elemental analyses on the Pd contents of the Pd-Amp-CPG were
carried out by Medac LTD Analytical and chemical consultancy
services (UK) by ICP-OES. The samples for TEM imaging were
done by sonicating the Pd-Amp-CPG particles in EtOH, and then
dropping the suspension on a standard TEM grip, and letting it dry
in air. The TEM was done on a JEOL 2000FX (JEOL) microscope
at an accelerate voltage of 160 KV (Figure 1S and 2S, see Support-
ing Information).
night under vacuum. Next, the dry Pd(II)-CPG catalyst was sus-
pended in deionized H2O (30 mL) followed by the slow addition of
NaBH4 (15 equiv), which had been dissolved in deionized H2O (15
mL) at r.t. After stirring for 30 min, the obtained Pd(0)-CPG cata-
lyst was transferred to a 45 mL centrifuge vial, washed [3 × H2O (40
mL), 3 × acetone (40 mL)], and dried overnight under vacuum.
Some of the catalysts were also further washed [3 × MeOH (40
mL), 3 × CH2Cl2 (40 mL)] and dried overnight under vacuum. Ele-
mental analyses on the Pd contents of the Pd-Amp-CPG were car-
ried out by Medac LTD Analytical and chemical consultancy
services (UK) by ICP-OES.
Pd(0)-CPG Nanoparticles
Pd(0)-Amp-CPG/Chiral Amine-Catalyzed Catalytic Aerobic
Oxidation–Michael–Carbocyclization Relay Sequence: Typical
Procedure
Amine-functionalized Amp-CPG (pore size 533 Å, amine 166
μmol/g), CPG-Hybrid VBC (pore size 526 Å, amine 398 μmol/g),
CPG-Hybrid COPO (pore size 590 Å, amine 360 μmol/g), and
CPG-Hybrid (pore size 1400 Å, amine 353 μmol/g) obtained from
Prime Synthesis were used as supports. Thus, each amine-function-
alized CPG (1 g, 1 equiv, amine content) was added to a deionized
water solution (45 mL, pH 9). In parallel, Li2PdCl4 (2 equiv) was
solubilized in a pH adjusted deionized water solution (pH 9) and
next added to the suspension. After stirring for 24 h, the Pd(II)-CPG
catalyst was transferred to a centrifuge vial (45 mL) and washed
[3 × H2O (40 mL), 3 × acetone (40 mL)] followed by drying over-
To a suspension of Pd(0)-Amp-CPG (6 mol% Pd to 1, 36 mg) in tol-
uene (0.5 mL) placed in a microwave vial was added alcohol 1 (0.12
mmol, 1.2 equiv). The vial was capped, evacuated and an O2 bal-
loon was connected to the reaction vessel. The reaction mixture was
stirred at 70 °C for the time shown in Table 2. Next, the mixture was
cooled to r.t. Propargyl derivative 3 (0.1 mmol, 1 equiv) and the chi-
ral amine 5 (20 mol%) were added and the reaction mixture was vig-
orously stirred for the time shown in Table 2. After removal of the
Pd catalyst, the crude mixture was directly loaded on a silica gel col-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1303–1310

1308
L. Deiana et al.
SPECIAL TOPIC
Table 3 Recycling of the Heterogeneous Pd-CPG Nanoparticle Catalysta
5
Pd(0)-Amp-CPG
(20 mol%)
O
(6 mol%)
r.t.
Ph
Ph
OH
O
Ph
O2, toluene, 70 °C
NC
CO2Me
CN
2a
1a
MeO2C
3
4a
Aerobic oxidation
Time (h)
Michael–Carbocyclization
Cycle
Conv. (%)b
Time (h)
Yield (%)c
drb
erd
1
2
3
4
5
1
1
1
2
4
100
100
100
100
100
3.5
4
63
60
65
67
64
19:1
17:1
18:1
20:1
18:1
98:2
98:2
5
98:2
5
97.5:2.5
98:2
6
a To a suspension of Pd(0)-Amp-CPG (6 mol% Pd to 1, 72 mg) in toluene placed in a microwave vial (1.0 mL) was added alcohol 1 (0.24 mmol,
1.2 equiv). The vial was capped, evacuated and an O2 balloon was connected to the reaction vessel. The reaction mixture was stirred at 70 °C
for the time shown. Next, the mixture was cooled to r.t. Propargyl derivative 3 (0.1 mmol, 1 equiv) and the chiral amine 5 (20 mol%) were
added and the mixture was vigorously stirred for the time shown.
b Determined by 1H NMR analysis of the crude reaction mixture.
c Isolated yield of pure 4.
d Determined by chiral-phase HPLC analysis.
umn and eluted with pentane–EtOAc to afford the corresponding
products 4.
Methyl (1R,2R)-1-Cyano-3-formyl-4-methyl-2-(p-tolyl)cyclo-
pent-3-enecarboxylate (4c)
Yield: 18 mg (63%); oil; [α]D25 –85.2 (c = 1.3 CHCl3).
Methyl (1R,2R)-1-Cyano-3-formyl-4-methyl-2-phenylcyclo-
pent-3-enecarboxylate (4a)
The enantiomeric excess was determined by HPLC analysis in com-
parison with an authentic racemic material (ODH-column, n-hex-
ane–i-PrOH, 90:10, λ = 250 nm, 1.0 mL/min); tR (major
enantiomer) = 23.6 min; tR (minor enantiomer) = 32.9 min.
1H NMR (400 MHz, CDCl3): δ = 9.91 (s, 1 H), 7.16 (d, J = 6.4 Hz,
2 H), 7.04 (d, J = 6.4 Hz, 2 H), 4.68 (br s, 1 H), 3.88 (s, 3 H), 3.39
(d, J = 14.8 Hz, 1 H), 3.25 (d, J = 14.8 Hz, 1 H), 2.33 (s, 3 H).
Yield: 18 mg (67%); oil; [α]D25 –70.9 (c = 1.0 CHCl3).
The enantiomeric excess was determined by HPLC analysis in com-
parison with an authentic racemic material (ODH-column, n-hex-
ane–i-PrOH, 85:15, λ = 210 nm, 1.0 mL/min); tR (major
enantiomer) = 19.3 min; tR (minor enantiomer) = 29.9 min.
1H NMR (400 MHz, CDCl3): δ = 9.92 (s, 1 H), 7.38–7.32 (m, 3 H),
7.17–7.15 (m, 2 H), 4.72 (br s, 1 H), 3.89 (s, 3 H), 3.41 (d, J = 14.8
Hz, 1 H), 3.26 (dt, J = 12.4 Hz, 1.2, 1 H), 2.33 (d, J = 0.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 186.3, 168.9, 157.7, 138.4, 136.8,
133.6, 129.8, 127.9, 117.6, 58.2, 54.4, 51.8, 47.8, 21.4, 14.3.
HRMS (ESI): m/z [M + Na] calcd for C17H17NO3 + Na: 306.1101;
found: 306.1104.
13C NMR (100 MHz, CDCl3): δ = 186.2, 168.8, 157.8, 136.8, 136.6,
129.1, 128.7, 128.0, 117.4, 58.4, 54.4, 51.7, 47.9, 14.3.
HRMS (ESI): m/z [M + Na] calcd for C16H15NO3 + Na: 292.0944;
found: 292.0946.
Methyl (1R,2R)-2-(2-Chlorophenyl)-1-cyano-3-formyl-4-meth-
ylcyclopent-3-enecarboxylate (4d)
Yield: 19 mg (63%); oil; [α]D25 –80.3 (c = 1, CHCl3).
Methyl (1R,2R)-1-Cyano-3-formyl-4-methyl-2-(4-nitrophe-
nyl)cyclopent-3-enecarboxylate (4b)
The enantiomeric excess was determined by HPLC analysis in com-
parison with an authentic racemic material (AD-column, i-hexane–
i-PrOH, 90:10, λ = 254 nm, 1.0 mL/min); tR (major
enantiomer) = 33.2 min; tR (minor enantiomer) = 41.9 min.
1H NMR (400 MHz, CDCl3): δ = 9.93 (s, 1 H), 7.47 (dd, J = 6.4, 1.6
Hz, 1 H), 7.29–7.20 (m, 2 H), 6.97 (dd, J = 6.0, 1.6 Hz, 1 H), 5.30
(br s, 1 H), 3.89 (s, 3 H), 3.41 (d, J = 18.8 Hz, 1 H), 3.27 (d, J = 18.8
Hz, 1 H), 2.34 (d, J = 0.8 Hz, 3 H).
Yield: 18 mg (57%); oil; [α]D25 –88.2 (c = 1, CHCl3).
The enantiomeric excess was determined by HPLC analysis in com-
parison with an authentic racemic material (ODH-column, n-hex-
ane–i-PrOH, 75:25, λ = 254 nm, 1.0 mL/min); tR (major
enantiomer) = 33.6 min; tR (minor enantiomer) = 41.1 min.
1H NMR (400 MHz, CDCl3): δ = 9.95 (s, 1 H), 8.22 (d, J = 8.8 Hz,
2 H), 7.34 (d, J = 8.8 Hz, 2 H), 4.82 (br s, 1 H), 3.91 (s, 3 H), 3.49
(d, J = 18.8 Hz, 1 H), 3.32 (d, J = 18.8 Hz, 1 H), 2.36 (d, J = 1.2 Hz,
1 H).
13C NMR (100 MHz, CDCl3): δ = 185.9, 169.0, 158.4, 136.3, 134.8,
134.4, 130.3, 129.9, 128.4, 127.2, 117.3, 54.8, 54.5, 50.9, 48.9,
14.4.
13C NMR (100 MHz, CDCl3): δ = 185.8, 168.2, 159.0, 148.1, 144.1,
136.2, 129.2, 124.2, 117.0, 57.7, 54.7, 51.3, 48.3, 14.4.
HRMS (ESI): m/z [M + Na] calcd for C16H14ClNO3 + Na: 326.0554;
found: 326.0562.
HRMS (ESI): m/z [M + Na] calcd for C16H14N2O5 + Na: 337.0792;
found: 337.0795.
Methyl (1R,2R)-1-Cyano-3-formyl-4-methyl-2-(3-nitrophe-
nyl)cyclopent-3-enecarboxylate (4e)
Yield: 18 mg (67%); oil; [α]D25 –89.3 (c = 1, CHCl3).
Synthesis 2014, 46, 1303–1310
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Integrated Heterogeneous Pd(0)-CPG Nanoparticle Catalysts
1309
The enantiomeric excess was determined by HPLC analysis in com-
parison with an authentic racemic material (ODH-column, n-hex-
ane–i-PrOH, 70:30, λ = 254 nm, 1.0 mL/min); tR (major
enantiomer) = 19.4 min; tR (minor enantiomer) = 34.6 min.
The enantiomeric excess was determined by HPLC analysis in com-
parison with an authentic racemic material (ODH-column, n-hex-
ane–i-PrOH, 98:2, λ = 230 nm, 1.0 ml/min); tR (minor
enantiomer) = 22.5 min; tR (majoror enantiomer) = 24.2 min.
1H NMR (400 MHz, CDCl3): δ = 9.97 (s, 1 H), 8.22–8.19 (m, 1 H),
7.98 (t, J = 1.2 Hz, 1 H), 7.59–7.53 (m, 2 H), 4.83 (br s, 1 H), 3.92
(s, 3 H), 3.49 (d, J = 18.8 Hz, 1 H), 3.33 (d, J = 18.8 Hz, 1 H), 2.38
(d, J = 1.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 185.8, 168.2, 159.3, 148.6, 139.0,
136.1, 134.7, 130.1, 123.8, 122.8, 117.1, 57.8, 54.8, 51.3, 48.1,
14.5.
1H NMR (400 MHz, CDCl3): δ = 9.93 (s, 1 H), 5.78 (m, 1 H), 5.08–
4.97 (m, 2 H), 3.83 (s, 3 H), 3.54 (m, 1 H), 3.22 (dd, J = 18.4, 36.3
Hz, 2 H), 2.18 (s, 3 H), 2.18–2.03 (m, 3 H), 1.88 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 186.9, 169.3, 157.1, 137.4, 137.3,
118.1, 115.8, 54.2, 52.0, 49.3, 48.5, 31.1, 30.5, 14.1.
HRMS (ESI): m/z [M + Na] calcd for C14H17NO3 + Na: 270.1102;
found: 270.1106.
HRMS (ESI): m/z [M + Na] calcd for C16H14N2O5 + Na: 337.0792;
found: 337.0794.
Methyl (1R,2R)-1-Cyano-3-formyl-4-methyl-2-(4-methoxyphe-
nyl)cyclopent-3-enecarboxylate (4j)
Yield: 21 mg (69%); yellow oil; [α]D25 –108.7 (c = 1.6, CHCl3).
Methyl (1R,2R)-2-Butyl-1-cyano-3-formyl-4-methylcyclopent-
3-enecarboxylate (4f)
The enantiomeric excess was determined by HPLC analysis in com-
parison with an authentic racemic material (AS-H-column, n-hex-
ane–i-PrOH, 85:15, λ = 210 nm, 1.0 mL/min); tR (major
enantiomer) = 43.1 min; tR (minor enantiomer) = 73.6 min.
1H NMR (400 MHz, CDCl3): δ = 9.91 (s, 1 H), 7.08 (d, J = 8.7 Hz,
2 H), 6.88 (d, J = 8.7 Hz, 2 H), 4.68 (br s, 1 H), 3.88 (s, 3 H), 3.79
(s, 3 H), 3.38 (d, J = 18.6 Hz, 1 H), 3.24 (dt, J = 18.6, 3.0 Hz, 1 H),
2.32 (s, 3 H).
Yield: 17 mg (68%); oil; [α]D25 +30.2 (c = 1.0 CHCl3).
The enantiomeric excess was determined by HPLC analysis in com-
parison with an authentic racemic material (ODH-column, n-hex-
ane–i-PrOH, 98:2, λ = 230 nm, 1.0 mL/min); tR (major
enantiomer) = 17.7 min, tR (minor enantiomer) = 19.7 min.
1H NMR (400 MHz, CDCl3): δ = 9.93 (s, 1 H), 3.83 (s, 3 H), 3.53
(br s, 1 H), 3.26 (d, J = 18.8 Hz, 1 H), 3.13 (d, J = 20.0 Hz, 1 H),
2.18 (s, 3 H), 1.99–1.90 (m, 1 H), 1.82–1.73 (m, 1 H), 1.40–1.28 (m,
4 H), 0.90 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 186.3, 168.9, 159.8, 157.6, 136.9,
129.2, 128.6, 117.6, 114.4, 57.9, 55.3, 54.4, 51.9, 47.7, 14.3.
13C NMR (100 MHz, CDCl3): δ = 186.9, 169.5, 156.9, 137.5, 118.2,
54.2, 52.5, 49.5, 48.5, 33.4, 20.2, 14.1, 14.0.
HRMS (ESI): m/z [M + Na] calcd for C17H17NO4 + Na: 322.1050;
found: 322.1051.
HRMS (ESI): m/z [M + Na] calcd for C14H19NO3 + Na: 272.1257;
found: 272.1270.
Acknowledgment
Methyl (1R,2R)-2-(4-Bromophenyl)-1-cyano-3-formyl-4-meth-
ylcyclopent-3-enecarboxylate (4g)
We gratefully acknowledge financial support from the European
Union, Mid Sweden University, and Swedish National Research
Council. Dr. Marc Rothstein and Dr. Diane Rothstein (Prime Syn-
thesis) are acknowledged for valuable discussions. Prime Synthesis
Ltd. U.S.A. generously gave CPGs.
Yield:18 mg (52%); oil; [α]D25 –55.8 (c = 1, CHCl3).
The enantiomeric excess was determined by HPLC analysis in com-
parison with an authentic racemic material (AD-column, n-hexane–
i-PrOH, 90:10, λ = 250 nm, 1.0 mL/min); tR (major
enantiomer) = 22.3 min; tR (minor enantiomer) = 34.9 min.
1H NMR (400 MHz, CDCl3): δ = 9.91 (s, 1 H), 7.48 (d, J = 6.8 Hz,
2 H), 7.09 (d, J = 6.8 Hz, 2H), 4.67 (br s, 1 H), 3.88 (s, 3 H), 3.42
(d, J = 14.8 Hz, 1 H), 3.25 (d, J = 12.8 Hz, 1 H), 2.32 (d, J = 0.8 Hz,
1 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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References
13C NMR (100 MHz, CDCl3): δ = 186.0, 168.6, 158.3, 136.5, 135.7,
132.2, 129.8, 122.8, 117.3, 57.8, 54.3, 51.3, 47.9, 14.3.
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Methyl (1R,2R)-1-Cyano-3-formyl-4-methyl-2-propylcyclo-
pent-3-enecarboxylate (4h)
Yield: 19 mg (81%); oil; [α]D25 +15.5 (c = 1.0 CHCl3).
The enantiomeric excess was determined by HPLC analysis in com-
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enantiomer) = 18.1 min; tR (minor enantiomer) = 19.8 min.
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Yield: 16.5 mg (63%); oil; [α]D25 +12.3 (c = 1.0 CHCl3).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1303–1310

1310
L. Deiana et al.
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Synthesis 2014, 46, 1303–1310
© Georg Thieme Verlag Stuttgart · New York