Chemodivergent and Diastereoselective Synthesis of γ-Lactones and γ-Lactams: A Heterogeneous Palladium-Catalyzed Oxidative Tandem Process

Article abstract of DOI:10.1021/jacs.8b09562

A palladium-catalyzed oxidative tandem process of enallenols was accomplished within a homogeneous/heterogeneous catalysis manifold, setting the stage for the highly chemodivergent and diastereoselective synthesis of γ-lactones and γ-lactams under mild co

Full text of DOI:10.1021/jacs.8b09562

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Communication
Chemodivergent and Diastereoselective Synthesis of #-Lactones and #-
Lactams: A Heterogeneous Palladium-Catalyzed Oxidative Tandem Process
Man-Bo Li, A. Ken Inge, Daniels Posevins, Karl P. J. Gustafson, Youai Qiu, and Jan-E. Bäckvall
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b09562 • Publication Date (Web): 25 Oct 2018
Downloaded from http://pubs.acs.org on October 25, 2018
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Journal of the American Chemical Society
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Chemodivergent and Diastereoselective Synthesis of
γ-Lactones and γ-Lactams: A Heterogeneous
Palladium-Catalyzed Oxidative Tandem Process
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Man-Bo Li,† A. Ken Inge,‡ Daniels Posevins,† Karl P. J. Gustafson,† Youai Qiu,*,† and Jan-E.
Bäckvall*,†
†Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
‡Department of Materials and Environmental Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91
Stockholm, Sweden
Supporting Information
recent interest in Pd(II)-catalyzed oxidative carbocyclization of
allenes for construction of synthetically important carbocyclic
skeletons,5 we have now designed an oxidative tandem route to
ABSTRACT: A palladium-catalyzed oxidative tandem process of
enallenols was accomplished within homoge-
neous/heterogeneous catalysis manifold, setting the stage for
highly chemodivergent and diastereoselective synthesis of
γ-lactones and γ-lactams under mild conditions.
a
ring fused γ-lactones (Scheme 1). We envisioned that Int-A
would be generated from the palladium complex of 1 via allene
attack on Pd(II). In the presence of carbon monoxide (CO),
insertion of CO into the Pd–C bond of Int-A would produce
Int-B, which could undergo an insertion of the olefin to form
Int-C. A subsequent CO insertion into the Pd–C bond of Int-C
would produce Int-D, which would be trapped by the hydroxyl
group to give cyclopentenone-fused γ-lactone 2 with two chiral
centers. This bicyclic skeleton is a structural element of many
natural and bioactive compounds (Figure 1).6 Some typical
γ-Lactones and γ-lactams are core structures of a large variety
of natural and bioactive compounds, as well as versatile
intermediates in the synthesis of complex molecules and
recyclable polymers.1 As a result, many studies have been
directed toward the selective construction of this structural unit.2
examples include the strigolactone family6a-e members: strigol,6a
orobanchol6d and GR24,6e which are new plant hormones that
attracted much attention recently. The envisioned tandem process
for the construction of this valuable skeleton would undergo
selective carbonylation-carbocyclization-carbonylation-lactoniza-
tion which involves four-step bond formation including twice CO
insertion with high atom- and step-economy. In addition, the
hydroxyl group of enallenol 1 would potentially act as a directing
group to control the diastereoselectivity of the tandem reaction.
However, considering the possible side-reactions during each step
(Scheme 1), the control of chemoselectivity during the tandem
process would be highly challenging.
In most cases, γ-lactones and γ-lactams are fused with other cyclic
units to form bicyclic or polycyclic structures with several chiral
centers (Figure 1).1-3 Notable progress was obtained in the past
decade.2,3 Despite these major advances, the procedures reported
typically require multistep synthesis with unsatisfactory atom- and
step-economy.1a-d,2a-e,3 Thus, economical and efficient access to
ring fused γ-lactones and γ-lactams with high regio- and
diastereoselectivity is still of high demand.
Figure 1. Representative bioactive compounds
O
O
O
O
O
O
O
O
O
O
O
O
OH
OH
Scheme 1. Proposed tandem approach for formation of
O
O
O
cyclopentenone-fused γ-lactone skeleton
strigol
isolated from cotton
orobanchol
isolated from red clover roots
GR24
synthetic analogue of strigol
OH
R
R
O
*
*
Pd(II)-catalyst, oxidant
CO
strigolactone family
seed germination stimulant
O
O
1
2
OH
H
O
allene attack
lactonization
O
O
OH
O
O
(II)
Pd
O
HO
HO
OH
OH
O
(II)
Pd
CO
olefin
R
CO
R
O
R
R
*
*
O
H
O
insertion
insertion
insertion
sinularone C
isolated from soft coral
Sinularia sp.
scrodentoid F
isolated from scophularia
dentata
didemnenone A
isolated from trididemnum
cyanophorum
Pd
(II)
*
*
Pd
(II)
O
O
O
Int-B
Int-A
Int-C
Int-D
antifouling activity
anti-inflammatory activity
antimicrobial and antifungal activity
An efficient way to construct complicated molecular structures
with high atom- and step-economy is to employ a multistep
tandem process, in which a consecutive series of reactions occur
via multiple bond formation and cyclization.4 Following our
OH
R
OH
R
R
O
PdX
O
O
C
A
B
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Our initial attempt of the Pd(II)-catalyzed oxidative tandem
amino-functionalized mesocellular foam (AmP-MCF) could act as
ideal support for Pd and excellent host for CO gas.10 We assume
1
2
3
4
5
6
7
8
process began with the reaction of enallenol 1a in the presence of
Pd(TFA)2 (TFA = trifluoroacetate) (5 mol%). To our delight, the
cyclopentenone-fused γ-lactone 2a was obtained in 28% yield as a
sole diastereomer (eq 1). Another γ-lactone product 3a was also
formed in 65% yield due to the reaction of acyl palladium with
the hydroxyl group (in Int-B, Scheme 1).
that two factors may lead to the aggregation of CO in
Pd-AmP-MCF to favor the formation of 2a (Figure 2). First, the
physical adsorption of CO in the porous AmP-MCF would
increase the concentration of CO in the reaction mixture. Control
experiments showed that compared to Pd(TFA)2 or Pd(OAc)2, the
Pd(TFA)2 + AmP-MCF or Pd(OAc)2 + AmP-MCF catalytic
system improved the chemoselectivity of the reaction for
formation of cyclopentenone-fused γ-lactone 2a (see Supporting
Information, Table S1, entries 7, 10, and Table S2, entries 4, 5). In
addition, an increase of the ratio of 2a:3a from 36:40 to 47:30 was
observed with the gradual increase of the amount of AmP-MCF
with Pd(OAc)2 as the catalyst (see Supporting Information, p. S8,
Table S2, entries 5-7). Second, in the presence of CO, Pd(II) in
the heterogeneous catalyst was partially reduced to Pd(0). We
observed a mixture of Pd(0) and Pd(II) atoms accommodated in
the Pd-AmP-MCF after reaction.11 The coexistence of Pd(0) and
Pd(II) atoms in Pd-AmP-MCF was also detected in our very
recent work by using Pd0-AmP-MCF in Pd-catalyzed
carbocyclization, in which the Pd(II) was generataed from the
oxidation of Pd(0) by BQ.7g The Pd(0) atoms in PdII-AmP-MCF
can adsorb CO efficiently for the next carbonylative step (Figure
2). Control experiments showed that compared to Pd(II) salts, a
Pd colloid improved the chemoselectivity of the reaction for
formation of cyclopentenone-fused γ-lactone 2a (see Supporting
Information, P. S8, Table S2, entries 11, 12).12
OH
n-Bu
n-Bu
Pd(TFA)2 (5 mol %)
n-Bu
O
+
CO
+
O
O
(1)
BQ (1.1 equiv)
DCE, rt, 12 h
1 atm
O
O
9
1a
2a
3a
, 65%
, 28%
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With these inspiring results in hand, we turned to optimize the
reaction conditions for the chemoselective formation of
cyclopentenone-fused γ-lactone 2a. However, γ-lactone 3a was
always the major product no matter how the homogeneous
reaction conditions were changed (Table 1, entries 1-8, for more
details, see Supporting Information, P. S7). We then turned our
attention to the heterogeneous Pd catalyst comprising of
palladium immobilized on amino-functionalized siliceous
mesocellular foam (Pd-AmP-MCF), which is
a
new
heterogeneous palladium catalyst developed by our group.7 It was
used for catalytic hydrogenation of nitro compounds, alkenes and
alkynes with H2, and exhibited excellent reactivity and selectivity
compared to homogeneous and other heterogeneous Pd
catalyst.7c-f Surprisingly, the non-reduced form, PdII-AmP-MCF,
increased the yield of 2a to 68% and suppressed the yield of 3a to
20% (Table 1, entry 9). By changing the solvent from DCE to
CH2Br2, oxidant from BQ to methyl-BQ, and the amount of
PdII-AmP-MCF from 5 mol % to 2 mol %, 2a was obtained in
80% yield and with a 20:1 chemoselectivity (Table 1, entry 10, for
more details, see Supporting Information, P. S8).
On the other hand, the use of Pd(TFA)2 or Li2PdCl4 (the
precursor of PdII-AmP-MCF) as the catalyst did not lead to any
increase of the chemoselectivity for formation of 2a with
propylamine as the additive (see Supporting Information, Table
S1, entry 7, and Table S2, entries 8-10). This observation suggests
that coordination of amine to Pd in Pd-AmP-MCF is not causing
the switch of the observed chemoselectivity. Based on these
results, we propose that Pd-AmP-MCF adsorb CO efficiently to
favor selective formation of 2a. To be noted, 2a was obtained
only in 15% yield with Pd(TFA)2 as the catalyst in the presence of
15 bar of CO (Table 1, entry 11), demonstrating that the
chemoselectivity of the reaction for the formation of 2a cannot be
improved by simply increasing the CO pressure in the
homogeneous catalytic system. Interestingly, chemoselective
formation of γ-lactone 3a was achieved in 86% yield and with
>20:1 chemoselectivity by using 10 mol % of CH3CO2H as the
additive in the homogeneous catalytic system (Table 1, entry 12).
Table 1. Optimization of the reaction conditions
OH
n-Bu
n-Bu
n-Bu
Pd source (5 mol %)
O
O
+
CO
+
O
BQ (1.1 equiv)
solvent, rt, 12 h
1 atm
O
O
1a
2a
3a
Entry Pd source
Solvent Yield of Yield of
2a (%)a 3a (%)a
1
2
3
Pd(TFA)2
Pd(OAc)2
DCE
DCE
DCE
28
17
12
65
50
44
Pd(PPh3)2Cl2
O
O
Figure 2. Aggregation of CO in Pd-AmP-MCF for switching
chemoselectivity
.
S
Ph
S
Ph
4
DCE
17
35
Pd(OAc)2
CO
5
6
7
8
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
PdII-AmP-MCF
PdII-AmP-MCF
Pd(TFA)2
DCM
CHCl3
CH2Br2 35
THF
DCE
CH2Br2 80
CH2Br2 15
CHCl3
28
20
67
70
55
52
20
4
H2
N
NH2
H2
N
H2
NH2
NH2
NH2
NH2
NH2
N
H2
N
H2
H2
H2
N
N
26
68
OH
N
NH2
n-Bu
Aggregation
of CO in
Pd-AmP-MCF
n-Bu
O
9
O
H2
H2
H2
H2
H2
H2
H2
N
NH2
10b
11c
12d
N
N
NH2
NH2
NH2
NH2
NH2
NH2
O
N
N
57
86
N
CO
N
CO
CO
CO
H2
N
Pd(TFA)2
3
Pd(II) atom
Pd(0) atom
OC
aDetermined by NMR using anisole as the internal standard. 2
mol% of PdII-AmP-MCF and methyl-BQ was used. c15 bar of CO
was used. d10 mol% of CH3CO2H was used.
b
Pd-AmP-MCF
CO
CO
Under the optimized reaction conditions, we investigated the
scope for the chemo- and diastereoselective formation of
cyclopentenone-fused γ-lactones 2 (Scheme 2). Enallenols 1a-1h
with an aliphatic, aromatic or hydrogen substituent in the R1
position worked equally well to give cyclopentenone-fused
γ-lactones 2a-2h in good yields. An ester as functional group was
tolerated in the tandem reaction (2g). In addition to two methyl
substituents, the substrates with cyclopentylidene and
Despite the elegant work on ligand- and solvent-controlled
chemoselective carbonylative reactions developed in homogene-
ous systems,8,9 up to now, there are no reports on catalyst-con-
trolled chemo- and diastereoselective carbonylations achieved
with heterogeneous palladium catalysts. As a result of its high
surface area (500-800 m2g-1) and large pore sizes (~26 nm),
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OH
CO (1 atm)
R1
O
cyclooctylidene substituents on the allene moiety also worked
R1
H
H
S
R
PdII-AmP-MCF (2 mol %)
O
1
2
3
4
well, affording the corresponding products 2i and 2j in good
yields. Unsymmetrical enallenol 1k bearing phenyl and methyl
groups afforded 2k in 77% yield. To our delight, enallenol 1l
bearing a tertiary alcohol led to the corresponding product 2l with
a quaternary carbon stereocenter in good yield, and enallenol 1m
bearing methyl group in R4 position afforded the corresponding
cyclopentenone-fused γ-lactone 2m as a sole diastereomer with
three chiral centers in 52% yield. To be noted, all of the
cyclopentenone-fused γ-lactones 2 were obtained as single
diastereomers with high diastereoselectivity.13
O
Methyl-BQ (1.1 equiv)
CH2Br2, r.t., 12 h
1
2
(S)-
(3R,6S)-
Ph
n-Bu
Me
5
O
O
O
O
O
6
O
7
8
O
O
O
2a
2b
2d
(R,S)-
(R,S)-
(R,S)-
72%, >99% ee
82%, >99% ee
76%, >99% ee
9
Scheme 2. Scope for selective formation of 2
n-Bu
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O
O
HO R2
O
R1
O
O
R2
R3
R1
R3
R4
O
PdII-Amp-MCF (2 mol %)
O
O
O
O
+
CO
O
(R,S)-
71%, >99% ee
Methyl-BQ (1.1 equiv)
CH2Br2, r.t., 12 h
1 atm
O
R4
2f
2h
2i
(R,R)-
55%, >99% ee
(R,S)-
75%, >99% ee
1
2
Optically pure (>99% ee) cyclopentenone-fused γ-lactones
(R,S)-2 were synthesized in high yields (Scheme 3) by using
(S)-enallenols 1 which were readily obtained from kinetic resolu-
tion of enallenols 1 with Candida antarctica lipase B (CalB).14
This strategy provides an efficient way towards chiral cyclopente-
none-fused γ-lactones with high step-economy and selectivity.
recycling test
leaching test
n-Bu
O
2nd: 78%, >50:1 d.r.
3rd: 76%, >50:1 d.r.
4th: 77%, >50:1 d.r.
5th: 75%, >50:1 d.r.
6th: 77%, >50:1 d.r.
7th: 76%, >50:1 d.r.
8th: 75%, >50:1 d.r.
9th: 75%, >50:1 d.r.
Pd leaching < 0.1 ppm
O
Recyclable
Recoverable
Without leaching
O
2a
(
)
79%, >50:1 d.r.
Ph
O
Ph
Me
O
We next explored the substrate scope for chemoselective
formation of γ-lactones 3 (Scheme 4). Enallenols with alkyl, aryl,
ester functional groups, and Cyclopentylidene, cyclooctylidene,
and unsymmetrical phenyl and methyl substituents worked
equally well to afford the γ-lactones 3a-3K in excellent yields.
With alkyl or aromatic substituents in R2, R3 and R4 positions,
enallenols 1l-1o worked equally well to furnish substituted
γ-lactones 3l-3o in good yields. Due to the electronic effect on the
olefin moiety, a prolonged reaction time was required for the
formation of 3n. Interestingly, a spiro-γ-lactone 3p was obtained
with good selectivity in 77% yield under the standard
homogeneous reaction conditions.
O
O
O
O
O
O
O
O
O
O
2b
2c
2d
2e
( )
(
)
(
)
(
)
75%, >50:1 d.r.
80%, >50:1 d.r.
75%, >50:1 d.r.
82%, >50:1 d.r.
CO2Et
O
n-Bu
O
O
O
O
O
O
O
O
O
O
O
2f
2g
2h
2i
( )
(
)
(
)
(
)
70%, >50:1 d.r.
73%, >50:1 d.r.
52%, >50:1 d.r.
78%, >50:1 d.r.
n-Bu
n-Bu
n-Bu
n-Bu
Me
O
O
O
O
O
O
O
O
Ph
Scheme 4. Scope for selective formation of 3
H
O
O
O
(
O
Me
2j
2k
2l
2m
( )
HO R2
R4
R3
R2
(
)
)
(
)
R1
R3
R4
72%, >50:1 d.r.
77%, >50:1 d.r.
78%, >50:1 d.r.
52%, >50:1 d.r.
R1
Pd(TFA)2 (5 mol %)
+
CO
It is noteworthy that the heterogeneous PdII-Amp-MCF catalyst
used for the selective formation of cyclopentenone-fused
γ-lactone 2 can be recovered and recycled many times without
any observed loss of activity or selectivity (Scheme 2).
Inductively Coupled Plasma Optical Emission Spectroscopy
(ICP-OES) analysis of the liquid aliquot after reaction and hot
filtration test during reaction (see Supporting Information, P. S18)
showed that there was no detectable leached Pd species during or
after the reaction, which rule out that leached Pd species catalyze
the reaction as a homogeneous catalyst.
O
BQ (1.1 equiv)
CH3CO2H (10 mol %)
CHCl3, r.t., 12 h
1 atm
O
3
1
Ph
n-Bu
Me
Ph
O
O
O
O
O
O
O
O
3a
3b
3c
3d
82% (
84% (
)
84% (
)
88% (
)
)
EtO2C
O
O
O
O
)
O
O
Scheme 3. Synthesis of optically pure 2
O
3e)
O
3f
3g
3h
)
89% (
n-Bu
85% (
79% (
n-Bu
)
75% (
Me
n-Bu
n-Bu
O
O
O
O
O
)
O
Ph
O
O
3i
3j
3k
3l
85% (
87% (
)
74% (
80% (
)
)
Me
Me
Ph
n-Bu
n-Bu
n-Bu
n-Bu
O
O
O
O
O
O
O
O
3m
3n
88% ( , 24 h)
3o
3p
77% ( )
72% (
)
86% (
)
The strategy for chemodivergent and diastereoselective
construction of γ-lactones can be extended to the synthesis of
γ-lactams. Using enallenamide 1ab as starting material,
switchable synthesis of cyclopentenone-fused γ-lactam 2ab and
γ-lactam 3ab were achieved in good yields and excellent
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BQ
diastereoselectivity under the standard heterogeneous and
Pd(II)
XH
1
2
3
4
5
6
7
8
homogeneous reaction conditions (Scheme 5).
R
XH
HQ
X
Scheme 5. Chemodivergent and diastereoselective synthesis of
γ-Lactams
Pd(0)
R
Pd
(II)
R
O
Standard
homogeneous
system
O
Standard
heterogeneous
system
NHTs
1
n-Bu
1) allene attack
2) CO
Ts
n-Bu
lactonization
n-Bu
N
2
O
NTs
CO
+
(II)
Pd
XH
1 atm
R
XH
O
O
3ab
82%
R
O
red.
elim.
R
R
Path a
X
2ab
78%, > 50:1 d.r.
X
1ab
Standard homogeneous system:
Pd
Pd
(II)
O
O
O
(II)
CO
3
9
Int-D
Int-A'
Int-A
Pd(TFA)2 (5 mol %), BQ (1.1 equiv), AcOH (10 mol %), CHCl3, rt, 12 h
10
11
12
13
14
15
16
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60
Path b
Standard heterogeneous system:
PdII-Amp-MCF (2 mol %), Methyl-BQ (1.1 equiv), CH2Br2, rt, 12 h
CO insertion
R
lactonization
XH
(II)
Pd
XH
R
Bearing multiple carbon-carbon double bonds, γ-lactones 2 and
3 were further transformed to their corresponding hydrogenation
derivatives selectively. In the presence of 1 bar of H2, by
switching catalyst between [Ir(COD)Cl]2 and Pd/C, we realized
the selective hydrogenation of γ-lactones 2 and 3 to mono-hydro-
genated products 4 and 6, and to di-hydrogenated products 5 and
7 in high yield and good selectivity (Scheme 6). To be noted, the
hydrogenated product cyclopentanone fused γ-lactone 5 was
obtained as a single diastereoisomer with four chiral centers. In
addition, the single crystal structure of 5 (Scheme 6, for details,
see Supporting Information, P. S35, 36) further confirmed the
cis-conformation of the cyclopentenone-fused γ-lactone skeleton
in product 2.13
Pd
(II)
O
O
Int-B
selective
olefin insertion
Int-C
X = O or NTs
In conclusion, we have developed an efficient
palladium-catalyzed oxidative tandem reaction of eanllenols for
the chemodivergent and diastereoselective synthesis of γ-lactone
and γ-lactam derivatives. Salient features of our findings include:
1) the catalyst controlled chemodivergent carbonylation is
achieved by switching between homogeneous and heterogeneous
catalysts, which disclose novel opportunities for control of
chemoselectivity in carbonylative reactions. 2) The tandem
strategy for synthesis of γ-lactones and γ-lactams is atom- and
step-economic with high selectivity, which will be beneficial in
synthetic chemistry. 3) Construction of enantioenriched
cyclopentenone-fused γ-lactones was realized by employing the
heterogeneous Pd-catalyzed tandem process on enantiopure
enallenols. Further studies on the use of the heterogeneous
Pd-AmP-MCF catalyst for other Pd-catalyzed transformations are
currently under way in our laboratory.
Scheme 6. Selective hydrogenation of 2 and 3
n-Bu
R
Ph
O
O
O
O
O
O
O
O
O
2
5
(R = Ph), 84%, >50:1 d.r.
4
(R = n-Bu), 90%
[Ir(COD)Cl]2
H2 (1 bar)
n-Bu
Pd/C
n-Bu
n-Bu
O
O
O
ASSOCIATED CONTENT
O
O
O
6
3
7
, 92%
, 85%
Supporting Information
Based on the experimental results and our previous work on
Pd(II)-catalyzed oxidative carbocyclization of allene derivatives,5
plausible mechanism for the chemodivergent and
Experimental procedures and compound characterization data,
including the H/13C NMR spectra. This material is available free
1
a
of charge via the Internet at http://pubs.acs.org.
diastereoselective synthesis of γ-lactones and γ-lactams is given in
Scheme 7. As the initial step, simultaneous coordination of the
hydroxyl group (sulfonamide group), allene and olefin unit to the
Pd(II) center would promote the allene attack and then CO
coordination to form Int-A. In the presence of homogeneous Pd,
attack by the XH group on coordinated CO would be favored with
formation of Int-A´ and give γ-lactones or γ-lactams 3 as the
product after reductive elimination (path a), while in the presence
of heterogeneous Pd, CO insertion into the Pd–C bond of Int-A
would be favored, affording Int-B (path b). Lactonization or
lactamization of Int-B could also lead to γ-lactones or γ-lactams
3, while selective olefin insertion in Int-B directed by the OH
group (for control experiment on diastereoselectivity, see
Supporting Information, P. S34) or NHTs group would produce
Int-C. In Int-C the alkyl palladium and hydroxyl group
(sulfonamide group) are on the same side of cyclopentenone
moiety. Further CO insertion of Int-C would produce Int-D,
which would undergo lactonization or lactamization to give
cyclopentenone-fused γ-lactones or γ-lactams 2.
AUTHOR INFORMATION
Corresponding Author
*jeb@organ.su.se
*qiuyouai@gmail.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from the European Research Council (ERC
AdG 247014), The Swedish Research Council (2016-03897), the
Berzelii Center EXSELENT, and the Knut and Alice Wallenberg
Foundation (KAW 2016.0072) is gratefully acknowledged.
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Scheme 7. Proposed mechanism
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P. S19
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Graphic Abstract
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XH
R
R
R
Homogeneous Pd
Heterogeneous Pd
X
X
O
CO
CO
O
O
up to 82% yield
>50:1 d.r.
Chirality transfer (> 99% ee)
up to 89% yield
X = O or NTs
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 catalyst-controlled chemodivergent carbonylation
 Heterogeneous Pd-catalyzed oxidative tandem process
 Diastereoselective construction of fused-lactone and lactam
6
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