What controls stereoselectivity and reactivity in the synthesis of a trans -decalin with a quaternary chiral center via the intramolecular Pauson-Khand reaction: A theoretical study

Article abstract of DOI:10.1021/om500840q

The Co₂(CO)₈-mediated intramolecular Pauson-Khand reaction is an efficient approach to the trans-decalin subunit with a defined C1 quaternary chiral center. The newly developed density functional theory method M11-L was employed to s

Full text of DOI:10.1021/om500840q

Communication
pubs.acs.org/Organometallics
What Controls Stereoselectivity and Reactivity in the Synthesis of a
trans-Decalin with a Quaternary Chiral Center via the Intramolecular
Pauson−Khand Reaction: A Theoretical Study
Song Liu,† Hongjuan Shen,‡ Zhaoyuan Yu,† Lili Shi,‡ Zhen Yang,*,‡ and Yu Lan*,†
†School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, People’s Republic of China
‡Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School,
Shenzhen 518055, People’s Republic of China
S
* Supporting Information
ABSTRACT: The Co2(CO)8-mediated intramolecular Pau-
son−Khand reaction is an efficient approach to the trans-
decalin subunit with a defined C1 quaternary chiral center.
The newly developed density functional theory method M11-L
was employed to study the mechanism, reactivity, and
stereoselectivity for this reaction. The rate- and stereo-
selectivity-determining step is the intramolecular alkene
insertion into the carbon−cobalt bond. Insertion of the alkene
by the re- and si-face was studied to explain the stereo-
selectivity. The effects of varying the substituent on the
acetylene and the C3 chirality were investigated experimentally
and theoretically.
he Pauson−Khand reaction (PKR) was first reported in
quaternary chiral center and was formed stereoselectively under
these conditions. Enynes with a TMS (trimethylsilyl)-protected
C5-hydroxyl group gave a better yield of product than those
protected with (t-butyldimethylsilyl) or MOM (methoxymeth-
yl). The reactivity of enyne 1 is controlled by the stereo-
chemistry at C3. An S configuration gave a higher yield of
product than those with an R configuration. Mechanistic studies
are needed to understand these experimental observations.
The accepted mechanism of the cobalt-mediated PKR was
proposed by Magnus in 1985.16 This involves reversible ligand
exchange of carbon monoxide and an alkene on a Co2(CO)8
complex, followed by olefin insertion to form a five-membered
metallocycle. Subsequently, carbonyl insertion and reductive
elimination afford a cyclopentenone complex.17 This mecha-
nism could also be applied to other metal-catalyzed PKRs,18
except those with palladium.19 The first density functional
theory (DFT) study on the mechanism of cobalt-mediated
intermolecular PKR was reported by Nakamura in 200120 and
supported Magnus’s mechanism. C−C bond formation leading
to the cobaltacycle is the rate-determining step. Theoretical
studies for intermolecular PKR indicated that the regioselec-
tivity of the alkyne is controlled by both steric and electronic
effects in the alkene insertion step.20,21 However, there are
relatively few high-level theoretical studies on the stereo-
selectivity of the intramolecular PKR.22 Herein we report DFT
calculations used to study the mechanism of the newly reported
T
1971.1 It is a cycloaddition with an alkyne, an alkene, and
carbon monoxide, used to generate synthetically useful
cyclopentenones.2 The PKR is normally catalyzed by cobalt,3
but other transition metal catalysts, such as titanium,4
zirconium,4b,5 nickel,6 molybdenum,7 ruthenium,8 rhodium,9
iridium,10 and palladium11 can also be used. Recently, some of
us reported a cobalt-mediated PKR using enynes to construct
6,6,5-tricyclic and 6,6-bicyclic skeletons.12 This could be used in
the synthesis of natural products containing trans-decalin
subunits. Cyclopentanaphthalenone 2 was prepared via a
PKR from enyne 1 (see SI for the synthesis of enyne 1) with
a stoichiometric amount of Co2(CO)8 at 110 °C under
nitrogen in yields of up to 80% (Scheme 1).13 In this PKR,
Scheme 1. Synthesis of Cyclopentanaphthalenone 2
toluene is used as solvent, while the trimethylamine N-oxide
(TMANO) is additive. It has been well known that amine N-
oxides could be employed to remove carbon monoxide ligands
from transition metal complexes by oxidation to carbon
dioxide.14 We have found that TMANO is the most effective
promoter for this PKR.15 The trans-decalin has a defined C1
Received: August 18, 2014
Published: November 5, 2014
© 2014 American Chemical Society
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Figure 1. Free-energy profiles and geometric information for the reaction pathway of Co2(CO)8-mediated PKR. The values given by kcal/mol are
the relative free energies and enthalpies calculated by the M11-L method in toluene solvent.
cobalt-mediated PKR to clarify the reactivity and stereo-
selectivity.
mol. Product 15 is then generated with the formation of
Co2(CO)6 from 14 with a 14.5 kcal/mol exotherm.
All DFT calculations were carried out with the GAUSSIAN
09 series of programs.23 DFT method B3LYP24 with a standard
6-31G(d) basis set (SDD basis set for cobalt atoms) was used
for geometry optimizations. Harmonic frequency calculations
were performed for all stationary points to confirm them as
local minima or transition state structures and to derive the
thermochemical corrections for the enthalpies and free
energies. The newly developed M11-L25 functional with a
standard 6-311+G(d) basis set (SDD for cobalt atoms),
proposed by the Truhlar group, was used to calculate single-
point energies in toluene with the conductor-like polarizable
continuum model (CPCM), which could give more accurate
energy information.26 All values are given in kcal/mol. The
M11-L-calculated free energy profiles of this intramolecular
PKR in toluene are shown in Figure 1. Compound 3 was used
initially to study the mechanism, which is set to the relative zero
with a Co2(CO)8 molecule. Compound 3 reacted with
Co2(CO)8 to form Co2/acetylene complex 4 with the release
of two molecules of CO, with a 6.7 kcal/mol exotherm. The
intramolecular coordination of the re-face of the alkene goes via
coordinatively unsaturated complex 5 to give thermodynami-
cally unfavorable complex 6 with the release of one molecule of
CO. The re-face of the coordinated alkenyl group then inserts
into the Co−C bond via transition state 7-ts with an activation
free energy of 27.0 kcal/mol. These values indicate that
insertion of this alkenyl group is the rate-determining step for
the PKR. Complex 8, which contains a 6,6-bicyclic skeleton,
coordinates with CO to give 9. A further CO insertion goes via
10-ts with a barrier of 10.9 kcal/mol with reversible formation
of intermediate 11. Further CO coordination (11 to 12) is
followed by reductive elimination to irreversibly give complex
14 via 13-ts. The activation energy for this step is 16.2 kcal/
Another case is indicated by red lines in Figure 1. The cobalt
in 5 coordinates with the si-face of the alkene to give 16 with a
2.9 kcal/mol endotherm. The relative free energy of 16 is 4.2
kcal/mol higher than that of 6. This insertion could take place
via 17-ts with an activation energy of 30.3 kcal/mol, which is
3.3 kcal/mol higher than for the re-face. The competing
insertion steps indicate that only complex 15 forms and the re-
face alkene insertion is observed experimentally.
The geometry information on important intermediates and
transition states is shown in Figure 1, in which most hydrogen
atoms are omitted for clarity. Complex 6 is formed with the
coordination of an alkenyl group with the re-face, in which the
configuration of the newly formed metal-containing seven-
membered ring is chair type. In complex 16, the si-face of the
alkene coordinates to cobalt, resulting in the change in
configuration, which leads to the higher relative free energy
of 16 compared with 6. In transition state 17-ts, the inserting
alkenyl group is closed with CO coordinated to cobalt (Figure
1). The distances between the inserting alkenyl group
hydrogens and coordinated CO carbons (H1···C11 and H2···
C12) are 2.63 and 2.65 Å, respectively. This is because the
configuration of the inserting alkene and the corresponding
Co(CO)2 is eclipsed in 17-ts. In 7-ts, the staggered
configuration of the two groups leads to longer distances
(H1···C11 and H2···C12) of 2.78 and 2.68 Å, respectively, to
reduce steric repulsion. Therefore, the relative free energy of
17-ts is higher than that of 7-ts.
The effect of varying the R group in complex 20 was studied
(Table 1). When R is an alkyl group, a lower yield was observed
(entries 1, 2). With an S configuration at C3 (entries 1, 2)
higher yields were observed than for enynes with an R
configuration (entries 3, 4).
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Communication
a
into 20a is harder than for 3, which is consistent with
experimental observations. The steric repulsion between the
terminal methyl group on acetylene and the CO coordinated
with cobalt leads to the CO moving close to the inserting
alkenyl group. The distances between the hydrogen atoms in
the inserting alkenyl group and carbon atoms in the
coordinated CO (H1···C11 and H2···C12) are 2.73 and 2.59
Å, respectively, which are about 0.05−0.09 Å shorter than those
in 7-ts.
Table 1. Syntheses of Cyclopentanones 21a−d
Enyne 20c was used to study the effect of C3 chirality on the
PKR (Figure 3). The reaction of enyne 20c with Co2(CO)8
Figure 3. Free energy profiles and geometry information for the alkene
insertion step of the PKR with 20c. The values given in kcal/mol are
the relative free energies and enthalpies calculated by the M11-L
method in toluene solvent.
a
TMS: trimethylsilyl; TBS: t-butyldimethylsilyl.
Complex 20a, with a terminal methyl on the acetylene, was
used to study the substituent effect (Figure 2). Coordination of
resulted in a 4.2 kcal/mol exotherm with the release of two
molecules of CO. The alkene inserted into the carbon−cobalt
bond via 27-ts with a barrier of 29.2 kcal/mol, which is 1.2
kcal/mol higher than the corresponding step for 20a via 23-ts.
The calculations indicate that the insertion step for enyne 20c
with the R configuration at C3 is harder than that for enyne 20a
with the S configuration. This is consistent with lower yields for
20c and 20d. In the newly formed six-membered ring, both the
methyl group on the alkene and the OTBS are axial. The 1,3-
repulsion between the two groups leads to a higher relative
energy for 27-ts. The distance of H5···O1 is 2.29 Å, which also
indicates 1,3-repulsion.
In summary, the newly reported DFT method, M11-L, has
been used to study the mechanism of the Co2(CO)8-mediated
PKR in the stereoselective synthesis of the trans-decalin subunit
with a defined C1 quaternary chiral center. The rate- and
stereoselectivity-determining steps are the intramolecular
alkene insertion into the carbon−cobalt bond. Theoretical
calculations indicate that re-face insertion of the alkene is
favorable, leading to the R configuration at C1. Experimental
results showed that the alkyl group on the acetylene gives a
lower yield, which can be explained theoretically by steric
repulsion leading to higher activation energy. The R
configuration at the C3 causes 1,3-repulsion in the formation
of the six-membered ring and increases the activation energy of
the alkene insertion transition state. Therefore, the S
configuration at the C3 is better, which is consistent with
experimental observations.
Figure 2. Free energy profiles and geometry information for the alkene
insertion step of the PKR with 20a. The values given in kcal/mol are
the relative free energies and enthalpies calculated by the M11-L
method in toluene solvent.
20a to Co2(CO)8 with the release of two molecules of CO
leads to a 1.3 kcal/mol free energy decrease (5.4 kcal/mol
higher than for unsubstituted 3). This is because of the steric
repulsion of the terminal methyl group from the CO on the
cobalt. The alkene insertion takes place via 23-ts with a barrier
of 28.0 kcal/mol (1.0 kcal/mol higher than for unsubstituted
3). This theoretical result indicates that insertion of the alkene
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ASSOCIATED CONTENT
* Supporting Information
Cartesian coordinates and energies of all reported structures
and full authorship of Gaussian 09. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
S
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AUTHOR INFORMATION
Corresponding Authors
*(Y. Lan) Tel: +86-18680805840. Fax: +86-023-65111067. E-
mail: lanyu@cqu.edu.cn.
*(Z. Yang) Tel: +86-10-62759105. Fax: +86-10-62759105. E-
mail: zyang@pku.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was supported by the National Science Foundation
of China (Grants 21372266 and 51302327), the 973 Program
(Grant No. 2012CB722602), and the Foundation of
Bairenjihua Chongqing University (Project 0903005203191).
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