Computationally designed and experimentally confirmed diastereoselective rhodium-catalyzed Pauson-Khand reaction at room temperature

Article abstract of DOI:10.1021/ja107895g

The computational analysis of the rhodium-catalyzed Pauson-Khand reaction indicates that the key transition state is highly charge-polarized, wherein different diastereoisomers have distinctively different charge polarization patterns. Experimental studie

Full text of DOI:10.1021/ja107895g

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Computationally Designed and Experimentally Confirmed
Diastereoselective Rhodium-Catalyzed Pauson-Khand
Reaction at Room Temperature
Mu-Hyun Baik,*,† Shivnath Mazumder,† Paolo Ricci,‡ James R. Sawyer,† Ye-Geun Song,† Huijun Wang,† and
P. Andrew Evans*,‡
†Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405, United States
‡Department of Chemistry, The University of Liverpool, Liverpool L69 7ZD, United Kingdom
S Supporting Information
b
ABSTRACT: The computational analysis of the rhodium-
catalyzed Pauson-Khand reaction indicates that the key
transition state is highly charge-polarized, wherein different
diastereoisomers have distinctively different charge polariza-
tion patterns. Experimental studies demonstrate that chloro-
enynes provide the optimal σ-electron-withdrawing group to
Figure 1. Computed partial charges at the oxidative addition transition
states (in red) and a conceptual view of the oxidative addition invoking
heterolytic π-bond cleavage.
promote polarization and thereby reduce the activation barrier
to provide a highly diastereoselective reaction at room tem-
perature.
critical feature in the development of transition metal-
A
catalyzed higher-order [mþnþo] carbocyclization reactions
is the ability to control the assembly of the individual π-com-
ponents in a chemo-, regio-, and stereoselective manner.1 A fun-
damental objective in this area is the ability to predict the
outcome of a specific transformation without having to revert
to extensive experimentation.2 In this context, we recently described
a combined theoretical and experimental study on the rhodium-
catalyzed Pauson-Khand (PK) reaction, which delineated the
impact of the coordination number of the metal center on dia-
stereocontrol.3-5 Nevertheless, a critical limitation with this trans-
formation remains the variance in diastereoselectivity that is ex-
hibited for a range of tethered 1,6-enynes, which impacts its
synthetic utility.6,7 We envisioned that this limitation could be over-
come by preferentially lowering the activation barrier for the favored
metallacycle, which is known to be rate-determining, through the
manipulation of the stereoelectronics of the π-components.
Herein, we now describe the theoretical impact of modifying
the stereoelectronics of the 1,6-enyne 1 in the rhodium-catalyzed
PK carbocyclization to provide the bicyclopentenones 2/3, and we
experimentally support this hypothesis with a highly stereoselec-
tive room-temperature reaction that favors 2 (eq 1).8
Figure 2. Structures of 1a-TS-1 and 1a-TS-2.
transition states 1a-TS-1 and 1a-TS-2 that furnish the major and
minor isomers 2a and 3a, respectively, reveals an interesting
electronic feature. Although both transition states are highly charge
polarized, they are polarized in opposite directions at the distal carbon
atoms in the metallacycle intermediates, as indicated by the partial
charges in the transition states (Figure 1). The computed partial
charge9 for the C3-position is positive for 1a-TS-1 (þ0.34) and
negative for 1a-TS-2 (-0.34). Furthermore, the C30 in 1a-TS-1 and
1a-TS-2 is polarized with opposite signs, -0.10 and þ0.11,
respectively, which suggests that the oxidative addition is best
conceptualized as a heterolytic cleavage of the π-bonds followed
by an electronic reorganization (Figure 1).10-13
Figure 2 provides insight into the origin of stereocontrol in this
process. As illustrated by the Newman projections, the methyl
group at the C2-position is in a trans disposition relative to the
sp2-hybridized orbital on C3, which will form a new σ-bond
with the C30-carbon in 1a-TS-1. This orientation is necessary for
obtaining 2a, since it provides the necessary syn orientation of the
C3-hydrogen relative to the C2-methyl group. Similarly, the forma-
Although we previously demonstrated that the oxidative addition
to provide the metallacycle intermediate for 1a (X = O, R1 = Me,
R2 = H) is rate determining,5 a more detailed analysis of the
Received: September 2, 2010
Published: April 27, 2011
r
2011 American Chemical Society
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Table 1. Effect of the C40 Substituent on the Computed
Table 2. Scope of the Rhodium-Catalyzed Pauson-Khand
Barrier for Metallacycle Formation (eq 1; 1, X = O, R1 = Me)a
Reaction with C40-Halogenated 1,6-Enynes (eq 1)a
ΔGqcalc (kcal/mol)
1,6-enyne 1
entry
R2
syn 2
anti 3
entry
X
R1
R2
H
yield (%)b ratio of 2:3c
1
2
3
4
H
Cl
Br
I
28.4
24.5
24.5
25.7
31.1
29.3
29.5
30.3
1
O
H
H
aa
NR
74
39
NR
74
81
80
73
84
82
84
87
-
-
2
O
Cl ab
Br ac
3
O
H
-
4
O
H
I
ad
-
a
5
C(CO2Me)2
H
Cl ae
Cl af
Cl ag
-
€
Jaguar 7.0, Schrodinger, LLC, New York, NY, 2007.
6
NTs
NTs
NTs
NTs
O
H
-
tion of the anti product 3a results from the sp2-hybridized orbital
becoming syn to the C2-methyl in 1a-TS-2 (Figure 2). Considering
the structural requirements in the transition state, the electronic
consequences are evident. In 1a-TS-1, hyperconjugation amplifies
the þI effect of the methyl group, which stabilizes the developing
positive charge on C3. Alternatively, in 1a-TS-2, the methyl group is
approximately orthogonal to the sp2 orbital on C3, which reduces
the electronic communication between the methyl group and the
C3 sp2 orbital. With the charge-directing effect of the methyl group
reduced by this structural arrangement, the -I effect of the meth-
ylene moiety (blue in Figure 2) stabilizes the developing negative
charge on the sp2 orbital on C3. This in turn causes a reversal of the
charge polarization in the metallacycle 1a-TS-2 compared to 1a-TS-
1 (Figure 1). Leveraging this conceptual understanding, we envi-
sioned that prepolarization of the enyne substrate to resemble the
charge polarization in 1a-TS-1 should increase the chemical reac-
tivity and improve the level of stereocontrol.
Theoretical analysis of several electron-withdrawing groups
(R2 = aryl, ester, and halide groups) indicates that the addition of
a halogen to the terminal alkyne position should induce a positive
partial charge at the C40-position and thereby decrease the barrier
for the rate-determining step significantly to provide the requisite
conditions for a spontaneous room-temperature reaction. This is
illustrated by the ability of the chloride-substituted terminal alkyne to
lower the activation barrier by 4 kcal/mol for thesyn diastereoisomer
2aj (Table 1, entry 2 vs 1).14 Interestingly, the addition of a halogen
not only reduces the barrier for both diastereoisomers but also
amplifies the preference for the syn diastereoisomer 2 significantly.
Table 2 outlines the examination of the C40-halogenated 1,6-
enynes in the rhodium-catalyzed PK reaction. In accord with our
hypothesis, preliminary studies clearly demonstrated the neces-
sity of the halogen in order to facilitate the room-temperature
reaction (entry 2 vs 1). Additional studies explored the suitability
of various halogens and their ability to promote the reaction
compared to the theoretical predictions. This study demon-
strates that chloride is optimal for this transformation (entries
2-4), which is somewhat consistent with the calculations
(Table 1).14 Moreover, this effect is quite general, since the PK
reaction using carbon- and nitrogen-based tethers also proceeds
at room temperature in high yield (entries 5 and 6).8 In light of
these promising results, we elected to reexamine the diastereos-
electivity for the sulfonamide and ether tethers, since there was a
large discrepancy between the levels of stereocontrol under the
previously reported conditions.6,7 Gratifyingly, the reactions with
the C2-substituted 1,6-haloenynes 1ag-al demonstrates excel-
lent diastereocontrol in each case (entries 7-12), thereby
circumventing the problems previously encountered with the
sulfonamide tethers.7 Moreover, the latent vinyl chloride pro-
vides a useful functional handle to facilitate an array of
7
Me
97:3
98:2
g99:1
98:2
g99:1
g99:1
8
CH2OBn Cl ah
9
Bn
Cl ai
Cl aj
10
11
12
Me
O
CH2OBn Cl ak
Bn Cl al
O
a All reactions were carried out on a 0.2 mmol scale utilizing 5 mol %
[RhCl(CO)2]2 in p-xylene (0.1 M) at 25 °C. b Isolated yields. NR = no
reaction. c Ratios of diastereoisomers were determined by HPLC or GC
analysis of the crude products.
well-established cross-coupling reactions that enhance the synthetic
utility of this process in the context of target-directed synthesis.15
In conclusion, computational analysis of the diastereoselective
rhodium-catalyzed Pauson-Khand reaction reveals that the key
transition state is highly charge-polarized, with the different diaster-
eoisomeric transition states having distinctively different charge
polarization patterns. The rationalization of this computational
observation utilizing a heterolytic bond-cleavage in the oxidative
addition indicated that σ-electron-withdrawing moieties on the
alkyne terminus, such as halogens, prepolarize the enyne and lower
the activation barrier for oxidative addition. Experimental studies
confirmed this hypothesis, with a chloride substituent providing the
optimal functionality on the alkyne to reduce the activation barrier
for this transformation. Finally, this approach enables diastereoselec-
tivity to be garnered in a PK reaction that was previously unselective.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
spectral data for the preparation of 1/2aa-al, along with
computational details and Cartesian coordinates for all struc-
tures. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
mbaik@indiana.edu; Andrew.Evans@liverpool.ac.uk
’ ACKNOWLEDGMENT
We thank the NIH (GM58877) and NSF (CHE-0116050 and
CHE-0645381) for financial support. We also thank the Royal
Society for a Wolfson Research Merit Award (P.A.E.), the
Research Corporation for a Cottrell Award (M.-H.B.), the Sloan
Foundation for a Sloan Fellowship (M.-H.B.), Eli Lilly for a
Graduate Fellowship (J.R.S.), and The University of Liverpool
for a Postgraduate Research Studentship (P.R.).
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