Reverse the diastereoselectivity of the Rh(I)-catalyzed Pauson-Khand cycloaddition

Article abstract of DOI:10.1021/ol201670c

It is discovered that the diastereoselectivity of the Rh(I)-catalyzed Pauson-Khand cycloaddition of chiral enynes can be reversed to generate the trans diastereomer as the major product in the absence of a chelate phosphine ligand when the substrate contains an appropriate functional group capable of chelate coordination to the Rh(I) center. This expands the application of the Rh(I)-based catalytic processes to prepare both the cis and trans stereoisomers.

Full text of DOI:10.1021/ol201670c

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4332–4335
Reverse the Diastereoselectivity
of the Rh(I)-Catalyzed
Pauson-Khand Cycloaddition
Mark Turlington and Lin Pu*
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904-4319,
United States
lp6n@virginia.edu
Received June 21, 2011
ABSTRACT
It is discovered that the diastereoselectivity of the Rh(I)-catalyzed PausonꢀKhand cycloaddition of chiral enynes can be reversed to generate the
trans diastereomer as the major product in the absence of a chelate phosphine ligand when the substrate contains an appropriate functional group
capable of chelate coordination to the Rh(I) center. This expands the application of the Rh(I)-based catalytic processes to prepare both the cis and
trans stereoisomers.
In recent years the metal catalyzed PausonꢀKhand
(PK) coupling of enynes with CO to generate cyclopente-
nones has become an increasingly popular alternative to
the PK reaction employing stoichiometric Co2(CO)8.1 A
variety of transition metal complexes have been utilized
including Ti,2 Zr,3 Ni,4 Mo,5 Ru,6 Rh,7 Ir,8 and Pd9 for the
catalytic PK-type reactions in the presence of a CO source.
Among the metals employed, the use of Rh has attracted
considerable attention. The use of Rh to catalyze the
PK-type reaction was first reported simultaneously
by Jeong and Narasaka in 1998. Jeong tested a range
of Rh catalysts bearing phosphine ligands, discover-
ing thattrans-[RhCl(CO)dppp]2 [dppp =1,3-bis(diphenyl-
phosphino)propane] was a suitable catalyst for a variety of
enynes.7a In contrast, Narasaka employed the phosphine-
free [RhCl(CO)2]2 as a catalyst under CO.7b,c The Rh-
catalyzed PK-type reaction was also shown to be viable
using aldehydes and alcohols as the CO source.10 In these
(1) Reviews: (a) Fletcher, A. J.; Christie, S. D. R. J. Chem. Soc.,
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S. L. J. Am. Chem. Soc. 1999, 121, 5881–5898 and references therein.
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r
10.1021/ol201670c
Published on Web 07/18/2011
2011 American Chemical Society

systems, Rh plays the dual role of decarbonylation of the
aldehyde and facilitating enyne cyclization. The tandem
allylic substitution and PK cycloadditions using a Rh
catalyst only or in combination with a Pd complex were
also developed.11 A number of reports for the Rh-
catalyzed enantioselective PK-cycloaddition with the use
of chiral phosphine ligands have appeared.12
Scheme 1. Examples of Diastereoselective Rh-Catalyzed PK-
Type Reactions of Enynes
The Rh(I)-catalyzed PK cycloadditions were found to
exhibit high diastereoselectivity when chiral enynes were
used. For example, Scheme 1a shows that [RhCl(CO)-
(dppp)]2 catalyzed the reaction of the enyne containing an
allylic chiral center to generate the product with a >99:1
ratio of the cis and trans diastereomers.13 In Scheme 1b, a
chiral propargylic ether-based enyne underwent the Rh(I)-
catalyzed PK reaction to give the cis stereoisomer as the
major product.7c Recently, we have initiated a study on the
PK cycloaddition of the chiral enynes derived from the 1,3-
diyne-based propargylic alcohols because the products
from these reactions contain additional enyne units for
further structural elaboration. As shown in Scheme 1c, we
found that with the use of benzaldehyde as the CO source a
Rh(I) complex catalyzed the PK reaction of the optically
active dienediyne 1 to generate the cis diastereomer with a
17:1diastereomeric ratio.14 Thisreaction wasalsofound to
be highly chemoselective with the double bond on the
allylic ether group undergoing the cycloaddition much
faster than the other one on the carbon chain. In the three
examples of Scheme 1aꢀc, although three different Rh(I)
catalysts were used under different reaction conditions,
their diastereoselectivities could all be explained by pro-
posing a preferred chairlike transition state for them. In
each of the proposed transition states A, B, and C, the
substituent at the chiral center is placed at the more
favorable equatorial position. Coupling of the enynes in
AꢀC followed by CO insertion and reductive elimination
will produce the observed predominate cis diastereomer.
In these reactions, the formation of the trans diastereo-
mer should involvea chairlike transition state suchas D for
the reaction in Scheme 1c in which the substituent Y needs
to be at the higher energy axial position (Figure 1).15
Therefore, when the desired product is the trans diaster-
eomer, the applicationoftheRh(I) catalystswillbelimited.
It would be synthetically very useful if both the cis
and trans diastereomers could be obtained from the
Rh(I)-catalyzed PK reaction. In order to reverse the
diastereoselectivity of the Rh(I)-catalyzed PK cycloaddi-
tions of the 1,3-diyne-based enynes, we propose to study
the reaction of the chiral enynes that can generate a
transitionstate like E inFigure1. In E, the axial substituent
Y is capable of coordinating to the Rh center to lower the
Figure 1. Proposed chair-like transition states for the formation
of the trans diastereomers in the Rh(I)-catalyzed PK cycloaddi-
tion of the chiral enynes.
(11) (a) Evans, P. A.; Robinson, J. E. J. Am. Chem. Soc. 2001, 123,
4609–4610. (b) Jeong, N.; Seo, S.-D.; Shin, J.-Y. J. Am. Chem. Soc. 2000,
122, 10220–10221.
(12) (a) Jeong, N.; Sung, B. K.; Choi, Y. K. J. Am. Chem. Soc. 2000,
122, 6771–6772. (b) Schmid, T. M.; Consiglio, G. Chem. Commun. 2004,
2318–2319. (c) Fan, B. M.; Xie, J. H.; Li, S.; Tu, Y. Q.; Zhou, Q. L.
Adv. Synth. Catal. 2005, 347, 759–762. (e) Kim, D. E.; Kim, I. S.;
Ratovelomanana-Vidal, V.; Genet, J.-P.; Jeong, N. J. Org. Chem. 2008,
73, 7985–7989. (f) Kim, D. E.; Kwak, J.; Kim, I. S.; Jeong, N. Adv. Synth.
Catal. 2009, 351, 97–102.
transition state energy in order to favor the formation of
the trans diastereomer. Herein, our promising results to-
ward this goal are reported.
We studied the Rh(I)-catalyzed PK cycloaddition of 2,
an analog of 1 but with a smaller substituent adjacent to
the chiral propargylic carbon center, in the presence of
two different Rh(I) catalysts (Scheme 2). In the presence
of [Rh(cod)Cl]2 (cod = 1,5-cyclooctadiene), rac-BINAP
[racemic 2,20-bis(diphenylphosphino)-1,10-binaphthyl], and
an aldehyde as the CO source (Method A), 2 gave the cis
(13) Wang, H.; Sawyer, J. R.; Evans, P. A.; Baik, M.-H. Angew.
Chem., Int. Ed. 2008, 47, 342–345.
(14) Turlington, M.; Du, Y.-H.; Ostrum, S. G.; Santosh, V.; Wren,
K.; Lin, T.; Sabat, M.; Pu, L. J. Am. Chem. Soc. 2011, ASAP.
(15) A recent computational study focused on the effects of the
electronics on the diastereoselectivity, but it is still consistent with the
chairlike transition state proposed here: Baik, M.-H.; Mazumder, S.;
Ricci, P.; Sawyer, J. R.; Song, Y.-G.; Wang, H.; Evans, P. A. J. Am.
Chem. Soc. 2011, 133, 7621–7623.
Org. Lett., Vol. 13, No. 16, 2011
4333

cycloaddition product as the major product.14 This is the
same as that shown in Scheme 1c except for the reduced
diastereoselectivity due to the reduced size of the substi-
tuent. However, when [RhCl(CO)2]2 was used as the
catalyst under 1 atm of CO in the absence of a chelate
phosphine ligand (Method B),7b,16 the major product was
the trans diastereomer. This reversal of the diastereoselec-
tivity is significant since previously the Rh(I)-catalyzed PK
cycloaddition of enynes with either an allylic or a pro-
pargylic chiral center normally gave the cis diastereomer as
the major product except in special cases.17 Using Method
B also gave a small amount of the product from the
cycloaddition of the double bond on the nonallylic ether
chain. Thus, the chemoselectivity of 2 with Method B is
much lower than that with Method A where no such
product was observed.
the phosphine ligand, the five-coordinated electronically
saturated complex III should be predominate.
On the basis of the above mechanistic analysis, we
propose a hypothesis to explain our observed opposite
diastereoselectivity of 2 for the reactions in Scheme 2
employing the two different Rh(I) catalysts. When [RhCl-
(CO)2]2 is used under 1 atm of CO, it could involve the
four-coordinated intermediate I which makes the transi-
tion state E1 possible. In E1, the axial homoallyllic group
could coordinate to the unsaturated Rh(I) center, leading
to the formation of the major trans diastereomer.18 How-
ever, in the presence of the chelate bisphosphine ligand rac-
BINAP, the five-coordinated and electronically saturated
intermediate III will be predominate. This makes the tran-
sition state like E1 less likely but a transition state like C
with an equatorial homoallyl group more favorable, giving
the major cis diastereomer. The smaller size of the sub-
stituent of 2 versus that of 1 makes the energy difference
between the axial and equatorial smaller, leading to the
reduced diastereoselectivity of 2 versus 1 in the reaction.
The transition state E1 could also explain the lower
chemoselectivity of 2 with the use of Method B since the
coordinated double bond of the nonallyloxy group in E1
could also couple with the coordinated triple bond to give
the corresponding PK cycloaddition product.
Scheme 2. Two Different Rh(I) Catalysts Led to the Reversal of
the Diastereoselectivity of the PK Cycloaddition of a Chiral
Enyne
We studied the effect of the chain length of the sub-
stituent of 2 on the Rh(I)-catalyzed PK cycloaddition. As
shown in Scheme 3a, when the chain of the substituent at
the chiral propargylic center is extended in 3, Method B
gave only a 1:1 mixture of the cis and trans diastereomers.
This demonstrates that the increased chain length of the
substituent in 3 makes the axial chelate coordination of the
substituent less favorable than that shown in E1 for 2,
giving the reduced trans isomer formation. However,
because there is little difference in the size of the substi-
tuents between 2 and 3 at the propargylic chiral center,
when Method A was used their diastereoselectivity is the
same. Compound 4 has a reduced chain length versus 2 for
the substituent at the propargylic chiral center. As shown
in Scheme 3b, with the use of Method B, the diastereos-
electivity for the formation of the trans isomer is increased
to 3:1. This could be explained by a better coordination of
the allyl group of 4 to the Rh(I) center than that of the
homoallyl group of 2 shown in E1. However, because the
size of an allyl group is also not significantly different from
those of the substituents in 2 and 3, the diastereoselectivity
of 4 with the use of Method A is the same as those of 2 and
3. Here, all the reactions of 3 and 4 showed high chemos-
electivity without the cycloaddition of the double bonds on
In a computational study on the mechanism of the
[RhCl(CO)2]2-catalyzed PK cycloaddition of enynes,13
Evans and Baik proposed that the reaction could involve
both the four-coodinated square planar 16 electron com-
plex I and the five-coordinated trigonal bipyrimidal 18-
electron complex II (Figure 2). At low CO pressure com-
plex I is more populated, and at high CO pressure complex
Figure 2. Four- and five-coordinated Rh-enyne complexes.
II is more populated. In the presence of a bisphosphine
ligand such as dppp, because of the chelate coordination of
(16) Fan, L.; Zhao, W.; Jiang, W.; Zhang, J. Chem.;Eur. J. 2008, 14,
9139–9142.
(17) (a) Jeong, N.; Kim, D. H.; Choi, J. H. Chem. Commun. 2004,
1134–1135. (b) Kim, D. E.; Lee, B. H.; Rajagopalasarma, M.; Genet,
J.-P.; Ratovelomanana-Vidal, V.; Jeong, N. Adv. Synth. Catal. 2008,
350, 2695–2700.
(18) For a reversal of the diastereoselectivity of a Mo(CO)6-mediated
PK cycloaddition by an additional substituent coordination, see:
Brummond, K. M.; Curran, D. P.; Mitasev, B.; Fischer, S. J. Org.
Chem. 2005, 70, 1745–1753.
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Org. Lett., Vol. 13, No. 16, 2011

the nonallyloxy group. The much greater chemoselectivity
of 3 and 4 compared to 2 withthe use of Method B could be
attributed to the slower rate of formation for the six- or
four-membered ring than the five-membered ring.
Rh(I) center is both sterically and electronically less favor-
able in a transition state like F. The stronger chelate
coordination of 6 as shown in F can be also used to explain
the reduced diastereoselectivity of 6 when Method A was
applied which gavea cis/trans ratio of1.5:1 for the product.
Here, the chelate coordination of the ester group to the
Rh(I) might be in competition with that of the phosphine
ligand. In contrast, with the use of Method A, 7 was
converted to its PK cycloaddition product with a much
better diastereoselectivity of 5:1 (cis/trans) due to the less
favorable MeO coordination (Scheme 4b). Therefore, by
properly choosing the functional groups on the chiral
enynes and matching them with the catalysts, both cis
and trans diastereomers can be obtained as the major
products from the Rh(I)-catalyzed PK cycloaddition.
We also studied the reaction of compound 5 that con-
tains no additional coordinating group for a transition
state like E1. For this compound, both Methods A and B
gave the cis diastereomer as the major product with the
same diastereoselectivity of 3:1. This is because 5 cannot
provide additional coordination to the Rh(I) center in
Method B to stabilize the axial orientation of its substi-
tuent and the transition state like C is more favorable. The
study of compounds 2ꢀ5 in the Rh(I)-catalyzed PK
cycloadditions with and without a chelate phosphine
ligand supports our proposed approach to reverse the
diastereoselectivity of this catalytic process.
Scheme 4. Matching the Functional Groups of the Chiral En-
ynes with the Catalytic Conditions to Obtain Both the trans and
cis Diastereomers of the PK Cycloaddition Products
Scheme 3. Two Different Rh(I) Catalysts Led to the Opposite
Diastereoselectivity for the PK Cycloaddition of the Chiral
Enynes
In conclusion, we have demonstrated that the generally
observed diastereoselectivity of the Rh(I)-catalyzed PK
cycloaddition of chiral enynes can be reversed through a
judicious choice of substrates and catalysts. It was found
that when an appropriate functional group capable of
chelate coordination toa coordinatively unsaturated Rh(I)
center is incorporated into the chiral enyne substrates, the
previously unfavorable trans diastereomer can be obtained
as the major product for the PK cycloaddition of chiral
enynes. This study should expand the application of the
Rh(I)-catalyzed diastereoselective PK cycloadditions in
organic synthesis.
In order to further develop this diastereoselectivity rever-
sal strategy, we studied the Rh(I)-catalyzed PK cycloaddi-
tion of the enyne 6 by incorporating an ester group for
potential chelate coordination (Scheme 4a). With the use
of Method B, we were pleased to find that 6 underwent the
PK cycloaddition to give the corresponding trans product
with a greatly enhanced diastereomeric ratio of 8:1. This
significantly improved diastereoselectivity indicates that,
in the transition state F, the chelate coordination of the
ester carbonyl oxygen should be more favorable than the
double bond coordination in E1. Steric factors may be
important here since the lone pair electrons of the carbonyl
oxygen in F should be more sterically accessible than the π
electrons of the double bond in E1. When the AcO group of
6 was replaced with a MeO group (compound 7), the dia-
stereoselectivity with the use of Method B was decreased
to 3:1 (trans/cis) since the coordination of the MeO to the
Acknowledgment. Partial support of this work from the
U.S. National Science Foundation (CHE-0717995 and
ECCS-0708923) is gratefully acknowledged.
Supporting Information Available. Synthesis and char-
acterization of the new compounds are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 16, 2011
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