Stereoselective rhodium-catalyzed [3 + 2 + 1] carbocyclization of alkenylidenecyclopropanes with carbon monoxide: Theoretical evidence for a trimethylenemethane metallacycle intermediate

Article abstract of DOI:10.1021/ja305467x

The theoretically inspired development of a Rh-catalyzed [3 + 2 + 1] carbocyclization of carbon- and heteroatom-tethered alkenylidenecyclopropanes (ACPs) with CO for the stereoselective construction of cis-fused bicyclohexenones is described. This study demonstrates that the ring opening of alkylidenecyclopropane proceeds through a Rh(III)-trimethylenemethane complex, which undergoes rate-determining carbometalation through a transition state that accurately predicts the stereochemical outcome for this process. The experimental studies demonstrate the validity of this approach and include the first highly enantioselective reaction involving an ACP to highlight further the synthetic utility of this transformation.

Full text of DOI:10.1021/ja305467x

Communication
pubs.acs.org/JACS
Stereoselective Rhodium-Catalyzed [3 + 2 + 1] Carbocyclization
of Alkenylidenecyclopropanes with Carbon Monoxide: Theoretical
Evidence for a Trimethylenemethane Metallacycle Intermediate
Shivnath Mazumder,† Deju Shang,§ Daniela E. Negru,§ Mu-Hyun Baik,*,†,‡ and P. Andrew Evans*,§
†Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405, United States
‡Department of Chemistry, Korea University, 208 Seochang, Chochiwon, Chung-nam 339-700, South Korea
§Department of Chemistry, The University of Liverpool, Liverpool L69 7ZD, United Kingdom
S
* Supporting Information
Scheme 1. Rh-Catalyzed [3 + 2 + 1] Carbocyclization
Reaction with Various Carbon and Heteroatom Tethers
ABSTRACT: The theoretically inspired development of
a Rh-catalyzed [3 + 2 + 1] carbocyclization of carbon- and
heteroatom-tethered alkenylidenecyclopropanes (ACPs)
with CO for the stereoselective construction of cis-fused
bicyclohexenones is described. This study demonstrates
that the ring opening of alkylidenecyclopropane proceeds
through a Rh(III)−trimethylenemethane complex, which
undergoes rate-determining carbometalation through a tran-
sition state that accurately predicts the stereochemical out-
come for this process. The experimental studies demonstrate
the validity of this approach and include the first highly
enantioselective reaction involving an ACP to highlight
further the synthetic utility of this transformation.
Figure 1. Square-planar Rh(I) complexes examined. Solution-phase
Gibbs free energies ΔG(Sol) (in kcal/mol) are given in parentheses.10
he design and implementation of new metal-catalyzed
Thigher-order carbocyclization reactions, which combine
three or more π-fragments, provides a powerful strategy for
target-directed synthesis.1,2 Notwithstanding the inherent utility
of this approach, the ability to join the π-components in a
chemo-, regio-, and stereoselective manner remains challeng-
ing due to the limited understanding of the factors that control
the selectivity. We3 and others4 have demonstrated the
importance of theoretical studies that predict reaction barriers
and thereby provide the basis for experimental studies.
For example, we recently demonstrated for the Pauson−Khand
(PK) reaction that the barrier for the rate-determining step
could be lowered by modifying the stereoelectronics of the
1,6-enyne3d and that the degree of stereocontrol could be
improved using a five-coordinate Rh complex.3b In a related
program, we developed a Rh-catalyzed [3 + 2 + 2] carbo-
cyclization of alkenylidenecyclopropanes (ACPs) with alkynes
for the construction of cis-fused bicycloheptadienes.5 We
envisioned that the combination of these programs would provide
an opportunity to develop a new type of carbocyclization reaction.
Herein we describe the combined theoretical and experimental
development of a Rh-catalyzed [3 + 2 + 1] carbocyclization of
ACPs 1 with CO to provide cis-fused bicyclohexenones 3 in a
highly efficient and stereoselective manner (Scheme 1).6
ligands bound to Rh and the ACP fragment to determine the
impact of the various combinations. Figure 1 summarizes the
relative energies of four plausible complexes, among which
complex i with the PPh3 ligand trans to the olefin of the ACP is
significantly more stable than the related complexes ii−iv and
provides the most mechanistically relevant complex for this
synthetic transformation (vide infra).7,8 These findings also
provide important insight into the dichotomy in reactivity
between neutral and cationic complexes in the Rh variant of the
PK reaction (see the Supporting Information).2,9
Scheme 2 outlines the proposed catalytic cycle. The formation
of complex i promotes oxidative addition to afford square-
pyramidal rhodacyclobutane v, which is 17.7 kcal/mol higher in
energy than the reactant complex and has an associated transi-
tion state i-TS at 23.0 kcal/mol (Figure 2). These energies are
surprising at first sight, as previous studies established that
the metallacycle-forming oxidative addition for these classes of
molecules is typically downhill because of the strong Rh−C
bonds formed during the reaction.3,11 The alternative pathway,
which requires an oxidative addition involving the proximal C−C
bond of the three-membered ring of the ACP, was found to be
too high in energy. Ring opening of the ACP without the
involvement of a rhodacyclobutane intermediate is also energeti-
cally irrelevant.7 Exploring the potential energy surface more
carefully, we found that v unexpectedly rearranges to afford vi,
Devising a reliable computer model without knowing the exact
composition of the catalytically active species requires the evalua-
tion of many possible metal complexes to identify the active
catalyst. In this context, we examined the effect of PPh3 with CO
Received: June 12, 2012
Published: August 28, 2012
© 2012 American Chemical Society
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a
Scheme 2. Proposed Catalytic Cycle
Figure 4. Structures of the diastereomeric intermediates vii and vii′ and
transition states vii-TS and vii′-TS. The H atoms at C4 and C5 are
depicted in white, and the others have been omitted for clarity.
a
Numbers in parentheses are ΔG(Sol) values in kcal/mol.
state vii-TS at 16.5 kcal/mol. Figure 4 highlights the structural
differences in the two transition states, in which the insertion of
the vinyl group (C5−C6) results in C4−C5 bond formation. The
relative orientation of the two hydrogens at the ring junction (C4
and C5) is syn in vii-TS and anti in vii′-TS, with the syn
diastereoisomer preferred by ∼7 kcal/mol. Structurally, the
C4···C5 distance of 3.34 Å in vii′ is notably longer than that of
3.22 Å in vii and becomes shorter in vii′-TS (2.05 Å) than in vii-
TS (2.13 Å). As illustrated in Figure 4, the tether in vii adopts a
classical chair-type envelope structure that is maintained in the
transition state vii-TS, while the conformation of the tether for
the other diastereoisomer changes significantly from envelope in
vii′ to twisted boat in vii′-TS. This change in the conformation
accounts for the higher activation energy required for the anti
orientation of the two hydrogens. To complete the catalytic
cycle, migratory insertion of a carbonyl in viii requires addition
of another ligand, which we propose to be a CO ligand, to form
the six-coordinate Rh(III) species ix. Migratory insertion of
a carbonyl into the Rh−C bond gives intermediate x, traversing
the transition state ix-TS at 9.4 kcal/mol. Reductive elimination
and concomitant C−C coupling yields the product complex xi.
This step is associated with a barrier of 26 kcal/mol. Finally, a
1,3-hydride shift leads to an isomerization of the exocyclic olefin
to afford the desired endocyclic olefin. Our calculations invoke a
Rh(III)−hydride intermediate and a very reasonable barrier of
∼15 kcal/mol (see the Supporting Information for details).13 We
also probed the fate of the mechanism proposed in Scheme 2 in
the presence of CO ligands without any phosphine present on
the Rh center. Replacement of the electron-donating PPh3 ligand
with an electron-withdrawing CO ligand makes the Rh center
electron-deficient, and as a result, the energy of transition state
for the insertion of the vinyl moiety becomes higher than that of
vii-TS.7
Figure 2. Diastereospecific reaction energy profiles for the Rh-catalyzed
[3 + 2 + 1] carbocyclization. The bold and lightface profiles are for the
cis- and trans-fused bicyclic systems, respectively. Transition states indi-
cated by * were not explicitly located and are shown for illustration only.
Figure 3. Optimized geometries of intermediates v and vi. H atoms have
been omitted for clarity.
a six-coordinate 18-electron Rh(III) trimethylenemethane (TMM)
complex. Although this intermediate was unanticipated,
this type of complex is known.12 Figure 3 illustrates the optimized
geometries of highly strained rhodacyclobutane intermediate
v and Rh(III)−TMM complex vi. The TMM moiety binds
facially to Rh to provide a three-legged piano stool type of
coordination. The binding is essentially symmetric with respect
to C1−C2, C1−C3, and C1−C4, since these bond distances are
essentially equal (1.436, 1.438, and 1.433 Å, respectively). We
propose that vi is the resting state of the catalytic cycle. To force
the reaction forward and promote C−C coupling, one CO ligand
must dissociate to expose a binding site for the pendant vinyl
moiety, affording vii, which is ∼10 kcal/mol higher in energy than
vi. The metal undergoes stereoselective carbometalation on the
vinyl group to furnish cis-fused bicycle viii, traversing the transition
Hence, the computational studies suggest that insertion of the
vinyl group (vi → viii) is most likely the rate-determining step
in the catalytic cycle. This finding is distinctively different from
those for related reactions, such as the Rh(I)-catalyzed [2 + 2 + 1]
carbocyclization2,3b,d and related metal-catalyzed [2 + 2 + 2]
reactions,11,14 where the initial oxidative addition step is rate-
determining.7 The shift in mechanism is a direct result of the
energy released in ring opening of the ACP (i → vi), which
makes the oxidative addition significantly more favorable. The
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a
ACP group also decouples C−C bond formation from the
oxidative addition step, thereby delegating the installation
of the stereocenter(s) to a later phase of the catalytic cycle.
As we demonstrated previously,3b,d coupling the stereo-
chemistry-determining C−C bond formation to the oxidative
addition necessarily gives control of the stereochemistry to
the electronics of the metal center, whereas when these two
events are decoupled, as described above, the stereochemistry
is primarily substrate-controlled. This subtle yet decisive
distinction is important and provides the mechanistic
hypothesis for the following experimental studies to validate
the theoretical work.
Table 2. Scope of the Rh-Catalyzed Carbocyclization
Encouraged by the theoretical prediction that the [3 + 2 + 1]
carbocyclization is associated with reasonable barriers and, more
importantly, that it should favor the cis-fused bicyclohexenones
3, we initiated experimental studies, focusing first on validating
the computed catalyst selection. Treatment of ACP 1a with the
catalyst derived from [Rh(CO)2Cl]2 and triphenylphosphine in the
presence of CO furnished cis-fused bicyclohexenone 3a in 68% yield
with ≥19:1 diastereoselectivity, which was confirmed by X-ray
crystallographic analysis (Table 1, entry 1). Interestingly, adding
more phosphine or a bidentate ligand gave similar results, albeit with
a
All reactions were carried out on a 0.1 mmol scale using RhCl(PPh3)3
a
(10 mol %) and AgCO2CF3 (15 mol %) under CO (1 atm) in p-xylene
(0.05 M) at 120 °C for ∼12 h. Isolated yields are shown. ds values
Table 1. Optimization of the Rh-Catalyzed Carbocyclization
1
were determined by H NMR analysis of the crude products.
provides unparalleled versatility with regard to the ability to
install a bridgehead quaternary carbon stereogenic center
(entries 2, 6, and 10 vs 3, 7, and 11), which is likely to have
significant utility for synthetic applications. Furthermore, the
cycloisomerization of trisubstituted alkenes provides an addi-
tional stereogenic center (entries 4, 8, and 12), albeit with slightly
lower diastereocontrol from the epimerization of 3 to provide
5. In contrast, the cis-alkene is unreactive, confirming that the
process is stereospecific. Overall, the experimental studies confirm
the theoretical hypothesis and provide a highly diastereoselective
approach to functionalized cis-fused bicyclohexenones, which
represent important synthetic intermediates.
a
b
All reactions were carried out on a 0.1 mmol scale at 0.05 M. Iso-
c
1
lated yields. Determined by H NMR analysis of the crude products.
On the basis of the proposed mechanism, we envisioned that
ACPs 6a and 6b would provide additional evidence for the π-allyl
intermediates viii−x. For instance, selective formation of 7 or 8
would be consistent with a stereospecific reductive elimination of
x, whereas the exclusive formation of 7 would demonstrate that
the π-allylrhodium species is fluxional and can preferentially
undergo reductive elimination from the less sterically hindered
terminus.7 Treatment of 6a and 6b under standard reaction
conditions furnished the cis-fused bicyclohexenone 7 (eq 1),
which supports the intermediacy of a fluxional π-allyl
intermediate. Hence, the ability to modify the β-position of the
bicyclohexenone selectively in this manner provides important
scope for this transformation.
slightly lower yields (entries 2 and 3), supporting the theoretical
results discussed above. The proposed catalytic cycle employs a
cationic complex, which is likely to be significantly more reactive.
In this context, we elected to use a mixed-ligand species to probe
the effect of neutral and cationic species. The cationic species was
superior (entry 5 vs 4), which is consistent with the computa-
tional studies and related synthetic studies on the Rh-catalyzed
PK reaction.2,7,9 In line with this reasoning, we elected to com-
plete the study using Wilkinson’s catalyst. Gratifyingly, the cationic
variant performed in an analogous manner (entry 7 vs 6), further
supporting the mechanistic hypothesis. Finally, the optimal reac-
tion conditions employed a rather unusual silver salt, silver
trifluoroacetate, which provided 3a in 91% overall yield (entry 8).
Table 2 outlines the application of the optimized reaction con-
ditions (Table 1, entry 8) to carbon- and heteroatom-tethered
ACPs 1 to illustrate the synthetic scope of this reaction. Inter-
estingly, the bridgehead diastereoselectivity is independent of
the nature of the ACP tether, alkene geometry, and substitution,
albeit the oxygen tethers are generally less efficient (entries 1 and
5 vs 9), again supporting the theoretically derived notion that
the tether portion of the substrate is not directly engaged
with the metal center in the rate-determining step. This process
Finally, we envisioned that the development of an enantio-
selective variant would further highlight the synthetic utility of this
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(2) For recent reviews of PK-type reactions, see: (a) Perez-Castells, J.
Top. Organomet. Chem. 2006, 19, 207. (b) Lee, H.-W.; Kwong, F.-Y. Eur.
J. Org. Chem. 2010, 789. (c) Shibata, T. Sci. Synth. 2011, 3, 125 and
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Chem. Soc. 2005, 127, 1602. (b) Wang, H.; Sawyer, J. R.; Evans, P. A.;
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Lord, R. L.; Baik, M.-H. J. Am. Chem. Soc. 2008, 130, 5821. (d) Baik, M.-
H.; Mazumder, S.; Ricci, P.; Sawyer, J. R.; Song, Y.-G.; Wang, H.; Evans,
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process. Interestingly, there are relatively few examples of enantio-
selective reactions involving ACPs,15 which is consistent with the
theoretical preference for a monodentate phosphine ligand.
Nevertheless, analysis of our computed mechanism coupled with
the insight gained from the experimental results suggested that
the enantiodetermining step, v → vi, may be able to tolerate a
bidentate ligand. Gratifyingly, treatment of ACP 1a with the catalyst
derived from Rh(COD)2OTf and the chiral P,N-ligand16,17 9 in
the presence of CO and tetramethylethylenediamine (TMEDA)18
furnished cis-fused bicyclohexenone ent-3a in 75% yield with 89%
enantiomeric excess (eq 2). This represents the first highly enantio-
selective reaction involving an ACP and provides an important
proof-of-principle for related transformations that contain this motif.
(5) Evans, P. A.; Inglesby, P. A. J. Am. Chem. Soc. 2008, 130, 12838.
(6) For related metal-catalyzed [3 + 2 + 1] carbocyclization reactions,
see: (a) Koga, Y.; Narasaka, K. Chem. Lett. 1999, 705. (b) Jiao, L.; Lin,
M.; Zhuo, L.-G.; Yu, Z.-X. Org. Lett. 2010, 12, 2528. (c) Li, C.; Zhang,
H.; Feng, J.; Zhang, Y.; Wang, J. Org. Lett. 2010, 12, 3082.
(7) See the Supporting Information (SI) for more details and
additional comments on other mechanistic pathways probed.
(8) For examples of Pd/Ni-catalyzed carbocyclizations with ACPs, see:
(a) Suzuki, T.; Fujimoto, H. Inorg. Chem. 2000, 39, 1113. (b) Gulías, M.;
In conclusion, we have developed a novel Rh-catalyzed [3 + 2 + 1]
carbocyclization reaction using theory to predict the catalyst
requirements and the critical steps in the catalytic cycle that
impact enantio- and diastereoselectivity. The mechanistic under-
standing garnered from this study provided a robust hypothesis for
the subsequent experimental studies. For example, the theoretical
analysis predicted the optimal metal complex, which provided
important insight into the precatalyst requirements for reactions
involving CO. Moreover, the theoretical studies indicated that
the stereodetermining steps occur at different points in the
catalytic cycle, permitting enantio- and diastereoselective variants
to be developed. Additional studies provided evidence for the
intermediacy of a fluxional π-allylrhodium complex, permitting
substitution at the β-position of the bicyclohexenone.
García, R.; Delgado, A.; Castedo, L.; Mascarenas, J. L. J. Am. Chem. Soc.
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ASSOCIATED CONTENT
* Supporting Information
■
Roglans, A.; Parella, T.; Osuna, S.; Sola, M. Chem.Eur. J. 2009, 15,
S
̀
5289. (c) Dachs, A.; Osuna, S.; Roglans, A.; Sola, M. Organometallics
Computational details and results, experimental procedures,
characterization data, and CIF files for 3a, 3h, and ent-3a. This
material is available free of charge via the Internet at http://pubs.
acs.org.
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30, 3151.
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(13) See the SI for the mechanism of the isomerization of 2 to 3.
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AUTHOR INFORMATION
Corresponding Author
mbaik@indiana.edu; Andrew.Evans@liverpool.ac.uk
■
Notes
The authors declare no competing financial interest.
(15) Gulías, M.; Duran
Am. Chem. Soc. 2007, 129, 11026.
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, J.; Lopez, F.; Castedo, L.; Mascarenas, J. L. J.
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̃
ACKNOWLEDGMENTS
■
We thank the EPSRC (EP/G010250) and NSF (CHE-0645381
and CHE-1001589) for financial support, the Royal Society for a
Wolfson Research Merit Award (P.A.E.), the Research
Corporation for a Cottrell Scholarship and Scialog Award (M.-H.B.),
the WCU Program of the National Research Foundation of
Korea (M.-H.B.), and the EPSRC National Mass Spectrometry
Service Centre (Swansea, U.K.) for HR-MS analyses.
(16) For the first preparation of this class of ligands, see: (a) Richards,
C. J.; Damalidis, T.; Hibbs, D. E.; Hursthouse, M. B. Synlett 1995, 74.
(b) Sammakia, T.; Latham, H. A.; Schaad, D. R. J. Org. Chem. 1995, 60,
10. (c) Nishibayashi, Y.; Uemura, S. Synlett 1995, 79.
(17) Although the enantioselectivity was excellent for this particular
example, other substrates provided slightly lower enantioselectivities
(e.g., 80% ee for 3e and 3f).
(18) The presence of TMEDA is important for catalyst recovery, since
we observed significantly reduced turnover frequency in its absence.
REFERENCES
■
(1) For recent reviews of higher-order carbocyclization reactions, see:
(a) Inglesby, P. A.; Evans, P. A. Chem. Soc. Rev. 2010, 39, 2791.
(b) Aubert, C.; Malacria, M.; Ollivier, C. Sci. Synth. 2011, 3, 145 and
references cited therein.
NOTE ADDED AFTER ASAP PUBLICATION
Revised SI files were posted and refs 8 and 12 were revised on
December 13, 2012.
■
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