Regiodivergent ligand-controlled rhodium-catalyzed [(2+2)+2] carbocyclization reactions with alkyl substituted methyl propiolates

Article abstract of DOI:10.1002/anie.201002117

(Figure Presented) Choice is yours: In the title reaction the selective formation of either regioisomer can be controlled through judicious choice of the ancillary ligands (see scheme). Central to this accomplishment was the realization that residual silver salts from the salt metathesis of the neutral complex have a strong effect on the regio- and diastereoselectivity.

Full text of DOI:10.1002/anie.201002117

Communications
DOI: 10.1002/anie.201002117
Metal-Catalyzed Reactions
Regiodivergent Ligand-Controlled Rhodium-Catalyzed [(2+2)+2]
Carbocyclization Reactions with Alkyl Substituted Methyl
Propiolates**
P. Andrew Evans,* James R. Sawyer, and Phillip A. Inglesby
Dedicated to Professor Jack R. Norton on the occasion of his 65th birthday
The importance of transition metal-catalyzed reactions may
be attributed, at least in part, to the manner in which they can
control the formation of a specific product using ancillary
ligands on the metal center.[1] In this context, metal-catalyzed
[2+2+2] carbocyclization reactions present a formidable
challenge with respect to controlling chemo-, regio-, and
various aspects of stereoselectivity.[2–4] A fundamental objec-
tive in this area is the ability to predict and control the
outcome of a specific transformation without recourse to
extensive experimentation.[5] In a program directed towards
the development and understanding of this type of trans-
formation, we described the first regio- and enantioselective
rhodium-catalyzed [(2+2)+2] carbocyclization of 1,6-enynes
1 with aryl substituted methyl propiolates 2 for the con-
struction of bicyclohexa-1,3-dienes 3 (Scheme 1).[4,6] As a
consequence of this study, we were intrigued by the factors
that control regioselectivity and whether the ancillary ligands
could be modified to switch the regioselective outcome to
provide selective access to both regioisomers.[7]
Herein, we now describe the regiodivergent rhodium-
catalyzed [(2+2)+2] carbocyclization of 1,6-enynes 1 with
alkyl substituted methyl propiolates 2 for the construction of
the bicyclohexa-1,3-dienes 3 and 4 (Scheme 1).[8,9] Further-
more, these studies provide another example of the detri-
mental role that silver salts have on selectivity in a metal-
catalyzed reaction, which has important implications for
development and rationalization of related higher-order
carbocyclization reactions.[10]
Table 1 outlines the preliminary studies to probe the
feasibility of the regiodivergent carbocyclization reaction.
Treatment of the 1,6-enyne 1a (X = NTs) and methyl 2-
Table 1: Optimization of the regioselective rhodium-catalyzed [(2+2)+2]
carbocyclization reaction (Scheme 1; 1a X=NTs, 2a R=Me,
E=CO2Me).[a]
Entry Rhodium
complex
Ligand
Ratio of AgX[b] Yield Ratio of
Rh:L
[%][c] 4a:3a[d]
1
2
3
4
[Rh(PPh3)3Cl]
[Rh(cod)2]OTf PPh3
[Rh(cod)2]OTf PPh3
[Rh(cod)2]OTf PPh3
–
–
OTf
–
–
90
57
63
75
7:1
1:1
15:1
ꢀ19:1
7:1
1:1
1:2
1:3
–
–
5
[Rh(PPh3)3Cl]
–
OTf[e] 90
Scheme 1. Regiodivergent rhodium-catalyzed [(2+2)+2] carbocycliza-
tion reactions.
6
7
[Rh(PPh3)3Cl] cod
[Rh(cod)2]OTf PPh3
[Rh(cod)2]OTf PPh3
1:2
1:3
1:3
OTf
Cl
OTf
–
42
60
45
91
5:1
6:1
7:1
ꢁ1:19
8
9[f]
[Rh(cod)2]OTf Xyl-binap 1:1.5
[a] All reactions were carried out on a 0.25 mmol reaction scale utilizing
5 mol% of the rhodium catalyst in benzene at 608C. [b] 5 mol%.
[c] Yields of isolated products. [d] Ratios determined by 500 MHz
1H NMR on the crude reaction mixture. [e] The insoluble silver salts
were filtered through a 13 mm syringe filter with a 0.2 mm PTFE
membrane prior to the introduction of 1a and 2a. [f] Reaction performed
in tetrahydrofuran for solubility of the ligand.[13]
[*] Prof. Dr. P. A. Evans, P. A. Inglesby
Department of Chemistry, The University of Liverpool
Liverpool, L69 7ZD (UK)
Fax: (+44)151-794-1377
E-mail: andrew.evans@liverpool.ac.uk
Homepage: http://osxs.ch.liv.ac.uk/
J. R. Sawyer
Department of Chemistry, Indiana University
Bloomington, IN 47405 (USA)
butynoate 2a (R = Me, E = CO2Me) with silver triflate
modified Wilkinsonꢀs catalyst in benzene, furnished the
bicyclohexa-1,3-dienes 4a and 3a in 90% yield, with 7:1
regioselectivity favoring 4a (Table 1, entry 1). Although the
selectivity was modest, the reaction provides the opposite
regioselectivity to that obtained with an axially chiral
phosphine ligand (see below).[4b] In order to further improve
the selectivity we elected to examine the reaction under salt-
free conditions using the cationic rhodium complex, [Rh-
[**] We thank the National Institutes of Health (GM54623) for generous
financial support. We also thank the Royal Society for a Wolfson
Research Merit Award (P.A.E.), Eli Lilly for a Graduate Fellowship
(J.R.S.) and AstraZeneca (Alderley Park) for a studentship (P.A.I.)
through the EPSRC–Pharma Managed Programme for (Synthetic)
Organic Chemistry. We also acknowledge Dr. Sam Butterworth (AZ)
for his support and helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002117.
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(cod)2]OTf (cod = cyclooctadiene), which obviates the need
for the counterion exchange and thereby allows the recon-
stitution of the cationic version of Wilkinsonꢀs catalyst in the
absence of silver salts.[10] Interestingly, this study clearly
demonstrated the importance of the ligand stoichiometry
(Table 1, entries 2–4) and the detrimental effect of the silver
salts on regioselectivity. For example, the optimal reaction
conditions provide the bicyclohexa-1,3-diene 4a in 75% yield
with ꢀ 19:1 regioselectivity (Table 1, entry 4 vs. 1).[11]
Although these conditions should provide the same active
pre-catalyst, the absence of the residual silver salt clearly has
an impact on the level of regiocontrol. Additional control
experiments indicate that the partial solubility of both silver
chloride and triflate are sufficient to provide lower selectivity
(Table 1, entries 5–8).[10] Having established optimal reaction
conditions for the formation of 4a, we elected to reexamine
the axially chiral phosphine ligands for the formation of 3a,
which had previously proven suboptimal.[4b,6] Gratifyingly,
Xyl-binap (2,2’-bis[di(3,5-xylyl)phosphanyl]-1,1’-binaphthyl)
proved to be the optimal ligand for the formation of
bicyclohexa-1,3-diene 3a, which was obtained in 91% yield
with ꢀ 19:1 regioselectivity (Table 1, entry 9), to provide a
selective protocol for the more challenging alkyl substituted
methyl propiolates.[12]
gent metal-catalyzed [(2+2)+2] carbocyclization reaction for
the construction of novel bicyclohexa-1,3-dienes, which pro-
vide useful synthons for target directed synthesis.[2–4]
Additional studies focused on further enhancing the scope
through the examination of the combined regio- and diaste-
reoselective reaction. The phenyl-substituted 1,6-enyne 5 was
selected to facilitate the direct comparison with prior inves-
tigations in related higher-order carbocyclization reactions.
Whereas the silver salt modified Wilkinsonꢀs catalyst fur-
nished the bicyclohexa-1,3-dienes 6a and 6b with poor regio-
and stereocontrol, the salt-free conditions afforded 6a in 83%
yield with ꢀ 19:1 regio- and diastereoselectivity [Eq. (1)].[14]
X-ray crystallographic analysis of 6a confirmed the regio- and
stereochemical assignment, which is consistent with our
related studies.
Table 2 summarizes the application of the optimized
reaction conditions (Table 1, entry 4) to various tethers and
substituted methyl propiolates to determine the scope and
Outlined in Scheme 2 is a plausible mechanistic hypo-
thesis for the regiodivergent behavior, which occurs as the
result of switching the ancillary ligands. As illustrated, the
Table 2: Scope of the intermolecular rhodium-catalyzed [(2+2)+2]
carbocyclization reaction (Scheme 1; E=CO2Me).[a]
Entry
1,6-Enyne 1
X=
Alkyne 2
R=
Yield of 4
Ratio of
[%][b]
4:3[c]
1
2
3
4
5
6
7
8
NTs
NTs
NTs
NTs
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
O
O
O
O
a
a
a
a
b
b
b
b
c
c
c
c
Me
iPr
c-Pr
CH2OBn
Me
iPr
c-Pr
CH2OBn
Me
iPr
a
b
c
d
a
b
c
d
a
b
c
75
79
82
83
77
74
71
78
71
84
69
69
a
b
c
d
e
f
g
h
i
ꢀ19:1
ꢀ19:1
ꢀ19:1
ꢀ19:1
ꢀ19:1
ꢀ19:1
ꢀ19:1
ꢀ19:1
ꢀ19:1
ꢀ19:1
ꢀ19:1
ꢀ19:1
9
Scheme 2. Proposed catalytic cycles for the regiodivergent rhodium-
catalyzed [(2+2)+2] carbocyclization reaction.
10
11
12
j
k
l
c-Pr
CH2OBn
d
[a] All reactions were carried out on a 0.25 mmol reaction scale using
5 mol% of [Rh(cod)2]OTf, modified with 15 mol% PPh3 in benzene at
608C under argon. [b] Yields of isolated products. [c] Ratios determined
by 400 MHz 1H NMR on crude reaction mixtures.
first step in each of these processes is the formation of the
metallabicyclopentene b and e from the oxidative addition of
the metal into the 1,6-enyne 1.[15] The divergence occurs for
the preferential migratory insertion of the metal–alkyl bond
in b to provide metallabicycloheptadiene c (cycle A), versus
the metal–vinyl bond in e to provide the metallabicyclohep-
tadiene f (cycle B).[16,17] Reductive elimination of the isomeric
metallacycles provides the bicyclohexa-1,3-dienes 3 and 4,
respectively. The preferential migration of the metal–alkyl
versus metal–vinyl bond is presumably the consequence of
the axially chiral bidentate ligand preventing the necessary
cis-alignment with the vinyl group in b, which promotes the
generally less-favorable alkyl migration.[16,18]
limitations of this transformation. This study demonstrates
that nitrogen, carbon, and oxygen containing tethered enynes
1a–c undergo the carbocyclization with exquisite regiocontrol
with an array of straight chain and branched alkyl, including
benzyl-protected hydroxymethyl-substituted methyl propio-
lates 2a–d, to furnish the corresponding bicyclohexa-1,3-
dienes 4a–l in good to excellent yield. X-ray crystallographic
analysis of the cycloadducts 4a and 4d allowed the correlation
of the NMR spectra to confirm the regiochemical assignment
in each case. Overall, this work provides the first regiodiver-
In conclusion, we have described the regio- and diaste-
reoselective intermolecular rhodium-catalyzed [(2+2)+2]
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Communications
Jiao, Y. Liang, D. Yang, S. Zhang, P. A. Wender, Z.-X. Yu, J. Am.
Chem. Soc. 2007, 129, 10060; b) H. Wang, J. R. Sawyer, P. A.
Evans, M.-H. Baik, Angew. Chem. 2008, 120, 348; Angew. Chem.
Int. Ed. 2008, 47, 342.
carbocyclization of carbon- and heteroatom tethered terminal
1,6-enyne derivatives with a range of alkyl substituted methyl
propiolates. A key feature of this study is an intriguing
mechanistic dichotomy that provides the ability to control the
formation of either regioisomer through the judicious choice
of the ancillary ligand. Central to this accomplishment was the
realization that residual silver salts from the salt metathesis of
the neutral complex have a detrimental effect on regio- and
diastereoselectivity. We anticipate the ability to reverse the
regiocontrol in this manner in conjunction with the elimi-
nation of unnecessary silver salts, provide fundamentally
important considerations for future developments in this
important area.
[6] Although the aryl substituted methyl propiolates undergo
selective carbocyclization with axially chiral bidentate phos-
phines, the alkyl-substituted derivatives only proceed with
modest regiocontrol. For example, the analogous enantioselec-
tive carbocyclization of 1a with 2a using the chiral complex
derived from [{Rh(cod)Cl}2] and (S)-Xyl-P-Phos modified with
AgBF4, afforded 3a/4a with 4:1 regioselectivity favoring 3a with
excellent enantioselectivity (90% ee).[4b]
[7] For a recent example of ligand-controlled carbocyclization
reactions, see: P. Mauleꢁn, R. M. Zeldin, A. Z. Gonzꢂlez, F. D.
Toste, J. Am. Chem. Soc. 2009, 131, 6348.
[8] The term regiodivergent, adapted from Nꢁgrꢂdiꢀs definition of
stereoconvergence, refers to the formation of two isomeric
products from the same starting material(s). M. Nꢁgrꢂdi in
Stereoselective Synthesis, VCH, New York, 1996.
[9] Although Oh et al. have reported the ability to switch the
regiochemistry in the rhodium-catalyzed dimerization of 1,6-
enynes, we have recently demonstrated that these reaction
conditions provide the same regioisomer as originally reported
by Grigg and co-workers, namely the formation of 7. This
misassignment by Oh is presumably the result of the analysis of
the cycloadducts in [D1]chloroform rather than [D6]benzene.[3d]
Experimental Section
[Rh(cod)2]OTf (5.9 mg, 0.0125 mmol) and triphenylphosphine
(9.8 mg, 0.0375 mmol) were suspended in benzene (5 mL) under an
atmosphere of argon. The catalyst mixture was warmed to 608C using
a preheated oil bath and the mixture stirred for approximately 30 min
to afford a homogeneous solution. Methyl-2-butynoate (2a; 73.5 mg,
0.75 mmol) was added through a tared microliter syringe, followed by
the syringe pump addition of the 1,6-enyne 1a (62.3 mg, 0.25 mmol) in
benzene (1 mL) over approximately 2 h. The reaction was allowed to
stir at 608C for an additional approximately 2 h (t.l.c. control), cooled
to room temperature, and evaporated in vacuo to afford a crude oil.
Purification by flash chromatography (eluting with a gradient of 10–
30% ethyl acetate/hexanes) furnished the bicyclohexa-1,3-diene 4a
(65.4 mg, 75%) as a white crystalline solid.
Received: April 9, 2010
Published online: July 13, 2010
Keywords: carbocyclization · diastereoselective · metallacycle ·
regiodivergent reactions · rhodium
.
[10] For other transition metal-catalyzed reactions that have impli-
cated the silver salt for poor selectivity, see: a) F. Miyazaki, K.
Uotsu, M. Shibasaki, Tetrahedron 1998, 54, 13073; b) T. M.
Schmid, G. Consiglio, Chem. Commun. 2004, 2318; c) K. C.
Nicolaou, A. Li, D. J. Edmonds, G. S. Tria, S. P. Ellery, J. Am.
Chem. Soc. 2009, 131, 16905.
[1] a) P. W. N. M. van Leeuwen, P. C. J. Kamer, J. N. H. Reek, P.
Dierkes, Chem. Rev. 2000, 100, 2741; b) P. W. N. M. van
Leeuwen in Homogeneous Catalysis: Understanding the Art,
Kluwer, Dordrecht, 2004, pp. 10 – 25.
[11] The monodentate ligands also switch the regioselectivity for the
aryl-substituted methyl propiolates that were originally inves-
tigated.[4b] For example, treatment of enyne 1b with methyl
phenyl propiolate 2e (R = Ph) under the optimal conditions,
furnished the bicyclohexa-1,3-diene 4m in 52% yield and with
ꢀ 19:1 regioselectivity.
[2] For excellent reviews on metal-catalyzed [2+2+2] carbocycliza-
tions involving 1,6-enynes, see: a) M. Malacria, C. Aubert, J. L.
Renaud in Science of Synthesis: Houben-Weyl Methods for
Molecular Transformations, Vol. 1 (Eds.: M. Lautens, B. M.
Trost), Thieme, New York, 2001, pp. 439 – 530; b) P. A. Inglesby,
P. A. Evans, Chem. Soc. Rev. 2010, 39, DOI: 10.1039/b913110h.
[3] For examples of metal-catalyzed and metal-mediated intermo-
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alkynes, see: a) Co: C.-A. Chang, J. A. King, Jr., K. P. C.
Vollhardt, J. Chem. Soc. Chem. Commun. 1981, 53; b) Ir: S.
Kezuka, T. Okado, E. Niou, R. Takeuchi, Org. Lett. 2005, 7, 1711;
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Nishiyama, K. Itoh, J. Org. Chem. 2004, 69, 6697; d) Rh: R.
Grigg, R. Scott, P. Stevenson, J. Chem. Soc. Perkin Trans. 1 1988,
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2005, 7, 4955.
[12] Interestingly, the salt-free conditions dramatically improve the
regioselective formation of the bicyclohexa-1,3-diene 3a (X =
NTs, R = Me), which is significantly lower in the presence of
silver salts (r.s. = 4:1).[4b,6]
[13] The analogous carbocyclization reaction (Table 1, entry 1) in
tetrahydrofuran furnished the bicyclohexa-1,3-diene 4a in 76%
yield as the major regioisomer (r.s. = 4:1), which indicates the
solvent is not playing a major role on the reversal of the
regioselection.
[14] The origin of diastereocontrol is consistent with our previous
studies and a related iridium-catalyzed [(2+2)+2] carbocycliza-
tion with a symmetrical alkyne.[2b,3b]
[15] For examples of selective formation of metallacyclopentenes in
the presence of both alkynes and alkenes, see: M. Jeganmohan,
C.-H. Cheng, Chem. Eur. J. 2008, 14, 10876.
[16] For selected examples of metal–vinyl versus metal–alkyl migra-
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Commun. 2005, 3971; b) P. A. Evans, K. W. Lai, J. R. Sawyer, J.
Am. Chem. Soc. 2005, 127, 12466.
[5] For recent examples of DFT predicted metal-catalyzed carbo-
cyclization reactions, see: a) Y. Wang, J. Wang, J. Su, F. Huang, L.
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