Asymmetric intermolecular cobalt-catalyzed pauson-khand reaction using a p-stereogenic bis-phosphane

Article abstract of DOI:10.1021/ol503329g

The asymmetric intermolecular and catalytic Pauson-Khand reaction has remained an elusive goal since Khand and Pauson discovered this transformation. Using a novel family of P-stereogenic phosphanes, we developed the first catalytic system with useful lev

Full text of DOI:10.1021/ol503329g

Letter
pubs.acs.org/OrgLett
Asymmetric Intermolecular Cobalt-Catalyzed Pauson−Khand
Reaction Using a P‑Stereogenic Bis-phosphane
Sílvia Orgue,† Thierry Leon,† Antoni Riera,*,†,‡ and Xavier Verdaguer*,†,‡
́
́
†Institute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10, 08028 Barcelona, Spain
‡Departament de Química Organ
ica, Universitat de Barcelona, Martí i Franques 1, 08028 Barcelona, Spain
̀
̀
S
* Supporting Information
ABSTRACT: The asymmetric intermolecular and catalytic
Pauson−Khand reaction has remained an elusive goal since
Khand and Pauson discovered this transformation. Using a
novel family of P-stereogenic phosphanes, we developed the
first catalytic system with useful levels of enantioselection for
the reaction of norbornadiene and trimethylsilylacetylene. The
results demonstrate that Co−bisphosphane systems are
sufficiently reactive and that they lead to high selectivity in
the intermolecular process.
he Pauson−Khand reaction (PKR), disclosed in 1973, has
Scheme 2. PKR Reaction between Norbornadiene and
Terminal Alkynes Catalyzed by P,S-Co2−Alkyne Complexes
T
become a textbook method for the synthesis cyclopentanic
compounds.1 The intramolecular PKR has been widely used in
the syntheses of highly complex polycyclic compounds.2
Although the intermolecular process has the great advantage of
being able to rapidly assemble simple building blocks (alkyne,
alkene, and CO) into valuable cyclopentenones, it has been less
exploited in synthesis. Nevertheless, our group and others have
reported several total syntheses of biologically active compounds
using the intermolecular PKR as a key step, thus showing its value
in synthesis.3 While several effective catalytic systems have been
developed for the asymmetric intramolecular PKR, this goal
remains elusive for the intermolecular process.4,5
unable to maintain the original bridged disposition on the Co2−
alkyne core under the required CO atmosphere.
Over the past two decades, we have developed several Co2−
ligand systems (e.g., PuPHOS, CamPHOS, and PNSO) that
provide excellent selectivity (up to 99% ee) in the enantiose-
lective stoichiometric intermolecular PKR (Scheme 1).6
Chiral bis-phosphanes do not have this limitation; however;
they have barely been explored in this process because double-
phosphane substitution in Co2 complexes usually results in
impaired reactivity.8 One of the few exceptions is the report of
Gimbert and co-workers in which the stoichiometric PKR of a
binol-derived bisamidophosphinite−Co2−alkyne complex with
norbornene proceeded in excellent yield, although with poor
selectivity (17% ee) (Scheme 2).9
Scheme 1. Hemilabile P,S-Ligands Used in the Asymmetric
Intermolecular Pauson−Khand Reaction
Inspired by this report, we envisaged the feasibility of an
asymmetric catalytic system bearing an aminodiphosphane
ligand. The challenge was to improve the stereocontrol without
reducing the reactivity. In this respect, a ligand system with a
large steric bias was required. We considered oxazaphospholidine
1 (Scheme 3), which we had previously developed in the context
of P-stereogenic phosphane synthesis,10 was ideally suited for
this purpose since it could be further derivatized to yield a novel
family of C1-symmetric bis-phosphane ligands with a bulky tert-
butyl group on one of the phosphorus atoms. Here, we report on
the synthesis of the ThaxPHOS family of ligands and how the use
However, when these ligands are applied to the catalytic reaction,
the selectivity drops dramatically. The Co-catalyzed PKR
between norbornadiene (NBD) and a bulky propiolamide
using CamPHOS ligand provides the corresponding PKR
product in only 28% ee (Scheme 2).7 We attributed this lack
of selectivity to the hemilabile nature of these ligands, which were
Received: November 17, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503329g
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Synthesis of the ThaxPHOS Family of Ligands
Table 1. Catalytic Intermolecular PKR with Norbornadiene
a
b
c
entry catalyst
R
conditions
yield (%) ee (%)
1
3a
3a
3b
3c
3a
3a
3a
3a
3a
3b
3e
3a
3b
3a
Ph
atm, 100 °C, toluene
1 bar, 100 °C, toluene
atm, 100 °C, toluene
atm, 85 °C, toluene
54
54
53
97
39
77
51
38
30
25
10
40
32
42
2
3
2
nBu
3
nBu
40
28
97
89
86
93
86
87
1
4
nBu
5
TMS
atm, 100 °C, toluene
1 bar, 130 °C, toluene
2 bar, 130 °C, toluene
1 bar, 100 °C, DME
2 bar, 160 °C, diglyme
1 bar, 120 °C, toluene
1 bar, 120 °C, toluene
1 bar, 120 °C, toluene
1 bar, 120 °C, toluene
1 bar, 120 °C, toluene
of these ligands in the asymmetric intermolecular Co-catalyzed
PKR provides unprecedented levels of selectivity.
6
TMS
7
TMS
Oxazaphospholidine 1 can be synthesized in a single step by
condensation with either (+)- or (−)-cis-1-amino-2-indanol with
t-BuPCl2 and protection with borane.10 From 1, lithium amide
formation with 1 equiv of BuLi and reaction with several diaryl-
and dialkylchlorophosphanes leads to the borane-monopro-
tected bis-phosphanes 2a−e (Scheme 3). Borane protection was
found to be unnecessary since the isolation of pure 2a−e was
achieved by direct crystallization from MeOH. With these
ligands in hand, we sought to prepare a suitable cobalt−
phosphane complex to use as catalyst in the intermolecular PKR.
The preparation of the corresponding Co2(CO)6−ThaxPHOS
complexes was unsuccessful because of the low stability of such
compounds.11 Finally, we resolved that the most effective way to
bind the ligand and the Co2(CO)8 moiety was with the
intermediacy of an alkyne moiety to generate a precatalyst.
Thus, deprotection of the borane group with 1,4-
diazabicyclo[2.2.2]octane (DABCO) and in situ complexation
with (μ-HCCTMS)Co2(CO)6 at 85 °C provided a mixture of
diastereomeric cobalt complexes. These compounds were then
treated with tetrabutylammonium fluoride (TBAF) to yield the
acetylene complexes 3a, 3b, 3c, and 3e as single isomers (Scheme
4). Although the initial complexation of 2d proceeded smoothly,
8
TMS
9
TMS
10
11
12
13
14
TMS
TMS
SiMe2Ph
SiMe2Ph
SiMe2Bn
48
72
90
a
Reactions were run in a glass pressure tube at the designated CO
b
pressure (atm = atmospheric CO pressure). Yields refer to isolated
product after flash chromatography. Enantiomeric excess was
determined by either chiral GC or HPLC.
c
catalyst 3b containing a bis(p-CF3C6H4)phosphane group led to
the PKR product with 40% ee. The breakthrough came when the
alkyne partner was switched to trimethylsilylacetylene (TMSA).
Under atmospheric CO pressure (balloon), using 3a as a catalyst,
the corresponding PKR adduct was obtained in 39% yield but
with an unprecedented 97% ee (Table 1, entry 5). Increasing the
temperature and the CO pressure to 130 °C and 1 bar,
respectively, led to an increased yield of 77% accompanied by a
slight decline in selectivity (Table 1, entry 6). A further increase
in the CO pressure (2 bar) slowed the reaction down, and after
24 h only a 51% yield of the product was achieved (Table 1, entry
7). Changing the toluene for a coordinating solvent (DME) or
switching to a higher boiling point solvent (diglyme) to run the
catalytic PKR at higher temperatures did not improve the results
(Table 1, entries 8 and 9). The use of complex 3e with a
diisopropylphosphane group completely inhibited the reactivity
(Table 1, entry 11). Finally, we demonstrated that other
trialkylsilyl-substituted acetylenes also provided elevated selec-
tivity (Table 1, entries 13 and 14).
a
Scheme 4. Synthesis of ThaxPHOS−Co−Alkyne Catalysts
In an attempt to clarify the underlying mechanism and to
reveal the origin of the high selectivity encountered, we examined
the different catalytic events and the intermediates involved. We
first centered our attention on the initial alkyne exchange
process. Reaction of precatalyst 3a with NBD and TMSA under
atmospheric CO pressure (balloon) at the reduced temperature
of 80 °C afforded the corresponding acetylene PKR adduct 4 and
a mixture of diastereomeric complexes TMS-3a and TMS-3a′
(Scheme 5). These complexes, with the opposite orientation of
the TMS substituent, were obtained in a 12:1 diastereomeric
ratio. This experiment revealed that under the catalytic reaction
conditions, after the initial PKR affording 4,12 the subsequent
coordination of the TMSA takes place with high stereocontrol.
We next addressed the structural elucidation of TMS-3a by X-
ray diffraction studies; however, crystallization of this inter-
mediate complex was elusive. Finally, suitable single crystals of
the corresponding analogue TMS-3d were grown;13 the
corresponding solid-state structure is shown in Figure 1. As
a
Yields correspond to complexation and removal of the TMS group.
complex 3d could not be isolated because it decomposed during
the treatment with TBAF. The bridged structure of the
ThaxPHOS precatalyst complexes was confirmed by X-ray
crystallography of 3b (see the Supporting Information).
We next examined the catalytic intermolecular PKR between
norbornadiene and various terminal alkynes using complexes
3a−e as catalysts (Table 1). Reaction of phenylacetylene
provided the corresponding exo-cyclopentenone with 54%
yield but with no enantioselectivity (Table 1, entry 1). However,
when we switched to 1-hexyne, significant levels of enantiomeric
excess were revealed (Table 1, entries 2−4). Here, the use of
B
DOI: 10.1021/ol503329g
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
These findings thus confirm that TMS-3a/TMS-3a′ are
catalytically significant intermediates.
Scheme 5. Alkyne-Exchange Experiment with Complex 3a
under Catalytic Conditions
With all this information in hand, the following catalytic cycle
is proposed (Scheme 7). PKR of precatalyst I with NBD provides
Scheme 7. Proposed Catalytic Cycle
an equimolar amount of enone 4 and generates intermediate
complex II. Ligand exchange of II with the terminal alkyne
produces a mixture of diastereomeric alkyne complexes IIIa/
IIIb. Intermediates IIIa and IIIb are in equilibrium in the
reaction conditions, IIIa being the complex most favored (see
the Supporting Information).14 Stereoselective formation of
complex IIIa over IIIb appears to be essential for the final
outcome of the reaction. From this point, CO → NBD ligand
exchange leads to complex IVa.15 By analogy with the previous
dicobalt−PNSO ligand system and the absolute configuration of
the products obtained, we assume that coordination of the olefin
takes place at the pro-R cobalt atom.16 The pseudo-axial carbon
monoxide of the pro-R cobalt center is the less crowded of the
CO ligands since it is eclipsed to the −O− fragment of the
oxazaphospholidine ring (Figure 1). Finally, alkene insertion in
IVa will give rise to the corresponding PKR product and
regenerate the active intermediate II. We believe that the
diphosphane ligand remains firmly attached to the dicobalt
cluster in a bridged-mode throughout the catalytic cycle and that
it does not act as a hemilabile ligand. We consider that the
unprecedented selectivity observed for this process and the
absence of monophosphane complexes support this hypothesis.
In summary, we have described the synthesis of a novel P-
stereogenic diphosphane ligand system called ThaxPHOS. The
use of these ligands in the Co-catalyzed intermolecular PKR has
led to the development of the first catalytic system with useful
levels of selectivity. Our results demonstrate that some Co−
diphosphane complexes are sufficiently reactive in intermolec-
ular PKR to provide high yields and enantioselectivities.
Although the challenge remains to develop catalysts with greater
activity and a wider reaction scope, it is worth noting that the
TMS-substituted cyclopentenone obtained in the present study
is a general cyclopentenone synthon that has been used in the
asymmetric synthesis of bioactive compounds.3d,e
Figure 1. X-ray structure of the major complex TMS-3d. The
phosphane tert-butyl group and the alkyne−methyne fragments are
highlighted in green.
described previously for similar complexes, the bridged
diphosphane ligand and the alkyne-TMS substituent are placed
in an anti-arrangement.6a,b The origin of the selectivity in the
alkyne ligand exchange is found in the steric bias caused by the
bulky tert-butyl group. Thus, in the major diastereomer, the tert-
butyl fragment is placed eclipsed with a CO ligand, away from the
alkyne−methyne moiety (Figure 1).
Finally, we tested the stoichiometric reaction of a mixture of
TMS-3a/TMS-3a′ (12:1) in the presence of an excess of NBD in
toluene (Scheme 6). The reaction provided the PKR as the major
reaction product in 84 and 83% ee depending on whether the
reaction was performed under CO or nitrogen atmosphere.
Scheme 6. Stoichiometric PKR of a Mixture of Complexes
TMS-3a/TMS-3a′
ASSOCIATED CONTENT
* Supporting Information
■
S
Ligand-exchange experiments between different ThaxPHOS
ligands and of TMSA−Co2(CO)6, experimental procedures,
C
DOI: 10.1021/ol503329g
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Reves
́
, M.; Riera, A.; Verdaguer, X. Angew. Chem., Int. Ed. 2007, 46,
compound characterization data, and spectra for all new
compounds. X-ray data for complexes 3b and TMS-3d (CIF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
́ ̀
5020−5023. (c) Reves, M.; Achard, T.; Sola, J.; Riera, A.; Verdaguer, X.
J. Org. Chem. 2008, 73, 7080−7087. (d) Ji, Y.; Riera, A.; Verdaguer, X.
Org. Lett. 2009, 11, 4346−4349.
́ ̀
(7) Lledo, A.; Sola, J.; Verdaguer, X.; Riera, A.; Maestro, M. A. Adv.
Synth. Catal. 2007, 349, 2121−2128.
AUTHOR INFORMATION
Corresponding Authors
■
(8) (a) Billington, D. C.; Helps, I. M.; Pauson, P. L.; Thomson, W.;
Willison, D. J. Organomet. Chem. 1988, 354, 233−242. (b) Gimbert, Y.;
Robert, F.; Durif, A.; Averbuch, M.-T.; Kann, N.; Greene, A. E. J. Org.
Chem. 1999, 64, 3492−3497.
*E-mail: antoni.riera@irbbarcelona.org.
*E-mail: xavier.verdaguer@irbbarcelona.org.
Notes
(9) Konya, D.; Robert, F.; Gimbert, Y.; Greene, A. E. Tetrahedron Lett.
2004, 45, 6975−6978.
(10) Leon
́
, T.; Riera, A.; Verdaguer, X. J. Am. Chem. Soc. 2011, 133,
The authors declare no competing financial interest.
5740−5743.
(11) To our knowledge, the only example of an isolated bridged
diphosphane−Co2(CO)6 complex is the one reported by Hong and co-
workers; see: Lee, J.-C.; Hong, F.-E. Organometallics 2005, 24, 5686−
5695.
(12) Compound 4 was detected by TLC and could not be isolated due
to its high volatility. For the preparation of 4, see: Iqbal, M.; Duffy, P.;
ACKNOWLEDGMENTS
■
We thank the Spanish Ministerio de Economia y Competitividad
(CTQ2011-23620), the Generalitat de Catalunya (2014SGR-
234, and the IRB Barcelona for financial support. S.O. and T.L.
thank the Generalitat de Catalunya for an FI fellowship.
Evans, P.; Cloughley, G.; Allan, B.; Lledo,
Org. Biomol. Chem. 2008, 6, 4649−4661.
(13) Pure TMS-3d was synthesized by ligand-exchange reaction of
TMSA−Co2(CO)6 with 2d in the presence of DABCO.
́
A.; Verdaguer, X.; Riera, A.
DEDICATION
■
Dedicated to the memory of Professor Peter L. Pauson (1925−
2013).
(14) Ligand-exchange reaction between different ThaxPHOS ligands
and of TMSA−Co2(CO)6 has been studied. It has been found that
higher temperatures increase the selectivity of the reaction. See the
Supporting Information for more details.
(15) Olefin complex IVa depicted in Scheme 7 derives from the major
intermediate IIIa; this hypothesis has not been proven. Although
unlikely, productive olefin coordination could also occur at the minor
isomer IIIb. The lowest energy pathway will ultimately determine the
stereochemical outcome of the reaction.
REFERENCES
■
(1) (a) Jeong, N. In Comprehensive Organic Synthesis II; Elsevier: New
York, 2014; pp 1106−1178. (b) The Pauson−Khand Reaction, Rios, R.,
Ed.; Wiley: Chichester, 2012. (e) Lee, H. W.; Kwong, F. Y. Eur. J. Org.
Chem. 2010, 789−811. (c) Park, J. H.; Chang, K.-M.; Chung, Y. K.
Coord. Chem. Rev. 2009, 253, 2461−2480. (d) Blanco-Urgoiti, J.;
Anorbe, L.; Perez-Serrano, L.; Dominguez, G.; Per
Soc. Rev. 2004, 33, 32−42.
́
ez-Castells, J. Chem.
(16) (a) Castro, J.; Moyano, A.; Pericas
Larena, A.; Piniella, J. F. J. Am. Chem. Soc. 2000, 122, 7944−7952.
(b) Verdaguer, X.; Pericas, M. A.; Riera, A.; Maestro, M. A.; Mahia, J.
Organometallics 2003, 22, 1868−1877.
̀
, M. A.; Riera, A.; Alvarez-
(2) For recent examples of intramolecular PKR in total synthesis, see:
(a) McKerrall, S. J.; Joergensen, L.; Kuttruff, C. A.; Ungeheuer, F.;
Baran, P. S. J. Am. Chem. Soc. 2014, 136, 5799−5810. (b) Williams, D.
R.; Shah, A. A. J. Am. Chem. Soc. 2014, 136, 8829−8836. (c) Fustero, S.;
̀
́ ́
Lazaro, R.; Aiguabella, N.; Riera, A.; Simon-Fuentes, A.; Barrio, P. Org.
Lett. 2014, 16, 1224−1227. (d) Huang, J.; Fang, L.; Long, R.; Shi, L.-L.;
Shen, H.-J.; Li, C.; Yang, Z. Org. Lett. 2013, 15, 4018−4021. (e) Itoh, N.;
Iwata, T.; Sugihara, H.; Inagaki, F.; Mukai, C. Chem.Eur. J. 2013, 19,
8665−8672.
(3) For examples of the use of intermolecular PKR in total synthesis of
bioactive compounds, see: (a) Aiguabella, N.; Pesquer, A.; Verdaguer,
́
X.; Riera, A. Org. Lett. 2013, 15, 2696−2699. (b) Vazquez-Romero, A.;
Verdaguer, X.; Riera, A. Eur. J. Org. Chem. 2013, 1716−1725. (c) Su, S.;
Rodriguez, R. A.; Baran, P. S. J. Am. Chem. Soc. 2011, 133, 13922−
́ ́
13925. (d) Vazquez-Romero, A.; Rodríguez, J.; Lledo, A.; Verdaguer, X.;
Riera, A. Org. Lett. 2008, 10, 4509−4512. (e) Iqbal, M.; Evans, P.; Lledo,
́
A.; Verdaguer, X.; Pericas, M. A.; Riera, A.; Loeffler, C.; Sinha, A. K.;
̀
Mueller, M. J. ChemBioChem 2005, 6, 276−280. (f) Rivero, M. R.; De la
Rosa, J. C.; Carretero, J. C. J. Am. Chem. Soc. 2003, 125, 14992−14993.
̀
(g) Bernardes, V.; Kann, N.; Riera, A.; Moyano, A.; Pericas, M. A.;
Greene, A. E. J. Org. Chem. 1995, 60, 6670−6671.
(4) The asymmetric intramolecular PKR has been reported with
different metals. For Co, see: (a) Hiroi, K.; Watanabe, T.; Kawagishi, R.;
Abe, I. Tetrahedron Lett. 2000, 41, 891−895. (b) Sturla, S. J.; Buchwald,
S. L. J. Org. Chem. 2002, 67, 3398−3403. (c) Gibson, S. E.; Lewis, S. E.;
Loch, J. A.; Steed, J. W.; Tozer, M. J. Organometallics 2003, 22, 5382−
5384. For Ti, see: (d) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J.
Am. Chem. Soc. 1999, 121, 5881−5898. For Rh, see: (e) Jeong, N.; Sung,
B. K.; Choi, Y. K. J. Am. Chem. Soc. 2000, 122, 6771−6772. (f) Kim, D.
E.; Ratovelomanana-Vidal, V.; Jeong, N. Adv. Synth. Catal. 2010, 352,
2032−2040.
(5) For the only example of catalytic intermolecular asymmetric PKR,
see: Shibata, T.; Takagi, K. J. Am. Chem. Soc. 2000, 122, 9852−9853.
(6) (a) Verdaguer, X.; Moyano, A.; Pericas
M. A.; Mahia, J. J. Am. Chem. Soc. 2000, 122, 10242−10243. (b) Sola,
̀
, M. A.; Riera, A.; Maestro,
J.;
̀
D
DOI: 10.1021/ol503329g
Org. Lett. XXXX, XXX, XXX−XXX