Distinctive meta-directing group effect for iridium-catalyzed 1,1-diarylalkene enantioselective hydrogenation

Article abstract of DOI:10.1021/ol303465c

An iridium-catalyzed asymmetric hydrogenation of 1,1-diarylkenes is described. Employing a novel, modular phosphoramidite ligand, PhosPrOx, in this transformation affords biologically relevant 1,1-diarylmethine products in good enantiomeric ratios (96.5:3

Full text of DOI:10.1021/ol303465c

ORGANIC
LETTERS
2013
Vol. 15, No. 3
646–649
Distinctive Meta-Directing Group Effect for
Iridium-Catalyzed 1,1-Diarylalkene
Enantioselective Hydrogenation
Elizabeth N. Bess and Matthew S. Sigman*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City,
Utah 84112, United States
sigman@chem.utah.edu
Received December 18, 2012
ABSTRACT
An iridium-catalyzed asymmetric hydrogenation of 1,1-diarylkenes is described. Employing a novel, modular phosphoramidite ligand, PhosPrOx,
in this transformation affords biologically relevant 1,1-diarylmethine products in good enantiomeric ratios (96.5:3.5 to 71:29). We propose that a
meta-directing group, 3,5-dimethoxyphenyl, is responsible for the observed enantioselection, the highest reported, to date, for iridium-catalyzed
hydrogenation of 1,1-diarylalkenes lacking ortho-directing groups.
For several years, we and others have taken a keen interest
in accessing the biologically relevant 1,1-diarylmethine
scaffold.1 Although several methods exist for effectively
accessing these molecules,2 approaches for their enantio-
selective synthesishavebeenlimited.2b,3 Of particular note,
Jarvo and co-workers have developed a nickel-catalyzed
stereospecific cross-coupling reaction whereby enantio-
merically enriched 1,1-diarylethers undergo inversion of
configuration in the process to afford similarly enriched
1,1-diarylmethines.3a,b Another attractive approach was
reported by Carreira and co-workers, where enantiomeri-
cally enriched β,β-diarylpropionaldehydes are converted
to 1,1-diarylmethines using a stereoretentive rhodium-
catalyzed decarbonylation protocol.3d We envisioned a
complementary method to access this important pharma-
cophore wherein the stereocenter is set in the key bond
forming event. Specifically, we wanted to develop an
enantioselective hydrogenation of 1,1-diarylmethylenes,
as this approach would be operationally simple and the
substrates would be easily accessed. Additionally, this
substrate class is especially challenging, as few examples
of high enantioselectivity have been reported for the
hydrogenation of 1,1-diarylalkenes.
ꢀ
(1) (a) Messaoudi, S.; Hamze, A.; Provot, O.; Treguier, B.; Rodrigo
De Losada, J.; Bignon, J.; Liu, J.-M.; Wdzieczak-Bakala, J.; Thoret, S.;
Dubois, J.; Brion, J.-D.; Alami, M. ChemMedChem 2011, 6, 488. (b)
Moree, W. J.; Li, B.-F.; Zamani-Kord, S.; Yu, J.; Coon, T.; Huang, C.;
Marinkovic, D.; Tucci, F. C.; Malany, S.; Bradbury, M. J.; Hernandez,
L. M.; Wen, J.; Wang, H.; Hoare, S. R. J.; Petroski, R. E.; Jalali, K.;
Yang, C.; Sacaan, A.; Madan, A.; Crowe, P. D.; Beaton, G. Bioorg.
Med. Chem. Lett. 2010, 20, 5874. (c) Liang, H.; Wu, X.; Yalowich, J. C.;
Hasinoff, B. B. Mol. Pharmacol. 2008, 73, 686. (d) Moriconi, A.; Cesta,
M. C.; Cervellera, M. N.; Aramini, A.; Coniglio, S.; Colagioia, S.;
Beccari, A. R.; Bizzarri, C.; Cavicchia, M. R.; Locati, M.; Galliera, E.;
Di Benedetto, P.; Vigilante, P.; Bertini, R.; Allegretti, M. J. Med. Chem.
2007, 50, 3984. (e) Barda, D. A.; Wang, Z.-Q.; Britton, T. C.; Henry,
S. S.; Jagdmann, G. E.; Coleman, D. S.; Johnson, M. P.; Andis, S. L.;
Schoepp, D. D. Bioorg. Med. Chem. Lett. 2004, 14, 3099. (f) Cheltsov,
A. V.; Aoyagi, M.; Aleshin, A.; Yu, E. C.-W.; Gilliland, T.; Zhai, D.;
Bobkov, A. A.; Reed, J. C.; Liddington, R. C.; Abagyan, R. J. Med.
Chem. 2010, 53, 3899.
Ingeneral, rhodium-, ruthenium-, and iridium-catalyzed
asymmetric hydrogenation reactions can be divided into
(3) (a) Greene, M. A.; Yonova, I. M.; Williams, F. J.; Jarvo, E. R.
Org. Lett. 2012, 14, 4293. (b) Taylor, B. L. H.; Swift, E. C.; Waetzig,
J. D.; Jarvo, E. R. J. Am. Chem. Soc. 2011, 133, 389. (c) Wang, X.;
Guram, A.; Caille, S.; Hu, J.; Preston, J. P.; Ronk, M.; Walker, S. Org.
Lett. 2011, 13, 1881. (d) Fessard, T. C.; Andrews, S. P.; Motoyoshi, H.;
Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 9331. (e) Wilkinson,
J. A.; Rossington, S. B.; Ducki, S.; Leonard, J.; Hussain, N. Tetrahedron
2006, 62, 1833. (f) Wilkinson, J. A.; Rossington, S. B.; Ducki, S.;
Leonard, J.; Hussain, N. Tetrahedron: Asymmetry 2004, 15, 3011. (g)
(2) (a) Pathak, T. P.; Sigman, M. S. Org. Lett. 2011, 13, 2774. (b)
Podhajsky, S. M.; Iwai, Y.; Cook-Sneathen, A.; Sigman, M. S. Tetra-
hedron 2011, 67, 4435. (c) Gligorich, K. M.; Iwai, Y.; Cummings, S. A.;
Sigman, M. S. Tetrahedron 2009, 65, 5074. (d) Iwai, Y.; Gligorich, K. M.;
Sigman, M. S. Angew. Chem., Int. Ed. 2008, 47, 3219. (e) Gligorich,K.M.;
Cummings, S. A.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 14193.
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Prat, L.; Dupas, G.; Duflos, J.; Queguiner, G.; Bourguignon, J.;
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r
10.1021/ol303465c
Published on Web 01/11/2013
2013 American Chemical Society

Scheme 1. Synthetic Route to Novel Iridium-Phosphoramidite
Complexa
a THF: tetrahydrofuran. NMM: N-methylmorpholine. IBCF: isobutyl
chloroformate. TsCl: tosyl choride. DMAP: 4-(dimethylamino)pyridine.
DCE: 1,2-dichloroethane. COD: cyclooctadiene. NaBArF: sodium tetrakis-
[3,5-bis(trifluoromethyl)phenyl]borate.
products from substrates lacking ortho-directing groups,
we investigated the use of a new class of modular phos-
phoramidite ligands. The origin of this new ligand’s design
is the application of an aminooxazoline core structure with
a proline-derived pyrrolidine as a key element for impart-
ing rigidity. Synthesis of this ligand proceeds through
standard amino alcohol/amino acid coupling, followed
by cyclization to form the oxazoline, and N-pyrrolidine
deprotection, all of which proceed in good yields and were
perfomed according to previously published procedures.7
The phosphite moiety, a typical element in many iridium-
based hydrogenation catalysts, is incorporated to afford
the phosphoramidite ligand PhosPrOx (Scheme 1).8 Stir-
ring PhosPrOx with [IrCODCl]2 yields the precatalyst
[IrCODPhosPrOx]BArF, although in poor yield.9
We evaluated this new catalyst’s performance in the
hydrogenation of 1 (see Supporting Information for con-
ditions optimization). Excitingly, hydrogenation using this
unique catalyst affords the product in 92:8 er. To the best
of our knowledge, this result represents the highest re-
ported er for an iridium-catalyzed hydrogenation of this
substrate type (i.e., non-ortho-substituted 1,1-diarylalkenes).
As this substrate has two rings displaying unique func-
tional groups, the effects of both were systematically
evaluated to determine the potential structural origin for
face selection.
Figure 1. Previous reported enantioselective hydrogenation of
1,1-diarylalkene derivatives.
two broad classes: those that require coordination of a
Lewis basic functional group in order to achieve high
enantioselectivity and those that require no such coordina-
tion that is auxiliary to the alkene. Of these two classes,
ruthenium- and rhodium-catalyzed hydrogenations typi-
cally fall into the former category, and iridium-catalyzed
hydrogenation is associated with the latter.4 When con-
sidering the asymmetric hydrogenation of 1,1-diarylalk-
enes, the auxiliary coordination requirement of rhodium-
and ruthenium-catalyzed systems constrains the potential
substrate scope to those with Lewis basic groups at the
ortho position on the aryl ring, which has been accom-
plished using oxygen directing groups (Figure 1).3c While
this coordination constraint does not exist for iridium-
catalyzed systems, a steric bias at an ortho-position is required
to achieve excellent enantioselectivity in the hydrogenation of
1,1-diarylalkenes.5 In the absence of such bulk proximal to
the prochiral site, enantioselectivity dramatically erodes, with
the best reported enantiomeric ratio (er) being 82.5:17.5
(Figure 1).6
With an interest in developing a hydrogenation system
capable of yielding highly enantioenriched 1,1-diarylmethine
As a first experiment, removal of one methoxy substi-
tuent, as in substrate 2, led to a significant reduction in
(4) (a) Gridnev, I. D.; Imamoto, T. Acc. Chem. Res. 2004, 37, 633. (b)
Roseblade, S. J.; Pfaltz, A. Acc. Chem. Res. 2007, 40, 1402. (c) Church,
T. L.; Andersson, P. G. Coord. Chem. Rev. 2008, 252, 513.
(5) While this manuscript was under review, an ortho-carboxy-directed
iridium-catalyzed hydrogenation of 1,1-diarylalkenes was reported: Song,
S.; Zhu, S.-F.; Yu, Y.-B.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2012
10.1002/anie.201208606.
(7) For synthetic procedures, see: (a) McKennon, M. J.; Meyers,
A. I.; Drauz, K.; Schwarm, M. J. Org. Chem. 1993, 58, 3568. (b) Miller,
J. J.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 2752. (c) Rajaram, S.;
Sigman, M. S. Org. Lett. 2005, 7, 5473. (d) Jensen, K. H.; Sigman, M. S.
Angew. Chem., Int. Ed. 2007, 46, 4748.
(8) For synthetic procedure, see: Bernsmann, H.; van den Berg, M.;
Hoen, R.; Minnaard, A. J.; Mehler, G.; Reetz, M. T.; De Vries, J. G.;
Feringa, B. L. J. Org. Chem. 2005, 70, 943.
ꢁ
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(6) (a) Pamies, O.; Andersson, P. G.; Dieguez, M. Chem.;Eur. J.
€
2010, 16, 14232. (b) Mazuela, J.; Verendel, J. J.; Coll, M.; Schaffner,
ꢁ
B. n.; Borner, A.; Andersson, P. G.; Pamies, O.; Dieguez, M. J. Am.
€
ꢀ
(9) For synthetic procedure, see: Smidt, S. P.; Menges, F.; Pfaltz, A.
Org. Lett. 2004, 6, 2023.
Chem. Soc. 2009, 131, 12344.
Org. Lett., Vol. 15, No. 3, 2013
647

Table 1. Exploration of Substrate Meta-Directing Group
Effects
Table 2. Substrate Scope
a Absolute configurations of products were assigned by analogy (see
Supporting Information). b Conversion, measured by 1H NMR, is an
average of two experiments. c Er, determined by SFC instrument fitted
with a chiral stationary phase, represents an average of two experiments.
d Reactions performed using 10 mol % catalyst to achieve >95%
conversion. e The same sense of stereoinduction is assumed although
not confirmed.
a Conversions, measured by 1H NMR, are an average of two experi-
ments. b Er, determined by SFC or HPLC instruments fitted with chiral
stationary phases, represents average of two experiments.
enantioselectivity upon hydrogenation (Table 1, entry 2,
er = 74:26). Changing this group further to a 3-n-butoxy
(3) had a negligible effect (Table 1, entry 3, er = 75:25).
These preliminary results suggest that 3,5-substitution on
the aryl ring is required for enhanced enantioselection. To
probe whether this is a purely steric effect or if substituents
containing heteroatoms are required, 3,5-dimethoxy aryl
was replaced by the 3,5-dimethyl variant. This change led
to a considerable lowering of er (Table 1, entry 4, er =
63:37), suggesting the importance of the heteroatom sub-
stituents. Interestingly, elimination of one of the methyl
groups results in a system wherein the catalyst had no
alkene facial preference (Table 1, entry 5). This combina-
tion of results is consistent with high enantioselectivity
resulting from a strongly influential effect of heteroatom
substitution, which is augmented by the steric effect of
having substituents at both the 3- and 5-positions.
As support for this hypothesis, the other aryl ring should
not have a major influence on the outcome of the reaction.
Evaluation of a substrate in which the N-Boc is truncated
leads to an excellent result wherein very similar enantios-
electivity is observed (Table 2, entry 1, er = 92.5:7.5).
Again, removal of one of the meta-substituted methoxy
groups (6) leads to a significant reduction in enantioselec-
tivity (Table 1, entry 6), and evaluation of the correspond-
ing para-methoxy-substituted substrate 7 leads to a nearly
racemic mixture of the hydrogenated product.
648
Org. Lett., Vol. 15, No. 3, 2013

While we had gathered considerable evidence indicating
the importance of etheric aryl substituents, there remained
a possibility that the steric bulk of the 3,5-dimethoxy
substituents was the crucial feature for enantioselection.
To assess this possibility, 8 was synthesized, incorporating
3,5-diethyl substitution as a surrogate to 3,5-dimethoxy. In
poignantsupport ofour hypothesis, 8 washydrogenatedto
yield a racemic product mixture (Table 1, entry 8).
Returning to the requisite 3,5-dimethoxy substitution
pattern on one aryl ring, we evaluated the reaction’s
enantioselective robustness to variation in the geminal aryl
ring. Installing an electron-donating methoxy substituent
at the 4-position (10) afforded the reduced product with
very little change in er (Table 2, entry 2, er = 91.5: 8.5).
Incorporating a 4-methyl substituent into the substrate
(Table 2, entry 3) resulted in a slightly diminshed er
(88.5:11.5). However, a neglible effect upon modification
of 4-position steric bulk from methyl (11) to phenyl is
observed (12, Table 2, entry 4, er = 89:11).
The influence of electron-poor substituents on enantio-
selection was evaluated via 4-chloro (13) and 4-trifluoro-
methyl (14) substrates, which were hydrogenated in 96:4 er
(Table 2, entry 5) and 96.5:3.5 er (Table 2, entry 6),
respectively. These er’s represent a significant improve-
ment in enantioselectivity over the best previously reported
er (82.5:17.5) obtained via an iridium-catalyzed hydrogena-
tion of a 1,1-diarylalkene that contains aryl substitution only
at positions distal (meta and para) from the prochiral site.6b
Convinced of the system’s enantioselective robustness to
substitution at the 4-position, we next investigated the
effect of the 3-position’s variation. Hydrogenation of
substrate 15, bearing the bulky and electron-rich 3-isopropyl
substitution (Table 2, entry 7), yielded the corresponding
diarylmethine in 85.5:14.5 er, representing only a slight
decrease in enantioselection from 4-substituted substrates.
Finally, to challenge the 3,5-dimethoxy substitution
pattern’s capacity for directing facial selection in the
presence of other potential directing groups, we evaluated
the hydrogenation of 16 (Table 2, entry 8), wherein the 3,5-
dimethoxy groups remain intact on one ring, and 3-meth-
oxy substitution is incorporated on the geminal ring. In
this scenario, the substitution patterns in both rings are
each, in the absence of the other, capable of inducing facial
descrimination, although to a lesser extent for 3-methoxy
than for 3,5-dimethoxy substitution. Interestingly, 16 was
reduced in a 71:29 er, nearly identical to that seen for
substrates 2 and 6 (er = 74:26 and 74:26, respectively),
which bear 3-methoxy substitution. We hypothesize that 3,5-
dimethoxy substitution still acts as the dominant force in
this transformation’s enantiodetermining step, while the
observed er erosion is a result of introducing another group
(3-methoxy) with competing directing group capabilities.10
While the scope of this transformation is somewhat
limited by the 3,5-dimethoxy substitution requirement,
this functionality can be considered a removable directing
group. That is, arylmethoxygroupscan befully reduced or
undergo a demethylation, tosylation, and cross-coupling
sequence to rapidly expand the possibilities for the molecular
complexity of these enantioenriched diarylmethines.11
Through our investigation of iridium-catalyzed asym-
metric hydrogenation of substituted 1,1-diarylalkenes, we
have developed a novel phosphoramidite ligand, Phos-
PrOx, and uncovered evidence suggesting that the enan-
tioselective outcome of this iridium-mediated reaction
cannot be easily assigned to either of the aforementioned
asymmetric hydrogenation classes, i.e., asymmetric induc-
tion dependent on coordination auxiliary to the alkene or
that dependent on the proximity of steric bulk to the
prochiral site. Alternatively, we propose that the Lewis
basicity of the 3,5-dimethoxy substitution acts as a direct-
inggroupforthesubstrate, perhapsbyprecoordinating the
substrate to iridium. Such a directed coordination event
would, presumably, orient one alkene face toward iridium,
poising the substrate for subsequent alkene coordination
and hydrogenation to yield distally substituted 1,1-diaryl-
methines in the best enantioselectivities reported, to date,
for an iridium-catalyzed hydrogenation.
Acknowledgment. This work was supported by the
National Science Foundation (CHE-1110599).
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data, and chiral separations
for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(11) (a) Kogan, V. Tetrahedron Lett. 2006, 47, 7515. (b) Nicolaou,
K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442.
(10) Substituting the 3,5-dimethoxy phenyl directing group for 3,4,5-
trimethoxy phenyl, a common biological motif, resulted in low conver-
sion of the starting material to product, and the er was not determined.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 3, 2013
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