Chiral allene-containing phosphines in asymmetric catalysis

Article abstract of DOI:10.1021/ja207748r

We demonstrate that allenes, chiral 1,2-dienes, appended with basic functionality can serve as ligands for transition metals. We describe an allene-containing bisphosphine that, when coordinated to Rh(I), promotes the asymmetric addition of arylboronic ac

Full text of DOI:10.1021/ja207748r

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pubs.acs.org/JACS
Chiral Allene-Containing Phosphines in Asymmetric Catalysis
Feng Cai,† Xiaotao Pu,† Xiangbing Qi,† Vincent Lynch,‡ Akella Radha,† and Joseph M. Ready†,*
†Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas,
Texas 75398-9038, United States
‡Department of Chemistry and Biochemistry, University of Texas at Austin, 1 University Station A5300, Austin, Texas 78712-0165,
United States
S Supporting Information
b
studies of the first optically active transition metalÀallene
ABSTRACT: We demonstrate that allenes, chiral 1,2-
dienes, appended with basic functionality can serve as
ligands for transition metals. We describe an allene-contain-
ing bisphosphine that, when coordinated to Rh(I), pro-
motes the asymmetric addition of arylboronic acids to α-
keto esters with high enantioselectivity. Solution and solid-
state structural analysis reveals that one olefin of the allene
can coordinate to transition metals, generating bi- and
tridentate ligands.
complexes.
Allenes can be formed in the presence of (and thus are stable
toward) many main-group10 and transition metals.11 Nonethe-
less, allenes are known to react with both electrophiles and
nucleophiles, and they are prone to racemization by transition
metals.12 To address this issue, we synthesized allene-containing
phosphines (AllenePhos ligands; Scheme 1). For example,
sulfoxide 2 was prepared as a single diastereomer by means of
an acetylide addition to the corresponding ketone according to a
protocol we recently disclosed.13 Subsequent acylation and
propargylic substitution with a dialkylcuprate provided allene
4. Lithiation of both the sulfoxide and aryl bromide moieties
followed by trapping with a chlorodiarylphosphine yielded bis-
phosphine 5. Recrystallization from hexanes provided Allene-
Phos 5 in optically pure form.
The use of electron-withdrawing groups on the phosphine
proved critical for the stability of the resulting ligand. For example,
trapping with chlorodiphenylphosphine was successful, but bi-
sphosphine 6a immediately oxidized to bisphosphine oxide 6b
upon exposure to air. This sensitivity is surprising in light of the
stability of triphenylphosphine and the fact that steric hindrance
impedes oxidation.14 Likewise, diphenylallene 7 was inaccessible
because the trapping with chlorodiarylphosphines failed. A pro-
duct was isolated that had the desired molecular weight but was
too polar. A clue to the structure of this product was provided by
the attempted syntheses of 8 and 9. In these cases, the phosphines
were obtained but displayed no optical activity. We hypothesized
that reversible cyclization to zwitterion 10 allowed rotation around
the CÀC single bond and consequent racemization.15 Thus, in the
case of phenyl-substituted bisphosphine 7, the zwitterion appears
to be more stable than the allene and was likely what we isolated.
We reasoned that the stereochemical integrity of 5 arises from
the steric environment around the allene. This congestion may
prevent addition to the allene and may prevent rotation of the
resultant zwitterion (i.e., 10) even if addition occurs. Accordingly,
we prepared optically active monophosphines 11 and 12
tereochemistry is often critical to the function of small
S
molecules. Indeed, it is instructive that nearly all natural
products and most new drugs are chiral,1 and there is increasing
pressure to manufacture chiral pharmaceuticals in optically active
form.2 Accordingly, synthetic chemists seek to prepare these
substances as single enantiomers to understand and exploit their
structure and function. Among common approaches for control-
ling absolute stereochemistry, asymmetric catalysis offers signifi-
cant advantages. These methods have been the subject of
academic inquiry and industrial implementation.3 In particular,
the last several decades have witnessed the continued introduc-
tion and development of chiral ligands for transition metals.4
Future developments in asymmetric catalysis will likewise de-
pend on the discovery of novel ligand scaffolds.
Most existing ligands for asymmetric catalysis are character-
ized by either of two types of chirality. Some species owe their
chirality to stereogenic atoms, usually tetrahedral carbon or
phosphorus. Many others are chiral by virtue of hindered
rotation around a CÀC single bond. Several successful catalysts
combine both central and axial chirality.5 Planar chirality and
spiro-type axial chirality6 have also been exploited in asymmetric
catalysis, although less frequently.
Allenes can be chiral but have never been incorporated into
ligands involved in asymmetric catalysis.7 In pioneering work,
Krause and co-workers reported allene-containing ligands for
silver, but catalysis, asymmetric or otherwise, was not
reported.8 Our own efforts in this area led to the invention
of bisphosphine oxide 1, which promotes the addition of SiCl4
to meso-epoxides with high enantioselectivity.9 We report here
a new class of phosphine-containing allenes that serve as
ligands for transition metals and enable asymmetric catalysis
with rhodium. Furthermore, we describe crystallographic
Received: August 16, 2011
Published: October 05, 2011
r
2011 American Chemical Society
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possessing bulky tert-butyl and ortho-substituted phenyl rings.
Additionally, we synthesized the diastereomeric sulfoxides 13 and
the unfunctionalized allene 14.16
We were interested in the coordination properties of the
AllenePhos class of ligands. Thus, bisphosphine 5 and Rh-
(CH2dCH2)2(acac) (acac = acetylacetonato) were combined
in CH2Cl2; single crystals of Rh(acac)(5) were deposited
upon slow evaporation of a pentane solution.17 X-ray analysis
revealed that 5 acts as a tridentate ligand (Figure 1) with both
phosphorus atoms and the less hindered olefin coordinating to
the Rh(I) center. The acac ligand completes a very distorted
trigonal-bipyramidal coordination sphere (PÀRhÀP angle =
147°). In effect, the allene ligand adopts a helical conforma-
tion, wrapping around the Rh center. Coordination to the
olefin bends the allene substantially (CÀCÀC angle = 148°),
but the π systems of the allene remain nearly orthogonal.
The solid-state structure appears to be maintained in solution,
as a 2JPÀP coupling (442 Hz) indicated trans chelation to Rh.18
AllenePhos ligands form stable complexes with several other
transition metals. For example, monophosphine 9 coordinated to
both Ag(I) and Pt(II) with 1:1 stoichiometry. Interestingly,
Ag(TFA)(9) features little interaction between the silver ion
and the allene, and the allene remains nearly linear (CÀCÀC
angle = 179°; Figure 2a). In contrast to silver, PtCl2 forms a
square-planar complex through interaction with both the phos-
phorus and allene functionalities (Figure 2b). Consequently, the
allene shows substantial bending, with a CÀCÀC bond angle of
152°. The allene is coordinated approximately perpendicular to
the coordination plane of Pt. Finally, PtCl2 was found to react
with bisphosphine 5 via the elimination of HCl and the formation
of a CÀPt covalent bond (Figure 2c). Allenes have been
observed in the coordination sphere of transition metals in a
variety of contexts. Complexes of Au,19 Os,20 Mn,21 W,22 and
Co23 that involve direct binding of an allene to a transition metal
are known. Furthermore, allene-containing phosphines have
been characterized as ligands for Fe24 and Os.25 However, this
study is the first to demonstrate that optically active allenes can
coordinate to transition metals and maintain their stereochemical
integrity. These observations suggested that they might be
effective ligands for asymmetric catalysis.
Scheme 1. Synthesis and Structures of Allene-Containing
Ligands
For our initial studies, we focused on the addition of aryl-
boronic acids to α-keto esters (Table 1).26 This transformation
provides synthetically valuable tertiary alcohols in a direct and
atom-economical way using air-stable nucleophilic reagents.
Previous work from the Zhou group revealed encouraging
asymmetric induction using a phosphite ligand.27 Thus, we
examined the addition of methoxyphenylboronic acid (16a) to
benzyl ester 15a in the presence of various allene-containing
ligands. Bisphosphine 5 gave the most promising reactivity and
stereoselectivity. We evaluated several Rh:ligand ratios and
Figure 1. Structures of Rh(acac)(5). (a) X-ray crystal structure. Two
molecules of pentane and disorder in one ÀCF3 group have been
removed for clarity. (b) X-ray crystal structure highlighting key contacts
between the ligands and Rh. Colors: P, orange; O, red; F, green; Rh,
purple; allene highlighted in blue. (c) Line drawing.
Figure 2. X-ray structures of M(AllenePhos) complexes formed between AllenePhos ligands and Ag(I) and Pt(II). Colors as in Figure 1. (a) AgÀCallene
distances: 325 and 339 pm. PÀAgÀO angle: 164°. CÀCÀCallene angle: 179°. (b) PtÀCallene distances: 221 and 209 pm. CÀCÀC allene angle: 152°.
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Table 1. Enantioselective Rh(I)-Catalyzed Addition of
Arylboronic Acids to α-Keto Esters: Evaluation of Ligands,
Solvents and Esters
Table 2. Enantioselective Rh(I)-Catalyzed Addition of
Boronic Acids to α-Keto Esters: Reaction Scope
Entrya
R
Ligand Rh:Lb Time (h) Yield (%)c ee (%)d
1
2
Bn (15a)
Bn
5
1:1
1:2
2:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
12
12
20
1
80
85
83
82
38
81
74
1
83
82
76
20
26
15
13
<5
91
86
80
5
3
Bn
5
4
Bn
11e
12
13a
13b
14
5
5
Bn
40
40
40
40
12
24
24
6
Bn
7
Bn
8
Bn
9
Cy (15b)
iPr (15c)
Ad (15d)
95
82
49
10
11
5
5
a Conditions: 0.06 mmol of 15, 0.12 mmol of 16a, 0.1 M under a N2
atmosphere. b Rh:Ligand ratio. c Isolated yields. d Determined by HPLC.
e Ligand 11 ∼75% ee.
observed no effect of excess ligand (entry 1 vs 2) and a small
decrease in selectivity and reaction rate in the presence of excess
Rh (entry 1 vs 3). Taken together, these data suggest that a 1:1
Rh:bisphosphine ratio is optimal, although precise control of this
ratio is not necessary. Monophosphines 11 and 12 proved much
less selective. Interestingly, ligand 11, in which the phosphine is
distal to the tert-butyl group, generated a more active catalyst than
12, in which the phosphine is proximal to the tert-butyl group (entry
4 vs 5). Likewise, the diastereomeric sulfoxides both promoted the
addition but with little asymmetry (entries 6 and 7).28 Finally,
unfunctionalized allene 14 did not form an active complex with Rh
(entry 8). Additional optimization demonstrated that cyclohexyl
esters performed better than either smaller (entry 1 vs 9) or larger
(entry 9 vs 11) groups, allowing the isolation of the tertiary alcohol
in nearly quantitative yield with >90% ee.
Several α-keto esters were subjected to the optimized reaction
conditions in the presence of AllenePhos 5 (Table 2). In general,
the additions were faster and more enantioselective with elec-
tron-deficient α-keto esters. For example, a cyano-substituted
ketone reacted completely with 16a within 6 h (91% ee; entry
10), while a methyl-substituted ketone required 48 h and reacted
less selectively (84% ee; entry 17). The opposite trend was
observed with the arylboronic acid component: electron-rich
arylboronic acids reacted more quickly than electron-deficient
ones (entry 1 vs 2; entry 21 vs 22), although the enantioselec-
tivities were similar. An electron-rich α-keto ester and an
electron-deficient arylboronic acid reacted inefficiently, even at
elevated temperatures (entry 20). However, the same product
could be accessed by reversing the components, using an
electron-rich arylboronic acid and an electron-deficient α-keto
ester (entry 21). While meta and para substitution on the α-keto
ester were tolerated under the standard conditions, ortho sub-
stitution necessitated elevated temperatures to obtain high yields.
Fortunately, high enantioselectivity was observed even at 40 °C
a Conditions: 0.06 mmol of 15, 0.12 mmol of 16, 0.1 M under a N2
atmosphere, unless otherwise noted. b Isolated yields. c 2.6 mmol of 15,
5.2 mmol of 16. d Reaction conducted at 40 °C. e Reaction at À20 °C.
(entry 25). The reaction was similar on small and multimillimolar
scales (entry 1). Hindered arylboronic acids did not perform well
in the reaction.
Vinylboronic acids can also participate in the addition (Table 2,
entries 27À33). High reactivity and moderate enantioselectivity
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were observed with a trans-disubstituted vinylboronic acid (entry
27). Lower temperature provided slight increases in optical purity.
The more hindered α-substituted vinylboronic acid gave good ee
with electron-deficient α-keto esters (entries 30 and 31) but lower
ee with more electron-rich α-keto esters (entries 32 and 33).
Several conclusions can be drawn from these studies. First,
substantial steric bulk around the allene appears to be necessary
to ensure chemical and stereochemical integrity. Even though
transition metals can racemize allenes,12 bisphosphine 5 retains
its optical activity in the presence of Rh(I), Ag(I), and even
cationic Au(I). Thus, it appears that significant opportunities for
catalysis exist.
’ REFERENCES
(1) Rouhi, A. M. Chem. Eng. News 2004, 82 (24), 47 .
(2) Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. J. Chem. Rev.
2006, 106, 2734.
(3) Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer-Verlag: Berlin, 1999.
(4) Examples of ligand development: (a) Cyclopropanation: Pellissier,
H. Tetrahedron 2008, 64, 7041. (b) Hydrogenation: Tang, W.; Zhang, X.
Chem. Rev. 2003, 103, 3029. (c) Addition to aldehydes: Binder, C. M.;
Singaram, B. Org. Prep. Proced. Int. 2011, 43, 139.
(5) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346.
(6) Fu, Y.; Xie, J.-H.; Hu, A.-G.; Zhou, H.; Wang, L.-X.; Zhou, Q.-L.
Chem. Commun. 2002, 480.
Second, all of the solid-state structures we obtained contain a
π-stacking interaction between two aryl rings on opposite
termini of the allene. This interaction does not require CF3
groups because we previously observed it in the crystal structure
of 1, which lacks CF3 groups.9 We speculate that this character-
istic may provide rigidity around the large coordination sphere
and may be beneficial to asymmetric induction.
(7) Sato, I.; Matsueda, Y.; Kadowaki, K.; Yonekubo, S.; Shibata, T.;
Soai, K. Helv. Chim. Acta 2002, 85, 3383.
(8) L€ohr, S.; Averbeck, J.; Sch€urmann, M.; Krause, N. Eur. J. Inorg.
Chem. 2008, 552.
(9) Pu, X.; Qi, X.; Ready, J. M. J. Am. Chem. Soc. 2009, 131, 10364.
(10) (a) Al: Claesson, A.; Olsson, L. I. J. Am. Chem. Soc. 1979,
101, 7302. (b) RLi and RMgCl: Satoh, T.; Kuramochi, Y.; Inoue, Y.
Tetrahedron Lett. 1999, 40, 8815.
Third, we observed an interaction between Rh or Pt and the
allene itself. In the case of Pt, this interaction is sufficiently
activating that in the presence of a second phosphine, elimina-
tion of HCl destroys the allene and forms a CÀPt bond.
However, in the case of Rh, the interaction may be important
for both catalysis and asymmetric induction. It is noteworthy
that in the solid state, coordination only to the less hindered
olefin (methyl-substituted) was observed. Furthermore, a com-
parison between monophosphines 11 and 12 is intriguing.
Ligand 11 should allow coordination to the less hindered olefin,
and the Rh complex derived from this ligand was very active
(Table 1, entry 4). In contrast, ligand 12 contains a more
hindered olefin proximal to the phosphine, and the correspond-
ing complex was much less active (Table 1, entry 5). Finally,
coordination to the allene in bisphosphine 5 may encourage the
formation of a trans-chelating complex. Consequently, the Rh
center is buried within a deep chiral cavity. Only a limited
number of trans-chelating bisphosphines have been developed
for asymmetric catalysis,29 so additional members of this class
should be valuable. The utility of these ligands is sure to be
expanded by continued developments in ligand design and the
exploration of additional chemical reactions.
(11) (a) Zr: Pu, X.; Ready, J. M. J. Am. Chem. Soc. 2008, 130, 10874.
(b) Cu: Lipshutz, B. H.; Sengupta, S. In Organic Reactions; Wiley: West Sussex,
U.K., 2004. (c) Pd: Yoshida, M.; Gotou, T.; Ihara, M. Tetrahedron Lett. 2004,
45, 5573. (d) Au: Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978.
(e) Fe: Li, C.-Y.; Wang, X.-B.; Sun, X.-L.; Tang, Y.; Xu, Z.-H.; Zhou, Y.-G.; Dai,
L.-X. J. Am. Chem. Soc. 2007, 129, 1494. (f) Zn: Varghese, J. P.; Zouev, I.;
Aufauvre, L.; Knochel, P.; Marek, I. Eur. J. Org. Chem. 2002, 4151. (g) Cr:
Molander, G. A.; Sommers, E. M. Tetrahedron Lett. 2005, 46, 2345. (h) Ti:
Buchwald, S. L.; Grubbs, R. H. J. Am. Chem. Soc. 1983, 105, 5490. (h)
Schlossarczyk, H.; Sieber, W.; Hesse, M.;Hansen, H.-J.;Schmid, H.Helv. Chim.
Acta 1973, 56, 875.
(12) (a) Molander, G. A.; Sommers, E. M.; Baker, S. R. J. Org. Chem.
2006, 71, 1563. (b) Zhang, Z.; Bender, C. F.; Widenhoefer, R. A. J. Am.
Chem. Soc. 2007, 129, 14148. (c) Gandon, V.; Lemiꢀere, G.; Hours, A.;
Fensterbank, L.; Malacria, M. Angew. Chem., Int. Ed. 2008, 47, 7534.
(13) Antczak, M. I.; Cai, F.; Ready, J. M. Org. Lett. 2011, 13, 184.
(14) Barder, T. E.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 5096.
(15) Lithiation did not cause racemization.
(16) See the Supporting Information for details.
(17) The catalyst derived from Rh(CH2dCH2)2(acac) and 10
catalyzed the reaction in Table 2, entry 4 in 68% yield with 81% ee
after 15 h at 40 °C.
(18) Duan, W.-L.; Iwamura, H.; Shintani, R.; Hayashi, T. J. Am.
Chem. Soc. 2007, 129, 2130.
(19) Brown, T. J.; Sugie, A.; Dickens, M. G.; Widenhoefer, R. A.
Organometallics 2010, 29, 4207.
(20) Castro-Rodrigo, R.; Esteruelas, M. A.; Lopez, A. M.; Mozo, S.;
Onate, E. Organometallics 2010, 29, 4071.
’ ASSOCIATED CONTENT
S
(21) Sentets, S.; Serres, R.; Ortin, Y.; Lugan, N.; Lavigne, G.
Organometallics 2008, 27, 2078.
(22) Lee, L.; Wu, I.-Y.; Lin, Y.-C.; Lee, G.-H.; Wang, Y. Organome-
tallics 1994, 13, 2521.
Supporting Information. Experimental details, charac-
b
terization data, and crystal structure files. This material is
available free of charge via the Internet at http://pubs.acs.org.
(23) O’Connor, J. M.; Chen, M.-C.; Fong, B. S.; Wenzel, A.; Gantzel,
P.; Rheingold, A. L.; Guzei, I. A. J. Am. Chem. Soc. 1998, 120, 1100.
(24) Doherty, S.; Elsegood, M. R. J.; Clegg, W.; Mampe, D.; Rees,
N. H. Organometallics 1996, 15, 5302.
’ AUTHOR INFORMATION
Corresponding Author
Joseph.ready@utsouthwestern.edu
(25) Zhang, H.; Lin, R.; Hong, G.; Wang, T.; Wen, T. B.; Xia, H.
Chem.—Eur. J. 2010, 16, 6999.
(26) Sakai, M.; Ueda, M.; Miyaura, N. Angew. Chem., Int. Ed. 1998,
37, 3279.
(27) Duan, H.-F.; Xie, J.-H.; Qiao, X.-C.; Wang, L.-X.; Zhou, Q.-L.
Angew. Chem., Int. Ed. 2008, 47, 4351.
(28) B€urgi, J. J.; Mariz, R.; Gatti, M.; Drinkel, E.; Luan, X.; Blumentritt,
S.; Linden, A.; Dorta, R. Angew. Chem., Int. Ed. 2009, 48, 2768.
(29) Freixa, Z.; van Leeuwen, P. W. N. M. Coord. Chem. Rev. 2008,
252, 1755.
’ ACKNOWLEDGMENT
Funding was provided by NIH (GM074822), NSF (CAREER),
and the Welch Foundation (I1612). Johnson-Matthey generously
provided Rh salts. Molecular images were produced using the UCSF
Chimera package from the University of California, San Francisco
(NIH P41 RR001081).
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