Practical P-chiral phosphane ligand for Rh-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1002/ejoc.200400690

A highly electron-donating and conformationally rigid P-chiral bis(trialkylphospholane) ligand 2 (DuanPhos) has been prepared in both enantiomeric forms through a concise synthesis. Rh-2 complex has exhibited remarkably high enantio-selectivities (up to >99% ee) and reactivities (up to 10,000 TON) for the hydrogenation of a wide variety of functionalized prochiral alkenes (5 different types), which provides a very practical catalytic system for the preparation of various synthetically useful chiral compounds. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400690

SHORT COMMUNICATION
Practical P-Chiral Phosphane Ligand for Rh-Catalyzed Asymmetric
Hydrogenation
Duan Liu[a] and Xumu Zhang*[a]
Keywords: Alkenes / Asymmetric hydrogenation / P-chiral phosphane ligand / Resolution / Rhodium
A highly electron-donating and conformationally rigid P-chi-
ral bis(trialkylphospholane) ligand 2 (DuanPhos) has been
prepared in both enantiomeric forms through a concise syn-
thesis. Rh-2 complex has exhibited remarkably high enantio-
selectivities (up to Ͼ99% ee) and reactivities (up to 10,000
TON) for the hydrogenation of a wide variety of function-
alized prochiral alkenes (5 different types), which provides a
very practical catalytic system for the preparation of various
synthetically useful chiral compounds.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Transition metal-catalyzed asymmetric hydrogenation of
prochiral double bonds using such elements as Rh, Ru and
Ir represents one of the most practical and efficient meth-
ods for the preparation of chiral building blocks.[1] Tremen-
dous effort has been devoted into this field during the last
few decades, especially the development of chiral phos-
phorus ligands that can provide not only high enantioselec-
tivities, but also high reactivities.[2] However, the substrate
scope of hydrogenation for a particular ligand or ligand
family is generally very limited with only few exceptions
such as BINAP[3] and DuPhos.[4] While there is no universal
Figure 1. Structures of a new class of highly electron-donating and
conformationally rigid bis(trialkylphospholane) ligands
ligand, the search for more practical ligands with ready reogenic center formation step or a tedious diastereomeric
availability, high enantioselectivity and reactivity, and broad derivatization, separation and deprotection sequence was
substrate scope remains an important goal in asymmetric involved. Thus, an overwhelming challenge in this field is
hydrogenation. to prepare both enantiomers of P-chiral ligands in a practi-
P-chiral phosphorus ligands are highly likely to be a su- cal way.
perior class of ligands for asymmetric catalysis because of
We have designed many conformationally rigid chiral bis-
their abilities to bring the chiral environment to the closest (phosphanes) for achieving high enantioselectivities in
proximity to the transition metal centers. Dramatic results asymmetric hydrogenation.[8] To reach high turnover
by Knowles using P-chiral DIPAMP ligand for Rh-cata- number (TON) and turnover frequency (TOF) as well, we
lyzed hydrogenation in 1970s opened the field of asymmet- envisioned that bis(trialkylphosphanes), especially with tert-
ric catalysis.[5] However, it took nearly two decades for butyl groups, would be a particular class of electron-donat-
other groups to discover efficient methods to prepare P- ing ligands and their Rh complexes would be highly active
chiral phosphane compounds largely due to the synthetic and represent a new generation of hydrogenation catalysts.
difficulties in construction of stereogenic phosphorus cen- For instance, a bis(trialkylphosphane) ligand developed by
ters.[6,7] Moreover, a major drawback of many P-chiral phos- Hoge[9] provided 10 times more turnovers for the hydrogen-
phane synthetic methods developed by Imamoto,[6a] ation of an alkene than the bis(dialkylarylphosphane)
Juge,[6b] Corey,[6c] Evans,[6e] and Livinghouse[6g] is that either DuPhos. Recently, we introduced a highly electron-donating
only one enantiomer of ligand is readily accessible due to P-chiral bis(trialkylphospholane) ligand (1, TangPhos),
the nature of the chiral auxiliaries they used in the ste- which is highly enantioselective and reactive for the Rh-
catalyzed hydrogenation of a wide variety of alkenes.[10]
However, only one enantiomer of 1 (1S,1SЈ,2R,2RЈ-
[a]
Department of Chemistry, The Pennsylvania State University,
TangPhos, Figure 1) is readily accessible due to the usage
of (–)-sparteine, which is available only in one enantiomeric
form, as a chiral induction base. Another very effective P-
chiral ligand BisP*,[11] introduced by Imamoto, is also only
University Park, PA 16802, USA
Fax: (internat.) +1-814-865-3292
E-mail: xumu@chem.psu.edu
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
646
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400690
Eur. J. Org. Chem. 2005, 646–649

Practical P-Chiral Phosphane Ligand for Rh-Catalyzed Asymmetric Hydrogenation
SHORT COMMUNICATION
available in one enantiomeric form for the same reason. triethylamine afforded (1R,1RЈ,2S,2SЈ)-2 [or (RC,S -2)] and
P
Herein, we like to report a concise and practical synthesis (1S,1SЈ,2R,2RЈ)-2 [or (SC,R -2)], respectively, as white solid
P
of a new P-chiral bis(trialkylphospholane) ligand 2 (named in high yields. The absolute configurations of both enantio-
as DuanPhos, Figure 1) in both enantiomeric forms and the mers of 2 were determined by chemical correlations with
highly enantioselective hydrogenation of various function- the single-crystal X-ray crystallography of the complex of
alized alkenes (five different types) using a cationic Rh-2 (–)-6 and (d)-DBT.[15]
complex as the catalyst.
In order to examine the catalytic properties of DuanPhos
The synthetic route to both enantiomers of DuanPhos (2), a cationic Rh complex {Rh(NBD)[(1R,1RЈ,2S,2SЈ)-2]}-
(2) is outlined in Scheme 1, in which a conversional resolu- SbF6 (7) (NBD = norbornadiene) was prepared and used
tion of a racemic bis(phosphane) oxide intermediate is ap- as the catalyst precursor in the hydrogenation of various
plied for the first time for making trialkyl P-chiral phos- prochiral alkenes. Some preliminary results are summarized
phorus ligand.[12] From readily available diol 3, cyclic sulf- in Table 1. Methyl α-(acetamido)acrylate (8a) and methyl
ate 4 was formed in high yield according to the literature α-(acetamido)-2-phenylacrylate (8b), two widely studied α-
procedure.[13] Treatment of 4 with tert-butylphosphane[14] in dehydroamino acid substrates in literature,[2] were explored
the presence of nBuLi, followed by in situ oxidation with with 7 under very mild conditions (methanol as solvent,
H2O2, provided phosphane oxide 5 in excellent yield. CuCl2 room temperature, 20 psi of H2 pressure). After 12 h (this
mediated homo-coupling of 5 in the presence of LDA gave is not optimal) quantitative yields and Ͼ99 % enantiomeric
racemic bis(phosphane) oxide 6. It is noteworthy that the excesses of the products were observed (Entry 1 and 2). It
meso diastereomer of 6, as well as all other possible stereo- is noteworthy that when 0.83 g of 8a was hydrogenated with
isomers, were not formed in an appreciable amount, which only 1 mg (0.01 mol%) of complex 7 under otherwise the
was indicated by the 31P NMR spectra of the crude coup- same reaction conditions, Ͼ99 % ee of (R)-13 were obtained
ling product. This is probably due to the highly selective quantitatively within 2 h (Scheme 2). Thus, high turnover
deprotonation directed by the bulky tert-butyl group and number (10,000) and high turnover frequency (5,000 h–1)
steric hindrance in the coupling step, which only favor the were achieved, indicating the high activity of the Rh-
formation of racemic product. To our delight, racemic 6 can DuanPhos catalyst.
be easily resolved with inexpensive (l)-DBT·H2O (DBT =
dibenzoyl tartaric acid) to afford enantiomerically pure (+)-
6 (Ͼ 99 % ee with one resolution, no further recrystalli-
Table 1. Asymmetric hydrogenation of alkenes with Rh-DuanPhos
complex 7
zation needed) in 30 % yield (of expected from 5). The re-
mainder of 6 was treated with (d)-DBT·H2O to give (–)-6
(Ͼ 99 % ee) in 34 % yield (of expected from 5). Reduction
of (+)-6 and (–)-6 with trichlorosilane in the presence of
[a] The hydrogenations were carried out at room temperature in
MeOH under 20 psi of hydrogen pressure with 7 (1 mol %) as the
catalyst precursor. [b] The ee values were determined by chiral GC
or chiral HPLC. For separation conditions, see ref.[10] [c] The abso-
lute configurations of the products were determined by comparing
the retention times of two enantiomers with reported data.
Scheme 2. Asymmetric hydrogenation of 8a with low catalyst load-
ing
Asymmetric hydrogenation of β-(acetamido)acrylate de-
rivatives, one of the most efficient and practical ways to
obtain unnatural enantiomerically enriched β-amino acids,
remains much less successful compared to the hydrogena-
Scheme 1. Synthesis of ligand 2 (DuanPhos)
www.eurjoc.org
tion of their α-analogues. Few catalysts can provide high
Eur. J. Org. Chem. 2005, 646–649
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
647

D. Liu, X. Zhang
SHORT COMMUNICATION
enantioselectivities for both E and Z isomers of β-(acet- gidity makes DuanPhos an overall more enantioselective
amido)acrylate derivatives,[16] which are formed simulta- ligand than TangPhos.
neously in most synthetic protocols. As shown in Entries 3
In conclusion, a concise and practical synthesis of a P-
and 4, using Rh complex 7 as the catalyst precursor, both chiral bis(phospholane) ligand 2 (DuanPhos) has been de-
ethyl (E)- and (Z)-3-acetamido-2-butenoate (9a and 9b) veloped. Both enantiomers of this highly electron-donating
were hydrogenated in remarkably high ee values (Ͼ99 % and conformationally rigid ligand are easily accessible
and 97 %, respectively). For more challenging β-aryl-substi- through a simple resolution procedure. Rh-DuanPhos com-
tuted substrates 9c and 9d, high ee values (92 %) were also plex has exhibited remarkably high enantioselectivity and
obtained (Entry 5 and 6).
reactivity in the hydrogenation of a wide variety of func-
Enantioselective hydrogenation of α-arylenamides 10 has tionalized prochiral olefins, which provides a very practical
also been investigated with many phosphorus ligands. As catalytic system for the preparation of various synthetically
shown in Entries 7–10, Rh complex 7 provided excellent useful chiral compounds. Optimization of DuanPhos syn-
enantioselectivities (97-Ͼ99 % ee) for the hydrogenation of thesis and further substrate scope expansion of hydrogena-
enamides 10 regardless of the E/Z mixture of tri-substituted tion are currently ongoing.
substrates or the substituents on the phenyl ring. These re-
sults are comparable to the best reported to date.
Acknowledgments
Compared to TangPhos, DuanPhos is expected to be
more conformationally rigid due to the fused benzene rings
on the phospholane rings. It has been demonstrated that
increasing the conformational rigidity would improve the
enatioselectivity.[8,17] Indeed, some preliminary results
showed that, for the hydrogenation of another two types of
functionalized alkenes enol acetates 11 and itaconic acid
derivatives 12, Rh-DuanPhos complex delivered higher en-
antioselectivities than Rh-TangPhos complex[10c] (Table 2).
Especially for an electron-rich enol acetate 12b, significant
increase in enantioselectivity (from 80 % to 96 % ee) was
observed with Rh-DuanPhos complex (Entry 2).
This work was supported by the National Institute of Health. We
also thank Dr. Yennawar and NSF grant for obtaining the X-ray
crystallography.
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[a] The hydrogenations were carried out at room temperature in
THF under 20 psi of hydrogen pressure with 1 mol % of Rh-
DuanPhos complex 7 as the catalyst precursor. All reactions pro-
ceeded completely. [b] The hydrogenations were carried out at room
temperature in EtOAc under 20 psi of hydrogen pressure with 1
mol % of [Rh(TangPhos)(NBD)]SbF6 as the catalyst precursor. All
reactions proceeded completely. [c] THF was used as the solvent.
It is worthy of mentioning that while TangPhos is very
useful for hydrogenation of a variety of alkene substrates to
offer one enantiomer of products, introduction of
DuanPhos is a significant improvement because that: 1) Both
enantiomers of ligand are readily available; 2) preliminary
study shows that, unlike TangPhos, DuanPhos is not par-
ticularly air sensitive, which makes its preparation and
handling more practical;[18] 3) increased conformational ri-
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Practical P-Chiral Phosphane Ligand for Rh-Catalyzed Asymmetric Hydrogenation
SHORT COMMUNICATION
Asymmetry 2004, 15, 2155; j) T. Imamoto, K. V. L. Crepy, K.
Katagiri, Tetrahedron: Asymmetry 2004, 15, 2213.
[8] X. Zhang, Enantiomer 1999, 4, 541.
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nature of that intermediate.
[9] During the course of this investigation, a highly selective un-
symmetrical P-chiral bis(trialkylphosphane) ligand was pre-
pared in both enantiomeric forms by Pfizer research group, but
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[14] tert-Butylphosphane was prepared on lab scale by reduction of
commercially available tert-butyldichlorophosphane with
LAH. It can also be prepared on industrial scale from phos-
phane and isobutene.
[10] a) W. Tang, X. Zhang, Angew. Chem. Int. Ed. 2002, 41, 1612; [15] For a representation of the X-ray crystallography of the com-
b) W. Tang, X. Zhang, Org. Lett. 2002, 4, 4159; c) W. Tang, D.
Liu, X. Zhang, Org. Lett. 2003, 5, 205.
plex of (–)-6 and (d)-DBT, see Supporting Information. The
X-ray crystallography data of this complex has been deposited
with the Cambridge Crystallographic Data Centre (CCDC-
257476). Experimental details of the ligand synthesis and a ge-
neral hydrogenation procedure are also available included in
the Supporting Information.
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[12] Resolution of racemic phosphane oxide with (l)- or (d)-DBT
was previously applied by Imamoto and Miura in the prepara-
tion of a dialkylaryl P-chiral phosphorus ligand, see: T. Miura,
T. Imamoto, Tetrahedron Lett. 1999, 40, 4833. However, an at-
[16] H.-J. Drexler, J. You, S. Zhang, C. Fischer, W. Baumann, A.
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and references cited therein.
[17] J. M. Brown, P. A. Chaloner, Homogeneous Catalysis with Me-
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York, 1983, p. 137.
[18] It was found that an ether solution of DuanPhos was exposed
to air for overnight without any oxidation detected.
Received October 1, 2004
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