Application of a chiral scaffolding ligand in catalytic enantioselective hydroformylation

Article abstract of DOI:10.1021/ja107433h

The synthesis of β-amino-aldehydes has been achieved through enantioselective hydroformylation of PMP-protected allylic amines. The reaction is accomplished by using a scalemic scaffolding ligand that covalently and reversibly binds to the substrate. These ligands behave like chiral auxiliaries because they are covalently attached to the substrate during hydroformylation; however, similar to traditional asymmetric ligands, they can be used in catalytic quantities. The directed hydroformylation of disubstituted olefins occurs under mild conditions (35 °C and 50 psi CO/H₂), and Z-olefins afford excellent enantioselectivities (up to 93% ee).

Full text of DOI:10.1021/ja107433h

Published on Web 09/30/2010
Application of a Chiral Scaffolding Ligand in Catalytic Enantioselective
Hydroformylation
Amanda D. Worthy,† Candice L. Joe,† Thomas E. Lightburn, and Kian L. Tan*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received August 25, 2010; E-mail: kian.tan.1@bc.edu
Our investigation began by developing an enantiomerically
Abstract: The synthesis of ꢀ-amino-aldehydes has been achieved
through enantioselective hydroformylation of PMP-protected allylic
amines. The reaction is accomplished by using a scalemic
scaffolding ligand that covalently and reversibly binds to the
substrate. These ligands behave like chiral auxiliaries because
they are covalently attached to the substrate during hydroformyl-
ation; however, similar to traditional asymmetric ligands, they can
be used in catalytic quantities. The directed hydroformylation of
enriched scaffolding ligand. In our initial studies on the regio- and
diastereoselective hydroformylation of homoallylic alcohols,7a we
developed a ligand (2) that contains two stereogenic centers (Figure
1). Preliminary experiments with racemic ligand 2 suggested that
the phosphorus stereocenter was not configurationally stable under
the substrate exchange conditions;9 therefore, we designed ligand
1, which contains an additional stereocenter that is readily
incorporated into the ligand synthesis via an enantioselective
asymmetric hydrogenation of 2-isopropylquinoline. By incorporat-
ing the stereocenter on the tetrahydroquinoline ring, thermodynamic
disubstituted olefins occurs under mild conditions (35 °C and 50
psi CO/H2), and Z-olefins afford excellent enantioselectivities (up
to 93% ee).
gearing controls the conformation of the other two stereocenters
even under the exchange conditions. Computational studies sug-
gested that the isopropyl group and C-O bond would have an anti
Hydroformylation is an efficient method for synthesizing alde-
hyde products from olefins. The practicality of this method is
evident with 9 million tons of aldehyde products being produced
relationship in order to minimize any syn-pentane-like interactions
(Figure 1). Upon synthesis of (iPrO)-1, we confirmed that the
per year by hydroformylation.1 The vast majority of these products
absolute and relative configuration of the ligand was the expected
anti-anti configuration by obtaining an X-ray structure of the
are achiral commodity chemicals. The efficiency and utility of
hydroformylation have led many researchers to pursue enantiose-
Rh((iPrO)-1)2(CO)Cl complex (Figure 2).
lective variants.2 Beyond inducing enantioselectivity, there are two
main challenges faced in performing enantioselective hydroformyl-
ation: (1) controlling regioselectivity such that a chiral product is
formed; (2) improving the reactivity of the catalyst system so that
substituted olefins can be employed under mild conditions. Over
the past 20 years there has been significant progress toward
overcoming these obstacles. In 1993 Takaya and co-workers3 as
well as Whiteker and Babin4 demonstrated the first practical
enantioselective hydroformylation of activated olefins such as
Figure 1. Chiral ligand design.
styrene and vinyl acetate. The reaction occurs with both high
regioselectivity (due to electronic preferences or chelation) and high
enantioselectivity. Since this ground-breaking work, efforts in
enantioselective hydroformylation have focused on substrates that
possess an inherent preference to form branched products or that
are symmetrical such that only one regioisomer can be formed.5
Recently, Zhang and co-workers reported the enantioselective
hydroformylation of terminal alkenes that bear nitrogen-based
directing groups (for example Boc and phthalimide) with good
regioselectivities (b/l ) 66:34 to 86:14).6 Our group7 and the Breit
group8 have developed a strategy that employs a catalytic directing
Figure 2. ORTEP structure of Rh(1)2(CO)Cl.
group that controls the regioselectivity in hydroformylation. This
strategy employs a metal-binding ligand (such as 2, Figure 1) that
can covalently and reversibly bind an organic substrate. These
ligands not only control the regioselectivity of the reaction but also
enhance the reactivity such that disubstituted olefins react under
mild conditions. In this publication we extend this concept to
enantioselective catalysis by designing and implementing an
With our enantioenriched ligand in hand we began our studies
of the hydroformylation of amine-based substrates.7b As a first step,
we investigated the ability of 3 to covalently bind to (()-2 and
found that exchange occurs with a Keq of 3.8 ( 0.5 (eq 1). Prior to
hydroformylation 3a was exchanged onto (()-2 and the free alcohol
was removed in Vacuo. Hydroformylation of 3a followed by
immediate reduction10 afforded the ꢀ-amino-alcohol product in 39%
enantioenriched scaffolding ligand. Using 15 mol % of chiral
1
yield by H NMR (37% isolated) with 54% of 3a remaining (eq
scaffolding ligand 1 we obtain ꢀ-amino-aldehyde products with
2).11 Though the conversion is modest we were encouraged that
good yield and enantioselectivity (up to 93% ee).
the regioselectivity was high. With chiral ligand (iPrO)-1 or (MeO)-
† These authors contributed equally.
1,12 the yield is significantly increased and excellent enantioselec-
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C O M M U N I C A T I O N S
tivity (92% ee) is observed (eq 2).13 As a testament to the benefit
of using directing groups the optimized conditions are very mild
for the hydroformylation of a disubstituted olefin, only 35 °C and
50 psi of CO/H2 (eq 2) are required.
decrease in ee to 76% ee is observed for (E)-4b (Table 1, entries
3 and 4). Phenyl substituted 5a affords the product with good
enantioselectivity though with a modest yield (Table 1, entry 5).
In this case 44% of 5a remains at the end of the reaction
demonstrating that the aldehyde is added selectively ꢀ to the
aromatic ring, rather than the electronically preferred R-position.
Entries 6-9 indicate a variety of functional groups are tolerated
under the reaction conditions. For example substrates with either
benzyl or silyl protected alcohols afford the desired product with
high yields and enantioselectivities (Table 1, entries 6 and 7,
respectively). A phthalamide and ester group are also compatible
and maintain high enantioselectivities (Table 1, entries 8 and 9).
Hydroformylation of a terminal olefin provides the product in 73%
ee similar to the selectivities of the E-olefins, emphasizing the
importance of a cis substituent to obtain excellent enantioselec-
tivities.
We have demonstrated that asymmetric hydroformylation can
be performed with good yield and high enantioselectivity by using
an enantioenriched scaffolding ligand. The scaffolding ligand
induces asymmetry more like a chiral auxiliary rather than a
traditional chiral ligand for asymmetric catalysis in that the substrate
is covalently bound to the group generating the stereoselectivity.
Given the robustness and reliability of chiral auxiliaries to induce
asymmetry, we believe scaffolding ligands will be able to afford
high enantioselectivity in a broad range of reactions.
Table 1. Substrate Scope for Enantioselective Hydroformylation
Acknowledgment. We thank Dr. Bo Li for determining the
X-ray structure in Figure 2. We thank the Kingsbury and Hoveyda
groups for use of their SFC and HPLC, respectively. We thank the
ACS-PRF (DNI-5001400) and NIGMS (RO1GM087581) for fund-
ing this project. Mass spectrometry instrumentation at Boston
College is supported by funding from the NSF (DBI-0619576).
Supporting Information Available: Experimental details, com-
pound characterization, and determination of absolute configurations.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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a (i)15 mol % (MeO)-1, 0.05 mol % p-TsOH, 45 °C, benzene; (ii)
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Having optimized the reaction parameters we investigated the
substrate scope. As stated previously (Z)-3a yields the desired
product in excellent enantioselectivity (Table 1, entry 1). When
(E)-3b is hydroformylated the product is formed with good
enantioselectivity (80% ee) and with the same absolute sense of
enantioinduction (Table 1, entry 2). When the olefin is substituted
with a more sterically demanding cyclohexyl group, the high
enantioselectivity is maintained at 86% ee for the Z-olefin but a
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(8) (a) Gru¨nanger, C. U.; Breit, B. Angew. Chem., Int. Ed. 2010, 49, 967–970.
(b) Gru¨nanger, C. U.; Breit, B. Angew. Chem., Int. Ed. 2008, 47, 7346–
7349.
(11) The regioselectivities cannot be determined, because the product of
hydroformylation of the carbon distal from the aniline functionality is not
stable under the reaction conditions. This product likely forms a cyclic
hemi-aminal that decomposes under the acidic conditions. Estimates of the
regioselectivities are provided in the Supporting Information.
(12) Ligand (MeO)-1 is a mixture of four diastereomers; see Supporting
Information for further discussion. The pre-equilibration with 3 prior to
hydroformylation forms a single diastereomer of substrate bound ligand.
We prefer to use (MeO)-1 over (iPrO)-1 because it can be synthesized in
greater yield and affords comparable results to (iPrO)-1 (see eq 2).
(13) At the request of a reviewer we performed the reaction without pre-
exchanging the substrate onto (MeO)-4. A comparable result is achieved
with a marginally lower yield (67%) and ee (91%).
(9) The configurational instability of the phosphorous is unusual given the
mild exchange conditions. We believe the instability arises from the
fact that an iminium ion is a likely intermediate under the acidic
exchange conditions. Rehybridization of the phosphorous to sp2 would
generate an aromatic heterocycle significantly lowering the barrier to
inversion. Alternatively, the heterocycle may be ring opening to the
secondary phosphine, which epimerizes and then ring closes to reform
the heterocycle.
(10) Attempts to isolate the aldehyde directly resulted in poor recovery. Hayashi
and co-workers had similar isolation problems: Hayashi, Y.; Tsuboi, W.;
Ashimine, I.; Urushima, T.; Shoji, M.; Sakai, K. Angew. Chem., Int. Ed.
2003, 42, 3677–3680.
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