Tunable P-Chiral Bisdihydrobenzooxaphosphole Ligands for Enantioselective Hydroformylation

Article abstract of DOI:10.1021/acs.orglett.6b01452

Air-stable and tunable chiral bisdihydrobenzooxaphosphole ligands (BIBOPs) were employed in rhodium-catalyzed asymmetric hydroformylation of various terminal olefins with excellent conversions (>99%), moderate-to-excellent enantioselectivities (up to 95:5 er), and branched to linear ratios (b:l) of up to 400.

Full text of DOI:10.1021/acs.orglett.6b01452

Letter
pubs.acs.org/OrgLett
Tunable P‑Chiral Bisdihydrobenzooxaphosphole Ligands for
Enantioselective Hydroformylation
Renchang Tan,† Xin Zheng,† Bo Qu,‡ C. Avery Sader,‡ Keith R. Fandrick,‡ Chris H. Senanayake,*,‡
and Xumu Zhang*,†
†Department of Chemistry and Chemical Biology and Department of Medicinal Chemistry, Rutgers, The State University of New
Jersey, Piscataway, New Jersey 08854, United States
‡Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, United
States
S
* Supporting Information
ABSTRACT: Air-stable and tunable chiral bisdihydrobenzooxaphosphole ligands (BIBOPs) were employed in rhodium-
catalyzed asymmetric hydroformylation of various terminal olefins with excellent conversions (>99%), moderate-to-excellent
enantioselectivities (up to 95:5 er), and branched to linear ratios (b:l) of up to 400.
symmetric hydroformylation (AHF) is a powerful
homogeneous catalytic process that constructs optically
A
active aldehydes by one-carbon homologation in a single step
from olefins.1 Since the discovery of the phosphine−phosphite
Binaphos ligand for Rh-catalyzed AHF in 1993,2 several P−O-
based phosphite and phosphonite ligands have been developed,
including Chiraphite,3 Kelliphite,4 Yanphos,5 and Ding’s
phosphonite ligands.6 Phosphites and phosphonites are good
π acceptors, favoring CO dissociation in the catalytic cycle and
accelerating the reaction rate.7 As a result, phosphine ligands
that are highly reactive for asymmetric hydrogenation are
generally not effective for AHF. There has been an extensive
search of chiral ligands from existing ones to join the family of
the few ligands that are effective for AHF.8 Recently,
phosphorus ligands with a bisphospholane backbone have
emerged as another effective ligand structure for this
application, such as Esphos,9 bis(diazaphospholane) (BDP)
ligands,10 Duanphos,11 and Ph-BPE.12 The development of
efficient chiral phosphorus ligands has greatly enhanced the
regio- and enantioselectivity in rhodium-catalyzed AHF.
Structurally tunable and operationally convenient chiral
phosphorus ligands remain of great interest in further
broadening the applications of AHF reactions.
Figure 1. BIBOP ligands for AHF reactions.
direct contrast to the highly air-sensitive Tangphos ligand.
Furthermore, these features greatly increase the conformational
rigidity of the ligands, which is essentially important to affect
the reactivity and selectivity of AHF. We envisioned that these
ligands could be effective for rhodium-catalyzed AHF.
Our initial investigation started with the classic vinyl acetate
(2) as the model substrate. Excess ligand with a high L/Rh ratio
is commonly required to stabilize the catalytically active
complex under high-temperature conditions in hydroformyla-
tion reactions to maintain the catalyst activity and enantiose-
lectivity.7 A Rh/L ratio of 1:3.0 was applied at 60 °C for 20 h in
toluene in the presence of 1.0 mol % Rh(acac)(CO)2 and 3.0
mol % (R)-BIBOP (1a) under 20 bar syngas (CO/H2 = 10/
10). To our delight, vinyl acetate was fully hydroformylated
We recently reported a series of air-stable, white-crystalline,
C2-symmetric, P-chiral bisdihydrobenzooxaphosphole ligands
(BIBOPs) (Figure 1) for highly enantioselective asymmetric
hydrogenation of N-acetyl enamides, α-arylenamides, α-
(acylamino)acrylic acids, and β-(acylamino)acrylate.13 These
crystalline dimeric ligands are stable in air and can be
conveniently synthesized on a kilogram scale.13a The air-
stability property results from the two benzene rings at the 4-
and 5-positions adjacent to the phosphorus atoms, which is in
Received: May 18, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01452
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
with a 25:1 branched to linear (b:l) regioisomeric ratio and
91:9 er of the branched isomer. Furthermore, the ligand was
found to be stable under the reaction conditions, and no access
ligand is required. The same conversion and enantioselectivity
were obtained with a slight excess ligand loading at a Rh/1a
ratio of 1:1.2 (Table 1, entry 3).
Table 2. AHF of Vinyl Acetate Derivatives
a
Table 1. AHF Screening of Vinyl Acetate 2
b
b
c
entry
L
Rh/L
CO/H2 conv (%)
b:l
er
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1b
1c
1d
1:3.0
1:2.0
1:1.2
1:0.9
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
10/10
10/10
10/10
10/10
5/15
>99
>99
>99
>99
>99
>99
>99
28
25:1
20.6:1
20:1
91.0:9.0
91.3:8.7
91.5:8.5
72.5:27.5
91.2:8.8
91.0:9.0
95.3:4.7
71.0:29.0
51.0:49.0
13:1
27:1
15/5
27:1
10/10
10/10
10/10
>200:1
12:1
a
1
Conversions and b:l ratios were determined by H NMR spectros-
b
96.4
20:1
copy (see the Supporting Information). Determined by chiral GC.
a
Reaction conditions: 2 (1.0 mmol) catalyzed by Rh−ligand in toluene
(0.5 mL) at 60 °C for 20 h under a syngas pressure of 20 bar.
b
Conversions and branched to linear (b:l) ratios of the products were
c
1
determined by H NMR spectroscopy. Determined by chiral GC.
Next, the CO partial pressure was varied since it affects both
the conversion and regio- and enantioselectivity of AHF.7 The
catalyst system turns out to be robust toward the CO pressure.
When the CO partial pressure in CO/H2 was decreased from
10/10 to 5/15 (Table 1, entry 5) or increased from 10/10 to
15/5 (Table 1, entry 6), the conversion remained >99%. Both
the b:l ratios and the enantiomeric ratios were the same under
different CO pressures (Table 1, entries 3, 5, and 6). A syngas
pressure of CO/H2 = 10/10 was selected for further studies.
Among the BIBOP ligands, the Ph substituent (1c) led to
low conversion and enantioselectivity (Table 1, entry 8). The
Me substituent (1d) also led to a low enantiomeric ratio,
although it provided almost full conversion (Table 1, entry 9).
To our delight, (R)-MeO-BIBOP (1b) provided an increased
regioselectivity with a b:l ratio of >200:1 and a higher
enantioselectivity of 95.3:4.7 er (Table 1, entry 7). On the
other hand, the structurally related Duanphos and Tangphos
ligands produced poor reactivity and enantioselectivity.
With the optimized reaction conditions in hand, AHF of
vinyl acetate derivatives was explored in the presence of the
MeO-BIBOP ligand (Table 2). The conditions are applicable to
both the aliphatic and aromatic substituents. All of the
substrates were successfully converted to the desired aldehydes
with excellent enantioselectivities of up to 95.3:4.7 er. It is
noteworthy that the regioselectivities are outstanding, with
aldehyde b:l ratios of up to 415:1 (entry 4).
Figure 2. DFT (UB3LYP/LanL2DZ for Rh; UB3LYP-gCP-D3/6-
31G(d) for all other atoms)-calculated transition state for the Rh−
hydride olefin insertion and stereochemical model.
corrections of Grimme and co-workers were applied to all of
the stationary points to correct for basis set superposition error
with 6-31G(d) and missing van der Waals dispersion in B3LYP,
respectively. On the basis of the reported mechanism,19 the
calculated rate-determining transition state of the stereochemi-
cally defining Rh−hydride olefin insertion shows that the vinyl
group binds to the rhodium center to position the acetate away
from the bulky tert-butyl group of the BIBOP ligand. In this
orientation, the Si face of the olefin is bound to the rhodium
center and ultimately receives the carbonyl functionality,
generating the R configuration of the aldehyde. This result is
consistent with the experimental data.
AHF of 1,1-disubstituted olefins has been a challenging task,
and only a few ligands can deliver acceptable enantioselectiv-
ities.11,20 BIBOPs were tested in the AHF of 1-
(trifluoromethyl)vinyl acetate (12) (Scheme 1). BIBOP (1a)
To obtain a better understanding of the origin of the
enantioselectivity, computational studies were conducted for
the hydroformylation process of vinyl acetate in the presence of
(R)-BIPOP (1a) as the ligand (Figure 2). All of the calculations
were performed with Gaussian 0914 using density functional
theory (DFT) employing the UB3LYP functional15 and the
LANL2DZ basis set with the effective core potential for Rh16
and UB3LYP-gCP-D3/6-31G(d) for all other atoms. The
geometrical counterpoise (gCP)17 and dispersion (D3)18
Scheme 1. AHF of 1,1-Disubstituted Olefin 12
B
DOI: 10.1021/acs.orglett.6b01452
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Letter
turned out to be an effective ligand. Chiral aldehyde 13 was
produced with a 90:10 er and a b:l ratio of 8.5:1. 13 is a key
precursor for enantiomerically pure 2-(trifluoromethyl)lactic
acid, which is an important building block for many active
pharmaceutical ingredients.21
To further expand the substrate scope, AHF was tested on a
series of allylic derivatives (Table 3). Allylic compounds are
good to excellent enantioselectivities. The ease of synthesis and
excellent air stability make BIBOP ligands stand out as a unique
ligand structure in the field of hydroformylation. Computa-
tional studies have provided insights into the reaction
mechanism, in particular the Rh−hydride olefin insertion
process. Application of these ligands on other olefin substrates
is currently ongoing.
ASSOCIATED CONTENT
* Supporting Information
Table 3. AHF of Allylic Substrates
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01452.
Experimental procedures and characterization data for all
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chris.senanayake@boehringer-ingelheim.com.
*E-mail: xumu@rci.rutgers.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by the National Science
Foundation (CHE 0956784).
■
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