Development of new P-chiral P,π-dihydrobenzooxaphosphole hybrid ligands for asymmetric catalysis

Article abstract of DOI:10.1021/ol5027798

A new family of P-chiral P,π-hybrid ligands was prepared from the dihydrobenzooxaphosphole core. These new ligands were demonstrated to be both sterically and electronically tunable at the substituents on the phosphorus atom and the π-system of the ligand. Application of these new ligands to the catalytic asymmetric addition of boronic acids to imine electrophiles was shown to proceed with high levels of enantioinduction. (Chemical Equation Presented).

Full text of DOI:10.1021/ol5027798

Letter
pubs.acs.org/OrgLett
Development of New P‑Chiral P,π-Dihydrobenzooxaphosphole
Hybrid Ligands for Asymmetric Catalysis
Joshua D. Sieber,* Divya Chennamadhavuni,† Keith R. Fandrick, Bo Qu, Zhengxu S. Han, Jolaine Savoie,
Shengli Ma, Lalith P. Samankumara, Nelu Grinberg, Heewon Lee, Jinhua J. Song, and Chris H. Senanayake
Department of Chemical Development, Boehringer Ingelheim Phamaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield,
Connecticut 06877-0368, United States
S
* Supporting Information
ABSTRACT: A new family of P-chiral P,π-hybrid ligands was
prepared from the dihydrobenzooxaphosphole core. These
new ligands were demonstrated to be both sterically and
electronically tunable at the substituents on the phosphorus
atom and the π-system of the ligand. Application of these new
ligands to the catalytic asymmetric addition of boronic acids to
imine electrophiles was shown to proceed with high levels of enantioinduction.
Scheme 1. Dihydrobenzooxaphosphole Ligands
symmetric catalysis is an indispensable tool for the rapid
1
Aand atom-economical
preparation of valuable chiral
nonracemic organic compounds.2 In particular, asymmetric
catalytic processes employing a transition metal catalyst in
conjunction with a chiral phosphine ligand have been widely
developed and applied to the synthesis of complex molecules.2,3
In general, the vast majority of these chiral ligands rely on
chirality on the ligand backbone rather than directly at
phosphorus (P-chirality).4 It has been argued that placing the
ligand chirality closer to the metal center may allow for better
control of enantioselectivity,4,5 and therefore, P-chiral ligands
should be highly efficient ligands for asymmetric catalysis.
While several P-chiral phosphine-based ligands are known,6 the
difficulty associated with the preparation of P-stereogenic
compounds in enantiomerically pure form is likely the reason
that there are significantly less of these ligands available
compared to their “backbone chiral” counterparts.7
Recently, our laboratories have developed a series of useful P-
chiral ligands (2, Scheme 1) derived from a dihydrobenzoox-
aphosphole core (1) prepared through alkyl/arylation of the
deprotonated phosphine oxide 1. This enables the synthesis of
monophosphines (BI-DIME) useful in hindered8 and asym-
metric9 cross-coupling reactions, bis(phosphines) (BIBOP,
POP) useful for asymmetric hydrogenation10,11 and propargy-
lation,12 and P,N-ligands (BoQPhos) useful for Ir-catalyzed
asymmetric hydrogenation.13 In an effort to further exploit the
chiral motif of 1 for useful catalytic asymmetric processes, we
envisioned that trapping the intermediate anion of 1 with a
cinnamyl electrophile would allow access to P-chiral P,π-hybrid
ligands (JoshPhos).14 Additionally, because we have recently
developed a powerful technique for the general synthesis of P-
chiral phosphine oxides15 that enables the synthesis of 1 with
variable R groups, this new P,π-hybrid ligand class would be
highly tunable, whereby both the steric and electronic
properties of the ligand may be modulated by modification of
the substituent on phosphorus (R) and/or the alkene (Ar).
Herein we disclose the development of this new family of P-
chiral P,π-hybrid ligands and describe their application in the
Rh-catalyzed addition of boronic acids to imine electrophiles.
The preparation of a series of JoshPhos ligands was
performed using the strategy outlined (Scheme 2). Deproto-
nation with LDA, followed by trapping with various cinnamyl
chloride derivatives, led to the required oxides in moderate to
good yields. Titanium-mediated reduction chemoselectively
generated the desired ligands. For ligands containing aryl
groups with strong electron-withdrawing groups (i.e., CF3), the
alkylation reaction using the corresponding cinnamyl derivative
failed. For these ligands, cross-metathesis between allylated
material 9 and the appropriate styrene derivative was employed.
Received: September 19, 2014
Published: October 9, 2014
© 2014 American Chemical Society
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Letter
Scheme 2. Synthesis of P-Chiral P,π-Hybrid Ligands
With access to a series of P,π-hybrid ligands realized, we next
examined their utility in asymmetric reactions. Because of the
prevalence of chiral nonracemic amines in biologically active
compounds and natural products, we first chose to investigate
the Rh-catalyzed addition of boronic acids to imine electro-
philes16 to make these important functional groups in an
enantioselective fashion. Initially, the reaction between tosyl
imine 12 and boronic acid 13 was investigated (Table 1).
proton sponge (entry 9) gave reduced amounts of 15a along
with good yields of 14a.
After having identified conditions that promoted the addition
of boronic acid 13 to imine 12 in good yield with excellent
enantiocontrol, we next examined this procedure with a more
synthetically useful imine (Table 2).17 Somewhat surprisingly,
a
Table 2. Boronic Acid Addition to Furfuralimine
a
Table 1. Boronic Acid Addition to Benzaldimine
b
b
c
entry
JoshPhos
% conv
17/18
% yield 17
er 17
d
1
L2
L2
42
70
62:38
80:20
96:4
26
36
41
95
59
62
56
92
96:4
96:4
10:90
86:14
97:3
97:3
97:3
97:3
b
b
c
2
3
4
5
6
7
8
entry
base
% conv
14a/15a
% yield 14a
er 14a
e
d
L3
60
1
TEA
TEA
TEA
83
33
90
95
74
<5
45
90
96
81:19
76:24
89:11
96:4
56
21
60
80
99:1
99:1
99:1
99:1
99:1
de
,
L4
L5
L6
L7
L8
>97
76
>97:3
94:6
2
3
4
5
6
7
8
9
94
81:19
74:26
93:7
DIPEA
f
89
2,6-Lut
>97:3
55
>97
DMAP
0
a
f
Reaction conditions: imine (0.15 mmol), boronic acid (0.30 mmol),
DBU
76:24
89:11
97:3
22
99:1
97:3
99:1
g
base (0.15 mmol), Rh (4 mol %), JoshPhos (5.2 mol %), 0.5 M KOH
DABCO
proton sponge
69
75
b
(6 mol %), toluene (0.62 mL), 60 °C, 6 h. Determined by 1H NMR
c
d
spectroscopy. Isolated yield. DIPEA used in place of proton sponge.
a
Reaction conditions: imine (0.19 mmol), boronic acid (0.38 mmol),
e
The opposite enantiomer of L3 used.
base (0.21 mmol), Rh (4 mol %), L2 (5.2 mol %), 0.5 M KOH (6 mol
b
%), toluene (0.78 mL), 60 °C, 6 h. Determined by 1H NMR
c
d
e
the optimal conditions for imine 12 using DIPEA as base were
not suitable for heterocyclic aldimine 16 (entry 1). Use of
proton sponge reduced the amount of hydrolysis product 18a
and improved the yield of 17a slightly (entry 2). At this point,
we examined the series of JoshPhos ligands we had prepared in
this reaction (entries 3−8). Modifying the substituent on
phosphorus from the bulky tert-butyl group to aromatic groups
gave good to excellent reactivity, but enantioselectivity was
reduced (entries 3 and 4). These results demonstrated the
necessity of the P-tert-butyl moiety for high enantioselectivity
and initially guided us to prepare the JoshPhos family (Scheme
2), whereby the electronic nature of the ligand was tuned by
modulating the aryl group of the ligand alkene. Gratifyingly, the
electronics of the alkene of the JoshPhos ligands had a
significant impact on reactivity and could be used as a suitable
tuning element for this series of new ligands (entries 5−8).
Ligand L8 containing the most electron-deficient π-system gave
the highest yield of 17a in conjunction with the highest
enantioselectivity (entry 8).
spectroscopy. Isolated yield. 2.0 equiv of base used. KOH omitted.
f
g
NMR yield. 0.55 equiv of base used.
Ligand L1 was first tested in this reaction, but no evidence for
the formation of 14a was observed. However, use of ligand L2
did afford the desired product in modest yield, and we were
excited to find that high levels of enantioinduction were
obtained in the reaction (entry 1). Additionally, the yield of 14a
was significantly reduced in the absence of KOH (entry 2). The
main byproduct of the reaction was a result of imine hydrolysis
followed by addition of 13 (15a). Reducing the amount of TEA
from 2.0 to 1.1 equiv led to a reduction in the amount of
product 15a (entry 1 vs 3). This result implied that the amine
base affected the rate of hydrolysis of 12, and therefore, we
hypothesized that the yield of 14a could be improved by tuning
the added base. After a survey of amine bases (entries 3−9), it
was discovered that bulky bases such as DIPEA (entry 4) or
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With identification of the optimal ligand for the addition of
boronic acids to imines, we next explored the scope of this new
catalytic system (Scheme 3). Electron-rich aldimines gave the
The mechanism of the Rh-catalyzed addition of boronic acids
to a variety of unsaturated electrophiles has been well-
established in the literature.18b,19 To verify that the π-system
of the JoshPhos ligand was involved in binding to the Rh atom
of the catalyst, the reaction of an equimolar mixture of ligand
L2 and [(η2-CH2CH2)2RhCl]2 was studied by NMR spectros-
copy (Scheme 4). By 31P NMR spectroscopy, free ligand was
no longer present, and only a single phosphorus doublet
resonance was observed at 107 ppm (JRh−P = 188 Hz).
a
Scheme 3. Addition of Boronic Acids to Tosyl Imines
1
Furthermore, by H NMR spectroscopy, the alkene protons of
the free phosphine were shifted upfield to 3.91 and 4.30 ppm in
the new complex, consistent with olefin binding. This data
supports the formation of complex 20 that is likely a dimer
based on similar reported complexes.20 Subsequent reaction of
20 with hydroxide led to the formation of 21 that was
characterized by X-ray crystallography (21•CH2Cl2).
The X-ray single-crystal structure of the [(L2)RhOH]2
catalyst enabled insight into the mechanism of enantiomeric
induction in these asymmetric processes. Transmetalation
between 21 and ArB(OH)2 followed by imine binding is
expected to furnish intermediate complexes 22/23. In these
complexes, the preferred geometry about the Rh atom would
place the Ar group trans to the olefin substituent of the
JoshPhos ligand and the imine electrophile trans to the
phosphorus group due to the “trans-effect”.21,22 The chirality of
the JoshPhos ligand bound to Rh places the arene group of the
ligand alkene in the “northwest” quadrant of the Rh complex.
This orientation forces imine binding to be preferred from the
si-face (22) to avoid a steric interaction between the aryl group
on the ligand alkene and the tosyl group of the imine (23).
Modeling of the transition state for the conversion of 22 to
product using DFT23,24 afforded TS-1 that is in agreement with
this proposal. Lastly, this catalytic system also affected the
addition of phenyl boronic acid to cyclohexenone with high
enantiocontrol. Modeling of this system using DFT was in
complete agreement with the proposed stereochemical
model.25
a
Reaction conditions: imine (0.175 mmol), boronic acid (0.35 mmol),
proton sponge (0.175 mmol), Rh (4 mol %), JoshPhos (5.2 mol %),
0.5 M KOH (6 mol %), toluene (0.71 mL), 60 °C, 6 h.
highest yields (19a), while a reduction in yield was observed as
the imine became more electron-poor due to the formation of
increased amounts of hydrolysis products (compare 19a vs 19b
vs 19c). More sterically hindered aldimines bearing ortho-
substitution participated well in the reaction (19d and 19e).
Aryl bromides were also tolerated in the reaction (19g). Using
an electron-poor boronic acid nucleophile led to reduced
reactivity (19h and 19j). In these cases, the yield could be
improved by switching to ligand L6.
In conclusion, we have designed and developed a new family
of P-chiral P,olefin hybrid ligands based on the dihydroben-
zooxaphosphole core. To the best of our knowledge, these are
the first P-chiral P,π-hybrid ligands reported. These new ligands
were demonstrated to be both sterically and electronically
tunable at the substituents on the phosphorus atom and the π-
Scheme 4. Catalyst Structure and Stereochemical Model
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Organic Letters
Letter
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(15) Han, Z. S.; Goyal, N.; Herbage, M. A.; Sieber, J. D.; Qu, B.; Xu,
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ASSOCIATED CONTENT
■
S
* Supporting Information
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Complete literature citations, experimental procedures, charac-
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: joshua.sieber@boehringer-ingelheim.com.
Present Address
†(D.C.) Department of Chemistry, University of Connecticut,
Storrs, CT 06269.
Notes
The authors declare no competing financial interest.
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