A Simple Strategy for the Preparation of P-Chirogenic Trost Ligands with Different Absolute Configurations

Article abstract of DOI:10.1002/ejoc.202000833

P-chirogenic compounds are useful ligands and organocatalysts in asymmetric synthesis. However, the lack of preparative methods and their configurational instability have significantly hampered their development. Herein, we report a simple strategy for the preparation of enantiomerically pure P,C-chirogenic diphosphines. Amidation of the borane adducts of rac-phosphinobenzoic acids with enantiomerically pure trans-1,2-diaminocyclohexane afforded a 1:2:1 mixture of the diastereomers (C*,C*,R_p,R_p), (C*,C*,R_p,S_p), and (C*,C*,S_p,S_p), which were separated by column chromatography on silica gel. The prepared (C*,C*,R_p,R_p) and (C*,C*,S_p,S_p) stereoisomers were identical to those obtained from the enantiopure phosphines, which were synthesized by a multi-step route using chiral auxiliaries. Hence, this simple, short and convenient route towards P,C-chirogenic diphosphines obviates the use of chiral auxiliaries and enables the access to diphosphines with differently configured P-stereocenters.

Full text of DOI:10.1002/ejoc.202000833

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: A Simple Strategy for the Preparation of P-Chirogenic Trost
Ligands with Different Absolute Configurations
Authors: Xiao-Bing Lu and Peng Du
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000833
Link to VoR: https://doi.org/10.1002/ejoc.202000833
01/2020

10.1002/ejoc.202000833
European Journal of Organic Chemistry
FULL PAPER
A Simple Strategy for the Preparation of P-Chirogenic Trost
Ligands with Different Absolute Configurations
Peng Du[a] and Xiao-Bing Lu*[a]
[a]
P. Du, Prof. X. Lu
State Key Laboratory of Fine Chemicals
Dalian University of Technology
2 Linggong Road, Dalian, 116024, China
E-mail: sdqddupeng@163.com; xblu@dlut.edu.cn
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: P-chirogenic compounds are useful ligands and
organocatalysts in asymmetric synthesis. However, the lack of
preparative methods and their configurational instability have
significantly hampered their development. Herein, we report a simple
strategy for the preparation of enantiomerically pure P,C-chirogenic
diphosphines. Amidation of the borane adducts of rac-
phosphinobenzoic acids with enantiomerically pure trans-1,2-
diaminocyclohexane afforded a 1:2:1 mixture of the diastereomers
(C*,C*,Rp,Rp), (C*,C*,Rp,Sp), and (C*,C*,Sp,Sp), which were
separated by column chromatography on silica gel. The prepared
(C*,C*,Rp,Rp) and (C*,C*,Sp,Sp) stereoisomers were identical to
those obtained from the enantiopure phosphines, which were
synthesized by a multi-step route using chiral auxiliaries. Hence, this
simple, short and convenient route towards P,C-chirogenic
diphosphines obviates the use of chiral auxiliaries and enables the
access to diphosphines with differently configured P-stereocenters.
stereoselective synthesis of P-chirogenic Trost ligands bearing a
D-labelled phenyl ring at each P-atom, and combined
computational and NMR studies to investigate the origin of the
selectivity in asymmetric allylic alkylation reactions catalyzed by
chiral palladium complexes.[16] These studies inspired the
synthesis of several diphosphine ligands, including tert-
BuBisPhos,[5] tert-BuMiniPhos,[4c,4d] BenzPphos, DioxyBenzPhos,
and QuinoxPhos, and the evaluation of their performance in
asymmetric hydrogenations.[17] Additionally, the successful
commercial application of DiPAMP in the L-DOPA production by
asymmetric hydrogenation in industrial scale further
demonstrated the efficiency of P-chirogenic ligands (Scheme
1b).[3] Consequently, chiral trans-1,2-diaminocyclohexane-based
diphosphine ligands bearing P-chirogenic phosphines are likely
to exhibit excellent activities and enantioselectivities in
asymmetric catalytic transformations.
Introduction
P-chirogenic phosphines are extensively employed in
asymmetric catalysis as chiral ligands[1] and organocatalysts.[2]
For example, the use of DiPAMP,[3] MiniPhos,[4,1g] BisPhos,[5]
SMSPhos,[6] TangPhos,[7] and DuanPhos[8] has led to excellent
enantioselectivities in various asymmetric transformations. In
contrast to the extensive studies on C-chirogenic
phosphines,[1a,1c,9] the development of P-chirogenic ligands has
been hampered by the scarcity of general preparative methods
and configurational instability of the P-stereocenter.
Scheme 1. Representative ligands bearing trans-1,2-diaminocyclohexane (a)
and tert-butyl or 2-methoxyphenyl (o-An) subunits (b).
Previous studies revealed that P,C-chirogenic phosphine
ligands provided higher levels of asymmetric induction than C-
chirogenic ones because of the proximity between the
chirogenic and catalyst activation centers.[7a,8,10] In addition, the
chiral C-atom possibly stabilizes the configuration of the P-
atom.[10b] Therefore, the presence of chiral C- and P-atoms in the
same framework would be particularly advantageous for the
asymmetric reactions because of the steric and electronic
contributions of each chirogenic moiety. Nevertheless, only a
few studies addressed the incorporation of both P- and C-
stereocenters into phosphine ligands.[11]
Trans-1,2-diaminocyclohexane is a versatile chiral building
block for the preparation of privileged chiral ligands such as
salen,[12] Trost,[13] and other iminophosphine ligands[14] (Scheme
1a). In 1998, Imamoto et al. reported the superior
enantioselectivity induced by tert-butyl and methyl substituted
diphosphine ligands in transition metal catalyzed asymmetric
reactions.[4a,5a,15] Later, the Lloyd-Jones group disclosed the
Scheme 2. Novel strategy for the preparation of P,C-chiral diphosphines.
1
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10.1002/ejoc.202000833
European Journal of Organic Chemistry
FULL PAPER
Herein, we report a simple, chiral auxiliary-free strategy for the
preparation of various P,C-chirogenic diphosphines by
condensation of enantiopure trans-1,2-diaminocyclohexane with
the borane adducts of rac-phosphinobenzoic acids followed by
column chromatographic purification (Scheme 2).
To this end, tert-butyldichlorophosphine was consecutively
reacted with LiAlH4, BH3–THF complex, and CH3I to give rac-
tert-butylmethylphosphine–borane adduct 2. The resulting
racemate was treated with n-BuLi and (–)-bornyl chloroformate 1
to afford bornyloxycarbonyl(tert-butyl)methylphosphine–borane
adduct 3 as a mixture of diastereomers. Enantiopure (Sp)-2 was
obtained in 81% yield after recrystallization and hydrolysis.
Next, the lithium derivative of enantiopure (Sp)-2 was reacted
Results and Discussion
o
with o-dibromobenzene at –78 C to furnish enantiopure (Rp)-4
as
Furthermore,
butylmethylphosphino)benzoic acid
crystalline solid in 62% yield by bubbling CO2 through a mixture
of n-BuLi and (Rp)-4.[18d,19]
a
crystalline solid upon recrystallization from hexane.
the borane adduct of (Rp)-2-(tert-
was achieved as
Initially, the synthesis of P,C-chirogenic diphosphines bearing
(R,R)- or (S,S)-P-stereocenters was adapted from modified
methods of literatures[15,17c,18] using enantiopure (Rp)-(2-
bromophenyl)tert-butylmethyl phosphine–borane adduct 4 or
(Rp)-tert-butyl(2-iodophenyl)(2-methoxyphenyl)phosphine–
borane adduct 9 as the key intermediates (Scheme 3).
5
a
In
addition,
tert-butyl
{[(1R,2S,5R)-2-isopropyl-5-
methylcyclohexyl]oxy}(2-methoxyphenyl)phosphine-borane
adduct 7 was obtained as a diastereomeric mixture in 70% yield
via
a similar route involving successive reaction of tert-
butyldichlorophosphine with sodium (1R,2S,5R)-menthoxide, (2-
methoxyphenyl)magnesium bromide, and BH3–THF complex.[18b]
The crude product was subjected to chromatographic separation
on silica gel and recrystallization from hexane to afford
enantiopure (Rp)-7 in 40% yield. Reductive cleavage of the P–O
bond by lithium naphthalenide and subsequent addition of 1 M
aq. HCl proceeded smoothly to produce (Sp)-tert-butyl(2-
methoxyphenyl)phosphine–borane adduct 8 in 90% yield with
inversion of configuration at the phosphorus atom.[18a]
The conversion of enantiopure (Sp)-8 into its halogenated
analog using o-dibromobenzene as a brominating reagent was
inefficient, and the isolation of the small amount of brominated
product was difficult. After extensive exploration of carefully
controlled reaction conditions, we were delighted to find that the
use of o-diiodobenzene led to the formation of (Rp)-tert-butyl(2-
iodophenyl)(2-methoxyphenyl)phosphine
9
in 60% yield.
Moreover, the haloarene moiety was efficiently converted to the
corresponding benzoic acid by treatment with n-BuLi and CO2 at
low
temperature,
delivering
(Sp)-2-(tert-butyl(2-
methoxyphenyl)phosphino)benzoic acid–borane adduct 10 as a
crystalline solid in 65% yield.
The absolute configuration of key intermediates such as (Rp)-4,
(Rp)-5, (Sp)-8, (Rp)-9, and (Sp)-10 was confirmed by X-ray
crystallography and enantiopurities were determined by chiral
HPLC analysis of the obtained compounds or their derivatives
(Rp)-methyl-2-(tert-butyl(methyl)phosphino)benzoate–borane
adduct
6
and
(Sp)-methyl-2-(tert-butyl(2-
methoxyphenyl)phosphino)benzoate–borane adduct 11.
Next, (Rp)-5 was activated with EDCI–HCl and HOBt, and
subsequently reacted with each enantiomer of trans-1,2-
diaminocyclohexane in the presence of 4-methylmorpholine,[16, 20]
delivering diphosphines (Rc,Rc,Rp,Rp)- and (Sc,Sc,Rp,Rp)-12 as
white solids in 70% and 65% yields, respectively (Scheme 4).
Scheme 3. Preparation of the borane adducts of (Rp)-2-(tert-
butyl(methyl)phosphino)benzoic
5
and
(Sp)-2-(tert-butyl(2-
methoxyphenyl)phosphino)benzoic acids 10 from tert-butyldichlorophosphine.
OMen = (–)-menthyl. Reagents and conditions: (1) (a) triphosgene, quinoline,
toluene, 0 to 60 °C; (b) (i) LiAlH4, butyl diglyme, 0 °C, (ii) BH3–THF, 0 °C, (iii)
n-BuLi, −78 °C, (iv) CH3I, −78 °C to rt; (c) n-BuLi, −78 °C to rt; (d)
recrystallization from hexane, 60 °C to rt; (e) KOH, CH3CN/CH3OH/H2O, rt; (f)
(i) n-BuLi, −78 °C, (ii) o-C6H4Br2, −78 °C to rt; (g) (i) n-BuLi, −78 °C, (ii) CO2,
−78 °C to rt, (iii) 1 M aq. HCl; (h) TMSCHN2, CH3OH/Et2O, rt. (2) (a) (i)
Although
the
similar
condensation
of
trans-1,2-
diaminocyclohexane and (Sp)-10 in the presence of EDCI–HCl
and HOBt led to the desired P,C-chirogenic diphosphines in low
yields, the use of the more reactive EDCI enabled reaction at
low temperatures. To this end, (Sp)-10 reacted with EDCI and
HOBt at –10 °C until the material was completely consumed.
Subsequently, (1S,2S)- or (1R,2R)-diaminocyclohexane was
carefully added to the activated intermediate at room
temperature to furnish (Sc,Sc,Sp,Sp) and (Rc,Rc,Sp,Sp)-13 72%
and 68% yields. Notably, racemization of the C-stereocenters
(1R,2S,5R)-menthoxide
sodium,
THF,
−78
oC
to
rt,
(ii)
2-
methoxyphenyimagnesium bromide, 0 °C to rf, (iii) BH3−THF, 0 °C to rt; (b)
recrystallization from hexane, 60 °C to rt; (c) lithium naphthalenide, −40 °C,
then 1M aq. HCl; (d) s-BuLi, −78 °C, (ii) o-C6H4I2, −78 °C to rt; (e) (i) n-BuLi,
−78 °C, (ii) CO2, −78 °C to rt, (iii) 1 M aq. HCl; (f) TMSCHN2, CH3OH/Et2O, rt.
2
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10.1002/ejoc.202000833
European Journal of Organic Chemistry
FULL PAPER
could be suppressed in the presence of HOBt at low
temperature.
1,2-diaminocyclohexane, furnishing three different phosphine–
borane adduct stereoisomers which could be conveniently
separated by simple column chromatography. This unexpected
finding prompted us to test the condensation of enantiopure
trans-1,2-diaminocyclohexanes with racemic phosphinobenzoic
acid–borane adducts for the straightforward preparation of
different diastereoisomers of P,C-chirogenic diphosphines
(Scheme 5).
Initially, we investigated the acylation of (1R,2R)-
diaminocyclohexane and racemic 5 in the presence of EDCI–
HCl and HOBt at room temperature. To our delight, the obtained
mixture of diphosphines 14 could be separated by column
chromatography on silica gel to deliver the enantiopure
diastereomers
(Rc,Rc,Rp,Rp)-14a,
(Rc,Rc,Rp,Sp)-14b
and
(Rc,Rc,Sp,Sp)-14c in 18%, 34%, and 16% yield, respectively.
Similarly, the reaction of (1S,2S)-diaminocyclohexane and
racemic 5 afforded diphosphine diastereomers (Sc,Sc,Sp,Sp)-15a,
(Sc,Sc,Sp,Rp)-15b and (Sc,Sc,Rp,Rp)-15c in 19%, 36%, and 18%
(approximately 1:2:1 ratio) yield, respectively (Scheme 6).
Scheme 4. Synthesis of (C*,C*,P*,P*)-diphosphines 12 and 13 from trans-1,2-
diaminocyclohexane and (Rp)-2-(tert-butyl(methyl)phosphino)benzoic acid–
borane adduct
acid–borane adduct 10. Reagents and conditions: (1) (a) (i) EDCI−HCl, HOBt,
CH2Cl2, °C, (ii) 4–methylmorpholine, (1R,2R)- or (1S,2S)-trans-
5 or (Sp)-2-(tert-butyl(2-methoxyphenyl)phosphino)benzoic
0
diaminocyclohexane, 0 °C to rt. (2) (a) (i) EDCI, HOBt, CH2Cl2, −10 °C, (ii)
(1R,2R)- or (1S,2S)-trans-diaminocyclohexane, 0 °C to rt.
Although the (C*,C*,Rp,Rp)- and (C*,C*,Sp,Sp)-diphosphine
stereoisomers could be synthesized by acylation of trans-1,2-
diaminocyclohexanes with P-chirogenic phosphinobenzoic acids,
their large-scale preparation is challenging because of the
tedious synthesis of the enantiopure P-chirogenic compounds
and the possibility of stereomutation of the P-stereocenters.
Therefore, the development of convenient and efficient methods
for accessing P,C-chirogenic diphosphines is highly desired.
Scheme 6. Synthesis of different diphosphine diastereomers from (1R,2R)- or
(1S,2S)-trans-diaminocyclohexane
and
rac-2-(tert-
butyl(methyl)phosphino)benzoic acid–borane adduct 5. Reagents and
conditions: (a) (i) EDCI−HCl, HOBt, CH2Cl2, 0 °C, (ii) 4–methylmorpholine,
(1R,2R)- or (1S,2S)-diaminocyclohexane, 0 °C to rt.
Scheme 5. Synthesis of P,C-chirogenic diphosphines with different absolute
configurations from trans-1,2-diaminocyclohexane and racemic carboxylic
acid-substituted phosphine–borane adducts. Reagents and conditions: (a) (i) i-
PrMgCl-LiCl, o-C6H4Br2 or o-C6H4I2, (ii) t-BuPCl2, (iii) RMgBr, (iv) BH3−THF; (b)
The 1H NMR spectra of the differently polar diastereomers
indicated the presence of the secondary amide, methyl, and tert-
butyl groups (see the Supporting Information for details).
Additionally, the chemical shifts and amount of 31P NMR signals
showed that both P-atoms in (Rc,Rc,Rp,Rp)-14a, (Rc,Rc,Sp,Sp)-
14c, (Sc,Sc,Sp,Sp)-15a and (Sc,Sc,Rp,Rp)-15c have the same
(i) n-BuLi, (ii) CO2, (iii)
1
M
aq. HCl; (c) (i) EDCI−HCl/HOBt/4–
methylmorpholine
or
EDCI/HOBt, (1R, 2R)- or (1S,2S)-trans-
diaminocyclohexane.
During the optimization of the reaction conditions for the
synthesis of enantiopure P-chirogenic phosphines (Rp)-5 and
(Sp)-10, materials obtained in low enantioselectivity were also
employed in the condensation reaction with enantiopure trans-
absolute
configuration,
while
(Rc,Rc,Rp,Sp)-14b
and
(Sc,Sc,Sp,Rp)-15b possess two differently configured P-atoms
(Figure 1). While the optical rotations of diastereomers 14a-c
3
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10.1002/ejoc.202000833
European Journal of Organic Chemistry
FULL PAPER
and 15a-c are different (Scheme 6), their molecular weight was
the same as confirmed by HRMS.
By comparing the 31P NMR spectra (Figure 1) and optical
rotations of these diastereomers, we confirmed that
(Rc,Rc,Rp,Rp)-14a is identical to (Rc,Rc,Rp,Rp)-12 produced from
the condensation of (Rp)-5 and (1R,2R)-diaminocyclohexane,
while (Sc,Sc,Rp,Rp)-15c is the same as (Sc,Sc,Rp,Rp)-12 resulted
from
the
corresponding
reaction
with
(1S,2S)-
diaminocyclohexane.
Scheme 7. Synthesis of different diphosphine diastereomersfrom (1R,2R)- or
Figure 1. 31P NMR spectra of the various diastereomers of diphosphines 12,
14 and 15.
(1S,2S)-trans-diaminocyclohexane
and
rac-2-(tert-butyl(2-
methoxyphenyl)phosphino)benzoic acid–borane adduct 10. Reagents and
conditions: (a) (i) EDCI, HOBt, CH2Cl2, −10 °C, (ii) (1R,2R)- or (1S,2S)-
diaminocyclohexane, 0 °C to rt.
Furthermore, this simple strategy was also employed to
prepare P,C-chirogenic diphosphines 16 and 17 by the
condensation
of
each
enantiomer
of
trans-1,2-
diaminocyclohexane with racemic 10 (Scheme 7). The
diastereomers
(Rc,Rc,Rp,Rp)-16a,
(Rc,Rc,Rp,Sp)-16b
and
(Rc,Rc,Sp,Sp)-16c
were obtained
from (1R,2R)-
diaminocyclohexane in 16%, 29%, and 18% yield, respectively,
whereas (Sc,Sc,Sp,Sp)-17a, (Sc,Sc,Sp,Rp)-17b and
(Sc,Sc,Rp,Rp)-17c were produced from the corresponding
(1S,2S)-enantiomer in 17%, 30%, and 15% isolated yield,
respectively.
The 31P NMR spectra (Figure 2) and optical rotations of these
diastereomers demonstrated that (Rc,Rc,Sp,Sp)-16c was fully
consistent with (Rc,Rc,Sp,Sp)-13 obtained from (Sp)-10 and
(1R,2R)-diaminocyclohexane, whilst (Sc,Sc,Sp,Sp)-17a was
identical to (Sc,Sc,Sp,Sp)-13 generated by the reaction of (Sp)-10
with (1S,2S)-diaminocyclohexane. Similarly, (Rc,Rc,Rp,Sp)-16b
and (Sc,Sc,Sp,Rp)-17b possess two of different absolute
configuration at P-atoms.
The corresponding free P,C-chirogenic diphosphines could be
obtained by treatment of the diborane adducts of diphosphines
using an excess of 1,4-diazabicyclo [2.2.2] octane (DABCO) in
degassed toluene at 30 oC in excellent yield with retention of
configuration at phosphorus (e.g., deboraned-(Rc,Rc,Rp,Rp)-12,
see the Supporting Information for details). Owning to the mild
conditions of the decomplexation, the epimerization of P-
stereogenic could be effectively suppressed.[10c,18c,18d,21]
Figure 2. 31P NMR spectra of the various diastereomers of diphosphines 13,
16 and 17.
Conclusion
In this paper, we reported a very simple and efficient strategy
for preparing P-chirogenic Trost ligands with differently
configured P-atoms from the borane adducts of racemic
phosphinobenzoic acids without addition of any chiral auxiliary.
The resulting diastereomers could be separated via simple
column chromatography because of their different polarities. The
4
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10.1002/ejoc.202000833
European Journal of Organic Chemistry
FULL PAPER
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analytical data of the thus isolated (C*,C*,Rp,Rp) and
(C*,C*,Sp,Sp) stereoisomers were identical to that of samples
obtained from the condensation of each enantiomer of trans-1,2-
diaminocyclohexane with the corresponding enantiopure P-
chirogenic phosphines, which were in turn synthesized from tert-
butyldichlorophosphine via a multi-step route using (–)-borneol
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facilitates the access to (C*,C*,Rp,Sp) stereoisomers with
opposite configurations at the P-atoms, which are difficult to
prepare by traditional methods involving the use of chiral
auxiliaries. And, the free P,C-chirogenic diphosphines with
retention of configuration at phosphorus atoms could be easily
available under relatively mild conditions of the decomplexation.
An exploration of the applications of the obtained P,C-chirogenic
diphosphines as ligands in various asymmetric reactions are
currently underway in our laboratory.
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Experimental Section
General details can be seen in the online supporting information. The
document contains detailed synthesis processes and analytical data of all
reaction products, details about the NMR spectra, HPLC spectra of key
intermediates (Rp)-4, (Rp)-6, (Sp)-8, (Rp)-9, (Sp)-11 and X-ray
crystallographic data of the (Rp)-4 (CCDC No. 1996507), (Rp)-5 (CCDC
No. 1997211), (Sp)-8 (CCDC No. 1997214), (Rp)-9 (CCDC No. 1997213)
and (Sp)-10 (CCDC No. 1997212).
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Acknowledgements
We gratefully acknowledge the Program for Changjiang
Scholars and Innovative Research Team in University (IRT-
17R14).
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Keywords: Chirality • Diastereoselectivity • Synthetic methods •
Phosphine ligands • P-stereocenters
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Entry for the Table of Contents
A simple, short and convenient route towards P-chirogenic Trost ligands obviates the use of chiral auxiliaries and enables the access
to diphosphines with differently configured P-stereocenters.
Key Topic:
P,C-chirogenic Synthesis
7
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