Dynamic Kinetic Resolution in Rhodium-Catalyzed Asymmetric Arylation of Phospholene Oxides

Article abstract of DOI:10.1021/jacs.7b04570

The reaction of 2,5-dihydro-1H-phosphole 1-oxide 1 with ArB(pin) 3 in the presence of a chiral (R)-segphos-rhodium catalyst under highly basic conditions (10 equiv of KOH) gave high yields of (1S,3S)-3-arylphospholane 1-oxide 4 with high diastereoselectivity as well as high enantioselectivity. Equilibration of 1 with its 2,3-dihydro isomer 2, which is chiral and racemic, by base-catalyzed olefin isomerization followed by kinetic resolution of 2 with the chiral rhodium catalyst realized the present dynamic kinetic resolution.

Full text of DOI:10.1021/jacs.7b04570

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Communication
Dynamic Kinetic Resolution in Rhodium-Catalyzed
Asymmetric Arylation of Phospholene Oxides
Kelvin Meng-Hui Lim, and Tamio Hayashi
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 06 Jun 2017
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Dynamic Kinetic Resolution in Rhodium-Catalyzed Asymmetric
Arylation of Phospholene Oxides
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Kelvin Meng-Hui Lim†,‡,§ and Tamio Hayashi*,†
†Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, 21 Nanyang Link, Singapore 637371, Singapore
‡
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
§Institute of Materials Research and Engineering, A*STAR, 2 Fusionopolis Way, Singapore 138634, Singapore
Supporting Information
Scheme 1. Dynamic Kinetic Resolution (DKR) at Catalytic
Asymmetric Transformations
ABSTRACT: The reaction of 2,5-dihydro-1H-phosphole 1-
oxide 1 with ArB(pin) 3 in the presence of a chiral (R)-
segphos–rhodium catalyst under highly basic conditions (10
equiv of KOH) gave high yields of (1S,3S)-3-arylphospholane
1-oxide 4 with high diastereoselectivity as well as high enanti-
oselectivity. Equilibration of 1 with its 2,3-dihydro isomer 2,
which is chiral and racemic, by base-catalyzed olefin isomeri-
zation followed by kinetic resolution of 2 with the chiral rho-
dium catalyst realized the present dynamic kinetic resolution.
Dynamic kinetic resolution (DKR) in asymmetric synthesis,
which is recognized to be an ideal method of synthesizing
enantioenriched products from racemic substrates, consists of
racemization of a chiral substrate and kinetic resolution of the
racemized substrate.1,2 In most cases, the racemization takes
place at sp3 carbon stereogenic center by way of achiral sp2
carbon intermediates. Typical examples are racemization
through enol formation in ruthenium-catalyzed asymmetric
hydrogenation3 and that through alcohol/ketone interconver-
sion in lipase-catalyzed asymmetric acylation4 (Scheme 1a). In
this communication, we wish to report a dynamic kinetic reso-
lution in rhodium-catalyzed asymmetric conjugate arylation5,6
Scheme 2. KOH-Catalyzed Isomerization–Racemization
of Dihydrophosphole Oxides 1a and 2a
where the racemization of starting olefinic substrates takes
place by a migration of carbon–carbon double bond. The sce-
nario of the present DKR is as follows (Scheme 1b): The 2,5-
dihydrophosphole oxide 1, which is achiral and is not reactive
towards the rhodium-catalyzed conjugate arylation, undergoes
olefin isomerization into 2,3-dihydro isomer 2, which is race-
mic and is reactive because of the olefin conjugation with
electron-withdrawing phosphine oxide.7 If the racemization of
2 takes place fast by way of 1, one of the enantiomers 2 is
much more reactive than the other enantiomer, and the asym-
metric arylation proceeds with high diastereoselectivity, we
have a chance to obtain the asymmetric arylation product as a
single stereoisomer. As a related asymmetric reaction in that
the olefin isomerization generates more reactive olefinic sub-
strates under the reaction conditions, asymmetric arylation of
3-sulfolene has been reported.8
tion takes place quickly with 1.4 M KOH in dioxane/H2O
(10/1) at 80 °C to reach the equilibration in 3 h. The equili-
brated ratio of 1a to 2a determined by 31P NMR is 26:74, indi-
cating that each enantiomer of 2a exists in 37% at equilibra-
tion.
Under the scenario in Scheme 1b with the isomerization
conditions in hand, we examined several reaction conditions
for the asymmetric hydrophenylation of 2,5-dihydrophosphole
oxide 1a and found that the target phenylation product 4aa is
obtained in a high yield with both high diastereoselectivity and
high enantioselectivity under the conditions shown in the reac-
tion scheme in Table 1. Thus, 1a was allowed to react with
PhB(pin)11 (3a. 3 equiv to 1a) in the presence of KOH (10
equiv) and a rhodium catalyst generated from [RhCl(coe)2]2 (5
Prior to the asymmetric arylation, 1-phenyl-2,5-dihydro-1H-
phosphole 1-oxide (1a),9 which is readily prepared through
ring-closing metathesis of a (diallyl)phosphine oxide,10 was
examined for its isomerization into 2,3-dihydro isomer 2 under
basic conditions (Scheme 2). It was found that the isomeriza-
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mol % of Rh) and (R)-segphos12 (10 mol %) in dioxane/H2O
Table 1. Rhodium-Catalyzed Asymmetric Phenylation of
1-Phenyl-2,5-dihydro-1H-phosphole 1-Oxide (1a) a
(10/1) at 80 °C for 16 h (Table 1, entry 1). 31P NMR analysis
of the reaction mixture showed that 1a was all converted into
the hydrophenylation products with high diastereoselectivity
(4aa:5aa = 97:3), and the main diastereoisomer 4aa was de-
termined to be a (1S,3S) isomer of 96% ee (see Figure 1). The
absolute configuration (1S,3S) with the high % ee indicates
that (S)-2a is more reactive than its enantiomer (R)-2a under
the present conditions using (R)-segphos as a chiral ligand and
that the carbon–carbon double bond of (S)-2a undergoes the
phenylation from the side opposite to the phenyl group on
phosphine oxide to avoid the steric repulsion. The diastereose-
lectivity in giving 4aa over 5aa is always high irrespective of
the reaction conditions examined (vide infra).
1
2
3
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6
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The use of 10 mol % (2 equiv to Rh) of segphos ligand is es-
sential for the high conversion of 1a. The reaction was not
completed with 5 mol % (1 equiv to Rh) of segphos (Table 1,
entries 2 and 3). Monitoring the reaction progress showed that
the catalyst with 5 mol % of the ligand loses its catalytic activ-
ity in a short time (2 h). At 60 °C, the phenylation reaction is
much slower (entry 4). Rhodium complex with binap ligand is
as catalytically active as that with segphos, but the enantiose-
lectivity is lower (entry 5). Chiral dienes13 are not ligands of
choice for the present reaction. The enantiomeric purities of
4aa are low, while catalytic activity of the diene–rhodium
complexes is high to promote the reaction to 100% conversion
(entries 7 and 8). Interestingly, the reaction with the diene
ligands gave 16% of side product 6, which is assumed to be
formed through a reaction pathway involving the 1,4-shift of
rhodium from an alkyl-Rh intermediate to an aryl-Rh interme-
diate.14 The asymmetric phenylation also proceeded with high
diastereo- and enantioselectivity with PhB(OH)2 or PhBF3K
instead of PhB(pin), but the yield of 4aa was lower (entries 9
and 10). It is noted that, when the reaction was not completed,
the unreacted starting compound 1a was recovered as a mix-
ture of 1a and 2a in an equilibrated ratio (ca. 1:3) under the
reaction conditions using 10 equiv of KOH in all the entries.
With 5 equiv of KOH, the reaction is slower to leave 18% of a
mixture of alkenes 1a and 2a unreacted (entry 11). With 0.5
equiv of KOH, the isomerization of 1a into 2a is very slow,
and most of the starting 1a was recovered as it was without
isomerization into 2a (entry 12). The reaction of racemic 2a
instead of 1a under the same conditions as entry 1 gave essen-
tially the same result as that in entry 1, that is, 95% yield, 98:2
dr, and 96% ee of 4aa (entry 13). It follows that the isomeriza-
tion between 1a and 2a with 10 equiv of KOH is fast enough
for the equilibrium to be reached under the standard conditions
for the present asymmetric arylation.
The reaction of racemic and enantiomerically pure 2a15,16 in
the presence of 0.5 equiv of KOH which promotes the Rh-
catalyzed arylation5 but does not promote the fast isomeriza-
tion (see entry 12 in Table 1) gave us further insight into the
kinetic resolution of the present asymmetric reaction (Scheme
3). The reaction of (S)-2a (>99% ee) gave a high yield (96%)
of (1S,3S)-4aa (>99% ee) with high dr (4aa:5aa = 96:1). On
the other hand, the reaction of (R)-2a (>99% ee) gave 4aa in a
low yield (10%) with low enantioselectivity (36% ee) and low
dr (4aa:5aa = 10:3). These results demonstrate that (S)-2a is
much more reactive than its enantiomer (R)-2a under the ca-
talysis by (R)-segphos/Rh to realize efficient kinetic resolution.
It is noted that racemization of recovered 2a was observed to
some extent in the reaction of both enantiomers. The for-
mation of isomer 1a together with the racemization of 2a indi-
ratiob of
drb % eed
en- Variations from standard con-
try ditions
yield
(%)c
4+5
1:2:(4+5)
4:5 4 (5)
1 None
0:0:100 99 97:3 96 (33)
3:7:90 81 97:3 90 (61)
4:11:85 73 97:3 73 (63)
2 (R)-segphos (5 mol %)
3
(R)-segphos (5 mol %), at
100 °C
4 At 60 °C
8:24:68 56 99:1 99 (0)
0:0:100 99 96:4 87 (42)
6:19:75 65 99:1 8 (–15)
5 (R)-binap (10 mol %)
6
(R)-DTBM-segphos (10
mol %)
7 (S,S)-Fc-tfb (10 mol %)e
8 (R,R)-Ph-bod (10 mol %)e
0:0:84f 82 94:6 46 (83)
0:0:84f 84 98:2 31 (18)
9 PhB(OH)2 instead of PhB(pin) 3:7:90 86 97:3 96 (55)
10 PhBF3K instead of PhB(pin)
11 KOH (0.75 mmol, 5 equiv)
6:15:79 72 97:3 96 (0)
4:14:82 79 97:3 89 (56)
12 KOH (0.08 mmol, 0.5 equiv) 90:5:5
—
—
—
13 rac-2a instead of 1a 0:0:100 95 98:2 96 (38)
a Standard reaction conditions: 1a (0.15 mmol), PhB(pin) (3a, 0.45
mmol), KOH (1.50 mmol, 10 equiv to 1a), [RhCl(coe)2]2 (3.75
µmol, 5.0 mol % of Rh), (R)-segphos (15 µmol, 10 mol %) in
b
dioxane/H2O (0.70/0.07 mL) at 80 °C for 16 h. Determined by
1H and 31P NMR of the crude reaction mixture. c Isolated yield of
d
a mixture of 4aa and 5aa. The % ee was determined by HPLC
on a chiral stationary phase column. The absolute configuration of
e
4aa was assigned by analogy to 4ab (see Figure 1).
f
[RhCl(diene)]2 (5 mol % Rh) + diene (5 mol %). Compound 6
was formed in 16%.
cates that a slow racemization 2a by way of 1a is taking place
even with a small amount (0.5 equiv) of KOH. The result ob-
tained for racemic 2a is consistent with those for enantiopure
(S)- and (R)-2a. Thus, (S) isomer was consumed selectively to
give (1S,3S)-4aa (97% ee) and to leave (R) isomer unreacted.
Scheme 3. Asymmetric Phenylation of Enantiomerically
Pure and Racemic 2a Catalyzed by Rh/(R)-segphos
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Ph
Ph
Ph
Ph
O
O
O
O
Table 2. Rhodium-Catalyzed Asymmetric Arylation of
condition A
KOH (0.5 equv)
P
2,5-Dihydro-1H-phosphole Oxide 1 with ArB(pin) 3a
P
P
P
1
+ PhB(pin)
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
(S)-2a (51% ee)
(1S,3S)-4aa
(>99% ee)
(S)-2a
(>99% ee)
Ph
Ph
Ph
3a
1a : 2a : 4aa : 5aa = 1 : 2 : 96 : 1
Ph
Ph
O
Ph
Ph
O
O
O
condition A
KOH (0.5 equv)
P
P
P
P
+ PhB(pin)
1a (R)-2a (90% ee)
1a : 2a : 4aa : 5aa = 2 : 85 : 10 : 3
(1S,3S)-4aa
(36% ee)
(R)-2a
(>99% ee)
3a
drc
4:5
ee (%)d
4
entry 1: R
3: Ar
yield
(%)b
Ph
Ph
O
Ph
Ph
O
O
O
condition A
KOH (0.5 equv)
P
P
P
P
1
2
1a: Ph
3a: Ph
4aa: 99 97:3 96
+ PhB(pin)
1a: Ph
1a: Ph
1a: Ph
1a: Ph
1a: Ph
1a: Ph
3b: 3-MeOC6H4 4ab: 90 98:2 95
3c: 3-MeC6H4 4ac: 95 98:2 94
3d: 4-MeC6H4 4ad: 99 >99:1 94
3e: 4-MeOC6H4 4ae: 80 98:2 95
1a (R)-2a (79% ee)
1a : 2a : 4aa : 5aa = 2 : 38 : 58 : 2
(1S,3S)-4aa
(97% ee)
dl-2a
3a
3
condition A: 3a (3 equiv), [RhCl(coe)2]2 (5.0 mol% Rh), (R)-segphos (10 mol%)
in dioxane/H2O (10/1) at 80 °C for 16 h
4
5
The optimized condition for the dynamic kinetic resolution
6
3f: 4-FC6H4
3g: 3,5-F2C6H4 4ag: 74 97:3 97
4ba: 99 >99:1 >99
4af: 73 >99:1 96
of 1a with PhB(pin) (3a) (entry 1 in Table 1) was applied to
several other phospholene oxides 1 and arylboron reagents 3.
The results summarized in Table 2 show that the efficient dy-
namic kinetic resolution takes place for ArB(pin) reagents 3b-
3e where Ar groups are phenyls substituted with methyl or
methoxy group at para or meta position, the corresponding
hydroarylation products 4 being produced with high diastereo-
and enantioselectivity (entries 2–5). The selectivity was also
high for the arylboron reagents 3f and 3g bearing fluoride(s)
on the phenyl ring, although the yields are lower (entries 6 and
7). The same level of high dr (99:1 or higher) and ee (≥95%
ee) were observed in the hydroarylation of phospholene oxides
1b-1e where substituents R on the phosphine oxide are para-
or meta-substituted aryl groups (entries 8–12). Those with
secondary alkyl groups on the phosphine oxide can be also
used as starting substrates, although they are less reactive (en-
tries 13–15). By increasing the amount of the (R)-segphos/Rh
catalyst to 10 mol %, the arylation products 4fb and 4gb,
which are substituted with 2-propyl and cyclohexyl groups,
respectively, were obtained with high selectivity (dr = >99:1,
97–98% ee). The diastereoselectivity was low (dr = 82:18) for
1-hexyl-substituted phospholene oxide 1h (entry 16) and the
reactivity of tert-butyl-substituted one was too low to give
only a low yield of the arylation product (entry 17). It is noted
that an alkenyl group is also successfully introduced with high
selectivity (entries 18 and 19).
17
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7
8
1b: 4-CF3C6H4 3a: Ph
9
1b: 4-CF3C6H4 3b: 3-MeOC6H4 4bb: 90 99:1 95
1c: 4-MeOC6H4 3b: 3-MeOC6H4 4cb: 74 >99:1 97
1d: 3-MeC6H4 3b: 3-MeOC6H4 4db: 95 >99:1 97
10
11
12
3b: 3-MeOC6H4 4eb: 94 >99:1 97
1e: 3,5-Me2-4-
MeOC6H2
13
1f: 2-propyl
1f: 2-propyl
3b: 3-MeOC6H4 4fb: 24 >99:1 97
3b: 3-MeOC6H4 4fb: 71 >99:1 97
14e
15e
16
1g: cyclohexyl 3b: 3-MeOC6H4 4gb: 63 >99:1 98
1h: 1-hexyl
1i: t-butyl
1a: Ph
3b: 3-MeOC6H4 4hb: 82 82:18 90
3b: 3-MeOC6H4 4ib: 7 >99:1
3h: c-hexenyl 4ah: 95 >99:1 97
17
—
18f
19f
1b: 4-CF3C6H4 3h: c-hexenyl 4bh: 89 >99:1 93
a
Reaction conditions: 1 (0.15 mmol), ArB(pin) 3 (0.45 mmol),
KOH (1.5 mmol), [RhCl(coe)2]2 (5 mol% of Rh), (R)-segphos (10
mol%), dioxane/H2O (0.7/0.07 mL) at 80 °C for 16 h. Isolated
yield. c Determined by H and 31P NMR of the crude reaction
mixture. d The % ee was determined by HPLC on chiral stationary
phase columns. The absolute configurations of products 4 were
assigned by analogy to 4ab. e With 10 mol% of Rh and 20 mol%
of segphos. f With 7 mol% of Rh and 14 mol% of segphos.
b
1
Me Me
Ph
Ph
O
Me Me
Me
N
Cl
P
P
Me
N
(S)-8
Cl
2
PhSiH3
(a)
Pd
Ph
Pd
toluene
100 °C, 16 h Ar
CH2Cl2
P
Ar
(1S,3S)-4ab
(1R,3S)-7
9
(S)-8
94%
of the phosphine 7 with enantiopure palladacycle (S)-819 (Fig-
ure 1a). Metal complexes coordinated with axially chiral (R)-
biarylbisphosphine ligands including (R)-segphos are well-
known to have a structure where the 2nd and 4th quadrants are
occupied by phenyl rings on the phosphino groups.20 The
(1S,3S) configuration of the product 4 with the (R)-segphos
ligand is rationalized by the selective coordination of (S)-
isomer of 2a to an aryl–rhodium intermediate with its re face
where the steric repulsions between 2a and phenyl rings of
segphos ligand are minimized (A in Figure 1b). Arylrhodation
on the intermediate A will lead to the product (1S,3S)-4a.
There would be serious steric repulsions at coordination of
(S)-2a with the other enantioface si between the phenyl group
on the ligand and the phosphine oxide moiety of 2a (B). The
(R)-isomer of 2a would suffer from repulsions at both re face
and si face coordination as shown in C and D, respectively.
X-ray structure
Ar
Ar = 3-MeOC6H4
Ph
O
P
P
P
Ph
P
P
O
P
P
P
P
P
Rh
Rh
O
Rh
Rh
(b)
Ph
Ar
Ar
Ar
Ar
P
P
Ph
O
Ph
O
re face
(S)-2a
si face
(S)-2a
re face
(R)-2a
si face
(R)-2a
P
A
B
C
D
(1S,3S)-4a
Ar
Figure 1. Absolute configuration of product 4 and proposed
stereochemical pathway.
The relative and absolute configuration of the arylation
product 4ab was determined unequivocally to be (1S,3S) by
X-ray crystallographic analysis of its palladium complex 9,17
which is obtained by reduction of 4ab18 followed by treatment
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tions; Córdova, A., Ed.; Wiley-VCH: Weinheim, Germany, 2010;
In summary, we have succeeded in developing a new type
of dynamic kinetic resolution in rhodium-catalyzed asymmet-
ric arylation which gives high yields of the hydroarylation
products with high dr and high ee. The reaction opened a new
synthetic route to chiral organophosphorus compounds con-
taining two stereogenic centers, one on phosphorus and the
other on carbon.21,22
1
2
3
4
5
6
Chapter 1, p 1. (e) Edwards, H. J.; Hargrave, J. D.; Penrose, S. D.;
Frost, C. G. Chem. Soc. Rev. 2010, 39, 2093. (f) Johnson, J. B.; Rovis,
T. Angew. Chem., Int. Ed. 2008, 47, 840. (g) Hayashi, T. Pure Appl.
Chem. 2004, 76, 465. (h) Darses, S.; Genet, J.-P. Eur. J. Org. Chem.
2003, 4313.
(6) Very recently, a DKR in rhodium-catalyzed asymmetric aryla-
tion of α-keto esters has been reported: Bartlett, S. L.; Keiter, K. M.;
Johnson, J. S. J. Am. Chem. Soc. 2017, 139, 3911.
7
8
9
ASSOCIATED CONTENT
(7) Rhodium-catalyzed asymmetric arylation of alkenylphospho-
nates has been reported: Hayashi, T.; Senda, T.; Takaya, Y.;
Ogasawara, M. J. Am. Chem. Soc. 1999, 121, 11591.
(8) Lim, K. M.-H.; Hayashi, T. J. Am. Chem. Soc. 2015, 137, 3201.
(9) Asymmetric Mizoroki-Heck reaction of 1a has been recently re-
ported: (a) de Azambuja, F.; Carmona, R. C.; Chorro, T. H. D.;
Heerdt, G.; Correia, C. R. D. Chem. Eur. J. 2016, 22, 11205. See also,
(b) Desmazeau, P.; Legros, J.-Y.; Fiaud, J.-C. Tetrahedron Lett. 1998,
39, 6707.
(10) Trevitt, M.; Gouverneur, V. Tetrahedron Lett. 1999, 40, 7333.
(11) ArB(pin) has been used for the rhodium-catalyzed asymmetric
arylation: see, for example (a) Sakuma, S.; Sakai, M.; Itooka, R.;
Miyaura, N. J. Org. Chem. 2000, 65, 5951. (b) Albrecht, F.; Sowada,
O.; Fistikci, M.; Boysen, M. M. K. Org. Lett. 2014, 16, 5212.
(12) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.;
Miura, T.; Kumobayashi, H. Adv. Synth. Catal. 2001, 343, 264.
(13) For reviews on chiral diene ligands: see, (a) Defieber, C.;
Grützmacher, H.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47,
4482. (b) Shintani, R.; Hayashi, T. Aldrichimica Acta 2009, 42, 31.
(c) Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. Synlett 2011, 1345. (d) Feng,
X.; Du, H. Asian J. Org. Chem. 2012, 1, 204.
(14) (a) Oguma, K.; Miura, M.; Satoh, T.; Nomura, M. J. Am. Chem.
Soc. 2000, 122, 10464. (b) Ming, J.; Hayashi, T. Org. Lett. 2016, 18,
6452, and references cited therein.
(15) Enantiomerically enriched 2a has been reported: see, Moeller,
S.; Drzazga, Z.; Pakulski, Z.; Pietrusiewicz, K. M.; Duddeck, H. Chi-
rality 2006, 18, 395.
(16) A kinetic resolution of 2a at a 1,3-dipolar cycloaddition has
been reported: see, Goti, A.; Cicchi, S.; Brandi, A.; Pietrusiewicz, K.
M. Tetrahedron Asymmetry 1991, 2, 1371.
Supporting Information. Experimental procedures, com-
pound characterization data, and crystallographic data (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
hayashi@ntu.edu.sg
ACKNOWLEDGMENT
This work was supported by funding from Nanyang Tech-
nological University and the Singapore Ministry of Educa-
tion (Academic Research Fund Tier 1: 2016-T1-001-247).
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W.-L. Angew. Chem., Int. Ed. 2015, 54, 6265. A conceptually similar
asymmetric reaction forming both C and P chiral centers has been
reported, see: (k) Tang, W.; Zhang, X. Angew. Chem., Int. Ed. 2002,
41, 1612.
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R
O
R
Rh/(R)-segphos
O
1
2
3
4
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6
7
8
(5.0 mol% Rh)
P
P
high yield
≥97:3 dr
94–99% ee
+ ArB(pin)
R = aryl, sec-alkyl
KOH (10 equiv)
dioxane/H2O (10/1)
80 °C, 16 h
Ar
ArB(pin)
R
R
R
O
(S)
P
O
O
Rh/(R)-segphos
(catalyst)
(R)
P
P
KOH
KOH
kinetic resolution
at hydroarylation
racemization by olefin isomerization
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