Asymmetric Allylic C-H Alkylation via Palladium(II)/ cis-ArSOX Catalysis

Article abstract of DOI:10.1021/jacs.8b05668

We report the development of Pd(II)/cis-aryl sulfoxide-oxazoline (cis-ArSOX) catalysts for asymmetric C-H alkylation of terminal olefins with a variety of synthetically versatile nucleophiles. The modular, tunable, and oxidatively stable ArSOX scaffold is key to the unprecedented broad scope and high enantioselectivity (37 examples, avg. > 90% ee). Pd(II)/cis-ArSOX is unique in its ability to effect high reactivity and catalyst-controlled diastereoselectivity on the alkylation of aliphatic olefins. We anticipate that this new chiral ligand class will find use in other transition metal catalyzed processes that operate under oxidative conditions.

Full text of DOI:10.1021/jacs.8b05668

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Communication
Asymmetric Allylic C–H Alkylation via Palladium(II)/cis-ArSOX Catalysis
Wei Liu, Siraj Ali, Stephen Ammann, and M. Christina White
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b05668 • Publication Date (Web): 09 Aug 2018
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Journal of the American Chemical Society
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Asymmetric Allylic C–H Alkylation via Palladi-
um(II)/cis-ArSOX Catalysis
Wei Liu, Siraj Ali, Stephen Ammann,† M. Christina White*
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Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois, 61801, United States
Supporting Information Placeholder
Asymmetric
A. Previous work on asymmetric allylic C–H alkylation
Allylic
C–H
Alkylation
ABSTRACT: We report the development of of Pd(II)/cis-
aryl sulfoxide-oxazoline (cis-ArSOX) catalysts for asymmet-
ric C–H alkylation of terminal olefins with a variety of syn-
thetically versatile nucleophiles. The modular, tunable, and
oxidatively stable ArSOX scaffold is key to the unprecedent-
ed broad scope and high enantioselectivity (37 examples,
avg. >90% ee). Pd(II)/cis-ArSOX is unique in its ability to
effect high reactivity and catalyst-controlled diastereoselec-
tivity on the alkylation of aliphatic olefins. We anticipate that
this new chiral ligand class will find use in other transition
metal catalyzed processes that operate under oxidative con-
ditions.
O
O
R’
Pd(dba)2
R’
H
Ligand 1
R
Ar
N
+
N
Ar
R
Chiral acid 2
under argon
N
N
Me
Me
2 equiv.
Pyrazol-5-ones
R = arene or alkene
Ar1
Ar2
O
O
O
Chiral
phosphoric acid 2
Ligand 1
P
N
P
O
OH
O
Ar2
Ar1 = 3,5-(CF3)2C6H3
Ar2 = 4-biphenyl
O
Ar1
B. This work
O2N
Pd(II)
O
R2
H
R1
>90% ee
R3O2C
cis-ArSOX
H
*
+
catalyst
R1
1 equiv.
O
prochiral
R1
>90% ee
X
H
O
O
The enantioselective transformation of C(sp3)–H to
C(sp3)–C(sp3) bond allows for the construction of a stereo-
chemically enriched carbon framework via the union of two
requisite fragments with minimal pre-activation.1 Transition
metal-catalyzed asymmetric C–C bond forming reactions
under oxidative conditions are relatively rare.2 For example,
while Pd(0)-catalyzed allylic substitution has been estab-
lished with broad scope to form chiral C(sp3)–C(sp3)
bonds,3 the direct asymmetric alkylation of allylic C–H
bonds is underdeveloped.4-6 Existing methods only demon-
strate limited reactivity towards a focused set of olefins (e.g.
electron deficient/neutral allylarenes4 or 2 equiv. of olefins5,
6) with specialized nucleophiles (e.g. 1,3-diketone,4 pyrazol-
5-one,5 2-aryl propionaldehyde6) that are not readily amena-
ble to diversification. One potential reason for such limita-
tions is the paucity of chiral ligands designed for transition
metal mediated processes proceeding under acidic, oxidative
conditions. Herein, we report a novel and highly tunable
(S,S)-aryl sulfoxide-oxazoline ligand class that enables the
Pd(II)-catalyzed asymmetric C–H alkylation of a broad
scope of allylarenes and aliphatic olefins (1 equiv.) with a
variety of synthetically versatile nucleophiles leading to high
levels of asymmetric induction (avg. >90% ee; avg. 10:1 d.r.).
Asymmetric allylic alkylation using prochiral nucleo-
philes requires a ligand framework that can establish a chiral
N
N
S
S
R3O2C
O
O
Pd
O
Pd
H
AcO
OAc
AcO
cis (this work)
Pd/ArSOX complex
OAc
trans (previous)
N
O
Boc
17:1 d.r.
chiral phosphoramidite ligands that have demonstrated
modest enantioselectivity alone (avg. 75% ee)4 and must be
combined with a BINOL-derived chiral phosphoric acid co-
catalyst to afford high asymmetric induction5. Additionally,
phosphoramidite ligands are sensitive to the oxidative reac-
tion conditions, necessitating iterative addition of the cata-
lyst4 and/or rigorous exclusion of oxygen5. Oxidatively stable
palladium(II)/bis-sulfoxide catalysis has demonstrated
broad scope for allylic C–H alkylations; however due to flux-
ional binding of the sulfoxide ligand to the metal, it cannot be
rendered asymmetric.7 Pd(II)/aryl sulfoxide-oxazoline (Ar-
SOX) catalysis8 has been shown to display static ligand bind-
ing to Pd8a and to effect intramolecular asymmetric allylic C–
H oxidation, where the Pd(II)/trans-(S,R)-ArSOX complex
is able to impose high levels of π-allyl enantiofacial selec-
tion.8b Intermolecular allylic C–H alkylation generally pro-
ceeds with linear regioselectivity, dictating that the enantio-
facial selectivity be achieved via a prochiral nucleophile,
which occurs relatively remote from the ligand environment.
Previous studies of phosphinoxazoline (PHOX) ligands in
asymmetric allylic substitutions have shown that unsymmet-
rically substituted phosphines could significantly impact the
remote chiral environment by placing large groups on the
environment opposite to the ligand/π-allylPd complex.3 Pre-
vious C–H alkylation methods relied upon Scheme 1.
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Journal of the American Chemical Society
phosphine cis to substituents on the oxazoline.3b We envi-
Page 2 of 5
boosting the enantioselectivity to 92% ee (entry 9). The
amount of Zn(OAc)2 additive could be lowered to 25 mol%
(entry 10, 11), with 50 mol% being the most broadly appli-
cable (vide infra). With fragment coupling amounts of nu-
cleophile (1 equiv.), a preparative yield was maintained
(60%) without diminished enantioselectivity (91% ee, entry
12).
1
2
3
4
5
6
7
8
sioned the stereogenic sulfoxide moiety would allow us to
access the Pd(II)/cis-(S,S)-ArSOX complex that may be able
to extend its chiral environment to influence nucleophile
enantiofacial selection. Moreover, the highly modular nature
of ArSOX scaffold allows for extensive exploration of both
steric and electronic parameters of the ligand, potentially
leading to greater generality in nucleophile scope.
Table
2.
Asymmetric
Alkylation
with
2-
Nitrotetralonea
Table 1. Reaction Development with Nitrotetralonea
9
Pd(OAc)2 (10 mol%)
ArSOX L7 (10 mol%)
O
Pd(OAc)2 (10 mol%)
Ligand (10 mol%)
Zn(OAc)2 (x mol%)
Ar
O
NO2
O
H
O
H
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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42
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50
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57
58
59
60
NO2
+
NO2
NO2
R
+
Ar
Zn(OAc)2 (50 mol%)
DMBQ (150 mol%)
R
3
2,6-DMBQ (150 mol%)
Benzene/dioxane
(1:1 v/v, 0.17M)
isolated yields; ee
>20:1 E/Z, >20:1 L/B
1
2
Dioxane/Benzene, 5oC, 72 h
2
1
R1 = Me (3a): 60%; 92% ee
OMe (3b): 51%; 90% eeb
Br (3c): 66%; 92% ee
O
O
NO2
NO2
L4: R2 = CF3
L5: R2 = tBu
L6: R2 = OMe
L7: R2 = OtBu
OtBu
O
S
O
O
N
L2
1 = tBu
R2
N
N
S
N
L7
CO2Me (3d): 68%; 90% eeb
CH2OH (3e): 65%; 91% ee
R
O
R1
L1
tBu
Ligand
CH3
S
O
S
O
L3
R1 = Me
O
O
O
O
O
NO2
NO2
R1
CH3
T (oC)
Yield (%)b
ee (%)c
O
O
O
Entry
Zn(OAc)2 2H2O (x mol%)
O
3f, 65%;
90% ee
3g, 65%;
3h, 64%;
92% ee
1d
2d
3d
4
5
6
7
8
9
L1
L2
L3
L3
L3
L4
L5
L6
L7
L7
L7
L7
0%
0%
0%
45
45
45
45
5
65
78
80
82
70
78
77
74
81
83
79
60
-20
64
66
79
88
87
90
89
92
92
92
91
93% ee
O
O
NO2
NO2
NO2
100%
100%
100%
100%
100%
100%
50%
25%
25%
S
N
Boc
NBoc
5
5
5
5
5
5
5
3i, 57%;
92% ee
3j, 63%;
3k, 54%;
91% ee
92% ee
O
O
O
NO2
NO2
NO2
MeO
10
11
12e
R2
=
OPiv
OBn
OMe
(3m); 64%; 90% ee
(3n); 58%; 93% ee
(3o); 48%; 88% ee
78%; 84% eec
R2
Br
3l, 67%;
90% ee
3p, 58%;
92% ee
aReaction conditions: Nuc 1 (0.2 mmol), Olefin 2 (0.1 mmol), Pd(OAc)2 (0.01 mmol), Ligand
(0.01 mmol), 2,6-DMBQ (0.15 mmol) in benzene/dioxane (0.17 M) at 45oC for 24 h or at
5oC for 72 h. bIsolated yields. cDetermined by chiral HPLC. din toluene. e1 equiv. of Nuc 1
Synthetic utilityd
O
O
O
(b) Allylation
(c) RCM
(d) [H]
NO2
NH2
(a) SnCl2
81% yield
We commenced our study of asymmetric alkylation be-
tween 2-nitrotetralone (1) and allylbenzene (2). Using pre-
viously reported conditions for asymmetric allylic oxidation
with (S,R)-ArSOX L1,8b the alkylated product was obtained
in 65% yield and -20% ee (Table 1, entry 1). Consistent with
our hypothesis, (S,S)-ArSOX L2 furnished significant im-
provements in enantioselectivity (64% ee, entry 2). Para-
tolyl sulfoxide (L3) performed comparably (entry 3), and
was preferred for its relative ease of synthesis. Allylic C–H
alkylation utilizing acidic pro-nucleophiles undergoes in situ
deprotonation by the acetate anion of the Pd(II) catalyst.
The nature of the cation/anionic nucleophile pairing has
been shown to influence the facial bias and therefore signifi-
cantly impact the stereoselectivity.3a, 9 We wished to exploit
the effect of ion pairing by introducing alternate sources of
acetate with different cations. We surveyed seven acetate
salts (see Table S2 in supporting information), known to
Ph
Ph
N
H
5
4
α-amino ketone
pharmacophore
92% ee
(f)
(e)
This route:
43% yield, 91% eee
OH
OH
NH2
NH2
65% yield
90% yield
>20:1 d.r.
Ph
Previous:
6% yield, 0% ee
Ph
>20:1 d.r.
aReaction conditions: Nuc 1 (0.4 mmol), Olefin 2 (0.2 mmol), Pd(OAc)2 (0.02 mmol), Ligand (0.02 mmol),
Zn(OAc)2 2H2O (0.1 mmol), 2,6-DMBQ (0.3 mmol), Dioxane/Benzene (1:1, 1.2 ml) at 5oC for 72 h; Yields
are isolated; e.e. determined by chiral HPLC analysis; Absolute stereochemistry assigned based on X-ray
crystallography of 3p, all other compounds assigned by analogy. bArSOX L5 was used. cat 25oC.
d(a)SnCl2 2H2O (10 equiv.), THF/H2O, 45oC, 24 h. 81% yield. (b)allyl bromide (1.1 equiv.), K2CO3 (1.1
equiv.), MeCN, 50oC, 18 h. 72% yield. (c)Grubbs II (10 mol%), TsOH (1 equiv.), DCM, reflux, 24 h. 94%
yield. (d)Pd/C (20 wt.%), H2 (1 atm), MeOH,
2
h, quantitative. (e)NaBH4 (1.1 equiv.), MeOH, 0oC.
(f)vinylmagnesium bromide (3 equiv.), THF, -78oC. e5 was acetylated before chiral HPLC anaylsis.
Using L7 as the optimal ligand for 2-nitrotetralone, the
scope for the terminal olefin partner was examined (Table
2). A wide range of para-substituted allylarenes were well
tolerated: both electron neutral/donating (3a, b) and elec-
tron-withdrawing groups (3c, d) afforded preparative yields
and enantioselectivities and provide useful handles for fur-
ther manipulation. 4-Allylanisole 3b afforded 90% ee using
L5: previous asymmetric C–H alkylation methods have
found this electron rich allylarene to be unreactive.4 A sub-
strate containing a primary, benzylic alcohol (3e) underwent
smooth alkylation, with no alcohol oxidation observed. A
variety of biologically relevant heteroaromatics were also
successfully coupled with 2-nitrotetralone in good yield and
high enantioselectivity, including coumarin (3f), chromene
(3g), benzofuran (3h), benzothiophene (3i), 5’ and 3’-
indoles (3j, k). Notably, benzothiophene (3i) housing a
chelating and oxidizable sulfur moiety was alkylated with
good yields and high enantioselectivity (92% ee). We next
examined
10, 11
form enolate complexes with nitroketones.10a Zn(OAc)2
was identified to be the optimal additive with ben-
zene/dioxane as the solvent, increasing the selectivity to 79%
ee (entry 4). Lowering the temperature to 5oC further im-
proved the enantioselectivity (entry 5). We next turned to
ligand modifications on the oxazoline: a trifluoromethyl
group at the para-position of the aryl substituents was not
beneficial (entry 6), whereas a bulky tert-butyl group (L5)
or electron-rich methoxy group (L6) led to increases in se-
lectivity (entry 7, 8). A cooperative effect between sterics and
electronics was found using a tert-butoxy (L7) substituent,
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Table
O
3.
Asymmetric
Allylic
B.
C–H
Alkylation
with
β-ketoesters.
1
2
3
4
5
6
7
8
H
O
Pd(OAc)2/ArSOX
(5-10 mol%)
O
CO2R
N
Y =
9d, 90%;
O
O
H
CO2tBu
yield eea
CO2iPr
X =
CO2tBu
O
CO2tBu
O
94% eea
Ar
or
+
O
S
Ar
O
O
Zn(OAc)2 (50 mol%)
O
OMe (9b) 81% 92%
F (9c)
O
DMBQ (150 mol%)
O
iPr
Y
9e, 89%;c
N
6
7
8
isolated yields; ee
93% 90%
92% eea,d
X
O
O
A. Optimization (Ar = Ph):
Entry Nuc. Ligand Yield (%) ee (%)
O
O
O
O
CO2tBu
CO2tBu
CO2tBu
O
CO2tBu
OMe
OMe
OMe
CH3
1
2
3
4
5
6
6
6
6
6
7
7
L5
L7
L8
L9
L9
85
91
88
94
81
66
74
70
89
91
87
90
O
O
O
O
O
O
O
N
N
O
N
Boc
9f, 88%;
92% eea
9g, 96%;
9h, 91%;
9i, 83%;
S
R1
90% eea
93% eea
79% eea,e
O
L10
O
O
O
O
CO2tBu
CO2Me
CO2Me
CO2Me
O
OEt
OEt
O
L8: R1 = H
L9: R1 = CF3
P
9
Me
Me
Me
EtO
OEt
O
O
O
O
~3 Å
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OMe
OMe
O
O
9j, 81%;
10b, 83%;
10c, 67%;
10d, 74%;
93% eeb
S
O
N
91% eeb
93% eeb
79% eea,e,f
Et
Et
yield eeb,g
O
O
R2
=
Z =
CO2Me
O
CO2Me
O
O
OMe
CO2R3
L10
(11a)h
H
4-Br 86% 79%
O
O
Me
Me
S
(11b)i Ph 4-H 82% 91%
(11c)i
(11d)i
O
N
Boc
Z
O
O
3-OMe
71% 93%
4-CF3
76% 91%
Ph
Ph
10e, 58%;
10f, 90%;
91% eeb
R2
95% eeb
Pd(OAc)2/L9 complex Et
Et
aCondition A: Nuc 6 (0.4 mmol), Olefin 8 (0.2 mmol), Pd(OAc)2 (0.01 mmol), L9 (0.01 mmol), Zn(OAc)2 2H2O (0.1 mmol), 2,6-DMBQ (0.3 mmol), Benzene (1.2 ml) at 5oC for 72 h. bCondition B: Nuc 7 (0.1 mmol), Olefin 8 (0.1 mmol),
Pd(OAc)2 (0.01 mmol), L10 (0.01 mmol), Zn(OAc)2 2H2O (0.05 mmol), 2,6-DMBQ (0.15 mmol), Dioxane at 5oC for 72 h. cPd(OAc)2/L9 (2.5 mol%) gave 72% yield. dAbsolute stereochemistry assigned based on X-ray crystallography of 9e,
all other compounds assigned by analogy. e25oC. fee determined by converting the acetal group to an aldehyde. g2 equiv. of Nuc. hR3 = methyl. iR3 = benzyl.
the substitution on the tetralone moiety. Commercially
available O-substituted tetralone at 5’, 6’, 7’–positions (3l,
n, p) all served as competent nucleophiles, as well as a 6-
bromo moiety useful for further derivatizations (3m). Incor-
porating an electron-donating O-benzyl group at 6’-position
(3o) led to diminished reactivity and enantioselectivity
(88% ee). The yield could be improved to 78% when run-
ning the reaction at room temperature. The absolute config-
uration was assigned to be (R) from the crystal structure of
3p. Contrasting previous asymmetric allylic C–H alkylations
between the cis-substituents on the oxazoline and sulfoxide
may modulate the orientation of the steric elements towards
the approaching trajectory of the compact 5-membered ring
nucleophile. Given the benefits of electron-rich aromatics in
promoting π–π interactions,16 we examined the electron-
donating 3,4,5-trimethoxyphenyl moiety on the oxazoline
(L8), which led to a substantial increase in asymmetric in-
duction to 89% ee (entry 3). Combined with a CF3 group on
the backbone (L9), a further increase in selectivity to 91% ee
was achieved with excellent reactivity (entry 4). Crystallo-
graphic analysis of Pd(OAc)2/L9 complex suggests a poten-
tial π–π interaction that orients the substituents on the tri-
methoxy aryl group outward, possibly accounting for the
enhanced enantioselectivity. Switching to the smaller nucle-
ophile 7, L9 resulted in 87% ee (entry 5). We made modifi-
cations to further extend the ligand out towards the plane of
that employ nucleophiles not easily diversifiable,4, α-
5
nitroketones are versatile intermediates that can be trans-
formed into a diverse array of common functionality.
Chemoselective reduction of the nitro group revealed the
medicinally relevant α-amino ketone motif 4 without ero-
sion in enantioselectivity. Upon N-allylation of 4 with allyl
bromide, ring-closing metathesis12 furnished the spirocyclic
tetralone-piperidine motif. Chemoselective olefin hydro-
genation in the presence of benzylic ketone afforded 5, a
precursor to potassium-competitive acid blockers.13 Im-
portantly, the synthetic route based on asymmetric alkylation
is highly efficient (43% overall yield and 91% ee) when com-
pared to a previous racemic synthesis13 (6% overall yield).
Additionally, the ketone moiety in 4 serves as a synthetic
handle: both hydride reduction and Grignard addition of the
ketone is achieved with high diastereoselectively to afford
functionalized 1, 2-amino alcohol motifs as useful chiral
building blocks.
the π-allylPd: an expanded π-surface (9-anthracenyl, L10)
on the sulfoxide lead to 90% ee (entry 6).
β-ketoesters 6 and 7 underwent alkylation with a broad
scope (Table 3B). Using Pd(II)/L9 catalyst, nucleophile 6
was found to be highly reactive even with lowered catalyst
loading (5 mol%). Electronic variation on the nucleophile
was well tolerated with 6-methoxy and 6-fluorine substitu-
tion both giving high yields and enantioselectivities in alkyl-
ated products 9b and 9c, respectively. For the terminal ole-
fins, a wide range of sterically and electronically varied al-
lylarenes were alkylated with excellent reactivity and high
enantioselectivity. Important pharmacophores and heterocy-
cles such as unprotected cyclopropyl amide (9d), sulfona-
mide (9e), safrole (9f), tetrahydroquinoline (9g), benzoxa-
zinone (9h) are well tolerated. The absolute configuration
was assigned to be (R) from the crystal structure of 9e. Fur-
thermore, whereas previous asymmetric allylic C–H alkyla-
tions have not been demonstrated with unactivated terminal
olefins, the Pd(II)/ArSOX catalysis could be extended to
this important olefin class (9i, 9j), with good yields and
β-ketoesters represent an important nucleophile class, fur-
nishing versatile synthetic intermediates that can rapidly
afford core skeletons of complex molecules.14 We evaluated
β-ketoesters 6 and 7 featuring the furan-3-one core, found in
natural products with
a broad range of medicinal
properties.15 With the previously optimal SOX ligands L5
and L7, modest enantioselectivity (74% and 70%) was ob-
tained with the benzofuranone nucleophile 6 (Table 3A).
We hypothesized that taking advantage of the interactions
promising enantioselectivity. For the furanone-based β-
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Journal of the American Chemical Society
ketoester 7, the incorporation of thiophene (10b) and furan
Page 4 of 5
crystallography (see supporting information). We addition-
ally observed good to excellent levels of catalyst-controlled
diastereoselectivity in a wide range of aliphatic substrates
having nitrogen, oxygen and carbon stereogenic centers in
the homoallylic positions that allow for the access of either
diastereomer in stereoenriched form: pyrrolidine (12b),
Weinreb amide (12c), 1, 2-diol (12d) and androsterone
derivative (12e). Collectively, these examples demonstrate
the ability of Pd(II)/ArSOX to exert significant catalyst-
controlled asymmetric induction with chiral substrates.
1
2
3
4
5
6
7
8
(10c) into the nucleophile was tolerated with high enanti-
oselectivities. Importantly, 10c establishes the requisite car-
bon skeleton that is found in a family of natural products
such as cephalymysins with diverse biological activities.17
The allylarene component could be rapidly varied to incor-
porate medicinally relevant phenylphosphate (10d), 3’-
indole (10e) and safrole (10f), all in high enantioselectivi-
ties. Challenging indanone-based β-ketoester nucleophiles
furnishing all-carbon quaternary stereocenters (11a) were
also evaluated. Analogous to previous observations in asym-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In conclusion, we have developed
a new class of
18
metric allylic substitutions,9, this nucleophile proceeded
Pd(II)/cis-ArSOX catalysts for asymmetric allylic C–H al-
kylation. The continued study and development of SOX en-
abled catalysis will contribute novel ligands and reactivity
platforms for organometallic reactions proceeding via oxida-
tive pathways.
with a moderate level of enantioselectivity (79% ee). Inter-
estingly, 4-substitution at the indanone (11b) was found to
be beneficial for enantioinduction, leading to >90% ee with a
range of electronically varied allylarenes (11c, d).
Scheme 2. Diastereoselective Allylic C–H Alkyla-
tiona
ASSOCIATED CONTENT
O
O
tBuO2C
tBuO2C
Me
Me
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website at DOI.
Experimental procedures, spectroscopic data for all new com-
pounds and HPLC traces of racemic and enantiomerically en-
riched products (PDF);
O
MeO
N
racemic ligand
1.5:1 d.r.
O
AcO
O
AcO
S
O
L11
Me
same
except
ent-L9
H
Pd(OAc)2 (10 mol%)
L9 (10 mol%)
standard condition
25oC
H
H
H
OAc
H
H
H
(10 mol%)
H
13a
13b
89% yield
16:1 d.r.
90% yield
18:1 d.r.b
X-ray crystallographic data for 3p (CIF: CCDC 1856938);
X-ray crystallographic data for Pd(OAc)2/L9 complex (CIF:
CCDC 1856936);
X-ray crystallographic data for 9e (CIF: CCDC 1856939);
X-ray crystallographic data for 13b (CIF: CCDC 1856937)
H
H
HO
HO
12
HO
+
OMe
OMe
O
N
O
O
OMe
OMe
OMe
OMe
N
O
F3C
S
O
F3C
S
O
O
OtBu
L9
CH3
CH3
ent-L9
6
Ligand Yield d.r.c
Ligand Yield d.r.
O
N
AUTHOR INFORMATION
L12d
21%
1:1
L12d
L9
MeO
35% 1:1.3
91% 8:1
N
L9
93% 5:1
89% 1:4
Boc
Me
H
Corresponding Author
12c
12b
ent-L9 84% 1:17
ent-L9
OTMS
d.r.c
*mcwhite7@illinois.edu
Ligand Yield d.r.
Ligand
L11
Yield
H
H
L12d
L9
44% 1:1.2
92% 3:1
31% 1:1
90% 4:1
93% 1:5
PMBO
Present Addresses
H
OTBS
L9
12e
ent-L9 90% 1:20
ent-L9
12d
TBSO
†Gilead Sciences, 333 Lakeside Drive, Foster City, California,
94404, United States.
ORCID
aReaction condition: Olefin 12 (0.2 mmol), Nuc 6 (0.4 mmol), Pd(OAc)2 (0.02 mmol), Ligand (0.02 mmol),
Zn(OAc)2 2H2O (0.1 mmol), 2,6-DMBQ (0.3 mmol), Benzene (1.2 ml) at 25oC for 72 h. Yields are isolated;
d.r. are determined by 1H NMR anaylsis. bAbsolute stereochemistry assigned by X-ray crystallography of
13b, all other compounds assigned by analogy. cd.r. determined by chiral HPLC analysis. dL12: 1,2-
Bis(phenylsulfinyl)ethane is used, when L11 gave no reaction.
Wei Liu: 0000-0002-7825-4399
While achiral olefins are limited in structural diversity, chi-
ral aliphatic substrates offer the opportunity for sp3-sp3 cross-
coupling of complex fragments. For transformations lacking
substrate bias,19 catalyst-controlled asymmetric induction is
critical for forging such bonds selectively and may additional-
ly enable synthesis of both stereoisomers. We questioned if
the good levels of enantioselectivity observed for the achiral
aliphatic substrates (9i, 9j, Table 3) would translate into
synthetically useful levels of diastereoselectivity. We exam-
ined estrone derivative 12 and found that the inherent sub-
strate bias for alkylation with racemic Pd(II)/L11 catalyst
was minimal (1.5:1 d.r.). Under Pd(II)/L9 catalyzed
asymmetric alkylation with nucleophile 6, the reaction af-
forded product 13a in excellent yield (89%) and diastereose-
lectivity (16:1). Moreover, when ligand enantiomer ent-L9
was used, the sense of asymmetric induction was overturned
to favor the other diastereomer (18:1) in 90% yield. The
absolute stereochemistry of 13b was confirmed via X-ray
M.
Notes
Christina
White:
0000-0002-9563-2523
The University of Illinois has filed a patent application on Ar-
SOX ligands for allylic C–H functionalizations.
ACKNOWLEDGMENT
We thank the NIGMS MIRA (R35 GM122525) for generous
support of this research. SEA is a NSF Graduate Research Fel-
low. We thank Dr. Jennifer Howell for helpful discussions. We
thank R. Quevedo, C. Wendell and K. Feng for checking exper-
imental procedures and spectral data, Dr. Lingyang Zhu for
NMR data analysis, Dr. Toby Woods and Dr. Danielle Gray for
crystallographic data, the Denmark and Hull groups for use of
their polarimeter and HPLC. We thank Johnson Matthey for a
gift of Pd(OAc)2.
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Insert Table of Contents artwork here
O
O
R2O2C
O2N
O
R
R
N
S
O
O
Pd
H
AcO
OAc
α-nitroketones
β-ketoesters
20 examples
avg. 90% ee
Pd(II)/cis-ArSOX
O
17 examples
H
EWG
H
+
*
avg. 91% ee
R
O
O
tBuO2C
tBuO2C
OAc
R =
HO
R
R
S
R
H
O
O
H
H
(R,R)-ArSOX:
18:1 d.r.
(S,S)-ArSOX:
1:16 d.r.
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