Enantioselective Allylic C?H Oxidation of Terminal Olefins to Isochromans by Palladium(II)/Chiral Sulfoxide Catalysis

Article abstract of DOI:10.1002/anie.201603576

The enantioselective synthesis of isochroman motifs has been accomplished by palladium(II)-catalyzed allylic C?H oxidation from terminal olefin precursors. Critical to the success of this goal was the development and utilization of a novel chiral aryl sul

Full text of DOI:10.1002/anie.201603576

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201603576
German Edition: DOI: 10.1002/ange.201603576
Asymmetric Catalysis
À
Enantioselective Allylic C H Oxidation of Terminal Olefins to
Isochromans by Palladium(II)/Chiral Sulfoxide Catalysis
Stephen E. Ammann+, Wei Liu+, and M. Christina White*
Abstract: The enantioselective synthesis of isochroman motifs
resolutions,[2] however palladium-catalyzed asymmetric
À
À
has been accomplished by palladium(II)-catalyzed allylic C H
allylic C H functionalizations have been achieved hereto
oxidation from terminal olefin precursors. Critical to the
success of this goal was the development and utilization of
a novel chiral aryl sulfoxide-oxazoline (ArSOX) ligand. The
with only modest levels of asymmetric induction.[3–6] Addi-
À
À
tionally, palladium-catalyzed asymmetric C H to C O bond-
forming reactions in both areas are rare.[2d,3,5]
À
allylic C H oxidation reaction proceeds with the broadest
scope and highest levels of asymmetric induction reported to
date (avg. 92% ee, 13 examples with greater than 90% ee).
Palladium(II)/bis(sulfoxide) catalysis has proven to be
À
a uniquely general platform for effecting allylic C H oxida-
tion, amination, fluorination, and alkylation of terminal
olefins with broad scope, preparative yields, and excellent
regio- and E/Z-selectivity.[7] Many of these reactions proceed
by a serial ligand catalysis mechanism where the bis(sulf-
À
T
he enantioselective functionalization of prochiral C H
bonds represents a highly efficient transformation by instal-
ling both valuable oxidized functionality and absolute ste-
À
oxide) ligand promotes C H cleavage, and p-benzoquinone
À
reochemistry in a single step. Asymmetric allylic C H
(BQ), acting as a p-acidic ligand, promotes functionalization.
However, limited success has been achieved in adapting this
catalytic platform for asymmetric catalysis.[3] Mechanistic
studies have illuminated two significant challenges. The
oxidations have been pursued over the last five decades;
copper-catalyzed Kharasch–Sosnovsky reactions have ach-
ieved satisfactory enantiomeric excesses, however only with
symmetrical, cyclic olefins under synthetically undesirable
conditions (excess equivalents of olefin, days at cryogenic
temperatures; Scheme 1A).[1] Palladium has shown a broad
À
bis(sulfoxide) ligand, while effective for C H cleavage and
oxidatively stable, is transiently associated with the palladium
metal and does not exert influence during functionalization.
BQ acts as a ligand at high concentrations to promote
functionalization.[7a] Second, rapid p–s–p isomerization pre-
À
scope in enantioselective C H desymmetrizations and kinetic
À
cedes the C O bond-forming step and scrambles any chiral
À
information that may be imparted during C H cleavage by
a chiral bis(sulfoxide) ligand. Working within the constraints
of these challenges, a chiral chromium Lewis-acid cocatalyst
was identified and works with BQ to promote enantioinduc-
tion during functionalization, albeit with modest enantiomer-
ic excess (Scheme 1B).[3] Alternatively, chiral palladium/
À
phosphoramidite catalysts for allylic C H functionalizations
have demonstrated modest enantioselectivity (avg. 75% ee,
1 example ꢀ 90% ee,[4] avg. 83% ee, 2 examples at 90% ee[5]),
À
limited olefin scope (generally doubly activated C H bonds),
and high sensitivity to O2.[4,5] We hypothesized the ideal
catalytic platform would utilize an oxidatively stable, chiral
À
ligand capable of promoting both C H cleavage and func-
tionalization, thus circumventing the challenges of serial
ligand catalysis.
Chiral isochromans are well-represented in natural prod-
ucts and pharmaceuticals, and are classically furnished by
diastereoselective cyclizations or chiral resolution of race-
mates.[8] Enantioselective organocatalytic and metal-cata-
lyzed methods are emerging to furnish this motif, however,
generally starting from preoxidized precursors.[9] We recently
reported the synthesis of racemic cyclic ethers by palladium-
À
Scheme 1. Enantioselective allylic C H oxidation.
[*] S. E. Ammann,[+] W. Liu,[+] Prof. Dr. M. C. White
Roger Adams Laboratory, Department of Chemistry
University of Illinois at Urbana-Champaign
Urbana, IL 61801 (USA)
À
(II)/bis(sulfoxide)-catalyzed, BQ-promoted allylic C H oxi-
dation.[10] Given that pre-coordination of the alcohol to
palladium was found to be important for functionalization, we
hypothesized that such a system might enable high levels of
E-mail: mcwhite7@illinois.edu
[+] These authors contributed equally to this work.
À
asymmetric induction in the C O bond-forming step, and
provide a valuable means to furnish chiral isochromans.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603576.
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Table 1: Reaction development.
Drawing inspiration from the success of mixed P,N-donor
ligands in asymmetric catalysis,[11] we hypothesized that
À
combining a sulfoxide (promotes C H cleavage) with the p-
acidic/s-donor properties of an oxazoline (may promote
functionalization and effect a static chiral environment at the
metal) would enable an efficient asymmetric reaction. Mixed
S,N ligands are known to effect asymmetric induction in
palladium(0)-catalyzed allylic substitutions, however with
a
very limited scope (1,3-diphenylpropenyl acetate).[12]
Alkyl-substituted sulfoxide-oxazoline ligands were recently
À
shown to promote palladium-catalyzed branched allylic C H
acetoxylations, however with no asymmetric induction.[13]
Herein we report the development of a chiral diarylated
sulfoxide-oxazoline (ArSOX) ligand/palladium(II)-catalyzed
À
asymmetric allylic C H oxidation system which proceeds
with broad scope and high asymmetric induction (avg. 92%
ee, 13 examples with ꢀ 90% ee).
We identified ArSOX [(S,R)-L1; Table 1, entry 1) as
effective for asymmetric palladium(II)-catalyzed[14] formation
of the isochroman 2a, though in low yield. Based on our
recent studies showing that Brønsted acids enhance the
Entry Ligand
Additive
Yield [%][a] ee [%][a]
1
2
3
4
5
6
7
8
9
10
11
12
13[b]
14[b]
15[c]
16[d]
(S,R)-L1
(S,R)-L1
(S,R)-L1
(S,R)-L1
(S,R)-L1
(S,S)-L2
(S,R)-L3
(S,R)-L4
(S,R)-L5
(S,R)-L6
none
8
13
54
47
63
32
31
8
24
60
70
49
31
13
<5
59
83
84
87
82
87
19
76
25
88
86
92
93
À6
12
n.d.
77
benzoic acid
(nBuO)2PO2H
(PhO)2PO2H
Ph2PO2H
Ph2PO2H
Ph2PO2H
Ph2PO2H
Ph2PO2H
Ph2PO2H
À
reactivity of palladium(II) sulfoxide catalyzed allylic C H
oxidations,[7g] we surveyed Brønsted acid additives (entries 2–
5) for the reaction. Whereas the Brønsted acid did not
significantly impact asymmetric induction, a significant en-
hancement in yield was observed. Utilizing the diastereomer
(S,S)-L2 resulted in dramatically lowered yield and enan-
tioinduction (entry 6), thus suggesting that the relative
stereochemistry of the sulfoxide and the oxazoline is impor-
tant. Examining the previously reported alkyl-substituted
sulfoxide-oxazoline ligands[13] resulted in significantly dimin-
ished yields and enantioselectivity (entries 7 and 8). We next
turned to modifications at the sulfoxide: utilizing an isopropyl
group was beneficial for enantioselectivity, but significantly
diminished reactivity (entry 9).[15] Further examination of aryl
sulfoxides revealed that a para-methoxy-substituent was not
beneficial (entry 10), however both para-tert-butyl- and para-
trifluoromethyl-benzene moieties resulted in enantioselectiv-
ities above 90% ee (entries 11 and 12).[16] We selected tBu-
ArSOX [(S,R)-L7] for further study because of its combina-
tion of high enantioinduction and reactivity, and its relative
ease of synthesis. However, CF3-ArSOX [(S,R)-L8] is optimal
in cases where enantiomeric excesses fall below 90% ee, and
product yields may be improved by extending reaction times.
Utilizing either the chiral bis(sulfoxide) (R,R)-L9 (entry 13)
or chiral oxazoline (S)-L10 (entry 14) ligands resulted in
minimal enantioinduction. Notably, examination of the phos-
phoramidite (S)-L11 under both our standard conditions and
O2-free conditions previously reported[5] resulted in trace
formation of 2a (entry 15). Replacing the sterically-bulky 2,6-
dimethylbenzoquinone (2,6-DMBQ) with BQ as the stoichio-
metric oxidant diminished enantioselectivity (entry 16), pos-
sibly because of an undesirable competition between BQ and
(S,R)-tBu-ArSOX L7 as a ligand for palladium(II).[7f]
(S,R)-tBu-ArSOX (L7) Ph2PO2H
(S,R)-CF3-ArSOX (L8) Ph2PO2H
(R,R)-L9
(S)-L10
(S)-L11
(S,R)-L7
Ph2PO2H
Ph2PO2H
Ph2PO2H
Ph2PO2H
[a] Reactions run open to air. Yield is that of the isolated product and an
average of two runs. The ee value was determined by GC using a chiral
column. [b] Reaction run for 72 hours at [0.5m]. [c] Reaction run under
argon using reaction conditions reported in Ref. [5] also resulted in trace
amounts of product (see S.I.). [d] p-Benzoquinone used in place of 2,6-
DMBQ. 2,6-DMBQ=2,6-dimethylbenzoquinone. n.d.=not determined.
enantioselectivities. Broad tolerance for electronic substitu-
tion on aryls has not been previously shown for other
asymmetric allylic C H methods, which show either
À
decreased enantioselectivity for electron-rich aryl moieties,[4]
or inconsistent trends for aryl tolerance.[5] Bromide and
chloride substitution is well tolerated, and these groups serve
as handles for further manipulation (2e,h). The ee values of
the products 2d and 2i were improved to greater than 90% by
utilizing (S,R)-CF3-ArSOX L8 in place of (S,R)-tBu-ArSOX
L7.
Stereochemically defined substitutions in isochromans at
both the 3- and 4-positions are well represented in biologically
active compounds. In the case of the 1,3-disubstituted 4 (see
Table 2), a motif found in such compounds as the antibiotic
elutherin and D1 agonist A77636, syntheses are generally
achieved by Pictet–Spengler reaction under diastereoselec-
tive substrate control, and catalyst-controlled diastereoselec-
We next examined the scope of the reaction for furnishing
the vinylisochroman motif (Figure 1). Gratifyingly, broad
aromatic substitution is tolerated, with both electron-rich
substrates (2b–d) and electron-deficient substrates (2e–i)
furnishing the desired products in good yields and high
tivity has not been demonstrated.[17] Notably, allylic C H
oxidation in the presence of the achiral palladium(II)/L12
À
2
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1:2.8, thus favoring the trans-diastereomer 4b. The ability to
influence diastereoselectivity with this palladium(II)/tBu-
À
ArSOX L7-catalyzed asymmetric C H oxidation method is
similarly observed in the formation of the structurally distinct
À
1,4-disubstituted 6. Allylic C H oxidation in the presence of
achiral palladium(II)/L12 furnishes the cis-diastereomer in
3.6:1 d.r. The use of matched palladium(II)/(S,R)-tBu-ArSOX
L7 once again increased the d.r. value to greater than 20:1 in
favor of 6a, and mismatched palladium(II)/(R,S)-tBu-ArSOX
L7 d.r. led to a d.r. value of 1:1.4 in favor of 6b (Table 2B).
PNU-109291 (8) is a pharmaceutical compound that
functions as a selective 5HT1D agonist.[18] Previous asymmet-
ric syntheses of this target suffered from the need for chiral
resolution of racemates. We evaluated our enantioselective
method in the context of a more efficient synthesis (Fig-
ure 2A). Starting from the aryl amide 1k (see the Supporting
Information for preparation), the vinylisochroman 2k is
À
formed by C H oxidation in good yield and enantioselectiv-
ity, thus demonstrating this reactionꢀs tolerance of N-Boc
protected amides which may chelate palladium.[19] Subse-
quent hydroboration/oxidation of 2k furnished the alcohol 7
in 80% yield. Nucleophilic displacement of 7 with aryl
Figure 1. Enantioselective formation of isochromans. Reaction condi-
tions: alcohol 1 (0.2 mmol), Pd(OAc)2 (0.1 equiv), (S,R)-L7 (0.1 equiv),
Ph2PO2H (0.1 equiv), 2,6-DMBQ (1.1 equiv), toluene (0.15m), 458C.
Yields reported are those of the isolated product and are an average of
three runs. The ee values were determined by chiral GC and chiral high
performance liquid chromatography (HPLC). [a] (S,R)-L8 used in place
of (S,R)-L7. [b] Reaction run for 9 h. [c] Reaction run for 10 h. [d] Reac-
tion run for 48 h.
furnishes 4 with a modest 1.5:1 d.r. value favoring the cis-
diastereomer 4a (Table 2A). When the reaction is run with
palladium(II)/(S,R)-tBu-ArSOX L7, the d.r. value is
increased to greater than 20:1 favoring 4a. Significantly,
when the reaction is run with the mismatched palladium-
(II)/(R,S)-tBu-ArSOX L7, the d.r. value is overturned to
À
Table 2: Catalyst influence on diastereoselective C H cyclization.
Entry Ligand
Yield
[%][a]
d.r.[b]
(4a/4b)
1
2
3
meso-1,2-bis(phenylsulfinyl)ethane (L12)
(S,R)-tBu-ArSOX L7
(R,S)-tBu-ArSOX L7
16
62
49
1.5:1
>20:1
1:2.8
Figure 2. Vinylisochromans as versatile chiral intermediates. Reaction
conditions: a) 9-BBN (1.5 equiv), THF, 08C, then NaBO3 (5 equiv),
80% yield. b) MsCl (1.05 equiv), DMAP (5 mol%), DIPEA (2.5 equiv),
THF; then aryl piperazine (1.5 equiv), 50% yield, 93% ee. c) Hoveyda–
Grubbs II (7 mol%), olefin (2 equiv), CH2Cl2. d) Cu(OAc)2 (4 mol%),
DTBM-SEGPHOS (4.4 mol%), amine (1.2 equiv), DEMS (2 equiv),
THF. e) 9-BBN (1.5 equiv), THF; then NaBO3 (5 equiv). 9-BBN=
9-borabicyclo[3.3.l]nonane, DEMS=diethoxymethylsilane, DTBM-SEG-
PHOS=(R)-5,5’-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-
4,4’-bi-1,3-benzodioxole, DIPEA=diisopropylethylamine, Ms=metha-
nesulfonyl, THF=tetrahydrofuran.
Entry Ligand
Yield
[%]
d.r.
(6a/6b)
1
2
3
meso-1,2-bis(phenylsulfinyl)ethane (L12)
(S,R)-tBu-ArSOX L7
(R,S)-tBu-ArSOX L7
60
67
68
3.6:1
>20:1
1:1.4
[a] Yield is that of the isolated product, average of three runs.
[b] Determined by 1H NMR analysis.
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piperazine furnished the piperazine 8. Overall, starting from
2a, and no change in isochroman enantioenrichment was
observed over time (see the Supporting Information). Thus,
from these experiments we infer that the catalyst imparts
asymmetric induction during functionalization.
À
commercial materials, the asymmetric C H oxidation route
resulted in a higher overall yield.[20] Additionally, we sought to
exploit the latent reactivity of the allylic-substituted terminal
olefin, thus demonstrating orthogonality to past efforts which
have focused on late-stage modifications to the aryl moiety.[18]
The isochroman 2a may be diversified into the a,ß-unsatu-
rated amide 9 by ruthenium-catalyzed cross-metathesis,[21]
into the aliphatic amine 10 by copper-catalyzed hydroamina-
tion,[22] and also into terminal the alcohol 11 via hydro-
boration oxidation (Figure 2B). Importantly, all of these
manipulations proceeded without racemization of the stereo-
center. The compound 11 is a precursor to (S)-Sonepiprazole
In conclusion, we have reported a catalytic system for
À
enantioselective palladium(II)-catalyzed allylic C H oxida-
À
tions, with an ArSOX ligand which enables both C H
cleavage and a stable chiral environment for asymmetric
induction during functionalization. We have demonstrated
the utility of this operationally simple method (open to air
and moisture) to furnish isochromans with broad scope, in
good yields and high enantioselectivities. Further investiga-
tions are underway to evaluate PdII/ArSOX in other allylic
À
À
(12), whose synthesis by asymmetric C H oxidation proceeds
C H functionalizations.
with a higher overall yield than the reported synthesis by
kinetic resolution.[23]
As a preliminary mechanistic investigation, we sought to Experimental Section
À
To a 1= dram vial was added the ligand (S,R)-tBu-ArSOX L7 (8.1 mg,
0.02 mmol) and Pd(OAc)2 (4.4 mg, 0.02 mmol). Toluene (0.4 mL) was
distinguish between an oxypalladation or C H cleavage/
2
p-allyl palladium pathway. To evaluate an olefin isomeriza-
tion/oxypalladation mechanism, we subjected the internal
olefin 13 to the reaction conditions, and observed no
formation of 2a (Figure 3A), thus indicating an oxypallada-
added, and the vial was capped and heated to 458C until all solids had
dissolved. Separately, to a 1 dram vial with stir bar was added 1a
(32.4 mg, 0.20 mmol), 2,6-dimethylbenzoquinone (30 mg, 0.22 mmol),
and diphenylphosphinic acid (4.4 mg, 0.02 mmol), with no precau-
tions to exclude air or moisture. The catalyst solution was subse-
quently added to the reaction flask, and toluene (0.9 mL) was used to
rinse (total volume toluene = 1.3 mL). The 1 dram vial was sealed
with a Teflon cap, and allowed to stir for 8 hours at 458C, until
complete conversion of the starting material was observed by TLC.
Afterward, the vial was cooled to room temperature. The majority of
the toluene was removed under reduced pressure, and the remaining
mixture was directly subjected to flash column chromatography (10%
EtOAc in hexanes) to provide the vinylisochroman as a clear oil.[24]
Acknowledgments
Financial support provided by the NIH/NIGMS (2R01 GM
076153B). SEA is a NSF Graduate Research Fellow. We
thank Rulin Ma for assistance with preliminary studies in
ligand design, Connor Delaney for checking the experimental
in Figure 1 for 2h, and Dr. Lingyang Zhu for helpful
discussions related to spectral characterization. We thank
Dr. Danielle Gray for X-Ray crystallographic analysis. We
thank Johnson Matthey for a generous gift of Pd(OAc)2.
Figure 3. Mechanistic investigation.
tion pathway is not operative. We probed the capacity of this
catalyst system to effect allylic C H cleavage with unacti-
À
À
À
vated C H bonds, which has been demonstrated previously
Keywords: asymmetric catalysis · C H activation · oxidation ·
palladium · S ligands
under palladium/bis(sulfoxide) catalysis.[10] With chiral cata-
lyst palladium/(R,S)-tBu-ArSOX L7, the alcohol 14 furnishes
pyran 15 in good yield and enhanced diastereoselectivity
relative to the achiral palladium(II)/L12 (19:1 d.r. versus 8:1
d.r., Figure 3B). We next sought to elucidate which step of the
reaction is responsible for asymmetric induction. Evaluation
of the reaction with substrate [D]-1a furnished [D]-2a with
complete scrambling of the deuterium at the terminal alkene
(Figure 3C). This scrambling signifies p–s–p isomerization of
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to the reaction conditions does not result in enantioenriched
4
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À
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X. Cai, W.-H. Wang, Z.-J. Shi, J. Am. Chem. Soc. 2008, 130,
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[8] E. L. Larghi, T. S. Kaufman, Synthesis 2006, 2, 187 – 220.
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Received: April 12, 2016
Revised: May 18, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Asymmetric Catalysis
S. E. Ammann, W. Liu,
M. C. White*
&&&& — &&&&
À
Enantioselective Allylic C H Oxidation of
Terminal Olefins to Isochromans by
Palladium(II)/Chiral Sulfoxide Catalysis
Selective and general: Palladium(II)/
chiral sulfoxide catalysis affords an
palladium(II)/ArSOX catalyst furnishes
chiral isochromans from terminal olefin
precursors and the reactions are run open
to the air and moisture.
À
asymmetric allylic C H oxidation reaction
which proceeds with broad scope and
high levels of enantioselectivity. The
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!