Controllable Stereoselective Synthesis of (Z)- and (E)-Homoallylic Alcohols Using a Palladium-Catalyzed Three-Component Reaction

Article abstract of DOI:10.1021/acs.orglett.7b02979

Diastereoselective synthesis of (Z)- and (E)-homoallylic alcohols using a Pd-catalyzed three-component reaction of 3-(pinacolatoboryl)allyl benzoates, aldehydes, and aryl stannanes was developed, which provides an alternative method for the allylboration of aldehydes using α, γ-diaryl-substituted allylboronates. Both sets of reaction conditions enable access to either (Z)- or (E)-homoallylic alcohols with good to high alkene stereocontrol. The present method showed good functional group compatibility and generality. Efficient chirality transfer reactions to afford enantioenriched (Z)- and (E)-homoallylic alcohols were also achieved.

Full text of DOI:10.1021/acs.orglett.7b02979

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Controllable Stereoselective Synthesis of (Z)- and (E)‑Homoallylic
Alcohols Using a Palladium-Catalyzed Three-Component Reaction
Yoshikazu Horino,*,† Miki Sugata,† Itaru Mutsuura,† Keisuke Tomohara,‡ and Hitoshi Abe†
†Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan
‡Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
S
* Supporting Information
ABSTRACT: Diastereoselective synthesis of (Z)- and (E)-
homoallylic alcohols using a Pd-catalyzed three-component
reaction of 3-(pinacolatoboryl)allyl benzoates, aldehydes, and
aryl stannanes was developed, which provides an alternative
method for the allylboration of aldehydes using α,γ-diaryl-
substituted allylboronates. Both sets of reaction conditions
enable access to either (Z)- or (E)-homoallylic alcohols with
good to high alkene stereocontrol. The present method
showed good functional group compatibility and generality. Efficient chirality transfer reactions to afford enantioenriched (Z)-
and (E)-homoallylic alcohols were also achieved.
Scheme 1. Transition-Metal-Catalyzed Isomerization/
Allylation Reactions
llylboration of carbonyl compounds is well established as
Aone of the most important and promising methods for the
stereoselective synthesis of homoallylic alcohols.1 Recent
advances in the preparation of allylic boronates have contributed
in making this reaction more reliable and useful.2 For example,
highly diastereo- and enantioselective allylborations of aldehydes
using α,γ-disubstituted allylic boronates, without changing the
substituents around the boron atom, were reported.3 However,
this elegant method still lacks alkene stereocontrol. In addition,
the rather narrow functional group compatibility hampers its
general and practical use due to the intrinsic difficulty in the
elaboration of functional-group-tolerated α,γ-disubstituted allylic
boronates.4 Alternative methods, including catalytic variants, for
the diastereoselective synthesis of functional-group-tolerated
(Z)- and (E)-homoallylic alcohols is highly desired.
Transition-metal-catalyzed alkene isomerization of alkenyl
boronates has emerged as a surrogate reaction to the stereo-
selective synthesis of allylic boronates5 because alkenyl boronates
are stable, easy-to-handle, and readily available.6 Murakami and
Miura reported the Ir-catalyzed alkene isomerization of alkenyl
boronates into (E)-allylic boronates that gives anti-homoallylic
alcohols enantio- and diastereoselectively (Scheme 1a).7,8 The
Ni-catalyzed alkene isomerization/allylation reaction affords
complementary stereochemical results (Scheme 1b).9 Notably,
Ru-catalyzed isomerization of N-allyl amides produce thermo-
dynamically less-stable (Z)-γ-aminoallylic boronates, which then
react with aldehydes to provide syn-homoallylic alcohols
(Scheme 1c).10 Although these precedents offer more convenient
stereoselective synthesis of homoallylic alcohols with terminal
alkenes, catalytic methods for the synthesis of homoallylic
alcohols bearing E- or Z-disubstituted alkenes,11 especially aryl-
substituted alkenes, have been less explored.12
boryl and Pd/stannyl species are useful intermediates for the
umpolung allylation of aldehydes14 to provide (Z)- and (E)-
homoallylic alcohols, respectively, with good to high stereo-
selectivity.15 However, such methods require the independent
preparation of different starting materials. Although alkyl groups
can be installed at the alkene terminus with high Z-stereo-
selectivity, poor Z-stereoselectivity was observed when the
To overcome such limitations, we reported that catalytically
Received: September 22, 2017
generated allylic heterobimetallic species13 such as allylic Pd/
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02979
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
triphenylborane was used as a coupling partner. Stereocontrolled
synthesis of (Z)- and (E)-homoallylic alcohols from the same
starting materials is a highly appealing prospect. Herein, we
report the controllable stereoselective synthesis of (Z)- and (E)-
homoallylic alcohols using a Pd-catalyzed three-component
reaction of 3-(pinacolatoboryl)allyl benzoates, aldehydes, and
aryl stannanes. This method shows good functional group
compatibility and generality and allows for the preparation of
enantioenriched (Z)- and (E)-homoallylic alcohols 4 using
chirality transfer reactions.
Scheme 2. Scope and Limitations
Our initial investigation focused on the three-component
reaction of 1a, 2a, and 3a (Table 1). Optimization of ligands,
a
Table 1. Optimization of Reaction Conditions
4aaa
b
5aa
b
c
entry
1
Pd/ligand
solvent
(%)
E/Z
(%)
Pd2(dba)3/PPh3
Pd2(dba)3/PPh3
Pd2(dba)3/PPh3
Pd(OAc)2/PPh3
THF
69
45
69
62
73
1:3
2
0
3
5
4
d
2
DMF
1:4.5
1:6
3
MeCN
MeCN
MeCN
d
4
e
1:10
1:13
5
Pd(OAc)2/
P(4-MeOC6H4)3
d
6
Pd(OAc)2/
P(4-CF3C6H4)3
MeCN
55
1:1
5
7
8
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
THF
56
66
62
65
13:1
10
13
13
13
toluene
THF
8:1
11:1
13:1
f
9
10 ,
fg
THF
a
Pd (5 mol % as Pd), ligand (10 mol %), 1a (0.5 mmol), 2a (1.2
mmol), 3a (1.2 mmol), and solvent (3 mL) at 70 °C for 1−3 h.
b
c
d
Isolated yield. Determined by NMR analysis. Yields of 6aa vary
e
from 13 to 14% (E/Z = 1:>20). 6aa was obtained in 6% (E/Z =
1:>20). 2a (1.8 mmol) was used. 5 Å MS (500 mg) was used.
f
g
solvents, and coupling partners was proven to be crucial in
obtaining high (Z)-stereoselectivity.16 It was also found that the
leaving group plays an important role on the yield of the
reaction.16 The use of MeCN as a solvent increased the (Z)-
stereoselectivity (entries 1−3). During ligand screening, the
Pd(OAc)2/P(4-MeOC6H4)3 catalyst system afforded 4aaa in
73% yield with high (Z)-stereoselectivity (entries 4−6). The
homoaldol equivalent product 6aa17 did not react with 3a to
provide 4aaa under the Pd(OAc)2/P(4-MeOC6H4)3 catalyst
system. In addition, isomerization of (Z)-4aaa to (E)-4aaa was
not observed under the reaction conditions. Conversely,
stereochemical changes to give (E)-isomer were observed when
Pd2(dba)3 was employed in the absence of ligands (entries 7−8).
Further optimization of the reaction conditions revealed that the
use of 3.6 equiv of 2a along with addition of molecular sieves (5 Å
MS) provided some increase in (E)-selectivity (entries 9 and 10).
The relative stereochemistry of 4aaa was determined to be anti by
derivatization to give a literature-known material.16 With the
optimized reaction conditions in hand, we subsequently explored
the reaction scope using various aldehydes 2 with 1a and 3a under
both sets of conditions (Scheme 2). A broad range of aromatic
aldehydes was tolerated to provide (Z)- and (E)-homoallylic
alcohols 4 with good to high levels of alkene stereocontrol.
Indeed, the reactions proceeded without being influenced by the
a
Conditions A: Pd(OAc)2 (5 mol %), P(4-MeOC6H4)3 (10 mol %), 1
(0.5 mmol), 2 (1.8 mmol), 3a (1.2 mmol), and MeCN (3 mL) at 70
°C for 1−3 h. Conditions B: Pd2(dba)3 (2.5 mol %), 1 (0.5 mmol), 2
(1.8 mmol), 3a (1.2 mmol), 5 Å MS (500 mg), and THF (3 mL) at 70
b
°C for 1−3 h. E/Z ratio of 6 varies from 1:10 to 1: >20.
electronic nature of the substituents (methoxycarbonyl, cyano,
and methoxy) to afford 4aba−4aea under both sets of conditions.
Although a sterically hindered o-anisaldehyde did not participate
in the reaction under (Z)-selective conditions, the reaction
proceeded to give 4afa under the (E)-selective conditions.
Aromatic aldehydes bearing halide substituents also furnished
B
DOI: 10.1021/acs.orglett.7b02979
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good yields and alkene stereocontrol for products 4aga−4aja,
which can be used for further manipulation and diversification.
Moreover, the reaction of heterocyclic aldehydes, such as 3-
furaldehyde and 3-thiophenecarboxaldehyde, proceeded
smoothly to produce 4aka and 4ala, respectively, in good to
high yields and moderate to good levels of alkene stereocontrol.
Aliphatic aldehydes were also applicable to the three-component
reaction to afford the corresponding products 4ama and 4ana in
40%−56% yield and good to high E/Z ratios under both sets of
conditions. Excellent diastereoselectivities were observed for all
of the aldehydes examined.
high levels of alkene stereocontrol. Stereochemistry of 4aab was
assigned after X-ray analysis.18 Among them, an aryl stannane
bearing an ester group did not take part in the reaction to afford
(E)-4aac. In addition, tributyl(o-tolyl)stannane was not compat-
ible with the Z-selective conditions. Use of heteroaryl-substituted
aryl stannanes was imposed on the Z-selective conditions, giving
(Z)-4aai and (Z)-4aaj in 40 and 66% yields, respectively, having
E/Z ratio of 1/10. (Z)-4aaj was obtained with a decreased
diastereoselectivity.
To gain further mechanistic insights, we carried out chirality
transfer experiments using (R)-1a (97% ee) under both sets of
conditions (Scheme 4). Consistent with our previous report, a
Next, we examined the substrate generality of the reaction. A
variety of readily accessible aryl-substituted substrates were
subjected to the both sets of conditions. Substrates bearing
electron-withdrawing and -donating groups could be utilized to
give 4baa−4faa. A substrate bearing a 2-naphthyl group also
underwent this reaction to give 4gaa. Note that o-chloro-, m-
chloro-, and p-bromo-substituted phenyl substrates were
compatible with both sets of reaction conditions, providing
4haa−4jaa in 41−69% yield with good to high E/Z ratios.
Among them, (E)-4jaa was obtained with a decreased syn/anti
ratio. Heteroaryl-group-substituted substrates were also ame-
nable to the reaction, giving 4kaa−4laa in 50−62% yield with
good E/Z ratios. Unfortunately, only trace amounts of the desired
product were obtained when alkyl-substituted substrates, such as
methyl- and isopropyl-substituted substrates, were applied.
The scope of the Pd-catalyzed three-component reaction with
respect to aryl stannanes was also evaluated (Scheme 3). It was
found that the reactions showed wide generality for various aryl
stannanes containing trifluoromethyl, methoxycarbonyl, me-
thoxy, chloro, and methyl groups on the aromatic ring, furnishing
the desired (Z)- and (E)-4aab−4aag in good yields with good to
Scheme 4. Chirality Transfer Reactions
a
Scheme 3. Reactions with Various Organostannanes
similarly efficient chirality transfer was observed under Z-
selective conditions (Scheme 4a).15a Absolute stereochemistry
of (Z)- and (E)-4aaa was determined to be (1S,2R) by
transformation into known diols.15a When (R)-1a was subjected
to E-selective conditions, (E)-4aaa was produced with a high
degree of chirality transfer, from 97% ee of the starting material to
95% ee in the final product (98% es) (Scheme 4b). These
products are only accessible via enantioenriched α,γ-diphenyl-
substituted allylboronates.19 Absolute stereochemistry of (E)-
4aaa was opposite from that of the former case. These results
indicate that two different reaction pathways need to be invoked
to account for these transformations. In addition, both
diastereomers of alkenyl boronate (S)-1m and (R)-1m20 also
enabled the chirality transfer reaction (Scheme 4c,d). Notably,
stereochemical match/mismatch effects were observed. On the
other hand, no reactions were observed under the E-selective
conditions (Scheme 4e).
On the basis of the results of these chirality transfer reactions,
the stereochemical outcome under Z-selective conditions might
be rationalized in a manner similar to the previously reported
mechanism (Scheme 5).15a First, oxidative addition occurs with
an inversion of configuration, leading to η3-allylpalladium
intermediate A. The Pd atom in the η1-allylpalladium
intermediate would coordinate to a benzaldehyde to preferen-
a
b
Reaction conditions identical to those in Scheme 2. E/Z ratio of 6
varies from 1:10 to 1:>20.
C
DOI: 10.1021/acs.orglett.7b02979
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
Scheme 5. Plausible Reaction Pathway under Z-Selective
Conditions
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. Ryuta Miyatake (University of Toyama) for
assistance in X-ray crystallographic analysis. This work was
financially supported by JSPS KAKENHI Grant No.
JP15K05496.
REFERENCES
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Scheme 6. Plausible Reaction Pathway under E-Selective
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ASSOCIATED CONTENT
* Supporting Information
■
(15) (a) Horino, Y.; Aimono, A.; Abe, H. Org. Lett. 2015, 17, 2824.
(b) Horino, Y.; Sugata, M.; Abe, H. Adv. Synth. Catal. 2016, 358, 1023.
(16) For more information, see Supporting Information.
(17) Horino, Y.; Sugata, M.; Sugita, T.; Aimono, A.; Abe, H.
Tetrahedron Lett. 2017, 58, 2131.
(18) CCDC No. 1560306 [(E)-anti-4aab]. The crystallographic data
can be obtained free of charge from The Cambridge Crystallographic
Data Centre.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02979.
Experimental procedure, characterization data, and NMR
spectra (PDF)
X-ray crystallography data for (E)-anti-4aab (CIF)
(19) For the synthesis and reactions of enantioenriched α,γ-
disubstituted allylboronates, see refs 4b and 12d and refs cited therein.
(20) (a) Luithle, J. E. A.; Pietruszka, J. Liebigs Ann. 1997, 1997, 2297.
(b) Luithle, J. E. A.;Pietruszka, J.; Witt, A. Chem. Commun. 1998, 4, 2651.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: horino@eng.u-toyama.ac.jp.
ORCID
(d) Pietruszka, J.; Schone, N. Eur. J. Org. Chem. 2004, 2004, 5011.
̈
Yoshikazu Horino: 0000-0002-8916-6298
Keisuke Tomohara: 0000-0003-2305-5963
D
DOI: 10.1021/acs.orglett.7b02979
Org. Lett. XXXX, XXX, XXX−XXX