Enantioselective Synthesis of anti-1,2-Oxaborinan-3-enes from Aldehydes and 1,1-Di(boryl)alk-3-enes Using Ruthenium and Chiral Phosphoric Acid Catalysts

Article abstract of DOI:10.1021/jacs.7b06408

A cationic ruthenium(II) complex catalyzes double-bond transposition of 1,1-di(boryl)alk-3-enes to generate in situ 1,1-di(boryl)alk-2-enes, which then undergo chiral phosphoric acid catalyzed allylation of aldehydes producing homoallylic alcohols with a (Z)-vinylboronate moiety. 1,2-Anti stereochemistry is installed in an enantioselective manner. The (Z)-geometry forged in the products allows their isolation in a form of 1,2-oxaborinan-3-enes, upon which further synthetic transformations are operated.

Full text of DOI:10.1021/jacs.7b06408

Subscriber access provided by UNIV OF DURHAM
Article
Enantioselective Synthesis of anti-1,2-Oxaborinan-3-enes from Aldehydes and
1,1-Di(boryl)alk-3-enes Using Ruthenium and Chiral Phosphoric Acid Catalysts
Tomoya Miura, Junki Nakahashi, Wang Zhou, Yota Shiratori, Scott G. Stewart, and Masahiro Murakami
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b06408 • Publication Date (Web): 14 Jul 2017
Downloaded from http://pubs.acs.org on July 14, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 7
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Enantioselective Synthesis of anti-1,2-Oxaborinan-3-enes
from Aldehydes and 1,1-Di(boryl)alk-3-enes Using Ruthenium and
Chiral Phosphoric Acid Catalysts
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
Tomoya Miura,* Junki Nakahashi, Wang Zhou, Yota Shiratori, Scott G. Stewart,† and
Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510, Japan
ABSTRACT: A cationic ruthenium(II) complex catalyzes double-bond transposition of 1,1-di(boryl)alk-3-enes to generate in situ
1,1-di(boryl)alk-2-enes, which then undergo chiral phosphoric acid-catalyzed allylation of aldehydes producing homoallylic alco-
hols with a (Z)-vinylboronate moiety. 1,2-Anti stereochemistry is installed in an enantioselective manner. The (Z)-geometry forged
in the products allows their isolation in a form of 1,2-oxaborinan-3-enes, upon which further synthetic transformations are operated.
transition state, where a high enantioselectivity can be induced
by a chiral phosphoric acid.7 Transition-metal catalysts, which
are effective for double-bond transposition, are potentially
active in geometrical E/Z-isomerization of double bonds as
well.8 When 1,1-di(boryl)alk-3-enes are reacted with alde-
hydes mediated by a catalytic palladium(I) species,5d the ini-
tially produced d-boryl-substituted anti-homoallylic alcohols
contain a (Z)-vinylboronate moiety, which is more difficult to
shape than an (E)-vinylboronate moiety in general.9 Unfortu-
nately, this stereochemistry is not preserved under the reaction
conditions, instead isomerization occurs to the (E)-geometry
[Figure 1(b)]. With this scenario in mind we have been search-
ing for a transition-metal catalyst which is more specifically
effective for double-bond transposition of 1,1-di(boryl)alk-3-
enes to allow the preservation of the product with (Z)-
geometry. We now report a cationic ruthenium(II) complex
that specifically catalyzes double-bond transposition without
touching the (Z)-geometry of the allylated product [Figure
1(c)].
n INTRODUCTION
The allylation reaction of aldehydes with g-substituted al-
lylboron reagents [1-(boryl)alk-2-enes] offers a convenient
and reliable method to stereoselectively construct homoallylic
alcohols with contiguous chiral centers. Many useful methods
for the preparation of g-substituted allylboron reagents have
been developed.1,2 For example, Roush has reported that enan-
tioenriched (S)-(E)-g-substituted a-stannyl allylic boranes are
generated from allenylstannane and diisopinocamphenyl-
borane.3 The following allylation reaction with aldehydes
forms (E)-d-stannyl-substituted anti-homoallylic alcohols with
high enantioselectivity [Figure 1(a)].4 On the other hand, we
have investigated an in-situ generation of allylboron species
from 1-(boryl)alkenes by way of double-bond transposition,
which is catalyzed by transition-metal catalysts.5,6 The arising
allylboron species immediately add to the aldehydes, also in
the reaction mixture, through a six-membered chair-like
a) Roush (Ref. 3)
OH
SnnBu3
n RESULTS AND DISCUSSION
SnnBu3
R1CHO
+
R1
Me
B(dIpc)2
(S)-(E)
–78 °C
Grotjahn et al. reported that the cationic ruthenium(II) com-
plex, [CpRu(P–N)(MeCN)]PF6 (P–N: 2-PiPr2-4-tBu-1-Me-
imidazole) promotes double-bond transposition by way of a p-
allyl intermediate.10 We found that the ruthenium(II) complex
performed as specifically as we desired: A mixture of benzal-
dehyde (1a, 0.20 mmol) and 1,1-di(boryl)but-3-ene 2a (0.22
mmol)11 in 1,2-dichloroethane (DCE) was stirred at 20 °C in
the presence of [CpRu(P–N)(MeCN)]PF6 (2.0 mol %), (R)-
TRIP (5.0 mol %; TRIP = 3,3'-Bis(2,4,6-triisopropylphenyl)-
1,1'-binaphthyl-2,2'-diyl hydrogen phosphate),12 and 4 Å mo-
lecular sieves (4 Å M.S.) (eq 1). After 3 hours, aldehyde 1a
was completely consumed and the reaction mixture was sub-
jected to aqueous workup. The following chromatographic
purification on silica gel afforded anti-1,2-oxaborinan-3-ene
3aa in 94% isolated yield in 98% ee.13 No syn isomer was
Me
(E)-anti
b) Previous work (Ref. 5d): Upper
c) This work: Lower
cat.
cat.
OH
[Pd(I)]2, PA*
Bpin
R1
20 °C
Me
OH
Bpin
(E)-anti
R1CHO
+
cat.
cat.
[Ru(II)]+, PA*
Bpin
B
O
20 °C
R1
Me
(Z)-anti
Figure 1. Diastereo- and enantioselective synthesis of d-
substituted homoallylic alcohols. a) (E)-geometry on the stannyl
group. b) (E)-geometry on the boryl group. c) (Z)-geometry on the
boryl group. dIpc = d-isopinocampheyl. Bpin = pinacolatoboronate.
PA* = chiral phosphoric acid.
1
detected by H NMR (400 MHz), proving the anti/syn selec-
tivity is >95:5. It is likely that an acyclic homoallylic alcohol
having (Z)-geometry is initially formed and then cyclizes into
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 7
a six-membered ring structure during workup/purification.14
significant than that by the 1,3-allylic strain, inducing the Z
selectivity.
1
2
3
4
5
6
7
8
The corresponding (E)-isomer 4aa remaining in the acyclic
form was observed in ca. 2% (NMR yield). Thus, 1a and 2a
were coupled by C–C bond formation with installation of two
chiral centers and a double bond in a stereoselective fashion.15
A larger scale experiment using 849 mg (8.0 mmol) of 1a also
gave a comparable result [96% yield, 96% ee (1.44 g of 3aa)].
Interestingly, the double-bond geometry of the product re-
versed from Z to E when 1,1-di(boryl)-3-methylbut-3-ene 2b
was used in place of a-olefin 2a. The (E)-isomer of anti-
homoallylic alcohol 4ab was obtained in 67% yield in a race-
mic form from 2b (eq 2). The corresponding 1,2-oxaborinan-
3-ene was not detected. The alkene 2b structurally differs from
2a in that it possesses an additional methyl group at the 3-
position. Six-membered transition states TS A’ and TS B’
which are analogous to TS A and TS B are postulated. In this
second example, the 1,3-allylic strain between the additional
methyl group and the boryl group both located in pseudo-axial
positions in TS B’ governs the outcome of this reaction. This
destabilizing interaction would be significant enough to re-
verse the energetic balance between TS A’ and TS B’. Thus,
the contrast in the double-bong geometry observed with 2a
and 2b endorses the afore-mentioned stereochemical explana-
tion (Scheme 1).
PF6
Ru
N
P
i
Pr2
Me
MeCN
9
N
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
t
Bu
PhCHO
[Ru(II)]+ (2.0 mol %)
OH
B
(1)
Bpin
1a
OH
(R)-TRIP (5.0 mol %)
O
+
+
Ph
DCE, 4 Å M.S.
20 °C, 3 h
Ph
Me
(E)-4aa 2% (NMR)
Bpin
Me
Bpin
3aa 94%
2a
(1.1 equiv)
98% ee (1R,2R)
anti:syn >95:5
[Ru(II)]+ (10 mol %)
OH
We presume the following stepwise scenario brings about
this transformation: Initially, (E)-1,1-di(boryl)but-2-ene 5a is
generated from 1,1-di(boryl)but-3-ene 2a through double-bond
transposition. As soon as (E)-5a is generated, it undergoes (R)-
TRIP-catalyzed enantioselective addition to aldehyde 1a via
TS B, as mentioned in Scheme 1 (vide infra), to form the (Z)-
isomer of anti-homoallylic alcohol 4aa’, which cyclizes to 3aa
upon workup.
Me Bpin
(R)-TRIP (10 mol %)
Bpin
+
PhCHO
(2)
Ph
Bpin
2b (1.5 equiv)
DCE, 4 Å M.S.
40 °C, 72 h
1a
Me Me
4ab 67%, racemic
*
O
‡
‡
*
O
O
O
P
P
O
O
Me
Me
Me
Me
H
H
O
O
The six-membered chair-like transition-state structures TS
A and B depicted in Scheme 1 are assumed to account for the
selective formation of the (Z)-isomer of anti-homoallylic alco-
hol 4aa’, as with the palladium(I)-catalyzed case we have pre-
viously reported.5d One of the two boryl groups (represented as
B) takes an exocyclic position, either pseudo-equatorial one
leading to E isomer, or pseudo-axial one leading to Z isomer.
The boryl group located in a pseudo-equatorial position in TS
A suffers from gauche interactions with the pinacolato ligand
of the other boryl group, whereas the boryl group located in a
pseudo-axial position in TS B suffers from 1,3-allylic strain to
an adjacent hydrogen atom. The gauche interactions is more
Me
Me
H
O
Me
Me
O
H
B
B
Ph
Me
Ph
Me
O
O
O
O
H
B
gauche
int.
Me
B
Me
TS A’
Favored
H
A1,3 strain
TS B’
Disfavored
B = Bpin
Following this, the process of double-bond transposition
from 1,1-di(boryl)but-3-ene 2a to 1,1-di(boryl)but-2-ene 5a
was monitored by 1H NMR in the absence of an aldehyde, and
the ruthenium(II) and palladium(I) catalysts were compared
(Scheme 2). 1,1-Di(boryl)but-3-ene 2a was simply treated
with 2.0 mol % of the ruthenium(II) complex or 2.5 mol % of
the palladium(I) dimer at 20 °C. In the case of ruthenium(II),
double-bond transposition proceeded expeditiously and 91%
of 2a isomerized to 5a after 30 min. The E/Z ratio of the aris-
ing 5a had been constantly over 95:5 from the early stage of
Scheme 1. Proposed Pathway for the Formation of 3aa
from 1a and (E)-5a
‡
*
O
O
P
O
Me
Me
OB
H
Scheme 2. A Control Experiment in the Absence of Alde-
hydes
O
Disfavored
B
Me
Me
O
H
Ph
B
Me
(E)-4aa'
Ph
Me
O
O
B
[Ru(II)]+
gauche
int.
B
Me
B
cat.
(2.0 mol %)
H
H
1a
2a
+
+
(R)-TRIP
TS A
Me
B
B
DCE, 20 °C
+
(E)-5a
(Z)-5a
‡
*
O
O
(E)-5a
time
3 min
30 min
2a:(E)-5a:(Z)-5a E/Z of 5a
P
OB
B
>95:5
>95:5
66:34:0
9:91:0
O
Me
Me
O
H
Ph
B
Me
Me
H
O
Me
B
2a
Favored
Ph
Me
[Pd(µ-Br)(PtBu3)]2
B
O
O
(Z)-4aa'
H
B
Me
B
(2.5 mol %)
workup
& SiO2
2a
+
+
H
B
Me
B
B
A1,3 strain
DCE/toluene, 20 °C
(E)-5a
(Z)-5a
TS B
3aa
B = Bpin
time
2a:(E)-5a:(Z)-5a E/Z of 5a
87:13
85:13:2
30 min
B = Bpin
ACS Paragon Plus Environment

Page 3 of 7
Journal of the American Chemical Society
transposition. In the case of palladium(I), only 15% of 2a were observed in all cases. The anti-1,2-oxaborinan-3-enes
1
2
3
4
5
6
7
8
isomerized to 5a after 30 min and the E/Z ratio was 87:13.
Thus, the ruthenium(II) catalyst proved to be both more active
and stereoselective for the double-bond transposition of 2a.
3aa–3ea were obtained in yields ranging from 91% to 97%
each derived from an electronically and sterically diverse array
of aromatic aldehydes 1a–1e (entries 1–5). Heteroaromatic
aldehyde 1f and a,b-unsaturated aldehyde 1g could also be
applied to this reaction (entries 6 and 7). Not only aromatic
aldehydes but aliphatic ones such as 2-phenylacetaldehyde
(1h) and cyclohexanecarbaldehyde (1i) successfully partici-
pated in the reaction (entries 8 and 9). On the whole, the yields
of the allylated products in the Ru(II)-catalyzed reactions are
relatively higher than those by using Pd(I).
The (E)-5a was prepared by the afore-mentioned Ru(II)-
catalyzed reaction and isolated by florisil column chromatog-
raphy. The isolated (E)-5a was reacted with benzaldehyde (1a)
at 20 °C for 3 hours16 both in the absence and presence of (R)-
TRIP (5.0 mol %) (Scheme 3). In the absence of (R)-TRIP,
racemic 3aa was formed in 79% yield together with 10%
(NMR) of (E)-anti-homoallylic alcohol 4aa. In the presence of
(R)-TRIP, 3aa was formed in 92% yield, 96% ee, accompa-
nied by only an insignificant amount (1%) of 4aa. We pre-
sume that the energy difference between TS A and TS B is
reflected into a higher Z/E selectivity when accelerated by the
phosphoric acid.17
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
The allylation reaction of a-branched chiral aldehyde
(2R,3S)-1j3b,18 with 2a was carried out in the absence and
presence of TRIP (5.0 mol %) (eq 3). In the absence of TRIP,
syn,anti-3ja (highlighted in gray) was formed in 42% total
yield with 88:12 diastereoselectivity (3ja/3ja’) together with
24% (NMR) of (E)-syn,anti-homoallylic alcohol 4ja. In the
presence of (R)-TRIP, syn,anti-3ja was formed in 69% total
yield, and higher diastereoselectivity (3ja/3ja’ >95:5) and Z/E
selectivity (3ja/4ja) were observed. On the other hand, a lower
diastereoselectivity (3ja/3ja’ = 55:45) and Z/E selectivity
(3ja/4ja) were observed in the presence of (S)-TRIP. These
Scheme 3. The Allylation Reaction of Benzaldehyde (1a)
with (E)-5a in the Absence and Presence of (R)-TRIP
OH
OH
B
Bpin
Bpin
(E)-5a
(1.1 equiv)
O
Bpin
+
1a
+
Ph
Me
DCE, 4 Å M.S.
20 °C, 3 h
Ph
Me
OH
B
Me
3aa
79%
92%, 96% ee
(E)-4aa
OMe O
OMe
CHO
none
10% (NMR)
1% (NMR)
Ph
Ph
(R)-TRIP (5.0 mol %)
Me Me
Me
[Ru(II)]+ (2.0 mol %)
(2R,3S)-1j
syn,anti-3ja
+
This allylation reaction could be carried out using a wide
scope of aldehydes (Table 1). Enantioselectivities over 90% ee
(3)
+
OH
B
DCE, 4 Å M.S.
20 °C, 3 h
Bpin
OMe O
Table 1. Asymmetric Allylation Reactions of Various Al-
dehydes 1a–1i with 2aa
Bpin
Ph
2a
(1.1 equiv)
Me Me
anti,anti-3ja’
OH
[Ru(II)]+
OH
B
Bpin
Bpin
(R)-TRIP
O
none
(R)-TRIP
Bpin
3ja 42% total yield (3ja/3ja’ = 88:12), (E)-4ja 24% (NMR)
3ja 69% total yield (3ja/3ja’ >95:5), (E)-4ja 2% (NMR)
R1CHO
+
+
R1
DCE, 4 Å M.S.
20 °C, 3 h
R1
1
Me
2a (1.1 equiv)
(S)-TRIP 3ja 48% total yield (3ja/3ja’ = 55:45), (E)-4ja 13% NMR
4
Me
3
O
O
Me
H
cat. Ru(II)
cat. Pd(I)j
yield of ee of
entry R1 (1)
3
yield of
3 (%)b,c
ee of
3 (%)d
R
R
4 (%)
4 (%)
H
H
H
Me
97f
98
97
97
96
96
97
93
90
80
90
80
82
78
67
68
72
71
98
99
98
98
97
91
97
92
96
ent-3aae
Favored (Felkin-Anh)
Disfavored
1
2
3
4
5
6
7
8
9
Ph (1a)
91
‡
‡
H
H
H
4-ClC6H4 (1b)
3ba
95
R
B
H
B
B
Me
Me
O
3ja
O
3ja’
4-MeOC6H4 (1c) 3ca
97
Me
H
R
Me
B
B
H
4-MeC6H4 (1d)
2-MeC6H4 (1e)
2-furyl (1f)
3da
3ea
3fa
96
TS C
TS D
93
‡
H
R
93
H
O
(E)-4ja
Me
B
PhCH CH (1g) 3ga
PhCH2 (1h)
88
Me
H
3ha
69g,h
78g,i
TS E
(R)
Cy (1i)
3ia
‡
‡
*
O
*
(R)
O
P
O
O
P
aOn a 0.20 mmol scale. See eq 1 for reaction conditions. bIsolated
Me
O
O
H
Me
Me
Me
Me
Me
O
H
O
c
yield after chromatographic purification. Anti/syn ratio of 3 and
3ja
O
3ja’
Me
Me
H
O
product ratio (3/4) were determined to be >95:5 by 1H NMR in all
H
H
R
B
H
O
d
B
Me
Me
O
O
cases. As determined by chiral HPLC of phenylated products.
O
Me
H
R
f
g
e(S)-TRIP was used. (1S,2S). 10 mol % of (R)-TRIP was used.
Me
B
B
i
j
hNMR yield. 10 °C, 5 h. Data reported in Ref. 5d. Reaction con-
ditions: 1 (0.20–0.40 mmol), 2a (2.0 equiv), [Pd(µ-Br)(PtBu3)]2
(2.5 mol %), (R)-TRIP (5.0 mol %), DCE/toluene, 4 Å M.S.,
20 °C, 17 h.
H
TS C’
Matched with (R)-TRIP
TS D’
Mismatched with (R)-TRIP
B = Bpin
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 7
results suggest that, in the absence of phosphoric acid, the Under these conditions, a carbon–carbon double bond could
1
2
3
4
5
6
7
8
reaction proceeds via TS C and TS E which accord with the
Felkin-Anh model. (R)-TRIP has the matched stereochemical
orientation to assist in TS C’ by the chelation through the pi-
nacolato oxygen and aldehyde proton.
also transpose itself from a more remote position to an allylic
position relative to boron (Scheme 4).10a,19 1,1-Di(boryl)pent-
4-ene 6 and 1,1-di(boryl)hex-5-ene 7 both successfully acted
as the allylboron precursor. In these examples, anti-1,2-
oxaborinan-3-enes 3ac and 3ad were formed in 76% and 88%
yields respectively both with high enantioselectivities. In the
extreme case of 1,1-di(boryl)dodec-11-ene 8, the double-bond
transposition took place nine times to give the corresponding
product 3ai in 72% yield and 54% ee along with a small
amount of (E)-isomer 4ai (7% NMR yield).
A variety of 1,1-di(boryl)alk-3-enes 2c–2g having Me, Et,
iPr, CF3, and Ph groups as the R2 substituent11 were subjected
to the allylation reaction with benzaldehyde (1a) (Table 2).
More forcing conditions were applied in those cases ([Ru]+
(5.0 mol %), (R)-TRIP (10 mol %), 40 °C, 72 hours) because
double-bond transposition was slower. Yet, the yields of 3ac–
3af were good and the enantioselectivities were over >90% ee
(entries 1–4)). The phenyl-substituted derivative 2g failed to
undergo the double-bond transposition even at 80 °C (entry 5).
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
Scheme 4. The Utilization of 1,1-Di(boryl)alk-n-enes 5–7 (n
= 4, 5, 11) as the Allylboron Precursors
[Ru(II)]+ (5.0 mol %)
OH
Table 2. Asymmetric Allylation Reactions of Benzaldehyde
(1a) with Various 1,1-Di(boryl)alk-3-enes 2b–2ea
B
(R)-TRIP (10 mol %)
Bpin
Bpin
O
+
1a
DCE, 4 Å M.S.
40 °C, 24 h
Ph
OH
[Ru(II)]+ (5.0 mol %)
B
6 (1.5 equiv)
Et
Bpin
O
(R)-TRIP (10 mol %)
3ac
76%, 95% ee
R2
+
+
4
PhCHO
Bpin
2 (1.5 equiv)
DCE, 4 Å M.S.
40 °C, 72 h
Ph
1a
R2
[Ru(II)]+ (5.0 mol %)
OH
3
B
(R)-TRIP (10 mol %)
Bpin
cat. Pd(I)g
O
cat. Ru(II)
+
1a
R2 (2)
3
yield of ee of
3 (%)b,c 3 (%)d
yield of ee of
Bpin
7 (1.5 equiv)
entry
DCE, 4 Å M.S.
40 °C, 24 h
Ph
4 (%)
4 (%)
nPr
3ad
88%, 93% ee
1
2
3
4
5
Me (2c)e
Et (2d)
90
93
82
76
0f
95
93
90
91
–
85
67
85
77
82
96
97
95
96
92
3ac
3ad
3ae
3af
1a
[Ru(II)]+ (15 mol %)
OH
B
iPr (2e)
CF3 (2f)
Ph (2g)
+
(R)-TRIP (5.0 mol %)
Bpin
Bpin
O
DCE, 4 Å M.S.
40 °C, 72 h
Ph
8 (1.5 equiv)
3ag
C9H19
3ai
72%, 54% ee
aOn a 0.20 mmol scale. bIsolated yield after chromatographic
c
purification. Anti/syn ratio of 3 and product ratio (3/4) were de-
1
d
The synthetic utility of the boryl-substituted product 3aa
was exemplified by further transformations. The Suzuki-
Miyaura cross-coupling reaction with iodides (iodobenzene
and ethyl (Z)-3-iodoacrylate) was executed using PdCl2(PPh3)2
as the catalyst. Importantly, the coupled alkenes 9 and 10 were
formed with retention of the double-bond geometry (Z/E
>95:5) (eq 5).
termined to be >95:5 by H NMR in all cases. As determined by
e
f
g
chiral HPLC of phenylated products. E/Z = 79:21. 80 °C. Data
reported in Ref. 5d except for entry 2 (R2 = Et). Reaction condi-
tions: 1 (0.20 mmol), 2a (2.0 equiv), [Pd(µ-Br)(PtBu3)]2 (2.5
mol %), (R)-TRIP (5.0 mol %), DCE/toluene, 4 Å M.S., 20–30 °C,
17–41 h.
4-Boryl-substituted 1,1-di(boryl)but-3-ene 2h was newly
prepared by an SN2 reaction of bis(pinacolatoboryl)methane
with (E)-1-boryl-3-bromoprop-1-ene under basic conditions. It
was subjected to the allylation reaction with benzaldehyde
(1a). The allylboronate intermediate F having two reactive
sites (a) and (b) was expected to be generated in situ from 2h.
The anti-1,2-oxaborinan-3-ene 3ah was selectively obtained in
83% yield and 86% ee (eq 4). Thus, the intermediate F is more
reactive at (a) than at (b).
OH
PhI (1.0 equiv)
Ph
OH
B
PdCl2(PPh3)2
(5.0 mol %)
Me Ph
9 86%
O
(5)
I
CO2Et
CsF (2.0 eqiv)
CH2Cl2
OH
Ph
(1.0 equiv)
Me
3aa
Ph
40 °C, 8 h
Me
10 81%
CO2Et
OH
[Ru(II)]+ (5.0 mol %)
B
Treatment with CuBr2 resulted in the formation of the bro-
mide 11 again without a loss of geometrical purity (Z/E >95:5)
(eq 6).20 An intramolecular Chan-Lam coupling reaction of
3aa afforded the 2,3-dihydrofuran 12 (eq 7).21
Bpin
O
(R)-TRIP (10 mol %)
+
(4)
PhCHO
pinB
Bpin
2h (1.5 equiv)
DCE, 4 Å M.S.
40 °C, 72 h
Ph
1a
Bpin
3ah
83%, 86% ee
OH
site
(a)
CuBr2 (5.0 equiv)
Ph
(6)
3aa
Bpin
Me Br
11 89%
EtOH/H2O, 80 °C, 21 h
pinB
Bpin
site
F
(b)
ACS Paragon Plus Environment

Page 5 of 7
Journal of the American Chemical Society
chlorochromate (eq 11).23
[Cu]
O
Cu(OAc)2 (3.0 equiv)
Et3N, CH2Cl2, rt, 22 h
1
2
3
4
5
6
7
8
9
Ph
O
3aa
n CONCLUSION
(7)
Ph
Me
In summary, we have developed a new relay system consisting
Me
12 67%
of the cationic ruthenium(II) and phosphoric acid catalysts for
the diastereo- and enantioselective synthesis of anti-1,2-
oxaborinan-3-enes starting from aldehydes and 1,1-
di(boryl)alk-3-enes. This new system complements the previ-
ously reported system using palladium(I)5d to make both stere-
ochemical options available for the double-bond geometry of
the allylated products.
Hydrogenation of the double bond moiety contained within
3aa was carried out (H2, Pd/C), yielding 1,2-oxaborinan-2-ol
13 (eq 8). A boron-tethered intramolecular Diels-Alder reac-
tion using (E)-3,5-hexadiene-1-ol22 proceeded well to give
tricycle 14 with high diastereoselectivity (>95:5) (eq 9).
OH
B
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
H2 (1.0 atm), Pd/C (10 mol %)
O
n ASSOCIATED CONTENT
(8)
3aa
Ph
Supporting Information
MeOH, rt, 30 min
Me
The Supporting Information is available free of charge on the
ACS Publications website.
13 79%
i)
HO
Experimental procedures, characterization of the new com-
pounds, and spectroscopic data (PDF)
O
B
O
B
ii)
n AUTHOR INFORMATION
H
H
H
(2.0 equiv)
BHT
O
O
3aa
(9)
Corresponding Author
THF, 4 Å M.S.
rt, 13 h
toluene
190 °C
18.5 h
Ph
Ph
*tmiura@sbchem.kyoto-u.ac.jp
*murakami@sbchem.kyoto-u.ac.jp
ORCID
Tomoya Miura: 0000-0003-2493-0184
Notes
The authors declare no competing financial interest.
† S.G.S. is on leave from School of Chemistry and Biochemistry,
The University of Western Australia.
Me
Me
14 71%
The product 3ah containing two boryl groups was subjected
to the palladium-catalyzed cross-coupling reaction with iodo-
benzene. Coupling occurred selectively at the boryl group on
the sp2 carbon with retention of the double-bond geometry
with the B–C(sp3) bond intact. The crude coupling product
was next treated with sodium peroxoborate to oxidize the re-
maining B–C(sp3) bond. 1,3-Diol 15 was isolated in 54% yield
(eq 10). Thus, it was easy to differentiate the two B–C bonds
in further synthetic transformations.
n ACKOWLEDGEMET
This work was supported by Grants-in-Aid for Scientific Research
(S) (15H05756) and (C) (16K05694) from MEXT and the ACT-C
Program (JPMJCR12Z9) from the JST. W.Z. acknowledges a
JSPS postdoctoral fellowship for foreign researchers. S.G.S.
acknowledges an invitation fellowship for research from The
Kyoto University Foundation.
i) PhI (1.3 equiv)
OH
PdCl2(dppf) CH2Cl2
R
B
B
O
(5.0 mol %)
O
Ph
Ph
K3PO4 (1.3 eqiv)
THF/H2O
Ph
R = OCMe2CMe2OH or OH
OH
n REFERENCES
Bpin
70 °C, 2 h
3ah
(1) (a) Hall, D. G. Boronic Acids, Wiley-VCH, Weinheim, 2011.
(b) Hall, D. G.; Lachance, H. Allylboration of Carbonyl Compounds,
Wiley, Hoboken, New Jersey, 2012. (c) Yus, M.; González-Gómez, J.
C.; Foubelo, F. Chem. Rev. 2013, 113, 5595. (d) Diner, C.; Szabó, K.
J. J. Am. Chem. Soc. 2017, 139, 2. See also: (e) Feng, J.; Kasun, Z.
A.; Krische, M. J. J. Am. Chem. Soc. 2016, 138, 5467.
O
H
ii) NaBO3 4H2O
(10)
Ph
THF/H2O
rt, 1 h
Ph
15 54%
(2) For the synthesis and reactions of enantioenriched g,a-
disubstituted allylboron reagents, see: (a) Fang, G. Y.; Aggarwal, V.
K. Angew. Chem. Int. Ed. 2007, 46, 359. (b) Althaus, M.; Mahmood,
A.; Suárez, J. R.; Thomas, S. P.; Aggarwal, V. K. J. Am. Chem. Soc.
2010, 132, 4025. (c) Chen, J. L.-Y.; Scott, H. K.; Hesse, M. J.; Willis,
C. L.; Aggarwal, V. K. J. Am. Chem. Soc. 2013, 135, 5316. (d) Luo,
Y.; Roy, I. D.; Madec, A. G. E.; Lam, H. W. Angew. Chem. Int. Ed.
2014, 53, 4186. (e) Chen, J. L.-Y.; Aggarwal, V. K. Angew. Chem. Int.
Ed. 2014, 53, 10992. (f) Yamamoto, E.; Takenouchi, Y.; Ozaki, T.;
Miya, T.; Ito, H. J. Am. Chem. Soc. 2014, 136, 16515. (g) Potter, B.;
Szymaniak, A. A.; Edelstein, E. K.; Morken, J. P. J. Am. Chem. Soc.
2014, 136, 17918. (h) Zhou, Q.; Srinivas, H. D.; Zhang, S.; Watson,
M. P. J. Am. Chem. Soc. 2016, 138, 11989. (i) Edelstein, E. K.;
Namirembe, S.; Morken, J. P. J. Am. Chem. Soc. 2017, 139, 5027. For
the synthesis and reactions of enantioenriched a-substituted al-
lylboron reagents, see: (j) Carosi, L.; Hall, D. G. Angew. Chem. Int.
Ed. 2007, 46, 5913. (k) Ito, H.; Ito, S.; Sasaki, Y.; Matsuura, K.;
Sawamura, M. J. Am. Chem. Soc. 2007, 129, 14856. (l) Fernández, E.;
Pietruszka, J.; Frey, W. J. Org. Chem. 2010, 75, 5580. (m) Hesse, M.
J.; Essafi, S.; Watson, C. G.; Harvey, J. N.; Hirst, D.; Willis, C. L.
Aggarwal, V. K. Angew. Chem. Int. Ed. 2014, 53, 6145. (n) Brauns,
(+)-trans-Whisky lactone 16 was stereoselectively synthe-
sized through three steps of the allylation reaction of pentanal
(1k) with 2a, B–C bond oxidation to a hemiacetal with sodium
peroxoborate, and oxidation to the lactone with pyridinium
nBuCHO
OH
i) [Ru(II)]+
OH
1k
B
(S)-TRIP
ii) NaBO3 4H2O
O
O
+
DCE
THF/H2O
rt, 3 h
nBu
Bpin
4 Å M.S.
nBu
Me
Me
Bpin
2a
(1.1 equiv)
O
iii) PCC, NaOAc
CH2Cl2, rt, 17 h
O
(11)
nBu
Me
16 63%, 95% ee
trans:cis >95:5
(+)-trans-whisky lactone
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
M.; Muller, F.; Gülden, D.; Böse, D.; Frey, W.; Breugst, M.; Pie-
Grotjahn, D. B. Org. Lett. 2014, 16, 2818. See also: (d) Higman, C.
1
2
3
4
5
6
7
8
truszka, J. Angew. Chem. Int. Ed. 2016, 55, 1548. (o) Allais, C.;
Roush, W. R. Org. Lett. 2017, 19, 2646.
(3) (a) Chen, M.; Roush, W. R. J. Am. Chem. Soc. 2011, 133, 5744.
(b) Chen, M.; Roush, W. R. J. Am. Chem. Soc. 2012, 134, 3925. See
also: (c) Chen, M.; Ess, D. H.; Roush, W. R. J. Am. Chem. Soc. 2010,
132, 7881.
(4) For asymmetric allylation using chiral allylboron reagents func-
tionalized with another semi-metal element, see: [B] (a) Chen, M.;
Handa, M.; Roush, W. R. J. Am. Chem. Soc. 2009, 131, 14602. (b)
Ferris, G. E.; Hong, K.; Roundtree, I. A.; Morken, J. P. J. Am. Chem.
Soc. 2013, 135, 2501. (c) Zhao, T. S. N.; Zhao, J.; Szabó, K. J. Org.
Lett. 2015, 17, 2290. [Si] (d) Peng, F.; Hall, D. G. J. Am. Chem. Soc.
2007, 129, 3070. (e) Chen, M.; Roush, W. R. Org. Lett. 2013, 15,
1662.
(5) (a) Shimizu, H.; Igarashi, T.; Miura, T.; Murakami, M. Angew.
Chem. Int. Ed. 2011, 50, 11465. (b) Miura, T.; Nishida, Y.; Morimoto,
M.; Murakami, M. J. Am. Chem. Soc. 2013, 135, 11497. (c) Miura,
T.; Nishida, Y.; Murakami, M. J. Am. Chem. Soc. 2014, 136, 6223.
(d) Miura, T.; Nakahashi, J.; Murakami, M. Angew. Chem. Int. Ed.
2017, 56, 6989.
(6) For related reactions using olefinic organoboron compounds,
see: (a) Moriya, T.; Suzuki, A.; Miyaura, N. Tetrahedron Lett. 1995,
36, 1887. (b) Ohmura, T.; Oshima, K.; Suginome, M. Angew. Chem.
Int. Ed. 2011, 50, 12501. (c) Lin, L.; Yamamoto, K.; Matsunaga, S.;
Kanai, M. Angew. Chem. Int. Ed. 2012, 51, 10275. (d) Hemelaere, R.;
Carreaux, F.; Carboni, B. Chem. Eur. J. 2014, 20, 14518. (e) Weber,
F.; Ballmann, M.; Kohlmeyer, C.; Hilt, G. Org. Lett. 2016, 18, 548.
(f) Trost, B. M.; Cregg, J. J.; Quach, N. J. Am. Chem. Soc. 2017, 139,
5133.
(7) (a) Jain, P.; Antilla, J. C. J. Am. Chem. Soc. 2010, 132, 11884.
(b) Grayson, M. N.; Pellegrinet, S. C.; Goodman, J. M. J. Am. Chem.
Soc. 2012, 134, 2716. (c) Fustero, S.; Rodríguez, E.; Lázaro, R.; Her-
rera, L.; Catalán, S.; Barrio, P. Adv. Synth. Catal. 2013, 355, 1058. (d)
Barrio, P.; Rodriguez, E.; Saito, K.; Fustero, S.; Akiyama, T. Chem.
Commun. 2015, 51, 5246. (e) Koukal, P.; Ulč, J.; Nečas, D.; Kotora,
M. Eur. J. Org. Chem. 2016, 2110. (f) Grayson, M. N.; Yang, Z.;
Houk, K. N. J. Am. Chem. Soc. 2017, 139, 7717.
(8) Gauthier, D.; Lindhardt, A. T.; Olsen, E. P. K.; Overgaard, J.;
Skrydstrup, T. J. Am. Chem. Soc. 2010, 132, 7998 and references
therein.
(9) Cross-metathesis of vinylboronate with terminal alkenes offers
an attractive strategy for the synthesis of (Z)-alkenylboronates. See:
(a) Kiesewetter, E. T.; O’Brien, R. V.; Yu, E. C.; Meek, S. J.; Schrock,
R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2013, 135, 6026. (b)
Quigley, B. L.; Grubbs, R. H. Chem. Sci. 2014, 5, 501.
S.; de Araujo, M. P.; Fogg, D. E. Catal. Sci. Technol. 2016, 6, 2077.
(e) Jana, A.; Misztal, K.; Zak, A.; Grela, K. J. Org. Chem. 2017, 82,
4226.
(11) 1,1-Di(boryl)alk-3-enes were easily prepared by an SN2 reac-
tion of commercially available bis(pinacolatoboryl)methane with
allylic halides under basic conditions (LDA). See: Zhang, Z.-Q.; Yang,
C.-T.; Liang, L.-J.; Xiao, B.; Lu, X.; Liu, J.-H.; Sun, Y.-Y.; Marder, T.
B.; Fu, Y. Org. Lett. 2014, 16, 6342.
(12) For TRIP as the chiral phosphoric acid catalyst, see: (a) Aki-
yama, T. WO 2004096753, 2004; Chem. Abstr. 2004, 141, 411087.
(b) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem. Int. Ed. 2005,
44, 7424. For seminal work on chiral phosphoric acids, see: (c) Aki-
yama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed.
2004, 43, 1566. (d) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004,
126, 5356.
(13) The absolute configuration of 3aa was assigned as (1R,2R)
based on the optical rotation data of the phenylated product 9.2a
(14) For synthesis of 1,2-oxaborinan-2-ol derivatives, see: (a) Mi-
calizio, G. C.; Schreiber, S. L. Angew. Chem., Int. Ed. 2002, 41, 3272.
(b) Hansen, E. C.; Lee, D. J. Am. Chem. Soc. 2006, 128, 8142. (c)
McNulty, L.; Kohlbacher, K.; Borin, K.; Dodd, B.; Bishop, J.; Fuller,
L.; Wright, Z. J. Org. Chem. 2010, 75, 6001.
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
(15) For recent reviews on sequential processes involving double-
bond transposition, see: (a) Larionov, E.; Li, H.; Mazet, C. Chem.
Commun. 2014, 50, 9816. (b) Vasseur, A.; Bruffaerts, J.; Marek, I.
Nature Chem. 2016, 8, 209.
(16) The progress of the reaction was monitored after 10 min by 1H
NMR. Whereas 38% of 1a was converted in the absence of (R)-TRIP,
1a was already fully converted in the presence of (R)-TRIP (5 mol %),
demonstrating acceleration of the allylboration by TRIP.
(17) (a) Carosi, L.; Lachance, H.; Hall, D. G. Tetrahedron Lett.
2005, 46, 8981. (b) Incerti-Pradillos, C. A.; Kabeshov, M. A.; Malkov,
A. V. Angew. Chem. Int. Ed. 2013, 52, 5338.
(18) Chen, M.; Roush, W. R. Org. Lett. 2012, 14, 1880.
(19) For a recent example of functional group transposition from a
remote position for C–C bond formation, see: Juliá-Hernández, F.;
Moragas, T.; Cornella, J.; Martin, R. Nature 2017, 545, 84.
(20) Murphy, J. M.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc.
2007, 129, 15434.
(21) Körner, C.; Starkov, P.; Sheppard, T. D. J. Am. Chem. Soc.
2010, 132, 5968.
(22) Batey, R. A.; Thadani, A. N.; Lough, A. J. J. Am. Chem. Soc.
1999, 121, 450.
(23) For similar transformation via hemiacetals, see: Liang, T.;
Zhang, W.; Chen, T.-Y.; Nguyen, K. D.; Krische, M. J. J. Am. Chem.
Soc. 2015, 137, 13066.
(10) (a) Grotjahn, D. B.; Larsen, C. R.; Gustafson, J. L.; Nair, R.;
Sharma, A. J. Am. Chem. Soc. 2007, 129, 9592. (b) Erdogan, G.;
Grotjahn, D. B. J. Am. Chem. Soc. 2009, 131, 10354. (c) Erdogan, G.;
ACS Paragon Plus Environment

Page 7 of 7
Journal of the American Chemical Society
1
2
3
TOC Graphic:
4
OH
cat. [Ru(II)]+
5
6
7
B
O
Bpin
Bpin
cat. (R)-TRIP
O
+
R2
R1
H
R1
8
9
R2
up to 98% ee
(Z)-anti
1
2
transposition allylboration
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
ACS Paragon Plus Environment