Rh-catalyzed aldehyde - Aldehyde cross-aldol reaction under base-free conditions: In situ aldehyde-derived enolate formation through orthogonal activation

Article abstract of DOI:10.1002/asia.201300928

The chemoselective generation of aldehyde-derived enolates to realize an aldehyde - aldehyde cross-aldol reaction is described. A combined Rh/dippf system efficiently promoted the isomerization/aldol sequence by using primary allylic, homoallylic, and bishomoallylic alcohols; secondary allylic and homoallylic alcohols; and trialkoxyboranes that were derived from primary allylic and homoallylic alcohols. The reaction proceeded at ambient temperature under base-free conditions, thus giving cross-aldol products with high chemoselectivity. Mechanistic studies, as well as its application to double-aldol processes under protecting-group-free conditions, are also described. Copyright

Full text of DOI:10.1002/asia.201300928

FULL PAPER
DOI: 10.1002/asia.201300928
À
Rh-Catalyzed Aldehyde Aldehyde Cross-Aldol Reaction under Base-Free
Conditions: In Situ Aldehyde-Derived Enolate Formation through
Orthogonal Activation
Luqing Lin,[a, b] Kumiko Yamamoto,[a] Shigeki Matsunaga,*[a, c] and Motomu Kanai*[a, b]
Chem. Asian J. 2013, 8, 2974 – 2983
2974
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Shigeki Matsunaga, Motomu Kanai et al.
Abstract: The chemoselective genera-
tion of aldehyde-derived enolates to re-
and homoallylic alcohols; and trialkox-
yboranes that were derived from pri-
mary allylic and homoallylic alcohols.
The reaction proceeded at ambient
temperature under base-free condi-
tions, thus giving cross-aldol products
with high chemoselectivity. Mechanistic
studies, as well as its application to
double-aldol processes under protect-
ing-group-free conditions, are also de-
scribed.
À
alize an aldehyde aldehyde cross-aldol
reaction is described. A combined Rh/
dippf system efficiently promoted the
isomerization/aldol sequence by using
primary allylic, homoallylic, and bisho-
moallylic alcohols; secondary allylic
Keywords: aldol reaction · boron ·
homogeneous catalysis · rhodium ·
synthetic methods
Introduction
À
Aldol reactions are fundamental and important carbon
carbon bond-forming reactions.[1] A cross-aldol reaction be-
tween two different aldehydes provides straightforward
redox-[2] and step-economical[3] access to 1,3-polyol frame-
works.[4,5] The classical aldol-condensation reaction, which is
usually performed under acid or base catalysis, is an early
example of a highly atom-economical reaction.[6] However,
À
the classical conditions are not useful for aldehyde alde-
hyde cross-aldol reactions, owing to chemoselectivity prob-
lems. In the cross-aldol reaction between two different alde-
hydes, the chemoselective activation of one aldehyde as
a donor and the other as an acceptor is difficult and often
affords complex mixtures of homoaldols and heteroaldols
(Scheme 1a). Therefore, most modern aldol methods utilize
ketones, thioesters, esters, and other carboxylic-acid deriva-
tives as donors to circumvent the inherent problem of che-
À
moselectivity in aldehyde aldehyde cross-aldol reactions.
Scheme 1. Cross-aldol reactions between two different aldehydes: a) con-
ventional method, starting from two aldehydes; b) Maruoka’s functional-
group-differentiation strategy to realize chemoselective cross-aldol reac-
tions; and c) this work, which proceeds through the chemoselective gen-
eration of aldehyde enolates from primary allylic alcohols and related
compounds.
These processes and, in particular, their catalytic enantiose-
lective variants that have been developed during the last
two decades,[7] are synthetically useful and reliable. Howev-
er, there remains much room for improvement in the appli-
cation of these processes to the synthesis of 1,3-polyols in
terms of the redox- and step-economy, because additional
multistep transformations of aldol products, including pro-
tection and redox processes, are inevitably needed to gener-
ate b-hydroxy-protected aldehydes for the second aldol pro-
cess.
Since the early reports by MacMillan and co-workers, sev-
eral “state-of-the-art” organocatalytic enantioselective
À
direct aldehyde aldehyde cross-aldol reactions have been
developed.[8] Enamine catalysis is simply based on the inher-
ent steric and/or electronic bias between the two different
aldehydes. Cross-aldol reactions that override such a bias,
such as those that use propanal as an acceptor and other
sterically more-hindered aldehydes as donors, are extremely
difficult to achieve. To realize high chemoselectivity in orga-
nocatalytic cross-aldol reactions between two different ali-
phatic aldehydes, Maruoka and co-workers recently report-
ed an elegant solution based on the concept of functional-
group differentiation.[9] As shown in Scheme 1b, a-chloroal-
dehydes that contained a sterically hindered electron-with-
drawing group selectively acted as acceptors and the a-
chloro group in the aldol product was removed by treatment
with LiAlH4.
[a] L. Lin, K. Yamamoto, Dr. S. Matsunaga, Prof. Dr. M. Kanai
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax : (+81)3-5684-5206
E-mail: smatsuna@mol.f.u-tokyo.ac.jp
kanai@mol.f.u-tokyo.ac.jp
[b] L. Lin, Prof. Dr. M. Kanai
Kanai Life Science Catalysis Project, ERATO
Japan Science and Technology Agency
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
[c] Dr. S. Matsunaga
Therefore, a method for the generation of an aldehyde-
derived enolate from a non-carbonyl precursor through an
orthogonal activation mode[10] should provide an alternative
ACT-C
Japan Science and Technology Agency
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
À
and complementary approach to chemoselective aldehyde
aldehyde cross-aldol products. Herein, we report a Rh-cata-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300928.
Chem. Asian J. 2013, 8, 2974 – 2983
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Shigeki Matsunaga, Motomu Kanai et al.
lyzed one-pot isomerization/cross-aldol sequence by using
primary allylic, homoallylic, and bishomoallylic alcohols
with their related allyloxy- and homoallyloxyboranes as
donor precursors (Scheme 1c).[11] The isomerization and
cross-aldol reaction proceeds at ambient temperature under
neutral, base-free conditions.
peratures, even under neutral conditions. Thus, it is essential
to perform the isomerization and successive aldol processes
under base-free neutral conditions, preferably at ambient
(or lower) temperature.
Based on these above-mentioned points, we investigated
the model reaction between aliphatic aldehyde 1a and allyl
alcohol 2a at ambient temperature without the addition of
a bases or Lewis acid; optimization studies are summarized
in Table 1. Although Rh complexes are well-known to iso-
Results and Discussion
As a donor precursor, we planned to use primary allylic al-
cohols, which could, in principle, be readily isomerized
under transition-metal catalysis to generate aldehyde-de-
rived enolates or enols. Despite several reports on the use
of secondary allylic alcohols as ketone-derived enolate pre-
cursors in aldol processes under transition-metal cataly-
sis,[12,13] the use of primary allylic alcohols in the isomeriza-
tion/aldol sequence has not been reported.[14–16] We expected
difficulties with known transition-metal catalysts for isomeri-
zation/aldol processes with primary allylic alcohols, owing to
the following factors: Most catalysts that are used for the
isomerization of secondary allylic alcohols into either enols
or enolates require high reaction temperatures and/or
a strong base or Lewis acid additive to efficiently promote
the isomerization/aldol sequence. Because unprotected b-hy-
droxy aldehydes are notoriously unstable, they may cause
various side reactions in the presence of a base or Lewis
acid additive, such as dimerization, hemiacetal formation,
dehydration, and retroaldol reactions (Scheme 2).[17] Unpro-
tected b-hydroxy aldehydes are often unstable at high tem-
Table 1. Optimization studies of the isomerization/cross-aldol sequence
with primary allyl alcohol 2a.
Entry
Metal source
(mol%)
Ligand
(mol%)
d.r.[a] (syn/ Yield
anti)
[%][a]
1
2
3
[{Rh
[{Rh
[{Rh
U
dppe (10)
dppp (10)
ND
ND
ND
0
0
0
ACHTUNGTRENNUNG
4
5
6
7
8
9
10
[{Rh
[{Rh
U
dppf (10)
dippf (10)
dippf (10)
dippf (10)
dippf (10)
dippf (10)
dippf (10)
ND
75:25
75:25
75:25
ND
trace
75
65
15
0
[{Rh
[Rh(PPh3)3Cl] (10)
[Rh(cod)2]BF4 (10)
[Rh(acac)(cod)] (10)
(p-cymene)Cl2}2]
(5)
(PPh3)3Cl2] (10)
(cod)Cl}2] (1.25)
(C2H4)2Cl}2] (5)
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
C
E
ND
ND
0
0
[{Ru
A
11
12
[Ru
A
dippf (10)
dippf (2.5)
ND
75:25
0
72
[{Rh
A
[a] Determined by 1H NMR spectroscopy of the crude mixture. [b] Yield
of the isolated product after conversion into the corresponding dimethyl
acetal with PPTS/MeOH and purification by column chromatography on
silica gel. acac=acetylacetonate, ND=not determined.
merize primary allylic alcohols into enols and aldehydes,[18]
initial screening revealed that the isomerization/aldol se-
quence at room temperature under neutral conditions with-
out any base or acid was not a trivial task. The desired aldol
product (3a) was not obtained with common ligands, such
as dppe, dppp, and (rac)-BINAP (Table 1, entries 1–3). Be-
cause trace amounts of product 3a were detected with dppf
(Table 1, entry 4), we further modified this ferrocene-based
ligand and dippf was found to be effective for this reaction.
Scheme 2. Properties of unstable, unprotected b-hydroxyaldehyde.
Abstract in Japanese:
Indeed, a [{RhACHTUNRGTNEUNG(cod)Cl}2]/dippf mixed system promoted the
desired isomerization/aldol sequence to give compound 3a
in 75% yield (as determined by 1H NMR spectroscopy;
Table 1, entry 5). Other Rh sources, including cationic cata-
lyst [RhACHTNUGTRNEUNG(cod)2]BF4, and various Ru sources were screened
with the dippf ligand, but none of them gave superior yields
(Table 1, entries 6–11). The loading of the optimized cata-
lyst, [{RhACHTUNTGRNENG(U cod)Cl}2]/dippf (1:2), was successfully decreased
to 2.5 mol% (based on Rh), whilst maintaining the yield
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Shigeki Matsunaga, Motomu Kanai et al.
Table 3. Rh-catalyzed isomerization/cross-aldol sequence with secondary
allylic and homoallylic alcohols 4a–4e.[a]
Scheme 3. Control experiment with propanal 1b instead of allyl alcohol
2a.
and diastereoselectivity (Table 1, entry 12). A control ex-
periment by using propanal (1b) instead of allyl alcohol 2a
resulted in no reaction (Scheme 3); neither homoaldols nor
heteroaldols were observed under the Rh/dippf catalysis.
Thus, the Rh/dippf catalyst did not activate the aldehyde as
a donor, but chemoselectively generated the aldehyde-de-
rived enol (or enolate) from compound 2a and promoted
the desired cross-aldol process.
Entry
R
1
R’
R’’
4
t
5
d.r.[b]
(syn/anti) [%][c]
Yield
[h]
1
2
3
4
Ph
n-pentyl
Ph
1c
1d
1c
1c
H
H
H
H
Me
Me
Et
n-
pentyl
Me
4a 10 5a
4a 11 5b
4b 14 5c
4c 15 5d
86:14
83:17
86:14
88:12
90
96
91
95
Ph
5
Ph
1c (E)-
4d 13 5e
81:19
87
Me
The scope of the Rh/dippf catalysis in terms of the donors
was investigated and is summarized in Table 2 and Table 3.
Because the unprotected b-hydroxy aldehydes were unstable
and partially decomposed during purification by column
chromatography on silica gel, the yields of the products in
Table 2 were determined after their transformation into
stable compounds, either the corresponding dimethyl acetal
6
7
8
Ph
1c
H
H
H
Me
Me
Me
4e 72 5e
4e 72 5 f
4a 10 5a
82:18
78:22
86:14
97
70
90
PhCH2CH2 1a
Ph 1c
[a] Reaction conditions: compound 1 (0.4 mmol), compound 4 (2.0 mol e-
quiv), in 1,4-dioxane (0.2m) under an Ar atmosphere at ambient temper-
ature. [b] Determined by 1H NMR spectroscopy of the crude mixture.
[c] Yield of the isolated product in its b-hydroxy-ketone form after purifi-
cation by column chromatography on silica gel.
obtained in 44% yield after 144 h (Table 2, entry 7).
Table 2. Rh-catalyzed isomerization/cross-aldol sequence with primary allylic alcohols
Alcohol 2g (n=4), with a C=C double bond at
more-remote position, was also investigated
À
2a–2d and other primary alcohols 2e–2g, which contained a remote C C double
bond.[a]
a
(Table 2, entry 8), but the isomerization of a C=C
double bond was not observed at room tempera-
ture. The results in Table 2, entries 6–8 implied that
a consecutive 1,3-hydride shift under the Rh/dippf
catalysis was possible at room temperature, but ap-
propriate directing of the Rh catalyst through coor-
dination with the oxygen atom of the alcohol would
be required. To compare the reactivity and diaste-
reoselectivity of this Rh catalyst with previously re-
ported systems, secondary alcohols were also briefly
investigated as donor precursors. As summarized in
Table 3, allylic secondary alcohols 4a–4d gave their
corresponding b-hydroxy ketones in 87–96% yield
and 88:12–81:19 d.r. at room temperature (Table 3,
entries 1–5). Homoallylic secondary alcohol 4e was
also tolerated, but its reactivity was only moderate.
A long reaction time (72 h) was required to obtain
products 5e and 5 f in 97% and 70% yield, respec-
tively (Table 3, entries 6–7).
Entry
R
1
R’
n
2
t [h]
24 3a
3b
22 3c
25 3d
22 3e
24 3d
3
d.r.[b] (syn/anti) Yield [%][c]
1
2
3
4
5
6
7
8
PhCH2CH2 1a
H
H
Me
1
1
1
1
1
2
3
4
2a
2a
2b
2c
2d
2e
75:25
86:14
83:17
82:18
83:17
83:17
74:26
ND
72
73
90
73
68
74
44
0
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1c
1c
8
1c (Z)-Et
1c (Z)-Pr
1c
1c
1c
H
H
H
2 f 144 3e
2g 144 3 f
[a] Reaction conditions: compound 1 (0.4 mmol), compound 2 (2.0 mol equiv), in 1,4-
dioxane (0.2m) under an Ar atmosphere at ambient temperature. [b] Determined by
1H NMR spectroscopy of the crude mixture. [c] Yield of the isolated product after
conversion into either the corresponding dimethyl acetal with PPTS/MeOH or the 1,3-
diol with NaBH4 and purification by column chromatography on silica gel.
with PPTS/MeOH or the 1,3-diol with NaBH4. Allyl alcohol
2a (R’=H), as well as other substituted primary allylic alco-
hols (2b–2d), gave their corresponding products in 68-90%
yield and 86:14–82:18 d.r. (Table 2, entries 2–5). Notably,
the scope of the primary alcohols was not limited to allylic
alcohols. Homoallylic alcohol 2e (n=2) gave product 3d in
74% yield and 83:17 d.r. after 24 h (Table 2, entry 6). Bisho-
moallyl alcohol 2 f (n=3) was also tolerated, but the reactiv-
ity of compound 2 f was much lower than those of allylic
and homoallylic alcohols 2a and 2e. Product 3e was only
Although the Rh/dippf catalyst successfully promoted the
isomerization/aldol sequence under base-free conditions at
room temperature as initially planned, there remained
a problem to be solved if using primary allylic alcohols as
donor precursors. In the isomerization/aldol sequence, the
À
isomerization of primary allylic alcohols into enols (or Rh
enolates) proceeded without problem, but the aldol reaction
(Scheme 4, path a) competed with the undesired protonation
pathway to generate aldehydes (Scheme 4, path b). The gen-
erated aldehydes did not act as donors, as indicated by the
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Shigeki Matsunaga, Motomu Kanai et al.
Table 4. Ligand and metal re-screening in the isomerization/cross-aldol
sequence with triallyloxyborane 6a.
Scheme 4. Competitive undesired homoaldol formation through the un-
desirable tautomerization of enol intermediates into aldehydes.
Entry
Ligand
Metal source (mol%)
t
d.r.[a] (syn/ Yield
anti)
[h]
[%][a]
1
2
3
4
5
6
7
8
9
dppf
dippf
dcypf
dtbpf
bdtbpb
dcypb
dppe
[{Rh
[{Rh
[{Rh
[{Rh
[{Rh
[{Rh
[{Rh
[{Rh
[{Rh
N
ND
94:6
91:9
ND
ND
ND
ND
ND
ND
<5
99
85
<5
0
0
0
0
0
control experiment in Scheme 3. Rather, the aldehydes that
were generated through path b acted as acceptors, thereby
generating undesired homoaldols that were derived from
two molecules of allylic alcohols as minor byproducts. Sepa-
ration of the homoaldols from the desired cross-aldol prod-
ucts in Table 2 was often problematic, in particular if an ali-
phatic aldehyde was used as an acceptor. To realize a more-
efficient and truly chemoselective isomerization/aldol pro-
cess, undesired isomerization of the enol (or enolate) inter-
mediate into the corresponding aldehyde must be prevented
whilst accelerating the desired cross-aldol pathway.
dppp
(rac)-
BINAP
[b]
10
11
12
13
PCy3
[{Rh
[{Rh
ND
ND
91:9
92:8
0
0
77
89
[b]
PiPr3
dippf
dippf
[Rh
A
23
23
[{RhAHCTNUGTRENNNUG
14
15
16
dippf
dippf
dippf
[Rh
[Rh
N
36
ND
ND
ND
0
0
0
To suppress the above-mentioned undesired pathway, we
planned to use an allyloxyborane as a donor precursor in-
stead of an allyl alcohol. In contrast to the recent advances
by using silyl enol ethers that were derived from aldehydes
U
ACHTUNGTREN(NUNG cod)] (2.5) 36
AHCTUNGTRENNUNG
(1.25)
17
18
dippf
dippf
[Ru
[RuHCl(CO)
(2.5)
(cod)Cl}2] (1.25)
N
ND
ND
0
0
À
G
ACHTUNGTRENNUNG
to demonstrate the aldehyde aldehyde cross-aldol pro-
cess,[19–21] the use of aldehyde-derived enol boranes is rare,
possibly owing to their instability and propensity for poly-
merization.[22] We envisioned that the in situ generation of
aldehyde-derived enol boranes through the isomerization of
a C=C double bond under neutral conditions would provide
a new convenient method for utilizing various aldehyde-de-
rived enol boranes in organic synthesis.[23] Optimization of
the reaction of triallyloxyborane 6a is summarized in
Table 4. Because the reaction rate of triallyloxyborane 6a
was slightly slower than those of allyl alcohols, screening
was performed by using aldehyde 1e, which contained an
electron-withdrawing group. The trends in the metal and
ligand effects in Table 4 were quite similar to those in
Table 1. Ferrocene-based alkyl-phosphine ligands were criti-
cal for promoting the isomerization/aldol sequence and
19
dippf
[{Ir
A
36
ND
0
[a] Determined by 1H NMR spectroscopy of the crude mixture.
[b] 5 mol% of the ligand was used. dppf=1,1’-bis(diphenylphosphanyl)-
ferrocene, dcypf=1,1’-bis(dicyclohexylphosphanyl)ferrocene, dtbpf=1,1’-
bis(di-t-butylphosphanyl)ferrocene,
bdtbpb=1,2-bis(di-t-butylphospha-
nyl)benzene, dppe=1,2-bis(diphenylphosphino)ethane, dppp=1,3-bis(di-
phenylphosphino)propane, BINAP=2,2’-bis(diphenylphosphino)-1,1’-bi-
naphthyl.
gave the desired products at room temperature. Thus, the
RhACHTNUTRGNEUNG(cod)Cl dimer, in combination with the dippf ligand, was
re-confirmed to be the optimal catalyst for the reaction by
using triallyloxyborane 6a.
The substrate scope of the isomerization/cross-aldol se-
quence is summarized in Table 5.[25] High syn selectivity was
observed in Table 5, entries 1–11 by using compound 6a and
various aromatic and heteroaromtic aldehydes (>95:5–90:10
d.r.). Substituents at the ortho, meta, and para positions on
the aromatic ring of the aldehydes were compatible and
even sterically hindered 2,6-disubstituted aldehyde 1k
(Table 5, entry 7) and the less-electrophilic aldehyde 1l,
which contained two electron-donating MeO groups at the
ortho and para positions (Table 5, entry 8), gave their corre-
sponding aldol adducts without problem. The results with
substituted triallyloxyboranes 6b–6d are summarized in
Table 5, entries 12–15. Triallyloxyboranes 6b (as a 15:1 E/Z
mixture), (Z)-6c, and (Z)-6d showed good reactivity, thus
[{RhACHTUNGTRENNUNG(cod)Cl}2], in combination with dippf, gave the highest
reactivity, thereby affording product 3g in 99% yield and
94:6 d.r. (Table 4, entry 2). The reaction also proceeded in
85% yield with dcypf, which contained two PACTHNURTGNENG(U c-hex)2 units
(Table 4, entry 3); sterically more-hindered dtbpf, which
contained PtBu2 units, had poor reactivity (Table 4, entry 4).
We also re-screened other bidentate alkyl phosphines, bi-
dentate aryl phosphines, and monodentate alkyl phosphines,
but none of them gave good results (Table 4, entries 5–11).
Other Rh sources showed less-satisfactory reactivities
(Table 4, entries 12–15). Several Ru and Ir complexes were
also screened (Table 4, entries 16–19),[24] but none of them
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Shigeki Matsunaga, Motomu Kanai et al.
Table 5. Rh/dippf-catalyzed isomerization/cross-aldol sequence with vari-
ous trialkoxyboranes.[a]
under this Rh/dippf catalysis. This Rh catalyst was also ap-
plicable to enolizable aliphatic aldehydes (Table 5, en-
tries 16–19). Although the syn selectivity was somewhat de-
creased, the desired cross-aldol adduct was obtained chemo-
selectively. In Table 5, entry 19, propanal chemoselectively
reacted as an acceptor with the butanal-derived enolate that
was generated from compound 6b and cross-aldol adduct 3s
was obtained in 71% yield as an unprotected b-hydroxy al-
dehyde. In Table 5, entry 19, the homoaldol adduct that was
derived from propanal was not detected, thus indicating the
synthetic utility of this method based on the orthogonal acti-
vation of allyloxyboranes. In Table 5, entries 20–24, homoal-
lyloxyborane 6e was applied for aromatic, heteroaromatic,
and aliphatic aldehydes. Although the reactivity of com-
pound 6e was lower than that of allyloxyboranes, the prod-
ucts were obtained in 60–97% yield and 91:9–83:17 d.r.
However, the reaction with trialkoxyborane 6 f, which con-
tained a remote C=C double bond did not proceed at room
temperature (Table 5, entry 25).
Entry
R
1
6
n
t
3
d.r.[b] (syn/
anti)
Yield
[%][c]
[h]
1
2
3
4
5
6
7
8
2-Br-C6H4
3-Br-C6H4
4-Br-C6H4
3-Cl-C6H4
4-F-C6H4
4-NO2-C6H4
2,6-Cl2-C6H3 1k
2,4-(MeO)2-
C6H3
1e
1 f
1g
1h
1i
6a
6a
6a
6a
6a
6a
6a
6a
1
1
1
1
1
1
1
1
23 3g
36 3h 93:7
94:6
99
72
83
95
87
90
85
78
36
36
3i
3j
93:7
91:9
36 3k 93:7
36 3l 94:6
36 3m >95:5
36 3n 90:10
1j
1l
9
Ph
1c
1m
1n
1c
1c (E)-
6c
1c (Z)-
6c
1c (Z)-
6d
6a
6a
6a
6b
1
1
1
1
1
36 3b 90:10
36 3o 90:10
81
75
60
93
57
Because this Rh/dippf-catalyzed reaction was performed
under mild conditions, that is, at room temperature in the
absence of a strong base, chiral aldehyde 1q successfully
gave compound 7a as the major isomer without racemiza-
tion in >99% ee (Scheme 5). The C2/C3 diastereoselectivity
(7a+7c/7b+7d) was modest, but good C3/C4 diastereose-
10
11
12
13
2-naphthyl
2-furyl
Ph
36 3p
94:6
24 3c 90:10
Ph
48 3d 88:12
12 3d 87:13
12 3e 86:14
14
15
Ph
Ph
1
1
84
89
16
17
18
19
20
21
22
23
24
25
n-pentyl
PhCH2CH2
cyclohexyl
Et
Ph
4-Br-C6H4
1d
1a
1o
1b
1c
1g
6a
6a
6a
6b
6e
6e
6e
6e
6e
6 f
1
1
1
1
2
2
2
2
2
3
27 3q 85:15
36 3a 84:16
73
90
62
71
97
87
84
60
60
0
32
24
24
84
3r 74:26
3s 75:25
3c 86:14
3t
91:9
4-MeO-C6H4 1p
84 3u 84:16
60 3v 84:16
96 3w 83:17
2-furyl
PhCH2CH2
Ph
1n
1a
1c
36 3d
ND
[a] Reaction conditions: compound 1 (0.4 mmol), compound 6 (1 mol e-
quiv), in 1,4-dioxane (0.2m) under an Ar atmosphere at ambient temper-
ature. [b] Determined by 1H NMR spectroscopy of the crude mixture.
[c] Yield of the isolated product after conversion into either the corre-
sponding dimethyl acetal with PPTS/MeOH or the 1,3-diol with NaBH4
and purification by column chromatography on silica gel. [d] Yield of the
isolated product in its b-hydroxy-aldehyde form after careful purification
Scheme 5. Isomerization/aldol sequence with chiral aldehyde 1q.
by column chromatography on silica gel. [e] 2.5 mol% of [{Rh
and 5 mol% of dippf were used.
ACHTUNGTRNEN(UNG cod)Cl}2]
lectivity (7a+7b/7c+7d) was observed. To further demon-
strate the utility of this Rh/dippf catalysis, protecting-group-
free consecutive aldol reactions with two different donors,
that is, compounds 6a and 4a, were investigated (Scheme 6).
The first aldol adduct (3m) was used in the second aldol re-
action without protection of its b-hydoxy group. Although
the second aldol reaction by using secondary allylic alcohol
4a as a donor precursor required a long reaction time, possi-
bly owing to steric hindrance, the double-aldol adducts (8)
were obtained in 61% yield (from compound 3m) in the
ratio 8a/8b/8c/8d=54:33:13:trace. Double-aldol adduct 8a
was predominantly obtained in its open form, whilst adducts
8b and 8c were obtained as mixtures of their open- and
closed forms in equilibrium. Aldehyde 1k was chosen for
giving the cross-aldol adducts in 84–93% yield with good
syn selectivity (Table 5, entries 12, 14, and 15). On the other
hand, compound (E)-6c showed much-lower reactivity, pos-
sibly owing to slow isomerization, and the product was ob-
tained in only 57% yield after 48 h (Table 5, entry 13),
whereas the diastereoselectivity was similar to that with
compound (Z)-6c. The diastereoselectivities in Table 5, en-
tries 1–15 were higher than those in other related transition-
metal-catalyzed isomerization/aldol sequences with secon-
dary allylic alcohols. These results suggested that epimeriza-
tion of the aldol products, which had caused erosion of the
diastereoselectivity in some previous reports, was negligible
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Shigeki Matsunaga, Motomu Kanai et al.
Scheme 6. Protecting-group-free consecutive aldol reactions by using two
different donors, compounds 6a and 4a.
Figure 1. ORTEPs of compounds 8a, 8b’ (closed form), and 8c’ (closed
form); thermal ellipsoids are set at 50% probability.
the consecutive aldol reaction in Scheme 6, because the
double-aldol adducts that contained a 2,6-Cl2-C6H3 unit was
highly crystalline. The relative stereochemistry in com-
pounds 8a, 8b, and 8c was unequivocally determined by
single-crystal X-ray analysis (Figure 1).[26]
This Rh/dippf catalyst promoted the isomerization/aldol
sequence at ambient temperature. however, when triallylox-
yborane 6a was treated with the Rh/dippf catalyst (5 mol%)
in the absence of an aldehyde acceptor, only 5% of the iso-
merized enol boronate (Z-major) was observed after 48 h at
room temperature (Scheme 7a).[27] Because the Ru-cata-
lyzed isomerization of triallyloxyborane 6a into the corre-
sponding enol boronate (E/Z mixture) has been reported,[24]
the isomerized enol boronate should be thermodynamically
more favorable than the starting triallyloxyborane (6a).
Therefore, the result shown in Scheme 7a simply indicated
that the isomerization in the absence of an aldehyde was
much slower than that in the sequential isomerization/aldol
process; indeed, the aldol reaction was complete within 36 h
in many cases (Table 5, entries 1–19). To gain further insight
into the reaction mechanism, deuterated triallyloxyborane
[D2]-6a was used in the isomerization/aldol sequence. As
shown in Scheme 7b, deuterium labeling was not only ob-
served at the methyl group, but also at the methine group in
the product.[28] This result indicates that a reaction pathway
that proceeds through the oxidative addition of RhI to the
Scheme 7. Mechanistic investigations: a) isomerization in the absence of
an aldehyde; b) isomerization/aldol sequence with deuterated allyloxy-
borane [D2]-6a.
A plausible catalytic cycle for the Rh-catalyzed isomeriza-
tion/aldol sequence from allyloxy- and homoallyloxyboranes
is shown in Scheme 8. On the basis of results in Scheme 7,
À
we assume that a Rh hydride species, which is initially gen-
erated by oxidative addition to the aldehyde, would be an
active species for the isomerization process. Reversible hy-
drometalation/b-hydride-elimination processes should afford
an enol-boronate intermediate.[29] In this Rh-catalyzed reac-
tion, the scope of applicable phosphines was quite narrow
(Table 4, entries 1–11) and only the dippf and dcypf ligands
showed good performance. We think that the dippf and
dcypf ligands, which are alkylphosphines with a ferrocene
À
allylic C H bond to form a p-allyl intermediate is less prob-
able; in such a case, the deuterium label should be exclu-
sively found on the methyl group.
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Experimental Section
General Procedure for the Isolation of Dimethyl Acetals
A
solution of 1,1’-bis(diisopropylphosphino)ferrocene (dippf, 4.3 mg,
2.5 mol%) and [{RhACHTNUTRGNEUNG(cod)Cl}2] (2.5 mg, 1.25 mol%, cod=1,5-cycloocta-
diene) in 1,4-dioxane (2.0 mL) was added to a mixture of trialkoxyborane
6 (0.40 mmol) or primary alcohol 2 (0.80 mmol) and freshly distilled alde-
hyde 1 (0.40 mmol) in a flame-dried test tube. After completion of the re-
action, the mixture was passed through a pad of silica gel and the filtrate
was concentrated in vacuo to give the crude aldol adduct. Water (10 mL)
was added to the residue and then products were extracted with Et2O
(3ꢁ10 mL). The combined organic phases were dried over anhydrous
sodium sulfate, evaporated, and re-dissolved in MeOH (3.0 mL). Pyridi-
nium p-toluenesulfonate (PPTS, 5 mol%) was added to the solution and
the mixture was stirred for 12 h at RT. The mixture was poured into a sa-
turated aqueous solution of NaHCO3 (10 mL) and the products were ex-
tracted with Et2O (5ꢁ10 mL). The combined organic phases were dried
over anhydrous sodium sulfate and concentrated to give the crude acetal
product. Purification by column chromatography on silica gel gave the di-
methyl-acetal adducts.
Scheme 8. Plausible catalytic cycle of the Rh/dippf-catalyzed isomeriza-
tion/aldol sequence of allyloxy boranes.
General Procedure for the Isolation of 1,3-Diols
A
solution of 1,1’-bis(diisopropylphosphino)ferrocene (dippf, 4.3 mg,
2.5 mol%) and [{Rh(cod)Cl}2] (2.5 mg, 1.25 mol%) in 1,4-dioxane
AHCTUNGTRENNUNG
(2.0 mL) was added to a mixture of trialkoxyborane 6 (0.40 mmol) or pri-
mary alcohol 2 (0.80 mmol) and freshly distilled aldehyde 1 (0.40 mmol)
in a flame-dried test tube. After completion of the reaction, MeOH
(2.0 mL) was added and the mixture was cooled to 08C. Then, NaBH4
(1.2 mmol) was added and the mixture was stirred overnight under an
argon atmosphere. After evaporation, water (10 mL) and Et2O (10 mL)
were added to the residue and the organic phase was separated. The
water phase was further extracted with Et2O (3ꢁ10 mL). The combined
organic phases were dried over anhydrous sodium sulfate, passed through
a short pad of silica gel (eluted with Et2O), and concentrated in vacuo.
The diastereomeric ratio was determined by 1H NMR spectroscopy of
the crude 1,3-diol product and the crude material was purified by column
chromatography on silica gel to give the 1,3-diol products.
backbone, play a key role in accelerating the desired isomer-
ization reaction at room temperature, whilst preventing un-
desirable pathways, such as decarbonylation and hydroacyla-
tion. The stereochemical outcome in the aldol reactions with
enol boronates is known to be quite different from that with
well-established enol borinates,[30,31] possibly owing to the
differences in the Lewis acidities of the boron centers. Hoff-
mann et al. systematically studied aldol reactions with enol
boronates that were derived from ketones and syn-aldol ad-
ducts were obtained as the major products, irrespective of
the geometry of the enolate.[31] Thus, we assumed that the
aldol reaction with the enol boronates that were derived
from aldehydes would also give syn-aldol adducts as the
major products, regardless of the geometry of the enol-boro-
nate intermediate.[32,33]
Acknowledgements
This work was supported by the ACT-C program of the JST (S.M.), by
ERATO program of the JST (M.K.), by a Grant-in-Aid for Scientific Re-
search on Innovative Areas “Molecular Activation Directed toward
Straightforward Synthesis” from MEXT (S.M.), and by the Naito Foun-
dation. L.L. thanks the Uehara Memorial Foundation for a fellowship.
K.Y. thanks the JSPS for a fellowship.
Conclusions
In summary, we have reported the chemoselective genera-
tion of aldehyde-derived enolates to realize an aldehyde al-
À
dehyde cross-aldol reaction. A combined Rh/dippf system
efficiently promoted the isomerization/aldol sequence by
using primary allylic, homoallylic, and bishomoallylic alco-
hols; secondary allylic and homoallylic alcohols; and trial-
koxyboranes that were derived from primary allylic and ho-
moallylic alcohols. The reaction proceeded at ambient tem-
perature under base-free conditions, thus giving cross-aldol
products with high chemoselectivity. The limitations of this
system, in particular in consecutive protecting-group-free
aldol reactions, were also clarified. Work to improve the re-
activity and stereoselectivity of the aldol step, including the
development of enantioselective variants, is actively under-
way in our group.[33]
[1] Comprehensive Organic Chemistry, Addition to C-X p Bonds, Part 2
(Ed.: C. H. Heathcock), Pergamon Press, 1991, p. 99.
[2] For redox-economy, see: N. Z. Burns, P. S. Baran, R. W. Hoffman,
Angew. Chem. 2009, 121, 2896; Angew. Chem. Int. Ed. 2009, 48,
2854.
[3] For step-economy, see: P. A. Wender, B. L. Miller, Nature 2009, 460,
197.
[4] For reviews, see: a) B. Schetter, R. Mahrwald, Angew. Chem. 2006,
118, 7668; Angew. Chem. Int. Ed. 2006, 45, 7506; b) J. Li, D.
Menche, Synthesis 2009, 2293.
[5] For the rapid total synthesis of polyketide natural product and 1,3-
polyols through aldol reactions of “supersilyl” aldehyde-derived
enolates, see: a) B. J. Albert, Y. Yamaoka, H. Yamamoto, Angew.
Chem. 2011, 123, 2658; Angew. Chem. Int. Ed. 2011, 50, 2610;
b) P. B. Brady, H. Yamamoto, Angew. Chem. 2012, 124, 1978;
Angew. Chem. Int. Ed. 2012, 51, 1942; See also reference [19].
[6] For atom-economy, see: B. M. Trost, Science 1991, 254, 1471.
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Shigeki Matsunaga, Motomu Kanai et al.
[7] For reviews, see: a) B. M. Trost, C. S. Brindle, Chem. Soc. Rev. 2010,
39, 1600; b) Modern Aldol Reactions (Ed.: R. Mahrwald), Wiley-
VCH, Weinheim, Germany, 2004. For early examples of atom-eco-
nomical direct catalytic asymmetric aldol reactions with ketone
donors, see: c) N. Yoshikawa, Y. M. A. Yamada, J. Das, H. Sasai, M.
Shibasaki, J. Am. Chem. Soc. 1999, 121, 4168; d) B. List, R. A.
Lerner, C. F. Barbas, III., J. Am. Chem. Soc. 2000, 122, 2395;
e) B. M. Trost, H. Ito, J. Am. Chem. Soc. 2000, 122, 12003.
8331; c) N. Ahlsten, A. Bartoszewicz, S. Agrawal, B. Martꢄn-Matute,
Synthesis 2011, 2600.
[17] a) E. R. Alexander, E. N. Marvell, J. Am. Chem. Soc. 1950, 72, 1396;
b) J. Hine, J. G. Houston, J. H. Jensen, J. Org. Chem. 1965, 30, 1184;
c) S. D. Rychnovsky, D. J. Skalitzky, J. Org. Chem. 1992, 57, 4336.
[18] For Rh-catalyzed enol formation from primary allylic alcohols
through a 1,3-hydride shift, see: S. H. Bergens, B. Bosnich, J. Am.
Chem. Soc. 1991, 113, 958.
[19] a) M. B. Boxer, H. Yamamoto, J. Am. Chem. Soc. 2006, 128, 48;
b) M. B. Boxer, H. Yamamoto, J. Am. Chem. Soc. 2007, 129, 2762;
c) M. B. Boxer, M. Akakura, H. Yamamoto, J. Am. Chem. Soc.
2008, 130, 1580; d) B. J. Albert, H. Yamamoto, Angew. Chem. 2010,
122, 2807; Angew. Chem. Int. Ed. 2010, 49, 2747; e) J. Saadi, M.
Akakura, H. Yamamoto, J. Am. Chem. Soc. 2011, 133, 14248. For
a related work, also see: f) P. B. Brady, B. J. Albert, M. Akakura, H.
Yamamoto, Chem. Sci. 2013, 4, 3223.
À
[8] For leading examples of organocatalytic direct aldehyde aldehyde
cross-aldol reactions, see: a) A. B. Northrup, D. W. C. MacMillan, J.
Am. Chem. Soc. 2002, 124, 6798; b) N. S. Chowdari, D. B. Ramach-
ary, A. Cꢂrdova, C. F. Barbas, III, Tetrahedron Lett. 2002, 43, 9591;
c) I. K. Mangion, A. B. Northrup, D. W. C. MacMillan, Angew.
Chem. 2004, 116, 6890; Angew. Chem. Int. Ed. 2004, 43, 6722;
d) A. B. Northrup, D. W. C. MacMillan, Science 2004, 305, 1752;
e) A. Cꢂrdova, I. Ibrahem, J. Casas, H. Sundꢃn, M. Engqvist, E.
Reyes, Chem. Eur. J. 2005, 11, 4772; f) T. Kano, Y. Yamaguchi, Y.
Tanaka, K. Maruoka, Angew. Chem. 2007, 119, 1768; Angew. Chem.
Int. Ed. 2007, 46, 1738; g) Y. Hayashi, T. Itoh, S. Aratake and H.
Ishikawa, Angew. Chem. 2008, 120, 2112; Angew. Chem. Int. Ed.
2008, 47, 2082; h) T. Kano, Y. Yamaguchi, K. Maruoka, Chem. Eur.
J. 2009, 15, 6678; i) M. Markert, U. Schetter, R. Mahrwald, J. Am.
Chem. Soc. 2009, 131, 16642; j) R. K. Boeckman, Jr., J. R. Miller,
Org. Lett. 2009, 11, 4544; k) J. Li, N. Fu, X. Li, S. Luo, J.-P. Cheng, J.
Org. Chem. 2010, 75, 4501.
[20] a) S. E. Denmark, S. K. Ghosh, Angew. Chem. 2001, 113, 4895;
Angew. Chem. Int. Ed. 2001, 40, 4759; b) S. E. Denmark, T. Bui,
Proc. Natl. Acad. Sci. USA 2004, 101, 5439; c) S. E. Denmark, T.
Bui, J. Org. Chem. 2005, 70, 10190.
[21] For other early work on cross-aldol reactions by using aldehyde-de-
rived metal enolates and enol silanes, see: a) T. Mukaiyama, K.
Banno, N. Narasaka, J. Am. Chem. Soc. 1974, 96, 7503; b) C. H.
Heathcock, C. T. Buse, W. A. Kleschick, M. C. Pirrung, J. E. Sohn, J.
Lampe, J. Org. Chem. 1980, 45, 1066; c) B. A. B. Kohler, Synth.
Commun. 1985, 15, 39; d) R. Mahrwald, B. Costisella, B. Gꢅndogan,
Tetrahedron Lett. 1997, 38, 4543; e) K. Yachi, H. Shinokubo, K.
Oshima, J. Am. Chem. Soc. 1999, 121, 9465; f) X. Wang, Q. Meng,
A. J. Nation, J. L. Leighton, J. Am. Chem. Soc. 2002, 124, 10672.
[22] a) R. W. Hoffmann, K. Ditrich, S. Frçch, Liebigs Ann. Chem. 1987,
977; b) G. Wulff, A. Hansen, Angew. Chem. 1986, 98, 552; Angew.
Chem. Int. Ed. Engl. 1986, 25, 560; c) G. Wulff, P. Birnbrich, A.
Hansen, Angew. Chem. 1988, 100, 1197; Angew. Chem. Int. Ed.
Engl. 1988, 27, 1158.
[23] For partially successful example of Rh-catalyzed isomerization/alky-
lation sequences by using allyloxyborates, see: a) G. L. Edwards,
W. B. Motherwell, D. M. Powell, D. A. Sandham, J. Chem. Soc.
Chem. Commun. 1991, 1399; For related Rh-catalyzed isomeriza-
tion/allylation sequences by using alkenylboronates and aldehydes,
see: b) H. Shimizu, T. Igarashi, T. Miura, M. Murakami, Angew.
Chem. 2011, 123, 11667; Angew. Chem. Int. Ed. 2011, 50, 11465.
[24] The Ru-catalyzed isomerization of a triallyloxyborane into an enol
borane has been reported, but high reaction temperatures were re-
quired in those studies; see: a) S. Krompiec, J. Suwinski, J. Grobel-
ny, Polish J. Chem. 1996, 70, 813; b) S. Krompiec, J. Suwinski, J.
Grobelny, P. Wagner, Polish J. Chem. 1997, 71, 747. The dippf ligand
was essential for promoting the isomerization process at ambient
temperature under neutral conditions in the absence of a strong
base.
[9] T. Kano, H. Sugimoto, K. Maruoka, J. Am. Chem. Soc. 2011, 133,
18130.
[10] For a review on alternative methods of enolate generation, see:
T. D. Sheppard, Synlett 2011, 1340.
[11] Some of the results in this manuscript were previously reported as
a communication, see: L. Lin, K. Yamamoto, S. Matsunaga, M.
Kanai, Angew. Chem. 2012, 124, 10421; Angew. Chem. Int. Ed. 2012,
51, 10275.
[12] For a review of ketone-derived-enolate-generation/aldol sequences
through the isomerization of secondary allylic alcohols, see: a) N.
Ahlsten, A. Bartoszewicz, B. Martꢄn-Matute, Dalton Trans. 2012, 41,
1660; For leading examples, also see: b) R. Uma, M. Davies, C.
Crꢃvisy, R. Grꢃe, Tetrahedron Lett. 2001, 42, 3069; c) X. F. Yang, M.
Wang, R. S. Varma, C.-J. Li, Org. Lett. 2003, 5, 657; d) D. Cuperly, J.
Petrignet, C. Crꢃvisy, R. Grꢃe, Chem. Eur. J. 2006, 12, 3261; e) J.
Petrignet, T. Roisnel, R. Grꢃe, Tetrahedron Lett. 2006, 47, 7745; f) J.
Petrignet, I. Prathap, S. Chandrasekhar, J. S. Yadav, R. Grꢃe,
Angew. Chem. 2007, 119, 6413; Angew. Chem. Int. Ed. 2007, 46,
6297; g) J. Petrignet, T. Roisnel, R. Grꢃe, Chem. Eur. J. 2007, 13,
7374; h) A. Bartoszewicz, M. Livendahl, B. Martꢄn-Matute, Chem.
Eur. J. 2008, 14, 10547; i) N. Ahlsten, B. Martꢄn-Matute, Adv. Synth.
Catal. 2009, 351, 2657; j) A. Mizuno, H. Kusama, N. Iwasawa, Chem.
Eur. J. 2010, 16, 8248.
[13] For the gold-catalyzed generation of ketone-derived enol boranes
from alkynes and boronic acids, see: a) C. Kçrner, P. Starkov, T. D.
Sheppard, J. Am. Chem. Soc. 2010, 132, 5968; For related works on
enolate generation from alkynes, b) B. M. Trost, S. Oi, J. Am. Chem.
Soc. 2001, 123, 1230; c) N. P. Grimster, D. A. A. Wilton, L. K. M.
Chan, C. R. A. Godfrey, C. Green, D. R. Owen, M. J. Gaunt, Tetra-
hedron 2010, 66, 6429 and references therein.
[25] Although triallyloxyboranes 6 contained three allyloxy units, 1.0 mo-
l equiv of compound 6 was required to obtain good reactivity and
diastereoselectivity. In the reaction of aldehyde 1c with 0.33 mol e-
quiv of compound 6a, the Rh/dippf catalyst gave product 3b in
51% yield with 83:17 d.r. after 36 h. In Table 5, the reaction be-
tween the aldehyde unit in the first aldol product and the enolate
was only observed as a minor pathway in some cases, because steri-
cally hindered branched aliphatic aldehydes showed much-lower re-
activities than aryl aldehydes and linear alkyl aldehydes.
[14] For reviews on the isomerization of primary allylic alcohols into al-
dehydes and their synthetic utility, see: a) L. Mantilli, C. Mazet,
Chem. Lett. 2011, 40, 341; b) K. Tani, Pure. Appl. Chem. 1985, 57,
1845.
[26] CCDC 890240 (8a), CCDC 890241 (8b’, closed form), and
CCDC 890242 (8c’, closed form) contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[27] The yield in Scheme 7a was calculated based on the ratio of enol/al-
lyloxy units in the boronate.
[28] The deuterium label of the aldol adduct in Scheme 7b was analyzed
by NMR spectroscopy after conversion into its corresponding 1,3-
diol, because the b-hydroxy aldehyde was unstable.
[15] For the isomerization of primary allylic alcohols into aldehydes, fol-
À
lowed by organocatalytic C C bond formation, see: A. Quintard, A.
Alexakis, C. Mazet, Angew. Chem. 2011, 123, 2402; Angew. Chem.
Int. Ed. 2011, 50, 2354.
[16] For Ir-catalyzed isomerization/halogenation sequences from primary
and secondary allylic alcohols under base-free conditions, see: a) N.
Ahlsten, A. Bermejo Gꢂmez, B. Martꢄn-Matute, Angew. Chem.
2013, 125, 6393; Angew. Chem. Int. Ed. 2013, 52, 6273. For related
Ir-catalyzed functionalization from secondary allylic alcohols, also
see: b) N. Ahlsten, B. Martꢄn-Matute, Chem. Commun. 2011, 47,
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I
[29] RhIII hydride species that are generated from Rh catalysts and al-
dehydes are common intermediates in the Rh-catalyzed hydroacyla-
tion of alkenes. The Rh-catalyzed hydroacylation reaction also in-
volves reversible hydrometalation/b-hydride-elimination processes
(Scheme 7a), we could not determine the enolate geometry in the
presence of an aldehyde.
[33] All attempts to induce enantioselectivity in this present Rh-cata-
lyzed process with chiral Rh complexes and triallyloxyboranes
failed. Thus, we believe that the Rh complex does not play a key
À
of RhIII hydride species with alkenes. For a comprehensive review
À
À
on transition-metal-catalyzed hydroacylation, including detailed
mechanistic discussion, see: M. C. Willis, Chem. Rev. 2010, 110, 725.
[30] For a comprehensive review on aldol reactions with enol borinates,
see: C. J. Cowden, I. Paterson, Org. React. 1997, 51, 1.
role in the C C bond-forming process. Thus, we are currently pursu-
ing different approaches to achieve the catalytic asymmetric alde-
À
hyde aldehyde cross-aldol reaction.
Received: July 13, 2013
[31] R. W. Hoffmann, K. Ditrich, Tetrahedron Lett. 1984, 25, 1781.
[32] Although the isomerization of allyloxyborane in the absence of an
aldehyde gave the (Z)-enol boronate as the major product
Published online: September 23, 2013
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