Copper(I)-catalyzed enantioselective synthesis of α-chiral linear or carbocyclic (e)-(γ-alkoxyallyl)boronates

Article abstract of DOI:10.1021/ja506284w

A new method has been developed for the catalytic asymmetric synthesis of α-chiral linear or carbocyclic (γ-alkoxyallyl)boronates via the copper(I)-catalyzed γ-boryl substitution of allyl acetals. This reaction afforded the products in high yields with ex

Full text of DOI:10.1021/ja506284w

Article
pubs.acs.org/JACS
Copper(I)-Catalyzed Enantioselective Synthesis of α‑Chiral Linear or
Carbocyclic (E)‑(γ-Alkoxyallyl)boronates
Eiji Yamamoto, Yuta Takenouchi, Taichi Ozaki, Takanori Miya, and Hajime Ito*
Division of Chemical Process Engineering & Frontier Chemistry Center, Graduate School of Engineering, Hokkaido University,
Sapporo 060-8628, Japan
S
* Supporting Information
ABSTRACT: A new method has been developed for the catalytic
asymmetric synthesis of α-chiral linear or carbocyclic (γ-alkoxyallyl)-
boronates via the copper(I)-catalyzed γ-boryl substitution of allyl acetals.
This reaction afforded the products in high yields with excellent E:Z
selectivities and enantioselectivities [only (E)-product, 91−98% ee] and
also exhibited high functional group compatibility. Subsequent allylation
of aldehydes with the α-chiral (γ-alkoxyallyl)boronates provided the anti-
1,2-diol derivatives in a highly stereospecific manner, and the utility of the
α-chiral (γ-alkoxyallyl)boronates was further demonstrated by a convergent coupling of a complex polyol derivative using a (γ-
alkoxyallyl)boronate and a chiral α-oxyaldehyde. The stereoselective modular construction of a complex 3,3-disubstituted
cyclopentene containing three consecutive stereocenters including a quaternary chiral carbon was also reported. Useful
transformations of the α-chiral linear (γ-alkoxyallyl)boronates were also demonstrated.
Scheme 1. Convergent Synthesis of Complex Molecules
Bearing 3-Ene-1,2-diol Structures Using Aldehyde Allylation
with α-Chiral (γ-Alkoxyallyl)boronates
INTRODUCTION
■
The chiral 1,2-diol structure is important and is often found in
natural products such as carbohydrates and polyketides.1
Consequently, stereoselective coupling reactions constructing
chiral 1,2-diol motifs with concurrent C−C bond formation
between two functionalized synthetic fragments can be
powerful tools for the efficient convergent synthesis of the
complex polyols containing multiple stereocenters.2 Addition
reactions of enantioenriched γ-alkoxyallyl organometallic
reagents to a carbonyl compound have been employed for
the construction of the stereodefined 3-ene-1,2-diol structure
with a concomitant C−C bond formation, and the double bond
in the product can be further utilized through a number of
selective functionalization reactions.2n,o,3,4 Among the γ-
alkoxyallyl organometallic reagents, (γ-alkoxyallyl)boron com-
pounds are commonly used as versatile reagents for asymmetric
synthesis because they react both reliably and predictably,
exhibiting high levels of stability under atmospheric conditions
and low toxicity.5 Following from the initial studies of
Hoffmann6 and Wuts,7 the stereoselective allylation of
aldehydes with (γ-alkoxyallyl)boron compounds8 has been
used for the synthesis of polyoxygenated natural products and
pharmaceuticals.9 (γ-Borylallyl)- or (γ-silylallyl)boron com-
pounds were also reported as flexible alternative reagents for
the reaction.10 In most cases, these reactions involve (γ-
alkoxyallyl)boron compounds bearing an achiral primary C−B
bond with a chiral boron auxiliary, which give 1,2-diol
derivatives containing a terminal alkene moiety via aldehyde
allylation (Scheme 1a). Although these known enantioenriched
(γ-alkoxyallyl)boron compounds are highly useful, the boron
compounds lack the substituent at the α-position and need a
stoichiometric chiral auxiliary to construct the stereodefined 3-
ene-1,2-diol unit after the aldehyde allylation step.
In contrast, aldehyde allylation involving α-chiral (E)- or (Z)-
(γ-alkoxyallyl)boronates affords stereodefined anti- or syn-1,2-
diols containing an internal alkene moiety, the stereochemistry
of which is controlled by the chiral C−B bond structure
without the use of a chiral auxiliary.11,12 This aldehyde allylation
of the boronates is expected to be suitable for the convergent
synthesis of complex molecules containing 3-ene-1,2-diol
structures; it can make a new linkage between the function-
alized fragments of the boronate and aldehyde moieties through
the stereodefined 3-ene-1,2-diol unit in a highly stereospecific
Received: June 27, 2014
© XXXX American Chemical Society
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manner (Scheme 1b). However, only a few synthetic methods
are available for the asymmetric construction of α-chiral (γ-
alkoxyallyl)boronates. In addition, synthetic methods for other
related optically active α-chiral γ-alkoxyallyl organometallic
reagents such as organostannane13 or organosilane14 com-
pounds are also limited. Hall et al. developed two catalytic
methods for the construction of the boronates, including a
Cr(III)-catalyzed enantioselective inverse electron demand
hetero-[4 + 2] reaction15a and a Pd-catalyzed enantioselective
boryl substitution15b (Scheme 2). Furthermore, the utility of
RESULTS AND DISCUSSION
■
Copper(I)-catalyzed borylation has emerged as a powerful
method for the synthesis of organoboron compounds.18 We
previously reported a copper(I)-catalyzed asymmetric boryla-
tion using diboron that provided optically active allylboro-
nates.19 Guided by these successes, we proceeded to investigate
the development of a copper(I)-catalyzed asymmetric synthesis
of (γ-alkoxyallyl)boronates via the enantioselective γ-boryl
substitution of allyl acetals (Scheme 2).20 Pleasingly, while an
extensive review of the literature revealed reports concerning
the catalytic asymmetric α-substitution of allyl acetals, we could
not find any reports describing the catalytic asymmetric γ-
substitution of allyl acetals with nucleophiles of any type.21
We initially investigated suitable reaction conditions for the
reaction of allyl acetal (Z)-1a with bis(pinacolato)diboron
(Table 1). The results revealed that (R,R)-BenzP* was the best
Scheme 2. Enantioselective Synthesis of α-Chiral (γ-
Alkoxyallyl)boronates and Subsequent Aldehyde Allylation
Table 1. Optimization of the Reaction Conditions for the
Copper(I)-Catalyzed Enantioselective Boryl Substitution of
a
Allyl Acetal (Z)-1a
b
c
entry
1
catalyst
time (h) yield (%)
ee (%)
CuCl/(R,R)-BenzP*
CuCl/(R,R)-BenzP*
Cu(O-t-Bu)/(R,R)-BenzP*
CuCl/(R,R)-QuinoxP*
CuCl/(R,R)-Me-Duphos
CuCl/(R)-Segphos
3
24
3
95 (83)
97
96
d
2
81
e
3
88
97
4
5
6
7
8
63
93
these chiral boronates was demonstrated in the synthesis of
highly oxygenated natural products16 such as thiomarinol.
These approaches, however, are limited to six-membered ring
oxacyclic (Z)-(γ-alkoxyallyl)boronates. To the best of our
knowledge, there have been no reports in the literature
pertaining to the catalytic asymmetric synthesis of α-chiral
linear or carbocyclic (γ-alkoxyallyl)boronates to date, and the
development of an effective method for their synthesis is
therefore highly desirable.
Herein, we report a novel approach to enantioenriched α-
chiral linear or carbocyclic (E)-(γ-alkoxyallyl)boronates via the
copper(I)/chiral bisphosphine-catalyzed γ-boryl substitution of
allyl acetals and the subsequent conversion of these boronates
to the corresponding anti-1,2-diol derivatives, which are
generally more difficult to prepare than syn-1,2-diol derivatives,
through a newly developed ZnBr2-catalyzed aldehyde allylation
(Scheme 2). This borylation/allylation process was found to be
effective for the convergent synthesis of a complex polyol
derivative with high stereoselectivity and functional group
compatibility. The aldehyde allylation with carbocyclic (γ-
alkoxyallyl)boronates afforded sterically congested anti-1,2-diol
derivatives,17 which were used for the unprecedented stereo-
selective modular synthesis of complex 3,3-disubstituted
cyclopentenes containing three consecutive chiral centers,
including a quaternary chiral carbon, via the iterative
borylation/aldehyde allylation. We have also demonstrated
useful transformations of the α-chiral linear boronates.
24
24
45
3
14
73
38
43
21
CuCl/(R,S)-Josiphos
CuCl/(R,R)-BenzP*
Ni(cod)2/PPh3
11
f
8
86 (73)
0
34 (R)
f g
9 ,
24
a
Reagents and conditions: CuCl (0.025 mmol), ligand (0.025 mmol),
(Z)-1a (0.5 mmol), bis(pinacolato)diboron (0.75 mmol), and K(O-t-
Bu)/THF (1.0 M, 0.5 mL, 0.5 mmol) in THF (0.5 mL) at 0 °C.
b
c
NMR yield. The isolated yield is shown in parentheses. The ee value
of (S,E)-2a was determined by HPLC analysis of the alcohol derived
from the product boronate. A 10 mol % concentration of K(O-t-Bu)
was used. Isolated Cu(O-t-Bu) was used, and K(O-t-Bu) was not
added. (E)-1a (E:Z = 95:5) was used as the substrate. Reagents and
conditions: Ni(cod)2 (10 mol %), PPh3 (10 mol %), and
bis(pinacolato)diboron (0.5 mmol) in EtOAc (0.4 mL) at 60 °C, 24 h.
d
e
f
g
ligand for the reaction.22 The boryl substitution of (Z)-1a with
CuCl/(R,R)-BenzP* (5 mol %), bis(pinacolato)diboron (1.5
equiv), and K(O-t-Bu) (1.0 equiv) in THF afforded the
corresponding (S,E)-2a in excellent yield (95%) and ee (97%)
(Table 1, entry 1). This reaction employed CuCl as a catalyst
precursor, which can be used without a glovebox.19e It is
noteworthy that none of the minor (Z)-product was observed.
The boryl substitution reaction also proceeded smoothly in the
presence of 10 mol % K(O-t-Bu), although the yield was
slightly lower than that of the reaction conducted with a
stoichiometric charge of the base and required a longer reaction
time (Table 1, entry 2). The use of Cu(O-t-Bu) provided
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reactivity and stereoselectivity levels similar to those observed
for CuCl/K(O-t-Bu) (Table 1, entry 3). The other ligands gave
inferior results (Table 1, entries 4−7). Interestingly, the
application of the optimum reaction conditions to (E)-1a
instead of (Z)-1a resulted in a significantly lower ee (Table 1,
entry 8). Recently, Morken et al. reported Ni-catalyzed γ-
borylation of alkenyl acetal with a terminal carbon−carbon
double bond.20 We thus tested the Ni-catalyzed reaction of the
substrate (E)-1a, which has an internal carbon−carbon double
bond. However, no reaction occurred after 24 h at 60 °C
(Table 1, entry 9).
reacted smoothly to give the corresponding products in high
yields and excellent enantioselectivities [(S,E)-2g, 81% yield,
97% ee; (S,E)-2h, 83% yield, 97% ee; (S,E)-2i, 93% yield, 97%
ee; (R,E)-2j, 86% yield, 97% ee]. The use of nitrogen-
containing substrates (Z)-1k and (Z)-1l provided the
corresponding products (S,E)-2k and (S,E)-2l in high yields
and excellent enantioselectivities without any degradation of
the functional groups [(S,E)-2k, 97% yield, 98% ee; (S,E)-2l,
98% yield, 96% ee]. However, the products could not be fully
isolated because of the presence of the byproducts; thus, the
derivatizations of the crude products were conducted to check
the product structure and yields (62% and 88% isolated yields,
respectively). The reactions of substrate (R,Z)-1m containing
an optically active silyl ether moiety are shown in Scheme 3.
With the optimized conditions in hand, we examined the
substrate scope of this reaction (Table 2). Pleasingly, the
Table 2. Substrate Scope of the Copper(I)-Catalyzed
Enantioselective Boryl Substitution of Allyl Acetal (Z)-1
a
Scheme 3. γ-Borylation of Substrate (R,Z)-1m with CuCl/
Xantphos or Chiral BenzP* Ligands
a
The dr values of the products were determined by 1H NMR analysis
b
of the crude products. The dr values of the products were determined
by HPLC analysis of the alcohols derived from the corresponding
boronates.
The use of the Xantphos ligand afforded (1E,3R,5R)-2m in
80% yield and a diastereomeric ratio of 16:84, which was
attributed to the steric effect of the chiral silyl ether group. The
reactions of (R,Z)-1m with CuCl/(S,S)- and (R,R)-BenzP*
proceeded to give the corresponding (1E,3R,5R)-2m and
(1E,3S,5R)-2m, respectively, in good yields and excellent
catalyst-controlled stereoselectivity (75% and 75% yields,
0.4:99.6 and 97:3 dr, respectively).
a
Reagents and conditions: CuCl (0.025 mmol), (R,R)-BenzP* (0.025
mmol), (Z)-1 (0.5 mmol), bis(pinacolato)diboron (0.75 mmol), and
K(O-t-Bu)/THF (1.0 M, 0.5 mL, 0.5 mmol) in THF (0.5 mL) at 0 °C.
The ee values of the products were determined by HPLC analysis of
the saturated alcohols derived from the corresponding boronates.
To date, there have been no reports in the literature
describing the allylation of aldehydes with linear enantioen-
riched α-chiral (E)-(γ-alkoxyallyl)boronates to give the
corresponding 1,2-diol derivatives with high E:Z and anti:syn
selectivities and enantioselectivities. With this in mind, we
investigated the optimum reaction conditions for the aldehyde
allylation with the (γ-alkoxyallyl)boronates (Table 3). Without
any catalyst, the allylboronate (S,E)-2c or (S,E)-2i reacted with
benzaldehyde in CH2Cl2 or THF to give products with low E:Z
selectivity but high enantiospecificity (es)23 (Table 3, entries
1−4). It has been reported that the selectivity of aldehyde
allylation can be improved by the presence of an acid catalyst.
Carreaux reported the BF3-catalyzed reaction of racemic (E)-(γ-
alkoxyallyl)boronates to give products with high levels of
anti:syn selectivity,11 although the E:Z ratios were still in need
of improvement. With this in mind, we screened a variety of
Lewis acids, including BF3·OEt2, AlCl3, FeCl3, Sc(OTf)3,
TMSOTf, and ZnBr2. The results revealed that ZnBr2, which
had never been used as a Lewis acid catalyst for the allylation of
aldehydes with allylboron reagents,24,25 turned out to be the
b
The ee was determined after derivatization of (R,E)-2j to the related
c
p-nitrobenzoyl ester. NMR yield of the boronate in the crude reaction
mixture. The hydrogenated derivative was isolated in 62% yield after
hydrogenation of crude (S,E)-2k. The ee value was determined by
HPLC analysis of the hydrogenated derivative. The alcohol derivative
was isolated in 88% yield after hydrogenation of the alkene moiety and
subsequent oxidation of the crude (S,E)-2l. The ee value was
determined by HPLC analysis of the alcohol derivative.
d
e
application of the optimized conditions to allyl dibenzyl acetal
(Z)-1b gave the corresponding product (S,E)-2b in 94% yield
with 98% ee. Substrates containing a methyl, hexyl, or
methylcyclohexyl group [(Z)-1c−e] also afforded the products
in high yields with excellent enantioselectivities [(S,E)-2c, 88%
yield, 96% ee; (S,E)-2d, 85% yield, 97% ee; (S,E)-2e, 79% yield,
96% ee]. The (γ-alkoxyallyl)boronate (S,E)-2f, bearing a
trisubstituted alkenyl group, was also formed in 91% yield
with 95% ee. The allyl acetals (Z)-1g−j, bearing methox-
ymethyl ether, acetoxy, and silyl ether groups, respectively, also
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Table 3. Aldehyde Allylation with Optically Active (γ-Alkoxyallyl)boronates 2
a
b
c
entry
substrate
R2CHO
PhCHO
solvent
E:Z (3:4)
yield (%)
es (%)
de
,
1
(S,E)-2i
(S,E)-2c
(S,E)-2i
(S,E)-2c
(S,E)-2i
(S,E)-2c
(S,E)-2i
(S,E)-2c
(S,E)-2i
(S,E)-2i
(S,E)-2i
(S,E)-2c
(S,E)-2g
CH2Cl2
CH2Cl2
THF
34:66
18:82
29:71
15:85
98:2
94
80
80
78
68
81
91
89
79
79
73
72
81
100
100
98
d
d
d
f
2
PhCHO
3
PhCHO
4
PhCHO
THF
100
100
100
100
100
97
5
PhCHO
CH2Cl2
CH2Cl2
THF
f
6
PhCHO
92:8
ef
,
7
PhCHO
33:67
18:82
96:4
f
8
PhCHO
THF
f
9
C7H15CHO
cinnamaldehyde
2-octynal
C7H15CHO
PhCHO
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ef
,
10
11
12
13
93:7
100
98
ef
,
87:13
85:15
f
100
ef
,
86:14
100
a
b
The E:Z ratios (3:4) of the anti-products were determined by 1H NMR and HPLC analysis. Isolated yield of anti-products. The minor syn-isomers
c
of 3 and 4 were present in less than trace amounts, which could be determined by 1H NMR analysis of the crude reaction mixtures. See ref 23. The
ee values of the major products were determined by HPLC analysis. Reagents and conditions: (S,E)-2 (0.2 mmol) and the aldehyde (0.4 mmol) in
a solvent (0.4 mL) at 30 °C. (S,E)-2i with 94% ee was used. Reagents and conditions: (S,E)-2 (0.2 mmol), aldehyde (0.4 mmol), and dry ZnBr2
d
e
f
(10 mol %) in a solvent (0.4 mL) at 0 °C. The use of dry ZnBr2 is necessary for the high stereoselectivity.
most effective Lewis acid catalyst for the highly stereoselective
aldehyde allylation with our boron compounds (Table 3,
entries 5−13). The stereoselectivities of this aldehyde allylation
were in good agreement with the mechanism that had been
previously postulated in the literature (see the Supporting
Information).11,25 The use of CH2Cl2 solvent is necessary for
the high stereoselectivity of this reaction; allylation in THF
solvent in the presence of ZnBr2 catalyst afforded inferior
results, which would be due to the coordination of THF to
ZnBr2 catalyst (Table 3, entry 1 vs entry 7, entry 2 vs entry 8).
The reaction of (S,E)-2i with octanal, cinnamaldehyde, or 2-
octynal also afforded the corresponding alcohol products with
high stereoselectivity (Table 3, entries 9−11). The reaction of
(S,E)-2c with octanal provided the corresponding product in
high selectivity and good E:Z ratio (Table 3, entry 12). The
boronate (S,E)-2g bearing the methoxymethyl group also gave
the product in high es and good E:Z ratio (Table 3, entry 13,
E:Z = 86:14, 100% es). The reactions in entries 5, 11, and 12
resulted in slightly lower yields than those in other entries, but
the anti:syn ratios were not changed. The reaction conditions
were compatible with a chiral α-oxyaldehyde substrate leading
to the desired product in 58% yield, high E:Z ratio, and high dr
{Scheme 4, E:Z [(3ie + 3ie′):4ie] = 91:9, dr (3ie:3ie′) = 99:1}.
The dr value [(3ie + 3ie′):4ie = 99:1] was higher than the
expected value (97:3) based on the enantiomeric purity of
(S,E)-2i (94% ee). This would be attributed to the kinetic
resolution upon addition of the optically active allylboronate to
the chiral α-oxyaldehyde.
Scheme 4. Aldehyde Allylation of (R)-Glyceraldehyde
Acetonide and Optically Active (γ-Alkoxyallyl)boronate 2i
a
The E:Z ratio [(3ie + 3ie′):4ie] was determined by 1H NMR analysis
after derivatization to the corresponding p-nitrobenzoic acid esters.
b
The dr (3ie:3ie′) was determined by HPLC analysis of the
corresponding p-nitrobenzoic acid esters.
We then proceeded to examine the borylation of cyclic allyl
ketals, which could provide access to 1,2-diol derivatives
containing sterically congested vicinal stereogenic centers
through a subsequent aldehyde allylation (Scheme 6). The
boryl substitution of allyl ketal 1n proceeded smoothly under
the standard conditions, although the isolation of the product
boronate was not successful. Thus, we carried out borylation of
1n and sequential allylation of aldehyde without isolation of the
allylboronate, which afforded the corresponding product
(1R,1′S)-4n in good yield with high levels of diastereo- and
enantioselectivity without the need for a Lewis acid catalyst. No
proton signals of the minor diastereomer were detected in the
Having established conditions for the aldehyde allylation, we
probed the feasibility of the convergent synthesis of complex
polyol deriatives using the borylation/aldehyde allylation
procedure (Scheme 5). The reaction of the boronate
(1E,3S,5R)-2m with (R)-glyceraldehyde acetonide successfully
proceeded to afford the desired complex allylation product 3m
in good yield and selectivity {total 56% yield, E:Z [(3m +
3m′):4m] = 80:20, dr (3m:3m′) = 97:3}.
D
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to give the diol (1R,1′S)-4o in good yield, with excellent
diastereo- and enantioselectivity (dr of the crude reaction
mixture, 98:2; 60% isolated yield after recrystallization as a
single isomer with 97% ee). In this reaction, the allylation of
benzaldehyde proceeded with high diastereoselectivity. Follow-
ing TBS protection of the hydroxy groups in (1R,1′S)-4o, a
second diastereoselective borylation with the achiral copper(I)/
Xantphos catalyst19e was conducted to give the corresponding
allylboronate (1S,3′R)-5o via a syn-SN2′ mechanism (90:10 dr),
which occurred as a consequence of the steric effect imposed by
the bulky silyl group.26 The configurations of (1R,1′S)-4o and
(1S,3′R)-5o were determined by X-ray crystallographic analysis
(see the Supporting Information). Finally, a second allylation of
p-bromobenzaldehyde with (1S,3′R)-5o provided monopro-
tected 1,3-diol (1S,2R,3R)-6o in good yield with high diastereo-
and enantioselectivity (72% yield, single diastereomer, 96% ee).
During the allylation of p-bromobenzaldehyde with (1S,3′R)-
5o, the reaction of the major isomer of (1S,3′R)-5o proceeded
selectively prior to that of the minor isomer, which led to the
observed higher diastereomeric ratio of the product. The
absolute configuration of the product (1S,2R,3R)-6o was
determined by X-ray crystallographic analysis of the corre-
sponding deprotected 1,3-diol (see the Supporting Informa-
tion). This synthetic method could be used as a general strategy
to provide novel chirally functionalized cycloalkene scaffolds for
drug discovery.27
Scheme 5. Convergent Coupling for Polyol Derivative
Synthesis via Aldehyde Allylation of Complex Boronates and
Aldehydes
a
The E:Z ratio [(3m + 3m′):4m] was determined by 1H NMR
analysis after derivatization to the corresponding p-nitrobenzoic acid
esters. The dr (3m:3m′) was determined by HPLC analysis of the
corresponding p-nitrobenzoic acid esters.
b
Scheme 6. Enantioselective Boryl Substitution/Aldehyde
Allylation of Allyl Ketal 1n
We further demonstrated the transformations of these α-
chiral linear (E)-(γ-alkoxyallyl)boronates (Scheme 8). The
Scheme 8. Transformations of α-Chiral Linear (E)-(γ-
Alkoxyallyl)boronates
1H NMR spectra of the crude reaction mixture. The single
isomeric product was isolated in 60% yield with 91% ee after
chromatographic purification.
The above borylation/aldehyde allylation procedure gen-
erated an allyl ether moiety in the products, and it was
envisaged that this structural feature could be used as a reactive
site for the subsequent copper(I)-catalyzed borylation. With
this in mind, we proceeded to investigate the stereoselective
modular construction of an optically active 3,3-disubstituted
cyclopentene scaffold, which contained three consecutive chiral
centers, including a quaternary carbon, using an iterative
borylation/aldehyde allylation procedure19c (Scheme 7).
Substrate 1o underwent the first borylation/aldehyde allylation
a
The ee value was determined by HPLC analysis after derivatization to
a known compound.
Scheme 7. Stereoselective Modular Construction of a
Complex 3,3-Disubstituted Cyclopentene
boronate (S,E)-2c underwent homologation to give the
corresponding homoallylboronate (R,E)-7 in 80% yield
followed by oxidation to afford alcohol (S,E)-8 in 76% yield
with 96% ee, where the alkenyl ether moiety remained intact. In
addition, the feasibility of 3-ene-anti-1,2-diols was also
confirmed by using lithium di-tert-butylbiphenyl (LiDBB)
reagent. Deprotection of the benzyl group in the allylation
product from (S,E)-2c and octyl aldehyde provided the
corresponding diol in 78% yield without lowering its
enantiomeric purity and anti:syn and E:Z ratios [97% ee,
(R,S,E)-9:(S,R,Z)-9 = 87:13; the syn-isomer could not be
1
observed by H NMR] . The boronate (R,E)-2p prepared by
the present enantioselective borylation was subjected to a Pd-
catalyzed hydrolysis28 to give the β-boryl aldehyde (R)-10 in
88% yield.29 We further carried out a total synthesis of
E
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(−)-massoialactone from (R)-10 (Supporting Information, p
S50).
A reaction mechanism has been proposed to account for the
stereochemical outcome of this boryl substitution (Scheme 9).
University) for a fruitful discussion. We appreciate Prof. M.
Sawamura and S. Ito for their assistance. The Funding Program
for Next Generation World-Leading Researchers (NEXT
Program, GR002) is gratefully acknowledged. This work was
supported by JSPS KAKENHI Grant 26·2447. E.Y. was
supported by a Grant-in-Aid for Japan Society for the
Promotion of Science (JSPS) Fellows.
Scheme 9. Proposed Mechanism [L* = (R,R)-BenzP*]
REFERENCES
■
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strain, which would also account for the observed preferential
formation of (E)-products. Subsequent β-alkoxy elimination
would afford the optically active (γ-alkoxyallyl)boronate (S,E)-
2.
CONCLUSION
■
In conclusion, we have developed a copper(I)-catalyzed
enantioselective boryl substitution of allyl acetals, providing a
novel approach to optically active α-chiral linear or carbocyclic
(E)-(γ-alkoxyallyl)boronates. Furthermore, we have developed
a highly stereoselective, zinc Lewis acid-catalyzed aldehyde
allylation with these boronates. This borylation represents the
first example of an enantioselective γ-substitution of allylic
acetals. The utility of the borylation/aldehyde allylation
procedure has been demonstrated by the convergent synthesis
of the complex polyol derivatives and the stereoselective
modular construction of a complex cyclopentene scaffold.
Furthermore, we have demonstrated the useful transformations
of the enantioenriched linear (E)-(γ-alkoxyallyl)boronate.
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ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental procedures, preparation of allyl acetal
substrates, characterization of boryl substitution products,
procedures for aldehyde allylations and characterization of the
products, single-crystal X-ray structural analyses, application of
linear (γ-alkoxyallyl)boronates, chiral stationary-phase HPLC
charts, 1H and 13C NMR spectra, and CIF data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
hajito@eng.hokudai.ac.jp
■
Notes
Kruger, J.; Bruckner, D. New J. Chem. 2001, 25, 102. (f) Munoz-
̈
̈
̃
The authors declare no competing financial interest.
Hernan
́
dez, L.; Soderquist, J. A. Org. Lett. 2009, 11, 2571.
(9) For several examples of applications for natural product synthesis,
see: (a) Burgess, K.; Chaplin, D. A.; Henderson, I. J. Org. Chem. 1992,
57, 1103. (b) Jadhav, P. K.; Woerner, F. J. Tetrahedron Lett. 1994, 35,
8973. (c) Ramachandran, P. V.; Chandra, J. S.; Reddy, M. V. R. J. Org.
Chem. 2002, 67, 7547. (d) Yin, N.; Wang, G.; Qian, M.; Negishi, E.
ACKNOWLEDGMENTS
■
We thank Prof. T. Seki and K. Sakurada (Hokkaido University)
for their great technical assistance with the X-ray crystallo-
graphic analysis. We thank Prof. K. Tanino (Hokkaido
F
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