Copper-Catalyzed Tandem Hydrocupration and Diastereo- and Enantioselective Borylalkyl Addition to Aldehydes

Article abstract of DOI:10.1002/anie.201806937

We report the copper-catalyzed stereoselective addition of in situ generated chiral boron-α-alkyl intermediates to various aldehydes including α,β-unsaturated aldehydes under mild conditions. This tandem and multicomponent method facilitated the synthesis of enantiomerically enriched 1,2-hydroxyboronates bearing contiguous stereocenters in good yield with high diastereo- and enantioselectivity up to a ratio greater than 98:2. In particular, α,β-unsaturated aldehydes were successfully used as electrophiles in Cu?H catalysis through 1,2-addition without significant reduction. The resulting 1,2-hydroxyboronates were used in various transformations.

Full text of DOI:10.1002/anie.201806937

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Accepted Article
Title: Copper-Catalyzed Tandem Hydrocupration and Diastereo- and
Enantioselective Borylalkyl Addition to Aldehydes
Authors: Jaesook Yun and Won Jun Jang
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10.1002/anie.201806937
Angewandte Chemie International Edition
COMMUNICATION
Copper-Catalyzed Tandem Hydrocupration and Diastereo- and
Enantioselective Borylalkyl Addition to Aldehydes
Won Jun Jang and Jaesook Yun*
Abstract: We report the copper-catalyzed stereoselective addition of
in-situ generated chiral boron-α-alkyl intermediates to various
aldehydes including α,β-unsaturated aldehydes under mild
conditions. This tandem and multicomponent method facilitated the
synthesis of enantiomerically enriched 1,2-hydroxyboronates bearing
contiguous stereocenters in good yield with high diastereo-, and
been developed to produce useful structural organic
frameworks.[8] However, alkenylboron compounds were rarely
used, since alkenylboronates themselves can be used as
organic nucleophiles generating by-products with copper
catalysts.[9]
Therefore,
copper-catalyzed
reactions
of
alkenylboronates were reported only with heteroatom-based
electrophiles such as pinacolborane[7a] and hydroxylamine O-
benzoate,[7c] not with unsaturated electrophiles. Only recently,
the enantioselective Cu–H catalyzed reductive coupling of
alkenylboron with allylic electrophiles has been developed by
our group and by the Hoveyda group independently.[10]
enantioselectivity up to
a ratio of >98:2. In particular, α,β-
unsaturated aldehydes were successfully used as electrophiles via
1,2-addition without significant reduction under Cu–H catalysis. The
resulting
1,2-hydroxyboronates
were
utilized
in
various
transformations.
On the other hand, carbonyl compounds such as aldehydes
and ketones are useful electrophile candidates in asymmetric
addition reactions as they produce enantiomerically pure
alcohols.[11] In general, ketones are more challenging substrates
Enantiomerically enriched organoboron compounds are
important and versatile intermediates in chemical synthesis due
to the wide applicability of the C–B bond and their stereospecific
transformation.[1] Therefore, catalytic methods for the
preparation of organoboron compounds with a carbon‒boron
stereogenic center have been developed and extensively
investigated via introduction of a boron moiety to unsaturated C–
C
bonds with transition metal catalysts.[2] An alternative
approach is to use boron-α-chiral reagents with various
electrophiles or nucleophiles for C–C bond formation (Scheme
1). Traditionally, boron-α-chiral reagents such as asymmetric (α-
haloalkyl)boronic esters were prepared by reaction of chiral
boronic esters with stoichiometric (dichloromethyl)lithium and
zinc chloride.[3] They reacted with a nucleophilic reagent such as
Grignard and organolithium reagents[3] or were converted to
organometallic species for further derivatization.[4] Since the
stoichiometric use of chiral auxiliaries and strongly basic
organometallic reagents limit their synthetic efficiency, catalytic
strategies generating enantiomerically enriched boron-α-chiral
derivatives from prochiral precursors are highly desired.
Recently, generation of boron-α-chiral organometallic species
have been reported by deborylation of 1,1-diborylalkanes
despite their poor boron atom economy.[5] For example, Meek
and co-workers reported copper-catalyzed enantioselective
transmetalation of 1,1-diborylethane and its addition to
aldehydes (Scheme 1b).[5c] The same group also reported
borylative coupling of vinylboronate with aldehydes (Scheme
1c).[6] In contrast, hydrometalation of alkenylboronates[7]
provides an efficient way to generate boron-α-chiral nucleophiles,
and successful reactions with electrophiles could establish
useful catalytic methodologies for the preparation of chiral
organoboron compounds.
CuH‒catalyzed
reductive
coupling
of
unsaturated
compounds with electrophiles for asymmetric synthesis has
a]
W. J. Jang, Prof. J. Yun
Department of Chemistry
Sungkyunkwan University
Suwon 16419 (Korea)
E-mail: jaesook@skku.edu
Scheme 1. Overview of Enantioselective Synthesis of 1,2-Hydroxyboronates
using Cu–H Catalyst
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201806937
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COMMUNICATION
Table 1: Optimization of Reaction Conditions.[a]
in nucleophilic addition reactions, However, in view of
multicomponent and tandem reactions, aldehydes offer a greater
chemoselectivity challenge due to their high reactivity, especially
under Cu–H catalysis.[12] It is known that aldehyde compounds
including α,β-unsaturated carbonyl compounds are highly
reducible
substrates
by
Cu–H
catalysts,
causing
chemoselectivity issues. Consequently, the successful copper-
catalyzed reductive couplings with carbonyls have been reported
with active olefins such as alkenylazaarenes,[8f] enynes,[8g] and
allenes[8j] in combination with ketones. To the best of our
knowledge, the use of aldehydes as carbonyl electrophiles has
not been reported in copper-catalyzed asymmetric reductive
coupling.
Herein, we report a highly enantio- and diastereoselective,
Cu–H catalyzed reaction of vinylboronate with aldehydes
yielding 1,2-hydroxyboronates (Scheme 1B). This process
generates two contiguous stereogenic centers bearing C–O and
C–B bonds. A successful reaction: (1) generated α-chiral
organocopper species via regio- and enantioselective
hydrocupration (Scheme 1B), (2) resolved chemoselectivity
issues between vinylboronate and competing aldehydes
(Scheme 1C), and (3) led to subsequent diastereoselective
addition of I to aldehydes (Scheme 1B).
Initially, we monitored the reactions of vinylboronate with
benzaldehyde (2a) under various reaction conditions (Table 1).
1,1,3,3-Tetramethyldisiloxane (TMDSO) was an efficient source
of stoichiometric hydride, and a catalytic combination of CuCl
and racemic bisphosphine ligand L1 afforded the desired
product in good yield and high diasteromeric ratio (entry 1). The
racemic results led to investigation of various chiral
bisphosphine ligands. L2 and L3 ligands appropriate for the
allylation[10a] of α-boryl organocopper species resulted in poor
yield and low diasteromeric ratio (entry 2–3). The short-tethered
ligands L4 and L5 increased the product yield and diasteromeric
ratio, but displayed poor enantioselectivity (entry 4–5). Low
reactivity and selectivity also resulted with L6 (entry 6). With the
josiphos ligand (L7), the desired product (4a) was obtained in
good yield and high enantioselectivity, but with moderate
diasteroselectivity (entry 7). The use of CF3-Josiphos ligand (L8)
significantly increased the diasteromeric ratio to 91:9, but with
slightly reduced enantioselectivity (entry 8). Next, we carried out
the reaction using a more challenging α,β-unsaturated aldehyde,
α-methyl-cinnamaldehyde (3a) as the electrophile. It is known
that enals are easily reduced by Cu–H catalyst to produce 1,2-
or 1,4-reduction products.[12] Surprisingly, both reaction
conditions using the L7 and L8 ligands resulted in the formation
of the corresponding 1,2-addition product in high yield, and
stereoselectivity without significant reduction of the aldehyde,
proving 1 as a better Michael acceptor[13] than aldehyde 3. When
using L7, slightly higher enantioselectivity was obtained (entries
9 and 10). Therefore, we selected entry 8 for simple aldehydes
and entry 9 for α,β-unsaturated aldehydes as the optimal
conditions.[14]
Entry
Aldehyde
2a
Ligand
L1
Yield [%][b]
d.r[c]
e.r[d]
-
1
2
3
4
5
6
7
8
9
10
90
0
96:4
2a
L2
-
-
2a
L3
28
63
94
44
71
70
74
76
65:35
95:5
68:32
55:45
55:45
53:47
99:1
95:5
98:2
95:5
2a
L4
2a
L5
97:3
2a
L6
60:40
72:28
91:9
2a
L7
2a
L8
3a
L7
>98:<2
>98:<2
3a
L8
[a] General reaction conditions: 1 (0.5 mmol), 2a or 3a (1 mmol), CuCl (0.025
mmol), ligand (0.0275 mmol), LiOMe (1 mmol) and 1,1,3,3-
tetramethyldisiloxane (1 mmol) in THF (1 mL); see the Supporting Information
for details. [b] Isolated yield as
a mixture of two diastereomers. [c]
Diastereomeric ratio (d.r) was determined by 1H NMR analysis of crude
reaction mixture. [d] Enantiomeric ratio (e.r) was determined using HPLC.
The copper-catalyzed coupling reaction of 1 and 2a could
be conducted on a large scale; 1.5 mol% loading of catalyst was
efficient enough to yield 4a, which was isolated as a single
diastereomer by silica gel column chromatography. Aryl
aldehydes with halogen-, electron-withdrawing, electron-
donating group, and
a meta-substituent were appropriate
Under the optimized conditions, various aldehydes were
explored in the reductive coupling with vinylborontate 1 (Table
2).[15] A variety of aldehydes were accommodated, yielding the
corresponding chiral 1,2-hydroxyboronates in good yield with
high diastereo- and enantioselectivities.
substrates, affording the desired products (4b–4f). Sterically
hindered, ortho-substituted aryl aldehyde also yielded 4g with
high enantioselectivity. A naphthyl group and heteroaryl groups
were also incorporated (4h–4j).
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10.1002/anie.201806937
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Table 2: Copper-Catalyzed Diastereo- and Enantioselective Addition to Aldehydes.[a]
[a] Isolated yields containing a mixture of two diastereomers run on a 0.5 mmol scale. Ligand L8 was used for simple aldehydes (2), and L7 was used for α,β-
unsaturated aldehydes (3). The diastereomeric ratio (d.r) was determined by 1H NMR analysis of a crude reaction mixture. Enantiomeric ratio (e.r) was
determined by HPLC analysis. [b] 1.5 mol % of copper catalyst on a 2 mmol scale. [c] L8 was used instead of L7. [d] Yield of purified diol after oxidation of 5
We next examined reductive coupling with α,β-unsaturated
aldehydes using the josiphos ligand (L7) as the optimal ligand. A
variety of unsaturated aldehydes containing aryl, heteroaryl, and
alkyl substituents resulted in enantiomerically enriched
homoallylic boronates containing an allylic alcohol in good yield
via 1,2-addition. Aldehyde without an α-substituent resulted in
moderate yield and diastereomeric ratio of product,[16] but with
good enantioselectivity (5b). However, α,β-unsaturated
aldehydes with both α,β-substituents resulted in high diastereo-
and enantioselectivity. The reaction of α-methyl cinnamaldehyde
derivatives yielded the corresponding homoallylic boronates
(5c–5e) with high diasteromeric ratio (>98:2) and enantiomeric
ratio (96:4–99:1). An electron-donating, electron-withdrawing,
and halogen-substituted aryl group and heteroaromatic (5f)
substituents at the β-position did not significantly affect the
stereoselectivity of the reaction. Furthermore, the α,β-dialkyl-
substituted substrate (3g), aldehydes with ethyl, and phenyl
groups at the α-position (3h‒3i), and cyclopentene-derived vinyl
aldehyde (3j) also generated the corresponding products (5g‒5j)
with high levels of diastereo- and enantioselectivity. Moreover,
the tetrasubstituted α,β-unsaturated aldehyde was reactive
under the standard reaction conditions to give 5k in good yield.
Finally, 2-methyl-5-phenyl-2,4-pentadienal produced only 1,2-
addition product (5l) in 70% yield and good diastereo- (>98:2)
and enantioselectivity (96:4) without chemoselectivity issues.[17]
Transformations of the 1,2-hydroxyboronates obtained by
our protocol were carried out to demonstrate their synthetic
utility (Scheme 2). The C–B bond of 5a was converted to C–O
bond by oxidation, and the alkene moiety of the resulting diol
compound was further oxidized to tetraol 6a via the Sharpless
asymmetric dihydroxylation.[18] 1,2-Hydroxyboronate 4a was
protected by the TBS group and aminated with lithiated
methoxyamine[19] to yield amino alcohol 7a without deterioration
of the original diastereo- and enantiomeric ratio. In addition, the
oxidation of 4a and sequential treatment with SOCl2 and sodium
azide generated 1,2-azido alcohol 7b in 69% overall yield, which
is a known intermediate in the synthesis of (R)-Selegiline for
Parkinson's disease treatment.[20]
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Scheme 2. Transformation of 1,2-hydroxyboronates
In summary, we developed a copper-catalyzed chemo-,
diastereo-, and enantioselective reductive coupling of
vinylboronate with various aldehydes, providing direct catalytic
synthesis of versatile 1,2-hydroxyboronates with high
efficiencies. In the presence of a copper catalyst combined with
josiphos-type ligands, the reaction facilitated installation of two
contiguous stereogenic centers. In particular, the successful use
of α,β-unsaturated aldehydes in this multicomponent and
tandem protocol resulted in efficient synthesis of homoallylic
boronates bearing multi-functional groups. The resulting chiral
1,2-hydroxyboronates were transformed to various compounds
of value. Further studies are in progress.
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This research was supported by National Research Foundation
of Korea (NRF) grants (NRF-2016R1A2B4011719 and NRF-
2016R1A4A1011451), funded by the Korean government
(MEST).
Keywords: copper • vinylboronate • aldehyde addition •
asymmetric catalysis • enantioselective synthesis
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[14] For more screening results, see the Supporting Information (Table S1).
[15] With the currently developed catalytic conditions, the reaction of
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with ketones did not afford the desired products, which need further
improvement. See Scheme S1‒S3 in the supporting information.
[16] 1,2-Reduction of cinnamaldehyde occurred to give the corresponding
allylic alcohol as a side product, which reduced the yield of the coupled
product 5b. See Scheme S2 in the Supporting Information.
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COMMUNICATION
Won Jun Jang, Jaesook Yun*
Page No. – Page No.
Copper-Catalyzed Tandem
Hydrocupration and Diastereo- and
Enantioselective Borylalkyl Addition
to Aldehydes
Stereoselective addition of in-situ generated chiral boron-α-alkyl intermediates via
copper catalyst to various aldehydes under mild conditions is reported. This tandem
and multicomponent system facilitated the synthesis of enantiomerically enriched
1,2-hydroxyboronates bearing contiguous stereocenters in good yield with high
diastereo-, and enantioselectivity up to a ratio of >98:2.
This article is protected by copyright. All rights reserved.